Synthesis studies on the lomaiviticin A aglycone core: Development of a divergent, two-directional strategy

Article abstract of DOI:10.1021/jo4005074

The enantiomer of the bicyclic lomaiviticin aglycone A core was prepared via a two-directional, divergent approach featuring (1) a double Ireland Claisen rearrangement to establish key core bonds with correct relative stereochemistry and (2) a double olefin metathesis reaction to deliver both cyclohexene rings of the target.

Full text of DOI:10.1021/jo4005074

Article
pubs.acs.org/joc
Synthesis Studies on the Lomaiviticin A Aglycone Core:
Development of a Divergent, Two-Directional Strategy
Ken S. Feldman* and Brandon R. Selfridge
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
ABSTRACT: The enantiomer of the bicyclic lomaiviticin
aglycone A core was prepared via a two-directional, divergent
approach featuring (1) a double Ireland Claisen rearrangement
to establish key core bonds with correct relative stereo-
chemistry and (2) a double olefin metathesis reaction to
deliver both cyclohexene rings of the target.
Lomaiviticins D and E differ from lomaiviticin C only by the O-
methylation level in the oleandrose fragments. Lomaiviticins A,
C, D, and E all demonstrate potent cytotoxicity (IC50’s of low
nM to μM) against several cancer cell lines,1,2 and the
chemical/structural basis of this activity (and the cytotoxicity of
the structurally related monodiazoparaquinone-containing
kinamycins) has been the subject of much speculation.3 It is
noteworthy that the more active lomaiviticin structures have
two diazoparaquinone units. He et al. in the original isolation
report described the lomaiviticins as cleaving dsDNA under
reducing conditions, but no further details were forthcoming.1
The intriguing structures of the lomaiviticins coupled with
the aforementioned profound cytotoxicity and mechanism-of-
action mystery has fueled a number of synthesis studies in the
area, culminating in the remarkably concise preparation of the
lomaiviticin aglycone by Herzon in 2011.4 The dimeric (or
almost dimeric) structure of the lomaiviticins naturally evokes
retrosynthesis strategies that can be classified as either divergent
or convergent, as illustrated in Scheme 1. Herzon’s chemistry
followed the convergent approach and featured a heroic
dimerization sequence that coupled the two halves together.
Approaches to the lomaiviticin structure that also suggested a
planned monomer dimerization convergent strategy were
authored by Shair5a,c and by Nicolaou.5b An alternative
divergent strategy focuses on the early construction of a
dimeric core structure with late-stage two-directional additions
of the remainder of the polycyclic framework to that core. This
approach can be seen in the work of Nicolaou6a and of
Sulikowski.6b,c A priori, the convergent (dimerization) strategy
would appear to enjoy the large benefit of synthesis efficiency,
but at a high price; the late-stage dimerization is fraught with
potential problems in the area of yield and diastereoselectivity.
In fact, the successful Herzon chemistry illustrates this
dichotomy; the entire route to the lomaiviticin aglycone
proceeds in only 11 steps via tetracycle 4, but the penultimate
monomer dimerization step proceeds in <43% yield and
INTRODUCTION
■
Lomaiviticins A and B1 (Figure 1) along with more recently
reported lomaiviticins C, D and E2 constitute a small but
Figure 1. Lomaiviticins A and B.
growing class of dimeric (or almost dimeric) isolates from a
marine actinomycetes species that are characterized by
incorporation of an unusual diazoparaquinone moiety.
Although the similarity in structures have led to the suggestive
speculation that 1 and 2 might be interconvertible by
deglycosylation/glycosylation chemistry,2 no experimental
evidence addresses this point to date. Lomaiviticin C (mono
diazo, monoacylfulvene) has been converted into lomaiviticin A
(1) by treatment with a diazo transfer reagent by Herzon et al.2
Received: March 8, 2013
© XXXX American Chemical Society
A
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Scheme 1. Convergent and Divergent Conceptualizations of
a Lomaiviticin Synthesis
Scheme 2. Lomaiviticin A Aglycone, the (Enantiomeric)
Bicyclic Core, and a Retrosynthetic Approach to This
Bicyclic Core
delivers a mixture of three diastereomers in an approximately
5:2:<1 ratio favoring the desired species.4 Thus, there may be
room for improvement by pursuit of a perhaps more
conservative divergent strategy wherein the key stereochemical
information (cf. 5) is set with complete and predictable control
early on in the route. Of course, such as divergent, two-
direction growth strategy must necessarily place a high
premium on optimizing (double) reaction yields.
rearrangement through the standard chairlike transition state
model.10 However, the literature on glycolate Claisen
rearrangements with C(2) alkylated substrates is less clear,
with product formation rationalized through the intermediacy
of either Z- or E-enolates.7c Since our system will utilize C(2)
ethylated glycolates, some scouting experiments to test this
stereochemical issue were pursued, Scheme 3.11 After much
We initiated a synthesis project directed toward the
lomaiviticins, based upon a divergent strategic approach,
which was designed to pass through a symmetrical, chiral, bis
cyclohexenone core 7 en route to the final octacyclic material,
Scheme 2. At the outset of this project, the absolute
configurations of the lomaiviticins were not yet established,2
and so we arbitrarily picked the enantiomer resulting from the
cheaper chiral starting point. Both enantiomers should be
accessible via this strategy. The crux of this approach can be
seen in the precursor structures 8−11, wherein a double Ireland
Claisen rearrangement will be utilized to set the central C(2)−
C(2′) relative and absolute stereochemistry, and then double
ring-closing metathesis (RCM) will be employed to deliver the
desired bicyclic core. Whereas the Claisen/RCM strategy has
been used in many synthesis endeavors to set key stereo-
chemistry in ring systems,7 this work describes the first example
of a double Claisen/double RCM sequence as a cornerstone for
the construction of symmetrical (dimeric) bicycles. An
important consideration in executing this strategy is the ability
to conveniently access large amounts of a C2-symmetric chiral
diester such as 11, and it is here where Wang’s chiral ligand-
mediated asymmetric addition of alkyne anions to aldehydes8
was used to great advantage. A preliminary account of this work
has been published.9
Scheme 3. Ireland−Claisen Diastereoselectivity of Simple
(E)- and (Z) Allylic 2-Ethyl Glycolates
optimization involving variation in silyl reagent, base, solvent,
and Lewis acid additive, we arrived at the conclusion that the
glycolate Claisen rearrangement protocol introduced by
McIntosh (KN(TMS)2, TIPSOTf)12 offered the best outcome
with respect to yield and diastereoselectivity in the simple
monocyclic systems examined. Thus, the E-alkene substrates
12a and 12b both proceeded to acid products 14a and 14b,
respectively, in moderate yield but with nearly complete
diastereoselectivity for the isomers shown. This stereochemical
outcome can be explained via reaction through the orthodox
chairlike Claisen rearrangement model 13 with a Z-silyl ketene
acetal, although a boat-like alternative and an E-silyl ketene
Preliminary glycolate Claisen rearrangement studies were
examined in order to test the feasibility of the basic premise
that this transformation can deliver the desired C−C bonds
with appropriate stereochemical control. Claisen rearrange-
ments of simple (i.e., C(2) H and not alkyl) glycolates have
been well-documented to proceed via chelation-controlled
enolization to give a Z-enolate that then participates in [3,3]
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acetal cannot be rigorously excluded. This mechanistic
conclusion was reinforced by use of the Z-alkene analogue
15; once again, the stereochemical outcome supports reaction
through the Z-silyl ketene acetal and a chairlike transition state.
Since the lomaiviticin core synthesis objective requires access to
the stereochemical arrangement shown in 17, a double Z-
alkene substrate is indicated (i.e., 11 in Scheme 2 with Z-
alkenes).
substrate 25. The remainder of the lomaiviticin core synthesis
route then focuses on Z,Z-diene diol 25 with the goals of (1)
introducing C(4a)/C(4a′), (2) building in the correct stereo-
chemistry for the C(3)−C(2)−C(2′)−C(3) array, and (3)
attaching C(1)/C(1′) to C(11b)/C(11b′) (lomaiviticin
numbering).
Since the planned downstream double Claisen rearrange-
ment chemistry has scarcely been described,15 we decided to
prepare the analogous E,E-diene diol 20 as well with the
expectation that we would use it as a simpler exploratory model
system to probe both the feasibility and the stereochemical
consequences of double Claisen rearrangement in this system.
Simple LiAlH4-mediated reduction of diyne diol 19 provided
the E,E-series substrate 20 in modest yield. The diene diol 20
was acylated with the glycolic acid chloride 21 to provide the
simple, unalkylated bis glycolate ester 22.
RESULTS AND DISCUSSION
■
The synthesis of the diene diester Claisen rearrangement
precursor 25 commenced with chiral propargyl alcohol 18,
Scheme 4. This alcohol is commercially available, but it was
Scheme 4. Synthesis of Dienyl Bis Glycolates as Ireland−
Claisen Substrates
The simple bis glycolate 22 was examined first in the Ireland
Claisen rearrangement sequence, Scheme 5. The initial forays
into double Claisen rearrangement of 22 utilized NaN(TMS)2
or LDA as base (−78 °C) and either TIPSCl or TIPSOTf as
the silylating agent (≥ room temperature or higher). These
scouting experiments produced uniformly unfavorable results,
with compound destruction and no evidence for rearrangement
Scheme 5. Double Ireland-Claisen Rearrangements of
Dienyl Glycolates 22 and 25
more conveniently prepared by the addition of (trimethylsilyl)-
acetylene to benzaldehyde under the influence of both Et2Zn
and the chiral ligand PhCH2CH(NHTs)C(Et)2OH as reported
by Wang.8 Whereas several related approaches to chiral
propargyl alcohol 25 have been described,13 the Wang
procedure in our hands proved to be quite convenient to
execute, especially upon scale-up to 10−20 g batches. The
enantiomeric excess of alcohol 25 was assayed by conversion to
its Mosher ester and subsequent NMR analysis, which indicated
an ee of >95% (NMR detection limit), in accord with the
original Wang procedure. Simple Glaser coupling of alcohol 18
furnished the 6-carbon segment 19, which contains atoms
C(3)−C(2)−C(2′)−C(3′) of the lomaiviticin structure. Thus,
in this early C−C bond forming step, the key connection
between the two identical halves of the target structure (C(2)−
C(2′)) has been formed. Reduction of the diyne within 19 to
the requisite Z,Z-diene of 23 appeared problematic initially, as
several attempts at semireduction via various Lindlar recipes
invariably gave a monoene, monoyne product.14 Fortunately,
the Boland procedure14 for diyne reduction (Zn/Cu/Ag
couple) performed satisfactorily with 19, and the Z,Z-diene
diol 23 was procured in good yield and free of isomeric
congeners. This “real” substrate 23 was acylated with the more
complex ethylated glycolic acid 24 to give the double Claisen
C
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product(s) forthcoming (we had not yet completed our model
system study of Claisen rearrangement conditions to guide us
(Scheme 3) at this point). A subsequent control experiment
whereby bis glycolate 22 was treated with NaN(TMS)2 at −78
°C followed by AcOD provided a glimpse of the problem; the
recovered 22 was deuterium-labeled at the allylic/benzylic
position! Thus, it appeared that the dual acidifying effects of
both the diene and the phenyl ring, as well as the deacidifying
effects of the OBn moiety on the glycolate proton, conspired to
direct deprotonation away from the COCH2OBn unit. To
overcome this problem, perhaps a more Lewis acidic metal
counterion (and inclusion of a bone fide Lewis acid as well?) to
activate the glycolate carbonyl and hence selectively acidify the
glycolate proton might suffice. In the event, switching the base
to LiN(TMS)2 and including 4 mol % SnCl4 in the reaction
solution completely changed the reaction outcome and the
desired double Ireland Claisen rearrangement proceeded in
excellent yield to deliver, after basic hydrolysis of an
intermediate bis trimethylsilyl ester, the bis acid 29 as a single
stereoisomer. The structure and stereochemistry of 29 was
secured by single crystal X-ray analysis.16 The stereochemical
outcome can be rationalized by citing reaction of Z-silyl ketene
acetals through two consecutive [3,3] sigmatropic reorganiza-
tions that proceed through the typically invoked canonical
chairlike transition states17 with equatorial phenyl anchors, 22
→ 26 → 27 → 28. Therefore, there was nothing surprising
about this result; the only real issue to be tested was whether
the formation of a sterically congested carbon center (C(2) in
27) adjacent to the locus of C−C bond formation in the second
[3,3] rearrangement (C(3′)-to-C(2′) bond formation) might
negatively impact on the stereochemical fidelity of this second
Claisen reaction. That only one diastereomer of 29 was formed
would support the notion that this potential complication was
not realized.
rearrangement of 25 can be understood through application
of the classic transition state model, as applied to the two
sequential transition states 30 and 31 (Scheme 5). Thus, at this
juncture in the synthesis route, we have gained access to a
complex intermediate featuring both correct relative stereo-
chemistry and correct functionality in the C(3)−C(2)−C(2′)−
C(3′) sector of the lomaiviticin core in just four steps.
Continuing the lomaiviticin core synthesis from diacid 33
requires several “double” reactions as we extend outward in two
directions. Thus, yield maximization becomes paramount and
so yield optimization chemistry with a monomeric model
system was explored first, Scheme 6. Initial extension of the
Scheme 6. Monomeric Model System Explorations: Part 1
acid residue in 17 (available as per Scheme 3) with a three
carbon unit introduces C(4a) and C(11a) (lomaiviticin
numbering); this task was accomplished by conversion of the
acid into its corresponding Weinreb amide, and then treatment
of this acyl derivative with an allyl Grignard reagent. The two
alkene units of 34 set the stage for a ring closing metathesis
reaction, which proceeded smoothly to join C(11b) to C(1)
(lomaiviticin numbering) and deliver 35. Introduction of C(1)
oxygenation was the next goal, a sequence that has been
reported to occur smoothly in related cyclohex-3-ene-1-one
systems by straightforward mCPBA-mediated alkene epoxida-
tion followed by SiO2-promoted epoxide isomerization.18
Surprisingly, that chemistry did not work with 35; the alkene
was not epoxidized by mCPBA under a variety of conditions.
Perhaps the electronegative OPMB substituent was just too
inductively electron depleting, even two atoms removed from
the alkene. Resorting to the more powerful oxidant DMDO did
work as desired to form an intermediate epoxide as a single
isomer (stereochemistry not determined). Treatment of this
β,γ-ketoepoxide with mild base served to isomerize it to the
desired allylic alcohol 36, again as a single (unassigned)
stereoisomer. That we could form 36 from 17 was encouraging,
but the resistance of the alkene in 35 to oxidation was a
warning flag, as we were soon to learn.
The mixed success with the simple monomeric model system
of Scheme 6 prompted an examination of similar chemistry in a
dimeric system, the des ethyl diacid 29, Scheme 7. We already
know that introduction of oxygen at C(1) will not be
straightforward based upon the results with 35; at issue here
was the planned double Grubbs metathesis reaction. Would the
two cyclohexenes be formed as desired, or would other
pathways intervene?19 To probe this question, the diacid 29
was converted directly into the corresponding bis Weinreb
amide via the protocol of Hu,20 and then into the bis allyl
ketone 37 by allyl Grignard reagent addition to this bis
Weinreb amide. The Grubbs II catalyst-mediated double ring
This favorable result prompted examination of the “real”
system 25 bearing both Z-alkenes and the α-ethyl unit in the
glycolate portion of the substrate. This substrate raises the
degree-of-difficulty in that now a more sterically hindered C−C
bond (quaternary carbon-to-tertiary carbon) must be formed
proximate to the nascent sterically hindered C(2) carbon (cf.
31, C(3′)-to-C(2′) bond formation adjacent to C(2)). Much
optimization was necessary to find conditions where this more
challenging Ireland Claisen rearrangement proceeded in good
yield. In this vein, variations in the base (KN(TMS)2,
LiN(TMS)2, NaN(TMS)2, LDA), silylating agent (TIPSCl,
TIPSOTf, TBSCl, TMSCl, TMSOTf), Lewis acid additive
(none, SnCl4, TiCl4, ZnCl2) and solvent (THF, toluene,
CH3CN, Et2O) were examined. From this collection of reaction
conditions, a few trends emerged; (1) only the potassium salt
of hexamethylsilazide gave any productall other bases failed
to provide even trace amounts of product, (2) the presence (or
absence) of catalytic amounts of Lewis acids either had no
material effect or decreased product yield, and (3) the yield
increased in going from THF to 50:50 THF/toluene to Et2O.
In the final analysis, the optimized conditions (KN(TMS)2,
TIPSOTf, Et2O) afforded the diacid product 33 in excellent
yield following fluoride-mediated desilylation of the first-
formed bis silyl ester. Once again, the stereoselectivity was
1
absolute (within H NMR detection limits), and the structure
and relative stereochemistry of the product diacid 33 was
ascertained by single crystal X-ray analysis of the downstream
intermediate 40 (Scheme 8). As with the simpler system 22, the
stereochemical outcome of the double Ireland Claisen
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Happily, the double ring closing metathesis reaction of 40 was
not victimized by this added C(3) steric burden, and the
desired bis cyclohexene product 41 was formed in overall good
yield, in analogy with the 37 → 38 conversion in the simpler
model system. Much reagent exploration undergirded the
identification of the optimized conditions for this pivotal ring
closing metathesis. The critical observation was that even trace
oxygen exposure depressed the yield dramatically, and so only
after thoroughly degassing the sample via three sequential
freeze−thaw cycles were reproducible and satisfactory yields of
41 obtained.
Scheme 7. More Complex Model System; Divergent
Synthesis of a Chiral Bis Cyclohexenone Core
The failure to oxidize the simple monomeric model system
35 (Scheme 6) with mCPBA was a concern, but since DMDO
did achieve this oxidation, that reagent served as a starting point
for the double oxidation of the bis cyclohexene 41, Scheme 9.
closing metathesis sequence proceeded uneventfully to deliver
the desired bis cyclohexene product 38 in good yield and free
of any isomers at the 1H NMR detection limit. Thus, a
potential complication with cycloheptene formation remained
unrealized. We decided to focus our C(1) oxygenation
approaches on the real ethyl-containing system (vide infra)
rather than 38, given its greater steric hindrance compared to
the simpler 38.
Scheme 9. Failed Epoxidation of Bis Cyclohexene 41;
Formation of a Cage Compound
Work on the real system 33 commenced with the two-
directional chain extension of the carboxylic acid units into the
allyl ketones required for the double ring closing metathesis
sequence, Scheme 8. The increased steric hindrance at C(3) in
Scheme 8. Preparation of a Chiral Bis Cyclohexenone En
Route to the Ent-lomaiviticin A Core
Unfortunately, DMDO as well as an assortment of other alkene
oxidation protocols (e.g., peracetic acid, trifluoroperacetic acid,
Mn(ppei)(OAc)6) all failed to yield bis epoxide product 42 or
even a monoepoxide analogue. An attempt to access a bis
homoallylic alcohol system 43 that might presage hydroxyl-
directed epoxidation led instead via double hemiketalization to
the caged compound 44. Thus, a major reconfiguration of the
synthesis route was in order.
Further model system work to address the C(1) oxygenation
problem seemed appropriate at this juncture, Scheme 10.
Toward this end, the cyclohexenone 48 was prepared from E-
allylic alcohol 45 through the chemistry we established for the
synthesis of 48’s diastereomer 35 (Scheme 6). The choice of 48
as a model was predicated on its ease of synthesis; E-isomer 45
was available in quantity from acrolein whereas the perhaps
more stereochemically relevant model 35 required a precursor
Z-allylic alcohol that was difficult to access at scale in our hands.
The new plan involved formation of a dienyl silyl ether derived
from 48, a species that now potentially offered enhanced
reactivity at C(1) compared to 48 itself. Both the trimethylsilyl-
and the (t-butyl)dimethylsilyl dienol ethers 49a and 49b,
respectively, could be prepared from 48 under standard
conditions; these species were formed in essentially quantitative
yields (1H NMR assay) but were not stable enough to be
purified by chromatography without substantial loss and thus
were used “as is” in subsequent transformations. One such
thrust utilized a [4π + 2π] cycloaddition of 49a with
nitrosobenzene, which, after product desilylation, furnished
the hydroxylamine product 50 as a single stereoisomer in
modest yield. The structure and stereochemistry of 50 was
the butyric acid chain of 33 had immediate impact on the
chemistry, as the convenient one-step Weinreb amidation
procedure of Hu that was successful with 29 failed completely
with 33. Consequently, a standard two-step workaround was
executed, leading to the bis Weinreb amide 39 in good yield.
Fortunately, using an oxalyl chloride-based procedure activated
both acid units faster than monoactivation/cyclization to form a
7-membered anhydride, a problem that derailed the use of
milder (i.e., MeNH(OMe), EDC) acid activators. Allylation of
the bis amide 39 did not proceed smoothly with a Grignard
reagent as per 29 → 30, as only mixtures of products that
appeared to incorporate just one allyl unit resulted. Apparently,
once again the enhanced steric hindrance abutting the carbonyl
became manifest, and so an alternative was required. The more
nucleophilic allyl lithium sufficed, and by this procedure the
desired bis allyl ketone metathesis substrate 40 was formed in
satisfactory yield. The structure and stereochemistry of this
species was determined by single crystal X-ray analysis.17
E
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Implementation of the C(1) oxygenation fix developed with
the monocyclic model 49b with the real system 41 constitutes
the final task en route to completion of the lomaiviticin bicyclic
core synthesis, Scheme 11. This approach to C(1) oxygenation
Scheme 10. Further Monomeric Model System Work in
Support of Cyclohexenone γ-Oxidation; Part 2
Scheme 11. Completion of the Ent-lomaiviticin A Core
Bicycle
secured by single crystal X-ray analysis.17 The plan for 50
involved activation of the alcohol as a leaving group and then
E2 elimination to give a transient imine en route to the
corresponding C(1) ketone via imine hydrolysis. However, this
indirect approach to C(1) oxygenation failed at the E2
elimination stage; the tosylate derived from 50 (TsCl, pyridine)
was destroyed upon treatment with either DBU or KOH/
EtOH without any evidence for formation of an imine or
carbonyl product.
is not without its perils in the double reaction series, as
attempts to form a bis enolate juxtaposed on a compact
framework conjures up concerns about internal aldol and/or
Michael additions that might divert the chemistry of obligatory
monoenolate/monoenone intermediates. These concerns
turned out to be unfounded, however, as bis deprotonation
of the two carbonyls in 41 was not hampered by competitive
destructive processes, and bis silylation of the stable bis
dienolates afforded the bis silyl dienol ether 53 in almost
quantitative yield. As with the monocyclic series, chromato-
graphic instability precluded purification of 53 without
significant yield loss, and so typically it was used in the
subsequent oxygenation reaction as a crude isolate. Exposure of
this tetraene to the singlet oxygenation conditions established
in the monocyclic model series led to isolation of a single bis
endoperoxide 54, whose structure and stereochemistry were
determined unambiguously via single crystal X-ray analysis,17 in
A more productive direction was found, however, upon
singlet-oxygen-promoted [4π + 2π] cycloaddition to 49b. In
this instance, a single diastereomer of the endoperoxide 51
resulted. The stereochemical assignment of 51 rests on an
argument-by-analogy with the stereochemistry of the PhNO
cycloadduct and therefore should be considered as provisional.
This endoperoxide could in principle be processed on to the
desired C(1) oxygenated cyclohexenone 52 by two operations;
(1) desilylative rupture of the endoperoxide bridge, and (2)
reduction of the O−O bond. That both of these operations
occurred when 51 was treated with a fluoride source was
surprising, as it was not clear what species served as the O−O
bond reductant. [Note: we cannot exclude the possibility that
O−O bond reduction occurred either during workup or
chromatographic purification.] The modest yield of this
transformation may relate to that concern. A far better yield
attended a two-step procedure wherein first a C(1) hydro-
peroxide was liberated by HF-mediated desilylation, and then
the peroxide was reduced to the desired alcohol by added PPh3.
An alternative C(1) oxygenation procedure with 49b was
explored briefly; Rubottom oxidation (mCPBA) of the dienyl
silyl ether led to α-oxygenation only. Thus, by the 1O2
cycloaddition chemistry, we have identified a potential solution
to the C(1) oxygenation problem; whether it exports
successfully to the double reaction system 41 remains to be
seen.
1
good yield. Apparently O2 cycloaddition proceeded on the
diene faces opposite of the bulky attached rings in each case.
The two-step desilylation/O−O bond reduction sequence
developed earlier worked satisfactorily in the double reaction
system as well, with one caveat; the desilylation accomplished
with HF(aq.)/CH3CN on the monomeric model system 51
gave irreproducible results with the dimeric bis endoperoxide
substrate 54, and so a screening of alternative fluoride sources
was undertaken. Hexafluorosilicic acid almost uniquely cleaved
the silyl ether without competitive compound destruction.
Thus, the desired bis C(1)/C(1′) diol product 7 was formed in
overall moderate yield from the bis endoperoxide 54. In
addition, the bis hydroperoxide 55 served as an effective
precursor to the bis enedione 56 via an acylation/elimination
sequence. This compound was stable to storage and showed no
tendency to eliminate the elements of p-methoxybenzyl alcohol.
F
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(R,R)-Benzyloxyacetic Acid 6-(2-Benzyloxyacetoxy)-1,6-di-
phenylhexa-2,4-dienyl Ester (22). To a stirring solution of bis
alkyne 19 (1.23 g, 4.69 mmol) in 45 mL of THF at 0 °C was added
LiAlH4 (0.710 g, 26.9 mmol) and the solution was warmed to room
temperature. After stirring for 2 h at room temperature, another
portion of LiAlH4 (0.710 g, 26.9 mmol) was added. After stirring for
an additional 14 h at room temperature, H2O (1.42 mL) followed by
1.42 mL of 15% NaOH(aq.) and then 4.26 mL of H2O were added.
The suspension was filtered and rinsed with EtOAc. The filtrate was
dried with Na2SO4, filtered, and concentrated in vacuo to give a
colorless oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 5 → 40% EtOAc/hexanes as eluent)
gave diene 20 (0.597 g, 48%) as a yellow solid. IR (thin film) 3342
cm−1; 1H NMR (300 MHz, THF-d8) δ 7.45 (d, J = 7.7 Hz, 2H), 7.36
(app. t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 6.38 (m, 1H), 5.92
(m, 1H), 5.24 (m, 1H), 4.87 (d, J = 3.6 Hz, 1H); 13C NMR (75 MHz,
THF-d8) δ 145.3, 137.7, 129.7, 128.8, 127.6, 127.0, 74.7.
Advancing this bicyclic core unit to lomaiviticinone requires
two-directional growth of the oxygenated naphthyl cyclo-
penteneone units from the enone moieties. The functionality
present in the bis γ-hydroxyenone 53 (or bis enedione 54) is, in
principle, set up to enable this extension in a regioselective
manner. One example of how the hydroxyl group might be
employed to direct addition of an aryl ring into the enone unit
is illustrated with the monomeric model system 52 (prepared in
Scheme 10), eq 1. Acylation of the sterically hindered alcohol
To a stirring solution of diol 20 (0.343 g, 1.29 mmol) in 13 mL of
CH2Cl2 at 0 °C was added pyridine (437 μL, 2.84 mmol) and
benzyloxyacetyl chloride (448 μL, 2.84 mmol). The solution was
warmed to room temperature, stirred for 1 h at that temperature, and
concentrated in vacuo. To the crude mixture was added H2O (15 mL).
The resulting solution was partitioned between EtOAc and H2O and
the aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo to give a colorless oil. Purification of this oil by
SiO2 flash column chromatography (gradient, 1:1:98 → 50:2:48
EtOAc/benzene/hexanes as eluent) gave bis benzyloxyglycolate 22
(0.553 g, 76%) as a colorless oil. [α]20D = +7° (c 1.2, CHCl3); IR (thin
film) 1749 cm−1; 1H NMR (360 MHz, CDCl3) δ 7.38−7.26 (m, 20H),
6.39 (d, J = 6.5 Hz, 2H), 6.25 (dd, J = 11.7, 2.9 Hz, 2H), 5.90−5.84
(m, 2H), 4.62 (s, 4H), 4.16 (d, J = 18.0 Hz, 2H), 4.11 (d, J = 18.0 Hz,
2H); 13C NMR (90 MHz, CDCl3) δ 169.2, 138.2, 136.9, 132.2, 131.5,
128.5, 128.31, 128.25, 127.9, 127.8, 126.9, 75.9, 73.2, 67.1; LRMS
with 2-iodobenzoyl chloride furnished the ester 57, a substrate
for Heck-type cyclization. Toward that end, treatment of this
aryl iodide under modified Jeffrey conditions21 led to formation
of a tricyclic product 58 that effectively established the required
C(11a)/C(11b) connection for lomaiviticinone. This model
system points out the possible, but there are other approaches
that also may be fruitful; work toward that goal is ongoing.
CONCLUSIONS
■
An enantiomeric version of the bicyclic lomaiviticinone core 7
was prepared with complete diastereoselectivity over the course
of 11 steps from the chiral and commercially available alkynol
18. This chemistry hews to a two-directional inside-out strategy
for lomaiviticinone synthesis in which the critical core C−C
bond and adjacent stereochemistry is set early in the route. The
fulcrum of the synthesis plan is a double Ireland-Claisen-
rearrangement/double-ring-closing-metathesis sequence that
transforms a linear precursor into the bis cyclohexenone core.
This core will serve as the platform for exploration of the
double ring annelation chemistry required to complete the
synthesis of lomaiviticinone.
+
(ESI) m/z (relative intensity) 580.3 (10%, M + NH4 ); HRMS (ESI)
m/z calcd for [C36H38NO6]+, 580.2699, found 580.2671.
(S,S)-1,6-Diphenyl-hexa-2,4(Z,Z)-diene-1,6-diol (23). Argon
was bubbled through a stirring suspension of Zn dust (70 g, 1.1
mol) in 420 mL of H2O. After 15 min, Cu(OAc)2·H2O (7.0 g, 35
mmol) was added. After an additional 15 min, AgNO3 (7.0 g, 41
mmol) was added. After stirring for 30 min, the mixture was filtered
and the solid was washed successively with H2O, MeOH, acetone, and
Et2O. The solid was added to 250 mL of a 1:1 mixture of MeOH/H2O
followed by a solution of (R,R)-diyne diol 19 (3.50 g, 13.3 mmol) in
30 mL of MeOH. The reaction mixture was heated at 40 °C for 36 h,
filtered through Celite with MeOH, and concentrated in vacuo. The
remaining aqueous layer was extracted with EtOAc (3 × 400 mL). The
combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo to give a crude orange solid. Purification of this
solid by SiO2 flash column chromatography (gradient, 15 → 60%
EtOAc/hexanes as eluent) gave (S,S)-diene diol 23 (2.71 g, 76%) as an
orange solid. mp 107−110 °C; [α]20D = +69 (c 6.20, MeOH); IR (thin
film) 3284 cm−1; 1H NMR (400 MHz, THF-d8) δ 7.35 (d, J = 7.3 Hz,
4H), 7.24 (t, J = 7.5 Hz, 4H), 7.14 (t, J = 7.3 Hz, 2H), 6.60−6.58 (m,
2H), 5.63 (s, 4H), 4.53 (m, 2H); 13C NMR (75 MHz, THF-d8) δ
145.8, 137.4, 128.8, 127.4, 126.6, 123.7, 69.4; LRMS (ESI) m/z
(relative intensity) 249.1 (100%, M − OH−); HRMS (ESI) m/z calcd
for [C18H17O], 249.1279, found 249.1261.
EXPERIMENTAL SECTION
■
Note that copies of 1H NMR and 13C NMR spectra for 19, 23, 25, 33,
39, 40, 41, 44, 54, 7, and 56 can be found in the Supporting
Information of ref 9; in addition, ref 9’s Supporting Information
includes CIF files for 40 and 54.
(R,R)-1,6-Diphenyl-hexa-2,4-diyne-1,6-diol (19). To a stirring
solution of CuCl (0.98 g, 9.3 mmol) in 450 mL of acetone was added
TMEDA (1.50 mL, 10.0 mmol) dropwise followed by bubbling O2
through the solution. A solution of propargyl alcohol 188 (12.3 g, 92.7
mmol) in 50 mL of acetone was added and the solution was heated to
40 °C. After stirring for 14 h at this temperature while bubbling O2
through the solution, the mixture was concentrated in vacuo. To the
crude mixture was added 250 mL of 1 M HCl. The resulting solution
was partitioned between EtOAc and H2O and the aqueous layer was
extracted with EtOAc (3 × 250 mL). The combined organic fractions
were dried over Na2SO4, filtered, and concentrated in vacuo to give an
orange solid. Purification of this solid by SiO2 flash column
chromatography (gradient, 3 → 30% EtOAc/hexanes as eluent)
gave (R,R)-diyne diol 19 (8.54 g, 70%) as an orange solid. mp 82−84
(S,S)-2-(4-(Methoxy)benzyloxy)butyric Acid 6-[2-(4-
(Methoxy)benzyloxy)-butyryloxy]-1,6-diphenylhexa-(Z,Z)-2,4-
dienyl Ester (25). To a stirring solution of 2-(4-(methoxy)-
benzyloxy)butyric acid (24)11 (5.90 g, 26.3 mmol) and (S,S)-diene
diol 23 (3.19 g, 12.0 mmol) in 120 mL of CH2Cl2 was added DMAP
(365 mg, 4.00 mmol) and DCC (5.92 g, 28.7 mmol). After 16 h at
room temperature, the solution was concentrated in vacuo to give a
crude yellow oil. Purification of this oil by deactivated silica (2% Et3N
in hexanes) flash column chromatography (gradient, 5 → 15% EtOAc/
hexanes as eluent) gave bis PBM glycolate 25 (5.41 g, 67%) as a
colorless oil (1:1 mixture of diastereomers). An 84% yield was
°C; [α]20 = −34 (c 10.0, MeOH); IR (thin film) 3272, 2355 cm−1;
D
1H NMR (360 MHz, MeOD) δ 7.39 (d, J = 3.6 Hz, 4H), 7.26−7.18
(m, 6H), 5.40 (s, 2H); 13C NMR (90 MHz, MeOD) δ 141.4, 129.4,
129.2, 127.5, 81.1, 70.4, 65.0; LRMS (ESI) m/z (relative intensity)
371.2 (5%, M + Na+). HRMS (ESI) m/z calcd for [C18H13O]+,
245.0966, found 245.0972.
1
obtained on a 94 mg scale. IR (thin film) 1737 cm−1; H NMR (400
G
dx.doi.org/10.1021/jo4005074 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
MHz, CDCl3) δ 7.43−7.33 (m, 10H), 7.29 (d, J = 8.1 Hz, 4H), 6.90
(d, J = 9.3 Hz, 4H), 6.86 (d, J = 4.2 Hz, 2H), 6.82−6.79 (m, 2H),
5.93−5.85 (m, 2H), 4.68 (d, J = 9.5 Hz, 1H), 4.65 (d, J = 9.5 Hz, 1H),
4.37 (d, J = 12.5 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 3.84 (s, 6H), 1.87−
1.80 (m, 4H), 1.00 (t, J = 7.7 Hz, 3H), 0.96 (t, J = 7.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.84, 171.78, 159.3 (×2), 139.0, 138.9,
131.3, 131.2 (2 carbons), 131.1, 129.6 (2 carbons), 128.6 (2 carbons),
128.2, 128.1, 126.6, 126.5, 125.7, 125.5, 113.7 (2 carbons), 78.9, 78.8,
71.7 (2 carbons), 71.4, 71.2, 55.2 (2 carbons), 26.2, 26.1; LRMS (ESI)
IR (thin film) 3354, 1702 cm−1; H NMR (360 MHz, CDCl3) δ 7.37
(d, J = 7.3 Hz, 4H), 7.28 (t, J = 7.2 Hz, 4H), 7.22 (d, J = 7.2 Hz, 2H),
7.17 (d, J =8.2 Hz, 4H), 6.81 (d, J = 8.5 Hz, 4H), 6.50 (d, J = 15.8 Hz,
2H), 6.37 (dd, J = 15.6, 10.6 Hz, 2H), 4.29 (d, J = 9.2 Hz, 2H), 4.20
(d, J = 9.4 Hz, 2H), 3.80 (s, 6H), 3.32 (d, J = 10.4 Hz, 2H), 1.73−1.58
(m, 4H), 0.82 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
175.2, 159.9, 137.6, 135.4, 130.2, 128.9, 127.3, 127.1, 125.8, 114.1,
83.8, 65.0, 55.7, 45.4, 26.5, 7.1; LRMS (ESI) m/z (relative intensity)
+
696.3 (100%, M + NH4 ). HRMS (ESI) m/z calcd for [C42H50NO8]+,
+
m/z (relative intensity) 696.4 (20%, M + NH4 ). HRMS (ESI) m/z
696.3536, found 696.3550.
calcd for [C42H50NO8]+, 696.3536, found 696.3520.
5-Ethyl-5-(4-methoxybenzyloxy)-6-methyl-8-phenylocta-
1,7-dien-4-one (34). To a stirring solution of DMAP (0.276 g, 2.26
mmol) and N,O-dimethylhydroxylamine hydrochloride (0.147 g, 1.50
mmol) in 7 mL of CH2Cl2 was added a solution of carboxylic acid 1712
(0.267 g, 0.752 mmol) in 1 mL of CH2Cl2, followed by EDC (0.288 g,
1.50 mmol). After stirring the mixture for 14 h at room temperature,
saturated NaHCO3 (10 mL) was added. The resulting solution was
partitioned between EtOAc and H2O and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic fractions
were dried over Na2SO4, filtered, and concentrated in vacuo to give a
colorless oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 2 → 10% EtOAc/hexanes as eluent)
gave an intermediate Weinreb amide as a colorless oil (0.221 g, 74%).
IR (thin film) 1649 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J =
7.4 Hz, 2H), 7.38−7.30 (m, 4H), 7.23 (m, 1H), 6.94 (d, J = 8.6 Hz,
2H), 6.54 (dd, J = 15.9, 7.5 Hz, 1H), 6.46 (d, J = 16.0 Hz, 1H), 4.56
(d, J = 10.3 Hz, 1H), 4.43 (d, J = 10.2 Hz, 1H), 3.82 (s, 3H), 3.68 (s,
3H), 3.43 (s, 3H), 3.09−3.04 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H),
1.27 (d, J = 6.9 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.2, 158.8, 137.4, 132.2, 130.1, 129.5, 128.8, 128.2, 126.7,
125.9, 113.5, 87.0, 64.4, 60.1, 54.9, 43.0, 36.7, 26.1, 15.6, 8.4; LRMS
(ESI) m/z (relative intensity) 398.3 (30%, M + H+).
(R,R,S,S)-2,5-Bis(benzyloxy)3,4-distyrylhexanedioic Acid
(29). To a stirring solution of LHMDS (267 μL, 1.0 M in THF,
0.27 mmol) in 1 mL of THF at −78 °C was added dropwise TMSCl
(34 μL, 0.27 mmol). A solution of bis benzyloxyglycolate 22 (0.050 g,
0.089 mmol) in 200 μL of THF was added dropwise followed by
SnCl4 (4 μL, 1.0 M in CH2Cl2, 0.004 mmol). The solution was stirred
at −78 °C for 30 min, at 0 °C for 30 min, and then warmed to room
temperature. After stirring the mixture for an additional 14 h at room
temperature, 1 M NaOH (6 mL) was added and the reaction mixture
was stirred vigorously for 1 h. Et2O (10 mL) then was added. The
resulting solution was partitioned between Et2O and 1 M NaOH and
the organic layer was extracted with 1 M NaOH (10 mL). The
combined aqueous fractions were acidified with 3 M HCl, extracted
with EtOAc (3 × 20 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to give dicarboxylic acid 29 (0.043 g, 87%) as
a light-yellow solid that decomposed >200 °C. A portion of this solid
was crystallized from MeCN/hexanes to obtain X-ray quality crystals.
[α]20D = −78° (c 4.0, MeOH); IR (thin film) 3400−3000, 1719 cm−1;
1H NMR (400 MHz, MeOD) δ 7.28−7.03 (m, 20H), 6.08 (d, J = 15.7
Hz, 2H), 5.91 (dd, J = 15.7, 10.0 Hz, 2H), 4.53 (d, J = 11.5 Hz, 2H),
4.15 (d, J = 11.5 Hz, 2H), 3.76 (d, J = 9.7 Hz, 2H), 3.07 (td, J = 10.0,
2.3 Hz, 2H); 13C NMR (75 MHz, THF-d8) δ 172.9, 139.0, 138.3,
135.3, 129.1, 129.0, 128.4, 128.3, 128.0, 127.3, 125.7, 81.0, 72.6, 47.5;
To a stirring solution of the Weinreb amide from above (0.221 g,
0.557 mmol) in 6 mL of THF at 0 °C, was added dropwise
allylmagnesium bromide (1.0 M in Et2O, 1.7 mL, 1.7 mmol). The
solution was stirred for 30 min at 0 °C and then for 1 h at room
temperature. The reaction mixture was added to a cold solution of
saturated NH4Cl (10 mL). The resulting solution was partitioned
between EtOAc and H2O and the aqueous layer was extracted with
EtOAc (3 × 25 mL). The combined organic fractions were dried over
Na2SO4, filtered, and concentrated in vacuo to give a colorless crude
oil. Purification of this oil by SiO2 flash column chromatography
(gradient, 2 → 4% Et2O/hexanes as eluent) gave allylation product 34
+
LRMS (ESI) m/z (relative intensity) 580.2 (100%, M + NH4 );
HRMS (ESI) m/z calcd for [C36H38NO6]+, 580.2699, found 580.2704.
(2R,3S,4S,5R)-2,5-Diethyl-2,5-bis-(4-(methoxy)benzyloxy)-
3,4-(distyryl)hexanedioic Acid (33). To a stirring solution of
KHMDS (0.50 M in toluene, 31.6 mL, 15.8 mmol) in 20 mL of Et2O
at −100 °C was added a solution of bis PMB glycolate 25 (1.58 g, 2.32
mmol) in 10 mL of Et2O. After stirring for 40 min at that temperature,
TIPSOTf (2.49 mL, 9.28 mmol) was added dropwise. After stirring for
an additional 30 min at −100 °C, the solution was warmed to −60 °C.
After stirring for 2 h at −60 °C, the solution was warmed to −20 °C.
After stirring for 2 h at −20 °C, the solution was warmed to room
temperature. After stirring for 2.5 h at room temperature, saturated
NaHCO3 (40 mL) was added. The resulting solution was partitioned
between Et2O and H2O and the aqueous layer was extracted with Et2O
(3 × 40 mL). The combined organic fractions were dried over
Na2SO4, filtered, and concentrated in vacuo to give bis TIPS ester 32
(1.81 g, 79%) as a yellow oil that was used without further purification.
1
(0.176 g, 84%) as a colorless oil. IR (thin film) 1713 cm−1; H NMR
(300 MHz, CDCl3) δ 7.50−7.45 (m, 4H), 7.39 (t, J = 7.6 Hz, 2H),
7.29 (m, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.48 (d, J = 15.8 Hz, 1H), 6.38
(dd, J = 15.8, 8.5 Hz, 1H), 6.05 (m, 1H), 5.26 (d, J = 10.3 Hz, 1H),
5.17 (dd, J = 17.2, 1.4 Hz, 1H), 4.61 (d, J = 10.6 Hz, 1H), 4.49 (d, J =
10.6 Hz, 1H), 3.89 (s, 3H), 3.58 (d, J = 6.4 Hz, 2H), 2.91 (m, 1H),
2.10 (m, 1H), 1.89 (m, 1H), 1.22 (d, J = 7.0 Hz, 3H), 0.91 (t, J = 7.4
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 213.1, 158.9, 137.3, 131.2,
130.9, 130.4, 130.3, 128.4, 128.36, 127.0, 126.1, 118.1, 113.7, 89.5,
63.0, 55.1, 45.9, 42.8, 26.3, 15.7, 7.9; LRMS (ESI) m/z (relative
intensity) 401.4 (100%, M + Na+); HRMS (ESI) m/z calcd for
[C25H31O3]+, 379.2273, found 379.2257.
6-Ethyl-6-(4-methoxybenzyloxy)-5-methylcyclohex-3-enone
(35). To a refluxing solution of diene 34 (0.151 g, 0.399 mmol) in 4
mL of CH2Cl2 was added dropwise a solution of Grubbs II catalyst22
(60 mg, 0.71 mmol) in 1 mL of CH2Cl2. After refluxing for 2 h, the
solution was cooled to room temperature and concentrated in vacuo
to give a crude brown oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 4 → 10% Et2O/hexanes as eluent) gave
β,γ-unsaturated enone 35 (0.092 g, 84%) as a light brown oil. IR (thin
film) 1719 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.6 Hz,
2H), 6.86 (d, J = 8.6 Hz, 2H), 5.77 (m, 1H), 5.62 (dt, J = 9.8, 3.4 Hz,
1H), 4.48 (d, J = 10.8 Hz, 1H), 4.35 (d, J = 10.8 Hz, 1H), 3.80 (s, 3H),
2.97−2.95 (m, 2H), 2.85 (m, 1H), 2.11 (m, 1H), 1.94 (m, 1H), 1.04
(d, J = 7.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 208.5, 158.8, 132.0, 130.8, 128.3, 122.1, 113.5, 84.9, 63.9,
55.1, 40.2, 39.7, 23.5, 15.6, 7.9; LRMS (ESI) m/z (relative intensity)
1
IR (thin film) 1713 cm−1; H NMR (400 MHz, CDCl3) δ 7.37−7.20
(m, 14H), 6.79 (d, J = 8.5 Hz, 4H), 6.51 (d, J = 15.8 Hz, 2H), 6.23
(dd, J = 15.8, 10.9 Hz, 2H), 4.56 (d, J = 10.0 Hz, 2H), 4.41 (d, J = 10.1
Hz, 2H), 3.84−3.81 (m, 2H), 3.81 (s, 6H), 2.07−1.89 (m, 4H), 1.22−
1.14 (m, 6H), 1.00−0.91 (m, 42H); 13C NMR (90 MHz, CDCl3) δ
171.8, 158.6, 137.5, 134.3, 131.4, 129.0, 128.1, 127.4, 126.9, 126.4,
113.2, 84.8, 65.5, 55.2, 45.7, 25.7, 17.8, 17.71, 17.67, 12.3, 11.9, 7.4;
+
LRMS (ESI) m/z (relative intensity) 948.8 (100%, M + NH4 ).
To a stirring solution of crude bis TIPS ester 32 (1.28 g, 1.29
mmol) in 15 mL of THF at 0 °C was added Bu4NF (1.0 M in hexanes,
3.89 mL, 3.9 mmol) dropwise. After stirring for 30 min, H2O (20 mL)
was added. The resulting solution was partitioned between EtOAc and
H2O and the aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo to give a crude yellow solid. CH3CN (20 mL)
was added and this solution was washed with hexanes (5 × 20 mL)
and the CH3CN phase was separated and concentrated in vacuo to
give diacid 33 (0.876 g, 100%) as a white solid which was used without
further purification. mp 116−118 °C; [α]20 = −42 (c 5.00, MeOH);
D
H
dx.doi.org/10.1021/jo4005074 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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+
297.5 (100%, M + Na+); HRMS (ESI) m/z calcd for [C17H26NO3]+,
292.1913, found 292.1901.
intensity) 628.3 (100%, M + NH4 ); HRMS (ESI) m/z calcd for
[C42H46NO4]+, 628.3427, found 628.3425.
6-Ethyl-4-hydroxy-6-(4-methoxybenzyloxy)-5-methylcyclo-
hex-2-enone (36). To a stirring solution of β,γ-unsaturated enone 35
(0.044 g, 0.16 mmol) in 1 mL of acetone was added freshly prepared
DMDO (0.10 M in acetone, 3.2 mL, 0.32 mmol). The solution was
stirred for 30 min at room temperature and concentrated in vacuo to
give an epoxide product as a colorless crude oil (single diastereomer,
unassigned) that was used without further purification. IR (thin film)
1725 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.6 Hz, 2H),
6.88 (dd, J = 6.8, 1.9 Hz, 2H), 4.41 (d, J = 11.2 Hz, 1H), 4.02 (d, J =
11.2 Hz, 1H), 3.81 (s, 3H), 3.47 (t, J = 3.0 Hz, 1H), 3.02 (d, J = 3.9
Hz, 1H), 2.88 (dd, J = 17.0, 3.3 Hz, 1H), 2.76 (d, J = 17.0 Hz, 1H),
2.40 (q, J = 7.4 Hz, 1H), 2.16 (m, 1H), 1.53 (m, 1H), 1.28 (t, J = 7.4
Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H); LRMS (ESI) m/z (relative
intensity) 313.3 (30%, M + Na+).
(R,R,S,S)-2,2′-Bis-benzyloxy-bicyclohexyl-5,5′-diene-3,3′-
dione (38). To a refluxing solution of tetraene 37 (0.100 g, 0.164
mmol) in 35 mL of freeze−pump−thawed CH2Cl2 was added
dropwise a solution of Grubbs II catalyst22 (7 mg, 0.008 mmol) in 250
μL of CH2Cl2. After holding at reflux for 2 h, the solution was cooled
to room temperature and concentrated in vacuo to give a crude white
solid. Purification of this solid by SiO2 flash column chromatography
(gradient, 20 → 40% Et2O/hexanes as eluent) gave bicycle 38 (0.041
g, 62%) as a tacky white solid. A yield of 81% was obtained on a 15 mg
1
scale. [α]20 = +123° (c 0.86, CHCl3); IR (thin film) 1719 cm−1; H
D
NMR (300 MHz, CDCl3) δ 7.32−7.24 (m, 10H), 5.65 (dd, J = 9.9, 2.4
Hz, 2H), 5.32 (d, J = 10.0 Hz, 2H), 4.87 (d, J = 11.7 Hz, 2H), 4.39 (d,
J = 11.7 Hz, 2H), 3.98 (d, J = 10.2 Hz, 2H), 3.16 (d, J = 9.1 Hz, 2H),
3.04 (d, J = 23.0 Hz, 2H), 2.94 (d, J = 20.9 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 207.2, 137.2, 128.4, 128.3, 127.9, 125.7, 124.2, 79.9,
72.2, 43.3, 40.2; LRMS (ESI) m/z (relative intensity) 420.2 (80%, M +
To a stirring solution of this crude epoxide in 1 mL of benzene was
added Et3N (45 μL, 0.32 mmol). The solution was stirred for 12 h at
room temperature and then concentrated in vacuo to give a colorless
crude oil. Purification of this oil by SiO2 flash column chromatography
(gradient, 10 → 30% EtOAc/hexanes as eluent) gave γ-hydroxyenone
36 (0.018 g, 39% from 35, single diastereomer, unassigned) as a
+
NH4 ); HRMS (ESI) m/z calcd for [C26H30NO4]+, 420.2175, found
420.2161.
(2R,3S,4S,5R)-2,5-Diethyl-2,5-bis-(4-(methoxy)benzyloxy)-
3,4-(distyryl)hexanedioic Acid Bis-(methoxymethylamide)
(39). To a stirring solution of diacid 33 (0.045 g, 0.066 mmol) in 1
mL of benzene was added pyridine (32 μL, 0.40 mmol). After stirring
for 15 min, oxalyl chloride (23 μL, 0.26 mmol) was added dropwise.
After stirring for an additional 30 min, the reaction mixture was
concentrated in vacuo, Et2O (10 mL) was added, and the suspension
was filtered through a thin pad of Celite with Et2O rinsing (10 mL).
The combined organics were concentrated in vacuo to afford the bis
acid chloride, which was used without further purification. IR (thin
film) 1778 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.43−7.25 (m, 14H),
6.84 (d, J = 10.0 Hz, 4H), 6.66 (d, J = 15.5 Hz, 2H), 6.34 (dd, J = 15.8,
10.7 Hz, 2H), 4.53 (d, J = 10.1 Hz, 2H), 4.47 (d, J = 10.2 Hz, 2H),
3.85 (s, 6H), 3.65 (d, J = 10.6 Hz, 2H), 2.14−2.00 (m, 4H), 0.98 (t, J
= 7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 177.2, 159.0, 136.9,
136.7, 129.7, 128.9, 128.5, 127.7, 126.6, 124.2, 113.5, 90.3, 65.5, 55.2,
47.3, 27.0, 7.2; LRMS (ESI−) m/z (relative intensity) 677.5 (100%, M
− H − Cl−).
1
colorless oil. IR (thin film) 3425, 1672 cm−1; H NMR (360 MHz,
CDCl3) δ 7.10 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 10.3, 1.8 Hz, 1H),
6.82 (d, J = 8.7 Hz, 2H), 5.93 (dd, J = 10.3, 2.1 Hz, 1H), 4.49 (m, 1H),
4.35 (d, J = 11.0 Hz, 1H), 4.02 (d, J = 11.0 Hz, 1H), 3.78 (s, 3H), 2.47
(m, 1H), 2.11 (m, 1H), 1.77 (d, J = 7.2 Hz, 1H), 1.46 (m, 1H), 1.25
(d, J = 6.6 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 196.5, 158.9, 152.5, 130.9, 128.6, 126.6, 113.6, 81.9, 64.9,
64.6, 55.2, 44.8, 21.1, 10.0, 8.4; LRMS (ESI) m/z (relative intensity)
313.2 (100%, M + Na+); HRMS (ESI) m/z calcd for [C17H26NO4]+,
308.1862, found 308.1867.
(R,R,S,S)-5,8-Bis-benzyloxy-6,7-distyryldodeca-1,11-diene-
4,9-dione (37). To a stirring solution of dicarboxylic acid 29 (1.48 g,
2.62 mmol) in 25 mL of toluene was added P[NCH3(OCH3)]320 (517
μL, 2.62 mmol). The solution was heated to 60 °C, stirred for 2 h at
that temperature, cooled to room temperature, and saturated NaHCO3
(25 mL) was added. The resulting solution was partitioned between
EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 ×
25 mL). The combined organic fractions were dried over Na2SO4,
filtered, and concentrated in vacuo to give a yellow crude oil.
Purification of this oil by SiO2 flash column chromatography (gradient,
25 → 60% EtOAc/hexanes as eluent) gave an intermediate bis
Weinreb amide (1.23 g, 73%) as a pale yellow oil. A yield of 100% was
To a stirring solution of this crude bis acid chloride in 45 mL of
benzene was added pyridine (32 μL, 0.40 mmol) dropwise followed by
N,O-dimethylhydroxylamine (23 μL, 0.26 mmol). After stirring for 15
h, the reaction mixture was concentrated in vacuo to afford a crude
pale yellow oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 20 → 50% EtOAc/hexanes as eluent)
gave bis Weinreb amide 39 (0.037 g, 73% from 33) as a yellow solid. A
1
obtained on a 20 mg scale. IR (thin film) 1666 cm−1; H NMR (300
MHz, CDCl3) δ 7.41−7.28 (m, 20H), 6.33 (d, J = 15.7 Hz, 2H),
6.20−6.13 (m, 2H), 4.72 (d, J = 13.4 Hz, 2H), 4.43−4.31 (m, 4H),
3.40 (s, 6H), 3.4 (m, 2H), 2.99 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 173.7, 138.2, 137.7, 135.5, 128.9, 128.8, 128.7, 128.3, 127.9, 126.8,
125.0, 73.7, 72.1, 61.7, 48.0, 33.2; LRMS (ESI) m/z (relative intensity)
649.4 (100%, M + H+).
42% yield was obtained from 25 on a 2.69 g scale. mp 51−54 °C;
1
[α]20 = +13 (c 2.67, MeOH); IR (thin film) 1637 cm−1; H NMR
D
(400 MHz, CDCl3) δ 7.39 (d, J = 7.5 Hz, 4H), 7.32−7.19 (m, 10H),
6.74 (d, J = 8.2 Hz, 4H), 6.55−6.50 (m, 4H), 4.50 (d, J = 9.5 Hz, 2H),
4.42−4.37 (m, 2H), 3.79 (s, 6H), 3.63−3.57 (m, 2H), 3.46 (s, 6H),
3.08 (br s, 6H), 2.13−2.07 (m, 4H), 0.99 (t, J = 6.7 Hz, 6H); 13C
NMR (90 MHz, CDCl3) δ 172.5, 158.7, 138.0, 132.5, 130.9, 129.5,
128.8, 128.4, 126.8, 126.4, 113.2, 87.3, 64.9, 60.7, 55.2, 47.8, 35.5, 26.4,
8.5; LRMS (ESI) m/z (relative intensity) 765.4 (100%, M + H+).
HRMS (ESI) m/z calcd for [C46H56N2O8]+, 765.4115, found
765.4119.
To a stirring solution of this bis Weinreb amide (1.23 g, 1.90 mmol)
in 20 mL of THF at 0 °C was added dropwise allylmagnesium
bromide (1.0 M in Et2O, 11.4 mL, 11 mmol). The solution was stirred
for 30 min at 0 °C and then added to a cold solution of saturated
NH4Cl (20 mL) and HOAc (1 ML). The resulting solution was
partitioned between EtOAc and H2O and the aqueous layer was
extracted with EtOAc (3 × 25 mL). The combined organic fractions
were dried over Na2SO4, filtered, and concentrated in vacuo to give a
colorless crude oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 4 → 5% EtOAc/hexanes as eluent) gave
bis allylation product 37 (0.517 g, 45%) as a colorless oil. A yield of
64% was obtained on a 176 mg scale. [α]20D = −73° (c 11.1, MeOH);
(2R,3S,4S,5R)-5,8-Diethyl-5,8-bis-(4-(methoxy)benzyloxy)-
6,7-(distyryl)dodeca-1,11-diene-4,9-dione (40). To a stirring
solution of freshly prepared allyllithium23 (0.48 M in 2:1 THF/
Et2O, 14.5 mL, 6.7 mmol) at −78 °C was added dropwise a solution of
bis Weinreb amide 39 (1.28 g, 1.67 mmol) in 4 mL of THF. After
stirring for 1 h at −78 °C, saturated NH4Cl (25 mL) was added. The
resulting solution was partitioned between Et2O and H2O and the
aqueous layer was extracted with Et2O (3 × 25 mL). The combined
organic fractions were dried over Na2SO4, filtered, and concentrated in
vacuo to give a yellow oil. Purification of this oil by SiO2 flash column
chromatography (2 → 8% Et2O/hexanes then 15% EtOAc/hexanes as
eluent) gave tetraene 40 (0.83 g, 72%) as a yellow solid. A 77% yield
was obtained on a 109 mg scale. A sample of this solid was crystallized
1
IR (thin film) 1708 cm−1; H NMR (400 MHz, CDCl3) δ 7.39−7.38
(m, 10H), 7.30−7.21 (m, 6H), 7.18−7.16 (m, 4H), 6.01 (dd, J = 15.9
Hz, 4.8 Hz, 2H), 5.84−5.72 (m, 4H), 5.12−5.03 (m, 4H), 4.58 (d, J =
11.7 Hz, 2H), 4.29 (d, J = 11.6 Hz, 2H), 3.78 (d, J = 10.0 Hz, 2H),
3.38−3.32 (m, 2H), 3.20−3.13 (m, 4H); 13C NMR (75 MHz, CDCl3)
δ 209.5, 136.9, 136.2, 135.3, 130.2, 128.6, 128.5, 128.4, 128.2, 127.8,
126.4, 122.9, 118.7, 85.1, 72.5, 45.7, 42.4; LRMS (ESI) m/z (relative
from EtOH to give an X-ray quality crystal. mp 116−118 °C; [α]20
=
D
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Article
−58 (c 2.10, MeCN); IR (thin film) 1713 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 7.4 Hz, 4H), 7.34 (t, J = 7.5 Hz, 4H), 7.28−7.25
(m, 6H), 6.95 (d, J = 8.5 Hz, 4H), 6.52 (dd, J = 15.8, 9.4 Hz, 2H), 6.43
(d, J = 15.8 Hz, 2H), 5.51−5.37 (m, 2H), 4.86 (d, J = 10.3 Hz, 2H),
4.67 (d, J = 17.2 Hz, 2H), 4.45 (d, J = 11.2 Hz, 2H), 4.41 (d, J = 11.2
Hz, 2H), 3.88 (s, 6H), 3.47 (dd, J = 19.0, 6.0 Hz, 2H), 3.39 (d, J = 9.3
Hz, 2H), 3.32 (dd, J = 19.0, 7.6 Hz, 2H), 2.00−1.91 (m, 2H), 1.80−
1.71 (m, 2H), 0.76 (t, J = 7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
212.9, 158.8, 136.9, 133.4, 130.9, 130.2, 128.4, 127.6, 127.4, 127.3,
126.5, 117.8, 113.7, 88.5, 62.5, 55.2, 48.6, 47.1, 28.4, 7.6; LRMS (ESI)
toluene. The solution was stirred for 15 min at −78 °C and TIPSOTf
(7.6 mL, 28.3 mmol) was added dropwise. The reaction mixture was
stirred for 30 min at −78 °C, stirred for 20 min at 0 °C, and then
allowed to warm to room temperature. After stirring for 30 min at
room temperature, saturated NH4Cl (50 mL) was added. The
resulting solution was partitioned between EtOAc and H2O and the
aqueous layer was extracted with EtOAc (3 × 100 mL). The combined
organic fractions were dried over Na2SO4, filtered, and concentrated in
vacuo to give an intermediate TIPS ester as colorless oil that was
carried on without any further purification.
To a stirring solution of this crude TIPS ester in 60 mL of THF at 0
°C was added dropwise Bu4NF (1.0 M in hexanes, 30.3 mL, 30.3
mmol). After 20 min at 0 °C, H2O (50 mL) was added. The resulting
solution was partitioned between EtOAc and H2O and the aqueous
layer was extracted with EtOAc (3 × 50 mL). The combined organic
fractions were dried over Na2SO4, filtered, and concentrated in vacuo
to give a carboxylic acid product as a white solid that was carried on
without further purification.
To a stirring solution of the crude carboxylic acid from above in 50
mL of benzene was added pyridine (2.3 mL, 28 mmol). After stirring
the mixture for 15 min, oxalyl chloride (1.6 mL, 19 mmol) was added
dropwise. After stirring for 1 h, the reaction solution was concentrated
in vacuo, Et2O (50 mL) was added, and the suspension was filtered
through Celite with Et2O rinsing (50 mL). The resulting solution was
concentrated in vacuo to afford a crude acid chloride product as a
yellow solid that was carried on without further purification.
To this crude acid chloride in 50 mL of benzene was added pyridine
(2.3 mL, 28 mmol) followed by N,O-dimethylhydroxylamine (1.2 mL,
13 mmol). After stirring for 14 h at room temperature, the solution
was concentrated in vacuo and filtered through Celite with Et2O to
give a crude yellow solid. Purification of this solid by SiO2 flash column
chromatography (gradient, 2 → 20% EtOAc/hexanes as eluent) gave
the corresponding Weinreb amide (2.42 g, 64% over 4 steps) as a
yellow solid.
To a stirring solution of this Weinreb amide (2.42 g, 6.08 mmol) in
40 mL of THF at 0 °C was added dropwise allylmagnesium bromide
(1.0 M in Et2O, 18.2 mL, 18.2 mmol). The solution was stirred for 30
min at 0 °C and then for 1 h at room temperature. This reaction
mixture then was added to a cold solution of saturated NH4Cl (50
mL). The resulting solution was partitioned between EtOAc and H2O
and the aqueous layer was extracted with EtOAc (3 × 100 mL). The
combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo to give a colorless crude oil. Purification of this
oil by SiO2 flash column chromatography (gradient, 2 → 10% Et2O/
hexanes as eluent) gave the allylation product (1.88 g, 84%) as a
colorless oil.
+
m/z (relative intensity) 744.5 (100%, M + NH4 ). HRMS (ESI) m/z
calcd for [C48H58NO6]+, 744.4264, found 744.4262.
(1S,1′S,2R,2′R)-2,2′-Diethyl-2,2′-bis-(4-(methoxy)-
benzyloxy)-bicyclohexyl-5,5′-diene-3,3′-dione (41). To a
freeze−pump−thawed solution of tetraene 40 (0.147 g, 0.202
mmol) in 10 mL of toluene in a sealable tube was added Grubbs II
catalyst (0.069 g, 0.081 mmol) and the tube was sealed. After freeze−
pump−thawing the solution again, the reaction mixture was heated at
100 °C. After heating at this temperature for 4 h, the crude solution
was cooled to room temperature and concentrated in vacuo to give a
green oil. Purification of this oil by SiO2 flash column chromatography
(10 → 30% EtOAc/hexanes as eluent) gave bis cyclohexenone 41
(0.067 g, 64%) as a green solid. mp 135−137 °C; [α]20 = −100 (c
D
1.00, MeCN); IR (thin film) 1719 cm−1; 1H NMR (360 MHz, CDCl3)
δ 7.39 (d, J = 8.6 Hz, 4H), 6.93 (d, J = 8.6 Hz, 4H), 5.76−5.70 (m,
4H), 4.81 (d, J = 10.8 Hz, 2H), 4.41 (d, J = 10.9 Hz, 2H), 3.85 (s, 6H),
3.41 (d, J = 3.6 Hz, 2H), 2.87 (s, 4H), 1.99−1.85 (m, 4H), 0.82 (t, J =
7.3 Hz, 6H); 13C NMR (90 MHz, CDCl3) δ 209.8, 158.9,130.9, 128.3,
126.8, 126.3, 113.7, 83.7, 64.3, 55.2, 45.3, 40.7, 24.8, 7.1; (ESI) m/z
+
(relative intensity) 536.4 (100%, M + NH4 ); HRMS (ESI) m/z calcd
for [C32H42NO6]+, 536.3012, found 536.3008.
Pentacyclic Bis Hemiacetal Diene (44). To a solution of bis
cyclohexenone 41 (0.022 g, 0.042 mmol) in 1 mL of CH2Cl2 at 0 °C
was added TFA (32 μL, 0.42 mmol). After stirring for 15 min at 0 °C,
the reaction mixture was concentrated in vacuo to give a crude yellow
oil. Purification of this oil by SiO2 flash column chromatography (10
→ 15% EtOAc/hexanes as eluent) gave pentacyclic bis hemiketal
diene 44 (8 mg, 70%) as a yellow solid. mp 167−170 °C; [α]20
=
D
1
−64 (c 0.44, MeCN);IR (thin film) 3413 cm−1; H NMR (300 MHz,
CDCl3) δ 5.77 (m, 2H), 5.47 (m, 2H), 3.84 (s, 2H), 2.48−2.31 (m,
6H), 1.83 (m, 2H), 1.46 (m, 2H), 0.91 (t, J = 7.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 130.5, 123.0, 97.9, 73.4, 41.2, 38.2, 23.8, 6.9;
LRMS (ESI) m/z (relative intensity) 261.1 (100%, M − OH−);
HRMS (ESI) m/z calcd for [C16H21O3]−, 261.1491, found 261.1474.
1-Phenylbut-2-enyl 2-(4-Methoxybenzyloxy)butyrate (47).
To a stirring solution of alcohol 4524 (2.32 g, 15.6 mmol) and
carboxylic acid 2411 (3.74 g, 16.6 mmol) in 150 mL of CH2Cl2 was
added DMAP (198 mg, 1.62 mmol) and EDC (3.29 mg, 17.2 mmol).
After stirring the mixture for 14 h at room temperature, the organics
were washed with H2O (25 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to give a colorless oil. Purification of this oil by
deactivated SiO2 (2% Et3N/hex) flash column chromatography (2 →
15% Et2O/hexanes as eluent) gave PMB glycolate 47 (3.36 g, 57%) as
a colorless oil (1:1 mix of diastereomers). IR (thin film) 1749 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.46−7.26 (m, 12H), 6.92−6.87 (m,
4H), 6.35 (d, J = 6.8 Hz, 2H), 5.88−5.72 (m, 4H), 4.65 (d, J = 11.2
Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 4.36 (d, J = 11.2 Hz, 1H), 4.35 (d,
J = 11.2 Hz, 1H), 3.94−3.89 (m, 4H), 3.84 (s, 3H), 3.83 (s, 3H),
1.89−1.80 (m, 4H), 1.77 (d, J = 4.7 Hz, 3H), 1.76 (d, J = 3.4 Hz, 3H),
0.99 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.7, 171.68, 159.2 (two signals), 139.4, 139.37, 129.9,
129.63, 129.6, 129.57, 129.52, 129.5, 129.22, 129.2, 128.3, 127.9,
127.8, 126.8, 126.6, 113.9, 113.6, 78.9, 78.8, 76.4, 76.39, 71.65, 71.58,
55.0 (two signals), 26.06, 26.0, 17.6 (×2), 9.6, 9.5; LRMS (ESI) m/z
To a refluxing solution of this crude allylation product (1.14 g, 3.02
mmol) in 48 mL of CH2Cl2 was added dropwise a solution of Grubbs
II catalyst22 (256 mg, 0.302 mmol) in 1 mL of CH2Cl2. After holding
at reflux for 2 h, the solution was cooled to room temperature and
concentrated in vacuo to give a crude brown oil. Purification of this oil
by SiO2 flash column chromatography (gradient, hexanes →10%
Et2O/hexanes as eluent) gave β,γ-unsaturated enone 48 (0.640 g,
1
77%) as a light brown oil. IR (thin film) 1713 cm−1; H NMR (300
MHz, CDCl3) δ 7.33 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H),
5.75−5.64 (m, 2H), 4.54 (d, J = 10.7 Hz, 1H), 4.17 (d, J = 10.7 Hz,
1H), 3.83 (s, 3H), 3.14 (m, 1H), 3.02 (m, 1H), 2.85 (m, 1H), 1.95 (m,
1H), 1.77 (m, 1H), 0.97 (d, J = 7.3 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 210.4, 158.9, 131.3, 130.6, 128.6, 121.9,
113.7, 85.4, 65.7, 55.2, 40.2, 39.2, 20.5, 15.2, 6.3; LRMS (ESI) m/z
(relative intensity) 297.5 (60%, M + Na+); HRMS (ESI) m/z calcd for
[C17H26NO3]+ 292.1913, found 292.1897.
6-Ethyl-4-(hydroxyphenyl-amino)-6-(4-methoxybenzyloxy)-
5-methyl-cyclohex-2-enone (50). To a stirring solution of freshly
prepared LDA (230 μL i-Pr2NH + 612 μL of 2.5 M n-BuLi in hexanes;
1.53 mmol) in 10 mL of THF at −78 °C was added dropwise a
solution of β,γ-unsaturated enone 48 (0.400 g, 1.46 mmol) in 3 mL of
THF. After 15 min, freshly distilled TMSCl (389 μL, 3.08 mmol) was
added. After stirring the mixture for 2 h at −78 °C, saturated NH4Cl
(10 mL) was added. The resulting solution was partitioned between
+
(relative intensity) 372.3 (100%, M + NH4 ); HRMS (ESI) m/z calcd
for C22H26NaO4, 377.1729, found 377.1718.
6-Ethyl-6-(4-methoxybenzyloxy)-5-methylcyclohex-3-enone
(48). To a stirring solution of KHMDS (0.5 M in toluene, 56.8 mL,
28.4 mmol) in 40 mL of toluene at −78 °C was added dropwise a
solution of PMB glycolate 47 (3.36 g, 9.47 mmol) in 10 mL of
J
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EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 ×
20 mL). The combined organic fractions were dried over Na2SO4,
filtered, and concentrated in vacuo to give TMS dienol ether 49a as a
yellow oil which required no further purification. IR (thin film) 1696
(d, J = 8.6 Hz, 2H), 6.60 (dd, J = 8.6, 5.5 Hz, 1H), 6.37 (d, J = 8.6 Hz,
1H), 4.76 (d, J = 11.6 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.32 (m,
1H), 3.82 (s, 3H), 2.69 (m, 1H), 1.76−1.59 (m, 2H), 1.03 (t, J = 7.4
Hz, 3H), 1.00−0.95 (m, 3H), 0.96 (s, 9H), 0.21 (s, 3H), 0.19 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 158.6, 136.3, 132.3, 131.5, 128.2, 113.4,
1
cm−1; H NMR (360 MHz, CDCl3) δ 7.31 (d, J = 8.6 Hz, 2H), 6.88
(d, J = 8.5 Hz, 2H), 5.76 (ddd, J = 9.4, 5.9, 1.3 Hz, 1H), 5.53 (dd, J =
9.3, 4.2 Hz, 1H), 5.28 (d, J = 5.8 Hz, 1H), 4.44 (br s, 2H), 3.82 (s,
3H), 2.86 (m, 1H), 2.09 (m, 1H), 1.45 (m, 1H), 1.00 (d, J = 7.4 Hz,
3H), 0.99 (t, J = 7.6 Hz, 3H), 0.29 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 158.6, 153.3, 132.2, 12.8, 127.3, 120.7, 113.4, 103.2, 81.6,
65.1, 55.2, 47.3, 36.8, 22.5, 19.2, 13.3, 7.4, 0.2; LRMS (ESI) m/z
104.3, 80.9, 77.5, 65.0, 55.2, 41.0, 25.7, 24.2, 18.0, 14.9, 9.4, −2.3,
−3.0; LRMS (ESI) m/z (relative intensity) 421.3 (30%, M + H+);
HRMS (ESI) m/z calcd for [C23H36O5SiNa]+, 443.2230, found
443.2233.
6-Ethyl-4-hydroxy-6-(4-methoxybenzyloxy)-5-methylcyclo-
hex-2-enone (52). To a stirring solution of endoperoxide 51 (0.111
g, 0.271 mmol) in 3 mL of MeCN at 0 °C was added 46% HF(aq.)
(18 μL, 0.410 mmol). After stirring the mixture for 1 min, H2O (5
mL) was added. The resulting solution was partitioned between
EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 ×
10 mL). The combined organic fractions were dried over Na2SO4,
filtered, and concentrated in vacuo to give a yellow oil. Purification of
this oil by SiO2 flash column chromatography (gradient, 10 → 50%
EtOAc/hexanes as eluent) gave a peroxide-containing product (0.085
+
(relative intensity) 405.3 (60%, M + MeCN + NH4 ).
To a stirring solution of the crude TMS dienol ether 49a (0.506 g,
1.46 mmol) in 13 mL of chloroform was added nitrosobenzene (158
mg, 1.47 mmol, recrystallized from EtOH). After 24 h, the reaction
mixture was concentrated in vacuo to give the alkylhydroxylamine
bridged product as a crude green oil that was used without further
purification. IR (thin film) 1696 cm−1; 1H NMR (360 MHz, CDCl3) δ
7.39 (d, J = 8.5 Hz, 2H), 7.25 (t, J = 7.6 Hz, 2H), 7.09 (d, J = 7.8 Hz,
2H), 6.95 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.30 (d, J = 8.4
Hz, 1H), 6.14 (dd, J = 8.4, 5.3 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.67
(d, J = 11.5 Hz, 1H), 4.19 (m, 1H), 3.83 (s, 3H), 2.71 (m, 1H), 1.70
(m, 1H), 1.59 (m, 1H), 1.07 (d, J = 7.5 Hz, 3H), 1.04 (t, J = 7.4 Hz,
3H), 0.29 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.3, 151.3, 135.4,
132.1, 129.1, 128.3, 128.1, 121.4, 116.7, 113.2, 103.4, 81.5, 64.7, 62.6,
54.9, 39.1, 24.2, 16.3, 9.0, 2.0.
To a stirring solution of this crude hydroxylamine bridged species
from above (662 mg, 1.46 mmol) in 15 mL of MeOH was added
anhydrous KF (102 mg, 1.75 mmol). After stirring the mixture for 1 h
at room temperature, Et2O (15 mL) and H2O (15 mL) were added
and the aqueous layer was extracted with Et2O (3 × 20 mL). The
combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo to give a crude green solid. Purification of this
green solid by SiO2 flash column chromatography (gradient, 20 →
40% Et2O/hexanes as eluent) gave hydroxylamine 50 (0.246 g, 44%
from 49a) as a white solid. A portion of this solid was crystallized from
EtOH to obtain X-ray quality crystals. mp 127−129 °C; IR (thin film)
1678 cm−1; 1H NMR (360 MHz, THF-d8) δ 7.45 (d, J = 8.4 Hz, 2H),
7.34−7.23 (m, 4H), 6.96 (t, J = 6.8 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H),
6.78 (d, J = 10.4 Hz, 1H), 6.02 (dd, J = 10.3, 1.9 Hz, 1H), 4.50 (d, J =
10.0 Hz, 1H), 4.33 (d, J = 10.1 Hz, 1H), 4.26 (br d, J = 10.0 Hz, 1H),
3.80 (s, 3H), 3.26 (m, 1H), 1.98 (m, 1H), 1.68 (m, 1H), 1.35 (d, J =
6.6 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (90 MHz, THF-d8) δ
197.8, 159.2, 152.8, 147.8, 131.5, 130.0, 128.9, 128.5, 121.1, 116.2,
113.1, 84.1, 69.4, 67.3, 64.6, 54.4, 38.7, 25.5, 24.1, 10.4, 6.8; LRMS
(ESI) m/z (relative intensity) 382.3 (10%, M + H+); HRMS (ESI) m/
z calcd for [C23H28NO4]+, 382.2018, found 382.2015.
1
g, 100%) as a yellow oil. IR (thin film) 3353, 1682 cm−1; H NMR
(360 MHz, CDCl3) δ 8.42 (br s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.08
(dd, J = 10.4, 2.0 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.14 (dd, J = 10.4,
2.0 Hz, 1H), 4.54 (m, 1H), 4.43 (d, J = 10.0 Hz, 1H), 4.24 (d, J = 10.0
Hz, 1H), 3.83 (s, 3H), 2.90 (m, 1H), 1.90 (m, 1H), 1.55 (m, 1H), 1.26
(d, J = 6.7 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 199.3, 158.9, 147.4, 130.5, 129.5, 129.2, 113.6, 84.9, 83.9,
65.0, 55.2, 38.7, 24.3, 10.5, 7.1; LRMS (ESI) m/z (relative intensity)
+
324.4 (5%, M + NH4 ); HRMS (ESI) m/z calcd for [C17H26NO5]+,
324.1811, found 324.1801.
To a stirring solution of this peroxide (0.024 g, 0.077 mmol) in 1
mL of CHCl3 was added PPh3 (30 mg, 0.12 mmol). After stirring for 5
min at room temperature, the reaction mixture was concentrated in
vacuo to give a crude green oil. Purification of this oil by SiO2 flash
column chromatography (gradient, 20 → 40% EtOAc/hexanes as
eluent) gave γ-hydroxyenone 52 (0.020 g, 91%). IR (thin film) 3448,
1
1678 cm−1; H NMR (360 MHz, CDCl3) δ 7.21 (d, J = 8.2 Hz, 2H),
6.87 (d, J = 8.2 Hz, 2H), 6.87 (m, 1H), 6.03 (d, J = 10.1 Hz, 1H), 4.33
(d, J = 10.1 Hz, 1H), 4.05 (d, J = 10.1 Hz, 1H), 4.05 (m, 1H), 3.81 (s,
3H), 3.48 (br s, 1H), 2.60 (m, 1H), 2.13 (m, 1H), 1.52 (m, 1H),
0.98−0.93 (m, 6H); 13C NMR (90 MHz, CDCl3) δ 198.6, 159.3,
147.2, 129.5, 129.4, 126.7, 113.8, 83.9, 70.6, 65.4, 55.2, 41.0, 19.8, 13.0,
+
5.6; LRMS (ESI) m/z (relative intensity) 313.3 (100%, M + NH4 );
HRMS (ESI) m/z calcd for [C17H26NO4]+, 308.1862, found 308.1867.
Preparation of Alcohol 52 Directly from Endoperoxide 51.
To a stirring solution of endoperoxide 51 (0.148 g, 0.351 mmol) in 3
mL of THF at −78 °C was added dropwise Bu4NF (1.0 M in hexanes,
386 μL, 0.386 mmol), and the solution was warmed to −45 °C. After
stirring the mixture for 30 min at −45 °C, H2O (5 mL) was added.
The resulting solution was partitioned between EtOAc and H2O and
the aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo to give a colorless oil. Purification of this oil by
SiO2 flash column chromatography (gradient, 10 → 60% EtOAc/
hexanes as eluent) gave γ-hydroxyenone 52 (0.037 g, 37%) as a
colorless oil. A yield of 91% was obtained on a 24 mg scale.
tert-Butyl-[7-ethyl-7-(4-methoxybenzyloxy)-8-methyl-2,3-
dioxa-bicyclo[2.2.2]oct-5-en-1-yloxy]dimethylsilane (51). To a
stirring solution of KHMDS (292 μL, 0.50 M in toluene, 0.156 mmol)
in 1 mL of THF at −78 °C was added dropwise a solution of β,γ-
unsaturated enone 48 (0.020 g, 0.073 mmol) in 200 μL of THF. After
40 min at −78 °C, TBSOTf (34 μL, 0.15 mmol) was added. After
stirring the mixture for 2 h at −78 °C, saturated NaHCO3 (10 mL)
was added. The resulting solution was partitioned between EtOAc and
H2O and the aqueous layer was extracted with EtOAc (3 × 15 mL).
The combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo to give a yellow oil. Purification of this oil by
SiO2 flash column chromatography (gradient, hexanes → 5% Et2O/
hexanes as eluent) gave TBS dienol ether 49b as a yellow oil (0.027 g,
96%) that was used as crude material in the next transformation.
To a solution of TBS dienol ether 49b (0.027 g, 0.070 mmol) in
CH2Cl2 at −78 °C was added tetraphenylporphyrin (2 mg, 0.003
mmol). The sample was irradiated with a 275W sun lamp while
bubbling O2 through the solution at −78 °C. After 45 min, the
reaction mixture was warmed to room temperature and concentrated
in vacuo to give a pink oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 2 → 20% Et2O/hexanes as eluent) gave
endoperoxide 51 as a pink oil (0.016 g, 54%). IR (thin film) 1249
1,1′-Bis-(tert-butyl(dimethyl)silanyloxy)-6,6′-diethyl-6,6′-
bis-(4-(methoxy)benzyloxy)-[5,5′]bi[2,3-dioxabicyclo[2.2.2]-
octyl]-7,7′-diene (54). To a stirring solution of KHMDS (0.50 M in
toluene, 848 μL, 0.424 mmol) in 800 μL of THF at −78 °C was added
dropwise a solution of bis cyclohexenone 41 (0.055 g, 0.11 mmol) in
400 μL of THF. After stirring for 40 min at −78 °C, TBSOTf (98 μL,
0.42 mmol) was added. After stirring for 2 h at −78 °C, saturated
NaHCO3 solution (10 mL) was added. The resulting solution was
partitioned between EtOAc and H2O and the aqueous layer was
extracted with EtOAc (3 × 15 mL). The combined organic fractions
were dried over Na2SO4, filtered, and concentrated in vacuo to give bis
TBS dienol ether 53 as a crude yellow oil that was used without
further purification.
To a solution of this crude bis OTBS dienyl ether 53 in 10 mL of
CH2Cl2 at −78 °C was added tetraphenylporphyrin (2 mg, 0.003
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 8.6 Hz, 2H), 6.89
K
dx.doi.org/10.1021/jo4005074 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mmol). The sample was irradiated with a 275W sun lamp while
bubbling O2 through the solution. After irradiation for 45 min at −78
°C, the reaction mixture was concentrated in vacuo to give a pink oil.
Purification of this oil by SiO2 flash column chromatography (gradient,
2 → 20% Et2O/hexanes as eluent) gave bis endoperoxide 54 (0.057 g,
67% over 2 steps) as a pink solid. A sample of this solid was
crystallized from 1:1 hexanes/THF to obtain colorless X-ray quality
eluent) gave ester 57 as a white solid (0.027 g, 76%). mp. 132−133
1
°C; IR (thin film) 1731, 1684 cm−1; H NMR (300 MHz, CDCl3) δ
8.05 (d, J = 7.9 Hz, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H), 7.42 (m, 1H),
7.41 (d, J = 8.5 Hz, 2H), 7.22 (td, J = 7.6, 1.6 Hz, 1H), 6.90 (d, J = 8.7,
2H), 6.89 (m, 1H), 6.15 (dd, J = 10.4, 2.0 Hz, 1H), 5.80 (dt, J = 9.3,
2.0 Hz, 1H), 4.45 (d, J = 10.0 Hz, 1H), 4.24 (d, J = 10.0 Hz, 1H), 3.82
(s, 3H), 2.96 (m, 1H), 1.98 (m, 1H), 1.71 (m, 1H), 1.25 (d, J = 6.8
Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ
198.3, 165.9, 159.0, 145.0, 141.5, 134.2, 133.0, 130.9, 130.5, 129.9,
129.2, 128.0, 113.6, 94.2, 83.8, 75.0, 65.1, 55.2, 41.1, 24.0, 10.9, 7.0;
crystals. mp 120−122 °C; [α]20 = +94 (c 1.80, MeCN); IR (thin
D
film) 1243 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.18 (d, J = 8.4 Hz,
4H), 6.88 (d, J = 8.5 Hz, 4H), 6.58 (dd, J = 8.6, 5.6 Hz, 2H), 6.38 (d, J
= 8.3 Hz, 2H), 4.81 (d, J = 6.1 Hz, 2H), 4.64 (d, J = 11.2 Hz, 2H), 4.53
(d, J = 11.3 Hz, 2H), 3.81 (s, 6H), 3.04 (br s, 2H), 2.19−2.16 (m,
4H), 1.18 (t, J = 7.3 Hz, 6H), 1.01 (s, 18H), 0.24 (s, 12H); 13C NMR
(90 MHz, CDCl3) δ 158.6, 135.1, 131.8, 131.2, 127.8, 113.8, 103.5,
82.4, 74.2, 65.8, 55.2, 43.3, 25.7, 21.7, 18.0, 8.5, −2.4, −3.3; LRMS
(ESI) m/z (relative intensity) 811.6 (100%, M + H+). HRMS (ESI)
m/z calcd for [C44H67O10Si2]+, 811.4273, found 811.4238.
+
LRMS (ESI) m/z (relative intensity) 538.1 (10%, M + NH4 ); HRMS
(ESI) m/z calcd for [C24H29NO5I]+, 538.1091, found 538.1093.
3-Ethyl-3-(4-methoxybenzyloxy)-4-methyl-3,4-dihydro-1H-
benzo[c]chromene-2,6-dione (58). To a solution of aryl iodide 57
(0.020 g, 0.038 mmol) in 1 mL of DMF in a sealable tube was added
Pd(OAc)2 (1 mg, 0.004 mmol), Bu4NBr (5 mg, 0.02 mmol), Et3N (54
μL, 0.38 mmol) and 8 μL of MeOH. The tube was sealed and the
reaction mixture was warmed to 120 °C. After stirring for 14 h at 120
°C, the reaction mixture was cooled to room temperature, filtered
through Celite and concentrated in vacuo to give a crude yellow oil.
Purification of this oil by SiO2 flash column chromatography (10%
EtOAc/hexanes as eluent) gave cyclization product 58 as a yellow oil
2,2′-Diethyl-6,6′-dihydroxy-2,2′-bis-(4-(methoxy)-
benzyloxy)-bicyclohexyl-4,4′-diene-3,3′-dione (53). To a stir-
ring solution of bis endoperoxide 54 (0.036 g, 0.045 mmol) in 1 mL of
MeCN at 0 °C was added dropwise fluorosilicic acid (117 μL, 20−25
wt % in H2O, ∼ 0.2 mmol). After stirring for 40 min at 0 °C, H2O (1
mL) was added. The resulting solution was partitioned between
EtOAc (10 mL) and H2O (10 mL) and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The combined organic fractions
were dried over Na2SO4, filtered, and concentrated in vacuo to give
crude bis peroxide 55 as a yellow oil that was used without further
purification.
1
(8 mg, 56%). IR (thin film) 1721, 1719 cm−1; H NMR (360 MHz,
CDCl3) δ 8.37 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.57 (t, J =
7.6 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.77
(d, J = 8.6 Hz, 2H), 4.52 (d, J = 11.2 Hz, 1H), 4.19 (d, J = 11.2 Hz,
1H), 3.77 (s, 3H), 3.57 (d, J = 19.2 Hz, 1H), 3.35 (d, J = 19.4 Hz, 1H),
3.31 (q, J = 7.5 Hz, 1H), 2.17 (m, 1H), 1.80 (m, 1H), 1.18 (d, J = 7.3
Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H) ; 13C NMR (90 MHz, CDCl3) δ
207.4, 162.5, 159.2, 153.4, 136.6, 135.0, 130.2, 129.6, 128.5, 127.0,
121.4, 120.3, 113.8, 105.1, 84.6, 66.1, 55.3, 42.3, 36.1, 18.8, 14.9, 5.9;
To a stirring solution of the crude bis peroxide 55 in 1 mL of
CH2Cl2 at 0 °C was added PPh3 (0.035 g, 0.13 mmol). After stirring
for 30 min at 0 °C, the crude mixture was concentrated in vacuo to
give a crude yellow oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 15 → 30% EtOAc/hexanes as eluent) gave
lomaiviticinone core 7 (0.014 g, 57% over 2 steps) as a yellow oil
contaminated by a small amount of an inseparable unidentified
+
LRMS (ESI) m/z (relative intensity) 410.2 (100%, M + NH4 );
HRMS (ESI) m/z calcd for [C24H28NO5]+, 410.1967, found 410.1980.
ASSOCIATED CONTENT
* Supporting Information
■
compound. [α]20 = +131 (c 6.2, MeCN); IR (thin film) 3425, 1672
S
D
1
cm−1; H NMR (360 MHz, CDCl3, major isomer) δ 7.08 (d, J = 8.5
General experimental, details from the X-ray crystallographic
determination of 29 and 50 including CIF files, and copies of
1H and 13C NMR spectra for 20, 22, 29, 34, 35, 36, 37, 38, 47,
48, 49a, 50, 51, 52, 57, and 58. This material is available free of
charge via the Internet at http://pubs.acs.org.
Hz, 4H), 6.97 (d, J = 10.3 Hz, 2H), 6.82 (d, J = 8.4 Hz, 4H), 6.01 (d, J
= 10.2 Hz, 2H), 5.53 (s, 2H), 4.76 (d, J = 8.0 Hz, 2H), 4.41 (d, J =
10.3 Hz, 2H), 4.12 (d, J = 10.2 Hz, 2H), 3.77 (s, 6H), 2.71 (d, J = 8.4
Hz, 2H), 2.31 (m, 2H), 1.89 (m, 2H), 1.63 (m, 2H), 0.96 (t, J = 7.3
Hz, 6H); 13C NMR (90 MHz, CDCl3, major isomer) δ 195.3, 159.6,
153.9, 129.8, 127.7, 124.6, 114.0, 83.8, 66.7, 64.8, 55.2, 49.6, 21.4, 8.7;
LRMS (ESI) m/z (relative intensity) 573.2 (80%, M + Na+). HRMS
(ESI) m/z calcd for [C32H38O8Na]+, 573.2464, found 573.2449.
6,6′-Diethyl-6,6′-bis-(4-(methoxy)benzyloxy)-bicyclohexyl-
3,3′-diene-2,5,2′,5′-tetraone (56). To a solution of crude bis
peroxide 55 (0.0050 g, 0.0085 mmol) in 500 μL of acetic anhydride
was added pyridine (2 μL, 0.03 mmol). After 14 h of stirring at room
temperature, the reaction mixture was concentrated in vacuo to give a
crude yellow oil. Purification of this oil by SiO2 flash column
chromatography (gradient, 10 → 30% EtOAc/hexanes as eluent) gave
bis enedione 56 (0.014 g, 49% from 55) as a light yellow oil. IR (thin
film) 1691 cm−1; 1H NMR (360 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz,
4H), 6.87 (d, J = 8.5 Hz, 4H), 6.27 (br s, 4H), 4.88 (m, 2H), 4.43 (d, J
= 10.5 Hz, 2H), 3.84 (s, 6H), 3.79 (s, 2H), 2.08 (m, 2H), 1.94 (m,
2H), 0.95 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 197.5(2
carbons), 159.1, 139.2 (2 carbons), 129.9, 129.6, 113.5, 93.8, 82.2,
68.0,, 55.2,, 25.6, 7.7; LRMS (ESI) m/z (relative intensity) 564.2
AUTHOR INFORMATION
Corresponding Author
*E-mail: ksf@chem.psu.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation (CHE
0956458) is gratefully acknowledged. The X-ray facility is
supported by NSF CHE 0131112.
REFERENCES
■
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