Model Studies Towards Stephaoxocanes: Construction of the 2-Oxa-4-azaphenalene Core of Stephaoxocanidine and Eletefine

Article abstract of DOI:10.1002/ejoc.200300548

The construction of the polysubstituted 1H,3H-2-oxa-4-azaphenalene 4 by means of consecutive oxa-Pictet-Spengler and Jackson cyclizations is reported. This compound contains the ABC ring system of the novel isoquinoline alkaloids stephaoxocanidine and ele

Full text of DOI:10.1002/ejoc.200300548

SHORT COMMUNICATION
Model Studies Towards Stephaoxocanes: Construction of the 2-Oxa-4-aza-
phenalene Core of Stephaoxocanidine and Eletefine
[a]
[a]
[a]
´
Darıo A. Bianchi, Marcos A. Cipulli, and Teodoro S. Kaufman*
´
Dedicated to Professor Edmundo A. Ruveda on the occasion of his 70th birthday
Keywords: Electrophilic substitution / Cyclization / Nitrogen heterocycles / Natural products
The construction of the polysubstituted 1H,3H-2-oxa-4-aza- cepharantha and Cissampelos glaberrima. Both these species
phenalene 4 by means of consecutive oxa-Pictet−Spengler are Menispermaceæ used in folk medicine in the Far East
and Jackson cyclizations is reported. This compound con-
tains the ABC ring system of the novel isoquinoline alkaloids
stephaoxocanidine and eletefine, found in Stephania
and Brazil.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003
Introduction
The novel tetracyclic stephaoxocane skeleton 1a is com-
mon to a small family of isoquinoline alkaloids, revealed in
recent years through the work of Japanese,[1,2] Chinese[3,4]
and Brazilian[5] research groups.
To date, the isolation of only five stephaoxocanes (1bϪf)
has been reported, their source being plants of the Menis-
permaceæ family employed in folk medicine.[6,7] Stephaox-
ocanidine (1b, isolated from Stephania cepharantha) and ele-
tefine (1c, which occurs in Cissampelos glaberrima, better
known as C. pareira), have fully unsaturated AB rings,
whereas their congeners stephaoxocanine 1d, eccentricine
1e, and N-methyleccentricine 1f display dihydro and tetra-
hydro-substituted AB ring systems, respectively. Most note-
worthy is the fact that the stephaoxocanes bear a close
structural relationship to other tetracyclic isoquinoline de-
rivatives, such as the tropoloisoquinolines grandirubrine 2a
and imerubrine 2b, and the azafluoranthenes, exemplified
by telitoxine 3a and imeluteine 3b. These are biosynthet-
ically related alkaloids isolated from Menispermaceæ
(including C. pareira[8,9]), which have demonstrated interest-
ing cytotoxic and antitumor activity as well as healing
properties.[10,11]
Previously, we have shown that appropriate modifications
of the scarcely used Jackson sulfonamidoacetal cyclization
protocol[12] result in useful intermediates for the elaboration
of polysubstituted isoquinolines,[13] tetrahydroisoquinol-
ines,[14,15] and tetahydroprotoberberines.[16] We have also re-
ported the synthesis of a tetrahydro-2-oxa-4-azaphenalene
lactone derivative related to the stephaoxocanes.[17]
We describe here a short synthesis of the substituted 2-
oxa-4-azaphenalene 4 (which contains the ABC ring system
of stephaoxocanidine 1b and eletefine 1c), starting from the
aldehyde 5. This tricyclic structural unit, unique to the ste-
phaoxocanes, constitutes an unprecedented heterocyclic
ring system.
[a]
´
´
´
Instituto de Quımica Organica de Sıntesis (CONICET-UNR)
´
´
y Farmaceuticas,
and Facultad de Ciencias Bioquımicas
Universidad Nacional de Rosario,
Suipacha 531, (S2002LRK) Rosario, Argentina,
Fax: (internat.) ϩ54-341-4370477
E-mail: tkaufman@fbioyf.unr.edu.ar
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2003, 4731Ϫ4736
DOI: 10.1002/ejoc.200300548
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4731

D. A. Bianchi, M. A. Cipulli, T. S. Kaufman
SHORT COMMUNICATION
Our approach is based on the application of an intramol- 15.6 Hz), especially differential NOE spectroscopy. The H-
ecular version of the poorly exploited oxa-PictetϪSpengler 2 proton coupled to the methyl group (J ϭ 6.6 Hz) showed
cyclization of β-phenethyl alcohols[18] for isochroman ring a signal enhancement of 14 % upon irradiation of its aro-
formation and the use of a novel modification[19] of the pro- matic neighbor (H-3Ј), whereas irradiation of H-2 produced
tocol originally reported by Jackson and co-workers[12,20] a 6 % increase in the size of H-3Ј doublet.
for the construction of the isoquinoline moiety.
Continuing with the synthesis, the OsO4-catalyzed dihy-
droxylation of (E)-7 [employing N-methyl morpholine N-
oxide (NMO) as co-oxidant] cleanly furnished threo-diol 8
in 85 % yield. This was transacetalized with acetaldehyde
dimethyl acetal and a catalytic amount of camphorsulfonic
acid to provide the epimeric acetals 9a and 9b as an insepar-
able mixture in 95 % yield (9a:9b approx. 2.7:1).[23] Using
the oxa-PictetϪSpengler conditions, this was cyclized with
TiCl4 at Ϫ78 °C to afford a 2:1 mixture of isochroman-4-
ols in a combined yield of 84 %. These were identified as
10 and 11 on the basis of their NMR spectra, including
differential NOE experiments and results from Giles and
co-workers.[24] These authors studied in detail the isomeriz-
ation of 4-phenyldioxolanes (related to 9) to the corre-
Results and Discussion
In order to favor the construction of the required isoch-
roman bearing a contiguously substituted aromatic moiety,
the aldehyde 5 was first brominated,[21] furnishing 6 in 93
% yield,[22] as depicted in Scheme 1. Next, olefination of
bromoaldehyde 6 with MeCHϭPPh3 afforded an insepar-
able mixture of isomeric β-methylstyrene derivatives (E/Z
approx. 0.7:1) in 90 % yield, which was equilibrated to the
most stable isomer (E)-7 (E/Z Ͼ 20:1) with thiophenol in
toluene at 80 °C under AIBN promotion, in almost quanti-
tative yield. The stereochemical assignment of (E)-7 was sponding isochroman-4-ols, and found that the stereochem-
supported by 1H NMR spectroscopic data (JH-1,H-2
ϭ
istry at C-4 and C-5 was transferred unchanged to C-4 and
Scheme 1. Reagents and conditions: a) Br2 (3 equiv.), AcOH, 5 °C Ǟ room temp., overnight (93 %); b) (1) NaH, DMSO/THF, 60 °C,
2 h, (2) EtPϩPh3IϪ, THF, 60 °C, 20 min, (3) Bromoaldehyde 6, 60 °C, 2 h, room temp., overnight (90 %, E/Z ഠ 0.7); c) PhSH, AIBN,
PhCH3, 80 °C, 2 h, (99 %, E/Z Ͼ 20); d) OsO4 (0.02 equiv.), NMO (1.25 equiv.), acetone/H2O (2:1), 0 °C Ǟ room temp., overnight (85
%); e) CH3CH(OCH3)2 (3 equiv.), CSA (0.1 equiv.), CH2Cl2, 4 h, 35 °C (95 %); f) TiCl4 (2 equiv.), CH2Cl2, Ϫ78 °C (84 %); g) (1) DMSO,
TFAA, CH2Cl2, Ϫ60 °C, 20 min, (2) 10 or 14, in CH2Cl2, 10 min, (3) Et3N, Ϫ60 °C Ǟ room temp., 30 min (10 Ǟ 12, 96 %; 14 Ǟ 15,
94 %); h) NaCNBH3, H2NCH2CH(OCH3)2 (5 equiv.), AcOH, EtOH, room temp. (12 Ǟ 10, 84 %; 15 Ǟ 14, 87 %); i) Bu3SnH, C6H12,
hν (254 nm), room temp., 2 h (97 %); j) MsCl, Et3N, CH2Cl2, Ϫ10 °C, overnight (17, 84 %; 18, Ͻ 5 %); k) H2NCH2CH(OCH3)2, iPr2NEt,
DMSOϪPhCH3 (1:1), 70 °C, 48 h (79 %); l) TsCl, Et3N, CHCl3, reflux, 36 h (96 %); m) 6  HCl, dioxane, reflux, 2.5 h (86 %); n) 6 
HCl, dioxane, EtOH, reflux, 2.5 h (19 Ǟ 21, 81 %; 20 Ǟ 21, 79 %); o) KtBuO, pyridine, 100 °C, 1 h (97 %).
4732
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Eur. J. Org. Chem. 2003, 4731Ϫ4736

Model Studies Towards Stephaoxocanes
SHORT COMMUNICATION
C-3, respectively. Isochroman-4-ol 10[25] was then employed
Tosylation of aminoacetal 16 under forcing conditions
for the construction of the nitrogen-containing ring in a then furnished a nearly quantitative yield of 19, which,
strategy involving Jackson’s isoquinoline synthesis. How- when submitted to the conventional Jackson cyclization
ever, initial efforts directed to effect a one-pot introduction protocol,[35] surprisingly resulted in only small amounts of
of the aminoethyl residue (required to form the isoquinoline the 1,2-dihydroisoquinoline 21. The related aldehyde 20
ring) by sulfonamidation of 10 with N-tosyl aminoacetal[26] (δCHO ϭ 9.23 ppm, t, J ϭ 2.2 Hz) accounted for the mass
were unsuccessful. In addition, in spite of the fact that oxi- difference. After considerable experimentation, it was con-
dation of bromo alcohol 10 gave 96 % of ketone 12, at- cluded that acetal hydrolysis and acetal cyclization were
tempts to reductively aminate 12 with the aid of sodium competing transformations and that the rigidity and strain
cyanoborohydride[27] failed to provide aminoacetal 13, fur- introduced by the heterocyclic ring hindered cyclization of
nishing instead precursor 10. This outcome was presumably 19 in favor of aldehyde formation.[36] This would necessitate
due to steric hindrance, which might have made the conden- minimizing hydrolysis in order to drive the cyclization to
sation step between the amine and the carbonyl to form a completion.
reducible imine intermediate difficult. Therefore, aryl bro-
The simplest and most expedient way of doing this con-
mide 10 was subjected to a photochemically assisted debro- sisted of adding excess ethanol to the reaction medium in
mination with tributyltin hydride,[28] furnishing an excellent order to regenerate the acetal in situ. Gratifyingly, this pro-
yield of 14,[23] which was smoothly oxidized to the related vided the tricyclic compound 21 in 81 % yield after 2.5 h.
ketone 15 in 90 % yield from 10. Nevertheless, 15 was also Interestingly enough, recycling of the aldehyde by addition
reluctant to undergo reductive amination to 16, being pref- of ethanol[37] to pure 20 in a mixture of dioxane and 6 
erentially reduced to its precursor, the isochroman-4-ol 14. HCl was also successful, rapidly and efficiently turning the
In the hope that amination of benzylic halide 17 would otherwise uncyclizable aldehyde 20 into the desired sulfona-
lead to successful CϪN bond formation, alcohol 14 was mide 21 in 79 % yield.[38] The final step was oxidative desul-
halogenated with the novel thionyl chlorideϪbenzotriazole fonylation. However, submission of 21 to the conditions for
reagent;[29] however, only low yields of 17 (15Ϫ20 %) were elimination of sulfonamide (potassium tert-butoxide in re-
obtained. The non-inverted sulfite was the major reaction fluxing tert-butyl alcohol, as in the original literature pro-
product, presumably because of steric crowding at the cedure[35]) resulted in extensive decomposition; only small
benzylic position. Therefore, 14 was treated with the meth- amounts of the desired oxazaphenalene 4 could be isolated.
anesulfonyl chlorideϪtriethylamine reagent, smoothly pro- In a search for more effective conditions, it was observed
viding the inverted pseudoequatorial chloride 17[30,31] in 84 that by performing the elimination in refluxing pyridine,
% yield with perfect stereocontrol (JH-3,H-4 ϭ 8.9 Hz), pre- clean and complete desulfonylation could be readily
sumably by nucleophilic inversion of the initially formed achieved. Moreover, when the reaction was performed in
1
mesylate.
[D5]pyridine in an NMR tube and the H NMR spectrum
Excess methanesulfonyl chloride (3 equiv.) was required of the mixture taken after 30 minutes at room temperature,
in order to achieve complete conversion, probably due to approximately 10 % conversion was apparent. The structure
the poor stability of the sulfene intermediate. A similar and stereochemical assignment of compound 4 was un-
transformation yielding a pseudoaxial chloride from the equivocally confirmed by NMR analysis, including 2D
corresponding pseudoequatorial alcohol had previously NMR (HETCOR) experiments.
been reported, employing a different set of reagents.[32] In
our reaction, small amounts (Ͻ 5 %) of the dehydration
product 18 were also isolated. This compound was recog-
nized by the characteristic coupling between H-4 (δ ϭ
5.51 ppm, q, J ϭ 0.8 Hz) and Me-3 (δ ϭ 1.89 ppm, d, J ϭ
Conclusion
0.8 Hz).
To our delight, benzylic chloride 17 was cleanly and com-
The synthesis of 2-oxa-4-azaphenalene 4, related to the
pletely aminated[33] with 2,2-dimethoxyethylamine after two ABC ring system of the novel stephaoxocanes stephaox-
days at 70 °C in a 1:1 DMSO/toluene solvent mixture con- ocanidine 1b and eletefine 1c, was conveniently achieved
taining N-ethyl diisopropylamine as a promoter and acid by sequential application of an intramolecular oxa-
scavenger. This afforded 86 % of acetal 16, the spectro- PictetϪSpengler reaction and Jackson’s tosylacetal cycliza-
scopic data of which (JH-3,H-4 ϭ 2.4 Hz) provided evidence tion. Three simple but critical modifications to Jackson’s
of configurational inversion.[32] Worthy of note is that the original protocol resulted in (i) incorporation of the amino-
reaction proceeded without formation of the elimination ethyl residue required for the construction of the nitrogen
product 18. It has been observed that this transformation heterocycle in high yield, (ii) efficient formation of the 1,2-
is highly sensitive to steric bulk;[34] therefore, assuming that dihydroisoquinoline derivative 21, and (iii) the clean trans-
the reaction time required for completion is a measure of formation of this compound into the final product, the 2-
the steric hindrance at the benzylic center, this unusually oxa-4-azaphenalene 4. Use of the above strategy for the
slow reaction may imply that steric crowding was respon- synthesis of more advanced stephaoxocane intermediates is
sible for the reluctance of 12 and 15 to undergo reductive currently under investigation and will be reported in due
amination.
course.
Eur. J. Org. Chem. 2003, 4731Ϫ4736
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4733

D. A. Bianchi, M. A. Cipulli, T. S. Kaufman
SHORT COMMUNICATION
J ϭ 8.9 Hz, 1 H, OH-4), 3.80 (s, 3 H, OCH3), 4.11 (dq, J1 ϭ 1.7,
J2 ϭ 6.4, 1 H, H-3), 4.44 (dd, J1 ϭ 1.7, J2 ϭ 8.9, 1 H, H-4), 5.08
(q, J ϭ 6.6 Hz, 1 H, H-1), 6.69 (d, J ϭ 8.7 Hz, 1 H, H-7), 7.45 (d,
J ϭ 8.7 Hz, 1 H, H-6) ppm. 13C NMR: δ ϭ 16.82 (CH3Ϫ3), 17.80
(CH3Ϫ1), 55.40 (OCH3), 66.20 (C-4), 67.01 (C-1), 68.44 (C-3),
111.19 (C-7), 115.79 (C-5), 130.27 (C-8a), 131.36 (C-6), 135.46 (C-
4a), 154.46 (C-8) ppm. HRMS: calcd. C12H15BrO3: 286.02046;
found 286.02039. C12H15BrO3 (286.02): calcd. C 50.19, H 5.27;
found C 50.03, H 5.37.
Experimental Section
General Remarks: Melting points are uncorrected and were taken
on an Ernst Leitz Wetzlar model 350 hot-stage microscope appar-
atus. FT-IR spectra were taken with a Bruker IFS 25 spectrophoto-
meter as dispersions in KBr disks (for solids) or as thin films held
between NaCl cells (for oils). The 1H NMR (200.13 MHz) and 13
C
NMR (50.33 MHz) spectra were acquired in CDCl3 with tetra-
methylsilane as the internal standard, employing a Bruker AC200-
E spectrometer. Assignments were made with the aid of differential
NOE and selective irradiation techniques, DEPT experiments and
2D NMR spectra; an asterisk means that assignments may be ex-
changed. HRMS data were obtained from Kent Electronics (UK)
and UMyMFOR (Argentina). Reactions were carried out under
dry N2 or Ar atmospheres, employing oven-dried glassware. Com-
mercially obtained reagents were used without further purification.
Anhydrous CH2Cl2 and CHCl3 were purified by refluxing over
P2O5 and distillation; dry pyridine was purified by refluxing over
NaOH pellets followed by distillation; anhydrous DMSO was ob-
tained by distillation from CaH2 under reduced pressure; toluene
and cyclohexane were distilled from sodium benzophenone ketyl
prior to use; dry solvents were stored in dry Schlenk flasks. All new
compounds gave single spots on TLC plates run in different solvent
systems. Spots were detected by exposure to UV light (254 and
365 nm), followed by spraying with ethanolic p-anisaldehyde/sulf-
uric acid and careful heating. Standard workup procedures con-
sisted of adding brine (5Ϫ20 mL) and extracting the products with
EtOAc (3 ϫ 20Ϫ40 mL); the organic extracts were then combined,
washed once with brine, dried over Na2SO4, concentrated under
reduced pressure and the residue chromatographed. Flash column
chromatography was carried out with silica gel 60 H, eluting with
hexane/EtOAc mixtures of increasing polarity. Supporting Infor-
mation for this article (Synthesis and spectroscopic data for com-
pounds 6Ϫ9, 12, 15, 18 and 20 and spectra of 4, 10Ϫ12, 14 and
16Ϫ21) is available; see also the footnote on the first page of this ar-
ticle.
(1S*,3S*,4S*)-8-Methoxy-1,3-dimethylisochroman-4-ol (14): A sus-
pension of bromo alcohol 10 (125 mg, 0.44 mmol) in dry, oxygen-
free cyclohexane (7.35 mL) was treated with Bu3SnH (0.35 mL,
1.31 mmol) under a dry argon atmosphere and the reaction was
irradiated (254 nm radiation) for 2 h. The resultant pale yellow
solution was concentrated under reduced pressure; chromatography
of the residue furnished debrominated alcohol 14 (88 mg,
0.42 mmol, 97 %) as a white solid. M.p. 58Ϫ60 °C (hexane/EtOAc).
IR: ν˜ ϭ 3429, 3384, 2973, 2938, 2928, 2919, 2904, 1590, 1473, 1461,
1436, 1353, 1257, 1129, 1105, 1082, 1065, 1048, 987, 832, 808, 756,
1
748 cmϪ1. H NMR: δ ϭ 1.37 (d, J ϭ 6.4 Hz, 3 H, CH3Ϫ3), 1.50
(d, J ϭ 6.6 Hz, 3 H, CH3Ϫ1), 1.83 (d, J ϭ 10.1 Hz, 1 H, OH-4),
3.82 (s, 3 H, OCH3), 4.14 (dq, J1 ϭ 1.8, J2 ϭ 6.4 Hz, 1 H, H-3),
4.19 (dd, J1 ϭ 1.8, J2 ϭ 10.1 Hz, 1 H, H-4), 5.11 (q, J ϭ 6.6 Hz,
1 H, H-1), 6.81 (dd, J1 ϭ 1.0, J2 ϭ 8.2, 1 H, H-7), 7.01 (dd, J1 ϭ
1.0, J2 ϭ 7.6, 1 H, H-5), 7.26 (dd, J1 ϭ 7.6, J2 ϭ 8.2, 1 H, H-6)
ppm. 13C NMR: δ ϭ 16.81 (CH3Ϫ3), 17.87 (CH3Ϫ1), 55.10
(OCH3), 66.03 (C-3), 68.00 (C-4)*, 68.63 (C-1)*, 109.64 (C-7),
121.88 (C-5), 127.34 (C-8a), 127.68 (C-6), 136.70 (C-4a), 154.94 (C-
8) ppm. HRMS: calcd. C12H16O3: 208.10995; found 208.10988.
(1S*,3S*,4S*)-(2,2-Dimethoxyethyl)(8-methoxy-1,3-dimethyl-
isochroman-4-yl)amine (16): An ice-water-cooled solution of meth-
anesulfonyl chloride (0.19 mL, 2.41 mmol) in CH2Cl2 (7 mL) was
slowly (3 h) added to
a mixture of triethylamine (0.50 mL,
3.62 mmol) and alcohol 14 (251 mg, 1.21 mmol) in CH2Cl2
(25 mL). The mixture was stirred overnight under an argon atmos-
phere at Ϫ10 °C. The reaction was submitted to the standard
workup procedure, furnishing chloride 17 (230 mg, 1.02 mmol, 84
(1S*,3S*,4S*)-5-Bromo-8-methoxy-1,3-dimethylisochroman-4-ol
(10) and (1R*,3S*,4S*)-5-Bromo-8-methoxy-1,3-dimethylisochro-
man-4-ol (11): A freshly prepared solution of TiCl4 in CH2Cl2 %) as a slightly unstable, colorless oil. IR: ν˜ ϭ 2976, 2934, 2898,
(0.902 , 3.85 mL, 3.47 mmol) was added to a mixture of dioxol- 2838, 1588, 1472, 1456, 1440, 1384, 1360, 1348, 1304, 1262, 1202,
anes 9a and 9b (453 mg, 1.58 mmol) in dry CH2Cl2 (33 mL) cooled 1148, 1114, 1084, 1066, 1024, 802, 790, 754, 720 cmϪ1. H NMR:
1
to Ϫ78 °C. The reaction was stirred for 2 h at Ϫ78 °C under an
argon atmosphere, quenched with MeOH (1.5 mL) and allowed to
warm to room temperature. Saturated NaHCO3 (5 mL) was added
and the reaction was submitted to the standard workup procedure,
furnishing isochroman-4-ol 11 (132 mg, 0.46 mmol, 29 %), as a col-
orless oil. IR: ν˜ ϭ 3430, 2976, 2836, 1577, 1466, 1367, 1285, 1253,
δ ϭ 1.44 (d, J ϭ 6.1 Hz, 3 H, CH3Ϫ3), 1.56 (d, J ϭ 6.6 Hz, 3 H,
CH3Ϫ1), 3.82 (s, 3 H, OCH3), 4.14 (dq, J1 ϭ 6.1, J2 ϭ 8.8 Hz, 1
H, H-3), 4.72 (d, J ϭ 8.8 Hz, 1 H, H-4), 5.08 (q, J ϭ 6.6 Hz, 1 H,
H-1), 6.76 (dd, J1 ϭ 0.6, J2 ϭ 8.4 Hz, 1 H, H-7), 7.19 (dd, J1
ϭ
0.6, J2 ϭ 7.7 Hz, 1 H, H-5), 7.25 (dd, J1 ϭ 7.7, J2 ϭ 8.4, 1 H, H-
6) ppm. 13C NMR: δ ϭ 18.62 (CH3Ϫ1), 19.21 (CH3Ϫ3), 55.19
1193, 1166, 1117, 1066, 993, 812, 777, 622 cmϪ1 1H NMR: δ ϭ (OCH3), 59.57 (C-4)*, 68.14 (C-1)*, 68.67 (C-3), 109.00 (C-7),
.
1.40 (d, J ϭ 6.4 Hz, 3 H, CH2Ϫ3), 1.56 (d, J ϭ 6.2 Hz, 3 H, 120.94 (C-5), 127.48 (C-6), 128.57 (C-8a), 134.30 (C-4a), 154.47 (C-
CH3Ϫ1), 2.09 (d, J ϭ 9.6 Hz, 1 H, OH-4), 3.69 (dq, J1 ϭ 1.2, J2 ϭ 8) ppm. Without delay, N-ethyldiisopropylamine (0.306 mL,
6.4 Hz, 1 H, H-3), 3.81 (s, 3 H, OCH3), 4.49 (dd, J1 ϭ 1.2, J2 ϭ
1.76 mmol) was added to a solution of chloride 17 (203 mg,
9.6 Hz, 1 H, H-4), 4.93 (q, J ϭ 6.2 Hz, 1 H, H-1), 6.72 (d, J ϭ 0.90 mmol) and 2,2-dimethoxyethylamine (0.5 mL, 4.4 mmol) in
8.8 Hz, 1 H, H-7) and 7.45 (d, J ϭ 8.8 Hz, 1 H, H-6) ppm. 13C anhydrous toluene/DMSO (1:1, 4 mL). The reaction was heated for
NMR: δ ϭ 16.69 (CH3Ϫ3), 21.57 (CH3Ϫ1), 55.23 (OCH3), 68.33 2 days at 70 °C; 10 % NaOH (20 mL) was then added and the
(C-4), 70.83 (C-1), 71.98 (C-3), 111.58 (C-7), 115.73 (C-5), 130.52 reaction was submitted to the standard workup procedure, fur-
(C-8a), 131.07 (C-6), 136.53 (C-4a), 155.23 (C-8) ppm. HRMS:
calcd. C12H15BrO3: 286.02046; found 286.02024. Increasing the sol-
vent polarity allowed the isolation of isochroman-4-ol 10 (248 mg,
nishing amine 16 (208 mg, 0.70 mmol, 79 %) as an oil. IR: ν˜ ϭ
3500, 2972, 2932, 2906, 2834, 2540, 1586, 1470, 1440, 1354, 1258,
1196, 1132, 1110, 1066, 1024, 746 cmϪ1 1H NMR: δ ϭ 1.36 (d,
.
0.86 mmol, 55 %) as a white solid. M.p. 116Ϫ117 °C (hexane/ J ϭ 6.4 Hz, 3 H, CH3Ϫ3), 1.47 (d, J ϭ 6.5 Hz, 3 H, CH3Ϫ1), 1.56
EtOAc). IR: ν˜ ϭ 3415, 2976, 2932, 1577, 1464, 1438, 1399, 1355, (s, 1 H, NH), 2.59 (dd, J1 ϭ 5.0, J2 ϭ 12.1 Hz, 1 H, CH2CH), 2.83
1323, 1285, 1256, 1195, 1152, 1125, 1098, 1061, 991, 954, 940, 852, (dd, J1 ϭ 6.2, J2 ϭ 12.1 Hz, 1 H, CH2CH), 3.29 (s, 3 H, CHOCH3),
818, 809, 777, 721, 647, 614 cmϪ1
6.4 Hz, 3 H, CH3Ϫ3), 1.47 (d, J ϭ 6.6 Hz, 3 H, CH3Ϫ1), 2.00 (d,
.
1H NMR: δ ϭ 1.40 (d, J ϭ
3.31 (s, 3 H, CHOCH3), 3.36 (d, J ϭ 2.4 Hz, 1 H, H-4), 3.81 (s, 3
H, OCH3Ϫ8), 4.16 (dq, J1 ϭ 2.4, J2 ϭ 6.4 Hz, 1 H, H-3), 4.38 (dd,
4734
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 4731Ϫ4736

Model Studies Towards Stephaoxocanes
SHORT COMMUNICATION
J1 ϭ 5.0, J2 ϭ 6.2 Hz, 1 H, CH2CH), 5.08 (q, J ϭ 6.5 Hz, 1 H, H-
and the mixture was submitted to the standard workup procedure,
1), 6.74 (dd, J1 ϭ 0.9, J2 ϭ 8.2 Hz, 1 H, H-7), 6.85 (dd, J1 ϭ 0.9, furnishing 4 (23 mg, 0.1 mmol, 97 %) as a colorless oil. IR: ν˜ ϭ
J2 ϭ 7.6 Hz, 1 H, H-5), 7.18 (dd, J1 ϭ 7.6, J2 ϭ 8.2 Hz, 1 H, 2975, 2934, 2840, 1590, 1574, 1504, 1449, 1430, 1309, 1260, 1133,
1
H-6) ppm. 13C NMR: δ ϭ 17.49 (CH3Ϫ1), 18.58 (CH3Ϫ3), 48.41
1106, 1095, 1073, 1049, 1041, 1018, 843 cmϪ1. H NMR: δ ϭ 1.61
(CH2CH), 53.69 (CHOCH3), 53.53 (CHOCH3), 54.97 (OCH3Ϫ8), (d, J ϭ 6.7 Hz, 3 H, CH3Ϫ1), 1.78 (d, J ϭ 6.4 Hz, 3 H, CH3Ϫ3),
56.41 (C-4), 66.53 (C-1), 68.45 (C-3), 104.43 (CH2CH), 108.69 (C-
3.97 (s, 3 H, OCH3), 5.30 (q, J ϭ 6.4 Hz, 1 H, H-3), 5.51 (q, J ϭ
6.7 Hz, 1 H, H-1), 7.44 (d, J ϭ 9.0 Hz, 1 H, H-8), 7.48 (d, J ϭ
7), 121.28 (C-5), 126.72 (C-6), 127.54 (C-8a), 136.89 (C-4a), 155.19
(C-8) ppm. HRMS: calcd. C16H26NO4 (MHϩ): 296.18618; found 5.8 Hz, 1 H, H-6), 7.74 (d, J ϭ 9.0 Hz, 1 H, H-7), 8.34 (d, J ϭ
296.18639.
5.8 Hz, 1 H, H-5) ppm. 13C NMR: δ ϭ 18.30 (CH3Ϫ1), 18.76
(CH3Ϫ3), 56.02 (OCH3), 67.06 (C-3), 67.25 (C-1), 116.94 (C-8),
118.78 (C-6), 121.69 (C-6a), 124.11 (C-9a), 126.06 (C-7), 129.94 (C-
6b), 139.49 (C-5), 151.16 (C-9), 158.06 (C-3a) ppm. C14H15NO2
(229.28): calcd. C 73.34, H 6.59, N 6.11; found C 73.29, H 6.64,
N 6.07.
(1S*,3S*,3aS*)-9-Methoxy-1,3-dimethyl-4-(tolyl-4-sulfonyl)-3,3a-
dihydro-1H,4H-2-oxa-4-azaphenalene (21): Amine 16 (110 mg,
0.37 mmol) was dissolved in anhydrous CHCl3 (10 mL) and suc-
cessively treated with triethylamine (0.26 mL, 1.9 mmol) and tosyl
chloride (210 mg, 1.11 mmol). After heating 8 h at 60 °C, the reac-
tion was submitted to the standard workup protocol, affording sul-
fonamide 19 (160 mg, 0.36 mmol, 96 %) as a colorless oil. IR: ν˜ ϭ
2924, 2872, 2854, 1590, 1470, 1438, 1380, 1340, 1314, 1288, 1262,
1204, 1186, 1164, 1114, 1088, 1068, 1032, 1020, 976, 932, 894, 816,
Acknowledgments
The authors thank SECyT-UNR, CONICET, ANPCyT and
´
Fundacion Antorchas for financial support. D. A. B. thanks
748, 712, 688, 662, 650 cmϪ1. H NMR: δ ϭ 1.17 (d, J ϭ 6.5 Hz,
3 H, CH3Ϫ3), 1.45 (d, J ϭ 6.6 Hz, 3 H, CH3Ϫ1), 2.46 (s, 3 H, Ar-
CH3), 3.01 (dd, J1 ϭ 4.9, J2 ϭ 15.4 Hz, 1 H, CH2CH), 3.06 (s, 3
1
CONICET for his Doctoral fellowship.
[1]
N. Kashiwaba, S. Morooka, M. Kimura, M. Ono, J. Nat. Prod.
H, CHOCH3), 3.09 (s, 3 H, CHOCH3), 3.60 (dd, J1 ϭ 5.6, J2
ϭ
1996, 59, 803Ϫ805.
N. Kashiwaba, S. Morooka, M. Kimura, M. Ono, J. Toda, H.
15.4 Hz, 1 H, CH2CH), 3.80 (s, 3 H, OCH3Ϫ8), 4.05 (dd, J1 ϭ 4.9,
J2 ϭ 5.6 Hz, 1 H, CH2CH), 4.17 (dq, J1 ϭ 3.3, J2 ϭ 6.5 Hz, 1 H,
H-3), 4.81 (d, J ϭ 3.3 Hz, 1 H, H-4), 5.07 (q, J ϭ 6.6 Hz, 1 H, H-
1), 6.56 (dd, J1 ϭ 0.8, J2 ϭ 7.9 Hz, 1 H, H-7), 6.73 (dd, J1 ϭ 0.8,
J2 ϭ 8.2 Hz, 1 H, H-5), 7.06 (dd, J1 ϭ 7.9, J2 ϭ 8.2 Hz, 1 H, H-
6), 7.32 (dd, J1 ϭ 1.9, J2 ϭ 8.0 Hz, 2 H, tosyl H-3Ј and H-5Ј), 7.86
(dd, J1 ϭ 1.9, J2 ϭ 8.0, 2 H, tosyl H-2Ј and H-6Ј) ppm. 13C NMR:
δ ϭ 17.69 (CH3Ϫ1), 17.75 (CH3Ϫ3), 21.40 (Ar-CH3), 46.98
(CH2CH), 53.43 (CHOCH3), 54.01 (CHOCH3), 55.05 (OCH3Ϫ8),
55.40 (C-4), 66.34 (C-1), 68.11 (C-3), 102.96 (CH2CH), 109.12 (C-
7), 121.77 (C-5), 127.39 (C-6), 127.89 (C-3Ј and C-5Ј), 129.13 (C-
2Ј and C-6Ј), 129.53 (C-8a), 132.49 (C-1Ј), 138.54 (C-4a), 142.95
(C-4Ј), 154.83 (C-8) ppm. Tosylacetal 19 (56 mg, 0.12 mmol) was
dissolved in dioxane (2 mL) and treated with 6  HCl (0.2 mL,
1.2 mmol) and EtOH (0.1 mL, 1.74 mmol). The mixture was heated
at 105 °C under a nitrogen atmosphere for 2.5 h. The reaction was
then allowed to cool to room temperature, 10 % NaHCO3 (3 mL)
was added and after standard workup conditions, sulfonamide 21
(39 mg, 0.10 mmol, 81 %) was obtained as a colorless oil. IR: ν˜ ϭ
2958, 2924, 2854, 1598, 1488, 1466, 1406, 1380, 1364, 1352, 1324,
1266, 1250, 1228, 1186, 1170, 1120, 1092, 1052, 1024, 980, 818, 736,
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M. Pıo-Correa, in Dicionario das Plantas Uteis do Brasil e das
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706, 674, 648 cmϪ1 1H NMR: δ ϭ 1.18 (d, J ϭ 6.5 Hz, 3 H,
.
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CH3Ϫ3), 1.38 (d, J ϭ 6.4 Hz, 3 H, CH3Ϫ1), 2.43 (s, 3 H, Ar-CH3),
3.76 (s, 3 H, OCH3), 4.62 (d, J ϭ 4.5 Hz, 1 H, H-3a), 4.93 (q, J ϭ
6.4 Hz, 1 H, H-1), 5.00 (dq, J1 ϭ 4.5, J2 ϭ 6.5 Hz, 1 H, H-3), 5.56
(d, J ϭ 8.2 Hz, 1 H, H-6), 6.62 (d, J ϭ 8.4 Hz, 1 H, H-8), 6.73 (d,
J ϭ 8.2 Hz, 1 H, H-5), 6.75 (d, J ϭ 8.4 Hz, 1 H, H-7), 7.36 (dd,
J1 ϭ 1.9, J2 ϭ 8.0 Hz, 2 H, tosyl H-3Ј and H-5Ј), 7.76 (dd, J1 ϭ
1.9, J2 ϭ 8.0 Hz, 2 H, tosyl H-2Ј and H-6Ј) ppm. 13C NMR: δ ϭ
12.83 (CH3Ϫ3), 21.34 (CH3Ϫ1)*, 21.45 (Ar-CH3)*, 55.08 (OCH3),
55.79 (C-3a), 65.17 (C-1), 70.78 (C-3), 106.74 (C-6), 109.08 (C-8),
121.39 (C-6a), 123.64 (C-5), 124.34 (C-7), 125.06 (C-9a), 126.39 (C-
6b), 127.72 (C-1Ј), 129.84 (C-3Ј and C-5Ј), 132.61 (C-2Ј and C-
6Ј), 144.28 (C-4Ј), 154.41 (C-9) ppm. HRMS: calcd. C21H23NO4S:
385.13478; found 385.13493.
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(4): Freshly sublimed potassium tert-butoxide (120 mg, 1.1 mmol)
was added to a solution of sulfonamide 21 (40 mg, 0.1 mmol) in
dry pyridine (2.5 mL) and the reaction was heated to 60 °C under
an argon atmosphere. After 2 h, NaOH (10 %, 1 mL) was added
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4735

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4736
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4731Ϫ4736