Variable strategy toward carbasugars and relatives. 4. Viable access to (4a-carbapentofuranosyl)amines, (5a-carbahexopyranosyl)amines, and amino acids thereof

Article abstract of DOI:10.1021/jo0257905

A chiral, divergent synthesis of two carbafuranosylamines, 1 and 2, two carbapyranosylamines, 3 and 4, two carbafuranosylamino acids, 5 and 6, and two carbapyranosylamino acids, 7 and 8, has been achieved. Highlights of the procedure include the following: a diastereoselective crossed vinylogous Mukaiyama aldol coupling between N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)-oxy]pyrrole (TBSOP, 9) and 2,3-O-isopropylidene-D-glyceraldehyde (10) for the assembly of the target compound carbon backbone; a high-yielding silylative cycloaldolization that gives the cyclopentanoid and cyclohexanoid motifs; and a reductive or hydrolytic breakage of the lactam C(O)-N link to liberate the carbasugar and install the desired pseudo-anomeric amine and the hydroxymethyl or carboxyl functionalities. The sequences leading to trans-configured carbafuranosyl compounds 1 and 5 and carbapyranosyl compounds 3 and 7 were 12- and 13-step processes, with overall yields of 34%, 35%, 17%, and 16%. Cis-configured isomers 2, 4, 6, and 8 were obtained only in minor yields.

Full text of DOI:10.1021/jo0257905

Va r ia ble Str a tegy tow a r d Ca r ba su ga r s a n d Rela tives. 4.1 Via ble
Access to (4a -Ca r ba p en tofu r a n osyl)a m in es,
(5a -Ca r ba h exop yr a n osyl)a m in es, a n d Am in o Acid s Th er eof
Gloria Rassu,*,§ Luciana Auzzas,§ Luigi Pinna,† Vincenzo Zambrano,† Franca Zanardi,‡
Lucia Battistini,‡ Lucia Marzocchi,‡ Domenico Acquotti,# and Giovanni Casiraghi*,‡
Istituto di Chimica Biomolecolare del CNR, Sezione di Sassari, Traversa La Crucca 3, Regione Baldinca,
I-07040 Li Punti, Sassari, Italy, Dipartimento di Chimica, Universita` di Sassari, Via Vienna 2,
I-07100 Sassari, Italy, Dipartimento Farmaceutico, Universita` di Parma, Parco Area delle Scienze 27A,
I-43100 Parma, Italy, and Centro Interfacolta` di Misure “G. Casnati”, Universita` di Parma,
Parco Area delle Scienze 23A, I-43100 Parma, Italy
giovanni.casiraghi@unipr.it
Received April 3, 2002
A chiral, divergent synthesis of two carbafuranosylamines, 1 and 2, two carbapyranosylamines, 3
and 4, two carbafuranosylamino acids, 5 and 6, and two carbapyranosylamino acids, 7 and 8, has
been achieved. Highlights of the procedure include the following: a diastereoselective crossed
vinylogous Mukaiyama aldol coupling between N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)-
oxy]pyrrole (TBSOP, 9) and 2,3-O-isopropylidene-D-glyceraldehyde (10) for the assembly of the target
compound carbon backbone; a high-yielding silylative cycloaldolization that gives the cyclopentanoid
and cyclohexanoid motifs; and a reductive or hydrolytic breakage of the lactam C(O)-N link to
liberate the carbasugar and install the desired pseudo-anomeric amine and the hydroxymethyl or
carboxyl functionalities. The sequences leading to trans-configured carbafuranosyl compounds 1
and 5 and carbapyranosyl compounds 3 and 7 were 12- and 13-step processes, with overall yields
of 34%, 35%, 17%, and 16%. Cis-configured isomers 2, 4, 6, and 8 were obtained only in minor
yields.
In tr od u ction
glycuronylamines 5, 6, 7, and 8. These compounds, other
than finding a possible application as anticancer and
antiviral agents due to their ability to inhibit the glyco-
sydase enzymes,3 may also be envisioned as secondary
structure-inducing platforms with which designed gly-
copeptidomimetics (from e.g. 5-8) or functionality rich
biomimetic structures may be engineered.4
Varied repertoires of natural and natural product-like
small molecules form the basis for the discovery of new
bioactive lead candidates and for understanding the
structural determinants involved in molecular recogni-
tion events of pharmacological importance. As part of an
ongoing program targeted at the assemblage of collections
of structurally diverse carbasugar entities, we have
envisaged a variable, highly efficient synthetic pathway
with which a number of 4a-carbapentofuranose and 5a-
carbahexopyranose compounds have been accessed.1,2
Capitalizing on the knowledge gained from these studies,
we have now moved on to synthesize a further series of
carbasugar constructs embodying amino functionalities.
Herein disclosed is the synthesis of (4a-carbapento-
furanosyl)amines 1 and 2, (5a-carbahexopyranosyl)-
amines 3 and 4, as well as the corresponding carba-
§ CNR, Sassari.
† Universita` di Sassari.
‡ Universita` di Parma. E-mail: giovanni.casiraghi@unipr.it.
#
Centro Interfacolta` di Misure.
(1) 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.
(2) (a) Rassu, G.; Auzzas, L.; Pinna, L.; Zanardi, F.; Battistini, L.;
Casiraghi, G. Org. Lett. 1999, 1, 1213-1215. (b) Rassu, G.; Auzzas,
L.; Pinna, L.; Battistini, L.; Zanardi, F.; Marzocchi, L.; Acquotti, D.;
Casiraghi, G. J . Org. Chem. 2000, 65, 6307-6318. (c) 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.
Resu lts a n d Discu ssion
Syn th esis P la n . Synthesis of the nitrogen-containing,
highly oxygenated structure of the targeted compounds
10.1021/jo0257905 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/27/2002
5338
J . Org. Chem. 2002, 67, 5338-5342

Synthesis of Carbasugar Amines and Amino Acids
SCHEME 1. Retr osyn th etic An a lysis of
(Ca r ba glycosyl)a m in es A a n d B
SCHEME 2
described (Scheme 2).2a,b After saturation of the carbon-
carbon double bond (NiCl2, NaBH4) and protection of the
free secondary hydroxyl as a TBS ether (TBSOTf, 2,6-
lutidine), the fully protected lactam 12 was isolated in
93% yield (two steps).
To arrive at the key aldehyde intermediate 13, we had
to excise the terminal C6-C7 bond oxidatively, and this
was effected by acetonide deprotection (aq AcOH, 50 °C)
followed by periodate oxidation. Aldehyde 13 was thus
obtained as a white solid in 86% yield for the two steps.
The stage was set now for the crucial cyclization maneu-
ver of connecting the carbon atom R to the lactam
carbonyl to the formyl group. The installation of the new
carbon-carbon bond to generate the requisite cyclitol
frame was attempted by direct treatment of aldehyde 13
with a 1:1 mixture of DIPEA/TBSOTf (3.0 mol equiv) at
room temperature. Rather unexpectedly, this treatment,
which had already proved successful with a number of
lactone and thiolactone aldehydes,1,2c failed with N-Boc
lactam 13, and provided the silylated bicyclic azetidine
14 as the sole reaction product (65% yield).5 Treatment
of 13 with silyl triflate likely promoted an unwanted,
competitive fission of the N-Boc linkage, ultimately
resulting in a diastereoselective silylative amination of
the aldehyde terminus.
is a main challenge in itself. Specifically, this involves
the stereocontrolled installation of an amino function at
the pseudo-anomeric site of the cycloalkane moiety, the
implementation of hydroxymethyl or carboxyl fragments
in γ to the amino group, and the incorporation of
hydroxyls at two or three carbon atoms of the ring.
Basically, our resulting retrosynthesis of carbafura-
noses A and carbapyranoses B (Scheme 1) is based on
two key aldol-type disconnections across C1/C2 and
C3/C4 (or C4/C5) leading back to two complementary
fragments, namely the aminated four-carbon dianion C
and the appropriately oxygenated acceptors D′ or D′′. We
envisioned substrate C arising from pyrrole-based di-
enoxy silane E, and frames D′ or D′′ originating from
glyceraldehyde F .
To overcome this obstacle, an alternative route had to
be pursued, whereby the nitrogen of the lactam precursor
13 was protected with a group that could withstand silyl
triflate exposure. Our choice fell on the benzyl protecting
group as it is resistant to silyl triflate treatment. First
of all, we decided to reprogram the synthesis by employ-
ing N-benzyl-2-[(tert-butyldimethylsilyl)oxy]pyrrole as the
initial building block. Disappointingly, the Lewis acid-
mediated vinylogous aldol addition to glyceraldehyde 10
under varied conditions resulted in, at best, a low yield
of the expected aldol product. We thus abandoned this
approach and opted to change the N-Boc protective group
to N-Bn in a later phase of the synthesis. Hence, the
advanced intermediate 12 was subjected to selective
Syn th esis of (4a -Ca r ba -â-D-xylofu r a n osyl)a m in e
(1), (4a -Ca r ba -â-D-r ibofu r a n osyl)a m in e (2), (4a -Ca r -
ba -â-D-xylofu r a n u r on yl)a m in e (5), a n d (4a -Ca r ba -
â-D-r ibofu r a n u r on yl)a m in e (6). The project was initi-
ated with a 10-g-scale preparation of N-Boc-protected
unsaturated lactam 11 by joining N-(tert-butoxycarbo-
nyl)-2-[(tert-butyldimethylsilyl)oxy]pyrrole (TBSOP, 9) to
2,3-O-isopropylidene-D-glyceraldehyde (10), as previously
(3) (a) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem. 1990,
48, 21-90. (b) Carbohydrate Mimics: Concepts and Methods; Chapleur,
Y., Ed.; Wiley-VCH: Weinheim, Germany, 1998.
(4) (a) Advances in Amino Acid Mimetics and Peptidomimetics; Abell,
A., Ed.; J ai Press: Greenwich, CT, 1997; Vol 1. (b) Advances in Amino
Acid Mimetics and Peptidomimetics; Abell, A., Ed.; J ai Press: Stam-
ford, CT, 1999; Vol 2. (c) Gruner, S. A. W.; Locardi, E.; Lohof, E.;
Kessler, H. Chem. Rev. 2002, 102, 491-514. (d) Recent Advances in
Peptidomimetics; Tetrahedron Symposia-in-Print, Nï. 83; Aube´, J .,
Guest Ed.; Pergamon Press: Oxford, UK, 2000; Tetrahedron 2000, 56
(50).
(5) The 6,7-trans configuration of [3.2.0]-azabicycloheptanone 14 was
ascertained by the absence of any NOE contact between trans-located
H-C5 and H-C7.
J . Org. Chem, Vol. 67, No. 15, 2002 5339

Rassu et al.
SCHEME 3
SCHEME 5
configuration of the stereocenter C5 was completely
preserved. Individual bicycloheptanoids 18 and 19 were
isolated in a pure state by chromatography on silica gel
and readily analyzed by a combination of 1H and 13C
NMR experiments. The rigid nature of the bicyclic core
of these compounds facilitated the analysis, allowing us
to assign their full stereostructures. In particular, the
presence in both isomers of a W long-range coupling
between the protons involved in the juncture (H-C1 and
H-C4) suggested that the bicycle is cis-fused. Further-
SCHEME 4
1
more, the H NMR coupling values between H-C2 and
3
H-C3 (3J 2,3 ) 1.2 Hz for 18; J 2,3 ) 5.7 Hz for 19) and
strong NOE contacts involving H-C3-H-C4aR in 18
and H-C2-H-C3 in 19 accounted for a pseudoequatorial
(2,3-trans) or pseudoaxial (2,3-cis) location of the oxygen
substituent at C3 for 18 and 19.
At this point we had to face the issue of disconnecting
the C(O)-N lactam bond to liberate the amino and
hydroxyl (or carboxyl) functions at C1 and C4. To help
us in this task, we had to weaken the amide linkage by
positioning a carbamate en lieu of the N-benzyl protec-
tion. Working in parallel, bicycles 18 and 19 were first
exposed to sodium in liquid ammonia to cleave the
N-benzyl group and then to Boc2O in MeCN to reinstate
the tert-butoxycarbonyl moiety. Compounds 20 and 21
were thus prepared in 96% and 94% yields, respectively
(two steps). As expected, treatment of 20 and 21 with
NaBH4 in wet THF cleanly led to the corresponding
protected cyclopentanoids 22 and 23 (88% and 98%
yields), which were finally fully liberated by acidic
treatment (aq HCl, THF, MeOH) followed by DOWEX
(H+ form). 4a-Carba-â-D-xylofuranose (1)2b and 4a-carba-
â-D-ribofuranose (2)6 were isolated in 95% and 99% yields,
which correspond to 34% and 10% overall yields from the
starting pyrrole 9 (12 steps each).
removal of the N-Boc function (TBSOTf, DIPEA, -15 °C)
followed by N-Bn protection (BnCl, KH), as illustrated
in Scheme 3, to give compound 15 in a 79% yield for the
two steps. Acetonide deblocking (aq AcOH) and subse-
quent oxidative fragmentation of the diol moiety (aq
NaIO4) then furnished N-Bn-protected aldehyde 17 (92%,
two steps) ready for the intramolecular aldolization step.
We were pleased to observe that addition of lactam
aldehyde 17 to a 3-fold molar excess of a preformed 1:1
mixture of TBSOTf and DIPEA at room temperature
resulted in complete conversion of 17 producing a 80:20
mixture of silylated bicycloheptanoids 18 and 19 in a 98%
combined yield (Scheme 4). Interestingly, this annulative
aldo-silylation proved to be completely chemoselective,
as the DIPEA-promoted enolization exclusively involves
the carbon adjacent to the lactam carbonyl group, leaving
the although-acid H-C5 of the carbon atom adjacent to
the formyl group unscathed. As a consequence, the
To access carbocyclic amino acids 5 and 6, the lactam
junction within bicycles 20 and 21 had to be opened
hydrolytically, and this was favorably effected by treat-
ment with aqueous LiOH in THF at room temperature
(93% and 88% yields) (Scheme 5). Global deprotection (aq
HCl, then DOWEX H+ form) finally provided (4a-carba-
â-D-xylofuranuronyl)amine (5) and (4a-carba-â-D-ribo-
furanuronyl)amine (6) in 92% and 98% yields, respec-
tively (35% and 9% overall yields covering 12 steps).
Structural analysis of the target carbasugars 1 and 2,
as well as the amino acids 5 and 6, carried out via
1
extensive H and 13C NMR studies confirmed the stere-
ochemical asset of the constructs, just as was the case
for the corresponding bicyclic precursors (vide supra).7
(6) Boyer, S. J .; Leahy, J . W. J . Org. Chem. 1997, 62, 3976-3980.
5340 J . Org. Chem., Vol. 67, No. 15, 2002

Synthesis of Carbasugar Amines and Amino Acids
SCHEME 6
SCHEME 7
Syn th esis of (5a -Ca r ba -â-D-gu lop yr a n osyl)a m in e
(3), (5a -Ca r ba -â-D-a llop yr a n osyl)a m in e (4), (5a -Ca r -
ba -â-D-gu lop yr a n u r on yl)a m in e (7), a n d (5a -Ca r ba -
â-D-a llop yr a n u r on yl)a m in e (8). To overcome the prob-
lems associated with our previous route to 3, encountered
during the LDA-assisted annulative aldolization,2a,b we
decided to apply a revised synthetic sequence, in which
the crucial carbon-carbon bond-forming reaction, which
ultimately gives rise to the cyclohexane ring, was per-
formed with use of the DIPEA/TBSOTf promoted silyla-
tive aldo-cyclization protocol exploited above. The special
objective was to have a practical and scaleable procedure
with the potential of delivering gram quantities of
pyranosylamines 3 and 4, as well as their amino acid
counterparts 7 and 8. The point of departure was the
advanced intermediate diol 16, which was accessed in 6
steps (56% overall yield) by the same sequence outlined
in the previous section (see Schemes 2 and 3). The next
stage of the synthesis (Scheme 6) required selective
oxidation of the hydroxymethyl terminus of 16 to arrive
at aldehyde 27, onto which the requested C2-C7 bond
connection could then be made.
SCHEME 8
Avoiding an elaborate protection/deprotection scheme,
an interesting protocol was identified, consisting of direct
oxidative conversion of TES-protected carbinols to alde-
hydes.8 Thus, diol 16 was first persilylated (TESOTf,
pyridine, DMAP) to give TES ether 26, which was directly
subjected to Swern oxidation ((COCl)2, DMSO; then
Et3N). We were pleased to find that the secondary TES-
protected hydroxyl survived the oxidation conditions,
allowing formation of lactam aldehyde 27 in 96% yield
for the two steps. With the desired aldehyde 27 in hand,
the silylative aldol cyclization with the TBSOTf-DIPEA
mixture (3.3 mol equiv, rt) was investigated. As we had
hoped, the cycloaddition proceeded nicely, to provide a
70:30 mixture of two bicyclooctanoid compounds, namely,
the 3,4-trans-configured product 28 and the 3,4-cis-
disposed isomer 29 in 84% combined yield (Scheme 7).
The problems connected with the chromatographic pu-
rification and isolation of individual 28 and 29 enticed
us to proceed along the synthetic path, leaving this task
to be sorted out at a later stage of the synthesis. Only a
small fraction of the 28/29 mixture was subjected to
chromatographic separation enabling us to isolate 28 and
29 as pure products and completely characterize their
structure.
1D and 2D 1H NMR spectra. Because of the bicyclic
structure of 28 and 29, the six-membered ring is expected
to adopt a stable 1C4 conformation; therefore, the analysis
The configuration of the reaction products was as-
signed as that of 28 and 29 mainly by inspection of their
3
was straightforward. For 28, the J 3,4 was calculated to
be 8.7 Hz, which suggested that both C3 and C4 hydroxy
substituents are in equatorial positions. On the other
3
(7) Notable NOE contacts: compound 1, H-C2-H-C4aâ, H-C1-
H-C4aR, H-C3-H-C4; compound 2, H-C1-H-C4aR, H-C1-
H-C4, H-C5a,â-H-C4aâ, H-C2-H-C4aâ; compound 5, H-C2-
H-C4aâ, H-C1-H-C4aR, H-C4aR-H-C4, H-C3-H-C4, H-C1-
H-C4; compound 6, H-C1-H-C4aR, H-C1-H-C4, H-C2-
H-C4aâ, H-C3-H-C4aâ.
hand, the J 3,4 value of 4.1 Hz for 29 revealed a cis-
stereodisposition (equatorial-axial) for the C3 and C4
hydroxy substituents. In both compounds, the signal of
H-C2 showed small couplings to the protons H-C1 and
3
3
3
H-C3 (28, J 1,2 ) 4.2 Hz and J 2,3 ) 4.3 Hz; 29, J 1,2
)
(8) Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J . J . Tetrahe-
dron Lett. 1999, 40, 5161-5164.
3
4.3 Hz and J 2,3 ) 4.3 Hz), and this confirmed an axial
J . Org. Chem, Vol. 67, No. 15, 2002 5341

Rassu et al.
positioning for the C2 silyloxy group. The presence of
strong NOE contacts between axially located H-C4 and
H-C5aR for 28 and equatorially located H-C4 and
H-C5 for 29 further corroborated the assignment.
The 28/29 isomeric mixture was then manipulated
further to arrive at either carbasugars 3 and 4 or carba-
amino acids 7 and 8. Thus, the N-Bn protection within
28/29 was first switched to N-Boc (Na, NH3 liquid; then
Boc2O) delivering, after meticulous chromatographic
purification on silica gel (1,2-dichloroethane/Et2O/
CH2Cl2 90:5:5), a 66% yield of 3,4-trans isomer 30 along
with a minor amount (28%) of its C4-epimer 31. Indi-
vidual lactams 30 and 31 were then fragmented, reduc-
tively or hydrolytically, as previously disclosed for their
cyclopentanoid analogues (Scheme 8). Both operations
proceeded smoothly, with the reductive opening of 30 and
31 providing amino alcohols 32b and 4 (83% and 72%
yield, respectively, two steps) and hydrolytic cleavage
affording amino acids 7 and 8 in 77% and 88% yield,
respectively.
amino acids 5-8 has been established. As foreseen in the
retrosynthetic analysis of Scheme 1, the carbasugar
products were assembled by conjoining two readily ac-
cessible substructures, TBSOP 9 (ex pyrrole) and glyc-
eraldehyde 10 (ex D-mannitol). The pathways are high-
lighted by three key transformations: (1) a crossed
vinylogous Mukaiyama-type aldolization to install the
first carbon-carbon juncture between 9 and 10; (2) a
novel silylative cycloaldolization10 to implement the
second carbon-carbon linkage and complete the con-
struction of the desired cyclopentanoid and cyclohexanoid
structures; and (3) a reductive or hydrolytic cleavage of
the lactam tether, which liberates both the amino and
the hydroxymethyl or carboxyl functionalities within the
cyclitol frames. This approach, whose scope could be
enlarged to include aldehyde acceptors other than D-
glyceraldehyde, enabled us to provide preparatively
useful quantities of enantiopure amino alcohol or amino
acid entities with which many diverse, oxygen-decorated
oligomeric architectures may be assembled.
Once the C(O)-N bond holding the five-membered ring
together had been broken, the cyclohexanoid ring in
compounds 3, 4, 7, and 8 preferentially assumed a 4C1
conformation where the majority of substituents were
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
2000). A doctoral fellowship to V.Z. from the European
Community Ph.D. Scheme of the University of Sassari
is gratefully acknowledged. We also wish to thank the
Centro Interfacolta` di Misure “G. Casnati”, Universita`
di Parma, for the access to the analytical instrumenta-
tion.
1
able to lie in the equatorial position. With the H NMR
spectra of these four compounds easy to interpret, it was
not at all difficult to decipher the stereostructures on the
basis of H-H coupling constants and NOE contacts of
1H-1H NOESY spectra.9
Con clu sion s
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data for all synthesized compounds
A highly efficient, “chiral-pool” synthetic grid delivering
preparatively useful yields of amino alcohols 1-4 and
1
and H and 13C NMR spectra of compounds 1-8. This material
is available free of charge via the Internet at http://pubs.acs.org.
(9) Notable NOE contacts: compound 3, H-C1-H-C5, H-C2-
H-C5aâ; compound 4, H-C2-H-C5aâ, H-C1-H-C5, H-C4-
H-C5aâ, H-C5-H-C5aR; compound 7, H-C1-H-C5, H-C2-
H-C5aâ; compound 8, H-C2-H-C4, H-C4-H-C5aâ, H-C2-
H-C5aâ, H-C1-H-C5.
J O0257905
(10) For a related silylative Michael-aldol annulation, see: Takasu,
K.; Ueno, M.; Ihara, M. J . Org. Chem. 2001, 66, 4667-4672.
5342 J . Org. Chem., Vol. 67, No. 15, 2002