Chemoenzymatic Total Synthesis of Hydromorphone by an Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition Sequence: A Second-Generation Approach

Article abstract of DOI:10.1021/acs.joc.6b01990

A second-generation approach to the synthesis of hydromorphone by oxidative dearomatization/Diels-Alder cycloaddition was investigated. Detailed analysis of the stereochemical outcome of the [4 + 2] cycloaddition was performed first on a truncated model system as well as on the material leading to ent-hydromorphone. The stereochemical assignments were made by NMR and X-ray methods. The second-generation synthesis of hydromorphone was completed in both enantiomeric series. Improvements in the dearomatization conditions were attained using hypervalent iodine reagents instead of Pb(OAc)₄. Electrochemical methods of oxidative dearomatization were also investigated. New conditions enabling the rearomatization of ring A from the methoxyketal were developed, and a formal synthesis of the natural enantiomer of hydromorphone was completed. Experimental and spectral data are provided for all new compounds.

Full text of DOI:10.1021/acs.joc.6b01990

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Article
Chemoenzymatic total synthesis of hydromorphone
by an oxidative dearomatization/intramolecular [4+2]
cycloaddition sequence: a 2nd generation approach
Lukas Rycek, John J. Hayward, Marwa Abdel Latif, James Tanko, Razvan Simionescu, and Tomas Hudlicky
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Sep 2016
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Chemoenzymatic total synthesis of hydromorphone by an oxidative
dearomatization/intramolecular [4+2] cycloaddition sequence: a 2nd generation
approach
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Lukas Rycek,a John J. Hayward, a Marwa Abdel Latif, b James Tanko,b* Razvan
Simionescu,a and Tomas Hudlicky a*
a. Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir
Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada
thudlicky@brocku.ca
b. Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA
jtanko@vt.edu
Key words-morphine alkaloids; intramolecular Diels-Alder cycloaddition; oxidative
dearomatization; stereochemistry of cycloaddition; hydromorphone synthesis;
hypervalent iodine reagents; anodic oxidation
Graphical abstract
Abstract
A 2nd generation approach to the synthesis of hydromorphone by oxidative
dearomatization/Diels-Alder cycloaddition was investigated. Detailed analysis of the
stereochemical outcome of the [4+2] cycloaddition was performed first on a truncated
model system as well as on the material leading to ent-hydromorphone. The
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stereochemical assignments were made by NMR and X-ray methods. The 2nd generation
synthesis of hydromorphone was completed in both enantiomeric series. Improvements in
the dearomatization conditions were attained by using hypervalent iodine reagents instead
of Pb(OAc)4. Electrochemical methods of oxidative dearomatization were also
investigated. New conditions enabling the rearomatization of ring A from the
methoxyketal were developed and a formal synthesis of the natural enantiomer of
hydromorphone was completed. Experimental and spectral data are provided for all new
compounds.
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Introduction
The long-term goals of our research in the synthesis of morphine alkaloids and their
medicinally important derivatives are focused on the practicality and efficiency of the
synthetic sequence leading to a particular target.1 The academic effort of many years that
we have invested into designing a potentially practical route to these important targets
has recently been summarized.2 In addition, we have also been engaged in process
development for the industrially viable synthesis of various opiate-derived agents, as
reported in a recent review.3 We have published improvements for the synthesis of
naltrexone (1), naloxone (2), buprenorphine (3), and nalbuphone (4), among others.3 In
the industrially relevant projects we focused on the approaches to nororipavine (5) and
noroxymorphone (6) as potentially useful intermediates for the large-scale synthesis of
the medicinal agents3 (Figure 1) (See the Supporting Information Section for the relevant
references to process development of the above-named opiate-derived agents).
The challenge of designing a de novo synthesis of any morphinan in a manner that would
be competitive in cost with compounds derived from naturally occurring alkaloids is
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formidable. The most efficient preparation of a morphine alkaloid to date was reported by
Rice in 1980;4 however, no synthesis applicable to commercial production is yet
available.
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Figure 1. Opiate-derived agents produced by semi-synthesis from natural
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In 2014 we reported a chemoenzymatic synthesis of ent-hydromorphone (7)5 by the
intramolecular [4+2] cycloaddition6 of tetraenone 11, obtained by oxidative
dearomatization of phenol 10 (Scheme 1).
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CHO
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9
1. Ph3PMeBr, BuLi
2. ZnBr2, C12H25SH
Br
Ref. 11
MOMO
NMeBoc
HO
NMeBoc
HO
HO
O
O
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TBSO
TBSO
Pb(OAc)4
HO
TsO
O
4
AcO
12
1. TFA
NMeBoc
O
O
O
H
O
H
2. TsCl,
Et3N, DCM
13
AcO O
NMe
5
6
14
H
NMeTs
O
TBSO
TBSO
NMeBoc
TBSO
13
12
11
ent-hydromorphone
(7)
Scheme 1. Synthesis of ent-hydromorphone via oxidative dearomatization/[4+2]
cycloaddition strategy.
The synthesis began with the enzymatic dihydroxylation of β-bromoethyl benzene by
toluene dioxygenase over-expressed in E.coli JM109(pDTG601A).7 Diene diol 8 is
produced in the whole cell fermentation on a scale of 10-15 L in multi-gram quantities
(10-15 g/L).8 Diol 8 is converted in five operations to the aryl ether 9 and in two more
steps to the key precursor phenol 10. The cycloadduct 12 rearomatized when treated with
trifluoroacetic acid and then immediately reacted with tosyl chloride to provide the
protected phenol 13. The final closure of the ethylamino bridge was accomplished from
the N-,O-ditosylate by employing Parker’s method.9 This relatively short synthesis of
hydromorphone in twelve steps from β-bromoethyl benzene constituted, by academic
standards, a pleasing accomplishment, yet is still far from having the potential of
becoming practical.To achieve practicality several issues need to be addressed. First, the
oxidation should be rendered more environmentally benign by using different conditions,
such as the use of hypervalent iodine reagents10 or electrochemical oxidations, instead of
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toxic lead tetraacetate. Second, the yields of the cycloaddition reaction needed to be
improved. Third, a detailed analysis of the stereochemical outcome of the cycloaddition
needed to be performed so that possible double stereoselection could be achieved by
using chiral alcohols as the trapping nucleophiles in the oxidative dearomatization. In this
paper we report the results of the 2nd generation approach to hydromorphone,
improvement in the conditions, and details of the stereochemical course of the key
cycloaddition reaction.
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Results and discussion
Studies on a model system.
We began the 2nd generation approach by studying other oxidants and the stereochemical
course of the cycloaddition reaction on a model substrate 18 (Scheme 2).
Scheme 2. Synthesis of the model compound 18.
The synthesis of 18 started by selective protection of the para-hydroxyl group of 3,4-
dihydroxybenzaldehyde 14 with the ethoxymethyl (EOM) group, providing phenol 15 in
60%. Alkylation of 15 with 1-chloro-2-cyclohexene (prepared by LiAlH4 reduction of
cyclohex-2-enone and chlorination11 of the allylic alcohol with acetyl chloride) under
basic conditions provided the required ether 16 in 59-70% yield. Deprotection of the
EOM group using PPTS in ethanol provided phenol 17 in up to 63% yield, with cleavage
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of the allylic C−O bond being the main side reaction. Subsequent Wittig olefination
yielded the required model substrate 18 on a multigram scale in 89-93% yield.
Electrochemical oxidation of the model substrate.
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The electrochemical oxidation and subsequent [4+2] cycloaddition of 2-alkoxyphenols
has previously been reported;12 it was therefore assumed that anodic oxidation of 18 and
subsequent Diels-Alder reaction of 19 would yield the desired tetracycle 20 (Scheme 3,
a). Cyclic voltammograms of 18 in the presence of increasing concentrations of methanol
(in distilled acetonitrile) were recorded (Figure 2). In dry acetonitrile, a broad (and
somewhat flattened) wave is observed at ca. 0.9 V, and no reverse current is observed,
suggesting that the initially formed oxidation product is not long lived under the reaction
conditions. As increasing amounts of methanol are added, two sharper oxidation peaks
appear, the first of which shifts to more negative potentials as the concentration of
methanol is increased. The shifts observed in the presence of methanol suggest that the
initially formed oxidation product reacts directly with methanol, presumably via
nucleophilic attack.
A preparative scale galvanostatic (50 mA) oxidation was performed according to the
conditions reported by Quideau. Under these conditions (undivided cell open to the air,
methanol, LiClO4 as the supporting electrolyte) only extensive decomposition resulted.
We hypothesized that the reaction mixture was absorbing atmospheric moisture due to
the open vessel, which would assist in hydrolytic cleavage of 18; thus the reaction was
repeated in a sealed cell under argon and in anhydrous methanol. To our surprise the
major product of the reaction was the trimethoxy phenol 21, with a small quantity of
dimethoxy phenol 22 (Scheme 3, b). When the electrolysis was performed using constant
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potentials of either 1.2 V or 0.9 V (vs Ag/Ag+ (0.1 M)) the same products were observed.
Quideau also performed electrolyses with a 9:1 mixture of acetonitrile and methanol as
the solvent; however this did not change the course of the reaction when we attempted
this modification.
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Figure 2. Cyclic voltammograms of 18 in 10 mL anhydrous MeCN with added
nucleophile (methanol); scan rate = 500 mV/s, reference electrode = Ag/Ag+ (0.1 M)
in MeCN; supporting electrolyte = nBu4NClO4
.
This result was rationalized by considering the red-ox half equations (Scheme 3, c).
While the intended process is neutral overall, methoxide is generated at the cathode and
protons are produced at the anode. It can be expected that the acetal product 19 is the
kinetic product, with the methanol adding to the most highly cationic position. However,
the strongly acidic conditions local to the cathode resulted in the protonation of the
acetal, leading to hydrolysis and subsequent double addition of methanol to the exo-vinyl
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group, affording the energetically favorable aromatic product (Scheme 3, d). In an
attempt to neutralize the acid generated at the cathode, pyridine (with either 2 or 50
equivalents) was added to the electrolysis cell; however, only the methanol addition
products were observed.
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Scheme 3. Attempts at electrochemical oxidation of the model compound 18. (a)
Proposed transformation. (b) Outcome of the electrochemical oxidation. (c) Redox
half reactions. (d) Suggested mechanistic explanation of the side product formation.
Chemical oxidation of the model substrate using Pb(OAc)4 and alternative oxidants.
When phenol 18 was oxidized using Pb(OAc)4 in refluxing dichloroethane a single
isomer 24 could be isolated, albeit in low yields (32-45% over several attempts), along
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with up to 10% of the aromatized product 25 (Scheme 4, a). Reaction of 18 with
thallium(III) nitrate in methanol did not lead to dearomatization and the use of cerium
ammonium nitrate (CAN) led to decomposition. Treatment of 18 with
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phenyliodinetrifluoroacetate (PIFA) led to the formation of methanol adduct 21 in 67%.
We propose that the reaction is catalyzed by trifluoroacetic acid, formed as a by-product
during the oxidation step. Treatment of the model substrate 18 with
diacetoxyiodobenzene (DAIB) in various solvents (which also served the function of the
required nucleophile) led to different outcomes. The use of iso-propanol led to a partial
conversion, but we observed the formation of a complex mixture containing at least nine
products. Hexafluoroisopropanol led to a complete degradation of the starting material.
The use of methanol at room temperature resulted in the desired oxidative
dearomatization providing dienone 19.
The [4+2] cycloaddition occurred on heating the crude dienone 19 in toluene (120 °C,
pressure vial, overnight). [Intermediate 19 was never isolated. However, in situ NMR
experiment (reaction carried out in the NMR tube) showed the presence (and
disappearance) of intermediate 19, with the progress of the reaction.]
The reaction provided three products; two were identified as diastereomers of the desired
cycloadduct (minor 20a and major 20b, the stereochemistry of which will be discussed
later in this paper) and the third compound, tetracyclic ketone 26, was identified as the
product of an endocyclic [4+2] cycloaddition (Scheme 4, b).
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a
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O
O
HO
HO
H
AcO
Pb(OAc)4,
DCE, 80 °C
AcO
4
5
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13
O
O
O
O
+
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8
H
H
H
H
9
H
H
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24, 32-45%
23
25, <10%
18
b
O
O
HO
O
1. I(III) reagent,
MeOH, MgSO4,
–15 °C
H
H
MeO
MeO
MeO
O
O
+
O
O
I(III) =
DAIB
2. PhMe/MeOH
reflux
H
H
H
H
H
H
18
20a, 11%
20b
, 43%
19
I(III) = PIFA
+
O
H
H
HO
OMe
O
OMe
OMe
H
MeO
26
, 16%
21
, 67%
Scheme 4. Oxidation of the model substrate 18 with(a) Pb(OAc)4;and(b) hypervalent
iodine [I(III)] reagents.
In 2012 the Rodrigo group performed similar cycloadditions on structurally similar
compounds.13 Despite the fact that Rodrigo’s and our system differ with respect to
several crucial features (e.g. position of the diene and the dienophile within the structure),
the formation of the product derived from the endocyclic cycloaddition pathway was
observed in both cases (Figure 3).
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O
R
O
MeO
O
H
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MeO
O
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H
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27, R = H or
29, R = H or
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30
, R = COOMe
, R = COOMe
Figure 3. [4+2] Cycloadditions reported by Rodrigo.
The overall yield of the isolated compounds was 50% (ratio 20a:20b:26 = 1:3:1, Table 1,
Entry 1). In addition, we have observed the formation of additional products arising from
the hydrolysis of the ether bond in 18, perhaps caused by the presence of adventitious
water. We did not observe any formation of the side product 21 that was produced during
the electrochemical (Scheme 3, b) or PIFA (Scheme 4, b) oxidations. This can be
explained by the weaker acidity of acetic acid (formed as a by-product of the oxidation
with DAIB) compared to trifluoroacetic acid (formed as a by-product of the oxidation
with PIFA), with the stronger acid catalyzing the addition of methanol to the vinyl group
(Scheme 3, d).
The results of the optimization studies are summarized in Table 1.When the reaction was
carried out at −15°C, followed by the addition of toluene and heating the mixture at
reflux, the cycloadducts were isolated in 70% overall yield (Table 1, Entry 2). Lowering
the temperature further to −30 and −78 °C did not lead to any improvement (Table 1,
Entries 3 and 4, respectively). The effect of the temperature on the cycloaddition was
investigated as well. Performing the reaction at 0 °C, followed by heating the mixture at
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80 °C led to an improvement compared to heating the mixture at 120 °C (50% at reflux vs
61% at 120 °C in a pressure vial, Table 1, Entry 5 vs Entry 1). Finally, when the
oxidation was carried out at −15 °C in methanol, followed by heating at 80 °C in the
toluene/methanol mixture, the products were isolated in overall 68% yield (Table 1, Entry
6). The reaction temperature did affect the yields somewhat but not the distribution of the
reaction products, which was in all cases found to be close to 1:3:1 (20a:20b:26).
Table 1. Optimization of reaction conditions for the chemical oxidation of 18.
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Yields
(%)c
Overall
(%)
Entry Oxidant
Solvent
Temperaturea
Time (h)a
1
2
3
4
5
6
DAIB
MeOH / Tol
0 °C/reflux
1/18
1/18
1/18
1/18
1/18
1/18
10/30/10
11/43/16
12/41/13
10/41/16
7/38/16
50
70
66
67
61
68
DAIB MeOH / Tol −15 °C/reflux
DAIB
DAIB
DAIB
MeOH / Tol −30 °C/reflux
MeOH / Tol −78 °C/reflux
MeOH / Tol
0 °C/80 °C
DAIB MeOH / Tol −15 °C/80 °C
7/45/16
aOxidation / Cycloaddition
b20a/20b/26. Yield of 20a is for an isolated compound. 20b and 26 were obtained as an
inseparable mixture and the ratio was determined by 1H NMR spectroscopic analysis.
A formal synthesis of ent-hydromorphone with DAIB as the oxidant in the key step.
The key intermediate 10 has been synthesized previously.5 The synthesis began with
enzymatic dihydroxylation of 2-bromoethylbenzene to the cis-diol 8, which was
transformed by the published procedures into aldehyde 9 [[α] D 20 =-37.8 (c = 1.5, CHCl3;
lit.5 [α] D 20 =-27.6 (c = 1.48, CHCl3) and further to phenol 10 (Scheme 5). In analogy to
the model compound 18, phenol 10 was subjected to the oxidative dearomatization with
DAIB (instead of Pb(OAc)4) at −15°C. The reaction mixture was transferred to toluene
and heated to either 80 °C or 120 °C (closed pessure vessel) overnight. However, this
approach did not result in the desired cyclization and degradation of the material was
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observed. It was found that the work-up of the reaction mixture after the oxidation step
and performing the cycloaddition in dry, degassed toluene was required to successfully
facilitate the cyclization, yielding 20-30% of the desired product 31 (Scheme 5).
Contrary to the results observed in the model study, we did not detect any product from
the endocyclic cycloaddition nor any minor diastereomers (Scheme 5). Attempts to re-
aromatize 31 with TFA failed because of the fast Boc cleavage and subsequent 1,6-
conjugated addition of secondary amine to enone. Therefore, conditions, allowing the
aromatization prior the Boc cleavage were developed. Treatment of 31 with TMSI at
−78°C resulted in re-aromatization of the product, however, according to a 1H NMR
analysis of the crude reaction mixture, Boc group remained intact. When compound 31 is
first treated with TMSI at −78°C and the reaction mixture is then warmed to 0 °C and
treated with TFA, product 33 can be detected by 1H NMR. Treatment of the crude
product 33 with TsCl in presence of Et3N leads to the formation of compound 13, a
known intermediate in the ent-hydromorphone synthesis (Scheme 5).
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37
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39
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7
8
O
X
H
Br
MeO
4
1. DAIB, MeOH
–15 °C, 1h
2. PhMe, 80°C
20-30%
RO
NMeBoc
12
HO
HO
O
13
O
14
ref. 5
5
H
H
6
TBSO
8
TBSO
NMeBoc
9
31
1. Ph3PCH3Br, n-BuLi, THF, 82%
2. CH3(CH2)11SH, ZnBr2, DCM, 93%
9, R = MOM, X = O
10, R = H, X = CH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TMSI, DCM,
–78 °C to 0 °C
then TFA
HO
TsO
HO
TsCl, Et3N
DCM, 0 °C to rt
O
O
O
41%
H
H
H
H
H
H
TBSO
33
TBSO
NHMe
TBSO
NMeTs
NMeBoc
13
32
Scheme 5. A formal synthesis of ent-hydromorphone (7) with DAIB as an oxidant in
the key oxidative dearomatization/[4+2]cycloaddition step, instead of toxic lead
tetraacetate.
A formal synthesis of the natural enantiomer.
The unnatural enantiomer of hydromorphone (7, (−)-hydromorphone) is a useful
synthetic target as any route to it validates a significant percentage of the chemistry
required to synthesize the natural, bioactive enantiomer. We have previously reported a
strategy for the enantiodivergent synthesis of (+)- and (−)-codeine from 2-
phenethylbromide;14 this strategy can also applied to (+)-hydromorphone. The epoxide
37, obtained in 7 stepsfrom diol 8. The diene moiety in 8 was selectively reduced with
potassium azodicarboxylate (PAD), the diol functionality was protected as an acetonide,
and the halide was displaced by methylamine to yield 34, as described in literature.5
Further protection of the amine, hydrolysis of the acetonide, Mitsunobu reaction of 35 at
the allylic hydroxyl site and tosylation of the distal hydroxyl provided tosylate 36.
Hydrolysis of the nitrobenzoate led to an in situ formation of epoxide 37, which was
opened with potassium phenolate 38 to yield alcohol 39. Protection of the alcohol using
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TBS-Cl and imidazole provided TBS ether 40, i.e. ent-9, constituting a formal synthesis
5
6
of (+)-hydromorphone (Scheme 6).
7
8
9
1. PAD, AcOH
83%
HCl, H2O,
EtOH
Br
NMeBoc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeHN
O
NMeBoc
p-NO2BzO
HO
HO
HO
1. O2NBzOH,
DEAD, PPh3,
71%
2. TsCl, Et3N,
73%
then
Boc2O,
NaHCO3, 74%
2. 2,2-DMP,
TsOH, 80%
O
HO
TsO
8
3. MeNH2,
K2CO3, 93%
34
35
36
MeONa,
MeOH, THF
88%
CHO
CHO
NMeBoc
CHO
O
MOMO
NMeBoc
MOMO
NMeBoc
O
O
78%
TBS-Cl, DCM
imidazole
85%, "brsm"*
MOMO
OK
38
TBSO
HO
40
39
37
Scheme 6. Formal synthesis of (+)-hydromorphone (7). [* “brsm” = based on
recovered starting material].
Stereochemical outcome of the oxidation/[4+2] cycloaddition sequence in the model
system, with Pb(OAc)4 or DAIB as oxidants.
In our 1st generation approach5 the relative stereochemistry at C-4, C-12, and C-13 was
not assigned in adduct 12 (Scheme 1), although the stereochemistry at C-13 was
ultimately proved by the completion of the total synthesis. We therefore turned our
attention to the assignment of the relative stereochemistry of the cycloadducts.
Stereochemical analysis of the cycloadducts was carried out, where possible, by single
crystal X-ray diffraction or, in the cases where a suitable single crystal could not be
grown, by NMR methods.
The stereochemistry of the major product obtained during the Pb(OAc)4
oxidation/cycladdition sequence of the model substrate 18, namely 24, was analyzed by
selective 1D NOESY NMR. The observed NOE correlations allowed us to assign the
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stereochemistry to be all syn around the central furan ring (Figure 4, a; see SI Section for
a detailed analysis). A crystal structure was subsequently obtained and confirmed this
assignment.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the case of the oxidation with DAIB, column chromatography of the reaction mixture
following the cycloaddition step only allowed for the isolation of the minor diastereomer
20a; the major diastereomer 20b and the endocyclic adduct 26 were obtained as an
inseparable mixture. The relative configuration of the minor diastereomer 20a was
assigned by 1H and 2D NOESY NMR. Although NOE correlation between H-12 and H-
13 could not be directly resolved because of a signal overlap, several other NOE
correlations revealed a syn configuration among hydrogens H-5, H-12 H-13, H-14 and
methoxy group (Figure 4, b).The coupling constant between H-12 an H-13 was found to
be 9.8 Hz, similar to the constant found in acetate 24. Moreover, reduction of the enone
and further esterification led to NMR signal separation that allowed observation of NOE
correlation between H-12 an H-13. (see SI Section for detailed discussion of assignment).
Figure 4. Stereochemistry and structure of cycloadducts: (a) Isolated product of
Pb(OAc)4 oxidation/cycloaddition with observed NOE correlations and crystal
structure. (b) Minor diastereomer of DAIB oxidation/cycloaddition sequence with
observed NOE correlations. (c) Reduced major diastereomer of DAIB
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oxidation/cycloaddition sequence and crystal structure. (d) Esterified endocyclic
side product from DAIB oxidation/cycloaddition sequence with crystal structure.
6
7
8
9
In order to separate the major isomer 20b and endocyclic adduct 26, the mixture was
subjected to Luche reduction conditions to reduce carbonyl functionalities in 20b and 26.
The reaction provided allylic alcohols 41 and 42, respectively, which were then separable
by column chromatography (Scheme 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
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57
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HO
MeO
O
MeO
H
H
4
5
12
13
O
O
14
H
H
H
H
H
+
H
NaBH4, MeOH
.
20b
CeCl3 7H2O
41
, 57%
+
O
H
H
p-BrBzCl, TEA
DMAP, DCM,
O
H
H
OH
H
O
OMe
OMe
OMe
H
H
H
O
O
O
H
H
Br
H
26
42
43
, 14%
, 79%
Scheme 7. Luche reduction of the inseparable mixture of the main isomer 20b and
endocyclic product 26 and functionalization of endocyclic alcohol 42.
Single crystal X-ray analysis of 41 revealed a syn relationship between hydrogens H-5,
H-13 and H-14, with H-12 anti. The orientation of the methoxy group was shown to be
syn to hydrogen H-12 (Figure 4, c).
In order to grow single crystals suitable for X-ray diffraction, alcohol 42 needed to be
functionalized with a p-bromobenzoyl group to yield ester 43 (Scheme 7). The X-ray
structure (Figure 4, d) confirms the assignment of structure 26, which is consistent with
the observation made for similar compounds prepared by Rodrigo (Figure 3).13
(For a detailed discussion on stereochemistry analysis see the SI Section).
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Stereochemical outcome of the oxidation/[4+2] cycloaddition sequence of intermediate
10.
7
8
9
After the determination of the stereochemistry for the model system, we turned our
attention to cycloadducts 12 and 31. The stereochemistry of both compounds was
determined by NMR methods. The assignment was more straightforward in the case of
methoxyketal compound 31, where we could observe a NOE correlation between proton
H-6 and H-12, implying that both hydrogens are on the same side of the tetracyclic core
and thus anti to hydrogens H-5, H-14 and the ethylamino bridge (Figure 5). Such relative
stereochemistry would then correspond to the relative stereochemistry of the major
product 20b formed during the model study (Figure 4; a, b, c).
10
11
12
13
14
15
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17
18
19
20
21
22
23
24
25
26
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29
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31
32
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40
41
42
43
44
45
46
47
48
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50
51
52
53
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59
60
In contrast to the methoxyketal 31 or model compound 24, the stereochemistry of acetate
12 could not be ascertained by NOESY. However, consideration of the 1H NMR data
lead us to propose all-syn stereochemistry around the tetrahydrofuran ring in 12.
Comparison of the spectra of acetate 12 and methoxyketal 31 showed substantial
disparity (see SI), indicating that the structures were not analogous. In particular,
chemical shifts for H-10 and H-6 in 12 and 31 were 0.47 and 0.80 ppm apart. We
hypothesized that an all-syn geometry would result in the H-6 proton in 12 to be in
comparatively close proximity to the π-system of the dienone, resulting in an anisotropic
shielding effect of this atom. The same phenomenon was observed on H-6α in the related
model compound 24 where the H-6−C10 distance was determined to be 2.80 Å. We thus
concluded that the correct stereochemical assignment for the cycloadduct 12 is as
depicted in (Figure 5).
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O
O
O
O
6.63 ppm
H
H12
6.16 ppm
H
H
H
H
H
H
AcO
MeO
AcO
MeO
10
O
O
O
O
NOE
H
H
H
H
H
H
H
H
H
H
2.80 Å
TBSO
TBSO
2.02 ppm
H6
NMeBoc
2.05 ppm
H
H
NMeBoc
H
3.15 ppm
1.54 ppm
3.95 ppm
0.95 ppm
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
12
20b
24
31
Figure 5. Proposed stereochemical assignments of 31 and acetate 12 and comparison
of NMR data (12 and 31 in DMSO-d6 at 100 °C, 24 and 20b in CDCl3 at room
temperature; the C-10−H-6 distance was determined from the crystal structure).
Conclusion
We have developed a 2nd generation formal total synthesis of ent-hydromorphone 7,
replacing toxic Pb(OAc)4 by hypevalent iodine compound in the key oxidative
dearomatization/[4+2] cycloaddition step. Conditions for this step were investigated on a
simplified model system and later applied to the synthesis of methoxyketal 13 a known
intermediate in the synthesis of 7. By establishing conditions for rearomatization of
methoxyketal 31, the formal synthesis of the ent-7 was finalized. In addition, we have
reported also a formal total synthesis of the (+)- enantiomer of hydromorphone 7.
The stereochemical analysis of the cycloadducts from the oxidation/cycloaddition
sequence on the model compound 18 was carried out and indicates that using Pb(OAc)4
or DAIB has a crucial impact on the course of the cycloaddition. In the case of Pb(OAc)4,
the cycloaddition proceeds from an intermediate syn-23 (syn refers to the relationship
between the C-4 acetoxy group and hydrogen H-5) that underwent cyclization in an endo
fashion. In contrast, the outcome of the DAIB oxidation/cyclization sequence is different.
The main isolated cycloadduct is formed from an intermediate anti-19 (anti refers to the
relationship between the C-4 methoxy group and hydrogen H-5) in an exo fashion. The
minor diastereomer 20a and endocyclic side product 26 are both formed from syn-19, in
endo and exo fashion, respectively (Scheme 8).
The same trend was observed during the oxidation/cyclization sequence of 10. Using
Pb(OAc)4, the main product obtained was compound 12, with the all syn stereochemistry
around the furan ring (Figure 5) formed from an intermediate syn-44 in endo fashion.
When DAIB was used as an oxidant, the only cycloadduct isolated was compound 31,
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originating from intermediate anti-45. We did not detect any minor diastereomer 46 nor
endocyclic side product 47 (or only trace amounts of 46, when cyclization was carried
out at 120 °C).The reaction mixture after the cyclization was subjected to a careful
analysis. Attempts to detect the unreacted diastereomer anti-45, were unsuccessful.
Instead, several aliphatic products resulting from the decomposition of the starting
material were detected. Among these the major product was compound 48, resulting from
the elimination of the cyclohexenyl ether (likely from anti-45) and isolated in 32-37%
(Scheme 9).14 No explanation for this switch in selectivity when Pb(OAc)4 or DAIB is
used in the dearomatization is immediately apparent, though we tentatively hypothesize
that the residual Pb2+ salts formed as by-products of the oxidation may in some way
promote the endo process over the exo. Finally, several attempts were made at potential
double diastereoselection in the trapping of intermediates in the oxidative
dearomatization with chiral alcohols. These attempts did not lead to positive outcomes.
We attempted to perform the DAIB oxidations in the presence of secondary alcohols as
isopropanol, hexafluoroisopropanol, and 2-butanol. In each case the use of any larger
alcohol led to very complex mixtures and this approach was, for the time being,
abandoned.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, the quest for practical synthesis of morphinans must continue. We have
gained a good understanding of the stereochemical course of the [4+2] cycloaddition
approach to hydromorphone and produced 2nd generation, relatively short, formal total
syntheses of hydromorphone in both enantiomeric series. However, a true practicality is
still a distant task. We will continue to devote further effort to designing shorter
approaches to morphinans, as delineated in our recent review.2
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O
O
Pb(OAc)4,
DCE, 80°C
H
endo
[4+2]
AcO
AcO
4
5
12
13
O
O
14
H
7
H
H
H
8
9
23
syn-
24, 32-45%
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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58
59
60
O
O
O
H
MeO
MeO
exo
[4+2]
O
O
18
H
H
H
H
20b - major isomer, 43%
exo [4+2]
anti-19
1. DAIB,
MeOH
+
2. Tol, ꢀ
O
O
MeO
H
MeO
O
endo
[4+2]
H
+
OMe
O
O
H
O
H
H
H
H
H
20a
26
, 16%
- minor isomer, 11%
19
syn-
Scheme 8. Stereochemical course of oxidation of the model compound.
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O
O
AcO
H
Pb(OAc)4,
DCE, 80°C
AcO
4
5
12
13
endo [4+2]
O
O
H
14
TBSO
7
H
H
8
9
NMeBoc
TBSO
NMeBoc
, 50%
44
syn-
12
HO
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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60
TBSO
O
O
MeO
H
MeO
NMeBoc
exo [4+2]
O
H
O
10
TBSO
H
H
NMeBoc
TBSO
NMeBoc
1. DAIB,
MeOH
45
anti-
31
, 20-30%
exo [4+2]
2. Tol, ꢀ
X
+
O
O
H
MeO
H
O
MeO
OMe
+
O
O
H
O
TBSO
BocMeN
H
H
H
NMeBoc
TBSO
NMeBoc
syn-45
46
47
, 0%
X
(trace amounts)
endo [4+2]
NMeBoc
HO
TBSO
48
, 32-37%
Scheme 9. Oxidation of intermediate 10 using DAIB, leading to the formation of
desired product 31 and product of degradation 48.
Experimental Section
Materials and methods.
All solvents were used as obtained unless otherwise stated. All reagents were obtained
from commercial sources. NMR analysis was carried out on 300, 400 and 600
spectrometers running Topspin 2.1 and 3.5 software. Probes were equipped with
gradients and VT (variable temperature) accessory.
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Chemical shifts are given in δ-scale, coupling constants J are given in Hz. Melting points
were determined using a capillary melting point apparatus. Mass spectra (HRMS)
measurements were recorded using LTQ Orbitrap XL or double focusing sector (DFS)
mass spectroscopy and the mass ion was determined by electrospray ionization, fast atom
bombardment or electron ionization. Infrared spectra were recorded on a FT-IR
spectrophotometer as CHCl3 solutions and are reported in wave numbers (cm-1). Flash
grade 60 silica gel was used for column chromatography. TLC was performed on silica
gel 60 F254-coated aluminum sheets.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(Ethoxymethoxy)-3-hydroxybenzaldehyde (15) The selective protection of the para-
hydroxyl group in 3,4-dihydroxybenzaldehyde was performed according to a published
procedure for protections with the MOM group.15 3,4-Dihydroxybenzaldehyde 14 (30g,
0.22 mol) and oven-dried K2CO3 (90g, 0.65 mol) were dissolved in freshly distilled
acetonitrile (350 mL). The reaction mixture was stirred for 30 min and kept under
positive argon pressure. Then, EOMCl (20.15 mL, 0.22 mol) was added at once (an
exotherm was observed) and the mixture was stirred overnight. After 15 h, water was
added followed by 10% NaOH (350 mL). The mixture was washed with ethyl acetate
(350 mL). The aqueous layer was acidified to pH 8-9 and the mixture was extracted three
times with ethyl acetate (500 mL). The residual starting material was washed away by
saturated solution of sodium carbonate. The organic layer was washed with brine and
dried over MgSO4. Evaporation of the solvent provided 21.4-25.9 g (49-60%) of the
desired mono-protected phenol as a brown oil.
15: Rf = 0.2 [hexane/EtOAc (2:1)]; IR(neat) ν 3367, 2977, 2896, 1678, 1606, 1585, 1504,
1460, 1442, 1416, 1394, 1345, 1269, 1243, 1201, 1153, 1104, 1081, 964, 881, 787, 755,
655, 621, 583, 541, 499, 459 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 7.44 (d, J
= 1.9 Hz, 1H), 7.39-7.36 (dd, J = 8.3, 1.9 Hz, 1H), 7.22 (d, J = 8.3Hz, 1H), 3.74 (q, J =
13
7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H) C NMR (75 MHz, CDCl3) δ 191.4, 149.9, 131.5,
124.3, 115.0, 114.5, 94.1, 65.3, 15.1; HRMS (TOF MS ES+) calcd for [C10H12O4 + H+]:
197.0814. Found 197.0813; Anal.Calcd for C10H12O4: C, 61.22; H, 6.16. Found C, 60.77;
H, 6.26.
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3-(Cyclohex-2-en-1-yloxy)-4-(ethoxymethoxy)benzaldehyde (16) LiAlH4 (4.9 g) was
suspended in dry Et2O (125 mL) and cooled to 0 °C. After stirring for 15 min a solution
of cyclohex-2-enone (25 mL) in Et2O (50 mL) was added dropwise. Once the addition
was complete the reaction mixture was allowed to warm to room temperature and stirred
for 3 h. The reaction was then cooled to 0 °C and quenched according to the Fieser
procedure: H2O (4.9 mL), 15% NaOH (4.9 mL) and water (14.7 mL) were added
dropwise, after which the reaction mixture was stirred at room temperature for 1 h, and
the salts removed by filtration. The solids were washed with Et2O and the combined
ethereal solution was washed with brine, dried (Na2SO4), and the solvent removed in
vacuo to yield the pure allylic alcohol (24.1 g, 95%), which was used as such in the next
step.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a solution of cyclohex-2-enol (5 mL, 50 mmol) in dichloromethane (6 mL) at 0 °C
was added acetyl chloride (4 mL, 56 mmol) dropwise. The reaction mixture was stirred
for 3 h at 0 °C, after which it was diluted with hexanes (20 mL) and washed with water (2
× 20 mL). The organic layer was dried (MgSO4) and the solvents removed in vacuo to
yield the corresponding allylic chloride (5.4 g, 93%), which was used without further
purification.
To a suspension of K2CO3 (0.76 g, 5.5 mmol) in acetone (5 mL) was added phenol 15 (1
g, 5.1 mmol) followed by the addition of the cyclohexenyl chloride (0.64 g, 5.5 mmol).
The resulting suspension was refluxed for 18 h. The reaction mixture was allowed to cool
to room temperature, filtered, and the solids were washed with acetone (25 mL). The
filtrate was evaporated, the crude product was adsorbed on silica gel, and purified by
column chromatography (hexane/EtOAc 19:1 to 9:1) to yield the desired product as a
yellowish oil (0.99 g, 70%).
16: Rf = 0.1 [hexane/EtOAc (9:1)]; IR(neat) ν 2975, 1686, 1503, 1433, 1392, 1334, 1315,
1255, 1223, 1158, 1125, 1104, 1082, 974, 847, 814, 760, 726, 667, 619, 586 cm-1;1H
NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.48-7.47 (d, J = 1.9 Hz, 1H), 7.43-7.40 (dd, J =
8.3, 1.9 Hz, 1H), 7.27-7.25 (d, J = 8.3 Hz, 1H), 5.99-5.96 (m, 1H), 5.88-5.85 (m, 1H),
5.33 (s, 2H), 4.85 (br, 1H), 4.78-4.72 (q, J = 7.1 Hz, 2H), 2.16-1.98 (m,2H), 1.97-1.81
(m, 3H), 1.69-1.59 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 13C NMR (75 MHz, CDCl3) δ 191.1,
153.7, 148.7, 132.6, 131.1, 126.3, 126.1, 116.0, 114.3, 93.8, 72.8, 64.8, 28.3, 25.2, 19.2,
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15.2; HRMS (TOF MS ES+) calcd for [C16H20O4+H]+: 277.1434 Found 277.1441; Anal.
Calcd for C16H20O4: C, 69.54; H, 7.30.Found C, 69.73; H, 7.36.
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3-(Cyclohex-2-en-1-yloxy)-4-hydroxybenzaldehyde (17) The protected phenol 16 (4g,
14.5 mmol) was dissolved in ethanol (150 mL) and PPTS (1.3g, 5.2 mmol) was added.
The reaction mixture was heated to 60°C and stirred for 24 h, after which the solvent was
evaporated, the remaining mixture was adsorbed on silica gel and subjected to column
chromatography (hexanes/EtOAc 9:1 to 4:1), yielding 17 as a white solid (715 mg, 63%).
17: Rf = 0.1 (hexane/EtOAc 9:1); mp 82-83 °C (Hexanes/Ethyl Acetate); IR(neat) ν 3265,
2931, 2863, 1666, 1591, 1508, 1439, 1391, 1255, 1151, 1116, 1034, 925, 903, 860, 805,
728, 655, 629, 583, 529, 463, 454 cm-1;1H NMR (300 MHz, CDCl3) δ 9.81 (s, 1H), 7.45
(d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.0, 1.8 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H),
6.08 – 5.97 (m, 1H), 5.84 (dd, J = 10.2, 2.9 Hz, 1H), 4.94 (m, J = 3.7, 1.8 Hz, 1H), 2.09
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(m, 2H), 2.03 – 1.94 (m, 2H), 1.94 – 1.88 (m, 1H), 1.88 – 1.81 (m, 1H); C NMR (75
MHz, CDCl3) δ 191.0, 152.7, 145.4, 133.4, 127.4, 125.3, 114.7, 111.3, 72.8, 28.3, 25.1,
19.0, HRMS (TOF MS ES+) calcd for [C13H14O3+H]+: 219.1021 Found 219.1019; Anal.
Calcd for C13H14O3: C, 71.54; H, 6.47. Found C, 71.48; H, 6.47.
2-(Cyclohex-2-en-1-yloxy)-4-vinylphenol (18) A Schlenk tube was charged with
methyltriphenylphosphonium bromide (5.8 g, 16.2 mmol) and placed under argon
atmosphere. THF (30 mL) was added and the mixture was cooled to −78 °C. n-BuLi
(5.98 mL, 2.6M) was added slowly and the mixture was allowed to warm to room
temperature. The reaction mixture turned orange. After 30 min the mixture was cooled to
−78 °C and a solution of the aldehyde 17 (1.01g, 4.6 mmol) in THF (30 mL) was added.
The resulting mixture was allowed to slowly warm up to room temperature and then was
stirred overnight. Adsorption on silica gel and suction filtration column
chromatography16 with hexane/ethyl acetate mixture (19:1 to 9:1) provided 18 as a
yellowish oil (3.3 g, 93%).
18: Rf = 0.2 [hexane/EtOAc (9:1)]; IR(film) ν 3514, 2931, 1628, 1603, 1506, 1432, 1398,
1370, 1265, 1233, 1195, 1151, 1115, 1058, 1022, 9878, 964, 935, 899, 855, 819, 799,
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731, 696, 601, 553, 443 cm-1; H NMR (300 MHz, CDCl3) δ 6.99-7.00 (d, J = 1.9 Hz,
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1H), 6.92-6.91 (d, J = 1.9 Hz, 1H), 6.90 (s, 1H), 6.67-6.58 (dd, J = 17.6, 10.9 Hz, 1H),
6.03-5.97 (m, 1H), 5.90-5.84 (m, 1H), 5.76 (s, 1H), 5.60-5.54 (dd, J = 17.6, 0.8 Hz, 1H),
5.13-5.10 (dd, J = 17.6, 0.8 Hz, 1H), 4.85 (br, 1H), 2.22-2.04 (m, 2H), 2.02-1.89 (m, 2H),
1.87-1.77 (m, 1H), 1.74-1.61 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 146.9, 144.8, 136.8,
132.9, 130.3, 126.0, 120.3, 114.7, 111.5, 111.2, 72.8, 28.6, 25.2, 19.1;HRMS (TOF MS
ES+) calcd for C14H16O2 + Na+: 239.1059 Found 239.1060; Anal. Calcd for C14H16O2: C,
77.75; H, 7.46. Found: C, 77.71; H, 7.62.
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4-(1,2-Dimethoxyethyl)-2-methoxyphenol (21) To a cylindrical electrochemical cell
equipped with a platinum wire working electrode and copper wire counter-electrode was
added phenol 16 (53 mg, 0.24 mmol) and NaClO4 (750 mg, 6.1mmol). The cell was
purged with argon and dry, freshly distilled, methanol (50 mL) was added. The solution
was stirred for 10 min while being de-gassed with a flow of argon. The solution was then
subjected to electrolysis at 50 mA for 15 min (95% conversion). The solvent was
removed under reduced pressure, water (10 mL) was added, and the mixture was
extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried
(Na2SO4), the solvent removed in vacuo, and the residue was purified by column
chromatography (gradient column, 9:1 to 1:1 hexanes/EtOAc), and the product was
isolated as a colourless oil (35 mg, 67%).
21: Rf = 0.2 [hexane/EtOAc (2:1)]; IR(neat) ν 3514, 2931, 1628, 1603, 1506, 1432, 1398,
1370, 1265, 1233, 1195, 1151, 1115, 1058, 1022, 9878, 964, 935, 899, 855, 819, 799,
1
731, 696, 601, 553, 443 cm-1; H NMR (300 MHz, CDCl3) δ 6.91 (d, J = 8.0 Hz, 1H),
6.87 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 8.0, 1.8 Hz, 1H), 5.66 (s, 1H), 4.33 (dd, J = 8.2, 3.5
Hz, 1H), 3.92 (s, 3H), 3.59 (dd, J = 10.4, 8.2 Hz, 1H), 3.42 (dd, J = 10.4, 3.5 Hz, 1H),
3.41 (s, 3H), 3.30 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 146.9, 145.6, 130.9, 120.4,
114.4, 109.1, 82.9, 77.5, 59.4, 56.9, 56.1. HRMS (TOF MS EI+) calcd for [C11H16O4]+:
212.1049 Found 212.1043.
General procedure for the oxidation. Phenol 18 (50 mg, 0.23 mmol) and
diacetoxyiodobenzene (89.0 mg, 0.28 mmol) were weighed in two separate 20 mL
Wheaton vials, sealed with rubber septa, and the atmosphere was exchanged for argon,
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following the Schlenk technique. Freshly distilled methanol (5 mL) was added to both
vials and the solution of phenol was cooled to −15 °C degrees. The solution of DAIB was
then transferred into the solution of the phenol via syringe pump over 1 h. After the
transfer was finished, the solution was poured into 50 mL round bottom flask or a
pressure vial and toluene (10 mL) was added. The resulting mixture was degassed by
purging argon through the solution, while the flask was submerged in an ultrasonic bath.
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After 15 min, the mixture was heated to 80 oC (in a 50 mL round bottom flask) or 120 C
(in a pressure vial) and stirred for 18 h. After the reaction was complete, the mixture was
adsorbed onto silica gel and the product was purified by column chromatography
(hexane/EtOAc 9:1).
3a-Methoxy-3a1,4a,4a1,5,6,7,7a,8-octahydrophenanthro[4,5-bcd]furan-3(3aH)-one
(20a) Isolated as a yellowish oil (6.2 mg, 11%). Rf = 0.2 [hexane/EtOAc (9:1)]; 1H NMR
(300 MHz, CDCl3) δ 7.01 (d, J = 10.2 Hz, 1H), 6.28 (dd, J = 6.8, 3.8 Hz, 1H), 5.91 (d, J
= 9.8 Hz, 1H), 4.52 – 4.23 (m, 1H), 3.56 (s, 3H), 3.20 – 2.77 (m, 2H), 2.50 – 2.29 (m,
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1H), 2.19 (m, 1H), 1.94 (m, 1H), 1.55 (s, 3H), 1.32 – 1.04 (m, 3H); C NMR (75 MHz,
CDCl3) δ 193.3, 145.1, 136.0, 134.5, 124.6, 100.6, 79.5, 51.7, 47.8, 38.3, 31.4, 30.9, 28.2,
27.9, 18.7; HRMS (TOF MS I+) calcd for [C15H18O3]+: 246.1256 Found 246.1246; Anal.
Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.41; H, 7.51.
3-Oxo-3,3a,3a1,4a,4a1,5,6,7,7a,8-decahydrophenanthro[4,5-bcd]furan-3a-yl acetate
(24) Phenol 18 (216 mg, 1 mmol) was dissolved in 1,2-dichloroethane (10 mL) and the
solution was heated to reflux, at which point a solution of lead tetraacetate (531 mg, 1.2
equiv) in 1,2-dichloroethane (10 mL) was added dropwise. The reaction mixture was
stirred at reflux for 2 h, after which it was allowed to cool to room temperature, filtered
through a pad of Celite, and the solvent was removed in vacuo. The dark yellow residue
was purified by column chromatography (hexane/EtOAc 19:1 to 4:1) to yield the product
(114 mg, 42%) as a yellowish oil.
24: Rf = 0.1 [hexane/EtOAc (9:1)]; 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 9.9 Hz,
1H), 6.43 (dt, J = 6.8, 3.6 Hz, 1H), 6.00 (d, J = 9.9 Hz, 1H), 4.62 (td, J = 9.9, 6.8 Hz,
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1H), 3.41 (d, J = 9.5 Hz, 1H), 3.15 – 3.03 (m, 1H), 2.55 – 2.42 (m, 1H) 2.33 (d, J = 1.9
Hz, 1H), 2.12 – 1.93 (m, 1H), 1.83 – 1.55 (m, 2H), 1.45 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ138.3, 132.4, 125.6, 122.7, 108.6, 77.7, 73.1, 50.0, 46.0, 36.7, 32.8, 31.1, 30.5,
29.8, 22.2; HRMS (FAB, NBA matrix) calcd for [C16H18O4+Na]+: 297.1097 Found
297.1111.
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4a,4a1,5,6,7,7a-Hexahydrophenanthro[4,5-bcd]furan-3-ol (25) Isolated as a yellowish
oil (21.4 mg, 10%). 1H NMR (300 MHz, CDCl3) δ 6.66 (dd, J = 7.9, 1.1 Hz, 1H), 6.56 (d,
J = 7.9 Hz, 1H), 6.41 (d, J = 9.6, 1H), 5.83 (dd, J = 9.6, 6.3 Hz, 1H), 5.14 (dt, J = 10.0,
8.1 Hz, 1H), 4.82 (s, 1H), 3.60 (t, J = 8.1 Hz, 1H), 2.69 – 2.49 (m, 1H), 2.14 – 2.04 (m,
1H), 1.71 – 1.51 (m, 2H), 1.37 – 1.27 (m, 1H), 1.15 – 1.00 (m, 1H), 0.97 – 0.86 (m, 1H).
13C NMR (150 MHz, CDCl3) δ 143.3, 140.6, 130.7, 124.0, 117.6, 115.7, 100.1, 86.9,
77.4, 38.6, 34.3, 29.2, 28.0, 20.3. HRMS (TOF MS EI+) calcd for [C14H14O2]+: 214.0988
Found 214.0989.
tert-Butyl (2-((3S,3aS,3a1R,4aS,4a1R,9aR)-3-((tert-butyldimethylsilyl)oxy)-4a-
methoxy-5-oxo-1,2,3,3a,3a1,4a,4a1,5,9,9a-decahydrophenanthro[4,5-bcd]furan-3a1-
yl)ethyl)(methyl)carbamate (31) Phenol 10 (100 mg, 0.2 mmol) and
diacetoxyiodobenzene, (DAIB), (83.1 mg, 0.26 mmol) were weighed into two 20 mL
Schlenk flasks, each sealed with a rubber septum, and the atmosphere was exchanged for
argon, following the Schlenk technique. Freshly distilled methanol (4.2 mL) was added
into both vials and the solution of phenol was cooled to −15 °C degrees. The solution of
DAIB was then transferred into the solution of phenol via a syringe pump over 1 h. After
the transfer was finished, a saturated solution of NaHCO3 was added slowly to the
mixture. The mixture was then extracted with dichloromethane (3 ×15 mL), the combined
organic layers were dried over MgSO4, and solvents were evaporated under reduced
pressure. Crude material was re-dissolved in dry toluene (10 mL).The resulting mixture
was degassed by purging argon through the solution, while the flask was submerged in an
ultrasonic bath. After 15 min, the mixture was heated to reflux and stirred for 18 h. After
the reaction was complete, the mixture was adsorbed on silica gel and the product was
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purified by column chromatography (hexane/EtOAc 9:1), yielding the title compound as
a yellow oil (21.4 – 32.0 mg 20-30%).
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31: Rf= 0.2 [hexane/EtOAc (7:3)]; IR(film) ν 2959, 2927, 2858, 1681, 1622, 1482, 1462,
1393, 1266 cm-1; [α] D 20 = +25.0 (c = 0.45, CHCl3); 1NMR (300 MHz, CDCl3) δ 7.07 (d,
J = 9.8 Hz, 1H), 6.03 (s, 1H), 5.95 (d, J = 9.8 Hz, 1H), 3.92 (dt, J = 19.6, 6.2 Hz, 2H),
3.48 (b, 1H), 3.37 (s, 3H), 3.09 (s, 1H), 2.71 (s, 3H), 2.24 (b, 1H), 2.06 (d, J = 17.0 Hz,
2H), 1.78 (m, 3), 1.42 (s, 9H), 1.29 – 1.06 (m, 4H), 0.90 (s, 9H), 0.12 (s, 3H), 0.08 (s,
3H).13C NMR (75 MHz, DMSO, 100°C) δ 189.4, 154.1, 142.8, 132.3, 131.7, 124.6, 99.3,
87.4, 72.4, 51.0, 49.7, 49.3, 43.9, 33.1, 32.5, 31.7, 31.5, 28.2, 27. 6, 26.9, 25.2, 17.1, -4.9,
-5.1; HRMS (TOF MS FAB+) calcd for [C29H47NO6Si+Na]+: 556.3065 Found 556.3075.
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(4aS,4a1R,5S)-5-((tert-Butyldimethylsilyl)oxy)-4a1-(2-(N,4-
dimethylphenylsulfonamido)ethyl)-4a,4a1,5,6,7,7a-hexahydrophenanthro[4,5-
bcd]furan-3-yl 4-methylbenzenesulfonate (13) Enone 31 (36 mg, 0.06 mmol) was
dissolved in dry dichloromethane (0.65 mL) and the mixture was cooled to -78 °C. TMSI
(18.2 ꢁL, 0.13 mmol) was added at once and the mixture was stirred for 30 min. Solution
of TFA in dichloromethane (1:4, 4 mL) was added and mixture was stirred at 0°C for 10
min. The reaction mixture was quenched by saturated solution of NaHCO3 and the layers
were separated. The organic layer was dried with Na2SO4, and the solvent was removed
under reduced pressure. The resulting crude mixture was re-dissolved in dichloromethane
(0.65 mL), and triethylamine (19.6 ꢁL, 0.14 mmol) and tosyl chloride (27 mg, 0.14
mmol) were added. The mixture was stirred overnight at room temperature. Saturated
solution of NH4Cl was then added and the layers were separated. The organic layer was
dried over Na2SO4 after which the mixture was adsorbed on silica gel and subjected to
column chromatography, yielding the title compound as a yellowish oil (17.4 mg, 41%).
Spectral data were in agreement with those in the literature.5
tert-Butyl (2-((5R,6R)-6-(5-formyl-2-(methoxymethoxy)phenoxy)-5-
hydroxycyclohex-1-en-1-yl)ethyl)(methyl)carbamate (39) Epoxide 37 was prepared
according to the procedure described in reference 14. To a solution of 37 in DME (0.5
mL) was added potassium phenoxide 38 followed by the addition of 18-crown-6-ether (3
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