Nickel-catalyzed α-glycosylation of C(1)-hydroxyl d-myo-inositol: A formal synthesis of mycothiol

Article abstract of DOI:10.1039/c2cc35823a

Formal synthesis of mycothiol has been developed via nickel-catalyzed α-glycosylation of the C(1)-hydroxyl group of d-myo-inositols with C(2)-N-substituted benzylideneamino N-phenyl trifluoroacetimidate donors. The pseudo-oligosaccharides were obtained in good yield and with excellent α-selectivity. Removal of the C(2)-N-2-trifluoromethylphenyl-benzylidene group under mild conditions provides a pseudo-disaccharide, completing the formal synthesis of mycothiol.

Full text of DOI:10.1039/c2cc35823a

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Nickel-catalyzed a-glycosylation of C(1)-hydroxyl
D-myo-inositol: a formal synthesis of mycothiol†‡
Cite this: Chem. Commun., 2013,
49, 4313
Matthew S. McConnell,y Fei Yuy and Hien M. Nguyen*
Received 11th August 2012,
Accepted 31st August 2012
DOI: 10.1039/c2cc35823a
www.rsc.org/chemcomm
Formal synthesis of mycothiol has been developed via nickel-catalyzed has prompted a number of synthetic efforts.8,9 There are several
a-glycosylation of the C(1)-hydroxyl group of D-myo-inositols with C(2)- challenges to be addressed in the chemical synthesis of MSH:
N-substituted benzylideneamino N-phenyl trifluoroacetimidate donors. (1) selective preparation of the C(1)-hydroxyl group of the
The pseudo-oligosaccharides were obtained in good yield and with D-myo-inositol acceptor, (2) prevention of epimerization of
excellent a-selectivity. Removal of the C(2)-N-2-trifluoromethylphenyl- the cysteine residue, and (3) a-stereoselective formation of the
benzylidene group under mild conditions provides a pseudo- glycosidic linkage. A number of elegant approaches to prevention
disaccharide, completing the formal synthesis of mycothiol.
of cysteine epimerization and regioselective inositol protection
have been reported in several syntheses. However, the stereo-
Mycothiol (MSH, 1, Fig. 1), isolated from Streptomyces sp. controlled formation of a-glycosidic linkage that connects the
AJ9463,1 is a protective low molecular weight thiol present in D-glucosamine residue to inositol remains underdeveloped. The
Mycobacterium tuberculosis and other actinomycetes.1 MSH (1) is current systems provide the desired pseudo-disaccharide of MSH
used by mycobacteria for defense against foreign electrophilic in poor to moderate selectivity (a:b = 1:1–6:1),8,9 except for the
agents such as oxidants, radicals, and drugs.2,3 Since mycothiol intramolecular a-glucosaminidation9c and desymmetrization of
was discovered in the 1990s,4 extensive efforts have been focused meso-inositol strategies.9d
on the identification of its biosynthesis and its role in oxidative
Given our experience with nickel-catalyzed 1,2-cis-2-amino
stress.5 Disruption of mycothiol’s metabolism is fatal to glycosylation,10 we realize that mycothiol (1) offers a unique platform
M. tuberculosis, the tuberculosis causative agent. Because to answer interesting questions: (1) would the nickel method provide
M. tuberculosis has developed resistance to many therapies at the pseudodisaccharide of MSH in high yield and a-selectivity? and
an alarming rate, development of an efficient strategy for the (2) could a high yielding synthesis of this scarce natural product 1
synthesis of MSH analogs can provide a promising platform for and its analogs be developed so that their biological activity might be
potential therapeutic use to prevent mycothiol biosynthesis.6
addressed? We chose to employ building blocks such as D-glucos-
Currently, one liter of the M. smegmatis cell culture produces amine imidate donor 2,10 inositol acceptor 3,11 and cysteine residue
less than 1.5 mg of mycothiol (MSH).7 This limited availability 4 (Fig. 1).9c The use of these units will allow for efficient preparation
of a variety of mycothiol analogs with minimal additional effort.
Table 1 Initial studies with trichloroacetimidatesa
Fig. 1 Retrosynthetic analysis of mycothiol (MSH, 1).
Entry Donors
Inositols
Products Yieldb (%) a : bc
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA.
E-mail: hien-nguyen@uiowa.edu
1
2
3
4
5
5: X = 4-CF3 9: R = R0 = Ac
5: X = 4-CF3 10: R = R0 = Bn
12
13
63
NR
66
54
94
6 : 1
—
20 : 1
14 : 1
20 : 1
† This article is part of the ‘‘Emerging Investigators’’ themed issue for
ChemComm.
5: X = 4-CF3 11: R = Ac, R0 = Bn 14
6: X = 4-F
7: X = 2-CF3 11: R = Ac, R0 = Bn 16
11: R = Ac, R0 = Bn 15
‡ Electronic supplementary information (ESI) available: Experimental details and
characterization and spectral data for new compounds. See DOI: 10.1039/
c2cc35823a
a
b
All reactions were performed with 1.2 equiv. of inositol. Isolated
yield. c 1H NMR ratio.
§ These authors contributed equally to this work.
c
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Table 3 Survey of saccharide imidate donorsa
In formulating a reaction design for an a-glycosylation that
proceeds with high yield and selectivity, we first explored
the coupling of peracetylated inositol 9 (Table 1, entry 1) with
C(2)-N-4-fluorobenzylideneamino trichloroacetimidate 5, which
has been shown to be an effective imidate under nickel
conditions.10a,b The reaction proceeded with 10 mol% of Ni-
(4-F-PhCN)4(OTf)2 to provide the desired pseudodisaccharide
12 (entry 1) in 63% yield and with good a-selectivity (a : b = 6 : 1).
To improve the coupling efficiency and selectivity, the more
electron-donating perbenzylated inositol 10 (entry 2) was inves-
tigated as the glycosyl acceptor. Unfortunately, the coupling
product 13 was not observed. We reasoned that the glycosylation
did not proceed because inositol 10 was too sterically hindered to
react with donor 5. Thus, a less hindered and partially reactive
inositol 11 (Table 1, entry 3) was then explored. Pseudodisaccharide
14 was isolated in 66% yield and with an excellent a-selectivity
(a:b = 20 : 1). A significant decrease in a-selectivity (a:b = 20:1 -
14 : 1) and yield (66 - 54%) was observed when the coupling
process was further examined with another electron-withdrawing
benzylidene donor 6 (entry 4), C(2)-N-4-fluoro-benzylideneamino
trichloroacetimidate. Switching to the C(2)-N-2-trifluoromethyl-
benzylideneamino donor 7 (entry 5) led to the improved yield of
the coupling product (66 - 94%).
Although a-trichloroacetimidate 7 (Table 1, entry 5) was the
most effective donor, it was a minor isomer resulting from the
reaction of hemiacetal with trichloroacetonitrile (a : b = 1 : 3).
Unfortunately, the major b-isomer of 7 did not undergo glyco-
sylation with inositol 11 in the presence of the nickel catalyst,
Ni(4-F-PhCN)4(OTf)2, even though the reaction was allowed to
stir for a prolonged period. To further improve the efficiency of
the glycosylation, N-phenyl trifluoroacetimidate 1712 (Table 2)
was explored as the glycosyl donor. Because 17 is a less reactive
donor than trichloroacetimidate 7 (Table 1), the reaction proceeded
a
b
All reactions were performed with 1.5 equiv. of imidate. Isolated
yield. c 1H NMR ratio.
at 35 1C. Gratifyingly, it was found that both a- and b-isomers of the reaction, affording 16 in 78% yield and with complete a-
imidate 17 (entries 1–3) reacted to provide exclusively a-pseudo- selectivity.
disaccharide 16. We hypothesize that because the b-isomer 17
With optimized conditions and the glycosyl donor and
reacted much slower than its a-isomer counterpart (entry 1 vs. acceptor identified, we explored the scope of the nickel-catalyzed
entry 2),13 the desired coupling product 16 was obtained in a-selective glycosylation with a wide variety of monosaccharide and
much lower yield (48% vs. 77%). Prolonged glycosylation time disaccharide N-phenyl trifluoroacetimidate donors 18–22 (Table 3).
allowed b-isomer 17 to undergo full conversion at 12 h (entry 3), Coupling of the C(1)-hydroxyl group of inositol 11 with tribenzoy-
providing 16 in good yield (81%). Based on these results, a lated substrate 18 provided pseudodisaccharide 23 (entry 1) in
mixture of a- and b-isomers 17 (entry 4) was then employed in comparable yield (55%) and a-selectivity (13 : 1) to that of triacety-
lated donor 17 (Table 2). The utility of the current a-glycosylation
strategy was also investigated with the galactosamine donors 19
and 2010 (entries 2 and 3) to evaluate the substrate and protecting
group tolerance of the present nickel catalysis. Gratifyingly, the
corresponding pseudodisaccharides 24 and 25 were obtained in
good yields (56–85%) and with good a-selectivity. Encouraged by
these results, the scope of the glycosylation reaction was further
examined with the more challenging disaccharide N-phenyl tri-
fluoroacetimidates 21 and 22 (entries 4 and 5). Coupling of inositol
11 with 1,6-linked disaccharide donor 21 (entry 4) provided
exclusively a-pseudo-trisaccharide 26 in 64% yield. We discovered
that 1,3-linked disaccharide 22 (entry 5) did not perform well with
10 mol% of Ni(4-F-PhCN)4(OTf)2. The desired pseudo-trisaccharide
27 (entry 5) was obtained in only 36% yield, albeit exclusively as an
a-isomer. Overall, the results in Table 3 illustrate the efficacy of the
Table 2 Studies with N-phenyl trifluoroacetimidatea
Entry
Imidate donor
Time (h)
Yieldb (%)
a : bc
1
2
3
4
17a
17b
17b
17a/b mixture
4
4
12
18
77
48
81
78
a only
a only
a only
a only
a
b
All reactions were performed with 1.5 equiv. of imidate. Isolated
yield. c 1H NMR ratio.
c
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excellent a-selectivity utilizing nickel-catalyzed glycosylation
of C(2)-N-2-trifluoromethyl benzylideneamino imidates with
C(1)-hydroxy D-myo-inositol. This process was optimized for
glycosyl acceptor and donor reactivity and demonstrates versatility
over a number of monosaccharide and disaccharide N-phenyl
trifluoroacetimidates. The ability of these mycothiol analogs as
anti-TB agents is currently under investigation and will be reported
in due course.
Scheme 1 Nickel-catalyzed coupling with the C(2)-azido donor.
We thank University of Iowa and NSF (CHEM 1106082) for
their financial support.
Notes and references
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Scheme 2 Formal synthesis of mycothiol.
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nickel catalyst in promoting the a-selective coupling of C(1)-hydroxy
inositol 11 with C(2)-N-2-trifluoromethyl-benzylideneamino
donors. Furthermore, nickel-catalyzed a-selective glycosylation
of inositols will allow rapid generation of mycothiol analogs in
good yields.
Currently, the most common method for the stereoselective
synthesis of the pseudodisaccharide unit of mycothiol (1, Fig. 1)
employs C(2)-azido glycosyl donors.8,9 Although the azido
method provides the coupling products in good yields, the
a-selectivity varies (a : b = 1 : 1–6 : 1). To explore the limitation of
the current method, we performed the glycosylation of inositol
11 with C(2)-azido imidate donor 28 (Scheme 1). The desired
pseudodisaccharide 29 was isolated with excellent a-selectivity
(a : b = 12 : 1), albeit in much lower yield (18%).15 This control
experiment clearly demonstrates that the nickel catalyst is more
efficient and selective for C(2)-N-substituted benzylideneamino
imidates than for the C(2)-azido donor.
The synthetic utility of the nickel-catalyzed a-glycosylation
strategy was illustrated by the formal synthesis of mycothiol
(1, Fig. 1). The 2-trifluoromethyl-benzylidene group in 16
(Scheme 2) was removed with 5 N HCl in less than 5 minutes
to provide the corresponding amine salt 31 in 98% yield.
Subsequent hydrogenolysis of the benzyl protecting groups in
31 was carried out using Pd(OH)2/C and H2 in a mixture of
t-BuOH and pH 4 phosphate buffer.14 Removal of the acetyl
groups provided pseudo-disaccharide 32 (Scheme 2) in 55%
11 F. Yu and Z. Guo, Bioorg. Med. Chem. Lett., 2009, 19, 3852.
12 (a) B. Yu and H. Tao, Tetrahedron Lett., 2001, 42, 2405; (b) S. Cai and
B. Yu, Org. Lett., 2003, 5, 3827.
13 To determine if b-isomer imidate 17 undergoes anomerization to
the corresponding a-iosmer prior to the coupling process, b-isomer
17 was subjected to the nickel conditions in the absence of inositol
11. The a-isomer was not detected.
14 Y.-H. Hu, S.-Y. Lin, C.-Y. Huang, M. M. L. Zulueta, J.-Y. Liu,
W. Chang and S.-C. Hung, Nat. Chem., 2011, 3, 557.
15 Employing the C(2)-azido N-phenyl trifluoroacetimidate donor
provided 29 in similar yield and a-selectivity to that of trichloro-
acetimidate 28.
yield over 2 steps. Product 32 showed matching H NMR, 13C
1
NMR, IR, and high resolution mass spectroscopy (HRMS)
spectra as previously reported.9c,d Coupling of amine 32 with
a known cysteine residue 4 to form mycothiol (1)16 will follow
methodologies used in previous synthesis.9c,d
In summary, we have demonstrated an effective method of
generating mycothiol and its analogs in good yields and with
16 We only demonstrated the utility of our method to the preparation
of compound 32, which is a common advanced intermediate toward
the synthesis of mycothiol (1).
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 4313--4315 4315