Access to C-protected β-amino-aldehydes via transacetalization of 6-alcoxy tetrahydrooxazinones and use for pseudo-peptide synthesis

Article abstract of DOI:10.1016/j.tet.2012.01.002

Efficient access to masked β-amino-aldehydes was performed starting from 6-alcoxy tetrahydrooxazinone 6a-d (6-ATO). Transacetalization leads to the opening of the cycle to form either unsymmetric acetal 7 or symmetric acetals 16-18. These amino acetals ar

Full text of DOI:10.1016/j.tet.2012.01.002

Tetrahedron 68 (2012) 2179e2188
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Access to C-protected b-amino-aldehydes via transacetalization of 6-alcoxy
tetrahydrooxazinones and use for pseudo-peptide synthesis
*
Pavlo Shpak-Kraievskyi, Biaolin Yin, Arnaud Martel, Robert Dhal, Gilles Dujardin, Mathieu Y. Laurent
ꢀ
UCO2MdUMR 6011, Universite du Maine, av. O. Messiaen, 72085 Le Mans, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient access to masked
b-amino-aldehydes was performed starting from 6-alcoxy tetrahydroox-
Received 25 October 2011
Received in revised form 3 January 2012
Accepted 4 January 2012
azinone 6aed (6-ATO). Transacetalization leads to the opening of the cycle to form either unsymmetric
acetal 7 or symmetric acetals 16e18. These amino acetals are key compounds, obtained with 99% ee,
which can be engaged in efficient peptide coupling. This method could easily provide peptides aldehydes
or small amido aldehydes as exemplified with the formal synthesis of ent-Maraviroc.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 8 January 2012
Keywords:
Transacetalization
Peptide aldehyde
b
-Amino acetal
Maraviroc
Peptide coupling
1. Introduction
steps, the epimerization problem and the low number of accessible
amino acids.13 These problems make the synthetic access to
peptide aldehydes still a challenging problem.
b-
Since the discovery of C-terminal peptide aldehydes as natural
products,1 this moiety has been the center of a constant interest.
The aldehyde, under its hydrated form, can mimic the tetrahedric
transition state adduct of a terminal carboxylic acid in proteases.2
Therefore, it can be designed as inhibitors for various carboxyl
terminal proteases, such as serine, cysteine, and aspartyl pro-
teases.3,4 Moreover, peptide aldehydes have also found a deep in-
terest in chemoselective ligation chemistry with the hydrazone and
the oxime method.5,6 It is also used as a reactive precursor to form
reduced peptides7 and carbapeptides.8
Methods for the synthesis of peptide aldehyde or protected
amino aldehyde involved classically the transformation of a pre-
cursor (Weinreb amide, ester, alcohol, acetal) into an aldehyde9 as
one of the final steps to generate the aldehyde moiety at the end.
This approach has been conjugated in various ways including
supported syntheses.10 This procedure is also important to prevent
Our laboratory is engaged for several years in a stereocontrolled
synthesis of -amino-aldehydes. These could be obtained in
b
a benzoyl protected form by SnCl4-promoted cycloaddition be-
tween the (R)-O-vinyl pantolactone 4 with N-benzoyl benzaldimine
1 or their N,O-acetals equivalent 2.14 Reaction with N-Boc benzal-
dimine methoxy-acetal 3 shows the formation of a 6-alcoxy tet-
rahydrooxazinone 6 (6-ATO) resulting from the elimination of the
tert-butyl moiety15 (Fig. 1). These compounds are obtained with
a high facial stereoselectivity (>98/2) and could deliver the alde-
hyde function upon acidic treatment.
Ph
O
Ph
O
Ph
SnCl4
N
or
N
HN
Ph
OMe
epimerization of the carbon
problem with the
-peptide aldehydes.11
By contrast, -peptide aldehydes have been relatively un-
explored even though they are more stable to epimerization than
the
-peptide aldehydes.12 They are usually obtained by homolo-
a to the aldehyde, which is a crucial
O
Ph
O
a
b
Ph
O
O
1
2
5
O
O
Ph
Ph
a
O
4
HN
HN
tBuO
OMe
gation of the corresponding amino acid despite the low yielding
O
SnCl4
O
O
O
O
O
3a
6a
* Corresponding author. E-mail address: Mathieu.Laurent@univ-lemans.fr (M.Y.
Laurent).
Fig. 1. Previous work with diastereoselective hetero-DielseAlder reaction.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.002

2180
P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
In order to exploit intensively the potentiality of this sequence
The resulting product is a mixture of two diastereoisomeric
mixed acetals 7 and a dimethoxy symmetric acetal 8. These were
identified from the 1H NMR spectra by the position of the acetal
proton, respectively at 4.53, 5.06, and 4.38 ppm. The two di-
astereoisomers of 7 possess both one methoxy group appearing at
3.76 and 3.34 ppm with all signals of the pantolactone moiety. The
symmetric dimethoxy acetal 8 is distinguished by two methoxy
groups at 3.33 and 3.30 ppm. The ratio of mixed acetals versus
symmetric acetal is in the range of 90:10 to 50:50. The mixture of
acetals is used without further purification and coupled with an N-
phthalyl-phenylalanine 9a. Coupling was carried out using classical
conditions with 43% yield (Scheme 1). The mixture of acetals
10ae11a is deprotected in acidic medium with high yield to give
12a as a single diastereoisomer. No epimerization occurs during the
coupling step. A similar procedure19 was used to couple phthalyl
of reactions, it was necessary to study the incorporation of such
moieties to a peptidic sequence. We would here report a general
pathway to obtain peptide aldehyde by the formation of amino-
acetal moiety via transacetalization allowing further classical
peptide coupling.
2. Results and discussions
Compounds 615 are doubly masked
b-amino-aldehydes. When
the nitrogen is engaged in an amide bond, it was previously shown
that the free aldehyde is easily provided upon acidic treatment with
high yields.16 It allows further modification at the C-terminus of
this modified b-amino-aldehyde.
However, if N-acetylation or N-Boc protection of 6-ATO 6a is
efficient, their N-coupling with an amino acid proved to be difficult.
It was only achieved with amino acids N-protected with a phthalyl
moiety, which is difficult to remove.16 Amino acids protected with
a carbamate or dibenzyl groups did not couple efficiently. More-
over, their coupling requires DMAP in stoichiometric amount,
which could cause some epimerization.
This prompted us to modify the initial strategy and to consider
the coupling with a free amine moiety. As deprotection of the ni-
trogen must be done with a masked aldehyde, the aldehyde pro-
tecting group must be interchanged. We planned to do it in one step
by transacetalization.17
Whereas transacetalization is commonly used to convert pro-
tecting groups on carbonyl functions,16 very few examples exist
where an intramolecular acyl acetal is opened to generate a dia-
lcoxy acetal.18 Compounds, such as 6a could be transacetalized to
liberate the endo-cyclic moiety with CO2 emission and give com-
pound 7 (Scheme 1). It was anticipated that the liberation of CO2
would favor the desired formation of compound 7 with a free
amino group instead of the elimination of the exo-cyclic alcoxy
group (pantolactone).
( )-Phe giving 10b and 11b then after deprotection 12b, which was
D
not accessible with previous method.16
The phthalyl group could be deprotected by hydrazinolysis
(Scheme 2) and the resulting amine could be directly engaged in
a peptidic coupling. This sequence starting from 10a gives 13 with
43% yield. The aldehyde function is liberated upon acidic treatment
with 71% yield.
This sequence is not protecting-group-dependent and could be
adapted to amino acids bearing more usual protecting groups.
Under the same conditions, amino acids equipped with a CBz20
(Table 1, entries 1 and 3) or a Bz (entry 2) moieties are efficiently
coupled with amino acetals 7 (yields from 76%). As compound 7 is
used as a mixture of diastereoisomers, 10cee are formed as mix-
tures. No epimerization during the coupling step was observed in
1H NMR.
The aldehyde function could be deprotected in acidic conditions
and generate dipeptide aldehydes 12 as single diastereoisomers
(Table 1, second step). In the case of CBz-glycine amido acetal 10e
(entry 3, Table 1), the elimination product 15 was only observed
instead of the desired product 12e. The corresponding cinnamic
Ph
OH
O
Ph
PhthN
O
Ph
PhthN
Ph
PhthN
Ph
O
(iv)
9a
Ph
O
N
N
Ph
H
H
(i)
O
HN
MeO
OR
(ii)
H2N
MeO
O
12a
O
crude 87 %
10a R = pantolactone
11a R = Me
O
O
O
O
64%
O
6a
43%
7
7:8 90:10
Ph
O
Ph
O
Ph
H2N
MeO
PhthN
Ph
PhthN
Ph
(iii)
(iv)
N
N
H
H
OMe
MeO
OR
O
Ph
8
12b
10b R = pantolactone
11b R = Me
OH
PhthN
76%
O
9b
73%
Scheme 1. Transacetalization of 6a leading to mixed acetal 7 and access to N-phthaloyl dipeptide aldehyde 12. Conditions: (i) p-TsOH, MeOH/CH2Cl2, rt, overnight; (ii) EDCI$HCl,
HOBt, CH2Cl2, 0 ꢀC, 1 h, then rt overnight; (iii) EDCI$HCl, HOBt, NMM, CH2Cl2, 0 ꢀC, 1 h, then rt overnight; (iv) HCl 5 N, CH3CN, rt, overnight.
As expected, the transacetalization reaction of the masked al-
dehyde 6a is performed upon acid catalysis in methanol generating
a free primary amine with the aldehyde moiety protected (Scheme
1). It proceeds with complete conversion and a crude yield of 87%.
No aldehyde formation is observed on crude NMR spectra and no
polymer or degradation product was detected during this step. This
could indicate that the aldehyde function remained fully protected.
acid 15 was indeed clearly distinguished on the 1H NMR spectrum
of the crude mixture with a characteristic doublet of doublet at
6.73 ppm. The cinnamic aldehyde 15 was also observed in the crude
mixture of 12c,d in a level lower than 10%.21
This procedure generates efficiently short peptidic sequence.
However, even if all diastereomeric acetals were finally deprotected
to liberate only one aldehyde, one could prefer working with only

P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
2181
Ph
Ph
O
Ph
O
Ph
O
Ph
H
H
1. NH2NH2, MeOH
PhthN
Ph
HCl 5N
CH3CN
71%
N
N
N
CBzHN
N
CBzHN
N
H
O
H
O
H
2. EDCI.HCl, HOBt
NMM, CH2Cl2
O
O
MeO
O
Ph
MeO
O
O
Ph
O
13
O
14
Ph
10a
OH
CBzHN
O
9c
43 %
Scheme 2. Formation of N-protected tripeptide aldehyde 14 from 10a.
Table 1
benefit (ThorpeeIngold) to the formation of 18. Pure compounds
are obtained by precipitation as an oxalate salt leading to pure 16a,
17, 18 in moderate yields (19e44 %). The low isolated yields are
mainly due to high polarity of amino acetals and to the difficulty to
eliminate completely the pantolactone.
Compounds 6aed were transacetalized using previous condi-
tions with ethylene glycol (Table 2). Conversions were high but
isolated yields were smaller due to the difficulty to remove com-
pletely the pantolactone. The optical purity of new compounds
16aed was controlled by chiral gas chromatography or chiral HPLC
of the crude mixture and was compared to the corresponding ra-
cemic mixture. In all cases, enantiomeric purity was found to be
excellent showing the excellent facial selectivity during the SnCl4-
promoted cyclization and the complete absence of racemization.
Synthesis of analogs of dipeptides 10 and hydrolysis to dipeptide aldehydes 12
R
OH
PGHN
O
O
Ph
Ph
9c-e
PGHN
EDCI.HCl
HOBt, NMM
N
H2N
H
O
O
R
MeO
O
MeO
O
CH2Cl2
O
O
10c-e
7
O
Ph
PGHN
HCl 5N
CH3CN
N
O
+
Ph
H
R
O
15
12c-e
Table 2
Cyclic amino acetals 16aed
Entry
Amino acid
First step
Yielda [%]
Second step
Yieldb [%]
ethylene glycol
R
R
O
pTsOH
CH2Cl2
1
2
3
CBzPhe
Bz-Pro
CBz-Gly
10c
10d
10e
35
63
99
12c
12d
12e
81
78
/
HN
H2N
O
O
O
O
O
a
O
Yield of isolated product from 6-ATO 6a (two steps).
Yield of isolated product.
6a-d
b
16a-d
Entry
R
Yielda [%]
eeb [%]
one compound as mixtures of acetals could be difficult to handle on
a longer synthesis. We thus tried to favor the formation of the
symmetric dimethoxy compound. Unfortunately, whereas it was
found easy to open the endo-cyclic carbamate function to form the
mixed acetal, pantolactone moiety (exo-cyclic) is difficult to remove
quantitatively. Even in pure methanol, mixed acetal remained the
major product.
1
2
3
4
Ph (6a)
tBu (6b)
iBu (6c)c
Bn (6d)
41 (80)
39 (72)
44 (81)
33
99
99
99
99
a
Yield of isolated product (yield of crude product determined by NMR).
Determination: cf. Experimental section.
Ref. 22.
b
c
To circumvent this problem, we envisaged to form the second
alcoxy bond intramolecularly to obtain a cyclic acetal (Scheme 3).
Several cyclic acetals were synthetized varying the size of the cycle
and the substitution. Transacetalization of 6a with ethylene glycol,
1,3-propanediol, and 2,2-dimethyl-1,3-propanediol gave the ami-
noacetal 16a, 17, 18, respectively with high crude yields (76e83 %,
Scheme 3). It should be noticed that the dimethyl effect has no
Amino acetals 16 could then be engaged in a peptidic coupling
under classical conditions (Scheme 4). As an example, 16a was
coupled with benzoyl proline 9d with 98% yield with EDCI, HOBt.
The aldehyde was then deprotected leading 12d with 81% yield.23
Ph
CO2H
9d
O
Ph
O
N
O
Ph
HCl 5N
MeCN
Bz
Ph
Ph
H2N
N
N
diol
H
H
PTSA
NBz
NBz
EDCI.HCl
HOBt
HN
H2N
O
O
81 %
O
O
O
O
+
HO
CH2Cl2
O
O
O
98 %
O
O
12d
16a
19d
O
O
6a
OH OH
16a, 17, 18
OH OH OH OH
OH
Scheme 4. Peptidic coupling with amino acetal 16a.
HO
=
As purification of 16 remains a poor-yielding step, this sequence
could be conducted without any intermediate purification. Table 3
shows, for different 6-ATO 6aed, the sequence of three steps in
a one-pot procedure. After the final purification, yields are ranging
around 34e56 % for three steps showing that residual pantolactone
16a
80 %
41 %
17
83 %
44 %
18
76 %
19 %
crude
purified
Scheme 3. Transacetalization of 6a leading to symmetric cyclic acetals.

2182
P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
Table 3
protecting group gives a wide access to b-peptide aldehydes. It has
also been applied for the synthesis of ent-Maraviroc.
Sequence of peptidic coupling in a one-pot sequence with a final chromatographic
purification
1. ethylene glycol
PTSA
2. Amino acid 9c-d
EDCI.HCl, HOBt
4. Experimental section
R1
O
R1
PGN
HN
4.1. General methods
N
H
O
R2
O
O
O
3. HCl 5N, MeCN
O
O
Reagents were purchased from commercial suppliers and used
without purification. Commercial (R)-(ꢁ)-pantolactone was
recrystallized from xylene before use (99.5%, determined by chiral
GC). N-phthaloyl or N-CBz amino acids were prepared according
literature procedures. All solvents were dried following standard
12
6a-d
Entry
R1
Amino acid
Product
Yielda [%]
1
2
3
4
5
6
7
Ph (6a)
Ph (6a)
tBu (6b)
tBu (6b)
iBu (6c)
iBu (6c)
Bn (6d)
Phth-
Bz- -Pro (9d)
CBz- -Phe (9c)
Bz- -Pro (9d)
CBz- -Phe (9c)
L-Phe (9a)
12a
12d
12f
12g
12h
12i
56
36
36
34
41
42
41
L
L
procedures. Chromatography was performed with 40e60 mm silica
L
gel under medium pressure (1 bar). All melting points are un-
corrected. Infrared spectra were performed on an FT spectropho-
tometer. 1H and 13C NMR spectra were recorded on 200- and 400-
MHz spectrometers in CDCl3 with TMS as reference. High-resolution
mass spectra were performed on a GCT Premier Micromass. Com-
pounds 3a,b,d and 6b,d were fully described in reference.15
L
Bz-
L
-Pro (9d)
-Pro (9d)
Bz-L
12j
a
Yield of isolated product over three steps.
did not interfere with the coupling step. As a comparison, 12a is
obtained with 56% yield with the cyclic acetal method (Table 3,
entry 1), whereas yield of 12a with the mixed acetal method was
24% for three steps (Scheme 1).
4.1.1. (1-Methoxy-3-methyl-butyl)-carbamic acid tert-butyl ester
3c. A solution of tert-butyl carbamate (1.48 g, 12.6 mmol), sodium
benzenesulfinate (0.15 g, 25.2 mmol), iso-valeraldehyde (2.18 g,
25.2 mmol), and formic acid (0.96 mL, 25.2 mmol) in 17 mL of
a THF/water mixture (1:3) was stirred at room temperature for
12 h. THF was removed under reduced pressure and the resulting
mixture was cooled to 0 ꢀC. A white solid was filtered, dissolved in
30 mL of dichloromethane, dried over MgSO4, and concentrated to
afford 3.85 g of crude product. In 53 mL of dry methanol was
added sodium (506 mg, 2 equiv) in small portions. After complete
dissolution, the crude product was added and the reaction mixture
was stirred for 14 h. The reaction was quenched with 120 mL of
water. It was concentrated under reduced pressure, and cooled to
As an example of the versatility of amino acetals 16, we have
applied this methodology to a formal synthesis of ent-Maraviroc,
a potent antagonist of the CCR5 receptor used in the treatment of
HIV infection.24 The 6-ATO 6a, available in three steps from the
corresponding aldehyde, was engaged in the three-step sequence:
transacetalization, coupling with the acid 2024a and final aldehyde
deprotection (Scheme 5) leading to aldehyde 21 in 52% yield with
only one final purification step. Compound 21 is the direct pre-
cursor of ent-Maraviroc formed in one step by reductive amina-
tion.25 This methodology permits a quick access to Maraviroc
amido aldehyde 21 formed from 6a, which could easily be trans-
posed to synthetize analogs varying the central diaminopropyl core
with the diversity of the starting aldehyde precursor.
0
ꢀC. A white solid was filtered, dissolved in 150 mL of dichloro-
methane, dried over MgSO4, and concentrated to give 1.91 g of
compound 3c (63% for two steps). 1H NMR (400 MHz, CDCl3)
d
4.86 (1H, m), 3.33 (3H, s), 1.72 (1H, m), 1.52 (1H, m), 1.46 (9H, s),
1.37 (1H, m), 0.93 (3H, d, J¼2.9 Hz), 0.91 (3H, d, J¼2.9 Hz). 13C NMR
(100 MHz, CDCl3)
d 155.5, 81.8, 79.6, 55.2, 44.6, 28.3, 24.6, 22.6,
22.4. IR (neat, cmꢁ1): 3316, 2956, 1683, 1523, 1365, 1251, 1154,
1048, 960. HRMS (CI) [MꢁOCH3]þ (C10H20NO2): calcd: 186.1489,
found: 186.1490.
1. ethylene glycol
PTSA
2. Acid 20
EDCI.HCl, HOBt
O
Ph
Ph
O
N
H
Ph
3 steps
54 %
HN
O
F
O
O
O
O
F
3. HCl 5N, MeCN
49 % for 3 steps
21
O
4.1.2. (4R,6R)-6-[(3R)-4,4-Dimethyl-2-oxo-tetrahydro-furan-3-
6a
yloxy]-4-phenyl-1,3-oxazinan-2-one 6a.15 To
a cooled solution
O
O
Ph
at ꢁ40 ꢀC under nitrogen of (R)-(þ)-O-vinyl pantolactone 4 (4.33 g,
27.73 mmol) and N-Boc,O-Me-acetal 3a (7.23 g, 30.50 mmol,
1.1 equiv) in anhydrous dichloromethane (275 mL) was rapidly
added dropwise SnCl4 (30.5 mL, 1.1 equiv, 1 M in dichloromethane).
After stirring 1 h at the same temperature, the mixture was
quenched with saturated aqueous NaHCO3 solution (76 mL). After
return to room temperature and extraction with dichloromethane
(2ꢂ150 mL), the resulting organic layer was dried (MgSO4) and
concentrated in vacuo at room temperature. The crude tetrahy-
OH
N
ref [21]
H
F
F
N
N
N
N
F
F
20
ent-Maraviroc
Scheme 5. Access to precursor of ent-Maraviroc.
3. Conclusion
6-Alcoxy tetrahydrooxazinone is an efficient masked
drooxazinone 6a (exo-
acetalization without further purification. Analytical sample of pure
tetrahydrooxazinone 6a-exo- was obtained after chromatography
b/endo-b/exo-a: 93/6/1) was used for trans-
b
-amino
b
aldehyde, which could be used in peptide synthesis to generate
b
-
(silica gel 10/1, cyclohexane/ethyl acetate 80:20 to 0:100). The
resulting oil was treated in a mixture 1/3 of diethylether/petroleum
ether to give a white solid (66%). Rf¼0.05 (eluant: cyclohexane/
peptide aldehyde. Transacetalization of the cyclic carbamate have
been performed to form either mixed acetals or symmetric cyclic
acetals. It allows to keep the aldehyde protected, whereas the ni-
trogen function is liberated. Amino acids were then coupled on the
free amino group leaving acetal untouched. The acetal could be
removed under acidic conditions. This strategy involving a doubly
masked amino aldehyde and a transformation of the aldehyde
ethyl acetate 1/1, UV detection). ½a D20
ꢃ
ꢁ30.4 (c 0.92, CH2Cl2). 1H
NMR (400 MHz, CDCl3)
d
7.3e7.4 (5H, m), 5.49 (1H, t, J¼2.3 Hz), 5.43
(1H, br s), 4.95 (1H, dd, J¼4.3, 11.6 Hz), 4.50 (1H, s), 4.01 and 3.95
(2H, 2d, J¼9.0 Hz), 2.28 (1H, ddd, J¼2.3, 4.4, 13.8 Hz), 2.06 (1H, ddd,
J¼2.8, 11.7, 14.2 Hz), 1.28 (3H, s), 1.14 (3H, s). 13C NMR (100 MHz,

P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
2183
CDCl3)
d
173.4, 151.4, 140.0, 129.2, 128.7, 126.4, 97.4, 79.3, 75.5, 51.2,
temperature for 15 min. Then crude mixture of 7 and 8 (150 mg,
0.502 mmol) in 5 mL of dry dichloromethane was slowly added to
the reaction. The reaction was stirred at 0 ꢀC for 1 h then at room
temperature overnight. H2O (10 mL) was added to quench the re-
action. The solution was extracted with ethyl acetate (10 mLꢂ3).
The combined organic extracts were dried (MgSO4), filtered, and
evaporated under reduced pressure. The residue was purified by
flash chromatography using ethyl acetate/cyclohexane (1:3) as el-
uent affording 10a as a gum (62 mg, 43%). Rf¼0.63 (eluant: PE/EA 1/
1, UV detection). 1H NMR (400 MHz, CDCl3) major mixed acetal
40.5, 34.9, 23.4, 19.6. IR (neat, cmꢁ1): 3216, 3190, 1790, 1718, 1423,
1300, 1159, 1132, 1076, 1055, 1012, 949, 764, 706, 656. HRMS
(LSIMS) [MþH]þ (C16H20NO5): calcd: 306.1342, found: 306.1343.
4.1.3. (4R,6R)-6-[(3R)-4,4-Dimethyl-2-oxo-tetrahydro-furan-3-
yloxy]-4-isobutyl-1,3-oxazinan-2-one 6c. To
a cooled solution
at ꢁ78 ꢀC under nitrogen of (R)-(þ)-O-vinyl pantolactone 4
(327 mg, 2.1 mmol) and N-Boc,O-Me-acetal 3c (500 mg, 2.3 mmol)
in anhydrous dichloromethane (20 mL) was added dropwise SnCl4
(2.3 mmol, 1 M in dichloromethane). After stirring 1 h at the same
temperature, the mixture was quenched with saturated aqueous
NaHCO3 solution (5.75 mL). After return to room temperature and
extraction with dichloromethane (3ꢂ25 mL), the resulting organic
layer was dried (MgSO4) and concentrated in vacuo at room tem-
d
7.73 (2H, m), 7.62 (2H, m), 7.53 (1H,d, J¼7.3 Hz), 7.32e7.08 (10H,
m), 5.26 (1H, q, J¼6.4 Hz), 5.16 (1H, dd, J¼7, 10 Hz), 4.41 (1H, t,
J¼5.2 Hz), 3.91 (1H, s), 3.69 (3H, s), 3.64 (2H, m), 3.44 (1H, d,
J¼11.4 Hz), 3.33 (1H, d, J¼11.4 Hz), 2.20 (2H, m), 1.01 (3H,s), 0.88
(3H, s). Characteristic signals of dimethyl acetal d 7.77 (m), 7.67 (m),
perature. The crude tetrahydrooxazinone 6c (exo-
3.6) was used for transacetalization without further purification.
Analytical sample of pure tetrahydrooxazinone 6c-exo- was ob-
b
/endo-
b
: 96.4/
7.34 (d, J¼7.4 Hz), 4.14 (t), 3.58 (m), 3.18, 3.06 (2s), 2.03 (m). 13C
NMR (100 MHz, CDCl3) major mixed acetal
d 169.2, 168.1, 167.6,
b
141.2, 137.1, 134.0, 131.8, 129.0, 128.6, 128.5, 127.1, 126.8, 126.0, 123.3,
100.0, 82.9, 77.5, 55.9, 51.9, 50.6, 40.0, 34.8, 32.9, 21.8, 19.4. Char-
tained after chromatography (cyclohexane/AcOEt 50:50 to cyclo-
hexane/acetone 50:50) (white solid, 234 mg, 40%). Rf[0.1 (eluant:
acteristic signals of dimethyl acetal d 167.9, 167.5, 141.1, 136.9, 134.3,
cyclohexane/AcOEt 1/1, KMnO4 detection). ½a D20
ꢃ
ꢁ61.8 (c 1, CHCl3).
131.4, 128.8, 128.7, 127.2, 126.9, 123.5, 102.4, 53.5, 52.7, 50.8, 38.5,
34.6. IR (neat, cmꢁ1): 3385, 3064, 2958, 2873, 1776, 1713, 1666,
1525, 1385. HRMS (DCI, NH3) [MþH]þ (C33H35N2O7): calcd:
571.2444, found: 571.2444.
1H NMR (400 MHz, CDCl3)
d 5.43 (2H, s), 4.42 (1H, s), 4.02e3.84 (3H,
m), 2.10 (1H, tdd, J¼2.2, 4.2, 13.7 Hz), 1.72e1.65 (2H, m), 1.46e1.31
(2H, m), 1.25 (3H, s), 1.10 (3H, s), 0.95 (3H, d, J¼6.6 Hz), 0.94 (3H, d,
J¼6.6 Hz). Characteristic signals for endo-
b: 5.81 (1H, dd), 5.61 (1H,
s), 4.35 (1H, s), 2.33 (1H, m). 13C NMR (100 MHz, CDCl3)
d
173.4,
4.1.6. (2R)-N-[(1R,3RS)-3-((3R)-4,4-Dimethyl-2-oxo-tetrahydro-fu-
ran-3-yloxy)-3-methoxy-1-phenyl-propyl]-2-(1,3-dioxo-1,3-dihydro-
151.8, 97.8, 79.4, 75.5, 44.8, 44.4, 40.5, 32.2, 24.2, 23.4, 22.7, 22.6,
19.5. IR (neat, cmꢁ1): 2959, 1785, 1715, 1421, 1296, 1132, 1077, 1037,
994, 763, 601. HRMS (CI) [MþH]þ (C14H24NO5): calcd: 286.1654,
found: 286.1647.
isoindol-2-yl)-3-phenyl-propionamide 10b. To the mixture of
D-
phthalyl-phenylalanine 9b (150 mg, 0.512 mmol) in 5 mL of dry
dichloromethane was added EDCI$HCl (98 mg, 0.511 mmol), HOBt
(51 mg, 0.377 mmol), NMM (52 mg, 0.514 mmol) at 0 ꢀC. The
mixture was stirred at the same temperature for 15 min. Then
crude mixture of 7 and 8 (100 mg, 0.341 mmol) in 5 mL of dry
dichloromethane was slowly added to the reaction. The reaction
was stirred at 0 ꢀC for 1 h then at room temperature overnight. H2O
(10 mL) was added to quench the reaction. The solution was
extracted with ethyl acetate (10 mLꢂ3). The combined organic
extracts were dried (MgSO4), filtered, and evaporated under re-
duced pressure. The residue was purified by flash chromatography
using ethyl acetate/cyclohexane (1:0.8) as eluent affording 10b as
a gum (143 mg, 73%). Rf¼0.69 (eluant: PE/EA 1/1, UV detection). 1H
4.1.4. (3R)-3-[(1RS,3R)-3-Amino-1-methoxy-3-phenyl-prop-oxy]-
4,4-dimethyl-dihydro-furan-2-one 7 and 3,3-dimethoxy-1-phenyl-
propylamine 8. To the solution of 6a (305 mg, 1 mmol) in 5 mL of
methanol was added p-TsOH (285 mg, 1.5 mmol). The mixture was
stirred overnight until the disappearance of starting material
according to TLC. Then 5 mL of saturated NaHCO3 solution was
added to quench the reaction. The solvent was removed under
reduced pressure and the residue was extracted with ethyl acetate
(10 mLꢂ3). The combined organic extracts were dried (MgSO4),
filtered, and evaporated under reduced pressure to afford an oil
(255 mg, 87%), which was a 65:25:10 mixture (1H NMR) of the two
diastereoisomeric mixed acetal 7 and symmetric dimethyl acetal 8.
It is submitted in the next step without further purification. 1H NMR
NMR (400 MHz, CDCl3) major mixed acetal d 7.74 (2H, m), 7.64 (2H,
m), 7.54 (1H, d, J¼7.6 Hz), 7.35e7.05 (10H, m), 5.35 (1H, m), 5.18 (1H,
dd, J¼5.5, 11.2 Hz), 4.33 (1H, dd, J¼4.7, 6.0 Hz), 3.84 (1H, s), 3.66 (3H,
s), 3.7e3.5 (2H, m), 3.38 (1H, d, J¼11.4 Hz), 3.26 (1H, d, J¼11.4 Hz),
2.21 (2H, m), 0.88 (3H, s), 0.84 (3H, s). Characteristic signals of di-
(400 MHz, CDCl3) major mixed acetal
d 7.4e7.2 (5H, m), 4.53 (1H,
dd, J¼4.4, 5.5 Hz), 4.23 (1H, dd, J¼5.7, 8.0 Hz), 4.0 (1H, s), 3.76 (3H,
s), 3.61 (1H, d, J¼11.4 Hz), 3.43 (1H, d, J¼11.4 Hz), 2.10 (2H, m), 1.81
(2H, br s), 1.11 (3H, s), 0.91 (3H, s). Characteristic signals of minor
methyl acetal
(t), 3.16, 3.03 (2s), 3.58 (m), 2.04 (m). 13C NMR (100 MHz, CDCl3)
major mixed acetal 169.1, 167.9, 167.6, 141.0, 137.1, 133.9, 131.8,
d
7.80 (m), 7.70 (m), 5.18 (1H, dd, J¼5.6, 11.2 Hz), 4.15
mixed acetal
d
5.06 (dd, J¼4.5, 7.2 Hz), 4.17 (dd, J¼4.8, 8.9 Hz), 4.12
d
(s), 3.34 (3H, s), 3.99 (d, J¼8.9 Hz), 3.92 (d, J¼8.9 Hz), 2.0 (m), 1.20
129.1, 128.5, 128.4, 127.1, 126.7, 126.0, 123.2, 99.9, 82.7, 77.4, 55.4,
51.9, 50.3, 39.9, 34.7, 32.8, 21.7, 19.3. Characteristic signals of di-
methyl acetal d 167.8, 167.5, 141.1, 137.0, 134.3, 131.4, 128.9, 128.7,
128.6, 127.3, 126.8, 126.1, 123.4, 102.4, 55.5, 53.8, 52.2, 50.4, 38.3,
34.3. IR (neat, cmꢁ1): 3370, 3062, 3030, 2956,1776,1713,1681,1522,
1385, 1106. HRMS (DCI, NH3) [MþH]þ (C33H35N2O7) calcd:
571.2444, found: 571.2460.
(s), 1.11 (s). Characteristic signals of dimethyl acetal 8
d 4.38 (t,
J¼5.7 Hz), 4.06 (m), 3.33, 3.30 (2s), 1.95 (m). 13C NMR (100 MHz,
CDCl3) major mixed acetal
d
169.3, 145.6, 128.5, 127.1, 126.4, 100.7,
83.5, 77.8, 51.9, 51.8, 43.5, 32.9, 21.7, 19.6. Characteristic signals of
minor mixed acetal 127.1, 126.3, 101.2, 78.1, 76.3, 51.8, 52.2, 42.3,
d
23.0, 19.5. Characteristic signals of dimethyl acetal
d 102.9, 53.1,
52.6, 52.7, 42.1. IR (neat, cmꢁ1): 2963, 2869, 1749, 1635, 1456, 1395,
1182, 1121, 1032, 1009, 699. HRMS (CI) [MþH]þ (C16H24NO4): calcd:
196.1338, found: 196.1327.
4.1.7. (2S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-[(1R)-3-oxo-1-
phenyl-propyl]-3-phenyl-propionamide 12a.16 To the mixture of
crude 10a (170 mg, 0.250 mmol) in 5 mL of acetonitrile was added
5 mL of 5 N HCl, the reaction was stirred at room temperature
overnight. The reaction mixture is then treated with a solution of
NaOH 2 N (12 mL/mmol of 6a) and with a saturated solution of
NaHCO3. Then the mixture was extracted with ethyl acetate
(15 mLꢂ3). The combined organic extracts were washed with H2O
to remove the pantolactone, dried (MgSO4), and filtered. The
4.1.5. (2S)-N-[(1R,3RS)-3-((3R)-4,4-Dimethyl-2-oxo-tetrahydro-fu-
ran-3-yloxy)-3-methoxy-1-phenyl-propyl]-2-(1,3-dioxo-1,3-dihydro-
isoindol-2-yl)-3-phenyl-propionamide 10a. To the mixture of
L-
phthalyl-phenylalanine 9a (222 mg, 1.753 mmol) in 5 mL of dry
dichloromethane was added EDCI$HCl (144 mg, 0.753 mmol), HOBt
(67 mg, 0.502 mmol) at 0 ꢀC. The mixture was stirred at the same

2184
P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
solvent was removed under reduced pressure. Flash chromatogra-
phy on silica gel (cyclohexane/acetone 80:20, then cyclohexane/
acetone 50:50) afforded 26 mg of 12a as a white solid (24% for three
mixture of 13 (60 mg, 0.083 mmol) in 2 mL of acetonitrile was
added 2 mL of 5 N HCl, the reaction mixture was stirred at room
temperature overnight. Then the mixture was extracted with ethyl
acetate (10 mLꢂ3). The combined organic extracts were washed
with H2O to remove the pantolactone, dried (MgSO4), and filtered.
The solvent was removed under reduced pressure. It was purified
by flash chromatography affording 14 as an oil (34 mg, 71%).
steps). 1H NMR (400 MHz, CDCl3)
d
9.61 (1H, dd, J¼1.2, 2.1 Hz), 7.69
(2H, m), 7.60 (2H, m), 7.30e7.00 (10H, m), 6.90 (1H, d, J¼8.2 Hz),
5.43 (1H, q, J¼6.9 Hz), 5.03 (1H, dd, J¼6.0, 10.6 Hz), 3.50 (1H, dd,
J¼6.0, 14.1 Hz), 3.40 (1H, dd, J¼10.6, 14.1 Hz), 2.96 (1H, ddd, J¼2.1,
6.5, 17.0 Hz), 2.86 (1H, ddd, J¼1.2, 6.1, 17.0 Hz).
Rf¼0.57 (PE/acetone 0.8:1, UV detection). ½a D20
ꢁ10.1 (c 0.6, CH2Cl2).
ꢃ
1H NMR (400 MHz, CDCl3)
d 9.54 (1H, s), 7.03e7.34 (18H, m), 6.97
4.1.8. (2R)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-[(1R)-3-oxo-
1-phenyl-propyl]-3-phenyl-propionamide 12b.16 To the mixture of
11b (100 mg, 0.175 mmol) in 3 mL of acetonitrile was added 3 mL of
5 N HCl, the reaction was stirred at room temperature overnight.
Then the mixture was extracted with ethyl acetate (10 mLꢂ3). The
combined organic extracts were washed with H2O to remove the
pantolactone, dried (MgSO4), and filtered. The solvent was removed
under reduced pressure to afford 57 mg of 12b as an oil (76%). 1H
(2H, s), 6.85 (1H, d, J¼7.8 Hz), 6.53 (1H, d, J¼7.8 Hz), 5.40 (1H, m),
5.27 (1H, d, J¼5.8 Hz), 4.94 (1H, d, J¼12.1 Hz), 4.77 (1H, d,
J¼12.1 Hz), 4.63 (1H, m), 4.35 (1H, m), 3.12 (1H, dd, J¼5.3, 13.6 Hz),
2.90e3.02 (2H, m), 2.80e2.90 (2H, m), 2.69 (1H, dd, J¼5.8, 16.2 Hz).
13C NMR (100 MHz, CDCl3)
d 199.9 (CH), 170.7, 169.6, 156.3, 140.2,
136.1, 135.8, 135.7, 126.4e129.3 (CH), 67.2 (CH2), 56.5 (CH), 54.1
(CH), 48.7 (CH2), 48.5 (CH), 37.8 (2 CH2). IR (neat, cmꢁ1): 3292,
3063, 3031, 2925, 1698, 1645, 1538, 1260, 698. HRMS (FD) [M]þ
(C35H35N3O5) calcd: 577.2577, found: 577.2628.
NMR (400 MHz, CDCl3)
d
9.61 (1H, dd, J¼1.2, 2.1 Hz), 7.69 (2H, m),
7.60 (2H, m), 7.30e7.00 (10H, m), 6.90 (1H, d, J¼8.2 Hz), 5.43 (1H, q,
J¼6.9 Hz), 5.03 (1H, dd, J¼6.0, 10.6 Hz), 3.50 (1H, dd, J¼6.0, 14.1 Hz),
3.40 (1H, dd, J¼10.6, 14.1 Hz), 2.96 (1H, ddd, J¼2.1, 6.5, 17.0 Hz), 2.86
(1H, ddd, J¼1.2, 6.1, 17.0 Hz).
4.1.11. {(1S)-1-[(1R,3RS)-3-((3R)-4,4-Dimethyl-2-oxo-tetrahydro-fu-
ran-3-yloxy)-3-methoxy-1-phenyl-propylcarbamoyl]-2-phenyl-
ethyl}-carbamic acid benzyl ester 10c. To a solution of L-CBz-phe-
nylalanine 9c (299 mg, 1 mmol) in 10 mL of dry dichloromethane
was added EDCI$HCl (191 mg, 1 mmol), HOBt (67 mg, 0.5 mmol),
NMM (101 mg, 1 mmol) at 0 ꢀC. The mixture was stirred at the same
temperature for 15 min. Then 7 (146 mg, 0.5 mmol) in 5 mL of dry
dichloromethane was added slowly to the reaction. The reaction
was stirred at 0 ꢀC for 1 h then at room temperature overnight. H2O
(10 mL) was added to quench the reaction. The solution was
extracted with ethyl acetate (10 mLꢂ3). The combined organic
extracts were dried (MgSO4), filtered, and evaporated under re-
duced pressure to remove the solvents. The residue was purified by
flash chromatography using ethyl acetate/cyclohexane (1:0.5) as
eluent affording a gum (100 mg, 35%) as a 52:48 mixture (1H NMR)
of the two diastereoisomeric mixed acetals 10c. Rf¼0.49 (eluant:
PE/EA 1/0.8, UV detection). 1H NMR (400 MHz, CDCl3) major mixed
4.1.9. (1-{1-[3-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-3-
methoxy-1-phenyl-propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-
phenyl-ethyl)-carbamic acid benzyl ester 13. To a solution of 10a
(210 mg, 0.369 mmol) in 10 mL of methanol was added a solution of
hydrazine monohydrate (36.9 mg, 0.737 mmol) in 2 mL of metha-
nol. The mixture was refluxed for 2.5 h until the disappearance of
starting material according to TLC. The solvent was removed under
reduced pressure and the residue was submitted to the next step
without further purification. To the mixture of L-CBz-phenylalanine
9c (156.6 mg, 0.523 mmol) in 5 mL of dry dichloromethane was
added EDCI$HCl (105.7 mg, 0.551 mmol), HOBt (49 mg,
0.363 mmol), NMM (55 mg, 0.544 mmol) at 0 ꢀC. The mixture was
stirred at the same temperature for 15 min. Then the compound
obtained from the previous step in 5 mL of dry dichloromethane
was added slowly to the reaction. The reaction was stirred at 0 ꢀC
for 1 h then at room temperature overnight. H2O (10 mL) was added
to quench the reaction. The solution was extracted with ethyl ac-
etate (10 mLꢂ3). The combined organic extracts were dried
(MgSO4), filtered, and evaporated under reduced pressure. The
residue was purified by flash chromatography using ethyl acetate/
cyclohexane (1:1) as eluent affording a gum (115 mg, 43%), which
was a 89:11 mixture (1H NMR) of the two diastereoisomeric mixed
acetal 13. Rf¼0.53 (eluant: PE/EA 1/1, UV detection). 1H NMR
acetal
d
7.50 (1H, d, J¼7.6 Hz), 7.4e7.15 (13H, m), 7.12 (2H, d,
J¼7.1 Hz), 5.64 (1H, d, J¼8.2 Hz), 5.14 (1H, m), 5.05 (2H, m), 4.51 (1H,
m), 4.18 (1H, dd, J¼3.6, 7.5 Hz), 3.81 (1H, s), 3.78 (3H, s), 3.44 (1H, d,
J¼11.4 Hz), 3.22 (1H, m), 3.2e2.95 (2H, m), 2.09 (1H, ddd, J¼3.6, 6.2,
15.5 Hz), 1.88 (1H, m), 1.01 (3H, s), 0.89 (3H, s). Minor mixed acetal
d
7.43 (1H, d, J¼7.0 Hz), 7.4e7.15 (m), 7.03 (2H, d, J¼6.9 Hz), 5.77
(1H, d, J¼8.3 Hz), 5.24 (1H, q, J¼5.9 Hz), w5.05 (m), 4.51 (m), 4.35
(1H, t, J¼4.4 Hz), 3.80 (1H, s), 3.84 (3H, s), 3.49 (1H, d, J¼11.5 Hz),
3.26 (1H, d, J¼11.5 Hz), 3.2e2.95 (m), 2.12 (2H, m), 1.01 (3H, s), 0.87
(3H, s). 13C NMR (100 MHz, CDCl3) major mixed acetal
d 169.9,
(400 MHz, acetone-d6) major mixed acetal
d
7.80 (1H,d, J¼7.9 Hz),
169.2, 155.8, 140.7, 136.7, 136.4, 129.4, 128.6, 128.5, 128.1, 128.0,
127.0, 126.9, 125.9, 99.6, 82.6, 77.4, 66.8, 56.5, 52.1, 49.8, 39.3, 39.1,
32.9, 21.8, 19.3. Minor mixed acetal d 170.3, 169.5, 155.8, 141.1, 136.8,
136.6, 129.5, 128.6, 128.5, 127.9, 127.1, 126.8, 126.0, 99.4, 82.7, 77.4,
66.7, 66.6, 52.2, 49.6, 39.7, 39.0, 33.1, 21.8, 19.5. IR (neat, cmꢁ1):
3308, 3031, 2955, 1714, 1659, 1536, 1241, 1143. HRMS (DCI, NH3)
[MþH]þ (C33H39N2O7) calcd: 575.2757, found: 575.2764.
7.60 (1H, d, J¼7.6 Hz), 7.4e7.1 (20H, m), 6.58 (1H, d, J¼7.5 Hz), 5.17
(1H, q, J¼6.9 Hz), 5.03, 4.92 (2H, 2d, JAB¼12.5 Hz), 4.72 (1H, q,
J¼7.0 Hz), 4.48 (1H, m), 4.44 (1H, t, J¼4.9 Hz), 4.06 (1H, s), 3.78 (3H,
s), 3.55 (1H, d, J¼11.2 Hz), 3.41 (1H, d, J¼11.2 Hz), 3.13 (1H, dd, J¼6.9,
13.7 Hz), 3.04 (1H, dd, J¼7.4, 13.7 Hz), 3.08 (1H, m), 2.88 (1H, m),
2.13 (1H, m), 2.04 (1H, m), 1.05 (3H, s), 0.91 (3H, s). Characteristic
signals of minor mixed acetal
d
7.87 (d, J¼7.9 Hz), 6.70 (d, J¼7.1 Hz),
5.28 (m), 4.59 (m), 4.12 (s), 3.58, 3.47 (d, J¼11.2 Hz), 3.08, 2.99 (dd,
4.1.12. (2S)-1-Benzoyl-pyrrolidine-2-carboxylic acid [(1R,3RS)-3-
((3R)-4,4-dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-3-methoxy-1-
phenyl-propyl]-amide 10d. To a stirred solution of L-N-benzoyl-
J¼5.3, 13.9 Hz). 13C NMR (100 MHz, acetone-d6) major mixed acetal
d
171.9, 170.3, 169.9, 157.1, 143.4, 138.5, 138.4, 138.0, 130.4, 130.2,
129.3, 129.2, 129.2, 129.1, 128.6, 128.5, 127.8, 127.4, 127.3, 127.3,
100.3, 83.6, 78.0, 66.9, 57.4, 55.6, 52.0, 50.3, 41.4, 38.8, 38.6, 33.5,
proline 9d (159 mg, 0.725 mmol) in 5 mL of dry dichloromethane
was added at 0 ꢀC HOBt (69 mg, 0.51 mmol), EDCI$HCl (146 mg,
0.762 mmol), NMM (52 mg, 0.51 mmol) under N2 atmosphere. The
mixture was stirred at 0 ꢀC for 15 min and a solution of 7 (150 mg,
0.51 mmol) in 5 mL of dry dichloromethane was added. The re-
action was stirred at room temperature overnight. H2O (10 mL) was
added to quench the reaction. The mixture was extracted with ethyl
acetate (10 mLꢂ3). The combined organic extracts were dried
(MgSO4), filtered, and evaporated to afford the residue. It was
21.9, 19.9. Characteristic signals of minor mixed acetal d 172.2, 83.8,
66.9, 57.9, 55.4, 50.0, 41.6, 33.4, 20.1. IR (neat, cmꢁ1): 3295, 3063,
3030, 2955, 1705, 1645, 1533, 1231, 699. HRMS (FD) [M]þ
(C42H47N3O8) calcd: 721.3363, found: 721.3394.
4.1.10. {1-[1-(3-Oxo-1-phenyl-propylcarbamoyl)-2-phenyl-ethyl-
carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester 14. To the

P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
2185
purified by flash chromatography using cyclohexane/ethyl acetate
(1:5) as eluent affording an oil (160 mg, 63%) as a 85:15 mixture (1H
NMR) of the two diastereoisomeric mixed acetals 10d. Rf¼0.37
(eluant: PE/EA 1/5, UV detection). 1H NMR (400 MHz, CDCl3) major
reaction was stirred at room temperature overnight. Then the
mixture was extracted with ethyl acetate (10 mLꢂ3). The combined
organic extracts were washed with H2O to remove the pan-
tolactone, dried (MgSO4), and filtered. The solvent was removed
under reduced pressure to afford 32 mg of 12d as an oil. The
compound was purified by flash chromatography affording 12d
mixed acetal
d
7.89 (1H, d, J¼7.9 Hz), 7.46 (2H, d, J¼7.4 Hz), 7.40 (3H,
m), 7.28 (4H, m), 7.19 (1H, m), 5.21 (1H, q, J¼6.8 Hz), 4.81 (1H, dd,
J¼5.4, 7.5 Hz), 4.43 (1H, t, J¼5.1 Hz), 3.99 (1H, s), 3.79 (3H, s), 3.53
(1H, m), 3.50 (1H, d, J¼11.3 Hz), 3.43 (1H, m), 3.35 (1H, d, J¼11.3 Hz),
2.36 (1H, m), 2.22 (2H, m), 2.10 (1H, m), 2.03 (1H, m), 1.62 (1H, m),
1.06 (3H, s), 0.88 (3H, s). Characteristic signals of minor mixed ac-
(29 mg, 78%). Rf¼0.26 (cyclohexane/acetone 1:1). ½a D20
þ13.4 (c 1,
ꢃ
EtOH). 1H NMR (400 MHz, CDCl3)
d 9.75 (1H, s), 7.88 (1H, ld,
J¼7.8 Hz), 7.45e7.30 (5H, m), 7.30e7.23 (5H, m), 5.52 (1H, m), 4.82
(1H, dd, J¼4.5, 7.4 Hz), 3.44 (2H, m), 3.01 (1H, ddd, J¼2.3, 7.6,
16.8 Hz), 2.91 (1H, ddd, J¼1.4, 5.8, 16.8 Hz), 2.46 (1H, m), 2.02 (2H,
etal
(100 MHz, CDCl3) major mixed acetal
d
4.74 (m), 4.36 (m), 3.92 (s), 3.76 (s), 1.12 (s), 0.84 (s). 13C NMR
d
170.6, 170.4, 169.1, 141.7,
m), 1.81 (1H, m). 13C NMR (100 MHz, CDCl3)
d 198.8 (CH), 170.2,
136.3, 130.0, 128.4, 128.2, 127.0, 126.8, 126.0, 99.8, 83.1, 77.5, 59.8,
51.8, 50.2, 50.0, 40.4, 32.8, 27.7, 23.4, 21.7, 19.5. IR (neat, cmꢁ1):
3304, 3062, 2956, 1754, 1681, 1627, 1415, 1144. HRMS (DCI, NH3)
[MþH]þ (C28H35N2O6) calcd: 495.2495, found: 495.2477.
169.2, 139.6, 135.0, 129.1 (CH), 127.6 (2CH), 127.2 (2CH), 126.4 (CH),
125.7 (2CH), 125.2 (2CH), 58.6 (CH), 49.2 (CH2), 48.6 (CH2), 47.6
(CH), 25.8 (CH2), 24.2 (CH2). IR (neat, cmꢁ1): 2954, 2849, 1751, 1732,
1643,1615,1467,1257,1186. HRMS (CI) [MþH]þ (C21H23N2O3) calcd:
351.1709, found: 351.1709.
4.1.13. {[(1R,3RS)-3-((3R)-4,4-Dimethyl-2-oxo-tetrahydro-furan-3-
yloxy)-3-methoxy-1-phenyl-propylcarbamoyl]-methyl}-carbamic
acid benzyl ester 10e. To a stirred solution of CBz-glycine 9e
(160 mg, 0.765 mmol) in 5 mL of dry dichloromethane was added at
4.1.16. Procedure to obtain 12d via the symmetric acetal. Dipeptide
aldehyde 12d was prepared following the three-step sequence
starting from 6a (177 mg, 0.58 mmol). After preparation of ami-
noacetal 16a, it was engaged in the coupling with benzoyl proline
(161 mg, 0.74 mmol, 1.5 equiv) to form 19d. A pure sample of 19d
could be obtained by chromatography. 1H NMR (400 MHz, CDCl3)
0
ꢀC HOBt (69 mg, 0.51 mmol), EDCI$HCl (146 mg, 0.762 mmol),
NMM (76 mg, 0.75 mmol) under N2 atmosphere. The mixture was
stirred at 0 ꢀC for 15 min and a solution of 7 (150 mg, 0.51 mmol) in
5 mL of dry dichloromethane was added. The reaction was stirred
for 1 h at 0 ꢀC and then overnight at room temperature. H2O (10 mL)
was added to quench the reaction. The mixture was extracted with
ethyl acetate (10 mLꢂ3). The combined organic extracts were dried
(MgSO4), filtered, and evaporated to afford the residue. It was pu-
rified by flash chromatography using cyclohexane/ethyl acetate
(1:5) as eluent affording 10e as a unique major mixed acetal (minor
mixed acetal was not detected) (252 mg, quantitative). Rf¼0.43
(eluant: PE/EA 1.2/1, UV detection). 1H NMR (400 MHz, CDCl3)
d
7.81 (1H, d), 7.50e7.15 (10H, m), 5.20 (1H, m), 4.86 (1H, m), 4.78
(1H, m), 3.91 (2H, m), 3.75 (2H, m), 3.59e3.40 (2H, m), 2.37 (1H, m),
2.17 (1H, m), 2.14e2.04 (2H, m), 2.00 (1H, m), 1.82 (1H, m). The
crude mixture was further deprotected affording 103 mg of crude
product. Flash chromatography on silica gel (cyclohexane/acetone
80:20, then cyclohexane/acetone 50:50) afforded 12d as a white
solid (73 mg, 36% for three steps).
4.2. General procedure for synthesis of symmetric acetals
major mixed acetal
d
7.59 (1H, d, J¼7.0 Hz), 7.4e7.25 (7H, m), 7.21
16aed, 17, and 18
(3H, m), 5.90 (1H, t), 5.29 (1H, q, J¼6.2 Hz), 5.16 (1H, d, J¼12.3 Hz),
5.08 (1H, d, J¼12.3 Hz), 4.42 (1H, t, J¼4.3 Hz), 4.02 (1H, dd, J¼5.8,
16.8 Hz), 3.86 (1H, s), 3.85 (1H, dd, J¼4.9 Hz), 3.78 (3H, s), 3.53 (1H,
d, J¼11.4 Hz), 3.32 (1H, d, J¼11.4 Hz), 2.17 (2H, m), 1.03 (3H, s), 0.89
To the mixture of 6a (1 equiv) in dry dichloromethane (20 mL/
mmol of 6a) was added 1.5 equiv of para-toluenesulfonic acid and
3 equiv of diol. The mixture was heated to 35 ꢀC and stirred during
48 h. After completion of the reaction (disappearance of starting
material monitored by TLC), saturated aqueous NaHCO3 (1.7 mL/
mmol of 6a) was added. The aqueous layer was extracted with
dichloromethane three times. The organic layers were combined,
dried over MgSO4, and concentrated under vacuum affording crude
symmetric acetal in mixture with pantolactone. This crude product
could be used without further purification in a peptide coupling
reaction. Pure product was obtained by precipitation with oxalic
acid (1.1 equiv dissolved in minimum of ethyl acetate) in ether
(50 mL/g of crude product). White solid was filtered, dissolved in
a 3:1 mixture of ether and a 1 M solution of NaOH (1 mL/mmol)
and stirred during 1 h. The aqueous layer was extracted with
ether twice. The organic layers were combined, dried over MgSO4,
and concentrated under vacuum affording pure symmetric
aminoacetal.
(3H, s). 13C NMR (100 MHz, CDCl3) major mixed acetal
d 169.6,
168.3, 156.6, 141.3, 136.6, 128.6, 128.5, 128.1, 128.0, 127.2, 126.0, 99.5,
82.8, 77.4, 66.8, 52.1, 49.5, 44.5, 39.8, 32.9, 21.8,19.4. IR (neat, cmꢁ1):
3389, 3064, 2957, 1727, 1677, 1531, 1233, 1143. HRMS (DCI, NH3)
[MþH]þ (C26H33N2O7) calcd: 485.2288, found: 485.2270.
4.1.14. [(2S)-1-((1R)-3-Oxo-1-phenyl-propylcarbamoyl)-2-phenyl-
ethyl]-carbamic acid benzyl ester 12c. To the mixture of 10c
(100 mg, 0.174 mmol) in 3 mL of acetonitrile was added 3 mL of 5 N
HCl, the reaction was stirred at room temperature overnight. Then
the mixture was extracted with ethyl acetate (10 mLꢂ3). The
combined organic extracts were washed with H2O to remove the
pantolactone, dried (MgSO4), and filtered. The solvent was removed
under reduced pressure to afford 68 mg of 12c as an oil. The
compound was purified by flash chromatography affording 12c
(61 mg, 81%). Rf¼0.67 (EP/acetone 1:1, UV detection). ½a D20
ꢁ64 (c 1,
ꢃ
EtOH). 1H NMR (400 MHz, CDCl3)
d
9.51 (1H, s), 7.10e7.34 (15H, m),
4.2.1. (1R)-2-[1,3]Dioxolan-2-yl-1-phenyl-ethylamine
16a. Follo-
6.54 (1H, s), 5.43 (1H, m), 5.34 (1H, dd, J¼6.5, 14.1 Hz), 5.05 (2H, s),
4.40 (1H, m, J¼6.6 Hz), 3.12 (1H, dd, J¼5.6, 13.4 Hz), 2.97 (1H, dd,
J¼7.8, 13.6 Hz), 2.84 (1H, dd, J¼6.0, 17.0 Hz), 2.64 (1H, dd, J¼6.0,
wing the general protocol, 16a was synthetized from 6a (1.00 g,
3.28 mmol) leading to 1.003 g of crude product (80% crude yield).
After purification, 16a was obtained as a colorless oil (260 mg,
41%, ee 99%). Rf¼0.2 (cyclohexane/AcOEt/Et3N 1:1:0.02, KMnO4
17.0 Hz). 13C NMR (100 MHz, CDCl3)
d 199.6, 170.2, 155.9, 139.8,
136.4,136.1,126.3e129.4, 67.2, 56.4, 48.7, 48.6, 38.6. IR (neat, cmꢁ1):
3304, 3030, 2925, 1658, 1537, 1454, 1257, 1028, 747, 698. HRMS (FD)
[M]þ (C26H26N2O4) calcd: 430.1893, found: 430.1906.
detection).
30 mꢂ0.25 mm 0.25
15 min, 3 mL/min) retention time 11.46 min (minor enantiomer:
retention time 11.80 min). 1H NMR (400 MHz, CDCl3)
7.34 (4H,
½
a 2D0
ꢃ
þ20.7 (c 1.0, CHCl3). GC (Restek
b
-Dex-sm
m
m, Helium, 100 ꢀC 1 min, 2 ꢀC/min 160 ꢀC
d
4.1.15. (2S)-1-Benzoyl-pyrrolidine-2-carboxylic acid [(1R)-3-oxo-1-
phenyl-propyl]-amide 12d. To the mixture of 10d (50 mg,
0.101 mmol) in 3 mL of acetonitrile was added 3 mL of 5 N HCl, the
m), 7.24 (1H, m), 4.88 (1H, t, J¼4.9 Hz), 4.18 (1H, dd, J¼5.6, 7.9 Hz),
4.01e3.94 (2H, m), 3.90e3.80 (2H, m), 2.03 (2H, m), 1.78 (2H, s).
13C NMR (100 MHz, CDCl3)
d 145.5, 128.4 (2CH), 127.0 (CH), 126.1

2186
P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
(2CH), 103.0 (CH), 64.7 (CH2), 64.5 (CH2), 52.3 (CH), 42.7 (CH2). IR
(CH2). IR (neat, cmꢁ1): 2962, 2854, 1549, 1458, 1344, 1306, 1127,
1007, 766. HRMS (CI) [MþH]þ (C12H18NO2) calcd: 208.1338, found:
208.1340.
(neat, [MþH]þ (C11H16NO2) calcd: 194.1181, found: 194.1185.
4.2.2. (1R)-1-[1,3]Dioxolan-2-ylmethyl-2,2-dimethyl-propylamine
16b. Following the general protocol, 16b was synthetized from 6b
(500 mg,1.75 mmol) leading to 378 mg of crude product (72% crude
yield). After purification, 16b was obtained as a colorless oil
4.2.6. (1R)-2-(5,5-Dimethyl-[1,3]dioxan-2-yl)-1-phenyl-ethylamine
18. Following the general protocol, 18 was synthetized from 6a
(420 mg, 1.38 mmol) and 2,2-dimethyl-1,3-propanediol (172 mg,
1.2 equiv) leading to 380 mg of crude product (76% crude yield).
After purification, 18 was obtained as a colorless oil (60 mg, 19%).
Rf¼0.15 (cyclohexane/AcOEt/Et3N 1:1:0.02, vaniline detection). 1H
(118 mg, 39%, ee 99%). ½a D20
ꢃ
þ18.5 (c 1.0, CHCl3). GC (Restek
b-Dex-
sm 30 mꢂ0.25 mm 0.25
m
m, Helium, 100 ꢀC 1 min, 2 ꢀC/min 150 ꢀC
10 min, 5 ꢀC/min 200 ꢀC 10 min, 3 mL/min) retention time
10.16 min (minor enantiomer: retention time 20.67 min). 1H NMR
NMR (400 MHz, CDCl3)
d 7.34 (4H, m), 7.25 (1H, m), 4.43 (1H, t,
(400 MHz, CDCl3)
d
5.01 (1H, t, J¼4.9 Hz), 4.00 (2H, m), 3.84 (2H, m),
J¼5.1 Hz), 4.19 (1H, dd, J¼5.8, 8.1 Hz), 3.60 (2H, ddd, J¼2.7, 7.2,
2.65 (1H, dd, J¼1.8, 10.7 Hz), 1.89 (1H, ddd, J¼1.8, 4.9, 13.7 Hz), 1.53
11.2 Hz), 3.38 (2H, d, J¼10.9 Hz), 1.99 (2H, m), 1.62 (2H, s), 1.20 (3H,
(2H, s), 1.45 (1H, ddd, J¼4.9, 10.7, 13.7 Hz), 0.88 (9H, s). 13C NMR
s), 0.70 (3H, s). 13C NMR (100 MHz, CDCl3)
d 146.2, 128.5 (2CH)
(100 MHz, CDCl3)
d
104.6 (CH), 64.9 (CH2), 64.5 (CH2), 56.8 (CH)
127.0 (CH), 126.3 (2CH), 100.8 (CH), 77.19 (CH2), 77.23 (CH2), 52.0
(CH), 44.1 (CH2), 30.2, 23.1 (CH3), 21.9 (CH3). IR (neat, cmꢁ1): 2953,
2869, 1783, 1646, 1520, 1470, 1394, 1362, 1132, 1038, 1011, 762,
699. HRMS (CI) [MþH]þ (C14H22NO2) calcd: 236.1651, found:
236.1653.
36.3 (CH2), 34.2, 25.9 (3CH3). IR (neat, cmꢁ1): 2954, 2872, 1573,
1538, 1456, 1428, 1362, 1292, 1275, 1122, 1052, 1030, 979, 943, 812,
705, 540. HRMS (CI) [MþH]þ (C9H20NO2) calcd: 174.1494, found:
174.1499.
4.2.3. (1S)-1-[1,3]Dioxolan-2-ylmethyl-3-methyl-butylamine
16c. Following the general protocol, 16c was synthetized from 6c
(390 mg, 1.37 mmol) leading to 319 mg of crude product (81%
crude yield). After purification, 16c was obtained as a colorless oil
4.3. General procedure for the three-step synthesis of
dipeptide aldehydes 12
(104 mg, 44%, ee 99%). ½a D20
ꢃ
þ22.1 (c 1.0, CHCl3). GC (Restek
b
-Dex-
To the mixture of 6 (1 equiv) in dry dichloromethane (20 mL/
mmol of 6) was added 1.5 equiv of para-toluenesulfonic acid and
3 equiv of diol. The mixture was heated to 35 ꢀC and stirred during
48 h. After completion of the reaction (disappearance of starting
material monitored by TLC), saturated aqueous NaHCO3 (1.7 mL/
mmol of 6) was added. The aqueous layer was extracted with
dichloromethane three times. The organic layers were combined,
dried over MgSO4, and concentrated under vacuum affording
crude symmetric acetal 16 in mixture with pantolactone. In
a second step, to the N-protected amino acid 9 (1.2 equiv) in so-
lution in dry dichloromethane (9 mL/mmol of 6) under nitrogen
atmosphere was added EDCI (1.2 equiv) and HOBt (0.8 equiv) at
sm 30 mꢂ0.25 mm 0.25
m
m, Helium, 100 ꢀC 1 min, 2 ꢀC/min
150 ꢀC 10 min, 5 ꢀC/min 200 ꢀC 10 min, 3 mL/min) retention time
12.17 min (minor enantiomer: retention time 20.60 min). 1H NMR
(400 MHz, CDCl3)
d
4.98 (1H, t, J¼4.9 Hz), 3.98 (2H, m), 3.84 (2H,
m), 3.05 (1H, m), 1.79 (1H, m), 1.71 (1H, m), 1.63 (2H, s), 1.57 (1H,
m), 1.24 (2H, m), 0.91 (3H, d, J¼6.6 Hz), 0.90 (3H, d, J¼6.6 Hz). 13C
NMR (100 MHz, CDCl3)
d 103.6 (CH), 64.8 (CH2), 64.6 (CH2), 48.0
(CH2), 45.6 (CH), 41.9 (CH2), 24.6 (CH), 23.3 (CH3), 22.0 (CH3). IR
(neat, cmꢁ1): 2953, 2869, 1574, 1467, 1410, 1366, 1127, 1029, 942,
808, 721. HRMS (CI) [MþH]þ (C9H20NO2) calcd: 174.1494, found:
174.1496.
0
ꢀC. After 15 min, the preformed aminoacetal 16 was added in
4.2.4. (1S)-1-Benzyl-2-[1,3]dioxolan-2-yl-ethylamine
16d. Follo-
solution in dichloromethane (7 mL/mmol of 6). The solution was
warmed up to room temperature and stirred overnight. Water
(15 mL/mmol of 6) was added and the reaction mixture was
extracted with dichloromethane. The combined organic phases
were dried over MgSO4 and concentrated under vacuum to give
crude product. Finally, acetal was deprotected by dissolving crude
mixture in acetonitrile (12 mL/mmol of 6) and HCl 5 N (12 mL/
mmol of 6) and by stirring at room temperature overnight. The
reaction mixture is then treated with a solution of NaOH 2 N
(30 mL/mmol of 6) and with a saturated solution of NaHCO3 to
complete neutralization.
wing the general protocol, 16d was synthetized from 6d (55 mg,
0.17 mmol) leading to 85 mg of crude product. After purification,
16d was obtained as a colorless oil (11.6 mg, 33%, ee 99%). ½a D20
ꢁ8.0
ꢃ
(c 1.0, CHCl3). HPLC (Phenomenex Lux Cellulose-1250ꢂ4.60 mm
5
m
m, 1 mL/min, trimethylpentane/iPrOH/Et2NH 1000/10/1, UV
247 nm) retention time 14.15 min (minor enantiomer: retention
time 19.03 min). 1H NMR (400 MHz, CDCl3)
7.35e7.26 (2H, m),
d
7.26e7.20 (3H, m), 5.01 (1H, t, J¼4.9 Hz), 4.00e3.95 (2H, m),
3.90e3.82 (2H, m), 3.30 (1H, dddd, J¼3.7, 5.1, 8.4, 8.9 Hz), 2.81 (1H,
dd, J¼5.1, 13.3 Hz), 2.59 (1H, dd, J¼8.4, 13.3 Hz), 1.89 (1H, ddd, J¼3.7,
4.9, 14.1 Hz), 1.71 (1H, ddd, J¼4.9, 8.9, 14.1 Hz), 1.58 (2H, s). 13C NMR
(100 MHz, CDCl3)
d
139.0, 129.3 (2CH), 128.4 (2CH), 126.3 (CH),
4.3.1. {(1S)-1-[(1R)-1-(1,1-Dimethylethyl)-3-oxo-propylcarbamoyl]-
2-phenyl-ethyl}-carbamic acid benzyl ester 12f. Dipeptide aldehyde
12f was prepared following the three-step sequence starting from
6b (182 mg, 0.64 mmol). After preparation of aminoacetal 16b, it
was engaged in the coupling with CBzPhe (409 mg, 1.37 mmol,
2.1 equiv). The crude mixture was further deprotected affording
166 mg of crude product. Flash chromatography on silica gel (cy-
clohexane/acetone 80:20, then cyclohexane/acetone 50:50) affor-
ded 12f as a white solid (94 mg, 36% for three steps). Rf¼0.50
103.5 (CH), 64.8 (CH2), 64.6 (CH2), 49.2 (CH), 45.0 (CH2), 40.9 (CH2).
IR (neat, cmꢁ1): 2924, 1724, 1600, 1453, 1410, 1271, 1133, 1029, 943,
803, 744, 699. HRMS (CI) [MþH]þ (C12H18NO2) calcd: 208.1338,
found: 208.1337.
4.2.5. (1R)-2-[1,3]Dioxan-2-yl-1-phenyl-ethylamine 17. Following
the general protocol, 17 was synthetized from 6a (200 mg,
0.66 mmol) and 1,3-propanediol (60 mg, 1.2 equiv) leading to
184 mg of crude product (83% crude yield). After purification, 17
was obtained as a colorless oil (60 mg, 44%). Rf¼0.3 (cyclohexane/
(cyclohexane/acetone 1:1).
(400 MHz, CDCl3)
½
a 2D0
ꢃ
ꢁ41.5 (c 1, EtOH). 1H NMR
d
9.48 (1H, d, J¼2.4 Hz), 7.40e7.15 (10H, m), 6.12
AcOEt/Et3N 1:1:0.02, UV detection). ½a D20
ꢃ
þ7.1 (c 1.0, CHCl3). 1H
(1H, m), 5.54 (1H, d, J¼8.3 Hz), 5.05 (2H, 2d, J¼12.7 Hz), 4.37 (1H, dt,
J¼7.2, 7.2 Hz), 4.22 (1H, dt, J¼3.7, 9.9 Hz), 3.01 (2H, m), 2.48 (1H,
ddd, J¼1.2, 3.7, 15.9 Hz), 2.10 (1H, ddd, J¼3.7, 9.9, 15.9 Hz), 0.80 (9H,
NMR (400 MHz, CDCl3)
d 7.32 (4H, m), 7.24 (1H, m), 4.55 (1H, t,
J¼5.1 Hz), 4.17 (1H, dd, J¼5.6, 8.1 Hz), 4.10 (2H, m), 3.72 (2H, m),
2.09 (1H, m), 1.96 (2H, m), 1.82 (2H, s), 1.34 (1H, m). 13C NMR
s). 13C NMR (100 MHz, CDCl3)
d 201.1 (CH), 170.8, 156.2, 136.6, 136.2,
(100 MHz, CDCl3)
100.8 (CH), 66.8 (CH2), 66.7 (CH2), 51.9 (CH), 44.4 (CH2), 25.8
d
146.1, 128.7 (2CH) 126.9 (CH), 126.2 (2CH),
130.2e127.0 (8CH), 67.1 (CH2) 53.5 (CH), 52.6 (CH), 44.8 (CH2), 38.2
(CH2), 34.3, 26.2 (3CH3). IR (neat, cmꢁ1): 3286, 3027, 2955, 1721,

P. Shpak-Kraievskyi et al. / Tetrahedron 68 (2012) 2179e2188
2187
1698, 1655, 1533, 1454, 1367, 1231, 1083. HRMS (CI) [MþH]þ
following the three-step sequence starting from 6d (78 mg,
0.24 mmol). After preparation of aminoacetal 16d, it was engaged
in the coupling with BzPro (83 mg, 0.38 mmol, 1.6 equiv). The crude
mixture was further deprotected affording 74 mg of crude product.
Flash chromatography on silica gel (cyclohexane/acetone 80:20,
then cyclohexane/acetone 50:50) afforded 12j as a white solid
(37 mg, 41% for three steps). Rf¼0.38 (cyclohexane/acetone 1:1).
(C24H31N2O4) calcd: 411.2284, found: 411.2267.
4.3.2. (2S)-1-Benzoyl-pyrrolidine-2-carboxylic acid [(1R)-1-(1,1-
dimethyl-ethyl)-3-oxo-propyl]-amide 12g. Dipeptide aldehyde 12g
was prepared following the three-step sequence starting from 6b
(250 mg, 0.87 mmol). After preparation of aminoacetal 16b, it was
engaged in the coupling with BzPro (206 mg, 0.95 mmol, 1.1 equiv).
The crude mixture was further deprotected affording 190 mg of
crude product. Flash chromatography on silica gel (cyclohexane/
acetone 80:20, then cyclohexane/acetone 50:50) afforded 12g as
a white solid (97 mg, 34% for three steps). Rf¼0.36 (cyclohexane/
½
a 2D0
ꢃ
ꢁ21.2 (c 1, EtOH). 1H NMR (400 MHz, CDCl3)
d 9.71 (1H, s),
7.50e7.30 (5H, m), 7.25e7.11 (6H, m), 4.69 (1H, m), 4.61 (1H, m),
3.42 (2H, m), 2.89 (2H, d, J¼7.1 Hz), 2.64 (2H, d, J¼6.0 Hz), 2.33 (1H,
m), 1.99 (1H, m), 1.90 (1H, m), 1.78 (1H, m). 13C NMR (100 MHz,
CDCl3)
d 200.9 (CH), 171.3, 170.8, 137.6, 136.0, 130.4 (CH), 129.3
acetone 1:1). ½a D20
ꢃ
ꢁ69.3 (c 1, EtOH). 1H NMR (400 MHz, CDCl3)
(2CH), 128.6 (2CH), 128.4 (2CH), 127.2 (2CH), 126.8 (CH), 60.1 (CH),
50.5 (CH2), 47.6 (CH2), 46.3 (CH), 40.4 (2CH2), 27.4 (CH2), 25.3 (CH2).
IR (neat, cmꢁ1): 3709, 2933,1719,1684, 1613,1574,1530, 1446, 1408,
1243, 1090, 1028. HRMS (CI) [MþH]þ (C22H25N2O3) calcd: 365.1865,
found: 365.1853.
d
9.73 (1H, d, J¼2.9 Hz), 7.50e7.35 (5H, m), 7.41 (1H, m), 4.77 (1H,
dd, J¼4.6, 7.8 Hz), 4.33 (1H, dt, J¼3.2, 10.2 Hz), 3.47 (2H, m), 2.65
(1H, ddd, J¼1.2, 3.2,15.6 Hz), 2.50 (1H, m), 2.36 (1H, ddd, J¼3.2,10.2,
15.6 Hz), 2.03 (1H, m), 1.97 (1H, m), 1.82 (1H, m), 0.93 (9H, s). 13C
NMR (100 MHz, CDCl3)
d 201.5 (CH), 171.4, 170.5, 136.3, 130.2 (CH),
128.5 (2CH), 126.8 (2CH), 59.7 (CH), 52.8 (CH), 50.4 (CH2), 45.3
(CH2), 34.4, 26.5 (CH2), 26.3 (3CH3), 25.4 (CH2). IR (neat, cmꢁ1):
2951, 2912, 1723, 1661, 1612, 1574, 1446, 1238. HRMS (CI) [MþH]þ
(C19H27N2O3) calcd: 331.2022, found: 331.2012.
4.3.6. 4,4-Difluorocyclohexanecarboxylic acid [(1R)-3-oxo-1-phenyl-
propyl]-amide 21.25b Aldehyde 21 was prepared following the
three-step sequence starting from 6a (250 mg, 0.8 mmol). After
preparation of aminoacetal 16a, it was engaged in the coupling
with 4,4-difluorocyclohexanecarboxylic acid 20 (144 mg, 0.8 mmol,
1.0 equiv). The crude mixture was further deprotected affording
195 mg of crude product. Flash chromatography on silica gel (cy-
clohexane/acetone 80:20, then cyclohexane/acetone 50:50) affor-
4.3.3. {(1S)-1-[(1S)-3-Methyl-1-(2-oxo-ethyl)-butylcarbamoyl]-2-
phenyl-ethyl}-carbamic acid benzyl ester 12h. Dipeptide aldehyde
12h was prepared following the three-step sequence starting from
6c (234 mg, 0.82 mmol). After preparation of aminoacetal 16c, it
was engaged in the coupling with CBzPhe (368 mg, 1.23 mmol,
1.5 equiv). The crude mixture was further deprotected affording
284 mg of crude product. Flash chromatography on silica gel (cy-
clohexane/acetone 80:20, then cyclohexane/acetone 50:50) affor-
ded 12h as a white solid (137 mg, 41% for three steps). Rf¼0.53
ded 21 as a white solid (115 mg, 49% for three steps). ½a D20
þ44.2 (c
ꢃ
1, CHCl3). 1H NMR (400 MHz, CDCl3)
d 9.75 (1H, s), 7.38e7.22 (5H,
m), 6.19 (1H, br d), 5.49 (1H, m), 3.05 (1H, ddd, J¼2.6, 6.7, 16.9 Hz),
2.96 (1H, ddd, J¼1.3, 5.9, 16.9 Hz), 2.18 (3H, m), 2.00e1.55 (6H, m).
Acknowledgements
(cyclohexane/acetone 1:1).
(400 MHz, CDCl3)
½
a 2D0
ꢃ
ꢁ17.9 (c 1, EtOH). 1H NMR
d
9.56 (1H, s), 7.44e7.18 (10H, m), 5.96 (1H, d,
ꢀ
The Region des Pays de la Loire and CNRS are deeply acknowl-
J¼8.8 Hz), 5.40 (1H, s), 5.13 (2H, s), 4.41e4.26 (2H, m), 3.16 (1H, dd,
J¼6.3, 13.6 Hz), 3.00 (1H, dd, J¼8.0, 13.6 Hz), 2.45 (2H, d, J¼5.2 Hz),
1.54e1.38 (2H, m), 1.28e1.18 (1H, m), 0.90 (3H, d, J¼8.5 Hz), 0.88
edged for financial support (doctoral grant to P.S.-K. and post-
doctoral grant to B.Y.). We would also acknowledge M. Ping and F.
Legros for technical assistance, P. Gangnery for recording HRMS and
A. Durand for recording NMR spectra. The authors are indebted to
(3H, d, J¼8.5 Hz). 13C NMR (100 MHz, CDCl3)
d 200.8 (CH), 170.3,
155.9,136.4, 136.1,129.4 (2CH),128.8 (2CH),128.6 (2CH),128.3 (CH),
128.2 (2CH), 127.2 (CH), 67.2 (CH2), 56.6 (CH), 48.4 (CH2), 43.4 (CH),
43.3 (CH2), 38.6 (CH2), 24.9 (CH), 22.9 (CH3), 21.9 (CH3). IR (neat,
cmꢁ1): 3323, 3296, 1725, 1683, 1650, 1525, 1286, 1242, 1038. HRMS
(CI) [MþH]þ (C24H31N2O4) calcd: 411.2284, found: 411.2265.
ꢁ
ꢀ
Dr. M. Calmes (Universite de Montpellier) for helpful discussions.
References and notes
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1-(2-oxo-ethyl)-butyl]-amide 12i. Dipeptide aldehyde 12i was pre-
pared following the three-step sequence starting from 6c (195 mg,
0.68 mmol). After preparation of aminoacetal 16c, it was engaged in
the coupling with BzPro (180 mg, 0.82 mmol, 1.2 equiv). The crude
mixture was further deprotected affording 151 mg of crude prod-
uct. Flash chromatography on silica gel (cyclohexane/acetone
80:20, then cyclohexane/acetone 50:50) afforded 12i as a white
solid (94 mg, 42% for three steps). Rf¼0.35 (cyclohexane/acetone
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ꢃ
ꢁ77.6 (c 1, EtOH). 1H NMR (400 MHz, CDCl3)
d 9.75 (1H, s),
ꢀ
Bacterial signal peptidase type I: Buzder-Lantos, P.; Bocstael, K.; Anne, J.; Her-
7.50e7.38 (5H, m), 7.16 (1H, m), 4.73 (1H, m), 4.41 (1H, m),
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d 200.5
(CH), 170.6, 170.1, 135.6, 129.7 (CH), 127.8 (2CH), 126.3 (2CH), 59.3
(CH), 49.8 (CH2), 48.7 (CH2), 43.2 (CH2), 42.9 (CH), 26.6 (CH2), 24.8
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2867,1723,1669, 1611, 1557, 1446, 1427,1365,1340, 1243,1144,1027.
HRMS (CI) [MþH]þ (C19H27N2O3) calcd: 331.2022, found: 331.2027.
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4.3.5. (2S)-1-Benzoyl-pyrrolidine-2-carboxylic acid [(1S)-1-benzyl-
3-oxo-propyl]-amide 12j. Dipeptide aldehyde 12j was prepared
ꢁ
Am. Chem. Soc.1994,116, 30e33; (b) Lelievre, D.; Turpin, O.; El Kazzouli, S.; Delmas,
ꢁ
A. Tetrahedron 2002, 58, 5525e5533; (c) Cremer, G.-A.; Bureaud, N.; Lelievre, D.;

2188
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ꢁ
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