Variable strategy toward carbasugars and relatives. 5. Focus on preparation of chiral nonracemic medium-sized carbocycles

Article abstract of DOI:10.1021/jo0344539

The feasibility of sequential vinylogous aldol (intermolecular)/silylative aldol (intramolecular) addition reactions involving furan- and pyrrole-based dienoxysilanes, 6 and 12, in the synthesis of carbasugar frameworks is illustrated by the preparation of the scantily investigated carbaseptanose and carbaoctanose representatives of this class of compounds. The target compounds, 1, 2, 3, ent-2, ent-3, and 4, were obtained from readily available carbohydrate precursors (5 and 19) in yields of 21-30% over 8-12 steps. The irreversible silylative ring-closing aldolisation of γ-substituted dihydro-5H-furan-2-one and pyrrolidin-2-one aldehydes (9, 16, ent- 16, and 22) driven by the TBSOTf/ Prⁱ₂EtN Lewis acid-Lewis base couple was shown to be a practical, diastereoselective maneuver to forge the densely functionalized, medium-sized core carbocycles.

Full text of DOI:10.1021/jo0344539

Va r ia ble Str a tegy tow a r d Ca r ba su ga r s a n d Rela tives. 5.1 F ocu s on
P r ep a r a tion of Ch ir a l Non r a cem ic Med iu m -Sized Ca r bocycles
Gloria Rassu,*,‡ Luciana Auzzas,‡ Luigi Pinna,† Vincenzo Zambrano,† Franca Zanardi,§
Lucia Battistini,§ Enrico Gaetani,§ Claudio Curti,§ 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, and Dipartimento Farmaceutico, Universita` di Parma,
Parco Area delle Scienze 27A, I-43100 Parma, Italy
giovanni.casiraghi@unipr.it.
Received April 10, 2003
The feasibility of sequential vinylogous aldol (intermolecular)/silylative aldol (intramolecular)
addition reactions involving furan- and pyrrole-based dienoxysilanes, 6 and 12, in the synthesis of
carbasugar frameworks is illustrated by the preparation of the scantily investigated carbaseptanose
and carbaoctanose representatives of this class of compounds. The target compounds, 1, 2, 3, ent-
2, ent-3, and 4, were obtained from readily available carbohydrate precursors (5 and 19) in yields
of 21-30% over 8-12 steps. The irreversible silylative ring-closing aldolisation of γ-substituted
dihydro-5H-furan-2-one and pyrrolidin-2-one aldehydes (9, 16, ent-16, and 22) driven by the TBSOTf/
Pri EtN Lewis acid-Lewis base couple was shown to be a practical, diastereoselective maneuver
2
to forge the densely functionalized, medium-sized core carbocycles.
In tr od u ction
carbocycles,1,6 prompted us to embark on a synthetic
venture targeting a set of cycloheptanoid and cyclooc-
tanoid carbasugars in a nonracemic format. From the
synthetic perspective, the challenging feature of these
carbocycles lies in the long carbon chain adorned by
multiple, adjacent chiral centers and in its being blocked
in a macrocyclic motif.
As a further addition to the works of this series,1,6
herein we describe, in full, the total asymmetric synthesis
of a small repertoire of medium-sized carbasugars,
comprising septanoses 1, 2, 3, ent-2, and ent-3 (6a-
J ust as Nature has elected, for its various functions,
the five- and six-membered ring monosaccharides as
favorite structural motifs2 while neglecting the ring-
expanded homologues,3 organic synthesis practitioners,
in their quest for novel sugar-product mimicking entities,
have dedicated themselves to the construction of cyclo-
pentane and cyclohexane polyols4 while pushing the
higher carbocycles into the sidelines of their interests.5
The scanty occurrence of medium-sized-ring sugar ana-
logues and the unforeseen biological properties these
structures could display, in conjunction with our long-
standing interest in the construction of differently shaped
(5) For selected references on the synthesis of carbaseptanose and
carbaoctanose derivatives, see: (a) Wang, W.; Zhang, Y.; Sollogoub,
M.; Sinay¨, P. Angew. Chem., Int. Ed. 2000, 39, 2466-2467. (b) Wang,
W.; Zhang, Y.; Zhou, H.; Ble´riot, Y.; Sinay¨, P. Eur. J . Org. Chem. 2001,
1053-1059. (c) Marco-Contelles, J .; de Opazo, E. J . Org. Chem. 2002,
67, 3705-3717. (d) Marco-Contelles, J .; de Opazo, E. J . Org. Chem.
2000, 65, 5416-5419. (e) Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651-
2654. (f) Boyer, F.-D.; Hanna, I.; Nolan, S. P. J . Org. Chem. 2001, 66,
4094-4096. (g) van Hooft, P. A. V.; Litjens, R. E. J . N.; van der Marel,
G. A.; van Boeckel, C. A. A.; van Boom, J . H. Org. Lett. 2001, 3, 731-
733. (h) McNulty, J .; Grunner, V.; Mao, J . Tetrahedron Lett. 2001, 42,
5609-5612. (i) Pearson, A. J .; Katiyar, S. Tetrahedron 2000, 56, 2297-
2304. (j) Roy, A.; Chakrabarty, K.; Dutta, P. K.; Bar, N. C.; Basu, N.;
Achari, B.; Mandal, S. B. J . Org. Chem. 1999, 64, 2304-2309. (k) Patra,
R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal, S. B.
Tetrahedron 1996, 52, 11265-11272. (l) Le Merrer, Y.; Gravier-
Pelletier, C.; Maton, W.; Numa, M.; Depezay, J .-C. Synlett 1999, 1322-
1324. (m) Gravier-Pelletier, C.; Maton, W.; Lecourt, T.; Le Merrer, Y.
Tetrahedron Lett. 2001, 42, 4475-4478. (n) Ble´riot, Y.; Giroult, A.;
Mallet, J .-M.; Rodriguez, E.; Vogel, P.; Sinay¨, P. Tetrahedron: Asym-
metry 2002, 13, 2553-2565.
* To whom correspondence should be addressed.
‡ CNR, Sassari.
† Universita` di Sassari.
§ Universita` di Parma.
(1) 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.
(2) (a) Dwek, R. A. Chem. Rev. 1996, 96, 683-720. (b) Varki, A.
Glycobiology 1993, 3, 97-130. (c) Glycoscience: Chemistry and Chemi-
cal Biology; Fraser-Reid, B., Tatsuta, K., Thiem, J ., Eds.; Springer-
Verlag: Berlin, 2001; Vols. I-III.
(3) For selected references on the synthesis of septanose and
octanose derivatives, see: (a) Defaye, J .; Gadelle, A.; Movilliat, F.;
Nardin, R.; Baer, H. H. Carbohydr. Res. 1991, 212, 129-157. (b)
Baschang, G. Liebigs Ann. Chem. 1963, 663, 167-173. Maier, M. E.
Angew. Chem., Int. Ed. 2000, 39, 2073-2077. (c) Gurjar, M. K.;
Chakrabarti, A.; Rao, B. V.; Kumar, P. Tetrahedron Lett. 1997, 38,
6885-6888. (d) Ng, C. J .; Stevens, J . D. Methods Carbohydr. Chem.
1968, 7, 7-14. (e) Butcher, M. E.; Ireson, J . C.; Lee, J . B.; Tyler, M. J .
Tetrahedron 1977, 33, 1501-1507.
(4) (a) Carbohydrate Mimics: Concepts and Methods; Chapleur, Y.,
Ed.; Wiley-VCH: Weinheim, 1998. (b) Suami, T. Top. Curr. Chem.
1990, 154, 257-283. (c) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 21-90. (d) Crimmins, M. T. Tetrahedron 1998, 54,
9229-9272.
(6) (a) 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. (b) Rassu, G.; Auzzas, L.; Pinna, L.; Zam-
brano, V.; Battistini, L.; Zanardi, F.; Marzocchi, L.; Acquotti, D.;
Casiraghi, G. J . Org. Chem. 2001, 66, 8070-8075. (c) Rassu, G.;
Auzzas, L.; Pinna, L.; Battistini, L.; Zanardi, F.; Marzocchi, L.;
Acquotti, D.; Casiraghi, G. J . Org. Chem. 2000, 65, 6307-6318.
10.1021/jo0344539 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/27/2003
J . Org. Chem. 2003, 68, 5881-5885
5881

Rassu et al.
SCHEME 1
SCHEME 2
carbaheptoseptanoses), as well as octanose 4 (7a-car-
baoctooctanose).7
Syn th etic Str a tegy. Our analysis of the generic
target A (Scheme 1) emphasized two strategic discon-
nections of the macrocycle, along the two carbon-carbon
bonds C(1)-C(2) and C(5)-C(6) (n ) 1) or C(6)-C(7) (n
) 2). This unveiled two subunits that trace the top half
back to the butanoic acid dianion B and the bottom half
to the hydroxylated dicarbonyl frame C. Our experience
in these constructs enticed us to correlate fragment B to
the heterocyclic dienoxysilanes D (X ) O, NR)8 and
fragment C to the four-membered and five-membered
aldoses E. In the synthetic direction, we envisioned the
C(1)-C(2) junction first to be installed via a vinylogous
crossed aldolization of dienoxysilanes D with aldoses E,9
followed by completion of the macrocycle via a cycloal-
dolization maneuver. In substance, this design is flexible,
and one can easily imagine various heterocyclic dienoxy-
silanes as precursors to the top half of the ring and a
wide range of readily available, ex chiral-pool synthons
for the bottom half, the nature of which ultimately
dictates ring size and chirality.
acid dimethyl ester (Scheme 2).10 Boron trifluoride as-
sisted vinylogous aldol reaction between aldehyde 5 and
2-[(tert-butyldimethylsilyl)oxy]furan (6) proceeded smoothly
to provide the butenolide adduct 7 both in a high yield
(80%) and excellent diastereomeric excess (>95%). The
4,5-threo-5,6-erythro configuration of 711 was only hy-
pothesized at this point, principally on the basis of our
previous experiences where intermolecular vinylogous
aldol addition reactions between heterocyclic silyloxy-
dienes (e.g., 6 and 12) and chiral nonracemic R-alkoxy-
aldehydes (e.g., 2,3-O-isopropylidene-D-glyceraldehye)
inexorably gave rise to a highly diastereoselective be-
havior in favor of aldol adducts with a 4,5-threo-5,6-
erythro relative configuration.8 In such instances, a
Felkin-Ahn-type induction was called upon to justify the
facial (5,6-erythro) diastereoselectivity, whereas a steri-
cally and an electronically favorable Diels-Alder-like
transition state was contemplated to account for the
simple (4,5-threo) diastereoselectivity observed.8 The
relative and absolute configurations of the stereocenters
within 7 were eventually confirmed at a later stage of
Resu lts a n d Discu ssion
Syn th esis of Ca r ba sep ta n ose 1. Our point of depar-
ture for construction of carbasugar 1 was the known
L-threose 5, prepared in four steps from (R,R)-tartaric
(7) For a comprehensive, updated treatise on sugar and carbasugar
nomenclature, see: McNaught, A. D. Carbohydr. Res. 1997, 297, 1-92.
(8) (a) Casiraghi, G.; Rassu, G.; Zanardi, F.; Battistini, L. In
Advances in Asymmetric Synthesis; Hassner, A., Ed.; J AI Press:
Stamford; 1998; Vol. 3, pp 113-189. (b) Rassu, G.; Zanardi, F.;
Battistini, L.; Casiraghi, G. Chem. Soc. Rev. 2000, 109-118. (c) Rassu,
G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999, 1333-1350.
(9) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev.
2000, 100, 1929-1972.
(10) (a) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetra-
hedron 1990, 46, 265-276. (b) Hungerbu¨hler, E.; Seebach, D. Helv.
Chim. Acta 1981, 64, 687-702.
(11) A handy form of numeration was adopted throughout this text
both for the intermediate and target compounds which does not
correspond to IUPAC nomenclature. IUPAC nomenclature was, how-
ever, adopted in the Supporting Information chapter of the Experi-
mental Section.
5882 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Carbaseptanoses and Carbaoctanoses
SCHEME 3
the synthesis (vide infra) and were found to agree with
the hypothetical assignments.
Chemoselective saturation of the butenolide double
bond (NiCl2, NaBH4),12 followed by silylation (TBSOTf,
2,6-lutidine) delivered orthogonally protected lactone 8
in a 81% yield (two steps). Installation of the terminal
formyl function to give aldehyde 9 was performed via two
clean maneuvers, namely, debenzylation of the primary
carbinol group (H2, Pd(OH)2) followed by Swern oxidation;
the overall yield from 8 was 76% (two steps). The crucial
cycloaldolization reaction that installs the heptanoid ring
was carried out on aldehyde 9 using a highly efficient,
direct silylative protocol driven by the TBSOTf/DIPEA
reagent mixture at room temperature.1 To our pleasure,
this operation furnished silylated 4,5-trans-configured
tricyclic compound 11 in a 78% yield, with little, if any,
diastereomeric contamination (<2%). Presumably, this
transformation proceeds via transition state 10, where
the aldehyde acceptor site exposes its re face to the in-
coming C(6)-enolate donor (re face). Indeed, the conforma-
tional restraint impressed onto the aldehyde side chain
by the acetonide group at C(3)-C(4) together with the
possibility of allocating the C(5)-siloxyl group of product
11 in a thermodynamically favorable pseudoequatorial
position emerge as crucial factors in driving the reaction
toward the stereochemical outcome disclosed in this
study. The structure of 11 was secured via extensive
spectroscopic analysis. As a result of the conformationally
SCHEME 4
1
locked nature of 11, H NMR diagnosis was straightfor-
ward, allowing complete assignment of the relative and
absolute stereochemistry as 1R,2S,3S,4S,5R,6S.13 It should
be emphasized at this point that the stereochemistry in
7, 8, and 9 was thus established, as shown.
Having secured the construction of the seven-mem-
bered carbon ring, synthesis of 1 was completed by
reductive opening of the lactone moiety (LiBH4), followed
by global deprotection (6 N aqueous HCl, THF, MeOH;
79%, two steps). Chiral nonracemic â-D-glycero-D-gulo-
configured carbasugar 1 was thus successfully synthe-
sized via a highly diastereoselective, eight-step sequence
with a good 30% global yield from 6.
learnt from previous experience that the N-Boc protection
does not tolerate our reaction promoter (TBSOTf-DI-
PEA),1 we were obliged to change the protecting group
to a N-Bn group. Thus, N-Boc-protected lactam 14 was
transformed into the corresponding N-benzyl derivative
15 via chemoselective removal of the carbamoyl protec-
tion (CAN, MeCN)14 followed by benzylation (BnCl, KH,
60 °C) (69%, two steps). Subsequent elaboration of 15 into
aldehyde 16 occurred smoothly, by selective oxygen
debenzylation (H2, Pd(OH)2) and Swern oxidation (78%,
two steps).
We were now ready to install the requisite seven-
membered cycle via the proposed silylative intramolecu-
lar aldol reaction (Scheme 4). Once again, the TBSOTf/
DIPEA couple proved an ideal candidate to drive this
pivotal maneuver to success. Indeed, when aldehyde 16
was exposed to 3.0 mole equiv of the amine/triflate
mixture, tricyclic adduct 17 was formed, in a good 85%
isolated yield. Remarkably, 4,5-trans-configured com-
pound 17 was obtained as the single diastereoisomer,
with complete consumption of the starting aldehyde 16.
As for oxygenated compound 11, the stereostructure of
17 was unambiguously ascertained via 1H NMR spec-
troscopy and NOE studies.13
Syn th esis of Am in ocycloh ep ta n e Der iva tives 2
a n d 3. The aminated nature of the title compounds called
for the use of pyrrole-based building block 12, which
yields the upper four carbon atoms of the targeted
constructs. At first, aldol coupling between N-(tert-
butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy]pyrrole (12)
and aldehyde 5 under SnCl4 guidance furnished the
desired unsaturated lactam 13 in a 80% yield with little
or no recovery of other diastereomeric isomers (Scheme
3). Even in this case, the considerations made for
compound 7 led to the preliminary 4,5-threo-5,6-erythro
stereoassignment of compound 13 (vide supra).
Paralleling the previously disclosed protocol of 1,
compound 13 was then converted into fully protected
intermediary compound 14 (83% yield, two steps). With
the crucial cycloaldolization step in mind and having
(12) Caggiano, T. J . In Handbook of Reagents for Organic Synthesis.
Oxidizing and Reducing Agents; Burke, S. D., Danheiser, R. L., Eds.;
Wiley: Chichester; 1999; pp 246-250.
(13) Selected 1H NMR resonances, coupling constants, and 1H-1H
NOE contacts for 11, 17, and 23 are reported in Supporting Information
(Tables S1-S3).
(14) Hwu, J . R.; J ain, M. L.; Tsay, S.-C.; Hakimelahi, G. H.
Tetrahedron Lett. 1996, 37, 2035-2038.
J . Org. Chem, Vol. 68, No. 15, 2003 5883

Rassu et al.
SCHEME 5
SCHEME 6
Because of the reluctance of N-benzyl lactams to
undergo both hydrolytic and reductive amide fission, it
was necessary at this point to remove the benzyl group
in 17 and substitute it with a carbamate moiety. This
was cleanly effected by a standard treatment with sodium
in liquid ammonia followed by exposure to Boc2O (93%,
two steps).
Lactam 18 thus formed represents a branching point
in the synthesis where one can imagine this key precur-
sor giving rise to either aminated polyols (via reductive
opening) or carbocylic γ-amino acids (via hydrolytic
opening) (Scheme 5).
This did indeed turn out to be the case, and lactam
reduction (NaBH4, THF, H2O) followed by complete
deprotection (6 N aqueous HCl, THF, MeOH) led smoothly
to the amino carbasugar 2 (84% yield, two steps), whereas
its direct hydrolysis (6 N aqueous HCl) yielded the
expected amino acid 3 (85% yield). On the whole, starting
from 5, synthesis of carbasugar 2 encompassed 12
individual steps and gave a global yield of 24%, whereas
preparation of amino acid 3 necessitated 11 steps for a
total yield of 24%.
Syn th esis of Am in ocycloh ep ta n es en t-2 a n d en t-3
a n d Am in ocycloocta n e 4. In pursuing synthetic diver-
gency, the scaffolding of the lower part of the target
compounds necessitated a common aldose embodied with
the possibility of either yielding a polyol frame four
carbon atoms long (to enter ent-2 and ent-3) or giving rise
to a five carbon atom length (for compound 4). Our choice
fell on 2,3:4,5-di-O-isopropylidene-D-arabinose (19) (Scheme
6), easily obtainable from inexpensive D-arabinose,15 as
its carbon skeleton could be shortened by one carbon
atom or left as such.
Initially we proceeded as already planned, with the
first step being the SnCl4-promoted vinylogous aldol
reaction between arabinose 19 and pyrrole 12. As we
expected, the reaction worked efficiently to form nine-
carbon lactam 20 in a 81% yield and with a gratifying
98% diastereoselectivity. At this point, the 4,5-threo-5,6-
erythro configuration of 20 was only a hypothesis based
on the considerations made for the previous analogues 7
and 13 and was confirmed at a later stage in the
synthesis.
N-Boc protection for N-Bn, and selective removal of the
terminal acetonide blockage (48% overall yield). Focusing
on seven-membered structures ent-2 and ent-3 and to
achieve a chemical correlation with their respective
enantiomers 2 and 3 already mentioned, the polyol chain
in 21 was oxidatively shortened by one carbon atom
(aqueous NaIO4) to furnish aldehyde ent-16, whose
spectral characteristics proved identical in all respects
to the spectral data derived from 16, apart from chirop-
tical data, which proved to be opposite in sign {e.g., ent-
16, [R]20 ) +21.4 (c 0.7, CHCl3); 16, [R]20 ) -21.0 (c
D
D
1.2, CHCl3)}.
From here onward, we paralleled the chemistry previ-
ously disclosed for the enantiomeric series (vide supra).
In short, ent-16 was elaborated to ent-18 (via ent-17, 72%
yield, three steps), the useful precursor for both the
amino carbasugar ent-2 (80% yield, two steps) and the
amino acid ent-3 (85% yield). This arabinose-based
synthesis provided ent-2 within 12 steps (22% global
yield) and ent-3 within 11 steps (23% global yield), with
a synthetic efficiency comparable to that of the above-
discussed synthesis of enantiomers 2 and 3 from L-
threose.
The divergent lactam intermediate 21 was then ac-
cessed by a five-step sequence encompassing reduction
of the carbon-carbon double bond, silylation, changing
(15) (a) Zinner, H.; Brandner, H.; Rembarz, G. Chem. Ber. 1956,
89, 800-813. (b) Zinner, H.; Wittenburg, E.; Rembarz, G. Chem. Ber.
1959, 92, 1614-1617.
5884 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Carbaseptanoses and Carbaoctanoses
SCHEME 7
21% overall yield for the 12-step sequence from arabinose
aldehyde 19. Unlike cycloheptane lactams 18 and ent-
18, the amide bond within cyclooctanoid 24 proved
extremely reluctant to reductive fragmentation, thus
precluding direct access to the corresponding cyclooc-
tanose amino carbasugar. For example, exposure of 24
to 10-fold molar excess NaBH4 in wet THF left its
structure unmarred, while a prolonged LiAlH4 treatment
only resulted in partial cleavage of NBoc and OTES
protections. Equally unproductive was the use of LiBH4
where the reduction of the amide functionality drew to a
close with hemiaminal formation.19
Su m m a r y
An adaptable, ex chiral-pool synthesis of scarcely
represented medium-sized carbasugar compounds has
been established. Key features of the unified synthetic
scheme include the stereocontrolled construction of the
multifunctional carbon framework of the targeted mol-
ecules via a vinylogous Mukaiyama-aldol reaction and
the assembly of the medium-sized cyclic domain via
diastereoselective intramolecular silylative aldolization.
Installation of the exocyclic hydroxymethyl or carboxylic
groups was eventually achieved by simple reductive or
hydrolytic fragmentations. As demonstrated by the prepa-
ration of chiral nonracemic carbaseptanoses 1, 2, 3, ent-
2, and ent-3 and carbaoctanose 4, our methodology proved
feasible, stereocontrolled, and synthetically efficient, with
overall yields ranging from 21% to 30% for 8- to 12-step
sequences. The successful exploitation of the silylative
aldol annulation in the implementation of seven- and
eight-membered ring systems presents itself as a viable
solution to the challenging task of assembling these
expanded carbocyclic motifs and establishes the basis for
future applications.
On the other hand, 21 in maintaining all of its carbon
length lent itself to forge cyclooctane amino acid 4
(Scheme 7). After persilylation (TESOTf, pyridine, DMAP),
an adaptation of the Swern oxidation was chosen to
arrive at aldehyde 22.16 This direct variation uses a
strong excess of reagents and calls for higher tempera-
tures to attain oxidation. The resulting compound 22 was
obtained in a 81% yield over the two steps.
At this point, the formation of the eight-membered ring
awaited the decisive step of ring closure. We embarked
on this step with some trepidation, well aware of the
problems aldol-based macrocyclization inherently pre-
sents.17 However, exposure of 22 to the aforementioned
TBSOTf/DIPEA reagent mixture (0.1 M CH2Cl2) pleas-
ingly afforded tricycle 23 as the only product detectable
in an 85% yield. Whereas the configurations of the C(1)-
C(5) stereocenters of 23 had already been established
(vide supra), the stereochemistry of C(6) and C(7) had
yet to be ascertained and this was evinced through
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). 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
instrumentation.
1
extensive H NMR and NOE evaluation.13
Swapping the N-benzyl protection within 23 for the Boc
group proceeded smoothly to deliver lactam 24, which
was readily transformed into novel â-L-erythro-D-manno-
configured cyclooctane amino acid 4 via exposure to
refluxing 6 N aqueous HCl.18 Thus, completion of 4 was
achieved in a 86% yield, corresponding to a remarkable
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data for all synthesized compounds
1
1
and H NMR resonances, coupling constants, and H-1H NOE
correlations for 11, 17, and 23 (Tables S1-S3). This material
is available free of charge via the Internet at http://pubs.acs.org.
J O0344539
(16) Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J . J . Tetra-
hedron Lett. 1999, 40, 5161-5164.
(18) Contrary to the observations made for its seven-membered
analogues 3 and ent-3, cyclooctane 4 showed a strong propensity
towards reannulation into the bicyclic lactam. For this reason,
compound characterizations were carried out on the hydrochloride salt.
(19) A less straightforward attempt to convert intermediate 24 to
the corresponding amino-carbasugar via sequential hydrolytic opening
(LiOH, aqueous THF) and reduction was frustrated owing to the
unpredictable robustness of the C(O)-NH linkage.
(17) (a) Molander, G. Acc. Chem. Res. 1998, 31, 603-609. (b)
Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-102. (c)
Yet, L. Chem. Rev. 2000, 100, 2963-3008. (d) Yet, L. Tetrahedron 1999,
55, 9349-9403. (e) Petasis, N. A.; Patane, M. A. Tetrahedron 1992,
48, 5757-5821. (f) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881-
930.
J . Org. Chem, Vol. 68, No. 15, 2003 5885