Palladium catalysed tandem cyclisation-anion capture. Part 6: Synthesis of sugar, nucleoside, purine, benzodiazepinone and β-lactam analogues via capture of in situ generated vinylstannanes

Article abstract of DOI:10.1016/S0040-4020(00)00661-X

The regioselective palladium catalysed hydrostannylation of alkynes bearing a β-heteroatom affords mainly α-vinyltin(IV) compounds that are used as terminating species in palladium catalysed cyclisation-anion capture processes. The pharmacophore attached

Full text of DOI:10.1016/S0040-4020(00)00661-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7553–7560
Palladium Catalysed Tandem Cyclisation–Anion Capture.
Part 6:1 Synthesis of Sugar, Nucleoside, Purine, Benzodiazepinone
and b-lactam Analogues via Capture of in situ
Generated Vinylstannanes
*
´
Adele Casaschi, Ronald Grigg and Jose M. Sansano
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, Leeds University, Leeds LS2 9JT, UK
Received 1 December 1999; revised 29 June 2000; accepted 20 July 2000
Abstract—The regioselective palladium catalysed hydrostannylation of alkynes bearing a b-heteroatom affords mainly a-vinyltin(IV)
compounds that are used as terminating species in palladium catalysed cyclisation–anion capture processes. The pharmacophore attached
to the alkyne moiety permits the synthesis of sugars, nucleosides, purines, benzodiazepinones and b-lactams analogues in good yields.
᭧ 2000 Elsevier Science Ltd. All rights reserved.
Organotin(IV) reagents (RSnBu3) are, in general, readily
prepared, stable to air and moisture and capable of a wide
variation of the R group. The Stille coupling reaction2 is the
most important and versatile transformation involving such
species. We have shown that organotin(IV) reagents are
excellent anion capture agents in our intramolecular1,3 and
intermolecular4 palladium catalysed cascade cyclisation–
anion capture processes. Our published work on the inter-
molecular version of these processes4 employs previously
prepared or commercially available organotin(IV) reagents,
whilst the intramolecular version can be achieved by in situ
generated vinyltin species via the ready Pd(0) catalysed
hydrostannylation of alkynes.3,5 The latter cascade
processes also permit easy access to the unexplored inter-
molecular sp2–sp3 Stille coupling. Moreover, this synthetic
sequence permits activation of a wide variety of pharmaco-
phores by attachment of the tributyltin(IV) moiety.
The alkynes 2a–h have at least one heteroatom located b to
the triple bond to take advantage of the well known regio-
selectivity of the palladium(0) catalysed hydrostannylation
in the presence of a b- or g-heteroatom.3,5 Thus 2a–h are
typical anion capture agents for our methodology and these,
together with appropriate reactants containing starter/relay
species such as 4a–c, allow the catalytic cascade cycli-
sation–anion capture to proceed (Scheme 2).
The palladium(0) catalysed hydrostannylation of 2a–h was
performed in toluene at 0ЊC for 1 h using tributyltin hydride
and a catalyst comprised of 5 mol% Pd2(dba)3 and 20 mol%
tris(2-furyl)phosphine. When the reaction was judged
complete (TLC monitoring) the ratio of vinyltributyl-
1
stannanes 3a:3b was determined by H NMR. In all cases
3a was the major regioisomer (Scheme 3 and Table 1). Aryl
iodide 4 was then added and the temperature increased to
110ЊC to initiate a 5-exo-trig cyclisation followed by sp3–
sp2 Stille coupling of 5 with the appropriate a-vinylstannane
3a (Scheme 3). The selected catalyst gave the best results
for this coupling process.3,6 Other catalysts [Pd(PPh3)4,
Pd(AcO)2/PPh3, Pd2(dba)3/AsPh3)],6 solvents (NMP, aceto-
nitrile, DMF) and additives (CuI,7 CuCl,8 CuO9) were tested
without any noticeable improvement of yield.
These features prompted us to prepare propargylic deriva-
tives of a range of key pharmacophores which would serve,
after the corresponding Pd(0) catalysed hydrostannylation
reaction, as terminating species in our palladium(0)
catalysed cascades.4
Initially, we therefore prepared a series of O- and N-
propargylic derivatives of protected sugars (2a, 2b), nucleo-
sides (2c, 2d), purines (2e, 2f), benzodiazepinones (2g) and
b-lactam (2h) (Scheme 1).
The coupling reaction of the corresponding b-vinylstan-
nanes 3b furnished small amounts of 7 that were discarded
during isolation of the desired major compounds 6.
Keywords: cascade reactions; palladium catalysis; hydrostannylation; Stille coupling; cyclisation.
* Corresponding author. Tel.: ϩ44-113-233-6501; fax: ϩ44-113-233-6501; e-mail: r.grigg@chem.leeds.ac.uk
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00661-X

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A. Casaschi et al. / Tetrahedron 56 (2000) 7553–7560
Scheme 1.

A. Casaschi et al. / Tetrahedron 56 (2000) 7553–7560
7555
Scheme 2.
Scheme 3.
using a Carlo Erba MOD 11016 instrument. Thin layer
chromatography was carried out on Whatman PESIL G/
UV polyester plates coated with a 0.2 mm layer of silica-
gel 60 (Merck 9385). Column chromatography was
performed with silica gel 60 (Merck 9385). Petroleum
ether refers to the fraction with bp 40–60ЊC. Anhydrous
DMF was commercially available (Aldrich), THF and
toluene were sodium dried under a nitrogen atmosphere
and n-hexane was distilled prior to use.
In all cases, except when 2e, 2f and 2g were employed, a 1:1
mixture of diastereoisomers was obtained according to H
NMR data. A similar ratio was observed in the earlier stages
of the reaction, even at lower temperatures.
1
Synthesis of Alkynes (2)
2a. Sodium hydride (60% dispersion in mineral oil, 720 mg,
18 mmol) was added to a stirred solution of diacetone-d-
glucose (5 g, 19 mmol) in dry THF (20 ml) and the mixture
was stirred and boiled under reflux for 2 h. Tetraethyl-
ammonium iodide (1 g, 3.8 mmol, 20%) and a solution of
propargyl bromide (80% solution in toluene, 4 g, 27 mmol)
were then added and the mixture stirred at room temperature
for 16 h, diluted with Et2O (100 ml) and washed with water.
The organic layer was separated, dried (MgSO4), filtered
and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography eluting with
70:30 v/v hexane/ethyl acetate affording 2a as a pale yellow
oil (4.2 g, 78%). (Found: C, 60.10; H, 7.4. C15H22O6
requires: C, 60.40; H, 7.5%). d 1.32, 1.36, 1.43, 1.50
(4×s, 12H, 4×CH3), 2.52 (t, Jˆ2.0 Hz, 1H, CCH), 3.95–
4.17 (m, 5H, 3×CCHO and CH2CuC), 4.28 (m, 2H,
CH2O),4.68 (d, Jˆ3.5 Hz, 1H, CHO), and 5.92 (d,
Jˆ3.5 Hz, OCHO). m/z (%) 299 (Mϩϩ1, 4), 298 (Mϩ, 6),
283 (95), and 101 (100).
Selective deprotection of the THP group of the primary
alcohol in the product arising from 2c and 4b to afford 6e
was achieved after treatment of the crude product with 0.2N
hydrochloric acid/THF at room temperature for 1 day.
However, the same deprotection was not possible in 6f in
the product arising from 2c and 4c. In this case, to afford 6f,
total deprotection of primary and secondary alcohols was
carried out by treatment with 2N hydrochloric acid/THF at
room temperature for 1 day.
Finally, N-propargylbenzodiazepinone 2g needed 2 mol
equiv. of tributyltin hydride in order to obtain a good
yield of corresponding vinylstannanes and also 2 mol
equiv. of 4b and 4c to generate products 6m and 6n in
good yield.
In conclusion, a wide variety of interesting compounds can
be accessed through a simple one-pot cascade protocol
proceeding via palladium(0) catalysed hydrostannylation
followed by cyclisation–anion capture.
2b. Sodium hydride (60% dispersion in mineral oil, 308 mg,
7.7 mmol) was added slowly to a stirred solution of 1,2:3,4-
di-O-isopropylidenegalactopyranose (194 mg, 7.7 mmol) in
dry THF (10 ml) and the mixture stirred and heated under
reflux for 2 h. Tetraethylammonium iodide (396 mg,
3.8 mmol, 20%) and a solution of propargylbromide (80%
solution in toluene, 4 g, 27 mmol) were then added and the
reaction stirred at room temperature for 16 h. Work up as
above afforded 2b (178 mg, 70%) as colourless prisms, mp
55–56ЊC. (Found: C, 60.45; H, 7.5. C15H22O6 requires: C,
60.4; H, 7.5%). d 1.28, 1.29, 1.40, 1.49 (4×s, 12H, 4×CH3),
2.40 (t, Jˆ2.4 Hz, 1H, CCH), 3.65 (m, 2H, CH2O), 3.95 (m,
1H, CHOCO), 4.17 (dd, Jˆ2.3 Hz, 2H, CuCCH2O), 4.21
Experimental
Melting points were determined on a Koffler hot-stage appa-
ratus and are uncorrected. Mass spectral data were obtained
from a VG Autospec mass spectrometer operating at 70 eV.
Nuclear magnetic resonance spectra were recorded on
Bruker QE300 and AM 400 machines operating at 300
and 400 MHz, respectively. Unless otherwise specified,
deuterochloroform was used as solvent with tetramethyl-
silane as internal standard. Microanalyses were obtained

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A. Casaschi et al. / Tetrahedron 56 (2000) 7553–7560
Table 1. Cascade hydrostannylation–cyclisation–anion capture for the synthesis of 6a–o
Alkyne
Aryl Iodide
HSnBu3:4 (equiv.)
3a:3ba
Time (h)
Product
Yield (%)b
2a
2a
4a
4c
1:1
1:1
80:20
80:20
2
2
(64)c
(66)c
2b
2b
4a
4c
1:1
1:1
80:20
80:20
3
3
(65)c
(63)c
2c
2c
4b
4c
1:1
1:1
85:15
85:15
2
2
(59)c,d
(59)c,e
2d
2d
4b
4c
1:1
1:1
70:30
70:30
2f
2f
(60)c
(60)c
2e
2e
4a
4c
1:1
1:1
90:10
90:10
2
2
(67)
(68)
2f
2f
4b
4c
1:1
1:1
90:10
90:10
4
4
(63)
(66)
2g
2g
4b
4c
2:2
2:2
90:10
90:10
2
2
(72)
(80)
2h
4a
1:1
(5:5
4
(64)c
1
a Calculated by H NMR.
b Isolated compounds, based on 2, after column chromatography.
c Obtained as a 1:1 mixture of diastereomers (1H NMR).
d Isolated compound after treatment with 0.2 M HCl/THF, rt, 1 days.
e Isolated compound after treatment with 2 M HCl/THF, rt, 1 days.
f The cyclisation–anion capture reaction was carried out at 90ЊC.

A. Casaschi et al. / Tetrahedron 56 (2000) 7553–7560
7557
(q, Jˆ7.4, 1.8 Hz, 1H, CHO), 4.27 (q, Jˆ5.0, 2.5 Hz, 1H,
CHO), 4.56 (q, Jˆ2.5, 7.9 Hz, 1H, CHO), and 5.48 (d,
Jˆ5.0 Hz, 1H, OCHO). m/z (%) 299 (Mϩϩ1, 4), 298
(Mϩ, 10), 283 (95), and 101 (100).
the filtrate concentrated in vacuo. Crystallisation of the resi-
due from methanol yielded 2e (1.45 g, 80%) as colourless
needles, mp 209ЊC. (Found: C, 54.85; H, 4.35; N, 25.7.
C10H10N4O2 requires: C, 55.05; H, 4.6, N, 25.7%). d 2.19
(t, Jˆ2.5 Hz, 1H, CuCH), 3.59 (s, 3H, 3-CH3), 4.00 (s, 3H,
7-CH3), 4.78 (t, Jˆ2.5 Hz, 2H, 5-NCH2), and 7.55 (s, 1H,
ArH). m/z (%) 218 (Mϩ, 100), 190 (17), and 135 (10).
2c. A solution of 2,3-O-isopropylideneuridine (2.84 g,
10 mmol), 3,4-dihydro-2H-pyran (1.0 ml, 11 mmol) an
p-toluenesulfonic acid (90 mg) in THF (40 ml) was stirred
at room temperature for 1 days. The solvent was removed
under reduced pressure and the product was N-alkylated
with propargyl bromide following the same procedure as
that described for the synthesis of 2a, furnishing 2c
(3.09 g, 76%) as a colourless sticky oil. (Found: C, 58.9;
H, 6.3; N, 6.5. C20H26N2O7 requires: C, 59.1; H, 6.45; N,
6.85%). d (1:1 mixture of diastereoisomers) 1.37, 1.38 (2×s,
2f.10 Sodium hydride (60% dispersion in mineral oil,
400 mg, 10 mmol) was added portionwise to a stirred
suspension of adenine (1.35 g, 10 mmol) in dry DMF
(40 ml) at 0ЊC and stirring continued at room temperature
for 1 h. Propargyl bromide (80% solution in toluene,
2.23 ml, 20 mmol) was then added and stirring continued
for 16 h. DMF was evaporated under reduced pressure and
the residue partitioned between ethyl acetate (50 ml) and
water (50 ml). The organic layer was separated, dried
(Na2SO4) and evaporated under reduced pressure. The
residue was dissolved in DMF (100 ml), DMAP (3.65 g,
30 mmol) and di-tert-butyldicarbonate (6.5 g, 30 mmol)
were added and the resulting mixture was stirred at room
temperature for 1 days. After the usual work-up the residue
was chromatographed eluting with 1:1 v/v n-hexane/ether
affording product 2f (1.76 g, 48%) as colourless needles
from n-hexane/ether, mp 112–113ЊC. (Found: C, 57.9; H,
6.2; N, 18.8. C18H23N5O4 requires: C, 57.9; H, 6.2; N,
18.75%). d 1.46 (s, 18H, 6×CH3), 2.61 (t, Jˆ2.3 Hz, 1H,
CuCH), 5.08 (d, Jˆ2.3 Hz, 2H, CH2CuC), 8.32 (s, 1H,
H-2), and 8.89 (s, 1H, H-8). m/z (%) 373 (Mϩ, 47), 274 (51),
218 (45), 200 (63), 174 (65), 173 (100), 146 (31), 144 (21),
57 (98), 41 (38) and 39 (20).
3H, CH3CO), 1.05–1.82 (m with
s at 1.60, 9H,
CH2CH2CH2CO, CH3CO), 2.10 (t, Jˆ2.3 Hz, 1H,
CuCH), 3.51–3.61 (m, 2H, CH2CH2O), 3.68 (dd,
Jˆ11.0, 2.3 Hz, 1H, CH2CHOCN), 3.85 (m, 2H,
CH2CHOCN), 3.98 (dd, Jˆ11.0, 2.3 Hz, 1H, CH2CHOCN),
4.44–4.87 (m, 6H, CH2CuC, 2×CHOCCH3, OCHO and
CHOCHN), 5.75, 5.78 (2×d, Jˆ8.2 Hz, 1H, HCvCHN),
5.95 (d, Jˆ2.7 Hz, 1H, OCHN), 7.69 and 7.75 (2×d,
Jˆ8.2 Hz, 1H, CHvCHN). m/z (%) 406 (Mϩ, 0.3), 150
(23), 88 (21), 86 (71), 85 (82), 84 (77), 71 (62), 57 (39),
56 (36), 55 (43), 47 (25), 43 (100), 42 (52), 41 (58) and 39
(32).
2d. A solution of 2,3-O-isopropylideneuridine (1.42 g,
5 mmol) in dry DMF (15 ml) was treated with sodium
hydride (60% dispersion in mineral oil, 200 mg, 5 mmol),
the reaction mixture was stirred at room temperature for
30 min when benzyl bromide (655 ml, 5.5 mmol) was
added and stirring continued at room temperature for 1 h.
After the usual work-up, the residue was chromatographed
(SiO2) affording N-benzyluridine (1.23 g, 73%). O-Alkylation
was carried out as described for the synthesis of 2a but in
this case, the reaction mixture was stirred at room tempera-
ture for 1 day. Compound 2d was isolated as a colourless
sticky oil (740 mg, 54%). (Found: C, 64.2; H, 6.0; N, 6.55.
C22H24N2O6 requires: C, 64.05; H, 5.85; N, 6.8%). d 1.36,
1.58 (2s, 6H, 2×CH3), 2.45 (t, Jˆ2.2 Hz, 1H, CuCH), 3.68
(dd, Jˆ10.3, 3.8 Hz, 1H, OCH2CO), 3.81 (dd, Jˆ10.3,
2.5 Hz, 1H, OCH2CO), 4.12, 4.18 (2×dd, Jˆ16.0, 2.2 Hz,
2H, CH2CuC), 4.43 (ddd, Jˆ3.8, 2.5, 2.5 Hz, 1H,
CH2CHO), 4.77 (dd, Jˆ6.4, 2.0 Hz, 1H, OCHCHN), 4.80
(dd, Jˆ6.4, 2.5 Hz, 1H, OCHCHN), 4.80 (dd, Jˆ6.4,
2.5 Hz, 1H, OCHCHCH2), 5.06, 5.14 (2×d, Jˆ13.7 Hz,
2H, CH2N), 5.76 (d, Jˆ8.1 Hz, 1H, NCHvCH), 5.87 (d,
Jˆ2.0 Hz, 1H, OCHN), 7.22–7.49 (m, 5H, ArH), and 7.51
(d, Jˆ8.1 Hz, 1H, NCHvCH). m/z (%) 412 (Mϩ, 28), 397
(25), 337 (22), 211 (31), 203 (24), 202 (43), 129 (53), 96
(45), 95 (20), 91 (100), 85 (30), 69 (52), 68 (36), 59 (30), 55
(32), 43 (52), 41 (39) and 39 (60).
2g. Benzodiazepinone 1f11 was alkylated by the same
experimental procedure as that used for the synthesis of
2a. Compound 2g (73%) was obtained as colourless needles
from n-hexane/ether, mp 46–48ЊC. (Found: C, 78.6; H, 4.9;
N, 10.25. C18H14N2O requires: C, 78.8; H, 5.1; N, 10.2%). d
2.28 (t, Jˆ2.4 Hz, 1H, CuCH), 3.81 (d, Jˆ10.6 Hz,
1H, CH2CO), 4.51, 4.69 (2×dd, Jˆ17.4, 2.4 Hz, 2H,
CH2CuC), 4.82 (d, Jˆ10.6 Hz, 1H, CH2CO) and
7.21–770 (m, 9H, ArH). m/z (%) 274 (Mϩ, 99), 273
(93), 247 (48), 246 (100), 234 (25), 205 (33), 91 (39), 77
(27) and 39 (25).
2h.12 Propiolic acid (62 mg, 0.89 mmol) was added drop-
wise to a solution of cephalosporin 1g (300 mg, 0.9 mmol)
and N,N0-dicyclohexylcarbodiimide (206 mg, 1 mmol) in of
dry THF (2 ml) at 0ЊC and the mixture was stirred for 16 h at
room temperature. The solvent was removed in vacuo, the
residue dissolved in dichloromethane and washed with
water. The organic layer was separated, dried (MgSO4),
filtered and the filtrate concentrated under reduced pressure.
The residue was purified by column chromatography eluting
with 70:30 v/v hexane/ethyl acetate to yield 2h (180 mg,
53%) as light brown prisms, mp 76ЊC. (Found: C, 53.5; H,
5.2; N, 7.3; S, 8.3. C17H20N2O6S requires: C, 53.6; H, 5.3, N,
7.3; S, 8.4%). d 1.52 (s, 9H, t-Bu), 2.07 (s, 3H, OCOCH3),
3.03 (s, 1H, CuCH), 3.37 (d, Jˆ18.5 Hz, 1H, 2-Ha), 3.56
(d, Jˆ18.5 Hz, 1H, 2-Hb), 4.79 (d, Jˆ18.4 Hz, 1H,
2-CHaOAc), 4.96 (d, Jˆ4.8 Hz, 1H, 8-H), 5.10 (d, Jˆ
18.4 Hz, 1H, 2-CHbOAc), 5.81 (t, Jˆ4.8 Hz, 8.7 Hz, 1H,
7-H), and 7.55 (d, Jˆ8.7 Hz, 1H, NH). m/z (%) 380 (Mϩ,
3), 216 (64), 156 (100).
2e. A solution of propargyl bromide in (80% solution in
toluene, 2.4 g, 16.6 mmol) was added to a solution of
3,7-dimethylxanthine 1d (1.5 g, 8.3 mmol) and tetra-n-butyl-
ammonium fluoride (1 M solution in THF, 16.6 ml) in dry
THF (50 ml) and the mixture was stirred at room tempera-
ture for 16 h. The mixture was concentrated in vacuo, the
residue dissolved in dichloromethane and washed with
water. The organic layer was dried (MgSO4), filtered and

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A. Casaschi et al. / Tetrahedron 56 (2000) 7553–7560
Synthesis of 2-iodoarylalkenes 4
Table 1. Products 6a–h and 6o were obtained as 1:1
mixtures of diastereomers.
4a. Sodium hydride (60% dispersion in mineral oil, 960 mg,
24 mmol) was added slowly to a stirred solution of N-o-
iodophenyl acrylamide (7 g, 24 mmol) in dry DMF
(20 ml). After 2 h at room temperature the mixture was
cooled to 0ЊC followed by the addition of iodomethane
(3.4, 24 mmol) and stirring continued at room temperature
for further 2 h. The mixture was diluted with Et2O (200 ml)
and washed with water. The organic layer was separated,
dried (MgSO4), filtered and the filtrate concentrated in
vacuo. Purification of the residue by column chroma-
tography afforded 4a (5.36 g, 78%) as colourless prisms
from benzene, mp 75ЊC. (Found: C, 43.9; H, 3.8; N, 4.4;
I, 42.2. C11H12 INO requires: C, 43.8; H, 4.0; N, 4.6; I,
42.1%). d 1.80 (s, 3H, CCH3), 3.22 (s, 3H, NCH3), 4.98
and 5.03 (2×s, 2H, CvCH2), 7.03 (t, 1H, ArH), 7.18 (d,
1H, ArH), 7.38 (t, 1H, ArH) and 7.92 (d, 1H, ArH). m/z (%)
301 (Mϩ, 0.3), 203 (4), and 174 (100).
6a. Pale yellow oil. (HRMS found: 473.2403. C24H35NO7
requires: 473.2403). d (mixture of diastereoisomers) 1.20–
1.60 (m, 15H, 5×CH3), 2.65 (q, Jˆ16.5 Hz, 2H, CH2CvC),
3.18 (s, 2H, NCH3), 3.35, 3.45, 3.52, 3.63 (4×d, Jˆ13.5 Hz,
2H, CvCCH2O), 3.60–4.40 (m, 7H, 5×CHO and
CH2OCO), 4.75, 4.79, 4.88, 4.92 (4×s, 2H, CvCH2), and
6.80–7.20 (m, 4H, ArH). m/z (%) 473 (Mϩ, 1), 214 (91), 160
(100).
6b. Pale yellow oil. (HRMS found: 447.2308. C25H34O7
requires: 447.2338). d (mixture of diastereoisomers) 1.30,
1.36, 1.39, 1.42, 1.48 (5×s, 15H, 5×CH3), 2.37, 2.51 (2×d,
Jˆ13.8 Hz, 1H, CCH2CvC), 2.38, 2.49 (2×d, Jˆ13.0 Hz,
1H, CCH2CvC), 3.57, 3.78 (2×d, Jˆ12 Hz, 2H,
CvCCH2O), 4.16, 4.53 (2×d, Jˆ8 Hz, 2H, ArOCH2),
3.70–4040 (m, 7H, 5×OCH and CH2OCO), 4.91, 5.15
(2×s, 2H, CvCH2), and 6.73–7.20 (m, 4H, ArH). m/z (%)
446 (Mϩ, 0.4), 314 (5), and 133 (100).
4b. Sodium hydride (60% dispersion in mineral oil, 880 mg,
22 mmol) was added slowly to a solution of N-sulphonyl-2-
iodoaniline (3.9 g, 10 mmol) in dry DMF (25 ml). After 2 h
at room temperature, the mixture was cooled to 0ЊC,
3-chloro-1-methylpropene (1.1 g, 10 mmol) added and
stirring continued at 0ЊC for 4 h. The mixture was then
diluted with Et2O (200 ml) and washed with water. The
organic layer was separated, dried (MgSO4) filtered and
the filtrate concentrated in vacuo. Purification of the residue
by column chromatography eluting with 5:1 v/v hexane/
ether yielded 4b (3.3 g, 75%) as a colourless oil. (Found:
C, 43.1; H, 3.6; N, 3.2. C16H16INO2S requires: C, 43.2; H,
3.6; N, 3.3%). d 1.84 (s, 3H, CH3), 3.96 (s, 2H, CH2N), 5.10,
5.24 (2×s, 2H, CvCH2), and 7.00–7.68 (m, 9H, ArH). m/z
(%) 445 (Mϩ, 11), 304 (42), 141 (100), 123 (18), 77 (40),
and 55 (54).
6c. Pale yellow oil. (HRMS found: 473.2414. C26H35NO7
requires: 473.2414). d (mixtures of diastereoisomers) 1.30–
1.60 (5×s, 15H, 5×CH3), 2.38 (m, 2H, CCH2CvC), 3.18 (s,
3H, NCH3), 3.35 (m, 2H, OCCH2O), 3.65–5.60 (m, 7H,
5×CHO, and CvCCH2O), and 6.80–7.15 (m, 4H, ArH).
m/z (%) 473 (Mϩ, 0.8), 313 (26), and 245 (92).
6d. Pale yellow oil. (Found: C, 67.5; H, 7.8. C25H34O7
requires: C, 67.25; H, 7.65%). d (mixture of diastereo-
isomers) 1.32, 1.35, 1.43, 1.44, 1.53 (5×s, 15H, 5×CH3),
2.38, 2.51 (2×d, Jˆ13.8 Hz, 2H, CCH2CvC), 3.45 (m,
2H, OCCH2O), 3.62, 3.78 (2×d, Jˆ15 Hz, 2H, ArOCH2);
d 3.72 (s, 2H, CH2O), 3.95 (m, 1H, CHO), 4.16 (dq, Jˆ9.95,
1.2 Hz, CHO), 4.27 (d, Jˆ9.8 Hz, 1H, CvCCH2O), 4.31
(dd, Jˆ5.0, 2.3 Hz, CHO), 4.52 (d, Jˆ9.8 Hz, 1H,
CvCCH2O), 4.59 (dd, Jˆ10.0, 2.3 Hz, 1H, CHO), 4.21,
4.87 (2× s, 2H, CvCH2), 5.52 (d, Jˆ5.0 Hz, 1H, OCHO),
and 6.67–7.18 (m, 4H, ArH). m/z (%) 446 (Mϩ, 0.5), 314
(1), and 133 (100).
4c. Prepared as for 4b but using 2-iodophenol. The product
(79%) was obtained as a colourless oil. (Found: C, 43.8; H,
4.0; I, 46.4. C10H11IO requires: C, 43.6; H, 4.3; I, 46.1%). d
1.84 (s, 3H, CH3),4.42 (s, 2H, CH2), 4.96, 5.18 (2×s, 2H,
CvCH2), 6.65 (t, 1H, ArH), 6.75 (d, 1H, ArH), 7.21 (m, 1H,
ArH), and 7.88 (d, 1H, ArH). m/z (%) 274 (Mϩ, 58.5), 220
(32), and 147 (60).
6e. Colourless prisms from n-hexane/ether, mp 49–51ЊC.
(Found: C, 61.15; H, 5.5; N, 6.6; S, 5.05. C31H35N3O8S
requires: C, 61.1; H, 5.9; N, 6.9; S, 5.25%). d (mixture of
diastereoisomers) 1.21 (s, 3H, CH3CCN), 1.37, 1.58 (2×s,
6H, 2×CH3CO), 2.21, 2.28 (2×d, Jˆ14.0 Hz, 2H,
CCH2CvC), 2.59 (br. s, 1H, OH), 3.53, 3.54 (2×d, Jˆ
10.3 Hz, 1H, CH2NAr), 3.88 (dd, Jˆ12.0, 3.3 Hz, 1H,
CH2O), 3.93 (dd, Jˆ12.0, 2.5 Hz, 1H, CH2O), 4.00 (d, Jˆ
10.3 Hz, 1H, CH2NAr), 4.18, 4.25 (2×m, 2H, NCH2CvC),
4.32 (br. s, 1H, CHCH2O), 4.59, 4.61, 4.66 (3×s, 2H,
CH2vC), 5.00 (br. s, 2H, 2×CHOCCH3), 5.58 (d, Jˆ
1.6 Hz, 1H, OCHN), 5.76 (d, Jˆ8.0 Hz, 1H, NCHvCH)
and 6.98–7.96 (m with d at 7.47, Jˆ8.0 Hz, 10H,
NCHvCH and ArH). m/z (%) 609 (Mϩ, 3), 468 (22), 338
(27), 273 (34), 272 (100), 184 (31), 166 (60), 141 (48), 132
(42), 131 (30), 130 (59) and 77 (58).
General procedure for cyclisation–anion capture
Tri-n-butyltin hydride (0.5 or 1 mmol, see Table 1) was
added dropwise to a stirred solution of 2 (0.5 mmol),
Pd2(dba)3 (11.2 mg, 0.025 mmol), and tri-(2-furyl)phos-
phine (11.6 mg, 0.10 mmol) in anhydrous toluene (5 ml)
at 0ЊC, and the mixture stirred at room temperature for
1 h. Aryl iodide 4 (0.5 or 1 mmol, see Table 1) and toluene
(2 ml) were then added and the mixture boiled under reflux
for the time indicated in Table 1. The reaction mixture was
cooled to room temperature, ethyl acetate (10 ml) and 2 M
aqueous solution of potassium fluoride (10 ml) added and
the resulting mixture vigorously stirred for 1 h. The mixture
was then filtered, the organic layer separated, dried
(Na2SO4) and evaporated under reduced pressure. The resi-
due was purified by flash chromatography eluting with
mixtures of n-hexane/ether or n-hexane/ethyl acetate to
furnish 6a–o. Yields and reaction times are collected in
6f. Colourless prisms from n-hexane/ether, mp 53–55ЊC.
(Found: C, 61.6; H, 6.0; N, 6.3. C22H26N2O7 requires: C,
61.4; H, 6.1; N, 6.5%). d (mixture of diastereoisomers)
1.26 (s, 3H, CH3), 2.44, 2.49 (2×d, Jˆ14.0 Hz, 2H,

A. Casaschi et al. / Tetrahedron 56 (2000) 7553–7560
7559
CCH2CvC), 2.23 (br. s, 1H, OH), 3.47, 3.86 (2×d,
Jˆ11.5 Hz, 2H, NCH2CvC), 4.06–4.20 (m, 8H, CH2OH,
3×CHO and 1H of CH2OAr), 4.49 (d, Jˆ8.6 Hz, 1H,
CH2OAr), 4.61, 4.70 (2×s, 2H, CH2vC), 5.73 (d,
Jˆ3.2 Hz, 1H, OCHN), 5.75 (d, Jˆ8.2 Hz, 1H, NCHvCH)
and 6.77–7.27 (m, 4H, ArH) and 7.75 (d, Jˆ8.2 Hz, 1H,
NCHvCH). m/z (%) 430 (Mϩ, 1), 298 (36), 166 (46), 151
(21), 134 (22), 133 (100), 132 (14), 131 (13) and 105 (50).
2H, CH2NAr), 4.24, 4.36 (2×d, Jˆ16.4 Hz, 2H,
NCH2CvC), 4.51, 4.81 (2×s, 2H, CvCH2) and 7.01–
7.88 (m with s at 7.79, 10H, H-8 and ArH). m/z (%) 660
(Mϩ, 0.01), 345 (56), 272 (50), 215 (27), 214 (23), 185 (24),
184 (100), 141 (50), 131 (32), 130 (67), 77 (71), 59 (42), 44
(22), 41 (38) and 39 (20).
6l. Colourless oil. (Found: C, 64.55; H, 6.75; N, 13.85.
C28H35N5O5 requires: C, 64.5; H, 6.75; N, 13.5%). d 1.44
(s, 18H, 6×CH3CO), 1.47 (s, 3H, CH3CCN), 2.39 (s, 2H,
CCH2CvC), 4.23(d, Jˆ8.9 Hz, 1H, CH2O), 4.26, 4.42
(2×d, Jˆ16.5 Hz, 2H, NCH2CvC), 4.56 (d, Jˆ8.9 Hz,
1H, CH2O), 4.62, 4.97 (2×s, 2H, CvCH2), 6.85–7.20 (m,
4H, ArH), 7.73 (s, 1H, H-8) and 8.84 (s, 1H, H-2). m/z (%)
521 (Mϩ, 6), 389 (45), 348 (27), 322 (31), 289 (23), 215
(71), 214 (30), 189 (84), 188 (50), 133 (100), 105 (63), 57
(64) and 41 (27).
6g. Colourless needles from n-hexane/ether, mp 58–59ЊC.
(Found: C, 65.0; H, 5.9; N, 5.8; S, 4.6. C38H41N3O8S
requires: C, 65.2; H, 5.9; N, 6.0; S, 4.6%). d (mixture of
diastereoisomers) 1.13–1.43 (2×s, 3H, CH3CCN), 1.37,
1.58 (2×s, 6H, 2×CH3CO), 2.10–2.29 (m, 2H, CCH2CvC),
3.31–3.53, (m, 5H, CH2OCH2 and 1H of CH2NAr), 3.94,
3.92 (2×d, Jˆ10.2 Hz, 1H, CH2NAr), 4.32 (br. s, 1H,
CH2CHO), 4.67–4.79 (m, 3H, 2×CHOCCH3 and 1H of
CH2vC), 4.92 (br. s, 1H, CH2vC), 5.07, 5.13 (2×d,
Jˆ13.8 Hz, 2H, CH2N), 5.63, 5.66 (2×d, Jˆ8.0 Hz, 1H,
NCHvCH), 5.86 (d, Jˆ5.4 Hz, 1H, OCHN) and 6.94–
7.83 (m with d at 7.62, Jˆ8.0 Hz, 15H, ArH and
NCHvCH). m/z (%) 669 (Mϩ, 1), 428 (29), 272 (100),
141 (39), 132 (34), 131 (25), 130 (63), 91 (47), 77 (56)
and 43 (22).
6m. Colourless needles from n-hexane/ether, mp 59–60ЊC.
(Found: C, 72.8; H, 5.55; N, 7.2; S, 5.7. C34H31N3O3S
requires: C, 72.7; H, 5.55; N, 7.5; S, 5.7%). d 1.03–1.10
(2×s, 3H, CH3), 2.03, 2.09 (m, 2H, CCH2CvC), 3.40 (d,
Jˆ8.4 Hz, 1H, CH2NAr), 3.77–3.83 (m, 2H, 1H of CH2NAr
and 1H of CH2CO), 3.94–4.44 (m, 2H, NCH2CvC), 4.50–
4.82 (m, 3H, CH2CvC and 1H of CH2CO) and 6.76–7.83
(m, 18H, ArH). m/z (%) 561 (Mϩ, 1), 421 (36), 290 (96), 289
(76), 272 (74), 184 (37), 141 (56), 132 (51), 131 (33), 130
(83), 91 (31) and 77 (100).
6h. Colourless sticky oil. (Found: C, 68.2; H, 6.5; N, 4.7.
C32H36N2O7 requires: C, 68.55; H, 6.5; N, 5.0%). d (mixture
of diastereoisomers) 1.34, 1.35 (2×s, 3H, CH3CCN), 1.36,
1.57 (2×s, 6H, 2×CH3CO2), 2.24–2.38 (m, 2H,
CCH2CvC), 3.34–3.50, (m, 4H, CvCCH2OCH2), 4.13
(d, Jˆ8.7 Hz, 1H, CH2OAr), 4.33 (br. s, 1H, CH2CHO),
4.44, 4.46 (2×d, Jˆ8.7 Hz, 1H, CH2OAr) 4.74 (m, 2H,
2×CHOCCH3), 4.84, 5.05 (2 br. s, 2H, CH2vC), 5.06,
5.12 (2×d, Jˆ13.8 Hz, 2H, CH2N), 5.67, 5.68 (2×d,
Jˆ8.0 Hz, 1H, NCHvCH), 5.86 (br. s, 1H, OCHN) and
6.82–7.48 (m, 10 H, ArH and NCHvCH). m/z (%) 560
(Mϩ, 0.1), 428 (27), 269 (25), 203 (17), 202 (16), 134
(22), 133 (100), 105 (63), 91 (47), 84 (18), 69 (15), 55
(20), 46 (36) and 41 (28).
6n. Colourless prisms from n-hexane/ether, mp 37–38ЊC.
(Found: C, 79.3; H, 6.1; N, 6.55. C28H26N2O2 requires: C,
79.6; H, 6.2; N, 6.65%). d 1.30 (s, 3H, CH3), 2.23 (m, 2H,
CCH2CvC), 3.78, 3.81 (2×d, Jˆ9.5 Hz, 1H, CH2CO),
3.98–4.56 (m, 4H, CH2O and NCH2CvC), 4.71–4.83 (m,
3H, CH2CvC and 1H of CH2CO) and 6.70–7.62 (m, 13H,
ArH). m/z (%) 422 (Mϩ, 2), 291 (35), 290 (100), 289 (80),
262 (19), 261 (22), 235 (17), 208 (16), 207 (17), 133 (80),
105 (53), 91 (22) and 77 (16).
6o. Colourless prisms from petroleum ether/ethyl acetate,
mp 88ЊC. (HRMS found: 555.2034. C28H31N3O5S requires:
555.2039). m/z (%) (mixed isomers) 555 (Mϩ, 0.3), 228
(81), and 160 (100). d (Isomer A) 1.53 [s, 9H, C(CH3)3],
2.07 (s, 1H, OCCH3), 2.90 (s, 2H, 17-CH2), 3.18 (s, 3H,
NCH3), 3.33 (d, Jˆ19.9 Hz, 1H, 8-Ha), 3.52 (d,
Jˆ19.9 Hz, 1H, 8-Hb), 4.79 (d, Jˆ12.7 Hz,, 1H, CHaOAc),
4.88 (d, Jˆ4.9 Hz, 1H, 18a-H), 5.07 (d, Jˆ12.7 Hz, 1H,
CHbOAc), 5.16, 5.20 (2×s, 2H, 9-CH2), 5.38 (dd, Jˆ7.9,
4.9 Hz, 1H, 12-H), 6.08 (d, Jˆ7.9 Hz, 1H, 11-NH), and
6.80–7.30 (m, 4H, ArH). d (Isomer B) 1.54 [s, 9H,
C(CH3)3], 2.08 (s, 1H, OCCH3), 2.78 (d, Jˆ13.3 Hz, 1H,
17-Ha), 3.05 (d, Jˆ13.3 Hz, 1H, 17-Hb), 3.19 (s, 3H, NCH3),
3.31 (d, Jˆ19.8 Hz, 1H, 8-Ha), 3.55 (d, Jˆ19.8 Hz, 1H, 8-
Hb), 4.82 (d, Jˆ18.6 Hz,, 1H, CHaOAc), 4.91 (d, Jˆ4.9 Hz,
1H, 18a-H), 5.02 (d, Jˆ18.6 Hz, 1H, CHbOAc), 5.48, 5.56
(2×s, 2H, 9-CH2), 5.68 (dd, Jˆ8.7, 4.9 Hz, 1H, 12-H), 6.42
(d, Jˆ8.7 Hz, 1H, 11-NH), and 6.8–7.30 (m, 4H, ArH).
6i. Colourless prisms from ethyl acetate/petroleum ether,
mp 181ЊC. (Found: C, 64.1; H, 5.7; N, 17.8. C21H23N5O3
requires: C, 64.1; H, 5.9; N,17.8%). d 1.44 (s, 3H, CCH3),
2.70, 2.72 (d, Jˆ13.2 Hz, 1H, CvCCH2), 3.25 (s, 3H,
NCH3), 3.51 (s, 3H, NCNCH3), 3.98 (s, 3H, OCNCH3),
4.01, 4.18 (2×d, Jˆ15.5 Hz, 1H, NCH2CvC), 4.50, 4.62
(2×s, 2H, CvCH2), 6.82–7.38 (m, 4H, ArH), and 7.49 (s,
1H, NvCH). m/z (%) 393 (Mϩ, 5), 233 (100), and 160 (32).
6j. Colourless prisms from pentane, mp 51ЊC. (HRMS
found: 366.1697. C20H22N4O3 requires: 366.1697). d 1.47
(s, 3H, 3-CH3), 2.55 (dd, Jˆ13.1 Hz, 2H, CCH2CvC), 3.58
(s, 3H, NCNCH3), 3.98 (s, 3H, OCNCH3), 4.23 (d,
Jˆ8.7 Hz, 1H, ArOCH2), 4.37 (s, 2H, NCH2CvC), 4.58
(d, Jˆ8.7 Hz, ArOCH2), 4.73, 4.79 (2×s, 2H, CvCH2),
6.80–7.22 (m, 4H, ArH), and 7.53 (s, 1H, NvCH). m/z
(%) 366 (Mϩ, 1), 234 (54), and 133 (100).
6k. Colourless needles from n-hexane/ether, mp 57–58ЊC.
(Found: C, 61.65; H, 6.0; N, 12.8; S, 4.9. C34H40N6O6S
requires: C, 61.8; H, 6.1; N, 12.7; S, 4.8%). d 1.29 (s, 3H,
CH3CCN), 1.44 (s, 18H, 6×CH3CO), 2.25, 2.31 (2×d,
Jˆ14.2 Hz, 2H, CCH2CvC), 3.53, 4.04 (2×d, Jˆ10.2 Hz,
Acknowledgements
We thank the EPSRC, the Spanish Government (MEC) and

7560
A. Casaschi et al. / Tetrahedron 56 (2000) 7553–7560
55, 1857–1867. (b) Ito, Y.; Inouye, M.; Yokata, H.; Murakami, M.
J. Org. Chem. 1990, 55, 2567–2568. (c) Mikaye, H.; Yamamura,
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the E. U. Human Capital and Mobility Scheme and Leeds
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