Total synthesis of (-)-dysithiazolamide

Article abstract of DOI:10.1021/ol800551g

(Chemical Equation Presented) The tetrachlorinated natural product (-)-dysithiazolamide was synthesized from L-glutamic acid in a convergent way, confirming the previously proposed (2S,4S,6S,8S) absolute stereochemistry.

Full text of DOI:10.1021/ol800551g

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2175-2178
Total Synthesis of (-)-Dysithiazolamide
Ana Ardá, Raquel G. Soengas, M. Isabel Nieto, Carlos Jiménez,* and
Jaime Rodríguez*
Departamento de Qu´ımica Fundamental, Facultade de Ciencias, Campus da Zapateira,
UniVersidade da Corun˜a, 15071 A Corun˜a, Spain
carlosjg@udc.es; jaimer@udc.es
Received March 10, 2008
ABSTRACT
The tetrachlorinated natural product (-)-dysithiazolamide was synthesized from L-glutamic acid in a convergent way, confirming the previously
proposed (2S,4S,6S,8S) absolute stereochemistry.
More than 4500 natural products of both marine and
terrestrial origin have in common some biohalogenation
processes.1 Very recently, Walsh and co-workers described
a novel class of halogenating enzymes capable of carrying
out halogenations at aliphatic carbon centers of peptidyl
carrier protein-linked amino acid residues such L-leucines.2
This mechanism of chlorination was first proposed by
Gerwick et al. in the biosynthetic studies of barbamide (1),3
a mixed polypeptide-polyketide natural product that con-
tains a trichloromethyl group and whose biosynthetic gene
cluster was isolated and characterized.4 They have shown
that the chlorination of the pro-R methyl group of leucine
gives a dichloroleucine intermediate, which in turn is
trichlorinated at the C5 methyl group of the amino acid
attached to a peptidyl carrier.2,5,6a
Recently, we reported the structure of a new member of
this class of compounds,6 the tetrachlorinated dipeptide
dysithiazolamide (2), the relative configuration of which was
deduced through configurational analysis using proton-proton
and proton-carbon coupling constants.7 Furthermore, the
absolute configuration was proposed by comparison with
previous compounds isolated from Dysidea species. In order
to confirm the absolute configurations of the four chiral
centers present in 2, in this paper we describe the total
synthesis of (-)-(2S,4S,6S,8S)-dysithiazolamide.
(1) (a) Gribble, G. W. J. Chem. Educ. 2004, 81, 1441–1449. (b) Gribble,
G. W. Am. Sci. 2004, 92, 342–349. (c) Gribble, G. W. In Natural Production
of Organohalogen Compounds; Gribble, G. W., Ed.; Springer-Verlag, New
York, 2003. (d) Neidleman, S. L.; Geigert, J. Biohalogenation: Principles,
Basic Roles and Application; Halsted: New York, 1986.
(2) Galonic, D. P.; Vaillancourt, F. H.; Walsh, C. T. J. Am. Chem. Soc.
2006, 128, 3900–3901.
(3) (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) Sitachitta,
N.; Ma´rquez, B. L.; Williamson, R. T.; Rossi, J.; Roberts, M. A.; Gerwick,
W. H.; Nguyen, V.-A.; Willis, C. L Tetrahedron 2000, 55, 9103–9113.
(4) Chang, Z.; Flatt, P.; Gerwick, W. H.; Nguyen, V.-A.; Willis, C. L.;
Sherman, D. H. Gene 2002, 296, 235–247.
The preparation of this kind of compounds, which contain
a gem-dichloromethyl group, has hardly been described,
probably due to the difficulty in the selective generation of
this functionality. Some examples include the synthesis of
10.1021/ol800551g CCC: $40.75
Published on Web 05/07/2008
2008 American Chemical Society

Figure 1.
1H NMR (500 MHz, CDCl3) spectra of synthetic (top) and natural (bottom) dysithiazolamide.
dysamide B8 and both anti- and syn-5,5-dichloroleucines
reported by us,9 in which the dichloromethyl group was
introduced by treatment of an aldehyde with hydrazine and
CuCl2.10
Willis and co-workers,6 different methods were tried (SOCl2,
PCl5 and Ph3P/CCl4), but in all cases products were not
obtained. We recently reported a variation of the Takeda
conditions in the synthesis of gem-dihalides, and these
involve treatment of the aldehyde with hydrazine monohy-
drate in anhydrous MeOH followed by reaction with cop-
per(II) chloride.7 In this way, we converted aldehyde 6 into
the target gem-dichloride 7 in moderate yield.
Using this methodology, our overall retrosynthetic plan
(Scheme 1) was supported by a convergent synthesis from
fragments A and B, which can be obtained from a common
precursor. To achieve this goal, compound 5 was found to
be a good choice. It was easily accessible from L-glutamic
acid in five steps (Scheme 2), and it allowed us the
manipulation of all the functional groups in an orthogonal
way. Having obtained compound 3 using a 1-3 asymmetric
induction reported by Hanessian and co-workers,11 a steri-
cally bulky reductant was needed for the selective reduction
of the γ-ester. At this stage, a second Boc protecting group
was introduced on the nitrogen to avoid cyclization due to
nucleophilic attack by nitrogen on the aldehyde.12 Two
different precursors to fragment A were easily accessible
from compound 5. The dichloromethyl was introduced after
oxidation of the hydroxyl group to give the expected
aldehyde (Scheme 3). Several methods are known for the
conversion of aldehydes to dichlorides. In the same way as
Scheme 1
(5) Murphy, C. Nat. Prod. Rep. 2006, 23, 147–152.
(6) (a) Flatt, P. M.; O’Connell, S. J.; McPhail, K. L.; Zeller, G.; Willis,
C. L.; Sherman, D. H.; Gerwick, W. H. J. Nat. Prod. 2006, 69, 938–944.
(b) Hartung, J. Angew. Chem., Int. Ed. 1999, 38, 1209–1211.
(7) Arda´, A.; Rodriguez, J.; Nieto, R.; Bassarello, C.; Gomez-Paloma,
L.; Bifulco, G.; Jime´nez, C. Tetrahedron 2005, 61, 10093–10098.
(8) Durow, A. C.; Long, G. C.; O’Connell, S. J.; Willis, C. L Org. Lett.
2006, 8, 5401–5404.
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Org. Lett., Vol. 10, No. 11, 2008

the nitrogen; the formation of the thiazole ring from the
carbonyl function; and the synthesis of the dichloromethyl
group from the aldehyde at position 5. Therefore, the alcohol
group in 5 was protected with TBDPS and in order to reduce
the acidity in the R-position, which could lead to side
methylation, the corresponding methyl ester was hydrolyzed
with LiOH in THF. Treatment of the acid with NaH and
MeI in THF yielded compound 13.
Scheme 2
The synthesis of the thiazole ring was carried out using
the Hantzsch methodology through reaction of chloroacetal-
dehyde (prepared from the corrresponding dimethyl acetal
under reflux with 1.5 M H2SO4)14 and the corresponding
thiamide (Scheme 4). Therefore, carboxylic acid 13 was
In order to obtain two possible fragments to test in the
final coupling with fragment B, we carried out the syntheses
of the corresponding acids 9 and 11, with and without the
N-propionyl group, respectively. Compound 9 was easily
obtained from 7 by selective deprotection of one Boc group13
and basic hydrolysis in Ba(OH)2; meanwhile, total depro-
tection of the amine group in acidic media, introduction of
the N-propionyl group, and basic hydrolysis gave 11 in very
good yield.
Scheme 4
Scheme 3
transformed into amide 14 with Boc2O in the presence of
ammonium bicarbonate and pyridine.15 Treatment of 14 with
Lawesson′s reagent gave the expected thiamide, which was
then treated with chloroacetaldehyde in the presence of
potassium bicarbonate in DME. This led to the isolation of
the thiazoline while avoiding the imine-enamine tautomer-
ization that would lead to epimerization at the chiral center
adjacent to the thiazole ring. Dehydration with TFAA in
DME and pyridine16 allowed us to obtain the thiazolic
compound 15. After removal of the silyl protecting group
we turned our attention to the oxidation of the alcohol with
Dess-Martin periodinane, which gave the key aldehyde 16.
This compound was then converted to the gem-dichloride
17 in good yield.
For the synthesis of fragment B we needed to achieve three
With compounds 9, 11, and 17 in hand, we considered
the final coupling to obtain dysithiazolamide. First, we
investigated the most obvious coupling between 11 and the
analogous amine derived from 17. Acid-mediated removal
of the Boc group from 17 followed by addition of 1.0 equiv
of 11 in the presence of the coupling agent bromo-tris-
key transformations: the introduction of the methyl group at
(9) (a) Arda´, A.; Jime´nez, C.; Rodr´ıguez, J. Tetrahedron Lett. 2004,
45, 3241–3243. (b) Arda´, A.; Jime´nez, C.; Rodr´ıguez, J. Eur. J. Org. Chem.
2006, 3645–3651.
(10) Takeda, T.; Sasaki, R.; Yamamuchi, S.; Fujiwara, T. Tetrahedron
1997, 53, 557–566.
(11) (a) Padro´n, J. M.; Kokotos, G.; Mart´ın, T.; Markidis, T.; Gibbons,
W.; Mart´ın, V. S. Tetrahedron: Asymmetry 1998, 9, 3381–3394. (b)
Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39, 5887–5890.
(12) Gerwick, W. H.; Lesli, P.; Long, G. C.; Marquez, B. L.; Willis,
C. L. Tetrahedron Lett. 2003, 44, 285–288.
(14) McCann, W. P.; Hall, L. M.; Nonidez, W. K. Anal. Chem. 1983,
55, 1454–1455.
(15) Pozdnev, V. F. Tetrahedron Lett. 1995, 36, 7115–7118.
(16) Bredenkamp, M. W.; Holzapfel, C. W.; Snyman, R. M.; Van Zyl,
W. Synth. Commun. 1992, 22, 3029–3039.
(13) Herna´ndez, J. N.; Ram´ırez, M. A.; Mart´ın, V. A. J. Org. Lett. 2003,
68, 743–746.
Org. Lett., Vol. 10, No. 11, 2008
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lamide (21), all of which were identified by HR-ESIMS and
2D NMR spectroscopy.
Scheme 5
The synthetic product 2 was spectroscopically indistin-
guishable from the natural material, showing a very similar
optical rotation.17 The dehydrochlorination products 19-21
can be explained as side products formed under the coupling
conditions used for the union of 17 and 9. Although this
type of transformation has rarely been described in the
literature,18 it is a process that we also observed in our
synthesis of (2S,4R)-5,5-dichloroleucine.9b
In conclusion, a practical and reasonably efficient synthesis
of dysithiazolamide has been developed, confirming the
initially proposed (2S,4S,6S,8S) absolute stereochemistry. It
is also important to note the robustness and the extremely
useful spectroscopic tool provided by the J-based configu-
rational analysis, which almost 10 years after its disclosure
to the scientific community is a widely used methodology
for the assignment of relative configurations of polysubsti-
tuted acyclic carbon chains, including nitrogen-containing
compounds.
Acknowledgment. This work was financially supported
by the Ministerio de Educacio´n y Ciencia, project CQT2005-
00793, and the Xunta de Galicia (PGIDI06PXIC103118PN
and PGIDIT05RMA10302PR). We also thank CESGA. R.G.S.
and M.I.N. acknowledge the Xunta de Galicia for the Parga
Pondal Program.
pyrrolidinophosphoniumhexafluorophosphate, PyBroP, in
DIEA did not give coupled product. However, under the
same conditions the reaction between the amine derived from
17 and 9 gave the expected coupled compound 18, which
was used in the next synthetic step without further purifica-
tion. Final substitution of the Boc nitrogen-protecting group
for the propionyl moiety gave the natural compound 2, along
with four unexpected analogs, 1,1-didehydrochlorodysithiazo-
lamide (19), 1,9,9-tridehydrochlorodysithiazolamide (20 Z/E)
in a 3:1 ratio and 1,1,9,9-tetradehydrochlorodysithiazo-
Supporting Information Available: Synthesis and spec-
troscopic data for all intermediates and copies of 1H and 13
C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL800551G
(17) Natural [R]25D -35 (c 0.08, CH2Cl2); 2 [R]25D -42 (c 0.28 CH2Cl2).
(18) (a) Riemschneider, R.; Ahrle, I.; Cohnen, W.; Heilman, E. Chem.
Ber. 1959, 92, 900–909. (b) Ashby, E. C.; Mehdizadeh, A.; Deshpande,
A. K. J. Org. Chem. 1996, 61, 1322–1330.
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