Structure assignment of aminoconduritols by 15N NMR correlation spectroscopy; synthesis of a positional isomer of 7-deoxypancratistatin

Article abstract of DOI:10.1139/v01-139

A positional isomer of 7-deoxypancratistatin was synthesized in 12 steps from epoxyaziridines 4 and 5. An intermolecular opening of the aziridine rather than the epoxide in the early stages of the synthesis led to 13, which did not match the properties of

Full text of DOI:10.1139/v01-139

1659
15
Structure assignment of aminoconduritols by N
NMR correlation spectroscopy; synthesis of a
positional isomer of 7-deoxypancratistatin
Stefan Schilling, Uwe Rinner, Collin Chan, Ion Ghiviriga, and Tomas Hudlicky
Abstract: A positional isomer of 7-deoxypancratistatin was synthesized in 12 steps from epoxyaziridines 4 and 5. An
intermolecular opening of the aziridine rather than the epoxide in the early stages of the synthesis led to 13, which did
not match the properties of tetraacetate 10 derived from 7-deoxypancratistatin. At no stage of the synthesis did stan-
1
1
dard NMR techniques, involving H–1H or H–13C coupling, prove adequate for the structure assignment. Unambiguous
1
structure was assigned by H–15N correlation NMR spectroscopy as well as by the conversion of epoxide 11 to diol 29
synthesized independently by another route. Experimental and spectral details are reported for all new compounds.
Key words: 15N NMR spectroscopy, iso-7-deoxypancratistatin, Lewis acid catalyzed intramolecuar opening of epoxides,
aminoconduritols.
Résumé : On a synthétisé un isomère de position de la 7-désoxypancrastistatine en douze étapes à partir des époxyazi-
ridines 4 et 5. Au cours des premières étapes de la synthèse, une ouverture intermoléculaire de l’aziridine à la place
d’une ouverture de l’époxyde a conduit au produit 13 dont les propriétés ne correspondent pas à celles du tétraacétate
1
1
10 qui dérive de la 7-désoxypancratistatine. Les techniques normales de RMN impliquant les couplages H–1H ou H–
13C ne se sont avérés adéquates pour faire des attributions de structures. La structure a été attribuée sans ambiguïté par
spectroscopie RMN de corrélation H–15N ainsi que par conversion de l’époxyde 11 en diol 29 qui a été synthétisé de
1
façon indépendante par une autre voie. On rapporte les détails expérimentaux et les spectres de tous les nouveaux com-
posés.
Mots clés : spectroscopie 15N RMN, iso-7-désoxypancratistatine, ouverture intramoléculaire d’époxydes catalysée par un
acide de Lewis, aminoconduritols.
[Traduit par la Rédaction] Schilling et al. 1667
Introduction
the nucleophilic opening of either isomer of epoxide with
piperonol 6 followed by alkylation of the resulting alcohol
with piperonyl bromide 7 will provide an intermediate in
which both oxygens bear identical functionality. Such redun-
dant operations (7) greatly improve the practicality of a syn-
thesis because no attention need be paid either to the control
of stereochemistry at the intermediate stage or to the separa-
tion of the isomers of epoxides 4 and 5. Lewis acid cata-
lyzed aziridine opening, oxidation, and recyclization would
lead to the phenanthridine core of the alkaloid. We are
aware of only three previous examples of intramolecular
opening of aziridines (8) before we applied the technique to
our synthesis, which is conceptually similar to the opening
of the epoxide derived from myo-inositol as reported by
Bender (9).
Several total syntheses of the Amaryllidaceae alkaloids
have been recently completed by our research group and by
others (1–4). We have reported the first asymmetric synthesis
of pancratistatin (1b, c), as well as brief routes to
lycoricidine (4j), 7-deoxypancratistatin (2c), ent-7-deoxy-
pancratistatin (5), and narciclasine (3b). Attempting to im-
prove on the 14-step preparation of pancratistatin, which
featured an intermolecular aziridine opening by an aryl
cuprate (2c), we chose to pursue what appeared to be a more
efficient strategy based on a novel intramolecular opening of
the aziridine in 3, Fig. 1.
Our strategy, shown in Fig. 1, relies on the availability of
epoxyaziridines 4 and 5, which can be rapidly synthesized
from the commercially available diene 8 by established
methods (6). Stereoelectronic considerations indicate that
In this paper we report the synthesis of tetracetate 13, a
positional isomer of 10, shown in Fig. 2. The latent func-
Received February 22, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on November 12, 2001.
Dedicated to Professor Victor A. Snieckus in recognition of his contributions to synthetic organic chemistry.
S. Schilling, U. Rinner, C. Chan,1 I. Ghiviriga,2 and T. Hudlicky.3 Department of Chemistry, University of Florida, Gainesville,
Fl 32611, U.S.A.
1NSF REU participant, Summer 2000.
2Author to whom correspondence regarding NMR work may be addressed (telephone: (352) 846- 3001; fax: (352) 846-3001;
e-mail: ion@chem.ufl.edu).
3Corresponding author (telephone: (352) 392-9844; fax: (352) 846-1203; e-mail: hudlicky@chem.ufl.edu).
Can. J. Chem. 79: 1659–1667 (2001)
DOI: 10.1139/cjc-79-11-1659
© 2001 NRC Canada

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Can. J. Chem. Vol. 79, 2001
Fig. 1. Design of synthesis.
O
O
O
N
Ts
OH
NH
4 α-epoxy
5 β-epoxy
Br
HO
OAr
OH
OH
OH
O
O
O
O
O
O
O
+
OH
O
N
X
R
O
Ts
O
R
3
8
1 R = OH
2 R = H
6 X = OH
7 X = Br
Fig. 2. Pathway to positional isomer of 7-deoxypancratistatin.
OAc
OAc
AcO
OBn
O
O
O
O
O
O
projected
OAc
NH
O
N
O
O
Ts
O
9
10
O
O
N
Ts
O
O
O
O
O
O
4, 5
OAc
O
O
actual
O
AcO
OAc
NRTs
NHAc
11 R = H
12 R = Bn
13
tional symmetry of epoxyaziridines 4 and 5 and their ten-
dency to react with nucleophiles made structural assignment
difficult throughout the synthesis. The inherent difficulties
in precise stereochemical and regiochemical assignments in
all intermediates propagated the errors resulting from the
initial incorrect assignment of regiochemistry in the opening
of aziridines 4 and 5 under basic conditions. A full structural
correlation is reported along with experimental details for
the preparation of tetraacetyl aminolactone 13.
and 5, respectively. In our group, earlier work on nucleo-
philic opening of this material indicated that carboxylate
salts (12) opened the epoxide under slightly basic conditions
and that alcohols (13) under BF3·Et2O catalysis also opened
the epoxide with the aziridine ring intact. Following this pre-
cedent, the potassium salt of piperonol was reacted with the
epoxyaziridines 4 and 5 and the product subjected to benzyl-
ation. Spectroscopic evidence, as presented below, suggested
that compound 9 had been obtained, and therefore the rest of
the synthesis was carried out. However, the compound, iso-
lated in 71% yield as a single isomer, turned out to be
epoxide 12, ascertained only at the end of the synthesis
when tetracetate 13 was identified.
The analysis of 1H NMR spectra of conduramine and
conduritol derivatives is not trivial, viz. the patterns of epoxy
vs. aziridinyl methines and the chemical shift differences be-
tween O-benzyl vs. N-benzyl groups in structures where var-
ious shielding parameters could lead to pronounced shifts of
the benzylic protons. This error in structure assignment was
propagated through 12 steps without detection or ambiguity.
The functional symmetry of epoxy aziridines 4 and 5 and the
difficulty in deciphering the outcome of the first step con-
tributed to the error.
Results and discussion
Enantiomerically pure diol 8 was obtained by whole-cell
biooxidation with recombinant E. coli JM109 (pDTG601)
according to the established procedure (10). Diol 8 was pro-
tected as its acetonide and then reacted with (N-tosyli-
mino)phenyliodinane according to the protocol established
by Evans et al. (11a) and Jacobsen and co-workers (11b) to
produce aziridine 14 in 45% overall yield (1c), as shown in
Scheme 1. Dehalogenation of 14 with n-Bu3SnH–THF gen-
erated vinylaziridine 15 (1c), which was subsequently oxi-
dized (mCPBA, 1,2-dichloroethane, 85°C) to furnish an
inseparable mixture (2.6:1) of a- and b-epoxyaziridines 4
© 2001 NRC Canada

Schilling et al.
1661
Scheme 1. Reagents and conditions: (a) DMP, p-TSA (cat.), acetone, rt; (b) PhI=NTs, Cu(acac)2, CH3CN, rt, 63% (over 2 steps);
(c) Bu3SnH, AIBN, THF, reflux, 78%; (d) mCPBA, C2H4Cl2, reflux, 80%; (e) potassium piperonoxide, 18-C-6, DME, rt; (f) (i) NaH,
THF, (ii) BnBr, Bu4NI, rt, 71% (over 2 steps); (g) Me2AlCl, CH2Cl2, –25°C, 77%; (h) DDQ, 2-methoxyethanol, CH2Cl2, rt, 78%;
(i) NaH, (BOC)2O, THF, reflux; (j) Na–naphthalene, DME, –50°C, 85% (over 2 steps); (k) CSA, THF, H2O, rt; (l) PCC, CH2Cl2, rt,
72% (over 2 steps); (m) C6H5CO2Na, MeOH–H2O, reflux; (n) p-TsOH, MeOH, 84% (over 2 steps); (o) K2CO3, MeOH, 44%;
(p) Ac2O, DMAP, pyridine, 61%; (q) (i) H2, Pd(OH)2, MeOH, (ii) Ac2O, DMAP, pyridine, 55% (over 2 steps).
O
Br
X
O
O
O
OH
OH
O
O
O
O
O
O
a, b
d
e
O
NXTs
N
N
Ts
Ts
8
14 X = Br
15 X = H
4, 5
11 X = H
12 X = Bn
c
f
g
O
O
O
O
O
O
OBOC
O
OH
OH
O
O
O
O
i, j
h
O
O
O
O
O
O
CH3O
NHBn
CH3O
N(Bn)Ts
N(Bn)Ts
17
16
18
k, l
O
O
O
O
O
O
OR
o
OR'
OR'
RO
OR'
O
O
OR'
NHR''
NHR''
21 R = R' = H, R'' = Bn
22 R = R' = Ac, R'' = Bn
13 R = R' = R'' = Ac
19 R = BOC, R' = C(CH3)2, R'' = Bn
20 R = H, R' = H, R'' = Bn
p
q
m, n
The actual sequence of steps was as follows: treatment of
piperonyl ether 12 with Me2AlCl resulted in cyclization to
pentacycle 16 in 77% yield. Benzylic oxidation of ether 16 by
means of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
in the presence of 2-methoxyethanol gave acetal 17 in 78%
yield. Acylation of acetal 17 followed by reductive
detosylation (sodium–naphthalene–DME) generated acetal
18 in 85% overall yield. Deprotection of the acetal followed
by oxidation of the resulting lactol provided lactone 19 in
72% yield. Removal of the carbamate by thermolysis
followed by deketalization gave amino diol 20, which upon hy-
drolysis (K2CO3–methanol) furnished lactone 21 in 44% yield.
stable lactone 21, with distinctly different chromatographic
and spectral properties; at the time we assumed that we were
observing the expected equilibrium-driven transformation to
the lactam.
OH
O
HO
OH
O
O
O
OBn
OH
O
O
NHBn
O
H2N
O
OH
20 actual
23 projected
The last stages of the synthesis were reached with what
we thought to be lactone 23, to which the conditions of
Paulsen (2b) were applied for the final lactone–lactam
interconversion, a sequence driven by the greater stability of
the trans-fused lactam. Following this rearrangement, a pro-
tocol for debenzylation was carried out, ultimately leading to
1H NMR, 13C NMR, and other analytical methods failed
to confirm the structure of this material, which had evidently
undergone a lactone rearrangement of some kind. An unam-
biguous assignment was finally made by means of 15N
HMQC spectroscopy, described in the next section.
1
the isolation of a compound whose tetraacetate provided H
NMR remarkably similar to the 1H NMR of the known
tetraacetate of 7-deoxypancratistatin (2c), but whose Rf value
in thin layer chromatography was lower by 0.6. The interest-
ing point here is that lactone 20 did isomerize to the more
Assignment of regio- and stereochemistry of tosylamide 16
Throughout the synthesis, 2D NMR was employed to con-
firm the structural integrity of key compounds, namely 16,
© 2001 NRC Canada

1662
Can. J. Chem. Vol. 79, 2001
Fig. 3. Proton assignment of tosylamide 16.
19, and 21. However, the H–1H couplings and NOE’s, and
1
the one-bond and long-range H–13C couplings fail to dis-
1
7.12
criminate between compounds from the projected and actual
7.14
7.22
1
series. In the case of compound 16 for instance, the H–1H
4.49
4.38
and 1H–13C correlations indicate functionalized benzo-
phyranyl system 24, where X, Y, and Z are two O atoms and
one NTs group. Uncertainty arises because there can be no
1H–13C long range coupling between atoms in the tosyl
group and atoms at its point of attachment.
6.29
O
O
O
4.51
4.44
5.68
4.16
N
2.40
3.86
HO
3.84
4.64
SO2
6.82
7.83
7.11
O
4.22
2.93
O
7
6
O
1.33
2.27
7a
X
6a
11a
9
1.28
16
Y
4a
11b
O
10a
4
3
11
1
2
HZ
O
O
Conclusion
24
The latent functional symmetry of epoxyaziridines 4 and 5
made it difficult to differentiate clearly the outcome of the
initial nucleophilic opening of either of the three-membered
rings. Standard structural assignment could not distinguish
between the two regioisomers during a 12 step synthesis un-
til a physical match was made. Philosophically, this case
should raise interesting questions about the global probabil-
ity of similar errors, undetected because of limited or nonex-
isting comparisons of physical properties, in today’s
literature.
Formula 24 describes a compound in the projected series
for X, Y = O and Z = NTs, as well as the actual 16, for X,
Z = O and Y = NTs. The same ambiguity is seen in com-
pound 17; however, compounds produced after the reductive
detosylation step possess a proton attached to nitrogen,
which in theory can be used to reveal the location of the tri-
valent nitrogen. In reality though, fast exchange with resid-
ual water in the sample precluded the observation of any
coupling of this proton and even of its chemical shift for
both 18 and 19. The peracetylated derivative of 20 (R = R> =
Experimental
>>
R = Ac) displayed coupling of the NH proton with the pro-
ton in position 4 and not with the proton in position 1 as ex-
pected, thus revealing that the compounds synthesized were
different from the projected ones.
All reactions were carried out in an argon atmosphere
with standard techniques for the exclusion of air and mois-
ture. Glassware used for moisture-sensitive reactions was
flame-dried under vacuum. Tetrahydrofuran (THF) and 1,2-
dimethoxyethane (DME) were distilled from sodium benzo-
phenone ketyl. Dichloromethane and 1,2-dichloroethane
were distilled from calcium hydride. Reactions were moni-
tored by thin layer chromatography on K6F silica gel
(Whatman) plates. Flash column chromatography was per-
formed on Merck silica gel (grade 60, 230–400 mesh).
Melting points were determined on a Thomas-Hoover Uni-
melt apparatus and are uncorrected. Infrared spectra were ob-
tained on a PerkinElmer 1600 Series FT-IR spectrometer.
High resolution mass spectra (HRMS) were measured on a
Finnigan Mat 95Q mass spectrometer. Nuclear magnetic reso-
nance spectra were recorded on either a Varian VXR-300,
Gemini 300, or Inova 500 FT NMR spectrometer in CDCl3
unless otherwise noted. Coupling constants are measured in
Hertz and chemical shifts are reported in ppm downfield
from tetramethylsilane. Optical rotations were measured on
a PerkinElmer model 341 polarimeter.
Direct evidence for the structure of compound 16 came
from the long-range 1H–15N couplings, revealed by the
gHMBC spectrum at natural abundance (Fig. 3). Enough
sample for the experiment was obtained by repeating the
synthesis to provide 100 mg of tosylamide 16. The nitrogen
signal at 277.9 ppm on the nitromethane scale displayed
cross-peaks with the benzylic protons (4.44 and 4.51 ppm)
and the proton at 4.16 ppm of the cyclohexyl unit.
Chemical proof via structure correlation
In addition to the evidence for the structure of tosylamide 16
1
1
based on spectroscopy, including H–13C as well as H–15N
correlation experiments, its structural integrity was con-
firmed through an independent synthesis. As illustrated in
Scheme 2, opening of vinylaziridine 15 with the potassium
salt of piperonol generated tosylamide 25, which was con-
verted to olefin 26 following benzylation. Stereoselective
dihydroxylation of the olefin furnished cis-diol 27; more-
over, opening of epoxide 12, derived from opening of the
mixture of epoxyaziridines 4 and 5, with hydroxide pro-
vided the trans–diol 28. Cleavage of the diol functionalities
in both tosylamides 27 and 28 gave rise to the corresponding
dialdehydes, which upon reduction afforded N-benzyl
tosylamide 29, whose spectral and physical properties
(1H NMR, Rf, mass spectrum fragmentation pattern) were
identical for the materials obtained by two independent syn-
thetic routes.
(1S,2S,4R,5S,6S,7S)-5,6-(Isopropylidenedioxy)-3-(4>-
methylphenylsulfonyl)-8-oxa-3-aza-tricyclo[5.1.0.0]octane
(4) and (1R,2S,4R,5S,6S,7R)-5,6-(isopropylidenedioxy)-3-
(4>-methylphenylsulfonyl)-8-oxa-3-aza-tricyclo[5.1.0.0]-
octane (5)
To a degassed solution of aziridine 15 (2.18 g, 6.79 mmol)
in 1,2-dichloroethane (70 mL) was added mCPBA (8.37 g,
70%, 34.0 mmol) along with 3-tert-butyl-4-hydroxy-5-
© 2001 NRC Canada

Schilling et al.
1663
Scheme 2. Reagents and conditions: (a) potassium piperonoxide, 18-C-6, DME, rt, 56%; (b) (i) NaH, THF, (ii) BnBr, Bu4NI, rt, 84%;
(c) RuCl3·3H2O, NaIO4, CH3CN, EtOAc, 0°C, 66%; (d) (i) NaIO4, CH3COCH3, H2O, (ii) NaBH4, MeOH, rt, 52% (over 2 steps);
(e) potassium piperonoxide, 18-C-6, DME, rt; (f) (i) NaH, THF, (ii) BnBr, Bu4NI, rt 71%; (g) KOH, H2O, 1,4-dioxane, reflux, 56%;
(h) (i) NaIO4, CH3COCH3, H2O, (ii) NaBH4, MeOH, rt, 49% (over 2 steps).
O
O
O
O
O
N
Ts
N
Ts
4, 5
15
a
e
O
O
O
O
O
O
O
O
O
O
O
NR
Ts
NR
Ts
25 R = H
26 R = Bn
11 R = H
12 R = Bn
b
f
c
g
OH
OH
HO
O
HO
O
O
O
O
O
O
O
O
O
N(Bn)
Ts
N(Bn)
Ts
28
27
OH
d
h
HO
O
O
O
O
O
N(Bn)Ts
29
methylphenyl sulfide (1.21 g, 3.40 mmol) as a radical in-
hibitor. The resulting solution was heated at reflux for
12 h. After allowing the solution to cool to room tempera-
ture, the reaction mixture was diluted with CH2Cl2 and
washed sequentially with saturated NaHSO3 and saturated
NaHCO3 solution. The organic phase was dried over
Na2SO4 and the solvent was removed under reduced pres-
sure. The residue was purified by chromatography (10%
deactivated silica gel, hexanes – ethyl acetate, 4:1) to give
a mixture of epoxyaziridines 4 and 5 (1.83 g, 80%) as a
white solid; mp 107–108°C. [a]2D8 –56.5 (c 0.8, CHCl3).
Rf = 0.43 (hexanes – ethyl acetate, 2:1) FAB-HRMS calcd.
for C16H20NO5S: 338.1062; found: 338.1061. IR (neat)
(cm–1): 3000, 1595, 1330, 1255, 1158, 1082. 1H NMR
(300 MHz, CDCl3) d: 7.84 (d, J = 8.4 Hz, 2H), 7.35 (d, J =
8.1 Hz, 2H), 4.36 (d, J = 5.7 Hz, 1H), 4.24 (d, J = 6.3 Hz,
1H), 3.53 (t, J = 3.6 Hz, 1H), 3.37 (dd, J = 6.8, 3.8 Hz,
1H), 3.12 (dd, J = 3.3, 1.2 Hz, 1H), 3.03 (dd, J = 6.9,
1.2 Hz, 1H), 2.45 (s, 3H), 1.44 (s, 3H), 1.35 (s, 3H). 13C
NMR (75 MHz, CDCl3) d: 144.8, 134.1, 129.6, 127.7,
109.9, 70.6, 69.5, 49.9, 46.5, 37.1, 35.4, 27.2, 25.0, 21.5.
Anal. calcd. for C16H19NO5S: C 56.97, H 5.68, N 4.56;
found: C 57.37, H 5.96, N 3.72.
N-Benzyl-N-[(1R,2R,3S,4S,5S,6S)-2-(benzo[1,3]dioxolo-5-
ylmethoxy)-4,5-(isopropylidenedioxy)-7-oxa-bicyclo-
[4.1.0]hept-3-yl]-4>-methylbenzenesulfonamide (12)
To a suspension of KH (757 mg, 18.9 mmol) in DME
(12 mL) was added a solution of piperonol (2.51 g,
16.5 mmol) in DME (7 mL), and the mixture was stirred for
20 min. A solution of epoxyaziridine 4, 5 (1.59 g,
4.72 mmol) in DME (8 mL) was added dropwise followed
by the addition of 18-crown-6 (436 mg, 1.65 mmol). The re-
sulting solution was stirred for 20 h. The reaction was
quenched with saturated NH4Cl solution and the reaction
mixture was extracted with CH2Cl2 (4 × 75 mL). The com-
bined organic extracts were dried over MgSO4 and concen-
trated in vacuo to provide 11, which was used without
further purification. A solution of the remaining residue in
THF (35 mL) was added dropwise to a suspension of NaH
(841 mg, 35.0 mmol) in THF (35 mL). The solution was
stirred for 20 min, then benzyl bromide (4.30 mL,
© 2001 NRC Canada

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Can. J. Chem. Vol. 79, 2001
36.2 mmol) was added followed by a catalytic amount of
tetrabutylammonium iodide. The solution was allowed to stir
for 44 h and then quenched with water. The reaction mixture
was extracted with ethyl acetate (4 × 60 mL), and the com-
bined organic extracts were dried over MgSO4. The solvent
was removed under reduced pressure and the residue puri-
fied by chromatography (silica gel, hexanes – ethyl acetate,
5:1) to provide epoxide 12 (1.40 g, 71%) as a white solid;
mp 63–65°C. [a]2D6 –6.9 (c 1.0, CHCl3). Rf = 0.27 (hexanes –
ethyl acetate, 3:1) FAB-HRMS calcd. for C31H34NO8S:
580.2005; found: 580.2050. IR (KBr) (cm–1): 2987, 1492,
in CH2Cl2 (25 mL) and 2-methoxyethanol (0.33 mL,
4.2 mmol) was treated with DDQ (188 mg, 0.828 mmol). The
resulting solution was stirred at room temperature for 23 h.
The solvent was removed under reduced pressure and the re-
maining residue was purified by chromatography (silica gel,
hexanes – ethyl acetate – triethylamine, 2.5:2:1) to afford
acetal 17 (282 mg, 78%) as a white solid ; mp 87–90°C. [a]D27
+2.7 (c 1.0, CHCl3). Rf = 0.31 (hexanes – ethyl acetate, 1:1)
FAB-HRMS calcd. for C34H40NO10S: 654.2373; found:
654.2409. IR (KBr) (cm–1): 3448, 1485, 1328, 1242, 1039.
1H NMR (500 MHz, CDCl3) d: 7.83 (d, J = 8.0 Hz, 2H),
7.25 (d, J = 8.5 Hz, 2H), 7.19–7.13 (m, 5H), 6.72 (s, 1H),
6.69 (s, 1H), 5.91 (m, 2H), 5.46 (s, 1H), 4.73–4.62 (m, 2H),
4.44 (ABq, J = 15.3 Hz, 2H), 4.30 (t, J = 7.3 Hz, 1H), 3.93–
3.86 (m, 3H), 3.71–3.59 (m, 3H), 3.43 (s, 3H), 2.42 (s, 3H),
2.38 (d, J = 12.0 Hz, 1H), 2.07 (s, 1H), 1.35–1.33 (m, 6H).
13C NMR (75 MHz, CDCl3) d: 147.2, 146.9, 143.1, 137.8,
135.7, 129.2, 129.0, 128.2, 128.0, 127.7, 127.3, 124.5,
110.5, 109.8, 107.1, 101.0, 96.8, 81.1, 73.7, 72.0, 69.7, 68.3,
67.2, 63.6, 59.0, 52.5, 39.6, 27.1, 24.9, 21.5.
1
1445, 1251, 1036. H NMR (300 MHz, CDCl3) d: 7.82 (d,
J = 8.0 Hz, 2H), 7.18–7.10 (m, 7H), 6.81–6.79 (m, 3H), 5.99
(s, 2H), 4.54–4.48 (m, 2H), 4.31–4.26 (m, 2H), 4.16–4.04
(m, 3H), 3.38 (d, J = 3.3 Hz, 1H), 3.30 (d, J = 3.0 Hz, 1H),
2.40 (s, 3H), 1.46–1.33 (m, 6H). 13C NMR (75 MHz,
CDCl3) d: 147.7, 147.4, 142.8, 138.0, 136.4, 130.9, 129.0,
128.7, 128.3, 128.2, 127.6, 122.1, 110.1, 109.2, 108.0,
101.0, 72.7, 71.3, 57.2, 52.1, 27.3, 25.6, 21.5. Anal. calcd.
for C31H33NO8S: C 64.23, H 5.74, N 2.42; found: C 64.51,
H 5.93, N 2.28.
(1S,2R,3S,4R,5S,6R)-4-Benzylamino-1-(tert-butoxy-
carbonyloxy)-2,3-(isopropylidenedioxy)-6-(2>-methoxy-
ethoxy)-2,3,4,4a,6,11b-hexahydro-1H-5,8,10-trioxa-cyclo-
penta[b]phenanthrene (18)
(1S,2R,3S,4R,5S,6R)-1-Hydroxy-2,3-(isopropylidenedioxy)-
4-[N-benzyl-(4>-methylphenylsulfonyl)amino]-2,3,4,4a,6,11b-
hexahydro-1H-5,8,10-trioxa-cyclopenta-[b]phenanthrene
(16)
To a suspension of NaH (12 mg, 0.50 mmol) in THF
(5 mL) was added a solution of acetal 17 (208 mg,
0.319 mmol) in THF (8 mL). The resulting solution was
stirred at room temperature for 20 min after which a solu-
tion of di-tert-butyl dicarbonate (105 mg, 0.481 mmol) in
THF (2 mL) was added dropwise. The solution was heated
at reflux for 5 h. After the solution cooled to room temper-
ature, the reaction was quenched with water, and the mix-
ture extracted with ethyl acetate (3 × 30 mL). The
combined organic extracts were dried over MgSO4 and
concentrated in vacuo. A solution of the remaining residue
in DME (5 mL) cooled to –50°C was treated with a 0.6 M
solution of Na–naphthalene in DME until a dark color per-
sisted. The resulting solution was stirred at –50°C for
30 min, and then the reaction was quenched with water. Af-
ter it had warmed to room temperature, the reaction mix-
ture was extracted with ethyl acetate (3 × 25 mL), and the
combined organic extracts were dried over MgSO4. Re-
moval of the solvent under reduced pressure and purifica-
tion of the residue by chromatography (hexanes – ethyl
acetate – triethylamine, 3:1:1) gave carbonate 18 (163 mg,
85%) as a white foam; [a]2D5 +21.5 (c 1.0, CHCl3). Rf = 0.24
(hexanes – ethyl acetate, 1:1). FAB-HRMS calcd. for
C32H42NO10: 600.2809; found: 600.2813. IR (KBr) (cm–1):
A solution of epoxide 12 (210 mg, 0.36 mmol) in
CH2Cl2 (25 mL) at –25°C was treated with a 1.0 M solu-
tion of Me2AlCl in hexanes (400 L, 0.4 mmol) and
stirred at –25°C for 2 h; it was slowly warmed to room
temperature. The reaction was quenched with saturated
NH4Cl solution, and the reaction mixture was extracted
with CH2Cl2 (4 × 20 mL). The combined organic extracts
were dried over MgSO4 and the solvent removed under re-
duced pressure. The remaining residue was purified by
chromatography (silica gel, hexanes – ethyl acetate, 4:1) to
furnish tosylamide 16 (161 mg, 77%) as a white solid; mp
114–116°C. [a]D27 –49.0 (c 1.0, CHCl3). Rf = 0.44
(hexanes – ethyl acetate, 1:1) CI-HRMS calcd. for
C31H34NO8S: 580.2005; found: 580.2001. IR (KBr)
(cm–1): 3504, 1484, 1329, 1238, 1156, 1038. 1H NMR
(500 MHz, CDCl3) d: 7.83 (d, J = 7.8 Hz, 2H), 7.26 (d,
J = 9.0 Hz, 2H), 7.19 (m, 5H), 6.75 (s, 1H), 6.43 (s, 1H),
5.89 (s, 2H), 4.75 (dd, J = 9.7, 7.4 Hz, 1H), 4.58 (d, J =
15.1 Hz, 1H), 4.55–4.43 (m, 3H), 4.28 (t, J = 7.4 Hz, 1H),
4.21 (dd, J = 5.9, 4.5 Hz, 1H), 3.89 (dd, J = 11.2, 7.1 Hz,
1H), 3.69 (dd, J = 9.4, 6.6 Hz, 1H), 2.47 (dd, J = 11.6,
4.2 Hz, 1H), 2.42 (s, 3H), 1.92 (s, 1H), 1.30 (m, 6H). 13C
NMR (75 MHz, CDCl3) d: 146.8, 145.9, 143.2, 137.9,
136.1, 129.3, 128.7, 128.2, 128.1, 127.8, 127.6, 123.4,
111.1, 109.8, 104.1, 100.9, 81.0, 75.9, 73.3, 70.9, 67.4,
64.3, 52.4, 39.8, 27.1, 25.0, 21.5. Anal. calcd. for
C31H33NO8S: C 64.23, H 5.74, N 2.42; found: C 63.97,
H 5.87, N 2.36.
1
3448, 1751, 1508, 1490, 1243, 1039. H NMR (300 MHz,
CDCl3) d: 7.34–7.32 (m, 5H), 6.74 (s, 1H), 6.63 (s, 1H),
5.86 (d, J = 18.0 Hz, 2H), 5.64 (s, 1H), 5.09 (dd, J = 11.7,
7.8 Hz, 1H), 4.43–4.38 (m, 2H), 4.20 (t, J = 5.9 Hz, 1H),
4.01–3.82 (m, 4H), 3.58 (m, 2H), 3.34 (s, 3H), 3.23 (dd,
J = 6.7, 3.3 Hz, 1H), 2.64 (dd, J = 11.6, 2.9 Hz, 1H), 1.69
(br s, 1H), 1.45 (s, 3H), 1.35 (s, 3H), 1.32 (s, 9H). 13C
NMR (75 MHz, CDCl3) d: 152.8, 147.7, 147.3, 140.3,
128.9, 128.7, 127.6, 126.6, 112.6, 110.2, 109.9, 108.1,
101.3, 98.0, 82.6, 78.0, 77.9, 76.4, 72.4, 69.9, 68.0, 59.4,
59.2, 52.7, 38.8, 28.3, 27.9, 26.4.
(1S,2R,3S,4R,5S,6R)-1-Hydroxy-2,3-(isopropylidenedioxy)-
6-(2>-methoxyethoxy)-4-[N-benzyl-(4>-methylphenyl-
sulfonyl)-amino]-2,3,4,4a,6,11b-hexahydro-1H-5,8,10-
trioxa-cyclopenta[b]phenanthrene (17)
A degassed solution of tosylamide 16 (320 mg, 0.55 mmol)
© 2001 NRC Canada

Schilling et al.
1665
(s, 1H), 7.29 (t, J = 7.4 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H),
6.89 (s, 1H), 6.10 (m, 2H), 4.75 (td, J = 2.9, 1.3 Hz, 1H),
4.14 (m, 1H), 3.91 (ABq, J = 14.0 Hz, 2H), 3.85 (m, 2H),
3.68–3.38 (m, 4H); 3.32 (t, J = 2.6 Hz, 1H), 3.11 (m, 1H).
13C NMR (75 MHz, CDCl3) d: 164.8, 152.0, 147.5, 137.8,
129.8, 128.5, 128.3, 128.1, 117.2, 109.7, 108.9, 101.9,
78.7, 72.8, 69.8, 59.4, 52.3, 41.1.
(1S,2R,3S,4R,5S,6R)-4-Benzylamino-1-(tert-butoxy-
carbonyloxy)-2,3-(isopropylidenedioxy)-2,3,4,4a,6,11b-
hexahydro-1H-5,8,10-trioxa-cyclopenta[b]phenanthrene-6-
one (19)
A solution of acetal 18 (204 mg, 0.340 mmol) in 30%
aqeous THF (13 mL) was treated with CSA (395 mg,
1.70 mmol) and stirred at room temperature for 21 h. The
solution was then diluted with ethyl acetate and washed
successively with saturated NaHCO3 solution, water, and
brine. The organic layer was dried over Na2SO4 and then
concentrated in vacuo. To a solution of the remaining resi-
due in CH2Cl2 (9 mL) and molecular sieves (3 Å) was
added PCC (112 mg, 0.520 mmol). The resulting solution
was stirred at room temperature for 3 h. The reaction mix-
ture was then filtered over silica and was subsequently
washed with several portions of CH3OH. Removal of the
solvent under reduced pressure and purification of the resi-
due by chromatography (silica gel, hexanes – ethyl ace-
tate, 1:1) provided lactone 19 (131 mg, 72%) as a white
solid; mp 201–203°C. [a]2D7 –28.1 (c 1.0, CHCl3). Rf =
0.23 (hexanes – ethyl acetate, 1:1) FAB-HRMS calcd. for
C29H34NO9: 540.2234; found: 540.2238. IR (KBr) (cm–1):
3318, 1733, 1702, 1501, 1485, 1260, 1038. 1H NMR
(500 MHz, CDCl3) d: 7.55 (s, 1H), 7.33–7.26 (m, 5H), 6.72
(s, 1H), 6.05 (m, 1H), 5.96 (m, 1H), 5.07 (dd, J = 11.5,
7.5 Hz, 1H), 4.72 (t, J = 3.5 Hz, 1H), 4.40 (dd, J = 7.5,
5.8 Hz, 1H), 4.22 (t, J = 5.4 Hz, 1H), 3.94 (ABq, J =
12.9 Hz, 2H), 3.48 (dd, J = 5.0, 3.4 Hz, 1H), 2.99 (dd, J =
11.5, 3.4 Hz, 1H), 1.63 (br s, 1H), 1.43 (s, 3H), 1.36 (s,
3H), 1.30 (s, 9H). 13C NMR (75 MHz, CDCl3) d: 163.5,
152.2, 152.1, 148.1, 139.6, 134.6, 128.8, 128.4, 127.6,
118.9, 110.3, 110.2, 108.7, 102.2, 82.9, 79.3, 77.4, 76.9,
75.2, 58.3, 52.7, 38.8, 28.1, 27.6, 26.2.
(1S,2R,3S,4R,4aS,11bR)-2-Benzylamino-1,3,4-trihydroxy-
1,2,3,4,4a,11b-hexahydro-1H-5,8,10-trioxa-cyclopenta[b]-
phenanthrene-6-one (21)
A solution of triol 20 (43 mg, 0.11 mmol) in MeOH
(4 mL) was treated with K2CO3 (31 mg, 0.22 mmol) and sub-
sequently heated at reflux for 13 h. The reaction was diluted
with ethyl acetate and quenched with saturated NH4Cl solu-
tion. The organic and aqueous phases were separated and the
aqueous phase was extracted with ethyl acetate (4 × 30 mL).
The combined organic extracts were dried over Na2SO4 and
the solvent removed under reduced pressure. The remaining
residue was purified by chromatography (silica gel, CHCl3–
MeOH, 9:1) to give triol 21 (19 mg, 44%) as a thin film: [a]D25
–60.4 (c 1.0, CHCl3). Rf = 0.42 (CHCl3–MeOH, 9:1). FAB-
HRMS calcd. for C21H22NO7: 400.1396; found: 400.1379. IR
(neat) (cm–1): 3410, 1690, 1484, 1261, 1026. 1H NMR
(500 MHz, acetone) d: 7.40 (d, J = 7.2 Hz, 2H), 7.36 (s, 1H),
7.30 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 6.94 (d, J =
0.8 Hz, 1H), 6.10 (m, 2H), 4.68 (s, 1H), 4.58 (dd, J = 12.2,
9.4 Hz, 1H), 4.37 (s, 1H), 4.27 (td, J = 3.2, 1.3 Hz, 1H), 4.22
(dd, J = 9.4, 3.2 Hz, 1H), 3.91 (s, 2H), 3.45 (ddd, J = 12.3,
2.6, 0.7 Hz, 1H), 3.38 (t, J = 2.8 Hz, 1H), 3.0–2.62 (m, 3H).
13C NMR (126 MHz, acetone) d: 163.8, 152.5, 147.0, 140.8,
138.0, 128.3, 126.9, 120.1, 108.7, 105.6, 102.3, 78.5, 74.2,
70.3, 69.1, 60.3, 52.0, 39.7.
(1S,2R,3S,4R,5S,6R)-4-Benzylamino-1,2,3-trihydroxy-
2,3,4,4a,6,11b-hexahydro-1H-5,8,10-trioxa-cyclopenta-
[b]phenanthrene-6-one (20)
(1S,2R,3S,4R,4aS,11bR)-2-Benzylamino-1,3,4-triacetoxy-
1,2,3,4,4a,11b-hexahydro-1H-5,8,10-trioxa-cyclopenta-
[b]phenanthrene-6-one (22)
A solution of carbonate 19 (17.5 mg, 0.0295 mmol) in
MeOH–H2O (3:2, 3.5 mL) was treated with a catalytic
amount of sodium benzoate and then heated at reflux for
17 h. After the solution cooled to ambient temperature, the
reaction mixture was extracted with ethyl acetate (4 ×
15 mL). The combined organic extracts were dried over
Na2SO4 and the solvent removed under reduced pressure.
The residue was dissolved in MeOH (1.2 mL) to which p-
toluenesulfonic acid (95 mg, 0.50 mmol) was added. The
resulting solution was stirred at room temperature for 38 h.
The reaction mixture was diluted with ethyl acetate, and
the organic phase was washed with saturated NaHCO3 so-
lution. Following separation of the aqueous and organic
phases, the aqueous phase was extracted with ethyl acetate
(4 × 25 mL). The combined organic extracts were dried
over Na2SO4 and the solvent removed under reduced pres-
sure. The residue was purified by chromatography (silica
gel, CHCl3–MeOH, 9:1) to give diol 20 (9.9 mg, 84% over
A solution of triol 21 (8.2 mg, 0.016 mmol) in pyridine
(0.25 mL) was treated with neat acetic anhydride (58 L,
0.61 mmol) and a catalytic amount of DMAP. The reaction
was allowed to stir for 32 h. The solvent was removed
and the remainder purified by chromatography (silica
gel, hexanes – ethyl acetate, 1:1) to give triacetate 22
(6.6 mg, 61%) as an oil: [a]2D6 –16.2 (c 1.0, CHCl3). Rf =
0.44 (hexanes – ethyl acetate, 1:1). FAB-HRMS calcd. for
C27H28NO10: 526.1713; found: 526.1718. IR (neat) (cm–1):
3441, 1742, 1505, 1485, 1372, 1230, 1040. 1H NMR
(300 MHz, CDCl3) d: 7.54 (s, 1H), 7.38–7.28 (m, 5H), 6.40
(s, 1H), 6.06 (m, 2H), 5.61–5.56 (m, 2H), 5.52 (m, 1H), 4.91
(dd, J = 20.7, 12.2 Hz, 1H), 3.96 (ABq, J = 13.2 Hz, 2H),
3.77 (dd, J = 12.3, 3.0 Hz, 1H), 3.30 (t, J = 2.6 Hz, 1H),
2.10 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H), 1.7 (br s, 1H).
(1S,2R,3S,4R,4aS,11bR)-2-Acetylamino-1,3,4-triacetoxy-
1,2,3,4,4a,11b-hexahydro-1H-5,8,10-trioxa-cyclopenta-
[b]phenanthrene-6-one (13)
two steps) as a white solid; mp 173–176°C (dec.). [a]D26
–
81.0 (c 1.0, CHCl3). Rf = 0.28 (CHCl3–MeOH, 9:1) FAB-
HRMS calcd. for C21H22NO7: 400.1396; found: 400.1312.
A solution of triacetate 22 (5.7 mg, 0.011 mmol) and
Pd(OH)2 (25 mg) in MeOH (1.5 mL) was subjected to an at-
mosphere of hydrogen for 40 min. The reaction mixture was
1
IR (KBr) (cm–1): 3417, 1703, 1503, 1482, 1260, 1034. H
NMR (500 MHz, acetone) d: 7.38 (d, J = 7.4 Hz, 2H), 7.32
© 2001 NRC Canada

1666
Can. J. Chem. Vol. 79, 2001
filtered over Celite, and the filtrate concentrated in vacuo.
The remaining residue was dissolved in pyridine to which
acetic anhydride (15 L, 0.16 mmol) was added followed by
a cataytic amount of DMAP. The reaction was stirred for
19 h. The solvent was removed and the residue purified by
chromatography (hexanes – ethyl acetate, 1:1) to provide
tetraacetate 13 (2.8 mg, 55%) as a film. 1H NMR (300 MHz,
CDCl3) d: 7.44 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.62 (s,
1H), 6.06 (m, 2H), 5.71 (s, 1H), 5.53–5.46 (m, 2H), 4.89
(dd, J = 12.2, 10.1 Hz, 1H), 4.54 (m, 1H), 3.53 (dd, J =
10.5, 1.8 Hz, 1H), 2.08 (m, 9H), 1.98 (s, 3H).
(c 1.0, CHCl3). Rf = 0.21 (hexanes – ethyl acetate, 5:1).
FAB-HRMS calcd. for C31H34NO7S: 564.2056; found:
564.2099. IR (neat) (cm–1): 1599, 1503, 1492, 1445, 1330,
1
1251, 1156, 1040. H NMR (300 MHz, CDCl3) d: 7.86 (d,
J = 8.1 Hz, 2H), 7.22–7.15 (m, 7H), 6.81–6.78 (m, 3H),
5.97–5.94 (m, 3H), 5.80 (d, J = 9.9 Hz, 1H), 4.57–4.31 (m,
6H), 2.40 (s, 3H), 1.32–1.25 (m, 6H). 13C NMR (75 MHz,
CDCl3) d: 147.6, 142.9, 138.1, 136.4, 133.0, 131.7, 129.1,
128.9, 128.2, 127.5, 123.0, 121.6, 112.0, 110.3, 108.9,
107.9, 100.9, 73.6, 72.7, 70.6, 27.5, 25.7, 21.5.
(1R,2R,3S,4S,5S,6S)-3,4-Dihydroxy-5,6-(isopropylidenedi-
oxy)-2-(3>,4>-methylenedioxyphenylmethyl)-1-cyclohexyl-
benzenesulfonamide (27)
N-[(1R,2S,5R,6S)-2-(Benzo[1,3]dioxol-5-ylmethoxy)-5,6-
(isopropylidenedioxy)cyclohex-3-enyl]-4>-methylbenzene-
sulfonamide (25)
A solution of tosylamide 26 (16.2 mg, 0.0288 mmol) in
CH3CN–EtOAc (1:1, 0.80 mL) at 0°C was treated with a so-
lution of NaIO4 (10.1 mg, 0.0432 mmol) and a catalytic
amount of RuCl3·3H2O in water (0.5 mL). The resulting so-
lution was stirred at 0°C for 3 min and then quenched with
saturated Na2S2O3 solution. The reaction mixture was ex-
tracted with CH2Cl2 (4 × 10 mL) and the combined organic
extracts dried over Na2SO4. The solvent was removed under
reduced pressure and the residue purified by chromatogra-
phy (silica gel, hexanes – ethyl acetate, 1:2) to provide diol
27 (11.3 mg, 66%) as a film; [a]2D6 –27.9 (c 1.0, CHCl3).
Rf = 0.34 (hexanes – ethyl acetate, 1:2). FAB-HRMS calcd.
for C31H36NO9S: 598.2111; found: 598.2108. IR (neat) (cm–1):
To a suspension of KH (108 mg, 2.69 mmol) in DME
(3 mL) was added a solution of piperonol (378 mg,
2.49 mmol) in DME (5 mL). The resulting solution was
stirred for 20 min, then a solution of vinylaziridine 15
(228 mg, 0.710 mmol) in DME (3 mL) was added dropwise
followed by 18-crown-6 (66 mg, 0.25 mmol). The reaction
mixture was stirred for 24 h and then the reaction quenched
with saturated NH4Cl solution. The reaction mixture was ex-
tracted with CH2Cl2 (4 × 50 mL) and the combined organic
extracts dried over Na2SO4. The solvent was removed under
reduced pressure and the remainder purified by chromatog-
raphy (silica gel, hexanes – ethyl acetate, 2:1) to furnish
tosylamide 25 (223 mg, 56%) as a white foam; [a]2D9 –10.5
(c 1.0, CHCl3). Rf = 0.38 (hexanes – ethyl acetate, 1:1).
FAB-HRMS calcd. for C24H28NO7S: 474.1586; found:
474.1587. IR (neat) (cm–1): 3269, 1503, 1599, 1492, 1445,
1
3460, 1504, 1492, 1445, 1328, 1251, 1156, 1040. H NMR
(300 MHz, acetone) d: 7.75 (d, J = 7.8 Hz, 2H), 7.24–7.15
(m, 7H), 6.88 (s, 1H), 6.80–6.78 (m, 2H), 6.00 (s, 2H), 4.60
(d, J = 11.1 Hz, 1H), 4.45–4.38 (m, 3H), 4.28–4.14 (m, 4H),
4.03–3.79 (m, 3H), 3.93 (br s, 1H), 2.38 (s, 3H), 1.28–1.24
(m, 6H). 13C NMR (75 MHz, CDCl3) d: 147.7, 147.3, 142.8,
138.3, 136.2, 131.8, 129.1, 128.8, 128.2, 128.0, 127.5,
122.1, 109.3, 109.2, 108.1, 101.0, 76.5, 73.0, 69.7, 27.4,
25.4, 21.4.
1
1326, 1251, 1156, 1094, 1039. H NMR (500 MHz, CDCl3)
d: 7.80 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 6.73 (d,
J = 8.0 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.68 (dd, J = 7.9,
1.8 Hz, 1H), 5.94 (s, 2H), 5.88 (dd, J = 10.3, 1.0 Hz, 1H),
5.84 (ddd, J = 10.1, 3.2, 1.8 Hz, 1H), 5.10 (d, J = 7.4 Hz,
1H), 4.53 (dd, J = 6.3, 3.4 Hz, 1H), 4.36 (d, J = 11.6 Hz,
1H), 4.27 (d, J = 11.5 Hz, 1H), 4.05 (dd, J = 9.4, 6.1 Hz,
1H), 3.80 (dq, J = 9.2, 1.6 Hz, 1H), 3.55 (td, J = 9.2, 7.4 Hz,
1H), 2.37 (s, 3H), 1.36 (s, 3H), 1.29 (s, 3H). 13C NMR
(126 MHz, CDCl3) d: 147.9, 147.2, 142.9, 139.0, 132.6,
131.9, 129.3, 127.6, 124.5, 121.6, 110.8, 109.0, 108.2,
101.0, 76.4, 75.7, 72.2, 70.8, 57.3, 27.8, 26.0, 21.7.
(1R,2R,3R,4S,5S,6S)-3,4-Dihydroxy-5,6-(isopropylidenedi-
oxy)-2-(3>,4>-methylenedioxyphenylmethyl)-1-cyclohexyl-
benzenesulfonamide (28)
A solution of epoxide 12 (17.2 mg, 0.0297 mmol) in a
mixture of 1,4-dioxane–H2O (1:1, 1 mL) was treated with
KOH (16.7 mg, 0.297 mmol) and then heated at reflux for
48 h. The reaction mixture was diluted with ethyl acetate
and the organic and aqueous layers were separated. The
aqueous layer was extracted with ethyl acetate (4 × 20 mL)
and the combined organic extracts dried over Na2SO4. Re-
moval of the solvent under reduced pressure afforded a resi-
due that was purified by chromatography (silica gel,
hexanes – ethyl acetate, 1:4) to give diol 28 (9.9 mg, 56%)
as a film; [a]2D7 –35.4 (c 1.0, CHCl3). Rf = 0.36 (hexanes –
ethyl acetate, 1:24). FAB-HRMS calcd. for C31H35NO9S +
Na: 620.1930; found: 620.1910. IR (neat) (cm–1): 3478,
N-Benzyl-N-[(1R,2S,5R,6S)-2-(benzo[1,3]dioxol-5-ylmeth-
oxy)-5,6-(isopropylidenedioxy)cyclohex-3-enyl]-4>-methyl-
benzenesulfonamide (26)
To a suspension of NaH (10.8 mg of 60% reagent,
0.270 mmol) in THF (2 mL) was added a solution of
tosylamide 25 (117 mg, 0.208 mmol) in THF (5 mL). The
resulting solution was stirred for 20 min then benzyl bro-
mide (36 L, 0.28 mmol) was added, followed by a catalytic
amount of tetrabutylammonium iodide. The solution was
stirred for 18 h and then quenched with water. The reaction
was diluted with ethyl acetate and the aqueous and organic
layers separated. The aqueous phase was extracted with
ethyl acetate (4 × 40 mL) and the combined organic extracts
dried over Na2SO4. Removal of the solvent in vacuo pro-
vided a residue which was purified by chromatography (sil-
ica gel, hexanes – ethyl acetate, 3:1) generating tosylamide
26 (114 mg, 84%) as a solid; mp 157–160°C. [a]2D5 +3.2
1
1493, 1445, 1326, 1246, 1156, 1038. H NMR (300 MHz,
CDCl3) d: 7.82 (d, J = 8.1 Hz, 2H), 7.24–7.20 (m, 7H),
6.76–6.75 (m, 3H), 5.97 (s, 2H), 4.48 (m, 2H), 4.38–4.24
(m, 3H), 4.10–4.06 (m, 2H), 3.98–3.90 (m, 2H), 3.73 (t, J =
6.0 Hz, 1H), 2.42 (s, 3H), 1.35 (s, 3H), 1.25 (s, 3H). 13C
NMR (75 MHz, CDCl3) d: 147.7, 147.4, 143.1, 137.8,
136.3, 131.2, 129.2, 128.8, 128.4, 128.0, 127.7, 122.0,
© 2001 NRC Canada

Schilling et al.
1667
(f) P. Magnus and I.K. Sebhat. J. Am. Chem. Soc. 120, 5341
(1998); (g) J.H. Rigby, U.S.M. Maharoof, and M.E. Mateo. J.
109.5, 109.1, 108.1, 101.0, 77.8, 75.3, 74.1, 72.5, 70.5, 69.4,
61.0, 50.9, 27.4, 25.2, 21.5.
Am. Chem. Soc. 122, 6624 (2000).
2. 7-Deoxypancratistatin: (a) S. Ohta and and S. Kimoto. Chem.
(2R,3R,4S,5R)-[2-(Benzo[1,3]-dioxol-5-ylmethoxy)-3-(N-
benzyl-(4>-methylphenylsulfonyl)amino)-1,6-dihydroxy-
4,5-(isopropylidenedioxy)]hexane (29)
Pharm. Bull. 24, 2977 (1976); (b) G.E. Keck, S.F. McHardy,
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A solution of diol 27 (21.1 mg, 0.0353 mmol) in a 40%
aqueous acetone solution (2 mL) was treated with a solution
of NaIO4 (10.2 mg, 0.0477 mmol) in water (0.2 mL) and
stirred at room temperature for 3 h. The reaction mixture
was concentrated in vacuo and the resulting solution was ex-
tracted with ethyl acetate (4 × 25 mL). The combined or-
ganic extracts were dried over Na2SO4 and the solvent
removed under reduced pressure. The remaining residue was
dissolved in MeOH (1 mL), cooled to 0°C, and treated with
neat NaBH4. The solution was slowly warmed to room tem-
perature and stirred for 18 h. The reaction mixture was
treated with water and then concentrated in vacuo. The re-
maining solution was extracted with ethyl acetate (4 ×
20 mL) and the combined organic extracts dried over
Na2SO4. Removal of the solvent under reduced pressure
gave a residue, which was purified by chromatography (sil-
ica gel, hexanes – ethyl acetate, 1:2) furnishing diol 29
(11.1 mg, 52%) as a film; [a]2D5 +66.8 (c 1.0, CHCl3). Rf =
0.30 (hexanes – ethyl acetate, 1:2). FAB-HRMS calcd. for
C31H38NO9S: 600.2267; found: 600.2264. IR (neat) (cm–1):
3. Narciclasine: (a) J.H. Rigby and M.E. Mateo. J. Am. Chem.
Soc. 119, 12655 (1997); (b) D. Gonzalez, T Martinot, and T.
Hudlicky. Tetrahedron Lett. 40, 3077 (1999); (c) G.E. Keck,
T.T. Wager, and J.F.D. Rodriguez. J. Am. Chem. Soc. 121,
5176 (1999).
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2279 (1975); (b) S. Ohta and S. Kimoto. Chem. Pharm. Bull.
24, 2969, (1976); (c) S. Ohta and S. Kimoto. Chem. Pharm.
Bull. 24, 2977 (1976); (d) H. Paulsen and M. Stubbe. Tetrahe-
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Liebigs Ann. Chem. 535 (1983); (f) S. Ogawa, M. Ohtsuka,
and N. Chida. Tetrahedron Lett. 32, 4525 (1991); (g) T.
Hudlicky and H.F. Olivo. J. Am. Chem. Soc. 114, 9694
(1992); (h) S.F. Martin and H.H. Tso. Heterocycles, 35, 85
(1993); (i) S. Ogawa, M. Ohtsuka, and N. Chida. J. Org.
Chem. 58, 4441 (1993); (j) T. Hudlicky, H.F. Olivo, and B.
McKibben. J. Am. Chem. Soc. 116, 5108 (1994).
1
3501, 1503, 1491, 1445, 1332, 1251, 1157, 1039. H NMR
(300 MHz, CDCl3) d: 7.56 (d, J = 8.1 Hz, 2H), 7.36–7.34
(m, 2H), 7.21–1.15 (m, 5H), 6.73 (d, J = 8.7 Hz, 1H),
6.62–6.60 (m, 2H), 5.93 (m, 2H), 4.60 (d, J = 15.9 Hz,
1H), 4.39–4.27 (m, 4H), 4.13 (d, J = 11.7 Hz, 1H), 3.93 (m,
1H), 3.69–3.58 (m, 2H), 3.44–3.40 (m, 4H), 2.37 (s, 3H),
2.03 (br s, 1H), 1.13 (s, 3H), 1.0 (s, 3H). 13C NMR
(75 MHz, CDCl3) d: 147.8, 147.5, 143.0, 138.1, 137.0,
131.2, 128.8, 128.0, 127.7, 126.8, 121.9, 108.8, 108.0,
107.9, 101.1, 78.5, 73.2, 72.3, 61.2, 58.9, 55.2, 49.6, 27.7,
25.0, 21.4. (Note: an analagous procedure can be applied to
diol 28 which also affords diol 29).
5. H. Akgun amd T. Hudlicky. Tetrahedron Lett. 40, 3081 (1999).
6. (a) H.G. Viehe amd J.L. Vaerman. Tetrahedron, 45, 3183
(1989); (b) H.G. Viehe, J.L. Vaerman, F.P. Schmidtchen, G.
Kresze, W. Burger, and H. Braun. Tetrahedron: Asymmetry, 1,
403 (1990).
7. For definitions of redundant operations, see T. Hudlicky.
Chem. Rev. 96, 3 (1996).
8. (a) S.C. Bergmeier, W.K. Lee, and H. Rapoport. J. Org. Chem.
58, 5019 (1993); (b) S.C. Bergmeier, and P.P. Seth. Tetrahe-
dron Lett. 36, 3793 (1995); (c) S.C. Bergmeier and P.P. Seth. J.
Org. Chem. 64, 3237 (1999); (d) S.C. Bergmeier, S.L. Fundy,
and P.P. Seth. Tetrahedron, 55, 8025 (1999).
9. D.R. Gauthier and S.L. Bender. Tetrahedron Lett. 37, 13 (1996).
10. (a) T. Hudlicky, E.E. Boros, and C.H. Boros. Tetrahedron:
Asymmetry, 4, 1365, (1993); (b) T. Hudlicky, E.E. Boros, and
C.H. Boros. Synthesis, 174 (1992); (c) T. Hudlicky, M.R. Sta-
bile, D.T. Gibson, and G.M. Whited. Org. Syn. 76, 77 (1999).
11. (a) D.A. Evans, M.M. Faul, and M.T. Bilodeau. J. Org. Chem.
56, 6744 (1991); (b) Z. Li, K.R. Conser, and E.N. Jacobsen. J.
Am. Chem. Soc. 115, 5326 (1993); (c) J.G. Knight and M.P.
Muldowney. Synlett, 949 (1995).
12. (a) S. Miah. Unpublished results. 1995; (b) R.D. Guthrie, I.D.
Jenkins, S. Thang, J. Watters, and R. Yamasaki. Carbohydr.
Res. 103, 1 (1982).
13. S. McLamore. Studies directed towards the total synthesis of
ent-7-deoxypancratistatin. PhD thesis. University of Florida.
1997.
Acknowledgments
The authors thank the National Science Foundation (CHE-
9 615 112), TDC Research, Inc., and the University of
Florida for financial support.
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© 2001 NRC Canada