First total synthesis of the marine natural products clavulolactones II and III

Article abstract of DOI:10.1039/c5ob00074b

The first total synthesis of the marine prostanoids clavulolactones II and III is presented from an easily accessible chiral, non-racemic cyclopentenone intermediate. Key steps involve selective TBDMS deprotection, selective reduction of the β-side chain and aldol condensation. Clavulolactones II and III were successfully prepared from (S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1-one over nine steps, in overall yields of 21 and 7% respectively. This journal is

Full text of DOI:10.1039/c5ob00074b

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First total synthesis of the marine natural products
clavulolactones II and III†
Charlotte M. Miller,a Tore Benneche*a and Marcus A. Tiusb
Cite this: Org. Biomol. Chem., 2015,
13, 4051
The first total synthesis of the marine prostanoids clavulolactones II and III is presented from an easily
accessible chiral, non-racemic cyclopentenone intermediate. Key steps involve selective TBDMS
deprotection, selective reduction of the β-side chain and aldol condensation. Clavulolactones II and III
were successfully prepared from (S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1-one over nine
steps, in overall yields of 21 and 7% respectively.
Received 14th January 2015,
Accepted 20th February 2015
DOI: 10.1039/c5ob00074b
www.rsc.org/obc
include clavulones I–III4,5 and the chlorovulones I–IV.6 These
have been shown to possess antiproliferative and cytotoxic
Introduction
Clavulolactones II and III were isolated from the Okinawan activity in several cancer cell lines as well as antiviral
soft coral Clavularia viridis by Iguchi et al. in 1995, with clavulo- activity.7–12 It is thought that the efficacy of these compounds
lactone I reported later, in 1999 (Fig. 1).1,2 These compounds may be due to the cyclopentenone core, which is susceptible to
are the first examples of natural prostanoids possessing a attack by sulphur containing amino acids but not by weaker
γ-lactone moiety in the α side chain.
nucleophiles, such as DNA.13,14
Clavulolactones II and III differ in the alkene configuration
at C-7, whereas clavulolactone I has Z-configuration at C-5.
Given the interesting biological activities of the clavulones
and chlorovulones, the total synthesis of the clavulolactones
C. viridis has been a continuing source of structurally and subsequent biological testing is of significant interest.
diverse and biologically interesting prostanoids since the early Here we present the first total synthesis of clavulolactones II
1980s, with the most recent compounds in the series isolated and III from an easily accessible chiral, non-racemic cyclo-
in 2008.3 Structurally related prostanoids from C. viridis pentenone intermediate.
Results and discussion
Our synthetic strategy focused on a key aldol condensation,
which has previously been utilized in the preparation of the
structurally similar prostanoids.15–20 To begin the synthesis,
(S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1-one 4 was
prepared in six steps from cyclopentadiene on a multigram
scale (via literature procedures), with an overall yield of
31%.21,22 The stereochemistry was determined by Mosher’s
analysis to be 98% ee. Next, the Grignard reagent, oct-2-yn-1-
ylmagnesium bromide was prepared23 and reacted with 4, but
the allene 5 was isolated in 97% as a 3.9 : 1 mixture of diaster-
eoisomers, rather than the desired alkyne 7 (Scheme 1). Such
long chain alkynyl-Grignard reagents have previously been
reported to preferentially produce allenes, so this reaction was
not investigated further. Instead, propargylmagnesium
bromide was prepared and the desired terminal alkyne 6 was
obtained in 74% yield, along with 10% of the undesired dia-
stereoisomer. These compounds were separable by column
chromatography and the stereochemistry was determined by
selective nOe experiments of both isomers.
Fig. 1 Clavulolactones I–III.
aDepartment of Chemistry, University of Oslo, Blindern, 0315 Oslo, Norway.
E-mail: tore.benneche@kjemi.uio.no
bDepartment of Chemistry, University of Hawaii, 2545 McCarthy Mall, Honolulu,
Hawaii 96822, USA
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
See DOI: 10.1039/c5ob00074b
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Scheme 1 Introduction of β-side chain.
Direct introduction of the pentyl chain was attempted several only trace amounts of the desired products were isolated.
times on the terminal alkyne 6, however this yielded approxi- These two problematic reactions resulted in a re-thinking of
mately 1 : 1 mixtures of starting material and product under the strategy. Since sufficient amounts of compound 9 had
various conditions, requiring a laborious separation by column been prepared, we wondered if a selective deprotection of the
chromatography. It was thought that the presence of the free 2° TBDMS protected alcohol was possible.
alcohol may be the source of this problem, so the tertiary
The selective deprotection of 1° TBDMS protected alcohols
alcohol 6 was protected using TBDMS-triflate to give the di-silyl in the presence of 2° TBDMS protected alcohols has been
compound 8 in 89% yield. Deprotonation followed by alkylation reported many times in the literature, however reports of 2°
with 1-iodopentane gave 9 in an excellent yield of 91%.
TBDMS protected alcohols selectively deprotected in the pres-
Removal of both TBDMS groups of 9 was effected with ence of 3° TBDMS protected alcohols are much less common.
excess TBAF in THF in 88% yield (10, Scheme 2). Oxidation to To our delight, the gradual portion-wise addition of TBAF to 9
the cyclopentenone 12 proved straightforward (93%), however at 0 °C, coupled with TLC monitoring, gave the selectively
hydrogenation with Lindlar’s catalyst gave a 3 : 1 mixture of the deprotected compound 11 in 83% yield. This was then oxi-
desired Z-alkene 14 and the over-reduced side product 16. Sep- dized to the cyclopentenone 13 in 90% yield.
aration of these compounds by column chromatography was
Hydrogenation of 13 was initially carried out using
difficult and was only slightly aided by the use of AgNO3-doped Lindlar’s catalyst in methanol for 18 hours. As previously, this
silica gel, to give pure 14 in 38% yield. Moreover, when this resulted in a mixture of the desired product 15 and the over-
compound was subjected to the subsequent aldol reaction reduced side product 17. Switching the catalyst to palladium
on barium sulfate with quinoline as poison gave a significant
improvement, with 15 isolated in 98% yield after chromato-
graphy on one occasion. However these conditions were not
always reliable and sometimes a significant amount of side
product 17 was also formed. This unusual over-reduction of
the cyclopentenone ring was also reported by Zhu et al. in the
synthesis of clavulones.17 In our case, the problem was largely
overcome by the addition of a sacrificial alkene (1-octene) and
careful monitoring of the reaction by TLC. This gave consistent
results on repetition and an 82% yield of pure alkene 15.
The γ-lactone side chain 19 was prepared via Swern oxi-
dation24 of the commercially available enantiopure alcohol 18
and in situ Wittig reaction (Scheme 3).
The aldehyde intermediate was found to be highly unstable
and the pre-prepared phosphorus ylide was added directly to
the reaction after quenching with triethylamine, giving yields
between 36–42% after column chromatography. The oxidation
of 18 was also attempted with PCC, PDC and Dess–Martin
Scheme 2 Selective deprotection and partial reduction.
4052 | Org. Biomol. Chem., 2015, 13, 4051–4058
periodinane with no success. Alternatively, Rosenmund
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CH3CN–H2O;28 NaIO4 in THF–H2O;29 HF–pyr in THF.30 Other
reported methods gave decomposition, including TASF in
DMF31,32 and BF3·OEt2 in CH3CN.33,34 At this point, several
methods for direct conversion of TBDMS to acetyl groups were
investigated: AcBr in CH2Cl2;35 FeCl3–Ac2O;36 Cu(OTf)2–Ac2O
in CH2Cl2;37 Sc(OTf)3–Ac2O in CH3CN38 – all were unsuccess-
ful. The deprotection was finally achieved with 40% aqueous
HF in CH3CN,39 which resulted in excellent yields – 91% of 22
and 97% of 23.
Scheme 3 Preparation of γ-lactone side chain.
reduction25 of the corresponding acid followed by Wittig reac-
tion gave the aldehyde 19 in yields of 15–20%.
Finally, acetylation with acetic anhydride, DMAP and
Hünigs base proceeded smoothly to give clavulolactone II
(87%) and clavulolactone III (91%). 1H & 13C NMR, IR, and
specific rotation analyses are all in excellent agreement with
those reported by Iguchi et al. when the clavulolactones were
first isolated.1
With both the lactone side chain and substituted cyclo-
pentenone in hand, the key aldol condensation was under-
taken (Scheme 4). The cyclopentenone 15 was deprotonated
with LDA over 30 minutes at −78 °C, followed by addition of
the lactone 19. After quenching and work-up, the crude
mixture of diastereomeric alcohols (ratio 1.6 : 1 from NMR ana-
lysis) was treated with triethylamine and mesyl chloride to
afford the C-7 E and Z isomers 20 and 21, which were separ-
ated by careful column chromatography (61% and 18%
respectively). The crude 1H NMR after elimination showed
approximately the same ratio of isomers as that of the inter-
mediate alcohols, however, purification of the mixture was
challenging, leading to a lower than expected yield of the Z
isomer 21.
Conclusions
In summary, clavulolactones II and III have been synthesized
for the first time, in 10 linear steps from an easily accessible
chiral cyclopentenone intermediate, and in overall yields of
21% and 7% respectively. These interesting natural products
will now undergo biological testing in order to elucidate their
activities and establish possible leads for future development.
Removal of the TBDMS groups of 20 and 21 was initially
attempted with TBAF in THF, however cleavage of the silyl
group was accompanied by partial decomposition, resulting in
yields below 30%. Several other methods were attempted but
gave no reaction (starting material recovered): AcOH–H2O–
THF;26 TBAF–AcOH in THF;27 conc. HCl in THF; CsF in
Experimental
General procedures
1
The H NMR spectra were recorded at 600 MHz with a Bruker
AVI 600 instrument, at 400 MHz with a Bruker AVII 400 instru-
Scheme 4 Aldol condensation and completion of synthesis.
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ment, or at 300 MHz with a Bruker Avance DPX 300 instru- (1.57 g, 10%). Compound 6: νmax/cm−1 (film): 3400 (OH,
ment. The decoupled 13C NMR spectra were recorded at 150, broad), 3311(CuC–H stretch), 2121 (CuC), 1721(CvC), 1472,
100, or 75 MHz using instruments mentioned previously. All 1367, 1256 (C–O); δH (400 MHz, CDCl3): 5.89 [2 H, s C(2)H,
spectra were recorded at room temperature (∼20 °C) in deuter- C(3)H], 4.75 [1 H, dd, J 6.7, 3.9, C(4)H], 2.53 [1 H, dd, J 13.8,
ated chloroform (CDCl3). Chemical shifts (δH and δC) are 6.7, one of C(5)H2], 2.51–2.48 [2 H, m, C(6)H2], 2.01 [1 H, t,
expressed in parts per million (ppm) relative to the solvent J 2.6, C(8)H)], 1.79 [1 H, dd, J 13.8, 3.9, one of C(5)H2], 0.89
reference peak. Coupling constants (J) are expressed in Hertz [9 H, s, SiC(CH3)3], 0.09 [6 H, s, Si(CH3)2]; δC (100.6 MHz,
(Hz). Splitting patterns in 1H NMR spectra are designated as CDCl3): 137.5 C(2)H or C(3)H, 136.9 C(2)H or C(3)H, 82.7 C(1),
s (singlet), br s (broad singlet), d (doublet), t (triplet), 80.7 C(7), 75.6 C(4)H, 70.2 C(8)H, 48.7 C(5)H2, 30.6 C(6)H2,
q (quartet), dd (doublet of doublets), dt (doublet of triplets), 26.0 SiC(CH3)3, 18.3 SiC(CH3)3, −4.5 Si(CH3)2; m/z (CI+): 235
ddd (doublet of doublet of doublets), tt (triplet of triplets) and [(M + H − H2O)+, 100%]; HRMS (CI+): Exact mass calculated
m (multiplet). COSY (Correlation Spectroscopy) experiments for C14H23OSi+ 235.1518. Found 235.1525. (1R,4S) configur-
were used to assign ambiguous 1H NMR spectra. 13C NMR ation was assigned to compound 6 based on selective nOe
spectra were assigned with the aid of DEPT (Distortionless experiments of both major and minor products.
Enhancement by Polarisation Transfer) experiments, HSQC
(Heteronuclear Single Quantum Correlation) & HMBC (Hetero- bis(tert-butyldimethylsilane) 8. (1R,4S)-4-((tert-Butyldimethyl-
nuclear Multiple-Bond Correlation) experiments. All spectro- silyl)oxy)-1-(prop-2-yn-1-yl) cyclopent-2-en-1-ol (10.1 g,
scopic details for compounds previously made were in 39.9 mmol) was dissolved in CH2Cl2 (95 mL) and cooled to
agreement with those previously reported. 0 °C under Ar. 2,6-Lutidine (11.6 mL, 99.75 mmol 2.5 eq.) was
(((1R,4S)-1-(Prop-2-yn-1-yl)cyclopent-2-ene-1,4-diyl)bis(oxy))-
6
Mass spectra under CI conditions were recorded with a VG added in one portion, followed by drop-wise addition of
Prospec instrument. Infrared spectra were recorded as a thin tert-butyldimethylsilyl trifluoromethanesulfonate (18.3 mL,
film on sodium chloride plates on a Perkin Elmer Spectrum 79.7 mmol, 2 eq.). The solution was stirred at 0 °C for 1 h and
One FT-IR spectrometer.
at room temp. for 3 h. The solvent was evaporated and the
Dry tetrahydrofuran (THF), diethyl ether (Et2O) dichloro- residue was dissolved in ethyl acetate (500 mL). This was
methane (CH2Cl2) and acetonitrile (CH3CN) were obtained washed with 1 M HCl (3 × 200 mL), sat. aq. NaHCO3 (3 ×
from a solvent purification system, MB SPS-800, from MBraun, 200 mL), H2O (2 × 200 mL) and brine (200 mL), then dried and
Garching, Germany. Hexane was distilled prior to use and evaporated. Purification by column chromatography with
toluene was distilled from CaH2 and stored over 4 Å molecular hexane–ethyl acetate (99 : 1–96 : 4) gave the desired compound
sieves. Alkyllithium and Grignard reagents were titrated prior as a colourless oil (12.9 g, 89%). Compound 8: νmax/cm−1
to use. All other reagents were commercially available and (film): 3314 (CuC–H stretch), 2930 (CH), 2122 (CuC), 1728
used as received. Organic phases were dried using anhydrous (CvC), 1472, 1255 (C–O); δH (400 MHz, CDCl3): 5.79 [2 H, s,
magnesium sulphate. All flash column chromatography was C(2)H, C(3)H], 4.75–4.63 [1 H, m, C(4)H], 2.57 [1 H, dd, J 13.6,
performed with silica gel 60 from Merck (0.040–0.063 mm). 7.2, one of C(5)H2], 2.42 [2 H, d, J 2.5, C(6)H2], 1.90 [1 H, t, J
Thin layer chromatography (TLC) was carried out on pre- 2.5, C(8)H], 1.83 [1 H, dd, J 13.6, 4.9, one of C(5)H2], 0.86 and
coated silica gel plates (Merck 60 PF254). Visualisation was 0.89 (18 H, two overlapping singlets, SiC(CH3)3 × 2], 0.12–0.04
achieved by UV light detection (254 nm) along with vanillin or (12 H, m, Si(CH3)2 × 2]; δC (100.6 MHz, CDCl3): 137.4 C(2)H or
p-anisaldehyde stains.
C(3)H, 136.2 C(2)H or C(3)H, 84.7 C(1), 81.5 C(7), 75.4 C(4)H,
(1R,4S)-4-((tert-Butyldimethylsilyl)oxy)-1-(prop-2-yn-1-yl)cyclo- 69.3 C(8)H, 49.3 C(5)H2, 33.4 C(6)H2, 26.0 and 25.9 SiC(CH3)3 ×
pent-2-en-1-ol 6. Propargylmagnesium bromide was prepared 2, 18.2 and 18.2 SiC(CH3)3 × 2, −2.1, −2.4, −4.5 and −4.5
as described by Acharya et al.3 and titrated with menthol and Si(CH3)2 × 2; m/z (CI+): 368 [(M + H)+ 1%], 327 [(M + H −
4-(phenylazo)diphenylamine in tetrahydrofuran. The resulting C3H4)+ 70%]; HRMS (CI+): Exact mass calculated for
0.19 M solution was used within 1 h. (S)-4-((tert-butyl dimethyl- C17H35O2Si2+ 327.2175. Found 327.2167.
silyl)oxy)cyclopent-2-en-1-one 4 (13.0 g, 61.2 mmol) was dis-
(((1R,4S)-1-(Oct-2-yn-1-yl)cyclopent-2-ene-1,4-diyl)bis(oxy))bis-
solved in THF (650 mL) and cooled to −105 °C under Ar. (tert-butyldimethylsilane) 9. A solution of (((1R,4S)-1-(prop-2-
Propargylmagnesium bromide (490 mL, 93.1 mmol, 0.19 M yn-1-yl)cyclopent-2-ene-1,4-diyl)bis(oxy))bis(tert-butyldimethyl-
soln.) was added via cannula over 30 minutes at a rate to keep silane) 8 (7.62 g, 20.8 mmol) in diethyl ether (270 mL) at
the reaction temperature below −90 °C. The mixture was −40 °C under Ar was treated with HMPA (44 mL, 253 mmol,
stirred for a further 60 minutes at −100 °C, allowed to warm to 12 eq.) and then n-BuLi (12.5 mL, 31.13 mmol, 1.5 eq., 2.49 M
−50 °C, and then quenched with sat. aq. NH4Cl (100 mL) and soln.). After stirring at −35 °C for 1 h, 1-iodopentane (8.1 mL,
water (300 mL). The layers were separated and the aqueous 62.0 mmol, 3 eq.) was added and the mixture was stirred at
layer was extracted with ethyl acetate (3 × 300 mL). The com- −30 °C for 18 h. The reaction was quenched with sat. aq.
bined organic layers were washed with water (2 × 200 mL) and NH4Cl (50 mL) and then H2O (200 mL) was added. The layers
brine (200 mL), then dried and evaporated. The product was were separated and the aqueous layer was extracted with
purified by column chromatography with dichloromethane to diethyl ether (3 × 150 mL). The combined organic extracts were
give the desired product 6 as a colourless oil (11.5 g, 74%) washed with water (7 × 200 mL, excess used to remove HMPA)
along with a small amount of the minor diastereoisomer and brine (200 mL), then dried and evaporated. The product
4054 | Org. Biomol. Chem., 2015, 13, 4051–4058
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was purified by dry flash column chromatography with hexane for 3.5 h, at which point TLC indicated complete consumption
(600 mL) followed by hexane–ethyl acetate (98 : 2) to give the of starting material. The mixture was filtered through a well
desired product 9 as a colourless oil (8.77 g, 97%). Compound packed bed of Celite and washed with CH2Cl2 (500 mL).
9: νmax/cm−1 (film): 2956 (CH), 2858 (CH), 2213 (CuC), 1717 Further purification was carried out using a short column
(CvC), 1472, 1367, 1252 (C–O); δH (400 MHz, CDCl3): 5.77 (6 cm), eluting with 90 : 10 hexane–EtOAc and collecting in 3 ×
[2 H, s, C(2)H, C(3)H], 4.69 [1 H, dd, J 7.1, 5.1, C(4)H], 2.56 500 mL fractions to give the pure product 13 as a colourless oil
[1 H, dd, J 13.4, 7.1, one of C(5)H2], 2.38 [2 H, t, J 2.3, C(6)H2], (2.49 g, 90%). Compound 13: νmax/cm−1 (film): 2956 (CH),
2.11 [2 H, tt, J 7.1, 2.3, C(9)H2], 1.79 [1 H, dd, J 13.4, 5.1, one of 2859 (CH), 2216 (CuC), 1727 (CvO), 1680, 1472, 1254 (C–O);
C(5)H2], 1.50–1.28 [6 H, m, C(10)H2, C(11)H2, C(12)H2], δH (400 MHz, CDCl3): 7.39 [1 H, d, J 5.7, C(3)H], 6.15 [1 H, d,
0.93–0.82 [21 H, m, C(13)H3, SiC(CH3)3 × 2], 0.11–0.04 [12 H, J 5.7, C(2)H], 2.70 [1 H, d, J 18.2, one of C(5)H2], 2.66–2.53
m, Si(CH3)2 × 2]; δC (100.6 MHz, CDCl3): 137.8 C(2)H or C(3)H, [2 H, m, C(6)H2], 2.42 [1 H, d, J 18.2, one of C(5)H2], 2.07 [2 H,
135.8 C(2)H or C(3)H, 85.1 C(1), 81.4 C(8), 77.4 C(7), 75.5 C(4)- t, J 7.0, C(9)H2], 1.47–1.36 [2 H, m, C(10)H2], 1.34–1.23 [4 H, m,
H, 49.5 C(5)H2, 33.6 C(6)H2, 31.3 C(11)H2, 29.0 C(10)H2, 26.0 C(11)H2, C(12)H2], 0.93–0.82 [12 H, m, C(13)H3, SiC(CH3)3],
and 25.9 SiC(CH3)3 × 2, 22.4 C(12)H2, 18.9 C(9)H2, 18.3 and 0.07 [3 H, s, one of Si(CH3)2], 0.06 [3 H, s, one of Si(CH3)2]; δC
18.2 SiC(CH3)3 × 2, 14.2 C(13)H2, −2.1, −2.4, −4.4, −4.5 (100.6 MHz, CDCl3): 206.4 C(1)vO, 165.3 C(3)H, 133.8 C(2)H,
Si(CH3)2 × 2; m/z (CI+): 421 [(M + H − CH3)+ 80%] 379 (100%); 83.7 C(8), 80.7 C(4), 75.1 C(7), 49.1 C(5)H2, 32.6 C(6)H2, 31.2
HRMS (CI+): Exact mass calculated for C24H45O2Si2 421.2958. C(11)H2, 28.6 C(10)H2, 25.7 SiC(CH3)3, 22.3 C(12)H2, 18.7 C(9)-
+
Found 421.2944.
H2, 18.1 SiC(CH3)3, 14.1 C(13)H2, −2.3 one of Si(CH3)2, −2.5
(1S,4R)-4-((tert-Butyldimethylsilyl)oxy)-4-(oct-2-yn-1-yl) cyclo- one of Si(CH3)2; m/z (CI+): 321[(M + H)+ 60%] 263 (100%);
pent-2-en-1-ol 11. A solution of (((1R,4S)-1-(oct-2-yn-1-yl)cyclo- HRMS (CI+): Exact mass calculated for C19H33O2Si+ 321.2249.
pent-2-ene-1,4-diyl)bis(oxy))bis(tert-butyldimethylsilane)
9
Found 321.2242.
(5.16 g, 11.8 mmol) in THF (65 mL) was cooled to 0 °C under
(R,Z)-4-((tert-Butyldimethylsilyl)oxy)-4-(oct-2-en-1-yl)cyclopent-
Ar and treated with TBAF (11.8 mL, 11.8 mmol, 1 eq., 1 M 2-en-1-one 15. See results and discussion section for details
soln.). The mixture was stirred at r.t. and monitored by TLC. on advantages of method 2 over method 1.
Two additional portions of TBAF (4.7 mL + 4.7 mL) were added
Method 1: a degassed solution of (R)-4-((tert-butyldimethyl-
at 2 h and 4 h based on TLC analysis. After 5 h the reaction silyl)oxy)-4-(oct-2-yn-1-yl)cyclopent-2-en-1-one 13 (0.794 g,
was quenched with sat. aq. NH4Cl (5 mL) and then H2O 2.48 mmol) in methanol (39 mL) was treated with quinolone
(100 mL) and EtOAc (100 mL) were added. The layers were sep- (72 μL, 10% w/w) and Pd/BaSO4 (79 mg, 10% w/w) and then
arated and the aqueous layer was extracted with EtOAc (3 × rapidly stirred under H2 at approx. 1 atm for 1.5 h. The
100 mL). The combined organic extracts were washed with mixture was filtered through Celite, washed with methanol
water (2 × 200 mL) and brine (200 mL), then dried and evapor- (20 mL) and concentrated. Purification by column chromato-
ated. The product was purified by column chromatography graphy with 30 : 70 hexane–CH2Cl2 gave 15 as a colourless oil
with hexane–EtOAc (99 : 1–60 : 40) to give the pure product 11 (782 mg, 98%). Analysis identical to that given below.
(2.805 g, 74%) and unreacted starting material 9 (0.579 g, 11%
recovery) −83% yield of 11 taking recovered starting material BaSO4 (47 mg, 10% w/w) were added to (R)-4-((tert-butyl-
into consideration. Compound 11: νmax/cm−1 (film): 3430 dimethylsilyl)oxy)-4-(oct-2-yn-1-yl)cyclopent-2-en-1-one
13
Method 2: quinolone (0.24 mL), 1-octene (2.4 mL) and Pd/
(OH), 2956 (CH), 2858 (CH), 2215 (CuC), 1726 (CvC), 1463, (474 mg, 1.48 mmol) in degassed methanol (24 mL) and
1253 (C–O); δH (400 MHz, CDCl3): 5.91 [1 H, dd, J 5.6, 1.7, stirred under H2 for 1.25 hours. The reaction was monitored
C(2)H], 5.88 [1 H, dd, J 5.6, 0.9, C(3)H], 4.69 [1 H, br s, C(1)H], by TLC using a microliter syringe to withdraw approx. 5 μL of
2.66 [1 H, dd, J 13.7, 7.2, one of C(5)H2], 2.48–2.36 [2 H, m, reaction mixture and adding to approx. 3 drops of CH2Cl2.
C(6)H2], 2.10 [2 H, tt, J 7.1, 2.4, C(9)H2], 1.76 [1 H, dd, J 13.7, When the starting material had been consumed, the mixture
4.7, one of C(5)H2], 1.56 [1 H, br s, C(1)OH], 1.50–1.40 [2 H, m, was filtered through Celite, washed with methanol (40 mL)
C(10)H2], 1.38–1.26 [4 H, m, C(11)H2, C(12)H2], 0.93–0.83 and evaporated. Purification by column chromatography with
[12 H, m, C(13)H3, SiC(CH3)3], 0.10 [3 H, s, one of Si(CH3)2], hexane–EtOAc on 10% w/w AgNO3 doped silica gel gave the
0.10 [3 H, s, one of Si(CH3)2]; δC (100.6 MHz, CDCl3): 139.5 pure alkene 15 as a colourless oil (392 mg, 82%). Compound
C(3)H, 135.1 C(2)H, 85.3 C(4), 81.8 C(8), 76.5 C(7), 75.7 C(1)H, 15: νmax/cm−1 (film): 2956 (CH), 2858 (CH), 1724 (CvO), 1406,
49.4 C(5)H2, 33.1 C(6)H2, 31.2 C(11)H2, 28.8 C(10)H2, 25.8 1360, 1252 (C–O); δH (400 MHz, CDCl3): 7.40 [1 H, d, J 5.7,
SiC(CH3)3, 22.4 C(12)H2, 18.8 C(9)H2, 18.1 SiC(CH3)3, 14.2 C(3)H], 6.10 [1 H, d, J 5.7, C(2)H], 5.57–5.48 [1 H, m, C(8)H],
C(13)H2, −2.1 one of Si(CH3)2, −2.2 one of Si(CH3)2; m/z (CI+): 5.40–5.31 [1 H, m, C(7)H], 2.54–2.38 [4 H, m, C(5)H2, C(6)H2],
323 [(M + H)+ 20%], 305 (100%); HRMS (ESI+): Exact mass 2.03–1.94 [2 H, m, C(9)H2], 1.38–1.22 [6 H, m, C(10)H2, C(11)-
calculated for C19H35O2Si+ 323.2406. Found 323.2393.
H2, C(12)H2], 0.93–0.85 [12 H, m, C(13)H3, SiC(CH3)3], 0.07
(R)-4-((tert-Butyldimethylsilyl)oxy)-4-(oct-2-yn-1-yl)cyclopent- [3 H, s, one of Si(CH3)2], 0.05 [3 H, s, one of Si(CH3)2]; δC
2-en-1-one 13. (1S,4R)-4-((tert-Butyldimethylsilyl)oxy)-4-(oct-2- (100.6 MHz, CDCl3): 206.8 C(1)vO, 166.6 C(3)H, 133.7 C(8)H,
yn-1-yl) cyclopent-2-en-1-ol 11 (2.78 g, 8.61 mmol) was dis- 133.2 C(2)H, 123.3 C(7)H, 81.1 C(4), 49.2 C(5)H2, 39.7 C(6)H2,
solved in CH2Cl2 (50 mL) and treated with PDC (4.86 g, 31.7 C(11)H2, 29.3 C(10)H2, 27.6 C(9)H2, 25.8 SiC(CH3)3, 22.7
12.9 mmol, 1.5 eq.). The reaction was stirred at r.t. under Ar C(12)H2, 18.2 SiC(CH3)3, 14.2 C(13)H2, −2.2 one of Si(CH3)2,
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−2.4 one of Si(CH3)2; m/z (CI+): 323 [(M + H)+ 100%]; HRMS hour. The reaction mixture was cooled and water (20 mL) was
(CI+): Exact mass calculated for C19H35O2Si+ 323.2406. Found added. The layers were separated and the aqueous layer was
323.2413.
extracted with CH2Cl2 (3 × 20 mL). The combined organic
(R,E)-3-(5-Oxotetrahydrofuran-2-yl)acrylaldehyde 19. Formyl- extracts were washed with water (2 × 20 mL) and brine (20 mL),
methyltriphenylphosphonium chloride (865 mg, 2.54 mmol) then dried and evaporated to give the crude product. Careful
in CH2Cl2 (10 mL) was treated with Et3N (0.37 mL, 2.65 mmol) purification by column chromatography with hexane–EtOAc
and stirred at r.t. for 1 h.
(90 : 10–60 : 40) gave 21 first (167 mg, 18%), followed by 20
In a separate flask, CH2Cl2 (7 mL) was cooled to −78 °C (582 mg, 61%).
under Ar and treated with oxalyl chloride (343 μL, 4.06 mmol,
Compound 20: νmax/cm−1 (film): 2955 (CH), 2856 (CH),
1.2 eq.), followed by drop-wise addition of DMSO (0.60 mL, 1783 (CvO lactone), 1701 (CvO cyclopentenone), 1642
8.45 mmol, 2.5 eq.). The mixture was stirred at −78 °C for (CvC), 1462, 1252, 1169; δH (400 MHz, CDCl3): 7.34 [1 H, d,
5 minutes and (R)-5-(hydroxymethyl)dihydrofuran-2(3H)-one J 6.0, C(11)H)], 7.04 [1 H, dd, J 15.2, 11.9, C(6)H], 6.89 [1 H, d,
(393 mg, 3.38 mmol) was added drop-wise in CH2Cl2 (5 mL). J 11.9, C(7)H], 6.35 [1 H, d, J 6.0, C(10)H], 6.15 [1 H, dd, J 15.2,
The reaction was stirred at −78 °C for 30 minutes, quenched 5.8, C(5)H], 5.51–5.42 [1 H, m, C(15)H], 5.31–5.22 [1 H, m,
with Et3N (2.35 mL, 16.9 mmol, 5 eq.) and allowed to warm to C(14)H], 5.11–5.03 [1 H, m, C(4)H], 2.70 [1 H, dd, J 14.4, 6.4,
−20 °C. The solution of phosphorus ylide was added and one of C(13)H2], 2.63–2.44 [4 H, m, one of C(13)H2, C(2)H2,
stirred at r.t. for 18 h. The solvent was evaporated and purified one of C(3)H2], 2.08–1.99 [1 H, m, one of C(3)H2], 1.95–1.88
by column chromatography, first with CH2Cl2–MeOH (98 : 2) to [2 H, m, C(16)H2], 1.32–1.19 [6 H, m, C(17)H2, C(18)H2, C(19)-
remove triphenylphosphine oxide and a second time with H2], 0.91–0.83 [12 H, m, C(20)H3, SiC(CH3)3], 0.00 [3 H, s, one
hexane–EtOAc (40 : 60) to give the pure product 19 as a pale of Si(CH3)2], −0.14 [3 H, s, one of Si(CH3)2]; δC (100.6 MHz,
yellow oil (200 mg, 42%). Compound 19: νmax/cm−1 (film): CDCl3): 194.9 C(9)vO, 176.3 C(1)vO, 162.2 C(11)H, 141.1
2932 (CH), 1775 (CvO lactone), 1691 (CvO aldehyde), 1180 C(8), 139.8 C(5)H, 134.6 C(10)H, 133.8 C(15)H, 129.6 C(7)H,
(C–O lactone); δH (400 MHz, CDCl3): 9.60 (1 H, d, J 7.5, CHO), 127.2 C(6)H, 122.9 C(14)H, 81.2 C(12), 79.4 C(4)H, 39.6 C(13)
6.79 [1 H, dd, J 15.8, 4.7, C(5)H], 6.32 [1 H, ddd, J 15.8, 7.5, 1.5, H2, 31.7 C(18)H2, 29.3 C(17)H2, 28.7 C(3)H2, 28.5 C(2)H2, 27.6
C(6)H], 5.29–5.13 [1 H, m, C(4)H], 2.63–2.52 [3 H, m, C(2)H2, C(16)H2, 25.9 SiC(CH3)3, 22.7 C(19)H2, 18.3 SiC(CH3)3, 14.2
one of C(3)H2], 2.15–2.02 [1 H, m, one of C(3)H2]; δC C(20)H3, −2.0 one of Si(CH3)2, −3.0 one of Si(CH3)2; m/z (CI+):
(100.6 MHz, CDCl3): 192.4 CHO, 175.8 CvO lactone, 151.2 445 [(M + H)+ 100%]; HRMS (CI+): Exact mass calculated for
C(5)H, 131.8 C(6)H, 77.6 C(4)H, 27.9 C(2)H2 and C(3)H2; m/z C26H41O4Si+ 445.2774. Found 445.2766.
(CI+): 141 [(M + H)+ 100%]; HRMS (CI+): Exact mass calculated
for C7H9O3+ 141.0551. Found 141.0553.
Compound 21: νmax/cm−1 (film): 2955 (CH), 2857 (CH),
1781 (CvO lactone), 1697 (CvO cyclopentenone), 1641
(R)-5-((1E,3E)-3-((S)-2-((tert-Butyldimethylsilyl)oxy)-2-((Z)-oct- (CvC), 1463, 1251, 1166; δH (400 MHz, CDCl3): 7.80 [1 H, dd,
2-en-1-yl)-5-oxocyclopent-3-en-1-ylidene)prop-1-en-1-yl)dihydro- J 15.3, 11.5, C(6)H], 7.28 [1 H, d, J 6.0, C(11)H)], 6.51 [1 H, d,
furan-2(3H)-one 20 and (R)-5-((1E,3Z)-3-((S)-2-((tert-butyl- J 11.5, C(7)H], 6.28 [1 H, d, J 6.0, C(10)H], 6.07 [1 H, dd, J 15.3,
dimethylsilyl)oxy)-2-((Z)-oct-2-en-1-yl)-5-oxocyclopent-3-en-1- 6.8, C(5)H], 5.54–5.44 [1 H, m, C(15)H], 5.39–5.30 [1 H, m,
ylidene)prop-1-en-1-yl)dihydrofuran-2(3H)-one
21. n-Butyl- C(14)H], 5.15–5.06 [1 H, m, C(4)H], 2.64–2.42 [5 H, m, C(13)H2,
lithium (1.18 mL, 2.78 mmol, 2.35 M soln.) was added drop- C(2)H2, one of C(3)H2], 2.13–2.03 [1 H, m, one of C(3)H2],
wise to a solution of diisopropylamine (0.45 mL, 3.21 mmol) 1.98–1.88 [2 H, m, C(16)H2], 1.33–1.20 [6 H, m, C(17)H2, C(18)-
in THF (8 mL) under Ar at −78 °C and stirred for 15 minutes. H2, C(19)H2], 0.89–0.85 [12 H, m, C(20)H3, SiC(CH3)3], −0.03
(R,Z)-4-((tert-butyldimethylsilyl)oxy)-4-(oct-2-en-1-yl)cyclopent- [3 H, s, one of Si(CH3)2], −0.12 [3 H, s one of Si(CH3)2]; δC
2-en-1-one 15 (691 mg, 2.14 mmol) in THF (10 mL) was added (100.6 MHz, CDCl3): 195.4 C(9)vO, 176.6 C(1)vO, 160.8 C(11)-
drop-wise over 10 minutes. After stirring at −78 °C for a H, 140.6 C(8), 139.2 C(5)H, 135.8 C(10)H, 133.7 C(15)H, 133.2
further 30 minutes, (R,E)-3-(5-oxotetrahydrofuran-2-yl)acryl- C(7)H, 128.0 C(6)H, 123.2 C(14)H, 80.6 C(12), 80.1 C(4)H, 40.0
aldehyde 19 (430 mg, 3.07 mmol) in THF (10 mL) was added C(13)H2, 31.7 C(18)H2 or C(19)H2, 29.3 C(17)H2, 28.8 two over-
drop-wise. The reaction was stirred at −78 °C for 1 hour and lapping peaks C(3)H2 and C(2)H2, 27.5 C(16)H2, 25.8
then allowed to warm to −20 °C before quenching with sat. aq. SiC(CH3)3, 22.7 C(18)H2 or C(19)H2, 18.2 SiC(CH3)3, 14.2 C(20)-
NH4Cl (5 mL). Water (20 mL) was added and the aqueous layer H3, −2.3 one of Si(CH3)2, −2.7 one of Si(CH3)2; m/z (CI+): 445
`
was extracted with diethyl ether (3 × 20 mL). The combined [(M + H)+ 100%]; HRMS (CI+): Exact mass calculated for
organic extracts were washed with water (2 × 20 mL) and brine C26H41O4Si+ 445.2774. Found 445.2768.
(20 mL), then dried and evaporated to give the intermediate
(R)-5-((1E,3E)-3-((S)-2-Hydroxy-2-((Z)-oct-2-en-1-yl)-5-oxocyclo-
alcohol as a mixture of diastereomers (1 : 1.6 ratio from 1H pent-3-en-1-ylidene)prop-1-en-1-yl)dihydrofuran-2(3H)-one 22.
NMR). This material was immediately dissolved in CH2Cl2 (R)-5-((1E,3E)-3-((S)-2-((tert-Butyldimethylsilyl)oxy)-2-((Z)-oct-2-
(25 mL), cooled to 0 °C and treated with triethylamine (0.6 mL, en-1-yl)-5-oxocyclopent-3-en-1-ylidene)prop-1-en-1-yl)dihydro-
4.28 mmol) and methanesulfonyl chloride (0.25 mL, furan-2(3H)-one 20 (31 mg, 0.070 mmol) in acetonitrile
3.21 mmol). The mixture was heated to reflux and monitored (0.3 mL) was carefully treated with 40% aq. HF solution
by TLC. After 2 hours additional MsCl (0.25 mL, 3.21 mmol) (130 µL) and stirred at r.t. for 20 h. The reaction was slowly
was added and the reaction was heated to reflux for a further quenched with sat. aq. NaHCO3 (4 mL) and extracted with
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diethyl ether (3 × 4 mL). The combined organic extracts were extracts were washed with 0.5 M HCl (3 mL), sat. aq. NaHCO3
washed with water (5 mL) and brine (5 mL), then dried and (3 mL) and brine (3 mL), then dried and evaporated to give the
evaporated to give a yellow oil. Purification by column crude product. Purification by column chromatography with
chromatography with hexane–EtOAc (50 : 50–30 : 70) gave 22 as hexane–EtOAc (60 : 40) gave 2 as a clear oil (13 mg, 92%). Com-
a colourless oil (21 mg, 91%). Compound 22: δH (400 MHz, pound 2: νmax/cm−1 (film): 2929 (CH), 2857 (CH), 1779 (CvO),
CDCl3): 7.33 [1 H, dd, J 6.0, 0.7, C(11)H)], 7.05 [1 H, ddd, 1745 (CvO), 1704 (CvO), 1644 (CvC), 1368, 1231, 1170; δH
J 15.0, 11.9, 1.2, C(6)H], 6.88 [1 H, d, J 11.9, C(7)H], 6.34 [1 H, (400 MHz, CDCl3): 7.49 [1 H, d, J 6.1, C(11)H)], 6.91 [1 H, d,
d, J 6.0, C(10)H], 6.16 [1 H, dd, J 15.0, 6.4, C(5)H], 5.58–5.45 J 12.0, C(7)H], 6.82 [1 H, ddd, J 14.8, 12.0, 1.5, C(6)H], 6.41
[1 H, m, C(15)H], 5.27–5.13 [1 H, m, C(14)H], 5.13–5.03 [1 H, [1 H, d, J 6.1, C(10)H], 6.17 [1 H, dd, J 14.8, 4.8, C(5)H],
m, C(4)H], 2.84–2.29 [6 H, m, C(13)H2, C(2)H2, one of C(3)H2, 5.58–5.44 [1 H, m, C(15)H], 5.20–5.08 [2 H, m, C(14)H, C(4)H],
C(12)OH], 2.14–2.01 [1 H, m, one of C(3)H2], 2.00–1.90 [2 H, 2.92 [1 H, dd, J 14.2, 6.9, one of C(13)H2], 2.70 [1 H, dd, J 14.2,
m, C(16)H2], 1.35–1.23 [6 H, m, C(17)H2, C(18)H2, C(19)H2], 8.2, one of C(13)H2], 2.63–2.43 [3 H, m, C(2)H2, one of C(3)H2],
0.87 [3 H, t, J 6.8, C(20)H3]; δC (100.6 MHz, CDCl3): 195.1 2.10–1.99 [4 H, m, C(22)H3, one of C(3)H2], 1.97–1.88 [2 H, m,
C(9)vO, 176.5 C(1)vO, 161.6 C(11)H, 140.5 C(5)H, 140.4 C(8), C(16)H2], 1.34–1.19 [6 H, m, C(17)H2, C(18)H2, C(19)H2], 0.87
134.9 broad (two overlapping peaks) C(10)H and C(15)H, 130.0 [3 H, t, J 6.9, C(20)H3]; δC (100.6 MHz, CDCl3): 193.5 C(9)vO,
C(7)H, 126.8 C(6)H, 122.1 C(14)H, 79.6 C(4)H, 37.0 C(13)H2, 176.4 C(1)vO, 169.5 C(21)vO, 158.2 C(11)H, 141.0 C(5)H,
31.7 C(18)H2, 29.3 C(17)H2, 28.7 C(2)H2 or C(3)H2, 28.5 C(2)H2 137.3 C(8), 135.3 C(10)H or C(15)H, 135.2 C(10)H or C(15)H,
or C(3)H2, 27.6 C(16)H2, 22.7 C(19)H2, 14.2 C(20)H3; 129.0 C(7)H, 125.1 C(6)H, 121.1 C(14)H, 85.3 C(12), 78.8 C(4)H,
[α]2D0 −45.3° (c = 0.3, CHCl3); m/z (CI+): 331 [(M + H)+ 100%]; 36.0 C(13)H2, 31.6 C(18)H2, 29.2 C(17)H2, 28.4 C(3)H2, 27.9
HRMS (CI+): Exact mass calculated for C20H27O4 331.1909. C(2)H2, 27.6 C(16)H2, 22.6 C(19)H2, 21.4 C(22)H3, 14.2 C(20)-
+
Found 331.1902.
H3; [α]2D0 −25.7° (c = 0.26, CHCl3); m/z (CI+): 373 [(M + H)+
(R)-5-((1E,3Z)-3-((S)-2-Hydroxy-2-((Z)-oct-2-en-1-yl)-5-oxocyclo- 15%], 313 (100%); HRMS (CI+): Exact mass calculated for
pent-3-en-1-ylidene)prop-1-en-1-yl)dihydrofuran-2(3H)-one 23. C22H29O5+ 373.2015. Found 373.2007.
Prepared and purified as described for compound 22 from (R)-
Clavulolactone III, (S,Z)-1-((Z)-oct-2-en-1-yl)-4-oxo-5-((E)-3-
5-((1E,3Z)-3-((S)-2-((tert-butyldimethylsilyl)oxy)-2-((Z)-oct-2-en-1- ((R)-5-oxotetrahydrofuran-2-yl)allylidene)cyclopent-2-en-1-yl
yl)-5-oxocyclopent-3-en-1-ylidene)prop-1-en-1-yl)dihydrofuran-2 acetate 3. Prepared and purified as described for compound 2
(3H)-one 21 (19 mg, 0.043 mmol) giving 23 as a colourless oil from (R)-5-((1E,3Z)-3-((S)-2-hydroxy-2-((Z)-oct-2-en-1-yl)-5-oxo-
(13.7 mg, 97%). Compound 23: δH (400 MHz, CDCl3): 7.78 cyclopent-3-en-1-ylidene)prop-1-en-1-yl)dihydrofuran-2(3H)-one
[1 H, ddd, J 15.5, 11.3, 1.1, C(6)H], 7.29 [1 H, d, J 6.0, C(11)H)], 23 (34.6 mg, 0.105 mmol) giving 3 as a colourless oil (34 mg,
6.61 [1 H, d, J 11.3, C(7)H], 6.30 [1 H, d, J 6.0, C(10)H], 6.08 87%). Compound 3: νmax/cm−1 (film): 2929 (CH), 2857 (CH),
[1 H, dd, J 15.5, 7.2, C(5)H], 5.61–5.50 [1 H, m, C(15)H], 5.35–5.23 1778 (CvO), 1743 (CvO), 1702 (CvO), 1644 (CvC), 1626
[1 H, m, C(14)H], 5.09 [1 H, m, C(4)H], 2.67–2.52 [4 H, m, C(13) (CvC), 1231, 1170; δH (400 MHz, CDCl3): 7.82 [1 H, dd, J 15.6,
H2, C(2)H2], 2.52–2.40 [1 H, m, one of C(3)H2], 2.27 [1 H, s, 11.2, C(6)H], 7.49 [1 H, d, J 6.1, C(11)H)], 6.53 [1 H, d, J 11.2,
C(12)OH], 2.12–2.03 [1 H, m, one of C(3)H2], 2.03–1.93 [2 H, C(7)H], 6.38 [1 H, d, J 6.1, C(10)H], 6.08 [1 H, dd, J 15.6, 7.2,
m, C(16)H2], 1.36–1.20 [6 H, m, C(17)H2, C(18)H2, C(19)H2], C(5)H], 5.60–5.43 [1 H, m, C(15)H], 5.28–5.15 [1 H, m, C(14)H],
0.87 [3 H, t, J 6.9, C(20)H3]; δC (100.6 MHz, CDCl3): 195.38 5.15–5.05 [1 H, m, C(4)H], 2.84 [1 H, dd, J 14.4, 7.4, one of
C(9)vO, 176.72 C(1)vO, 160.05 C(11)H, 140.27 C(8), 139.65 C(13)H2], 2.71–2.40 [4 H, m, C(2)H2, one of C(3)H2, one of
C(5)H, 136.26 C(10)H 134.88 C(15)H 133.01 C(7)H, 127.93 C(6)- C(13)H2], 2.14–2.01 [4 H, m, one of C(3)H2, C(22)H3], 2.01–1.91
H, 122.26 C(14)H, 80.23 C(4)H, 79.00 C(12), 37.38 C(13)H2, [2 H, m, C(16)H2], 1.35–1.19 [6 H, m, C(17)H2, C(18)H2, C(19)
31.65 C(18)H2, 29.25 C(17)H2, 28.73 broad (two overlapping H2], 0.88 [3 H, t, J 6.8, C(20)H3]; δC (100.6 MHz, CDCl3): 194.2
peaks) C(2)H2 and C(3)H2, 27.50 C(16)H2, 22.66 C(19)H2, 14.18 C(9)vO, 176.6 C(1)vO, 169.8 C(21)vO, 156.5 C(11)H, 140.0
C(20)H3; [α]2D0 −14.2° (c = 0.3, CHCl3); m/z (CI+): 331 [(M + H)+ C(5)H, 136.8 C(10)H, 136.8 C(8), 135.2 C(15)H, 132.6 C(7)H,
100%]; HRMS (CI+): Exact mass calculated for C20H27O4
331.1909. Found 331.1900.
127.8 C(6)H, 121.3 C(14)H, 85.2 C(12), 80.2 C(4)H, 35.9 C(13)-
H2, 31.7 C(18)H2, 29.2 C(17)H2, 28.8 C(2)H2, 28.8 C(3)H2, 27.6
+
Clavulolactone II, (S,E)-1-((Z)-oct-2-en-1-yl)-4-oxo-5-((E)-3- C(16)H2, 22.7 C(19)H2, 21.8 C(22)H3, 14.2 C(20)H3; [α]2D0 −7.8°
((R)-5-oxotetrahydrofuran-2-yl)allylidene)cyclopent-2-en-1-yl (c = 0.20, CHCl3); m/z (CI+): 373 [(M + H)+ 20%], 313 (100%);
acetate 2. (R)-5-((1E,3E)-3-((S)-2-Hydroxy-2-((Z)-oct-2-en-1-yl)-5- HRMS (CI+): Exact mass calculated for C22H29O5 373.2015.
+
oxo
cyclopent-3-en-1-ylidene)prop-1-en-1-yl)dihydrofuran-2- Found 373.2019.
(3H)-one 22 (34.6 mg, 0.105 mmol) was dissolved in CH2Cl2
Note: Analysis for both Clavulolactone II and III is in excel-
(0.15 mL) under Ar. Hünigs base (33 µL, 0.189 mmol, 1.8 eq.), lent agreement with that reported by Iguchi et al.1
Ac2O (17 µL, 0.180 mmol, 1.7 eq.) and DMAP (0.6 mg,
0.005 mmol, 0.05 eq.) were added and the reaction was stirred
at r.t. under Ar for 18 h. The reaction was quenched with 0.5
M HCl (1 mL), followed by addition of H2O (2 mL) and CH2Cl2
Acknowledgements
(2 mL). The layers were separated and the aqueous layer was The authors thank Norges Forskningsråd (NFR, Research
extracted with CH2Cl2 (3 × 2 mL). The combined organic Council of Norway) for funding. (grant no. 209330).
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20 K. Mori and T. Takeuchi, Tetraheron, 1988, 44, 333.
21 L. Tietze, C. Stadler, N. Böhnke, G. Brasche and A. Grube,
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22 M. Le Liepvre, J. Ollivier and D. J. Aitken, Eur. J. Org.
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Notes and references
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1995, 58, 790.
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4058 | Org. Biomol. Chem., 2015, 13, 4051–4058
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