Total synthesis and structural elucidation of ent-micropyrone and (+)-ascosalipyrone

Article abstract of DOI:10.1039/c2ob25501d

The total synthesis of 6-[(1S,3S)-1,3-dimethyl-2-oxopentyl]-4-hydroxy-3,5- dimethyl-2H-pyran-2-one (22), the enantiomer of the natural product micropyrone (1), was achieved in 9 linear steps (10% overall yield), from Evans auxiliary (R)-12 with key coupli

Full text of DOI:10.1039/c2ob25501d

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PAPER
Total synthesis and structural elucidation of ent-micropyrone and
(+)-ascosalipyrone†
Claire Gregg and Michael V. Perkins*
Received 8th March 2012, Accepted 12th June 2012
DOI: 10.1039/c2ob25501d
The total synthesis of 6-[(1S,3S)-1,3-dimethyl-2-oxopentyl]-4-hydroxy-3,5-dimethyl-2H-pyran-2-one
(22), the enantiomer of the natural product micropyrone (1), was achieved in 9 linear steps (10% overall
yield), from Evans auxiliary (R)-12 with key coupling of the dianion of dione 17 and aldehyde 11.
Formation of the pyrone ring and subsequent oxidation at C7 was achieved without epimerization of the
sensitive position α to both the pyrone ring and the carbonyl. The same sequence using the alternate
dione 24 achieved the total synthesis of 6-[(1S,3S)-1,3-dimethyl-2-oxopentyl]-4-hydroxy-3-methyl-
2H-pyran-2-one (28), the (+)-enantiomer of the natural product, ascosalipyrone (2). In both cases
diastereomeric aldehydes 11 and 16 were taken through the synthetic sequence to give two possible
diastereomers of the natural products. Comparison of the 1H and 13C NMR data for the synthetic isomers
with that reported for the natural products determined their relative stereochemistry. Comparison of the
optical rotation obtained for 22 established it to be the enantiomer of micropyrone.
Introduction
The α-pyrone ring is a structural feature present in numerous
polyketide natural products isolated from a wide variety of
sources and is associated with many key biological processes
including defense and intercellular communication.1 Many bio-
logically important compounds contain the α-pyrone moiety,
including pheromones, coumarins and elasnin, and they display
broad spectrum pharmaceutical properties including use in the
Fig. 1 Structures of micropyrone3 and ascosalipyrone.6
treatment of HIV, Alzheimer’s disease and cancer.1 4-Hydroxy-
α-pyrones in particular have become one of the most important
classes of anti-HIV agents.2
determined, but it appeared from a single set of 1H and 13C
resonances to be a single stereoisomer. The isolation of this com-
pound as a single isomer implies that the presence of the carbo-
nyl β to the pyrone ring does not lead to rapid epimerization of
the α-stereocentre under physiological conditions or during the
isolation process. A structurally related compound, ascosalipyr-
one (2), had previously been isolated from the endophytic and
obligate marine fungus Ascochyta salicorniae of the green alga
Ulva sp. in 2000 by the group of König.6 Ascosalipyrone (2)
was subsequently tested for its inhibition of a variety of protein
phosphatases, but showed no activity.7 Ascosalipyrone (2) was
reported6 to have a structure which differed from micropyrone
only in the absence of the methyl at C4 of the pyrone ring.
The relative and absolute configuration of ascosalipyrone (2)
was not determined and it appeared from some split signals in
the 13C NMR that it was an unequal mixture of diastereomers.
There are four possible stereoisomers 3–6 (two pairs of
enantiomers) each for micropyrone (1) and ascosalipyrone (2)
Micropyrone (1) (Fig. 1) was isolated from Helichrysum
italicum ssp. microphyllum in 2007 by Appendino and
coworkers.3 The structure of micropyrone (1) was assigned on
the basis of 1H and 13C NMR data to contain a 4-hydroxy-
α-pyrone ring and is potentially related to a series of β-diketones
isolated from the essential oil of H. italicum.4,5 The absolute and
relative configuration of the two stereocentres was not
School of Chemical and Physical Sciences, Flinders University, GPO
Box 2100, Adelaide, South Australia 5001, Australia.
E-mail: mike.perkins@flinders.edu.au; Fax: +618 8201 2905;
Tel: +618 8201 2496
†Electronic supplementary information (ESI) available: General exper-
imental details, detailed experimental procedures and spectroscopic data
for compounds 11, 13–17, 26–30, and 33–46, copies of 1H and 13C
NMR spectra of compounds 11, 14, 16, 18, 20, 22, 23, 25–29, 37, 39,
41, 43 & 44 and X-ray crystallographic data and cif files for compounds
22 & 23. CCDC 870497 and 870498. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c2ob25501d
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Fig. 2 Possible isomers of micropyrone (R = Me) and ascosalipyrone
(R = H).
(Fig. 2). We proposed to use a common strategy to prepare the
two isomers 3 and 4 (8S configuration in each case) of each
natural product in order to establish their absolute and relative
configurations.
Results and discussion
Scheme 2 Synthesis of aldehydes 11 and 16.
The common synthetic strategy for the preparation of both
micropyrone (1) and ascosalipyrone (2) is shown in Scheme 1.
It was hoped that oxidation of the alcohol at C7 in compound 7
would give the β-ketone pyrones without epimerization of the
C6 stereocentre in the final synthetic step. It was further pro-
posed that cyclisation of the trione 8 and subsequent deprotec-
tion would give the pyrone ring containing 7. Compound 8 was
to be prepared by oxidation of the product from addition of the
dianion of 9 to aldehyde 10. Compound 9 (R = Me) will give
micropyrone (1) and alternately use of 9 (R = H) will give asco-
salipyrone (2). Use of two different isomers of 10 will allow
specific preparation of the 6R and 6S stereoisomers of the two
natural products. Stereocontrolled synthesis of appropriate
isomers of 10 was to be achieved using an Evans auxiliary8
based benzyl oxazolidinone protocol.
Synthesis of the syn–anti aldehyde 11 began with an asym-
metric aldol reaction between the dibutylboron enolate of the
Evans auxiliary8–10 (R)-12 and the α-chiral aldehyde 13
(obtained by Swern oxidation11 of (S)-2-methylbutan-1-ol) as
shown in Scheme 2. This double stereodifferentiating aldol reac-
tion of Evans auxiliary8–10 (R)-12 is expected to be matched
with the anti-Felkin preference12 of aldehyde 13 and gave the
product 1413 with no detectable minor isomer (66%, >98% ds).
Silyl protection (TBSOTf, 2,6-lutidine)14 yielded compound
1515 in good yield. Conversion to aldehyde 11 was achieved by
reduction to the primary alcohol (LiBH4), and subsequent Swern
oxidation11 (71% yield over 2 steps). Use of the enantiomer of
the Evans auxiliary (S)-12 and the α-chiral aldehyde 13 in the
same four step sequence gave the isomeric syn–syn aldehyde 16
in 51% yield. In this sequence the stereoselectivity of the aldol
between (S)-12 and the α-chiral aldehyde 13 is equally high
(>98% ds) indicating little effect from any facial preference of
aldehyde 13. When the two diastereomeric aldehydes 11 and 16
are taken through the subsequent sequence they will give the
two possible C6 epimers of the natural products.
With the two required aldehydes 11 and 16 in hand we
attempted the dianion addition using 17 prepared by the dimeri-
sation of ethyl propionate (Scheme 3).16 Dione 17 was first
deprotonated with NaH followed by n-butyl lithium, then alde-
hyde 11 was added giving the product 18 as an inseparable
mixture of isomers (98%). Oxidation of the product with Dess–
Martin17 periodinane gave the trione 19 as an isomeric mixture
with a number of keto and enol forms apparent by NMR
spectroscopy. The trione was cyclised using DBU in benzene at
60 °C to give pyrone 20 as a single stereoisomer. The t-butyl-
dimethylsilyl protecting group was simply removed using
aqueous HF/CH3CN to give alcohol 21. Compound 21 proved to
be very insoluble but could be purified simply by triturating with
acetone. It was envisioned that a mild neutral oxidation would
Scheme 1 Retrosynthetic analysis of micropyrone (1) and ascosalipyr-
one (2).
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Scheme 4 Synthesis of two possible isomers (28 and 29) of
ascosalipyrone.
Scheme 3 Synthesis of two possible isomers (22 and 23) of
micropyrone.
the unfavorable A1,3 strain that would be present in the planar
enol tautomer.
The preparation of the two possible isomers of ascosalipyrone
(2) is shown in Scheme 4. The same 5 step sequence as indicated
in Scheme 3 was employed using the dianion of 24 with each
aldehyde 11 and 16. In this case addition of the dianion of dione
24 to aldehyde 11 uneventfully gave product 25. However, after
Dess–Martin oxidation (95%) and cyclisation using DBU, the
product 26 was isolated as a ∼3 : 1 mixture of the product 26
and the C6 epimer 27. Thus it appeared that partial epimerization
had occurred at C6 during cyclisation to form the pyrone ring.
As separation was not possible, this mixture was taken through
the last two steps of deprotection and oxidation. Again, insolu-
bility meant that Jones oxidation proved to be the only viable
oxidant and product 28 was isolated, contaminated with ∼25%
of its C6 epimer 29. The same reaction sequence was also carried
out using dione 24 and aldehyde 16 to give pyrone 29 as the
major product (contaminated with ∼25% of the C6 epimer 28).
With the two possible diastereomers of each of the natural pro-
Fig. 3 X-ray crystal structures of the two possible isomers (22 and 23)
of micropyrone.
be employed in the final step of the synthesis to avoid epimeriza-
tion of the C6 stereocentre of β-keto pyrone 22. But attempted
oxidation of 21 using either Swern or Dess–Martin conditions
were not successful, apparently as a result of the insolubility of
21. Fortunately, oxidation using Jones reagent18 was successful
giving the desired product 22 as a single isomer without C6
epimerization.
Use of dione 17 and the diastereomeric aldehyde 16 in the
same five step sequence gave the C6 epimeric β-ketone pyrone
23. Notably both these products were crystalline solids and crys-
tals suitable for X-ray analysis were grown. Single crystal struc-
tural analysis confirmed the assigned structures of the two
isomers including the configuration at C6 (Fig. 3). Notably in
both cases the conformation around the C5–C6 bond places the
small C6–H eclipsing the C4–Me thus minimising the A1,3 strain
of this flanking methyl. This low energy conformation also
suggests the configurational stability of the C6 stereocentre
(between the pyrone ring and the carbonyl) may be explained by
1
ducts micropyrone (1) and ascosalipyrone (2) in hand, H and
13C NMR spectral comparison and optical rotation comparison
were then used to assign the relative and absolute configurations
of the natural products. Fig. 4 shows the difference between the
13C NMR data for micropyrone (1) and synthetic isomers 22 and
23. The chemical shifts observed for carbons 6, 9 and 11 of syn
isomer 23 are significantly different (≥1 ppm) from those
reported for micropyrone (1) while all the 13C chemical shifts of
anti isomer 22 are ≤0.2 ppm different from those reported for
the natural product. There is also a near perfect match between
1
the H NMR of anti isomer 22 and the natural product whereas
significant differences are seen for the syn isomer 23. On this
basis the relative configuration of micropyrone (1) is assigned as
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the differences in the 13C chemical shifts, the relative configura-
tion of ascosalipyrone (4) is assigned as anti isomer 28. The
observed rotation for diastereomer 28 (as a 3 : 1 mixture with its
C6 epimer (6R,8S)-4) was [α]2D0 = +60.7 (c 1.57, MeOH),
however no optical rotation was reported for the natural product
so the absolute configuration could not be assigned.
Conclusion
The total synthesis of diastereomer 22, the enantiomer of the
natural product micropyrone (1), was achieved in 9 linear steps
(10% overall yield) without epimerization of the sensitive C6
position α to both the pyrone ring and the carbonyl. The syn-
thesis of compound 28, the (+)-enantiomer of the natural product
ascosalipyrone, was achieved in 9 linear steps (6% overall yield),
from the common aldehyde intermediate 11. Compound 28 was
isolated as an unequal mixture of diastereomers due to partial
epimerization of C6 upon formation of the pyrone ring, but this
epimerization did not occur during the synthesis of ent-micro-
pyrone (22). The lack of epimerization in this case can be ration-
alized by the presence of the C4 methyl and the resulting
increased A1,3 strain that would be present in the planar enol
epimerization intermediate.
Fig. 4 Difference in chemical shift (Δδ) for micropyrone (1) and syn-
thetic isomers 22 and 23.
Experimental
Ethyl (6S,7S,8S)-7-[(tert-butyl)dimethylsilyloxy]-5-hydroxy-
2,4,6,8-tetramethyl-3-oxodecanoate (18)
To a stirred suspension of NaH (183 mg; 7.63 mmol) in THF
(22 mL) at 0 °C was added ethyl 2-methyl-3-oxo-pentanoate
(17) (690 mg; 4.36 mmol) and the resulting mixture was stirred
at 0 °C for 10 min, before cooling to −10 °C. n-BuLi (2.73 mL;
1.6 M in hexanes; 4.36 mmol) was then added, with stirring at
−10 °C for a further 10 min. The reaction mixture was cooled to
−78 °C and a solution of aldehyde (11) (563 mg; 2.18 mmol) in
THF (5 mL) was added dropwise via cannula and the reaction
mixture was stirred at −78 °C for 1 h. The reaction was
quenched by addition of sat. aq. NH4Cl (20 mL) and allowed to
warm to rt. The mixture was extracted with Et2O (4 × 20 mL)
and the combined organic extracts were washed with brine
(40 mL), dried (Na2SO4) and concentrated in vacuo. Residual
ethyl 2-methyl-3-oxo-pentanoate was removed under high
vacuum and the crude product was filtered through a plug of
buffered silica (100% CH2Cl2) to give a complex mixture of
Fig. 5 Difference in chemical shift (Δδ) for ascosalipyrone (2) and
synthetic isomers 28 and 29.
1
isomers of alcohol (18) (890 mg; 98%) as a clear oil. H NMR
(600 MHz, CDCl3) δ 4.19–4.12 (2H, m), 3.97–3.77 (1.5H, m),
3.75, 3.73, 3.68 & 3.65 (4 × 0.25H, q, J = 7.2 Hz), 3.63 (0.5H,
dd, J = 7.2, 3.0 Hz) 2.95 (0.5H, dq, J = 7.2, 6.6 Hz), 2.86
(2 × 0.25H, dq, J = 7.2, 6.6 Hz), 1.75–1.35 (3H, m), 1.32–1.29
(3H, m), 1.26–1.22 (3.75H, m), 1.18, 1.08 & 1.07 (3 × 0.75H, d,
J = 7.2 Hz), 1.07–0.95 (1H, m), 0.92–0.83 (16.5H, m), 0.78 &
0.74 (2 × 0.75H, d, J = 7.2 Hz), 0.08–0.04 (6H, m) (OH not
assigned); 13C NMR (151 MHz, CDCl3) δ 211.9, 211.8, 210.9,
210.0, 209.5, 170.6, 170.4, 170.4, 170.2, 170.1, 167.9, 84.5,
80.4, 80.0, 79.5, 79.1, 78.3, 77.0, 76.0, 75.7, 75.5, 75.3, 71.8,
71.2, 61.60, 61.53, 61.49, 61.47, 61.3, 54.4, 53.8, 52.7, 52.0,
51.8, 50.92, 50.87, 50.0, 49.9, 49.0, 48.8, 48.6, 47.5, 47.4, 47.0,
40.89, 40.87, 40.76, 40.6, 39.9, 39.7, 39.4, 39.0, 38.7, 38.3,
anti isomer 22. The observed rotation for anti isomer 22 was
[α]2D0 = +28.8 (c 1.36, MeOH) which is of the opposite sign to
that reported ([α]2D0 = −21 (c 1.0, MeOH)) for the natural
product, showing that the natural product micropyrone (1) is the
enantiomer of compound 22.
Fig. 5 shows a comparison of the 13C NMR data for ascosali-
pyrone (2) and synthetic isomers 28 and 29. All the 13C chemi-
cal shifts of isomer 28 are ≤0.1 ppm different from those
reported for the natural product, while variation of >0.1 ppm is
seen in carbons 5–9 and 11 of the 13C chemical shifts of isomer
29. In this case however there are no significant differences in
1
the H NMR chemical shifts for either isomer. On the basis of
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37.9, 37.1, 36.8, 35.5, 34.5, 33.8, 32.0, 30.4, 29.8, 29.5, 23.4,
22.8, 22.3, 18.53, 18.49, 18.45, 18.40, 18.38, 18.35, 16.5, 16.2,
15.8, 15.7, 15.6, 15.4, 15.24, 15.18, 15.0, 14.19, 14.17, 14.14,
14.0, 13.3, 13.2, 13.11, 13.05, 13.00, 12.9, 12.7, 12.55, 12.50,
12.41, 12.37, 12.35, 12.29, 12.23, 12.16, 12.0, 11.9, 11.7, 11.5,
10.5, 9.1, 9.0, 8.8, 8.4, 8.1, 7.8, 7.5, −3.30, −3.39, −3.40, −3.8,
−4.00, −4.07, −4.11, −4.16, −4.20, −4.29, −4.31, −4.35.
in vacuo. The resulting residue was triturated with hexanes to
give α-pyrone (20) as a single isomer (193 mg; 45%) as colour-
less needles. Rf = 0.27 (10% Et2O/CH2Cl2); mp. 179–181 °C;
1
[α]2D0 = −50.3 (c 0.80, MeOH); H NMR (600 MHz, CDCl3)
δ 9.39 (1H, br s), 3.84 (1H, dd, J = 9.0, 2.4 Hz), 2.98 (1H, dq,
J = 9.0, 6.6 Hz), 2.03 (3H, s), 1.99 (3H, s), 1.36–1.30 (1H, m),
1.28–1.21 (1H, m), 1.18 (3H, d, J = 6.6 Hz), 0.91–0.88 (1H, m),
0.88 (9H, s), 0.86 (3H, d, J = 7.2 Hz), 0.79 (3H, dd, J = 7.8,
7.2 Hz), 0.02 (3H, s), 0.01 (3H, s); 13C NMR (151 Mz, CDCl3)
δ 167.1, 166.5, 161.1, 107.5, 98.5, 78.2, 40.8, 38.2, 26.2, 24.3,
Ethyl (6R,7S,8S)-7-[(tert-butyl)dimethylsilyloxy]-2,4,6,8-
tetramethyl-3,5-dioxodecanoate (19)
18.4, 17.1, 16.0, 12.8, 10.0, 9.0, −3.8, −3.9; IR (KBr, cm−1
)
2961, 2933, 2874, 2859, 1680, 1659, 1573, 1543, 1462, 1379,
1343, 1256, 1177, 1153, 1124, 1080, 1061, 1032, 1006, 936,
854, 836, 777, 758, 695, 670, 619, 514, 472.
To a stirred solution of alcohol (18) (913 mg; 2.19 mmol) in
CH2Cl2 (22 mL) at rt in the dark was added Dess–Martin period-
inane (1.39 g; 3.29 mmol), followed immediately by addition of
a H2O–CH2Cl2 mixture (3.65 mL of sat. aq. CH2Cl2) and
addition of the moist CH2Cl2 continued every 5 min for 1 h (i.e.
12 × 3.65 mL aliquots). The reaction mixture was stirred at rt for
2 days before diluting with Et2O (100 mL). Sat. aq. NaHCO3
(60 mL) containing Na2S2O3·5H2O (7.7 g) was added to quench
the reaction with stirring for 5 min. The layers were separated
and the organic layer was washed with sat. aq. NaHCO3 (60 mL)
and brine (60 mL), dried (Na2SO4) and concentrated in vacuo.
The residue was filtered through buffered silica (100% CH2Cl2)
to afford tricarbonyl (19) (900 mg; 99%) as a clear oil. 1H NMR
(600 MHz, CDCl3) δ 4.20–4.08 (2.5H, m), 4.04, 4.03 (2 ×
0.25H, q, J = 7.2 Hz), 3.95 (0.25H, dd, J = 5.4, 3.6 Hz),
3.88–3.84 (0.5H, m), 3.83 (0.25H, dd, J = 6.0, 3.6 Hz),
3.75–3.70 (0.5H, m), 3.62 (0.25H, q, J = 7.2 Hz), 3.61 (0.25H,
q, J = 7.2 Hz), 2.91–2.86 (0.5H, m), 2.84 (0.25H, dq, J = 6.6,
6.0 Hz), 2.78 (0.25H, dq, J = 7.2, 6.0 Hz), 1.55–1.26 (5.5H, m),
1.25–1.16 (5.5H, m), 1.12–0.79 (1.5H, m), 1.06–1.03 (1.5H, m),
1.07–0.99 (1H, m), 0.88–0.83 (15H, m), 0.03 to −0.03 (6H, s);
13C NMR (151 MHz, CDCl3) δ 210.5, 210.0, 209.1, 208.8,
207.0, 203.40, 203.37, 202.35, 202.29, 195.3, 195.1, 193.2,
192.0, 191.9, 171.0, 170.9, 170.1, 103.6, 103.4, 77.30, 77.27,
77.25, 76.7, 76.0, 75.8, 75.5, 75.4, 75.1, 61.64, 61.62, 61.56,
61.55, 61.29, 61.26, 60.9, 59.2, 58.8, 58.7, 57.5, 53.5, 52.3,
51.6, 50.8, 50.0, 49.8, 49.7, 49.4, 48.8, 48.5, 48.2, 46.1, 45.9,
44.04, 44.00, 42.4, 41.2, 41.10, 41.08, 41.02, 40.9, 40.78,
40.74, 40.71, 40.66, 37.8, 37.4, 37.1, 34.4, 33.7, 32.0, 30.9,
30.4, 29.8, 27.14, 26.12, 26.09, 26.07, 24.72, 24.69, 24.66,
24.59, 24.4, 24.3, 23.3, 18.43, 18.41, 18.39, 18.37, 16.9, 16.24,
16.16, 16.13, 16.09, 16.08, 16.06, 15.99, 15.92, 15.6, 15.5,
14.2, 14.14, 14.11, 14.10, 14.0, 13.9, 13.8, 13.6, 13.5, 13.4,
13.3, 13.18, 13.14, 13.10, 12.91, 12.86, 12.63, 12.57, 12.29,
12.24, 12.15, 12.11, 12.09, 12.04, 8.0, 7.7, 7.4, −3.82, −3.86,
−3.94, −3.96, −4.04, −4.07, −4.10, −4.12.
6-[(1R,2S,3S)-2-Hydroxy-1,3-dimethylpentyl]-4-hydroxy-3,5-
dimethyl-2H-pyran-2-one (21)
To a stirred solution of TBS–ether (20) (193 mg; 523 μmol) in a
1 : 1 mixture of CH3CN–CH2Cl2 (26 mL) at rt was added 40%
aq. HF (2.20 mL) and the resulting mixture stirred at rt for 3.5 h.
The reaction was quenched by addition of H2O (25 mL) and the
mixture was extracted with EtOAc (3 × 40 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo
to give a white slurry, which was triturated with acetone to afford
alcohol (21) (126 mg; 95%) as clear needles. Rf = 0.50 (100%,
EtOAc); mp. 143–145 °C; [α]2D0 = −108.6 (c 1.05, MeOH);
1H NMR (600 MHz, CD3OD) δ 5.13 (1H, br s), 3.63 (1H, dd,
J = 9.0, 3.6 Hz, CHOH), 3.08 (1H, dq, J = 9.0, 6.6 Hz), 1.99
(3H, s), 1.92 (3H, s), 1.46 (1H, ddq, J = 13.2, 7.8, 3.0 Hz), 1.29
(1H, s), 1.27 (3H, d, J = 7.2 Hz), 1.20 (1H, m), 1.09 (1H, ddq,
J = 13.2, 9.6, 7.2 Hz), 0.94 (3H, d, J = 6.6 Hz), 0.84 (3H, dd,
J = 7.8, 7.2 Hz); 13C NMR (151 Mz, CD3OD) δ 168.4, 168.1,
162.0, 109.2, 98.9, 78.9, 39.6, 39.3, 23.8, 17.0, 15.4, 12.4, 10.0,
8.8; IR (KBr, cm−1) 3188, 2962, 2930, 2878, 1662, 1617, 1566,
1460, 1381, 1273, 1213, 1144, 1100, 1031, 996, 963, 944, 881,
765, 707, 672, 579, 520, 473; HRESIMS calculated for
C14H22O4Na+: 277.1410; found 277.1417.
6-[(1S,3S)-1,3-Dimethyl-2-oxopentyl]-4-hydroxy-3,5-dimethyl-
2H-pyran-2-one (22)
To a stirred solution of alcohol (21) (105 mg; 439 μmol) in
acetone (11 mL) at 0 °C was added Jones reagent (760 μL) drop-
wise. The reaction mixture was warmed to rt for 10 min and
quenched by addition of isopropanol (600 μL), followed by
addition of NaHCO3 (600 mg). The solution was filtered and the
filtrate was concentrated in vacuo. The residue was taken up in
Et2O (10 mL), washed with H2O (10 mL), dried (Na2SO4)
and concentrated in vacuo. The crude product was triturated
with hexanes to remove impurities, giving 6-[(1S,3S)-1,3-
dimethyl-2-oxopentyl]-4-hydroxy-3,5-dimethyl-2H-pyran-2-one
(22) (57.5 mg; 55%) as colourless needles. Rf = 0.46 (100%
6-[(1R,2S,3S)-2-[(tert-Butyl)dimethylsilyloxy]-1,3-dimethylpentyl]-
4-hydroxy-3,5-dimethyl-2H-pyran-2-one (20)
To a stirred solution of tricarbonyl (19) (486 mg; 1.17 mmol) in
benzene (12 mL) was added DBU (88 μL; 586 μmol) dropwise,
and the resulting solution heated to 60 °C for 3 h. The reaction
mixture was then cooled to 0 °C and quenched by addition of
1 M HCl (10 mL). The mixture was extracted with EtOAc
(3 × 20 mL) and the combined organic extracts were washed
with brine (2 × 20 mL), dried (Na2SO4) and concentrated
1
EtOAc); mp. 152–154 °C; [α]2D0 = +28.8 (c 1.36, MeOH); H
NMR (600 MHz, CDCl3) δ 8.84 (1H, br s), 3.83 (1H, q), 2.58
(1H, ddq, J = 13.2, 7.2, 6.6 Hz), 2.02 (3H, s), 1.99 (3H, s), 1.59
(1H, ddq, J = 13.8, 7.2, 6.6 Hz,), 1.36 (3H, d, J = 7.2 Hz), 1.34
(1H, m), 0.98 (3H, d, J = 7.2 Hz), 0.81 (3H, t, J = 7.2 Hz,
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CH2CH3); 13C NMR (151 Mz, CDCl3) δ 210.9, 166.4, 165.7,
155.8, 109.6, 99.6, 48.4, 45.5, 27.1, 16.3, 13.5, 11.7, 10.1, 8.9;
IR (KBr, cm−1) 3209, 2934, 2967, 1722, 1662, 1635, 1576,
1455, 1380, 1212, 1176, 1124, 1079, 1041, 971, 871, 755, 478;
HRESIMS calculated for C14H20O4Na+: 275.1254; found:
274.1265.
(60 mL) containing Na2S2O3·5H2O (7.7 g) was added to quench
the reaction with stirring for 5 min. The layers were separated
and the organic layer was washed with sat. aq. NaHCO3 (60 mL)
and brine (60 mL), dried (Na2SO4) and concentrated in vacuo.
The residue was filtered through buffered silica (100% CH2Cl2)
to afford tricarbonyl (30) (720 mg; 95%) as a yellow oil.
1
Enol tautomer H NMR (600 MHz, CDCl3) δ 5.58 (0.5H, s),
5.57 (0.5H, s), 4.14 (2H, q, J = 7.2 Hz), 3.80 (1H, dd, J = 5.4,
4.8 Hz), 3.34 (2 × 0.5H, q, J = 7.2 Hz), 2.48 (1H, dq, J = 7.2,
6.6 Hz), 1.50–1.36 (1H, m), 1.34 (2 × 1.5H, J = 7.2 Hz),
1.32–1.16 (1H, m), 1.22 (3H, t, J = 7.2 Hz), 1.15–1.00 (1H, m),
1.08 (3H, d, J = 7.2 Hz), 0.89–0.80 (15H, m), −0.01 (3H, s),
−0.07 (3H, s), (enol OH not assigned); 13C NMR (151 MHz,
CDCl3) δ 195.07, 194.96, 193.2, 193.0, 170.8, 169.3, 99.3, 98.1,
77.4, 77.04, 77.01, 75.2, 73.8, 73.2, 72.7, 61.35, 61.34, 53.5,
49.7, 49.6, 44.7, 43.9, 43.7, 41.4, 40.6, 38.8, 34.6, 33.2, 30.9,
29.8, 26.1, 25.03, 25.01, −4.1, −4.23, −4.26.
Ethyl (6S,7S,8S)-7-[(tert-butyl)dimethylsilyloxy]-5-hydroxy-2,6,8-
trimethyl-3-oxodecanoate (25)
To a stirred suspension of NaH (170 mg; 7.07 mmol) in THF
(20 mL) at 0 °C was added ethyl-2-methylacetoacetate (572 μL;
4.04 mmol) and the resulting mixture was stirred at 0 °C for
10 min, before cooling to −10 °C. n-BuLi (2.53 mL; 1.6 M in
hexanes; 4.04 mmol) was then added, with stirring at −10 °C for
a further 10 min. The reaction mixture was cooled to −78 °C
and a solution of aldehyde (11) (522.8 mg; 2.02 mmol) in THF
(5 mL) was added dropwise via cannula and the reaction mixture
was stirred at −78 °C for 1 h. The reaction was quenched
by addition of sat. aq. NH4Cl (20 mL) and allowed to warm to
rt. The mixture was extracted with Et2O (4 × 20 mL) and the
combined organic extracts were washed with brine (40 mL),
dried (Na2SO4) and concentrated in vacuo. Residual ethyl-
2-methylacetoacetate was removed under high vacuum and the
residue was filtered through a plug of buffered silica (100%
CH2Cl2) to give a complex mixture of isomers of alcohol (25)
6-[(1R,2S,3S)-2-[(tert-Butyl)dimethylsilyloxy]-1,3-dimethylpentyl]-
4-hydroxy-3-methyl-2H-pyran-2-one (26) and 6-[(1S,2S,3S)-2-
[(tert-butyl)dimethylsilyloxy]-1,3-dimethylpentyl]-4-hydroxy-3-methyl-
2H-pyran-2-one (27)
To a stirred solution of tricarbonyl (30) (337.2 mg; 842 μmol) in
benzene (8.4 mL) was added DBU (63 μL) dropwise, and the
resulting solution heated to 60 °C for 3 h. The reaction mixture
was then cooled to 0 °C and quenched by addition of 1 M HCl
(10 mL). The mixture was extracted with EtOAc (3 × 20 mL)
and the combined organic extracts were washed with brine (2 ×
20 mL), dried (Na2SO4) and concentrated in vacuo. The result-
ing residue was triturated with hexanes to remove any impurities,
resulting in a 78 : 22 mixture of α-pyrones (26) and (27)
(75.1 mg; 25%) as white needles. Rf = 0.31 (10% Et2O/CH2Cl2);
mp. 153–155 °C; [α]D20 = +93.2 (c 0.81, MeOH); 1H NMR
(600 MHz, CDCl3) major isomer: δ 10.41 (1H, br s), 6.22 (1H,
s), 3.82 (1H, dd, J = 4.8, 4.2 Hz), 2.72 (1H, dq, J = 6.6, 5.4 Hz),
1.96 (3H, s), 1.50–1.42 (1H, m), 1.47–1.39 (1H, m), 1.18 (3H,
d, J = 6.6 Hz),1.01–0.94 (1H, m), 0.89 (3H, d, J = 7.2 Hz), 0.86
(3H, dd, J = 7.8, 7.2 Hz) 0.85 (9H, s), 0.00 (3H, s), −0.15 (3H,
s); minor isomer: δ 10.41 (1H, br s), 6.24 (1H, s), 3.80 (1H, dd,
J = 7.2, 3.6 Hz), 2.76–2.71 (1H, m), 1.96 (3H, s), 1.57–1.51
(1H, m), 1.47–1.39 (1H, m), 1.16 (3H, d, J = 7.2 Hz), 1.00–0.94
(1H, m), 0.88 (3H, d, J = 7.2 Hz), 0.86 (3H, dd, J = 7.8, 7.2 Hz)
0.81 (9H, s), 0.01 (3H, s), −0.19 (3H, s); 13C NMR (151 Mz,
CDCl3) major isomer: δ 168.6, 167.4, 166.1, 101.4, 98.8, 77.0,
41.2, 40.5, 26.2, 25.2, 18.3, 15.5, 13.6, 12.4, 8.3, −3.9, −4.4;
minor isomer: δ 168.7, 167.5, 165.8, 102.0, 98.9, 77.8, 43.1,
38.9, 26.1, 24.0, 18.4, 16.0, 15.6, 12.4, 8.3, −3.9, −4.7; IR
(KBr, cm−1) 3153, 2962, 2890, 2859, 2704, 1653, 1590, 1456,
1410, 1372, 1293, 1252, 1173, 1150, 1120, 1084, 1054, 966,
937, 864, 835, 774, 754, 675, 645, 534, 483.
1
(785 mg; 96%) as a yellow oil. H NMR (600 MHz, CDCl3)
δ 4.18–4.14 (2H, m), 4.08–4.04 (0.5H, m), 3.91–3.85 (0.5H, m),
3.84 (0.5H, ddd, J = 6.0, 3.6, 1.8 Hz), 3.68 (0.5H, m), 3.55,
3.54, 3.51, 3.51 (4 × 0.25H, q, J = 7.2 Hz), 2.81 (0.25H, dd,
J = 16.8, 2.4 Hz), 2.77 (0.25H, dd, J = 17.4, 2.4 Hz), 2.72
(0.25H, dd, J = 17.4, 5.4 Hz), 2.72 (0.25H, dd, J = 16.8,
2.4 Hz), 2.65 (0.25H, dd, J = 16.8, 8.4 Hz), 2.64 (0.25H, dd,
J = 17.4, 3.6 Hz), 2.59 (0.25H, dd, J = 15.6, 9.0 Hz), 2.53
(0.25H, dd, J = 17.4, 9.0 Hz), 1.68–1.50 (1H, m), 1.58–1.49
(1H, m), 1.50–1.35 (1H, m), 1.32 (0.75H, d, J = 7.2 Hz), 1.31
(1.5H, d, J = 7.2 Hz), 1.30 (0.75H, d, J = 7.2 Hz), 1.24 (3H, t,
J = 7.2 Hz), 1.11–0.99 (1H, m), 0.89 (1.5H, d, J = 7.2 Hz),
0.88–0.85 (13.5H, m), 0.83 (1.5H, d, J = 7.2 Hz), 0.76 (1.5H, d,
J = 6.6 Hz), 0.06 (1H, s), 0.06 (1H, s), 0.04 (2H, s) 0.04 (2H, s),
(OH not assigned); 13C NMR (151 MHz, CDCl3) δ 207.4,
207.2, 206.64, 206.56, 170.41, 170.35, 170.32, 77.6, 77.5, 75.5,
70.8, 70.5, 69.8, 69.7, 61.54, 61.51, 53.7, 53.52, 53.48, 53.45,
46.6, 46.5, 46.3, 46.1, 43.9, 40.9, 40.8, 40.7, 40.6, 39.67, 39.66,
39.64, 39.58, 38.8, 26.2, 26.1, 25.9, 25.71, 25.66, 23.34, 23.33,
23.32, 22.8, 22.3, 18.45, 18.42, 18.41, 15.89, 15.87, 15.38,
15.36, 14.2, 12.8, 12.68, 12.63, 12.60, 12.4, 12.1, 11.4, 9.9, 9.8,
−3.5, −3.99, −4.02, −4.11, −4.13, −4.22, −4.24.
Ethyl (6R,7S,8S)-7-[(tert-butyl)dimethylsilyloxy]-2,6,8-trimethyl-
3,5-dioxodecanoate (30)
To a stirred solution of alcohol (25) (762 mg; 1.89 mmol) in
CH2Cl2 (19 mL) at rt in the dark was added Dess–Martin period-
inane (1.20 g; 2.84 mmol), followed immediately by addition of
a H2O–CH2Cl2 mixture (3.15 mL of sat. aq. CH2Cl2) and
addition of the moist CH2Cl2 continued every 5 min for 1 h (i.e.
12 × 3.15 mL aliquots). The reaction mixture was stirred at rt for
2 days before diluting with Et2O (100 mL). Sat. aq. NaHCO3
6-[(1R,2S,3S)-2-Hydroxy-1,3-dimethylpentyl]-4-hydroxy-3-methyl-
2H-pyran-2-one (31) and 6-[(1S,2S,3S)-2-hydroxy-1,3-dimethylpentyl]-
4-hydroxy-3-methyl-2H-pyran-2-one (32)
To a stirred solution of a 78 : 22 mixture of TBS–ethers (26) and
(27) (98.7 mg; 297 μmol) in a 1 : 1 mixture of CH3CN–CH2Cl2
6552 | Org. Biomol. Chem., 2012, 10, 6547–6553
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(15 mL) at rt was added 40% aq. HF (1.30 mL) and the resulting
mixture was stirred at rt for 3.5 h. The reaction was quenched by
addition of H2O (15 mL) and the mixture was extracted with
EtOAc (3 × 30 mL). The combined organic extracted were dried
(Na2SO4) and concentrated in vacuo to give a white slurry,
which was triturated with acetone to afford alcohol (31) (as a
mixture with its C6 epimer 32) (66.9 mg; 96%) as a white
J = 7.2 Hz), 1.35 (1H, m), 1.07 (3H, d, J = 7.2 Hz), 0.80 (3H, t,
J = 7.2 Hz); 13C NMR (151 Mz, CDCl3) major isomer: δ 211.6,
167.8, 166.5, 160.8, 101.8, 99.9, 49.4, 47.1, 26.1, 16.0, 14.4,
11.7, 8.3; minor isomer: δ 211.4, 167.8, 166.4, 160.7, 101.8,
99.9, 49.2, 47.0, 25.8, 16.5, 14.6, 11.7, 8.3; IR (KBr, cm−1
)
2970, 2933, 2879, 2668, 1718, 1665, 1632, 1569, 1459, 1271,
1242, 1181, 1141, 1099, 1028, 994, 949, 936, 859, 757, 617,
565, 531; HRESIMS calculated for C13H18O4Na+: 261.1097;
found: 261.1109.
powder. Rf = 0.46 (100%, EtOAc); mp. 212–214 °C; [α]D20
=
+51.4 (c 0.92, MeOH); 1H NMR (600 MHz, CD3OD) major
isomer: δ 6.06 (1H, s), 5.24 (1H, br s), 3.57 (1H, dd, J = 6.6,
5.4 Hz), 3.45 (1H, s), 2.71 (1H, dq, J = 7.2, 6.6 Hz), 1.85 (3H,
s), 1.68 (1H, ddq, J = 13.2, 7.8, 3.0 Hz), 1.40–1.35 (1H, m),
1.27 (3H, d, J = 6.6 Hz), 1.17–1.10 (1H, m), 0.92 (3H, d, J =
6.6 Hz), 0.89 (3H, dd, J = 7.8, 7.2 Hz); minor isomer: δ 6.11
(1H, s), 5.24 (1H, br s), 3.51 (1H, dd, J = 7,2, 4.8 Hz),
3.35 (1H, s), 2.80–2.75 (1H, m), 1.85 (3H, s), 1.57 (1H, ddq,
J = 13.2, 7.8, 3.0 Hz), 1.55–1.49 (1H, m), 1.20 (3H, d, J =
7.2 Hz), 1.17–1.10 (1H, m), 0.98 (3H, d, J = 7.2 Hz), 0.92 (3H,
dd, J = 7.8, 7.2 Hz); 13C NMR (151 Mz, CDCl3) major isomer:
δ 169.1, 168.1, 167.0, 101.4, 99.1, 77.4, 42.0, 39.1, 25.1, 16.0,
12.1, 11.7, 8.2; minor isomer: δ 169.3, 168.2, 167.4, 102.2,
99.1, 78.4, 43.0, 38.2, 23.5, 16.6, 16.3, 11.9, 8.2; IR (KBr,
cm−1) 3149, 1973, 2924, 2882, 2729, 1682, 1660, 1593, 1462,
1414, 1391, 1299, 1270, 1233, 1178, 1114, 1076, 1045, 974,
957, 935, 826, 748, 680, 634, 535; HRESIMS calculated for
C13H20O4Na+: 263.1254; found: 263.1263.
Acknowledgements
The authors thank the Australian Research Council (Grant
DP0771098) and Flinders University for financial support and
the Bragg X-ray Crystallography Facility for crystallography
assistance. C. G. acknowledges the receipt of an Australian Post
Graduate Research Award.
Notes and references
1 G. P. McGlacken and I. J. S. Fairlamb, Nat. Prod. Rep., 2005, 22,
369–385.
2 A. S. Bourinbaiar, X. Tan and R. Nagorny, Acta Virol., 1993, 37, 241.
3 G. Appendino, M. Ottino, N. Marquez, F. Bianchi, A. Giana, M. Ballero,
O. Sterner, B. L. Fiebich and E. Munoz, J. Nat. Prod., 2007, 70,
608–612.
4 S. Tira, G. Di Modica, C. G. Casinovi, C. Galeffi and A. Pela, Tetra-
hedron Lett., 1967, 8, 143–148.
5 P. Manitto, D. Monti and E. Colombo, Phytochemistry, 1972, 11,
2112–2114.
6-[(1S,3S)-1,3-Dimethyl-2-oxopentyl]-4-hydroxy-3-methyl-2H-
pyran-2-one (28)
6 C. Osterhage, R. Kaminsky, G. M. König and A. D. Wright, J. Org.
Chem., 2000, 65, 6412–6417.
7 S. F. Seibert, E. Eguereva, A. Krick, S. Kehraus, E. Voloshina, G. Raabe,
J. Fleischhauer, E. Leistner, M. Wiese, H. Prinz, K. Alexandrov,
P. Janning, H. Waldmann and G. M. Konig, Org. Biomol. Chem., 2006,
4, 2233–2240.
8 J. R. Gage and D. A. Evans, Org. Synth., 1989, 68, 77.
9 D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103,
2127.
10 D. A. Evans, Aldrichimica Acta, 1982, 15, 23.
11 A. J. Mancuso and D. Swern, Synthesis, 1981, 165.
12 W. R. Roush, J. Org. Chem., 1991, 56, 4151.
13 S. D. Rychnovsky, T. I. Richardson and B. N. Rogers, J. Org. Chem.,
1997, 62, 2925.
14 (a) E. J. Corey, H. Cho, C. Rucker and D. H. Hua, Tetrahedron Lett.,
1981, 22, 3455; (b) E. J. Corey and A. Venkateswarlu, J. Am. Chem.
Soc., 1972, 94, 6190.
15 K. Kinoshita, C. Khosla and D. E. Cane, Helv. Chim. Acta, 2003, 86,
3889.
16 J. R. Hanley, H. S. Killam, R. D. Lanyon and S. MacKenzie, J. Org.
Chem., 1958, 23, 1461.
17 (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155–4156;
(b) D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113,
7277–7287.
To a stirred solution of alcohol (31) (as a mixture with its C6
epimer 32) (56.8 mg; 236 μmol) in acetone (6 mL) at 0 °C was
added Jones reagent (410 μL) dropwise. The reaction mixture
was warmed to rt for 10 min and quenched by addition of iso-
propanol (300 μL), followed by addition of NaHCO3 (300 mg).
The solution was filtered and the filtrate was concentrated
in vacuo. The residue was taken up in Et2O (10 mL), washed
with H2O (10 mL), dried (Na2SO4) and concentrated in vacuo.
The crude product was triturated with hexanes to remove impuri-
ties, giving 6-[(1S,3S)-1,3-dimethyl-2-oxopentyl]-4-hydroxy-
3-methyl-2H-pyran-2-one (28) (31.3 mg; 56%) as a yellow
powder. Rf = 0.54 (100% EtOAc); mp. 115–117 °C; [α]D20
=
+60.7 (c 1.57, MeOH); 1H NMR (600 MHz, CDCl3) major
isomer: δ 9.91 (1H, br s), 6.25 (1H, s), 3.80 (1H, q, J = 7.2 Hz),
2.70 (1H, ddq, J = 13.8, 7.2, 6.6 Hz), 1.94 (3H, s), 1.67 (1H,
ddq, J = 13.8, 7.8, 6.6 Hz), 1.38 (1H, m), 1.36 (3H, d, J =
7.2 Hz), 1.05 (3H, d, J = 6.6 Hz), 0.85 (3H, dd, J = 7.8, 7.2 Hz);
minor isomer: δ 9.91 (1H, br s), 6.25 (1H, s), 3.81 (1H, q, J =
7.2 Hz), 2.68 (1H, m), 1.94 (3H, s), 1.68 (1H, m), 1.35 (3H, d,
18 R. L. Shone, J. R. Deason and M. Miyano, J. Org. Chem., 1986, 51, 268.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6547–6553 | 6553