Synthetic studies of sesquiterpenes with the dunniane skeleton

Article abstract of DOI:10.1002/ejoc.201101614

The first synthetic approach to the entire carbon skeleton of the sesquiterpenes dunniane and cumacrene has been developed. The sequence features a [2+2] photochemical reaction of a chiral 2(5H)-furanone with ethylene to form the cyclobutane, a Meyer-Schu

Full text of DOI:10.1002/ejoc.201101614

FULL PAPER
DOI: 10.1002/ejoc.201101614
Synthetic Studies of Sesquiterpenes with the Dunniane Skeleton
Sònia Parés,[a] Ramon Alibés,*[a] Marta Figueredo,[a] Josep Font,[a] and Teodor Parella[b]
Keywords: Photochemistry / Cycloaddition / Natural products / Small ring systems
The first synthetic approach to the entire carbon skeleton of
the sesquiterpenes dunniane and cumacrene has been devel-
oped. The sequence features a [2+2] photochemical reaction
of a chiral 2(5H)-furanone with ethylene to form the cyclo-
butane, a Meyer–Schuster-type rearrangement of an α-acety-
lenic alcohol to an α,β-unsaturated aldehyde, and a micro-
wave-assisted Diels–Alder reaction of an elaborated dien-
amine with methyl acrylate to construct the six-membered
ring with the desired 1,4-substitution pattern.
pended to a cyclobutane substituted by vicinal methyl and
isopropenyl groups arranged in a cis relative configuration.
Unfortunately, the stereochemical assignment at C-4 was
not established at the time of isolation.[3]
The peculiar cyclohexenylcyclobutane structure of dun-
niane was subsequently identified as a structural motif of
cumacrene (2), a compound isolated from the foliage of Cu-
pressus macroparga (Monterey cypress).[4] Besides the sub-
stitution at C-1, cumacrene differs from dunniane in the
relative configuration of C1Ј and C2Ј. This epimeric rela-
tionship is similar to that found in the cyclobutane mono-
terpenoids fraganol[5] (3) and grandisol[6] (4).
The challenging structural features and the lack of any
synthetic studies render dunniane and cumacrene attractive
targets for further exploration. As part of our research pro-
gram directed towards the preparation of naturally occur-
ring cyclobutane compounds,[7] we have recently embarked
on the synthesis of dunniane and cumacrene. Herein, we
report our endeavors towards the preparation of the entire
carbon skeleton of 1 and 2.
Introduction
Cyclobutanes are found in many naturally occurring
compounds with biological activities that have important
implications in the fields of agriculture and pharmaceuti-
cals.[1] Illicium dunianum Tutcher is a poisonous plant indig-
enous to Southern China, the extracts of which have long
been used as folk medicines in Hong Kong. This ethnobot-
anical information has stimulated research efforts to ident-
ify the biologically active components of the extract.
Among them, the sesquiterpenoid carboxylic acid 1, known
as dunniane, was recently isolated by Sy and Brown (Fig-
ure 1).[2] The structure and relative configuration of 1 was
determined by NMR spectroscopy and it was proposed that
it is formed in vivo by farnesyl pyrophosphate cyclization.
This novel sesquiterpene presents a cyclohexene moiety ap-
Results and Discussion
Our retrosynthetic analysis of the sesquiterpenes 1 and 2
proceeds by the initial interconversion of the isopropenyl
chain to the methyl ketones 5 and 6 as possible precursors
(Scheme 1). In considering a general approach that would
provide 1 and 2, we envisaged the methyl ketone fragment
as a means to modulate the configuration at C-2Ј. An epi-
merization step is intended to serve as a branching point
from which 1 and 2 can be accessed. The cyclohexene moi-
ety was visualized to be formed by a Diels–Alder reaction
(DAR) through two alternative pathways involving either
the vinyl sulfone 9 or the dienamine 11. We traced both
Diels–Alder intermediates back to triol 12, which in turn
can be derived from the bicyclic lactone 13. Disassembly
of the cyclobutane suggests 2(5H)-furanone 14 as a chiral
Figure 1. Cyclobutane terpenoids.
[a] Department de Química, Universitat Autònoma de Barcelona,
08193 Bellaterra, Barcelona, Spain
Fax: +34-935811265
E-mail: ramon.alibés@uab.cat
[b] Servei de Ressonància Magnètica Nuclear, Universitat
Autónoma de Barcelona,
08193 Bellaterra, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101614.
1404
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1404–1417

Synthesis of Sesquiterpenes with the Dunniane Skeleton
platform in a diastereoselective [2+2] photochemical cyclo-
addition reaction with ethylene. Finally, 14 can be prepared
from the known lactone 15.
Scheme 1. Retrosynthetic analysis of sesquiterpenoids 1 and 2.
From the outset, the construction of the cyclohexene
moiety with a 1,4-substitution pattern was considered the
central issue of our synthetic strategy. Phenyl vinyl sulfones
Scheme 2. Photochemical reaction and attempts to prepare 9.
have been used as a convenient terminal olefin equivalent be isolated in 64% yield. The relative configurations of the
in the DAR with isoprene (7) and other dienes because the cycloadducts was determined by the chemical shift of the
sulfonyl group can be easily removed reductively.[8] Never- angular carbon of the methyl group, which, because of the
theless, in our approach the regiochemical outcome of the larger “steric compression” due to the cis arrangement of
cycloaddition of 9 to 7 or 2-methoxycarbonyl-1,3-butadi- the methyl and the silyloxymethyl substituents, is shifted
ene[9] (8) was uncertain and should be investigated. On the upfield (δ = 17.7 ppm) in the anti isomer compared with in
other hand, the use of dienamines as Diels–Alder dienes is the syn isomer (δ = 22.3 ppm).[12]
well documented and it has been shown that they react
Lactone 13 was then subjected to reduction with
readily with methyl acrylate (10) in a highly regioselective DIBAL-H in toluene to provide exclusively lactol 17 in 80%
manner to afford cycloadducts with the appropriate regi- yield, which was sequentially treated with MeLi and TBAF
ochemistry for our synthetic purposes.[10] After the cyclo- to afford a 1:1 mixture of the epimeric triols (1ЈЈR)- and
addition, removal of the amino activating group can be ef- (1ЈЈS)-12 in 91% overall yield for the two steps. The forma-
ficiently accomplished.
tion of 12 as a mixture is not problematic as both epimers
Attention was initially focused on the strategy involving would give access to the same intermediate ketone 5 or 6.
the vinyl sulfone 9 because the synthesis of the dienamine Condensation of 12 with 1,1Ј-thiocarbonyldiimidazole
11 was expected to be more intricate. Our synthetic venture (TCDI) provided a 1:1 mixture of the two cyclic thionocar-
started from lactone 15,[11] which was transformed into 14 bonates (1ЈЈR)- and (1ЈЈS)-18 in excellent yield. The second-
in 70% yield by a 1,3-dipolar cycloaddition reaction ary alcohol was protected as the benzoate ester 19 prior to
with CH2N2 followed by pyrolysis in dioxane at reflux treatment with the Corey–Hopkins reagent 20 in the
(Scheme 2).[12]
Corey–Winter reaction,[14] which delivered the olefins
The diastereoselective construction of the cyclobutane (1ЈЈR)- and (1ЈЈS)-21 in 56% yield for the two steps. Intro-
ring was accomplished as planned through a photochemical duction of the phenyl sulfone appendix at the terminal ole-
[2+2] reaction.[13] Thus, irradiation of an acetone solution fin of 21 was next examined through two different method-
of 14 saturated with ethylene with a 400-W high-pressure ologies:[15] photochemically induced selenosulfonation fol-
mercury lamp through a Pyrex filter for 8 h delivered a mix- lowed by oxidative elimination[16] and cross-metathesis with
ture of the anti and syn photoadducts 13 and 16 in a ratio phenyl vinyl sulfone.[17] Unfortunately, despite considerable
of 2.3:1 in 89% yield from which the major isomer 13 could experimentation, all the attempts to obtain 9 from 21 met
Eur. J. Org. Chem. 2012, 1404–1417
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1405

S. Parés, R. Alibés, M. Figueredo, J. Font, T. Parella
FULL PAPER
with failure, leading either to decomposition products or acy of dienamine 11 (Scheme 4). The new sequence started
recovery of the starting material. from acetonide 22. We decided to reverse the configuration
As a consequence, we were forced to find an alternative at C-2Ј prior to cyclohexene elaboration because the use of
approach to the preparation of 9 (Scheme 3). The new se- methyl acrylate as the dienophile would furnish a product
quence began with the protection of the vicinal diol of 12 structurally closer to dunniane than to cumacrene. We an-
by a standard procedure[18] that delivered a mixture of ticipated that the bulky acetonide group at the neighboring
(1ЈЈR)- and (1ЈЈS)-22 in 84% yield along with a small carbon C-1Ј would favor the epimerization process. Thus,
amount of the 1,3-dioxepane 23. The secondary alcohol 22 the mixture of 22 was converted into the corresponding
was then protected as the benzoate ester 24, which was sub- methyl ketone by oxidation with Dess–Martin periodinane
mitted to selective removal of the acetonide group to afford (DMP) and, without isolation, the ketone generated was
the diol 25. Finally, oxidative glycol cleavage followed by treated with Na2CO3 in MeOH[23] at 80 °C under micro-
stereoselective Wittig–Horner reaction with [(diethoxyphos- wave irradiation[24] to provide, after 3 h, a mixture of epi-
phoryl)(phenylsulfonyl)methyl]lithium[19] delivered the α,β- meric ketones (trans/cis = 3.8:1), which was reduced imme-
unsaturated E sulfone 9 in 73% yield as a 1:1 mixture of diately with NaBH4 to deliver three of the four possible
epimers at C-1ЈЈ thereby setting the stage for the Diels– alcohols, (1ЈЈR)-27 (57%), (1ЈЈS)-27 (5%), and (1ЈЈS)-22
Alder reaction.
(18%). The inversion of configuration at C-2Ј in 27 was
proven by NOESY experiments in which cross-peaks be-
tween 2Ј-H and 4-H were observed, and the configuration
at C-1ЈЈ of the major isomer was tentatively assigned as R
based on the Felkin–Anh transition-state model.[25] For the
sake of simplicity, the synthesis was first continued with the
major alcohol (1ЈЈR)-27, although the synthetic sequence
has also been carried out with the mixture of the two iso-
mers 27. Thus, the secondary alcohol was protected as the
benzyl ether 28 because the benzoyl protection used in the
first approach was not compatible with the reaction condi-
Scheme 3. Synthesis of 9 and attempted DAR.
Unfortunately, the cycloaddition reaction of 9 with iso-
prene under a variety of experimental conditions did not
provide any of the expected cycloadducts. Only the starting
sulfone 9 was recovered, even in the presence of a Lewis
acid and/or by using microwave irradiation. Similarly, treat-
ment of 9 with 2-methoxycarbonyl-1,3-butadiene[20] (8) led
to the recovery of the starting dienophile along with di-
methyl mikanekate,[21] the dimerization product of 8, which
suggests that in this case the cycloaddition process cannot
compete with dimerization.
The poor reactivity of 9 in the DAR was evidenced by
the absence of any cycloadduct in the attempted reaction
with Danishefsky’s diene, which has been reported to react
readily with other substituted vinyl sulfones.[22] It is likely
that the presence of the allylic quaternary centre seriously
hampers the ability of 9 to undergo [4+2] cycloaddition re-
actions.
In view of these results, the route involving the vinyl sulf-
one 9 was abandoned and attention was directed towards
developing the alternative approach through the intermedi- acrylate.
Scheme 4. Synthesis of dienamine 11 and the key DAR with methyl
1406
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1404–1417

Synthesis of Sesquiterpenes with the Dunniane Skeleton
tions envisioned for the preparation of 11. Next, 28 was
exposed to a mild acid medium to induce acetonide depro-
tection to furnish diol 29 in 98% overall yield. After oxidat-
ive cleavage of the glycol, the resulting aldehyde 30 was
methylated by treatment with MeLi in THF to produce a
diastereomeric 1:1 mixture of alcohols 31 in 88% yield for
the two steps. This mixture was then oxidized by using
Dess–Martin periodinane (DMP) to give the corresponding
ketone 32.
The stage was now set for the preparation of dienamine
11 and the subsequent DAR.[26] To this end, ketone 32 was
treated with ethynylmagnesium chloride to afford in 93%
yield a 10:1 mixture of the tertiary propargyl alcohols (4S)-
and (4R)-33, which were converted into the α,β-unsaturated
aldehyde 34 by a [3,3] sigmatropic rearrangement catalyzed
by a silylvanadate.[27] Thus, treatment of the mixture of α-
acetylenic alcohols 33 with tris(triphenylsilyl)vanadate(V)
in toluene at 120 °C under microwave irradiation[24] gave
the expected aldehyde 34 along with a minor amount of its
β,γ-unsaturated isomer, but only 34 could be isolated by
purification by column chromatography on silica gel. Treat-
ment of 34 with 40% aq. Me2NH solution in toluene at
90 °C directly afforded the targeted dienamine 11, which,
due to its instability was immediately used in the crucial
DAR. Thus, a solution of 11 and methyl acrylate in toluene
was heated at 150 °C under microwave irradiation[24] for
Scheme 5. Synthesis of 40 with the entire carbon skeleton of dunni-
ane.
The structure and stereochemistry of 40 were established
2.5 h to produce a mixture of four cycloadducts, which were by a series of 1D and 2D NMR experiments. A 1H–1H
not isolated but immediately treated with silica gel in tolu- TOCSY experiment defined the coupled proton system 2Ј-
ene at 90 °C to eliminate Me2NH to afford the cyclohexadi- H/3Ј-H/4Ј-H and the HSQC spectrum allowed the assign-
enoate 35 in 51% yield from 33. The structure of 35 was ment of all the protons and carbons. The trans/cis 1,4-sub-
assigned by 1D and 2D NMR spectroscopy. The 1,4-substi- stitution pattern of the cyclohexane moiety was established
tution pattern of the cyclohexadiene moiety was established on the basis of the chemical shift of 1-H in each isomer.
by an HMBC experiment, which showed an intense three- Assuming an equatorial orientation of the bulky cyclobutyl
bond correlation between C-4 and the vinyl proton 2-H and substituent, the upfield 1-H chemical shift (δ = 2.21 ppm)
the two methylenic protons 6-H and between C-1 and the was correlated with a chair conformation with the ester
vinyl proton 3-H and the two methylenic protons 5-H. group in an equatorial disposition (1,4-cis relationship)
Microwave irradiation was crucial to improve the outcome whereas the downfield shift of 1-H (δ = 2.64 ppm) suggests
of the DAR,[28] affording better yields in shorter reaction a chair conformation with the ester group in an axial dispo-
times in comparison with the reaction performed merely by sition (1,4-trans relationship).
thermal activation.
The 13C NMR spectroscopic data of the synthesized
Having succeeded in elaborating the cyclohexane moiety, compounds 40 were compared with those reported for dun-
we then focused on attaching an additional carbon atom at niane (1)[2] and cumacrene (2).[4] Close inspection of these
C-1ЈЈ of 35 to complete the entire carbon backbone of the data showed that, because of greater steric congestion, the
targeted natural products. Scheme 5 shows our preliminary signals of the angular methyl group in 40 and 1 appear at
studies towards this goal. The envisaged simultaneous hy- a higher field (δ = 17.4 and 17.1 ppm, respectively) than
drogenation of the γ,δ-olefinic linkage and cleavage of the that in 2 (δ = 25.2 ppm). The opposite trend is observed in
benzyl group proved challenging.[29] Thus, standard hydro- the chemical shift of C-4 (δ = 47.4 and 43.4 ppm in 40 and
genation procedures led within minutes to a mixture of the 1, respectively, and 37.8 ppm in 2). These results corrobo-
monohydrogenated compound 36, the saturated benzyl de- rate the cis relative configuration of the vicinal methyl and
rivative 37, and the saturated alcohol 38. When the reaction isopropenyl groups in 1.
was left for 10 min, only 38 was isolated in excellent yield
The investigations were then focused on the introduction
(95%) as a 1:1 mixture of epimers at C-1. At this point, it of the α,β-unsaturation into the six-membered carbocycle
was decided to complete the isopropenyl chain on 38. The of 40. Unfortunately, this transformation proved more
alcohol was oxidized under Dess–Martin conditions to pro- problematic than was expected. Our attempts, including α-
vide ketone 39, which was immediately subjected to a bromination/dehydrobromination (Br2, diethyl ether,
methylenation reaction to afford compound 40, with the en- –10 °C/DBU, dioxane, 100 °C)[31] and α-selenation/selen-
tire carbon skeleton of 1, as a 1:1 mixture of inseparable oxide elimination (LDA, PhSeBr, prepared by cleavage of
diastereomers in 77% overall yield for the two steps.[30]
PhSeSePh with Br2, THF, –78 °C/H2O2, CH2Cl2)[32] either
Eur. J. Org. Chem. 2012, 1404–1417
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1407

S. Parés, R. Alibés, M. Figueredo, J. Font, T. Parella
FULL PAPER
with a mass spectrometer. Optical rotations were measured at
22Ϯ2 °C.
led to no chemical change or, under more drastic condi-
tions, afforded complex mixtures of products.
Microwave reactions were conducted with a CEM DiscoverTM Mi-
crowave synthesizer. The machine consists of a continuous focused
microwave power delivery system with operator-selectable power
output in the range of 0 to 300 W. The temperature of the contents
of the vessel was monitored by using a calibrated infrared tempera-
ture control mounted under the reaction vessel. All experiments
were performed by using a stirring option whereby the contents of
the vessel were stirred by means of a rotating magnetic plate located
below the floor of the microwave cavity and a TeflonTM-coated
magnetic stirring bar in the vessel.
In the light of these results, consideration was then given
to the selective hydrogenation of the γ,δ-olefinic linkage
prior to the hydrogenolysis of the benzyl group in com-
pound 35. We were pleased to find that the catalytic hydro-
gen-transfer reduction[33] with 1 equiv. of ammonium for-
mate in the presence of 10% Pd/C in THF/MeOH delivered
a 1:1 chromatographically inseparable mixture of the
monohydrogenation compounds (4S)- and (4R)-36 in high
yield. Interestingly, the reaction with 2 equiv. of ammonium
formate afforded a mixture of compounds 36–38. Next,
cleavage of the benzyl protecting group without affecting
the alkene function was targeted.[34] Thus, 36 was exposed
to BBr3 in CH2Cl2 at –78 °C. However, this reaction deliv-
ered only a minor amount of the expected alcohols 41
(13%) together with their dehydration products 42 (47%).
Unfortunately, and although a number of experimental
(S)-5-tert-Butyldimethylsilyloxymethyl-4-methyl-2(5H)-furanone
(14): A freshly distilled solution of diazomethane (2.18 g,
10.2 mmol), generated in situ from N-methyl-N-nitroso-p-toluene-
sulfonamide, in diethyl ether, was added dropwise to an ice-cooled
solution of 15 (621 mg, 2.72 mmol) in THF (8 mL) in a non-frosted
conical flask. The mixture, protected from light, was warmed to
room temp. and stirred for 72 h. Evaporation of the solvent pro-
variables (Lewis acid, temperature, and reaction time) were vided an oil (669 mg, 2.47 mmol, 91% yield), which was dissolved
in dioxane (30 mL) and heated at reflux for 72 h. Then the solvent
was evaporated and the crude was purified by column chromatog-
raphy (hexane/EtOAc, 6:1) to afford 14 (462 mg, 1.91 mmol, 70%
yield) as a white crystalline solid; m.p. 34–36 °C (pentane/EtOAc).
examined, the yield of 41 could not be improved. Further-
more, attempts to increase the production of 41 by using
other debenzylation methodologies were also unsuccess-
ful.[35]
The impossibility of introducing α,β-unsaturation into 40
or accomplishing a clean debenzylation in 36 led our syn-
thetic sequence to a dead end. Nevertheless, we believe that
the preparation and full characterization of the methyl es-
ters trans- and cis-40 will enable, in the near future, the full
[α]D = –81.4 (c = 1.45, CHCl ). IR (ATR): ν = 2996, 1772, 1668,
˜
3
1461, 1176, 853 cm–1. H NMR (360 MHz, CDCl3): δ = 5.82 (m,
1
3
4
1 H, 3-H), 4.81 (ddq, JH,H = 3.8, 3.6, JH,H = 0.7 Hz, 1 H, 5-H),
2
3
2
3.93 (dd, JH,H = 11.3, JH,H = 3.8 Hz, 1 H, 6-H), 3.89 (dd, JH,H
3
4
= 11.3, JH,H = 3.6 Hz, 1 H, 6-H), 2.09 (dd, JH,H = 1.5, 0.7 Hz, 3
H, CH3), 0.85 [s, 9 H, (CH3)3CSi], 0.06 (s, 3 H, CH3Si), 0.05 (s, 3
stereochemical elucidation of the natural sesquiterpenes H, CH3Si) ppm. 13C NMR (90 MHz, CDCl3): δ = 173.2 (C=O),
166.7 (C, C-4), 117.8 (CH, C-3), 84.7 (CH, C-5), 61.7 (CH2, C-6),
25.6 [CH3, (CH3)3CSi], 18.1 [C, (CH3)3CSi], 14.1 (CH3), –5.5 [CH3,
(CH3)2Si], –5.6 [CH3, (CH3)2Si] ppm. HRMS (ESI+): calcd. for
[C12H22O3Si + Na]+ 265.1230; found 265.1230.
dunniane and cumacrene, the complete carbon skeleton of
which has been synthesized for the first time in this work.
(1R,4S,5S)- and (1S,4S,5R)-4-tert-Butyldimethysilyloxymethyl-5-
methyl-3-oxabicyclo[3.2.0]heptan-2-one (13 and 16): A solution of
2(5H)-furanone 14 (2.00 g, 8.25 mmol) in acetone (800 mL) was
placed in a photochemical reactor. The reactor was immersed in a
cooling bath at –40 °C and a stream of MeOH at –15 °C was circu-
lated through the refrigeration jacket. The reaction mixture was
initially degassed by passing ethylene through the solution for
15 min. Then the solution was saturated with ethylene and irradi-
ated through a Pyrex filter for 8 h under nitrogen. Evaporation of
the solvent and purification by column chromatography (hexane to
Conclusions
We have presented herein a synthetic approach to the
entire carbon framework of dunniane in 5% overall yield in
a 20-step sequence. The synthetic route takes advantage of
the inherent chirality of lactone 15 and the key steps are
the stereoselective [2+2] photochemical reaction to con-
struct the cyclobutane ring and a Diels–Alder reaction to
elaborate the six-membered carbocycle. Further efforts
towards the total synthesis of cumacrene and dunniane are hexane/EtOAc, 30:1) provided the anti cycloadduct 13 as a white
solid (1.422 g, 5.26 mmol, 64% yield) and the syn cycloadduct 16
as a colorless oil (557 mg, 2.06 mmol, 25% yield).
currently underway and will be reported in due course.
13: M.p. 73–76 °C (hexane). [α]D = –20.0 (c = 1.2, CHCl3). IR
(ATR): ν = 2928, 2857, 1776, 1462, 1254, 1111, 841 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 4.13 (dd, JH,H = 2.7, 1.5 Hz, 1 H, 4-H),
˜
Experimental Section
3
2
3
2
General: Commercially available reagents were used as received.
The solvents were dried by distillation over the appropriate drying
agents. All reactions were performed avoiding moisture by standard
procedures and under nitrogen. Flash column chromatography was
performed by using silica gel (230–400 mesh). and 13C NMR spec-
tra were recorded at 250, 360, 400, or 600 MHz and 62.5, 90, 100,
or 150 MHz, respectively. NMR signals were assigned with the help
of DEPT, COSY, HMBC, HMQC, and NOESY experiments. 1H
and 13C chemical shifts are reported in ppm (CDCl3, δ = 7.26 and
77.2 ppm, respectively). Infrared peaks are reported in cm–1. Melt-
ing points were determined on a hot stage. HRMS were recorded
3.80 (dd, JH,H = 11.5, JH,H = 2.7 Hz, 1 H, 8-H), 3.69 (dd, JH,H
3
3
= 11.5, JH,H = 1.5 Hz, 1 H, 8-H), 2.63 (d, JH,H = 9.2 Hz, 1 H, 1-
2
3
H), 2.50 (dddd, JH,H = 11.7, JH,H = 9.9, 9.7, 9.2 Hz, 1 H, 7-H),
2.29 (ddd, 2JH,H = 11.7, 3JH,H = 9.7, 9.1 Hz, 1 H, 6-H), 2.04 (dddd,
2JH,H = 11.7, 3JH,H = 9.1, 3.0, 2.1 Hz, 1 H, 7-H), 1.83 (dddd, 2JH,H
= 11.7, JH,H = 9.9, 3.0, JH,H = 2.2 Hz, 1 H, 6-H), 1.40 (s, 3 H,
CH3), 0.85 [s, 9 H, (CH3)3CSi], 0.04 (s, 3 H, CH3Si), 0.03 (s, 3 H,
CH3Si) ppm. 13C NMR (100 MHz, CDCl3): δ = 180.7 (C=O), 86.5
(CH, C-4), 62.2 (CH2, C-8), 44.7 (CH, C-1), 43.7 (C, C-5), 31.9
(CH2, C-6), 25.7 [CH3, (CH3)3CSi], 21.8 (CH2, C-7), 17.9 [C,
(CH3)3CSi], 17.7 (CH3), –5.8 (CH3Si), –5.9 (CH3Si) ppm. HRMS
3
4
1408
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1404–1417

Synthesis of Sesquiterpenes with the Dunniane Skeleton
(ESI+): calcd. for [C14H26O3Si + Na]+ 293.1543; found 293.1554. H, 1ЈЈ-H), 3.85–3.67 (br. s, 3 H, OH), 3.67–3.45 (m, 2 H, 2-H),
C14H26O3Si (270.44): C 62.18, H 9.69; found C 61.85, H 9.83.
2.10–1.87 (m, 2 H, 2Ј-H, 3Ј-H/4Ј-H), 1.84–1.36 (m, 3 H, 3Ј-H/4Ј-
3
H), 1.13 (s, 3 H, CH3C-1Ј), 1.08 (d, JH,H = 6.4 Hz, 3 H, 2ЈЈ-
16: [α]D = +18.9 (c = 2.1, CHCl ). IR (ATR): ν = 2953, 2857, 1780,
˜
3
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 75.0 (CH, C-1), 68.8
(CH, C-1ЈЈ), 62.7 (CH2, C-2), 52.7 (CH, C-2Ј), 42.9 (C, C-1Ј), 27.7
(CH2, C-3Ј/C-4Ј), 22.6 (CH3, CH3C-1Ј), 19.7 (CH3, C-2ЈЈ), 18.5
1462, 1256, 1114, 839 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.11
3
2
3
(dd, JH,H = 6.4, 6.0 Hz, 1 H, 4-H), 3.90 (dd, JH,H = 10.9, JH,H
2
3
= 6.0 Hz, 1 H, 8-H), 3.72 (dd, JH,H = 10.9, JH,H = 6.4 Hz, 1 H,
8-H), 2.67 (m, 1 H, 1-H), 2.44 (m, 1 H, 7-H), 2.40 (m, 1 H, 6-H),
1.98 (m, 1 H, 7-H), 1.70 (m, 1 H, 6-H), 1.38 (s, 3 H, CH3), 0.87 [s,
9 H, (CH3)3CSi], 0.06 (s, 3 H, CH3Si), 0.05 (s, 3 H, CH3Si) ppm.
13C NMR (100 MHz, CDCl3): δ = 179.7 (C=O), 86.1 (CH, C-4),
61.4 (CH2, C-8), 44.7 (CH, C-1), 43.9 (C, C-5), 25.7 [CH3,
(CH3)3CSi], 25.3 (CH2, C-6), 22.3 (CH3), 20.4 (CH2, C-7), 18.1 [C,
(CH3)3CSi], –5.5 (CH3Si), –5.6 (CH3Si) ppm. HRMS (ESI+): calcd.
for [C14H26O3Si + Na]+ 293.1543; found 293.1542.
1
(CH2, C-3Ј/C-4Ј) ppm. Isomer B: H NMR (250 MHz, CDCl3): δ
= 4.18–4.04 (m, 1 H, 1ЈЈ-H), 3.99–3.90 (m, 1 H, 1-H), 3.85–3.67
(br. s, 3 H, OH), 3.67–3.45 (m, 2 H, 2-H), 2.10–1.87 (m, 2 H, 2Ј-
3
H, 3Ј-H/4Ј-H), 1.84–1.36 (m, 3 H, 3Ј-H/4Ј-H), 1.06 (d, JH,H
=
6.0 Hz, 3 H, 2ЈЈ-H), 1.05 (s, 3 H, CH3C-1Ј) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 75.4 (CH, C-1), 65.8 (CH, C-1ЈЈ), 63.0
(CH2, C-2), 52.0 (CH, C-2Ј), 45.0 (C, C-1Ј), 28.8 (CH2, C-3Ј/C-4Ј),
23.2 (CH3, CH3C-1Ј), 20.9 (CH3, C-2ЈЈ), 15.6 (CH2, C-3Ј/C-
4Ј) ppm. IR (ATR): ν = 3379, 3216, 2966, 2879, 1378, 1101 cm–1.
˜
(1R,2R,4S,5S)-4-tert-Butyldimethylsilyloxymethyl-5-methyl-3-oxa-
bicyclo[3.2.0]heptan-2-ol (17): A 1.0 m solution of DIBAL-H
(2.5 mL, 2.5 mmol) was added dropwise to a solution of lactone 13
(270 mg, 0.99 mmol) in dry toluene (25 mL) under nitrogen at
–78 °C. The reaction mixture was stirred at –78 °C for 45 min. The
reaction was quenched by the slow addition of MeOH and then
the mixture was warmed to room temp. Then EtOAc (1.5 mL) and
a saturated solution of NaHCO3 (0.7 mL) were added and the mix-
ture was stirred for 1 h before the addition of anhydrous Na2SO4
(1.0 g). The resulting suspension was stirred vigorously overnight.
The mixture was filtered through Celite and concentrated to dry-
ness under reduced pressure. The crude was purified by column
chromatography (hexane/EtOAc from 30:1 to 20:1) to afford lactol
17 (217 mg, 0.80 mmol, 80% yield) as a colorless oil. [α]D = –8.42
HRMS (ESI+): calcd. for [C9H18O3 + Na]+ 197.1148; found
197.1157.
(4S)-4-{(1S,2R)-2-[(1S)- and (4S)-4-{(1S,2R)-2-[(1R)-1-Hydroxy-
ethyl]-1-methylcyclobutyl}-1,3-dioxolane-2-thione [(1ЈЈS)-18 and
(1ЈЈR)-18]: TCDI (172 mg, 0.86 mmol) was added to a solution of
a mixture of triol 12 (75 mg, 0.43 mmol) in dry THF (8 mL). The
mixture was heated to 55 °C and stirred for 5 h. The solvent was
removed and the crude was purified by column chromatography
(hexane/EtOAc, 2:1) to afford a 1:1 mixture of (1ЈЈS)- and (1ЈЈR)-17
(85 mg, 0.39 mmol, 91% yield). Further column chromatography
(hexane/EtOAc, 3:1) afforded analytical samples of (1ЈЈS)- and
(1ЈЈR)-18.
(1ЈЈS)-18: M.p. 86–89 °C (pentane/EtOAc). [α]D = –10.0 (c = 0.81,
(c = 1.9, CHCl ). IR (ATR): ν = 3369, 2929, 2856, 1462, 1253,
˜
3
CHCl ). IR (ATR): ν = 3429, 2973, 1784, 1484, 1289, 1155 cm–1.
˜
3
1125 cm–1
.
1H NMR (360 MHz, CDCl3): δ = 5.21 (d, JH,H
=
3
1H NMR (360 MHz, CDCl3): δ = 5.28 (dd, JH,H = 8.7, 7.1 Hz, 1
3
3
11.3 Hz, 1 H, 2-H), 4.93 (d, JH,H = 11.3 Hz, 1 H, OH), 3.85 (m,
1 H, 4-H), 3.73 (dd, JH,H = 11.1, JH,H = 2.6 Hz, 1 H, 8-H), 3.63
(dd, JH,H = 11.1, JH,H = 1.8 Hz, 1 H, 8-H), 2.30 (ddd, JH,H
H, 4-H), 4.70 (dd, 2JH,H = 8.8, 3JH,H = 8.7 Hz, 1 H, 5-H), 4.48 (dd,
2
3
2JH,H = 8.8, JH,H = 7.1 Hz, 1 H, 5-H), 3.91 (dq, JH,H = 10.0,
6.2 Hz, 1 H, 1ЈЈ-H), 2.18 (m, 1 H, 2Ј-H), 1.98 (m, 1 H, 3Ј-H), 1.78
(m, 1 H, 4Ј-H), 1.58 (m, 1 H, 4Ј-H), 1.57 (m, 1 H, 3Ј-H), 1.23 (s, 3
3
3
2
3
3
=
4
8.9, 2.7, JH,H = 2.7 Hz, 1 H, 1-H), 2.18 (m, 1 H, 7-H), 2.04 (m, 1
H, 6-H), 1.71 (m, 1 H, 6-H), 1.64 (m, 1 H, 7-H), 1.34 (s, 3 H, CH3),
0.91 [s, 9 H, (CH3)3CSi], 0.11 (s, 6 H, 2 CH3Si) ppm. 13C NMR
(90 MHz, CDCl3): δ = 105.0 (CH, C-2), 88.4 (CH, C-4), 63.7 (CH2,
C-8), 52.9 (CH, C-1), 46.2 (C, C-5), 32.5 (CH2, C-6), 25.8 [CH3,
(CH3)3CSi], 19.4 (CH3), 18.9 (CH2, C-7), 18.1 [C, (CH3)3CSi], –5.8
(CH3Si), –5.9 (CH3Si) ppm. HRMS (ESI+): calcd. for [C14H28O3Si
+ Na]+ 295.1700; found 295.1698.
H, CH3C-1Ј), 1.09 (d, JH,H = 6.2 Hz, 3 H, 2ЈЈ-H) ppm. 13C NMR
3
(90 MHz, CDCl3): δ = 191.4 (C=S), 84.2 (CH, C-4), 70.6 (CH2, C-
5), 68.4 (CH, C-1ЈЈ), 51.9 (CH, C-2Ј), 43.1 (C, C-1Ј), 26.8 (CH2, C-
4Ј), 22.1 (CH3, CH3C-1Ј), 20.3 (CH3, C-2ЈЈ), 18.9 (CH2, C-3Ј) ppm.
HRMS (ESI+): calcd. for [C10H16O3S + Na]+ 239.0713; found
239.0712.
(1ЈЈR)-18: IR (ATR): ν = 3432, 2966, 1793, 1484, 1284, 1175 cm–1.
˜
(1S)-1-{(1S,2R)-2-[(1R)- and (1S)-1-{(1S,2R)-2-[(1S)-1-Hydroxy-
ethyl]-1-methylcyclobutyl}ethane-1,2-diol [(1ЈЈR)- and (1ЈЈS)-12]: A
1.6 m solution of MeLi in diethyl ether (1.5 mL, 2.34 mmol) was
carefully added dropwise to a solution of lactol 17 (160 mg,
0.59 mmol) in dry THF (20 mL) under nitrogen at –78 °C. The
mixture was stirred for 1 h at –78 °C and 2 h at room temp. The
reaction was quenched by the slow addition of a saturated solution
of NH4Cl (30 mL). The layers were separated and the aqueous one
was extracted with CH2Cl2 (3ϫ20 mL) and EtOAc (3ϫ20 mL).
The combined organic layers were washed with brine, dried with
anhydrous Na2SO4, filtered, and the solvents evaporated to dry-
ness. The crude material was purified by column chromatography
(hexane/EtOAc, 2:1) to render a colorless oil, which was dissolved
in dry THF (20 mL). A 1.0 m solution of TBAF in THF (1.7 mL,
1.7 mmol) was then added dropwise. The mixture was stirred for
5 min at room temp. Then the solvent was removed under reduced
pressure and the crude was purified by column chromatography
(from hexane/EtOAc, 2:1, to EtOAc) to afford a 1:1 mixture of
triols (1ЈЈR)- and (1ЈЈS)-12 (94 mg, 0.53 mmol, 91% yield) as a col-
orless oil.
3
1H NMR (250 MHz, CDCl3): δ = 5.41 (dd, JH,H = 8.7, 5.9 Hz, 1
H, 4-H), 4.68 (dd, 2JH,H = 8.9, 3JH,H = 8.7 Hz, 1 H, 5-H), 4.33 (dd,
2JH,H = 8.9, JH,H = 5.9 Hz, 1 H, 5-H), 4.19 (dq, JH,H = 9.4,
3
3
6.2 Hz, 1 H, 1ЈЈ-H), 2.31 (m, 1 H, 2Ј-H), 2.14 (m, 1 H, 3Ј-H), 1.86
3
(m, 1 H, 3Ј-H), 1.72 (m, 1 H, 4Ј-H), 1.58 (d, JH,H = 6.2 Hz, 3 H,
2
3
2ЈЈ-H), 1.49 (ddd, JH,H = 11.7, JH,H = 9.4, 2.8 Hz, 1 H, 4Ј-H),
1.19 (s, 3 H, CH3C-1Ј) ppm. 13C NMR (90 MHz, CDCl3): δ =
191.6 (C=S), 82.7 (CH, C-4), 70.3 (CH2, C-5), 59.4 (CH, C-1ЈЈ),
52.1 (CH, C-2Ј), 44.5 (C, C-1Ј), 26.2 (CH2, C-4Ј), 24.7 (CH3, C-2ЈЈ),
20.6 (CH2, C-3Ј), 20.4 (CH3, CH3C-1Ј) ppm. C10H16O3S (216.29):
calcd. C 55.53, H 7.46; found C 55.91, H 7.62.
(1S)- and (1R)-1-{(1R,2S)-2-Methyl-2-[(4S)-2-thioxo-1,3-dioxolan-
4-yl]cyclobutyl}ethyl Benzoate [(1S)- and (1R)-19]: Pyridine
(0.3 mL, 3.6 mmol) was added to a solution of a mixture of (1ЈЈS)-
and (1ЈЈR)-18 (57 mg, 0.26 mmol) in dry CH2Cl2 (10 mL) under
nitrogen and the reaction mixture was cooled to 0 °C. Then BzCl
(0.5 mL, 3.9 mmol) was added dropwise and the mixture was
warmed to room temp. and stirred overnight. The reaction mixture
was washed with 5 % HCl (3 ϫ 10 mL), a saturated solution of
From the Mixture of (1ЈЈR)- and (1ЈЈS)-12. Isomer A: 1H NMR NaHCO3 (3ϫ10 mL), and brine, dried with anhydrous Na2SO4,
(250 MHz, CDCl3): δ = 4.11–4.02 (m, 1 H, 1-H), 4.03–3.91 (m, 1 and concentrated to dryness under reduced pressure. The crude
Eur. J. Org. Chem. 2012, 1404–1417
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1409

S. Parés, R. Alibés, M. Figueredo, J. Font, T. Parella
FULL PAPER
material was purified by column chromatography (hexane/EtOAc,
CH3), 1.20 (d, 3JH,H = 6.1 Hz, 3 H, 2-H) ppm. 13C NMR (90 MHz,
4:1) to afford a 1:1 mixture of (1S)- and (1R)-19 (75 mg, 0.23 mmol, CDCl3): δ = 166.2 (C=O), 142.0 (CH, C-1ЈЈ), 132.5, 130.9, 129.5,
91% yield). Further column chromatography (hexane/EtOAc, 5:1) 128.3 (6 C-Ar), 112.4 (CH2, C-2ЈЈ), 72.8 (CH, C-1), 50.6 (CH, C-
afforded analytical samples of (1S)- and (1R)-19.
1Ј), 43.2 (C, C-2Ј), 30.5 (CH2, C-3Ј), 27.0 (CH3, CH3C-2Ј), 19.6
(CH2, C-4Ј), 18.8 (CH3, C-2) ppm. HRMS (ESI+): calcd. for
[C16H20O2 + Na]+ 267.1356; found 267.1354.
(1S)-19: M.p. 99–102 °C (pentane/EtOAc). [α]D = –8.02 (c = 1.25,
1
CHCl3). H NMR (360 MHz, CDCl3): δ = 8.04 (m, 2 H, o-Ar-H),
3
7.53 (m, 1 H, p-Ar-H), 7.43 (m, 2 H, m-Ar-H), 5.22 (dd, JH,H
=
(1S)- and (1R)-1-{(1R,2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-
2-methylcyclobutyl}ethan-1-ol [(1S)- and (1R)-22]: Anhydrous
Na2SO4 (6.0 g) and anhydrous CuSO4 (1.6 g, 10.2 mmol) were
added to a solution of triols 12 (178 mg, 1.02 mmol) in dry acetone
(45 mL, freshly distilled from anhydrous CaCl2). Then 2 drops of
concentrated HCl were added, which gave rise to an orange solu-
tion. The reaction mixture was stirred for 3 h. The reaction was
quenched by the addition of concentrated NH3 (6 drops, until the
solution became blue-violet) and the mixture filtered through Ce-
lite. The solvent was removed under reduced pressure and the crude
was purified by column chromatography (hexane/EtOAc, 5:1) to
furnish a 1:1 mixture of (1S)- and (1R)-22 (184 mg, 0.85 mmol,
84 % yield) and a 1:1 mixture of (6ЈS)- and (6ЈR)-23 (13 mg,
0.06 mmol, 6% yield). Further column chromatography (hexane/
EtOAc, 6:1) afforded analytical samples of (1S)- and (1R)-22.
3
8.6, 6.6 Hz, 1 H, 4ЈЈ-H), 5.18 (dq, JH,H = 10.4, 6.2 Hz, 1 H, 1-H),
2
3
2
4.63 (dd, JH,H = 8.9, JH,H = 8.6 Hz, 1 H, 5ЈЈ-H), 4.31 (dd, JH,H
3
= 8.9, JH,H = 6.6 Hz, 1 H, 5ЈЈ-H), 2.53 (m, 1 H, 1Ј-H), 2.12 (m, 1
H, 4Ј-H), 1.81 (m, 1 H, 3Ј-H), 1.66 (m, 2 H, 3Ј-H, 4Ј-H), 1.28 (d,
3JH,H = 6.2 Hz, 3 H, 2-H), 1.28 (s, 3 H, CH3C-2Ј) ppm. 13C NMR
(90 MHz, CDCl3): δ = 191.3 (C=S), 166.3 (C=O), 132.8, 130.5,
129.7, 128.3 (6 C-Ar), 84.3 (CH, C-4ЈЈ), 71.4 (CH, C-1), 70.1 (CH2,
C-5ЈЈ), 48.6 (CH, C-1Ј), 43.3 (C, C-2Ј), 26.5 (CH2, C-3Ј), 21.8 (CH3,
CH3C-2Ј), 18.9 (CH2, C-4Ј), 17.8 (CH3, C-2) ppm. HRMS (ESI+):
calcd. for [C17H20O4S + Na]+ 343.0975; found 343.0969.
(1R)-19: M.p. 95–99 °C (pentane/EtOAc). [α]D = –12.0 (c = 0.52,
CHCl ). IR (ATR): ν = 2967, 1707 (C=S), 1350, 1280, 1189 cm–1.
˜
3
1H NMR (250 MHz, CDCl3): δ = 8.02 (m, 2 H, o-Ar-H), 7.58 (m,
1 H, p-Ar-H), 7.46 (m, 2 H, m-Ar-H), 5.42 (dq, 3JH,H = 8.1, 6.1 Hz,
3
1 H, 1-H), 5.41 (dd, JH,H = 8.8, 6.0 Hz, 1 H, 4ЈЈ-H), 4.64 (dd,
(1S)-22: M.p. 107–110 °C (pentane/EtOAc). [α]D = +14.1 (c = 1.03,
3
3JH,H = 8.9, 8.8 Hz, 1 H, 5ЈЈ-H), 4.32 (dd, JH,H = 8.9, 6.0 Hz, 1
CHCl ). IR (ATR): ν = 3510, 3071, 2922, 2852, 1453, 1277,
˜
3
934 cm–1. H NMR (360 MHz, CDCl3): δ = 4.60 (dd, JH,H = 7.0,
6.4 Hz, 1 H, 4ЈЈ-H), 4.03 (dd, 2JH,H = 8.3, 3JH,H = 7.0 Hz, 1 H, 5ЈЈ-
H), 3.88 (ddq, 3JH,H = 8.3, 6.2, 2.0 Hz, 1 H, 1-H), 3.74 (br. s, 1 H,
1
3
H, 5ЈЈ-H), 2.40 (m, 1 H, 1Ј-H), 2.10–1.91 (m, 2 H, 3Ј-H/4Ј-H), 1.80
(m, 1 H, 3Ј-H/4Ј-H), 1.57 (m, 1 H, 3Ј-H/4Ј-H), 1.40 (d, JH,H
3
=
6.1 Hz, 3 H, 2-H), 1.24 (s, 3 H, CH3C-2Ј) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 191.6 (C=S), 165.9 (C=O), 133.7, 132.9,
129.4, 128.4 (6 C-Ar), 83.1 (CH, C-4ЈЈ), 71.1 (CH, C-1), 70.1 (CH2,
C-5ЈЈ), 49.2 (CH, C-1Ј), 43.7 (C, C-2Ј), 27.1 (CH2, C-3Ј), 20.5, 19.6,
18.6 (CH3, CH3C-2Ј; CH2, C-4Ј; CH3, C-2) ppm. HRMS (ESI+):
calcd. for [C17H20O4S + Na]+ 343.0975; found 343.0964.
OH), 3.68 (dd, 2JH,H = 8.3, JH,H = 6.4 Hz, 1 H, 5ЈЈ-H), 2.02 (ddd,
3
3JH,H = 9.2, 9.1, 8.3 Hz, 1 H, 1Ј-H), 1.85 (dddd, 2JH,H = 10.9, 3JH,H
= 9.1, 8.7, 2.5 Hz, 1 H, 4Ј-H), 1.66 (ddd, 2JH,H = 11.0, 3JH,H = 9.0,
2
3
8.7 Hz, 1 H, 3Ј-H), 1.52 (dddd, JH,H = 10.9, JH,H = 10.7, 9.2,
9.0 Hz, 1 H, 4Ј-H), 1.42 (s, 3 H, CH3C-2ЈЈ), 1.40 (m, 1 H, 3Ј-H),
3
1.37 (s, 3 H, CH3C-2ЈЈ), 1.14 (s, 3 H, CH3C-2Ј), 1.00 (d, JH,H
=
(1S)- and (1R)-1-[(1R,2R)-2-Methyl-2-vinylcyclobutyl]ethyl Benzo-
ate [(1S)- and (1R)-21]: A mixture of benzoates (1S)- and (1R)-19
(170 mg, 0.53 mmol) was placed in a Schlenk tube under nitrogen.
Then 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholane (20; 286 μL,
1.59 mmol) was added dropwise. The mixture was heated to 40 °C
and stirred at this temperature for 24 h. It was then allowed to cool
to room temp. and purified by column chromatography (pentane/
diethyl ether, 20:1) to afford a 1:1 mixture of (1S)- and (1R)-21
(82 mg, 0.34 mmol, 67% yield) as a colorless and volatile oil. The
solvent was removed by fractionated distillation at atmosphere
pressure. Further column chromatography (pentane/diethyl ether,
30:1) afforded analytical samples of (1S)- and (1R)-21.
6.2 Hz, 3 H, 2-H) ppm. 13C NMR (90 MHz, CDCl3): δ = 109.6 (C,
C-2ЈЈ), 77.2 (CH, C-4ЈЈ), 68.9 (CH, C-1), 65.4 (CH2, C-5ЈЈ), 52.8
(CH, C-1Ј), 41.9 (C, C-2Ј), 27.5 (CH2, C-3Ј), 26.0 (CH3, CH3C-
2ЈЈ), 24.8 (CH3, CH3C-2ЈЈ), 22.4 (CH3, CH3C-2Ј), 19.0 (CH3, C-2),
18.8 (CH2, C-4Ј) ppm. HRMS (ESI+): calcd. for [C12H22O3
+
Na]+ 237.1461; found 237.1448.
(1R)-22: IR (ATR): ν = 3521, 2929, 2872, 1457, 1370, 1210,
˜
1005 cm–1. 1H NMR (360 MHz, CDCl3): δ = 4.55 (dd, 3JH,H = 7.1,
7.0 Hz, 1 H, 4ЈЈ-H), 3.99 (m, 1 H, 1-H), 3.97 (dd, 2JH,H = 8.2, 3JH,H
2
3
= 7.0 Hz, 1 H, 5ЈЈ-H), 3.63 (dd, JH,H = 8.2, JH,H = 7.1 Hz, 1 H,
5ЈЈ-H), 3.17 (br. s, 1 H, OH), 2.11–1.90 (m, 2 H, 1Ј-H, 4Ј-H), 1.90–
1.74 (m, 1 H, 4Ј-H), 1.63–1.48 (m, 2 H, 3Ј-H), 1.40 (s, 3 H, CH3C-
2ЈЈ), 1.32 (s, 3 H, CH3C-2ЈЈ), 1.06 (s, 3 H, CH3C-2Ј), 1.05 (d, 3JH,H
= 6.4 Hz, 3 H, 2-H) ppm. 13C NMR (90 MHz, CDCl3): δ = 109.2
(C, C-2ЈЈ), 77.5 (CH, C-4ЈЈ), 66.1 (CH, C-1), 65.6 (CH2, C-5ЈЈ), 52.1
(CH, C-1Ј), 42.9 (C, C-2Ј), 28.3 (CH2, C-3Ј), 26.0 (CH3, CH3C-2ЈЈ),
24.7 (CH3, CH3C-2ЈЈ), 22.1 (CH3, CH3C-2Ј), 20.7 (CH3, C-2), 16.6
(CH2, C-4Ј) ppm. HRMS (ESI+): calcd. for [C12H22O3 + Na]+
237.1461; found 237.1458.
1
(1S)-21: H NMR (360 MHz, CDCl3): δ = 8.02 (m, 2 H, o-Ar-H),
3
7.54 (m, 1 H, p-Ar-H), 7.44 (m, 2 H, m-Ar-H), 5.98 (dd, JH,H
=
3
17.2, 10.7 Hz, 1 H, 1ЈЈ-H), 5.01 (dq, JH,H = 10.5, 6.1 Hz, 1 H, 1-
3
2
H), 5.00 (dd, JH,H = 10.7, JH,H = 1.4 Hz, 1 H, 2ЈЈ-H), 4.96 (dd,
2
3
3JH,H = 17.2, JH,H = 1.4 Hz, 1 H, 2ЈЈ-H), 2.41 (ddd, JH,H = 10.5,
9.6, 8.1 Hz, 1 H, 1Ј-H), 2.06–1.92 (m, 2 H, 3Ј-H, 4Ј-H), 1.76 (m, 1
H, 3Ј-H), 1.65 (m, 1 H, 4Ј-H), 1.26 (s, 3 H, CH3C-2Ј), 1.19 (d,
3JH,H = 6.1 Hz, 3 H, 2-H) ppm. 13C NMR (90 MHz, CDCl3): δ =
165.9 (C=O), 142.0 (CH, C-1ЈЈ), 132.6, 130.9, 129.4, 128.3 (6 C-
Ar), 112.3 (CH2, C-2ЈЈ), 73.1 (CH, C-1), 50.4 (CH, C-1Ј), 43.3 (C,
C-2Ј), 29.1 (CH2, C-3Ј), 28.1 (CH3, CH3C-2Ј), 19.0 (CH2, C-4Ј),
17.5 (CH3, C-2) ppm. HRMS (ESI+): calcd. for [C16H20O2 + Na]+
267.1356; found 267.1356.
From the mixture of (6ЈS)- and (6ЈR)-23. Isomer A: 1H NMR
3
(400 MHz, CDCl3): δ = 4.55 (dd, JH,H = 8.7, 8.1 Hz, 1 H, 2Ј-H),
2
3
4.06–3.95 (m, 2 H, 1-H, 6Ј-H), 3.68 (dd, JH,H = 8.2, JH,H
=
8.1 Hz, 1 H, 1-H), 3.40 (br. s, 1 H, OH), 2.57 (ddd, J = 11.7, 8.7,
3.2 Hz, 1 H, 7Ј-H), 2.39–2.05 (m, 4 H, 8Ј-H, 9Ј-H), 1.49 (s, 3 H,
1
(1R)-21: H NMR (360 MHz, CDCl3): δ = 8.00 (m, 2 H, o-Ar-H), CH3C-4Ј), 1.35 (s, 3 H, CH3C-4Ј), 1.25 (s, 3 H, CH3C-1Ј), 1.05 (d,
3
7.54 (m, 1 H, p-Ar-H), 7.45 (m, 2 H, m-Ar-H), 6.17 (dd, JH,H
=
3JH,H = 6.5 Hz, 3 H, CH3C-6Ј) ppm. 13C NMR (62.5 MHz,
3
17.2, 11.0 Hz, 1 H, 1ЈЈ-H), 5.11 (dq, JH,H = 9.1, 6.1 Hz, 1 H, 1- CDCl3): δ = 109.6 (C, C-4Ј), 77.6 (CH, C-2Ј), 65.5 (CH, C-6Ј), 63.9
3
2
H), 5.05 (dd, JH,H = 11.0, JH,H = 1.5 Hz, 1 H, 2ЈЈ-H), 5.05 (dd,
(CH2, C-1), 55.7 (CH, C-7Ј), 48.4 (C, C-1Ј), 28.9, 25.9, 24.6, 21.1,
17.1 ppm. Isomer B: 1H NMR (400 MHz, CDCl3): δ = 4.38 (dd,
2
3JH,H = 17.2, JH,H = 1.5 Hz, 1 H, 2ЈЈ-H), 2.30 (m, 1 H, 1Ј-H),
2.07–1.85 (m, 3 H, 4Ј-H, 3Ј-H), 1.79 (m, 1 H, 3Ј-H), 1.25 (s, 3 H, 3JH,H = 6.9, 6.5 Hz, 1 H, 2Ј-H), 4.21 (dd, JH,H = 8.6, JH,H
=
2
3
1410
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1404–1417

Synthesis of Sesquiterpenes with the Dunniane Skeleton
6.9 Hz, 1 H, 1-H) 4.06–3.95 (m, 1 H, 6Ј-H), 3.86 (br. s, 1 H, OH),
ganic layer was dried with anhydrous MgSO4 and evaporated under
reduced pressure. The resulting crude was purified by column
chromatography (hexane/diethyl ether, 2:1 to 1:2) to afford a 1:1
mixture of (1S)- and (1R)-25 (96 mg, 0.35 mmol, 80% yield) as a
colorless oil. Further column chromatography (hexane/diethyl
2
3
3.80 (dd, JH,H = 8.6, JH,H = 6.5 Hz, 1 H, 1-H), 2.39–2.05 (m, 5
H, 7Ј-H, 2ϫ8Ј-H, 2ϫ9Ј-H), 1.43 (s, 3 H, CH3C-4Ј), 1.36 (s, 3 H,
3
CH3C-4Ј), 1.17 (s, 3 H, CH3C-1Ј), 1.06 (d, JH,H = 6.2 Hz, 3 H,
CH3C-6Ј) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 109.8 (C, C-
4Ј), 77.1 (CH, C-2Ј), 67.1 (CH, C-6Ј), 64.6 (CH2, C-1), 55.6 (CH, ether, 1:1 to 1:2) provided analytical samples of (1S)- and (1R)-25.
C-7Ј), 49.9 (C, C-1Ј), 32.2, 25.8, 24.6, 20.4, 20.0 ppm. HRMS
(1S)-25: [α]D = +9.78 (c = 1.52, CHCl ). IR (ATR): ν = 3401, 2955,
˜
3
(ESI+): calcd. for [C12H22O3 + Na]+ 237.1461; found 237.1450.
1709, 1451, 1277 cm–1. H NMR (360 MHz, CDCl3): δ = 8.02 (m,
1
(1S)- and (1R)-1-{(1R,2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-
2-methylcyclobutyl}ethyl Benzoate [(1S)- and (1R)-24]: Pyridine
(1.0 mL, 12.0 mmol) was added to a solution of a 1:1 mixture of
(1S)- and (1R)-22 (443 mg, 2.06 mmol) in dry CH2Cl2 (75 mL) un-
der nitrogen and the reaction mixture was cooled to 0 °C. Then
BzCl (1.3 mL, 10.1 mmol) was added dropwise and the mixture was
warmed to room temp. and stirred for 2 weeks. The reaction mix-
ture was washed with 5% HCl (3ϫ50 mL), a saturated solution of
2 H, o-Ar-H), 7.55 (m, 1 H, p-Ar-H), 7.43 (m, 2 H, m-Ar-H), 5.31
3
3
(dq, JH,H = 10.4, 6.1 Hz, 1 H, 1-H), 3.99 (ddd, JH,H = 8.8, 3.5,
3.0 Hz, 1 H, 1ЈЈ-H), 3.58 (m, 1 H, 2ЈЈ-H), 3.44 (m, 1 H, 2ЈЈ-H),
3
2.52 (d, JH,H = 3.5 Hz, 1 H, OH), 2.34 (m, 1 H, 1Ј-H), 2.03 (m, 2
3
H, 4Ј-H, OH), 1.68 (m, 3 H, 2 ϫ 3Ј-H, 4Ј-H), 1.25 (d, JH,H
=
6.1 Hz, 3 H, 2-H), 1.16 (s, 3 H, CH3C-2Ј) ppm. 13C NMR
(90 MHz, CDCl3): δ = 166.5 (C=O), 132.9, 130.6, 129.4, 128.4 (6
C-Ar), 73.8 (CH, C-1ЈЈ), 72.7 (CH, C-1), 62.9 (CH2, C-2ЈЈ), 50.2
NaHCO3 (3ϫ50 mL) and brine (3ϫ40 mL), dried with anhydrous (CH, C-1Ј), 43.6 (C, C-2Ј), 28.0 (CH2, C-3Ј), 22.4 (CH3, CH3C-2Ј),
Na2SO4, and concentrated to dryness under reduced pressure. The
crude was purified by column chromatography using first a mixture
of hexane/CH2Cl2 (2:1) and then a mixture of hexane/EtOAc (10:1)
to provide a 1:1 mixture of (1S)- and (1R)-24 (553 mg, 1.74 mmol,
84% yield). Further column chromatography (hexane/EtOAc, 20:1
to 10:1) provided analytical samples of (1S)- and (1R)-24.
19.4 (CH2, C-4Ј), 17.8 (CH3, C-2) ppm. HRMS (ESI+): calcd. for
[C16H22O4 + Na]+ 301.1410; found 301.1417.
1
(1R)-25: IR (ATR): ν = 3400, 2951, 1712, 1435, 1270 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 8.04 (m, 2 H, o-Ar-H), 7.55 (m, 1
3
H, p-Ar-H), 7.44 (m, 2 H, m-Ar-H), 5.54 (dq, JH,H = 6.4, 6.1 Hz,
3
1 H, 1-H), 4.00 (dd, JH,H = 8.9, 2.6 Hz, 1 H, 1ЈЈ-H), 3.61 (dd,
3
2
(1S)-24: M.p. 109–112 °C (pentane/EtOAc). [α]D = –9.33 (c = 0.49,
2JH,H = 10.9, JH,H = 2.6 Hz, 1 H, 2ЈЈ-H), 3.46 (dd, JH,H = 10.9,
CHCl ). IR (ATR): ν = 2833, 2552, 1678, 1420, 1286, 931 cm–1. 1H 3JH,H = 8.9 Hz, 1 H, 2ЈЈ-H), 2.21 (m, 1 H, 1Ј-H), 1.99 (m, 2 H, 4Ј-
˜
3
3
NMR (360 MHz, CDCl3): δ = 8.04 (m, 2 H, o-Ar-H), 7.62 (m, 1
H), 1.77 (m, 1 H, 3Ј-H), 1.61 (m, 1 H, 3Ј-H), 1.35 (d, JH,H
=
H, p-Ar-H), 7.41 (m, 2 H, m-Ar-H), 5.22 (dq, 3JH,H = 10.9, 6.2 Hz, 6.1 Hz, 3 H, 2-H), 1.16 (s, 3 H, CH3C-2Ј) ppm. 13C NMR
3
1 H, 1-H), 4.49 (dd, JH,H = 7.3, 7.0 Hz, 1 H, 4ЈЈ-H), 3.95 (dd,
(100 MHz, CDCl3): δ = 166.5 (C=O), 132.8, 130.8, 129.5, 128.4 (6
C-Ar), 74.1 (CH, C-1ЈЈ), 72.1 (CH, C-1), 63.2 (CH2, C-2ЈЈ), 50.6
3
3
2JH,H = 8.0, JH,H = 7.0 Hz, 1 H, 5ЈЈ-H), 3.56 (dd, JH,H = 8.0,
3JH,H = 7.3 Hz, 1 H, 5ЈЈ-H), 2.42 (m, 1 H, 1Ј-H), 1.97 (m, 1 H, 4Ј- (CH, C-1Ј), 43.3 (C, C-2Ј), 28.7 (CH2, C-3Ј), 22.3 (CH3, CH3C-2Ј),
H), 1.69 (m, 2 H, 3Ј-H, 4Ј-H), 1.47 (m, 1 H, 3Ј-H), 1.22 (d, JH,H 19.8 (CH3, C-2), 18.4 (CH2, C-4Ј) ppm. HRMS (ESI+): calcd. for
3
= 6.2 Hz, 3 H, 2-H), 1.19 (s, 3 H, CH3C-2Ј), 1.14 (s, 3 H, CH3C- [C16H22O4 + Na]+ 301.1410; found 301.1411.
2ЈЈ), 1.83 (s, 3 H, CH3C-2ЈЈ) ppm. 13C NMR (90 MHz, CDCl3): δ
(1S)- and (1R)-1-{(1R,2S)-2-Methyl-2-[(E)-2-(phenylsulfonyl)-1-
= 166.1 (C=O), 132.3, 129.5, 129.3, 128.0 (6 C-Ar), 109.2 (C, C-
ethenyl]cyclobutyl}ethyl Benzoate [(1S)- and (1R)-9]: A solution of
2ЈЈ), 76.8 (CH, C-4ЈЈ), 72.2 (CH, C-1), 65.5 (CH2, C-5ЈЈ), 49.6 (CH,
a 1:1 mixture of (1S)- and (1S)-25 (80 mg, 0.28 mmol) in dry THF
C-1Ј), 42.2 (C, C-2Ј), 27.6 (CH2, C-3Ј), 25.6 (CH3, CH3C-2ЈЈ), 24.3
(4 mL) under nitrogen was cooled to –20 °C (CCl4/CO2 bath) be-
(CH3, CH3C-2ЈЈ), 22.3 (CH3, CH3C-2Ј), 19.1 (CH2, C-4Ј), 17.6
fore anhydrous pyridine was added (4 drops). Then Pb(OAc)4
(CH3, C-2) ppm. HRMS (ESI+): calcd. for [C19H26O4 + Na]+
(188 mg, 0.42 mmol) was slowly added and the reaction mixture
341.1723; found 341.1727.
was warmed to room temp. and stirred for 4 h. At the same time,
MeSO2Ph (220 mg, 1.4 mmol) was dissolved in dry THF (5 mL)
(1R)-24: IR (ATR): ν = 2845, 2530, 1681, 1417, 1289, 939 cm–1. 1H
˜
NMR (250 MHz, CDCl3): δ = 8.02 (m, 2 H, o-Ar-H), 7.55 (m, 1
and cooled to 0 °C. Then a 1.5 m solution of BuLi in diethyl ether
3
H, p-Ar-H), 7.44 (m, 2 H, m-Ar-H), 5.48 (dq, JH,H = 8.9, 6.3 Hz, (1.88 mL, 2.8 mmol) was added dropwise and the reaction mixture
3
1 H, 1-H), 4.06 (dd, JH,H = 8.4, 6.3 Hz, 1 H, 4ЈЈ-H), 3.78 (dd,
was stirred at 0 °C for 30 min before (EtO)2POCl (228 μL,
1.40 mmol) was added. The reaction mixture was warmed to room
3
3
2JH,H = 7.8, JH,H = 6.3 Hz, 1 H, 5ЈЈ-H), 3.36 (dd, JHH = 8.4,
2JH,H = 7.8 Hz, 1 H, 5ЈЈ-H), 2.40 (m, 1 H, 1Ј-H), 2.11 (m, 1 H, 3Ј- temp. and stirred for 3.5 h. The mixture was then cooled to –78 °C
H), 1.92 (m, 1 H, 4Ј-H), 1.74 (m, 1 H, 4Ј-H), 1.63 (m, 1 H, 3Ј-H), and the crude of the oxidative cleavage was added dropwise. The
2
1.41 (s, 3 H, CH3C-2ЈЈ), 1.25 (s, 3 H, CH3C-2ЈЈ), 1.20 (d, JH,H
=
reaction mixture was stirred for 2 h at –78 °C and 3 h at room temp.
6.3 Hz, 3 H, 2-H), 1.06 (s, 3 H, CH3C-2Ј) ppm. 13C NMR Then brine (10 mL) was added and the mixture was diluted with
(90 MHz, CDCl3): δ = 165.2 (C=O), 132.7, 130.2, 129.4, 128.4 (6
C-Ar), 109.1 (C, C-2ЈЈ), 78.4 (CH, C-4ЈЈ), 73.2 (CH, C-1), 66.0
diethyl ether (10 mL). After separation of the layers, the aqueous
one was extracted with diethyl ether (3ϫ10 mL). The combined
(CH2, C-5ЈЈ), 49.9 (CH, C-1Ј), 41.2 (C, C-2Ј), 26.6 (CH3, CH3C- organic extracts were dried with MgSO4 and evaporated under re-
2ЈЈ), 25.7 (CH3, CH3C-2ЈЈ), 25.5 (CH2, C-3Ј), 25.3 (CH3, CH3C- duced pressure. The crude was purified by column chromatography
2Ј), 19.3 (CH2, C-4Ј), 17.8 (CH3, C-2) ppm. HRMS (ESI+): calcd. (pentane/diethyl ether, 4:1) to afford a 1:1 mixture of (1S)- and
for [C19H26O4 + Na]+ 341.1723; found 341.1716.
(1R)-9 (81 mg, 0.21 mmol, 73% yield) as a colorless oil. Repeated
column chromatography allowed us to isolate analytical samples of
(1S)- and (1R)-9.
(1S)- and (1R)-1-{(1R,2S)-2-[(2S)-1,2-Dihydroxyethyl]-2-methyl-
cyclobutyl}ethyl Benzoate [(1S)- and (1R)-25]: pTsOH (37 mg,
0.21 mmol) and water (2 drops) were added to a solution of a 1:1
(1S)-9: [α]D = –2.91 (c = 3.66, CHCl ). IR (ATR): ν = 3060, 2958,
˜
3
mixture of (1S)- and (1R)-24 (137 mg, 0.43 mmol) in MeOH 1710, 1615, 1447, 1274, 1149 cm–1. 1H NMR (250 MHz, CDCl3):
(10 mL). The reaction mixture was stirred for 1 week at room temp.
The crude was concentrated to a quarter of the initial volume and
diluted with diethyl ether before being washed with a saturated
solution of NaHCO3 (3ϫ10 mL) and brine (3ϫ10 mL). The or-
δ = 7.84 (m, 4 H, o-Ar-H), 7.57–7.36 (m, 6 H, p-Ar-H, m-Ar-H),
3
3
7.35 (d, JH,H = 15.1 Hz, 1 H, 1ЈЈ-H), 6.19 (d, JH,H = 15.1 Hz, 1
3
H, 2ЈЈ-H), 4.93 (dq, JH,H = 9.9, 6.1 Hz, 1 H, 1-H), 2.57 (m, 1 H,
1Ј-H), 2.12–1.78 (m, 4 H, 3Ј-H, 4Ј-H), 1.32 (s, 3 H, CH3C-2Ј), 1.18
Eur. J. Org. Chem. 2012, 1404–1417
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1411

S. Parés, R. Alibés, M. Figueredo, J. Font, T. Parella
FULL PAPER
(d, 3JH,H = 6.1 Hz, 3 H, 2-H) ppm. 13C NMR (62.5 MHz, CDCl3):
C-2Ј), 26.5 (CH2, C-3Ј), 25.9 (CH3, CH3C-2ЈЈ), 24.6 (CH3, CH3C-
2ЈЈ), 19.9 (CH2, C-4Ј), 19.2 (CH3, CH3C-2Ј), 13.3 (CH3, C-2) ppm.
δ = 165.4 (C=O), 150.0 (CH, C-1ЈЈ), 140.4, 133.0, 132.8, 130.3,
129.4 (6 C-Ar), 129.1 (CH, C-2ЈЈ), 128.7, 128.3, 127.7 (6 C-Ar), HRMS (ESI+): calcd. for [C12H22O3 + Na]+ 237.1461; found
72.6 (CH, C-1), 50.8 (CH, C-1Ј), 43.4 (C, C-2Ј), 30.1 (CH2, C-
3Ј), 26.5 (CH3, CH3C-2Ј), 18.9 (CH2, C-4Ј), 17.5 (CH3, C-2) ppm.
HRMS (ESI+): calcd. for [C22H24O4S + Na]+ 407.1288; found
407.1296.
237.1454.
(1S)-27: IR (ATR): ν = 3450, 2950, 1461, 1365, 1207, 1070 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 3.97 (dd, JH,H = 6.7, 6.5 Hz, 1
3
2
3
H, 4ЈЈ-H), 3.92 (dd, JH,H = 7.6, JH,H = 6.7 Hz, 1 H, 5ЈЈ-H), 3.79
3
2
3
(dq, JH,H = 12.3, 6.2 Hz, 1 H, 1-H), 3.63 (dd, JH,H = 7.6, JH,H
= 6.5 Hz, 1 H, 5ЈЈ-H), 2.08 (m, 1 H, 1Ј-H), 1.92 (m, 1 H, 4Ј-H),
1.89–1.77 (m, 2 H, 3Ј-H, 4Ј-H), 1.40 (s, 3 H, CH3C-2ЈЈ), 1.33 (m,
(1R)-9: [α]D = –57.0 (c = 0.92, CHCl ). IR (ATR): ν = 3070, 2929,
˜
3
1712, 1616, 1448, 1269, 1147 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.99 (m, 1 H, o-Ar-H), 7.85 (m, 1 H, o-Ar-H), 7.57 (m, 2 H,
p-Ar-H), 7.53 (m, 2 H, m-Ar-H), 7.43 (m, 2 H, m-Ar-H), 7.37 (d,
3
1 H, 3Ј-H), 1.33 (s, 3 H, CH3C-2ЈЈ), 1.15 (d, JH,H = 6.2 Hz, 3 H,
2-H), 1.09 (s, 3 H, CH3C-2Ј) ppm. 13C NMR (100 MHz, CDCl3):
δ = 109.9 (C, C-2ЈЈ), 83.0 (CH, C-4ЈЈ), 68.9 (CH, C-1), 65.4 (CH2,
C-5ЈЈ), 47.2 (CH, C-1Ј), 41.4 (C, C-2Ј), 26.7 (CH2, C-3Ј), 26.4 (CH3,
CH3C-2ЈЈ), 25.1 (CH3, CH3C-2ЈЈ), 22.7 (CH3, C-2), 18.9 (CH2, C-
4Ј), 16.7 (CH3, CH3C-2Ј) ppm. HRMS (ESI+): calcd. for [C12H22O3
+ Na]+ 237.1461; found 237.1449.
3
3JH,H = 15.2 Hz, 1 H, 1ЈЈ-H), 6.27 (d, JH,H = 15.2 Hz, 1 H, 2ЈЈ-
3
H), 5.03 (dq, JH,H = 8.4, 6.2 Hz, 1 H, 1-H), 2.46 (m, 1 H, 1Ј-H),
2.13–1.99 (m, 3 H, 3Ј-H, 2ϫ4Ј-H), 1.90 (m, 1 H, 3Ј-H), 1.30 (s, 3
3
H, CH3C-2Ј), 1.09 (d, JH,H = 6.2 Hz, 3 H, 2-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.8 (C=O), 150.2 (CH, C-1ЈЈ), 140.6,
133.3, 132.9, 130.3, 129.5 (6 C-Ar), 129.3 (CH, C-2ЈЈ), 129.0, 128.3,
127.6 (6 C-Ar), 71.7 (CH, C-1), 51.0 (CH, C-1Ј), 43.2 (C, C-2Ј),
30.6 (CH2, C-3Ј), 26.1 (CH3, CH3C-2Ј), 19.4 (CH2, C-4Ј), 18.4
(CH3, C-2) ppm. HRMS (ESI+): calcd. for [C22H24O4S + Na]+
407.1288; found 407.1301.
(4S)-4-{(1S,2S)-2-[(1R)- and (4S)-4-{(1S,2S)-2-[(1S)-1-Benzyloxy-
ethyl]-1-methylcyclobutyl}-2,2-dimethyl-1,3-dioxolane [(1ЈЈR)- and
(1ЈЈS)-28]: NaH (60wt.-%, 228 mg, 1.14 mmol) was washed suc-
cessively with hexane under nitrogen prior to the addition of dry
THF (7.4 mL). The resulting suspension was stirred for 15 min.
Then a solution of (1R)-27 (245 mg, 1.14 mmol) in dry THF
(7.4 mL) was added and the mixture was stirred for a further
30 min. NaI (507 mg, 3.4 mmol) was placed in another flask under
nitrogen and dry THF (7.4 mL) was added. Then BnBr (409 μL,
3.4 mmol) was added dropwise and the resulting suspension was
stirred for 30 min. The BnI solution was then slowly added to the
initial solution. The mixture was heated at reflux and stirred for
2 h. The reaction was quenched with a saturated solution of NH4Cl
and concentrated to a third of the initial volume. Then CH2Cl2
(30 mL) and a saturated solution of NH4Cl (30 mL) were added.
The layers were separated and the organic phase was washed with
a saturated solution of NaHCO3 and brine, dried with anhydrous
MgSO4, and the solvents evaporated to dryness. Purification by
column chromatography (hexane/EtOAc, 15:1) afforded (1ЈЈR)-28
(341 mg, 1.12 mmol, 98% yield) as a colorless oil.
(1R)- and (1S)-{(1S,2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-
methylcyclobutyl}ethan-1-ol [(1R)- and (1S)-27]: A commercially
available solution of Dess–Martin periodinane in CH2Cl2 (15 wt.-
%, 10 mL, 4.88 mmol) was added to a solution of a 1:1 mixture of
alcohols 22 (700 mg, 3.27 mmol) in dry CH2Cl2 (35 mL) and the
mixture was stirred for 2 h under nitrogen at room temp. The solu-
tion was washed with a saturated solution of NaHCO3 containing
a seven-fold excess of Na2S2O3 (30 mL). The layers were separated
and the aqueous layer was extracted with CH2Cl2 (2ϫ30 mL). The
combined organic extracts were dried with anhydrous Na2SO4 and
concentrated under reduced pressure to provide a reaction crude
which was dissolved in dry MeOH (30 mL) and Na2CO3 (350 mg,
3.3 mmol) was added. The mixture was heated at reflux for 24 h.
Then the mixture was allowed to cool to room temp. and used in
the next step without evaporation of the solvent nor further purifi-
cation. The previous step can be carried out on a small scale under
microwave irradiation: A tenth part of the first crude was placed
in a microwave vessel and dissolved in MeOH (3 mL), Na2CO3
(35 mg, 0.33 mmol) was added, and the system was sealed and irra-
diated at 80 °C, with the PowerMAX function on, for three cycles
of 1 h each. NaBH4 (150 mg) was added to the previous solution
crude and the reaction mixture was stirred at room temp. for 2 h.
The reaction was quenched with a saturated solution of NH4Cl
and diluted with CH2Cl2 and water. The layers were separated, the
organic layer was washed with a saturated solution of NH4Cl
(2 ϫ 30 mL) and brine (2 ϫ 30 mL), and dried with anhydrous
MgSO4. The solvent was removed under reduced pressure. Purifica-
tion by column chromatography (hexane/EtOAc, 20:1 to 1:1) pro-
vided the starting material (1S)-22 (130 mg, 0.60 mmol, 18%) as a
colorless oil, (1R)-27 (401 mg, 1.87 mmol, 57% yield) as a colorless
oil, and (1S)-27 (36 mg, 0.17 mmol, 5% yield) as a colorless oil.
The reaction performed starting from (1S)-27 (30 mg, 0.14 mmol)
afforded (1ЈЈS)-28 (38 mg, 0.12 mmol, 90% yield) as a colorless oil.
The reaction performed starting a the mixture of (1R)- and (1S)-
27 (60 mg, 0.28 mmol) delivered a mixture of (1ЈЈR)- and (1ЈЈS)-28
(84 mg, 0.27 mmol, 98% yield) as a colorless oil.
(1ЈЈR)-28: [α]D = –12.0 (c = 1.0, CHCl ). IR (ATR): ν = 2969, 2870,
˜
3
1497, 1455, 1369, 1213, 1065 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.35–7.30 (m, 5 H, Ar), 4.59 (d, 2JH,H = 11.4 Hz, 1 H, CH2Ph),
4.33 (d, 2JH,H = 11.4 Hz, 1 H, CH2Ph), 3.91 (dd, 2JH,H = 7.3, 3JH,H
= 5.1 Hz, 1 H, 5-H), 3.89 (dd, 2JH,H = 7.3, JH,H = 4.2 Hz, 1 H, 5-
3
H), 3.82 (dd, 3JH,H = 5.1, 4.2 Hz, 1 H, 4-H), 3.51 (dq, 3JH,H = 10.2,
3
6.0 Hz, 1 H, 1ЈЈ-H), 2.35 (ddd, JH,H = 10.2, 9.6, 9.2 Hz, 1 H, 2Ј-
2
3
H), 2.02 (ddd, JH,H = 11.0, JH,H = 9.3, 9.3 Hz, 1 H, 4Ј-H), 1.84
2
3
(dddd, JH,H = 11.5, JH,H = 9.3, 9.2, 2.8 Hz, 1 H, 3Ј-H), 1.51
2
3
(1R)-27: [α]D = –23.7 (c = 0.9, CHCl ). IR (ATR): ν = 3449, 2966,
(dddd, JH,H = 11.5, JH,H = 9.7, 9.6, 9.3 Hz, 1 H, 3Ј-H), 1.42 (s, 3
˜
3
1458, 1379, 1216, 1072 cm–1. 1H NMR (400 MHz, CDCl3): δ =
H, CH3C-2), 1.36 (s, 3 H, CH3C-2), 1.33 (ddd, 2JH,H = 11.0, JH,H
3
3
2
4.04 (dd, JH,H = 6.9, 5.7 Hz, 1 H, 4ЈЈ-H), 3.93 (dd, JH,H = 8.3,
= 9.7, 2.8 Hz, 1 H, 4Ј-H), 1.07 (d, 3JH,H = 6.2 Hz, 3 H, 2ЈЈ-H), 1.04
(s, 3 H, CH3C-1Ј) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.8
(C, Ar), 128.2, 127.7, 127.3 (5 CH, Ar), 108.4 (C, C-2), 81.9 (CH,
3JH,H = 6.9 Hz, 1 H, 5ЈЈ-H), 3.70 (dd, JH,H = 8.3, JH,H = 5.7 Hz,
1 H, 5ЈЈ-H), 3.68 (dq, JH,H = 10.0, 6.2 Hz, 1 H, 1-H), 2.04 (m, 1
2
3
3
H, 1Ј-H), 1.83 (m, 1 H, 4Ј-H), 1.71–1.55 (m, 2 H, 3Ј-H, 4Ј-H), 1.42 C-4), 75.7 (CH, C-1ЈЈ), 70.0 (CH2Ph), 65.8 (CH2, C-5), 43.2 (CH,
(s, 3 H, CH3C-2ЈЈ), 1.36 (m, 1 H, 3Ј-H), 1.32 (s, 3 H, CH3C-2ЈЈ),
C-2Ј), 41.6 (C, C-1Ј), 26.6 (CH3, CH3C-2), 26.1 (CH2, C-4Ј), 25.7
(CH3, CH3C-2), 18.9 (CH2, C-3Ј), 18.4 (CH3, CH3C-1Ј), 15.9 (CH3,
3
1.11 (s, 3 H, CH3C-2Ј), 1.01 (d, JH,H = 6.2 Hz, 3 H, 2-H) ppm.
13C NMR (90 MHz, CDCl3): δ = 109.0 (C, C-2ЈЈ), 83.8 (CH, C- C-2ЈЈ) ppm. HRMS (ESI+): calcd. for [C19H28O3 + Na]+ 327.1931;
4ЈЈ), 67.0 (CH, C-1), 64.6 (CH2, C-5ЈЈ), 50.7 (CH, C-1Ј), 41.6 (C,
found 327.1934.
1412
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1404–1417

Synthesis of Sesquiterpenes with the Dunniane Skeleton
(1ЈЈS)-28: [α]D = +21.4 (c = 1.9, CHCl ). IR (ATR): ν = 2968, 2870,
(1S,2S)-2-[(1R)-1-Benzyloxyethyl]-1-methylcyclobutane-1-carb-
aldehyde [(1ЈЈR)-30]: A solution of (1ЈЈR)-29 (190 mg, 0.72 mmol)
in dry THF (11 mL) under nitrogen was cooled to –20 °C (CCl4/
CO2 bath) and then anhydrous pyridine was added (10 drops).
Then Pb(OAc)4 (492 mg, 1.10 mmol) was slowly added and the re-
action mixture was warmed to room temp. and stirred for 4 h. Then
the solvent was removed under reduced pressure and diethyl ether
˜
3
1455, 1369, 1215, 1065 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.36–7.22 (m, 5 H, Ar), 4.59 (d, 2JH,H = 11.5 Hz, 1 H, CH2Ph), 4.33
2
3
(d, JH,H = 11.5 Hz, 1 H, CH2Ph), 4.02 (dd, JH,H = 8.0, 6.4 Hz, 1
H, 4-H), 3.84 (dd, 2JH,H = 8.1, 3JH,H = 6.4 Hz, 1 H, 5-H), 3.53 (dq,
3JH,H = 10.4, 6.1 Hz, 1 H, 1ЈЈ-H), 3.45 (dd, JH,H = 8.1, JH,H
=
2
3
8.0 Hz, 1 H, 5-H), 2.39 (m, 1 H, 2Ј-H), 2.03 (m, 1 H, 4Ј-H), 1.82
(m, 1 H, 3Ј-H), 1.54 (m, 1 H, 3Ј-H), 1.35 (m, 1 H, 4Ј-H), 1.42 (s, 3 (10 mL) was added. The solution was washed with brine
3
H, CH3C-2), 1.35 (s, 3 H, CH3C-2), 1.07 (d, JH,H = 6.1 Hz, 3 H, (3ϫ10 mL), dried with anhydrous MgSO4, and concentrated under
2ЈЈ-H), 1.01 (s, 3 H, CH3C-1Ј) ppm. 13C NMR (100 MHz, CDCl3): vacuum to afford a reaction crude that was used in the next step
δ = 138.9 (C, Ar), 128.2, 127.6, 127.3 (5 CH, Ar), 108.5 (C, C-2),
without further purification. For characterization of the product,
82.2 (CH, C-4), 75.8 (CH, C-1ЈЈ), 69.6 (CH2Ph), 65.7 (CH2, C-5), a fraction of the crude was purified by column chromatography
44.2 (CH, C-2Ј), 41.6 (C, C-1Ј), 26.5 (CH3, CH3C-2), 25.5 (CH3, (hexane/diethyl ether, 5:1) to furnish (1ЈЈR)-30 as a colorless oil.
CH3C-2), 25.3 (CH2, C-4Ј), 19.1 (CH2, C-3Ј), 16.3 (CH3, CH3C- [α]D = –23.6 (c = 2.2, CHCl ). IR (ATR): ν = 2917, 1719, 1454,
˜
3
1Ј), 15.9 (CH3, C-2ЈЈ) ppm. HRMS (ESI+): calcd. for [C19H28O3 +
1261, 1094 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.56 (s, 1 H,
2
Na]+ 327.1931; found 327.1937.
1ЈЈ-H), 7.37–7.25 (m, 5 H, Ar), 4.58 (d, JH,H = 11.4 Hz, 1 H,
3
3
CH2Ph), 4.33 (d, JH,H = 11.4 Hz, 1 H, CH2Ph), 3.53 (dq, JH,H
=
10.0, 6.0 Hz, 1 H, 1ЈЈ-H), 2.56 (ddd, 3JH,H = 10.0, 8.9, 8.7 Hz, 1 H,
2Ј-H), 2.28 (dt, 2JH,H = 10.5, 3JH,H = 10.5, 8.9 Hz, 1 H, 4Ј-H), 1.91
(1S)-1-{(1S,2S)-2-[(1R)- and (1S)-1-{(1S,2S)-2-[(1S)-1-Benzyloxy-
ethyl]-1-methylcyclobutyl}ethane-1,2-diol [(1ЈЈR)- and (1ЈЈS)-29]:
pTsOH (70 mg, 0.39 mmol) was added to a solution of (1ЈЈR)-28
(228 mg, 0.75 mmol) in MeOH (15 mL). The reaction mixture was
stirred for 3 h at room temp. Then the crude was concentrated to
a quarter of the initial volume and diluted with CH2Cl2 (20 mL)
before being washed with a saturated solution of NaHCO3
(2ϫ20 mL) and brine (2ϫ20 mL). The organic layer was dried
with anhydrous MgSO4 and evaporated under reduced pressure.
The resulting crude was purified by column chromatography (hex-
ane/diethyl ether, 2:1) to give (1ЈЈR)-29 (194 mg, 0.73 mmol, 98%
yield) as a colorless oil.
2
3
(ddt, JH,H = 10.5, JH,H = 10.5, 8.7, 2.3 Hz, 1 H, 3Ј-H), 1.77 (dq,
2JH,H = 10.5, JH,H = 8.9, 8.9, 8.9 Hz, 1 H, 3Ј-H), 1.46 (ddd, 2JH,H
3
3
= 10.5, JH,H = 8.9, 2.3 Hz, 1 H, 4Ј-H), 1.26 (s, 3 H, CH3C-1Ј),
1.11 (d, JH,H = 6.0 Hz, 3 H, 2ЈЈ-H) ppm. 13C NMR (100 MHz,
3
CDCl3): δ = 204.3 (C=O), 138.6 (C, Ar), 128.3, 127.5, 127.4 (5 CH,
Ar), 74.6 (CH, C-1ЈЈ), 69.9 (CH2Ph), 50.2 (C, C-1Ј), 44.2 (CH, C-
2Ј), 24.5 (CH2, C-4Ј), 19.8 (CH2, C-3Ј), 15.6 (CH3, CH3C-1Ј), 14.3
(CH3, C-2ЈЈ) ppm. HRMS (ESI+): calcd. for [C15H20O2 + Na]+
255.1366; found 255.1360.
(1R)- and (1S)-{(1S,2S)-2-[(1R)-1-Benzyloxyethyl]-1-methyl-
cyclobutyl}ethan-1-ol [(1R)- and (1S)-31]: A 1.6 m solution of MeLi
in diethyl ether (2.8 mL, 4.48 mmol) was carefully added dropwise
to a solution of aldehyde (1ЈЈR)-30 (from the previous reaction
crude) in dry THF (25 mL) under nitrogen at –78 °C. The mixture
was stirred for 1 h at –78 °C and 2 h at room temp. Then the reac-
tion was quenched by the slow addition of a saturated solution of
NH4Cl. The two layers were separated and the aqueous one was
extracted first with CH2Cl2 (3 ϫ 20 mL) and then with EtOAc
(3ϫ20 mL). The combined organic layers were washed with a satu-
rated solution of NaCl (20 mL), dried with anhydrous Na2SO4, fil-
tered, and the solvents evaporated to dryness. Column chromatog-
raphy (hexane/diethyl ether, 5:1 to 3:1) provided two isomers of 31
[isomer A: 77 mg, 0.31 mmol, 43% yield from (1ЈЈR)-29; isomer B:
81 mg, 0.33 mmol, 45% yield from (1ЈЈR)-29] both as colorless oils.
The stereochemistry at C-1 could not be assigned.
The reaction performed from (1ЈЈS)-28 (25 mg, 0.08 mmol) deliv-
ered (1ЈЈS)-29 (20 mg, 0.07 mmol, 90% yield) as a colorless oil.
The reaction performed from a mixture (1ЈЈR)- and (1ЈЈS)-28
(100 mg, 0.33 mmol) afforded a mixture of (1ЈЈR)- and (1ЈЈS)-29
(84 mg, 0.32 mmol, 97% yield) as a colorless oil.
(1ЈЈR)-29: [α]D = –58.4 (c = 1.86, CHCl ). IR (ATR): ν = 3423,
˜
3
2966, 2870, 1455, 1374, 1089 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.35–7.24 (m, 5 H, Ar), 4.58 (d, 2JH,H = 11.1 Hz, 1 H, CH2Ph),
2
4.34 (d, JH,H = 11.1 Hz, 1 H, CH2Ph), 3.48 (m, 1 H, 2-H), 3.44
(m, 1 H, 1ЈЈ-H), 3.43 (m, 1 H, 1-H), 3.40 (m, 1 H, 2-H), 2.10 (m,
1 H, 2Ј-H), 1.80 (m, 2 H, 3Ј-H, 4Ј-H), 1.57 (m, 1 H, 3Ј-H), 1.32
3
(m, 1 H, 4Ј-H), 1.06 (d, JH,H = 5.9 Hz, 3 H, 2ЈЈ-H), 0.96 (s, 3 H,
CH3C-1Ј) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.1 (C, Ar),
128.3, 128.3, 128.2 (5 CH, Ar), 80.0 (CH, C-1), 74.5 (CH, C-1ЈЈ),
70.1 (CH2Ph), 62.2 (CH2, C-2), 48.6 (CH, C-2Ј), 43.3 (C, C-1Ј),
27.2 (CH2, C-4Ј), 19.5 (CH2, C-3Ј), 15.3 (CH3, CH3C-1Ј), 13.9
(CH3, C-2ЈЈ) ppm. HRMS (ESI+): calcd. for [C16H24O3 + Na]+
287.1618; found 287.1628.
Isomer A: [α]D = –23.7 (c = 0.9, CHCl ). IR (ATR): ν = 3466, 2968,
˜
3
1454, 1372, 1104 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.27
(m, 5 H, Ar), 4.60 (d, 2JH,H = 11.0 Hz, 1 H, CH2Ph), 4.39 (d, 2JH,H
3
= 11.0 Hz, 1 H, CH2Ph), 3.57 (q, JH,H = 6.4 Hz, 1 H, 1-H), 3.45
3
(dq, JH,H = 10.3, 6.0 Hz, 1 H, 1ЈЈ-H), 2.01 (m, 1 H, 2Ј-H), 1.80
(m, 1 H, 3Ј-H), 1.56 (m, 1 H, 3Ј-H), 1.56 (m, 1 H, 4Ј-H), 1.34 (m,
(1ЈЈS)-29: [α]D = +23.8 (c = 1.4, CHCl ). IR (ATR): ν = 3403, 2963,
˜
1 H, 4Ј-H), 1.09 (d, 3JH,H = 6.0 Hz, 3 H, 2ЈЈ-H), 0.99 (s, 3 H, CH3C-
3
2929, 1454, 1372, 1071 cm–1. 1H NMR (400 MHz, CDCl3): δ =
3
1Ј), 0.94 (d, JH,H = 6.4 Hz, 3 H, 2-H) ppm. 13C NMR (100 MHz,
2
7.35–7.29 (m, 5 H, Ar), 4.60 (d, JH,H = 11.1 Hz, 1 H, CH2Ph),
CDCl3): δ = 137.5 (C, Ar), 128.5, 128.2, 127.9 (5 CH, Ar), 76.4
(CH, C-1), 74.7 (CH, C-1ЈЈ), 70.2 (CH2Ph), 50.5 (CH, C-2Ј), 45.5
(C, C-1Ј), 27.7 (CH2, C-4Ј), 19.1 (CH2, C-3Ј), 15.5 (CH3, C-2), 15.4
(CH3, C-2ЈЈ), 11.9 (CH3, CH3C-1Ј) ppm. HRMS (ESI+): calcd. for
[C16H24O2 + Na]+ 271.1669; found 271.1668.
2
4.36 (d, JH,H = 11.1 Hz, 1 H, CH2Ph), 3.64 (m, 1 H, 2-H), 3.51
3
(dq, JH,H = 10.3, 6.0 Hz, 1 H, 1ЈЈ-H), 3.46 (m, 1 H, 2-H), 3.40
(dd, 3JH,H = 7.6, 4.6 Hz, 1 H, 1-H), 2.59 (br. s, 2 H, OH), 2.34 (m,
1 H, 2Ј-H), 1.82 (m, 1 H, 3Ј-H), 1.85 (m, 1 H, 4Ј-H), 1.57 (m, 1 H,
3
3Ј-H), 1.39 (m, 1 H, 4Ј-H), 1.12 (s, 3 H, CH3C-1Ј), 1.08 (d, JH,H
= 6.0 Hz, 3 H, 2ЈЈ-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
137.4 (C, Ar), 128.5, 128.4, 128.0 (5 CH, Ar), 77.7 (CH, C-1), 75.3
(CH, C-1ЈЈ), 70.4 (CH2Ph), 63.6 (CH2, C-2), 44.1 (CH, C-2Ј), 43.3
Isomer B: [α]D = –45.1 (c = 1.7, CHCl ). IR (ATR): ν = 3431, 3031,
˜
3
2965, 1454, 1080 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.26
(m, 5 H, Ar), 4.58 (d, 2JH,H = 11.1 Hz, 1 H, CH2Ph), 4.36 (d, 2JH,H
3
(C, C-1Ј), 27.1 (CH2, C-4Ј), 19.4 (CH2, C-3Ј), 17.4 (CH3, CH3C- = 11.1 Hz, 1 H, CH2Ph), 3.47 (dq, JH,H = 10.0, 6.0 Hz, 1 H, 1ЈЈ-
3
1Ј), 15.6 (CH3, C-2ЈЈ) ppm.
H), 3.46 (q, JH,H = 6.4 Hz, 1 H, 1-H), 2.32 (m, 1 H, 2Ј-H), 1.82
Eur. J. Org. Chem. 2012, 1404–1417
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1413

S. Parés, R. Alibés, M. Figueredo, J. Font, T. Parella
FULL PAPER
(m, 1 H, 4Ј-H), 1.78 (m, 1 H, 3Ј-H), 1.56 (m, 1 H, 3Ј-H), 1.30 (m, 128.3, 127.9 (5 CH, Ar), 88.2 (C, CϵCH), 74.4 (CH, C-1ЈЈ), 73.1
1 H, 4Ј-H), 1.15 (s, 3 H, CH3C-1Ј), 1.13 (d, 3JH,H = 6.4 Hz, 3 H, 2ЈЈ-
(C, C-2), 72.4 (CH, CϵCH), 70.2 (CH2Ph), 47.1 (C, C-1Ј), 45.6
(CH, C-2Ј), 27.4 (CH2, C-4Ј), 23.1 (CH3, C-1), 18.6 (CH2, C-3Ј),
15.5 (CH3, C-2ЈЈ), 13.6 (CH3, CH3C-1Ј) ppm. HRMS (ESI+):
3
H), 1.09 (d, JH,H = 6.0 Hz, 3 H, 2-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 138.0 (C, Ar), 128.4, 128.2, 127.7 (5 CH, Ar), 75.2
(CH, C-1), 72.9 (CH, C-1ЈЈ), 70.3 (CH2Ph), 45.6 (C, C-2Ј), 42.5 calcd. for [C18H24O2 + Na]+ 295.1669; found 295.1670.
(CH, C-1Ј), 26.5 (CH2, C-3Ј), 18.8 (CH3, C-2ЈЈ), 18.8 (CH3C-2Ј),
(2R)-33: 1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H, Ar),
18.6 (CH2, C-4Ј), 15.7 (CH3, C-2) ppm. HRMS (ESI+): calcd. for
2
2
4.57 (d, JH,H = 11.0 Hz, 1 H, CH2Ph), 4.37 (d, JH,H = 11.2 Hz,
1 H, CH2Ph), 3.62 (br. s, 1 H, OH), 3.47 (dq, 3JH,H = 10.4, 6.0 Hz,
1 H, 1ЈЈ-H), 2.45 (m, 1 H, 2Ј-H), 2.34 (s, 1 H, CϵCH), 1.92 (m, 1
[C16H24O2 + Na]+ 271.1669; found 271.1666.
1-{(1S,2S)-2-[(1R)-1-Benzyloxyethyl]-1-methylcyclobutyl}ethan-1-
one [(1ЈЈR)-32]: A commercially available solution of Dess–Martin
periodinane in CH2Cl2 (15wt.-%, 3.5 mL, 1.75 mmol) was added
to a solution of a 1:1 mixture of (1R)- and (1S)-31 (290 mg,
1.17 mmol) in dry CH2Cl2 (13 mL) and the mixture was stirred for
2 h under nitrogen at room temp. The solution was washed with a
saturated solution of NaHCO3 containing a seven-fold excess of
Na2S2O3 (15 mL). The layers were separated and the aqueous
phase was extracted with CH2Cl2 (2ϫ10 mL). The combined or-
ganic extracts were dried with anhydrous Na2SO4 and concentrated
under reduced pressure. Purification by column chromatography
(pentane/diethyl ether, 5:1) provided (1ЈЈR)-32 (273 mg, 1.11 mmol,
95% yield) as a colorless oil. [α]D = –8.57 (c = 0.7, CHCl3). IR
H, 4Ј-H), 1.79 (m, 1 H, 3Ј-H), 1.56 (m, 1 H, 3Ј-H), 1.51 (s, 3 H, 1-
H), 1.40 (m, 1 H, 4Ј-H), 1.32 (s, 3 H, CH3C-1Ј), 1.10 (d, JH,H
3
=
6.0 Hz, 3 H, 2ЈЈ-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.3
(C, Ar), 128.5, 128.4, 127.9 (5 CH, Ar), 86.6 (C, CϵCH), 74.7 (CH,
C-1ЈЈ), 71.8 (C, C-2), 71.6 (CH, CϵCH), 70.3 (CH2Ph), 47.9 (C,
C-1Ј), 42.8 (CH, C-2Ј), 26.8 (CH2, C-4Ј), 26.2 (CH3, C-1), 18.1
(CH2, C-3Ј), 16.8 (CH3, C-2ЈЈ), 15.7 (CH3, CH3C-1Ј) ppm. HRMS
(ESI+): calcd. for [C18H24O2 + Na]+ 295.1669; found 295.1657.
3-{(1S,2S)-2-[(1R)-Benzyloxyethyl]-1-methylcyclobutyl}-2-butenal
(34): [V(O)(OSiPh3)3] (11 mg, 0.012 mmol) was added to a solution
of a 9:1 mixture of (2S)- and (2R)-33 (67 mg, 0.24 mmol) in dry
toluene (1.1 mL). The mixture was irradiated under pressure in a
focused microwave reactor at 120 °C for five cycles of 1 h. The reac-
tion mixture was passed through a short column filled with a silica
gel plug and used in the next step without further purification. For
characterization purposes, a fraction of the crude was purified by
column chromatography (hexane/diethyl ether, 5:1) to afford 34. 1H
(ATR): ν = 2968, 2928, 2870, 1699, 1455, 1372 cm–1. 1H NMR
˜
2
(400 MHz, CDCl3): δ = 7.35–7.25 (m, 5 H, Ar), 4.62 (d, JH,H
=
11.2 Hz, 1 H, CH2Ph), 4.36 (d, 2JH,H = 11.2 Hz, 1 H, CH2Ph), 3.59
(dq, 3JH,H = 10.0, 6.0 Hz, 1 H, 1ЈЈ-H), 2.52 (ddd, 3JH,H = 10.0, 9.6,
2
3
9.1 Hz, 1 H, 2Ј-H), 2.36 (ddd, JH,H = 11.0, JH,H = 9.7, 9.4 Hz, 1
2
3
H, 4Ј-H), 2.11 (s, 3 H, CH3CO), 1.82 (dddd, JH,H = 11.0, JH,H
=
3
NMR (400 MHz, CDCl3): δ = 9.99 (d, JH,H = 8.0 Hz, 1 H, 1-H),
2
3
9.4, 9.1, 2.6 Hz, 1 H, 3Ј-H), 1.57 (dddd, JH,H = 11.0, JH,H = 9.7,
9.6, 9.6 Hz, 1 H, 3Ј-H), 1.43 (m, 1 H, 4Ј-H), 1.29 (s, 3 H, CH3C-
1Ј), 1.10 (d, 3JH,H = 6.0 Hz, 3 H, 2ЈЈ-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 213.1 (C=O), 138.5 (C, Ar), 128.3, 127.8, 127.5 (5 CH,
Ar), 75.3 (CH, C-1ЈЈ), 70.0 (CH2Ph), 51.7 (C, C-1Ј), 45.6 (CH, C-
2Ј), 26.4 (CH2, C-4Ј), 25.1 (CH3, CH3CO), 18.6 (CH2, C-3Ј), 17.4
(CH3, CH3C-1Ј), 15.7 (CH3, C-2ЈЈ) ppm. HRMS (ESI+): calcd. for
[C16H22O2 + Na]+ 269.1512; found 269.1521.
7.36–7.27 (m, 5 H, Ar), 6.19 (dd, 3JH,H = 8.0, JH,H = 1.3 Hz, 1 H,
4
2
2
2-H), 4.63 (d, JH,H = 11.6 Hz, 1 H, CH2Ph), 4.35 (d, JH,H
=
11.6 Hz, 1 H, CH2Ph), 3.54 (dq, 3JH,H = 10.1, 6.0 Hz, 1 H, 1ЈЈ-H),
4
2.45 (m, 1 H, 2Ј-H), 2.09 (d, JH,H = 1.3 Hz, 3 H, 4-H), 1.98 (m, 1
H, 4Ј-H), 1.81 (m, 1 H, 3Ј-H), 1.65 (m, 1 H, 4Ј-H), 1.58 (m, 1 H,
3
3Ј-H), 1.19 (s, 3 H, CH3C-1Ј), 1.09 (d, JH,H = 6.0 Hz, 3 H, 2ЈЈ-
H) ppm. HRMS (ESI+): calcd. for [C18H24O2 + Na]+ 295.1669;
found 295.1665. The β,γ-unsaturated aldehyde could not be iso-
lated by column chromatography.
(2R)- and (2S)-2-{(1S,2S)-2-[(1R)-1-Benzyloxyethyl]-1-methyl-
cyclobutyl}-3-butyn-2-ol [(2R)- and (2S)-33]: A 0.5 m solution of
ethynylmagnesium chloride in THF (2.4 mL, 1.21 mmol) was care-
fully added dropwise to a solution of ketone (1ЈЈR)-32 (60 mg,
0.24 mmol) in dry THF (2 mL) under nitrogen at –78 °C. The mix-
ture was stirred for 1 h at –78 °C and 2 h at room temp. Then the
reaction mixture was quenched by the slow addition of a saturated
solution of NH4Cl. The two layers were separated and the aqueous
one was extracted with diethyl ether (3ϫ5 mL). The combined or-
ganic layers were washed with a saturated solution of NaCl, dried
with anhydrous MgSO4, filtered, and the solvents evaporated to
dryness. Column chromatography (hexane/diethyl ether, 5:1) pro-
vided (2S)-33 (56 mg, 0.20 mmol, 85% yield) as a white solid and
(2R)-33 (5 mg, 0.02 mmol, 8% yield) as a colorless oil.
Methyl 4-{(1S,2S)-2-[(1R)-Benzyloxyethyl]-1-methylcyclobutyl}-1,3-
cyclohexadiene-1-carboxylate (35): A 40 % aqueous solution of
Me2NH (140 μL, 1.04 mmol) was added to a solution of aldehydes
34 (67 mg, 0.24 mmol) in toluene (1.4 mL). The system was heated
to 90 °C and stirred for 2 h. The reaction mixture was used in the
next step without further purification. The crude containing the
enamine intermediate was placed in a microwave vessel. Then
methyl acrylate (109 μL, 1.18 mmol) was added. The mixture was
irradiated under pressure in a focused microwave reactor at 150 °C
for two cycles of 1.3 h. SiO2 (262 mg, 4.36 mmol) was added to the
crude containing the cycloadducts. The reaction mixture was
heated to 90 °C and stirred overnight. The reaction mixture was
filtered off, concentrated under reduced pressure, and purified by
column chromatography (pentane/diethyl ether, 10:1) to afford 35
(43 mg, 0.12 mmol, 51% yield, four steps) and the ethanone 32
(5 mg, 0.02 mmol).
(2S)-33: M.p. 62–67 °C (pentane/EtOAc). [α]D = –37.2 (c = 1.2,
CHCl ). IR (ATR): ν = 3410, 3248, 2966, 2929, 2859, 1453, 1396,
˜
3
1138, 1105, 1296 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.36–7.26
(m, 5 H, Ar), 4.60 (d, 2JH,H = 11.2 Hz, 1 H, CH2Ph), 4.38 (d, 2JH,H
35: [α]D = +50.0 (c = 2.0, CHCl ). IR (ATR): ν = 2926, 2868, 1704,
˜
3
4
= 11.2 Hz, 1 H, CH2Ph), 4.36 (d, JH,H = 0.5 Hz, 1 H, OH), 3.43 1578, 1454, 1434, 1268 cm–1. 1H NMR (600 MHz, CDCl3): δ =
(dq, 3JH,H = 10.4, 6.0 Hz, 1 H, 1ЈЈ-H), 2.81 (ddd, 3JH,H = 10.4, 9.0,
7.33–7.27 (m, 5 H, Ar), 7.02 (dt, JH,H = 5.8, JH,H = 1.4 Hz, 1 H,
3
4
2
3
4
8.7 Hz, 1 H, 2Ј-H), 2.50 (s, 1 H, CϵCH), 2.09 (q, JH,H = 10.6,
2-H), 6.07 (dt, JH,H = 5.8, JH,H = 1.3 Hz, 1 H, 3-H), 4.60 (d,
2
3
2
3JH,H = 10.3, 10.3 Hz, 1 H, 4Ј-H), 1.82 (dddd, JH,H = 10.6, JH,H
2JH,H = 11.5 Hz, 1 H, CH2Ph), 4.36 (d, JH,H = 11.5 Hz, 1 H,
3
3
3
= 10.3, 8.7, 1.8 Hz, 1 H, 3Ј-H), 1.53 (dq, JH,H = 10.6, JH,H
=
CH2Ph), 3.74 (s, 3 H, CO2CH3), 3.55 (dq, JH,H = 10.0, 6.0 Hz, 1
10.3, 9.0, 9.0 Hz, 1 H, 3Ј-H), 1.33 (dddd, 2JH,H = 10.6, 3JH,H = 9.0, H, 1ЈЈ-H), 2.47 (m, 1 H, 2Ј-H), 2.39 (m, 2 H, 6-H), 2.27 (m, 1 H,
4
4
1.8, JH,H = 0.8 Hz, 1 H, 4Ј-H), 1.28 (d, JH,H = 0.5 Hz, 3 H, 1- 5-H), 2.13 (m, 1 H, 5-H), 1.97 (m, 1 H, 4Ј-H) 1.82 (m, 1 H, 3Ј-H),
3
3
H), 1.11 (d, JH,H = 6.0 Hz, 3 H, 2ЈЈ-H), 1.08 (s, 3 H, CH3C- 1.59 (m, 2 H, 3Ј-H, 4Ј-H), 1.18 (s, 3 H, CH3C-1Ј), 1.10 (d, JH,H
=
1Ј) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.2 (C, Ar), 128.5, 6.0 Hz, 3 H, 2ЈЈ-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.1
1414
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1404–1417

Synthesis of Sesquiterpenes with the Dunniane Skeleton
(C=O), 156.9 (C, C-4), 138.8 (C, Ar), 134.0 (CH, C-2), 128.2, 127.6, (CH, C-1trans), 38.8 (CH, C-1cis), 30.1, 30.0 (2 CH3, C-2ЈЈtrans, C-
127.3 (5 CH, Ar), 124.1 (C, C-1), 116.7 (CH, C-3), 75.8 (CH, C- 2ЈЈcis), 29.4, 29.3 (2 CH, C-4Јtrans, C-4Јcis), 29.1, 29.1 (2 CH2, C-
1ЈЈ), 70.3 (CH2Ph), 51.4 (CH3, CO2CH3), 48.0 (CH, C-2Ј), 46.5 (C,
2trans), 27.6, 27.6 (2 CH2, C-2cis), 26.3, 26.0 (2 CH2, C-3trans), 23.6,
C-1Ј), 29.9 (CH2, C-4Ј), 23.6 (CH2, C-5), 22.0 (CH2, C-6), 20.3 23.3 (2 CH2, C-3cis), 17.5, 17.2 (2 CH3, CH3C-1Јtrans, CH3C-1Јcis),
(CH3, CH3C-1Ј), 19.1 (CH2, C-3Ј), 16.0 (CH3, C-2ЈЈ) ppm. HRMS 16.6, 16.3 (2 CH2, C-3Јtrans, C-3Јcis) ppm. HRMS (ESI+): calcd. for
(ESI+): calcd. for [C22H28O3 + Na]+ 363.1931; found 363.1930.
[C15H24O3 + Na]+ 275.1618; found 275.1619.
Methyl trans- and Methyl cis-4-[(1R,2S)-2-Isopropenyl-1-methylcy-
clobutyl]cyclohexane-1-carboxylate (trans- and cis-40): BuLi
(128 μL, 0.20 mmol, 1.6 m in THF) was added dropwise to a sus-
pension of Ph3PCH3I (80 mg, 0.18 mmol) in THF (1.0 mL) at 0 °C.
The mixture was stirred for 1 h at 0 °C. Then the previous crude
containing the 1:1 mixture of ketone 39 (23 mg, 0.09 mmol) in THF
(0.7 mL) was added. The mixture was warmed to room temp. and
stirred overnight. Then the reaction mixture was diluted with di-
ethyl ether and quenched by the slow addition of NH4Cl saturated
solution. The two layers were separated and the aqueous one was
extracted with diethyl ether (2ϫ1 mL). The combined organic lay-
ers were dried with anhydrous MgSO4, filtered through Celite, and
carefully concentrated (150 mbar). The crude was purified by col-
umn chromatography (pentane/diethyl ether, 25:1) to afford a 1:1
mixture of trans- and cis-40 (18 mg, 0.07 mmol, 77% yield from
38).
Methyl trans- and Methyl cis-4-[(1R,2S)-2-(1-Hydroxyethyl)-1-
methylcyclobutyl]cyclohexane-1-carboxylate (trans- and cis-38): Pd/
C 10% (50 mg) was added to a solution of 35 (160 mg, 0.47 mmol)
in diethyl ether (14 mL). The reaction mixture was stirred under
H2 (1 bar) overnight. The reaction mixture was filtered through
Celite and purified by column chromatography (pentane/diethyl
ether, 15:1) to afford a volatile 1:1 mixture of trans- and cis-38
(113 mg, 0.44 mmol, 95 % yield) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 3.74 (m, 2 H, 1ЈЈtrans-H, 1ЈЈcis-H), 3.68, 3.65
(2 s, 6 H, CO2CH3,trans, CO2CH3,cis), 2.63 (m, 1 H, 1cis-H), 2.21 (m,
1 H, 1trans-H), 2.20 (m, 2 H, 2cis-H), 2.00 (m, 2 H, 2trans-H), 1.90
(m, 3 H, 3trans-H, 2Јtrans-H, 2Јcis-H), 1.79 (m, 2 H, 3Јtrans-H, 3Јcis
-
H), 1.76 (m, 2 H, 4Јtrans-H, 4Јcis-H), 1.71 (m, 1 H, 3cis-H), 1.64 (m,
1 H, 3trans-H), 1.55 (m, 1 H, 3cis-H), 1.45 (m, 2 H, 2cis-H), 1.43 (m,
2 H, 3Јtrans-H, 3Јcis-H), 1.42 (m, 1 H, 3cis-H), 1.40 (m, 2 H, 2trans
-
H), 1.38 (m, 2 H, 4Јtrans-H, 4Јcis-H), 1.17 (m, 2 H, 4trans-H, 4cis-H),
3
1.13 (m, 1 H, 3cis-H), 1.05, 1.03 (2 d, JH,H = 6.0 Hz, 6 H, CH3,
trans-40: 1H NMR (600 MHz, CDCl3): δ = 4.84 (d, 2JH,H = 6.1 Hz,
2ЈЈtrans-H, 2ЈЈcis-H), 0.99, 0.97 (2 s, 6 H, CH3C-1Јtrans, CH3C-1Јcis),
2
1 H, 2ЈЈ-H), 4.66 (d, JH,H = 6.1 Hz, 1 H, 2ЈЈ-H), 3.69 (s, 3 H,
0.94 (m, 1 H, 3trans-H), 0.89 (m, 1 H, 3trans-H) ppm. 13C NMR
CO2CH3), 2.69 (m, 1 H, 2Ј-H), 2.21 (m, 1 H, 1-H), 2.03 (m, 2 H,
2-H), 1.91 (m, 1 H, 3Ј-H), 1.80 (m, 2 H, 3-H), 1.77 (m, 1 H, 3Ј-H),
1.70 (m, 1 H, 4Ј-H), 1.65 (s, 3 H, 3ЈЈ-H), 1.40 (m, 2 H, 2-H), 1.30
(m, 1 H, 4Ј-H), 1.24 (m, 1 H, 4-H), 1.05 (m, 1 H, 3-H), 0.94 (m, 1
H, 3-H), 0.86 (s, 3 H, CH3C-1Ј) ppm. 13C NMR (150 MHz,
CDCl3): δ = 175.5 (C=O), 146.2 (C, C-1ЈЈ), 110.3 (CH2, C-2ЈЈ), 51.4
(CH3, CO2CH3), 47.9 (C, C-4), 47.0 (CH, C-2Ј), 45.7 (C, C-1Ј),
43.4 (CH, C-1), 29.3 (CH2, C-2), 29.2 (CH2, C-2), 28.2 (CH2, C-
4Ј), 26.7 (CH2, C-3), 26.5 (CH2, C-3), 23.6 (CH3, C-3ЈЈ), 19.1 (CH2,
C-3Ј), 17.4 (CH3, CH3C-1Ј) ppm.
(100 MHz, CDCl3): δ = 176.7, 175.7 (2 C=O, CO2CH3,trans
,
CO2CH3,cis), 68.8 (CH, C-1ЈЈtrans, C-1ЈЈcis), 51.5, 51.4 (2 CH3,
CO2CH3,trans, CO2CH3,cis), 50.3, 50.3 (2 CH, C-2Јtrans, C-2Јcis), 49.4,
48.9 (2 CH, C-4trans, C-4cis), 43.7, 43.7 (2 C, C-1Јtrans, C-1Јcis), 43.5
(CH, C-1trans), 39.0 (CH, C-1cis), 29.8, 29.8, 29.4, 29.3 (4 CH2, C-
2trans, C-4Јtrans, C-4Јcis), 27.8, 27.7 (2 CH2, C-2cis), 26.2, 25.9 (2 CH2,
C-3trans), 23.6, 23.1 (2 CH2, C-3cis), 20.8, 20.6 (2 CH3, C-2ЈЈtrans, C-
2ЈЈcis), 18.8, 18.8 (2 CH2, C-3Јtrans, C-3Јcis), 15.8, 15.7 (2 CH3,
CH3C-1Јtrans, CH3C-1Јcis) ppm. HRMS (ESI+): calcd. for
[C15H26O3 + Na]+ 277.1774; found 277.1769.
1
2
cis-40: H NMR (600 MHz, CDCl3): δ = 4.84 (d, JH,H = 6.1 Hz,
Methyl trans- and Methyl cis-4-[(1R,2S)-2-Acetyl-1-methylcyclobut-
yl]cyclohexane-1-carboxylate (trans- and cis-39): A commercially
available solution of Dess–Martin periodinane in CH2Cl2 (15wt.-
%, 308 μL, 0.15 mmol) was added to a solution of a 1:1 mixture of
trans- and cis-38 (24 mg, 0.09 mmol) in dry CH2Cl2 (1.0 mL) and
the mixture was stirred for 3 h under nitrogen at room temp. The
solution was washed with a saturated solution of NaHCO3 contain-
ing a seven-fold excess of Na2S2O3 (3 mL). The layers were sepa-
rated and the aqueous phase was extracted with CH2Cl2
(2ϫ3 mL). The combined organic extracts were dried with anhy-
drous Na2SO4, concentrated under reduced pressure, and used for
the next step without further purification. For characterization pur-
poses, a fraction of the crude was purified by column chromatog-
raphy (pentane/diethyl ether, 25:1) to afford a 1:1 mixture of trans-
and cis-39 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 3.69,
3.66 (2 s, 6 H, CO2CH3,trans, CO2CH3,cis), 3.01 (m, 2 H, 2Јtrans-H,
2Јcis-H), 2.67 (m, 1 H, 1cis-H), 2.30 (m, 2 H, 3Јtrans-H, 3Јcis-H), 2.25
(m, 2 H, 2cis-H), 2.24 (m, 1 H, 1trans-H), 2.06, 2.06 (2 s, 6 H, CH3,
2ЈЈtrans-H, 2ЈЈcis-H), 2.05 (m, 2 H, 2trans-H), 2.05 (m, 2 H, 4Јtrans-H,
4Јcis-H), 1.83 (m, 2 H, 3trans-H), 1.78 (m, 2 H, 3Јtrans-H, 3Јcis-H),
1.64 (m, 2 H, 3cis-H), 1.49 (m, 1 H, 3cis-H), 1.47 (m, 2 H, 2cis-H),
1.43 (m, 2 H, 2trans-H), 1.37 (m, 2 H, 4trans-H, 4cis-H), 1.25 (m, 2
2
1 H, 2ЈЈ-H), 4.66 (d, JH,H = 6.1 Hz, 1 H, 2ЈЈ-H), 3.66 (s, 3 H,
CO2CH3), 2.69 (m, 1 H, 2Ј-H), 2.64 (m, 1 H, 1-H), 2.22 (m, 2 H,
2-H), 1.91 (m, 1 H, 3Ј-H), 1.77 (m, 1 H, 3Ј-H), 1.70 (m, 1 H, 4Ј-
H), 1.65 (s, 3 H, 3ЈЈ-H), 1.60 (m, 2 H, 3-H), 1.45 (m, 2 H, 2-H),
1.30 (m, 1 H, 4Ј-H), 1.25 (m, 1 H, 4-H), 1.20 (m, 1 H, 3-H), 1.08
(m, 1 H, 3-H), 0.88 (s, 3 H, CH3C-1Ј) ppm. 13C NMR (150 MHz,
CDCl3): δ = 175.6 (C=O), 146.2 (C, C-1ЈЈ), 110.3 (CH2, C-2ЈЈ), 51.5
(CH3, CO2CH3), 47.4 (CH, C-4), 47.1 (CH, C-2Ј), 45.7 (C, C-1Ј),
38.9 (CH, C-1), 27.7 (CH2, C-2), 27.6 (CH2, C-2), 28.2 (CH2, C-
4Ј), 23.9 (CH2, C-3), 23.8 (CH2, C-3), 23.6 (CH3, C-3ЈЈ), 19.1 (CH2,
C-3Ј), 17.4 (CH3, CH3C-1Ј) ppm. HRMS (ESI+): calcd. for
[C16H26O2 + Na]+ 273.1825; found 273.1830 from the mixture.
Methyl (4S)- and Methyl (4R)-4-{(1R,2S)-2-[(1R)-1-Benzyloxy-
ethyl]-1-methylcyclobutyl}-1-cyclohexene-1-carboxylate [(4S)- and
(4R)-36]: Pd/C 10 % (40 mg) and ammonium formate (19 mg,
0.29 mmol) were added to a solution of 35 (100 mg, 0.29 mmol) in
THF/MeOH (2:1, 0.6 mL). The reaction mixture was heated to
80 °C and stirred for 30 min. The reaction mixture was filtered off
through Celite and purified by column chromatography (pentane/
diethyl ether, 20:1) to afford a colorless oil identified as a 1:1 mix-
ture of the cyclohexenes (4S)- and (4R)-36 (93 mg, 0.27 mmol, 93%
yield).
H, 4Јtrans-H, 4Јcis-H), 1.12 (m, 1 H, 3cis-H), 1.03 (m, 2 H, 3trans
-
H), 0.91, 0.91 (2 s, 6 H, CH3C-1Јtrans, CH3C-1Јcis) ppm. 13C NMR Mixture of (4S)- and (4R)-36: 1H NMR (400 MHz, CDCl3): δ =
(100 MHz, CDCl3): δ = 209.3 (2 C=O, C-1ЈЈtrans, C-1ЈЈcis), 176.4, 7.35–7.29 (m, 10 H, Ar), 6.96 (m, 1 H, 2-H), 6.84 (m, 1 H, 2-H),
2
2
175.5 (2 C=O, CO2CH3,trans, CO2CH3,cis), 53.0, 52.8 (2 CH, C-
2Јtrans, C-2Јcis), 51.5, 51.4 (2 CH3, CO2CH3,trans, CO2CH3,cis), 48.5, 1 H, CH2Ph), 4.34 (d, 2JH,H = 11.6 Hz, 1 H, CH2Ph), 4.31 (d, 2JH,H
48.2 (2 CH, C-4trans, C-4cis), 46.8, 46.6 (2 C, C-1Јtrans, C-1Јcis), 43.3 = 11.1 Hz, 1 H, CH2Ph), 3.71 (s, 3 H, CO2CH3), 3.70 (s, 3 H,
4.57 (d, JH,H = 11.1 Hz, 1 H, CH2Ph), 4.57 (d, JH,H = 11.6 Hz,
Eur. J. Org. Chem. 2012, 1404–1417
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1415

S. Parés, R. Alibés, M. Figueredo, J. Font, T. Parella
FULL PAPER
CO2CH3), 3.47 (m, 2 H, 1ЈЈ-H), 2.45 (m, 1 H, 6-H), 2.33 (m, 2 H,
3-H), 2.10 (m, 7 H, 2ϫ2Ј-H, 2ϫ3-H, 3ϫ6-H), 1.98–1.37 (m, 12
H, 4ϫ5-H, 4ϫ3Ј-H, 4ϫ4Ј-H), 1.42 (m, 2 H, 4-H), 1.06 (d, JH,H
[1]
For some examples of naturally occurring cyclobutanes and
their applications, see: a) J. C. Namyslo, D. E. Kaufmann,
Chem. Rev. 2003, 103, 1485–1538; b) A. Sergeiko, V. V. Po-
roikov, L. O. Hanus, V. M. Dembitsky, Open Med. Chem. J.
2008, 2, 26–37.
3
= 5.9 Hz, 3 H, 2ЈЈ-H), 1.06 (d, 3JH,H = 6.0 Hz, 3 H, 2ЈЈ-H), 0.96 (s,
3 H, CH3C-1Ј), 0.93 (s, 3 H, CH3C-1Ј) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.1 (2 C=O), 141.0 (CH, C-2), 140.2 (CH, C-2),
138.8 (C, Ar), 138.6 (C, Ar), 129.4 (C, C-1), 129.3 (C, C-1), 128.3,
128.2, 128.0, 128.0, 127.9, 127.4 (10 CH, Ar), 75.8 (2 CH, C-1ЈЈ),
70.4 (CH2Ph), 70.3 (CH2Ph), 51.4 (2 CH3, CO2CH3), 48.8 (2 CH,
C-2Ј), 45.1 (CH, C-4), 44.3 (CH, C-4), 43.2 (C, C-1Ј), 43.1 (C, C-
1Ј), 29.9, 28.9, 27.5 (3 CH2), 26.8 (CH2, C-3), 25.5 (CH2, C-6),
23.2, 23.0, 19.3, 19.1 (4 CH2), 16.0 (CH3, C-2ЈЈ), 15.9 (CH3, C-2ЈЈ),
15.9 (CH3, CH3C-1Ј), 15.4 (CH3, CH3C-1Ј) ppm. HRMS (ESI+):
calcd. for [C22H30O3 + Na]+ 365.2087; found 365.2085.
[2] L.-K. Sy, G. D. Brown, Phytochemistry 1998, 47, 301–302.
[3] Dunniane numbering of the carbon atoms is used throughout
the text. Systematic numbering is used in the Exp. Sect.
[4] L. G. Cool, Phytochemistry 2005, 66, 249–260.
[5] F. Bohlman, C. Zdero, U. Faas, Chem. Ber. 1973, 106, 2904–
2909.
[6]
J. H. Tumilson, D. D. Hardee, R. C. Gueldner, A. C. Thomp-
son, P. A. Hedin, J. P. Minyard, Science 1969, 166, 1010–1012.
[7] For the synthesis of (+)-grandisol, see: a) R. Alibés, J. L. Bour-
delande, J. Font, T. Parella, Tetrahedron 1996, 52, 1279–1292;
b) P. de March, M. Figueredo, J. Font, J. Raya, A. Álvarez-
Larena, J. F. Piniella, J. Org. Chem. 2003, 68, 2437–2447; for
the synthesis of (+)-lineatin, see: c) R. Alibés, P. de March, M.
Figueredo, J. Font, M. Racamonde, T. Parella, Org. Lett. 2004,
6, 1449–1452; d) M. Racamonde, R. Alibés, M. Figueredo, J.
Font, P. de March, J. Org. Chem. 2008, 73, 5944–5952.
[8] L. A. Paquette, R. V. C. Carr, R. V. Williams, J. Org. Chem.
1983, 48, 4976–4986.
Methyl (4S)- and Methyl (4R)-4-{(1R,2S)-2-[(1R)-1-Hydroxyethyl]-
1-methylcyclobutyl}-1-cyclohexene-1-carboxylate [(4S)- and (4R)-
41]: A 1.0 m solution of BBr3 in CH2Cl2 at –95 °C (140 μL,
0.14 mmol) was added over 2 min to a solution of a mixture of
(4S)- and (4R)-36 (40 mg, 0.12 mmol) in dry CH2Cl2 (4 mL) at
–78 °C. The mixture was stirred at –78 °C for 10 min. Then MeOH/
CH2Cl2 at –78 °C (1:9, 4 mL) was added and the mixture was
stirred for a further 10 min. After concentration of the solvent un-
der reduced pressure (250 mbar, 18 °C), the crude was purified by
column chromatography (pentane/diethyl ether, 20:1) to afford a
mixture of olefins 42 (13 mg, 0.06 mmol, 47% yield) as a colorless
oil and a 1:1 mixture of (4S)- and (4R)-41 (4 mg, 0.02 mmol, 13%
yield) as a colorless oil.
[9] J. M. McIntosh, R. A. Sieler, J. Org. Chem. 1978, 43, 4431–
4433.
[10] For a review of dienamines as Diels–Alder dienes, see, for ex-
ample: M. Petrzilka, J. I. Grayson, Synthesis 1981, 753–786.
[11] A. K. Ghosh, S. Leshchenko, M. Noetzel, J. Org. Chem. 2004,
69, 7822–7829.
[12] R. Alibés, J. L. Bourdelande, J. Font, A. Gregori, T. Parella,
Tetrahedron 1996, 52, 1267–1278.
1
(4S)- and (4R)-41: H NMR (600 MHz, CDCl3): δ = 6.98 (m, 2 H,
[13] For examples of photochemical reactions as key steps in natu-
ral product synthesis, see: a) J. Iriondo-Alberdi, M. F. Greaney,
Eur. J. Org. Chem. 2007, 4801–4815; b) N. Hoffmann, Chem.
Rev. 2008, 108, 1052–1103; c) T. Bach, J. P. Hehn, Angew.
Chem. Int. Ed. 2011, 50, 1000–1045.
[14] E. J. Corey, B. Hopkins, Tetrahedron Lett. 1982, 23, 1979–1982.
[15] D. C. Meadows, J. Gervay-Hague, Med. Res. Rev. 2006, 26,
793–814.
2-H), 3.72 (s, 6 H, 2 CO2CH3), 3.30 (m, 2 H, 1ЈЈ-H), 2.56–1.10 (m,
24 H, 4ϫ3-H, 4ϫ4-H, 4ϫ5-H, 6-H, 2ϫ2Ј-H, 4ϫ3Ј-H, 4ϫ4Ј-H),
3
3
1.06 (d, JH,H = 6.0 Hz, 3 H, 2ЈЈ-H), 1.05 (d, JH,H = 6.1 Hz, 3 H,
2ЈЈ-H), 0.89 (s, 3 H, CH3C-1Ј), 0.86 (s, 3 H, CH3C-1Ј) ppm. 13C
NMR (100 MHz, CDCl3): δ = 167.9 (2 C=O), 140.2, 139.8 (2 CH,
C-2), 129.5, 125.8 (2 C, C-1), 86.1, 85.8 (2 CH, C-1ЈЈ), 51.9 (CH,
C-2Ј), 51.5 (2 CH3, CO2CH3), 50.3 (CH, C-2Ј), 45.6, 45.5 (2 C, C-
1Ј), 40.2, 40.1 (2 CH, C-4), 34.8, 34.0, 31.3, 28.1, 27.8, 25.4, 25.4,
[16] J. L. Kice, Y.-H. Kang, J. Org. Chem. 1984, 49, 1507–1511.
24.3, 24.2, 23.8 (10 CH2, C-3, C-5, C-6, C-3Ј, C-4Ј), 18.4, 18.2 (2 [17] K. Grela, M. Bieniek, D. Koloda, Org. Lett. 2006, 8, 5689–
CH3, C-2ЈЈ), 16.7, 16.2 (2 CH3, CH3C-1Ј) ppm. HRMS (ESI+):
5692.
calcd. for [C15H24O3 + Na]+ 275.1618; found 275.1621.
[18] N. R. Kotecha, S. V. Ley, S. Mantegani, Synlett 1992, 395–399.
[19] J. W. Le, D. Y. Oh, Synth. Commun. 1989, 19, 2209–2212.
[20] Y.-Z. An, A. L. Viado, M. J. Arce, Y. Rubin, J. Org. Chem.
1995, 60, 8330–8331.
1
Mixture of 42: H NMR (400 MHz, CDCl3): δ = 6.98 (m, 3 H, 2-
H), 5.22–5.08 (m, 3 H, 1ЈЈ-H), 3.72 (s, 9 H, CO2CH3), 2.80–1.10
(m, 33 H, 6ϫ3-H, 3ϫ4-H, 6ϫ5-H, 6ϫ6-H, 6ϫ3Ј-H, 6ϫ4Ј-H),
1.70, 1.69, 1.68 (3 s, 9 H, 2ЈЈ-H), 0.99, 0.98, 0.96 (3 s, 9 H, CH3C-
1Ј) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.9 (C=O), 140.3,
140.2, 140.1 (3 CH, C-2), 138.8, 138.7 (3 C, C-2Ј), 132.4, 132.1,
122.6 (3 CH, C-1ЈЈ), 130.0 (C, C-1), 51.4 (3 CH3, CO2CH3), 43.3,
42.2, 36.2, 36.2, 35.1, 35.0, 31.4, 30.3, 30.1, 29.6, 29.3, 29.3, 28.2,
28.0, 28.0, 25.4, 25.3, 24.1, 24.0 (2 CH3, CH3C-1Ј), 24.0 (CH3,
CH3C-1Ј), 16.6, 16.6, 15.2 (3 CH3, C-2ЈЈ) ppm. HRMS (ESI+):
calcd. for [C15H22O2 + Na]+ 257.1512; found 257.1504.
[21] M. E. Jung, C. N. Zimmerman, J. Am. Chem. Soc. 1991, 113,
7813–7814.
[22] W. Kinney, G. D. Crouse, L. A. Paquette, J. Org. Chem. 1983,
48, 4986–5000.
[23] C. R. Johnson, R. L. de Jong, J. Org. Chem. 1992, 57, 594–599.
[24] The reactions under microwave irradiation were performed in
a sealed reaction vessel, a CEM Discover microwave reactor,
the temperature was monitored by an IR thermometer.
[25] a) M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968,
9, 2199–2204; b) N. T. Anh, O. Eisenstein, Nouv. J. Chim. 1976,
61–70.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of all new compounds and 2D
NMR spectra of compounds cis- and trans-40.
[26] a) R. L. Snowden, M. Wüst, Tetrahedron Lett. 1986, 27, 699–
702; b) R. L. Snowden, S. M. Linder, M. Wüst, Helv. Chim.
Acta 1989, 72, 892–905.
[27]
a) H. Pauling, D. A. Andrews, N. C. Hindley, Helv. Chim. Acta
1976, 59, 1233–1243; b) M. B. Erman, I. S. Aul’chenco, L. A.
Kheifits, Y. N. Dulova, M. E. VolЈpin, Tetrahedron Lett. 1976,
34, 2981–2984; c) P. Chabardes, E. Kuntz, J. Vargnat, Tetrahe-
dron 1977, 33, 1775–1783; d) B. M. Trost, C. Jonasson, Angew.
Chem. 2003, 115, 2109–2112; Angew. Chem. Int. Ed. 2003, 42,
2063–2066.
Acknowledgments
We acknowledge financial support from the Dirección General de
Investigación (project numbers CTQ2007-60613/BQU, CTQ2010-
15380/BQU and CTQ2009-08324) and a grant from the Ministerio
de Educación y Ciencia (MEC) (to S. P.).
[28]
For examples of microwave-assisted Diels–Alder reactions, see:
a) A. M. Sarotti, M. M. Joullie, R. A. Spanavello, A. G. Suá-
1416
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1404–1417

Synthesis of Sesquiterpenes with the Dunniane Skeleton
rez, Org. Lett. 2006, 8, 5561–5564; b) A. Loupy, F. Maurel, A.
Sabatié-Gogová, Tetrahedron 2004, 60, 1683–1691.
[29] a) D. Cayne, A. S. Frobese, V. C. Ukachukwu, J. Org. Chem.
1983, 48, 740–741; b) P. L. DeRoy, A. B. Charette, Org. Lett.
2003, 5, 4163–4165; c) E. J. Corey, S. Giroux, J. Am. Chem.
Soc. 2007, 129, 9866–9867.
[30] Because these olefins are very volatile, precaution has to be
taken when solvents are evaporated.
[31] a) G. L. Lange, J. A. Otulakowski, J. Org. Chem. 1982, 47,
5093–5096; b) E. Ferrer, R. Alibés, F. Busqué, M. Figueredo,
J. Font, P. de March, J. Org. Chem. 2009, 74, 2425–2432.
[32] a) H. J. Reich, J. M. Renga, I. L. Reich, J. Am. Chem. Soc.
1975, 97, 5434–5447; b) V. S. Babu, S. Raghavan, Tetrahedron
2011, 67, 2044–2050.
[33] Z. Paryzec, H. Koenig, B. Tabaczka, Synthesis 2003, 2023–
2026.
[34] V. Liautard, V. Desvergnes, K. Itoh, H. Liu, O. R. Martin, J.
Org. Chem. 2008, 73, 3103–3115.
[35] S. Hanessian, Y. Guindon, Tetrahedron Lett. 1980, 21, 2305–
2308.
Received: November 7, 2011
Published Online: January 12, 2012
Eur. J. Org. Chem. 2012, 1404–1417
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1417