Novel Chimeric Scaffolds to Extend the Exploration of Receptor Space: Hybrid β-D-Glucose-Benzoheterodiazepine Structures for Broad Screening. Effect of Amide Alkylation on the Course of Cyclization Reactions

Article abstract of DOI:10.1021/jo0352068

New molecular platforms which are hybrids of two scaffolds-namely, β-D-glucose and benzodiazepine, each able to bind several proteins-were designed, synthesized and functionalized to serve as probes for broad biological screening. Herein, we describe the syntheses and chemical properties of these novel chimeric scaffolds. Attempted cyclization of the functionalized analogues (-)-96 and (-)-97 afforded the corresponding dimers (-)-98 and (-)-99, respectively, under a variety of reaction conditions, even at concentrations of only 0.001 N. Consideration of factors affecting the conformation of amide bonds and their effects on cyclization reactions led us to alkylate the amide bond. As expected, the cyclization of the N-methyl derivative (-)-110 afforded exclusively the unimolecular cyclization product (+)-111. These compounds are only now undergoing broad screening and represent therefore at present a "prospecting library".

Full text of DOI:10.1021/jo0352068

Novel Ch im er ic Sca ffold s to Exten d th e Exp lor a tion of Recep tor
Sp a ce: Hybr id â-D-Glu cose-Ben zoh eter od ia zep in e Str u ctu r es for
Br oa d Scr een in g. Effect of Am id e Alk yla tion on th e Cou r se of
Cycliza tion Rea ction s
Le¨ıla Abrous,† Patrick A. J okiel,‡ Sarah R. Friedrich,§ J ohn Hynes, J r.,|
Amos B. Smith, III,* and Ralph Hirschmann*
University of Pennsylvania, Department of Chemistry, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323
rfh@sas.upenn.edu
Received August 16, 2003
New molecular platforms which are hybrids of two scaffoldssnamely, â-D-glucose and benzodi-
azepine, each able to bind several proteinsswere designed, synthesized and functionalized to serve
as probes for broad biological screening. Herein, we describe the syntheses and chemical properties
of these novel chimeric scaffolds. Attempted cyclization of the functionalized analogues (-)-96 and
(-)-97 afforded the corresponding dimers (-)-98 and (-)-99, respectively, under a variety of reaction
conditions, even at concentrations of only 0.001 N. Consideration of factors affecting the conformation
of amide bonds and their effects on cyclization reactions led us to alkylate the amide bond. As
expected, the cyclization of the N-methyl derivative (-)-110 afforded exclusively the unimolecular
cyclization product (+)-111. These compounds are only now undergoing broad screening and
represent therefore at present a “prospecting library.”
In tr od u ction
then led to a ligand at the latter receptor with an IC50 of
10 nM. Remarkably, a closely related congener of the
original glucoside was found to block a protein-protein
interaction.6
The design and synthesis of novel molecular platforms
which can project substituents into multiple regions of
receptor space remains an important goal in the search
for new leads for drug discovery. Platforms that have
been called promiscuous because of their ability to bind
multiple protein targets include the so-called tricyclic
scaffold1 and the steroids. Benzodiazepines have at-
tracted much attention because of their ability to bind
not only G-protein coupled receptors, but also enzymes
such as farnesyl transferase, reverse transcriptase, and
γ-secretase,2 and they can modulate ion channels.3
Similarly, research carried out in our laboratories has
demonstrated that the â-D-glucose scaffold can also bind
diverse proteins by virtue of radial symmetry.4 Thus, a
fully substituted â-D-glucose was designed to bind a
receptor of the peptide hormone somatostatin-14 as an
agonist. Lead optimization, a modest effort by industrial
standards, led to a KI of 53 nM.5 Without any formal
screening, the same lead was found serendipitously also
to be a â2 andrenergic blocking agent and a substance P
antagonist at the NK-1 receptor. Synthesis of analogues
(2) Farnesyl transferase: (a) Angibaud, P. R.; Venet, M. G.; Poncelet,
V. S.; World Patent WO 0242296, May 30, 2002. (b) Ding, C. Z.; Hunt,
J . T.; Leftheris, K.; Bhide, R. S. World Patent WO 0181322, November
1, 2001. (c) Ding, C. Z.; Hunt, J . T.; Leftheris, K.; Bhide, R. S. World
Patent WO 9918951, April 22, 1999. (d) Schmittberger, T.; Waldmann,
H. Synlett 1998, 574. (e) Graham, S. L.; Anthony, N. J .; Wai, J . S.
World Patent WO 9736879, October 9, 1997. (f) Ding, C. Z.; Hunt, J .
T.; Kim, S.; Mitt, T.; Bhide, R. S.; Leftheris, K. World Patent WO
9730992, August 28, 1997. (g) Graham, S. L.; Anthony, N. J .; Wai, J .
S. World Patent WO 9532191, November 30, 1995. (h) Marsters, J .
C., J r.; Brown, M. S.; Crowley, C. W.; Goldstein, J . L.; J ames, G. L.;
Macdowell, R. S.; Oare, D.; Rawson, T. E.; Reynolds, M.; Somers, T.
G. World Patent WO 9426723, November 24, 1994. (i) Ripka, W. C.;
De Lucca, G. V.; Bach, A. C., II; Pottorf, R. S.; Blaney, J . M.
Tetrahedron 1993, 49, 3593. Reverse transcriptase: (j) Hargrave, D.
K.; Proudfoot, J . R.; Grozinger, K. G.; Cullen, E.; Kapadia, S. R.; Patel,
U. R.; Fuchs, V. U.; Mauldin, S. C.; Vitous, J .; Behnke, M. L.; Klunder,
J . M.; Pal, K.; Skiles, J . W.; McNeil, D. W.; Rose, J . M.; Chow, G. C.;
Skoog, M. T.; Wu, J . C.; Schmidt, G.; Engel, W. W.; Eberlein, W. G.;
Saboe, T. D.; Campbell, S. J .; Rosenthal, A. S.; Adams, J . J . Med. Chem.
1991, 34, 2231. (k) Merluzzi, V. J .; Hargrave, K. D.; Labadia, M.;
Grozinger, K.; Skoog, M.; Wu, J . C.; Shih, C.-K.; Eckner, K.; Hattox,
S.; Adams, J .; Rosenthal, A. S.; Faanes, R.; Eckner, R. J .; Koup, R. A.;
Sullivan, J . L. Science 1990, 250, 1411-1413. γ-Secretase: (l) Church-
er, I.; Nadin, A. J .; Owens, A. P. World Patent WO 0230912, April 18,
2002.
† Present address: Wyeth-Ayerst Research, Pearl River, NY 10965.
‡ Present address: Pharmacopeia, Inc. P.O. Box 5350 Princeton, NJ
08543.
(3) Salata, J . J .; J urkiewicz, N. K.; Wang, J .; Evans, B. E.; Orme,
H. T.; Sanguinetti, M. C. Mol. Pharmacol. 1998, 53, 220.
(4) (a) Liu, J .; Underwood, D. J .; Cascieri, M. A.; Rohrer, S. P.;
Cantin, L.-D.; Chicchi, G.; Smith, A. B., III; Hirschmann, R. J . Med.
Chem. 2000, 43, 3827-3831. (b) Hirschmann, R.; Nicolaou, K. C.;
Piettranico, S.; Leahy, E. M.; Arison, B.; Cichy, M. A.; Spoors, P. G.;
Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith, A. B., III;
Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.;
Freidinger, R. M.; Cascieri, M. R.; Strader, C. D. J . Am. Chem. Soc.
1993, 115, 12550-12568. (c) McVaugh, C.; Savinov, S.; Prasad, V.;
Smith, A. B., III; Hirschmann, R. Manuscript in preparation.
§ Present address: GlaxoSmithKline Pharmaceuticals, Collegeville,
PA 19426.
| Present address: Bristol-Myers Squibb Pharmaceutical Research
Institute, Princeton, NJ 08453.
(1) (a) Arie¨ns, E. J .; Beld, A. J .; Rodrigues de Miranda, J . F.;
Simonis, A. M. In The Receptors: A Comprehensive Treatise; O’Brien,
R. D., Ed.; Plenum: New York, 1979; pp 33-91. (b) Davis, M. A. Ann.
Rep. Med. Chem. 1968, 2, 13.
10.1021/jo0352068 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003
280
J . Org. Chem. 2004, 69, 280-302

Novel Chimeric Scaffolds
Scaffolds such as those mentioned above are useful,
because adequate specificity and potency can generally
be achieved efficiently via modulation of the sub-
stituents1-5 as long as the desired and the unwanted
biological effects are the result of the interaction of the
ligand with different macromolecules. Indeed, Nature
herself allows a degree of promiscuity in the physiologic
compounds which she releases in humans.7
Given the biological relevance of the â-D-glucose and
benzodiazepine scaffolds, the hybrid scaffold described
herein lends itself well to the development of “prospect-
ing” small molecule libraries, a descriptor coined by
Bartlett.8
Sca ffold Design . In a preliminary report,9 we de-
scribed the design and synthesis of hybrids of two
promiscuous scaffolds: benzoheterodiazepines and â-D-
glucose. While the molecular bases for the interaction of
a given platform with diverse receptors has not been
defined, we speculate that aromaticity and nonplanarity
are structural elements common to such platforms.10 We
refer to such structural features as “elements of privi-
lege”. The benzodiazepine portion of the hybrid scaffold
contributes aromaticity and nonplanarity, and the â-D-
glucose component adds a third ring as well as chiral
centers via the C1, C4, and C6 positions of the sugar.
These centers provide points of attachment for diverse
side chains, facilitating their projection into areas of
receptor space previously inaccessible to the classical
benzodiazepines. Herein we report in detail the design
and synthesis of the trans-fused benzodiazepine-sugar
hybrids (+)-1 and (-)-2, the trans-fused benzoxazepine-
sugar hybrid (-)-3, the 2- and 4-pyridyldiazepine-sugar
hybrids (-)-4 and (-)-5, and the cis-fused benzodi-
azepine-sugar hybrids 6 and (-)-7 (Scheme 1). Com-
SCHEME 1
F IGURE 1. Minimized structures of (-)-2, (-)-7, and diaz-
epam.
emphasis placed on functionalizing the carbohydrate
hydroxyls and the aniline and lactam nitrogens of the
benzodiazepine scaffold. The relative reactivities of these
nucleophilic sites are discussed. Monosaccharides, as
(5) Prasad, V.; Birzin, E. T.; McVaugh, C. T.; van Rijn, R. D.; Rohrer,
S. P.; Chicchi, G.; Underwood, D. J .; Thornton, E. R.; Smith, A. B., III;
Hirschmann, R. J . Med. Chem. 2003, 46, 1858-1869 and references
cited.
(6) Prasad, V. Ph.D. Dissertation, University of Pennsylvania, 2001.
We are indebted to Dr. Carl DeCicco, BristolMyers Squibb, for this
information.
(7) Thus, the target of cortrisol is the glucocorticoid receptor, but it
activates also the mineralocorticoid receptor. The reverse is true of
aldosterone, which targets primarily the latter receptor. Interestingly,
the manmade 1-dehydrocortisol (prednisolone) is more selective than
cortisol.
parison of the minimized structures11 of (-)-2, (-)-7, and
the benzodiazepine-derived drug Valium (Figure 1) sug-
gests that the former have the potential for increased
sampling of receptor space relative to the classical
benzodiazepines. In addition, we describe our efforts
toward the controlled introduction of functionality, with
J . Org. Chem, Vol. 69, No. 2, 2004 281

Abrous et al.
previously pointed out,4b represent an attractive building
block, due to the ready availability of diastereomers.
Thus, we have usefully employed the L-mannose12 and
the L-glucose scaffolds.13 Broad-screen biological evalu-
ation of functionalized targets is currently in progress;14
the results of these binding studies will be reported in
due course.
SCHEME 3
Resu lts a n d Discu ssion
Sca ffold Syn th esis. Gen er a l Str a tegy. Our ap-
proach to the various tricyclic hybrids entails the union
of two coupling partners: a suitably functionalized amino
sugar is acylated with a benzoic acid derivative followed
by an intramolecular SNAr reaction to generate the
benzoheterodiazepine ring. In the following sections, we
describe the synthesis of the requisite amino sugar
intermediates and their conversion to the tricyclic hy-
brids.
Syn th esis of 2-Am in o-â-glycoside Bu ildin g Blocks.
â-Glycosid es (+)-11, (+)-13, a n d (-)-14. Amino sugar
(+)-11, an intermediate in the synthesis of the trans-
fused benzodiazepine-sugar hybrid (+)-1, was prepared
in six steps from the known triol (-)-8.15 Treatment of
(-)-8 (Scheme 2) with 2,2-dimethoxypropane and
SCHEME 2
Selectride to furnish alcohol (-)-10 in 67% yield for the
two steps with a dr of 99:1 in favor of the C(2), C(3) cis
isomer. Activation of the C(3) hydroxyl as the mesylate
(MsCl, TEA, DCM) followed by treatment with sodium
azide at 100 °C led to the azide. The trifluoroacetyl
protecting group was then removed by methanolysis to
provide the amino sugar building block (+)-11 in 83%
yield for the three steps.
Similarly, amino sugar (+)-13, the required building
block for the synthesis of the cis-fused benzodiazepine-
sugar hybrid (-)-7, was prepared in three steps from
compound (-)-9 in 57% overall yield (Scheme 3), while
amino sugar (-)-14 was prepared in 94% yield from (-)-9
via methanolysis of the trifluoroacetamide functionality.
Syn th esis of Tr a n s-Fu sed Tr icyclic Hybr ids: Ben -
zod ia zep in e-Su ga r (+)-1, Ben zoxa zep in e-Su ga r
(-)-3, a n d th e 2- a n d 4-P yr id yld ia zep in e-Su ga r s
(-)-4 a n d (-)-5. With the requisite amino sugars (+)-
11 and (-)-14 in hand, we constructed a variety of trans-
fused tricyclic hybrids as depicted in Scheme 4 and Table
1. Our initial attempt to elaborate the chimeric 1,4-
benzodiazepin-5-one (-)-2 involved acylation of (+)-11 by
15 to afford the amide 19 in 93% yield. Subsequent azide
reduction, using the Staudinger protocol,16 provided
amine 20. Since attempts to effect ring closure of 20 were
unsuccessful using either metal catalysis or heating, we
explored the cyclization of congener (-)-22, incorporating
an activating p-nitro group. Toward this end, amide (+)-
21, prepared in 95% yield via acylation of (+)-11 (EDAC,
16, DCM, 0 °C), followed by Staudinger reduction, led to
(-)-22 in 74% yield. Cyclization of (-)-22 now proceeded
in 70% yield by heating in dilute acetonitrile to provide
(+)-1. The dimer (+)-28 was formed in appreciable
amounts, when the reaction was carried out at concen-
p-toluenesulfonic acid (pTSA) in DMF at reflux gave (-)-9
in 88% yield. Oxidation of the remaining C(3) hydroxyl
(Ac2O, DMSO) provided the corresponding ketone. Di-
astereoselective reduction was then effected using L-
(8) Spaller, M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A. Curr.
Opin. Chem. Biol. 1997, 1, 47-53.
(9) Abrous, L.; Hynes, J ., J r.; Friedrich, S. R.; Smith, A. B., III;
Hirschmann, R. Org. Lett. 2001, 3, 1089-1092.
(10) Hirschmann, R.; Savinov, S.; Angeles, A.; Smith, A. B., III.
Manuscript in preparation.
(11) Minimized structures were obtained by Monte Carlo confor-
mational search using MacroModel v6.0, (AMBER force field, PRCG
algorithm, solvent ) H2O).
(12) Hirschmann, R.; Hynes, J ., J r.; Cichy-Knight, M. A.; van Rijn,
R. D.; Sprengeler, P. A.; Spoors, P. G.; Shakespeare, W. C.; Pietranico-
Cole, S.; Barbosa, J .; Liu, J .; Yao, W.; Rohrer, S.; Smith, A. B., III. J .
Med. Chem. 1998, 41, 1382-1391.
(13) Hynes, J ., J r. Ph.D. Dissertation, University of Pennsylvania,
1996.
(14) We are indebted to Dr. Carl DeCicco, then at DuPont Phar-
maceuticals, for helpful discussions.
(15) Midoux, P.; Grivet, J . P.; Delmotte, F.; Monsigny, M. Biochem.
Biophys. Res. Comm. 1984, 119, 603.
(16) Staudinger, H.; Meyer, J . Helv. Chim. Acta 1919, 2, 635.
282 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
SCHEME 4
The corresponding benzoxazepine-sugar scaffold was
prepared in an analogous fashion. Cyclization of (-)-23
(Scheme 4) to establish the benzoxazepine ring system
led to extensive dimerization, even under significantly
higher dilution than the cyclization of (-)-22. Basic
conditions (CsF, DMF, 100 °C) resulted in the formation
of the tricyclic hybrid (-)-3 in 38% yield. The dimer (+)-
29 was formed in 25% yield. Alternatively, treatment
with potassium carbonate in DMF at 25 °C gave exclu-
sively (+)-29 in 75% yield. A rationalization for the
formation of such macrocyclic structures is provided in
the final section of this account. Single-crystal X-ray
analysis again confirmed the structure of (-)-3.
In a similar fashion, the syntheses of (-)-4 and (-)-5
(Scheme 4) were achieved from (-)-25 and (-)-27 in 36%
and 71% yield, respectively. Again, CsF was required to
effect cyclization. Presumably, the reaction pathway
involves an initial ipso-substitution17 of the aryl chloride
to give the more reactive aryl fluoride.
Syn th esis of th e Cis-F u sed Ben zod ia zep in e-Su ga r
Tr icyclic Hybr id (-)-7. Our initial approach to a cis-
fused sugar-benzodiazepine is depicted in Scheme 5.
Azide (-)-30 was prepared in 99% yield by coupling
amino sugar (+)-13 with acid 16 exploiting the sequence
illustrated in Table 1. Staudinger reduction of the azide
using trimethylphosphine at -78 °C afforded (-)-31 in
43% yield.18 Nitroamide (-)-31, however, failed to yield
6 under either neutral (MeCN, ∆) or basic (NaH, THF)
conditions.
We therefore turned to the approach illustrated in
Scheme 6, employing imine formation followed by reduc-
tion. The requisite cyclization precursor (-)-32 was
prepared via acylation of the primary amine of (-)-14,
followed by oxidation of the C(3) hydroxyl (Ac2O, DMSO);
the overall yield of (-)-32 was 53%. Palladium-catalyzed
hydrogenolysis afforded the free amine which underwent
intramolecular condensation to give the imine intermedi-
ate. Hydrogenation resulted in a 20% yield of the desired
cis-fused tricycle (-)-7 accompanied by 5% of the trans-
fused congener (-)-2.
Sca ffold F u n ction a liza tion : (1) Ester ifica tion of
th e P yr a n ose Hyd r oxyls. The pyranose diols (+)-33
and (+)-34 comprise powerful synthons that permit
controlled derivatization. We first examined functional-
ization by acylation, given the abundance of effective
methods for acylation of alcohols and amines. While the
resulting esters would be potentially labile in vivo,
congeners that prove to be interesting on the basis of in
vitro screening could be converted into more stable
derivatives. A variety of acyl substituents were effectively
introduced selectively at the primary hydroxyl. For
example, acetonide (+)-1 was treated with 5% hydrochlo-
ric acid in THF to afford the benzodiazepine-sugar diol
(+)-33 in 99% yield (Table 2). Acylation of the primary
hydroxyl of (+)-33 with pyrazinoyl chloride19 then fur-
nished the pyrazine ester (+)-35 in 72% yield. In general,
use of collidine gave higher selectivity for the primary
(17) Finger, G. C.; Kruse, C. W. J . Am. Chem. Soc. 1956, 78, 6034.
(18) See the Supporting Information for more details.
(19) Prepared by reaction of commercially available pyrazine-2-
carboxylic acid with thionyl chloride in benzene at reflux and purified
by sublimation. Cynamon, M. H.; Gimi, R.; Gyenes, F.; Sharpe, C. A.;
Bergmann, K. E.; Han, H. J .; Gregor, L. B.; Rapolu, R.; Luciano, G.;
Welch, J . T. J . Med. Chem. 1995, 38, 3902.
trations above 0.005 M (Table 1). The structure of (+)-1
was confirmed by single-crystal X-ray analysis.
J . Org. Chem, Vol. 69, No. 2, 2004 283

Abrous et al.
TABLE 1. Cou p lin g of Am in o Su ga r s w ith F u n ction a lized Ben zoic a n d Nicotin ic Acid Der iva tives a n d Su bsequ en t
Cycliza tion
entry
amino sugar
coupling conditions
coupling product (%)
cyclization conditions
MeCN, ∆
MeCN, ∆ (0.0025 M)
MeCN, ∆ (0.005 M)
cyclization product (%)
1
2
3
(+)-11
15, TEA, DCM, 0 °C
16, EDAC, DCM, 0 °C
19 (93)
(+)-21 (95)
NR
(+)-1 (70)
(+)-1 (52)
(+)-28 (>5)
(+)-1 (42)
(+)-28 (>10)
(+)-1 (30)
(+)-28 (>20)
(-)-3 (38)
(+)-29 (25)
(+)-29 (75)
(-)-4 (36)
4
5
6
MeCN, ∆ (0.01 M)
MeCN, ∆ (0.02 M)
(-)-14
(+)-11
16, DMTMM, THF, r.t.
(-)-23 (93)
CsF, DMF, 100 °C (0.01 M)
7
8
K2CO3, DMF, rt
CsF, DMF, 100°C
(c ) 0.01 M)
CsF, DMF, 75 °C
(c ) 0.01 M)
17, DIPEA, DCM, 0°C
18, DCC, DCM, 0°C
(-)-24 (99)
(-)-26 (33)
9
(-)-5 (71)
TABLE 2. F u n ction a liza tion of Diols (+)-33 a n d (+)-34
entry
diol
conditions
product (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(+)-33
(+)-33
(+)-33
(+)-33
(+)-34
(+)-34
(+)-34
(+)-33
(+)-33
(+)-33
(+)-34
(+)-33
(+)-33
(+)-33
pyrazinoyl chloride (1 equiv), collidine, -40 °C
acetyl chloride (1 equiv), collidine, -40 °C
acetyl chloride (3 equiv), TEA, 0°
2-furoyl chloride (1 equiv), collidine, -40 °C
acetyl chloride (5 equiv), TEA, DCM, 0 °C
benzoyl chloride (1 equiv), collidine, -40 °C
nicotinic acid, BOP, HOAt, DMAP, DIPEA, DMF
nicotinic acid (4 equiv), DIPCDI, HOAt, NMP, 60 °C
3-pyridyl carboxaldehyde, pTSA, DMF, ∆
p-anisaldehyde, ZnCl2, sonication
benzaldehyde dimethyl acetal, pTSA, DMF, ∆
NaH, MeI (3 equiv), DMF
3-picolyl chloride‚HCl, NaH, TBAI, DMF-THF
(1) (Bu2SnO)n, benzene, ∆; (2) BnBr, TBAI, benzene, ∆
(+)-35 (72)
(+)-36 (89)
(-)-37 (85)
(-)-38 (71)
(-)-40, (-)-41, (-)-42 (82)
(-)-47 (28)
(-)-48 (42)
(+)-53 (70)
(-)-64 (74)
(-)-65 (88)
(-)-66 (98)
(+)-67 (54)
(-)-68 (24)
(-)-70 (82)
hydroxyl than did Hu¨nig’s base.20 The same protocol was
used to prepare the benzodiazepine-sugar derived mono-
acetyl (+)-36 (89%) and 2-furoyl (-)-38 (71%) derivatives.
Monoacetate (+)-33 was then converted to the diacety-
lated congener (-)-37 in 85% yield on exposure to an
additional equivalent of acetyl chloride. Similarly, furoyl
ester (-)-38 was converted via treatment with an ad-
(20) Ishihara, K.; Kurihara, H.; Yamamoto, H. J . Org. Chem. 1993,
58, 3791.
284 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
SCHEME 5
SCHEME 6
ditional equivalent of 2-furoyl chloride to the difuroyl
derivative (+)-39 in 78% yield. Of note, the aniline
nitrogen was not acylated under these conditions. This
series of constructs appends pyrazine and furan hetero-
cycles to the scaffold, which may differ in their ability to
bind diverse receptors.5
We also investigated the treatment of the benzox-
azepine-sugar diol (+)-34 [obtained in 99% yield via
hydrolysis of the acetonide protecting group in (-)-3] with
an excess of acetyl chloride (5 equiv) in the presence of
triethylamine (Table 2). A mixture of the mono-, di-, and
triacetylated derivatives (-)-40, (-)-41, and (-)-42,
respectively, was obtained in a combined yield of 82%.
Having demonstrated the chemoselective introduction
of diverse acyl groups at the primary hydroxyl of diols
(+)-33 and (+)-34, we undertook the synthesis of a series
of mixed diacyl derivatives 43-46 (Figure 2).21 Concerned
that these targets might be prone to acyl migration, the
C-6 monobenzoyl compound (-)-47 (Table 2) was sub-
jected to the conditions employed for the second acylation
(pyridine, 25 °C, 17 h). No migration of the benzoyl
substituent was observed. Encouraged by this result, we
proceeded with the synthesis of mixed diacyl derivatives.
We were particularly interested in the incorporation of
side chains bearing basic heterocycles, namely pyridine,
as these constructs would have the potential to interact
with biological receptors via such noncovalent inter-
actions as hydrogen bonding and salt bridge formation.
Moreover, we have recently demonstrated significant
differences between benzene and pyridine rings on π-π
interactions.5 Unfortunately, all attempts to introduce a
nicotinoyl substituent at the C(4) hydroxyl of (-)-47
under diverse conditions proved unsuccessful, leading
only to the recovery of starting material.
derivatives employing more forcing conditions. To this
end, diol (+)-34 was subjected to a series of vigorous
coupling protocols (BOP, HOAt, DIPEA, cat. DMAP, and
DMF). Pleasingly, only the C(6) hydroxyl was acylated
furnishing the mononicotinate (-)-48 in a moderate yield
(42%). We speculate that the aniline functionality in (+)-
33 may participate in the acylation of the C-4 hydroxyl.
Due to the difficulties encountered in the introduction
of a second acyl substituent onto (-)-47, along with the
problem of extensive dimer formation in the synthesis
of (-)-3, we focused our efforts on the preparation of
analogues 49-52 (Figure 2) which contain the benzodi-
azepine scaffold. Introduction of the nicotinoyl substitu-
ent at C-6 again proved challenging. No reaction was
observed employing the coupling conditions used suc-
cessfully in the preparation of (-)-47 and (-)-48. More-
over, treatment of (+)-33 with nicotinic anhydride pre-
pared in situ [nicotinic acid, EDCI, HOAt, DMF; then
(+)-33, DMAP] yielded only the recovered diol. However,
the coupling conditions developed by Rich et al.22 for the
preparation of hindered tertiary amides [nicotinic acid
(4 equiv), DIPCDI, HOAt, NMP, 60 °C], led to acylation
Since the selective introduction of a nicotinoyl sub-
stituent onto the C(4) hydroxyl was unsuccessful, we
sought to generate a mixture of C(4) and C(6) nicotinate
(21) In addition to providing a diverse collection of compounds for
broad screening, exploring the synthesis of mixed diacyl derivatives
will address the important chemical question of stability to acyl
migration.
J . Org. Chem, Vol. 69, No. 2, 2004 285

Abrous et al.
SCHEME 7
F IGUR E 2. Proposed mixed diacyl derivatives 43-46 and
49-52.
of both hydroxyls, affording (+)-53 (Table 2) in 70% yield.
Unfortunately, treatment of (+)-33 with 1 equiv of
nicotinic acid, isonicotinic acid, 3-pyrrolecarboxylic acid,
and 3-tryptophancarboxylic acid employing the above
Rich protocol was unsuccessful.
cation of (+)-33 with p-anisaldehyde and freshly fused
zinc chloride led to (-)-65 in 88% yield. Similarly, the
benzylidene acetal (-)-66 was prepared in nearly quan-
titative yield from the corresponding oxazepine-sugar diol
(+)-34 employing transacetalization conditions (benzal-
dehyde dimethyl acetal, pTSA, DMF, ∆). Little decom-
position was observed on incubation with simulated
gastric juice at 37 °C for 2 h.24 Thus, we anticipate that
the acetal derivatives will possess adequate stability after
oral administration.
(4) Eth er Der iva tives. As noted above, the afore-
mentioned ester and acetal derivatives are potentially
labile under physiological conditions. Ether derivatives
of the pyranose hydroxyls would overcome this problem,
but chemoselectivity was expected to become a problem.
Indeed, treatment of (+)-33 with sodium hydride and
methyl iodide afforded predominantly the trimethylated
product (+)-67 (Table 2) in 54% yield. Fortunately,
introduction of substituents larger than methyl proceeded
with excellent selectivity for the hydroxyls over the
aniline nitrogen. For example, alkylation of diol (+)-33
with 3-picolyl chloride hydrochloride (1 equiv, NaH,
TBAI, DMF-THF) furnished the C-6 monoalkylated
product (-)-68, accompanied by a minor amount of the
C-4 alkylated product in a combined yield of 24%, the
(2) Der iva tiza tion via Ca r ba m a te F or m a tion . Due
to these difficulties, the reaction of diol (+)-33 with
isocyanates was explored. A variety of commercially
available isocyanates were employed leading to selective
acylation of the primary hydroxyl to furnish carbamate
derivatives 54-63 (Scheme 7). Although the reaction
with phenyl isocyanate proceeded under neutral condi-
tions to give the phenyl carbamate (+)-54 in quantitative
yield, more substituted isocyanates proved to be much
less reactive. Addition of a catalytic amount of anhydrous
ZnBr223 significantly improved the efficiency of acylation,
without compromising selectivity for the C-6 hydroxyl.
A trace amount of C-4 acylated product was isolated from
the reaction of (+)-33 with p-methoxyphenyl isocyanate.
(3) Aceta l Der iva tives. The C(4) and C(6) hydroxyls
of glucose derivatives form a single acetal with the R
substituent of the acetal equatorially disposed in the
resulting trans-fused chair conformer. Thus, acetal de-
rivatives of diols typified by (+)-33 (Scheme 7) serve as
rigid templates for the spatial projection of a variety of
functional groups. Table 2 contains a series of acetal
derivatives of the diols (+)-33 and (+)-34. The 3-pyridyl
acetal (-)-64 (Table 2) was obtained in 74% yield upon
treatment of (+)-33 with 3-pyridyl carboxaldehyde. Soni-
(22) Raman, P.; Stokes, S. S.; Angell, Y. M.; Flentke, G. R.; Rich, D.
H. J . Org. Chem., 1998, 63, 5734-5735.
(23) Berrier, J . V. Process for Preparing Carbamates. European
Patent EP0967199, 1999.
(24) Compounds (-)-64, (-)-65, and (-)-66 were incubated at 37
°C in pH 1 buffer (hydrochloric acid, Fisher Chemical Co.). Minimal
decomposition was observed by reverse phase HPLC (Zorbax SE 5911
column, 9.6 × 250 mm; 35% MeCN/H2O) after 2 h.
286 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
SCHEME 8
balance being starting material. A trace amount of the
O,O-dialkylated analogue (-)-69 was also formed and
was separable from the monoalkyl derivatives by flash
chromatography. Treatment of the monoalkylated mix-
ture with an excess (3 equiv) of 3-picolyl chloride‚HCl
then gave (-)-69 in 29% yield. No N-alkylation of the
aniline was observed. The monobenzylated secondary
alcohol (-)-70 (Table 2) was prepared in 82% yield via
alkylation of the intermediate stannylidene acetal25 of
diol (+)-33 with benzyl bromide (3 equiv) [TBAI, benzene,
∆].
(5) Der iva tiza tion of th e Nitr ogen s of th e Seven -
Mem ber ed Rin g. In addition to the sugar functional-
ization sites, the two nitrogens of the benzodiazepine ring
offer additional points for selective derivatization (Table
3). Treatment of (+)-1 with an excess of benzyl bromide
afforded the dibenzylated adduct (+)-71 in 90% yield,
along with a minor amount (5%) of the monobenzyl
derivative (+)-72. Selective debenzylation of the aniline
nitrogen in (+)-71, accompanied by hydrolysis of the
acetonide protecting group, was easily effected by treat-
ment with wet chloroform to yield (+)-73 in nearly
quantitative yield. Similarly, treatment of (+)-1 with an
excess of NaH and MeI in THF furnished the dimeth-
ylated heterocycle (+)-74 in 94% yield. On the other hand,
acylation could be achieved selectively at the more basic
aniline nitrogen. Treatment of (+)-1 with an excess of
trifluoroacetic anhydride furnished the trifluoroacet-
amide (+)-75 in 74% yield.
TABLE 3. Syn th esis of Ben zoh eter od ia zep in e
Der iva tives
followed by cyclization to establish the respective tricyclic
structure. This protocol was applied to the preparation
of analogues 84-86 (Scheme 8), containing benzyl, p-
methoxybenzyl, and 2-picolyl substituents, respectively,
on the lactam nitrogen. Thus, the C(3) hydroxyl of amino
sugar (-)-14 was protected as the TES ether to furnish
(-)-77 in 60% yield. Reductive alkylation afforded the
secondary amino sugars 78-80, which were coupled to
acid 16 in the presence of 4-(4,6-dimethoxy[1.3.5]triazin-
2-yl)-4-methylmorpholinium chloridehydrate (DMTMM)
to give the tertiary amides 81-83. Heating the latter in
dilute DMF in the presence of CsF (5 equiv) effected
cleavage of the TES ether, followed by SNAr cyclization
to furnish the alkylated tricycles 84-86. No dimer
formation was observed upon cyclization of 81-83.
(6) Der iva tiza tion via th e Ar om a tic Nitr o Gr ou p .
The aromatic nitro group was also used successfully to
introduce diversity. Reduction of the nitro group in (+)-1
(Table 3) was achieved by catalytic hydrogenation to
afford the air-sensitive aniline, which was directly sub-
jected to reductive deamination using the method of
Doyle26 [isoamyl nitrite, DMF, 40 °C] to afford (-)-2 in
42% yield for the two steps. Alternatively, exchange of
starting
entry material
conditions
product (%)
1
(+)-1
BnBr (3.1 equiv), TBAI,
THF, 0 °C
NaH, MeI (4 equiv), THF
(COCF3)2O, TEA, DCM,
0 °C
H2, 5% Pd/C, MeOH
isoamyl-ONO, DMF, 40 °C
H2, 5% Pd/C, MeOH
tert-butyl-ONO, MeCN,
CuCl2, 0 °C f rt
(+)-71 (90), (+)-72 (5)
2
3
(+)-1
(+)-1
(+)-74 (94)
(+)-75 (74)
4
5
(+)-1
(-)-3
(-)-2 (42, two steps)
(-)-76 (35, two steps)
In an alternative approach to analogues containing
diverse alkyl groups at the lactam nitrogen, we reacted
the secondary amino sugars with acid 16 (Scheme 8),
(25) (a) For a review: David, S.; Hanessian, S. Tetrahedron 1985,
41, 643. (b) Boons, G.-J .; Castle, G. H.; Clase, J . A.; Grice, P.; Ley, S.
V.; Pinel, C. Synlett 1993, 913.
J . Org. Chem, Vol. 69, No. 2, 2004 287

Abrous et al.
SCHEME 9
SCHEME 11
the nitro functionality in (-)-3 for a halogen via the
Sandmeyer reaction27 was also explored (Table 3). Cata-
lytic hydrogenation as with (+)-1, followed in turn by
diazotization [tert-butyl nitrite, MeCN, 0 °C f rt] and
treatment of the resulting diazonium species with copper
(II) chloride furnished the aryl chloride (-)-76. The
resulting aryl chlorides hold considerable potential for
further substitution via Buchwald/Hartwig chemistry.28
The lactam carbonyl represents the final site for
potential functionalization. Preparation of the corre-
sponding thiolactam from (+)-1 using Lawesson’s re-
agent29 proceeded to give (-)-87 in 43% yield after a mild
acidic workup (Scheme 9). Further elaboration of the
thiolactam can be envisioned.
Tow a r d th e Syn th esis of a Sm a ll Libr a r y of
Com p ou n d s Ba sed on th e Tr icylic Hybr id Sca ffold .
Having secured access to the tricyclic hybrids 1-7 in
which the anomeric hydroxyl is methylated and the C4
and C6 hydroxyls (sugar numbering) are protected as
acetals, we sought to construct a series of small libraries
functionalized at C1, C4, and C6. A tryptophan-mimick-
ing indole residue was chosen as the anomeric substitu-
ent (Scheme 10).
SCHEME 10
Initial efforts were directed toward the synthesis of
compound 90, as earlier efforts in our sugar peptidomi-
metics found that similar substitution of the â-D-glucose
scaffold led to a ligand for hNK-1 with an IC50 of 240
nM.4b For the synthesis of 90, amino sugars (-)-94 and
(-)-95 were each prepared in two steps from known triol
(-)-91, exploiting the methodology of Cichy-Knight
(Scheme 11).30 N-Acylation of (-)-94 and (-)-95 provided
cyclization precursors (-)-96 and (-)-97 (Table 4). At-
tempted SNAr cyclization of these substrates employing
diverse conditions resulted instead in the exclusive
formation of the 14-membered macrocycles (-)-98 and
(-)-99, the products of two consecutive SNAr reactions.
Structural assignments of (-)-98 and (-)-99 were com-
plicated by their C2 axes of symmetry. In addition, mass
spectrometric analysis gave divergent results.31 To es-
tablish unequivocally the structure of the cyclization
products, chemical transformation to a system lacking
this element of symmetry was undertaken. To this end,
partial hydrolysis of the acetonide protecting groups in
(26) Doyle, M. P.; Dellaria, J . F., J r.; Siegfried, B.; Bishop, S. W. J .
Org. Chem. 1977, 42, 3494.
(27) Doyle, M. P.; Siegfried, B.; Dellaria, J . F., J r. J . Org. Chem.
1977, 42, 2426.
(28) For a review, see: Hartwig, J . F. Angew. Chem., Int. Ed. 1998,
37, 2046.
(29) Pedersen, B. S.; Lawesson, S. O. Tetrahedron 1979, 35, 2433.
(30) Cichy-Knight, M. Ph.D. Dissertation, University of Pennsylva-
nia, 1997.
288 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
TABLE 4. Cou p lin g of Am in o Su ga r s (-)-94 a n d (-)-95 w ith F u n ction a lized Ben zoic Acid Der iva tives a n d Su bsequ en t
Cycliza tion
entry
amino sugar
coupling conditions
coupling product (%)
cyclization conditions
cyclization product (%)
1
2
3
4
5
6
7
(-)-94
16, EDAC, DCM, 0 °C
(-)-96 (75)
CsF, DMF, 60 °C (c ) 0.03 M)
CsF, DMF, 25 °C (c ) 0.03 M)
CsF, DMSO, 25 °C (c ) 0.03 M)
CsF, DMA, 90 °C (c ) 0.03 M)
K2CO3, DMF, 25 °C (c ) 0.03 M)
CsF, DMF, 90 °C (c ) 0.03 M)
K2CO3, DMF, 25 °C (c ) 0.01 M)
(-)-98 (45)
(-)-98 (38)
(-)-98 (37)
(-)-98 (45)
(-)-98 (62)
(-)-99 (30)
(-)-99 (75)
(-)-95
16, DMTMM, THF, rt
(-)-97 (90)
SCHEME 12
To understand why (-)-96 and (-)-97 favor the inter-
molecular reaction manifold, we modeled the s-cis and
s-trans conformers of (-)-97 for the global minimum
conformations.34 As anticipated, the resultant computa-
tions suggest that the s-trans amide bond is greatly
favored (∆Ecalc ) 4.5 kcal/mol). Intermolecular SNAr
reaction via the s-trans conformation thus predomi-
nates.35
F a ctor s In flu en cin g th e Con for m a tion of Am id e
Bon d s a n d Th eir Effect on Cycliza tion Rea ction s.
To inhibit dimer formation, we therefore sought to modify
the conformation of the amide bond. In 1998, Scherer et
al.36 determined the conformation of secondary amide
bonds in 399 protein structures. The frequency of the
(33) Even under conditions of very high dilution (c ) 0.001 N), only
dimer formation was observed.
(34) Monte Carlo conformational searches were performed on Mac-
roModel Version 6.0, using the MM2 force field and the Polak-Ribiere
conjugate gradient as algorithm.
(35) We also synthesized the glucosamine derivative (-)-103, which
afforded the macrocycle (-)-104 on treatment with potassium carbon-
ate in DMF. Similarly, (-)-108 gave only the dimeric (+)-109 under
conditions of high dilution. For details, see the Supporting Information.
(+)-10032 (Scheme 12) was achieved with 5% HCl (aq).
Both unchanged starting material and the monoacetonide
(+)-101 were isolated, respectively, in 17% and 25% yield.
1
The H and 13C NMR spectra of (+)-101 are consistent
with the elimination of the C2 symmetry axis inherent
in the starting material. While the formation of dimeric
products was not unexpected, the exclusive formation of
dimers under the conditions of high dilution was unex-
pected.33
(31) Under chemical ionization (CI) conditions, a molecular ion
having the same mass-to-charge ratio as the desired product was
observed. Under electrospray ionization (ESI) conditions, a molecular
ion corresponding to dimer formation was observed under both positive
and negative ionization conditions. Signals corresponding to dimer-
ization of molecules in the mass spectrometer is not uncommon under
ESI conditions.
(32) Details regarding the preparation of compound (+)-100 are
presented in the Supporting Information.
J . Org. Chem, Vol. 69, No. 2, 2004 289

Abrous et al.
trans conformer was found to be 99.97%. On the other
hand, the frequency of cis-prolyl bonds in protein struc-
tures was 4.8%.36 Further, Beausoleil reported that amide
linkages N-terminal to proline possess energetically
similar cis and trans isomers that are separated by a
significant barrier.37 Williams and Deber made the
significant observation that proline and sarcosine have
similar effects on amide bond conformation.38 Taken
together, these and other publications demonstrate that
the instability of cis amide bonds is greatly reduced in
all tertiary amide bonds, a conclusion that is also
consistent with the calculations by Zimmerman and
Scheraga using the Empirical Conformational Energy
Program for Peptides (ECEPP).39 Deber also investigated
factors that favor the cyclization of peptide chains and
identified amino acid residues typified by proline and
sarcosine as building blocks that facilitate ring closure.40
Finally, Veber et al. reported that the amide bond
between Phe and the respective amino acid of c-(Phe-Pro-
Phe-D-Trp-Lys-Val) and of c-(Phe-N-Me-Ala-Phe-D-Trp-
Lys-Val) have the cis conformation.41
of constructs such as (-)-96, (-)-97, and (-)-103] in the
synthesis of more functionalized analogues, has been
developed and this rationale verified experimentally.
Finally, the synthesis of a minilibrary based on the
benzoheterodiazepine hybrid scaffold is underway in our
laboratory and will be reported in due course, in conjunc-
tion with the results from broad biological screening.
Exp er im en ta l Section
Met h yl
2-Deoxy-4,6-O-isop r op ylid en e-N-(t r iflu or o-
a ceta m id o)-â-D-a llosa m in e (-)-10. Freshly distilled acetic
anhydride (3.5 mL) was added in one portion, at rt, to a stirred
solution of (-)-9 in DMSO (anhydrous, 7 mL). The reaction
flask was covered in aluminum foil, stirred overnight, and then
diluted with ether (150 mL) and washed with H2O (100 mL).
The aqueous wash was extracted with ether (2 × 100 mL),
and the combined ether extracts were dried over MgSO4,
filtered, and concentrated. Residual DMSO was removed by
vacuum distillation. Flash chromatography (2.5% MeOH/
DCM) gave 84 mg (85% yield) of the ketone as an off-white
solid: [R]20 -25.5 (c 0.51, CHCl3); IR (CHCl3) 3400, 3010,
D
2900, 1740, 1540, 1380, 1240, 1180, 1130, 1100, 840, 720 cm-1
;
For these reasons, we examined the effect of alkylation
of the lactam nitrogen on the course of the cyclization
reaction (Scheme 13). We prepared the N-methyl amide
derivative (-)-110 and examined the subsequent SNAr
reaction. As expected, cyclization of the N-methyl deriva-
tive (-)-110 afforded the benzoxazepine-sugar hybrid
(+)-111 on treatment with cesium fluoride in DMF in an
unoptimized yield of 38% (Scheme 13).42 No dimer
formation was observed.
As demonstrated earlier in Scheme 8, alkylation of the
amide nitrogen was effective in promoting the intra-
molecular cyclization of the methyl glycosides 81-83 to
furnish the corresponding N-alkylated tricyclic hybrids
84-86. The cyclization of the N-picolyl derivative (-)-
83, in particular, proceeded in very high yield.
1H NMR (500 MHz, CDCl3) δ 1.53 (s, 3 H), 1.56 (s, 3 H), 3.51
(m, 1 H), 3.58 (s, 3 H), 4.00 (dd, J 1 ) J 2 ) 10.5 Hz, 1 H), 4.13
(dd, J ) 10.9 and 5.3 Hz, 1 H), 4.50 (d, J ) 7.9 Hz, 1 H), 4.70
(dd, J ) 10.1 and 1.4 Hz, 1 H), 4.76 (dd, J 1 ) J 2 ) 8.3 Hz, 1
H), 6.90 (d, J ) 7.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
195.2, 158.9, 104.5, 100.3, 76.2, 67.9, 62.1, 60.5, 57.3, 30.1, 28.7,
19.0; high-resolution mass spectrum (CI, NH3) m/z 270.0977
[(M)+, calcd for C12H16N6F3 270.0967].
The ketone (103 mg, 0.315 mmol) was azeotropically dried
with benzene (3 × 5 mL) and dissolved in THF (anhydrous,
6.5 mL). The solution was sparged with argon and cooled to
-78 °C, and L-Selectride (1.0 M solution in THF, 0.63 mL,
0.63 mmol) was added dropwise via syringe over 10 min. The
resultant yellow solution was stirred 4 h at -78 °C, and then
quenched with distilled H2O (4 mL), followed by an excess of
NaHCO3 (250 mg). The suspension was stirred overnight at
rt and then transferred to a separatory funnel. The layers were
separated, and the aqueous phase was extracted with ether
(3 × 20 mL). The combined organic layers were washed with
brine (10 mL), dried over MgSO4, and concentrated to give the
crude product as a yellow oil. Flash chromatography (2.5%
MeOH/DCM) gave 138 mg (79% yield) of (-)-10 as a white
solid: mp 118-120 °C: [R]20D -73.4 (c 0.5, CHCl3); IR (CHCl3)
3600, 3600-3200, 3430, 3000, 2910, 1745, 1545, 1380, 1180,
SCHEME 13
1
875 cm-1; H NMR (500 MHz, CDCl3) δ 1.45 (s, 3 H), 1.53 (s,
3 H), 2.55 (br m, 1 H), 3.50 (s, 3 H), 3.71 (m, 1 H), 3.82 (m, 2
H), 3.99 (m, 1 H), 4.14 (m, 2 H), 4.60 (d, J ) 8.1 Hz, 1 H), 6.81
(br t, 1 H); 13C NMR (125 MHz, CDCl3) δ 156.9 (q, J C-F ) 37
Hz), 100.8, 99.9, 71.2, 68.4, 64.3, 62.2, 57.1, 52.5, 28.9, 19.2;
high-resolution mass spectrum (CI, NH3) m/z 347.1441 [(M +
NH4)+, calcd for C12H18NO6F3 347.1430].
Con clu sion s
Meth yl 2-Deoxy-3-a zid o-4,6-O-isop r op ylid en e-â-D-glu -
cosa m in e (+)-11. To a stirred solution of (-)-10 (0.95 g, 2.9
mmol) in DCM (50 mL) at 0 °C were added TEA (0.80 mL, 5.8
mmol) and methanesulfonyl chloride (0.45 mL, 5.8 mmol).
The synthesis of the chimeric benzoheterodiazepine
â-D-glucopyranoside scaffold, a template from which to
project a variety of substituents into previously un-
explored receptor space, has been achieved. A rationale
for the difficulties encountered [i.e., the influence of
amide rotational isomerism on the course of cyclization
(41) (a) Veber, D. F.; Freidinger, R. M.; Perlow, D. S.; Paleveda, W.
J .; Holly, F. W.; Strachan, R. G.; Nutt, R. F.; Arison, B. H.; Homnick,
C.; Randall, W. C.; Glitzer, M. S.; Saperstein, R.; Hirschmann, R.
Nature 1981, 292, 55. (b) Veber, D. F.; Saperstein, R.; Nutt, R. F.;
Freidinger, R. M.; Brady, S. F.; Curley, P.; Perlow, D. S.; Paleveda,
W. J .; Colton, C. D.; Zacchei, A. G.; Tocco, D. J .; Hoff, D. R.; Vandlen,
R. L.; Gerich, J . E.; Hall, L.; Mandarino, L.; Cordes, E. H.; Anderson,
P. S.; Hirschmann, R. Life Sci. 1984, 34, 371.
(42) It is relevant to note that Schultz and co-workers reported a
convenient method for the preparation of macrocycles via the bimo-
lecular cyclization of o-fluorobenzamides; this protocol failed with the
corresponding tertiary amide, affording the undesired unimolecular
reaction products: Schultz, A. G.; Pinto, D. J . P.; Welch, M.; Kullnig,
R. K. J . Org. Chem. 1988, 53, 1372-1380.
(36) Scherer, G.; Kramer, M. L.; Schutkowski, M.; Reimer, U.;
Fischer, G. J . Am. Chem. Soc. 1998, 120, 5568-5574.
(37) Beausoleil, E.; L’Archeveˆque, B.; Be´lec, L.; Atfani, M.; Lubell,
W. D. J . Org. Chem. 1996, 61, 9447-54.
(38) Williams, K. A.; Deber, C. M. Biochemistry 1991, 30, 8919-
8923.
(39) Zimmerman, S. S.; Scheraga, H. A. Macromolecules 1976, 9,
408-416.
(40) Deber et al. 3rd American Peptide Symposium.
290 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
After being stirred for 2 h at 0 °C, the reaction was warmed
to rt, and stirring was continued for 18 h. The mixture was
diluted with DCM (50 mL) and shaken with 5% HCl (aq, 50
mL) and H2O (50 mL). The organic layer was dried over
MgSO4, filtered, and concentrated. Flash chromatography
(40% ethyl acetate/hexanes) gave 1.07 g (91% yield) of the
J ) 10.9, 5.4 Hz, 1 H), 4.79 (d, J ) 8.2 Hz, 1 H), 4.87 (dd, J 1
) J 2 ) 9.7 Hz, 1 H), 6.78 (d, J ) 7.8 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ 151.0, 120.0, 100.9, 100.1, 78.5, 72.0, 66.7, 61.8,
56.5, 51.5, 38.4, 28.9, 19.1; high-resolution mass spectrum (CI,
NH3) m/z 425.0960 [(M + NH4)+, calcd for C13H24F3N2O8S
425.1206].
mesylate as a white solid: mp 160 °C dec; [R]20 -108.9 (c
D
To a solution of the mesylate (425 mg, 1.1 mmol) in DMF
(4.6 mL) was added sodium azide (279.5 mg, 4.3 mmol),
followed by a catalytic amount of tetrabutylammonium hy-
drogen sulfate. (CAUTION: hydrazoic acid is generated under
these conditionssthe use of a blast shield is recommended.)
The reaction mixture was heated to 70 °C for 48 h, cooled to
rt, and then diluted with H2O (15 mL) and extracted with ethyl
acetate (4 × 20 mL). The combined organic extracts were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(33% ethyl acetate/hexanes) gave 307 mg (85% yield) of (+)-
0.8, CHCl3); IR (CHCl3) 3700-3200, 3010, 1735, 1550, 1375,
1
1180, 930 cm-1; H NMR (500 MHz, CDCl3) δ 1.44 (s, 3 H),
1.55 (s, 3 H), 3.16 (s, 3 H), 3.53 (s, 3 H), 3.83 (m, 3 H), 4.03
(dd, J ) 9.9 and 4.3 Hz, 1 H), 4.20 (ddd, J ) 8.5, 8.5, 2.8 Hz,
1 H), 4.65 (d, J ) 8.5 Hz, 1 H), 5.14 (dd, J 1 ) J 2 ) 2.5 Hz, 1
H), 6.62 (br m, 1 H); 13C NMR (125 MHz, MeOH-d4) δ 159.1
(q, J C-F ) 37 Hz), 101.4, 100.5, 79.0, 70.8, 66.1, 63.2, 57.2,
54.5, 39.3, 29.2, 19.3; high-resolution mass spectrum (CI, NH3)
m/z 425.1208 [(M + NH4)+, calcd for C13H24F3N2O6 425.1205].
Anal. Calcd for C13H20F3NO6: C, 38.33; H, 4.95; N, 3.44.
Found: C, 38.63; H, 4.71; N, 3.32.
12 as a white solid: [R]20 +20 (c 0.27, CHCl3); IR (CHCl3)
D
3390, 3000, 2900, 2100, 1725, 1540, 1450, 1370, 1150, 1040,
940, 880, 830 cm-1 1H NMR (500 MHz, CDCl3) δ 1.43 (s, 3
;
To a solution of the mesylate (2.26 g, 5.5 mmol) in DMF (25
mL) were added sodium azide (1.44 g, 22 mmol) and tetrabu-
tylammonium hydrogen sulfate (cat., 100 mg). (CAUTION:
hydrazoic acid is generated under these conditionssthe use
of a blast shield is recommended.) The reaction mixture was
heated at 100 °C for 36 h. The reaction was cooled to rt, diluted
with ethyl acetate (100 mL), and washed with H2O (75 mL),
and the aqueous layer further extracted with ethyl acetate (3
× 100 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated. Flash chromatography
(33% ethyl acetate/hexanes) gave 1.74 g (92% yield) of the azide
H), 1.49 (s, 3 H), 3.44 (s, 3 H), 3.84 (s, 3 H), 3.98 (dd, J ) 9.4,
3.8 Hz, 1 H), 4.04 (ddd, J ) 8.5, 8.5, 3.6 Hz, 1 H), 4.15 (dd, J 1
) J 2 ) 3.2 Hz, 1 H), 4.42 (d, J ) 8.2 Hz, 1 H), 6.43 (d, J ) 8.0
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 156.6 (q, J C-F ) 37.7
Hz, 1 H), 115.7, 100.3, 100.1, 72.1, 65.2, 62.1, 60.4, 57.0, 51.3,
28.8, 18.9; high-resolution mass spectrum (CI, NH3) m/z
372.1261 [(M + NH4)+, calcd for C12H21F3N5O5 372.1495].
Meth yl 2,3-Deoxy-3-a zid o-4,6-O-isop r op ylid en e-N-(2-
flu or o-5-n itr oben za m id o)-â-D-glu cop yr a n osid e (+)-21. To
a stirred suspension of amine (+)-11 (101.8 mg, 0.39 mmol)
and acid 16 (135 mg, 0.47 mmol) was added a solution of EDAC
(105 mg, 0.51 mmol) in DCM (1.0 mL) via cannula. After the
addition was complete, the reaction mixture became homoge-
neous. The mixture was stirred for 45 min at 0 °C and then
warmed to rt, diluted with DCM (25 mL), and washed with
H2O (25 mL). The aqueous wash was further extracted with
DCM (3 × 25 mL). The combined DCM extracts were dried
over Na2SO4, filtered, and concentrated. Flash chromatography
(2% MeOH/DCM) gave 160 mg (95% yield) of (+)-21 as a white
as a white solid: mp 218-220 °C; [R]20 +1.3 (c 0.46, CHCl3);
D
IR (CHCl3) 3450, 2110, 1735, 1550, 1090, 850 cm-1; H NMR
1
(500 MHz, CDCl3) δ 1.47 (s, 3 H), 1.55 (s, 3 H), 3.34 (dt, J )
10.9, 8.1 Hz, 1 H), 3.42 (ddd, J ) 9.8, 9.8, 5.3 Hz, 1 H), 3.51 (s,
3 H), 3.65 (dd, J 1 ) J 2 ) 9.5 Hz, 1 H), 3.82 (dd, J 1 ) J 2 ) 10.7
Hz, 1 H), 3.99 (dd, J ) 10.9, 5.3 Hz, 1 H), 4.10 (dd, J ) 10.8,
9.6 Hz, 1 H), 4.77 (d, J ) 8.2 Hz, 1 H), 6.60 (br m, 1 H); 13C
NMR (125 MHz, CDCl3) δ 157.5 (q, J C-F ) 37 Hz), 100.6, 100.1,
73.7, 68.1, 62.1, 60.9, 57.3, 56.8, 28.9, 19.0; high-resolution
mass spectrum (CI, NH3) m/z 372.1499 [(M + NH4)+, calcd for
solid: mp 211-213 °C dec; [R]20 +6.1 (c 0.59, CHCl3); IR
D
C
12H21F3N5O5 372.1495].
(CHCl3) 3460, 3005, 2110, 1685, 1635, 1535, 1480, 1355, 1095,
To a stirred solution of the azide (0.60 g, 1.75 mmol) in
1
855 cm-1; H NMR (500 MHz, CDCl3) δ 1.47 (s, 3 H), 1.56 (s,
MeOH (10 mL) was added 5 M KOH (aq, 1 mL), and the
mixture was heated at reflux for 24 h. The reaction was cooled
to rt and concentrated in vacuo. Flash chromatography (33%
ethyl acetate/hexanes) gave 0.44 g (99% yield) of (+)-11 as a
yellow oil: [R]20D +2.9 (c 0.65, CHCl3); IR (CHCl3) 3400, 3005,
3 H), 3.40 (m, 1 H), 3.51 (s, 3 H), 3.55 (m, 1 H), 3.67 (dd, J 1
)
J 2 ) 9.5 Hz, 1 H), 3.84 (dd, J 1 ) J 2 ) 10.5 Hz, 1 H), 4.00 (dd,
J ) 10.9, 5.4 Hz, 1 H), 4.21 (dd, J ) 10.7, 9.5 Hz, 1 H), 4.91
(d, J ) 8.2 Hz, 1 H), 6.89 (dd, J ) 11.4, 8.1 Hz, 1 H), 7.35 (dd,
J ) 10.3, 9.1 Hz, 1 H), 8.40 (ddd, J ) 7.3, 4.3, 3.0 Hz, 1 H),
8.96 (dd, J ) 6.5, 2.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
163.3 (d, J C-F ) 257 Hz), 161.4, 144.8, 128.7 (d, J C-F ) 11.4
Hz), 128.2 (d, J C-F ) 3.9 Hz), 122.3 (d, J C-F ) 14.7 Hz), 117.7
(d, J C-F ) 27.6 Hz), 101.3, 100.0, 73.6, 68.1, 62.2, 61.6, 57.2,
28.9, 19.0; high-resolution mass spectrum (CI, NH3) m/z
425.1429 [(M)+, calcd for C17H20FN5O7 425.1347].
1
2895, 2120, 1375, 1270, 1100, 850 cm-1; H NMR (500 MHz,
CDCl3) δ 1.46 (s, 3 H), 1.55 (s, 3 H), 1.57 (br s, 2 H), 2.67 (dd,
J ) 10.1, 7.8 Hz, 1 H), 3.35 (m, 2 H), 3.55 (s, 3 H), 3.69 (t, J
) 9.5 Hz, 1 H), 3.82 (dd, J 1 ) J 2 ) 10.5 Hz, 1 H), 3.96 (dd, J 1
) J 2 ) 5.3 Hz, 1 H), 4.19 (d, J ) 7.8 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ 105.7, 100.0, 73.3, 68.4, 65.3, 62.3, 57.4, 56.4,
56.4, 29.0, 19.0; high-resolution mass spectrum (CI, NH3) m/z
259.1406 [(M + H)+, calcd for C10H19N4O4 259.1402]. Anal.
Calcd for C10H18N4O4: C, 46.48; H, 7.03; N, 21.69. Found: C,
46.51; H, 6.94; N, 21.42.
Meth yl 2,3-Deoxy-3-a m in o-4,6-O-isop r op ylid en e-N-(2-
flu or o-5-n itr oben za m id o)-â-D-glu cosa m in e (-)-22. To a
solution of (+)-21 (153 mg, 0.383 mmol) in THF (10 mL) was
added H2O (100 µL), followed by triphenylphosphine (141 mg,
0.54 mmol), and the reaction mixture was heated at 55 °C for
48 h. The mixture was concentrated in vacuo, and the residue
was purified by flash chromatography (2.5% MeOH/DCM) to
give 106.7 mg (74% yield) of (-)-22 as a yellow solid: mp 166-
Met h yl 2-Deoxy-3-a zid o-4,6-O-isop r op ylid en e-N-(t r i-
flu or oa ceta m id o)-â-D-a llosa m in e (+)-12. A solution of (-)-9
(9.52 g, 28.9 mmol) in DCM (296 mL) was cooled to 0 °C, and
TEA (12.4 mL, 88.8 mmol) was added, followed by addition of
methanesulfonyl chloride (4.6 mL, 59.3 mmol). The reaction
mixture was warmed to rt over 1 h and then stirred for an
additional 2 h. The mixture was diluted with DCM (500 mL),
washed with 5% HCl (aq, 500 mL) and brine (500 mL), dried
over MgSO4, and concentrated. The residue was purified by
flash chromatography (5% MeOH/DCM) to give the mesylate
168 °C; [R]20 -21.0 (c 0.31, CHCl3); IR (CHCl3) 3460, 3005,
D
1680, 1635, 1535, 1355, 1200, 1095, 860 cm-1; H NMR (500
1
MHz, CDCl3) δ 1.46 (s, 3 H), 1.55 (s, 3 H), 1.58 (br s, 2 H),
3.25 (dd, J ) 10.4, 9.1 Hz, 1 H), 3.38-3.51 (m, 2 H), 3.52 (s, 3
H), 3.81 (m, 1 H), 3.83 (dd, J 1 ) J 2 ) 10.6 Hz, 1 H), 3.97 (dd,
J ) 11.0, 5.7 Hz, 1 H), 6.66 (dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 7.34
(dd, J ) 10.4, 9.2 Hz, 1 H), 8.39 (ddd, J ) 9.0, 4.1, 3.1 Hz, 1
H), 9.00 (dd, J ) 6.5, 2.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 163.3 (d, J C-F ) 257 Hz), 161.4, 144.8, 128.5, 128.5, 122.7
(d, J C-F ) 14.9 Hz), 117.6 (d, J C-F ) 27.9 Hz), 102.3, 99.8, 75.1,
68.6, 62.2, 58.4, 56.9, 54.8, 29.1, 19.2; high-resolution mass
(10.6 g, 90% yield) as a white solid: [R]20 -26.8 (c 1.04,
D
CHCl3); IR (CHCl3) 3400, 3000, 2900, 1740, 1550, 1360, 1260,
1
1180, 1130, 1100, 970, 850 cm-1; H NMR (500 MHz, CDCl3)
δ 1.39 (s, 3 H), 1.49 (s, 3 H), 3.04 (s, 3 H), 3.38 (ddd, J ) 10.0,
10.0, 5.4 Hz, 1 H), 3.48 (s, 3 H), 3.68 (m, 1 H), 3.76 (dd, J 1
)
J 2 ) 9.5 Hz, 1 H), 3.80 (dd, J 1 ) J 2 ) 10.6 Hz, 1 H), 3.98 (dd,
J . Org. Chem, Vol. 69, No. 2, 2004 291

Abrous et al.
spectrum (CI, NH3) m/z 400.1533 [(M + H)+, calcd for C17H23
-
3426, 2920, 1684, 1600, 1576, 1508, 1251, 1160, 1004, 823
cm-1; 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 3 H), 1.54 (s, 3 H),
3.44 (m, 2 H), 3.53 (s, 3 H), 3.64 (dd, J 1 ) J 2 ) 9.7 Hz, 1 H),
3.81 (dd, J 1 ) J 2 ) 10.5 Hz, 1 H), 3.98 (dd, J ) 10.8 and 5.4
Hz, 1 H), 4.27 (dd, J 1 ) J 2 )10.1 Hz, 1 H), 4.91 (d, J ) 8.2 Hz,
1 H), 6.61 (d, J ) 7.7 Hz, 1 H), 7.35 (dd, J ) 4.8, 2.8 Hz, 1 H),
8.06 (dd, J ) 5.7, 2.0 Hz, 1 H), 8.48 (dd, J ) 2.9, 1.9 Hz, 1 H);
13C NMR (125 MHz, CDCl3) δ 165.1, 151.2, 147.1, 139.1, 131.0,
122.8, 101.2, 99.9, 73.5, 68.0, 62.2, 61.7, 57.5, 57.3, 28.9, 18.9;
high-resolution mass spectrum (FAB) m/z 398.1231 [(M + H)+,
calcd for C16H21ClN5O5 398.1231].
FN3O7 400.1520].
Meth yl 2-Deoxy-4,6-O-isop r op ylid en e-N-(2-flu or o-5-n i-
tr oben za m id o)-â-D-glu cosa m in e (-)-23. To a solution of
(-)-14 (320 mg, 1.37 mmol) in THF (anhydrous, 10 mL) was
added acid 16 (212 mg, 1.15 mmol). The resulting solution was
stirred for 15 min at rt, and DMTMM (0.382 g, 1.38 mmol)
was added in portions to give a white suspension. Stirring was
maintained for 4 h at rt, and the mixture was concentrated in
vacuo. The residue was purified by flash chromatography to
give 428 mg (93% yield) of (-)-23 as a white foam: [R]20D -36.1
(c 0.13, CH2Cl2); IR (thin film) 3400, 3060, 2890, 2880, 1650,
1525, 1480, 1350, 1090, 940, 850, 740 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.43 (s, 3 H), 1.52 (s, 3 H), 3.35 (ddd, J ) 10.0, 10.0,
5.4 Hz, 1 H), 3.50 (s, 3 H), 3.62 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H),
3.73 (m, 1 H), 3.81 (m, 1 H), 3.95 (dd, J ) 10.8, 5.4 Hz, 1 H),
4.07 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H), 4.69 (d, J ) 8.2 Hz, 1 H), 6.83
(br s, 1 H), 7.31 (dd, J 1 ) J 2 ) 9.7 Hz, 1 H), 8.35 (m, 1 H), 8.96
(dd, J ) 6.5, 2.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 163.3
(d, J C-F ) 258 Hz), 161.9 (d, J C-F ) 3 Hz), 144.8, 128.7 (d,
J C-F ) 11.4 Hz), 122.3, 117.6 (d, J C-F ) 27.8 Hz), 101.7, 99.9,
74.4, 71.6, 67.3, 62.0, 59.2, 57.1, 29.0, 19.1; high-resolution
mass spectrum (CI, NH3) m/z 381.1293 [(M + H)+, calcd for
2-Deoxy-4,6-O-isop r op ylid en e-N-(2-ch lor o-3-n icot in -
a m id o)-â-D-glu cosa m in e (-)-25. To a solution of (-)-24 (0.33
g, 0.83 mmol) in THF (16 mL) were added triphenylphosphine
(0.52 g, 1.9 mmol) and H2O (0.8 mL, 0.05 mmol). The reaction
flask was fitted with a reflux condenser and heated at 65 °C
for 19 h. The mixture was concentrated under reduced pres-
sure, and the residue was azeotropically dried with benzene
(10 mL). Flash chromatography (33% ethyl acetate/hexanes)
provided 0.28 g (91% yield) of (-)-25: [R]20 -21.0 (c 1.23,
D
CHCl3); IR (CHCl3) 3410, 3290, 2930, 2870, 1660, 1580, 1400,
1
1090, 850 cm-1; H NMR (500 MHz, CDCl3) δ 1.39 (s, 3 H),
1.49 (s, 3 H), 1.61 (s, 2 H), 3.17 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H),
3.30 (m, 1 H), 3.38 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H), 3.47 (s, 3 H),
3.67 (dd, J ) 10.2, 8.7 Hz, 1 H), 3.76 (dd, J 1 ) J 2 ) 10.4 Hz,
1 H), 3.89 (dd, J ) 5.6, 5.2 Hz, 1 H), 4.60 (d, J ) 8.3 Hz, 1 H),
6.98 (d, J ) 8.7 Hz, 1 H), 7.25 (dd, J ) 4.8, 2.8 Hz, 1 H), 7.91
(dd, J ) 5.8, 1.8 Hz, 1 H), 8.37 (dd, J ) 2.9, 1.8 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 165.5, 150.6, 146.9, 138.9, 131.6,
122.5, 102.2, 99.6, 74.6, 68.4, 62.0, 58.1, 56.8, 54.3, 28.9, 19.0;
high-resolution mass spectrum (FAB) m/z 372.1326 [(M + H)+,
calcd for C16H23ClN3O5 372.1326].
C
17H21N2O8 381.1297].
Tr icyclic Hybr id (+)-1. A solution of (-)-22 (86.8 mg, 0.20
mmol) in acetonitrile (80 mL, c ) 0.0025 M) was heated at 80
°C for 48 h. The mixture was concentrated in vacuo and
purified by flash chromatography (50% ethyl acetate/hexanes)
to give 34.5 mg (70% yield) of (+)-1 as yellow crystals: mp
150-152 °C; [R]20 +29.3 (c 0.45, CHCl3); IR (CHCl3) 3405,
D
3005, 1665, 1620, 1535, 1515, 1345, 1130, 1100, 860 cm-1; UV
(ꢀ356 ) 14,762); 1H NMR (500 MHz, CDCl3) δ 1.50 (s, 3 H),
1.60 (s, 3 H), 3.51 (m, 2 H), 3.58 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H),
2-P yr id yld ia zep in e Tr icyclic Hybr id (-)-4. Cesium
fluoride (39.1 mg, 0.11 mmol) was added to a stirred solution
of (-)-25 (21.9 mg, 0.11 mmol) in DMF (10 mL, c ) 0.01 M),
and the mixture was heated at 100 °C for 5 days. The mixture
was poured into NaHCO3 (saturated aqueous, 5 mL), and the
resultant mixture was extracted with CHCl3 (3 × 20 mL). The
combined organic extracts were dried over Na2SO4 and K2CO3,
filtered and concentrated in vacuo. The residue was purified
by preparative TLC (500 µm, 10% MeOH/DCM) to give 12.0
3.66 (s, 3 H), 3.69 (dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 3.85 (dd, J 1
)
J 2 ) 10.5 Hz, 1 H), 4.03 (dd, J ) 11.0, 5.5 Hz, 1 H), 4.49 (d, J
) 7.8 Hz, 1 H), 5.26 (br s, 1 H), 6.69 (d, J ) 9.1 Hz, 1 H), 7.29
(br s, 1 H), 8.09 (dd, J ) 9.1, 2.7 Hz, 1 H), 9.08 (d, J ) 2.7 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 167.0, 149.6, 139.5, 131.4,
127.7, 118.8, 115.4, 102.5, 100.6, 72.1, 68.0, 61.7, 59.8, 57.6,
56.7, 29.0, 19.2; high-resolution mass spectrum (CI, NH3) m/z
397.1727 [(M + NH4)+, calcd for C17H25N4O7 397.1724].
mg (36% yield) of (-)-4 as a white solid: [R]20 -57.6 (c 0.76,
Tr icyclic Hybr id (-)-3. Cesium fluoride (22 mg, 0.15
mmol) was added to a stirred solution of alcohol (-)-23 (39
mg, 0.097 mmol) in DMF (dry, 10 mL) at 100 °C. The resulting
orange-yellow solution was stirred for 7 h at 100 °C. The
reaction mixture was concentrated in vacuo, and the residue
was purified by flash chromatography (5% MeOH/DCM) to give
14 mg (38% yield) of (-)-3 as a white solid, accompanied by 9
D
CHCl3); IR (CHCl3) 3386, 3017, 1636, 1590, 1510, 1450, 1380,
1210, 1090, 920, 850, 764 cm-1; 1H NMR (500 MHz, CDCl3) δ
1.44 (s, 3 H), 1.55 (s, 3 H), 3.46 (m, 2 H), 3.49 (m, 1 H), 3.58 (s,
3 H), 3.71 (d, J ) 9.3 Hz, 1 H), 3.71 (d, J ) 9.3 Hz, 1 H), 3.82
(dd, J 1 ) J 2 ) 10.6 Hz, 1 H), 3.95 (dd, J ) 10.8, 5.4 Hz, 1 H),
4.38 (d, J ) 7.4 Hz, 1 H), 5.67 (s, 1 H), 6.81 (s, 1 H), 8.22 (dd,
J ) 2.8, 1.8 Hz, 1 H), 8.48 (dd, J ) 9.0, 1.8 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 166.8, 156.4, 152.5, 143.3, 114.9, 110.7,
102.7, 100.5, 71.8, 68.3, 61.8, 57.9, 57.8, 57.4, 28.9, 19.0; high-
resolution mass spectrum (FAB) m/z 336.1548 [(M + H)+, calcd
for C16H22N3O5 336.1559].
mg (25% yield) of the dimer (+)-29. For (-)-3: [R]20 -113 (c
D
0.686, CHCl3); IR (CHCl3) 2920, 2840, 1650, 1620, 1520, 1350,
1
1250, 990, 850 cm-1; H NMR (500 MHz, CDCl3) δ 1.45 (s, 3
H), 1.58 (s, 3 H), 3.41 (ddd, J ) 10.0, 10.0, 5.3 Hz, 1 H), 3.60
(m, 1 H), 3.87 (dd, J 1 ) J 2 ) 10.5 Hz, 1 H), 3.93 (dd, J 1 ) J 2
) 9.4 Hz, 1 H), 4.02 (dd, J ) 10.9, 5.3 Hz, 1 H), 4.18 (dd, J 1
)
2,3-Deoxy-3-a zid o-4,6-O-isop r op ylid en e-N-(6-ch lor o-3-
n icotin a m id o)-â-D-glu cosa m in e (-)-26. To a solution of (+)-
11 (92.1 mg, 0.35 mmol) in DCM (10 mL) were added N,N-
dicyclohexylcarbodiimide (DCC, 77.2 mg, 0.37 mmol) and acid
18 (54.5 mg, 0.35 mmol) at 0 °C. The mixture was gradually
warmed to rt, and the resultant suspension was concentrated
in vacuo. The residue was recrystallized from ethanol (abso-
lute, 50 mL) to give 45.2 mg (33% yield) of (-)-26 as a white
solid: [R]20D -7.0 (c 0.49, CHCl3); IR (CHCl3) 2160, 1640, 1570,
J 2 ) 8.8 Hz, 1 H), 4.94 (d, J ) 7.9 Hz, 1 H), 7.18 (d, J ) 9.0
Hz, 1 H), 4.94 (d, J ) 7.9 Hz, 1 H), 7.18 (d, J ) 9.0 Hz, 1 H),
7.24 (s, 1 H), 8.25 (dd, J ) 9.0, 2.9 Hz, 1 H), 9.16 (d, J ) 2.9
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 164.2, 160.9, 142.9,
130.1, 128.2, 122.1, 120.7, 102.6, 100.3, 81.8, 71.5, 67.5, 61.8,
58.2, 57.6, 28.9, 19.0; high-resolution mass spectrum (CI, NH3)
m/z 381.1293 [(M + H)+, calcd for C17H21N2O8 381.1297].
2,3-Deoxy-3-a zid o-4,6-O-isop r op ylid en e-N-(2-ch lor o-3-
n icotin a m id o)-â-D-glu cosa m in e (-)-24. To a solution of acyl
chloride 17 (0.28 g, 1.6 mmol) in DCM (3 mL) at 0 °C was
added Hu¨nig’s base (0.42 mL, 2.4 mmol) followed by slow
addition of a solution of (+)-11 (0.21 g, 0.80 mmmol) in DCM
(5 mL). The mixture was diluted with DCM (24 mL) and
washed with H2O (3 × 10 mL), and the aqueous layer was
extracted with DCM (2 × 15 mL). The combined extracts were
dried over Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography (5% MeOH/DCM) gave 0.33 g of (-)-24 (99%
yield) as a white solid: [R]20D -8.10 (c 0.63, CHCl3); IR (CHCl3)
1
1080, 850 cm-1; H NMR (500 MHz, CDCl3) δ 1.43 (s, 3 H),
1.51 (s, 3 H), 3.32 (m, 2 H), 3.45 (m, 1 H), 3.51 (s, 3 H), 3.59
(dd, J 1 ) J 2 ) 9.5 Hz, 1 H), 3.79 (dd, J 1 ) J 2 ) 10.5 Hz, 1 H),
3.96 (dd, J ) 10.8 and 5.4 Hz, 1 H), 4.30 (dd, J 1 ) J 2 ) 10.1
Hz, 1 H), 4.94 (d, J ) 8.2 Hz, 1 H), 6.41 (d, J ) 7.6 Hz, 1 H),
7.35 (d, J ) 5.4 Hz, 1 H), 8.54 (d, J ) 5.4 Hz, 1 H), 8.80 (s, 1
H); 13C NMR (125 MHz, CDCl3) δ 164.8, 151.9, 150.5, 140.9,
130.7, 124.9, 101.0, 99.9, 73.6, 68.0, 62.2, 61.5, 57.7, 57.4, 28.9,
18.9; high-resolution mass spectrum (FAB, NBA matrix) m/z
398.1224 [(M + H)+, calcd for C16H21ClN5O5 398.1231].
292 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
1
Met h yl 2-Deoxy-4,6-O-isop r op ylid en e-N-(6-ch lor o-3-
n icotin a m id o)-â-D-glu cosa m in e (-)-27. To a stirred solu-
tion of (-)-26 (25.5 mg, 0.064 mmol) in THF (1.3 mL) were
added triphenylphosphine (44.1 mg, 0.17 mmol) and H2O (12.8
µL). The reaction flask was fitted with a Dean-Stark trap and
condenser and heated at 65 °C for 12 h. The mixture was
concentrated in vacuo, and the residue was azeotropically dried
with benzene (5 mL). Preparative TLC (500 µm, 10% MeOH/
DCM) provided 20.9 mg (88% yield) of (-)-27 as a white solid:
[R]20D -17.9 (c 0.56, CHCl3); IR (CHCl3) 3400, 3000, 2100, 1690,
1220, 1090, 760 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 3
H), 1.49 (s, 3 H), 1.69 (s, 2 H), 3.29 (dd, J 1 ) J 2 ) 9.7 Hz, 1 H),
3.38 (m, 2 H), 3.49 (s, 1 H), 3.63 (dd, J ) 10.3, 8.4 Hz, 1 H),
3.77 (dd, J 1 ) J 2 ) 10.3 Hz, 1 H), 3.92 (dd, J ) 10.6, 5.3 Hz,
1 H), 4.68 (d, J ) 8.2 Hz, 1 H), 6.40 (d, J ) 8.3 Hz, 1 H), 7.33
(d, J ) 5.4 Hz, 1 H), 8.51 (d, J ) 5.4 Hz, 1 H), 8.79 (s, 1 H);
13C NMR (125 MHz, CDCl3) δ 164.7, 151.7, 150.7, 140.7, 130.9,
124.9, 102.1, 99.8, 74.8, 68.6, 62.2, 58.7, 56.9, 54.2, 29.1, 19.1;
high-resolution mass spectrum (FAB) m/z 406.0941 [(M + Cl)-,
calcd for C16H21Cl2N3O5 406.0936].
1588, 1525, 1450, 1214, 1094, 1043, 855 cm-1; H NMR (500
MHz, CDCl3) δ 1.41 (s, 3 H), 1.48 (s, 3 H), 2.15 (s, 1 H), 3.26
(ddd, J ) 10.0, 10.0, 5.3 Hz, 1 H), 3.44 (s, 1 H), 3.55 (dd, J 1
)
J 2 ) 9.3 Hz, 1 H), 3.63 (m, 1 H), 3.77 (dd, J 1 ) J 2 ) 10.5 Hz,
1 H), 3.91 (dd, J ) 10.7, 5.3 Hz, 1 H), 3.97 (dd, J 1 ) J 2 ) 9.3
Hz, 1 H), 4.64 (d, J ) 8.1 Hz, 1 H), 5.14 (s, 2 H), 6.70 (d, J )
7.2 Hz, 1 H), 6.91 (t, J ) 7.5 Hz, 1 H), 7.36 (m, 10 H), 8.24 (d,
J ) 8.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 170.1, 153.7,
139.5, 136.1, 132.8, 128.5, 128.3, 128.2, 127.6, 127.1, 127.0,
122.1, 120.2, 101.7, 99.9, 74.5, 71.6, 67.1, 66.9, 65.3, 62.0, 58.5,
57.0, 29.0, 19.1; high-resolution mass spectrum (CI, NH3) m/z
509.1905 [(M + Na)+, calcd for C25H30N2O8Na 509.1900].
To a stirred solution of the coupled product (100 mg, 0.25
mmol) in DMSO (anhydrous, 7 mL) was added, in a single
portion, acetic anhydride (distilled, 3.5 mL) at rt. The reaction
flask was covered in aluminum foil, stirred overnight, and then
diluted with ether (150 mL) and washed with H2O (100 mL).
The aqueous wash was extracted with ether (2 × 100 mL),
and the combined ether extracts were dried over MgSO4,
filtered, and concentrated. Residual DMSO was removed by
vacuum distillation. Flash chromatography (2.5% MeOH/
DCM) gave 63 mg (65% yield) of (-)-32 as an off white solid:
[R]20D -7.1 (c 0.7, CHCl3); IR (thin film) 3342, 2062, 2994, 2882,
1737, 1648, 1589, 1524, 1450, 1214, 1097, 830 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.39 (s, 3 H), 1.44 (s, 3 H), 3.44 (s, 3 H),
3.45 (m, 1 H), 3.88 (dd, J 1 ) J 2 ) 10.4 Hz, 1 H), 3.99 (dd, J )
10.9, 5.3 Hz, 1 H), 4.36 (dd, J ) 10.3, 1.4 Hz, 3 H); 4.62 (d, J
) 7.9 Hz, 1 H), 4.75 (dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 5.08 (s, 2 H),
6.90 (dd, J 1 ) J 2 ) 8.5 Hz, 1 H), 7.27 (m, 5 H), 7.58 (dd, J )
7.9, 1.4 Hz, 1 H), 7.79 (d, J ) 8.4 Hz, 1 H), 8.25 (d, J ) 7.9 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 196.5, 173.9, 169.1, 153.5,
140.0, 136.2, 132.8, 128.4, 128.1, 128.0, 127.6, 121.6, 119.6,
104.7, 100.3, 75.8, 67.1, 66.6, 62.4, 61.2, 57.3, 40.5, 28.7, 20.9,
18.7; high-resolution mass spectrum (CI, NH3) m/z 507.1755
[(M + Na)+, calcd for C25H28N2O8Na 507.1744].
4-P yr id yld ia zep in e Tr icyclic Hybr id (-)-5. Cesium
fluoride (anhydrous, 16 mg, 0.045 mmol) was added to a stirred
solution of amine (-)-27 (3.2 mg, 0.009 mmol) in DMF (dry,
0.9 mL), and the mixture was heated at 75 °C for 12 h. The
solvent was removed in vacuo, and the residue was purified
by flash chromatography (10% MeOH/DCM) to give 2.0 mg
(71% yield) of (-)-5 as a white solid: [R]20 -36.0 (c 0.40,
D
CHCl3); IR (CHCl3) 3360, 3010, 1636, 1590, 1456, 1370, 1215,
1
1089, 852, 764 cm-1; H NMR (500 MHz, CDCl3) δ 1.48 (s, 3
H), 1.56 (s, 3 H), 3.42 (dd, J ) 7.4 and 1.3 Hz, 1 H), 3.47 (m,
2 H), 3.58 (s, 3 H), 3.65 (dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 3.82 (dd,
J 1 ) J 2 ) 10.6 Hz, 1 H), 4.00 (dd, J ) 11.0, 5.5 Hz, 1 H), 4.38
(d, J ) 7.6 Hz, 1 H), 4.99 (s, 1 H), 6.21 (s, 1 H), 6.48 (d, J )
5.8 Hz, 1 H), 8.27 (d, J ) 5.8 Hz, 1 H), 9.18 (s, 1 H); 13C NMR
(125 MHz, CDCl3) δ 167.5, 155.9, 151.4, 111.8, 102.6, 100.5,
71.9, 70.5, 68.0, 61.7, 58.9, 57.3, 56.6, 29.6, 28.9, 19.2; high-
resolution mass spectrum (FAB) m/z 336.1564 [(M + H)+, calcd
for C16H22N3O5 336.1559].
Met h yl 2-Deoxy-3-a m in o-4,6-O-isop r op ylid en e-N-(o-
a m in oben zoyl)-â-D-a llosa m in e-1,4-ben zod ia zep in -5-on e
(-)-7. A solution of (-)-32 (89 mg, 0.18 mmol) in THF (18 mL)
was sparged with argon and then charged with a catalytic
amount of 5% palladium on activated carbon (dry). The
reaction flask was repeatedly (3×) evacuated and sparged with
hydrogen. The reaction was stirred 24 h at rt under hydrogen
atmosphere. Upon completion, the reaction mixture was
repeatedly (3×) evacuated and sparged with argon and then
filtered through Celite 545. The filtrate was concentrated in
vacuo, and the residue was purified by preparatory TLC (500
µm, 5% MeOH/DCM) to afford 12 mg (20% yield) of (-)-7 as a
beige solid accompanied by 4 mg (5% yield) of (-)-2. For (-)-
7: [R]20D -48.7 (c 0.115, CHCl3); IR (CHCl3) 3300, 2900, 2850,
Meth yl 2-Deoxy-3-a zid o-4,6-O-isop r op ylid en e-N-(2-flu -
or o-5-n itr oben za m id o)-â-D-a llosa m in e (-)-30. A solution
of EDAC (101 mg, 0.47 mmol) in DCM (4 mL) was slowly added
to a stirred solution of amino sugar (+)-13 (46.6 mg, 0.18
mmol) and acid 16 (40 mg, 0.22 mmol) in DCM (3.6 mL) at 0
°C. Stirring was continued for 30 min, and the mixture was
then warmed to rt, diluted with DCM, and washed with
NaHCO3 (saturated aqueous, 100 mL), and brine (100 mL).
The organic layer was dried over MgSO4, filtered, and con-
centrated. Flash chromatography (2% MeOH/DCM) gave 76
mg (99% yield) of (-)-30 as a white solid: [R]20D -0.44 (c 0.64,
CHCl3); IR (CHCl3) 3050, 3000, 2900, 2120, 1680, 1530, 1350,
1620, 1480, 1200, 990, 850, 740 cm-1 1H NMR (500 MHz,
;
1270, 1200, 1100, 840, 800-650 cm-1
;
1H NMR (500 MHz,
CDCl3) δ 1.50 (s, 3 H), 1.60 (s, 3 H), 3.32 (m, 1 H), 3.52 (s, 3
H), 3.89 (m, 5 H), 4.58 (br s, 1 H), 4.67 (d, J ) 8.0 Hz, 1 H),
6.40 (br s, 1 H), 6.25 (d, J ) 8.0 Hz, 1 H), 6.92 (t, J ) 7.2 Hz,
1 H), 7.29 (m, 1 H), 8.75 (d, J ) 2.7 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ 166.9, 148.2, 134.0, 132.9, 119.9, 118.5, 117.6,
102.3, 100.0, 70.6, 65.3, 62.5, 58.3, 57.5, 55.6, 28.9, 19.1; high-
resolution mass spectrum (CI, NH3) m/z 334.1521 [(M)+, calcd
for C17H22N2O5 334.1529].
CDCl3) δ 1.44 (s, 1 H), 1.51 (s, 3 H), 3.45 (s, 3 H), 3.83 (m, 2
H), 3.96 (m, 2 H), 4.25 (dd, J 1 ) J 2 ) 3.2 Hz, 1 H), 4.33 (m, 2
H), 4.50 (d, J ) 8.3 Hz, 1 H), 6.94 (m, 1 H), 7.34 (dd, J ) 10.4,
9.0 Hz, 1 H), 8.36 (dd, J 1 ) J 2 ) 2.5 Hz, 1 H), 8.95 (dd, J )
6.5, 2.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 163.3 (d, J C-F
) 257 Hz), 160.5 (d, J C-F ) 3 Hz), 144.7, 128.6 (d, J C-F ) 4.0
Hz), 117.6 (d, J C-F ) 27.5 Hz), 100.7, 99.9, 72.9, 72.9, 65.2,
62.2, 61.4, 56.9, 51.6, 28.8, 28.7, 18.9; high-resolution mass
Meth yl 2-Deoxy-3-a m in o-O-6-a cylp yr a zin e-N-(o-a m i-
n oben zoyl)-r-D-glu cosa m in e Ben zod ia zep in on e (+)-35. A
solution of diol (+)-33 (3.1 mg, 0.009 mmol) in 2,4,6-collidine
(180 µL) was cooled to -40 °C. Freshly sublimed pyrazinoyl
chloride (1.4 mg, 0.009 mmol) was added, and the reaction
mixture was warmed gradually to rt overnight. The mixture
was concentrated in vacuo, and the residue was purified by
flash chromatography to give 2.9 mg (72% yield) of (+)-35 as
spectrum (CI, NH3) m/z 426.1427 [(M + H)+, calcd for C17H21
FN5O7 426.1425].
-
Meth yl 2-Deoxy-4,6-O-isop r op ylid en e-N-[(o-ben zyloxy-
ca r bon yla m in o)ben zoyl]-â-D-r iboh ex-3-u losa m in e (-)-32.
To a stirred solution of amino sugar (-)-14 (1.03 g, 4.4 mmol)
in DCM (10 mL) at 0 °C was added a solution of N-Cbz-
protected anthranilic acid (1.4 g, 5.3 mmol) and EDAC (1.1 g,
5.8 mmol) in DCM (5 mL). The mixture was warmed to rt,
diluted with DCM, and then washed with NaHCO3 (saturated)
and brine, dried over MgSO4, filtered, and concentrated. Flash
chromatography (50% ethyl acetate/hexanes) gave 1.7 g (82%
a yellow solid: [R]20 +121.8 (c 0.055, MeOH); IR (thin film)
D
3400, 2900, 2850, 1720, 1630, 1310, 1140, 960 cm-1; 1H NMR
(500 MHz, acetone-d6) δ 3.30 (m, 1 H), 3.47 (ddd, J ) 10.5,
10.5, 3.3 Hz, 1 H), 3.53 (s, 3 H), 3.68 (dd, J 1 ) J 2 ) 9.9 Hz, 1
H), 3.87 (br dd, J ) 11.8, 5.3 Hz, 1 H), 3.98 (ddd, J ) 9.9, 5.3,
2.6 Hz, 1 H), 4.66 (dd, J ) 10.5, 5.3 Hz, 1 H), 4.72 (d, J ) 8.1
yield) of the N-acylated product as a white solid: [R]20 -10.4
D
(c 0.22, CHCl3); IR (thin film) 3331, 2993, 2883, 1735, 1636,
J . Org. Chem, Vol. 69, No. 2, 2004 293

Abrous et al.
Hz, 1 H), 4.78 (dd, J ) 12.0, 5.2 Hz, 1 H), 5.18 (br s, 1 H), 6.77
(br s, 1 H), 7.10 (d, J ) 10.5 Hz, 1 H), 8.02 (dd, J ) 10.5, 3.3
Hz, 1H), 8.78 (br s, 1 H), 8.83 (m, 1 H), 9.24 (d, J ) 1.4 Hz, 1
H); 13C NMR (125 MHz, acetone-d6) δ 164.4, 151.6, 148.8,
146.8, 145.6, 144.5, 131.1, 127.5, 120.1, 120.0, 116.7, 102.8,
75.4, 70.1, 65.0, 64.9, 64.8, 56.9, 56.4; high-resolution mass
spectrum (CI, NH3) m/z 480.0943 [(M + Cl)-, calcd for
C19H19N5O8Cl 480.0922].
To a solution of monofuroyl derivative (-)-38 (2.1 mg, 0.0048
mmol) in 2,4,6-collidine (1 mL) at -40 °C was added 2-furoyl
chloride (0.4 µL, 0.052 mmol). The reaction mixture was
warmed to rt over 20 min and concentrated in vacuo. The
residue was purified by preparative TLC (500 µm, 5% MeOH/
DCM) to give 1.9 mg (78% yield) of (+)-39 as a yellow solid:
[R]20D +4.7 (c 0.15, CHCl3); IR (CHCl3) 3350, 2926, 2853, 1723,
1656, 1614, 1471, 1324, 1296, 1179, 1121, 1074, 759 cm-1; 1H
NMR (500 MHz, CDCl3) δ 3.56 (ddd, J ) 8.5, 8.5, 1.2 Hz, 2
H), 3.62 (s, 3 H), 3.75 (ddd, J ) 9.0, 9.0, 1.2 Hz, 1 H), 4.12 (m,
1 H), 4.47 (m, 2 H), 4.61 (dd, J ) 12.1, 2.7 Hz, 1 H), 5.22 (dd,
J 1 ) J 2 ) 9.5 Hz, 1 H), 6.29 (br s, 1 H), 6.49 (dd, J ) 3.5, 1.7
Hz, 1 H), 6.55 (dd, J ) 3.6, 1.7 Hz, 1 H), 6.63 (d, J ) 9.0 Hz,
1 H), 6.76 (br s, 1 H), 7.17 (d, J ) 3.5 Hz, 1 H), 7.33 (d, J ) 3.5
Hz, 1 H), 7.63 (s, 1 H), 8.03 (dd, J ) 9.0, 2.7 Hz, 1 H), 9.08 (d,
J ) 2.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 166.3, 159.6,
158.0, 149.9, 148.2, 146.9, 142.6, 139.7, 131.3, 127.7, 121.1,
119.0, 118.8, 115.0, 112.7, 112.0, 102.3, 72.6, 71.2, 62.5, 61.9,
57.8, 57.4; high-resolution mass spectrum (CI, NH3) m/z
527.1182 [(M)+, calcd for C24H21N3O11 527.1176].
Met h yl 2-Deoxy-3-a m in o-O-6-a cet yl-N-(o-a m in ob en -
zoyl)- r-D-glu cosa m in e ben zod ia zep in on e (+)-36. A solu-
tion of diol (+)-33 (10 mg, 0.03 mmol) in 2,4,6-collidine (300
µL) was cooled to -40 °C. After the solution was stirred for
20 min, acetyl chloride (2.5 µL, 0.035 mmol) was added. The
mixture was stirred an additional 3 h at -40 °C,warmed to
rt, and concentrated in vacuo. Flash chromatography (5%
MeOH/DCM) afforded 7.2 mg (89% yield) of (+)-36 as a yellow
solid: [R]20 +0.5 (c 0.2, CHCl3); IR (thin film) 3390, 3100,
D
2930, 1645, 1330, 1120, 1080, 830, 745 cm-1
;
1H NMR (500
MHz, CDCl3) δ 2.46 (s, 3 H), 3.37 (m, 2 H), 3.49 (dd, J 1 )J 2
)
9.2 Hz, 1 H), 3.56 (ddd, J ) 9.6, 9.6, 2.4 Hz, 1 H), 3.60 (s, 3 H),
4.19 (dd, J ) 12.4, 2.4 Hz, 1 H), 4.38 (d, J ) 7.8 Hz, 1 H), 4.78
(dd, J ) 12.7, 2.6 Hz, 1 H), 5.64 (s, 1 H), 6.64 (d, J ) 9.0 Hz,
1 H), 6.83 (s, 1 H), 8.03 (dd, J ) 9.0, 2.7 Hz, 1 H), 9.01 (d, J )
2.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) (lactam carbonyl C
not obsd due to long relax time) δ 174.7, 171.4, 150.3, 139.2,
131.0, 128.2, 119.1, 115.5, 102.5, 73.0, 70.1, 62.0, 57.3, 30.5,
21.0; high-resolution mass spectrum (CI, NH3) m/z 382.1238
[(M + H)+, calcd for C16H20N3O8 382.1250].
Meth yl 2-Deoxy-6-O-a cetyl-N-(o-h yd r oxyben zoyl)-â-D-
glu cosa m in e oxa zep in on e (-)-40. To a stirred solution of
diol (+)-34 (150 mg, 0.439 mmol) in DCM (10 mL) at 0 °C was
added TEA (370 µL, 2.6 mmol) followed by acetyl chloride (154
µL, 2.2 mmol). The solution was warmed to rt, stirred
overnight, and concentrated in vacuo, and the residue was
purified by flash chromatography (50% ethyl acetate/hexanes)
to afford 34.5 mg (82% yield) of a mixture of isomeric acylation
products (-)-40, (-)-41, and (-)-42. For (-)-40: [R]20 -16.0
Meth yl 2-Deoxy-3-am in o-O-4,6-diacetyl-N-(o-am in oben -
zoyl)-r-D-glu cosa m in e Ben zod ia zep in on e (-)-37. A solu-
tion of diol (+)-33 (44.7 mg, 0.132 mmol) was dissolved in DMF
(anhydrous, 6.6 mL) and cooled to 0 °C, and TEA (370 µL, 2.6
mmol) was added. After 5 min, acetyl chloride (28 µL, 0.40
mmol) was added, and the reaction was stirred overnight at
rt. The reaction was quenched with H2O (5 mL), and the layers
were separated. The aqueous layer was extracted with ethyl
acetate (3 × 10 mL), and the combined organic extracts were
washed with brine (10 mL), dried over MgSO4, filtered, and
concentrated. Flash chromatography (50% ethyl acetate/hex-
anes) gave 51.3 mg (85% yield) of (-)-37 as a yellow solid:
D
(c 0.2, CHCl3); IR (CHCl3) 3450, 2900, 2850, 1720, 1680, 1650,
1450, 1330, 1250, 1080, 1020 cm-1; 1H NMR (500 MHz, CDCl3)
δ 2.17 (s, 3 H), 3.02 (d, J ) 3.7 Hz, 1 H), 3.55 (dd, J 1 ) J 2
)
8.6 Hz, 1 H), 3.59 (m, 1 H), 3.61 (s, 3 H), 3.85 (m, 1 H), 4.07
(dd, J 1 ) J 2 ) 8.9 Hz, 1 H), 4.32 (d, J ) 7.9 Hz, 1 H), 4.39 (dd,
J ) 12.3, 2.2 Hz, 1 H), 4.59 (dd, J ) 12.3, 4.1 Hz, 1 H), 6.48 (s,
1 H), 7.19 (d, J ) 9.0 Hz, 1 H), 8.28 (dd, J ) 9.0, 2.9 Hz, 1 H),
9.25 (d, J ) 2.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 171.6,
163.1, 161.1, 143.3, 130.5, 128.4, 121.5, 102.2, 84.3, 74.0, 68.3,
62.5, 57.4, 57.3, 29.6, 20.7; high-resolution mass spectrum
(ESI) m/z 417.0721 [(M + Cl)-, calcd for C16H18N2O9Cl 417.0700].
[R]20 -7.6 (c 0.145, CHCl3); IR (thin film) 3300, 2900, 2350,
D
Meth yl 2-Deoxy-3-a m in o-6-O-ben zoyl-N-(2-h yd r oxy-5-
n itr oben zoyl)-â-D-glu cosa m in e Ben zod ia zep in on e (-)-47.
To a stirred solution of (+)-34 (11 mg, 0.032 mmol) in 2,4,6-
collidine (0.65 mL) at -40 °C was added benzoyl chloride (3.7
µL, 0.032 mmol). The reaction mixture was warmed to rt,
stirred for 15 h, and concentrated in vacuo. Preparative TLC
(500 µm, 5% MeOH/DCM) gave 4.0 mg (28% yield) of (-)-47
1785, 1650, 1600, 1330, 1240, 1040, 740 cm-1; H NMR (500
1
MHz, CDCl3) δ 2.12 (s, 3 H), 2.22 (s, 3H), 3.50 (br m, 1 H),
3.61 (m, 1 H), 3.63 (s, 3 H), 3.84 (m, 1 H), 4.22 (dd, J ) 9.4,
2.5 Hz, 1 H), 4.40 (d, J ) 8.1 Hz, 1 H), 4.47 (dd, J ) 11.3, 3.8
Hz, 1 H), 4.96 (dd, J 1 ) J 2 ) 9.5 Hz, 1 H), 6.13 (s, 1 H), 6.59
(d, J ) 9.0 Hz, 1 H), 6.82 (br s, 1 H), 8.05 (d, J ) 9.0 Hz, 1 H),
9.09 (br s, 1 H); 13C NMR (125 MHz, CDCl3) δ 173.1, 170.6,
139.6, 131.4, 127.7, 118.8, 114.9, 102.4, 76.5, 72.7, 69.9, 62.0,
61.6, 57.8, 57.5, 29.7, 20.9, 20.7; high-resolution mass spectrum
(CI, NH3) m/z 458.0971 [(M + Cl)-, calcd for C18H21N3O9Cl
458.0966].
as a yellow, waxy solid: [R]20 -44.5 (c 0.20, CHCl3); IR (thin
D
film) 3366, 3199, 3072, 2923, 2853, 1718, 1653, 1617, 1522,
1
1451, 1337, 1276, 1245, 1130, 1083, 748, 713 cm-1; H NMR
(500 MHz, CDCl3) δ 3.56 (dd, J 1 ) J 2 ) 8.6 Hz, 1 H), 3.62 (s,
3 H), 3.73 (ddd, J ) 9.9, 2.3, 2.3 Hz, 1 H), 3.93 (dd, J 1 ) J 2
)
9.8 Hz, 1 H), 4.12 (dd, J 1 ) J 2 ) 8.9 Hz, 1 H), 4.37 (d, J ) 8.0
Hz, 1 H), 4.64 (dd, J ) 12.3, 2.2 Hz, 1 H), 4.84 (dd, J ) 12.3,
4.3 Hz, 1 H), 6.60 (br s, 1 H), 7.16 (d, J ) 9.0 Hz, 1 H), 7.47 (t,
J ) 7.8 Hz, 2 H), 7.62 (t, J ) 7.4 Hz, 1 H), 8.09 (d, J ) 8.3 Hz,
2 H), 8.26 (dd, J ) 9.0 and 2.9 Hz, 1 H), 9.23 (d, J ) 2.9 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 167.2, 163.2, 161.2, 143.3,
133.6, 130.6, 129.9, 129.4, 128.6, 128.5, 121.6, 121.0, 102.3,
84.4, 74.4, 68.5, 63.1, 57.5, 57.4; high-resolution mass spectrum
(ESI) m/z 479.0869 [(M + Cl)-, calcd for C21H20ClN2O9 479.0857].
Meth yl 2-Deoxy-3-am in o-O-6-(2-fu r oyl)-N-(o-am in oben -
zoyl)-r-D-glu cosa m in e Ben zod ia zep in on e (-)-38. To a
solution of diol (+)-33 (4.9 mg, 0.0144 mmol) in 2,4,6-collidine
(1 mL) at -40 °C was added 2-furoyl chloride (1.5 µL, 0.015
mmol). The reaction mixture was warmed to rt over 20 min
and concentrated in vacuo. The residue was purified by
preparative TLC (500 µm, 5% MeOH/DCM) to give 4.4 mg
(71% yield) of (-)-38 as a white solid: [R]20 -12.5 (c 0.120,
D
CHCl3); IR (CHCl3) 3316, 2922, 2851, 1713, 1649, 1463, 1322,
1298, 1171, 1122, 1081, 762, 742 cm-1 1H NMR (500 MHz,
;
Meth yl 2-Deoxy-3-a m in o-6-O-n icotin oyl-N-(2-h yd r oxy-
5-n itr oben zoyl)-â-D-glu cosa m in e ben zod ia zep in on e (-)-
48. To a stirred solution of (+)-34 (4.2 mg, 0.012 mmol) in DMF
(anhydrous, 200 µL) were added nicotinic acid (1.5 mg, 0.012
mmol), DIPEA (8 µL, 0.05 mmol), BOP coupling reagent (11
mg, 0.024 mmol), HOAt (4.9 mg, 0.036 mmol), and a catalytic
amount of DMAP. The resultant bright yellow mixture was
stirred for 20 h at rt and concentrated in vacuo to give a brown
residue. Preparative TLC (500 µm, 5% MeOH/DCM) gave 2.0
CDCl3) δ 3.34-3.66 (m, 8 H), 4.13 (br s, 1 H), 4.45 (m, 1 H),
5.10 (d, J ) 8.2 Hz, 1 H), 5.30 (s, 1 H), 5.62 (s, 1 H), 6.31 (s, 1
H), 6.79 (d, J ) 9.0 Hz, 1 H), 7.40 (d, J ) 3.0 Hz, 1 H), 7.81 (s,
1 H), 8.05 (dd, J ) 9.0, 3.0 Hz, 1 H), 9.1 (s, 1 H); 13C NMR
(125 MHz, CDCl3) δ 166.1, 161.6, 155.2, 149.0, 147.6, 140.7,
138.8, 134.9, 132.4, 125.5, 114.7, 115.9, 101.9, 74.8, 72.1, 63.7,
61.9, 56.7; high-resolution mass spectrum (CI, NH3) m/z
433.1123 [(M)+, calcd for C19H19N3O9 433.1121].
Meth yl 2-Deoxy-3-a m in o-O-4,6-d i(2-fu r oyl)-N-(o-a m i-
n oben zoyl)-r-D-glu cosa m in e Ben zod ia zep in on e (+)-39.
mg (42% yield) of (-)-48 as a white powder: [R]20 -62.5 (c
D
0.080, CHCl3); IR (thin film) 3406, 3183, 3061, 2920, 2849,
294 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
1725, 1659, 1619, 1593, 1512, 1436, 1355, 1284, 1239, 1127,
was poured into ethyl acetate (10 mL) and washed with 1 N
NaOH (aq., 2 × 5 mL). The combined aqueous washes were
adjusted to pH 5-6 with acetic acid and re-extracted with ethyl
acetate (4 × 10 mL). The combined organic extracts were dried
over MgSO4, filtered, and concentrated. The residue was
passed through a short column of silica gel, eluting with 5%
MeOH/DCM, to give 20.0 mg (74%) of (-)-64 as a yellow
1
1082, 1041 cm-1; H NMR (500 MHz, CDCl3) δ 3.13 (br s, 1
H), 3.56 (dd, J 1 ) J 2 ) 8.6 Hz, 1 H), 3.61 (s, 3 H), 3.77 (ddd,
J ) 9.8, 2.4, 2.4 Hz, 1 H), 3.96 (dd, J 1 ) J 2 ) 9.1 Hz, 1 H),
4.11 (dd, J 1 ) J 2 ) 9.0 Hz, 1 H), 4.37 (d, J ) 7.9 Hz, 1 H), 4.73
(dd, J ) 12.2, 2.3 Hz, 1 H), 4.80 (dd, J ) 12.2, 4.5 Hz, 1 H),
6.49 (br s, 1 H), 7.19 (d, J ) 9.0 Hz, 1 H), 7.43 (dd, J ) 8.0, 4.9
Hz, 1 H), 8.28 (dd, J ) 9.0, 2.9 Hz, 1 H), 8.34 (ddd, J ) 7.9,
1.9, 1.9 Hz, 1 H), 8.82 (dd, J ) 4.9, 1.7 Hz, 1 H), 9.26 (d, J )
2.8 Hz, 1 H), 9.28 (d, J ) 1.9 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 165.5, 163.1, 161.1, 160.2, 153.9, 151.1, 143.4, 137.3,
130.7, 128.5, 125.5, 123.4, 121.6, 120.8, 102.3, 84.5, 74.0, 68.6,
57.5, 57.4; high-resolution mass spectrum (ESI) m/z 480.0830
[(M + Cl)-, calcd for C20H19ClN3O9 480.0810].
Met h yl 2-Deoxy-3-a m in o-4,6-O-d in icot in oyl-N-(o-h y-
d r oxyben zoyl)-â-D-glu cosa m in e ben zod ia zep in on e (+)-
53. To a stirred solution of diol (+)-33 (15 mg, 0.044 mmol) in
NMP (peptide synthesis grade, 0.15 mL) in a 1-dram vial were
added nicotinic acid (22 mg, 0.18 mmol), diisopropyl carbodi-
imide (DIPCDI, 28 µL, 0.18 mmol), and HOAt (25 mg, 0.18
mmol). The vial was closed, and the mixture was stirred 17.5
h at 60 °C. The reaction mixture was loaded directly onto a
silica gel column and purified by flash chromatography (5%
MeOH/DCM) to give 17 mg (70% yield) of (+)-53 as a yellow
foam: [R]20D +78.3 (c 0.925, CHCl3); IR (thin film) 3349, 3300,
3188, 3080, 2925, 2854, 1733, 1699, 1653, 1615, 1591, 1549,
1506, 1482, 1423, 1325, 1283, 1196, 1122, 1079, 1025, 991, 966,
915, 827, 739, 701 cm-1; 1H NMR (500 MHz, acetone-d6) δ 3.62
(s, 3 H), 3.79 (ddd, J ) 8.6, 8.6, 3.2 Hz, 1 H), 4.31 (t, J ) 9.3
Hz, 1 H), 4.39-4.43 (m, 1 H), 4.57 (dd, J ) 12.2, 4.8 Hz, 1 H),
4.67 (dd, J ) 12.2, 3.0 Hz, 1 H), 4.94 (d, J ) 8.0 Hz, 1 H), 5.54
(dd, J 1 ) J 2 ) 9.6 Hz, 1 H), 6.81 (br s, 1 H), 6.91 (d, J ) 9.2
Hz, 1 H), 7.48 (dd, J ) 7.9, 4.8 Hz, 1 H), 7.54 (dd, J ) 8.0, 4.8
Hz, 1 H), 7.56 (br s, 1 H), 8.01 (dd, J ) 9.1, 2.8 Hz, 1 H), 8.28
(ddd, J ) 7.9, 1.8, 1.8 Hz, 1 H), 8.38 (d, J ) 8.0 Hz, 1 H), 8.76-
8.78 (m, 1 H), 8.81 (d, J ) 3.5 Hz, 1 H), 9.13 (s, 1 H), 9.21 (s,
1 H); 13C NMR (125 MHz, acetone-d6) δ 167.8, 166.1, 165.4,
154.8, 154.5, 151.3, 151.1, 151.0, 139.7, 138.0, 137.5, 130.4,
127.6, 126.5, 124.4, 124.3, 120.8, 120.7, 118.6, 102.8, 73.2, 72.8,
64.2, 63.5, 57.1, 56.3; high-resolution mass spectrum (ESI) m/z
550.1576 [(M + H)+, calcd for C26H24N5O9 550.1574].
solid: [R]20 -22.4 (c 0.165, CHCl3); IR (CHCl3) 3400, 2900,
D
2850, 1720, 1630, 1310, 1140, 960 cm-1; H NMR (500 MHz,
1
MeOH-d4) δ 3.49 (dd, J 1 ) J 2 ) 8.8 Hz, 1 H), 3.58 (s, 3 H),
3.71 (ddd, J ) 8.8, 8.8, 5.9 Hz, 1 H), 3.76 (dd, J 1 ) J 2 ) 9.9
Hz, 1 H), 3.80 (dd, J ) 13.2, 10.2 Hz, 1 H), 3.87 (dd, J 1 ) J 2
)
7.9 Hz, 1 H), 4.39 (dd, J ) 7.9, 5.3 Hz, 1 H), 4.68 (d, J ) 8.1
Hz, 1 H), 5.80 (s, 1 H), 6.99 (d, J ) 9.9 Hz, 1 H), 7.47 (dd, J )
9.8, 4.0 Hz, 1 H), 8.04 (dd, J ) 9.9, 1.4 Hz, 1 H), 8.56 (d, J )
3.9 Hz, 1 H), 8.73 (s, 1 H), 8.78 (d, J ) 1.4 Hz, 1 H) (amido,
amine NH’s not obsd due to exchange with CD3OD); 13C NMR
(125 MHz, MeOH-d4) δ 164.4, 151.6, 148.8, 146.8, 145.6, 144.5,
131.1, 127.5, 120.1, 120.0, 116.7, 102.8, 101.6, 75.4, 70.1, 65.0,
64.9, 64.8, 56.9, 56.4; high-resolution mass spectrum (CI, NH3)
m/z 429.1411 [(M + H)+, calcd for C20H21N4O7 429.1410].
Meth yl 2-Deoxy-3-a m in o-4,6-O-d im eth yl-N-(2-a m in o-5-
n itr oben zoyl)-N-m eth yl-â-D-glu cosa m in e Ben zod ia zep i-
n on e (+)-67. To a stirred solution of diol (+)-33 (4.0 mg, 0.012
mmol) in DMF (100 µL) at 0 °C was added iodomethane (3.2
µL, 0.052 mmol), followed by sodium hydride (60% dispersion
in mineral oil, 14 mg, 0.65 mmol). The reaction was stirred
overnight at rt, poured into H2O, and extracted with DCM.
Combined organic extracts were dried over MgSO4, filtered,
and concentrated. Flash chromatography (5% MeOH/DCM)
gave 2.4 mg (54% yield) of (+)-67 as a yellow solid: [R]20D +156
(c 0.08, CHCl3); IR (thin film) 2900, 2850, 1620, 1480, 1440,
1300, 1030, 880, 750, 720 cm-1; 1H NMR (500 MHz, CDCl3) δ
3.12 (s, 3 H), 3.28 (m, 1 H), 3.35 (m, 1 H), 3.40 (s, 3 H), 3.54 (s,
3 H), 3.62 (s, 3 H), 3.62-3.68 (m, 4 H), 4.61 (d, J ) 7.7 Hz, 1
H), 5.81 (br s, 1 H), 6.65 (d, J ) 8.9 Hz, 1 H), 8.11 (dd, J ) 8.9,
2.7 Hz, 1 H), 8.59 (d, J ) 2.7 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 168.2, 148.2, 141.5, 128.5, 127.3, 124.8, 119.9, 101.0,
70.7, 63.5, 60.6, 59.3, 57.8, 56.4, 29.7, 28.6, 14.1; high-
resolution mass spectrum (CI, NH3) m/z 382.1603 [(M + H)+,
calcd for C17H24N3O7 382.1614].
Meth yl 2-Deoxy-3-a m in o-6-O-(p h en ylca r ba m a te)-N-(2-
a m in o-5-n itr oben zoyl)-â-D-glu cosa m in e Ben zod ia zep i-
n on e (+)-54. Diol (+)-33 (2.0 mg, 0.0060 mmol) was dissolved
in DMF (anhydrous, 100 µL), and phenyl isocyanate (1 µL,
0.009 mmol) was added. The resulting yellow solution was
stirred 18 h at rt and then concentrated in vacuo. Preparative
TLC (500 µm, 10% MeOH/DCM) gave 4.0 mg (99% yield) of
(+)-54 as a yellow solid: [R]20D +83.6 (c 0.11, MeOH); IR (thin
film) 3335, 3082, 2954, 2925, 1700, 1636, 1613, 1541, 1507,
Meth yl 2-Deoxy-3-a m in o-6-O-(3-p icolyl)-N-(2-a m in o-5-
n itr oben zoyl)-â-D-glu cosa m in e Ben zod ia zep in on e (-)-68.
A solution of (+)-33 (10 mg, 0.029 mmol) in DMF (anhydrous,
200 µL) was added to a stirred suspension of sodium hydride
(anhydrous powder, 3.5 mg, 0.15 mmol) and 3-picolyl chloride‚
HCl (9.5 mg, 0.058 mmol) via syringe. A crystal of TBAI was
added, and the resultant red mixture was stirred for 17 h at
rt. The mixture was quenched with NH4Cl (50 mg) and
concentrated in vacuo to give a yellow-orange residue, which
was purified by preparative TLC (500 µm, 10% MeOH/DCM)
to give 3.2 mg (24% combined yield) of (-)-68 accompanied by
a minor amount of the C-6 alkylated isomer, which was
removed using semi-prep HPLC {Waters NovaPak Silica 6 µm,
19 × 300 mm, 50% IPA/hexanes, tR [(-)-68] ) 34.75 min, flow
rate ) 10 mL/min} to give 2.0 mg of purified (-)-68 as a yellow
solid: [R]20D -22.2 (c 0.045, CHCl3); IR (thin film) 3322, 3181,
3078, 2953, 2918, 2852, 1657, 1648, 1642, 1632, 1613, 1585,
1548, 1534, 1477, 1463, 1435, 1317, 1247, 1125, 1068, 913, 829,
791 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.39 (dd, J 1 ) J 2 ) 8.2
Hz, 1 H), 3.47 (d, J ) 9.0 Hz, 1 H), 3.57 (s, 3 H), 3.64-3.73
(m, 2 H), 3.75-3.81 (m, 2 H), 3.94 (dd, J ) 9.8, 4.1 Hz, 1 H),
4.35 (d, J ) 7.7 Hz, 1 H), 4.61 (d, J ) 12.2 Hz, 1 H), 4.70 (d,
J ) 12.2 Hz, 1 H), 5.72 (br s, 1 H), 6.45 (br s, 1 H), 6.70 (d, J
) 9.0 Hz, 1 H), 7.36 (br s, 1 H), 7.69 (d, J ) 8.0 Hz, 1 H), 8.06
(dd, J ) 9.0, 2.6 Hz, 1 H), 8.63 (br s, 2 H), 9.08 (d, J ) 2.7 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 166.6, 150.2, 149.0, 139.3,
136.8, 131.4, 131.1, 129.2, 127.7, 118.7, 114.8, 102.3, 73.5, 71.6,
71.4, 70.9, 68.1, 61.8, 57.2, 55.7; high-resolution mass spectrum
(ESI) m/z 453.1380 [(M + Na)+, calcd for C20H22N3O7Na
453.1386].
1445, 1320, 1227, 1158, 1123, 1057, 966, 914, 821, 749 cm-1
;
1H NMR (500 MHz, acetone-d6) δ 3.38 (ddd, J ) 8.2, 3.4, 3.4
Hz, 1 H), 3.55 (s, 3 H), 3.62 (dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 3.67
(dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 3.78 (ddd, J ) 9.3, 2.2, 2.2 Hz, 1
H), 4.43 (dd, J ) 11.7, 2.1 Hz, 1 H), 4.49 (dd, J ) 12.1, 4.4 Hz,
1 H), 4.67 (d, J ) 8.0 Hz, 1 H), 5.20 (br s, 1 H), 6.85 (br s, 1
H), 7.03 (t, J ) 7.4 Hz, 1 H), 7.07 (br s, 1 H), 7.10 (d, J ) 9.2
Hz, 1 H), 7.29 (d, J ) 8.4 Hz, 1 H), 7.30 (d, J ) 8.4 Hz, 1 H),
7.56 (d, J ) 8.2 Hz, 2 H), 8.01 (dd, J ) 9.0, 2.7 Hz, 1 H), 8.79
(br s, 1 H), 8.84 (dd, J 1 ) J 2 ) 2.7 Hz, 1 H); 13C NMR (125
MHz, MeOH-d4) δ 170.1, 155.9, 152.2, 140.1, 139.6, 131.1,
129.8, 128.4, 124.2, 120.4, 119.9, 119.6, 102.9, 76.4, 70.5, 65.6,
64.6, 57.2, 56.9; high-resolution mass spectrum (FAB, NBA
matrix) m/z 481.1335 [(M + Na)+, calcd for C21H22N4O8Na
481.1346].
Meth yl 2-Deoxy-3-a m in o-4,6-O-(3-p yr id yla ceta l)-N-(o-
a m in oben zoyl)-â-D-glu cosa m in e ben zod ia zep in on e (-)-
64. To a stirred solution of diol (+)-33 (18.3 mg, 0.05 mmol) in
DMF (anhydrous, 540 µL) was added 3-pyridyl carboxaldehyde
(13.2 µL, 0.14 mmol), followed by pTSA (20 mg, 0.065 mmol).
A reflux condenser was affixed, and the mixture was brought
to reflux. After being stirred overnight at 100 °C, the mixture
J . Org. Chem, Vol. 69, No. 2, 2004 295

Abrous et al.
Meth yl 2-Deoxy-3-am in o-4,6-O-bis(3-picolyl)-N-(2-am in o-
5-n itr oben zoyl)-â-D-glu cosa m in e Ben zod ia zep in on e (-)-
69. A solution of (-)-68 (6.1 mg, 0.014 mmol; accompanied by
a minor amount of the C-6 alkylated isomer) in DMF (anhy-
drous, 200 µL) was added to a stirred suspension of sodium
hydride (99%, anhydrous powder, 2.2 mg, 0.070 mmol) and
3-picolyl chloride‚HCl (7.2 mg, 0.044 mmol) via syringe. A
crystal of TBAI was added, and the resultant red mixture was
stirred for 20 h at rt. The mixture was quenched with NH4Cl
(50 mg) and concentrated in vacuo to give a red residue, which
was purified by preparative TLC (500 µm, 10% MeOH/DCM)
MHz, CDCl3) δ 169.1, 149.6, 143.2, 137.6, 137.2, 133.5, 128.6,
128.0, 128.0, 127.9, 127.7, 127.4, 126.5, 125.9, 122.9, 100.2,
99.4, 74.0, 67.7, 66.7, 62.1, 62.0, 56.4, 55.8, 46.0, 29.2, 19.2;
high-resolution mass spectrum (CI, NH3) m/z 560.2396 [(M +
H)+, calcd for C31H34N3O7 560.2397].
Meth yl 2-Deoxy-3-a m in o-N-(o-a m in oben zoyl)-N-ben -
zyla m id e-â-D-glu cosa m in e Ben zod ia zep in on e (+)-73. A
solution of (+)-71 (11.6 mg, 0.02 mmol) in wet CHCl3 was
stirred at rt for 2 h and concentrated in vacuo. Flash chroma-
tography (5% MeOH/DCM) gave the acetonide deprotection
product, which was stirred overnight in wet CHCl3 to give 7.3
to give 3.2 mg (29% yield) of (-)-69 as a yellow solid: [R]20
mg (82% yield, two steps) of (+)-73 as a yellow solid: [R]20
D
D
-10 (c 0.060, CHCl3); IR (thin film) 2922, 2855, 1658, 1606,
+143 (c 0.065 CH2Cl2); IR (thin film) 3327, 2916, 2839, 1621,
1477, 1316, 1259, 1121, 1069, 831, 793, 722 cm-1 1H NMR
;
1
1491, 1445, 1323, 1070, 745 cm-1; H NMR (500 MHz, CD2-
(500 MHz, CDCl3) δ 3.37 (ddd, J ) 7.7, 7.7, 1.7 Hz, 1 H), 3.48
Cl2) δ 1.87 (m, 1 H), 2.77 (d, J ) 4.8 Hz, 1 H), 3.13 (m, 1 H),
3.28 (dd, J 1 ) J 2 ) 11.5 Hz, 1 H), 3.40 (s, 3 H), 3.53 (m, 1 H),
3.75 (dd, J ) 11.5, 7.9 Hz, 1 H), 3.78 (m, 2 H), 3.79 (m, 1 H),
4.26 (d, J ) 16.0 Hz, 1 H), 4.70 (d, J ) 7.9 Hz, 1 H), 5.13 (br
s, 1 H), 5.56 (d, J ) 16.0 Hz, 1 H), 6.78 (d, J ) 8.8 Hz, 1 H),
7.35 (m, 4 H), 8.10 (dd, J ) 8.8, 2.7 Hz, 1 H), 8.57 (d, J ) 2.7
Hz, 1 H); 13C NMR (125 MHz, CD2Cl2) δ 168.6, 148.7, 141.1,
137.7, 128.6, 128.6, 128.5, 127.5, 127.3, 127.1, 124.2, 120.3,
100.0, 75.0, 71.3, 65.3, 62.2, 58.3, 55.8, 45.8, 29.6; high-
resolution mass spectrum (ESI) m/z 464.1224 [(M + Cl)-, calcd
for C21H23N3O7Cl 464.1224].
1
(dd, J ) J 2 ) 9.3 Hz, 1 H), 3.59 (s, 3 H), 3.63-3.64 (m, 1 H),
3.73 (dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 3.88 (dd, J ) 11.6, 1.8 Hz, 1
H), 3.96 (dd, J ) 11.5, 2.9 Hz, 1 H), 4.34 (d, J ) 7.8 Hz, 1 H),
4.61 (d, J ) 12.2 Hz, 1 H), 4.67 (d, J ) 12.1 Hz, 1 H), 4.78 (d,
J ) 12.2 Hz, 1 H), 4.86 (d, J ) 12.2 Hz, 1 H), 5.93 (d, J ) 9.0
Hz, 1 H), 6.47 (br s, 1 H), 7.33 (dd, J ) 7.7, 4.7 Hz, 1 H), 7.39
(dd, J ) 7.6, 4.9 Hz, 1 H), 7.65 (d, J ) 7.5 Hz, 1 H), 7.74 (d, J
) 7.5 Hz, 1 H), 7.96 (dd, J ) 9.0, 2.7 Hz, 1 H), 8.60 (br m, 1
H), 8.66 (br m, 2 H), 8.73 (br m, 2 H), 8.98 (d, J ) 2.7 Hz, 1
H); 13C NMR (125 MHz, CDCl3) δ 166.7, 150.4, 149.8, 149.5,
149.3, 149.2, 136.2, 135.6, 132.8, 132.6, 131.0, 127.7, 124.0,
123.4, 118.5, 102.3, 75.9, 75.7, 71.4, 71.0, 61.1, 59.2, 57.1, 55.8,
24.2, 19.7; high-resolution mass spectrum (ESI) m/z 544.1793
[(M + Na)+, calcd for C26H27N5O7Na 544.1808].
Met h yl 2-Deoxy-3-a m in o-4,6-O-isop r op ylid en e-N-(o-
a m in oben zoyl)-N,N-d im eth yl-â-D-glu cosa m in e Ben zod i-
a zep in on e (+)-74. To a stirred solution of (+)-1 (11.0 mg, 0.03
mmol) in THF (600 µL) at 0 °C was added sodium hydride
(60% dispersion in mineral oil, 11.6 mg, 0.29 mmol). The
resultant suspension was stirred for 20 min at 0 °C, and
iodomethane (7.2 µL, 0.12 mmol) was added. The mixture was
warmed to rt, quenched with NH4Cl (saturated aqueous, 5
mL), and poured into H2O (5 mL). The resulting solution was
extracted with DCM (3 × 10 mL), and the combined organic
layers were dried over MgSO4, filtered, and concentrated.
Flash chromatography (5% MeOH/DCM) gave 11.0 mg (94%
Meth yl 2-Deoxy-3-a m in o-6-O-ben zyl-N-(2-a m in o-5-n i-
tr oben zoyl)-â-D-glu cosa m in e Ben zod ia zep in on e (-)-70.
A solution of (+)-33 (6.3 mg, 0.018 mmol) and dibutyltin oxide
(4.6 mg, 0.018 mmol) was heated at reflux in benzene
overnight with azeotropic removal of water. The mixture was
concentrated to ca. 1 mL and TBAI (cat.) was added, followed
by benzyl bromide (4.6 mL, 0.04 mmol). The resulting solution
was brought to reflux, stirred for 24 h, cooled to rt, and
concentrated in vacuo. Flash chromatography gave 6.4 mg
(82% yield) of (-)-70: [R]20D -31.1 (c 0.045 CDCl3); IR (CDCl3)
3320, 2910, 2820, 1620, 1400, 1310, 1120, 1060, 740 cm-1; 1H
yield) of (+)-74 as a yellow solid: [R]20 +223 (c 0.4 CHCl3);
D
IR (CHCl3) 3100, 2950, 2890, 1650, 1600, 1520, 1490, 1340,
1220, 1000, 800-650 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.44
(s, 3 H), 1.48 (s, 3 H), 3.10 (s, 3 H), 3.11 (s, 3 H), 3.28 (m, 1 H),
3.52 (s, 3 H), 3.53 (m, 2 H), 3.69 (m, 2 H), 3.92 (dd, J ) 11.0,
5.3 Hz, 1 H), 4.66 (d, J ) 7.8 Hz, 1 H), 7.01 (d, J ) 8.9 Hz, 1
H), 8.22 (dd, J ) 8.9, 2.8 Hz, 1 H), 8.49 (d, J ) 2.8 Hz, 1 H);
13C NMR (125 MHz, CDCl3) δ 168.4, 151.2, 142.2, 130.9, 127.0,
126.4, 121.0, 100.9, 99.4, 74.4, 68.1, 67.1, 62.2, 60.8, 56.4, 41.6,
29.2, 28.2, 19.1; high-resolution mass spectrum (CI, NH3) m/z
408.1770 [(M + H)+, calcd for C19H26N3O7 408.1771].
NMR (500 MHz, CDCl3) δ 1.65 (br s, 1 H), 3.46 (dd, J 1 ) J 2
)
9.0 Hz, 1 H), 3.55 (s, 3 H), 3.69 (m, 3 H), 3.91 (m, 1 H), 4.33
(d, J ) 7.8 Hz, 1 H), 4.58 (d, J ) 11.7 Hz, 1 H), 4.63 (d, J )
11.7 Hz, 1 H), 5.55 (br s, 1 H), 6.44 (br s, 1 H), 6.66 (d, J ) 9.0
Hz, 1 H), 7.36 (m, 5 H), 8.06 (dd, J ) 9.0, 2.7 Hz, 1 H), 9.08 (d,
J ) 2.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 166.9, 150.2,
139.4, 136.7, 131.4, 128.8, 127.9, 127.8, 127.7, 118.8, 115.0,
102.3, 72.9, 72.7, 71.2, 61.9, 57.3, 55.6, 29.7; high-resolution
mass spectrum (ESI) m/z 428.1472 [(M - H)-, calcd for
Met h yl 2-Deoxy-3-a m in o-4,6-O-isop r op ylid en e-N-(o-
a m in ob en zoyl)-N-t r iflu or oa cet a m id e-â-D-glu cosa m in e
Ben zod ia zep in on e (+)-75. To a stirred solution of (+)-1 (35.0
mg, 0.092 mmol) in DCM (10 mL) at 0 °C was added TEA (76
µL, 0.55 mmol) followed by trifluoroacetic anhydride (39 µL,
0.27 mmol). The reaction mixture was warmed to rt, stirred
for 3.5 h, and then concentrated in vacuo. Flash chromatog-
raphy (50% ethyl acetate/hexanes) gave 33.5 mg (74% yield)
C
21H22N3O7 428.1458].
Meth yl 2-Deoxy-3-a m in o-4,6,-O-isop r op ylid en e-N-(o-
a m in oben zoyl)-N,N-d iben zyl-â-D-glu cosa m in e Ben zod i-
a zep in on e (+)-71. To a stirred solution of (+)-1 (15.1 mg, 0.04
mmol) in THF (600 µL) at 0 °C was added sodium hydride
(60% dispersion in mineral oil, 3.6 mg, 0.09 mmol). The
mixture was stirred for 20 min at 0 °C, and benzyl bromide
(15 µL, 0.125 mmol) was added, followed by TBAI (cat.). The
mixture was stirred at rt overnight, quenched with saturated
NH4Cl, poured into water (5 mL), and extracted with DCM (3
× 10 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated. Flash chromatography
(33% ethyl acetate/hexanes) provided 20.1 mg (90% yield) of
of (+)-75 as a yellow solid: [R]20 +12 (c 0.8, CHCl3); IR
D
(CHCl3) 3020, 2890, 1680, 1540, 1350, 1220, 1160, 1090 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.46 (s, 6 H), 3.01 (m, 1 H), 3.42
(m, 1 H), 3.56 (s, 3 H), 3.57 (m, 1 H), 3.71 (dd, J 1 ) J 2 ) 10.5
Hz, 1 H), 3.96 (dd, J ) 10.9, 5.1 Hz, 1 H), 4.70 (d, J ) 7.6 Hz,
1 H), 5.04 (m, 1 H), 6.87 (s, 1 H), 7.42 (d, J ) 8.3 Hz, 1 H),
8.45 (dd, J ) 8.5, 2.6 Hz, 1 H), 8.63 (d, J ) 2.6 Hz, 1 H);
(trifluoroacetamide carbonyl C not obsd due to long relax time)
13C NMR (125 MHz, CDCl3) δ 167.0, 149.0, 138.0, 136.5, 131.0,
127.0, 125.5, 117.0, 115.0, 101.5, 100.1, 70.0, 64.5, 62.0, 57.5,
56.5, 29.0, 19.0; high-resolution mass spectrum (CI, NH3) m/z
493.1546 [(M + NH4)+, calcd for C19H24F3N4O8 493.1547].
(+)-71 as a bright yellow solid: [R]20 +448 (c 0.3, CHCl3); IR
D
(CHCl3) 3005, 2925, 2890, 2840, 2395, 1650, 1600, 1530, 1440,
1380, 1200, 1090, 710 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.46
(s, 3 H), 1.49 (s, 3 H), 3.10 (m, 1 H), 3.21 (s, 3 H), 3.34 (m, 1
H), 3.50 (dd, J 1 ) J 2 ) 9.2 Hz, 1 H), 3.61 (m, 2 H), 3.82 (dd, J
) 11.0, 5.4 Hz, 1 H), 4.40 (d, J ) 15.2 Hz, 1 H), 4.53 (d, J )
15.2 Hz, 1 H), 4.57 (d, J ) 10.0 Hz, 1 H), 4.68 (d, J ) 15.2 Hz,
1 H), 5.21 (d, J ) 15.7 Hz, 1 H), 7.12 (d, J ) 7.0 Hz, 1 H), 7.18
(m, 2 H), 7.26 (m, 4 H), 7.30 (m, 2 H), 7.37 (m, 2 H), 8.11 (dd,
J ) 8.8, 2.7 Hz, 1 H), 8.50 (d, J ) 2.7 Hz, 1 H); 13C NMR (125
Tr icyclic Hybr id (-)-2. To a stirred solution of (+)-1 (10
mg, 0.026 mmol) in MeOH (1 mL) was added a catalytic
amount of 5% palladium on activated carbon. The reaction
vessel was repeatedly evacuated and purged with argon and
296 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
then hydrogen. The suspension was stirred under hydrogen
for 1 h and then repeatedly evacuated and purged with argon.
The reaction mixture was filtered through Celite, and the filter
cake was washed with MeOH. The pale green filtrate was
concentrated maintaining the water bath at 25 °C in the dark.
The light- and air-sensitive aniline was rapidly transferred to
a 5 mL conical flask and taken up in DMF (100 µL). In a
separate flask, a solution of isoamyl nitrite (5.3 µL, 0.04 mmol)
in DMF (160 µL) was heated to 40 °C, and the aniline solution
was added slowly via cannula. Stirring was maintained for 5
h, and H2O (5 mL) was added to the resultant red mixture.
The layers were separated, and the aqueous phase was
extracted with ethyl acetate (4 × 10 mL). The combined
organic extracts were dried over Na2SO4, filtered, and con-
centrated. The residue was purified by preparative TLC
(500 µm, 5% MeOH/DCM) to give 3.6 mg (42% yield, two steps)
2.5 mmol) was added, and the mixture was stirred for 2 h at
-78 °C and then brought to rt. The solvent was removed under
reduced pressure to give a yellow oily residue. Flash chroma-
tography (hexanes-ethyl acetate, 1:1) gave 175 mg (60% yield)
of (-)-77 as a colorless, viscous oil: [R]20 -36.8 (c 0.226,
D
CHCl3); IR (thin film) 3394, 3314, 2993, 2954, 2912, 2876,
2837, 1458, 1381, 1200, 1173, 1147, 1125, 1100, 1085, 1017,
1
949, 857, 806, 735 cm-1; H NMR (500 MHz, CDCl3) δ 0.58-
0.71 (m, 6 H), 0.96 (t, J ) 7.9 Hz, 9 H), 1.40 (s, 3 H), 1.46 (s,
3 H), 1.59 (br s, 2 H), 2.77 (t, J ) 8.3 Hz, 1 H), 3.22 (ddd, J )
9.9, 9.9, 5.4 Hz, 1 H), 3.48 (t, J ) 4.5 Hz, 2 H), 3.52 (s, 3 H),
1
3.78 (dd, J ) J 2 ) 10.6 Hz, 1 H), 3.90 (dd, J ) 10.7, 5.4 Hz,
1 H), 4.17 (d, J ) 7.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
105.5, 99.4, 75.4, 74.0, 67.6, 62.2, 58.8, 57.3, 29.1, 18.9, 6.9,
5.1; high-resolution mass spectrum (ESI) m/z 370.2018 [(M +
Na)+, calcd for C16H33NO5SiNa 370.2025].
of (-)-2 as a yellow oil: [R]20 -59 (c 0.2, CHCl3); IR (CHCl3)
D
Meth yl 2-Deoxy-3-tr ieth ylsilyl-4,6-O-isop r op ylid en e-N-
ben zyl-â-D-glu cosa m in e (-)-78. Amino sugar (-)-77 (175
mg, 0.504 mmol) was dissolved in toluene (10 mL), and
benzaldehyde (0.15 mL, 1.5 mmol) was added via syringe. The
reaction flask was fitted with a Dean-Stark trap and con-
denser, and the mixture was heated at reflux, with azeotropic
removal of water, for 14 h. Concentration gave a viscous yellow
oil, which was taken up in MeOH-CHCl3 (1:1, 14 mL). Sodium
borohydride (34 mg, 0.91 mmol) was added to the stirred
solution in portions over 10 min. The resulting mixture was
stirred 1 h at rt and then concentrated. The residue was
treated with DCM (4 × 2 mL). The combined DCM washings
were concentrated, and the residue was purified by flash
chromatography (20% ethyl acetate in hexanes) to furnish 193
mg (87% yield) of (-)-78 as a colorless, viscous oil: [R]20D -64.5
(c 1.28, CHCl3); IR (thin film) 3357, 3063, 3027, 2993, 2953,
2910, 2875, 1495, 1456, 1381, 1309, 1272, 1240, 1202, 1177,
1122, 1091, 1011, 955, 885, 862, 805, 740, 699 cm-1; 1H NMR
(500 MHz, CDCl3) δ 0.61-0.74 (m, 6 H), 0.99 (t, J ) 7.9 Hz, 9
H), 1.41 (s, 3 H), 1.45 (s, 3 H), 1,74 (br s, 1 H), 2.52 (dd, J )
8.1, 2.4 Hz, 1 H), 3.47 (dd, J ) 9.3, 2.0 Hz, 1 H), 3.52 (s, 3 H),
3.73 (dd, J 1 ) J 2 ) 10.2 Hz, 1 H), 3.79 (ddd, J ) 9.8, 9.8, 4.8
Hz, 1 H), 3.89-3.96 (m, 3 H), 4.15 (br m, 1 H), 4.50 (d, J ) 8.1
Hz, 1 H), 7.23 (t, J ) 7.5 Hz, 1 H), 7.31 (t, J ) 7.5 Hz, 2 H),
7.36 (d, J ) 7.5 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 140.6,
128.3, 127.9, 126.7, 103.7, 99.2, 72.7, 69.9, 63.4, 62.6, 60.9, 56.9,
51.1, 28.8, 19.1, 7.0, 5.3; high-resolution mass spectrum (ESI)
m/z 460.2500 [(M + Na)+, calcd for C23H39NO5SiNa 460.2496].
3010, 2910, 1630, 1480, 1370, 1200, 1090, 850 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.49 (s, 3 H), 1.58 (s, 3 H), 3.48 (m, 2 H),
3.59 (s, 3 H), 3.75 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H), 3.83 (dd, J 1
)
J 2 ) 10.5 Hz, 1 H), 4.00 (dd, J ) 10.9 and 5.3 Hz, 1 H), 4.40
(d, J ) 7.5 Hz, 1 H), 4.57 (s, 1 H), 6.33 (s, 1 H), 6.69 (d, J )
8.1 Hz, 1 H), 6.88 (dd, J 1 ) J 2 ) 6.1 Hz, 1 H), 7.29 (dd, J )
15.2, 1.6 Hz, 1 H), 8.17 (dd, J ) 8.1, 1.6 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 167.0, 146.0, 133.0, 134.0, 119.0, 118.5,
103.0, 100.5, 72.0, 68.5, 62.0, 60.0, 58.0, 57.5, 30.0, 29.0, 19.0;
high-resolution mass spectrum (CI, NH3) m/z 335.1612 [(M +
H)+, calcd for C17H23N2O5 335.1607].
Meth yl 2-Deoxy-4,6-O-isop r op ylid en e-N-(2-h yd r oxy-5-
ch lor oben zoyl)-â-D-glu cosa m in e Ben zod ia zep in on e (-)-
76. To a solution of (-)-3 (35.8 mg, 0.094 mmol) in methanol
(3 mL) was added a catalytic amount of 5% palladium on
activated carbon. The reaction vessel was repeatedly evacuated
and purged with argon and then hydrogen. The suspension
was stirred under hydrogen for 1 h and then repeatedly
evacuated and purged with argon. The reaction mixture was
filtered through Celite, and the filter cake was washed with
MeOH. Concentration of the combined filtrates followed by
flash chromatography (5% MeOH/DCM) furnished 28.8 mg
(87% yield) of the aniline: [R]20 -103 (c 0.06, CHCl3); IR
D
(CHCl3) 3020, 1630, 1530, 1500, 1410, 1260, 1160, 940, 800,
1
650 cm-1; H NMR (500 MHz, CDCl3) δ 1.44 (s, 3 H), 1.55 (s,
3 H), 3.33 (ddd, J ) 10.0, 10.0, 5.3 Hz, 1 H), 3.48 (m, 1 H),
3.55 (s, 3 H), 3.59 (br s, 2 H), 3.82 (m, 2 H), 3.97 (m, 2 H), 4.34
(d, J ) 8.0 Hz, 1 H), 6.29 (s, 1 H), 6.75 (dd, J ) 8.5, 2.9 Hz, 1
H), 6.87 (d, J ) 8.5 Hz, 1 H), 7.43 (d, J ) 2.9 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 166.8, 149.3, 142.1, 122.9, 121.9,
121.0, 117.9, 102.7, 100.1, 81.5, 71.5, 68.2, 62.0, 58.8, 57.3, 29.0,
19.1; high-resolution mass spectrum (CI, NH3) m/z 351.1567
[(M + H)+, calcd for C17H23N2O6 351.1556].
Meth yl 2-Deoxy-3-tr ieth ylsilyl-4,6-O-isop r op ylid en e-N-
4-m eth oxyben zyl-â-D-glu cosa m in e (-)-79. Amino sugar
(-)-77 (36.8 mg, 0.106 mmol) was dissolved in toluene (HPLC
grade, 10 mL) and p-anisaldehyde (15 µL, 0.13 mmol) was
added. The mixture was concentrated on the rotary evaporator,
and more toluene (10 mL) was added. This sequence was
repeated four times to give the crude imine as a viscous oil.
The imine was dissolved in methanol (HPLC, 2 mL), and
NaBH4 (20 mg, 0.53 mmol) was added in portions to the stirred
solution over 5 min. The mixture was stirred 1 h at rt to
complete the reaction and concentrated. The residue was
purified by preparative TLC (500 µm, 50% ethyl acetate in
hexanes) to give 28 mg (57% yield) of (-)-79 as a viscous yellow
A solution of tert-butyl nitrite (5.3 µL, 0.0445 mmol) and
copper(II) chloride (anhydrous, 4.8 mg, 0.0356 mmol) in
acetonitrile (anhydrous, 120 µL) was cooled to 0 °C, and the
aniline (10.4 mg, 0.0297 mmol) was added over 15 min. The
mixture was concentrated in vacuo, and the residue was
purified by flash chromatography (50% ethyl acetate/hexanes)
to give 6.8 mg (40% yield) of (-)-76: [R]20 -41.8 (c 0.225,
D
CHCl3); IR (CHCl3) 2900, 2820, 1660, 1590, 1460, 1200, 990,
920, 840, 740 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.44 (s, 3
oil: [R]20 -11.3 (c 0.14, CHCl3); IR (thin film) 3332, 2993,
D
H), 1.57 (s, 3 H), 3.35 (ddd, J ) 10.0, 10.0, 5.3 Hz, 1 H), 3.52
(m, 1 H), 3.57 (s, 3 H), 3.86 (m, 2 H), 4.00 (m, 2 H), 4.33 (d, J
) 7.8 Hz, 1 H), 6.36 (s, 1 H), 7.00 (d, J ) 8.6 Hz, 1 H), 7.36
(dd, J ) 8.6, 2.7 Hz, 1 H), 8.21 (d, J ) 2.7 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 164.9, 155.6, 133.7, 132.8, 128.5, 122.4,
102.7, 100.2, 81.2, 71.6, 68.0, 62.0, 58.8, 57.5, 29.7, 29.0, 19.1;
high-resolution mass spectrum (CI, NH3) m/z 370.1042 [(M +
H)+, calcd for C17H21ClNO6 370.1057].
Meth yl 2-Deoxy-3-tr ieth ylsilyl-4,6-O-isop r op ylid en e-â-
D-glu cosa m in e (-)-77. A stirred solution of amino sugar (-)-
14 (197 mg, 0.845 mmol) in DCM (dry, 40 mL) was cooled to
-78 °C, and TEA (0.59 mL, 4.2 mmol) was added dropwise
via syringe. Triethylsilane trifluoromethanesulfonate (0.57 mL,
2954, 2876, 2835, 1612, 1513, 1465, 1381, 1246, 1201, 1174,
1097, 1075, 1042, 1008, 861, 818, 742 cm-1; 1H NMR (500 MHz,
CDCl3) δ 0.56-0.67 (m, 6 H), 0.92 (t, J ) 7.9 Hz, 9 H), 1.40 (s,
3 H), 1.46 (s, 3 H), 1.80 (br s, 1 H), 2.59 (dd, J 1 ) J 2 ) 8.5 Hz,
1 H), 3.19 (ddd, J ) 10.1, 10.1, 5.0 Hz, 1 H), 3.49 (dd, J )
16.3, 8.4 Hz, 2 H), 3.54 (s, 3 H), 3.78 (d, J ) 13.0 Hz, 1 H),
3.79 (s, 3 H), 3.90 (dd, J ) 10.8, 5.3 Hz, 1 H), 3.97 (d, J ) 12.8
Hz, 1 H), 4.27 (d, J ) 7.9 Hz, 1 H), 6.84 (d, J ) 8.6 Hz, 2 H),
7.22 (d, J ) 8.5 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 133.0,
129.5, 113.8, 106.8, 99.4, 74.3, 74.1, 67.3, 64.6, 62.2, 57.1, 55.3,
53.3, 29.3, 29.0, 18.9, 6.9, 5.1; high-resolution mass spectrum
(ESI) m/z 468.2769 [(M + Na)+, calcd for C24H41NO6SiNa
468.2781].
J . Org. Chem, Vol. 69, No. 2, 2004 297

Abrous et al.
Meth yl 2-Deoxy-3-tr ieth ylsilyl-4,6-O-isop r op ylid en e-N-
2-p icolyl-â-D-glu cosa m in e (-)-80. Amino sugar (-)-77 (45.2
mg, 0.130 mmol) was dissolved in toluene (HPLC grade, 10
mL), and 2-pyridyl carboxaldehyde (15 µL, 0.16 mmol) was
added. The mixture was concentrated on the rotary evaporator,
and more toluene (10 mL) was added. This sequence was
repeated four times to give the crude imine as a white solid.
The imine was dissolved in methanol (HPLC, 2 mL), and
NaBH4 (25 mg, 0.65 mmol) was added in portions to the stirred
solution over 5 min. The mixture was stirred 24 h at rt to
complete the reaction and concentrated. The residue was
purified by preparative TLC (500 µm, 50% ethyl acetate in
hexanes) to give 31 mg (55% yield) of (-)-80 as a viscous yellow
mg, 0.050 mmol), and the mixture was stirred for 5 min at rt.
DMTMM (17 mg, 0.060 mmol) was added, and the resulting
white suspension was stirred 14 h at rt and then diluted with
EtOAc (5 mL). The suspension was filtered through Celite, and
the filter cake was washed with EtOAc (3 × 2 mL). The
combined filtrates were concentrated to give the crude product
as a yellow residue. Preparative TLC (500 µm, 25% ethyl
acetate/hexanes) furnished 27 mg (72% yield) of (+)-82 as a
white foam: [R]20 +5.7(c 0.75, CHCl3); IR (thin film) 3084,
D
2994, 2956, 2877, 2842, 1650, 1613, 1585, 1533, 1514, 1448,
1349, 1247, 1201, 1176, 1125, 1094, 1017, 857, 809, 747 cm-1
;
1H NMR (500 MHz, CDCl3, complex spectrum due to slow
rotational isomerism) δ 0.59-0.80 (br m, 6 H, major + minor),
1.01 (t, J ) 7.8 Hz, 9 H, major + minor), 1.40 (s, 3 H, major +
minor), 1.42 (s, 3 H, major + minor), 1.47 (s, 1 H, minor), 2.91
(br s, 3 H, major + minor), 2.94 (ddd, J ) 9.9, 9.9, 5.4 Hz, 1 H,
major + minor), 3.28-3.32 (br m, 1 H, major + minor), 3.38-
3.41 (br m, 1 H, major + minor), 3.52 (br d, J ) 18.0 Hz, 1 H,
major + minor), 3.60 (dd, J 1 ) J 2 ) 10.6 Hz, 1 H, major +
minor), 3.74 (dd, J 1 ) J 2 ) 5.5 Hz, 1 H, major + minor), 3.77-
3.80 (br m, 2 H, major + minor), 3.82 (s, 3 H, major + minor),
3.89-3.92 (br m, 1 H, major + minor), 4.04-4.07 (br m, 1 H,
major + minor), 4.37-4.49 (br m, 1 H, major + minor), 6.78
(d, J ) 8.3 Hz, 1 H, minor), 6.92 (d, J ) 8.6 Hz, 2 H, major +
minor), 7.08 (d, J ) 8.5 Hz, minor H), 7.23 (d, J ) 8.4 Hz,
minor H), 7.38 (d, J ) 8.2 Hz, 2 H, major + minor), 8.15 (br s,
1 H, minor), 8.25 (ddd, J ) 9.0, 3.5 and 3.5 Hz, 1 H, major +
minor), 8.37 (br s, 1 H, major); 13C NMR (125 MHz, CDCl3) δ:
166.1, 158.7, 158.5, 129.6, 129.1, 128.6, 127.7, 126.5, 125.8,
124.8, 116.6, 116.4, 113.7, 113.6, 103.6, 99.6, 99.5, 98.8, 98.4,
73.8, 72.6, 72.3, 72.2, 72.1, 69.7, 63.7, 63.3, 62.9, 62.8, 62.6,
62.5, 61.9, 58.5, 56.9, 56.0, 55.9, 55.3, 55.2, 50.4, 50.2, 29.6,
28.7, 28.6, 28.5, 19.2, 19.1, 7.0, 6.9, 5.3, 5.2, 5.0; high-resolution
mass spectrum (ESI) m/z 657.2620 [(M + Na)+, calcd for
C31H43FN2O9SiNa 657.2601].
oil: [R]20 -13.6 (c 0.155, CHCl3); IR (thin film) 3320, 3061,
D
2993, 2954, 2876, 1592, 1570, 1472, 1435, 1381, 1265, 1236,
1175, 1100, 1049, 1009, 942, 861, 818, 744 cm-1; 1H NMR (500
MHz, CDCl3) δ 0.60-0.72 (m, 6 H), 0.94 (t, J ) 7.8 Hz, 9 H),
1.41 (s, 3 H), 1.46 (s, 3 H), 2.60 (dd, J ) 9.1, 8.0 Hz, 1 H), 3.21
(ddd, J ) 9.9, 9.9, 5.3 Hz, 1 H), 3.50 (s, 3 H), 3.50-3.53 (m, 1
H), 3.60 (dd, J 1 ) J 2 ) 9.0 Hz, 1 H), 3.77 (dd, J 1 ) J 2 ) 10.5
Hz, 1 H), 3.90 (dd, J ) 10.7, 5.3 Hz, 1 H), 4.00 (d, J ) 14.5 Hz,
1 H), 4.16 (d, J ) 14.5 Hz, 1 H), 4.30 (d, J ) 7.8 Hz, 1 H), 7.12
(dd, J 1 ) J 2 ) 6.2 Hz, 1 H), 7.27 (d, J ) 8.3 Hz, 1 H), 7.60 (dd,
J 1 ) J 2 ) 7.7 Hz, 1 H), 8.54 (d, J ) 4.1 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 149.2, 136.0, 122.0, 121.6, 106.7, 99.4,
74.4, 74.1, 67.3, 65.2, 62.2, 58.8, 57.0, 54.9, 29.0, 18.9, 6.9, 5.1;
high-resolution mass spectrum (ESI) m/z 461.2448 [(M + Na)+,
calcd for C22H38N2O5SiNa 461.2450].
Meth yl 2-Deoxy-3-tr ieth ylsilyl-4,6,-O-isop r op ylid en e-
N -(2-flu or o-5-n it r ob e n za m id o)-N -(b e n zyl)-â-D-glu cos-
a m in e (+)-81. To a solution of (-)-78 (25.5 mg, 0.0583 mmol)
in THF (anhydrous, 600 µL) was added acid 16 (9.0 mg, 0.049
mmol), and the mixture was stirred for 5 min at rt. DMTMM
(17 mg, 0.060 mmol) was added, and the resulting white
suspension was stirred 19 h at rt and then diluted with ethyl
acetate (5 mL). The suspension was filtered through Celite,
and the filter cake was washed with EtOAc (3 × 2 mL). The
combined filtrates were concentrated, and the residue was
purified by preparative TLC (500 µm, 25% ethyl acetate/
hexanes) to give 22 mg (65% yield) of (+)-81 as a white foam:
Meth yl 2-Deoxy-3-tr ieth ylsilyl-4,6-O-isop r op ylid en e-N-
(2-flu or o-5-n it r ob e n za m id o)-N -(2-p icolyl)-â-D-glu cos-
a m in e (-)-83. To a solution of (-)-80 (26.4 mg, 0.0602 mmol)
in THF (anhydrous, 0.7 mL) was added acid 16 (9.3 mg, 0.050
mmol), and the mixture was stirred for 5 min at rt. DMTMM
(17 mg, 0.060 mmol) was added, and the resulting white
suspension was stirred for 48 h at rt. The reaction mixture
was diluted with ethyl acetate (2 mL) and filtered through
Celite. The filter cake was washed with ethyl acetate (3 × 2
mL), and the combined filtrates were concentrated to give the
crude product as a yellow residue. Preparative TLC (500 µm,
50% ethyl acetate/hexanes) furnished 16 mg (52% yield) of (-)-
83 as a white foam: [R]20D -28.4 (c 0.80, CHCl3); IR (thin film)
3084, 2993, 2956, 2877, 1651, 1533, 1448, 1373, 1350, 1259,
[R]20 +38.6 (c 0.14, CHCl3); IR (thin film) 3072, 2937, 2870,
D
1647, 1585, 1535, 1451, 1423, 1373, 1345, 1255, 1205, 1172,
1127, 1082, 1004, 948, 853, 797, 730; 1H NMR (500 MHz,
CDCl3, complex spectrum due to slow rotational isomerism) δ
0.77 (app. q, J ) 8.0 Hz, 6 H, major + minor), 1.03 (t, J ) 8.0
Hz, 9 H, major + minor), 1.39 (s, 1 H, minor), 1.41 (s, 2 H,
major), 1.46 (s, 2 H, major), 1.53 (s, 2 H, minor), 1.84-1.87
(m, 5 H, major + minor), 2.76 (br s, 2 H, major + minor), 3.20
(s, 1 H, major + minor), 3.27 (br m, 1 H, major + minor), 3.40-
3.42 (br m, 1 H, major + minor), 3.61 (dd, J 1 ) J 2 ) 10.4 Hz,
1 H, major + minor), 3.74-3.83 (m, 4 H, major), 3.83-3.93
(m, 4 H, major + minor), 3.84-3.93 (m, 2 H, minor), 3.98 (dd,
J ) 9.6 and 4.6 Hz, 1 H, major + minor), 4.08 (s, 1 H, major
+ minor), 4.52 (d, J ) 17.9 Hz, 1 H, major), 4.56 (d, J ) 17.9
Hz, 1 H, minor), 4.71 (d, J ) 8.0 Hz, 1 H, major + minor),
4.77 (br s, 1 H, major), 4.82 (d, J ) 17.5 Hz, 1 H, major +
minor), 4.96 (d, J ) 7.3 Hz, 1 H, major + minor), 5.49 (d, J )
15.6 Hz, 1 H, major + minor), 7.05-7.10 (m, 2 H, major +
minor), 7.15 (t, J ) 7.5 Hz, 1 H, major + minor), 7.33 (t, J )
8.6 Hz, 1 H, major + minor), 7.36-7.37 (m, 2 H, major +
minor), 7.89 (br s, 1 H, major), 8.05-8.08 (br m, 1 H, major +
minor), 8.31 (br s, 1 H, minor); 13C NMR (125 MHz, CDCl3) δ
166.2, 165.8, 162.4, 162.0, 160.3, 160.0, 143.7, 137.6, 128.3,
127.3, 127.2, 127.0, 126.7, 126.6, 126.4, 126.0, 125.2, 116.7,
116.5, 73.8, 72.4, 72.2, 63.7, 62.8, 62.5, 62.0, 58.7, 56.1, 55.9,
50.7, 31.9, 28.7, 28.5, 19.2, 19.1, 7.1, 7.0, 5.3, 5.1; high-
resolution mass spectrum (ESI) m/z 627.2488 [(M + Na)+, calcd
for C30H41FN2O8SiNa 627.2514].
1242, 1201, 1125, 1094, 1017, 857, 810, 748 cm-1 1H NMR
;
(500 MHz, CDCl3, complex spectrum due to slow rotational
isomerism) δ 0.64-0.73 (br m, 6 H, major + minor), 0.99 (t, J
) 7.8 Hz, 9 H, major + minor), 1.26 (s, 1 H, minor), 1.38 (s, 3
H, major), 1.41 (s, 3 H, major), 1.43 (s, 1 H, minor), 1.48 (s, 1
H, minor), 1.62 (br s, 1 H, minor), 2.61 (dd, J 1 ) J 2 ) 6.2 Hz,
1 H, minor), 2.88 (br s, 3 H, major), 3.12 (ddd, J ) 9.8, 9.8 and
5.4 Hz, 1 H, major + minor), 3.30 (dd, J 1 ) J 2 ) 8.9 Hz, 1 H,
major + minor), 3.43-3.50 (br m, 2 H, major + minor), 3.61
(dd, J 1 ) J 2 ) 10.6 Hz, 1 H, major), 3.66 (dd, J 1 ) J 2 ) 6.3 Hz,
1 H, minor), 3.74 (dd, J 1 ) J 2 ) 10.4 Hz, 1 H, minor), 3.79
(dd, J ) 10.8 and 5.4 Hz, 1 H, major + minor), 3.91-3.93 (br
m, 1 H, minor), 4.12-4.15 (br m, 2 H, major), 4.25 (br d, J )
15.3 Hz, 1 H, major + minor), 4.50-4.54 (br m, 1 H, major),
4.64-4.68 (br m, 1 H, minor), 4.79 (br s, 1 H, minor), 5.47 (br
s, 1 H, minor), 5.61 (d, J ) 15.4 Hz, 1 H, major + minor), 5.76
(br m, 1 H, minor), 7.13-7.16 (br m, 1 H, minor), 7.23-7.24
(br m, 2 H, major + minor), 7.56 (br s, 1 H, minor), 7.65 (ddd,
J ) 7.7, 7.7, 1.6 Hz, 1 H, minor), 7.73-7.75 (br m, 2 H, major),
8.26 (ddd, J ) 9.0, 3.5, 3.5 Hz, 1 H, major + minor), 8.39 (br
m, 1 H, minor), 8.42 (dd, J ) 5.5, 2.8 Hz, 1 H, major + minor),
8.54 (br d, J ) 4.7 Hz, 1 H, major + minor); 13C NMR (125
MHz, CDCl3) δ 166.6, 157.4, 149.2, 148.7, 143.6, 136.9, 136.5,
Meth yl 2-Deoxy-3-tr ieth ylsilyl-4,6,-O-isop r op ylid en e-
N-(2-flu or o-5-n itr oben za m id o)-N-(4-m eth oxyben zyl)-â-D-
glu cosa m in e (+)-82. To a solution of (-)-79 (28 mg, 0.060
mmol) in THF (anhydrous, 0.70 mL) was added acid 16 (9.3
298 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
126.5, 126.4, 126.3, 125.8, 125.7, 125.5, 125.4, 123.9, 122.7,
122.6, 117.5, 117.3, 117.2, 117.0, 100.6, 99.5, 74.7, 71.7, 69.9,
66.9, 66.8, 66.5, 66.4, 62.1, 61.7, 56.3, 47.7, 29.7, 29.0, 28.9,
18.8, 18.7, 7.0, 6.8, 5.3, 5.0; high-resolution mass spectrum
(ESI) m/z 606.2656 [(M + H)+, calcd for C29H41FN3O8Si
606.2647].
Meth yl 2-Deoxy-N-(o-h yd r oxyben zoth ioyl)-â-D-glu cos-
a m in e-oxa zep in th ion e (-)-87. To a solution of (+)-1 (12 mg,
0.035 mmol) in freshly distilled toluene was added Lawesson’s
reagent (15 mg, 0.037 mmol) and the mixture heated at reflux
for 24 h. The solvent was evaporated in vacuo, and the residue
was purified by flash chromatography (10% MeOH/DCM) to
give 5.3 mg (43% yield) of (-)-87: [R]20 -140 (c 0.5, MeOH-
D
N-Ben zyl Tr icyclic Hybr id (+)-84. To a solution of
cyclization precursor (+)-81 (30.2 mg, 0.0499 mmol) in DMF
(anhydrous, 16 mL, c ) 0.003 M) was added CsF (anhydrous,
38.0 mg, 0.250 mmol). The mixture was sparged 5 min with
argon and heated at 90 °C for 22 h. Solvent was removed by
vacuum distillation to give the crude product as a bright yellow
residue. Preparative TLC (500 µm, 50% ethyl acetate/hexanes)
d4); IR (thin film) 3300-2920, 2850, 1705, 1580, 1500, 1320,
1150, 990, 850, 400 cm-1; 1H NMR (500 MHz, MeOH-d4) δ 3.33
(m, 1 H), 3.49 (dd, J ) 10.9, 7.9 Hz, 1 H), 3.53 (s, 3 H), 3.59
(dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 3.71 (dd, J ) 12.0, 5.1 Hz, 1 H),
3.87 (dd, J ) 12.0, 2.3 Hz, 1 H), 4.48 (dd, J ) 10.8, 9.1 Hz, 1
H), 4.67 (d, J ) 7.9 Hz, 1 H), 4.80 (m, 1 H), 7.28 (s, 1 H), 8.28
(dd, J ) 8.8, 2.9 Hz, 1 H), 8.81 (d, J ) 2.9 Hz, 1 H); 13C NMR
(125 MHz, MeOH-d4) δ 167.6, 152.2, 128.4, 121.4, 116.0, 114.9,
111.7, 87.8, 79.0, 64.5, 55.3, 48.5, 47.0, 43.7; high-resolution
mass spectrum (ESI) m/z 355.0591 [(M - H)-, calcd for
furnished 15 mg (62% yield) of (+)-84 as a white solid: [R]20
D
+5.9 (c 0.17, CHCl3); IR (thin film) 2989, 2918, 2849, 1653,
1
1458, 1375, 1339, 1268, 1199, 1087, 944, 846 cm-1; H NMR
(500 MHz, CDCl3) δ 1.36 (s, 3 H), 1.44 (s, 3 H), 3.33 (s, 3 H),
3.44 (ddd, J ) 9.4, 9.4, 4.9 Hz, 1 H), 3.79 (dd, J 1 ) J 2 ) 10.6
Hz, 1 H), 3.86 (dd, J ) 10.7, 4.9 Hz, 1 H), 4.27 (d, J ) 7.7 Hz,
1 H), 4.59 (d, J ) 14.9 Hz, 1 H), 4.89 (s, 1 H), 5.23 (d, J ) 13.8
Hz, 1 H), 5.74 (s, 1 H), 7.05 (d, J ) 9.1 Hz, 1 H), 7.25-7.26
(m, 2 H), 7.30-7.34 (m, 1 H), 7.36-7.38 (m, 2 H), 8.21 (d, J )
9.4 Hz, 1 H), 8.88 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ 165.7,
139.2, 138.7, 136.2, 132.1, 128.8, 128.4, 128.4, 128.1, 126.9,
118.7, 116.1, 100.1, 99.0, 70.9, 67.1, 62.5, 56.9, 53.0, 31.9, 29.0,
14.1; high-resolution mass spectrum (ESI) m/z 469.1597 [(M
- H)-, calcd for C24H25N2O8 469.1611].
C
14H16N2O7S 355.0599].
2-(1-P h en ylsu lfon ylin d ol-3-yl)eth yl 2-Deoxy-4,6-O-ben -
zylid en e-N-tr iflu or oa ceta m id o-â-D-glu cosa m in e (-)-92.
To a stirred solution of triol (-)-91 (6.6 g, 12 mmol) in DMF
(120 mL) were added benzaldehyde dimethyl acetal (6.6 g, 43
mmol) and PPTS (1.2 g, 4.8 mmol). The mixture was heated
at 85 °C for 2 h, cooled to rt, poured into H2O (1 L), and
extracted with ethyl acetate (3 × 200 mL). Combined organic
extracts were dried over MgSO4, filtered, and concentrated.
Flash chromatography (5% MeOH/DCM) furnished 6.4 g (85%
yield) of (-)-92 as a white solid: [R]20D -42.3 (c 1.24, acetone);
IR (thin film) 3500-3200, 3000, 2920, 2840, 1540, 1350, 1170,
1080, 850 cm-1; 1H NMR (500 MHz, acetone-d6) δ 2.56 (dd, J 1
) J 2 ) 2.3 Hz, 1 H), 2.94-2.97 (m, 2 H), 3.46 (ddd, J ) 9.7,
9.7, 5.0 Hz, 1 H), 3.60 (dd, J 1 ) J 2 ) 9.2 Hz, 1 H), 3.79 (dd, J 1
) J 2 ) 10.2 Hz, 1 H), 3.88 (ddd, J ) 9.8, 6.1, 6.1 Hz, 1 H),
3.93 (dd, J 1 ) J 2 ) 8.9 Hz, 1 H), 4.00 (dd, J 1 ) J 2 ) 9.3 Hz, 1
H), 4.09 (ddd, J ) 9.8, 7.2, 7.2 Hz, 1 H), 4.25 (dd, J ) 10.3, 5.0
Hz, 1 H), 4.87 (d, J ) 8.4 Hz, 1 H), 5.64 (s, 1 H), 7.25 (t, J )
7.5 Hz, 1 H), 7.33 (t, J ) 7.9 Hz, 1 H), 7.35 (d, J ) 1.9 Hz, 2
H), 7.36 (d, J ) 2.0 Hz, 1 H), 7.48 (d, J ) 2.0 Hz, 1 H), 7.50 (d,
J ) 4.2 Hz, 1 H), 7.55-7.58 (m, 3 H), 7.60 (s, 1 H), 7.65 (t, J
) 7.4 Hz, 1 H), 7.97-7.99 (m, 3 H), 8.54 (d, J ) 9.2 Hz, 1 H);
13C NMR (125 MHz, acetone-d6) δ 139.0, 135.9, 134.8, 132.0,
130.3, 129.5, 129.0, 128.7, 127.6, 127.2, 125.4, 124.9, 124.0,
120.8, 120.5, 114.3, 102.2, 102.1, 82.5, 71.5, 69.2, 67.3, 58.0,
30.1, 30.0, 29.2, 26.0 (trifluoroacetamide carbonyl, CF3 C’s not
obsd due to long relax time); high-resolution mass spectrum
(ESI) m/z 681.1302 [(M + Cl)-, calcd for C31H29ClF3N2O8S
681.1285].
N-(4-Meth oxyben zyl) Tr icyclic Hybr id (+)-85. To a
solution of cyclization precursor (+)-82 (27 mg, 0.043 mmol)
in DMF (anhydrous, 14 mL, c ) 0.003 M) was added CsF
(anhydrous, 28.3 mg, 0.186 mmol). The mixture was sparged
5 min with argon and heated at 90 °C for 24 h. Solvent was
removed by vacuum distillation to give the crude product as a
bright yellow residue. Preparative TLC (500 µm, 50% ethyl
acetate/hexanes) furnished 12 mg (56% yield) of (+)-85 as a
white, waxy solid: [R]20 +42.0 (c 0.60, CHCl3); IR (thin film)
D
3084, 2938, 2888, 2836, 1654, 1613, 1583, 1513, 1441, 1373,
1345, 1267, 1247, 1223, 1203, 1175, 1091, 1029, 1004, 946, 914,
885, 855, 724 cm-1 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 3
;
H), 1.48 (s, 3 H), 3.00 (ddd, J ) 9.8, 9.8, 5.4 Hz, 1 H), 3.46 (dd,
J 1 ) J 2 ) 9.5 Hz, 1 H), 3.50 (s, 3 H), 3.62-3.69 (m, 2 H), 3.84
(s, 3 H), 3.87 (dd, J ) 10.9, 3.8 Hz, 1 H), 4.03-4.08 (m, 2 H),
4.72 (d, J ) 7.8 Hz, 1 H), 5.75 (d, J ) 15.6 Hz, 1 H), 6.92 (d,
J ) 8.7 Hz, 2 H), 7.08 (d, J ) 8.8 Hz, 1 H), 7.30 (d, J ) 8.6 Hz,
2 H), 8.31 (dd, J ) 8.8, 2.8 Hz, 1 H), 8.66 (d, J ) 2.8 Hz, 1 H);
13C NMR (125 MHz, CDCl3) δ 166.9, 159.4, 156.0, 144.8, 130.4,
129.0, 128.9, 127.8, 126.6, 123.7, 114.5, 99.9, 84.8, 70.7, 67.1,
61.7, 60.0, 56.4, 55.3, 44.8, 29.7, 28.9, 19.0; high-resolution
mass spectrum (ESI) m/z 523.1681 [(M + Na)+, calcd for
2-(1-P h en ylsu lfon ylin d ol-3-yl)eth yl-2-d eoxy-4,6-O-ben -
zy lid e n e -N -(2-flu o r o -5-n it r o b e n za m id o )-â-D -g lu c o s -
a m in e (-)-96. To a solution of (-)-94 (4.1 g, 6.7 mmol) and
acid 16 (1.36 g, 7.37 mmol) in DCM (135 mL) at 0 °C was added
a solution of ethyl (dimethylamino)propylcarbodiimide (EDAC,
1.54 g, 8.04 mmol) in DCM (135 mL). Stirring was continued
for 0.5 h. The reaction mixture was warmed to rt, diluted with
DCM, and washed with saturated NaHCO3 (aq) and brine. The
organic layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (5% MeOH/
C
25H28N2O9Na 523.1693].
N-(2-P icolyl) Tr icyclic Hybr id (+)-86. To a solution of
cyclization precursor (-)-83 (16 mg, 0.04328 mmol) in DMF
(anhydrous, 10 mL, c ) 0.003 M) was added CsF (anhydrous,
24 mg, 0.16 mmol). The mixture was sparged 5 min with argon
and heated at 90 °C for 2.5 h. Solvent was removed by vacuum
distillation to give the crude product as a yellow solid. Flash
chromatography (50% ethyl acetate/hexanes) gave 11 mg (93%
yield) of (+)-86 as a white solid: [R]20D +69.6 (c 0.135, CHCl3);
IR (thin film) 2992, 2925, 2853, 1657, 1615, 1591, 1526, 1474,
1346, 1306, 1267, 1223, 1203, 1174, 1150, 1091, 1003, 944, 886,
DCM) gave 3.5 g (75% yield) of (-)-96 as a white foam: [R]20
D
-12.8 (c 3.0, CHCl3); IR (thin film) 3500-3100, 2840, 1650,
1
1620, 1520, 1450, 1350, 1175, 1090, 990, 850 cm-1; H NMR
1
855 cm-1; H NMR (500 MHz, CDCl3) δ 1.48 (s, 3 H), 1.51 (s,
(500 MHz, CDCl3) δ 2.89-2.97 (m, 2 H), 3.36 (br s, 1 H), 3.55-
3.68 (m, 3 H), 3.81-3.87 (m, 2 H), 4.25 (ddd, J ) 9.8, 6.0, 6.0
Hz, 1 H), 4.33 (dd, J 1 ) J 2 ) 8.9 Hz, 1 H), 4.39 (dd, J ) 10.5,
4.6 Hz, 1 H), 5.03 (d, J ) 8.3 Hz, 1 H), 5.58 (s, 1 H), 6.74 (dd,
J ) 13.0, 6.3 Hz, 1 H), 7.13-7.16 (m, 2 H), 7.24 (dd, J ) 10.5,
9.0 Hz, 1 H), 7.36-7.42 (m, 6 H), 7.49-7.51 (m, 4 H), 7.73-
7.75 (m, 1 H), 7.77-7.80 (m, 2 H), 8.31 (ddd, J ) 9.1, 4.2, 3.0
Hz, 1 H), 8.74 (dd, J ) 6.5, 3.0 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) 162.1, 161.7, 144.5, 138.1, 136.9, 134.8, 133.6, 130.8,
129.2, 129.1, 128.6, 128.5, 128.2, 127.9, 126.4, 124.4, 123.3,
123.0, 121.7, 121.6, 119.6, 119.3, 117.8, 117.6, 113.3, 101.9,
100.0, 81.7, 77.3, 70.6, 68.6, 66.3, 59.4, 25.1; high-resolution
3 H), 3.24 (ddd, J ) 9.8, 9.8, 5.4 Hz, 1 H), 3.47 (s, 3 H), 3.53
(dd, J 1 ) J 2 ) 9.5 Hz, 1 H), 3.66-3.74 (m, 2 H), 3.94 (dd, J )
10.9, 5.4 Hz, 1 H), 4.32-4.37 (m, 2 H), 5.22 (d, J ) 7.7 Hz, 1
H), 5.60 (d, J ) 15.5 Hz, 1 H), 7.05 (d, J ) 8.8 Hz, 1 H), 7.25-
7.28 (m, 1 H), 7.55 (d, J ) 7.8 Hz, 1 H), 7.71 (ddd, J ) 7.7, 7.7,
1.7 Hz, 1 H), 8.29 (dd, J ) 8.8, 2.8 Hz, 1 H), 8.58 (br d, J ) 3.4
Hz, 1 H), 8.64 (d, J ) 2.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 166.8, 157.2, 156.3, 149.0, 144.6, 137.4, 130.0, 127.9, 127.8,
126.6, 123.6, 123.1, 100.1, 84.9, 71.0, 67.0, 61.9, 60.0, 56.4, 47.6,
29.7, 28.9, 19.0; high-resolution mass spectrum (FAB, NBA
matrix) m/z 472.1722 [(M + H)+, calcd for C23H26N3O8 472.1720].
J . Org. Chem, Vol. 69, No. 2, 2004 299

Abrous et al.
mass spectrum (CI, NH3) m/z 740.1659 [(M + H)+, calcd for
119.4, 119.1, 113.5, 100.3, 99.1, 81.4, 73.8, 68.5, 67.6, 62.0, 59.7,
29.0, 25.0, 18.9; high-resolution mass spectrum (ESI) m/z
1321.3358 [(M + Na)+, calcd for C64H62N6O20S2Na 1321.3260].
C36H32FN3O10S 740.1690].
2-(1-P h en ylsu lfon ylin d ol-3-yl)eth yl 2-Deoxy-4,6,-O-iso-
p r op ylid e n e -N -(2-flu or o-5-n it r ob e n za m id o)-â-D -glu -
cosa m in e (-)-97. To a stirred solution of (-)-95 (204 mg,
0.406 mmol) in THF (anhydrous, 3 mL) was added acid 16
(63 mg, 0.34 mmol). After the mixture was stirred for 10 min
at rt, DMTMM (112 mg, 0.406 mmol) was added. The resultant
white suspension was stirred for 2.5 h at rt. The mixture was
concentrated in vacuo, and the residue was purified by flash
chromatography (50% ethyl acetate/hexanes) to give 247 mg
Bis(p h th a lim id e-p r otected ) An ilin e (+)-100. To a solu-
tion of (-)-99 (175 mg, 0.261 mmol) in glacial acetic acid (35
mL) was added 10% Pd on activated carbon (175 mg). The
resulting black suspension was purged with argon and then
stirred under hydrogen (1 atm) at rt for 4 h. The resulting
aniline (126 mg, 0.203 mmol) was dissolved in toluene (freshly
distilled, 10 mL), and phthalic anhydride (60 mg, 0.41 mmol)
was added. The flask was fitted with a Dean-Stark trap and
condenser, and the mixture was heated at reflux, with azeo-
tropic removal of water, for 8.5 h. Concentration in vacuo gave
the crude product as yellow residue. Purification by prepara-
tory TLC (500 µm, 5% MeOH/DCM) gave 120 mg (69% yield,
(90% yield) of (-)-97 as a white foam: [R]20 -7.7 (c 0.93,
D
CHCl3); IR (thin film) 3419, 3085, 2993, 2924, 2887, 1661,
1629, 1584, 1531, 1479, 1448, 1350, 1267, 1175, 1121, 1087,
1
1041, 857, 837, 745, 668 cm-1; H NMR (500 MHz, CDCl3) δ
1.45 (s, 3 H), 1.55 (s, 3 H), 2.92 (m, 2 H), 3.38 (ddd, J ) 10.0,
10.0, 5.4 Hz, 1 H), 3.64 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H), 3.79-3.84
(m, 1 H), 3.84 (dd, J 1 ) J 2 ) 10.5 Hz, 1 H), 3.97 (dd, J ) 10.8,
5.4 Hz, 1 H), 4.11 (dd, J 1 ) J 2 ) 9.4 Hz, 1 H), 4.23 (dd, J )
6.0, 3.7 Hz, 1 H), 4.90 (d, J ) 8.3 Hz, 1 H), 6.68 (dd, J ) 13.1,
6.5 Hz, 1 H), 7.15 (ddd, J ) 9.0, 9.0, 1.7 Hz, 1 H), 7.23 (d, J )
9.1 Hz, 1 H), 7.36 (s, 1 H), 7.38-7.42 (m, 5 H), 7.50 (t, J ) 7.5
Hz, 1 H), 7.74 (d, J ) 6.7 Hz, 2 H), 7.78 (d, J ) 7.3 Hz, 2 H),
8.32 (ddd, J ) 4.1, 4.1, 3.0 Hz, 1 H), 8.76 (dd, J ) 6.5, 3.0 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 164.2, 162.1, 161.9, 144.5,
138.1, 134.8, 133.7, 130.8, 129.2, 128.6, 128.5, 127.9, 126.6,
124.5, 123.4, 123.1, 121.7, 121.6, 119.7, 119.4, 117.9, 113.3,
100.3, 99.9, 74.4, 71.3, 68.5, 67.3, 61.9, 59.3, 25.2, 19.0; high-
resolution mass spectrum (ESI) m/z 692.1670 [(M + Na)+, calcd
for C32H32FN5O10SNa 692.1690].
two steps) of (+)-100 as a yellow solid: mp 225-228 °C; [R]20
D
+55.6 (c 1.16, CHCl3); IR (thin film) 3399, 3062, 2992, 2926,
2886, 1721, 1662, 1540, 1492, 1447, 1420, 1377, 1285, 1267,
1227, 1202, 1174, 1099, 1020, 988, 855, 744, 718, 686 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.51 (s, 6 H), 1.56 (s, 6 H), 2.97
(t, J ) 7.0 Hz, 4 H), 3.41 (ddd, J ) 10.0, 10.0, 7.5 Hz, 2 H),
3.62 (ddd, J ) 9.8, 9.8, 5.3 Hz, 2 H), 3.90-3.95 (m, 4 H), 3.99-
4.06 (m, 4 H), 4.15 (ddd, J ) 9.7, 9.7, 7.5 Hz, 2 H), 5.47 (dd, J 1
) J 2 ) 9.7 Hz, 2 H), 5.53 (d, J ) 7.9 Hz, 2 H), 7.20 (t, J ) 7.2
Hz, 2 H), 7.27 (t, J ) 7.2 Hz, 2 H), 7.38 (t, J ) 7.8 Hz, 4 H),
7.45-7.48 (m, 4 H), 7.50 (d, J ) 2.9 Hz, 2 H), 7.52 (d, J ) 2.8
Hz, 2 H), 7.74 (dd, J ) 5.5 and 3.0 Hz, 4 H), 7.83 (d, J ) 8.5
Hz, 4 H), 7.86 (s, 2 H), 7.87-7.90 (m, 4 H), 7.94 (d, J ) 8.3
Hz, 2 H), 8.06 (d, J ) 2.8 Hz, 2 H), 8.69 (d, J ) 6.9 Hz, 2 H);
13C NMR (125 MHz, CDCl3) δ 166.9, 164.1, 157.6, 134.3, 133.7,
131.8, 131.5, 131.0, 129.4, 129.2, 128.4, 126.7, 126.6, 124.7,
123.7, 123.6, 123.1, 121.6, 120.2, 119.5, 119.4, 113.7, 99.9, 80.6,
74.2, 69.3, 67.3, 62.2, 60.0, 29.1, 25.5, 19.1; high-resolution
mass spectrum (ESI) m/z 1521.4140 [(M + Na)+, calcd for
Dim er ic Ma cr ocyle (-)-98. Cesium fluoride (350 mg, 9.3
mmol) was added to a stirred solution of (-)-96 (140 mg, 0.35
mmol) in DMF (anhydrous, 46 mL), and the mixture was
heated at 60 °C for 24 h. Concentration in vacuo gave a yellow
residue, which was purified by flash chromatography (5%
MeOH/DCM) to give 720 mg (45% yield) of (-)-98 as a yellow
C
80H70N6O20S2Na 1521.3984].
Mon o(p h th a lim id e-p r otected ) An ilin e (+)-101. To a
solid: [R]20 -113 (c 0.686, CHCl3); IR (CHCl3) 3200, 3100-
stirred solution of (+)-100 (12 mg, 0.0080 mmol) in THF (1
mL) was added 5% HCl (aq, 122 µL). The mixture was stirred
4.5 h at rt and then concentrated. Water was removed by
azeotropic distillation with benzene (2 × 3 mL). The crude
residue was purified by preparative TLC (500 µm, 5% MeOH/
DCM) to give 3 mg (25% yield) of (+)-101 as a yellow solid:
D
3000, 2840, 1650, 1610, 1520, 1350, 1250, 990, 850, 750 cm-1
;
1H NMR (500 MHz, CDCl3) δ 2.82-2.88 (m, 2 H), 2.92-2.98
(m, 2 H), 3.54 (ddd, J ) 10.0, 7.5, 7.5 Hz, 2 H), 3.80 (ddd, J )
9.6, 9.6, 4.8 Hz, 2 H), 3.96-4.01 (m, 4 H), 4.16 (dd, J 1 ) J 2
)
9.3 Hz, 2 H), 4.22-4.26 (m, 2 H), 4.51 (dd, J ) 10.5, 4.8 Hz, 2
H), 5.51 (d, J ) 8.0 Hz, 2 H), 5.79 (s, 2 H), 7.04-7.08 (m, 4 H),
7.32 (t, J ) 7.5 Hz, 6 H), 7.39-7.43 (m, 8 H), 7.45 (t, J ) 7.5
Hz, 2 H), 7.53-7.56 (m, 4 H), 7.64-7.68 (m, 6 H), 7.82 (d, J )
9.3 Hz, 2 H), 8.01 (dd, J ) 9.3, 3.0 Hz, 2 H), 8.34 (d, J ) 6.8
Hz, 2 H), 8.48 (d, J ) 3.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3)
δ 162.8, 161.9, 144.5, 138.2, 134.7, 133.6, 130.6, 129.2, 129.1,
128.5, 128.3, 127.4, 126.4, 124.4, 123.5, 123.0, 121.1, 119.4,
119.0, 113.4, 101.7, 99.2, 80.6, 80.4, 68.6, 68.5, 66.7, 59.6, 25.1;
high-resolution mass spectrum (ESI) m/z 1417.3376 [(M +
Na)+, calcd for C72H62N6O20S2Na 1417.3358].
[R]20 +39.2 (c 0.355, CHCl3); IR (thin film) 3398, 3122, 3058,
D
2923, 2853, 1720, 1653, 1539, 1491, 1447, 1378, 1281, 1230,
1174, 1098, 719 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.55 (s, 6
H), 2.36 (dd, J 1 ) J 2 ) 6.5 Hz, 1 H), 2.85 (ddd, J ) 16.6, 5.6,
5.6 Hz, 1 H), 2.95 (ddd, J ) 13.5, 13.5, 6.9 Hz, 3 H), 3.29-
3.31 (m, 2 H), 3.60 (ddd, J ) 9.9, 9.9, 5.3 Hz, 1 H), 3.71-3.73
(m, 1 H), 3.90-4.09 (m, 8 H), 4.12-4.23 (m, 3 H), 5.35 (dd, J 1
) J 2 ) 9.7 Hz, 1 H), 5.47 (dd, J 1 ) J 2 ) 8.1 Hz, 2 H), 5.52 (d,
J ) 8.1 Hz, 1 H), 7.06 (t, J ) 4.7 Hz, 2 H), 7.20 (t, J ) 7.5 Hz,
1 H), 7.26 (t, J ) 7.8 Hz, 1 H), 7.30-7.35 (m, 5 H), 7.39 (d, J
) 7.5 Hz, 1 H), 7.42 (d, J ) 6.1 Hz, 1 H), 7.44-7.51 (m, 5 H),
7.54 (s, 1 H), 7.65-7.69 (m, 3 H), 7.73 (d, J ) 3.1 Hz, 1 H),
7.74 (d, J ) 2.9 Hz, 2 H), 7.75 (d, J ) 3.0 Hz, 1 H), 7.79 (d, J
) 9.0 Hz, 1 H), 7.84-7.89 (m, 7 H), 7.94 (d, J ) 8.3 Hz, 1 H),
7.96 (d, J ) 2.8 Hz, 1 H), 8.54 (d, J ) 6.8 Hz, 1 H), 8.72 (d, J
) 6.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 166.9, 166.7,
163.9, 157.8, 157.6, 138.4, 137.6, 135.1, 134.9, 134.2, 134.2,
133.8, 133.7, 131.8, 131.8, 131.4, 131.1, 131.1, 130.6, 129.3,
129.2, 129.2, 128.8, 128.3, 126.7, 126.6, 126.6, 124.9, 124.7,
124.6, 123.7, 123.7, 123.6, 123.6, 123.4, 123.3, 123.1, 121.9,
120.6, 120.5, 120.4, 119.6, 119.6, 119.4, 119.3, 119.2, 113.6,
113.3, 99.9, 99.6, 99.3, 83.4, 80.9, 75.4, 74.0, 71.5, 68.9, 68.2,
67.3, 62.8, 59.8, 59.3, 29.7, 29.0, 25.5, 25.4, 19.0; high-
resolution mass spectrum (ESI) m/z 1481.3688 [(M + Na)+,
calcd for C77H66N6O20S2Na 1481.3671].
Dim er ic Ma cr ocyle (-)-99. Representative procedure: A
solution of (-)-97 (63 mg, 0.16 mmol) and K2CO3 (111 mg,
0.803 mmol) in DMF (anhydrous, 16 mL) was stirred 18 h at
rt. The solvent was removed by vacuum distillation to furnish
the crude product as a yellow residue. Flash chromatography
(50% ethyl acetate/hexanes) gave 44 mg (75% yield) of (-)-99
as a yellow solid: mp 145-150 °C; [R]20 -25.0 (c 0.660,
D
CHCl3); IR (thin film) 3396, 3199, 3068, 2994, 2940, 2888,
2812, 2704, 1662, 1533, 1481, 1447, 1350, 1296, 1175, 1122,
1
1087, 986, 842, 746 cm-1; H NMR (500 MHz, CDCl3) δ 1.57
(s, 6 H), 1.61 (s, 6 H), 2.84 (ddd, J ) 16.1, 5.4, 5.4 Hz, 2 H),
2.95-3.01 (m, 2 H), 3.46 (ddd, J ) 10.0, 10.0, 7.5 Hz, 2 H),
3.63 (ddd, J ) 9.7, 9.7, 5.3 Hz, 2 H), 3.94-3.99 (m, 4 H), 4.05-
4.09 (m, 4 H), 4.16-4.21 (m, 2 H), 5.43 (dd, J 1 ) J 2 ) 9.7 Hz,
2 H), 5.46 (d, J ) 7.9 Hz, 2 H), 7.13-7.21 (m, 4 H), 7.36-7.39
(m, 8 H), 7.48 (t, J ) 7.5 Hz, 2 H), 7.76 (m, 4 H), 7.88 (d, J )
9.3 Hz, 2 H), 8.19 (dd, J ) 9.3, 3.0 Hz, 2 H), 8.39 (d, J ) 6.8
Hz, 2 H), 8.45 (d, J ) 3.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3)
δ 162.8, 162.4, 142.9, 138.3, 134.8, 133.7, 130.8, 130.7, 129.2,
128.8, 128.6, 127.3, 126.5, 124.7, 123.3, 123.3, 121.3, 120.5,
2-(In d ol-3-yl)et h yl-2-d eoxy-4,6-O-isop r op ylid en e-â-D-
glu cosa m in e (-)-102. To a solution of (-)-95 (21 mg, 0.042
mmol) in absolute ethanol (4 mL) was added 5 M NaOH (aq,
0.71 mL, 3.6 mmol) via syringe. The resulting solution was
heated at reflux for 1 h. The mixture was concentrated in
300 J . Org. Chem., Vol. 69, No. 2, 2004

Novel Chimeric Scaffolds
vacuo, and the residue was azeotropically dehydrated with
benzene (2 × 25 mL). Purification by preparative TLC (500
µm, 5% MeOH/DCM) afforded 14 mg (90% yield) of (-)-102
2-(Ben zofu r an -3-yl)eth yl 2-Deoxy-N-tr iflu or oacetam ido-
â-D-glu cosa m in e (-)-106. A suspension of 2-(2-benzofuranyl)-
ethanol (3.50 g, 21.6 mmol), Ag2CO3 (3.57 g, 12.9 mmol), and
powdered, freshly activated 3 Å MS (1.9 g) in DCM (dry, 25
mL) was cooled to 0 °C. To this stirred solution was added,
via cannula, a solution of glycosyl bromide (+)-105 (3.360 g,
6.163 mmol) in DCM (dry, 25 mL). The resulting suspension
was warmed to rt, and stirring was maintained for 20 h. The
reaction mixture was filtered through Celite, and the filter
cake was washed with DCM (4 × 50 mL). The combined
filtrates were condensed under reduced pressure to give the
crude product as a viscous orange oil. Purification by flash
chromatography eluting first with 25% ethyl acetate in hex-
anes, then 25% ethyl acetate in hexanes, afforded 3.360 g (57%
yield) of the glycosidation product as a white solid: mp 145-
147 °C; [R]20D -15.2 (c 0.690, CHCl3); IR (thin film) 3314, 3113,
2958, 2894, 1752, 1560, 1454, 1368, 1226, 1168, 1077, 1041,
as a white solid: [R]20 -36.3 (c 3.6, CHCl3); IR (thin film)
D
3364, 3057, 2993, 2884, 2247, 1587, 1457, 1428, 1382, 1267,
1201, 1175, 1093, 1052, 1010, 910, 851, 735 cm-1 1H NMR
;
(500 MHz, CDCl3) δ 1.43 (s, 3 H), 1.51 (s, 3 H), 1.69 (br s, 2
H), 2.75 (dd, J ) 9.4, 8.0 Hz, 1 H), 3.04-3.13 (m, 3 H), 3.24
(ddd, J ) 9.9, 9.9, 5.4 Hz, 1 H), 3.42 (dd, J 1 ) J 2 ) 9.2 Hz, 1
H), 3.58 (dd, J 1 ) J 2 ) 9.1 Hz, 1 H), 3.76-3.83 (m, 2 H), 3.90
(dd, J ) 10.8, 5.4 Hz, 1 H), 4.18-4.22 (m, 1 H), 4.24 (d, J )
8.0 Hz, 1 H), 7.05 (s, 1 H), 7.12 (t, J ) 7.5 Hz, 1 H), 7.19 (t, J
) 7.6 Hz, 1 H), 7.35 (d, J ) 8.1 Hz, 1 H), 7.61 (d, J ) 7.8 Hz,
1 H), 8.10 (br s, 1 H); 13C NMR (125 MHz, CDCl3) δ 136.2,
127.5, 122.2, 122.0, 119.3, 118.7, 112.5, 111.3, 104.2, 99.8, 73.9,
73.1, 70.2, 67.4, 62.1, 58.0, 29.0, 25.6, 19.1; high-resolution
mass spectrum (ESI) m/z 385.1729 [(M + Na)+, calcd for
1
C
19H26N2O5Na 385.1740].
749 cm-1; H NMR (500 MHz, CDCl3) δ 2.02 (s, 3 H), 2.03 (s,
3 H), 2.96 (dd, J 1 ) J 2 ) 6.4 Hz, 2 H), 3.70 (ddd, J ) 9.9, 4.8,
2.5 Hz, 1 H), 3.78 (dd, J ) 9.8, 7.0 Hz, 1 H), 3.96 (ddd, J )
19.3, 19.3, 18.6 Hz, 1 H), 4.15 (dd, J ) 12.4, 2.3 Hz, 1 H), 4.17-
4.20 (m, 1 H), 4.27 (dd, J ) 12.3, 4.8 Hz, 1 H), 4.67 (d, J ) 8.2
2-(In d ol-3-yl)eth yl-2-d eoxy-4,6-O-isop r op ylid en e-N-(2-
flu or o-5-n itr oben za m id o)-â-D-glu cosa m in e (-)-103. Acid
16 (8.0 mg, 0.041 mmol) was suspended in DCM (dry, 0.5 mL)
and cooled to -78 °C. DIPEA (14 µL, 0.082 mmol) was added
via syringe, followed by the sequential addition of HATU (16
mg, 0.041 mmol) and HOAt (7.0 mg, 0.049 mmol). The mixture
was stirred 10 min at rt, and amino sugar (-)-102 (15 mg,
0.041 mmol) was added in portions. The reaction mixture was
allowed to warm to rt gradually over 20 h. The resultant yellow
solution was concentrated in vacuo, and the crude residue was
purified by prep TLC (500 µm, 5% MeOH/DCM) to afford 16
mg (73% yield) of the N-coupled product (-)-103 as a yellow
Hz, 1 H), 5.10 (dd, J 1 ) J 2) 9.5 Hz, 1 H), 5.24 (dd, J 1 ) J 2
)
9.3 Hz, 1 H), 6.25 (d, J ) 8.8 Hz, 1 H), 7.23 (t, J ) 7.4 Hz, 1
H), 7.29 (t, J ) 7.6 Hz, 1 H), 7.45 (s, 1 H), 7.46 (d, J ) 7.3 Hz,
1 H), 7.52 (d, J ) 7.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
167.1, 163.2, 161.3, 157.3, 143.3, 133.6, 130.6, 129.9, 128.5,
121.2, 102.3, 84.4, 74.4, 68.4, 63.1, 57.5, 57.4, 31.9, 24.2, 22.7,
20.8; high-resolution mass spectrum (ESI) m/z 568.1428 [(M
+ Na)+, calcd for C24H26F3NO10Na 568.1408].
solid: [R]20 -21.9 (c 0.54, CHCl3); IR (thin film) 3406, 3082,
The glycosidation product (116 mg, 0.213 mmol) was dis-
solved in methanol (HPLC, 1 mL), and sodium methoxide
solution (30 wt. % in methanol) was added dropwise via
syringe. The reaction was quenched after 2 h by the addition
of solid NH4Cl (40 mg, 0.75 mmol). The reaction mixture was
concentrated under reduced pressure, and the residue was
partitioned between water (5 mL) and EtOAc (5 mL) in a
separatory funnel. The layers were separated, and the aqueous
phase was extracted with EtOAc (3 × 10 mL). The combined
organic extracts were washed with brine (10 mL), dried over
Na2SO4, and concentrated to afford the crude product as an
oily residue. Flash chromatography, eluting with hexanes:ethyl
acetate (1:1) gave 30.0 mg (37%) of triol (-)-106 as a white
D
2996, 2942, 2887, 1661, 1628, 1532, 1479, 1457, 1422, 1350,
1265, 1201, 1175, 1117, 1086, 1039, 924, 837, 745 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 1.45 (s, 3 H), 1.54 (s, 3 H), 3.01 (dd,
J 1 ) J 2 ) 6.6 Hz, 2 H), 3.36 (ddd, J ) 9.9, 9.9, 5.4 Hz, 1 H),
3.55 (br s, 1 H), 3.65 (dd, J 1 ) J 2 ) 9.3 Hz, 1 H), 3.75-3.86
(m, 3 H), 3.96 (dd, J ) 10.8, 5.4 Hz, 1 H), 4.04 (br dd, J 1 ) J 2
) 9.4 Hz, 1 H), 4.21 (ddd, J ) 9.7, 9.7, 6.5 Hz, 1 H), 4.80 (d, J
) 8.3 Hz, 1 H), 6.66 (dd, J ) 11.7, 6.7 Hz, 1 H), 6.99 (s, 1 H),
7.01 (d, J ) 5.7 Hz, 1 H), 7.04 (d, J ) 6.7 Hz, 1 H), 7.08-7.13
(m, 2 H), 7.48 (d, J ) 8.2 Hz, 1 H), 7.95 (br s, 1 H), 8.24 (ddd,
J ) 8.9, 3.6, 3.6 Hz, 1 H), 8.72 (dd, J ) 6.4, 2.9 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 164.0, 162.0 (d, J C-F ) 9.9 Hz),
144.4, 135.9, 128.2 (d, J C-F ) 11.3 Hz), 127.8 (d, J C-F ) 3.6
Hz), 127.4, 122.1, 121.8, 119.1, 118.5, 117.4, 117.2, 112.4,
110.8, 100.7, 99.9, 74.3, 71.5, 70.0, 67.2, 61.9, 59.2, 29.0, 25.4,
19.0; high-resolution mass spectrum (ESI) m/z 552.1763 [(M
+ Na)+, calcd for C26H28FN3O8Na 552.1758].
solid: mp 183-185 °C dec; [R]20 -17.6 (c 0.625, MeOH); IR
D
(thin film) 3389, 3279, 3119, 2928, 2888, 1700, 1569, 1453,
1212, 1186, 1076, 1032, 744 cm-1; 1H NMR (500 MHz, DMSO-
d6) δ 2.85 (dd, J 1 ) J 2 ) 6.5 Hz, 2 H), 3.10-3.16 (m, 2 H),
3,42-3.43 (br m, 1 H), 3.48-3.57 (m, 2 H), 3.70 (ddd, J ) 9.9,
9.9, 6.6 Hz, 2 H), 4.02 (ddd, J ) 9.9, 9.9, 6.6 Hz, 1 H), 4.49 (d,
J ) 8.4 Hz, 1 H), 4.55 (br s, 1 H), 5.09 (br s, 1 H), 5.18 (br s,
1 H), 7.22 (t, J ) 7.4 Hz, 1 H), 7.28 (t, J ) 7.0 Hz, 1 H), 7.51
(d, J ) 7.4 Hz, 1 H), 7.61 (d, J ) 7.3 Hz, 1 H), 7.67 (s, 1 H),
9.18 (d, J ) 9.1 Hz, 1 H); 13C NMR (125 MHz, DMSO-d6) δ
156.7 (q, J C-F ) 35.7 Hz), 154.9, 142.8, 128.2, 124.6, 122.8,
120.1, 117.6, 117.3, 111.6, 100.5, 77.6, 73.8, 70.9, 67.9, 61.3,
56.5, 23.8; high-resolution mass spectrum (FAB, NBA matrix)
m/z 442.1084 [(M + Na)+, calcd for C18H20F3NO7Na 442.1090].
Ma cr ocycle (-)-104. To a solution of amide (-)-103 (13
mg, 0.025 mmol) in DMF (dry, 2.5 mL) was added K2CO3
(anhydrous, 17 mg, 0.125 mmol). The resulting suspension was
stirred 23 h at rt, and the mixture was concentrated in vacuo
to give the crude product as an orange solid. Purification by
prep TLC (500 µm, 5% MeOH/DCM) furnished 11 mg (88%
yield) of (-)-104 as a bright yellow solid: [R]20 -107 (c 0.55,
D
CHCl3); IR (thin film) 3349, 3281, 3078, 2923, 2852, 1724,
1650, 1605, 1582, 1523, 1489, 1453, 1375, 1343, 1264, 1201,
1174, 1126, 1094, 1006, 939, 855, 741 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.35 (s, 3 H), 1.47 (s, 3 H), 2.65 (br s, 1 H), 2.96 (ddd,
2-(Ben zofu r an -3-yl)eth yl 2-Deoxy-4,6,-O-isopr opyliden e-
â-D-glu cosa m in e (-)-107. To a solution of (-)-106 (881 mg,
2.10 mmol) in DMF (anhydrous, 20 mL) were added pTSA (40
mg, 0.21 mmol) and 2,2-dimethoxypropane (1.3 mL, 10.5
mmol). The mixture was stirred 2 h at rt and then partitioned
between cold water (100 mL) and EtOAc (100 mL). The layers
were separated, and the organic phase was extracted with cold
water (100 mL) and saturated NaHCO3 (50 mL), dried over
Na2SO4, and concentrated to give the crude product as a
viscous, yellow oil. Flash chromatography, eluting with hex-
anes/ethyl acetate (2:1), gave 854 mg (89%) of the acetonide-
protected compound as a white solid: mp 195-197 °C dec;
J ) 9.8, 9.8, 5.5 Hz, 1 H), 3.04-3.07 (m, 2 H), 3.19 (dd, J 1
)
J 2 ) 9.4 Hz, 1 H), 3.37 (ddd, J ) 10.3, 10.3, 5.3 Hz, 1 H), 3.52
(dd, J 1 ) J 2 ) 9.5 Hz, 2 H), 3.74 (dd, J 1 ) J 2 ) 10.6 Hz, 1 H),
3.84 (dd, J ) 10.8, 5.5 Hz, 1 H), 4.02-4.10 (m, 1 H), 4.29-
4.35 (m, 1 H), 4.60 (d, J ) 8.7 Hz, 1 H), 7.11 (s, 1 H), 7.31
(quint, J ) 7.4 Hz, 2 H), 7.50 (d, J ) 8.0 Hz, 1 H), 7.65 (d, J
) 7.5 Hz, 1 H), 8.51 (dd, J ) 8.7, 2.5 Hz, 1 H), 8.79 (d, J ) 2.3
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 165.8, 146.3, 141.2,
135.8, 133.7, 130.1, 128.0, 127.8, 126.9, 126.4, 123.7, 121.9,
119.2, 114.7, 110.0, 104.2, 99.8, 73.8, 73.4, 70.4, 66.5, 61.8, 56.6,
28.9, 25.7, 19.0; high-resolution mass spectrum (FAB, NBA
matrix) m/z 532.1690 [(M + Na)+, calcd for C26H27N3O8Na
532.1696].
[R]20 -32.8 (c 0.80, CHCl3); IR (thin film) 3413, 3324, 3117,
D
2995, 2925, 2887, 1705, 1560, 1453, 1369, 1265, 1216, 1184,
1
1095, 1037, 850, 745 cm-1; H NMR (500 MHz, acetone-d6) δ
J . Org. Chem, Vol. 69, No. 2, 2004 301

Abrous et al.
1.32 (s, 3 H), 1.49 (s, 3 H), 2.94 (ddd, J ) 6.7, 6.7, 1.1 Hz, 2
H), 3.25 (ddd, J ) 9.8, 9.8, 5.5 Hz, 1 H), 3.60 (dd, J 1 ) J 2
at rt. The reaction mixture was concentrated in vacuo to give
the crude product as a yellow, waxy residue. Purification by
preparatory TLC, eluting with hexanes-ethyl acetate (1:1),
)
9.2 Hz, 2 H), 3.75-3.90 (m, 5 H), 4.09 (ddd, J ) 9.7, 6.7, 6.7
Hz, 1 H), 4.76 (d, J ) 8.3 Hz, 1 H), 7.23 (t, J ) 7.4 Hz, 1 H),
7.29 (t, J ) 7.7 Hz, 1 H), 7.46 (d, J ) 8.2 Hz, 1 H), 7.60-7.62
(m, 2 H), 8.46 (br d, J ) 8.5 Hz,m 1 H); 13C NMR (125 MHz,
acetone-d6) δ 157.9 (q, J ) 36.4 Hz), 156.0, 143.2, 129.0, 124.9,
123.1, 120.4, 117.9, 111.8, 101.9, 100.0, 75.1, 71.9, 71.8, 69.0,
68.3, 62.5, 58.0, 29.3, 24.6, 19.3; high-resolution mass spectrum
(ESI) m/z 482.1414 [(M + Na)+, calcd for C21H24F3NO7Na
482.1398].
gave 6.0 mg of (+)-109 (43% yield) as a yellow solid: [R]20
D
+81.2 (c 0.085, CHCl3); IR (thin film) 3411, 3117, 3076, 1665,
1615, 1581, 1544, 1521, 1480, 1453, 1346, 1289, 1228, 1201,
1172, 1097, 1029, 940, 856, 748 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 1.58 (s, 6 H), 1.62 (s, 6 H), 2.94 (dd, J 1 ) J 2 ) 6.2
Hz, 4 H), 3.29-3.34 (m, 2 H), 3.62 (ddd, J ) 9.8, 9.8, 5.4 Hz,
2 H), 3.90-3.95 (m, 4 H), 3.99 (dd, J 1 ) J 2 ) 9.4 Hz, 2 H),
4.08 (dd, J ) 11.0, 5.3 Hz, 2 H), 4.23 (ddd, J ) 10.0, 6.3, 6.3
Hz, 2 H), 5.37 (d, J ) 8.0 Hz, 2 H), 5.43 (dd, J 1 ) J 2 ) 9.8 Hz,
2 H), 7.07-7.11 (m, 4 H), 7.21-7.22 (m, 2 H), 7.39 (s, 2 H),
7.43 (dd, J ) 5.5, 2.2 Hz, 2 H), 7.78 (d, J ) 9.3 Hz, 2 H), 8.20
(dd, J ) 9.3, 2.9 Hz, 2 H), 8.23 (d, J ) 7.1 Hz, 2 H), 8.56 (d, J
) 2.8 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 162.7, 162.2,
155.1, 143.0, 141.9, 128.7, 127.8, 127.6, 124.1, 122.3, 121.3,
120.0, 119.2, 116.6, 111.3, 100.2, 99.6, 81.0, 73.9, 69.2, 67.4,
62.1, 59.9, 29.1, 24.2, 19.1; high-resolution mass spectrum
(ESI) m/z 1043.3139 [(M + Na)+, calcd for C52H52N4O18Na
1043.3174].
To a solution of TFA-protected amino sugar (821 mg, 1.79
mmol) in methanol (HPLC, 45 mL) were added distilled H2O
(4 mL) and K2CO3 (742 mg, 5.37 mmol). The mixture was
stirred 24 h at rt and then concentrated to minimum volume
on the rotary evaporator. The aqueous residue was transferred
to a separatory funnel and extracted with DCM (3 × 25 mL).
The combined organic extracts were washed with brine (25
mL), dried over Na2SO4, and concentrated to give the crude
product as a white foam. Purification by chromatography gave
599 mg (92% yield) of amino sugar (-)-107 as a white solid:
mp 130-132 °C; [R]20 -35.5 (c 0.65, CHCl3); IR (thin film)
N-Meth yl Tr icyclic Hybr id (+)-111. To a solution of the
cyclization precursor (-)-110 (8.0 mg 0.012 mmol) in DMF
(anhydrous, 5 mL, c ) 0.0025 M) was added CsF (3.0 mg, 0.018
mmol). The resultant mixture was heated at 85 °C for 19 h,
and the solvent was removed by vacuum distillation to give a
yellow residue. Preparative TLC (500 µm, 5% MeOH/DCM)
gave 3 mg (38% yield) of (+)-111 as a yellow solid: [R]20D +22.0
(c 0.15, CHCl3); IR (thin film) 2924, 2854, 1650, 1615, 1525,
D
3476, 3375, 3309, 3114, 3061, 2992, 2940, 2882, 1576, 1453,
1381, 1266, 1201, 1176, 1092, 1067, 1053, 1014, 856, 747 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.43 (s, 3 H), 1.50 (s, 3 H), 2.09
(br s, 2 H), 2.76 (dd, J ) 9.4, 8.0 Hz, 1 H), 2.97-3.05 (m, 2 H),
3.25 (ddd, J ) 9.9, 9.9, 5.3 Hz, 1 H), 3.43 (dd, J 1 ) J 2 ) 9.2
Hz, 1 H), 3.57 (dd, J 1 ) J 2 ) 9.2 Hz, 1 H), 3.76-3.82 (m, 2 H),
3.90 (dd, J ) 10.8, 5.4 Hz, 1 H), 4.20 (ddd, J ) 9.5, 9.5, 6.5
Hz, 1 H), 4.26 (d, J ) 7.9 Hz, 1 H), 7.24 (t, J ) 7.4 Hz, 1 H),
7.29 (t, J ) 7.6 Hz, 1 H), 7.46 (d, J ) 8.2 Hz, 1 H), 7.50 (s, 1
H), 7.56 (d, J ) 8.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
19.1, 24.2, 29.0, 57.8, 62.1, 67.4, 69.2, 73.6, 73.9, 99.7, 104.7,
111.5, 117.0, 119.5, 122.3, 124.2, 128.3, 141.9, 155.2; high-
resolution mass spectrum (ESI) m/z 364.1745 [(MH)+, calcd
for C19H25NO6 364.1758].
1472, 1455, 1344, 1267, 1175, 1089, 881, 855, 750 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 1.52 (s, 3 H), 1.54 (s, 3 H), 2.97 (dd,
J 1 ) J 2 ) 6.8 Hz, 1 H), 3.00 (s, 3 H), 3.29 (ddd, J ) 9.7, 9.7,
5.4 Hz, 1 H), 3.58-3.63 (m, 1 H), 3.75 (dd, J 1 ) J 2 ) 10.6 Hz,
2 H), 3.82 (ddd, J ) 9.1, 6.8, 6.8 Hz, 1 H), 3.94 (dd, J ) 10.9,
5.3 Hz, 1 H), 4.16 (ddd, J ) 9.2, 6.8, 6.8 Hz, 1 H), 4.31 (dd, J 1
) J 2 ) 6.7 Hz, 1 H), 4.54 (dd, J ) 11.1, 9.3 Hz, 1 H), 4.81 (d,
J ) 7.8 Hz, 1 H), 7.10 (d, J ) 8.8 Hz, 1 H), 7.22 (t, J ) 7.1 Hz,
1 H), 7.34 (ddd, J ) 8.4, 8.4, 1.2 Hz, 1 H), 7.39 (s, 1 H), 7.43
(t, J ) 8.2 Hz, 2 H), 7.51-7.54 (m, 2 H), 7.85-7.87 (m, 2 H),
7.97 (d, J ) 8.4 Hz, 1 H), 8.31 (dd, J ) 8.8, 2.8 Hz, 1 H), 8.62
(d, J ) 2.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 164.1, 162.1,
161.9, 144.4, 138.0, 134.7, 133.7, 130.8, 129.1, 128.4, 128.3,
127.7, 126.5, 124.5, 123.3, 123.0, 122.0, 121.8, 119.7, 119.4,
117.8, 117.6, 113.3, 100.4, 99.8, 74.4, 68.4, 67.2, 61.9, 59.0, 28.9,
25.1, 19.0; high-resolution mass spectrum (ESI) m/z 686.1804
[(M + Na)+, calcd for C33H33N2O10Na 686.2724].
2-(Ben zofu r an -3-yl)eth yl 2-Deoxy-4,6,-O-isopr opyliden e-
N-(2-flu or o-5-n itr oben za m id o)-â-D-glu cosa m in e (-)-108.
To a solution of amino sugar (-)-107 (13 mg, 0.036 mmol) in
THF (dry, 2 mL) was added carboxylic acid 16 (6.0 mg, 0.030
mmol), and the resulting mixture was stirred for 10 min at
rt. DMTMM (10 mg, 0.036 mmol) was added, and the resulting
white suspension was stirred at rt for 1 h. The reaction mixture
was concentrated, and the residue was taken up in EtOAc (0.5
mL) and purified by preparatory TLC (500 µm, 5% MeOH in
DCM) to give 15 mg of amide (-)-108 (78%) as a white solid:
mp 232 °C dec; [R]20D -22.8 (c 0.75, CHCl3); IR (thin film) 3398,
3314, 3117, 3084, 2993, 2925, 2885, 1654, 1628, 1584, 1531,
1477, 1453, 1349, 1265, 1200, 1175, 1120, 1087, 1040, 923, 857,
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (Institute for General Medical Sciences)
for generous support of this work through Grant No.
GM-41821. We also thank Drs. Carl P. DeCicco, Charles
Deber, and Roger Freidinger for helpful discussions and
Drs. George T. Furst, Patrick Carroll, and Rakesh K.
Kohli of the University of Pennsylvania Spectroscopic
Service Center for assistance in securing and interpret-
ing high-field NMR spectra, X-ray crystal structures,
and high-resolution mass spectra, respectively. We are
also indebted to Dr. J effrey P. Honovich of the Mass
Spectrometric Facility at Drexel University for perform-
ing high-resolution FAB-MS analysis.
1
745 cm-1; H NMR (500 MHz, CDCl3) δ 1.45 (s, 3 H), 1.54 (s,
3 H), 2.94 (dd, J 1 ) J 2 ) 6.5 Hz, 2 H), 3.33 (d, J ) 2.7 Hz, 1
H), 3.37 (ddd, J ) 10.0, 10.0, 5.3 Hz, 1 H), 3.63 (dd, J 1 ) J 2
)
9.3 Hz, 1 H), 3.67-3.73 (m, 1 H), 3.79-3.85 (m, 2 H), 3.96
(dd, J ) 10.8, 5.4 Hz, 1 H), 4.09 (ddd, J ) 9.8, 9.8, 2.8 Hz, 1
H), 4.24 (ddd, J ) 9.7, 9.7, 6.0 Hz, 1 H), 4.86 (d, J ) 8.3 Hz,
1 H), 6.62 (q, J ) 6.3 Hz, 1 H), 7.12-7.15 (m, 1 H), 7.17-7.21
(m, 2 H), 7.39 (s, 1 H), 7.46-7.48 (m, 1 H), 88.31-8.34 (m, 1
H), 8.80 (dd, J ) 6.5, 3.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 162.1, 161.8, 142.0, 128.5 (d, J C-F ) 11.4 Hz), 128.19, 128.16,
128.0, 124.1, 122.3, 119.4, 117.6, 117.4, 116.9, 111.1, 100.5,
99.9, 74.4, 71.4, 68.9, 67.3, 62.0, 59.3, 44.0, 29.0, 24.0, 19.1;
high-resolution mass spectrum (ESI) m/z 553.1574 [(M + Na)+,
calcd for C26H27FN2O9Na 553.1598].
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Dim er ic Ma cr ocycle (+)-109. Cyclization precursor (-)-
108 (15 mg, 0.028 mmol) was dissolved in DMF (anhydrous, 5
mL). Potassium carbonate (anhydrous, 19 mg, 0.14 mmol) was
added, and the resulting yellow solution was stirred for 8.5 h
J O0352068
302 J . Org. Chem., Vol. 69, No. 2, 2004