Variable Strategy toward Carbasugars and Relatives. 6. Diastereoselective Synthesis of 2-Deoxy-2-amino-5a-carba-β-L-mannopyranuronic Acid and 2-Deoxy-2-amino-5a-carba-β-L-mannopyranose

Article abstract of DOI:10.1021/jo0357216

Efficient, total syntheses of novel 2-deoxy-2-amino-5a-carba-β -L-mannopyranuronic acid (1) and 2-deoxy-2-amino-5a-carba-β -L-mannopyranose (2), a positional stereoisomer of validamine, have been achieved in 28% and 24% overall yields and in 12 steps and 13 steps, respectively, from 2-[(tert-butyldimethylsilyl)oxy]furan (3) and (2S)-2,3-O-isopropylideneglyceraldehyde N-benzyl imine (4) via two highly diastereoselective Mukaiyama aldol-related chemical maneuvers. The strategy, which furnishes the targeted carbasugars in enantiopure forms, allows for complete control of the configuration at all five contiguous stereocenters of the targets by utilizing the sole element of chirality present in the aldimine progenitor 4.

Full text of DOI:10.1021/jo0357216

Va r ia ble Str a tegy tow a r d Ca r ba su ga r s a n d Rela tives. 6.1
Dia ster eoselective Syn th esis of
2-Deoxy-2-a m in o-5a -ca r ba -â-L-m a n n op yr a n u r on ic Acid a n d
2-Deoxy-2-a m in o-5a -ca r ba -â-L-m a n n op yr a n ose
Gloria Rassu,*,† Luciana Auzzas,† Vincenzo Zambrano,‡ Paola Burreddu,† Luigi Pinna,‡
Lucia Battistini,§ Franca Zanardi,§ and Giovanni Casiraghi*,§
Istituto di Chimica Biomolecolare del CNR, Sezione di Sassari, Traversa La Crucca 3, I-07040 Li Punti,
Sassari, Italy, Dipartimento di Chimica, Universita` di Sassari, Via Vienna, 2, I-07100 Sassari, Italy, and
Dipartimento Farmaceutico, Universita` di Parma, Parco Area delle Scienze 27A, I-43100 Parma, Italy
giovanni.casiraghi@unipr.it
Received November 24, 2003
Efficient, total syntheses of novel 2-deoxy-2-amino-5a-carba-â-L-mannopyranuronic acid (1) and
2-deoxy-2-amino-5a-carba-â-L-mannopyranose (2), a positional stereoisomer of validamine, have
been achieved in 28% and 24% overall yields and in 12 steps and 13 steps, respectively, from 2-[(tert-
butyldimethylsilyl)oxy]furan (3) and (2S)-2,3-O-isopropylideneglyceraldehyde N-benzyl imine (4)
via two highly diastereoselective Mukaiyama aldol-related chemical maneuvers. The strategy, which
furnishes the targeted carbasugars in enantiopure forms, allows for complete control of the
configuration at all five contiguous stereocenters of the targets by utilizing the sole element of
chirality present in the aldimine progenitor 4.
In tr od u ction
As shown in Figure 1, the first component of the
construction of a generic carbapyranose F (A + B f C)
involves the use of a Lewis acid-promoted vinylogous
crossed Mukaiyama-aldol reaction between heterosub-
stituted dienoxy silanes A and suitable chiral aldehyde
progenitors B to build the stereocenters at the future
carbons 1-3, while the second decisive maneuver (D f
E) contemplates adoption of a novel, highly productive
intramolecular silylative aldolization to create the ste-
reocenters at carbons 4 and 5 and to complete the joining
of the carbocycle framework. This approach was designed
with diversity in mind, to enable chemical and stereo-
chemical modification of both the core and substituents
of the targets by varying chirality, substituents, and
carbon chain length of the chiral predecessor B as well
as the nature of the heteroatom embodied in the nucleo-
philic diene A.
To illustrate our progress, an efficient stereocontrolled
synthetic sequence to â-L-configured 5a-carbapyranuronic
δ-amino acid 1 and 5a-carbapyranosylamine 2, a posi-
tional stereoisomer of validamine,5 is described in this
paper. The method we planned to use in this study
(Figure 2) is based on a rational adaptation of our original
project and involves the use of a suitable chiral nonra-
Diversity is a leading concern in medicinal organic
chemistry, and synthetic methodologies oriented toward
this end can provide a solid foundation for the discovery
of novel pharmaceutical leads and biological probes.2
Among the more versatile of small functional organic
molecules, the carbasugar matrix emerges as an ideal
architecture for diversity, being its robust carbocyclic
structure generously adorned with various attributes
including ring size, poly-functionality, and multiple
chirality.3 In the context of a program concerned with
the exploitation of carbasugars and carbasugar amino
acids as leads for new therapeutic agents and constrained
scaffolds in peptidomimetic studies,1,4 we formulated a
general vision toward a malleable synthesis of these
entities and demonstrated that the approach could be
used to construct a vast repertoire of diverse, enantiopure
carbocycles, encompassing carbafuranoid4b,d and carba-
pyranoid4c,d structures, as well as rare medium-sized ring
congeners.1
† CNR, Sassari.
‡ Universita` di Sassari.
§ Universita` di Parma.
(1) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.;
Battistini, L.; Gaetani, E.; Curti, C.; Casiraghi, G. J . Org. Chem. 2003,
68, 5881-5885.
(2) For recent reviews on diversity-oriented synthesis, see: (a)
Schreiber, S. L. Science 2000, 287, 1964-1969. (b) Burke, M. D.;
Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613-618.
(3) For recent reviews on carbasugars and relatives, see: (a) Rassu,
G.; Auzzas, L.; Pinna, L.; Battistini, L.; Curti, C. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science B.V.:
Amsterdam, The Netherlands, 2003; Vol. 29, pp 449-520. (b) Bere-
cibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99, 779-
844. (c) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J . Chem.
Rev. 1996, 96, 1195-1220.
(4) (a) Rassu, G.; Auzzas, L.; Pinna, L.; Battistini, L.; Zanardi, F.;
Marzocchi, L.; Acquotti, D.; Casiraghi, G. J . Org. Chem. 2000, 65,
6307-6318. (b) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.;
Battistini, L.; Zanardi, F.; Marzocchi, L.; Acquotti, D.; Casiraghi, G.
J . Org. Chem. 2001, 66, 8070-8075. (c) Zanardi, F.; Battistini, L.;
Marzocchi, L.; Acquotti, D.; Rassu, G.; Pinna, L.; Auzzas, L.; Zambrano,
V.; Casiraghi, G. Eur. J . Org. Chem. 2002, 1956-1964. (d) Rassu, G.;
Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.; Battistini, L.;
Marzocchi, L.; Acquotti, D.; Casiraghi, G. J . Org. Chem. 2002, 67,
5338-5342.
10.1021/jo0357216 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/11/2004
J . Org. Chem. 2004, 69, 1625-1628
1625

Rassu et al.
SCHEME 1
methylsilyl trifluoromethanesulfonate (TBSOTf), to gov-
ern the present addition.8
Extreme care was needed for this maneuver, since the
expected unsaturated adduct (i.e. 5) is exceedingly prone
to epimerization and retrograde addition. In fact, at-
tempts to isolate 5 in a pure state by the usual crystal-
lization or chromatographic procedures failed, and vari-
able epimeric adduct mixtures formed, which proved very
difficult to separate. Upon further study, we surmounted
the obstacle by adopting a two-stage protocol where the
crude unsaturated product 5 was immediately subjected
to double bond saturation with nickel boride. In the
event, stable butanolide 6 was obtained as a single isomer
in a gratifying 68% isolated yield for the two steps. The
4S,5S,6S-stereochemistry in 6 (and in its unsaturated
precursor 5) could not be established with certainty at
this point and was inferred from the structure of a more
advanced intermediate, i.e., compound 12, and the final
products (vide infra).9
F IGURE 1. Vinylogous aldol/silylative aldol approach to
carbasugars: access to carbapyranoses.
F IGURE 2. Structures of 5a-carbapyranuronic amino acid 1
and 5a-carbapyranosylamine 2: synthetic strategy.
With ready access to 6, we now had to deal with the
delicate question of forming the carbocyclic ring. We
opted to tackle this problem by using a sequence featur-
ing the mild silylative cycloaldolization protocol we had
already experienced during our syntheses of carbasugars.
As depicted in Figure 3, there were two plausible op-
tions: (1) elaboration of 6 into γ-lactone aldehyde A
followed by cyclization to oxabicyclo[3.2.1]octanone B and
(2) ring enlargement to δ-lactam aldehyde C followed by
annulation to azabicyclo[2.2.2]octanone D. With selectiv-
ity in mind, we reasoned that, during carbon-carbon
bond formation, the more compact structure of lactam
C, as compared to the flexible lactone A, would have
guaranteed a more precise positioning of the C(4) alde-
hyde carbonyl vis-a`-vis the incoming nucleophilic C(5),
thus ensuring superior facial diastereocontrol.10
cemic aldimine predecessor, in lieu of the aldehyde
component, to position the requisite amine function at
carbon 2 of the targeted carbasugars 1 and 2.
Resu lts a n d Discu ssion
Our synthesis commenced with 2-[(tert-butyldimeth-
ylsilyl)oxy]furan (3), which was coupled to enantiopure
(2S)-2,3-O-isopropylideneglyceraldehyde N-benzyl imine
(4) via a Mukaiyama-type vinylogous imino-aldol (Man-
nich-type) crossed addition (Scheme 1).6 Literature pre-
cedents in this field7 indicated that silicon triflates were
suitable triggers to initiate similar transformations; thus
we employed a triflate Lewis acid, namely tert-butyldi-
(5) For related examples, see: (a) Ogawa, S.; Tsunoda, H. Liebigs
Ann. Chem. 1992, 637-641. (b) Mehta, G.; Lakshminath, S.; Talukdar,
P. Tetrahedron Lett. 2002, 43, 335-338. (c) Miyamoto, M.; Baker, M.
L.; Lewis, M. D. Tetrahedron Lett. 1992, 33, 3725-3728. (d) Augy-
Dorey, S.; Dalko, P.; Ge´ro, S. D.; Quiclet-Sire, B.; Eustache, J .; Stu¨tz,
P. Tetrahedron 1993, 49, 7997-8006. (e) Ogawa, S.; Nishi, K.; Shibata,
Y. Carbohydr. Res. 1990, 206, 352-360. (f) Barton, D. H.; Ge´ro, S. D.;
Augy, S.; Quiclet-Sire, B. Chem. Commun. 1986, 18, 1399-1401.
(6) Reviews: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu,
G. Chem. Rev. 2000, 100, 1929-1972. (b) Bur, S. K.; Martin, S. F.
Tetrahedron 2001, 57, 3221-3242. (c) Martin, S. F. Acc. Chem. Res.
2002, 35, 895-904.
On these bases, we moved ahead with the transforma-
tion of lactone 6 into aldehyde 11 (Scheme 2). Thus,
(8) A screen of various silyl triflates (TMSOTf, TESOTf, TBSOTf,
TIPSOTf) indicated commercial TBSOTf to be the optimal promoter
in this reaction.
(9) A plausible transition state to anti,anti-configured adduct 5
involves a synclinal-type approach of the silyloxy diene C(5) re-face to
the C(1) si-face of the imine acceptor according to a relatively
uncongested open-chain (Felkin-Ahn) model described here.
(7) (a) Barnes, D. M.; McLaughlin, M. A.; Oie, T.; Rasmussen, M.
W.; Stewart, K. D.; Wittenberger, S. J . Org. Lett. 2002, 4, 1427-1430.
(b) DeGoey, D. A.; Chen, H.-J .; Flosi, W. J .; Grampovnik, D. J .; Yeung,
C. M.; Klein, L. L.; Kempf, D. J . J . Org. Chem. 2002, 67, 5445-5453.
(c) Martin, S. F.; Barr, K. J .; Smith, D. W.; Bur, S. K. J . Am. Chem.
Soc. 1999, 121, 6990-6997. (d) Martin, S. F.; Barr, K. J . J . Am. Chem.
Soc. 1996, 118, 3299-3300. (e) Lombardo, M.; Trombini, C. Tetrahe-
dron 2000, 56, 323-326. See also: Dilman, A. D.; Ioffe, S. L. Chem.
Rev. 2003, 103, 733-772.
1626 J . Org. Chem., Vol. 69, No. 5, 2004

Synthesis of 2-Amino-Carbapyranose Derivatives
F IGURE 4. Reactive “near attack” conformers for the silyla-
tive intramolecular aldol reaction leading to carbocycle 12.
F IGURE 3. Strategic options toward six-membered car-
bocycles. Target numbering is adopted.
cycloaldolization of 11, employing the prescribed condi-
tions, yielded trans-configured trihydroxy-azabicyclooc-
tanone 12 as a single isomer in an exquisite 89% isolated
yield. It is useful to note that the cis stereoisomer (not
shown), which should have arisen from the attack of C(5)
on the opposite face of the aldehyde C(4) carbonyl, was
not detected at all.
SCHEME 2
A plausible mechanism to explain the exclusive forma-
tion of 12 under the reaction conditions used is shown
in Figure 4. The initially formed enolsilane (from 11) is
envisaged to participate in a straightforward intramo-
lecular nucleophilic attack of C(5) (convex si-face) onto
the proximate C(4) carbonyl (si-face), which should result
in the formation of 3,4-trans-configured bicycle 12 (see
model A). The control element in A (as compared to B)
is the antiperiplanar disposition of the C(3) heteroatom
substituent and C(4) carbonyl oxygen, which minimizes
the dipolar interaction between these electronegative
groups. Definitive confirmation for the relative (and
absolute) configuration in the bicycle 12 (and hence in
its predecessors) was obtained by a detailed analysis of
its solution structure with various NMR techniques. The
assignments were carried out with the help of two-
dimensional TOCSY and COSY experiments and were
further confirmed by 1H-1H NOESY measurements
which, in addition, provided diagnostic information on
the proximity of the protons in the rigid bicycle backbone
of 12.13
To complete the synthesis of both carbapyranuronic
amino acid 1 and carbapyranosylamine 2, conversion of
12 into the protected amino acid 15 (a common predeces-
sor) was planned (Scheme 3). Thus, benzyl-substituted
bicycle 12 was transformed into the N-Boc derivative 14
in a 84% global yield via debenzylation with Na in liquid
ammonia (i.e. 12 f 13) followed by N-Boc reprotection
(Boc2O, MeCN, DMAP). Hydrolysis of 14 with LiOH in
THF/water then provided protected amino acid 15 (93%
yield), which was fully deprotected to 1 by exposure to 6
N HCl in THF/MeOH (1:2:1 ratio) followed by DOWEX
(98% yield).
exposure of 6 to neat DBU at 140 °C cleanly furnished
piperidinone 7 (96% yield), which was protected as the
TBS ether 8 in 92% yield. To arrive at aldehyde 11, we
chose to employ direct Swern oxidation of triethylsilyl-
protected terminal diols,11 which required preparation of
the predecessor 10. Thus, the lactam 8 was exposed to
80% aqueous acetic acid at 80 °C to deliver diol 9, which
was protected as the bis-triethylsilyl ether 10 (76%, two
steps). Treatment of 10 with a mixture of oxalyl chloride
(10 mol equiv) and DMSO (20 mol equiv) in CH2Cl2 at
-10 °C, followed by Et3N (36 mol equiv) finally gave rise
to the fully protected aldehyde 11 in a respectable yield
of 91%.
With the key aldehyde 11 successfully prepared, the
next step in the synthesis entailed the intramolecular
union of the enolizable carbon 5 to the C(4) carbonyl
terminal, and this was accomplished under the guidance
of a freshly prepared mixture of TBSOTf and DIPEA (3
mol equiv each) in CH2Cl2 at room temperature.12 Our
line of reasoning was indeed confirmed: the silylative
In a divergent way (Scheme 4), acid 15, when treated
with an excess of a 2 M solution of BH3‚DMS in THF (8
mol equiv), delivered the protected amino alcohol 16 (86%
(10) In truth, the alternative cyclization protocol A to B was actually
attempted. However, the extremely low yields obtained in elaborating
adduct 6 into a suitably protected aldehyde lactone of type A (i.e., NPG
) Cbz; OPG ) TES) forced us to back down from this strategic option
and follow the second and more fruitful route reported in this study.
(11) Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J . J . Tetra-
hedron Lett. 1999, 40, 5161-5164.
(12) For a recent example of a silylative Mukaiyama intermolecular
aldol reaction with TBSOTf and Hu¨nig’s base, see: J ung, M. E.; van
den Heuvel, A. Org. Lett. 2003, 5, 4705-4707. See also: Evans, D. A.;
Tedrow, J . S.; Shaw, J . T.; Downey, C. W. J . Am. Chem. Soc. 2002,
124, 392-393.
(13) Stereochemical proofs for 12, as well as 1 and 2‚HCl, are
compiled in the Supporting Information (Tables S1-S3).
J . Org. Chem, Vol. 69, No. 5, 2004 1627

Rassu et al.
SCHEME 3
glyceraldehyde imine 4 (28% and 24% overall yields; 12
steps and 13 steps, respectively). Success was achieved,
as planned, by interfacing the silyloxy diene chemistry,
developed in our laboratories in the 1990s,14 with the
potent silylative aldol-cyclization protocol we validated
during this carbasugar synthesis program. These syn-
theses could easily be adapted for the preparation of â-D-
manno-configured enantiomers of 1 and 2 by using (2R)-
2,3-O-isopropylideneglyceraldehyde N-benzyl imine, which
is available from the corresponding L-glyceraldehyde
acetonide (ex L-ascorbic acid).15 Highly functionalized
δ-amino acid 1, reported in this study, and its â-D-manno-
configured enantiomer ent-1 offer interesting topologies
that could be useful in the study of constrained dipeptide
surrogates16 and as platforms for novel peptidomimetic
constructions.17
SCHEME 4
Ack n ow led gm en t. This work was supported by a
research grant from the Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica (MURST, COFIN 2002)
and Fondi per gli Investimenti della Ricerca di Base
(FIRB 2002). We also wish to thank the Centro Inter-
facolta` di Misure “G. Casnati”, Universita` di Parma, for
access to the analytical instrumentation.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data for all synthesized compounds
as well as 1H NMR resonances, coupling constants, and 1H-
1H NOE correlations for 12, 1, and 2‚HCl (Tables S1-S3). This
material is available free of charge via the Internet at
http://pubs.acs.org.
yield), which was liberated by acidic treatment to furnish
amine 2 in 96% yield. Free amino acid 1 and its
hydrochloride salt, as well as amino alcohol 2 (HCl salt),
were shown (1H NMR, D2O, 25 °C) to adopt the expected
1C4 (L-manno) solution conformation, as judged by the
measurement of the vicinal and long-range coupling
constants and inspection of the critical NOE correla-
tions.13
J O0357216
(14) Representative reviews: (a) Casiraghi, G.; Rassu, G.; Zanardi,
F.; Battistini, L. In Advances in Asymmetric Synthesis; Hassner, A.,
Ed.; J AI Press: Stamford, CT, 1998; Vol. 3, pp 113-189. (b) Rassu,
G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999, 1333-1350.
(c) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc. Rev.
2000, 109-118.
(15) Hubschwerlen, C. Synthesis 1986, 962-964.
To conclude, enantiopure 2-deoxy-2-amino-5a-carba-â-
L-mannopyranuronic acid (1) and validamine isomer
2-deoxy-2-amino-5a-carba-â-L-mannopyranose (2) were
synthesized from furan-based dienoxy silane 3 by utiliz-
ing the sole element of chirality present in the precursor
(16) Interestingly,
1 and ent-1 can be viewed as new, locked
hydroxyethylene isosteres of D-Ser-D-Ser and L-Ser-L-Ser dipeptides,
respectively.
(17) Lohof, E.; Burkhart, F.; Born, M. A.; Planker, E.; Kessler, H.
In Advances in Amino Acid Mimetics and Peptidomimetics; Abell, A.,
Ed.; J AI Press: Stamford, CT, 1999; Vol. 2, pp 263-292.
1628 J . Org. Chem., Vol. 69, No. 5, 2004