Synthetic studies toward mannopeptimycin-E: Synthesis of the O-linked tyrosine 1,4-α,α-manno,manno-pyranosyl pyranoside

Article abstract of DOI:10.1021/ol060254a

The enantioselective synthesis of the C-4′ acylated 1,4-α,α-manno,manno-disaccharide fragment of mannopeptimycin-E has been achieved in seven steps from D-tyrosine. The route relies upon diastereoselective palladium-catalyzed glycosylation, diastereoselec

Full text of DOI:10.1021/ol060254a

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1605-1608
Synthetic Studies toward
Mannopeptimycin-E: Synthesis of the
O-Linked Tyrosine
1,4-r,r-manno,manno-Pyranosyl
Pyranoside
Ravula Satheesh Babu, Sanjeeva R. Guppi, and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received January 29, 2006
ABSTRACT
The enantioselective synthesis of the C-4′ acylated 1,4-r,r-manno,manno-disaccharide fragment of mannopeptimycin-E has been achieved in
seven steps from -tyrosine. The route relies upon diastereoselective palladium-catalyzed glycosylation, diastereoselective reduction, and
D
diastereoselective bis-dihydroxylation. The efficiency of the synthesis is demonstrated by the high overall yield (37%) and the preparation of
various analogues.
The continuing emergence of bacterial resistance to tradi-
tional antibiotics has inspired a never-ending search for new
antibiotics.1 The five mannopeptimycins (1a-e) were iso-
lated from the fermentation broths of Streptomyces hygro-
scopicus LL-AC98 and related mutant strains.2 The key
structural features of the mannopeptimycins are a cyclic
hexapeptide core with alternating D- and L-amino acids, three
of which are rare. Two of the amino acids (â-D-hydroxy-
enuricididine and D-tyrosine) are glycosylated with mannose
sugars. The glycosylated amino acids are an N-glycosylated
â-hydroxyenuricididine with an R-mannose and an O-
glycosylated tyrosine with a R-(1,4-linked)-bis-manno-pyra-
nosyl pyranoside.
labs at Wyeth Pharmaceuticals. Among the mannopeptimy-
cins, mannopeptimycin-E (1e, Scheme 1) was reported as
the most active member against methicillin-resistant staphy-
lococci and vancomycin-resistant enterococci (Table 1).5
A particularly interesting aspect of the SAR for the
mannopeptimycins is how the specific placement of the
isovalerate group on the bis-manno-disaccharide correlates
with its antibacterial activity. It has been shown that C-4
isovalerate substitution on the terminal mannose leads to a
(3) (a) Petersen, P. J.; Wang, T. Z.; Dushin, R. G.; Bradford, P. A.
Antimicrob. Agents Chemother. 2004, 48, 739-746. (b) Sum, P. E.; How,
D.; Torres, N.; Petersen, P. J.; Lenoy, E. B.; Weiss, W. J.; Mansour, T. S.
Bioorg. Med. Chem. Lett. 2003, 13, 1151-1155. (c) He, H.; Shen, B.;
Petersen, P. J.; Weiss, W. J.; Yang, H. Y.; Wang, T.-Z.; Dushin, R. G.;
Koehn, F. E.; Carter, G. T. Bioorg. Med. Chem. Lett. 2004, 14, 279-282.
(4) (a) Wang, T.-Z.; Wheless, K. L.; Sutherland, A. G.; Dushin, R. G.
Heterocycles 2004, 62, 131-135. (b) Dushin, R. G.; Wang, T. Z.; Sum, P.
E.; He, H.; Sutherland, A. G.; Ashcroft, J. S.; Graziani, E. I.; Koehn, F. E.;
Bradford, P. A.; Petersen, P. J.; Wheless, K. L.; How, D.; Torres, N.; Lenoy,
E. B.; Weiss, W. J.; Lang, S. A.; Projan, S. J.; Shlaes, D. M.; Mansour, T.
S. J. Med. Chem. 2004, 47, 3487-3490.
The unique structure and unprecedented biological activity
have inspired both biological2,3 and synthetic studies4 from
(1) Walsh, C. T. Nature 2000, 406, 775-781.
(2) He, H.; Williamson, R. T.; Shen, B.; Grazaini, E. I., Yang, H. Y.;
Sakya, S. M.; Petersen, P. J.; Carter, G. T. J. Am. Chem. Soc. 2002, 124,
9729-9736.
10.1021/ol060254a CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/21/2006

Table 1. Activities of the Mannopeptimycins5
Scheme 1. Structure of Mannopeptimycin-E 1e
substantial increase in antibacterial potency. For instance,
mannopeptimycins-C and -D, which have C-2 and C-3
isovalerate groups, respectively, have reduced activity,
whereas mannopeptimycins-A and -B, which lack isovalerate
substitution, have even lower activity (Table 1).5
Although the total synthesis of mannopeptimycin has not
been reported, Wang et al. have reported a synthesis of cyclic
peptides related to mannopeptimycin having a C-4/C-6 acetal
as an isovalerate substitute.4a This work also confirmed the
importance of the C-4 isovaleryl group for antibiotic activity.
The critical role isovalerate substitution has on the antibacte-
rial activity of the mannopeptimycin-E inspired us to pursue
a synthesis of an appropriate O-glycosylated D-tyrosine with
C-4 isovalerate substitution (e.g., 2a and 2b, Scheme 1).6 In
addition to our desire to synthesize and test the mannopep-
timycin analogues 2a and 2b, we felt that the synthesis of
2a would serve as part of a model study for our synthesis of
the natural product. In addition, the preparation of 3b, a fully
protected bis-glycosylated tyrosine (Scheme 2), would be
of use for the synthesis of mannopeptimycin E. Herein, we
report the successful implementation of our palladium-
catalyzed glycosylation reaction7,8 for the de novo installation
of both a D,D- and an L,L-bis-manno-disaccharide fragment
on a D-tyrosine. The flexibility of the approach is demon-
strated by the syntheses of bis-2,3-dideoxy analogues in their
D,D- and an L,L-forms.9
a Methicillin-resistant S. aureus. b A range of activities vs four lines of
vancomycin resistant. c i-val ) i-valerate.
2. We envisioned that the manno-stereochemistry in both
2a and 3b could be installed by a diastereoselective ketone
reduction and a bis-dihydroxylation of a 1,4-linked pyran/
pyranone 4. Similarly, we believed that the pyran/pyranone
4 could be assembled using a diastereoselective palladium-
catalyzed glycosylation of tyrosine 5.7 Recently, we reported
a diastereoselective palladium-catalyzed glycosylation reac-
tion that used alcohols as nucleophiles and pyranones such
as 6 as glycosyl donors. Thus, sequential application of our
Pd(0)-glycosylation/NaBH4 reduction/Pd(0)-glycosylation se-
quence to tyrosine 5 and pyranone 6 was expected to allow
for the rapid preparation of 4. Replacing the above-mentioned
bis-dihydroxylation with a bis-diimide reduction might also
allow for the preparation of the deoxy analogue 2b. Previ-
ously, we have shown that pyranone 6 can be prepared in
either enantiomeric form. Thus, this procedure was expected
to allow the incorporation of either D- or L-sugars.10
Our retrosynthetic analysis of the disaccharide fragment
2a and its fully protected variant 3b is outlined in Scheme
(5) Singh, M. P.; Petersen, P. J.; Weiss, W. J.; Janso, J. E.; Luckman, S.
W.; Lenoy, E. B.; Bradford, P. A.; Testa, R. T.; Greenstein, M. Antimicrob.
Agents Chemother. 2003, 47, 62-69.
(6) We were mindful of Kahne’s discovery of simple disaccharide
fragments of vancomycin with significant activity toward vancomycin
resistance bacteria, see: Sun, B.; Chen, Z.; Eggert, U. S.; Shaw, S. J.;
LaTour, J. V.; Kahne, D. J. Am. Chem. Soc. 2001, 123, 12722-12723.
(7) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125, 12406-
12407.
(8) (a) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004,
126, 3428-3429. (b) Babu, R. S.; O’Doherty, G. A. J. Carbohydr. Chem.
2005, 24, 169-177. (c) VanRheenen, V.; Cha, D. Y.; Hartley, W. M.
Organic Syntheses; Wiley & Sons: New York, 1988; Collect. Vol. VI, p
342.
Our synthesis studies began with the protected D-tyrosine
5 and pyranone 6 which, when exposed to 1 mol % Pd2-
(dba)3‚CHCl3 and 2.5 mol % of PPh3, underwent a diaste-
reoselective glycosylation with complete R-selectivity to
afford the pyranone 8 in 92% yield. A diastereoselective 1,2-
(9) Presumably, the L,L-diastereomer and the bis-2,3-dideoxy analogues
of mannopeptimycin-E would have improved bioavailability.
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Org. Lett., Vol. 8, No. 8, 2006

the same reduction conditions as before (8 to 9, Scheme 3)
gave allylic alcohol 10 in excellent yield (91%) and diaste-
reoselectivity (>20:1). The isovalerate group was installed
by treating allylic alcohol 10 with isovaleric acid and DCC/
DMAP in CH2Cl2, which provided the C-4 isovalerate
disaccharide precursor 11 in excellent yield (96%). The
manno-stereochemistry in 3a was diastereoselectively intro-
duced11 upon exposure of 11 to the Upjohn conditions (OsO4/
NMO, 85%).8 Removal of both TBS-ethers was accom-
plished with TBAF (0 °C in THF) affording the R-1,4-linked-
bis-manno-disaccharide 2a in good yield (76%).
Scheme 2. Retrosynthetic Analysis of Mannopeptimycins
Scheme 4. Synthesis of Tyrosine Bis-manno-disaccharide
reduction of the enone 8, when subjected to NaBH4 in CH2-
Cl2/MeOH (1:1) at -24 °C, afforded allylic alcohol 9 as a
single diastereomer (dr > 20:1). We next investigated the
viability of the C-4 alcohol in the Pd-catalyzed glycosylation.
Exposing allylic alcohol 9 to a second glycosylation using
1.2 equiv of pyranone 6 and 1 mol % of Pd catalyst (1:2.5,
Pd2(dba)3‚CHCl3/PPh3) afforded the 1,4-linked-R-bis pyra-
none 4 in good yield (82%) and virtually complete stereo-
control (Scheme 3).
Scheme 3. De Novo Synthesis of Pyran/Pyranone 4
Finally the bis-manno-sugar 3a could also be converted
to the fully protected R-1,4-linked-bis-manno-disaccharide
3b without any ester migration (Scheme 5). This was easily
Scheme 5. Synthesis of Fully Protected
Bis-manno-disaccharide
The final post-glycosylation transformation of 4 is shown
in Scheme 4. Treatment of 1,4-linked pyran/pyranone 4 under
(10) Pyranones such as 6 can be prepared in three steps from achiral
acylfurans such as 7 in either enantiomeric form (D/L). The pyranone
asymmetry is derived from a Noyori reduction; see ref 7 and: Li, M.; Scott,
J. G.; O’Doherty, G. A. Tetrahedron Lett. 2004, 45, 1005-1009.
accomplished by treating a CH2Cl2 solution of tetraol 3a with
2,2-dimethoxypropane and 10 mol % of CSA, conditions
which provided the bis-acetonide 3b in good yield (80%).
(11) The relative stereochemistry of 3a and 14a was determined by
analysis of various coupling constants from their 1H NMR spectra; see the
Supporting Information.
Org. Lett., Vol. 8, No. 8, 2006
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Replacing pyranone 6 with its L-enantiomer (ent)-6
resulted in an equally efficient synthesis of the L,L-bis-
manno-sugar diastereomer of 2a, 14 (Scheme 6). Thus, in
three analogous steps, D-tyrosine was converted into pyran/
pyranone 12 (69% overall yield). The L,L-1,4-linked pyran/
pyranone 12 was stereoselectively reduced and acylated to
form 13 in good overall yield (86%). Once again, two
diastereoselective dihydroxylations occurred upon exposure
of 13 to the Upjohn conditions. This bis-dihydroxylation
occurred with near perfect stereocontrol, as with the dia-
stereomeric series (cf. Scheme 4).11 The tetraol product was
converted to the unprotected bis-sugar 14 via a TBS group
deprotection (TBAF, 78%) or to the fully protected diaste-
reomer 15 by means of an acetonide protection (10 mol %
of CSA/2,2-DMP, 81%).
Scheme 7. Synthesis of Bis-2,3-dideoxydisaccharide
Analogues
Scheme 6. Synthesis of L,L-Disaccharide Analogues
pyran 13 reduced to give an excellent yield of the bis-dideoxy
analogue 17 (97%).13
In conclusion, an enantioselective synthesis of the manno-
disaccharide fragments of mannopeptimycin-E has been
achieved in seven steps and 37% overall yield from D-
tyrosine via an iterative palladium-glycosylation strategy.
Key to the success of this approach was the ease with which
the C-4 isovalerate group was introduced, and the high
diastereoselectivity of the palladium-catalyzed glycosylation
and bis-dihydroxylation reactions. The use of this methodol-
ogy for the synthesis of mannopeptimycin-E as well as
various analogues is ongoing.
Acknowledgment. We thank the NIH (GM63150) and
NSF (CHE-0415469) for their generous support of our
research program. Funding for a 600 MHz NMR by the NSF-
EPSCoR (No. 0314742) is also gratefully acknowledged.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds
can be found in the Supporting Information. This material
is available free of charge via the Internet at http://pubs.acs.org.
Having synthesized the key disaccharide fragment of
mannopeptimycin E (2a and 3b) along with its L,L-diaster-
eomers (14 and 15), we turned our attention to the preparation
of deoxy analogues (Scheme 7). The simplest 2,3-deoxy
analogue 16 was obtained by an exhaustive diimide reduc-
tion.12 Both double bonds of 11 were reduced using an excess
of the diimide precursor in CH2Cl2 to afford the 2,3-deoxy-
bis-pyranoside 16 in nearly quantitative yield (95%).13 Under
identical conditions, the diasteromeric L,L-1,4-linked bis-
OL060254A
(12) We have found o-nitrophenylsulfonylhydrazide/triethylamine to be
an excellent diimide precursor, ideal for reducing pyrans of this type; see
ref 8 and: Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771-
1774.
(13) To achieve complete conversion, occasionally the crude reaction
mixture may need to be resubjected to the diimide conditions.
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Org. Lett., Vol. 8, No. 8, 2006