Cross-metathesis of C-allyl iminosugars with alkenyl oxazolidines as a key step in the synthesis of C-iminoglycosyl α-amino acids. A route to iminosugar containing C-glycopeptides

Article abstract of DOI:10.1021/jo050494o

A general access to a novel class of sugar α-amino acids composed of iminofuranose and iminopyranose residues anomerically linked to the glycinyl group through an alkyl chain is described. A set of eight compounds was prepared by the same reaction sequenc

Full text of DOI:10.1021/jo050494o

Cross-Metathesis of C-Allyl Iminosugars with Alkenyl Oxazolidines
as a Key Step in the Synthesis of C-Iminoglycosyl r-Amino Acids.1
A Route to Iminosugar Containing C-Glycopeptides
Alessandro Dondoni,* Pier Paolo Giovannini, and Daniela Perrone
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di Ferrara, Via L. Borsari 46,
44100-Ferrara, Italy
adn@dns.unife.it
Received March 11, 2005
A general access to a novel class of sugar R-amino acids composed of iminofuranose and
iminopyranose residues anomerically linked to the glycinyl group through an alkyl chain is
described. A set of eight compounds was prepared by the same reaction sequence involving as an
initial step the Grubbs Ru-carbene-catalyzed cross-metathesis (CM) of various N-Cbz-protected
allyl C-iminoglycosides with N-Boc-vinyl- and N-Boc-allyloxazolidine. The isolated yields of the
CM products (mixtures of E- and Z-alkenes) varied in the range 40-70%. Each mixture was
elaborated by first reducing the carbon-carbon double bond using in situ generated diimide and
then unveiling the N-Boc glycinyl group [CH(BocNH)CO2H] by oxidative cleavage of the oxazolidine
ring by the Jones reagent. All amino acids were characterized as their methyl esters. The insertion
of a model C-iminoglycosyl-2-aminopentanoic acid into a tripeptide via sequential carboxylic and
amino group coupling with L-phenylalanine derivatives was carried out as a demonstration of the
potential of these sugar amino acids in designed glycopeptide synthesis.
Introduction
as well.7 These enzyme-promoted processes are key steps
in a multitude of events either beneficial or detrimental
for living organisms and which essentially involve cell
growth, regulation, and proliferation. Hence, iminosugars
that inhibit these enzymes are useful as probes for
Densely hydroxylated chiral pyrrolidines and pip-
eridines, currently known as imino- or azasugars,2 be
they obtained by chemical synthesis or extracted from
natural sources,3 owe their importance in glycomedicine
and glycobiology4 to their effectiveness and specificity
against the action of carbohydrate-processing enzymes
such as glycosidases5 and glycosyltransferases.5a,6 The
inhibition of glycoconjugate-associated enzymes such as
nucleoside phosphorylases has been recently discovered
(5) (a) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300.
(b) Ossor, A.; Elbein, A. D. Glycoprotein Processing Inhibitors. In
Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay¨,
P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Part II, Vol. 3, p 513.
(c) Asano, N. Curr. Top. Med. Chem. 2003, 3, 471. (d) Lillend, V. H.;
Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515.
(6) (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077.
(b) Schuster, M.; Blechert, S. Bioorg. Med. Chem. Lett. 2001, 11, 1809.
(c) Bastida, A.; Fernandez-Mayoralas, A.; Arrayas, R. G.; Iradier, F.;
Carretero, J. C.; Garcia-Junceda, E. Chem. Eur. J. 2001, 7, 2390. (d)
Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541. (e)
Marotte, K.; Ayad, T.; Ge´nisson, Y.; Besra, G. S.; Baltas, M.; Prandi,
J. Eur. J. Org. Chem. 2003, 2557.
(7) (a) Miles, R. W.; Tyler, P. C.; Furneaux, R. H.; Bagdassarian,
C.; Schramm, V. L. Biochemistry 1998, 37, 8615. (b) Evans, G. B.;
Furneaux, R. H.; Hutchinson, T. L.; Kezar, H. S.; Morris, P. E., Jr.;
Schramm, V. L.; Tyler, P. C. J. Org. Chem. 2001, 66, 5723. (c) Fedorov,
A.; Shi, W.; Kicska, G.; Fedorov, E.; Tyler, P. C.; Furneaux, R. H.;
Hanson, J. C.; Gainsford, G. J.; Larese, J. Z.; Schramm, V. L.; Almo,
S. C. Biochemistry 2001, 40, 853. (d) Evans, G. B.; Furneaux, R. H.;
Hausler, H.; Larsen, J. S.; Tyler, P. C. J. Org. Chem. 2004, 69, 2217.
(1) The trivial name C-iminoglycosyl amino acid has to be used only
for compounds featuring the iminosugar fragment linked by the
pseudoanomeric center (C1) to the glycinyl group (CH(NH2)CO2H)
through a carbon tether.
(2) (a) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199. (b)
Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors; Nojirimycin and
Beyond; Wiley-VCH: Weinheim, Germany, 1999.
(3) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645. (b) Watson, A. A.; Fleet, G.
W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry 2001,
56, 265.
(4) For a basic treatise on this topic, see: Essentials of Glycobiology;
Varki, A., Cummings, R., Esko, J., Freeze, H., Hart, G., Marth, J., Eds.;
Cold Spring Harbor Laboratory Press: Cold Spring Harbor, 1999.
10.1021/jo050494o CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/02/2005
5508
J. Org. Chem. 2005, 70, 5508-5518

Synthesis of C-Iminoglycosyl R-Amino Acids
studies on structure/function of enzymatic catalysis and
serve as leads for the development of new efficient drugs
against diabetes,8 cancer metastasis,9viral infections,10
particularly that of the human immunodeficiency virus
(HIV),11 tuberculosis,12 lysosomal storage diseases,13 and
parasitic protozoa.14 Aiming at broadening the scope of
iminosugars in drug discovery, more recent and increas-
ing interest is being addressed to the design and syn-
thesis of iminosugar C-glycosides of some complexity,15
i.e., compounds in which the iminosugar is linked through
the psuedoanomeric carbon (C1) to another carbohydrate
residue or an aglycon moiety by an all-carbon tether. For
instance, the attention to aza-C-disaccharides16 which
followed the synthesis of the (1,6)-methylene-linked
iminomannose-glucose couple A reported by Johnson and
co-workers17 (Figure 1) was supported by the suggestion
that the attachment of an aglycon-mimicking sugar unit
to an iminosugar would result in increased potency and
specificity.18,19 Carbon-linked iminosugar-containing nu-
cleosides such as B and C were reported as well (Figure
(8) Truscheit, E.; Frommer, W.; Junge, B.; Mu¨ller, L.; Schmidt, D.
D.; Wingender, W. Angew. Chem., Int. Ed. Engl. 1981, 20, 744. (b)
Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K.
J. Med. Chem. 1986, 29, 1038. (c) Horii, S.; Fukase, H.; Matsuo, T.;
Kameda, Y.; Asano, N.; Matsui, K. Drugs Future 1986, 11, 1039. (d)
Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497. (e) Anzeveno, P. B.;
Creemer, L. J.; Daniel, J. K.; King, C.-H. R.; Liu, P. S. J. Org. Chem.
1989, 54, 2539. (f) Andersen, B.; Rassov, A.; Westergaard, N.; Lundgren,
K. Biochem. J. 1999, 342, 545.
(9) Bernacki, R. J.; Niedbala, M. J.; Korytnyk, W. Cancer Metastasis
Rev. 1985, 4, 81. (b) Humphries, M. J.; Matsumoto, K.; White, S. L.;
Olden, K. Cancer Res. 1986, 46, 5215. (c) Spearman, M. A.; Jamieson,
J. C.; Wright, J. A. Exp. Cell. Res. 1987, 168, 116. (d) Tsukamoto, K.;
Uno, A.; Shimada, S.; Imokaw, G. Clin. Res. 1989, 37A, 722. (e) Goss,
P. E.; Baptiste, J.; Fernandes, B.; Baker, M.; Dennis, J. W. Cancer
Res. 1994, 54, 1450. (f) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis,
J. W. Clin. Cancer. Res. 1995, 1, 935. (g) Nishimura, Y.; Satoh, T.;
Adachi, H.; Kondo, S.; Takeuchi, T.; Azetaka, M.; Fukuyasu, H.;
Lizuka, Y. J. Med. Chem. 1997, 40, 2626.
(10) (a) Ha¨usler, H.; Kawakami, P.; Mlaker, E.; Severn, W. B.;
Wrodnigg, T. M.; Stu¨tz, A. E. J. Carbohydr. Chem. 2000, 19, 435. (b)
Durantel, D.; Branza-Nichita, N.; Carrouee-Durantel, S.; Butters, T.
D.; Dwek, R. A.; Zitzmann, N. J. Virol. 2001, 75, 8987.
(11) (a) Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; de Goede, R.
E. Y.; Tulp; A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature
1987, 330, 74. (b) Datema, R.; Olafsson, S.; Romero, P. A. Pharmacol.
Ther. 1987, 33, 221. (c) Tyms, A. S.; Berrie, E. M.; Ryder, T. A.; Nash,
R. J.; Hegarty, M. P.; Taylor, D. L.; Mobberley, M. A.; Davis, J. M.;
Bell, E. A.; Jeffries, D. J.; Taylor-Robinson, D.; Fellows, L. E. Lancet
1987, 2, 1025. (d) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson,
S.; Namgoong, S. K.; Ramsden, N. G.; Jacob, J. S.; Rademacher, T. W.
Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229. (e) Fenouillet, E.;
Papandreou, M. J.; Jones, I. M. Virology 1997, 231, 89.
FIGURE 1. Examples of complex iminosugar C-glycosides:
A, ref 17; B, ref 7d; C, ref 20; D, ref 22.
1). Compound C is just an example of various thiazolyl
nucleosides with stereochemical diversity in the imino-
sugar residue which have been recently prepared in our
laboratory.20 Noteworthy as a member of a large family
of iminosugar C-glycoside natural products is compound
D, called broussonetine G, isolated by Kusano and co-
workers21 and whose total synthesis has been recently
performed in the Trost laboratory.22
On the other hand, we are not aware of the existence
of carbon-linked iminosugar-containing peptides (C-imi-
noglycopeptides). These compounds would constitute a
new class of unnatural peptides combining hydrolytic
stability with inhibitory properties. As the preparation
of C-glycopeptides requires easy access to C-glycosyl
amino acids,23 key precursors to their iminosugar-
containing analogues are C-iminoglycosyl R-amino acids
I (Scheme 1). With this goal in mind, Fuchss and Schmidt
reported a few years ago24 on the first synthesis of a
compound of type I called nojirimycinyl C-L-serine be-
cause the iminosugar moiety was â-linked to an (S)-R-
aminobutanoic acid residue serving as L-serine methylene
isostere. The key operation in this synthesis involved the
construction of the chiral glycinyl group by hydrogenation
of an enamide ester group linked to the sugar moiety
(12) (a) Davis, B. G.; Brandstetter, T. W.; Hackett, L.; Winchester,
B. G.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.; Smith, C.; Fleet, G.
W. J. Tetrahedron 1999, 55, 4489 (b) Shilvock, J. P.; Wheatley, J. R.;
Nash, R. J.; Watson, A. A.; Griffiths, R. C.; Butters, T. D.; Muller, M.;
Watkin, D. J.; Winkler, D. A.; Fleet, G. W. J. J. Chem. Soc., Perkin
Trans. 1 1999, 2735.
(13) Fan, J. Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nat. Med. 1999, 5,
112.
(19) It is worth recalling that also Wong and co-workers were at
the forefront of azasugar-containing disaccharide and nucleoside
synthesis “...in an effort to develop specific glycosidase inhibitors, as
many glycosidases which recognize the same glycon moiety may differ
only with the substrate aglycon portion and the type of glycosidic
linkage”. However, the compounds prepared by the Wong group
featured an aminomethyl bridge between the two molecular residues.
See: Wong, C.-H.; Provencher, L. Porco, J. A., Jr.; Jung, S.-H.; Wang,
Y.-F.; Chen, L.; Wang, R.; Steensma, D. H. J. Org. Chem. 1995, 60,
1492.
(14) (a) Li, C. M.; Tyler, P. C.; Furneaux, R. H.; Kicska, G.; Xu, Y.
M.; Grubmeyer, C.; Girvin, M. E.; Schramm, V. L. Nat. Struct. Biol.
1999, 6, 582. (b) Miles, R. W.; Tyler, P. C.; Evans, G. B.; Furneaux, R.
H.; Parkin, D. W.; Schramm, V. L. Biochemistry 1999, 38, 13147.
(15) Martin, O. R. Toward Azaglycoside Mimics: Aza-C-glycosyl
Compounds and Homoazaglycosides. In Carbohydrate Mimics. Con-
cepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, Ger-
many, 1998; p 259.
(16) Robina, I.; Vogel, P. Synlett 2005, 5, 675.
(20) (a) Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem.
2002, 67, 7203. (b) Dondoni, A.; Perrone, D. Tetrahedron 2003, 59,
4261.
(17) (a) Johnson, C. R.; Miller, M. W.; Golebiowski, A.; Sundram,
H.; Ksebati, M. B. Tetrahedron Lett. 1994, 35, 8991. (b) Johns, B. A.;
Pan, Y. T.; Elbein, A. D.; Johnson, C. R. J. Am. Chem. Soc. 1997, 119,
4856.
(21) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles 2002, 57,
1539.
(18) Legler, G. The Catalytic Efficiency of Glycoside Hydrolases and
Models of the Transition State Based on Substrate Related Inhibitors.
In Carbohydrate Mimics. Concepts and Methods; Chapleur, Y., Ed.;
Wiley-VCH: Weinheim, Germany, 1998; p 463.
(22) Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew. Chem., Int.
Ed. 2003, 42, 5987.
(23) Dondoni, A.; Marra, A. Chem. Rev. 2000, 100, 4395.
(24) Fuchss, T.; Schmidt, R. R. Synthesis 2000, 259.
J. Org. Chem, Vol. 70, No. 14, 2005 5509

Dondoni et al.
TABLE 1. Conversion of N-Benzyl Iminosugars 1a-d
into N-Benzyloxycarbonyl Iminosugars 2a-d
SCHEME 1. Retrosynthetic Plan to
Carbon-Linked Iminosugar r-Amino Acids
through a methylene bridge. This reaction afforded a 6:1
mixture of the two aminoester epimers in good overall
yield (81%). However, the efficiency of this approach
cannot be generalized since the stereochemical outcome
may vary substantially by changing the iminosugar
residue25 and the length of the side chain. This consti-
tutes a substantial drawback in the preparation of
collections of C-glycosyl amino acids with a stereochem-
ical uniformity. Hence, we report here our own method
which stems from a simple disconnection of I and is
centered on the cross-metathesis (CM)26 of alkenes II and
III featuring an iminosugar residue and a glycinyl group
respectively (Scheme 1). The transformation of the
resulting CM product into I will simply require the
reduction of the newly formed carbon-carbon double
bond connecting the two functionalized moieties. The
unveiling of the glycinyl group might be required in case
that a protected form or a synthetic equivalent had been
employed. This method avoids the problems that are
encountered in synthetic approaches involving the con-
struction of the two key stereocenters, i.e., the pseudoa-
nomeric carbon of the sugar fragment and the carbon
bearing the amino group in the glycinyl moiety. This
work represents an extension to iminosugars of our
recent CM-centered synthesis of C-glycosyl amino acids.27
a Isolated yield.
and the alkenes thus obtained transformed into aza-C-
disaccharides.20a In analogy to that, we planned to take
advantage of the easy access to known20 C-allyl imino-
sugars 1a-c (Table 1) and the new member 1d and
submit these alkenes to the CM with alkenes of type III
according to the retrosynthetic plan shown in Scheme 1.
However, recent reports from other laboratories28 pointed
out that the CM was incompatible with the endocyclic
N-Bn group, very likely because of the coordinating
ability of the latter with the Ru-carbene catalyst. Hence,
we followed a similar stratagem to that of Martin and
co-workers28b and converted the tertiary amines 1a-d
into the less coordinating benzyloxycarbonyl (Cbz) de-
rivatives 2a-d. This transformation was carried out by
a reaction sequence consisting of removing the benzyl
group by cerium ammonium nitrate (CAN) followed by
treatment with benzyl chloroformiate in the presence of
a base. In all cases the overall yield of this N-dealkyla-
tion-carbamoylation sequence was rather low very likely
because of the inefficiency of the CAN-promoted dealkyl-
ation.28b We considered this drawback largely compen-
sated by the advantages associated with the inexpensive
and easy preparation in a multigram scale of the N-
benzyl derivatives 1a-d. However, the use of the more
easily dealkylable N-naphthalenemethyl (NAP)-protected
analogues according to the work of Martin and co-
workers28b might provide access to N-Cbz C-allyl imino-
sugars 2a-d more effectively.
Results and Discussion
Preparation of Alkenes for CM Reactions. In the
context of a program directed at the synthesis of a variety
of C-iminoglycoconjugates, we have developed a general
method that allows furanose and pyranose derived N-
benzyl hydroxylamines (hidden polyhydroxyalkyl ni-
trones) to be transformed into five- and six-membered
iminosugars bearing a reactive carbon-linked functional
group at C1 such as formyl, ethynyl, and allyl.20b As these
groups provide easily exploitable reactivity, they can
serve to introduce the iminosugar fragment into a variety
of substrates by suitable carboligation methods. Accord-
ingly a set of C-formyl iminosugars was recently submit-
ted to a Wittig-type reaction with a sugar phosphorane
(25) Fuchss, T.; Schmidt, R. R. Synthesis 1998, 753.
(26) For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18. (b) Louie, J.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2001, 40, 247. (c) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. Engl. 2003, 42, 1900. (d) Grubbs, R. H. Tetrahedron 2004, 60,
7117.
(28) (a) Hu, Y.-J.; Roy, R. Tetrahedron Lett. 1999, 40, 3305 (b) Godin,
G.; Compain, P.; Martin, O. R. Org. Lett. 2003, 5, 3269. (c) Vernall, A.
J.; Abell, A. D. Aldrichim. Acta 2003, 36, 93.
(27) Dondoni, A.; Giovannini, P. P.; Marra, A. J. Chem. Soc., Perkin
Trans. 1 2001, 2380
5510 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of C-Iminoglycosyl R-Amino Acids
2-ylideneruthenium carbene 833 (0.2 equiv) in CCl4 at 100
°C (sealed vial) for 3.5 h. Our own experimentation and
the data from a recent communication by Martin and co-
workers28b led us to establish appropriate conditions for
a satisfactory CM reaction. Hence, the above model
reaction between 2a and 5 was performed under milder
conditions in CH2Cl2 at 40 °C for 18 h with a higher
excess (3 equiv) of the vinyloxazolidine 5 and 20 mol %
of the Ru-carbene catalyst 8 (Scheme 3). This reaction
afforded the desired CM olefin 9a (E,Z mixture) in 50%
isolated yield by column chromatography. In addition,
the unchanged reactants 2a and 5 were partly recovered
(15-20%) while the remaining material was composed
of a complex mixture of products. The elaboration of 9a
was effectively carried out by first reducing the carbon-
carbon double bond by in situ generated diimide from
tosylhydrazine and sodium acetate and then by submit-
ting the product 10a to the oxidative cleavage of the
oxazolidine ring by the Jones reagent. The use of diimide
left unaffected the Bn and Cbz protective groups which
would instead be removed by Pd-catalyzed hydrogena-
tion. The R-amino acid 11a obtained in this way was
isolated and characterized as its methyl ester 12a. The
configuration of the stereocenter of the glycinyl group was
assigned as that for the oxazolidine ring in the reactant
5 on the basis of the reasonable assumption that the
above reaction sequence leading to 11a occurs without
disrupting the integrity of any stereocenter. This as-
sumption was corroborated by the recovery of the unal-
tered reactants 2a and 5 in the CM step and the lack of
formation of epimers of 11a. In addition, the one-step
oxidative cleavage of the N-Boc-2,2-dimethyloxazolidine
ring is well-documented to occur with preservation of the
configuration of its stereocenter.27,29 Although we were
quite gratified by the successful synthesis of 11a, we
wondered whether the yield could be improved by a more
effective olefin CM. As we thought that the sluggish
reaction of 2a with 5 was due to the bulky and rigid
N-Boc oxazolidine ring flanking the carbon-carbon double
bond, the CM was carried out using the more flexible
N-Boc vinylglycinate 7. Unfortunately this change failed
to provide the desired improvement as the CM product
13a was obtained in slightly lower yield (40%) than 9a.
The only advantage that we could see in this route was
the straightforward entry to the ester 12a by diimide
reduction of the carbon-carbon double bond. In the
event, saponification of this ester into the free acid 11a
had to be carried out in order to construct a suitable
building block for peptide synthesis from the C-terminus.
This transformation was simply performed by treating
the ester overnight at room temperature with NaOH in
ethanol.34 However, an optimized synthesis of the vinyl
glycinate 7 from a readily available starting material is
needed in order to make this route superior to that
employing the masked equivalent 5.
SCHEME 2. Synthesis of Alkenes Bearing Masked
and Unmasked Glycinyl Groupsa
a Reagents and conditions: (a) see ref 30; (b) Ph3PCH3Br,
KHMDS, THF, -78 °C to rt; (c) Jones’ reagent (1 M), acetone, 0
°C to rt; (d) CH2N2, Et2O, MeOH, 0 °C.
The alkenes 5 and 6 that we intended to use in the
CM with C-allyl iminosugars 2a-d were bearing the
N-Boc-2,2-dimethyloxazolidine residue. This represented
a convenient masked glycinyl group that proved to be
stable under a variety of reaction conditions yet readily
convertible to amino acid by a one pot cleavage-oxidation
procedure29 (Scheme 2). The known N-Boc-vinyloxazoli-
dine 530 and the hitherto unreported allyl homologue 6
were prepared in very good yields by olefination of the
known aldehydes 331 and 4,32 respectively, with the ylide
generated in situ from Ph3PMeBr/KHMDS. As the for-
mation of 5 in high optical purity had been earlier
established,30 the same result was assumed with enough
confidence for 6 since this was generated from the
enantiomerically pure and configurationally stable alde-
hyde 4. To compare the reactivity of 5 with that of a free
glycinyl containing alkene, we also prepared the N-Boc-
vinyl glycinate 7. This compound was obtained in a
straightforward way from 5, albeit in low yield (20%),
by oxidative cleavage of the oxazolidine ring by the Jones
reagent (CrO3, H2SO4-H2O) and esterification by diaz-
omethane.
CM Reactions and Synthesis of C-Iminoglycosyl
R-Amino Acids. At the outset of this work we were quite
disappointed at not being able to carry out a model CM
of two alkenes of type II and III under the optimized
conditions established in our earlier C-glycosyl amino
acid synthesis.27 Specifically, only traces of the CM
product 9a were detected by MALDI TOF analysis of the
crude reaction mixture formed on mixing the â-linked
C-allyl iminosugar 2a, the N-Boc-vinyloxazolidine 5 (2
equiv) and the Grubbs 1,3-dimesityl-4,5-dihydroimidazol-
(29) (a) Dondoni, A.; Marra, A.; Massi, A. Chem. Commun. 1998,
1741. (b) Dondoni, A.; Massi, A.; Marra, A. Tetrahedron Lett. 1998,
39, 6601. (c) Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1999,
64, 933. (d) Dondoni, A.; Giovannini, P. P.; Marra, A. J. Chem. Soc.,
Perkin Trans. 1 2001, 2380. (e) Dondoni, A.; Mariotti, G.; Marra, A.;
Massi, A. Synthesis 2001, 2129. (f) Dondoni, A.; Mariotti, G.; Marra,
A. J. Org. Chem. 2002, 67, 4475. (f) Dondoni, A.; Catozzi, N., Marra,
A. J. Org. Chem. 2004, 69, 5023.
The same route was followed for the conversion of the
allyl side-chain of three more iminosugars 2b, 2c, and
2d into the R-aminopentanoic acid group (Table 2, entries
(33) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(34) The crude amino acid 11a obtained from the hydrolysis of 12a
showed identical 1H NMR spectrum with that of the product derived
from 10a. Moreover, esterification of the above crude acid 11a afforded
12a whose 1H NMR spectrum and optical rotation value were identical
with those of the starting material.
(30) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. Synthesis
1994, 31
(31) (a) Dondoni, A.; Perrone, D. Synthesis 1997, 527. (b) Dondoni,
A., Perrone, D. Org. Synth. 1999, 77, 64.
(32) Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V. Tetrahedron
2004, 60, 2311.
J. Org. Chem, Vol. 70, No. 14, 2005 5511

Dondoni et al.
SCHEME 3. Synthesis of 11a and 12aa
a Reagents and conditions: (a) 8 (20%), CH2Cl2, 40 °C; (b) TsNHNH2, AcONa (1 M), DME, 85 °C; (c) Jones’ reagent (1 M), acetone, 0
°C to rt; (d) CH2N2, Et2O, MeOH, 0 °C; (e) NaOH (1 M), EtOH.
2, 4, and 6). In all cases, the key carbon-carbon bond-
forming CM was carried out under the conditions of
Scheme 3 (CH2Cl2, 40 °C, 18 h) and catalyzed by the
Grubbs ruthenium-carbene catalyst 8 (20 mol %). Yields
of the CM products 9b-d were in the range 40-45% and
unaltered starting reactants were isolated as well. The
transformation of alkenes 9b-d into amino acids (not
shown) and then amino esters 12b-d was carried out
as described in Scheme 3. In addition, these amino esters
were proved by NMR analysis to be diastereomerically
pure, and the configuration of the glycinyl group was
assigned with high confidence as commented above for
12a.
Aiming at extending the scope of the above synthetic
route, we examined the reaction of 2a with the N-Boc-
allyloxazolidine 6 since this would lead to C-iminoglycosyl
R-aminohexanoic acids. However, the need for new ap-
propriate conditions for CM became apparent. The reac-
tion carried out with a 3-fold excess of the alkene 6 under
the same conditions (catalyst, temperature, solvent)
employed with the vinyl derivative 5, afforded a complex
mixture of products, none of which resulted by NMR and
MALDI TOF analysis to be the desired CM product.
Hence, we found that just by inverting the 2a/6 ratio from
1:3 to 2:1 while keeping unaltered the amount of catalyst
8 and the reaction conditions, the CM product 14a was
formed in a rewardingly fair isolated yield (50%) (Table
2, entry 1). Even more productive was the reaction of 6
with 2b which scored a good 70% yield for the product
14b (entry 3). On the other hand, the reactions with 2c
and 2d (entries 5 and 7) afforded the products 14c and
14d, respectively (about 50% yields), together with
substantial amounts (up to 40%) of self-metathesis
products derived by dimerization of the iminosugar
moiety. We also observed that the homodimerization of
2d decreased substantially (around 10%) when the 2d/6
ratio was 1:1. The alkenes 14a-d were then elaborated
by the usual reactions, namely diimide reduction of the
double bond to give the alkyl substituted oxazolidines
15a-d and oxidative cleavage of the heterocyclic ring to
unmasking the target amino acids. These products were
isolated and characterized as the C-iminoglycosyl N-Boc-
2-aminohexanoates 16a-d, all showing NMR spectra
consistent with their structure and high diastereomeric
purity.
Before closing this section, a short remark is worth-
while. In this and in our earlier work27on C-glycosyl
amino acid synthesis, the CM of functionalized olefins,
one bearing the sugar and the other the glycinyl moiety,
affords the product in a moderate yield with an average
value of about 50%. While one can appreciate the
synthetic utility of this carbon-carbon bond forming
reaction, the low efficiency in convergent synthetic ap-
proaches involving substituted olefins of some complexity
is quite apparent. Hence, an improvement of this step
in our syntheses is highly recommended. Unfortunately
our efforts to overcome this limitation has been so far
unsuccessful.
Synthesis of a Tripeptide with a Pendant C-
Linked Iminosugar. To validate the utility of this new
family of C-glycosyl amino acids in peptide synthesis, the
incorporation of one of these compounds into a tripeptide
was considered as a necessary test (Scheme 4). This
operation served to evaluate the reactivity of the C-
iminoglycosyl amino acid despite the bulkiness of the O-
and N-protected sugar residue and demonstrate the
stability of this fragment under the reaction conditions
of peptide formation. To this end, we started from crude
amino acid 11a obtained as shown in Scheme 3 by
oxidative cleavage of the oxazolidine ring of 10a. Since
this acid was judged to be more than 90% pure by NMR
analysis, it was considered suitable for the first amide
bond formation by coupling with L-phenylalanine methyl
ester (H-Phe-OMe). Hence, the one-pot carboxylic group
5512 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of C-Iminoglycosyl R-Amino Acids
TABLE 2. Synthesis of C-Iminoglycosyl r-Aminopentanoates 12 and r-Aminohexanoates 16
a All CM reactions were carried out in CH2Cl2 at 40 °C using the Grubbs catalyst 8 (20 mol %). b All yields refer to isolated and pure
products. In the case of the CM products, the yields were calculated with respect to the initial amount of the minor reactant. c Homodimer
of 2d was isolated (40%) when the CM was performed with 2 equiv of iminosugar.
activation with PyBop in the presence of diisopropylethy-
lamine (DIEA) and then treatment with H-Phe-OMe‚HCl
in CH2Cl2 furnished the dipeptide 17 in a rewarding 80%
isolated yield by chromatographic purification. Then
extension from the N′-terminus of this compound was
performed. After Boc removal by treatment with TFA,
the coupling of the resultant free amine with tert-
butoxycarbonyl-L-phenylalanine (Boc-Phe-OH) using Py-
Bop and DIEA afforded the desired tripeptide 18 in 60%
overall yield (two steps).
J. Org. Chem, Vol. 70, No. 14, 2005 5513

Dondoni et al.
SCHEME 4. Synthesis of Di- and Tripeptides Containing a Carbon-Linked Iminosugar Residuea
a Reagents and conditions: (a) H-Phe-OMe‚HCl, PyBop, DIEA, CH2Cl2, rt; (b) TFA/CH2Cl2 (1:4), 0 °C to rt; (c) Boc-Phe-OH, PyBop,
DIEA, CH2Cl2, rt.
for 60 min and then cooled to -78 °C, and a solution of
aldehyde 4 (1.60 g, 6.58 mmol) in THF (20 mL) was added
dropwise. The cooling bath was removed and the mixture
allowed to reach rt over 2 h. The reaction was quenched with
aqueous phosphate buffer (pH 7, 20 mL) and the resulting
mixture was extracted with Et2O (3 × 20 mL). The combined
organic extract were dried (Na2SO4) and concentrated. The
resulting syrup was purified by flash chromatography (8:1
cyclohexane-AcOEt) to give 6 as a colorless oil (1.48 g, 93%):
[R]D ) +19.3 (c 1.5, CHCl3; 1H NMR (DMSO-d6, 140 °C) δ
5.88-5.72 (m, 1H), 5.12-5.03 (m, 2H), 3.98-3.85 (m, 2H), 3.72
(dd, 1H, J ) 1.2, 8.0 Hz), 2.80-2.20 (m, 2H), 1.47 (s, 3H), 1.45
(s, 9H), 1.42 (s, 3H); MALDI-TOF MS (241.3) 242.8 (M + H).
Anal. Calcd for C14H26NO3: C, 65.59; H, 10.22; N, 5.46.
Found: C, 65.63; H, 10.40; N, 5.37.
Methyl (S)-2-(tert-Butoxycarbonylamino)but-3-enoate
(7). To a cooled (0 °C), stirred solution of oxazolidine 5 (0.35
g, 1.54 mmol) in acetone (15 mL) was added freshly prepared
1 M Jones reagent (4.62 mL). The mixture was allowed to
warm to room temperature during 30 min and then was stirred
for an additional 4 h. To the orange suspension was added
dropwise propan-2-ol until a green color was observed, and
then the reaction mixture was diluted with AcOEt (50 mL)
and washed with brine (3 × 20 mL). The organic phase was
dried (Na2SO4) and concentrated to afford crude R-amino acid.
The methyl ester was prepared by adding ethereal diaz-
omethane to an Et2O-MeOH (1:1) solution of the above crude
R-amino acid cooled at 0 °C. After for 10 min, the solution was
evaporated to dryness. The crude residue was purified by flash
chromatography (4:1 cyclohexane-AcOEt) to give the title
compound 7 (62 mg, 20%) as a colorless oil: [R]D ) +12.2 (c
1.2, CHCl3); 1H NMR (CDCl3) δ 5.92 (ddd, 1H, J2,3 ) 5.5, J3,4a
) 17.0, J3,4b ) 10.5 Hz, H-3), 5.35 (ddd, 1H, J2,4a ) 0.7, J4a,4b
) 1.5 Hz, H-4a), 5.28 (ddd, 1H, J2,4b ) 0.7 Hz, H-4b), 5.27-
5.17 (m, 1H, NH), 4.94-4.84 (m, 1H, H-2), 3.80 (s, 3H, OMe),
1.47 (s, 9H, Boc); 13C NMR (CDCl3) δ 171.2 (CO), 162.6 (CO),
132 (CH)), 117.4 (CH2)), 80.1 (C(CH3)3), 55.7 (CH), 52.6
(CH3), 28.3 (C(CH3)3); MALDI-TOF MS (215.2) 216.8 (M + H).
Anal. Calcd for C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found:
C,55.65; H, 8.03; N, 6.78.
Conclusion
Collectively, a synthetic route to a new family of
C-glycosyl amino acids featuring polyhydroxylated pip-
eridine or pyrrolidine rings (iminosugars) has been
opened. The main concept in planning this route was the
exclusion of steps involving the generation of new ste-
reocenters since these were already in place in the
reactants employed. Key to the process were the mild and
neutral conditions under which the olefin CM catalyzed
by a second generation Grubbs metal-carbene complex
proceeded without disrupting the stereochemical integ-
rity of the reactants. Although a small collection of eight
amino acids was prepared so far, this path can be
profitably followed for the preparation of a large library
of compounds whose diversity elements are as follows:
(a) the substitution pattern and ring size of the imino-
sugar, (b) the length of the carbon tether, and (c) the
configuration of the pseudoanomeric and glycinyl carbon
atoms. Notably, one of the compounds so far prepared
was incorporated into a peptide. Thus, this chemistry
appears to have great potential as a source of C-
glycosylated amino acid precursors to glycopeptides
decorated with iminosugar residues.
Experimental Section
General Methods. All moisture-sensitive reactions were
performed under a nitrogen atmosphere using oven-dried
glassware. Solvents were dried over standard drying agent35
and freshly distilled prior to use. Reactions were monitored
by TLC on silica gel 60 F254 with detection by charring with
sulfuric acid, or alcoholic solutions of ninhydrin. Flash column
chromatography36 was performed on silica gel 60 (230-400
mesh). Optical rotations were measured at 20 (2 °C in the
stated solvent; [R]D values are given in 10-1 deg cm2 g-1
.
Nuclear magnetic resonance (NMR) spectra were recorded on
a 300 spectrometer in the stated solvent and at the specified
temperature. MALDI-TOF mass spectra were acquired using
R-cyano-4-hydroxycinnamic acid as the matrix. Piperidines 1a
and 1b and pyrrolidine 1c were synthesized as described.20b
Pyrrolidine 1d is a new compound prepared according to the
procedure described in ref 20b. For its characterization see
below. Aldehyde 4 was prepared as reported in ref 32.
General Procedure for the Conversion of N-Benzyl
Iminosugars 1a-d into N-Benzyloxycarbonyl Iminosug-
ars 2a-d. To a stirred solution of N-benzyl iminosugar 1 (4.0-
5.0 mmol) in a 5:1 mixture of THF-H2O (260-330 mL) was
added ammonium cerium(IV) nitrate (4.0 equiv) in portions.
When the reaction was complete, the mixture was treated with
an aqueous saturated solution of NaHCO3, until basic pH was
reached, and then extracted with Et2O. The organic phase was
dried (Na2SO4) and concentrated. The crude compound was
dissolved in CH3CH2OH-H2O (1:1) to obtain a 0.1 M solution,
cooled (0 °C), and treated with NaHCO3 (3 equiv). After 10
min, benzyl chloroformate (3 equiv) was added to the mixture,
and the stirring was continued for 1 h at 0 °C. The mixture
was partitioned between brine and Et2O, and then the organic
1,1-Dimethylethyl 4-(S)-2,2-Dimethyl-4-(2-propenyl)-
oxazolidine-3-carboxylate (6). Methyltriphenylphospho-
nium bromide (4.10 g, 11.5 mmol) was suspended in THF (100
mL) at rt and KHMDS (0.5 M in toluene, 22.0 mL, 11.0 mmol)
was added. The resulting yellow suspension was stirred at rt
(35) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals, 5th ed.; Butterworth-Heinemann; Oxford, 2003.
(36) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
5514 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of C-Iminoglycosyl R-Amino Acids
phase was dried (Na2SO4) and concentrated. The crude residue
was purified by flash chromatography.
7 (3 equiv) and the Grubbs catalyst 8 (0.2 equiv). The mixture
was heated to 40 °C for 18 h while stirring and then cooled to
room temperature and concentrated. The crude residue was
purified by flash chromatography.
(2S,3S,4R,5S,6S)-N-Benzyloxycarbonyl-6-benzyloxy-
methyl-3,4,5-tribenzyloxy-2-(2-propenyl)piperidine (2a).
Chromatography on silica gel (6:1 cyclohexane-AcOEt): syrup
6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-pen-
tadeoxy-1-O,2-N-isopropylidene-L-erythro-L-galacto-un-
dec-3-enitol (9a). Chromatography on silica gel (from 8:1 to
3:1 cyclohexane-AcOEt): syrup (50% yield); compound 9a was
a 75/25 mixture of E/Z olefins (by 1H NMR analysis); 1H NMR
(selected data) (DMSO-d6, 120 °C) δ 7.40-7.20 (m, 25H), 5.60-
5.28 (m, 2H), 5.07 (d, 0.25H, J ) 12.0 Hz), 5.03 (d, 0.75H, J )
12.0 Hz), 4.98 (d, 0.25H, J ) 12.0 Hz), 4.92 (d, 0.75H, J )
12.0 Hz), 4.36-4.22 (m, 1H), 4.18 (ddd, 1H, J ) 2.5, 6.0, 6.0
Hz), 4.05 (dd, 0.25H, J ) 3.0, 6.0 Hz), 4.01 (dd, 0.75H, J )
3.0, 6.0 Hz), 3.54 (dd, 0.75H, J ) 3.0, 9.0 Hz), 3.39 (dd, 0.25H,
J ) 3.5, 8.5 Hz), 1.50 (s, 2.25H), 1.45 (s, 2.25H), 1.40 (s, 6.75H),
1.38 (s, 2.25H); MALDI-TOF MS (897.1) 919.6 (M + Na), 935.5
(M + K). Anal. Calcd for C55H64N2O9: C, 73.64; H, 7.19; N, 3.12.
Found: C, 73.26; H, 7.48; N, 3.19.
6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-pen-
tadeoxy-1-O,2-N-isopropylidene-L-threo-L-galacto-undec-
3-enitol (9b). Chromatography on silica gel (6:1 cyclohexane-
AcOEt): syrup (40% yield); compound 9b was a 75/25 mixture
of E/Z olefins (by 1H NMR analysis); 1H NMR (selected data)
(DMSO-d6, 140 °C) δ 7.40-7.20 (m, 25H), 5.60-5.40 (m, 2H),
5.10 (s, 2H), 4.23 (ddd, 0.75H, J ) 2.5, 6.0, 6.0 Hz), 3.57 (dd,
0.75H, J ) 3.0, 8.5 Hz), 1.55 (s, 0.75H), 1.50 (s, 2.25 H), 1.49
(s, 0.75H), 1.46 (s, 2.25H), 1.42 (s, 2.25H), 1.40 (s, 6.75H);
MALDI-TOF MS (897.1) 920.1 (M + Na), 937.0 (M + K). Anal.
Calcd for C55H64N2O9: C, 73.64; H, 7.19; N, 3.12. Found: C,
73.20; H, 7.08; N, 3.21.
6,9-Anhydro-7,8,10-tri-O-benzyl-6-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-penta-
deoxy-1-O,2-N-isopropylidene-D-talo-D-glycero-dec-3-en-
itol (9c). Chromatography on silica gel (from 6:1 to 3:1
cyclohexane-AcOEt): syrup (40% yield); 9c was a 95/5
mixture of E/Z olefins (by 1H NMR analysis); 1H NMR (major
isomer) (DMSO-d6, 120 °C) δ 7.40-7.20 (m, 20H), 5.54 (ddd,
1H, J ) 5.5, 7.5, 15.5 Hz), 5.42 (dd, 1H, J ) 6.5, 15.5 Hz),
5.14 (d, 1H, J ) 12.5 Hz), 5.06 (d, 1H, J ) 12.5 Hz), 4.58 (d,
1H, J ) 12.0 Hz), 4.53 (d, 1H, J ) 12.0 Hz), 4.49 (d, 1H, J )
12.0 Hz), 4.46 (s, 2H), 4.42 (d, 1H, J ) 12.0 Hz), 4.23 (ddd,
1H, J ) 2.5, 6.5, 6.5 Hz), 4.17 (s, 1H), 4.06 (dd, 1H, J ) 4.0,
10.0 Hz), 3.96 (dd, 1H, J ) 6.0, 9.0 Hz), 3.96 (s, 1H), 3.88-
3.80 (m, 2H), 3.58 (dd, 1H, J ) 2.5, 9.0 Hz), 3.49 (t, 1H, J )
9.5 Hz), 2.70-2.59 (m, 1H), 2.32 (ddd, 1H, J ) 7.5, 10.5, 14.5
Hz), 1.50 (s, 3H), 1.48 (s, 3H), 1.40 (s, 9H); MALDI-TOF MS
(776.9) 800.1 (M + Na), 816.3 (M + K). Anal. Calcd for
C47H56N2O8: C, 72.66; H, 7.26; N, 3.61. Found: C, 72.81; H,
7.35; N, 3.52.
6,9-Anhydro-7,8,10-tri-O-benzyl-6-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-penta-
deoxy-1-O,2-N-isopropylidene-D-manno-L-glycero-dec-3-
enitol (9d). Chromatography on silica gel (from 6:1 to 3:1
cyclohexane-AcOEt); syrup (45% yield); 9d was a 80/20
mixture of E/Z olefins (by 1H NMR analysis); 1H NMR (selected
data for major isomer) (DMSO-d6, 120 °C) δ 5.50-5.35 (m, 2H),
5.11 (s, 2H), 4.70 (d, 1H, J ) 12.0 Hz), 4.62 (d, 1H, J ) 12.0
Hz), 4.44 (s, 2H), 4.30 (dd, 1H, J ) 4.0, 7.0 Hz), 4.21 (dt, 1H,
J ) 3.0, 6.5 Hz), 4.11 (dd, 1H, J ) 6.5, 9.5 Hz), 1.52 (s, 3H),
1.50 (s, 9H), 1.49 (s, 3H); MALDI-TOF MS (777.0) 799.8 (M +
Na), 816.0 (M + K). Anal. Calcd for C47H56N2O8: C, 72.66; H,
7.26; N, 3.61. Found: C, 72.55; H, 7.18; N, 3.73.
1
(65% yield); [R]D ) -6.3 (c 1.7, CHCl3); H NMR (DMSO-d6,
140 °C) δ 7.38-7.20 (m, 25H), 5.83-5.68 (m, 1H), 5.18 (d, 1H,
J ) 11.5 Hz), 5.05 (d, 1H, J ) 12.5 Hz), 5.03-4.90 (m, 2H),
4.94 (d, 1H, J ) 12.5 Hz), 4.61-4.50 (m, 7H), 4.32-4.25 (m,
1H), 4.01 (dd, 1H, J ) 3.0, 6.5 Hz), 3.93 (t, 1H, J ) 3.0 Hz),
3.82 (dd, 1H, J ) 5.5, 10.5 Hz), 3.77 (dd, 1H, J ) 3.5, 6.5 Hz),
3.74-3.65 (m, 2H), 2.85-2.72 (m, 1H), 2.65-2.54 (m, 1H);
MALDI-TOF MS (697.9): 699.0 (M + H), 720.9 (M + Na).
Anal. Calcd for C45H47NO6: C, 77.45; H, 6.79; N, 2.01. Found:
C, 77.05; H, 6.83; N, 1.98.
(2S,3S,4R,5R,6S)-N-Benzyloxycarbonyl-6-benzyloxy-
methyl-3,4,5-tribenzyloxy-2-(2-propenyl)piperidine (2b).
Chromatography on silica gel (6:1 cyclohexane-AcOEt): syrup
1
(58% yield); [R]D ) -42.8 (c 1.2, CHCl3); H NMR (DMSO-d6,
140 °C) δ 7.40-7.20 (m, 25H), 5.67-5.83 (m, 1H), 5.22-4.92
(m. 4H), 4.74-4.40 (m, 9H), 4.15-4.02 (m, 1H), 3.99 (t, 1H, J
) 6.0 Hz), 3.92 (dd, 1H, J ) 6.0, 11.5 Hz), 3.89-3.84 (m, 1H),
3.73-3.64 (m, 2H), 2.60-2.50 (m, 1H), 2.48-2.34 (m, 1H);
MALDI-TOF MS (697.9) 698.8 (M + H), 720.8 (M + Na). Anal.
Calcd for C45H47NO6: C, 77.45; H, 6.79; N, 2.01. Found: C,
77.20; H, 6.71; N, 2.05.
(2R,3R,4R,5R)-N-Benzyloxycarbonyl-3,4-dibenzyloxy-
5-benzyloxymethyl-2-(2-propenyl)pyrrolidine (2c). Chro-
matography on silica gel (8:1 cyclohexane-AcOEt): syrup (45%
1
yield); [R]D ) -27.0 (c 0.6, CHCl3); H NMR (DMSO-d6, 160
°C) δ 7.40-7.20 (m, 20H), 5.85-5.69 (m, 1H), 5.18 (d, 1H, J )
11.5 Hz), 5.13 (d, 1H, J ) 12.0 Hz), 5.10 (d, 1H, J ) 12.0 Hz),
5.06-4.95 (m, 2H), 4.58 (d, 1H, J ) 11.5 Hz), 4.55 (d, 1H, J )
11.5 Hz),4.51-4.40 (m, 4H), 4.24-4.16 (m, 1H), 4.09 (dd, 1H,
J ) 4.0, 9.5 Hz), 3.92-3.82 (m, 2H), 3.54 (t, 1H, J ) 2.5 Hz),
2.72-2.62 (m, 1H), 2.44-2.35 (m, 1H); MALDI-TOF MS (577.7)
578,5 (M + H), 600.6 (M + Na). Anal. Calcd for C37H39NO5:
C, 76.92; H, 6.80; N, 2.42. Found: C, 76.78; H, 6.52; N, 2.28.
(2S,3S,4R,5S)-N-Benzyl-3,4-dibenzyloxy-5-benzyloxy-
methyl-2-(2-propenyl)pyrrolidine (1d). Chromatography
on silica gel (10:1 cyclohexane-AcOEt): syrup (64% overall
yield from 1-(N-benzylhydroxylamino)-2,3,5-tri-O-benzyl-1-
deoxy-D-ribose20a): [R]D ) -2.7 (c 1.2, CHCl3); 1H NMR (CDCl3)
δ 7.38-7.18 (m, 20 H), 5.78-5.66 (m, 1H, H-2′), 5.00-4.90 (m,
2H, H-1′a, H-1′b), 4.67 and 4.54 (2d, 2H, J ) 12.0 Hz, CH2-
Ph), 4.59 and 4.53 (2d, 2H, J ) 12.0 Hz, CH2Ph), 4.08 and
3.82 (2d, 2H, J ) 14.0 Hz, NCH2Ph), 3,98 (dd, 1H, J3,4 ) 5.5,
J4,5 ) 6.0 Hz, H-4), 3.92 (dd, 1H, J5,6a ) 6.5, J6a,6b ) 10.0 Hz,
H-6a), 3.85 (dd, 1H, J5,6b ) 3.0 Hz, H-6b), 3.71 (dd, 1H, J2,3
)
2.0 Hz, H-3), 3.55 (ddd, 1H, H-5), 3.08-3.03 (m, 1H, H-2),
2.21-2.13 (m, 1H, H-3′a), 2.04-1.94 (m, 1H, H-3′b; 13C NMR
δ 140.7, 139.2, 139.0, 138.8, 135.5, 128.8-126.8 (Ph), 117.3,
80.7, 78.7, 73.4, 72.4, 72.3, 68.4, 66.8, 61.7, 52.9, 37.1); MALDI-
TOF MS (533.7) 534,6 (M + H). Anal. Calcd for C36H39NO3:
C, 81.02; H, 7.37; N, 2.62. Found: C, 81.13; H, 7.51; N, 2.12.
(2S,3S,4R,5S)-N-Benzyloxycarbonyl-3,4-dibenzyloxy-5-
benzyloxymethyl-2-(2-propenyl)pyrrolidine (2d). Chro-
matography on silica gel (8:1 cyclohexane-AcOEt): syrup (35%
1
yield); [R]D ) -15.3 (c 0.8, CHCl3); H NMR (DMSO-d6, 120
°C) δ 7.40-7.20 (m, 20H), 5.80-5.60 (m, 1H), 5.11 (s, 2H),
5.06-4.98 (m, 2H), 4.71 (d, 1H, J ) 12.0 Hz), 4.62 (d, 1H, J )
12.0 Hz), 4.60 (d, 1H, J ) 12.0 Hz), 4.58 (d, 1H, J ) 12.0 Hz),
4.45 (d, 1H, J ) 12.0 Hz), 4.40 (d, 1H, J ) 12.0 Hz), 4.31 (dd,
1H, J ) 4.0, 7.5 Hz), 4.22 (ddd, 1H, J ) 3.0, 6.5, 7.0 Hz), 4.12
(dd, 1H, J ) 6.5, 9.5 Hz), 3.94 (dd, 1H, J ) 0.5, 4.0 Hz), 3.82
(ddd, 1H, J ) 0.5, 3.5, 9.0 Hz) 3.64 (dd, 1H, J ) 3.0, 9.5 Hz),
2.58-2.42 (m, 1H), 2.20-2.05 (m, 1H); MALDI-TOF MS (577.7)
578.9 (M + H), 601.0 (M + Na). Anal. Calcd for C37H39NO5:
C, 76.92; H, 6.80; N, 2.42. Found: C, 77.10; H, 6.88; N, 2.21.
Methyl 6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-ben-
zyloxycarbonylamino-2-tert-butoxycarbonylamino-2,3,
4,5,6-pentadeoxy-L-erythro-L-galacto-undec-3-enonate
(13a). Chromatography on silica gel (from 10:1 to 4:1 cyclo-
hexane-AcOEt): syrup (40% yield); 13a was a 95/5 mixture
of E/Z olefins (by 1H NMR analysis); 1H NMR (major isomer)
(DMSO-d6, 120 °C) δ 7.38-7.20 (m, 25H), 6.51 (d, 1H, J ) 7.5
General Procedure for Cross-Metathesis Reaction of
Iminosugar 2 and Alkenes 5 and 7. To a 0.05 M solution of
2 (0.30-0.40 mmol) in dry CH2Cl2 were added the olefin 5 or
J. Org. Chem, Vol. 70, No. 14, 2005 5515

Dondoni et al.
Hz), 5.72 (dt, 1H, J ) 6.5, 15.5 Hz), 5.54 (dd, 1H, J ) 5.5, 15.5
Hz), 5.04 (d, 1H, J ) 12.5 Hz), 4.93 (d, 1H, J ) 12.5 Hz), 4.56
(s, 2H), 4.56 (d, 1H, J ) 12.0 Hz), 4.53 (s, 2H), 4.50 (d, 1H, J
) 12.0 Hz), 4.50-4.00 (m, 1H), 4.46 (s, 2H), 4.25 (q, 1H, J )
5.5 Hz), 4.0 (dd, 1H, J ) 2.5, 6.0 Hz), 3.91 (t, 1H, J ) 3.0 Hz),
3.80 (dd, 1H, J ) 5.0, 10.0 Hz), 3.74 (dd, 1H, J ) 3.5, 6.0 Hz),
3.72-3.64 (m, 1H), 3.68 (dd, 1H, J ) 5.5, 10.0 Hz), 3.60 (s,
3H), 2.80-2.67 (m, 1H), 2.65-2.54 (m, 1H); MALDI-TOF MS
(885.0) 886.4 (M + H). Anal. Calcd for C53H60N2O10: C, 71.92;
H, 6.83; N, 3.17. Found: C, 72.05; H, 6.71; N, 3.23.
General Procedure for Cross-Metathesis Reaction of
Iminosugar 2 and Alkene 6. To a 0.05 M solution of olefin
6 (0.30-0.40 mmol) in dry CH2Cl2 were added the iminosugar
2 (see Table 2 for the equiv) and the Grubbs catalyst 8 (0.2
equiv). The mixture was heated to 40 °C for 18 h while stirring
and then cooled to room temperature and concentrated. The
crude residue was purified by flash chromatography.
7,11-Anhydro-8,9,10,12-tetra-O-benzyl-7-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-
hexadeoxy-1-O,2-N-isopropylidene-L-erythro-L-galacto-
dodec-4-enitol (14a). Chromatography on silica gel (from 8:1
to 3:1 cyclohexane-AcOEt): syrup (50% yield); 14a was a 70/
30 mixture of E/Z olefins (by 1H NMR analysis); 1H NMR
(selected data) (DMSO-d6, 120 °C) δ 7.38-7.15 (m, 25H), 5.50-
5.28 (m, 2H), 5.04 (d, 0.70H, J ) 12.5 Hz), 5.01 (d, 0.30H, J )
12.5 Hz), 4.92 (d, 0.70H, J ) 12.5 Hz), 4.90 (d. 0.30H, J )
12.5 Hz), 1.44 (s, 2.70H), 1.42 (s, 6.30H); MALDI-TOF MS
(911.1) 933.2 (M + Na), 949.2 (M + K). Anal. Calcd for
C56H66N2O9: C, 73.82; H, 7.30; N, 3.07. Found: C, 73.66; H,
7.39; N, 3.25.
7,11-Anhydro-8,9,10,12-tetra-O-benzyl-7-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-
hexadeoxy-1-O,2-N-isopropylidene-L-threo-L-galacto-
dodec-4-enitol (14b). Chromatography on silica gel (from 6:1
to 3:1 cyclohexane-AcOEt): syrup (70% yield); 14b was a 60/
40 mixture of E/Z olefins (by 1H NMR analysis); 1H NMR
(selected data) (DMSO-d6, 140 °C) δ 7.40-7.18 (m, 25H), 5.30-
5.50 (m, 2H), 5.10 (s, 1.2H), 5.08 (s, 0.8H), 1.44 (s, 5.4H), 1.42
(s, 3.6H); MALDI-TOF MS (911.1) 932.9 (M + Na), 949.0 (M
+ K). Anal. Calcd for C56H66N2O9: C, 73.82; H, 7.30; N, 3.07.
Found: C, 73.91; H, 7.15; N, 3.12.
solution of alkene 9 or 14 (0.12-0.16 mmol) in 1,2-dimethoxy-
ethane was added freshly recrystallized toluene-p-sulfonylhy-
drazide (6.0 equiv). To the stirred and warmed (85 °C) solution
was added 1 M aq sodium acetate (6.0 equiv) by a syringe-
pump apparatus during 4 h. After an additional 1 h at 85 °C
the mixture was cooled to room temperature, diluted with
water, and extracted with CH2Cl2. The organic phase was dried
(Na2SO4) and concentrated. The crude residue was purified
by flash chromatography.
6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-pen-
tadeoxy-1-O,2-N-isopropylidene-L-erythro-L-galacto-un-
decitol (10a). Chromatography on silica gel (4:1 cyclohexane-
AcOEt): syrup (82% yield); [R]D ) -4.4 (c 0.9, CH3OH); 1H
NMR (DMSO-d6, 120 °C) δ 7.38-7.20 (m, 25H), 5.03 (d, 1H, J
) 12.5 Hz), 4.89 (d, 1H, J ) 12.5 Hz), 4.57 (s, 2H), 4.57 (d,
1H, J ) 12.0 Hz), 4.54 (d, 1H, J ) 11.0 Hz), 4.50 (d, 1H, J )
12.0 Hz), 4.48 (d, 1H, J ) 11.0 Hz), 4.48 (d, 1H, J ) 11.0 Hz),
4.29-4.21 (m, 1H), 3.95 (dd, 1H, J ) 3.0, 7.0 Hz), 3.94-3.88
(m, 1H), 3.86 (dd, 1H, J ) 5.2, 10.0 Hz), 3.80 (dd, 1H, J ) 6.0,
9.0 Hz), 3.75-3.63 (m, 3H), 3.57-3.47 (m, 1H), 3.53 (dd, 1H,
J ) 2.0, 9.0 Hz), 2.10-1.97 (m, 1H), 1.86-1.72 (m, 1H), 1.68-
1.54 (m, 1H), 1.52-1.18 (m, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.42
(s, 9H). MALDI-TOF MS (899.1) 922.0 (M + Na), 937.9 (M +
K). Anal. Calcd for C55H66N2O9: C, 73.47; H, 7.40; N, 3.12.
Found: C, 73.26; H, 7.48; N, 3.19.
6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-pen-
tadeoxy-1-O,2-N-isopropylidene-L-threo-L-galacto-undeci-
tol (10b). Chromatography on silica gel (4:1 cyclohexane-
AcOEt): syrup (71% yield); [R]D ) -11.6 (c 0.9, CHCl3); 1H
NMR (DMSO-d6, 140 °C) δ 7.38-7.20 (m, 25H), 5.09 (s, 2H),
4.66 (d, 1H, J ) 11.5 Hz), 4.64 (s, 2H), 4.61 (d, 1H, J ) 11.5
Hz), 4.55 (d, 1H, J ) 12.0 Hz), 4.52 (d, 1H, J ) 12.0 Hz), 4.43
(s, 2H), 4.40-4.46 (m, 1H), 4.00-3.91 (m, 3H), 3.86 (dd, 1H, J
) 2.0, 8.0 Hz), 3.81 (dd, 1H, J ) 6.0, 8.5 Hz), 3.74-3.66 (m,
2H), 3.63 (dd, 1H, J ) 12.0, 4.5 Hz), 3.55 (dd, 1H, J ) 2.0, 8.5
Hz), 2.80-1.55 (m, 4H), 1.50 (s, 3H), 1.42 (s, 12H), 1.35-1.20
(m, 2H); MALDI-TOF MS (899.1) 921.9 (M + Na), 937.9 (M +
K). Anal. Calcd for C55H66N2O9: C, 73.47; H, 7.40; N, 3.12.
Found: C, 73.78; H, 7.56; N, 3.01.
7,10-Anhydro-8,9,11-tri-O-benzyl-7-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-hexa-
deoxy-1-O,2-N-isopropylidene-D-talo-DD-glycero-undec-
4-enitol (14c). Chromatography on silica gel (from 6:1 to 3:1
cyclohexane-AcOEt): syrup (45% yield); 14c was a 60/40
mixture of E/Z olefins (by 1H NMR analysis), 1H NMR
(selected data) (DMSO-d6, 120 °C) δ 7.40-7.15 (m, 20H), 5.13
(d, 1H, J ) 12.5 Hz), 5.07 (d, 1H, J ) 12.5 Hz), 4.16 (d, 1H, J
) 3.5 Hz) 3.71 (dd, 0.4H, J ) 2.0, 8.5 Hz), 3.64 (dd, 0.6H, J )
2.0, 8.5 Hz), 3.05 (dd, 0.6H, J ) 3.0, 9.5 Hz), 3.46 (dd, 0.4H, J
) 3.0, 9.5 Hz), 2.65-2.55 (m, 1H), 2.5-2.12 (m, 3H); MALDI-
TOF MS (791.0) 813.9 (M + Na), 829.8 (M + K). Anal. Calcd
for C48H58N2O8: C, 72.89; H, 7.39; N, 3.54. Found: C, 72.71;
H, 7.45; N, 3.43.
7,10-Anhydro-8,9,11-tri-O-benzyl-7-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-hexa-
deoxy-1-O,2-N-isopropylidene-D-manno-L-glycero-undec-
4-enitol (14d). Chromatography on silica gel (7:1 toluene-
Et2O): syrup (54% yield); 14d was a 80/20 mixture of E/Z
olefins (by 1H NMR analysis); 1H NMR (selected data for major
isomer) (DMSO-d6, 120 °C) δ 5.42-5.36 (m, 2H), 5.11 (s, 2H),
4.71 (d, 1H, J ) 12.0 Hz), 4.63 (d, 1H, J ) 12.0 Hz), 4.62 (d,
1H, J ) 12.0 Hz), 4.59 (d, 1H, J ) 12.0 Hz), 4.43 (s, 2H), 4.28
(dd, 1H, J ) 4.0, 7.0 Hz), 4.21 (dt, 1H, J ) 3.0, 6.5 Hz), 4.11
(dd, 1H, J ) 6.5, 9.5 Hz), 3.88 (dd, 1H, J ) 5.5, 8.5 Hz), 3.65
(dd, 2H, J ) 2.0, 9.0 Hz), 1.52 (s, 3H), 1.50 (s, 9H), 1.48 (s,
3H); MALDI-TOF MS (911.1) 813.5 (M + Na), 829.5 (M + K).
Anal. Calcd for C48H58N2O8: C, 72.89; H, 7.39; N, 3.54.
Found: C, 72.91; H, 7.27; N, 3.29.
6,9-Anhydro-7,8,10-tri-O-benzyl-6-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-penta-
deoxy-1-O,2-N-isopropylidene-D-talo-D-glycero-decitol
(10c). Chromatography on silica gel (3:1 cyclohexane-
AcOEt): syrup (80% yield); [R]D ) -22.0 (c 0.8, CHCl3); 1H
NMR (DMSO-d6, 120 °C) δ 7.40-7.20 (m, 20H), 5.13 (d, 1H, J
) 12.5 Hz), 5.06 (d, 1H, J ) 12.5 Hz), 4.58 (d, 1H, J ) 12.0
Hz), 4.53 (d, 1H, J ) 12.0 Hz), 4.50 (s, 2H), 4.49 (d, 1H, J )
12.0 Hz), 4.42 (d, 1H, J ) 12.0 Hz), 4.17 (s, 1H), 4.05 (dd, 1H,
J ) 4.0, 10.0 Hz), 3.93 (s, 1H), 3.89-3.79 (m, 2H), 3.75 (dd,
1H, J ) 3.0, 10.0 Hz), 3.74-3.67 (m, 1H), 3.59 (dd, 1H, J )
2.0, 9.0 Hz), 3.48 (t, 1H, J ) 9.0 Hz), 1.92-1.75 (m, 1H), 1.72-
1.52 (m, 3H), 1.50 (s, 3H), 1.45 (s, 3H), 1.42 (s, 9H), 1.35-1.15
(m, 2H); MALDI-TOF MS (778.9) 801.9 (M + Na), 817.8 (M +
K). Anal. Calcd for C47H58N2O8: C, 72.47; H, 7.50; N, 3.60.
Found: C, 72.18; H, 7.38; N, 3.72.
6,9-Anhydro-7,8,10-tri-O-benzyl-6-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-penta-
deoxy-1-O,2-N-isopropylidene-D-manno-L-glycero-deci-
tol (10d). Chromatography on silica gel (3:1 cyclohexane-
AcOEt): syrup (82% yield); [R]D ) +6.0 (c 1.6, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 7.40-7.20 (m, 20H), 5.12 (d, 1H, J ) 11.5
Hz), 5.08 (d, 1H, J ) 11.5 Hz), 4.72 (d, 1H, J ) 11.5 Hz), 4.65
(d, 1H, J ) 12.0 Hz), 4.64 (d, 1H, J ) 11.5 Hz), 4.61 (d, 1H, J
) 12.0 Hz), 4.45 (d, 1H, J ) 11.5 Hz), 4.42 (d, 1H, J ) 11.5
Hz), 4.30 (dd, 1H, J ) 4.0, 7.0 Hz), 4.22 (ddd, H, J ) 3.0, 6.5,
6.5 Hz), 4.17-4.08 (m, 2H), 3.96-3.84 (m, 2H), 3.78-3.68 (m,
2H), 3.63 (dd, 1H, J ) 2.0, 9.0 Hz), 1.80-1.20 (m, 6H), 1.51 (s,
3H), 1.45 (s, 3H), 1.42 (s, 9H); MALDI-TOF MS (778.9) 802.3
(M + Na), 818.1 (M + K). Anal. Calcd for C47H58N2O8: C, 72.47;
H, 7.50; N, 3.60. Found: C, 72.22; H, 7.48; N, 3.45.
General Procedure for the Reduction of the Double
Bond. Synthesis of Oxazolidines 10 and 15. To a 0.05 M
5516 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of C-Iminoglycosyl R-Amino Acids
7,11-Anhydro-8,9,10,12-tetra-O-benzyl-7-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-
hexadeoxy-1-O,2-N-isopropylidene-L-erythro-L-galacto-
dodecitol (15a). Chromatography on silica gel (8:1 toluene-
Et2O): syrup (75% yield); [R]D ) +6.7 (c 0.8, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 7.38-7.20 (m, 25H), 5.03 (d, 1H, J ) 12.5
Hz), 4.58 (s, 2H), 4.57 (d, 1H, J ) 11.5 Hz), 4.56 (d, 1H, J )
11.5 Hz), 4.52 (d, 1H, J ) 11.5 Hz), 4.50 (d, 1H, J ) 11.5 Hz),
4.47 (s, 2H), 4.31-4.24 (m, 1H), 3.96 (dd, 1H, J ) 2.5, 9.5 Hz),
3.92 (t, 1H, J ) 3.0 Hz), 3.87 (dd, 1H, J ) 2.5, 5.5 Hz), 3.86-
3.82 (m, 1H), 3.76-3.68 (m, 3H), 3.60 (dd, 1H, J ) 2.0, 8.5
Hz), 3.60-3.51 (m, 1H), 2.15-2.0 (m, 1H), 1.85-1.18 (m, 7H),
1.50 (s, 3H), 1.44 (s, 3H), 1.42 (s, 9H); MALDI-TOF MS (913.1)
935.9 (M + Na), 951.9 (M + K). Anal. Calcd for C56H68N2O9:
C, 73.66; H, 7.51; N, 3.07. Found: C, 73.71; H, 7.63; N, 3.10.
7,11-Anhydro-8,9,10,12-tetra-O-benzyl-7-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-
hexadeoxy-1-O,2-N-isopropylidene-L-threo-Dl-galacto-
dodecitol (15b). Chromatography on silica gel (5:1 cyclo-
hexane-AcOEt): syrup (73% yield); [R]D ) -13.4 (c 1.3,
CHCl3); 1H NMR (DMSO-d6, 140 °C) δ 7.40-7.20 (m, 25H),
5.08 (d, 2H, J ) 5.0 Hz), 4.70-4.40 (m, 9H), 3.99-3.80 (m,
5H), 3.76-3.58 (m, 4H), 1.85-1.52 (m, 4H), 1.52 (s, 3H), 1.48
(s, 3H), 1.42 (s, 9H), 1.75-1.38 (m, 4H); MALDI-TOF MS
(913.1) 936.0 (M + Na), 952.1 (M + K). Anal. Calcd for
C56H68N2O9: C, 73.66; H, 7.51; N, 3.07. Found: C, 73.72; H,
7.48; N, 3.11.
7,10-Anhydro-8,9,11-tri-O-benzyl-7-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-hexa-
deoxy-1-O,2-N-isopropylidene-D-talo-D-glycero-undeci-
tol (15c). Chromatography on silica gel (5:1 cyclohexane-
AcOEt): syrup (65% yield); compound 15c was slightly
contaminated by 14c not separable by flash chromatography:
1H NMR (DMSO-d6, 120 °C) δ 7.40-7.20 (m, 20H), 5.12 (d,
1H, J ) 12.5 Hz), 5.06 (d, 1H, J ) 12.5 Hz), 4.57 (d, 1H, J )
12.0 Hz), 4.53 (d, 1H, J ) 12.0 Hz), 4.51 (s, 2H), 4.49 (d, 1H,
J ) 12.0 Hz), 4.44 (d, 1H, J ) 12.0 Hz), 4.15 (s, 1H), 4.05 (dd,
1H, J ) 4.0, 10.0 Hz), 3.95 (s, 1H), 3.89-3.79 (m, 2H), 3.77
(dd, 1H, J ) 3.0, 10.0 Hz), 3.74-3.63 (m, 1H), 3.61 (dd, 1H, J
) 2.0, 9.0 Hz), 3.52-3.45 (m, 1H), 1.92-1.51 (m, 6H), 1.50 (s,
3H), 1.45 (s, 3H), 1.42 (s, 9H), 1.35-1.15 (m, 2H); MALDI-
TOF MS (793.0) 815.9 (M + Na), 831.8 (M + K).
7,10-Anhydro-8,9,11-tri-O-benzyl-7-N-benzyloxycarbo-
nylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-hexa-
deoxy-1-O,2-N-isopropylidene-D-manno-L-glycero-undeci-
tol (15d). Chromatography on silica gel (5:1 cyclohexane-
AcOEt): syrup (71% yield); [R]D ) +10.8 (c 1.0, CHCl3); 1H
NMR (DMSO-d6, 120 °C) δ 7.40-7.20 (m, 20H), 5.12 (d, 1H, J
) 12.0 Hz), 5.08 (d, 1H, J ) 12.0 Hz), 4.72 (d, 1H, J ) 12.0
Hz), 4.64 (d, 1H, J ) 12.0 Hz), 4.44 (d, 1H, J ) 12.0 Hz), 4.40
(d, 1H, J ) 12.0 Hz), 4.30 (dd, 1H, J ) 4.0, 6.5 Hz), 4.21 (ddd,
1H, J ) 2.5, 6.5, 6.5 Hz), 4.13 (dd, 1H, J ) 6.5, 10.0 Hz), 3.96-
3.60 (m, 6H), 1.80-1.20 (m, 8H), 1.51 (s 3H), 1.44 (s, 3H), 1.42
(s, 9H); MALDI-TOF MS (793.0) 815.7 (M + Na), 831.6 (M +
K). Anal. Calcd for C48H60N2O8: C, 72.70; H, 7.63; N, 3.53.
Found: C, 72.56; H, 7.43; N, 3.37.
was evaporated to dryness. The crude residue was purified by
flash chromatography.
6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-pen-
tadeoxy-L-erythro-L-galacto-undeconic Acid (11a). From
10a (See General Procedure Above). Crude 11a: syrup
(∼90% yield; 90% pure by 1H NMR analysis); 1H NMR (DMSO-
d6, 140 °C) δ 7.20-7.40 (m, 25 H), 6.15-6.02 (m, 1H), 5.02 (d,
1H, J ) 12.5 Hz), 4.91 (d, 1H, J ) 12.5 Hz), 4.57 (s, 2H), 4.55-
4.49 (m, 4H), 4.48 (d, 1H, J ) 12.0 Hz), 4.45 (d, 1H, J ) 12.0
Hz), 4.30-4.22 (m, 1H), 3.98-3.88 (m, 3H), 3.83 (dd, 1H, J )
5.5, 10.0 Hz), 3.75-3.68 (m, 2H), 3.59-3.50 (m, 1H), 2.15-
2.02 (m, 1H), 1.85-1.50 (m, 3H), 1.42 (s, 9H), 1.40-1.20 (m
4H); MALDI-TOF MS (873.0) 896.6 (M + Na), 912.6 (M + K).
From 12a. To a solution of 12a (70 mg, 0.08 mmol) in EtOH
(7 mL) was added 1.0 M NaOH (0.25 mL, 0.25 mmol). The
solution was stirred for 14 h at rt, then cooled (0 °C) and
treated with1.0 M HCl until pH 3-4. The mixture was diluted
with H2O and extracted with Et2O (3 × 15 mL). The combined
organic extracts were dried (Na2SO4) and then evaporated to
dryness to give crude 11a (∼70% yield; 90% pure by 1H NMR
analysis).
Methyl 6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-ben-
zyloxycarbonylamino-2-tert-butoxycarbonylamino-2,3,
4,5,6-pentadeoxy-L-erythro-L-galacto-undeconate (12a).
Chromatography on silica gel (3:1 cyclohexane-AcOEt): syrup
(81% yield); [R]D ) -12.3 (c 0.7, CH3OH); 1H NMR (DMSO-d6,
140 °C) δ 7.38-7.22 (m, 25H), 6.50-6.40 (m, 1H), 5.02 (d, 1H,
J ) 12.5 Hz), 4.90 (d, 1H, J ) 12.5 Hz), 4.56 (s, 2H), 4.55 (d,
1H, J ) 12.0 Hz), 4.53-4.53 (m, 4H), 4.48 (d, 1H, J ) 12.0
Hz), 4.28-4.21 (m, 1H), 3.95-3.88 (m, 3H), 3.82 (dd, 1H, J )
5.5, 10.5 Hz), 3.73-3.66 (m, 2H), 3.60 (s, 3H), 3.54-3.45 (m,
1H), 2.12-2.00 (m, 1H),1.82-1.68 (m, 1H), 1.65-1.50 (m, 2H),
1.42-1.25 (m, 2H), 1.40 (s, 9H); MALDI-TOF MS (887.1) 909.6
(M + Na), 925.6 (M + K). Anal. Calcd for C53H62N2O10: C,
71.76; H, 7.04; N, 3.16. Found: C, 72.10; H, 7.24; N, 3.02.
Methyl 6,10-Anhydro-7,8,9,11-tetra-O-benzyl-6-N-ben-
zyloxycarbonylamino-2-tert-butoxycarbonylamino-2,3,
4,5,6-pentadeoxy-L-threo-L-galacto-undeconate (12b). Chro-
matography on silica gel (3:1 cyclohexane-AcOEt): syrup (81%
1
yield); [R]D ) -11.4 (c 0.7, CHCl3); H NMR (DMSO-d6, 120
°C) δ 7.38-7.15 (m, 25H), 6.50-6.42 (m, 1H), 5.08 (s, 2H), 4.64
(d, 1H, J ) 12.0 Hz), 4.63 (s, 2H), 4.59 (d, 1H, J ) 12.0 Hz),
4.54 (d, 1H, J ) 12.0 Hz), 4.51 (d, 1H, J ) 12.0 Hz), 4.44-
4.38 (m, 1H), 4.42 (s, 2H), 4.00-3.87 (m, 4H), 3.84 (dd, 1H, J
) 2.0, 7.0 Hz), 3.67 (dd, 1H, J ) 5.0, 11.5 Hz), 3.64-3.60 (m,
1H), 3.62 (s, 3H), 1.80-1.30 (m, 6H), 1.40 (s, 9H); MALDI-
TOF MS (887.1) 909.8 (M + Na), 925.8 (M + K). Anal. Calcd
for C53H62N2O10: C, 71.76; H, 7.04; N, 3.16. Found: C, 71.88;
H, 7.15; N, 3.06.
Methyl 6,9-Anhydro-7,8,10-tri-O-benzyl-6-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-pen-
tadeoxy-D-talo-D-glycero-deconate (12c). Chromatography
on silica gel (3:1 cyclohexane-AcOEt): syrup (76% yield); [R]D
1
) -21.8 (c 0.7, CHCl3); H NMR (DMSO-d6, 120 °C) δ 7.40-
7.20 (m, 20H), 6.45 (d, 1H, J ) 8.0 Hz), 5.12 (d, 1H, J ) 12.5
Hz), 5.07 (d, 1H, J ) 12.5 Hz), 4.58 (d, 1H, J ) 12.0 Hz), 4.54
(d, 1H, J ) 12.0 Hz), 4.50 (d, 1H, J ) 12.0 Hz), 4.48 (d, 1H, J
) 12.0 Hz) 4.47 (d, 1H, J ) 12.0 Hz), 4.41 (d, 1H, J ) 12.0
Hz), 4.15 (s, 1H), 4.03 (dd, 1H, J ) 4.0, 10.0 Hz), 4.00-3.90
(m, 1H), 3.92 (s, 1H), 3.81 (dd, 1H, J ) 4.0, 9.0 Hz), 3.75 (dd,
1H, J ) 3.0, 10.0 Hz), 3.64 (s, 3H), 3.47 (t, 1H, J ) 9.5 Hz),
1.84-1.75 (m, 1H), 1.70-1.52 (m, 3H), 1.42 (s, 9H), 1.40-1.25
(m, 2H); MALDI-TOF MS (766.9) 790.1 (M + Na), 805.9 (M +
K). Anal. Calcd for C45H54N2O9: C, 70.47; H, 7.10; N, 3.65.
Found: C, 70.89; H, 7.00; N, 3.75.
General Procedure for the Oxidative Cleavage of
Oxazolidines 10 and 15. Synthesis of R-Amino Esters 12
and 16. To a cooled (0 °C), stirred solution of oxazolidines 10
or 15 (0.1 mmol) in acetone (2 mL) was added freshly prepared
1 M Jones reagent (0.30 mL). The mixture was allowed to
warm to room temperature during 30 min and then was stirred
for an additional 3 h. To the orange suspension was added
dropwise propan-2-ol until a green color was observed, then
the reaction mixture was diluted with CH2Cl2 (30 mL) and
washed with brine (3 × 10 mL). The organic phase was dried
(Na2SO4) and concentrated to afford crude R-amino acids which
were employed without any purification. The methyl esters
were prepared by adding ethereal diazomethane to an Et2O-
MeOH (1:1) solution of the above crude R-amino acids cooled
at 0 °C. After for 10 min, a small amount of AcOH was added
to quench any remaining diazomethane, and then the solution
Methyl 6,9-Anhydro-7,8,10-tri-O-benzyl-6-N-benzyloxy-
carbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6-pen-
tadeoxy-D-manno-L-glycero-deconate (12d). Chromatog-
raphy on silica gel (2:1 cyclohexane-AcOEt): syrup (78%
yield); [R]D ) +5.1 (c 0.6, CHCl3); 1H NMR (DMSO-d6, 120 °C)
δ 7.40-7.20 (m, 20H), 6.55 (d, 1H, J ) 6.0 Hz), 5.10 (s, 2H),
J. Org. Chem, Vol. 70, No. 14, 2005 5517

Dondoni et al.
4.71 (d, 1H, J ) 12.0 Hz), 4.63 (d, 1H, J ) 12.0 Hz), 4.62 (d,
1H, J ) 12.0 Hz), 4.61 (d, 1H, J ) 12.0 Hz), 4.44 (d, 1H, J )
11.5 Hz), 4.40 (d, 1H, J ) 12.0 Hz), 4.30 (dd, 1H, J ) 4.0, 7.0
Hz), 4.21 (ddd, 1H, J ) 2.5, 6.5, 6.5 Hz), 4.12 (dd, 1H, J ) 6.5,
9.5 Hz), 4.01-3.91 (m, 2H), 3.74-3.58 (m, 2H), 3.65 (s, 3H),
1.78-1.22 (m, 6H), 1.40 (s, 9H); MALDI-TOF MS (766.9) 789.6
(M + Na), 805.6 (M + K). Anal. Calcd for C45H54N2O9: C, 70.47;
H, 7.10; N, 3.65. Found: C, 70.21; H, 7.28; N, 3.51.
Methyl 7,11-Anhydro-8,9,10,12-tetra-O-benzyl-7-N-ben-
zyloxycarbonylamino-2-tert-butoxycarbonylamino-2,3,
4,5,6,7-hexadeoxy-L-erythro-L-galacto-dodeconate (16a).
Chromatography on silica gel (4:1 cyclohexane-AcOEt): syrup
(80% yield); [R]D ) -12.1 (c 1.0, CH3OH); 1H NMR (DMSO-d6,
120 °C) δ 7.38-7.20 (m, 25H), 6.47 (d, 1H, J ) 7.0 Hz), 5.02
(d, 1H, J ) 12.5 Hz), 4.90 (d, 1H, J ) 12.5 Hz), 4.57 (s, 2H),
4.56 (d, 1H, J ) 11.5 Hz), 4.54 (d, 1H, J ) 11.5 Hz), 4.51 (d,
1H, J ) 11.5 Hz), 4.49 (d, 1H, J ) 11.5 Hz), 4.47 (s, 2H), 4.29-
4.21 (m, 1H), 4.00-3.89 (m, 3H), 3.83 (dd, 1H, J ) 5.5, 10.0
Hz), 3.74-3.67 (m, 2H), 3.63 (s, 3H), 3.55-3.46 (m, 1H), 2.15-
1.98 (m, 1H), 1.80-1.65 (m, 1H), 1.65-1.45 (m, 2H), 1.40 (s,
9H), 1.37-1.20 (m, 4H); MALDI-TOF MS (901.1) 923.6 (M +
Na), 939.5 (M + K). Anal. Calcd for C54H64N2O10: C, 71.98; H,
7.16; N, 3.11. Found: C, 72.21; H, 7.11; N, 3.23.
Anal. Calcd for C46H56N2O9: C, 70.75; H, 7.23; N, 3.59.
Found: C, 70.61; H, 7.18; N, 3.41.
Dipeptide 17. To a cooled (0 °C), stirred solution of amino
acid 11a (100 mg, 0.11 mmol), l-phenylalanine methyl ester
hydrochloride (30 mg, 0.17 mmol), and (benzotriazol-1-yloxy)-
tripyrrolidinophosphonium hexafluorophosphate (68 mg, 0.13
mmol) in dry CH2Cl2 (1.5 mL) was added N,N-diisopropyl-
ethylamine (57 µL, 0.33 mmol). The solution was warmed to
rt, stirred for an additional 2 h, and then concentrated. The
residue was suspended with AcOEt (15 mL) and washed with
H2O. The organic phase was dried (Na2SO4) and concentrated.
The crude residue was purified by flash chromatography (2:1
cyclohexane-AcOEt) to give compound 17 (91 mg, 80% yield)
1
as a syrup: [R]D ) +5.4 (c 0.8, CHCl3); H NMR (DMSO-d6,
120 °C) δ 7.65 (d, 1H, J ) 8.0 Hz), 7.40-7.15 (m, 30 H), 6.14
(d, 1H, J ) 8.0 Hz), 5.01 (d, 1H, J ) 12.5 Hz), 4.90 (d, 1H, J
) 12.5 Hz), 4.63-4.41 (m, 9H), 4.28-4.20 (m, 1H), 3.96-3.86
(m, 3H), 3.80 (dd, 1H, J ) 5.5, 10.0 Hz), 3.73-3.65 (m, 2H),
3.58 (s, 3H), 3.55-3.45 (m, 1H), 3.06 (dd, 1H, J ) 6.0, 14.0
Hz), 2.97 (dd, 1H, J ) 7.5, 14.0 Hz), 2.11-1.98 (m, 1H), 1.82-
1.69 (m, 1H), 1.64-1.43 (m, 2H), 1.38 (s, 9H), 1.38-1.26 (m,
2H); MALDI-TOF MS (1034.2) 1056.6 (M + Na), 1072.6 (M +
K). Anal. Calcd for C62H71N3O11: C, 72.00; H, 6.92; N, 4.06.
Found: C, 72.25; H, 6.83; N, 4.16.
Methyl 7,11-Anhydro-8,9,10,12-tetra-O-benzyl-7-N-ben-
zyloxycarbonylamino-2-tert-butoxycarbonylamino-2,3,
4,5,6,7-hexadeoxy-L-threo-L-galacto-dodeconate (16b).
Chromatography on silica gel (3:1 cyclohexane-AcOEt): syrup
Tripeptide 18. To a cooled (0 °C), stirred solution of the
above dipeptide 17 (103 mg, 0.10 mmol) in CH2Cl2 (2.5 mL)
was slowly added a solution of 1/3 TFA-CH2Cl2 (2 mL). Stirring
was continued at 0 °C for an additional 30 min, the solution
was warmed to rt. After 30 min at this temperature the
solution was cooled again (0 °C), neutralized with an aqueous
saturated solution of Na2CO3, and then extracted with CH2-
Cl2. The combined organic phases were dried (Na2SO4) and
concentrated to give the corresponding crude free amine (85
mg) suitable for the next step.
To a cooled (0 °C), stirred solution of the above free amine
(85 mg, 0.09 mmol), tert-butoxycarbonyl-L-phenylalanine (34
mg, 0.13 mmol), and (benzotriazol-1-yloxy)-tripyrrolidinophos-
phonium hexafluorophosphate (70 mg, 0.13 mmol) in dry CH2-
Cl2 (2 mL) was added N,N-diisopropylethylamine (47 µL, 0.27
mmol). The solution was warmed to rt, stirred for an additional
2 h, and then concentrated. The residue was suspended with
AcOEt (15 mL) and washed with H2O. The organic phase was
dried (Na2SO4), concentrated. The crude residue was purified
by flash chromatography (cyclohexane-AcOEt) to give com-
pound 18 (71 mg, 60% yield from 17) as a syrup: [R]D ) -14.0
(c 0.8, CHCl3); 1H NMR (DMSO-d6, 120 °C) δ 7.81 (d, 1H, J )
8.0 Hz), 7.52 (d, 1H, J ) 8.0 Hz), 7.40-7.15 (m, 35H), 6.27 (d,
1H, J ) 8.0 Hz), 5.01 (d, 1H, J ) 12.5 Hz), 4.90 (d, 1H, J )
12.5 Hz), 4.62-4.40 (m, 9H), 4.34-4.18 (m, 3H), 3.95-3.87 (m,
2H), 3.80 (dd, 1H, J ) 5.5, 10.0 Hz), 3.74-3.65 (m, 2H), 3.55
(s, 3H), 3.55-3.47 (m, 1H), 3.11-2.73 (m, 4H), 2.15-2.00 (m,
1H), 1.90-1.60 (m, 2H), 1.60-1.30 (m, 3H), 1.28 (s, 9H);
MALDI-TOF MS (1181.4) 1203.8 (M + Na), 1219.7 (M + K).
Anal. Calcd for C71H80N4O12: C, 72.18; H, 6.83; N, 4.74.
Found: C, 72.43; H, 6.91; N, 4.78.
1
(78% yield); [R]D ) -13.5 (c 1.0, CHCl3); H NMR (DMSO-d6,
120 °C) δ 7.38-7.18 (m, 25H), 6.47 (d, 1H, J ) 7.5 Hz), 5.09
(s, 2H), 4.66 (d, 1H, J ) 11.5 Hz), 4.63 (s, 2H), 4.60 (d, 1H, J
) 11.5 Hz), 4.54 (d, 1H, J ) 11.5 Hz), 4.51 (d, 1H, J ) 11.5
Hz), 4.45-4.39 (m, 1H), 4.42 (s, 2H), 4.00-3.87 (m, 4H), 3.84
(dd, 1H, J ) 2.0, 7.0 Hz), 3.67 (dd, 1H, J ) 5.0, 11.5 Hz), 3.66-
3.60 (m, 1H), 3.64 (s, 3H), 1.80-1.50 (m, 4H), 1.42 (s, 9H),
1.35-1.20 (m, 4H); MALDI-TOF MS (901.1) 923.9 (M + Na),
939.8 (M + K). Anal. Calcd for C54H64N2O10: C, 71.98; H, 7.16;
N, 3.11. Found: C, 71.47; H, 7.24; N, 3.17.
Methyl 7,10-Anhydro-8,9,11-tri-O-benzyl-7-N-benzyl-
oxycarbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-
hexadeoxy-L-talo-L-glycero-undeconate (16c). Chroma-
tography on silica gel (3:1 cyclohexane-AcOEt): syrup (83%
1
yield); [R]D ) -21.7 (c 0.6, CHCl3); H NMR (DMSO-d6, 120
°C) δ 7.40-7.20 (m, 20H), 6.49 (d, 1H, J ) 8.0 Hz), 5.13 (d,
1H, J ) 12.0 Hz), 5.07 (d, 1H, J ) 12.0 Hz), 4.58 (d, 1H, J )
12.0 Hz), 4.54 (d, 1H, J ) 12.0 Hz), 4.49 (s, 2H), 4.48 (d, 1H,
J ) 12.0 Hz), 4.44 (d, 1H, J ) 12.0 Hz), 4.15 (s, 2H), 4.04 (dd,
1H, J ) 4.0, 9.5 Hz), 4.00-3.94 (m, 1H), 3.91 (s, 1H), 3.82 (dd,
1H, J ) 4.0, 9.5 Hz), 3.75 (dd, 1H, J ) 3.0, 9.5 Hz), 3.64 (s,
3H), 3.48 (t, 1H, J ) 9.5 Hz), 1.87-1.74 (m, 1H), 1.7-1.50 (m,
3H), 1.40 (s, 9H), 1.35-1.20 (m, 4H); MALDI-TOF MS (780.9)
803.5 (M + Na), 819.4 (M + K). Anal. Calcd for C46H56N2O9:
C, 70.75; H, 7.23; N, 3.59. Found: C, 70.81; H, 7.17; N, 3.49.
Methyl 7,10-Anhydro-8,9,11-tri-O-benzyl-7-N-benzyl-
oxycarbonylamino-2-tert-butoxycarbonylamino-2,3,4,5,6,7-
hexadeoxy-D-manno-L-glycero-undeconate (16d). Chro-
matography on silica gel (3:1 cyclohexane-AcOEt): syrup (85%
yield); [R]D ) +5.8 (c 0.8, CHCl3); 1H NMR (DMSO-d6, 120 °C)
δ 7.40-7.20 (m, 20H), 6.61-6.48 (m, 1H), 5.12 (d, 1H, J ) 12.0
Hz), 5.08 (d, 1H, J ) 12.0 Hz), 4.71 (d, 1H, J ) 12.0 Hz), 4.64
(d, 1H, J ) 12.0 Hz), 4.63 (d, 1H, J ) 12.0 Hz) 4.61 (d, 1H, J
) 12.0 Hz), 4.44 (d, 1H, J ) 12.0 Hz), 4.40 (d, 1H, J ) 12.0
Hz), 4.30 (dd, 1H, J ) 4.0, 6.5 Hz), 4.21 (ddd, 1H, J ) 2.5, 6.5,
6.5 Hz), 4.12 (dd, 1H, J ) 6.5, 10.0 Hz), 4.02-3.90 (m, 2H),
3.72-3.58 (m, 2H), 3.65 (s, 3H), 1.80-1.20 (m, 8H), 1.40 (s,
9H); MALDI-TOF MS (780.9) 803.4 (M + Na), 819.3 (M + K).
Acknowledgment. We thank Mr. P. Formaglio for
technical assistance with the NMR spectroscopy.
Supporting Information Available: 1H NMR spectra of
compounds 9a-d, 13a, and 14a-d. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO050494O
5518 J. Org. Chem., Vol. 70, No. 14, 2005