Polychlorinated leucine derivatives: Synthesis of (2S,4R)-5,5- dichloroleucine and its J-based analysis

Article abstract of DOI:10.1002/ejoc.200600154

A total synthesis of (2S,4R)-5,5-dichloroleucine is reported in 13 steps from (S)-methyl 2-(hydroxymethyl)propanoate. A density functional J-based analysis of this compound and a comparison with that of its (2S,4S) epimer is also performed in order to com

Full text of DOI:10.1002/ejoc.200600154

FULL PAPER
DOI: 10.1002/ejoc.200600154
Polychlorinated Leucine Derivatives: Synthesis of (2S,4R)-5,5-Dichloroleucine
and Its J-Based Analysis
Ana Ardá,[a] Carlos Jiménez,[a] and Jaime Rodríguez*[a]
Keywords: Amino acids / Density functional calculations
A total synthesis of (2S,4R)-5,5-dichloroleucine is reported in
13 steps from (S)-methyl 2-(hydroxymethyl)propanoate. A
density functional J-based analysis of this compound and a
comparison with that of its (2S,4S) epimer is also performed
in order to complete our study of J-configurational assign-
ments in 1,3-nitrogen-containing acyclic moieties.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Apart from proteinogenic and other naturally occurring
amino acids, non-natural synthetic amino acids have re-
ceived increasing attention due to their enzyme inhibitory
and anti-metabolite properties and their ability to induce a
certain conformation when incorporated into proteins.
Among these, halogen α-amino acids have been shown to
frequently act as antagonists of naturally occurring α-
amino acids.[1] Furthermore, they are present in nature,
either as free amino acids or as constituents of peptides,
and have been isolated from different natural sources.[2] For
example, a 5,5-dichloroleucine (1) was found and character-
ised without configuration assignment from the hydrolysed
portion of victorin, also known as HV-toxin, isolated from
the fungus Helminthosporium victoriae.[3] Sponges of the
Dysidea genus are also a rich source of unique polychlori-
nated metabolites derived from amino acids.[4] It has been
postulated that these chlorinated peptides are actually bi-
osynthesised by blue-green algae living in association with
the sponge.[5] However, the incorporation of chlorine in
such compounds is intriguing and efforts have been made
to establish the mechanism of biochlorination.[1a,6–8] Some
precursors that have been used for feeding experiments are
amino acids 2 and 3, which along with 1 have been recently
synthesised in a stereospecific way by different research
groups.[9,10] The preparation of more leucine derivatives
could be very helpful for further biosynthesis experiments.
The use of J-based analysis, also known as Murata’s
method, has become one of the best tools for the elucida-
tion of the relative stereochemistry in acyclic compounds.
Although many examples have been published with com-
pounds bearing oxygenated or alkyl substituents, few com-
pounds carrying chiral nitrogen-substituted acyclic systems
have been reported.[11] For this reason, more examples are
needed in order to obtain a new set of values to build up
2
[12]
reliable curves, especially for JC,H
,
which may describe
angular dependence vs. heteronuclear coupling constants.
Results and Discussion
Very recently, we reported a new structure from the
sponge Dysidea sp., namely the polychlorinated dipeptide
dysithiazolamide (6),[11e] whose relative configuration was
proposed on the basis of the J-based analysis configura-
tion.[13,14] The stereochemistry elucidation implied the ap-
plication of Murata’s methodology, first to the new amino
acid derivative 5, which was used as a model, and then to
the natural product.[11e] In order to complete our study of
J-configurational assignments to 1,3-nitrogen-containing
acyclic moieties of this type, we now want to report the
synthesis of its epimer, (2S,4R)-dichloroleucine (4), using
chiral auxiliary strategies, and the corresponding J-based
analysis along with QM calculations (Figure 1).
[a] Departamento de Química Fundamental, Facultade de Cien-
cias, Campus da Zapateira, Universidade de A Coruña,
15071 A Coruña, Spain
E-mail: jaimer@udc.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2006, 3645–3651
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A. Ardá, C. Jiménez, J. Rodríguez
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Figure 1. Retrosynthetic analysis of syn- and anti-5,5-dichloroleucines.
We have synthesised the α-azide carboximide 11 in five oxazolidinone 10 with trisyl azide at low temperature, ac-
steps from commercially available (S)-methyl 2-(hy- cording to Evans’ procedure,[19] to afford 11 as a single dia-
droxymethyl)propanoate (7) following a similar route to stereomer. After reduction of the azide moiety in 11 and
that described for the synthesis of cyclomarin;[15] for the Boc protection of the resulting amine group, removal of
dichlorination process we used Takeda’s transformation of the chiral auxiliary was achieved by treatment with lithium
aldehydes into gem-dihalides via the hydrazone.[16,17]
hydroxyperoxide to provide compound 12 in a very good
The synthetic strategy begun with a silyl protection of 7 yield. Esterification of the resulting acid as its tert-butyl es-
followed by reduction and subsequent Wadsworth–Em- ter, and introduction of a second Boc group under more
mons condensation of the resulting aldehyde with the chiral drastic conditions, afforded ester 13. The poor conversion
auxiliary phosphonate 8, which was simultaneously pre- of the latter reaction (37%)[20] was overcome by recovering
pared from -phenylglycine.[18] The second stereogenic cen- the unreacted starting material and recycling it.
tre at C2 was introduced in a stereocontrolled syn manner
Removal of the silyl ether group in 13 by treatment with
by electrophilic azidation of the potassium enolate of the TBAF in THF under standard conditions produced epi-
Figure 2. Reagents and conditions: i: (a) TBDPSCl, imidazole, DMF, 0 °CǞroom temp., 92%. (b) DIBAL-H, Et2O, –80 °C, 93 %; ii: (a)
LiCl, iPr2NEt, 8, CH3CN, 0 °C, 24 h, 70%. (b) H2, 10% Pd/C, EtOAc, quantitative; iii: (a) KHMDS, THF, –80 °C, trisyl azide, –80 °C.
(b) AcOH, 68%; iv: (a) H2, 10% Pd/C. (b) Boc2O, EtOAc, 99%. (c) LiOH, H2O2, THF/H2O, 91 %; v: (a) Boc2O, DMAP, tBuOH, 75%.
(b) Boc2O, DMAP, Et3N, 1,4-dioxane, 100 °C (37%, along with recovered starting material); vi: (a) TBAF, AcOH, THF, quantitative. (b)
Dess–Martin periodinane, CH2Cl2, 87%; vii: (a) NH2NH2·H2O, MeOH. (b) 4-Å molecular sieves. (c) CuCl2, Et3N, MeOH, room temp.,
35%; viii: TFA, CH2Cl2, 50%.
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Polychlorinated Leucine Derivatives
FULL PAPER
merisation at C2, although when the reaction was per- hyde 14, which was transformed into its hydrazone by treat-
formed in the presence of acetic acid it resulted in the total ment with NH2NH2·H2O, with further water removal using
retention of chirality.[21] The resulting primary alcohol was 4 Å molecular sieves. This hydrazone was quickly treated
then oxidized with the Dess–Martin reagent to give alde- with CuCl2 in dry methanol in the presence of triethyl-
3
2,3
Table 1. JH,H and
J
C,H
values [Hz] around the C2–C3 and C3–C4 bonds for epimers 4 (syn) and 5 (anti) and comparison with the
predicted values for the six possible staggered rotamers for each bond.
[a] For DFT calculations see ref.[11e]. [b] At 298 K. [c] At 263 K. [d] At 243 K. [e] The sign of the coupling constant in the J-HMBC
experiment is based on the HETLOC experiment. MAD = (∑|Jexp. – Jtheor.|)/n, where n = number of measured coupling constants; n.o.
= coupling not observed; n.m. = coupling not measured for overlapped signals.
Eur. J. Org. Chem. 2006, 3645–3651
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A. Ardá, C. Jiménez, J. Rodríguez
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amine[11,16] to give, after HPLC purification, the desired combination of the predicted conformers and the experi-
dichloro amino acid derivative 4 in 35% yield, along with mental coupling constants leads to the correct syn configu-
an unexpected alkene 15 in 7% yield. Final removal of the ration of compound 4.
Boc groups was achieved by hydrolysis with trifluoroacetic
There has been a notable difficulty in classifying the J
acid to yield the free amino acid 16 (Figure 2).
values in this type of system due to a poorly defined range
2,3
At this point, in order to complete the NMR J-based for the
J
coupling constant. Even though dihedral-an-
C,H
3
analysis of this type of system we compared the JH,H and gle dependence is the main factor, other effects such as sub-
2,3
J
values of 4 (syn) with those of its epimer 5 (anti). stituents, electronegativity, position and orientation, non-
C,H
3
Firstly, the JH,H measurements, obtained directly from bonded electrons, through-space interactions, hydrogen
their 1H NMR spectra, show important differences. The bonding, etc. may produce deviations from the expected
medium/large values obtained around the C2–C3 (6.3 and values obtained from the Karplus equation. The DFT cal-
8.4) and C3–C4 (6.5 and 6.4 Hz) bonds in compound 4 culations permitted us to predict these deviations and to
indicate the presence of two main conformers for each bond classify the coupling constants into a range of values that
in fast interconversion. This situation clearly differs from can shift slightly depending on the system.[25] However,
that for compound 5, where only the anti conformer is pres- when two or more conformers coexist in rapid equilibrium,
ent around both C2–C3 and C3–C4.
the values predicted by DFT do not allow us to identify
Next, the heteronuclear couplings were measured in them by comparison with the experimental values. When a
HETLOC and J-HMBC experiments.[22] For the C2–C3 major rotamer is present the comparison allowed us to
3
3
bond in 4, the small values found for JC1,H3l and JC4,H2 identify this conformer directly.
show a gauche relation for this pair of atoms. The large
In conclusion, we have been able to apply the J-based
2JC2,H3h value suggests that H3h is gauche to the nitrogen. methodology to syn and anti 5,5-dichloroleucine deriva-
3
2
Finally, the medium values found for JC1,H3h and JC2,H3l tives; the results are merely a demonstration of the use of
are in agreement with an equilibrium between the anti and computational techniques among heteronuclear coupling
the gauche (–) conformers shown in Table 1, where the pop- constants for the determination of the relative stereochemis-
ulation of the first one should be higher than that of the try in acyclic 1,3-nitrogen-containing moieties. The inconve-
2,3
second one. The homonuclear coupling constants measured niences found in having wide ranges of
J
values in this
C,H
at low temperature agree with the situation in which pop- type of system can be overcome through a systematic, and
ulation of the anti conformer increases while that of the consequently reliable, study of suitable models with a
gauche conformer (–) decreases. DFT calculations using the known relative configuration in order to better describe the
B3LYP functional and 6-311G(d,p) basis set were used to angular dependences of heteronuclear coupling constants.
compare coupling constants for the six possible staggered
rotamers. The mean absolute deviation (MAD)[23] values
obtained for 4 (syn epimer) confirmed the lack of a major
conformer, in contrast to compound 5 (anti epimer), where
the MAD value of 0.49 is in agreement with the presence
of a major rotamer.
Experimental Section
General: Most reactions were run under an inert atmosphere (ar-
gon) with strict exclusion of moisture in oven-dried vessels. Sol-
vents were distilled prior to use: THF and diethyl ether from Na/
Around the C3–C4 bond, the intermediate values found
3
3
3
for JH4,H3l, JH4,H3h, JMe,H3l, along with the large one for
benzophenone; acetonitrile, ethyl acetate and triethylamine from
CaH2; pyridine from KOH; methanol from Na followed by mole-
cules sieves (4 Å). DMF, tBuOH and 1,4-dioxane were purchased
as anhydrous grade. Trisyl azide was dried under vacuum prior to
use; all other reagents were commercial and were used without any
purification. TLC was carried out on pre-coated sheets (silica gel 60
F254, Merck). Spot visualisation was accomplished by illumination
with UV light and/or spraying with phosphomolybdic acid solu-
tion. Flash chromatography was performed using the indicated sol-
vents on Merck silica gel 60 (0.04–0.063 mm). NMR spectra were
recorded with a Bruker AC 200F, Bruker Avance 300 MHz or
Bruker Avance 500 MHz spectrometer. Chemical shifts are re-
ported in ppm relative to the signals due to the solvent. ESI+ spec-
tra were obtained using a Thermo Navigator or Thermo ESI-
FTMS APEXIII mass spectrometers. Optical rotations were re-
corded with a JASCO digital polarimeter. Melting points were
measured with a Bibby Stuart Scientific SMP3.
2JC4,H3h and the small one for JMe,H3h suggest the presence
3
of a more complex equilibrium with a slight predominance
for that represented in Table 1. This situation is also in
3
3
agreement with the inspection of the JH4,H3l and JH4,H3h
values at low temperature. These values change from inter-
3
mediate to larger, in the case of JH4,H3l, and to smaller in
3
the case of JH4,H3h. The coupling constants involving car-
3
bon C5 (3JC5,H3l and JC5,H3h) seem, however, to be larger
3
than expected from this equilibrium, as JC5,H3l should be
3
small and JC5,H3h medium. These values can also be ex-
plained when attention is paid to the values predicted by
DFT. The coupling of C5 with its proton in the anti posi-
tion clearly shows larger values (11–14 Hz, italicized in
Table 1) than the usual 7–10 Hz. This α-substitution effect
has already been reported by others[24] and depends on the
substituent’s orientation with respect to the coupled hydro-
gen. Again, a comparison of the DFT and experimental
values do not allow us to extract any conclusions about
the main conformer/s due to the existence of a complex
QM Calculations: Calculations were carried out using the
Gaussian03W software package (ver. C-2).[26] The structures and
energies of the species considered were optimised at the DFT levels
using the functionals B3LYP and mPW1PW91 and the 6-31G(d)
conformational equilibrium around the C3–C4 bond. A or 6-311G (d) basis set.
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Polychlorinated Leucine Derivatives
FULL PAPER
The coupling constants were calculated using a GIAO approach by
DFT methods employing the B3LYP and mPW1PW91 functionals.
For each of the approaches considered, the 6-31G(d,p) and 6-
311G(d,p) basis sets were utilized.
were dissolved in EtOAc (45 mL) and the black slurry was stirred at
room temp. under H2. After 18 h the mixture was filtered through a
pad of celite, and the solvent was evaporated to afford 10 (2.0 g,
1
quantitative) as a colourless oil. H NMR (200 MHz, CDCl3): δ =
7.69 (m, 4 H, TBDPS), 7.43–7.27 (m, 11 H, TBDPS and Ph), 5.43
(dd, JH,H = 8.7 and 3.5 Hz, 1 H, 4-H), 4.68 (t, JH,H = 8.7 Hz, 1 H,
5-H), 4.27 (dd, JH,H = 8.7 and 3.5 Hz, 1 H, 5-H), 3.51 (m, 2 H, 10-
H), 2.65 (m, 1 H, 9-H), 3.07–2.87 (m, 2 H, 7-H), 1.89–1.65 (m, 2
Synthesis of (R)-3-tert-Butyldiphenylsilyloxy-2-methylpropanal (9):
tert-Butyldiphenylsilyl chloride (17.5 mL, 67.3 mmol, 1.6 equiv.)
and imidazole (13.7 g, 4.8 equiv.) were added to a solution of (S)-
methyl 2-(hydroxymethyl)propanoate (5 g, 1 equiv.) in DMF
(42 mL) at 0 °C. The reaction was allowed to reach room temp.
and was stirred for 20 h. 5% HCl aqueous solution was then added
and the aqueous layer was extracted three times with diethyl ether.
The organic layers were washed with water and brine, and dried
with MgSO4. After solvent evaporation, the residue was purified
by chromatography on silica gel, with hexane/ethyl acetate
(9.5:0.5Ǟ9:1) as eluent, to provide (R)-methyl 2-(tert-butyldiphen-
ylsilyloxymethyl)propanoate (13.8 g, 92%) as a colourless oil. 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 7.71–7.66 (m, 4 H, TBDPS),
7.44–7.43 (m, 6 H, TBDPS), 3.83 (m, 2 H, CH2O), 3.71 (s, 3 H,
CH3O), 2.75 (m, 1 H, CHCO), 1.90 (d, 3JH,H = 6.8 Hz, 3 H, CH3),
1.07 (s, 3 H, TBDPS) ppm. 13C NMR (50 MHz, CDCl3): δ = 175.3
(C-1), 135.6, 133.5, 129.7, 127.7 (all TBDPS), 65.9 (C3), 51.5
(COCH3), 42.4 (C-2), 26.7 (TBDPS), 13.5 (C-4) ppm. MS (ESI+,
MeOH): m/z 379 [M+Na]+. HR-ESI-MS calcd. for C21H28O3N-
aSi: 379.16999; found 379.17046. C21H28O3Si (356.53): calcd. C
70.74, H 7.92; found C 70.50, H 8.63.
H), 1.54–1.43 (m, 1 H), 1.08 (s, 9 H, TBDPS), 0.94 (d, JH,H
=
6.6 Hz, 3 H, 11-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 170.2
(C-6), 152.9 (C-2), 153.8 (C-2), 139.3, 134.0, 133.9, 129.6, 129.3,
128.7, 127.7, 126.0 (TBDPS and Ph), 70.0 (C-5), 68.6 (C-10), 57.6
(C-4), 35.2 (C-9), 33.5 (C-7), 27.6 (C-8), 26.9 (TDBPS), 19.4
(TBDPS), 16.6 (C-11) ppm. [α]2D2 = +32.8 (c = 1.63, CHCl3). MS
(ESI+, MeOH): m/z 538 [M + Na]+. HR-ESI-MS calcd. for
C31H37NNaO4Si: 538.23841; found 538.23878. C31H37NO4Si
(515.72): calcd. C, 72.20, H 7.23, N 2.72; found C 72.20, H 8.24,
N 2.40.
Synthesis of (4S)-3-[(2S,4R)-2-Azido-5-tert-butyldiphenylsilyloxy-4-
methylpentanoyl]-4-phenyl-2-oxazolidinone (11): A solution of 10
(110 mg, 1 equiv.) in THF (1 mL) was added to a solution of
KHMDS (0.5  in toluene; 0.518 mL, 1.2 equiv.) in THF (1 mL)
at –80 °C. After 40 min a solution of trisyl azide (1.2 equiv.) in
THF (1.5 mL) prepared over molecular sieves was added followed,
4 min later, by acetic acid (61 µL). The mixture was then warmed
to room temp. and stirred overnight. Diethyl ether and brine were
added, and the organic layer was washed with a saturated aqueous
solution of NaHCO3 and brine. After drying over MgSO4, the sol-
vent was evaporated and the residue obtained purified by
chromatography on silica gel, using hexane/ethyl acetate
(9.5:0.5Ǟ8:2) as eluent, to give compound 11 as a colourless oil
DIBAL-H (1  in toluene; 18.7 mL, 1.6 equiv.) was slowly added,
over 20 min, to a solution of (R)-methyl 2-(tert-butyldiphenylsilyl-
oxymethyl)propanoate (4.1 g, 1 equiv.) in diethyl ether at –80 °C
and the mixture was stirred for 1.25 h. The reaction was quenched
by addition of water, and, once it had warmed to room temp., was
filtered through a pad of celite. An oil was obtained after solvent
evaporation, which was purified by chromatography on silica gel,
using hexane/ethyl acetate (9:1Ǟ8:2) as eluent, to provide 9 as a
1
(81.6 g, 68%). H NMR (200 MHz, CDCl3, 25 °C): δ = 7.71–7.68
(m, 4 H, TBDPS), 7.45–7.27 (m, 11 H, TBDPS and Ph), 5.40 (dd,
JH,H = 8.3 and 3.9 Hz, 1 H, 4-H), 5.06 (dd, JH,H = 4.8 and 8.8 Hz,
1 H, 7-H), 4.69 (t, JH,H = 8.7 Hz, 1 H, 5-H), 4.31 (dd, JH,H = 8.7
and 3.9 Hz, 1 H, 5-H), 3.67–3.49 (m, 2 H, 10-H), 2.12–1.88 (m, 2
1
colourless oil (3.4 g, 93%). H NMR (200 MHz, CDCl3, 25 °C): δ
= 9.81 (s, 1 H, CHO), 7.73–7.70 (m, 4 H, TBDPS), 7.46–7.43 (m,
6 H, TBDPS), 3.94 (m, 2 H, CH2O), 2.61 (m, 1 H, CH), 1.15 (d,
JH,H = 6.8 Hz, 3 H, CH3), 1.11 (s, 9 H, TBDPS) ppm.
H), 1.73–1.57 (m, 1 H), 1.09 (s, 9 H, TBDPS), 1.05 (d, JH,H
=
6.8 Hz, 3 H, 11-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 173.0
(C-6), 152.9 (C-2), 138.1, 135.6, 133.7, 129.6, 129.3, 128.9, 127.6,
125.8 (TBDPS and Ph), 70.3 (C-5), 68.1 (C-10), 58.7 (C-4), 57.8
(C-7), 34.2 (C-8), 33.3 (C-9), 26.8 (TDBPS), 19.4 (TBDPS), 17.3
(C-11) ppm. MS (ESI+, MeOH): m/z 579 [M+Na]+. HR-ESI-MS
calcd. for C31H36N4NaO4Si: m/z 579.23980; found 579.24039.
Synthesis of (4S)-3-[(4R)-5-tert-butyldiphenylsilyloxy-4-methyl-
pentanoyl]-4-phenyl-2-oxazolidinone (10): iPr2NEt (0.97 mL,
1 equiv.) was added to a solution of 9 (1.85 g, 1 equiv.), (4S)-N-
diethoxyphosphonoacetyl-4-phenyloxazolidin-2-one (2.2 g, 6.45
mmol, 1.1 equiv.) and LiCl (2.3 g, 9.6 equiv.) in CH3CN (35 mL)
at 0 °C. The solution was allowed to reach room temp. and stirred
for 24 h. The mixture was partitioned between water and diethyl
ether and the organic layer was washed with brine and dried with
Na2SO4. Removal of the solvent followed by chromatography on
silica gel, using hexane/ethyl acetate (8:2Ǟ1:2) as eluent, provided
(4S)-3-[(4R,2E)-5-tert-butyldiphenylsilyloxy-4-methyl-2-pentenoyl]-
4-phenyl-2-oxazolidinone (2.04 g, 70%) as a colourless oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.72–7.63 (m, 4 H, TBDPS),
7.43–7.27 (m, 12 H, TBDPS, Ph and 7-H), 7.12 (dd, JH,H = 6.8
and 15.1 Hz, 1 H, 8-H), 5.51 (dd, JH,H = 8.5 and 3.6 Hz, 1 H, 4-
H), 4.70 (t, JH,H = 6.8 Hz, 1 H, 5-H), 4.28 (dd, JH,H = 8.7 and
3.4 Hz, 1 H, 5-H), 3.62 (m, 2 H, 10-H), 2.65 (m, 1 H, 9-H), 1.11
Synthesis of (2S,4R)-2-tert-Butoxycarbonylamino-5-tert-butyldi-
phenylsilyloxy-4-methylpentanoic Acid (12): Boc2O (213.8 mg,
2 equiv.) and 10% Pd/C (71.1 mg) were added to a solution of 11
(272.8 mg, 1 equiv.) in EtOAc (4.8 mL) and the mixture was stirred
under H2 atmosphere at room temp. for 15 h. After filtration
through a pad of celite the solvent was evaporated and the obtained
oil was purified by chromatography on silica gel, using hexane/ethyl
acetate (6:1Ǟ4:1) as eluent, to give (4S)-3-[(2S,4R)-2-tert-butoxy-
carbonylamino-5-tert-butyldiphenylsilyloxy-4-methylpentanoyl]-4-
phenyl-2-oxazolidinone (306 mg, 99 %) as a colourless oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.68 (m, 4 H, TBDPS), 7.43–
7.33 (m, 11 H, TBDPS and Ph), 5.49 (br. m, 7-H), 5.38 (m, 1 H,
4-H), 5.32 (br. m, 1 H, NH), 4.69 (t, JH,H = 8.7 Hz, 1 H, 5-H), 4.25
(dd, JH,H = 8.7 and 3.9 Hz, 1 H, 5-H), 3.60 and 3.52 (m, 2 H, 10-
H), 1.97–1.86 (m, 2 H), 1.62–1.50 (m, 1 H), 1.36 (s, 9 H, Boc), 1.06
(s, 9 H, TBDPS), 0.95 (d, JH,H = 6.6 Hz, 3 H, 11-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 173.8 (C-6), 155.4 (C-2), 153.0, 138.4,
153.0, 138.4, 137.7, 129.7, 122.2, 127.7 (TBDPS and Ph), 79.8
(Boc), 70.4 (C-5), 68.0 (C-10), 58.2 (C-4), 51.7 (C-7), 35.2 (C-8),
33.0 (C-9), 28.3 (Boc), 27.0 (TDBPS), 19.4 (TBDPS), 17.4 (C-11)
3
(d, JH,H = 6.8 Hz, 3 H, 11-H), 1.06 (s, 9 H, TBDPS) ppm. 13C
NMR (75 MHz, CDCl3): δ = 173.0 (C-6), 153.8 (C-2), 139.2, 135.6,
133.5, 129.6, 129.1 128.6 127.6, 125.9 133.5, 129.7, 127.7 (TBDPS
and Ph), 119.9 (C-7), 69.9 (C-5), 67.5 (C-10), 57.7 (C-9), 39.6 (C-
4), 26.8 (TDBPS), 19.3 (TBDPS), 15.6 (C-11) ppm. MS (ESI+,
MeOH): m/z 536 [M+Na]+. HR-ESI-MS calcd. for C31H35NO4N-
aSi: 536.22275; found 536.22386.
(4S)-3-[(4R,2E)-5-tert-Butyldiphenylsilyloxy-4-methyl-2-penteno-
yl]-4-phenyl-2-oxazolidinone (2.0 g, 1 equiv.) and 10% Pd/C (0.9 g)
Eur. J. Org. Chem. 2006, 3645–3651
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3649

A. Ardá, C. Jiménez, J. Rodríguez
FULL PAPER
ppm. [α]2D2 = +40.2 (c = 0.24, CHCl3). MS (ESI+, MeOH): m/z 653
(ESI+, MeOH): m/z 664 [M + Na]+. HR-ESI-MS calcd. for
[M+Na]+. HR-ESI-MS calcd. for C36H46N2NaO6Si: 653.30173; C36H55NNaO7Si: 664.36400; found 664.36466.
found 653.30315.
Synthesis of (2S,4R)-tert-Butyl 2-Di-tert-butoxycarbonylamino-5-
formyl-4-methylpentanoate (14): Acetic acid (56 µL, 2.2 equiv.) and
TBAF (1  in THF; 0.37 mL, 4.1 equiv.) were added to a solution
of compound 13 (57 mg, 1 equiv.) in THF and the mixture was
stirred at room temp. for 3 d. The solution was then partitioned
between ethyl acetate and an aqueous solution of NH4Cl. The or-
ganic layer was washed with aqueous NH4Cl and dried with
MgSO4. Purification by chromatography on silica gel, using hex-
ane/ethyl acetate (8.5:1.5Ǟ7:3) as eluent, provided (2S,4R)-tert-bu-
tyl 2-di-tert-butoxycarbonylamino-5-hydroxy-4-methylpentanoate
(15 mg, quantitative) as a colourless oil. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 4.80 (m, 1 H, 2-H), 3.51 (m, 2 H, 5-H), 2.23
(m, 1 H), 1.82–1.57 (m, 2 H), 1.51 (s, 18 H, Boc), 1.44 (OtBu), 0.97
(d, JH,H = 6.5 Hz, 3 H, 6-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 170.4 (C-1), 152.5 (Boc), 82.9 (Boc), 81.6 (OtBu), 67.3 (C-5),
57.54 (C-2), 33.5 (C-4 and C-3), 28.0 [(CH3)3-Boc], 17.7 (C-6) ppm.
MS (ESI+, MeOH): m/z 426 [M +Na]+. HR-ESI-MS calcd. for
C20H37NNaO7: 426.24622; found 426.24636.
LiOH (1 ; 0.87 mL, 8 equiv.) and 30% aqueous H2O2 (0.34 mL,
2 equiv.) were added successively to a solution of (4S)-3-[(2S,4R)-
2-tert-butoxycarbonylamino-5-tert-butyldiphenylsilyloxy-4-methyl-
pentanoyl]-4-phenyl-2-oxazolidinone (274 mg, 1 equiv.) in THF/
H2O (5:1.5 mL) at 0 °C, and the reaction mixture was stirred for
24 h at room temp. The solution was acidified at 0 °C with a 1 
aqueous solution of KHSO4, and extracted three times with
EtOAc. The organic layer was dried with MgSO4 and the solvent
evaporated. Purification was carried out by crystallisation of the
product from hexane/diethyl ether (1:1) containing 1% acetic acid.
Evaporation of the solvent under vacuum afforded compound 12
(192 mg, 92%) as a colourless oil. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 10.1 (br. s, 1 H, OH), 7.68 (m, 4 H, TBDPS), 7.43–7.33
(m, 11 H, TBDPS and Ph), 5.34 (m, 1 H, NH), 4.36 (m, 1 H, 2-
H), 3.54 (m, 2 H, 5-H), 2.06 (m, 1 H), 1.88 (m, 1 H), 1.59 (m, 1
H), 1.44 (s, 9 H, Boc), 1.08 (s, 9 H, TBDPS), 0.96 (d, JH,H = 5.8 Hz,
3 H, 6-H) ppm. MS (ESI+, MeOH): m/z 508 [M+Na]+. HR-ESI-
MS calcd. for C27H39NNaO5Si: 508.24897; found 508.24965.
Dess–Martin periodinane (59 mg, 1.4 equiv.) was added to a solu-
tion of (2S,4R)-tert-butyl 2-di-tert-butoxycarbonylamino-5-hy-
droxy-4-methylpentanoate (40 mg, 1 equiv.) in CH2Cl2 (2 mL), and
the reaction mixture was stirred at room temp. for 30 min. The
mixture was then poured into a solution of Na2S2O3 in saturated
NaHCO3 (12 mg in 50 mL) and diluted with diethyl ether. The or-
ganic layer was dried with MgSO4 and, after solvent evaporation,
purification by chromatography on silica gel, using hexane/ethyl
acetate (8:2) as eluent. afforded 14 (34.5 mg, 87%) as a colourless
Synthesis of (2S,4R)-tert-Butyl 2-Di-tert-butoxycarbonylamino-5-
tert-butyldiphenylsilyloxy-4-methylpentanoate (13): Compound 12
(101.8 mg, 1 equiv.), Boc2O (91.5 mg, 2 equiv.) and DMAP (7.6 mg,
0.3 equiv.) were dissolved in tert-butanol (2 mL), and the mixture
was stirred for 30 min at room temp. The solvent was then removed
under vacuum, and the residue purified by chromatography on sil-
ica gel, using hexane/ethyl acetate (2%Ǟ5%Ǟ10%) as eluent, to
afford (2S,4R)-tert-butyl 2-di-tert-butoxycarbonylamino-5-tert-bu-
tyldiphenylsilyloxy-4-methylpentanoate as a colourless oil. 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 7.67–7.65 (m, 4 H, TBDPS),
7.42–7.38 (m, 6 H, TBDPSO), 5.13 (br. d, JH,H = 7.8 Hz, 1 H,
NH), 4.22 (m, 1 H, 2-H), 3.59 (dd, JH,H = 10.0 and 5.1 Hz, 1 H,
5-H), 3.47 (dd, JH,H = 10.0 and 5.6 Hz, 1 H, 5-H), 2.01 (m, 1 H),
1.82 (m, 1 H), 1.48 (s, 9 H, Boc), 1.44 (s, 9 H, OtBu), 1.07 (s, 9 H,
TBDPS), 0.98 (d, JH,H = 6.3 Hz, 3 H, 6-H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 172.3 (C-1), 155.3 (Boc), 135.6, 133.6, 129.5,
127.6, (TBDPS), 81.5 [Boc and (CH3)3], 79.4 (TBDPSO), 67.8 (C-
5), 52.6 (C-2), 36.3 (C-3), 32.5 (C-4), 28.3 [(CH3)3], 27.9 (Boc), 26.8
(TDBPS), 19.2 (TBDPSO), 17.1 (C-6) ppm. MS (ESI+, MeOH):
m/z 564 [M + Na]+. HR-ESI-MS calcd. for C31H47NNaO5Si:
564.31157; found 564.31225.
1
oil that rapidly crystallised. H NMR (200 MHz, CDCl3, 25 °C): δ
= 9.66 (s, 1 H, CHO), 4.82 (dd, JH,H = 4.8 and 9.1 Hz, 1 H, 2-H),
2.62–2.47 (m, 2 H), 1.86 (t, JH,H = 9.1 Hz, 1 H), 1.50 (s, 18 H,
Boc), 1.45 (OtBu), 1.14 (d, JH,H = 6.8 Hz, 3 H, 6-H) ppm.
Synthesis of (2S,4R)-tert-Butyl 2-Di-tert-butoxycarbonylamino-5,5-
dichloro-4-methylpentanoate (4): Hydrazine monohydrate
(0.035 mL, 10 equiv.) was slowly added to a solution of 14 (40 mg,
1 equiv.) in methanol and the reaction was stirred for 2 h at room
temp. Molecular sieves (4 Å) were added and were then filtered off;
they were washed with diethyl ether. After solvent evaporation, the
excess of hydrazine was removed under vacuum at 30 °C. A solu-
tion of the hydrazone in MeOH (0.25 mL) was added to a solution
of anhydrous CuCl2 (80 mg, 6 equiv.) and Et3N (41 µL, 3 equiv.) in
MeOH (0.5 mL) at 0 °C. The reaction was stirred at room temp.
for 1 h and was then quenched by addition of a 3.5% aqueous
solution of NH3 and extracted with EtOAc. The organic layer was
washed with brine, dried with MgSO4, and the solvent removed
under vacuum. Purification by chromatography on silica gel using
hexane/ethyl acetate (9.5:0.5Ǟ9:1Ǟ8:2) as eluent afforded a mix-
ture of compounds, which were separated by reverse-phase HPLC
on a Whatman column with MeOH/6% H2O at 1 mLmin–1. The
peak at 37.9 min corresponds to compound 4 (15.9 mg, 35 %),
which was obtained as a clear oil that crystallised. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 6.03 (d, JH,H = 2.7 Hz, 1 H, 5-H),
Et3N (0.05 mL, 1.2 equiv.) was added to a solution of (2S,4R)-tert-
butyl 2-tert-butoxycarbonylamino-5-tert-butyldiphenylsilyloxy-4-
methylpentanoate (179 mg, 1 equiv.) and DMAP (9 mg, 0.2 equiv.)
in 1,4-dioxane (3 mL) and the mixture was heated to 100 °C. A
solution of Boc2O (136 m, 2 equiv.) in 1,4-dioxane (1.5 mL) was
then added, and the reaction was stirred at that temperature for
12 h. After cooling, the solvent was evaporated under vacuum. Pu-
rification by chromatography on silica gel, using hexane/ethyl ace-
tate (9:1) as eluent, gave compound 13 (45.6 mg, 23%) along with
some recovered starting material (106 mg), which was re-used in
subsequent reactions. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 4.76 (dd, JH,H = 6.3 and 8.4 Hz, 1 H, 2-H), 2.38 (m, 1 H, 3-H),
7.67–7.65 (m, 4 H, TBDPSO), 7.42–7.38 (m, 6 H, TBDPSO), 4.77
(dd, JH,H = 8.7 and 5.3 Hz, 1 H, 2-H), 3.61 (dd, JH,H = 9.7 and
4.4 Hz, 1 H, 5-H), 3.50 (dd, JH,H = 10.1 and 5.8 Hz, 1 H, 5-H),
2.32 (m, 1 H), 1.88–1.56 (m, 2 H), 1.48 (s, 18 H, Boc), 1.45 (s, 9
2.28 (m, 1 H, 4-H), 1.83 (m, 1 H, 3-H), 1.52 (s, 18 H, Boc2), 1.46
(s, 9 H, COtBu), 1.19 (d, JH,H = 6.5 Hz, 3 H, 6-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 169.3 (C-1), 152.3 (Boc2), 83.3 (Boc2), 81.7
(OtBu), 77.9 (C-5), 56.5 (C-2), 40.9 (C-4), 33.4 (C-3), 28.1 (Boc2),
H, OtBu), 1.06 (s, 9 H, TBDPS), 1.00 (d, JH,H = 6.3 Hz, 3 H, 6- 28.1 (OtBu), 14.4 (C-6) ppm. MS (ESI+, MeOH): m/z 478/480
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 169.9 (C-1), 152.3 (Boc), [M+Na]+, 378/380 [M+Na – 100]+. [α]2D2 = –14.3 (c = 0.465,
135.6, 133.9, 129.4, 127.5 (TBDPSO), 82.5 [Boc and (CH3)3], 80.9 CH2Cl2). M.p. 60 °C (uncorrected). HR-ESI-MS calcd. for
(TBDPS), 67.8 (C-5), 57.4 (C-2), 33.1 (C-4), 32.9 (C-3), 27.9 [(CH3)3 C2 0 H3 53 5Cl2 NNaO6/C2 0H35 35 Cl37 ClNNaO6: 478.17336/
and Boc], 26.8 (TDBPS), 19.3 (TBDPS), 17.6 (C6) ppm. MS
479.175900; found 478.17403/479.17742.
3650
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3645–3651

Polychlorinated Leucine Derivatives
FULL PAPER
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The HPLC peak at 36.2 min was identified as compound 15
1
(2.6 mg, 7%). H NMR (500 MHz, CDCl3): δ = 4.97 (dd, JH,H
=
10.0 and 5.5 Hz, 1 H, 2-H), 4.80 (s, 1 H, 5-H), 4.72 (s, 1 H, 5-H),
2.70 (m, 2 H, 3-H), 1.76 (s, 3 H, 6-H), 1.50 (s, 18 H, Boc), 1.46
[(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 169.8 (C-1), 152.4
(Boc), 141.8 (C-4), 113.8 (C-5), 82.6 (Boc), 81.7 [(CH3)3], 56.9 (C-
2), 37.4 (C-3), 28.0 (Boc), 27.9 [(CH3)3], 21.9 (C-6) ppm. MS (ESI+,
MeOH): m/z 408 [M+Na]+.
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(16): TFA (0.1 mL) was added to a solution of 4 (3 mg) in CH2Cl2
(1 mL) and the reaction was stirred for 24 h. The solvent was then
removed under vacuum and the unreacted TFA was removed azeo-
tropically by evaporating with diethyl ether. Purification on a silica
gel microcolumn eluting with isobutyl alcohol/acetic acid/water
(8:2:2) afforded compound 16 (1.1 mg, 50%) as its trifluoroacetate
salt. 1H NMR (200 MHz, D2O, 25 °C): δ = 5.92 (d, JH,H = 2.8 Hz,
1 H, 5-H), 3.62 (m, 1 H, 2-H), 2.28 (m, 1 H), 2.05 (m, 1 H), 1.61
(m, 1 H), 1.02 (d, JH,H = 6.5 Hz, 3 H, 6-H) ppm. 13C NMR
(50 MHz, D2O): δ = 174.3 (C-1), 163.0 (q, COCF3), 116.2 (q, CF3),
77.9 (C-5), 52.8 (C-2), 39.9 (C-4), 33.2 (C-3), 14.6 (C-6) ppm.
[α]2D2 = –11.6 (c = 0.13, H2O).
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This work was financially supported by CICYT (grants SAF2002-
00733 and CQT2005-00793) and the Xunta de Galicia (PGID-
IT03PXIC10302PN). A. A. also thanks the Xunta de Galicia for a
fellowship. We are grateful to the Centro de Supercomputación de
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Received: February 23, 2006
Published Online: June 7, 2006
Eur. J. Org. Chem. 2006, 3645–3651
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3651