Rapid assembly of the polyhydroxylated β-amino acid constituents of microsclerodermins C, D, and e

Article abstract of DOI:10.1021/ol702962z

A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated β-amino acid residues present in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.

Full text of DOI:10.1021/ol702962z

ORGANIC
LETTERS
2008
Vol. 10, No. 5
841-844
Rapid Assembly of the Polyhydroxylated
-Amino Acid Constituents of
Microsclerodermins C, D, and E
â
Thomas Hjelmgaard,† Sophie Faure,† Pascale Lemoine,‡ Bernard Viossat,‡ and
David J. Aitken*,§
Laboratoire de Synthe`se et Etude de Syste`mes d’Inte´reˆt Biologique, SEESIB
(UMR 6504 - CNRS), UniVersite´ Blaise Pascal - Clermont-Ferrand 2, 24 aVenue des
Landais, 63177 Aubie`re cedex, France, Laboratoire de Cristallographie et RMN
Biologiques (UMR 8015 - CNRS), UniVersite´ Rene´ Descartes - Paris 5, 4 aVenue de
l’ObserVatoire, 75270 Paris cedex 06, France, and Laboratoire de Synthe`se Organique
et Me´thodologie, ICMMO (UMR 8182 - CNRS), UniVersite´ Paris-Sud 11, Baˆt. 420, 15
rue Georges Clemenceau, 91405 Orsay cedex, France
DaVid.Aitken@u-psud.fr
Received December 11, 2007
ABSTRACT
A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated
â
-amino acid residues present
in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The
key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.
The microsclerodermins A-I and two dehydro derivatives
constitute a family of complex cyclic peptides isolated from
the lithistid sponges Microscleroderma sp. and Theonella
sp. which possess antifungal and antitumor activities.1 The
family is characterized by a 23-atom macrocyclic ring
comprising six amino acid residues, three of which are
common. The more complex residues, which vary within
the family, are a modified tryptophan, an unusual 3-ami-
nopyrrolidone-4-acetic acid moiety, and a polyhydroxylated
â-amino acid residue containing four or five contiguous chiral
centers. In microsclerodermins C and D (Figure 1) as well
as their dehydro counterparts which contain a dehydropyr-
rolidone moiety, the latter constituent is (2S,3R,4S,5S,7E)-
3-amino-8-phenyl-2,4,5-trihydroxyoct-7-enoic acid (APTO).
In microsclerodermin E (Figure 1) this component is
(2S,3R,4S,5S,7E,9E)-3-amino-10-(4-ethoxyphenyl)-2,4,5-tri-
hydroxydeca-7,9-dienoic acid (AETD) (Figure 1).
To date, only the total synthesis of microsclerodermin E
has been reported,2 in which the AETD fragment was
obtained in 16 steps and 10% overall yield. Recently, 12-
step synthetic pathways to APTO (12% overall) and AETD
(9% overall) derivatives were disclosed.3 In related studies,
† Universite´ Blaise Pascal - Clermont-Ferrand 2.
‡ Universite´ Rene´ Descartes - Paris 5.
§ Universite´ Paris-Sud 11.
(1) (a) Bewley, C. A.; Debitus, C.; Faulkner, D. J. J. Am. Chem. Soc.
1994, 116, 7631. (b) Schmidt, E. W.; Faulkner, D. J. Tetrahedron 1998,
54, 3043. (c) Qureshi, A.; Colin, P. L.; Faulkner, D. J. Tetrahedron 2000,
56, 3679. (d) Erdogan, I.; Tanaka, J.; Higa, T. FABAD J. Pharm. Sci. 2000,
25, 7.
(2) Zhu, J.; Ma, D. Angew. Chem., Int. Ed. 2003, 42, 5348.
(3) Shuter, E. C.; Duong, H.; Hutton, C. A.; McLeod, M. D. Org. Biomol.
Chem. 2007, 5, 3183.
10.1021/ol702962z CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/07/2008

Initial studies of the Wittig reaction of acetonide 1 with
PhCHdPPh3 provided the olefin 2 as an inseparable mixture
of E/Z-isomers. Complete E-selectivity was achieved using
Horner-Wadsworth-Emmons methodology (Scheme 2).
Scheme 2. Synthesis of Chiral Sulfinimines 5a-c
Best results (see Supporting Information) were obtained using
nBuLi as base, which afforded pure 2 in 52% yield. A
modified Swern oxidation7 of hydroxy acetonide 2 provided
aldehyde 3 in 85% yield. Ensuing epimerization of the
R-stereocenter with K2CO3 in methanol using an adaptation
of the literature method8 gave aldehyde 4 with the requisite
stereochemistry in 83% yield. Aldehyde 4 was then converted
into chiral sulfinimines 5a (50%), 5b (74%), and 5c (69%)
by reaction with (R)-(-)-p-toluenesulfinamide, (R)-(+)-tert-
butanesulfinamide, and (S)-(-)-tert-butanesulfinamide, re-
spectively, in the presence of Ti(OEt)4.9
In support of the planned two-carbon homologation, we
were encouraged by a recent report that the addition of
enolates of R-hydroxyacetates bearing a bulky O-protecting
group (Boc) to simple chiral sulfinimines proceeded in a
highly diastereoselective manner.10 This observation was
exploited in an illustrative synthesis of the taxol side chain
with a 2R,3S configuration. Thus, we examined this reported
procedure with a view to obtaining protected APTO frag-
ments 7 with a 2S,3R configuration by reaction of sulfin-
imines 5 with protected R-hydroxyacetates 6 (Table 1).
Initially, the products were obtained in disappointingly low
yields, but inversing the reagent addition order (addition of
sulfinimine to the enolate) provided a dramatic improvement.
tBu-sulfinimines 5b and 5c (entries 3, 4, 6) provided much
higher selectivities and better yields than p-tolylsulfinimine
Figure 1. Microsclerodermins C, D, and E, with the APTO and
AETD fragments highlighted in blue and red, respectively.
some synthetic approaches to building blocks for the
construction of microsclerodermins A and B have appeared.4
Herein, we present our synthetic efforts in this field,
providing a rapid and efficient construction of protected
APTO and AETD derivatives. The retrosynthetic analysis
for protected APTO, the first target, is outlined in Scheme
1. We envisaged construction of the R-hydroxy-â-amino acid
Scheme 1. Retrosynthetic Analysis for Protected APTO
(5) For reviews on chiral sulfinimines, see: (a) Davis, F. A.; Zhou, P.;
Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (b) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (c) Zhou, P.; Chen,
B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (d) Brinner, K.;
Ellman, J. A. In EnantioselectiVe Synthesis of â-Amino Acids, 2nd ed.;
Juaristi, E., Soloshonok, V. A., Eds.; Wiley-VCH: New Jersey, 2005;
Chapter 8.
(6) Barbat, J.; Gelas, J.; Horton, D. Carbohydr. Res. 1983, 116, 312.
(7) Hjelmgaard, T.; Søtofte, I.; Tanner, D. J. Org. Chem. 2005, 70,
5688.
structural feature by stereocontrolled two-carbon homolo-
gation of chiral sulfinimine A2 with anion A1.5 Sulfinimine
A2 should be accessible via a differentiated dialdehyde
synthon A3, for which a convenient precursor should be the
readily available 2-deoxy-D-ribose acetonide 1.6
(4) (a) Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1997, 38,
3013. (b) Sasaki, S.; Hamada, Y.; Shioiri, T. Synlett 1999, 453. (c) Sasaki,
S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1999, 40, 3187. (d) Shioiri,
T.; Sasaki, S.; Hamada, Y. ARKIVOC 2003, 103. (e) Chandrasekhar, S.;
Sultana, S. S. Tetrahedron Lett. 2006, 47, 7255.
(8) Servi, S. J. Org. Chem. 1985, 50, 5865.
(9) Davis, F. A.; Prasad, K. R.; Carroll, P. J. J. Org. Chem. 2002, 67,
7802.
(10) Wang, Y.; He, Q.-F.; Wang, H.-W.; Zhou, X.; Huang, Z.-Y.; Qin,
Y. J. Org. Chem. 2006, 71, 1588.
842
Org. Lett., Vol. 10, No. 5, 2008

Table 1. Synthesis of Protected APTO 7
entry
5/7
6 (R1/Pg)
yield (%)
dra
config.e
1
2
3
4
5
6
a
a
b
b
b
c
Boc/Boc
All/Boc
All/Boc
Me/Boc
Me/Tr
56
57
72
66
d
b
b
-
-
-
2R,3S
-
78:22:0:0
>99:0:0:0c
-
Me/Boc
94
>99:0:0:0c
2S,3R
a As judged by NMR. b Complex mixtures obtained. c Only one isomer
observed. d Reagent decomposed. e Determined by X-ray crystallography.
All ) allyl; Tr ) trityl.
5a (entries 1, 2). The system appeared very sensitive to
substituent effects: changing the enolate from 6 (All/Boc)
to 6 (Me/Boc) improved the stereoselectivity to effective
completeness, whereas the enolate from 6 (Me/Tr) decom-
posed in the same conditions (entries 3-5). The reactions
of 6 (Me/Boc) with 5b and 5c thus satisfyingly provided
pure APTO fragments 7b and 7c (R ) tBu, R1 ) Me, Pg )
Boc) as single diastereomers in 66% and 94% yield,
respectively (entries 4, 6).
The absolute stereochemistry of 7b and 7c was determined
by means of single-crystal X-ray diffraction (Figure 2). To
our surprise we found that 7b (derived from (R)-(+)-tert-
butanesulfinamide) possessed the 2R,3S configuration, whereas
7c (derived from (S)-(-)-tert-butanesulfinamide) possessed
the desired 2S,3R configuration!11
Figure 2. X-ray structures of 7b (top) and 7c (bottom).
Having developed this short stereoselective pathway to the
protected APTO fragment of microsclerodermins C and D,
we then turned our attention to the synthesis of the AETD
fragment of microsclerodermin E (Scheme 3). In contrast to
the results obtained in the synthesis of olefin 2, all attempts
to use Horner-Wadsworth-Emmons methodology proved
fruitless for the synthesis of olefin 9 from 1. After numerous
explorations (see Supporting Information), access to the
desired alcohol was only found possible through use of
phosphonium bromide 8 in benzene solution in the presence
of KHMDS as base.3 The product was obtained as an E/Z-
The formation of 7c from 5c cannot be explained rationally
by a 6/4 bicyclic transition-state model. A more comfortable
explanation for the observed stereoselectivity might be a
nonchelated reaction pathway (Figure 3a), proposed earlier
for similar systems.12 Alternatively, a 6/6 chelated bicyclic
chairlike transition state where the most bulky groups are in
equatorial positions can be proposed (Figure 3b). Both these
models are in accordance with the observed steric demands
of our system: the sulfinimine moiety and the O-protecting
group of 6 need to be as bulky as possible, while only the
diminutive methyl ester of 6 gives complete selectivity.
It is noteworthy that the stereochemical outcome of this
two-carbon homologation is controlled by the sulfinyl group
only and thus proceeds independently of other neighboring
chiral centers in the molecule. This chiral predominance
phenomenon was previously noted for sulfinimine one-
carbon homologation with cyanide.9
(11) These stereochemical observations are in contradiction with the
chemical structures presented in ref 10 and, in consequence, are in disaccord
with arguments presented therein to account for the stereoselectivity.
(12) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996,
37, 3881.
Figure 3. Two plausible models, (a) nonchelated and (b) chelated,
for interactions of enolate 6 (Me/Boc) with 5c leading to the
observed selectivity of 7c.
Org. Lett., Vol. 10, No. 5, 2008
843

with methyl O-Boc-hydroxyacetate 6 (Me/Boc) according
to our optimized conditions then provided the protected
AETD fragment 13 in 79% yield as a single diastereomer.
Compound 13 showed spectral data which were very similar
to those of 7c.
Scheme 3. Synthesis of Protected AETD 13
In conclusion, we have established very short and effective
syntheses of protected APTO 7c and protected AETD 13.
These proceed in 23% and 16% overall yield, respectively,
in only 5 steps from the readily available acetonide-protected
2-deoxy-D-ribose 1. This approach compares favorably with
the existing pathways for the preparation of comparable
intermediates for the synthesis of microsclerodermins C, D,
and E and is furthermore not restricted to small-scale
synthesis.
Acknowledgment. We thank the French Ministry for
Research for financial support.
Supporting Information Available: Full experimental
procedures, characterization data, and NMR spectra for all
intermediates and final products; optimization data for the
synthesis of alcohols 2 and 9; CIF files for 7b and 7c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
mixture which was easily separated by column chromatog-
raphy to furnish the desired pure (E)-9 in 49% yield as well
as 19% of pure (Z)-9. Swern oxidation of (E)-9 (78%)
followed by isomerization with K2CO3 (78%) provided
aldehyde 11. The latter was converted into sulfinimine 12
using (S)-(-)-tert-butanesulfinamide in 70% yield. Reaction
OL702962Z
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Org. Lett., Vol. 10, No. 5, 2008