An approach to seco-prezizaane sesquiterpenoids: Enantioselective total synthesis of (+)-1S-minwanenone

Article abstract of DOI:10.1021/jo301258g

A strategy of general applicability toward seco-prezizaane sesquiterpenes, from a chiral, tricyclic synthon, readily available via an enzymatic resolution step from the Diels-Alder adduct of cyclopentadiene and p-benzoquinone, has been devised. Our approach enables harnessing of the stereochemical proclivities of the norbornyl system to install the desired stereochemistry at the key stereogenic centers. Recourse to an interesting stratagem to realign a stereochemical divergence into stereoreconvergence forms the cornerstone of our successful approach. The first total synthesis of (+)-1S-minwanenone, a prototypical member of seco-prezizaane subclass, has been accomplished.

Full text of DOI:10.1021/jo301258g

Article
pubs.acs.org/joc
An Approach to seco-Prezizaane Sesquiterpenoids: Enantioselective
Total Synthesis of (+)‑1S‑Minwanenone
Goverdhan Mehta*,†,‡ and Harish M. Shinde†
†Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
‡School of Chemistry, University of Hyderabad, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: A strategy of general applicability toward seco-prezizaane
sesquiterpenes, from a chiral, tricyclic synthon, readily available via an
enzymatic resolution step from the Diels−Alder adduct of cyclopentadiene
and p-benzoquinone, has been devised. Our approach enables harnessing of
the stereochemical proclivities of the norbornyl system to install the desired
stereochemistry at the key stereogenic centers. Recourse to an interesting
stratagem to realign a stereochemical divergence into stereoreconvergence
forms the cornerstone of our successful approach. The first total synthesis of
(+)-1S-minwanenone, a prototypical member of seco-prezizaane subclass, has
been accomplished.
INTRODUCTION
■
seco-Prezizaane-type sesquiterpenoids constitute a biosyntheti-
cally fascinating, architecturally variegated, and rapidly growing
class of natural products that are found widely distributed
among the exotic Illicium species.1,2 From a structural perspec-
tive, seco-prezizaanes are compact, caged, polycyclic constructs
that are adorned with an array of dense and diverse oxygen
functionalities with attendant stereochemical intricacies. A few
representative examples (1−4) of seco-prezizaane-type sesqui-
terpenoids are displayed in Figure 1. Owing to their many un-
common structural features and rich functionalization patterns,
seco-prezizaanes harbor attributes of being promising new scaf-
folds for exploring their therapeutical potential. Indeed, several
members of this family exhibit wide-ranging bioactivity profiles.
However, it is the specific and encouraging role of seco-prezizaanes
as promoters of neurite growth and as effective inhibitors of GABA
action3e,f in the central nervous system (CNS) that has captured a
great deal of attention.2,3 This is particularly so because neuro-
degeneration and attendant disorders are emerging as a major
public health challenge in the 21st century in view of the ad-
vancing age profile of the world population.
It is hardly surprising therefore that total synthesis endeavors
toward seco-prezizaane natural products has emerged as an
arena of contemporary interest and holds considerable syn-
thetic challenge, not only for developing and validating new
methodologies and strategies for total synthesis but also for
amplifying Nature’s repertoire through diverted total synthesis
and make available new natural product inspired entities for
therapeutic profiling, particularly as neurotrophic agents. A
spate of publications4 in the recent past, from various research
groups spread across continents and our own efforts5 in the
area, bear testimony to the emergent interest of the synthesis
community in seco-prezizaane natural products. In this regard,
pioneering contributions of Danishefsky and more recently of
Figure 1. Representative seco-prezizaane sesquiterpenoids.
Theodorakis and Fukuyama groups among others are notable.4 In
our laboratory, there are ongoing efforts directed toward developing
general protocols to access diverse members of seco-prezizaanes and
related natural products, particularly those that are neurotrophically
active.5 As an offering from such endeavors, we describe in detail the
first total synthesis of (+)-1S-minwanenone 5, an enantiomer of
natural product (−)-1R-minwanenone 1a and a prototypical
member of the seco-prezizaane family.5c,6 En route our successful
journey toward (+)-1S-minwanenone 5, we have witnessed the
formation of the tetracyclic core present in the natural product
merrillianone 2, which in turn underlines the inbuilt flexibility of
our synthetic approach for adaptation toward the other members
of this complex natural product family.4,5
Received: June 24, 2012
Published: August 16, 2012
© 2012 American Chemical Society
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The Johnson orthoester rearrangement in γ-hydroxycyclohex-
enone 9 was expected to stereoselectively set up the C9 quaternary
center in 8. The cyclohexenone 9 was to be obtained through
elaboration of the previously reported7 endo-tricyclo-[6.2.1.02,7]-
undeca-4,9-dien-3-one (+)-10. The choice of the chiral endo-
tricyclic synthon (+)-10, as the launching platform, was a key
tactic as it harnessed the well established propensity of the
endo-norbornyl-fused systems toward exo-face selectivity due to
inherent topological bias. This was expected to facilitate the
stereoselective installation of critical C5,C6 stereogenic centers
during the early stages of the synthesis.
RESULTS AND DISCUSSION
■
In order to pursue the retrosynthetic theme outlined in Figure 2,
starting chiral synthon (+)-10 was accessed in enantiomerically
pure (>99% ee) form and in multigram quantity from the
readily available Diels−Alder adduct of cyclopentadiene and
p-benzoquinone, following a reported procedure and involving
enzymatic resolution as the key step.7 The choice of (+)-10
rather than its enantiomer (−)-10 was dictated by the more
convenient (relatively speaking) access to it. Michael addition
of methyl-cuprate on enone (+)-10 proceeded smoothly in
the presence of TMSCl as an additive and after acidic workup
delivered (−)-11 as a single diastereomer.8 Methylation of
(−)-11 under kinetically controlled conditions was once again
stereoselective (>90%) and afforded the dimethylated product
(+)-12 (see Scheme 1). The C5 quaternary center with re-
quisite relative disposition with respect to the C6 stereocenter
was now set through stereoselective α-hydroxymethylation in
(+)-12 from the exo-face to deliver the diol (−)-13 as a single
diastereomer. Both hydroxyl groups in (−)-13 were now
protected as MOM derivative (−)-14 prior to the removal of
the norbornyl scaffold. Thermal activation in (−)-14 disen-
gaged the norbornyl scaffold through a facile retro-Diels−Alder
process to afford cyclohexenone (−)-15. Deprotection of the
TBS protecting group in (−)-15 provided the γ-hydroxycyclo-
hexenone (−)-16 (see Scheme 1), the precursor for the pro-
jected [3,3] sigmatropic rearrangement (see Figure 2).
Figure 2. Retrosynthetic analysis of target natural product 5.
The Fukuyama group's extensive and pioneering search for
biologically active substances from the Illicium species led to the
isolation of (−)-1R-minwanenone 1a and its epimer (−)-1S-
minwanenone 1b along with several other seco-prezizaane type
sesquiterpenoids from the methanol extract of the pericarps
of Illicium minwanense in 2003.1 The stereostructures of min-
wanenones 1a and 1b were established through incisive NMR
studies, and their biosynthetic kinship with other co-occurring
sibling natural products was employed to deduce their absolute
configuration.1 The bioactivity profile of 1a,b has not yet been
reported. However from a truly synthetic perspective, the
tricyclic skeleton of minwanenones 1a,b embodying five stereo-
centers (two of which are quaternary) and with an array of func-
tional groups such as a bridged lactone, enone, and a primary
hydroxyl group, accounting for four oxygens, poses consid-
erable total synthesis challenge. While conceptualizing our syn-
thetic strategy toward minwanenones, we also factored in the
possibility of generalizing it toward the other members of the
seco-prezizaanes family.2
Retrosynthetically, it was envisaged that the bridged lactone
segment of tricyclic (+)-1S-minwanenone 5 could be installed at the
end on an appropriately functionalized bicyclic enone 6, which in
turn could be obtained via stereoselective methylation, one carbon
homologation, and functional group adjustment in the protected
derivative 7. Access to enone 7 was contemplated from keto-ester 8
through an intramolecular Horner−Wadsworth−Emmons reaction.
The Johnson-orthoester rearrangement9 in (−)-16 could be
implemented under standard protocol and was expectedly stereo-
selective and furnished the keto-ester (+)-18 along with the simple
dehydrated (under thermal activation) 1,3-diene product (−)-17 in
2.6:1 ratio (based on isolated yields), respectively (see Scheme 2).
Scheme 1. Synthesis of γ-Hydroxycyclohexenone (−)-16
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Scheme 2. Preparation of Bicyclic Aldehyde 25
Chemoselective addition of lithiated dimethyl methylphosphonate
on keto-ester (+)-18 proceeded smoothly and delivered the
β-ketophosphonate (+)-19 quite conveniently. Subsequent
exposure of (+)-19 to NaH in refluxing THF executed the
desired HWE cyclization and provided the bicyclic enone
(+)-20 in excellent yield.10 Kinetically controlled methylation
in (+)-20 was again stereoselective with addition from the face
opposite to the bridgehead substituent and furnished the (+)-21
as a single diastereomer. At this stage it was considered essential
to confirm the stereochemical integrity of (+)-21, and therefore
and base, solvent, and temperature or recourse to Peterson
olefination12b or Wittig−Horner reaction12a with (alkoxymethyl)-
phosphonate ester failed to deliver the desired aldehyde 25 in
acceptable yield. It is reasonable to speculate that steric conges-
tion engendered by the neopentyl nature of the aldehyde func-
tionality in (+)-23 is the causative factor for the poor out-
come of the homologation reaction. In addition, formation of
undesired dehydration product (−)-17 during the [3,3]-
sigmatropic rearrangement of (−)-16 was also a significant
liability. Overall, access to functionally garnished and stereo-
chemically secured bicycle (+)-23 in a concise manner was a
satisfying outcome; however, our repeated failures to obtain key
aldehyde 25 in preparatively viable amounts warranted some
reflection and underscored the need to rework our synthetic
strategy at this juncture. Grudgingly, it was decided to revert
back to the chiral synthon (+)-10 and craft a de novo strategy as
depicted in Figure 3.
1
a detailed NMR analysis based on H−1H COSY and NOESY
was carried out to secure its formulation (see Supporting
Information). After the successful installation of the four out of
five stereocenters present in (+)-1S-minwanenone 5 in a stereo-
selective manner, the next objective was to transform the
primary-hydroxyl functionality at the bridgehead position in
(+)-21 to the precursor aldehyde 25 to implement one carbon
homologation reaction. After considerable efforts, conditions
could be devised for the regioselective deprotection of the MOM
group in (+)-21, using CF3CO2H at 0 °C, to afford the bicyclic
alcohol (+)-22. It was expected that the C10-MOM group in
(+)-21 would undergo deprotection in preference to the C13-
MOM group due to the relatively less steric congestion in its
vicinity. In the event, the primary hydroxyl group in (+)-22 was
oxidized to aldehyde (+)-23 using triphosgene and DMSO (see
Scheme 2).11 The stereostructure of (+)-23 was secured from
1
1
the results of H−1H COSY and H−1H NOESY experiments.
In the NOESY experiments, H-1 showed cross peak to H-10
(aldehyde proton), whereas CH3 at C-12 showed cross peak to
CH2 at C-14 and H-6 (see Supporting Information).
Exposure of (+)-23 to triphenylphosphonium methoxymethylene-
chloride and n-BuLi furnished the 1:1 mixture of E- and
1
Z- methylenolethers 24a,b (as indicated by H NMR analysis)
but in dismal yield (∼5−10%). Acid-catalyzed hydrolysis of
24a,b led to the formation of aldehyde 25 (see Scheme 2).
While the key precursor 25 was realized, its meager quantities
precluded further pursuit of the end game. Several attempts12
to augment access to 25 through change in reaction conditions
Figure 3. Redefined retrosynthetic strategy toward 5.
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Scheme 3. Synthesis of Cyclohexenone (−)-28
Scheme 4. Synthesis of Aldol Precursor (−)-40
In our redefined strategy toward (+)-1S-minwanenone 5, de-
lineated through the retrosynthetic theme depicted in Figure 3,
an appropriately functionalized bicyclic enone 26a or 26b was
identified as the pivotal precursor, which in turn could be
crafted through an intramolecular aldol condensation in a 1,4-
dicarbonyl precursor obtainable from either of the diastereo-
meric allyl group bearing cyclohexanones 27a,b. Indeed, the
allyl group in 27a,b is strategically placed to function either as a
“masked acetaldehyde” or as an “acetone equivalent” to render
both the anticipated diastereomers serviceable toward the target
structure. Similarly, the acetaldehyde acetal moiety in 27a,b
could either function directly as “protected aldehyde” or elab-
orated as an acetone equivalent. Access to 27a,b was contem-
plated from cyclohexenone 28 through appropriate FGIs and
α-allylation. The functionally embellished precursor cyclohexenone
28 was to be obtained from our chiral synthon (+)-10 via the
intermediacy of 29 (see Figure 3). Once again, the choice of the
endo-tricyclic chiral synthon (+)-10 (available in both the en-
antiomeric forms), as the chiral synthon, was crucial for build-
ing the requisite C5,C6 stereochemistry through exploitation of
its inherent topological bias in favor of exo-face selectivity.
Our second generation approach to 5 emanated with the
smooth and stereoselective allylation of (+)-10 to furnish exo-
allylated (+)-29. Copper(I) mediated 1,4-addition of MeMgI to
(+)-29 proceeded with expected exo-face selectivity and in situ
capture of the resulting enolate with TMSCl delivered the
TMS-enol ether (−)-30 as a single diastereomer.13 Metalation
of TMS-enol ether (−)-30 and quenching the resulting lithium
enolate with MeI led to the vicinally dimethylated product
(−)-31 (see Scheme 3). In order to establish the C5 quaternary
center with requisite relative stereochemical disposition, (−)-31
was subjected to α-hydroxymethylation, which occurred pre-
ferentially from the exo-face to stereoselectively furnish alcohol
(−)-32. This maneuver, besides establishing the C5 quaternary
center, also secured the relative C5,C6 sterochemistry. The
newly introduced hydroxyl group in (−)-32 was protected
as MOM derivative (−)-33 prior to the jettisoning of the
norbornyl moiety. A retro Diels−Alder process was executed in
(−)-33 through thermal activation to disengage the norbornyl
moiety and liberate functionally enriched cyclohexenone
(−)-28 (Scheme 3). At this stage, chemoselective reduction
of the enone double bond in (−)-28 and subsequent alkylation
with 2-bromoacetaldehyde acetal was expected to deliver a dia-
stereomeric mixture of allylated cyclohexenones 27a,b as en-
visioned in the retrosynthetic theme depicted in Figure 3. How-
ever, attempts toward the chemoselective reduction of the
enone double bond in (−)-28 employing various 1,4-reduction
protocols such as LAH/CuI,14a,b DIBAL-H/MeCu,14c Et3SiH/
Wilkinson’s catalyst,14d sodium dithionate/aliquot,14e,f or Li/
liquid ammonia failed to deliver the desired 1,4-reduction prod-
uct. Since selective reduction of the enone double bond in (−)-28
proved to be unexpectedly difficult, an alternative strategy was
planned that involved the oxidative cleavage of the allyl group
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Scheme 5. Synthesis of Desmethyl-minwanenone 48
in (−)-28 and protection of the resulting aldehyde group prior
to the reduction of the enone double bond (see Scheme 4).
Accordingly, a single-pot OsO4−NaIO4 mediated oxidative
cleavage15 of the allyl group in (−)-28 furnished the aldehyde
(−)-34, which was protected as acetal (−)-35, Scheme 4.
Reduction of the enone double bond in (−)-35 under catalytic
hydrogenation over PtO2 was now quite uneventful, and the
resulting cyclohexanone 36a,b upon NaH mediated allylation
afforded a mixture of diastereomers (−)-37 and (−)-38 (40:60
ratio) in excellent yield. The relative stereochemistry at the
newly generated C9 quaternary center in (−)-37 and (−)-38
was secured on the basis of 1H−1H COSY and 1H−1H NOESY
experiments (see Supporting Information). The anticipated
stereochemical divergence leading to the formation of both
(−)-37 and (−)-38, though irksome at first sight, could be
fashioned into stereochemical convergence that rendered both
the diastereomers serviceable (vide infra). Our initial advance
toward the natural product target 1 was quite understandably
through the major diastereomeric product (−)-38, and the
intent was to elaborate the protected acetaldehyde arm into a
1,4-dicarbonyl moiety bearing an acetone equivalent for the
projected aldol cyclization. Toward this end, acetal moiety in
(−)-38 was carefully deprotected to free aldehyde (−)-39.
Chemo- and regioselective addition of MeLi to (−)-39 and
PCC oxidation furnished the 1,4-dicarbonyl bearing (−)-40
(see Scheme 4).
itating the intramolecular lactol formation. For this purpose, the
TBS group in (+)-41 was selectively deprotected with TBAF to
deliver alcohol (+)-42, and further PCC mediated oxidation
provided the ketone (+)-43 in excellent yield. As anticipated,
NaBH4 reduction in (+)-43 was regio- and stereoselective with
hydride delivery from the less hindered β-face to afford (+)-44
having the desired C7 α-hydroxyl stereochemistry. A one-pot
OsO4/NaIO4 mediated oxidative cleavage of the allyl group15 in
bicyclic enone (+)-43 proceeded smoothly and furnished
diastereomeric lactols 45a,b in good yield. Attempted oxidation
of the resulting lactols 45a,b to the lactone with PCC led to the
formation of the tetracyclic framework of (+)-46, most likely
through intramolecular displacement of the intermediate
chromate ester 46a by distal but sterically well poised OMOM
group or more likely via the oxocarbenium ion intermediate 46b
(see Scheme 5).19 Formation of the tetracyclic acetal (+)-46 was
a bonus as it represented a conspicuous motif present in cyclo-
parvifloralone type natural products such as merrillianone 2.
However, lactols 45a,b could be conveniently oxidized using
Fetizon oxidation16 and led to the formation of desired tricyclic
lactone (+)-47 in excellent yield. After several trials, the MOM
group in (+)-47 could be deprotected using triphenylcarbenium
tetrafluoroborate in DCM at 0 °C to obtain desmethyl-min-
wanenone (+)-48 in moderate yield (see Scheme 5).17
Having tested the waters and established a synthetically
viable route to access desmethyl-minwanenone (+)-48 from the
advanced bicyclic enone (+)-40, attention was immediately tur-
ned toward (+)-1S-minwanenone 5. En route to 5, it was con-
sidered prudent to first install the C1 methyl group in (+)-41.
Accordingly, (+)-41 was subjected to methylation under
kinetically controlled conditions to furnish (+)-49 as a single
Intramolecular aldol cyclization in (−)-40 was smoothly
effected with NaH in THF to eventuate into bicyclic enone
(+)-41 (see Scheme 5). At this stage, the next key move was to
install the required α-hydroxyl stereochemistry at C7 in (+)-41,
through inversion of the existing C7 stereochemistry, for facil-
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Scheme 6. Completion of Synthesis of (+)-1S-Minwanenone 5
Scheme 7. Formation of Merrillianone Framework (+)-46
isomer in a stereoselective manner (see Scheme 6). Deprotec-
tion of the TBS group in (+)-49 proceeded smoothly to furnish
alcohol (+)-50, which upon PCC oxidation provided the bicyclic
keto-enone (+)-51. Regio- and stereoselective reduction of the
cyclohexanone functionality in (+)-51 furnished (+)-26a with
the desired C7 α-hydroxyl stereochemistry. Oxidative cleavage
of the allyl group in (+)-26a was achieved following a one-pot
oxidation protocol with OsO4/NaIO4 to furnish a mixture of
lactols 52a,b.15 Fetizon oxidation16 of lactols 52a,b led to
tricyclic lactone (+)-53. Lastly, the MOM protecting group in
(+)-53 could be removed employing triphenylcarbenium-
tetrafluoroborate17 to provide (+)-1S-minwanenone 5, which
was found to be spectroscopically (1H and 13C NMR spectrum)
identical to the natural product (−)-1R-minwanenone 1 (see
Scheme 6).1 However, the specific rotation, [α]D +23.3°, of our
synthetic (+)-1S-minwanenone 5 was found to be opposite in
sign to that reported, [α]D −17.9°, for the natural (−)-1R-
minwanenone 1.1 Since our synthesis emanated from the endo-
tricyclic chiral synthon (+)-10 of well established absolute stereo-
chemistry, the present effort independently validated the
previously inferred1 absolute configuration of the natural product.
Having completed an enantioselective total synthesis of (+)-5
from a functionally adorned and stereochemically well-defined
cyclohexanone (−)-38, it was considered useful to explore and
demonstrate the serviceability of its diastereomeric sibling
(−)-37 (see Scheme 4). The intent was to showcase an
interesting feature of our strategy that enabled stereochemical
convergence in the face of stereodivergence, when a seemingly
unwanted diastereomer was encountered along a reaction path.
Thus, the objective was to realign the diastereomer (−)-37 into
the main pathway leading to minwanenone and its sibling seco-
prezizaane natural products. Wacker oxidation18 of the allyl
group in (−)-37 generated the 1,4-dicarbonyl bearing moiety
(−)-54, which underwent aldol cyclization on exposure to NaH
in THF to furnish functionally embellished bicyclic enone
(+)-55 (see Scheme 7). Deprotection of the TBS group in
(+)-55 to (+)-56 and PCC oxidation led to the enedione
(+)-57 and set the stage for the inversion of the C7 hydroxyl
group stereochemistry. Controlled chemo- and stereoselective
reduction of (+)-57 with NaBH4 furnished (+)-58 having the
desired stereochemistry at the C7-hydroxyl group. At this stage,
deprotection of the acetal moiety in (+)-58 was expected to
reveal the aldehyde group and engage the C7-hydroxyl to lactols
45a,b (Scheme 5), which on further oxidation was expected to
deliver the tricyclic skeleton of minwanenone. However,
attempts to deprotect the acetal group in (+)-58 under a
range of acidic conditions drew a blank and led instead to the
generation of a tetracyclic framework (+)-46, obtained
previously (vide supra) from the major diastereomer (+)-38.
Thus, both of the diastereomers (−)-37 and (+)-38 have been
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acetate in hexane) to afford a ketone (−)-11 (1.4 g, 90%) as a colorless
shown to converge to the same tetracyclic seco-prezizaane frame-
work (+)-46 present in natural products such as merrillianone 2
(see Scheme 7). Interestingly, facile formation of (+)-46 reveals
the interactive proclivities of scattered but well directed func-
tionalities on this framework and augurs well for extending the
applicability of the present approach to access other seco-prezizaane
natural products.1,2
oil: [α]22 −36.0 (c 1.0, CHCl3); IR (Neat) 2956, 2931, 2858, 1701,
D
1253 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.19−6.16 (m, 1H), 6.05−
6.02 (m, 1H), 3.80−3.75 (m, 1H), 3.33 (s, 1H), 3.15 (s, 1H), 2.86−
2.77 (m, 2H), 2.22−2.11 (m, 1H), 1.90−1.82 (m, 2H), 1.36 (d(1/
2ABq), J = 8.4 Hz, 1H), 1.25 (d(1/2ABq), J = 8.4 Hz, 1H), 0.96 (s,
9H), 0.86 (d, J = 5.7 Hz, 3H), 0.14 (s, 3H), 0.08 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 212.4, 137.0, 135.8, 75.6, 52.3, 49.4, 47.5, 47.1,
46.0, 44.9, 31.9, 25.9, 19.0, 18.1, −4.0, −4.9; HRMS(ES) m/z calcd for
C18H30NaO2Si (M + Na) 329.1913, found 329.1912.
SUMMARY
■
(2S,4S,5R,6R,7R)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4,5-
dimethyltricyclo[6.2.1.02,7]undec-9-en-3-one (12). To a stirred
solution of LiHMDS in dry THF (12 mL, 0.5 M, freshly prepared
from equimolar amount of HMDS and n-BuLi, at 0 °C) and kept at
−78 °C, was added a solution of ketone (−)-11 (1.4 g, 4.6 mmol) in
dry THF (10 mL) over a period of 15 min. The resulting solution was
stirred at −20 °C for 1 h and then recooled to −78 °C prior to the
sequential addition of HMPA (1 mL, 6.0 mmol) and MeI (0.37 mL,
6.0 mmol). The reaction mixture was allowed to warm to 0 °C, stirred
for 1 h, and then quenched with satd NH4Cl solution. The aqueous
layer was extracted with ether (2 × 50 mL), and the combined organic
extracts were washed water and brine and dried over Na2SO4. After the
evaporation of solvent, the resulting crude material was purified by
silica gel column chromatography (eluent: 5% ethyl acetate in hexane)
to afford the dimethylated ketone (+)-12 (1.24 g, 85%) as a colorless
In summary, the first total synthesis of (+)-1S-minwanenone, a
prototypical seco-prezizaane, has been accomplished from a
readily available chiral building block in 21 steps and in 2.5%
overall yield. The strategy unfolded here harnesses the topo-
logical preferences of a norbornyl fused system to build the
requisite stereochemistry. Our synthesis of (+)-1S-minwane-
none is regio- and stereoselective, and in one case of significant
deviation in stereoselectivity a strategic concept of realigning
stereochemical divergence to achieve overall convergence is
demonstrated. Access to several functionally embellished
derivatives bearing the bicyclo[4.3.0]nonane core present in
seco-prezizaanes, through an adaptable strategy, opens oppor-
tunities to target other members of this exotic family.
oil: [α]24 +76.7 (c 1.5, CHCl3); IR (Neat) 2958, 2937, 2857, 1703,
D
1461, 1251, 1080 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.22 (dd, J =
5.4 and 3.0 Hz, 1H), 5.94 (dd, J = 5.4 and 3.0 Hz, 1H), 4.08−4.01 (m,
1H), 3.29 (bs, 1H), 3.04 (bs, 1H), 2.88−2.80 (m, 2H), 2.29 (dq, J =
7.2 and 3.9 Hz, 1H), 1.85−1.75 (m, 1H), 1.37−1.25 (m, 2H), 0.97 (d,
J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.85 (d, J = 6.9 Hz, 3H), 0.14 (s, 3H),
0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 216.1, 137.9, 133.3, 71.5,
50.9, 49.3, 47.2, 46.4, 45.6, 44.4, 39.2, 26.0(3C), 18.1, 13.7, 11.32,
−4.18, −5.00; HRMS(ES) m/z calcd for C19H32NaO2Si (M + Na)
343.2069, found 343.2073.
EXPERIMENTAL SECTION
■
General Experimental Methods. All moisture- and air-sensitive
reactions were performed under argon atmosphere with dry, freshly
distilled solvents under anhydrous conditions using standard syringe-
septum technique. Low temperatures were maintained using liquid
nitrogen in combination with appropriate solvent. Hexane refers to the
petroleum ether fraction boiling between 60 and 80 °C. Dry solvents
such as THF, ether, 1,4-dioxane, DME, benzene, and toluene were
prepared by distilling them from sodium benzophenone radical anion.
Dry DCM, CHCl3, pyridine, DMSO, TEA, DIPA, HMDS, and HMPA
were distilled freshly from calcium hydride. Acetone was distilled over
preactiviated K2CO3. Methanol was distilled from its alkoxide (formed
by the reaction with activated magnesium) and stored over 4 Å molec-
ular sieves. Reactions were monitored by thin layer chromatography
(TLC), which was performed either on (10 × 5 cm) glass plates or on
microscopic slides coated with silica gel G or GF254 (250 mmol),
containing 13% calcium sulfate as a binder. Visualization of the spots
on TLC plates was achieved either by exposure to iodine vapor or by
using UV light or by spraying with either ethanolic vanillin or 30%
methanol/sulfuric acid solution and heating the plates at ∼120 °C.
Commercial silica gel (100−200 mesh particle size) was used for
column chromatography. All yields reported are of isolated products
used for characterization and wherever applicable are based on re-
(2S,4R,5R,6R,7R)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4-
di(hydroxymethyl)-4,5-dimethyltricyclo[6.2.1.02,7]undec-9-en-
3-one (13). To an ice-cooled solution of a dimethylated ketone
(+)-12 (1.0 g, 3.14 mmol) in 10 mL of distilled THF were added DBU
(0.88 mL, 6.3 mmol) and formalin (2 mL of 35% of aqueous solution,
22 mmol) successively. The reaction was continued at 25 °C for 12 h
and then diluted with water (25 mL). The aqueous phase was ex-
tracted with ethyl acetate (2 × 50 mL), and the combined organic
phases were washed with water and brine and dried over Na2SO4.
After the evaporation of the solvent, the crude residue was purified by
silica gel column chromatography (eluent: EA/ hexane = 1:20 to 1:5)
to afford a starting material (+)-12 (0.2 g, 20%) and a diol (−)-13
(0.836 g, 73%, 88% borsm): [α]24 −25.0 (c 0.8, CHCl3); IR (Neat)
D
3350, 2956, 2929, 1687, 1471, 1253 cm−1; 1H NMR (300 MHz,
CDCl3) δ 6.32 (dd, J = 5.4 and 3.0 Hz, 1H), 5.91 (dd, J = 5.4 and
3.0 Hz, 1H), 4.50 (dd, J = 11.4 and 6.9 Hz, 1H), 4.28 (d, J = 9.6 Hz,
1H), 3.62 (s, 2H), 3.52 (d, J = 9.6 Hz, 1H), 3.24 (s, 1H), 2.88 (s, 1H),
2.73−2.67 (bs, 1H), 2.65 (dd, J = 6.9 and 3.0 Hz, 1H), 1.75−1.69 (m,
1H), 1.47−1.23 (m, 3H), 0.97 (s, 9H), 0.96 (d, J = 6.9 Hz, 3H), 0.85
(s, 3H), 0.15 (s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
224.0, 138.6, 134.7, 73.0, 72.3, 69.6, 61.3, 53.2, 52.0, 50.0, 48.6, 45.9,
40.3, 26.0(3C), 19.9, 18.2, 12.5, −3.9, −4.8; HRMS(ES) m/z calcd for
C21H36NaO4Si (M + Na) 403.2281, found 403.2278.
1
covered starting material. H and 13C NMR samples were generally
made in CDCl3 ,and chemical shifts are expressed in parts per million
(δ) scale using tetramethylsilane (Me4Si) as the internal standard. The
standard abbreviations s, d, t, q, and m refer to singlet, doublet, triplet,
quartet, and multiplet, respectively. Coupling constant (J), whenever
discernible, have been reported in Hz. High resolution mass spectra
(HRMS) were recorded on Q-TOF Micromass mass spectrometer.
(2S,5R,6S,7R)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-5-methyl-
tricyclo[6.2.1.02,7]undec-9-en-3-one (11). To
a cooled
(2S,4R,5R,6R,7R)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4-
di[(methoxymethoxy)methyl]-4,5-dimethyltricyclo[6.2.1.02,7]-
undec-9-en-3-one (14). To the stirred ice-cooled solution of
compound (−)-13 (0.7 g, 1.84 mmol) in 7 mL of dry DCM were
added DIPEA (1.9 mL, 11.04 mmol), DMAP (0.18 mmol) and
MOMCl (0.56 mL, 7.36 mmol) successively. The resulting solution was
stirred at 25 °C for 6 h and then quenched with satd NaHCO3. The
aqueous layer was extracted with DCM (2 × 50 mL), and the combined
organic layers were washed with water and brine and dried over Na2SO4.
After the removal of solvent, the crude material was purified by passing
through a silica gel column (eluent: EA/hexane = 1:9) to obtain
(0 °C) THF (20 mL) solution of CuI (1.1 g, 6.2 mmol) was added
methyl lithium (8.3 mL, 1.5 M ethereal solution), and the resulting
clear solution was cooled to −78 °C prior to the sequential addition of
enone-TBS (+)-10 (1.5 g, 5.17 mmol, in 10 mL THF) and TMSCl
(0.72 mL, 5.7 mmol). The reaction mixture was allowed to warm
to −50 °C over a period of 2 h and then quenched carefully with
dropwise addition of water. The aqueous phase was extracted with
ether (2 × 60 mL). The combined organic extracts were washed suc-
cessively with 10% HCl (20 mL × 3), water, and brine and dried over
Na2SO4. After the evaporation of solvent, the crude residue was
purified through a silica gel column chromatography (eluent: 5% ethyl
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Article
compound (−)-14 (800 mg, 93%): [α]24 −48.9 (c 0.9, CHCl3); IR
64.0, 55.3, 54.8, 21.9, 19.2, 19.2; HRMS(ES) m/z calcd for C14H22O5
(M + Na) 293.1365, found 293.1369. Data for 18: [α]24 = +25.0°
(c 0.8, CHCl3); IR (Neat) 2935, 2885, 1735, 1710, 1047 cm−D1; 1H NMR
(300 MHz, CDCl3) δ 5.80−5.70(m, 2H), 4.55(s, 2H), 4.54(s, 2H),
4.05(dq, J = 7.2 and 1.8 Hz, 2H), 3.77(d, J = 9.6 Hz, 1H), 3.62(d, J =
9.6 Hz, 1H), 3.52(d, J = 9.6 Hz, 1H), 3.45(d, J = 9.6 Hz, 1H), 3.33(s,
3H), 3.31(s, 3H), 2.99(d(1/2ABq), J = 15.6 Hz, 1H), 2.78−2.70(m,
1H), 2.56(d(1/2ABq), J = 15.6 Hz, 1H), 1.30(s, 3H), 1.21(t, J =
7.5 Hz, 3H), 1.06(d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) 212.5,
170.9, 133.8, 127.2, 96.9, 96.6, 72.0, 69.8, 60.4, 55.5, 55.2, 51.4, 50.1,
40.8, 38.3, 19.6, 15.8, 14.1; HRMS(ES) m/z calcd for C18H30NaO7
(M + Na) 381.1889, found 381.1875.
D
(Neat) 2951, 2930, 2883, 1687, 1471, 1061 cm−1; 1H NMR (300 MHz,
CDCl3): δ 6.29 (dd, J = 5.4 and 3.0 Hz, 1H), 5.95 (dd, J = 5.4 and
3.0 Hz, 1H), 4.56 (s, 2H), 4.46 (s, 2H), 4.26 (dd, J = 11.4 and 7.2 Hz,
1H), 3.85 (d, J = 9.3 Hz, 1H), 3.55−3.51 (m, 2H), 3.38 (d, J = 9.3 Hz,
1H), 3.34 (s, 3H), 3.30 (s, 3H), 3.16 (s, 1H), 2.93 (s, 1H), 2.65 (dd,
J = 6.6 and 3.0 Hz, 1H), 1.76−1.58 (m, 3H), 1.60−1.58 (m, 1H),
1.34−1.23 (m, 3H), 0.96 (s, 9H), 0.90 (d, J = 6.6 Hz, 3H), 0.12 (s,
3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 217.8, 138.4, 135.9,
96.7, 96.6, 75.5, 71.6, 71.2, 59.7, 55.3, 55.2, 52.6, 51.6, 49.2, 48.7, 45.6,
39.9, 26.0, 19.7, 18.2, 12.7, −3.9, −4.8; HRMS(ES) m/z calcd for
C25H44NaO6Si (M + Na) 491.2805, found 491.2785.
Dimethyl (3-(1S,4S,5S)-1,5-Di[(methoxymethoxy)methyl]-
4,5-dimethyl-6-oxo-2-cyclohexenyl-2-oxopropyl)phosphonate
(19). To a cooled (−78 °C) solution of dimethyl methylphosphonate
(0.18 mL, 1.68 mmol) in 2 mL of dry THF was added n-BuLi (1.0 mL,
1.6M) over a period of 5 min, and the resulting cloudy mixture was
stirred at the same temperature for 30 min. To this mixture was added
a solution of ester (+)-18 (100 mg, 0.28 mmol) in 1 mL of dry THF,
and the reaction was continued at −78 °C for a further 1 h. The
reaction was quenched carefully by addition of water (5 mL), and the
aqueous phase was extracted with ethyl acetate (3 × 10 mL). The
combined organic extracts were washed with water and brine and dried
over Na2SO4. The solvent was removed under vacuum, and the crude
residue was filtered through a short pad of silica gel (eluent: EA/
hexane = 1:2 to 1:0) to afford β-keto phosphonate (+)-19 (115 mg,
95%) as a colorless oil: [α]24D +20.0 (c 0.7, CHCl3); IR (Neat) 2933,
(4R,5R,6S)-4-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,6-di-
[(methoxymethoxy)methyl]-5,6-dimethyl-2-cyclohexen-1-one
(15). To compound (−)-14 (0.8 g, 1.7 mmol) placed in a 50 mL RB
flask, fitted with an air condenser, was added 15 mL of diphenyl ether.
The reaction mixture was stirred at 210 °C (oil bath temperature) for
about 15 min. The reaction mixture was allowed to cool to 25 °C and
then directly charged on a silica gel column. Eluting the column with
2% ethyl acetate in hexane removed the solvent (diphenyl ether)
and further elution with 15% ethyl acetate in hexane furnished the
cyclohexenone (−)-15 (0.62 g, 90%): [α]24D −62.0 (c 1.0, CHCl3); IR
1
(Neat) 2931, 1668, 1471, 1151, 1043 cm−1; H NMR (300 MHz,
CDCl3) δ 6.77 (s, 1H), 4.66 (s, 2H), 4.53−4.44 (m, 3H), 4.21 (s, 2H),
3.65 (d(1/2ABq), J = 9.6 Hz, 1H), 3.49 (d(1/2ABq), J = 9.6 Hz, 1H),
3.37 (s, 3H), 3.27 (s, 3H), 2.04−1.94 (m, 1H), 1.13 (s, 3H), 1.13 (d,
J = 6.6 Hz, 3H), 0.93 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 201.5, 148.3, 134.1, 96.5, 96.3, 71.5, 70.7, 64.3,
55.3, 49.7, 46.3, 25.8(3C), 19.8, 18.0, 12.4, −4.1, −4.7; HRMS(ES)
m/z calcd for C20H38NaO6Si (M + Na) 425.2335, found 425.2333.
(4R,5R,6S)-4-Hydroxy-2,6-di[(methoxymethoxy)methyl]-5,6-
dimethyl-2-cyclohexen-1-one (16). To a solution of compound
(−)-15 (600 mg, 1.49 mmol) in 2 mL of dry THF was added freshly
prepared equimolar solution of TBAF (785 mg, 3.0 mmol) and AcOH
(0.017 mL, 3.0 mmol) in 1 mL of THF, and the reaction was stirred
for 10 h at 25 °C. After the completion of reaction (as indicated by
TLC analysis), the solvent was removed under reduced pressure. The
crude residue was directly loaded on a silica gel column and eluted
with 50% ethyl acetate in hexane to obtain the γ-hydroxy-cyclo-
1
2884, 2823, 1712, 1587, 1261 cm−1; H NMR (300 MHz, CDCl3) δ
5.69 (bs, 2H), 4.55 (s, 2H), 4.53 (s, 2H), 3.80−3.72 (m, 6H), 3.55−
3.34 (m, 4H), 3.33 (s, 3H), 3.32 (s, 3H), 3.12−2.88 (m, 4H), 1.28 (s,
3H), 1.09 (d, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 212.3,
198.8, 133.7, 126.8, 96.8, 96.6, 72.2, 69.9, 55.5, 55.3, 53.1(d, J = 9.0
Hz), 51.6, 50.8, 49.6, 42.4, 40.7, 38.5, 19.0, 15.5; HRMS(ES) m/z
calcd for C19H33NaO9P (M + Na) 459.1760, found 459.1757.
(4S,5S,7aR)-4,7a-Di[(methoxymethoxy)methyl]-4,5-dimethyl-
2-methylene-2,4,5,7a-tetrahydro-1H-indene (20). To a solution
of phosphonate (+)-19 (100 mg, 0.22 mmol) in 5 mL of dry THF
was added NaH (27 mg, 1.14 mmol) at 25 °C. The reaction mixture
was refluxed for 2 h, then cooled to 0 °C, and quenched with water.
The organic phase was diluted with ether (20 mL), washed with water
(5 mL × 2) and brine, and dried over Na2SO4. After the evaporation of
solvent the crude material was purified on a silica gel column (eluent:
40% ethyl acetate in hexane) to furnish the bicyclic enone (+)-20
(65 mg, 92%) as a colorless oil: [α]24D +58.7 (c 0.8, CHCl3); IR (Neat)
2931, 2883, 1712, 1695, 1604, 1043 cm−1; 1H NMR (300 MHz,
CDCl3) δ 6.09 (s, 1H), 5.79(dd, J = 9.9 and 3.0 Hz, 1H), 5.46 (d, J =
9.9 Hz, 1H), 4.58 (s, 4H), 3.79 (d, J = 9.6 Hz, 1H), 3.66 (d, J = 9.6 Hz,
1H), 3.51 (d, J = 9.6 Hz, 1H), 3.37 (d, J = 9.6 Hz, 1H), 3.36 (s, 3H),
3.34 (s, 3H), 2.78 (d(1/2ABq), J = 17.1 Hz, 1H), 2.29−2.26 (m, 1H),
2.22 (d(1/2ABq), J = 17.1 Hz, 1H), 1.39 (s, 3H), 1.08 (d, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 206.1, 185.0, 131.8, 130.8, 128.4,
96.9, 96.6, 73.3, 70.2, 55.7, 55.5, 49.8, 49.3, 42.9, 42.8, 22.0, 15.3;
HRMS(ES) m/z calcd for C17H26NaO5 (M + Na) 333.1678, found
333.1678.
hexenone (−)-16 (387 mg, 90%) as a colorless oil: [α]24 −21.0
D
1
(c 1.0, CHCl3); IR (Neat) 3440, 2927, 2886, 1670 cm−1; H NMR
(300 MHz, CDCl3) δ 6.91 (d, J = 1.5 Hz, 1H), 4.68 (s, 2H), 4.52 (bs, 1H),
4.46 (ABq, J = 6.6 Hz, 2H), 4.23 (bs, 1H), 3.65 (d, J = 9.6 Hz, 1H),
3.49 (d, J = 9.6 Hz, 1H), 3.38 (s, 3H), 3.26(s, 3H), 2.04−1.90 (m,
1H), 1.74 (bs, 1H), 1.24 (d, J = 7.2 Hz, 3H), 1.14 (s, 3 H); 13C NMR
(75 MHz, CDCl3) δ 201.4, 147.4, 134.8, 96.4, 96.3, 71.4, 70.3, 64.1,
55.3, 49.7, 46.7, 19.5, 11.9; HRMS(ES) m/z calcd for C14H24NaO6
(M + Na) 311.1471, found 311.1472.
Ethyl 2-(1S,4S,5S)-1,5-Di[(methoxymethoxy)methyl]-4,5-di-
methyl-6-oxo-2-cyclohexenylacetate (18) and (6S)-2,6-Di-
[(methoxymethoxy)methyl]-5,6-dimethyl-2,4-cyclohexadien-
1-one (17). To a γ-hydroxy-cyclohexenone (−)-16 (185 mg,
0.64 mmol), placed in a sealed tube, were added freshly distilled
triethylorthoacetate (3.0 mL) and catalytic amount of propionic acid
(0.05 mL). The sealed tube was flushed with nitrogen and placed in an
oil bath kept at 190 °C. Reaction was monitored by TLC. After
completion of the reaction (40−45 h, as indicated by TLC analysis),
the reaction mixture was diluted with ethyl acetate (30 mL) and
washed successively with 5% HCl, water, and brine. The organic phase
was dried over Na2SO4 prior to the evaporation of solvent, and the
crude residue was purified through a silica gel column (eluent: EA/
hexane = 1:9 to 1:2) to obtain the dienone (−)-17 (59 mg, 27%) and
(1R,4S,5S,7aS)-4,7a-Di[(methoxymethoxy)methyl]-1,4,5-tri-
methyl-2-methylene-2,4,5,7a-tetrahydro-1H-indene (21). To a
cooled (−40 °C) solution of LiHMDS (1 mL, 0.5 M, freshly prepared
from equimolar amount of HMDS and n-BuLi, at 0 °C) in dry THF
was added dropwise a solution of bicyclic enone (+)-20 (50 mg,
0.16 mmol) in 1 mL of dry THF. The resulting solution was stirred
at −20 °C for 1 h and then cooled to −78 °C prior to the sequential
addition of HMPA (0.1 mL, 0.56 mmol) and MeI (0.035 mL, 0.56
mmol). The reaction mixture was allowed to warm to 0 °C, stirred for
1 h, and then quenched with water. The aqueous phase was extracted
with ether (2 × 15 mL), and the combined organic layers were washed
with water (5 mL) and brine and dried over Na2SO4. After the evap-
oration of solvent, the resulting crude material was purified through a
silica gel column chromatography (eluent: 40% ethyl acetate in hexane)
to obtain the methylated enone (+)-21 (49.4 mg, 95%) as a colorless
the keto-ester (+)-18 (150 mg, 70%) respectively. Data for 17: [α]22
D
−47.5 (c 0.8, CHCl3); IR (neat) 2933, 2855, 2823, 1662, 1641, 1592
cm−1 ; 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J = 6.3 Hz, 1H), 6.16
(d, J = 6.3 Hz, 1H), 4.69 (s, 2H), 4.51 (d, J = 6.6 Hz, 1H), 4.47 (d, J =
6.6 Hz, 1H), 4.37 (d(1/2ABq), J = 13.5 Hz, 1H), 4.26 (d(1/2ABq),
J = 13.5 Hz, 1H), 4.04 (d, J = 9.0 Hz, 1H), 3.67 (d, J = 9.0 Hz, 1H),
3.38 (s, 3H), 3.27 (s, 3H), 2.02 (s, 3H), 1.13 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 203.4, 153.7, 138.9, 130.1, 119.5, 96.6, 96.2, 72.6,
oil: [α]23 +55.7 (c 0.7, CHCl3); IR (Neat) 2967, 2929, 2883, 1707,
D
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1604, 1047 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.01 (s, 1H), 5.68(dd,
J = 9.9 and 3.0 Hz, 1H), 5.57 (dd, J = 9.9 and 1.8 Hz, 1H), 4.57 (s, 2H),
4.56 (s, 2H), 3.80 (d, J = 9.6 Hz, 1H), 3.66 (d, J = 9.0 Hz, 1H), 3.50 (d,
J = 9.6 Hz, 1H), 3.35 (s, 3H), 3.33 (s, 3H), 3.28 (d, J = 9.0 Hz, 1H),
2.67 (q, J = 7.8 Hz, 1H), 2.25−2.23 (m, 1H), 1.38 (s, 3H), 1.08 (d, J =
7.8 Hz, 3H), 0.97 (d, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
211.0, 183.7, 133.4, 128.4, 126.3, 96.9, 96.6, 74.3, 70.2, 55.6, 55.4, 53.4,
51.5, 42.9, 42.1, 21.8, 15.7, 15.3; HRMS(ES) m/z calcd for C18H28NaO5
(M + Na) 347.1834, found 347.1822
(1R,4S,5S,7aS)-4-[(Methoxymethoxy)methyl]-1,4,5-trimethyl-2-
methylene-2,4,5,7a-tetrahydro-1H-7-indenylmethanol (22). To
an ice-cooled solution of methylated enone (+)-21 (25 mg,
0.077 mmol) in 2 mL of distilled DCM was added CF3CO2H
(0.1 mL). The resulting solution was stirred at 0 °C for 2 h and then
kept in refrigerator for about 6−8 h. The reaction was quenched with
triethylamine (0.1 mL) and diluted with DCM (15 mL). The organic
phase was washed with water (2 × 5 mL) and brine and dried over
Na2SO4. After the evaporation of solvent, the resulting oily residue was
purified by silica gel column chromatography (eluent: 60% ethyl
acetate in hexane) to furnish the alcohol (+)-22 (17 mg, 80%) as a
colorless oil: [α]23D +65.0 (c 0.7, CHCl3); IR (Neat) 3436, 1705 cm−1;
1H NMR (300 MHz, CDCl3) δ 6.09 (s, 1H), 5.62−5.48 (m, 2H), 4.57
over anhydrous Na2SO4, and concentrated in vaccuo. The residue
obtained was chromatographed over silica gel by eluting first with
hexane to remove traces of triphenyl phosphine, followed by elution
with 40% ethyl acetate/hexane to obtain methoxy Wittig product
24a,b (∼1 mg) in about 10% yield: IR (Neat) 2929, 1705, 1651, 1045
1
cm−1; H NMR (300 MHz, CDCl3) δ 6.30 (s, 1H), 6.26 (s, 1H),
6.02−5.92 (m, 4H), 5.71−5.56 (m, 4H), 4.73−4.04 (m, 4H), 3.84−
3.68 (m, 4H), 3.58 (s, 3H), 3.44 (s, 3H), 3.35 (s, 3H), 3.32 (s, 3H),
2.65 (q, J = 6.9 Hz, 1H), 2.39 (q, J = 7.5 Hz, 1H), 2.25−2.17 (m, 2H),
1.36 (s, 6H), 1.08−0.98 (m, 12H); HRMS(ES) m/z calcd for
C18H26NaO4 (M + Na) 329.1729, found 329.1726
2-(1S,4S,5S,7aR)-4-[(Methoxymethoxy)methyl]-1,4,5-tri-
methyl-2-oxo-2,4,5,7a-tetrahydro-1H-7-indenylacetaldehyde
(25). To an ice-cooled solution of Wittig product 24a,b (1 mg, 0.0032
mmol) in 1 mL of distilled DCM was added 10 μL of CF3CO2H, and
the resulting reaction mixture was stirred at ice-bath temperature for
1 h. Then, the reaction mixture was diluted with satd NaHCO3 (1 mL),
and the aqueous phase was extracted with DCM (2 × 5 mL). The
combined organic extracts were washed with brine, dried over Na2SO4,
and concentrated in vaccuo. The organic residue was filtered through a
short pad of silica gel column (eluent: 50% EA in hexane) to obtain
aldehyde 25 (0.5 mg, 60%): IR (Neat) 2927, 1705, 1604, 1014 cm−1;
1H NMR (300 MHz, CDCl3) δ 9.66 (s, 1H), 6.04 (s, 1H), 5.77 (dd,
J = 9.9 and 2.4 Hz, 1H), 5.51 (d, J = 9.9 Hz, 1H), 4.58−4.53 (m, 2H),
3.85 (d, J = 9.9 Hz, 1H), 3.52 (d, J = 9.1 Hz, 1H), 3.35 (s, 3H), 2.83
(d, J = 17.1 Hz, 1H), 2.59−2.50 (m, 2H), 2.24−2.20 (m, 1H), 1.41 (s,
3H), 1.07 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.3 Hz, 3H); HRMS(ES)
m/z calcd for C17H24NaO4 (M + Na) 315.1572, found 315.1570.
(2S,6S,7R)-2-Allyl-6-[1-(tert-butyl)-1,1-dimethylsilyl]oxytricyclo-
[6.2.1.02,7]undeca-4,9-dien-3-one (29). To the stirred solution
of LiHMDS (41.2 mL, 0.5 M, freshly prepared from equimolar
amount of HMDS and n-BuLi, at 0 °C) in dry THF at −20 °C, was
added dropwise a solution of enone (+)-10 (2.0 g, 6.9 mmol) in
10 mL of dry THF. The resulting solution was stirred at −20 °C for
1 h and then cooled to −40 °C prior to the sequential addition of
HMPA (3.6 mL, 20.7 mmol) and allyl bromide (1.8 mL, 20.7
mmol). The reaction mixture was allowed to warm to −20 °C,
stirred for 2 h, and then quenched with water. The aqueous phase was
extracted with ether (2 × 150 mL). The combined organic layers were
washed with water and brine and dried over Na2SO4. After evaporation
of solvent, the resulting crude material was purified through a silica gel
column chromatography (eluent: 5% ethyl acetate in hexane) to afford
the allylated enone (+)-29 (2.1 g, 93%) as a colorless oil: [α]24
+113.3 (c 1.5, CHCl3); IR (Neat) 2956, 2931, 2858, 1666, 1253 cm−1D;
1H NMR (300 MHz, CDCl3) δ 6.33 (dd, J = 10.5 and 0.9 Hz, 1H),
(ABq, J = 6.6 Hz, 2H), 3.89 (d, J = 9.3 Hz, 1H), 3.61−3.50 (m, 2H),
3.46 (d, J = 9.3 Hz, 1H), 3.36 (s, 3H), 2.49 (q, J = 7.8 Hz, 1H), 2.29
(q, J = 7.8 Hz, 1H), 2.16 (dd, J = 11.1 and 4.2 Hz, 1H), 1.38 (s, 3H),
1.05 (d, J = 7.5 Hz, 3H), 0.98 (d, J = 7.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 210.3, 180.4, 133.7, 129.9, 125.8, 97.2, 71.2, 68.1, 55.9, 55.6,
51.8, 42.6, 42.0, 22.3, 14.9; HRMS(ES) m/z calcd for C16H24NaO4
(M + Na) 303.1572, found 303.1570.
(1R,4S,5S,7aS)-4-[(Methoxymethoxy)methyl]-1,4,5-trimethyl-2-
methylene-2,4,5,7a-tetrahydro-1H-7a-indenecarbaldehyde (23).
To a stirred solution of bis(trichloromethyl)carbonate (triphosgene)
(60 mg, 0.2 mmol) in 2 mL of dry DCM at −45 °C was added
dry DMSO (0.087 mL, 1.23 mmol), and the reaction mixture was
stirred at the same temperature for 15 min. Then a solution of alcohol
(+)-22 (23 mg, 0.08 mmol) in 1 mL of dry DCM was slowly added at
the same temperature. After 15 min of stirring, triethyl amine (0.3 mL)
was added dropwise, maintaining the temperature below −40 °C.
The resulting suspension was allowed to come to 25 °C over a period
of 2 h. The reaction was monitored by TLC. The reaction mixture
was diluted with DCM (20 mL), washed with water (2 × 5 mL) and
brine, and dried over Na2SO4. After the evaporation of solvent
the crude material was purified through a silica gel column (eluent:
40% ethyl acetate in hexane) to furnish aldehyde (+)-23 (20 mg,
90%): [α]23 +10.0 (c 0.4, CHCl3); IR (Neat) 2969, 2929, 2850,
D
1709, 1608, 1043 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H),
6.23 (s, 1H), 5.77 (m, 2H), 4.43 (d(1/2ABq), J = 6.6 Hz, 1H), 4.35
(d(1/2ABq), J = 6.6 Hz, 1H), 3.47 (d(1/2ABq), J = 9.0 Hz, 1H), 3.40
(d(1/2ABq), J = 9.0 Hz, 1H), 3.30 (s, 3H), 2.57 (q, J = 7.5 Hz, 1H),
2.29 (q, J = 7.5 Hz, 1H), 1.41 (s, 3H), 1.07 (d, J = 7.5 Hz, 3H), 1.06
(d, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 208.4, 197.1,
181.6, 135.7, 129.3, 122.4, 96.5, 68.5, 63.8, 55.6, 47.6, 43.4, 41.9, 21.0,
14.8, 14.0; HRMS(ES) m/z calcd for C16H22NaO4 (M + Na)
301.1416, found 301.1423.
(1S,4S,5S,7aS)-7a-[(E)-2-Methoxy-1-ethenyl]-4-[(methoxy-
methoxy)-methyl]-1,4,5-trimethyl-2,4,5,7a-tetrahydro-1H-2-in-
denone and (1S,4S,5S,7aS)-7a-[(Z)-2-Methoxy-1-ethenyl]-4-
[(methoxymethoxy)methyl]-1,4,5-trimethyl-2,4,5,7a-tetrahydro-
1H-2-indenone (24a,b). To cooled (−20 °C) solution of predried
methoxymethyltriphenyl-phosphonium chloride (72 mg, 0.21 mmol)
in 2 mL of dry THF was added n-BuLi (0.1 mL, 1.6 M solution in
dry hexane). The resulting suspension was stirred at 0 °C for a
period of 30 min and then allowed to stand for 10 min. The
supernatant blood red ylide (about 1.0 mL) was added to a cooled
(−20 °C) solution of the aldehyde 23 (10 mg, 0.036 mmol) in dry
THF (1 mL), and the reaction mixture was stirred further for 1 h at
the same temperature. The reaction mixture was quenched with water
(2 mL) and diluted with ether (10 mL). The organic layer separated,
and the aqueous layer was extracted with ether (1 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
6.11−6.09 (m, 1H), 5.81−5.56 (m, 3H), 5.12−4.98 (m, 2H), 4.62 (d,
J = 9.3 Hz, 1H), 3.13 (s, 1H), 3.06 (dd, J = 12.9 and 5.7 Hz, 1H), 2.92
(s, 1H), 2.64−2.61 (m, 1H), 2.06 (dd, J = 12.9 and 8.7 Hz, 1H), 1.53
(d(1/2ABq), J = 8.7 Hz, 1H), 1.38 (d(1/2ABq), 8.7 Hz, 1H), 0.95 (s,
9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 203.1,
151.1, 137.1, 135.1, 135.0, 130.0, 117.1, 66.8, 55.9, 55.7, 48.3, 46.6,
44.8, 25.8, 18.1, −4.9, −5.0; HRMS(ES) m/z calcd for C20H30NaO2Si
(M + Na) 353.1913, found 353.1918.
[(2R,3S,4R,7S)-7-Allyl-6-(tert-butoxy)-4-methyltricyclo-
[6.2.1.02,7]undeca-5,9-dien-3-yl]oxy(tert-butyl)dimethylsilane
(30). To a cooled (−78 °C) THF (20 mL) solution of CuBr.Me2S
(154 mg, 0.75 mmol) was added freshly prepared ethereal solution
of methylmagnesiumiodide (prepared from 15 mmol of MeI and
15 mmol of magnesium in 15 mL of dry ether) and HMPA (2.35 mL,
13.5 mmol). To this mixture were added sequentially TMSCl (1.7 mL,
13.5 mmol) and allylated enone (+)-29 (2.0 g, 6.1 mmol, in 10 mL
THF) over a period of 30 min, and the resulting suspension was
stirred at −60 °C for 3 h. The reaction was quenched with
triethylamine (5 mL) and water and diluted with hexane (200 mL).
The aqueous layer was extracted with hexane (200 mL), and the
combined extracts were washed with water (50 mL) and brine and
dried over Na2SO4. After the evaporation of solvent, the crude residue
was purified through a short pad of silica gel column (eluent: 1% ethyl
acetate in hexane) to afford enol-TMS ether (−)-30 (2.33 g, 92%):
[α]23D −82.0 (c 1.5, CHCl3); IR (Neat) 2929, 1658, 1253, 1076 cm−1;
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1H NMR (300 MHz, CDCl3) δ 6.10−6.07(m, 1H), 5.98−5.95
138.2, 135.9, 116.4, 96.8, 74.0, 71.7, 58.9, 55.8, 54.1, 51.6, 51.0, 49.0,
45.6, 40.2, 26.1, 20.5, 18.3, 12.6, −3.8, −4.6; HRMS(ES) m/z calcd for
C25H42NaO4Si (M + Na) 457.2741, found 457.2741.
(m, 1H), 5.77−5.63 (m, 1H), 5.06−4.99 (m, 2H), 4.18 (d, J = 1.5 Hz,
1H), 3.33 (dd, J = 9.3 and 7.2 Hz, 1H), 3.03 (s, 1H), 2.81 (dd, J = 12.9
and 5.4 Hz, 1H), 2.53 (s, 1H), 2.10 (dd, J = 6.6 and 3.0 Hz, 1H),
1.88−1.77 (m, 2H), 1.50 (d(1/2ABq), J = 8.7 Hz, 1H), 1.43 (d(1/
2ABq), 8.7 Hz, 1H), 0.93 (s, 9H), 0.88 (d, J = 6.9 Hz, 3H), 0.20 (s,
9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.7,
136.1, 135.2, 134.7, 115.0, 106.2, 75.5, 51.7, 51.4, 49.7, 47.6, 45.2, 42.7,
34.5, 25.6, 19.9, 17.8, 0.0, −4.3, −5.1; HRMS(ES) m/z calcd for
C24H42NaO2Si2 (M + Na) 441.2621, found 441.2621.
((1R,5S,6R)-3-Allyl-5-[(methoxymethoxy)methyl]-5,6-di-
methyl-4-methylene-2-cyclohexenyloxy)(tert-butyl)dimethyl-
silane (28). Reaction was performed using (−)-33 (1.44 g,
3.29 mmol) under exactly the identical experimental conditions as
reported earlier for preparation of substrate 15. Column chromato-
graphic purification (Mobile phase -2% ethyl acetate in hexane to 15%
ethyl acetate in hexane) afforded the cyclohexenone (−)-28 (1.15 g,
95%) as a colorless oil: [α]27 = −79.0° (c 2.2, CHCl3); IR (Neat)
D
(2S,4S,5R,6S,7R)-2-Allyl-6-[1-(tert-butyl)-1,1-dimethylsilyl]-
oxy-4,5-dimethyltricyclo[6.2.1.02,7]undec-9-en-3-one (31). To
an ice-cooled solution of enol-TMS ether (−)-30 (2.33 g, 5.57 mmol)
in dry THF (20 mL) were added n-BuLi (4.2 mL, 1.6M) and HMPA
(1.2 mL, 6.7 mmol) successively, and the resulting solution was stirred
for a further 0.5 h at 0 °C. The reaction mixture was cooled to −40 °C
prior to the addition of MeI and allowed to warm to 0 °C over a
period of 1 h. The reaction was quenched with water and diluted with
ether (300 mL), and the organic layer was washed with water (50 mL)
and brine and dried over Na2SO4. After the evaporation of the solvent,
the crude residue was charged on a silica gel column (eluent: 5% ethyl
acetate in hexane) to furnish the dimethylated ketone (−)-31 (1.72 g,
85%) as a colorless oil: [α]24D −98.0 (c 1.0, CHCl3); IR (Neat) 3074,
3079, 1670, 1641, 1471 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.48 (s,
1H), 5.86−5.73 (m, 1H), 5.09−5.03 (m, 2H), 4.54−4.40 (m, 3H),
3.64 (d(1/2ABq), J = 9.6 Hz, 1H), 3.49 (d(1/2ABq), J = 9.6 Hz, 1H),
3.28 (s, 3H), 2.95 (d, J = 7.2 Hz, 2H), 2.92−2.04 (m, 1H), 1.13 (s, 3H),
1.12 (d, J = 7.8 Hz, 3H), 0.93 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 201.8, 147.7, 136.0, 135.3, 116.5, 96.5, 71.5,
70.9, 55.3, 49.5, 46.4, 33.6, 25.8, 20.0, 18.0, 12.4, −4.1, −4.7; HRMS(ES)
m/z calcd for C20H36NaO4Si (M + Na) 391.2281, found 391.2278.
2-(3R,4R,5S)-3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-5-[(me-
thoxymethoxy)-methyl]-4,5-dimethyl-6-methylene-1 Cyclo-
hexenylacetaldehyde (34). To a cooled (0 °C) solution of com-
pound (−)-28 (200 mg, 0.54 mmol) in 1,4-dioxane/water (3:1, 8 mL)
were added 2,6-lutidine (0.1 mL, 0.81 mmol), NaIO4 (347 mg, 1.62
mmol), and OsO4 (0.054 mmol). The reaction mixture was stirred
for a further 1.5−2 h at 0 °C. After the reaction was complete (as
indicated by TLC analysis), water (5 mL), and ethyl acetate (30 mL)
were added. The organic layer was separated, and the aqueous phase
was extracted with ethyl acetate (20 mL × 2). The combined organic
layers were washed with brine (10 mL) and dried over Na2SO4. The
solvent was removed under reduced pressure, and the resulting oily
residue was purified by silica gel column chromatography (eluent: 15%
ethyl acetate in hexane) to afford 1,4-keto-aldehyde (−)-34 (130 mg,
65%): [α]24D −78.0 (c 1.0, CHCl3); IR (Neat) 2929, 1728, 1670, 1043
1
2958, 1693, 1639, 1083 cm−1; H NMR (300 MHz, CDCl3) δ 6.26−
6.24 (m, 1H), 5.98−5.96 (m, 1H), 5.79−5.65 (m, 1H), 5.07−5.01 (m,
2H), 3.92 (dd, J = 11.4 and 6.9 Hz, 1H), 3.11 (s, 1H), 2.93 (s, 1H),
2.67 (dd, J = 13.2 and 7.2 Hz, 1H), 2.40 (dd, J = 7.2 and 3.3 Hz, 1H),
2.26−1.92 (m, 3H), 1.51 (d(1/2ABq), J = 8.7 Hz, 1H), 1.37 (d(1/
2ABq), 8.7 Hz, 1H), 0.95 (s, 9H), 0.93 (d, J = 6.0 Hz, 3H), 0.79 (d, J =
7.2 Hz, 3H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 218.9, 137.9, 135.9, 134.8, 117.4, 71.0, 59.6, 53.5, 51.5, 48.4, 47.8,
46.7, 45.9, 33.3, 25.9, 18.2, 15.1, 12.2, −4.0, −4.8; HRMS(ES) m/z
calcd for C22H36NaO2Si (M + Na) 383.2382, found 383.2381
(2S,4R,5R,6S,7R)-2-Allyl-6-[1-(tert-butyl)-1,1-dimethylsilyl]-
oxy-4-(hydroxymethyl)-4,5-dimethyltricyclo[6.2.1.02,7]undec-
9-en-3-one (32). The reaction was performed using (−)-31 (1.7 g,
4.74 mmol) under exactly the identical experimental conditions as
reported earlier for preparation of substrate 13. The crude residue was
purified by silica gel column chromatography (eluent: EA/hexane =
1:20 to 1:8) to afford starting ketone (−)-31 (0.25 g, 15%) and
1
cm−1; H NMR (300 MHz, CDCl3) δ 9.62 (s, 1H), 6.63 (s, 1H),
4.54−4.45 (m, 3H), 3.66 (d(1/2ABq), J = 9.3 Hz, 1H), 3.49 (d(1/
2ABq), J = 9.3 Hz, 1H), 3.34− 3.16 (m, 2H), 3.27 (s, 3H), 2.08−1.98
(m, 1H), 1.14 (s, 3H), 1.13 (d, J = 6.3 Hz, 3H), 0.92 (s, 9H), 0.13 (s,
3H), 0.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 201.7, 198.7, 151.6,
130.5, 96.6, 71.6, 70.6, 55.3, 49.3, 46.4, 44.7, 25.8, 19.9, 18.0, 12.3,
−4.2, −4.8; HRMS(ES) m/z calcd for C19H34NaO5Si (M + Na)
393.2073, found 393.2076.
primary alcohol (−)-32 (1.39 g, 75%, 90% borsm), respectively: [α]24
D
1
−16.9 (c 1.6, CHCl3); IR (Neat) 3488, 2956, 1685, 1471 cm−1; H
tert-Butyl((1R,5S,6R)-3-(1,3-dioxolan-2-ylmethyl)-5-[(me-
thoxymethoxy)-methyl]-5,6-dimethyl-4-methylene-2-cyclo-
hexenyloxy) Dimethylsilane (35). To a solution of aldehyde
(−)-34 (250 mg, 0.67 mmol) in 5 mL of dry benzene were added
ethylene glycol (0.11 mL, 2.0 mmol) and PPTS (34 mg, 0.13 mmol).
The resulting solution was refluxed for 2 h, and water formed during
reaction was removed continuously by azeotropic distillation using
Dean−Stark apparatus. After the completion of reaction, satd
NaHCO3 (10 mL) and ether (20 mL) were added. The organic
layer was separated, and aqueous phase was extracted with ether
(20 mL × 2). The combined organic layers were washed with water
(15 mL) and brine and dried over Na2SO4. The solvent was removed
in vaccuo, and the product was purified using silica gel column
chromatography (eluent: 15% ethyl acetate in hexane) to afford the
acetal (−)-35 (245 mg, 88%): [α]26D −91.0 (c 1.1, CHCl3); IR (Neat)
2884, 1672, 1471, 1043 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.66 (s,
1H), 4.95 (t, J = 4.8 Hz, 1H), 4.50−4.44 (m, 3H), 3.95−3.92 (m, 2H),
3.84−3.79 (m, 2H), 3.62 (d(1/2ABq), J = 9.3 Hz, 1H), 3.52 (d(1/
2ABq), J = 9.3 Hz, 1H), 3.28 (s, 3H), 2.58−2.56 (m, 2H), 2.01−1.95
(m, 1H), 1.14 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H), 0.14 (s,
3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 201.8, 149.7, 132.3,
102.8, 96.5, 71.4, 70.8, 64.8, 64.7, 55.2, 49.4, 46.2, 34.1, 25.76, 20.0,
18.0, 12.4, −4.2, −4.7; HRMS(ES) m/z calcd for C21H38NaO6Si (M +
Na) 437.2335, found 437.2328.
NMR (300 MHz, CDCl3) δ 6.33−6.30 (m, 1H), 5.96−5.93 (m, 1H),
5.85−5.71 (m, 1H), 5.13−5.05 (m, 2H), 4.03 (dd, J = 11.7 and 6.6 Hz,
1H), 3.52−3.44 (m, 2H), 3.18 (bs, 1H), 2.93−2.86 (m, 2H), 2.46 (dd,
J = 6.6 and 3.3 Hz, 1H), 2.16 (dd, J = 13.2 and 7.5 Hz, 1H), 1.88 (dd,
J = 7.5 and 4.2 Hz, 1H), 1.82−1.74 (m, 1H), 1.55 (d(1/2ABq), J = 9.0
Hz, 1H), 1.43 (d(1/2ABq), J = 9.0 Hz, 1H), 0.97 (s, 3H), 0.95 (s,
9H), 0.85 (d, J = 6.9 Hz, 3H), 0.12 (s, 3H), 0.07 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 221.8, 138.3, 135.0, 117.8, 71.7, 64.1, 59.3, 55.5,
52.1, 50.9, 49.1, 46.8, 46.0, 39.8, 25.99, 25.96, 19.4, 18.2, 12.4, −3.9,
−4.7; HRMS(ES) m/z calcd for C23H38NaO3Si (M + Na) 413.2488,
found 413.2483.
(2S,4R,5R,6S,7R)-2-Allyl-6-[1-(tert-butyl)-1,1-dimethylsilyl]-
oxy-4-[(methoxymethoxy)methyl]-4,5-dimethyltricyclo-
[6.2.1.02,7]undec-9-en-3-one (33). Reaction was performed using
(−)-32 (1.39 g, 3.54 mmol) under exactly the identical experimental
conditions as reported earlier for preparation of substrate 14. The
crude oily material was purified through a silica gel column (eluent:
EA/hexane = 1:9) to yield the methoxymethyl (MOM) derivative
(−)-33 (1.44 g, 93%) as a colorless oil: [α]24 −70.0 (c 2.2, CHCl3);
D
IR (Neat) 2929, 2856, 1687, 1471 cm−1; 1H NMR (300 MHz, CDCl3)
δ 6.28−6.26 (m, 1H), 5.95−5.82 (m, 2H), 5.02−4.97 (m, 2H), 4.47
(ABq, J = 6.6 Hz, 2H), 4.27 (dd, J = 11.7 and 6.6 Hz, 1H), 3.46 (d(1/
2ABq), J = 9.0 Hz, 1H), 3.36 (d(1/2ABq), J = 9.0 Hz, 1H), 3.31 (s,
3H), 3.11(s, 1H), 2.88(s, 1H), 2.72 (dd, J = 14.1 and 7.2 Hz, 1H), 2.41
(dd, J = 6.0 and 3.0 Hz, 1H), 2.31 (dd, J = 13.5 and 8.4 Hz, 1H),
1.74−1.64 (m, 1H), 1.54 (d(1/2ABq), J = 9.0 Hz, 1H), 1.37 (d(1/
2ABq), 9.0 Hz, 1H), 0.95 (s, 9H), 0.90 (d, J = 6.9 Hz, 3H), 0.87 (s,
3H), 0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 220.3,
(2S,3R,4R,6S)-4-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-6-(1,3-
dioxolan-2-ylmethyl)-2,3-dimethyl-2-pentylcyclohexan-1-one
and (2S,3R,4R,6R)-4-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-6-(1,3-
dioxolan-2-ylmethyl)-2,3-dimethyl-2-pentylcyclohexan-1-one
(36a,b). In a 25 mL RB flask, fitted with three-way stopcock, were
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added 20 mg of PtO2 and 2 mL of ethyl acetate. The reaction setup
was flushed with hydrogen, the mixture was stirred for 5 min prior to
the addition of solution of acetal (−)-35 (245 mg, 0.59 mmol) in 2 mL
of ethyl acetate, and once again the system was flushed with hydrogen.
The reaction was continued at 25 °C for 1 h under the atmospheric
pressure of hydrogen and then filtered through a short pad of a silica
gel column (eluent: 10% ethyl acetate in hexane) to afford mixture of
reduced products 36a,b (234 mg, 95%). Data for more polar
gel column (eluent: 10% ethyl acetate in hexane) to afford the
aldehyde (−)-39 (88 mg, 65%) as a colorless oil: [α]23D −52.7 (c 1.5,
1
CHCl3); IR (Neat) 3077, 2931, 1725, 1694, 1638, 1065 cm−1; H
NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 5.74−5.60 (m, 1H), 5.17−
5.07 (m, 2H), 4.50 (ABq, J = 6.6 Hz, 2H), 4.17 (dt, J = 9.9 and 3.9 Hz,
1H), 3.54 (d(1/2ABq), J = 9.0 Hz, 1H), 3.40 (d(1/2ABq), J = 9.0 Hz,
1H), 3.31 (s, 3H), 3.17 (d, J = 18.6 Hz, 1H), 2.47 (d, J = 18.6 Hz, 1H),
2.24 (dd, J = 14.4 and 6.6 Hz, 1H), 2.07−1.98 (m, 1H), 1.85−1.78 (m,
2H), 1.63 (d, J = 3.9 Hz, 1H), 1.18 (s, 3H), 1.08(d, J = 6.9 Hz, 3H),
0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 218.0, 199.8, 133.2, 119.3, 96.7, 74.3, 68.2, 55.7, 53.3, 52.3, 47.8,
46.6, 41.1, 40.6, 25.92, 25.86, 22.7, 18.0, 12.1, −4.1, −4.6; HRMS(ES)
m/z calcd for C22H40NaO5Si (M + Na) 435.2543, found 435.2541.
1-(1R,3S,4R,5R)-1-Allyl-5-[1-(tert-butyl)-1,1-dimethylsilyl]-
oxy-3-[(methoxymethoxy)methyl]-3,4-dimethyl-2-methylene-
cyclohexylacetone (40). To a cooled (−78 °C) THF (5 mL)
solution of aldehyde (−)-39 (88 mg, 0.21 mmol) was added methyl
lithium (0.5 mL, 1.5 M ethereal solution), and the resulting solu-
tion was stirred for 30 min at the same temperature. Reaction was
quenched with satd NH4Cl, and the aqueous layer was extracted with
ether (2 × 20 mL). The combined extracts were washed with water
and brine and dried over Na2SO4. After the evaporation of the solvent,
the crude residue was purified by passing through a short silica gel
column (eluent: 10% ethyl acetate in hexane) to afford the mixture of
alcohols. To a solution of the above obtained mixture of alcohols
(90 mg) in 3 mL of dry DCM, kept at 0 °C, was added NaOAc (51 mg,
0.63 mmol), PCC (135 mg, 0.63 mmol) and silica gel (135 mg, 100−
200 mesh) successively. The resulting orange colored suspension was
stirred at 25 °C for 5−6 h and then directly charged on a silica gel
column (eluent: 50% ethyl acetate in hexane) to afford the 1,4-
compound): [α]24 +16.7 (c 1.2, CHCl3); IR (Neat) 2953, 2931,
D
1718, 1470, 1042 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.90 (dd, J =
6.0 and 3.9 Hz, 1H), 4.54 (ABq, J = 6.9 Hz, 2H), 3.98−3.64 (m, 6H),
3.38 (d, J = 8.4 Hz, 1H), 3.32 (s, 3H), 3.01−2.91 (m, 1H), 2.33−2.26
(m, 2H), 1.59−1.33 (m, 3H), 1.15 (s, 3H), 1.03 (d, J = 6.9 Hz, 3H),
0.88 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 212.41,
102.99, 96.74, 71.26, 71.19, 64.66, 64.61, 55.47, 51.91, 49.56, 42.19,
40.55, 33.51, 25.79, 19.28, 17.96, 12.81, −3.98, −4.69; HRMS(ES)
m/z calcd for C21H40NaO6Si (M + Na) 439.2492, found 439.2492.
Data for less polar compound): [α]22 −33.3 (c 0.3, CHCl3); IR
D
1
(Neat) 2929, 1702, 1043 cm−1; H NMR (300 MHz, CDCl3) δ 4.92
(t, J = 4.8 Hz, 1H), 4.58 (s, 2H), 3.96−3.79 (m, 6H), 3.65 (d, J = 9.6
Hz, 1H), 3.43 (d, J = 9.6 Hz, 1H), 3.34 (s, 3H), 2.29−2.07 (m, 4H),
1.82−1.72 (m, 1H), 1.40 (s, 3H), 0.93 (s, 9H), 0.87 (d, J = 6.9 Hz,
3H), 0.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 215.7, 103.1, 96.9,
72.5, 71.5, 64.8, 64.6, 55.4, 51.2, 45.6, 38.4, 36.85, 32.45, 25.8, 23.21,
18.0, 14.8, −4.8 (2C); HRMS(ES) m/z calcd for C21H40NaO6Si (M + Na)
439.2492, found 439.2492.
((1R,2R,3S,5R)-5-Allyl-5-(1,3-dioxolan-2-ylmethyl)-3-[(me-
thoxymethoxy)-methyl]-2,3-dimethyl-4-methylenecyclohexyl-
oxy)(tert-butyl)dimethylsilane (−)-38 and ((1R,2R,3S,5S)-5-
Allyl-5-(1,3-dioxolan-2-ylmethyl)-3-[(methoxymethoxy)-methyl]-
2,3-dimethyl-4-methylenecyclohexyloxy)(tert-butyl)-
dimethylsilane (−)-37. To a solution of compounds 36a,b (210 mg,
0.5 mmol) in 6 mL of dry THF were sequentially added NaH (61 mg,
2.5 mmol) and allyl bromide (0.22 mL, 2.5 mmol) at 25 °C. The
reaction mixture was refluxed for 2 h and then quenched at 0 °C with
water. The aqueous phase was extracted with ether (2 × 25 mL), and
the combined organic layers were washed with water (10 mL) and
brine and dried over Na2SO4. After the evaporation of solvent, the
crude material was purified on a silica gel column (eluent: 8% ethyl
acetate in hexane) to afford allylated cyclohexenones (−)-38 (135 mg,
58%) and (−)-37 (90 mg, 38%) respectively. Data for 38: [α]22
−25.0 (c 1.0, CHCl3); IR (Neat) 3077, 2930, 2857, 1695, 1638 cm−1D;
1H NMR (300 MHz, CDCl3) δ 5.74−5.55 (m, 1H), 5.11−5.01 (m,
diketone (−)-40 (77 mg, 85% for 2 steps) as a colorless oil: [α]24
D
1
−58.3 (c 1.2, CHCl3); IR (Neat) 3077, 1717, 1694 cm−1; H NMR
(300 MHz, CDCl3) δ 5.74−5.60 (m, 1H), 5.15−5.05 (m, 2H), 4.52
(d(1/2ABq), J = 6.6 Hz, 1H), 4.47 (d(1/2ABq), J = 6.6 Hz, 1H), 4.17
(dt, J = 10.5 and 4.5 Hz, 1H), 3.51 (d, J = 9.3 Hz, 1H), 3.38 (d, J = 9.3
Hz, 1H), 3.31 (s, 3H), 3.21 (d, J = 18.6 Hz, 1H), 2.47−2.41 (m, 2H),
2.20−2.07 (m, 1H), 2.06 (s, 3H), 1.85−1.65 (m, 3H), 1.18 (s, 3H),
1.07 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 218.8, 206.3, 133.7, 118.9, 96.7, 74.5, 68.2,
55.7, 53.3, 52.3, 48.1, 46.3, 40.8, 40.7, 29.8, 25.9, 22.6, 18.0, 12.1, −4.1,
−4.6; HRMS(ES) m/z calcd for C23H42NaO5Si (M + Na) 449.2699,
found 449.2697.
(4S,5R,6R,7aR)-7a-Allyl-6-[1-(tert-butyl)-1,1-dimethylsilyl]-
oxy-4-[(methoxymethoxy)methyl]-4,5-dimethyl-2,4,5,6,7,7a-
hexahydro-1H-2-indenone (41). To a solution of compound
(−)-40 (75 mg, 0.18 mmol) in 12 mL of dry THF was added NaH
(22 mg, 0.9 mmol) at 25 °C. The reaction mixture was refluxed for 2 h
and then quenched at 0 °C with water. The aqueous phase was
extracted with ether (2 × 15 mL). The combined organic phases were
washed with water (5 mL × 2), brine and dried over Na2SO4. After the
evaporation of solvent, the crude material was purified on a silica gel
column (eluent: 30% ethyl acetate in hexane) to furnish the bicyclic
2H), 4.80 (dd, J = 5.1 and 3.9 Hz, 1H), 4.53 (d(1/2ABq), J = 6.9 Hz,
1H), 4.47 (d(1/2ABq), J = 6.9 Hz, 1H), 4.13 (dt, J = 9.9 and 4.2 Hz,
1H), 3.97−3.70 (m, 4H), 3.48 (ABq, J = 9.1 Hz, 2H), 3.32 (s, 3H),
2.59 (dd, J = 13.5 and 6.6 Hz, 1H), 2.24 (dd, J = 13.5 and 5.4 Hz, 1H),
2.07−1.66 (m, 5H), 1.05 (d, J = 6.9 Hz, 3H), 1.02 (s, 3H), 0.91 (s,
9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
217.91, 134.15, 118.82, 102.27, 96.74, 73.76, 69.10, 64.65, 64.23,
55.58, 51.88, 49.81, 47.08, 43.01, 41.57, 40.58, 25.91, 22.35, 18.08,
12.53, −4.18, −4.72; HRMS(ES) m/z calcd for C24H44SiO6 (M + Na)
479.2805, found 479.2805. Data for 37: [α]27 −55.0 (c 1.0, CHCl3);
enone (+)-41 (61 mg, 85%) as a colorless oil: [α]24 +48.0 (c 1.0,
D
D
IR (Neat) 2954, 2929, 1695, 1471 cm−1; 1H NMR (300 MHz, CDCl3)
δ 5.76−5.63 (m, 1H), 5.14−5.08 (m, 2H), 4.80 (t, J = 5.1 Hz, 1H),
4.50 (ABq, J = 6.6 Hz, 2H), 4.12 (dt, J = 9.9 and 3.9 Hz, 1H), 3.82−
3.67 (m, 3H), 3.99−3.80 (m, 1H), 3.47 (s, 2H), 3.31 (s, 3H), 2.46 (dd,
J = 14.1 and 7.8 Hz, 1H), 2.29−2.18 (m, 2H), 2.04−1.81 (m, 3H), 1.69
(dd, J = 14.1 and 4.8 Hz, 1H), 1.06 (d, J = 6.6 Hz, 3H), 1.06 (s, 3H),
0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 217.5, 133.8,
118.7, 102.4, 96.7, 74.2, 68.7, 64.8, 64.0, 55.6, 51.9, 49.2, 47.0, 41.9, 40.9,
40.4, 25.9, 22.8, 18.1, 12.3, −4.0, −4.6; HRMS(ES) m/z calcd for
C24H44NaO6Si (M + Na) 479.2805, found 479.2813.
CHCl3); IR (Neat) 3077, 2930, 1698, 1043 cm−1; 1H NMR (300 MHz,
CDCl3) δ 6.02 (s, 1H), 5.77−5.63 (m, 1H), 5.13−5.07 (m, 2H),
4.56 (s, 2H), 3.85−3.75 (m, 2H), 3.49 (d(1/2ABq), J = 9.6 Hz, 1H),
3.34 (s, 3H), 2.51 (d(1/2ABq), J = 18.0 Hz, 1H), 2.42 (d, J = 6.9 Hz,
2H), 2.24 (dd, J = 13.2 and 4.2 Hz, 1H), 2.10 (d(1/2ABq), J = 18.0
Hz, 1H), 1.49−1.37 (m, 2H), 1.35 (s, 3H), 1.06 (d, J = 6.9 Hz, 3H),
0.89 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 207.2,
187.5, 133.9, 131.6, 119.2, 97.0, 71.2, 68.9, 55.7, 50.8, 49.2, 47.4, 46.8,
43.9, 42.5, 25.8, 24.6, 17.9, 12.0, −4.0, −4.7; HRMS(ES) m/z calcd for
C23H40NaO4Si (M + Na) 431.2594, found 431.2596.
2-(1R,3S,4R,5R)-1-Allyl-5-[1-(tert-butyl)-1,1-dimethylsilyl]-
oxy-3-[(methoxymethoxy)methyl]-3,4-dimethyl-2-methylene-
cyclohexylacetaldehyde (39). To a solution of compound (−)-38
(150 mg, 0.33 mmol) in 3 mL of acetone was added Amberlyst-15
(50 mg), and the resulting reaction mixture was stirred at 25 °C for 3 h
and then filtered through a short pad of Celite. The solvent was
removed in vaccuo, and the crude oily residue was charged on a silica
(4S,5R,6R,7aR)-7a-Allyl-6-hydroxy-4-[(methoxymethoxy)-
methyl]-4,5-dimethyl-2,4,5,6,7,7a-hexahydro-1H-2-indenone
(42). To a solution of compound (+)-41 (28 mg, 0.07 mmol) in 1 mL
of dry THF was added TBAF (37 mg, 0.14 mmol) at 25 °C, and reac-
tion was continued for a further 8 h. Solvent was removed under
reduced pressure, and the crude residue was directly loaded on a silica
gel column (eluent: 80% ethyl acetate in hexane) to afford the alcohol
8066
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Article
(+)-42 (19 mg, 93%) as a colorless oil: [α]24 = +95.0° (c 0.8,
(d, J = 18.6 Hz, 1H), 2.39 (dd, J = 13.8 and 4.2 Hz, 1H), 2.32 (d, J =
18.6 Hz, 1H), 1.88−1.78 (m, 2H), 1.34 (s, 3H), 1.25 (d, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 205.0, 186.5, 169.6, 131.0, 96.4, 78.7,
D
1
CHCl3); IR (Neat) 3427, 2931, 1689, 1597, 1043 cm−1; H NMR
(300 MHz, CDCl3) δ 6.03 (s, 1H), 5.75−5.62 (m, 1H), 5.11−5.05 (m,
2H), 4.54 (s, 2H), 3.85 (dt, J = 10.8 and 3.9 Hz, 1H), 3.74 (d(1/
2ABq), J = 9.6 Hz, 1H), 3.50 (d(1/2ABq), J = 9.6 Hz, 1H), 3.32 (s,
3H), 2.52 (d(1/2ABq), J = 18.0 Hz, 1H), 2.43−2.34 (m, 3H), 2.10
(d(1/2ABq), J = 18.0 Hz, 1H), 1.75 (bs, 1H), 1.44−1.38 (m, 2H), 1.
36 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
207.0, 187.9, 133.7, 131.8, 119.2, 97.0, 71.0, 68.3, 55.7, 50.7, 49.1, 47.3,
46.6, 43.9, 42.4, 24.4, 11.5; HRMS(ES): m/z calcd for C17H26NaO4
(M + Na) 317.1729, found 317.1737.
71.6, 55.7, 50.8, 45.1, 42.3, 42.1, 41.7, 37.9, 25.7, 12.2; HRMS(ES)
m/z calcd for C16H22NaO5 (M + Na) 317.1365, found 317.1364.
1R,6S,7R,8S)-6-(Hydroxymethyl)-6,7-dimethyl-9-oxatricyclo-
[6.3.1.01,5]dodec-4-ene-3,10-dione (48). To a cooled (0 °C)
solution of compound (+)-47 (5 mg, 0.02 mmol) in 2 mL of dry
DCM was added a solution of triphenylcarbenium-tetrafluoroborate
(20 mg, 0.06 mmol) in 1 mL of dry DCM. The resulting dark yellow
solution was stirred at ice bath temperature for 1 h and then directly
loaded on a silica gel column. Elution with 10% ethyl acetate in hexane
removed the reagent derived impurities, further elution with 60% ethyl
acetate in hexane afforded the starting material (+)-47 (1 mg), and
further elution with neat ethyl acetate afforded the demethyl-
(4S,5R,7aS)-7a-Allyl-4-[(methoxymethoxy)methyl]-4,5-di-
methyl-2,4,5,6,7,7a-hexahydro-1H-2,6-indenedione (43). To a
solution of compound (+)-42 (19 mg, 0.065 mmol) in 2 mL of
dry DCM, kept at 0 °C, were sequentially added NaOAc (16 mg,
0.2 mmol), PCC (43 mg, 0.2 mmol), and silica gel (43 mg, 100−200
mesh). The resulting orange colored suspension was stirred at 25 °C
for 3 h and then filtered through a short pad of a silica gel column
(eluent: 50% ethyl acetate in hexane) to obtain the compound (+)-43
minwanenone (+)-48 (2.5 mg, 70%): [α]22 +65.0 (c 0.2, CHCl3);
D
IR (Neat) 3421, 2929, 1724, 1695 cm−1; 1H NMR (300 MHz, CDCl3)
δ 6.09 (s, 1H), 4.65−4.60 (m, 1H), 3.72 (d, J = 11.1 Hz, 1H), 3.56 (d,
J = 12.0 Hz, 1H), 2.88 (dd, J = 18.6 and 2.7 Hz, 1H), 2.76 (d, J =
19.2 Hz, 1H), 2.52 (d, J = 18.6 Hz, 1H), 2.40 (dd, J = 15.9 and 5.7 Hz,
1H), 2.33 (d, J = 18.6 Hz, 1H), 1.90−1.78 (m, 2H), 1.70 (bs, 1H),
1.37 (s, 3H), 1.24 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
204.6, 185.1, 169.7, 131.8, 79.1, 65.1, 50.5, 45.1, 43.6, 41.9, 41.5, 38.1,
24.6, 12.1; HRMS(ES) m/z calcd for C14H18NaO4 (M + Na)
273.1103, found 273.1100.
(17 mg, 90%) as a colorless oil: [α]24 +121.2 (c 0.8, CHCl3); IR
D
(Neat) 3077, 2929, 1712, 1698, 1602, 1044 cm−1; 1H NMR (300 MHz,
CDCl3) δ 6.20 (s, 1H), 5.71−5. 57 (m, 1H), 5.12−5.06 (m, 2H),
4.50 (s, 2H), 3.53 (d(1/2ABq), J = 9.9 Hz, 1H), 3.44 (d(1/2ABq), J =
9.9 Hz, 1H), 3.31 (s, 3H), 2.78 (d(1/2ABq), J = 12.6 Hz, 1H), 2.65−
2.50 (m, 3H), 2.40 (dd, J = 15.9 and 5.4 Hz, 1H), 2.30−2.21 (m, 2H),
1.49 (s, 3H), 1.10 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 208.2, 205.8, 183.6, 132.7, 132.6, 120.2, 96.9, 70.7, 55.8, 52.6, 52.4,
50.2, 49.9, 47.1, 42.8, 24.5, 8.2; HRMS(ES) m/z calcd for C17H24NaO4
(M + Na) 315.1572, found 315.1581.
(1S,4S,5R,6R,7aR)-7a-Allyl-6-[1-(tert-butyl)-1,1-dimethylsilyl]-
oxy-4-[(methoxymethoxy)methyl]-1,4,5-trimethyl-2,4,5,6,7,7a-
hexahydro-1H-2-indenone (49). To a cooled (−40 °C) solution of
LiHMDS (0.7 mL, 0.5 M, freshly prepared from equimolar amount of
HMDS and n-BuLi in THF, at 0 °C) was added THF (2 mL) solution
of enone (+)-41 (55 mg, 0.13 mmol) over a period of 5 min. The re-
sulting pale yellow colored solution was stirred at 0 °C for 1 h and
then cooled to −40 °C prior to the sequential addition of HMPA
(0.05 mL, 0.27 mmol) and MeI (0.02 mL, 0.27 mmol). The reaction
mixture was allowed to warm to 0 °C, stirred for 1 h, and then
quenched with water. The aqueous phase was extracted with ether
(2 × 15 mL). The combined organic layers were washed with water
and brine and dried over Na2SO4. After the evaporation of solvent, the
resulting crude residue was purified by silica gel column chromatog-
raphy to furnish the methylated enone (+)-49 (42 mg, 74%) as
(4S,5R,6S,7aR)-7a-Allyl-6-hydroxy-4-[(methoxymethoxy)-
methyl]-4,5-dimethyl-2,4,5,6,7,7a-hexahydro-1H-2-indenone
(44). To a cooled (−78 °C) solution of ketone (+)-43 (17 mg, 0.06
mmol) in 1.5 mL of THF/MeOH (1:1) was added NaBH4 (3.5 mg,
0.09 mmol). The resulting white suspension was stirred for 2 min and
then quenched with satd NH4Cl. The aqueous phase was extracted
with ethyl acetate (2 × 15 mL), and the combined extracts were
washed with water (5 mL) and brine and dried over Na2SO4 prior to
the evaporation of solvent. The crude oily residue was filtered through
a short pad of silica gel column (eluent: 70% ethyl acetate in hexane)
to afford the alcohol (+)-44 (16 mg, 95%) as a colorless oil: [α]24
+146.7 (c 0.6, CHCl3); IR (Neat) 3446, 3074, 1683, 1593, 1044 cm−1D;
1H NMR (300 MHz, CDCl3) δ 6.05 (s, 1H), 5.82−5.69 (m, 1H),
5.09−5.04 (m, 2H), 4.56 (s, 2H), 4.32 (d, J = 9.6 Hz, 1H), 3.96−3.95
(m, 1H), 3.53 (d, J = 9.3 Hz, 1H), 3.33 (s, 3H), 2.73 (d, J = 7.5 Hz,
2H), 2.55 (d, J = 18.3 Hz, 1H), 2.42−2.36 (m, 1H), 2.10 (bs, 1H),
2.04 (d, J = 18.3 Hz, 1H), 1.62−1.56 (m, 2H), 1.36 (s, 3H), 1.16 (d,
J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 207.5, 189.2, 134.9,
131.6, 118.5, 96.8, 71.7, 71.2, 55.5, 52.0, 46.5, 45.4, 44.2, 43.8, 43.7,
24.6, 12.6; HRMS(ES) m/z calcd for C17H26NaO4 (M + Na)
317.1729, found 317.1730.
colorless oil: [α]24 = +42.0° (c 1.0, CHCl3); IR (Neat) 3078, 2930,
D
1705, 1601, 1043 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.99 (s, 1H),
5.80−5.66 (m, 1H), 5.14−5.08 (m, 2H), 4.57 (s, 2H), 3.89 (dt, J =
10.8 and 3.6 Hz, 1H), 3.78 (d, J = 9.6 Hz, 1H), 3.49 (d, J = 9.6 Hz,
1H), 3.34 (s, 3H), 2.58−2.48 (m, 1H), 2.43−2.23(m, 2H), 1.96 (dd,
J = 12.9 and 3.9 Hz, 1H), 1.39−1.32 (m, 2H), 1.35 (s, 3H), 1.06 (d,
J = 6.0 Hz, 3H), 1.04 (d, J = 7.5 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 210.9, 186.8, 134.1, 129.7, 119.2, 97.0,
71.5, 69.4, 55.7, 50.7, 49.9, 49.4, 44.0, 43.5, 41.0, 25.8, 24.7, 18.0, 12.6,
12.1, −3.9, −4.6; HRMS(ES) m/z calcd for C24H42NaO4Si (M + Na)
445.2750, found 445.2744.
(1R,6S,7R,8S)-6-[(Methoxymethoxy)methyl]-6,7-dimethyl-9-
oxatricyclo[6.3.1.01,5]dodec-4-ene-3,10-dione (47). To a cooled
(0 °C) solution of compound (+)-44 (16 mg, 0.054 mmol) in 1,4-
dioxane/water (3:1, 4 mL) were added 2,6-lutidine (0.018 mL, 0.15
mmol), NaIO4 (63 mg, 0.3 mmol), and OsO4 (0.1 equiv). The re-
sulting suspension was stirred at 0 °C for a further 1.5− 2 h. After the
completion of reaction (as indicated by TLC analysis), reaction
mixture was filtered through a short pad of silica gel and eluted with
ethyl acetate. The organic solvent was removed under vacuum, and the
crude material was purified through a silica gel column (eluent: 80%
ethyl acetate in hexane) to afford the lactol 45a,b (13.4 mg, 85%). To
a solution of the above lactol 45a,b (13 mg) in 5 mL of dry benzene
was added Ag2CO3 on Celite (100 mg). The reaction mixture was
refluxed for about 10 h and then filtered through a short pad of silica
gel column (eluent: 90% ethyl acetate in hexane) to obtain the bridge
(1S,4S,5R,6R,7aR)-7a-Allyl-6-hydroxy-4-[(methoxymethoxy)-
methyl]-1,4,5-trimethyl-2,4,5,6,7,7a-hexahydro-1H-2-inden-
one (50). To a solution of methylated enone (+)-49 (40 mg, 0.095
mmol) in 1 mL of dry THF was added TBAF (50 mg, 0.019 mmol) at
25 °C, and the reaction was further continued for 8 h. The solvent was
removed under reduced pressure, and the crude residue was directly
charged on a silica gel column. Eluting the column with 80% ethyl
acetate in hexane furnished the alcohol (+)-50 (27 mg, 92%): [α]24
+95.0 (c 0.2, CHCl3); IR (Neat) 3424, 3076, 2931, 1697, 1043 cm−1D;
1H NMR (300 MHz, CDCl3) δ 6.02 (s, 1H), 5.76−5.67 (m, 1H),
5.14−5.07 (m, 2H), 4.56 (s, 2H), 3.93 (dt, J = 10.8 and 3.6 Hz, 1H),
3.76 (d, J = 9.6 Hz, 1H), 3.51 (d, J = 9.6 Hz, 1H), 3.34 (s, 3H), 2.63−
2.34 (m, 3H), 2.11 (dd, J = 12.3 and 4.2 Hz, 1H), 1.42−1.32 (m, 2H),
1.40 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 7.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 210.7, 186.3, 133.8, 130.0, 119.2, 97.0, 71.2,
68.9, 55.7, 50.5, 49.8, 49.3, 44.0, 43.3, 40.9, 24.6, 12.5, 11.5;
HRMS(ES) m/z calcd for C18H28NaO4 (M + Na) 331.1885, found
331.1884.
lactone (+)-47 (11 mg, 90%) as a colorless oil: [α]24 +106.7 (c 0.3,
D
1
CHCl3); IR (Neat) 2932, 1731, 1699, 1604, 1045 cm−1; H NMR
(300 MHz, CDCl3) δ 6.08 (s, 1H), 4.64−4.60 (m, 1H), 4.52 (s, 2H),
3.60 (d, J = 9.9 Hz, 1H), 3.37 (d, J = 9.9 Hz, 1H), 3.32 (s, 3H),
2.83 (dd, J = 18.6 and 2.4 Hz, 1H), 2.72 (d, J = 18.6 Hz, 1H), 2.52
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Article
(1S,4S,5R,7aR)-7a-Allyl-4-[(methoxymethoxy)methyl]-1,4,5-
trimethyl-2,4,5,6,7,7a-hexahydro-1H-2,6-indenedione (51). To
the solution of alcohol (+)-50 (25 mg, 0.08 mmol) in 2 mL of dry
DCM, kept at 0 °C, were added NaOAc (20 mg, 0.24 mmol), PCC
(51 mg, 0.24 mmol), and silica gel (51 mg, 100−200 mesh) suc-
cessively. The resulting orange colored suspension was stirred at 25 °C
for 3 h and then filtered through a short pad of silica gel column
(eluent: 50% ethyl acetate in hexane) to furnish the compound (+)-51
and then directly loaded on a silica gel column. Elution with 10% ethyl
acetate in hexane removed the reagent derived impurities, further
elution with 60% ethyl acetate in hexane afforded starting material
(+)-53 (1 mg), and elution with neat ethyl acetate afforded the desired
(+)-1S-minwanenone 5 (2.4 mg, 56% yield, 70% yield borsm): [α]22
+23.3 (c 0.3, EtOH); IR (Neat) 3424, 2930, 1729, 1703, 1603 cm−1D;
1H NMR (500 MHz, CD3OD) δ 6.04 (s, 1H), 4.68 (m, 1H), 3.63 (d,
J = 11.5 Hz, 1H), 3.49 (d, J = 11.5 Hz, 1H), 2.89 (d, J = 19.0 Hz, 1H),
2.81 (dd, J = 19.0 and 2.0 Hz, 1H), 2.32 (dd, J = 13.5 and 4.0 Hz, 1H),
2.18 (q, J = 7.5 Hz, 1H), 1.85 (dq, J = 7.5 and 3.0 Hz, 1H), 1.80 (ddd,
J = 14.0, 2.0, and 2.0 Hz, 1H), 1.36 (s, 3H), 1.19 (d, J = 7.0 Hz, 3H),
1.10 (d, J = 8.0 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 211.1, 188.2,
173.5, 130.8, 81.3, 65.4, 53.0, 46.8, 46.2, 45.4, 41.7, 35.1, 24.8, 12.1,
10.0; HRMS(ES) m/z calcd for C15H20NaO4 (M + Na) 287.1259,
found 287.1260.
(22 mg, 90%) as a colorless oil: [α]23 = +91.4° (c 0.7, CHCl3); IR
D
(Neat) 3078, 1706, 1604, 1044 cm−1; 1H NMR (300 MHz, CDCl3) δ
6.18 (s, 1H), 5.74−5.61 (m, 1H), 5.15−5.04 (m, 2H), 4.52 (s, 2H),
3.56 (d, J = 9.9 Hz, 1H), 3.44 (d, J = 9.6 Hz, 1H), 3.32 (s, 3H), 2.56−
2.45 (m, 5H), 2.35 (d, J = 7.5 Hz, 1H), 1.50 (s, 3H), 1.10 (d, J = 7.2 Hz,
3H), 1.06 (d, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 209.6,
209.4, 182.9, 132.7, 130.8, 120.3, 96.8, 70.8, 55.8, 52.8, 52.5, 49.8, 47.5,
47.2, 43.4, 24.7, 12.7, 8.2; HRMS(ES) m/z calcd for C18H26NaO4
(M + Na) 329.1729, found 329.17333.
1-(1R,3S,4R,5R)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-(1,3-
dioxolan-2-ylmethyl)-3-[(methoxymethoxy)methyl]-3,4-di-
methyl-2-methylene-cyclohexylacetone (54). To a solution of
allylated cyclohexenone (−)-37 (90 mg, 0.2 mmol) in 2 mL of DMF/
water (9:1) were sequentially added PdCl2 (9 mg, 0.05 mmol) and
CuCl (40 mg, 0.4 mmol). The resulting dark brown colored sus-
pension was stirred under an atmospheric pressure of oxygen for a
further 8 h. After the completion of reaction (as indicated by TLC
analysis), water (5 mL) and ethyl acetate (20 mL) were added. The
organic layer was separated, and aqueous phase was extracted with
ethyl acetate (20 mL × 2). The combined organic layers were washed
with water (5 mL × 3) and brine and dried over Na2SO4. The solvent
was removed under reduced pressure, and the crude product was
purified by silica gel column chromatography (eluent: 20% ethyl
acetate in hexane) to afford the 1,4-diketone (−)-54 (75 mg, 80%). as
(1S,4S,5R,6S,7aR)-7a-Allyl-6-hydroxy-4-[(methoxymethoxy)-
methyl]-1,4,5-trimethyl-2,4,5,6,7,7a-hexahydro-1H-2-inden-
one (26a). To a solution of compound (+)-51 (20 mg, 0.065 mmol)
in 1.5 mL of THF/MeOH (1:1) was added NaBH4 (4 mg, 0.1 mmol)
at −78 °C. The resulting white colored suspension was stirred for
2 min and then quenched with satd NH4Cl. The aqueous phase was
extracted with ethyl acetate (2 × 15 mL), and the combined organic
layers were washed with water and brine and dried over Na2SO4 prior
to evaporation of solvent. The crude material was filtered through a
silica gel column (eluent: 70% ethyl acetate in hexane) to afford the
alcohol (+)-26a (19 mg, 95%) as a colorless oil: [α]24D +170.9 (c 0.55,
CHCl3); IR (Neat) 3460, 2925, 1689, 1044 cm−1; 1H NMR (300 MHz,
CDCl3) δ 6.02 (s, 1H), 5.84−5.73 (m, 1H), 5.11−5.01 (m, 2H), 4.57
(s, 2H), 4.34 (d, J = 9.6 Hz, 1H), 4.02 (s, 1H), 3.54 (d, J = 9.6 Hz,
1H), 3.34 (s, 3H), 2.93 (dd, J = 13.8 and 8.4 Hz, 1H), 2.61 (dd, J =
13.8 and 5.7 Hz, 1H), 2.42 (q, J = 7.8 Hz, 1H), 2.12 (dd, J = 14.7 and
3.0 Hz, 1H), 2.01 (bs, 1H), 1.59−1.46 (m, 2H), 1.36 (s, 3H), 1.16 (d,
J = 7.2 Hz, 3H), 1.01 (d, J = 7.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 211.1, 188.6, 135.2, 129.7, 118.5, 96.8, 71.9, 71.4, 55.5, 51.7,
48.9, 45.9, 44.7, 44.0, 38.3, 24.9, 12.5, 12.4; HRMS(ES) m/z calcd for
C18H28NaO4 (M + Na) 331.1885, found 331.1887.
a colorless oil: [α]23 −56.0 (c 1.0, CHCl3); IR (Neat) 2929, 2885,
D
1
2857, 1716, 1693, 1063 cm−1; H NMR (300 MHz, CDCl3) δ 4.77−
4.74 (m, 1H), 4.50 (ABq, J = 6.6 Hz, 2H), 4.21−4.13 (m, 1H), 3.97−
3.72 (m, 5H), 3.53 (d, J = 9.6 Hz, 1H), 3.52 (d, J = 18.6 Hz, 1H), 3.35
(d, J = 2.7 Hz, 1H), 3.32 (s, 3H), 2.62 (d, J = 18.6 Hz, 1H), 2.08(s,
3H), 2.04 (s, 1H), 1.94−1.77 (m, 3H), 1.19 (s, 3H), 1.06 (d, J = 6.9 Hz,
3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 218.4, 206.5, 102.2, 96.7, 74.6, 68.3, 64.9, 64.1, 55.6, 53.5,
52.4, 46.6, 46.3, 42.5, 39.4, 29.8, 25.9, 22.6, 18.0, 12.1, −4.2, −4.7;
HRMS(ES) m/z calcd for C24H44NaO7Si (M + Na) 495.2754, found
495.2752.
(1S,2S,6S,7R,8S)-6-[(Methoxymethoxy)methyl]-2,6,7-tri-
methyl-9-oxatricyclo[6.3.1.01,5]dodec-4-ene-3,10-dione (53).
To an ice-cooled solution of compound (+)-26a (19 mg, 0.06
mmol) in 1,4-dioxane/water (3:1, 4 mL) were added 2,6-lutidine
(0.018 mL, 0.15 mmol), NaIO4 (63 mg, 0.3 mmol), and OsO4 (0.006
mmol) successively. The resulting suspension was stirred for a further
1.5−2 h at 0 °C. After the completion of reaction (as indicated by
TLC analysis) the reaction mixture was filtered through a short pad of
silica gel and eluted with ethyl acetate. The organic solvent was
removed under reduced pressure, and the crude material was again
purified through a silica gel column (eluent: 80% ethyl acetate in
hexane) to afford the lactol 52a,b (15 mg, 80%). To a solution of the
above lactol in 5 mL of dry benzene was added Ag2CO3 on Celite
(100 mg), and the resulting suspension was refluxed for about 10 h and
then filtered through a short pad of silica gel column (eluent: 90% ethyl
acetate in hexane) to obtain the lactone (+)-53 (13 mg, 90%) as a
(4S,5R,6R,7aR)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-7a-
(1,3-dioxolan-2-ylmethyl)-4-[(methoxymethoxy)methyl]-4,5-
dimethyl-2,4,5,6,7,7a-hexahydro-1H-2-indenone (55). To a
solution of diketone (−)-54 (75 mg, 0.16 mmol) in dry THF
(15 mL) was added NaH (19 mg, 0.8 mmol) at 25 °C. The resulting
reaction mixture was refluxed for 2 h and then quenched at 0 °C with
water. The aqueous phase was extracted with ether (2 × 15 mL), and
the combined organic phases were washed with water (10 mL) and
brine and dried over Na2SO4. After the evaporation of solvent, the
crude material was purified through a silica gel column (eluent: 30%
ethyl acetate in hexane) to afford the bicyclic enone (+)-55 (58 mg,
80%) as a colorless oil: [α]24D +51.0 (c 1.0, CHCl3); IR (Neat) 2954,
1
2858, 2857, 1699, 1601, 1044 cm−1; H NMR (300 MHz, CDCl3) δ
colorless oil: [α]24 +56.7 (c 0.3, CHCl3); IR (Neat) 1732, 1704,
6.03 (s, 1H), 4.76 (t, J = 4.5 Hz, 1H), 4.58 (d, J = 6.6 Hz, 2H), 4.52 (d,
J = 6.6 Hz, 1H), 3.99−3.69 (m, 6H), 3.49 (d, J = 9.9 Hz, 1H), 3.34 (s,
3H), 2.81 (d, J = 18.3 Hz, 1H), 2.38 (dd, J = 12.9 and 4.2 Hz, 1H),
2.17 (d, J = 18.3 Hz, 1H), 2.05 (d, J = 4.8 Hz, 2H), 1.49−1.36 (m,
2H), 1.35 (s, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.09 (s, 3H),
0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.2, 187.5, 131.7,
102.8, 96.9, 71.0, 69.0, 65.1, 64.0, 55.7, 51.1, 49.4, 47.5, 45.8, 44.0,
41.3, 25.8, 24.7, 18.0, 12.1, −4.1, −4.7; HRMS(ES) m/z calcd for
C24H42NaO6Si (M + Na) 477.2648, found 477.2648.
(4S,5R,6R,7aR)-7a-(1,3-Dioxolan-2-ylmethyl)-6-hydroxy-4-
[(methoxy methoxy)methyl]-4,5-dimethyl-2,4,5,6,7,7a-hexa-
hydro-1H-2-indenone (56). To a solution of bicyclic enone
(+)-55 (25 mg, 0.055 mmol) in 1 mL of dry THF was added
TBAF (29 mg, 0.11 mmol) at rt, and the reaction was continued for a
further 10 h. The solvent was removed under reduced pressure,
and the crude residue was directly charged on a silica gel column
D
1605, 1041 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.07 (s, 1H), 4.65−
4.63 (m, 1H), 4.55−4.50 (m, 2H), 3.63 (d, J = 10.2 Hz, 1H), 3.40 (d,
J = 10.2 Hz, 1H), 3.32 (s, 3H), 2.80 (dd, J = 19.2 and 2.4 Hz, 1H),
2.68 (d, J = 19.2 Hz, 1H), 2.22 (dd, J = 13.2 and 3.9 Hz, 1H), 2.15 (q,
J = 7.5 Hz, 1H), 1.78−1.68 (m, 2H), 1.36 (s, 3H), 1.25 (d, J = 7.2 Hz,
3H), 1.13 (d, J = 7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 207.8,
185.2, 169.9, 129.7, 96.5, 78.7, 71.4, 55.7, 52.1, 45.7, 44.9, 42.5, 41.5,
34.7, 25.6, 12.2, 9.9; HRMS(ES) m/z calcd for C17H24NaO5 (M + Na)
331.1521, found 331.1523.
(1S,2S,6S,7R,8S)-6-(Hydroxymethyl)-2,6,7-trimethyl-9-
oxatricyclo[6.3.1.01,5]dodec-4-ene-3,10-dione (5). To an ice-
cooled solution of tricyclic lactone (+)-53 (5 mg, 0.02 mmol) in
2 mL of dry DCM was added dropwise a solution of triphenylcarbenium-
tetrafluoroborate (20 mg, 0.06 mmol) in 1 mL of dry DCM. The resulting
dark yellow colored solution was stirred at ice bath temperature for 1 h
8068
dx.doi.org/10.1021/jo301258g | J. Org. Chem. 2012, 77, 8056−8070

The Journal of Organic Chemistry
Article
(eluent: 80% ethyl acetate in hexane) to obtain the alcohol (+)-56
46.3, 45.0, 41.5, 40.2, 37.4, 21.0, 12.6; HRMS(ES) m/z calcd for
C14H18NaO3 (M + Na) 257.1154, found 257.1156.
(17.7 mg, 93%) as a colorless oil: [α]22 +94.0 (c 0.5, CHCl3); IR
D
1
(Neat) 3440, 2929, 1694, 1598, 1041 cm−1; H NMR (300 MHz,
CDCl3) δ 6.05 (s, 1H), 4.77 (dd, J = 5.4 and 3.3 Hz, 1H), 4.58 (d(1/
2ABq), J = 6.6 Hz, 1H), 4.52 (d(1/2ABq), J = 6.6 Hz, 1H), 3.99−3.70
(m, 5H), 3.51 (d(1/2ABq), J = 9.9 Hz, 1H), 3.34 (s, 3H), 2.86 (d(1/2ABq),
J = 18.3 Hz, 1H), 2.48 (dd, J = 12.9 and 3.9 Hz, 1H), 2.19 (d(1/2ABq), J =
18.3 Hz, 1H), 2.07−2.05 (m, 2H), 1.68−1.64 (m, 3H), 1.42−1.36 (m,
1H), 1.37 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 207.1, 187.0, 132.0, 102.6, 96.8, 70.8, 68.4, 65.1, 64.1, 55.7,
51.0, 49.1, 47.2, 45.8, 43.9, 41.2, 24.6, 11.5; HRMS(ES) m/z calcd for
C18H28NaO6 (M + Na) 363.1784, found 363.1783.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Scanned copies of H NMR spectra, 13C NMR spectra of all
new compounds and 1H−1H COSY and 1H−1H NOESY
spectra of compounds (+)-21, (+)-23, (−)-37 and (−)-38.
This material is available free of charge via the Internet at
http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail: gm@orgchem.iisc.ernet.in; gmehta43@gmail.com.
Notes
(4S,5R,7aS)-7a-(1,3-Dioxolan-2-ylmethyl)-4-[(methoxyme-
thoxy)- methyl]-4,5-dimethyl-2,4,5,6,7,7a-hexahydro-1H-2,6-
indenedione (57). To the solution of compound (+)-56 (17 mg,
0.05 mmol) in 3 mL of dry DCM, kept at 0 °C, were added NaOAc
(12 mg, 0.15 mmol), PCC (32 mg, 0.15 mmol), and silica gel (32 mg,
100−200 mesh) successively. The resulting orange colored suspension
was stirred at 25 °C for 3 h and then passed through a short pad of
silica gel column (eluent: 50% ethyl acetate in hexane) to afford
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
compound (+)-57 (15 mg, 90%) as a colorless oil: [α]27 +120.0
D
This research was carried out at the Indian Institute of Science
(IISc), Bangalore and the content is based on the Ph. D
dissertation of HMS at IISc. HMS thanks CSIR, India for the
award of a research fellowship. GM thanks Government of
India for the award of National Research Professorship and
acknowledges current research support from Eli Lilly and
Jubilant-Bhartia Foundations.
1
(c 0.6, CHCl3); IR (Neat) 2887, 1699, 1603, 1043 cm−1; H NMR
(400 MHz, CDCl3) δ 6.23 (s, 1H), 4.77 (dd, J = 6.4 and 2.2 Hz, 1H),
4.54 (d(1/2ABq), J = 6.8 Hz, 1H), 4.49 (d(1/2ABq), J = 6.8 Hz, 1H),
3.96−3.68 (m, 4H), 3.48 (s, 2H), 3.33 (s, 3H), 3.08 (d(1/2ABq), J =
18.0 Hz, 1H), 2.87 (d(1/2ABq), J = 12.8 Hz, 1H), 2.54−2.48 (m, 2H),
2.31 (d(1/2ABq), J = 12.8 Hz, 1H), 2.07 (dd, J = 14.8 and 2.4 Hz,
1H), 1.91 (dd, J = 14.4 and 6.6 Hz, 1H), 1.49 (s, 3H), 1.11 (d, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.9, 206.0, 183.4, 132.9,
101.9, 96.7, 70.4, 64.9, 64.1, 55.8, 53.6, 52.4, 50.6, 48.4, 47.1, 41.5,
24.7, 8.2; HRMS(ES) m/z calcd for C18H26NaO6 (M + Na) 361.1627,
found 361.1616.
(4S,5R,6S,7aR)-7a-(1,3-Dioxolan-2-ylmethyl)-6-hydroxy-4-
[(methoxymethoxy)methyl]-4,5-dimethyl-2,4,5,6,7,7a-hexahy-
dro-1H-2-indenone (58). To a solution of the compound (+)-57
(15 mg, 0.044 mmol) in 1.5 mL of THF-MeOH (1:1) was added
NaBH4 (3 mg, 0.07 mmol) at −78 °C. The resulting white suspension
was stirred for 2 min and then quenched with satd NH4Cl. The aque-
ous phase was extracted with ethyl acetate (2 × 10 mL), and the
combined organic extracts were washed with water (4 mL) and brine
and dried over Na2SO4 prior to evaporation of solvent. The crude
material was filtered through a short silica gel column (eluent: 70%
ethyl acetate in hexane) to afford the hydroxy compound (+)-58
(14 mg, 95%) as a colorless oil: [α]27D +120.0 (c 0.6, CHCl3); IR (Neat)
3465, 2885, 1687, 1595 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.06 (s,
1H), 4.90 (d, J = 7.2 Hz, 1H), 4.56 (ABq, J = 6.6 Hz, 2H), 4.46 (d, J =
9.9 Hz, 1H), 4.03−3.77 (m, 5H), 3.50 (d(1/2ABq), J = 9.3 Hz, 1H),
3.33 (s, 3H), 3.25 (s, 1H), 2.71−2.59 (m, 3H), 2.18 (d(1/2ABq), J =
18.3 Hz, 1H), 1.94 (d, J = 14.1 Hz, 1H), 1.54−1.49 (m, 2H), 1.37 (s,
3H), 1.17 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 206.9,
189.8, 131.5, 103.8, 96.8, 71.5, 71.2, 65.1, 64.2, 55.5, 52.5, 45.5, 44.6,
43.8, 42.8, 42.6, 25.1, 12.4; HRMS(ES) m/z calcd for C18H28NaO6
(M + Na) 363.1784, found 363.1776.
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(1S,6R,8S,13R)-1,13-Dimethyl-9,11-dioxatetracyclo-
[6.4.1.16,10.02,6]tetradec-2-en-4-one (46). In 25 mL RB flask, fitted
with reflux condenser, were added compound (+)-58 (8 mg, 0.023
mmol), PPTS (2.5 mg, 0.01 mmol), and 2 mL of acetone. The
resulting reaction mixture was heated at reflux for 8 h and then diluted
with ethyl acetate (15 mL). The organic layer was washed with water
(5 mL × 2) and brine and dried over Na2SO4. After the evaporation of
solvent, the resulting crude material was purified by passing through a
silica gel column (eluent: 40% ethyl acetate in hexane) to furnish the
tetracyclic acetal (+)-46 (5 mg, 92%) as a white solid: mp 131−131.5 °C;
[α]27 +122.5 (c 0.6, CHCl3); IR (Neat) 2939, 1701, 1682, 1599
D
1
cm−1; H NMR (300 MHz, CDCl3) δ 5.83 (s, 1H), 5.34 (d, J =
5.1 Hz, 1H), 3.96−3.94 (m, 1H), 3.84 (d(1/2ABq), J = 12.3 Hz, 1H),
3.54 (d(1/2ABq), J = 12.0 Hz, 1H), 2.29−2.18 (m, 4H), 1.83−1.78 (m,
2H), 1.65−1.62 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H), 1.24 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 207.2, 191.5, 123.6, 94.8, 72.6, 71.5, 49.6,
8069
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(19) Facile formation of (+)-46 can be rationalized either through
the protonation of the intermediate lactol 59 and displacement by the
distant but stereochemically well poised oxygen of MOM protective
group or through the direct attack of the C7-hydroxyl group on the
activated acetal 60 to give intermediate 61, which on displacement by
the distal but stereochemically well poised oxygen of the MOM group
results in (+)-46. As indicated in Scheme 5, formation of 46 can also
be reconciled in terms of an oxocarbenium ion intermediate 46b.
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