Synthesis of complex nucleoside antibiotics

Article abstract of DOI:10.1081/NCN-200059769

Herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside antibiotics, were synthesized using a samarium diiodide (SmI ₂) mediated aldol reaction with the use of α-phenylthioketone as an enolate. The characteristics of

Full text of DOI:10.1081/NCN-200059769

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SYNTHESIS OF COMPLEX NUCLEOSIDE ANTIBIOTICS
Satoshi Ichikawa a & A. Matsuda a
a Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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To cite this article: Satoshi Ichikawa & A. Matsuda (2005): SYNTHESIS OF COMPLEX NUCLEOSIDE ANTIBIOTICS, Nucleosides,
Nucleotides and Nucleic Acids, 24:5-7, 319-329
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5--7):319–329, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200059769
SYNTHESIS OF COMPLEX NUCLEOSIDE ANTIBIOTICS
5
Satoshi Ichikawa and A. Matsuda
Graduate School of Pharmaceutical Sciences,
Hokkaido University, Sapporo, Japan
5
Herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside antibiotics,
were synthesized using a samarium diiodide (SmI2) mediated aldol reaction with the use of
a-phenylthioketone as an enolate. The characteristics of the SmI2-mediated aldol reaction are that the
enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition.
This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside antibiotics. The
synthesis of caprazol, the core structure of caprazamycins, was conducted by the strategy including
b-selective ribosylation without using a neighboring group participation and the construction of a
diazepanone by a modified reductive amination. Our synthetic route would provide a range of key
analogues with partial structures to define the pharmacophore, which can be a lead for the development
of more effective anti-bacterial agents.
Keywords Nucleoside Antibiotics, Samarium Diiodide, Aldol Reaction, Herbicidins,
Tunicaminyluracil, Caprazol
INTRODUCTION
Some of nucleoside antibiotics include complex structures as well as sensitive
functionality, which are challenging targets for organic chemists.[1] Among complex
nucleoside antibiotics, there are also good drug candidates because they possess a
variety of interesting biological properties. Here we describe the synthesis of
complex nucleoside antibiotics, including herbicidin B, protected tumicaminylur-
acil, and caprazol.
Address correspondence to Satoshi Ichikawa, Graduate School of Pharmaceutical Sciences, Hokkaido
University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Fax: +81-11-706-4980; E-mail: ichikawa@pharm.
hokudai.ac.jp
319
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S. Ichikawa and A. Matsuda
RESULTS AND DISCUSSION
Synthesis of Undecose Nucleosides via SmI2 Mediated
Aldol Reaction
Total Synthesis of Herbicidin B2
Herbicidins (Figure 1, 1) were isolated from Streptomyces saganonensis in 1976.[3]
They inhibit the growth of Xanthomonas oryzae, which causes rice leaf blight. These
compounds have some interesting structural features; the sugar moeiety is an
unusual undecose constructing a tricyclic structure including the internal hemiketal
linkage and all the substituents on it are installed in axial positions. Because of their
unique and complex structures, considerable efforts has been devoted to the total
synthesis; however, none of these attempts had been yet successful.
Our retrosynthetic analysis of herbicidin B is shown in Scheme 1. This
molecule is equivalent to a xlyoadenosine derivative A. Compound B would be
simply obtained by aldol condensation between a xyloadenosine 5’-aldehyde
derivative C and a sugar enolate D. Other group reported that the enolate addition
to adenosine 5’-aldehyde derivative failed to occur because of the sensitivity of the
aldehyde. In addition to this sensitivity of nucleoside part, regioselective generation
of 1-enolate from 2-urose also has a drawback in the regioselectivity. We have
developed SmI2 mediated aldol reaction with 1-phenylthio-2-urose (Scheme 2, E) as
an enolate source to generate 1-enolate F selectively.[4] Since this reaction proceeds
under neutral condition, it was expected to be suitable for the use of the sensitive
substrates (Scheme 2).
1-Phenylthio-2-urose protected with TIPDS group 2 was prepared from
D-glucuronolactone for 10 steps. This compound was treated with 2 equiv. of SmI2
in THF at À78°C, which was followed by the addition of a xyloadenosine
5’-aldehyde derivative 3. The aldol products 4 and 5 were obtained in 75% yield as
a mixture of products, among which the desired 6’S product 4 was the major
diastereomer. Dehydration of aldol product 4 followed by catalytic hydrogenation
provided 6’-b-compound 7. Deprotection of the benzoyl group and silyl groups
resulted in spotaneus cyclization to afford tricyclic nucleoside 8. However, only the
FIGURE 1 Structure of herbicidins.

S. Ichikawa and A. Matsuda
321
SCHEME 1 Retrosynthetic analysis of herbicidin B.
epimer at the 6’-position of herbicidin B was obtained. All our attempts to
1
epimerize to herbicidin B were unsuccessful. H NMR analysis suggested the
conformation of the enone 6 preferentially adopts a half-boat conformation. Since
hydrogenation from b-face of the alkenly bond would be disfavored due to the
steric repulsion for the 9’-axial proton, a-face attack proceeded to give the
undesired diastereomer 7. We recognized that it would be essential to provide the
6’-a-stereochemistry before the cyclization (Scheme 3).
We planned to apply this conformation flip to reverse the stereoselectivity of
the hydrogenation. Namely, hygrogenation of the substrate preferentially with a
flipped conformation such as 11 might proceed from the b-face, due to the steric
repulsion for the axial substituent at 9’-position when the hydrogenation proceeds
from the a-face. Thus, we made a screening of enones protected with bulky silyl
groups at 8’ and 9’-hydroxyl groups (Scheme 4). Small coupling constants between
H-8’,9’ and H-9’,10’ in the 1H NMR spectra, indicated that enone 11 preferentially
adoped fliped conformation. Hydrogenation of 11 followed by a two-step
SCHEME 2 SmI2-mediated aldol-type C-glycosidation.

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S. Ichikawa and A. Matsuda
SCHEME 3 Synthesis of 6’-epi-herbicidin B.
deprotection sequence successfully afforded herbicidin B. This was the first total
synthesis of herbicidin.[2]
Synthesis of Fully Protected Tunicaminyluracil
Tunicamycins (Figure 2, 13) were isolated from the fermentation broths of
Streptomyces glysosuperficus in 1971.[5,6] These are nucleoside antibiotics composed
of uridine, N-acetylglucosamine (GlcNAc), an aminoundecose which is a unique
higher carbon sugar called tunicamine, and an amide-linked fatty acyl side chain.
They exhibit a variety of biological properties including antibacterial and anti-
tumor activities.

S. Ichikawa and A. Matsuda
323
SCHEME 4 Total synthesis of herbicidin B.
We thought that SmI2-mediated aldol reaction can also be applied to the
synthesis of tunicaminyluracil (Scheme 5). Namely, aldol reaction between a
phenylthioketone K and a uridine 5’-aldehyde J would provide an aldo product I.
As for the construction of hexapyranosyl moiety, we planned to utilize an
intramolecular Pummerer reaction between 7’-oxygen and 11’-carbon by installing
the phenylthio group at 11’-position of H.
The synthesis of tunicaminyluracil 21 was shown in Scheme 6. Treatment of
14, which was prepared from D-galactose, with 2.2 equiv. of SmI2 followed by
addition of 1.0 equiv. of uridine 5’-aldehyde derivative 15 at À78°C gave the
desired aldol products 16 and 17 in only 13% yield. The large amount of 14 was
observed in the reaction mixture and it was indicated that the a-phenylthio ketone
without a hetero atom at this position is less reactive to the two-electron reduction
FIGURE 2 Structure of tunicamycins.

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S. Ichikawa and A. Matsuda
SCHEME 5 Retrosynthetic analysis of tunicaminyluracil.
than that with an oxygen atom, which was the case in the herbicidin synthesis. The
treatment of 14 with SmI2 at À40°C gave complete consumption of 14 and the
addition of 15 at À78°C provided the aldol products 16 and 17 in 71% and the
ratio was 5’R/5’S = 66/34. Intramolecular hydride delivery from NaBH(OAc)3 via a
6-membered transition state selectively afforded the desired anti-diol 18. Oxidation
of 18 with mCPBA provided the corresponding sulfoxide 19. Treatment of 19
with Tf2O in the presence of pyridine at À15°C provided the desired product 20 in
53% yield. It should be noted that this ketone was also obtained, probably via the
intramolecular oxidation of hydroxyl group. Finally, the protecting group manip-
ulations afforded a fully protected tunicaminyluracil 21.[5]
The characteristics of the SmI2-mediated aldol reaction with the use of a-
phenylthioketone as an enolate are that the enolate can be regioselectively
generated and the aldol reaction proceeds under near neutral condition. This
reaction is proved to be a powerful reaction for the synthesis of complex nucleoside
antibiotics because it is suitable for the introduction of variety of complex units at a
time to the sensitive nucleoside derivatives.
Synthetic Study of Antibacterial Nucleoside Antibiotics:
Total Synthesis of Caprazol
Concerned that the bacteria will acquire resistance to the new drugs,
development of new antibacterial drugs has still been necessary for the next
defense against the drug-resistant bacteria such as vancomycin-resistant Staphylo-
coccus aureus (VRSA).[7] Liposidomycins (LPSs, 22), isolated from Streptomyces
griseosporeus in 1985, show antibacterial activity against Gram-positive bacteria
including Mycobacterium spp.[8] and did not exhibit any significant toxicity in mice.
It is reported that LPS strongly inhibit Mra Y, one of the enzymes responsible for
peptidoglycan biosynthesis and expected to be a good target for the development
of antibacterial agents. Recently isolated caprazamycins (CPZs, 23) show
antibacterial activities against Mycobacterium, which cause tuberculosis, and thus

S. Ichikawa and A. Matsuda
325
SCHEME 6 Synthesis of fully protected tunicaminyluracil.
they are expected to be potent antitubercrosis agents.[9] The structure of LPSs and
CPZs contain uridine, ribose, and fatty acyl moieties and a class of one of the most
complex nucleoside antibiotics. Very recently, the absolute stereochemistry of the
deacylated compound, named caprazole (24), was determined by X-ray crystal
structure analysis. We are interested in the biological activity of this class of natural
products as well as structural complexity and started the synthesis of LPS core
structure, which might be the same as caprazole. More than 6 groups have studied
the total synthesis of LPS. Difficulty in the synthesis of this class of molecules may lie
with the introduction of 5-aminoribose moiety found in 22--24 after construction
of a uridyldiazepanone moiety because the tertiary amine contained in the
diazepanone structure inhibited the usual ribosylation promoted by Lewis acid. In

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S. Ichikawa and A. Matsuda
SCHEME 7 Retrosynthetic analysis of caprazol.
FIGURE 3 Structures of liposidomycins, caprazamycins, and caprazol.

S. Ichikawa and A. Matsuda
327
addition, 22--24 would be sensitive to basic conditions because they contain a
b-heterosubstituted carboxyl moiety. There is a general method for the construction
of b-glycosides to use a glycosyl donor protected with a 2-O-acyl group, via a
neighboring group participation, which is usually deprotected under basic
conditions. We planned to introduce the aminoribose protected with an acid
labile protecting group at an early stage of the synthesis as shown in Scheme 7 and
control b-selective introduction via a steric hindrance installed at the a-face of the
ribofuranosyl donor (Figure 3).
SCHEME 8 Total synthesis of caprazol.

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S. Ichikawa and A. Matsuda
Compound 25 was prepared by the IBX oxidation of 2’,3’-O-isopropylideneur-
idine followed by 2-carbon elongation by Wittig reaction and protection of 3-
position with BOM group. Then, the Sharpless’ aminohydroxylation was
conducted with the use of [DHQD]2AQN ligand, the (5’S,6’S)-aminoalcohol 26
was obtained as a major diastereomer. When the ribosyl fluoride 27a was activated
with BF3Á Et2O at À30°C, the stereoselectivity was observed up to a/b = 27/73. We
thought the stereoselectivity was enhanced by introducing the more sterically
hindered protecting group at the a-face of ribose. When the pentylidene protected
ribosyl fluorides 27b was activated with BF3Á Et2O at À30°C, the stereoselectivity
was dramatically increased and the ratio of the anomer was a/b = 4/96. Since our
method is simple and quite effective, it would be an alternative entry to construct
b-ribosides without using a neighboring group participation.
The azide group of the riboside 28 was reduced to the corresponding amine,
which was protected with a Boc group to give 29. Basic hydrolysis of the methyl
ester was troublesome, the desired carboxylic acid 30 was obtained only when it
was treated with Ba(OH)2 in aqueous THF. Thus, the basic treatment should be
avoided through the synthesis. Coupling the carboxylic acid 30 with the secondary
amine 31 using DEPBT as a coupling reagent gave the amide 32. The vinyl group
was converted to the aldehyde and the hydrogenolysis of Cbz group in i-PrOH
followed by the hydride reduction with NaBH(OAc)3 provided the desired
diazepanone 34. Interestingly, its N-methylated compound 35, one step advanced
compound, was also obtained in 34%. It is supposed that the methyl source in the
formation of 35 was the formaldehyde generated in the course of BOM group
deprotection. The conversion of the alcohol 36 to carboxylic acid 37 was
conducted by the sequential oxidation of the TBDPS deprotected compound.
Finally, global deprotection of isopropylidene, pentylidene, Boc, and TBS group
with aqueous HF was applied to compound 37, and successfully provided 24. This
synthetic material was identical in all respects with the properties for the authentic
caprazol (Scheme 8).
This approach would provide a range of key analogues with partial structures
to define the pharmacophore, which can be a lead for the development of more
effective antibacterial agents.
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tricyclic undecose moiety by a conformational restriction strategy using steric repulsion between adjacent bulky
silyl protecting groups on a pyranose ring. J. Am. Chem. Soc. 1999, 121, 10270.
3. Arai, M.; Haneishi, T.; Kitahara, N.; Enokita, R.; Kawakubo, K.; Kondo, Y. Herbicidin A and B, two new
antibiotics with herbicidal activity. I. Producing organism and biological activities. J. Antibiot. 1976, 29, 863.
4. Ichikawa, S.; Shuto, S.; Matsuda, M. A novel aldol-type C-glycosidation reaction promoted by samarium
diiodide. Regioselective generation of a ulose-1-enolate from phenyl 3,4,6-tri-O-benzyl-1-thio-b-D-arabino-
hexopyranosid-2-ulose. Tetrahedron Lett. 1998, 39, 4525.
5. Ichikawa, S.; Matsuda, A. Synthesis of fully protected tunicaminyluracil. Nucleosides Nucleotides Nucleic
Acids 2004, 23, 239.

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