1400
D. Balducci et al. / Tetrahedron: Asymmetry 20 (2009) 1398–1401
twisted with respect to the plane of the dimethylphenyl ring
[dihedral angles: 28.0(8)° and 51.1(4)° for one conformer and
32.9(6)° and 51.1(5)° for the second one].
The absolute configuration of the stereogenic centres at C(13),
C(15), C(23) and C(32) is (S). Comparison with other cyclic dipep-
tide structures of DKP derivatives8,9 shows that the presence of
two conformers is common and, depending on the nature of the
substituents, the DKP ring can adopt a boat, flattened boat or
planar conformation.
inert atmosphere. After 1 h the iodo derivative 2 (4.25 g, 12.7 mmol)
was added and the reaction mixture, under stirring, was monitored
by TLC. When the starting reagent 1 was consumed, the second
aliquot of LHMDS (12.7 mL) was added and the reaction mixture
was stirred for 1 h. Then, the second aliquot of 2 (4.25 g, 12.7 mmol)
was added and the reaction was stirred for about 4 h, monitoring by
TLC. The reaction wasthenquenched with water, extractedwithethyl
acetate and the organic solution was evaporated under vacuum to
dryness. From the residue the pure reaction product 3 was isolated
in 50% yield after crystallization from methanol (mp 171.5–
173.5 °C). The mother liquor was evaporated to dryness under
reduced pressure and the residue submitted to silica gel chromato-
graphic separation eluting with hexane/ethyl acetate to recover an
additional 25% of the pure title product. 1H NMR d: 1.30 (d, 6H, J = 7,
CH–CH3), 1.40 (t, 6H, J = 7, CH2–CH3), 2.33 (s, 12H, CH3–Ph), 3.43 (m,
4H, CH–CH2), 4.08 (m,2H, CH–CH2), 4.32 (q, 4H, J = 7,CH2–CH3), 5.68
(q, 2H, J = 7,CH–CH 3), 6.90 (s, 4ArH), 7.00 (m, 4ArH), 7.30 (m, 6ArH).
13C NMR d: 14.1, 16.8, 21.3, 35.5, 53.1, 57.7, 64.7, 120.9, 127.2,
128.1, 128.7, 131.5, 138.5, 139.0, 149.4, 153.6, 167.7. IR (solid state)
4. Conclusion
In conclusion we can assume that the synthesis reported herein
offers some advantages: a total stereoselectivity, a good overall
yield [about 50% estimated on the starting (S)-phenylethylamine],
low to moderate cost of reagents, simplicity of experimental proce-
dures and product isolation. Therefore, we believe that this
approach, which is an application of our previous procedure, is
an efficient improvement in the asymmetric synthesis of (S)-DMT
with respect to the methodologies reported in the literature. It is
also noteworthy that this approach is reliable to prepare the enan-
tiomerically pure target product on a multi-gram scale.
m
2984.4, 1755.3, 1660.8, 1598.7, 1231.7, 1186.4. [
a
]
D = ꢁ61.1 (c 0.9,
CHCl3). Anal. Calcd for C44H50N2O8: C, 71.91; H, 6.86; N, 3.81. Found:
C, 72.25; H, 6.84; N, 3.81.
Finally, since the diastereoselectivity of the alkylation of syn-
thon 1 is controlled by the chiral group bound at both (N-1) and
(N-4), the enantiomerically pure (R)-Dmt can be easily obtained
by using the (R)-phenylethylamine instead of the (S)-enantiomer.
Further work is currently underway to extend the methodology
5.4. (S)-20,60-Dimethyltyrosine [(S)-Dmt] 4
Intermediate 3 (1.2 g, 1.6 mmol) was refluxed in 57% HI (12 mL)
for 3 h. The reaction solution was then evaporated under vacuum,
the residue dissolved in water (15 mL) and extracted with ethyl
acetate. The aqueous solution was eluted more than once on a col-
umn filled with the acid ion-exchange resin Dowex 50 WX 8 (20–
50 mesh) carefully washed with distilled water. The resin was
again washed with distilled water until neutral pH of eluent and
then the title product was eluted with 5 M NH4OH. The aqueous
solution was evaporated under vacuum to dryness and the pure
(S)-Dmt was obtained practically in quantitative yield as a white
solid which decomposes at 239–240 °C. 1H NMR (D2O) d: 2.09 (s,
to other unnatural
a-aminoacids present in biologically active
compounds. The procedure described herein was patented on
2008, deposition number RM2008A000118.
5. Experimental
5.1. General
1H- and 13C NMR spectra were recorded on a Gemini spectrom-
eter at 300 MHz using CDCl3, unless otherwise stated. Chemical
shifts are reported in ppm relative to CDCl3 and the coupling con-
stants (J) are in hertz. Optical rotation values were measured at
25 °C on a Perkin–Elmer 343 polarimeter. IR data were recorded
on a Perkin–Elmer spectrum 100. Melting points are uncorrected.
Dry tetrahydrofuran (THF) was distilled from sodium benzophe-
none ketyl. Chromatographic separations were performed with
Silica gel 60 (230–400 mesh).
6H), 2.83 (dd, 1H, JAX = 8, JAB = 14.5), 3.05 (dd, 1H, JBX = 8, JAB
=
14.5), 3.62 (t, 1H, JAX = 8, JBX = 8), 6.45 (s, 2H). 13C NMR (D2O vs
1,4-dioxane) d: 20.0, 30.8, 55.1, 115.7, 125.1, 140.0, 154.6, 174.7.
[a]
D = +72.9 (c 0.5, 0.5 M HCl).
(S)-Dmt 4 was dissolved in diluted HCl and after evaporation
under vacuum to dryness the (S)-Dmt.HCl was recovered as a
white solid. 1H NMR (CD3OD) d: 2.29 (s,2H), 3.14 (dd, 1H, JAX = 8,
JAB = 14.5), 3.30 (dd, 1H, JBX = 8, JAB = 14.5), 4.0 (t, 1H, J = 8), 6.53
(s, 2H). 13C NMR (CD3OD) d: 20.5, 31.4, 54.0, 116.5, 123.9, 139.9,
The spectroscopic and physical data of the chiral synthon 1 are
reported in Ref. 5c.
157.0, 172.1. [a]
D = +39.8 (c 1.1, CH3OH) [lit.3 +39.4 (c 1, CH3OH)].
5.5. X-ray crystallography
5.2. 4-Iodomethyl-3,5-dimethylphenyl ethylcarbonate 2
Single crystals of 3 suitable for an X-ray diffraction study were
grown from a methanolic solution by slow evaporation. The X-ray
intensity data were measured on a Bruker Apex II CCD area detector
diffractometer. Cell dimensions and the orientation matrix were ini-
tially determined from a least-squares refinement on reflections
measured in three sets of 20 exposures, collected in three different
Compound 2 was prepared by treatment of 4-chloromethyl-3,5-
dimethylphenyl ethylcarbonate4 (5.8 g, 23.9 mmol) with NaI (7.2 g,
48 mmol) in 60 mL of acetone and the reaction mixture was stirred
at rt. After about 50 h the organic solvent was evaporated under re-
duced pressure. Water was added to the residue and the reaction
product extracted with ethyl acetate. The organic phase was dried
and the title product isolated as oil in 90% yield after total evapo-
ration of organic solvent under vacuum. 1H NMR d: 1.39 (t, 3H,
J = 7), 2.35 (s, 6H), 4.31 (q, 2H, J = 7), 4.41 (s, 2H), 6.84 (s, 2H). 13C
NMR d: 2.1, 14.2, 19.4, 64.8, 120.9, 132.7, 138.6, 150.2, 153.5.
x
regions, and eventually refined against all data. For the crystal, a
full sphere of reciprocal space was scanned by 0.3°
x steps. The soft-
ware SMART10 was used for collecting frames of data, indexing
reflections and determination of lattice parameters. The collected
frames were then processed for integration by the SAINT program,10
11
and an empirical absorption correction was applied using SADABS
.
The structure was solved by direct methods (SIR 97)12 and subse-
quent Fourier syntheses and refined by full-matrix least-squares
5.3. 1,4-N,N-[(S)-Phenylethyl]-3,6-bis[4-O-carbethoxy-2,6-dime-
thyl-benzyl]-piperazine-2,5-dione 3
on F2 SHELXTL),13 using anisotropic thermal parameters for all non-
(
The chiral synthon 1 (4.1 g, 12.7 mmol) in dry THF (60 mL) was
metalled with 1 M solution of LHMDS (12.7 mL) at ꢁ78 °C under an
hydrogen atoms. Two independent molecules were found in the
asymmetric unit. All hydrogen atoms were added in calculated