First enantioselective synthesis of marine diterpene ambliol-A

Article abstract of DOI:10.1002/ejoc.201403610

The first enantioselective synthesis of furanditerpene ambliol-A, which is a major metabolite of marine sponge Dysidea amblia, has been accomplished by starting from racemic α-ionone. The key steps of the synthesis include lipase-mediated resolution of 4-hydroxy-γ-ionone, its stereoselective transformation into trans-α-epoxy-dihydroionone, C₂ homologation to trans-α-epoxy-monocyclofarnesyl acetate and Li₂CuCl₄-catalysed sp³-sp³ cross-coupling reaction of the latter ester with (furan-3-ylmethyl)magnesium chloride. This work confirms the chemical structure previously assigned to ambliol-A and proves that the natural levorotatory isomer does not possess (1S,2S) absolute configuration, as previously indicated, but is the opposite enantiomer, (1R,2R)-2-[(E)-6-(furan-3-yl)-3-methylhex-3-enyl]-1,3,3-trimethylcyclohexanol.

Full text of DOI:10.1002/ejoc.201403610

Job/Unit: O43610
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FULL PAPER
DOI: 10.1002/ejoc.201403610
First Enantioselective Synthesis of Marine Diterpene Ambliol-A
Stefano Serra*[a] and Veronica Lissoni[b]
Keywords: Natural products / Total synthesis / Biocatalysis / Terpenoids / Cross-coupling
The first enantioselective synthesis of furanditerpene ambli-
ol-A, which is a major metabolite of marine sponge Dysidea
amblia, has been accomplished by starting from racemic α-
ter ester with (furan-3-ylmethyl)magnesium chloride. This
work confirms the chemical structure previously assigned to
ambliol-A and proves that the natural levorotatory isomer
ionone. The key steps of the synthesis include lipase-medi- does not possess (1S,2S) absolute configuration, as previously
ated resolution of 4-hydroxy-γ-ionone, its stereoselective indicated, but is the opposite enantiomer, (1R,2R)-2-[(E)-6-
transformation into trans-α-epoxy-dihydroionone, C2 homol- (furan-3-yl)-3-methylhex-3-enyl]-1,3,3-trimethylcyclohexan-
ogation to trans-α-epoxy-monocyclofarnesyl acetate and
Li2CuCl4-catalysed sp3–sp3 cross-coupling reaction of the lat-
ol.
basis of both spectroscopic data and chemical degradation
experiments.
Introduction
Diterpene Ambliol-A (1) is a major metabolite of marine
More specifically, both the hydroxy group and the side
sponge Dysidea amblia and occurs alongside structurally re- chain of ambliol-A proved to be equatorial with respect to
lated metabolite dehydroambliol-A (2; Figure 1). These the cyclohexane ring. Ozonolysis of 1 provided enol ether
furanditerpenes were isolated for the first time by Faulkner 3, which was identical to the known synthetic material ob-
et al.[1] who determined their chemical structures on the tained through cyclization reaction of geranylacetone.
Figure 1. The chemical structures previously assigned to natural ambliol-A (1) and dehydroambliol-A (2). Enol ether 3 obtained by
ozonolysis of ambliol-A. Other natural compounds (4–7) that feature a substituted hydroxy-monocyclofarnesane moiety with the hydroxy
group and side chain in relative trans configuration.
[a] C.N.R., Istituto di Chimica del Riconoscimento Molecolare,
The absolute configuration was depicted as (1S,2S), al-
though there was no evidence to indicate which one of the
two enantiomers was the natural one. The latter study did
not clearly state how the assignment was done, which left
some ambiguity on this point. Afterwards, ambliol-A was
also isolated from the sponge Oceanapia bartschi[2] and a
number of natural products of terpenic origin that featured
Via Mancinelli 7, 20131 Milano, Italy
E-mail: stefano.serra@cnr.it
stefano.serra@polimi.it
http://www.icrm.cnr.it/serra.htm
[b] Dipartimento di Scienze Farmaceutiche, Università degli Studi
di Milano,
Via L. Mangiagalli 25, 20133 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403610.
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S. Serra, V. Lissoni
FULL PAPER
a substituted hydroxy-monocyclofarnesane moiety and pos-
It is worth noting that only two syntheses of racemic am-
sessed relative trans configuration, as described above, were bliol-A have been reported so far.[8] The most recent re-
also identified. These compounds were isolated from search[8b] described the preparation of racemic 1 by using
sources very different from each other. For example ful- trans-epoxy-α-dihydroionone as a key intermediate, which
vanin-2 (4),[3] enol-acetate 5,[4] triterpene 6-α-hydroxy- was in turn obtained by epoxidation with m-chloroper-
achilla-9,13,17,21-tetraene (6)[5] and sesquiterpene 7[6] were oxybenzoic acid (mCPBA) of α-dihydroionone. These re-
isolated from sponge, seaweed, fern, and plant, respectively, sults seem to be in disagreement with the general behavior
and the absolute configuration was assigned unambigu- of α-ionone and α-damascone isomers, which react with
ously only for compounds 6 and 7.
peracids to give cis-epoxy derivatives.[9]
All the aforementioned natural products are difficult to
This stereochemical outcome has been unambiguously
access through chemical synthesis. More specifically, the in- demonstrated only for the epoxidation of α-ionone.[9b] In
troduction of the hydroxy functional group with the re- principle, mCPBA epoxidation could proceed with opposite
quired trans stereochemistry is especially demanding. As a stereoselectivity when α-dihydroionone is used as the sub-
consequence, the attribution of the stereochemical structure strate. To verify the stereochemical trend of this reaction
of some of them is still unconfirmed, because their total and to exclude the fact that ambliol-A could possess a cis-
synthesis has not been accomplished yet. In this context, relationship between the hydroxy group and the side chain,
we recently described the synthesis of (S)-dehydroambliol- we decided to prepare this isomeric form of ambliol by
A,[7a] which showed an optical rotation sign opposite to starting from cis-epoxy-α-dihydroionone. Accordingly, we
that recorded for natural 2. Because the latter metabolite is began with the experiments described in Scheme 1.
most likely derived from ambliol-A through elimination of
water, this study suggests that both natural 1 and 2 could
have been assigned the wrong absolute configuration.
By taking advantage of our previously acquired expertise
in the enantioselective synthesis of monocyclofarnesyl de-
rivatives,[7] we investigated a new stereoselective synthesis of
ambliol-A. Herein we describe the results of this study,
which assign unambiguously the (1R,2R)-configuration of
natural 1 as well as outline a new synthetic approach to
natural compounds of similar structure.
Scheme 1. The stereochemical outcome of the epoxidation reaction
between α-ionone and α-dihydroionone with mCPBA. Reagents
and conditions: (a) mCPBA, CH2Cl2, 0 °C; (b) H2, atmospheric
pressure, Raney Ni, THF/MeOH; (c) H2, atm. pressure, Pd BaCO3,
Results and Discussion
EtOH.
Epoxidation reaction of racemic α-ionone with mCPBA
gave diastereoselectively cis-epoxy-ionone 12, which was
hydrogenated with Pd/BaCO3 as catalyst to afford cis-ep-
oxy-α-dihydroionone 13. The NMR spectroscopic data of
the latter compound were identical in all respects to those
recorded for the epoxide obtained from α-dihydroionone
(14) by reaction with mCPBA. These results demonstrated
that the previous synthesis of ambliol-A afforded the epi-
mer of racemic 1 instead of 1, which raises new doubts
about the attribution of the relative configuration of the
natural product. Therefore, to analyze the experimental
data of these isomers, we decided to synthesize epi-ambliol-
A from cis-epoxy-α-dihydroionone (13; Scheme 2).
According to a retrosynthetic analysis (Figure 2), we
planned to synthesize ambliol-A from enantioenriched
trans-epoxy-α-dihydroionone 11 by exploiting three dif-
ferent stereoselective transformations. The tertiary carbinol
is obtained through regioselective reduction of epoxide 8,
the C20 framework of which is prepared by means of a cop-
per-catalyzed cross-coupling reaction between C15 acetate 9
and C5 Grignard reagent 10. The trisubstituted double
bond of 9 is stereoselectively created through Horner–
Wadsworth–Emmons reaction of triethylphosphonoacetate
with ketone 11. The latter compound requires a particular
enantioselective synthesis, which was also studied.
By following the previously described retrosynthetic
analysis, racemic 13 was treated with an excess of triethyl-
phosphonoacetate sodium salt in tetrahydrofuran (THF)
solution. Obtained ester 15 consisted of a 5:1 mixture of E/
Z isomers, which were not separated and were reduced with
diisobutylaluminium hydride (DIBAH) to give the corre-
sponding allylic alcohols. The latter mixture was treated
with 3,5-dinitrobenzoyl chloride and pyridine and the re-
sulting esters were recrystallized twice from hexane. The
collected crystals were isomerically pure ester 16, which
possessed both the required cis-epoxide and the E double
bond configuration.
Figure 2. Retrosynthetic analysis of ambliol-A.
2
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First Enantioselective Synthesis of Marine Diterpene Ambliol-A
Table 1. The 13C NMR spectroscopic data of natural ambliol-A,
epi-ambliol-A, and synthetic ambliol-A.
Position[a]
Natural
Synthetic
Synthetic
ambliol-A[a]
δC (C6D6)[b]
epi-ambliol-A
ambliol-A
δC (C6D6)[b]
δC (C6D6)[b]
1
2
3
73.7
56.7
35.6
72.5
54.1
35.0
73.6
56.8
35.6
4, 6, 2Ј
5
1Ј, 5Ј, 6Ј
43.9, 43.2, 41.8 44.0, 42.4, 41.7
20.8 18.8
28.8, 25.3, 25.3 28.9, 25.4, 25.2
44.0, 43.2, 41.9
20.9
28.9, 25.4, 25.3
33.0, 23.6, 21.6
137.1
Me(1), Me(3) 33.0, 23.5, 21.6 32.3, 31.1, 21.8
3Ј
137.0
136.7
Me(3Ј)
4Ј
2ЈЈ, 5ЈЈ
3ЈЈ
16.2
124.1
139.2, 142.8
125.2
111.3
16.3
124.0
139.2, 142.9
125.2
111.3
16.2
124.2
139.2, 142.8
125.2
111.3
Scheme 2. The synthesis of epi-ambliol-A. Reagents and condi-
tions: (a) (EtO)2POCH2CO2Et, NaH, THF; (b) DIBAH, THF,
–40 °C; (c) 3,5-dinitrobenzoyl chloride, Py, DMAP cat.;
(d) crystallization from hexane; (e) NaOH, MeOH, room tempera-
ture; (f) Ac2O, Py; (g) Li2CuCl4 cat., THF, 10 (1.5 equiv.), –20 °C
to 0 °C; (h) LiAlH4, THF, reflux.
4ЈЈ
[a] Data reported in ref.[1]. [b] 100 MHz, room temperature.
of the obtained enantioenriched derivatives can be epoxi-
dized diastereoselectively to give, after a number of func-
tional-group transformations, trans-epoxide 11.
The hydrolysis of the latter ester afforded the corre-
sponding alcohol, which was acetylated by using acetic an-
hydride and pyridine. According to our previous studies,[7a]
Li2CuCl4 catalyzed the coupling of monocyclofarnesyl de-
rivative 17 with Grignard reagent 10 with very high chemo-
selectivity. Actually, the addition of 10 to a cooled THF
solution of acetate 17 that contained Li2CuCl4 (0.05 equiv.)
smoothly afforded SN2 derived product 18 without any de-
tectable amount of the corresponding SN2Ј adduct, double
bond isomerized derivatives or epoxide-opened side prod-
ucts. Lastly, reduction of epoxide 18 with LiAlH4 in THF
at reflux temperatures afforded diastereoisomerically pure
epi-ambliol-A 19.
The NMR spectroscopic data of this synthetic material
was analyzed with that reported for natural ambliol-A.[1]
1
Although the H NMR spectra of the two compounds are
very similar, the 13C NMR spectra show significant differ-
ences in the signals of some specific carbons. More specifi-
cally, the chemical shifts of the carbons in position 1, 2, and
5, as well as that of one of the methyl groups, clearly allow
us to distinguish natural ambliol-A from its synthetic epi-
mer (Table 1). As a consequence, we can conclude that the
hydroxy group and the side chain of ambliol-A has trans
relationship, as correctly indicated by Faulkner et al.[1]
Therefore, the product obtained by Ray et al.[8b] was epi-
ambliol-A, which could not be differentiated from its epi-
1
mer by means of H NMR spectroscopic analysis alone.
Because our approach to epi-ambliol-A was effective and
reliable, we decided to study a stereoselective preparation
of enantioenriched trans-epoxy-α-dihydroionone to be used
as a chiral building block for the synthesis of ambliol-A. To
this end, we planned to transform racemic α-ionone into
racemic 4-hydroxy-γ-ionone (20; Scheme 3) through a two-
step process of epoxidation of the ionone followed by base-
mediated rearrangement of the obtained epoxy-ionone.[10]
Racemic alcohol 20 can be resolved by means of lipase-
Scheme 3. Stereoselective synthesis of trans-epoxy-α-dihydroion-
one. Reagents and conditions: (a) H2O2·NH2CONH2, (CF3CO)2O,
CH3CN/CH2Cl2, K2CO3, –78 °C then –50 °C; (b) LDA, THF,
–78 °C then reflux; (c) lipase PS, tBuOMe, vinyl acetate; (d) H2,
atm. pressure, Raney Ni, THF/MeOH; (e) mCPBA, CH2Cl2, room
temperature; (f) (MeO)3CH, PPTS, MeOH; (g) LiAlH4, Et2O, re-
flux; (h) MsCl, Py, DBU, room temperature; (i) LDA (1 equiv.),
THF, 0 °C then MsCl 30 min.; LDA (1 equiv.) then room tempera-
ture; (j) LiEt3BH, THF, room temperature then diluted HCl aq.;
mediated acetylation reaction. The exocyclic double bond (k) THF/H2O, catalytic pyridinium p-toluenesulfonate.
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Because we intended to have access to both enantiomeric tionship between the epoxide functional group and the side
forms of this compound, we improved the stereoselective chain moiety.
synthesis of racemic 20. We have previously demon-
Because the quaternary carbinol on the cyclohexanic ring
strated[10] that lipase PS catalyzes the acetylation reaction reacts quickly with the ketone on the side chain to give the
of (4R,6S)-4-hydroxy-γ-ionone with very high enantio- corresponding dihydropyranyl derivative,[14] we decided to
selectivity and complete diastereoselectivity to lead to protect the latter functional group before reduction of the
enantiopure (+)-22 and enantioenriched alcohol (+)-20 spiro-epoxide. Hence, compound (–)-24 in methanol was
contaminated with racemic trans-4-hydroxy-γ-ionone (21). treated with trimethyl orthoformate in the presence of a
The latter compound derives from trans-epoxy-ionone, the catalytic amount of pyridinium p-toluenesulfonate. Re-
formation of which is a result of incomplete diastereoselec- sulting dimethylketal 25 was reduced with LiAlH4 to per-
tivity of the epoxidation reaction step with mCPBA. By form simultaneously the acetate functional group removal
taking inspiration from Fehr’s work,[9e] which indicated tri- and the regioselective epoxide reduction. Unfortunately, ob-
fluoroperacetic acid as a more diastereoselective reagent for tained diol 26 turned out to be very unstable in acidic envi-
this kind of transformation, we selected the combined use ronments. Therefore, after work-up under basic conditions,
of hydrogen peroxide–urea adduct with trifluoroacetic an- it was used directly in the preparation of epoxide (–)-28.
hydride[11] as the most convenient and safe procedure to To this end, we checked the intramolecular ring closure of
generate this unstable peracid on a preparative scale. The vicinal diol 26. The secondary hydroxy group was activated
reaction of the latter reagent with α-ionone at low tempera- by means of its transformation into a mesylate group and
ture (–78 °C) gave the corresponding epoxy derivative with then treated with base to promote the nucleophilic displace-
expected high diastereoselectivity (94% of cis isomer). The ment of the mesyl group. A first experiment based on treat-
following treatment with more than two equivalents of lith- ment of 26 with an excess of pyridine, 1,8-diazabicyclo-
ium diisopropylamide (LDA) afforded racemic compound [5.4.0]undec-7-ene (DBU), and mesyl chloride gave disap-
20, which was then resolved by means of lipasePS-mediated pointing results and led to the exclusive formation of enol
acetylation. Because (4R,6S)-4-acetoxy-γ-ionone [(+)-22] ether (–)-27. However, stepwise treatment of 26 with an
possesses the same absolute configuration as natural equimolar amount of LDA and one equivalent of mesyl
ambliol-A, we used this compound as the starting material chloride followed by addition of a further equivalent of
for our planned synthesis.
LDA afforded epoxide (–)-28 in satisfactory yield. The acid-
Accordingly, the conjugated double-bond of compound catalyzed hydrolysis of the latter compound gave desired
(+)-22 was regioselectively hydrogenated by using Raney Ni trans-epoxy-α-dihydroionone [(–)-11], the spectroscopic
as catalyst.[12] Resulting ketone (–)-23 was treated with data of which confirmed the diastereoisomeric relationship
mCPBA to afford spiro-epoxide (–)-24 as the major prod- between 11 and 13 and thus the trans configuration of 11.
uct. We can explain the latter stereochemical outcome by In addition, the regioselective reduction of epoxide (–)-11
assuming that the peracid attaches preferentially the less with LiEt3BH followed by acid work-up smoothly afforded
hindered face of the exocyclic double bond. It is worth not- bicyclic enol ether (–)-3, which turned out to be spectro-
ing that similar stereoselectivity has been described for scopically identical to the enol ether obtained by ozonolysis
mCPBA epoxidation of structurally related cis-4-hydroxy-γ- of natural ambliol-A.[1]
ionone.[13] Finally, we were able to confirm a posteriori the
Encouraged by the latter results, we employed epoxide
stereochemistry of compound 24, by means of its transfor- (–)-11 as a chiral building block for the synthesis of am-
mation into trans-epoxy-dihydroionone [(–)-11], the quater- bliol-A by following the same experimental approach devel-
nary stereocenter of which was created through the above oped for the preparation of epimer 19 (Scheme 4). Accord-
described epoxidation reaction and establishes a trans rela- ingly, epoxide (–)-11 was treated with an excess of triethyl-
Scheme 4. Stereoselective synthesis of (1S,2S)-ambliol-A. Reagents and conditions: (a) (EtO)2POCH2CO2Et, NaH, THF; (b) DIBAH,
THF, –40 °C; (c) 3,5-dinitrobenzoyl chloride, Py, DMAP cat.; (d) NaOH, MeOH, room temperature; (e) Ac2O, Py; (f) Li2CuCl4 cat.,
THF, 10 1.5 equiv., –20 °C to 0 °C; (g) LiEt3BH, THF, 0 °C then room temperature.
4
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First Enantioselective Synthesis of Marine Diterpene Ambliol-A
chloride (10), which was prepared immediately before the use as
described previously.[7a] Lipase PS from Pseudomonas cepacia (Am-
ano Pharmaceuticals Co., Japan) 30 units/mg was employed in this
work. TLC was performed with Merck silica gel 60 F254 plates.
Column chromatography was performed with silica gel. GC–MS
phosphonoacetate sodium salt in THF solution. Obtained
ester 29 (5:1 mixture of E/Z isomers) was reduced with
DIBAH to the corresponding allylic alcohols. The latter
mixture was treated with 3,5-dinitrobenzoyl chloride and
pyridine but the resulting ester mixture proved to be oil,
which hampered the isolation of pure E isomer by frac-
tional crystallization.
analyses were measured on
a HP-6890 gas chromatograph
equipped with a 5973 mass detector with a HP-5MS column
(30 mϫ 0.25 mm, 0.25 μm film thickness; Hewlett–Packard) and
the following temperature program: 60° (1 min)–6°/min–150°
(1 min)–12°/min–280° (5 min); carrier gas, He; constant flow 1 mL/
Luckily, we were able to increase the purity of the E iso-
mer through chromatographic purification of the ester mix-
ture. A sample of compound (–)-30, with a 92:8 E/Z ratio, min; split ratio, 1:30; tR given in min: tR(3) 15.07, tR(11) 19.04,
tR(13) 18.48, tR(21, corresponding acetate) 20.50, tR(22) 20.80,
tR(23) 21.31, tR(24) 22.82 and tR(27) 24.40. Chiral GC analyses
were measured with a DANI-HT-86.10 gas chromatograph and
enantiomer excesses determined with a Chirasil-DEX-CB column
with the following temperature program; 60° (3 min) – 3°/min –
180° (5 min), carrier gas, He; constant flow 1 mL/min; tR(+)-22:
32.51, tR(–)-22: 32.65. Mass spectra of compounds 1, 8, 15, 16, 18,
19, 25, 28, 29, and 30 were recorded with a Bruker ESQUIRE 3000
PLUS spectrometer (ESI detector). Optical rotations were recorded
was hydrolyzed to give the corresponding alcohol, which
was acetylated with acetic anhydride and pyridine. The
Li2CuCl4 catalyzed coupling of the latter acetate with Grig-
nard reagent 10 smoothly afforded SN2 deriving product
(–)-8. Lastly, reduction of the epoxide functional group with
LiAlH4 in THF at reflux temperatures did not work as ef-
fectively as reported for the cis-isomer. Therefore we
switched to the use of the more nucleophilic LiEt3BH,
which smoothly reduced (–)-8 to afford ambliol-A (+)-1 in
very good yields.
The obtained synthetic ambliol-A showed spectroscopic
data in perfect agreement with those reported for the natu-
ral diterpene (Table 1) with exception of the optical rotation
sign. We recorded a value of + 4.0 (c 1.8, CHCl3), whereas
Faulkner et al. recorded a value of –3.9 (c 2.5 CHCl3).
1
with a Jasco-DIP-181 digital polarimeter. H and 13C NMR Spec-
tra and DEPT experiments were recorded at room temperature
with a Bruker AC-400 spectrometer at 400, 100, and 100 MHz,
respectively. Chemical shifts are reported relative to SiMe4. Melting
points were measured with a Reichert apparatus equipped with a
Reichert microscope.
4-[(1SR,2SR,6RS)-1,3,3-Trimethyl-7-oxabicyclo[4.1.0]heptan-2-yl]-
Overall, these data demonstrate unambiguously that butan-2-one (13)
natural ambliol-A is the (1R,2R)-2-[(E)-6-(furan-3-yl)-3-
(a) By Epoxidation of α-Dihydroionone: A solution of racemic α-
methylhex-3-enyl]-1,3,3-trimethylcyclohexanol, confirm the
chemical structure previously assigned, and corrects its ab-
solute configuration.
ionone (10 g, 52 mmol) in THF/methanol (5:1, 80 mL) was hydro-
genated at room temperature and atmospheric pressure by using
activated Raney nickel as catalyst. After 1.04 mol-equiv. of
hydrogen were absorbed the catalyst was filtered and the organic
phase was concentrated under reduced pressure. The residue was
dissolved in CH2Cl2 (80 mL) and mCPBA (12.7 g, 77 % w/w,
56.7 mmol) was added portionwise at 0 °C whilst stirring. As soon
as starting ketone 14 could no longer detected by TLC analysis
Conclusions
We report here the first enantioselective synthesis of (+)-
ambliol-A 1 as well as the diastereoselective synthesis of (6 h), the precipitated m-chlorobenzoic acid was filtered off and the
organic phase was diluted with CH2Cl2 (100 mL) and was washed
in turn with aqueous solution of Na2S2O5 (5%, 80 mL), saturated
aqueous NaHCO3 (150 mL), and brine. The obtained organic solu-
tion was dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by chromatography by eluting with hex-
ane/ethyl acetate (9:1–8:2) as eluent to afford pure 13 (7.75 g, 71%
non-natural epimer 19. This work confirms the chemical
structure assigned to natural (–)-ambliol-A and proves that
the diterpene isolated from the marine sponge Dysidea am-
blia is not the (1S,2S) isomer, as previously indicated, but
its enantiomer, (1R,2R)-2-[(E)-6-(furan-3-yl)-3-methylhex-
3-enyl]-1,3,3-trimethylcyclohexanol. Because our synthetic
approach is based on the use of (4R,6S)-4-acetoxy-γ-ionone
as a chiral building block and both enantiomeric forms of
the latter compound can be prepared by lipase-mediated
1
yield) as a colorless oil. H NMR (400 MHz, CDCl3): δ = 2.93 (s,
1 H), 2.74 (ddd, J = 16.6, 9.9, 5.4 Hz, 1 H), 2.51 (ddd, J = 16.6,
9.9, 5.9 Hz, 1 H), 2.16 (s, 3 H), 1.92 (dd, J = 15.6, 6.2 Hz, 1 H),
1.88–1.77 (m, 1 H), 1.76–1.66 (m, 1 H), 1.63–1.51 (m, 1 H), 1.39
resolution of the corresponding racemic material, formal (ddd, J = 10.3, 4.6, 1.2 Hz, 1 H), 1.36–1.25 (m, 1 H), 1.32 (s, 3 H),
0.89 (s, 3 H), 0.87–0.79 (m, 1 H), 0.84 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 208.9 (C), 59.9 (CH), 59.0 (C), 46.1 (CH),
43.0 (CH2), 31.4 (C), 29.8 (Me), 27.6 (Me), 27.2 (Me), 26.9 (Me),
26.6 (CH2) 22.0 (CH2), 21.4 (CH2) ppm. GC–MS (EI): m/z (%) =
synthesis of (–)-ambliol-A is also accomplished. Lastly, it is
worth noting that this synthetic approach opens the way to
the preparation of other natural terpenoids that feature a
substituted hydroxy-monocyclofarnesane moiety with the
210 [M]+ (7), 195 (100), 177 (16), 167 (21), 153 (68), 137 (49), 125
quaternary hydroxy group and the side chain in a relative
(39), 111 (66), 95 (62), 81 (35), 69 (40), 55 (53).
trans configuration.
(b) By Epoxidation of α-Ionone: A sample of α-ionone (10 g,
52 mmol) in CH2Cl2 (80 mL) was transformed into epoxy-α-ionone
(8.1 g, 38.9 mmol) by using mCPBA, as described previously.[9f]
The purified epoxide in EtOH (80 mL) was hydrogenated at room
Experimental Section
General Experimental: All moisture-sensitive reactions were carried
out under an atmosphere of nitrogen. All reagents were of commer-
temperature and atmospheric pressure with 10% w/w Pd/BaCO3 as
catalyst. After 1.05 mol-equiv. of hydrogen was absorbed the cata-
cial quality with the exception of (furan-3-ylmethyl)magnesium lyst was filtered and the organic phase was concentrated under re-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O43610
/KAP1
Date: 16-02-15 12:49:09
Pages: 10
S. Serra, V. Lissoni
FULL PAPER
duced pressure. The residue was purified by chromatography by
eluting with hexane/ethyl acetate (9:1–8:2) as eluent to afford pure
(1SR,2SR,6RS)-2-[(E)-6-(Furan-3-yl)-3-methylhex-3-enyl]-1,3,3-tri-
methyl-7-oxabicyclo[4.1.0]heptane (18): A solution of ester 16 (2 g,
4.63 mmol) in methanol (20 mL) was treated with a solution of
NaOH (2 g, 50 mmol) in methanol (20 mL) at room temperature.
After hydrolysis was complete (1 h), the reaction was diluted with
water and extracted twice with ether. The combined organic phases
were washed with brine, dried (Na2SO4), and concentrated under
reduced pressure. The residue was dissolved in pyridine (10 mL)
and acetic anhydride (10 mL) and was set aside until the acetylation
reaction was complete (1 h). The solvents were removed under re-
duced pressure to leave almost pure acetate 17. Grignard reagent
10 (13 mL of a 0.57 m solution in THF) was added dropwise under
an atmosphere of nitrogen to a stirred and cooled (–20 °C) solution
of ester 17 in dry THF (10 mL) to which Li2Cu2Cl4 (0.7 mL of a
0.5 m solution in THF) had been previously added.
1
13 (6.3 g, 58% overall yield) as a colorless oil. H NMR and 13C
NMR spectra were identical to those recorded for 13 obtained
through epoxidation of α-dihydroionone.
(E)-Ethyl 3-Methyl-5-[(1SR,2SR,6RS)-1,3,3-trimethyl-7-oxabi-
cyclo[4.1.0]heptan-2-yl]pent-2-enoate (15): Triethyl phosphonoacet-
ate (14 g, 62.4 mmol) was added dropwise under nitrogen over a
period of 1 h to a stirred suspension of NaH (60% in mineral oil;
2.5 g, 62.4 mmol) in dry THF (40 mL) at 0 °C. To the resulting
mixture was slowly added a solution of epoxide 13 (6 g, 28.5 mmol)
in dry THF (10 mL). When the addition was complete, the reaction
was slowly heated at 50 °C and stirring was continued until the
starting ketone was no longer detectable by TLC analysis (3 h).
After cooling, the reaction was poured onto a mixture of crushed
ice and saturated aqueous NH4Cl (100 mL). The mixture was ex-
tracted with diethyl ether (2 ϫ 150 mL). The combined organic
phases were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by chromatog-
raphy with n-hexane/diethyl ether (95:5–9:1) as eluent to afford
pure 15 (7.2 g, 90% yield) as a colorless oil consisting of an E/Z
mixture of isomers (E/Z ratio, 5:1, by NMR analysis). E Isomer: 1H
NMR (400 MHz, CDCl3): δ = 5.71 (m, 1 H), 4.15 (q, J = 7.1 Hz, 2
H), 2.94 (br. s, 1 H), 2.44 (dddd, J = 13.6, 11.2, 5.4, 0.8 Hz, 1 H),
2.22–2.11 (m, 1 H), 2.19 (d, J = 1.2 Hz, 3 H), 1.92 (ddt, J = 15.5,
6.2, 1.6 Hz, 1 H), 1.88–1.77 (m, 1 H), 1.65–1.22 (m, 4 H), 1.33 (s,
3 H), 1.27 (t, J = 7.1 Hz, 3 H), 0.90 (s, 3 H), 0.89–0.78 (m, 1 H),
0.83 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.8, 160.4,
115.5, 60.0, 59.3, 59.2, 47.0, 40.6, 31.5, 29.6, 27.7, 27.3, 26.9, 25.6,
22.0, 18.9, 14.3 ppm. MS (ESI): m/z = 303.5 [M + Na]+.
After stirring for 1 h, the reaction was slowly allowed to warm to
0 °C, stirred at this temperature for a further 2 h and then poured
into a ice-cooled mixture of diethyl ether (100 mL) and saturated
aqueous NH4Cl (100 mL). The organic phase was separated, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
chromatography with n-hexane/diethyl ether (99:1–95:5) as eluent
1
to afford pure epoxide 18 (1.21 g, 86% yield) as a colorless oil. H
NMR (400 MHz, CDCl3): δ = 7.32 (t, J = 1.5 Hz, 1 H), 7.21 (br.
s, 1 H), 6.27 (s, 1 H), 5.21 (t, J = 7.0 Hz, 1 H), 2.93 (s, 1 H), 2.49–
2.42 (m, 2 H), 2.31–2.20 (m, 3 H), 2.06–1.96 (m, 1 H), 1.92 (dd, J
= 15.5, 6.0 Hz, 1 H), 1.87–1.76 (m, 1 H), 1.62 (s, 3 H), 1.57–1.38
(m, 2 H), 1.36–1.24 (m, 2 H), 1.32 (s, 3 H), 0.88 (s, 3 H), 0.84–0.76
(m, 1 H), 0.82 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
142.5, 138.8, 136.5, 125.0, 123.6, 111.1, 60.1, 59.7, 46.9, 39.5, 31.5,
28.5, 27.7, 27.4, 27.1, 26.8, 26.0, 25.0, 22.1, 16.1 ppm. MS (ESI):
m/z = 303.5 [M + H+], 325.5 [M + Na]+.
(E)-3-Methyl-5-[(1SR,2SR,6RS)-1,3,3-trimethyl-7-oxabicyclo-
[4.1.0]heptan-2-yl]pent-2-enyl 3,5-Dinitrobenzoate (16): DIBAH
(37.9 mL of a 1.7 m solution in toluene, 64.4 mmol) was added
dropwise to a stirred solution of ester 15 (9 g, 32.1 mmol) in dry
THF (80 mL) at –40 °C. The reaction was then quenched by ad-
dition of a saturated aqueous solution of NH4Cl (80 mL), followed
by acidification with diluted aqueous HCl. The mixture was ex-
tracted with diethyl ether (3ϫ100 mL) and the combined organic
phases were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was dissolved in CH2Cl2
(30 mL) and was treated with pyridine (10 mL) with 4-dimethyl-
aminopyridine (DMAP; 0.1 g, 0.8 mmol) and with a solution of
3,5-dinitrobenzoyl chloride (9 g, 39 mmol) in CH2Cl2 (20 mL). As
soon as the starting alcohol was no longer detectable by TLC
analysis, the reaction was diluted with CH2Cl2 and water. The or-
ganic phase was washed with a saturated aqueous solution of
NaHCO3 then brine, dried (Na2SO4), and concentrated under re-
duced pressure. The residue was purified by chromatography elut-
ing with hexane/diethyl ether (95:5–8:2) to afford an E/Z mixture
of the ester 16. The latter oil was dissolved in hexane and stored
overnight at –20 °C. The obtained solid material was recrystallized
twice from hexane to afford isomerically pure ester 16 (E Ͼ 98%
by NMR spectroscopic analysis, 7.2 g, 52% yield) as colorless crys-
(1RS,2SR)-2-[(E)-6-(Furan-3-yl)-3-methylhex-3-enyl]-1,3,3-trimeth-
ylcyclohexanol (19): A solution of epoxide 18 (0.32 g, 1.06 mmol)
in dry THF (4 mL) was added dropwise to a stirred suspension of
LiAlH4 (0.15 g, 3.95 mmol) in THF (10 mL) at reflux temperatures.
As soon as the starting epoxide was no longer detectable by TLC
analysis (3 h), the reaction was cooled (0 °C), diluted with diethyl
ether (50 mL), and quenched by dropwise addition of aqueous
NaOH (40%, 5 mL). The resulting heterogeneous mixture was fil-
tered through a Celite pad and the organic phase was washed with
brine, dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by chromatography by eluting with hex-
ane/diethyl ether (95:5–9:1) to afford pure 19 (215 mg, 67% yield)
as a colorless oil. 1H NMR (400 MHz, C6D6): δ = 7.13 (t, J =
1.5 Hz, 1 H), 7.08 (s, 1 H), 6.11 (s, 1 H), 5.26 (t, J = 7.0 Hz, 1 H),
2.39–2.31 (m, 2 H), 2.20 (q, J = 7.3 Hz, 2 H), 2.11–1.95 (m, 2 H),
1.83 (qt, J = 13.7, 3.3 Hz, 1 H), 1.67–1.56 (m, 1 H), 1.58 (s, 3 H),
1.50–0.95 (m, 6 H), 1.09 (s, 3 H), 1.00 (s, 3 H), 0.88 (s, 3 H), 0.70
(dd, J = 4.9, 2.7 Hz, 1 H), 0.50 (br. s, 1 H) ppm. 13C NMR
(100 MHz, C6D6): δ = 142.9 (CH), 139.2 (CH), 136.7 (C), 125.2
(C), 124.0 (CH), 111.3 (CH), 72.5 (C), 54.1 (CH), 44.0 (CH2), 42.4
(CH2), 41.7 (CH2), 35.0 (C), 32.3 (Me), 31.1 (Me), 28.9 (CH2), 25.4
(CH2), 25.2 (CH2), 21.8 (Me), 18.8 (CH2), 16.3 (Me) ppm. MS
(ESI): m/z = 327.6 [M + Na]+.
1
tals, m.p. 68–70 °C. H NMR (400 MHz, CDCl3): δ = 9.21 (t, J =
2.1 Hz, 1 H), 9.16 (d, J = 2.1 Hz, 2 H), 5.54 (t, J = 7.2 Hz, 1 H),
4.98 (d, J = 7.2 Hz, 2 H), 2.95 (s, 1 H), 2.44–2.35 (m, 1 H), 2.18–
2.08 (m, 1 H), 1.93 (dd, J = 15.5, 6.2 Hz, 1 H), 1.88–1.77 (m, 1 H),
(4R,6S)-4-Acetoxy-γ-ionone (22), (4S,6R)-4-Hydroxy-γ-ionone (20),
and (4R,6S)-4-Acetoxy-γ-dihydroionone (23): Trifluoroacetic an-
hydride (54 g, 257 mmol) was added dropwise at 0 °C to a stirred
1.84 (s, 3 H), 1.62–1.45 (m, 2 H), 1.41–1.20 (m, 2 H), 1.34 (s, 3 H), suspension of hydrogen peroxide-urea adduct (25 g, 266 mmol) in
0.90 (s, 3 H), 0.90–0.79 (m, 1 H), 0.84 (s, 3 H) ppm. 13C NMR
CH3CN (70 mL). As soon as the solid dissolved, the resulting solu-
(100 MHz, CDCl3): δ = 162.5, 148.7, 145.2, 134.3, 129.4, 122.2, tion (the temperature of which was kept constant at 0 °C) was
116.8, 63.7, 60.1, 59.5, 47.0, 39.4, 31.5, 27.8, 27.3, 26.9, 26.9, 25.7, added over 10 min, to a cooled (–78 °C) and mechanically stirred
22.0, 16.8 ppm. MS (ESI): m/z = 455.4 [M + Na]+.
mixture of K2CO3 (100 g, 724 mmol), α-ionone (38 g, 198 mmol),
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43610
/KAP1
Date: 16-02-15 12:49:09
Pages: 10
First Enantioselective Synthesis of Marine Diterpene Ambliol-A
and CH2Cl2 (300 mL). The reaction was allowed to warm to –50 °C
and was stirred at this temperature for a further hour. The reaction
was then added to a stirred solution of Na2S2O5 (30 g, 158 mmol)
in iced water (400 mL). The organic phase was separated and the
aqueous layer was extracted with CH2Cl2 (150 mL). The combined
organic phases were washed with brine, dried (Na2SO4), and con-
less oil. The latter compound is very unstable in acid environments,
so TLC analysis and optical rotation measurements in chloroform
gave unreliable results. Therefore, a small amount (about 0.1%
w/w) of Cy2NMe was added to compound 25 to ensure chemical
stability and to perform NMR spectroscopic analysis. 1H NMR
(400 MHz, CDCl3): δ = 4.85 (dd, J = 9.8, 4.6 Hz, 1 H), 3.14 (s, 6
centrated under reduced pressure. The residue was purified by H), 2.85 (d, J = 4.7 Hz, 1 H), 2.63 (d, J = 4.7 Hz, 1 H), 2.03–1.93
chromatography by eluting with hexane/ethyl acetate (9:1–7:3) as
(m, 1 H), 2.01 (s, 3 H), 1.80–1.70 (m, 1 H), 1.70–1.62 (m, 1 H),
1.62–0.98 (m, 6 H), 1.23 (s, 3 H), 1.03 (s, 3 H), 0.86 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.7, 101.5, 71.7, 58.9, 49.1,
47.9, 47.9, 46.0, 37.7, 36.8, 36.0, 29.6, 27.1, 22.0, 20.9, 20.7,
18.5 ppm. MS (ESI): m/z (%) = 337.1 [M + Na]+.
eluent to afford pure epoxy-α-ionone 12 (37.2 g, 90% yield) as a
1
colorless oil; cis/trans ratio, 94:6 by H NMR spectroscopic analy-
sis.
According to the procedure described in ref.[10] a sample of cis-
epoxy-α-ionone 12 (35 g, 168 mmol) obtained as above was trans-
formed into cis-4-hydroxy-γ-ionone (20; 27.7 g, 133 mmol, 79%
yield, 96% chemical purity by GC, cis/trans ratio, 93:7 by NMR
spectroscopic analysis). The following lipase PS-mediated acetyl-
ation reaction afforded (4R,6S)-4-acetoxy-γ-ionone [(+)-22; 12.4 g,
49.6 mmol, 37% yield, 98% chemical purity and more than 98%
(1R,2R,6S)-6-(3,3-Dimethoxybutyl)-1,5,5-trimethylcyclohexane-1,2-
diol (26): Epoxide 25 (7.3 g, 23.2 mmol) in dry diethyl ether (30 mL)
was added dropwise to a stirred suspension of LiAlH4 (1.3 g,
34.2 mmol) in diethyl ether (50 mL) at reflux temperatures. As soon
as the starting epoxide was transformed into diol 26 (TLC analysis,
1 h), the reaction was cooled (0 °C), diluted with ether (100 mL),
and quenched by dropwise addition of aqueous NaOH (40 %,
30 mL), before being stirred vigorously for 1 h. The resulting
heterogeneous mixture was filtered through a Celite pad and the
organic phase was washed with brine, dried (Na2SO4), and concen-
trated under reduced pressure. The residue of almost pure diol 26
(5.95 g, 93% yield), which was very unstable in acid environments,
could not be purified by chromatography. Therefore compound 26
was immediately used without further purification in the next step.
de by GC analysis, ee 95% by chiral GC analysis] with a [α]2D0
=
+21.5 (c = 1.9, CHCl3), and (4S,6R)-4-hydroxy-γ-ionone [(+)-20;
14.9 g, 71.6 mmol, 54 % yield, 70 % ee, cis/trans ratio, 88:12 by
NMR analysis] with a [α]2D0 = +5.2 (c = 1.9, CHCl3).
According to the procedure described in ref.[12] the hydrogenation
of (4R,6S)-4-acetoxy-γ-ionone [(+)-22; 12 g, 48 mmol] in THF/
methanol (5:1, 120 mL) with activated Raney nickel as catalyst gave
(4R,6S)-4-acetoxy-γ-dihydroionone [(–)-23; 10.8 g, 89% yield, 96%
chemical purity by GC] with a [α]2D0 = –22.8 (c = 1.8, CHCl3).
(4aS,8R,8aR)-2,5,5,8a-Tetramethyl-4a,5,6,7,8,8a-hexahydro-4H-
chromen-8-yl Methanesulfonate (27): A solution of crude diol 26
(0.14 g, 0.51 mmol) in pyridine (5 mL) was treated with mesyl
chloride (0.2 mL, 2.58 mmol) and DBU (0.4 mL, 2.68 mmol), and
stirred at room temperature overnight. The reaction was diluted
with CH2Cl2 and the organic phase was washed with saturated
aqueous NaHCO3 and brine, and then dried (Na2SO4) and concen-
trated under reduced pressure. The residue was purified by
chromatography by eluting with hexane/ethyl acetate (9:1–8:2) to
afford pure (–)-27 (90 mg, 61% yield) as colorless crystals, m.p. 65–
(3S,4R,8S)-7,7-Dimethyl-8-(3-oxobutyl)-1-oxaspiro[2.5]octan-4-yl
Acetate (24): mCPBA (5.8 g, 77% w/w, 25.9 mmol) was added por-
tionwise to a cooled (0 °C) and stirred solution of ketone (–)-23
(5.5 g, 21.8 mmol) in CH2Cl2 (40 mL). After the addition was com-
plete, the reaction was left to warm to room temperature and stir-
ring was continued for 12 h. The precipitated m-chlorobenzoic acid
was filtered off and the organic phase was diluted with CH2Cl2
(80 mL) and was washed in turn with aqueous Na2S2O5 (5 %,
50 mL), saturated aqueous NaHCO3 (100 mL), and with brine. The
obtained organic solution was dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by chromatog-
raphy by eluting with hexane/ethyl acetate (9:1–7:3) as eluent to
67 °C. [α]2D0 = –1.4 (c = 2.1, CHCl3). H NMR (400 MHz, CDCl3):
1
δ = 4.51–4.47 (m, 1 H), 4.51 (dd, J = 12.2, 4.9 Hz, 1 H), 3.11 (s, 3
H), 2.05–1.76 (m, 4 H), 1.66 (br. s, 3 H), 1.57–1.39 (m, 3 H), 1.22
(s, 3 H), 0.92 (s, 3 H), 0.85 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 147.3, 95.1, 88.5, 77.8, 47.6, 39.2, 38.1, 32.8, 31.4,
27.1, 20.5, 19.9, 18.9, 13.7 ppm. GC–MS (EI): m/z (%) = 288
[M]+ (45), 192 (44), 177 (75), 159 (21), 149 (88), 136 (96), 121 (79),
107 (100), 93 (95), 79 (52), 69 (29), 55 (30).
1
afford pure (–)-24 (4.15 g, 71% yield) as a colorless oil. H NMR
(400 MHz, CDCl3): δ = 4.89 (dd, J = 10.6, 4.8 Hz, 1 H), 2.84 (d,
J = 4.6 Hz, 1 H), 2.67 (d, J = 4.6 Hz, 1 H), 2.65 (ddd, J = 17.8,
9.5, 5.3 Hz, 1 H), 2.41 (ddd, J = 17.8, 9.5, 6.1, Hz, 1 H), 2.09 (s, 3
H), 2.01 (s, 3 H), 1.96 (dq, J = 12.9, 4.4 Hz, 1 H), 1.72–1.51 (m, 3
H), 1.50–1.39 (m, 2 H), 1.31–1.18 (m, 1 H), 1.03 (s, 3 H), 0.86 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 208.6, 169.9, 71.5,
59.6, 48.1, 45.7, 44.4, 37.7, 36.2, 29.9, 29.8, 27.3, 21.3, 20.9,
17.9 ppm. GC–MS (EI): m/z (%) = 268 [M]+ (Ͻ1), 250 (1), 226 (2),
208 (29), 190 (26), 175 (26), 165 (100), 151 (71), 138 (79), 123 (60),
109 (81), 95 (64), 81 (58), 67 (35), 55 (40). [α]2D0 = –9.8 (c = 2.2,
CHCl3).
(1R,2S,6S)-2-(3,3-Dimethoxybutyl)-1,3,3-trimethyl-7-oxabicyclo-
[4.1.0]heptane (28): A solution of diol 26 (4.2 g, 15.3 mmol) in dry
THF (25 mL) at 0 °C under nitrogen was treated with LDA
(14.9 mL of a 1.05 m solution in THF) followed by dropwise ad-
dition of mesyl chloride (1.9 g, 16.6 mmol, in 4 mL of dry THF).
The mixture was stirred for half an hour at 0 °C, then LDA
(14.9 mL of a 1.05 m solution in THF) was added dropwise, the
(3S,4R,8S)-8-(3,3-Dimethoxybutyl)-7,7-dimethyl-1-oxaspiro[2.5]- reaction was left to warm to room temperature. The reaction mix-
octan-4-yl Acetate (25): A solution of (–)-24 (2.4 g, 8.94 mmol) in
methanol (20 mL) and trimethyl orthoformate (10 mL) was treated
with pyridinium p-toluenesulfonate (0.2 g, 0.8 mmol) and stirred at
room temperature for 6 h. The reaction was then quenched by ad-
dition of Et3N (2 mL), diluted with ethyl acetate (100 mL), and
washed with saturated aqueous NaHCO3 and with brine. The ob-
tained organic solution was dried (Na2SO4) and concentrated un-
der reduced pressure, and the residue was purified by filtration
through a short silica gel column by eluting with hexane/ethyl acet-
ate (7:3) as eluent to afford pure 25 (2.62 g, 93% yield) as a color-
ture was stirred for a further 12 h, before being quenched by di-
lution with diethyl ether (250 mL) and water (100 mL). The organic
phase was washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by chromatog-
raphy by eluting with hexane/diethyl ether (95:5–9:1) to afford pure
1
(–)-28 (2.55 g, 65% yield) as a colorless oil. H NMR (400 MHz,
CDCl3): δ = 3.19 (s, 3 H), 3.17 (s, 3 H), 2.89 (br. s, 1 H), 2.01–1.78
(m, 3 H), 1.72–1.59 (m, 1 H), 1.56–1.43 (m, 1 H), 1.42–1.21 (m, 3
H), 1.35 (s, 3 H), 1.29 (s, 3 H), 1.11–1.00 (m, 1 H), 0.90 (s, 3 H),
0.75 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 101.7, 61.0,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 16-02-15 12:49:09
Pages: 10
S. Serra, V. Lissoni
FULL PAPER
58.8, 50.4, 48.0, 48.0, 38.9, 33.9, 32.0, 29.5, 22.6, 22.1, 21.7, 20.9,
19.9 ppm. MS (ESI): m/z = 279.4 [M + Na]+. [α]2D0 = –26.5 (c = 2,
CHCl3).
(E)-3-Methyl-5-[(1R,2S,6S)-1,3,3-trimethyl-7-oxabicyclo[4.1.0]-
heptan-2-yl]pent-2-enyl 3,5-Dinitrobenzoate (30): According to the
procedure outlined for the synthesis of compound 16, ester 29
(2.75 g, 9.82 mmol) was transformed into ester 30 as a 5:1 mixture
of E/Z isomers. The latter material remained an oil even at low
temperature (–20 °C) and by using either hexane or methanol as
solvents. Through chromatographic separation by using n-hexane/
diethyl ether (99:1–95:5) as eluent a sample of (–)-30 was obtained
as a colorless oil as a 92:8 E/Z mixture (2.1 g, 49% yield). 1H NMR
(400 MHz, CDCl3): δ = 9.20 (t, J = 2.1 Hz, 1 H), 9.16 (d, J =
2.1 Hz, 2 H), 5.54 (t, J = 7.3 Hz, 1 H), 4.98 (d, J = 7.3 Hz, 2 H),
2.89 (s, 1 H), 2.42–2.29 (m, 1 H), 2.18–2.07 (m, 1 H), 1.95 (dd, J
= 15.3, 5.8 Hz, 1 H), 1.91–1.78 (m, 1 H), 1.84 (s, 3 H), 1.65–1.20
(m, 4 H), 1.36 (s, 3 H), 1.07 (ddd, J = 13.5, 6.0, 1.8 Hz, 1 H), 0.88
(s, 3 H), 0.75 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
162.5, 148.7, 144.2, 134.3, 129.4, 122.2, 117.6, 63.6, 60.9, 58.7, 49.4,
41.6, 34.0, 31.9, 29.5, 25.6, 22.7, 21.6, 19.9, 16.8 ppm. MS (ESI):
m/z = 455.4 [M + Na]+. [α]2D0 = –9.9 (c = 1.9, CHCl3).
(4aS,8aS)-2,5,5,8a-Tetramethyl-4a,5,6,7,8,8a-hexahydro-4H-
chromene (3): LiEt3BH (2 mL of a 1 m solution in THF) was added
dropwise under nitrogen to a stirred solution of epoxide (–)-28
(0.2 g, 0.78 mmol) in dry THF (3 mL) at 0 °C. After the addition
was complete, the reaction was left to warm to room temperature
and was stirred until the starting epoxide was not longer detectable
by TLC analysis (6 h). The mixture was then diluted with diethyl
ether, quenched with HCl (3% aq.), and stirred for 15 min. The
organic phase was separated and the aqueous phase was extracted
with diethyl ether. The combined organic phases were washed with
saturated aqueous NaHCO3 and brine, dried (Na2SO4), and con-
centrated under reduced pressure. The residue was purified by
chromatography by eluting with hexane/diethyl ether (95:5–8:2) fol-
lowed by bulb-to-bulb distillation to afford pure (–)-3 (0.115 g,
1
76% yield) as a colorless oil. H NMR (400 MHz, C6D6): δ = 4.45
(1R,2S,6S)-2-[(E)-6-(Furan-3-yl)-3-methylhex-3-enyl]-1,3,3-trimeth-
yl-7-oxabicyclo[4.1.0]heptane (8): According to the procedure out-
lined for the synthesis of compound 18, ester (–)-30 (0.29 g,
0.67 mmol) gave epoxide (–)-8 (0.18 g, 89% yield) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.33 (t, J = 1.5 Hz, 1 H), 7.21
(m, 1 H), 6.27 (s, 1 H), 5.21 (t, J = 7.0 Hz, 1 H), 2.88 (s, 1 H),
2.49–2.43 (m, 2 H), 2.31–2.18 (m, 3 H), 2.12–1.90 (m, 2 H), 1.89–
1.78 (m, 1 H), 1.61 (s, 3 H), 1.55–1.25 (m, 4 H), 1.35 (s, 3 H), 1.05
(ddd, J = 13.4, 6.0, 1.8 Hz, 1 H), 0.85 (s, 3 H), 0.73 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 142.5, 138.8, 135.7, 124.9, 124.3,
111.1, 60.9, 58.9, 49.3, 41.9, 34.0, 31.8, 29.5, 28.5, 26.1, 25.0, 22.7,
21.7, 19.9, 16.1 ppm. MS (ESI): m/z = 303.5 [M + H]+, 325.5 [M
+ Na]+. [α]2D0 = –19.9 (c = 1.8, CHCl3).
(br. d, J = 5.3 Hz, 1 H), 1.89–1.79 (m, 2 H), 1.74 (m, 3 H), 1.74–
1.66 (m, 1 H), 1.60–1.43 (m, 2 H), 1.42–1.26 (m, 2 H), 1.23 (dm, J
= 13.2 Hz, 1 H), 1.17 (s, 3 H), 1.14–1.02 (m, 1 H), 0.78 (s, 3 H),
0.68 (s, 3 H) ppm. 13C NMR (100 MHz, C6D6): δ = 148.6, 94.7,
76.3, 48.7, 42.0, 40.5, 33.3, 32.4, 20.9, 20.6, 20.1, 19.6, 19.4 ppm.
GC–MS (EI): m/z (%) = 194 [M]+ (30), 179 (11), 161 (19), 151 (7),
136 (13), 123 (27), 109 (100), 95 (22), 81 (24), 71 (21), 55 (16).
[α]2D0 = –20.8 (c = 1.5, CHCl3).
4-[(1R,2S,6S)-1,3,3-Trimethyl-7-oxabicyclo[4.1.0]heptan-2-yl]butan-
2-one (11): A solution of ketal (–)-28 (2.1 g, 8.2 mmol) in THF/
H2O (7:3, 20 mL) was treated with pyridinium p-toluenesulfonate
(60 mg, 0.24 mmol) and stirred at room temperature until the start-
ing ketal was not longer detectable by TLC analysis (4 h). The reac-
tion was quenched by addition of saturated aqueous NaHCO3
(50 mL) and the resulting mixture was extracted with CH2Cl2
(2ϫ60 mL). The combined organic phases were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. The resi-
due was purified by chromatography by eluting with hexane/ethyl
acetate (9:1–7:3) to afford pure (–)-11 (1.64 g, 95% yield) as a col-
orless oil. 1H NMR (400 MHz, CDCl3): δ = 2.88 (s, 1 H), 2.70
(ddd, J = 17.7, 9.9, 4.9 Hz, 1 H), 2.53 (ddd, J = 17.7, 9.3, 6.6 Hz,
1 H), 2.15 (s, 3 H), 1.95 (dd, J = 15.4, 6.0 Hz, 1 H), 1.90–1.75 (m,
2 H), 1.60–1.46 (m, 1 H), 1.37–1.22 (m, 2 H), 1.31 (s, 3 H), 1.10–
1.02 (m, 1 H), 0.90 (s, 3 H), 0.76 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 207.9 (C), 61.0 (CH), 58.5 (C), 49.6 (CH),
45.6 (CH2), 33.9 (CH2), 31.9 (C), 30.0 (Me), 29.4 (Me), 22.5 (Me),
21.5 (CH2), 21.1 (CH2), 19.7 (Me) ppm. GC–MS (EI): m/z (%) =
210 [M]+ (4), 195 (93), 177 (16), 167 (60), 152 (77), 137 (57), 121
(50), 109 (100), 95 (78), 81 (49), 69 (58), 55 (61). [α]2D0 = –34.8 (c =
1.7, CHCl3).
(1S,2S)-2-[(E)-6-(Furan-3-yl)-3-methylhex-3-enyl]-1,3,3-trimethyl-
cyclohexanol (1): LiEt3BH (2 mL of a 1 m solution in THF) was
added dropwise under nitrogen to a stirred solution of epoxide
(–)-8 (0.18 g, 0.60 mmol) in dry THF (3 mL) at 0 °C. After the
addition was complete, the reaction was left to warm to room tem-
perature and the reaction mixture was stirred until the starting ep-
oxide was not longer detectable by TLC analysis (6 h). The reaction
was then quenched with aqueous NaOH (5%, 20 mL) and ex-
tracted with diethyl ether (2ϫ30 mL). The combined organic
phases were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by chromatog-
raphy by eluting with hexane/diethyl ether (95:5–9:1) to afford pure
1
(+)-1 (165 mg, 91% yield) as a colorless oil. H NMR (400 MHz,
C6D6): δ = 7.13 (t, J = 1.5 Hz, 1 H), 7.09 (s, 1 H), 6.11 (s, 1 H),
5.29 (t, J = 7.0 Hz, 1 H), 2.45–2.09 (m, 6 H), 1.73–1.52 (m, 2 H),
1.62 (s, 3 H), 1.45–1.03 (m, 7 H), 1.07 (s, 3 H), 0.91 (s, 3 H), 0.74
(s, 3 H), 0.66 (br. s, 1 H) ppm. 13C NMR (100 MHz, C6D6): δ =
142.8 (CH), 139.2 (CH), 137.1 (C), 125.2 (C), 124.2 (CH), 111.3
(CH), 73.6 (C), 56.8 (CH), 44.0 (CH2), 43.2 (CH2), 41.9 (CH2),
35.6 (C), 33.0 (Me), 28.9 (CH2), 25.4 (CH2), 25.3 (CH2), 23.6 (Me),
21.6 (Me), 20.9 (CH2), 16.2 (Me) ppm. MS (ESI): m/z = 327.6 [M
+ Na]+. [α]2D0 = +4.0 (c = 1.8, CHCl3).
Ethyl (E)-3-Methyl-5-[(1R,2S,6S)-1,3,3-trimethyl-7-oxabicyclo-
[4.1.0]heptan-2-yl]pent-2-enoate (29): According to the procedure
outlined for the synthesis of compound 15, ketone (–)-11 (1.79 g,
8.51 mmol) gave ester 29 (2.18 g, 91% yield) as a colorless oil as
a E/Z mixture of isomers (E/Z ratio, 5:1, by NMR spectroscopic
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR spectra of the key intermediates and
final products.
1
analysis). E Isomer: H NMR (400 MHz, CDCl3): δ = 5.70 (m, 1
H), 4.16 (q, J = 7.1 Hz, 2 H), 2.89 (br. s, 1 H), 2.42 (ddd, J = 14.2,
11.2, 4.3 Hz, 1 H), 2.21–2.10 (m, 1 H), 2.19 (d, J = 1.2 Hz, 3 H),
1.96 (ddt, J = 15.4, 5.9, 1.7 Hz, 1 H), 1.90–1.80 (m, 1 H), 1.65–
1.56 (m, 1 H), 1.53–1.24 (m, 3 H), 1.35 (s, 3 H), 1.28 (t, J = 7.1 Hz,
3 H), 1.07 (ddd, J = 13.4, 5.9, 1.7 Hz, 1 H), 0.88 (s, 3 H), 0.74 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.7, 159.3, 115.8,
60.9, 59.5, 58.6, 49.6, 43.1, 33.9, 31.9, 29.4, 25.7, 22.6, 21.6, 19.8,
18.9, 14.3 ppm. MS (ESI): m/z = 303.5 [M + Na]+.
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First Enantioselective Synthesis of Marine Diterpene Ambliol-A
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Received: December 10, 2014
Published Online: ᭿
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9

Job/Unit: O43610
/KAP1
Date: 16-02-15 12:49:09
Pages: 10
S. Serra, V. Lissoni
FULL PAPER
Natural Products
S. Serra,* V. Lissoni ....................... 1–10
First Enantioselective Synthesis of Marine
Diterpene Ambliol-A
The enantioselective synthesis of diterpene
(+)-ambliol-A and diastereoselective syn-
thesis of its non-natural epimer are ac-
complished from racemic α-ionone. The
key steps are diastereoselective epoxid-
ation, lipase-mediated resolution, and cop-
per-catalyzed cross coupling. The chemical
structure of natural ambliol-A is confirmed
and its absolute configuration corrected
and now assigned as (1R,2R).
Keywords: Natural products / Total syn-
thesis / Biocatalysis / Terpenoids / Cross-
coupling
10
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