Ketone-imide versus ketone-oxime reductive cross-coupling promoted by samarium diiodide: New mechanistic insight gained from a failed aminocyclopentitol synthesis

Article abstract of DOI:10.1021/jo050185y

The intramolecular 1,6-ketone/imide reductive coupling promoted by samarium diiodide competes favorably with an alternative 1,5-ketone/oxime ether coupling in a keto-oxime substrate derived from D-glucosamine N-protected with a phthalimido group. This pin

Full text of DOI:10.1021/jo050185y

Ketone-Imide versus Ketone-Oxime Reductive Cross-Coupling
Promoted by Samarium Diiodide: New Mechanistic Insight
Gained from a Failed Aminocyclopentitol Synthesis
Jose Luis Chiara,* AÄ ngela Garc´ıa, and Gabriella Cristo´bal-Lumbroso
Instituto de Quı´mica Orga´nica General, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain
jl.chiara@iqog.csic.es
Received January 28, 2005
The intramolecular 1,6-ketone/imide reductive coupling promoted by samarium diiodide competes
favorably with an alternative 1,5-ketone/oxime ether coupling in a keto-oxime substrate derived
from D-glucosamine N-protected with a phthalimido group. This pinacol coupling reaction affords
new homochiral R-hydroxylactam scaffolds that could be useful in diversity-oriented synthesis. A
mechanistic proposal for this reaction that explains the experimental results is supported by DFT
quantum-mechanical calculations on model compounds.
Introduction
In formulating the synthetic plan for the 1,2-di-
aminocyclopentane skeleton I, we envisioned the use of
D-glucosamine IV as a readily available homochiral
The stereochemical diversity and high degree of func-
tionalization of carbohydrates render them particularly
attractive as scaffolds for the synthesis of libraries of
polyfunctional, rigid, and geometrically diverse com-
pounds suitable for broad screeening.1 Pyranose2 and, less
frequently, their furanose3 counterparts have been mostly
used in this endeavor. Carbocycles derived from carbo-
hydrates represent an interesting alternative that re-
mains little explored.4 In the context of our work5 on the
synthesis of natural products with an aminocyclopentitol
moiety using carbohydrates as starting materials, we
became interested in the preparation of libraries of
compounds based on polyhydroxylated diaminocyclopen-
tane scaffolds (I) for the discovery of new and specific
glycosidase inhibitors inspired in the structure of natural
carbocyclic inhibitors6 (Chart 1).
(2) (a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.;
Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Strader, C. D.; Smith, A.
B., III; Cascieri, M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.;
Maechler, L. J. Am. Chem. Soc. 1992, 114, 9217-9218. (b) Hirschmann,
R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; 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) Nicolaou, K. C.;
Trujillo, J. I.; Chibale, K. Tetrahedron 1997, 53, 8751-8778. (d) Sofia,
M. J.; Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina, R.; Wang, H.;
Gange, D. J. Org. Chem. 1998, 63, 2802-2803. (e) Wong, C.-H.;
Hendrix, M.; Manning, D. D.; Rosenbohm, C.; Greenberg, W. A. J. Am.
Chem. Soc. 1998, 120, 8319-8327. (f) Wunberg, T.; Kallus, C.; Opatz,
T.; Henke, S.; Schmidt, W.; Kunz, H. Angew. Chem., Int. Ed. 1998,
37, 2503-2505. (g) Kallus, C.; Opatz, T.; Wunberg, T.; Schmidt, W.;
Henke, S.; Kunz, H. Tetrahedron Lett. 1999, 40, 7783-7786. (h)
Hirschmann, R.; Ducry, L.; Smith, A. B., III. J. Org. Chem. 2000, 65,
8307-8316. (i) Hanessian, S.; Saavedra, O. M.; Xie, F.; Amboldi, N.;
Battistini, C. Bioorg. Med. Chem. Lett. 2000, 10, 439-442. (j) Opatz,
T.; Kallus, C.; Wunberg, T.; Schmidt, W.; Henke, S.; Kunz, H.
Carbohydr. Res. 2002, 337, 2089-2110. (k) Opatz, T.; Kallus, C.;
Wunberg, T.; Schmidt, W.; Henke, S.; Kunz, H. Eur. J. Org. Chem.
2003, 1527-1536. (l) Murphy, P. V.; O’Brien, J. L.; Gorey-Feret, L. J.;
Smith, A. B., III. Tetrahedron 2003, 59, 2259-2271. (m) Abrous, L.;
Jokiel, P. A.; Friedrich, S. R.; Hynes, J.; Smith, A. B., III; Hirschmann,
R. J. Org. Chem. 2004, 69, 280-302. (n) Huenger, U.; Ohnsmann, J.;
Kunz, H. Angew. Chem., Int. Ed. 2004, 43, 1104-1107.
(1) For recent reviews, see: (a) Le Giang, T.; Abbenante, G.; Becker,
B.; Grathwohl, M.; Halliday, J.; Tometzki, G.; Zuegg, J.; Meutermans,
W. Drug Discovery Today 2003, 8, 701-709. (b) Marcaurelle, L. A.;
Seeberger, P. H. Curr. Opin. Chem. Biol. 2002, 6, 289-296. (c) Gruner,
S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491-
514.
10.1021/jo050185y CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/12/2005
4142
J. Org. Chem. 2005, 70, 4142-4151

R-Hydroxylactam Scaffolds from D-Glucosamine
CHART 1. Natural Aminocyclopentitol
Glycosidase Inhibitors and Structurally Related
Compounds
SCHEME 2a
a Reagents and conditions: (a) NBS, acetone/H2O (10:1), -15
°C to rt; (b) BnONH2‚HCl, pyridine, MeOH, 50 °C; (c) Dess-Martin
periodinane, CH2Cl2, rt (7); (d) (i) (COCl)2, DMSO, CH2Cl2, -70
°C, (ii) Et3N, -70 °C to rt (8).
conditions or using the Dess-Martin reagent followed by
column chromatography purification provided exclusively
the cyclic hemiaminal V when the amino group was
monoprotected as an acetamide or as a t-BOC carbamate.
Surprisingly,7 when a Swern oxidation/reductive coupling
protocol5f was employed to avoid the isolation of the
intermediate ketone, a complex mixture of products was
obtained from which the expected diaminocyclopentitol
I could not be isolated. In an attempt to overcome these
unanticipated difficulties, we selected the N-phthalimido
group as a more suitable protecting group for the amino
function of our substrate. In doing this selection, we were
confronted with a different potential problem, as it has
been recently shown that imides are able to cross-couple
inter-8 and intramolecularly9 with carbonyl compounds
in the presence of SmI2. However, we expected that the
ketone-oxime ether cross-coupling could successfully
compete because oxime ethers are highly efficient C-
radical acceptors.5,10 In addition, the ketone/oxime ether
cross-coupling reaction, being a 5-exo-trig cyclization in
this case, would have an entropic advantage over the
alternative 6-exo-trig ketone/imide reaction.
SCHEME 1
starting material and a ketone-oxime ether reductive
carbocyclization and hydroxylamine reduction cascade5
promoted by SmI2 as an effective tool to prepare the key
carbocycle I (Scheme 1).
Two differently O-protected keto-oximes, 7 and 8, were
selected as substrates for the pinacol coupling reaction
(Scheme 2). These compounds were readily obtained from
the known protected D-glucosamine derivatives 111 and
2,12 respectively, following a three-step sequence5d that
consists of: (i) mild hydrolysis of the thiophenyl glycoside
Results and Discussion
Initial attempts at preparing target cyclopentitol I by
reductive cyclization of keto-oximes II met with failure.
Thus, oxidation of oxime III (R1 ) Bn) under Swern
(3) (a) Papageorgiou, C.; Haltiner, R.; Bruns, C.; Petcher, T. J.
Bioorg. Med. Chem. Lett. 1992, 2, 135. (b) Krueger, E. B.; Hopkins, T.
P.; Keaney, M. T.; Walters, M. A.; Boldi, A. M. J. Comb. Chem. 2002,
4, 229-238. (c) Timmer, M. S. M.; Verdoes, M.; Sliedregt, L.; van der
Marel, G. A.; van Boom, J. H.; Overkleeft, H. S. J. Org. Chem. 2003,
68, 9406-9411.
(7) We had successfully used previously our one-pot oxidation-
reductive coupling protocol for the carbocyclization of a closely related
keto-aldehyde derived from D-glucosamine protected as N-acetamide
or as N-t-Boc carbamate.5f
(8) (a) Farcas, S.; Namy, J.-L. Tetrahedron Lett. 2000, 41, 7299-
7302. (b) Yoda, H.; Matsuda, K.; Nomura, H.; Takabe, K. Tetrahedron
Lett. 2000, 41, 1775-1780.
(9) Yoda, H.; Nakahama, A.; Koketsu, T.; Takabe, K. Tetrahedron
Lett. 2002, 43, 4667-4670.
(4) Phon, C. W.; Abell, C. J. Comb. Chem. 1999, 1, 485-492.
(5) (a) Chiara, J. L.; Marco-Contelles, J.; Khiar, N.; Gallego, P.;
Destabel, C.; Bernabe, M. J. Org. Chem. 1995, 60, 6010-11. (b) Marco-
Contelles, J.; Gallego, P.; Rodriguez-Fernandez, M.; Khiar, N.; Desta-
bel, C.; Bernabe, M.; Martinez-Grau, A.; Chiara, J. L. J. Org. Chem.
1997, 62, 7397-7412. (c) Storch de Gracia, I.; Dietrich, H.; Bobo, S.;
Chiara, J. L. J. Org. Chem. 1998, 63, 5883-5889. (d) Storch de Gracia,
I.; Bobo, S.; Martin-Ortega, M. D.; Chiara, J. L. Org. Lett. 1999, 1,
1705-1708. (e) Bobo, S.; Storch de Gracia, I.; Chiara, J. L. Synlett 1999,
1551-1554. (f) Chiara, J. L.; Storch de Gracia, I.; Bastida, A. Chem.
Commun. 2003, 1874-1875. (g) Chiara, J. L.; Storch de Gracia, I.;
Garc´ıa, AÄ .; Bastida, AÄ .; Bobo, S.; Mart´ın-Ortega, M. ChemBioChem
2005, 6, 186-191.
(10) (a) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J. Am. Chem.
Soc. 1988, 110, 1633-1634. (b) Grissom, J. W.; Klingberg, D. J. Org.
Chem. 1993, 58, 6559-64. (c) Kim, S.; Kim, Y.; Yoon, K. S. Tetrahedron
Lett. 1997, 38, 2487-2490. (d) Miyabe, H.; Shibata, R.; Sangawa, M.;
Ushiro, C.; Naito, T. Tetrahedron 1998, 54, 11431-11444. For recent
reviews, see: (e) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543-17594. (f) Friestad, G. K. Tetrahedron 2001, 57, 5461-5496.
(11) Sofia, M.; Allanson, N.; Chen, A.; Liu, D.; Chan, T. Y. PCT Int.
Appl., WO 9734623, 1997.
(6) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999,
99, 779-844.
(12) Ogawa, T.; Nakabayashi, S.; Sasajima, K. Carbohydr. Res. 1981,
95, 308-312.
J. Org. Chem, Vol. 70, No. 10, 2005 4143

Chiara et al.
SCHEME 3
excess of SmI2 (6.7 equiv) was used, reduction of the
oxime to the amine took place upon addition of H2O5a-e
to give compound 1214 after N-acetylation, isolated as a
single diastereoisomer.
The stereochemistry of the two contiguous quaternary
carbons of compounds 11 and 12 was determined through
a combination of molecular modeling and NMR studies.
First, geometry optimization calculations were performed
for the four possible diastereoisomers at the two contigu-
ous carbinol centers (two trans and two cis diols) of
compound (E)-11 using the MM2 force field. To reduce
the number of possible conformers, O-benzyl ethers were
replaced by O-methyl ethers in this theoretical study.
Figure 1 shows the calculated geometries of the global
minimum energy conformer for each diasteroisomer. Due
to its rather rigid polycyclic structure, other possible ring
conformers lie >2 kcal/mol above the global minimum,
thus allowing their exclusion. Inspection of all of the
minimized structures revealed that the distance between
the aromatic proton ortho to the aminal group (H-11) and
the methylenic protons at C-1 (H-1a and H-1b) could be
of diagnostic value for the stereochemical assignment.
The pertinent interproton distances are reported in Table
1 together with the total energies calculated for each
conformer. Next, a full assignment of the 1H and 13C
NMR signals of compounds 11 and 12 was performed by
a combination of DQ-COSY, HSQC, HMBC, and NOESY
spectra (see the Supporting Information). Figure 2 shows
selected NOESY correlations observed for these com-
pounds. Protons H-1a (δ 4.30, 4.17, and 4.31 ppm in (E)-
11, (Z)-11, and 12, respectively) and H-1b (δ 4.58, 4.50,
and 4.74 ppm in (E)-11, (Z)-11, and 12, respectively) were
readily differentiated in the NOESY spectra, because
only H-1b showed a cross-peak with the acetalic proton
H-3 (δ 5.68, 5.72, and 5.81 ppm in (E)-11, (Z)-11, and
12, respectively). The assignment of the H-11 resonance
(δ 7.45, 7.42, and 7.51 ppm in (E)-11, (Z)-11, and 12,
respectively) was straightforward too because this is the
only aromatic proton that gave a cross-peak with the
aminal carbon C-11b (δ 88.6, 89.3, and 89.6 ppm in (E)-
11, (Z)-11, and 12, respectively) in the HMBC spectra
SCHEME 4a
a Reagents and conditions: (a) SmI2 (3 equiv), t-BuOH/THF, -30
°C; (b) SmI2 (6.7 equiv), t-BuOH/THF, -30 °C to rt; (c) H2O (30
equiv); (d) Ac2O, pyridine.
under oxidative conditions,13 (ii) condensation with O-
benzylhydroxylamine, and (iii) oxidation under Swern
conditions or using the Dess-Martin periodinane. Keto-
oximes 7 and 8 were obtained as a mixture of isomeric
oxime ethers [E/Z ratio ) 4.7:1 (7), 2.5:1 (8)].
When the mixture of keto-oximes 7 was treated with
a solution of SmI2 (3 equiv) in THF containing t-BuOH
at -30 °C, a fast intramolecular pinacol coupling reaction
took place, but instead of the expected cyclopentitol I, a
mixture of four diastereoisomeric tricyclic R-hydroxylac-
tams was formed in good yield (Scheme 3). This mixture
could be separated by column chromatography into (E)-
oxime 9 (17:1) and (Z)-oxime 10 (3.5:1), each as a mixture
of diastereoisomers at the new stereocenters. The 9/10
n
(optimized for an average JCH value of 8 Hz). The
NOESY spectra of compounds (E)-11, (Z)-11, and 12
showed a cross-correlation of H-11 with H-1a but not with
H-1b, thus excluding the two isomers with an (R)-
configuration at C-11c, for which the predicted H-11/H-
1a distance is >3.5 Å (see Table 1). NOESY correlations
between the hydroxyl protons and proximal CH protons
of the molecule allowed us to assign the (R)-configuration
to C-11b quaternary center and confirmed the previous
assignment of the (S)-configuration to C-11c. Thus, the
OH at C-11c (δ 2.83, 2.87, and 2.90 ppm in (E)-11, (Z)-
11, and 12, respectively) gives cross-peaks with H-1a and
H-5, as expected for a (11cS)-stereochemistry. Conversely,
the hemiaminal hydroxyl at C-11b (δ 5.41, 7.50 ppm in
(E)-11 and 12, respectively; this signal could not be
observed in (Z)-11 due to fast exchange catalyzed by
acidic impurities) showed cross-correlation with H-1b, as
expected for a (11bR)-stereochemistry. In the case of the
acetamido derivative 12, the displacement to low field
(∆δ ) +2.09 ppm, with respect to (E)-11) of the 1H signal
of the hydroxyl at C-11b reveals the involvement of this
proton in a stable intramolecular hydrogen bond. The
global energy minimum conformation calculated for the
1
ratio was 1.3:1, as determined by H NMR analysis of
the crude reaction mixture. The stereochemistry at the
two new stereocenters in these mixtures could not be
determined due to strong spectral overlap. On the other
hand, cyclization of keto-oximes 8 under the same condi-
tions yielded a separable mixture of two diastereoiso-
meric R-hydroxylactams, (E)-1114 and (Z)-11,14 which
differed only in the configuration of the oxime group
(Scheme 4). As was previously observed for related
reductive cyclizations involving a cyclic ketone,5d,e,15
single stereoisomer is obtained at the quaternary carbinol
center arising from the ketone carbonyl. When a large
a
(13) (a) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze,
T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A.
L.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593. (b) Motawia,
M. S.; Marcussen, J.; Moeller, B. L. J. Carbohydr. Chem. 1995, 14,
1279.
(14) The structure of all new compounds was determined by 1D
NMR (1H and 13C) and 2D NMR (DQ-COSY, NOESY, HSQC, and
HMBC) experiments (see the Supporting Information).
(15) Boiron, A.; Zilling, P.; Faber, D.; Giese, B. J. Org. Chem. 1998,
63, 5877-5882.
4144 J. Org. Chem., Vol. 70, No. 10, 2005

R-Hydroxylactam Scaffolds from D-Glucosamine
FIGURE 1. Global minimum energy conformers of the four possible diastereoisomers of a methyl ether analogue of compound
(E)-11 calculated in the gas phase using the MM2 force field. Two different views, from perpendicular planes, are shown for each
isomer together with the corresponding structural formula.
TABLE 1. Calculated MM2 Gas-Phase Total Energies
and Selected Through-Space Interproton Distances for
the Global Energy Minimum Conformers of the Four
Possible Diastereoisomers of a Methyl Ether Analogue of
Compound (E)-11
diastereoisomer Et (kcal/mol) dH-11/H-1a (Å) dH-11/H-1b (Å)
11bR,11cS
11bS,11cR
11bS,11cS
11bR,11cR
30.02
38.83
37.69
37.93
2.254
3.582
2.445
3.924
3.150
2.166
3.817
3.148
(11bR,11cS)-isomer of this compound using the MM2
force field (Figure 3) correctly predicts this situation,
revealing the presence of a nine-membered ring hydrogen
bond with the acetamido carbonyl group. The interproton
distances calculated for this optimized structure, in
particular those involving the methylenic protons of the
side chain at C-6 (see Table in Figure 2), completely agree
with the NOESY cross-peaks observed for 12 (Figure 2).
The fact that no cyclopentitol arising from the alterna-
tive ketone/oxime ether pinacol coupling was detected in
FIGURE 2. Selected NOESY correlations measured for
compounds (E/Z)-11 and 12 in CDCl3 at 27 °C.
the crude reaction mixtures provides some clues on the
possible mechanistic pathway of this reductive process
(Scheme 5). Thus, the experimental observations can be
J. Org. Chem, Vol. 70, No. 10, 2005 4145

Chiara et al.
FIGURE 3. Global minimum energy conformer (a) and selected interproton distances (b) of a methyl ether analogue of compound
12 calculated in the gas phase using the MM2 force field. Two different views, from perpendicular planes, are shown together
with the corresponding structural formula.
SCHEME 5. Mechanistic Proposal for the
Intramolecular Ketone/Imide Reductive Coupling
To support our mechanistic proposal, we have per-
formed quantum mechanical DFT calculations on simple
model systems representing the different reducible func-
tional groups in our substrates: acetone, N-methylphthal-
imide, and acetaldehyde O-methyl-oxime.17 Table 2 shows
the vertical electron affinity (VEA) and the adiabatic
electron affinity (AEA) calculated at the B3LYP/6-311G-
(d,p) level in the gas phase for the model compounds.22,23
The calculated values24 show that the phthalimido car-
bonyl of N-methylphthalimide is a much better electron-
accepting group than the ketone carbonyl of acetone, the
(17) The relative thermodynamic ease of reduction of the three
different CdX (X ) O, N) groups in our substrates might be inferred
from available redox potentials for organic molecules containing each
of these functional groups.18 However, care should be taken when
comparing electrochemical data obtained under different experimental
conditions due to the sensitivity of the E1/2 values to solvent, pH, and
supporting electrolyte used. The E1/2 values reported for acetone and
for N-methylphthalimide are -2.16 eV (in H2O containing 0.01 M Et4-
NI)19 and -1.32 eV (in DMF containing 0.5 M Et4NClO4, value for wave
I),20 respectively, indicating that the former is less readily reduced.
Values reported for oximes and oxime ethers18b are less negative than
those above, but correspond to the electroreductive cleavage of the N-O
bond of the oxime, a process that is not observed under our reaction
conditions. Shono et al.21 have shown that oxime ethers are not
electrochemically reducible under the same conditions as they are
coupled to ketones, which led them to propose the intermediacy of ketyl
radical-anions for the corresponding electrochemical cross-coupling.
(18) (a) Encyclopedia of Electrochemistry of the Elements; Bard, A.
J., Lund, H., Eds.; Marcel Dekker: New York, 1979; Vol. 12. (b)
Encyclopedia of Electrochemistry of the Elements; Bard, A. J., Lund,
H., Eds.; Marcel Dekker: New York, 1984; Vol. 15.
explained postulating that the reaction is initiated by
single electron transfer from Sm(II) to the imide16 to
produce an intermediate ketyl radical-anion A. This
radical-anion can then evolve in two different ways: (1)
via (reversible) 4-exo-trig addition to the oxime carbon,
or (2) via (reversible) 6-exo-trig addition to the ketone
carbonyl. It can be reasonably assumed that this last
process is much faster than the first and leads to the
O-radical anion B, which is then (irreversibly) reduced
by Sm(II) and protonated to yield the final product.
(19) Smirnov, V. A.; Sidorenko, N. F. Gidrokhim. Mater. 1971, 55,
126-128 (Chem. Abs. 75: 129147).
(16) Preferential electron transfer to the imide has been previously
proposed by Farcas and Namy6a for the intermolecular pinacol coupling
reaction between N-acyl lactams and carbonyl compounds. However,
these authors favor the formation of an acyl radical intermediate, which
is subsequently reduced to a transient acyl samarium species.
(20) Farnia, G.; Romanin, A.; Capobianco, G.; Torzo, F. J. Electroa-
nal. Chem. 1971, 33, 31-44.
(21) Shono, T.; Kise, N.; Fujimoto, T.; Yamanami, A.; Nomura, R.
J. Org. Chem. 1994, 59, 1730-1740.
4146 J. Org. Chem., Vol. 70, No. 10, 2005

R-Hydroxylactam Scaffolds from D-Glucosamine
TABLE 2. Calculated B3LYP/6-311G(d,p) Gas-Phase
Vertical Electron Affinities (VEA) and Adiabatic Electron
Affinities (AEA) for Acetone, N-Methylphthalimide, and
Acetaldehyde O-Methyl Oxime
compound
VEAa (eV)
AEAb (eV)
acetone
-1.97
0.52
-2.53
-1.40
N-methylphthalimide
0.78
c
acetaldehyde O-methyl oxime
-
a VEA values correspond to the energy difference between the
optimized neutral molecule and the radical-anion at the geometry
of the optimized neutral molecule. b AEA values correspond to the
energy difference between the neutral molecule and the radical-
anion at their optimized geometries. c The radical-anion is un-
stable at the UB3LYP/6-311G(d,p) level of theory in the gas phase
and dissociates through homolytic cleavage of the N-O bond, in
parallel with that observed under electrochemical reduction
conditions.18b
oxime ether being the most difficult to reduce via single
electron transfer, in agreement with our mechanistic
proposal and with the experimental redox potentials
available.19,20 However, a note of caution on the inter-
pretation of the quantum mechanical calculations should
be added. Our theoretical results are only strictly ap-
plicable if the electron transfer is outer-sphere. Yet,
recent studies25 led to the conclusion that the electron
transfer from SmI2 in THF to a ketone carbonyl is an
inner-sphere process and the same almost certainly
applies to an imide carbonyl. In such a case, the electron-
transfer process should be influenced by the nature of
the metal-oxygen bond that is being formed during the
reaction as well as the energy required for reorganization
of the ligands around the metal center on going from
oxidation state 2+ to 3+.
Two different mechanistic scenarios can be proposed
to explain the stereochemical outcome of the cyclization
of substrate 8. First, preferential formation of the most
stable (11bR,11cS)-isomer (see calculated total energies
in Table 1) could be the result of the stereodirecting step
being under thermodynamic control, as is implicit in
Scheme 5. In an alternative scenario, if the cyclization
is under kinetic control, formation of this isomer could
FIGURE 4. Possible transition states for the cyclization of
compound 8 (for clarity, the metal cation is not shown).
be a consequence of geometrical constraints imposed by
the cyclic acetal in the transition state of the C-C bond-
forming step. Figure 4 shows the different transition
states that can be proposed for the four possible stereo-
chemical outcomes of the cyclization in this situation. If
we assume a late, product-like transition state, equatorial
attack of a planar imide radical anion on the ketone
carbonyl is geometrically possible for the most stable
chair conformation of the benzylidene acetal ring (transi-
tion states A and C), while axial attack requires this ring
to attain a less stable skew conformation (transition
states B and D). The chairlike transition state A leading
to the observed (11bR,11cS) trans-diol product is expected
to be energetically more favorable than the skew-
like transition state C, which leads to the alternative
(11bS,11cS) cis-diol. However, in this oversimplified
scenario, we have neglected the possible role played by
the metal ion. Metal chelation could favor transition state
C over A leading to the initial formation of the
(11bS,11cS)-hemiaminal, which could then equilibrate to
the corresponding more stable (11bR,11cS)-isomer. The
stereochemical outcome observed in this ketone/imide
coupling is different from that observed5d,e,g,15 for the
ketone/oxime ether reductive cyclization of closely related
systems containing a cyclic ketone, revealing the different
mechanisms involved in each case.
Finally, we have performed some simple transforma-
tions of tetracycles 11 to obtain other novel scaffolds that
could be useful in diversity-oriented synthesis (Scheme
6). Hydrolysis of the oxime ether and reduction of the
resultant aldehyde afforded alcohol 13 in very high yield.
This compound was characterized as its corresponding
acetyl ester 14.14 The 1H NMR chemical shift of the
hydroxyl group at C-11b in 14 (δ 5.12 ppm) is within the
expected range for a hemiaminal hydroxyl, indicating
that, at difference with that observed in the case of the
acetamido derivative 12, this hydroxyl does not partici-
pate in a stable intramolecular hydrogen bond with the
ester carbonyl. This fact explains also the absence of cross
correlation between OH11b and the methylenic protons
(22) We employed the strategy of using a relatively large basis set
but without diffuse functions, which confines the excess electron to
the molecular framework allowing relative estimates for molecules with
negative valence electron affinities using the DFT method: (a) Li, Y.;
Cai, Z.; Sevilla, M. D. J. Phys. Chem. A 2002, 106, 1596-1603. (b) Li,
P.; Bu, Y.; Ai, H. J. Phys. Chem. A 2004, 108, 1200-1207.
(23) Ab initio calculations were carried out using the Gaussian 98
program package: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.;
Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;
Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli,
C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P.
Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu,
G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R.
L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.3; Gaussian, Inc.:
Pittsburgh, PA, 1998.
(24) By convention, a positive EA indicates that the binding reaction
of a neutral molecule with an electron is an exoergic process. For a
recent review on electron affinity covering theoretical computations,
see: Rienstra-Kiracofe, J.; Tschumper, G. S.; Schaefer, H. F., III;
Nandi, S.; Ellison, G. B. Chem. Rev. 2002, 102, 231-282.
(25) (a) Miller, R. S.; Sealy, J. M.; Shabangi, M.; Kuhlman, M. L.;
Fuchs, J. R.; Flowers, R. A., II. J. Am. Chem. Soc. 2000, 122, 7718-
7722. (b) Enemaerke, R. J.; Daasbjerg. K.; Skrydstrup, T. Chem.
Commun. 1999, 343-344.
J. Org. Chem, Vol. 70, No. 10, 2005 4147

Chiara et al.
SCHEME 6a
and Bu4NI (52 mg, 0.13 mmol). To the mixture was added
slowly NaH (60% dispersion in mineral oil, 251 mg, 6.27
mmol), and it was stirred at 0 °C for 30 min and at rt for 2 h.
The reaction was quenched by addition of AcOH, diluted with
CH2Cl2 (20 mL), and washed with H2O (3 × 20 mL). The
organic phase was dried over Na2SO4, concentrated at reduced
pressure, and the crude was purified by flash chromatography
(hexanes/EtOAc 10:1) to give 1 (675 mg, 72%) as a colorless
1
oil. [R]20 -1.3 (c 0.9, CHCl3); H NMR (300 MHz, CDCl3) δ
D
7.78-7.62 (m, 4H), 7.41-7.14 (m, 16H), 7.13-6.81 (m, 4H),
5.53 (d, 1H, J ) 10.2 Hz, H-1), 4.83 (d, 1H, J ) 11.1 Hz, OCH2-
Ph), 4.77 (d, 1H, J ) 12.0 Hz, OCH2Ph), 4.66 (d, 1H, J ) 10.8
Hz, OCH2Ph), 4.64 (d, 1H, J ) 12.0 Hz, OCH2Ph), 4.56 (d, 1H,
J ) 11.7 Hz, OCH2Ph), 4.43 (d, 1H, J ) 12.0 Hz, OCH2Ph),
4.38 (dd, 1H, J ) 8.1, 10.8 Hz, H-2), 4.25 (t, 1H, J ) 10.5 Hz,
H-5), 3.88-3.65 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 165.1,
138.2, 137.9, 137.7, 133.8, 132.5, 132.0, 131.5, 129.0, 128.7,
128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5,
127.3, 123.2, 83.2, 80.2, 79.3, 79.3, 74.9, 74.4, 73.3, 68.8, 54.8;
MS (ES+) m/z ) 694.3 [M + Na+].
a Reagents and conditions: (a) HCHO, CSA, THF/H2O, rt; (b)
NaBH4, MeOH, rt; (c) Ac2O, pyridine, rt; (d) DIAD, Ph3P, toluene,
rt.
Compound 2.12 To a solution of phenyl 2-deoxy-2-phthal-
imido-1-thio-â-D-glucopyranoside27 (550 mg, 1.87 mmol) in
anhydrous CH3CN (10 mL) was added PhCH(OMe)2 (1.03 mL,
6.85 mmol). After stirring at rt for 1 h, 0.5 mL of Et3N was
added to give a colorless solution. The mixture was concen-
trated at reduced pressure, and the crude was purified by flash
chromatography (hexanes/EtOAc 3:1) to give the corresponding
4,6-O-benzylidene acetal derivative (552 mg, 60%) as a white
solid. Mp 103 °C; [R]D20 -1.9 (c 2.7, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.88-7.83 (m, 2H), 7.75-7.69 (m, 2H), 7.49-7.45 (m,
2H), 7.40-7.34 (m, 5H), 7.29-7.24 (m, 3H), 5.67 (d, 1H, J )
10.5 Hz, H-1), 5.55 (s, 1H), 4.61 (ddd, 1H, J ) 3.9, 9.3, 10.2
Hz, H-3), 4.38 (dd, 1H, J ) 4.2, 10.5 Hz, H-6), 4.32 (t, 1H, J )
9.9 Hz, H-2), 3.81 (t, 1H, J ) 9.9 Hz, H-4), 3.64 (ddd, 1H, J )
5.1, 9.3, 9.9 Hz, H-5), 3.58 (t, 1H, J ) 9 Hz, H-6′), 2.8 (d, 1H,
J ) 3.9 Hz, OH); 13C NMR (75 MHz, CDCl3) δ 168.2, 167.4,
136.8, 134.1, 132.5, 131.7, 131.5, 131.4, 129.3, 128.9, 128.3,
128.0, 126.2, 123.8, 123.3, 101.8, 84.2, 81.7, 70.2, 69.6, 68.9,
55.4; MS (ES+) m/z ) 694.2 [M + Na+].
FIGURE 5. Selected NOESY correlations measured for
compounds 14 and 15 in CDCl3 at 27 °C.
of the ester side chain at C-6 in the NOESY spectrum
(Figure 5). Treatment of 13 under Mitsunobu conditions
provided the rigid pentacyclic scaffold 1514 in very good
yield. The facile formation of 15 provides a further proof
of the (R)-stereochemistry at C-11b in this series of
compounds, confirmed by the NOESY spectrum (Figure
5).
In summary, we have synthesized a series of novel
polyhydroxylated R-hydroxylactam scaffolds by an in-
tramolecular ketone/imide pinacol coupling reaction of
substrates readily obtained from D-glucosamine. The
6-exo-trig ketone/imide reductive cyclization takes place
in preference to an alternative 5-exo-trig ketone/oxime
ether coupling. This preference can be rationalized in
terms of the very facile single-electron-transfer reduction
of N-alkylphthalimides as compared to ketones and oxime
ethers, as predicted by DFT model calculations. Based
on this mechanistic insight, further developments on
ketyl radical-anion carbon-carbon bond-forming reac-
tions involving N-substituted phthalimides with diverse
radicophiles await to be explored. The R-hydroxylactam
moiety is a precursor for N-acyliminium ion chemistry,26
which could allow further structural modifications of the
scaffold.
To a solution of the former benzylidene acetal (630 mg, 0.93
mmol) in anhydrous DMF (8 mL) at 0 °C were added BrBn
(0.34 mL, 2.81 mmol) and Bu4NI (35 mg, 0.09 mmol). To the
mixture was added slowly NaH 60% (112 mg, 2.81 mmol), and
it was stirred at 0 °C for 30 min and at rt for 18 h. The reaction
was diluted with CH2Cl2 (15 mL) and washed with H2O (3 ×
10 mL). The organic phase was dried over Na2SO4, concen-
trated at reduced pressure, and the crude was purified by flash
chromatography (hexanes/EtOAc 6:1) to give 2 (650 mg, 90%)
as a colorless oil. [R]20 +4.2 (c 3.5, CHCl3); IR (KBr) 3437,
D
2862, 1774, 1714, 1382, 1095, 751, 720, 699 cm-1
;
1H NMR
(300 MHz, CDCl3) δ 8.00-7.27 (m, 15H), 7.12-6.81 (m, 4H),
5.65 (s, 1H), 5.64 (d, 1H, J ) 10.2 Hz, H-1), 4.78 (d, 1H, J )
12.4 Hz, OCH2Ph), 4.57-4.39 (m, 3H), 4.30 (t, 1H, J ) 10 Hz,
H-6), 3.90-3.65 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 167.6,
167.1, 137.5, 137.1, 133.9, 133.8, 132.6, 131.5, 131.4, 128.9,
128.8, 128.2, 128.0, 128.0, 127.9, 127.3, 125.9, 123.4, 123.3,
123.3, 101.2, 84.0, 82.7, 75.3, 74.1, 70.2, 68.5, 54.6. MS (ES+)
m/z ) 580.1 [M + H+].
Compound 3. To a solution of 1 (680 mg, 0.89 mmol) in
acetone (7 mL) and H2O (0.7 mL) at -15 °C was added NBS
(794 mg, 4.46 mmol). After being stirred at -15 °C for 1 h,
the yellow solution was diluted with CH2Cl2 (10 mL) and
washed with a saturated aqueous solution of NaHCO3 (2 ×
10 mL). The phases were separated, and the organic phase
was washed with an aqueous 10% solution of Na2S2O3 (2 × 10
mL) and brine (2 × 10 mL) and dried over Na2SO4. After
concentration at reduced pressure, the crude was purified by
flash chromatography (hexanes/EtOAc 3:1) to give 3 (450 mg,
99%) as a colorless oil. [R]D20 +0.6 (c 1.5, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.71-7.65 (m, 4H), 7.39-7.18 (m, 11H), 7.09-
6.84 (m, 4H), 5.36 (t, 1H, J ) 7.5 Hz, H-1), 4.82 (d, 1H, J )
9.9 Hz, OCH2Ph), 4.79 (d, 1H, J ) 11.4 Hz, OCH2Ph), 4.63 (d,
Experimental Section
Compound 1.11 To a solution of phenyl 2-deoxy-2-phthal-
imido-1-thio-â-D-glucopyranoside27 (500 mg, 1.39 mmol) in
DMF (5 mL) at 0 °C were added BrBn (1.9 mL, 16.68 mmol)
(26) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431-1628.
(27) Ogawa, T.; Nakabayashi, S.; Sasajima, K. Carbohydr. Res 1981,
95, 308-312.
4148 J. Org. Chem., Vol. 70, No. 10, 2005

R-Hydroxylactam Scaffolds from D-Glucosamine
1H, J ) 12.3 Hz, OCH2Ph), 4.60 (d, 1H, J ) 10.8 Hz, OCH2-
Ph), 4.54 (d, 1H, J ) 12 Hz, OCH2Ph), 4.44 (d, 1H, J ) 12.0
Hz, OCH2Ph), 4.42 (t, 1H, J ) 8.1 Hz, H-3), 4.15-4.08 (m,
2H), 3.79-3.67 (m, 3H), 3.43-3.41 (bs, 1H, OH); 13C NMR (75
MHz, CDCl3) δ 168.0, 137.9, 137.7, 133.7, 131.5, 128.6, 128.4,
128.0,127.9, 127.8, 127.7, 127.3, 126.8, 123.2, 92.8, 80.2, 79.4,
78.8, 74.8, 74.7, 73.5, 68.4, 57.5; MS (ES+) m/z ) 602.1 [M +
Na+].
J ) 12 Hz, OCH2Ph), 4.52 (d, 1H, J ) 11.7 Hz, OCH2Ph), 4.24
(dd, 1H, J ) 5.0, 10.4 Hz, H-6), 3.88 (m, 1H, J ) 9.4, 10.4,
10.4 Hz, H-5), 3.71 (dd, 1H, J ) 2.4, 9.4 Hz, H-4), 3.50 (t, 1H,
J ) 10.4 Hz, H-6); 13C NMR (75 MHz, CDCl3) ((E)+(Z)-Oxime)
δ 167.7, 167.4, 149.5, 145.2, 145.1, 137.4, 137.3, 137.2, 137.1,
137.0, 136.9, 133.8, 133.7, 131.6, 128.6, 128.5, 128.3, 128.3,
128.2, 128.1, 128.0, 127.7, 127.6, 126.1, 126.1, 123.1, 123.2,
101.4, 101.1, 80.8, 80.5, 76.3, 76.0, 74.2, 74.0, 73.6, 73.4, 70.9,
70.9, 61.4, 50.6, 45.3; MS (ES+) m/z ) 593.1 [M + H+], 615.2
[M + Na+].
Compound 4. To a solution of 2 (160 mg, 0.21 mmol) in
acetone (2 mL) and H2O (0.2 mL) at -15 °C was added NBS
(187 mg, 1.05 mmol). After being stirred at -15 °C for 1 h,
the yellow solution was diluted with CH2Cl2 (15 mL) and
washed with an aqueous solution of NaHCO3 (3 × 15 mL).
The combined organic phases were washed with an aqueous
10% solution of Na2S2O3 (3 × 15 mL) followed by brine (3 ×
15 mL). After being dried over Na2SO4, the mixture was
concentrated at reduced pressure, and the crude was purified
by flash chromatography (hexanes/EtOAc 4:1) to give 4 (94
mg, 97%) as a white solid. Mp 116-118 °C; [R]D20 -1.4 (c 1.6,
CHCl3); IR (KBr) νmax ) 3437, 2942, 1747, 1717, 1386, 1228,
1073, 1038, 720 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.74-7.60
(m, 4H), 7.53-7.47 (m, 2H), 7.42-7.32 (m, 4H), 7.05-6.80 (m,
4H), 5.62 (s, 1H, H-7), 5.49 (dd, 1H, J ) 6.3, 8.1 Hz, H-1), 4.81
(d, 1H, J ) 12.3 Hz, OCH2Ph), 4.51 (d, 1H, J ) 12.3 Hz, OCH2-
Ph), 4.51 (dd, 1H, J ) 9, 10.2 Hz, H-3), 4.40 (dd, 1H, J ) 4.8,
10.8 Hz, H-6), 4.15 (dd, 1H, J ) 8.7, 10.2 Hz, H-2), 3.83 (dd,
2H, J ) 9.9, 10.2 Hz, H-4, H-6′), 3.69 (ddd, 1H, J ) 4.8, 9.9,
10.2 Hz, H-5), 3.30 (d, 1H, J ) 8.1 Hz, OH); 13C NMR (75 MHz,
CDCl3) δ 168.0, 137.8, 137.2, 133.9, 131.5, 129.0, 128.3, 128.0,
127.4, 126.0, 123.4, 101.3, 93.4, 83.0, 74.3, 74.1, 68.6, 66.2, 57.6;
MS (ES+) m/z ) 488.1 [M + H+], 510.1 [M + Na+].
Compound 7. To a solution of 5 (80 mg, 0.11 mmol) in CH2-
Cl2 (1.2 mL) was added a solution of Dess-Martin periodinane
(75 mg, 0.17 mmol) in CH2Cl2 (0.5 mL). After being stirred at
rt for 2 h, the reaction mixture was diluted with CH2Cl2 (10
mL) and washed with a saturated solution of NaHCO3 (2 ×
10 mL). To the organic phase was added a 10% aqueous
solution of Na2S2O3 (5 mL), and the mixture was vigorously
stirred for 10 min. The mixture was extracted with CH2Cl2 (2
× 15 mL), and the organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated at reduced pressure. The
crude was purified by flash chromatography (hexanes/EtOAc
4:1) to give 7 as a colorless oil, 4.7:1 E/Z mixture of oximes
(78 mg, 99%), which was used immediately in the next
reaction. IR (KBr) νmax ) 2925, 1715, 1384, 1087, 1027, 737,
721, 697 cm-1 1H NMR (300 MHz, CDCl3) δ 7.80-7.67 (m,
;
7H), 7.35-7.22 (m, 14H), 7.13-6.89 (m, 5H), 5.30 (dd, 1H, J
) 6.0, 8.0 Hz), 5.28-4.13 (m, 11H); MS (ES+) m/z ) 591.1 [M
+ H+], 613.2 [M + Na+].
Compound 8. To a solution of (COCl)2 (29.4 µL, 0.33 mol)
in THF (0.2 mL) at -78 °C was added DMSO (47.6 µL, 0.67
mmol). After being stirred at -78 °C for 20 min, a solution of
6 (90 mg, 0.15 mmol) in THF (1 mL) was added dropwise. The
reaction mixture was stirred at -20 °C for 2 h, and Et3N (140
µL, 1.00 mmol) was added dropwise. The reaction mixture was
allowed to slowly attain 0 °C. After being stirred at 0 °C for
15 min, the crude was diluted with EtOAc (15 mL) and washed
with an aqueous saturated solution of NH4Cl (2 × 5 mL). The
organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated at reduced pressure to a give 8 as a mixture of
the E and Z oximes 4:1 (88 mg, 99%) as a colorless oil, which
Compound 5. To a solution of 3 (132 mg, 0.22 mmol) in
MeOH (2 mL) were added O-benzylhydroxylamine (130 mg,
0.81 mmol) and pyridine (0.16 mL, 2.04 mmol), and the
mixture was heated at reflux for 3 h. After concentration at
reduced pressure, the crude was purified by flash chromatog-
raphy (hexanes/EtOAc 3:1) to afford 5 as a colorless oil,
mixture of E and Z oximes 3:1 (137 mg, 92%). IR (KBr) νmax
)
3470, 2923, 1713, 1386, 1088, 1027, 737, 721, 697 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 7.84-7.82 (d, 0.75H, J ) 7.8 Hz,
H-1E), 7.77-7.60 (m, 4H), 7.37-7.18 (m, 13.25H), 7.09-6.84
(m, 7H), 5.86 (dd, 0.25H, J ) 6.3, 10.2 Hz, H-3Z), 5.42 (dd,
0.75H, J ) 7.8, 10.5 Hz, H-3E), 5.01 (s, 2H), 5.00 (dd, 0.75H,
J ) 3.9, 8.1 Hz), 4.79 (t, 0.25H, J ) 10.8 Hz), 4.71-4.31 (m,
6H), 4.13-4.04 (m, 2H), 3.84-3.61 (m, 2H), 2.7 (bs, 1H, OH);
13C NMR (75 MHz, CDCl3) δ 167.6, 147.8, 145.7, 138.5, 138.0,
138.0, 137.9, 137.8, 137.7, 137.6, 137.1, 137.0, 133.6, 131.6,
131.5, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
127.8, 127.6, 127.5, 127.2, 123.1, 86.7, 79.5, 79.3, 76.2, 76.0,
74.8, 74.7, 74.6, 74.3, 73.4, 73.3, 73.2, 70.8, 69.8, 68.5, 66.8,
52.5, 51.0; MS (ES+) m/z ) 685.1 [M + H+], 707.1 [M + Na+].
was used immediately in the next reaction. IR (KBr) νmax
)
2927, 1713, 1388, 1090, 1027, 752, 721, 697 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.84-7.81 (d, 0.8H, J ) 6.9 Hz, H-1E),
7.74-6.92 (m, 19.2H, H-1Z), 5.95 (dd, 0.2H, J ) 6.2, 8 Hz,
H-2Z), 5.81 (s, 0.2H, H-7Z), 5.61 (s, 0.8H, H-7E), 5.42 (dd, 0.8H,
J ) 7.2, 9.6 Hz, H-2E), 5.05 (s, 2H), 5.00 (m, 1H), 4.80 (dd,
0.2H, J ) 1.6, 8 Hz, H-3Z), 4.6-4.3 (m, 4.8H); 13C NMR (75
MHz, CDCl3) δ 207.3, 204.9, 168.0, 167.9, 145.3, 144.4, 137.6,
137.5, 136.8, 133.8, 133.8, 131.8, 131.6, 129.1, 128.3, 128.2,
128.07, 127.9, 127.5, 126.2, 126.1, 123.2, 99.0, 98.9, 82.1, 82.0,
75.6, 75.6, 74.9, 74.5, 74.4, 72.6, 72.1, 71.8, 50.6, 45.9.
Compound 6. To a solution of 4 (250 mg, 0.51 mmol) in
MeOH (6 mL) were added O-benzylhydroxylamine (295 mg,
1.84 mmol) and pyridine (0.37 mL, 4.61 mmol), and the
mixture was heated at reflux for 3 h. After concentration at
reduced pressure, the crude was purified by flash chromatog-
raphy (hexane/EtOAc 3:1) to give 6 as an oil, mixture of E and
Compounds 9 and 10. To a 0.1 M solution of SmI2 in THF
(5.0 mL, 0.50 mmol) and t-BuOH (81 µL, 0.84 mmol) at -30
°C was added dropwise a solution of 7 (100 mg, 0.14 mmol) in
THF (3 mL). After the mixture was stirred at -30 °C for 3 h,
the flask was opened to air to oxidize excess SmI2, and the
crude reaction mixture was filtered through Florisil, eluting
with CH2Cl2/MeOH 10:1. The filtrate was evaporated at
reduced pressure, and the residue was purified by flash
chromatography (hexanes/EtOAc 4:1) to give 9 (45 mg, 44%)
and 10 (34 mg, 34%) as colorless oils, each as a mixture of
diastereoisomers at the new stereocenters. Compound 9 (17:1
mixture of diastereoisomers): νmax ) 3369, 1681, 1454, 1364,
20
Z oximes 3.3:1 (300 mg, 98%). (E)-Oxime: [R]D +0.6 (c 1.5,
CHCl3); IR (KBr) νmax ) 3468, 2927, 1713, 1387, 1090, 1027,
752, 721, 697 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.90 (d, 1H,
J ) 7.5 Hz, H-1), 7.76-7.70 (m, 3H), 7.69-7.66 (m, 2H), 7.49-
7.46 (m, 2H), 7.33-7.31 (m, 4H), 7.30-7.23 (m, 4H), 7.14-
7.10 (m, 2H), 7.09-7.04 (m, 2H), 5.47 (dd, 1H, J ) 7.8, 9.6
Hz, H-2), 5.12 (s, 1H), 5.04 (s, 2H, OCH2Ph), 4.69 (dd, 1H, J )
2.4, 9.9 Hz, H-3), 4.60 (d, 1H, J ) 12 Hz, OCH2Ph), 4.52 (d,
1H, J ) 11.7 Hz, OCH2Ph), 4.24 (dd, 1H, J ) 5.1, 10.5 Hz,
H-6), 3.95 (m, 1H, J ) 4.8, 5.1, 9.3, 10.2 Hz, H-5), 3.65 (dd,
1H, J ) 2.1, 9.3 Hz, H-4), 3.46 (t, 1H, J ) 10.2 Hz, H-6), 1.69
(d, 1H, J ) 4.8 Hz, OH). (Z)-Oxime: 1H NMR (300 MHz,
CDCl3) δ 7.71-7.61 (m, 4H), 7.49-7.42 (m, 3H), 7.30-7.06 (m,
13H), 5.95 (dd, 1H, J ) 6.2, 8.4 Hz, H-2), 5.36 (s, 1H), 5.04 (s,
2H, OCH2Ph), 4.45 (dd, 1H, J ) 2.0, 8.2 Hz, H-3), 4.22 (d, 1H,
1
1093, 1024 cm-1; H NMR (300 MHz, CDCl3) δ 7.83 (m, 1H),
7.72 (d, 1H, J ) 3.9 Hz, H-4′), 7.63-7.13 (m, 21H), 6.76-6.73
(m, 2H), 5.46 (dd, 0.95H, J ) 4.5, 6.6 Hz, H-4major), 5.35 (dd,
0.05H, J ) 4.5, 6.6 Hz, H-4minor), 5.10 (s, 0.1H, NOCH2Phminor),
5.01 (s, 1.9H, NOCH2Phmajor), 4.89 (d, 1H, J ) 11.1 Hz, OCH2-
Ph), 4.83 (d, 1H, J ) 11.1 Hz, OCH2Ph), 4.71 (s, 1H, OH-10b),
4.69 (d, 1H, J ) 11.1 Hz, OCH2Ph), 4.64 (d, 1H, J ) 11.1 Hz,
OCH2Ph), 4.01 (d, 1H, J ) 12.0 Hz), 3.89-3.77 (m, 2H), 3.41
(s, 1H, OH-1), 3.37 (d, 1H, J ) 9.9 Hz, H-1′b), 3.03 (d, 0.05H,
J. Org. Chem, Vol. 70, No. 10, 2005 4149

Chiara et al.
J ) 9.3 Hz, H-1aminor), 2.96 (d, 0.95H, J ) 9.3 Hz, H-1′amajor);
13C NMR (75 MHz, CDCl3) δ 166.8, 149.7, 145.9, 144.7, 138.7,
137.7, 136.6, 132.3, 131.2, 130.3, 129.4, 128.6, 128.5, 128.4,
128.2, 128.1, 127.9, 127.7, 127.6, 127.5, 127.3, 124.6, 123.5,
123.2, 88.7, 83.9, 81.5, 75.3, 73.4, 73.2, 68.4, 65.9, 62.0, 48.6,
48.1. MS (ES+) m/z ) 685.0 [M + H+], 707.0 [M + Na+].
Compound 10 (3.5:1 mixture of diastereoisomers): νmax ) 3369,
1694, 1454, 1364, 1098, 1028 cm-1; 1H NMR (300 MHz, CDCl3)-
δ 7.81 (m, 1H), 7.61-7.06 (m, 22H, H-4′), 6.78-6.75 (m, 2H),
5.96 (t, 0.77H, J ) 6.9 Hz, H-4major), 5.68 (t, 0.23H, J ) 6.9
Hz, H-4minor), 5.10 (d, 1H, J ) 10.8 Hz, NOCH2Ph), 5.05 (d,
1H, J ) 10.8 Hz, NOCH2Ph), 4.90 (d, 1H, J ) 11.4 Hz, OCH2-
Ph), 4.85 (d, 1H, J ) 11.1 Hz, OCH2Ph), 4.67 (d, 1H, J ) 11.7
Hz, OCH2Ph), 4.53 (d, 1H, J ) 11.7 Hz, OCH2Ph), 4.22 (d, 1H,
J ) 10.5 Hz, H-2), 4.02-3.95 (m, 2H, H-3, OCH2Ph), 3.81 (d,
1H, J ) 12.3 Hz, OCH2Ph), 3.56 (d, 0.23H, J ) 9.3 Hz,
H-1bminor), 3.22 (d, 0.77H, J ) 9.3 Hz, H-1bmajor), 3.09 (d, 0.77H,
J ) 9.3 Hz, H-1amajor), 2.99 (d, 0.23H, J ) 9.3 Hz, H-1aminor);
13C NMR (75 MHz, CDCl3) δ 163.9, 149.7, 145.9, 143.0, 138.7,
137.7, 136.6, 132.3, 129.4, 128.4, 128.2, 127.8, 127.7, 127.6,
127.5, 127.3, 123.5, 123.2, 88.7, 83.9, 81.7, 75.3, 73.4, 73.2, 68.4,
65.9, 63.9, 48.6; MS (ES+) m/z ) 685.0 [M + H+], 707.0 [M +
Na+].
dried over Na2SO4, and the solvent was removed at reduced
pressure. The crude was purified by flash chromatography
(hexanes/EtOAc 3:1) to give 12 (52 mg, 65%) as a light yellow
oil. [R]D20 -3.7 (c 0.2, CHCl3); IR (KBr) νmax ) 3340, 1731, 1682
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.72 (d, 1H, J ) 7.6 Hz),
7.57-7.25 (m, 14H, OH-11b), 6.15 (br dd, 1H, J ) 4.5, 9.9 Hz,
NH), 5.81 (s, 1H, H-3), 4.91 (d, 1H, J ) 9.9 Hz, H-4a), 4.82 (d,
1H, J ) 11.7 Hz, OCH2Ph), 4.78 (ddd, 1H, J ) 3.9, 7.5, 10.8
Hz, H-6), 4.74 (d, 1H, J ) 11.1 Hz, H-1b), 4.64 (d, 1H, J )
11.7 Hz, OCH2Ph), 4.36 (ddd, 1H, J ) 9.9, 10.8, 14.4 Hz, H-6′a),
4.31 (d, 1H, J ) 11.1 Hz, H-1a), 4.15 (d, 1H, J ) 7.5, 9.9 Hz,
H-5), 3.43 (dt, 1H, J ) 3.9, 4.1, 14.4 Hz, H-6′b), 2.90 (s, 1H,
OH-11c), 1.83 (s, 3H, CH3CO); 13C NMR (75 MHz, CDCl3) δ
173.2, 167.6, 149.7, 138.0, 137.3, 132.4, 131.0, 129.5, 129.0,
128.4, 128.2, 127.8, 127.6, 125.8, 123.4, 122.4, 101.4 (C-3), 89.6
(C-11b), 78.6 (C-4a), 74.2 (OCH2Ph), 73.7 (C-5), 71.7(C-1), 70.8
(C-11c), 50.5 (C-6), 39.2 (C-6′), 23.2 (CH3CO); MS (ES+) m/z
) 553.2 [M + Na+].
Compound 13. To a solution of 11 (151 mg, 0.25 mmol) in
THF (2 mL) was added dropwise a 37% solution of formalde-
hyde in water (15 mL, 25.9 mmol), and the mixture was stirred
for 16 h at rt. After dilution with EtOAc (10 mL), the organic
phase was washed with a saturated aqueous solution of
NaHCO3 (3 × 10 mL), brine (2 × 10 mL), and dried over Na2-
SO4. The mixture was concentrated at reduced pressure, and
the crude was dissolved in THF/MeOH (1:1, 4 mL). To this
solution was added NaBH4 (236 mg, 1.01 mmol) at 0 °C, and
the mixture was stirred for 1 h at 0 °C and for 16 h at rt. After
dilution with EtOAc (10 mL), the organic phase was washed
with H2O (3 × 10 mL), brine (2 × 10 mL), dried over Na2SO4,
and concentrated at reduced pressure. The crude was purified
by flash chromatography (hexanes/EtOAc 3:1) to give 13 (112
mg, 91%) as a white solid. Mp 185-187 °C; [R]D25 +5.2 (c 0.4,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 2H), 7.60-7.27
(m, 12H), 5.78 (s, 1H, H-3), 5.65 (s, 1H, OH-11b), 4.96 (ddd,
1H, J ) 3.5, 4.9, 8.5 Hz, H-6), 4.86 (d, 1H, J ) 9.7 Hz, H-4a),
4.81 (d, 1H, J ) 11.6 Hz, OCH2Ph), 4.71 (d, 1H, J ) 11.7 Hz,
OCH2Ph), 4.66 (d, 1H, J ) 11.2 Hz, H-1b), 4.33 (d, 1H, J )
11.1 Hz, H-1a), 4.27 (dd, 1H, J ) 5.1, 11.3 Hz, H-6′b), 4.18
(dd, 1H, J ) 7.7, 9.6 Hz, H-5), 3.91 (dd, 1H, J ) 3.8, 11.3 Hz,
H-6′a), 3.04 (m, 1H, OH-6′), 2.91 (s, 1H, OH-11c); 13C NMR
(100 MHz, CDCl3) δ 168.5, 140.4, 137.7, 136.9, 133.8, 132.8,
130.7, 129.2, 128.5, 128.3, 127.9, 127.6, 125.8, 125.0, 123.0,
102.5 (C-3), 97.0 (C-11b), 82.0 (C-4a), 75.2 (C-5), 72.9 (OCH2-
Ph), 71.7(C-1), 71.6 (C-6′), 71.6 (C-11c), 52.7 (C-6); MS (ES+)
m/z ) 512.3 [M + Na+].
Compound 14. To a solution of 13 (33 mg, 0.06 mmol) in
anhydrous pyridine (0.3 mL) was added Ac2O (7.62 µL, 0.08
mmol). After being stirred for 5 h at rt, the mixture was
concentrated at reduced pressure, and the crude was purified
by flash chromatography (hexanes/EtOAc 3:1) to give 14 (34
mg, 98%) as a colorless oil. [R]D25 +10.6 (c 0.1, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, 1H, J ) 6.8 Hz), 7.60-7.25 (m,
13H), 5.80 (s, 1H, H-3), 5.22 (dd, 1H, J ) 10.8, 11.6 Hz, H-6′b),
5.12 (s, 1H, OH-11b), 5.07 (ddd, 1H, J ) 3.2, 7.2, 10.8 Hz, H-6),
4.83 (d, 1H, J ) 9.6 Hz, H-4a), 4.82 (d, 1H, J ) 11.6 Hz, OCH2-
Ph), 4.73 (d, 1H, J ) 11.6 Hz, OCH2Ph), 4.70 (d, 1H, J ) 11.2
Hz, H-1b), 4.40 (dd, 1H, J ) 3.2, 11.6 Hz, H-6′a), 4.31 (d, 1H,
J ) 11.2 Hz, H-1a), 4.18 (dd, 1H, J ) 7.6, 10.0 Hz, H-5), 2.88
(s, 1H, OH-11c), 1.99 (s, 3H, CH3CO); 13C NMR (100 MHz,
CDCl3) δ 173.7, 167.0, 144.2, 137.7, 137.1, 132.4, 131.1, 129.8,
129.1, 128.4, 128.2, 128.0, 127.9, 127.6, 125.8, 123.7, 122.2,
101.4 (C-3), 89.6 (C-11b), 78.4 (C-4a), 74.0 (OCH2Ph), 73.1 (C-
5), 71.5 (C-1), 70.4 (C-11c), 63.0 (C-6′), 49.6 (C-6), 21.0 (CH3-
CO); MS (ES+) m/z ) 554.3 [M + Na+].
Compounds (E)-11 and (Z)-11. To a 0.1 M solution of SmI2
in THF (5.0 mL, 0.50 mmol) and t-BuOH (81 µL, 0.84 mmol)
at -30 °C was added dropwise a solution of 8 (100 mg, 0.16
mmol) in THF (3 mL). After the mixture was stirred at -30
°C for 3 h, the flask was opened to air to oxidize excess SmI2,
and the crude reaction mixture was filtered through Florisil,
eluting with CH2Cl2/MeOH 10:1. The filtrate was evaporated
at reduced pressure, and the residue was purified by flash
chromatography (hexanes/EtOAc 4:1) to give (E)-11 (45 mg,
20
45%) and (Z)-11 (25 mg, 25%) as colorless oils. (E)-11: [R]D
+3.1 (c 0.8, CHCl3); IR (KBr) νmax ) 3429, 1697 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.91 (d, 1H, J ) 4.2 Hz, H-6′), 7.81 (d,
1H, J ) 7.4 Hz, H-8), 7.6-7.3 (m, 18H), 5.71 (dd, 1H, J ) 4.1,
7.5 Hz, H-6), 5.68 (s, 1H, H-3), 5.41 (s, 1H, OH-11b), 5.06 (d,
1H, J ) 11.7 Hz, NOCH2Ph), 5.03 (d, 1H, J ) 11.7 Hz, NOCH2-
Ph), 4.80 (d, 1H, J ) 11.7 Hz, OCH2Ph), 4.68 (d, 1H, J ) 11.7
Hz, OCH2Ph), 4.58 (d, 1H, J ) 11.3 Hz, H-1b), 4.54 (d, 1H, J
) 9.8 Hz, H-4a), 4.30 (d, 1H, J ) 11.3 Hz, H-1a), 4.21 (dd, 1H,
J ) 7.5, 9.6 Hz, H-5), 2.83 (s, 1H, OH-11c); 13C NMR (75 MHz,
CDCl3) δ 166.8, 149.7, 144.6, 137.6, 137.1, 136.4, 132.6, 130.6,
129.7, 129.1, 128.5, 128.5, 128.4, 128.2, 128.2, 127.9, 127.6,
125.7, 123.9, 122.0, 118.3, 101.8 (C-3), 88.6 (C-11b), 78.1 (C-
4a), 76.3 (NOCH2Ph), 74.0 (OCH2Ph), 73.8 (C-5), 71.5 (C-1),
70.7 (C-11c), 49.1 (C-6). Anal. Calcd for C35H32N2O7: C, 70.93;
H, 5.44; N, 4.73. Found: C, 70.78; H, 5.60; N, 4.67. (Z)-11:
[R]D -2.5 (c 0.6, CHCl3); IR (KBr) νmax ) 3429, 1710 cm-1
;
20
1H NMR (300 MHz, CDCl3) δ 7.9-6.94 (m, 19H), 7.38 (d, 1H,
J ) 5.6 Hz, H-6′), 5.89 (dd, 1H, J ) 5.6, 6.8 Hz, H-6), 5.72 (s,
1H, H-3), 5.03 (d, 1H, J ) 11.6 Hz, NOCH2Ph), 4.99 (d, 1H, J
) 12.0 Hz, NOCH2Ph), 4.68 (d, 1H, J ) 9.6 Hz, H-4a), 4.66 (s,
2H, OCH2Ph), 4.50 (d, 1H, J ) 10.8 Hz, H-1b), 4.17 (d, 1H, J
) 11.2 Hz, H-1a), 4.07 (dd, 1H, J ) 6.8, 10.0 Hz, H-5), 2.87 (s,
1H, OH-11c); 13C NMR (75 MHz, CDCl3) δ 164.8, 147.6 (C-6′),
142.8, 137.7, 137.0, 132.1, 130.2, 129.1, 128.5, 128.3, 128.2,
128.1, 127.8, 127.7, 127.6, 125.8, 123.8, 121.9, 101.5 (C-3), 89.3
(C-11b), 78.1 (C-4a), 76.2 (NOCH2Ph), 73.2 (OCH2Ph), 72.5 (C-
5), 71.4 (C-1), 70.1 (C-11c), 43.6 (C-6); MS (ES+) m/z ) 593.3
[M + H+], 615.3 [M + Na+].
Compound 12. To a 0.1 M solution of SmI2 (10.0 mL, 1.0
mmol) in THF and tBuOH (0.162 mL, 1.69 mmol) at -30 °C
was added dropwise a solution of 8 (90 mg, 0.15 mmol) in THF
(3 mL). After the mixture was stirred at -30 °C for 3 h, water
was added (60.8 µL, 3.38 mmol), and the reaction mixture was
stirred at rt overnight. The flask was opened to air to oxidize
excess SmI2, and pyridine (0.79 mL, 0.98 mmol) and Ac2O (0.4
mL, 0.36 mmol) were added. After the mixture was stirred for
2 h at rt, saturated aqueous NaHCO3 (10 mL) was added, and
the mixture was extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (3 × 10 mL),
Compound 15. To a solution of 13 (20 mg, 0.04 mmol) in
anhydrous toluene (0.5 mL) was added PPh3 (10.4 mg, 0.04
mmol). After the mixture was stirred at rt for 15 min, DIAD
(11 µL, 0.05 mmol) was added dropwise, and the mixture was
stirred for 5 h. The mixture was diluted with Et2O (10 mL)
and washed with a saturated aqueous solution of NaHCO3 (2
× 3 mL), and brine (2 × 3 mL), dried over anhydrous Na2SO4,
4150 J. Org. Chem., Vol. 70, No. 10, 2005

R-Hydroxylactam Scaffolds from D-Glucosamine
and concentrated at reduced pressure. The crude was purified
of theory using the 6-311G(d,p) standard basis set. After
geometry optimization, analytical frequency calculations were
carried out at the same level of theory to determine the nature
of the stationary points found and to obtain zero point
corrections to energies using standard procedures (no scaling
factor was employed in the frequency calculations). The
electron affinity is the energy of the neutral molecule minus
that of the radical anion (E° - E-). The calculation of the
adiabatic electron affinity (AEA) is based on the optimized
geometry of the neutral species and the optimized geometry
of the radical anion species. The calculation of the vertical
electron affinity (VEA) employs the optimized neutral geom-
etry for both neutral and radical anion species.
by flash chromatography (hexanes/EtOAc 7:1) to give 15 (18
20
mg, 93%) as a yellow solid. Mp 109-111 °C; [R]D +1.82 (c
1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, 1H, J ) 6.8
Hz), 7.60-7.50 (m, 4H), 7.41-7.23 (m, 9H), 5.81 (s, 1H, H-3),
4.79 (d, 1H, J ) 12 Hz, OCH2Ph), 4.76 (m, 1H, H-6), 4.74 (d,
1H, J ) 12 Hz, OCH2Ph), 4.58 (d, 1H, J ) 10.4 Hz, H-1b),
4.42 (d, 1H, J ) 10.0 Hz, H-6′b), 4.40 (m, 1H, H-4a), 4.37 (d,
1H, J ) 10.8 Hz, H-1a), 4.09 (ddd, 1H, J ) 1.2, 4.0, 9.2 Hz,
H-5), 3.99 (ddd, 1H, J ) 1.2, 4.4, 8.4 Hz, H-6′a), 3.14 (s, 1H,
OH-11c); 13C NMR (100 MHz, CDCl3) δ 168.5, 140.4, 137.7,
136.9, 133.8, 132.8, 130.7, 129.2, 128.5, 128.3, 127.9, 127.6,
125.8, 125.0, 123.0, 102.5 (C-3), 97.0 (C-11b), 82.0 (C-4a), 75.2
(C-5), 72.9 (OCH2Ph), 71.7 (C-6′), 71.6 (C-11c), 71.6 (C-1), 52.7
(C-6); MS (ES+) m/z ) 472.3 [M + H+], 494.1 [M + Na+].
Theoretical Calculations. Molecular mechanics calcula-
tions were carried out using the MM2 force field (as imple-
mented in the Chem3D Ultra 9.0 program). All force-field
calculations were done in vacuo (dielectric constant ) 1).
Global minimum energy conformations were obtained by
manual construction and subsequent geometry optimization
of different combinations of chair, skew, and boat conforma-
tions of the two heterocyclic six-membered ring systems of
compounds 11 and 12, replacing the benzyl ether groups for
methyl ethers to simplify the number of possible conformers
of these side chains.
Acknowledgment. Financial support by the Min-
istry of Science and Technology of Spain (project
BQU2000-1501-C02-01) is gratefully acknowledged.
Supporting Information Available: General experimen-
tal procedures, 1D (1H and 13C) and 2D NMR (DQ-COSY,
NOESY, HSQC, and HMBC) spectra for compounds 11-15,
and energies and Cartesian coordinates for compounds in
Table 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ab initio calculations were carried out using the Gaussian
9823 program package at the density functional (B3LYP) level
JO050185Y
J. Org. Chem, Vol. 70, No. 10, 2005 4151