Pheromone synthesis. Part 264: Synthesis of the core 3-oxabicyclo[3.3.0]octane structures of gomadalactones A, B and C, the components of the contact sex pheromone of the white-spotted longicorn beetle, Anoplophora malasiaca

Article abstract of DOI:10.1016/j.tet.2019.04.055

The core bicyclic cyclopentanelactone structures of gomadalactones A, B and C with α-hydroxyketone system were synthesized from (R)-pulegone, employing deconjugation of an α,β-unsaturated lactone as the key step. Comparison of the CD spectra of the synthetic compounds with those of the natural products confirmed the absolute configuration of the natural pheromone components as proposed in 2007. X-ray crystallographic analysis of the model compound of gomadalactone B core structure was carried out.

Full text of DOI:10.1016/j.tet.2019.04.055

Accepted Manuscript
Pheromone synthesis. Part 264: Synthesis of the core 3-oxabicyclo[3.3.0]octane
structures of gomadalactones A, B and C, the components of the contact sex
pheromone of the white-spotted longicorn beetle, Anoplophora malasiaca
Kenji Mori
PII:
S0040-4020(19)30467-3
https://doi.org/10.1016/j.tet.2019.04.055
TET 30300
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 March 2019
Revised Date: 19 April 2019
Accepted Date: 23 April 2019
Please cite this article as: Mori K, Pheromone synthesis. Part 264: Synthesis of the core 3-
oxabicyclo[3.3.0]octane structures of gomadalactones A, B and C, the components of the contact sex
pheromone of the white-spotted longicorn beetle, Anoplophora malasiaca, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.04.055.
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Pheromone synthesis. Part 264: Synthesis of the core 3-oxabicyclo[3.3.0]octane
structures of gomadalactones A, B and C, the components of the contact sex pheromone
of the white-spotted longicorn beetle, Anoplophora malasiaca☆
Kenji Mori
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, 4-2-1 Wakahagi,
Inzai-shi, Chiba, 270-1609, Japan
ARTICLE INFO
Article history:
Received
2019
Received in revised form
2019
Keywords:
Anoplophora malasiaca
CD analysis
Deconjugation
Pheromone
X-ray analysis
ABSTRACT
The core bicyclic cyclopentanelactone structures of gomadalactones A, B and C with
α-hydroxyketone system were synthesized from (R)-pulegone, employing
deconjugation of an α, β-unsaturated lactone as the key step. Comparison of the CD
spectra of the synthetic compounds with those of the natural products confirmed the
absolute configuration of the natural pheromone components as proposed in 2007.
X-ray crystallographic analysis of the model compound of gomadalactone B core
structure was carried out.
ꢀ For Part 263. see Ref.1
E-mail address: kjk-mori@arion.ocn.ne.jp
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1. Introduction
The white-spotted longicorn beetle, Anoplophora malasiaca (Thomson)
(Coleoptera: Cerambycidae), is a serious pest of citrus, apple, pear and willow. Its
female contact pheromone components were extensively studied by Yasui and
co-workers, and found to be a mixture of eight hydrocarbons, five ketones and three
lactones.2,3 Although the structures of the hydrocarbons and the ketones are all trivial,
the lactones possess non-trivial and unique structures. They were given the names
gomadalactone A (1, Figure 1), B (2) and C (3).2 The uniqueness of their structures is
represented by the presence of an angular hydroxy group at C-5.
Figure 1. Structures of gomadalactones A (1), B (2) and C (3), and the synthesis of the
model compounds 6 and 7. The numbering system depicted in 1 is those employed in
refs.2,4
I became interested in synthesizing 1, 2, and 3, so as to establish their structures
including absolute configuration. In 2007, as the first step to the goal, synthesis and
CD measurements of two model compounds (1R,5R)-6 and (1S,5R,8S)-7 were reported
as a short communication.4 CD spectra of 1, 2 and 3 were compared with those of 6
and 7. Since 65 and 7 were synthesized from (R)-carvone (4) via (1R,5R)-carvenolide
(5), their absolute configurations were as depicted. It was therefore concluded that
gomadalactones A (1), B (2) and C (3) must possess the absolute configuration as shown
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in Figure 1.
Since the discovery of gomadalactones in 2007, there is reported only one
successful synthesis of the (1R,4R,5R,8R)-isomer (14, Scheme 1) of gomadalactone C in
a patent claimed in 2017 by Suzuki et al.6 Their synthesis is summarized in Scheme 1.
(+)-Tartaric acid (8) was converted to diene 9, which afforded 10 after ring-closing
olefin metathesis.
Scheme 1.
Suzuki’s 26-step-synthesis of the (1R,4R,5R,8R)-isomer (14) of
gomadalactone C (3).
Deprotection of the acetonide group of 10 gave 11, whose IBX oxidation resulted in
transannular cyclization to give a mixture of 12 and 13. Further conversion of 13 over
eleven steps gave (1R,4R,5R,8R)-isomer (14) of gomadalactone C. Although only 4.4
mg of 14 was obtained without describing the [α]D value, 14 was shown to be
pheromonally active against Anoplophora malasiaca. Two additional analogues of
gomadalactone C were also pheromonally active, indicating that the ligand specificity of
the pheromone receptor of A. malasiaca does not seem to be extremely selective.
Suzuki’s synthesis, however, is too lengthy to be practical. I therefore decided to
explore possibilities for more concise synthesis of the pheromone components 1–3.
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2. Results and discussion
2.1. Selection of target model compounds, and initial attempts to take advantage of the
late-stage oxidation of monoterpene intermediates
Since the peculiar structural feature of gomadalactones A, B and C lies in the
highly functionalized bicyclic lactones part, three bicyclic lactones 7, 15 and 16 were
selected as the target model compounds (Figure 2).
Figure 2. Structures of the target model compounds 7, 15 and 16 and their relatives 6
and 17.
The first attempt was to explore C–H functionalization7 of (1R,5R)-64 or (R)-178.
Unfortunately, however, neither functionalization of C-5 of 6 nor that at C-6 of 17 was
unsuccessful employing SeO2, NBS or Pb(OAc)4 as an oxidant. Accordingly, various
additional attempts were made to introduce a hydroxy group at the angular position of
bicyclic lactones as detailed in 2.2–2.5.
2.2. Cyclopentane ring formation by tandem conjugate addition/cyclization
Intramolecular ring closure is one of the classic ways to construct a ring system.
Cyclization of 18 to give 19 seemed plausible by means of Me2CuLi (Scheme 2).
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Scheme 2. Cyclopentane ring formation by tandem conjugate addition/cyclization.
Reagents: (a) MCPBA, CH2Cl2 (86%); (b) HClO4, THF, H2O (quant.); (c) (COCl)2,
DMSO, CH2Cl2; then Et3N (43%); (d) Me2CuLi, Et2O (27%).
The precursor 18 was readily available from the known ester 20.9,10 through epoxidation
to give 21, followed by its hydrolysis to yield diol 22, and final Swern oxidation of 22
to furnish 18. Treatment of 18 with Me2CuLi in Et2O was followed by
chromatographic purification to give (±)-19 in a modest yield of 27%. In the IR
spectrum of 19, the ester C=O group showed an absorption at 1705 cm−1, clearly
indicating the presence of a hydrogen bonding between the ester C=O group and the OH
group at C-2. This implied that the lactone formation might not be induced between
–C(Me)2OH and –CO2Et. The above consideration together with the observed low
yield of cyclization (27%) made me to explore other possibilities.
2.3. Attempted synthesis of diketoheptenolide (24) via
2,2-dimethyl-3-PMBoxy-cycloheptanone (23)
Suzuki et al. cleverly employed transannular cyclization (11→12, Scheme 1) to
construct the bicyclic system.6 In analogy with Suzuki’s synthesis, intramolecular
conjugate addition/cyclization of 24 (Scheme 3) to give 15 might solve the problem.
The diketolactone 24 would be prepared from 23. Synthesis of 23 was therefore
executed as shown in Scheme 3.
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Scheme 3. Synthesis of 2,2-dimethyl-3-PMBoxycycloheptanone (23). Reagents: (a)
azadol, NaOCl·5H2O, (n-Bu)4NHSO4, CH2Cl2, H2O (80%); (b) CH2=CHCH2MgCl,
THF (73% for 27, 91% for 31); (c) p-MeOC6H4CH(OMe)2, CSA, DMF (34%); (d)
(i-Bu)2AlH, CH2Cl2 (quant.); (e) azadol, PhI(OAc)2, CH2Cl2 (75%); (f) Grubbs II,
CH2Cl2 (92%); (g) Jones CrO3, acetone (81%); (h) H2, Pd-BaSO4 (84%).
The known starting material 2511 was oxidized with NaOCl·5H2O12 in the presence
of azadol13 to give aldehyde 26. Treatment of 26 with allylmagnesium bromide
furnished 27. p-Methoxybenzaldehyde dimethylacetal and camphorsulfonic acid
(CSA) in DMF converted 27 to 28, which was reduced with diisobutylaluminum
hydride to give 29. Oxidation of 29 with (diacetoxy)iodobenzene (DAIB) in the
presence of azadol afforded 30, to which was added allylmagnesium chloride yielding
31. Ring-closing metathesis of 31 with second-generation Grubbs catalyst14 gave 32.
Chromic acid oxidation of 32 was followed by hydrogenation to give 23 via 33.
Although the above synthetic route was straightforward, it was rather lengthy and
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inefficient. The attempt to convert 23 to 24 was therefore abandoned at this stage.
2.4. Synthesis of ketone 34 and lactone 35 and attempted Michael addition of
crotonaldehyde to them
The next plan was to synthesize ketone 34 and lactone 35 to explore the possibility
of Michael addition of them to crotonaldehyde (Scheme 4). If this plan were
successful, the products 36 and 37 would give bicycles 38 and 39 after reductive C–C
bond formation with low-valent titanium15 or SmI2.16
Scheme 4. Synthesis of ketone 34 and tetronic acid 35. Reagents: (a) NaH, HCO2Et,
Et2O (67%); (b) MgSO4, CuSO4 (58%); (c) H2, Pd-C, AcOMe (77%); (d) Jones CrO3,
acetone (39%).
According to Margaretha, 3-hydroxy-3-methyl-2-butanone (40) was formylated to
give 41.17 Treatment of 41 with anhydrous CuSO4 and MgSO4 furnished 42. This
was hydrogenated over Pd-C to give 34. Chromic acid oxidation of 41 smoothly
afforded crystalline 5,5-dimethyltetronic acid (35).18,19 It must be added that the
present procedure is a concise and new method for the preparation of 35. Judging
from its 1H and 13C NMR spectra in DMSO-d6, 35 adopts entirely enolic form 35’.
Michael addition between crotonaldehyde or acrolein and 34 or 35 was attempted
under various different conditions. Unfortunately, all the attempts were in vain, and I
was forced to examine another plan.
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2.5. Synthesis and alkylation of lactone 43
It was expected that alkylation of lactone 43 with 1-iodo-3-butene would give 44
by concomitant deconjugation of the α,β-unsaturated lactone system of 43, if the
equilibration to give back the original α,β-unsaturated lactone system does not take
place so quickly. The product 44 would then give the bicyclic lactone system 45 after
ring-closing olefin metathesis (Scheme 5).
Scheme 5. Synthesis and alkylation of lactone 43. Reagents: (a) MeC(OEt)3,
EtCO2H, heat; (b) KOH, MeOH, H2O (70%, 2 steps); (c) I2, KI, NaHCO3, H2O (97%);
(d) DBU, C6H6 (70%); (e) KOH, H2O (quant.); (f) P2O5, H3PO4 (48%); (9) LDA,
CH2=CHCH2CH2I, THF (44%).
Preparation of the key lactone 43 was executed by the method published by Jäger
and co-workers.20,21 Some modifications were made to secure 43 in a multi-gram scale.
Johnson-Claisen rearrangement of 46 with ethyl orthoacetate gave 47, which was
hydrolyzed to furnish 48. Iodolactonization of 48 afforded 49, which was treated with
1,8-diazabicyclo[5.4.0]-7-undecene (DBU) to give 50. Alkaline hydrolysis of 50
yielded 51. Finally 51 was heated with polyphosphoric aid (PPA) to give 43 as a low
melting solid.
Treatment of 43 with lithium diisopropylamide (LDA) in THF at −75oC was
followed by alkylation with 1-iodo-3-butene at −75oC for 1 h and at room temperature
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for 1 h. After quenching with NH4Cl solution, the product was purified by SiO2
chromatography. The distilled product (44% yield) turned out to be 52, not the desired
44. It was thus shown that 44, even when it was generated, rapidly isomerized to the
more stable α,β-conjugated lactone 52. The present route was therefore abandoned.
At this stage it occurred to me that a compound similar to 45 might be obtained by
deconjugation/protonation of (R)-17 as shown in the next section.
2.6. Synthesis of the target model compounds 7, 15 and 16 employing
deconjugation/protonation of 17 as the key-step
In order to explore the feasibility of the deconjugation/protonation of (R)-17, it was
necessary to provide multi-gram quantities of (R)-17, a known lactone.8,22 As reported
by Wolinsky,22,23 commercially available (R)-pulegone (54) was first treated with Br2 to
give 55 (Scheme 6). Sodium ethoxide in ethanol induced the Favorskii rearrangement
of 55 to give a mixture of ethyl cis- and trans-pulegenate (56). Alkaline hydrolysis of
56 was followed by distillation of the resulting acid to give (1S,5R)-pulegenic acid (57).
This was subjected to the conventional iodolactonization conditions. The product was
purified by SiO2 chromatography and recrystallization to give pure iodolactone (58).
Finally, treatment of 58 with DBU in benzene afforded (R)-17. A sufficient amount
(5.72 g) of (R)-17 could be secured.
Scheme 6. Synthesis of pulegonolide (17). Reagents: (a) Br2, AcOH; (b) NaOEt,
EtOH (72%, 2 steps); (c) KOH, EtOH, H2O (57%); (d) NaHCO3, I2, NaI (52%); (e)
DBU, C6H6 (78%).
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Deconjugation of (R)-17 was examined employing either LDA or KH as the base.
Since the presence of mineral oil in commercially available KH was problematic in the
later purification of the product, LDA was selected as the base of choice. Acetic acid
in Et2O at −78oC was chosen as the protonation agent. Deconjugation/protonation of
(R)-17 with LDA/AcOH furnished a mixture of 53a and 53b as a solid. Protonation of
the enolate with AcOH/Et2O at −78oC was considerably stereoselective, and a mixture
of the major and minor isomers (4:1–10:1) was obtained. Since this protonation
proceeded under kinetic control, the structure of the major isomer was thought to be 53a,
which was verified by the observation of NOE between 1-H and 8-H as depicted in
Scheme 7.
Scheme 7. Synthesis of the model compounds 7, 15 and 16. Reagents: (a) i) LDA,
THF; ii) AcOH, Et2O (76%); (b) i) BH3·THF, THF; ii) Jones CrO3, acetone (8%); (c)
OsO4, NMO, acetone, t-BuOH, H2O (98%); (d) (n-Pr)4NRuO4, NMO, CH2Cl2, MS 4A
(7%); (e) i) KN(TMS)2, PhSeBr, toluene, THF; ii) NaIO4, THF, H2O (7%).
Hydroboration of the deconjugated lactone 53a + 53b was followed by chromic
acid oxidation to give keto lactone (1R,5S,8R)-7, whose (1S,5R,8S)-isomer had been
reported by myself in 2007.4 In the present case, only (1R,5S,8R)-7 could be isolated
as crystals in 8% yield (two steps) after chromatographic purification and
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recrystallization, whereas (1S,5R,8R)-7 was not observed. The physical properties of
(1R,5S,8R)-7 (mp, IR, 1H and 13C NMR spectra) as well as its magnitude of the specific
rotation {[α]D22 −309.4 (c 0.216, Et2O); cf. its opposite enantiomer: [α]D25 +319 (c
1.014, Et2O)} were in good accord with the reported values of (1S,5R,8S)-7.4
Introduction of a hydroxy group at the angular C-5 position could be readily
achieved by OsO4-catalyzed dihydroxylation24 of 53a + 53b, and the two isomers were
converted almost quantitatively to a mixture of two diastereomeric dihydroxylactones
(1R,5S,6R,8R)- 39 and (1S,5R,6S,8R)-39, respectively. Unfortunately, complete
separation of these two crystalline diastereomers was difficult even after
chromatography and recrystallization.
Oxidation of diol 39 to the desired model compound 15 required some
experimentation. Routine oxidants such as Dess-Martin periodinane, azadol-DAIB,
Swern oxidation and chromic acid oxidation did not give even a trace of 15. In 2013
Lei and co-workers reported that Ley oxidation25 employing tetrapropylammonium
perruthenate (TPAP) and 4-methylmorpholine N-oxide (NMO) in the presence or
absence of MS 4A in CH2Cl2 was effective in synthesizing α-hydroxy ketones from
vicinal diols related to Lycopodium alkaloids.26 To my pleasure Ley oxidation could
successfully be applied to the present case, giving (1R,5R,8R)-15 in reproducible yield
of 7–10%. The hydroxyketolactone (1R,5R,8R)-15 was crystalline, and showed a large
negative rotation, mp 153–155oC, [α]D16 −332.8 (c 0.035, Et2O). Because the two
diastereomers of 15 seemed to co-crystallize, it was difficult to obtain pure
(1R,5R,8R)-15 without contamination of a small amount of its diastereoisomer. The
structure (1R,5R,8R)-15 assigned to the isolated oxidation product was in accord with
its 1H and 13C NMR data (see 4.31), and this model compound possesses the
enantiomeric bicyclic nucleus part of gomadalactone C (3).
Finally, the third model compound (1R,5R)-16, which represents the nucleus portion
of gomadalactone B (2), was synthesized from (1R,5R,8R)-15 by organoselenium-based
desaturation at C6-C7.27 Treatment of 15 with excess potassium hexamethyldisilazide
[KN(TMS)2] in toluene/THF at −78oC gave the dianion of 15, to which was added
PhSeBr to give a phenylselenylated product at C-7. Oxidation of the selenylated
ketone with NaIO4 in THF/H2O furnished crude (1R,5R)-16 (14%) after
chromatographic purification. Recrystallization of crude 16 from EtOAc/pentane gave
pure (1R,5R)-16 (7%) as pale yellow prisms, mp 132.5–133.5oC, [α]D20 −248.7 (c
0.0215, EtOAc). All the spectral data of (1R,5R)-16 were in accord with the assigned
structure. The structure (1R,5R)-16 was conclusively established by its single crystal
X-ray analysis. Figure 3 shows the X-ray structure of (1R,5R)-16. Its
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(1R,5R)-absolute configuration is clearly seen from the structure. It must be added that
gomadalactone B (2) was isolated as an amorphous solid, and therefore its X-ray
crystallographic data are unavailable. Accordingly, the X-ray data of (1R,5R)-16 are
important to precisely examine its molecular shape, which will be required in future
study on the interaction between the pheromone and its receptor.
Figure 3. X-ray structure of (1R,5R)-16.
2.7. CD spectral analysis of the three model compounds (1R,5S,8R)-7, (1R,5R,8R)-15
and (1R,5R)-16
The absolute stereochemistries assigned to the three model compounds
(1R,5S,8R)-7, (1R,5R,8R)-15 and (1R,5R)-16 were supported by their CD spectra.
Figure 4 shows the CD spectra of 7, 15 and 16. The CD spectrum of the keto lactone
(1R,5S,8R)-7 was indeed the mirror image of that of its (1S,5R,8S)-isomer recorded in
ref.4 This fact supports the (1R,5S,8R)-stereochemistry of the keto lactone 7 reported
in the present paper. In the case of (1R,5R,8R)-15, its CD spectrum is almost the
mirror image of that of gomadalactone C (3). Finally, the CD spectrum of 16 was in
good accord with that of gomadalactone B (2).
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Figure 4. CD Spectra of (1R,5S,8R)-7, (1R,5R,8R)-15 and (1R,5R)-16. They were
measured in MeOH using a 10 mm cell at the concentrations of 6.6 x 10−5 M (7), 5.4 x
10−5 M (15) and 6.22 × 10−5 M (16), respectively, on a Jasco J-1500 CD spectrometer.
3. Conclusion
After several unsuccessful attempts, (R)-pulegone (54) was converted to the three
model compounds 7, 15 and 16 of the core 3-oxabicyclo[3.3.6]octane structures of
gomadalactones A (1), B (2) and C (3). Synthesis coupled with CD and X-ray analyses
allowed the assignments of absolute stereochemistries to all of the three model
compounds as (1R,5S,8R)-7, (1R,5R,8R)-15 and (1R,5R)-16. The present paper
conclusively establishes the absolute configuration of gomadalactones A (1), B (2) and
C (3), confirming my 2007 proposal.4
4. Experimental
4.1. General
All bps and mps are uncorrected values. Refractive indices were measured on an
Atago DMT-1 refractometer. IR spectra were measured on a Jasco FT/IR-410
spectrometer. 1H NMR spectra (400 MHz, TMS at δ = 0.00 as the internal standard)
and 13C NMR spectra (100 MHz, CDCl3 at δ = 77.0 as the internal standard) were
recorded on a Jeol JNM-ECZ 400S/L1 spectrometer. GC-MS were measured on
Agilent Technologies 5975 inert XL. HRMS were recorded on Jeol JMS-700V or
JMS-T100GV. Silica gel column chromatography was carried out on Merck Kieselgel
60 Art 1.00734.
4.2. (±)-Ethyl 6,7-epoxy-7-methyl-2-octenoate (21)
m-Chloroperbenzoic acid (70% purity, 4.90 g, 20 mmol) was added portionwise to
a stirred and ice-cooled solution of 20 (E/Z = 94:6; 3.36 g, 18.5 mmol) in CH2Cl2 (30
mL). After stirring for 2 h at 0–10oC, the mixture was diluted with hexane, and
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filtered. The filtrate was washed with Na2CO3 solution and brine, dried (MgSO4), and
concentrated in vacuo. The residue (3.95 g) was chromatographed over SiO2 (50 g).
Elution with hexane/EtOAc (20:1) gave 21 (3.53 g, 96%) as a colorless oil, νmax (film):
2980 (m), 2963 (m), 2929 (m), 1720 (s), 1655 (m), 1315 (m), 1267 (m), 1202 (m), 1163
(m), 1044 (m); δH (CDCl3): 1.27 (3H, s), 1.29 (3H, t, J = 7 Hz), 1.31 (3H, s), 1.68–1.74
(2H, m), 2.31–2.50 (2H, m), 2.73 (1H, t, J = 6 Hz), 4.19 (2H, q, J = 7 Hz), 5.87 (1H, dd,
J = 15, 14 Hz). HRMS calcd for [C11H18O3]+ (M+): 198.1250, found: 198.1248.
4.3. (±)-Ethyl 6,7-dihydroxy-7-methyl-2-octenoate (22)
Perchloric acid (70%, 0.14 mL) was added to a vigorously stirred solution of 21 in
THF (18 mL) and H2O (10 mL). The mixture was stirred for 50 min at room temp. It
was then neutralized with NaHCO3, and extracted with EtOAc. The extract was
washed with brine, dried (MgSO4), and concentrated in vacuo to give 22 (1.15 g, quant.)
as a colorless oil, νmax (film): 3427 (s), 2978 (s), 2904 (m), 1718 (s), 1653 (s), 1279 (s),
1200 (s), 1077 (s), 1044 (s), 979 (m), 928 (m); δH (CDCl3): 1.17 (3H, s), 1.22 (3H, s),
1.29 (3H, t, J = 7 Hz), 1.45–1.56 (1H, m), 1.56–1.66 (1H, m), 1.80–1.90 (1H, m), 1.93–
2.10 (1H, m), 2.24–2.36 (2H, m), 2.45–2.65 (2H, m), 3.35–3.42 (1H, m), 3.90–4.00 (1H,
m), 4.18 (2H, q, J = 7 Hz), 5.58–5.60 (0.4H, m), 5.87 (0.6H, d, J = 16 Hz), 6.90–7.03
(1H, m). HRMS calcd for [C11H22O3]+ [(M−H2O)+]: 198.1256, found: 198.1257.
4.4. (±)-Ethyl 7-Hydroxy-7-methyl-6-oxo-2-octenoate (18)
A solution of DMSO (0.66 mL, 4.2 mmol, 1.1 eq) in CH2Cl2 (6 mL) was added
dropwise to a stirred and cooled solution of (COCl)2 (0.42 mL, 4.8 mmol, 1.2 eq) in
CH2Cl2 (6 mL) at −78oC under argon. After 5 min, a solution of 22 (850 mg, 3.94
mmol) in CH2Cl2 (5 mL) was added to the stirred solution at −78oC. The stirring was
continued for 15 min at −78oC. Subsequently, Et3N (2.8 mL, 20 mmol, 5.0 eq) was
added in one portion, and the stirring was continued for 10 min at −78oC. The
temperature was gradually raised to room temperature. The mixture was diluted with
Et2O, and the Et2O solution was washed with NH4Cl solution and brine, dried (MgSO4),
and concentrated in vacuo. The residue (0.81 g) was chromatographed over SiO2 (25
g). Elution with hexane/EtOAc (25:1→15:1→10:1) gave various by-products.
Further elution with hexane/EtOAc (5:1) gave 18 (374 mg, 43%) as a colorless oil, νmax
(film): 3487 (m), 2980 (s), 1715 (s), 1655 (s), 1193 (s), 1045 (s); δH (CDCl3): 1.26 (3H,
t, J = 7 Hz), 1.39 (6H, s), 2.52 (2H, q, J = 7 Hz), 2.75 (2H, t, J = 7 Hz), 3.62 (1H, s),
4.18 (2H, q, J = 7 Hz), 5.85 (1H, dd, J = 1.5, 16 Hz), 6.89–6.96 (1H, m). GC-MS
[column: HP-5MS,5% phenylmethylsiloxane, 0.25 mm i.d. × 30 m; carrier gas He,
press 61 kPa; temp 70–230oC (+10oC/min)]: tR 12.97 min (96%); MS (70 eV, EI): m/z:
196 (<1) [(M−H2O)+], 171 (11), 151 (8), 128 (100), 100 (95), 82 (21), 68 (14), 59 (96),
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43 (44). HRMS calcd for [C11H16O3]+ [(M−H2O)+]: 196.1099, found: 196.1102.
4.5.
(±)-Ethyl
2-hydroxy-2-(1-hydroxy-1-methylethyl)-6-methyl-cyclopentane-1-carboxylate (19)
A solution of MeLi in Et2O (0.75 M, 1.2 mL, 9 mmol) was added to a stirred and
cooled suspension of CuI (950 mg, 5 mmol) in dry Et2O (10 mL) at −25oC under argon.
The mixture was stirred for 30 min at −5oC to generate Me2CuLi. Subsequently, a
solution of 18 (261 mg, 1.2 mmol) in dry Et2O (4 mL) was added dropwise to the
Me2CuLi solution at −50–−40oC. The mixture was stirred for 30 min at −50–−40oC,
then quenched by the addition of NH4Cl solution, and extracted with Et2O. The Et2O
solution was washed with brine, dried (MgSO4), and concentrated in vacuo. The
residue (232 mg) was chromatographed over SiO2 (5 g). Elution with hexane/EtOAc
(10:1) gave 19 (74 mg, 27%) as a colorless oil, νmax (film): 3460 (m), 2957 (s), 2929 (s),
2870 (m), 1705 (s), 1377 (s), 1185 (s), 1026 (m), 954 (m); δH (CDCl3): 1.05 (3H, d, J =
6 Hz), 1.22 (3H, s), 1.23 (3H, s), 1.29 (3H, t, J = 7 Hz), 1.65–1.75 (2H, m), 1.84–1.93
(1H, m), 2.05–2.14 (1H, m), 2.20 (1H, m), 2.46 (1H), 2.48–2.58 (1H, m), 4.19 (2H, q, J
= 7 Hz), 4.57 (1H); δC (CDCl3): 14.1, 19.1, 24.8, 25.1, 31.3, 34.9, 38.6, 55.1, 60.9, 74.5,
88.3, 177.0; GC-MS (same conditions as those used for 18): tR 11.7 min (76%) MS (70
eV, EI): m/z: 212 (2) [(M−H2O)+], 171 (57), 125 (100), 115 (13), 97 (14), 83 (15), 69
(24), 59 (11), 43 (12). HRMS calcd for [C12H20O3]+ [(M−H2O)+]: 212.1412, found:
212.1400.
4.6. 3-t-Butyldimethylsilyloxy-2,2-dimethylpropanol (25)
Azadol (80 mg, 0.52 mmol) and 25 (22.3 g, 102 mmol) were dissolved in CH2Cl2
(300 mL) containing H2O (3 mL). Crystals of NaOCl·5H2O (20.1 g, 122 mmol, 1.2
eq) was added in one portion to the stirred and ice-cooled CH2Cl2 solution of 25. The
color of the mixture turned red and then faded to faint yellow. The stirring was
continued for 30 min. Then the reaction was quenched by the addition of Na2S2O3 and
NaHCO3 (aqueous solution). The CH2Cl2 layer was separated and the aqueous layer
was extracted with Et2O. The combined organic solution was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was distilled to give 26 (17.7 g,
25
80%) as a colorless oil, bp 66–70oC/0.5 kPa: nD = 1.4260; νmax (film): 2957 (s), 2931
(s), 2887 (m), 2858 (s), 1733 (s), 1472 (m), 1257 (m), 1104 (s), 839 (s), 777 (m); δH
(CDCl3): 0.03 (6H, s), 0.86 (9H, s), 1.04 (6H, s), 3.58 (2H, s), 9.56 (1H, s); GC-MS
(same conditions as those used for 18): tR 8.38 min (93%); MS (70 eV, EI): m/z: 201
(<1) [(M−CH3)+], 159 (100), 129 (29), 115 (73), 89 (9), 75 (66), 59 (13). HRMS calcd
for [C10H21O2Si]+ [(M− CH3)+]: 201.1311, found: 201.1313.
4.7. (±)-2,2-Dimethyl-5-hexene-1,3-diol 1-TBS ether (27)
~ 15 ~

ACCEPTED MANUSCRIPT
A solution of 25 (8.76 g, 40.6 mmol) in THF (30 mL) was added dropwise to a
stirred and ice-cooled solution of CH2=CHCH2MgCl in THF (1
M, 50 mL, 50 mmol) at
10–20oC. The mixture was stirred for 30 min at room temperature. It was then
quenched by the addition of ice and NH4Cl solution, and extracted with Et2O. The
Et2O extract was washed with water and brine, dried (MgSO4), and concentrated in
vacuo. The residue (10.81 g) was chromatographed over SiO2 (80 g). Elution with
25
hexane/EtOAc (20:1) gave 27 (7.69 g, 73%) as a colorless oil, nD = 1.4450; νmax
(film): 3501 (br m), 3076 (w), 2956 (s), 2930 (s), 2886 (m), 2858 (s), 1640 (w), 1472
(m), 1254 (m), 1094 (s), 838 (s), 776 (s); δH (CDCl3): 0.06 (6H, s), 0.96 (15H, br s),
1.26 (1H, br s), 2.08–2.11 (1H, m), 2.24–2.25 (1H, m), 3.46 (2H, m), 3.56 (1H, m),
5.06–5.13 (2H, m), 5.90–5.97 (1H, m); GC-MS (same conditions as those used for 18):
tR 10.9 min (99%); MS (70 eV, EI): m/z: 217 (14), 159 (13), 145 (13), 109 (59), 105 (35),
89 (24), 75 (100), 73 (36), 67 (17), 41 (13). This was used for the next step without
further characterization.
4.8. (±)-2,2-Dimethyl-5-hexene-1,3-diol p-methoxybenzylidene acetal (28)
Camphorsulfonic acid (150 mg, 0.6 mmol) was added to a solution of 27 (7.09 g,
27.3 mmol) and p-methoxybenzaldehyde dimethylacetal (9.83 g, 54 mmol) in DMF (30
mL). The mixture was stirred for 4 h at room temperature, then poured into ice and
NaHCO3 solution, and extracted with Et2O. The Et2O extract was washed with
NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The residue
(13.92 g) was fractionally distilled to give first the recovered p-methoxybenzaldehyde
dimethylacetal (bp 100oC/0.2 kPa) and then 28 (2.96 g, 34%) as a colorless oil, bp 150–
24
158oC/0.2 kPa; nD = 1.5144; νmax (film): 3075 (w), 2956 (m), 2838 (m), 1642 (w),
1615 (m), 1589 (w), 1518 (s), 1467 (m), 1392 (s), 1358 (m), 1303 (m), 1250 (s), 1172
(m), 1114 (s), 1036 (s), 826 (s); δH (CDCl3): 0.80 (3H, s), 1.15 (3H, s), 2.24–2.27 (2H,
m), 3.52–3.60 (2H, m), 3.69 (1H, m), 3.80 (3H, s), 5.03–5.13 (2H, m), 5.44 (1H, s),
5.91–5.98 (1H, m), 6.89 (2H, d, J = 8 Hz), 7.43 (2H, d, J = 8 Hz); GC-MS (same
conditions as those used for 18): tR 16.43 min (91%); MS (70 eV, EI):m/z: 262 (26) [M+]
261 (31), 221 (12), 137 (60), 136 (100), 135 (96), 109 (18), 108 (12), 81 (15), 77 (15).
HRMS calcd for [C16H22O3]+ (M+): 262.1569, found: 262.1531.
4.9. (±)-2,2-Dimethyl-5-hexene-1,3-diol 3-PMB ether (29)
A solution of (i-Bu)2AlH in CH2Cl2 (1
M, 37 mL, 37 mmol) was added dropwise to
a stirred and ice-cooled solution of 28 (2.96 g, 11 mmol) in CH2Cl2 (10 mL) at 5–10oC
under argon. After stirring for 3 h at 5oC, the mixture was quenched with ice and dil.
HCl (containing 10 mL of conc HCl), and extracted with Et2O. The Et2O solution was
washed successively with NaHCO3 solution and brine, dried (MgSO4), and concentrated
~ 16 ~

ACCEPTED MANUSCRIPT
25
in vacuo to give 29 (2.97 g, quant.) as a colorless oil, nD = 1.5088; νmax (film): 3437
(br m), 3074 (w), 2598 (m), 2911 (m), 2873 (m), 2837 (m), 1639 (w), 1613 (m), 1586
(w), 1514 (s), 1466 (m), 1302 (m), 1249 (s), 1173 (m), 1078 (s), 1038 (s), 912 (m), 812
(m); δH (CDCl3): 0.88 (3H, s), 0.98 (3H, s), 2.29–2.50 (2H, m), 2.76 (1H, t, J = 6 Hz),
3.30–3.40 (2H, m), 3.55–3.62 (1H, m), 3.80 (3H, s), 4.41 (1H, d, J = 7 Hz), 4.61 (1H, d,
J = 7 Hz), 5.04–5.20 (2H, m), 5.90–6.20 (1H, m), 6.87 (2H, d, J = 8 Hz), 7.25 (2H, d, J
= 8 Hz); GC-MS (same conditions as those used for 18): tR 17.12 min (97%); MS (70
eV, EI): m/z: 264 (<1) [M+], 191 (10), 138 (2), 137 (5), 122 (12), 121 (100), 91 (3), 78
(5), 77 (5), 55 (2), 41 (2). HRMS calcd for [C16H24O3]+ (M+): 264.1725, found:
264.1715.
4.10. (±)-2,2-Dimethyl-3-p-methoxybenzyloxy-5-hexenal (30)
Diacetoxyiodobenzene (3.50 g, 11 mmol) was added quickly to a solution of 29
(2.70 g, 10 mmol) and azadol (20 mg, 0.13 mmol) in CH2Cl2 (70 mL) with stirring and
ice-cooling. The mixture was stirred for 10 min at 5–10oC, when it became
homogeneous.
It was then diluted with Et2O, washed successively with
Na2S2O3/NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The
residue (6.6 g) was chromatographed over SiO2 (50 g). Elution with hexane gave
iodobenzene (1.58 g), and further elution with hexane/EtOAc (50:1–10:1) gave 30
26
(2.00 g, 75%) as a colorless oil, nD = 1.5074; νmax (film): 3075 (w), 2960 (m), 2936
(m), 2909 (m), 2871 (m), 2873 (m), 2709 (w), 1726 (s), 1640 (w), 1613 (m), 1586 (w),
1514 (s), 1466 (m), 1302 (m), 1249 (s), 1173 (m), 1083 (s), 1037 (s), 916 (m), 822 (m);
δH (CDCl3): 1.05 (3H, s), 1.11 (3H, s), 1.30–2.40 (2H, m), 3.58 (1H, t, J = 5 Hz), 3.80
(3H, s), 4.40 (1H, d, J = 7 Hz), 4.58 (1H, d, J = 7 Hz), 5.08–5.20 (2H, m), 5.82–5.98
(1H, m), 6.86 (2H, d, J = 9 Hz), 7.21 (2H, d, J = 9 Hz), 9.55 (1H, s): GC-MS (same
conditions as those used for 18): tR 16.40 min (95%); MS (70 eV, EI): m/z: 262 (<1)
[M+], 150 (5), 137 (9), 122 (11), 121 (100), 91 (3), 78 (5), 77 (6), 41 (3). HRMS calcd
for [C16H22O3]+ (M+): 262.1569, found: 262.1561.
4.11. 5,5-Dimethyl-6-p-methoxybenzyloxy-1,8-nonadien-4-ol (31)
A solution of 30 (2.00 g, 7.5 mmol) in THF (5 mL) was added to a stirred and
ice-cooled solution of CH2=CHCH2MgCl in THF (1
M, 15 mL, 15 mmol) under argon.
The mixture was stirred and heated for 1 h at 40oC. After cooling, it was poured into
ice and NH4Cl solution, and extracted with Et2O. The Et2O solution was successively
washed with water and brine, dried (MgSO4), and concentrated in vacuo. The residue
(2.56 g) was chromatographed over SiO2 (20 g). Elution with hexane/EtOAc (20:1)
26
gave 31 (2.10 g, 91%) as a colorless oil, nD = 1.5132; νmax (film): 3481 (br m), 3074
(w), 2973 (m), 2912 (m), 2876 (m), 1639 (m), 1613 (m), 1586 (w), 1514 (s), 1249 (s),
~ 17 ~

ACCEPTED MANUSCRIPT
1065 (s), 1037 (s), 912 (m), 822 (m); δH (CDCl3): 0.84 (1.7H, s), 0.86 (1.3H, s), 0.97
(1.7H, s), 1.00 (1.3H, s), 1.69 (0.4H, s), 2.00–2.60 (4H, m), 2.78 (0.6H, s), 3.30–3.48
(1H, m), 3.54–3.72 (1H, m), 3.79 (3H, s), 4.38–4.48 (1H, m), 4.60–4.68 (1H, m), 5.02–
5.20 (4H, m), 5.80–6.04 (2H, m), 6.80–6.90 (2H, m), 7.20–7.30 (2H, m); GC-MS (same
conditions as those used for 18): tR 19.03 min (100%); MS (70 eV, EI): m/z: 191 (3),
138 (6), 137 (8), 122 (12), 121 (100), 109 (3), 78 (3), 77 (3), 43 (3), 41 (3). HRMS
calcd for [C19H28O3]+ (M+): 304.2038, found: 304.2033.
4.12. 2,2-Dimethyl-5-cycloheptene-1,3-diol 1-p-methoxybenzyl ether (32)
Grubbs II catalyst (42 mg, 0.005 mmol, 0.7 mol%) was added to a solution of 31
(2.08 g, 6.8 mmol) in CH2Cl2 (50 mL). The solution was stirred and heated under
reflux for 1 h under argon. (Evolution of H2C=CH2 ceased after 30 min.) The mixture
was concentrated in vacuo, and the residue was chromatographed over SiO2 (20 g).
27
Elution with hexane/EtOAc (20:1–10:1) gave 32 (1.74 g, 92%) as a colorless oil, nD
=
1.5178; νmax (film): 3451 (br m), 3022 (w), 2956 (m), 2933 (m), 2910 (m), 2870 (m),
2837 (m), 1655 (w), 1613 (m), 1586 (w), 1514 (s), 1465 (m), 1302 (m), 1249 (s), 1173
(m), 1072 (s), 1037 (s), 822 (m); δH (CDCl3): 0.97 (2H, s), 1.049 (1H, s), 1.056 (1H, s),
1.23 (2H, s), 1.56 (0.35H, br s), 1.69 (0.65H, br s), 2.25–2.58 (4H, m), 3.26–3.32 (1H,
m), 3.58 (1H, d, J = 7 Hz), 3.80 (3H, s), 4.24–4.34 (1H, m), 4.52–4.58 (1H, m), 5.60–
5.80 (2H, m), 6.84–6.90 (2H, m), 7.22–7.28 (2H, m); GC-MS (same conditions as those
used for 18): tR 19.38 min (100%); MS (70 eV, EI): m/z: 258 (1.5) [(M−H2O)+], 137 (4),
122 (11), 121 (100), 91 (2), 78 (3), 77 (4), 55 (2), 43 (2), 41 (1). HRMS calcd for
[C17H24O3]+ (M+): 276.1725, found: 276.1414.
4.13. (±)-2,2-Dimethyl-3-p-methoxybenyloxy-5-cyclohepten-1-one (33)
Jones chromic acid (8
M in oxygen, 2 mL, 16 meq) was added to a stirred and
ice-cooled solution of 32 (1.58 g, 5.7 mmol) in acetone (20 mL) at 5–10oC. The
mixture was stirred for 10 min, then concentrated in vacuo, and partitioned between
Et2O and water. The Et2O solution was washed successively with water, NaHCO3
solution and brine, dried (MgSO4), and concentrated in vacuo to give 33 (1.27 g, 81%)
26
as a colorless oil, nD = 1.5156; νmax (film): 2969 (m), 2934 (m), 2907 (m), 2870 (m),
2836 (m), 1703 (s), 1655 (w), 1613 (m), 1586 (w), 1514 (s), 1465 (m), 1302 (m), 1249
(s), 1173 (m), 1090 (m), 1036 (m), 822 (m); δH (CDCl3): 1.13 (3H, s), 1.21 (3H, s),
2.40–2.62 (2H, m), 3.12–3.26 (1H, m), 3.36–3.50 (1H, m), 3.68 (1H, m), 3.81 (3H, s),
4.38 (1H, d, J = 7 Hz), 4.61 (1H, d, J = 7 Hz), 5.59 (2H, m), 6.87 (2H, d, J = 9 Hz),
7.24–7.36 (2H, m); δC (CDCl3): 21.1, 23.9, 29.9, 41.7, 52.8, 55.4, 71.5, 80.7, 113.8,
122.0, 127.5, 129.2, 130.6, 159.2, 211.3; GC-MS (same conditions as those used for
18): tR 18.88 min (100%); MS (70 eV, EI): m/z: 274 (2) [M+], 138 (2), 137 (6), 122 (9),
~ 18 ~

ACCEPTED MANUSCRIPT
121 (100), 91 (3), 78 (4), 77 (4), 43 (1), 41 (1), 41 (2). HRMS calcd for [C17H22O3]+
(M+): 274.1569, found: 274.1556.
4.14. (±)-2,2-Dimethyl-3-p-methoxybenzyloxy-1-cyclroheptanone (23)
Palladium on barium sulfate (5%, 150 mg) was added to a solution of 33 (1.23 g,
4.5 mmol) in EtOAc (5 mL)/hexane (10 mL). The mixture was stirred under H2
(balloon) for 1 h at room temperature. The mixture was passed through a column of
SiO2 (10 g), and the column was washed with hexane/EtOAc (15:1). The eluent was
26
concentrated in vacuo to give 23 (1.03 g, 84%) as a colorless oil, nD = 1.5153; νmax
(film): 2935 (s), 2863 (m), 1699 (s), 1612 (m), 1514 (s), 1465 (m), 1302 (m), 1249 (s),
1173 (m), 1100 (m), 1074 (m), 1036 (m), 821 (m); δH (CDCl3): 1.09 (3H, s), 1.14 (3H,
s), 1.50–1.70 (3H, m), 1.70–1.90 (3H, m), 2.42–2.52 (1H, m), 2.60–2.70 (1H, m), 3.43–
3.50 (1H, m), 3.81 (3H, s), 4.32 (1H, d, J = 12 Hz), 4.60 (1H, d, J = 12 Hz), 6.88 (2H, d,
J = 7 Hz), 7.27 (2H, d, J = 7 Hz); δC (CDCl3): 20.9, 24.7, 25.4, 26.1, 28.6, 41.3, 52.6,
55.3, 71.1, 82.5, 113.9, 129.2, 130.7, 159.2, 217.0; GC-MS (same conditions as those
used for 18): tR 18.94 min (100%); MS (70 eV, EI): m/z: 276 (<1) [M+], 140 (5), 137
(14), 125 (2), 122 (10), 121 (100), 91 (2), 78 (3), 77 (4), 55 (2), 41 (3). HRMS calcd
for [C17H24O3]+ (M+): 276.1725, found: 276.1754.
4.15. 2-Hydroxy-5,5-dimethyltetrahydrofuran-4-one (41)
A solution of 40 (24.0 g, 235 mmol) and ethyl formate (26.0 g, 351 mmol) in Et2O
(20 mL) was added dropwise over 1 h to a stirred and ice-cooled suspension of NaH
(60% NaH in mineral oil, 19.2 g, 480 mmol) in Et2O (400 mL) under argon. The H2
evolved was released frequently. The mixture was stirred for 4 h at room temperature
to give a thick solid mass. It was then acidified with ice and conc H2SO4 (16 mL, 29.4
g, 300 mmol) diluted with water (160 mL). The mixture was extracted with Et2O.
The extract was washed with brine, dried (MgSO4), and concentrated in vacuo. The
residue (35.9 g) was distilled to give 41 (20.7 g, 67%) as a colorless oil, bp 80–84oC/0.4
23
25
kPa; nD = 1.4471 (ref.17 nD = 1.4424); νmax (film): 3425 (br s), 2981 (m), 2934 (m),
2871 (w), 1759 (s), 1460 (m), 1379 (m), 1361 (m), 1200 (m), 1173 (m), 1146 (m), 1112
(s), 1058 (m), 984 (s), 965 (m), 927 (m); δH (CDCl3): 1.24 (3H, s), 1.39 (3H, s), 2.52
(1H, d, J = 18 Hz), 2.78 (1H, dd, J = 6, 18Hz), 3.70 (1H, br s), 5.78 (1H, d, J = 6 Hz);
δC (CDCl3): 24.9, 26.3, 43.0, 80.6, 94.3, 216.2; GC-MS (same conditions as those used
for 18): tR 4.57 min (99%); MS (70 eV, EI): m/z: 102 (14) [(M−H2O)+], 71 (4), 69 (4),
59 (100), 44 (16), 43 (34). HRMS calcd for [C6H10O3]+ (M+): 130.0630, found:
130.0631.
4.16.
∆
2-5,5-Dimethyldihydrofuran-4-one (42)
Powdered CuSO4 (20 g, 125 mmol) and MgSO4 (5 g, 42 mmol) were added to a
~ 19 ~

ACCEPTED MANUSCRIPT
stirred solution of 41 (16.0 g, 123 mmol) in Et2O (200 mL) containing ten drops of conc
HCl, and the mixture was stirred for 2 d at room temperature. The mixture was
filtered, and the solid was washed with Et2O. The combined filtrate and washings
were concentrated (Vigreux column) under atmospheric pressure, and the residue was
distilled to give 42 (7.65 g, 58%) as a colorless oil, bp 63–65oC/4.4 kPa, nD25 = 1.4478;
νmax (film): 3110 (w), 3067 (w), 2982 (m), 2934 (w), 2870 (w), 1706 (s), 1562 (s), 1454
(w), 1379 (m), 1365 (m), 1279 (w), 1198 (s), 1172 (s), 1089 (v), 1043 (m), 953 (w), 848
(w), 795 (m), 513 (m); δH (CDCl3): 1.37 (6H, s), 5.58 (1H, d, J = 2 Hz), 8.13 (1H, d, J =
2 Hz); δC (CDCl3): 22.7, 87.6, 104.8, 176.3, 207.8; GC-MS (same conditions as those
used for 18): tR 3.91 min (94%); MS (70 eV, EI): m/z: 112 (100) [M+], 71 (24), 69 (8),
58 (23), 54 (53), 43 (57), 42 (11), 41 (13). HRMS calcd for [C6H8O2]+ (M+): 112.0524,
found: 112.0530.
4.17. 2,2-Dimethyltetrahydrofuran-3-one (34)
Palladium-charcoal (10%, 1.0 g) was added to a solution of 42 (13.1 g, 117 mmol)
in AcOMe (40 mL), and the mixture was stirred under H2 atmosphere (balloon) for 6 h
at room temperature, when H2 uptake ceased. The mixture was filtered through Celite,
and the Celite layer was washed with AcOMe. The filtrate was concentrated (Vigreux
column), and the residue was distilled to give 10.24 g (77%) of 34 as a colorless oil, bp
25
65–66oC/4.0 kPa, nD = 1.4240; νmax (film): 2979 (m), 2932 (w), 2876 (w), 1757 (s),
1715 (sh), 1182 (s), 1103 (s), 1018 (m), 968 (m), 834 (m), 508 (m), δH (CDCl3): 1.20
(6H, s), 2.52 (2H, t, J = 7 Hz), 4.11 (2H, t, J = 7 Hz); δC (CDCl3): 22.4, 35.9, 61.5; 79.2,
217.7; GC-MS (same conditions as those used for 18): tR 3.80 min (95%); MS (70 eV,
EI): m/z: 114 (9) [M+], 86 (43), 58 (20), 43 (100). HRMS calcd for [C6H10O2]+ (M+):
114.0681, found: 114.0687.
4.18. 5,5-Dimethyltetronic acid (5,5-dimethyltetrahydrofuran-2,4-dione (35)
Jones chromic acid (8
M for oxygen, 39 mL, 312 meq) was added dropwise over 10
min to a stirred and ice-cooled solution of 41 (20.7 g, 159 mmol) at 10–15oC. The
mixture was stirred for further 10 min at 5–10oC. It was then concentrated in vacuo.
The residue was diluted with water, and extracted with EtOAc. The extract was
washed with brine, dried (MgSO4), and concentrated in vacuo. The residual semi-solid
(18.9 g) was recrystallized from EtOAc/hexane to give 35 (8.00 g, 39%) as colorless
rhombs, mp 145–146oC (ref.18 mp 151–152oC; ref.19 mp 142–143oC; νmax (nujol): 2600–
2400 (br m), 1748 (w), 1697 (s), 1677 (s), 1651 (m), 1558 (s), 1304 (s), 1235 (m), 1194
(m), 1109 (m), 985 (m), 800 (m); δH (DMSO-d6, 500 MHz): 1.38 (6H, s), 4.79 (1H, s),
12.65 (1H, br s); δC (DMSO-d6, 126 MHz): 24.0, 81.3, 86.0, 171.8, 185.2. HRMS
calcd for [C5H8O3]+ (M+): 128.0473, found; 128.0469.
~ 20 ~

ACCEPTED MANUSCRIPT
4.19. 3,3-Dimethyl-4-pentenoic acid (48)
A stirred mixture of 46 (68.8 g, 0.80 mol), MeC(OEt)3 (194.4 g, 1.20 mol) and
EtCO2H (2 mL) was gradually heated to raise up the inner temperature at 145oC, while
ca. 150 mL of EtOH was removed by distillation. An additional amount of EtCO2H
(2 mL) was then added, and the mixture was stirred and heated at 145–150oC for 3 h,
while removing ca 40 mL of EtOH. After cooling below 60oC, dil HCl (1 mL of conc
HCl and 100 mL of water) was added to the mixture to destroy excess MeC(OEt)3.
(Addition of conc HCl as reported in ref.20 damages the product 47, and therefore dil
HCl must be used.) Then the mixture was stirred and heated at 120oC (bath
temperature to remove 120 mL of a mixture of EtOAc, EtOH and water to give crude
47. The crude 47 was diluted with MeOH (180 mL) and water (300 mL), and KOH
(93.0 g, 1.66 mol) was added portionwise with stirring. The mixture was stirred and
heated under reflux for 2 h, then concentrated under atmospheric pressure removing
320 mL of distillates at bath temperature of 110oC. After cooling, neutral impurities
were removed by extraction with Et2O. The aqueous layer was diluted with ice and
water, and acidified with conc HCl (160 mL, 1.92 mol). The separated acid was
extracted with Et2O. The Et2O extract was dried (MgSO4), and concentrated in vacuo.
The residue was distilled to give 48 (71.2 g, 70%) as a colorless oil, bp 80–90oC/1.7
kPa; νmax (film): ~3086–2674 (br s), 2967 (s), 1710 (s), 1640 (m), 1415 (m), 1250 (m),
998 (m), 916 (m); δH (CDCl3): 1.16 (6H, s), 2.33 (2H, s), 4.95–5.02 (2H, m), 5.87–
13
5.94 (1H, m); δC (CDCl3): 27.0, 36.1, 46.7, 111.2, 146.6, 178.6. The C NMR data
were identical with those reported in ref.20
4.20. 5-Iodomethyl-4,4-dimethyltetrahydrofuran-2-one (49)
Powdered NaHCO3 (75.0 g, 0.89 mol) was added portionwise to a vigorously
stirred mixture of 48 (71.2 g, 0.56 mol) in water (1.5 L). After the addition, the
vigorous stirring was continued for 15 min to dissolve 48 as its Na salt. Subsequently,
NaI (19.6 g, 0.13 mol) was added to the aqueous solution. Iodine (141 g, 0.55 mol)
was added portionwise over 4 h to the stirred mixture. The flask was wrapped with
aluminum foil, and the stirring was continued for 3 d at room temperature. It was then
extracted with CH2Cl2. The extract was washed with 10% Na2S2O3 solution, dried
(MgSO4), and concentrated in vacuo to give 49 (137.1 g, 97%) as a colorless oil, νmax
(film): 2964 (m), 1783 (s), 1467 (m), 1417 (m), 1286 (m), 1232 (m), 1200 (m), 1177 (s),
1122 (s), 991 (s), 972 (s), 929 (m), 736 (m), 622 (m); δH (CDCl3): 1.10 (3H, s), 1.28 (3H,
s), 2.47 (2H, s), 3.21–3.25 (1H, m), 3.29–3.33 (1H, m), 4.39–4.42 (1H, m); δC (CDCl3):
−0.7, 20.8, 26.1, 40.0, 44.7, 87.9, 174.2. The NMR data were in good accord with
those reported in ref. 20
~ 21 ~

ACCEPTED MANUSCRIPT
4.21. 3,3-Dimethyl-4-penten-4-olide (50)
A solution of DBU (89.6 g, 0.59 mol) in C6H6 (100 mL) was added dropwise to a
stirred solution of 49 (137.1 g, 0.556 mol) in C6H6 (500 mL). The mixture was stirred
and heated under reflux for 2 h. After cooling, the mixture was filtered to remove
precipitated DBU·HI salt, and the solid was washed thoroughly with Et2O. The
combined filtrate and washings were washed with dil HCl and brine, dried (MgSO4),
and concentrated in vacuo. The residue was distilled to give 50 (52.0 g, 76%) as a
colorless oil, bp 60–61oC/0.6 kPa, νmax (film): 2970 (m), 2932 (w), 2874 (w), 1806 (s),
1670 (s), 1466 (w), 1419 (w), 1371 (w), 1257 (m), 1232 (m), 1199 (m), 1096 (s), 981 (s),
843 (m); δH (CDCl3): 1.33 (6H, s), 2.50 (2H, s), 4.30 (1H, s), 4.66 (1H, s); δC (CDCl3):
28.0, 39.1, 43.0, 86.2, 165.9, 173.2. The 13C NMR data were in good accord with
those reported in ref.20
4.22. 3,3-Dimethyl-4-oxopentanoic acid (51)
A solution of KOH (30.8 g, 0.55 mol) in water (200 mL) was slowly added to
stirred 50 (51.9 g, 0.41 mol). Exothermic hydrolysis of 50 took place. The mixture
was stirred for 15 min at room temperature, acidified with conc HCl (50 mL, 0.55 mol)
and ice, and extracted with CH2Cl2. The extract was dried (MgSO4), and concentrated
in vacuo to give 51 (61.2 g, quant) as a colorless oil, νmax (film): ~3500–~2650 (m),
2975 (s), 1708 (s), 1366 (m), 1241 (m), 1172 (s), 1127 (m), 923 (m); δH (CDCl3): 1.22
(6H, s), 2.17 (3H, s), 2.60 (2H, s); δC (CDCl3): 25.0, 25.3, 43.8, 45.9, 177.2, 213.0.
The 13C NMR data were in good accord with those reported in ref.21.
4.23. 3,4-Dimethyl-2-penten-4-olide (43)
Polyphosphoric acid was prepared by adding P2O5 (90 g, 0.63 mol) to 85% H3PO4
(60 mL), and heating the stirred mixture at 110oC for 1 h. The oily 51 (18.6 g, 0.13
mol) was added slowly to the stirred polyphosphoric acid, and the mixture was stirred
and heated at 130oC for 30 min. After cooling, the mixture was diluted with ice and
water, saturated with NaCl, and extracted with Et2O. The extract was washed
successively with water, NaHCO3 solution and brine, dried (MgSO4), and concentrated
in vacuo. The residue was distilled to give 43 (7.78 g, 48%) as a slightly yellowish
solid, bp 73–75oC/0.3 kPa, mp 40–41oC; νmax (film): 3104 (w), 1737 (s), 1665 (m),
1642 (m), 1460 (s), 1385 (m), 1368 (m), 1275 (m), 1171 (m), 1091 (m), 968 (s), 735 (m),
588 (m); δH (CDCl3): 1.42 (6H, s), 2.01 (3H, s), 5.66 (1H, s); δC (CDCl3): 13.0, 24.6,
87.4, 115.6, 172.2, 173.3. The 13C NMR data were in good accord with those reported
in ref.21. HRMS calcd for [C7H10O2]+ (M+): 126.0681, found: 126.0681.
4.24. 2-(3-Butenyl)-3,4-dimethyl-2-penten-4-olide (52)
A solution of lithium diisopropylamide (1.5
M in THF/heptane/toluene, 20 mL, 30
~ 22 ~

ACCEPTED MANUSCRIPT
mmol) was added dropwise to a stirred and cooled solution of 43 (3.78 g, 30 mmol) in
THF (10 mL) at −75oC under argon. The mixture was stirred and −75oC for 30 min.
Then a solution of 1-iodo-3-butene (6.00 g, 33 mmol) in THF (15 mL) was added
dropwise over 10 min to the stirred and cooled mixture at −75oC. After stirring for 1 h
at −75oC, the mixture was further stirred for 1 h at room temperature. It was then
quenched with NH4Cl solution. The mixture was diluted with water, and extracted
with Et2O. The Et2O solution was washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue (5.95 g) was chromatographed over SiO2 (100 g).
Elution with hexane/EtOAc (5:1) gave 52 (2.35 g, 44%). A portion of the crude 52
24
was distilled to give pure 52 as a colorless oil, bp 104–106oC/0.2 kPa; nD = 1.4734;
νmax (film): 3078 (w), 2979 (m), 2932 (w), 2869 (w), 1749 (s), 1679 (m), 1640 (w),
1291 (m), 1202 (m), 1073 (m), 969 (m), 912 (m); δH (CDCl3): 1.35 (6H, s), 1.87 (3H, s),
2.21–2.26 (4H, m), 4.89–4.97 (2H, m), 5.66–5.73 (1H, m); δC (CDCl3): 11.1, 22.9, 24.8,
24.9, 32.0, 85.6, 115.7, 125.1, 137.2, 164.8, 173.1; GC-MS (same conditions as those
used for 18): tR 18.21 min (91%); MS (70 eV, EI): m/z: 180 (21) [M+], 165 (45), 135
(45), 121 (74), 107 (32), 93 (48), 79 (35), 43 (100). HRMS Calcd for [C11H16O2]+
(M+): 180.1150, found: 180.1149.
4.25. (1S,5R)-trans-Pulegenic acid (57)
4.25.1 (R)-Pulegone dibromide (55)
Bromine (19 mL, 370 mmol) was added dropwise over 30 min to a stirred and
ice-cooled solution of 54 (54.2 g, 357 mmol) in glacial AcOH (75 mL) at 5–15oC. The
mixture was stirred for 30 min after the addition of Br2, poured into ice-water, and
extracted with pentane. The pentane solution was washed with water, NaHCO3
solution and brine, dried (MgSO4), and filtered to give a pentane solution of 55.
4.25.2. A cis/trans-mixture of ethyl pulegenates (56)
The above solution of 55 was added dropwise to a stirred and heated solution of
NaOEt (68 g, 1 mol) in EtOH (400 mL). After distilling off the pentane, the mixture
was stirred and heated at 80–100oC for 2 h to remove 100 mL of EtOH. After cooling,
the mixture was poured into ice and 10% HCl (500 mL), and extracted with Et2O. The
extract was washed with water, dried (MgSO4), and concentrated in vacuo to give 50.4 g
(72%) of 56 as a 1:3 mixture of cis/trans-isomers of 56 as judged by GC analysis (same
conditions as those used for 18): tR 16.23 min (77%), 16.56 min (23%).
4.25.3. (1S,5R)-trans-Pulegenic acid (57)
A solution of KOH (20 g, 357 mmol) in water (60 mL) was slowly added to a
solution of 56 (50.4 g, 257 mmol) in 95% EtOH (200 mL). The mixture was stirred
and heated under reflux for 3 h, and EtOH was removed by distillation. After cooling,
~ 23 ~

ACCEPTED MANUSCRIPT
the residue was diluted with water, and extracted with Et2O to remove neutral impurities.
The Et2O layer was extracted with water. The combined aqueous solution was
acidified with conc HCl (40 mL, 480 mmol) and ice. The mixture was extracted with
Et2O. The Et2O solution was washed successively with water and brine, dried
(MgSO4), and concentrated in vacuo. The residue was distilled to give 57 (24.5 g,
57%) as a colorless oil, νmax (film): ~3500– ~2500 (br m), 2956 (s), 1701 (s), 1456 (m),
1415 (m), 1375 (m), 1292 (m), 1213 (m), 952 (w), 893 (w), 813 (w), 707 (w); δH
(CDCl3): 1.08 (3H, d, J = 7 Hz), 1.64 (3H, s), 1.67 (3H, s), 1.90–2.05 (2H, m), 2.23–
2.45 (3H, m), 2.97 (1H, d, J = 5 Hz); δC (CDCl3): 19.9, 21.67, 21.74, 30.4, 33.8, 40.9,
55.6, 126.9, 133.9, 182.2; GC-MS (same conditions as those used for 18): tR 17.45 min
(89%); MS (70 eV, EI): m/z: 168 (35) [M+], 125 (14), 123 (100), 107 (21), 91 (10), 81
(56), 67 (13), 41 (13).
4.26. Iodolactone (58)
A solution of I2 (76.2 g, 0.3 mol) and NaI (135.0 g, 0.9 mol) in water (300 mL) was
added over 10 min to a stirred solution of 57 (24.5 g, 0.146 mol) and NaHCO3 (12.6 g,
0.150 mol) in a mixture of Et2O (400 mL) and H2O (400 mL) at room temperature.
The mixture was stirred for 4 d at room temperature, while the flask was wrapped with
an aluminum foil. Then sodium thiosulfate was added to destroy the excess I2, and the
Et2O layer was separated. The aqueous layer was extracted with Et2O. The Et2O
solution was successively washed with NaHCO3 solution and brine, dried (MgSO4), and
concentrated in vacuo to give a solid residue (37 g). This was recrystallized from
pentane to give 58 (22.2 g, 52%) as colorless needles, mp 55–56oC; [α]D22 +1.82 (c 1.65,
Et2O); νmax (nujol): 1775 (s), 1375 (s), 1267 (s), 1225 (m), 1209 (m), 1120 (m), 1078 (s),
1029 (m), 947 (s), 802 (m), 731 (m), 607 (m); δH (CDCl3): 1.39 (3H, d, J = 7 Hz), 1.49
(3H, s), 1.74 (3H, s), 1.78–1.94 (2H, m), 2.10–2.20 (2H, m), 2.55–2.65 (1H, m), 2.88
(1H); δC (CDCl3): 21.1, 23.0, 33.0, 34.9, 37.1, 42.3, 53.0, 63.1, 86.9, 177.4. GC (same
conditions as those used for 78): tR 22.66 min (100%); MS (70 eV, EI): m/z: 167 (100),
123 (67), 95 (15), 91 (12), 81 (64), 43 (23). HRMS calcd for [C10H15O2I]+ (M+):
294.0117, found: 294.0109.
4.27. Unsaturated lactone (17)
1,8-Diazabicyclo[5.4.0]-7-undecene (DBU, 12.0 g, 65.9 mmol) was added to a
solution of 58 (12.12 g, 41.2 mmol) in C6H6 (120 mL). The mixture was stirred for 3 h
at room temperature. White precipitates of DBU·HI salt appeared soon afterwards
(exothermic). Subsequently the mixture was acidified with dil HCl and ice. The
benzene layer was separated, and the aqueous layer was extracted with Et2O. The
combined organic solution was washed successively with water, NaHCO3 solution and
~ 24 ~

ACCEPTED MANUSCRIPT
brine, dried (MgSO4), and concentrated in vacuo. The residue was recrystallized from
20
pentane to give 17 (5.72 g, 78%) as colorless prisms, mp 43–43.5oC, [α]D +6.39 (c
1.32, Et2O); νmax (nujol): 1766 (s), 1663 (m), 1336 (m), 1279 (m), 1182 (m), 1124 (m),
1049 (m), 1006 (s), 902 (m), 786 (m), 615 (m), 575 (m); δH (CDCl3): 1.18 (3H, d, J = 7
Hz), 1.44 (3H, s), 1.46 (3H, s), 1.90–2.00 (1H, m), 2.38–2.56 (2H, m), 2.60–2.72 (1H,
m), 2.92–3.02 (1H, m): δC (CDCl3): 19.3, 25.0, 26.4, 33.9, 38.1, 83.3, 139.3, 168.6,
180.4. GC (same conditions as those used for 18): tR 17.30 min (100%); MS (70 eV,
EI): m/z: 151 (28), 123 (100), 107 (7), 79 (14), 43 (21). HRMS calcd for [C10H14O2]+
(M+): 166.0994, found: 166.1004.
4.28. Unsaturated lactone 53a + 53b
Deconjugation/protonation of (R)-17 to a mixture of 53a/53b could be achieved
either KH or lithium diisopropylamide (LDA) as a base. The use of LDA was more
convenient, and therefore recorded here.
A solution of LDA (TCI, 1.5
M in THF/heptane/toluene; 54 mL, 81 mmol) was
added dropwise to a stirred and cooled solution of (R)-17 (9.64 g, 58 mmol) in THF
(100 mL) over 10 min at −60 to −50oC under argon. The mixture was stirred at −78oC
for 30 min, and then the dry ice/acetone bath was removed to raise the inner temperature
to 0oC. The resulting enolate solution was taken into a syringe, and added over 5 min
to a stirred and cooled solution of AcOH (24 mL) in Et2O (200 mL) at −78oC under
argon. The solution was stirred for 5 min, poured into iced-water, and extracted with
Et2O. The Et2O extract was washed successively with NaHCO3 solution and brine,
dried (MgSO4), and concentrated in vacuo to give 12.1 g of an oil. This was
chromatographed over SiO2 (90 g). After washing the column with hexane to remove
toluene and heptane, a mixture of 53a/53b (7.30 g, 76%) was eluted with hexane/EtOAc
23
(10:1). The oily 53a/53b, nD = 1.4770, solidified in a deep freezer, although its
23
recrystallization from pentane was unsuccessful: [α]D −36.5 (c 1.52, Et2O); νmax
(film): 3060 (w), 2977 (s), 2931 (s), 2871 (s), 2850 (s), 1765 (s), 1675 (m), 1460 (m),
1371 (m), 1297 (s), 1219 (s), 1194 (s), 1125 (s), 1104 (m), 1083 (s), 1036 (m), 963 (s),
898 (m), 846 (m), 593 (m), 552 (m); δH (CDCl3): 0.95 (3H, d, J = 7 Hz), 1.47 (3H, s),
1.53 (3H, s), 2.14 (1H, m). 2.70–2.80 (1H, m), 2.85–2.93 (1H, m), 3.82–3.89 (1H, br),
5.58–5.62 (1H, m); The minor isomer (53b) showed its CH3CH at δ1.28 (3H, d, J = 7
Hz); δC (CDCl3): 16.3, 26.1, 26.5, 35.5, 45.2, 54.4, 83.6, 121.6, 147.4, 173.9; GC-MS
(same conditions as those used for 18): tR 15.37 min (10.5%), 15.81 min (89.5%); MS
(70 eV, EI): m/z: 166 (11) [M+], 122 (26), 121 (33), 107 (100), 105 (26), 9 (37), 79 (23),
43 (15); The two isomers showed entirely similar MS spectra. HRMS calcd for
[C10H14O2]+ (M+): 166.0994, found: 166.1006.
~ 25 ~

ACCEPTED MANUSCRIPT
4.29. Ketolactone (1R,5S,8R)-7
A solution of 53a/53b (1.53 g, 9.2 mmol) in Et2O (15 mL) was added dropwise over
5 min to a stirred and ice-cooled solution of BH3·THF in THF (0.9 , 10 mL, 9.0
M
mmol) at 9–15oC under argon. The mixture was stirred for 75 min at 5–8oC. Excess
BH3·THF was then destroyed by slow addition of water (3 mL). After stirring for 5
min, the mixture was concentrated in vacuo (rotary evaporator). The residue was
diluted with Et2O (20 mL), acetone (10 mL) and water (10 mL), and stirred vigorously
under ice-cooling. Jones chromic acid (8
M in oxygen, 9 mL, 72 mmol) was added
dropwise to the stirred mixture, and the stirring was continued for 20 min. After
destroying excess CrO3 with MeOH, the mixture was diluted with water, and extracted
with Et2O. The Et2O solution was washed successively with water, NaHCO3 solution
and brine, dried (MgSO4), and concentrated in vacuo. The residue (1.06 g) was
chromatographed over SiO2 (10 g). Elution with hexane gave 0.26 g of an oil, and
further elution with hexane/EtOAc (20:1) gave 0.58 g of an oil. Subsequently, elution
with hexane/EtOAc (20:1) gave 0.72 g of an oil, from which crystals of (1R,5S,8R)-7
separated. Recrystallization from EtOAc/pentane gave 140 mg (8%) of (1R,5S,8R)-7
as colorless rhombs, mp 85–86oC (ref.4: mp 83.0–84.0oC for its opposite enantiomer);
22
25
[α]D −309.4 (c 0.216, Et2O); [ref.4: [α]D +319 (c 1.014, Et2O) for its opposite
1
13
enantiomer]. Its IR, H and C NMR spectra were identical with those reported for
the enantiomer.4: νmax (nujol): 1764 (s), 1741 (s), 1375 (m), 1257 (m), 1204 (m), 1170
(m), 1135 (m), 1109 (m), 1086 (m), 968 (m), 935 (m), 747 (m); δH (CDCl3): 1.40 (3H, d,
J = 7 Hz), 1.41 (3H, s), 1.45 (3H, s), 1.94 (1H, dd, J = 16, 13 Hz). 2.43–2.58 (2H, m),
2.73 (1H, d, J = 9 Hz), 3.43 (1H, dd, J = 9, 7Hz); δC (CDCl3): 15.8, 24.4, 30.9, 32.1,
46.8, 47.2, 58.4, 83.6, 174.8, 213.7; GC-MS (same conditions as those used for 18): tR
18.99 min (98.5%); MS (70 eV, EI): m/z: 182 (15) [M+], 113 (10), 97 (17), 96 (100), 81
(36), 69 (24), 43 (12). HRMS calcd for [C10H18O3]+ (M+): 182.0943, found: 182.0942.
4.30. Dihydroxylactone (1R,5S,6R,8R)-39 + (1S,5R,6S,8R)-39
An aqueous solution of 4-methylmorpholine-N-oxide (50%, 4.8
M, 5 mL, 24
mmol) and OsO4 (1% solution in t-BuOH, 2 mL = 20 mg OsO4, 0.08 mmol) were added
to a stirred solution of 53a/53b (2.50 g, 15 mmol) in a mixture of acetone (30 mL),
t-BuOH (10 mL) and water (2 mL) at room temperature under argon. The mixture was
stirred for 9 d under argon. Subsequently, Na2SO3·7H2O was added to destroy excess
NMO and OsO4. The mixture was diluted with brine, and extracted with EtOAc.
The EtOAc solution was dried (MgSO4), and concentrated in vacuo to give a residue
(4.17 g). This was chromatographed over SiO2 (30 g). Elution with hexane gave
0.14 g of an oil, and further elution with hexane/EtOAc (5:1–2:1) gave 3.06 g (98%) of
~ 26 ~

ACCEPTED MANUSCRIPT
a mixture of (1R,5S,6R,8R)-39 and (1S,5R,6S,8R)-39 as a solid.
This was
recrystallized from acetone/pentane to give 1.93 g of the 1st crop as colorless prisms,
20
mp 112–114oC; [α]D −54.8 (c 0.70, Et2O) 0.61 g of 2nd crop and 0.25 g of the 3rd
crop. Analytical data of the 1st crop were as follows: νmax (nujol): 3443 (m), 3304 (m),
1742 (s), 1380 (m), 1281 (m), 1266 (m), 1232 (m), 1197 (w), 1119 (m), 1096 (m), 1086
(m), 1027 (m), 864 (m); δH (CDCl3, major signals): 1.18 (3H, d, J = 7 Hz) 1.42 (3H, s),
1.43 (3H, s), 1.62–1.72 (1H, m), 2.01–2.10 (1H, m), 2.58–2.70 (1H, m), 2.72 (1H, br),
2.97 (1H, d, J = 9 Hz), 3.61 (1H, s-like), 4.41 (1H, dd, J = 12, 6 Hz); δC (CDCl3, major
signals): 16.3, 21.8, 25.5, 30.9, 41.6, 53.1, 72.1, 85.3, 86.2, 174.5; GC-MS (same
conditions as those used for 18): tR 23.99 min [10.1%, (1S,5R,6S,8R)-39], 24.74 min
[89.9%, (1R,5S,6R,8R)-39]; MS of the major isomer (= that of the minor isomer, 70 eV,
EI): m/z: 130 (37), 114 (100), 99 (61), 96 (49), 81 (45), 70 (23). HRMS calcd for
[C10H16O4]+ (M+): 200.1049, found for the major isomer: 200.1060, found for the minor
isomer: 200.1039. GC of the 2nd crop showed it to be a 3:1 mixture of
(1R,5S,6R,8R)-39 and (7S,5R,6S,8R)-39. The 3rd crop contained substantial amount of
impurities different from 39.
4.31. Hydroxyketolactone (1R,5R,8R)-15
4-Methylmorpholine N-oxide (Aldrich, 1.89 g, 14 mmol), powdered MS 4A (2.84
g)
and (n-Pr)4NRuO4 (98 mg, 0.28 mmol) were added to a stirred and ice-cooled solution
of (1R,5S,6R,8R)-39/(1S,5R,6S,8R)-39 (3:1, 559 mg, 2.8 mmol) in CH2Cl2 (15 mL).
After the initial exothermic reaction, the mixture was stirred for 2 h at room temperature.
Then the dark-colored mixture was poured onto a column of SiO2 (20 g) in hexane.
Elution with hexane and hexane/EtOAc (5:1) gave nothing. Further elution with
hexane/EtOAc (3:1) gave 102 mg (18%) of (1R,5R,8R)-15 as a solid. This was
recrystallized from EtOAc/pentane to give 50 mg (9%) of (1R,5R,8R)-15 as colorless
16
rhombs, mp 153–155oC (sinter at 120oC); [α]D −332.8 (c 0.035, Et2O); νmax (film):
3427 (m), 1744 (s), 1308 (m), 1061 (m), 1033 (m), 897 (m); δH (CDCl3, major isomer):
1.29 (3H, s), 1.40 (3H, d, J = 7 Hz), 1.45 (3H, s), 2.19 (1H, dd, J = 16, 2 Hz), 2.50–2.61
(2H, m), 2.81 (1H, s), 3.15 (1H, dd, J = 7, 2 Hz); δC (CDCl3, major isomer): 15.5, 23.2,
25.6, 30.6, 45.9, 51.7, 85.0, 85.7, 172.4, 214.9; GC-MS (same conditions as those used
for 18): tR 18.85 min [87%, (1R,5R,8R)-15], 19.00 min [13%, (1S,5S,8R)-15]; MS (70
eV, EI): m/z:113 (13), 112 (100), 97 (21),84 (21), 69 (72), 59 (14), 43 (22). The two
isomers showed the same MS spectra. HRMS calcd for [C10H14O4]+ (M+): 198.0892,
found: 198.0906 (major isomer), 198.0901 (minor isomer).
4.32. Unsaturated hydroxyketolactone (1R,5R)-16
~ 27 ~

ACCEPTED MANUSCRIPT
A solution of KN(TMS)2 (0.5
M
, 11% in toluene, 24 mL, 12 mmol) was added
dropwise to a stirred and cooled solution of (1R,5R,8R)-15 (654 mg; 3 mmol) in THF
(15 mL) at −78–−65oC under argon. The mixture was stirred for 15 min at −78oC.
Subsequently a solution of PhSeBr (1.18 g, 5 mmol) in THF (5 mL) was added
dropwise to the stirred mixture at −78oC, and the stirring was continued for 1 h at −78oC.
Then the mixture was quenched with NH4Cl solution and extracted with Et2O. The
Et2O solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give
an oil (2.12 g). This was chromatographed over SiO2 (40 g). Elution with
hexane/EtOAc (2:1) gave 670 mg (quant based on the consumed 15) of C-7
phenylselenylated product. Further elution with hexane/EtOAc (2:1) gave 340 mg
(52%) of the recovered 15. A solution of the crude phenylselenoketone (670 mg, 1.4
mmol) in THF (16 mL) was added dropwise to the vigorously stirred solution of NaIO4
(2.14 g, 10 mmol) in H2O (8 mL). The solution was stirred for 1 h at room
temperature to give a suspension of NaIO3. The suspension was diluted with Na2CO3
solution, and extracted with Et2O. The Et2O solution was washed successively with
water and brine, dried (MgSO4), and concentrated in vacuo to give an oil (370 mg).
This was chromatographed over SiO2 (20 g). After some unidentified materials,
elution with hexane/EtOAc (2:1) gave 42 mg (14% based on 15) of (1R,5R)-16 as
crystals. This was recrystallized (EtOAc/pentane) to give 20 mg (7%) of pure
(1R,5R)-16 as pale yellow prisms, mp 132.5–133.5oC; [α]D20 −248.7 (c 0.0215, EtOAc);
νmax (nujol): 3370 (m), 1766 (s), 1698 (vs), 1615 (m), 1376 (m), 1254 (m), 1133 (m),
1088 (m), 964 (w), 907 (w), 873 (w), 729 (w); δH (CDCl3): 1.34 (3H, s), 1.53 (3H, s),
1.65 (1H, s), 2.36 (3H, s), 3.03 (1H, s), 3.67 (3H, s), 6.06 (1H, s-like), 7.27 (1H, s), δC
(CDCl3): 18.0, 24.4, 25.7, 59.8, 83.4, 87.9; 128.9, 170.4, 173.8; 204.8; GC-MS (same
conditions as those used for 18): tR 20.14 min (98.9%); MS (70 eV, EI): m/z: 152 (31),
138 (25), 110 (100), 109 (43), 82 (87), 70 (19), 53 (20), 39 (22). HRMS calcd for
[C10H12O]+ (M+): 196.0736, found: 196.0747.
4.33. CD spectral measurements
Instrument: Jasco J-1500; Solvent: MeOH; Cell length: 10 mm; Temp: 21.56oC.
(A) (1R,5S,8R)-7: c 6.6 × 10−5 M; Mol. CD (1) 304 nm, −3.889; (2) 233 nm, 0.13247;
(3) 203 nm, −1.12416. (B) (1R,5R,8R)-15: c 5.4 × 10−5 M; Mol. CD (1) 314 nm,
−3.0068; (2) 253 nm, 0.05325; (3) 227 nm, −0.61590; (4) 212 nm, −0.01093; (5) 203
nm, −1.2648. (C) (1R,5R)-16: c 6.22 × 10−5 M; Mol. CD (1) 242.7 nm, −26.0; (2)
218.9 nm 25.6; (3) 201.7 nm, −22.0.
4.34. X-Ray crystal structure analysis of (1R,5R)-16
Crystal data: C10H12O4, FW = 196.20, monoclinic P21, a = 6.35336 (9), b =
~ 28 ~