Preparation of modified peptides: Direct conversion of α-amino acids into β-amino aldehydes

Article abstract of DOI:10.1039/c2ob25433f

A direct method for the transformation of α-amino acids into β-amino aldehydes was developed, and applied to the modification of the C-terminal residue of peptides. The method takes place in good yields and under mild conditions. The application of this methodology to the preparation of small peptides with γ-amino alcohol units, which are precursors of analogues of peptaibol antibiotics, is also described.

Full text of DOI:10.1039/c2ob25433f

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PAPER
Preparation of modified peptides: direct conversion of α-amino acids into
β-amino aldehydes†‡
Carlos J. Saavedra, Alicia Boto* and Rosendo Hernández*
Received 28th February 2012, Accepted 18th April 2012
DOI: 10.1039/c2ob25433f
A direct method for the transformation of α-amino acids into β-amino aldehydes was developed, and
applied to the modification of the C-terminal residue of peptides. The method takes place in good yields
and under mild conditions. The application of this methodology to the preparation of small peptides with
γ-amino alcohol units, which are precursors of analogues of peptaibol antibiotics, is also described.
Some bioactive peptides also present α-unsubstituted β-amino
Introduction
aldehyde units,6 such as product 3, a potent inhibitor of interleu-
The replacement of amino acid residues in peptides by amino
aldehyde units has provided several peptide analogues with
remarkable biological activities.1 Some derivatives presenting an
α-amino aldehyde unit are potent inhibitors of proteases, such as
papain, thrombin, trypsin, calpain, caspases and viral proteases.
Their applications range from antiviral drugs to antithrombotic,
anticataract or antitumoral agents.2
On the other hand, there are few examples of peptide deriva-
tives with β-amino aldehyde units.3 In most cases, an amino
glyoxal residue4 is introduced, as occurs with the caspase-3
inhibitor 15a (Fig. 1) and the collagen-degradation inhibitor 2.5b
kin 1-β converting enzyme, used as a drug lead for the treatment
of inflammatory diseases.6a
The development of new derivatives, especially those with
α-substituted β-amino aldehyde residues, could be useful to dis-
cover new drug leads. We reasoned that a peptide aldehyde 4
(Scheme 1) could be formed by addition of carbon nucleophiles
(such as vinyl ethers or silylenol ethers) to the N,O-acetals 5.7
These acetals, in turn, could be generated by radical decarboxy-
lation–oxidation of α-peptides such as substrate 6.8 The direct
formation of peptide aldehydes 4 from α-peptides 6 would be
particularly interesting. With the one-pot process, a single
α-peptide 6 could be transformed into a variety of peptide alde-
hydes with different substituents, allowing the generation of
libraries of derivatives 4 to study structure–activity relationships.
In previous work from our group,8 the oxidative decarboxyla-
tion of α-amino acids followed by addition of different carbon
nucleophiles had proven useful to obtain unnatural amino acids,
Fig. 1 Bioactive peptides with β-amino aldehyde units.
Instituto de Productos Naturales y Agrobiología del CSIC, Avda.
Astrofísico Francisco Sánchez 3, 38206-La Laguna, Tenerife, Spain.
E-mail: alicia@ipna.csic.es, rhernandez@ipna.csic.es;
Fax: +34 922260135
†Dedicated to Prof. Gerry Pattenden.
‡Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of the amino acids 8, 14, 16, 18, 19, 21, 24, and 26–29,
the peptide aldehydes 38–48 and the amino alcohol derivatives 52–57.
See DOI: 10.1039/c2ob25433f.
Scheme 1 Formation of peptide aldehydes from α-peptides.
4448 | Org. Biomol. Chem., 2012, 10, 4448–4461
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Table 1 One-pot oxidative radical decarboxylation–alkylation
Table 2 One-pot oxidative radical decarboxylation–alkylationa
Entry
Substrate
Nu (equiv)b
Productsc (%)
1
2
3
Bz-Ala-OH 10
A (3)
B (3)
C (3)
14 R = Me (69)
15 R = H (45)
15 R = H (79)
DIB/I2
Entry (equiv)
Nucleophile/Lewis acid
(equiv)a
Products
T (°C) (%)b
1
2
3
4
5
6
7
8
9
2.0/1.0
1.5/0.5
1.5/0.3
1.5/0.3
1.5/0.3
1.5/0.3
1.5/0.3
1.5/0.3
1.5/0.3
A (5)/BF3·OEt2 (2)
A (3)/BF3·OEt2 (2)
A (3)/BF3·OEt2 (2)
A (3)/TMSOTf (2)
A (3)/SnCl4 (2)
0
0
0
0
−78
−78
0
0
0
8 (38)
8 (53)
8 (61)
8 (58)
8 (51)
8 (25)
9 (41)
9 (40)
9 (60)
4
5
6
Bz-Leu-OH 11
A (3)
B (3)
C (3)
16 R = Me (60)
17 R = H (55)
17 R = H (56)
A (3)/TiCl4 (2)
B (3)/BF3·OEt2 (2)
B (3)/TMSOTf (2)
C (3)/BF3·OEt2 (2)
a A = (TMSO)–CHvC(Me)2; B = (TMSO)CHvCH2; C = (EtO)-
CHvCH2. b Yield for products purified by chromatography.
alkaloid precursors and α,β-peptide hybrids. In the current
article, a variation of this methodology is described, to allow the
direct conversion of α-amino acids or α-peptides into β-amino
aldehydes or peptide β-aldehydes, under mild conditions and
good overall yields.
7
8
9
Bz-Glu(OEt)-OH 12
A (3)
B (3)
C (3)
18 R = Me (66)
19 R = H (51)
19 R = H (45)
Results and discussion
The initial studies on the one-pot decarboxylation–alkylation
process were carried out with the DL-phenyl alanine derivative 7
(Table 1),8e which was treated with (diacetoxyiodo)benzene
(DIB) and iodine under irradiation with visible light, to induce
the oxidative decarboxylation.8 The scission generated an N,O-
acetal intermediate, which was not isolated, but treated with a
Lewis acid and a nucleophile (entries 1–9). When 1-(trimethyl-
silyloxy)-2-methyl-1-propene was used as the nucleophile, the
β-aminoaldehyde 8 was formed, while the use of 1-(trimethyl-
silyloxy)-1-ethene or ethyl vinyl ether as nucleophiles provided
the β-amino aldehyde 9.9
The amount of the scission reagents was important to obtain
satisfactory yields (entries 1–3). The best result was obtained
with a substrate/DIB/I2 ratio of 1/1.5/0.3 (entry 3). Different
Lewis acids were also tried (entries 3–6 and 7–8); boron trifluor-
ide and TMSOTf provided the best yields. The nucleophiles B
10
13
A (3)
20 → 21 (83)
20 X = NHCO2Me
21 X = C(Me)2-CHO
a DIB, I2, hν, then 0 °C, nucleophile, Lewis acid. b A = (TMSO)–
CHvC(Me)2; B = (TMSO)CHvCH2; C = (EtO)CHvCH2; BF3·OEt2
was used as the Lewis acid. c Yield for products purified by
chromatography.
Similar products were obtained when the DL-proline and
hydroxy L-proline derivatives 2213 (Table 3, entries 1–3) and
2314 (entries 4–6) underwent the decarboxylation–alkylation
reaction. In the case of the proline derivative 22, the process
took place in 82–86% yields, affording products 24 (R = Me) or
25 (R = H).15a–d When hydroxyproline substrate 23 was used,
the process afforded compounds 26–27 (R = Me) and 28–29
(R = H).15e Remarkably, the 2,4-cis products predominated over
the 2,4-trans isomers, due to an stereoelectronic effect described
by Woerpel and coworkers.16
[1-(tert-butyldimethylsilyloxy)-1-ethene] and
C [1-ethoxy-1-
ethene] were then compared (entries 7 and 9), and the vinyl
ether C proved superior to the silyl enol ether B, probably due to
increased reagent stability.
The best conditions for each nucleophile were then used with
other amino acids, such as DL-substrates 10–138e,10 (Table 2), to
afford the β-amino aldehyde derivatives 14–21.11
The one-pot process was then tried with peptides, using com-
pounds 30–3617 (Scheme 2) as substrates. Interestingly, with
peptides TMSOTf proved superior to boron trifluoride as the
Lewis acid (conversions 30 → 37 and 31 → 38).
Interestingly, the oxidative decarboxylation–alkylation of the
ornithine derivative 13 (Table 2, entry 10) afforded the proline
analogue 21, probably due to intramolecular cyclization of the
intermediate N,O-acetal to give the N,N-acetal 20,12 which then
reacted with the Lewis acid to give a five-membered acylimi-
nium ion, followed by the addition of the nucleophile.
In the case of substrates 30 and 31, whose N-terminal residue
was an α,α-disubstituted amino acid, the process afforded a
racemic mixture of the peptide aldehydes 37 and 38, respectively.
In the case of substrates 32–36, the reacting residue was attached
to a chiral amino acid, so the process was stereoselective (dr from
3 : 2 to 3 : 1), affording compounds 39–46 in good overall yields.
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Table 3 One-pot oxidative radical decarboxylation–alkylationa
Entry
Substrate
Nu (equiv)b
Productsc (%)
1
2
3
22
A (3)
B (3)
C (3)
24 R = Me (86)
25 R = H (82)
25 R = H (85)
4
23
A (3)
26 (2R) (63)
27 (2S) (19)
5
6
23
23
B (3)
C (3)
28 (2R) (34)
29 (2S) (20)
28 (2R) (27)
29 (2S) (13)
a DIB, I2, hν, then 0 °C, nucleophile, Lewis acid. b A = (TMSO)–
CHvC(Me)2; B = (TMSO)CHvCH2; C = (EtO)CHvCH2. c Yield for
products purified by chromatography.
Their stereochemistry was unambiguously determined by corre-
lation to known compounds, as will be commented later.
The aldehydes are not only potential drug candidates, but also
useful precursors of other compounds, such as diamines, amino
alcohols, etc. Especially interesting are the amino alcohol deriva-
tives (Scheme 3) which are precursors of analogues of the pep-
taibol antibiotics.18 The peptaibols present a short peptidic chain
with a C-terminal β-amino alcohol unit. The presence of non-
proteinogenic amino acids (in particular Aib, α-amino isobutyric
acid) is key for their potent activity against bacteria and fungi.
These antibiotics present interesting folding patterns which can
allow the creation of holes in the bacterial membrane.
Our scission–alkylation methodology, followed by mild
reduction of the aldehydes, would allow the preparation of pre-
cursors of peptaibol analogues, such as compounds 47–56
(Scheme 3). These precursors present unusual C-terminal β,β-di-
methyl γ-amino alcohol units (instead of the peptaibol β-amino
alcohol units), and with their β,β-substitution they also resemble
an Aib-derived amino alcohol. This new terminal residue could
modify the conformational and biological properties of the
derivatives, and thus be useful to understand SAR relationships.
The reduction of peptide aldehydes 39–46 was tried under
different conditions (DIBAL-H, NaBH4, or LiBH4 in different
solvents), and the best results were obtained with LiBH4 in
iPrOH, affording the amino alcohols in good yields (69–79%).
To our satisfaction, in the case of aldehyde mixtures, such as
compounds 45 and 46, the reduction allowed the separation of
the diastereomeric products.
Scheme 2 Conversion of α-dipeptides into derivatives with a C-ter-
minal β-amino aldehyde. Reaction conditions: [a] DIB, I2, hν, then 0 °C,
BF3·OEt2, (TMSO)CHvC(Me)2; [b] DIB, I2, hν, then 0 °C, TMSOTf,
(TMSO)CHvC(Me)2.
The stereochemistry of the amino aldehydes and the amino
alcohols was determined by correlation to known compounds
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Scheme 4 Determination of the stereochemistry of the aldehydes by
correlation to known compounds. Reaction conditions: [a] DIBAL-H,
CH2Cl2, −78 °C; [b] DIBAL-H, CH2Cl2, 0 °C.
Scheme 3 Conversion of dipeptides with a β-amino aldehyde unit into
Scheme 5 Determination of the stereochemistry of the aldehydes by
correlation to known compounds. Reaction conditions: [i] DIBAL-H,
CH2Cl2, 0 °C.
alcohol derivatives. Reaction conditions: [a] LiBH4, iPrOH.
(Scheme 4).8e Thus, the acids 32 and 33 were transformed into
the known β-amino esters 52–53 and 54–55, respectively, using
a sequential scission–alkylation process.8e
The known esters 52–55 were then reduced with DIBAL-H to
give the corresponding aldehydes 39–42 or the amino alcohols
47–50,19 confirming the assigned stereochemistries. In a similar
way, the amino ester 578e (Scheme 5) was reduced to give the
γ-amino alcohol derivative 51. In all the cases, the major isomer
presented the “natural” (3S) configuration.
Conclusions
An efficient and mild one-pot process for the conversion of
α-amino acid derivatives into β-amino aldehydes has been devel-
oped, and applied to the selective modification of the C-terminal
residue in small peptides, giving peptide aldehydes in good
overall yields. With this procedure, a single α-peptide could be
transformed into a library of α,β-peptidyl aldehydes with differ-
ent α-substituents. The aldehydes are useful precursors of other
compounds, as illustrated by transformation of several peptide
aldehydes into precursors of peptaibol analogues, which present
γ-hydroxyamino units.
The formation of peptaibol analogues from these simpler pre-
cursors is under way, and together with their conformational
properties, will be reported in due course.
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14.2 Hz, 4-Hb), 4.69 (1H, ddd, J = 4.1, 10.2, 10.8 Hz, 3-H),
6.38 (1H, d, J = 9.8 Hz, NH), 7.18 (1H, dd, J = 6.8, 6.8 Hz, Ar),
7.23–7.28 (4H, m, Ar), 7.36 (2H, dd, J = 7.5, 7.8 Hz, Ar), 7.45
(1H, dd, J = 7.1, 7.8 Hz, Ar), 7.52 (2H, d, J = 7.1 Hz, Ar), 9.59
(1H, s, CHO); δC (125.7 MHz, CDCl3) 19.5 (CH3), 20.1 (CH3),
36.7 (CH2), 50.5 (C), 54.7 (CH), 126.7 (3 × CH), 128.5 (4 ×
CH), 128.9 (2 × CH), 131.3 (CH), 134.6 (C), 137.8 (C), 167.4
(C), 205.3 (CH); m/z 295 (M+, <1%), 105 (100, [PhCO]+);
HRMS calcd for C19H21NO2 295.1572, found 295.1580; calcd
for C7H5O 105.0340, found 105.0343. C19H21NO2 requires C,
77.26; H, 7.17; N, 4.74%. Found: C, 77.18; H, 7.43; N, 4.74.
Experimental section
General remarks
Commercially available reagents and solvents were analytical
grade or were purified by standard procedures prior to use.20 All
reactions involving air- or moisture-sensitive materials were
carried out under nitrogen atmosphere. Three alternative spray
reagents for TLC analysis were used: (a) 0.5% vanillin in
H2SO4–EtOH (4 : 1); (b) 0.25% ninhydrin in ethanol; and (c)
Fleet’s reagent [Ce(SO4)2 (0.5 g) and ammonium phospho-
molybdate hydrate (2.5 g) in H2SO4 (5 mL) and water (65 mL)].
Once sprayed, the TLC was heated until development of color.
Merck silica gel 60 PF254 and 60 (0.063–0.2 mm) were used for
rotatory chromatography and column chromatography, respect-
ively. Melting points were determined with a hot-stage apparatus
and are uncorrected; the term “net” is used for crystals resulting
from evaporation of the chromatography eluents. Optical
rotations were measured at the sodium line at ambient tempera-
ture (26 °C). NMR spectra were determined at 500 or 400 MHz
for 1H and 125.7 or 100.6 MHz for 13C in CDCl3 as solvent and
at 25 °C (δH 7.26; δC 77.0), unless otherwise stated.
N-Benzoyl-DL-β-homophenylalaninal
(9).9 N-Benzoyl-DL-
phenylalanine (7) was treated as in Method A, using ethyl vinyl
ether as the nucleophile. The reaction mixture was purified by
chromatography (hexanes–EtOAc, 60 : 40), giving the aldehyde
( )-9 (60%) as a syrup; νmax/cm−1 3437, 3065, 1723, 1657;
δH (500 MHz, CDCl3) 2.73 (1H, ddd, J = 1.6, 6.0, 17.3 Hz, 2-
Ha), 2.77 (1H, ddd, J = 1.3, 5.4, 17.7 Hz, 2-Hb), 2.97 (1H, dd,
J = 7.6, 13.6 Hz, 4-Ha), 3.09 (1H, dd, J = 6.9, 13.6 Hz, 4-Hb),
4.76 (1H, m, 3-H), 6.58 (1H, d, J = 8.2 Hz, NH), 7.21–7.25
(3H, m, Ar), 7.32 (2H, dd, J = 7.3, 7.6 Hz, Ar), 7.40 (2H, dd,
J = 7.6, 7.6 Hz, Ar), 7.48 (1H, dd, J = 7.3, 7.6 Hz, Ar), 7.68
(2H, d, J = 7.6 Hz, Ar), 9.77 (1H, dd, J = 0.6, 0.9 Hz, CHO); δC
(125.7 MHz, CDCl3) 40.1 (CH2), 46.7 (CH2), 46.9 (CH), 126.9
(3 × CH), 128.6 (2 × CH), 128.8 (2 × CH), 129.2 (2 × CH),
131.6 (CH), 134.3 (C), 137.3 (C), 167.0 (C), 201.2 (CH); m/z
268 (M+ + H, 12%), 176 (69, M+ − PhCH2), 105 (100,
[PhCO]+), 91 (37, [PhCH2]+), 77 (81, [Ph]+); HRMS calcd for
C17H18NO2 268.1338, found 268.1327; calcd for C10H10NO2
176.0712, found 176.0708; calcd for C7H5O 105.0340, found
105.0341; calcd for C7H7 91.0548, found 91.0549; calcd for
C6H5 77.0391, found 77.0388. C17H17NO2 requires C, 76.38;
H, 6.41; N, 5.24%. Found: C, 76.38; H, 6.41; N, 5.03.
Amino aldehyde derivatives 9, 15, 17, and 25 are known but
some are partially described; for comparison purposes their
spectroscopic and physical data are also included.
General procedures for the scission–oxidation–alkylation
sequence
Method A. To a solution of the starting amino acid or peptide
(0.2 mmol) in dry dichloromethane (8 mL) were added iodine
(15 mg, 0.06 mmol, 0.3 equiv) and (diacetoxyiodo)benzene
(DIB) (97 mg, 0.3 mmol, 1.5 equiv). The reaction mixture was
stirred at 25–26 °C for 4 h, under irradiation with visible light.
Then the solution was cooled to 0 °C, and 2-methyl-1-(tri-
methylsilyloxy)-1-propene (110 μL, 86 mg, 0.6 mmol, 3 equiv)
or vinyloxytrimethylsilane (89 μL, 70 mg, 0.6 mmol, 3 equiv) or
ethyl vinyl ether (86 μL, 65 mg, 0.6 mmol, 3.0 equiv) was
injected, followed by dropwise addition of BF3·OEt2 (51 μL,
57 mg, 0.4 mmol, 2 equiv). The mixture was allowed to reach
room temperature and stirred for 3 h; then it was poured into
10% aqueous Na2S2O3-saturated aqueous NaHCO3 (1 : 1,
10 mL) and extracted with CH2Cl2. The organic layer was dried
over sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by chromatography on silica
gel (hexanes–EtOAc) to give the products.
N-Benzoyl-α,α-dimethyl-DL-β-homoalaninal
(14). Obtained
from N-benzoyl-DL-alanine (10) according to Method A, using
2-methyl-1-(trimethylsilyloxy)-1-propene as the nucleophile.
The reaction mixture was purified by chromatography (hexanes–
EtOAc, 70 : 30), giving the aldehyde ( )-14 (69%) as a syrup;
νmax/cm−1 3439, 3081, 1725, 1650, 1519, 1487; δH (500 MHz,
CDCl3) 1.14 (3H, s, 2-Mea), 1.18 (3H, s, 2-Meb), 1.23 (3H, d,
J = 6.9 Hz, 3-Me), 4.43 (1H, m, 3-H), 6.58 (1H, d, J = 8.8 Hz,
NH), 7.41 (2H, dd, J = 7.3, 7.6 Hz, Ar), 7.48 (1H, dd, J = 7.3,
7.6 Hz, Ar), 7.73 (2H, d, J = 6.9 Hz, Ar), 9.54 (1H, s, CHO); δC
(125.7 MHz, CDCl3) 16.3 (CH3), 18.9 (CH3), 20.0 (CH3), 49.4
(CH), 49.9 (C), 126.8 (2 × CH), 128.6 (2 × CH), 131.5 (CH),
134.5 (C), 166.8 (C), 205.9 (CH); m/z 220 (M+ + H, 6%), 219
(M+, <1%), 148 (32, M+ − H − Me2CCHO), 105 (100,
[PhCO]+), 77 (36, [Ph]+). HRMS calcd for C13H18NO2
220.1338, found 220.1333; calcd for C13H17NO2 219.1259,
found 219.1270; calcd for C9H10NO 148.0762, found 148.0764;
calcd for C7H5O 105.0340, found 105.0339; calcd for C6H5
77.0391, found 77.0394. C13H17NO2 requires C, 71.21; H, 7.81;
N, 6.39%. Found: C, 71.10; H, 8.04; N, 6.51.
Method B. As in Method A but using trimethylsilyl triflate
(TMSOTf) (72 μL, 89 mg, 0.4 mmol, 2 equiv) as the Lewis
acid.
N-Benzoyl-α,α-dimethyl-DL-β-homophenylalaninal
(8). Obtained from N-benzoyl-DL-phenylalanine (7) according to
Method A, using 2-methyl-1-(trimethylsilyloxy)-1-propene as
the nucleophile. The reaction mixture was purified by rotatory
chromatography (hexanes–EtOAc, 90 : 10), giving the aldehyde
( )-8 (61%) as a crystalline solid; Mp 133–134 °C (EtOAc–
n-hexane); νmax/cm−1 3439, 3083, 3067, 1724, 1660; δH
(500 MHz, CDCl3) 1.25 (3H, s, 2-Mea), 1.31 (3H, s, 2-Meb),
2.75 (1H, dd, J = 11.2, 14.6 Hz, 4-Ha), 3.10 (1H, dd, J = 4.1,
N-Benzoyl-DL-β-homoalaninal (15).11a,b N-Benzoyl DL-alanine
(10) was treated as in Method A, using ethyl vinyl ether as the
nucleophile. The reaction mixture was purified by chromato-
graphy (hexanes–EtOAc, 50 : 50), giving the aldehyde ( )-15
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(79%) as an oil; νmax/cm−1 3440, 3063, 1724, 1656, 1517;
δH (500 MHz, CDCl3) 1.36 (3H, d, J = 6.8 Hz, 3-Me), 2.74 (1H,
dd, J = 5.7, 17.3 Hz, 2-Ha), 2.80 (1H, ddd, J = 1.9, 5.7, 17.3 Hz,
2-Hb), 4.61 (1H, m, 3-H), 6.56 (1H, br b, NH), 7.40 (2H, dd,
J = 7.3, 7.9 Hz, Ar), 7.48 (1H, dd, J = 7.6 Hz, Ar), 7.73 (2H, d,
J = 8.2 Hz, Ar), 9.81 (1H, s, CHO); δC (125.7 MHz, CDCl3)
20.5 (CH3), 41.6 (CH), 49.6 (CH2), 126.9 (2 × CH), 128.5 (2 ×
CH), 131.5 (CH), 134.3 (C), 166.8 (C), 201.1 (CH); m/z 191
(M+, <1%), 163 (2, M+ − CO), 121 (4, [PhCONH2]+), 105 (100,
[PhCO]+), 77 (75, [Ph]+); HRMS calcd for C11H13NO2
191.0946, found 191.0941; calcd for C10H13NO 163.0997,
found 163.1004; calcd for C7H7NO 121.0528, found 121.0524;
calcd for C7H5O 105.0340, found 105.0344; calcd for C6H5
77.0391, found 77.0389. C11H13NO2 requires C, 69.09; H, 6.85;
N, 7.32%. Found: C, 69.23; H, 7.02; N, 7.43.
C6H5 77.0391, found 77.0394. C14H19NO2 requires C, 72.07; H,
8.21; N, 6.00%. Found: C, 72.23; H, 8.24; N, 6.01.
Ethyl 4-benzamido-5,5-dimethyl-6-oxo hexanoate (18). Obtained
from Bz-Glu(OEt)-OH (12) according to Method A, using 2-
methyl-1-(trimethylsilyloxy)-1-propene as the nucleophile. The
reaction mixture was purified by rotary chromatography
(hexanes–EtOAc, 85 : 15), giving the aldehyde ( )-18 (66%) as
an oil; νmax/cm−1 3428, 1725, 1658, 1519; δH (500 MHz,
CDCl3) note: the usual numbering (CHO as C-1) is used, not the
one given by IUPAC nomenclature: 1.13 (3H, dd, J = 6.7, 7.0
Hz, Et), 1.15 (3H, s, 2-Mea), 1.20 (3H, s, 2-Meb), 1.81 (1H, m,
4-Ha), 1.96 (1H, dddd, J = 3.2, 6.9, 6.9, 13.9 Hz, 4-Hb),
2.30–2.45 (2H, m, 5-H2), 3.94–4.08 (2H, m, Et), 4.35 (1H, ddd,
J = 3.2, 9.8, 12.9 Hz, 3-H), 6.55 (1H, d, J = 9.8 Hz, NH), 7.41
(2H, dd, J = 7.3, 7.6 Hz, Ar), 7.48 (1H, dd, J = 7.3, 7.6 Hz, Ar),
7.74 (2H, d, J = 7.5 Hz, Ar), 9.53 (1H, s, CHO); δC
(125.7 MHz, CDCl3) 14.1 (CH3), 19.1 (CH3), 19.8 (CH3),
25.0 (CH2), 31.3 (CH2), 50.3 (C), 53.6 (CH), 60.6 (CH2), 126.9
(2 × CH), 128.6 (2 × CH), 131.7 (CH), 133.9 (C), 167.3 (C),
173.6 (C), 205.4 (CH); m/z 306 (M+ + H, 1%), 234 (43, M+ −
Me2CCHO), 105 (100, [PhCO]+), 77 (48, [Ph]+). HRMS calcd
for C17H24NO4 306.1705, found 306.1714; calcd for
C13H16NO3 234.1130, found 234.1131; calcd for C7H5O
105.0340, found 105.0343; calcd for C6H5 77.0391, found
77.0388. C17H23NO4 requires C, 66.86; H, 7.59; N, 4.59%.
Found: C, 66.63; H, 7.77; N, 4.58.
N-Benzoyl-α,α-dimethyl-DL-β-homoleucinal
(16). Obtained
from N-benzoyl DL-leucine (11) according to Method A, using
2-methyl-1-(trimethylsilyloxy)-1-propene as the nucleophile.
The reaction mixture was purified by chromatography (hexanes–
EtOAc, 9 : 1), giving the aldehyde ( )-16 (60%) as an oil;
νmax/cm−1 3440, 3081, 3065, 1725, 1706, 1657, 1519; δH
(500 MHz, CDCl3) 0.91 (3H, d, J = 6.7 Hz, 5-Mea), 0.95 (3H,
d, J = 6.7 Hz, 5-Meb), 1.13 (3H, s, 2-Mea), 1.17 (3H, s, 2-Meb),
1.30 (1H, ddd, J = 2.6, 9.8, 14.4 Hz, 4-Ha), 1.46 (1H, ddd,
J = 3.6, 11.4, 14.0 Hz, 4-Hb), 1.64 (1H, m, 5-H), 4.44 (1H, ddd,
J = 2.6, 9.8, 11.0 Hz, 3-H), 6.29 (1H, br d, J = 9.3 Hz, NH),
7.42 (2H, dd, J = 7.3, 7.9 Hz, Ar), 7.49 (1H, dd, J = 7.2, 7.8 Hz,
Ar), 7.74 (2H, d, J = 7.2 Hz, Ar), 9.54 (1H, s, CHO);
δC (125.7 MHz, CDCl3) 19.2 (CH3), 19.6 (CH3), 21.4 (CH3),
23.8 (CH3), 25.2 (CH), 39.8 (CH2), 50.5 (C), 51.9 (CH),
126.8 (2 × CH), 128.6 (2 × CH), 131.5 (CH), 134.5 (C), 167.3
(C), 205.8 (CH); m/z 262 (M+ + H, 3%), 190 (31, M+ − H −
Me2CCHO), 105 (100, [PhCO]+). HRMS calcd for C16H24NO2
262.1807, found 262.1801; calcd for C12H16NO 190.1232,
found 190.1223; calcd for C7H5O 105.0340, found 105.0344.
C16H23NO2 requires C, 73.53; H, 8.87; N, 5.36%. Found: C,
73.43; H, 9.09; N, 5.27.
Ethyl 4-benzamido-6-oxohexanoate (19). Obtained from
Bz-Glu(OEt)-OH (12) according to Method A, using vinyloxy-
trimethylsilane as the nucleophile. The reaction mixture was
purified by chromatography (hexanes–EtOAc, 50 : 50), giving
the aldehyde ( )-19 (51%) as a oil; νmax/cm−1 3434, 1724, 1658,
1518; δH (500 MHz, CDCl3) 1.18 (3H, dd, J = 6.9, 7.3 Hz, Et),
1.97 (1H, m, 4-Ha), 2.06 (1H, m, 4-Hb), 2.38–2.51 (2H, m,
5-H2), 2.75 (1H, dd, J = 5.7, 17.1 Hz, 2-Ha), 2.83 (1H, ddd,
J = 1.9, 5.7, 17.3 Hz, 2-Hb), 4.01–4.11 (2H, m, Et), 4.51 (1H,
m, 3-H), 6.94 (1H, d, J = 8.2 Hz, NH), 7.40 (2H, dd, J = 7.8,
7.9 Hz, Ar), 7.47 (1H, dd, J = 7.3, 7.6 Hz, Ar), 7.75 (2H, d,
J = 7.3 Hz, Ar), 9.79 (1H, s, CHO); δC (125.7 MHz, CDCl3)
14.0 (CH3), 28.9 (CH2), 31.2 (CH2), 45.7 (CH), 48.5 (CH2),
60.7 (CH2), 126.9 (2 × CH), 128.5 (2 × CH), 131.6 (CH), 133.9
(C), 167.0 (C), 173.7 (C), 200.8 (CH); m/z 278 (M+ + H, 6%),
234 (12, M+ − CH2CHO), 172 (99, M+ − PhCO), 144 (60, M+
− PhCO − CHO), 105 (100, [PhCO]+), 77 (99, [Ph]+); HRMS
calcd for C15H20NO4 278.1392, found 278.1395; calcd for
C13H16NO3 234.1130, found 234.1123; calcd for C8H14NO3
172.0974, found 172.0976; calcd for C7H14NO2 144.1025,
found 144.1020; calcd for C7H5O 105.0340, found 105.0344;
calcd for C6H5 77.0391, found 77.0393. C15H19NO4 requires C,
64.97; H, 6.91; N, 5.05%. Found: C, 64.98; H, 6.96; N, 5.19.
N-Benzoyl-DL-β-homoleucinal (17).11c N-Benzoyl DL-leucine
(11) was treated as in Method A, using ethyl vinyl ether as the
nucleophile. The reaction mixture was purified by chromato-
graphy (hexanes–EtOAc, 70 : 30), giving the aldehyde ( )-17
(56%) as a oil; νmax/cm−1 3437, 3065, 1704, 1655, 1518, 1486;
δH (500 MHz, CDCl3) 0.94 (3H, d, J = 6.6 Hz, 5-Mea), 0.95
(3H, d, J = 6.9 Hz, 5-Meb), 1.42 (1H, ddd, J = 5.0, 10.1, 15.1
Hz, 4-Ha), 1.67 (1H, m, 4-Hb), 1.68 (1H, m, 5-H), 2.72 (1H,
ddd, J = 2.2, 5.9, 17.3 Hz, 2-Ha), 2.78 (1H, br dd, J = 5.5, 17.3
Hz, 2-Hb), 4.61 (1H, m, 3-H), 6.50 (1H, br d, J = 8.8 Hz, NH),
7.40 (2H, dd, J = 7.3, 7.9 Hz, Ar), 7.48 (1H, dd, J = 7.6, 7.8 Hz,
Ar), 7.73 (2H, d, J = 7.0 Hz, Ar), 9.80 (1H, s, CHO); δC
(125.7 MHz, CDCl3) 22.0 (CH3), 22.9 (CH3), 25.2 (CH), 43.7
(CH2), 44.0 (CH), 48.8 (CH2), 126.9 (2 × CH), 128.6 (2 × CH),
131.5 (CH), 134.4 (C), 167.0 (C), 201.4 (CH); m/z 234 (M+ +
H, 3%), 233 (M+, <1%), 190 (3, M+ − CH2CHO), 105 (100,
[PhCO]+), 77 (53, [Ph]+). HRMS calcd for C14H20NO2
234.1494, found 234.1502; calcd for C14H19NO2 233.1416,
found 233.1419; calcd for C12H16NO 190.1232, found
190.1228; calcd for C7H5O 105.0340, found 105.0345; calcd for
N-Methoxycarbonyl-α,α-dimethyl-DL-β-homoprolinal
(21). Obtained from the ornithine derivative 13 according to
Method A, using 2-methyl-1-(trimethylsilyloxy)-1-propene as
the nucleophile. The reaction mixture was purified by chromato-
graphy (hexanes–EtOAc, 60 : 40), giving the aldehyde ( )-21
(83%) as a syrup; νmax/cm−1 1719, 1690, 1454, 1386; δH
(500 MHz, CDCl3, 70 °C) 1.00 (3H, s, 2-Mea), 1.01 (3H, s, 2-
Meb), 1.74–1.90 (3H, m, 4-Ha + 5-H2), 2.00 (1H, m, 4-Hb), 3.19
This journal is © The Royal Society of Chemistry 2012
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Product 26. Syrup; [α]D +8 (c 1.05 in CHCl3); νmax/cm−1
1724, 1691, 1471; δH (500 MHz, CDCl3, 70 °C) note: the usual
numbering (CHO as C-1) is used, not the one given by IUPAC
nomenclature: 0.07 (3H, s, SiMea), 0.08 (3H, s, SiMeb), 0.91
(9H, s, tBu), 1.00 (3H, s, 2-Mea), 1.07 (3H, s, 2-Meb), 1.72 (1H,
ddd, J = 7.6, 7.6, 13.2 Hz, 4-Ha), 2.27 (1H, ddd, J = 7.5, 7.5,
13.2 Hz, 4-Hb), 2.96 (1H, dd, J = 7.9, 11.3 Hz, 6-Ha), 3.99 (1H,
dd, J = 7.3, 11.1 Hz, 6-Hb), 4.19 (1H, dd, J = 8.0, 8.1 Hz, 3-H),
4.24 (1H, dddd, J = 7.4, 7.5, 7.5, 7.6 Hz, 5-H), 5.04 (1H, br d,
J = 12.6 Hz, OCHaPh), 5.13 (1H, d, J = 12.3 Hz, OCHbPh),
7.30–7.35 (5H, m, Ar), 9.56 (1H, br b, CHO); δC (125.7 MHz,
CDCl3, 70 °C) −4.8 (2 × CH3), 16.0 (CH3), 18.0 (C), 20.2
(CH3), 25.8 (3 × CH3), 36.3 (CH2), 50.2 (C), 54.6 (CH2), 60.7
(CH), 67.3 (CH2), 69.7 (CH), 128.1 (2 × CH), 128.2 (CH),
128.5 (2 × CH), 136.7 (C), 155.7 (C), 203.2 (CH); m/z 334 (14,
M+ − Me2CCHO), 290 (41, M+ − Me3CSi(Me)2), 91 (100,
[PhCH2]+). HRMS calcd for C18H28NO3Si 334.1838, found
334.1823; calcd for C16H20NO4 290.1392, found 290.1378;
calcd for C7H7 91.0548, found 91.0545. C22H35NO4Si requires
C, 65.15; H, 8.70; N, 3.45%. Found: C, 65.02; H, 8.82; N, 3.56.
Product 27. Syrup; [α]D −37 (c 0.18 in CHCl3); νmax/cm−1
1722, 1694, 1469, 1415; δH (500 MHz, CDCl3, 70 °C) 0.04
(3H, s, SiMea), 0.06 (3H, s, SiMeb), 0.86 (9H, s, tBu), 1.00 (6H,
s, 2-Me2), 1.86 (1H, ddd, J = 3.5, 7.9, 13 Hz, 4-Ha), 1.97 (1H,
m, 4-Hb), 3.20 (1H, dd, J = 3.6, 11.9 Hz, 6-Ha), 3.77 (1H, m, 6-
Hb), 4.33 (1H, m, 5-H), 4.38 (1H, br dd, J = 7.6, 7.9 Hz, 3-H),
5.06 (1H, m, OCHaPh), 5.14 (1H, m, OCHbPh), 7.28–7.34 (5H,
m, Ar), 9.56 (1H, br b, CHO); δC (125.7 MHz, CDCl3, 70 °C)
−4.8 (2 × CH3), 15.9 (CH3), 18.0 (C), 20.0 (CH3), 25.7 (3 ×
CH3), 37.0 (CH2), 50.0 (C), 56.8 (CH2), 61.0 (CH), 67.3 (CH2),
70.8 (CH), 128.0 (2 × CH), 128.1 (CH), 128.5 (2 × CH), 136.9
(C), 156.8 (C), 203.5 (CH); m/z 334 (5, M+ − Me2CCHO), 290
(20, M+ − Me3CSi(Me)2), 91 (100, [PhCH2]+). HRMS calcd for
C18H28NO3Si 334.1838, found 334.1850; calcd for C16H20NO4
290.1392, found 290.1400; calcd for C7H7 91.0548, found
91.0548. C22H35NO4Si requires C, 65.15; H, 8.70; N, 3.45%.
Found: C, 65.45; H, 8.88; N, 3.67.
(1H, m, 6-Ha), 3.65 (3H, s, OMe), 3.71 (1H, m, 6-Hb), 4.14 (1H,
m, 3-H), 9.53 (1H, s, CHO); δC (125.7 MHz, CDCl3, 70 °C)
16.3 (CH3), 20.0 (CH3), 24.4 (CH2), 27.1 (CH2), 47.9 (CH2),
50.5 (C), 52.2 (CH3), 62.0 (CH), 156.4 (C), 203.4 (CH); m/z
200 (M+ + H, <1%), 199 (M+, <1%), 128 (100, M+
−
Me2CCHO). HRMS calcd for C10H18NO3 200.1287, found
200.1284; calcd for C10H17NO3 199.1208, found 199.1199;
calcd for C6H10NO2 128.0712, found 128.0717. C10H17NO3
requires C, 60.28; H, 8.60; N, 7.03%. Found: C, 59.99; H, 8.61;
N, 7.36.
N-Benzyloxycarbonyl-α,α-dimethyl-DL-β-homoprolinal (24).
Obtained from DL-proline benzyl carbamate (22) according to
Method A, using 2-methyl-1-(trimethylsilyloxy)-1-propene as
the nucleophile. The reaction mixture was purified by chromato-
graphy (hexanes–EtOAc, 70 : 30), giving the aldehyde ( )-24
(86%) as a syrup; νmax/cm−1 1689, 1451, 1416; δH (500 MHz,
CDCl3, 70 °C) 1.01 (3H, s, 2-Me), 1.02 (3H, s, 2-Me),
1.74–1.90 (3H, m, 3-Ha + 4-H2), 1.98 (1H, m, 3-Hb), 3.24 (1H,
m, 5-Ha), 3.75 (1H, m, 5-Hb), 4.18 (1H, m, 2-H), 5.06 (1H, d,
J = 12.4 Hz, OCHaPh), 5.12 (1H, d, J = 12.3 Hz, OCHbPh),
7.25–7.36 (5H, m, Ar), 9.54 (1H, s, CHO); δC (125.7 MHz,
CDCl3, 70 °C) 16.5 (CH3), 20.1 (CH3), 22.4 (CH2), 27.1 (CH2),
47.9 (CH2), 50.5 (C), 62.1 (CH), 67.2 (CH2), 128.0 (2 × CH),
128.1 (CH), 128.5 (2 × CH), 136.9 (C), 155.9 (C), 203.5 (CH);
m/z 275 (M+, <1%), 204 (80, M+ − Me2CCHO), 91 (100,
[PhCH2]+). HRMS calcd for C16H21NO3 275.1521, found
275.1512; calcd for C12H14NO2 204.1025, found 204.1026;
calcd for C7H7 91.0548, found 91.0548. C16H21NO3 requires C,
69.79; H, 7.69; N, 5.09%. Found: C, 69.62; H, 7.75; N, 5.13.
N-Benzyloxycarbonyl-DL-β-homoprolinal (25).15a–d Obtained
from the proline derivative 22 according to Method A, using 2-
ethyl vinyl ether as the nucleophile. The reaction mixture was
purified by chromatography (hexanes–EtOAc, 50 : 50), giving
the aldehyde ( )-25 (85%) as a syrup; νmax/cm−1 1717, 1692,
1420; δH (500 MHz, CDCl3, 70 °C) 1.69 (1H, m, 3-Ha),
1.81–1.92 (2H, m, 4-H2), 2.14 (1H, m, 3-Hb), 2.50 (1H, ddd,
J = 1.9, 7.9, 16.4 Hz, 1′-Ha), 2.90 (1H, br b, 1′-Hb), 3.43 (1H,
ddd, J = 5.4, 6.9, 10.7 Hz, 5-Ha), 3.49 (1H, m, 5-Hb), 4.30 (1H,
m, 2-H), 5.13 (2H, s, OCH2Ph), 7.28–7.35 (5H, m, Ar), 9.75
(1H, br s, CHO); δC (125.7 MHz, CDCl3, 70 °C) 23.5 (CH2),
31.5 (CH2), 46.6 (CH2), 48.9 (CH2), 53.0 (CH), 66.9 (CH2),
128.0 (2 × CH), 128.5 (3 × CH), 137.0 (C), 154.8 (C), 200.0
(CH); m/z 247 (M+, 2%), 204 (27, M+ − CH2CHO), 91 (100,
[PhCH2]+). HRMS calcd for C14H17NO3 247.1208, found
247.1205; calcd for C12H14NO2 204.1025, found 204.1027;
calcd for C7H7 91.0548, found 91.0546. C14H17NO3 requires C,
68.00; H, 6.93; N, 5.66%. Found: C, 68.35; H, 7.14; N, 5.30.
(2R,4R)-Benzyl 4-(tert-butyldimethylsilyloxy)-2-(2-oxoethyl)
pyrrolidine-1-carboxylate (28) and (2S,4R)-benzyl 4-(tert-butyl-
dimethylsilyloxy)-2-(2-oxoethyl)pyrrolidine-1-carboxylate (29).
Obtained from hydroxyproline derivative 23 according to
Method A, using vinyloxytrimethylsilane as the nucleophile.
The reaction mixture was purified by rotatory chromatography
(hexanes–EtOAc, 90 : 10), giving the 2,4-cis product 28 (34%)
and the 2,4-trans isomer 29 (20%).
Product 28. Colorless oil; [α]D +5 (c 0.63 in CHCl3); νmax
/
cm−1 1694, 1417; δH (500 MHz, CDCl3, 70 °C) note: the usual
numbering (CHO as C-1) is used, not the one given by IUPAC
nomenclature: 0.08 (6H, s, SiMe2), 0.90 (9H, s, tBu), 1.78 (1H,
br d, J = 13.2 Hz, 4-Ha), 2.24 (1H, ddd, J = 5.2, 8.4, 13.5 Hz,
4-Hb), 2.85 (1H, m, 2-Ha), 3.09 (1H, m, 2-Hb), 3.37 (1H, br d,
J = 12.6 Hz, 6-Ha), 3.64 (1H, m, 6-Hb), 4.37 (1H, m, 3-H), 4.39
(1H, m, 5-H), 5.13 (1H, d, J = 12 Hz, OCHaPh), 5.16 (1H, d,
J = 11.5 Hz, OCHbPh), 7.30–7.36 (5H, m, Ar), 9.77 (1H, br b,
CHO); δC (100.6 MHz, CDCl3, 25 °C) A mixture of rotamers
was observed: −5.0 (CH3), −4.9 (CH3), 17.9 (C), 25.7 (3 ×
CH3), 39.7/40.4 (CH2), 49.2/49.9 (CH2), 51.9/52.5 (CH), 55.2/
55.7 (CH2), 66.9/67.1 (CH2), 70.6/71.3 (CH), 127.9 (2 × CH),
(2R,4R)-Benzyl 4-(tert-butyldimethylsilyloxy)-2-(2-methyl-1-
oxopropan-2-yl)pyrrolidine-1-carboxylate (26) and (2S,4R)-
benzyl 4-(tert-butyldimethylsilyloxy)-2-(2-methyl-1-oxo propan-
2-yl)pyrrolidine-1-carboxylate (27). Obtained from hydroxypro-
line derivative 23 according to Method A, using 2-methyl-1-(tri-
methylsilyloxy)-1-propene as the nucleophile. The reaction
mixture was purified by rotatory chromatography (hexanes–
EtOAc, 90 : 10), giving the 2,4-cis product 26 (63%) and the
2,4-trans isomer 27 (19%).
4454 | Org. Biomol. Chem., 2012, 10, 4448–4461
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128.1 (CH), 128.5 (2 × CH), 136.5/136.7 (C), 154.5/154.8 (C),
201.1/201.2 (CH); m/z 320 (M+ − Me3C, 9%), 292 (11, M+ −
Me3C − CO), 276 (15, M+ − Me3C − CH2CHO), 91 (100,
[PhCH2]+). HRMS calcd for C16H22NO4Si 320.1318, found
320.1320; calcd for C15H22NO3Si 292.1369, found 292.1363;
calcd for C7H7 91.0548, found 91.0544. C20H31NO4Si requires
C, 63.63; H, 8.28; N, 3.71%. Found: C, 63.59; H, 8.15; N, 3.78.
(61%) as a crystalline solid; Mp 138–139 °C (EtOAc–n-hexane);
νmax/cm−1 3439, 3088, 1722, 1671, 1512, 1484; δH (500 MHz,
CDCl3) 1.19 (3H, s, 2-Me or 2′-Me), 1.21 (3H, s, 2-Me or 2′-
Me), 1.37 (3H, s, 2-Me or 2′-Me), 1.41 (3H, s, 2-Me or 2′-Me),
2.59 (1H, dd, J = 11.7, 14.2 Hz, 4-Ha), 2.98 (1H, dd, J = 4.1,
14.2 Hz, 4-Hb), 4.48 (1H, ddd, J = 4.1, 9.8, 11.7 Hz, 3-H), 6.62
(1H, br s, NH), 7.07 (1H, br d, J = 9.8 Hz, NH), 7.13–7.20 (5H,
m, Ar), 7.42 (2H, dd, J = 7.3, 7.9 Hz, Ar), 7.50 (1H, dd, J = 7.6,
7.8 Hz, Ar), 7.70 (2H, d, J = 6.9 Hz, Ar), 9.50 (1H, s, CHO);
δC (125.7 MHz, CDCl3) 19.1 (CH3), 19.5 (CH3), 24.6 (CH3),
25.3 (CH3), 36.4 (CH2), 50.5 (C), 54.2 (CH), 57.8 (C), 126.5
(CH), 126.9 (2 × CH), 128.3 (2 × CH), 128.6 (2 × CH), 129.0 (2
× CH), 131.6 (CH), 134.7 (C), 137.9 (C), 167.5 (C), 173.9 (C),
204.8 (C); m/z 381 (M+ + H, 5%), 309 (6, M+ − Me2CCHO),
190 (64, M+ − NHCH(CH2Ph)-C(Me)2-CHO), 162 (70, M+ −
CONHCH(CH2Ph)-C(Me)2-CHO), 105 (100, [PhCO]+). HRMS
calcd for C23H29N2O3 381.2178, found 381.2170; calcd for
C19H21N2O2 309.1603, found 309.1616; calcd for C11H12NO2
190.0868, found 190.0861; calcd for C10H12NO 162.0919,
found 162.0925; calcd for C7H5O 105.0340, found 105.0343.
C23H28N2O3 requires C, 72.61; H, 7.42; N, 7.36%. Found: C,
72.77; H, 7.68; N, 7.07.
Product 29. Colorless oil; [α]D −35 (c 0.26 in CHCl3);
νmax/cm−1 1694, 1416, 1357; δH (500 MHz, CDCl3, 70 °C) 0.06
(3H, s, SiMea), 0.07 (3H, s, SiMeb), 0.88 (9H, s, tBu), 1.77 (1H,
ddd, J = 4.7, 7.3, 12.0 Hz, 4-Ha), 2.17 (1H, m, 4-Hb), 2.58 (1H,
br dd, J = 6.9, 16.0 Hz, 2-Ha), 2.96 (1H, m, 2-Hb), 3.46 (1H, dd,
J = 4.4, 11.4 Hz, 6-Ha), 3.50 (1H, m, 6-Hb), 4.37 (1H, m, 5-H),
4.41 (1H, m, 3-H), 5.12–5.18 (2H, m, OCH2Ph), 7.29–7.35 (5H,
m, Ar), 9.75 (1H, br b, CHO); δC (100.6 MHz, CDCl3, 25 °C)
A mixture of rotamers was observed: −4.9 (CH3), −4.8 (CH3),
17.9 (C), 25.7 (3 × CH3), 40.9/41.8 (CH2), 48.5/49.4 (CH2),
51.3/51.9 (CH2), 55.0/55.3 (CH), 66.8/67.0 (CH2), 69.5/70.0
(CH), 127.8 (2 × CH), 128.0 (CH), 128.5 (2 × CH), 136.8 (C),
155.4 (C), 200.3/200.5 (CH); m/z 292 (M+ − Me3C − CO,
33%), 91 (100, [PhCH2]+). HRMS calcd for C15H22NO3Si
292.1369, found 292.1364; calcd for C7H7 91.0548, found
91.0544. C20H31NO4Si requires C, 63.63; H, 8.28; N, 3.71%.
Found: C, 63.61; H, 8.28; N, 3.70.
N-(N-Benzoyl-L-phenylalanyl)-α,α-dimethyl-L-β-homoalaninal
(39) and N-(N-benzoyl-L-phenylalanyl)-α,α-dimethyl-D-β-homo-
alaninal (40). Obtained from the dipeptide 32 according to
Method B, but using DIB (0.4 mmol) and iodine (0.1 mmol) in
the scission step, and 2-methyl-1-(trimethylsilyloxy)-1-propene
as the nucleophile in the addition step. The reaction mixture was
purified by chromatography (hexanes–EtOAc, 75 : 25), giving
the diastereomeric products 39 (49%) and 40 (37%), in 86%
overall yield.
N-(N-Benzoyl-1-aminocyclohexanecarbonyl)-α,α-dimethyl-DL-
β-homoleucinal (37). Obtained from the dipeptide 30 according
to Method B, using 2-methyl-1-(trimethylsilyloxy)-1-propene as
the nucleophile. The reaction mixture was purified by rotatory
chromatography (hexanes–EtOAc, 70 : 30), giving product 37
(50%) as a syrup; νmax/cm−1 3433, 1724, 1662, 1515;
δH (500 MHz, CDCl3) 0.86 (3H, d, J = 6.6 Hz, 5-Me), 0.88 (3H,
d, J = 6.3 Hz, 5-Me), 1.02 (3H, s, 2-Me), 1.05 (3H, s, 2-Me),
1.15 (1H, ddd, J = 2.5, 11.8, 13.3 Hz, 4-Ha), 1.33 (1H, ddd,
J = 3.2, 11.7, 14.1 Hz, 4-Hb), 1.38 (1H, m, 5′-Ha), 1.46 (2H, m,
4′-Ha + 6′-Ha), 1.56 (1H, m, 5-H), 1.66 (1H, m, 5′-Hb), 1.70
(2H, m, 4′-Hb + 6′-Hb), 1.96 (2H, m, 3′-Ha + 7′-Ha), 2.25 (2H,
dd, J = 13.2, 13.2 Hz, 3′-Hb + 7′-Hb), 4.23 (1H, ddd, J = 2.2,
9.8, 11.8 Hz, 3-H), 6.05 (1H, s, NH), 7.45 (2H, dd, J = 7.3, 7.9
Hz, Ar), 7.50 (1H, d, J = 7.6 Hz, NH), 7.53 (1H, dd, J = 7.3, 7.6
Hz, Ar), 7.73 (2H, d, J = 7.0 Hz, Ar), 9.46 (1H, s, CHO);
δC (125.7 MHz, CDCl3) 18.0 (CH3), 18.6 (CH3), 21.4 (CH3),
21.6 (CH2), 21.7 (CH2), 23.8 (CH3), 25.0 (CH), 25.2 (CH2),
32.2 (CH2), 32.5 (CH2), 39.4 (CH2), 50.6 (CH), 50.8 (C), 61.1
(C), 126.8 (2 × CH), 128.8 (2 × CH), 131.9 (CH), 134.8 (C),
168.5 (C), 173.8 (C), 205.1 (CH); m/z 387 (M+ + H, <1%), 230
(21, M+ − NH-CH(CH2CHMe2)-C(Me)2-CHO), 202 (73, M+ −
CONH-CH(CH2CHMe2)-C(Me)2-CHO), 105 (100, [PhCO]+).
HRMS calcd for C23H35N2O3 387.2648, found 387.2641; calcd
for C14H16NO2 230.1181, found 230.1183; calcd for C13H16NO
202.1232, found 202.1235; calcd for C7H5O 105.0340, found
105.0341. C23H34N2O3 requires C, 71.47; H, 8.87; N, 7.25%.
Found: C, 71.36; H, 8.97; N, 6.93.
Product 39. Crystalline solid; Mp 133–134 °C (EtOAc–
n-hexane); [α]D −8 (c 0.24 in CHCl3); νmax/cm−1 3423, 3310,
1723, 1653, 1512; δH (500 MHz, CDCl3) 0.90 (3H, s, 2-Mea),
0.94 (3H, s, 2-Meb), 1.02 (3H, d, J = 6.9 Hz, 3-Me), 3.12 (1H,
dd, J = 7.9, 13.9 Hz, 3′-Ha), 3.21 (1H, dd, J = 6.6, 13.9 Hz,
3′-Hb), 4.17 (1H, m, 3-H), 4.86 (1H, ddd, J = 6.6, 7.6, 7.9 Hz,
2-H), 6.43 (1H, d, J = 9.5 Hz, NH), 6.91 (1H, d, J = 7.6 Hz,
NH), 7.21–7.30 (5H, m, Ar), 7.40 (2H, dd, J = 7.3, 7.9 Hz, Ar),
7.49 (1H, dd, J = 7.3, 7.6 Hz, Ar), 7.71 (2H, d, J = 7.3 Hz, Ar),
9.35 (1H, s, CHO); δC (125.7 MHz, CDCl3) 16.1 (CH3), 18.4
(CH3), 19.0 (CH3), 38.3 (CH2), 49.0 (CH), 49.6 (C), 55.2 (CH),
127.0 (2 × CH), 127.1 (CH), 128.6 (2 × CH), 128.8 (2 × CH),
129.3 (2 × CH), 131.8 (CH), 133.7 (C), 136.5 (C), 167.4 (C),
170.5 (C), 204.8 (CH); m/z 366 (M+, 1%), 224 (17, M+
−
CONHCH(Me)-C(Me)2-CHO), 105 (100, [PhCO]+). HRMS
calcd for C22H26N2O3 366.1943, found 366.1944; calcd for
C15H14NO 224.1075, found 224.1074; calcd for C7H5O
105.0340, found 105.0338. C22H26N2O3 requires C, 72.11; H,
7.15; N, 7.64%. Found: C, 72.24; H, 7.35; N, 7.76.
Product 40. Syrup; [α]D −13 (c 0.21 in CHCl3); νmax/cm−1
3423, 3310, 1723, 1648, 1510; δH (500 MHz, CDCl3) 0.90 (3H,
d, J = 6.9 Hz, 3-Me), 0.93 (3H, s, 2-Mea), 0.95 (3H, s, 2-Meb),
3.12 (1H, dd, J = 8.2, 13.6 Hz, 3′-Ha), 3.24 (1H, dd, J = 6.3,
13.6, 3′-Hb), 4.15 (1H, m, 3-H), 4.88 (1H, ddd, J = 6.9, 7.9, 7.9
Hz, 2′-H), 6.59 (1H, br b, NH), 7.16 (1H, m, Ar), 7.20–7.30
(5H, m, Ar + NH), 7.39 (2H, dd, J = 6.8, 7.3 Hz, Ar), 7.49 (1H,
dd, J = 7.3, 7.6 Hz, Ar), 7.72 (2H, d, J = 8.1 Hz, Ar), 9.32 (1H,
N-(N-Benzoyl-2-methylalanyl)-α,α-dimethyl-β-α,α-dimethyl-
β-homophenylalaninal (38). Obtained from the dipeptide 31
according to Method B, using 2-methyl-1-(trimethylsilyloxy)-1-
propene as the nucleophile. The reaction mixture was purified by
chromatography (hexanes–EtOAc, 60 : 40), giving product 38
This journal is © The Royal Society of Chemistry 2012
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br b, CHO); δC (125.7 MHz, CDCl3) 15.6 (CH3), 18.0 (CH3),
18.7 (CH3), 38.3 (CH2), 48.5 (CH), 49.6 (C), 55.2 (CH), 127.0
(CH), 127.1 (2 × CH), 128.5 (2 × CH), 128.7 (2 × CH), 129.3 (2
× CH), 131.8 (CH), 133.7 (C), 136.7 (C), 167.6 (C), 170.6 (C),
204.3 (CH); m/z 366 (M+, 5%), 224 (18, M+ − CONHCH(Me)-
C(Me)2-CHO), 105 (100, [PhCO]+). HRMS calcd for
C22H26N2O3 366.1943, found 366.1948; calcd for C7H5O
105.0340, found 105.0343. C22H26N2O3 requires C, 72.11; H,
7.15; N, 7.64%. Found: C, 72.23; H, 6.89; N, 7.77.
chromatography (hexanes–EtOAc, 80 : 20), affording com-
pounds 43 (47%) and 44 (22%).
Compound 43. Syrup; [α]D −85 (c 0.65 in CHCl3); νmax/cm−1
3300, 1723, 1674, 1610, 1536; δH (500 MHz, CDCl3) 0.91 (3H,
d, J = 6.6 Hz, 5-Mea), 0.92 (3H, d, J = 6.6 Hz, 5-Meb), 0.96
(3H, s, 2-Mea), 1.05 (3H, s, 2-Meb), 1.18 (1H, ddd, J = 2.2, 9.8,
12.6 Hz, 4-Ha), 1.32 (1H, ddd, J = 3.5, 11.3, 13.0 Hz, 4-Hb),
1.65 (1H, m, 5-H), 1.81 (1H, m, 4′-Ha), 1.91–2.04 (2H, m, 4′-Hb
+ 3′-Ha), 2.50 (1H, m, 3′-Hb), 3.37 (1H, m, 5′-Ha), 3.50 (1H, m,
5′-Hb), 4.26 (1H, dd, J = 10, 11.7 Hz, 3-H), 4.82 (1H, m, 2′-H),
7.26 (1H, d, J = 9.8 Hz, NH), 7.41 (3H, m, Ar), 7.54 (2H, m,
Ar), 9.47 (1H, s, CHO); δC (125.7 MHz, CDCl3) 17.0 (CH3),
18.9 (CH3), 21.4 (CH3), 23.8 (CH3), 25.0 (CH), 25.2 (CH2),
26.3 (CH2), 38.6 (CH2), 50.0 (CH2), 50.5 (CH), 51.0 (C), 59.5
(CH), 126.8 (2 × CH), 128.5 (2 × CH), 130.1 (CH), 136.3 (C),
170.7 (C), 171.5 (C), 204. 7 (CH); m/z 358 (M+, 3%), 202 (50,
N-(N-Benzoyl-L-leucyl)-α,α-dimethyl-L-β-(41)
and
N-(N-
benzoyl-L-leucyl)-α,α-dimethyl-D-β-homoalaninal (42). The pro-
ducts were generated from dipeptide 33 according to Method B,
using 2-methyl-1-(trimethylsilyloxy)-1-propene as the nucleo-
phile. The reaction mixture was purified by rotatory chromato-
graphy (hexanes–EtOAc, 80 : 20), affording compounds 41
(57%) and 42 (29%).
M+ − NHCH(CH2CHMe2)-C(Me)2-CHO), 174 (95, M+
−
CONHCH(CH2CHMe2)-C(Me)2-CHO), 105 (100, [PhCO]+).
HRMS calcd for C21H30N2O3 358.2256, found 358.2262; calcd
for C12H12NO2 202.0868, found 202.0858; calcd for C11H12NO
174.0919, found 174.0921; calcd for C7H5O 105.0340, found
105.0341. C21H30N2O3 requires C, 70.36; H, 8.44; N, 7.81%.
Found: C, 70.48; H, 8.42; N, 8.10.
Compound 41. Crystalline solid; Mp 184–185 °C (EtOAc–
n-hexane); [α]D −22 (c 0.43 in CHCl3); νmax/cm−1 3428, 1723,
1656, 1517; δH (500 MHz, CDCl3) 0.95 (6H, d, J = 6.3 Hz,
4′-Me2), 1.05 (3H, d, J = 8.2 Hz, 3-Me), 1.06 (3H, s, 2-Mea),
1.07 (3H, s, 2-Meb), 1.67–1.72 (3H, m, 3′-H2 + 4′-H), 4.23 (1H,
dddd, J = 6.8, 6.8, 6.8, 9.4 Hz, 3-H), 4.67 (1H, ddd, J = 7.5, 7.5,
7.5 Hz, 2′-H), 6.87 (1H, br b, NH), 6.94 (1H, d, J = 7.9 Hz,
NH), 7.40 (2H, dd, J = 7.7, 7.7 Hz, Ar), 7.49 (1H, dd, J = 7.3,
7.6 Hz, Ar), 7.78 (2H, d, J = 7.5 Hz, Ar), 9.45 (1H, s, CHO); δC
(100.6 MHz, CDCl3) 15.8 (CH3), 17.9 (CH3), 19.2 (CH3), 22.2
(CH3), 22.8 (CH3), 25.0 (CH), 41.4 (CH2), 48.6 (CH), 50.0 (C),
52.5 (CH), 127.1 (2 × CH), 128.6 (2 × CH), 131.8 (CH), 133.8
(C), 167.6 (C), 171.9 (C), 204.7 (CH); m/z 333 (M+ + H, 1%),
190 (100, M+ − CONHCH(Me)CMe2CHO), 105 (91, [PhCO]+);
HRMS calcd for C19H29N2O3 333.2178, found 333.2181; calcd
for C12H16NO 190.1232, found 190.1239. C19H28N2O3 requires
C, 68.65; H, 8.49; N, 8.43%. Found: C, 68.90; H, 8.35; N, 8.14.
Compound 44. Syrup; [α]D −97 (c 0.34 in CHCl3); νmax/cm−1
3424, 3303, 1725, 1674, 1660, 1602, 1420; δH (500 MHz,
CDCl3) 0.83 (3H, d, J = 6.9 Hz, 5-Mea), 0.90 (3H, d, J = 6.6
Hz, 5-Meb), 1.07 (3H, s, 2-Mea), 1.08 (3H, s, 2-Meb), 1.16 (1H,
m, 4-Ha), 1.31 (1H, m, 4-Hb), 1.56 (1H, m, 5-H), 1.83 (1H, m,
4′-Ha), 1.99–2.08 (2H, m, 4′-Hb + 3′-Ha), 2.43 (1H, m, 3′-Hb),
3.45 (1H, m, 5′-Ha), 3.53 (1H, m, 5′-Hb), 4.24 (1H, dd, J = 9.5,
9.8 Hz, 3-H), 4.76 (1H, dd, J = 4.8, 7.3 Hz, 2′-H), 7.11 (1H,
br d, J = 9.8 Hz, NH), 7.40–7.50 (5H, m, Ar), 9.49 (1H, s,
CHO); δC (125.7 MHz, CDCl3) 18.4 (CH3), 18.7 (CH3), 21.5
(CH3), 23.8 (CH3), 25.2 (CH), 25.4 (CH2), 27.1 (CH2), 39.6
(CH2), 50.4 (CH2), 50.5 (C), 51.0 (CH), 59.9 (CH), 126.9 (2 ×
CH), 128.5 (2 × CH), 130.3 (CH), 136.2 (C), 170.9 (C), 171.5
(C), 205.2 (CH); m/z 358 (M+, 2%), 202 (27, M+ − NHCH
Compound 42. Crystalline solid; Mp 152–153 °C (net); [α]D
−28 (c 0.60 in CHCl3); νmax/cm−1 3428, 1721, 1656, 1517; δH
(500 MHz, CDCl3) 0.96 (3H, d, J = 6.5 Hz, 4′-Mea), 0.97 (3H,
d, J = 6.3 Hz, 4′-Meb), 1.00 (3H, s, 2-Mea), 1.03 (3H, s, 2-Meb),
1.13 (3H, d, J = 6.9 Hz, 3-Me), 1.63–1.82 (3H, m, 3′-H2 + 4′-
H), 4.24 (1H, dddd, J = 6.9, 6.9, 6.9, 9.5 Hz, 3-H), 4.61 (1H,
ddd, J = 6.0, 6.3, 8.2 Hz, 2′-H), 6.67 (1H, d, J = 8.2 Hz, NH),
6.75 (1H, d, J = 9.8 Hz, NH), 7.43 (2H, dd, J = 7.4, 7.4 Hz, Ar),
7.50 (1H, dd, J = 7.3, 7.6 Hz, Ar), 7.78 (2H, d, J = 6.9 Hz, Ar),
9.43 (1H, s, CHO); δC (100.6 MHz, CDCl3) 16.0 (CH3), 17.9
(CH3), 19.0 (CH3), 22.3 (CH3), 22.9 (CH3), 25.0 (CH), 40.4
(CH2), 48.4 (CH), 50.1 (C), 52.2 (CH), 127.1 (2 × CH), 128.6
(2 × CH), 131.8 (CH), 133.9 (C), 167.9 (C), 171.3 (C), 204.8
(CH); m/z 333 (M+ + H, 2%), 190 (86, M+ − CONHCH(Me)
CMe2CHO), 105 (100, [PhCO]+); HRMS calcd C19H29N2O3
333.2178, found 333.2177; calcd for C7H5O 105.0340, found
105.0340. C19H28N2O3 requires C, 68.65; H, 8.49; N, 8.43%.
Found: C, 68.80; H, 8.32; N, 8.10.
(CH2CHMe2)-C(Me)2-CHO), 174 (74, M+
− CONHCH
(CH2CHMe2)-C(Me)2-CHO), 105 (100, [PhCO]+). HRMS calcd
for C21H30N2O3 358.2256, found 358.2251; calcd for
C12H12NO2 202.0868, found 202.0863; calcd for C11H12NO
174.0919, found 174.0925; calcd for C7H5O 105.0340, found
105.0336. C21H30N2O3 requires C, 70.36; H, 8.44; N, 7.81%.
Found: C, 70.19; H, 8.43; N, 7.76.
N-(N-Benzoyl-L-alanyl)-α,α-dimethyl-DL-β-homoleucinal (45).
The products were generated from dipeptide 35 according to
Method B, using 2-methyl-1-(trimethylsilyloxy)-1-propene as
the nucleophile. The reaction mixture was purified by rotatory
chromatography (hexanes–EtOAc, 75 : 25), affording compound
45 (78%) as a 9 : 6 mixture of diastereomers; νmax/cm−1 3422,
3307, 1724, 1676, 1645, 1514; δH (500 MHz, CDCl3) major
isomer: 0.90 (3H, d, J = 6.8 Hz, 5-Mea), 0.91 (3H, d, J = 6.6
Hz, 5-Meb), 0.98 (3H, s, 2-Mea), 1.01 (3H, s, 2-Meb), 1.14 (1H,
m, 4-Ha), 1.39 (1H, m, 4-Hb), 1.49 (3H, d, J = 6.9 Hz, 2′-Me),
1.61 (1H, m, 5-H), 4.24 (1H, m, 3-H), 4.81 (1H, m, 2′-H), 7.07
(1H, br d, J = 10.4 Hz, NH), 7.22 (1H, br d, J = 7.6 Hz, NH),
7.40 (2H, dd, J = 7.8, 7.8 Hz, Ar), 7.49 (1H, dd, J = 7.3, 7.5 Hz,
Ar), 7.79 (2H, d, J = 8.1 Hz, Ar), 9.46 (1H, s, CHO); minor
N-(N-Benzoyl-L-prolyl)-α,α-dimethyl-L-β-homoleucinal (43) and
N-(N-benzoyl-L-prolyl)-α,α-dimethyl-D-β-homoleucinal (44). The
products were generated from dipeptide 34 according to
Method B, using 2-methyl-1-(trimethylsilyloxy)-1-propene as
the nucleophile. The reaction mixture was purified by rotatory
4456 | Org. Biomol. Chem., 2012, 10, 4448–4461
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isomer: 0.75 (3H, d, J = 6.7 Hz, 5-Mea), 0.84 (3H, d, J = 6.5
Hz, 5-Meb), 1.08 (3H, s, 2-Mea), 1.09 (3H, s, 2-Meb), 1.12 (1H,
m, 4-Ha), 1.34 (1H, m, 4-Hb), 1.50 (3H, d, J = 6.9 Hz, 2′-Me),
1.51 (1H, m, 5-H), 4.24 (1H, m, 3-H), 4.81 (1H, m, 2′-H), 7.04
(1H, br d, J = 10.4 Hz, NH), 7.24 (1H, br d, J = 8.2 Hz, NH),
7.40 (2H, dd, J = 7.8, 7.8 Hz, Ar), 7.49 (1H, dd, J = 7.3, 7.5 Hz,
Ar), 7.76 (2H, d, J = 7.5 Hz, Ar), 9.51 (1H, s, CHO); δC
(125.7 MHz, CDCl3) major isomer: 18.2 (CH3), 18.4 (CH3),
18.6 (CH3), 21.2 (CH3), 23.8 (CH3), 25.1 (CH), 39.1 (CH2),
49.4 (CH), 50.7 (C), 50.9 (CH), 127.1 (2 × CH), 128.5 (2 ×
CH), 131.8 (CH), 133.7 (C), 167.6 (C), 172.5 (C), 204.9 (CH);
minor isomer: 18.0 (CH3), 18.4 (CH3), 19.1 (CH3), 21.2 (CH3),
23.6 (CH3), 24.9 (CH), 38.8 (CH2), 49.4 (CH), 50.7 (C), 50.9
(CH), 127.1 (2 × CH), 128.5 (2 × CH), 131.8 (CH), 133.8 (C),
167.4 (C), 172.5 (C), 204.8 (CH); m/z 333 (M+ + H, 1%), 176
(31, M+ − NHCH(CH2CHMe2)-C(Me)2-CHO), 148 (55, M+ −
CONHCH(CH2CHMe2)-C(Me)2-CHO), 105 (100, [PhCO]+).
HRMS calcd for C19H29N2O3 333.2178, found 333.2166; calcd
for C10H10NO2 176.0712, found 176.0706; calcd for C9H10NO
148.0762, found 148.0763; calcd for C7H5O 105.0340, found
105.0345. C19H28N2O3 requires C, 68.65; H, 8.49; N, 8.43%.
Found: C, 68.50; H, 8.61; N, 8.69.
91.0548, found 91.0552. C22H34N2O4 requires C, 67.66; H,
8.78; N, 7.17%. Found: C, 67.57; H, 8.93; N, 7.11.
General procedure for the reduction of the amino aldehydes to
the amino alcohols
To a solution of the starting β-peptide aldehydes (0.4 mmol) in
i
dry PrOH (12 mL) cooled at 0 °C, was added LiBH4 (17 mg,
0.8 mmol, 2.0 equiv). The reaction mixture was stirred at 0 °C
for 40 min. Then it was poured into saturated brine and extracted
with EtOAc. The organic layer was dried over anhydrous sodium
sulfate, filtered and evaporated under vacuum. The residue was
purified by chromatography on silica gel (hexanes–EtOAc)
giving the γ-amino alcohol derivatives.
N-(N-Benzoyl-L-phenylalanyl)-α,α-dimethyl-L-β-homoalaninol
(47). Obtained by reduction of the peptide aldehyde 39 accord-
ing to the General Procedure. The reaction mixture was purified
by rotatory chromatography (hexanes–EtOAc, 70 : 30), affording
compound 47 (78%) as a crystalline solid: Mp 187–188 °C
(EtOAc–n-hexane); [α]D −17 (c 0.27 in CHCl3); νmax/cm−1
3423, 1650, 1509, 1484; δH (500 MHz, CDCl3) 0.47 (3H, s,
2-Mea), 0.90 (3H, s, 2-Meb), 1.01 (3H, d, J = 6.9 Hz, 3-Me),
2.91 (1H, d, J = 11.7 Hz, 1-Ha), 3.10 (1H, d, J = 11.7 Hz, 1-Hb),
3.15 (1H, dd, J = 8.5, 13.9 Hz, 3′-Ha), 3.25 (1H, dd, J = 6.3,
13.9 Hz, 3′-Hb), 3.93 (1H, dddd, J = 6.8, 6.8, 6.9, 8.7 Hz, 3-H),
4.92 (1H, ddd, J = 6.3, 7.9, 8.2 Hz, 2′-H), 6.34 (1H, br d,
J = 9.0 Hz, NH), 6.85 (1H, brd, J = 7.3 Hz, NH), 7.24 (1H, m,
Ar), 7.29–7.34 (4H, m, Ar), 7.42 (2H, dd, J = 7.3, 7.9 Hz, Ar),
7.51 (1H, dd, J = 7.3, 7.6 Hz, Ar), 7.72 (2H, d, J = 8.2 Hz, Ar);
δC (125.7 MHz, CDCl3) 15.3 (CH3), 18.3 (CH3), 23.0 (CH3),
38.5 (CH2 + C), 49.6 (CH), 55.2 (CH), 69.6 (CH2), 127.0 (2 ×
CH), 127.2 (CH), 128.6 (2 × CH), 128.9 (2 × CH), 129.3 (2 ×
CH), 131.9 (CH), 133.6 (C), 136.4 (C), 167.4 (C), 171.3 (C);
m/z 368 (M+, 1%), 350 (3, M+ − H2O), 252 (26, M+ − NHCH
N-(N-Benzyloxycarbonyl-L-valyl)-α,α-dimethyl-DL-β-homo-
leucinal (46). The products were generated from dipeptide 36
according to Method B, using 2-methyl-1-(trimethylsilyloxy)-1-
propene as the nucleophile. The reaction mixture was purified by
rotatory chromatography (hexanes–EtOAc, 85 : 15), affording
compound 46 (76%) as a 10 : 7 mixture of diastereomers: syrup;
νmax/cm−1 3426, 1714, 1672, 1506, 1469; δH (500 MHz,
CDCl3) major isomer: 0.86–0.90 (9H, m, 5-Me2 + 3′-Mea), 0.95
(3H, d, J = 6.6 Hz, 3′-Meb), 1.01 (3H, s, 2-Mea), 1.06 (3H, s,
2-Meb), 1.16 (1H, m, 4-Ha), 1.32 (1H, m, 4-Hb), 1.52 (1H, m,
5-H), 2.14 (1H, m, 3′-H), 3.92 (1H, ddd, J = 8.8, 8.8, 8.9 Hz,
2′-H), 4.21 (1H, br dd, J = 12.0, 12.0 Hz, 3-H), 5.08 (1H, d,
J = 12.0 Hz, OCHaPh), 5.11 (1H, d, J = 12.5 Hz, OCHbPh),
5.37 (1H, br b, NH), 6.11 (1H, br d, J = 9.8 Hz, NH), 7.30–7.35
(5H, m, Ar), 9.44 (1H, s, CHO); minor isomer: 0.85 (3H, d,
J = 6.6 Hz, 5-Mea), 0.86–0.90 (6H, m, 5-Meb + 3′-Mea), 0.95
(3H, d, J = 6.5 Hz, 3′-Meb), 1.01 (3H, s, 2-Mea), 1.03 (3H, s,
2-Meb), 1.15 (1H, m, 4-Ha), 1.32 (1H, m, 4-Hb), 1.52 (1H, m,
5-H), 2.14 (1H, m, 3′-H), 3.92 (1H, ddd, J = 8.8, 8.8, 8.9 Hz,
2′-H), 4.21 (1H, br dd, J = 12.0, 12.0 Hz, 3-H), 5.09–5.15 (2H,
m, OCH2Ph), 5.38 (1H, br b, NH), 6.14 (1H, br d, J = 12.0 Hz,
NH), 7.30–7.35 (5H, m, Ar), 9.45 (1H, s, CHO); major isomer:
δC (125.7 MHz, CDCl3) 17.7 (CH3), 18.7 (CH3), 19.0 (CH3),
19.4 (CH3), 21.1 (CH3), 23.8 (CH3), 24.9 (CH), 30.3 (CH), 39.3
(CH2), 50.3 (C), 51.0 (CH), 61.0 (CH), 67.1 (CH2), 128.0 (2 ×
CH), 128.2 (CH), 128.5 (2 × CH), 136.2 (C), 156.5 (C), 171.2
(C), 205.0 (CH); minor isomer: δC (125.7 MHz, CDCl3) 17.7
(CH3), 18.5 (CH3), 18.7 (CH3), 19.4 (CH3), 21.2 (CH3), 23.7
(CH3), 25.0 (CH), 30.1 (CH), 39.4 (CH2), 50.4 (C), 51.2 (CH),
61.0 (CH), 67.1 (CH2), 128.0 (2 × CH), 128.2 (CH), 128.5 (2 ×
CH), 136.2 (C), 156.6 (C), 171.2 (C), 204.9 (CH); m/z 391 (M+
+ H, <1%), 390 (M+, <1%), 319 (8, M+ − C(Me)2-CHO), 234
(Me)C(Me)2CH2OH), 224 (21, M+
− CONHCH(Me)C-
(Me)2CH2OH), 105 (100, [PhCO]+); HRMS calcd for
C22H28N2O3 368.2100, found 368.2107; calcd for C22H26N2O2
350.1994, found 350.1985; calcd for C16H14NO2 252.1025,
found 252.1019; calcd for C15H14NO 224.1075, found
224.1070; calcd for C7H5O 105.0340, found 105.0343.
C22H28N2O3 requires C, 71.71; H, 7.66; N, 7.60%. Found: C,
71.79; H, 7.68; N, 7.68.
N-(N-Benzoyl-L-phenylalanyl)-α,α-dimethyl-D-β-homoalaninol
(48). Obtained by reduction of the peptide aldehyde 40 accord-
ing to the General Procedure. The reaction mixture was purified
by rotatory chromatography (hexanes–EtOAc, 75 : 25), affording
compound 48 (69%) as a crystalline solid: Mp 134–135 °C
(EtOAc–n-hexane); [α]D −11 (c 0.19 in CHCl3); νmax/cm−1
3423, 1731, 1650, 1510; δH (500 MHz, CDCl3) 0.54 (3H, s, 2-
Mea), 0.86 (3H, d, J = 6.9 Hz, 3-Me), 0.91 (3H, s, 2-Meb), 2.92
(1H, d, J = 11.7 Hz, 1-Ha), 3.14 (1H, dd, J = 7.9, 13.2 Hz, 3′-
Ha), 3.21 (1H, dd, J = 6.6, 13.3 Hz, 3′-Hb), 3.25 (1H, d, J = 12
Hz, 1-Hb), 3.87 (1H, dddd, J = 6.6, 6.6, 6.7, 9.1 Hz, 3-H), 4.02
(1H, OH), 4.99 (1H, ddd, J = 6.6, 8.2, 8.2 Hz, 2′-H), 6.95 (1H,
br d, J = 9.5 Hz, NH), 7.19 (1H, m, Ar), 7.21–7.25 (4H, m, Ar),
7.35 (1H, brb, NH), 7.37 (2H, dd, J = 7.6, 7.8 Hz, Ar), 7.49
(1H, dd, J = 7.3, 7.6 Hz, Ar), 7.70 (2H, d, J = 8.2 Hz, Ar);
(12, M+
− NHCH(CH2CHMe2)-C(Me)2-CHO), 91 (100,
[PhCH2]+). HRMS calcd for C22H34N2O4 390.2518, found
390.2519; calcd for C18H27N2O3 319.2022, found 319.2027;
calcd for C13H16NO3 234.1130, found 234.1122; calcd for C7H7
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4448–4461 | 4457

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δC (100.6 MHz, CDCl3) 14.8 (CH3), 18.1 (CH3), 22.9 (CH3),
38.6 (C), 38.8 (CH2), 49.0 (CH), 55.2 (CH), 69.7 (CH2), 126.9
(CH), 127.1 (2 × CH), 128.5 (4 × CH), 129.4 (2 × CH), 131.8
(CH), 133.6 (C), 136.6 (C), 167.6 (C), 171.8 (C); m/z 368 (M+,
1%), 350 (1, M+ − H2O), 252 (58, M+ − NHCH(Me)C-
(Me)2CH2OH), 224 (44, M+ − CONHCH(Me)C(Me)2CH2OH),
105 (100, [PhCO]+); HRMS calcd for C22H28N2O3 368.2100,
found 368.2104; calcd for C22H26N2O2 350.1994, found
350.1984; calcd for C16H14NO2 252.1025, found 252.1014;
calcd for C15H14NO 224.1075, found 224.1072; calcd for
C7H5O 105.0340, found 105.0341. C22H28N2O3 requires C,
71.71; H, 7.66; N, 7.60%. Found: C, 71.64; H, 7.48; N, 7.62.
(C), 172.7 (C); m/z 335 (M+ + H, 1%), 261 (9, M+ − C
(Me)2CH2OH), 218 (97, M+ − NHCH(Me)C(Me)2CH2OH), 190
(92, M+ − CONHCH(Me)C(Me)2CH2OH), 105 (100, [PhCO]+);
HRMS calcd for C19H31N2O3 335.2335, found 335.2343; calcd
for C15H20N2O2 260.1525, found 260.1515; calcd for
C13H16NO2 218.1181, found 218.1177; calcd for C12H16NO
190.1232, found 190.1229; calcd for C7H5O 105.0340, found
105.0342. C19H31N2O3 requires C, 68.23; H, 9.04; N, 8.38%.
Found: C, 68.06; H, 8.88; N, 8.41.
N-(N-Benzoyl-L-prolyl)-α,α-dimethyl-L-β-homoleucinol (51).
Obtained by reduction of the peptide aldehyde 43 according to
the General Procedure. The reaction mixture was purified by
rotatory chromatography (hexanes–EtOAc, 1 : 1), affording com-
N-(N-Benzoyl-L-leucyl)-α,α-dimethyl-L-β-homoalaninol (49).
Obtained by reduction of the peptide aldehyde 41 according to
the General Procedure. The reaction mixture was purified by
rotatory chromatography (hexanes–EtOAc, 60 : 40), affording
compounds 49 (76%) as a crystalline solid; Mp 186–187 °C
(EtOAc–n-hexane); [α]D −35 (c 0.62 in CHCl3); νmax/cm−1
3427, 1651, 1516; δH (500 MHz, CDCl3) 0.69 (3H, s, 2-Mea),
0.95 (6H, d, J = 6.6 Hz, 2 × Me), 0.96 (3H, s, 2-Meb), 0.97 (3H,
d, J = 6.3 Hz, Me), 1.71 (1H, m, 3′-Ha), 1.77 (1H, m, 4′-H),
1.82 (1H, m, 3′-Hb), 3.03 (1H, brdd, J = 9.1, 11.0 Hz, 1-Ha),
3.33 (1H, brd, J = 11.4 Hz, 1-Hb), 3.92 (1H, dddd, J = 6.6, 6.9,
6.9, 8.8 Hz, 3-H), 4.09 (1H, brb, OH), 4.89 (1H, ddd, J = 5.1,
5.4, 8.8 Hz, 2′-H), 7.34 (1H, dd, J = 7.3, 8.2 Hz, Ar), 7.46 (1H,
dd, J = 7.3, 7.6 Hz, Ar), 7.44–7.50 (2H, brb, 2 × NH), 7.81 (1H,
d, J = 8.0 Hz, Ar); δC (100.6 MHz, CDCl3) 14.9 (CH3), 18.4
(CH3), 22.1 (CH3), 22.9 (CH3), 23.0 (CH3), 25.0 (CH), 38.9 (C),
41.8 (CH2), 49.0 (CH), 52.5 (CH), 69.8 (CH2), 127.2 (2 × CH),
128.4 (2 × CH), 131.7 (CH), 133.8 (C), 167.6 (C), 173.4 (C);
m/z 335 (M+ + H, <1%), 261 (5, M+ − C(Me)2CH2OH), 218
pound 51 (77%) as a syrup; [α]D −92 (c 0.41 in CHCl3); νmax
/
cm−1 3426, 1656, 1613; δH (500 MHz, CDCl3) 0.64 (3H, s, 2-
Mea), 0.89 (3H, d, J = 6.6 Hz, 5-Mea), 0.94 (3H, d, J = 6.6 Hz,
5-Meb), 1.00 (3H, s, 2-Meb), 1.28–1.33 (2H, m, 4-H2), 1.64 (1H,
m, 5-H), 1.84 (1H, m, 4′-Ha), 2.03 (1H, m, 3′-Ha), 2.08 (1H, m,
4′-Hb), 2.48 (1H, m, 3′-Hb), 2.93 (1H, brb, OH), 3.01 (1H, d, J =
11.7 Hz, 1-Ha), 3.30 (1H, d, J = 11.9 Hz, 1-Hb), 3.46 (1H, m, 5′-
Ha), 3.55 (1H, m, 5′-Hb), 3.92 (1H, ddd, J = 3.5, 10.2, 10.7 Hz,
3-H), 4.80 (1H, m, 2′-H), 7.02 (1H, brd, J = 9.5 Hz, NH),
7.40–7.48 (5H, m, Ar); δC (125.7 MHz, CDCl3) 18.3 (CH3),
21.3 (CH3), 23.1 (CH3), 23.9 (CH3), 25.4 (CH), 25.5 (CH2),
27.0 (CH2), 38.1 (CH2), 39.0 (C), 50.3 (CH2), 51.2 (CH), 59.7
(CH), 70.3 (CH2), 126.8 (2 × CH), 128.5 (2 × CH), 130.3 (CH),
136.0 (C), 171.2 (C), 172.4 (C); m/z 360 (M+, 1%), 287 (73, M+
− C(Me)2CH2OH), 202 (51, M+ − NHCH(CH2CHMe2)C-
(Me)2CH2OH), 174 (54, M+ − CONHCH(CH2CHMe2)C-
(Me)2CH2OH), 105 (100, [PhCO]+); HRMS calcd for
C21H32N2O3 360.2413, found 360.2404; calcd for C17H23N2O2
287.1760, found 287.1752; calcd for C12H12NO2 202.0868,
found 202.0864; calcd for C11H12NO 174.0919, found
174.0918; calcd for C7H5O 105.0340, found 105.0345.
C21H32N2O3 requires C, 69.97; H, 8.95; N, 7.77%. Found: C,
70.13; H, 9.01; N, 7.83.
(66, M+ − NHCH(Me)C(Me)2CH2OH), 190 (57, M+
−
CONHCH(Me)C(Me)2CH2OH), 105 (100, [PhCO]+); HRMS
calcd for C19H31N2O3 335.2335, found 335.2339; calcd for
C15H21N2O2 261.1603, found 261.1592; calcd for C13H16NO2
218.1181, found 218.1180; calcd for C12H16NO 190.1232,
found 190.1227; calcd for C7H5O 105.0340, found 105.0340.
C19H31N2O3 requires C, 68.23; H, 9.04; N, 8.38%. Found: C,
68.59; H, 8.95; N, 8.48.
N-(N-Benzoyl-L-prolyl)-α,α-dimethyl-D-β-homoleucinol (52).
Obtained by reduction of the peptide aldehyde 44 according to
the General Procedure. The reaction mixture was purified by
rotatory chromatography (hexanes–EtOAc, 1 : 1), affording com-
N-(N-Benzoyl-L-leucyl)-α,α-dimethyl-D-β-homoalaninol (50).
Obtained by reduction of the peptide aldehyde 42 according to
the General Procedure. The reaction mixture was purified by
rotatory chromatography (hexanes–EtOAc, 60 : 40), affording
compounds 50 (79%) as a crystalline solid; Mp 163–164 °C
(EtOAc–n-hexane); [α]D −39 (c 0.66 in CHCl3); νmax/cm−1
3425, 1654, 1510; δH (500 MHz, CDCl3) 0.62 (3H, s, 2-Mea),
0.95 (3H, d, J = 6.9 Hz, Me), 0.96 (3H, s, 2-Meb), 0.97 (3H, d,
J = 6.9 Hz, Me), 1.12 (3H, d, J = 6.9 Hz, Me), 1.67–1.75 (2H,
m, 3′-Ha + 4′-H), 1.77 (1H, m, 3′-Hb), 2.94 (1H, d, J = 11.7 Hz,
1-Ha), 3.25 (1H, d, J = 11.9 Hz, 1-Hb), 3.98 (1H, dddd, J = 6.6,
6.8, 6.9, 9.4 Hz, 3-H), 4.69 (1H, ddd, J = 6.0, 6.3, 7.9 Hz, 2′-H),
6.95 (1H, brd, J = 8.2 Hz, NH), 7.03 (1H, br d, J = 9.5 Hz, NH),
7.41 (2H, dd, J = 7.3, 7.9 Hz, Ar), 7.50 (1H, dd, J = 7.3, 7.6 Hz,
Ar), 7.76 (2H, d, J = 8.0 Hz, Ar); δC (125.7 MHz, CDCl3) 15.3
(CH3), 18.3 (CH3), 22.4 (CH3), 22.8 (CH3), 23.1 (CH3), 25.0
(CH), 38.9 (C), 40.7 (CH2), 49.1 (CH), 52.5 (CH), 69.8 (CH2),
127.1 (2 × CH), 128.6 (2 × CH), 131.9 (CH), 133.8 (C), 167.9
pound 51 (79%) as a syrup; [α]D −130 (c 0.13 in CHCl3); νmax
/
cm−1 3449, 1656, 1615; δH (500 MHz, CDCl3) 0.68 (3H, s, 2-
Mea), 0.82 (3H, d, J = 6.6 Hz, 5-Mea), 0.87 (3H, d, J = 6.6 Hz,
5-Meb), 1.02 (3H, s, 2-Meb), 1.26–1.32 (2H, m, 4-H2), 1.52 (1H,
m, 5-H), 1.85 (1H, m, 4′-Ha), 1.99–2.09 (2H, m, 3′-Ha + 4′-Hb),
2.50 (1H, m, 3′-Hb), 3.02 (1H, d, J = 11.7 Hz, 1-Ha), 3.38 (1H,
d, J = 11.6 Hz, 1-Hb), 3.47 (1H, m, 5′-Ha), 3.53 (1H, m, 5′-Hb),
3.89 (1H, ddd, J = 4.4, 9.4, 9.5 Hz, 3-H), 4.88 (1H, dd, J = 4.4,
7.3 Hz, 2′-H), 7.12 (1H, brd, J = 9.5 Hz, NH), 7.41–7.48 (5H,
m, Ar); δC (125.7 MHz, CDCl3) 18.4 (CH3), 21.3 (CH3), 23.0
(CH3), 23.8 (CH3), 25.4 (CH2), 25.5 (CH), 26.9 (CH2), 38.3
(CH2), 38.9 (C), 50.4 (CH2), 51.5 (CH), 59.7 (CH), 70.3 (CH2),
126.9 (2 × CH), 128.5 (2 × CH), 130.4 (CH), 136.0 (C), 171.7
(C), 172.3 (C); m/z 360 (M+, 1%), 287 (7, M+ − C-
(Me)2CH2OH), 202 (36, M+
−
NHCH(CH2CHMe2)C-
(Me)2CH2OH), 174 (55, M+ − CONHCH(CH2CHMe2)C-
(Me)2CH2OH), 105 (100, [PhCO]+); HRMS calcd for
4458 | Org. Biomol. Chem., 2012, 10, 4448–4461
This journal is © The Royal Society of Chemistry 2012

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C21H32N2O3 360.2413, found 360.2415; calcd for C12H12NO2
202.0868, found 202.0875; calcd for C11H12NO 174.0919,
found 174.0924; calcd for C7H5O 105.0340, found 105.0344.
C21H32N2O3 requires C, 69.97; H, 8.95; N, 7.77%. Found: C,
69.76; H, 8.87; N, 7.68.
105.0340, found 105.0336; calcd for C5H12N 86.0970, found
86.0968; calcd for C6H5 77.0391, found 77.0391. C19H30N2O3
requires C, 68.23; H, 9.04; N, 8.38%. Found: C, 68.58; H, 9.10;
N, 8.22.
N-(N-Benzoyloxycarbonyl-L-valyl)-α,α-dimethyl-L-β-homoleu-
cinol (55) and N-(N-benzoyloxycarbonyl-L-valyl)-α,α-dimethyl-
D-β-homoleucinol (56). Obtained by reduction of the peptide
aldehyde 46 according to the General Procedure. The reaction
mixture was purified by rotatory chromatography (hexanes–
EtOAc, 85 : 15), affording compounds 55 (46%) and 56 (32%).
N-(N-Benzoyl-L-alanyl)-α,α-dimethyl-L-β-homoleucinol (53)
and N-(N-benzoyl-L-alanyl)-α,α-dimethyl-D-β-homoleucinol (54).
Obtained by reduction of the peptide aldehyde 45 according to
the General Procedure. The reaction mixture was purified by
rotatory chromatography (hexanes–EtOAc, 60 : 40), affording
compounds 53 (41%) and 54 (29%).
Product 53. Syrup; [α]D +1 (c 0.29 in CHCl3); νmax/cm−1
3421, 1653, 1647, 1512; δH (500 MHz, CDCl3) 0.59 (3H, s, 2-
Mea), 0.87 (3H, d, J = 6.3 Hz, 5-Mea), 0.90 (3H, d, J = 6.6 Hz,
5-Meb), 0.98 (3H, s, 2-Meb), 1.26 (1H, ddd, J = 2.5, 10.5, 13.3
Hz, 4-Ha), 1.41 (1H, ddd, J = 3.5, 11.3, 13.9 Hz, 4-Hb), 1.51
(3H, d, J = 6.9 Hz, 2′-Me), 1.62 (1H, m, 5-H), 2.92 (1H, d, J =
11.7 Hz, 1-Ha), 3.26 (1H, d, J = 11.7 Hz, 1-Hb), 3.90 (1H, ddd,
J = 2.5, 9.5, 12.0 Hz, 3-H), 4.88 (1H, dddd, J = 6.9, 6.9, 7.3, 7.3
Hz, 2′-H), 7.28 (1H, d, J = 9.5 Hz, NH), 7.38 (1H, d, J = 7.6
Hz, NH), 7.41 (2H, dd, J = 7.3, 7.9 Hz, Ar), 7.51 (1H, dd, J =
7.3, 7.6 Hz, Ar), 7.79 (2H, d, J = 7.8 Hz, Ar); δC (125.7 MHz,
CDCl3) 18.3 (CH3), 18.6 (CH3), 21.0 (CH3), 23.0 (CH3), 23.9
(CH3), 25.4 (CH), 37.8 (CH2), 38.9 (C), 49.4 (CH), 51.4 (CH),
70.1 (CH2), 127.1 (2 × CH), 128.6 (2 × CH), 131.9 (CH), 133.5
(C), 167.6 (C), 174.0 (C); m/z 335 (M+ + H, <1%), 316 (2, M+
− H2O), 176 (34, [BzNH-CH(Me)CO), 148 (45, [BzNHvCH
(Me)]+), 105 (96, [PhCO]+), 86 (100, [NH2vCHCH2CH
(Me)2]+), 77 (32, [Ph]+); HRMS calcd for C19H31N2O3
335.2335, found 335.2351; calcd for C19H28N2O2 316.2151,
found 316.2141; calcd for C10H10NO2 176.0712, found
176.0707; calcd for C9H10NO 148.0762, found 148.0760; calcd
for C7H5O 105.0340, found 105.0338; calcd for C5H12N
86.0970, found 86.0973; calcd for C6H5 77.0391, found
77.0392. C19H30N2O3 requires C, 68.23; H, 9.04; N, 8.38%.
Found: C, 68.44; H, 8.96; N, 8.30.
Product 55. Amorphous solid; [α]D +2 (c 0.21 in CHCl3);
νmax/cm−1 3425, 1718, 1653, 1506; δH (500 MHz, CDCl3) 0.61
(3H, s, 2-Mea), 0.86 (3H, d, J = 6.3 Hz, 5-Mea), 0.91 (3H, d,
J = 6.6 Hz, 5-Meb), 0.94 (3H, d, J = 6.9 Hz, 3′-Mea), 0.97 (3H,
d, J = 6.9 Hz, 3′-Hb), 0.98 (3H, s, 2-Meb), 1.24–1.30 (2H, m, 4-
H2), 1.55 (1H, m, 5-H), 2.11 (1H, m, 3′-H), 2.95 (1H, d,
J = 11.9 Hz, 1-Ha), 3.23 (1H, d, J = 11.7 Hz, 1-Hb), 3.87–3.95
(2H, m, 3-H + 2′-H), 5.07 (1H, d, J = 12.0 Hz, OCHaPh), 5.12
(1H, d, J = 12.3 Hz, OCHbPh), 5.40 (1H, d, J = 8.8 Hz, NH),
6.10 (1H, d, J = 9.5 Hz, NH), 7.31–7.37 (5H, m, Ar); δC
(125.7 MHz, CDCl3) 17.9 (CH3), 18.5 (CH3), 19.4 (CH3), 21.0
(CH3), 23.1 (CH3), 24.0 (CH3), 25.3 (CH), 30.2 (CH), 38.2
(CH2), 38.9 (C), 51.5 (CH), 61.1 (CH), 67.1 (CH2), 70.0 (CH2),
128.0 (2 × CH), 128.2 (CH), 128.6 (2 × CH), 136.1 (C), 156.6
(C), 172.8 (C); m/z 393 (M+ + H, 1%), 319 (9, M+ − C(Me)2-
CHO), 234 (14, M+ − NHCH(CH2CHMe2)-C(Me)2-CH2OH),
108 (18, [PhCH2OH]+), 91 (100, [PhCH2]+), 86 (29,
[NH2vCHCH2CH(Me)2]+). HRMS calcd for C22H37N2O4
393.2753, found 393.2749; calcd for C18H27N2O3 319.2022,
found 319.2015; calcd for C13H16NO3 234.1130, found
234.1130; calcd for C7H8O 108.0575, found 108.0574; calcd for
C7H7 91.0548, found 91.0549; calcd for C5H12N 86.0970,
found 86.0967. C22H36N2O4 requires C, 67.32; H, 9.24; N,
7.14%. Found: C, 67.34; H, 8.98; N, 7.29.
Product 54. Crystalline solid; Mp 158–159 °C (EtOAc–
n-hexane); [α]D −40 (c 0.36 in CHCl3); νmax/cm−1 3421, 1655,
1649, 1512, 1484; δH (500 MHz, CDCl3) 0.71 (3H, s, 2-Mea),
0.76 (3H, d, J = 6.6 Hz, 5-Mea), 0.79 (3H, d, J = 6.6 Hz, 5-
Meb), 1.02 (3H, s, 2-Meb), 1.25 (1H, m, 4-Ha), 1.31 (1H, ddd,
J = 3.5, 11.0, 14.5 Hz, 4-Hb), 1.48 (1H, m, 5-H), 1.55 (3H, d,
J = 6.9 Hz, 2′-Me), 3.05 (1H, d, J = 11.7 Hz, 1-Ha), 3.35 (1H, d,
J = 11.9 Hz, 1-Hb), 3.90 (1H, ddd, J = 2.5, 9.5, 11.7 Hz, 3-H),
4.88 (1H, dddd, J = 6.9, 6.9, 7.3, 7.3 Hz, 2′-H), 7.01 (1H, br d,
J = 9.1 Hz, NH), 7.13 (1H, br d, J = 7.3 Hz, NH), 7.43 (2H, dd,
J = 7.6, 7.8 Hz, Ar), 7.52 (1H, dd, J = 7.3, 7.6 Hz, Ar), 7.78
(2H, d, J = 8.2 Hz, Ar); δC (125.7 MHz, CDCl3) 18.6 (CH3),
19.1 (CH3), 21.1 (CH3), 23.0 (CH3), 23.7 (CH3), 25.2 (CH),
37.9 (CH2), 39.0 (C), 49.3 (CH), 51.5 (CH), 70.2 (CH2), 127.0
(2 × CH), 128.6 (2 × CH), 131.9 (CH), 133.6 (C), 167.4 (C),
173.7 (C); m/z 335 (M+ + H, <1%), 316 (1, M+ − H2O), 176
(23, [PhCONH-CH(Me)CO]), 148 (37, [PhCONHvCH(Me)]+),
105 (100, [PhCO]+), 86 (100, [NH2vCHCH2CH(Me)2]+), 77
(31, [Ph]+); HRMS calcd for C19H31N2O3 335.2335, found
335.2344; calcd for C19H28N2O2 316.2151, found 316.2156;
calcd for C10H10NO2 176.0712, found 176.0711; calcd for
C9H10NO 148.0762, found 148.0760; calcd for C7H5O
Product 56. Amorphous solid; [α]D −30 (c 0.26 in CHCl3);
νmax/cm−1 3422, 1715, 1653, 1520, 1506; δH (500 MHz,
CDCl3) 0.63 (3H, s, 2-Mea), 0.83 (3H, d, J = 6.6 Hz, 5-Mea),
0.89 (3H, d, J = 6.6 Hz, 5-Meb), 0.92 (3H, d, J = 6.6 Hz, 3′-
Mea), 0.99 (3H, d, J = 6.9 Hz, 3′-Hb), 1.00 (3H, s, 2-Meb),
1.23–1.30 (2H, m, 4-H2), 1.50 (1H, m, 5-H), 2.21 (1H, m, 3′-H),
3.01 (1H, br d, J = 11.5 Hz, 1-Ha), 3.34 (1H, br d, J = 12.0 Hz,
1-Hb), 3.89 (1H, m, 3-H), 3.96 (1H, m, 2′-H), 5.08 (1H, d,
J = 12.3 Hz, OCHaPh), 5.13 (1H, d, J = 12.3 Hz, OCHbPh),
5.27 (1H, br b, NH), 6.03 (1H, br d, J = 8.8 Hz, NH), 7.32–7.38
(5H, m, Ar); δC (125.7 MHz, CDCl3) 17.7 (CH3), 18.7 (CH3),
19.5 (CH3), 21.1 (CH3), 23.1 (CH3), 23.9 (CH3), 25.2 (CH),
30.0 (CH), 38.3 (CH2), 38.8 (C), 51.6 (CH), 61.0 (CH), 67.2
(CH2), 70.0 (CH2), 128.1 (2 × CH), 128.3 (CH), 128.6 (2 ×
CH), 136.0 (C), 156.5 (C), 172.4 (C); m/z 393 (M+ + H, 1%),
319 (12, M+ – C(Me)2-CHO), 234 (20, M+ − NHCH
(CH2CHMe2)-C(Me)2-CH2OH), 91 (100, [PhCH2]+), 86 (21,
[NH2vCHCH2CH(Me)2]+). HRMS calcd for C22H37N2O4
393.2753, found 393.2743; calcd for C13H16NO3 234.1130,
found 234.1138; calcd for C7H7 91.0548, found 91.0544; calcd
for C5H12N 86.0970, found 86.0967. C22H36N2O4 requires C,
67.32; H, 9.24; N, 7.14%. Found: C, 67.37; H, 9.13; N, 7.18.
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General procedure for the reduction of the β-amino esters to the
β-amino aldehydes
A solution of the β-amino ester (0.2 mmol) in methanol (8 mL),
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stirred for 6 h; then the solution was poured into a saturated solu-
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A solution of the β-amino ester (0.2 mmol) in methanol (8 mL),
was cooled to 0 °C; then DIBAL-H was added (1 M solution in
dichloromethane, 2 mL, 2 mmol; except in the case of substrate
57, where 0.6 mmol of the reducing agent were used). The reac-
tion mixture was stirred for 3 h at 0 °C, and then was extracted,
evaporated and purified as before to give the γ-amino alcohols.
Acknowledgements
This work was supported by the Research Projects CTQ2006-
14260/PPQ and CTQ2009-07109 of the Plan Nacional de Inves-
tigación Científica, Desarrollo e Innovación Tecnológica, Minis-
terio de Educación y Ciencia (MEC) and Ministerio de Ciencia e
Innovación (MICINN), Spain. We also acknowledge financial
support from FEDER funds. C.J.S. thanks the Gobierno de
Canarias for a predoctoral fellowship.
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This journal is © The Royal Society of Chemistry 2012
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