Polyhydroxylated indolines and oxindoles from C-glycosides via sequential Henry reaction, Michael addition, and reductive amination/amidation

Article abstract of DOI:10.1021/jo070014o

6-Nitro-2′-carbonyl-C-glycofuranosides synthesized via Henry reaction from 1-C-allyl 5-aldo-C-glycoside underwent an intramolecular Michael addition to afford nitrocyclohexanol derivatives in good to excellent yield. Reduction of the nitro group followed

Full text of DOI:10.1021/jo070014o

the pseudoglucosylamines (aminocyclohexenol and aminocy-
clohexanol) in acarbose3 and voglibose4 actively inhibit R-gly-
cosidase (R-amylase) activity. Several other glycosidase inhibi-
tors such as allosamidin (Chitinase),5 trehalostatin (R,R-
trehalase),6 and mannostatin (R-D-mannosidase)7 all contain
aminocyclopentanol. Accordingly, various aminocyclopentanols8
as well as glycoimidazoles and glycotriazoles (fused heterobi-
cycles) were designed and synthesized as inhibitors.9 In addition,
some plant alkaloids with polyhydroxylated indoline, oxindole,
and quinoline skeletons10 are also able to inhibit glycosidases,11
likely due to the presence of the aminocyclopentanol/aminocy-
clohexanol subunit. Thus, we reasoned that polyhydroxylated
indolines and quinolines might be potential glycosidase inhibi-
tors.
Polyhydroxylated Indolines and Oxindoles from
C-Glycosides via Sequential Henry Reaction,
Michael Addition, and Reductive Amination/
Amidation
Wei Zou,*,† An-Tai Wu,†,‡ Milan Bhasin,†
Mahendra Sandbhor,† and Shih-Hsiung Wu‡
Institute for Biological Sciences, National Research Council of
Canada, Ottawa, Ontario, Canada K1A 0R6, and Institute of
Biological Chemistry, Academia Sinica,
Taipei 115, Taiwan, ROC
wei.zou@nrc-cnrc.gc.ca
Recently, we have reported the syntheses of aza-C-glyco-
sides,12 thio-C-glycosides,13 and hydroxylated quinolizidines14
from 2′-carbonyl-C-glycosides by an intramolecular hetero-
Michael reaction, in which an R,â-conjugated carbonyl inter-
ReceiVed January 3, 2007
(3) (a) Asano, N. Curr. Top. Med. Chem. 2003, 3, 471-484. (b) Puls,
W.; Keup, U.; Krause, H. P.; Thomas, G.; Hoffmeister, F. Naturwissen-
schaften 1977, 64, 536-537. (c) Schmidt, D. D.; Frommer, W.; Junge, B.;
Muller, L.; Wingender, W.; Truscheit, E.; Schafter, D. Naturwissenschaften
1977, 64, 535-536.
(4) (a) Matsumoto, K.; Yano, M.; Miyake, S.; Ueki, Y.; Yamaguchi,
Y.; Akazawa, S.; Tominaga, Y. Diabetes Care 1998, 21, 256-260. (b) Horii,
S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K. J. Med.
Chem. 1986, 29,1038-1046.
(5) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A. Tetrahedron Lett.
1986, 27, 2475-2478.
(6) Nakayama, T.; Amachi, T.; Murao, S.; Sakai, T.; Shin, T.; Kenny,
P. T. M.; Iwashita, T.; Zagorski, M.; Komura, H.; Nomoto, K. J. Chem.
Soc., Chem. Commun. 1991, 919-921.
(7) Aoyagi, T.; Yamamoto, T.; Kojiti, K.; Morishima, H.; Nagai, M.;
Hamada, M.; Takeuchi, T.; Umezawa, H. J. Antibiot. 1989, 42, 883-889.
(8) (a) Kleban, M.; Hilgers, P.; Greul, J. N.; Kugler, R. D.; Li, J.; Picasso,
S.; Vogel, P.; Jager, V. ChemBioChem 2001, 5, 365-368. (b) Greul, J. N.;
Kleban, M.; Schneider, B.; Picasso, S.; Jager, V. ChemBioChem 2001, 5,
368-370. (c) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993,
113, 444-458.
(9) (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV.
2002, 102, 515-553. (b) Tagmose, T. M.; Bols, M. Chem.-Eur. J. 1997,
3, 453-462. (c) Sondergaard, K.; Liang, X.; Bols, M. Chem.-Eur. J. 2001,
7, 2324-2331. (d) Tschamber, T.; Siendt, H.; Boiron, A.; Gessier, F.;
Deredas, D.; Frankowski, A.; Picasso, S.; Steiner, H.; Aubertin, A.-M.;
Streith, J. Eur. J. Org. Chem. 2001, 1335-1347. (e) Panday, N.; Granier,
T.; Vasella, A. HelV. Chim. Acta 1998, 81, 475-490. (f) Kru¨lle, T. M.; de
la Fuente, C.; Pickering, L.; Aplin, R. T.; Tsitsanou, K. E.; Zographos, S.
E.; Oikonomakos, N. G.; Nash, R. J.; Griffiths, R. C.; Fleet, G. W. J.
Tetrahedron: Asymmetry 1997, 8, 3807-3820.
(10) (a) Okamoto, T.; Torii, Y.; Isogai, Y. Chem. Pharm. Bull. 1968,
16, 1860-1864. (b) Piozzi, F.; Fuganti, C.; Mondelli, R.; Ceriotti, G.
Tetrahedron 1968, 24, 1119-1131. (c) Abou-Donia, A. H.; De Giulio, A.;
Evidente, A.; Gaber, M.; Habib, A.; Lanzeta, R.; Seif El Din, A.
Phytochemistry 1991, 30, 3445-3448. (d) Ghosal, S.; Singh, S.; Kumar,
Y.; Srivastava, R. S. Phytochemistry 1989, 28, 611-613. (e) Pettit, G. R.;
Gaddamidi, V.; Cragg, G. M.; Herald, D. L.; Sagawa, Y. J. Chem. Soc.,
Chem. Commun. 1984, 1693-1694. (f) Pettit, G. R.; Backhaus, R. A.;
Boettner, F. E. J. Nat. Prod. 1995, 58, 37-43. (g) Keck, G. E.; McHardy,
S. F.; Murry, J. A. J. Org. Chem. 1999, 64, 4465-4476.
(11) Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kefauver, D. F.;
Pettit, G. R.; Groszek, G.; Hollingshead, M.; Kirsi, J. J.; Shannon, W. M.;
Schubert, E. M.; Dare, J.; Ugarkar, B.; Ussery, M. A.; Phelan, M. J. J. Nat.
Prod. 1992, 55, 1569-1581.
(12) Yi, T.; Wu, A.; Wu, S.-H.; Zou, W. Tetrahedron 2005, 61, 11716-
11722.
(13) (a) Yi, T.; Wu, S. H.; Zou, W. Carbohydr. Res. 2005, 340, 235-
244. (b) Zou, W.; Lacroix, E.; Wang, Z. R.; Wu, S. H. Tetrahedron Lett.
2003, 44, 4431-4433.
(14) Zou, W.; Sandbhor, M.; Bhasin, M. J. Org. Chem. 2007, 72, 1226-
1234.
6-Nitro-2′-carbonyl-C-glycofuranosides synthesized via Henry
reaction from 1-C-allyl 5-aldo-C-glycoside underwent an
intramolecular Michael addition to afford nitrocyclohexanol
derivatives in good to excellent yield. Reduction of the nitro
group followed by intramolecular amination with ketone and
aldehyde and amidation with ester produced indoline and
oxindole derivatives, respectively, in excellent yield.
Azasugars inhibit glycosidases by mimicking the oxocarbe-
nium ion transition state generated from cleavage of the
glycosidic bond in enzymatic catalysis.1 Because the initial step
of glycoside hydrolysis is likely the protonation of the glycosidic
oxygen,2 compounds that mimic an exocyclic oxonium ion could
also be potential glycosidase inhibitors. In fact, it is known that
* Corresponding author. Tel: 1-(613)-991-0855. Fax: 1-(613)-952-9092.
† National Research Council of Canada.
‡ Academia Sinica.
(1) (a) Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T. Angew.
Chem., Int. Ed. 1995, 34, 521-546. (b) Stu¨tz, A. Iminosugars as glycosidase
inhibitors; Wiley-VCH: Weinheim, 1999.
(2) (a) Sinnott, M. L. Chem. ReV. 1990, 90, 1171-1202. (b) Zechel, D.
L.; Withers, S. G. Acc. Chem. Res. 2000, 33, 11-18. (c) Heightman, T.
D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 750-770.
10.1021/jo070014o CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/09/2007
2686
J. Org. Chem. 2007, 72, 2686-2689

SCHEME 1. Synthesis of 1-(2′-Oxoalkyl)-C-glycosides
Although high stereoselectivity may be achieved using various
catalysts,21 no attempt was made to improve the stereoselectivity.
Instead, nitroalcohol 3 was converted to nitroalkene 4 via
â-elimination (MsCl/TEA).22 Further reduction of the double
bond of 4 with NaBH4 afforded nitroalkane 5. Because these
reactions proceeded efficiently, we were also able to obtain 5
from 1, without chromatographic purification of the intermedi-
ates, in 50-60%.
To introduce a latent Michael acceptor at the anomeric center,
the allyl group of 5 was converted to 2′-ketone 6 using Hg-
(OAc)2/Jones reagent23 and the 2′-aldehyde 7 by ozonolysis
using dimethyl sulfide as the reducing reagent24 (see Scheme
1). 2′-Ester 8 was obtained by oxidation of aldehyde 7 using
KMnO4 to a carboxylic acid followed by treatment with
iodomethane in the presence of NaHCO3.13
Treatment of 6 with base (4% NaOMe or 1% K2CO3 in
MeOH) at room temperature produced nitrocyclohexanols, 9
and 10, via â-elimination followed by an intramolecular Michael
addition. As expected, the thermodynamically more stable 9,
with 1,6-trans configuration, was obtained as the major product
(60-70%), and 1,6-cis 10 was obtained as the minor product
(20-30%). We were unable to completely convert 10 to 9 even
with prolonged reaction time (overnight) because of equilibrium
between 9 and 10, as evidenced by the fact that both purified 9
and 10 were able to partially convert to the other under the
same basic conditions. On the other hand, the base treatment
of 2′-aldehyde 7 under the same conditions led to many
byproducts and the desired nitrocyclohexanol 13 was isolated
in low yield (20-45%), likely due to undesirable intra- and
intermolecular Henry reactions associated with the high reactiv-
ity of the aldehyde. We reasoned that the reaction could likely
be improved with a less basic and more dilute solution at lower
temperature. Consequently, compound 7 was treated with 1.25%
NaOMe at 0 °C for 1 h, which resulted in a clean reaction to
give products 13 and 14 in a ratio of 1:1, in excellent yield
(see Scheme 2).25 The diastereoselectivity is more likely a result
of the epimerization at C6 after Michael addition. Apparently,
such epimerization (from 14 to 13) was greatly suppressed under
mild conditions resulting in the isolation of equal amounts of
13 and 14 before they reach a thermodynamic equilibrium.
mediate was generated by â-elimination.15 Here, we exploit
similar chemistry for the synthesis of aminocyclohexanols from
1-C-(2′-carbonyl)-6-nitro-C-glycosides. This strategy requires
an intramolecular Michael addition between the nitronate anion
and the R,â-conjugated carbonyl intermediate generated under
basic conditions. In addition, the presence of both nitro and
carbonyl groups in the resultant nitrocyclohexanols allows us
to explore the reductive amination and amidation to obtain
polyhydroxylated indoline and oxindole derivatives.16
The key functional group manipulations involved the intro-
duction of 6-nitro and 1-C-2′-oxoalkyl groups. The nitroaldol
(Henry) reaction provides C-C bond formation17 and is
commonly used to extend the carbon chain and to prepare
aminosugars in carbohydrate chemistry.18 Thus, the primary
alcohol 113 was converted to the 5-aldehyde 2 (Scheme 1) by
Swern oxidation19 and by a modified procedure using cyanuric
chloride activated DMSO.20 Both procedures were effective, but
the former appears more reliable. Henry reaction between the
aldehyde and nitromethane in 1% NaOMe-methanol produced
a diastereomeric mixture of nitroalcohol 3 in a ratio of ca. 2:1.
The attempt to convert 9 to a hydroxylated indoline in a single
step by catalytic hydrogenation was not successful due to the
incomplete removal of the O-benzyl groups. Repetitive catalytic
hydrogenation led to low recovery yield, and catalytic reduction
of the nitro group in other systems has also been problematic.
As an alternative, zinc dust under acidic conditions was
successfully used.26 Accordingly, we reduced the nitro groups
of 9, 10, 13, and 14 to the respective amines using Zn-HOAc,
which spontaneously underwent intramolecular reductive ami-
(15) (a) Wang, Z.; Shao, H.; Lacroix, E.; Wu, S. H.; Jennings, H. J.;
Zou, W. J. Org. Chem. 2003, 68, 8097-8105. (b) Shao, H.; Wang, Z.;
Lacroix, E.; Wu, S. H.; Jennings, H. J.; Zou, W. J. Am. Chem. Soc. 2002,
124, 2130-2131.
(16) To avoid confusion in the assignment of NMR data, the carbon
numbering used in this paper corresponds to the numbering of the original
carbohydrates.
(17) (a) Rosini, G. In ComprehensiVe Organic Synthesis; Trost, Fleming,
Heathcock, Eds.; Pergamon: Oxford, 1996; Vol. 2, pp 321-340. (b) Luzzio,
F. A. Tetrahedron 2001, 57, 915-945. (c) Ono, N. The Nitro Group in
Organic Synthesis; Wiley-VCH: New York, 2001.
(18) (a) Hough, L.; Richardson, A. C. Synthesis of Monosaccharides.
In The Carbohydrates: Chemistry and Biochemistry, 2nd ed.; Pigman,
Horton, Eds.; Academic Press: New York, 1980; Vol. IA, pp 114-164.
(b) Horton, D.; Wander, J. D. Amino Sugars. In The Carbohydrates:
Chemistry and Biochemistry, 2nd ed.; Pigman, Horton, Eds.; Academic
Press: New York, 1980; Vol. IB, pp 644-760. (c) Chakraborty, C.; Dhaval,
D. D. Carbohydr. Res. 2006, 341, 912-917. (d) Liu, F. W.; Yan, L.; Liu,
H. M. Carbohydr. Res. 2006, 341, 332-338. (e) Andersch, J.; Bols, M.
Chem.-Eur. J. 2001, 7, 3744-3747.
(19) Mancuso, A.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2483.
(20) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001,
66, 7907-7909.
(21) For a recent review of catalytic asymmetric nitroaldol reactions,
see: Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004,
43, 5442-5444.
(22) Torii, S.; Inokuchi, T.; Oi, R.; Kondo, K.; Kobayashi, T. J. Org.
Chem. 1986, 51, 254-256.
(23) (a) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J.
Chem. Soc. 1953, 2555-2560. (b) Rogers, H. R.; McDermott, J. X.;
Whitesides, G. M. J. Org. Chem. 1975, 40, 3577-3580. (c) Shao, H.;
Ekthawatchai, S.; Chen, C.-S.; Wu, S.-H.; Zou, W. J. Org. Chem. 2005,
70, 4726-4734.
(24) (a) Pappas, J. J.; Klaveney, W. P.; Gancher, E.; Berger, M.
Tetrahedron Lett. 1966, 4272-4278. (b) Danishefsky, S. J.; Behar, V.;
Randolph, J. T.; Lloyd, K. O. J. Am. Chem. Soc. 1995, 117, 5701-5711.
(25) We also treated substrate 6 under the same conditions, but the
reaction was extremely slow.
J. Org. Chem, Vol. 72, No. 7, 2007 2687

SCHEME 2. Synthesis of Indolines
SCHEME 3. Synthesis of Oxindole
removal of solvent, the intermediate was treated with K2CO3
in MeOH to afford oxindole 18 as a single product, which was
isolated by chromatography in 88% yield (Scheme 3).
The 1,6-trans bicyclic compounds (11, 15, and 18) and 1,6-
cis indolines (12 and 16) provided a distinctive 1H NMR pattern
(see Supporting Information). NMR analysis indicated that the
cyclohexane ring (carbosugar) of 1,6-trans bicycles was in a
1
4C1 conformation as indicated by H-1H coupling constants
(e.g., J1,2 ) 10.8 Hz, J2,3 ) 2.0 Hz, J3,4 < 1.0 Hz in 11), NOEs
observed among axial protons (H-2, H-4, and H-6) (see Figure
1), and significant downfield H5ax (2.0-2.1 ppm) resonance in
FIGURE 1. Important NOEs observed in 11 and 12-S.
nation with the 2′-ketone and 2′-aldehyde to give indolines 11,
12, 15, and 16 in quantitative yield. The products obtained as
ammonium acetates after filtration and removal of acetic acid
were fairly pure. Free amines were obtained by dissolving the
ammonium salt in organic solvent followed by washing with
NaHCO3. As a result, a marked upfield shift of H-2′ and H-6
4
comparison to that of H5eq (1.5-1.6 ppm). However, the C1
conformation of cyclohexane in 12 and 16 was slightly twisted
around C5-C6 as suggested by the fact that two H-5 protons
were observed with similar chemical shifts (1.8-1.9 ppm). In
addition, the newly created chiral C-2′ of 11 was assigned
R-configuration (endo) on the basis of the observation of strong
NOEs between H-1 and H-1′a and between H-1′a and 2′-Me as
well as the weak NOE between H-1 and 2′-Me (Figure 1).
Similarly, we also determined the stereochemistry of the major
diastereomer 12-S obtained from 10 (see Figure 1), which has
an S-configuration (endo) at C-2′.
In summary, we described an effective method for the
synthesis of hydroxylated indolines and oxindoles from 2′-
carbonyl-C-glycosides via Henry reaction, intramolecular Michael
addition, and reductive amination/amidation. In addition to the
mild reaction conditions and the use of common reagents, this
synthetic strategy is very concise and atom-economical. The
method provides an entry to diverse polyhydroxylated indoline
and oxindole structures.
1
signals was observed in H NMR spectra.
Apparently, the reduction of the imine intermediate derived
from 9 was totally stereoselective producing a single diastere-
omer 11. The conversion of 10 to indoline 12 was somewhat
less selective providing a mixture of two diastereomers in a
ratio of 4:1 (S/R or endo/exo) as indicated by NMR analysis.
The difference in stereoselectivity between 11 and 12 likely
resulted from the fact that the imine intermediate from 9 with
a 1,6-trans configuration is quite rigid and that from 10 with a
1,6-cis configuration is relatively flexible.
Similarly, we applied the same reaction to 2′-ester 8. The
reaction under basic conditions was much slower than its
counterparts (6 and 7). Before complete consumption of starting
material, significant polar byproducts were observed at the
original spot on TLC, likely due to the hydrolysis of methyl
ester of starting material and/or product. Therefore, after
treatment of 8 with 1% K2CO3 in methanol for 2 days, the 1,6-
trans product 17 was isolated in 44% yield. We did not obtain
the other diastereomer, but we did observe a very minor product
on TLC very close to the starting material. Reduction of the
nitro group of 17 was again achieved using Zn/HOAc overnight,
which produced an amine intermediate with an intact methyl
Experimental Section
(1S,2S,3R,4R,6S)-1-Acetylmethyl-2,3-di-O-benzyl-4-hydroxyl-
6-nitrocyclohexane (9) and (1S,2S,3R,4R,6R)-1-Acetylmethyl-
2,3-di-O-benzyl-4-hydroxyl-6-nitrocyclohexane (10). A solution
of 6 (100 mg, 0.24 mmol) in 1% K2CO3-MeOH (3 mL) was kept
at room temperature overnight. The mixture was partitioned between
ethyl acetate and water, and the aqueous solution was extracted
with ethyl acetate. The combined organic phase was dried and
concentrated. Purification by chromatography (hexane/EtOAc 1:1)
afforded 9 as white amorphous (68 mg, 68%) and 10 as crystals
(20 mg, 20%).
1
ester as indicated by H NMR analysis. After filtration and
(26) (a) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262-
1269. (b) Battersby, A. R.; Baker, M. G.; Broadbent, H. A.; Fookes, C. J.
R.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1987, 2027-2048. (c)
Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998, 63,
3528-3529. (d) Sole, D.; Bonjoch, J.; Garcia-Rubio, S.; Peidro, E.; Bosch,
J. Angew. Chem., Int. Ed. 1999, 38, 395-397.
1
For 9: [R]D -56 (c 0.34, MeOH); H NMR (CDCl3) δ 7.37-
7.28 (m, 10H, 2 × Ph), 5.07 (d, J ) 11.6 Hz, 1H, PhCH2), 4.76
(m, 1H, H-6), 4.68 (d, J ) 11.2 Hz, 1H, PhCH2), 4.60 (d, J ) 11.2
Hz, 1H, PhCH2), 4.40 (d, J ) 11.6 Hz, 1H, PhCH2), 4.06 (bs, 1H,
2688 J. Org. Chem., Vol. 72, No. 7, 2007

H-3), 3.70 (bd, J ) 11.2 Hz, 1H, H-2), 3.63 (m, 1H, H-4), 2.87
(m, 1H, H-1), 2.79 (m, 1H, H-1a′), 2.39 (m, 1H, H-1b′), 2.29-
2.24 (m, 2H, H-5a, 5b), 2.13 (d, J ) 11.2 Hz, 1H, OH), 2.02 (s,
3H, CH3); 13C NMR (CDCl3) δ 207.3 (C-2′), 138.2, 137.1, 128.6,
128.2, 128.0, 127.8, 83.1 (C-6), 78.2 (C-2), 75.9 (C-3), 74.6
(PhCH2), 72.2 (PhCH2), 67.2 (C-4), 39.1 (C-1′), 37.1 (C-1), 34.1
(C-5), 30.4 (CH3); HRMS calcd for C23H28NO6 414.1917 (M +
H), found 414.1954.
acetate. The combined organic phase was dried and concentrated.
Purification by chromatography (hexane/EtOAc 1:1) afforded 17
as a white amorphous (12 mg, 44%): [R]D -25 (c 0.4, CHCl3); 1H
NMR (CDCl3) δ 7.39-7.26 (m, 10H, 2 × Ph), 5.08 and 4.59 (d
and d, J ) 11.6 Hz, 1H each, PhCH2), 4.75 (m, 1H, H-6), 4.71 and
4.46 (d and d, J ) 11.6 Hz, 1H each, PhCH2), 4.08 (dd, J ) 2.0,
2.0 Hz, 1H, H-3), 3.65-3.60 (m, 2H, H-2, 4), 3.58 (s, 3H, OMe),
2.94 (m, 1H, H-1), 2.78 (dd, J ) 4.5, 17.2 Hz, 1H, H-1′a), 2.31
(dd, J ) 5.2, 17.2 Hz, 1H, H-1′b), 2.30-2.25 (m, 2H, H-5a, 5b),
2.18 (d, J ) 10.8 Hz, 1H, 4-OH); 13C NMR (CDCl3) δ 172.0 (C-
2′), 138.4, 137.3, 128.9, 128.8, 128.3, 128.2, 128.1, 83.4 (C-6),
78.3 (C-2), 76.0 (C-3), 74.9 (PhCH2), 72.5 (PhCH2), 67.4 (C-4),
51.8 (OMe), 37.2 (C-1), 34.5 (C-5), 30.5 (C-1′); HRMS calcd for
C23H28NO7 430.1866 (M + H), found 430.1862.
Di-O-benzyl Oxindole Derivative 18. To a solution of 17 (12
mg) in acetic acid (2 mL) was added zinc dust (20 mg), and the
mixture was stirred at room temperature overnight. The filtrate was
diluted by the addition of water and lyophilized to a residue. To a
solution of the above residue in methanol (3 mL) was added K2-
CO3 (10 mg), and the mixture was stirred overnight. The reaction
mixture was neutralized by the addition of acetic acid and
concentrated. Purification by chromatography (EtOAc) provided
18 (9 mg, 88%) as a syrup: [R]D 0 (c 0.3, CHCl3); 1H NMR
(CDCl3) δ 7.38-7.26 (m, 10H, 2 × Ph), 5.48 (s, 1H, NH), 5.13
and 4.58 (d and d, J ) 11.2 Hz, 1H each, PhCH2), 4.73 and 4.61
(d and d, J ) 12.0 Hz, 1H each, PhCH2), 4.09 (dd, J ) 2.4, 2.8
Hz, 1H, H-3), 3.57 (m, 1H, H-4), 3.41 (dd, J ) 2.4, 10.8 Hz, 1H,
H-2), 2.95 (ddd, J ) 3.2, 11.2, 11.2 Hz, 1H, H-6), 2.62 (m, 1H,
H-1), 2.53 (m, 1H, H-1′a), 2.28 (d, J ) 10.8 Hz, 1H, 4-OH), 2.09
(m, 1H, H-5a), 2.03 (m, 1H, H-1′b), 1.64 (ddd, J ) 11.6, 11.6,
11.6 Hz, 1H, H-5b); 13C NMR (CDCl3) δ 178.2 (C-2′), 138.6, 138.0,
128.8, 128.3, 128.2, 128.1, 127.8, 79.8 (C-2), 78.6 (C-3), 75.5
(PhCH2), 71.7 (PhCH2), 69.5 (C-4), 54.5 (C-6), 43.0 (C-1), 35.6
(C-1′), 34.5 (C-5); HRMS calcd for C22H26NO4 368.1862 (M +
H), found 368.1851.
For 10: mp 99-100 °C (needles from EtOAc-hexanes); [R]D
1
-66 (c 0.45, CHCl3); H NMR (CDCl3) δ 7.37-7.28 (m, 10H, 2
× Ph), 5.05 (m, 1H, H-6), 4.91 (d, J ) 10.8 Hz, 1H, PhCH2), 4.74
(d, J ) 11.6 Hz, 1H, PhCH2), 4.55 (d, J ) 11.6 Hz, 1H, PhCH2),
4.51 (d, J ) 10.8 Hz, 1H, PhCH2), 4.21 (m, 1H, H-4), 4.03 (bs,
1H, H-3), 3.72 (bd, J ) 10.4 Hz, 1H, H-2), 3.07 (m, 1H, H-1),
2.77 (m, 1H, H-1a′), 2.22 (m, 1H, H-1′b), 2.17 (m, 1H, H-5a), 2.07
(m, 1H, H-5b), 2.07 (s, 3H, CH3); 13C NMR (CDCl3) δ 206.2 (C-
2′), 138.1, 137.3, 128.7, 128.6, 128.2, 128.0, 127.9, 83.6 (C-6),
78.1 (C-2), 76.1 (C-3), 74.5 (PhCH2), 72.4 (PhCH2), 66.4 (C-4),
40.5 (C-1′), 34.1 (C-1), 31.9 (C-5), 30.4 (CH3); HRMS calcd for
C23H28NO6 414.1917 (M + H), found 414.1921.
Di-O-benzyl Indoline Derivative 11. A mixture of 9 (40 mg,
0.097 mmol) and zinc dust (140 mg) in acetic acid (3 mL) was
stirred overnight. The filtrate was diluted by the addition of water
and lyophilized to a solid residue (salt form of 11) in quantitative
yield. The amine form was obtained by dissolving the salt in
dichloromethane followed by washing with aqueous sodium
bicarbonate. The organic phase was dried and concentrated to give
1
syrupy 11: [R]D -25 (c 0.4, CHCl3); H NMR (CDCl3) δ 7.38-
7.26 (m, 10H, 2 × Ph), 5.12 and 4.58 (d and d, J ) 11.6 Hz, 1H
each, PhCH2), 4.70 and 4.62 (d and d, J ) 12.0 Hz, 1H each,
PhCH2), 4.03 (dd, J ) 2.4, 3.2 Hz, 1H, H-3), 3.55 (ddd, J ) 3.2,
4.4, 9.8 Hz, 1H, H-4), 3.42 (m, 1H, H-2′), 3.22 (dd, J ) 2.4, 10.8
Hz, 1H, H-2), 2.33 (ddd, J ) 3.2, 11.6, 11.6 Hz, 1H, H-6), 2.13
(m, 1H, H-1), 2.06 (m, 1H, H-5a), 1.75 (m, 1H, H-1′a), 1.66 (m,
1H, H-1′b), 1.55 (ddd, J ) 11.6, 11.6, 11.6 Hz, 1H, H-5b), 1.19
(d, J ) 6.4 Hz, 3H, 2′-Me); 13C NMR (CDCl3) δ 139.0, 138.5,
128.7, 128.0, 127.9, 127.8, 81.7 (C-2), 78.7 (C-3), 75.1 (PhCH2),
71.6 (PhCH2), 70.4 (C-4), 60.0 (C-6), 53.3 (C-2′), 44.5 (C-1), 35.9
(C-1′), 35.0 (C-5), 23.3 (2′-CH3); HRMS calcd for C23H30NO3
368.2226 (M + H), found 368.2199.
Acknowledgment. This is NRCC publication No. 42517.
The authors thank Ken Chan and Jacek Stupak for mass
spectroscopic analysis and Dean Williams for helpful discussion.
Supporting Information Available: General methods, synthetic
procedures for 2-8 and 12-16, and NMR spectra (1H, 13C, COSY,
NOESY, HSQC) of compounds (3-18). This material is available
free of charge via the Internet at http://pubs.acs.org.
(1S,2S,3R,4R,6S)-1-Methoxycarbonylmethyl-2,3-di-O-benzyl-
4-hydroxyl-6-nitrocyclohexane (17). A solution of compound 8
(27 mg) in 1% K2CO3-MeOH (5 mL) was kept at room
temperature for 2 days. The mixture was partitioned between ethyl
acetate and water, and the aqueous solution was extracted with ethyl
JO070014O
J. Org. Chem, Vol. 72, No. 7, 2007 2689