A de Novo stereocontrolled approach to syn- and anti-disubstituted acyclic β2,3-amino acid enantiomers

Article abstract of DOI:10.1002/ejoc.201301281

The stereocontrolled syntheses of functionalized acyclic β^2,3-amino acid derivatives in enantiomerically pure form were performed by starting from enantiopure cis- and trans-2-aminocyclopent-3- enecarboxylates, which were derived from a racemic bicyclic β-lactam. The synthetic strategy involves the stereoselective dihydroxylaton of the C-C double bond of the cyclopentene β-amino esters. The subsequent NaIO ₄-mediated ring cleavage affords dialdehyde intermediates that undergo functionalization by a Wittig reaction. The stereocontrolled syntheses of functionalized acyclic β^2,3-amino acid derivatives in enantiomerically pure form have been performed in five steps by starting from enantiopure cis- and trans-2-aminocyclopent-3-enecarboxylates, which were derived from a racemic bicyclic β-lactam. Copyright

Full text of DOI:10.1002/ejoc.201301281

FULL PAPER
DOI: 10.1002/ejoc.201301281
A De Novo Stereocontrolled Approach to syn- and anti-Disubstituted Acyclic
β2,3-Amino Acid Enantiomers
[a]
[a]
[a]
[a,b]
˝
Maria Cherepanova, Loránd Kiss, Eniko Forró, and Ferenc Fülöp*
Keywords: Synthetic methods / Amino acids / Kinetic resolution / Diastereoselectivity / Wittig reactions / Lactams
The stereocontrolled syntheses of functionalized acyclic β2,3
-
volves the stereoselective dihydroxylaton of the C–C double
bond of the cyclopentene β-amino esters. The subsequent
NaIO4-mediated ring cleavage affords dialdehyde intermedi-
ates that undergo functionalization by a Wittig reaction.
amino acid derivatives in enantiomerically pure form were
performed by starting from enantiopure cis- and trans-2-
aminocyclopent-3-enecarboxylates, which were derived
from a racemic bicyclic β-lactam. The synthetic strategy in-
rearrangement of enamino esters,[5] the oxidative ring cleav-
age of 2,3-dihydropyridones,[6] and the ring-opening of 4,5-
disubstituted 1,3-oxazinanones.[7] Several other methods
may be used to access these compounds in either racemic
or enantiomerically pure form. For instance, the Michael
conjugate addition of chiral amines to α,β-unsaturated es-
ters followed by alkylation,[8] the dipolar cycloaddition of
nitrones to olefins followed by an isoxazolidine ring-open-
ing and oxidation,[9] the asymmetric hydrogenation of en-
amino esters,[10] the addition of carboxylic acid derivatives
or aldehydes to aldimines under standard or organocata-
lytic conditions through a Mannich reaction followed by an
oxidation,[11] the addition of ester enolates to chiral sulfin-
ylimines,[12] and the diastereoselective intramolecular radi-
cal addition to oxime ethers[13] are important procedures
that facilitate the syntheses of β2,3-amino acids.
Although a wide range of synthetic methods offer ef-
ficient and practical approaches to different β2,3-amino acid
derivatives, most of them suffer from limitations that relate
to the control of the stereochemistry of the transformations
(e.g., syn vs. anti diastereoselectivity), the availability of ap-
propriately substituted synthons, the large-scale applica-
bility, and, in some cases, the cost of the reagents and mate-
rials.
Our present goal is to develop a new stereocontrolled
synthetic approach to acyclic β2,3-amino acid species that
are derived from cyclopentene cis- and trans-disubstituted
β-amino acids through dihydroxylation and oxidative ring-
opening reactions followed by a Wittig transformation.[14]
The stereochemistry of the acyclic target compounds was
predetermined by the configuration of the cyclic starting
material. The syntheses based on the cis- and trans-disubsti-
tuted unsaturated five-membered β-amino acid species from
the racemic β-lactam are expected to give acyclic anti- and
syn-disubstituted β2,3-amino acid derivatives, respectively
(see Scheme 1).
Introduction
During the past 20 years, there has been an increasing
interest in β-amino acids in view of the number of valuable
biological properties that they possess. They exhibit note-
worthy pharmacological activities and are components of
many bioactive natural products such as the anticancer
agent Taxol or Taxotere, the antitumoral agents cryptophy-
cin, bestatin, microginin, and amastatin, and the antifungal
agent jasplakinolide.[1a,1b] β-Amino acids are also structural
building blocks of peptides and peptidomimetics.[1a–1d]
Moreover, β2,3-amino acids comprise a subclass of β-amino
acids, and some are also elements of bioactive natural prod-
ucts. Dolastatins 11, 12, 16, and D, majusculamide C, and
onchidin are natural products with activity against leuke-
mia, whereas guineamides C and D, ulongapeptin, and ma-
levamide C are natural antitumoral agents with structures
that include a β2,3-disubstituted amino acid moiety with dif-
ferent alkyl chains.[1a,1b]
A number of synthetic methods are currently available
for the preparation of racemic disubstituted β2,3-amino ac-
ids. The general methods include a Curtius rearrangement
of 2,3-disubstituted 1,4-dicarboxylic acid derivatives, a ring-
opening of disubstituted β-lactams, and an oxidation of 2,3-
disubstituted 1,3-amino alcohols,[1] yet more special routes
involve the alkylation of β3-amino acid derivatives at the α
position,[2] the rearrangement of imides with hypervalent
iodine reagents,[3] reactions of carboxylic acid esters with
imidoyl chlorides,[4] the Ireland–Claisen [3,3]-sigmatropic
[a] Institute of Pharmaceutical Chemistry, University of Szeged,
6720 Szeged, Eötvös u. 6, Hungary
E-mail: fulop@pharm.u-szeged.hu
http://www2.pharm.u-szeged.hu/gyki/
[b] Stereochemistry Research Group of the Hungarian Academy of
Sciences, University of Szeged,
6720 Szeged, Eötvös u. 6, Hungary
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301281.
Eur. J. Org. Chem. 2014, 403–409
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Cherepanova, L. Kiss, E. Forró, F. Fülöp
FULL PAPER
liminary experiments were first performed by employing
racemic substances, and the well-established protocol was
then extended to obtain enantiomerically pure compounds.
The stereoselective dihydroxylation of (1R,2S)-(–)-3 in
the presence of OsO4 and N-methylmorpholine-N-oxide
(NMO) yielded vicinal diol (+)-5, and the subsequent oxi-
dative C–C bond cleavage with NaIO4 gave access to dialde-
hyde intermediate 6 (for analogous transformations, see
ref.[14]). It is noteworthy that intermediate 6 could not be
isolated, and, therefore, further experiments were conducted
with the diformyl derivative formed in situ. Dialdehyde 6
was then treated with Wittig reagents that were generated
from either methyltriphenylphosphonium or benzyltri-
phenylphosphonium bromide with tBuOK in (tetra-
hydrofuran) THF to furnish the corresponding diolefinated
anti-β-amino esters (+)-7 and (–)-8 in moderate yields. A
subsequent catalytic hydrogenation of the C–C double
bonds in the presence of Pd/C led to optically pure satu-
rated acyclic dialkylated β2,3-amino esters (–)-9 and (–)-10
(see Scheme 3).
Scheme 1. Retrosynthetic scheme.
Results and Discussion
Racemic β-lactam (Ϯ)-1 was first subjected to a kinetic
resolution by employing an enzyme-catalyzed enantioselec-
tive β-lactam hydrolysis by using a slightly modified litera-
ture procedure.[15] Compound (Ϯ)-1 was treated with CAL-
B (Candida antarctica lipase B) in tBuOMe, and the re-
sulting mixture was then shaken by an incubator shaker at
70 °C to give enantiomerically pure amino acid (+)-2
(Ͼ99%ee) and unreacted β-lactam (–)-1 (99%ee), which
were separated. Next, (–)-1 was treated with HCl/EtOH,
which was followed by a benzoylation to afford the optically
pure N-benzoyl-protected amino ester (–)-3. After (+)-2
underwent group protection procedures, (+)-3 was submit-
Further anti-β-amino acid derivatives were successfully
synthesized by the treatment of the key diformyl intermedi-
ate 6 with commercially available phosphoranes. The reac-
tion between dialdehyde 6 and either ethyl (triphenylphos-
ted to a base-induced epimerization to afford the trans dia- phoranylidene)acetate or 1-(triphenylphosphoranylidene)-
stereomer (1S,2S)-(+)-4 in good yield (see Scheme 2). Pre- 2-propanone resulted in disubstituted enantiomers (+)-11
Scheme 2. Enzymatic resolution of racemic β-lactam 1 and preparation of cis- and trans-β-amino esters.
Scheme 3. Synthesis of disubstituted, open-chain β-amino acid derivatives (–)-9 and (–)-10 from cis-β-amino ester (–)-3.
Scheme 4. Synthesis of disubstituted, open-chain β-amino acid derivatives (–)-13 and (–)-14 from dialdehyde 6.
404
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Stereocontrolled Approach to Acyclic β2,3-Amino Acid Enantiomers
Scheme 5. Synthesis of disubstituted, open-chain β-amino acid derivatives (–)-19 and (–)-20 from trans β-amino ester (+)-4.
Scheme 6. Synthesis of disubstituted, open-chain β-amino acid derivatives (–)-23 and (–)-24 from dialdehyde 16.
and (–)-12, respectively, in good yields. The catalytic re- cis- ands trans-β-aminocyclopentenecarboxylate enantio-
duction of the olefinic bonds then afforded the difunction- mers, which were derived by an enzymatic resolution of a
alized anti-β2,3-amino acid derivatives (–)-13 and (–)-14, racemic bicyclic β-lactam. The syntheses involved the dihy-
respectively, in high yields (see Scheme 4).
droxylation of the C–C double bond of the cyclic starting
This well-established protocol was subsequently extended materials followed by an oxidative ring cleavage and Wittig
to the syntheses of syn-β-amino acid derivatives. The cata- functionalization of the dialdehyde intermediates. As the
lytic, 100% diastereoselective dihydroxylation of the C–C stereogenic centers of the starting compounds were not af-
double bond of (+)-4 by treatment with OsO4 followed by fected during the transformations, their stereochemistry de-
the NaIO4-mediated oxidative ring cleavage gave key inter- termined the configuration of the chiral centers in the final
mediate dialdehyde 16, which displayed the similar instabil- acylic β-amino acid derivatives.
ity as that of its previously described analog 6. Dialkenyl-
ated acyclic β-amino acid derivatives (–)-17 and (–)-18 were
Experimental Section
obtained in moderate yields through an in situ Wittig reac-
tion by using either a methyltriphenylphosphonium or
benzyltriphenylphosphonium salt and tBuOK. Further
catalytic hydrogenations afforded access to the optically
pure saturated syn-dialkylated products (–)-19 and (–)-20 in
good yields (see Scheme 5).
Similar to the transformations depicted in Scheme 4, the
reactions of dialdehyde 16 with either ethyl (triphenylphos-
phoranylidene)acetate or 1-(triphenylphosphoranylidene)-
2-propanone resulted in Wittig products (–)-21 and (–)-22,
respectively, in good yields. The saturation of the olefinic
bonds under catalytic hydrogenation conditions yielded the
corresponding enantiopure syn derivatives, that is, difunc-
tionalized β2,3-amino acid derivatives (–)-23 and (–)-24 (see
Scheme 6).
General Methods: The chemicals were purchased from Sigma–Ald-
rich. The NMR spectroscopic data were recorded at 400 MHz with
either the solvents CDCl3 or [D6]dimethyl sulfoxide ([D6]DMSO),
and with tetramethylsilane as the internal standard. The solvents
were used as received from the suppliers. Melting points were deter-
mined with a Kofler apparatus. Elemental analyses were recorded
with a Perkin–Elmer CHNS-2400 Ser II elemental analyzer. Silica
gel 60 F254 was purchased from Merck. All the experiments were
first performed with the racemic substances. The 1H and 13C NMR
spectra of the enantiomeric substances were the same as those of
the corresponding racemic counterparts. The elemental analyses
confirmed the results.
Gram-Scale Resolution of 7-Azabicyclo[4.2.0]oct-3-en-8-one [(؎)-1]:
Racemic 1 (6 g, 54.96 mmol) was dissolved in tBuOMe (80 mL),
and CAL-B (4 g, 50 mg/mL) and water (0.96 mL, 54.96 mmol)
were added. The resulting mixture was shaken in an incubator
shaker at 80 °C for 4.5 h, and the reaction was stopped by filtration
of the enzyme at 50% conversion. After evaporation of the solvent,
the residue was crystallized to afford crystalline (1S,5R)-1 (2.3 g,
47%); [α]2D5 = –33.6 (c = 0.32, CHCl3), Ͼ98%ee. The enzyme that
was removed by filtration was washed with distilled water (3ϫ
Conclusions
In summary, a simple and efficient stereocontrolled pro-
cedure has been developed for the syntheses of enantio-
meric acyclic β2,3-amino acid derivatives by starting from 20 mL), and the water was evaporated to yield crystalline β-amino
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M. Cherepanova, L. Kiss, E. Forró, F. Fülöp
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acid (1R,2S)-2 (3.2 g, 47%); [α]2D5 = +94.9 (c = 0.37, H2O),
Ͼ98%ee.
EtOH).[15] 1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.15 Hz,
3 H), 2.62–2.73 (m, 1 H, CH2), 2.79–2.86 (m, 1 H, CH2), 2.97–3.05
(m, 1 H, 1-H), 4.12–4.20 (m, 2 H, OCH2), 5.47–5.55 (m, 1 H, 2-
H), 5.72–5.77 (m, 1 H, 4-H), 5.95–6.01 (m, 1 H, 3-H), 6.18 (br. s,
1 H, NH), 7.43–4.55 (m, 3 H, Ar), 7.78–7.75 (m, 2 H, Ar) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 14.9, 36.3, 49.7, 60.2, 61.0,
128.2, 129.0, 131.8, 131.9, 132.1, 135.1, 166.7, 175.1 ppm.
General Procedure for Dihydroxylation of N-Benzoyl-Protected
Amino Esters: To a solution of N-benzoyl-protected β-amino ester
3 or 4 (see ref.[15]; 2 g, 7.7 mmol) and N-methylmorpholine N-oxide
(3 mL, 29 mmol) in acetone (40 mL) was added OsO4 (0.5 mL,
0.03 mmol) in tBuOH (0.06 m), and the resulting mixture was
stirred at room temperature for 12 h. After completion of the reac-
tion (monitored by TLC), a saturated aqueous Na2SO3 solution
(120 mL) was added, and the reaction mixture was extracted with
CH2Cl2 (3ϫ 150 mL). The combined organic phases were dried
with Na2SO4 and filtered, and the filtrate was concentrated in
vacuo.
Ethyl (1S,2S,3R,4S)-2-Benzamido-3,4-dihydroxycyclopentanecarb-
oxylate [(+)-5]: White solid (77% yield); m.p. 125–126 °C. Rf = 0.3
(n-hexane/EtOAc, 1:4). [α]2D5 = +102 (c = 0.3, EtOH). 1H NMR
(400 MHz, CDCl3): δ = 1.29 (t, J = 7.18 Hz, 3 H, CH3), 2.15–2.33
(m, 2 H, 4-H), 3.48 (q, J = 8.9 Hz, 1 H, 5-H), 4.05–4.12 (m, 2 H,
2-H, 3-H), 4.18–4.25 (m, 2 H, OCH2), 4.51–4.58 (m, 1 H, 1-H),
7.41–7.83 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 14.7, 33.7, 43.9, 55.6, 60.7, 70.6, 76.4, 128.2, 128.9, 131.9, 135.5,
167.5, 174.0 ppm. C15H19NO5 (293.32): calcd. C 61.42, H 6.53, N
4.78; found C 61.19, H 6.32, N 4.48.
General Procedure for In Situ Dialdehyde Formation Followed by
Wittig Reaction: To a solution of 5 or 15 (200 mg, 0.68 mmol) in
THF/H2O (10:1 v/v, 11 mL) was added NaIO4 (291 mg,
1.36 mmol), and the reaction mixture was stirred at room tempera-
ture for 1 h under Ar to give diformyl derivative 6 or 16. Water
(20 mL) was then added, and the mixture was extracted with
CH2Cl2 (2ϫ 15 mL). The combined organic phases were dried with
Na2SO4 and filtered. The filtrate was concentrated in vacuo to give
the diformyl derivative 6 or 16, which was then dissolved in dry
THF (5 mL). The Wittig reagent (1.36 mmol) was then added to
the solution. After stirring at room temperature for 1 h, the reac-
tion mixture was concentrated in vacuo, and the residue was puri-
fied by column chromatography on silica gel (n-hexane/EtOAc).
Ethyl (1S,2R,3S,4R)-2-Benzamido-3,4-dihydroxycyclopentanecarb-
oxylate [(+)-15]: White solid (77% yield); m.p. 74–77 °C. Rf = 0.3
1
(n-hexane/EtOAc, 1:4). [α]2D5 = +40.5 (c = 0.415, EtOH). H NMR
(400 MHz, CDCl3): δ = 1.20 (t, J = 7.06 Hz, 3 H, CH3), 2.03–2.22
(m, 2 H, 4-H), 3.06 (q, J = 7.43 Hz, 1 H, 5-H), 3.72–3.76 (m, 1 H,
2-H), 4.09–4.20 (m, 2 H, OCH2), 4.27–4.33 (m, 1 H, 3-H), 4.57–
4.65 (m, 1 H, 1-H), 6.98 (d, J = 8.52 Hz, 1 H, NH), 7.35–7.79 (m,
5 H, Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.9, 34.3,
46.2, 55.4, 60.9, 72.2, 73.6, 128.2, 129.0, 132.0, 135.3, 167.0,
175.7 ppm. C15H19NO5 (293.32): calcd. C 61.42, H 6.53, N 4.78;
found C 61.19, H 6.32, N 4.48.
General Procedure for In Situ Dialdehyde Formation Followed by
the In Situ Wittig Reaction: To a solution of 5 or 15 (200 mg,
0.68 mmol) in THF/H2O (10:1 v/v, 11 mL) was added NaIO4
(291 mg, 1.36 mmol), and the reaction mixture was stirred at room
temperature for 1 h under Ar to give diformyl derivative 6 or 16.
Water (20 mL) was then added, and the mixture was extracted with
CH2Cl2 (2ϫ 15 mL). The combined organic phases were dried with
Na2SO4 and filtered. The filtrate was concentrated in vacuo to give
the diformyl derivative 6 or 16. The Wittig reagent was prepared
separately by the addition of tBuOK (1.36 mmol) to a solution of
the phosphonium salt (1.36 mmol) in dry THF (5 mL), and the
resulting mixture was stirred for 10 min. The diformyl derivative 6
or 16 (200 mg, 0.68 mmol) was dissolved in dry THF (5 mL), and
the resulting solution was added dropwise to the solution of the in
situ generated Wittig reagent. After stirring at room temperature
for 1 h, the reaction mixture was concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (n-
hexane/EtOAc).
Triethyl (1E,3R,4S,6E)-3-Benzamidohepta-1,6-diene-1,4,7-tricarb-
oxylate [(+)-11]: White solid (78% yield); m.p. 28–30 °C. Rf = 0.4
(n-hexane/EtOAc, 1:1). [α]2D5 = +15.3 (c = 0.32, EtOH). H NMR
1
(400 MHz, CDCl3): δ = 1.24–1.33 (m, 9 H, 3 CH3 overlapping),
2.40–2.49 (m, 1 H, 3-H), 2.70–2.79 (m, 1 H, 5-H), 2.92–2.99 (m, 1
H, 4-H), 4.10–4.25 (m, 6 H, OCH2), 5.06–5.17 (m, 1 H, 5-H), 5.82–
6.06 (m, 2 H, 2-H, 6-H), 6.85–6.95 (m, 2 H, 1-H, 7-H), 7.39–7.89
(m, 5 H, Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.9,
31.9, 48.7, 52.2, 60.7, 61.0, 61.4, 123.2, 123.7, 128.3, 129.2, 132.4,
134.8, 145.9, 146.2, 166.1, 167.1, 172.6 ppm. C23H29NO7 (431.48):
calcd. C 64.02, H 6.77, N 3.25; found C 63.79, H 6.52, N 3.53.
Ethyl (2S,3R,E)-3-Benzamido-6-oxo-2-[(E)-4-oxopent-2-enyl]hept-4-
enoate [(–)-12]: Colorless oil (71% yield); Rf = 0.5 (n-hexane/
EtOAc, 1:4). [α]2D5 = –3 (c = 0.255, EtOH). 1H NMR (400 MHz,
CDCl3): δ = 1.25–1.33 (m, 3 H, CH3), 2.26 (s, 3 H, CH3), 2.28 (s,
3 H, CH3), 2.47–2.55 (m, 1 H, 1Ј-H), 2.72–2.83 (m, 1 H, 1Ј-H),
3.01–3.07 (m, 1 H, 2-H), 4.18–4.26 (m, 2 H, OCH2), 5.10–5.17 (m,
1 H, 3-H), 6.17 (d, J = 15.7 Hz, 1 H, 2-H), 6.30 (d, J = 15.9 Hz, 1
H, 4-H), 6.73–6.82 (m, 2 H, 3Ј-H, 5-H), 7.08 (d, J = 8.84 Hz, 1 H,
NH), 7.37–7.85 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 14.9, 27.9, 28.1, 32.0, 48.8, 52.5, 61.8, 128.3, 129.1,
131.9, 132.5, 133.1, 134.9, 144.5, 145.2, 167.1, 172.8, 198.4,
198.6 ppm. C21H25NO5 (371.43): calcd. C 67.91, H 6.78, N 3.77;
found C 67.66, H 6.33, N 4.08.
General Procedure for Catalytic Hydrogenation: A solution of 7, 8,
11, 12, 17, 18, 21, or 22 (200 mg, 0.68 mmol) and 10mol-% Pd/C
(20 mg) in EtOAc (20 mL) was stirred under H2 atmosphere for
1 h. The reaction mixture was then filtered through silica gel and
Celite. The filtrate was concentrated under reduced pressure, and
the residue was purified by column chromatography on silica gel (n-
hexane/EtOAc). The ee values were determined by HPLC analysis.
Ethyl
(1S,2R)-2-Benzamidocyclopent-3-enecarboxylate
[(–)-3]:
White solid (72% yield); m.p. 83–85 °C. [α]2D5 = –99 (c = 0.28,
EtOH).[15] 1H NMR (400 MHz, CDCl3): δ = 1.16 (t, J = 7.15 Hz,
3 H), 2.57–5.66 (m, 1 H, CH2), 2.84–2.91 (m, 1 H, CH2), 3.44–3.50
(m, 1 H, 1-H), 4.01–4.11 (m, 2 H, OCH2), 5.55–5.62 (m, 1 H, 2-
H), 5.70–5.73 (m, 1 H, 4-H), 5.96–5.99 (m, 1 H, 3-H), 6.51 (br. s,
1 H, NH), 7.38–7.51 (m, 3 H, Ar), 7.71–7.75 (m, 2 H, Ar) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 14.8, 34.5, 47.0, 56.7, 60.6,
128.2, 128.9, 130.1, 131.9, 134.2, 135.4, 166.8, 172.8 ppm.
Triethyl (3S,4S,6E)-3-Benzamidohepta-(1E)-1,6-diene-1,4,7-tricarb-
oxylate [(–)-21]: White solid (77% yield); m.p. 39–41 °C. Rf = 0.6
(n-hexane/EtOAc, 1:1). [α]2D5 = –43 (c = 0.265, EtOH). 1H NMR
(400 MHz, CDCl3): δ = 1.22–1.28 (m, 9 H, 3 CH3 overlapping),
2.53–2.68 (m, 2 H, 5-H), 2.93–3.06 (m, 1 H, 4-H), 4.12–4.22 (m, 6
H, OCH2), 5.09–5.15 (m, 1 H, 3-H), 5.87 (d, J = 15.5 Hz, 1 H, 1-
H), 5.97 (dd, J = 15.6 Hz, J = 1.52 Hz, 1 H, 7-H), 6.82–6.94 (m,
2 H, 2-H, 6-H), 7.41–7.91 (m, 5 H, Ar) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 14.9, 31.9, 48.7, 52.4, 60.6, 60.9.0, 61.2, 123.5,
123.7, 128.2, 129.2, 132.4, 134.8, 145.8, 146.5, 166.2, 167.1, 172.5,
1
2
Ethyl
(1S,2S)-2-Benzamidocyclopent-3-enecarboxylate
[(+)-4]:
White solid (76% yield); m.p. 94–96 °C. [α]2D5 = +104 (c = 0.275,
406
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Stereocontrolled Approach to Acyclic β2,3-Amino Acid Enantiomers
179.1 ppm. C23H29NO7 (431.48): calcd. C 64.02, H 6.77, N 3.25; propyl alcohol, 80:20), flow rate: 0.5 mL/min, detection at 250 nm]:
found C 64.36, H 6.47, N 2.96.
Rt (retention time, min) = 17.25 (antipode 19.83). 1H NMR
(400 MHz, CDCl3): δ = 0.90–1.04 (m, 3 H, CH3), 1.27–1.87 (m, 12
H, 3 CH2 and 2 CH3), 2.64–2.70 (m, 1 H, 2-H), 4.21 (q, J =
7.31 Hz, 2 H, OCH2), 4.29–4.38 (m, 1 H, 3-H), 7.43–7.87 (m, 5 H,
Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 11.4, 14.7, 14.9,
20.9, 26.3, 31.9, 50.7, 53.1, 60.8, 128.2, 129.1, 132.0, 135.6, 167.5,
174.9 ppm. C17H25NO3 (291.39): calcd. C 70.07, H 8.65, N 4.81;
found C 69.77, H 8.91, N 4.53.
Ethyl (2S,3S,E)-3-Benzamido-6-oxo-2-[(E)-4-oxopent-2-enyl]hept-4-
enoate [(–)-22]: Yellow oil (71% yield); Rf = 0.5 (n-hexane/EtOAc,
1:4). [α]2D5 = –17.7 (c = 0.31, EtOH). 1H NMR (400 MHz, CDCl3):
δ = 1.26–1.34 (m, 3 H, CH3), 2.23 (s, 3 H, CH3), 2.28 (s, 3 H, CH3),
2.60–2.74 (m, 2 H, 1Ј-H), 2.99–3.05 (m, 1 H, 2-H), 4.17–4.27 (m,
2 H, OCH2), 5.15–5.22 (m, 1 H, 3-H), 6.15 (d, J = 15.9 Hz, 1 H,
1
2
2Ј-H), 6.25 (dd, J = 15.8 Hz, J = 1.85 Hz, 1 H, 4-H), 6.70–6.82
(m, 2 H, 3Ј-H, 5-H), 7.40–7.93 (m, 5 H, Ar) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 14.9, 27.6, 28.0, 29.9, 32.1, 48.8, 52.7,
61.3, 128.2, 129.0, 129.2, 132.4, 133.3, 134.9, 144.5, 145.3, 166.9,
172.9, 198.4 ppm. C21H25NO5 (371.43): calcd. C 67.91, H 6.78, N
3.77; found C 67.63, H 7.06, N 3.42.
Ethyl (2S,3R)-3-Benzamido-5-phenyl-2-(3-phenylpropyl)pentanoate
[(–)-10]: White solid (90% yield); m.p. 106–108 °C. Rf = 0.5 (n-
hexane/EtOAc, 3:1). [α]2D5 = –2 (c = 0.3, EtOH), 99%ee. HPLC
[Chiralpack IA column, n-hexane/IPA (80:20), flow rate: 0.5 mL/
min, detection at 250 nm]: Rt (min) = 17.86 (antipode 22.20). 1H
NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.12 Hz, 3 H, CH3),
1.48–2.01 (m, 6 H, 3 CH2 overlapping 2.61–2.82 (m, 5 H, 2-H, 2
PhCH2 overlapping), 4.15–4.25 (m, 2 H, OCH2), 4.43–4.52 (m, 1
H, 3-H), 6.45 (d, J = 9.29 Hz, 1 H, NH), 7.14–7.78 (m, 15 H,
Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.9, 28.9, 29.5,
32.8, 35.0, 35.6, 50.9, 51.0, 60.8, 126.5, 128.1, 129.1, 132.0, 135.7,
142.5, 142.6, 167.7, 174.6 ppm. C29H33NO3 (443.58): calcd. C
78.52, H 7.50, N 3.16; found C 78.19, H 7.21, N 2.82.
Ethyl (2S,3R)-2-Allyl-3-benzamidopent-4-enoate [(+)-7]: Colorless
oil (45% yield); Rf = 0.3 (n-hexane/EtOAc, 3:1). [α]2D5 = +9.1 (c =
0.31, EtOH). 1H NMR (400 MHz, [D6]DMSO): δ = 1.13 (t, J =
6.99 Hz, 3 H, CH3), 2.20–2.30 (m, 2 H, 1Ј-H), 2.70–2.80 (m, 1 H,
2-H), 4.03 (q, J = 7.07 Hz, 2 H, OCH2), 4.68 (q, J = 8.74 Hz, 1 H,
3-H), 4.92–5.17 (m, 4 H, 5-H, 3Ј-H), 5.61–5.88 (m, 2 H, 3-H, 2Ј-H),
7.41–7.84 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 15.2, 31.4, 50.2, 54.1, 60.9, 117.3, 117.7, 128.2, 129.2, 132.1,
135.3, 136.0, 137.1, 167.1, 173.6 ppm. C17H21NO3 (287.36): calcd.
C 71.06, H 7.37, N 4.87; found C 70.73, H 6.99, N 4.58.
Triethyl (3R,4S)-3-Benzamidoheptane-1,4,7-tricarboxylate [(–)-13]:
White solid (90% yield); m.p. 41–42 °C. Rf = 0.3 (n-hexane/EtOAc,
1:1). [α]2D5 = –3.3 (c = 0.37, EtOH), 98%ee. HPLC [Chiralpack IA
column, n-hexane/IPA (80:20), flow rate: 0.5 mL/min, detection at
Ethyl (2S,3R)-3-Benzamido-(E)-2-cinnamyl-5-phenylpent-4-enoate
[(–)-8]: White solid (46% yield); m.p. 85–88 °C. Rf = 0.4 (n-hexane/
1
250 nm]: Rt (min) = 29.83 (antipode 33.05). H NMR (400 MHz,
EtOAc, 3:1). [α]2D5 = –6.4 (c = 0.31, EtOH). H NMR (400 MHz,
1
CDCl3): δ = 1.12–1.31 (m, 9 H, 3 CH3 overlapping), 1.54–2.08 (m,
6 H, 5-H, 2-H, 6-H), 2.29–2.50 (m, 4 H, 1-H, 7-H), 2.64–2.70 (m,
1 H, 4-H), 3.95–4.26 (m, 6 H, OCH2), 4.33–4.42 (m, 1 H, 3-H),
6.67 (d, J = 9.23 Hz, 1 H, NH), 7.40–7.80 (m, 5 H, Ar) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 14.9, 23.2, 28.1, 28.9, 31.4, 34.1,
50.6, 50.8, 60.5, 60.6, 60.9, 128.1, 129.0, 132.1, 135.3, 167.3, 173.2,
174.2 ppm. C23H33NO7 (435.52): calcd. C 63.43, H 7.64, N 3.22;
found C 63.11, H 7.32, N 2.89.
CDCl3): δ = 1.26–1.32 (m, 3 H, CH3), 2.51–2.61 (m, 1 H, 4-H),
2.75–2.87 (m, 1 H, 1Ј-H), 2.96–3.11 (m, 1 H, 2-H), 4.24 (q, J =
7.19 Hz, 2 H, OCH2), 5.15–5.23 (m, 1 H, 3-H), 6.22–6.35 (m, 2 H,
2Ј-H, 4-H), 6.52 (d, J = 16.1 Hz, 1 H, 3Ј-H), 6.72 (d, J = 15.8 Hz,
1 H, 5-H), 6.97–7.04 (m, 1 H, NH), 7.13–7.87 (m, 15 H, Ar) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 15.0, 33.4, 50.9, 53.9, 60.9,
126.8, 127.1, 127.7, 128.3, 128.6, 129.2, 129.4, 129.6, 131.3, 132.0,
132.2, 132.4, 135.3, 137.2, 137.8, 166.7, 173.4 ppm. C29H29NO3
(439.55): calcd. C 79.24, H 6.65, N 3.19; found C 79.52, H 6.30, N
2.80.
Ethyl (2S,3R)-3-Benzamido-6-oxo-2-(4-oxopentyl)heptanoate [(–)-
14]: Colorless oil (91% yield); Rf = 0.4 (n-hexane/EtOAc, 1:4).
[α]2D5 = –27.2 (c = 0.33, EtOH), 99%ee. HPLC [Chiralpack IA col-
umn, n-hexane/IPA (80:20), flow rate: 0.5 mL/min, detection at
Ethyl (2S,3S)-2-Allyl-3-benzamidopent-4-enoate [(–)-17]: Colorless
oil (42% yield); Rf = 0.2 (n-hexane/EtOAc, 5:1). [α]2D5 = –43 (c =
0.215, EtOH). 1H NMR (400 MHz, CDCl3): δ = 1.28–1.33 (m, 3
H, CH3), 2.32–2.56 (m, 2 H, 1-H), 2.83–2.99 (m, 1 H, 2-H), 4.20
(q, J = 7.01 Hz, 2 H, OCH2), 4.95–5.02 (m, 1 H, 3-H), 5.05–5.38
(m, 4 H, 5-H, 3Ј-H), 5.72–5.98 (m, 2 H, 3-H, 2Ј-H), 7.44–7.44 (m,
5 H, Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.9, 34.0,
50.0, 54.4, 60.8, 117.8, 118.1, 128.1, 129.2, 132.1, 136.2, 137.0,
137.1, 166.3, 173.5 ppm. C17H21NO3 (287.36): calcd. C 71.06, H
7.37, N 4.87; found C 70.74, H 7.02, N 5.03.
1
250 nm]: Rt (min) = 18.22 (antipode 24.52). H NMR (400 MHz,
CDCl3): δ = 1.32 (t, J = 6.94 Hz, 3 H, CH3), 1.53–3.27 (m, 18 H,
2-H, 3-H, 3 CH2, 2 COCH2, 2 COCH3 overlapping), 4.17–4.28 (m,
2 H, OCH2), 7.41–7.64 (m, 5 H, Ar) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 14.9, 22.1, 27.2, 29.1, 30.7, 43.4, 46.4, 50.9, 59.5,
61.0, 61.4, 128.1, 131.2, 132.0, 135.3, 167.4, 169.9, 174.1,
174.4 ppm. C21H29NO5 (375.46): calcd. C 67.18, H 7.79, N 3.73;
found C 66.85, H 8.00, N 3.99.
Ethyl (2S,3S)-3-Benzamido-2-propylpentanoate [(–)-19]: Colorless
oil (76% yield); Rf = 0.4 (n-hexane/EtOAc, 5:1). [α]2D5 = –26.4 (c =
0.33, EtOH), 99%ee. HPLC [Chiralpack IA column, n-hexane/IPA
(80:20), flow rate: 0.5 mL/min, detection at 250 nm]: Rt (min) =
11.71 (antipode 12.53). 1H NMR (400 MHz, CDCl3): δ = 0.90–
1.04 (m, 3 H, CH3), 1.25–1.88 (m, 12 H, 2 CH3, 3 CH2 overlapping
2.64–2.75 (m, 1 H, 2-H), 4.17–4.27 (m, 2 H, OCH2), 4.28–4.37 (m,
1 H, 3-H), 7.43–7.89 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 11.4, 14.7, 15.0, 21.2, 25.4, 31.3, 50.2, 52.9, 60.7,
127.9, 129.1, 132.0, 135.8, 166.9, 174.6 ppm. C17H25NO3 (291.39):
calcd. C 70.07, H 8.65, N 4.81; found C 69.74, H 8.30, N 4.51.
Ethyl (2S,3S)-3-Benzamido-(E)-2-cinnamyl-5-phenylpent-4-enoate
[(–)-18]: Yellow solid (40% yield); m.p. 69–73 °C. Rf = 0.4 (n-hex-
ane/EtOAc, 3:1). [α]2D5 = –43 (c = 0.27, EtOH). 1H NMR (400 MHz,
CDCl3): δ = 1.22–1.26 (m, 3 H, CH3), 2.60–2.79 (m, 2 H, 1Ј-H),
2,98–3.05 (m, 1 H, 2-H), 4.16–4.26 (m, 2 H, OCH2), 5.14–5.26 (m,
1 H, 3-H), 6.19–6.31 (m, 2 H, 3-H, 2Ј-H), 6.47–6.71 (m, 2 H, 5-H,
3Ј-H), 7.22–7.97 (m, 15 H, Ar) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 15.0, 33.4, 50.8, 54.2, 60.8, 126.8, 127.2, 127.8, 128.1,
128.6, 129.2, 129.4, 129.6, 131.3, 132.0, 132.2, 132.4, 135.4, 137.2,
137.8, 166.3, 173.6 ppm. C29H29NO3 (439.55): calcd. C 79.24, H
6.65, N 3.19; found C 78.89, H 6.30, N 3.41.
Ethyl (2S,3S)-3-Benzamido-5-phenyl-2-(3-phenylpropyl)pentanoate
[(–)-20]: Colorless oil (89% yield); Rf = 0.5 (n-hexane/EtOAc, 3:1).
[α]2D5 = –26.5 (c = 0.32, EtOH), 99%ee. HPLC [Chiralpack IA col-
umn, n-hexane/IPA (80:20), flow rate: 0.5 mL/min, detection at
Ethyl (2S,3R)-3-Benzamido-2-propylpentanoate [(–)-9]: Colorless oil
(81% yield); Rf = 0.3 (n-hexane/EtOAc, 3:1). [α]2D5 = –7 (c = 0.285,
EtOH); 98%ee. HPLC [Chiralpack IA column, n-hexane/IPA (iso-
Eur. J. Org. Chem. 2014, 403–409
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
407

M. Cherepanova, L. Kiss, E. Forró, F. Fülöp
FULL PAPER
1
250 nm]: Rt (min) = 13.51 (antipode 16.49). H NMR (400 MHz,
CDCl3): δ = 1.32 (t, J = 7.19 Hz, 3 H, CH3), 1.56–1.98 (m, 6 H, 2
CH2 overlapping), 2.59–2.81 (m, 5 H, 2-H, PhCH2 overlapping),
4.22 (q, J = 6.96 Hz, 2 H, OCH2), 4.45–4.52 (m, 1 H, 3-H), 7.13–
7.87 (m, 15 H, Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
15.0, 28.3, 29.8, 32.7, 34.1, 35.6, 50.2, 51.0, 60.7, 126.6, 128.1,
129.1, 131.9, 135.7, 142.6, 167.1, 174.4 ppm. C29H33NO3 (443.58):
calcd. C 78.52, H 7.50, N 3.16; found C 78.20, H 7.23, N 3.35.
Ethyl 3-benzamido-2-propylpentanoate (9): Colorless oil (81%
yield).
Ethyl 3-benzamido-5-phenyl-2-(3-phenylpropyl)pentanoate (10):
White solid (90% yield); m.p. 105–106 °C.
Triethyl 3-benzamidoheptane-1,4,7-tricarboxylate (13): White solid
(90% yield); m.p. 41–42 °C.
Ethyl 3-benzamido-6-oxo-2-(4-oxopentyl)heptanoate (14): Colorless
oil (89% yield).
Triethyl (3S,4S)-3-Benzamidoheptane-1,4,7-tricarboxylate [(–)-23]:
Colorless oil (90% yield); Rf = 0.5 (n-hexane/EtOAc, 1:1). [α]2D5
=
Ethyl 3-benzamido-2-propylpentanoate (19): Colorless oil (79%
–32 (c = 0.41, EtOH), 99%ee. HPLC [Chiralpack IA column, n-
hexane/IPA (80:20), flow rate: 0.5 mL/min, detection at 250 nm]:
Rt (min) = 19.79 (antipode 21.25). 1H NMR (400 MHz, CDCl3): δ
= 1.22–1.40 (m, 9 H, 3 CH3 overlapping), 1.51–2.71 (m, 11 H, 2-
H, 5 CH2 overlapping), 4.18–4.28 (m, 6 H, OCH2), 4.31–4.39 (m,
1 H, 3-H), 7.41–7.87 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 14.9, 23.4, 27.4, 28.5, 31.0, 33.9, 50.3, 50.7, 52.1, 60.9,
128.0, 129.1, 132.1, 135.4, 167.1, 173.8, 174.0 ppm. C23H33NO7
(435.52): calcd. C 63.43, H 7.64, N 3.22; found C 63.16, H 7.29, N
3.56.
yield).
Ethyl 3-benzamido-5-phenyl-2-(3-phenylpropyl)pentanoate (20): Col-
orless oil (87% yield).
Triethyl 3-benzamidoheptane-1,4,7-tricarboxylate (23): Colorless oil
(90% yield).
Ethyl 3-benzamido-6-oxo-2-(4-oxopentyl)heptanoate (24): Yellow oil
(91% yield).
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the H and 13C NMR spectra.
1
Ethyl (2S,3S)-3-Benzamido-6-oxo-2-(4-oxopentyl)heptanoate [(–)-
24]: Yellow oil (91% yield); Rf = 0.4 (n-hexane/EtOAc, 1:4). [α]2D5
= –14.5 (c = 0.32, EtOH), 98%ee. HPLC [Chiralpack IA column,
n-hexane/IPA (80:20), flow rate: 0.5 mL/min, detection at 250 nm]:
Rt (min) = 22.42 (antipode 26.31). 1H NMR (400 MHz, CDCl3): δ
= 1.34 (t, J = 7.10 Hz, 3 H, CH3), 1.61–2.00 (m, 6 H, 3 CH2), 2.28–
2.54 (m, 7 H, 1-H, COCH3 overlapping), 2.66–2.72 (m, 1 H, 2-H),
3.64 (m, 4 H, COCH2), 4.24 (q, J = 7.18 Hz, 2 H, OCH2), 4.39–
4.47 (m, 1 H, 3-H), 7.43–7.87 (m, 5 H, Ar) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 14.9, 22.2, 26.4, 28.6, 30.4, 30.7, 43.3,
46.3, 50.9, 60.9, 128.0, 129.1, 132.1, 135.4, 167.0, 170.0, 174.4,
208.9 ppm. C21H29NO5 (375.46): calcd. C 67.18, H 7.79, N 3.73;
found C 67.44, H 8.09, N 3.49.
Acknowledgments
The authors are grateful to the Hungarian Research Foundation
(OTKA Nos. NK81371 and K100530) and TAMOP-4.2.2.A-II/1/
KONV-2012-0035 for the financial support. This paper was sup-
ported by the Hungarian Academy of Sciences (János Bolyai Re-
search Scholarship to L. K.).
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Received: August 26, 2013
Published Online: November 13, 2013
Eur. J. Org. Chem. 2014, 403–409
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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