From chiral ortho-benzoquinone monoketals to nonracemic indolinocodeines through diels-alder and cope reactions

Article abstract of DOI:10.1021/jo3014098

The S-dienol (-)-4 containing 10 carbons and one oxygen of the final product was prepared in 98.6% ee and 39% yield from cyclohexan-1,3-dione. It was attached to the aromatic ring as a monoether of catechol S-(-)-6 and subsequently subjected to oxidative ketalization in methanol. The allylated phenanthrofuran obtained was selectively oxidized at the terminal double bond. The fifth ring was completed by a one-pot amidation-cyclization process promoted by palladium acetate. The final homochiral indolinocodeine (-)-31 was obtained in 16 steps and 3.6% overall yield from cyclohexan-1,3-dione.

Full text of DOI:10.1021/jo3014098

Article
pubs.acs.org/joc
From Chiral ortho-Benzoquinone Monoketals to Nonracemic
Indolinocodeines through Diels−Alder and Cope Reactions
Jihong Gao, Josephine Orso Simon,† Russell Rodrigo,* and Abdeljalil Assoud*
Department of Chemistry, University of Waterloo Waterloo, Ontario, Canada, N2L 3G1
S
* Supporting Information
ABSTRACT: The S-dienol (−)-4 containing 10 carbons and
one oxygen of the final product was prepared in 98.6% ee and
39% yield from cyclohexan-1,3-dione. It was attached to the
aromatic ring as a monoether of catechol S-(−)-6 and
subsequently subjected to oxidative ketalization in methanol.
The allylated phenanthrofuran obtained was selectively
oxidized at the terminal double bond. The fifth ring was
completed by a “one-pot” amidation−cyclization process
promoted by palladium acetate. The final homochiral
indolinocodeine (−)-31 was obtained in 16 steps and 3.6%
overall yield from cyclohexan-1,3-dione.
quinones of Xestospongia species5,6 as well as the furanosteroid
ring systems of viridin and wortmannolone7 were synthesized
by application of these methods. In a concurrent effort, a
complex homochiral dienol 4 was prepared and subjected to
the same synthetic protocol with methyl vanillate to produce a
chiral phenanthrofuran.8 Several theoretical uncertainties and
practical shortcomings were left unaddressed, but the work did
constitute the first example of the successful use of a
homochiral reactant in the three-step oxidative ketalization,
intramolecular cycloaddition, and Cope rearrangement se-
quence. In this paper, we modify the structures of the substrates
to improve overall yields substantially and overcome some
serious experimental difficulties that plagued the existing
process. We are also able to gain some insights into the
stereochemical options chosen by the reaction and to complete
a synthesis of the fifth ring of a morphine-like system.
INTRODUCTION
■
The prolific Diels−Alder chemistry of transient ortho-
benzoquinonoid monoketals has captured the attention of
many research groups.1 The presence of an s-cis diene unit
constrained in the six-membered ring together with a
conjugated carbonyl group at C-1 confers remarkable diene
and dienophilic reactivity on these structures and results in
facile dimerization2 during their preparation. The diene
reactivity3 is well-known and has been exploited imaginatively
by incorporating a dienophilic unit in one of the pendant alkoxy
groups of the ketal, resulting in intramolecular cycloadditions
that generate bicyclo[2,2,2]octenone adducts4 in good yields.
In seeking to solve a difficult problem in our research
program in natural product synthesis, we extended the scope of
the intramolecular cycloaddition by incorporating a diene unit
in the ketal. This was easily accomplished by merely oxidizing a
guaiacol in the presence of a dienol, used in excess to retard
dimerization of the quinone ketal. The resulting ketals 1 reacted
in situ by Diels−Alder cycloadditions to form endo adducts 2
(quinone as diene) and 3 (quinone as dienophile). The relative
yields of each varied with the nature of the substituent at C-4 of
the guaiacol in the expected manner, but the bridged adducts 2
always predominated (Scheme 1).
The excess dienol was recovered by vacuum distillation, but
this becomes experimentally troublesome when larger, more
complex dienols like 4 are used. The synthetic value of the
reaction was much enhanced when we discovered that the
predominant bridged adducts 2 were smoothly transformed
into naphthofuranones 3 with the endo stereochemistry, by
thermally induced [3,3] sigmatropic rearrangements.5 In
addition, the two-step sequence was found to be tolerant of
major structural variations in both the guaiacol and dienol
segments of the o-benzoquinone ketal. The pentacyclic
RESULTS AND DISCUSSION
■
Synthesis of a New Substrate for the Three-Step
Process. Our initial attempts to increase yields were directed at
optimizing the intramolecular Diels−Alder reaction of the o-
benzoquinone monoketals. We therefore made several
structural adjustments to the dienol component to improve
its electron-donating character. It was extremely disappointing
to find that incorporating an ethoxy group in the dienol
reactant as in 5 was of little value in the reaction with methyl
vanillate (Scheme 2).
Special Issue: Robert Ireland Memorial Issue
Received: July 25, 2012
Published: September 11, 2012
© 2012 American Chemical Society
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Scheme 1. Diels−Alder Reactions of o-Benzoquinone Monoketals
Scheme 2. Unsuccessful Attempts To Employ an Electron-Rich Dienol in the Reaction
Scheme 3. Pd(II)-Catalyzed Coupling of Catechol with a Dienyl Carbonate
Every variation of solvent, temperature, time, and ratio of
reactants that we tested did not help and nor did the presence
of sodium bicarbonate in the mixture. Similar failure attended
our modifications of the position and number of ester groups
on the guaiacol. Although frustrating, these results seemed to
indicate that the problem resided with formation of the ketal
and not its subsequent reaction. We therefore set out to explore
the feasibility of attaching the dienol to the aromatic reactant as
a phenyl ether and then conducting the oxidative dearomatiza-
tion in methanol, now acting as both a solvent and nucleophile.
There are ancillary advantages to this strategy. The methanol, a
less hindered nucleophile, is in vast excess, but the dienol, a
bulky secondary alcohol, was not. The methanol is easily
removed after the reaction, unlike the high boiling dienol.
However, there is an obvious hazard associated with this plan.
The configurational integrity at C-1 of the dienol had to be
assured in any preparation of such a catechol monoether. In
order to avoid difficult regiochemical obstacles, we decided to
exclude the ester substituent and settled on the simpler catechol
monoethers S-(−)-6 as our initial synthetic objective. Our
starting material, 1,3-cyclohexanedione, was allylated at C-2,9
O-methylated,10 and reacted with freshly prepared vinyl
magnesium bromide. The C-1 keto group of the resultant 3-
ethenyl-2-(2-propenyl)-2-cyclohexen-1-one was reduced with
catecholborane in the presence of 20 mol % of the CBS reagent
R-oxazaborolidine, at −78 °C for 18 h to form S-(−)-4 in 89%
yield11 with 98.6% ee and [α]D = −272. This was established by
chromatography on an OD-H column (see Supporting
Information). The use of catecholborane at −78 °C compared
to our earlier reduction8 with borane at 35 °C largely avoids
hydroboration of the double bonds, improving the yield and ee
of the product considerably. Having established a reliable,
reproducible four-step synthetic route to S-(−)-4 in 39% yield
from 1,3-cyclohexanedione, we turned our attention to the next
objective, the homochiral catechol monoether S-(−)-6. This
was not a trivial undertaking because any method contemplated
for construction of the ether link could not risk disturbing the
absolute configuration at C-1 of the dienol S-(−)-4. Although
some examples were available in the literature of Mitsunobu
coupling of phenols with secondary allyl alcohols,12 the reaction
between S-(−)4 and catechol failed under every set of
conditions we tried and, indeed, we could not find Mitsunobu
conditions that made cyclohexanol react with catechol in good
yield. Another published protocol that was attempted was the
Larock Pd-catalyzed coupling of phenols with allylic carbo-
nates.13 This did produce an ether 7 in 50% yield (Scheme 3),
and even though the reaction mechanism implied that some
racemization at C-1 was likely, we were encouraged enough to
attempt the coupling with S-(−)-4 in order to access an ether
that could be tested in the oxidative dearomatization sequence.
However, our enthusiasm was premature because the reaction
failed under five different sets of experimental conditions.
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Scheme 4. Preparation of Aromatic Ether S-(−)-6
The one remaining option, the reliable nucleophilic aromatic
substitution, was well-known and well-tested. The best
prospects of success are with fluoroaromatic substrates bearing
an electron-withdrawing group (EWG) ortho or para to the
fluorine. Again, success was elusive because our initial choices
and combinations of EWG (CHO, CO2Me) and base (NaH)
were ineffective. However, o-fluorobenzonitrile, in THF at 0−
25 °C, with KHMDS as the base14 did provide a substitution
product 8, [α]D −304.8, in 89% yield. Although the reduction
of an aromatic nitrile to an aldehyde is a well-known process,
this one was tricky. A modified hydride reagent, preformed
from N,N′-dimethylethylenediamine and LAH15 was used at 0
°C, and the precooled nitrile dissolved in THF was added also
at 0 °C and stirred for 1.5 h to produce the aldehyde 9 in 84%
yield ([α]D = −266). If the temperature is not carefully
controlled in this manner, over-reduction to the benzylamine is
followed upon acidic workup by condensation with the
aldehyde to form an imine 10 whose presence was revealed
discuss and interpret the differences observed in products and
yields. The oxidative ketalization of S-6 in methanol (solvent
and nucleophile) produced diastereomeric ketals 12 (SS) and
13 (RS). Similar ketals, 14 (SS) and 15 (RS) are formed8 from
methyl vanillate and S-(−)-4 in THF. These transient
intermediates react in intramolecular cycloadditions to form
endo adducts with the quinonoid segment acting as a diene (17
and 19) and as a dienophile (16 and 18). Adducts 16 and 17
arise from SS-12 (R = H) in a combined yield17 of 64%, while
those from SS-14 (R = CO2Me) were produced in much lower
yields (11% for 18 and 17% for 19). Our new strategy produces
useful adducts in more than double the previous yields and
amply rewards the effort involved in the four-step attachment of
S-(−)-4 to the aromatic segment. Furthermore, this increase
occurs in spite of the greater dienophilicity of the C4−C5
double bond in 14 (R = CO2Me) over 12 (R = H). The failure
of dienol 5 (Scheme 2) to react with methyl vanillate can thus
be understood in terms of the lesser nucleophilicity of 5 in the
oxidative ketalization step and the intervention of deleterious
side reactions instead. Methanol, a nucleophile superior to the
bulky secondary allylic alcohols 4 and 5 is also employed as the
solvent in the new procedure.
An interesting divergence is evident in the reaction of RS
ketals 13 and 15. For steric reasons, neither intermediate is able
to assume a conformation that assures endo cycloaddition. Exo
addition aided by the presence of the C-4 ester in 15 is favored,
and the adduct 20 was isolated in 13% yield.8 The ketal 13 (R =
H), however, is much more prone to dimerization and converts
to the expected18a dimer 21 in 28% yield by an intermolecular
Diels−Alder reaction. We have secured an X-ray of ( )-21 to
confirm its structure and relative stereochemistry and note that
both monomer units of the compound possess the RS
configuration of the ketal 13 (Figure 1). The combined yield
of three products 16, 17, and 21 isolated from the oxidative
ketalization of S-(−)-6 was 92%. Unlike our earlier work,8
where the dienol S-(−)-4 had to be used in at least a 5-fold
excess, the present procedure did not involve a tedious
separation of a surplus reactant. The solvent/nucleophile
1
by a H NMR signal at 8.05 ppm, instead of the usual 10.46
ppm for the desired aldehyde (Scheme 4)
The next step, the Baeyer−Villiger oxidation of (−)-9, was
best accomplished with 30% aqueous H2O2 and 20 mol % of
diphenyl diselenide,16 which is converted to phenylseleninic
acid, the actual oxidizing agent. The formate 11 is obtained in
94% yield and hydrolyzed with aqueous methanolic potassium
carbonate to furnish the catechol monoether (−)-6 in 78%
yield. Thus, the much desired attachment of the dienol (−)-4
to the aromatic segment was achieved with the C-1
stereochemistry preserved in four steps, without the need for
chromatographic purification of any of the intermediates 8, 9,
or 11. The crucial ether (−)-6 was produced in 55% yield from
S-(−)-4, which in turn is available in 39% overall yield from
commercial 1,3-cyclohexanedione.
Oxidative Ketalization of (−)-6. The catechol monoether
6 contains all of the atoms correctly arranged for initiating and
completing the benzoquinone monoketal sequence by oxidative
dearomatization. In Scheme 5, we outline and compare the
pathways followed by two very similar reactants and attempt to
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Scheme 5. Oxidative Ketalizations of Catechol Monoethers
Figure 1. X-ray structure of ( )-21.18b
methanol was simply removed in vacuo. Since the isolated
product yield is almost 100%, and each individual product can
be traced to its ketal precursor, it can be reasonably argued that
the ratio (yield of 16 + 17):(yield of 21) is approximately equal
to the relative abundance of the SS and RS ketals formed in the
oxidative dearomatization step.19 This implies that a modest
diastereoselectivity (64:28 or 2.3:1) exists in favor of 12 (SS)
over 13 (RS) during their formation.
Control of stereochemistry in the formation of o-
benzoquinone monoketals has attracted some attention
recently.20 In one study, a chiral ethanol unit was preattached
to the ortho-position of a phenol and subsequent intramolecular
ketalization conducted with a hypervalent iodine reagent to
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Scheme 6. Oxidative Processing of Allyl Phenanthrofurans
Scheme 7. Hydration and Cyclization of Nitriles 24 and 25
generate RR and RS (or SS and SR) diastereomers of
spiroketals. Excellent diastereoselection (95:5) in favor of the
SS and the RR diastereomers was achieved in some instances.
The chiral auxiliary (the ketal) was then used to induce
asymmetry in a reaction of the neighboring carbonyl group. It
was removed by hydrolysis and, unlike our chiral dienol, not
involved in subsequent synthetic manipulations.
16 and 17 was converted to the acetoxy phenanthrofuran 22 in
70% yield, with [α]D = −208.
The oxidative modification of the allyl substituent in 22 was
achieved by selective hydroxylation of C2′−C3′ double bond
with OsO4/DMAP. The selectivity of this reaction may be
attributed to better steric accessibility of the reagent to this
bond rather than to C7a−C8 or to better π-stacking21 of the
osmate/DMAP complex with the aromatic ring of the substrate.
The diastereomeric mixture of C2′−C3′ diols was then cleaved
with sodium periodate to produce the desired aldehyde 23
([α]D = −51.8). This two-step oxidative degradation was
completed in 85.5% yield.
Further Synthetic Elaboration of Adducts 16 and 17.
The availability of advanced homochiral intermediates 16 and
17 in good yields persuaded us to attempt the incorporation of
a nitrogen atom and closure of the fifth ring. Success in this
initiative would afford access to a morphine-like system. The
inseparable mixture of 16 and 17 was treated briefly with TFA
and acetic anhydride to aromatize and acetylate 16 to
phenanthrofuran 22, leaving bridged adduct 17 unaffected.
Separation of 17 from 22 was now possible by column
chromatography. The pure bridged adduct was heated in
tetrachloroethane at 140 °C for 4 days to effect the desired
Cope rearrangement, which proceeded directly to the phenol
this time. Again, a small amount of acetic anhydride was added
for in situ acetylation of the phenol to reduce its decomposition
during the reaction. Another practical advantage of our current
strategy became apparent in this step. The absence of the ester
substituent in 17 (unlike 19) meant that an aromatic product
was formed directly in the rearrangement. Thus the separation
of the starting material 17 from an equilibrium mixture that was
necessary earlier8 was avoided. In this manner, the mixture of
The nitrogen atom was introduced by conversion of the
aldehyde to the nitrile 24. Many methods are known for this
transformation, but the most convenient for our substrate was a
one-pot, two-step process through a dimethyl hydrazone
intermediate22 with magnesium monoperoxyphthalate
(MMPP) in methanol. It involved mild conditions and a
simple workup, yielding the desired nitrile (Scheme 6) after
column chromatography (77%, [α]D = −89.8).
A Cope elimination of N,N-dimethylhydroxylamine from the
hydrazone-N-oxide is probably responsible for formation of the
product. To reach our next objective, to connect the nitrogen
to either terminus of the C7a−C8 double bond, we envisaged
the intermediacy of a primary amide in place of the nitrile. In
selecting a method for hydrating the nitrile, we were careful to
avoid methods that may cause hydrolysis of the phenyl acetate.
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After evaluating the options, we settled on a recently
published23a Pd-catalyzed hydration of nitriles in aqueous
THF with acetamide. The latter reagent used in a 4-fold excess
exchanges the elements of water with the substrate, and in spite
of this source of water for hydration of the nitrile, the additional
water in the solvent is absolutely necessary. Without it, no
reaction occurs, but its actual role has not been assigned. In our
studies of the hydration, we found that the use of catalytic
amounts of Pd(II) resulted in incomplete reaction, and
stoichiometric quantities of Pd(OAC)2 took the reaction to
completion only after 3 days. The product was not the amide
26 that we had anticipated, but a lactam 27 (93% yield, [α]D =
−158.5). It was presumably formed from the initial product 26
by the intervention of Pd(II) and the C2′−C3′ double bond. A
mechanistic proposal23 reflecting these features is outlined in
Scheme 7. It has been suggested23b that bimetallic species are
intermediates in the hydration step. The second step is more
recognizable and similar to the cyclization of carboxamides and
sulforamide with allylic double bonds.24
In addition, the coupling constant of H-5β is significantly
different from our data, which are the same in all of the
indolinocodeines 27−31 that we synthesized in this work. The
NMR data recorded for compound 32, V in the same 1969
paper, are much closer to our’s, however. The MS of 32 has
also been reported28 and is similar to the fragmentation pattern
we observe for 31 (SI), which contains one double bond less. It
therefore displays each ion at 2 mass units more than the
corresponding ion in 32.
Our synthetic indolinocodeine 31 ([α]D = −169) has
structural and stereochemical similarities to (+)-cepharamine
33 (the unnatural enantiomer) synthesized29 by Schultz in
1998 to test his hypothesis that valuable analgesic activity may
reside in such compounds. Both 31 and 33 combine the C-13
stereochemistry of the morphine alkaloids with the pyrrolidine
ring structure of the hasubanan alkaloids. The unnatural
enantiomers of the morphine alkaloids, like the natural
Hasubanans and Isohasubanans,30 show no pain relieving
activity. Unfortunately, no pain relief data have been published
for (+)-cepharamine or for any indolinocodeine as yet.
The structure of 27 was supported by the presence of two
doublets at δ 5.59 (1H, J = 9.6 Hz) and δ 6.39 (1H, J = 9.6 Hz)
1
in its H NMR spectrum. The HRMS showed the molecular
EXPERIMENTAL SECTION
■
ion at m/z 311.1157 corresponding to a formula of C18H17NO4.
The acetyl group in 24 was replaced with methyl (25) ([α]D =
−108.3) by hydrolysis (NaOH, aqueous MeOH) and
methylation (Me2SO4/K2CO3/acetone). Chiral HPLC of a
sample of 25 on an OD-H column in 1% isopropyl alcohol/
hexane indicated an ee of 98.6% (see Supporting Information).
The C-3 methoxylated pentacyclic lactam was produced in the
same way in comparable yield (91%, [α] = −172). Both 27 and
28 were N-methylated with NaH/MeI to form 29 and 30 ([α]D
= −167, 89%), respectively. Reduction of the amide in 29 was
complicated by sensitivity of the 3-acetyl group to hydride
reducing agents, but 30 was converted to the amine 31 in good
yield (77%, [α]D = −179) with Red-Al in benzene. This
completes the synthesis of a pentacycle with an absolute
configuration similar to that of (−)-codeine and a pyrrolidine
ring similar to that of (+)-cepharamine 33. Ring systems such
as 31 have been named indolinocodeine.25 Our example was
synthesized in 3.6% overall yield from cyclohexan-1,3-dione in
16 steps (Scheme 8).
2-Allyl-1,3-cyclohexanedione.9 To a 5% aqueous KOH solution
(250 mL, 0.223 mol) were added cyclohexanedione (25 g, 0.223 mol)
and copper powder (14.2 g, 0.223 mol). While stirring, allyl bromide
(26 mL, 0.307 mol) was added dropwise within 1 h, and the reaction
mixture was stirred at room temperature for 2 h more. After filtration,
the residue was stirred in CH2Cl2 (250 mL). The mixture was filtered
again, and the filtrate was dried over Na2SO4 and evaporated to afford
the solid. Washing with ether (2 × 50 mL) gave a white solid product
(19.3 g, 57%) which was used without further purification in the next
1
step: H NMR (300 MHz) δ 1.95 (2H, m), 2.43 (2H, t, J = 6.4 Hz),
2.55 (2H, t, J = 6.4 Hz), 3.05 (2H, d, J = 6.4 Hz), 5.01 (1H, d, J = 10.2
Hz), 5.10 (1H, d, J = 17.3 Hz), 5.82 (1H, m, J = 17.3, 10.2, 7.2 Hz).
2-Allyl-3-methoxy-2-cyclohexenone.10 2-Allyl-1,3-cyclohexane-
dione (20 g, 0.13 mol) was refluxed with Me2SO4 (11.3 mL, 0.14 mol)
and K2CO3 (20.7 g, 0.15 mol) in acetone (300 mL) at 80 °C. After 3
h, acetone was removed in vacuo, and the residue was washed with
water (250 mL) and extracted with EtOAc (2 × 300 mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo. Purification
by distillation (0.01 mm, 82 °C) gave the product (18.7 g, 87%) as a
pale yellow liquid: 1H NMR (300 MHz) δ 1.96 (2H, m), 2.32 (2H, t, J
= 6.2 Hz), 2.55 (2H, t, J = 6.2 Hz), 3.0 (2H, d, J = 6.2 Hz), 3.78 (3H,
s), 4.85 (1H, dd, J = 10.2, 1.8 Hz), 4.95 (1H, dd, J = 17.3, 1.8 Hz),
5.75 (1H, m, J = 17.3, 10.2, 6.2 Hz).
Scheme 8. Final Steps in the Synthesis of
(−)-Indolinocodeine 31
3-Ethenyl-2-(2-propenyl)-2-cyclohexen-1-one. Vinylmagnesi-
um bromide (1.0 M in THF, 80 mL, 79.5 mmol) was added dropwise
over 1 h to a solution of 2-allyl-3-methoxy-2-cyclohexenone (8.8 g, 53
mmol) in dry THF (120 mL) at 0 °C. The mixture was stirred for 5 h.
A 3 N aqueous HCl solution was added until pH 2−3 was reached,
and the resulting solution was stirred for 2 h more at room
temperature. The reaction was extracted with ether (2 × 150 mL),
dried over Na2SO4, and concentrated in vacuo. The residue was
purified on a silica column (EtOAc/hexanes 1:1) to give the product
1
(7 g, 81%) as yellow oil: H NMR (300 MHz) δ 2.00 (2H, m), 2.43
(2H, t, J = 6.6 Hz), 2.51 (2H, t, J = 6.6 Hz), 3.19 (2H, d, J = 6.0 Hz),
4.93 (2H, m), 5.45 (1H, d, J = 11.0 Hz), 5.67 (1H, d, J = 17.5 Hz,),
5.78 (1H, m, J = 17.8, 9.5, 6.0 Hz), 6.87 (1H, dd, J = 17.5, 11.0 Hz).
Anal. Calcd for C11H14O: C, 81.48; H, 8.64. Found: C, 81.57; H, 8.80.
(S)-3-Ethenyl-2-(2-propenyl)-2-cyclohexen-1-ol 4.11 To a
solution of 3-ethenyl-2-(2-propenyl)-2-cyclohexen-1-one (8 g, 0.049
mol) in dry toluene (200 mL) and methyl oxazaborolidine (1.0 M in
toluene, 7.4 mL, 0.0074 mol) at −78 °C was added a solution of
catecholborane (9.5 mL, 0.089 mol) in toluene (80 mL) via syringe
pump over 1 h. After stirring for 18 h at −78 °C, NaOH solution (1 N,
600 mL) was added; the resulting solution was stirred at room
temperature for an additional 30 min. The organic phase was
In the mid to late 1960s and early 1970s, the rearrangement
of the morphine ring system to the indolinocodeine via bromo-
and iodocodeines was studied by two groups of Japanese26 and
British27 researchers. One of the products isolated in the course
of their work was assigned a structure and stereochemistry
1
identical to that of synthetic product 31. Only fragmentary H
NMR data at 60 MHz were provided,26 and some differences
were apparent between the spectra (Table 1).
It does appear from the data in the table that the chemical
shift of H-10 in compound VII has been incorrectly recorded.
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1
Table 1. Comparison of Selected H NMR Chemical Shifts (ppm) and Coupling Constants (Hz) for Indolinocodeines 31 and
3226
NMe
OMe
H-5β
H-9, H-10
H-1, H-2
(1) 31, 300 MHz, CDCl3, current work
(2) 31 (VII in ref 26) 60 MHz, CDCl3
(3) 32 (V in ref 26) 60 MHz, CDCl3
2.37 (s)
2.42 (s)
2.47 (s)
3.86 (s)
3.90 (s)
3.88 (s)
4.73, 4.86 (dd, J = 10.3, 7.0)
4.72 (dd, J = 6.6, 3.0)
4.89 (t, J = 7.2)
5.79, 6.40 (dd, J = 9.6)
5.78, 6.70 (dd, J = 10)
5.72, 6.42 (dd, J = 10)
6.62, 6.66 (dd, J = 8)
6.68 (s)
6.6 (s)
separated, and the aqueous phase was extracted with diethyl ether (2 ×
300 mL). The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. The resulting oil was purified by flash
chromatography (hexane/EtOAc = 3:1) to give the product (7.2 g,
36.1, 62.9, 66.5, 83.6, 115.8, 134.5, 134.5, 137.7, 161.6; HRMS(EI) m/
z calcd for C13H20O2 M+ 208.1463, found 208.1461. Anal. Calcd for
C13H20O2: C, 74.96; H, 9.68. Found: C, 74.70; H, 9.40.
3-Vinylcyclohex-2-en-1-yl Methyl Carbonate. Dimethyl py-
rocarbonate (40 mmol) was added dropwise to a stirred solution of
allylic alcohol (20 mmol) and DMAP (2.5 mmol) in dry CH2Cl2 (50
mL) at 0 °C (some bubbling was observed). The ice bath was
removed and the reaction stirred for 1 h at rt. The solvent was
evaporated, and the residue was taken up in CH2Cl2 (50 mL) and
treated with dimethyl pyrocarbonate (40 mmol). This evaporation/
retreatment with dimethyl pyrocarbonate sequence was repeated until
no starting material remained by TLC. Purification by silica gel
chromatography using 1:1 hexane/ether afforded the 3-vinylcyclohex-
2-en-1-yl methyl carbonate in 73% yield as a yellow oil: IR (neat)
1
89%) as light yellow oil: H NMR (300 MHz) δ 1.56 (1H, d, J = 6.9
Hz), 1.65−1.85 (4H, m), 2.10−2.35 (2H, m), 3.10 (2H, d, J = 6.0 Hz),
4.15 (1H,br), 5.00−5.20 (3H, m), 5.30 (1H, d, J = 17.2 Hz), 5.84 (1H,
m, J = 17.2, 11.0, 6.0 Hz), 6.76 (1H, dd, J = 17.2, 11.0 Hz); 13C NMR
(75 MHz) δ 17.5, 25.0, 31.8, 34.3, 68.2, 114.0, 115.4, 132.9, 134.6,
135.0, 136.7; LRMS(EI) 164 (6), 123 (100); HRMS(EI) m/z calcd for
C11H16O M+ 164.1201, found 164.1200; [α]D = −271.5 (c = 0.73,
CHCl3); ee = 98.66% (see Supporting Information).
3-(1-Ethoxyethenyl)-2-allyl-2-cyclohexen-1-one. tert-Butyl-
lithium (38 mL, 64 mmol, 1.7 M in hexane) was added dropwise to
a solution of freshly distilled ethyl vinyl ether (8.5 mL, 84 mmol) in
anhydrous THP (30 mL) at −78 °C under N2. The solution turned
yellow, and it was stirred for 10 min at −78 °C and for 40 min at 3−5
°C (at this temperature, the yellow precipitate redissolved). After the
reaction was recooled to −78 °C, the solution was diluted with 50 mL
of dry THF, and 2-allyl-3-methoxy-2-cyclohexenone (7 g, 42 mmol) in
30 mL of dry THF was added. Stirring was continued for 15 min and
the mixture warmed to 0 °C for 50 more minutes. The solution was
diluted with ether and brine, extracted with ether (3 × 50 mL), washed
once with water and brine, dried, and concentrated. Flash
chromatography (2:1 EtOAc/hexane) gave 6.30 g of a mixture of
alcohols. To this mixture were added 40 g of silica gel and 100 mL of
dry CH2Cl2 and stirred for approximately 2 h (monitoring by TLC) at
rt. The suspension was filtered, concentrated, and purified by silica gel
chromatography (1:3 EtOAc/hexane) to give 3-(1-ethoxyethenyl)-2-
allyl-2-cyclohexen-1-one (6 g, 70%) as a yellow oil: IR (neat) 2977,
1674, 1636, 1610, 1273 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.31
(3H, t, J = 7.0 Hz), 2.01 (2H, m), 2.40 (2H, t, J = 6.5 Hz), 2.52 (2H, t,
J = 6.5 Hz) 3.15 (2H, d, J = 6.0 Hz), 3.75 (2H, q, J = 6.5 Hz), 4.15
(1H, d, J = 2.3 Hz), 4.21 (1H, d, J = 2.3 Hz), 4.90 (2H, m), 5.82 (1H,
ddt, J = 15.0, 9.6, 6.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.3, 22.4,
29.9, 31.2, 38.1, 63.1, 85.5, 114.8, 134.3, 136.7, 152.8, 159.7, 199.2;
HRMS(EI) m/z calcd for C13H18O2 M+ 206.1279, found 206.1307.
3-(1-Ethoxyethenyl)-2-allyl-2-cyclohexen-1-ol 5. Compound
3-(1-ethoxyethenyl)-2-allyl-2-cyclohexen-1-one (5.7 g, 27.7 mmol) was
added dropwise to a suspension of LiAlH4 (1.1 g, 30.5 mmol) in 100
mL of dry ether at 0 °C. The resulting mixture was stirred for 1 h at 0
°C. The reaction was quenched with two spatulas of Na2SO4·10 H2O,
10 mL of 1 N NaOH, and 20 mL of H2O. The suspension was then
filtered through a Celite pad to remove the lithium salts and the filtrate
extracted with ether (3 × 100 mL). The organic layer was washed with
water and brine, dried, and concentrated to give product 5 (4.3 g,
1
2943, 1744, 1607, 1442, 1270 cm−1; H NMR (CDCl3, 300 MHz) δ
1.65−2.30 (6H, m), 3.75 (3H, s, OCH3), 5.10 (2H, m), 5.20 (1H, d, J
= 17.5 Hz), 5.75 (1H, br), 6.34 (1H, dd, J = 17.5, 10.8 Hz); 13C NMR
(CDCl3, 75 MHz) δ 18.2, 23.3, 28.0, 54.2, 72.3, 113.5, 125.2, 138.6,
140.8, 155.2.
2-[(3-Vinylcyclohex-2-en-1-yl)oxy]phenol 7. To a flask were
added 3-vinylcyclohex-2-en-1-yl methyl carbonate (120 mg, 0.66
mmol), catechol (145 mg, 1.32 mmol), PPh3 (28 mg, 0.10 mmol),
Pd(OAc)2 (6 mg, 0.026 mmol), and 10 mL of CH2Cl2. The resulting
mixture was stirred under reflux for 12 h. The solvent was evaporated,
and the residue was purified by flash chromatography using ether/
1
hexane (1:1) as eluent to give 7 (70 mg, 50%) as a yellow oil: H
NMR (CDCl3, 300 MHz) δ 1.69−2.41 (6H, m), 4.93 (1H, br), 5.07
(1H, d, J = 10.7 Hz), 5.26 (1H, d, J = 17.5 Hz), 5.69 (1H, s, OH), 5.85
(1H, br), 6.34 (1H, dd, J = 17.5, 10.7 Hz), 6.85 (4H, m); 13C NMR
(CDCl3, 75 MHz) δ 18.8, 23.7, 28.4, 74.7, 113.4, 113.6, 114.5, 121.6,
123.2, 128.4, 138.8, 140.3, 144.5, 146.6; HRMS(EI) m/z calcd for
C14H16O2 M+ 216.1150, found 216.1138.
(S)-2-[(2-Allyl-3-vinylcyclohex-2-en-1-yl)oxy]benzonitrile 8.
The general method of Wandless and co-workers14 was employed.
NaHMDS (1.0 M in THF, 60 mL, 60 mmol) was added dropwise over
1 h to a solution of (S)-4 (7.5 g, 46 mmol) and 2-fluorobenzonitrile
(7.2 g, 60 mmol) in dry THF (180 mL) at 0 °C. The mixture was
allowed to warm to room temperature and was stirred for 3 h. CH2Cl2
(400 mL) was added and washed once with saturated aqueous NH4Cl
(300 mL). The aqueous layer was back-extracted once with CH2Cl2
(300 mL). The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified on a silica column
(EtOAc/hexanes 1:4) to give the product (10.8 g, 89%) as a yellow oil:
1H NMR (300 MHz) δ 1.63−1.71 (2H, m), 1.85−2.17 (3H, m),
2.37−2.44 (1H, m), 2.87−2.95 (1H, dd, J = 15.7, 7.6 Hz), 3.19−3.25
(1H, dd, J = 15.7, 4.8 Hz), 4.82 (1H, br), 4.90−5.00 (2H, m), 5.16
(1H, d, J = 11.0 Hz), 5.34 (1H, d, J = 17.4 Hz), 5.79 (1H, m), 6.78
(1H, dd, J = 17.4, 11.0 Hz), 6.93−7.03 (2H, m), 7.45−7.56 (2H, m);
13C NMR (75 MHz) δ 17.5, 25.0, 27.5, 34.2, 75.1, 103.4, 113.8, 114.9,
115.7, 116.6, 120.7, 130.9, 134.0, 134.1, 134.3, 135.4, 136.0, 160.4;
LRMS(EI) 265(2.2), 147(100), 105(35), 91(35); HRMS(EI) m/z
calcd for C18H19ON M+ 265.1467, found 265.1465. Anal. Calcd for
1
75%) as a colorless oil: IR (neat) 3368, 2977, 1635, 1606 cm−1; H
NMR (CDCl3, 300 MHz) δ 1.31 (3H, t, J = 7.0 Hz), 1.64 (4H, m),
2.15 (2H, m), 3.04 (2H, d, J = 6.0 Hz), 3.75 (2H, q, J = 7.0 Hz), 3.95
(1H, d, J = 1.9 Hz), 4.05 (1H, d, J = 1.9 Hz), 4.14 (1H, br), 5.02 (1H,
d, J = 10.3 Hz), 5.06 (1H, dd, J = 17.2, 1.7 Hz), 5.85 (1H, ddt, J = 17.2,
10.3, 6.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.5, 17.8, 29.6, 31.4,
54
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C18H19ON: C, 81.51; H, 7.17. Found: C, 81.91; H, 6.72; [α]D
−304.8 (c = 1.3, CHCl3).
=
the methanol was removed in vacuo, the residue was extracted with
EtOAc (2 × 40 mL), washed with water (50 mL) and brine (40 mL),
dried, and evaporated. The residue was purified on a silica column
(CH2Cl2/hexane/CH3OH = 5:1:0.1) to give the endo-16 and bridged
compound 17 mixture (714 mg, 64%, endo/bridged = 1.2:1) as a
yellow oil and the dimer 21 (312 mg, 28%) as a yellow solid. The
dimer 21 was crystallized from the mixture using CH2Cl2/pentane as
small prisms, and X-ray was obtained. The endo-16 and bridged
compound 17 mixture could not be separated in any solvent system;
therefore, it was used directly for the next reaction.
(S)-2-[(2-Allyl-3-vinylcyclohex-2-en-1-yl)oxy]benzaldehyde
9.15 Ice cold N,N′-dimethylethylenediamine (1.5 mL, 0.0139 mol) was
added via cannula to a suspension of LAH (0.53 g, 0.0139 mol) in dry
THF (30 mL) at −78 °C under argon. The suspension was stirred for
1 h, and hydrogen was released through a bubbler. Then the mixture
was diluted with dry THF (24 mL) and allowed to warm to 0 °C.
To the above mixture was added a cooled solution of benzonitrile 8
(2.45 g, 0.0093 mol) in THF (20 mL), and the mixture was stirred at 0
°C for 1.5 h. Cold 3 N HCl (30 mL) was added until the pH reached
2−3 and stirring continued for 10 min. The mixture was extracted with
EtOAc (3 × 50 mL), and the combined organic layer was washed
successively with saturated aqueous NaHCO3 (30 mL) and brine (20
mL), dried, and concentrated to give the product used directly without
purification for the next step. For the purpose of accurate rotation
measurement, the residue was purified on a silica column (EtOAc/
1
Dimer Compound 21: H NMR (300 MHz) δ 1.15−1.75 (4H,
m), 1.85−2.15 (5H, m), 2.16−2.30 (2H, m), 2.65−2.85 (2H, m),
2.86−3.05 (2H, m), 3.15−3.25 (3H, m), 3.30 (1H, s), 3.42 (4H, br),
3.49 (3H, s), 3.79 (1H, br), 4.24 (1H, br), 4.87−4.97 (4H, m), 5.02−
5.09 (2H, m), 5.21−5.27 (2H, dd, J = 17.3, 10.0 Hz), 5.50−5.72 (2H,
m), 5.75−5.82 (1H, t, J = 7 Hz), 6.05−6.13 (1H, d, J = 10 Hz), 6.27−
6.35 (1H, t, J = 7 Hz), 6.45−6.55 (1H, dd, J = 10 Hz, J = 4 Hz), 6.58−
6.75 (2H, m); 13C NMR (75 MHz) δ 17.5, 17.7, 24.9, 24.9, 28.4, 29.3,
30.8, 31.8, 32.9, 40.0, 41.1, 42.4, 49.7, 50.6, 53.0, 72.1, 72.3, 96.9,
100.2, 114.4, 114.8, 115.3, 115.5, 127.3, 129.4, 133.1, 133.4, 134.4,
134.4, 134.4, 134.6, 135.2, 136.1, 146.8, 193.8, 202.5; [α]D = −118.6 (c
= 0.57, CHCl3); mp 52−54 °C.
1
hexanes = 1:2) to give the product (2.1 g, 84%) as a yellow oil: H
NMR (300 MHz) δ 1.72−1.82 (3H, m), 2.08−2.21 (2H, m), 2.42
(1H, m), 2.87−2.95 (1H, dd, J = 15.7, 7.0 Hz), 3.19−3.25 (1H, dd, J =
15.7, 4.8 Hz), 4.91 (1H, br), 4.94−5.06 (2H, m), 5.22 (1H, d, J = 11.0
Hz), 5.39 (1H, d, J = 17.4 Hz), 5.81 (1H, m), 6.83 (1H, dd, J = 17.4,
11.0 Hz), 6.96−7.24 (2H, m), 7.49 (1H, m), 7.82 (1H,m), 10.50 (1H,
s); 13C NMR (75 MHz) δ 17.7, 25.0, 27.5, 34.3, 74.3, 113.7, 114.9,
115.7, 120.5, 125.9, 128.3, 131.2, 134.2, 135.2, 135.8, 135.9, 161.1,
190.1; LRMS(EI) 268(2), 147(100), 105(35), 91(35); HRMS(EI) m/
z calcd for C18H20O2 M+ 268.1463, found 268.1465; [α]D = −265.7 (c
= 1.8, CHCl3).
3 - A c e t o x y - 9 c - ( 2 ′ - p r o p e n y l ) - 4 a , 5 , 6 , 7 , 9 , 9 c -
pentahydrophenanthro[4,5-bcd]furan 22. TFA (3.0 mL) and
acetic anhydride (3.0 mL) were added to a solution of a mixture of
endo-16 and bridged compound 17 (500 mg, 1.75 mmol) in CH2Cl2
(80 mL) and stirred at rt for 15 min. NaHCO3 was added in small
portions until the pH reached 7, then washed with water (2 × 30 mL).
The layers were partitioned, and the organic layer was dried and
concentrated to give an oil that was further purified by column
chromatography (hexane/ether = 6:1) to give the product (214 mg,
76%) as a light yellow oil (Rf = 0.33) and the unchanged bridged
adduct (225 mg) as a light yellow oil (Rf = 0.2).
(S)-2-[(2-Allyl-3-vinylcyclohex-2-en-1-yl)oxy]phenylformate
11. To a solution of PhSeSePh (230 mg, 0.74 mmol) in CH2Cl2 (50
mL) was added H2O2 (1.7 g, 15 mmol, 30% w/w).16 The yellow
solution was stirred until colorless, and a solution of benzaldehyde 9
(1 g, 3.7 mmol) in CH2Cl2 (30 mL) was added. The reaction was
stirred vigorously at rt overnight. Water (50 mL) was added, and the
reaction mixture was separated. The organic layer was washed
successively with 10% aqueous NaHSO3 (20 mL), saturated aqueous
NaHCO3 (20 mL), and brine (30 mL), dried, and concentrated. The
resulting yellow oil (1.0 g, 94%) was directly used for the next step
To a solution of bridged compound 17 (225 mg, 0.79 mmol) in
tetrachloroethane (20 mL) was added acetic anhydride (3 mL). The
reaction mixture was stirred at 140 °C for 4 days. After the
tetrachloroethane was removed by vacuum distillation, the residue was
extracted with EtOAc (50 mL) and washed with water (2 × 20 mL).
The organic layer was dried and concentrated. The residue was
purified by column chromatography (hexane/ether = 6:1) to give the
1
without further purification: H NMR (300 MHz) δ 1.57−1.69 (3H,
m), 1.98−2.04 (2H, m), 2.34 (1H, m), 2.89−2.93 (1H, dd, J = 15.7,
7.2 Hz), 3.14−3.17 (1H, dd, J = 15.7, 4.6 Hz), 4.74 (1H, br), 4.92−
5.01 (2H, m), 5.15 (1H, d, J = 11.0 Hz), 5.33 (1H, d, J = 17.4 Hz),
5.78 (1H, m), 6.78 (1H, dd, J = 17.4, 11.0 Hz), 6.91−6.97 (1H, m),
7.03−7.11 (2H, m), 7.17−7.20 (1H, m), 8.23 (1H,s); 13C NMR (75
MHz) δ 17.5, 25.0, 27.3, 34.0, 74.4, 114.5, 115.0, 115.5, 120.9, 122.9,
127.2, 131.6, 134.4, 135.0, 135.8, 136.1, 149.6, 159.3; LRMS(CI) [M +
NH4]+ 302.2.
1
product (147 mg, 63%) as a light yellow oil: H NMR (500 MHz) δ
1.10−1.24 (1H, m), 1.45−1.60 (1H, m), 1.70−1.78 (2H, m), 2.29−
2.37 (7H, m), 3.11−3.17 (1H, dd, J = 19.2, 6.0 Hz), 3.29−3.30 (1H,
dd, J = 19.2, 3.5 Hz), 4.74−4.78 (1H, dd, J = 12.2, 4.2 Hz), 5.05−5.09
(2H, m), 5.72−5.80 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.80 (1H, d, J =
8.0 Hz); 13C NMR (75 MHz) δ 17.5, 20.8, 25.3, 25.7, 29.7, 42.0, 50.1,
90.2, 118.4, 118.9, 121.1, 123.3, 132.5, 133.7, 134.0, 134.2, 140.5,
147.0, 168.7; LRMS(EI) 296(6), 255(87), 213(75), 195(100),
167(45); HRMS(EI) m/z calcd for C19H20O3 M+ 296.1412, found
296.1411; [α]D = −208 (c = 0.19, CHCl3).
(S)-2-[(2-Allyl-3-vinylcyclohex-2-en-1-yl)oxy]phenol 6. Ice
cold aqueous K2CO3 solution (12.2 mL, 3.52 mmol, 4% v/v) was
added dropwise over 30 min to the solution of phenyl formate 11 (1 g,
3.52 mmol) in methanol (20 mL) at 0 °C. The reaction mixture was
stirred at 0 °C for 1 h. After methanol was evaporated, the mixture was
neutralized with dry ice to pH 7, then extracted with EtOAc (2 × 30
mL). The combined organic layer was dried and concentrated. The
residue was purified on a silica column (EtOAc/hexanes = 1:4) to give
the product (0.7 g, 78%) as a yellow oil: 1H NMR (300 MHz) δ 1.56−
1.75 (3H, m), 2.01−2.07 (2H, m), 2.37 (1H, m), 2.97−3.00 (1H, dd, J
= 15.7, 7.0 Hz), 3.08−3.10 (1H, dd, J = 15.7, 5.0 Hz), 4.75 (1H, br),
4.96−5.05 (2H, m), 5.18 (1H, d, J = 11.0 Hz), 5.35 (1H, d, J = 17.2
Hz), 5.75−5.95 (2H, m), 6.78−6.94 (5H, m); 13C NMR (75 MHz) δ
17.7, 24.9, 27.5, 34.3, 75.2, 112.8, 114.7, 114.8, 115.6, 120.0, 121.4,
131.5, 134.3, 135.2, 136.3, 145.1, 146.7; LRMS(EI) 256 (2), 147
(100), 105(40), 91(35); HRMS(EI) m/z calcd for C17H20O2 M+
256.1461, found 256.1463; [α]D = −247 (c = 1.2, CHCl3).
1
Bridged Compound 17: H NMR (500 MHz) δ 1.45 (1H, m),
1.57−1.60 (2H, m), 1.75−1.95 (3H, m), 2.10 (1H, dd, J = 14.3, 7.0
Hz), 2.17 (1H, dd, J = 14.3, 7.8 Hz), 2.88−2.90 (1H, dd, J = 6.5, 1.1
Hz), 3.20−3.22 (1H, dd, J = 6.4, 1.7 Hz), 3.49 (3H, s), 4.28 (1H, t),
5.04−5.12 (4H, m), 5.75−5.85 (1H, m), 5.97−6.03 (1H, dd, J = 17.5,
11.1 Hz), 6.18−6.28 (2H, m); 13C NMR (75 MHz) δ 16.0, 25.6, 32.2,
38.3, 44.3, 48.4, 48.5, 48.9, 60.0, 80.0, 99.5, 113.4, 118.7, 128.3, 131.8,
134.2, 141.7, 201.8; LRMS(EI) 258(50), 217(100), 157(45), 131(52);
LRMS(CI) [M + NH4]+ 304.2 (100); HRMS(EI) m/z calcd for
C17H22O2 [M − CO]+ 258.1620, found 258.1621; [α]D = +299 (c =
0.34, CHCl3).
3 - A c e t o x y - 9 c - ( 2 ′ , 3 ′ - d ih yd r o xy ) - 4 a , 5 , 6 , 7 , 9 , 9 c -
pentahydrophenanthro[4,5-bcd]furan. To a solution of DMAP
(644 mg, 5.28 mmol) and phenanthrofuran 22 (650 mg, 2.20 mmol)
in THF (150 mL) was added OsO4 (676 mg, 2.64 mmol) at 0 °C. The
reaction mixture was allowed to stir at 0 °C for 12 h, then 10%
NaHSO3 solution (30 mL) was added and stirring continued for
another hour. The mixture was extracted with EtOAc (2 × 40 mL),
and the organic layer was separated washed with brine (80 mL), then
dried and concentrated to give the product (661 mg, 91%), a colorless
Oxidation and Intramolecular Diels−Alder Reaction of
(−)-2-[(2-Allyl-3-vinylcyclohex-2-en-1-yl)oxy]phenol 6. To a
solution of phenol 6 (1 g, 3.9 mmol) in methanol (50 mL) was
added a solution of DAIB (1.50 g, 4.66 mmol) in methanol (70 mL)
via syringe pump over 1 h. The reaction mixture was stirred overnight;
NaHCO3 (1.25 g) was added and the mixture stirred for 20 min. After
55
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oil, as a diastereomeric mixture which was used directly without further
purification for the next step: 1H NMR (500 MHz, mixture of
diastereomers) δ 1.10−1.75 (4H, m), 1.85−1.95 (1H, m), 2.17 (1H,
m), 2.30−2.50 (7H, m), 3.19−3.55 (4H, m), 3.65 (0.55H, m), 4.00
(0.45H, m), 4.86−4.88 (0.45H, dd, J = 12.5, 4.5 Hz), 5.00−5.04
(0.55H, dd, J = 12.5, 4.5 Hz), 5.79−5.81 (0.45H, m), 5.73−5.75
(0.55H, m), 6.73−6.82 (2H, m); 13C NMR (75 MHz) δ 19.0, 19.1
(1C), 20.7, 24.9, 25.5, 29.3, 29.4 (1C), 39.9, 40.1 (1C), 48.6, 48.8
(1C), 67.1, 67.2 (1C), 69.6, 69.9 (1C), 90.9, 91.0(1C), 119.2, 119.3
(1C), 120.7, 122.4, 123.4 (2C), 132.2, 133.3, 133.8, 134.3, (2C),
141.4, 141.6 (1C), 146.7, 147.1 (1C), 168.8, 169.1 (1C); LRMS(EI)
330 (25), 288(40), 255(55), 213(100), 195(60); HRMS(EI) m/z
calcd for C19H22O5 M+ 330.1467, found 330.1462; [α]D = −29.2 (c =
0.76, CHCl3).
3 - M e t h o x y - 9 c - ( 2 ′ - c y a n o e t h y l ) - 4 a , 5 , 6 , 7 , 9 , 9 c -
pentahydrophenanthro[4,5-bcd]furan 25. NaOH (5 mL, 1 N)
was added to a solution of acetoxy nitrile 24 (50 mg, 0.17 mmol) in
MeOH (15 mL). The reaction mixture was stirred at rt overnight.
Methanol was removed in vacuo, and dry ice was added to reach a pH
of 6−7. The resulting mixture was extracted with EtOAc (2 × 10 mL).
The organic layer was dried and concentrated to obtain crude 3-
hydroxy-9c-(2′-cyanoethyl)-4a,5,6,7,9,9c-pentahydrophenanthro[4,5-
bcd]furan. To the solution of above product and dimethylsulfate (74.8
mg, 0.68 mmol) in acetone (10 mL) was added K2CO3 (234.6 mg, 1.7
mmol). The mixture was stirred at rt for 16 h, and acetone removed in
vacuo. The residue was extracted with CH2Cl2 (20 mL) and washed
with water (15 mL). The aqueous layer was extracted with CH2Cl2 (2
× 10 mL), and the combined organic extracts were dried,
concentrated, and purified by column chromatography (CH2Cl2) to
3 - A c e t o x y - 9 c - ( 2 ′ - o x o e t h y l ) - 4 a , 5 , 6 , 7 , 9 , 9 c -
pentahydrophenanthro[4,5-bcd]furan 23. NaIO4 (1.52 g, 7.1
mmol) was added to a solution of 3-acetoxy-9c-(2′,3′-hydroxy)-
4a,5,6,7,9,9c-pentahydrophenanthro[4,5-bcd]furan (650 mg, 1.97
mmol) in water and t-BuOH (25 mL/25 mL) and stirred at rt for
1.5 h. The reaction mixture was extracted with EtOAc (80 mL), and
the organic layer was washed with water (2 × 30 mL), dried, and
concentrated to give a colorless oil (552 mg, 94%) directly used for the
1
give a white solid (41 mg, 91%): H NMR (300 MHz) δ 1.13−1.86
(4H, m), 2.38−2.65 (4H, m), 3.11−3.20 (1H, dd, J = 19.8, 6.0 Hz),
3.36−3.51 (1H, dd, J = 19.8, 3.5 Hz), 3.85 (3H, s), 4.76−4.82 (1H, dd,
J = 12.1, 4.4 Hz), 5.94−5.97 (1H, m), 6.71 (2H, s); 13C NMR (75
MHz) δ 17.3, 25.1, 25,4, 25.6, 29.3, 47.5, 56.5, 89.7, 113.2, 117.6,
119.5, 126.6, 128.5, 130.3, 137.9, 143.3, 145.3; LRMS(EI) 267(85),
227(58), 195(100); HRMS(EI) m/z calcd for C17H17NO2 M+
267.1257, found 267.1259; [α]D = −108.3 (c = 0.45, CHCl3); ee =
98.62%.
1
next reaction without further purification: H NMR (500 MHz) δ
1.17−1.79 (3H, m), 2.29−2.50 (6H, m), 2.59−2.65 (1H, dd, J = 14.9,
3.0 Hz), 2.68−2.73 (1H, dd, J = 14.9, 2.6 Hz), 3.23−3.26 (2H, m),
4.82−4.86 (1H, dd, J = 12.2, 4.6 Hz), 5.83−5.86 (1H, m), 6.75−6.77
(1H, d, J = 8.0), 6.83−6.86 (1H, d, J = 8.0), 9.65 (1H, t, J = 2.8 Hz);
13C NMR (75 MHz) δ 17.5, 20.7, 25.0, 25.4, 29.6, 47.5, 50.2, 90.7,
119.5, 121.9, 124.5, 132.7, 132.8, 133.9, 139.7, 147.1, 168.5, 200.9;
LRMS(EI) 298(20), 256(65), 212(100), 195(35); HRMS(EI) m/z
calcd for C18H18O4 M+ 298.1211, found 298.1205; [α]D = −51.8 (c =
0.95, CHCl3).
3-Acetoxy-9c-(2′-oxoethyl-N,N-dimethylhydrazone)-
4a,5,6,7,9,9c-pentahydrophenanthro[4,5-bcd]furan. N,N-Dime-
thylhydrazine (0.12 mL, 1.57 mmol) was added to a solution of
aldehyde 23 (334 mg, 1.12 mmol) in methanol (60 mL). The mixture
was stirred for 2 h at rt, and methanol was removed in vacuo. The
residue was extracted with EtOAc (70 mL), washed with water (50
mL), and separated. The organic layer was dried and concentrated to
give a colorless oil (339 mg, 89%) used directly for the next reaction
without further purification: 1H NMR (300 MHz, mixture of
diastereomers) δ 1.11−1.72 (4H, m), 2.25−2.39 (6H, m), 2.48−
2.52 (1H, m), 2.68−2.71 (6H, m), 3.08−3.35 (2H, dd, J = 19.1, 5.7
Hz), 4.78−4.84 (1H, m), 5.73−5.76 (1H, m), 6.35−6.40 (1H, m),
6.60−6.79 (2H, d, J = 8.0 Hz); 13C NMR (75 MHz) δ 17.4, 17.6 (1C),
20.7, 25.1, 25.4 (1C), 29.3, 29.5, 29.7 (2C), 39.9, 40.1 (1C), 43.0, 43.2,
49.7, 49.9 (1C), 89.4, 89.9 (1C), 115.5, 119.0, 119.2 (1C), 121.2,
123.0, 132.4, 133.5, 133.9, 140.4, 140.6 (1C), 147.5, 168.5; LRMS(EI)
340(30), 255(80), 213(100), 195(90), 86(45); HRMS(EI) m/z calcd
for C20H24N2O3 M+ 340.1787, found 340.1794.
Palladium-Catalyzed Cyclization of Tetracyclic Nitriles. 3-
Acetoxy-7a,9c-(amidoethano)-4a,5,6,7,9c-pentahydrophenanthro-
[4,5-bcd]furan 27 and 3-Methoxy-7a,9c-(amidoethano)-
4a,5,6,7,9c-pentahydrophenanthro[4,5-bcd]furan 28. The nitrile
24 or 25 (0.15 mmol) was dissolved in a mixture of H2O/THF =
1:3 (12 mL). Acetamide (0.60 mmol) and Pd(OAc)2 (0.16 mmol)
were added, and the mixture was stirred at rt for 3 days. THF was
removed in vacuo, and the resulting mixture was extracted with
CH2Cl2 (2 × 20 mL). The organic layer was washed with water (20
mL), dried, and concentrated. The residue was purified by column
chromatography (CH2Cl2/CH3OH = 99:1) to give the product.
3 - A c e t o x y - 7 a , 9 c - ( a m i d o e t h a n o ) - 4 a , 5 , 6 , 7 , 9 c -
pentahydrophenanthro[4,5-bcd]furan 27: obtained in 93% yield as a
1
light yellow solid by the above procedure; H NMR (300 MHz) δ
1.20−1.59 (4H, m), 1.78−1.83 (1H, m), 2.05−2.15 (1H, m), 2.29
(3H, s), 2.52−2.59 (1H, d, J = 16.9 Hz), 2.61−2.67 (1H, d, J = 16.9
Hz), 4.74−4.81 (1H, dd, J = 10.3, 7.0 Hz), 5.59 (1H, d, J = 9.6 Hz),
5.91 (1H, br) 6.39 (1H, d, J = 9.6 Hz), 6.78−6.81 (1H, d, J = 8.0 Hz),
6.85−6.88 (1H, d, J = 8.0 Hz); 13C NMR (75 MHz) δ 15.2, 20.7, 28.1,
31.8, 42.8, 47.7, 62.9, 92.3, 118.4, 122.6, 123.2, 126.8, 127.3, 133.7,
134.7, 147.7, 168.4, 176.6; LRMS(EI) 311(19), 269(100); HRMS(EI)
m/z calcd for C18H17NO4 M+ 311.1158, found 311.1157; [α]D
−158.5 (c = 1.1, CHCl3).
=
3 - M e t h o x y - 7 a , 9 c - ( a m i d o e t h a n o ) - 4 a , 5 , 6 , 7 , 9 c -
pentahydrophenanthro[4,5-bcd]furan 28: . obtained in 91% yield as
1
a light yellow solid by the above procedure; H NMR (300 MHz) δ
1.19−1.52 (4H, m), 1.80−1.85 (1H, m), 2.05−2.15 (1H, m), 2.50−
2.56(1H, d, J = 16.8 Hz), 2.57−2.64 (1H, d, J = 16.8 Hz), 3.86 (3H, s),
4.73−4.80 (1H, dd, J = 10.3, 7.0 Hz), 5.59 (1H, d, J = 9.6 Hz), 6.34
(1H, d, J = 9.6 Hz), 6.57 (1H, br), 6.65−6.68 (1H, d, J = 8.0 Hz),
6.69−6.72 (1H, d, J = 8.0 Hz); 13C NMR (75 MHz) δ 14.1, 28.3, 31.9,
43.0, 48.1, 56.3, 62.8, 91.4, 113.1, 118.6, 121.9, 122.8, 126.4, 131.8,
144.8, 145.3, 176.6; LRMS(EI) 283(100), 240(10); HRMS(EI) m/z
calcd for C17H17NO3 M+ 283.1206, found 283.1208; [α]D = −172.3 (c
= 1.3, CHCl3).
N-Methylation of Pentacyclic Lactams. 3-Acetoxy-7a,9c-
(methylamidoethano)-4a,5,6,7,9c-pentahydrophenanthro[4,5-
bcd]furan 29 and 3-Methoxy-7a,9c-(methylamidoethano)-
4a,5,6,7,9c-pentahydrophenanthro[4,5-bcd]furan 30. NaH (0.14
mmol, 60% in mineral oil) was added to a solution of amide 27 or 28
(0.096 mmol) and MeI (6.6 mL) in THF (20 mL) at 0 °C. The
reaction mixture was continued to stir at 0 °C for 3 h and warmed to
rt. After adding saturated NH4Cl (15 mL), the aqueous layer was
extracted with diethyl ether (2 × 15 mL). The combined organic layers
were washed with brine (10 mL), separated, and dried. The residue
was purified by column chromatography (CH2Cl2/CH3OH = 99:1) to
give the product.
3 - A c e t o x y - 9 c - ( 2 ′ - c y a n o e t h y l ) - 4 a , 5 , 6 , 7 , 9 , 9 c -
pentahydrophenanthro[4,5-bcd]furan 24. To a solution of
MMPP·6H2O (890 mg, 1.8 mmol) in methanol (10 mL) was added
a solution of 3-acetoxy-9c-(2′-oxoethyl-N,N-dimethylhydrazone)-
4a,5,6,7,9,9c-pentahydrophenanthro[4,5-bcd]furan (259 mg, 0.76
mmol) in methanol (30 mL) at 0 °C. The mixture was allowed to
stir for 5 min, and H2O (180 mL) was added. The mixture was
extracted with CH2Cl2 (60 mL), and the aqueous layer was extracted
again with CH2Cl2 (2 × 50 mL), and the combined organic extracts
were dried and concentrated. The residue was purified by column
chromatography (CH2Cl2) to give a white solid product (173 mg,
1
77%): H NMR (300 MHz) δ 1.18−1.86 (4H, m), 2.31−2.50 (4H,
m), 2.54−2.73 (3H, m), 3.20−3.28 (1H, dd, J = 19.8, 6.0 Hz), 3.43−
3.55 (1H, dd, J = 19.8 Hz, 3.5 Hz), 4.80−4.87 (1H, dd, J = 12.1, 4.4
Hz), 5.99−6.01 (1H, m), 6.77−6.84 (1H, d, J = 8.1 Hz), 6.87−6.91
(1H, d, J = 8.1 Hz); 13C NMR (75 MHz) δ 17.2, 20.7, 25.0, 25.3, 25.6,
29.7, 47.5, 90.5, 117.5, 119.7, 122.5, 126.3, 131.3, 132.9, 134.3, 137.9,
147.0, 168.5; LRMS(EI) 295(25), 253(85), 213(100), 195(57),
167(25); HRMS(EI) m/z calcd for C18H17N O3 M+ 295.1208,
found 295.1214; [α]D = −89.8 (c = 1.1, CHCl3).
56
dx.doi.org/10.1021/jo3014098 | J. Org. Chem. 2013, 78, 48−58

The Journal of Organic Chemistry
Article
3-Acetoxy-7a,9c-(methylamidoethano)-4a,5,6,7,9c-
the chiral HPLC of compound 25, and Stuart Mahoney for his
careful reading of the manuscript and for his valuable
suggestions for improving it.
pentahydrophenanthro[4,5-bcd]furan 29: obtained in 87% yield as a
1
light yellow solid; H NMR (300 MHz) δ 0.99−1.29 (4H, m), 1.99−
2.23 (2H, m), 2.29 (3H, s), 2.58 (2H, s), 2.84 (3H, s), 4.68−4.75 (1H,
dd, J = 10.3, 7.0 Hz), 5.67 (1H, d, J = 9.6 Hz), 6.41 (1H, d, J = 9.6
Hz), 6.69−6.72 (1H, d, J = 8.0 Hz), 6.86−6.89 (1H, d, J = 8.0 Hz);
13C NMR (75 MHz) δ 16.0, 20.3, 28.1, 30.2, 31.8, 40.8, 44.7, 62.9,
DEDICATION
■
Dedicated to the memory of Robert E. Ireland.
92.3, 118.4, 122.8, 123.6, 127.1, 127.3, 133.7, 134.7, 147.7, 168.4,
174.8; LRMS(EI) 325(25), 283(100); HRMS(EI) m/z calcd for
C19H19NO4 M+ 325.1314, found 325.1315; [α]D = −153.1 (c = 0.89,
CHCl3).
REFERENCES
■
(1) Reviews: (a) Liao, C.-C. Pure Appl. Chem. 2005, 77, 1221.
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66, 2235.
3-Methoxy-7a,9c-(methylamidoethano)-4a,5,6,7,9c-
pentahydrophenanthro[4,5-bcd]furan 30: obtained (89%) as a light
1
yellow solid; H NMR (300 MHz) δ 1.03−1.33 (2H, m), 1.44−1.56
(2H, m), 1.99−2.17 (2H, m), 2.49−2.54(1H, d, J = 16.5 Hz), 2.56−
2.63 (1H, d, J = 16.5 Hz), 2.83 (3H, s), 3.87 (3H, s), 4.67−4.74 (1H,
dd, J = 10.3, 7.0 Hz), 5.56 (1H, d, J = 9.6 Hz), 6.38 (1H, d, J = 9.6
Hz), 6.65−6.68(1H, d, J = 8.0 Hz), 6.69−6.73 (1H, d, J = 8.0 Hz); 13C
NMR (75 MHz) δ 15.1, 24.6, 28.2, 29.9, 42.5, 46.7, 56.3, 66.1, 91.4,
113.1, 118.6, 122.1, 123.3, 126.8, 126.9, 144.8, 145.3, 174.3;
LRMS(EI) 297(100), 283(10); HRMS(EI) m/z calcd for
C18H19NO3 M+ 297.1360, found 297.1365; [α]D = −166.7 (c =
0.67, CHCl3).
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3-Methoxy-7a,9c-(methyliminoethano)-4a,5,6,7,9c-
pentahydrophenanthro[4,5-bcd]furan 31. Compound 30 (10 mg,
0.034 mmol) in benzene (3 mL) was added to a solution of Red-Al
(15 μL, 0.051 mmol, 65% w/w) in benzene (0.5 mL). The reaction
mixture heated spontaneously, and the apparatus was connected with a
condenser. The mixture was stirred at rt for 1.5 h. Water (6 mL) was
added until precipitation occurred, and the mixture was extracted with
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concentrated, and purified by column chromatography (CH2Cl2/
(8) Carlini, R.; Higgs, K.; Rodrigo, R.; Taylor, N. Chem. Commun.
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1
CH3OH = 95:5) to give a white solid (7.4 mg, 77%): H NMR (300
MHz) δ 1.03−1.87 (6H, m), 2.11−2.25 (2H, m), 2.37 (3H, s), 2.40−
2.44 (1H, m), 3.17−3.20 (1H, m), 3.86 (3H, s), 4.73−4.80 (1H, dd, J
= 10.3, 7.0 Hz), 5.79 (1H, d, J = 9.6 Hz), 6.40 (1H, d, J = 9.6 Hz),
6.61−6.64 (1H, d, J = 8.0 Hz), 6.65−6.68 (1H, d, J = 8.0 Hz); 13C
NMR (75 MHz) δ 15.1, 20.4, 24.6, 28.2, 42.5, 46.7, 48.0, 56.7, 66.1,
92.4, 112.3, 117.4, 122.1, 123.3, 125.8, 126.1, 144.5, 145.1; LRMS(EI)
283 (100), 268(50), 149(50), 57(48); HRMS(EI) m/z calcd for
C18H21NO2 M+ 283.1568, found 283.1572; [α]D = −169.1 (c = 0.15,
CHCl3).
ASSOCIATED CONTENT
■
S
* Supporting Information
(15) Cha, J. S.; Jang, S. H.; Kwon, S. Y. Bull. Korean Chem. Soc. 2002,
23, 1697.
1
Copies of H NMR and 13C NMR spectra of compounds 4, 5,
(16) (a) Brink, G. T.; Vis, J. M.; Arends, I. W. C. E.; Sheldon, R. A. J.
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(17) These adducts were not separable by column chromatography,
but their presence was inferred from their methoxy signals at 3.21 and
3.46 ppm in the NMR spectrum of the mixture. They were processed
further as such.
(18) (a) Gagnepain, J.; Mereau, R.; Dejugnac, D.; Leger, J.-M.;
Castet, F.; Deffieux, D.; Pouysegu, L.; Quideau, S. Tetrahedron 2007,
63, 6493. (b) This X-ray structure was obtained by the late Dr. N. J.
Taylor.
(19) It should be noted that the assignments of absolute
stereochemistry to 16 (endo) and 20 (exo) are based on the relative
configurations of similar adducts determined by X-ray crystallography
(ref 8).
6, 7, 8, 9, 11, 17, and 21−31, LRMS of 31, general
experimental methods, and details of columns, solvent, and
flow rates for chiral HPLC determination of ee. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rrodrigo@uwaterloo.ca. Enquiries about X-ray data
should be addressed to A.A.: aassoud@sciborg.uwaterloo.ca.
Present Address
†School of Pharmacy, University of Waterloo, Waterloo, ON,
N2L 3G1, Canada.
Notes
The authors declare no competing financial interest.
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1993, 34, 141.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council for support of this research and Dr. H. Plaumann of
BASF for a generous gift of R-oxazaborolidine. We also thank
Val Goodfellow and Nan Chen of this department for running
57
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The Journal of Organic Chemistry
Article
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58
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