The Knight route to cyclopiazonic acid: Enantioselective synthesis of a key intermediate

Article abstract of DOI:10.1016/j.tet.2010.06.092

The indole alkaloid α-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) besides thapsigargin and artemisinin. Inhibitors of SERCA hold promise as novel anticancer and antimalarial drugs. Since its structure elucidation three racemic syntheses of α-cyclopiazonic acid have been published. We report now the first enantioselective and high yielding synthesis of a key-intermediate of the Knight synthesis, currently the most efficient route to CPA. Our synthesis is based on a diastereoselective 1,4-cuprate addition followed by an enolate azidation of an indolylacrylic acid modified with the Evans auxiliary.

Full text of DOI:10.1016/j.tet.2010.06.092

Tetrahedron 66 (2010) 7119e7123
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The Knight route to cyclopiazonic acid: enantioselective synthesis of a key
intermediate
*
Christian Beyer, Jürgen Scherkenbeck , Frank Sondermann, Axel Figge
€
Bergische Universitat Wuppertal, Fachgruppe Chemie Gaußstraße 20, 42119 Wuppertal, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2010
Received in revised form 29 June 2010
Accepted 30 June 2010
Available online 6 July 2010
The indole alkaloid
a-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)
plasmic reticulum Ca2þ-ATPase (SERCA) besides thapsigargin and artemisinin. Inhibitors of SERCA hold
promise as novel anticancer and antimalarial drugs. Since its structure elucidation three racemic
syntheses of a-cyclopiazonic acid have been published. We report now the first enantioselective and
high yielding synthesis of a key-intermediate of the Knight synthesis, currently the most efficient route
to CPA. Our synthesis is based on a diastereoselective 1,4-cuprate addition followed by an enolate
azidation of an indolylacrylic acid modified with the Evans auxiliary.
Keywords:
Indole alkaloid
Cylopiazonic acid
SERCA
Ó 2010 Elsevier Ltd. All rights reserved.
Key-intermediate
Enantioselective synthesis
Evans auxiliary
1. Introduction
The mycotoxins
a-cyclopiazonic acid (CPA, 1) and b-cyclo-
piazonic acid (2) have been isolated from the fungus Penicillium
cyclopium Westling, which grows worldwide on stored grain and
cereal products.1 Toxicity and mode of action of
a-cyclopiazonic
acid, the major toxic principle of P. cyclopium have been studied
thoroughly as a consequence of several poisonings after ingestion of
contaminated grain products.2,3 CPA (1) specifically inhibits a Ca2þ
-
ATPase of the sarcoendoplasmic reticulum (SERCA), which is es-
sential for calcium reuptake in the muscle contractionerelaxation
cycle.4,5 Other inhibitors of SERCAs comprise the terpenoids thap-
sigargin and most interesting artemisinin, an antimalarial drug.6,7
While thapsigargin and in particular
a-cyclopiazonic acid show
a remarkable toxicity against mammals, this was not found for
artemisinin. Taken all these findings together SERCA inhibitors
represent promising lead structures for the development of novel
anticancer and antimalarial drugs (Fig. 1).
Since the structure elucidation of CPA in 1968 three racemic
syntheses were published by Kozikowski8 (1984), Natsume9 (1985)
and Knight10 (2005), all starting from the indole ring system.
Abbreviations: DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCM, Dichlorometh-
ane; DMF, Dimethylformamide; KHMDS, Potassium hexamethyldisilazide; Ns, p-
Nosyl; TBDPS, tert-Butyl-diphenylsilyl; THF, Tetrahydrofurane; Ts, Tosyl.
* Corresponding author. Tel.: þ49 202 439 2654; e-mail address: scherkenbeck@
uni-wuppertal.de (J. Scherkenbeck).
Figure 1. Known inhibitors of SERCA.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.092

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C. Beyer et al. / Tetrahedron 66 (2010) 7119e7123
A biomimetic approach via
Aggarwal11 in 2007.
We wish to report here the first enantioselective synthesis of the
tryptophan analogue 6, a central precursor in the ‘Knight synthesis’
(Scheme1), whichcurrentlyrepresentsthemostefficientroutetoCPA
(1). Inparticular, the tetracyclic scaffold 5 is established from 6 in only
b
-cyclopiazonic (2) acid was detailed by
addition of isobutenyl cuprate and the 1,2-enolate addition of
trisyl azide as electrophilic nitrogen source (Scheme 3). Due to
their syn-arrangement only one auxiliary is needed to induce the
correct absolute configuration at both chiral centers. Di-
astereomeric ratios of up to 94:6 were achieved in the Michael-
addition and up to 98:2 in the azidation reaction with the (4S)-
O
H
H
O
N
N
H
H
TBDPSO
CO2Et
H
CO2Et
NHNs
OH
H
H
NTs
N
H
NTs
1
5
6
CO2Et
TBDPSO
CO2Me
NTs
N
H
7
8
Scheme 1. Retrosynthetic analysis of CPA (1) according to the Knight synthesis.
one step by an elegant carbocationic cascade cyclization. Precursor 6
can be prepared in enantiomerically pure form by a minor modifica-
tion of the Knight synthesis via the chiral indolylacrylic acid imide 13.
phenyloxazolidone auxiliary. Somewhat reduced selectivities were
observed in the 1,4-addition with the (4S)-isopropyl- (85:15) and
(4S)-benzyl-oxazolidones (83:17). In case of the one-carbon ex-
tended benzyl-oxazolidone the reduced induction can be
explained by an unfavourable steric interaction with the bulky
TBDPS-protecting group, which turns the benzyl group away from
an ideal shielding position of the double bond. The indolylacrylic
imide 13 was prepared in good yield by HornereEmmons olefi-
nation of aldehyde 9 with the chiral phosphonic ester 12.
2. Results and discussion
Indolyl-carbaldehyde
9 was prepared in four steps from
commercially available indole-4-carboxylic acid methyl ester (8)
(Scheme 2) according to literature procedures.12e14 Our first
Scheme 2. Synthesis of 7 and further transformations. Reagents: (i) LiAlH4, THF, rt, 12 h, 94%; (ii) imidazole (3.0 equiv), TBDPSCl (1.7 equiv), DMF, 0 ꢀC then rt, 12 h, 85%; (iii) DMF
(3.5 equiv), POCl3 (1.1 equiv), DMF, 0 ꢀC then rt, 12 h, 78%; (iv) TsCl (1.5 equiv), NEt3 (1.5 equiv), DCM, 12 h, 97%; (v) (EtO)2P(O)CH2CO2Et (2.4 equiv), LiCl (2.4 equiv), DBU (2.0 equiv),
MeCN, 24 h, 83%; (vi) PhINNs (0.67 equiv), (þ)-2,20-isopropylidenebis[(4R)-4-phenyl-2-oxazoline] (0.067 equiv), Cu(OTf)2 (0.033 equiv), DCM, rt, 12 h; (vii) methane sulfonamide
(3 equiv), AD-mix alpha (0.01 equiv K2Os2O2(OH)4), tBuOH, H2O, 24 h, rt.
approach towards intermediate 6 was based on a catalytic enan-
tioselective aziridination of acrylic ester 7. Enantioselective azir-
idinations of diverse cinnamic esters have been reported in several
recent papers.15e17 However, with PhINNs as electrophilic nitrogen
source, catalytic amounts of Cu(OTf)2 and the chiral ligand (þ)-2,20-
isopropylidenebis[(4R)-4-phenyl-2-oxazoline], only very low yields
of 10 were obtained, possibly due to the tosylate protected
electron-poor indole system. On the other hand a catalytic enan-
tioselective Sharpless dihydroxylation afforded diol 11 in sufficient
yield but with low enantioselectivity (55% ee).18,19
Remarkably, reduction of the azide function in the oxazolidonyl
imide 15a and subsequent protection with the nosyl group proved
to be significantly more difficult compared to ethyl ester 16. While
reduction of the azido group with SnCl2 afforded 61% of the re-
spective amine 15b, nosylation of 15b failed almost completely. The
reduced reactivity of 15a and 15b (Scheme 3) can be attributed to
a considerable sterical shielding of the azido group surrounded by
the indolyl-/isobutenyl group on one side and the bulky oxazoli-
done on the other side. Consequently, the oxazolidone moiety was
removed first using standard conditions (H2O2/LiOH) followed by
esterification with K2CO3/EtI in 86% over two steps. As expected,
the reduction (93%) and introduction of the nosyl group (87%) now
By far better results were obtained with the classical Evans
chiral oxazolidones, which controlled excellently both the 1,4-

C. Beyer et al. / Tetrahedron 66 (2010) 7119e7123
7121
Scheme 3. Diastereoselective synthesis of key intermediate 6. (i) 12 (1.2 equiv), KOtBu (1.0 equiv), THF, rt, 94% (ii) THF, thiophenol copper (1.0 equiv) then 2-methyl-1-prope-
nylmagnesium bromide (3.0 equiv), ꢁ40 ꢀC to rt, ꢁ60 ꢀC to 0 ꢀC, 1 h at 0 ꢀC, 74%, dr 94:6 (iii) KHMDS 0.5 M in toluene, (1.1 equiv), ꢁ78 ꢀC, add to 14 (1.0 equiv) in THF at ꢁ78 ꢀC, then
add enolate to trisyl azide (1.25 equiv), ꢁ78 ꢀC, 3 min, hydrolyse with HOAc and warm up immediately to 30 ꢀC, 30 min, 81%, dr 98:2; (iv) H2O2 30% (4 equiv), LiOH (2 equiv), THF/
H2O 3:1, 0 ꢀC to rt, 2 h; (v) K2CO3 (5 equiv), EtI (3 equiv), acetone, rt, 18 h, 86% over two steps; (vi) SnCl2 (2.0 equiv), MeOH, rt, 12 h, 89%; (vii) 4-NO2C6H4SO2Cl (1.5 equiv), iPr2NEt
(3.5 equiv), MeCN, 0 ꢀC, 30 min, 87%.
succeeded in excellent yields to afford key intermediate 6, from
which CPA (1) is available in three additional steps according to the
Knight synthesis.
4.51 (d, J¼12.3 Hz,1H), 4.44 (d, J¼12.6 Hz,1H), 4.29 (dd, J¼8.9, 3.9 Hz,
1H); 13C NMR (100 MHz, CDCl3):
165.3,153.1,138.0,129.0 (CH),128.8
(CH), 125.9 (CH), 70.3 (CH2), 57.7 (CH), 27.9 (CH2); ESI-MS m/z (%)¼
284.0 (96, [MþH]þ), 286.0 (100, [MþH]þ), 301.0 (26, [MþNH4]þ),
303.0 (26, [MþNH4]þ), 589.0 (4, [2MþNa]þ), 591.0 (4, [2MþNa]þ).
d
3. Experimental section
3.1. General
3.1.2. (S)-Dimethyl 2-oxo-2-(2-oxo-4-phenyl-oxazolidin-3-yl) ethyl-
phosphonate (12). Freshly distilled trimethyl phosphite (55 mL,
465 mmol) was added to (S)-3-(2-bromoacetyl)-4-phenyl-oxazoli-
din-2-one (41.4 g, 146 mmol). The reaction mixture was stirred for
3 h at 55e60 ꢀC. Then the excess trimethyl phosphite was removed
in vacuo. Crystallization of the crude product from ethyl acetate
Solvents and reagents were purchased from commercial sources.
Triethylamine and diisopropylethylamine were dried over CaH2 and
distilled prior to use. Methanol was distilled from magnesium.
Chloroform and dichloromethane were dried by passing the solvents
through a basic aluminium oxide filled column. Precoated plates
yielded 12 (44.1 g, 97%) as a colourless solid. Rf (ethyl acetate): 0.24;
25
(silica gel 60 F254, 250
mm, Merck, Darmstadt, Germany) were used
mp 110.3e112.7 ꢀC; [
a]
D
þ78.8 (c 1.0, DCM); 1H NMR (400 MHz,
for TLC. Silica gel 0.04e0.063 mm from MachereyeNagel was used
for chromatographic purification. HPLC-MS was performed on
a Varian 500 IonTrap LC-ESI-MS system (column: 5 mm RP18). High-
CDCl3):
d
7.29e7.38 (m, 5H), 5.44 (dd, J¼8.7, 3.9 Hz, 1H), 4.68 (t,
J¼8.9 Hz,1H), 4.26 (dd, J¼9.0, 3.9 Hz,1H), 3.73 (d, J¼3.5 Hz, 3H), 3.71
(d, J¼3.5 Hz, 3H), 3.69e3.86 (m, 2H); 13C NMR (100 MHz, CDCl3):
resolution MS were measured on a Bruker MicroTOF. Analytical 1H
and 13C NMR spectra were recorded at 25 ꢀC on a BRUKER AVANCE
400 (400.13 MHz for 1H NMR, 100.62 MHz for 13C NMR) or BRUKER
AVANCE 600 (600.13 MHz for 1H NMR, 150.90 MHz for 13C NMR)
spectrometer using tetramethylsilane as an internal standard.
Melting points (mp) were determined with a Buechi 535 melting
point apparatus and are uncorrected. IR-spectra were measured on
a JASCO FT/IR-4200.
d
164.2 (d, J¼6.8 Hz), 153.5, 138.4, 129.0 (CH), 128.7 (CH), 126.0 (CH),
69.8 (CH2), 57.8 (CH), 53.0, 53.1 (2ꢂd, CH3), 34.3 (d, J¼130.4 Hz, CH2);
31P NMR (162 MHz, CDCl3):
23.08; HR-ESI-MS m/z¼336.0606
(calcd 336.0607 for C13H16NO6PNa); IR: v 1771, 1676, 1607 cmꢁ1
d
.
3.1.3. (S)-3-{(E)-3-[4-(tert-Butyl-diphenyl-silanyloxymethyl)-1-(tol-
uene-4-sulfonyl)-1H-indol-3-yl]-acryloyl}-4-phenyl-oxazolidin-2-
one (13). KOtBu (4.0 g, 35.2 mmol) was added to a solution of 12
(13.2 g, 42.3 mmol) in THF (375 mL). The solution was stirred for
30 min at room temperature followed by dropwise addition of indo-
lylaldehyde 9 (20.0 g, 35.2 mmol) in THF (375 mL). The reaction was
stirred over night, neutralized with aqueous saturated ammonium
chloride solution and extracted three times with DCM. The combined
organic layers were dried over Na2SO4. After removal of the solvent and
chromatographic purification (cyclohexane/ethyl acetate 10/1 and
cyclohexane/ethyl acetate 4/1) starting material (6.25 g) and pure 13
3.1.1. (S)-3-(2-Bromoacetyl)-4-phenyl-oxazolidin-2-one20. n-BuLi
(1.6 M in hexane, 76.6 mL, 123 mmol) was added dropwise to a solu-
tion of (S)-4-phenyl-oxazolidin-2-one (20.0 g, 123 mmol) in dry THF
(600 mL) at ꢁ78 ꢀC under an inert gas atmosphere. The solution was
warmed to ꢁ20 ꢀC over a period of 30 min. After cooling again to
ꢁ78 ꢀC 2-bromoacetyl bromide (10.6 mL,123 mmol) dissolved in dry
THF (200 mL) was added and the mixture was allowed to warm up to
room temperature. The reaction was hydrolysed with phosphate
buffer (pH 7) and extracted with DCM. The combined organic layers
were dried with Na2SO4 and the solvent was removed under reduced
pressure. The crude product (33.0 g) was purified by column chro-
matography (cyclohexane/DCM 1/1) to yield (S)-3-(2-bromoacetyl)-
4-phenyl-oxazolidin-2-one (25.3 g, 73%) as a colourless solid. The
analytical and spectroscopic data are in accordance with those
reported in the literature. Rf (cyclohexane/ethyl acetate 1/1): 0.41; mp
119.5e121.5 ꢀC (lit20: 121e122 ꢀC); 1H NMR (400 MHz, CDCl3):
(17.2 g, 65%, foam) were obtained. Rf (DCM): 0.35; [
a
]
25 þ22.0 (c 1.02,
D
DCM); 1H NMR (400 MHz, CDCl3):
d
8.27 (d, J¼15.4 Hz,1H), 8.05 (s,1H),
7.91 (d, J¼8.3 Hz,1H), 7.82 (d, J¼8.3 Hz, 2H), 7.79(d, J¼15.4 Hz,1H), 7.64
(m, 4H), 7.17e7.40 (m, 14H), 7.02 (d, J¼7.4 Hz, 1H), 5.56 (dd, J¼8.7,
3.9 Hz, 1H), 4.95 (s, 2H), 4.74 (t, J¼8.7 Hz, 1H), 4.33 (dd, J¼8.8, 3.7 Hz,
1H), 2.36 (s, 3H), 0.93 (s, 9H); 13C NMR (100 MHz, CDCl3):
d164.0,153.9,
145.4, 139.3, 139.2 (CH), 135.7 (CH), 135.7 (CH), 135.6 (C), 134.9, 134.1,
133.3, 133.2, 130.0 (CH), 129.6 (CH), 129.5 (CH), 129.1 (CH), 128.6 (CH),
127.5 (CH), 127.5 (CH), 127.2, 127.1 (CH), 126.9, 126.1 (CH), 125.4 (CH),
124.8 (CH), 123.5 (CH), 119.5, 117.4 (CH), 113.1 (CH), 70.0 (CH2), 64.5
d
7.30e7.40 (m, 5H), 5.41 (dd, J¼8.8, 3.9 Hz,1H), 4.71 (t, J¼8.8 Hz,1H),

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C. Beyer et al. / Tetrahedron 66 (2010) 7119e7123
(CH2), 57.8 (CH), 26.7 (CH3), 21.6 (CH3),19.1; HR-ESI-MS m/z¼777.2427
(calcd 777.2425 for C44H42N2O6SSiNa); IR: v 1770, 1682 cmꢁ1
ester (16). Compound 15a (37.0 g, 31.7 mmol) was dissolved in THF
(160 mL), water (50 mL) was added and the resulting solution was
cooled to 0 ꢀC. Then H2O2 (12.9 mL, 30%,126.7 mmol) and LiOH (1.5 g,
63.3 mmol) were added. The reaction mixture was warmed to room
temperature and stirred for 2 h. After recooling to 0 ꢀC aqueous
Na2SO3 solution (80 mL, 1.5 M, 139 mmol) was added followed by
saturated aqueous ammonium chloride (160 mL) solution. The mix-
ture was extracted three times with DCM (100 mL) and the combined
organic layers were dried with Na2SO4. After removal of the solvent
theresiduewasdriedunderhighvacuumandusedforthesubsequent
reaction without further purification. K2CO3 (21.9 g,158.3 mmol) and
EtI (7.6 mL, 95.0 mmol) were added to a solution of the crude acid
(26.8 g)in acetone (50 mL). The reactionmixturewasstirred for 2 h at
room temperature. After that time the solvent was removed, the
residue resolved in DCM and washed with a saturated aqueous am-
monium chloride solution. The crude product (27.2 g) obtained after
drying and removal of the solvent was purified by column chroma-
tography (DCM/cyclohexane 7/3) to yield ethyl ester 16 (20.0 g, 86%)
.
3.1.4. (S)-3-{(R)-3-[4-(tert-Butyl-diphenyl-silanyloxymethyl)-1-(tol-
uene-4-sulfonyl)-1H-indol-3-yl]-5-methyl-hex-4-enoyl}-4-phenyl-
oxazolidin-2-one (14). Thiophenol copper (1.72 g, 9.93 mmol) was
suspended in THF (37.5 mL) under inert gas atmosphere and cooled
to ꢁ40 ꢀC. (2-Methylprop-1-enyl)magnesium bromide (59.6 mL,
29.8 mmol) was added dropwise over a period of 10 min. The
solution was warmed to room temperature and stirred for 20 min.
After cooling to ꢁ60 ꢀC indolylacrylic imide 13 (7.50 g, 9.93 mmol) in
THF (12.5 mL) was added dropwise over a period of 20 min. After
stirring for 1 h at 0 ꢀC the solution was poured into cold saturated
aqueous ammonia (200 mL), stirred for 15 min at room temperature
and extracted three times with DCM (100 mL). Drying and removal
of the solvent under reduced pressure afforded a crude product
(7.85 g), which was purified by column chromatography (DCM) to
yield the Michael-addition product 14 (5.96 g, 74%) as a yellowish
25
foam. Rf (DCM): 0.59; [
a
]
þ17.0 (c 1.0, DCM); 1H NMR (400 MHz,
asayellowfoam. Rf (cyclohexane/ethylacetate1/1):0.60;[
a
]
25 þ5.9(c
D
D
CDCl3):
d
7.88 (d, J¼8.2 Hz, 1H), 7.72 (d, J¼8.3 Hz, 2H), 7.63e7.66 (m,
1.0, DCM); 1H NMR (400 MHz, CDCl3):
d
7.94 (d, J¼8.2 Hz,1H), 7.77 (d,
4H), 7.48 (d, J¼7.3 Hz, 1H), 7.39 (s, 1H), 7.10e7.37 (m, 14H), 5.26 (d,
J¼15.0 Hz, 1H), 5.23 (dd, J¼9.0, 4.1 Hz, 1H), 5.09 (d, J¼14.0 Hz, 1H),
5.00 (d, J¼9.0 Hz, 1H), 4.57 (t, J¼8.8 Hz, 1H), 4.26 (q, J¼7.6 Hz, 1H),
4.17 (dd, J¼8.8, 3.9 Hz, 1H), 3.29 (dd, J¼16.2, 7.5 Hz, 1H), 3.16 (dd,
J¼16.2, 7.5 Hz, 1H), 2.34 (s, 3H), 1.42 (s, 3H), 1.08 (s, 3H), 1.07 (s, 9H);
J¼8.3 Hz, 2H), 7.63e7.69 (m, 4H), 7.52 (s,1H), 7.23e7.45 (m,10H), 5.38
(d, J¼9.4 Hz, 1H), 5.19e5.27 (m, 2H), 4.40 (dd, J¼9.4, 4.3 Hz, 1H),
3.95e4.03 (m, 2H), 3.82e3.90 (m,1H), 2.37 (s, 3H),1.69 (s, 3H),1.38 (s,
3H), 1.01 (s, 9H), 0.97 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
168.5, 144.9, 136.2, 135.6 (CH), 135.5 (CH), 135.2, 135.1, 134.0, 133.3,
13C NMR (100 MHz, CDCl3):
d
170.0, 153.6, 144.6, 138.8, 135.6 (CH),
133.1, 129.8 (CH), 129.8 (CH), 127.7 (CH), 127.7 (CH), 126.9 (CH), 126.1,
125.6 (CH), 124.5 (CH), 122.6, 121.9 (CH), 120.7 (CH), 112.8 (CH), 66.3
(CH), 63.6 (CH2), 61.6 (CH2), 38.5 (CH), 26.8 (CH3), 25.7 (CH3), 21.5
(CH3), 19.3, 18.5 (CH3), 13.8 (CH3); HR-ESI-MS m/z¼757.2848 (calcd
135.4, 135.3, 134.7, 133.5, 133.4, 133.4, 129.7 (CH), 129.5 (CH), 129.5
(CH), 128.9 (CH), 128.4 (CH), 127.6 (CH), 127.2, 127.0 (CH), 126.8 (CH),
126.6, 126.3, 125.7 (CH), 124.4 (CH), 123.0 (CH), 120.8 (CH), 112.3 (CH),
69.8 (CH2), 63.2 (CH2), 57.4 (CH), 41.8 (CH2), 32.7 (CH), 26.8 (CH3),
25.4 (CH3), 21.5 (CH3), 19.3, 17.7 (CH3); HR-ESI-MS m/z¼833.3056
757.2850 for C41H46N4O5SSiNa); IR: v 1731, 1598 cmꢁ1
.
(calcd 833.3051 for C48H50N2O6SSiNa); IR: v 1778, 1703 cmꢁ1
.
3.1.7. (2S,3R)-3-[4-(tert-Butyl-diphenyl-silanyloxymethyl)-1-(tolu-
ene-4-sulfonyl)-1H-indol-3-yl]-5-methyl-2-(4-nitro-benzenesulfonyl-
amino)-hex-4-enoic acid ethyl ester (6). Compound 16 (7.78 g,
10.6 mmol) was dissolved in MeOH (100 mL), SnCl2 (4.78 g,
21.2 mmol) was added and the resulting mixture was stirred over
night at room temperature. The solvent was removed under reduced
pressure, water (50 mL) and aqueous sodium hydroxide (6 M,
0.5 mL) were added to the residue and the mixture was stirred for
20 min at room temperature. Threefold extraction with DCM, fol-
lowed by removal of the solvent afforded the crude amine (6.67 g,
89%) as a yellowish foam. Rf (cyclohexane/ethyl acetate 1/1): 0.40; 1H
3.1.5. (S)-3-{(2S,3R)-2-Azido-3-[4-(tert-Butyl-diphenyl-silanyloxy-
methyl)-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-5-methyl-hex-4-
enoyl}-4-phenyl-oxazolidin-2-one (15a). A solution of 14 (23.2 g,
28.5 mmol) in THF (65 mL) was cooled to ꢁ78 ꢀC and transferred
through a metal cannula to a KHMDS (62.8 mL, 0.5 M in toluene,
31.4 mmol) solution in THF (65 mL) at ꢁ78 ꢀC. Stirring was con-
tinued for 90 min at this temperature and the resulting solution
transferred through a metal cannula into a stirred solution of trisyl
azide (11.0 g, 35.7 mmol) in THF (65 mL) at ꢁ78 ꢀC. After 3 min the
reaction was stopped by addition of acetic acid (8.2 mL,
142.7 mmol), immediately warmed to 30 ꢀC and stirred for 30 min
at this temperature. Water was added (500 mL) and the solution
was extracted three times with DCM (250 mL). After drying and
removal of the solvent a crude product (33.0 g) was obtained,
NMR (600 MHz, CDCl3): d 7.93 (s, 1H), 7.87e7.90 (m, 3H), 7.62e7.68
(m, 4H), 7.38e7.42 (m, 2H), 7.29e7.34 (m, 5H), 7.21e7.23 (m, 3H),
5.72 (d, J¼9.5 Hz, 1H), 5.15e5.22 (m, 2H), 4.52 (d, J¼9.5, 4.0 Hz, 1H),
4.02 (br d,1H), 3.93 (q, J¼7.1 Hz, 2H), 2.33 (s, 3H),1.65 (s, 3H),1.31 (s,
3H), 1.07 (s, 9H), 0.91 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3):
which was purified by column chromatography (DCM/CH 7:3) to
d 168.8, 144.7, 137.9, 135.5 (CH), 135.5 (CH), 135.2, 135.0, 133.9, 133.3,
25
afford 15a (17.6 g, 73%) as a colourless foam. Rf (DCM): 0.5; [
a
]
133.1,129.8 (CH),129.7 (CH),129.7 (CH),127.7 (CH),127.2 (CH),126.1,
125.8 (CH), 124.4 (CH), 121.6 (CH), 119.8 (CH), 112.6 (CH), 63.6 (CH2),
62.2 (CH2), 58.2 (CH), 57.5 (CH), 37.7 (CH), 26.8 (CH3), 25.7 (CH3), 21.5
(CH3), 19.3, 18.6 (CH3), 13.6 (CH3); HR-ESI-MS m/z¼709.3124 (calcd
D
þ12.9 (c 1.0, DCM); 1H NMR (400 MHz, CDCl3):
d
7.87 (d, J¼8.4 Hz,
1H), 7.79 (d, J¼8.3 Hz, 2H), 7.60e7.66 (m, 5H), 7.49 (s, 1H), 7.14e7.37
(m, 14H), 5.46 (d, J¼14.1 Hz, 1H), 5.35 (d, J¼10.0 Hz, 1H), 5.08 (d,
J¼10.4 Hz, 1H), 5.05 (d, J¼14.2 Hz, 1H), 4.85 (dd, J¼8.5, 3.6 Hz, 1H),
4.21 (t, J¼8.8 Hz, 1H), 4.19 (t, J¼9.9 Hz, 1H), 4.09 (dd, J¼8.9, 3.6 Hz,
1H), 2.37 (s, 3H), 1.54 (s, 3H), 1.17 (s, 3H), 1.08 (s, 9H); 13C NMR
709.3126 for C41H49N2O5SiNa); IR: v¼3386, 1731 cmꢁ1
.
The crude material of the previous reaction (6.67 g, 9.40 mmol)
was dissolved in dry MeCN (80 mL) and 4-nitrobenzene-1-sulfonyl
chloride (3.13 g, 14.10 mmol) was added at 0 ꢀC followed by iPr2NEt
(5.6 mL, 32.91 mmol). After a reaction time of 30 min at 0 ꢀC the
solvent was removed under reduced pressure. The residue was
partitioned between a saturated aqueous ammonium chloride so-
lution and DCM. The aqueous phase was extracted twice with DCM.
The crude product (9.29 g) obtained after drying and removal of the
solvent was purified by column chromatography (cyclohexane/
ethyl acetate 1/1) to yield the nosyl protected key intermediate 6
(100 MHz, CDCl3): d 167.7, 153.0, 145.0, 138.1 (CH), 136.7, 135.5 (CH),
135.5 (CH), 135.4, 135.3, 134.7, 133.5, 133.2, 129.9 (CH), 129.6 (CH),
129.2 (CH), 128.8 (CH), 127.7 (CH), 127.7 (CH), 127.1 (CH), 125.8,
125.7 (CH), 124.8 (CH), 123.9 (CH), 123.6 (CH), 122.6, 120.4 (CH),
111.9 (CH), 70.0 (CH2), 63.8 (CH), 63.1 (CH2), 57.6 (CH), 38.5 (CH),
26.9 (CH3), 25.7 (CH3), 21.6 (CH3), 19.4, 18.2 (CH3); HR-ESI-MS m/
z¼874.3063 (calcd 874.3065 for C48H49N5O6SSiNa); IR: v 1777,
1702 cmꢁ1
.
(7.27 g, 87%) as a yellow foam. Rf (cyclohexane/ethyl acetate 1/1):
25
3.1.6. (2S,3S)-3-[4-(tert-Butyl-diphenyl-silanyloxymethyl)-1-(tolu-
ene-4-sulfonyl)-1H-indol-3-yl]-2,5-dimethyl-hex-4-enoic acid ethyl
0.70;
d
[
a]
ꢁ15.1 (c 1.0, DCM); 1H NMR (600 MHz, CDCl3):
D
7.92e7.94 (m, 2H), 7.75 (d, J¼8.5 Hz, 2H), 7.68e7.70 (m, 3H),

C. Beyer et al. / Tetrahedron 66 (2010) 7119e7123
7123
7.62e7.63 (m, 2H), 7.48e7.50 (m, 2H), 7.41e7.45 (m, 2H), 7.41 (s,
References and notes
1H), 7.36 (t, J¼7.4 Hz, 2H), 7.33 (t, J¼7.6 Hz, 2H), 7.24 (d, J¼8.3 Hz,
2H), 7.21 (d, J¼7.3 Hz, 1H), 7.16 (t, J¼7.8 Hz, 1H), 5.61 (br d, J¼9.6 Hz,
1H), 5.34 (d, J¼13.2 Hz, 1H), 5.10 (d, J¼13.5 Hz, 1H), 4.03 (br dd,
J¼9.7, 3.2 Hz, 1H), 3.88e3.97 (m, 2H), 2.34 (s, 3H), 1.72 (s, 3H), 1.36
(s, 3H), 1.09 (s, 9H), 0.99 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz,
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CDCl3):
d
¼169.8, 149.6, 145.0, 144.6, 137.4, 135.5 (CH), 135.5 (CH),
134.9, 134.8, 133.5, 133.2, 133.1, 129.8 (CH), 129.8 (CH), 127.7 (CH),
127.6 (CH), 127.5 (CH), 126.9 (CH), 125.6, 125.3 (CH), 124.4
(CH), 123.8 (CH), 122.0 (CH), 121.1, 118.4 (CH), 112.5 (CH), 63.6 (CH2),
62.0 (CH2), 59.9 (CH), 38.1 (CH), 26.8 (CH3), 25.8 (CH3), 21.5 (CH3),
19.2, 18.5 (CH3), 13.8 (CH3); HR-ESI-MS m/z¼892.2769 (calcd
892.2763 for C47H50N3O9S2Si); IR: v 3284, 1736 cmꢁ1
.
12. Somei, M.; Kizu, K.; Kunimoto, M.; Yamada, F. Chem. Pharm. Bull. 1985, 33,
3696e3708.
Acknowledgements
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Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.06.092.