A study of polychlorinated leucine derivatives: Synthesis of (2S,4S)-5,5-dichloroleucine

Article abstract of DOI:10.1016/j.tetlet.2004.02.118

The first total synthesis of (2S,4S)-5,5-dichloroleucine has been achieved in 11 steps from L-pyroglutamic acid. A key step is the dichlorination process on the hydrazone of aldehyde 13 with CuCl₂ in triethylamine.

Full text of DOI:10.1016/j.tetlet.2004.02.118

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3241–3243
A study of polychlorinated leucine derivatives: synthesis of
(2S,4S)-5,5-dichloroleucine
*
ꢀ
Ana Arda, Carlos Jimenez and Jaime Rodrıguez
ꢀ
ꢀ
Departamento de Quꢀımica Fundamental, Facultade de Ciencias, Campus da Zapateira, Universidade de A Coru~na,
15071 A Coru~na, Spain
Received 9 February 2004; revised 25 February 2004; accepted 25 February 2004
Abstract—The first total synthesis of (2S,4S)-5,5-dichloroleucine has been achieved in 11 steps from
is the dichlorination process on the hydrazone of aldehyde 13 with CuCl2 in triethylamine.
Ó 2004 Elsevier Ltd. All rights reserved.
L-pyroglutamic acid. A key step
Dysidea herbacea is an Indopacific sponge that is able to
produce several secondary metabolites belonging to a
wide variety of structural types. These include poly-
brominated diphenyl ethers, nonhalogenated terpenes
and a series of unique polychlorinated metabolites
derived from amino acid precursors, particularly leu-
cine.1 One example of a compound belonging to this
latter category is the hexachlorinated compound
dysidenin (1),1a–c which is biosynthesised from an
assemblage between the sponge and its associated sym-
biont––the filamentous cyanobacteria Oscillatoria
spongeliae2––an involvement also found in the isolation
of chlorinated diketopiperazine derivatives.1h;3
Several studies have been aimed at determining the role
of certain amino acids bearing aliphatic side chains in
the inter and intramolecular hydrophobic interactions
and the final tertiary structure of a polypeptide. It is
known that leucine residues are important in such
arrangements. For this reason it is very important to
have synthetic routes to access different leucine-derived
amino acids (labelled or unlabelled) in order to complete
these studies.4 In addition, it is believed that the
majority of the halogen atoms found in marine natural
products are incorporated through Xþ species, which
can be related to haloperoxidases already isolated from
several marine organisms.5 In order to understand all of
the halogen-incorporation processes, including the
addition of chlorine to prochiral methyl groups, samples
of diverse leucine derivatives labelled in different posi-
tions are required and a total synthesis of this type of
compound also needs to be taken into account. Fur-
thermore, there are several secondary metabolites of
sponge and bacterial origin that possess halogenated
moieties for which the electronic nature of the haloge-
nating source remains unknown. Well known examples
include barbamide (2)6 and dechlorobarbamide (3),7
both of which were isolated from the cyanobacteria
Lyngbya majuscula. These metabolites have been bio-
synthetically studied through their production in
laboratory cultures of L. majuscula and their precursors
determined using stable-isotope biochlorination
labelling methods via chloroleucine analogues.7;8 Amino
acids such as 4 and 5 have been very recently synthesised
in a stereospecific way. Nevertheless, a synthesis has
not been reported for dichloro derivatives such
as (2S,4S)-5,5-dichloroleucine (6),9 an amino acid that
has only been isolated in nature from the hydrolysed
CCl3
O
N
Cl3C
NH
O
S
1
N
Me
N
OMe R
H
H
CH3
O
N
S
R= CCl3, 2
R=CHCl2, 3
Keywords: Dysidea; Polychlorinated amino acids.
* Corresponding author. Tel.: +34-981-167000; fax: +34-981-167065;
e-mail: jaimer@udc.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.118

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A. Ardꢀa et al. / Tetrahedron Letters 45 (2004) 3241–3243
portion of the HV-Toxin M,
a
host-specific
13CH3 NH2
CO2H
Cl
CH3 NH2
CO2H
compound of the phytopathogenic fungus Helmintho-
sporium victoriae,10a and also from an analogous
phytotoxin, victorin, produced by the fungus Cochio-
bolus victoriae.10b
Cl
Cl
4
5
CH3 NH2
CO2H
Cl
The route for the synthesis of 6 is shown in Scheme 1.
Treatment of commercially available L-pyroglutamic
acid with tert-butyl acetate in perchloric acid gave the
ester, which was converted to the N-Boc derivative 7.
Our synthetic strategy was based on the studies of
Cl
6
ꢀ
Having obtained the aldehyde, different approaches to
the final gem-dichloroleucine analogue were examined.
Several attempts involved treatment of 13 with Ph3P/
CCl4 with different concentrations, temperatures and
solvents––conditions also investigated by Willis and
co-workers.9 In all cases epimerisation at C-4 and a lack
of reaction was observed by proton NMR spectroscopy.
The final synthesis of 14 was achieved in moderate yield
using a modification of Takedaꢀs transformation of
ketones and aldehydes to gem-dihalides via the hydra-
zone.13 The preparation required stirring of the aldehyde
with excess hydrazine monohydrate in anhydrous
MeOH. Molecular sieves were added to the resulting
hydrazone after the work-upand this compound was
further converted in the desired dichloromethyl deriva-
tive 14 with copper(II) chloride and Et3N as base.
Epimerisation at C-4 was not observed and 14 was
detected as the sole product after chromatographic
separation.14 Final hydrolysis in a standard acid
medium gave the amino acid 6.15
Najera and co-workers for the synthesis of 4-methylene-
L
-glutamic acid,11 and it included the conversion of the
diprotected pyroglutamate 7 into tert-butyl N-Boc-4-
methylenepyroglutamate (9) via the adduct 8. The lith-
ium lactam enolate of 7 was prepared by deprotonation
with lithium hexamethyldisilazane and then reacted with
commercially available Eschenmoserꢀs salt to give 8,
which by subsequent in situ quaternisation with methyl
iodide followed by elimination in basic conditions pro-
vided 9 in moderate yield. When olefin 9 was catalyti-
cally hydrogenated in EtOAc with Pd/C, tert-butyl
(2S,4S)-N-(tert-butoxycarbonyl)-4-methylpyroglutamate
(10) was obtained in a stereoselective manner in 95%
yield. The structure of 10 was confirmed by X-ray
analysis. At this point the stereocentre at C-4 was
maintained by ring-opening hydrolysis of 10 with LiOH
in THF at 0 °C; evidence of epimerisation was not found
by NMR spectroscopy. The resulting acid was converted
into the methyl ester 11 by treatment with methyl
chloroformate in the presence of DMAP and triethyl-
amine. After protecting the amide at C-2 as the di-tert-
butoxycarbonyl derivative 12 using standard proce-
dures, different attempts to directly convert the ester to
the aldehyde 1312 gave negative results in that the
aldehyde, starting material and alcohol were always
present in the reaction mixture. This problem was cir-
cumvented by using an excess of DIBALH and the
resulting alcohol was further oxidized with the Dess–
Martin reagent.
A different approach was also used to prepare 6 and this
involved the hydrolysis of 7 and transformation into its
methyl ester derivative 15. 1,3-Diastereoselective
induction of 15, proposed by Hanessian and
Margarita16 gave the anti methylation product at C-4
(11) in good yield. This product was then converted to 6
in a similar way to that shown in Scheme 2. It is
important to notice that this second route up compound
Scheme 1. Reagents and conditions: (i) (a) t-BuOAc, HClO4; (b) Boc2O, Et3N, DMAP, DCM 46% (ii) LiHMDS, Eschenmoser salt, THF )78 °C,
74% (iii) (a) MeI, MeOH; (b) NaHCO3, H2O (Ref. 12) (iv) H2, Pd/C 10%, EtOAc, 95% (v) (a) LiOH, THF, 0 °C; (b) ClCO2Me, DMAP; Et3N, DCM,
ꢁ
0 °C 70% (vi) Boc2O, DMAP; CH3CN; 71% (vii) (a) DIBALH, Et2O )78 °C; (b) Dess–Martin, DCM, 66% (viii) (a) NH2NH2ÆH2O, 2 A molecular
sieves; (b) CuCl2, Et3N; MeOH, rt 40% (ix) HCl 4 N, reflux, 75%.

A. Ardꢀa et al. / Tetrahedron Letters 45 (2004) 3241–3243
3243
1133–1138; (m) Stapleton, B. L.; Cameron, G. M.;
Garson, M. J. Tetrahedron 2001, 57, 4603–4607; (n)
NHBoc
CO2t-Bu
ii
i
MeO
7
ꢀ
Jimenez, J. I.; Scheuer, P. J. J. Nat. Prod. 2001, 64, 200–
O
203; (o) Dumrongchai, N.; Ponglimantont, C.; Stapleton,
B. L.; Garson, M. J. 2001, ACGC Chem. Commun. 3, 17–
22.
15
CH3 NHBoc
CO2t-Bu
iii
2. Hinde, R.; Pironet, F.; Borowitza, M. A. Mar. Biol. 1994,
119, 99–104.
6
MeO
O
3. Fu, X.; Zeng, L.-M.; Su, J.-Y.; Pais, M. J. Nat. Prod. 1993,
56, 637–642.
11
4. Examples of synthesis of labelled leucine-derived compo-
uds: (a) August, R. A.; Khan, J. A.; Moody, C. M.;
Young, D. W. Tetrahedron Lett. 1992, 33, 4617–4620; (b)
Durand, X.; Hudhomme, P.; Khan, J. A.; Young, D. W.
Tetrahedron Lett. 1995, 36, 1351–1354; (c) Durand, X.;
Hudhomme, P.; Khan, J. A.; Young, D. W. J. Chem. Soc.,
Perkin. Trans. 1 1996, 1131–1139.
5. Butler, A. Curr. Opin. Chem. Biol. 1998, 2, 279–285.
6. Orjala, J. O.; Gerwick, W. H. J. Nat. Prod. 1996, 59, 427–
430.
Scheme 2. Reagents and conditions: (i) (a) LiOH, THF, 0 °C; (b)
ClCO2Me, DMAP, Et3N, DCM, 0 °C 50% (ii) HMDS, n-BuLi, THF
)78 °C, then MeI, )78 °C, 68% (iii) Steps (vi–ix) in Scheme 1.
12 was used before by Gerwick et al. in the synthesis
of 5.9
The amino acid (2S,4S)-5,5-dichloroleucine (6) is pres-
ent in several polychlorinated compounds isolated from
sponges belonging to the genus Dysidea. These com-
pounds include the monodechloro-demethylisodyde-
ꢀ
7. Sitachitta, N.; Marquez, B. L.; Williamson, R. T.; Rossi,
J.; Roberts, M. A.; Gerwick, W. H.; Nguyen, V.-A.; Willis,
C. L. Tetrahedron 2000, 56, 9103–9113.
8. (a) Sitachitta, N.; Rossi, J.; Roberts, M. A.; Gerwick, W.
H.; Fletcher, M. D.; Willis, C. L. J. Am. Chem. Soc. 1998,
120, 7131–7132; (b) Williamson, R. T.; Sitachitta, N.;
Gerwick, W. H. Tetrahedron Lett. 1999, 40, 5175–5178.
sidenins,1d
dysideathiazoles and
its
N-methyl
derivatives,1f;h;m or the dysideaprolines and barbaleuc-
amides.10 The synthesis of 6 described here provides the
opportunity to approach a total synthesis of these
compounds and incorporate another metabolite in the
feeding experiments aimed at discovering the biosyn-
thesis of barbamide and dechlorobarbamide.
ꢀ
9. Gerwick, W. H.; Leslie, P.; Long, G. C.; Marquez, B. L.;
Willis, C. L. Tetrahedron Lett. 2003, 44, 285–288.
10. (a) Konoi, Y.; Kinoshita, T.; Takeuchi, S.; Daly, J. M.
Agric. Biol. Chem. 1989, 53, 505–511; (b) Gloer, J. B.;
Meinwald, J.; Walton, J. D.; Earle, E. D. Experientia
1985, 41, 1370–1374.
ꢀ
ꢀ
11. Ezquerra, J.; Pedregal, C.; Mico, I.; Najera, C. Tetrahe-
Acknowledgements
dron: Asymmetry 1994, 5, 921–926.
1
12. Compound 13: H NMR (200 MHz, CDCl3, dH ppm, m):
This work was financially supported by a Grant from
CICYT (SAF2002-00733) and Xunta de Galicia (PGI-
DIT03PXIC10302PN). A.A. also thanks Xunta de
Galicia for a fellowship.
9.60 (1H, d, J ¼ 1:0 Hz, H5); 4.82 (1H, dd, J ¼ 4:9 and
9.3 Hz, H2); 2.46–2.32 (2H, m); 2.01 (1H, m); 1.50 (Boc2,
18H, s); 1.45 (COtBu, 9H, s); 1.13 (3H, d, J ¼ 6:7 Hz, H2).
13C NMR (50 MHz, CDCl3, dc ppm): 203.7 (C5); 169.5
(C1); 152.3 (N(COt2Bu)2); 83.1 (Boc); 81.6 (COt2Bu); 56.7
(C2); 43.8 (C4); 30.1 (CH2); 27.9 (COt2Bu); 27.8 (CO2t Bu);
13.1 (C6).
References and notes
13. Takeda, T.; Sasaki, R.; Yamauchi, S.; Fujiwara, T.
Tetrahedron 1997, 53, 557–566.
1. Examples of polychlorinated peptides (a) Kazlauskas, R.;
Lidgard, R. O.; Wells, R. J. Tetrahedron Lett. 1977, 3183–
3186; (b) Charles, C.; Braekman, J. C.; Daloze, D.;
Tursch, B. Tetrahedron 1980, 36, 2133–2135; (c) Bisku-
piak, J. E.; Ireland, C. M. Tetrahedron Lett. 1984, 28,
2935–2936; (d) Erickson, K.; Wells, R. J. Aust. J. Chem.
1982, 35, 31–38; (e) Lee, G. E.; Molinski, T. Tetrahedron
Lett. 1992, 50, 7671–7674; (f) Unson, M. D.; Rose, C. B.;
Faulkner, D. J.; Brinen, L. S.; Rios-Steiner, J.; Clardy, J.
J. Org. Chem. 1993, 58, 6336–6343; (g) Clark, W. D.;
Crews, P. Tetrahedron Lett. 1995, 36, 1185–1188; (h)
Dudmdei, E. J.; Simpson, J. S.; Garson, M. J.; Byriel, K.
A.; Kennard, C. H. L. Aust. J. Chem. 1997, 50, 139–144;
(i) Fu, X.; Ferreira, M. L. G.; Schmitz, F. J.; Kelly-Borges,
M. J. Nat. Prod. 1998, 61, 1226–1231; (j) MacMillan, J. B.;
Molinski, T. J. Nat. Prod. 2000, 53, 155–157; (k)
MacMillan, J. B.; Trousdale, E. K.; Molinski, T. Org.
Lett. 2000, 2, 2721–2723; (l) Harrigan, G. G.; Goetz, G.
H.; Luesch, H.; Yang, S.; Likos, J. J. Nat. Prod. 2001, 64,
14. Compound 14:1H NMR (200 MHz, CDCl3, dH ppm, m):
5.78 (1H, d, J ¼ 2:8 Hz, H5); 4.79 (1H, dd, J ¼ 4:4 and
10.6 Hz,); 2.29 (1H, m); 2.18–1.95 (2H, m); 1.51 (Boc2,
18H, s); 1.45 (COtBu, 9H, s); 1.19 (3H, d, J ¼ 6:3 Hz, H6).
13C NMR (50 MHz, CDCl3, dc ppm): 169.4 (C1); 152.3
(Boc2); 83.1(Boc2); 81.4 (OtBu); 78.8 (C5); 56.6 (C2); 41.2
(C4); 31.4 (C3); 28.0 (Boc2); 27.9 (OtBu); 14.9 (C6).
LRFABMS (thioglycerol) m=z (%): 456 (18); 458 (11). ½aꢀ
D
)25.5 (c 0.95, CH2Cl2).
15. Compound 6: 1H NMR (200 MHz, D2O, dH ppm, m): 5.95
(1H, d, J ¼ 3:1 Hz, H5); 3.61 (1H, dd, J ¼ 5:1 and
J ¼ 9:3 Hz, H2); 2.21 (1H, m, H4); 1.95–1.83 (2H, m,
H23); 1.04 (3H, d, J ¼ 6:7 Hz, H6). 13C NMR (50 MHz,
CDCl3, dc ppm): 175.1 (C1); 79.2 (C5); 53.8 (C2); 41.1
(C4); 34.6 (C3); 15.5 (C6). ESI MS (positive ion) m=z (%):
200 (100); 202 (64). ½aꢀ )23.0 (c 0.16, HCl 1 N).
D
16. Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39,
5887–5890.