Consecutive sigmatropic rearrangements in the enantioselective total synthesis of (-)-joubertinamine and (-)-mesembrine

Article abstract of DOI:10.1016/j.tet.2008.10.048

Joubertinamine and mesembrine are two related alkaloids isolated from Sceletium plants. From the perspective of chemical synthesis, the major challenge posed by joubertinamine and mesembrine is undoubtedly the construction of the benzylic quaternary stere

Full text of DOI:10.1016/j.tet.2008.10.048

Tetrahedron 65 (2009) 3261–3269
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Consecutive sigmatropic rearrangements in the enantioselective total synthesis
of (ꢀ)-joubertinamine and (ꢀ)-mesembrine
Elizabeth A. Ilardi, Michael J. Isaacman, Ying-chuan Qin, Sommer A. Shelly, Armen Zakarian
*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Joubertinamine and mesembrine are two related alkaloids isolated from Sceletium plants. From the
perspective of chemical synthesis, the major challenge posed by joubertinamine and mesembrine is
undoubtedly the construction of the benzylic quaternary stereogenic center. We became intrigued by
the prospect of applying successive sigmatropic rearrangements to build the key structural features of
these alkaloids in enantioselective manner. In this article, we detail our results in this area, which include
the enantioselective total synthesis of (ꢀ)-joubertinamine and (ꢀ)-mesembrine.
Received 15 September 2008
Received in revised form 14 October 2008
Accepted 16 October 2008
Available online 1 November 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Sigmatropic rearrangements
Sceletium alkaloids
Mesembrine
Joubertinamine
1. Introduction
case of mesembrine, several strategies have been employed for its
enantioselective formation. These include chiral auxiliary-based
Beneficial properties of plants of the Sceletium family have been
known for centuries to populations of the southern regions of
Africa, including the Khoikhoi and Sans peoples.1a Dried leaves of
Sceletium plants have been used widely in shamanic practices to
elevate mood and to alleviate anxiety and tension, and by shep-
herds as appetite suppressants during long journeys in arid areas.
These intriguing biological properties have been associated with
the presence of alkaloids like mesembrine and joubertinamine
(Fig. 1), which are found in Sceletium plants in significant concen-
trations. Mesembrine has been recently shown to be a potent
serotonin uptake inhibitor.1
Joubertinamine can be converted to mesembrine in one step by
oxidation with activated manganese(II) oxide through the in-
termediacy of the corresponding enone, which undergoes a spon-
taneous Michael cyclization to mesembrine.3f Although more than
a dozen of syntheses of mesembrine have been reported,2 some
enantioselective, only a few are amenable for the synthesis of
joubertinamine,3 and no enantioselective synthesis of joubertin-
amine has been described.
stereoselective alkylation,2f,m tandem [4þ2]/[3þ2] cycloaddition of
a nitroalkene,2g tandem epoxidation–ring expansion of cyclo-
propylidene alcohols,2j [2þ2]-cycloaddition of vinyl sulfoxides,2l
enantioselective Birch–Cope sequence,2a palladium catalyzed al-
lylic substitution followed by zirconium mediated cyclization,2h
asymmetric dihydroxylation of a 1-aryl-1-cyclohexene,2e,i opening
of aryl-substituted epoxides with Grignard reagents,2b an intra-
molecular cycloaddition of azomethine ylides,2k and a direct for-
mation and allylation of enamines.3g We became intrigued by the
prospect of applying successive sigmatropic rearrangements to
build the key structural features of these alkaloids in enantiose-
lective manner. In this article, we detail our results in this area,
which include the enantioselective total synthesis of both
(ꢀ)-joubertinamine and (ꢀ)-mesembrine.
OMe
OMe
OMe
OMe
From the perspective of chemical synthesis, the major challenge
posed by joubertinamine and mesembrine is undoubtedly the
construction of the benzyllic quaternary stereogenic center. In the
NH
N
Me
OH
(–)-joubertinamine
Figure 1.
O
H
(–)-mesembrine
* Corresponding author. Tel.: þ1 805 893 3717; fax: þ1 805 893 4120.
E-mail address: zakarian@chem.ucsb.edu (A. Zakarian).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.048

3262
E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
2. Results and discussion
stereocenter in compound 1.7 Alkylation of ester 6 with 1-iodo-3-
butene followed by the Sharpless asymmetric dihydroxylation de-
livered a mixture of diastereomers 8, which, as we established later,
corresponded to an unoptimized ee of about 55%. Lactonization to 9
occurred in 83% yield.
Rather than optimizing the dihydroxylation reaction, we mod-
ified our strategy as shown in Scheme 4. Known iodide 11 was
prepared in two steps and in 88% overall yield from commercially
available (S)-1,2,4-butanetriol,8 and used to alkylate the zinc-ate
enolate generated from ester 10. Using Noyori’s protocol, ester 12
was formed in 96% yield.9 The yield with the corresponding lithium
enolate was w50%. Subsequent removal of the acetonide and lac-
tonization occurred upon exposure of ethyl ester 12 to a mixture of
THF and 2 M hydrochloric acid.
2.1. General synthesis plan
Our analysis of the cyclohexenol substructure of joubertinamine
led us to consider a tandem [3,3]/[2,3]-sigmatropic reorganization
of sulfinylvinyl dihydropyran 1 (Scheme 1). Under the conditions
required for the initial Claisen rearrangement of 1, the resulting
allylic sulfoxide (2) is expected to undergo a Mislow–Evans rear-
rangement to cyclohexenol 3 with complete diastereocontrol.
OMe
OMe
MeO
OMe
Silylation of the lactone delivered 13 in 87% overall yield. Re-
duction of the lactone to lactol and dehydration (MsCl, Et3N)
afforded dihydropyran 14. The sulfinylvinyl substituent was
appended in four steps after desilylation. Thus, oxidation to the
aldehyde, addition of the lithiated (S)-methyl p-tolyl sulfoxide,
silylation, and elimination upon treatment with LDA provided 16.
The diastereomer at the sulfinyl center (17) was prepared analo-
gously employing (R)-methyl p-tolyl sulfoxide in 49% overall yield
from 15.
The tandem Claisen–Mislow–Evans rearrangements of 16 and
17 were attempted next. We have discovered that, in contrast to 4,
these substrates do not undergo the rearrangement at tempera-
tures up to 150 ꢁC (Scheme 5). Only the starting material was re-
covered. At higher temperatures, decomposition was observed.
Presently, the reasons for the difference in reactivity comparing
to sulfoxide 4 are unclear, and after extensive attempts to improve
the outcome of the tandem rearrangement we opted to modify our
approach.
O
NH
R
OH
S
1
joubertinamine
O
[3,3]-sigma-
tropic shift
R = Ph or tolyl
OMe
OMe
OMe
OMe
[2,3]-sigma-
tropic shift
O
P(OMe)3
O
S
OH
R
O
3
2
Scheme 1. General outline of the synthesis plan.
The basis for this key element of our synthesis plan was pro-
vided by our earlier work directed at the synthesis of a marine
natural product (þ)-pinnatoxin A.4 We developed a similar process,
efficiently converting a more complex sulfinylvinyl dihydropyran
(4) to cyclohexenol 5 in high yield (Scheme 2).5 A tight, highly or-
ganized transition structure required for the Claisen rearrangement
of vinyl dihydropyrans ensured complete diastereoselectivity dur-
ing the formation of the quaternary stereocenter and the tertiary
alcohol.6
2.3. Consecutive sigmatropic rearrangements using vinyl
sulfides
We next explored the Claisen rearrangement of vinyl sulfides
related to sulfoxides 16 and 17. The substrates were prepared using
a Wittig olefination as illustrated in Scheme 6.
The Wittig reaction produced a mixture of E- and Z-isomer, and,
as can be seen in Table 1, the Z-isomer is the major product under all
conditions we employed. In a polar solvent (THF–DMPU) with
a weakly coordinating counterion (KHMDS), a 70:30 inseparable
mixture of Z- and E-vinyl sulfides 18 was obtained in 95% yield over
two steps. Without DMPU as an additive, the Z/E-selectivity was
increased to 82%. In a non-polar solvent (toluene) with a more
coordinating counterion (NaHMDS), 78% of the Z-isomer was
formed along with 22% of the E-isomer. Thus, our brief survey of the
reaction conditions revealed that there appears to be only a slight
effect of the nature of solvent or base on the stereoselectivity of the
olefination without any discernable pattern.
In comparison with the known example, the differences in the
planned transformation of 1 to 3 include (a) a lack of substitution at
positions 2 and 6 of the dihydropyran ring system and (b) an
electron-rich aromatic substituent in the place of b-branched alkyl
group at position 3. In order to determine the effect of the changes
on the tandem rearrangement, we set out to prepare vinyl sulfoxide
1 and its diastereomer in enantiopure form.
2.2. The synthesis of sulfoxides of the structure 1 and
attempted tandem rearrangement
Our first approach to 1 is illustrated in Scheme 3. It relied on
the Sharpless asymmetric dihydroxylation to introduce the
Production of Z-18 as the major isomer in the olefination re-
action was a significant setback, because the Z double bond
PvO
PvO
P(OEt)3, s-collidine
MeOCH2CH2OCH2CH2OH
150 °C,15h
O
PMBO
O
S
O
OH
O
87-91%
O
PMBO
O
O
4
5
Scheme 2. An example of the tandem Claisen–Mislow–Evans rearrangement.

E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
3263
OMe
LDA, THF, -78 °C;
AD-mix , t-BuOH
MeO
MeO
MeO
OMe
I
-H2O, 0 °C
O
81%
97%
MeO
O
6
7
OMe
OMe
MeO
10% aq. NaOH-THF (4:1),
rt,1 h; then aq. HCl (pH<2)
MeO
OH
OH
83%
O
O
MeO
O
OH
8
9
Scheme 3.
LDA, -78 °C,THF;
Et2Zn, DMPU
I
O
O
MeO
MeO
O
MeO
MeO
OEt
O
11, 1.0 eq
96%
O
EtO
O
10
12
OMe
OMe
O
MeO
1. 2 M HCl-THF
2. TBSCl, ImH,
CH2Cl2
MeO
1. DIBAL
2. MsCl, Et3N
87%
63%
O
O
OTBS
OTBS
14
13
OMe
1. Swern ox.
2. LDA, THF
(S)-MeS(O)p-Tol
3. TESCl, ImH
4. LDA, THF
MeO
OMe
MeO
TBAF
THF
95%
O
p-Tol
O
40%
S
O
OH
16
15
Scheme 4.
geometry would be translated into the undesired configuration of
the allylic sulfide upon the Claisen rearrangement. Although, based
on the seminal studies by Bu¨chi more than three decades ago,6 we
could expect that the Z-isomer would not undergo the [3,3]-sig-
matropic rearrangement, resulting in the selective formation of
only the desired diastereomer (19) (Scheme 7), the overall yield
would be low. Indeed, when a mixture of E-18 and Z-18 was heated
at 120 ꢁC for 24 h, a smooth rearrangement of only E-18 was
observed, giving the desired diastereomer and recovering the
unreacted Z-sulfide.
The lack of reactivity of Z-18 also suggested a solution: if under
certain reaction conditions suitable for the [3,3]-sigmatropic shift
the olefins could undergo E/Z-isomerization, then only the rear-
rangement of E-18 would take place, converting all material to the
desired diastereomer of the product (19).
OMe
OMe
MeO
MeO
OR
O
O
p-Tol
p-Tol
S
O
S
O
17
16
P(OEt)3, s-collidine
MeOCH2CH2OCH2CH2OH
150 °C, 24 h
MeO
MeO
O
It is known that E- and Z-alkene can efficiently interconvert
under radical conditions in the presence of a catalytic amount of
thiophenol and a radical initiator (2,20-azaisobutyronitrile, AIBN) at
elevated temperatures, presumably through a radical addition–
elimination mechanism.10 These reaction condition appeared to be
OH
Scheme 5.

3264
E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
OMe OMe
OMe
MeO
MeO
MeO
0.06 eq. PhSH, AIBN
OMe
2-methoxyethanol
115 °C, 24 h
1.Swern ox.
MeO
O
O
O
2.Ph3PCH2SPh+Cl-
base, solvent
equilibration under
reaction conditions
PhS
PhS
Z-18
SPh
see Table1
E-18
Z-18
OMe
O
MeO
OH
15
OMe
OMe
MeO
O
MeO
0.06 eq. PhSH, AIBN
2-methoxyethanol
115 °C, 24 h
O
SPh
E-18
70%
O
Scheme 6.
PhS
18
SPh
Z:E 82:18
19
Scheme 8.
Table 1
Stereoselectivity of the Wittig olefination shown in Scheme 6
bearing a sulfide substituent at the 6-position has been well
established. Studies by the groups of Paquette and Houk report
a three order of magnitude rate enhancement in the anionic oxy-
Cope rearrangements for phenylsulfido-substituted substrates
compared to the parent unsubstituted analogs.11 Although a mild
decelerating effect of electron-withdrawing substituents at position
6 on [3,3]-sigmatropic shifts is known,12 the low reactivity of 16 and
17 is still surprising, especially compared to that of 4. Consequently,
it is possible that there is a notable effect of the electron-rich aryl
substituent at the 3 position of the dihydropyran, either steric or
electronic. This hypothesis will be tested in our subsequent studies.
Having prepared the desired allylic sulfide 19, we were well
positioned to investigate the second sigmatropic rearrangement.
This operation required oxidation of the phenyl sulfide to the cor-
responding sulfoxide. In order to anticipate the aldehyde homolo-
gation, which will be required subsequently, and to eliminate
potential complications during the oxidation that might be due to
the presence of the aldehyde functional group, a Wittig olefination
with triphenyl(methoxymethyl)phosphorane was carried out first
(Scheme 9). Methoxyalkenes 21 were isolated in 96% yield as a 3:1
mixture of E- and Z-isomer. At this stage, a clean oxidation of sulfide
21 was achieved upon a brief exposure to dimethyldioxirane at
ꢀ78 ꢁC. The diastereomeric mixture of the allylic sulfoxides was
Entry
Base
Solvent, temperature, time
Ratio Z/E
Yield over
two steps (%)
1
2
3
KHMDS
KHMDS
NaHMDS
THF, 20 ꢁC, 1 h
THF–DMPU [3:1], 20 ꢁC, 1 h
Toluene, 20 ꢁC, 2 h
82:18
70:30
78:22
92
95
93
ideally suitable for our purposes because no interference of the
isomerization with the sigmatropic transposition would be expec-
ted, thus allowing for a dynamic kinetic separation process. Indeed,
we were delighted to find out that exposure of an 82:18 mixture of
the Z/E-vinyl sulfides 18 to a catalytic amount of thiophenol in the
presence of AIBN at 115 ꢁC for 24 h resulted in the formation of 19 in
70% yield, and no diastereomer could be isolated. When the re-
action was terminated after about 2 h and the starting material was
isolated, the ratio of the alkenes ranged from 2:1 to 1:1, favoring the
E-sulfide, which initially was the minor stereoisomer (18%). This
observation supports our hypothesis that the rearrangement pro-
ceeds through olefin isomerization followed by selective rear-
rangement of the trans-vinylsulfide only (Scheme 8).
The difference in reactivity between sulfoxides 16 and 17 and
sulfides 18 is quite remarkable. The striking rate acceleration in
[3,3]-sigmatropic rearrangements of 1,5-unsaturated systems
OMe
OMe
MeO
MeO
MeO
MeO
SPh
[3,3]-shift
O
O
PhS
H
SPh
*
19
O
E-18
desired
OMe
OMe
MeO
MeO
MeO
MeO
SPh
H
O
O
PhS
Z-18
O
PhS
*
20
A1,3-strain
undesired
Scheme 7.

E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
3265
OMe
3. Conclusions
OMe
MeO
O
MeO
CH3OCH2PPh3+Cl-
KHMDS, THF
96%, E:Z 72:28
1.0 eq. DMDO,
The synthesis of (ꢀ)-joubertinamine described in this article
proceeds in 13 steps from ethyl (3,4-dimethoxyphenyl)acetate (14
steps from (S)-1,2,4-butanetriol) and in 20% overall yield. In turn,
(ꢀ)-mesembrine is reached in 14 steps and 16% overall yield. The
key transformations in the synthesis are the consecutive sigma-
tropic rearrangements. Thus, a Claisen rearrangement of a 2-(phe-
nylthio)vinyl dihydropyrans 18 is followed by the Mislow–Evans
rearrangement after oxidation of the intermediate allylic sulfide.
The originally designed tandem sequence of these two reactions
was not successful due to low reactivity of the corresponding sulf-
oxides. Further studies to gain a better mechanistic understanding
on the sigmatropic process are underway in our laboratory.
acetone, -78 °C
MeO
PhS
PhS
21
19
OMe
OMe
[2,3]-sigmatropic shift
MeO
MeO
P(OMe)3, i-Pr2NH
MeOH, 20 °C, 12 h
MeO
MeO
92%
O
OH
S
4. Experimental section
4.1. General information
Ph
23
22
Scheme 9.
All non-aqueous reactions were carried out under an inert
atmosphere of dry argon in oven or flame-dried glassware. Tetra-
hydrofuran (THF) and ether (Et2O) were distilled from sodium–
benzophenone under an atmosphere of argon. Dichloromethane,
di-iso-propylamine, pyridine, triethylamine, and chlorotrimethyl-
silane were distilled from calcium hydride in a continuous still
under and atmosphere of argon. Chlorotriethylsilane (TESCl) and
di-iso-propylethylamine (Hunig’s Base) were distilled from calcium
hydride under an inert atmosphere of dry argon and stored over
calcium hydride. Reaction temperatures were controlled by IKA
ETS-D4 fuzzy thermo couples. Room temperature reactions were
carried out between 20 and 24 ꢁC. Analytical thin-layer chroma-
tography (TLC) was performed using pre-coated TLC plates with
Silica Gel 60 F254 (EMD no. 5715-7) and visualized using combi-
nations of UV, anisaldehyde, ceric ammonium molybdate (CAM),
potassium permanganate, and iodine staining. Flash column
subjected to the Mislow–Evans rearrangement without purifica-
tion.13 The [2,3]-sigmatropic transposition occurred smoothly at
ambient temperature, providing the desired allylic alcohol in 92%
overall yield. Di-iso-propylamine was used as a buffer to prevent
complications associated with partial hydrolysis of the methyl
alkenyl ether, which was observed when no basic additive was used.
2.4. Completion of the total synthesis of (L)-joubertinamine
and (L)-mesembrine
The enantioselective total synthesis of (ꢀ)-joubertinamine was
completed in two steps from methyl alkenyl ether 23. Hydrolysis of
the ether in aqueous acetone in the presence of p-toluenesulfonic
acid afforded aldehyde 24. The last three steps, that is, oxidation of
the sulfide to sulfoxide with DMDO, the Mislow–Evans rearrange-
ment, and the hydrolysis of 23 were conveniently carried out in
one-pot in 85% overall yield, simply replacing the solvent by
evaporation and dissolution of the residue after each step. Alde-
hyde 24 was converted to the natural alkaloid by reductive
amination with methylammonium chloride and sodium cyano-
borohydride (Scheme 10). This reductive amination is similar to
that employed recently by Cho and Tam in the synthesis of racemic
joubertinamine.3a Finally, oxidation with manganese oxide pro-
duced (ꢀ)-mesembrine in 81% yield.
chromatography was preformed using 40–63 mm silica gel (Merck,
Geduran, no. 11567-1) as the stationary phase. Proton magnetic
resonance spectra were recorded at 300, 400, and 500 MHz on
Varian Mercury, Varian Unity Inova, and Varian VXR spectrometers,
respectively. Carbon magnetic resonance spectra were recorded at
75 and 125 MHz on Varian Mercury and Varian VXR spectrometers,
respectively. All chemical shifts were reported in
d units relative to
tetramethylsilane. Optical rotations were measured on a Jasco
P-2000 polarimeter. High resolution mass spectral data were
obtained by the Mass Spectrometry laboratory at Florida State
University or at the University of California, Santa Barbara. Optical
rotations were measured on a Jasco DIP-2000 polarimeter with
a sodium lamp.
OMe
OMe
MeO
MeO
O
CH3NH3+Cl-, NaBH3CN
MeOH, 20 °C
p-TsOH, acetone
4.2. Experimental procedures
H2O, 20 °C
MeO
85% over 3 steps
77%
4.2.1. Methyl 2-(3,4-dimethoxyphenyl)hex-5-enoate (7)
from 21
Methyl (3,4-dimethoxyphenyl)acetate 614 and 1-iodo-3-butene15
were prepared according to literature protocols. n-Butyllithium
(2.46 M in hexane, 44.0 mmol, 17.9 mL) was added to a solution
of di-iso-propylamine (6.7 mL, 48.4 mmol) in 80 mL of dry THF
dropwise at ꢀ78 ꢁC, and the mixture was stirred for 30 min. A
solution of ester 6 (4.60 g, 22.0 mol) in 10 mL of THF was added and
the reaction mixture was stirred at ꢀ78 ꢁC for 20 min. A solution of
1-iodo-3-butene (6.0 g, 33.0 mmol) in 5 mL of THF was added to the
resulting mixture and the solution was stirred at ꢀ78 ꢁC for 1 h and
then at 0 ꢁC for 1 h. Saturated ammonium chloride (40 mL) was
added and the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over an-
hydrous sodium sulfate, and concentrated on a rotary evaporator.
The residue was purified by flash column chromatography (10%
OH
OH
23
24
OMe
OMe
MeO
MeO
MnO2, benzene
81%
OH
MeHN
N
O
H
Me
(–)-mesembrine
(–)-joubertinamine
Scheme 10.

3266
E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
EtOAc–hexanes) to give pure ester 7 (4.69 g, 17.8 mmol, 81%). 1H
NMR (300 MHz, CDCl3) (ppm): 6.89–6.74 (m, 3H), 5.78 (dddd,
J¼17.0, 10.5, 6.5, 6.5 Hz, 1H), 5.02 (m, 1H), 4.97 (m, 1H), 3.88 (s, 3H),
3.86 (s, 3H), 3.66 (s, 3H), 3.51 (t, J¼7.57 Hz, 1H), 2.22–2.07 (m, 1H),
2.06–1.92 (m, 2H), 1.92–1.76 (m, 1H). 13C NMR (75 MHz, CDCl3)
extracted with ethyl acetate. The organic layers were combined,
washed with brine, dried over sodium sulfate, and concentrated on
a rotary evaporator. The residue was purified by flash column
chromatography (silica, 35% ethyl acetate–hexanes) to give pure
ester 12 (4.75 g, 13.48 mmol, 96%) as a mixture of diastereomers. 1H
d
d
(ppm): 174.5, 148.9, 148.2, 137.5, 131.3, 120.1, 115.3, 111.1, 110.9,
NMR (400 MHz, CDCl3) d (ppm): 6.85–6.75 (m, 3H), 4.18–3.96 (m,
55.9, 55.8, 51.9, 50.2, 32.5, 31.4. HRMS (ESIþ) calcd for C15H20NaO4
(MNa)þ 287.1266, found 287.1259.
4H), 3.86 (s, 3H), 3.85 (s, 3H), 3.50–3.42 (m, 2H), 2.21–2.12 (m,
0.5H), 2.06–1.97 (m, 0.5H), 1.93–1.84 (m, 0.5H), 1.79–1.70 (m, 0.5H),
1.61–1.45 (m, 2H), 1.38 (s, 1.5H), 1.36 (m, 1.5H), 1.32 (s, 3H), 1.20 (t,
4.2.2. Methyl 2-(3,4-dimethoxyphenyl)-5,6-dihydroxyhexanoate (8)
Ester 7 (3.96 g, 15.0 mmol) was added to a solution of 21.0 g of
AD-mix
J¼7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3)
d (ppm): 174.1, 149.1,
148.4, 131.5, 120.3, 111.2, 110.9, 110.8, 109.0, 75.91, 75.86, 69.55,
69.45, 60.9, 56.0, 51.3, 51.2, 31.8, 31.6, 29.9, 27.1, 25.85, 25.84, 14.3.
a (Aldrich) in water (80 mL) and tert-butanol (80 mL) at
0 ꢁC, and the reaction mixture was stirred at 0 ꢁC for 8 h. The re-
action was quenched with 50 mL of 2 M Na2SO3 and the resulting
mixture was stirred at room temperature for 1 h. The mixture was
extracted with ethyl acetate (3ꢂ100 mL), and the organic layers
were combined and washed with brine. The organic phase was
dried over sodium sulfate and concentrated on a rotary evapora-
tor. The residue was purified by flash column chromatography
(30% EtOAc–CH2Cl2) to give pure product diol 8 as a mixture of
diastereomers (4.10 g, 14.6 mmol, 97%). 1H NMR (300 MHz, CDCl3)
FTIR (CH2Cl2), n
(cmꢀ1): 3437, 2984, 2936, 2871, 1727, 1591, 1515,
1261, 1155, 1030. HRMS (ESIþ) calcd for C18H26NaO6 (MNa)þ
361.1612, found 361.1627.
4.2.5. (S)-6-((tert-Butyldimethylsilyloxy)methyl)-3-(3,4-
dimethoxyphenyl)tetrahydro-2H-pyran-2-one (13)
An aqueous solution of hydrochloric acid (2 M, 85 mL) was
added to a solution of ester 12 (4.27 g, 12.12 mmol) in 85 mL of dry
THF at 0 ꢁC, and the mixture was stirred vigorously at room tem-
perature for 1 h. Brine (250 mL) was added and the aqueous layer
was extracted with ethyl acetate (150 mL, then 3ꢂ50 mL). The
combined organic layers were dried over sodium sulfate and
concentrated. The residue was dissolved in 20 mL of ethyl acetate
and stirred with 4.5 g of silica for 1.5 h at room temperature. The
solution was filtered using 80 mL of ethyl acetate and concentrated.
The crude product was dissolved in dichloromethane (25 mL), and
imidazole (2.45 g, 36.0 mmol) and tert-butylchlorodimethylsilane
(2.17 g, 14.4 mmol) were added. The mixture was stirred at room
temperature for 1 h. The reaction mixture was diluted with 100 mL of
dichloromethane and transferred to a separatory funnel. The organic
phase was washed with 1 M HCl, brine, saturated sodium bi-
carbonate, dried over sodium sulfate, and concentrated on a rotary
evaporator. The residue was purified by flash column chromatogra-
phy (silica, 35% ethyl acetate–hexanes) to give pure 13 (4.00 g,
10.51 mmol, 87% for two steps) as a mixture of diastereomers. 1H
d
(ppm): 6.91–6.63 (m, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.67 (m, 1H),
3.66 (s, 3H), 3.50 (m, 1H), 3.42 (m, 1H), 2.38–1.61 (m, 3H), 1.39 (m,
2H). 13C NMR (125 MHz, CDCl3)
(ppm): 173.4, 172.3, 149.3,
d
148.1, 131.8, 130.5, 121.8, 114.7, 74.7, 70.5, 56.2, 50.3, 30.6, 26.3.
HRMS (ESIþ) calcd for C15H22NaO6 (MþNa)þ 321.1311, found
321.1314.
4.2.3. (S)-3-(3,4-Dimethoxyphenyl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-2-one (9)
A 10% aqueous solution of sodium hydroxide (10 mL) was added
to a solution of diol 8 (3.98 g, 13.4 mmol) in 40 mL of dry THF at
0 ꢁC, and the mixture was stirred vigorously at room temperature
for 1 h. The reaction mixture was carefully acidified to pH <5 with
6 N HCl and then to pH <2 with 1 N HCl. The resulting mixture was
transferred to a separatory funnel and extracted with dichloro-
methane (12ꢂ30 mL). The organic layers were washed with brine,
dried over anhydrous sodium sulfate, and concentrated on a rotary
evaporator. The residue was dried under high vacuum overnight
and purified by flash column chromatography (silica, 30% ethyl
acetate–hexanes) to give pure lactone 9 as a mixture of di-
astereomers (2.95 g, 11.1 mmol, 83%). 1H NMR (300 MHz, CDCl3)
NMR (400 MHz, CDCl3)
d (ppm): 6.97–6.64 (m, 3H), 4.50–4.42 (m,
1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.84–3.71 (m, 2H), 3.58 (dd, J¼12.0,
8.0 Hz, 0.5H), 2.27–2.16 (m, 1H), 2.14–1.86 (m, 3H), 0.89 (two s, 9H),
0.08 (two s, 6H). 13C NMR (100 MHz, CDCl3)
d (ppm): 173.2, 172.3,
149.1, 148.3, 132.0, 131.3, 120.5, 120.3, 111.8, 111.5, 111.4, 111.2, 81.3,
79.4, 65.4, 65.1, 56.0, 48.1, 45.5, 28.6, 26.5, 26.0, 25.1, 22.8,18.46,18.43,
ꢀ5.2, ꢀ5.3. HRMS (ESIþ) calcd for C20H32NaO5Si1 (MNa)þ 403.1911,
found 403.1917.
d
(ppm): 6.79 (m, 3H), 4.58 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.71
(m, 1H), 3.59 (m, 1H), 2.32 (m, 1H), 2.16 (m, 2H), 1.96 (m, 2H). 13C
NMR (125 MHz, CDCl3) (ppm): 173.8, 172.7, 149.2, 148.4, 131.6,
130.8, 120.6,120.3, 111.7,111.5,111.3, 82.3, 79.8, 65.0, 64.7, 56.0, 48.0,
d
45.2, 28.6, 26.4, 24.5, 22.2. FTIR (CH2Cl2),
n
(cmꢀ1): 3790, 3437, 3060,
4.2.6. (S)-tert-Butyl((5-(3,4-dimethoxyphenyl)-3,4-dihydro-2H-
pyran-2-yl)methoxy)dimethylsilane (14)
2936, 1726, 1593, 1517, 1259, 1145, 1026. HRMS (ESIþ) calcd for
C14H18NaO5 (MNa)þ 289.1062, found 289.1052.
To
a solution of lactone 13 (3.795 g, 9.97 mmol) in dry
dichloromethane (85 mL) was added DIBAL (1 M in toluene, 20 mL,
20 mmol) dropwise for 20 min at ꢀ78 ꢁC. The reaction mixture was
stirred at ꢀ78 ꢁC for additional 30 min, quenched with saturated
Rochelle’s salt (80 mL), and stirred for 3 h at room temperature.
The resulting mixture was separated and the aqueous layer was
extracted with dichloromethane. The combined organic layers
were washed with brine, dried over anhydrous sodium sulfate, and
concentrated. The crude product was dissolved in dichloromethane
(50 mL), and triethylamine (5.4 mL, 38.7 mmol) followed by
methanesulfonyl chloride (1.0 mL, 12.9 mmol) was added dropwise
at 0 ꢁC. The reaction mixture was stirred at 0 ꢁC for 30 min and
then at room temperature for 10 min. The resulting mixture was
diluted with dichloromethane, washed with saturated aqueous
sodium bicarbonate, water, and brine, dried over anhydrous
sodium sulfate, and concentrated on a rotary evaporator. The res-
idue was purified by flash column chromatography (silica, 13%
ethyl acetate–hexanes) to give 2.408 g (6.61 mmol, 63%) of the
4.2.4. (S)-Ethyl 2-(3,4-dimethoxyphenyl)-4-(2,2-dimethyl-1,3-
dioxolan-4-yl)butanoate (12)
Iodide 11 was prepared according to a literature procedure.16
n-Butyllithium (2.38 M in hexane, 7.1 mL, 16.9 mmol) was added to
a solution of di-iso-propylamine (2.6 mL, 18.6 mmol) in 21 mL of
dry THF dropwise at ꢀ78 ꢁC and the mixture was stirred at ꢀ78 ꢁC
for 30 min. A solution of ester 10 (3.14 g, 14.00 mol) in dry THF
(5 mL total with rinses) was added to the reaction mixture and the
reaction mixture was stirred for 10 min at ꢀ78 ꢁC. Diethylzinc
(1.9 mL, 18.5 mmol) was added to the resulting light yellow
solution, followed by DMPU (15 mL) and a solution of (S)-4-(2-
iodoethyl)-2,2-dimethyl-1,3-dioxolane 11 (3.60 g, 14.0 mmol) in
THF (5 mL total with rinses), and the mixture was stirred for 1 h at
ꢀ78 ꢁC and then slowly warmed to ꢀ25 ꢁC for 4.5 h. The mixture
was warmed to room temperature and carefully quenched with
saturated ammonium chloride (4 mL), and the aqueous layer was

E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
3267
20
dihydropyran 14. [
a
]
þ127.6 (c 1.0, CH2Cl2). 1H NMR (300 MHz,
vacuum. The crude product was used in the next step without
further purification.
D
CDCl3)
d
(ppm): 6.83 (s, 1H), 6.82 (m, 3H), 3.89 (s, 3H), 3.87 (s, 3H),
3.81 (dd, Jd1¼10.6 Hz, Jd2¼5.3 Hz, 1H), 3.70 (dd, J¼10.6, 5.5 Hz,
n-Butyllithium (2.45 M in hexanes, 0.40 mL, 1.00 mmol) was
added to a solution of di-iso-propylamine (0.16 mL, 1.14 mmol) in
THF (2.0 mL) and the mixture was stirred for 20 min at ꢀ78 ꢁC. A
solution of the sulfoxides obtained in the previous step in THF
(1.5 mL total with rinses) was added dropwise. After stirring for
15 min, the reaction mixture was quenched by the addition of
saturated aqueous ammonium chloride and the resultant mixture
was extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and concentrated. The residue was puri-
fied by column chromatography (50–80% ethyl acetate–hexanes) to
1H), 2.42 (m, 2H), 2.13–1.97 (m, 1H), 1.85–1.72 (m, 1H), 0.92 (s, 9H),
0.10 (s, 6H). 13C NMR (75 MHz, CDCl3)
d
(ppm): 148.8, 147.5, 140.7,
132.6, 116.5, 112.6, 111.3, 107.9, 75.4, 65.4, 55.9, 55.8, 25.9, 24.1, 22.3,
18.4, ꢀ5.3. FTIR (CH2Cl2),
n
(cmꢀ1): 3489, 3060, 2928, 2856, 1726,
1639, 1517, 1465, 1251, 1163, 1029. HRMS (ESIþ) calcd for
C20H32NaO4Si (MNa)þ 387.1960, found 387.1967.
4.2.7. (S)-(5-(3,4-Dimethoxyphenyl)-3,4-dihydro-2H-pyran-2-
yl)methanol (15)
Tetra-n-butylammonium fluoride (2.1 g, 6.7 mmol) was added
to a solution of dihydropyran 14 (0.830 g, 2.28 mmol) in dry THF
(12 mL). The reaction mixture was stirred for 1 h at room temper-
ature and quenched with saturated ammonium chloride. The
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried over an-
hydrous sodium sulfate, and concentrated on a rotary evaporator.
The residue was purified by flash column chromatography (silica,
afford the desired vinyl sulfoxide 16 (61 mg, 0.159 mmol, 55% over
20
two steps). [
a
]
D
þ247.8 (c 4.2, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
(ppm): 7.50 (d, J¼8.0 Hz, 2H), 7.29 (d, J¼8.5 Hz, 2H), 6.81–6.77 (m,
4H), 6.63 (dd, J¼15.0, 4.0 Hz, 1H), 6.51 (dd, J¼15.0, 2.0 Hz, 1H), 4.61–
4.58 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.49–2.36 (m, 5H), 2.19–2.14
(m,1H),1.89–1.81 (m,1H).13C NMR (125 MHz, CDCl3)
d (ppm): 149.0,
147.8,142.0,140.4,139.9,135.8,135.3,132.1,130.3,125.0,116.8,113.4,
111.4, 108.0, 73.4, 56.1, 56.0, 29.8, 27.4, 22.3, 21.6. FTIR (CH2Cl2),
1% triethylamine in 75% ethyl acetate–hexanes) to give 0.544 g
n
(cmꢀ1): 3662, 2925, 2852,1639,1517,1249,1045. HRMS (ESIþ) calcd
20
(2.17 mmol, 95%) of the dihydropyran 15. [
a
]
þ185.4 (c 1.0,
for C22H24NaO4S (MþNa)þ 407.1293, found 407.1295.
D
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
(ppm): 6.84 (m, 3H), 6.83 (s,
1H), 4.02 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.78 (m, 1H), 3.72 (m,
4.2.9. (S)-5-(3,4-Dimethoxyphenyl)-2-((E)-2-((R)-p-
tolylsulfinyl)vinyl)-3,4-dihydro-2H-pyran (17)
1H), 2.46 (m, 2H), 2.07–1.78 (m, 3H). 13C NMR (75 MHz, CDCl3)
d
(ppm): 148.7, 147.5, 140.3, 132.1, 116.5, 112.9,111.2, 107.8, 75.3, 65.1,
Sulfoxide 17 was prepared by a four-step reaction sequence
described above for 16, starting from 0.100 g (0.40 mmol) of alcohol
15, which furnished 75 mg (0.165 mmol, 49% over four steps) of the
55.8, 55.7, 23.6, 22.4. FTIR (CH2Cl2), n
(cmꢀ1): 3498, 2998, 2932,
2838, 1638, 1518, 1250, 1142, 1026. HRMS (ESIþ) calcd for
C14H18NaO4Si1 (MNa)þ 273.1107, found 273.1103.
20
final product. [
d
a
]
D
þ10.1 (c 4.9, CH2Cl2). 1H NMR (500 MHz, CDCl3)
(ppm): 7.49 (d, J¼8.0 Hz, 2H), 7.26 (d, J¼8.0 Hz, 2H), 6.80–6.74 (m,
4.2.8. (S)-5-(3,4-Dimethoxyphenyl)-2-((E)-2-((S)-p-
tolylsulfinyl)vinyl)-3,4-dihydro-2H-pyran (16)
4H), 6.59 (dd, J1¼15.0 Hz, J2¼3.5 Hz, 1H), 6.51 (dd, J¼15.0, 1.5 Hz,
1H), 4.66–4.62 (m, 1H), 3.86 (s, 6H), 2.59–2.35 (m, 5H), 2.19–2.13
A
solution of dimethyl sulfoxide (0.12 mL, 1.7 mmol) in
(m, 1H), 1.88–1.80 (m, 1H). 13C NMR (125 MHz, CDCl3)
d (ppm):
dichloromethane (0.5 mL) was added to a solution of oxalyl chloride
149.0, 147.8, 142.1, 140.4, 139.9, 135.8, 135.2, 132.2, 130.3, 125.2,
115.9, 113.4, 111.3, 108.0, 73.3, 56.1, 56.0, 29.9, 27.4, 22.4, 21.6. FTIR
(73
m
L, 0.86 mmol) in 1 mL of dichloromethane at ꢀ78 ꢁC. The
mixture was stirred for 15 min and then a solution of alcohol 15
(0.10 g, 0.40 mmol) in dichloromethane (1.0 mL total with rinses)
was added dropwise. After stirring for 20 min at ꢀ78 ꢁC, triethyl-
amine (0.36 mL, 2.6 mmol) was added dropwise, and, after 5 min,
the reaction mixture was stirred at 0 ꢁC for 15 min. HCl (3 M, 2.6 mL)
was added and the mixture was extracted with dichloromethane.
The organic layers were washed with water and saturated aqueous
sodium bicarbonate, dried over anhydrous sodium sulfate, and
concentrated. The crude aldehyde was used directly in the next step.
n-Butyllithium (2.45 M in hexanes, 0.25 mL, 0.61 mmol) was
(CH2Cl2), n
(cmꢀ1): 3661, 3050, 2924, 2851, 1639, 1518, 1464, 1249,
1141, 1046, 1027. HRMS (ESIþ) calcd for C22H24O4S (MþNa)þ
407.1295, found 407.1293.
4.2.10. (S)-5-(3,4-Dimethoxyphenyl)-2-(2-(phenylthio)vinyl)-3,4-
dihydro-2H-pyrans (Z-18 and E-18)
Dimethylsulfoxide (0.47 mL, 6.62 mmol) was added to a solution
of oxalyl chloride (0.28 mL, 3.31 mmol) in CH2Cl2 (12 mL) dropwise
at ꢀ78 ꢁC. The mixture was stirred at ꢀ78 ꢁC for 15 min, and
a solution of alcohol 15 (0.53 g, 2.12 mmol) in CH2Cl2 (4 mL total
with rinses) was added dropwise. The resulting mixture was stirred
for 25 min at ꢀ78 ꢁC and then triethylamine (1.40 mL, 10 mmol)
was added after 5 min, the reaction mixture was warmed to 0 ꢁC,
and stirred for 15 min. The resulting mixture was diluted with
dichloromethane, washed with 1 M HCl, water, and brine, dried
over anhydrous sodium sulfate and concentrated on a rotary
evaporator. The residue (0.578 g) was used in the next step without
further purification.
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 8.5 mL,
4.25 mmol) was added to a suspension of (phenylthiomethyl)-
triphenylphosphonium chloride (1.80 g, 4.28 mmol) in THF (20 mL)
dropwise at 0 ꢁC and the mixture was stirred at 0 ꢁC for 1 h. A
solution of the aldehyde (0.578 g, 2.12 mmol) in THF (5 mL total
with rinses) was added to the above yellow solution and the
resulting mixture was stirred for 2 h at 0 ꢁC, and quenched with
saturated aqueous ammonium chloride. The aqueous layer was
separated and extracted with ethyl acetate (30 mLꢂ3), and the
combined organic phase was washed with brine, dried over anhy-
drous sodium sulfate, and concentrated on a rotary evaporator. The
residue was purified by flash column chromatography (silica, 20%
ethyl acetate–hexanes) to give vinyl sufides 18 (0.691 g, 1.95 mmol,
added to a solution of di-iso-propylamine (91 mL, 0.65 mmol) in THF
(0.75 mL) and the mixture was stirred for 20 min at ꢀ20 ꢁC. (S)-
Methyl p-tolyl sulfoxide (0.100 g, 0.65 mmol) was added and then
stirring was continued for 20 min at ꢀ20 ꢁC. The solution was
cooled to ꢀ78 ꢁC and a solution of the aldehyde from the previous
step (w0.40 mmol) in THF (1.2 mL total with rinses) was added
dropwise. After 30 min, the cooling bath was removed and a solu-
tion of saturated aqueous ammonium chloride was added. The
mixture was extracted with ethyl acetate, and the combined or-
ganic layers were washed with brine, dried over anhydrous sodium
sulfate, and concentrated. The residue was purified by column
chromatography (silica, 100% ethyl acetate containing 0.1% tri-
ethylamine) to provide 0.115 g (0.286 mmol, 72% over two steps) of
the addition product as a mixture of diastereomers.
Chlorotriethylsilane (0.14 mL, 0.83 mmol) was added to a solu-
tion of the above product (0.115 g, 0.286 mmol) and imidazole
(0.17 g, 2.5 mmol) in dichloromethane (1.7 mL). After stirring for
20 min at room temperature, the reaction mixture was diluted with
dichloromethane and washed with 1 M hydrochloric acid, water,
and saturated aqueous sodium bicarbonate. The organic layer was
dried over anhydrous sodium sulfate, concentrated, and dried in

3268
E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
92%) as a mixture of E- and Z-isomer (18:82). 1H NMR (500 MHz,
CDCl3) (ppm): 7.39–7.37 (m, 2H), 7.34–7.31 (m, 3H), 7.27–7.25 (m,
1H), 6.87 (s, 1H), 6.86–6.82 (m, 3H), 6.53 (dd, J¼16.0, 1.0 Hz, 1H,
E-isomer), 6.43 (dd, J¼9.5, 1.5 Hz, 1H, Z-isomer), 5.95–5.92 (m, 1H),
4.88–4.85 (m, 1H, Z-isomer), 4.49–4.46 (m, 1H, E-isomer), 3.90 (s,
3H, Z-isomer), 3.89 (s, 3H, E-isomer), 3.87 (s, 3H, E- and Z-isomer),
2.56–2.42 (m, 2H), 2.13–2.07 (m, 1H), 1.98–1.83 (m, 1H). 13C NMR
methyl ethers 21 (0.130 g, 0.340 mmol) in acetone (2.0 mL) drop-
wise at ꢀ78 ꢁC. After 5 min, two more portions of the DMDO
solution (0.33 mL each) were added in 5 min intervals, until TLC
indicated completion. The resulting mixture was warmed to room
temperature, concentrated on a rotary evaporator, and dried under
vacuum. The crude sulfoxide was used without further purification.
HRMS (ESIþ) calcd for C23H26NaO4S (MNa)þ 421.1450, found
421.1450.
d
(125 MHz, CDCl3)
d (ppm): 149.0, 147.7, 140.7, 140.5, 135.5, 132.6,
131.1,130.8,130.1,129.6,129.3,127.2,127.1,126.9,126.0,116.8,113.03,
113.00, 111.4, 108.0, 74.8, 72.4, 56.1, 56.0, 28.0, 27.5, 22.54, 22.48.
The above crude product was dissolved in methanol (5.7 mL).
Di-iso-propylamine (0.24 mL, 1.71 mmol) and trimethylphosphite
(0.20 mL,1.70 mmol) were added. The resulting mixture was stirred
at room temperature for 25 h and then concentrated on a rotary
evaporator. The residue was dried in vacuum and used in the next
step without purification. Partial data for 23 after column chro-
matography (silica, 60% ethyl acetate–hexanes) (E/Z¼3:1). 1H NMR
4.2.11. (1R,2S)-1-(3,4-Dimethoxyphenyl)-2-(phenylthio)cyclohex-
3-enecarbaldehyde (19)
A mixture of Z-18 and E-18 (82:18, 50 mg, 0.141 mmol) was
dissolved in 2.5 mL of 2-methoxyethanol freshly distilled from
calcium hydride. The solution was degassed by applying vacuum at
room temperature until bubbling was observed and then back-
filling with argon after about 10 s. This process was repeated twice.
(500 MHz, CDCl3)
d
(ppm): 6.86 (m, 1H), 6.32 (d, J¼12.9 Hz, 1H,
E-isomer), 6.07 (d, J¼10.0 Hz, 1H, Z-isomer), 5.97–5.85 (m, 1H), 5.79
(d, J¼10.1 Hz, 1H), 4.98 (d, J¼12.9 Hz, 1H, E-isomer), 4.54 (d,
J¼6.8 Hz,1H), 4.27 (m,1H, E-isomer), 4.25 (m,1H, Z-isomer), 3.88 (s,
3H), 3.86 (s, 3H), 3.55 (s, 3H, E-isomer), 3.51 (s, 3H, Z-isomer), 2.25
(m, 1H, Z-isomer), 2.00–1.67 (m, 4H, E-isomer), 2.00–1.67 (m, 3H, Z-
isomer).
The reaction flask was charged with thiophenol (0.8 mL, 7.8 mmol,
6 mol %) and AIBN (w1 mg), and the flask was sealed and heated at
115 ꢁC for 24 h. After cooling to room temperature, the reaction
mixture was concentrated on a rotary evaporator and the residue
was purified by column chromatography to afford the requisite
23
allylic sulfide 19 (35 mg, 0.987 mmol, 70%). [
a
]
þ378.7 (c 1.0,
4.2.14. 2-((1R,4S)-1-(3,4-Dimethoxyphenyl)-4-hydroxycyclohex-2-
enyl)acetaldehyde (24)
D
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
(ppm): 9.32 (s, 1H), 7.49–7.46
(m, 2H), 7.32–7.24 (m, 3H), 6.82–6.78 (m, 2H), 6.68 (d, J¼2.0 Hz,1H),
6.12–6.08 (m, 1H), 5.76–5.73 (m, 1H), 4.30 (d, J¼4.5 Hz, 1H), 3.84 (s,
3H), 3.81 (s, 3H), 2.24–2.19 (m, 1H), 2.10–2.01 (m, 2H), 1.59–1.52 (m,
p-Toluenesulfonic acid monohydrate (0.150 g, 0.789 mmol) was
added to a solution of E/Z-vinyl ethers 23 from the previous re-
action in 15 mL of acetone–water (15:1) at room temperature. After
stirring at room temperature for 28 h, the reaction mixture was
neutralized with solid sodium bicarbonate (0.4 g) to pH w7 and
concentrated. The residue was extracted with ethyl acetate (25 mL)
and the organic layer was washed with water. The aqueous layer
was extracted with ethyl acetate (3ꢂ10 mL), and the combined
organic layers were dried over anhydrous sodium sulfate and
concentrated on a rotary evaporator. The residue was purified by
flash column chromatography (silica, 50%, 75, 90% ethyl acetate–
1H). 13C NMR (125 MHz, CDCl3)
d (ppm): 198.0, 149.2, 148.6, 135.4,
133.0, 130.0, 129.1, 129.4, 128.1, 126.1, 120.6, 111.2, 111.0, 58.5, 56.2,
56.0, 48.8, 25.2, 22.8. HRMS (ESIþ) calcd for C21H22NaO3S (MþNa)þ
377.1189, found 377.1187.
4.2.12. ((1S,6S)-6-(3,4-Dimethoxyphenyl)-6-(2-
methoxyvinyl)cyclohex-2-enyl)(phenyl)sulfane (21)
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 2.80 mL,
1.40 mmol) was added to a suspension of (methoxymethyl)-
triphenylphosphonium chloride (0.480 g, 1.40 mmol) in THF
(10 mL) dropwise at 0 ꢁC and the mixture was stirred at 0 ꢁC for 1 h.
A solution of aldehyde 19 (0.250 g, 0.705 mmol) in THF (2 mL) was
added to the above mixture, the resulting mixture was stirred for
2 h at room temperature, and then quenched with saturated am-
monium chloride. The aqueous layer was separated and extracted
with ethyl acetate (2ꢂ10 mL), and the combined organic phase was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated on a rotary evaporator. The residue was purified by
flash column chromatography (silica, 20% ethyl acetate–hexanes) to
give 21 (E/Z¼72:28, 0.258 g, 0.674 mmol, 96%). 1H NMR (300 MHz,
hexanes) to give aldehyde 24 (80 mg, 0.290 mmol, 85% over three
21
steps). [
d
a]
ꢀ106.2 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
D
(ppm): 9.58 (t, J¼2.6 Hz, 1H), 6.84–6.79 (m, 3H), 6.10–6.06 (m,
2H), 4.18 (br s, 1H), 3.86 (m, 3H), 3.85 (m, 3H), 2.86 (dd, J¼15.0,
2.6 Hz, 1H), 2.75 (dd, J¼15.0, 2.6 Hz, 1H), 2.02 (ddd, J¼14.0, 8.0,
4.5 Hz, 1H), 1.93 (br s, 1H), 1.87 (ddd, J¼14.0, 6.0, 4.0 Hz, 1H), 1.71–
1.64 (m, 2H). 13C NMR (125 MHz, CDCl3)
d (ppm): 202.6,149.0,147.8,
137.3, 135.0, 131.1, 119.0, 111.1, 110.0, 64.0, 56.1, 56.0, 54.5, 41.4, 33.1,
28.1. HRMS (ESIþ) calcd for C16H20NaO4 (MþNa)þ 299.1258, found
299.1259.
4.2.15. (ꢀ)-Joubertinamine
CDCl3)
d
(ppm): 7.37 (m, 2H), 7.24–7.11 (m, 3H), 7.08–6.86 (m, 1H),
Methylamine hydrochloride (85 mg, 1.26 mmol) and sodium
cyanoborohydride (76 mg, 1.21 mmol) were added to a solution of
aldehyde 24 (50 mg, 0.180 mmol) in methanol (3.6 mL) at room
temperature under argon. The resulting mixture was stirred at
room temperature for 4 h and then quenched with 15 mL of 3 M
aqueous sodium hydroxide. Chloroform (15 mL) was added, and the
layers were separated, and the aqueous layer was extracted with
chloroform (3ꢂ5 mL). The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate, and concentrated
on a rotary evaporator. The residue was purified by flash column
chromatography (alumina [basic, activity I, particle size 0.063–
6.92 (s, 1H), 6.84–6.72 (m, 1H), 6.16 (d, J¼13.0 Hz, 1H, E-isomer),
6.97 (m, 1H), 5.83 (d, J¼7.7 Hz, 1H, Z-isomer), 5.63 (m, 1H), 4.83 (d,
J¼13.0 Hz, 1H, E-isomer), 4.57 (d, J¼6.8 Hz, 1H, Z-isomer), 4.26 (m,
1H, E-isomer), 4.08 (m, 1H, Z-isomer), 3.85 (s, 3H), 3.83 (s, 3H), 3.42
(s, 3H, Z-isomer), 3.21 (s, 3H, E-isomer), 2.48 (m, 1H, Z-isomer),
2.27–1.81 (m, 3H), 1.70 (m, 1H, E-isomer). 13C NMR (125 MHz,
CDCl3)
d (ppm): 148.3, 148.2, 147.7, 147.6, 147.4, 147.2, 140.7, 138.8,
137.9, 137.8, 132.0, 131.0, 129.7, 129.3, 128.9, 128.8, 127.6, 127.0,
126.6, 126.4, 119.5,119.1, 116.8, 111.6, 111.3, 111.2, 110.32, 110.26, 72.5,
59.9, 56.1, 56.0, 55.9, 55.5, 54.0, 46.5, 45.7, 32.9, 30.4, 27.5, 24.2,
23.3, 22.6. HRMS (ESIþ) calcd for C23H26NaO3S (MþNa)þ 405.1487,
found 405.1487.
0.200 mm], 2% triethylamine in 50% ethyl acetate–methanol) to
22
give (ꢀ)-joubertinamine (42 mg, 0.144 mmol, 77%). [
a
]
ꢀ77.3 (c
D
1.0, CHCl3). 1H NMR (500 MHz, CDCl3)
d
(ppm): 6.81–6.76 (m, 3H),
4.2.13. (1S,4S)-4-(3,4-Dimethoxyphenyl)-4-(2-
methoxyvinyl)cyclohex-2-enol (23)
A solution of freshly titrated dimethyldioxirane in acetone
(0.073 M, 4.7 mL, 0.34 mmol) was added to a solution of vinyl
6.01 (s, 2H), 4.13 (br t, J¼4.5 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.53
(ddd, J¼11.0, 10.0, 5.5 Hz, 1H), 2.40 (ddd, J¼11.0, 9.5, 5.5 Hz, 1H),
2.36 (s, 3H), 1.99 (m, 1H) 1.92 (m, 2H), 1.78 (m, 1H), 1.63 (m, 2H). 13C
NMR (125 MHz, CDCl3)
d (ppm): 148.7, 147.2, 139.0, 136.1, 130.0,

E.A. Ilardi et al. / Tetrahedron 65 (2009) 3261–3269
3269
2. (a) Paul, T.; Malachowski, W. P.; Lee, J. Org. Lett. 2006, 8, 4007–4010; (b) Taber,
D. F.; He, Y. J. Org. Chem. 2005, 70, 7711–7714; (c) Chavan, S. P.; Khobragade, D.
A.; Pathak, A. B.; Kalkote, U. R. Tetrahedron Lett. 2004, 45, 5263–5265; (d) Rigby,
J. H.; Dong, W. Org. Lett. 2000, 2, 1673–1675; (e) Ogasawara, K.; Yamada, O.
Tetrahedron Lett. 1998, 39, 7747–7750; (f) Langlois, Y.; Dalko, P. I.; Brun, V.
Tetrahedron Lett. 1998, 39 8979–8982; (g) Denmark, S. E.; Marcin, L. R. J. Org.
Chem. 1997, 62, 1675–1686; (h) Mori, M.; Kuroda, S.; Zhang, C.; Sato, Y. J. Org.
Chem. 1997, 62, 3263–3270; (i) Yoshimitsu, T.; Ogasawara, K. Heterocycles 1996,
42, 135–140; (j) Nemoto, H.; Tanabe, T.; Fukumoto, K. J. Org. Chem. 1995, 60,
6785–6790; (k) Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett. 1990, 1239–
1242; (l) Kosugi, H.; Miura, Y.; Kanna, H.; Uda, H. Tetrahedron: Asymmetry 1993,
4, 1409–1412; (m) Meyers, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem. Soc.
1985, 107, 7776–7778.
3. (a) Tam, N. T.; Cho, C.-G. Org. Lett. 2007, 9, 3391–3392; (b) Hoshino, O.;
Ishizaki, M.; Sawaki, S.; Yuasa, M.; Umezawa. Chem. Pharm. Bull. 1988, 36,
3373–3380; (c) Jeffs, P. W.; Redfearn, R.; Wolfram, J. J. Org. Chem. 1983, 48,
3861–3863; (d) Sa´nchez, I. H.; Soria, J. J.; Larraza, M. I.; Flores, H. J. Tetra-
hedron Lett. 1983, 24, 551–554; (e) Psotta, K.; Wiechers, A. Tetrahedron 1979,
35, 255–257; (f) Psotta, K.; Strelow, F.; Wiechers, A. J. Chem. Soc., Perkin Trans.
1 1979, 1063–1065; For synthesis of O-methyljoubertiamine and mesembrine,
see: (g) Martin, S. F.; Puckette, T. A.; Colapret, J. A. J. Org. Chem. 1979, 44,
3391–3396.
4. (a) Stivala, C.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774–3776; (b) Lu, C.-D.;
Zakarian, A. Org. Lett. 2007, 9, 3161–3163; (c) Stivala, C. E.; Zakarian, A. Tetra-
hedron Lett. 2007, 48, 6845–6848.
5. (a) Pelc, M. J.; Zakarian, A. Org. Lett. 2005, 7, 1629–1631; (b) Pelc, M. J.; Zakarian,
A. Tetrahedron Lett. 2006, 47, 7519–7523.
6. Bu¨ chi, G.; Powell, J. E. J. Am. Chem. Soc. 1970, 92, 3126–3133.
7. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
8. (a) Taber, D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem. Soc. 2002, 124, 13121–13126;
(b) Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 295–304.
118.8, 110.7, 110.0, 64.2, 55.9, 55.8, 47.8, 41.8, 41.7, 36.4, 32.7, 28.4.
FTIR (CH2Cl2), n
(cmꢀ1): 3660, 3309, 2933, 2853, 1588, 1516, 1464,
1259, 1146, 1027. HRMS (ESIþ) calcd for C17H26NO3 (MþH)þ
292.1888, found 292.1913.
4.2.16. (–)-Mesembrine
Activated manganese(IV) dioxide (Aldrich, 0.215 g, 2.47 mmol)
was added to a solution of (ꢀ)-joubertinamine (18 mg, 0.062 mmol)
in benzene (5 mL) and the mixture was stirred at room temperature
for 24 h. The resulting suspension was filtered through a thin pad of
aluminum oxide, washed thoroughly with methanol, and concen-
trated on a rotary evaporator. The residue was purified by flash
column chromatography (alumina [basic, activity I, particle size
0.063–0.200 mm], 100% ethyl acetate) to give (ꢀ)-mesembrine
20
(14.5 mg, 0.050 mmol, 81%). [
(500 MHz, CDCl3)
a]
ꢀ61.6 (c 0.20, MeOH). 1H NMR
D
d (ppm): 6.90 (m, 3H), 3.90 (s, 3H), 3.88 (s, 3H),
3.16 (m, 1H), 2.96 (t, J¼3.2 Hz, 1H), 2.61 (d, J¼3.4 Hz, 1H), 2.44 (m,
1H), 2.33 (s, 3H), 2.24–2.06 (m, 5H). 13C NMR (125 MHz, CDCl3)
d
(ppm): 212.4, 149.1, 147.6, 140.3, 117.9, 111.1, 110.0, 70.4, 56.0, 55.9,
54.9, 47.5, 40.6, 40.1, 38.9, 36.2, 35.3. HRMS (ESIþ) calcd for
C17H24NO3 (MþH)þ 290.1751, found 290.1756.
Acknowledgements
We are grateful to the NSF (CAREER, CHE-0836757) and the
Department of Chemistry and Biochemistry, University of Cal-
ifornia, Santa Barbara, for financial support of this work. Partial
funding was also provided by the ACS Petroleum Research Fund
(43838-G1).
9. Noyori, R.; Morita, Y.; Suzuki, M. J. Org. Chem. 1989, 54, 1785–1787.
10. For a recent example, see: O’Doherty, G. A.; Harris, J. M. Tetrahedron 2001, 57,
5161–5171.
11. (a) Paquette, L. A.; Reddy, Y. R.; Haeffner, F.; Houk, K. N. J. Am. Chem. Soc. 2000,
122, 740–741; (b) Paquette, L. A.; Reddy, Y. R.; Vayner, G.; Houk, K. N. J. Am.
Chem. Soc. 2000, 12
2, 10788–10794.
12. A review: Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219–225.
13. (a) Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672–3674; (b) Evans,
D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147–155.
References and notes
14. Gardiner, J. M.; Bryce, M. R. J. Org. Chem. 1990, 55, 1261–1266.
15. Liu, J. F.; Heathcock, C. H. J. Org. Chem. 1999, 64, 8263–8266.
16. Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.; Caulkett, P. R.
Tetrahedron Lett. 2003, 44, 8677–8680.
1. (a) Smith, M. T.; Crouch, N.; Gericke, N.; Hirst, M. J. Ethnopharmacol. 1996, 50,
119–130; (b) Gericke, N. P.; VanWyk, B.-E. PCT Int. Appl., WO 9746234 CAN 128:
80030, 1997.