Intramolecular nitrogen delivery for the synthesis of C-glycosphingolipids. Application to the C-glycoside of the immunostimulant KRN7000

Article abstract of DOI:10.1021/ol5002686

The key reaction in this approach to C-glycosphingolipids is the stereoselective iodocyclization of a sugar-linked homoallylic carbonimidothioate. E and Z reaction substrates were assembled in a convergent fashion via an alkene metathesis strategy and exhibited the same alkene facial selectivity in the iodocyclization irrespective of alkene geometry, although the E alkene was found to be less reactive.

Full text of DOI:10.1021/ol5002686

Letter
pubs.acs.org/OrgLett
Intramolecular Nitrogen Delivery for the Synthesis of
C‑Glycosphingolipids. Application to the C‑Glycoside of the
Immunostimulant KRN7000
Ahmad S. Altiti and David R. Mootoo*
Department of Chemistry, Hunter College, City University of New York, New York, New York 10065, United States
S
* Supporting Information
ABSTRACT: The key reaction in this approach to C-
glycosphingolipids is the stereoselective iodocyclization of a
sugar-linked homoallylic carbonimidothioate. E and Z reaction
substrates were assembled in a convergent fashion via an
alkene metathesis strategy and exhibited the same alkene facial
selectivity in the iodocyclization irrespective of alkene
geometry, although the E alkene was found to be less reactive.
The general approach centers on intramolecular delivery of
the C2 nitrogen on a homoallylic alcohol template 3. This
strategy is appealing for analog libraries because the latter can
be assembled in a modular fashion from relatively simple sugar
and lipid precursors 4 and 5, and be relayed to diverse
analogues through different alkene functionalization reactions.
The specific tactic of intramolecular nitrogen delivery on an
alkene precursor is to be distinguished from, and complements,
less direct methods for introducing nitrogen in C-glycosphin-
golipids, through epoxide and allyl cyanate precursors.16−18
To this end, we envisaged the stereoselective Knapp
halocyclization of a homoallylic carbonimidothioate to give a
cyclic carbamate precursor of C-KRN7000. However, while
these reactions have been reported for cyclopentenol and
cyclohexenol derivatives, to the best of our knowledge
conformationally unrestrained, noncyclic carbonimidothioates,
as required here, have not been examined.19,20 Related
electrophilic cyclizations on acyclic unsaturated imidates
suggested a homoallylic over an allylic carbonimidothioate
precursor in order to obtain the stereochemical motif present in
C-KRN7000.21,22 A priori, the Z-alkene was expected to favor
the desired syn selectivity for the newly created 1,3-amino
alcohol residue, and the E-alkene to favor the 1,3-anti motif.23
However, given the stereochemical uncertainty for such highly
substituted frameworks, it was appropriate to examine both Z
and E substrates.
he implication of glycosphingolipids in a variety of cellular
Tpathways has generated much interest in analogues for use
as biomechanistic probes.1−5 Structures that are modified in the
polar head region of the sphingosine residue are especially
important because changes in this region generally have a
profound impact on their biological properties.6−10 In this
context, C-glycoside frameworks are particularly interesting
because they can answer structure−activity questions relating to
hydrolytic stability and conformation, while also allowing for
the introduction of potentially new receptor contacts in a
region that is often in intimate contact with receptor sites.11,12
Herein, in the synthesis of 2, the C-glycoside of the potent
immunostimulatory glycolipid KRN7000 1, we illustrate a C-
glycoside synthesis that is well-suited to C-glycosphingolipids
that are structurally diverse in the polar head region (Figure
1).13−18
An alkene metathesis strategy was selected for its long-term
synthetic potential. Accordingly, compatibility with diverse
functionality and delivery of both E and Z alkenes from the
same sugar and lipid precursors were considered attractive
attributes. In particular, while syntheses via anion-based
Figure 1. Intramolecular nitrogen delivery for synthesis of C-
glycosphingolipids.
Received: January 24, 2014
Published: February 21, 2014
© 2014 American Chemical Society
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Letter
olefinations or alkyne precursors can be envisaged for the
specific case of the C-glycoside 2, these methods are not as
general for vicinal disubstituted alkenes with electronegative
substituents on both allylic carbons.15,24 Such materials are
required for C-glycosides in which there is an electronegative
substituent on the pseudoanomeric carbon, an especially
interesting subgroup of C-KRN7000 analogues.25 Thus, a
tethered RCM was envisaged for the Z and a CM for the E
substrates. The precursors were the known materials C-allyl
glycoside 6 and (3S,4R)-octadec-1-ene-3,4-diol 8 (Scheme 1).
Scheme 2. Synthesis of E- and Z-Homoallylic Alcohols
Scheme 1. Carbohydrate and Lipid Alkene Precursors
The former was obtained via an established C-allylation
procedure on penta-O-acetyl-β-D-galactopyranose.14,17,26 The
latter can be prepared via Sharpless asymmetric epoxidation
methodology on divinylcarbinol but, for this study, was
obtained from D-ribose (Supporting Information).27,28
Scheme 3
For the Z alkene synthesis, 6 was converted to hydroxyalkene
7 via a known two-step iodoetherification−reductive elimi-
nation protocol.29 Methoxybenzylidination on 8 and reductive
acetal cleavage with DIBAL-H provided the lipid partner 10.
Hydroxyalkenes 7 and 10 were then converted to the mixed
phthalate 12, in 83% yield over two steps (Scheme 2). RCM on
12 using Grubbs II catalyst led to the Z cycloalkene 13 in 93%
yield, with no evidence for the E isomer. The diester 13 was
then transformed into the desired Z-homoallylic alcohol 14 in
75% yield over three straightforward alcohol protecting group
steps. For the E isomer, alkene partners 6 (2 equiv) and 11
(derived via routine protecting group operations on 10) were
subjected to CM using the Grubbs II catalyst. The CM product
was obtained exclusively as the E isomer 15 within the limits of
NMR detection, in approximately 48% yield based on alkene
11. The stereochemistry of the E and Z alkenes were assigned
from J values of the alkene protons.
The carbonimidothioate precursors 16 and 18 for the key
electrophilic cyclization were next prepared by sequential
treatment of 14 and 15 respectively, with sodium hydride,
benzyl isothiocyanate, and iodomethane, following the Knapp
protocol (Scheme 3).19 Treatment of the Z substrate 16 with
iodonium dicollidine perchlorate (IDCP) in dichloromethane
provided the iodocarbamate 17 in 80% yield, as the only
observable iodocyclization product. The stereochemistry at the
newly created 1,3-amino alcohol was assigned as syn by
conversion of 17 to the eventual target (vide infra). The relative
stereochemistry at the iodinated carbon was deduced from the
established anti addition in these reactions. Iodocyclization of
the E substrate 18 also produced a single iodocarbamate 19,
albeit more slowly, and in an appreciably lower yield (ca. 54%).
The absolute stereochemistry at the aminated carbon in 19 was
shown to be the same as in 17, by subsequent deiodination of
both 17 and 19 to the identical product 20 (vide infra)
(Scheme 4). Thus, the reactions of these homoallylic
carbonimidothioates show identical facial selectivity in the
iodocyclization on the alkene, regardless of alkene geometry
(i.e., in both E and Z cases the syn-1,3-amino alcohol is
formed). The result is in contrast to the iodocyclizations of E-
and Z-trichloroacetimidates and related electrophilic cycliza-
tions, in which disubstituted Z-alkenes give the syn-1,3-motif,
but the E-substrates give the anti-1,3 pattern.22,23
The different stereochemical result seen for the E-alkenes in
the carbonimidothioate vs trichloroacetimidate substrates may
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Organic Letters
Letter
destabilizing steric interactions in the carbonimidothioate
substrate is not present. The Z-alkenes favor the syn-1,3 motif
for both the carbonimidothioate and trichloroacetimidate
substrates, because, in both susbtrates, the Z TS corresponding
to A′ is destabilized by A-1,3 strain (with the OBn group),
relative to the A TS.
Scheme 4. End Games for C-KRN7000
Bu3SnH deiodination of 17 and 19 provided in 70 and 45%
yields, respectively, the identical product 20, as judged by
HRMS as well as 1H and 13C NMR (Scheme 4). The synthetic
ramification of these results is that either E and Z alkene
precursors can be used for C-KRN7000, albeit the Z precursor
would be more productive. Following procedures for the
processing of related derivatives, 20 was transformed to 2 in
54% yield over a three-step sequence including carbamate
hydrolysis, cleavage of benzyl protecting groups, and amidation
with p-nitrophenyl hexacosanoate. The 1H and 13C NMR of the
final product were essentially identical to the literature data for
2. Clear differences between the NMR spectra for 2 and its
amine epimer further supported the stereochemical integrity of
2 (Supporting Information).
In conclusion, a modular strategy for C-glycosphingolipids
that centers on the alkene metathesis union of relatively simple
carbohydrate and lipid precursors has been described. Analog
diversity can be further facilitated by functionalization of the
products from the metathesis step. One such strategy entailing
intramolecular nitrogen delivery via electrophilic cyclization on
a homoallylic carbonimidothioate has been illustrated in the
synthesis of the C-glycoside of the immunostimulatory
glycolipid KRN7000. More extensive investigations on these
carbonimidothioate cyclizations and evaluation of other alkene
functionalization strategies toward more diverse C-glycosphin-
golipids are underway.
be due to steric effects brought about by the benzyl substituent
that is present on the nucleophilic nitrogen in the carboni-
midothioate but not on the nitrogen of the trichloroactimidate.
Thus, following a reactant-like transition state (TS) generally
invoked for such cyclizations competing TSs, A and A′, in
which the alkene is eclipsed with the allylic C−H or C−O bond
are envisaged (Figure 2).23,30 TS A′ is disfavored in the
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data for all new
compounds, and copies of 1H and 13C NMR spectral for 2, 8−
21. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dmootoo@hunter.cuny.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(#1301330). A Research Centers in Minority Institutions
Program grant from the National Institute of Health Disparities
(MD007599) of the National Institutes of Health (NIH),
which supports the infrastructure at Hunter College, and a
Clinical Translational Science Center award (TR000457) from
the NIH are also acknowledged.
Figure 2. Transition states for iodocyclization of E-carbonimido-
thioates.
carbonimidothioate cyclization even though it is electronically
stabilized (alkene eclipsing the allylic OBn), because steric
interactions involving the forming pseudoaxial substituent and
the pseudoaxial hydrogen and the benzyl group on the nitrogen
are more crucial. Therefore TS A, which matches the syn-1,3
product 19, is favored. In the case of the E-trichloroacetimidate,
the electronically favored TS corresponding to A′ is favored
over A, because the benzyl group that is responsible for
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