Variable strategy toward carbasugars and relatives. 1. Stereocontrolled synthesis of pseudo-β-D-gulopyranose, pseudo-β-D-xylofuranose, (Pseudo-β-D-gulopyranosyl)amine, and (pseudo-β-D-xylofuranosyl)amine

Article abstract of DOI:10.1021/jo000604l

Four novel, chiral nonracemic carbasugars have been synthesized from 1,2-O-isopropylidene-D-glyceraldehyde. Furan- and pyrrole-based 2-silyloxy dienesmimics of the α,γ-dianions of γ-hydroxy- and γ-aminobutanoic acid, respectivelynicely served to complete the syntheses of two all-oxygen compounds, pseudo-β-D-gulopyranose and pseudo-β-D-xylofuranose, and two 'anomeric' amino derivatives, (pseudo-β-D-gulopyranosyl)amine (1,2,4-tri-epi-validamine) and (pseudo-β-D-xylofuranosyl)amine. Two sequential, highly diastereoselective carboncarbon bond-forming maneuvers, i.e., a vinylogous crossed aldol addition and an intramolecular aldolization, proved central to these constructions. The fact that readily available heterocyclic diene scaffolds can be employed in the assembly of a varied repertoire of carbasugars and analogues widens the prospects of dienoxy silane chemistry.

Full text of DOI:10.1021/jo000604l

J . Org. Chem. 2000, 65, 6307-6318
6307
Va r ia ble Str a tegy tow a r d Ca r ba su ga r s a n d Rela tives. 1.
Ster eocon tr olled Syn th esis of P seu d o-â-D-gu lop yr a n ose,
P seu d o-â-D-xylofu r a n ose, (P seu d o-â-D-gu lop yr a n osyl)a m in e, a n d
(P seu d o-â-D-xylofu r a n osyl)a m in e
Gloria Rassu,*,† Luciana Auzzas,† Luigi Pinna,‡ Lucia Battistini,§ Franca Zanardi,§
Lucia Marzocchi,§ Domenico Acquotti,| and Giovanni Casiraghi*,§
Istituto per l’Applicazione delle Tecniche Chimiche Avanzate ai Problemi Agrobiologici del CNR,
I-07100 Sassari, Italy, Dipartimento di Chimica, Universita` di Sassari, I-07100 Sassari, Italy,
Dipartimento Farmaceutico, Universita` di Parma, I-43100 Parma, Italy, and Centro Interdipartimentale
di Misure “G. Casnati”, Universita` di Parma, I-43100 Parma, Italy
giovanni.casiraghi@unipr.it
Received April 19, 2000
Four novel, chiral nonracemic carbasugars have been synthesized from 1,2-O-isopropylidene-D-
glyceraldehyde. Furan- and pyrrole-based 2-silyloxy dienessmimics of the R,γ-dianions of γ-hydroxy-
and γ-aminobutanoic acid, respectivelysnicely served to complete the syntheses of two all-oxygen
compounds, pseudo-â-D-gulopyranose and pseudo-â-D-xylofuranose, and two “anomeric” amino
derivatives, (pseudo-â-D-gulopyranosyl)amine (1,2,4-tri-epi-validamine) and (pseudo-â-D-xylofura-
nosyl)amine. Two sequential, highly diastereoselective carbon-carbon bond-forming maneuvers,
i.e., a vinylogous crossed aldol addition and an intramolecular aldolization, proved central to these
constructions. The fact that readily available heterocyclic diene scaffolds can be employed in the
assembly of a varied repertoire of carbasugars and analogues widens the prospects of dienoxy silane
chemistry.
In tr od u ction
Carbasugars,1 otherwise known as pseudo-sugars, are
a subclass of the largely represented family of cyclitols,
of which inositols, condutirols, cyclophellitols, mannost-
atins, validamine, and aristeromycin are the most at-
tractive and biologically interesting representatives.2
Strictly speaking, the term carbasugar is restricted to
the carbocyclic analogues of monosaccharides, where the
ring oxygen is replaced by a methylene group. Nonethe-
less, in a broader sense, structurally modified carbafura-
nose and carbapyranose rings possessing either different
heteroatom substituents, an unsaturated framework, or
† CNR, Sassari. E-mail: rassu@hpj.area.ss.cnr.it.
‡ Universita` di Sassari.
§ Universita` di Parma.
| Centro Interdipartimentale di Misure.
(1) For review articles on carbasugars, see: (a) Suami, T.; Ogawa,
S. Adv. Carbohydr. Chem. Biochem. 1990, 48, 21. (b) Suami, T. Top.
F igu r e 1.
Curr. Chem. 1990, 154, 257. (c) Suami, T. Pure Appl. Chem. 1987, 59,
1509. (d) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand,
oxidized functionalities may also be considered to be
carbasugars (Figure 1).
S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (e) Marquez,
V. E.; Lim, M. Med. Res. Rev. 1986, 6, 1. (f) Hudlicky, T.; Cebulak, M.
Cyclitols and Their Derivatives. A Handbook of Physical, Spectral, and
Synthetic Data; VCH: New York, 1993. (g) Nishimura, Y. In Studies
in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Pub-
lishers B. V.: Amsterdam, 1992; Vol 10, p 495.
(2) For leading references, see: (a) Berecibar, A.; Grandjean, C.;
Siriwardena, A. Chem. Rev. 1999, 99, 779. (b) Ogawa, S.; Washida, K.
Eur. J . Org. Chem. 1998, 1929. (c) Ogawa, S.; Ashiura, M.; Uchida,
C.; Watanabe, S.; Yamaziki, C.; Yamagishi, K.; Inokuchi, J .-I. Bioorg.
Med. Chem. Lett. 1996, 6, 929. (d) Lee, M. D.; Fantini, A. A.; Morton,
G. O.; J ames, J . C.; Borders, D. B.; Testa, R. T. J . Antibiot. 1984, 37,
1149. (e) Marquez, V. E. Adv. Antiviral Drug Des. 1996, 2, 89. (f)
Mansour, T. S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227. (g) Parmely,
M. J .; Hausmann, E. H.; Morrison, D. C. Infect. Dis. Ther. 1996, 19,
253. (h) Ganem, B. Acc. Chem. Res. 1996, 29, 340. (i) Humphries, M.
J .; Matsumoto, K.; White, S. L.; Olden, K. Proc. Natl. Acad. Sci. U.S.A.
1986, 83, 1752. (j) Montefiori, D. C.; Robinson, W. E.; Mitchell, W. M.
Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9248.
After the pioneering synthesis of racemic pseudo-R-
talopyranose by McCasland in 1966,3 numerous research-
ers have been challenged by the chemical synthesis of
furanose and pyranose carbasugars and their efforts have
resulted in the assembly of a growing repertoire of
constructs possessing the most diverse structural and
stereochemical arrangements.2a,4 In this paper we have
developed a flexible approach to carbasugar synthesis
and confirmed its viability by preparing four carbapyra-
nose and carbafuranose representatives.
(3) McCasland, G. E.; Furuta, S.; Durham, L. J . J . Org. Chem. 1966,
31, 1516.
10.1021/jo000604l CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

6308 J . Org. Chem., Vol. 65, No. 20, 2000
Rassu et al.
Sch em e 1
Sch em e 2
acid-based R,γ-dianion E′ and malondialdehyde F ′ or
glyoxal-related fragment F ′′. Here, two common retrons,
the enoxy silane E and the chiral glyceraldehyde-related
unit F , are envisioned as synthetic equivalents of dianion
E′ and dialdehydes F ′ or F ′′, respectively.
The route we hoped to pursue involves formation of
the divergent intermediary adduct D via implementation
of the C1-C2 juncture before the annulation processes
(C f B or G f H; C4-C5 or C3-C4 junctures), which
ultimately produce pseudopyranoses A or pseudofura-
noses I. Two formal [3 + 3] or [3 + 2] cycloadditive
maneuvers featuring a sequential vinylogous cross al-
dolization-cycloaldolization protocol are central to these
constructions. Worthy of note is the malleability of this
scheme, which allows one to play around with a wide
panel of heteroatom and chirality combinations. This
project was then put into practice in the form of stereo-
controlled syntheses of chiral, nonracemic pseudo-â-D-
gulopyranose (13), pseudo-â-D-xylofuranose (19), (pseudo-
â-D-gulopyranosyl)amine (33) (1,2,4-tri-epi-validamine),
and (pseudo-â-D-xylofuranosyl)amine (39).
Resu lts a n d Discu ssion
P la n n in g a n d Str a tegy. For this enterprise, we opted
to take advantage of the availability of a variable set of
nucleophilic building blocks, the furan-, pyrrole-, and
thiophene-based dienoxy silanes denoted as E in Scheme
1. This was an obvious choice in keeping with our long-
standing familiarity with this class of reagents.5 To arrive
at the carbasugar constructs, we addressed the retrosyn-
thetic plan contemplated in Scheme 1, where both
carbapyranoses A and carbafuranoses I were assembled
by conjoining two complementary subunits, the butyric
(4) For leading references, see: (a) Ferrier, R. J .; Middleton, S.
Chem. Rev. 1993, 93, 2779. (b) Carbohydrate Mimics: Concepts and
Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1998. (c) Ogawa,
S. Synth. Org. Chem. J pn. 1985, 43, 26. (d) Dalko, P. I.; Sinay¨, P.
Angew. Chem., Int. Ed. Engl. 1999, 38, 773. (e) Hudlicky, T.; Entwistle,
D. A.; Pitzer, K. K.; Thorpe, A. J . Chem. Rev. 1996, 96, 1195.
(5) (a) Casiraghi, G.; Rassu, G. Synthesis 1995, 607. (b) Casiraghi,
G.; Rassu, G.; Zanardi, F.; Battistini, L. In Advances in Asymmetric
Synthesis; Hassner, A., Ed.; J AI Press: Stamford, CT, 1998; Vol. 3, p
113. (c) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999,
1333. (d) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem.
Soc. Rev. 2000, 109.
Syn th esis of P seu d o-â-D-gu lop yr a n ose (13). Analy-
sis of 13 suggested an all-oxygen option, where the X, Y,
Z, and W variables expressed in our plan are oxygen
functionalities. Accordingly (Scheme 2), the synthesis
commenced with the vinylogous cross aldolization of
furan-based silyloxy diene 1 to glyceraldehyde 2.
Under the guidance of BF3 etherate (CH2Cl2, -80 °C),
coupling occurred in a strict vinylogous sense (γ-alkyla-

Carbasugars and Relatives
J . Org. Chem., Vol. 65, No. 20, 2000 6309
Sch em e 3
tion only) giving rise to a 94:6 mixture of two diastere-
oisomers. The major adduct, isolated in 75% yield, was
the syn,anti butenolide 3. Saturation of the butenolide
double bond to 4 followed by silylation of the free
hydroxyl gave rise to the substituted furanone 5 in 82%
yield for the two steps. Exposure of 5 to 70% aqueous
acetic acid ensured selective removal of the terminal
isopropylidene blockage, providing a 96% yield of the
partially protected triol 6, a key divergent intermediate
in our syntheses (vide infra). A two-stage protocol,
consisting of full protection to 7 followed by selective
desilylation of the primary hydroxyl, was then adopted
in order to obtain the diprotected triol 8 which was
isolated in 56% yield over two steps. Subsequently, a
Swern oxidative maneuver ensured arrival at aldehyde
9 (97%), ready for the crucial intramolecular aldolization.
We were delighted to observe that following brief expo-
sure to LDA in THF at -80 °C, compound 9 was
transformed into the bicyclic lactone 10, which was
isolated as the sole detectable (4S,5S)-configured stere-
oisomer (51% yield).6 The rather constrained structure
of the bicyclic scaffold 10 strongly facilitated its structural
diagnosis, based on careful inspection of the 1H NMR
spectral data (vide infra). At this point, all that remained
was the liberation of the carbasugar cyclohexane ring
within the bicycle 10, and this was effected via reductive
breakage of the lactone C(O)-O linkage. The free C4-
hydroxyl was first temporarily protected as the trieth-
ylsilyl ether 11, whose lactone junction was cleaved upon
LiAlH4 treatment to give the protected pseudo-pyranose
12 in 88% yield (two steps). This was then quantitatively
liberated to pseudo-â-D-gulopyranose (13) (6 N HCl,
MeOH, THF), the relative (and hence absolute) config-
uration of which was firmly established by NMR analysis
(vide infra). Remarkably, the 1H NMR data in our
possession nicely matched the data reported more than
30 years ago by McCasland7 for its racemic counterpart.
Exposure of the free sugar 13 to Ac2O/pyridine finally
gave the crystalline peracetate 14 in 90% isolated yield.
located hydroxyl function then provided the fully pro-
tected lactone 17 the NOE experiments of which allowed
us to ascertain its stereochemistry as shown (vide infra).
Having constructed the desired cyclopentane ring, we
turned to the elaboration of the lactone moiety. Exposure
of 17 to LiAlH4 in THF cleanly gave pseudo-pentofura-
nose 18, which was liberated to give pseudo-â-D-xylo-
furanose (19) by acidic treatment (86%, two steps). Apart
from a few discrepancies, possibly due to the use of
different solvents (D2O vs CD3OD), the H and 13C NMR
1
characteristics of the nonracemic sugar 19 were in good
accordance with the data reported by Griengl for its
racemic counterpart.9,10 Peracetylation of 19, following
the usual protocol (Ac2O, pyridine, DMAP), ensured
preparation of the peracetate 20 which was obtained as
a crystalline solid in 95% yield. As a whole, the synthesis
of the enantiopure carbasugar 19 was accomplished in
nine steps from aldehyde 2, with a reasonable overall
yield of 20% (five steps, 34% starting from 6).
Syn t h esis of (P seu d o-â-D-gu lop yr a n osyl)a m in e
(33).11 According to our basic project in Scheme 1, a
nitrogen function can be implemented into the target
pseudosugar A or I by adopting either a nitrogen-
containing dienoxy silane E or a nitrogen-containing
aldehyde F . To obtain the anomeric title-compound 33,
the heteroatom choice was obvious; we selected the
readily available N-(tert-butoxycarbonyl)-2-[(tert-butyldi-
methylsilyl)oxy]pyrrole (21) and aldehyde 2 as our start-
ing materials.
As shown in Scheme 4, the synthesis started with the
intermolecular vinylogous aldol addition of 21 to (R)-
glyceraldehyde 2 (SnCl4, Et2O, -80 °C). As previously
experienced,5 the crystalline syn,anti-configured buteno-
lide adduct 22 was obtained in a good chemical yield
(80%) and with an excellent level of regio- and diaste-
reoselectivity (g 95% de). From here on, apart from only
modest adaptations, the synthesis paralleled the route
to 13. Catalytic hydrogenation easily provided lactam 23,
which was protected as the silyl ether 24 (85% yield for
the two steps). Permutation of the isopropylidene protec-
tion to TBS was then effected via deacetonidation to 25
1
The H NMR is consistent with the reported data for the
â-L-gulo enantiomer; apart from the sign of rotation, the
[R]D value of 14 matches that of the reported compound
([R]D -19.3 (c 3.4, CHCl3); lit.8 [R]D +20.5 (c 1.0,
CHCl3)). The total synthesis of pseudosugar 13 was thus
completed, covering 11 individual steps with a 14%
overall yield starting from aldehyde 2.
20
20
Syn th esis of P seu d o-â-D-Xylofu r a n ose (19). In light
of our synthesis, outlined in Scheme 1, the preparation
of 19 initiated with the excision of the terminal chain
carbon in the previously synthesized seven-carbon lactone
6. Treatment of 6 with silica gel-supported NaIO4 in CH2-
Cl2/water solvent mixture resulted in the breakage of the
C6-C7 carbon-carbon bond, giving aldehyde 15 in 85%
yield (Scheme 3). Once compound 6 was tailored to the
requisite six-carbon skeleton, the key cycloaldolization
could be performed. Noteworthily, the maneuver (LDA,
THF, -80 °C) worked diastereoselectively, giving rise to
a reasonable yield (50%) of a single 2,3-trans-3,4-cis-
configured bicyclic lactone 16.6 Silylation of the free C3-
(6) After this work was completed, the efficiency of the intramo-
lecular aldolisation reaction was greatly improved (> 80% yield) by
adopting a Mukaiyama aldol-type protocol (TBSOTf, DIPEA, -78 °C
to room temperature). Details of this investigation will be com-
municated shortly.
(7) McCasland, G. E.; Furuta, S.; Durham, L. J . J . Org. Chem. 1968,
33, 2835.
(9) Marschner, C.; Baumgartner, J .; Griengl, H. J . Org. Chem. 1995,
60, 5224.
(10) Synthesis of pseudo-â-L-xylofuranose, see: Yoshikawa, M.; Cha,
B. C.; Okaichi, Y.; Kitagawa, I. Chem. Pharm. Bull. 1988, 36, 3718.
(11) For a preliminary account of this synthesis, see: Rassu, G.;
Auzzas, L.; Pinna, L.; Zanardi, F.; Battistini, L.; Casiraghi, G. Org.
Lett. 1999, 1, 1213.
(8) Pingli, L.; Vandewalle, M. Synlett 1994, 228.

6310 J . Org. Chem., Vol. 65, No. 20, 2000
Rassu et al.
Sch em e 4
Sch em e 5
The protected six-membered ring intermediate 32 was
thus constructed in 77% yield for two steps. Exposure of
32 to 6 N HCl in THF/MeOH finally completed the
synthesis, giving (pseudo-â-D-gulopyranosyl)amine (33)
(1,2,4-tri-epi-validamine), which was isolated as the free
base in 95% yield. Crystalline penta-N,O,O,O,O-acetyl
derivative 34 was also synthesized, by subjecting free
amino sugar 33 to acetic anhydride/pyridine treatment.
The diastereoselective synthesis of the targeted pyrano-
sylamine 33 has been achieved, utilizing the vinylogous
aldol-cycloaldol combination, in 20% overall yield over
12 steps.
Syn th esis of (P seu do-â-D-xylofu r an osyl)am in e (39).
For the synthesis of the title amino-carbasugar, we
followed the reaction pathway portrayed in Scheme 5,
which closely resembles the sequence used for its all-
oxygen cousin 19 (vide supra). The intermediate triol 25
was thus shortened by one carbon atom via periodate
fission, giving rise to aldehyde 35 (95% yield), which, in
turn, was subjected to cycloaldolization (LDA, THF, -80
°C, 15 min).
The ring forming event showed a spectacular diaste-
reocontrol, resulting exclusively in the formation of 2,3-
trans-3,4-cis-disposed 5-azabicyclo[2.2.1]heptan-6-one 36
in 52% yield. To obtain the target carbasugar, the free
hydroxy function was first protected giving 37, and the
lactam N-C(O) bond was then cleaved under reductive
conditions (NaBH4, wet THF). The functionalized cyclo-
pentane 38 formed (81% yield from 36) was totally
deprotected by acidic treatment to give the free (pseudo-
â-D-xylofuranosyl)amine (39) in 94% yield (23% overall
yield for the nine-step sequence from 2). Peracetylation
of 39 proceeded smoothly, to afford the tetra-N,O,O,O-
acetyl derivative 40 in 96% yield. It is worth noting that
the synthesis of racemic 39 and 40 was reported in 1984
by Vince et al.;12 however, their given characterization
data were barely readable and did not prove useful for
comparison with the spectroscopic data in our possession.
Mech a n istic In sigh ts. According to the “chiron”
concept,13 all of the syntheses herein disclosed utilize
>98% ee (R)-glyceraldehyde acetonide 2 (ex D-mannitol)
as the source of chirality. Indeed, the single stereogenic
element of 2 is transmitted to the various synthesis
intermediates and ultimately emerges in the multichiral
followed by persilylation. Because of the sluggish nature
of this protection reaction, no conditions were found that
obviated concomitant unmasking of the NH group. There-
fore, reintroduction of the Boc function was required. We
thus arrived at 27, through the intermediacy of protected
triol 26 (79% yield for three steps). After the primary
hydroxyl group was liberated (compound 28, 92%), Swern
oxidation ensured formation of the aldehyde 29 in 94%
yield. Exposure of 29 to ring-closing aldol conditions
(LDA, THF, -80 °C, 15 min) resulted in exclusive
formation of 6-azabicyclo[3.2.1]octan-7-one 30 in 45%
isolated yield and with 33% aldehyde recovery. Recycling
unconverted 29 resulted in the formation of an additional
quantity of 30, and brought the overall yield up to 60%
for both cycles.
The stereochemical course of this intramolecular aldol
reaction (29 f 30) is a mirror image of the behavior of
the cycloaldolization of the all-oxygen aldehyde counter-
part 9 (Scheme 2, 9 f 10), resulting in formation of the
3,4-trans-4,5-cis-configured aldol adduct 30, as expected.
Following silylaton to 31, the lactam ring cleavage was
reductively effected by exposure to NaBH4 in wet THF.
(12) Vince, R.; Brownell, J .; Daluge, S. J . Med. Chem. 1984, 27, 1358.
(13) Hanessian, S. The Total Synthesis of Natural Compounds: the
Chiron Approach; Pergamon Press: Oxford, 1983.

Carbasugars and Relatives
Sch em e 6
J . Org. Chem., Vol. 65, No. 20, 2000 6311
pseudo-furanose and pyranose target structures. Com-
mon to all processes are two pivotal carbon-carbon bond
constructions, namely, the opening vinylogous cross-
aldolization and the conclusive ring-forming aldolization
(Scheme 6).
As already discussed, the stereochemical outcome of
the diastereocontrolled vinylogous cross-aldolization which
favors syn,anti aldol adducts can be rationalized based
on the putative transition state model TS1, which
displays a low-energy Diels-Alder-like conformation.5 As
for the transition states associated with the extremely
diastereoselective aldol cyclizations, leading to either
bicyclooctanoids 10 and 30 or bicycloheptanoids 16 and
36, a plausible explanation might reside in the structures
TS2 and TS3, respectively. It is worth noting that, in
all instances, the newly formed C4-C5 and C3-C4
junctures cause the hydroxyl functions at C4 and C3 to
emerge trans to the corresponding vicinal C3 and C2
hydroxyls. This implies that the aldehyde carbonyl is
oriented so as to expose its si face to the incoming
nucleophilic carbon. On the other hand, the geometry of
the molecules, with the C1 side chains â oriented, forces
the aldehyde carbonyl to enter the re face of the E-enolate
carbon. The Zimmerman-Traxler-like models TS2 and
TS3, where the enolate lithium counterion coordinates
to the aldehyde carbonyl, probably represent favorable
orientations capable of delivering the aldol products with
the indicated 3R,4â or 2R,3â trans stereochemistries.
F igu r e 2.
range coupling constants between H-C2 and H-C5aâ
and between H-C1 and H-C5 in both compounds was
suggestive of an equatorial-coplanar disposition for these
protons. The presence of a strong NOE contact between
H-C4 and H-C5aR in both 11 and 31 further cor-
roborated the suggested assignments.
In the bicycloheptanoid couple 17 and 37, the cyclo-
pentane ring was blocked in an E4a envelope conforma-
tion, where the dihydroxylated C2-C3 unit resides in the
flattened portion of the envelope. The R-disposition of
protons H-C3 in 17 and 37 was manifested by strong
NOE contacts with the corresponding H-C4a protons in
R-position and confirmed the (S) absolute configuration
for the C3 stereocenters. In particular, 2D-COSY experi-
ments revealed that the H-C1 proton in both molecules
correlates with all of the remaining backbone protons,
with three vicinal couplings (3J 1,2 , 3J 1,4aR , 3J 1,4aâ) and two
Con figu r a tion a l a n d Con for m a tion a l An a lysis.
The chirality of the starter aldehyde 2, chosen as (R),
and the awareness of the syn,anti selective character of
the opening vinylogous aldolization (vide supra) allowed
us to fix the stereochemistry of C1-C2-C3 in bicyclooc-
tanoids 11 and 31 and C1-C2 in bicycloheptanoids 17
and 37, as indicated (Figure 2).
Hence, the critical stereochemical events were re-
stricted to the cycloaldolization steps, where the relation-
ships of C3, C4, and C5 in 11 and 31 and C2, C3, and C4
in 17 and 37 were established. The strongly reduced
conformational flexibility of these oxa- and azabicycles
facilitated the stereochemical assignment by inspection
of the respective 1H NMR parameters. The most diag-
nostic data derived from the measurements of interproton
coupling constants and detection of specific NOE con-
W long-range couplings (4J 1,4 and J 1,3). Considered
together, these measurements left no doubts about the
proposed configurational and conformational assignment
for 17 and 37.
The analysis of the four target pseudo-sugars of this
study proved reasonably viable, based on the various H
4
1
NMR measurements. As summarized in Figure 3, for the
six-membered ring compounds 13 and 33, the coupling
constants for the cyclohexane protons were suggestive
1
tacts. The H NMR analysis of bicyclooctanoids 11 and
31 suggested that the cyclohexane frames within the
3
4
1
constructs adopted C5a conformations, with four equa-
of C1 conformations, with all vicinal H-1H couplings
consistently fitting the expected values. Among the most
diagnostic coupling constants, we could mention the large
J values between H-C1 and H-C2 (9.9, 10.8 Hz), H-C1
and H-C5aâ (11.4, 12.6 Hz), and H-C5 and H-C5aâ
(12.6 Hz), which are disposed in a trans-diaxial relation-
torially disposed protons (1, 2, 5, and 5aâ) and three axial
protons (3, 4, and 5aR). In particular, the large coupling
constants between H-C3 and H-C4 (8.7 Hz for 11 and
31) were indicative of the trans-antiperiplanar location
of these protons, whereas the observation of two W long-

6312 J . Org. Chem., Vol. 65, No. 20, 2000
Rassu et al.
focused on two sequential, extremely diastereoselective
constructions, an intermolecular vinylogous aldol cou-
pling followed by a cycloaldolization. Future work will
define the extent to which such a versatile plan can be
used to construct variably substituted carbacycles of
different ring sizes and stereostructures.
Exp er im en ta l Section 15,16
Ma ter ia ls. N-(tert-Butoxycarbonyl)-2-[(tert-butyldimethyl-
silyl)oxy]pyrrole (21) was prepared from pyrrole (Aldrich)
according to a described protocol.17 2-[(tert-Butyldimethylsilyl)-
oxy]furan (1) was obtained from 2-furaldehyde (Aldrich) fol-
lowing a reported method.17 2,3-O-Isopropylidene-D-glyceral-
dehyde (2) was prepared from D-mannitol (Aldrich) according
to a recently optimized protocol.18
(1′S ,4′′R ,5R )-5-[(2,2-Dim e t h yl-1,3-d ioxola n -4-yl)h y-
d r oxym eth yl]-5H-fu r a n -2-on e (3). To a solution of 1 (6.43
mL, 30.7 mmol) in anhydrous CH2Cl2 (120 mL), under argon
atmosphere, was added 2,3-O-isopropylidene-D-glyceraldehyde
(2) (4.0 g, 30.7 mmol), and the resulting mixture was cooled
to -80 °C. BF3‚Et2O (3.78 mL, 30.7 mmol), cooled to the same
temperature, was added dropwise to the stirring solution, and
the reaction was allowed to proceed for 6 h at -80 °C. The
reaction was then quenched at -80 °C by the addition of
saturated aqueous NaHCO3, and after ambient temperature
was reached, the mixture was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated in a vacuum to give a solid
crude residue, which was subjected to flash chromatographic
purification (6:4 hexanes/EtOAc). 4.93 g (75%) of pure 3 were
20
obtained as white crystals: mp 125 °C; [R]D +69.6 (c 1.0,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.59 (dd, J ) 5.8, 1.7
Hz, 1H), 6.17 (dd, J ) 5.8, 1.9 Hz, 1H), 5.27 (m, 1H), 4.18 (m,
2H), 4.05 (m, 1H), 3.67 (m, 1H), 2.94 (d, J ) 6.6 Hz, 1H), 1.42
(s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.4, 154.3,
122.1, 109.8, 84.2, 75.5, 72.9, 67.1, 26.7, 25.1. Anal. Calcd for
F igu r e 3.
C
10H14O5: C, 56.07; H, 6.59. Found: C, 55.94; H, 6.71.
(1′S ,4′′R ,5R )-5-[(2,2-Dim e t h yl-1,3-d ioxola n -4-yl)h y-
ship. The values of the remaining coupling constants
involving axial/equatorial and equatorial/equatorial pro-
ton relationships also agreed with the suggested confor-
mations.
d r oxym eth yl]d ih yd r ofu r a n -2-on e (4). Palladium on carbon
(10%, 0.60 g) was added to a solution of R,â-unsaturated
lactone 3 (4.80 g, 22.4 mmol) in anhydrous THF (120 mL) in
the presence of a small amount of NaOAc (0.18 g) at room
temperature. The reaction vessel was evacuated by aspirator
and thoroughly purged with hydrogen (three times), and the
resulting heterogeneous mixture was stirred under a balloon
of hydrogen. After 24 h, the hydrogen was evacuated, the
catalyst filtered off, and the filtrate was concentrated under
vacuum to give a crude residue which was subjected to flash
chromatographic purification (6:4 EtOAc/hexanes) to yield 4.41
However, the detailed conformations of cyclopentanoid
structures 19 and 39 could not be established with
absolute certainty by inspection of inter-proton couplings,
since five-membered ring compounds are known to be
flexible and may exist as equilibrium mixtures.14 None-
theless, it might be plausible to assume that, in D2O
solution, the cyclopentane rings of 19 and 39 might
20
g (91%) of saturated lactone 4 as a colorless oil: [R]D -13.9
(c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.77 (td, J ) 7.5,
2
preferentially adopt twisted T1 conformations where the
exocyclic hydroxymethyl functions lie in a pseudoequa-
(15) General Experimental Methods. Flash chromatography was
performed on 32-63 µm silica gel ICN Biomedicals, using the indicated
solvent mixtures. Analytical thin-layer chromatography was performed
on Merck silica gel 60 F254 plates (0.25 mm). The compounds were
visualized by dipping the plates in an aqueous H2SO4 solution of cerium
sulfate/ammonium molybdate or in an ethanolic solution of ninhydrin,
followed by charring with a heat gun. 1H NMR spectra were obtained
on a Bruker AC-300 or Varian XL-300 and are reported in parts per
million (δ) relative to tetramethylsilane (0.0 ppm) as an internal
reference, with coupling constants in hertz (Hz). Rotations were
measured on a Perkin-Elmer 241 Polarimeter and are given in units
of 10-1 deg cm2 g-1. Elemental analyses were performed by the
Microanalytical Laboratory of University of Sassari. Melting points
were determined on an Electrothermal apparatus and are recorded
uncorrected. All the solvents were distilled before use: THF over Na/
benzophenone, Et2O over LiAlH4, CH2Cl2 over CaH2.
torial orientation (θH1-C1-C2-H2 ≈ θH2-C2-C3-H3 ≈ 145-
3
3
150°; J 1,2 ≈ J 2,3 ≈ 5.4-6.6 Hz).
Con clu sion s
We have planned an enantiospecific synthetic meth-
odology to access six-membered and five-membered car-
basugars and variants thereof, which embody large
malleability. This protocol was used to synthesize a
couple of novel nonracemic pseudo-pyranoses, 13 and 33,
and a couple of novel pseudo-furanoses, 19 and 39, all
belonging to the sugar D series. The component com-
pounds of these syntheses were the readily available
D-glyceraldehyde acetonide 2 (ex D-mannitol) and the
furan- and pyrrole-based dienoxy silane pair 1 and 21.
The protocols employed a rather uniform chemistry,
(16) In the Experimental Section each compound has been named
according to the conventional naming rules. As a consequence, the atom
numbering of the compounds throughout the text does not always
correspond to that reported in the Experimental Section.
(17) Rassu, G.; Zanardi, F.; Battistini, L.; Gaetani, E.; Casiraghi,
G. J . Med. Chem. 1997, 40, 168.
(18) Zanardi, F.; Battistini, L.; Rassu, G.; Pinna, L.; Marzocchi, L.;
Casiraghi, G. J . Org. Chem. 2000, 65, 2048.
(14) Fuchs, B. Top. Stereochem. 1978, 10, 1.

Carbasugars and Relatives
J . Org. Chem., Vol. 65, No. 20, 2000 6313
2.1 Hz, 1H), 4.14 (m, 2H), 4.01 (m, 1H), 3.53 (bs, 1H), 3.35
(bs, 1H), 2.5-2.7 (m, 2H), 2.31 (m, 2H), 1.41 (s, 3H), 1.35 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 109.3, 79.9, 75.6, 73.7,
66.8, 28.5, 26.6, 25.1, 23.6. Anal. Calcd for C10H16O5: C, 55.55;
H, 7.46. Found: C, 55.33; H, 7.60.
1.88 (bs, 1H), 0.91 (s, 9H), 0.90 (s, 9H), 0.16 (s, 3H), 0.13 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 176.7, 80.3, 75.2, 73.4, 62.6,
28.7, 25.9 (3C), 24.0, 18.3, 18.0, -4.2, -4.5, -4.6, -4.7. Anal.
Calcd for C19H40O5Si2: C, 56.39; H, 9.96. Found: C, 56.25; H,
10.09.
(1′S,4′′R,5R)-5-[(ter t-Bu tyld im eth ylsila n yloxy)-(2,2-d i-
m eth yl-1,3-d ioxola n -4-yl)m eth yl]d ih yd r ofu r a n -2-on e (5).
tert-Butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)
(5.02 mL, 21.9 mmol) and 2,6-lutidine (6.95 mL, 59.7 mmol)
were sequentially added to a stirred solution of the saturated
lactone 4 (4.3 g, 19.9 mmol) in anhydrous CH2Cl2 (50 mL)
under argon atmosphere at room temperature. After 6 h the
reaction was concentrated under vacuum to afford a crude
residue that was purified by flash chromatography (6:4 hex-
anes/EtOAc). Protected lactone 5 (5.90 g, 90%) was obtained
as a colorless oil: [R]D20 -9.5 (c 0.6, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 4.60 (dt, J ) 6.6, 3.6 Hz, 1H), 4.13 (m, 1H), 4.06 (dd,
J ) 8.1, 6.3 Hz, 1H), 3.87 (dd, J ) 8.1, 6.9 Hz, 1H), 3.78 (dd,
J ) 6.0, 3.6 Hz, 1H), 2.51 (m, 2H), 2.21 (m, 2H), 1.41 (s, 3H),
1.33 (s, 3H), 0.89 (s, 9H), 0.13 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 176.5, 109.0, 81.2, 76.3, 74.3, 66.6, 28.4, 26.5, 25.8
(3C), 27.2, 23.6, 18.1-4.0 (2C). Anal. Calcd for C16H30O5Si: C,
58.15; H, 9.15. Found: C, 58.30; H, 9.09.
(2S,2′R,3S)-2,3-Bis-(ter t-bu tyld im eth ylsila n yloxy)-3-(5-
oxo-tetr a h yd r ofu r a n -2-yl)p r op ion a ld eh yd e (9). To a solu-
tion of oxalyl chloride (2.33 mL, 26.7 mmol) in CH2Cl2 (130
mL) at -80 °C, under argon was added dropwise a solution of
DMSO (2.53 mL, 35.6 mmol) in CH2Cl2 (16 mL). After 30 min,
a solution of alcohol 8 (3.60 g, 8.9 mmol) in CH2Cl2 (16 mL)
was added dropwise. After 30 min at -80 °C, Et3N (12.40 mL,
88.9 mmol) was added. The reaction mixture was stirred at
-80 °C for 30 min and then warmed slowly to 0 °C over 1 h.
After 30 min of stirring at 0 °C, toluene (400 mL) was added
to the mixture, and the solution was filtered through a Celite
pad and concentrated in vacuo. The residue was dissolved in
hexanes (400 mL), filtered again, and concentrated under
reduced pressure to give aldehyde 9 (3.48 g, 97%) as a white
solid which was used without further purification in the aldol
20
1
reaction: mp 40-42 °C, [R]D -3.13 (c 0.9, CHCl3); H NMR
(300 MHz, CDCl3) δ 9.64 (d, J ) 1.2 Hz, 1H), 4.61 (td, J ) 7.5,
6.3 Hz, 1H), 4.09 (dd, J ) 3.0, 1.5 Hz, 1H), 4.00 (dd, J ) 6.3,
3.0 Hz, 1H), 2.55 (m, 2H), 2.26 (dq, J ) 12.9, 7.5 Hz, 1H), 2.01
(m, 1H), 0.93 (s, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 202.6, 176.3, 80.3, 79.6, 77.2, 28.5,
25.7 (6C), 23.7, 18.2, 18.1, -4.6, -4.7, -4.8, -5.0. Anal. Calcd
for C19H38O5Si2: C, 56.67; H, 9.51. Found: C, 56.51; H, 9.26.
(1S,2S,3R,4S,5R)-3,4-Bis-(ter t-bu tyldim eth ylsilan yloxy)-
2-h yd r oxy-6-oxa bicyclo[3.2.1]octa n -7-on e (10). A solution
of diisopropylamine (1.68 mL, 12.0 mmol) in dry THF (40 mL),
under argon, was treated at -20 °C with BuLi (6.45 mL of a
1.6 M solution in hexane, 10.3 mmol). The reaction was allowed
to react for 20 min after which time the solution was cooled to
-80 °C and treated with a solution of aldehyde 9 (3.45 g, 8.6
mmol) in dry THF (20 mL). The reaction was monitored by
TLC and was judged complete after 15 min. The reaction was
then quenched at -80 °C by the addition of saturated aqueous
NH4Cl (20 mL), and after ambient temperature was reached,
the mixture was extracted with CH2Cl2. The combined extracts
were dried (MgSO4), filtered, and concentrated to give a crude
residue that was purified by flash chromatography (85:15
hexanes/EtOAc). A pure binuclear adduct 10 (1.77 g, 51%) was
obtained as a glassy solid: [R]D20 +16.4 (c 0.6, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 4.59 (td, J ) 5.1, 0.6 Hz, 1H), 4.14 (td, J
) 4.5, 0.6 Hz, 1H), 3.82 (ddd, J ) 9.0, 5.1, 3.0 Hz, 1H), 3.61
(dd, J ) 9.0, 4.2 Hz, 1H), 2.73 (ddd, J ) 5.1, 3.0, 0.6 Hz, 1H),
2.45 (d, J ) 12.0 Hz, 1H), 2.20 (dtd, J ) 12.0, 5.1, 0.6 Hz, 1H),
1.91 (d, J ) 5.1 Hz, 1H), 0.92 (s, 9H), 0.89 (s, 9H), 0.12 (s,
3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 175.8, 79.5, 74.9, 71.3, 70.0, 43.6, 29.7, 26.0 (3C), 25.7
(3C), 18.2, 18.0, -3.6, -4.4, -4.6, -4.7. Anal. Calcd for
(1′S,2′R,5R)-5-[1-(ter t-Bu tyld im eth ylsila n yloxy)-2,3-d i-
h yd r oxyp r op yl]d ih yd r ofu r a n -2-on e (6). Protected lactone
5 (5.80 g, 17.6 mmol) was dissolved in 40 mL of 70% aqueous
acetic acid, and the resulting solution was allowed to react at
50 °C. The reaction was monitored by TLC and was judged
complete after 8 h. The solution was then diluted with CH2-
Cl2, the organic layer was separated and treated twice with
saturated NaHCO3 solution. The combined organic layers were
dried (MgSO4) and concentrated to give a crude residue that
was purified by flash chromatography (7:3 EtOAc/THF). Pure
terminal diol 6 (4.91 g, 96%) was obtained as a white solid:
20
mp 81-83 °C; [R]D -14.2 (c 2.0, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 4.76 (td, J ) 7.2, 3.0 Hz, 1H), 3.79 (m, 3H), 3.66 (m,
1H), 3.32 (bs, 2H), 2.55 (m, 2H), 2.27 (m, 1H), 2.14 (m, 1H),
0.90 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 177.6, 80.8, 74.3, 72.3, 63.1, 28.4, 25.7 (3C), 23.5, 18.0,
-4.4, -4.5. Anal. Calcd for C13H26O5Si: C, 53.76; H, 9.02.
Found: C, 53.69; H, 8.81.
(1′S,2′R,5R)-5-[1,2,3-Tr is-(ter t-bu tyldim eth ylsilan yloxy)-
p r op yl]d ih yd r ofu r a n -2-on e (7). To a solution of compound
6 (4.80 g, 16.5 mmol) in dry pyridine (50 mL), under argon
atmosphere, were added TBSCl (19.90 g, 132.0 mmol) and
imidazole (8.99 g, 132.0 mmol), and the mixture was stirred
at 45 °C for 5 h. One further addition of TBSCl (4.97 g, 33.0
mmol) was effected, and after 12 h, the reaction was quenched
with H2O (200 mL). The resulting slurry was extracted with
CH2Cl2, and the extracts were dried (MgSO4), filtered, and
evaporated under reduced pressure to give a crude product
which was flash chromatographed on silica gel (9:1 hexanes/
20
THF) to afford 7 (5.99 g, 70%) as an oil: [R]D -22.5 (c 1.2,
C
19H38O5Si2: C, 56.67; H, 9.51. Found: C, 56.55; H, 9.34.
CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.62 (dt, J ) 9.6, 6.6
Hz, 1H), 3.77 (m, 3H), 3.44 (m, 1H), 2.50 (m, 2H), 2.25 (m,
1H), 1.91 (dq, J ) 12.3, 9.9 Hz, 1H), 0.90 (s, 9H), 0.89 (s, 18H),
0.12 (s, 3H), 0.10 (s, 6H), 0.08 (s, 3H), 0.06 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 176.7, 82.3, 77.9, 74.3, 63.5, 29.2, 25.9 (9C),
24.9, 18.2 (3C), -4.5, -4.6 (2C), -4.7, -5.5 (2C). Anal. Calcd
for C25H54O5 Si3: C, 57.86; H, 10.49. Found: C, 57.66; H, 10.32.
(1′S,2′R,5R)-5-[1,2-Bis-(ter t-bu tyld im eth ylsila n yloxy)-
3-h yd r oxyp r op yl]d ih yd r ofu r a n -2-on e (8). Protected lac-
tone 7 (5.90 g, 11.4 mmol) was dissolved in 20 mL of 80%
aqueous acetic acid, and the resulting solution was allowed to
react at room temperature with stirring. The reaction was
monitored by TLC and was judged complete after 6 h. The
solution was then quenched with saturated NaHCO3 solution,
and the resulting mixture was extracted with CH2Cl2 and
EtOAc. The combined organic layers were dried (MgSO4),
filtered and concentrated under vacuum to give a crude residue
that was purified by flash chromatography (7:3 hexanes/THF).
A pure terminal alcohol intermediate 8 (3.69 g, 80%) was
obtained as a glassy solid: [R]D20 -18.4 (c 1.1, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 4.69 (td, J ) 7.5, 3.6 Hz, 1H), 3.80 (m,
2H), 3.68 (m, 2H), 2.53 (m, 2H), 2.25 (m, 1H), 2.08 (m, 1H),
(1S,2S,3R,4S,5R)-3,4-Bis-(ter t-bu tyldim eth ylsilan yloxy)-
2-(tr ieth ylsilan yloxy)-6-oxabicyclo[3.2.1]octan -7-on e (11).
To a solution of 10 (1.70 g, 4.2 mmol) in dry pyridine (15 mL),
under argon atmosphere, were sequentially added triethylsi-
lyltriflate (1.41 mL, 8.4 mmol) and a catalytic amount of DMAP
(50 mg). After being stirred at room temperature for 5 h,
further addition of pyridine (7.5 mL) and triethylsilyltriflate
(705 µL, 4.2 mmol) was effected, and the mixture was allowed
to stir overnight, quenched with H2O (100 mL), and extracted
with CH2Cl2. The combined organic layers were dried over
MgSO4, filtered, and concentrated in a vacuum to provide a
crude oily residue that was purified by flash chromatography
(95:5 hexanes/EtOAc) to yield 2.06 g (95%) of a binuclear
adduct 11 as an oil: [R]D20 +52.1 (c 2.8, CHCl3); 1H NMR (300
MHz, CDCl3) δ 4.52 (td, J ) 4.8, 1.0 Hz, 1H), 4.11 (td, J ) 4.8,
1.0 Hz, 1H), 3.86 (dd, J ) 8.7, 2.7 Hz, 1H), 3.62 (dd, J ) 8.7,
4.2 Hz, 1H), 2.57 (ddd, J ) 5.1, 2.7, 1.0 Hz, 1H), 2.40 (d, J )
12.0 Hz, 1H), 2.12 (dtd, J ) 12.0, 5.0, 1.0 Hz, 1H), 1.00 (t, J )
7.8 Hz, 9H), 0.91 (s, 9H), 0.90 (s, 9H), 0.66 (q, J ) 7.8 Hz,
6H), 0.12 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 175.2, 78.9, 74.4, 72.0, 70.6, 44.5,
29.9, 26.3 (3C), 25.8 (3C), 18.2, 18.0, 6.8 (3C), 5.1 (3C), -3.9,

6314 J . Org. Chem., Vol. 65, No. 20, 2000
Rassu et al.
-4.1, -4.3, -4.6. Anal. Calcd for C25H52O5Si3: C, 58.09; H,
10.14. Found: C, 58.12; H, 10.31.
(d, J ) 1.3 Hz, 1H), 4.88 (ddd, J ) 8.1, 5.4, 2.6 Hz, 1H), 4.04
(dd, J ) 2.6, 1.3 Hz, 1H), 2.57 (m, 2H), 2.37 (m, 1H), 2.19 (m,
1H), 0.95 (s, 9H), 0.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
201.9, 176.5, 79.6, 79.2, 27.7, 25.5 (3 C), 23.2, 18.0, -4.7, -5.2.
Anal. Calcd for C12H22O4Si: C, 55.78; H, 8.58. Found: C, 55.58;
H, 8.63.
(1R,2S,3R,4S,5R)-2,3-Di-O-(ter t-bu tyld im eth ylsila n yl)-
4-O-(tr ieth ylsilan yl)-5-h ydr oxym eth ylcycloh exan e-1,2,3,4-
tetr ol (12). To a reaction vessel containing lactone 11 (2.0 g,
3.9 mmol) cooled to 0 °C, under argon atmosphere, were
sequentially added 30 mL of dry THF and LiAlH4 (7.80 mL of
a 1 M solution in THF). After being stirred for 15 min, the
reaction mixture was quenched by addition of saturated
aqueous NH4Cl and with 5% aqueous citric acid solution until
neutral pH was reached. The reaction mixture was extracted
thoroughly with CH2Cl2 and EtOAc, and the extracts were
dried (MgSO4), filtered, and concentrated under reduced
pressure to give a residue which was purified by flash
chromatography (7:3 hexanes/EtOAc) to give partially pro-
(1R,4S,5S,6S)-6-(ter t-Bu t yld im et h ylsila n yloxy)-5-h y-
d r oxy-2-oxa bicyclo[2.2.1]h ep ta n -3-on e (16). A solution of
diisopropylamine (2.12 mL, 15.1 mmol) in dry THF (56 mL),
under argon, was treated at -20 °C with BuLi (8.13 mL of a
1.6 M solution in hexane, 13.0 mmol). The reaction was allowed
to react for 20 min after which time the solution was cooled to
-80 °C and treated with a solution of aldehyde 15 (2.80 g,
10.8 mmol) in dry THF (30 mL). The reaction was monitored
by TLC and was judged complete after 15 min. The reaction
was then quenched at -80 °C by the addition of saturated
aqueous NH4Cl (25 mL), and after ambient temperature was
reached, the mixture was extracted with CH2Cl2 and EtOAc.
The combined extracts were dried (MgSO4), filtered, and
concentrated to give a crude residue that was purified by flash
chromatography (6:4 hexanes/EtOAc). A pure binuclear adduct
16 (1.40 g, 50%) was obtained as a white solid: mp 83-85 °C;
20
tected carbasugar 12 (1.89 g, 93%) as an oil: [R]D -33.9 (c
1.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.90 (t, J ) 3.0 Hz,
1H), 3.83 (m, 1H), 3.79 (dd, J ) 3.5, 2.7 Hz, 1H), 3.73 (dd, J )
9.0, 2.4 Hz, 1H), 3.59 (m, 2H), 2.08 (m, 1H), 1.71 (dt, J ) 12.3,
4.2 Hz, 1H), 1.60 (bs, 2H), 1.45 (q, J ) 12.3 Hz, 1H), 0.99 (t, J
) 7.8 Hz, 9H), 0.93 (s, 9H), 0.88 (s, 9H), 0.63 (q, J ) 7.8 Hz,
6H), 0.13 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 75.6, 75.4, 72.8, 69.5, 64.3, 37.6, 28.8,
26.0 (3C), 25.8 (3C), 18.1, 18.0, 6.9 (3C), 4.9 (3C), -4.3, -4.4,
-4.7, -4.8. Anal. Calcd for C25H56O5Si3: C, 57.64; H, 10.83.
Found: C, 57.78; H, 10.68.
20
[R]D -32.3 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.48
(m, 1H), 4.17 (dt, J ) 4.2, 1.2 Hz, 1H), 3.90 (dt, J ) 2.1, 1.2
Hz, 1H), 2.96 (dq, J ) 4.5, 1.2 Hz, 1H), 2.28 (dq, J ) 11.1, 2.1
Hz, 1H), 2.18 (dd, J ) 11.1, 1.2 Hz, 1H), 1.68 (bs, 1H), 0.90 (s,
9H), 0.15 (s, 3H), 0.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
175.2, 82.1, 78.7, 78.1, 47.3, 35.9, 25.7 (3C), 17.9, -4.8, -4.9.
Anal. Calcd for C12H22O4Si: C, 55.78; H, 8.58. Found: C, 55.89;
H, 8.40.
(1R,2S,3R,4S,5R)-5-(Hydr oxym eth yl)cycloh exan e-1,2,3,4-
tetr ol [P seu d o-â-D-gu lop yr a n ose] (13). The partially pro-
tected carbasugar 12 (1.85 g, 3.6 mmol) was treated, at room
temperature, with a solution mixture of 6 N HCl-THF-MeOH
(1:2:2) (30 mL). The reaction was allowed to react for 1 h and
then concentrated to dryness under vacuum to leave an oily
crude residue which was flash chromatographed on silica gel
(1:1 EtOAc/MeOH) to afford fully deprotected carbasugar 13
(1R,4S,5S,6S)-6-(ter t-Bu tyld im eth ylsila n yloxy)-5-(tr i-
eth ylsila n yloxy)-2-oxa bicyclo[2.2.1]h ep ta n -3-on e (17). To
a solution of 16 (1.38 g, 5.3 mmol) in dry pyridine (15 mL),
under argon atmosphere, were sequentially added triethylsi-
lyltriflate (1.78 mL, 10.6 mmol) and a catalytic amount of
DMAP (60 mg). After being stirred at room temperature for 5
h, further addition of pyridine (7.5 mL) and triethylsilyltriflate
(910 µL, 5.42 mmol) was effected, the mixture was allowed to
stir overnight, and the reaction was quenched with H2O (100
mL) and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4, filtered, and concentrated in a vacuum
to provide a crude oily residue that was purified by flash
chromatography (95:5 hexanes/EtOAc) to yield 1.88 g (95%)
20
(622 mg, 97%) as a glassy solid: [R]D -60.9 (c 2.3, MeOH);
1H NMR (300 MHz, D2O) δ 3.94 (dd, J ) 3.2, 2.7 Hz, 1H), 3.92
(t, J ) 3.2 Hz, 1H), 3.74 (ddd, J ) 11.4, 9.9, 4.8 Hz, 1H), 3.61
(dd, J ) 11.0, 8.1 Hz, 1H), 3.60 (dd, J ) 9.9, 2.7 Hz, 1H), 3.50
(dd, J ) 11.0, 6.3 Hz, 1H), 1.99 (ddddd, J ) 12.6, 8.1, 6.3, 4.5,
3.2 Hz, 1H), 1.76 (dt, J ) 12.6, 4.5 Hz, 1H), 1.28 (dt, J ) 12.6,
11.4 Hz, 1H); 13C NMR (75 MHz, D2O) δ 73.1, 72.6, 69.9, 69.2,
62.5, 36.6, 29.4. Anal. Calcd for C7H14O5: C, 47.19; H, 7.92.
Found: C, 47.05; H, 7.99.
20
(1R,2S,3R,4S,5R)-1,2,3,4-Tet r a -O-a cet yl-5-(a cet yloxy-
m et h yl)cycloh exa n e-1,2,3,4-t et r ol (14). Acetic anhydride
(4.82 mL, 51.0 mmol) and a catalytic amount of DMAP (10
mg) were added under argon to a solution of deprotected
carbasugar 13 (610 mg, 3.4 mmol) in dry pyridine (10 mL).
The reaction was stirred for 5 h at room temperature. The
solution was then quenched with H2O, and the resulting
mixture was extracted with CH2Cl2 and EtOAc. The combined
organic layers were dried (MgSO4), filtered, and concentrated
to give a crude residue that was flash chromatographed on
silica gel eluting with EtOAc to afford 1.19 g (90%) of pure
of protected binuclear adduct 17 were obtained as an oil: [R]D
1
+12.9 (c 1.4, CHCl3); H NMR (300 MHz, CDCl3) δ 4.42 (m,
1H), 4.08 (dt, J ) 4.5, 1.2 Hz, 1H), 3.84 (dt, J ) 2.1, 1.2 Hz,
1H), 2.80 (dq, J ) 4.5, 1.5 Hz, 1H), 2.23 (dq, J ) 11.4, 2.1 Hz,
1H), 2.12 (dt, J ) 11.4, 1.2 Hz, 1H), 0.97 (t, J ) 8.1 Hz, 9H),
0.89 (s, 9H), 0.63 (q, J ) 8.1 Hz, 6H), 0.12 (s, 3H), 0.10 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 81.5, 79.2, 79.0, 47.4,
35.5, 25.6 (3C), 17.8, 6.7 (3C), 4.6 (3C), -4.6, -5.0. Anal. Calcd
for C18H36O4Si2: C, 58.02; H, 9.74. Found: C, 58.18; H, 9.84.
(1R,2S,3S,4R)-2-O-(ter t-Bu tyld im eth ylsila n yl)-3-O-(tr i-
et h ylsila n yl)-4-(h yd r oxym et h yl)cyclop en t a n e-1,2,3-t r i-
ol (18). To a reaction vessel containing lactone 17 (1.85 g, 5.0
mmol) cooled to 0 °C, under argon atmosphere, were sequen-
tially added 30 mL of dry THF and LiAlH4 (10 mL of a 1 M
solution in THF). After being stirring for 1 h, the reaction was
quenched by addition of saturated aqueous NH4Cl and with
5% aqueous citric acid solution until neutral pH was reached.
The reaction mixture was extracted thoroughly with CH2Cl2
and EtOAc, dried (MgSO4), filtered, and concentrated under
reduced pressure to give a residue which was purified by flash
chromatography (6:4 hexanes/EtOAc) to give partially pro-
20
protected carbasugar 14 as a white solid: mp 95-96 °C; [R]D
-19.3 (c 3.4, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.38 (dd, J
) 3.9, 2.7 Hz, 1H), 5.17 (m, 2H), 5.10 (t, J ) 3.5 Hz, 1H), 4.05
(dd, J ) 11.0, 8.4 Hz, 1H), 3.87 (dd, J ) 11.0, 6.6 Hz, 1H),
2.46 (m, 1H), 2.13 (s, 3H), 2.12 (s, 3H), 2.09 (m, 1H), 2.05 (s,
6H), 1.99 (s, 3H), 1.58 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
170.7, 170.3, 170.0, 169.2, 169.1, 70.3, 68.9, 68.3, 68.1, 63.1,
33.5, 27.5, 20.9, 20.7, 20.6 (3C). Anal. Calcd for C17H24O10: C,
52.58; H, 6.23. Found: C, 52.69; H, 6.09.
(2S,2′R)-2-(ter t-Bu tyldim eth ylsilan yloxy)-(5-oxotetr ah y-
d r ofu r a n -2-yl)a ceta ld eh yd e (15). The partially deprotected
lactone 6 (3.75 g, 12.9 mmol) was dissolved in CH2Cl2 (270
mL) and treated with a 0.65 M aqueous NaIO4 solution (26
mL) and chromatography grade SiO2 (29 g). The resulting
heterogeneous mixture was vigorously stirred at room tem-
perature until complete consumption of the starting material
(about 20 min, monitoring by TLC). The slurry was filtered
under suction, and the silica gel was thoroughly washed with
CH2Cl2 and EtOAc. The filtrates were evaporated to afford
aldehyde 15 (2.83 g, 85%) as colorless crystals: mp 60-61 °C;
20
tected carbasugar 18 (1.70 g, 90%) as an oil: [R]D -1.9 (c
1
1.2, CHCl3); H NMR (300 MHz, CDCl3) δ 4.07 (dt, J ) 5.1,
1.8 Hz, 1H), 3.89 (m, 2H), 3.84 (dd, J ) 11.0, 4.2 Hz, 1H), 3.73
(dd, J ) 11.0, 6.0 Hz, 1H), 2.73 (bs, 2H), 2.35 (m, 2H), 1.60
(m, 1H), 0.99 (t, J ) 8.1 Hz, 9H), 0.87 (s, 9H), 0.67 (q, J ) 8.1
Hz, 6H), 0.10 (s, 3H), 0.08 (s, 3H);13C NMR (75 MHz, CDCl3)
δ 83.5, 80.6, 78.3, 62.6, 43.3, 34.9, 25.7 (3C), 17.9, 6.8 (3C),
4.7 (3C), -4.6, -4.7. Anal. Calcd for C18H40O4Si2: C, 57.40;
H, 10.70. Found: C, 57.47; H, 10.66.
(1R,2S,3S,4R)-4-(H yd r oxym et h yl)cyclop en t a n e-1,2,3-
t r iol [P seu d o-â-D-xylofu r a n ose] (19). The partially pro-
[R]D -97.8 (c 2.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.67
20

Carbasugars and Relatives
J . Org. Chem., Vol. 65, No. 20, 2000 6315
tected carbasugar 18 (1.68 g, 4.5 mmol) was treated, at room
temperature, with a solution mixture of 6 N HCl-THF-MeOH
(1:2:2) (30 mL). The reaction was allowed to react for 30 min
and then concentrated to dryness under vacuum to leave an
oily crude residue which was flash chromatographed on silica
gel (1:1 EtOAc/MeOH) to afford fully deprotected carbasugar
19 (633 mg, 95%) as a glassy solid: [R]D20 +34.7 (c 0.2, MeOH);
1H NMR (300 MHz, D2O) δ 3.95 (dd, J ) 7.5, 5.4 Hz, 1H), 3.88
(ddd, J ) 8.4, 7.2, 6.6 Hz, 1H), 3.73 (bt, J ) 6.0 Hz, 1H), 3.72
(dd, J ) 11.1, 6.6 Hz, 1H), 3.53 (dd, J ) 11.1, 6.9 Hz, 1H),
2.24 (dquint, J ) 9.3, 6.9 Hz, 1H), 2.12 (dt, J ) 12.9, 7.8 Hz,
1H), 1.38 (dt, J ) 12.9, 9.0 Hz, 1H); 13C NMR (75 MHz, D2O)
δ 83.7, 75.9, 75.1, 61.7, 39.7, 32.6. Anal. Calcd for C6H12O4:
C, 48.64; H, 8.16. Found: C, 48.51; H, 8.26
3H); 13C NMR (75 MHz, CDCl3) δ 174.5, 151.7, 109.4, 83.6,
77.7, 74.5, 66.8, 60.4, 32.0, 28.0 (3C), 26.6, 25.1, 21.7. Anal.
Calcd for C15H25NO6: C, 57.13; H, 7.99; N, 4.44. Found: C,
57.26; H, 8.10; N, 4.37.
(1′S,4′′R,5R)-5-[(ter t-Bu tyld im eth ylsila n yloxy)-(2,2-d i-
m eth yl-1,3-d ioxola n -4-yl)m eth yl]-1-(ter t-bu tyloxyca r bo-
n yl)p yr r olid in -2-on e (24). tert-Butyldimethylsilyl trifluo-
romethanesulfonate (TBSOTf) (2.96 mL, 12.9 mmol) and 2,6-
lutidine (4.50 mL, 38.6 mmol) were sequentially added to a
stirred solution of the saturated lactam 23 (3.68 g, 11.7 mmol)
in anhydrous CH2Cl2 (30 mL) under argon atmosphere at room
temperature. After 6 h the reaction was concentrated under
vacuum to afford a crude residue that was purified by flash
chromatography (4:6 hexanes/EtOAc). Protected lactam 24
20
(1R,2S,3S,4R)-1,2,3-Tr i-O-a cetyl-4-((a cetyloxy)m eth yl)-
cyclop en ta n e-1,2,3-tr iol (20). Acetic anhydride (5.96 mL,
63.0 mmol) and a catalytic amount of DMAP (10 mg) were
added under argon to a solution of deprotected carbasugar 19
(620 mg, 4.2 mmol) in dry pyridine (12 mL). The reaction was
stirred for 30 min at room temperature. The reaction was then
quenched with H2O, and the resulting mixture was extracted
with CH2Cl2 and EtOAc. The combined organic layers were
dried (MgSO4), filtered, and concentrated to give a crude
residue that was flash chromatographed on silica (2:8 hexanes/
EtOAc) to afford 1.26 g (95%) of pure protected carbasugar 20
(4.62 g, 92%) was obtained as a pale yellow oil: [R]D +21.3
1
(c 0.8, CHCl3); H NMR (300 MHz, CDCl3) δ 4.14 (ddd, J )
8.1, 3.6, 1.2 Hz, 1H), 4.04 (dd, J ) 8.4, 3.3 Hz, 1H), 4.02 (dd,
J ) 8.4, 6.3 Hz, 1H), 3.90 (m, 1H), 3.66 (dd, J ) 8.1, 6.3 Hz,
1H), 2.51 (m, 1H), 2.33 (m, 1H), 2.11 (m, 1H), 1.93 (m, 1H),
1.46 (s, 9H), 1.24 (s, 3H), 1.20 (s, 3H), 0.80 (s, 9H), 0.07 (s,
3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 149.8,
109.8, 82.3, 75.2, 71.1, 68.6, 60.2, 31.8, 29.4, 28.0 (3C), 26.2,
25.4 (3C), 24.9, 17.6, -4.2, -5.0. Anal. Calcd for C21H39NO6-
Si: C, 58.71; H, 9.15; N, 3.26. Found: C, 58.79; H, 9.20; N,
3.12.
20
as an oil: [R]D -27.5 (c 0.4, CHCl3); 1H NMR (300 MHz,
(1′S,2′R,5R)-5-[1-(ter t-Bu tyld im eth ylsila n yloxy)-2,3-d i-
h yd r oxyp r op yl]-1-(ter t-b u t yloxyca r b on yl)p yr r olid in -2-
on e (25). Protected lactam 24 (4.6 g, 10.7 mmol) was dissolved
in 30 mL of 70% aqueous acetic acid, and the resulting solution
was allowed to react at 50 °C. The reaction was monitored by
TLC and was judged complete after 8 h. The solution was then
diluted with CH2Cl2, and the organic layer was separated and
treated twice with saturated NaHCO3 solution. The combined
organic layers were dried (MgSO4) and concentrated to give a
crude residue that was purified by flash chromatography (3:7
hexanes/EtOAc). Pure terminal diol 25 (3.75 g, 90%) was
obtained as a white solid: mp 118-120 °C; [R]D20 +45.4 (c 1.8,
CDCl3) δ 5.17 (t, J ) 7.0 Hz, 1H), 5.16 (dd, J ) 8.4, 4.0 Hz,
1H), 5.06 (td, J ) 7.8, 4.5 Hz, 1H), 4.14 (dd, J ) 11.1, 7.5 Hz,
1H), 4.08 (dd, J ) 11.4, 6.3 Hz, 1H), 2.62 (dtt, J ) 10.5, 7.5,
6.3 Hz, 1H), 2.42 (dt, J ) 13.5, 7.5 Hz, 1H), 2.09 (s, 3H), 2.08
(s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.67 (ddd, J ) 13.5, 10.8, 7.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 170.8, 170.3, 169.8,
169.7, 81.2, 76.4, 75.6, 62.3, 38.4, 32.0, 20.9, 20.8 (2C), 20.7.
Anal. Calcd for C14H20O8: C, 53.16; H, 6.37. Found: C, 53.24;
H, 6.48.
(1′S,4′′R,5R)-1-(ter t-Bu tyloxycar bon yl)-5-[(2,2-dim eth yl-
1,3-d ioxola n -4-yl)h yd r oxym et h yl]-1,5-d ih yd r op yr r ol-2-
on e (22). To a solution of 2,3-O-isopropylidene-D-glyceral-
dehyde 2 (2.15 g, 16.5 mmol) in anhydrous Et2O (120 mL) were
added silyl enol ether 21 (4.91 g, 16.5 mmol) and SnCl4 (1.93
mL, 16.5 mmol) under argon at -80 °C. The mixture was
stirred at this temperature for 3 h, and then a saturated
aqueous NaHCO3 solution was added at -80 °C. After ambient
temperature was reached, the resulting mixture was extracted
with Et2O. After the extracts were dried (MgSO4), the solution
was evaporated under reduced pressure, and the crude product
was crystallized from CH2Cl2/hexane to give 4.14 g (80%) of
R,â-unsaturated lactam 22 as a white solid: mp 138-140 °C;
1
CHCl3); H NMR (300 MHz, CDCl3) δ 4.28 (ddd, J ) 9.0, 4.0,
2.1 Hz, 1H), 4.05 (dd, J ) 8.0, 4.0 Hz, 1H), 3.75 (dd, J ) 10.7,
3.0 Hz, 1H), 3.62 (m, 1H), 3.52 (dd, J ) 10.7, 6.3 Hz, 1H), 3.24
(bs, 2H), 2.64 (dt, J ) 18.2, 10.3 Hz, 1H), 2.38 (ddd, J ) 18.1,
10.3, 2.9 Hz, 1H), 1.9-2.2 (m, 2H), 1.51 (s, 9H), 0.86 (s, 9H),
0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.3,
150.2, 82.9, 71.8, 70.2, 64.3, 60.0, 31.8, 28.0 (3C), 25.6 (3C),
17.7, 17.4, -4.3, -5.1. Anal. Calcd for C18H35NO6Si: C, 55.50;
H, 9.06; N, 3.60. Found: C, 55.37; H, 9.16; N, 3.74.
(1′S,2′R,5R)-5-[1,2,3-Tr is-(ter t-bu tyldim eth ylsilan yloxy)-
p r op yl]p yr r olid in -2-on e (26). A stirring solution of com-
pound 25 (3.70 g, 9.5 mmol) in anhydrous CH2Cl2 (100 mL),
under argon atmosphere, was sequentially treated with tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (8.73
mL, 38.0 mmol), 2,6-lutidine (8.85 mL, 76.0 mL), and Et3N
(2.65 mL, 19.0 mmol). The resulting mixture was warmed to
50 °C and allowed to stir for 2 h. The temperature was allowed
to raise to room temperature, and the reaction was left to
stirring for 12 h before being sequentially quenched with a
saturated aqueous NH4Cl solution and 5% aqueous citric acid
solution until neutral pH was reached. The reaction mixture
was extracted with CH2Cl2, and the combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the oily residue through flash
chromatography on silica gel (8:2 hexanes/EtOAc) furnished
pure Boc-deprotected lactam intermediate 26 (4.53 g, 92%) as
an oil: [R]D20 -22.5 (c 2.8, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 5.82 (bs, 1H), 3.82 (q, J ) 7.0 Hz, 1H), 3.71 (dd, J ) 8.4, 5.1
Hz, 1H), 3.65 (d, J ) 5.1 Hz, 1H), 3.52 (t, J ) 9.9 Hz, 1H),
3.42 (dd, J ) 10.2, 5.1 Hz, 1H), 2.24 (m, 2H), 2.10 (m, 1H),
1.78 (m, 1H), 0.85 (s, 9H), 0.84 (s, 9H), 0.83 (s, 9H), 0.06 (s,
3H), 0.05 (s, 3H), 0.03 (s, 6H), 0.01 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 177.2, 76.3, 76.2, 63.6, 54.8, 29.9, 25.9 (3C), 25.8 (3C),
25.7 (3C), 24.4, 18.0 (3C), -3.7, -4.6, -4.8, -5.3, -5.6, -5.7.
Anal. Calcd for: C25H55NO4Si3: C, 57.37; H, 10.70; N, 2.70.
Found: C, 57.21; H, 10.86; N, 2.59.
[R]D +197.6 (c 0.83, CHCl3); 1H NMR (300 MHz, CDCl3) δ
20
7.43 (dd, J ) 6.3, 2.1 Hz, 1H), 6.13 (dd, J ) 6.3, 1.5 Hz, 1H),
4.81 (dt, J ) 5.7, 2.4 Hz, 1H), 4.09 (ddd, J ) 6.0, 5.7, 3.9 Hz,
1H), 4.01 (q, J ) 6.0 Hz, 1H), 3.94 (dd, J ) 8.1, 6.0 Hz, 1H),
3.86 (dd, J ) 8.1, 6.0 Hz, 1H), 3.63 (d, J ) 3.9 Hz, 1H), 1.57
(s, 9H), 1.37 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 168.9, 150.9, 148.2, 126.9, 109.2, 83.8, 75.6, 72.6, 66.4, 65.6,
28.0 (3 C), 26.4, 25.1. Anal. Calcd for C15H23NO6: C, 57.50; H,
7.40; N, 4.47. Found: C, 57.31; H, 7.35; N, 4.32.
(1′S,4′′R,5R)-1-(ter t-Bu tyloxycar bon yl)-5-[(2,2-dim eth yl-
1,3-d ioxola n -4-yl)h yd r oxym eth yl]p yr r olid in -2-on e (23).
Palladium on carbon (10%, 420 mg) was added to a solution
of R,â-unsaturated lactam 22 (4.0 g, 12.8 mmol) in anhydrous
THF (60 mL) in the presence of a small amount of NaOAc (176
mg) at room temperature. The reaction vessel was evacuated
by aspirator and thoroughly purged with hydrogen (three
times), and the resulting heterogeneous mixture was stirred
under a balloon of hydrogen. After 24 h, the hydrogen was
evacuated, the catalyst filtered off, and the filtrate was
concentrated under vacuum to give a crude residue which was
subjected to flash chromatographic purification (6:4 hexanes/
EtOAc) to yield 3.71 g (92%) of saturated lactam 23 as a white
20
1
solid: mp 102-105 °C; [R]D -60.1 (c 1.0, CHCl3); H NMR
(300 MHz, CDCl3) δ 4.31 (ddd, J ) 7.7, 5.9, 1.9 Hz, 1H), 4.09
(m, 2H), 3.98 (m, 1H), 3.75 (t, J ) 6.0 Hz, 1H), 2.70 (ddd, J )
17.7, 12.1, 9.1 Hz, 1H), 2.39 (ddd, J ) 17.7, 8.7, 2.2 Hz, 1H),
2.16 (m, 2H), 1.75 (bs, 1H), 1.54 (s, 9H), 1.40 (s, 3H), 1.34 (s,
(1′S,2′R,5R)-5-[1,2,3-Tr is-(ter t-bu tyldim eth ylsilan yloxy)-
p r op yl]-1-(ter t-bu tyloxyca r bon yl)p yr r olid in -2-on e (27).

6316 J . Org. Chem., Vol. 65, No. 20, 2000
Rassu et al.
To a room-temperature solution of the Boc-deprotected com-
pound 26 (4.50 g, 8.7 mmol) in CH3CN (40 mL) were added
di-tert-butyl dicarbonate (1.90 g, 8.7 mmol) and DMAP (50 mg)
with stirring. The mixture was stirred at ambient temperature
for 8 h, and the solvent then was evaporated in vacuo. The
crude mixture was purified by flash chromatography on SiO2
(8:2 hexanes/EtOAc) to furnish 5.11 g (95%) of fully protected
lactam 27 as an oil: [R]D20 +36.7 (c 3.7, CHCl3); 1H NMR (300
MHz, CDCl3) δ 4.25 (dd, J ) 8.1, 6.0 Hz, 1H), 4.10 (dd, J )
6.0, 1.2 Hz, 1H), 3.77 (ddd, J ) 6.8, 3.9, 1.2 Hz, 1H), 3.64 (dd,
J ) 11.1, 3.9 Hz, 1H), 3.54 (dd, J ) 11.0, 6.9 Hz, 1H), 2.71
(ddd, J ) 18.0, 11.4, 9.6 Hz, 1H), 2.38 (ddd, J ) 18.0, 9.0, 1.0
Hz, 1H), 2.26 (m, 1H), 1.99 (m, 1H), 1.54 (s, 9H), 0.91 (s, 9H),
0.89 (s, 18H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 6H), 0.04 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 175.0, 150.0, 82.7, 77.4, 73.8,
65.6, 59.5, 31.7, 28.1 (3C), 26.0 (3C), 25.9 (3C), 25.8 (3C), 19.4,
18.3, 18.1, 18.0, -4.5 (2C), -4.6, -4.8, -5.3, -5.4. Anal. Calcd
for: C30H63NO6Si3: C, 58.30; H, 10.27; N, 2.27. Found: C,
58.44; H, 10.13; N, 2.09.
mL). The reaction was monitored by TLC and was judged
complete after 15 min. The reaction was then quenched at -80
°C by the addition of saturated aqueous NH4Cl (20 mL), and
after ambient temperature was reached, the mixture was
extracted with CH2Cl2. The combined extracts were dried
(MgSO4), filtered, and concentrated to give a crude residue that
was purified by flash chromatography (7:3 hexanes/EtOAc).
A pure binuclear adduct 30 (2.04 g, 60%) was obtained as an
oil: [R]D +23.3 (c 0.3, CHCl3); H NMR (300 MHz, CDCl3) δ
4.27 (td, J ) 3.9, 0.5 Hz, 1H), 4.17 (td, J ) 3.9, 0.6 Hz, 1H),
3.82 (dt, J ) 9.0, 3.0 Hz, 1H), 3.53 (dd, J ) 8.7, 3.9 Hz, 1H),
2.70 (ddd, J ) 5.1, 3.6, 0.6 Hz, 1H), 2.30 (d, J ) 12.0 Hz, 1H),
1.95 (dtd, J ) 12.0, 4.0, 0.5 Hz, 1H), 1.89 (d, J ) 2.4 Hz, 1H),
1.54 (s, 9H), 0.92 (s, 9H), 0.91 (s, 9H), 0.13 (s, 3H), 0.10 (s,
6H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.3, 149.1,
83.1, 75.0, 71.4, 69.6, 59.9, 47.9, 28.0 (3C), 26.9, 26.1 (3C), 25.8
20
1
(3C), 18.3, 18.0, -3.8, -4.4, -4.5, -4.6. Anal. Calcd for: C24H47
-
NO6Si2: C, 57.45; H, 9.44; N, 2.79. Found: C, 57.36; H, 9.31;
N, 2.90.
(1′S,2′R,5R)-5-[1,2-Bis-(ter t-bu tyld im eth ylsila n yloxy)-
3-h yd r oxyp r op yl]-1-(ter t-b u t yloxyca r b on yl)p yr r olid in -
2-on e (28). Protected lactam 27 (5.0 g, 8.1 mmol) was dissolved
in 20 mL of 80% aqueous acetic acid, and the resulting solution
was allowed to react at room temperature under stirring. The
reaction was monitored by TLC and was judged complete after
8 h. The reaction was then quenched with saturated NaHCO3
solution, and the resulting mixture was extracted with CH2-
Cl2 and EtOAc. The combined organic layers were dried
(MgSO4), filtered, and concentrated under vacuum to give a
crude residue that was purified by flash chromatography (7:3
hexanes/EtOAc). Pure terminal alcohol 28 (3.75 g, 92%) was
obtained as a glassy solid: [R]D20 +45.4 (c 3.8, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 4.38 (td, J ) 6.9, 1.8 Hz, 1H), 4.00 (dd, J
) 7.2, 1.8 Hz, 1H), 3.77 (td, J ) 6.0, 2.1 Hz, 1H), 3.68 (m, 3H),
2.62 (ddd, J ) 18.0, 11.1, 9.3 Hz, 1H), 2.44 (ddd, J ) 18.0, 9.3,
2.7 Hz, 1H), 2.05 (m, 2H), 1.53 (s, 9H), 0.91 (s, 9H), 0.90 (s,
9H), 0.14 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 174.1, 150.8, 83.5, 75.7, 74.5, 63.9,
58.9, 31.6, 28.2 (3C), 25.9 (6C), 20.8, 18.1 (2C), -4.4, -4.5, -4.6
(2C). Anal. Calcd for: C24H49NO6Si2: C, 57.22; H, 9.80; N, 2.78.
Found: C, 57.36; H, 9.68; N, 2.81.
(1S,2S,3R,4S,5R)-3,4-Bis-(ter t-bu tyldim eth ylsilan yloxy)-
6-(t er t -b u t y lo x y c a r b o n y l)-2-(t r ie t h y ls ila n y lo x y )-6-
a za bicyclo[3.2.1]octa n -7-on e (31). To a solution of 30 (2.0
g, 4.0 mmol) in dry pyridine (15 mL), under argon atmosphere,
were sequentially added triethylsilyltriflate (1.34 mL, 8.0
mmol) and a catalytic amount of DMAP (50 mg). After being
stirred at room temperature for 5 h, further addition of
pyridine (7.5 mL) and triethylsilyltriflate (671 µL, 4.0 mmol)
was effected, and the reaction was allowed to stir overnight,
quenched with H2O (100 mL), and extracted with CH2Cl2 and
EtOAc. The combined organic layers were dried over MgSO4,
filtered, and concentrated in a vacuum to provide a crude oily
residue that was purified by flash chromatography (9:1 hex-
anes/EtOAc) to yield 2.21 g (90%) of protected binuclear adduct
31 as an oil: [R]D +43.3 (c 1.5, CHCl3); H NMR (300 MHz,
CDCl3) δ 4.26 (td, J ) 3.6, 0.9 Hz, 1H), 4.11 (td, J ) 4.8, 1.2
Hz, 1H), 3.87 (dd, J ) 8.7, 2.7 Hz, 1H), 3.57 (dd, J ) 8.7, 3.9
Hz, 1H), 2.52 (ddd, J ) 5.4, 2.7, 1.2 Hz, 1H), 2.24 (d, J ) 13.5
Hz, 1H), 1.87 (dtd, J ) 13.5, 5.4, 0.9 Hz, 1H), 1.52 (s, 9H),
0.99 (t, J ) 8.1 Hz, 9H), 0.91 (s, 18H), 0.65 (q, J ) 8.1 Hz,
6H), 0.12 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 176.2, 145.1, 82.6, 74.2, 72.2, 70.2,
59.4, 48.9, 28.1 (3C), 27.1, 26.3 (3C), 25.8 (3C), 18.0 (2C), 6.8
20
1
(2S,2′R,3S)-2,3-Bis-(ter t-bu tyld im eth ylsila n yloxy)-3-[1-
(ter t-bu tyloxycar bon yl)-(5-oxopyr r olidin -2-yl)]pr opion al-
d eh yd e (29). To a solution of oxalyl chloride (1.91 mL, 21.9
mmol) in CH2Cl2 (130 mL) at -80 °C, under argon, was added
dropwise a solution of DMSO (2.07 mL, 29.2 mmol) in CH2Cl2
(16 mL). After 30 min, a solution of alcohol 28 (3.70 g, 7.3
mmol) in CH2Cl2 (16 mL) was added dropwise. After 30 min
at -80 °C, Et3N (10.17 mL, 73.8 mmol) was added. The
reaction mixture was stirred at -80 °C for 30 min and then
warmed slowly to 0 °C over 1 h. After 30 min of stirring at 0
°C, toluene (300 mL) was added to the mixture, filtered
through a Celite pad, and concentrated in vacuo. The residue
was dissolved in hexanes (300 mL), filtered again, and
concentrated under reduced pressure to give crude aldehyde
29 (3.44 g, 94%) as a colorless oil which was used without
(3C), 5.1 (3C), -4.0, -4.2 (2C), -4.7. Anal. Calcd for: C30H61
-
NO6Si3: C, 58.49; H, 9.98; N, 2.27. Found: C, 58.31; H, 9.75;
N, 2.39.
(1S,2R,3S,4R,6R)-2,3-Di-O-(ter t-bu tyld im eth ylsila n yl)-
4-(ter t-b u t yloxyca r bon yla m in o)-1-O-(t r iet h ylsila n yl)-6-
(h yd r oxym eth yl)cycloh exa n e-1,2,3-tr iol (32). To a reaction
vessel containing protected cyclohexanoid lactam 31 (2.15 g,
3.5 mmol) cooled to 0 °C, under argon atmosphere, were
sequentially added 30 mL of wet THF and 264 mg (7.0 mmol)
of NaBH4. After being stirred for 3 h, a further addition of
NaBH4 (264 mg, 7.0 mmol) was effected. The reaction mixture
was stirred for 2 h, and the reaction then was quenched by
addition of saturated aqueous NH4Cl until neutral pH was
reached. The reaction mixture was extracted thoroughly with
CH2Cl2 and EtOAc, and the extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure to give a
residue which was purified by flash chromatography (8:2
hexanes/EtOAc) to give partially protected carbasugar 32 (1.84
g, 85%) as a glassy solid: [R]D20 -42.4 (c 1.2, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 4.24 (bs, 1H), 3.91 (m, 1H), 3.83 (m, 1H),
3.78 (dd, J ) 3.9, 2.4 Hz, 1H), 3.67 (dd, J ) 10.2, 2.4 Hz, 1H),
3.54 (d, J ) 6.3 Hz, 2H), 2.11 (m, 1H), 1.76 (m, 1H), 1.70 (bs,
1H), 1.42 (s, 9H), 1.27 (q, J ) 12.7 Hz, 1H), 0.98 (t, J ) 8.1
Hz, 9H), 0.91 (s, 9H), 0.89 (s, 9H), 0.62 (q, J ) 8.1 Hz, 6H),
0.12 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 155.5, 78.8, 75.5, 72.7, 72.5, 64.2, 49.8, 37.5,
29.4, 28.5 (3C), 26.0 (3C), 25.8 (3C), 18.1 (2C), 6.9 (3C), 4.9
(3C), -3.5, -4.4, -4.7 (2C). Anal. Calcd for: C30H65NO6Si3:
C, 58.11; H, 10.57; N, 2.26. Found: C,58.23; H, 10.44; N, 2.18.
(1S,2R,3S,4R,6R)-4-Am in o-6-(h ydr oxym eth yl)cycloh ex-
a n e-1,2,3-tr iol [P seu d o-â-D-gu lop yr a n osyl)a m in e] (33).
The partially protected carbasugar 32 (1.8 g, 2.9 mmol) was
treated, at room temperature, with a solution mixture of 6 N
20
further purification in the aldol reaction: [R]D +46.7 (c 0.6,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.52 (d, J ) 2.1 Hz, 1H),
4.48 (dd, J ) 5.4, 1.8 Hz, 1H), 4.25 (ddd, J ) 7.8, 5.7, 2.1 Hz,
1H), 4.04 (t, J ) 2.1 Hz, 1H), 2.84 (dt, J ) 18.0, 10.5 Hz, 1H),
2.42 (ddd, J ) 18.0, 10.8, 2.7 Hz, 1H), 2.37 (ddt, J ) 13.5, 10.5,
2.5 Hz, 1H), 1.93 (dq, J ) 13.5, 10.8 Hz, 1H), 1.53 (s, 9H),
0.92 (s, 9H), 0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H), 0.09 (s,
3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.0, 175.1,
149.8, 83.5, 80.7, 74.2, 58.9, 31.4, 28.1 (3C), 25.7 (6C), 18.1,
18.0, 16.9, -4.6, -4.9 (3C). Anal. Calcd for: C24H47NO6Si2: C,
57.45; H, 9.44; N, 2.79. Found: C, 57.31; H, 9.57; N, 2.88.
(1S,2S,3R,4S,5R)-3,4-Bis-(ter t-bu tyldim eth ylsilan yloxy)-
6-(ter t-bu tyloxyca r bon yl)-2-h yd r oxy-6-a za bicyclo[3.2.1]-
octa n -7-on e (30). A solution of diisopropylamine (1.33 mL,
9.5 mmol) in dry THF (30 mL), under argon, was treated at
-20 °C with BuLi (5.12 mL of a 1.6 M solution in hexane, 8.2
mmol). The reaction was allowed to react for 20 min after
which time the solution was cooled to -80 °C and treated with
a solution of aldehyde 29 (3.41 g, 6.8 mmol) in dry THF (20

Carbasugars and Relatives
J . Org. Chem., Vol. 65, No. 20, 2000 6317
HCl-THF-MeOH (1:2:2) (30 mL). The reaction was allowed
to react for 5 h and then concentrated to dryness under
vacuum to leave an oily crude residue which was flash
chromatographed on silica gel (5:5:3 EtOAc/MeOH/25% aque-
ous NH4OH) to afford fully deprotected carbasugar 33 (488
83.1, 80.0, 79.1, 62.6, 52.1, 33.7, 28.1 (3C), 25.7 (3C), 17.9, -4.8,
- 4.9. Anal. Calcd for C17H31NO5Si: C, 57.11; H, 8.74; N, 3.92.
Found: C, 57.02; H, 8.80; N, 3.77.
(1R,4S,5S,6S)-6-(ter t-Bu tyld im eth ylsila n yloxy)-2-(ter t-
b u t yloxyca r b on yl)-5-(t r iet h ylsila n yloxy)-2-a za b icyclo-
[2.2.1]h ep ta n -3-on e (37). To a solution of 36 (1.5 g, 4.2 mmol)
in dry pyridine (15 mL), under argon atmosphere, were
sequentially added triethylsilyltriflate (1.41 mL, 8.4 mmol) and
a catalytic amount of DMAP (50 mg). After being stirred at
room temperature for 3 h, further addition of pyridine (7.5 mL)
and triethylsilyltriflate (705 µL, 4.19 mmol) was effected, and
the reaction was allowed to stir overnight, quenched with H2O
(100 mL), and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered, and concentrated in a
vacuum to provide a crude oily residue that was purified by
flash chromatography (8:2 hexanes/EtOAc) to yield 1.86 g
mg, 95%) as a glassy solid: [R]D -82.0 (c 0.5, D2O); 1H NMR
20
(300 MHz, D2O) δ 3.99 (dd, J ) 4.8, 3.0 Hz, 1H), 3.97 (t, J )
3.0 Hz, 1H), 3.82 (dd, J ) 10.8, 3.0 Hz, 1H), 3.63 (dd, J ) 11.1,
7.5 Hz, 1H), 3.52 (dd, J ) 11.1, 6.6 Hz, 1H), 3.32 (td, J ) 12.3,
4.2 Hz, 1H), 2.05 (m, 1H), 1.87 (dt, J ) 12.3, 4.2 Hz, 1H), 1.44
(q, J ) 12.6 Hz, 1H); 13C NMR (75 MHz, D2O) δ 72.2, 69.6,
69.4, 62.3, 50.5, 36.5, 25.7. Anal. Calcd for: C7H15NO4: C,
47.45; H, 8.53; N, 7.90. Found: C, 47.58; H, 8.71; N, 8.04.
(1S,2R,3S,4R,6R)-4-Acetamido-1,2,3-tri-O-acetyl-6-(acetyl-
oxym eth yl)cycloh exa n e-1,2,3-tr iol (34). Acetic anhydride
(3.83 mL, 40.5 mmol) and a catalytic amount of DMAP (10
mg) were added under argon to a solution of deprotected
carbasugar 33 (480 mg, 2.7 mmol) in dry pyridine (10 mL).
The reaction was stirred for 10 h at room temperature. The
solution was then quenched with H2O, and the resulting
mixture was extracted with CH2Cl2 and EtOAc. The combined
organic layers were dried (MgSO4), filtered, and concentrated
to give a crude residue that was flash chromatographed on
silica gel (9:1 EtOAc/MeOH) to afford 941 mg (90%) of pure
protected carbasugar 34 as a white solid: mp 194-195 °C;
20
(94%) of binuclear adduct 37 as an oil: [R]D +23.9 (c 1.8,
1
CHCl3); H NMR (300 MHz, benzene-d6) δ 4.15 (m, 1H), 4.04
(dt, J ) 2.8, 1.5 Hz, 1H), 4.01 (dt, J ) 4.2, 1.5 Hz, 1H), 2.48
(dq, J ) 4.2, 1.3 Hz, 1H), 1.61 (dt, J ) 10.5, 1.3 Hz, 1H), 1.42
(s, 9H), 1.37 (ddt, J ) 10.5, 2.3, 1.5 Hz, 1H), 1.01 (t, J ) 8.1
Hz, 9H), 0.93 (s, 9H), 0.60 (q, J ) 8.1 Hz, 6H), 0.18 (s, 3H),
0.17 (s, 3H); 13C NMR (75 MHz, benzene-d6) δ 172.1, 149.3,
82.0, 81.1, 80.7, 61.9, 52.6, 32.6, 28.1 (3C), 25.9 (3C), 17.8, 6.9
(3C), 5.1 (3C), -4.4, -4.9. Anal. Calcd for C23H45NO5Si: C,
58.56; H, 9.61; N, 2.97. Found: C, 58.66; H, 9.48; N, 2.75.
(1S,2S,3R,5R)-2-O-(ter t-Bu t yld im et h ylsila n yl)-3-(ter t-
b u t yloxyca r b on yla m in o)-1-O-(t r ie t h ylsila n yl)-5-(h y-
d r oxym eth yl)cyclop en ta n e-1,2-d iol (38). To a reaction
vessel containing protected cyclohexanoid lactam 37 (1.8 g, 3.8
mmol) cooled to 0 °C, under argon atmosphere, were sequen-
tially added 30 mL of wet THF and 288 mg (7.6 mmol) of
NaBH4. After being stirred for 3 h, a further addition of NaBH4
(288 mg, 7.6 mmol) was effected. The reaction mixture was
stirred for 2 h, and the reaction then was quenched by addition
of saturated aqueous NH4Cl until neutral pH was reached.
The reaction mixture was extracted thoroughly with CH2Cl2
and EtOAc, and the combined extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure to give a
residue which was purified by flash chromatography (8:2
hexanes/EtOAc) to give partially protected carbasugar 38 (1.55
20
1
[R]D +5.0 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3) δ 5.65
(d, J ) 8.7 Hz, 1H), 5.31 (t, J ) 3.6 Hz, 1H), 5.11 (m, 1H),
5.02 (dd, J ) 11.1, 3.3 Hz, 1H), 4.35 (tdd, J ) 12.0, 8.1, 4.5
Hz, 1H), 4.02 (dd, J ) 11.1, 8.4 Hz, 1H), 3.84 (dd, J ) 11.1,
6.6 Hz, 1H), 2.43 (m, 1H), 2.15 (s, 3H), 2.11 (s, 3H), 2.05 (s,
3H), 2.04 (s, 3H), 1.95 (s, 3H), 1.67 (m, 1H), 1.37 (q, J ) 12.9
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 171.7, 170.8, 169.9, 169.1
(2C), 70.7, 68.4, 68.3, 63.2, 47.4, 33.9, 29.1, 23.4, 20.9 (2C),
20.7 (2C). Anal. Calcd for: C17H25NO9: C, 52.71; H, 6.51; N,
3.62. Found: C, 52.85; H, 6.44; N, 3.69.
(2S,2′R)-(ter t-Bu tyld im eth ylsila n yloxy)-[1-(ter t-bu tyl-
oxycar bon yl)-5-oxopyr r olidin -2-yl]acetaldeh yde (35). The
partially deprotected lactam 25 (3.50 g, 9.0 mmol) was dis-
solved in CH2Cl2 (190 mL) and treated with a 0.65 M aqueous
NaIO4 solution (18 mL) and chromatography grade SiO2 (20
g). The resulting heterogeneous mixture was vigorously stirred
at room temperature until complete consumption of the
starting material (about 20 min, monitored by TLC). The
slurry was filtered under suction, and the silica gel was
thoroughly washed with CH2Cl2 and EtOAc. The filtrates were
evaporated to afford aldehyde 35 (3.06 g, 95%) as a white
solid: mp 93-95 °C; [R]D20 +34.3 (c 1.9, CHCl3); 1H NMR (300
MHz, CDCl3) δ 9.54 (d, J ) 1.2 Hz, 1H), 4.43 (dt, J ) 8.7, 2.4
Hz, 1H), 4.14 (dd, J ) 2.1, 1.2 Hz, 1H), 2.61 (dt, J ) 17.4, 10.2
Hz, 1H), 2.43 (ddd, J ) 17.4, 10.2, 2.7 Hz, 1H), 2.28 (dtd, J )
12.9, 10.2, 9.0 Hz, 1H), 1.95 (ddt, J ) 13.2, 9.3, 2.1 Hz, 1H),
1.52 (s, 9H), 0.92 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 200.7, 173.7, 150.5, 83.8, 79.9, 58.9, 31.8, 27.9 (3C),
25.6 (3C), 22.3, 17.9, -4.5, -5.2. Anal. Calcd for C17H31NO5-
Si: C, 57.11; H, 8.74; N, 3.92. Found: C, 57.26; H, 8.60; N,
3.96.
g, 86%) as an oil: [R]D +4.3 (c 0.7, CHCl3); 1H NMR (300
20
MHz, CDCl3) δ 4.93 (d, J ) 9.0 Hz, 1H), 4.00 (m, 1H), 3.89 (m,
1H), 3.83 (dd, J ) 11.1, 3.6 Hz, 1H), 3.75 (m, 1H), 3.70 (dd, J
) 11.1, 6.3 Hz, 1H), 2.35 (m, 2H), 1.80 (bs, 1H), 1.46 (m, 1H),
1.41 (s, 9H), 0.99 (t, J ) 7.6 Hz, 9H), 0.87 (s, 9H), 0.66 (q, J )
7.6 Hz, 6H), 0.13 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 154.9, 82.9, 80.6, 78.7, 62.4, 57.0, 43.3, 31.9, 28.3
(3C), 25.7 (3C), 17.8, 6.7 (3C), 4.7 (3C), -4.6, -4.8. Anal. Calcd
for C23H49NO5Si2: C, 58.06; H, 10.38; N, 2.94. Found: C, 58.24;
H, 10.23; N, 3.00.
(1S,2S,3R,5R)-3-Am in o-5-(h ydr oxym eth yl)cyclopen tan e-
1,2-d iol [P seu d o-â-D-xylofu r a n osyl)a m in e] (39). The par-
tially protected carbasugar 38 (1.5 g, 3.2 mmol) was treated,
at room temperature, with a solution mixture of 6 N HCl-
THF-MeOH (1:2:2) (20 mL). The reaction was allowed to react
for 30 min and then concentrated to dryness under vacuum
to leave an oily crude residue which was flash chromato-
graphed on silica gel (5:5:3 EtOAc/MeOH/25% aqueous NH4-
OH) to afford fully deprotected carbasugar 39 (433 mg, 94%)
as an oil: [R]D20 -22.5 (c 0.4, MeOH); 1H NMR (300 MHz, D2O)
δ 4.03 (dd, J ) 5.4, 5.1 Hz, 1H), 3.95 (t, J ) 5.4 Hz, 1H), 3.68
(dd, J ) 11.1, 6.6 Hz, 1H), 3.57 (dd, J ) 11.1, 6.0 Hz, 1H),
3.37 (td, J ) 8.4, 5.4 Hz, 1H), 2.33 (tq, J ) 8.7, 6.0 Hz, 1H),
2.28 (dt, J ) 12.6, 8.4 Hz, 1H), 1.51 (dt, J ) 12.6, 8.7 Hz, 1H);
13C NMR (75 MHz, D2O) δ 80.4, 76.1, 60.8, 55.1, 40.7, 29.3.
Anal. Calcd for C6H13NO3: C, 48.97; H, 8.90; N, 9.52. Found:
C, 48.85; H, 8.67; N, 9.57.
(1S,2S,3R,5R)-3-Acet a m id o-1,2-d i-O-a cet yl-5-(a cet yl-
oxym eth yl)cyclop en ta n e-1,2-d iol (40). Acetic anhydride
(4.14 mL, 43.8 mmol) and a catalytic amount of DMAP (10
mg) were added under argon to a solution of deprotected
carbasugar 39 (440 mg, 3.0 mmol) in dry pyridine (10 mL).
The reaction was stirred for 30 min at room temperature. The
reaction was then quenched with H2O, and the resulting
(1R,4S,5S,6S)-6-(ter t-Bu tyld im eth ylsila n yloxy)-2-(ter t-
bu tyloxyca r bon yl)-5-h yd r oxy-2-a za bicyclo[2.2.1]h ep ta n -
3-on e (36). A solution of diisopropylamine (1.65 mL, 11.8
mmol) in dry THF (56 mL), under argon, was treated at -20
°C with BuLi (6.31 mL of a 1.6 M solution in hexane, 10.1
mmol). The reaction was allowed to react for 20 min after
which time the solution was cooled to -80 °C and treated with
a solution of aldehyde 35 (3.0 g, 8.4 mmol) in dry THF (30
mL). The reaction was monitored by TLC and was judged
complete after 15 min. The reaction was then quenched at -80
°C by the addition of saturated aqueous NH4Cl and EtOAc.
The combined extracts were dried (MgSO4), filtered, and
concentrated to give a crude residue that was purified by flash
chromatography (6:4 hexanes/EtOAc). Pure binuclear adduct
20
36 (1.56 g, 52%) was obtained as an oil: [R]D +15.0 (c 0.4,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.19 (bd, J ) 4.5 Hz,
1H), 4.15 (m, 1H), 3.86 (m, 1H), 2.89 (dq, J ) 4.5, 1.8 Hz, 1H),
1.66 (bs, 1H), 1.53 (s, 9H), 1.50 (m, 2H), 0.91 (s, 9H), 0.15 (s,
3H), 0.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.9, 148.9,

6318 J . Org. Chem., Vol. 65, No. 20, 2000
Rassu et al.
mixture was extracted with CH2Cl2 and EtOAc. The combined
organic layers were dried (MgSO4), filtered, and concentrated
to give a crude residue that was flash chromatographed on
silica eluting with EtOAc to afford 908 mg (96%) of pure
Ack n ow led gm en t. The generous financial support
of the Ministero dell′Universita` e della Ricerca Scien-
tifica e Tecnologica, Italy (COFIN 1998-1999), and the
Regione Autonoma della Sardegna is gratefully acknowl-
edged. Thanks are due to the Centro Interdipartimen-
tale di Misure “Giuseppe Casnati”, Universita` di Parma,
for instrumental facilities.
20
protected carbasugar 40 as an oil: [R]D -7.1 (c 0.7, CHCl3);
1H NMR (300 MHz, CDCl3) δ 6.00 (d, J ) 6.9 Hz, 1H), 5.23
(dd, J ) 7.2, 4.5 Hz, 1H), 5.04 (dd, J ) 7.8, 4.8 Hz, 1H), 4.18
(dq, J ) 10.2, 7.5 Hz, 1H), 4.10 (dd, J ) 11.1, 6.6 Hz, 1H),
4.04 (dd, J ) 11.1, 6.9 Hz, 1H), 2.64 (dquint, J ) 10.5, 7.0 Hz,
1H), 2.51 (dt, J ) 12.6, 7.5 Hz, 1H), 2.10 (s, 3H), 2.08 (s, 3H),
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
2.05 (s, 3H), 1.97 (s, 3H), 1.45 (dt, J ) 12.6, 10.5 Hz, 1H); 13
C
and 13C NMR spectra of compounds 11, 13, 17, 19, 31, 33, 37,
and 39. This material is available free of charge via the
Internet at http://pubs.acs.org.
NMR (75 MHz, CDCl3) δ 171.1, 170.8, 170.2, 169.8, 81.3, 75.3,
62.4, 53.6, 37.3, 32.5, 23.2, 20.9, 20.8, 20.7. Anal. Calcd for
C
14H21NO7: C, 53.33; H, 6.71; N, 4.44. Found: C, 53.21; H,
6.88; N, 4.27.
J O000604L