A cyclic enamine derived from 1,2-O-isopropylidene-α-D-xylofuranose as a novel carbohydrate intermediate to achieve skeletal diversity

Article abstract of DOI:10.1021/jo0609531

The commercially available carbohydrate 1,2-O-isopropylidene-α-D- xylofuranose was efficiently transformed into the high-added-value synthetic scaffold 8. The transformation requires the synthesis of the 5-O-tosyl derivative 7 and its subsequent intramole

Full text of DOI:10.1021/jo0609531

A Cyclic Enamine Derived from
1,2-O-Isopropylidene-r-D-xylofuranose As a Novel Carbohydrate
Intermediate To Achieve Skeletal Diversity
Alessandra Cordeiro, Ernesto Quesada, Mar´ıa-Cruz Bonache, Sonsoles Vela´zquez,
Mar´ıa-Jose´ Camarasa, and Ana San-Fe´lix*
Instituto de Qu´ımica Me´dica (C.S.I.C.), Juan de la CierVa 3, 28006 Madrid, Spain
anarosa@iqm.csic.es
ReceiVed May 8, 2006
The commercially available carbohydrate 1,2-O-isopropylidene-R-D-xylofuranose was efficiently trans-
formed into the high-added-value synthetic scaffold 8. The transformation requires the synthesis of the
5-O-tosyl derivative 7 and its subsequent intramolecular cyclization under basic conditions to give the
cyclic enamine 8. Reaction of 8 with O-, N-, S-, and C-nucleophiles and amino acids allowed its efficient
transformation (one-step, high yields, and easy purifications) into fused cyclic sugar derivatives with
rather unusual molecular skeletons in a completely regio- and stereoselective manner. The characteristics
of the sugar derivative 8 established here, high reactivity, synthetic accessibility, and the potential for
conversion into a vast collection of products by the action of different nucleophiles, indicate that it will
prove to be a useful chiral intermediate for achieving skeletal diversity. The constrained structures and
dense functionalization of the polycyclic sugar derivatives generated from 8 make these compounds
promising candidates for use as starting agents for the production of new analogues and as drugs.
Introduction
cophoric groups in well-defined spatial orientations.8 These
findings, together with the easy accessibility of simple carbo-
hydrate derivatives, make carbohydrates attractive building
blocks for organic synthesis.
Carbohydrates have received much attention over the years
as valuable synthetic intermediates and as a source of chirality.
They can be used as scaffolds for the synthesis of naturally
occurring compounds1 as well as carbohydrate-derived bioactive
compounds2 and to mimic non-carbohydrate bioactive com-
pounds.3-5 In addition, a variety of C-C bond-forming reactions
and ring annulations have been accomplished using carbohy-
drates either as chiral auxiliaries6 or as chiral building blocks.7
On the other hand, carbohydrates are privileged structures with
a high density of functionalized and stereocontrolled centers
that can be used as molecular templates to display pharma-
In recent years carbohydrates have become established as
particularly attractive scaffolds for combinatorial chemistry9 and
(2) (a) Sears, P.; Mitchell H. J. Angew. Chem., Int. Ed. 1999, 38, 2300.
(b) Cipolla, L.; Peri, F.; Ferla, B. L.; Redaelli, C.; Nicotra, F. Curr. Org.
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van Rijn, R. D.; Sprengeler, P. A.; Spoors, P. G.; Schakespeare, W. C.;
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III. J. Med. Chem. 1998, 41, 1382. (d) Hirschman R.; Wenquing, Y.;
Cascieri, M.; Strader, C. D.; Maecheler, L.; Cichy-Knight, M. A.; Hynes,
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* To whom correspondence should be addressed. Fax: +34-91-5644853.
(1) (a) Hanessian, S. In Total Synthesis of Natural Products; The
”Chiron” Approach; Pergamon: Oxford, 1983; Organic Chemistry Series,
Vol. 3. (b) For a recent review see: Nicolau, K. C.; Mitchell, H. J. Angew.
Chem., Int. Ed. 2001, 40, 1576.
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2002, 102, 491.
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10.1021/jo0609531 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/12/2006
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J. Org. Chem. 2006, 71, 7224-7235

A NoVel Carbohydrate To AchieVe Skeletal DiVersity
SCHEME 1. Reaction of 5′-O-Tosyl TSAO-m3T 1 and Cyclic Enamine 5 with Alkylamines
for peptidomimetics.10 In this context, there has been great
interest in the synthesis of carbohydrate-derived scaffolds that
have enhanced conformational constraints but still retain func-
tionalities suitable for further functionalization. One possible
way to constrain the molecular conformation of carbohydrates
is through the synthesis of condensed cyclic compounds. The
design and synthesis of this class of compounds has attracted
the attention of the synthetic organic chemists in recent years.11
For more than a decade, our research has been directed toward
synthesizing hypermodified nucleosides as potential anti-HIV
agents.12-16 In this context, we have developed a family of
potent and highly specific inhibitors of HIV-1 reverse tran-
scriptase15,16 whose prototype is the thymine derivative [1-[2′,5′-
bis-O-(tert-butyldimethylsilyl)-â-D-ribofuranosyl]thymine]-3′-
spiro-5′′-(4′′-amino-1′′,2′′-oxathiole-2′′,2-dioxide) named TSAO-
T.
In an earlier work aimed at improving the activity/toxicity
profile of TSAO derivatives, we subjected 5′-O-Tosyl TSAO-
m3T 1,17 derived from TSAO-T,15 to nucleophilic attack by
different alkylamines in order to obtain the corresponding 5′-
alkylamino-substituted TSAO derivatives (Scheme 1). However,
our attempts were unsuccessful; instead of the desired product,
the bicyclic nucleosides 2 and 3 were unexpectedly obtained,
albeit in moderate yield (18%), together with the unsaturated
compound 4 in higher yield (25%). In our exploration of this
novel reaction, a key proposed intermediate (5) was isolated in
70% yield under basic non-nucleophilic conditions (potassium
carbonate, 80 °C and 6 h) as a result of an intramolecular attack
of the amino group on the tosyl leaving group at the 5′ position
of the sugar.17 In the same study, we showed that the conjugated
double bond of the R,â-unsaturated cyclic sulfonate ester in 5
is very reactive toward nucleophiles.17 In fact, formation of the
bicyclic nucleoside 2 could be explained by attack at the
conjugated double bond of 5 by an alkylamine followed by
opening of the spiroaminooxatioldioxide ring (Scheme 1).
Encouraged by this preliminary result, we investigated
whether this reaction could be used as the basis for the synthesis
of different classes of bi-, tri-, and tetracyclic nucleosides. In a
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Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors,
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Asensio, J. L. J. Am. Chem. Soc. 2006, 128, 100. (c) Timmer, M. S. M.;
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San-Fe´lix, A.; Balzarini, J.; De Clercq, E.; Camarasa, M. J. J. Med. Chem.
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Balzarini, J.; De Clercq, E.; Camarasa, M. J. J. Med. Chem. 1993, 36, 323
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C. F.; Vandamme, A. M.; Camarasa, M. J.; De Clercq, E. Proc. Natl. Acad.
Sci. U.S.A. 1992, 89, 4392. (b) Balzarini, J.; Pe´rez-Pe´rez, M. J.; San-Fe´lix,
A.; Vela´zquez, S.; Camarasa, M. J.; De Clercq, E. Antimicrob. Agents
Chemother. 1992, 36, 1073. (c) Balzarini, J.; Pe´rez-Pe´rez, M. J.; San-Fe´lix,
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Chem. 1992, 267, 11831. (d) Camarasa, M. J.; San-Fe´lix, A.; Pe´rez-Pe´rez,
M. J.; Vela´zquez, S.; Alvarez, R.; Chamorro, C.; Jimeno, M. L.; Pe´rez, C.;
Gago, F.; De Clercq, E.; Balzarini, J. J. Carbohydr. Chem. 2000, 19, 451.
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F.; Balzarini, J. Curr. Top. Med. Chem. 2004, 4, 945.
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M. J. J. Org. Chem. 1994, 59, 7661.
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Org. Chem. 2003, 68, 6695.
J. Org. Chem, Vol. 71, No. 19, 2006 7225

Cordeiro et al.
°C caused 14 to undergo an aldol-type cyclocondensation to
afford the C-branched-3-spiro derivative 7 (60%). Compared
to the original synthetic route, this second route involved two
less steps and gave double the yield (38% versus 19%).
Next, we attempted to obtain the cyclic enamine 8 via the
intramolecular nucleophilic substitution of 7 (Scheme 4). By
analogy with the conditions used for the synthesis of the cyclic
enamine nucleosides 5 and 6 derived from thymine, the reaction
was carried out at 80 °C for 6 h in the presence of potassium
carbonate as a non-nucleophilic base. However, 8 was not
formed under these conditions; instead, the unexpected crystal-
line compound 15 (mp 151 °C) was isolated in 80% yield.
In the1H NMR spectrum of 15, two sets of equivalent peaks
for protons H-1, H-2, H-4, and H-5 were observed, suggesting
that 15 has a dimeric structure comprised of two fragments,
which we denote A and B. In addition, the spectrum also
contained two singlet peaks, at δ 6.43 (broad) and 6.08 (narrow)
ppm, corresponding to the NH and H-3′ protons of fragments
A and B (Figure 2), respectively. On the other hand, an AB
system with signals at δ 4.38 and 4.47 ppm (Jgem ) 15.5 Hz)
corresponding to the H-3′ protons of fragment B was observed.
Unambiguous assignment of each subunit of the sugar-
derivative 15 was achieved by two-dimensional NMR spec-
troscopy techniques, namely, the gradient heteronuclear multiple-
bond correlation (gHMBC)22 and gradient heteronuclear single
quantum correlation (gHSQC)23 techniques. The gHMBC
experiment (Figure 2) was crucial for the identification of this
compound. For fragment A, a long-range correlation between
the H-5 protons (δ 3.47 and 3.65 ppm) and the C-4′ carbon (δ
155.6 ppm) was observed, whereas for fragment B, a long-range
correlation between the H-5 protons (δ 3.40 and 3.70 ppm) and
the C-4′ carbon (δ 97.6 ppm) was observed. In addition, for
fragment B a correlation was observed between the H-3′ protons
(δ 4.38 and 4.47 ppm) and the C-4′ carbon (δ 97.6 ppm).
The formation of the dimer 15 was further supported by the
mass spectrum, which showed a molecular peak of 551.3 m/z.
The formation of 15 as the major product indicates that the
cyclic enamine 8, once formed, readily undergoes self-
condensation via an intermolecular attack between the NH and
C-4′ positions of distinct molecules, leading to the formation
of a dimer. These findings stand in contrast to those for the
5′-O-tosyl derivative of nucleoside 1, which under similar
conditions afforded the cyclic enamine 5 in very good yield
(Scheme 1). Furthermore, it became apparent that the change
from the thymine in 1 to the 1,2-O-isopropylidene functionality
in 7 greatly enhanced the reactivity of the molecule, leading to
the formation of the dimer 15 as the major product of the
reaction.
FIGURE 1. Structures of compounds 6, 7, and 8.
subsequent study of the reactivity of the non-methylated thymine
cyclic enamine 6 against different nucleophiles (Figure 1), we
found that this enamine is in fact a very useful and versatile
intermediate that can be used to prepare novel types of
polycyclic nucleosides in high yields in a regio- and stereose-
lective manner.18
In the present work, we studied whether simple sugar
derivatives, such as the 1,2-O-isopropylidene-5-O-tosyl R-D-
ribofuranose 7, could be converted to a cyclic enamine 8 that
could then be used to achieve skeletal diversity (Figure 1). We
were also interested in the possibility that the unique reactivity
of the cyclic enamine in 8 would cause the compound to be
transformed into unusual classes of condensed cyclic com-
pounds. Moreover, we speculated that 8 might be used as a
common sugar precursor in glycosylation reactions to give a
variety of nucleosides or O-, S-, or N-glycosides.
Results
Chemistry. Originally, the tosylate precursor 7 of the cyclic
enamine 8 was prepared following a protocol similar to that
established by our group for the synthesis of 5′-O-tosyl TSAO-
m3T 1.17 Briefly, the 5′-TBDMS derivative 919 was first
synthesized via five steps starting from 1,2-O-isopropylidene-
R-D-xylofuranose. Then, 9 was selectively deprotected with 0.1
N methanolic HCl to yield 10,19 which was subsequently
activated with tosyl chloride to give the 5′-O-tosyl derivative 7
(Scheme 2).
Next we sought to establish an alternative, shorter synthetic
route to 5-O-tosyl derivative 7. In this second route, the tosyl
moiety was introduced into the sugar during the very first stage,
avoiding the two protection/deprotection steps with TBDMS
used in the original scheme. Thus, this route started from
commercially available 1,2-O-isopropylidene-R-D-xylofuranose,
which was selectively monotosylated at the primary hydroxyl
group to afford 11 (95%)20,21 (Scheme 3). Oxidation of the
remaining 3-hydroxyl group with pyridinium dichromate/Ac2O
afforded the 3-ulose 12, which was not purified. Addition of
sodium cyanide to 12 followed by mesylation of the corre-
sponding cyanohydrin 13 afforded the R-mesyloxynitrile 14
(67%). The high stereoselectivity observed in the formation of
13 could be explained by the presence of the conformationally
rigid 1,2-O-isopropylidene functionality, which dictates the
approach of the cyanide ion from the sterically less-hindered
â-face of the ulose.19 Subsequent treatment of 14 with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile at -20
To further investigate the above-mentioned transformation,
we performed the reaction under the conditions described above
while carefully monitoring the composition of the reaction
mixture using thin-layer chromatography (TLC). After 2 h, not
only was the expected dimer 15 detected, but also another
compound that had not been detected in the product mixture
when we ran the reaction for 6 h. Next, we sought to determine
the structure of the novel component, which was found to be
more polar than 15 on TLC. Immediate isolation of the novel
component from the reaction mixture by centrifugal circular
thin-layer chromatography (CCTLC) in which nucleophilic
(18) Bonache, M. C.; Chamorro, C.; Cordeiro, A.; Camarasa, M. J.;
Jimeno, M. L.; San-Fe´lix A. J. Org. Chem. 2004, 69, 8758.
(19) Pe´rez-Pe´rez, M. J.; Camarasa M. J.; Diaz-Ortiz, A.; San-Fe´lix A.;
de las Heras F. G. Carbohydr. Res. 1991, 216, 399.
(20) Sharma, G. V. M.; Gopinath, T. Tetrahedron Lett. 2001, 42, 6183.
(21) Moravcova´, J.; Capkova´, J.; Stanek, J.; Raich, I. J. Carbohydr. Chem.
1997, 16, 1061.
(22) Hurd, R. E.; John, B. K. J. Magn. Reson. 1991, 91, 1991.
(23) Kay, L. E.; Keifer P.; Saarinen, T. J. Am. Chem. Soc. 1992, 114,
10663.
7226 J. Org. Chem., Vol. 71, No. 19, 2006

A NoVel Carbohydrate To AchieVe Skeletal DiVersity
SCHEME 2. Original Method for Synthesizing 1,2-O-Isopropylidene-5′-O-tosyl Ribofuranose 7
TABLE 1. DifFerent Conditions Used for the Optimization of the
Yield of Cyclic Enamine 8
SCHEME 3. Improved Route for Synthesizing
1,2-O-Isopropylidene-5′-O-tosyl Ribofuranose 7
temp
7 (%)
8 (%)
15 (%)
entry
base
(°C)
time
2 h
6 h
24 h
tR ) 7.53 tR ) 1.83 tR ) 5.31
1
2
3
4
5
6
7
8
K2CO3
80
65
2
27
8
-
8
90
-
-
5
pyridine
Et3N
DBU
80
80
40
100
100
43
34
18
11
5
24 h
-
15 min
30 min
45 min
1 h
15 min
30 min
45 min
1 h
52
59
69
69
76
55
36
31
90
7
13
20
19
42
56
67
6
SCHEME 4. Reaction of 1,2-O-Isopropylidene-5′-O-tosyl
Ribofuranose 7 with Potassium Carbonate
9
DBU
DBU
80
80
10
11
12
13
3
8
2
4
10 min
base. After 2 h, starting compound 7 (retention time, tR ) 7.53)
was detected in 65% yield. The dimer 15 (8%) (tR ) 5.31) and
the cyclic enamine 8 (27%) (tR ) 1.83) were also detected (entry
1). After 6 h, the yield of 8 had decreased to 8% and the yield
of 15 had increased to 90% (entry 2).
When pyridine or Et3N were used as the base at 80 °C, only
the unreacted starting 5-O-tosyl derivative 7 was detected in
the reaction mixture, even after 24 h (entries 3 and 4).
By contrast, when DBU was used as the base at 40 °C, a
mixture in which compound 8 was the major component (69%)
resulted after a reaction time of 1 h (entry 8). Starting compound
7 (11%) and 15 (20%) were also detected. On increasing the
temperature to 80 °C, however, starting compound 7 was
consumed in a shorter time (entry 9). Moreover, consistent with
the behavior observed during the reaction of 7 with K2CO3
(entries 1 and 2), the amount of 15 increased and the amount
of 8 decreased with increasing reaction time (entries 9-12).
Among the sets of reaction conditions tested, the best
conditions were found to be basic media (DBU), 80 °C, and 10
min reaction time (entry 13). Under these conditions, the cyclic
enamine 8 was obtained in 90% yield, with the dimer 15 as a
minor derivative (6%).
solvents (ethanol, methanol, etc.) were avoided resulted in a
reasonable amount of the component. The H NMR spectrum
of this compound was fully consistent with the structure of the
desired cyclic enamine 8.
To identify conditions that afforded 8 in higher yields, we
analyzed the conversion of the tosyl derivative 7 to the desired
cyclic enamine 8 as a function of reaction time, temperature,
and base used. The reaction was monitored using HPLC (Table
1).
1
For comparison purposes, the reaction was repeated at 80
°C in the presence of potassium carbonate as a non-nucleophilic
It should be emphasized that 8 is not sufficiently stable to be
efficiently isolated. Thus, after 10 min of reaction, the process
must be quenched by addition of acetic acid (pH adjusted to
5-6), and the residue (compound 8) left to react in situ with a
nucleophile. For this reason, the reaction yields described here
are the result of two consecutive steps starting from 7 (intramo-
lecular cyclization to afford 8 and nucleophilic attack) carried
out in a “one-pot” fashion.
Having established a convenient protocol for efficiently
producing 8, we next focused on exploring its reactivity toward
FIGURE 2. gHMBC NMR correlations, indicated by arrows.
J. Org. Chem, Vol. 71, No. 19, 2006 7227

Cordeiro et al.
SCHEME 5. Reaction of 8 with (Thio)alcohols, Sodium Cyanide, Water, and Amines
oxygen-, sulfur-, carbon-, and nitrogen-based nucleophiles. In
addition, we examined the reaction of 8 with amino acids.
First, the reaction of 8 with primary alcohols, specifically,
methanol or ethanol (where the alcohol was used as both solvent
and nucleophile), were carried out. These reactions afforded the
corresponding O-substituted tricyclic sugars 16 (70%) and 17
(68%) in a completely regio- and stereoselective manner
(Scheme 5).
When, under the same conditions, 8 was reacted with
thioethanol as the nucleophile, the tricyclic sugar 18 (60%) was
obtained. Thus, all three nucleophiles, methanol, ethanol, and
thioethanol, behaved similarly in the reaction with 8. By contrast,
more hindered alcohols such as i-PrOH and t-ButOH reacted
with 8 to exclusively afford the unexpected bicyclic sugar
derivative 19, in which a γ-lactam ring is fused to the ribose
moiety. This compound was also obtained (52% yield) when 8
was reacted with a 1:1 mixture of acetonitrile and water. The
facile formation of 19 again highlighted the differences in
reactivity that exist between the nucleoside 6 and the sugar 8,
in that the γ-lactam ring in 6 only formed when potassium
carbonate was present in the reaction medium.
Next, we focused on the reaction of the cyclic enamine 8
with primary and secondary amines (Scheme 5). When 8 was
reacted with an excess of a primary amine (propyl or isopro-
pylamine), the bicyclic sugars 20 (55% yield) and 21 (76%
yield) were obtained. The fact that we obtained almost identical
results for isopropylamine and propylamine indicates that, in
contrast to the reactions of 8 with alcohols, branching at the
C-R has little effect on the course of the reaction with primary
amines. A similar treatment of 8 with secondary amines such
as dimethylamine (2 M in THF) or N,N-ethylmethylamine
afforded the bicyclic sugars 22 and 23 in 45% and 30% yields,
respectively.
We assigned the structures of the novel compounds 16-24
on the basis of their analytical and spectroscopic data. The
structures of the polycyclic sugar derivatives were assigned by
1H and 13C NMR spectroscopic analysis using mono- and
bidimensional techniques (gHMBC22 and gHSQC23) and by
comparison with the corresponding nucleoside derivatives.
The stereochemistry of the new stereogenic center created
on C-4′ in compounds 16-18 was determined as S on the basis
of NOE difference experiments carried out on 16, which was
chosen as a representative compound. Specifically, irradiation
of the signal corresponding to the methyl group of the OCH3
moiety caused the enhancement of the signals of the protons of
the sugar H-2 and H-5 (Figure 3), indicating that these protons
and the methanol group were on the same upper side of the
furanose ring. This result confirms that the conjugate addition
of the nucleophile proceeded with complete stereoselectivity
on the â-face of the sugar-fused cyclic enamine.
The 13C NMR spectrum for compounds 20 and 21 recorded
in acetone contained broadened signals for the carbon atoms
C-5, C-3, CH2-NH, and CdN, suggesting the existence of an
equilibrium between the unsaturated endo- and exocyclic
amidines (C and D). This equilibrium was studied for compound
20, which was chosen as a representative compound (Figure
4). According to literature data,24 the methylene carbon atom
appearing at δ 44.6 ppm is compatible with a CH2NH grouping
and therefore with tautomer C, whereas the methylene of a
CH2Nd grouping (as in tautomer D) should appear at lower
field (around δ 56 ppm). Therefore, our observations for com-
Next, we examined the reaction with a C-nucleophile. Sodium
cyanide (NaCN) was found to be a poor source of cyanide ions
because of its low solubility in the reaction solvent (acetonitrile).
When, as an alternative, NaCN, sodium bicarbonate, and 8 were
reacted in a 1:1 mixture of ethyl acetate/water with vigorous
stirring, only the sugar derivative 19, in which a γ-lactam ring
is fused to the ribose moiety, was obtained (data not shown).
However, reaction of 8 with trimethylsilylcyanide (TMSCN),
a cyanide species that is soluble in acetonitrile, afforded the
nitrile tricyclic sugar 24 in 60% yield (Scheme 5). It should be
highlighted that all of the above-mentioned transformations were
fully regio- and stereoselective.
FIGURE 3. Relevant NOE, indicated by arrows.
FIGURE 4. Tautomeric forms of compound 20.
7228 J. Org. Chem., Vol. 71, No. 19, 2006

A NoVel Carbohydrate To AchieVe Skeletal DiVersity
SCHEME 6. Proposed Mechanism for the Reaction of 8 with (thio)Alcohols, Water and Amines
SCHEME 7. Comparison of the Reactivity of 6 and 8 against L-Alanine [H-L-Ala-OMe‚HCl]
pound 20 in acetone solution suggests that both tautomers are
present, and that the equilibrium is shifted toward tautomer C.
The experimental results presented above for the reactions
of the sugar 8 with (thio)alcohols, water, amines, or trimeth-
ylsilylcyanide indicate that when 8 is reacted with these
compounds, it behaves in a manner similar to the nucleoside 6.
These results can be explained by our previously reported
mechanism (Scheme 6):17,18 the reaction is initiated by the attack
of the nucleophile on the C-4′ carbon atom of the spiroami-
noxathiole ring to give intermediate I, and then proton transfer
gives the tricyclic derivatives 16-18 and 24. When the
nucleophile is water, formation of intermediate II and subse-
quent ring opening of the spiroaminoxathiole moiety may occur
to afford the intermediate III. Although this intermediate can
exist in two tautomeric forms, III and 19, only the bicyclic sugar
19 with a γ-lactam ring fused to the ribose moiety was observed.
In the case of amines, the intermediate IV may undergo ring
opening of the spiroaminoxathiole moiety to give the bicyclic
sugar derivatives 20-23, in which a pyrroline ring is fused to
the ribose moiety.
that, when the nucleoside 6 reacts with the methyl ester
derivative of L-alanine [H-L-Ala-OMe‚HCl], the attack by the
amino acid occurs regioselectively at the sulfur of the SO2 group
to give compound E. In the case of 8, however, no reaction
was observed at this position. By contrast, treatment of 8 with
the same amino acid afforded the highly strained tetracyclic
compound 25 in very good yield (76% overall yield, after two
reaction steps) (Scheme 7). One explanation for the formation
of this compound is that the amino group attacks the C-4′
position of the sugar to give the intermediate I, and then the
NH of the pyrroline ring spontaneously displaces the ester group
of the amino acid to form a new fused five-membered ring
(Scheme 7). This extremely facile intramolecular attack is
consistent with the previously observed high reactivity of the
Finally, we investigated the reactivity of the cyclic sugar
derivative 8 with amino acids. We have previously observed
(24) Kalinowski, H.-O.; Berger, S.; Braun, S. Carbon-13 NMR Spec-
troscopy; John Wiley & Sons: Chichester, 1988.
FIGURE 5. gHMBC NMR correlations, indicated by arrows.
J. Org. Chem, Vol. 71, No. 19, 2006 7229

Cordeiro et al.
SCHEME 8. Reaction of 8 with r-Amino Acids
SCHEME 9. Formation of Five- versus Six- or Seven-Membered Extra Rings with Aspartic or Glutamic Amino Acids,
Respectively
NH of the pyrroline ring toward reagents that contain carbonyl
groups reported by our group.18
amino acids in which the side chain is protected as benzyl ester,
it should be possible to determine whether there exists competi-
tion in the intramolecular cyclization between the benzyl ester
groups of the side chain and the R-carboxy group. In addition,
we also investigated the compatibility of the reaction with the
most common protecting moieties used for the R-carboxy group
of the amino acid (methyl, benzyl, tert-butyl).
We found that the reaction of 8 with the corresponding
R-amino acid, carried out in the presence of triethylamine,
afforded the tetracyclic nucleosides 26-29 with an extra five-
membered ring in good yields (40-63%, two reaction steps),
regardless of the nature of the amino acid and the protected
ester form of the R-carboxy group (Scheme 8).
We additionally investigated whether the spatial disposition
of the side chain of the amino acid affected the formation of
the extra five-membered ring. To clarify this issue, we reacted
8 with the D-amino acid, H-D-Lys-(Z)-OMe, under the same
conditions as described above (Scheme 8). This reaction afforded
the corresponding tetracyclic derivative 30 in good yield (43%),
indicating that the intramolecular attack is independent of the
stereochemistry of the amino acid.
The 1H NMR spectrum of 25 was crucial for the identification
of this compound. Specifically, the spectrum contained a singlet
at δ 1.27 and a multiplet at δ 4.05 ppm, corresponding
respectively to the methyl side chain of the mesylate and H-R
protons of the amino acid, but did not contain signals corre-
sponding to the ester group. In the gHMBC experiment (Figure
5), a long-range correlation between the H-5 protons (δ 3.15
and 4.13 ppm) and the CO carbon (δ 175.8 ppm) was observed,
consistent with a cyclized structure.
This interesting result encouraged us to investigate the
reactions of 8 with various R-amino acids, to confirm whether
the reaction is always regioselective and to generalize the
methodology (Scheme 8). Thus, we studied the reactions of 8
with an aromatic (Phe) amino acid, and with amino acids with
acidic (Asp, Glu) or basic (Orn) side-chains. The reactions with
amino acids with acidic or basic side chains were examined for
two reasons. First, these compounds may allow the introduction
of carboxyl or amine functionalities into the five-membered ring
upon deprotection of the side chain, modifications that may give
rise to carbohydrates that are more suitable for use as building
blocks. Second, by examining the reactions of Asp and Glu
To generate carbohydrates that are more suitable for deriva-
tization, we sought to incorporate at least one amine or
7230 J. Org. Chem., Vol. 71, No. 19, 2006

A NoVel Carbohydrate To AchieVe Skeletal DiVersity
SCHEME 10. Reaction of 8 with â- and δ-Amino Acids
carboxylic acid functional group into the sugar ring. For this
purpose, hydrogenation of 27 and 29 in the presence of Pd/C
was attempted. Hydrogenation of 27 afforded the corresponding
carboxy deprotected derivative 31 in 70% yield (Scheme 8);
however, hydrogenation of 29 only gave a mixture of unidenti-
fied compounds.
As mentioned above, in the case of Asp and Glu amino acids
in which the side chain is protected as a benzyl ester, the benzyl
ester groups of the side chain (b in the scheme) and the
R-carboxy group (a in the scheme) may compete in the
cyclization reaction (Scheme 9). If this were to occur, Asp and
Glu could lead to the formation of six- and seven-membered
extra rings II, respectively, instead of or in addition to the five-
membered extra ring I. However, our results indicate that the
five-membered ring is preferentially formed.
formation of 33 involved an extra ring-closing step in which
the ester moiety was attacked by the N of the pyrroline ring.
Figure 6 shows the most important long-range correlations
observed in the gHMBC experiments for compounds 32 and
33.
Finally, we examined the reaction of 8 with a δ-amino acid,
namely, H-δ-aminovaleric acid. In this case, the amino acid
attacked the 4′ position, following by opening of the spiro ring
to give 34 (35%) as the only product. The corresponding eight-
membered cyclized product was not detected (Scheme 10).
These experimental results show that in the intramolecular
attack of the ester moiety of the amino acid by the NH of the
pyrroline or pyrrolidine ring, the formation of a five or six-
membered extra ring is much more favorable than the formation
of larger rings.
To investigate whether reaction with a â-amino acid would
effectively enable the formation of an extra six-membered ring,
we examined the reaction of 8 with â-L-alanine (Scheme 10).
In this case, the tetracyclic derivative 32 (20%) was obtained
along with the tricyclic derivative 33 (25%). Formation of 33
could be explained by the attack of the amino acid and the
subsequent opening of the spiro ring to give II. This intermediate
is similar to the compounds 20 and 21 obtained from the reaction
of 8 with primary and secondary amines (Scheme 6), although
Conclusions
We have reported a high-yielding method for synthesizing
the novel sugar cyclic enamine 8 from the commercially
available carbohydrate 1,2-O-isopropylidene-R-D-xylofuranose.
Compound 8 can be prepared in situ by cyclization of the
corresponding precursor, the O-tosyl derivative 7, under basic
conditions (DBU, 10 min, 80 °C).
The regio- and stereochemical behavior of 8 when reacted
with O-, N-, and S-nucleophiles allowed its efficient transforma-
tion (one-step reaction, high yields, and easy purifications) into
novel highly functionalized bi- and tricyclic sugar derivatives
with different molecular skeletons. A notable feature of 8 is its
reactivity with amino acids, which afforded a novel type of
highly strained tetracylic derivative. Similar behavior was not
detected when the nucleoside cyclic enamines 5 and 6 derived
from thymine were reacted with amino acids.
The constrained structures and dense functionalization of the
polycyclic sugar derivatives generated from 8 make these
FIGURE 6. gHMBC NMR correlations, indicated by arrows.
J. Org. Chem, Vol. 71, No. 19, 2006 7231

Cordeiro et al.
romethane (40 mL) was added. After refluxing for 3-4 h, the
solvent was removed, and residues were taken up in ethyl acetate
(100 mL). The mixture was filtered though a wet (ethyl acetate)
short column of silica gel using ethyl acetate as the eluent. The
eluent was concentrated and the residue was coevaporated with
toluene (3 × 25 mL) to give 12 (crude yield 4.93 g) as a yellow
syrup, which was used immediately without further purification.
IR (KBr): ν 1770 cm-1 (CO).
3-C-Cyano-1,2-O-isopropilidene-3-O-mesyl-5-O-tosyl-R-D-ri-
bofuranose (14). To a solution of the crude ulose 12 (4.93 g) in
diethyl ether (40 mL) were added water (20 mL), sodium hydro-
gencarbonate (2.63 g, 31.82 mmol), and sodium cyanide (0.76 g,
15.69 mmol). The heterogeneous mixture was stirred vigorously
at room temperature for 4 h. The two layers were separated, and
the aqueous phase was washed with diethyl ether (2 × 30 mL).
The combined ethereal phases were dried (Na2SO4), filtered, and
evaporated to give cyanohydrin 13 as a yellow syrup that was used
inmediately in the next step without purification.
To a cooled (0 °C) solution of the previously obtained cyano-
hydrin 13 (∼15.69 mmol) in dry pyridine (60 mL) was added
dropwise methane sulfonyl chloride (1.83 mL, 23.53 mmol). The
mixture was stirred at 5 °C overnight. The eluent was concentrated,
and the residue was coevaporated with ethanol (3 × 25 mL) and
toluene (3 × 25 mL). The residue was dissolved in dichloromethane
(50 mL) and washed with cold 1 N HCl (2 × 50 mL), a saturated
solution of NaHCO3 (2 × 50 mL), and finally with brine (2 × 50
mL). The organic layer was dried (Na2SO4), filtered, and concen-
trated. Flash column chromatography (hexane/ethyl acetate, 2:1)
of the residue afforded 4.7 g of 14 (67%) as a yellow syrup. [R]20
D -3.2 (c 0.6, CHCl3). 1H NMR [(CD3)2CO, 400 MHz] δ: 1.39-
1.52 (2s, 6H), 2.46 (s, 3H), 3.39 (s, 3H), 4.33-4.48 (m, 3H), 5.23
(d, 1H, J ) 3.6 Hz), 6.09 (d, 1H, J ) 3.6 Hz), 7.5-7.8 (m, 4H).
13C NMR [(CD3)2CO, 100 MHz] δ: 21.5 (CH3), 26.2-26.8 (CH3),
40.8 (CH3), 67.6 (CH2), 77.3 (CH), 79.45 (C), 82.2 (CH), 105.3
(CH), 115.4 (CN), 128.9-146.5 (CH). MS (ES+) m/z: 448.1 (M
+ H)+. Anal. Calcd for C17H21NO9S2: C, 45.63; H, 4.73; N, 3.13.
Found: C, 45.54; H, 4.87; N, 3.08.
[5,N4′Cyclo-3-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-dioxide)-
1,2-O-isopropilidene-R-D-ribofuranosyl] (N4′f 4′) 5,N4′cyclo-3-
spiro-5′-(4′-amino-1′,2′-oxathiolane-2′,2′-dioxide)-1,2-O-isopro-
pilidene-R-D-ribofuranose (15). To a solution of the 5-O-tosyl
derivative 7 (0.1 g, 0.22 mmol) in dry acetonitrile (4 mL) was added
dry potassium carbonate (0.034 g, 0.25 mmol). The solution was
refluxed for 6 h and evaporated to dryness. The residue was
dissolved in ethyl acetate (20 mL) and washed with water (2 × 20
mL). The organic layer was dried (Na2SO4), filtered, and evaporated
to dryness. The residue was purified by CCTLC (hexane/ethyl
compounds promising candidates for use as starting agents for
the production of new analogues and as drugs. In addition,
condensation of 8 with different nucleobases or with glycosyl
acceptors could be used to access a variety of nucleosides or
O-, S-, or N-glycosides, respectively, highlighting the potential
of this cyclic enamine as a precursor.
In conclusion, the high reactivity of the sugar derivative 8,
its synthetic accessibility, and the vast collection of products
into which it can be converted by the action of different
nucleophiles make this compound a very useful synthetic
intermediate to achieve skeletal diversity. We believe that on
the basis of its unique reactivity, compound 8 could play an
interesting role in the chemistry of carbohydrates.
Experimental Section
The names of polycyclic furanoses in this section are given
according to the IUPAC recommendations for polycyclic com-
pounds (extension of the Von Baeyer system).25 However, for easy
comparison, the assignments of the signals of the NMR spectra
follow standard carbohydrate numbering (i.e., the furanose skeleton
numbered 1-5).
1,2-O-Isopropylidene-3-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-
dioxide)-5-O-tosyl-R-D-ribofuranose (7). Method A. To a solution
of 1019 (2.0 g, 6.81 mmol) in dry pyridine (50 mL) was added
p-toluensulfonyl chloride (2.86 mL, 15.0 mmol). The reaction
mixture was kept at room temperature for 16 h, and then solvent
was evaporated and coevaporated with ethanol and toluene. A
solution of the residue in dichloromethane (30 mL) was washed
with cold 1 N HCl (2 × 30 mL), saturated solution of NaHCO3 (2
× 30 mL), and finally with brine (2 × 30 mL). The organic layer
was dried (Na2SO4), filtered, and evaporated to dryness. Flash-
column chromatography (hexane/ethyl acetate, 2:1) of the residue
afforded 2.65 g of 7 (87%) as a white solid: mp 87-89 °C. [R]20
D
+29.8 (c 0.5, CHCl3). HPLC: tR ) 7.53 (40:60). 1H NMR [(CD3)2-
CO, 300 MHz] δ: 1.33-1.48 (2s, 6H), 2.45 (s, 3H), 4.23-4.37
(m, 3H), 4.77 (d, 1H, J ) 3.9 Hz), 5.67 (s, 1H), 5.97 (bs, 2H),
6.12 (d, 1H, J ) 3.9 Hz), 7.46-7.83 (m, 5H). 13C NMR [(CD3)2-
CO, 75 MHz] δ: 20.6 (CH3), 25.8 (CH3), 66.5 (CH2), 75.9 (CH),
80.9 (CH), 87.6 (C), 89.2 (CH), 104.1 (CH), 113.9 (C), 127.8-
148.2 (CH), 152.2 (C). MS (ES+) m/z: 448.3 (M + H)+. Anal.
Calcd for C17H21NO9S2: C, 45.63; H, 4.73; N, 3.13. Found: C,
45.48; H, 4.85; N, 3.29.
Method B. To a cooled (0 °C) solution of 14 (2.0 g, 4.46 mmol)
in dry acetonitrile (50 mL) was added DBU (0.66 mL, 4.46 mmol).
The reaction was stirred at 0 °C for 20 min and then quenched
with acetic acid, and the solvent was evaporated under reduced
pressure. Flash-column chromatography (dichloromethane/metha-
nol, 50:1) of the residue afforded 1.2 g of 7 (60%).
5,N4 Cyclo-3-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-dioxide)-
1,2-O-isopropilidene-R-D-ribofuranose (8). To a solution of the
5-O-tosyl derivative 7 (0.1 g, 0.22 mmol) in dry acetonitrile (2
mL) was added DBU (0.067 g, 0.44 mmol). The solution was heated
in a sealed tube at 80 °C for 10 min, then acetic acid was added
until pH ) 5-6, and the cyclic enamine 8, thus formed, was treated
in situ with the corresponding nucleophile. HPLC: tR ) 1.83 (40:
60). 1H NMR [(CD3)2CO, 300 MHz] δ: 1.34-1.43 (2s, 6H), 2.52
(m, 1H), 3.23 (m, 1H), 3.98 (m, 1H), 4.95 (d, 1H, J ) 3.4 Hz),
5.58 (s, 1H), 5.86 (d, 1H, J ) 3.4 Hz).
acetate, 1:1) to give 0.05 g (80%) of 15 as a white solid: mp 151
1
°C. [R]20 +20.0 (c 0.25, CHCl3). HPLC: tR ) 5.31 (40:60). H
D
NMR (DMSO-d6, 300 MHz) δ: 1.32-1.54 (4s, 12H, C(CH3)2 A
and B), 3.40 (dd, 1H, H-5a B, J ) 2.6 Hz, J ) 11.1 Hz), 3.47 (d,
1H, H-5a A, J ) 11.0 Hz), 3.65 (dd, 1H, H-5b A, J ) 2.9 Hz, J )
11.0 Hz), 3.70 (dd, 1H, H-5b B, J ) 5.7 Hz, J ) 11.1 Hz), 4.38 (d,
1H, H-3′a B, J ) 15.5 Hz), 4.46 (d, 1H, H-4 A, J ) 2.9 Hz), 4.47
(d, 1H, H-3′b B, J ) 15.5 Hz), 4.60 (d, 1H, H-2 A, J ) 3.5 Hz),
4.89 (m, 1H, H-4 B), 5.04 (d, 1H, H-2 B, J ) 4.0 Hz), 5.83 (d,
1H, H-1 A, J ) 3.5 Hz), 6.08 (s, 1H, H-3′ A), 6.09 (d, 1H, H-1 B,
J ) 4.0 Hz). 6.43 (bs, 1H, NH-4′ B). 13C NMR [DMSO-d6, 75
MHz] δ: 26.9-27.3 (2CH3 A and B), 48.6 (CH2 B), 49.4 (CH2
B), 51.6 (CH2 A), 78.1 (CH B), 80.1 (CH A), 80.6 (CH B), 82.1
(CH A), 86.2 (C A), 86.6 (C B), 91.8 (CH A), 97.6 (C B), 105.1
(CH A), 105.7 (CH B), 112.8 (C A), 113.3 (C B), 155.6 (C A).
MS (ES+) m/z: 551.3 (M + H)+. Anal. Calcd for C20H26N2O12S2:
C, 43.63; H, 4.76; N, 5.09. Found: C, 43.54; H, 4.58; N, 5.22.
General Procedure for the Synthesis of Sugars 16-24. The
5-O-tosyl derivative 7 (0.1 g, 0.22 mmol) was treated with DBU
as described above to give the cyclic enamine 8 that was inmediately
treated in situ with the corresponding nucleophile. The solution
was heated at 80 °C for 3 h. Solvent was evaporated and the residue
1,2-O-Isopropylidene-5-O-tosyl-R-D-erythro-pentofuranose-3-
ulose (12). To a suspension of pyridinium dichromate (5.89 g, 15.7
mmol) in dry dichloromethane (40 mL) was added acetic anhydride
(7.26 mL, 70.6 mmol). The resulting mixture was stirred at room
temperature for 1 h. Then a solution of 1,2-O-isopropilidene-5-O-
tosyl-R-D-xylofuranose 1120,21 (5.4 g, 15.7 mmol) in dry dichlo-
(25) IUPAC nomenclaure home page. http://www.chem.qmul.ac.uk/iupac/
7232 J. Org. Chem., Vol. 71, No. 19, 2006

A NoVel Carbohydrate To AchieVe Skeletal DiVersity
was purified by CCTLC. The chromatography eluent and yield of
the isolated products (16-24) are indicated below for each reaction.
(1R,2R,6R,8R,11S)-10-Aza-4,4-dimethyl-13,13-dioxide-11-
methoxy-3,5,7,14-tetraoxa-13-thio-tetracyclo[6.6.0.02-6.01-11]-
tetradecane (16). Following the general procedure the cyclic
enamine 8 was treated in situ with methanol (1 mL). Chromatog-
(CH3), 22.5 (CH2), 26.6 (CH3), 39.4 (CH3), 44.6 (CH2), 58.7 (CH2),
80.1 (CH), 84.4 (CH), 96.2 (C), 106.2 (CH), 113.1 (C), 158.8
(CdN). MS (ES+) m/z: 335.0 (M + H)+. Anal. Calcd for
C13H22N2O6S: C, 46.69; H, 6.63; N, 8.38. Found: C, 46.58; H,
6.76; N, 8.44.
(1R,2R,6R,8R)-10-Aza-4,4-dimethyl-11-isopropylamino-1-
mesyloxy-3,5,7-trioxa-tricyclo[6.3.0.02-6]undec-10-ene (21). Fol-
lowing the general procedure the cyclic enamine 8 was treated in
situ with isopropylamine (0.01 mL, 1.1 mmol). Chromatography
with dichloromethane/methanol/ammonium hydroxide (10:1:0.01)
raphy with hexane/ethyl acetate (1:1) gave 0.05 g of 16 (70%) as
1
a yellow solid: mp 83-85 °C. [R]20 +37.4 (c 0.4, CHCl3). H
D
NMR [300 MHz, (CD3)2CO] δ: 1.28-1.49 (2s, 6H), 3.11 (d, 1H,
J ) 12.8 Hz), 3.34 (s, 3H), 3.48 (m, 1H), 3.63 (bs, 1H), 3.87 (s,
2H), 4.69 (d, 1H, J ) 4.0 Hz), 4.84 (d, 1H, J ) 3.4 Hz), 5.73 (d,
1H, J ) 3.4 Hz). 13C NMR [75 MHz, (CD3)2CO] δ: 26.7-27.5
(CH3), 51.4 (CH3), 51.5 (CH2), 55.9 (CH3), 79.6 (CH), 83.2 (CH),
97.5 (C), 106.7 (C), 108.3 (CH), 114.2 (C), MS (ES+) m/z: 308.1
(M + H)+, 330.1 (M +Na)+. Anal. Calcd for C11H17NO7S: C,
42.99; H, 5.58; N, 4.56. Found: C, 42.91; H, 5.49; N, 4.62.
(1R,2R,6R,8R,11S)-10-Aza-4,4-dimethyl-13,13-dioxide-11-
ethoxy-3,5,7,14-tetraoxa-13-thio-tetracyclo[6.6.0.02-6.01-11]-
tetradecane (17). Following the general procedure the cyclic
enamine 8 was treated in situ with ethanol (1 mL). Chromatography
with hexane/ethyl acetate (1:1) gave 0.05 g of 17 (68%) as a yellow
solid: mp 73-75 °C. [R]20D +25.9 (c 0.8, CHCl3). 1H NMR (300
MHz, CDCl3) δ: 1.22 (t, 3H, J ) 6.9 Hz), 1.43-1.62 (2s, 6H),
3.21-3.46 (m, 3H), 3.53 (d, 1H, J ) 13.4 Hz), 3.64 (d, 1H, J )
13.4 Hz), 3.79 (m, 1H), 4.76 (d, 1H, J ) 3.5 Hz), 4.84 (d, 1H, J
) 3.4 Hz), 4.79 (d, 1H, J ) 3.4 Hz).13C NMR [75 MHz, (CDCl3]
δ: 15.2 (CH3), 26.9-27.3 (CH3), 50.6 (CH2), 55.1 (CH2), 59.8
(CH2), 78.2 (CH), 82.2 (CH), 98.2 (C), 100.1 (C), 107.1 (C), 113.9
(C). MS (ES+) m/z: 322.1 (M + H)+. Anal. Calcd for C12H19-
NO7S: C, 44.85; H, 5.96; N, 4.36. Found: C, 44.65; H, 5.76; N,
4.06.
gave 0.06 g of 21 (76%) as a yellow syrup. [R]20 +56.1 (c 0.4,
D
1
CHCl3). H NMR [400 MHz, (CD3)2CO] δ: 1.15 (d, 3H, J ) 6.6
Hz), 1.18 (d, 3H, J ) 6.6 Hz), 1.35-1.53 (2s, 6H), 3.23 (s, 3H),
3.53 (d, 1H, J ) 15.0 Hz), 3.74 (dd, 1H, J ) 3.5 Hz, J ) 15.0 Hz),
3.85 (m, 1H), 4.78 (d, 1H, J ) 3.5 Hz), 4.95 (d, H-2, J ) 3.8 Hz),
5.83 (d, 1H, J ) 3.8 Hz). 13C NMR [100 MHz, (CD3)2CO] δ:
21.4-21.8 (CH3), 26.6 (CH3), 39.5 (CH3), 44.2 (CH), 59.2 (CH2),
80.2 (CH), 84.2 (CH), 96.4 (C), 106.2 (CH), 113.1 (C), 158.8
(CdN). MS (ES+) m/z: 335.0 (M + H)+. Anal. Calcd for
C13H22N2O6S: C, 46.69; H, 6.63; N, 8.38. Found: C, 46.74; H,
6.72; N, 8.38.
(1R,2R,6R,8R)-10-Aza-4,4-dimethyl-11-N,N-(dimethylamino)-
1-mesyloxy-3,5,7-trioxa-tricyclo[6.3.0.02-6]undec-10-ene (22). Fol-
lowing the general procedure the cyclic enamine 8 was treated in
situ with N,N-dimethylamine (0.06 mL, 1.1 mmol). The residue
was purified by CCTLC using dichloromethane/methanol/am-
monium hydroxide (10:1:0.01). The fastest moving fractions gave
0.01 g (9%) of the dimer derivative 15 and 0.08 g (13%) of the
bicyclic sugar derivative 19. From the slowest moving fractions,
0.02 g (31%) of 22 was isolated as a yellow syrup. [R]20 +25.2
D
(c 0.4, CHCl3). 1H NMR [300 MHz, (CD3)2CO] δ: 1.41-1.61 (2s,
6H), 3.12 (1s, 6H), 3.25 (s, 3H), 3.61 (d, 1H, J ) 14.6 Hz), 4.01
(dd, 1H, J ) 4.6 Hz, J ) 14.6 Hz), 4.92 (d, 1H, J ) 3.9 Hz), 5.15
(d, 1H, J ) 4.6 Hz), 6.02 (d, 1H, J ) 3.9 Hz). 13C NMR [75 MHz,
(CD3)2CO] δ: 27.6-28.2 (CH3), 40.1 (CH3), 40.3 (CH3), 58.3
(CH2), 82.9 (CH), 85.7 (CH), 94.4 (C), 107.2 (CH), 114.8 (C), 162.9
(CdN). MS (ES+) m/z: 321.1 (M + H)+ m/z: 343.1 (M + Na)+.
Anal. Calcd for C12H20N2O6S: C, 44.99; H, 6.29; N, 8.74. Found:
C, 44.84; H, 6.12; N, 8.87.
(1R,2R,6R,8R,11S)-10-Aza-4,4-dimethyl-13,13-dioxide-11-
ethylthio-3,5,7,14-tetraoxa-13-thio-tetracyclo[6.6.0.02-6.01-11]-
tetradecane (18). Following the general procedure the cyclic
enamine 8 was treated in situ with ethanethiol (1 mL). Chroma-
tography with hexane/ethyl acetate (1:1) gave 0.04 g of 18 (60%)
as a yellow solid: mp 69-71 °C. [R]20D +33.5 (c 1.4, CHCl3). 1H
NMR (300 MHz, CDCl3) δ: 1.31 (t, 3H, J ) 7.5 Hz), 1.42-1.63
(2s, 6H), 2.83 (m, 2H), 3.18 (m, 2H), 3.53 (d, 1H, J ) 13.9 Hz),
3.76 (d, 1H, J ) 13.9 Hz), 4.71 (d, 1H, J ) 2.3 Hz), 4.94 (d, 1H,
J ) 3.5 Hz), 5.79 (d, 1H, J ) 3.5 Hz).13C NMR [75 MHz, (CDCl3)]
δ: 14.4 (CH3), 24.9 (CH2), 26.8 (CH3), 49.5 (CH2), 57.3 (CH2),
66.1 (C), 79.5 (CH), 83.5 (CH), 100.2 (C), 106.4 (CH), 114.2 (C).
MS (ES+) m/z: 338.1 (M + H)+. Anal. Calcd for C12H19NO6S2:
C, 42.72; H, 5.68; N, 4.15. Found: 42.79; H, 5.75; N, 4.24.
(1R,2R,6R,8R)-10-Aza-4,4-dimethyl-1-mesyloxy-11-oxo-3,5,7-
trioxa-tricyclo[6.3.0.02-6]undecane (19). Following the general
procedure the cyclic enamine 8 was treated in situ with water (2
mL). Chromatography with hexane/ethyl acetate (1:1) gave 0.03 g
(1R,2R,6R,8R)-10-Aza-4,4-dimethyl-1-mesyloxy-11-N,N-
ethylmethylamino-3,5,7-trioxa-tricyclo[6.3.0.02-6]undec-10-
ene (23). Following the general procedure the cyclic enamine 8
was treated in situ with N,N-ethylmethylamine (0.06 mL, 1.1 mmol).
The residue was purified by CCTLC using dichloromethane/
methanol/ammonium hydroxide (10:1:0.01) to give 0.02 g (30%)
of 23 as a yellow syrup. [R]20D +2.3 (c 3.4, CHCl3). 1H NMR [400
MHz, (CD3)2CO] δ: 1.13 (t, 3H, J ) 7.1 Hz) 1.35-1.54 (2s, 6H),
2.98 (s, 3H), 3.21 (s, 3H), 3.25-3.45 (m, 2H), 3.52 (d, 1H, J )
14.7 Hz), 3.95 (dd, 1H, J ) 4.2 Hz, J ) 14.7 Hz), 4.78 (d, 1H, J
of 19 (52%) as a white solid: mp 154-156 °C. [R]20 +14.8 (c
) 4.3 Hz), 5.18 (d, 1H, J ) 4.2 Hz), 5.93 (d, 1H, J ) 4.3 Hz). 13
C
D
0.4, CHCl3). 1H NMR (300 MHz, CDCl3) δ: 1.42-1.63 (2s, 6H),
3.28 (s, 3H), 3.35 (d, 1H, J ) 11.2 Hz), 3.85 (dd, 1H, J ) 3.6 Hz,
J ) 11.2 Hz), 4.89 (d, 1H, J ) 3.6 Hz), 4.96 (d, 1H, J ) 3.6 Hz),
5.9 (d, 1H, J ) 3.6 Hz), 7.62 (bs, 1H). 13C NMR [75 MHz, CDCl3]
δ: 26.7-27.4 (CH3), 40.5 (CH3), 46.7 (CH2), 79.8 (CH), 81.6 (CH),
88.1 (C), 105.6 (CH), 114.8 (C), 169.9 (CO). MS (ES+) m/z: 315.9
(M + Na)+. Anal. Calcd for C10H15NO7S: C, 40.95; H, 5.15; N,
4.78. Found: C, 40.84; H, 5.03; N, 4.85.
NMR [100 MHz, (CD3)2CO] δ: 10.9 (CH3), 26.7 (CH3), 34.6
(CH3), 39.1 (CH3), 44.9 (CH2), 59.3 (CH2), 81.4 (CH), 85.8 (CH),
94.4 (C), 105.9 (CH), 112.9 (C), 160.3 (CdN). MS (ES+) m/z:
335.0 (M + H)+. Anal. Calcd for C13H22N2O6S: C, 46.69; H, 6.63;
N, 8.38. Found: C, 46.72; H, 6.84; N, 8.53.
(1R,2R,6R,8R,11S)-10-Aza-11-cyano-4,4-dimethyl-13,13-
dioxide-3,5,7,14-tetraoxa-13-thio-tetracyclo[6.6.0.02-6.01-11]-
tetradecane (24). Following the general procedure the cyclic
enamine 8 was treated in situ with trimethylsilyl cyanide (0.09 mL,
0.67 mmol) and boron trifluoride etherate (BF3‚OEt2, 2 drops). The
residue was purified by CCTLC using hexane/ethyl acetate (1:1)
(1R,2R,6R,8R)-10-Aza-4,4-dimethyl-1-mesyloxy-11-pro-
pylamino-3,5,7-trioxa-triciclo[6.3.0.02-6]undec-10-ene (20). Fol-
lowing the general procedure the cyclic enamine 8 was treated in
situ with propylamine (0.01 mL, 1.1 mmol). Chromatography with
dichloromethane: methanol: ammonium hydroxide (10:1:0.01)
to give 0.04 g (60%) of 24 as a white solid: mp 82-84 °C. IR
1
(KBr) ν 2243 cm-1 (CN). [R]20 +60.4 (c 0.5, CHCl3). H NMR
D
gave 0.04 g of 20 (55%) as a yellow syrup. [R]20 +57.0 (c 2.0,
(300 MHz, CDCl3) δ: 1.42-1.63 (2s, 6H), 3.02-3.39 (m, 3H),
3.40 (d, 1H, J ) 14.1 Hz), 4.03 (d, 1H, J ) 14.1 Hz), 4.76 (m,
1H), 5.05 (d, 1H, J ) 3.7 Hz), 5.98 (d, 1H, J ) 3.7 Hz). 13C NMR
(75 MHz, CDCl3) δ: ?26.8-27.9 (CH3), 49.8 (CH2), 55.1 (CH2),
64.2 (C), 80.1 (CH), 82.1 (CH), 98.4 (C), 105.6 (CH), 115.1 (C),
115.9 (CN). MS (ES+) m/z: 303.1 (M + H)+. Anal. Calcd for
D
1
CHCl3). H NMR [400 MHz, (CD3)2CO] δ: 0.91 (t, 3H, J ) 7.4
Hz) 1.35-1.53 (2s, 6H), 1.59 (m, 2H), 3.13-3.26 (m, 2H), 3.21
(s, 3H), 3.49 (d, 1H, J ) 14.8 Hz), 3.76 (dd, 1H, J ) 3.5 Hz, J )
14.8 Hz), 4.78 (d, 1H, J ) 3.5 Hz), 4.97 (d, 1H, J ) 3.8 Hz), 5.84
(d, 1H, J ) 3.8 Hz). 13C NMR [100 MHz, (CD3)2CO] δ: 10.9
J. Org. Chem, Vol. 71, No. 19, 2006 7233

Cordeiro et al.
C11H14N2O6S: C, 43.70; H, 4.67; N, 9.27. Found: C, 43.82; H,
4.73; N, 9.35.
(ES+) m/z: 481.1 (M + H)+. Anal. Calcd for C21H24N2O9S: C,
52.49; H, 5.03; N, 5.83. Found: C, 52.53; H, 5.16; N, 5.94.
(1R,2R,6R,8R,12S,14S)-12-Benzyloxycarbonylethyl-10,13-diaza-
4,4-dimethyl-16,16-dioxide-11-oxo-3,5,7,17-tetraoxa-16-thio-
pentacyclo[9.6.0.02-6.01-14.010-14]heptadecane (28). Following the
general procedure the cyclic enamine 8 was treated in situ with
H-L-Glu-(OBn)-OBn‚HCl (0.21 g, 0.44 mmol). The residue was
purified by CCTLC using dichloromethane/methanol (10:1) to give
0.06 g (43%) of 28 as a white solid: mp 80-82 °C. [R]20D +36.9
General Procedure for the Reaction of 8 with Amino Acids
(Compounds 25-29 and 31-34). To a solution of the 5-O-tosyl
derivative 7 (0.1 g, 0.22 mmol) in dry acetonitrile (2 mL) was added
DBU (0.067 g, 0.44 mmol). The solution was heated in a sealed
tube at 80 °C for 10 min, then acetic acid was added until pH )
5-6, and the cyclic enamine 8, thus formed, was treated in situ
with the corresponding C-protected amino acid (0.44 mmol) and
triethylamine (0.06 mL, 0.44 mmol). The reaction was refluxed
for 4 h and then evaporated to dryness. The residue was dissolved
in ethyl acetate (20 mL) and washed with cold 1 N HCl (2 × 30
mL), a saturated solution of NaHCO3 (2 × 30 mL), and finally
with brine (2 × 30 mL). The organic layer was dried (Na2SO4),
filtered, and evaporated to dryness. The residue was purified by
CCTLC. The yield of the isolated products together with the
analytic, and spectroscopic dates are indicated below for each
reaction.
1
(c 0.9, CHCl3). H NMR (300 MHz, CDCl3) δ: 1.40-1.60 (2s,
6H), 1.78 (m, 1H), 2.19 (m, 1H), 2.48 (m, 2H), 2.73 (d, 1H, J )
5.8 Hz), 3.30 (dd, 1H, J ) 2.4 Hz, J ) 13.5 Hz), 3.42 (d, 1H, J )
13.9 Hz), 3.58 (d, 1H, J ) 13.9 Hz), 3.98 (m, 1H), 4.16 (d, 1H, J
) 13.5 Hz), 4.68 (d, 1H, J ) 2.4 Hz), 4.92 (d, 1H, J ) 3.8 Hz),
5.10 (d, 1H, J ) 12.3 Hz), 5.13 (d, 1H, J ) 12.3 Hz), 5.7 (d, 1H,
J ) 3.8 Hz), 7.39 (m, 5H). 13C NMR (75 MHz, CDCl3) δ: 26.7
(CH3), 27.8 (CH2), 30.3 (CH2), 46.8 (CH2), 55.6 (CH2), 58.1 (CH),
66.5 (CH2), 78.6 (CH), 82.3 (CH), 87.1 (C), 96.6 (CH), 106.2 (CH),
114.2 (C), 128.4-135.5 (CH), 172.7 (CO), 174.3 (CO). MS (ES+)
m/z: 495.1 (M + H)+; 517.1 (M + Na)+. Anal. Calcd for
C22H26N2O9S: C, 53.43; H, 5.30; N, 5.66. Found: C, 53.32; H,
5.42; N, 5.72.
(1R,2R,6R,8R,12S,14S)-12-Benzyloxycarbonylaminopropyl-
10,13-diaza-4,4-dimethyl-16,16-dioxide-11-oxo-3,5,7,17-tetraoxa-
16-thio-pentacyclo[9.6.0.02-6.01-14.010-14]heptadecane (29). Fol-
lowing the general procedure the cyclic enamine 8 was treated in
situ with H-L-Orn-(Z)-OMe‚HCl (0.14 g, 0.44 mmol). The residue
was purified by CCTLC using hexane/ethyl acetate (1:1) to give
0.06 g (54%) of 29 as a white solid: mp 80-82 °C. [R]20D +54.2
(c 0.1, CHCl3). 1H NMR [300 MHz, (CD3)2CO] δ: 1.41-1.59 (2s,
6H), 1.42-1.64 (m, 4H), 2.03 (d, 1H, J ) 5.9 Hz), 3.02 (m, 2H),
3.63 (dd, 1H, J ) 2.3 Hz, J ) 13.4 Hz), 3.91 (m, 4H), 4.62 (d, 1H,
J ) 2.3 Hz), 5.05 (s, 2H), 5.09 (d, 1H, J ) 3.5 Hz), 5.62 (d, 1H,
J ) 3.5 Hz), 6.31 (bs, 1H), 7.23 (m, 5H). 13C NMR [75 MHz,
(CD3)2CO] δ: 25.8 (CH2), 26.2 (CH3), 28.9 (CH2), 40.1 (CH2),
46.8 (CH2), 54.8 (CH2), 63.0 (CH), 65.2 (CH2), 79.3 (CH), 82.3
(CH), 87.3 (C), 96.8 (C), 106.1 (CH), 113.2 (C), 127.2-137.7 (CH),
156.1 (CO), 175.4 (CO). MS (ES+) m/z: 546.1 (M + Na)+. Anal.
Calcd for C23H29N3O9S: C, 52.76; H, 5.58; N, 8.03. Found: C,
52.58; H, 5.49; N, 8.16.
(1R,2R,6R,8R,12R,14S)-12-Benzyloxycarbonylaminopropyl-
10,13-diaza-4,4-dimethyl-16,16-dioxide-11-oxo-3,5,7,17-tetraoxa-
16-thio-pentacyclo[9.6.0.02-6.01-14.010-14]heptadecane (30). Fol-
lowing the general procedure the cyclic enamine 8 was treated in
situ with H-D-Lys-(Z)-OMe‚HCl (0.14 g, 0.44 mmol). The residue
was purified by CCTLC using hexane/ethyl acetate (1:1) to give
0.05 g (43%) of 30 as a white solid: mp 70-72 °C. [R]20D +43.13
(c 0.5, CHCl3). 1H NMR [300 MHz, (CD3)2CO] δ: 1.33-1.51 (2s,
6H), 1.42-1.64 (m, 4H), 1.82 (m, 2H), 1.95 (d, 1H, J ) 5.5 Hz),
3.14 (m, 2H), 3.49 (m, 2H), 4.03 (dd, 1H, J ) 2.1 Hz, J ) 13.4
Hz), 4.13 (m, 2H), 4.65 (d, 1H, J ) 2.1 Hz), 5.03 (m, 3H), 5.72 (d,
1H, J ) 3.6 Hz), 5.62 (d, 1H, J ) 3.5 Hz), 6.31 (bs, 1H), 7.35 (m,
5H). 13C NMR [75 MHz, (CD3)2CO] δ: 24.2 (CH2), 27.5 (CH3),
30.5 (CH2), 34.3 (CH2), 41.3 (CH2), 49.2 (CH2), 56.8 (CH2), 62.1
(CH), 67.1 (CH2), 80.0 (CH), 83.4 (C), 90.4 (C), 98.7 (C), 107.5
(CH), 114.9 (C), 129.2-139.1 (CH), 158.2 (CO), 179.2 (CO). MS
(ES+) m/z: 560.1 (M + Na)+. Anal. Calcd for C24H31N3O9S: C,
53.62; H, 5.81; N, 7.82. Found: C, 52.58; H, 5.49; N, 8.16.
(1R,2R,6R,8R,12S,14S)-12-Carboxyethyl-10,13-diaza-4,4-
dimethyl-16,16-dioxide-11-oxo-3,5,7,17-tetraoxa-16-thio-
pentacyclo[9.6.0.02-6.01-14.010-14]heptadecane (31). A solution of
27 (0.1 g, 0.21 mmol) in methanol (10 mL) containing Pd/C (10%)
(0.010 g) was hydrogenated under atmospheric hydrogen pressure
at 40 °C for 4 h. The reaction mixture was filtered, and the filtrate
was evaporated to dryness under reduced pressure. The residue was
purified by CCTLC on the chromatotron using dichloromethane/
(1R,2R,6R,8R,12S,14S)-10,13-Diaza-16,16-dioxide-11-oxo-
3,5,7,17-tetraoxa-16-thio-4,4,12-trimethyl-pentacyclo-
[9.6.0.02-6.01-14.010-14]heptadecane (25). Following the general
procedure the cyclic enamine 8 was treated in situ with H-L-Ala-
OMe‚HCl (0.06 g, 0.44 mmol). The residue was purified by CCTLC
using hexane/ethyl acetate (1:1) to give 0.06 g (76%) of 25 as a
1
white solid: mp 128-130 °C. [R]20 +8.04 (c 4.15, CHCl3). H
D
NMR (300 MHz, CDCl3) δ: 1.27 (d, 3H, J ) 6.6 Hz), 1.38-1.57
(2s, 6H), 2.73 (d, 1H, J ) 5.8 Hz), 3.15 (dd, 1H, J ) 2.2 Hz, J )
13.4 Hz), 3.58 (s, 2H), 4.05 (m, 1H), 4.13 (d, 1H, J ) 13.4 Hz),
4.71 (d, 1H, J ) 2.2 Hz), 4.97 (d, 1H, J ) 3.7 Hz), 5.78 (d, 1H, J
) 3.7 Hz). 13C NMR (75 MHz, CDCl3) δ: 18.71 (CH3), 27.6-
28.4 (CH3), 47.3 (CH2), 55.2 (CH), 56.2 (CH2), 79.4 (CH), 82.8
(CH), 87.4 (C), 97.4 (C), 106.7 (CH), 114.7 (C), 175.8 (CO). MS
(ES+) m/z: 347.1 (M + H)+; 369.1 (M + Na)+. Anal. Calcd for
C13H18N2O7S: C, 45.08; H, 5.24; N, 8.09. Found: C, 45.17; H,
5.18; N, 8.25.
(1R,2R,6R,8R,12S,14S)-12-Benzyl-10,13-diaza-4,4-dimethyl-
16,16-dioxide-11-oxo-3,5,7,17-tetraoxa-16-thio-pentacyclo-
[9.6.0.02-6.01-14.010-14]heptadecane (26). Following the general
procedure the cyclic enamine 8 was treated in situ with H-L-Phe-
OMe‚HCl (0.09 g, 0.44 mmol) or with H-L-Phe-OtBut‚HCl (0.097
g, 0.44 mmol). The residue was purified by CCTLC using hexane/
ethyl acetate (1:1) to give 0.05 (40%) or 0.06 g (50%) of 26 as a
white solid: mp 65-68 °C. [R]20D +1.16 (c 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3) δ: 1.38-1.57 (2s, 6H), 2.51 (d, 1H, J ) 5.6
Hz), 2.63 (m, 1H), 3.12 (m, 2H), 3.53 (d, 2H, J ) 13.7 Hz), 4.18
(m, 2H), 4.63 (d, 1H, J ) 2.4 Hz), 4.91 (d, 1H, J ) 3.7 Hz), 5.23
(d, 1H, J ) 3.7 Hz), 7.23 (m, 5H). 13C NMR (75 MHz, CDCl3) δ:
27.4 (CH3), 38.8 (CH2), 47.1 (CH2), 56.1 (CH2), 61.2 (CH), 79.1
(CH), 82.9 (CH), 87.5 (CH), 97.1 (C), 106.6 (CH), 114.6 (C),
127.5-137.5 (CH), 173.8 (CO). MS (ES+) m/z: 423.1 (M + H)+,
m/z: 445.1 (M + Na)+. Anal. Calcd for C19H22N2O7S: C, 54.02;
H, 5.25; N, 6.63. Found: C, 54.18; H, 5.13; N, 6.72.
(1R,2R,6R,8R,12S,14S)-12-Benzyloxycarbonylmethyl-10,13-
diaza-4,4-dimethyl-16,16-dioxide-11-oxo-3,5,7,17-tetraoxa-16-
thio-pentacyclo[9.6.0.02-6.01-14.010-14]heptadecane (27). Follow-
ing the general procedure the cyclic enamine 8 was treated in situ
with H-L-Asp-(OBn)-OBn‚HCl (0.21 g, 0.44 mmol). The residue
was purified by CCTLC using dichloromethane/methanol (10:1)
to give 0.04 g (63%) of 27 as a white solid: mp 82-85 °C. [R]20
D
+32.5 (c 0.4, CHCl3). 1H NMR (300 MHz, MeOD) δ: 1.38-1.57
(2s, 6H), 2.18 (m, 1H), 2.61 (dd, 1H, J ) 4.1 Hz, J ) 16.6 Hz),
3.28 (dd, 1H, J ) 2.2 Hz, J ) 13.4 Hz), 3.68 (m, 3H), 3.95 (d, 1H,
J ) 6.1 Hz), 4.20 (m, 1H), 4.42 (d, 1H, J ) 2.4 Hz), 4.65 (d, 1H,
J ) 3.7 Hz), 4.84 (d, 1H, J ) 12.3 Hz), 4.93 (d, 1H, J ) 12.3 Hz),
5.43 (d, 1H, J ) 3.7 Hz), 7.15 (m, 5H). 13C NMR (75 MHz, MeOD)
δ: 27.9-28.1 (CH3), 39.9 (CH2), 49.7 (CH2), 55.6 (CH2), 58.1
(CH), 68.5 (CH2), 80.9 (CH), 84.6 (CH), 89.9 (C), 98.7 (C), 108.4
(CH), 115.9 (C), 128.8-138.1 (CH), 173.3 (CO), 177.9 (CO). MS
methanol (10:1) to give 0.08 g (70%) of 31 as a white solid: mp
1
132-135 °C. [R]20 +52.7 (c 0.5, MetOH). H NMR [300 MHz,
D
(CD3)2CO] δ: 1.32-1.58 (2s, 6H), 2.34 (dd, 1H, J ) 9.8 Hz, J )
7234 J. Org. Chem., Vol. 71, No. 19, 2006

A NoVel Carbohydrate To AchieVe Skeletal DiVersity
17.1 Hz), 2.82 (dd, 1H, J ) 3.4 Hz, J ) 17.1 Hz), 3.55 (dd, 1H, J
) 2.4 Hz, J ) 13.4 Hz), 3.98 (d, 1H, J ) 13.4 Hz), 4.12 (d, 1H, J
) 13.9 Hz), 4.23 (d, 1H, J ) 13.9 Hz), 4.46 (m, 1H), 4.72 (d, 1H,
J ) 2.4 Hz), 5.05 (d, 1H, J ) 3.7 Hz), 5.78 (d, 1H, J ) 3.7 Hz),
13C NMR [75 MHz, (CD3)2CO] δ: 27.4 (CH3), 39.1 (CH2), 49.3
(CH2), 55.4 (CH2), 57.2 (CH), 80.6 (CH), 84.1 (CH), 89.2 (C),
98.8 (C), 107.4 (CH), 114.8 (C), 173.3 (CO), 176.4 (CO). MS
(ES+) m/z: 391.1 (M + H)+. Anal. Calcd for C14H18N2O9S: C,
43.07; H, 4.65; N, 7.18. Found: C, 43.24; H, 4.53; N, 7.36.
(1R,2R,6R,8R,15S)-10,14-Aza-4,4-dimethyl-17,17-dioxide-11-
oxo-3,5,7,18-tetraoxa-17-thio-pentacyclo[10.6.0.02-6.01-15.010-15]-
octadecane (32) and (1R,2R,6R,8R,15S)-10,14-Aza-4,4-dimethyl-
11-oxo-1-mesyloxy-3,5,7-trioxa-tetracyclo[7.6.0.02-6.010-15]-
pentadecane (33). Following the general procedure the cyclic
enamine 8 was treated in situ with â-Ala-OMe‚HCl (0.06 g, 0.44
mmol). The residue was purified by CCTLC using hexane/ethyl
acetate (1:1). The fastest moving fractions gave 0.02 g (20%) of
(CdN), 168.5 (CO). MS (ES+) m/z: 349.1 (M + H)+. Anal. Calcd
for C13H20N2O7S: C, 44.82; H, 5.79; N, 8.04. Found: C, 44.95;
H, 5.64; N, 8.14.
(1R,2R,6R,8R)-10-Aza-11-N,N-benzyloxybutylamino-4,4-
dimethyl-1-mesyloxy-3,5,7-trioxa-tricyclo[6.3.0.02-6]-undec-10-
ene (34). Following the general procedure the cyclic enamine 8
was treated in situ with H-δ-aminovaleric-(OBn)‚pTos (0.09 g, 0.44
mmol). The residue was purified by CCTLC using hexane/ethyl
acetate (1:1) to give 0.03 g (35%) of 34 as a yellow solid: mp
77-79 °C. [R]20 +27.0 (c 0.1, CHCl3). 1H NMR [300 MHz,
D
CDCl3] δ: 1.33-1.51 (2s, 6H), 1.53-1.82 (m, 4H), 2.38 (m, 2H),
3.19 (s, 3H), 3.23 (m, 2H), 3.68 (d, 1H, J ) 15.4 Hz), 3.79 (dd,
1H, J ) 3.3 Hz, J ) 15.4 Hz), 4.65 (d, 1H, J ) 3.3 Hz), 4.84 (d,
1H, J ) 3.7 Hz), 5.13 (s, 2H), 5.82 (d, 1H, J ) 3.7 Hz), 6.23 (bs,
1H), 7.35 (m, 5H). 13C NMR (75 MHz, CDCl3) δ: 22.4 (CH2),
27.5 (CH3), 28.2 (CH2), 34.1 (CH2), 40.6 (CH3), 43.3 (CH2), 58.1
(CH2), 66.6 (CH2), 80.1 (CH), 88.7 (CH), 98.7 (C), 106.9 (CH),
114.2 (C), 129.2-139.4 (CH), 159.7 (CdN), 173.6 (CO). MS
(ES+) m/z: 483.1 (M + H)+. Anal. Calcd for C22H30N2O8S: C,
54.76; H, 6.27; N, 5.81. Found: C, 54.84; H, 6.12; N, 5.69.
32 as a white solid: mp 75-77 °C. [R]20 +84.7 (c 0.8, CHCl3).
D
1H NMR (300 MHz, CDCl3) δ: 1.42-1.63 (2s, 6H), 2.54 (m, 2H),
2.65 (bs, 1H, NH), 3.13-3.52 (m, 5H), 3.78 (d, 1H, J ) 13.4 Hz),
4.63 (dd, 1H, J ) 5.7 Hz, J ) 8.1 Hz), 4.92 (d, 1H, J ) 3.7 Hz),
5.82 (d, 1H, J ) 3.7 Hz). 13C NMR [75 MHz, CDCl3] δ: 27.6
(CH3), 31.6 (CH2), 39.9 (CH2), 47.3 (CH2), 52.1 (CH2), 79.3 (CH),
80.4 (CH), 84.1 (C), 98.4 (C), 106.1 (CH), 114.4 (C), 166.7 (CO).
MS (ES+) m/z: 347.1 (M + H)+. Anal. Calcd for C13H18N2O7S:
C, 45.08; H, 5.24; N, 8.09. Found: C, 45.18; H, 5.44; N, 8.29.
From the slowest moving fractions 0.02 g (25%) of 33 was
Acknowledgment. We thank Susana Ruiz for her excellent
technical assistance. We thank the Ministery of Education of
Spain for a grant to M.-C.B., and Consejo Superior de
Investigaciones Cient´ıficas for an I3P contract to E.Q. The
Spanish MEC (project SAF2003-07219-C02-01), and the Eu-
ropen Commission (Projects QLK2-CT-2000-0291 and HPAW-
CT-2002-90001) are also acknowledged for financial support.
isolated as a white solid: mp 78-80 °C. [R]20 +20.7 (c 0.8,
D
CHCl3). 1H NMR (300 MHz, CDCl3) δ: 1.41-1.65 (2s, 6H), 2.53
(m, 2H), 3.22 (s, 3H), 3.83 (m, 4H), 4.82 (d, 1H, J ) 3.4 Hz), 5.16
(d, 1H, J ) 3.7 Hz), 5.8 (d, 1H, J ) 3.7 Hz). 13C NMR (75 MHz,
CDCl3) δ: 27.3 (CH3), 31.2 (CH2), 40.6 (CH3), 45.8 (CH2), 47.4
(CH2), 78.4 (CH), 80.9 (CH), 90.4 (C), 105.6 (CH), 114.6 (C), 154.3
Supporting Information Available: General experimental
methods and NMR procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0609531
J. Org. Chem, Vol. 71, No. 19, 2006 7235