General synthesis of C-glycosyl amino acids via proline-catalyzed direct electrophilic α-amination of C-glycosylalkyl aldehydes

Article abstract of DOI:10.1021/ol801685x

(Chemical Equation Presented) Non-natural axially and equatorially linked C-glycosyl α-amino acids (glycines, alanines, and CH₂-serine isosteres) with either S or R α-configuration were prepared by D- and L-proline-catalyzed (de >95%) α-aminati

Full text of DOI:10.1021/ol801685x

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4485-4488
General Synthesis of C-Glycosyl Amino
Acids via Proline-Catalyzed Direct
Electrophilic r-Amination of
C-Glycosylalkyl Aldehydes
Andrea Nuzzi, Alessandro Massi,* and Alessandro Dondoni*
Dipartimento di Chimica, Laboratorio di Chimica Organica, UniVersita` di Ferrara,
Via L. Borsari 46, I-44100 Ferrara, Italy
adn@unife.it; msslsn@unife.it
Received July 24, 2008
ABSTRACT
Non-natural axially and equatorially linked C-glycosyl r-amino acids (glycines, alanines, and CH2-serine isosteres) with either S or R
r-configuration were prepared by D- and L-proline-catalyzed (de >95%) r-amination of C-glycosylalkyl aldehydes using dibenzyl azodicarboxylate
as the electrophilic reagent.
Out of infancy and now enjoying a renaissance,1 asymmetric
organocatalysis has firmly established itself in recent years
as a powerful tool in drug and natural product synthesis, as
in the transformation of readily available simple compounds
into chiral building blocks for the synthesis of more complex
molecular targets. Quite surprisingly, however, organoca-
talysis has scarcely been used in carbohydrate chemistry. The
only significant contribution is represented by the biomimetic
de novo synthesis of common and rare carbohydrates.2
Studies in glycobiology and glycomedicine are posing a
pressing need for natural and non-natural oligosaccharides
and glycoconjugates in meaningful amounts and with a well-
established structure and composition. These compounds may
serve as probes in studies aimed at clarifying the complex
functions at a molecular level that carbohydrates exert in
living systems,3a in addition to serving as new leads for the
development of carbohydrate-based drugs.3b It is in this
context, we report herein an organocatalytic-based synthetic
scheme for the asymmetric synthesis of carbon-linked sugar
amino acids such as C-glycosyl glycines, alanines, and
methylene isosteres of serines. The importance of non-natural
C-glycosyl R-amino acids4 relies mainly on their use as
building blocks for the cotranslational modification of natural
glycopeptides.5 A general method for the synthesis of these
amino acids with different chain length between the carbo-
hydrate and the glycinyl moiety has not so far been reported
(3) (a) Varki, A.; Cummings, R.; Esko, J.; Freeze, H.; Hart, G.; Marth,
J. Essentials of Glycobiology; Cold Spring Harbor Laboratory Press: New
York, 1999. (b) Wong, C.-H. Carbohydrate-based Drug DiscoVery; Wiley-
VCH: Weinheim, 2003; Vols. 1 and 5.
(1) For a focus review of recent and significant synthetic acquisitions
of organocatalysis, see: Dondoni, A.; Massi, A. Angew. Chem., Int. Ed.
2008, 47, 4638–4660.
(4) Dondoni, A.; Marra, A. Chem. ReV. 2000, 100, 4395–4421.
(5) For a brief introduction to this topic and leading references, see:
Dondoni, A.; Massi, A. Synthesis of Heterocycle-Linked C-Glycosyl
R-Amino Acids and C-Glycopeptides In Current Frontiers in Asymmetric
Synthesis and Application of a-Amino Acids, ACS Symposium Series;
Soloshonok, V. A., Izawa, K., Eds.; Oxford University Press, to be published
in 2008.
(2) A selection: (a) Co´rdova, A.; Notz, W.; Barbas, C. F., III Chem.
Commun. 2002, 3024–3025. (b) Northrup, A. B.; MacMillan, D. W. C.
Science 2004, 305, 1752–1755. (c) Enders, D.; Grondal, G. Angew. Chem.,
Int. Ed. 2005, 44, 1210–1212. (d) Suri, J. T.; Mitsumori, S.; Albertshofer,
K.; Tanaka, F.; Barbas, C. F., III J. Org. Chem. 2006, 71, 3822–3828. (e)
Ibrahem, I.; Zou, W.; Xu, Y.; Co´rdova, A. AdV. Synth. Catal. 2006, 348,
211–222. (f) Utsumi, N.; Imai, M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas,
C. F., III Org. Lett. 2007, 9, 3445–3448.
(6) Dondoni, A.; Massi, A.; Nuzzi, A Synlett 2007, 303–307, and
references therein.
10.1021/ol801685x CCC: $40.75
Published on Web 09/13/2008
2008 American Chemical Society

to the best of our knowledge. Hence, we first considered the
class of C-glycosyl glycines wherein a single carbon-carbon
bond is holding the two molecular fragments.6 We envisaged
a direct entry to these compounds with either R- or
S-configuration by stereospecific R-amination of glycosyl
acetaldehydes via an organocatalyzed asymmetric carbon-
nitrogen bond-forming reaction.7 The ready access to R
(axial) C-glycopyranosyl acetaldehydes by double bond
oxidative cleavage of allyl C-glycopyranosides and the
proline-catalyzed epimerization of R to ꢀ (equatorial) ano-
mers developed in our laboratory8 furnished the required
substrates for our synthetic program. The execution of this
plan starting from ꢀ-C-glucopyranosyl ethanal 1a to give
the corresponding R-configured C-glucosyl glycine 5a under
the effect of the simplest organocatalyst such as L-proline is
presented in Scheme 1. Guided by previous studies on direct
reduced in situ by sodium borohydride and ethanol to give
the nonepimerizable alcohol 3a which was isolated in very
good yield and high diastereomeric purity (de >95%).10
Hydrogenation of 3a over Raney Nickel selectively removed
the Cbz protective groups and cleaved the N-N bond to
give the free amine.11 Treatment of crude amine with Boc2O
furnished the N-Boc protected amino alcohol 4a (Scheme
1). This was readily transformed into the target R-amino ester
5a by oxidation with Jones reagent and esterification with
diazomethane. The configuration of the carbon stereocenter
of the glycinyl group of 5a was assigned7 as R by the
Dale-Mosher NMR method.12 To this end, the H NMR
1
analysis of the pair of Mosher amides derived from 5a
allowed us to calculate ∆δRS values (see Supporting Infor-
mation) as previously performed in our13a,b and other13c
laboratories for other C-glycosyl amino acids.
To firmly establish the key role of L-proline on the
stereochemical outcome of the aldehyde 1a and DBAD
asymmetric coupling, the reaction was carried out in
MeCN at 0 °C in the presence of an achiral base and a
Brønsted acid. To this aim, the couples pyrrolidine/acetic
acid and pyrrolidine/trifluoroacetic acid were employed.
In both cases, the reaction afforded a mixture of R-hy-
drazino aldehyde diastereoisomers as shown by the
isolation of alcohols 3a and epimer 6a in a 1:1 ratio (Table
1). Hence, an internal asymmetric induction by the chiral
glycoside moiety was reasonably excluded while the
presence of proline appeared to be crucial. Accordingly,
a reversal of diastereoselectivity was observed by per-
forming the reaction of 1a with DBAD in the presence of
D-proline as the catalyst (Table 1). This reaction led to
the S configured R-hydrazino alcohol 6a as a single
product in 73% isolated yield. This alcohol was processed
as described for 3a in Scheme 1 and transformed into the
corresponding ꢀ-C-glucosyl amino ester 7a (Table 1).
The organocatalytic enamine-enamine tandem sequence
which involved the proline-catalyzed anomerization of R-C-
glucosyl acetaldehyde 1b to the ꢀ-anomer 1a and the
subsequent R-amination of the latter was also investigated
(see Scheme S1 in Supporting Information). The combination
Scheme 1. L-Proline-Catalyzed R-Amination of Model
Perbenzylated ꢀ-C-Glucosyl Acetaldehyde 1a
electrophilic R-amination of simple R-enolizable ketones and
aldehydes by using enamine catalysis,9 the sugar aldehyde
1a was allowed to react in acetonitrile at 0 °C with a typical
electrophilic nitrogen source such as dibenzyl azodicarboxy-
late (DBAD) in the presence of 30 mol % of L-proline as
the catalyst. To our great delight, this coupling process turned
out to be highly effective because it afforded exclusively
the R-hydrazino aldehyde 2a as judged by TLC and NMR
analyses of the reaction mixture. This product, however, was
(10) The diastereomeric purity of hydrazino-alcohols 3 was evaluated
by 1H NMR analysis (DMSO-d6, 120-160 °C) of crude reaction mixtures
and by comparison with spectra of authentic samples of the corresponding
R-epimers. These were isolated from epimeric mixtures of 3 which were
obtained by treatment of crude aldehydes 2 with imidazole (CH2Cl2, rt,
72 h) and then with NaBH4. The diastereomeric purity of 3 was also
confirmed by 1H NMR analysis of crude N-Boc amino alcohols 4. The same
analysis was extended to hydrazino-alcohols 9a, 11a, 14a, and 16a
(Table 2).
(11) Crucial for the effective execution of this synthetic pathway was
the cleavage of the hydrazino group by the use of high-quality Raney Nickel
catalyst. Apparently deteriorated batches of this catalyst resulted in partial
or total debenzylation of the sugar moiety and the formation of hardly
processable intermediates.
(7) Preliminary data have been succinctly reported in ref 1. It has to be
noted, however, that because of a misprinting the representative ꢀ-C-glucosyl
glycine reported therein was erroneously depicted as having the S config-
uration.
(12) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–
519. (b) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17–
117.
(8) Massi, A.; Nuzzi, A.; Dondoni, A. J. Org. Chem. 2007, 72, 10279–
10282.
(13) (a) Dondoni, A.; Massi, A.; Sabbatini, S. Chem.-Eur. J. 2005, 11,
7110–7125. (b) Dondoni, A.; Massi, A.; Minghini, E. Synlett 2006, 539–
542. (c) Ro¨hrig, C. H.; Takhi, M.; Schmidt, R. R. Synlett 2001, 1170–
1172.
(9) A selection: (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656–5667.
(b) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 1790–1793. (c) Liu, T.-Y.; Cui,
H.-L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.-Q.; Chen, Y.-C. Org. Lett.
2007, 9, 3671–3674. (d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. ReV. 2007, 107, 5471–5569.
(14) Attempts to perform both proline-catalyzed cycles in either MeOH
or MeCN produced poorer results as confirmed by the lower yields of
isolated 3a. For a detailed scheme showing all the species involved, see
Scheme S1 in the Supporting Information.
4486
Org. Lett., Vol. 10, No. 20, 2008

Table 1. R-Amination of C-Glycosyl Acetaldehydes with DBAD to Give Glycines 5a-d and 7a through Hydrazino Alcohols 3a-d
and 6a
a All reactions were run with 0.40 mmol of aldehyde and 30 mol % of catalyst. b Isolated yield. c See ref 10.
of the two catalytic cycles produced optimal results by
changing the reaction solvent, i.e., MeOH in the first cycle
and MeCN in the second. In this way, the alcohol 3a obtained
by reduction of the aldehyde 2a was prepared in 75% overall
yield from 1b.14 This value is identical to that registered in
the stepwise protocol, thus demonstrating the maintenance
of proline activity during the two catalytic cycles.
The scope of the above R-amination protocol was extended
to other perbenzylated C-glycosyl acetaldehydes, i.e., the
R-C-glucosyl 1b, ꢀ-C-galactosyl 1c, and ꢀ-C-mannosyl 1d
derivatives (Table 1). In all cases, the key asymmetric C-N
bond-forming reaction between the aldehyde and DBAD
proceeded readily under the conditions described in Scheme
1 to give after reduction with NaBH4 the corresponding
hydrazino alcohols 3 in good yield and complete diastereo-
selectivity.10 Then, alcohols 3b-d were transformed into the
N-Boc methyl glycinates 5b-d whose configuration was
assigned as R by the Dale-Mosher method.12,15
R-configuration in these compounds was achieved by using
L- and D-proline catalysis, respectively (Table 2). C-Glycosyl
alanines of type 10a and 12a are challenging synthetic targets
as demonstrated by low stereoselectivity and lack of general-
ity of previously reported synthetic methods.16 Compounds
15a and 17a are methylene isosteres of O-glycosyl serines
that are largely diffused in natural O-linked glycoproteins.
Therefore, these isosteres bear special importance for the
preparation of C-glycopeptides4,13a since these will offer
substantial resistance to chemical and enzymatic degradation
while showing minimal steric variance and unaltered biologi-
cal activity. The starting sugar aldehydes C-glucosyl propanal
8a and butanal 13a were conveniently prepared by elabora-
tion of the same precursor, the butenyl ꢀ-C-glucopyranoside
(see Supporting Information). Each aldehyde was reacted
with DBAD in the presence of either L- or D-proline, and
the R-hydrazino aldehyde that formed was converted into
the corresponding sugar amino ester by the same reaction
sequence described in Scheme 1. The glycinyl group
configuration was assigned by the Dale-Mosher method12
and confirmed by the identical properties of products 15a
By analogy to the C-glycosyl glycine synthesis, we also
prepared the chain-lengthened ꢀ-C-glucosyl alanines 10a and
12a and CH2-serine isosteres 15a and 17a. The R and S
(15) Consistent with the configurational assignment by the NMR method,
compound 5c turned out to be identical with the R-configured ꢀ-C-galactosyl
glycinate whose structure was previously assigned from circular dichroism
spectra: Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.; Scherrmann,
(16) Nolen, E. G.; Kurish, A. J.; Potter, J. M.; Donahue, L. A.; Orlando,
M. D. Org. Lett. 2005, 7, 3383–3386, and references therein.
(17) (a) For 15a, see: Paterson, D. E.; Griffin, F. K.; Alcaraz, M.-L.;
Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1323–1336. For 17a, see: (b)
Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1999, 64, 933–944.
M.-C.; Tejero, T. J. Org. Chem. 1997, 62, 5484–5496
.
Org. Lett., Vol. 10, No. 20, 2008
4487

Table 2. R-Amination of C-Glucosyl Alkylaldehydes 8a and 13a with DBAD to Give Alanines 10a and 12a, and Serines 15a and 17a
a All reactions were run with 0.40 mmol of aldehyde and 30 mol % of catalyst. b Isolated yield. c See ref 10.
and 17a with those of known compounds.17 Gratifyingly,
the results of Table 2 were similar in terms of yield and
diastereoselectivity to those obtained with glycosyl glycines
and therefore provide evidence of the broad scope and
effectiveness of the whole reaction scheme leading to
C-glycosyl amino acids with carbon tethers of variable
length.
To account for the formation of R-configured R-aminated
products 5a-d, 10a, and 15a, we propose transition state
(TS) model A (Figure 1). This is similar to other models
conformer. The high (and unexpected) level of diastereose-
lectivity (de > 95%) registered in all cases investigated
indicates the preferential formation of a single TS structure
regardless of the sugar configuration and distance from the
prochiral carbon atom.
In conclusion, we have paved the way for an efficient and
general organocatalytic route to orthogonally protected
C-glycosyl R-amino acids which are suitable for cotransla-
tional incorporation into peptide sequences. The practicality
of the synthetic procedures represents a further advantage
of the described methodology as it requires simple reaction
conditions and an inexpensive chiral catalyst such as proline.
Therefore, we believe our organocatalytic strategy is more
convenient than the previosly reported DBAD-based asym-
metric R-hydrazination of glycosylalkyl carbonyls18 via
Evans’ asymmetric oxazolidinone enolate methodology.19
Acknowledgment. We gratefully acknowledge the Uni-
versity of Ferrara for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 1. Proposed transition state model A.
that have been previously introduced to rationalize proline-
catalyzed electrophilic aminations of simple aldehydes with
DBAD.9 Accordingly, DBAD is connected by hydrogen
bonding to the carboxylic group of the pyrrolidine moiety
and attacks the re face of the sugar (E)-enamine anti
OL801685X
(18) Ben, R. N.; Orellana, A.; Arya, P. J. Org. Chem. 1998, 63, 4817–
4820.
(19) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452–
6453, and references therein.
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