Double reduction of cyclic aromatic sulfonamides: Synthesis of (+)-mesembrine and (+)-mesembranol

Article abstract of DOI:10.1021/jo4000306

The synthesis of (+)-mesembrine (1) and (+)-mesembranol (2) has been achieved from the monoterpene (S)-(-)-perillyl alcohol. Key transformations include a diastereo- and regioselective Pd-mediated intramolecular Heck reaction, and a double reduction of the resultant cyclic sulfonamide, to afford the cis-3a-aryloctahydroindole skeleton.

Full text of DOI:10.1021/jo4000306

Note
pubs.acs.org/joc
Double Reduction of Cyclic Aromatic Sulfonamides: Synthesis of
(+)-Mesembrine and (+)-Mesembranol
Kimberly Geoghegan and Paul Evans*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: The synthesis of (+)-mesembrine (1) and
(+)-mesembranol (2) has been achieved from the mono-
terpene (S)-(−)-perillyl alcohol. Key transformations include a
diastereo- and regioselective Pd-mediated intramolecular Heck
reaction, and a double reduction of the resultant cyclic
sulfonamide, to afford the cis-3a-aryloctahydroindole skeleton.
esembrine 1 is a naturally occurring alkaloid isolated
from the plant species Sceletium tortuosum.1 Historically,
certain examples undergo a double-reduction reaction, whereby
both the C−S and N−S bonds are cleaved following exposure
to lithium, or sodium metal in liquid ammonia.6a The cyclic
sulfonamide starting materials required for this process may be
conveniently accessed by an intramolecular Heck reaction.
More recently we have demonstrated that this intramolecular
Heck-double reduction sequence can be utilized to access the
cis-aryloctahydroindole skeleton.6b
M
these plants have been used to make a concoction in Southern
Africa known as Channa, or Kougoed. It has been shown that 1
is the major active ingredient of Channa, and studies have
demonstrated that this naturally occurring alkaloid behaves as a
selective serotonin reuptake inhibitor (SSRI).1,2 This alkaloid,
and its congeners, contains the cis-3a-aryloctahydroindole
nucleus (Figure 1) and has been a popular synthetic target
Having previously achieved the racemic synthesis of
mesembrane 3,6b we considered the asymmetric synthesis of
this group of alkaloids, in specifically targeting the synthesis of
mesembrine 1. We anticipated that a double reduction reaction
of 8 would give access to the naturally occurring alkaloid. In
turn a diastereo- and regioselective intramolecular Heck
reaction performed on trisubstituted alkene 9 would afford
cyclic sulfonamide 8. It was envisaged that 9 could be
assembled as a single enantiomer from the monoterpenoid,
(S)-perillyl alcohol 108 which will constitute both the source of
asymmetry and the cyclohexyl ring (Scheme 1).
Scheme 1. Retrosynthetic Analysis
Figure 1. cis-3a-Aryloctahydroindole containing alkaloids.
for several decades.3 The main challenge in the synthesis of
these alkaloids is the controlled construction of the sterically
hindered, benzylic, quaternary stereogenic center.4 Another
attractive feature of this target is that the Sceletium alkaloids are
closely structurally related to the Amaryllidaceae alkaloids, such
as pretazettine (4) and the crinane-type alkaloids (e.g.,
saturated 5 and unsaturated 6).5 Additionally, more complex
compounds such as strychnine 7 also have embeded within
their structure a cis-3a-aryloctahydroindole motif.
For several years, we6 have studied the synthesis of cyclic
sulfonamides.7 Our primary motivation for this interest is that
Received: January 16, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
As outlined in Scheme 2, the starting point of the synthesis
was conversion of the commercially available (S)-perillyl
features regarding this cyclization deserve mention. First, the
regiochemical outcome of this Heck reaction is unusual, i.e., the
selective formation of a quaternary center from an unbiased
system, in terms of the size of the newly formed ring. Carbon−
carbon bond formation at either carbon 3 or 3a in 17 would
proceed via a 6-exo-trig mode of cyclization.16 Second, using
this process installation of the quaternary benzylic bond
(presented by the alkaloids in Figure 1) was achieved in a
stereoselective manner, governed by the stereogenic carbon-7a
set following the Overman rearrangement.
Scheme 2. Synthesis of Heck Precursor 17
After serving as a nonparticipating bystander in the RCM and
Heck process, our next challenge was to consider the
conversion of the isopropenyl group in 18 into a functional
group that could ultimately become the group present in the
target natural products (+)-1 and (+)-2.
Gratifyingly, a chemoselective epoxidation of the exocyclic
alkene proceeded smoothly with a slight excess of meta-
chloroperbenzoic acid (m-CPBA), with the endocyclic alkene
remaining unchanged (Scheme 4). The epoxide (not shown),
formed as a mixture of diastereoisomers, was then directly
treated with periodic acid (H5IO6) in a THF−H2O mixture,
which, following ring opening and oxidative cleavage of the
resultant 1,2-diol, gave the methyl ketone 19 (86% from 18).17
Subsequent hydrogenation of the remaining double bond
yielded the saturated cyclic sulfonamide 20 in quantitative yield.
Now we were in a position to employ a Baeyer−Villiger
oxidation reaction18 to install an oxygen atom at C-6. Although
this reaction proved sluggish, after some optimization, acetate
21 was obtained in 67% yield when 3 equiv of m-CPBA were
used in a deuterated solvent mixture (CDCl3−D2O; 1:1),
alcohol 10 into the corresponding trichloroacetimidate 11.9
An Overman rearrangement10 was effected on heating imidate
11 to reflux in dry toluene for 5 days, which afforded
trichloroacetamide 12 in 97% yield after purification as a 9:1
ratio of diastereoisomers; the major diastereomer contains the
correct stereochemistry for (+)-mesembrine (unnatural enan-
tiomer).11 Presumably the diastereoselectivity observed in this
[3,3]-sigmatropic rearrangement arises from a pseudo-axial
carbon−nitrogen bond formation from a conformer in which
the isopropenyl substituent occupies a pseudo-equatorial
position. The two diastereomers of 12 proved inseparable by
column chromatography at this stage. Thus, the mixture of
acetamides was cleaved under basic conditions (ethanolic
aqueous NaOH)12 to generate a mixture of diastereomeric
primary amines, which, due to volatility,13 were directly
converted into the corresponding sulfonamide with 2-bromo-
4,5-dimethoxybenzenesulfonyl chloride 13. At this point
chromatographic separation of diastereomers was possible
and the crystalline sulfonamide 14 was isolated (96% in two
steps from 12, based on 13). X-ray crystallography indicated
that the diastereoisomer necessary for the synthesis of (+)-1
had indeed been obtained.14 Subsequent alkylation with allyl
bromide, utilizing NaH as a base, followed by a ring-closing
metathesis (RCM) reaction in the presence of catalytic
amounts of Hoveyda−Grubbs second Generation catalyst 16,
efficiently generated the desired N-sulfonyldihydropyrrole
compound 17 in near-quantitative yield with no interference
from the isopropenyl olefin (Scheme 2).
1
enabling reaction monitoring by H NMR spectroscopy.
Our earlier work on the double reduction reaction had
shown that, using lithium, or sodium metal in liquid ammonia,
partial loss of the para-methoxy group to the sulfonyl moiety
takes place.6a,19 Thus, when we subjected sulfonamide 21 to
lithium (20 equiv) in liquid ammonia, we isolated, following
aqueous workup, appoximately a 1:1 mixture of mono- and
dimethoxy substituted amino alcohols. During this reaction, in
addition to the reductive sulfonyl excision, ammonia also
facilitated a deacetylation process to reveal the secondary
alcohol.
The crude mixture of amino alcohols was then submitted to
benzyl chloroformate (CbzCl) in CH2Cl2 with potassium
carbonate. This afforded carbamates 23 (23%) and 22 (28%),
which proved readily separable by flash column chromatog-
raphy. Although the reduction in yield associated with the
partial methoxy cleavage was detrimental in relation to the
synthesis of (+)-1, the monomethoxy side product is
synthetically useful since other alkaloids belonging to the
Sceletium family (for example, (+)-dihydro-O-methylscelete-
none and joubertiamine) possess this type of aromatic
substitution.20
With Heck precursor 17 in hand we turned our attention to
the planned intramolecular Mizoroki−Heck cyclization
(Scheme 3).15 Pleasingly, using standard conditions, formation
of cyclic sulfonamide 18 took place in 91% isolated yield. Two
Previously,6b we have reduced the Cbz-protecting group
strategically to reveal a methyl group on the nitrogen atom.21
Thus, when compound 23 was treated with lithium aluminum
hydride the N-methyl-amino alcohol 2 was obtained in
moderate yield. This amino alcohol 2 is in fact the enantiomer
of the naturally occurring alkaloid mesembranol,22 which is also
a known intermediate3i on route to the target molecule
mesembrine. To complete the synthesis of (+)-1 an oxidation
of the secondary alcohol in (+)-mesembranol was carried out.
In our hands, despite numerous attempts and different
conditions,23 the optimum conditions proved to be pyridinium
Scheme 3. Regio- and Diastereoselective Mizoroki−Heck
Reaction of 17
B
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The Journal of Organic Chemistry
Note
Scheme 4. Conversion of 18 to 21, Its Double Reduction, and the Synthesis of (+)-Mesembrine 1 and (+)-Mesembranol 2
and trichloroacetonitrile (0.98 mL, 9.87 mmol, 1.5 equiv) were added
sequentially. Stirring was continued for 2 h during which period room
temperature was reached. The reaction mixture was then filtered
through a plug of silica washing with CH2Cl2, and the filtrate was
concentrated in vacuo to give the imidate (1.92 g, 99%) as an orange
liquid. The thus obtained imidate 11 was used without further
purification. 1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 1H, NH), 5.89−
5.81 (m, 1H, CH), 4.77−4.69 (m, 2H, CH2), 4.68 (s, 2H, CH2), 2.24−
2.19 (m, 1H, CH), 2.20−2.13 (m, 3H, CH2), 2.06−1.97 (m, 1H,
CH2), 1.87 (m, 1H, CH2), 1.74 (s, 3H, CH3), 1.58−1.46 (m, 1H,
CH2); 13C NMR (CDCl3, 100 MHz): δ 162.9 (C), 149.7 (C), 132.4
(C), 126.2 (CH), 108.9 (CH2), 91.8 (C), 73.3 (CH2), 40.9 (CH), 30.6
(CH2), 27.5 (CH2), 26.4 (CH2), 20.98 (CH3).
dichromate (PDC) in anhydrous CH2Cl2, which gave (+)-1 in
48% yield with data consistent to those reported in the
literature.3f The Wolff−Kishner reduction of mesembrine (1)
has been reported to generate mesembrane (3).24
In conclusion, we have reported the stereoselective, total
synthesis of (+)-1, (+)-2 from the inexpensive, chiral alcohol
(S)-perillyl alcohol 10. During this synthesis the sulfonamide
functional group and the benzyl carbamate groups were both
used in strategic bond formation reactions, which therefore did
not require nonproductive, additional deprotection steps. The
partial methoxy cleavage observed, following the double
reduction, enables the access of monomethoxy members of
the Sceletium alkaloid family.20 Based on the route developed,
the natural enantiomer of mesembrine would be accessible
using noncommercially available (R)-(+)-perillyl alcohol, which
can be prepared by a biotransformation.8b It is additionally
notable that certain members of the Amaryllidaceae family of
natural products exhibit alternate stereochemistry to that found
in the Sceletium family (e.g., 6, Figure 1).5b,25
2,2,2-Trichloro-N-((1R,5S)-2-methylene-5-(prop-1-en-2-yl)-
cyclohexyl)acetamide 12. A solution of imidate 11 (1.9 g, 6.42
mmol) in anhydrous toluene (60 mL) was heated to reflux for 5 days
(oil bath temperature 130 °C). Once cooled, the mixture was
concentrated under pressure to give a brown oil, which was flushed
through a pad of silica (c-Hex/EtOAc, 3:1) to afford acetamide 12
(1.85 g, 97%) as a golden yellow liquid. Rf = 0.6 (c-Hex/EtOAc, 3:1);
20
[α]D = +40.3 (c = 2.0, CHCl3); IR (KBr, dep. from CH2Cl2) 3435,
3369, 3083, 2939, 2858, 1708, 1645, 1504, 893, 821 cm−1; HRMS
(ESI): calcd for C12H17NO35Cl3 ([M + H]+): 296.0376, found
EXPERIMENTAL SECTION
■
1
296.0365; H NMR (CDCl3, 500 MHz): δ 6.85−6.72 (m, 1H, NH),
General Directions. Reagents were obtained from commercial
suppliers and were used without further purification. Anhydrous
dimethylformamide (DMF) and toluene (PhMe) were used as
supplied and stored under an inert gas at room temperature.
Anhydrous tetrahydrofuran (THF) was distilled under nitrogen from
the sodium-benzophenone ketyl radical. Dichloromethane was
distilled, under nitrogen, from CaH2. Thin-layer chromatography
was performed on silica coated aluminum sheets (60 F254). Flash
column chromatography was performed under moderate pressure
4.97 (s, 1H, CH2), 4.89 (s, 1H, CH2), 4.78 (s, 1H, CH2), 4.76 (s, 1H,
CH2), 4.55 (dt, J = 8.0, 4.5 Hz, 1H, CH), 2.35 (dt, J = 14.0, 4.5 Hz,
1H, CH2), 2.25−2.19 (m, 2H, CH/CH2), 2.03 (m, 1H, CH2), 1.85
(m, 1H, CH2), 1.72 (s, 4H, CH2/CH3), 1.47 (m, 1H, CH2); 13C NMR
(CDCl3, 125 MHz): δ 160.6 (CO), 147.5 (C), 144.6 (C), 111.9
(CH2), 110.1 (CH2), 92.9 (C), 53.5 (CH), 39.4 (CH), 36.1 (CH2),
31.7 (CH2), 30.7 (CH2), 21.1 (CH3).
2-Bromo-4,5-dimethoxy-N-((1R,5S)-2-methylene-5-(prop-1-
en-2-yl)cyclohexyl)benzene Sulfonamide 14. A solution of 12
(2.20 g, 7.46 mmol) in EtOH−CH2Cl2 (2:1, 12 mL) was treated with
5 M NaOH (5 mL), and the reaction was heated to 50 °C for 15 h.12
Once the reaction cooled, CH2Cl2 (20 mL) was added and the organic
layer was washed with brine (1 × 20 mL), dried (MgSO4), and filtered.
The crude amine−CH2Cl2 solution was treated with 2-bromo-4,5-
dimethoxybenzene-1-sulfonyl chloride 13 (1.78 g, 5.64 mmol, 0.76
equiv) and Et3N (0.9 mL, 6.77 mmol, 1.2 equiv) at 0 °C. Stirring was
continued for 5 h, and the reaction gradually warmed to room
temperature. The reaction mixture was washed once with H2O, and
the organic layer was dried over MgSO4. The crude product, obtained
after solvent removal and filtration, was purified by column
chromatography (c-Hex/EtOAc, 6:1) which gave the title compound
14 (2.30 g, 96% - based on 13) as a light yellow solid. Rf = 0.3 (c-Hex/
using flash silica 60 Å (230−400 mesh). H and 13C NMR spectra
were recorded using 300, 400, and 500 MHz instruments as indicated.
Reported assignments are based on two-dimensional 1H−1H and
1H−13C spectra. Deuterochloroform was used as the solvent, and
1
chemical shifts are given in ppm relative to the standard reference
tetramethylsilane, or residual chloroform. Samples for infrared
spectroscopy were recorded as films on KBr plates using an FT-IR
spectrometer. Optical rotation measurements were recorded at 589
nm, 25 °C and are quoted in units of 10−1 deg cm2 g−1. Melting points
are uncorrected and were recorded on recrystallized material (from
indicated solvent), or material directly obtained following purification
by flash column chromatography. High resolution mass spectra (ESI-
HRMS) were obtained using a mass spectrometer with a TOF mass
analyzer.
20
EtOAc, 3:1); Mp 100−102 °C; [α]D = +62.5 (c = 2.0, CHCl3); IR
(S)-(4-(Prop-1-en-2-yl)cyclohex-1-enyl)methyl 2,2,2-Trichlor-
oacetimidate 11. A solution of 10 (1.04 mL, 6.58 mmol, 1 equiv) in
anhydrous CH2Cl2 (30 mL) was cooled to 0 °C. 1,8-
Diazabicyloc[5.4.0]undec-7-ene26 (1.17 mL, 7.9 mmol, 1.2 equiv)
(KBr, dep. from CH2Cl2) 3081, 2937, 1464, 1360, 1331, 1161, 1132,
690 cm−1; HRMS (ESI): calcd for C18H24NO4S79BrNa ([M + Na]+):
1
452.0507, found 452.0515; H NMR (CDCl3, 400 MHz): δ 7.56 (s,
C
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The Journal of Organic Chemistry
Note
1H, ArH), 7.09 (s, 1H, ArH), 5.34 (d, J = 6.0 Hz, 1H, NH), 4.71−4.64
(m, 1H, CH2), 4.65−4.57 (m, 2H, CH2), 4.53 (s, 1H, CH2), 3.91 (s,
3H, CH3), 3.89 (s, 4H, CH3/CH), 2.28 (tt, J = 12.0, 3.0 Hz, 1H, CH),
2.19−2.09 (m, 2H, CH2), 1.93 (dq, J = 13.5, 3.0 Hz, 1H, CH2), 1.83−
1.74 (m, 1H, CH2), 1.63 (s, 3H, CH3), 1.50−1.41 (m, 1H, CH2), 1.25
(td, J = 12.0, 5.0 Hz, 1H, CH2); 13C NMR (CDCl3, 100 MHz): δ
152.3 (C), 148.3 (C), 147.9 (C), 145.2 (C), 131.2 (C), 116.9 (CH),
114.2 (CH), 111.6 (CH), 111.5 (CH2), 109.6 (CH2), 56.6 (CH), 56.5
(CH3), 56.4 (CH3), 38.9 (CH), 37.9 (CH2), 32.2 (CH2), 30.4 (CH2),
20.9 (CH3).
further extracted with EtOAc (2 × 10 mL), and the combined organic
extracts were dried over MgSO4. Filtration followed by solvent
removal under reduced pressure gave the crude product which was
purified by flash column chromatography (c-Hex/EtOAc, 6:1→4:1)
affording the Heck product 18 (79 mg, 91%) as a colorless solid. Rf =
20
0.3 (c-Hex/EtOAc, 2:1); Mp 63−66 °C; [α]D = +10 (c = 0.5,
CHCl3); IR (KBr, dep. from CH2Cl2) 2920, 1562, 1470, 1361, 1334,
1146 cm−1; HRMS (ESI): calcd for C19H23NO4SNa ([M + Na]+):
1
384.1245, found 384.1245; H NMR (CDCl3, 300 MHz): δ 7.16 (s,
1H, ArH), 6.64 (s, 1H, ArH), 6.23 (d, J = 3.5 Hz, 1H, CH), 6.16 (d, J
= 3.5 Hz, 1H, CH), 4.94 (s, 1H, CH2), 4.90 (s, 1H, CH2), 4.74 (dd, J
= 11.0, 6.0 Hz, 1H, CH), 3.90 (s, 3H, CH3), 3.88 (s, 3H, CH3), 2.48
(s, 1H, CH), 2.46−2.39 (m, 1H, CH2), 2.16−2.12 (m, 2H, CH2),
2.11−2.05 (m, 1H, CH2), 1.98−1.90 (m, 1H, CH2), 1.75 (s, 3H,
CH3), 1.69−1.65 (m, 1H, CH2); 13C NMR (CDCl3, 75 MHz): δ
151.1 (C), 149.6 (C), 144.5 (C), 138.7 (C), 138.3 (CH), 132.5 (CH),
125.1 (C), 112.6 (CH2), 109.4 (CH), 105.3 (CH), 69.7 (CH), 56.4
(CH3), 56.3 (CH3), 48.4 (C), 37.3 (CH), 29.4 (CH2), 23.2 (CH2),
22.8 (CH2), 22.5 (CH3).
N-Allyl-2-bromo-4,5-dimethoxy-N-((1R,5S)-2-methylene-5-
(prop-1-en-2-yl)cyclohexyl)benzene Sulfonamide 15. A solution
of 14 (150 mg, 0.35 mmol) dissolved in DMF (4 mL) was cooled to 0
°C. Sodium hydride (60% w/w in mineral oil, 22 mg, 0.525 mmol, 1.5
equiv) was added, and the mixture was stirred for 0.5 h. Allyl bromide
(0.04 mL, 0.42 mmol, 1.2 equiv) was added in a dropwise fashion.
Stirring was continued for 15 h during which period room temperature
was reached. EtOAc (10 mL) and H2O (10 mL) were added, and the
phases were separated. The aqueous layer was further extracted with
EtOAc (2 × 10 mL), and the combined organic layers were dried over
MgSO4. The crude product, obtained after filtration and solvent
removal, was purified by column chromatography (c-Hex/EtOAc, 6:1)
to yield the title compound 15 (152 mg, 93%) as a white solid. Rf = 0.5
(c-Hex/EtOAc, 3:1); Mp 78−80 °C; [α]D20 = −8.8 (c = 0.8, CHCl3);
IR (KBr, dep. from CH2Cl2) 2846, 1584, 1503, 1437, 1360, 1330,
1158, 1116, 598 cm−1; HRMS (ESI): calcd for C21H29NO4S79Br ([M
(2S,4aR,10aS)-2-Acetyl-6,7-dimethoxy-4a,10-etheno-
2,3,4,4a,10,10a-hexahydro-1H-9-thia-10-aza-phenanthrene
9,9-dioxide 19. A solution of 18 (296 mg, 0.819 mmol, 1 equiv)
dissolved in CH2Cl2 (10 mL) was treated with m-CPBA (77% w/w,
275 mg, 1.23 mmol, 1.5 equiv) at room temperature. After 15 h,
sodium sulfite sat. (10 mL) and NaHCO3 sat. (10 mL) were added
and the reaction mixture was allowed to stir for 0.5 h, after which the
phases were separated. The aqueous layer was extracted with CH2Cl2
(20 mL), dried over MgSO4, and reduced under pressure to afford the
crude epoxide. The crude epoxide dissolved in THF−H2O (2:1, 12
mL) was treated to H5IO6 (446 mg, 1.64 mmol, 2 equiv) at 0 °C.
Stirring was continued for 15 h during which period room temperature
was reached. Et2O (20 mL) and H2O (15 mL) were added, and the
phases separated. The resultant aqueous layer was further extracted
with Et2O (2 × 20 mL), and the combined organic extracts were dried
over MgSO4. Filtration followed by solvent removal under reduced
pressure gave the crude product which was purified by flash column
chromatography (c-Hex/EtOAc, 2:1→1:2) affording the title com-
pound 19 (255 mg, 86%) as a white solid. Rf = 0.1 (c-Hex/EtOAc,
1
+ H]+): 470.1001, found 470.0986; H NMR (CDCl3, 400 MHz): δ
7.57 (s, 1H, ArH), 7.08 (s, 1H, ArH), 5.87 (ddt, J = 16.5, 10.5, 6.0 Hz,
1H, CH), 5.18 (d, J = 17.0 Hz, 1H, CH2), 5.09 (d, J = 11.0 Hz, 1H,
CH2), 4.84 (s, 1H, CH2), 4.81−4.76 (m, 2H, CH2), 4.72 (s, 1H, CH2),
4.51 (dd, J = 8.5, 4.5 Hz, 1H, CH), 4.19 (ddt, J = 17.0, 6.0, 1.5 Hz, 1H,
CH2), 4.03 (ddt, J = 17.0, 6.0, 1.5 Hz, 1H, CH2), 3.91 (s, 3H, CH3),
3.87 (s, 3H, CH3), 2.24−2.18 (m, 1H, CH), 2.10−2.04 (m, 2H, CH2),
2.02−1.95 (m, 2H, CH2), 1.64 (s, 3H, CH3), 1.60−1.57 (m, 2H,
CH2); 13C NMR (CDCl3, 100 MHz): δ 152.1 (C), 147.7 (C), 146.7
(C), 145.9 (C), 135.9 (CH), 132.5 (C), 117.3 (CH2), 117.2 (CH),
114.9 (CH), 112.3 (C), 110.8 (CH), 110.6 (CH), 58.6 (CH), 56.6
(CH3), 56.5 (CH3), 48.9 (CH2), 39.5 (CH), 35.3 (CH2), 31.2 (CH2),
30.5 (CH2), 21.9 (CH3).
20
1:1); Mp 78−81 °C; [α]D = −5.7 (c = 1.4, CHCl3); IR (KBr, dep.
from CH2Cl2) 2945, 2854, 1705, 1599, 1352, 1330, 1158, 1149 cm−1;
HRMS (ESI): calcd for C18H21NO5SNa ([M + Na]+): 386.1038,
(6S,7aR)-1-(2-Bromo-4,5-dimethoxyphenylsulfonyl)-6-
(prop-1-en-2-yl)-2,4,5,6,7,7a-hexahydro-1H-indole 17. Under
N2, a degassed solution of 15 (500 mg, 1.06 mmol, 1 equiv) in
CH2Cl2 (40 mL) was treated with Hoveyda−Grubbs second
generation catalyst 16 (20 mg, 0.0321 mmol, 3 mol %). Stirring was
continued at 40 °C for 15 h. Once cooled, the solvent was removed
under reduced pressure. Purification by flash column chromatography
(c-Hex/EtOAc, 6:1) gave 17 (450 mg, 96%) as a viscous oil. Rf = 0.4
1
found 386.1039; H NMR (CDCl3, 400 MHz): δ 7.11 (s, 1H, ArH),
6.58 (s, 1H, ArH), 6.18 (d, J = 3.5 Hz, 1H, CH), 6.13 (d, J = 3.5 Hz,
1H, CH), 4.82 (dd, J = 10.5, 6.5 Hz, 1H, CH), 3.86 (s, 3H, CH3), 3.85
(s, 3H, CH3), 2.82 (s, 1H, CH), 2.41 (dd, J = 14.0, 6.5 Hz, 1H, CH2),
2.26−2.23 (m, 2H, CH2), 2.16 (s, 3H, CH3), 1.81−1.73 (m, 1H,
CH2), 1.72−1.65 (m, 2H, CH2); 13C NMR (CDCl3, 150 MHz): δ
210.1 (C), 151.0 (C), 149.6 (C), 138.2 (C), 137.7 (CH), 132.6 (CH),
125.0 (C), 109.3 (CH), 105.3 (CH), 69.5 (CH), 56.3 (CH3), 56.2
(CH3), 48.0 (C), 45.4 (CH), 28.1 (CH3), 27.6 (CH2), 23.7 (CH2),
22.4 (CH2).
20
(c-Hex/EtOAc, 3:1); [α]D = +1.6 (c = 1.1, CHCl3); IR (KBr, dep.
from CH2Cl2) 2872, 1585, 1503, 1465, 1439, 1360, 1330, 1158, 1116
cm−1; HRMS (ESI): calcd for C19H25NO4S79Br ([M + H]+):
1
442.0688, found 442.0706; H NMR (CDCl3, 400 MHz): δ 7.55 (s,
1H, ArH), 7.13 (s, 1H, ArH), 5.23 (s, 1H, CH), 4.89 (s, 1H, CH2),
4.81 (s, 1H, CH2), 4.48−4.42 (m, 1H, CH), 4.34−4.29 (m, 1H, CH2),
4.21−4.15 (m, 1H, CH2), 3.91 (s, 3H, CH3), 3.88 (s, 3H, CH3), 2.45−
2.44 (m, 1H, CH2), 2.41 (s, 1H, CH), 2.32−2.26 (m, 1H, CH2), 2.19−
2.12 (m, 1H, CH2), 2.09−2.04 (m, 1H, CH2), 1.71 (s, 3H, CH3),
1.52−1.42 (m, 2H, CH2); 13C NMR (CDCl3, 150 MHz): δ 152.0 (C),
147.7 (C), 144.9 (C), 141.9 (C), 130.8 (C), 117.6 (CH), 113.9 (CH),
113.5 (CH), 112.1 (C), 111.4 (CH2), 62.8 (CH), 56.4 (CH3), 56.3
(CH3), 55.0 (CH2), 38.5 (CH), 36.8 (CH2), 28.3 (CH2), 24.3 (CH2),
22.6 (CH3).
(2S,4aR,10aS)-6,7-Dimethoxy-4a,10-etheno-2,3,4,4a,10,10a-
hexahydro-1H-2-isopropenyl-9-thia-10-aza-phenanthrene 9,9-
dioxide 18. Under N2, a solution of 17 (105 mg, 0.24 mmol, 1 equiv)
dissolved in DMF (2 mL) was degassed under a steady stream of
nitrogen (ca. 0.5 h). To this solution was added Pd(OAc)2 (6 mg,
0.024 mmol, 10 mol %), PPh3 (12 mg, 0.048 mmol, 20 mol %), and
K2CO3 (66 mg, 0.48 mmol, 2 equiv), and the mixture was heated to
110 °C for 15 h. The reaction vessel was cooled, and EtOAc (10 mL)
and H2O (10 mL) were added. The resultant aqueous layer was
(2S,4aR,10aS)-2-Acetyl-6,7-dimethoxy-4a,10-ethano-
2,3,4,4a,10,10a-hexahydro-1H-9-thia-10-aza-phenanthrene
9,9-dioxide 20. A mixture of 19 (300 mg, 0.826 mmol, 1 equiv) and
10% w/w Pd/C (9 mg, 0.083 mmol) in EtOAc (20 mL) was stirred
under an atmosphere of hydrogen (1 atm) for 19 h. The mixture was
filtered through Celite (washed with EtOAc 3 × 20 mL), and solvent
removal under reduced pressure afforded the alkane compound 20
(295 mg, 98%) as an oil. Rf = 0.1 (c-Hex/EtOAc, 1:1); [α]D20 = −5.4
(c = 3.7, CHCl3); IR (KBr, dep. from CH2Cl2) 2981, 1703, 1601,
1321, 1156 cm−1; HRMS (EI): calcd for C18H23NO5S ([M]+):
1
365.1297, found 365.1306; H NMR (CDCl3, 400 MHz): δ 7.20 (s,
1H, ArH), 6.69 (s, 1H, ArH), 4.28 (dd, J = 12.0, 5.5 Hz, 1H, CH), 3.92
(s, 3H, CH3), 3.90 (s, 3H, CH3), 3.87−3.81 (m, 1H, CH2), 3.59 (ddd,
J = 14.0, 10.0, 4.0 Hz, 1H, CH2), 2.83 (s, 1H, CH), 2.36−2.39 (m, 3H,
CH2), 2.28−2.20 (m, 1H, CH2), 2.18 (s, 3H, CH3), 1.95−1.87 (m,
1H, CH2), 1.82 (ddt, J = 18.5, 9.0, 4.5 Hz, 1H, CH2), 1.70 (ddd, J =
13.0, 9.5, 4.0 Hz, 1H, CH2), 1.64−1.55 (m, 1H, CH2); 13C NMR
(CDCl3, 150 MHz): δ 209.6 (C), 152.4 (C), 148.7 (C), 139.4 (C),
126.9 (C), 108.0 (CH), 106.1 (CH), 64.3 (CH), 56.3 (CH3), 56.2
D
dx.doi.org/10.1021/jo4000306 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
(CH3), 45.9 (CH2), 45.7 (CH), 44.3 (C), 33.3 (CH2), 28.1 (CH3),
27.6 (CH2), 25.4 (CH2), 21.6 (CH2).
for C17H26NO3 ([M + H]+): 292.1913, found 292.1906; H NMR
(CDCl3, 400 MHz): δ 6.91−6.77 (m, 2H, ArH), 6.82−6.79 (m, 1H,
ArH), 4.01 (m, 1H, CH), 3.88 (s, 3H, CH3), 3.86 (s, 3H, CH3), 3.30−
3.23 (m, 1H, CH2), 2.80 (s, 1H, CH), 2.38 (s, 3H, CH3), 2.34−2.30
(m, 1H, CH2), 2.21−2.16 (m, 1H, CH2), 2.04 (dd, J = 8.0, 3.0 Hz, 2H,
CH2), 1.97−1.87 (m, 1H, CH2), 1.86−1.82 (m, 1H, CH2), 1.80−1.71
(m, 1H, CH2), 1.59−1.49 (m, 1H, CH2), 1.25−1.16 (m, 1H, CH2);
13C NMR (CDCl3, 150 MHz): δ 148.9 (C), 147.2 (C), 139.0 (C),
(2S,4aR,10aS)-2-Acetoxy-6,7-dimethoxy-4a,10-ethano-
2,3,4,4a,10,10a-hexahydro-1H-9-thia-10-aza-phenanthrene
9,9-dioxide 21. A solution of ketone 20 (120 mg, 0.329 mmol, 1
equiv) dissolved in CDCl3−D2O (2.0 mL, 1:1) was treated with m-
CPBA 77% pure (221 mg, 0.986 mmol, 3 equiv) at room temperature.
The reaction was periodically monitored by 1H NMR until all starting
material was consumed (after approximately 48 h). Sodium sulfite sat.
(5 mL) and NaHCO3 sat. (5 mL) were added, and the reaction
mixture was allowed to stir for 0.5 h, after which the phases were
separated. The aqueous layer was extracted with CH2Cl2 (2 × 10 mL),
dried over MgSO4, and reduced under pressure to afford the crude
acetate which was purified by flash column chromatography (c-Hex/
118.9 (CH), 111.0 (CH), 110.6 (CH), 70.2 (CH), 66.7 (CH), 56.1
(CH3), 56.0 (CH3), 54.4 (CH2), 47.3 (C), 40.7 (CH2), 40.2 (CH2),
34.9 (CH2), 33.1 (CH2), 32.8 (CH2).
(+)-Mesembrine [(3aR,7aR)-3a-(3,4-Dimethoxyphenyl)-1-
methylhexahydro-1H-indol-6(2H)-one] 1. Under N2, a solution
of 2 (6 mg, 0.02 mmol, 1 equiv) dissolved in anhydrous CH2Cl2 (5
mL) was treated with PDC (23 mg, 0.062 mmol, 3 equiv). The
reaction mixture was allowed to stir at room temperature for 2 h. A
solution of 0.1 M NaOH (2 mL) was added, and the reaction was
allowed to stir for an additional 2 h before the addition of CH2Cl2 (10
mL). The organic layer was washed with H2O (10 mL), and the phases
were separated. The organic layer was further extracted with CH2Cl2
(3 × 10 mL), and the combined organic layers were dried over
MgSO4, filtered, and reduced under pressure. Purification by column
chromatography (CHCl3/Me2CO, 6:1) afforded the title compound as
a brown oil (6 mg, 48%). Rf = 0.2 (CHCl3/Me2CO, 6:1); [α]D20 = +43
(c = 0.8, MeOH) (+28.2 (c = 2.8, CHCl3)) lit. +53 (c = 0.53,
MeOH),3f lit. −61.6 (c = 0.2, MeOH);3b IR (KBr, dep. from CH2Cl2)
1709, 1653, 1456 cm−1; HRMS (ESI): calcd for C17H24NO3 ([M +
EtOAc, 2:1→1:2) affording the title compound 21 (125 mg, 67%) as a
20
white solid. Rf = 0.5 (c-Hex/EtOAc, 1:2); Mp 110−113 °C; [α]D
=
−28.6 (c = 1.8, CHCl3); IR (KBr, dep. from CH2Cl2) 2956, 2849,
1729, 1160, 1567, 1509, 1331, 1322, 1159, 1130 cm−1; HRMS (ESI):
calcd for C18H23NO6SNa ([M + Na]+): 404.1144, found 404.1137; 1H
NMR (CDCl3, 400 MHz): δ 7.27 (s, 1H, ArH), 6.78 (s, 1H, ArH),
5.23 (s, 1H, CH), 4.39 (dd, J = 12.0, 5.5 Hz, 1H, CH), 3.94 (s, 3H,
CH3), 3.92 (s, 3H, CH3) 3.90−3.85 (m, 1H, CH2), 3.65−3.58 (m, 1H,
CH2), 2.37−2.29 (m, 3H, CH2), 2.18−2.13 (m, 1H, CH2), 2.05 (s,
1H, CH2), 2.03 (s, 3H, CH3), 1.81−1.78 (m, 1H, CH2), 1.77−1.73
(m, 1H, CH2), 1.59−1.52 (m, 1H, CH2); 13C NMR (CDCl3, 100
MHz): δ 170.4 (C), 152.5 (C), 148.8 (C), 139.1 (C), 126.9 (C),
108.03 (CH), 106.1 (CH), 68.4 (C), 63.9 (C), 56.4 (CH3), 56.2
(CH3), 45.9 (CH2), 44.1 (C), 33.1 (CH2), 30.7 (CH2), 24.8 (CH2),
23.8 (CH2), 21.4 (CH3).
H]+): 290.1756, found 290.1766; H NMR (CDCl3, 400 MHz): δ
1
6.95−6.87 (m, 2H, ArH), 6.84 (d, J = 8.5 Hz, 1H, ArH), 3.90 (s, 3H,
CH3), 3.88 (s, 3H, CH3), 3.14−3.11 (m, 1H, CH2), 2.96−2.92 (m,
1H, CH), 2.60 (s, 2H, CH2), 2.49−2.37 (m, 2H, CH2), 2.37−2.27 (m,
4H, CH2/CH3), 2.24−2.19 (m, 2H, CH2), 2.15−2.09 (m, 2H, CH2);
13C NMR (CDCl3, 100 MHz): δ 211.6 (CO), 149.2 (C), 147.7 (C),
140.4 (C), 118.1 (CH), 111.2 (CH), 110.1 (CH), 70.5 (CH), 56.2
(CH3), 56.1 (CH3), 55.0 (CH2), 47.7 (C), 46.7 (CH2), 40.2 (CH3),
39.0 (CH2), 36.4 (CH2), 35.4 (CH2).
(+)-Mesembranol [(3aR,6S,7aR)-3a-(3,4-Dimethoxyphenyl)-
1-methyloctahydro-1H-indol-6-ol] 2. Under N2, small pieces of
Li (32 mg, 4.57 mmol, 20 equiv) were added to NH3 (ca. 75 mL) at
−78 °C. The mixture was stirred for 1 h before a solution of 21 (87
mg, 0.228 mmol, 1 equiv) in THF (5 mL + 5 mL to wash flask) was
added in a dropwise fashion. Stirring was continued for 0.5 h at −78
°C before the addition of solid NH4Cl (ca. 2 g). The NH3 was allowed
to evaporate on warming to room temperature, and the residue was
dissolved in CH2Cl2 (15 mL). A 1 M solution of NaOH (to pH 12)
was added, and the resultant aqueous layer was further extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were dried over
MgSO4. Filtration followed by solvent removal under reduced pressure
afforded a separable mixture of 3a-(3,4-dimethoxyphenyl)-
octahydroindol-6-ol (LRMS (ESI): calcd for C16H24NO3 ([M +
H]+): found 278.17) and 3a-(4-methoxyphenyl)octahydroindol-6-ol
(LRMS (ESI): calcd for C15H22NO2 ([M + H]+): found 247.16). The
crude mixture was dissolved in CH2Cl2 (30 mL) and treated
subsequently with benzyl chloroformate (0.05 mL, 0.342 mmol, 1.5
equiv) and K2CO3 (315 mg, 2.28 mmol, 10 equiv). Stirring was
continued at room temperature for 4 h before the addition of H2O (30
mL), and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2 × 20 mL), and the combined layers were dried over
MgSO4. Following filtration and solvent removal, column chromatog-
raphy (c-Hex/EtOAc, 6:1→1:1) afforded 23 (22 mg, 23%) and 22 (24
mg, 28%); [(3aR,6S,7aR)-benzyl 3a-(3,4-dimethoxyphenyl)-6-hydrox-
yoctahydro-1H-indole-1-carboxylate 23: HRMS (ESI): calcd for
C23H27NO4Na ([M + Na]+): 404.1838, found 404.1853;
(3aR,6S,7aR)-benzyl 6-hydroxy-3a-(4-methoxyphenyl)octahydro-1H-
indole-1-carboxylate 22: HRMS (ESI): calcd for C24H29NO5Na ([M
+ Na]+): 434.1943, found 434.2012]. Under N2, a solution of 23 (52
mg, 0.127 mmol, 1 equiv) dissolved in anhydrous THF (4 mL) was
treated with LiAlH4 (15 mg, 0.38 mmol, 3 equiv). The reaction
mixture was heated to reflux for 3 h. Once cooled, EtOAc (10 mL) was
added followed by 1 M NaOH (1 mL). H2O (10 mL) was added, and
the phases were separated. The aqueous layer was further extracted
with EtOAc (3 × 10 mL), and the combined organic layers were dried
over MgSO4, filtered, and purified by column chromatography
(CHCl3/MeOH, 8:1) to afford the title compound 2 (9 mg, 57%)
as a light pink solid. Rf = 0.18 (CHCl3/MeOH, 8:1); Mp 111−114 °C;
[α]D20 = +25.2 (c = 0.7, CHCl3) lit. −24 (c = 0.2, CHCl3);22 IR (KBr,
dep. from CH2Cl2) 3355, 1655, 1454, 1410 cm−1; HRMS (ESI): calcd
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of proton and carbon NMR spectra and X-ray
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: paul.evans@ucd.ie.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank University College Dublin for financial
support and the National University of Ireland for an NUI
Travelling Studentship (K.G.). We also thank Dr. Helge
Muller-Bunz for X-ray crystallography. Membership (PE) of
̈
COST CM0804 is acknowledged.
REFERENCES
■
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F
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