Efficient and highly enantioselective formation of the all-carbon quaternary stereocentre of lyngbyatoxin A

Article abstract of DOI:10.1039/b612578f

Indole 25, an advanced intermediate in a projected enantioselective total synthesis of lyngbyatoxin A 1, was prepared from allylic alcohol 11 in 9 steps and >95% ee, key transformations being the enantiospecific rearrangement of vinyl epoxide 14 and the H

Full text of DOI:10.1039/b612578f

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient and highly enantioselective formation of the all-carbon quaternary
stereocentre of lyngbyatoxin A
Paulo Vital and David Tanner*
Received 31st August 2006, Accepted 27th September 2006
First published as an Advance Article on the web 20th October 2006
DOI: 10.1039/b612578f
Indole 25, an advanced intermediate in a projected enantioselective total synthesis of lyngbyatoxin A 1,
was prepared from allylic alcohol 11 in 9 steps and >95% ee, key transformations being the
enantiospecific rearrangement of vinyl epoxide 14 and the Hemetsberger–Knittel reaction of azide 24.
2 via functional group manipulation. Key intermediate 2 would
be obtained from aldehyde 3 by means of a Hemetsberger–Knittel
Introduction
reaction,11 while the quaternary carbon stereocentre was planned
to be accessed via the enantiospecific Jung rearrangement9 of chiral
vinyl epoxide 4, itself available from allylic alcohol 5 by means
of the Sharpless asymmetric epoxidation reaction;12 a suitably
functionalised acetophenone 6 was to be the starting point for
the synthesis.
The Hawaiian blue–green alga Lyngbya majuscula Gomont is
implicated in the occasional outbreaks of a severe contact
dermatitis commonly known as “swimmers’ itch”.1 One of the
causative agents for this condition is lyngbyatoxin A 1 (Fig. 1), an
alkaloid first isolated in 1979 by Moore and co-workers from the
lipid extract of seaweed.2
Fig. 1 Structure of lyngbyatoxin A.
Lyngbyatoxin A is also a potent tumor promoter3 and, like
other indolactam alkaloids, exerts its biological activity through
activation of protein kinase C (PKC), a family of phosphory-
lating enzymes involved in the regulation of important cellular
processes.4 Investigation of the structural requirements for the
selective activation/inhibition of each PKC isotype is currently
an important goal in pharmaceutical research.5 This interesting
biological profile combined with a challenging molecular structure
makes lyngbyatoxin A and its analogues worthy targets for the
synthetic community.5,6
A critical step in any enantioselective approach towards lyng-
byatoxin A concerns the installation of the quaternary carbon at
C-14.7,8 We have previously addressed this issue by means of the
Jung rearrangement9 of chiral vinyl epoxides carrying an indole
moiety, but this approach was plagued by substantial loss of
enantiomeric purity during the rearrangement step.10 Herein we
report a successful (>95% ee) “second generation” approach to
this problem, involving epoxide rearrangement prior to formation
of the indole unit.
Scheme 1 Simplified retrosynthetic analysis for lyngbyatoxin A.
Results and discussion
After considerable experimentation to determine which functional
groups on the aromatic ring would be compatible with the above
strategy, the combination X = Br, Y = I (Scheme 1) was chosen.
Since the quaternary centre was planned to be installed by a
“chirality transfer” process, the enantiomeric purity of the starting
vinyl epoxide is critical, and this was the first issue to be addressed
(Scheme 2).
Following a literature procedure,13 p-aminoacetophenone 7
was treated with ICl to afford the corresponding iodinated
aniline 8 in good yield. Amine–halogen exchange was then
accomplished under Sandmeyer conditions14 (NaNO2 followed
by CuBr, in conc. HBr) to deliver ketone 9 in 86% yield. A
Horner–Wadsworth–Emmons reaction15 with the sodium salt of
According to the simplified retrosynthetic analysis shown in
Scheme 1, the target molecule was envisioned to arise from indole
Department of Chemistry, Technical University of Denmark, Building 201,
Kemitorvet, DK-2800, Kgs. Lyngby, Denmark. E-mail: dt@kemi.dtu.dk;
Fax: +45-45933968
4292 | Org. Biomol. Chem., 2006, 4, 4292–4298
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
Conversion of allylic epoxide 12 to vinyl epoxide 14 was
accomplished using the conditions previously reported9,10 for this
type of substrate. Swern oxidation16 of 12 delivered epoxy aldehyde
13, which upon Wittig reaction17 with KHMDS as base gave 14.
Due to the lability of compounds 13 and 14, these were either used
directly or submitted to rapid filtration through a short column
of silica gel. Subjection of vinyl epoxide 14 to the conditions
developed by Jung for the rearrangement reaction9 (BF3·Et2O,
CH2Cl2, −78 ◦C) delivered aldehyde 15 as the sole product in 52%
yield based on 12. Aldehyde 15 was not suitable for prolonged
storage, even at low temperature, so it was routinely subjected to
NaBH4 reduction to the corresponding primary alcohol 16. To
determine if the rearrangement had proceeded with complete 1,2-
chirality transfer, alcohol 16 was derivatized with the Alexakis
reagent 17a18 to the phosphorous adduct 17b. Whereas the 31P-
NMR spectrum of racemic 17b, prepared by MCPBA epoxidation
of 11 followed by an identical sequence of steps, showed two peaks
of equal intensity at 139.0 and 138.8 ppm, only the higher-field
peak was present for 17b produced via the Sharpless epoxidation.
This result implies that the desired vinyl migration in conformer
19, where the migrating group is correctly aligned with the adjacent
vacant p orbital, proceeds significantly faster than conformer
equilibration. The latter process would result in the population
of conformer 21, thus leading to vinyl migration onto the
enantiotopic face of the planar carbocation and in the undesired
formation of ent-15 (Scheme 4).
Scheme 2 Reagents and conditions: (a) ICl, CaCO3 aq., MeOH, rt, 86%;
(b) NaNO2 aq., HBr conc., −10 ◦C to 0 ◦C, then CuBr, HBr conc., 80 ◦C,
86%; (c) NaH, (EtO)2P(O)CH2CO2Et, THF, 0 ◦C to rt, 64%; (d) DIBAL,
◦
i
t
˚
Et2O, 0 C to rt, 96%; (e) L-(+)-DET, 4 A MS, Ti(O Pr)4, BuOOH, CH2Cl2,
−20 ◦C; quant. (crude), 92–94% ee.
triethylphosphonoacetate delivered a mixture of the correspond-
ing E : Z a,b-unsaturated esters in an unoptimised 3.7 : 1 ratio.
These isomers could be separated easily by flash chromatography,
allowing the isolation of pure E-unsaturated ester 10 in 64%
yield. Reduction of the ester functionality with DIBAL proceeded
uneventfully, providing allylic alcohol 11 in excellent yield. We
were then pleased to find that the key asymmetric epoxidation
step12 delivered 12 as a highly crystalline product in essentially
quantitative yield and with 92–94% ee, as determined by chiral
HPLC. A single recrystallisation from hot hexane–Et2O 2 : 1 (v :
v) yielded material which was enantiomerically pure within the
limits of detection.
Having secured our first chiral intermediate, we proceeded to
investigate the installation of the all-carbon quaternary centre of
the target (Scheme 3).8
Scheme 4 Intermediate 18 is formed from 14 and BF3·Et2O, giving 15 via
conformer 19.
With the quaternary centre installed in an enantioselective
manner, we then attended to the construction of the indole nucleus
(Scheme 5).19
Treatment of the (crude) primary alcohol 16 with TBSCl and
imidazole20 delivered silyl ether 22 in 80% yield based on 15.
Our annelation strategy calls for a benzaldehyde derivative, and
we planned to introduce the required formyl group via a regio-
and chemo-selective halogen–lithium exchange.21 Somewhat un-
expectedly, this step proved to be very problematic. When the
standard conditions for this transformation were used (BuLi,
DMF, THF–Et2O or THF, −100 ◦C or −78 ◦C, respectively),
only a complex mixture, containing at best trace amounts of the
expected aldehyde 22, was obtained. After extensive model studies
with o-bromoiodobenzene, we eventually found that when the
reaction was carried out in toluene at approximately −100 ◦C the
competing benzyne formation was comparatively slow, and thus
the initially formed lithiated species could be successfully trapped
Scheme 3 Reagents and conditions: (a) (COCl)2, DMSO then Et3N,
CH2Cl2, −78 ◦C; (b) Ph3PCH3Br, KHMDS, THF, 0 ◦C; (c) BF3·Et2O,
CH2Cl2, −78 ◦C, 52% (based on 12); (d) NaBH4, MeOH, 0 ◦C to rt, 81%.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 4292–4298 | 4293
©

View Article Online
generation of the characteristic all-carbon quaternary centre of
lyngbyatoxin A, thus solving a long-standing problem in the
synthesis of this biologically significant alkaloid.
Experimental
General
All moisture- and air-sensitive reactions were carried out under an
argon atmosphere using oven-dried or flame-dried glassware. Re-
action solvents were distilled prior to use by standard procedures.
Et2O, THF and toluene were distilled under nitrogen from sodium
benzophenone. CH2Cl2 and NEt3 were distilled under nitrogen
from CaH2. Anhydrous DMSO and DMF were purchased from
˚
Aldrich and stored over 4 A molecular sieves, under argon.
1H-NMR (300 MHz and 500 MHz) and 13C-NMR (75 MHz)
spectra were recorded on either a Varian Mercury 300 (300 MHz)
or a Varian Inova 500 (500 MHz) spectrometers at ambient
temperature. 31P-NMR (202 MHz) spectra were recorded on a
Varian Inova 500 (500 MHz) spectrometer at ambient temperature.
Chemical shifts (d) are reported in ppm. Undeuterated solvent
residues were used as internal standard (CHCl3, 1H: 7.27 ppm and
13C: 77.0 ppm). H3PO4 (30% aq., 0.0 ppm) was used as external
standard for 31P-NMR. Coupling constants (J) are given in Hertz
(Hz). Optical rotations were measured with a Perkin Elmer 241
polarimeter at ambient temperature, and the concentration (c)
is given in g per 100 mL. Analytical high performance liquid
chromatography (HPLC) was performed using a Varian 9012
solvent delivery system with a Varian 9065 polychrome diode
array detector. HPLC grade solvents were obtained from LAB-
SCAN. Electron impact (EI) low resolution mass spectra (LRMS)
were performed with a VG Trio-2 single quadrupole instrument at
the Department of Chemistry, Technical University of Denmark.
Melting points of crystalline materials were determined on a
Heidolph capillary melting point apparatus and are uncorrected.
Analytical thin layer chromatography (TLC) analyses were per-
formed using 0.25 mm Merck Kieselgel aluminium-backed 60
F254 silica gel plates. Visualization was achieved by i) exposure
to UV light, ii) brief exposure to iodine vapors, iii) dipping into
a solution of 5–10% of phosphomolybdic acid in EtOH, and iv)
gentle heating. Merck silica gel 60 (40–63 lm, 230–400 mesh)
was used for flash chromatography purification. Preparative thin
layer chromatography (PTLC) was performed on 20 × 20 cm,
1500 lm glass-backed plates with fluorescent indicator (Aldrich).
Microanalyses were performed at the Microanalysis Laboratory,
Institute of Physical Chemistry, University of Vienna, Austria.
Molecular sieves were dried at 150–160 ◦C for at least 12 h and then
allowed to reach room temperature under argon. Unless otherwise
stated, commercially available reagents, purchased from Aldrich,
Fluka or Merck, were used without further purification. “Aqueous
Scheme 5 (a) TBSCl, imid., DMF, rt, 80% (based on 15); (b) BuLi then
DMF, PhMe, approx. −100 ◦C, 65–71%; (c) N3CH2CO2Et, NaOEt, EtOH,
−15 ◦C to −10 ◦C, 60%; (d) xylene, 140 ◦C, 69%.
with DMF.22 Using these conditions, aldehyde 23 was finally
obtained reproducibly in 65–71% yield. Subsequent NaOEt-
promoted condensation with excess ethyl azidoacetate at low
temperature afforded azide 24 in 60% yield, thus setting the
stage for the planned Hemetsberger–Knittel reaction.11 This was
accomplished by heating 24 in xylene, which smoothly furnished
indole 25 in 69% yield.
Indole 25 is conveniently functionalised so as to allow its
conversion into lyngbyatoxin A: the C-3 indolic position is
intrinsically nucleophilic,23 whereas the bromine at C-4 provides
a suitable handle for insertion of the amino functionality;24
furthermore, the TBDMS-protected alcohol moiety will allow the
construction of the linalyl appendage (Fig. 2).
Fig. 2 Planned manipulations to convert indole 25 into lyngbyatoxin A.
Conclusion
The synthesis of enantiomerically pure indole 25, a late key
intermediate in the enantioselective total synthesis of lyngbyatoxin
A, was accomplished in 9 steps from the readily available allylic
alcohol 11. The salient features of this route are (i) Sharpless
asymmetric epoxidation for initial introduction of chirality, (ii)
completely enantiospecific Jung rearrangement of chiral epoxide
14 to install the all-carbon quaternary centre of the target
molecule, (iii) formylation of 22 via chemo- and regio-selective
halogen–lithium exchange, and (iv) clean formation of the indole
nucleus through the Hemetsberger–Knittel reaction. To the best
of our knowledge, this is the first example of stereocontrolled
1
2
1
saturated brine” and “aqueous saturated NaHCO3” refer to
3
a water–brine, 1 : 1 (v : v) and water–saturated NaHCO3, 2 : 1
(v : v) solutions, respectively. The following cooling baths were
used: ether–liquid nitrogen (ca. −110 to −85 ◦C); acetone–dry
ice (typically for −78 ◦C but also for temperatures above); ortho-
dichlorobenzene–liquid nitrogen (ca. −25 ◦C). Commercial NaH
(as a 60% dispersion in oil) was washed with pentane (2 portions
that cover the amount of NaH dispersion used), and the last traces
of pentane were removed under high vacuum.
4294 | Org. Biomol. Chem., 2006, 4, 4292–4298
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
4-Bromo-3-iodoacetophenone (9). i) Preparation of the diazo-
nium salt. To a suspension of 4-acetyl-2-iodoaniline 813 (8.45 g,
32.3 mmol) in aqueous 47% HBr (77 mL) at −10 C was added
10 (5.83 g, 14.8 mmol, 1.0 eq.) in Et2O (45 mL) was added
dropwise, over 20 min, a solution of DIBAL in toluene (1.0 M,
34.5 mL, 2.3 eq.). The solution obtained was allowed to reach
room temperature and stirred for a further 2.5 h, after which it
was re-cooled to ice bath temperature, diluted with Et2O (60 mL)
and quenched by careful addition of brine (50 mL). After vigorous
stirring for 5 min a gel-type biphasic system formed, to which was
then carefully added aqueous 4 M HCl (80 mL), and the mixture
was stirred at 0 ◦C for 10 min and then at room temperature
until a clear biphasic system was obtained (typically 20 min). The
aqueous layer was extracted with Et2O (2 portions of 40 mL), the
combined organic layers were washed with brine (40 mL), dried
(MgSO4) and the solvent removed under vacuum to afford a very
pale yellow oil. Purification by flash chromatography (hexane–
EtOAc, 1 : 1 (v : v)) afforded the title compound as a white solid
(5.0 g, 96%). Rf (hexane–EtOAc, 1 : 1 (v : v)) 0.30; mp 62–64 ◦C;
1H-NMR (CDCl3, 300 MHz) d 7.81 (d, J = 2.2 Hz, 1H), 7.47 (d,
J = 8.4 Hz, 1H), 7.15 (dd, J = 2.2, 8.4 Hz, 1H), 5.88 (tq, J =
1.4, 6.6 Hz, 1H), 4.26–4.30 (m, 2H), 1.94–1.95 (m, 3H); 13C-NMR
(CDCl3, 75 MHz) d 143.6, 137.8, 135.5, 132.5, 128.4, 128.3, 127.1,
101.5, 60.1, 16.1; LRMS (EI) m/z = 352 [M]+; Anal. Calcd. for
C10H10BrIO: C, 34.03; H, 2.86. Found: C, 33.98; H, 2.72.
◦
dropwise, over 15 min, a solution of NaNO2 (2.65 g, 38.0 mmol,
1.18 eq.) in water (35 mL). The deep-tan mixture obtained was
stirred for 10 min at this temperature, after which the temperature
was allowed to increase from −5 ◦C to 0 ◦C and stirring continued
for a further 1.5 h. The obtained mixture was then kept at
ice bath temperature. ii) Sandmeyer reaction. To a vigorously
stirred (purple) mixture of CuBr (5.57 g, 38.8 mmol, 1.2 eq.) in
aqueous 47% HBr (42 mL) at 60 ◦C was added portion-wise,
over 50 min, the above diazonium suspension (caution: significant
frothing occurred during additions), after which the temperature
was increased to 80 ◦C and stirring continued for a further 25 min.
The resulting dark mixture was cooled to ice-bath temperature and
partitioned between water (400 mL) and EtOAc (400 mL). The
aqueous layer was extracted with EtOAc (2 portions of 150 mL)
and the combined organic layers were washed with aqueous 1 M
1
2
HCl (300 mL), aqueous saturated NaHCO3 (200 mL), aqueous
saturated brine (250 mL), dried (MgSO4) and concentrated under
vacuum to afford a light-tan solid residue which was purified by
flash chromatography (hexane–EtOAc, 1 : 1 (v : v)). The title
compound was obtained as a pale yellow solid (9.0 g, 86%). Rf
(hexane–EtOAc, 1 : 1 (v : v)) 0.55; mp 79–82 ◦C; 1H-NMR (CDCl3,
300 MHz) d 8.39 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.2, 2.0 Hz, 1H),
7.71 (d, J = 8.2 Hz, 1H), 2.57 (s, 3H); 13C-NMR (CDCl3, 75 MHz)
d 196.0, 140.3, 137.1, 135.7, 133.1, 129.1, 101.9, 26.8; LRMS (EI)
m/z = 324 [M]+; Anal. Calcd. for C8H6BrIO: C, 29.57; H, 1.86.
Found: C, 29.18; H, 2.01.
((2S,3S)-3-(4-Bromo-3-iodophenyl)-3-methyloxiran-2-yl)metha-
˚
nol (12). To a suspension of powdered 4 A molecular sieves
(472 mg) in CH2Cl2 (47 mL) at −25 ◦C was added dropwise
a solution of L-(+)-diethyl tartrate (124 mg, 0.60 mmol, 7.5
mol%) in CH2Cl2 (1.5 mL), followed by Ti(OiPr)4 (117 lL,
0.4 mmol, 5 mol%) and finally a freshly prepared solution of
tBuOOH in toluene25 (4.2 ml, 15.9 mmol, 2.0 ◦eq.) with 5 min
intervals between additions. After 1.5 h at −25 C, a solution of
(E)-3-(4-bromo-3-iodophenyl)but-2-en-1-ol 11 (2.8 g, 7.93 mmol,
1.0 eq.) in CH2Cl2 (7 mL) was added dropwise over 20 min and
stirring continued for a further 4 h at this temperature. The
reaction was quenched at −25 ◦C by addition of aqueous 10%
NaOH in brine (0.73 mL) followed by Et2O (4.5 mL). After
stirring at −25 ◦C for 5 min, this suspension was allowed to reach
(E)-Ethyl 3-(4-bromo-3-iodophenyl)but-2-enoate (10). To an
ice-cold suspension of NaH (766 mg, 31.9 mmol, 1.3 eq.) in
THF (45 mL) was added dropwise , over 15 min, a solution of
triethylphosphonoacetate (7.16 g, 31.9 mmol, 1.3 eq.) in THF
(5 mL) during which gas evolution was observed. The resulting
pale yellow solution was stirred at ice bath temperature for 15 min
and at room temperature for a further 15 min, after which a
solution of 4-bromo-3-iodoacetophenone 9 (7.98 g, 24.6 mmol,
1.0 eq.) in THF (35 mL) was added dropwise at room temperature
over 10 min. The dark-tan mixture obtained was stirred at
room temperature overnight (for convenience), after which it was
◦
5 C over 10 min, and then mgSO4 (633 mg) and Celite (84 mg)
were simultaneously added. After stirring at room temperature for
10 min, the suspension was filtered through a short pad of Celite,
and the filtrate was concentrated under vacuum to afford a turbid
pale yellow oil which was then taken up in toluene (2 portions
of 150 mL) and concentrated under vacuum. The crude product
was obtained as a white solid (2.91 g, quantitative, 92–94% ee),
which typically was used without further purification. If desired,
it can be re-crystallized from hot hexane–Et2O, 2 : 1 (v : v)
(approximately 300 mL) affording the title compound as white
needles (2.6 g, 91%, >99% ee). Rf (hexane–EtOAc, 1 : 1 (v : v);
double elution) 0.50; mp 59–61 ◦C; 1H-NMR (CDCl3, 300 MHz)
d 7.75 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.11 (dd, J =
2.1, 8.3 Hz, 1H), 3.88 (dd, J = 4.4, 12.2 Hz, 1H), 3.75 (dd, J =
6.3, 12.2 Hz, 1H), 2.96 (dd, J = 4.4, 6.3, 1H), 1.93 (bs, 1H), 1.59
(s, 3H); 13C-NMR (CDCl3, 75 MHz) d 143.1, 137.2, 132.7, 129.0,
126.7, 101.5, 66.1, 61.3, 59.9, 17.7; LRMS (EI) m/z = 368 [M]+;
[a]2D5 −9.2 (c 2.2, CHCl3); Anal. Calcd. for C10H10BrIO2: C, 32.55;
H, 2.73. Found: C, 32.61; H, 2.67. HPLC retention times (Rt):
For the (2S,3S) enantiomer: Rt (OD-H column; hexane–iPrOH,
97 : 3 (v : v); 0.6 mL min−1) = 57.7 min.
1
2
partitioned between Et2O (450 mL) and aqueous saturated brine
(500 mL). The aqueous layer was extracted with Et2O (2 portions
of 100 mL) and the combined organic phases were washed with
brine (200 mL), dried (MgSO4) and the solvent removed under
vacuum to afford a dark tan oil. Purification by (repeated) flash
chromatography (hexane–Et2O, 3 : 1 (v : v)) delivered pure (E)-
(6.2 g, 64% as a white solid) and (Z)-(1.7 g, 17% as a yellow
oil) isomers. Combined yield: 81%. For (E)-ethyl 3-(4-bromo-3-
iodophenyl)but-2-enoate 10: Rf (hexane–Et2O, 3 : 1 (v : v)) 0.51;
mp 39–42 ◦C; 1H-NMR (CDCl3, 300 MHz) d 7.93 (d, J = 2.2 Hz,
1H), 7.59 (d, J = 8.3 Hz, 1H), 7.28 (dd, J = 2.2, 8.3 Hz, 1H), 6.08
(q, J = 1.3 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.50 (d, J = 1.3 Hz,
3H), 1.31 (t, J = 7.1 Hz, 2H); 13C-NMR (CDCl3, 75 MHz) d 166.5,
152.8, 142.8, 138.2, 132.8, 130.5, 127.5, 118.6, 101.7, 60.4, 18.0,
14.6; LRMS (EI) m/z = 394 [M]+; Anal. Calcd. for C12H12BrIO2:
C, 36.49; H, 3.06. Found: C, 36.63; H, 3.15.
(E)-3-(4-Bromo-3-iodophenyl)but-2-en-1-ol (11). To an ice-
cold solution of (E)-ethyl 3-(4-bromo-3-iodophenyl)but-2-enoate
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 4292–4298 | 4295
©

View Article Online
rac-3-(4-Bromo-3-iodophenyl)-3-methyloxiran-2-yl)methanol
(12). To an ice-cold suspension of commercial MCPBA (722 mg,
approximately 3.68 mmol of MCPBA, approximately 1.3 eq.)
in CH2Cl2 (6 mL) was added dropwise a solution of (E)-3-(4-
bromo-3-iodophenyl)but-2-en-1-ol 11 (1.0 g, 2.83 mmol, 1.0 eq.)
in CH2Cl2 (6 mL). The suspension obtained was stirred at ice
bath temperature for 15 min and then allowed to reach room
temperature, stirred for a further 3.5 h, after which it was re-
cooled to −5 ◦C and filtered through a short pad of Celite. To
the pale yellow filtrate obtained was added Ca(OH)2 (80 mg)
and this suspension was stirred for 5 min at −5 ◦C, after
which a small portion of Na2SO4 was added and stirring was
continued for a further 5 min at this temperature. After filtration
through a short pad of Celite, the solvent was removed under
vacuum to afford a viscous yellow oil which, upon standing
under high vacuum, crystallized. Purification by short-column
chromatography filtration (silica gel; fast elution; hexane–EtOAc,
1 : 1 (v : v) with 2% NEt3) afforded the title compound as a white
solid (950 mg, 91%). HPLC retention times (Rt): For the (2R,3R)
enantiomer: Rt (OD-H column; hexane–iPrOH, 97 : 3 (v : v);
0.6 mL min−1) = 51.7 min. For the (2S,3S) enantiomer: Rt (OD-H
column; hexane–iPrOH, 97 : 3 (v : v); 0.6 mL min−1) = 57.7 min.
temperature◦and stirred for a further 1.5 h, after which it was re-
cooled to 0 C and a solution of (crudely purified) (2R,3S)-3-(4-
bromo-3-iodophenyl)-3-methyloxirane-2-carbaldehyde 13 (3.33 g,
9.1 mmol, 1.0 eq.) in THF (17 mL) was then added dropwise over a
10 min period. The tan suspension obtained was allowed to reach
room temperature and stirred for a further 1.5 h, after which it
was re-cooled to ice bath temperature and filtered through a short
Celite pad to afford a deep-red solution. Removal of the solvent
under vacuum afforded a tan oil, which was crudely purified by
short-column chromatography filtration (silica gel; fast elution;
Et2O) to afford a tan oil that was used without further purification
1
(2.97 g). Rf (hexane–Et2O, 3 : 1 (v : v)) 0.60; H-NMR (CDCl3,
300 MHz) d 7.84 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H),
7.19 (dd, J = 2.2, 8.3 Hz, 1H), 5.82 (sept, J = 7.0, 10.5, 17.3 Hz,
1H), 5.51 (ddd, J = 0.9, 1.4, 17.3 Hz, 1H), 5.44 (ddd, J = 0.8, 1.4,
10.5 Hz, 1H), 3.24 (d, J = 7.0 Hz, 1H), 1.62 (s, 3H); 13C-NMR
(CDCl3, 75 MHz) d 143.4, 137.2, 133.8, 132.7, 132.5, 126.7, 121.7,
121.7, 101.5, 67.0, 61.3, 17.5; LRMS (EI) m/z =364 [M]+.
(R)-2-(4-bromo-3-iodophenyl)-2-methylbut-3-enal (15). To a
−78 ◦C cooled solution of (crudely purified) (2R,3S)-3(4-bromo-
3-iodophenyl)-2-methyl-3-vinyloxirane 14 (2.81 g, 7.70 mmol,
1.0 eq.) in CH2Cl2 (110 mL) was added BF3·Et2O (1.1 mL,
8.68 mmol, 1.12 eq.) and the resulting deep-pinkish solution was
stirred at this temperature for 10 min, after which it was poured
(2R,3S)-3-(4-Bromo-3-iodophenyl)-3-methyloxirane-2-carbalde-
hyde (13). A solution of oxalyl chloride (1.78 mL, 20.28 mmol,
2.0 eq.) in CH2Cl2 (90 mL) was cooled to −78 ◦C and treated
with a solution of DMSO (2.9 mL, 40.8 mmol, 4.0 eq.) in
CH2Cl2 (7 mL) over 15 min, during which period gas evolution
was observed. After stirring at this temperature for 15 min, a
solution of ((2S,3S)-3-(4-bromo-3-iodophenyl)-3-methyloxiran-
2-yl)methanol 12 (3.76 g, 10.19 mmol, 1.0 eq.) in CH2Cl2
(25 mL) was added dropwise over a period of 0.5 h, after which
a turbid-white mixture was obtained. This mixture was stirred
at −78 ◦C for 0.5 h, after which pre-cooled Et3N (11.26 mL,
81.52 mmol, 8.0 eq.) was added dropwise over 10 min, and the
resulting mixture was then allowed to warm to −30 ◦C over 1 h.
The yellow mixture obtained was poured at this temperature onto
hexane (140 mL) and CH2Cl2 (200 mL) and gently shaken with
pH 7 phosphate buffer (80 mL). The layers were separated and
the aqueous layer extracted with CH2Cl2 (2 portions of 30 mL).
The combined organic layers were washed with aqueous 1 M
1
3
onto Et2O (300 mL) and aqueous saturated NaHCO3 (200 mL).
The layers were separated and the aqueous phase was extracted
with Et2O (2 portions of 60 mL). The combined Et2O extracts were
washed with brine (100 mL), dried (Na2SO4) and concentrated to
a golden oil, which was then purified by flash chromatography
(hexane–Et2O, 3 : 1 (v : v)) to afford the title compound as a
pale yellow oil (1.9 g, 52% based on allylic alcohol 12) that was
either best kept frozen in a benzene matrix under argon or used
immediately. Rf (hexane–Et2O, 3 : 1 (v : v)) 0.47; 1H-NMR (CDCl3,
300 MHz) d 9.52, (s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.60 (d, J =
8.3 Hz, 1H), 7.07 (ddd, J = 0.4, 2.2, 8.3, Hz, 1H), 6.12 (ddd, J =
0.40, 10.7, 17.6 Hz, 1H), 5.46 (d, J = 10.7, 1H), 5.20 (d, J =
17.6, 1H), 1.51 (s, 3H); 13C-NMR (CDCl3, 75 MHz) d 198.5 141.1,
139.5, 137.4, 133.1, 129.2, 129.0, 118.7, 102.2, 57.4, 20.4; LRMS
(EI) m/z = 337 [M − C2H3]+; [a]D25 +27.8 (c 1.3, CHCl3).
(R)-2-(4-Bromo-3-iodophenyl)-2-methylbut-3-en-1-ol (16).
A
1
3
KHSO4 (2 portions of 150 mL), aqueous saturated NaHCO3
solution of (R)-2-(4-bromo-3-iodophenyl)-2-methylbut-3-enal 15
(1.18 g, 3.23 mmol, 1.0 eq.) in MeOH (35 mL) at 0 ◦C was treated
with NaBH4 (114 mg, 3.0 mmol, 0.9 eq.). After stirring for 15 min
at ice bath temperature, the solution was allowed to warm to
room temperature and stirred for a further 2 h, at which time
it was concentrated to half of its initial volume and partitioned
between water (15 mL) and Et2O (50 mL). The aqueous layer
was extracted with Et2O (20 mL) and EtOAc (20 mL) and the
combined organic phases were washed with brine (10 mL), dried
(NaSO4) and concentrated under vacuum to afford a yellow oil
residue which typically was used without further purification.
For analytical purposes the crude product was purified by flash
chromatography on silica gel (hexane–EtOAc, 1 : 1 (v : v)) (960 mg,
(2 portions of 30 mL), brine (150 mL) and dried (Na2SO4).
Removal of the solvent under vacuum afforded a thick yellow oil
which was crudely purified via a short-column chromatography
filtration (silica gel; fast elution; hexane–EtOAc, 1 : 1 (v : v)
with 2% NEt3) to afford a thick pale yellow oil that eventually
crystallized upon standing in the cold (3.40 g) and was used
without further purification. Rf (hexane–EtOAc, 1 : 1 (v : v))
1
0.57; H-NMR (CDCl3, 300 MHz) d 9.64, (d, J = 4.0 Hz, 1H),
7.96 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.40 (dd, J =
2.2, 8.3 Hz, 1H), 3.48 (d, J = 4.0, 1H), 1.82 (s, 3H); 13C-NMR
(CDCl3, 75 MHz) d 205.6, 142.2, 137.5, 132.9, 129.2, 127.3, 101.1,
66.2, 62.0, 16.9; LRMS (EI) m/z = 366 [M]+.
1
(2R,3S)-3-(4-bromo-3-iodophenyl)-2-methyl-3-vinyloxirane (14).
To an ice-cold slurry of methyltriphenylphosphonium bromide
(4.97 g, 13.90 mmol, 1.5 eq.) in THF (100 mL) was added a solution
of KHMDS in toluene (0.5 M, 24.1 mL, 1.3 eq.) over 15 min.
The bright-yellow suspension obtained was allowed to reach room
81%). Rf (hexane–EtOAc, 1 : 1 (v : v)) 0.52; H-NMR (CDCl3,
300 MHz) d 7.81 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H),
7.20 (dd, J = 2.3, 8.4 Hz, 1H), 5.98 (dd, J = 10.8, 17.6 Hz, 1H),
5.30 (dd, J = 0.9, 10.8, 2H), 5.14 (dd, J = 0.9, 17.6, 1H), 3.74
(s, 2H), 1.38 (s, 3H); 13C-NMR (CDCl3, 75 MHz) d 145.9, 142.6,
4296 | Org. Biomol. Chem., 2006, 4, 4292–4298
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
139.3, 132.6, 128.7, 127.9, 115.9, 101.7, 69.7, 46.8, 22.9; LRMS
5.23 (dd, J = 1.2, 10.9 Hz, 1H), 5.17 (dd, J = 1.2, 17.6 Hz, 1H),
3.86 (d, J = 0.8 Hz, 2H), 1.45 (s, 3H), 0.84 (s, 9H), 0.02 (s, 3H),
0.00 (s, 3H); 13C-NMR (CDCl3, 75 MHz) d 191.3, 146.5, 143.6,
135.3, 133.6, 133.1, 129.0, 124.0, 113.9, 70.2, 46.8, 25.5, 22.2,
18.0, −6.2; LRMS (EI) m/z = 384 [M]+.
(EI) m/z = 368 [M]+.
Determination of the ee of alcohol (16) using the Alexakis reagent.
To the Alexakis reagent18 (0.10 mL of a 0.2 M solution in benzene,
0.02 mmol, 1.1 eq.) was added a solution of (R)-2-(4-bromo-
3-iodophenyl)-2-methylbut-3-en-1-ol 16 (7.0 mg, 0.018 mmol,
1.0 eq.) in benzene (0.2 mL) and the resulting solution was
left stirring at room temperature under argon for 15 h. The
resulting solution was then transferred into an NMR tube and
approximately 100 lL of C6D6 were added for locking. For rac-17:
31P-NMR (C6D6, 202 MHz) d 139.0 and 138.8 (equal intensities).
For 17: 31P-NMR (C6D6, 202 MHz) d 138.8.
(R,Z)-Ethyl-2-azido-3-(2-bromo-5-(2-((tert-butyldimethylsilyl-
oxy)methyl)but-3-en-2-yl)phenyl)acrylate (24). Sodium metal
(35.9 mg, 1.56 mmol, 6.0 eq.) was dissolved in EtOH
(1.0 mL). To the resulting solution was slowly added, at
−15 ◦C and over 1 h, a solution of (R)-2-bromo-5-(2-((tert-
butyldimethylsilyloxy)methyl)but-3-en-2-yl)benzaldehyde
23
(100 mg, 0.26 mmol, 1.0 eq.) and ethyl azidoacetate (0.71 mL of a
2.39 M solution in EtOH, 1.69 mmol, 6.5 eq.). During addition
a milky pale yellowish suspension formed. The temperature was
then allowed to rise from −15 ◦C to −10 ◦C and stirring was
continued for a further 18 h. The orange suspension obtained was
then stirred at room temperature for 0.5 h, re-cooled to ice bath
temperature, quenched with aqueous saturated NH4Cl (0.7 mL)
and gently partitioned between Et2O–EtOAc (1 : 1 (v : v)) (30 mL)
(R)-(2-(4-Bromo-3-iodophenyl)-2-methylbut-3-enyloxy)(tert-
butyl)dimethylsilane (22). To a solution of TBDMSCl (131 mg,
0.89 mmol, 1.3 eq.) and imidazole (122 mg, 1.77 mmol, 2.6 eq.) in
DMF (0.65 mL) was added a solution of (crude) (R)-2-(4-bromo-
3-iodophenyl)-2-methylbut-3-en-1-ol 16 (245 mg, 0.66 mmol,
1.0 eq.) in DMF (1.35 mL) at room temperature. After stirring
at this temperature for 7 h, the resulting solution was partitioned
between aqueous 1 M HCl (15 mL) and Et2O (25 mL). The organic
layer was washed with a second portion of aqueous 1 M HCl
(15 mL) and the combined acidic layers were extracted with Et2O
(10 mL). The combined organic layers were washed with aqueous
1
2
and aqueous saturated NH4Cl (10 mL). The deep-tan aqueous
layer was further extracted with Et2O–EtOAc (1 : 1 (v : v)) (3
portions of 10 mL); the combined organic layers were washed
1
2
with aqueous saturated brine (10 mL) and dried (Na2SO4). The
obtained tan solution was then concentrated to approximately
5 mL and filtered through a short column of silica gel (Et2O).
After removal of the solvent under vacuum, a reddish oil was
obtained which was purified by PTLC (hexane–Et2O, 3 : 1 (v : v)).
The title compound was obtained as a colourless oil (78 mg, 60%).
Rf (1st elution, hexane–Et2O, 3 : 1 (v : v); 2nd elution, pentane)
0.63 (note: the Rf values for the starting material and the product
1
2
saturated NaHCO3 (25 mL), brine (15 mL), dried (Na2SO4)
and concentrated under vacuum to afford a pale yellow residue.
Purification by flash chromatography on silica gel (hexane–Et2O,
3 : 1 (v : v)) delivered the title compound as a clear oil (254 mg,
1
80% based on 15). Rf (hexane–Et2O 3 : 1 (v : v)) 0.69; H-NMR
(CDCl3, 300 MHz) d 7.89 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.4 Hz,
1H), 7.23 (dd, J = 2.2, 8.4 Hz, 1H), 6.04 (dd, J = 10.9, 17.6 Hz,
1H), 5.21 (dd, J = 1.2, 10.9 Hz, 1H), 5.10 (dd, J = 1.2, 17.6 Hz,
1H), 3.70 (s, 2H), 1.37 (s, 3H), 0.88 (s, 9H), 0.01 (s, 3H), 0.00 (s,
3H); 13C-NMR (CDCl3, 75 MHz) d 152.3, 148.8, 145.1, 137.5,
134.5, 132.5, 119.7, 106.3, 75.7, 51.9, 31.4, 28.2, 23.8, 0.0; LRMS
(EI) m/z = 482 [M]+; [a]D25 −10.9 (c 2.3, CHCl3).
1
are very similar); H-NMR (CDCl3, 300 MHz) d 8.14 (d, J =
2.4 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.6 Hz, 1H),
7.23 (dd, J = 2.6, 8.5 Hz, 1H), 6.11 (dd, J = 10.9, 17.6 Hz, 1H),
5.23 (dd, J = 1.2, 10.9 Hz, 1H), 5.13 (dd, J = 1.2, 17.6 Hz, 1H),
4.43 (q, J = 7.1 Hz, 2H), 3.77 (d, J = 1.6 Hz, 2H), 1.46 (t, J =
7.1 Hz, 3H; partial overlap with s at d = 1.43 ppm), 1.43 (s, 3H;
partial overlap with s at d = 1.46 ppm), 0.88 (s, 9H), 0.02 (s, 3H),
0.00 (s, 3H); 13C-NMR (CDCl3, 75 MHz) d 169.0, 150.6, 149.3,
137.8, 137.7, 136.0, 135.4, 132.7, 129.6, 128.3, 119.5, 76.0, 68.1,
52.3, 31.4, 28.2, 23.9, 19.9, 0.0.
(R)-2-Bromo-5-(2-((tert-butyldimethylsilyloxy)methyl)but-3-en-
2-yl)benzaldehyde (23). To a −105 ◦C to −100 ◦C cooled slurry
of (R)-(2-(4-bromo-3-iodophenyl)-2-methylbut-3-enyloxy)(tert-
butyl)dimethylsilane 22 (429 mg, 0.89 mmol, 1.0 eq.) in toluene
(14.8 mL) was added a solution of nBuLi in hexanes (1.6 M,
1.02 mmol, 0.64 mL, 1.15 eq.) over approximately 8 s. After
stirring at this temperature for 2 min, DMF (193 lL, 2.49 mmol,
2.8 eq.) was added over 5 s. The resulting pale yellow solution was
stirred at −103 ◦C to −95 ◦C for 1.5 h and then allowed to reach
−40 ◦C over 0.5 h, after which the cooling bath was replaced
by a water bath and stirring was continued for a further 10 min.
The resulting pale yellow solution was then partitioned between
Et2O (80 mL) and water (15 mL) and the aqueous layer was
extracted with Et2O (2 portions of 20 mL). The combined organic
(R)-Ethyl-4-bromo-7-(1-tert-butyldimethylsilyoxy)-2-methylbut-
3-en-2-yl)-1H-indole-2-carboxylate (25). A solution of (R,Z)-
ethyl
2-azido-3-(2-bromo-5-(1-tert-butyldimethylsilyoxy)-2-
methylbut-3-en-2-yl)phenyl)acrylate 24 (74 mg, 0.14 mmol) in
meta-xylene (1.3 mL) was added dropwise over 1 h to refluxing
meta-xylene (3.7 mL). The obtained solution was refluxed for a
further 3.5 h, after which the solvent was removed under vacuum
to afford a tan oil. Purification by PTLC (hexane–Et2O, 5 : 1 (v :
v)) afforded the title compound as a pale yellow oil (45 mg, 69%).
Rf (hexane–Et2O, 5 : 1 (v : v)) 0.27; 1H-NMR (CDCl3, 300 MHz)
d 9.87, (brs, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 2.3 Hz,
1H), 7.18 (d, J = 7.9 Hz, 1H), 6.24 (dd, J = 10.8, 17.7 Hz, 1H),
5.40 (dd, J = 1.1, 10.8 Hz, 1H), 5.31 (dd, J = 1.1, 17.7 Hz, 1H),
4.45 (q, J = 7.1 Hz, 2H), 4.02 (d, J = 10.0 Hz, 1H), 3.87 (d, J =
10.0 Hz, 1H), 1.51 (s, 3H), 1.46 (t, J = 7.1 Hz), 0.87 (s, 9 H), 0.01
(s, 3 H), 0.00 (s, 3 H); 13C-NMR (CDCl3, 75 MHz) d 167.3, 149.3,
141.7, 134.5, 134.0, 133.0, 129.8, 129.0, 120.5, 120.4, 113.9, 76.2,
1
2
layers were washed with brine (20 mL), dried (Na2SO4) and
concentrated under vacuum affording a pale yellow oil residue.
Purification by flash chromatography on silica gel (hexane,
hexane–Et2O, 6 : 1 (v : v)) delivered the title compound as a
colorless oil (242 mg, 71%). Rf (1st elution, hexane–Et2O, 6 : 1 (v :
1
v); 2nd elution, hexane) 0.71; H-NMR (d-acetone, 300 MHz) d
10.34 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H),
7.65 (dd, J = 2.5, 8.4 Hz, 1H), 6.16 (dd, J = 10.9, 17.6 Hz, 1H),
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 4292–4298 | 4297
©

View Article Online
66.8, 52.3, 31.6, 28,8, 24.1, 20.1, 0.0; LRMS (EI) m/z = 465 [M]+;
[a]2D5 +22.7 (c 2.15 in CHCl3).
14 T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1984, 17, 1633.
15 (a) L. Horner, H. Hoffmann, H. G. Wippel and G. Klahre, Chem. Ber.,
1959, 92, 2499; (b) W. S. Wadsworth, Jr. and W. D. Emmons, J. Am.
Chem. Soc., 1961, 62, 1733; (c) For a review, see: B. E. Maryanoff and
A. B. Reitz, Chem. Rev., 1988, 89, 863.
Acknowledgements
16 (a) S. L. Huang, K. Omura and D. Swern, J. Org. Chem., 1976, 41, 3329;
(b) S. L. Huang, K. Omura and D. Swern, Synthesis, 1978, 4, 297; T. T.
Tidwell, Org. React., 1990, 39, 297.
17 G. Wittig and U. Scho¨lkopf, Ber. Dtsch. Chem. Ges., 1954, 87, 1318.
18 A. Alexakis, S. Mutti and P. Mangeney, J. Org. Chem., 1992, 57, 1224.
19 For a general reference, see: J. A. Joule and K. Mills, in Heterocyclic
Chemistry, Blackwell Science, Oxford, 4th edn, 2000.
Financial support from the Portuguese Foundation for Science
and Technology is gratefully acknowledged.
References
20 (a) E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc., 1972, 94, 6190;
(b) T. W. Greene and P. G. M. Wuts, in Protective Groups in Organic
Synthesis, 3rd edn, Wiley, New York, 1999.
21 For the preparation of 2-bromophenyllithium via the regioselective
lithium–iodine exchange of o-bromoiodobenzene, see: (a) L.S. Chen,
G. J. Chen and C. Tamborski, J. Organomet. Chem., 1980, 193, 283;
For previous uses of 2-bromophenyllithium, see: (b) H. E. Katz,
Organometallics, 1986, 5, 2308; (c) F. Leroux and M. Schlosser, Angew.
Chem., Int. Ed., 2002, 41, 4272.
22 Fukuyama has recently reported similar conditions for the lithium–
iodine exchange of a 2,6-dibromoiodobenzene derivative: K. Yamada,
T. Kurokawa, H. Tokuyama and T. Fukuyama, J. Am. Chem. Soc.,
2003, 125, 6630.
1 R. E. Moore, Pure Appl. Chem., 1982, 54, 1919.
2 (a) J. H. Cardellina II, F.-J. Marner and R. E. Moore, Science, 1979, 204,
193; (b) S. Sakai, Y. Hitotsuyanagi, N. Aimi, H. Fujiki, M. Suganuma,
T. Sugimura, Y. Endo and K. Shudo, Tetrahedron Lett., 1986, 27, 5219.
3 (a) H. Fujiki and T. Sugimura, Cancer Survey, 1983, 2, 539; (b) H.
Fujiki, M. Suganuma, H. Hakii, G. Bartolini, R. E. Moore, S.
Takayama and T. Sugimura, J. Cancer Res. Clin. Oncol., 1984, 108,
174.
4 (a) Y. Kishi and R. R. Rando, Acc. Chem. Res., 1998, 31, 163; (b) A. C.
Newton, Chem. Rev., 2001, 101, 2353; (c) K. Hinterding, D. Alonso-
D´ıaz and H. Waldmann, Angew. Chem., Int. Ed., 1998, 37, 688;
(d) B. Meseguer, D. Alonso-D´ıaz, N. Griebenow, T. Herget and H.
Waldmann, Chem. Eur. J., 2000, 6, 3943.
23 The synthesis of enantiomeric pure tryptophans from indoles has
been achieved by a variety of methods. For leading references, see:
Asymmetric reduction: (a) K. Osanai, Y. Yokoyama, K. Kondo and
Y. Murakami, Chem. Pharm. Bull., 1999, 47, 1587; Resolution: (b) Y.
Yokoyama, K. Osanai, M. Mitsuhashi, K. Kondo and Y. Murakami,
Heterocycles, 2001, 55, 653; Scho¨llkopf chiral auxiliary: (c) P. Zhang,
R. Liu and J. M. Cook, Tetrahedron Lett., 1995, 35, 7411; Chiral iodo-
oxazolidinone: (d) D. K. Pyun, C. H. Lee, H.-J. Ha, C. S. Park, J.-W.
Chang and W. K. Lee, Org. Lett., 2001, 3, 4197; Ring-opening of chiral
aziridines: (e) T. Nishikawa, M. Ishikawa, K. Wada and M. Isobe,
Synlett, 2001, 945; (f) J. S. Yadav, B. V. S. Reddy, S. Abraham and G.
Sabitha, Tetrahedron Lett., 2002, 43, 1565; (g) V. G. Nenajdenko, A. S.
Karpov and E. S. Balenkova, Tetrahedron: Asymmetry, 2001, 12, 2517.
24 For selected possibilities to achieve bromine–amino exchange, see:
Buchwald–Hartwig amination: (a) J. F. Hartwig, Acc. Chem. Res.,
1998, 31, 852; (b) J. P. Wolfe, S. Wagaw, J.-F. Marcoux and S. L.
Buchwald, Acc. Chem. Res., 1998, 31, 805; (c) C. G. Frost and P. J.
Mendonc¸a, J. Chem. Soc., Perkin Trans. 1, 1998, 2615; (d) J. F. Hartwig,
M. Kawatsura, S. I. Hauck, K. H. Shaughnessy and L. M. Alcazar-
Roman, J. Org. Chem., 1999, 64, 5575; (e) X. Huang, K. W. Anderson,
D. Zim, L. Jiang, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc.,
2003, 125, 6653; (f) S. Lee, M. Jørgensen and J. F. Hartwig, Org. Lett.,
2001, 3, 2729; Curtius rearrangement: (g) T. Curtius, Ber. Dtsch. Chem.
Ges., 1890, 23, 3023; (h) P. A. S. Smith, Org. React., 1946, 337; (i) J. J.
Chen, J. M. Hinkely, D. S. Wise and L. B. Townsend, Synth. Commun.,
1996, 26, 617; (j) M. T. Migawa and E. E. Swayze, Org. Lett., 2000, 2,
3309; Electrophilic amination: (k) J. P. Genet and C. Greck, Synlett,
1997, 741; (l) N. Zheng, J. D. Armstrong III, J. C. McWilliams and R. P.
Volante, Tetrahedron Lett., 1997, 38, 2817; (m) E. Erdik and M. Ay,
Chem. Rev., 1989, 89, 1947.
5 For some selected references, see: (a) A. Masuda, K. Irie, Y. Nakagawa
and H. Ohigashi, Biosci., Biotechnol., Biochem., 2002, 66, 1615; (b) K.
Irie, T. Isaka, Y. Iwata, Y. Yanai, Y. Nakamura, F. Koizumi, H.
Ohigashi, P. A. Wender, Y. Satomi and H. Nishino, J. Am. Chem.
Soc., 1996, 118, 10733; (c) Y. Endo, K. Shudo, A. Itai, M. Hasegawa
and S. Sakai, Tetrahedron, 1986, 42, 5905; (d) Y. Nakagawa, K. Irie, Y.
Komiya, H. Ohigashi and K. Tsuda, Tetrahedron, 2004, 60, 7077; (e) Y.
Endo and A. Yokoyama, Bioorg. Med. Chem. Lett., 2000, 10, 63; (f) D.
Ma, G. Tang and A. P. Kozikowski, Org. Lett., 2002, 4, 2377.
6 For previous total syntheses of lyngbyatoxin A, all lacking stereochem-
ical control at the quaternary stereocentre, see: (a) H. Muratake and
M. Natsume, Tetrahedron Lett., 1987, 28, 2265; (b) H. Muratake and
M. Natsume, Tetrahedron, 1991, 47, 8535; (c) M. F. Semmelhack and
H. Rhee, Tetrahedron Lett., 1993, 34, 1399.
7 The following numbering order preference will be used throughout this
article: the indole ring, the nine-membered lactam ring and the other
substituents.
8 (a) J. Christoffers and A. Baro, in Quaternary Stereocentres, Challenges
and Solutions for Organic Synthesis, Wiley-VCH, Weinheim, 2005;
(b) E. J. Corey and A. Guzman-Perez, Angew. Chem., Int. Ed., 1998,
37, 388; (c) K. Fuji, Chem. Rev., 1993, 93, 2037.
9 (a) M. E. Jung and D. C. D’Amico, J. Am. Chem. Soc., 1995, 117, 7379;
(b) M. E. Jung and K. L. Anderson, Tetrahedron Lett., 1997, 38, 2605.
10 J. Tønder and D. Tanner, Tetrahedron, 2003, 59, 6937.
11 H. Hemetsberger, D. Knittel and H. Weidmann, Monatsh. Chem., 1970,
101, 161.
12 (a) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune
and B. K. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765; (b) For a
comprehensive review, see: T. Katsuki and V. S. Martin, Org. React.,
1996, 48, 1.
25 J. G. Hill, B. Rossiter and K. B. Sharpless, J. Org. Chem., 1983, 48,
3607.
13 K. Fujita, Y. Takahashi, M. Owaki, K. Yamamoto and R. Yamaguchi,
Org. Lett., 2004, 6, 2785.
4298 | Org. Biomol. Chem., 2006, 4, 4292–4298
This journal is
The Royal Society of Chemistry 2006
©