A Modular Approach to the Total Synthesis of Tunicamycins

Article abstract of DOI:10.1002/anie.201501890

The tunicamycins constitute a delicate mimic of the bisubstrate intermediates of N-acetyl-D-hexosamine-1-phosphate translocases and thus inhibit bacterial cell-wall synthesis and the N glycosylation of eukaryotic proteins. An efficient approach to the synthesis of this unique type of nucleoside antibiotics is now reported and features the assembly of five modules in a highly stereoselective and robust manner. A Mukaiyama aldol reaction, intramolecular acetal formation, gold(I)-catalyzed O and N glycosylation, and final Nacylation were used as the key steps. The modular and stereoselective synthesis of tunicamycins features a Mukaiyama aldol reaction, intramolecular acetal formation, gold(I)-catalyzed O and N glycosylation, and final N acylation as the key steps. These natural products are a unique type of nucleoside antibiotics with potent inhibitory activities against bacterial cell-wall synthesis and the N-glycosylation of eukaryotic proteins.

Full text of DOI:10.1002/anie.201501890

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501890
German Edition: DOI: 10.1002/ange.201501890
Total Synthesis
A Modular Approach to the Total Synthesis of Tunicamycins**
Jiakun Li and Biao Yu*
Abstract: The tunicamycins constitute a delicate mimic of the
bisubstrate intermediates of N-acetyl-d-hexosamine-1-phos-
phate translocases and thus inhibit bacterial cell-wall synthesis
and the N glycosylation of eukaryotic proteins. An efficient
approach to the synthesis of this unique type of nucleoside
antibiotics is now reported and features the assembly of five
modules in a highly stereoselective and robust manner. A
Mukaiyama aldol reaction, intramolecular acetal formation,
gold(I)-catalyzed O and N glycosylation, and final N acylation
were used as the key steps.
T
he tunicamycins, which were originally isolated from
Streptomyces lysosuperficus and S. chartreusis in 1971, consist
of five structural units, namely uracil, ribose, galactosamine
(GalN), N-acetylglucosamine (GlcNAc), and a fatty acid
(Figure 1).[1] Unique are the tail-to-tail C C linkage between
the ribose and GalN units (C5’ C6’), which leads to the
formation of an undecose (namely tunicamine), and the head-
to-head glycosidic linkage between the GalN and GlcNAc
À
À
À À
units (C11’ O C1’’). Similar antibiotics that were recently
isolated from other sources include the streptovirudins and
corynetoxins,[2,3] which show structural variations only at the
acyl moiety and the uracil unit (with 5,6-dihydrouracil as an
alternative).[1–4] Structurally, these acyl nucleoside antibiotics
constitute a delicate mimic of the bisubstrate intermediates of
bacterial translocase I and the eukaryotic GlcNAc-1-P trans-
ferase,[5] which synthesize precursors crucial to bacterial cell-
wall synthesis and the N glycosylation of eukaryotic proteins.
Therefore, tunicamycins show potent inhibitory effects
against microbes as well as mammalian cells.[4] Owing to
their capability of inhibiting protein N glycosylation, the use
of tunicamycins has become a routine method for studying the
functions of asparagine-linked glycans (N-glycans).[6] How-
ever, tunicamycins have always been used as a complex
mixture, and congeners with minor variations at the acyl
moiety might have different activities.[7] Furthermore, the
tunicamycins might also inhibit other glycosyltransferases or
even other enzymes that recognize the uridine motif.[5] To
conduct structure–activity relationship (SAR) studies and to
develop a specific inhibitor (especially of clinical usefulness),
Figure 1. Tunicamycins and a retrosynthetic analysis. Ac=acetyl,
Bz=benzoyl, Phth=phthaloyl, PMP=para-methoxyphenyl,
TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
a synthetic method that provides access to pure samples of
a single tunicamycin and modified analogues is required.[8]
Indeed, tremendous efforts have been devoted towards
the chemical synthesis of tunicamycins;[9–15] however, only two
successful total syntheses have been described.[9,10] Suami
À
et al. applied a Henry condensation to form the C5’ C6’ bond
and a Koenigs–Knorr-type glycosylation to construct the
À À
C11’ O C1’’ linkage, but both the elaboration of the 5’-
hydroxy group from the nitroaldol adduct and the formation
of the b,a-11’,1’’-trehalose were non-stereoselective and low-
yielding.[9b,c] Myers et al. achieved an elegant total synthesis
by employing a Schmidt glycosylation with a GalNPhth lactol
as the acceptor and a GlcN3 imidate as the donor to build the
b,a-trehalose linkage at an early stage of the synthesis. An
intramolecular reductive coupling of an exo-glycal with
a uridine acetal unit tethered via an O-dimethylsilyl hemi-
selenoacetal (between C8’ and C5’) was employed to build the
[*] Dr. J. Li, Prof. B. Yu
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: byu@mail.sioc.ac.cn
[**] This work was supported by the National Natural Science
Foundation of China (21372253 and 21432012) and the Ministry of
Science and Technology of China (2012ZX09502-002).
C5’ C6’ bond with high stereoselectivity.[10b,c] Both syntheses
À
installed the acyl moiety in the final step (from 2), so that
access to all of the tunicamycin congeners should be
feasible.[16]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501890.
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We attempted to condense the GalN and ribose units in
a stereoselective and intermolecular manner, encouraged by
À
a recent finding on the biosynthesis of the tunicamycin C5’
C6’ bond.[8a] Linear silyl enol ether 6 and aldehyde 7 were thus
successfully coupled through a Mukaiyama aldol reaction
(Figure 1). Furthermore, we envisioned that a fully modular
assembly could be possible by utilizing the recently developed
gold(I)-catalyzed glycosylation (with donors 5 and 3) for the
trehalose synthesis and a late-stage N glycosylation to install
the nucleobase unit.[17–19]
Silyl enol ether 6 was derived from d-GalN (Scheme 1).
Therefore, 2-azido-1-O-TBS derivative 8 was prepared from
Scheme 2. Synthesis of undecose derivative 4. BAIB=bis-
(acetoxy)iodobenzene, DIBAL-H=diisobutylaluminum hydride,
TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxyl, TFA=trifluoroacetic
acid.
Scheme 1. Synthesis of silyl enol ether 6. AIBN=2,2’-azobis(isobutyro-
nitrile), DCM=dichloromethane, DMP=Dess–Martin periodinane,
MMTr=monomethoxytrityl, p-TsOH=para-toluenesulfonic acid, pyr=
pyridine, TBAF=tetrabutylammonium fluoride, Tf=trifluoromethane-
sulfonyl.
MMTr ether was cleaved to provide triol 17 (89%). Selective
oxidation of the primary hydroxy group in 17 was achieved in
the presence of TEMPO and BAIB;[26] simultaneous acetal
formation led to pyranose 18, which, however, immediately
oxidized to lactone 19 (92%). Azidolactone 19 readily
underwent epimerization (CDCl3, RT) at the C10’ position
(Figure S2),[27] and was thus quickly reduced into lactol 18
with DIBAL-H. Subsequent acylation led to tunicamine
derivative 20 (90% over 2 steps). Transformation of the azido
group in 20 into an N-Phth moiety was found to be trouble-
some owing to the migration of the neighboring O-acetyl
group onto the nascent amino group under a variety of
conditions tested for the reduction of the azide (Ph3P, Zn/
HOAc, or PhSeH/Et3N). Therefore, the anomeric acetyl
group was replaced with a TBS group (96% over 2 steps).
Treatment of the resultant compound 21 with 1,3-propane-
dithiol led to the corresponding amine,[28] which was protected
with a phthaloyl group to afford 22 (92% over 2 steps).
Crystalline 22 could be analyzed by X-ray diffraction[34]
(Figure S3) to confirm the stereochemistry (at C5’ and C7’)
proposed in the previous syntheses. Selective cleavage of the
anomeric TBS ether in 22 was achieved with TBAF to afford
hemiacetal 4 (81%),[29] with the desired b anomer occurring
predominantly (b/a ꢀ 10:1).[10b,c,12a,d,e]
d-GalN following a literature approach;[20] removal of the
acetyl groups followed by selective protection of the resultant
3,4-hydroxy groups as their isopropylidene acetal gave 9
(82%).[21] The 6-hydroxy group in 9 was removed by triflate
formation, substitution with iodide, and radical reduction,
providing 6-deoxypyranoside 11 (66% over 3 steps). The
conditions of the radical reduction (Bu3SnH, AIBN, toluene,
758C, 1 h) did not considerably affect the 2-azido group. The
anomeric TBS group was then cleaved with TBAF, and the
resulting lactol was reduced into linear diol 12 with NaBH4
(88% over 2 steps).[22] The primary hydroxy group in 12 was
protected as its MMTr ether (85%), and the secondary
hydroxy group was then oxidized into the corresponding
ketone with DMP (93%). The resultant methyl ketone 14 was
converted into the desired silyl enol ether 6 (96%), which
could be easily purified and was found to be shelf-stable.
A chelation-controlled Mukaiyama aldol reaction of 6 and
aldehyde 7[23] would provide the desired b-hydroxyketone 15
in a stereoselective fashion (Scheme 2).[24] Commonly used
Lewis acid promoters (i.e., BF3·OEt2, MgBr2·OEt2, TiCl4, and
SnCl4) were examined for the present condensation (Sup-
porting Information, Figure S1); the best results were
attained with SnCl4 (CH2Cl2, À788C), leading to adduct 15
in 89% yield and 13:1 diastereoselectivity. A subsequent
Evans–Saksena 1,3-anti reduction provided diol 16 in excel-
lent yield and diastereoselectivity (98%, d.r. = 45:1).[15,25] The
The required GlcN ortho-alkynylbenzoate 5 was prepared
from d-GlcN (68% over 9 steps, see the Supporting Informa-
tion). The installation of the non-participating azide at the C2
position and a bulky TBDPS group at the 6-hydroxy moiety
were expected to facilitate the a-selective glycosylation.[30]
After briefly screening the reaction conditions for the
glycosylation of lactol 4 and donor 5 (Figure S4), we were
2
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able to obtain the desired b,a-trehalose 23 in a satisfactory
yield of 61% ([Ph3PAuNTf2] (0.4 equiv), toluene, RT;
Scheme 3), with the b,b-, a,a-, and a,b-trehaloses being
isolated in approximately 4–13% yield (compounds S16–
S18).
congener, as an example. Therefore, fatty acid 29 (6.0 equiv)
was activated by stirring with DCC (9.0 equiv) in CH2Cl2 at
RT for 30 minutes; aliquots of the solution (1.0 equiv each)
were then added to a solution of 2 in MeOH at eight-hour
intervals over two days, furnishing tunicamycin V (1) in 80%
yield.
In conclusion, an efficient approach to the total synthesis
of tunicamycins has been developed, and the assembly of the
five readily accessible and stable modules into the final
antibiotic required only 21 steps, which proceeded with an
overall yield of approximately 6%. The challenging glycosyl
À
À À
tail-to-tail (C5’ C6’) and head-to-head (C1’’ O C11’) link-
ages were constructed by a Mukaiyama aldol reaction (6 and
7) and a gold(I)-catalyzed glycosylation (4 and 5), respec-
tively; both processes occurred with high stereoselectivity.
With the gold(I)-catalyzed glycosylation, a later-stage nucleo-
side synthesis was also achieved (3 and uracil), which provides
an opportunity to prepare neo-tunicamycins with different
nucleobases. In fact, various tunicamycin analogues could be
accessed by varying any of the modules in the present
synthesis, which should facilitate SAR studies on this
important type of glycosyltransferase inhibitors.
Keywords: glycosylation · gold · nucleosides · total synthesis ·
tunicamycin
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Received: February 27, 2015
Published online: && &&, &&&&
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Communications
Total Synthesis
The modular and stereoselective synthe-
sis of tunicamycins features a Mukaiyama
aldol reaction, intramolecular acetal for-
mation, gold(I)-catalyzed O and N glyco-
sylation, and final N acylation as the key
steps. These natural products are
J. Li, B. Yu*
&&&& — &&&&
A Modular Approach to the Total
Synthesis of Tunicamycins
a unique type of nucleoside antibiotics
with potent inhibitory activities against
bacterial cell-wall synthesis and the N-
glycosylation of eukaryotic proteins.
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!