Control of the regio- and diastereoselectivity for the preparation of highly functionalized terpenic cyclopentanes through radical cyclization

Article abstract of DOI:10.1002/ejoc.201100400

The titanocene-mediated cyclization of suitably functionalized acyclic C10 epoxy-polyprenes leads, with moderate stereoselectivity, to high yields of functionalized terpenic cyclopentanes with three contiguous stereogenic centers. These highly functionalized cyclopentanes are useful intermediates for the synthesis of several natural compounds that include this interesting subunit in their structure. Both the regioselectivity of the process leading to cyclopentanes and the stereoselectivity of the cyclization could be controlled by using malonyl derivatives or α,β-unsaturated nitriles as radical acceptors. The titanocene-mediated cyclization of suitably functionalized acyclic C10 epoxy-polyprenes proceeds with acceptable stereochemical control and excellent yields. The process takes place through 5-exo-trig ring closures and gives cyclopentanes with three contiguous stereogenic centers with peripheral functional groups that are suitable for constructing structurally complex natural products. Copyright

Full text of DOI:10.1002/ejoc.201100400

FULL PAPER
DOI: 10.1002/ejoc.201100400
Control of the Regio- and Diastereoselectivity for the Preparation of Highly
Functionalized Terpenic Cyclopentanes through Radical Cyclization
Jesús F. Arteaga,*[a] Horacio R. Diéguez,[b] José A. González-Delgado,[a,b]
José F. Quílez del Moral,[b] and Alejandro F. Barrero*[b]
Keywords: Terpenoids / Titanium / Radical reactions / Cyclization / Fused-ring systems / Epoxide opening
The titanocene-mediated cyclization of suitably function-
alized acyclic C10 epoxy-polyprenes leads, with moderate
stereoselectivity, to high yields of functionalized terpenic cy-
clopentanes with three contiguous stereogenic centers.
These highly functionalized cyclopentanes are useful inter-
mediates for the synthesis of several natural compounds that
include this interesting subunit in their structure. Both the
regioselectivity of the process leading to cyclopentanes and
the stereoselectivity of the cyclization could be controlled by
using malonyl derivatives or α,β-unsaturated nitriles as radi-
cal acceptors.
Cyclopentenes and cyclopentanones do not show general
conformational preferences, and to reliably introduce or
modify functionality synthetic chemists must usually resort
to stereoselective methods that include such tactics as using
a bulky reagent that approaches from the less-hindered cy-
clopentane face, a chiral reagent with inherent enantioface
selectivity, a coordinating or hydrogen-bonding syn-direct-
ing group,[2] or a tethered nucleophile.[3] Stereochemically
intricate cyclopentanes surrounded by contiguous arrays of
heteroatoms at the periphery of the carbocycle and/or fused
to heterocyclic ring systems present some of the more
daunting challenges for modern synthetic chemistry.
Introduction
Highly functionalized cyclopentanes and cyclohexanes
are structural features found in many compounds of bio-
logical interest. Five-membered carbocyclic cores bearing
stereopentads of comparable molecular complexity are
found both in biologically relevant terpenoids, which is a
subset of the highly sought-after pyrrole-imidazole family
of marine alkaloids, and aminocyclopentitol-based glycos-
idase inhibitors (Figure 1).[1] Although cylopentanes are
common structural motifs in many natural products, the
synthesis of these segments is often lengthy and tedious,
especially when they are highly functionalized. In short,
achieving stereocontrol in the synthesis of these compounds
is quite challenging.
Radical reactions constitute a very useful tool in syn-
thetic organic chemistry;[4] they complement ionic and con-
certed processes and are able to take part in cascade reac-
tions, making them particularly interesting. An attractive
method for the preparation of cyclopentanes is intramolec-
ular radical cyclization, because radical cyclizations can be
performed under neutral conditions. Internal radical cycli-
zation of a suitable carbohydrate derivative possessing both
a radical donor and a radical acceptor gives rise to cyclic
products with all stereocenters preserved, and, ideally, with
stereocontrol at the new C–C bond formed during the ring-
Figure 1. Representative structures of aminocyclopentitol and pyr- closing reaction.[4b,4d] Within this context, [Cp2TiIIICl]-me-
role-imidazole marine alkaloid families.
diated radical cyclization of acyclic monoepoxy-polypreno-
ids is a powerful synthetic tool that permits the construc-
tion of rings of different sizes.[5] In contrast to reported cy-
[a] Department of Chemical Engineering, Physical Chemistry and
Organic Chemistry, University of Huelva,
clizations involving carbocations,[6] this kind of radical cy-
Campus de El Carmen, 21071 Huelva, Spain
Fax: +34-959-219983
E-mail: jesus.fernandez@diq.uhu.es
[b] Department of Organic Chemistry, University of Granada,
Avda. Fuentenueva s/n, 18071 Granada, Spain
Fax: +34-958-243318
clization can be used in cascade processes to create dif-
ferent-sized rings, after suitably modulating the electronic
distribution of the double bonds involved. A few years ago,
our research group reported that the [Cp2TiIIICl]-mediated
cyclization of methyl 6,7-epoxy-geraniate (1) led to the for-
mation of an equimolecular mixture of 2a and 2b through
E-mail: afbarre@ugr.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100400.
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Regio- and Diastereoselective Radical Cyclization
a 5-exo-trig process (Scheme 1),[7] thus generating two Table 1. TiIII-mediated cyclization of 6,7-epoxy-farnesyl derivatives.
stereogenic centers, albeit without stereoselectivity at the
quaternary center.
Entry SM[a]
Product
Time
[min]
Yield
[%]
Ratio
1
2
3
4
5
3
5
4
6 + 7
70
50
25
200
120
56
53
95
90
93
75:25
53:47
31:54:15
28:29:14:29
8
9 + 10
11
15
12 + 13 + 14
16[b]
[a] SM: Starting material. [b] Mixture of four diastereomers.
Scheme 1. Synthesis of diastereoisomers 2a and 2b.
The stereocontrolled synthesis of highly versatile cyclo-
pentane fragments to generate advanced intermediates for
the synthesis of biologically active natural products has
been achieved in recent years with jatrophane diterpenes,[8]
pactamycin,[9] kansuinine,[10] and viridenomycin.[11] The
preparation, in moderate yields, of five-membered car-
bocycles from 2,3-epoxy alcohols by using TiIII for the oxir-
ane opening has also been reported.[12] We describe here the
efficient synthesis of synthons containing highly function-
alized terpenic cyclopentane derivatives.
Results and Discussion
Scheme 3. Cyclization of 3 is prevented by the isoprenic chain at
We began our study by verifying the reactivity of a range
of 6,7-epoxy-farsenyl derivatives with [Cp2TiIIICl]. At this
juncture, we must mention the lack of precedents for radical
cyclization of epoxy-polyprenes with the oxirane located in
an intermediate position in an acyclic chain, and the pos-
sibility of also obtaining the desired highly functionalized
cyclopentanes with a functionalized carbon chain attached
to them, which adds to their importance as advanced syn-
thetic intermediates. Thus, when compound 3 (obtained
from farnesyl acetate by using standard transformations),
which possesses two acetate groups located at C1 and C12,
C8.
resulting products were again an acyclic allylic alcohol 6
(40% yield), together with a minor amount of the cycliza-
tion product 7 (13% yield), resulting from a 6-endo-trig pro-
cess (Scheme 4; Table 1, Entry 2). The formation of this
highly functionalized cyclohexane is understandable con-
sidering that the radical produced after the homolytic open-
ing of the oxirane adds to the Δ2,3 double bond. In com-
parison to the results obtained with 3, the formation here
of a significant quantity of the cyclization product seems to
suggest a higher degree of conformational freedom in the
intermediate radical, which progresses more easily to the
chair-like transition state, leading, in turn, to cyclization.
was allowed to react with a catalytic amount of [Cp2TiIII
-
Cl],[5p] the reaction led almost exclusively to the formation
of the opened allylic alcohol 4 (Scheme 2; Table 1, Entry 1).
We should point out that all the epoxides used in this study,
and therefore the resulting products, were racemic mixtures;
for the sake of convenience, a single enantiomer has been
drawn for each compound where applicable.
Scheme 4. Reaction of 5 to give 6 (40%) and 7 (13%).
Scheme 2. Epoxide ring opening of 3 with [Cp2TiIIICl].
In contrast to the situation with 6,7-epoxy-geranyl acet-
Reaction of acetoxy ester 8 with [Cp2TiIIICl] for 25 min,
ate, which, after treatment with TiIII, produced the 6-endo- following the catalytic protocol, afforded yields of 51 and
trig cyclization product,[13] the isoprenic chain at C8 in 3 44% of cyclopentanes 9 and 10, respectively (Scheme 5;
prevented the formation of the chair-like transition state II Table 1, Entry 3). Compound 10 formed as a result of spon-
needed to complete the cyclization process (Scheme 3).
taneous lactonization after the acidic workup of the reac-
When the epoxy-farnesyl derivative 5,[14] which has an tion mixture, which allowed the mixture of epimers to be
isopropenyl group at the end of the acyclic moiety, was al- easily separated, thus optimizing the method for their prep-
lowed to react with a catalytic amount of [Cp2TiIIICl], the aration.
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J. F. Arteaga, A. F. Barrero et al.
FULL PAPER
Scheme 6. Cyclization of 15 to give 16.
Compound 16 was obtained with low diastereoselectivity
as a mixture of four diastereomers (2ЈS,3ЈS), (2ЈR,3ЈS),
(2ЈS,3ЈR), and (2ЈR,3ЈR), which could be separated by col-
umn chromatography and HPLC in a ratio of 28:29:14:29
(Scheme 6; Table 1, Entry 5). The stereochemistry of 16a–d
was established by NOE experiments (Figure 3).
Scheme 5. Reaction of esters 8 and 11 with catalytic [Cp2TiIIICl].
The treatment of diester 11 with catalytic quantities of
[Cp2TiIIICl] led to 28 and 48% yields of cyclopentanes 12
and 13, respectively, together with a diastereomeric mixture
of hydrindane derivatives (14% yield), from which com-
pound 14 could be isolated. The stereochemistry of 14 was
established by NOE difference experiments (Figure 2) and
also by the coupling constant value (J = 12.0 Hz) observed
between 2-H and 10-H, which suggests an anti relationship
between these two protons. These hydrindane derivatives
were probably generated as a result of a cascade process
involving a radical cyclization and a Michael addition
(Scheme 5), the second step being brought about via the
enolate intermediate VI (Scheme 5) produced after the first
cyclization.
Figure 3. NOE experiments to establish the stereochemistry of
16a–d.
In the light of the excellent yields obtained for the closure
of the cyclopentane ring of these C15 precursors, and be-
cause of the absence of stereoselectivity, we focused our ef-
forts on studying the outcome of the radical 5-exo-trig cycli-
zation by using C10 epoxy-polyprenes derived from com-
mercial geraniol (17–21) (Table 2).
At this point it should be mentioned that the menthyl
esters 27 and 28, which are the precursors of epoxides 18
and 19, could not be prepared by using standard esterifica-
tion or transesterification transformations,[19] but only by
resorting to a convergent method involving the correspond-
ing 2-(diethyl phosphonates) (24 and 25) and subsequent
Wadsworth–Emmons condensation[20] with commercially
available 6-methylhept-5-en-2-one (26) (Scheme 7).[21]
The epoxy derivatives 17–19 showed moderate cycliza-
Figure 2. NOE experiments to establish the stereochemistry of 14.
In the light of previous work published by Fernández-
Mateos[15] and Gansäuer[16] on the use of acrylates or acry- tion yields but no diastereoselection in their reaction with
lonitriles to enforce cyclizations, we also studied the [Cp2TiIIICl] (Table 2, Entries 2–4). Thus, in the reaction of
[Cp2TiIIICl]-mediated cyclization of 6,7-epoxy-farnesyl- menthyl esters 18 and 19, two pairs of diastereomers were
1
nitrile derivative 15, which led to an excellent 93% yield obtained in each case, which were identified by H NMR
of the corresponding five-membered cyclization product 16 spectroscopic analysis as 29a (trans)/29b (cis) and 30a
(Scheme 6).
(trans)/30b (cis), respectively, in 50:50 ratios.
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Regio- and Diastereoselective Radical Cyclization
Table 2. TiIII-mediated cyclization of 6,7-epoxy-geranyl derivatives.
At this point, the influence of oxygenated functions on
the methyl groups located at the α-position adjacent to the
oxirane ring was assessed to find out how this new func-
tionalization affects the stereochemical outcome of the pro-
cess. We also bore in mind the fact that the presence of this
functional group in the chain attached to the resulting five-
membered ring is necessary to extend the chain farther and
thus facilitate the synthesis of several natural products.
Thus, the cyclization of 33 (Scheme 8) by using a cata-
lytic quantity of [Cp2TiIIICl] led to the formation of a mix-
ture of diastereomers 34, which could be resolved after lac-
tonization of 34b in an acidic medium to give 35. Dia-
stereomers 34 were produced in a 50:50 ratio, which proved
that, although formation of the new stereogenic center at
C2Ј proceeded with total stereochemical control (Figure 4),
no diastereoselectivity was observed in the formation of
C1Ј. Coordination between –OTiIVCp2, resulting from the
opening of the oxirane, and an oxygen atom from the
–OTBS group via a six-membered intermediate (I), possibly
determines the α stereochemistry of the –CH2OTBS chain
in the new stereogenic center created at C2Ј (Figure 4).
Entry SM[a]
R1
R2
RP[b] Yield Ratio
[%]
a/b
1
2
3
4
5
6
1
COOMe
COOtBu
COO-(–)-menthyl
COO-8-phenyl-(–)-menthyl
COOEt
H
H
H
H
2
86
81
71
69
93
99
50:50
50:50
50:50
50:50
67:33
80:20
17[17]
18
22
29
30
19
20[18]
21[c]
COOEt 31
32
CN
H
[a] SM: Starting material. [b] RP: Reaction product. [c] Dia-
stereomeric mixture of (E) and (Z).
Scheme 8. Cyclization of 33.
Scheme 7. Cyclization of menthyl ester derivatives. (a) 23, DMAP,
toluene, 120 °C, 140 h; (b) 26, NaH, THF, 25 °C; (c) m-CPBA,
DCM, 0 °C, 20 min; (d) 0.2 Cp2TiIVCl2, 8.0 Mn , 7.0 2,4,6-collidine,
4.0 TMSCl, THF, 25 °C, 80 min.
Figure 4. Coordination between –OTiIVCp2 from the oxirane open-
ing and an oxygen atom from the –OTBS group via a six-membered
intermediate.
Our next step was to test an epoxy derivative with a gem-
diester at the terminus of the chain, such as compound 20
(Table 2, Entry 5). This substrate offers the possibility of
Continuing with this study, cyclization of the phenylmen-
introducing an additional alkoxy-carbonyl group at C2, thyl epoxide 36 by using [Cp2TiIIICl] led to a 71% yield of
that is, at the position adjacent to the closure of the ring. the cyclopentane derivatives 37 (Scheme 9; Table 3, Entry 2)
Thus, treatment of diester 20 with [Cp2TiIIICl], following as a mixture of four diastereomers, which were distin-
1
the catalytic protocol, afforded an excellent 93% yield guished by H NMR spectroscopic analysis as two couples:
(Table 2, Entry 5) of cyclization products (31), with moder- 37a [trans; (1ЈR,2ЈR,3ЈS) and (1ЈS,2ЈS,3ЈR)] and 37b [cis;
ate stereoselectivity towards product 31a (67:33 ratio).
(1ЈS,2ЈR,3ЈS) and (1ЈR,2ЈS,3ЈR)] in a ratio of 57:43
When we studied the [Cp2TiIIICl]-mediated cyclization of (Scheme 9).
the 6,7-epoxy derivative of geranylnitrile (21), we found that
Subsequently, the behavior of the epoxy derivative 38,
the yield was almost quantitative, giving the mixture of cy- which has an additional ester at C2, was examined. Thus,
clopentanes 32 (Table 2, Entry 6) with a better diastereo- the reaction of 38 with [Cp2TiIIICl] resulted in the forma-
selectivity of 80:20 in favor of 32a; the coordination of the tion of cyclization product 39 (92% yield), showing a
TiIII species to the nitrile moiety, thus increasing its steric stereoselectivity of 71:29 in favor of compound 39a
requirements, is probably responsible for this selectivity.
(Table 3, Entry 3). Finally, the cyclization of 40, which is an
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J. F. Arteaga, A. F. Barrero et al.
FULL PAPER
cyclopentanes, and the stereoselectivity of the cyclization,
by using malonyl derivatives or α,β-unsaturated nitriles as
radical acceptors. Thus, the use of suitably functionalized
epoxy-polyprenes induces 5-exo-trig ring closures with ex-
cellent yields and acceptable stereochemical control of the
three stereogenic centers created. This process permits easy
access to highly functionalized cyclopentanes, which, in
turn, are useful in the synthesis of biologically active natu-
ral products.
Scheme 9. Cyclization of 36.
Table 3. Cyclization of C8-hydroxylated 6,7-epoxy-geranyl deriva-
tives.
Experimental Section
General: NMR spectra were recorded with Varian Direct-Drive 600
(1H 600 MHz/13C 150 MHz), 500 (1H 500 MHz/13C 125 MHz),
Bruker ARX 400 (1H 400 MHz/13C 100 MHz), or Varian Inova
Unity 300 (1H 300 MHz/13C 75 MHz) spectrometers. The accurate
mass determination was carried out with an AutoSpec-Q mass
spectrometer arranged in an EBE geometry (Micromass Instru-
ment, Manchester, UK) and equipped with an FAB (LSIMS)
source. The instrument was operated at 8 kV accelerating voltage,
and Cs+ was used as primary ion. Optical rotations were measured
with a Perkin–Elmer 141 polarimeter by using CHCl3 as the sol-
vent. Silica gel SDS 60 (35–70 μm) was used for flash column
chromatography. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm E. Merck silica gel
plates (60F-254) by using UV light as the visualizing agent and a
solution of phosphomolybdic acid in ethanol and heat as de-
veloping agent. All air- and water-sensitive reactions were per-
formed in flasks that were flame-dried under a positive flow of
argon and conducted under argon. Solvents were purified accord-
ing to standard literature techniques and stored under argon. THF
and toluene were freshly distilled immediately prior to use from
sodium/benzophenone and strictly deoxygenated for 30 min under
argon for each of the Cp2TiCl2/Mn reactions. Reagents were pur-
chased at the higher commercial quality and used without further
purification, unless otherwise stated. Preparation of all varieties of
epoxy-polyprenes used in cyclization reactions involving known
procedures are described in the Supporting Information.
Entry SM[a]
R1
R2
RP[b] Yield Ratio
[%]
a/b
1
2
3
4
33
36
COOMe
COO-8-phenyl-(–)-menthyl
H
H
34
37
76
71
92
95
50:50
57:43
71:29
80:20
38
COOEt
H
COOEt 39
CN 41
40[c]
[a] SM: Starting material. [b] RP: Reaction product. [c] Mixture of
diastereomers (E) and (Z).
oxirane derivative with an unsaturated nitrile group, led to
a nearly quantitative yield of cyclopentanes 41. The dia-
stereoselectivity of the closure of the ring was then accept-
able, because the 76% yield of the (1ЈR,2ЈR,3ЈS) isomer 41a
was four times higher than that of isomer 41b, with
(1ЈS,2ЈR,3ЈS) stereochemistry (Table 3, Entry 4).
These results may open the possibility of using these syn-
thons as chiral building blocks that could help in the syn-
thesis of complex structures such as toxicol A,[22] a hexa-
prenoid hydroquinone sulfate isolated from the Red Sea
sponge Toxiclona toxius, which has been reported to inhibit
the reverse transcriptase of human immune deficiency virus
(HIV) and to be active against Candida albicans. This com-
pound contains a five-membered ring (Cycle C) that might
be obtained with suitable functionalization from commer-
cially available sources by using this TiIII-mediated radical
cyclization process (Scheme 10).
General Procedure for Catalytic Cyclization of Epoxy-Polyprenes
Mediated by TiIII: A mixture of [Cp2TiCl2] (70.7 mg, 0.275 mmol)
and Mn dust (778.7 mg, 7.34 mmol) in strictly deoxygenated THF
(5 mL) under argon, was stirred at room temp. until the red solu-
tion became green. A solution of the corresponding epoxide
(0.918 mmol), 2,4,6-collidine (0.85 mL, 6.12 mmol), and TMSCl
(0.46 mL, 3.67 mmol) in strictly deoxygenated THF (2.0 mL) was
then added, and the mixture was stirred until disappearance of the
starting material (25–200 min) was observed. The reaction was
quenched with HCl (2 n, dropwise addition of 20 mL), extracted
with tBuOMe (3ϫ40 mL), washed with brine, dried with anhy-
drous Na2SO4, and concentrated under reduced pressure. The re-
sulting crude material was diluted with THF (40.0 mL) and stirred
at room temp.. TBAF (1 m in THF, 5.7 mmol) was added and the
mixture was stirred for 1 h.[23] The mixture was concentrated under
reduced pressure, diluted in H2O, extracted with EtOAc
(4ϫ10 mL), washed with brine, and concentrated under reduced
pressure. Final purification and isolation of the resulting com-
pounds were carried out by SiO2 column chromatography eluting
with hexane/tBuOMe mixtures.
Scheme 10. Possible application of the TiIII-mediated radical cycli-
zation process.
Conclusions
We have shown that in radical cyclizations of terpenic
epoxy-polyprenes mediated by [Cp2TiIIICl] it is possible to
General Procedure for Stoichiometric Cyclization of Epoxy-Poly-
prenes Mediated by TiIII: A mixture of [Cp2TiCl2] (707.0 mg,
control both the regioselectivity of the process leading to 2.75 mmol) and Mn dust (778.7 mg, 7.34 mmol) in strictly deoxy-
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Regio- and Diastereoselective Radical Cyclization
genated THF (5.0 mL) under argon was stirred at room temp. until
the red solution became green. A solution of the corresponding
epoxide (0.918 mmol) in strictly deoxygenated THF (2.0 mL) was
added, and the mixture was stirred until disappearance of the start-
ing material (25–200 min) was observed. The reaction was
quenched with HCl (2 n, dropwise addition of 20 mL), extracted
with tBuOMe (3ϫ40 mL), washed with brine, dried with anhy-
drous Na2SO4, and concentrated under reduced pressure. Final pu-
rification and isolation of the resulting compounds were carried
out by SiO2 column chromatography eluting with hexane/tBuOMe
mixtures.
(FAB): calcd. for C18H30O5Na [M + Na]+ 349.1985; found
349.1977.
(E)-2-Methyl-5-{(1S,5S,8S)-5,8-dimethyl-3-oxo-2-oxabicyclo-
[3.2.1]oct-8-yl}pent-2-enyl Acetate (10): Colorless oil. 1H NMR
(CDCl3, 500 MHz, 25 °C): δ = 5.35 (t, J = 7.2 Hz, 1 H), 4.38 (s, 1
H), 4.37 (t, J = 4.2 Hz, 2 H), 2.48 (dd, J = 18.9, 3.4 Hz, 1 H), 2.26
(d, J = 18.9 Hz, 1 H), 2.11–1.85 (m, 4 H), 2.01 (s, 3 H), 1.66 (m, 1
H), 1.60 (m, 3 H), 1.33–1.15 (m, 3 H), 1.00 (s, 3 H), 0.87 (s, 3 H)
ppm. 13C NMR (CDCl3, 125 MHz, 25 °C): δ = 171.5, 171.1, 131.1,
128.8, 86.7, 70.1, 46.3, 45.5, 43.2, 36.3, 33.1, 29.8, 22.4, 21.2, 19.1,
14.2, 13.5 ppm. HRMS (FAB): calcd. for C17H26O4Na [M + Na]+
317.1723; found 317.1727.
Radical Cyclization of 3. (2E,10E)-6-Hydroxy-3,11-dimethyl-7-
methylenedodeca-2,10-diene-1,12-diyl Diacetate (4): After sub-
jecting 3 (320 mg, 0.918 mmol) to the catalytic procedure, the re-
sulting crude material was purified by column chromatography
(hexane/tBuOMe, 4:1 to 2:1) on silica gel to afford non-cyclized 4
(173 mg, 0.514 mmol, 56% yield). Colorless oil. 1H NMR (CDCl3,
400 MHz, 25 °C): δ = 5.49 (t, J = 7.4 Hz, 1 H), 5.38 (t, J = 7.3 Hz,
1 H), 5.07 (s, 1 H), 4.88 (s, 1 H), 4.60 (d, J = 7.2 Hz, 2 H), 4.45 (s,
2 H), 4.07 (m, 1 H), 2.08 (s, 3 H), 2.05 (s, 3 H), 1.72 (s, 3 H), 1.69
(s, 3 H) ppm. HRMS (FAB): calcd. for C19H30O5Na [M + Na]+
361.1985; found 361.1983.
Radical Cyclization of 11: After subjecting 11 (297 mg, 0.92 mmol)
to the stoichiometric procedure conditions, the resulting crude ma-
terial (280 mg, 90%) was purified by column chromatography (hex-
ane/tBuOMe, 4:1) on silica gel to afford 12 (79 mg, 28% yield), 13
(125 mg, 48% yield), and 14 (40 mg, 14% yield).
Methyl (E)-5-{(1S,2R,5S)-5-Hydroxy-2-[(methoxycarbonyl)methyl]-
1,2-dimethylcyclopentyl}-2-methylpent-2-enoate (12): Colorless oil.
1H NMR (CDCl3, 300 MHz, 25 °C): δ = 6.80 (dt, J = 7.4, 1.4 Hz,
1 H), 3.91 (dd, J = 7.3, 1.3 Hz, 1 H), 3.72 (s, 3 H), 3.67 (m, 1 H),
3.63 (s, 3 H), 2.27–2.13 (m, 3 H), 1.85–1.10 (m, 6 H), 1.84 (s, 3 H),
1.11 (s, 3 H), 0.81 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz,
25 °C): δ = 173.6, 168.8, 143.0, 127.5, 80.8, 51.8, 51.3, 50.4, 45.7,
43.0, 36.6, 32.5, 29.4, 24.6, 22.2, 20.8, 12.4 ppm. HRMS (FAB):
calcd. for C17H28O5Na [M + Na]+ 335.1829; found 335.1834.
Radical Cyclization of 5: After subjecting 5 (220 mg, 0.536 mmol)
to the catalytic procedure, the resulting crude material was treated
with TBAF in THF (3.3 mmol) for 3 h. The corresponding diol
derivatives of 6 and 7, that is 6a and 7a, were purified by column
chromatography (hexane/tBuOMe, 4:1 to 2:1) on silica gel to afford
6a (88 mg, 40% yield) and 7a (29 mg, 13% yield).
Methyl (E)-2-Methyl-5-[(1S,5S,8S)-5,8-dimethyl-3-oxo-2-oxabicy-
clo[3.2.1]oct-8-yl]pent-2-enoate (13): Colorless oil. 1H NMR
(CDCl3, 300 MHz, 25 °C): δ = 6.72 (t, J = 7.4 Hz, 1 H), 4.43 (d, J
= 4.1 Hz, 1 H), 3.74 (s, 3 H), 2.59 (dd, J = 14.5, 1.4 Hz, 1 H), 2.36
(d, J = 14.5 Hz, 1 H), 2.35–1.13 (m, 8 H), 1.83 (s, 3 H), 1.04 (s, 3
H), 0.95 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz, 25 °C): δ =
171.3, 168.1, 141.4, 128.7, 86.7, 51.8, 46.6, 45.7, 43.4, 36.6, 33.1,
29.8, 28.3, 19.8, 14.6, 12.5 ppm. HRMS (FAB): calcd. for
C16H24O4Na [M + Na]+ 303.1719; found 303.1716.
(E)-6,10-Dihydroxy-3,11-dimethyl-7-methylenedodeca-2,11-dienyl
1
Acetate (6a): Colorless oil. H NMR (CDCl3, 500 MHz, 25 °C): δ
= 5.37 (t, J = 7.4 Hz, 1 H), 5.05 (s, 1 H), 4.96 (s, 1 H), 4.90 (s, 1
H), 4.85 (s, 1 H), 4.58 (d, J = 7.0 Hz, 2 H), 4.10 (m, 2 H), 2.19–
2.05 (m, 5 H), 2.05 (s, 3 H), 1.74 (s, 3 H), 1.71 (s, 3 H), 1.70–1.40
(m, 3 H) ppm. 13C NMR (CDCl3, 125 MHz, 25 °C): δ = 173.6,
150.1, 144.2, 135.3, 120.7, 113.7, 113.2, 77.9, 77.8, 63.9, 38.2, 36.0,
35.9, 29.6, 23.7, 20.2, 19.4 ppm. HRMS (FAB): calcd. for
C17H28O4Na [M + Na]+ 319.1880; found 319.1882.
Methyl (1S,3aR,4S,5S,7aS)-5-[(1-Methoxycarbonyl)ethyl]octahy-
dro-1-hydroxy-3a,7a-dimethyl-1H-indene-4-carboxylate (14): Color-
less oil. 1H NMR (CDCl3, 300 MHz, 25 °C): δ = 4.36 (dd, J = 9.1,
7.2 Hz, 1 H), 3.67 (s, 3 H), 3.64 (s, 3 H), 2.50 (dq, J = 7.1, 2.3 Hz,
1 H), 2.48 (d, J = 12.0 Hz, 1 H), 2.19–1.23 (m, 8 H), 1.90 (m, 1
H), 1.13 (d, J = 7.1 Hz, 3 H), 0.91 (s, 3 H), 0.79 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz, 25 °C): δ = 178.3, 177.1, 77.5, 54.6, 54.5,
54.4, 47.9, 48.2, 43.1, 41.9, 35.3, 32.6, 32.3, 24.5, 20.6, 20.1,
18.2 ppm. HRMS (FAB): calcd. for C17H28O5Na [M + Na]+
335.1834; found 335.1812.
[(1R,2S,3S)-3-Hydroxy-2-(3-hydroxy-4-methylpent-4-enyl)-2-meth-
yl-6-methylenecyclohexyl]methyl Acetate (7a): Colorless oil. 1H
NMR (CDCl3, 500 MHz, 25 °C): δ = 4.98 (m, 1 H), 4.85 (s, 1 H),
4.84 (s, 1 H), 4.64 (s, 1 H), 4.57 (dd, J = 13.2, 7.0 Hz, 1 H), 4.35
(dd, J = 11.2, 3.9 Hz, 1 H), 4.07 (m, 1 H), 3.61 (s, 1 H), 2.54 (dt,
J = 13.3, 4.0 Hz, 1 H), 2.18 (dd, J = 10.6, 3.8 Hz, 1 H), 2.00 (s, 3
H), 1.83 (m, 1 H), 1.74 (s, 3 H), 1.65–1.15 (m, 6 H), 0.88 (s, 3 H)
ppm. 13C NMR (CDCl3, 125 MHz, 25 °C): δ = 174.0, 150.1, 145.0,
114.6, 113.9, 79.2, 74.8, 65.8, 54.6, 33.2, 33.0, 30.7, 30.4, 23.7, 20.4,
16.0 ppm. HRMS (FAB): calcd. for C17H28O4Na [M + Na]+
319.1880; found 319.1862.
Radical Cyclization of 15: After subjecting 15 (200 mg, 0.86 mmol)
to the catalytic procedure conditions, the resulting crude material
(194 mg, 96%) corresponding to a mixture of four diastereomers
[a: (2ЈS,3ЈS); b: (2ЈR,3ЈS); c: (2ЈS,3ЈR), and d: (2ЈR,3ЈR)] of the five-
membered cyclization product 16 was purified by column
chromatography (hexane/tBuOMe, 88:12 to 87:13) on silica gel to
afford 16a (57 mg, 0.24 mmol, 28% yield), 16b (59 mg, 0.25 mmol,
28% yield), 16c (28 mg, 0.12 mmol, 14% yield), and 16d (59 mg,
0.25 mmol, 29% yield).
Radical Cyclization of 8: After subjecting 8 (350 mg, 1.08 mmol) to
the catalytic procedure, the resulting crude material (332 mg, 95%
yield) was purified by column chromatography (hexane/tBuOMe,
4:1) on silica gel to afford 9 (169 mg, 51% yield) and 10 (133 mg,
44% yield).
Methyl {(1R,2S,3S)-2-[(E)-5-Acetoxy-4-methylpent-3-enyl]-3-hy-
droxy-1,2-dimethylcyclopentyl}acetate (9): Colorless oil. 1H NMR
2-[(1S,2S,3S)-3-Hydroxy-1,2-dimethyl-2-(4-methylpent-4-enyl)cyclo-
(CDCl3, 500 MHz, 25 °C): δ = 5.45 (t, J = 7.2 Hz, 1 H), 4.39 (s, 2 pentyl]acetonitrile (16a): Colorless oil. 1H NMR (CDCl3, 600 MHz,
H), 3.83 (dd, J = 7.2, 2.2 Hz, 1 H), 3.58 (s, 3 H), 2.16 (dd, J = 25 °C): δ = 4.69 (d, J = 24.0 Hz, 2 H), 4.10 (t, J = 7.9 Hz, 1 H),
17.0, 13.0 Hz, 2 H), 2.05–1.10 (m, 8 H), 2.00 (s, 3 H), 1.60 (m, 3 2.62 (d, J = 16.6 Hz, 1 H), 2.32 (d, J = 6.6 Hz, 1 H), 2.21–2.14 (m,
H), 1.06 (s, 3 H), 0.75 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz, 2 H), 1.99 (t, J = 7.4 Hz, 2 H), 1.71 (s, 3 H), 1.64–1.60 (m, 2 H),
25 °C): δ = 173.8, 171.2, 130.4, 130.2, 81.1, 76.9, 70.35, 51.4, 50.6, 1.48–1.43 (m, 2 H), 1.33–1.29 (m, 2 H), 1.10 (s, 3 H), 0.88 (s, 3 H)
45.8, 43.1, 36.7, 32.3, 30.2, 23.7, 22.3, 20.9, 14.1 ppm. HRMS ppm. 13C NMR (CDCl3, 150 MHz, 25 °C): δ = 145.4, 119.2, 110.1,
Eur. J. Org. Chem. 2011, 5002–5011
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5007

J. F. Arteaga, A. F. Barrero et al.
FULL PAPER
79.2, 48.6, 45.0, 38.7, 35.4, 34.7, 30.5, 27.1, 22.5, 22.3, 22.2,
13.6 ppm. HRMS (FAB): calcd. for C15H25NONa [M + Na]+
258.1834; found 258.1841. 1D-NOESY: δ = 4.69 (d, J = 24.0 Hz, 2
H), 1.48–1.43 (m, 2 H), 1.10 (s, 3 H) ppm.
2 H), 0.95 (s, 3 H), 0.86 (s, 3 H), 0.82 (s, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz, 25 °C): δ = 171.5, 89.1, 44.9, 43.6, 41.9, 36.1,
29.7, 20.5, 19.2, 16.8 ppm. HRMS (FAB): calcd. for C10H16O2Na
[M + Na]+ 191.1048; found 191.1060.
2-[(1S,2R,3S)-3-Hydroxy-1,2-dimethyl-2-(4-methylpent-4-enyl)-
cyclopentyl]acetonitrile (16b): H NMR (CDCl3, 600 MHz, 25 °C):
(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl 2-(Diethoxyphosphoryl)-
acetate (24): A solution of (–)-menthol (600 mg, 3.84 mmol) in an-
hydrous toluene (10.0 mL), DMAP (142 mg, 1.15 mmol), and
(EtO)2P(O)CH2CO2Et (23; 2.34 mL, 11.54 mmol), was heated at
reflux under argon. After 27 h, the solvent was removed under re-
duced pressure, and the crude material was filtered through silica
gel eluting with hexane (100 mL) and tBuOMe (200 mL), dried
with anhydrous Na2SO4, and concentrated under reduced pressure.
Purification by column chromatography (hexane/tBuOMe, 3:1) on
silica gel afforded 24 as a colorless oil (1243 mg, 3.72 mmol, 97%
1
δ = 4.71 (d, J = 23.6 Hz, 2 H), 3.95 (s, J = 7.4 Hz, 1 H), 3.09 (d, J
= 16.7 Hz, 1 H), 2.31 (d, J = 15.2 Hz, 1 H), 2.19 (m, 2 H), 2.03 (t,
J = 6.5 Hz, 2 H), 1.72 (s, 3 H), 1.57 (m, 4 H), 1.30 (m, 2 H), 1.10
(s, 3 H), 0.82 (s, 3 H) ppm. 13C NMR (CDCl3, 150 MHz, 25 °C):
δ = 148.4, 122.8, 112.8, 83.4, 52.7, 48.2, 41.2, 38.0, 34.1, 32.3, 29.7,
29.3, 25.5, 25.1, 24.3 ppm. HRMS (FAB): calcd. for C15H25NONa
[M + Na]+ 258.1834; found 258.1828. 1D-NOESY: δ = 4.71 (d, J
= 23.6 Hz, 2 H), 2.19 (m, 2 H), 1.57 (m, 4 H), 0.82 (s, 3 H) ppm;
0.82 (s, 3 H), 1.10 (s, 3 H), 1.57 (m, 4 H), 1.72 (s, 3 H), 4.71 (d, 2
H, J = 23.6 Hz) ppm.
1
yield). H NMR (CDCl3, 400 MHz, 25 °C): δ = 4.68 (td, J = 10.9,
10.9, 4.4 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 4 H), 2.91 (d, J = 21.7 Hz,
2 H), 2.00–1.88 (m, 2 H), 1.67–1.60 (m, 2 H), 1.48–1.35 (m, 2 H),
1.30 (t, J = 7.1 Hz, 6 H), 1.06–0.92 (m, 2 H), 0.90–0.80 (m, 1 H),
0.87 (d, J = 2.7 Hz, 3 H), 0.85 (d, J = 3.2 Hz, 3 H), 0.71 (d, J =
7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 165.4,
75.6, 62.6, 62.5, 46.9, 40.6, 35.2, 34.1, 33.9, 31.4, 25.8, 23.1, 22.0,
20.8, 16.3, 16.0 ppm.
2-[(1S,2S,3R)-3-Hydroxy-1,2-dimethyl-2-(4-methylpent-4-enyl)-
1
cyclopentyl]acetonitrile (16c): H NMR (CDCl3, 600 MHz, 25 °C):
δ = 4.71 (d, J = 20.7 Hz, 2 H), 3.94 (d, J = 5.5 Hz, 1 H), 2.27 (s, 2
H), 2.18 (m, 2 H), 2.04 (t, J = 7.1 Hz, 2 H), 1.76 (m, 2 H), 1.73 (s,
3 H), 1.66 (m, 2 H), 1.38 (m, 2 H), 1.30 (s, 3 H), 0.84 (s, 3 H) ppm.
13C NMR (CDCl3, 150 MHz, 25 °C): δ = 148.4, 121.8, 112.7, 83.9,
52.4, 47.5, 41.2, 39.4, 33.9, 32.9, 29.6, 26.0, 25.8, 25.1, 23.4 ppm.
HRMS (FAB): calcd. for C15H25NONa [M + Na]+ 258.1834; found
258.1829. 1D-NOESY: δ = 4.71 (d, J = 20.7 Hz, 2 H), 2.27 (s, 2
H), 1.66 (m, 2 H), 0.84 (s, 3 H) ppm.
(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl (E)-3,7-Dimethylocta-
2,6-dienoate (27): A mixture of NaH (163 mg, 4.07 mmol) and an-
hydrous THF (15.0 mL) was stirred and cooled to 0 °C under ar-
gon. Compound 24 (1236 mg, 3.70 mmol) in anhydrous THF
(3.0 mL) was added, and the mixture was stirred for 7 min. Com-
mercial 26 (0.6 mL, 4.07 mmol) was added, and the solution was
stirred at room temp. for 4 h. The reaction was diluted with tBu-
OMe (50 mL), saturated aqueous NH4Cl was added dropwise, and
finally H2O (60 mL) was added. The aqueous layer was extracted
with tBuOMe (3ϫ80 mL), and the resulting organic mixture was
dried with anhydrous Na2SO4 and concentrated under reduced
pressure. Purification by column chromatography (hexane/tBu-
OMe, 10:1) on silica gel afforded condensation product 27 as a
colorless oil (780 mg, 2.70 mmol, 73% yield). 1H NMR (CDCl3,
300 MHz, 25 °C): δ = 5.62 (s, 1 H), 5.07 (m, 1 H), 4.68 (td, J =
10.8, 10.8, 4.4 Hz, 1 H), 2.62 (td, J = 7.8, 7.8, 1.6 Hz, 1 H), 2.14
(s, 3 H), 2.00 (d, J = 11.7 Hz, 1 H), 1.92–0.75 (m, 12 H), 1.86 (s, 3
H), 1.67 (s, 3 H), 1.59 (s, 3 H), 0.89 (d, J = 2.2 Hz, 3 H), 0.87 (d,
J = 2.6 Hz, 3 H), 0.75 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz, 25 °C): δ = 166.6, 166.0*, 159.7*, 159.4, 132.5, 132.0*,
123.8*, 123.2, 116.8*, 116.1, 73.2, 47.2, 41.3, 41.1, 34.4, 33.5, 31.5,
29.8, 26.9, 26.4, 26.2, 25.7, 25.4, 23.7, 22.1, 20.8, 18.9, 17.7,
16.5 ppm. *Signals corresponding to minor diastereomer (2Z).
HRMS (FAB): calcd. for C20H34O2Na [M + Na]+ 329.2456; found
329.2461.
2-[(1S,2R,3R)-3-Hydroxy-1,2-dimethyl-2-(4-methylpent-4-enyl)-
1
cyclopentyl]acetonitrile (16d): H NMR (CDCl3, 600 MHz, 25 °C):
δ = 4.69 (d, J = 24.5 Hz, 2 H), 4.03 (t, J = 7.8 Hz, 1 H), 2.27 (s, 2
H), 2.19–2.11 (m, 1 H), 1.99 (t, J = 7.5 Hz, 2 H), 1.74 (t, J =
7.9 Hz, 3 H), 1.71 (s, 3 H), 1.55–1.52 (m, 2 H), 1.36 (br. s, 1 H),
1.25–1.22 (m, 2 H), 1.17 (s, 3 H), 0.93 (s, 3 H) ppm. 13C NMR
(CDCl3, 150 MHz, 25 °C): δ = 145.3, 119.1, 110.2, 79.5, 48.3, 45.6,
38.7, 35.5, 34.3, 30.5, 26.7, 22.9, 22.4, 22.3, 14.1 ppm. HRMS
(FAB): calcd. for C15H25NONa [M + Na]+ 258.1834; found
258.1832. 1D-NOESY: δ = 4.69 (d, J = 24.5 Hz, 2 H), 2.27 (s, 2
H), 2.19–2.11 (m, 1 H), 1.55–1.52 (m, 2 H), 1.25–1.22 (m, 2
H) ppm; 1.17 (s, 3 H), 0.93 (s, 3 H) ppm.
Radical Cyclization of 17: After subjecting 17 (571 mg, 2.38 mmol)
to the catalytic procedure conditions, the resulting crude material
was purified by column chromatography (hexane/tBuOMe, 2:1) on
silica gel, yielding an equimolecular mixture of 22a and 22b
(455 mg, 1.93 mmol, 81% yield). A solution of this mixture (61 mg,
0.25 mmol) in Et2O was treated with an excess of TsOH at room
temp. for 26 h. The reaction mixture was washed with saturated
aqueous NaHCO3 solution (2ϫ25 mL) and brine (30 mL), dried
with anhydrous Na2SO4, and concentrated under reduced pressure.
The resulting crude material was purified by column chromatog-
raphy (hexane/tBuOMe, 4:1) on silica gel to afford the lactone of
22b (21 mg, 0.12 mmol) and 22a (30 mg, 0.12 mmol).
(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl (E)-5-(3,3-Dimethylox-
iran-2-yl)-3-methylpent-2-enoate (18): To a solution of 27 (400 mg,
1.31 mmol) in dichloromethane (7.0 mL) at 0 °C under argon, was
added dropwise mCPBA (271 mg, 1.57 mmol) in dichloromethane
(7 mL), and the mixture was stirred until disappearance of starting
material was observed. The mixture was diluted with dichlorometh-
ane (25 mL), washed with NaOH (2 n, 3 ϫ 40 mL) and brine
(2ϫ40 mL), dried with anhydrous Na2SO4 and concentrated under
reduced pressure. The resulting crude material was purified by col-
umn chromatography (hexane/tBuOMe, 5:1) on silica gel to afford
18 as a colorless oil (409 mg, 1.27 mmol, 97% yield). 1H NMR
(CDCl3, 300 MHz, 25 °C): δ = 5.66 (s, 1 H), 4.68 (td, J = 10.8,
10.8, 4.4 Hz, 1 H), 2.69 (t, J = 6.2 Hz, 1 H), 2.28 (m, 2 H), 2.16
(d, J = 1.2 Hz, 3 H), 1.98 (d, J = 11.7 Hz, 1 H), 1.92–0.75 (m, 10
tert-Butyl 2-[(1R,3S)-3-Hydroxy-1,2,2-trimethylcyclopentyl]acetate
1
(22a): Colorless oil. H NMR (CDCl3, 400 MHz, 25 °C): δ = 3.86
(dd, J = 8.4, 5.2 Hz, 1 H), 2.21–2.08 (m, 1 H), 2.07 (s, 2 H), 1.90–
1.79 (m, 1 H), 1.68–1.48 (m, 2 H), 1.45 (s, 9 H), 1.04 (s, 3 H), 0.85
(s, 3 H), 0.80 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C):
δ = 172.6, 81.4, 80.2, 47.3, 44.8, 43.7, 34.2, 31.0, 28.2, 22.8, 21.6,
17.4 ppm.
(1S,5S)-5,8,8-Trimethyl-2-oxabicyclo[3.2.1]octan-3-one (Lactone
Derived from 22b): Colorless oil. 1H NMR (CDCl3, 300 MHz,
25 °C): δ = 4.16 (d, J = 4.5 Hz, 1 H), 2.48 (dd, J = 18.8, 3.2 Hz, 1
H), 2.30 (d, J = 18.8 Hz, 1 H), 2.11–1.89 (m, 2 H), 1.88–1.63 (m, H), 1.28 (s, 3 H), 1.24 (s, 3 H), 0.89 (d, J = 2.2 Hz, 3 H), 0.87 (d,
5008
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5002–5011

Regio- and Diastereoselective Radical Cyclization
J = 2.6 Hz, 3 H), 0.75 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 25 °C): δ = 166.1, 159.4*, 159.0*, 151.8, 132.4, 128.0, 125.6, 125.0,
75 MHz, 25 °C): δ = 166.3, 158.2, 116.6, 73.3, 63.7, 58.6, 47.2, 41.2,
37.6, 34.4, 31.5, 27.0, 26.3, 24.8, 23.6, 22.1, 20.8, 18.9, 18.8,
16.5 ppm. HRMS (FAB): calcd. for C20H34O3Na [M + Na]+
345.2406; found 345.2407.
123.9*, 123.3, 116.9*, 116.2, 73.4, 73.3*, 50.8, 42.1, 40.9, 39.9, 34.8,
33.3*, 31.4, 27.3, 26.9, 26.8, 26.3*, 26.1, 25.9, 25.7, 25.2*, 21.9, 18.8,
17.8 ppm. *Signals corresponding to minor diastereoisomer (2Z).
HRMS (FAB): calcd. for C26H38O2Na [M + Na]+ 405.2770; found
405.2771.
Radical Cyclization of 18: After subjecting 18 (322 mg, 1.00 mmol)
to the catalytic procedure conditions, the resulting crude material
was purified by column chromatography (hexane/tBuOMe, 4:1 then
1:1) on silica gel to afford a diasteromeric mixture [(1ЈR,3ЈS),
(1ЈS,3ЈS), (1ЈS,3ЈR), and (1ЈR,3ЈR)] (230 mg, 71% yield) showing
two representative groups of signals in the 1H NMR spectra corre-
sponding to 29a (trans) and 29b (cis) in an equimolecular ratio.
(1S,2R,5S)-5-Methyl-2-(2-phenylprop-2-yl)cyclohexyl (E)-5-(3,3-Di-
methyloxiran-2-yl)-3-methylpent-2-enoate (19): To a solution of 28
(1073 mg, 2.81 mmol) in dichloromethane (9.0 mL) at 0 °C under
argon, was added dropwise mCPBA (582 mg, 3.37 mmol) in dichlo-
romethane (9.0 mL), and the mixture was stirred until disappear-
ance of starting material was observed. The mixture was diluted
with dichloromethane (25 mL), washed with NaOH 2 n
(3ϫ40 mL) and brine (2ϫ40 mL), dried with anhydrous Na2SO4,
and concentrated under reduced pressure. The resulting crude ma-
terial was purified by column chromatography (hexane/tBuOMe,
5:1) on silica gel to afford 19 (1085 mg, 2.73 mmol, 97% yield) as
a pale-yellow oil. 1H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.23 (m,
4 H), 7.07 (m, 1 H), 5.02–4.96 (m, 1 H), 4.78 (td, J = 10.8, 10.8,
4.2 Hz, 1 H), 2.67 (t, J = 6.2 Hz, 1 H), 2.28–1.93 (m, 2 H), 2.08 (s,
3 H), 1.92 (d, J = 12.3 Hz, 1 H), 1.70–1.56 (m, 5 H), 1.52–1.40 (m,
2 H), 1.29 (m, 6 H), 1.26 (s, 3 H), 1.21 (s, 3 H), 1.16–1.03 (m, 2
H), 0.85 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz,
25 °C): δ = 165.8, 157.6, 151.8, 127.9, 125.5, 124.9, 116.6, 116.5,
73.5, 63.6, 58.4, 50.7, 42.0, 39.8, 37.4, 34.7, 31.4, 27.7, 27.4, 26.9,
26.7, 25.6, 25.4, 25.1, 24.9, 21.9 ppm. HRMS (FAB): calcd. for
C26H38O3Na [M + Na]+ 421.2719; found 421.2717.
1
Compounds 29a1 + 29a2 + 29b1 + 29b2. Pale-yellow oil. H NMR
(CDCl3, 300 MHz, 25 °C): δ = 4.63 (tdd, J = 10.8, 10.8, 4.3, 1.4 Hz,
2 H), 3.96 (ddd, J = 9.1, 7.4, 2.3 Hz, 1 H), 3.85* (ddd, J = 8.1, 5.3,
1.9 Hz, 1 H), 2.33 (dd, J = 13.1, 4.5 Hz, 1 H), 2.20–1.75 (m, 31 H),
1.03* (s, 3 H), 0.92 (d, J = 2.1 Hz, 3 H), 0.87 (s, 6 H), 0.84 (s, 12
H), 0.78 (dd, J = 4.4, 1.7 Hz, 6 H), 0.71 (d, J = 7.0 Hz, 6 H) ppm.
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 172.8, 172.7, 81.3, 81.2,
74.1, 74.0, 49.4, 47.3, 47.2, 47.0, 46.5, 46.5, 44.8, 44.7, 44.2, 44.1,
42.8, 42.7, 42.7, 42.6, 41.0, 34.3, 34.3, 34.2, 34.0, 31.4, 31.0, 30.9,
*
30.0, 30.0, 27.0, 26.2, 23.3, 23.3, 22.8 ppm. Signals corresponding
to diastereomeric couple 29a.
(1S,2R,5S)-5-Methyl-2-(2-phenylprop-2-yl)cyclohexyl (Diethoxy-
phosphoryl)acetate (25): A solution of (–)-8-phenylmenthol
(1000 mg, 4.30 mmol) in anhydrous toluene (10.0 mL), DMAP
(158 mg, 1.29 mmol), and (EtO)2P(O)CH2CO2Et (23; 2.61 mL,
12.91 mmol) was heated to reflux under argon. After 140 h, the
solvent was removed under reduced pressure, and the crude mate-
rial was filtered through silica gel eluting with hexane (100 mL)
and tBuOMe (200 mL), dried with anhydrous Na2SO4, and concen-
trated under reduced pressure. Purification by column chromatog-
raphy (hexane/tBuOMe, 2:1) on silica gel afforded 25 (1720 mg,
4.17 mmol, 97 % yield) as a colorless oil. 1H NMR (CDCl3,
300 MHz, 25 °C): δ = 7.23 (m, 4 H), 7.07 (m, 1 H), 4.79 (td, J =
10.8, 10.8, 4.4 Hz, 1 H), 4.08–3.91 (m, 4 H), 2.35 (dd, J = 21.3,
14.3 Hz, 1 H), 2.03 (dd, J = 21.3, 14.4 Hz, 1 H), 2.00 (m, 1 H),
1.79 (tq, J = 13.4, 13.4, 3.4 Hz, 2 H), 1.63 (dt, J = 12.9, 2.8, 2.8 Hz,
1 H), 1.40 (m, 1 H), 1.30–0.80 (m, 3 H), 1.25 (m, 9 H), 1.15 (s, 3
H), 0.83 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz,
25 °C): δ = 165.0, 151.7, 127.9 (2 C), 125.3, 125.0, 75.1, 62.4, 62.3,
50.2, 41.3, 39.4, 34.7, 34.4, 33.0, 31.2, 29.1, 26.2, 23.2, 21.7, 16.3,
16.2 ppm.
Radical Cyclization of 19. Compounds 30a1 and 30a2: After sub-
jecting 19 (398 mg, 1.00 mmol) to the catalytic procedure condi-
tions, the resulting crude material was purified by column
chromatography (hexane/tBuOMe, 4:1 to 1:1) on silica gel to afford
a diastereomeric mixture (1ЈR,3ЈS), (1ЈS,3ЈS), (1ЈS,3ЈR), and
(1ЈR,3ЈR) showing two representative groups of signals in the 1H
NMR spectra corresponding to 30a (trans) and 30b (cis) (276 mg,
69% yield), in an equimolecular ratio. The general structure of this
mixture was determined after isolation of the trans diasteromeric
1
couple (30a). H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.28 (m, 4
H), 7.13 (m, 1 H), 4.78 (td, J = 10.7, 10.7, 4.3 Hz, 2 H), 3.71 (dd,
J = 8.2, 4.8 Hz, 1 H), 2.11–1.95 (m, 2 H), 1.89–1.78 (m, 2 H), 1.73–
1.65 (m, 1 H), 1.62 (d, J = 13.0 Hz, 1 H), 1.57–1.39 (m, 4 H), 1.35–
1.15 (m, 3 H), 1.29 (s, 3 H), 1.18 (s, 3 H), 0.98–0.84 (m, 1 H), 0.94
(s, 3 H), 0.87 (d, J = 6.5 Hz, 3 H), 0.80 (s, 3 H), 0.66 (s, 3 H) ppm.
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 172.4, 152.3, 128.0, 125.4,
124.8, 81.3, 73.9, 50.3, 47.2, 42.3, 41.8, 39.5, 34.7, 34.0, 31.4, 30.9,
29.5, 26.4, 23.2, 22.8, 21.9, 21.5, 17.2 ppm.
(1S,5S)-5-Methyl-2-(2-phenylprop-2-yl)cyclohexyl (E)-3,7-Dimeth-
ylocta-2,6-dienoate (28): A mixture of NaH (172 mg, 4.31 mmol)
and anhydrous THF (20.0 mL) was stirred and cooled to 0 °C un-
der argon. Compound 25 (1615 mg, 3.92 mmol) in anhydrous THF
(3.0 mL) was added, and the mixture was stirred for 7 min. Com-
mercial 26 (0.64 mL, 4.31 mmol) was added, and the solution was
stirred at room temp. for 4 h. The reaction mixture was diluted
with tBuOMe (50 mL), saturated aqueous NH4Cl was added drop-
wise, and finally H2O (60 mL) was added. The aqueous layer was
extracted with tBuOMe (3ϫ80 mL), and the resulting organic mix-
ture was then dried with anhydrous Na2SO4 and concentrated un-
der reduced pressure. Purification by column chromatography (hex-
ane/tBuOMe, 10:1) on silica gel afforded condensation product 28
(1093 mg, 2.86 mmol, 73 % yield) as a colorless oil. 1H NMR
Radical Cyclization of 20: After subjecting 20 (260 mg, 0.91 mmol)
to the catalytic procedure conditions, the resulting crude was puri-
fied by column chromatography on silica gel (hexane/tBuOMe, 4:1)
to yield a mixture of 31a and 31b in a 2:1 ratio (241 mg, 93% yield).
A solution of this mixture (241 mg, 0.84 mmol) in Et2O was treated
with an excess of TsOH at room temp. for 26 h. The reaction mix-
ture was washed with saturated aqueous NaHCO3 solution
(2ϫ25 mL) and brine (30 mL), dried with anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting crude material
was purified by column chromatography (hexane/tBuOMe, 4:1) on
silica gel to afford 31a (154.6 mg, 0.54 mmol, 63% yield) and the
lactone derived from 31b (61.1 mg, 0.27 mmol, 31% yield).
(CDCl3, 300 MHz, 25 °C): δ = 7.23 (m, 4 H), 7.07 (m, 1 H), 5.12* Diethyl 2-[(1R,3S)-3-Hydroxy-1,2,2-trimethylcyclopentyl]malonate
(m, 0.22 H), 5.05 (m, 0.77 H), 4.99 (s, 1 H), 4.78 (td, J = 10.7, 10.7, (31a): Colorless oil. H NMR (CDCl3, 500 MHz, 25 °C): δ = 4.18
1
4.3 Hz, 1 H), 2.68–2.48 (m, 1 H), 2.07 (s, 3 H), 1.92–0.75 (m, 12 (m, 4 H), 3.76 (dd, J = 3.6, 3.6 Hz, 1 H), 3.46 (s, 1 H), 2.19 (m, 1
H), 1.78 (s, 1 H), 1.68 (s, 3 H), 1.61 (s, 3 H), 1.30 (s, 3 H), 1.22 (s,
H), 1.84 (m, 2 H), 1.61 (m, 1 H), 1.34 (s, 3 H), 1.28 (t, J = 7.0 Hz,
3 H), 0.85 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz, 3 H), 1.25 (t, J = 7.0 Hz, 3 H), 0.95 (s, 6 H) ppm. 13C NMR
Eur. J. Org. Chem. 2011, 5002–5011
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5009

J. F. Arteaga, A. F. Barrero et al.
FULL PAPER
(CDCl3, 125 MHz, 25 °C): δ = 169.0, 168.8, 83.5, 61.2, 61.1, 58.1,
(FAB): calcd. for C16H30O3SiNa [M + Na]+ 321.1862; found
48.6, 48.2, 36.8, 31.1, 24.6, 19.1, 18.6, 14.3, 14.2 ppm. HRMS 321.1855.
(FAB): calcd. for C15H26O5Na [M + Na]+ 309.1672; found
Radical Cyclization of 36: After subjecting 36 (391 mg, 0.74 mmol)
to the catalytic procedure conditions, the resulting crude material
Ethyl (1S,4R,5S)-5,8,8-Trimethyl-3-oxo-2-oxabicyclo[3.2.1]octane- was purified by column chromatography (hexane/tBuOMe, 3:1) on
309.1667.
1
4-carboxylate (Lactone Derived from 31b): Colorless oil. H NMR
(CDCl3, 500 MHz, 25 °C): δ = 4.26 (m, 1 H), 4.24 (dd, J = 7.1,
7.1 Hz, 2 H), 3.48 (d, J = 2.2 Hz, 1 H), 2.34 (ddd, J = 13.9, 9.2,
silica gel to afford a diasteromeric mixture 37 [37a, trans:
(1R,2R,3S) and (1S,2S,3R); 37b, cis: (1S,2R,3S) and (1R,2S,3R)]
(278 mg, 0.54 mmol, 71% yield). Compound 37 was saponified by
4.2 Hz, 1 H), 2.08 (m, 2 H), 1.61 (m, 1 H), 1.31 (t, J = 7.1 Hz, 3 reaction with KOH/MeOH, and the corresponding crude material
H), 1.06 (s, 3 H), 1.05 (s, 3 H), 0.95 (s, 3 H) ppm. 13C NMR was treated with TMSCHN2 to obtain a mixture of compounds
(CDCl3, 125 MHz, 25 °C): δ = 169.0, 167.8, 89.1, 61.7, 58.3, 46.1,
45.5, 30.3, 29.7, 20.9, 18.0, 17.0, 14.4 ppm. HRMS (FAB): calcd.
for C13H20O4Na [M + Na]+ 263.1254; found 263.1252.
34a and 35 at a 1.3:1 ratio.
Radical Cyclization of 38: After subjecting 38 (216 mg, 0.72 mmol)
to the catalytic procedure conditions, the resulting crude material
was purified by column chromatography (hexane/tBuOMe, 3:1 and
2:1) on silica gel to afford 39a (145 mg, 0.47 mmol, 66% yield) and
39b (58 mg, 0.19 mmol, 26% yield).
Radical Cyclization of 21: After subjecting 21 (165 mg, 1.00 mmol)
to the catalytic procedure conditions, the resulting crude material
was purified by column chromatography on silica gel (hexane/tBu-
OMe, 5:1 and 2:1) to afford 32a (131.2 mg, 79% yield) and 32b
(32.8 mg, 20% yield).
Diethyl 2-[(1R,2R,3S)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-
hydroxy-1,2-dimethylcyclopentyl]malonate (39a): Colorless oil. H
1
2-[(1R,3S)-3-Hydroxy-1,2,2-trimethylcyclopentyl]acetonitrile (32a):
NMR (CDCl3, 500 MHz, 25 °C): δ = 4.16 (m, 4 H), 4.02 (d, J =
1H NMR (CDCl3, 500 MHz, 25 °C): δ = 5.12 (m, 1 H), 3.95 (dd, 9.9 Hz, 1 H), 3.96 (dd, J = 8.2, 4.2 Hz, 1 H), 3.47 (d, J = 9.9 Hz,
J = 8.2, 6.4 Hz, 1 H), 2.18 (m, 2 H), 1.75 (t, J = 7.2 Hz, 1 H), 1.61 1 H), 3.45 (s, 1 H), 2.14 (m, 1 H), 1.78 (m, 2 H), 1.65 (m, 1 H),
(m, 1 H), 1.50 (m, 2 H), 1.18 (s, 3 H), 0.93 (s, 3 H), 0.89 (s, 3 H) 1.39 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H),
ppm. 13C NMR (CDCl3, 125 MHz, 25 °C): δ = 119.4, 81.1, 46.6,
44.5, 34.8, 30.4, 27.3, 22.7, 22.4, 17.7 ppm.
0.95 (s, 3 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C
NMR (CDCl3, 125 MHz, 25 °C): δ = 174.3, 174.2, 88.0, 71.3, 66.7,
66.5, 63.5, 58.2, 53.0, 44.7, 35.2, 31.4 (3 C), 25.5, 23.6, 23.4, 19.7,
19.6, –5.6 (2 C) ppm. HRMS (FAB): calcd. for C21H40O6SiNa [M
+ Na]+ 439.2492; found 439.2517.
2-[(1S,3S)-3-Hydroxy-1,2,2-trimethylcyclopentyl]acetonitrile (32b):
1H NMR (CDCl3, 500 MHz, 25 °C): δ = 5.19 (m, 1 H), 3.93 (dd,
J = 7.6, 4.6 Hz, 1 H), 2.70 (d, J = 16.5 Hz, 1 H), 2.29 (d, J =
16.5 Hz, 1 H), 2.18 (m, 1 H), 1.90 (m, 1 H), 1.88–1.50 (m, 2 H),
Diethyl 2-[(1S,2R,3S)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-hy-
1.10 (s, 3 H), 0.90 (s, 3 H), 0.89 (s, 3 H) ppm. 13C NMR (CDCl3, droxy-1,2-dimethylcyclopentyl]malonate (39b): Colorless oil. 1H
125 MHz, 25 °C): δ = 118.4, 80.0, 45.6, 43.1, 33.6, 29.2, 25.7, 21.7,
21.3, 15.9 ppm.
NMR (CDCl3, 500 MHz, 25 °C): δ = 4.16 (m, 5 H), 3.69 (s, 1 H),
3.59 (d, J = 9.9 Hz, 1 H), 3.48 (d, J = 9.9 Hz, 1 H), 2.16 (m, 1 H),
1.95 (m, 1 H), 1.63 (ddd, J = 15.2, 9.5, 2.6 Hz, 1 H), 1.56 (m, 1
H), 1.32 (s, 3 H), 1.26 (m, 6 H), 0.92 (s, 3 H), 0.90 (s, 9 H), 0.06
(s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz, 25 °C):
δ = 174.5, 174.4, 84.4, 74.9, 66.7, 66.6, 62.5, 57.7, 53.4, 42.4, 37.2,
31.6 (3 C), 26.0, 23.9, 23.7, 19.8, 19.7, 0.0 (2 C) ppm. HRMS
(FAB): calcd. for C21H40O6SiNa [M + Na]+ 439.2492; found
439.2517.
Radical Cyclization of 33: After subjecting 33 (594 mg, 1.81 mmol)
to the catalytic procedure conditions, the resulting crude material
was purified by column chromatography (hexane/tBuOMe, 3:1) on
silica gel to afford an equimolecular mixture of 34a and 34b
(455 mg, 1.38 mmol, 76% yield). A solution of this mixture (53 mg,
0.16 mmol) in Et2O (5.0 mL) was treated with an excess of TsOH
at room temp. for 26 h. The reaction was quenched with saturated
aqueous NaHCO3 solution and washed with brine, dried with an-
hydrous Na2SO4, and concentrated under reduced pressure. The
resulting crude material was purified by column chromatography
(hexane/tBuOMe, 5:1) on silica gel to afford lactone 35 (14 mg),
34a (29 mg), and a mixture of both compounds (7 mg).
Radical Cyclization of 40: After subjecting 40 (502 mg, 1.81 mmol)
to the catalytic procedure conditions, the resulting crude material
was purified by column chromatography (hexane/tBuOMe, 5:1 and
3:1) on silica gel to afford 41a (381.6 mg, 1.38 mmol, 76% yield)
and 41b (95.4 mg, 0.34 mmol, 19% yield).
Methyl 2-[(1R,2R,3S)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-hy- 2-[(1R,2R,3S)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-hydroxy-
1
droxy-1,2-dimethylcyclopentyl]acetate (34a): H NMR (CDCl3, 1,2-dimethylcyclopentyl]acetonitrile (41a): Colorless oil. 1H NMR
400 MHz, 25 °C): δ = 4.20 (dd, J = 8.6, 6.8 Hz, 1 H), 3.64 (s, 3 H),
3.54 (d, J = 9.6 Hz, 1 H), 3.46 (d, J = 9.6 Hz, 1 H), 2.25 (q, J = (d, J = 10.1 Hz, 1 H), 3.58 (d, J = 10.1 Hz, 1 H), 2.81 (d, J =
13.2 Hz, 2 H), 2.17–2.05 (m, 1 H), 1.86–1.74 (m, 1 H), 1.65–1.46 16.5 Hz, 1 H), 2.41 (d, J = 16.5 Hz, 1 H), 2.19 (m, 1 H), 1.98 (m,
(m, 2 H), 1.07 (s, 3 H), 0.92 (s, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H) 1 H), 1.62 (m, 2 H), 1.12 (s, 3 H), 0.93 (m, 3 H), 0.90 (s, 9 H), 0.08
(CDCl3, 500 MHz, 25 °C): δ = 4.02 (dd, J = 7.9, 4.2 Hz, 1 H), 3.73
ppm. 13C NMR (CDCl3, 125 MHz, 25 °C): δ = 173.3, 78.2, 68.7,
51.4, 50.6, 44.8, 41.5, 34.1, 30.1, 25.9 (3 C), 22.6, 18.2, 13.1, –5.6
(2 C) ppm. HRMS (FAB): calcd. for C17H34O4SiNa [M + Na]+
353.2124; found 353.2106.
(s, 6 H) ppm. 13C NMR (CDCl3, 125 MHz, 25 °C): δ = 119.4, 81.4,
65.1, 50.6, 43.9, 36.4, 30.8, 26.5, 25.9 (3 C), 23.2, 19.1, 18.1, –5.6
(2 C) ppm. HRMS (FAB): calcd. for C16H31NO2Na [M + Na]+
320.2022; found 320.1974.
(1S,5S,8R)-8-{[(tert-Butyldimethylsilyl)oxy]methyl}-5,8-dimethyl- 2-[(1S,2R,3S)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-hydroxy-
2-oxabicyclo[3.2.1]octan-3-one (35): Colorless oil. 1H NMR 1,2-dimethylcyclopentyl]acetonitrile (41b): Colorless oil. 1H NMR
(CDCl3, 400 MHz, 25 °C): δ = 4.51 (d, J = 4.5 Hz, 1 H), 3.39 (dd, (CDCl3, 500 MHz, 25 °C): δ = 4.18 (t, J = 8.0 Hz, 1 H), 3.53 (d, J
J = 11.9, 10.2 Hz, 2 H), 2.49 (dd, J = 18.5, 2.9 Hz, 1 H), 2.24 (d, = 10.1 Hz, 1 H), 3.48 (d, J = 10.1 Hz, 1 H), 2.39 (d, J = 1.7 Hz, 2
J = 17.7 Hz, 1 H), 1.98 (m, 2 H), 1.75 (m, 2 H), 1.05 (s, 3 H), 0.86 H), 2.14 (m, 1 H), 1.75 (m, 2 H), 1.59 (m, 1 H), 1.19 (s, 3 H), 0.94
(s, 3 H), 0.84 (s, 9 H), 0.00 (s, 3 H), –0.01 (s, 3 H) ppm. 13C NMR (m, 3 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz, 25 °C): δ = 171.4, 86.2, 65.5, 49.0, 45.5, 41.5,
(CDCl3, 125 MHz, 25 °C): δ = 119.3, 76.8, 68.1, 50.0, 44.3, 35.0,
36.6, 29.6, 25.9 (3 C), 19.0, 18.3, 12.2, –5.6 (2 C) ppm. HRMS 29.9, 27.1, 25.9 (3 C), 23.5, 18.2, 13.5, –5.6 (2 C) ppm. HRMS
5010
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5002–5011

Regio- and Diastereoselective Radical Cyclization
(FAB): calcd. for C16H31NO2Na [M + Na]+ 320.2022; found
320.1974.
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Received: March 23, 2011
Published Online: July 28, 2011
Eur. J. Org. Chem. 2011, 5002–5011
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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