Total synthesis of a 6,6-spiroketal metabolite, dinemasone A

Article abstract of DOI:10.1002/ejoc.201201246

The stereoselective total synthesis of dinemasone A has been accomplished. The key reactions, Sharpless asymmetric epoxidation, lithium-mediated epoxy alcohol opening, and double-intramolecular hetero-Michael addition, gave access to dinemasone A from lac

Full text of DOI:10.1002/ejoc.201201246

FULL PAPER
DOI: 10.1002/ejoc.201201246
Total Synthesis of a 6,6-Spiroketal Metabolite, Dinemasone A
Chada Raji Reddy,*[a] Boinapally Srikanth,[a] Uredi Dilipkumar,[a]
Kakita Veera Mohana Rao,[b] and Bharatam Jagadeesh[b]
Keywords: Total synthesis / Asymmetric synthesis / Natural products / Spiro compounds / Michael addition
The stereoselective total synthesis of dinemasone A has been
accomplished. The key reactions, Sharpless asymmetric
epoxidation, lithium-mediated epoxy alcohol opening, and
double-intramolecular hetero-Michael addition, gave access
to dinemasone A from lactic acid esters. The stereochemistry
at the spiro carbon was determined using extensive NMR
studies.
Introduction
Spiroketal-containing natural products constitute an im-
portant class of bio-active molecules, due to their remark-
able and diverse biological activities.[1] The majority of
these compounds are non-racemic chiral molecules isolated
from various sources, including plants, insects, microbes,
fungi, marine organisms etc. As a result of their pharmaco-
logical significance, spiroketals have been of substantial
interest to synthetic organic chemists as well as medicinal
chemists.[2] Dinemasones A–C (1–3, Figure 1) are anti-mi-
crobial metabolites isolated from the ethyl acetate extracts
of a culture of the endophytic fungus, Dinemasporium stri-
gosum, which had been isolated from the roots of Calystegia
sepium.[3] The absolute configurations were established by
their carbonyl n–π* CD transitions and the exciton chirality
of their respective dibenzoate derivatives. One of these three
natural products, dinemasone A (1), has a [6,6]-spiroketal
skeleton containing five stereogenic centres. The presence
of a hydroxy group on the carbon adjacent to the spiroketal
carbon (quaternary carbon) is a unique feature of this natu-
ral product. Furthermore, 1 has shown considerable activity
against the Gram-positive bacterium Bacillus megaterium,
the fungus Microbotryum violaceum, and the alga Chlorella
fusca. The above features of 1 combined with our interest
in the synthesis of tetrahydropyran-containing natural
products[4] spurred us to synthesise dinemasone A.[5]
Figure 1. Structure of dinemasones A–C.
In this paper, we report the enantioselective total synthe-
sis of dinemasone A (1) using double-intramolecular het-
ero-Michael addition[6] as the key step.
Results and Discussion
As shown in Scheme 1, dinemasone A (1) was envisioned
to arise from ynone 4 by double-intramolecular hetero-
Michael addition. Enyne 4 was intended to come from alde-
hyde 5 and alkyne 6, which in turn could be obtained from
ethyl (–)-l-lactate and methyl (+)-d-lactate, respectively.
The desired propargylic alcohol functionality in 6 would
be obtained using Sharpless asymmetric epoxidation and
lithium-mediated opening of the epoxy alcohol as the key
steps.
[a] Division of Natural Products Chemistry, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500607, India
Fax: +91-40-27160512
E-mail: rajireddy@iict.res.in
Homepage: www.iictindia.org
[b] Center of Nuclear Magnetic Resonance,
CSIR – Indian Institute of Chemical Technology,
Hyderabad 500007, India
As outlined in Scheme 2, aldehyde fragment 5 was pre-
pared by a sequence of high-yielding steps. Following a lit-
erature procedure,[7] we prepared allylic alcohol 10 starting
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201246.
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C. Raji Reddy et al.
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93% yield. Next, ester 14 was again subjected to DIBAL-H
reduction and subsequent two-carbon homologation with
Ph3P=CHCOOEt to obtain exclusively (E)-α,β-unsaturated
ester 15 in 80% yield over two steps. The ester functionality
in 15 was selectively reduced to give allylic alcohol 16 using
DIBAL-H in dichloromethane (89%). The required chiral
epoxide was introduced at this stage by Sharpless catalytic
asymmetric epoxidation[8] using (+)-diethylisopropyl tar-
trate to yield epoxide 17 in 78% yield and with good dia-
stereoselectivity (dr Ͼ 95:5). The conversion of epoxy
alcohol 17 to chloro epoxide 18 was accomplished by treat-
ment with Ph3P in CCl4 at refluxing temperature (72%).
Treatment of chloro epoxide 18 with nBuLi in THF at
–78 °C gave the desired propargylic alcohol (i.e., 19) in 70%
yield.[9] Protection of the hydroxy group in 19 as its benzyl
ether provided the alkyne fragment (i.e., 6) in 72% yield.
Scheme 1. Retrosynthesis of dinemasone A.
from (–)-ethyl l-lactate (7) via ester 9. Alcohol 10 was ob-
tained with a 6:1 (anti/syn) diastereomeric ratio (in 72%
combined yield), and the diastereomers were separated at
the next stage. Benzyl protection of allylic alcohol 10 using
BnBr/Ag2O in dichloromethane at reflux temperature pro-
vided the desired benzyl ether (i.e., 11) in 71% yield. Oxi-
dative cleavage of the terminal double bond in 11 under
ozonolysis conditions gave aldehyde 5, which was used im-
mediately in the next step.
Scheme 3. Synthesis of fragment 6; Reagents and conditions:
(a) TBSCl, imidazole, CH2Cl2, 0 °C to room temp., 12 h, 91%;
(b) (i) DIBAL-H, CH2Cl2, –78 °C, 30 min; (ii) PPh3=CHCOOEt,
CH2Cl2, reflux, 1 h, 85% (over two steps); (c) H2, Pd-C, EtOH,
room temp., 4 h, 93%; (d) (i) DIBAL-H, CH2Cl2, –78 °C, 30 min;
(ii) PPh3=CHCOOEt, CH2Cl2, room temp., 12 h, 80% (over two
steps); (e) DIBAL-H, CH2Cl2, –78 °C to –20 °C, 1 h, 89%; (f) (+)-
DIPT, Ti(OiPr)4, TBHP, –20 °C, 4 h, 78%; (g) PPh3, CCl4,
NaHCO3, reflux, 3 h, 72%; (h) nBuLi, THF, –78 °C, 5 h, 70%;
(i) BnBr, NaH, TBAI, DMF, 0 °C to room temp., 12 h, 72% (DIPT
= diisopropyl tartrate; TBHP = tert-butyl hydroperoxide; TBAI =
tetrabutylammonium iodide).
Scheme 2. Synthesis of fragment 5; Reagents and conditions:
(a) TBSCl, imidazole, CH2Cl2, 0 °C to room temp., 12 h, 90%;
(b) (i) DIBAL-H, CH2Cl2, –78 °C, 1 h; (ii) vinylmagnesium brom-
ide, THF, –78 °C, 1 h, 72% (over two steps); (c) BnBr, Ag2O,
CH2Cl2, reflux, 24 h, 71% (yield of desired isomer); (d) O3/DMS,
CH2Cl2, –78 °C, 15 min, 82% (TBSCl = tert-butyldimethylsilyl
chloride; DIBAL-H = diisobutylaluminium hydride).
The synthesis of alkyne fragment 6 began with commer-
cially available (+)-methyl d-lactate, which was initially pro-
tected as its tert-butyldimethylsilyl ether (i.e., 12) using
TBSCl/imidazole in CH2Cl2 (91% yield; Scheme 3). The in-
stallation of the additional four-carbon chain was ac-
Having achieved the synthesis of both aldehyde 5 and
complished with sequential Wittig reactions. Thus, the re- alkyne 6, the coupling of these two units to give ynone 4
duction of ester 12 to the aldehyde, followed by the treat- was planned (Scheme 4). Thus, alkyne 6 was lithiated using
ment with the two-carbon ylide, ethoxycarbonyl methylene nBuLi, and the resulting anion underwent addition with al-
triphenylphosphorane (Ph3P=CHCOOEt), gave α,β-unsat- dehyde 5 to give propargylic alcohol 20 as a diastereomeric
urated ester 13 in 85% yield (E/Z = 9:1). Reduction of the mixture (1:1, 77%). This product was immediately oxidised
olefin functionality in 13 by hydrogenation gave ester 14 in with Dess–Martin periodinane[10] to give alkynone 4 in 85%
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Total Synthesis of a 6,6-Spiroketal Metabolite, Dinemasone A
yield. The conversion of compound 4 into spiroketal 22 was including 2D NMR spectroscopic techniques, COSY,
initially attempted in one pot under various acidic condi- HSQC, and NOESY (Figure 2),[11] were in full agreement
tions. However, all of these reactions resulted either in com- with those reported for natural dinemasone A. The specific
plex mixtures or in no reaction. Therefore, a two-step se- rotation observed for synthetic 1, [α]2D0 = –79.3 (c = 0.21,
quence was considered for this transformation. The reac- CHCl3) was also comparable with the reported value for
tion of 4 with aqueous HF in acetonitrile promoted the the natural product[3] {[α]D25 = –80.4 (c = 0.68, CHCl3)}.
desilylation of both silyl groups to give diol 21 in 88% yield.
The crucial spiroketalisation reaction was carried out by
treatment of 21 with pTSA·H2O in toluene at room tem-
perature for 24 h, which provided a seperable mixture of
two spiroketals 22 and 22a (3:7 ratio) in 89% combined
yield through double-intramolecular hetero-Michael ad-
dition.[6] At this juncture, we decided to carry out a debenz-
ylation to reach the target molecule, so that the characteri-
sation data of the synthetic product and the natural product
could be compared. Accordingly, spiroketals 22 and 22a
were independently subjected to debenzylation using 10%
Pd-C under a hydrogen atmosphere in ethyl acetate to give
diols 1 (78%) and 1a (76%), respectively. The spectroscopic
data of 1 (1H and 13C NMR, mass spectrometry, and IR)
Figure 2. (a) nOes observed for 1; (b) energy-minimised MD struc-
ture of 1.
Diol 1a was also analysed using 1D and 2D NMR spec-
troscopic techniques, COSY, HSQC and NOESY. Re-
strained MD simulation, with the help of observed NOE
cross-peaks between 2-H–10a-H, 2-HϪ10e-H, 8-HϪ10a-H,
3
11-HϪ5e-H, 3-HϪ5a-H, and 11-HϪ5a-H, as well as JH,H
couplings (Figure 3), suggest that the stereochemistry at C-
6 is “R”. This stereochemistry is “S” in the natural com-
pound, and therefore compound 1a is confirmed to be 6-
epi-dinemasone A (1a).
Figure 3. (a) nOes observed for 1a; (b) energy-minimised MD
structure of 1a.
The above results showed that unnatural 6-epi-dinema-
sone A was obtained as the major isomer, due to the favour-
able formation of axial–equatorial mono-anomeric spiroke-
tal 22a over axial–axial doubly anomeric spiroketal 22 (re-
Scheme 4. Coupling of 5 and 6. Reagents and conditions: (a) nBuLi,
quired for dinemasone A). This can be explained by con-
sidering the two possible transition states during the acid-
catalysed spiroketalisation of 21.[2f] The minor formation of
doubly anomeric spiroketal 22 through axial attack may be
due to unfavourable steric interactions between the axial C-
8-methyl group and the axial C-2-hydrogen (22-TS, Fig-
THF, –78 °C to room temp., 1 h, 77%; (b) Dess–Martin
periodinane, CH2Cl2, room temp., 30 min, 85%; (c) HF (aq.),
CH3CN, room temp., 5 h, 88%; (d) pTSA, toluene, room temp.,
24 h, 89% (combined yield); (e) Pd-C (10%), H2, EtOAc, room
temp., 12 h, 95% for 1; 93% for 1a; (f) ZnBr2, CH2Cl2, room temp.,
5 h, (1/1a, 2:1; 90% combined yield) (pTSA = p-toluenesulfnic
acid).
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C. Raji Reddy et al.
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grade EtOAc and hexanes used for column chromatography were
distilled before use. THF, when used as solvent for the reactions,
was freshly distilled from sodium benzophenone ketyl. Column
chromatography was carried on silica gel (60–120 mesh) packed in
glass columns. All the reactions were performed under N2 in flame-
dried or oven-dried glassware with magnetic stirring.
ure 4). As a result, the favourable mode of attack is equato-
rial attack (22a-TS) to give mono-anomeric spiroketal 22a,
which leads to the undesired 6-epi-dinemasone A (i.e., 1a).
However, the conversion of 1a into the desired natural
product, i.e., dinemasone A (1), was also accomplished by
equilibration using a Lewis acid.[12] After treatment with
zinc(II) bromide in dichloromethane for 5 h, a separable
mixture of epimers was formed in a 2:1 ratio in favour of
the desired dinemasone A (1, Scheme 4).[13] Prolonging the
reaction time or increasing the amount of the Lewis acid
did not improve the formation of 1, but simply promoted
the slow decomposition of the products (as observed in
TLC monitoring).
Ethyl (S)-2-(tert-Butyldimethylsilyloxy)propanoate (9): Imidazole
(2.0 g, 29.4 mmol) and then tert-butyldimethylsilyl chloride (4.2 g,
27.9 mmol) were added to a stirred solution of S-ethyl lactate 7
(3 g, 25.4 mmol) in dichloromethane (30 mL) at 0 °C. Then the re-
action temperature was raised to 25 °C and the mixture was stirred
for 12 h. The reaction was diluted with water (30 mL), and the
phases were separated. The organic phase was further washed with
brine (20 mL), dried with anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The crude residue was purified by
flash chromatography (5% ethyl acetate in hexanes) to give 9 (5.3 g,
90%) as a colourless liquid. IR (neat): ν = 2934, 2858, 1724, 1659,
˜
1467, 1261, 1155, 1094, 834, 778 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 4.5 (q, J = 7.0 Hz, 1 H), 4.15 (q, J = 4.0 Hz, 2 H),
1.36 (d, J = 7.0 Hz, 3 H), 1.27 (t, J = 7.0 Hz, 3 H), 0.89 (s, 9 H),
0.07 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
173.6, 68.2, 60.3, 25.4, 21.0, 18.0, 13.9, –5.1, –5.5 ppm. MS (ESI):
m/z = 255 [M + Na]+.
(3R,4S)-4-(tert-Butyldimethylsilyloxy)pent-1-en-3-ol (10): DIBAL-
H (25% solution in toluene, 4.9 mL, 8.6 mmol) was added to a
stirred solution of silyl ether 9 (2 g, 8.6 mmol) in dry dichlorometh-
ane (20 mL) at –78 °C. The reaction mixture was maintained at
same temperature for an additional 30 min, and then the reaction
was quenched with a saturated aqueous solution of potassium so-
dium tartrate (10 mL). The mixture was left to stir for 3 h until the
organic and aqueous phases had completely separated. The organic
phase was washed with brine (20 mL), dried with Na2SO4, filtered,
and concentrated under reduced pressure to give the crude product.
The crude residue was purified by flash chromatography (10% ethyl
acetate in hexanes) to give the corresponding aldehyde (1.3 g) as a
colourless oil.
Figure 4. Possible transition states in the spiroketalisation of 21.
Conclusions
In summary, we have described a stereoselective total
synthesis of dinemasone A and its 6-epimer. Key features
of the synthesis are: i) formation of both of the the required
fragments from lactic acid esters; ii) the use of double intra-
molecular hetero-Michael addition for spiroketalisation.
The major diastereomer obtained in the synthesis, 6-epi-di-
nemasone A, was transformed to dinemasone A by equili-
bration with ZnBr2. The synthesis required 18 steps with a
longest linear sequence of 14 steps. The overall yield of the
longest linear sequence for the synthesis of dinemasone A
was 5.2%.
Vinylmagnesium bromide (1 m in THF, 9 mL, 9.0 mmol) was added
to a stirred solution of the above aldehyde in dry tetrahydrofuran
(15 mL) at –78 °C. Stirring was continued for 1 h at the same tem-
perature, and then the reaction was quenched with saturated aque-
ous NH4Cl (20 mL). The phases were separated, and the aqueous
phase was extracted with ethyl acetate (3ϫ 20 mL). The combined
organic extracts were washed with brine (20 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude residue was purified by column chromatography (5% ethyl
acetate in hexanes) to give 10 (1.3 g, 72%; syn:anti = 1:6) as a
colourless oil. IR (neat): ν = 3454, 2930, 2858, 1463, 1378, 1256,
˜
1
1094, 1006, 937, 835, 775 cm–1. H NMR (500 MHz, CDCl3): δ =
5.78 (ddd, J = 6.0, 10.5, 17.3 Hz, 1 H), 5.27 (dd, J = 1.5, 17.3 Hz,
1 H), 5.17 (dd, J = 1.5, 10.5 Hz, 1 H), 4.01–3.95 (m, 1 H), 3.87–
3.78 (m, 1 H), 2.09 (d, J = 3.7 Hz, 1 H), 1.07 (d, J = 6.0 Hz, 3 H),
0.90 (s, 9 H), 0.08 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
136.2, 116.1, 76.3, 71.0, 25.4, 17.7, 17.3, –4.7, –5.1 ppm. MS (ESI):
m/z = 239 [M + Na]+.
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded in
CDCl3 with Bruker 300 MHz (Avance), Varian Unity 500 MHz
(Innova), Bruker 600 MHz, and Bruker 700 MHz spectrometers at
ambient temperature. Chemical shifts are reported in ppm relative
to TMS as internal standard. FTIR spectra were recorded with a
Perkin–Elmer 683 infra-red spectrometer, using neat compounds or
as thin films on KBr plates. Optical rotations were measured with
an Anton Paar MLP 200 modular circular digital polarimeter using
a 2 mL cell with a path length of 1 dm. Low-resolution MS were
recorded with an Agilent Technologies LC-MSD trap SL spectrom-
eter. All the reagents and solvents were of reagent grade, and were
used without further purification unless otherwise stated. Technical
[(2S,3R)-3-(Benzyloxy)pent-4-en-2-yloxy](tert-butyl)dimethylsilane
(11): Silver oxide (1.92 g, 8.33 mmol) and benzyl bromide (0.55 mL,
4.58 mmol) were added to a stirred solution of compound 10
(900 mg, 4.16 mmol) in dichloromethane (10 mL) at room tempera-
ture. Then, the reaction temperature was raised to reflux, and the
mixture was stirred for 24 h. The reaction mixture was filtered, and
concentrated under reduced pressure. The crude residue was puri-
fied by flash chromatography (2% ethyl acetate in hexanes) to give
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Total Synthesis of a 6,6-Spiroketal Metabolite, Dinemasone A
pure 11 (0.90 g, 83%) as a colourless liquid. [α]2D0 = –14.8 (c = 0.5,
21.2, 18.1, 14.2, –4.91, –4.98 ppm. MS (ESI): m/z = 281 [M + Na]+.
CHCl ). IR (neat): ν = 2929, 2856, 1458, 1255, 1112, 1053, 834,
HRMS-ESI: calcd. for C13H26O3NaSi [M + Na]+ 281.1548; found
˜
3
776 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.36–7.30 (m, 4 H), 281.1552.
7.29–7.25 (m, 1 H), 5.80 (ddd, J = 7.2, 10.5, 17.7 Hz, 1 H), 5.30
Ethyl (R)-4-(tert-Butyldimethylsilyloxy)pentanoate (14): Palladium
(d, J = 10.5 Hz, 1 H), 5.25 (d, J = 17.7 Hz, 1 H), 4.62 (d, J =
12.1 Hz, 1 H), 4.42 (d, J = 12.1 Hz, 1 H), 3.87–3.81 (m, 1 H), 3.57
(t, J = 5.6 Hz, 1 H), 1.18 (d, J = 6.4 Hz, 3 H), 0.88 (s, 9 H), 0.05
(s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.7,
136.4, 128.2, 127.6, 127.3, 118.5, 85.1, 70.8, 70.4, 25.8, 20.1, 18.1,
–4.52, –4.58 ppm. MS (ESI): m/z = 329 [M + Na]+.
on carbon (10% by weight, 500 mg) was added to a solution of
α,β-unsaturated ester 13 (4 g, 15.5 mmol) in ethanol (20 mL). The
reaction mixture was stirred for 4 h under a hydrogen atmosphere.
After completion of the reaction, the mixture was filtered through
Celite, and the filtrate was concentrated in vacuo. Flash chromatog-
raphy of the residue on silica gel (5% ethyl acetate in hexanes) gave
14 (3.7 g, 93%) as a colourless oil. [α]2D0 = –15.2 (c = 0.5, CHCl3).
(2S,3S)-2-(Benzyloxy)-3-[(tert-butyldimethylsilyl)oxy]butanal (5): A
solution of 11 (120 mg, 0.39 mmol) in CH2Cl2 (5 mL) was treated
at –78 °C with a stream of ozone until the starting material had
been consumed (as monitored by TLC). Then, dimethyl sulfide
(DMS, 2.5 mL) was added to the reaction mixture to reduce the
ozonide. The reaction mixture was allowed to warm slowly to room
temperature and then it was diluted with water (5 mL). The mixture
was extracted with CH2Cl2 (2ϫ 5 mL). The combined organic ex-
tracts were washed with brine (5 mL), dried with Na2SO4, and fil-
tered, and the filtrate was concentrated under reduced pressure to
give aldehyde 5 (100 mg, 82%), which was used immediately for the
preparation of 4.
IR (neat): ν = 2931, 2858, 1739, 1463, 1373, 1256, 1176, 1091, 836,
˜
1
775 cm–1. H NMR (500 MHz, CDCl3): δ = 4.1 (q, J = 7.5 Hz, 2
H), 3.89–3.78 (m, 1 H), 2.32 (t, J = 7.5 Hz, 2 H), 1.80–1.59 (m, 2
H), 1.26 (t, J = 7.5 Hz, 3 H), 1.13 (d, J = 6.0 Hz, 3 H), 0.88 (s, 9
H), 0.03 (d, J = 2.2 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 173.7, 67.3, 60.0, 34.2, 30.3, 25.7, 23.5, 17.9, 14.1, –4.5, –4.9 ppm.
MS (ESI): m/z = 283 [M + Na]+. HRMS-ESI: calcd. for
C13H28O3NaSi [M + Na]+ 283.1699; found 283.1692.
Ethyl
(R,E)-6-(tert-Butyldimethylsilyloxy)hept-2-enoate
(15):
DIBAL-H (25% solution in toluene, 7.6 mL, 13.4 mmol) was
added to a stirred solution of ester 14 (3.5 g, 13.4 mmol) in dry
dichloromethane (35 mL) at –78 °C. The reaction mixture was
stirred at same temperature for an additional 30 min, and then the
reaction was quenched with a saturated aqueous solution of potas-
sium sodium tartrate (20 mL). The mixture was left to stir for 3 h
until the organic and aqueous phases were completely separated.
The organic layer was washed with brine (15 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure to give
the crude product.
Methyl (R)-2-(tert-Butyldimethylsilyloxy)propanoate (12): Imid-
azole (3.9 g, 57.6 mmol) and then tert-butyldimethylsilyl chloride
(7.9 g, 52.8 mmol) were added to a stirred solution of d-methyl
lactate 7 (5 g, 48.0 mmol) in dichloromethane (50 mL) at 0 °C.
Then the reaction temperature was raised to 25 °C, and the mixture
was stirred for 12 h. After complete disappearance of the starting
material, the reaction was diluted with water (50 mL), and the lay-
ers were separated. The organic layer was washed with brine
(50 mL), dried with anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was purified by flash
chromatography (5% ethyl acetate in hexanes) to give 12 (9.5 g,
A mixture of the above crude aldehyde (3.2 g) and (ethoxycarbonyl-
methylene)triphenylphosphorane (6.2 g, 17.8 mmol) in dichloro-
methane (30 mL) was stirred for 12 h. The reaction mixture was
diluted with hexane and filtered through a pad of Celite. The fil-
trate was concentrated in vacuo, and the residue was purified by
column chromatography (5% ethyl acetate in hexanes) to give E
α,β-unsaturated ester 15 (3.1 g, 80% over two steps) as a colourless
91%) as a colourless liquid. IR (neat): ν = 2954, 2931, 2858, 1760,
˜
1463, 1257, 1148, 837, 779 cm–1. 1H NMR (500 MHz, CDCl3): δ =
4.28 (q, J = 6.7 Hz, 1 H), 3.70 (s, 3 H), 1.37 (d, J = 6.7 Hz, 3 H),
0.89 (s, 9 H), 0.08 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 174.3, 68.2, 51.6, 25.6, 21.2, 18.1, –5.0, –5.3 ppm. MS
(ESI): m/z = 241 [M + Na]+.
oil. [α]2D0 = –13.2 (c = 0.5, CHCl ). IR (neat): ν = 2930, 2857, 1722,
˜
3
1654, 1369, 1258, 1046, 835, 775 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 6.98–6.88 (m, 1 H), 5.78 (d, J = 15.4 Hz, 1 H), 4.16
(q, J = 6.7 Hz, 2 H), 3.86–3.78 (m, 1 H), 2.34–2.16 (m, 2 H), 1.62–
1.49 (m, 2 H), 1.28 (t, J = 6.7 Hz, 3 H), 1.14 (d, J = 6.7 Hz, 3 H),
0.88 (s, 9 H), 0.04 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.4, 149.0, 121.0, 67.6, 59.8, 37.6, 28.2, 25.6, 23.5, 17.8, 14.1,
–4.4, –4.9 ppm. MS (ESI): m/z = 309 [M + Na]+. HRMS-ESI:
calcd. for C15H30O3NaSi [M + Na]+ 309.1861; found 309.1870.
Ethyl
(R,E)-4-(tert-Butyldimethylsilyloxy)pent-2-enoate
(13):
DIBAL-H (25% solution in toluene, 13 mL, 22.9 mmol) was added
to a stirred solution of silyl ether 12 (5 g, 22.9 mmol) in dry dichlo-
romethane (50 mL) at –78 °C. The reaction mixture was stirred at
same temperature for an additional 30 min, and then the reaction
was quenched with a saturated aqueous solution of potassium so-
dium tartrate (20 mL). The mixture was left to stir for 4 h until the
organic and aqueous phases had completely separated. The organic
phase was washed with brine (30 mL), dried with Na2SO4, filtered,
and concentrated under reduced pressure to give the crude product.
(R,E)-6-(tert-Butyldimethylsilyloxy)hept-2-en-1-ol (16): DIBAL-H
(25% solution in toluene, 13.4 mL, 23.5 mmol) was added to a
stirred solution of ester 15 (2.7 g, 9.4 mmol) in dry dichlorometh-
ane (30 mL) at –78 °C. The reaction mixture was slowly warmed
to –20 °C and stirred for 1 h, then the reaction was quenched with
A mixture of the above crude aldehyde (4.3 g) and (ethoxycarbonyl-
methylene)triphenylphosphorane (9.5 g, 27.4 mmol) in dichloro-
methane (60 mL) was heated at reflux for 1 h. The reaction mixture
was diluted with hexane and filtered through a pad of Celite. The
filtrate was concentrated in vacuo, and the resulting residue was
purified by column chromatography (2% ethyl acetate in hexanes)
to give α,β-unsaturated esters 13 (5.0 g, 85%; E/Z = 9:1) which
a
saturated aqueous solution of potassium sodium tartrate
(25 mL). The mixture left to stir for 3 h until the organic and aque-
ous phases were completely separated. The organic phase was
washed with brine (15 mL), dried with Na2SO4, filtered, and con-
centrated under reduced pressure. The crude residue was purified
by column chromatography (10% ethyl acetate in hexanes) to give
were separable. IR (neat): ν = 2934, 2858, 1724, 1659, 1467, 1261,
˜
1
1155, 1094, 834, 778 cm–1. H NMR (500 MHz, CDCl3): δ = 6.87 alcohol 16 (2 g, 89%) as a colourless oil. [α]2D0 = –12.6 (c = 0.5,
(dd, J = 4.1, 15.4 Hz, 1 H), 5.92 (dd, J = 1.7, 15.4 Hz, 1 H), 4.49–
4.38 (m, 1 H), 4.16 (q, J = 7.3 Hz, 2 H), 1.37 (d, J = 6.7 Hz, 3 H),
1.30 (t, J = 6.9 Hz, 3 H), 0.9 (s, 9 H), 0.06 (s, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.7, 151.8, 118.9, 67.6, 60.2, 25.7, 23.4,
CHCl ). IR (neat): ν = 3337, 2930, 2857, 1462, 1374, 1255, 1137,
˜
3
1005, 835, 774 cm–1. H NMR (300 MHz, CDCl3): δ = 5.73–5.58
1
(m, 2 H), 4.05 (d, J = 3.7 Hz, 2 H), 3.84–3.73 (m, 1 H), 2.19–1.96
(m, 2 H), 1.57–1.39 (m, 2 H), 1.12 (d, J = 6.0 Hz, 3 H), 0.88 (s, 9
Eur. J. Org. Chem. 2013, 525–532
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529

C. Raji Reddy et al.
FULL PAPER
H), 0.04 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 133.1,
128.8, 68.0, 63.6, 39.0, 28.4, 25.8, 23.7, 18.0, –4.3, –4.7 ppm. MS
(ESI): m/z = 267 [M + Na]+. HRMS-ESI: calcd. for C13H28O2NaSi
[M + Na]+ 267.1756; found 267.1760.
CDCl3): δ = 4.40–4.27 (m, 1 H), 3.97–3.83 (m, 1 H), 2.89 (d, J =
6.0 Hz, 1 H), 2.35 (d, J = 2.2 Hz, 1 H), 1.81–1.66 (m, 2 H), 1.64–
1.49 (m, 2 H), 1.15 (d, J = 6.0 Hz, 3 H), 0.89 (s, 9 H), 0.06 (d, J =
1.5 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 84.9, 72.7,
67.9, 61.8, 33.9, 32.7, 25.8, 22.8, 18.1, –4.5, –4.8 ppm. MS (ESI):
m/z = 243 [M + H]+. HRMS-ESI: calcd. for C13H27O2Si [M +
H]+ 243.1775; found 243.1779.
{(2S,3S)-3-[(R)-3-(tert-Butyldimethylsilyloxy)butyl]oxiran-2-yl}-
methanol (17): Activated powdered 4 Å molecular sieves (6 g) and
dichloromethane (20 mL) were placed in a round-bottomed flask
under a nitrogen atmosphere. After cooling the flask to –20 °C,
the following reagents were added sequentially with stirring: d-(+)-
diisopropyl tartrate (0.43 mL, 2.0 mmol), Ti(OiPr)4 (0.48 mL,
1.6 mmol), and tBuOOH (6.5 mL, 32.5 mmol). After stirring the
reaction mixture for 1 h at –20 °C, a solution of allylic alcohol 16
(2 g, 8.2 mmol) in dichloromethane (10 mL) was added slowly. Af-
ter stirring for 4 h at –20 °C, the reaction was quenched with H2O
(9.6 mL) and 10% aq. NaOH saturated with NaCl (4.8 mL). The
mixture was stirred at room temperature for 4 h, then it was fil-
tered, and the organic phase was separated. The aqueous phase
was extracted with dichloromethane (3ϫ 10 mL). The organic ex-
[(2R,5S)-5-(Benzyloxy)hept-6-yn-2-yloxy](tert-butyl)dimethylsilane
(6): Sodium hydride (117 mg, 4.8 mmol) was added to a stirred
solution of tetrabutylammonium iodide (180 mg, 0.48 mmol) in di-
methylformamide (5 mL) at 0 °C, and then hydroxy compound 19
(600 mg, 2.4 mmol) in dimethylformamide (2 mL) was added. The
reaction mixture was stirred for 15 min at room temperature, then
it was recooled to 0 °C, and benzyl bromide (0.36 mL, 2.97 mmol)
was added. Then, the temperature was raised to room temperature,
and the mixture was stirred for 1 h, and then quenched with water
(30 mL). The two phases were separated, and the aqueous phase
was extracted with diethyl ether (3ϫ 30 mL). The combined or-
tracts were combined, washed with brine (20 mL), dried with ganic extracts were washed with brine (30 mL), dried with Na2SO4,
Na2SO4, and concentrated. The residual oil was purified by column
chromatography (10% ethyl acetate in hexanes) to give 17 (1.6 g,
78%) as a colourless oil. [α]2D0 = –26.4 (c = 0.5, CHCl3). IR (neat):
filtered, and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (5% ethyl acetate in
hexanes) to give 6 (0.59 g, 72%) as a colourless oil. [α]2D0 = –67.0 (c
ν = 3444, 2956, 2857, 1746, 1471, 1255, 1104, 1048, 1005, 836,
= 0.5, CHCl ). IR (neat): ν = 2956, 2857, 2111, 1458, 1734, 1253,
˜
3
˜
774 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.98–3.77 (m, 2 H), 1056, 834, 774 cm–1. H NMR (300 MHz, CDCl3): δ = 7.39–7.23
3.68–3.54 (m, 1 H), 3.0–2.88 (m, 2 H), 1.74–1.43 (m, 4 H), 1.12 (d, (m, 5 H), 4.80 (d, J = 11.8 Hz, 1 H), 4.50 (d, J = 11.8 Hz, 1 H),
J = 6.0 Hz, 3 H), 0.87 (s, 9 H), 0.04 (d, J = 1.8 Hz, 6 H) ppm. 13C 4.07 (td, J = 1.7, 6.2, 8.1 Hz, 1 H), 3.85–3.73 (m, 1 H), 2.46 (dd, J
NMR (75 MHz, CDCl3): δ = 67.9, 61.7, 58.4, 55.9, 35.4, 27.5, 25.8, = 1.7 Hz, 1 H), 1.94–1.67 (m, 2 H), 1.65–1.51 (m, 2 H), 1.12 (d, J
1
23.5, 18.0, –4.3, –4.7 ppm. MS (ESI): m/z = 283 [M + Na]+.
HRMS-ESI: calcd. for C13H28O3NaSi [M + Na]+ 283.1699; found
283.1698.
= 6.0 Hz, 3 H), 0.88 (s, 9 H), 0.03 (d, J = 1.5 Hz, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 137.9, 128.3, 127.9, 127.6, 82.8, 73.8,
70.4, 68.3, 68.0, 34.8, 31.7, 25.8, 23.7, 18.0, –4.3, –4.7 ppm. MS
(ESI): m/z = 355 [M + Na]+. HRMS-ESI: calcd. for C20H33O2Si
[M + H]+ 333.22443; found 333.22398.
tert-Butyl{(R)-4-[(2S,3R)-3-(chloromethyl)oxiran-2-yl]butan-2-
yloxy}dimethylsilane (18): NaHCO3 (96 mg, 1.1 mmol) and tri-
phenyl phosphene (1.5 g, 5.7 mmol) were added to a stirred solu-
tion of epoxy alcohol 17 (1.5 g, 5.7 mmol) in carbon tetrachloride
(15 mL) at room temperature. Then the temperature was raised to
reflux temperature, and the mixture was stirred for 3 h at reflux.
The reaction mixture was cooled to room temperature, the solvent
was evaporated, and the residue was purified by flash chromatog-
(5S,6S,10S,13R)-6,10-Bis(benzyloxy)-2,2,3,3,5,13,15,15,16,16-deca-
methyl-4,14-dioxa-3,15-disilaheptadec-8-yn-7-one (4): nBuLi (1.6 m
in hexane, 0.2 mL, 0.35 mmol) was added dropwise to a stirred
solution of compound 6 (129 mg, 0.38 mmol) in THF (2 mL) at
–78 °C. After stirring for 45 min at –78 °C, aldehyde 5 (100 mg,
0.32 mmol) in THF (1 mL) was added. The temperature was slowly
raphy (5% ethyl acetate in hexanes) to give 18 (1.15 g, 72%) as a raised to room temperature, the mixture was stirred for 1 h, and
colourless oil. [α]2D0 = –14.4 (c = 0.5, CHCl ). IR (neat): ν = 2929,
then the reaction was quenched with saturated aqueous NH4Cl
(5 mL). The two phases were separated. The aqueous phase was
extracted with ethyl acetate (3ϫ 5 mL), and the combined organic
˜
3
2856, 1462, 1255, 1131, 1042, 835, 774 cm–1. H NMR (300 MHz,
1
CDCl3): δ = 3.89–3.81 (m, 1 H), 3.60 (dd, J = 5.9, 11.8 Hz, 1 H),
3.39 (dd, J = 5.9, 11.8 Hz, 1 H), 2.94 (td, J = 1.9, 6.9 Hz, 1 H), extracts were washed with brine (5 mL), dried with Na2SO4, and
2.82 (td, J = 1.9, 6.9 Hz, 1 H), 1.48–1.47 (m, 4 H), 1.13 (d, J =
concentrated in vacuo. The residue was purified by column
chromatography (10% ethyl acetate in hexanes) to give the alcohol
5.9 Hz, 3 H), 0.88 (s, 9 H), 0.05 (d, J = 1.9 Hz, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 67.8, 58.9, 57.1, 44.7, 35.2, 27.4, 25.8, (160 mg, 77%) as a mixture of diastereomers.
23.6, 18.0, –4.3, –4.7 ppm. MS (ESI): m/z = 279 [M + H]+. HRMS-
Dess–Martin periodinane (148 mg, 0.35 mmol) was added in one
ESI: calcd. for C13H27O2NaSiCl [M + Na]+ 301.1366; found
301.1370.
portion to a stirred solution of the above diastereomeric mixture
of alcohols (150 mg, 0.23 mmol) in dry dichloromethane (5 mL).
The mixture was stirred for 30 min at room temperature, and then
the reaction was quenched with saturated aqueous Na2S2O3 (2 mL)
and saturated aqueous NaHCO3 (4 mL). The phases were sepa-
rated, and the aqueous phase was extracted with dichloromethane
(3ϫ 5 mL). The combined organic extracts were washed with brine
(5 mL), dried with Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography (5% ethyl acetate in hex-
anes) to give compound 4 (127 mg, 85%) as a colourless liquid.
(3S,6R)-6-(tert-Butyldimethylsilyloxy)hept-1-yn-3-ol (19): nBuLi
(2.5 m solution in THF, 5.7 mL, 14.3 mmol) was added to a stirred
solution of compound 18 (1.0 g, 3.59 mmol) in tetrahydrofuran
(10 mL) at –78 °C. The reaction mixture was stirred at –78 °C for
an additional 5 h, and then the reaction was quenched with satu-
rated aqueous NH4Cl (15 mL). The phases were separated, and the
aqueous phase was extracted with ethyl acetate (3ϫ 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The crude residue was purified by column chromatography (10%
ethyl acetate in hexanes) to give 19 (0.61 g, 70%) as a colourless
[α]2D0 = –75.4 (c = 0.5, CHCl ). IR (neat): ν = 2956, 2930, 2209,
˜
3
1683, 1455, 1373, 1255, 1219, 1119, 1094, 834, 774 cm–1. H NMR
1
(300 MHz, CDCl3): δ = 7.38–7.25 (m, 10 H), 4.76 (d, J = 12.0 Hz,
1 H), 4.73 (d, J = 12.0 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 4.48
oil. [α]2D0 = –21.0 (c = 0.5, CHCl ). IR (neat): ν = 3448, 2928, 1637,
˜
3
1463, 1255, 1139, 1040, 835, 774 cm–1
.
1H NMR (300 MHz, (d, J = 12.0 Hz, 1 H), 4.27–4.18 (m, 2 H), 3.81–3.72 (m, 2 H), 1.97–
530
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 525–532

Total Synthesis of a 6,6-Spiroketal Metabolite, Dinemasone A
1.89 (m, 1 H), 1.83–1.74 (m, 1 H), 1.60–1.54 (m, 2 H), 1.27 (d, J 3 H), 1.12 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
= 6.0 Hz, 3 H), 1.10 (d, J = 6.0 Hz, 3 H), 0.87 (s, 18 H), 0.06 (d, J
= 2.0 Hz, 6 H), 0.03 (s, 3 H), 0.02 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 188.1, 137.3, 128.3, 128.0, 127.9, 93.6, 89.1,
83.9, 72.8, 70.9, 69.4, 68.4, 67.9, 34.8, 31.2, 25.8, 25.7, 23.7, 20.1,
18.0, 17.9, –4.31, –4.36, –4.7, –4.8 ppm. MS (ESI): m/z = 661 [M
+ Na]+. HRMS-ESI: calcd. for C37H59O5Si2 [M + H]+ 639.3896;
found 639.3892.
δ = 206.0, 137.9, 137.2, 128.3, 127.9, 127.6, 100.2, 82.4, 73.3, 72.1,
71.0, 67.1, 60.3, 47.3, 26.1, 21.6, 21.4, 19.6 ppm. MS (ESI): m/z =
411 [M + H]+. HRMS-ESI: calcd. for C25H31O5 [M + H]+
411.2166; found 411.2160.
(2S,3S,6S,8R,11S)-3,11-Dihydroxy-2,8-dimethyl-1,7-dioxaspiro-
[5.5]undecan-4-one (1)
Method A, Hydrogenation of 22: Palladium on carbon (10% by
weight, 12 mg) was added to a solution of compound 22 (16 mg,
0.04 mmol) in EtOAc (3 mL). The reaction mixture was stirred
overnight under a hydrogen atmosphere. After completion of the
reaction, the mixture was filtered through Celite, and the filtrate
was concentrated in vacuo. Column chromatography of the residue
on silica gel (40 % ethyl acetate in hexanes) gave compound 1
(8.5 mg, 95%) as a white solid. M.p. 147–149 °C (ref.[3] 149 °C).
(2S,3S,7S,10R)-3,7-Bis(benzyloxy)-2,10-dihydroxyundec-5-yn-4-one
(21): Aqueous HF (25%, 1 mL) was added to a stirred solution of
compound 4 (120 mg, 0.18 mmol) in acetonitrile (20 mL) at room
temperature, and the mixture was stirred for 5 h. The reaction was
quenched with saturated aqueous NaHCO3 (15 mL). The phases
were separated, and the aqueous phase was extracted with ethyl
acetate (3ϫ 10 mL). The combined organic extracts were washed
with brine (10 mL), dried with Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (30% ethyl
acetate in hexanes) to give compound 21 (68 mg, 88%) as a colour-
[α]2D0 = –79.3 (c = 0.21, CHCl ). IR (neat): ν = 3485, 3422, 3380,
˜
3
2920, 2853, 1722, 1381, 1334, 1278, 1220, 1165, 1134, 1073, 993,
929, 772 cm–1. 1H NMR (700 MHz, CDCl3): δ = 4.06 (dq, J = 9.5,
6.1 Hz, 1 H), 3.89 (sext, J = 6.1 Hz, 1 H), 3.83 (dd, J = 9.5, 1.0 Hz,
1 H) 3.55 (m, 1 H), 3.52 (d, J = 4.0 Hz, 1 H), 2.90 (d, J = 13.8 Hz,
1 H), 2.83 (dd, J = 13.8, 1.0 Hz, 1 H), 2.50 (d, J = 6.3 Hz, 1 H),
1.98 (m, 1 H), 1.75 (m, 1 H), 1.66 (m, 2 H), 1.46 (d, J = 6.1 Hz, 3
H), 1.26 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR (175 MHz, CDCl3):
δ = 205.9, 101.3, 77.9, 72.5, 69.9, 69.6, 44.9, 27.5, 24.7, 20.7,
18.7 ppm. MS (ESI): m/z = 253 [M + Na]+. HRMS-ESI: calcd. for
C11H18O5Na [M + Na]+ 253.1046; found 253.1045.
less liquid. [α]2D0 = –117.6 (c = 0.5, CHCl ). IR (neat): ν = 3410,
˜
3
2967, 2921, 2871, 2208, 1671, 1453, 1261, 1218, 1084, 772,
1
699 cm–1. H NMR (300 MHz, CDCl3): δ = 7.40–7.25 (m, 10 H),
4.81 (d, J = 12.0 Hz, 1 H), 4.77 (d, J = 12.0 Hz, 1 H), 4.49 (dd, J
= 4.1, 11.5 Hz, 2 H), 4.30 (t, J = 6.2 Hz, 1 H), 4.23–4.15 (m, 1 H),
3.92 (d, J = 4.7 Hz, 1 H), 3.82–3.70 (m, 1 H), 2.03–1.77 (m, 2 H),
1.71–1.48 (m, 2 H), 1.26 (d, J = 6.2 Hz, 3 H), 1.15 (d, J = 6.2 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 187.6, 136.9, 136.8,
128.5, 128.1, 128.0, 94.4, 83.3, 84.0, 73.1, 71.2, 68.3, 67.3, 60.3,
34.4, 31.1, 23.4, 18.3 ppm. MS (ESI): m/z = 433 [M + Na]+.
HRMS-ESI: calcd. for C25H31O5 [M + H]+ 411.2166; found
411.2162.
Method B, Spiroepimerisation of 1a: Anhydrous ZnBr2 (14.6 mg,
0.06 mmol) was added to a stirred solution of 1a (15.0 mg,
0.06 mmol) in CH2Cl2 (2 mL) at room temperature. After 5 h, the
reaction was quenched with saturated aqueous NaHCO3 (3 mL),
and the mixture was extracted with EtOAc. The organic extract
was washed with brine (3 mL), dried with Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography over silica gel (30% EtOAc in hexanes) to give
dinemasone A (1, 9.5 mg, 63%) as a white solid, together with reco-
vered 1a (4.0 mg, 27%). These isolated products were fully charac-
terised and gave data comparable with that obtained above.
(2S,3S,6S,8R,11S)-3,11-Bis(benzyloxy)-2,8-dimethyl-1,7-dioxaspiro-
[5.5]undecan-4-one (22) and (2S,3S,6R,8R,11S)-3,11-Bis(benz-
yloxy)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecan-4-one (22a): p-Tolu-
enesulfonic acid monohydrate (48 mg, 0.25 mmol) was added to a
stirred solution of ynone 21 (70 mg, 0.17 mmol) in toluene (2 mL).
The mixture was stirred for 12 h. Then the reaction was quenched
with saturated aqueous NaHCO3 (2 mL), and the phases were sep-
arated. The aqueous phase was extracted with ethyl acetate (2ϫ
5 mL). The combined organic extracts were washed with brine
(5 mL), dried with Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (5% ethyl acetate in hex-
anes) to give compound 22 (19 mg) as a colourless solid, and 22a
(43 mg) as a colourless syrup (combined yield 89%).
(2S,3S,6R,8R,11S)-3,11-Dihydroxy-2,8-dimethyl-1,7-dioxaspiro-
[5.5]undecan-4-one (6-epi-dinemasone A, 1a): By the same protocol
as that described for the preparation of 1, 22a (40 mg, 0.1 mmol)
was converted into 1a (21 mg, 93%) as a colourless liquid. [α]D20
=
+64.4 (c = 0.5, CHCl ). IR (neat): ν = 3434, 2931, 1727, 1448,
˜
3
1071, 1010, 968, 757 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.28–
4.18 (m, 1 H), 4.15 (dd, J = 1.5, 9.8 Hz, 1 H), 3.67–3.56 (m, 2 H),
3.47 (d, J = 3.7 Hz, 1 H), 3.05 (d, J = 15.8 Hz, 1 H), 2.74 (dd, J =
1.5, 15.8 Hz, 1 H), 2.17–2.00 (m, 2 H), 1.80–1.68 (m, 2 H), 1.47 (d,
J = 6.0 Hz, 3 H), 1.18 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 207.1, 100.1, 76.7, 73.1, 66.9, 65.3, 45.8,
25.7, 25.4, 21.5, 19.7 ppm. MS (ESI): m/z = 253 [M + Na]+.
HRMS-ESI: calcd. for C11H18O5Na [M + Na]+ 253.1046; found
253.1045.
Data for 22: [α]2D0 = –140.2 (c = 0.8, CHCl ). IR (neat): ν = 2925,
˜
3
1731, 1451, 1218, 1118, 1075, 1012, 772, 698 cm–1
.
1H NMR
(300 MHz, CDCl3): δ = 7.39–7.27 (m, 10 H), 4.94 (d, J = 11.9 Hz,
1 H), 4.73 (d, J = 11.9 Hz, 1 H), 4.61 (d, J = 11.9 Hz, 1 H), 4.50
(d, J = 10.9 Hz, 1 H), 4.28 (qd, J = 6.0, 9.0 Hz, 1 H), 3.91 (sext, J
= 6.0 Hz, 1 H), 3.66 (dd, J = 1.0, 9.0 Hz, 1 H), 3.26 (dd, J = 4.0,
8.0 Hz, 1 H), 2.82 (dd, J = 1.0, 13.0 Hz, 1 H), 2.52 (d, J = 14.0 Hz,
1 H), 1.96 (m, 1 H), 1.77 (m, 1 H), 1.68 (m, 2 H), 1.41 (d, J =
6.0 Hz, 3 H), 1.25 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 204.8, 138.1, 137.5, 128.4, 128.2, 128.0, 127.9, 127.8,
101.5, 84.0, 76.1, 73.1, 71.6, 70.4, 69.5, 47.8, 29.6, 28.4, 21.4, 20.7,
18.6 ppm. MS (ESI): m/z = 411 [M + H]+.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR of all compounds, and
NOESY, COSY, and HSQC analysis of the target molecule.
Data for 22a: [α]2D0 = –23.0 (c = 1.0, CHCl ). IR (neat): ν = 2927,
˜
3
1732, 1452, 1216, 1118, 1076, 1013, 771, 698 cm–1
.
1H NMR
Acknowledgments
(300 MHz, CDCl3): δ = 7.37–7.24 (m, 10 H), 4.91 (d, J = 11.3 Hz,
1 H), 4.59 (d, J = 11.7 Hz, 1 H), 4.51 (d, J = 11.3 Hz, 1 H), 4.42
B. S., U. D., and K. V. M. R. thank Council of Scientific and Indus-
(d, J = 11.7 Hz, 1 H), 4.12–4.03 (m, 1 H), 3.93–3.85 (m, 2 H), 3.34 trial Research (CSIR), New Delhi, for research fellowships. The
(t, J = 3.0 Hz, 1 H), 2.88 (d, J = 15.6 Hz, 1 H), 2.76 (d, J = 15.6 Hz, authors are grateful to the reviewers of this article for their sugges-
1 H), 1.90–1.80 (m, 2 H), 1.70–1.52 (m, 2 H), 1.34 (d, J = 5.6 Hz, tions in improving the quality of the manuscript.
Eur. J. Org. Chem. 2013, 525–532
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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C. Raji Reddy et al.
FULL PAPER
Srikanth, P. P. Reddy, Org. Biomol. Chem. 2012, DOI: 10.1039/
C2OB26396C.
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[2]
[11] Restrained MD simulation, with the help of observed NOE
cross-peaks between 3-H–5a-H, 11-H–5a-H, 11-H–5e-H, 8-H–
5e-H, 8-Me–10a-H, 8-Me–2-H, and 2-Me–8-Me, as well as
3JH,H couplings, suggest the structure shown in Figure 2 for
Dinemasone A.
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[13] The use of zinc(II) chloride in dichloromethane resulted in the
equilibration of 1 and 1a to give a 1:1 mixture.
[5] The first total synthesis of dinemasone A has been reported
while this paper was under review, see: G. V. M. Sharma, G.
Received: September 18, 2012
Published Online: November 27, 2012
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