Syntheses of Structurally and Stereochemically Varied Forms of C7N Aminocyclitol Derivatives from Enzymatically Derived and Homochiral cis-1,2-Dihydrocatechols

Article abstract of DOI:10.1021/acs.orglett.8b03149

The structurally and stereoisomerically varied C₇N aminocyclitol derivatives 2-4 have been prepared, using a versatile and flexible range of protocols, from the cis-1,2-dihydrocatechols 5 and 6, homochiral metabolites derived from the whole-cell biotransformation of the corresponding halobenzene. Reaction sequences that enable syntheses of the enantiomeric forms of these derivatives have also been established.

Full text of DOI:10.1021/acs.orglett.8b03149

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Syntheses of Structurally and Stereochemically Varied Forms of C7N
Aminocyclitol Derivatives from Enzymatically Derived and
Homochiral cis-1,2-Dihydrocatechols
Michael Dlugosch, Xinghua Ma, Shuxin Yang, Martin G. Banwell,* Chenxi Ma, Jas S. Ward,
and Paul Carr
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: The structurally and stereoisomerically varied C7N aminocyclitol derivatives 2−4 have been prepared, using a
versatile and flexible range of protocols, from the cis-1,2-dihydrocatechols 5 and 6, homochiral metabolites derived from the
whole-cell biotransformation of the corresponding halobenzene. Reaction sequences that enable syntheses of the enantiomeric
forms of these derivatives have also been established.
he C7N aminocyclitols are microbially derived and
biologically active compounds that have been deployed
analysis. An 11-step total synthesis of this natural product was
established using methyl N-acetyl-D-glucosamine as starting
material and employed a Ferrier carbocyclization7 for the pivotal
ring-forming step.
T
in a number of therapeutic and agrochemical roles, either in their
own right or as components of structurally more complex
systems.1 So, for example, they are used as agents for the
treatment of bacterial infections and type-II diabetes and as
antifungal agents to treat rice blight.1 Given such pivotal
activities and the emergence of resistance to their more heavily
exploited forms,2 efforts continue apace to identify new
variants,3 to establish how they are produced in vivo4 and to
develop syntheses of them and structural analogues.5 The 2015
report6 by Gademann and co-workers on the isolation of the
C7N aminocyclitol kirkamide (1) (Figure 1) from an obligate
By virtue of their diverse biological activities and structural
variations, there remains an intense interest in developing new
methods for the synthesis of aminocyclitols, including C7
variants.5 As part of our ongoing efforts in this area,5b we now
report syntheses of compounds such as 4-epi-kirkamide (2), the
ent-kirkamide derivative 3, and the β,γ-unsaturated amide 4 from
the homochiral cis-dihydrocatechols 5 and 6 that are,
themselves, readily obtained through the whole-cell biotrans-
formation of bromo- and iodo-benzene, respectively (Figure 2).8
Means for accessing the enantiomeric forms of these C7N
aminocyclitol derivatives are also described.
The opening stages of the synthetic route to 4-epi-kirkamide
(2) are shown in Scheme 1 and involve the ready and well-
established conversion of diol 5 into the acetonide 7.9
Subjection of the latter compound to reaction with N-
bromoacetamide (NBA) in the presence of tin tetrachloride at
−40 °C afforded, in both a regio- and diastereo-selective
manner, the anticipated and previously reported adduct 810
(77%), the structure of which was confirmed by single-crystal X-
ray analysis (see Supporting Information (SI) for details). On
treating bromo-acetamide 8 with potassium hexamethyl-
disilazide (KHMDS) and tetra-n-butylammonium bromide
(TBAB) under conditions similar to those defined by Hudlicky
and co-workers for the formation of acylaziridine 9,10b then the
Figure 1. Recently reported C7N aminocyclitol kirkamide (1).
leaf nodule symbiont of the Rubiaceous shrub Psychotria kirkii
emphasizes the ongoing levels of interest in such systems. So, for
example, various biological studies established that kirkamide is
toxic to both aquatic anthropods and insects with the latter effect
suggesting that the compound plays a protective (antifeedant)
role in the plant hosting the symbiont. The structure of
kirkamide, which embodies a homoallylic rather than the
normally located allylic nitrogen, was determined by NMR
spectroscopic methods and confirmed by single-crystal X-ray
Received: October 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03149
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
converted (Scheme 2) into the corresponding iodide 12 (81%)
under Whitehead’s conditions13 in the expectation that the latter
Scheme 2. Closing Stages of the Route to Target 2 (4-epi-
Kirkamide)
Figure 2. Structures of the target C7N aminocyclitol derivatives 2−4
and the homochiral cis-1,2-dihydrocatechols 5 and 6 used as starting
materials.
Scheme 1. Opening Stages of the Route to C7N Aminocyclitol
2
would serve as a more effective cross-coupling partner. However,
even the latter electrophile proved ineffective in this regard until
we adapted a previously reported procedure14 allowing for the
formation of the Weinreb amide 13 (95%). O-Silylation of this
by now long-sought product was achieved under standard
conditions using tert-butyldimethylsilyl chloride (TBS-Cl) and
the resulting ether 14 (95%) subjected to reduction with lithium
aluminum hydride, so forming, after workup, the unsaturated
aldehyde 15 (84%). Luche reduction15 of the last compound
then afforded the hydroxymethylated product 16 (95%), the
structure of which was confirmed by single-crystal X-ray analysis
(see SI for details). Treatment of compound 16 with aqueous
acetic acid at 60 °C for 7 h then afforded target 2 (the C4-epimer
of kirkamide) (83%), the spectral data for which were in
complete accord with the assigned structure.
An alternate and more direct route to the kirkamide “scaffold”
that allows for the creation of a trans-relationship between the
amine residue and its neigbouring, homoallylic hydroxyl group,
as seen in the natural product 1, is shown in Scheme 3. This
starts with the conversion of diol 6 into the known bromohydrin
1716 (74%), and on treating the latter with sodium methoxide,
the previously reported epoxide 1816 (91%) was obtained.
Compound 18 itself could be engaged in a twofold Mitsunobu
oxazoline 10 was obtained in 39% yield. The structure of
compound 10 follows from the derived spectroscopic data and
the single-crystal X-ray analysis of a derivative (see below).
Subjection of an authentic sample of compound 910b to the
reaction conditions just described also afforded the isomeric
heterocycle 10, an observation consistent with the behavior of
other N-acyl aziridines.11 The regioselectivity associated with
the conversion 9 → 10 process (a Heine-type reaction11) is
intriguing and presumably the consequence of the mesomeri-
cally electron-donating properties of the flanking bromo-olefin
subunit within the substrate. On treating compound 10 with
aqueous acetic acid the associated oxazoline ring was cleaved,
thereby affording the aminocyclitol 11 (48%) wherein the amine
residue is in a homoallylic relationship with the cyclohexene
double bond, as seen in kirkamide.
The elaboration of compound 11 to target 2 requires the
introduction of a hydroxymethyl group at the bromine-bearing
carbon, and we sought to do this using one of various possible
palladium-catalyzed carbonylation processes.12 Unfortunately,
all such efforts proved unsuccessful and so bromide 11 was
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the corresponding dimethyl or Weinreb amides 3 (91%) and 24
(87%), respectively, using conditions similar to those employed
in the conversion 12 → 13. All of the NMR spectral data
obtained on these amide-containing products were entirely
consistent with the illustrated structures and that of compound 3
confirmed by single-crystal X-ray analysis.
Scheme 3. A Protocol for Establishing the Aminoconduritol
Core of ent-Kirkamide (ent-1)
On treating compound 3 with freshly prepared sodium
naphthalenide18 in THF at −78 °C, a smooth reductive
deoxygenation reaction, rather than a detosylation, took place
(Scheme 5), thus providing the novel C7N aminocyclitol 4 in
Scheme 5. Regiocontrolled, Reductive Deoxygenation of
Amide 3 Leading to Compound 4
81% yield. The structure of this product was also confirmed by
single-crystal X-ray analysis. Like congeners 2 and 3, compound
4 should be a useful precursor to a range of aminocarbasugars,19
compounds that display a range of important biological
properties including acting as inhibitors of enzymes that process
carbohydrates and as antibacterial agents.
Since the cis-1,2-dihydrocatechol ent-5 is available,20 the
reaction sequences shown in Schemes 1 and 2 also provide
access to compound ent-2. However, congener ent-6 is not
accessible by analogous means and so the protocols defined in
Schemes 3−5 cannot be used to gain access to the enantiomers
of compounds 3 and 4. Accordingly, the reaction sequence
shown in Scheme 6 was established to address this matter. Thus,
compound 5 was converted, using established protocols16 and
reaction using p-nitrobenzoic acid as the nucleophile and thus
produce the bis-ester 19 (98%), treatment of which with
potassium carbonate in methanol afforded the diol 20 (84%).
On treating this last compound with commercially available p-
toluenesulfonyl isocyanate (TsNCO), then reaction occurred
selectively at the hydroxyl group remote from the iodinated
carbon center, thereby forming, regioselectively and through
cyclization of the initially formed tosylcarbamate,17 the
anticipated oxazolidinone 21 (61%) that either could be
acetylated under standard conditions to give diacetate 22
(98%) or treated with methanolic sodium hydroxide to give triol
23 (90%). The structure of compound 22 was confirmed by
single-crystal X-ray analysis (see SI for details).
Scheme 6. Conversion of the Derivative 25 of cis-1,2-
Dihydrocatechol 5 into Iodo-triol 23
The reactions used in the elaboration of compound 23 to the
ent-kirkamide derivative 3 and its analogue 24 are shown in
Scheme 4. Thus, cyclohexenyl iodide 23 could be converted into
Scheme 4. Conversion of Triol 23 into Target 3 and Analogue
24
C
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via intermediate bromohydrin 25 (77%), into the known16
epoxide 26 (85%). Subjection of this last compound to a twofold
Mitsunobu reaction using p-nitrobenzoic acid as a nucleophile
then afforded ester 27 (64%) that upon saponification gave diol
28 (82%), the bromo-analogue of compound 20. Reaction of
compound 28 with TsNCO then afforded the anticipated cyclic
carbamate 29, and on treatment of this with methanolic sodium
hydroxide, then the brominated aminocondurtiol derivative 30
(77% from 28) was obtained. Application of a trans-
halogenation reaction to this last compound using the same
conditions as employed for the conversion 11 → 12 then gave
the iodo-triol 23 (57%), an advanced precursor to targets 3 and
4. As such a connection has been established between cis-1,2-
dihydrocatechol 5 and these C7N aminocyclitol derivatives, their
enantiomeric forms can now be obtained from ent-5.
Asamizu, S.; Lee, J. A.; Karplus, P. A.; Mahmud, T. ACS Chem. Biol.
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The protocols detailed above provide the capacity to generate
a range of novel C7N aminocyclitols in either enantiomeric form,
so allowing for the development of further structure−activity
relationship (SAR) profiles for these endlessly fascinating
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03149.
■
S
Experimental procedures, spectroscopic data, copies of
the NMR spectra of compounds 2, 3, 4, 7−28, and 30
together with the X-ray data and the derived ORTEPs for
compounds 3, 4, 8, 16, and 22 (PDF)
(13) Humphreys, J. L.; Lowes, D. J.; Wesson, K. A.; Whitehead, R. C.
Tetrahedron Lett. 2004, 45, 3429−3432.
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4290−4293.
Accession Codes
CCDC 1870597−1870601 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
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Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002, 67,
8726−8743.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Martin.Banwell@anu.edu.au.
ORCID
Martin G. Banwell: 0000-0002-0582-475X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council and the Institute of
Advanced Studies for financial support including the provision
of scholarships to M.D. and S.Y. as well as a postdoctoral
fellowship to X.M.
REFERENCES
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DOI: 10.1021/acs.orglett.8b03149
Org. Lett. XXXX, XXX, XXX−XXX