Toward the enantioselective total synthesis of lyngbyatoxin A: On the stereocontrolled introduction of the quaternary stereogenic centre

Article abstract of DOI:10.1016/S0040-4020(03)00822-6

This paper deals with an approach to the enantioselective total synthesis of Lyngbyatoxin A, with focus on the stereocontrolled introduction of the quaternary stereogenic centre. The key step in the synthesis involves an enantiospecific Lewis-acid mediate

Full text of DOI:10.1016/S0040-4020(03)00822-6

Tetrahedron 59 (2003) 6937–6945
Toward the enantioselective total synthesis of lyngbyatoxin A:
on the stereocontrolled introduction of the quaternary
stereogenic centre
*
Janne E. Tønder and David Tanner
Department of Chemistry, Technical University of Denmark, Building 201, Kemitorvet, DK-2800 Kgs. Lyngby, Denmark
Received 2 April 2003; revised 23 April 2003; accepted 12 May 2003
Dedicated to Professor K. C. Nicolaou, upon his receipt of the Tetrahedron Prize for 2002
Abstract—This paper deals with an approach to the enantioselective total synthesis of Lyngbyatoxin A, with focus on the stereocontrolled
introduction of the quaternary stereogenic centre. The key step in the synthesis involves an enantiospecific Lewis-acid mediated
rearrangement of chiral vinyl epoxides carrying a 7-substituted indole moiety.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
several syntheses of 2 have been documented15,16 we are
aware of only one total synthesis17 of 1 and two completed
routes18,19 to 3. A common feature of these approaches is
the lack of stereochemical control of the quaternary
stereogenic centre(s)20–23 of the targets. More recently,
Sames24 has reported a very intriguing approach to the
racemic form of teleocidin B-4 (which is the epimer of 3 at
both quaternary centres). We are currently engaged in
research into the chemical biology of structures which
activate PKC, and as part of that program we have
undertaken the total synthesis of 1. The present paper
describes a method for stereocontrolled introduction of the
quaternary centre of Lyngbyatoxin A.
Lyngbyatoxin A (1, also known as teleocidin A-1) is a
marine natural product isolated from the Hawaiian variant
of Lyngbya Majuscula Gomont.1 Alkaloids of this indo-
lactam family, which also includes indolactam-V (2) and
teleocidin B-3 (3), have attracted much biological interest
because they are potent activators of protein kinase C
(PKC)2 which is implicated in the regulation of various
cellular responses. Malfunction of PKC can lead inter alia
to tumor development and diabetic complications, and
members of the PKC family are thus promising targets for
medicinal chemistry; selective activators and inhibitors of
PKC are therefore perceived as useful tools for drug
development (Fig. 1).3–14
Our overall retrosynthetic analysis is shown in Scheme 1(a),
application of the indicated disconnections leading back to
trisubstituted indole 6, which was envisioned to derive from
7-bromoindole, 7. The synthetic sequence which takes 7 to 6
The structurally more elaborate teleocidins also present a
substantial challenge to chemical synthesis, and while
Figure 1.
Keywords: lyngbyatoxin A; teleocidins; vinyl epoxide rearrangement.
*
Corresponding author. Tel.: þ45-452-521-88; fax: þ45-459-339-68; e-mail: dt@kemi.dtu.dk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00822-6

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J. E. Tønder, D. Tanner / Tetrahedron 59 (2003) 6937–6945
Scheme 1. (a) Retrosynthetic analysis of Lyngbyatoxin A, 1. (b) Scheme for control of stereochemistry at the 48 stereogenic centre.
is thus (i) introduction of functionality at C-7; (ii) Vilsmeier
formylation25 at C-3 and (iii) regioselective iodination25 at
C-4. Scheme 1(b) shows our plan for elaboration of, and
control over, the stereogenic centre in the C-7 side-chain.
The key step involves methodology developed by Jung26,27
and relies on the enantiospecific Lewis-acid mediated
rearrangement of chiral vinyl epoxides,28 which are
themselves available via the Sharpless asymmetric epoxi-
dation29 reaction. Jung27 has made studies of migratory
aptitudes30 and the relative stability of cationic inter-
mediates involved in this type of rearrangement, and on
that basis we surmised that two regioisomeric vinyl
epoxides could serve our purpose: rearrangement of 11 via
migration of the indole moiety, or rearrangement of 12 via
vinyl migration. At the outset, we had no information
regarding the migratory aptitude of the indole nucleus, so 11
was chosen as the first target, to allow direct comparison
with the work of Jung27 which involved a phenyl group
instead of the indole system.
epoxides shown in Scheme 2 (and Scheme 5) were rather
unstable, and were used as soon as possible. This was
particularly true for the N-benzyl series leading to 11b, and
these intermediates could not be fully characterized. The
results of the rearrangement reactions (Scheme 3) are
collected in Table 1.
The rearrangement reactions were carried out according to
the published procedure26 and proved to be both rapid and
highly efficient processes, requiring only very short reaction
times at 2788C. We began by repeating earlier work27 with
11d (Table 1, entry 4) and could easily reproduce the
exclusive phenyl migration to the tertiary and allylic
carbocation. However, subjection of the N-allyl or N-benzyl
indole substrates (11a or 11b) to the same reaction
conditions gave exclusively the products of vinyl migration,
implying that the secondary indole-stabilized carbocation is
preferred to the tertiary allylic species (Table 1, entries 1
and 2). In order to attenuate the cation-stabilizing effect of
the indole nitrogen, the N-tosyl derivative 11c was chosen,
and rearrangement of this substrate did indeed deliver the
desired product, but as the minor component (Table 1, entry
3). The tertiary carbocation is now favoured, but hydride
migration is faster than migration of the indole moiety. This
quite surprising result can be explained on the basis of the
mechanistic rationale introduced and refined by Coxon34
and also invoked by Jung.26 Formation of the tertiary allylic
carbocation is followed by rotation of the O–BF3 unit
toward the sterically less demanding group on the adjacent
carbocation centre, which aligns the C–H bond with the
vacant p-orbital (Scheme 4). However, there is obviously
little energetic difference between this pathway and the
2. Results and discussion
The synthesis of three differently N-protected variants of 11
is shown in Scheme 2, the Heck reaction being used for
introduction of the embryonic C-7 side-chain.31 Apart from
15c all the cis/trans isomeric mixtures resulting from the
Heck reaction could be separated by flash chromatography.
In fact, the N-tosyl products proved impossible to separate at
any stage of the sequence, and were thus carried through as a
1:2 cis/trans mixture. The stereochemistry of the Heck
products was assigned by NMR spectroscopy.32,33 The

J. E. Tønder, D. Tanner / Tetrahedron 59 (2003) 6937–6945
6939
Scheme 2. The Tosyl-protected compounds (15c–18c and 11c) were obtained as a mixture of (Z/E)-isomers. (a) 2-Methyl methacrylate, PdCl2(P(o-Tol)3)2,
Bu4NBr, NEt3, DMF, 908C; (b) AllBr, NaH, DMF, 208C; (c) TosCl, NaH, DMF; (d) Dibal-H, toluene; (e) tert-BuOOH, D-(2)-DIPT, Ti(OiPr)4; (f) TPAP,
˚
NMO, 4 A molecular sieves, CH2Cl2, 208C; (g) KHMDS, Ph3PCH3Br, THF, 208C.
Scheme 3. Rearrangement of vinyl epoxides.
alternative clockwise rotation which correctly aligns the
indole moiety for migration. It should be noted that the
experiment with the N-tosyl species was carried out on
Table 1. Lewis acid catalysed rearrangement of vinyl epoxides
the inseparable cis/trans mixture of vinyl epoxides, and the
Compound
R
A
B
C
D
cis compound (not shown in Scheme 4) gives rise to
the enantiomer of each type of rearrangement product.
Products of type B and D (Table 1) quite rapidly isomerized
to the conjugated ketones.
11a
All-indole
Bn-indole
Tos-indole 40% (10c) 60% (20c)
Ph .99%
0
0
0
0
0
0
0
0
.99% (19a)
.99% (19b)
0
0
11b
11c
11d27
0
The product distribution was measured by 1H NMR spectroscopy.
A simple solution to the problem was found by switching to

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J. E. Tønder, D. Tanner / Tetrahedron 59 (2003) 6937–6945
Scheme 4. Ind¼N-tosyl, C-7-substituted indole.
Scheme 5. (a) BnBr, KOH, DMF, 208C; (b) ethyl crotonate, PdCl2(P(o-Tol)3)2, Bu4NBr, NEt3, DMF, 908C; (c) Dibal-H, toluene, 250!58C; (d) tert-BuOOH,
i
˚
L-(þ)-DET, Ti(O Pr)4, CH2Cl2, 2208C; (e) TPAP, NMO, 4 A molecular sieves, CH2Cl2, 208C; (f) KHMDS, Ph3PCH3Br, THF, 208C; (g) BF3·OEt2, CH2Cl2,
2788C, 2.5 min.
Scheme 6. Ind¼N-benzyl, C-7-substituted indole.

J. E. Tønder, D. Tanner / Tetrahedron 59 (2003) 6937–6945
6941
rearrangement of the regioisomeric vinyl epoxide 12, the
synthesis of which is shown in Scheme 5. In this
rearrangement a tertiary, indole-stabilized carbocation is
pitted against a secondary allylic centre. This process
requires the opposite sense of absolute configuration of the
epoxide, and relies on the assumption that vinyl migration
should be considerably faster30 than hydride migration.
Fortunately, this turned out to be the case and the desired
chiral aldehyde was obtained in 88% yield.
to give 819 mg (93%) of an orange oil. Column chroma-
tography (ethyl acetate/heptane 1:7) gave 474 mg (54%) of
the desired product as a violet oil, which solidified on
standing. 182 mg (37%) starting material was recovered. 1H
NMR (CDCl3) d 7.92 (d, J¼3.9 Hz, 1H), 7.69 (d, J¼8.4 Hz,
2H), 7.53 (dd, J¼7.8, 1.2 Hz, 1H), 7.46 (dd, J¼7.8, 1.2 Hz,
1H), 7.27 (d, J¼8.7 Hz, 2H), 7.06 (t, J¼7.8 Hz, 1H), 6.72
(d, J¼3.9 Hz, 1H), 2.40 (s, 3H). 13C NMR (CDCl3) d 144.7,
137.5, 135.0, 133.7, 130.8, 130.7, 129.8, 127.2, 124.6,
120.8, 107.7, 106.2, 21.8. MS (EI): 351, 204, 196, 155, 115,
91. HRMS (EI) m/z calcd for C15H12BrNO2S 348.9772,
found 348.9776.
However, the enantiomeric purity of the starting vinyl
epoxide (92% ee) was not reflected in that of the product
(71% ee), indicating that the rate of vinyl migration is only
slightly higher than the rate of conformer equilibration in
the complex formed after C–O bond cleavage. The absolute
configuration of the major enantiomer of the product
(Scheme 6) is assigned on the basis of the type of argument
presented earlier: anti-clockwise rotation in complex 26
places the OBF3 and indole moieties as far apart as possible,
and correctly aligns the vinyl group for migration, leading to
the desired absolute stereochemistry (10b).
3.2. General procedure for the Heck reaction
3.2.1. (E)-Methyl 3-(7-indolyl)-2-methacrylate (13). A
mixture of 7-bromoindole (2.77 g, 14.1 mmol), methyl
methacrylate (7.56 mL, 70.6 mmol), dichlorobis(tri-o-tolyl-
phosphine)palladium(II) (0.42 g, 0.53 mmol), triethylamine
(29 mL, 212 mmol), and tetrabutylammonium bromide
(0.909 g, 2.82 mmol) in DMF (75 mL) was stirred at 908C
under nitrogen for 2 h. Ethyl acetate (250 mL) was added
and the mixture was washed with brine (2£100 mL) and
water (100 mL), dried (MgSO4) and evaporated to give
4.05 g of a brown oil. 1H NMR showed the desired product
as a mixture of isomers in a Z/E relationship of 1:2. The
assignment was based on literature data.32 Column
chromatography (ethyl acetate/heptane 1:5) gave 1.22 g
(40%) of the desired product as a yellow oil.
In conclusion, we have developed the first enantioselective
method for stereocontrolled introduction of the quaternary
stereogenic centre of Lyngbyatoxin A. We are currently
exploring ‘second generation’ enantioselective approaches,
and results will be reported elsewhere.
3. Experimental
1H NMR (CDCl3) (E-isomer): d 8.29 (bs, 1H), 7.95 (s, 1H),
7.66 (dd, J¼8.0, 1.0 Hz, 1H), 7.25–7.22 (m, 1H), 7.22–7.21
(m, 1H), 7.17 (td, J¼8.0, 2.5 Hz, 1H), 6.62–6.60 (m, 1H),
3.87 (s, 3H), 2.13 (s, 3H). 13C NMR (CDCl3) (E-isomer): d
168.4, 134.5, 124.5, 122.7, 121.8, 121.6, 120.7, 119.8,
119.5, 103.3, 103.2, 52.3, 14.8. MS (EI): 215, 184, 154, 129,
77. HRMS (EI) m/z calcd for C13H13NO2 215.0946, found
215.0951.
3.1. General remarks
Tetrahydrofuran and toluene were distilled under nitrogen
from sodium/benzophenone prior to use. Triethylamine and
dichloromethane were distilled under nitrogen from calcium
hydride prior to use. Methyl methacrylate, ethyl crotonate
and Ti(OiPr)4, were vacuum distilled before use. All other
commercially available compounds were used as received.
N-Benzyl-7-bromoindole (21)35 and dichlorobis(tri-o-tolyl-
phosphine)palladium(II)36 were synthesised following
literature procedures. All air- and moisture-sensitive reac-
tions were carried out under nitrogen in oven-dried
3.2.2. (Z/E)-Methyl 3-(N-p-toluenesulfonylindol-7-yl)-2-
methacrylate (15c). Prepared from 7-bromo-1-p-toluene-
sulfonylindole (14) (1.10 g, 3.14 mmol), methyl metha-
crylate (3.36 mL, 31.4 mmol), PdCl2(P(o-tolyl)3)2 (0.123 g,
0.157 mmol), triethylamine (6.56 mL, 47.1 mmol), and
tetrabutylammonium bromide (0.202 g, 0.63 mmol) by the
general procedure for the Heck reaction. There was obtained
1.06 g (91%) of the desired product as a mixture of isomers
in a Z/E relationship of 1:2 (Assignment was based on
comparison with 15a and 22). 1H NMR (CDCl3) d (E)
8.14–8.13 (m, 1H), 7.84 (d, J¼3.9 Hz, 1H), 7.54 (d,
J¼7.8 Hz, 1H), 7.47 (d, J¼8.7 Hz, 1H), 7.22 (t, J¼7.8 Hz,
1H), 7.16 (dd, J¼8.7, 1.2 Hz, 2H), 6.98 (d, J¼7.8 Hz, 1H),
6.75 (d, J¼3.9 Hz, 1H), 3.90 (s, 3H), 2.35 (s, 3H), 1.60 (d,
J¼1.2 Hz, 3H). (Z) 7.79 (d, 3.9 Hz, 1H), 7.54 (d, J¼7.8 Hz,
1H), 7.51 (d, J¼8.7 Hz, 1H), 7.18 (t, J¼7.8 Hz, 1H), 7.16
(dd, J¼8.7, 1.2 Hz, 2H), 6.98 (d, J¼7.8 Hz, 1H), 6.71 (d,
J¼3.9 Hz, 1H), 3.75 (s, 3H), 2.36 (s, 3H), 1.60 (d,
J¼1.2 Hz, 3H). MS (EI): 369, 214, 198, 182, 155, 154,
91. HRMS (EI) m/z calcd for C20H19NO4S 369.1035, found
369.1026.
glassware. H (300 or 500 MHz) and 13C (75 or 125 MHz)
1
NMR spectra were recorded on a Varian Mercury 300 or a
Varian Inova 500, respectively. High resolution mass
spectra were provided by the Department of Chemistry,
University of Copenhagen. Enantiomeric excess (ee) was
determined by chiral HPLC analysis using a Daicel OD
column with heptane/isopropanol 90:10 as eluent. Com-
1
pounds 11b and 15b–19b were characterized only by H
NMR due to instability problems.
3.1.1. 7-Bromo-1-p-toluenesulfonylindole (14). Sodium
hydride (306 mg, 3.27 mmol) was added to a 08C solution of
7-bromoindole (493 mg, 2.51 mmol) in THF (20 mL). This
greyish mixture was stirred at 208C for 15 min, before
addition of p-toluenesulfonyl chloride (575 mg,
3.02 mmol). Stirring was continued at 208C overnight.
Water (5 mL) was added and the mixture was concentrated
in vacuo. To the residue was added water (25 mL), and the
mixture was extracted with dichlorormethane. The com-
bined organic phases were dried (MgSO4), and evaporated
3.2.3. (E)-Ethyl 3-(N-benzylindol-7-yl)-crotonate (22).
Prepared from 7-bromo-N-benzylindole (21) (3.00 g,

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10.5 mmol), ethyl crotonate (26.0 mL, 210 mmol), PdCl2-
(P(o-tolyl)3)2 (0.413 g, 0.525 mmol), triethylamine
(22.0 mL, 158 mmol), and tetrabutylammonium bromide
(0.677 g, 2.10 mmol) by the general procedure for the Heck
reaction. 947 mg (30%) of the pure desired product isomer
(22) was obtained as well as 599 mg (19%) of a (Z/E)-
mixture. The overall (Z/E)-ratio is 1:8. The assignment was
tration of the combined organic layers gave 286 mg of a
yellowish oil which turned red on standing. Column
chromatography (ethyl acetate/heptane 1:3) gave 179 mg
(92%) of the desired alcohol as a colourless oil.
1H NMR (CDCl3) d 7.57 (d, J¼7.8 Hz, 1H), 7.10 (dt, J¼7.8,
1.2 Hz, 1H), 7.05 (d, J¼3.0 Hz, 1H), 6.95–6.93 (m, 2H),
6.56 (dd, J¼3.3, 1.2 Hz, 1H) 6.05–5.94 (m, 1H), 5.17–5.12
(m, 1H), 4.92–4.82 (m, 3H), 4.28 (s, 2H), 1.82 (bs, 1H),
1.79 (s, 3H) 13C NMR (CDCl3) d 138.7, 135.4, 134.0, 129.6,
129.4, 123.9, 122.7, 121.8, 120.0, 119.4, 116.1, 101.9, 68.3,
50.6, 15.3. MS (EI): 227, 168, 154, 130, 117. HRMS (EI)
m/z calcd for C15H17NO 227.1310, found 227.1311.
1
based on literature data.33 (E)-isomer: H NMR (CDCl3) d
7.63 (dd, J¼8.0, 1.5 Hz, 1H), 7.26–7.21 (m, 3H), 7.12 (d,
J¼3.0 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 6.90 (dd, J¼7.5,
1.0 Hz, 1H), 6.83 (d, J¼8.0 Hz, 2H), 6.63 (d, J¼2.5 Hz,
1H), 5.73 (q, J¼1.5 Hz, 1H), 5.38 (bs, 2H), 4.20 (q,
J¼7.5 Hz, 2H), 2.29 (d, J¼1.0 Hz, 3H), 1.30 (t, J¼7.5 Hz,
3H). 13C NMR (CDCl3) d 167.0, 156.3, 139.0, 132.5, 131.5,
131.2, 129.3, 129.3, 128.0, 126.9, 122.3, 121.5, 121.1,
120.1, 103.2, 60.5, 52.8, 22.4, 15.0. MS (EI): 319, 246, 230,
168, 154, 91. HRMS (EI) m/z calcd for C21H21NO2
319.1572, found 319.1564.
3.3.2. (E)-3-(N-Benzylindol-7-yl)-2-methyl-2-propenol
(16b). Prepared from Dibal-H (1.2 M in toluene, 3.2 mL,
3.8 mmol) and 15b (0.286 g, 0.94 mmol) by the general
procedure. There was obtained 210 mg (81%) of the desired
1
alcohol as a colourless oil. H NMR (CDCl3) d 7.57 (d,
3.2.4. (E)-Methyl 3-(N-allylindol-7-yl)-2-methacrylate
(15a). A solution of (E)-methyl 3-(7-indolyl)-2-metha-
crylate (13) (500 mg, 2.3 mmol) in DMF (10 mL) was
added to a 08C suspension of sodium hydride in DMF
(5 mL). This mixture was stirred at 08C for 15 min, before
addition of allyl bromide (0.24 mL, 2.8 mmol). Stirring was
continued at 08C for 30 min and then the reaction was
allowed to warm to 208C. Water (200 mL) and NaCl
(200 mg) were added and the mixture was extracted with
diethyl ether (4£100 mL). The combined organic phases
were washed with water (2£50 mL), dried (MgSO4), and
evaporated. Column chromatography (ethyl acetate/heptane
1:5) afforded 282 mg (48%) of the desired product as a
yellow oil. 1H NMR (CDCl3) d 8.16 (s, 1H), 7.62 (d,
J¼7.8 Hz, 1H), 7.11 (t, J¼7.8 Hz, 1H), 7.07 (d, J¼3 Hz,
1H), 6.99 (d, J¼7.8 Hz, 1H), 6.57 (d, J¼3 Hz, 1H), 6.09–
5.94 (m, 1H), 5.19 (d, J¼10.5 Hz, 1H), 4.88 (d, J¼16.2 Hz,
1H), 4.83 (m, 2H), 3.87 (s, 3H), 2.03 (s, 3H). 13C NMR
(CDCl3) d 204.7, 169.0, 142.2, 137.7, 135.1, 129.8, 129.6,
123.4, 121.6, 120.2, 119.3, 116.6, 102.2, 52.2, 50.9, 14.2.
MS (EI): 255, 196, 180, 168, 167, 154. HRMS (EI) m/z
calcd for C16H17NO2 255.1259, found 255.1259.
J¼7.8 Hz, 1H), 7.30–7.25 (m, 1H), 7.25–7.19 (m, 2H),
7.09 (d, J¼3.6 Hz, 1H), 7.06 (d, J¼7.5 Hz, 1H), 6.90–6.82
(m, 3H), 6.66 (s, 1H) 6.58 (d, J¼3.3 Hz, 1H), 5.51 (s, 2H),
4.04 (s, 2H), 1.50 (d, J¼1.5 Hz, 1H), 1.19 (bs, 1H).
3.3.3. (Z/E)-3-(N-p-Toluenesulfonylindol-7-yl)-2-methyl-
2-propenol (16c). Prepared from Dibal-H (1.2 M in toluene,
9.3 mL, 11 mmol) and 15c (1.0 g, 2.7 mmol) by the general
procedure. There was obtained 782 mg (85%) of the desired
alcohol as a colourless oil. 1H NMR (CDCl3) (E) d 7.79 (d,
J¼3.9 Hz, 1H), 7.50 (d, J¼8.4 Hz, 1H), 7.46–7.40 (m, 2H),
7.23–7.14 (m, 3H), 7.00 (d, J¼7.2 Hz, 1H), 6.92 (s, 1H),
6.72 (d, J¼2.1 Hz, 1H), 4.15 (d, J¼1.5 Hz, 2H), 2.34 (s,
3H), 1.80 (bs, 1H), 1.46 (d, J¼1.5 Hz, 3H). MS (EI): 341,
323, 186, 168, 154, 130, 117, 91. HRMS (EI) m/z calcd for
C19H19NO3S 341.1086, found 341.1081.
3.3.4. (E)-3-(N-Benzylindol-7-yl)-but-2-en-1-ol (23). Pre-
pared from Dibal-H (1.2 M in toluene, 9.9 mL, 11 mmol)
and 22 (885 mg, 2.90 mmol) by the general procedure, with
the exception that the reaction mixture was allowed to
slowly reach 58C during 2.5 h, where upon extra Dibal-H
(1.2 mL, 1.45 mmol) was added. There was obtained
0.716 g (89%) of the desired product as a colourless oil.
1H NMR (CDCl3) d 7.76 (dd, J¼8.0, 1.0 Hz, 1H), 7.45–
7.36 (m, 3H), 7.26–7.24 (m, 2H), 7.05 (dd, J¼7.0, 0.5 Hz,
1H), 7.01 (d, J¼6.5 Hz, 2H), 6.79 (d, J¼3.0 Hz, 1H), 5.65–
5.58 (m, 3H), 4.35 (d, J¼7 Hz, 2H), 2.01 (d, J¼0.5 Hz, 3H),
1.17 (bs, 1H). 13C 140.0, 137.7, 133.3, 131.0, 130.9, 130.0,
130.0, 129.4, 127.9, 126.5, 123.2, 120.6, 120.2, 103.1, 78.0,
77.7, 77.5, 60.2, 52.3, 20.3. MS (EI): 277, 259, 244, 207,
168, 91. HRMS (EI) m/z calcd for C19H19NO 277.1467,
found 277.1468.
3.2.5. (E)-Methyl 3-(N-Benzylindol-7-yl)-2-methacrylate
(15b). Prepared from (E)-methyl 3-(7-indolyl)-2-metha-
crylate (500 mg, 2.30 mmol) (13) and benzyl bromide
(0.33 mL, 2.8 mmol) in 49% yield as described above for
1
15a. H NMR (CDCl3) d 7.92 (s, 1H), 7.66 (d, J¼8.1 Hz,
1H), 7.41–7.36 (m, 1H), 7.29–7.25 (m, 2H), 7.15 (d,
J¼3.0 Hz, 1H), 7.12 (d, J¼7.5 Hz, 1H), 6.96–6.90 (m, 3H),
6.63 (d, J¼3.3 Hz, 1H), 5.48 (s, 2H), 3.79 (s, 3H), 1.84 (d,
J¼1.5 Hz, 3H).
3.3. General procedure for the Dibal reduction
3.4. General procedure for the Sharpless asymmetric
epoxidation
3.3.1. (E)-3-(N-Allylindol-7-yl)-2-methyl-2-propenol
(16a). Dibal-H (1.2 M in toluene, 2.9 mL, 3.5 mmol) was
added to a 2508C solution of 15a (219 mg, 0.86 mmol) in
toluene (20 mL) over a period of 2 min. Stirring for 30 min
at 2408C led to completion of the reaction, and the reaction
was quenched with methanol (5 mL). Then water (25 mL)
and dichloromethane (50 mL) were added, the layers were
separated, and the aqueous layer was extracted with
dichloromethane (4£25 mL). Drying (MgSO4) and concen-
3.4.1. 2-Methyl-3-(N-allylindol-7-yl)-2(R),3(R)-epoxy-
propanol (17a). A mixture of diisopropyl D-tartrate
˚
(0.011 mL, 0.050 mmol) and 4 A molecular sieves
(40 mg) in dichloromethane (8 mL) was cooled to 2308C
before addition of titanium(IV) isopropoxide (0.010 mL,
0.033 mmol) and tert-butyl hydroperoxide (3.88 M in
toluene, 0.37 mL, 1.45 mmol). The solution was left stirring

J. E. Tønder, D. Tanner / Tetrahedron 59 (2003) 6937–6945
6943
at 2208C for 60 min. A solution of 16a (150 mg,
0.66 mmol) in dichloromethane (2 mL) was then added
over a period of 1 min at a temperature of 2308C. Stirring
was continued at 2208C for 2.5 h when NaOH (10% in
brine, 0.05 mL) and diethyl ether (2 mL) was added and the
cooling bath removed, allowing the mixture to warm to
108C. The mixture was stirred at 108C for 10 min, where-
upon MgSO4 (0.05 g) and Celite (7 mg) were added. The
mixture was stirred at 108C for 15 min and the inorganic
precipitate allowed to settle. The reaction mixture was
filtered through celite and concentrated in vacuo. Then
toluene (2£10 mL) was added and the solutions reconcen-
trated in vacuo. This afforded 174 mg of the crude product.
Column chromatography (ethyl acetate/heptane 1:2!1:1)
gave 77 mg (48%) of the desired product as a pale yellow oil
which crystallised and darkened on standing.
of the desired product as a colourless oil. The compound
turned out to be highly unstable even if kept under vacuum
and away from sunlight. 1H NMR (CDCl3), two rotamers, d
7.60 (bm, 1H), 7.36–7.18 (m, 4H), 7.12 (t, J¼7.5 Hz, 1H),
7.07–6.96 (m, 2H), 6.80 (d, J¼6.6 Hz, 1H), 6.63–6.56 (bm,
1H), 5.88 (d, J¼16.2 Hz, 0.5H), 5.67 (d, J¼16.8 Hz, 0.5H),
5.62 (d, J¼16.8 Hz, 0.5H), 5.54 (d, J¼16.8 Hz, 0.5H),
4.06–3.63 (m, 2H), 3.55 (bm, 0.5H), 3.05 (bm, 0.5H), 1.72
(bs, 1H), 1.58 (bs, 1.5H), 1.48 (bs, 1.5H). MS (EI): 293, 277,
263, 232, 218, 202, 91. HRMS (EI) m/z calcd for
C19H19NO2 293.1416, found 293.1415.
3.5. General procedure for the TPAP oxidation
3.5.1. 2-Methyl-3-(N-allylindol-7-yl)-2(S),3(R)-epoxy-
propanal (18a). TPAP (2.2 mg, 0.006 mmol) was added to
a stirred mixture of 17a (30 mg, 0.12 mmol), 4-methyl-
morpholine N-oxide monohydrate (25 mg, 0.18 mmol), and
1H NMR (CDCl3) d 7.58 (d, J¼7.8 Hz, 1H), 7.18 (dd,
J¼7.5, 0.9 Hz, 1H), 7.10 (t, J¼7.5 Hz, 1H), 7.05 (d,
J¼3.0 Hz, 1H), 6.56 (dd, J¼3.0, 0.9 Hz, 1H), 6.10–5.98
(m, 1H), 5.17 (d, J¼10.5 Hz, 1H), 4.99–4.83 (m, 2H), 4.78
(d, J¼17.1 Hz, 1H), 4.68 (s, 1H), 3.95–3.80 (m, 2H), 1.87–
1.83 (m, 1H), 1.09 (s, 3H). 13C NMR (CDCl3) d 134.9,
134.8, 129.7, 120.8, 120.8, 119.4, 118.9, 116.4, 102.5, 64.7,
64.2, 58.4, 51.0, 14.1. MS (CI): 244, 226, 214, 159, 130.
HRMS (EI) m/z calcd for C15H17NO2 243.1259, found
243.1255, [a]2D8¼297.18 (c¼2.26, CH2Cl2) ee¼91.0%.
˚
4 A molecular sieves (powdered, 60 mg) in dichloro-
methane (3 mL) at 208C under N2. When reaction was
complete (TLC) the reaction mixture was filtered through
silica and eluted with dichloromethane and ethyl acetate.
The filtrate was evaporated to give 28 mg of an orange oil.
Column chromatography (ethyl acetate/heptane 1:2) gave
8 mg (28%) of an oil which contained the desired product.
This material was carried on to the Wittig reaction without
further purification.
3.4.2. 2-Methyl-3-(N-benzylindol-7-yl)-2(R),3(R)-epoxy-
propanol (17b). Prepared from diethyl L-tartrate (11.0 mL,
1H NMR (CDCl3) d 9.22 (s, 1H), 7.63 (dd, J¼7.8, 1.5 Hz,
1H), 7.19 (d, J¼7.5 Hz, 1H), 7.12 (t, J¼7.5 Hz, 1H), 7.04
(d, J¼3.3 Hz, 1H), 6.57 (d, J¼3.0 Hz, 1H), 6.00–5.91 (m,
1H), 5.19 (d, J¼10.5 Hz, 1H), 4.81 (dm, J¼18 Hz, 1H), 4.76
(s, 1H), 4.73 (dm, J¼17 Hz, 1H), 4.66 (dm, J¼18 Hz, 1H),
1.23 (s, 3H). HRMS (EI) m/z calcd for C15H15NO2
241.1103, found 241.1071.
i
˚
0.051 mmol), 4 A molecular sieves (40 mg), Ti(O Pr)4
(10 mL, 0.034 mmol), tert-butyl hydroperoxide (3.88 M in
toluene, 0.39 mL, 1.51 mmol), and 16b (190 mg,
0.685 mmol) by the general procedure. There was obtained
117 mg (58%) of the desired product as a colourless oil. 1H
NMR (CDCl3) d 7.62 (dd, J¼8.1, 2.1 Hz, 1H), 7.30–7.22
(m, 3H), 7.13 (d, J¼1.8 Hz, 1H), 7.11–7.08 (m, 2H), 6.87–
6.83 (m, 2H), 6.62 (d, J¼3.3 Hz, 1H), 5.65 (d, J¼17.4 Hz,
1H), 5.51 (d, J¼17.4 Hz, 1H), 4.44 (s, 1H), 3.66 (dd,
J¼12.6, 3.6 Hz, 1H), 3, 48 (dd, J¼12.6, 8.7 Hz, 1H), 1.66
(dd, J¼8.4, 3.6 Hz, 1H), 0.85 (s, 3H).
3.5.2. 2-Methyl-3-(N-benzylindol-7-yl)-2(S),3(R)-epoxy-
propanal (18b). Prepared from TPAP (10 mg,
˚
0.028 mmol), 17b (45 mg, 0.15 mmol), 4 A molecular
sieves (100 mg), and 4-methylmorpholine N-oxide mono-
hydrate (23 mg, 0.17 mmol) by the general procedure.
There was obtained 12 mg (27%) of the desired product as a
1
3.4.3. 2-Methyl-3-(N-p-toluenesulfonylindol-7-yl)-2,3-
epoxypropanol (17c). Prepared from diisopropyl D-tartrate
colourless oil. H NMR (CDCl3), two rotamers, d 8.92 (s,
1H), 7.63 (d, J¼7.8 Hz, 1H) 7.30–7.04 (m, 6H), 6.87–6.83
(m, 1H), 6.79 (d, J¼7.5 Hz, 2H), 6.64 (d, J¼3.3 Hz, 1H),
5.51 (d, J¼17.4 Hz, 1H), 5.29 (d, J¼17.4 Hz, 1H), 4.30 (s,
0.6H), 3.79 (s, 0.4 H), 2.24 (s, 0.4H), 2.03 (s, 0.6H) 1.12 (s,
3H).
˚
(0.033 mL, 0.15 mmol), 4 A molecular sieves (120 mg),
Ti(OiPr)4 (0.030 mL, 0.10 mmol), tert-butyl hydroperoxide
(3.88 M in toluene, 1.16 mL, 4.51 mmol), and 16c (700 mg,
2.05 mmol) by the general procedure. There was obtained
426 mg (58%) of the desired product as a colourless oil. 1H
NMR (CDCl3) d 7.69 (d, J¼3.6 Hz, 1H), 7.53–7.49 (m,
3H), 7.39 (d, J¼7.8 Hz, 1H), 7.28 (t, J¼8.1 Hz, 1H), 7.21
(d, J¼8.1 Hz, 2H), 6.75 (d, J¼2.4 Hz, 1H), 4.40 (s, 1H),
3.98 (dd, J¼12.0, 9.3 Hz, 1H), 3.81 (dd, J¼12.0, 4.2 Hz,
1H), 2.36 (s, 3H), 2.28–2.23 (m, 1H), 1.13 (s, 3H). MS (EI):
339, 184, 168, 142, 141, 91. HRMS (EI) m/z calcd for
C19H19NO4S 357.1035, found 357.1023.
3.5.3. 2-Methyl-3-(N-p-toluenesulfonylindol-7-yl)-2,3-
epoxypropanal (18c). Prepared from TPAP (79 mg,
˚
0.22 mmol), 17c (400 mg, 1.12 mmol), 4 A molecular
sieves (560 mg), and 4-methylmorpholine N-oxide mono-
hydrate (166 mg, 1.23 mmol) by the general procedure.
There was obtained 231 mg (58%) of the desired product as
1
a colourless oil. H NMR (CDCl3) d 9.20 (s, 1H), 7.70 (d,
J¼4.0 Hz, 1H), 7.58 (dd, J¼7.2, 3.0 Hz, 1H), 7.41–7.13 (m,
5H), 6.78 (d, J¼4.0 Hz, 1H), 4.73 (s, 1H), 2.37 (s, 3H), 1.10
(s, 3H). MS (EI): 327, 220, 205, 172, 155, 130. HRMS (EI)
m/z calcd for C19H17NO4S 355.0878, found 355.0881.
3.4.4. 3-(N-Benzylindol-7-yl)-2(S),3(S)-epoxybutanol
(24). Prepared from diethyl L-tartrate (29.0 mL,
i
˚
0.167 mmol), 4 A molecular sieves (130 mg), Ti(O Pr)4
(33 mL, 0.11 mmol), tert-butyl hydroperoxide (3.88 M in
toluene, 1.26 mL, 4.89 mmol), and 23 (616 mg, 2.22 mmol)
by the general procedure. There was obtained 394 mg (60%)
3.5.4. 3-(1-Benzylindol-7-yl)-2(S),3(S)-epoxybutanal
(25). Prepared from TPAP (88 mg, 0.25 mmol), 24

6944
J. E. Tønder, D. Tanner / Tetrahedron 59 (2003) 6937–6945
˚
(367 mg, 1.25 mmol), 4 A molecular sieves (700 mg), and
N-methyl morpholine oxide monohydrate (186 mg,
1.38 mmol) by the general procedure. There was obtained
150 mg (41%) of the desired product as a yellow oil, which
contained the desired product. This material was carried on
to the Wittig reaction without further purification.
(258 mg, 0.72 mmol), and 18c (214 mg, 0.60 mmol) by
the general procedure. There was obtained 101 mg (48%) of
the desired product as a colourless oil as well as 34 mg
(16%) of unconverted starting material. 1H NMR (CDCl3) d
7.72 (d, J¼3.6 Hz, 1H), 7.52 (d, J¼7.8 Hz, 1H), 7.45 (d,
J¼8.1 Hz, 2H), 7.39 (d, J¼7.2 Hz, 1H), 7.26 (t, J¼7.8 Hz,
1H), 7.19 (d, J¼8.4 Hz, 2H), 6.74 (d, J¼3.9 Hz), 6.03 (dd,
J¼17.4, 10.8 Hz, 1H), 5.43 (dd, J¼17.1, 0.9 Hz, 1H), 5.32
(dd, J¼10.5, 0.9 Hz, 1H), 4.22 (s, 1H), 2.35 (s, 3H), 1.12 (s,
3H). MS (EI): 353, 342, 310, 198, 155, 91. HRMS (EI) m/z
calcd for C20H19NO3S 353.1086, found 353.1089.
1H NMR (CDCl3) d 9.46 (s, 1H), 7.65 (d, J¼7.2 Hz, 1H),
7.31–7.19 (m, 4H), 7.10–7.03 (m, 2H), 6.79 (d, J¼6.9 Hz,
1H), 6.66–6.60 (m, 1H), 5.60 (d, J¼16.8 Hz, 1H), 5.44 (d,
J¼16.8 Hz, 1H), 3.44 (s, 1H), 1.19 (s, 3H). MS (EI): 291,
275, 200, 172, 91. HRMS (EI) m/z calcd for C19H17NO2
219.1259, found 219.1259.
3.6.4. 4-(N-Benzylindol-7-yl)-(3R,4S)-epoxypropene (12).
Prepared from KHMDS (127 mg, 0.63 mmol), methyl-
triphenylphosphonium bromide (210 mg, 0.58 mmol), and
25 (143 mg, 0.49 mmol) by the general procedure. There
was obtained 72 mg (51%) of the desired product as a
colourless oil.
3.6. General procedure for the Wittig reaction
3.6.1. (2R,3R)-2-Methyl-3-(N-allylindol-7-yl)-2-vinyl
oxirane (11a). KHMDS (8.6 mg, 0.043 mmol) was added
to a suspension of methyltriphenylphosphonium bromide
(14 mg, 0.040 mmol) in THF (1 mL) at 258C under N2.
Stirring was continued at 258C for 30 min, whereupon 18a
(8.0 mg, 0.033 mmol) was added as a solution in THF
(1 mL). Stirring was continued at 258C for 90 min.
Dichlorormethane (5 mL) was added and the resulting
suspension was filtered through Hyflo Super-Cel. The
filtrate was concentrated in vacuo to give 21 mg of a
colourless oil. Column chromatography (ethyl acetate/
heptane 1:5) gave 6.0 mg (76%) of the desired product as
a colourless oil.
1H NMR (CDCl3), two rotamers, d 7.64 (d, J¼9.0 Hz, 1H),
7.40 (bm, 1H), 7.34–7.25 (m, 3H), 7.17 (bm, 1H), 7.10
(bm, 1H), 7.02 (bm, 1H), 6.84 (bm, 1H), 6.65 (bm, 1H), 5.95
(bm, 1H), 5.84–5.60 (m, 2H), 5.52 (s, 2H), 5.37
(d, J¼6.0 Hz, 1H), 5.15 (d, J¼9.9 Hz, 1H), 3.84 (bm,
0.3H), 3.45 (bm, 0.7H), 1.60 (s, 3H). 13C NMR (CDCl3),
two rotamers, d 132.3, 129.8, 128.9, 128.8, 127.6, 127.1,
126.2, 121.9, 121.3, 121.2, 121.1, 120.0, 119.8, 119.9,
103.7, 64.9, 51.3, 44.9, 20.4. MS (EI): 289, 232, 218, 198,
156, 154, 91. HRMS (EI) m/z calcd for C20H19NO
289.1467, found 289.1472, [a]2D0¼þ67.28 (c¼1.95,
CH2Cl2) ee¼92.1%.
1H NMR (CDCl3) d 7.58 (ddd, J¼7.8, 1.5, 0.9 Hz, 1H), 7.21
(dt, J¼7.2, 1.2 Hz, 1H), 7.10 (t, J¼7.8 Hz, 1H), 7.04 (d,
J¼3 Hz, 1H), 6.57 (d, J¼3.3 Hz, 1H), 5.98 (ddt, J¼17.1,
10.5, 4.5 Hz, 1H), 5.89 (dd, J¼17.4, 10.5 Hz, 1H), 5.50 (dd,
J¼17.4, 0.9 Hz, 1H), 5.38 (dd, J¼10.8, 0.9 Hz, 1H), 5.16
(td, J¼10.5, 0.9 Hz, 1H), 4.83–4.81 (m, 2H), 4.76 (ddt,
J¼17.1, 2.1, 0.9 Hz, 1H), 4.35 (s, 1H), 1.55 (s, 2H), 1.20 (s,
3H). 13C NMR (CDCl3) d 140.0, 135.0, 134.0, 129.6, 129.6,
120.9, 120.8, 119.5, 119.1, 117.5, 116.4, 102.5, 63.8, 62.9,
50.7, 14.7. MS (EI): 239, 196, 181, 168, 154. HRMS (EI)
m/z calcd for C16H17NO 239.1310, found 239.1306.
[a]2D1¼21718 (c¼0.350, CH2Cl2).
3.7. General procedure for the vinyl epoxide
rearrangement reaction
3.7.1. (S)-3-(N-Allylindol-7-yl)-4-penten-2-one (19a).
Boron trifluoride etherate (3.5 mL, 0.028 mmol) was
added to a solution of 11a (6.0 mg, 0.025 mmol) in
dichloromethane at 2788C. After 2.0 min at 2788C the
reaction mixture was poured into diethylether and shaken
with NaHCO3 (5% solution in water). The layers were
separated and the aqueous layer was extracted with
diethylether. The combined organic extracts were then
dried (MgSO4) and concentred in vacuo. Column chroma-
tography (ethyl acetate/heptane 1:4) gave 6.0 mg (.99%)
of the product resulting from vinyl-migration.
3.6.2. (2R,3R)-2-Methyl-3-(N-benzylindol-7-yl)-2-vinyl
oxirane (11b). Prepared from KHMDS (11 mg,
0.054 mmol), methyltriphenylphosphonium
(18 mg, 0.049 mmol), and 18b (12 mg, 0.041 mmol) by
bromide
the general procedure. There was obtained 4.0 mg (34%) of
1
the desired product as a colourless oil. H NMR (CDCl3),
1H NMR (CDCl3) d 7.59 (dd, J¼7.5, 1.5 Hz, 1H), 7.10 (t,
J¼7.5 Hz, 1H), 7.04 (d, J¼3.0 Hz, 1H), 6.90 (dd, J¼7.5,
1.2 Hz, 1H), 6.57 (d, J¼3.3 Hz, 1H), 6.34 (ddd, J¼17.1,
10.2, 6.0 Hz, 1H), 1H), 6.11 (ddt, J¼17.1, 10.2, 3.9 Hz, 1H),
5.29 (dt, J¼10.5, 1.5 Hz, 1H), 5.24 (ddt, J¼10.5, 1.8,
0.9 Hz, 1H), 4.97–4.80 (m, 5H), 2.06 (s, 3H). MS (EI): 239,
196, 181, 167, 154. HRMS (EI) m/z calcd for C16H17NO
239.1310, found 239.1382.
two rotamers, d 7.62 (ddd, J¼7.2, 1.5, 0.6 Hz, 1H), 7.31–
7.21 (m, 3H), 7.18–7.14 (m, 1H), 7.13 (d, J¼7.5 Hz, 1H),
7.09 (d, J¼3.0 Hz, 1H), 6.83–6.79 (m, 2H), 6.62 (d,
J¼3.0 Hz, 1H), 5.68 (dd, J¼17.4, 10.5 Hz, 1H), 5.46 (d,
J¼5.4 Hz, 2H), 5.41 (d, J¼2.4 Hz, 0.5H), 5.35 (dd, J¼1.8,
0.9 Hz, 1H), 5.31 (d, J¼1.2 Hz, 0.5H), 4.03 (s, 1H), 1.55 (s,
2H), 1.07 (s, 3H). 13C NMR (CDCl3), two rotamers, d 139.9,
139.0, 134.1, 130.3, 130.0, 129.0, 127.7, 125.6, 121.1,
121.0, 119.7, 119.5, 117.6, 102.8, 63.7, 62.9, 52.5, 52.1,
14.6.
3.7.2. (S)-3-(N-Benzylindol-7-yl)-4-penten-2-one (19b).
Prepared from the 11b and boron trifluoride etherate by
the general procedure. 1H NMR (CDCl3) d 7.62 (dd, J¼7.0,
1.0 Hz, 1H), 7.34–7.29 (m, 3H), 7.16 (d, J¼3.5 Hz, 1H),
7.10 (t, J¼7.5 Hz, 1H), 6.97 (d, J¼7.5 Hz, 2H), 6.82 (dd,
J¼7.5, 1.0 Hz, 1H), 6.64 (d, J¼3.5 Hz, 1H), 6.20 (ddd,
J¼16.5, 10.0, 6.5 Hz, 1H), 5.54 (s, 2H), 5.19 (ddd, J¼10.0,
3.6.3. 2-Methyl-3-(N-p-toluenesulfonylindol-7-yl)-2-
vinyl oxirane (11c). Prepared from KHMDS (156 mg,
0.78 mmol),
methyltriphenylphosphonium
bromide

J. E. Tønder, D. Tanner / Tetrahedron 59 (2003) 6937–6945
6945
7. Ma, D. Curr. Med. Chem. 2001, 8, 191–202.
1.0, 1.0 Hz, 1H), 4.76 (d, J¼6.0 Hz, 1H), 4.68 (ddd, J¼17.0,
8. Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook,
J. M. J. Org. Chem. 2001, 66, 4525–4542.
9. Nakagawa, Y.; Irie, K.; Nakamura, Y.; Ohigashi, H. Bioorg.
Med. Chem. Lett. 2001, 11, 723–728.
1.0, 1.0 Hz, 1H), 1.64 (s, 3H).
3.7.3. 2-Methyl-2-(N-p-toluenesulfonylindol-7-yl)-but-3-
enal (10c) and 1-(N-p-toluenesulfonylindol-7-yl)-2-
methyl-3-butenone (20c). Prepared from 11c (90 mg,
0.25 mmol) and boron trifluoride etherate (35 mL,
0.28 mmol) by the general procedure. There was obtained
44 mg (50%) of a colourless oil which was a 2:3 mixture of
10c and 20c as well as 10 mg (11%) of unconverted starting
material.
10. Irie, K.; Koizumi, F.; Iwata, Y.; Ishii, T.; Yanai, Y.;
Nakamura, Y.; Ohigashi, H.; Wender, P. A. Bioorg. Med.
Chem. Lett. 1995, 5, 453–458.
11. Irie, K.; Isaka, T.; Iwata, Y.; Yanai, Y.; Nakamura, Y.;
Koizumi, F.; Ohigashi, H.; Wender, P. A.; Satomi, Y.;
Nishino, H. J. Am. Chem. Soc. 1996, 118, 10733–10743.
12. Endo, Y.; Shudo, K.; Okamoto, T. Chem. Pharm. Bull. 1982,
30, 3457–3460.
1H NMR (CDCl3) 10c d 9.74 (s, 1H), 7.58–7.16 (m, 7H),
7.03 (d, J¼8.4 Hz, 2H), 6.58 (d, J¼3.9 Hz, 1H), 6.28 (dd,
J¼16.8, 12 Hz, 1H), 5.33 (d, J¼12 Hz, 1H), 5.02 (d,
J¼16.8 Hz, 1H), 2.28 (s, 3H), 1.88 (s, 3H). 20c d 7.58–7.16
(m, 7H), 7.09 (d, J¼8.4 Hz, 2H), 6.71 (d, J¼3.9 Hz, 1H),
5.92–5.72 (m, 1H), 5.01–4.86 (m, 2H), 4.07 (dq, J¼8 Hz,
1H), 2.28 (s, 3H), 1.37 (d, J¼8 Hz, 3H). MS (EI) (mixture of
10c and 20c): 353, 298, 198, 170, 168, 154, 143. HRMS (EI)
m/z calcd for C20H19NO3S 353.1086, found 353.1089.
13. Endo, Y.; Ohno, M.; Hirano, M.; Itai, A.; Shudo, K. J. Am.
Chem. Soc. 1996, 118, 1841–1855.
14. Endo, Y.; Imada, T.; Yamaguchi, K.; Shudo, K. Heterocycles
1994, 39, 571–579.
15. Kogan, T. P.; Somers, T. C.; Venuti, M. C. Tetrahedron 1990,
46, 6623–6632.
16. Quick, J.; Saha, B. Tetrahedron Lett. 1994, 35, 8553–8556.
17. Muratake, H.; Okabe, K.; Natsume, M. Tetrahedron 1991, 47,
8545–8558.
3.7.4. (R)-2-Methyl-2-(N-benzylindol-7-yl)-but-3-enal
(10b). Prepared from 12 (25 mg, 0.086 mmol) by the
general procedure. There was obtained 22 mg (88%) of
the desired product as a colourless oil.
18. Okabe, K.; Muratake, H.; Natsume, M. Tetrahedron 1991, 47,
8559–8572.
19. Nakatsuka, S.-I.; Masuda, T.; Goto, T. Tetrahedron Lett. 1987,
28, 3671–3674.
20. Corey, E. J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998,
37, 388–401.
1H NMR (CDCl3) d 9.64 (s, 1H), 7.79–7.74 (m, 1H), 7.35–
7.29 (m, 3H), 7.28–7.25 (m, 2H), 6.96 (dd, J¼3.0, 2.5 Hz,
1H), 6.84 (d, J¼8.0 Hz, 2H), 6.70 (dd, J¼3.0, 2.5 Hz, 1H),
6.56 (ddd, J¼17.5, 10.5, 2.5 Hz, 1H), 5.46 (d, J¼16.5 Hz,
1H), 5.28 (d, J¼16 Hz, 1H), 5.23 (dd, J¼10.5, 2.0 Hz, 1H),
4.91 (dd, J¼17.5, 1.5 Hz, 1H), 1.74 (s, 3H). 13C (CDCl3) d
169.0, 132.1, 131.2, 129.2, 128.0, 127.2, 123.9, 122.4,
120.4, 118.3, 104.4, 58.7, 53.8, 24.4. MS (EI): 289, 260,
168, 154, 130, 91. HRMS (EI) m/z calcd for C20H19NO
289.1467, found 289.1472, [a]2D0¼þ1378 (c¼0.500,
CH2Cl2) ee¼70.7%.
21. Christoffers, J.; Mann, A. Angew. Chem. Int. Ed. 2001, 40,
4591–4597.
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