Formal Total Synthesis of Actinoranone: Synthesis Approaches and Cytotoxic Studies

Article abstract of DOI:10.1021/acs.joc.8b00514

This article describes our efforts toward the total synthesis of actinoranone. Our synthesis strategies rely on a convergent route to connect the terpenoid and polyketide fragments, employing catalysis and powerful classical reactions for the assembly of

Full text of DOI:10.1021/acs.joc.8b00514

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Formal Total Synthesis of Actinoranone:
Synthetic Approaches and Cytotoxic Studies.
Luiz Fernando Toneto Novaes, Kaliandra de Almeida Gonçalves, Daniela B B Trivella, and Julio Cezar Pastre
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00514 • Publication Date (Web): 12 Apr 2018
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Formal Total Synthesis of Actinoranone: Synthetic
Approaches and Cytotoxic Studies
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Luiz F. T. Novaes, [a] Kaliandra de Almeida Gonçalves[b], Daniela B. B. Trivella[b] and
Julio C. Pastre*[a]
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[a] Institute of Chemistry, University of Campinas (Unicamp), P.O. Box 6154, Zip Code
13084ꢀ971, Campinas, SP, Brazil
[b] Brazilian Biosciences National Laboratory, National Center for Research in Energy
and Materials, Zip Code 13083ꢀ970, Campinas, SP, Brazil
[Ru]
CrossꢀMetathesis
[Ir] Krische
Hydroxymethylation
OMe
OH
OH
OMe
HWE
H
H
Olefination
Actinoranone Carbon Backbone
Total of 20 steps
Labdaꢀ7,13ꢀ(E)ꢀdienꢀ15ꢀol
Total of 8 steps
LLS: 11 steps
LLS: 8 steps
Enhanced Cytotoxicity in vitro
ABSTRACT: This full account describes our efforts towards the total synthesis of
actinoranone. Our synthetic strategies rely on a convergent route to connect the
terpenoid and polyketide fragments, employing catalysis and powerful classical reactions
for the assembly of these key fragments. A new transformation was disclosed during this
work, a domino ringꢀopening and esterification. Initial cytotoxic studies for selected
synthetic intermediates are also presented.
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■ INTRODUCTION
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Synthetic chemistry plays a crucial role in our world. In particular, medicine has
benefited from the creation of new drugs or the supply of scarce natural products via total
synthesis. Even with clear benefits for humankind, the scientific community has struggled
with funding constraints, and the current situation urges chemists to develop shorter and
more efficient synthetic routes. A few strategies have been employed with these aims,
which include redox economy,1 avoidance of protecting groups2 and application of
catalytic methods.
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Compounds isolated from natural sources present a seemingly limitless chemical
diversity, and are thus considered privileged scaffolds for drug discovery. In the review of
Newman and Cragg,3 which covers data from 1981 to 2014, natural products and
compounds inspired by their architectures comprise more than 50% of all approved
smallꢀmolecule drugs, showing the importance of their investigation.
In this scenario, we have been working on the development of total syntheses of
natural products and analogues, which could be applied in our medicinal chemistry
program.4 We have recently developed a concise formal total synthesis of actinoranone
(1),4a and a full account of our efforts is provided in this manuscript, including failed
approaches and preliminary cytotoxic evaluation.
Actinoranone. The meroterpene actinoranone (1, Scheme 1) was first isolated by
Fenical and coworkers in 2013 from the CNQꢀ027 strain of marine actinomycetes, and
presented in vitro cytotoxicity against the human colon carcinoma cell line HCTꢀ1116
(IC50 = 4.0 ꢁM).5 Interestingly, the connection between the diterpene labdane and the
tetralone fragments has never been observed in other natural products, making this a
unique structural feature of this natural product.
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Structural elucidation of actinoranone was performed via uni and bidimensional NMR
analyses. The relative configuration of the octalin fragment was established as
(5S,9S,10S) or (5R,9R,10R). The absolute configuration at C15 was ascribed as (R) after
analysis of respective Mosher esters, thereafter, C8’ was assigned as (R) using NOESY
experiments.
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During our efforts towards actinoranone, its first synthesis was reported
independently by Xu, Ye and coworkers.6 Their work detailed the preparation of four
diastereoisomers, varying the stereogenic centers at C15 and C8’, and after comparison
of spectroscopical data of the natural and synthetic samples, the assignment was revised
at C8’, and the correct absolute configuration was determined as (5S,9S,10S,15R,8’S).
Spectroscopical methods have evolved astonishingly over the last decades, however
unequivocal structural elucidation of natural products remain a challenge nowadays, as
observed in the case of actinoranone, for synthetic organic chemistry still plays an
important role in this field.7
The Xu and Ye synthesis was accomplished in a long sequence, a total of 29 steps,
being 19 steps for the longest linear sequence. We therefore sought to establish a
shorter synthesis of this natural product, allowing a quicker way to obtain analogues with
this new backbone, following cytotoxic studies of selected intermediates.
Our retrosynthetic plan (Scheme 1) focused on the disconnection of the C14ꢀC15
bond, which would be constructed with an aldol reaction (path A) or a sequence of metalꢀ
halogen exchange followed by the addition to a carbonyl compound (path B). The ketone
group from the tetralone bicycle would be masked as a ketal, thioketal or methylene
group.
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Scheme 1. Originally Proposed (Left) and Revised (Right) Structures for
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Actinoranone, and Retrosynthetic Disconnection
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Terpenoid fragment
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O
MeO
OMe
O
MeO
O
OMe
O
Polyketide fragment
O
H
MeO
OMe
X
8'
15
2
(Path A)
S
+
X =
OH
OH
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S
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I
A) Aldol reaction
5
O
or
H
H
CH2
B)
MꢀX exchange
and addition to
carbonyl
C5, C9, C10: relative configuration
Originally proposed
H
Masked ketone
group
Revised structure of
structure for actinoranone
Fenical and coꢀworkers[ref 5]
3 (Path B)
actinoranone (1)
Xu, Ye and coꢀworkers[ref 6]
■ RESULTS AND DISCUSSION
Terpenoid Fragment Synthesis. The terpenoid fragment (compounds 2 or 3)
synthesis required the installment of a trisubstituted endoꢀolefin as an initial challenge.
This task was first approached with a sequence developed by de la Torre and coꢀ
workers:8 conversion of (+)ꢀsclareolide (4) to its Weinreb amide and tertiary alcohol
elimination mediated by SOCl2 in pyridine, as outlined in Scheme 2. Unfortunately, the
desired endoꢀolefin was obtained in only 21% yield, and multiple chromatographic
purifications were necessary to obtain pure 6. An acidꢀcatalyzed isomerization of the
major exoꢀolefin into the desired endoꢀolefin 6 was reported by de la Torre,8 however, this
protocol produced poor results in our hands.
The desired endoꢀolefin 6 can be formed from alcohol 5 only by an E1 mechanism,
since the hydrogens marked in red do not have the required alignment with the hydroxyl
group to enable an E2 elimination. After this observation, an exchange of the hydroxyl
group from an equatorial position in compound 5 to an axial position in compound 8 was
hypothesized to be beneficial to the elimination step, as an E2 mechanism could take
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place with the hydrogen marked in blue. This strategy began with (+)ꢀsclareolide (4)
epimerization at C8,9 followed by the Weinreb amide 8 synthesis with Me2AlCl,10 where
the axial position of the hydroxyl group was confirmed by Xꢀray diffraction analysis.11
Pleasingly, the desired endoꢀolefin 6 was obtained as the major product from the
elimination of alcohol 8, applying the same conditions as before, and a small amount of
exoꢀolefin (<5%) was detected.
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This challenge was also addressed by Samadi and coꢀworkers during their
coscinosulfate synthesis,12 and a sequence of seven steps, including several redox
reactions, were necessary to install the trisubstituted endoꢀolefin from the tertiary alcohol
9 (Scheme 2).
Scheme 2. Amide 6 Synthesis
Thereafter, the methylketone (2) synthesis was evaluated. The first approach
employed a threeꢀstep sequence from Weinreb amide 6: reduction with LiAlH4, van
Leusen reaction,13 and Grignard addition to nitrile 12 (Scheme 3).
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Scheme 3. Methylketone 2 Synthesis
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A second approach to methylketone 2 was also developed, applying two oneꢀcarbon
homologations: a Wittig reaction from aldehyde 11 and a reaction of aldehyde 13 with the
anion of TMSCHN2, followed by a gold(I)ꢀcatalyzed alkyne hydration14 (Scheme 4).
The vinyl iodide (3) synthesis was then studied, as outlined in Scheme 4. As first
attempt, the use of a carbozirconation reaction of alkyne 14 and consecutive treatment
[15]
with I2
led to poor results, as only trace formation of 3 was observed by GC/MS
analysis. Next, a Takai olefination16 of ketone 2 was evaluated, generating CrCl2 in situ,17
however, no product was observed and starting material was recovered. The third
approach was conducted with a sequential HornerꢀWadsworthꢀEmmons olefination and
basic hydrolysis yielding carboxylic acid 16, which was successfully employed in a
decarboxylative iodination with Nꢀiodosuccinimide (NIS) in the presence of
cetyltrimethylammonium bromide (CTAB).18
The vinyl iodide (3) synthesis developed by Xu and Ye employed as key step a
carbozirconation of alkyne 18, which contained a free hydroxyl group, followed by
treatment with iodine, after which the endoꢀolefin was installed. Their sequence required
sixteen steps from (+)ꢀsclareolide (4), with use of protecting groups and several redox
reactions. Our approach to vinyl iodide 3 was concluded in only nine steps, as no
protecting groups were required and the use of redox reactions was minimized.
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The natural diterpene labdaꢀ7,13ꢀ(E)ꢀdienꢀ15ꢀol19 could also be synthesized from
ester 15; this synthesis was accomplished with a DIBALꢀH reduction of 15.
Scheme 4. Synthesis of Vinyl Iodide 3 and Labdaꢀ7,13ꢀ(E)ꢀdienꢀ15ꢀol
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Polyketide Fragment Synthesis. The initial approach to the polyketide fragment
started with the regioselective methoxylation of 6ꢀmethoxyꢀ1ꢀtetralone (20) (Scheme 5).
This transformation began with the insertion of methylꢀoxime as a directing group,
followed by a CꢀH activation using catalytic Pd(OAc)2 and oxone as reꢀoxidant,20 which
afforded methylꢀoxime 22 and a small amount of the desired tetralone 23. Thus, acidic
hydrolysis of the oxime completed the synthesis of 23, .
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Scheme 5. Tetralone 23 Synthesis
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In order to functionalize the benzylic position of 23 towards 26, the ketone would be
protected as a ketal group. Unexpectedly, a common protocol, heating ketone with pTSA
in ethylene glycol as solvent, led to a ringꢀopening reaction, which was further
investigated. The desired ketal was obtained with a weaker acid (pyridinium pꢀ
toluenesulfonate) using a DeanꢀStark apparatus21 in 50% yield, however this protecting
group presented lability upon storage and during benzylic functionalization attempts
(Scheme 6A).
At this point, our attention was turned to the ringꢀopening reaction. Two mechanisms
were proposed, as outlined in Scheme 6B. For path A, intermediate 27 would be
generated via a protonation of the aromatic ring of 23, followed by a retro FriedelꢀCrafts
acylation and esterification with ethylene glycol. For path B, ketal 24 would be formed
initially, following protonation of the aromatic ring, ringꢀopening and hydrolysis of oxonium
30.
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Scheme 6. A) Unexpected Ring Opening Reaction, B) Proposed Mechanisms
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The ringꢀopening reaction was next evaluated with different substrates. Thus, 1ꢀ
tetralone (31), 6ꢀmethoxyꢀ1ꢀtetralone (32) and 8ꢀmethoxyꢀ1ꢀtetralone (20) were subjected
to a standard condition, but the starting materials were recovered with no signal of ringꢀ
opening nor ketalization reaction (Scheme 7). Similar tests with these compounds were
performed at 180 °C, but the same results were observed.
Scheme 7. Evaluation of the Ring Opening Reaction
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On the other hand, 6,7,8ꢀtrimethoxyꢀ1ꢀtetralone (33) underwent the domino reaction.
Notably, compound 33 also produced the demethylated tetralone 34, which did not suffer
ringꢀopening nor ketalization, even with longer periods of heating using the standard
condition, probably due a high stability provided by an intramolecular hydrogen bonding,
evidenced by a downfield shift of the phenolic proton (δ 12.69 ppm).22 The presence of
both methoxy groups at the positions 6 and 8 of the aromatic ring seems to be necessary
to the success of the reaction, which agrees with the proposed mechanism shown in
Scheme 6B.
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Next, the size of the ring fused to the aromatic system was evaluated, and the
bicycles containing 5, 6 or 7 memberedꢀring were able to participate in the domino
reaction in high yields (Scheme 7).
After these experiments, we intended to explore other nucleophiles in order to expand
the scope of the reaction, but unfortunately the reaction was not successful when
replacing ethylene glycol with other alcohols as solvent. Moreover, these results suggest
that path B must be operating under these conditions. In view of the limited application of
this reaction, these studies were concluded at this point, and we turned our attention
back to the polyketide fragment synthesis.
After this initial approach, a series of asymmetric methods to achieve the second ring
with a stereogenic benzylic position was investigated. A route aiming the connection of a
nitrile group at the benzylic position began with the Krische allylation23 of alcohol 40,
obtaining homoallylic alcohol 41 with high enantioselectivity (ee 92%) (Scheme 8).
Unfortunately, both attempts to synthesize nitrile 42 via a Mitsunobu reaction24 from
alcohol 37 or a nucleophilic substitution from bromide 43 were unsuccessfull.
Scheme 8. Attempt to Construct Polyketide Fragment Protected with Dithiane
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In face of this difficulty, our strategy was slightly modified, by first generating the
stereogenic center with the three carbons attached to it already in place, followed by the
formation of the second ring.
The formation of the tertiary benzylic stereocenter was accomplished by a
diastereoselective alkylation of the acyloxazolidinone 47 with allyl bromide (Scheme 9).25
Next, the benzyloxazolidinone was replaced by a protected primary alcohol in two steps,
and the terminal alkene was oxidized to a carboxylic acid in two more steps. The second
ring was forged by an intramolecular FriedelꢀCrafts acylation mediated by SnCl4.
The next step would be the protection of the ketone group. As 1,3ꢀdioxolane showed
to be a labile protecting group, this time we chose 1,3ꢀdithiane as a protecting group, and
its formation under standard conditions (BF3•Et2O and 1,3ꢀdithiol) was successfully
achieved.
The primary alcohol was then deprotected and oxidized under ParikhꢀDoering
conditions,26 and the freshly purified aldehyde was employed in an aldol reaction with the
lithium enolate derived from ketone 2, but unfortunately the desired product 56 was
obtained as a mixture of four diastereoisomers, probably due to racemization of aldehyde
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44 under basic conditions and poor diastereoselectivity during the CꢀC bond formation
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step.
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Scheme 9. Synthesis of Polyketide Fragment Protected with Dithiane and Attempt
of Fragments Coupling
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The protecting group for the benzylic ketone became again an issue that needed to
be addressed, as the dithiane group was not compatible with other oxidizing conditions to
convert the primary alcohol to an aldehyde (DessꢀMartin periodinane and NaHCO3, PCC,
PDC), in order to avoid racemization. A new approach was disclosed after the first
actinoranone total synthesis was reported by Xu, Ye and coꢀworkers,6 where a benzylic
methylene group was employed as a masked ketone.
This route began with the synthesis of allylic acetate 58 from benzaldehyde 57 in two
steps. The formation of the tertiary benzylic stereocenter was conducted with a newly
developed enantioselective hydroxymethylation catalyzed by an iridium complex, which
was developed by the Krische group.27 Next, alcohol 60 was protected with a silyl group
and the alkene of 61 was subjected to a crossꢀmetathesis reaction with (E)ꢀ
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crotonaldehyde.28 Afterwards, alkene 62 was hydrogenated and the second ring was
produced by a domino FriedelꢀCrafts reaction and dehydration. Polyketide fragment 65
was obtained after a second hydrogenation step and a Oꢀdeprotection (Scheme 10).
Scheme 10. Polyketide Fragment Synthesis
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A protectingꢀgroupꢀfree synthesis of fragment 65 was explored from alcohol 60
(Scheme 11). Initially the alcohol group was converted to an acrylate, following a ringꢀ
closingꢀmetathesis reaction and a hydrogenation step. The reduction of lactone 68 with
DIBALꢀH cleanly afforded the corresponding lactol, which was employed in a domino
reaction involving a FriedelꢀCrafts reaction and a dehydration. This sequence afforded
the desired product, but the avoidance of protecting groups caused a low yield to this
cyclization step. The fragment synthesis was finished with a hydrogenation of alkene 69.
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Scheme 11. ProtectingꢀGroupꢀFree Synthesis of Polyketide Fragment
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As the protectingꢀgroupꢀfree approach would need further development, the route
outlined in Scheme 10 was chosen to finish the synthesis of actinoranone, as it
presented a higher overall yield and the same number of steps as the latter route.
Fragments Coupling. The actinoranone carbon backbone was forged by a metalꢀ
halogen exchange of vinyl iodide 3 with nꢀBuLi, followed by the addition to the freshly
prepared aldehyde 70, where alcohol 71 was obtained as the major product and could be
completely separated by flash column chromatography on silica (Scheme 12).
Pleasingly, no racemization of aldehyde 70 was observed during the oxidation with Dessꢀ
Martin periodinane buffered with NaHCO3 or the addition of the vinylꢀlithium reagent.
At this point, the formal synthesis of actinoranone was achieved. As Xu and Ye
reported,6 alcohol 71 could be converted to actinoranone in three more steps: a
Mitsunobu esterification, a CꢀH oxidation of the benzylic position and a hydrolysis of the
ester introduced during the Mitsunobu step.
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Scheme 12. Fragments Coupling and Actinoranone Formal Synthesis
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Cell assays. The cytotoxic activity of selected intermediates, compounds 17, 65 and
71, was evaluated in four human cell lines, using cell imaging assays. These three
compounds were chosen because they present the terpenoid and polyketide fragments,
isolated and joined, and the results from these cell assays could contribute to a better
understanding of the actinoranone pharmacophoric profile. The concentration of
compound responsible for a 50% reduction of the cell population was assigned as the
EC50 value to each compound, as shown in Table 1.
Table 1. Cytotoxicity of componds 17, 65 and 71 measured in human cell assays. Values
are reported as average ± SEM of at least three independent experiments (n).
17
65
71
Tacrine
compound/
cell line
EC50 average ±
SEM (µM)
EC50 average ±
SEM (µM)
EC50 average ±
SEM (µM)
EC50 average ±
SEM (µM)
n
n
n
n
HaCat a
U2ꢀOS b
SCCꢀ9 c
HSCꢀ3 d
12.9 ± 2.6
7.6 ± 1.6
4
3
5
5
> 200
> 200
> 200
> 200
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4
5
5
39.3 ± 10.8
25.8 ± 5.8
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4
3
5
25.0 ± 2.6
34.6 ± 4.4
3
3
53.7 ± 3.7
38.9 ± 5.8
3
3
13.9 ± 1.7
20.5 ± 8.2
115.3 ± 24.2
20.9 ± 2.7
a HaCat: immortalized, but not transformed epithelial cell line.
b U2ꢀOS: human bone osteosarcoma epithelial cells.
c
SCC9: squamous cell carcinoma, a tumor cell line originated from a human tongue squamous cell
carcinoma.
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d HSC3: human tongue squamous cell carcinoma cell line.
> 200 µM: concentrationꢀresponse curves in which 50% cell population reduction was not reached at the
highest compound concentration used (200 µM).
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Compound 17 was the most cytotoxic, displaying EC50 values ranging from 7.6 to
20.5 µM in the 4 cell lines tested. Compound 71 presented moderated cytotoxicity in
HaCat, U2ꢀOS and HSCꢀ3 cell lines (EC50 values ranging from 20.9 to 39.3 µM), and was
barely active in the SCCꢀ9 cell line (EC50 of 115. 3 µM). Compound 65 was inactive in all
the cell lines evaluated.
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Compound 71 carries both the diterpene and polyketide portions of the actinoranone
skeleton and was less active than compound 17, which carries only the diterpenoid
portion. Further, polyketide 65 was inactive in the biological assays. These results
suggest that the diterpene fragment (compound 17) is per se important for conferring the
cytotoxic activity of the actinoranone scaffold. Gademann and coꢀworkers have reviewed
similar findings, which include the use of natural product derived fragments achievable in
reduced synthetic routes, where the fragments display similar or even improved biological
activities, as compared to the parent natural products.29
■ CONCLUSIONS
This work demonstrates that the combination of classical and new reactions can
afford shortened routes to complex natural products. Here we described the construction
of the actinoranone carbon backbone in eleven steps for the longest linear sequence,
which was previously accomplished in seventeen steps. This was possible due to the
minimization of redox reactions and avoidance of protecting groups, when feasible.
In the present work, we have shown that the bicyclic diterpenoid fragment of
actinoranone (compound 17) displayed higher cell cytotoxicity in comparison to its carbon
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backbone (compound 71), the former being obtained in 8 steps instead of 20, as for the
full backbone (71).
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■ EXPERIMENTAL SECTION
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General Information. Starting materials and reagents were obtained from commercial sources
and used as received unless otherwise specified. Dichloromethane, triethylamine, diisopropylethylamine
(DIPEA) and pyridine were treated with calcium hydride and distilled before use. Tetrahydrofuran (THF)
and diethylether were treated with metallic sodium and benzophenone and distilled before use. Anhydrous
N,Nꢀdimethylformamide (DMF), dimethylsulfoxide (DMSO) and diglyme were obtained from Aldrich.
Anhydrous methanol, ethanol, isopropyl alcohol, acetonitrile, toluene and benzene were dried over
molecular sieves 3A (10% w/v) for more than one week before use. Anhydrous reactions were carried out
with continuous stirring under atmosphere of dry nitrogen or argon. Progress of the reactions was
monitored by thinꢀlayer chromatography (TLC) analysis (Merck, silica gel 60 F254 on aluminum plates),
unless otherwise stated. Flash chromatography purifications were performed with silica gel 60, 220ꢀ440
1
mesh, SigmaꢀAldrich. H NMR and 13C NMR were recorded on Bruker 250, the chemical shifts (δ) were
reported in parts per million (ppm) relative to deuterated solvent as the internal standard (CDCl3: 7.26 ppm
for 1H NMR and 77.0 ppm for 13C NMR), coupling constants (J) are in hertz (Hz). The following
abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, quint = quintet, m = multiplet, br. = broad signal. NMR spectra were processed using ACD/NMR
Processor Academic Edition version 12.01. High resolution mass spectra (HRMS) were recorded on a
Waters Xevo QꢀTof apparatus operating in electrospray mode (ES). Infrared spectra with Fourier transform
(FTIR) were recorded on a Therm Scientific Nicolet iS5, the principal absorptions are listed in cm−1. Optical
rotation were measured at 25 °C in a Perkin–Elmer 341 polarimeter, with sodium lamp, the measure is
T
described as follow [α]D (c (g/100 mL), solvent). GC/MS analyses were carried out on an Agilent 9870A
gas chromatography with quadrupole mass analyzer (GCꢀMS) equipped with a split/splitless injector; the
column set for all runs consisted of a 30 m × 0.250 mm HPꢀ5MS column; the oven temperature was
increased from 60 to 180 °C at the rate of 20 °C/min and was then further increased to 280 °C at 30
°C/min; the injector and MS transfer lines were at 280 and 230 °C, respectively, and the MS ionization
source was maintained at 230 °C using 70 eV; the spectrometer was operated with a mass scan range of
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30ꢀ400 m/z, resulting in an acquisition rate of 25 spectra/s; the data acquisitions were processed via the
GCꢀMS 5975C data analysis. IUPAC names of the compounds were generated using ChemBioDraw Ultra
13.0.
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2-((1R,2R,4aS,8aS)-2-Hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)-N-methoxy-N-
methylacetamide (5). Me3Al (1 M in heptane, 8.0 mL, 8.0 mmol, 2 equiv) was added to a suspension of
MeONHMe•HCl (756 mg, 7.7 mmol, 1 equiv) in dry CH2Cl2 (20 mL) at 0 °C (CAUTION! gas evolution). After
addition, the cooling bath was removed and the mixture was kept under magnetic stirring at room
temperature for 2 h. Next, a solution of (+)ꢀsclareolide (4, 97%, 1.00 g, 3.88 mmol, 1 equiv) in dry CH2Cl2
(10 mL) was added to the reaction, and the stirring continued for 18 h at room temperature. After cooling to
0 °C, an aqueous solution of HCl (1 M, 30 mL) was slowly added (CAUTION! gas evolution). The organic
phase was separated and the aqueous phase was extracted with CH2Cl2 (2 x 25 mL). The organic phases
were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography (SiO2, hexanes/EtOAc 50:50 to 30:70) to furnish amide 5 (908 mg, 2.9
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mmol) as a white solid in 75% yield. TLC (SiO2): Rf = 0.30 (hexanes/EtOAc 50:50); M.p.: 102ꢀ106 °C; [α]D
= +37 (c 1.0, CHCl3), [α]D,lit = +39.3 (c 0.98, CHCl3);30 1H NMR (250 MHz, CDCl3): δ 0.78 (s, 3H), 0.81 (s,
3H), 0.86 (s, 3H), 1.14 (s, 3H), 0.89ꢀ1.73 (m, 10H), 1.86ꢀ2.03 (m, 2H), 2.37ꢀ2.63 (m, 3H), 3.17 (s, 3H), 3.71
(s, 3H); 13C NMR (62.9 MHz, CDCl3): δ 15.7 (CH3), 18.4 (CH2), 20.5 (CH2), 21.3 (CH3), 23.2 (CH3), 26.8
(CH2), 33.1 (C), 33.2 (2CH3), 38.5 (C), 39.2 (CH2), 41.7 (CH2), 44.4 (CH2), 55.8 (CH), 56.1 (CH), 61.1
(CH3), 72.7 (C), 176.0 (C).
(3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldecahydronaphtho[2,1-b]furan-2(3aH)-one (7). Solid (+)ꢀ
sclareolide (4, 97%, 2.58 g, 10.0 mmol, 1 equiv) was added to a solution of sulfuric acid (95%, 1.68 mL,
30.0 mmol, 3 equiv) in formic acid (98%, 42 mL) at room temperature. After 4 h, the mixture was diluted
with cold H2O (100 mL) and extracted with Et2O (2 x 100 mL). The combined organic phases were washed
with saturated aqueous solution of NaHCO3 (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2,
hexanes/EtOAc 85:15) to furnish lactone 7 (2.25 g, 9.0 mmol) as a white solid in 90% yield. Note: The high
purity of formic acid (>97%) was essential for full conversion. The use of formic acid of 85% purity led to
incomplete conversion even with prolonged reaction time. TLC (SiO2): Rf = 0.70 (hexanes/EtOAc 50:50);
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M.p.: 87ꢀ89 °C; [α]D = −27 (c 1.0, CHCl3), [α]D,lit = −31.7 (c 0.4, CHCl3);9 1H NMR (250 MHz, CDCl3): δ
0.78 (s, 3H), 0.82 (s, 6H), 0.75ꢀ0.87 (m, 2H), 1.01ꢀ1.15 (m, 1H), 1.23 (s, 3H), 1.26ꢀ1.61 (m, 7H), 1.69 (d, J
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= 7.7 Hz, 1H), 2.14ꢀ2.26 (m, 1H), 2.27 (d, J = 18.0 Hz, 1H), 2.64 (dd, J = 17.9, 7.9 Hz, 1H); 13C NMR (62.9
MHz, CDCl3): δ 14.3 (CH3), 17.8 (CH2), 18.0 (CH2), 21.9 (CH3), 29.7 (CH3), 32.1 (CH2), 32.6 (C), 33.3
(CH3), 34.8 (CH2), 35.7 (C), 40.5 (CH2), 41.4 (CH2), 51.2 (CH), 54.4 (CH), 85.3 (C), 177.4 (C).
8
2-((1R,2S,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)-N-methoxy-N-
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methylacetamide (8). Me2AlCl (0.9 M in heptane, 8.0 mL, 7.2 mmol, 3 equiv) was added to a suspension of
MeONHMe•HCl (702 mg, 7.2 mmol, 1 equiv) in dry CH2Cl2 (20 mL) at 0 °C (CAUTION! gas evolution). After
addition, the cooling bath was removed and the mixture was kept under magnetic stirring at room
temperature for 2 h. Next, a solution of isosclareolide (7, 619 mg, 2.4 mmol, 1 equiv) in dry CH2Cl2 (20 mL)
was added to the reaction, and the stirring continued at room temperature for 18 h. After cooling to 0 °C, an
aqueous solution of HCl (1 M, 50 mL) was slowly added (CAUTION! gas evolution). The organic phase was
separated and the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The organic phases were
combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography (SiO2, hexanes/EtOAc 85:15 to 30:70) to furnish amide 8 (375 mg, 1.2
mmol) as a white solid in 50% yield (85% yield based on the recovery of starting material), along recovered
isosclareolide (7, 254 mg, 1.0 mmol) as a white solid in 41% yield. Note: Use of Me3Al led to little
conversion (<5%) and the use of Me2AlCl for prolonged reaction time at rt or use of refluxing conditions did
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not improve the yield. TLC (SiO2): Rf = 0.30 (hexanes/EtOAc 50:50); M.p.: 140ꢀ144 °C; [α]D = +24 (c 1.0,
1
CHCl3); IR (ATR, cmꢀ1): 3450, 2919, 2850, 1644, 1459, 1418, 1387, 1172, 1125, 1001, 915, 899; H NMR
(250 MHz, CDCl3): δ 0.78 (s, 3H), 0.83 (s, 3H), 0.93 (s, 3H), 1.00 (s, 3H), 0.87ꢀ1.07 (m, 2H), 1.08ꢀ1.76 (m,
10H), 1.81ꢀ1.89 (m, 1H), 2.28 (dd, J = 18.0, 2.7 Hz, 1H), 2.70 (dd, J = 18.0, 5.8 Hz, 1H), 3.13 (s, 3H), 3.67
(s, 3H); 13C NMR (62.9 MHz, CDCl3): δ 15.6 (CH3), 18.1 (CH2), 18.2 (CH2), 21.5 (CH3), 26.8 (CH2), 30.4
(CH3), 32.7 (CH3), 33.1 (C), 33.3 (CH3), 38.0 (C), 38.7 (CH2), 41.7 (CH2), 42.3 (CH2), 52.2 (CH), 55.3 (CH),
61.1 (CH3), 72.7 (C), 175.3 (C); HRMS (ESI +): m/z calculated for C18H33O3NNa+ [M+Na]+ 334.2353, found
334.2367.
N-methoxy-N-methyl-2-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-
yl)acetamide
(6)
and
N-methoxy-N-methyl-2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-
methylenedecahydronaphthalen-1-yl)acetamide. SOCl2 (1.16 mL, 16 mmol, 10 equiv) was added to dry
pyridine (7.5 mL) at 0 °C (CAUTION! exothermic process), this solution was stirred for 5 min, then was
transferred to a solution of alcohol 5 (498 mg, 1.60 mmol, 1 equiv) in dry pyridine (7.5 mL) at 0 °C. After 30
min, H2O (30 mL) was slowly added. The mixture was extracted with CH2Cl2 (2 x 30 mL), the organic
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phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography (SiO2, hexanes/EtOAc 85:15) to furnish endoꢀolefin 6 (100
mg, 0.34 mmol) as a colorless oil in 21% yield, along exoꢀolefin (330 mg, 1.12 mmol) as a white solid in
70% yield. Note: Attempts to isomerize the exoꢀolefin into the endoꢀolefin 6 as described by de la Torre and
coworkers8 led to poor results, obtaining at the best run 20% of the desired product as an inseparable
mixture with isosclareolide (7). The experimental procedure was conducted with 8 as reported for its epimer
(see above) to furnish the endoꢀolefin 6 (319 mg, 1.09 mmol) as a colorless oil in 68% yield, and trace
amounts (less than 5% yield) of the exoꢀolefin. Data for endoꢀolefin 6: TLC (SiO2): Rf = 0.26
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(hexanes/EtOAc 85:15); [α]D = +21 (c 1.0, CHCl3), [α]D,lit = +15.2 (c 0.25, CHCl3);8 1H NMR (250 MHz,
CDCl3): δ 0.79 (s, 3H), 0.85 (s, 3H), 0.87 (s, 3H), 1.52 (s, 3H), 1.00ꢀ2.06 (m, 9H), 2.28 (dd, J = 16.7, 2.5
Hz, 1H), 2.46 (dd, J = 16.7, 9.2 Hz, 1H), 2.61ꢀ2.72 (m, 1H), 3.17 (s, 3H), 3.68 (s, 3H), 5.40 (br. s, 1H); 13C
NMR (62.9 MHz, CDCl3): δ 14.0 (CH3), 18.5 (CH2), 21.1 (CH3), 21.6 (CH3), 23.5 (CH2), 28.9 (CH2), 32.6
(CH3), 32.7 (C), 32.9 (CH3), 35.7 (C), 38.7 (CH2), 41.9 (CH2), 48.8 (CH), 49.5 (CH), 60.9 (CH3), 121.9 (CH),
134.0 (C), 175.2 (C). Data for exoꢀolefin: TLC (SiO2): Rf = 0.19 (hexanes/EtOAc 85:15); M.p.: 82ꢀ85 °C (lit.:
84ꢀ86 °C); [α]D = −29 (c 1.0, CHCl3), [α]D,lit = −30.9 (c 0.99, CHCl3);30 1H NMR (250 MHz, CDCl3): δ 0.64
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(s, 3H), 0.72 (s, 3H), 0.79 (s, 3H), 0.98ꢀ1.70 (m, 9H), 1.93ꢀ2.11 (m, 1H), 2.21ꢀ2.34 (m, 2H), 2.39 (d, J =
10.3 Hz, 1H), 2.59 (dd, J = 15.5, 9.8 Hz, 1H), 3.05 (s, 3H), 3.62 (s, 3H), 4.34 (s, 1H), 4.62 (s, 1H); 13C NMR
(62.9 MHz, CDCl3): δ 14.4 (CH3), 18.9 (CH2), 21.4 (CH3), 23.7 (CH2), 26.8 (CH2), 32.1 (CH3), 33.1 (C), 33.2
(CH3), 37.2 (CH2), 38.47 (CH2), 38.53 (C), 41.7 (CH2), 51.2 (CH), 54.7 (CH), 60.9 (CH3), 105.5 (CH2), 149.2
(C), 174.2 (C).
2-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)acetaldehyde (11).
Solid LiAlH4 (361 mg, 9.5 mmol, 5 equiv) was added to a solution of amide 6 (558 mg, 1.90 mmol, 1 equiv)
in dry THF (38 mL) at 0 °C. After 2 h at the same temperature, an aqueous solution of HCl (1 M, 40 mL)
was slowly added (CAUTION! gas evolution). The mixture was extracted with EtOAc (80 mL), the organic
phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography (SiO2, hexanes/EtOAc 95:5) to furnish aldehyde 11 (388 mg, 1.65 mmol)
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as a colorless oil in 87% yield. TLC (SiO2): Rf = 0.32 (hexanes/EtOAc 95:5); [α]D = −15 (c 1.0, CHCl3),
[α]D,lit = −29.2 (c 0.161, CHCl3);31 1H NMR (250 MHz, CDCl3): δ 0.77 (s, 3H), 0.87 (s, 3H), 0.88 (s, 3H), 1.51
(s, 3H), 1.00ꢀ2.06 (m, 9H), 2.37ꢀ2.59 (m, 3H), 5.46 (br. s, 1H), 9.84 (t, J = 1.6 Hz, 1H); 13C NMR (62.9 MHz,
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CDCl3): δ 14.2 (CH3), 18.7 (CH2), 21.8 (CH3), 22.5 (CH3), 23.6 (CH2), 32.9 (C), 33.1 (CH3), 36.0 (C), 39.5
(CH2), 42.0 (CH2), 42.3 (CH2), 48.5 (CH), 49.8 (CH), 123.4 (CH), 132.9 (C), 203.5 (CH).
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3-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)propanenitrile (12).
TosMIC (83.7 mg, 0.42 mmol, 2 equiv) in dry diglyme (2 mL) was added dropwise to a mixture of tꢀBuOK
(74.4 mg, 0.63 mmol, 3 equiv) in diglyme (1 mL) at −60 °C, and the resulting mixture was stirred for 10 min.
A solution of aldehyde 11 (49.2 mg, 0.21 mmol, 1 equiv) in diglyme (2 mL) was added dropwise to the
reaction at −60 °C, the medium was stirred at this temperature for 1 h, and for 30 min at room temperature.
Next, dry MeOH (2.5 mL) was added, and the reaction was stirred at 60 °C for 1 h. After that, the volatiles
were removed under reduced pressure, and the residue was diluted with a saturated solution of NH4Cl and
the mixture was extracted with EtOAc (2 x 15 mL). The organic layers were combined, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to flash
chromatography (SiO2, hexanes/EtOAc 95:5 to 90:10) to give the nitrile 12 (26.5 mg, 0.108 mmol) as a
colorless oil in 51% yield. TLC (SiO2): Rf = 0.31 (hexanes/EtOAc 95:5);[α]D25 = − 1 (c 1.0, CHCl3); IR (ATR,
cm−1): 2923, 2848, 2245, 1457, 1388, 1168, 1051, 805; 1H NMR (250 MHz, CDCl3): δ 0.76 (s, 3H), 0.86 (s,
3H), 0.88 (s, 3H), 0.80ꢀ1.30 (m, 3H), 1.67 (s, 3H), 1.36ꢀ2.08 (m, 9H), 2.25ꢀ2.43 (m, 1H), 2.44ꢀ2.60 (m, 1H),
5.46 (br. s, 1H); 13C NMR (62.9 MHz, CDCl3): δ 13.6 (CH3), 18.6 (CH2), 18.9 (CH2), 21.8 (CH3), 22.0 (CH3),
23.1 (CH2), 23.7 (CH2), 32.9 (C), 33.1 (CH3), 36.6 (C), 39.0 (CH2), 42.0 (CH2), 49.8 (CH), 53.8 (CH), 119.9
(C), 123.9 (CH), 132.9 (C); HRMS (ESI +): m/z calculated for C17H27NNa+ [M+Na]+ 268.2036, found
268.2031.
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3-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)propanal (13). To a
suspension of (methoxymethyl)triphenylphosphonium chloride (163 mg, 0.46 mmol, 2 equiv) in dry THF (2
mL) was added a solution of LiHMDS (1 M in THF, 345 ꢁL, 0.345 mmol, 1.5 equiv) at 0 °C and the reaction
was stirred at this temperature for 30 min. After this period, the brownish mixture was transferred via
cannula to a flask containing a solution of aldehyde 11 (53.9 mg, 0.230 mmol, 1 equiv) in dry THF (2 mL) at
0 °C, and the resulting mixture was stirred for 30 min at 0 °C and 4 h at room temperature. Next, the
reaction was quenched by addition of saturated aqueous solution of NH4Cl (10 mL), and was extracted with
EtOAc (10 mL). The organic phase was washed with brine (5 mL), dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue obtained was subjected to flash chromatography (SiO2,
hexanes/EtOAc 95:5) to afford a mixture of (E) and (Z)ꢀenol ethers, which were immediately used in the
next reaction. TLC (SiO2): Rf = 0.45 (hexanes:EtOAc 95:5). The mixture of (E) and (Z)ꢀenol ethers obtained
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above was diluted in THF (2 mL) and a solution of HCl (6 M in H2O, 0.4 mL, 2.4 mmol, 10 equiv) was
added dropwise at 0 °C. The mixture was stirred at room temperature for 2 h, and was diluted with H2O (8
mL), followed by an extraction with EtOAc (8 mL). The organic phase was washed with brine (5 mL), dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to flash
chromatography (SiO2, hexanes/EtOAc 95:5) to give aldehyde 13 (44.0 mg, 0.177 mmol) as a colorless oil
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in 77% yield. TLC (SiO2): Rf = 0.30 (hexanes/EtOAc 95:5); [α]D = +21 (c 1.0, CHCl3); IR (ATR, cm−1):
2923, 2846, 1726, 1457, 1387, 1050, 983; 1H NMR (250 MHz, CDCl3): δ 0.79 (s, 3H), 0.85 (s, 3H), 0.88 (s,
3H), 0.81ꢀ1.04 (m, 1H), 1.15 (dd, J = 11.8, 5.0 Hz, 2H), 1.66 (s, 3H), 1.36ꢀ1.71 (m, 5H), 1.79ꢀ2.03 (m, 4H),
2.43 (dddd, J = 17.4, 8.8, 6.5, 1.9 Hz, 1H), 2.65 (dddd, J = 17.2, 9.9, 5.5, 1.6 Hz, 1H), 5.42 (br. s, 1H), 9.76
(t, J = 1.7 Hz, 1H); 13C NMR (62.9 MHz, CDCl3): δ 13.6 (CH3), 18.7 (CH2), 19.1 (CH2), 21.8 (CH3), 22.1
(CH3), 23.7 (CH2), 32.9 (C), 33.1 (CH3), 36.9 (C), 39.4 (CH2), 42.2 (CH2), 46.0 (CH2), 50.0 (CH), 54.3 (CH),
123.2 (CH), 134.1 (C), 202.4 (CH); HRMS (ESI +): m/z calculated for C17H28ONa+ [M+Na]+ 271.2032, found
271.2013.
(4aS,5S,8aS)-5-(but-3-yn-1-yl)-1,1,4a,6-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene
(14).
TMSCHN2 solution (2 M in hexanes, 0.76 mL, 1.52 mmol, 4 equiv) was added to THF (5 mL), the resulting
mixture was cooled to −78 °C, then a solution of nꢀBuLi (2.5 M in hexanes, 0.46 mL, 1.15 mmol, 3 equiv)
was added dropwise and the reaction was stirred at the same temperature for 30 min. Next, a solution of
aldehyde 13 (94.4 mg, 0.38 mmol, 1 equiv) in THF (3 mL) was added to the reaction and the resulting
mixture was stirred at −78 °C for 1 h, and then at room temperature for 1 h. The reaction was quenched by
addition of saturated aqueous solution of NH4Cl (10 mL), followed by the extraction with Et2O (2 x 10 mL).
The combined organic extracts were dried over anhydrous MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash chromatography (SiO2, hexanes) to afford the alkyne 14 (74.4
mg, 0.30 mmol) as a colorless oil in 80% yield. TLC (SiO2): Rf = 0.72 (hexanes); [α]D25 = +12 (c 1.0, CHCl3);
IR (ATR, cm−1): 3312, 2923, 2847, 2118, 1457, 1387, 1050, 983; H NMR (250 MHz, CDCl3): δ 0.76 (s,
1
3H), 0.86 (s, 3H), 0.88 (s, 3H), 0.80ꢀ1.29 (m, 4H), 1.96 (t, J = 2.6 Hz, 1H), 1.35ꢀ2.06 (m, 11H), 2.10ꢀ2.27
(m, 1H), 2.37 (dddd, J = 16.8, 9.0, 5.0, 2.5 Hz, 1H), 5.40 (br. s, 1H); 13C NMR (62.9 MHz, CDCl3): δ 13.6
(CH3), 18.7 (CH2), 20.3 (CH2), 21.8 (CH3), 22.1 (CH3), 23.8 (CH2), 26.2 (CH2), 32.9 (C), 33.1 (CH3), 36.6
(C), 39.1 (CH2), 42.2 (CH2), 50.0 (CH), 53.7 (CH), 68.3 (CH), 84.8 (C), 122.8 (CH), 134.5 (C); GC/MS (EI):
m/z calculated for C17H25 [M−CH3]+ 229, found: 229.
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4-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)butan-2-one
(2).
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Procedure A: MeMgBr solution (3 M in Et2O, 1.6 mL, 4.8 mmol, 3 equiv) was added dropwise to a solution
of nitrile 12 (393 mg, 1.6 mmol, 1 equiv) in dry Et2O (15 mL) at 0 °C, the reaction was warmed to room
temperature and was stirred for 16 h. The reaction was quenched by addition of saturated aqueous solution
of NH4Cl (10 mL), followed by extraction with EtOAc (2 x 20 mL). The combined organic extracts were
dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was subjected to
flash chromatography (SiO2, hexanes/EtOAc 90:10) to give the ketone 2 (295 mg, 1.1 mmol) as a colorless
oil in 70% yield. Note: Nitrile 12 and ketone 2 presented similar Rf using TLC with SiO2 and different
eluents, the progress of reaction was monitored by GC/MS analysis. Procedure B: To a pressure tube,
alkyne 14 (16.0 mg, 64 ꢁmol, 1 equiv), methanol (2 mL) and H2O (1 mL) were added, followed by
JohnPhosAuCl (1.7 mg, 3.2 ꢁmol, 5 mol %), the pressure tube was sealed and heated at 110 °C for 90
min. The mixture was cooled to room temperature, then methanol was removed under reduced pressure.
The remaining residue was extracted with CH2Cl2 (2 x 5 mL), the combined organic phases were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to flash
chromatography (SiO2, hexanes/EtOAc 95:5 to 90:10) to give ketone 2 (13.1 mg, 50 ꢁmol) as a colorless
oil in 78% yield. TLC (SiO2): Rf = 0.40 (hexanes/EtOAc 90:10); [α]D25 = +20 (c 1.0, CHCl3); IR (ATR, cm−1):
2924, 2851, 1717, 1662, 1463, 1365, 1331, 1162; 1H NMR (250 MHz, CDCl3): δ 0.77 (s, 3H), 0.85 (s, 3H),
0.88 (s, 3H), 0.81ꢀ1.24 (m, 4H), 1.66 (s, 3H), 1.33ꢀ1.71 (m, 4H), 1.72ꢀ2.05 (m, 4H), 2.14 (s, 3H), 2.41 (ddd,
J = 16.1, 9.9, 6.0 Hz, 1H), 2.64 (ddd, J = 16.7, 10.7, 5.3 Hz, 1H), 5.41 (br. s, 1H); 13C NMR (62.9 MHz,
CDCl3): δ 13.6 (CH3), 18.7 (CH2), 20.9 (CH2), 21.8 (CH3), 22.1 (CH3), 23.7 (CH2), 29.9 (CH3), 32.9 (C), 33.2
(CH3), 36.9 (C), 39.3 (CH2), 42.2 (CH2), 45.9 (CH2), 50.1 (CH), 54.3 (CH), 123.0 (CH), 134.4 (C), 208.8 (C);
HRMS (ESI +): m/z calculated for C18H30ONa+ [M+Na]+ 285.2189, found 285.2200.
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(E)-ethyl 3-methyl-5-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahy-dronaphthalen-1-
yl)pent-2-enoate (15). Triethyl phosphonoacetate (583 ꢁL, 2.85 mmol, 3 equiv) was added to a solution of
ketone 2 (249 mg, 0.95 mmol, 1 equiv) in dry toluene (9.5 mL) at room temperature. Next, sodium hydride
(60% w/w in mineral oil, 110 mg, 2.75 mmol, 2.9 equiv) was added to the mixture, which was then stirred
for 10 min at room temperature and for 14 h at 50 °C. After cooling to room temperature, the reaction was
quenched by the addition of brine (20 mL) and EtOAc (20 mL) was added to the mixture. The organic
phase was separated, dried over anhydrous MgSO4 and concentrated under reduced pressure. The
residue was subjected to flash chromatography (SiO2, hexanes/EtOAc 97:3) to give the ester 15 (236 mg,
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0.71 mmol) as a colorless oil in 75% yield. Note: The minor (Z)ꢀisomer was detected by GC/MS analysis of
the crude (ca. 5.5% of the product) and was separated from the (E)ꢀisomer during the chromatographic
purification. TLC (SiO2): Rf = 0.48 (hexanes/EtOAc 95:5); [α]D25 = +27 (c 1.0, CHCl3); IR (ATR, cm−1): 2923,
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1716, 1648, 1457, 1386, 1221, 1143, 1040, 861; H NMR (250 MHz, CDCl3): δ 0.75 (s, 3H), 0.85 (s, 3H),
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0.87 (s, 3H), 1.27 (t, J = 7.1Hz, 3H), 1.69 (s, 3H), 0.79ꢀ1.74 (m, 9H), 2.16 (d, J = 1.3 Hz, 3H), 1.74ꢀ2.22 (m,
4H), 2.26ꢀ2.43 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 5.40 (br. s, 1H), 5.66 (q, J = 1.0 Hz, 1H); 13C NMR (62.9
MHz, CDCl3): δ 13.5 (CH3), 14.3 (CH3), 18.7 (CH2), 18.9 (CH3), 21.8 (CH3), 22.1 (CH3), 23.8 (CH2), 25.3
(CH2), 32.9 (C), 33.1 (CH3), 36.8 (C), 39.1 (CH2), 42.2 (CH2), 43.4 (CH2), 50.1 (CH), 54.4 (CH), 59.4 (CH2),
115.5 (CH), 122.7 (CH), 134.7 (C), 160.3 (C), 166.8 (C); HRMS (ESI +): m/z calculated for C22H36O2Na+
[M+Na]+ 355.2608, found 355.2613.
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(E)-3-methyl-5-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydrona-phthalen-1-
yl)pent-2-enoic acid (16). Solid LiOH•H2O (298 mg, 12.2 mmol, 20 equiv) was added to a solution of ester
15 (203 mg, 0.610 mmol, 1 equiv) in a mixture of THF, iꢀPrOH and H2O (21 mL, 1:1:1). The reaction was
stirred at 60 °C for 20 h, then the volatiles were removed under reduced pressure. To the remaining
residue, EtOAc (30 mL) and HCl solution (1 M, 30 mL) were added. The organic phase was separated,
washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The
residue was subjected to flash chromatography (SiO2, hexanes/EtOAc 85:15) to give the carboxylic acid 16
25
(141 mg, 0.463 mmol) as a white solid in 76% yield. TLC (SiO2): Rf = 0.46 (hexanes/EtOAc 75:25); [α]D
=
+34 (c 1.0, CHCl3); IR (ATR, cm−1): 3441 (broad), 2946 (broad), 2924, 2849, 1693, 1639, 1437, 1257,
1
1173, 867; H NMR (250 MHz, CDCl3): δ 0.76 (s, 3H), 0.86 (s, 3H), 0.88 (s, 3H), 0.80ꢀ1.03 (m, 2H), 1.08ꢀ
1.73 (m, 7H), 1.70 (s, 3H), 2.19 (d, J = 1.1 Hz, 3H), 1.75ꢀ2.25 (m, 4H), 2.30ꢀ2.46 (m, 1H), 5.41 (br. s, 1H),
5.70 (q, J = 0.8 Hz, 1H), 11.46 (br. s, 1H); 13C NMR (62.9 MHz, CDCl3): δ 13.5 (CH3), 18.7 (CH2), 19.3
(CH3), 21.8 (CH3), 22.1 (CH3), 23.8 (CH2), 25.3 (CH2), 32.9 (C), 33.1 (CH3), 36.8 (C), 39.2 (CH2), 42.2
(CH2), 43.6 (CH2), 50.1 (CH), 54.4 (CH), 115.1 (CH), 122.8 (CH), 134.6 (C), 163.6 (C), 172.2 (C); HRMS
(ESI +): m/z calculated for C20H32O2Na+ [M+Na]+ 327.2295, found 327.2286.
(4aS,5S,8aS)-5-((E)-4-iodo-3-methylbut-3-en-1-yl)-1,1,4a,6-tetramethyl-1,2,3,4,4a,5,8,8a-
octahydronaphthalene (3). A flask was charged with carboxylic acid 16 (93.2 mg, 0.306 mmol, 1 equiv) and
CTAB (113 mg, 0.306 mmol, 1 equiv), the flask was purged with nitrogen, and dry acetonitrile (7 mL) was
added followed by NIS (138 mg, 0.612 mmol, 2 equiv). The reaction mixture was heated at 80 °C for 1 h
and, after cooling to room temperature, solvent was partially removed under reduced pressure to ~1 mL of
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crude reaction mixture. This residue was subjected to flash chromatography (SiO2, hexanes) to give the
iodide 3 (56.5 mg, 0.146 mmol) as a colorless oil in 48% yield. TLC (SiO2): Rf = 0.90 (hexanes); [α]D25 = +5
(c 1.0, CHCl3), [α]D,lit20 = +3 (c 0.8, CHCl3);6 1H NMR (250 MHz, CDCl3): δ 0.75 (s, 3H), 0.86 (s, 3H), 0.88 (s,
3H), 0.80ꢀ1.02 (m, 2H) 1.07ꢀ1.64 (m, 10H), 1.68 (s, 3H), 1.85 (d, J = 0.8 Hz, 3H), 1.75ꢀ2.06 (m, 3H), 2.16
(ddd, J = 14.1, 10.3, 6.3 Hz, 1H), 2.40 (ddd, J = 14.4, 11.4, 4.6 Hz, 1H), 5.40 (br. s, 1H), 5.90 (q, J = 0.8
Hz, 1H); 13C NMR (62.9 MHz, CDCl3): δ 13.6 (CH3), 18.8 (CH2), 21.8 (CH3), 22.2 (CH3), 23.8 (CH2), 24.0
(CH3), 25.6 (CH3), 32.9 (C), 33.1 (CH3), 36.8 (C), 39.2 (CH2), 42.0 (CH2), 42.3 (CH2), 50.1 (CH), 54.3 (CH),
74.9 (CH), 122.6 (CH), 134.8 (C), 148.5 (C).
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(E)-3-methyl-5-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-
yl)pent-2-en-1-ol (17). A freshly prepared solution of DIBALꢀH (1.0 M in CH2Cl2, 215 ꢁL, 215 ꢁmol, 5 equiv)
was added to a solution of ester 15 (14.3 mg, 43 ꢁmol, 1 equiv) in dry CH2Cl2 (2 mL) at 0 °C. After stirring
the reaction for 1 h at 0 °C, Et2O (10 mL) and saturated aqueous solution of Rochelle’s salt were added,
and the reaction was vigorously stirred for 30 min at 0 °C and 1 h at room temperature. After separation of
phases, the aqueous layer was extracted with Et2O (10 mL). The organic phases were combined, dried
over anhydrous MgSO4 and concentrated under reduced pressure. The residue was subjected to flash
chromatography (SiO2, hexanes/EtOAc 97:3 to 90:10) to afford the alcohol 17 (10 mg, 34 ꢁmol) as a
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colorless oil in 80% yield. TLC (SiO2): Rf = 0.27 (hexanes/EtOAc 90:10); [α]D = +5 (c 0.5, CHCl3), [α]D,lit
= +12 (c 0.690, CHCl3);19 1H NMR (250 MHz, CDCl3): δ 0.76 (s, 3H), 0.86 (s, 3H), 0.88 (s, 3H), 0.80ꢀ1.04
(m, 2H), 1.56 (s, 3H), 1.69 (s, 3H), 1.05ꢀ2.09 (m, 12H), 2.13ꢀ2.31 (m, 1H), 4.09ꢀ4.20 (m, 2H), 5.33ꢀ5.47 (m,
2H); 13C NMR (62.9 MHz, CDCl3): δ 13.5 (CH3), 16.4 (CH3), 18.8 (CH2), 21.8 (CH3), 22.2 (CH3), 23.8 (CH2),
25.6 (CH2), 32.9 (C), 33.1 (CH3), 36.8 (C), 39.1 (CH2), 42.0 (CH2), 42.3 (CH2), 50.1 (CH), 54.4 (CH), 59.4
(CH2), 122.3 (CH), 123.3 (CH), 135.2 (C), 140.4 (C).
(E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime (21). MeONH2•HCl (690 mg, 8.1
mmol, 2.7 equiv) and NaOAc (1.09 g, 13.2 mmol, 4.4 equiv) were added to a solution of tetralone 20 (534
mg, 3.0 mmol, 1 equiv) in a mixture of ethanol/H2O (15 mL, 4:1 v/v), then the mixture was stirred for 2 h at
70 °C. Next, the mixture was diluted with brine (25 mL), and was extracted with EtOAc (3 x 25 mL), the
organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure
to furnish the methyl oxime 21 (616 mg, 3.0 mmol) as a colorless oil in quantitative yield, which was used in
the next step without further purification. TLC (SiO2): Rf = 0.64 (hexanes/EtOAc 75:25); 1H NMR (250 MHz,
CDCl3): δ 1.83 (quint., J = 6.2 Hz, 2H), 2.71 (t, J = 6.5 Hz, 4H), 3.80 (s, 3H), 3.97 (s, 3H), 6.63 (d, J = 2.4
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Hz, 1H), 6.75 (dd, J = 8.8, 2.7 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H); 13C NMR (62.9 MHz, CDCl3): δ 21.5 (CH2),
24.1 (CH2), 30.0 (CH2), 55.1 (CH3), 61.7 (CH3), 112.7 (CH), 112.8 (CH), 123.4 (C), 125.7 (CH), 141.2 (C),
153.8 (C), 160.1 (C).
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(E)-6,8-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime (22) and 6,8-dimethoxy-3,4-
dihydronaphthalen-1(2H)-one (23). First step: Oxone (2.46 g, 4.0 mmol, 2.0 equiv) and Pd(OAc)2 (22.5 mg,
0.1 mmol, 5 mol %) were added to a solution of methyl oxime 21 (411 mg, 2.0 mmol, 1 equiv) in dry MeOH
(12 mL) at room temperature, and this mixture was stirred at this temperature for 24 h. Next, the reaction
mixture was diluted with EtOAc (50 mL) and washed with H2O (40 mL), saturated aqueous solution of
NaHCO3 (20 mL) and brine (20 mL). The organic phase was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2,
hexanes/EtOAc 75:25 to 50:50) to furnish methyl oxime 22 (193 mg, 0.82 mmol) as a yellow oil in 41%
yield and tetralone 23 (25 mg, 0.12 mmol) as an offꢀwhite solid in 6% yield. Second step: A solution of HCl
(6 M in H2O, 1.0 mL, 6.0 mmol, 22 equiv) was added to a solution of oxime 22 (64.0 mg, 0.27 mmol, 1
equiv) in 1,4ꢀdioxane (4.5 mL). After addition, the mixture was heated to 80 °C under magnetic stirring for 2
h. Next, the mixture was diluted with EtOAc (20 mL), washed with brine (2 x 10 mL), the organic phase was
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash
chromatography (SiO2, hexanes/EtOAc 50:50) to furnish tetralone 23 (46.2 mg, 0.22 mmol) as an offꢀwhite
solid in 82% yield. Data for methyl oxime 22: TLC (SiO2): Rf = 0.30 (hexanes/EtOAc 75:25); 1H NMR (250
MHz, CDCl3): δ 1.69 (quint., J = 6.3 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 3.77 (s, 3H),
3.82 (s, 3H), 3.96 (s, 3H), 6.29 (d, J = 2.4 Hz, 2H), 6.36 (d, J = 2.4 Hz, 2H); 13C NMR (62.9 MHz, CDCl3): δ
21.1 (CH2), 25.4 (CH2), 31.4 (CH2), 55.1 (CH3), 56.0 (CH3), 61.5 (CH3), 97.8 (CH), 104.6 (CH), 112.8 (C),
144.4 (C), 153.7 (C), 159.1 (C), 160.2 (C). Data for tetralone 23: TLC (SiO2): Rf = 0.36 (hexanes/EtOAc
50:50); M.p.: 62ꢀ64 °C; 1H NMR (250 MHz, CDCl3): δ 1.98 (quint., J = 6.2 Hz, 2H), 2.55 (t, J = 6.5 Hz, 2H),
2.85 (t, J = 6.1 Hz, 2H), 3.81 (s, 3H), 3.85 (s, 3H), 6.26ꢀ6.34 (m, 2H); 13C NMR (62.9 MHz, CDCl3): δ 22.7
(CH2), 31.5 (CH2), 40.7 (CH2), 55.3 (CH3), 55.8 (CH3), 97.1 (CH), 104.5 (CH), 116.3 (C), 149.2 (C), 162.5
(C), 163.7 (C), 196.0 (C).
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2-hydroxyethyl 4-(3,5-dimethoxyphenyl)butanoate (25). pTSA•H2O (1.9 mg, 10 ꢁmol, 10 mol %),
tetralone 23 (20.6 mg, 0.1 mmol, 1 equiv) and ethylene glycol (1 mL) were placed in an open flask, which
was heated at 140 °C for 24 h. Then, the reaction contents were diluted with EtOAc (20 mL) and saturated
solution of NaHCO3 (10 mL), the organic phase was separated, washed with H2O (10 mL) and brine (10
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mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by
flash chromatography (SiO2, hexanes:EtOAc 60:40) to afford ester 25 (26.3 mg, 98 ꢁmol) in 98% yield as a
colorless oil. TLC (SiO2): Rf = 0.52 (hexanes/EtOAc 50:50); IR (ATR, cm−1): 3432 (broad), 2940, 2841,
1731, 1596, 1461, 1205, 1150, 1070, 832; 1H NMR (250 MHz, CDCl3): δ 1.95 (quint., J = 7.5 Hz, 2H), 2.09
(br. s, 1H), 2.36 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 3.77 (s, 6H), 3.74ꢀ3.85 (m, 2H), 4.16ꢀ4.23 (m,
2H), 6.27ꢀ6.35 (m, 3H); 13C NMR (62.9 MHz, CDCl3): δ 26.0 (CH2), 33.2 (CH2), 35.1 (CH2), 55.0 (2CH3),
60.7 (CH2), 65.7 (CH2), 97.9 (CH), 106.4 (2CH), 143.5 (C), 160.6 (2C), 173.7 (C); HRMS (ESI +): m/z
calculated for C14H21O5+ [M+H]+ 269.1383, found 269.1380.
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6',8'-dimethoxy-3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-naphthalene] (24). PPTS (8.7 mg, 34 ꢁmol,
10 mol %) and ethylene glycol (57 ꢁL, 1 mmol, 3 equiv) were added to a solution of tetralone 23 (70.1 mg,
0.34 mmol, 1 equiv) in dry benzene (8 mL) in a DeanꢀStark apparatus, the reaction was stirred under
vigorous reflux for 14 h. After cooling to room temperature, solid K2CO3 (33 mg) was added and the
volatiles were removed under reduced pressure. The residue was purified by flash chromatography (SiO2,
hexanes/EtOAc/Et3N 75:25:1) to furnish ketal 24 (42.6 mg, 0.17 mmol) as a colorless oil in 50% yield. Note:
Ketal 24 started decomposing back to tetralone 23 in a few hours of storing. TLC (SiO2): Rf = 0.40
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(hexanes/EtOAc 75:25); H NMR (250 MHz, CDCl3): δ 1.75ꢀ2.07 (m, 4H), 2.66ꢀ2.82 (m, 2H), 3.75 (s, 3H),
3.80 (s, 3H), 4.00ꢀ4.30 (m, 4H), 6.20 (d, J = 2.0 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H); 13C NMR (62.9 MHz,
CDCl3): δ 21.0 (CH2), 31.0 (CH2), 36.7 (CH2), 55.1 (CH3), 55.7 (CH3), 65.3 (2CH2), 97.8 (CH), 104.1 (CH),
108.0 (C), 117.6 (C), 142.2 (C), 159.9 (C), 160.1 (C).
2-hydroxyethyl 4-(3,4,5-trimethoxyphenyl)butanoate (35) and 8-hydroxy-6,7-dimethoxy-3,4-
dihydronaphthalen-1(2H)-one (34). pTSA•H2O (1.9 mg, 10 ꢁmol, 10 mol %), tetralone 33 (23.6 mg, 0.1
mmol, 1 equiv) and ethylene glycol (1 mL) were placed in a flask, which was heated at 140 °C for 24 h.
Then, the reaction contents were diluted with EtOAc (20 mL) and saturated solution of NaHCO3 (10 mL),
the organic phase was separated, washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2,
hexanes:EtOAc 60:40 to 30:70) to afford ester 35 (18.0 mg, 60 ꢁmol) in 60% yield and tetralone 34 (7.1
mg, 32 ꢁmol) in 32% yield. Data for compound 35: TLC (SiO2): Rf = 0.36 (hexanes/EtOAc 30:70); IR (ATR,
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cm−1): 3448 (broad), 2941, 2841, 1730, 1590, 1508, 1458, 1238, 1125, 1006, 826; H NMR (250 MHz,
CDCl3): δ 1.90 (br. s, 1H), 1.95 (quint., J = 7.4 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H),
3.81 (s, 3H), 3.84 (s, 6H), 3.79ꢀ3.86 (m, 2H), 4.16ꢀ4.24 (m, 2H), 6.39 (s, 2H); 13C NMR (62.9 MHz, CDCl3):
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δ 26.5 (CH2), 33.4 (CH2), 35.5 (CH2), 56.1 (2CH3), 60.8 (CH3), 61.2 (CH2), 65.9 (CH2), 105.4 (2CH), 136.2
(C), 137.0 (C), 153.1 (2C), 173.8 (C); HRMS (ESI +): m/z calculated for C15H22O6Na + [M+Na]+ 321.1309,
found 321.1308. Data for compound 34: TLC (SiO2): Rf = 0.44 (hexanes/EtOAc 60:40); IR (ATR, cm−1):
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2923, 2844, 1634, 1574, 1422, 1289, 1104, 1012, 789; H NMR (400 MHz, CDCl3): δ 2.07 (quint., J = 6.2
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Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.91 (s, 3H), 6.29 (s, 1H), 12.69 (s,
1H); 13C NMR (62.9 MHz, CDCl3): δ 23.0 (CH2), 30.0 (CH2), 38.4 (CH2), 56.0 (CH3), 60.7 (CH3), 102.6
(CH), 112.5 (C), 134.4 (C), 141.9 (C), 157.1 (C), 158.3 (C), 203.6 (C); HRMS (ESI +): m/z calculated for
C12H15O4+ [M+H]+ 223.0965, found 223.0967.
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2-hydroxyethyl 3-(3,5-dimethoxyphenyl)propanoate (37). pTSA•H2O (1.9 mg, 10 ꢁmol, 10 mol %),
bicycle 36 (19.2 mg, 0.1 mmol, 1 equiv) and ethylene glycol (1 mL) were placed in a flask, which was
heated at 140 °C for 24 h. Then, the reaction contents were diluted with EtOAc (20 mL) and saturated
solution of NaHCO3 (10 mL), the organic phase was separated, washed with H2O (10 mL) and brine (10
mL), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2,
hexanes:EtOAc 50:50) furnished ester 37 (24.3 mg, 96 ꢁmol) in 93% yield. TLC (SiO2): Rf = 0.48
(hexanes/EtOAc 50:50); IR (ATR, cm−1): 3413 (broad), 2965, 2925, 2841, 1732, 1596, 1462, 1205, 1151,
1068, 835; 1H NMR (250 MHz, CDCl3): δ 1.60ꢀ1.74 (m, 4H), 2.01 (br. s, 1H), 2.37 (t, J = 7.0 Hz, 2H), 2.57
(t, J = 6.8 Hz, 2H), 3.77 (s, 6H), 3.77ꢀ3.85 (m, 2H), 4.16ꢀ4.23 (m, 2H), 6.30 (t, J = 2.0 Hz, 1H), 6.33 (d, J =
2.0 Hz, 2H); 13C NMR (62.9 MHz, CDCl3): δ 24.5 (CH2), 30.5 (CH2), 34.0 (CH2), 35.8 (CH2), 55.2 (2CH3),
61.2 (CH2), 65.9 (CH2), 97.7 (CH), 106.5 (2CH), 144.4 (C), 160.7 (2C), 173.9 (C); HRMS (ESI +): m/z
calculated for C13H18O5Na + [M+Na]+ 277.1046, found 277.1046.
2-hydroxyethyl 5-(3,5-dimethoxyphenyl)pentanoate (39). pTSA•H2O (1.9 mg, 10 ꢁmol, 10 mol %),
bicycle 38 (22.0 mg, 0.1 mmol, 1 equiv) and ethylene glycol (1 mL) were placed in a flask, which was
heated at 140 °C for 24 h. Then, the reaction contents were diluted with EtOAc (20 mL) and saturated
solution of NaHCO3 (10 mL), the organic phase was separated, washed with H2O (10 mL) and brine (10
mL), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2,
hexanes:EtOAc 50:50) furnished ester 39 (25.2 mg, 89 ꢁmol) in 89% yield. TLC (SiO2): Rf = 0.50
(hexanes/EtOAc 50:50); IR (ATR, cm−1): 3418 (broad), 2940, 2855, 2833, 1732, 1596, 1461, 1205, 1150,
1056, 831; 1H NMR (250 MHz, CDCl3): δ 1.88 (br. s, 1H), 2.67 (t, J = 7.5 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H),
3.77 (s, 6H), 3.77ꢀ3.84 (m, 2H), 4.17ꢀ4.25 (m, 2H), 6.32 (t, J = 2.2 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H); 13C
NMR (62.9 MHz, CDCl3): δ 31.2 (CH2), 35.5 (CH2), 55.2 (2CH3), 61.1 (CH2), 66.1 (CH2), 98.2 (CH), 106.3
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(2CH), 142.7 (C), 160.8 (2C), 173.1 (C); HRMS (ESI +): m/z calculated for C15H23O5 [M+H]+ 283.1540,
found 283.1538.
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(R)-1-(3,5-dimethoxyphenyl)but-3-en-1-ol (41). A pressure tube was charged with [Ir(cod)Cl2] (31 mg,
45 ꢁmol, 2.5 mol %), Cs2CO3 (117 mg, 0.36 mmol, 20 mol %), 4ꢀchloroꢀ3ꢀnitrobenzoic acid (37 mg, 0.18
mmol, 10 mol %), (R)ꢀBINAP (57 mg, 90 ꢁmol, 5 mol %) and alcohol 40 (303 mg, 1.8 mmol, 1 equiv). The
tube was purged with argon, and dry THF (6 mL) was added followed by allyl acetate (392 ꢁL, 3.6 mmol, 2
equiv), the pressure tube was sealed and heated at 100 °C for 40 h. The solvent was removed under
reduced pressure, and the brown residue was subjected to flash chromatography (SiO2, hexanes:EtOAc,
75:25) to give the alcohol 41 (280 mg, 1.3 mmol) as a colorless oil in 75% yield. TLC (SiO2): Rf = 0.40
(hexanes:EtOAc 75:25); ee = 92% (determined by 1H NMR of Mosher ester derivatives); [α]D25 = +39 (c 1.0,
CHCl3); 1H NMR (250 MHz, CDCl3): δ 2.19 (br. s, 1H), 2.44ꢀ2.53 (m, 2H), 3.78 (s, 6H), 4.65 (t, J = 6.4 Hz,
1H), 5.09ꢀ5.21 (m, 2H), 5.80 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H), 6.37 (t, J = 2.3 Hz, 1H), 6.52 (d, J = 2.2 Hz,
2H); 13C NMR (62.9 MHz, CDCl3): δ 43.7 (CH2), 55.3 (2CH3), 73.3 (CH), 99.4 (CH), 103.7 (2CH), 118.3
(CH2), 134.4 (CH), 146.5 (C), 160.8 (2C); IR (ATR, cm−1): 3404 (broad), 2937, 2840, 1596, 1460, 1430,
1296, 1205, 1151, 1054, 920, 838, 698; HRMS (ESI +): m/z calculated for C12H16O3Na+ [M+Na]+ 231.0992,
found 231.0985.
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(S)-1-(1-bromobut-3-en-1-yl)-3,5-dimethoxybenzene (43). CBr4 (1.61 g, 4.8 mmol, 2 equiv) and PPh3
(1.26 g, 4.8 mmol, 2 equiv) were added to a solution of alcohol 41 (500 mg, 2.4 mmol, 1 equiv) in CH2Cl2
(20 mL) at 0 °C. After stirring the reaction for 1 h at 0 °C, iceꢀcold H2O (20 mL) was added. The mixture
was extracted with CH2Cl2 (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2,
hexanes/EtOAc 95:5) to give the bromide 43 (530 mg, 1.95 mmol) as a colorless oil in 81% yield. TLC
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(SiO2): Rf = 0.28 (hexanes:EtOAc 95:5); [α]D = −78 (c 0.5, CHCl3); H NMR (250 MHz, CDCl3): δ 2.87ꢀ
3.05 (m, 2H), 3.80 (s, 6H), 4.87 (t, J = 7.4 Hz, 1H), 5.06ꢀ5.21 (m, 2H), 5.76 (ddt, J = 17.1, 10.3, 6.6 Hz, 1H),
6.39 (t, J = 2.3 Hz, 1H), 6.55 (d, J = 2.4 Hz, 2H); 13C NMR (62.9 MHz, CDCl3): δ 43.9 (CH2), 54.0 (CH),
55.4 (2CH3), 100.3 (CH), 105.5 (2CH), 118.1 (CH2), 134.7 (CH), 143.7 (C), 160.8 (2C); IR (ATR, cm−1):
3004, 2939, 2840, 1599, 1462, 1432, 1208, 1158, 1067, 927, 838, 724; HRMS (ESI +): m/z calculated for
C12H16O2Br+ [M+H]+ 271.0328, found 271.0329.
(R)-4-benzyl-3-(2-(3,5-dimethoxyphenyl)acetyl)oxazolidin-2-one (47). Et3N (418 ꢁL, 3 mmol, 3 equiv)
was added to a mixture of (R)ꢀ4ꢀbenzylꢀ2ꢀoxazolidinone (45, 181 mg, 1 mmol, 1 equiv), carboxylic acid 46
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