Synthesis of new series of iboga analogues

Article abstract of DOI:10.1016/j.tetlet.2011.09.040

Synthesis of new iboga-analogues, replacing the indole ring with a benzofuran moiety has been described. Starting materials are the suitably substituted benzofuran derivatives and have been synthesized by Pd-catalyzed reactions. The conversion of endo-6-m

Full text of DOI:10.1016/j.tetlet.2011.09.040

Tetrahedron Letters 52 (2011) 6166–6169
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new series of iboga analogues
⇑
Sibasish Paul, Sankha Pattanayak, Surajit Sinha
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2011
Revised 7 September 2011
Accepted 9 September 2011
Available online 16 September 2011
Synthesis of new iboga-analogues, replacing the indole ring with a benzofuran moiety has been
described. Starting materials are the suitably substituted benzofuran derivatives and have been synthe-
sized by Pd-catalyzed reactions. The conversion of endo-6-methylcarboxylate substituted dehydroisoqu-
inuclidine to exo-isomer, a key component of iboga-alkaloids has been achieved in the presence of
NaOMe in methanol under reflux conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Iboga-analogues
Dehydroisoquinuclidine
Palladium-catalyst
Heteroannulation
The iboga-alkaloids are naturally occurring indole alkaloids,
which are found in a variety of African shrubs of the Tabernanthe
genus. Members of this family of alkaloids combine the structural
features of indole and isoquinuclidinyl ring fused by a seven-mem-
bered indoloazepine ring1 (Fig. 1). Anti-addictive properties of ibo-
gaine have been known for decades.2,3 Apart from their anti-
addictive properties, iboga-alkaloids and their congeners show a
wide variety of pharamacological effects,3 such as antifungal or
antilipase, anti-HIV-1, anti-cholinesterasic and leishmanicide
activities (against Leishmania amazonensi). However, the clinical
application of ibogaine is limited because the natural ibogaine 2
is tremorigenic,4 and neurotoxic, particularly due to the degenera-
tion of brain cells (purkinje cells) if the dose is high.5 Chemical
modifications of iboga-alkaloids have been reported in order to
have more potent analogues or congeners. So far a limited number
of its analogues6a–d and congeners6e–g have been accessible.
Mostly, the analogues have been reported either on the modifica-
tion of indoloazepine ring6a,b of the natural scaffold (5,6-homo-
logues or 6-nor of the iboga alkaloid skeleton) or in the mode of
fusion of the indole ring to isoquinuclidine moiety (type 3,
indole-[3,2] fusion).6c,d
protection like indole. Moreover these compounds are expected
to be more stable than the natural ibogaine which is heat and light
sensitive and spontaneously oxidize in solution.1a CO2Me at the C
19 carbon could be easily manipulated for further derivatization,
as substitution at this carbon has biological importance.7 In this
direction, the conversion of endo-dehydroisoquinuclidine 6b into
exo-isomer 6a is reported.
Retrosynthetically, the benzofuran analogues 4 and 5 could be
broken into two components, 3- or 2-substituted benzofuran eth-
anol 8 or 9 and the common fragment, dehydroisoquinuclidine 7
(Scheme 1).
The requisite dehydroisoquinuclidine
6 was synthesized
according to the literature procedure8 (Scheme 2). Mixture of
exo- and endo- isomers was separated by alumina column using
dichloromethane as an eluent and obtained a ratio of 3.2:1 in
favour of the less polar endo-product 6b.9
The 1H NMR of both isomers were a little complicated particu-
larly, in case of exo-isomer, methylcarboxylate (CO2Me) which
gave two sharp singlets at d 3.46 and d 3.67 (Fig. 2).
Both isomers were further characterized by the iodolactoniza-
tion method (Supplementary data). Appearance of two peaks of
methylcarboxylate of exo-isomer 6a could be explained due to
In the continuation of our research towards the synthesis of
iboga-alkaloids,6d we describe herein the synthesis and character-
ization of iboga-analogues 4 and 5, replacing the indole ring with a
benzofuran moiety. The benzofuran moiety was chosen because it
is a bioisostere of indole, the pharmacological properties might be
unchanged and the synthesis of this compound could be easier
than the natural ibogaine as benzofuran does not require any
R1
19
CO2Me
3
N
C
3
N
N
H
2
N
H
2
Ibogamine (1), R1 = H
Ibogaine (2), R1 = OMe
Iboga analogues (3)
⇑
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ocss5@iacs.res.in (S. Sinha).
Figure 1. Analogues and congeners of ibogaine.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.040

S. Paul et al. / Tetrahedron Letters 52 (2011) 6166–6169
6167
Table 1
Conversion of endo-6-substituted dehydroisoquinuclidine to exo-isomera
O
3
3
N
OMe
OMe
16
Ratiob exo:endo
16
Entry Base
used
Quenching temp
Proton
source
N
19
O
O
O
2
2
(°C)
Iboga analogues; 4
Iboga analogues; 5
1
2
LDAc
50
H2O
Complex
mixture
Complex
mixture
56:44
LDA
50
t-BuOH
HO
R
OH
3
N
CO2Me
3
4
5
LDA
LDA
LDA
25
25
25
H2O
t-BuOH
HCl (0.5 N)
2
53:47
O
O
Complex
mixture
30:70
28:72
22:78
6
2-benzofuran-
3-benzofuran-
Dehydro-isoquinuclidine;
R = Cbz, 6a/6b (exo/endo)
R = H, 7a/7b (exo/endo)
ethanol; 9
ethanol; 8
6
7
8
9
LDA
LDA
LDA
LDA
0
0
À78
À78
65
H2O
t-BuOH
H2O
t-BuOH
MeOH
Scheme 1. Retrosynthetic strategy.
18:82
90:10
10
NaOMe
a
Experiments were carried out with pure endo isomer 6b.
Ratios were calculated on the basis of chemical yield (after purification using
b
(b)
(b)
more polar
exo, 6a, 17%
alumina column).
CBz
N
7a.HBr
7b.HBr
c
The solution of 6b in THF was added dropwise to LDA and stirred for 2 h at
À78 °C to generate the enolate.
CO2Me
(a)
alumina
column
6
mixture
exo- + endo-
lesspolar
endo, 6b, 55%
OTBDMS
Scheme 2. Synthesis of dehydoisoquinuclidine. aReagents and conditions: (a)
NaOMe (1.5 equiv), MeOH, reflux; (b) 20% HBr–AcOH.
OH
(c)
3
I
(a), (b)
+
OH
2-iodophenol
O
TBDMS
3-benzofuran-
ethanol; 8
disilylated
alkyne; 11
OTs
(d)
N
CO2Me
O
O
7a.HBr
or
12
exo; 13a (73%)
endo; 13b (79%)
7b.HBr
(e)
N
CO2Me
13a or 13b
O
exo; 4a (42%) and endo; 4b (22%)
Scheme 3. Synthesis of iboga analogues 4a and 4b. Reagents and conditions: (a)
Pd(OAc)2(10 mol %), LiCI (1.0 equiv), Na2C03 (6.0 equiv),DMF, 100 °C; (b) TBAF
(2.5 equiv), THF, 55% after two steps; (c) TsCI (1.2 equiv), Et3N (2.0 equiv), DMAP
(10 mol %) CH2CI2, 71%; (d) K2C03 (2.5 equiv), CH3CN, 80 °C; (e) PdCI2(CH3CN)2
(2.0 equiv.), AgBF4 (4.0 equiv), Et3N (1.0 equiv), CH3CN followed by NaBH4
(1.0 equiv), MeOH, 0 °C.
conversion at 25 °C. The epimerization of N-unprotected isoquinu-
clidine was reported earlier;8b however, experimental procedure or
the isolation method of the product was not included in this Letter.
We tried the isomerization of 7b following their conditions8b but
failed to isolate any product and the mass spectra of the crude
product show a peak corresponding to the free amino acid. How-
ever, under similar conditions, the Cbz-protected endo-isomer 6b
underwent 90% conversion to the exo-isomer10 (Table 1). Cbz-
deprotection of 6a and 6b was performed separately using 20%
HBr–AcOH and HBr salt of 7a and 7b was then used in the next step
for the synthesis of iboga-analogues (Scheme 2).
The 3-benzofuranethanol 8 was synthesized using Larock’s het-
eroannulation reaction11a between 2-iodophenol and internal
alkyne 11 followed by the treatment with tetrabutyl ammonium
fluoride and obtained 55% yield in two steps. The internal alkyne
11 was in turn synthesized from 3-butyn-1-ol in the presence of
n-BuLi and tert-butyldimethylsilyl chloride11b in 70% yield. The
TBDMS protection was chosen because it survived under the het-
eroannulation conditions, whereas other silyl-based protecting
Figure 2. 1H NMR (500 MHz) of compounds 6a and 6b.
the presence of rotamers and it is prominent in the case of 6a, as
exo-CO2Me lies in close proximity to Cbz group. Interestingly,
two peaks became a broad singlet at d 3.65 when the NMR spec-
trum was recorded at 60 °C in CDCl3.
Natural ibogaine 2 carries an exo-substituted ethyl side chain at
C 20. During cycloaddition reaction we obtained the exo-product as
the minor isomer, consequently we tried to improve the yield of
our exo-Diels–Alder product 6a. In the connection of the synthesis
of ibogaine analogues, Passarella, et al.6g were unsuccessful in
isomerization of dehydroisoquinuclidines in the presence of LDA.
Our initial effort for the conversion of kinetically controlled endo-
product to exo-isomer using LDA at 50 °C furnished a complex
mixture. Reducing the quenching temperature gave moderate

6168
S. Paul et al. / Tetrahedron Letters 52 (2011) 6166–6169
OX
2.86, dd, Jgem= 17.8 Hz
I
3.01, dt; Jgem= 12.5 Hz
(a)
(c)
2
3.73; br s
7a.HBr
O
OH
2-iodophenol
3.30, m
or
X= H, 9
N
7b.HBr
(b)
H
14
H
X= Ts,
H
H
CO2Me
(d)
CO2Me
H
O
H
CO2Me
H
N
N
O
4.2, t;
O
H
H
J= 9.0 Hz
H
exo; 5a (46%)
endo;5b (27%)
exo; 15a; 75%;
endo; 15b; 83%
2.38, 1.81; m
2.08; m
2.13; br s
Scheme 4. Synthesis of iboga analogues 5a and 5b. Reagents and conditions: (a) 3-
butyn-1-ol (1 equiv), Pd(OAc)2 (5 mol %), Cul (5 mol %), PPh3 (5 mol %), Et3N, rt,
16 h, 87%; (b) TsCI (1.2 equiv), Et3N (2.0 equiv), DMAP (10 mol %), CH2CI2, 71%; (c)
K2CO3 (2.5 equiv), CH3CN, 80 °C; (d) PdCI2(CH3CN)2 (2.0 equiv), AgBF4 (4.0 equiv.),
Et3N (1.0 equiv), CH3CN followed by NaBH4 (1.0 equiv), MeOH, 0 °C.
4b
1.79; m
2.29; m
1.97; br s
1.51; dq; J= 13.0, 3.3 Hz
2.06; m
H
H
H
3.16; m
H
H
H
3.57; m
groups (TMS or TES) gave a mixture of products.11b Compound 8
was then converted into the tosyl derivative 12, which was then
conjugated separately to isoquinuclidine 7a.HBr and 7b.HBr in
the presence of K2CO3/CH3CN at 80 °C to obtain 13a and 13b,
respectively. Pd(II)–Ag(I) mixed metal mediated cyclization was
originally developed by Trost for the synthesis of ibogamine12
and we applied this methodology to its analogues 13a and 13b
to obtain 4a13 and 4b in 42% and 22% yields, respectively (Scheme
3). It is worth to mention here that while synthesizing iboga-scaf-
folds,8a we had a difficulty in both heteroannulation and cycliza-
tion steps particularly using endo-isomers where a mixture of
regioisomers was obtained and 2-iodoaniline was required to pro-
tect with tosyl group. We also realized that handling the benzofu-
ran-substituted products and work-up procedures were much
easier than the corresponding iboga-alkaloids.
For the synthesis of iboga analogues 5, the requisite benzofuran
alcohol 9 was synthesized in one pot from 2-iodophenol via Sono-
gashira coupling with 3-butyn-1-ol at room temperature. Subse-
quent tosylation and conjugation to 7a. HBr and 7b.HBr afforded
15a and 15b in 75% and 83% yields, respectively.
When compound 15a was subjected to the mixed-metal-medi-
ated cyclization method, gratifyingly the reaction proceeded
smoothly to give the desired product 5a14 in 46% yield. A similar
cyclization of compound 15b also delivered the product 5b, though
in lower yield (27%) (Scheme 4). Surprisingly, the endo-isomers
13b and 15b were more polar than their exo-isomers which were
not in the case of 6b.
H
CO2Me
H
H
H
N
O
3.04; dt; J= 9.0, 3.0 Hz
2.95; d, J= 9.0 Hz
3.48; br s
5a
Figure 3. Proton assignments of compounds 4b and 5a.
and 5a have been assigned by the decoupled 1H NMR and their
coupling constants were confirmed as well (Fig. 3).
The structure of the compounds 4b and 5b was confirmed by
the X-ray crystallographic analysis (Fig. 4).
In summary, we have reported the synthesis of benzofuran-ana-
logues of iboga alkaloids. Our synthetic approach is non-biochem-
ical, extremely short, flexible and also anticipated that minor
modifications of the starting materials (phenol and alkyne) should
provide access to several other analogues of this alkaloid family for
biological screening. Also functional group transformation of C 19
ester can provide us the true SAR to optimize the potency and
efficacy of the analogues. Conversion of endo-6-substituted
dehydroisoquinuclidine into its exo-isomer, a key component of
iboga-alkaloids has been achieved.
All new compounds have been characterized by IR, NMR, and
mass spectroscopy. The protons of isoquinuclidine rings of 4b
Figure 4. Crystal structure of compounds 4b and 5b.

S. Paul et al. / Tetrahedron Letters 52 (2011) 6166–6169
6169
and 47.18, 47.22 and 47.52, 51.97, 66.96 and 67.01, 127.89, 127.95, 128.01,
128.53, 130.32 and 130.72, 135.19 and 135.50, 136.92, 154.85 and 155.27,
173.20; HRMS (ESI) (M + Na)+ calcld for C17H19NO4Na+ = 324.1212, Found
324.1213. ⁄(NMR spectra of both isomers are complicated due to CBz-
rotamers.)
Acknowledgements
S. S. thanks DST, India, for financial support by a grant [SR/S1/
OC-38/2007]. S. P. and S. P. are thankful to CSIR for their fellowship.
Crystal structure determination was performed at the DST-funded
National Single Crystal Diffractometer15,16 Facility at the Depart-
ment of Inorganic Chemistry, IACS.
10. Endo-exo conversion using NaOMe/MeOH: To
a reflux solution of sodium
methoxide (47 mg, 0.872 mmol) in anhydrous methanol (2.0 mL) was slowly
added the methanolic (3.0 mL) solution of compound 6b (175 mg, 0.581 mmol)
under argon atmosphere. The reaction mixture was refluxed for a period of 7 h.
Methanol was removed in vacuo, crude reaction mixture was diluted with
dichloromethane (20 mL). The organic extract was washed with brine (10 mL),
dried over Na2SO4 and concentrated in vacuo to give crude yield 90% (157 mg).
After purification by alumina column using dichloromethane as eluent, the
yield of exo-isomer was 141 mg (80.6%) and endo-isomer was recovered 16 mg
(9%).
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.040.
11. (a) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60,
3270–3271; (b) Bishop, B. C.; Cottrell, I. F.; Hands, D. Synthesis 1997, 1315–
1320.
References and notes
12. Trost, B. M.; Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc. 1978, 100, 3930–3931.
13. Preparation and characterization data for 4a: To
bis(acetonitrile)palladium dichloride (194 mg, 0.75 mmol) in CH3CN (1.5 mL)
was added Et3N (52 L, 0.37 mmol) under an argon atmosphere. Silver
a
slurry of
1. (a) Alper, K. R. The Alkaloids 2001, 56, 1–38; (b) Sundberg, R. J.; Smith, S. Q. The
Alkaloids 2002, 59, 281–376.
2. (a) Mash, D. C.; Staley, J. K.; Baumann, M. H.; Rothmann, R. B.; Hearn, W. L. Life
Sci. 1995, 57, 45–50; (b) Lotsof, H. S. Maps 1995, 5, 16–27; (c) Touchette, N. Nat.
Med. 1995, 1, 288–289; (d) Popik, P.; Layer, R. T.; Skolnick, P. Pharmacol. Rev.
1995, 47, 235–253.
3. (a) Maciulaitis, R.; Kontrimaviciute, V.; Bressolle, F. M. M.; Briedis, V. Hum. Exp.
Toxicol. 2008, 27, 181–194; (b) Gallo, C. C.; Renzil, P.; Loizzo, S.; Loizzo, A.;
Capasso, A. Pharmacologyonline 2009, 3, 906–920.
4. Glick, S. D.; Rossman, K.; Rao, N. C.; Maisonneuve, I. M.; Carlson, J. N.
Neuropharmacology 1992, 31, 497–500.
5. O’Hearn, E.; Molliver, M. E. J. Neurosci. 1997, 17, 8828–8841.
6. Analogues: (a) Sundberg, R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836–4842;
(b) Sundberg, R. J.; Cherney, R. J. J. Org. Chem. 1990, 55, 6028–6037; (c)
Sundberg, R. J.; Hong, J.; Smith, S. Q.; Sabat, M. Tetrahedron 1998, 54, 6259–
6292; (d) Jana, G. K.; Sinha, S. Tetrahedron Lett. 2010, 51, 1994–1996;
Congeners: (e) Repke, D. B.; Artis, D. R.; Nelson, J. T.; Wong, E. H. F. J. Org.
Chem. 1994, 59, 2164–2171; (f) Efange, S. M. N.; Mash, D. C.; Khare, A. B.;
Ouyang, Q. J. Med. Chem. 1998, 41, 4486–4491; (g) Passarella, D.; Favia, R.;
Giardini, A.; Lesma, G.; Martinelli, M.; Silvani, A.; Danieli, B.; Efange, S. M. N.;
Mash, D. C. Bioorg. Med. Chem. 2003, 11, 1007–1014.
7. Bandarage, U. K.; Kuehne, M. E.; Glick, S. D. Tetrahedron 1999, 55, 9405–9424.
8. (a) Jana, G. K.; Sinha, S. Tetrahedron Lett. 2010, 51, 1441–1443; (b) Street, L. J.;
Baker, R.; Book, T.; Kneen, C. O.; MacLeod, A. M.; Merchant, K. J.; Showell, G. A.;
Saunders, J.; Herbert, R. H.; Freedman, S. B.; Harley, E. A. J. Med. Chem. 1990, 33,
2690–2697.
l
tetrafluoroborate (290 mg, 1.48 mmol) was added and the orange
heterogeneous mixture immediately became yellow. After 15 min, a solution
of 13a (116 mg, 0.37 mmol) in CH3CN (2.0 mL) was added. The deep red
solution was then stirred for 1 h at room temperature then heated at 70 °C for
12 h under argon atmosphere. The reaction mixture was cooled to 0 °C, MeOH
(1.0 mL) was added, followed by addition of NaBH4 (16 mg, 0.43 mmol)
portionwise. The solution was stirred for 1 h at 0 °C. The reaction mixture was
filtered through a pad of Celite, washed with methanol (5 mL). The organic
extract was concentrated in vacuo and purified by column chromatography
(100–200 mesh Silica gel) using EtOAc in petroleum ether (PE:EtOAc, 9:1 to
1.5:1) as eluent to get the compound 4a (48 mg, 42%) as a colorless oil
(Rf = 0.39, PE:EtOAc, 2.3:1).
IR (neat, CHCl3):
m ;
2933, 2864, 1735, 1456, 1203, 748 cmÀ1 1H NMR (500 MHz,
CDCl3): d 1.71 (1H, dq, J = 15.0, 3.5 Hz), 1.77–1.83 (1H, m), 1.98 (1H, br s), 2.04–
2.09 (1H, m), 2.27–2.31 (1H, m), 2.52–2.54 (1H, m), 2.69 (1H, ddd, J = 11.0, 6.5,
1.6 Hz), 2.98 (1H, d, J = 9.0 Hz), 3.04 (1H, dt, J = 9.0, 3.0 Hz), 3.18–3.24 (2H, m),
3.29–3.36 (2H, m), 3.56 (1H, br s), 3.73 (3H, s), 7.19-7.23 (2H, m), 7.36 (1H, dd,
J = 6.8, 1.75 Hz), 7.40 (1H, dd, J = 6.5, 2.0 Hz); 13C NMR (125 MHz, CDCl3): d
19.2, 25.9, 26.4, 33.2, 39.6, 45.4, 49.1, 52.1, 52.9, 56.1, 110.7, 116.3, 118.8,
122.3, 123.5, 130.7, 153.7, 159.2, 175.2; HRMS (ESI) (M+H)+ calcld for
C
19H21NO3H+ = 312.1600. Found 312.1594.
14. Selected characterization data for 5a: The procedure was same as reported for
the synthesis of 4a (above). The crude product obtained from compound 15a
(115 mg, 0.37 mmol) was purified by column chromatography on silica gel
using EtOAc in PE as eluent to yield the compound 5a (53 mg, 46%) as a
9. Selected characterization data for 6a: IR (neat):
m 2953, 2874, 1732, 1694,
1415 cmÀ1 1H NMR (500 MHz, CDCl3)⁄: d 1.52–1.59 (1H, m), 2.08–2.09 and
;
colorless oil (Rf = 0.38, PE:EtOAc, 4:1). IR (neat, CHCl3):
m 2953, 1732, 1607,
1450, 1251, 745 cmÀ1 1H NMR (500 MHz, CDCl3): d 1.51 (1H, dq, J = 13.0,
;
2.118–2.123 (1H, m), 2.50–2.54 and 2.56–2.59 (1H, m), 2.76–2.76 (1H, m),
2.99–3.04 (1H, m), 3.37–3.40 and 3.43–3.45 (1H, dd, J = 10.2, 1.5), 3.46 and 3.65
(3H, s), 4.98–5.10 (3H, m), 6.41–6.49 (2H, m), 7.25–7.33 (5H, m); 13C NMR
(125 MHz, CDCl3)⁄: d 25.06 and 25.25, 30.16 and 30.36, 44.27 and 44.56, 47.41
and 47.81, 48.10 and 48.50, 51.95 and 52.25, 66.78 and 66.92, 127.68, 127.86,
127.98, 128.04, 128.48, 128.56, 128.67, 131.78, 132.25, 135.20 and 135.47,
137.00 and 137.17, 155.02 and 155.61, 173.63 and 174.06; HRMS (ESI) (M+Na)+
calcd for C17H19NO4Na+ = 324.1212. Found 324.1213.
3.3 Hz), 1.77–1.83 (1H, m), 1.97 (1H, br s), 2.05–2.11 (1H, m), 2.27–2.32 (1H,
m), 2.71–2.75 (2H, m), 2.95 (1H, d, J = 9.0 Hz), 3.04 (1H, dt, J = 9.0, 3.0 Hz),
3.13–3.26 (3H, m), 3.48 (1H, br s), 3.53–3.60 (1H, m), 3.73 (3H, s), 7.17–7.22
(2H, m), 7.35–7.38 (2H, m); 13C NMR (125 MHz, CDCl3): d 25.7, 26.11, 26.36,
33.2, 34.1, 45.9, 49.1, 50.8, 51.9, 58.1, 110.6, 118.3, 121.6, 122.2, 123.5, 129.7,
151.9, 153.8, 175.3; HRMS (ESI) (M+H)+ calcld for C19H21NO3H+ = 312.1600.
Found 312.1594.
Selected characterization data for 6b: IR (neat):
m 2915, 2879, 1432, 1693, 1415,
15. Bruker, version 2.1-0; Bruker AXS, Inc.: Madison, WI, 2006.
16. X-ray crystallographic data for compounds 4b and 5b have been deposited to
the Cambridge Crystallographic Data Centre and assigned the deposition
numbers CCDC 809688 for 4b and CCDC 809689 for 5b.
1112 cmÀ1 1H NMR (500 MHz, CDCl3): d 1.86–1.92 (2H, m), 2.83–2.87 (1H, m),
;
2.99–2.99 (1H, m), 3.01–3.13 (1H, m), 3.30–3.33 (1H, m), 3.67 (3H, s), 5.09–5.21
(3H, m), 6.32–6.39 (1H, m), 6.43–6.48 (1H, m), 7.31–7.38 (5H, m); 13C NMR
(125 MHz, CDCl3)⁄: d 26.10 and 26.25, 30.49 and 30.72, 43.82 and 44.12, 46.85