Further explorations into the synthesis of Dehydro-Hedione

Article abstract of DOI:10.1002/hlca.201200440

Dehydrohedione (DHH) 1 may be obtained in 20% overall yield by a Reformatsky reaction with enone methyl ether 3b, followed by acidic workup of the crude reaction mixture. Alternatively, epoxidation (3-chloroperbenzoic acid, CH₂Cl₂, 84% yield) of the tertiary allyl alcohol derivative 4 affords a 1: 2 mixture of 8a and 8b. The latter epoxy ester 8b may also be obtained stereoselectively either from 4 (^tBuO₂H, [Mo(CO)₆], 1,2-dichloroethane, 70°, 62% yield; or ^tBuO₂H, [VO(acac)₂], decane, 20°, 92% yield), or from 5 (AcOMe, LiN(SiMe₃)₂, THF, -78°, 84-87%). BF₃×Et₂O-Catalyzed cascade rearrangement and OH elimination of 8a afford selectively DHH 1 in 88% yield. The cis disposition of the side chains of the weakly odoriferous hedione-like analogues 2b and 2c was maintained by means of either an epoxy or a cyclopropane moiety. Copyright

Full text of DOI:10.1002/hlca.201200440

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Helvetica Chimica Acta – Vol. 96 (2013)
Further Explorations into the Synthesis of Dehydro-Hedioneꢀ
by Be´at Winter1), Christian Chapuis*, Robert Brauchli, and Jean-Yves de Saint Laumer
Firmenich SA, Corporate R & D Division, P. O. Box 239, CH-1211 Geneva 8
(phone: þ 41-22-7803610; fax: þ 41-22-7803334; e-mail: christian.chapuis@firmenich.com)
Dedicated to the memory of Professor J. Weber (University of Geneva)
Dehydrohedione (DHH) 1 may be obtained in 20% overall yield by a Reformatsky reaction with
enone methyl ether 3b, followed by acidic workup of the crude reaction mixture. Alternatively,
epoxidation (3-chloroperbenzoic acid, CH2Cl2, 84% yield) of the tertiary allyl alcohol derivative 4
affords a 1:2 mixture of 8a and 8b. The latter epoxy ester 8b may also be obtained stereoselectively either
from 4 (tBuO2H, [Mo(CO)6], 1,2-dichloroethane, 708, 62% yield; or tBuO2H, [VO(acac)2], decane, 208,
92% yield), or from 5 (AcOMe, LiN(SiMe3)2, THF, ꢀ 788, 84 – 87%). BF3 · Et2O-Catalyzed cascade
rearrangement and OH elimination of 8a afford selectively DHH 1 in 88% yield. The cis disposition of
the side chains of the weakly odoriferous hedione-like analogues 2b and 2c was maintained by means of
either an epoxy or a cyclopropane moiety.
Introduction. – The didehydro derivative 1 of Hedioneꢀ, called dehydrohedione
(DHH) [1], is a key intermediate for both racemic and asymmetric industrial
hydrogenations, directed towards either racemic cis-Hedioneꢀ 2a [2a – 2c], or its
olfactively more precious enantiomer (þ)-(1R,2S)-Paradisoneꢀ 2a [2d – 2j]2). DHH 1
was earlier prepared from racemic 2a (ca. 90 :10 trans/cis-stereoisomers) by either
brominationꢀelimination [1a] (< 80%), direct HIO3 oxidation [1b] (65%), or by
anodic [1c] (69%), or peracetic [1d] (63%) oxidation of the corresponding enol acetate.
Several approaches to 1 were also reported starting from the industrially available
cyclopentenone 3a [1c][9], like the unselective direct addition of methyl diazoacetate
[1e] (25%), or via either the CrO3 oxidation of 4 [1f][1g] (87%)3), or via a
HornerꢀWittig reaction of the epoxycyclopentanone 5 [12], and rearrangement of the
corresponding epoxy ester 6 [1h] (80%). Moreover, the desired compound 1 was also
obtained by electroreductive intramolecular coupling of a keto nitrile [1i][1j] (10%), or
1
)
)
Deceased on 21st June 2009. Work performed in 1997.
(ꢀ)-trans-(1R,2R)-Hedioneꢀ (ca. 94:6 trans/cis) was discovered in 1957 by hydrogenation of (ꢀ)-
methyl jasmonate, isolated from the Mediterranean Jasminum grandiflorum L. Its structure and use
were protected in 1960 [3], and published two years later [4]. It was then found in tea flavor [5], in
the nonacidic, intensely sweet, Brazilian Lima orange [6], as well as in several other plants [6], and
its trans- and cis-racemate, as well as the optically active Paradisoneꢀ (ca. 93:7 cis/trans mixture),
became ubiquitous bulk building blocks in perfumery [7], thus rendering their natural occurrence
more difficult to put into evidence, due to possible artefacts. For reviews and historical discussions
of methyl jasmonate and Hedioneꢀ, see [8].
2
3
)
As alternative to either pyridinium dichromate in CH2Cl2 at 08 [10], or TEMPO, iodosylbenzene in
CH2Cl2 in the presence of cat. Bi(OTf)3 and 4-ꢃ molecular sieves [11].
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 96 (2013)
247
more efficiently, via a BaylisꢀHillman reaction from simple cyclopent-2-en-1-one [13],
followed by a cascade orthoester Claisen rearrangement, with double-bond isomer-
ization [1b] (60%). Finally, the correct state of oxidation may also be reached by 1,4-
addition of dimethyl malonate either to the reported 3-methoxy-2-pentylcyclopent-2-
en-1-one 3b [1k][2a] (48%)4), or to the doubly unsaturated known cyclopentenone 7
[14] (45%) [1l], followed by de(methoxycarbonylation). We would like here to present
alternative approaches, starting from either intermediates 3b, 4, or 5 (Scheme).
Results and Discussion. – Epoxidation of the tertiary allyl alcohol derivative 45) (3-
chloroperbenzoic acid (MCPBA), CH2Cl2) afforded a 1:2 mixture of epoxy esters 8a/
8b in 84% yield6). They could be separated by column chromatography (CC; SiO2).
Alternatively, 8b could also be obtained stereoselectively, either in 87% yield by
addition of the LiN(SiMe3)2 generated methyl acetate enolate to the epoxy ketone 57),
or by applying the anhydrous conditions reported by Fehr [18]. Thus, when hydroxy
t
ester 4 was treated either with BuO2H, [Mo(CO)6], and Na2HPO4 in 1,2-dichloro-
t
ethane at 708, or with BuO2H and [VO(acac)2] in decane at 208, pure 8b could be
isolated in 62 and 92% yield, respectively8). The pure cis isomer 8b (cis of OH and
epoxy) was then treated with BF3 · Et2O in toluene at 208 to afford a 66 :34 mixture of
DHH 1 and dihydroxylactone 9b, isolated by CC (SiO2) in 52 and 31% yield,
respectively9).
We anticipated that the trans-diastereoisomer 8a (trans of OH and epoxy) would
react more selectively during the catalyzed cascade rearrangement and OH elimi-
nation, since the CH2COOMe moiety is not trans with respect to the epoxy moiety, and
thus less prone to ring closure forming the lactone 9a. Indeed, we were pleased to
observe the formation of a 97:3 mixture of DHH 1 and dihydroxylactone 9a after
treatment with BF3 · Et2O in toluene (91% yield). This latter diol was oxidized to
4
)
)
No chemical yield was reported in [2a].
5
Hydroxy ester 4 was obtained from 3a, either by addition of BrCH2CO2Me in the presence of Zn in
toluene (60% yield) [1f] or of AcOMe in the presence of LiN(SiMe3)2 in THF at ꢀ 788 (84% yield)
[1g], as an alternative to the AcOMe, addition in the presence of lithium diisopropylamide (LDA)
and CeF3 in THF at ꢀ 608 [15a]. An excess of base should be avoided since 3a readily self-
condenses into I. Furthermore, a nonacidic workup is imperative, otherwise 4 dehydrates into a 2:1
mixture of the uncharacterized (E)-ester II [16], and its unreported isomer III (see Fig. 1).
For an analogous 1:10 anti/syn epoxidation with MCPBA of identical diastereoselectivity directed
by the OH function, see [17]. The worse diastereoselectivity observed in our case may be
rationalized by H-bond complexation of the methoxycarbonyl group with either the hydroxy group
or the peracid.
Nucleophilic 1,2-Grignard additions to a keto group at such skeletons were earlier reported as
stereoselectively approaching anti to the epoxy moiety [17d].
For OH syn directing epoxidation using tBuO2H, see [19]. Alternatively, Sharpless conditions using
rac-DET or rac-BINOL gave no reaction [20].
When pure 8b was treated for 3 h at 2008 with neutral Alox (50% by weight), a 87:13 mixture of
DHH 1 and 9b was obtained, and 1 could be isolated in 40% yield by CC SiO2. Alternatively, when
treated with 0.25 mol-equiv. of TsOH in refluxing cyclohexane for 6 h, a 72:28 mixture of 1 and 9b
was isolated. Concurrent formation of lactone 9b is consistent with the anti-stereochemistry of the
carbomethoxy functionality in 8b. In some instances, under anhydrous conditions, alcohol IV could
be isolated as intermediate towards DHH 1 (see Fig. 1).
6
)
7
8
9
)
)
)

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme
t
i) BrCH2CO2Me, Zn, toluene; 26–60%. ii) a) MCPBA, CH2Cl2; 84%, 1:2; or b) BuO2H, [Mo(CO)6],
Na2HPO4, 1,2-dichloroethane; 62%. iii) BF3 · Et2O, toluene, 208; 52–91%. iv) 70% H2O2, KOH, K2CO3,
MeOH; 61%. v) (MeO)2P(O)CH2CO2Me, MeONa, pentane; 91%. vi) H2SO4, Et2O, 48, or SnCl4, toluene;
95%. vii) H2, 5% Pd/C, cyclohexane, 08; 98%. viii) NaBH4, iPrOH; 60%. ix) PCC, CH2Cl2; 54%. x) Jones
reagent, acetone; 77%. xi) tBuO2H, [VO(acac)2], H2O/cyclohexane or anh. decane/toluene, 20 –808; 10–
92%. xii) AcOMe, LiN(SiMe3)2, THF, ꢀ 788; 84–87%. xiii) CrO3, dioxane, H2SO4; 87%. xiv) 1. MeONa,
MeOH, dimethyl malonate; 45%; 2. NaCl, 1-methylpyrrolidin-2-one (NMP), 1808; 98%; xv) 10% aq. HCl,
20% from 3b. xvi) H2O2, (CF3CO)2O, Na2CO3, CH2Cl2; 56%. xvii) Et2Zn, CH2I2, CH2Cl2, 408; 87%. xviii)
10 mol-% of (R)-methyloxazaborolidine, BH3 · SMe2, THF; 92% ee, 92%. xix) Ac2O, Py; > 98%.

Helvetica Chimica Acta – Vol. 96 (2013)
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Fig. 1. Isolated by-products
ketone 10 (Jones reagent, acetone, 77% yield), and was recovered from 10, via
probable assistance of the free carbinol OH group, by stereoselective reduction with
NaBH4 in iPrOH (60% yield). Alternatively, oxidation of 9b (pyridinium chlorochro-
mate (PCC), CH2Cl2) also afforded ketone 10 in 54% yield. To reverse the
diastereoselectivity during the epoxidation10) [22], attempts to protect the tertiary
alcohol moiety as directing functionality with either a sterically demanding group
(Me3SiCl, 1H-imidazole, CH2Cl2, 208; or Me3SiOSO2CF3, Et3N, CH2Cl2, ꢀ 788, or 08
[23]), or as a simpler methyl ether (NaH, MeI, THF), or acetate (AcCl, AgCN,
toluene, 558) failed, and essentially resulted in exocyclic elimination.
The junction of two five-membered rings in lactones 9 (Fig. 2) implies a cis
relationship between the pentyl substituent and the tertiary-alcohol function. We
initially unsuccessfully tried to ascertain the configuration of 9 based on the
Overhauser effects. Indeed, for 9a, irradiation of the pseudoaxial HꢀC(6) at the
secondary-alcohol centre resulted in enhancement of the signals of CH2(1’) and CH2(2’)
of the pentyl side chain, as well as of those of CH2(4). For 9b the same irradiation on the
pseudoequatorial HꢀC(6) resulted in enhancement of the CH2(2’) signals of the pentyl
t
10
)
Treatment of 4 with 70% aq. BuO2H and [VO(acac)2] in cyclohexane at 808 [15] resulted in 10%
rearrangement into the corresponding unreported secondary-alcohol derivative 11a, as the transient
intermediate in the oxidation of 4 to 1 [1f][1g]. Hydroxy ester 11a was also earlier obtained by V.
Rautenstrauch via reduction of 1 (1992). Its octanoyl ester was used as a slow-release perfuming
ingredient after washing textile in the presence of a lipase-containing detergent [21]. Treatment of 4
with AcO2H in toluene furnished only the starting material 4 accompanied by a multitude of
nonisolated by-products. Exocyclic elimination towards II occurred when 4 was treated with 35%
H2O2 and maleic anhydride in CH2Cl2 at 208 for 24 h (53% yield). Treatment of 4 with CF3CO3H in
CH2Cl2 also afforded II (38% yield), besides epoxy ester 12b (56% yield). Alternatively, 12b was
t
also obtained in 47% yield by treatment of the allyl alcohol derivative 11a with anh. BuO2H,
[VO(acac)2] in toluene at 208. Further oxidation of 12b (PCC, CH2Cl2, 79 – 94 % yield) afforded
epoxy ester 2b. The alternative cyclopropanation of 11a (Et2Zn, CH2I2, CH2Cl2, 408; 87% yield)
afforded, after PCC oxidation of 12c (37 – 85% yield), the analogue 2c. The more volatile nor
analogue of 2c carrying a butyl instead of a pentyl side chain shall be reported in due course.

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1
Fig. 2. Attributions via H-NMR and conformational analyses of 9a and 9b
side chain, as well as of the CH2(5) signals. The problem is that the CH2(4) and CH2(5)
signals are superimposed, and this precludes any confirmation of the configuration. We
thus decided to compare the theoretical and experimental coupling constants of
HꢀC(6). The B3LYP/6-31G** [24] conformational analysis of 9a suggests that the
pseudoequatorial secondary-alcohol derivative is 1.5 kcal/mol more stable than the
conformation with this OH substituent in the pseudoaxial position. As a consequence,
large coupling constants (calculated 6.1 and 10.3 Hz) are expected and compare well
with the observed data (3J(6,5) ¼ 7.8 and 14.0 Hz). Alternatively, the cis-diol derivative
9b prefers to orientate its secondary-alcohol function in the pseudoaxial position as
compared to the 3.0 kcal/mol less stable pseudoequatorial conformer. Consequently,
this diastereoisomer should exhibit smaller coupling constants (calculated 2.0 and
3.7 Hz) as experimentally observed (3J(6,5) ¼ 2.6 and 2.7 Hz). These considerations
allowed definitive attributions.
Finally, treatment of cyclopentenone 3b with Zn and BrCH2CO2Me in toluene
(26% yield) afforded directly the conjugated ester 1311) as a 87:13 (E)/(Z) mixture.
This latter does not need to be isolated since a subsequent hydrolytic treatment (10%
aq. HCl) furnished DHH 112) in 20% global yield from 3b.
11
)
)
Ester 13 was also earlier obtained by V. Rautenstrauch via O-alkylation of the enolate derived from
DHH 1 (1994).
12
Reduction of 1 to (3S)-11a catalyzed by 10 mol-% of (R)-methyloxazaborolidine was performed
analogously to [16] (92% ee, 92% yield). The ee of (3S)-11a was measured by chiral GLC analysis
(Chirasil-Dex-CB column (25 m ꢁ 0.25 mm), He, 1.2 ml/min, 1508) of the corresponding base-line
separated acetate (3S)-11b: tR (minor) 22.33 and tR (major) 23.24 min, order of elution consistent
with [16]. The absolute configuration was tentatively ascertained by hydrogenation of (3S)-11a (H2,
2.5%/(w/w) Adams catalyst, AcOEt [25a]) to (1S,2R,3S)-Va [2g] (87% ee after PCC/CH2Cl2
oxidation to (ꢀ)-cis-(1S,2R)-Paradisoneꢀ), separated by CC/(SiO2) from a 7:3 trans/cis mixture
(42% ee) of (þ)-(1S,2S)/(ꢀ)-(1S,2R)-Paradisoneꢀ resulting from competing double bond
isomerization, as well as from (1R,2R,3S)-Vb (see Fig. 1; 82% ee after PCC/CH2Cl2 oxidation to
(ꢀ)-trans-(1R,2R)-Paradisoneꢀ). In the presence of 2.5%/(w/w) of Crabtreeꢄs catalyst in CH2Cl2
[25b], (3S)-11a gave (1R,2S,3S)-12a [2i] in 85% yield. Finally, this hydrogenation was unsuccessful
with Raney-Ni in MeOH under normal pressure. In 1995, V. Rautenstrauch showed that DHH 1,
treated with D2 and 5% Pd/C in cyclohexane, incorporates some D in all positions of the
cyclopentanone moiety, as well as in the first ring-attached CH2 group of each of its substituents (cf.
[8d]). For the sake of completeness, stereoisomer (1R,2R,3R)-Vc [2h] was obtained by NaBH4
reduction of (ꢀ)-(1R,2R)-Paradisoneꢀ [2d]. Interestingly, when treated with Crabtreeꢄs catalyst,
racemic 11a afforded essentially a ca. 1:1 mixture of VIa/VIb separated by CC/(SiO2) [26] (see
Fig. 1).

Helvetica Chimica Acta – Vol. 96 (2013)
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Conclusion. – The trans-epoxy-hydroxy ester 8a (trans of OH and epoxy) is
required for efficient cascade rearrangement and OH elimination towards DHH 1
(88% yield). This latter may also be obtained directly from 3b via a Reformatsky
reaction, followed by an acidic workup. The nonepimerizable cis-disposition of the side
chains in 2b and 2c, obtained by introduction of either an epoxy or a cyclopropane
moiety [27], led to less volatile and much weaker hedione-like analogues.
We are indebted to Mrs. S. Gallo-Fluckiger, as well as to our apprentices H. Belloto, L. Gachet, and
´
M. Cretignier for their experimental skill.
Experimental Part
General. See [28].
Methyl 3-Oxo-2-pentylcyclopent-1-ene-1-acetate (1). To a soln. of hydroxy ester 8a (120 mg,
0.5 mmol) in toluene (5 ml) at 208, was added BF3 · Et2O (0.05 ml, 0.4 mmol). After 20 h at 208, the
mixture was diluted with Et2O (20 ml), washed with sat. aq. NaHCO3 soln., dried (Na2SO4), and
concentrated: 1/9a 97:3 (91%).
Alternatively, to a stirred soln. of hydroxy ester 8b (1200 mg, 5 mmol) in toluene (30 ml) at 08 was
added BF3 · Et2O (1.24 ml, 10 mmol). After 40 h at 208, the mixture was worked up as described above: 1/
9b 67:33 (95%). A bulb-to-bulb distillation afforded pure 1 (52%) as well as pure 9b (37%). In this latter
case and in some instances, under anh. conditions, intermediate IV (see below) could be isolated in traces
for anal. purposes, by CC (SiO2).
DHH 1 was also obtained in 20% global yield from 3b, after bulb-to-bulb distillation, when the
workup of 13 was performed with 10% aq. HCl soln. B.p. 1758/0.3 mbar. For analyses, see [1].
Methyl (1RS,5SR)-4-Oxo-5-pentyl-6-oxabicyclo[3.1.0]hexane-1-acetate (2b). A mixture of 12b
(20 mg, 0.078 mmol), PCC (25.6 mg, 0.116 mmol), and Celiteꢀ (530 mg) in CH2Cl2 (20 ml) was stirred
for 2.5 h at 208. The mixture was filtered, the filtrate concentrated, and the residue purified by CC (SiO2,
cyclohexane/AcOEt 9 :1): 2b (79%). Very weak hedione-like, metallic scent. IR: 2954, 2929, 2870, 2858,
1
1739, 1456, 1436, 1350, 1326, 1270, 1199, 1177, 1144, 1111, 1054, 1007, 989, 863, 726, 703, 684. H-NMR:
0.89 (t, J ¼ 6.5, 3 H); 1.29 – 1.33 (m, 4 H); 1.44 – 1.51 (m, 2 H); 1.64 (br. s, 1 OH); 1.67 – 1.73 (m, 2 H);
2.05 – 2.16 (m, 2 H); 2.32 – 2.41 (m, 2 H); 2.75 (d, J ¼ 17, 1 H); 2.87 (d, J ¼ 17, 1 H); 3.75 (s, 3 H).
13C-NMR: 210.8 (s); 169.7 (s); 68.8 (s); 67.0 (s); 52.2 (q); 36.5 (t); 32.1 (t); 31.8 (t); 25.7 (t); 24.4 (t); 23.6
(t); 22.4 (t); 13.9 (q). MS: 240 (3, Mþ), 194 (7), 183 (21), 167 (54), 151 (29), 153 (50), 141 (67), 137 (25),
129 (87), 123 (65), 111 (100), 99 (51), 97 (29), 95 (34), 83 (97), 81 (38), 71 (43), 69 (35), 59 (45), 55 (84),
53 (33), 43 (78), 41 (48), 28 (41).
Methyl (1S,5R)-4-Oxo-5-pentyl-6-oxabicyclo[3.1.0]hexane-1-acetate ((1S,5R)-2b). As described for
2b: (1S,5R)-2b (94%). [a]2D0 ¼ þ38.0 (c ¼ 0.034, CHCl3). Without olfactive character, similar to 2b.
Methyl (1RS,5SR)-4-Oxo-5-pentylbicyclo[3.1.0]hexane-1-acetate (2c). As described for 2b, from 12c:
2c (37%). Very weak hedione-like scent, without character. IR: 3064, 2963, 2938, 2880, 1744, 1439, 1331,
1174, 1063, 1024. 1H-NMR: 0.88 (t, J ¼ 7.1, 3 H); 0.96 (d, J ¼ 5, 1 H); 1.19 (d, J ¼ 5, 1 H); 1.23 – 1.33 (m,
5 H); 1.34 – 1.46 (m, 3 H); 1.91 – 1.98 (m, 1 H); 2.09 – 2.12 (m, 2 H); 2.17 – 2.22 (m, 1 H); 2.43 (d, J ¼ 15,
1 H); 2.65 (d, J ¼ 15, 1 H); 3.73 (s, 3 H). 13C-NMR: 215.0 (s); 171.9 (s); 51.8 (q); 41.2 (s); 38.4 (t); 34.3 (s);
32.6 (t); 32.2 (t); 27.3 (t); 27.1 (t); 26.8 (t); 24.2 (t); 22.6 (t); 14.0 (q). MS: 238 (21, Mþ), 179 (30), 164
(100), 136 (44), 121 (37), 109 (63), 107 (60), 95 (37), 93 (43), 81 (34), 79 (55), 77 (33), 74 (24), 65 (25),
55 (38), 41 (29).
Methyl (1S,5R)-4-Oxo-5-pentylbicyclo[3.1.0]hexane-1-acetate ((1S,5R)-2c). As described for 2b,
from (1S,4S,5R)-12c: (1S,5R)-2c (85%). Weakly hedione-like, slightly mushroom. [a]2D0 ¼ þ30.0 (c ¼
0.04, CHCl3).
Methyl (1RS,2SR,5RS)-2-Hydroxy-1-pentyl-6-oxabicyclo[3.1.0]hexane-2-acetate (8a). As described
for 8b. IR: 3473, 2953, 2932, 2861, 1735, 1437, 1339, 1312, 1204, 1164, 1109, 1045, 1008, 957, 909, 886, 833,
1
729, 669. H-NMR: 0.88 (t, J ¼ 7, 3 H); 1.24 – 1.33 (m, 6 H); 1.49 – 1.58 (m, 1 H); 1.64 – 1.75 (m, 2 H);

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Helvetica Chimica Acta – Vol. 96 (2013)
1.87 – 1.94 (m, 2 H); 1.97 – 2.06 (m, 1 H); 2.57 (d, J ¼ 16, 1 H); 2.74 (d, J ¼ 16, 1 H); 3.47 (s, 1 H); 3.64 (s,
10 H); 3.72 (s, 3 H). 13C-NMR: 174.0 (s); 78.7 (s); 68.8 (s); 61.8 (d); 51.9 (q); 39.4 (t); 34.6 (t); 32.1 (t);
24.9 (t); 24.1 (t); 24.0 (t); 22.6 (t); 14.0 (q). MS: 242 (1, Mþ), 224 (16), 183 (10), 167 (60), 153 (62), 130
(50), 116 (31), 111 (45), 99 (40), 83 (35), 71 (36), 69 (40), 55 (85), 43 (100).
Methyl (1RS,2RS,5RS)-2-Hydroxy-1-pentyl-6-oxabicyclo[3.1.0]hexane-2-acetate (8b). To a soln. of
hydroxy ester 4 (820 mg, 3.6 mmol) in CH2Cl2 (20 ml) at 08 was added portionwise 50% MCPBA
(1720 mg, 5.0 mmol). After 3 h at 208, the mixture was washed with 10% aq. NaOH soln., 5% aq. NaOH
soln., and sat. aq. NaHCO3 soln., the org. phase dried (Na2SO4) and concentrated, and the residue
(0.78 g) bulb-to-bulb distilled: 8a/8b 1:2 (84%). Pure 8a (23%) and 8b (24%) were obtained after CC
(SiO2, toluene/AcOEt 4 :1). Alternatively, 1m of LiN(SiMe3)2 in THF (25 ml, 25 mmol) at ꢀ 788 was
added to AcOMe (2.0 ml, 25 mmol), and after 15 min at ꢀ 788, epoxy ketone 5 (3.36g, 20 mmol) was
added dropwise. After 30 min at ꢀ 788, pentane (10 ml) was added, then 10% aq. HCl soln. (15 ml), and
the mixture was allowed to reach 08 before dilution with Et2O (10 ml). The mixture was washed with
H2O, sat. aq. NaHCO3 soln., and brine, the org. phase dried (Na2SO4) and concentrated, and the reddish
oil (4.9 g, 8a/8b 4 :96) purified by bulb-to-bulb distillation: pure 8b (87%; 8a/8b 1:99).
Alternatively, a mixture of [Mo(CO)6] (10.6 mg, 0.04 mmol), 1,2-dichloroethane (5 ml), and 5.5m
tBuO2H in decane (0.66 ml, 3.63 mmol) was heated at 708 for 0.5 h and then introduced within 0.25 h into
a stirred mixture of 4 (510 mg, 2.14 mmol), Na2HPO4 (11 mg, 0.076 mmol), and 1,2-dichloroethane
(10 ml) at 708. After 3.5 h, the mixture was cooled and worked up as above: 8b (62%) after CC (SiO2,
cyclohexane/AcOEt 9 :1 ! 85 :15).
t
Alternatively, 5.5m BuO2H in decane (0.211 ml, 1.16 mmol) was added dropwise to a soln. of 4
(200 mg, 0.773 mmol) and [VO(acac)2] (6 mg, 0.023 mmol) in toluene (15 ml) at 208. After 6h at 208, the
red mixture was poured onto sat. aq. NaHCO3 soln., and diluted with Et2O. The org. phase was washed
with 20% aq. Na2SO3 soln. and H2O, dried (Na2SO4), and concentrated and the residue purified by CC
(SiO2, cyclohexane/AcOEt 8 :2): pure 8b (92%). B.p. 1208/0.3 mbar; 1258/0.5 mbar. IR: 3476, 3021, 2953,
2933, 2861, 1735, 1437, 1340, 1312, 1203, 1164, 1108, 1009, 958, 909, 886, 669. 1H-NMR: 0.88 (t, J ¼ 7, 3 H ) ;
1.24 – 1.34 (m, 4 H); 1.42 – 1.50 (m, 1 H); 1.57 – 1.70 (m, 4 H); 1.85 – 1.93 (m, 1 H); 1.96 – 2.08 (m, 2 H);
2.47 (d, J ¼ 14.7, 1 H); 2.70 (d, J ¼ 14.7, 1 H); 2.99 (s, 10 H); 3.37 (s, 1 H); 3.73 (s, 3 H). 13C-NMR: 171.8
(s); 79.3 (s); 69.0 (s); 61.0 (d); 51.9 (q); 40.4 (t); 33.4 (t); 32.2 (t); 25.4 (t); 25.3 (t); 23.8 (t); 22.5 (t); 14.0
(q). MS: 242 (1, Mþ), 224 (17), 183 (10), 167 (60), 153 (60), 130 (47), 116 (32), 111 (47), 99 (42), 83 (36),
71 (37), 69 (39), 55 (85), 43 (100).
(3aRS,6SR,6aSR)-Hexahydro-3a,6-dihydroxy-6a-pentyl-2H-cyclopenta[b]furan-2-one (9a). To a
i
soln. of keto lactone 10 (250 mg, 1.1 mmol) in PrOH (5 ml) at 08 was added NaBH4 (50 mg, 1.3 mol).
The mixture was allowed to reach 208, and after 1 h, the mixture was diluted with Et2O (20 ml) and
washed twice with brine (10 ml), the org. phase dried (Na2SO4) and concentrated and the residue bulb-
to-bulb distilled: pure 9a (60%). B.p. 1758/0.2 mbar. IR: 3396, 2955, 2931, 2872, 1749, 1456, 1408, 1379,
1
1312, 1255, 1237, 1207, 1161, 1091, 1043, 987, 952, 899, 816. H-NMR: 0.90 (t, J ¼ 7, 3 H); 1.30 – 1.36 (m,
4 H); 1.45 – 1.55 (m, 3 H); 1.69 – 1.73 (m, 1 H); 1.73 – 1.80 (m, 2 H); 2.06 – 2.13 (m, 2 H); 2.77 (d, J ¼ 19.5,
1 H); 2.86 (br. s, 1 OH); 2.91 (d, J ¼ 19.5, 1 H); 3.13 (br. s, 1 OH); 3.94 (dd, J ¼ 14, 7.8, 1 H). 13C-NMR:
175.5 (s); 95.7 (s); 81.5 (s); 75.9 (d); 45.0 (t); 37.1 (t); 32.4 (t); 32.3 (t); 29.9 (t); 22.8 (t); 22.5 (t); 14.0 (q).
MS: 228 (1, Mþ), 129 (100), 111 (34), 101 (40), 99 (45), 83 (70), 71 (23), 55 (41), 43 (52).
(3aRS,6RS,6aSR)-Hexahydro-3a,6-dihydroxy-6a-pentyl-2H-cyclopenta[b]furan-2-one (9b). See
procedure for 1. IR: 3440, 2955, 2931, 2871, 1748, 1459, 1448, 1412, 1375, 1312, 1256, 1239, 1215, 1161,
1
1137, 1118, 1096, 1040, 1023, 999, 950, 904, 882, 729, 634. H-NMR: 0.91 (t, J ¼ 7, 3 H); 1.31 – 1.37 (m,
4 H); 1.38 – 1.47 (m, 1 H); 1.52 – 1.68 (m, 2 H); 1.77 – 1.84 (m, 2 H); 1.86 – 1.95 (m, 1 H); 2.11 – 2.18 (m,
1 H); 2.20 – 2.30 (m, 1 H); 2.71 (d, J ¼ 18, 1 H); 2.92 (dd, J ¼ 3, 18, 1 H); 2.95 (br. s, 1 OH); 3.07 (br. s,
1 OH); 4.23 (dd, J ¼ 2.6, 2.7, 1 H). 13C-NMR: 174.6 (s); 98.1 (s); 82.7 (s); 75.5 (d); 43.5 (t); 40.4 (t); 32.4
(t); 30.3 (t); 29.4 (t); 23.1 (t); 22.6 (t); 14.0 (q). MS: 228 (1, Mþ), 129 (100), 111 (32), 101 (35), 99 (40), 83
(59), 71 (18), 55 (35), 43 (48).
(3aRS,6aRS)-Tetrahydro-3a-hydroxy-6a-pentyl-2H-cyclopenta[b]furan-2,6(3H)-dione (10). To a
suspension of PCC (860 mg, 4.0 mmol) in CH2Cl2 (10 ml) was added a soln. of 9b (460 mg, 2 mmol) in
CH2Cl2 (5 ml), and the mixture was stirred at 208 for 50 h. The mixture was diluted with Et2O (20 ml) and
filtered over Florisil, the filtrate concentrated, and the residue bulb-to-bulb distilled: pure 10 (54%).

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Alternatively, to a soln. of 9a (400 mg, 1.7 mmol) in acetone (10 ml) at 208 was added 2.1n Jones
reagent (1 ml, 2.1 mmol), and the mixture was stirred at 208 for 1 h. After dilution with Et2O, the mixture
was washed with sat. aq. NaHCO3 soln. and brine, the org. phase dried (Na2SO4) and concentrated, and
the residue purified by bulb-to-bulb distillation: pure 10 (77%). B.p. 1508/0.2 mbar. IR: 3638, 2965, 2880,
1818, 1774, 1460, 1425, 1176, 1125, 1019, 955, 728. 1H-NMR: 0.89 (t, J ¼ 7, 3 H); 1.28 – 1.35 (m, 4 H); 1.35 –
1.42 (m, 1 H); 1.44 – 1.54 (m, 1 H); 1.76 – 1.93 (m, 2 H); 2.13 – 2.22 (m, 1 H); 2.28 – 2.36 (m, 1 H); 2.42 –
2.52 (m, 1 H); 2.60 – 2.70 (m, 1 H); 2.73 (d, J ¼ 18.6, 1 H); 2.81 (d, J ¼ 18.6, 1 H); 3.67 (br. s, 1 OH).
13C-NMR: 211.9 (s); 174.5 (s); 91.8 (s); 80.6 (s); 42.3 (t); 35.1 (t); 32.2 (t); 30.7 (t); 29.1 (t); 22.3 (t); 22.2
(t); 14.0 (q). MS : 226 (0, Mþ), 208 (8), 184 (18), 170 (41), 127 (10), 99 (100), 86 (18), 71 (19), 55 (14), 43
(38).
Methyl (3RS)-3-Hydroxy-2-pentylcyclopent-1-ene-1-acetate (11a). By-product isolated in 10% yield
by CC (SiO2) after treatment of 4 with 70% aq. tBuO2H soln. (1.0 equiv.) and [VO(acac)2] (0.015 equiv.)
in refluxing cyclohexane for 7 h.
By analogy to [27], NaBH4 (0.39 g, 10.31 mmol) was added portionwise at 208 to a mixture of DHH 1
(0.5 g, 2.05 mmol) and anh. CeCl3 (518 mg, 2.08 mmol) in MeOH (15 ml). After 1.25 h at 208, the mixture
was poured onto ice/aq. sat. NaHCO3 soln. and then extracted with Et2O. The org. phase was washed with
aq. sat. NaHCO3 soln., dried (Na2SO4), and concentrated and the residue purified by CC (SiO2,
cyclohexane/AcOEt 8 :2): 11a (42%). IR: 3417, 2954, 2929, 2856, 1738, 1455, 1435, 1323, 1263, 1195, 1170,
1
1044, 972, 730, 662. H-NMR: 0.89 (t, J ¼ 7, 3 H); 1.21 – 1.40 (m, 6 H); 1.45 – 1.51 (m, 1 H); 1.59 (br. s,
1 OH); 1.63 – 1.71 (m, 2 H); 2.10 – 2.18 (m, 2 H); 2.24 – 2.33 (m, 2 H); 2.43 – 2.53 (m, 1 H); 3.12 (dd, J ¼ 5,
16, 1 H); 3.68 (s, 3 H). 13C-NMR: 171.6 (s); 142.2 (s); 132.0 (s); 79.1 (d); 51.8 (q); 34.5 (t); 33.4 (t); 32.8
(t); 31.9 (t); 27.8 (t); 25.7 (t); 22.6 (t); 14.0 (q). MS: 226 (0, Mþ), 208 (11), 165 (8), 152 (50), 134 (31), 119
(32), 109 (19), 107 (17), 105 (50), 91 (100), 79 (47), 77 (35), 67 (15).
Methyl (3S)-3-Hydroxy-2-pentylcyclopent-1-ene-1-acetate ((3S)-11a). (3S)-11a (92%), 92% ee. As
described in [16]. [a]2D0 ¼ ꢀ24.1 (c ¼ 0.03, CHCl3).
Methyl (3S)-3-(Acetyloxy)-2-pentylcyclopent-1-ene-1-acetate ((3S)-11b). Ac2O (1 ml) was added at
08 to a soln. of (3S)-11a (42 mg, 0.186 mmol) in pyridine (1 ml). After 1 h at 208, the mixture was poured
onto ice/10% aq. HCl soln. and then extracted with Et2O. The org. phase was washed to neutral with H2O,
dried (Na2SO4), and concentrated and the residue purified by bulb-to-bulb distillation: (3S)-11b
(> 98%). [a]2D0 ¼ ꢀ2.7 (c ¼ 0.56, CHCl3). IR: 2953, 2925, 2855, 1735, 1457, 1435, 1371, 1237, 1195, 1169,
1023, 963. 1H-NMR: 0.88 (t, J ¼ 7.3, 3 H); 1.10 – 1.43 (m, 6 H); 1.68 – 1.74 (m, 1 H); 1.98 – 2.14 (m, 2 H);
2.05 (s, 3 H); 2.28 – 2.39 (m, 2 H); 2.49 – 2.55 (m, 1 H); 3.11 (d, J ¼ 16.5, 1 H); 3.20 (d, J ¼ 16.5, 1 H); 3.68
(s, 3 H); 5.74 (br. t, J ¼ 5.3, 1 H). 13C-NMR: 171.2 (s); 171.1 (s); 138.2 (s); 135.0 (s); 81.5 (d); 51.9 (q); 34.5
(t); 33.9 (t); 31.8 (t); 29.7 (t); 29.6 (t); 27.6 (t); 25.9 (t); 22.5 (t); 21.3 (q); 14.0 (q). MS: 268 (0, Mþ), 208
(35), 152 (86), 149 (17), 134 (38), 119 (28), 105 (45), 91 (100), 79 (38), 77 (24), 43 (20).
Methyl (1R,2S,3S)-3-Hydroxy-2-pentylcyclopentaneacetate ((1R,2S,3S)-12a). A soln. of (3S)-11a
(100 mg, 0.398 mmol) in CH2Cl2 (5 ml) was hydrogenated over [Ir(cod)Py(PCy3)]PF6 (cod ¼ cycloocta-
1,5-diene, Cy ¼ cyclohexyl; 3 mg) for 22 h. The mixture was concentrated and the residue purified by CC
(SiO2, cyclohexane/AcOEt 8 :2): (1R,2S,3S)-12a (85%). Rf (cyclohexane/AcOEt 8 :2) 0.26. GLC: (DB-
1, 15 m, 250 mm, 0.25 mm, 1008, 1 min; 158/min ! 2208): tR 6.65 min. [a]2D0 ¼ þ13.6 (c ¼ 0.035, CHCl3). IR:
3415, 2953, 2926, 2858, 1737, 1459, 1436, 1376, 1258, 1194, 1170, 1060, 1011, 967, 886, 845, 721. 1H-NMR:
0.89 (t, J ¼ 7, 3 H); 1.10 – 1.19 (m, 1 H); 1.22 – 1.36 (m, 7 H); 1.49 – 1.58 (m, 1 H); 1.76 – 1.83 (m, 2 H);
1.90 – 1.98 (m, 1 H); 2.01 – 2.10 (m, 2 H); 2.14 (dd, J ¼ 10, 14.6, 1 H); 2.38 (dd, J ¼ 6.1, 14.6, 1 H); 2.58 –
2.67 (m, 1 H); 3.67 (s, 3 H); 3.98 (dt, J ¼ 4.4, 6.8, 1 H). 13C-NMR: 173.9 (s); 77.5 (d); 51.5 (q); 50.8 (d);
36.8 (d); 35.1 (t); 32.8 (t); 32.2 (t); 28.3 (t); 27.8 (t); 27.4 (t); 22.6 (t); 14.1 (q). MS: 228 (1, Mþ), 210 (8),
197 (13), 185 (28), 169 (15), 153 (25), 150 (22), 139 (30), 136 (60), 121 (11), 110 (33), 107 (18), 100 (20),
95 (41), 93 (21), 83 (40), 81 (41), 79 (30), 74 (100), 69 (37), 67 (34), 59 (18), 57 (20), 55 (42), 43 (26), 41
(31).
Methyl (1RS,4RS,5RS)-4-Hydroxy-5-pentyl-6-oxabicyclo[3.1.0]hexane-1-acetate (12b). At 08, 35%
aq. H2O2 soln. (0.265 g, 2.73 mmol) was added dropwise to a soln. of trifluoroacetic anhydride (1.25g,
5.9 mmol) in CH2Cl2 (15 ml). After 0.5 h at 08, this mixture was added dropwise at ꢀ 508 to a mixture of
4 (0.5 g, 2.1 mmol) and Na2CO3 (0.67g, 6.3 mmol) in CH2Cl2 (15 ml). After 1.5 h, the cold mixture was
poured onto 10% aq. Na2SO3 soln. and extracted. The org. phase was washed with aq. sat. NaHCO3 soln.

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Helvetica Chimica Acta – Vol. 96 (2013)
and brine, dried (Na2SO4), and concentrated and the residue purified by CC (SiO2, cyclohexane/AcOEt
95 :5 ! 8 :2): pure 12b (56%), besides the diene resulting from exocyclic elimination (38%).
Alternatively, 5.5m tBuO2H in decane (0.11 ml, 0.605 mmol) was added dropwise at 208 to a soln. of
11a (110 mg, 0.433 mmol) and [VO(acac)2] (2 mg, 0.0072 mmol) in toluene (10 ml). After 18 h at 208, the
mixture was quenched with H2O, and extracted with toluene. The org. phase was dried (MgSO4) and
concentrated and the residue purified by CC as described above: pure 12b (47%). IR: 3453, 2953, 2930,
2860, 1739, 1456, 1435, 1325, 1264, 1201, 1172, 1144, 1072, 990, 943, 926, 884, 850, 726, 615. 1H-NMR: 0.90
(t, J ¼ 7, 3 H); 1.21 – 1.35 (m, 5 H); 1.39 – 1.47 (m, 2 H); 1.50 – 1.58 (m, 1 H); 1.66 – 1.76 (m, 2 H); 1.94 –
2.01 (m, 2 H); 2.10 (dd, J ¼ 9, 14, 1 H); 2.61 (d, J ¼ 16, 1 H); 2.72 (d, J ¼ 16, 1 H); 3.72 (s, 3 H); 4.20 (br. q,
J ¼ 6.5, 1 H). 13C-NMR: 170.4 (s); 74.0 (d); 71.3 (s); 66.8 (s); 51.9 (q); 36.3 (t); 32.2 (t); 28.3 (t); 28.2 (t);
27.4 (t); 24.8 (t); 22.5 (t); 14.0 (q). MS: 242 (2, Mþ), 223 (28), 167 (43), 153 (84), 151 (65), 139 (13), 129
(53), 127 (42), 125 (31), 116 (51), 111 (100), 107 (21), 101 (22), 99 (55), 97 (35), 95 (28), 83 (42), 71 (38),
69 (130), 59 (38), 55 (62), 43 (68).
Methyl (1S,4S,5S)-4-Hydroxy-5-pentyl-6-oxabicyclo[3.1.0]hexane-1-acetate ((1S,4S,5S)-12b). As de-
scribed for 12b: (1S,4S,5S)-12b (63%). [a]2D0 ¼ þ1.5 (c ¼ 0.033, CHCl3).
Methyl (1RS,4RS,5SR)-4-Hydroxy-5-pentylbicyclo[3.1.0]hexane-1-acetate (12c). Diiodomethane
(126 mg, 0.47 mmol) was added dropwise at 208 to a soln. of 1m Et2Zn (2 ml, 2.0 mmol) in CH2Cl2
(15 ml) and 1,2-dimethoxyethane (0.21 ml) in the presence of 4 ꢃ molecular sieves. The mixture was
heated at 408, and a soln. of 11a (107 mg, 0.426 mmol) in CH2Cl2 (5 ml) was added dropwise. After 7 h,
the mixture was quenched at 208 by addition of NH4Cl and then extracted with Et2O. The org. phase was
washed with 15% NaOH soln., then 10% HCl soln., and brine to neutrality, dried (Na2SO4), and
concentrated and the residue purified by CC (SiO2, cyclohehane/AcOEt 8 :2): pure 12c (87%). IR: 3416,
2953, 2927, 2859, 1737, 1452, 1435, 1322, 1261, 1245, 1216, 1200, 1166, 1057, 1013, 976. 1H-NMR: 0.17 (d,
J ¼ 5.3, 1 H); 0.89 (t, J ¼ 7.3, 3 H); 0.91 (d, J ¼ 5.3, 1 H); 0.99 – 1.10 (m, 1 H); 1.23 – 1.68 (m, 9 H); 1.70 (br.
s, 1 OH); 1.85 – 1.96 (m, 2 H); 2.27 (d, J ¼ 15.5, 1 H); 2.43 (d, J ¼ 15.5, 1 H); 3.68 (s, 3 H); 4.38 (t, J ¼ 8.3,
1 H). 13C-NMR: 173.0 (s); 77.0 (d); 51.5 (q); 38.3 (t); 36.1 (s); 32.4 (t); 31.2 (t); 29.8 (t); 29.7 (t); 29.0 (s);
27.0 (t); 22.7 (t); 15.5 (t) ; 14.1 (q). MS: 240 (3, Mþ), 222 (7), 183 (12), 166 (70), 151 (24), 134 (18), 123
(19), 119 (12), 109 (41), 105 (47), 95 (39), 93 (34), 91 (100), 81 (29), 74 (59), 67 (23), 55 (35), 43 (29), 41
(30).
Methyl (1S,4S,5R)-4-Hydroxy-5-pentylbicyclo[3.1.0]hexane-1-acetate ((1S,4S,5R)-12c). As described
for 12c: (1S,4S,5R)-12c (47%). [a]2D0 ¼ ꢀ22.5 (c ¼ 0.02, CHCl3).
Methyl (2E)-2-(3-Methoxy-2-pentylcyclopent-2-en-1-ylidene)acetate ((E)-13). According to the
Reformatsky procedure described for its analogue 3a [1f]. Workup with H2O and purification by CC
(SiO2, cyclohexane/AcOEt 8 :2) gave (E)-13 (26%), i.e., 87:13 (E)/(Z) mixture. IR: 2930, 2857, 1699,
1584, 1459, 1433, 1373, 1324, 1251, 1242, 1154, 1123, 1026, 925, 831. 1H-NMR: 0.88 (t, J ¼ 7, 3 H); 1.20 –
1.40 (m, 6 H); 2.11 (t, J ¼ 7, 2 H); 2.67 (t, J ¼ 4, 2 H); 3.09 (dt, J ¼ 4, 2, 2 H); 3.68 (s, 3 H); 3.82 (s, 3 H);
5.46 (t, J ¼ 2, 1 H). 13C-NMR: 171.4 (s); 168.7 (s); 168.2 (s); 119.7 (s); 100.0 (d); 56.9 (q); 50.4 (q); 31.9
(t); 28.3 (t); 27.9 (t); 27.4 (t); 22.5 (2t); 14.1 (q). MS: 238 (18, Mþ), 207 (17), 182 (17), 165 (100), 149 (14),
135 (13), 123 (35), 121 (16), 109 (7), 91 (15), 79 (8), 77 (11).
(5E)-2-Pentyl-5-(2-pentylcyclopent-2-en-1-ylidene)cyclopent-2-en-1-one (I). When the procedures
reported in [1f] for deprotonation of AcOMe were not respected, by using an excess of LiN(SiMe3)2 (1.2
to 1.5 instead of 1.0 mol.-equiv.), self-condensation of 3a occurred, and I was isolated in 8 – 18% yield by
CC (SiO2, cyclohexane/AcOEt 98 :2 ! 8 :2). IR: 2954, 2926, 2858, 1687, 1645, 1625, 1590, 1458, 1377,
1342, 1260, 1241, 1162, 1105, 1033, 956, 918, 876, 850, 818, 787, 730. 1H-NMR: 0.90 (t, J ¼ 7, 3 H); 0.92 (t,
J ¼ 7, 3 H); 1.30 – 1.37 (m, 8 H); 1.52 (t, J ¼ 7, 2 H); 1.54 (t, J ¼ 7, 2 H); 2.25 (t, J ¼ 7, 2 H); 2.38 (t, J ¼ 7,
2 H); 2.48 – 2.52 (m, 2 H); 3.24 – 3.28 (m, 2 H); 3.37 (s, 2 H); 6.46 (s, 1 H); 7.05 (s, 1 H). 13C-NMR: 198.4
(s); 157.6 (s); 148.6 (s); 146.5 (s); 146.4 (d); 145.9 (d); 122.4 (s); 32.1 (t); 31.9 (t); 31.8 (t); 31.7 (t); 31.4 (t);
29.4 (t); 28.8 (t); 27.4 (t); 25.4 (t); 22.6 (t); 22.5 (t); 14.1 (q); 14.0 (q). MS: 286 (100, Mþ), 243 (17), 229
(80), 216 (10), 173 (17); 159 (12); 145 (10), 131 (10), 129 (12), 117 (12), 105 (10), 91 (20), 79 (11), 41
(12).
Methyl (2E)-2-(2-Pentylcyclopent-2-en-1-ylidene)acetate (II). For the preparation, see [16] or III.
Fatty, paper, weak odor. IR: 2952, 2926, 2858, 1709, 1611, 1432, 1350, 1291, 1214, 1157, 1030, 929, 906, 848,
727. 1H-NMR: 0.90 (t, J ¼ 7, 3 H); 1.23 – 1.36 (m, 4 H); 1.56 – 1.48 (m, 2 H); 2.16 (t, J ¼ 8.5, 2 H); 2.51 (m,

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2 H); 3.08 (m, 2 H); 3.72 (s, 3 H); 5.68 (br. s, 1 H); 6.35 (br. s, 1 H). 13C-NMR: 168.5 (s); 168.3 (s); 145.4
(s); 143.4 (d); 105.5 (d); 50.8 (q); 31.8 (t); 31.2 (t); 31.4 (t); 27.4 (t); 26.9 (t); 22.5 (t); 14.0 (q). MS: 208 (38,
Mþ), 179 (15), 177 (28), 151 (21), 134 (90), 119 (81), 105 (66), 93 (60), 91 (100), 79 (48), 77 (42), 65 (23),
43 (35), 41 (53).
Methyl 5-Pentylcyclopenta-1,4-diene-1-acetate (III). A soln. of crude 4 [1f][1g] (2260 mg, 10 mmol)
in THF (50 ml) was treated at 208 with 10% aq. HCl soln. (50 ml). After 10 min, the org. phase was
washed to neutral with brine, dried (Na2SO4), and concentrated: II/III 2 :1 (quant.). Purification by CC
(SiO2, cyclohexane/AcOEt 98 :2 ! 9 :1) afforded pure II (43%) and pure III (16%). III: IR: 2953, 2930,
2858, 1736, 1436, 1331, 1200, 1167, 1045, 730, 665. 1H-NMR: 0.89 (t, J ¼ 7, 3 H); 1.25 – 1.35 (m, 4 H); 1.46 –
1.51 (m, 2 H); 2.29 (t, J ¼ 7.4, 2 H); 3.04 (br. s, 2 H); 3.36 (s, 2 H); 3.67 (s, 3 H); 6.31 (dt, J ¼ 1.6, 5.5, 1 H);
6.39 (dt, J ¼ 1.6, 5.5, 1 H). 13C-NMR: 172.2 (s); 143.1 (s); 134.9 (d); 131.6 (d); 131.1 (s); 51.8 (q); 44.3 (t);
33.7 (t); 31.7 (t); 28.9 (t); 27.3 (t); 22.6 (t); 14.0 (q). MS: 208 (28, Mþ), 152 (43), 149 (12), 134 (24), 119
(19), 105 (35), 91 (100), 79 (29), 77 (21), 28 (24).
Methyl (1RS,2SR)-1-Hydroxy-3-oxo-2-pentylcyclopentaneacetate (IV). Isolated in < 5% yield
during the purification of 1/9b by CC (SiO2, cyclohexane/AcOEt 97:3 ! 8 :2). IR: 3505, 2954, 2929,
2859, 1731, 1438, 1405, 1379, 1345, 1268, 1195, 1174, 1093, 1036, 987, 632. 1H-NMR: 0.89 (t, J ¼ 7.1, 3 H ) ;
1.39 – 1.25 (m, 5 H); 1.48 – 1.41 (m, 1 H); 1.60 – 1.54 (m, 1 H); 1.7 – 1.62 (m, 1 H); 1.9 – 1.83 (m, 2 H); 2.23
(ddd, J ¼ 1.8, 9, 13, 1 H); 2.29 (ddt, J ¼ 1.5, 9, 19, 1 H); 2.44 (ddd, J ¼ 9, 11, 19, 1 H); 2.56 (d, J ¼ 16, 1 H);
2.89 (d, J ¼ 16, 1 H); 3.38 (d, J ¼ 1.5, 1 OH); 3.76 (s, 3 H). 13C-NMR: 217.4 (s); 172.9 (s); 76.8 (s); 58.6 (d);
52.0 (q); 42.8 (t); 34.6 (t); 34.0 (t); 32.1 (t); 28.4 (t); 23.5 (t); 22.5 (t); 14.1 (q). MS: 242 (12, Mþ), 224 (9),
210 (9), 169 (22), 167 (17), 154 (29), 153 (48), 151 (13), 140 (16), 129 (21), 111 (70), 99 (100), 97 (22), 83
(16), 69 (15), 55 (44), 43 (22).
Methyl (1S,2R,3S)-3-Hydroxy-2-pentylcyclopentaneacetate ((1S,2R,3S)-Va). A soln. of (3S)-11a
(100 mg, 0.44 mmol) in AcOEt (4 ml) was hydrogenated over PtO2 (2.5 mg) for 18 h. The mixture was
concentrated and the residue purified by CC (SiO2, cyclohexane/AcOEt 98 :2 ! 8 :2): (1S,2R,3S)-Va
(44%), then a 7:3 trans/cis mixture (þ)-((1S,2S)/(ꢀ)-(1S,2R)-Paradisoneꢀ (31%), and then the more
polar (1R,2R,3S)-Vb (20%). For analyses, see [2g], for optical purities, see Footnote 12. (1S,2R,3S)-Va :
Rf (cyclohexane/AcOEt 8 :2) 0.44. GLC (DB-1, 15 m, 250 mm, 0.25 mm, 1008, 1 min; 158/min ! 2208): tR
6.72 min. [a]2D0 ¼ ꢀ28.0 (c ¼ 0.34, CHCl3).
Methyl (1R,2R,3S)-3-Hydroxy-2-pentylcyclopentaneacetate ((1R,2R,3S)-Vb). See procedure for
((1S,2R,3S)-Va). Rf (cyclohexane/AcOEt 8 :2) 0.37. GLC (DB-1, 15 m, 250 mm, 0.25 mm, 1008, 1 min;
158/min ! 2208): tR 6.52 min. [a]2D0 ¼ þ57.8 (c ¼ 0.5, CHCl3). IR: 3659, 2962, 2934, 2871, 1757, 1441, 1169.
1H-NMR: 0.89 (t, J ¼ 7, 3 H); 1.25 – 1.45 (m, 6 H); 1.59 (br. s, 1 OH); 1.61 – 1.67 (m, 2 H); 1.83 – 1.91 (m,
2 H); 2.05 – 2.20 (m, 3 H); 2.32 (dd, J ¼ 16, 9, 1 H); 2.48 – 2.55 (m, 2 H); 3.67 (s, 3 H); 4.23 (br. t, J ¼ 4.3,
1 H). 13C-NMR: 173.7 (s); 74.0 (d); 51.4 (q); 51.1 (d); 39.3 (t); 38.8 (d); 33.5 (t); 32.3 (t); 29.2 (t); 28.0 (t);
27.4 (t); 22.6 (t); 14.1 (q). MS: 228 (1, Mþ), 210 (12), 196 (10), 185 (13), 169 (18), 153 (82), 136 (59), 110
(20), 97 (20), 95 (38), 83 (38), 81 (44), 74 (100), 67 (37), 55 (36), 43 (23), 41 (26).
Methyl (1R,2R,3R)-3-Hydroxy-2-pentylcyclopentaneacetate ((1R,2R,3R)-Vc). (ꢀ)-(1R,2R) Paradi-
soneꢀ (98% trans, 60% ee; 6.0 g, 26.5 mmol) was added at 08 to a mechanically stirred soln. of NaBH4
(840 mg, 22 mmol) in MeOH (50 ml). The cooling bath was removed, and stirring was continued for
15 min at 208. A soln. of conc. H2SO4 soln. (2.58 ml) in H2O (22.5 ml) was then added at 08. After
concentration (608/240 mbar), the product was extracted with Et2O and the org. phase washed with H2O,
sat. aq. NaHCO3, soln., and brine, dried (Na2SO4), and concentrated: (1R,2R,3R)-Vc/(1R,2R,3S)-Vb
60 :40 (quant.). Separation by CC (SiO2, cyclohexane/AcOEt 9 :1) afforded pure (1R,2R,3R)-Vc (6%)
as more polar stereoisomer. Rf (cyclohexane/AcOEt 8 :2) 0.30. GLC (DB-1, 15 m, 250 mm, 0.25 mm,
1008, 1 min; 158/min ! 2208): tR 6.35 min. [a]D20 ¼ þ14.8 (c ¼ 0.04, CHCl3). IR: 3417, 2953, 2925, 2857,
1737, 1457, 1436, 1376, 1333, 1255, 1199, 1170, 1146, 1094, 1071, 998, 879, 842, 724. 1H-NMR: 0.89 (t, J ¼ 7,
3 H); 1.26 – 1.52 (m, 6 H); 1.59 – 1.68 (m, 2 H); 1.76 – 1.92 (m. 4 H); 2.04 – 2.18 (m, 2 H); 2.32 (dd, J ¼ 9.1,
15.3, 1 H); 2.47 – 2.51 (m, 1 H); 2.53 (dd, J ¼ 4.9, 15.3, 1 H); 3.67 (s, 3 H); 3.92 (dt, J ¼ 4.0, 5.6, 1 H).
13C-NMR: 173.8 (s); 53.8 (d); 51.4 (q); 40.9 (d); 39.9 (t); 34.2 (t); 33.4 (t); 32.2 (t); 29.5 (t); 27.5 (t); 22.6
(t); 14.1 (q). MS: 228 (0, Mþ), 210 (8), 185 (27), 178 (12), 154 (21), 150 (30), 136 (100), 126 (13), 121
(11), 110 (38), 107 (15), 98 (25), 95 (32), 83 (48), 81 (50), 74 (79), 69 (30), 67 (40), 55 (43), 43 (23), 41
(36).

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Dimethyl (3RS,3’RS)-3,3’-Oxybis[2-pentylcyclopent-1-ene-1-acetate] (VIb) and Its meso-
(3RS,3’SR)-Stereoisomer VIa. After treatment of racemic-11a under the conditions described for
(1R,2S,3S)-12a, the mixture VIa/VIb 1:1 was separated by CC (SiO2, cyclohexane/AcOEt 9 :1): less
polar (35%) and more polar stereoisomer (30%), obviously formed before addition of H2. Less polar
stereoisomer: IR: 2952, 2926, 2853, 1738, 1434, 1314, 1262, 1193, 1167, 1142, 1081, 1046, 842, 727.
1H-NMR: 0.89 (t, J ¼ 7, 6 H); 1.20 – 137 (m, 10 H); 1.42 – 1.52 (m, 2 H); 1.70 – 1.80 (m, 2 H); 2.07 – 2.18
(m, 6 H); 2.28 – 2.37 (m, 2 H); 2.42 – 2.50 (m, 2 H); 3.02 (d, J ¼ 15.2, 2 H); 3.20 (d, J ¼ 15.2, 2 H); 3.67 (s,
6 H); 4.47 – 4.51 (m, 2 H). 13C-NMR: 171.6 (2s); 140.7 (2s); 132.2 (2s); 84.2 (2d); 51.7 (2q); 34.6 (2t); 33.6
(2t); 31.9 (2t); 29.7 (2t); 27.8 (2t); 25.8 (2t); 22.6 (2t); 14.1 (2q). MS: 450 (0, Mþ), 356 (1), 225 (51), 209
(71), 177 (19), 165 (9), 152 (65), 149 (48), 135 (44), 119 (28), 107 (22), 105 (43), 93 (78), 91 (100), 79
(57), 77 (30), 41 (12). More polar stereoisomer: IR: 2953, 2927, 2853, 1739, 1455, 1434, 1317, 1261, 1193,
1167, 1142, 1081, 1046, 842, 727. 1H-NMR: 0.89 (t, J ¼ 7, 6 H); 1.20 – 137 (m, 10 H); 1.42 – 1.52 (m, 2 H);
1.73 – 1.82 (m, 2 H); 2.07 – 2.22 (m, 6 H); 2.27 – 2.35 (m, 2 H); 2.39 – 2.47 (m, 2 H); 3.03 (d, J ¼ 15.2, 2 H);
3.19 (d, J ¼ 15.2, 2 H); 3.66 (s, 6 H); 4.48 – 4.53 (m, 2 H). 13C-NMR: 171.6 (2s); 141.1 (2s); 131.6 (2s); 86.9
(2d); 51.7 (2q); 34.6 (2t); 33.7 (2t); 32.0 (2t); 31.0 (2t); 27.9 (2t); 26.0 (2t); 22.7 (2t); 14.1 (2q). MS: 450 (0,
Mþ), 356 (1), 225 (39), 209 (96), 177 (24), 165 (8), 152 (68), 149 (53), 135 (51), 119 (27), 107 (25), 105
(44), 93 (82), 91 (100), 79 (61), 77 (28), 41 (12).
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