Cyclative cleavage via solid-phase supported stabilized sulfur ylides: Synthesis of macrocyclic lactones

Article abstract of DOI:10.1016/S0040-4039(01)02258-4

A new synthesis of macrolactones bearing a cyclopropyl ring condensed to the macrocycle is reported via a cyclization-release strategy making use of solid-phase supported stabilized sulfur ylides.

Full text of DOI:10.1016/S0040-4039(01)02258-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 761–766
Cyclative cleavage via solid-phase supported stabilized sulfur
ylides: synthesis of macrocyclic lactones
Elena La Porta,a Umberto Piarulli,a,b Francesca Cardullo,c Alfredo Paio,c Stefano Provera,c
Pierfausto Senecid and Cesare Gennaria,*
aDipartimento di Chimica Organica e Industriale, Universita` di Milano, Centro CNR per lo Studio delle Sostanze Organiche
Naturali, via G. Venezian 21, I-20133 Milano, Italy
bDipartimento di Scienze Chimiche, Fis. e Mat., Universita` dell’Insubria, via Valleggio 11, I-22100 Como, Italy
cGlaxo-SmithKline, Med. Res. Centre, via Fleming 4, I-37135 Verona, Italy
dNucleotide Analog Design AG, Landsbergerstrasse 50, D-80339 Munich, Germany
Received 31 October 2001; accepted 26 November 2001
Abstract—A new synthesis of macrolactones bearing a cyclopropyl ring condensed to the macrocycle is reported via a
cyclization-release strategy making use of solid-phase supported stabilized sulfur ylides. © 2002 Elsevier Science Ltd. All rights
reserved.
The convenient purification procedures and the other
known advantages associated with solid-phase synthesis
make it a powerful tool for the preparation of combina-
torial libraries, a fundamental element of contemporary
drug discovery processes. In this context, cyclization-
release techniques1 present distinct advantages over
more conventional approaches to solid-phase synthesis:
the polymer support. Cleavage is achieved by ‘depro-
tecting’ the heteroatom which, however, remains as a
vestigial stub on the final molecule. This is not a
problem in cyclative-cleavage approaches, where release
from the polymer support is obtained as a consequence
of the natural reactivity of the connecting functionality,
leaving no traces on the target molecules.
(a) Most traditional solid-phase methods incorporate a
heteroatom within a device that links the substrate to
(b) Since detachment from the resin is a step associated
with the correct reaction sequence, only substrates
Figure 1. Synthesis of macrocyclic lactones via the cyclative release strategy, using solid-phase supported stabilized sulfur ylides.
Keywords: solid-phase synthesis; macrocycles; cyclopropanes; sulfonium salts.
* Corresponding author. Tel. +39-025835.4091; fax: +39-025835.4072; e-mail: cesare.gennari@unimi.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02258-4

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E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766
from the solid-phase is made possible by alkylation of
the sulfur atom to the sulfonium salt, the immediate
precursor to ylide formation and reaction.
which possess the correct functionality and react in the
expected way are released into the solution in high
purity, leaving all unreacted systems and by-products
on the solid-phase.
Here we describe the application of this new cycliza-
tion-release strategy to the synthesis of macrolactones
bearing a cyclopropyl system condensed to the macro-
cyclic ring.9
(c) The cyclization step takes place while the substrate
is anchored on the polymer support, taking advantage
of the functional group isolation granted by the resin
and thus eliminating the risk of intermolecular reac-
tions and the need of high dilution conditions. The ring
closing metathesis (RCM),1 the Wittig–Horner reac-
tion,2 the Stille3 and Suzuki4 couplings have recently
been adapted to fit this scheme as carbonꢀcarbon bond
forming cyclization processes in a cyclorelease from the
solid-phase.
First of all, we investigated the preparation of resin-
bound thioglycolic acid on Argogel® resin, the stability
of the resin-bound sulfonium salt and the reactivity of
the resin-bound ylide with aldehydes.6 Argogel®-Cl
resin was reacted with potassium thioacetate according
to a published procedure,10 and the supported thioester
1 was successfully reduced with LiBH4 in THF to give
Argogel®-SH resin 2, which was characterized by
MAS–1H NMR and FT-IR (Scheme 1). Argogel®-SH
resin 2 was then reacted with 13C-enriched (99%) ethyl
bromoacetate and triethylamine in DMF at room tem-
perature. The supported ester 3 was characterized by
13C-gel phase NMR (32.0 ppm) and FT-IR (wCꢁO,
1730 cm−1). The ethyl ester was then saponified (NaOH,
THF–H2O), and the resulting acid 4 was characterized
by MAS–1H NMR, FT-IR (wCꢁO 1720 cm−1), 13C-gel
phase NMR (34.6 ppm) and transformed into the N-
benzyl,N-methylamide 5 characterized by MAS–1H
NMR, FT-IR (wCꢁO 1636 cm−1) and 13C-gel phase
We recognized in sulfur ylides5 a functional arrange-
ment with suitable characteristics for an original
cyclorelease strategy, featuring an activation phase
prior to the actual cyclization event, in a way reminis-
cent of the principle of safety catch linkers. In particu-
lar, we focused on sulfur ylides stabilized by
electron-withdrawing groups,6,7 which can be generated
under extremely mild conditions8 and are therefore
suitable for intramolecular reactions. Following the
anchoring of the ylide precursor onto the solid support
and elongation with a chain containing a Michael
acceptor terminal moiety (Fig. 1), the cyclative release
Scheme 1. Investigation on the stability of the resin-bound sulfonium salt 6 and on the reactivity of the resin-bound ylide with
aldehydes.

E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766
763
NMR (33.9 ppm). Sulfonium salt 6 was synthesized by
treatment of sulfide 5 with 0.3 M MeOTf in DCM
(room temperature, 1 h). The solid-supported sulfo-
nium salt 6 was shown to be stable to washings and
storage, and characterized by MAS–1H NMR, FT-IR
(wCꢁO 1646 cm−1) and 13C-gel phase NMR (48.5 ppm).
Finally, it was reacted with DBU and protected
glyceraldehyde6 in CD2Cl2 at room temperature: the
reaction was followed by 13C NMR in the gel phase-
NMR tube (coaxial insert), by disappearance of the
sulfonium–carbon peak at 48.5 ppm and appearance of
the new epoxide–carbon peak at 52.4/52.7 ppm (two
peaks because of the tertiary amide present in 7). The
same reaction was run successfully on a preparative
scale employing different aldehydes (p-chlorobenzalde-
hyde, propionaldehyde and protected glyceraldehyde)
and solvents (DCM and CH3CN), as reported in
Scheme 1. Flash-chromatography of the crudes deriving
from the washings of the resin allowed the isolation and
characterization of the desired epoxyamides 7 (41%),
( )-8 (10%), and ( )-9 (20%).6 Overall yields were calcu-
lated based on the initial loading of Argogel®-Cl resin
(0.44 mmol/g).
different resins bearing a thioglycolic acid unit. In the
case of Argogel® resin, a more straightforward route
was developed (Scheme 2) starting from methyl thiogly-
colate and leading in two steps to the desired function-
alized resin 10. In the case of Merrifield resin
(chloromethylated polystyrene crosslinked with 1%
divinylbenzene, 1.09 mmol/g), this was transformed to
the functionalized thiol resin 11, using a 1,4-butanediol
spacer according to a published procedure.11 Thiol-
resin 11 was then reacted with methyl bromoacetate
and triethylamine in DMF. The supported ester 12 was
characterized by MAS–1H NMR and FT-IR (wCꢁO,
1739 cm−1) and then saponified (NaOH, THF–H2O) to
the desired functionalized resin 13 (wCꢁO, 1730 cm−1)
(Scheme 2).
Functionalized resins 10 or 13 were reacted with v-
hydroxy vinylketone 1412 using DCC and DMAP in
DCM to give supported vinylketone 15 (Scheme 3). The
thioether of 15 was activated with MeOTf in DCM to
the corresponding resin bound sulfonium salt 16, which
was purified by filtration and washings. Treatment of
16 with DBU generated the stabilized sulfur ylide which
underwent cyclative cleavage to give the macrocyclic
lactone ( )-17, bearing a cyclopropyl ring7 condensed
to the macrocycle, in good yield and purity as a single
diastereoisomer (trans).15
Having established the stability of the resin-bound sul-
fonium salt and the reactivity of the resin-bound ylide,
we turned our attention to the preparation of two
Scheme 2. Preparation of resins 10 and 13, functionalized as thioglycolic acid.
Scheme 3. Solid-phase synthesis and cyclative release of macrocyclic lactone ( )-17.

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E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766
cyclization precursor 26, which underwent cyclative
cleavage under the usual conditions to give macrocyclic
lactones 27 and 28 (1:1)19 (Scheme 5).
After optimization, this methodology will be employed
for the synthesis of a library of macrocyclic lactones
with potential biological interest, bearing the uncom-
mon ‘condensed-cyclopropyl’ functionality.9
Acknowledgements
A graduate fellowship is gratefully acknowledged by E.
La Porta (Glaxo-SmithKline, Verona, Italy). We thank
Dr. Sergio Lociuro (Glaxo-SmithKline) for support and
helpful discussions.
References
1. Nicolaou, K. C.; Vorloumis, D.; Li, T.; Pastor, J.;
Winssinger, N.; He, Y.; Ninkovic, S.; Sarabia, F.; Vall-
berg, H.; Roschangar, F.; King, N. P.; Finlay, R. M. V.;
Giannakakou, P.; Verdier-Pinard, P.; Hamel, E. Angew.
Chem. 1997, 109, 2181–2187; Angew. Chem., Int. Ed.
Engl. 1997, 36, 2097–2103.
Scheme 4. Solid-phase synthesis and cyclative release of
macrocyclic lactone ( )-22.
The scope of the cyclative cleavage reaction was investi-
gated using propenylketones 18 (E)16 and 19 (Z),16
following the same procedure described above for
vinylketone 14. Macrocyclic lactone ( )-22 was
obtained as a single diastereoisomer from either E (20)
or Z (21) resin-bound propenylketone in poor yield17
(Scheme 4). Thus, the cyclization reaction seems quite
sensitive to enone b-substitution.
2. Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy, F.
J. Am. Chem. Soc. 1998, 120, 5132–5133.
3. Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Murphy, F.
Angew. Chem. 1998, 110, 2677–2680; Angew. Chem., Int.
Ed. Engl. 1998, 37, 2534–2537.
4. Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40, 6527–
6530.
5. Trost, B. M.; Melvin, L. S. Sulfur Ylides; Academic
Press: New York, 1975.
Another point of interest regards the introduction of a
more funtionalized chain in the macrocyclic ring. (+)-t-
6. N,N-Dimethyl-2-(dimethylsulfuranilidene)
acetamide
Butyl-(
)-lactate was coupled to Argogel® resin 10
D
reacts with chiral aldehydes and ketones with high
stereoselectivity to form trans 2,3-epoxy-amides, see: (a)
Valpuesta-Ferna´ndez, M.; Durante-Lanes, P.; Lo´pez-
Herrera, F. J. Tetrahedron 1990, 46, 7911–7922; (b)
(DIC, 4-DMAP) to give resin-bound t-butylester 23
which was hydrolized (TFA, DCM) to resin-bound acid
24. Coupling with v-hydroxy vinylketone 2518 gave
Scheme 5. Solid-phase synthesis and cyclative release of macrocyclic lactones 27 and 28.

E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766
765
Valpuesta, M.; Durante, P.; Lo´pez-Herrera, F. J. Tetra-
hedron 1993, 49, 9547–9560; (c) Lo´pez-Herrera, F. J.;
Sarabia-Garcia, F.; Pedraza-Cebrian, G. M.; Pino-Gon-
zalez, M. S. Tetrahedron Lett. 1999, 40, 1379–1380; (d)
Imashiro, R.; Yamanaka, T.; Seki, M. Tetrahedron:
Asymmetry 1999, 10, 2845–2851; (e) For chiral sulfur
ylides, see: Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X.; Xia,
L.-J.; Tang, M.-H. J. Chem. Soc., Perkin Trans. 1 1999,
77–80.
calculated from the original loading of the commercial
resin (0.44 mmol/g for Argogel®-Cl resin; 1.09 mmol/g
for Merrifield resin) and considering a 100% yield for
each solid-phase synthetic step preceding the cyclization.
The overall yield for the solid-phase synthesis of macro-
cycle ( )-17 was calculated based on the above loading
values: 52% from Argogel® precursor 15 (31% after flash
chromatography); 20% from Merrifield precursor 15
(10% after flash chromatography). Lactone ( )-17 was
also synthesized in solution-phase, following the same
chemistry described in Scheme 3 but using S-ethyl thio-
glycolic acid instead of resins 10 or 13. Sulfonium salt
formation (1.5 equiv. MeOTf, DCM, rt, 1 h) and macro-
cyclization (2 equiv. DBU) under high dilution conditions
(10−3 M in DCM, rt, 20 h) gave lactone ( )-17, which was
purified by flash-chromatography (60% yield) and charac-
7. Dimethylsulfonium phenacylide and ethyl(dimethylsul-
furanilidene)acetate (EDSA) are reported to react with a
variety of Michael acceptors to form cyclopropyl deriva-
tives, see: (a) Trost, B. M. J. Am. Chem. Soc. 1967, 89,
138–142; (b) Payne, G. B. J. Am. Chem. Soc. 1965, 87,
3351–3355; (c) Ma, D.; Cao, Y.; Yang, Y.; Cheng, D.
Org. Lett. 1999, 1, 285–287; (d) Ma, D.; Cao, Y.; Wu,
W.; Jiang, Y. Tetrahedron 2000, 56, 7447–7456; (e) Ma,
D.; Jiang, Y. Tetrahedron: Asymmetry 2000, 11, 3727–
3736.
8. (a) Collado, I.; Dominguez, C.; Ezquerra, J.; Pedregal,
C.; Monn, J. A. Tetrahedron Lett. 1997, 38, 2133–2136;
(b) Nozaki, H.; Tunemoto, D.; Matubara, S.; Kondoˆ, K.
Tetrahedron 1967, 23, 545–551.
9. For a macrocyclic antibiotic containing an a-ketocyclo-
propyl functionality (tolypomicin), see: Bellomo, P.; Bru-
fani, M.; Marchi, E.; Mascellani, G.; Melloni, W.;
Montecchi, L.; Stanzani, L. J. Med. Chem. 1977, 20,
1287–1291. For a review on cyclopropane containing
natural products, see: Donaldson, W. A. Tetrahedron
2001, 57, 8589–8627.
1
terized as follows. H NMR (CDCl3, 400 MHz): l 1.20–
1.45 (14H, bs), 1.40–1.56 (2H, m), 1.60–1.75 (4H, m),
2.10 (1H, ddd, J1=9.2 Hz, J2=5.9 Hz, J3=3.7 Hz), 2.35
(1H, ddd, J1=14.1 Hz, J2=8.0 Hz, J3=6.3 Hz), 2.51
(1H, ddd, J1=9.1 Hz, J2=5.7 Hz, J3=3.7 Hz), 2.70–2.80
(1H, m), 3.85–3.95 (1H, m), 4.53 (1H, ddd, J1=11.1 Hz,
J2=7.0 Hz, J3=4.2 Hz). 13C NMR (CDCl3, 50.13 MHz):
l 16.2, 24.9, 28.7, 24.3–27.8 (7C), 44.1, 64.6, 209.0.
HRMS [EI (70 eV)] calcd for [C16H26O3]+ 266.1882,
found 266.1825.
16. v-Hydroxy propenylketones 18 and 19 were prepared as
described in Ref. 12 for v-hydroxy vinylketone 14 but
using propenylmagnesium bromide instead of vinylmag-
nesium bromide (THF, −75 to 0°C, 2.5 h, 70%). The
allylic alcohols (E+Z) were in turn oxidized to the
propenylketones [DMP,13 DCM, rt, 1.5 h, 77%]. The
v-OTBDPS-protected propenylketones were separated by
flash-chromatography (E:Z=1:1) and deprotected
(TBAF, p-TsOH–H2O, THF, 0°C to rt, 20 h, 84%)14 to
give the v-hydroxy propenylketones 18 and 19.
10. Kobayashi, S.; Hachiya, I.; Suzuki, S.; Moriwaki, M.
Tetrahedron Lett. 1996, 37, 2809–2812.
11. Vanier, C.; Lorge´, F.; Wagner, A.; Mioskowski, C.
Angew. Chem. 2000, 112, 1745–1749; Angew. Chem., Int.
Ed. Engl. 2000, 39, 1679–1683. A modified procedure was
followed in one of the synthetic steps: PBr3, THF, 0°C to
rt was used instead of MsCl, Et3N, CH2Cl2, rt. We thank
Dr. Wagner for exchange of experimental procedures and
helpful discussions.
12. v-Hydroxy vinylketone 14 was prepared as follows: com-
mercially available 12-hydroxylauric acid was protected
at the terminal hydroxy group (TBDPS-Cl, imidazole,
DMF, rt, 1 h, 67%). The v-OTBDPS-protected acid was
transformed into the Weinreb amide (N,O-dimethylhy-
droxylamine hydrochloride, 1,1%-carbonyldiimidazole,
DCM, rt, 4 h, 91%) and subsequently reduced to alde-
hyde (DIBAl-H, THF, 0°C, 45 min, 80%). The aldehyde
was then treated with vinylmagnesium bromide (THF,
−75 to 0°C, 1.5 h, 60%) to give the allylic alcohol, which
was in turn oxidized to the vinylketone [Dess Martin
Periodinane (DMP),13 DCM, rt, 1 h, 92%]. The v-OTB-
DPS-protected vinylketone was deprotected (TBAF, p-
TsOH–H2O, THF, 0°C to rt, 80 h, 80%)14 to give the
v-hydroxy vinylketone 14.
17. The loading of cyclization precursor 20 or 21 (0.34 mmol/
g for Argogel® resin; 0.81 mmol/g for Merrifield resin)
was calculated from the original loading of the commer-
cial resin (0.44 mmol/g for Argogel®-Cl resin; 1.09 mmol/
g for Merrifield resin) and considering a 100% yield for
each solid-phase synthetic step preceding the cyclization.
The overall yield for the solid-phase synthesis of macro-
cycle ( )-22 was calculated based on the above loading
values: 15% from Argogel® precursor 20 or 21 (8% after
flash chromatography); 5% from Merrifield precursor 20
or 21 (2% after flash chromatography). Lactone ( )-22
was also synthesized in solution-phase, following the
same chemistry described in Scheme 4 but using S-ethyl
thioglycolic acid instead of resins 10 or 13. Sulfonium salt
formation (1.5 equiv. MeOTf, DCM, rt, 1 h) and macro-
cyclization (2 equiv. DBU) under high dilution conditions
(10−3 M in DCM, rt, 20 h) gave lactone ( )-22 which was
purified by flash-chromatography (10% yield) and charac-
1
terized as follows. H NMR (CDCl3, 400 MHz): l 1.20–
13. Dess Martin Periodinane (DMP): (a) Dess, D. B.; Mar-
tin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287; (b)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899–
2899.
14. Hitchcock, S. A.; Houldsworth, S. J.; Pattenden, G.;
Pryde, D. C.; Thomson, N. M.; Blake, A. J. J. Chem.
Soc., Perkin Trans. 1 1998, 3181–3206.
1.40 (17H, bs), 1.60–1.70 (4H, m), 1.91–2.03 (1H, m),
2.20 (1H, dd, J1=9.5 Hz, J2=4.4 Hz), 2.33 (1H, ddd,
J1=13.5 Hz, J2=8.1 Hz, J3=6.0 Hz), 2.47 (1H, dd,
J1=5.8 Hz, J2=4.4 Hz), 2.75 (1H, ddd, J1=13.5 Hz,
J2=7.3 Hz, J3=5.9 Hz), 3.87 (1H, ddd, J1=10.8 Hz,
J2=6.8 Hz, J3=3.5 Hz), 4.59 (1H, ddd, J1=10.8 Hz,
J2=7.4 Hz, J3=3.5 Hz). The relative stereochemistry was
assigned based on the coupling constants and on a COSY
NMR spectrum (CDCl3, 400 MHz).
15. The loading of cyclization precursor 15 (0.35 mmol/g for
Argogel® resin; 0.81 mmol/g for Merrifield resin) was

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E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766
18. Prepared from 1,10-decanediol via the following sequence
of reactions: (a) monoprotection (TBDPSCl, imidazole,
DMF, rt, 24 h, 80%); (b) oxidation to aldehyde (DMP,
DCM, rt, 1.5 h, 71%);13 (c) addition of vinylmagnesium
bromide (THF, 0°C, 1.5 h, 68%); (d) oxidation of the
allylic alcohol to the vinylketone (DMP, DCM, rt, 1.5 h,
92%);13 (e) TBDPS deprotection (TBAF, p-TsOH–H2O,
THF, 0°C to rt, 70 h, 77%).14
DBU) under high dilution conditions (10−3 M in DCM,
rt, 20 h) gave lactones 27 and 28 which were separated by
flash-chromatography (63% combined yield) and charac-
terized as follows. 1H NMR (CDCl3, 400 MHz) 27 (or
28): l 1.28–1.45 (10H, bs), 1.49 (3H, d, J=7.0 Hz),
1.50–1.54 (2H, m), 1.61–1.71 (3H, m), 1.82–1.92 (1H, m),
2.15 (1H, ddd, J1=10.3 Hz, J2=6.2 Hz, J3=3.9 Hz),
2.39–2.49 (1H, m), 2.70–2.80 (2H, m), 4.14–4.28 (2H, m),
5.07 (1H, q, J=7.0 Hz). 13C NMR DEPT (CDCl3, 100.6
MHz): l 16.4, 17.1, 24.4, 25.4, 24.6–28.1 (5C), 28.4, 29.0,
19. The loading (0.33 mmol/g) of Argogel® resin cyclization
precursor 26 was calculated from the original loading of
commercial Argogel®-Cl resin (0.44 mmol/g) and consid-
ering a 100% yield for each solid-phase synthetic step
preceding the cyclization. The overall yield for the solid-
phase synthesis of macrocycle 27 and 28 was calculated
based on the above loading value: 33% (18% after flash
chromatography). Lactones 27 and 28 were also synthe-
sized in solution-phase, following the same chemistry
described in Scheme 5 but using S-ethyl thioglycolic acid
instead of resin 10. Sulfonium salt formation (1.5 equiv.
MeOTf, DCM, rt, 1 h) and macrocyclization (2 equiv.
1
43.3, 65.9, 69.8. H NMR (CDCl3, 400 MHz) 28 (or 27):
l 1.20–1.45 (10H, bs), 1.48–1.52 (2H, m), 1.53 (3H, d,
J=7.0 Hz), 1.60–1.72 (3H, m), 1.85–1.95 (1H, m), 2.26
(1H, ddd, J1=9.0 Hz, J2=5.7 Hz, J3=3.8 Hz), 2.44 (1H,
ddd, J1=15.5 Hz, J2=8.1 Hz, J3=4.9 Hz), 2.60 (1H,
ddd, J1=8.8 Hz, J2=5.9 Hz, J3=3.8 Hz), 2.75 (1H, ddd,
J1=15.5 Hz, J2=8.5 Hz, J3=4.8 Hz), 4.10–4.29 (2H, m),
5.27 (1H, q, J=7.0 Hz). HRMS [EI (70 eV)] calcd for
[C17H26O5]+ 310.1780, found 310.1758.