Dramatic influence of the substitution of alkylidene-5H-furan-2-ones in Diels-Alder cycloadditions with o-quinonedimethide as diene partner: En route to the CDEF polycyclic ring system of lactonamycin

Article abstract of DOI:10.1039/c2ob25299f

An efficient and rapid synthesis of the CDEF ring system of lactonamycinone is reported via a highly chemo- and diastereoselective intermolecular Diels-Alder cycloaddition between trans-1,2-disilyloxybenzocyclobutene and the appropriate γ-alkylidenebutenolide. The feasibility and the total chemoselectivity of the [4 + 2] cycloaddition for the construction of a spirolactone moiety via an intramolecular approach (IMDA) using both partners is also described demonstrating the versatility of the γ- alkylidenebutenolide building block.

Full text of DOI:10.1039/c2ob25299f

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PAPER
Dramatic influence of the substitution of alkylidene-5H-furan-2-ones in
Diels–Alder cycloadditions with o-quinonedimethide as diene partner:
en route to the CDEF polycyclic ring system of lactonamycin†
Sébastien Dubois,a Fabien Rodier,a Romain Blanc,a Raphaël Rahmani,a Virginie Héran,a Jérôme Thibonnet,b
Laurent Commeiras*a and Jean-Luc Parrain*a
Received 10th February 2012, Accepted 12th April 2012
DOI: 10.1039/c2ob25299f
An efficient and rapid synthesis of the CDEF ring system of lactonamycinone is reported via a highly
chemo- and diastereoselective intermolecular Diels–Alder cycloaddition between trans-1,2-
disilyloxybenzocyclobutene and the appropriate γ-alkylidenebutenolide. The feasibility and the total
chemoselectivity of the [4 + 2] cycloaddition for the construction of a spirolactone moiety via an
intramolecular approach (IMDA) using both partners is also described demonstrating the versatility of the
γ-alkylidenebutenolide building block.
construction of spirolactones with concomitant formation of the
fused quaternary centre have also been reported. Notably, peri-
Introduction
Due to their intrinsic conformational features and their structural
implications in biological systems, the preparation of polycyclic
structures fused at a central carbon remains an important chal-
lenge in organic synthesis.1 The asymmetric character of the
molecule brought by the stereogenic spiro carbon is generally
responsible for the biological activities. In this context and over
the last two decades, numerous natural spirolactones have been
isolated from different sources and some of them exhibit
impressive biological activities. Selected examples include abys-
somicin C2 and lactonamycin,3 two potent antibacterial agents
against Gram-positive bacteria, including resistant Staphylococ-
cus aureus strains (Fig. 1).
From a structural point of view, lactonamycin presents a spiro-
lactone moiety and a 2,3-dihydronaphthalene-1,4-dione core.
The strategy usually used to access a 1,2,3,4-tetrahydronaphtha-
lene substructure is an inter- or intramolecular [4 + 2] reaction
using benzocyclobutene derivatives as diene partners.4 Regard-
ing the spirolactone part, most of the methods reported involve a
prior installation of the tertiary alcohol, which is then followed
by an intramolecular esterification. Numerous methods for the
cyclic reactions have demonstrated to be quite efficient in the
synthesis of natural products.5 Moreover, we recently disclosed a
highly chemo- and diastereoselective intermolecular Diels–Alder
cycloaddition between trans-1,2-disilyloxybenzocyclobutene 1
and methylprotoanemonine 2 to access the lambertellol back-
bone 3 (Scheme 1).6 It transpired from this work that the che-
moselectivity of such a transformation was highly dependent on
the nature of the substituents onto the lactone. Accordingly,
δ-substituted alkylidenebutenolides 4 furnished the naphthofura-
none moiety 5 whereas the α-bromo-β,δ-substituted lactones led
to the corresponding spiro-cycloadducts 6. However, when the
reaction was performed with lactone 7, no cycloadduct was
obtained and this is certainly due to both stereoelectronic and
steric factors.
It is worth to note that γ-alkylidenebutenolides have been
repeatedly used in Diels–Alder reactions,7–14 however we were
the first one to realise a full study of the reactivity of the δ-substi-
tuted ones in the intermolecular version.7e,9 In addition, different
laboratories have developed their approach to the title natural
product,15 however, only one total synthesis of lactonamycin16
and one total synthesis of its aglycone17 have been reported to
aAix-Marseille Université, Institut des Sciences Moléculaires de
Marseille iSm2, UMR 7313, avenue Escadrille Normandie Niemen,
13397 Marseille cedex 20, France. E-mail: laurent.commeiras@
univ-amu.fr, jl.parrain@univ-amu.fr; Fax: (+33)-(0)491-288-861;
Tel: (+33)-(0)491-289-126
bUniversité François Rabelais, Département de Chimie, Laboratoire
PCMB, 32 Avenue Monge, 37200 Tours, France
†Electronic supplementary information (ESI) available: Experimental
procedures and characterisation for all novel compounds. CCDC
849361. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25299f
Fig. 1 Examples of natural products containing the spirolactone
moiety.
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date. In connection with our interest in the total synthesis of
natural product possessing interesting biological properties and
in the development of new methodologies to efficiently prepare
spirolactone moiety,18 we have undertaken the synthesis of the
CDEF ring system of lactonamycinone via an intermolecular
Diels–Alder reaction. An account of the intramolecular silicon
tethered [4 + 2] cyclisation between a benzocyclobutene and a
γ-alkylidenebutenolide will also be given.
Results and discussion
As outlined in Scheme 2, our retrosynthesis consists in two main
disconnections to access the CDEF polycyclic ring system of
lactonamycinone. Accordingly, a late stage intramolecular oxa-
Michael addition would allow the formation of the E ring. On
the other hand, the CDF tricyclic spirolactone could efficiently
be reached via an intermolecular [4 + 2] reaction between 1 and
the appropriate lactone 8. Our program was started with confi-
dence as our previous results suggested that substituents onto the
α,β-double bond of the alkylidenebutenolides prevented the
cyclisation onto the endo-cyclic alkene and therefore, favoured
reaction onto the exo-cyclic one. Having this in mind, and in
connection with our approach toward the CDEF skeleton of lac-
tonamycinone, we thought of using a γ-alkylidenebutenolide
decorated with the electron donating methoxy group onto the β
position of the lactone. In order to validate this approach, lactone
(Z)-8 was chosen as model substrate and was prepared in two
steps from methyltetronate 919 and aldehyde 10 (Scheme 3).20
Addition of the homoenolate of 9 onto aldehyde 10 furnished
alcohol 11 in 74% yield as an inseparable 52 : 48 mixture of dia-
stereomers. Then, compound 11 underwent a dehydration to
afford a separable 67 : 33 mixture of γ-alkylidenebutenolides
(Z)-8 and (E)-8 respectively, in 56% yield. As for the dienophilic
benzocyclobutene partner 1, it was synthesised on a multigram
scale according to methods described by South and Liebeskind21
and Danishefsky et al.22 Having the two precursors in hand, we
were now ready for the key cyclisation step. Under the con-
ditions previously reported for the α-bromo-β,δ-substituted
lactone (i.e. 50 °C, 4 h in degassed benzene), the cycloaddition
Scheme 1 Diels–Alder cycloaddition between trans-1,2-disilyloxyben-
zocyclobutene 1 and γ-alkylidenebutenolides.
Scheme 2 Retrosynthetic analysis.
Scheme 3 Studies on the synthesis of the CDF ring system of lactonamycinone.
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Scheme 4 Synthesis of the CDEF ring system of lactonamycinone.
Scheme 5 Intramolecular approach.
only furnished a very small amount (up to 5%) of the expected
spirolactone 12. Starting materials 1 and (Z)-8 were recovered
unchanged at the end of the reaction. Gratifyingly, when the
reaction time was prolonged from four hours to three days,23 the
Diels–Alder reaction gave the desired spiro-cycloadduct 12 in a
quantitative manner and as a 1 : 1 mixture of diastereomers
arising from an endo- and an exo-approach respectively.
The feasibility of the intermolecular cycloaddition leading to
the desired spirolactone moiety thus validated, we next turn our
attention to the (E)-lactone 8. Accordingly, the hetero Michael
reaction to form the E-ring required the pending primary alcohol
onto compound 14 being cis to the single carbon–carbon bond
of the lactone. The only way to access such a cycloadduct was to
start with the (E)-double bond onto lactone 8. Pleasingly, the
cycloaddition reaction was not only efficient and provided the
expected compound 13 in a quantitative manner, but was also
totally diastereoselective in favour of the endo-approach. There-
after, an additional four steps were performed to access the
CDEF rings of lactonamicynone (Scheme 4). Deprotection of
the PMB group using DDQ in wet CH2Cl2 afforded primary
alcohol 14 in 94% yield.
The latter underwent the intramolecular oxa-Michael addition
under basic conditions to form the last E-ring 15 in 90% yield
and as a single diastereomer. Following which, a deprotection of
the bis silylether 15 in presence of tetrabutylammonium fluoride
gave the corresponding diol 16 in 73% yield. Finally, the sensi-
tive quinone 17 was obtained after oxidation of the diol in the
presence of an excess of Dess–Martin periodinane (10 equiv) in
a quantitative manner. To summarise, the tetracyclic skeleton of
lactonamycinone 17 was diastereoselectively synthesised in 62%
yield over five steps from lactone (E)-8. It goes without saying
that the method developed here is a powerful and competitive
tool to access rapidly and efficiently the scaffold of natural pro-
ducts containing spirolactone moieties.
As mentioned earlier in the introduction, the δ-substituted
α,β-unsubstituted alkylidenebutenolides failed to furnish the
desired spirolactones and led instead to the corresponding
naphthofuranone derivatives 5. In addition, lactone 7 proved to
be unreactive during this intermolecular [4 + 2] process. In order
to overturn the limits encountered and thus, to have access to a
range of analogs of the lactonamycine core, we envisioned an
intermolecular version of the previous strategy using a disposa-
ble silicon tether between the two cycloaddition partners.
According to numerous reports, such approaches are favoured
for entropic reasons and often lead to better chemo-, regio- and
stereoselectivities.23
The synthesis of the temporary silaketal tether derivative 18
required the prior preparation of alcohols 19 and 20. Monopro-
tected diol 19 (Scheme 5) was obtained in two steps from benzo-
cyclobutanedione. Bis reduction of the ketones in the presence
of NaBH4 in MeOH followed by treatment of the corresponding
crude diol in the presence of one equivalent of TBSCl furnished
the desired compound 19 in yields ranging from 33 to 76% yield
over two steps. Both alcohols 19 and 2024 were then linked
together by sequential reaction with iPr2SiCl2 (Scheme 5).25
Gratifyingly, silaketal 18 was obtained in 71% yield. The silicon
tethered molecule 18 was then heated at 55 °C for 4 h in
benzene. Unlike its intermolecular counterpart (Scheme 1;
lactone 7), silaketal 18 smoothly underwent the [4 + 2] cyclisa-
tion in a chemo-, regio- and diastereoselective manner. The
desired tetracyclic spirolactone 21 was pleasingly obtained in
57% yield. We then demonstrated the compatibility of the strat-
egy with the more hindered lactone 22 (Scheme 5). The cyclo-
adduct 23 was obtained in 74% yield with total control of the
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chemo-, regio- and diastereoselectivity. The relative configur-
ations of 21 and 23 were unambiguously established based on
NOESY NMR experiments and through X-ray crystallographic
analysis of 2326 thus, confirming the endo-approach of the intra-
molecular cycloaddition reaction. Furthermore, we have shown
that the chemoselectivity of the intermolecular approach could
be overturned thanks to the silylated tether. Accordingly, when
the benzocyclobutene is linked with an α,β-unsubstituted lactone
the sole product isolated resulted from the reaction onto the exo-
cyclic double bond of the lactone. No naphthofuranone 5 was
observed and the desired spirolactone 25 was obtained in 28%
isolated yield over two steps. While 10% of the cycloadduct
arising from the E-isomer of the starting lactone 24 was observed
(8 : 2 petroleum ether–ether) to afford (598 mg, 56% yield) (Z)-8
(404 mg) and (E)-8 (194 mg) in 67/33 ratio. (Z)-8: δH
(400 MHz, CDCl3) 3.81 (3H, CH3), 3.92 (3H, CH3), 4.30 (2H,
d, J = 6.8 Hz, CH2), 4.46 (2H, s, CH2), 5.24 (1H, br s, CH),
5.59 (1H, t, J = 6.8 Hz, CH), 6.88 (2H, d, J = 8.5, 2 × CHAr),
7.27 (2H, d, J = 8.5 Hz, 2 × CHAr); δC (75 MHz, CDCl3) 55.4
(CH3), 59.3 (CH3), 63.7 (CH2), 72.7 (CH2), 89.8 (CH), 106.5
(CH), 114.0 (2 × CHAr), 129.7 (2 × CHAr), 130.0 (C), 144.6 (C),
159.5 (C), 168.2 (C), 169.9 (C); HRMS found 277.1074 [M +
H]+, C15H17O5 requires 277.1071. (E)-8: δH (400 MHz, CDCl3)
3.80 (3H, s, CH3), 3,88 (3H, s, CH3), 4.39 (2H, d, J = 7.6, CH2),
4.46 (2H, s, 1H, CH2), 5.30 (1H, br d, J = 1.3 Hz, CH), 5.84
(1H, dt, J = 7.6 and 1.3 Hz, CH), 6.88 (2H, d, J = 8.7 Hz, 2 ×
CHAr), 7.27 (2H, d, J = 8.7 Hz, 2 × CHAr); δC (100 MHz,
CDCl3) 55.4 (CH3), 59.5 (CH3), 63.2 (CH2), 72.2 (CH2), 91.8
(CH), 111.8 (CH), 113.9 (2 × CHAr), 129.6 (2 × CHAr), 130.0
(C), 144.4 (C), 159.5 (C), 167.9 (C), 170.5 (C); HRMS found
277.1074 [M + H]+, C15H17O5 requires 277.1071.
1
in the crude H NMR spectrum, none was observed after purifi-
cation on silica gel. This is probably due to its instability and
might explain why the diastereomer 25 was isolated as the sole
product and in modest yield.
Conclusion
In summary, a new highly diastereoselective and convergent
approach towards the CDEF ring system of lactonamycinone has
been reported. The key intermolecular Diels–Alder reaction
between trans-1,2-disiloxybenzocyclobutene and the appropriate
γ-alkylidenebutenolide allowed the concomitant formation of the
fused spiro carbon together with the creation of three tertiary
stereocentres with total control of the diastereoselectivity and in
only 5 steps. In addition, an intramolecular cycloaddition using a
disposable silicon tether to reach the desired spirolactone moiety
has also been developed when its intermolecular counterpart
failed to give the desired spiro-cycloadduct (i.e. when δ- or
β,δ-substituted were used).
Compound 12
In a oven-dried Schlenk tube, trans-1,2-bis(tert-butyldimethyl-
silyloxy)-1,2-benzocyclobutene 121,22 (326 mg, 0.89 mmol, 1.5
equiv) and butenolide (Z)-8 (164 mg, 0.59 mmol, 1 equiv) were
dissolved in benzene-D6 (3.3 mL). The solution was degassed
for 10 min at −80 °C three times. The mixture was then heated
at 55 °C. The reaction was followed by 1H NMR and after disap-
pearance of (Z)-8 (3 days), the solvent was removed under
vacuum. The crude product was purified by flash chromato-
graphy (8 : 2 petroleum ether–ethyl acetate) to give a separable
1 : 1 mixture (374 mg, 100%) of exo-12 and endo-12. endo-12:
δH (400 MHz, C6D6) 0.03 (6H, s, 2 × CH3), 0.04 (3H, s, CH3),
0.37 (3H, s, CH3), 1.00 (9H, s, 3 × CH3), 1.04 (9H, s, 3 × CH3),
2.52–2.58 (1H, m, CH), 2.71 (3H, s, CH3), 3.32 (3H, s, CH3),
3.81 (3H, dd, J = 9 and 3.0 Hz, CH2), 3.89–3.94 (1H, m, CH2),
4.40 (1H, d, CH2, J = 11.1 Hz), 4.49 (1H, d, CH2, J = 11.1 Hz),
4.75 (1H, s, C), 5.00 (1H, d, J = 10 Hz, CH), 5.15 (1H, s, CH),
6.84 (2H, d, J = 8.7 Hz, 2 × CHAr), 7.21–7.28 (2H, m, 2 ×
CHAr), 7.35 (2H, d, J = 8.7 Hz, 2 × CHAr), 7.62–7.63 (1H, m,
CHAr), 7.68–7.70 (1H, m, CHAr); δC (100 MHz, C6D6) −4.7
(CH3), −4.6 (2 × CH3), −4.1 (CH3), 18.4 (C), 18.5 (C), 26.1 (3
× CH3), 26.2 (3 × CH3), 48.6 (CH), 54.8 (CH3), 58.3 (CH3),
67.1 (CH2), 67.5 (CH), 72.1 (CH), 73.5 (CH2), 86.6 (C), 90.3
(CH), 114.1 (2 × CHAr), 123.5 (CH), 124.2 (CH), 127.1 (CH),
127.4 (CH), 130.2 (2 × CHAr), 130.9 (C), 135.6 (C), 140.1 (C),
159.9 (C), 171.6 (C), 182.4 (C); IR (νmax/cm−1): 2956, 2930,
2889, 2856, 1759, 1637, 1613, 1510, 1460, 1366, 1247, 1173,
1131, 1098, 1070, 1036 cm−1; MS: m/z (ESI+) 663 (M + Na)+;
HRMS found 658.3588 [M + NH4]+, C35H56NO7Si2 requires
658.3590. exo-12: δH (400 MHz, C6D6) −0.12 (3H, s, CH3),
−0.01 (3H, s, CH3), 0.06 (3H, s, CH3), 0.12 (3H, s, CH3), 0.99
(9H, s, 3 × CH3), 1.04 (9H, s, 3 × CH3), 3.02 (3H, s, CH3),
3.11–3.16 (1H, m, CH), 3.25–3.32 (2H, m, CH2), 3.27 (3H, s,
CH3), 3.98 (1H, dd, J = 8.9 and 3 Hz, CH2), 4.08 (1H, d, CH2, J
= 11 Hz, H9), 4.38 (1H, d, CH2, J = 11 Hz), 4.82 (1H, s, CH),
4.94 (1H, s, CH), 5.11 (1H, d, J = 6.8 Hz, CH), 6.75 (2H, d, J =
8.7 Hz, 2 × CHAr), 7.20 (2H, d, J = 8.7 Hz, 2 × CHAr),
7.26–7.37 (2H, m, CHAr), 7.64 (1H, br d, J = 6.8 Hz, CHAr),
Experimental section
Compounds (Z)-8 and (E)-8
To a stirred solution of THF at −80 °C was added a solution of
n-BuLi (7.7 mL, 193 mmol, 1.1 equiv, 2.5 M in hexane). A pre-
cooled solution of methyltetronate 919 (2 g, 175 mmol, 1 equiv)
in THF (35 mL) was then added dropwise at −80 °C. After
20 min at −80 °C, a precooled solution of aldehyde 1020 (3.4 g,
175 mmol, 1 equiv) in THF (17 mL) was added to the mixture
and allowed to warm at room temperature. After 2 hours, ice
crush followed by diluted aqueous HCl were added to the
mixture. The aqueous phase was extracted with Et2O. The com-
bined organic phases were dried over Na2SO4 and concentrated
under vacuum. The crude product was then purified by flash
chromatography (3 : 7 petroleum ether–ethyl acetate) to afford a
inseparable 52 : 48 mixture of alcohol 11 (3.2 g) in 74% yield.
To a stirred solution of alcohol 11 (1.14 g, 3.87 mmol, 1 equiv)
in CH2Cl2 (7 mL), was added triethylamine (1.61 mL,
11.6 mmol, 3 equiv) followed by mesylchloride (0.419 mL,
5.43 mmol, 1.4 equiv) were added dropwise. The mixture was
heated at reflux overnight. The reaction was then quenched by
addition of saturated aqueous solution of NH4Cl. The aqueous
phase was extracted with CH2Cl2. The combined organic phases
were dried over Na2SO4 and concentrated under vacuum. The
crude material was finally purified by flash chromatography
This journal is © The Royal Society of Chemistry 2012
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7.77 (1H, br d, J = 7.5 Hz, CHAr); δC (100 MHz, C6D6) −5.5
(CH3), −5.0 (CH3), −4.8 (CH3), −4.3 (CH3), 18.4 (C), 18.6 (C),
26.0 (6 × CH3), 47.3 (CH), 54.7 (CH3), 58.5 (CH3), 66.1 (CH2),
67.6 (CH), 68.7 (CH), 73.4 (CH2), 86.0 (C), 91.0 (CH), 113.9 (2
× CHAr), 122.8 (CH), 124.7 (CH), 127.5 (CH), 127.6 (CH),
130.2 (2 × CHAr), 131.1 (C), 136.0 (C), 137.9 (C), 159.6 (C),
171.1 (C), 180.8 (C, C2); IR (νmax/cm−1) 2952, 2930, 2888,
2857, 1756, 1641, 1515, 1471, 1461, 1360, 1247, 1192, 1171,
1131, 1071, 1031; MS: m/z (ESI+) 663 (M + Na)+; HRMS
found 658.3589 [M + NH4]+, C35H56NO7Si2 requires 658.3590.
(3H, s, CH3), 0.17 (3H, s, CH3), 0.19 (3H, s, CH3), 0.23 (3H, s,
CH3), 0.96 (9H, s, 3 × CH3), 1.02 (9H, s, 3 × CH3), 2.67 (1H,
m, OH), 2.82 (1H, dt, J = 8.3 and 5.5 Hz, CH), 3.18 (1H, dd, J
= 11.6 and 4.8 Hz, CH2), 3.50 (1H, dd, J = 11.6 and 8.3 Hz,
CH2), 3.58 (3H, s, CH3), 4.89 (1H, s, CH), 5.03 (1H, s, CH),
5.21 (1H, d, CH, J = 5.5 Hz, H7), 7.30–7.37 (2H, m, 2 × CHAr),
7.41–7.48 (2H, m, 2 × CHAr); δC (75 MHz, CDCl3) −5.0 (CH3),
−4.93 (CH3), −4.87 (CH3), −4.8 (CH3), 18.1 (C), 18.3 (C), 25.9
(6 × CH3), 52.8 (CH), 58.9 (CH3), 60.6 (CH2), 69.1 (CH), 71.3
(CH), 88.6 (C), 90.6 (CH), 122.8 (CHAr), 123.5 (CHAr), 126.9
(CHAr), 127.0 (CHAr), 134.3 (CAr), 137.5 (CAr), 171.9 (C),
181.9 (C); IR (νmax/cm−1) 3451, 2952, 2929, 2888, 2857, 1738,
1628, 1471, 1459, 1252, 1185, 1130, 1068, 1049; MS: m/z
(ESI+) 543 (M + Na)+; HRMS found 521.2747 [M + H]+,
C27H45O6Si2 requires 521.2749.
Compound endo-13
In a oven-dried Schlenk tube, trans-1,2-bis(tert-butyldimethyl-
silyloxy)-1,2-benzocyclobutene 1 (253 mg, 0.69 mmol, 1.5 equiv)
and butenolide (E)-8 (128 mg, 0.46 mmol, 1 equiv) were dis-
solved in benzene-d6 (2.6 mL). The solution was degassed for
10 min at −80 °C three times. The mixture was then heated at
Compound 15
1
55 °C. The reaction was followed by H NMR and after disap-
A solution of 14 (145 mg, 0.279 mmol, 1 equiv), NEt3 (116 μL,
0.837 mmol, 3 equiv) in CHCl3 (15 mL) was stirred at room
temperature. After disappearance of the starting material (3
days), the solvent was removed under vacuum and the crude
product was purified by flash chromatography (9 : 1 petroleum
ether–ethyl acetate) to afford 15 (131 mg, 90%). δH (400 MHz,
CDCl3) 0.09 (3H, s, CH3), 0.17 (3H, s, CH3), 0.19 (3H, s, CH3),
0.20 (3H, s, CH3), 0.99 (9H, s, 3 × CH3), 1.03 (9H, s, 3 × CH3),
2.75 (1H, d, J = 16.8 Hz, CH2), 2.81 (1H, d, J = 16.8 Hz, CH2),
2.88 (3H, s, CH3), 3.13–3.19 (1H, m, CH), 3.30–3.35 (1H, m,
CH2), 4.03–4.08 (1H, m, CH2), 4.94 (1H, br s, CH), 5.02 (1H,
d, J = 6.5 Hz, CH), 7.26–7.39 (2H, m, 2 × CHAr), 7.39–7.46
(2H, m, 2 × CHAr), δC (75 MHz, CDCl3) −4.9 (CH3), −4.83
(CH3), −4.77 (CH3), −4.6 (CH3), 18.3 (2 × C), 25.9 (3 × CH3),
26.2 (3 × CH3), 39.1 (CH2), 50.5 (CH3), 51.5 (CH), 67.1 (CH),
68.8 (CH2), 70.8 (CH), 95.9 (C), 112.3 (C), 123.2 (CHAr), 123.7
(CHAr), 126.3 (CHAr), 126.6 (CHAr), 135.6 (CAr), 136.2 (CAr),
172.6 (C); IR (νmax/cm−1) 2954, 2930, 2888, 2857, 1791, 1472,
1461, 1251, 1211, 1182, 1126, 1076, 1061, 1013; MS: m/z
(ESI+) 543 (M + Na)+; HRMS found 538.3011 [M + NH4]+,
C27H48NO6Si2 requires 538.3015.
pearance of (E)-8 (3 days), the solvent was removed under
vacuum. The crude product was purified by flash chromato-
graphy (9 : 1 petroleum ether–ethyl acetate) to give endo-13
(269 mg, 100%). δH (400 MHz, C6D6) 0.03 (3H, s, CH3), 0.05
(3H, s, CH3), 0.6 (3H, s, CH3), 0.34 (3H, s, CH3), 0.95 (9H, s, 3
× CH3), 1.04 (9H, s, 3 × CH3), 2.9 (3H, s, CH3), 3.01–3.06 (1H,
m, CH2), 3.11–3.16 (1H, m, CH), 3.30 (3H, s, CH3), 3.88 (1H,
dd, J = 9.8 and 3.5 Hz, CH2), 4.02 (1H, d, CH2, J = 11.8 Hz),
4.07 (1H, d, CH2, J = 11.8 Hz), 4.86 (1H, s, CH), 5.24 (1H, br
s, CH), 5.32 (1H, d, J = 5.3 Hz, CH), 6.76 (2H, d, J = 8.5 Hz, 2
× CHAr), 7.07 (2H, d, J = 8.5 Hz, 2 × CHAr), 7.20–7.27 (2H, m,
2 × CHAr), 7.66 (1H, br d, J = 5.5 Hz, CHAr), 7.72 (1H, br d, J
= 5.8 Hz, CHAr); δH (400 MHz, CDCl3) 0.07 (3H, s, CH3), 0.17
(3H, s, CH3), 0.18 (3H, s, CH3), 0.19 (3H, s, CH3), 0.96 (9H, s,
3 × CH3), 0.98 (9H, s, 3 × CH3), 2.69–2.76 (1H, m, CH2),
2.81–2.87 (1H, m, CH), 3.52 (3H, s, CH3), 3.65 (1H, dd, J = 9.6
and 2.8 Hz, CH2), 4.15 (3H, s, CH3), 4.15 (2H, s, CH2), 4.96
(1H, br s, CH), 4.98 (1H, br s, CH), 5.08 (1H, d, J = 5.1 Hz,
CH), 6.80 (2H, d, J = 8.5 Hz, 2 × CHAr), 7.08 (2H, d, J = 8.5
Hz, 2 × CHAr), 7.29–7.32 (2H, m, 2 × CHAr), 7.40–7.46 (2H, m,
2 × CHAr); δ (75 MHz, CDCl3) δ −5.0 (CH3), −4.9 (CH3), −4.8
(CH3), −4.7 (CH3), 18.1 (C), 18.2 (C), 25.8 (3 × CH3), 25.9 (3
× CH3), 52.0 (CH), 55.2 (CH3), 58.8 (CH3), 64.7 (CH2), 66.6
(CH,), 71.6 (CH), 72.1 (CH2), 88.1 (C), 90.0 (CH), 113.6 (2 ×
CHAr), 122.3 (CH), 123.1 (CH), 126.7 (CH), 126.8 (CH), 128.5
(2 × CHAr), 130.4 (C), 134.6 (C), 138.3 (C), 158.9 (C), 172.3
(C), 182.9 (C); MS: m/z (ESI+) 664 (M + Na)+; HRMS found
641.3327 [M + H]+, C35H53O7Si2 requires 641.3324.
Compound 16
In an oven-dried flask, 15 (130 mg, 0.25 mmol, 1 equiv) was
dissolved in THF (8 mL). At 0 °C, a TBAF solution (0.625 mL,
0.625 mmol, 1M in THF, 2.5 equiv) was added dropwise. The
solution was stirred at room temperature and after completion of
the reaction (1 hour), the mixture was quenched with aqueous
saturated NaHCO3 solution. The aqueous layer was extracted
with EtOAc. The combined organic phases were dried over
Na2SO4 then concentrated under vacuum. The crude product
was purified by flash chromatography (1 : 1 petroleum ether–
ethyl acetate) to give the diol 16 (53 mg, 73%). mp 251 °C; δH
(400 MHz, CDCl3) 2.87 (1H, d, J = 17.6 Hz, CH2), 2.96 (1H, d,
J = 17.6 Hz, CH2), 3.16 (3H, s, CH3), 3.18–3.21 (1H, m, CH),
3.46 (1H, br d, J = 8.3 Hz, OH), 3.51–3.56 (1H, m, CH2),
4.23–4.27 (1H, m, CH2), 4.88 (1H, br d, J = 8.3 Hz) 5.07 (1H,
d, J = 6.3 Hz, CH), 7.36–7.38 (2H, m, 2 × CHAr), 7.48–7.52
(2H, m, 2 × CHAr); δC (75 MHz, CDCl3/MeOD) 38.8 (CH2),
Compound 14
To a stirred solution of endo-13 (260 mg, 0.405 mmol, 1 equiv)
in 10.5 mL of 5% aqueous CH2Cl2 was added at 0 °C DDQ
(102 mg, 0.446 mmol, 1.1 equiv). After 1 hour at 0 °C the sol-
ution was stirred at room temperature until disappearance of
starting material (1 hour) then filtered through a pad of florosil
and celite then concentrated. The crude product was purified by
flash chromatography (8 : 2 petroleum ether–ethyl acetate) to
give 14 (199 mg, 94%). mp 209 °C; δH (400 MHz, CDCl3) 0.07
4716 | Org. Biomol. Chem., 2012, 10, 4712–4719
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Compound 20
49.8 (CH3), 50.8 (CH), 65.1 (CH), 68.5 (CH2), 69.6 (CH), 96.5
(C), 112.0 (C), 122.2 (CHAr), 122.5 (CHAr), 126.0 (CHAr),
To a stirred solution of the γ-butenolide27 (400 mg, 1.57 mmol,
1 equiv) in anhydrous THF (8.2 mL) at 0 °C was added a sol-
ution of HF-pyridine (121 μL, 70% in pyridine, 4.72 mmol, 3
equiv). The reaction was stirred at room temperature and fol-
lowed by TLC. After disappearance of the starting material, the
reaction was quenched with a saturated aqueous solution of
NaHCO3. The aqueous phase was extracted with ether and the
combined organics layers were dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The resulting crude product
was purified by flash chromatography on silica gel (petroleum
ether–ethyl acetate 1 : 1) to give 20 (157 mg, 71%). δH
(400 MHz, C6D6) 1.27 (3H, d, J = 1.3 Hz, CH3), 4.23 (2H, d, J
= 6.8 Hz, CH2), 4.94 (1H, CH, td, J = 6.8 and 0.8 Hz, CH), 5.32
(1H, m, CH); δC (100 MHz, C6D6) 10.9 (CH3), 57.3 (CH2),
110.5 (CH), 117.1 (CH), 150.4 (C), 154.6 (C), 168.5 (C); MS:
m/z (ESI+) 163 (M + Na)+.
126.4 (CHAr), 135.2 (CAr), 135.7 (CAr), 173.5 (C); IR (νmax
/
cm−1) 3484, 3411, 2988, 2934, 2892, 1768, 1458, 1412, 1281,
1262, 1249, 1228, 1188, 1140, 1099, 1063, 1048, 1033, 1007;
MS: m/z (ESI+) 315 (M + Na)+; HRMS found 293.1019
[M + H]+, C15H17O6 requires 293.1020.
Compound 17
To a solution of diol 16 (16 mg, 0.055 mmol, 1 equiv) in
CH2Cl2 (7 mL), under argon, at 0 °C, was added Dess–Martin
periodinane (232 mg, 0.55 mmol, 10 equiv). The reaction
mixture was stirred at room temperature and monitored by TLC.
After disappearance of the starting material, the mixture was
poured into (1/1) mixture of saturated aqueous solution of
Na2S2O3 and saturated aqueous solution of NaHCO3 (25 mL)
and shaken vigorously for 5 min. The aqueous layer was
extracted with CH2Cl2. The combined organic layers were
washed with a saturated aqueous NaHCO3 solution, saturated
aqueous NaCl, dried over Na2SO4, dried over Na2SO4 and con-
centrated under vacuum to give the crude product 17 (16 mg,
100%). δH (400 MHz, CDCl3) 2.92 (1H, d, J = 16.8 Hz, CH2),
2.99 (1H, d, J = 16.8 Hz, CH2), 3.17 (3H, s, CH3), 3.80 (1H, dd,
J = 8.0 and 3.8 Hz, CH), 4.54 (1H, m, CH2), 4.75 (1H, dd, J =
9.0 and 3.8 Hz, CH2), 7.80–7.85 (2H, m, 2 × CHAr), 8.14–8.21
(2H, m, 2 × CHAr); δC (75 MHz, CDCl3) 36.6 (CH2), 52.6 (CH),
53.7 (CH3), 70.4 (CH2), 90.7 (C), 113.4 (C), 127.4 (CHAr),
127.7 (CHAr), 134.2 (CAr), 135.0 (CHAr), 135.3 (CAr), 135.4
(CHAr), 171.4 (C), 189.3 (C), 191.9 (C); IR (νmax/cm−1) 2958,
2919, 2850, 1730, 1711, 1668, 1641, 1591, 1563, 1437, 1340,
1328, 1306, 1258, 1245, 1175, 1140, 1087, 1015; HRMS found
306.0971 [M + NH4]+, C15H16NO6 requires 306.0972.
Compound 21
To a stirred solution of CH2Cl2 (0.6 mL), imidazole (38 mg,
0.56 mmol, 5 equiv) and iPr2SiCl2 (20 μL, 0.11 mmol, 1 equiv)
was added dropwise and at room temperature 19 (28 mg,
0.11 mmol, 1 equiv) in CH2Cl2 (0.35 mL). After disappearance
of 20 (5 min), lactone 20 (16 mg, 0.11 mmol, 1 equiv) was
added to the mixture. The reaction was stirred for 15 min, then
quenched with a saturated aqueous solution of NH4Cl. The
aqueous layer was extracted with CH2Cl2. The combined organic
phase were dried over Na2SO4 and concentrated under vacuum.
The crude product was purified by flash chromatography (pet-
roleum ether–diethylether 85 : 15) to give 18 (40 mg, 71%). δH
(300 MHz, CDCl3) 0.19 (6H, s, 2 × CH3), 0.94 (9H, s, 2 ×
CH3), 1.02–1.06 (3H, m, CH3), 1.09–1.16 (11H, m, 3 × CH3
and CH), 2.10 (3H, br s, CH3), 4.69 (2H, d, J = 6.3 Hz, CH2),
5.00 (1H, br s, CH), 5.11 (1H, br s, CH3), 5.40 (1H, t, J = 6.3
Hz, CH), 5.93 (1H, br s, CH3), 7.24–7.34 (4H, m, CHAr); MS:
m/z (ESI+) 525 [M + Na]+.
Compound 19
1
To a stirred solution of diketone21 (500 mg, 3.78 mmol) in
methanol (50 mL) at 0 °C was added sodium borohydride
(143 mg, 3.78 mmol) portionwise (10 mg per 10 min). After
1 hour, the solvent was removed under vacuum at 0 °C. The
crude product (370 mg) was dissolved in DCM (0.1 M) and
cooled to 0 °C. Imidazole (157 mg, 2.312 mmol, 0.85 equiv)
was added to the mixture and TBSCl (369 mg, 2.45 mmol, 0.9
equiv) dissolved in 20 mL of DCM was added via a seringe
pump (3.6 mL h−1). After one night at 0 °C, the reaction was
quenched by adding water. The aqueous layer was extracted with
DCM and the organic phases were dried over Na2SO4 and the
solvent removed under high vacuum. The crude product was
purified by flash chromatography (7 : 3: EP–Et2O) to give the
monoprotected benzocyclobutenediol 19 in variable amount
(33–76%). δH (300 MHz, CDCl3) 0.2 (6H, s, 2 × CH3), 0.97
(9H, s, 3 × CH3), 2.33 (1H, OH), 4.92 (1H, s, CH), 4.93 (1H, s,
CH), 7.27–7.36 (4H, m, 4 × CHAr); δC (75MHz, CDCl3) −4.5 (2
× CH3), 18.4 (C), 26.0 (3 × CH3), 79.9 (2 × CH), 123.4 (2 ×
CHAr), 129.6 (CHAr), 129.9 (CHAr), 143.3 (CAr), 144.3 (CAr);
MS: m/z 273 [M + Na]+; HRMS found 251.1462 [M + H]+,
C14H23O2Si requires 251.1462.
The H NMR revealed the formation of the cycloadduct 18.
Thus, no more characterisation was made on this kind of product.
In Schlenk tube, 18 (40 mg) was heated (55 °C) in degassed
C6D6 (2 mL) for 4 hours. The solution was then concentrated
and purified by flash chromatography (petroleum ether–diethyl-
ether 85 : 15) to give 21 (23 mg, 57%). δH (400 MHz, C6D6)
−0.03 (3H, s, CH3), 0.20 (3H, s, CH3), 0.96 (9H, s, 3 × CH3),
1.06 (3H, br s, CH3), 1.08–1.13 (14H, m, 4 × CH3 and 2 × CH),
1.96 (1H, td, J = 10.5 and 3.5 Hz, CH), 3.87 (1H, dd, J = 11.5
and 3.5 Hz, CH2), 4.40 (1H, t, J = 11.5 Hz, CH2), 4.91 (1H, s,
CH), 5.13 (1H, d, J = 10.5 Hz, CH), 5.33 (1H, br s, CH),
7.17–7.27 (2H, m, 2 × CHAr), 7.55 (1H, d, J = 7.5 Hz, CHAr),
7.84 (1H, d, J = 7.5 Hz, CHAr); δC (100 MHz, CDCl3) δ = −4.8
(CH3), −4.7 (CH3), 12.4 (CH3), 13.5 (2 × CH), 16.9 (CH3), 17.0
(CH3), 17.2 (CH3), 17.3 (CH3), 18.4 (C), 21.1 (3 × CH3), 47.7
(CH), 63.4 (CH2), 71.2 (CH), 71.7 (CH), 77.8 (CH), 90.9 (C),
118.5 (CH), 122.7 (CH), 123.5 (CH), 127.4 (CH), 127.8 (CH),
127.9 (CH), 134.7 (C), 140.1 (C), 168.3 (C), 171.0 (C); IR
(νmax/cm−1) 2953, 2928, 2861, 1771, 1463, 1261, 1133, 1071;
MS m/z (ESI+) 525 [M + Na]+; HRMS found 520.2907
+
[M + NH4 ], C27H46NO5Si2 requires 520.2909.
This journal is © The Royal Society of Chemistry 2012
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(C), 169.5 (C), 171.6 (C); IR (νmax/cm−1) 2933, 2891, 2863,
1756, 1645, 1465, 1348, 1253, 1201, 1133, 1073, 1028, 1016;
MS m/z (ESI+) 553 [M + Na]+; HRMS found 531.2957
[M + H+], C29H47O5Si2 requires 531.2957.
Compound 22
A dry Schlenk tube equipped with a Teflon-coated magnetic
stirrer was charged with anhydrous K2CO3 (1.3 g, 9.40 mmol, 2
equiv) and (Z)-α,β-insaturated-β-iodide acid (1 g, 4.70 mmol, 1
equiv). The mixture vessel was evacuated and backfilled with
argon. Then freshly distilled DMF (15 mL) was added and the
suspension was stirred for 15 min at room temperature. The
mixture was degassed at 0 °C for 5 min and backfilled with
argon. After reaching room temperature, the alkyne (0.461 g,
4.70 mmol, 1 equiv) and CuI (0.9 g, 4.70 mmol, 1 equiv) were
added. The Schlenk tube was sealed and then placed in a pre-
heated oil bath at 55 °C. Stirring was allowed for 4 hours. Then,
the mixture was placed in an ice bath and a saturated aqueous
solution of NH4Cl was added. Stirring at 0 °C was allowed for
10 min at which time the reactional mixture was diluted with
ether and filtered through a short pad of Celite. The filtrate was
washed with brine and the organic layer was dried over anhy-
drous MgSO4, filtered and concentrated in vacuo to yield the
expecting γ-butyrolactone 22 (700 mg, 88% yield) which was
engaged in the next step without further purifications. δH
(400 MHz, C6D6) 1.20 (3H, br d, J = 1.0 Hz, CH3), 1.36 (6H, s,
2 × CH3), 5.02 (1H, s, CH), 5.24 (1H, m, CH); δC (100 MHz,
C6D6) 11.0 (CH3), 30.2 (2 × CH3), 70.3 (C), 116.0 (CH), 118.7
(CH), 148.5 (C), 155.1 (C), 168.0 (C); IR (νmax/cm−1) 3429,
2976, 2932, 2873, 1745, 1664, 1608, 1362, 1341, 1310, 1220,
Compound 24
To a stirred solution of the γ-butenolide27 (500 mg, 2.08 mmol,
1 equiv) in anhydrous THF (11 mL) at 0 °C was added a sol-
ution of HF-pyridine (76 μL, 70% in pyridine, 4.17 mmol, 2
equiv). The reaction was stirred at room temperature and fol-
lowed by TLC. After disappearance of the starting material, the
reaction was quenched with a saturated aqueous solution of
NaHCO3. The aqueous phase was extracted with ether and the
combined organics layers were dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The resulting crude product
was purified by flash chromatography on silica gel (petroleum
ether–ethyl acetate 1 : 1) to give 24 (200 mg, 76%) as a
9 : 1 mixture of diastereomers. δH (400 MHz, C6D6) 4.06 (2H, d,
J = 6.8 Hz, CH2), 4.72 (1H, t, J = 6.8 Hz, CH), 5.44 (1H, d, J =
5.3 Hz, CH), 6.16 (1H, d, J = 5.3 Hz, CH); δC (100 MHz, C6D6)
57.2 (CH2), 114.2 (CH), 120.1 (CH), 143.1 (C), 149.2 (C),
168.8 (C); IR (νmax/cm−1) 3347, 2954, 2922, 2854, 1774, 1747,
1677, 1463, 1118, 1065; HRMS found 127.0389 [M + H]+,
C6H7O3 requires 127.0390.
+
1135, 1037; HRMS found 186.1129 [M + NH4 ], C9H16NO3
requires 186.1125.
Compound 25
To a stirred solution of CH2Cl2 (1.6 mL), imidazole (108 mg,
2.55 mmol, 5 equiv) and iPr2SiCl2 (58 μL, 0.32 mmol, 1 equiv)
was added dropwise and at room temperature 19 (80 mg,
0.32 mmol, 1 equiv) in CH2Cl2 (0.5 mL). After disappearance of
19 (5 min), lactone 24 (40 mg, 0.32 mmol, 1 equiv) in CH2Cl2
(1.5 mL) was added to the mixture. The reaction was stirred for
15 min, then quenched with a saturated aqueous solution of
NH4Cl. The aqueous layer was extracted with CH2Cl2. The com-
bined organic phase were dried over Na2SO4 and concentrated
under vacuum. The crude product was purified by flash chrom-
atography (petroleum ether–diethylether 8 : 2) to give the silicon
tethered (109 mg, 70%). In Schlenk tube, the silicon tethered
(109 mg) was heated (55 °C) in degassed C6D6 (6 mL) for
4 hours. The solution was then concentrated and purified by
flash chromatography (petroleum ether–diethylether 85 : 15) to
give 25 (44 mg, 40%). δH (400 MHz, C6D6) −0.17 (3H, s,
CH3), 0.01 (3H, s, CH3), 0.87 (9H, s, 3 × CH3), 1.08–1.12
(14H, m, 4 × CH3 and 2 × CH), 2.63 (1H, td, J = 10 and 4 Hz,
CH), 3.84 (1H, dd, J = 11 and 4 Hz, CH2), 4.01–4.07 (1H, m,
CH2), 4.43 (1H, s, CH), 5.24 (1H, d, J = 10 Hz, CH), 5.33 (1H,
d, J = 5.5 Hz, CH), 5.33 (1H, d, J = 5.5 Hz, CH), 7.10–7.24
(3H, m, 3 × CHAr), 7.82 (1H, d, J = 7.5 Hz, CHAr); δC
(100 MHz, CDCl3) −4.5 (CH3), −4.2 (CH3), 12.4 (CH), 13.6
(CH), 16.9 (CH3), 17.0 (CH3), 17.2 (CH3), 17.24 (CH3), 18.3
(C), 25.9 (3 × CH3), 44.2 (CH), 64.1 (CH2), 72.3 (CH), 73.8
(CH), 89.8 (C), 121.8 (CH), 125.6 (CH), 127.4 (CH), 127.5
(CH), 128.9 (CH), 134.3 (C), 139.1 (C), 156.7 (CH), 171.9 (C);
IR (νmax/cm−1) 2953, 2928, 2896, 2860, 1767, 1463, 1254,
1134, 1081, 1027; MS m/z (ESI+) 511 [M + Na]+; HRMS found
Compound 23
To a stirred solution of 22 (17 mg, 0.1 mmol, 1 equiv) in
CH2Cl2 (0.5 mL) was added at room temperature imidazole
(34 mg, 0.5 mmol, 5 equiv) followed by iPr2SiCl2 (17.4 μL,
0.1 mmol, 1 equiv) after complete dissolution of imidazole.
After disappearance of 22 (2 hours), 19 (25 mg, 0.1 mmol, 1
equiv) in CH2Cl2 (0.3 mL) was added to the mixture. The reac-
tion was stirred for 15 min, then quenched with a saturated
aqueous solution of NH4Cl. The aqueous layer was extracted
with CH2Cl2. The combined organic phase were dried over
Na2SO4 and concentrated under vacuum. The crude product was
purified by flash chromatography (petroleum ether–diethylether
8 : 2) to give the silicon tethered (23 mg, 43%). In Schlenk tube,
the silicon tethered (23 mg) was heated (55 °C) in degassed
C6D6 (1 mL) for 4 hours. The solution was then concentrated
and purified by flash chromatography (petroleum ether–diethyl-
ether 85 : 15) to give 23 (17 mg, 74%). mp 161 °C; δH
(400 MHz, C6D6) 0.04 (3H, s, CH3), 0.34 (3H, s, CH3), 0.91
(3H, br s, CH3), 1.00–1.07 (7H, m, 2 × CH3 and CH), 1.03 (9H,
s, 3 × CH3), 1.15–1.18 (7H, m, 2 × CH3 and CH),), 1.34 (3H, s,
CH3), 1.73 (3H, s, CH3), 2.12 (1H, d, J = 10.5 Hz, CH), 4.85
(1H, s, CH), 5.16 (1H, d, J = 10.5 Hz, CH), 5.43 (1H, br s, CH),
7.18 (1H, t, J = 7.5 Hz, CHAr), 7.24 (1H, t, J = 7.5 Hz, CHAr),
7.53 (1H, d, J = 7.5 Hz, CHAr), 7.84 (1H, d, J = 7.5 Hz, CHAr);
δC (100 MHz, CDCl3) −5.02 (CH3), −4.6 (CH3), 13.3 (CH),
13.9 (CH3), 14.2 (CH), 17.16 (CH3), 17.2 (CH3), 17.4 (CH3),
17.5 (CH3), 18.5 (C), 26.2 (4 × CH3), 31.5 (CH3), 55.0 (CH),
68.5 (CH), 71.5 (CH), 76.8 (CH), 90.2 (C), 119.5 (CH), 123.3
(CH), 123.4 (CH), 127.3 (CH), 128.1 (CH), 134.3 (C), 139.5
+
506.2751 [M + NH4 ], C26H44NO5Si2 requires 506.2753.
4718 | Org. Biomol. Chem., 2012, 10, 4712–4719
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Acknowledgements
The Agence Nationale pour la Recherche (A.N.R.-09-
JCJC-0036), the CNRS and Aix-Marseille Université (UMR
7313) are gratefully acknowledged for financial support. The
authors wish to thank Michel Giorgi for X-Ray analysis. Dr
Gaëlle Chouraqui is also gratefully thanked for her fruitful
participation.
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