Synthesis of alkylated sugar amino acids: Conformationally restricted l-Xaa-l-Ser/Thr mimics

Article abstract of DOI:10.1039/b705750d

Two synthetic strategies for the generation of δ-substituted pyranoid sugar amino acids (SAAs) are evaluated. The first employs chiral nonracemic tert-butane sulfinamides as key reagents. Regardless of the stereochemistry of the applied sulfinamide, the p

Full text of DOI:10.1039/b705750d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of alkylated sugar amino acids: conformationally restricted
L-Xaa-L-Ser/Thr mimics†
Martijn D. P. Risseeuw,a Jaroslaw Mazurek,b Arjan van Langenvelde,b Gijsbert A. van der Marel,a
Herman S. Overkleefta and Mark Overhand*a
Received 16th April 2007, Accepted 4th June 2007
First published as an Advance Article on the web 20th June 2007
DOI: 10.1039/b705750d
Two synthetic strategies for the generation of d-substituted pyranoid sugar amino acids (SAAs) are
evaluated. The first employs chiral nonracemic tert-butane sulfinamides as key reagents. Regardless of
the stereochemistry of the applied sulfinamide, the product formed has a stereochemistry resembling
that of a D amino acid at C7. Direct Grignard reaction on formyl-tetra-O-benzyl-b-D-C-
glucopyranoside in the second strategy and subsequent Mitsunobu inversion, yields the L,L-dipeptide
isosters.
Protected SAAs 1 were previously prepared using the stere-
oselective alkylation of R-tert-butanesulfinimide 4, which was
Introduction
As part of our ongoing research on artificial peptide-like materials,
we recently reported the synthesis of glucopyranose-based sugar
amino acids (SAAs) 1 (Fig. 1).1 In dipeptide isosteres 1, the
obtained by the condensation of formyl tetra-O-benzyl-b-D-C-
glucopyranoside 36 with R-tert-butanesulfinyl amide7 (Scheme 1).
Alkylation of compound 4, subsequent acid-mediated hydrolysis
stereocentre at C2 has the S-configuration, thereby resembling
of the R-tert-butanesulfonyl group and instalment of the Fmoc
the a-carbon in L-serine or L-threonine.2 The secondary amine
protective group gave compound 7, which could be transformed
at the N-terminus (C7) in 1 resembles the side-chain at the a-
into carboxylate 8 by selective acidolysis of the primary benzyl
carbon of amino acids other than glycine. By tuning the nature
ether, ester hydrolysis and oxidation. The alkylation of sulfinimide
4 proceeds in good diastereoselectivity. For instance, reaction
of the R1 group, functionalities corresponding to specific amino
acid side-chains can be incorporated into the SAAs.3 This feature
of 4 ◦with 3 equivalents of MeMgBr in methylene chloride at
distinguishes compounds 1 from SAAs reported in the literature,4
−78 C gave R-methyl adduct 5 in 20-fold excess over the other
of which the large majority are primary amines.5 As a whole, SAAs
1 can be viewed as conformationally constrained H-Xaa-Ser/Thr-
OH mimics. The configuration of C7 corresponds to that of the
a-carbons in D-amino acids, rather than the proteinogenic L-amino
diastereoisomer 6. Similar results were obtained by using toluene
as a solvent. Performing the alkylation in THF resulted in a drop
in diastereoselectivity (5–6 = 13 : 1).
Either the R-tert-butanesulfinyl chiral auxiliary or the chiral
acids. In contrast to stereochemical control over the C-terminal
carbohydrate template, or a combination of both may be respon-
portion, which originates from selection of the carbohydrate
sible for the observed diastereoselectivity. Would the first be true,
template, controlling the configuration of the newly introduced
stereocentre at C7 stems from asymmetric organic synthesis. The
then L,L-dipeptide isostere SAAs 2 would be directly accessible
by following the same synthetic scheme, but employing S-tert-
work presented here concerns adaptation of the synthetic strategy
butanesulfinimide as the chiral auxiliary. In order to investigate
we applied to prepare SAAs 1 to provide C7-S configured SAA
this possibility, we prepared S-tert-butanesulfinimide 9, the di-
building blocks 2.
astereoisomer of 4 with respect to the chirality at the sulfur
atom. Treatment of S-tert-butanesulfinimide 9 with 3 equivalents
aLeiden Institute of Chemistry, Department of Bioorganic Synthesis, PO
of MeMgBr (CH2Cl2, −78 ◦C) gave a diastereoisomeric ratio
box 9502, 2300 RA, Leiden, The Netherlands. E-mail: overhand@chem.
for 10–11 of 13 : 1, as monitored by inverse gated 13C NMR
leidenuniv.nl
measurements8 on the crude Grignard products (Scheme 1). The
absolute stereochemistry of 10 was unambiguously established
by acidic removal of the S-tert-butanesulfonyl group, giving,
after Fmoc-protection, a compound that in all spectroscopical
bAvantium Technologies, Zekeringstraat 29, 1014BV, Amsterdam, The
Netherlands
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b705750d
Fig. 1 Alkylated SAAs as Xaa-Ser/Thr mimics.
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Scheme 1 Reagents and conditions: (i) R-tert-butanesulfinamide, Ti(OiPr)4, CH2Cl2, 70%, (ii) S-tert-butanesulfinamide, Ti(OiPr)4, CH2Cl2, 72%,
(iii) MeMgBr, CH2Cl2 , −78 ◦C, (iv) HCl, MeOH, (v) FmocOSu, DIPEA, dioxane, CH2Cl2, (from 4: 71%, from 9: 75%, three steps), (vi) ZnCl2,
HOAc, Ac2O, (vii) HCl, MeOH, (viii) TEMPO, BAIB, CH2Cl2, H2O (64%, two steps).
aspects was identical to the previously synthesized 7 (R1 = CH3).1
From this it follows that the minor product 11 is the S-methyl
diastereomer of 10 with respect to the newly formed stereocentre.
Apparently, re-side addition is favored irrespective of the nature
of the chiral auxiliary on the imine nitrogen. Changing the solvent
system from CH2Cl2 to THF resulted in a slightly more favored si-
side addition, and 10 and 11 were formed in equal amounts. This
result is the best we obtained in favor of the desired diastereoisomer
11 and we conclude that at least in this system chiral sulfinylimides
are not useful intermediates in the construction of L,L-dipeptide
isosteres.
At the moment we do not have a satisfying model that
explains the different product ratios we observe, but it seems
likely that the chelation model proposed by Ellman and co-
workers in their explanation7f of chirality transfer (A to B, Fig. 2)
is counterbalanced by competing chelation of magnesium ions
to hetero-atoms on the carbohydrate template. This chelation
(for instance C, leading to D) may occur irrespective of the
configuration on the sulfur atom. Whether this reasoning is valid
or not, it does present an obvious strategy towards the desired L,L-
dipeptide isosteres. When one assumes that a formyl-C-glycoside
chelates just as the sulfinyl imides do with magnesium and that
Fig. 2 Transition states for Grignard reactions (A → B: sulfinimines in general, C → D: glycosyl sulfinimide through intramolecular chelation, E → F:
glycosyl aldehyde through intramolecular chelation).
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Scheme 2 Reagents and conditions: (i) PhMgBr, THF, −78 ◦C (66%), (ii) RMgBr or RMgCl, THF, 0 ◦C (a 66%; b 51%; c 36%; d 48%), (iii) HN3, DEAD,
PPh3, toluene (a 78%; b 83%; c 48%; d 92%), (iv) ZnCl2, HOAc, Ac2O, (v) NaOMe, MeOH (a 73%; b 78%; c 68%; d 81%, two steps), (vi) TEMPO,
PhI(OAc)2, CH2Cl2, H2O (a 89%; b 91%; c 76%; d 92%), (vii) first Me3P, THF, H2O, then FmocCl, CH2Cl2–dioxane, DIPEA (73%), (viii) H2, Lindlars
catalyst, Boc2O, MeOH (85%), (ix) Pd/C, H2, MeOH, (x) TFA (97%, two steps).
addition occurs with the same re-selectivity (E to F), then the
target compounds are within reach by introduction of a nitrogen
substituent by replacement of the resulting alcohol function with
concomitant reversal of configuration. This reasoning proved to
be valid, as is outlined in Scheme 2.
Grignard addition of 3 equivalents of either PhMgBr, MeMgBr,
iPrMgCl or iBuMgBr to aldehyde 3 proceeded in good diastere-
oselectivity to give 12a–d, respectively, as the single isolated
diastereomers in moderate to good yields (Scheme 2). The absolute
configuration of the newly formed stereocentre in alcohol 12b
could be assigned as R since its analytical data were in excellent
agreement with published values.9 The crystals obtained from
recrystallization of compound 12d proved to be suitable for
an X-ray structural determination to show the anticipated (R)-
configuration at the newly created stereocentre.10
Mitsunobu displacement of the secondary alcohols 12a–d with
azide (HN3, PPh3, DEAD, toluene)11 gave, with inversion of
configuration, azides 13a–d. Of these, phenylglycine analogue 13a
was transformed by a three step sequence (reduction of the azide
with concomitant Boc protection yielding derivative 17 followed
by hydrogenolytic cleavage of the benzylethers and TFA treatment)
into known glucosylamine derivative 18.12 All analytical data on
18 are in agreement with those reported in the literature for the
same compound hereby validating the assignment of the newly
formed stereocentre in azide 13a. The structural integrity of our
compounds was further established by transformation of azide 13b
into the corresponding Fmoc-protected amide 16 (first Staudinger
reduction, then treatment with fluoronylmethyloxycarbonyl chlo-
ride and DIPEA), which gave a compound with the same mass
but with otherwise distinct spectroscopical properties from R-
configured C-glycoside 7. Selective acidolysis of the primary
benzyl ether and subsequent oxidation of the resulting primary
hydroxyls gave, after ester hydrolysis, the L,L-dipeptide isosters
15a–d.
In conclusion, we have now at our disposal two related
synthesis strategies that enable us to prepare both D,L and L,L
glucopyranose derived Xaa–Ser(Thr) dipeptide isosteres. We are
currently investigating their structural properties in linear and
cyclic homo- and hetero-oligomers, and are pursuing adaptation
of the synthesis strategy to also incorporate other functionalised
amino acid side-chains.
Experimental
Full experimental procedures and physical data of the compounds
described in this paper can be found in the ESI.†
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Pure Appl. Chem., 2003, 75, 39–46; (g) D. Morton and R. A. Stockman,
Tetrahedron, 2006, 62, 8869–8905.
Crystallography
8 Inverse gated 13C NMR is a technique that allows quantitation of
carbon atoms by using longer relaxation times and removal of any
NOE enhancements. For more information see: T. D. W. Claridge, in
High-Resolution NMR Techniques in Organic Chemistry, Pergamon,
Oxford, 1999, ch. 4, pp. 111–146.
Compound 12d was crystallized from mixture of diethyl ether and
light petroleum at room temperature as parallelepiped blocks.‡
A crystal of approximately 0.6 × 0.35 × 0.15 mm was cut from
a larger one and analyzed on the Kappa CCD at 293 K using
MoKa1 radiation. The full sphere was collected up to h = 27.5◦.
The data collection and processing were done using the Scalepack
software.13,14 The structure was solved by the direct method and
refined using the SHELX97 package.15 All of the non-H atoms
were refined anisotropically while all H atoms were found on the
Fourier Difference map and refined isotropically. The absolute
configuration of the molecule was deducted knowing the absolute
configurations of the four stereocentres at C2, C3, C4 and C5 as
occurring in D-glucose, and the Flack parameters.16
9 C. F. Brewer, E. J. Hehre, J. Lehmann and W. Weiser, Liebigs Ann.
Chem., 1984, 1078–1087.
10 Ortep representation of the X-ray structure of compound 12d. Thermal
ellipsoids are set for 35%..
Acknowledgements
This work was financially supported by Leiden University. We
thank Hans van der Elst and Nico Meeuwenoord for their
technical assistance. Kees Erkelens and Fons Lefeber are gratefully
acknowledged for their assistance with the NMR experiments.
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