Strategies, Setbacks, and Successes in the Synthesis of (-)-Spiroleucettadine

Article abstract of DOI:10.1021/acs.joc.8b01404

Various strategies toward the synthesis of the marine natural product (-)-spiroleucettadine are described. In the original strategy, a biomimetic inspired oxidation of a 2-imidazoline scaffold uncovered unexpected reactivity, where benzylic oxidation followed by a Baeyer-Villiger reaction was observed. The second generation approach examined oxidative dearomatization of the phenol ring system first, where a competing spirocyclization process was uncovered. Efforts to forge the scaffold via a carbocation mediated benzyl migration were unsuccessful. Highlights of the successful synthesis include two consecutive hypervalent iodine reactions: the first formed the spirocyclic center and the second facilitated installation of an acetate group at the C-5 position to allow for subsequent introduction of the methyl amine side chain.

Full text of DOI:10.1021/acs.joc.8b01404

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Article
Strategies, Setbacks and Successes in the Synthesis of (-)-Spiroleucettadine
Richard A Lamb, Nigel T. Lucas, Guillaume Lessene, and Bill Corey Hawkins
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01404 • Publication Date (Web): 13 Jul 2018
Downloaded from http://pubs.acs.org on July 14, 2018
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Strategies, Setbacks and Successes in the Synthesis of (−)ꢀSpiroleucettadine
a
a
,b,c
,a
Richard A. Lamb, Nigel, T. Lucas, Guillaume Lessene* and Bill C. Hawkins*
a
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand
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b
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052,
Australia
c
Department of Medical Biology and Department of Pharmacology and Therapeutics, The
University of Melbourne, Parkville 3050, Australia
bhawkins@chemistry.otago.ac.nz
glessene@wehi.edu.au
Graphical Abstract
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Abstract
Various strategies toward the synthesis of the marine natural product (ꢀ)ꢀspiroleucettadine are
described. In the original strategy, a biomimetic inspired oxidation of a 2ꢀimidazoline
scaffold uncovered unexpected reactivity, where benzylic oxidation followed by a Baeyerꢀ
Villiger was observed. The second generation approach examined oxidative dearomatization
of the phenol ring system first, where a competing spirocyclization process was uncovered.
Efforts to forge the scaffold via a carbocation mediated benzyl migration were unsuccessful.
Highlights of the successful synthesis include two consecutive hypervalent iodine reactions:
the first formed the spirocyclic centre and the second facilitated installation of an acetate
group at the Cꢀ5 position to allow for subsequent introduction of the methyl amine side chain.
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Introduction
Marine natural products continue to be an invaluable source of biologically active and
structurally fascinating compounds. Among these is spiroleucettadine which was isolated
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from the Leucetta sea sponge in 2004. The discovery of spiroleucettadine was met with
international interest as it exhibited a novel structure featuring a highly strained 5,5ꢀtransꢀ
fused 2ꢀamino imidazoleꢀoxolane core that was seemingly able to sustain an unusual orthoꢀ
amide type functional group. Very few natural products contain 5,5ꢀtransꢀfused bicyclic ring
systems as opposed to the more common cisꢀisomer, however some examples have been
2ꢀ6
reported, the most famous being palau’amine. Additionally, spiroleucettadine was also
shown to possess moderate antiꢀbacterial activity (minimum inhibitory activity MIC <6.25
7
µg/mL against Enterococcus durans), making it an interesting target molecule for total
synthesis. In the following years, several independent groups published studies toward the
natural product, all of which relied on a hypervalent iodineꢀmediated oxidative
8
ꢀ10
dearomatization (Figure 1) to furnish the spirocylic core.
Isolation of the ringꢀopened
tautomer instead of the proposed natural product structure 8, cast doubt on the viability of the
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proposed structure. Furthermore, closer examination of the available analytical data revealed
several areas of concern regarding the regiochemistry of the oxygen atom in the oxolane
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ring.
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Figure 1. Originally assigned structure (1) and revised structure (2) of spiroleucettadine,
representative Leucetta alkaloids naamidine A (3), naamine A (4), spirocalcaridine A (5a),
8ꢀ
spirocalcaridine B (5b), spironaamidine (6) and failed oxidative spirocyclization towards 1.
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Prompted by these failures and the mystery still surrounding 1, the natural product
was reꢀisolated from some left over Leucetta sponge material, which ultimately led to the
structural revision of the natural product to 2, supported by Xꢀray crystal analysis and by
DFT calculations. The interesting spirocyclic framework of spiroleucettadine and its polar
core densely packed with heteroatoms, as well as its antibacterial activity amount to an
enticing synthetic target. We recently reported a nine step enantiospecific synthesis of (ꢀ)ꢀ
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11ꢀ12
spiroleucettadine.
Herein we detail some of the failed strategies and challenges we faced
that eventually led us to the successful route to complete the total synthesis of (ꢀ)ꢀ
spiroleucettadine.
Results and Discussion
Our first retrosynthetic analysis was inspired by the presumed biosynthetic link
between the naamines (4, Figure 1) and the more oxidized spirocyclic Leucetta congeners (2,
5a/b, 6, Figure 1), where a naamine type framework would be converted to the natural
product following oxidation of the 2ꢀimidazole double bond and oxidative dearomatization of
the phenol moiety. Our initial retrosynthetic analysis (Scheme 1) was drawn up with these
presumed biosynthetic links in mind. The natural product 2 could be accessed from the hemiꢀ
N
aminal 9 by a simple S 1 type substitution, which could in turn be synthesized from diol 10
by a hypervalent iodine mediated spirocyclization. Diol 10 would be accessed via
dihydroxylation of the olefin on imidazolone 11, which we envisioned constructing through
reaction of an αꢀamino ketone with an isocyanate synthon and subsequent condensation. It
was noted that this approach would ultimately lead to the racemate of 2, however this was not
of immediate concern as once the issues of chemical connectivity were dealt with, strategies
towards an asymmetric synthesis could be developed.
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Scheme 1. First generation retrosynthetic analysis of spiroleucettadine 2
In a forward synthetic sense our synthesis began with the commercially available
protected Lꢀtyrosine 13, which was smoothly converted to the corresponding Weinreb amide
13
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4 using EDCI and HOBT amide coupling reagents (Scheme 2). For the forthcoming
exploratory chemistry, we decided to initially substitute the requisite 4ꢀmethoxybenzyl
Grignard reagent with benzylmagnesium chloride as it was more synthetically tractable and
cheaper. With the chemistry established on the benzyl series we then applied the optimised
reaction conditions to the 4ꢀmethoxybenzyl series. Treatment of 14 with the appropriate
benzylmagnesium chloride smoothly provided ketones 15/16 in moderate yields. Boc
deprotection using concentrated HCl yielded the corresponding HCl salts (70ꢀ74%, not
shown) and reaction of these salts with Nꢀmethyl carbamoylimidazole furnished the
corresponding 2ꢀimidazolones in a 33ꢀ36% yield. Boc protection of the imidazolone
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nitrogens was achieved with two equivalents of Boc anhydride and stoichiometric DMAP
(72ꢀ76% yield) while the benzyl ether protecting groups could subsequently be removed
using standard hydrogenolysis reaction conditions (87ꢀ90% yield).
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Scheme 2. Synthesis of 2ꢀimidazolones.
With the Boc protected substrates 20ꢀ23 in hand, a series of dihydroxylation
experiments were conducted in order to probe the viability of the proposed synthetic
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sequence. Oxidation with DMDO and OsO resulted in decomposition of the starting
material, even at −78 °C in the case of DMDO. However, reaction of 20 with one equivalent
of mCPBA at 0 °C resulted in formation of the enamides 24a and 24b along with unreacted
starting material (Scheme 3). This mixture was resubjected to a further three equivalents of
mCPBA which resulted in the isolation of αꢀhydroxyꢀhydantoin 25 and overꢀoxidized
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compound 26. Presumably compound 25 arises from an epoxidationꢀBaeyerꢀVilliger over
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oxidation sequence followed by hydrolysis of the benzoate substituent (Scheme 3).
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Scheme 3. Attempted epoxidation of 20 using mCPBA, and proposed mechanism for the
formation of 25 and 26, BV = Baeyer Villiger.
Reaction of 20 with one equivalent of Davis’ oxaziridine resulted in formation of a
mixture of 24a and b in a 2:3 ratio, respectively, in a 40% combined yield with no sign of the
desired epoxide (Scheme 4). These compounds could not be entirely separated by column
chromatography as they both had very similar retention times on silica gel, however some
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pure fractions could be obtained for 2D NMR analysis. Interestingly, while more of the E
isomer 24a formed initially (based on the crude NMR spectrum), following purification this
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compound would slowly isomerize while standing in CDCl to form the E/Z mixture 24a and
b in a 1:3 ratio, respectively, thereby suggesting that the Z isomer 24b is the thermodynamic
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product.
Ph
SO Ph
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acetone, rt
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40%
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24a/b (2:3, E:Z)
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H+
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BnO
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Ph
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Me
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24b
Scheme 4. Attempted epoxidation of 20 using Davis’ oxaziridine.
Despite this disappointing result, we realized that a potentially simple way of solving
this problem would be to change the order of oxidations, that is, performing the oxidative
dearomatization first (Scheme 5). Spiroquinone 9 could be accessed from cyclohexadienone
27 through oxidation of the imidazolone double bond, which would in turn be accessed by
oxidative dearomatization of the phenol 28 in the presence of water. To this end, compound
23 was reacted with phenyliododiacetate (PIDA) in the presence of water, which resulted in
the isolation of the spirocarbamate 29 in a 34% yield (Scheme 6). Several examples of this
type of spirocyclization can be found in the literature, notably the synthesis of
15
dihydronavirine and atisine skeletons as well as the construction of the core structure for
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hetidines and hetisines. In order to block formation of the spirocarbamate 29, dimethyl
imidazolone 32 was prepared and subjected to the same oxidative conditions, which resulted
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in decomposition of the starting material. Acid and base catalyzed cleavage of the
spirocarbamate 29 was considered, which would presumably break open the carbamate
functional group to furnish the corresponding tertiary alcohol. Treatment of the
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spirocarbamate 29 with one equivalent of NaOMe at ꢀ78°C initially looked promising by
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TLC analysis which indicated the formation of one new compound, however following workꢀ
up, analysis of the NMR spectrum and TLC indicated formation of a complex mixture.
2 4
Compound 29 was also unreactive to acid hydrolysis using a few drops of conc. H SO with
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heating and did not appear to react with Davis’ oxaziridine, even at reflux in toluene.
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Hydrolysis of 29 with LiOH resulted in decomposition.
Scheme 5. Alternative order of oxidations: oxidative dearomatization of the phenol followed
by double bond oxidation.
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Scheme 6. Synthesis of spirocarbamate 29 and dimethyl imidazolone 32.
The next oxidative dearomatization strategy focussed on synthesis of the tertiary alcohol 37
through a speculative carbocation induced rearrangement of compound 34 (Scheme 7). There
is precedent for this type of transformation in the literature which involves tandem
transposition and πꢀcyclization of Nꢀacyl iminium species generated from αꢀ
20
hydroxyspirolactams. In our case, breaking the hemiꢀaminal ether bond of 34 would be
facilitated by addition of a Lewis or Brønsted acid to form the intermediate iminium ion 35.
Migration of the 4ꢀmethoxybenzyl group would then be driven by the formation of the more
stabilized tertiary carbocation/iminium ion 36 from a secondary carbocation/iminium ion,
which would then undergo elimination to form the desired compound 37. This would not
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only overcome the problematic hypervalent iodine oxidation discussed earlier, but would also
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Scheme 7. Alternative strategy for the synthesis of compound 37.
To this end the Boc protected hydantoin 40 was prepared from the tyrosine derivative in 64%
yield over three steps (Scheme 8). It was found that the most effective way to introduce the 4ꢀ
methoxybenzyl substituent was to use LiHMDS to generate the corresponding enolate at ꢀ78
°C in the presence of HMPA followed by treatment with 4ꢀmethoxybenzyl chloride which
provided compound 41 in a 65% yield. Boc deprotection followed by benzyl ether removal
gave compound 42, chemoselective carbonyl reduction was achieved by treatment with three
equivalents of DIBALꢀH at 0 °C to furnish 43 in a 23% yield over three steps. Unfortunately,
treatment of compound 43 with PIDA gave aldehyde 44 and the desired spiroquinone 34 in a
ratio of 5:1, respectively. The ratio of products could not be tipped in favour of the desired
compound 34 despite trying numerous reaction conditions, including conducting the reaction
in an acidic media and at lower reaction temperatures.
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 8. Synthesis of compound 34 and 44.
The aldehyde 44 arises from the nucleophilic attack on the ipso carbon of the phenol by the
ring opened urea nitrogen 45 (Scheme 9). The ratio of products 34 and 44 remained relatively
constant despite varying reaction conditions suggesting an equilibrium or a reversible
reaction from the cyclohexadienones.
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8
9
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1
2
3
4
5
6
7
8
9
0
Scheme 9. Postulated mechanism for the formation of aldehyde 44.
Assessing these initial attempts, we realised that many problems needed to be
overcome if we were to complete the synthesis. One of the main issues with the first
generation approach was that the syntheses of imidazolones 18 and 19 were low yielding
which made experiments exploring the viability of its further elaboration inconvenient. In
order to remedy this a new approach towards the important intermediates was conceived: a
nucleophilic addition of a suitable Grignard reagent to hydantoin 39 and subsequent
dehydration would form 18/19 (Scheme 10). To our surprise, treatment of hydantoin with
benzylmagnesium chloride resulted in formation of aminol 46 instead of the presumed
dehydrated product 18, when the reaction was quenched with a saturated aqueous solution of
4
NH Cl. Quenching the reaction with 1 M HCl or reaction of aminol 46 with a few drops of
1
M HCl in acetone resulted in formation of the eliminated product 18. It was also found that
when 46 was subjected to hydrogenolysis conditions, elimination to form compound 18 was
also observed. Interestingly, reaction of the Boc protected analogue 40 under the same
conditions resulted in formation of compound 47, where the addition had occurred at the
undesired carbonyl as confirmed by Xꢀray crystallography (Scheme 10). The unexpected
stability of 46, resulted in the formulation of a new retrosynthesis which is illustrated in
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2
2
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4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
6
Scheme 10. The natural product 2 would be accessed via a hypervalent iodine mediated
oxidative spirocyclization from compound 48 which in turn could be accessed from the
previously mentioned Grignard addition to 49. The αꢀamino hydantoin 49 would be accessed
by a suitable electrophilic amination methodology from the previously synthesized Boc
protected hydantoin 40.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
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0
H
N
H
N
H
N
O
BnMgCl
HO
O
HCl
THF
O
N
BnO
N
Et O
BnO
N
2
BnO
O
Me
Me
61%
94%
Me
39
46
18
Boc
N
BnMgCl
THF
Boc
N
OH
O
N
47%
BnO
O
N
BnO
O
Me
Me
40
47
MeHN
O
H
N
MeHN
H
MeHN
O
H
N
N
O
O
O
40
HO
O
N
BnO
N
BnO
N
Me
Me
Me
MeO
2
48
49
OMe
Scheme 10. Grignard addition to hydantoin 40 and single molecule Xꢀray crystal structure of
nd
47, along with 2 generation retrosynthetic analysis.
In the first instance, it was decided to use diethyl azodicarboxylate (DEAD) as an
electrophilic nitrogen source which, when using LiHMDS as a base, generated the desired
compound 50 in a 55% yield (Scheme 11). Encouraged by the success of this reaction, we
then turned to an electrophilic azide transfer reagent, which is more easily manipulated to the
desired amine. Using 4ꢀmethylbenzenesulfonyl azide under the same reaction conditions we
were able to isolate the azide 51 in 82% yield. Reduction of the azide could be carried out
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under Staudinger reaction conditions but problems with separating the triphenylphosphine
oxide from the product led us to apply a chemoselective hydrogenation using a poisoned
Pd/(en) catalyst. Pleasingly, these reaction conditions provided the corresponding amine 52 in
92% yield. Amine 52 was converted to compound 53 smoothly in a 47% yield over three
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
4
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5
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5
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0
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9
0
steps, which gave the desired substrate for the Grignard addition reaction. Despite screening
numerous reaction conditions including using elevated reaction temperatures and a large
excess of Grignard reagent, no reaction was observed with starting material returned on each
occasion. We reasoned this might be due to steric hindrance of the carbonyl by the bulky
MeCbz group, and to test this the dimethylamino derivative 54 was synthesized from 52 in a
6% yield over two steps (Scheme 11). This less sterically encumbered substrate proved to be
Nꢀ
8
just as unreactive as the Cbz protected substrate and as a result this synthetic route was
abandoned.
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EtO C
2
Boc
NH
N
EtO C
N
LiHMDS, THF,
then DEAD
2
Boc
O
N
N
Me
BnO
O
O
55%
N
Me
BnO
O
4
0
50
LiHMDS, THF
then
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8
9
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9
0
NHAc
Boc
N
N3
S
N3 Boc
N
O
O
2
O
N
Me
BnO
O
N
Me
82%
BnO
O
4
0
51
H , Pd(en)
2
MeOH
92%
1
. Cbz-Cl, Na CO ,
2 3
Me
THF/H O
2
CbzN
H
H N Boc
2
2
3
. MeI, NaH, DMF
.TFA, DCM
N
N
O
O
N
Me
47% over 3 steps
N
O
BnO
O
BnO
Me
53
52
H N Boc
Me2N
H
N
2
1
. MeI, K CO , DMF
N
2
3
2. TFA, DCM
O
O
N
Me
N
Me
BnO
O
86% over 2 steps
BnO
O
52
54
Scheme 11. Synthesis of substrates 53 and 54.
Our final retrosynthetic analysis, which would eventually lead to the total synthesis of
spiroleucettadine, relied on two key steps both mediated by hypervalent iodine reagents
(
Scheme 12). One, a late stage Cꢀ5 oxidation to install the methylamine sidechain from
compound 55, which was inspired by the cyclic guanidine hydroxylation of a late stage
intermediate in the total synthesis of (ꢀ)ꢀmassidines, (ꢀ)ꢀaxinellamines and (ꢀ)ꢀpalau’amine by
21
Baran and coꢀworkers using silver piconolate. The spiroquinone 55 would be accessed by a
hypervalent iodine mediated oxidative dearomatization from aminol 56 which we were
confident would be stable based on earlier experiments (e.g. synthesis of 46, Scheme 10).
22
Compound 56 would arise from careful elaboration of the known amino ketone 16.
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Furthermore, this approach should retain the stereochemical information from the chiral pool:
the spirocyclization step and oxidation of 56 would be controlled by the requirement for a
cisꢀfused system and the chiral centre of the tyrosine starting material.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
4
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5
5
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5
5
5
6
0
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9
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0
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2
3
4
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8
9
0
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2
3
4
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7
8
9
0
Scheme 12. Third generation retrosynthetic analysis of (ꢀ)ꢀspiroleucettadine (2).
To this end, hydrogenolysis of 16 using 5% Pd/C followed by Boc deprotection with TFA
and then treatment with
Nꢀmethyl carbamoyl imidazole in the presence of triethylamine
yielded 56 (Scheme 13, not isolated). This reaction had to be carefully monitored until
complete consumption of the starting material as concentration of the mixture led to selfꢀ
condensation products which ultimately formed the corresponding tetrasubstituted pyrazine.
Very mild acidic conditions also led to the corresponding imidazolone formation, including
3
small concentrations of HCl from CDCl in the NMR tube.
With compound 56 in hand, it was anticipated that phenol oxidation mediated by a
hypervalent iodine reagent would generate the key tricyclic compound 55. This indeed was
the case as a single product was obtained in 17% yield over two steps following treatment of
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6
the mixture with PIDA in 2,2,2ꢀtrifluoroethanol at 0 °C. Following this it was decided to
employ Nicolaou’s hypervalent iodine mediated oxidation of secondary amides to imides for
23
oxidation of the Cꢀ5 carbon (Scheme 13). We suspected that as Cꢀ5 was tertiary substituted,
oxidation would yield the corresponding hemiꢀaminal or imine depending on workꢀup
conditions. Gratifyingly, this transformation proceeded straightforwardly using DessꢀMartin
periodinane to furnish the corresponding acetate substituted derivative 58 in 75% yield.
0
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9
0
Substitution of the acetate for the requisite
Nꢀmethyl amine was achieved easily with
methylamine hydrochloride and triethylamine in THF at room temperature, furnishing the
natural product 2.
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8
9
0
Scheme 13. Synthesis of (ꢀ)ꢀspiroleucettadine (2).
Conclusion
The total synthesis of the heteroatom rich marine natural product spiroleucettadine is
described, along with the original unsuccessful synthetic approaches. The initial route
explored an oxidation of the imidazoline which unexpectedly provided the hydantoin 25,
which was postulated to arise from benzylic oxidation followed by a BaeyerꢀVilliger
followed by hydrolysis. In the second generation approach, efforts to perform an oxidative
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dearomatization on the imidazolone 23 led to the spirocarbamate 29 which was unable to be
hydrolyzed to the desired tertiary alcohol 30. The third generation looked to employ a
cationic induced benzylic migration to set the framework of the natural product. However,
the precursor compound for this key step was unable to be synthesized in meaningful
quantities due to an unexpected competing spirocyclization process. Efforts to add the benzyl
group to the fully elaborated hydantoin 53 via the Grignard reagent were unsuccessful.
0
1
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8
9
0
The successful strategy relied on an oxidative spirocyclization to forge the scaffold of
spiroleucettadine, while the methylamine side chain was installed via a transient acetate
group. The successful strategy should allow for the synthesis of unnatural products and
establishment of a structure activity profile.
Experimental
General Information
Thin layer chromatography (TLC) was performed on ALUGRAM® aluminiumꢀbacked
UV254 silica gel 60 (0.20 mm) plates. Compounds were visualized with either
pꢀ
anisaldehyde or 20% w/w phosphomolybdic acid in ethanol. Column chromatography was
performed using silica gel 60. Infrared spectra were recorded on a Bruker Optics Alpha ATR
FTꢀIR spectrometer. High resolution massꢀspectra (HRMS) were recorded on a Bruker
microTOFQ mass spectrometer using an electrospray ionisation (ESI) source in either the
1
positive or negative modes. H NMR spectra were recorded at either 400 MHz on a Varian
400ꢀMR NMR system or at 500 MHz on a Varian 500 MHz AR premium shielded
spectrometer. All spectra were recorded from samples in CDCl at 25 °C in 5 mm NMR
3
tubes. Chemical shifts are reported relative to the residual chloroform singlet at δ 7.26 ppm.
Resonances were assigned as follows: chemical shift (multiplicity, coupling constant(s),
number of protons, assigned proton(s)). Multiplicity abbreviations are reported by the
conventions: s (singlet), d (doublet), dd (doublet of doublets), ddd (doublet of doublet of
doublets), t (triplet), td (triplet of doublets), q (quartet), qd (quartet of doublets), m
13
(
multiplet). Proton decoupled C NMR spectra were recorded at either 100 MHz on a Varian
400ꢀMR NMR system or at 125 MHz on a Varian 500 MHz AR premium shielded
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1
spectrometer under the same conditions as the H NMR spectra. Dichloromethane (CH
2
Cl
2
),
tetrahydrofuran and diethyl ether were dried using a PURE SOLV MDꢀ6 solvent purification
system. Melting points were measured on a DigiMelt MPA 161 apparatus. Unless otherwise
noted, all experiments were conducted at room temperature.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
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General Procedures
1. Grignard addition
To a solution of Weinreb amide or hydantoin (1 mmol, 1 equiv.) in THF (10 mL), was added
the appropriate Grignard reagent (2.0 mmol, 2.0 equiv.) dropwise at 0 °C. The solution was
slowly allowed to warm to room temperature and monitored by TLC analysis until the
4
starting material was consumed. The reaction was quenched with sat. NH Cl(aq) solution and
partitioned between EtOAc (30 mL) and water (20 mL). The aqueous layer was extracted
twice with EtOAc (20 mL) and the combined organic layers were washed with brine, dried
over MgSO
4
and concentrated in vacuo. The compounds were purified using column
chromatography using EtOAc/40:60 petroleum ether as eluent.
2. Boc protection of imidazolones
To a stirred solution of imidazolone (1 mmol, 1 equiv.) and Boc
2
O (2 mmol, 2 equiv) in THF
(10 mL) was added DMAP (1 mmol, 1 equiv) at room temperature. The reaction was
monitored by TLC analysis and following the consumption of the starting material, was
quenched with sat. NH
mL). The aqueous layer was extracted twice with EtOAc (20 mL) and the combined organic
layers were washed with brine, dried over MgSO and concentrated in vacuo. The compounds
were purified using column chromatography using EtOAc/40:60 petroleum ether as eluent.
4
Cl(aq) solution and partitioned between EtOAc (30 mL) and water (20
4
3
. Boc deprotection with TFA procedure A
To a stirred solution of Boc protected substrate (1 mmol) in DCM (10 mL) was added TFA
dropwise (10 mmol, 10 equiv.) at 0 °C. The reaction was monitored by TLC analysis and
quenched with sat. NaHCO3(aq) and partitioned between EtOAc (30 mL) and water (20 mL).
The aqueous layer was extracted twice with EtOAc (20 mL) and the combined organic layers
were washed with brine, dried over MgSO
4
and concentrated in vacuo. The compounds were
purified using column chromatography using EtOAc/40:60 petroleum ether as eluent.
4
. Boc deprotection with TFA procedure B
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To a stirred solution of Boc protected substrate (1 mmol) in DCM (10 mL) was added TFA
dropwise (10 mmol, 10 equiv.) at 0 °C. The reaction was monitored by TLC analysis and for
Boc protected αꢀamino ketones, following the consumption of starting material was
concentrated in vacuo and triturated with diethyl ether to obtain the TFA salt, which was
collected by vacuum filtration and used without further purification
0
1
2
3
4
5
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8
9
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9
0
5. Boc deprotection with HCl
The Boc protected amino ketone was (1 mmol, 1 equiv.) was dissolved in acetone (5 mL), to
which was added concentrated HCl (2 mL). The solution was monitored by TLC until the
disappearance of starting material was observed. The solution was concentrated in vacuo, and
the diluted with ether (20 mL). The solid was collected by filtration and washed with cold
ether (3 × 10 mL) to give the HCl salt as a white solid, which was used without further
purification.
6. Benzyl ether hydrogenolysis
A suspension of benzyl ether starting material (1 mmol, 1 equiv.) and Pd/C 10% or Pd(en)/C
% (10% by wt.) in MeOH (10 mL) was stirred under an atmosphere of H (balloon) until the
5
2
starting material was consumed by TLC analysis. The solution was filtered through a plug of
celite and concentrated in vacuo. The products could be further purified by column
chromatography using EtOAc/40:60 petroleum ether as eluent if necessary.
tert-Butyl (1-(4-(benzyloxy)phenyl)-3-oxo-4-phenylbutan-2-yl)carbamate (15)
Compound 15 was prepared using general procedure 1 starting from the known Weinreb
13
amide 14 (2.27, 5.47 mmol) and using 1.1 M benzylmagnesium chloride. The title
1
compound was obtained as a white solid (1.61 g, 63%). M.P. 94ꢀ98°C. H NMR (400 MHz,
CDCl
3
) δ: 7.45ꢀ7.24 (m, 8H), 7.11 (d,
J
= 7.3 Hz, 2H), 7.04 (d,
J
= 8.5 Hz, 2H), 6.91 (d,
J
=
8.5 Hz, 2H), 5.11 (m, 1H), 5.05 (s, 2H), 4.60 (m, 1H), 3.72 and 3.63 (ABq, ∆δAB = 26.1 Hz,
J
13
=
3
16 Hz, 2Hz), 2.96 (m, 2H), 1.43 (s, 9H). C NMR (100 MHz, CDCl ) δ: 206.7, 157.8,
155.1, 136.9, 133.1, 130.3, 129.6, 128.6, 128.6, 128.4, 128.0, 127.4, 127.1, 115.0, 79.1, 70.0,
ꢀ1
5
9.7, 47.9, 37.0, 28.3. νmax (ATRꢀIR) cm 3354, 2957, 1717, 1683, 1600. HRMSꢀESI: calcd.
+
C
28
H
31NNaO
4
[M + Na ]: 468.2145, found 468.2132.
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5-(4-Benzyloxybenzyl)-4-benzyl-3-methyl-imidazol-2-one (18)
The primary amine HCl salt was prepared from benzyl ketone 15 (1.50 g, 3.21 mmol) using
1
general procedure 5: white solid (829 mg, 74%). M.P 195ꢀ196 °C. H NMR (400 MHz,
CDCl
3
) δ: 8.34 (s, 3H), 7.45ꢀ7.23 (m, 10 H), 7.10 (d,
J
= 7.5 Hz, 2H), 7.01 (d,
AB = 17.5 Hz, 2H), 3.17 and 3.08
SO) δ: 203.9, 157.7, 107.0, 133.2,
30.7, 129.8, 128.4, 127.8, 127.6, 126.8, 126.7, 115.0, 79.2, 69.2, 58.7, 46.3, 34.4. νmax
J = 7.5 Hz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2H), 5.10 (s, 2H), 4.43 (m, 1H), 3.95 and 3.78 (ABq,
J
13
3 2
(ABdd, J = 14.3, 6.7 Hz, 2H). C NMR (100 MHz, (CD )
1
ꢀ1
(
ATRꢀIR) cm 2984, 2728, 1724, 1609, 1583. HRMSꢀESI: calcd. C23
2
H24NO [M + Clꢀ]:
346.1802; found 346.1774.
To a solution of the above amine salt (1.09 g, 2.87 mmol) and Nꢀmethyl carbamoylimidazole
2
2
(718 mg, 5.74 mmol) in THF was added trimethylamine (0.80 ml, 5.74 mmol). The solution
was stirred at room temperature for 18 h before being concentrated and subjected to silica gel
column chromatography to afford the title compound as a white solid (420 mg, 36%). M.P.
1
>
250 °C. H NMR (400 MHz, CDCl
3
) δ: 7.44ꢀ7.13 (m, 10H), 7.08 (d,
J
= 9 Hz, 1H), 6.91 (d,
13
J
= 9 Hz, 1H), 5.05 (s, 2H), 3.82 (s, 2H), 3.69 (s, 2H), 2.98 (s, 3H). C NMR (100 MHz,
CDCl ) δ: 157.6, 154.4, 137.9, 137.0, 130.6, 129.5, 128.7, 128.6, 127.9, 127.4, 126.7, 117.4,
3
ꢀ1
1
17.1, 115.0, 70.0, 29.7, 29.2. νmax (ATRꢀIR) cm 3061, 2920, 1709, 1609. HRMSꢀESI:
+
24 2 2
calcd. C25H N NaO [M + Na ]: 407.1730, found 407.1698.
tert-Butyl (1-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-3-oxobutan-2-yl)carbamate (16)
4ꢀmethoxybenzyl ketone 16 was prepared using general procedure 1 from the known
13
Weinreb amide 14 (3.00 g, 7.23 mmol) in THF using a 0.33 M solution para
ꢀ
methoxybenzyl magnesium chloride (44 mL, 14.5 mmol). The title compound was obtained
25
1
as a white solid (2.30 g, 67%). [α]
400 MHz, CDCl ) δ: 7.44ꢀ7.29 (m, 5H), 7.02 (m, 4H), 6.90 (d,
8.6 Hz, 2H), 5.08 (d, = 7.7 Hz, 1H), 5.04 (s, 2H), 4.58 (m, 1H), 3.79 (s, 3H), 3.62 (ABq,
AB = 25.6 Hz, = 16.4 Hz), 2.95 (m, 2H), 1.43 (s, 9H). C NMR (100 MHz, CDCl
07.2, 158.8, 157.9, 155.3, 137.1, 130.7, 130.4, 128.7, 128.5, 128.1, 127.6, 125.2, 115.1,
D
= +18.6 (c = 1.93, CHCl
3
). M.P. 103ꢀ104°C. H NMR
(
3
J
= 8.6 Hz, 2H), 6.83 (d, J =
J
13
ꢁδ
J
3
) δ:
2
ꢀ1
114.2, 80.0, 70.1, 59.6, 55.4, 47.2, 37.2, 28.4. νmax (ATRꢀIR) cm 3351, 2980, 1718, 1613,
+
1512. HRMSꢀESI: calcd. C29
H
33NNaO
5
[M + Na ]: 498.2251, found 498.2251.
5-(4-Benzyloxybenzyl)-4-(4-methoxybenzyl)-3-methyl-imidazol-2-one (19)
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The primary amine HCl salt was prepared from benzyl ketone 16 (1.35 g, 2.83 mmol) using
25
to general procedure 5: white solid (1.16 g, 74%). [α] = + 61.2 (c = 1.03, MeOH). M.P.
D
1
1
30ꢀ131°C. H NMR (400 MHz, CDCl
3
) δ: 8.35 (br s, 3H),7.46ꢀ7.31 (m, 5H), 7.23 (d,
J
= 8.6
Hz, 2H), 7.23 (m, 4H), 6.87 (d,
J
= 8.7 Hz, 2H), 5.10 (s, 3H), 4.40 (t,
J
J
= 6.4 Hz, 1H), 3.87
=14.3, 6.9 Hz, 2H).
and 3.69 (ABq,
J
=17.3 Hz, 2H), 3.73 (s, 3H), 3.15 and 3.08 (two dd,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
C NMR (100 MHz, CDCl ) δ: 204.3, 158.2, 157.6, 137.6, 130.8, 130.7, 128.4, 127.9, 127.7,
3
ꢀ1
126.7, 125.1, 115.0, 113.8, 69.2, 58.5, 55.1, 45.5, 39.2, 34.3. νmax (ATRꢀIR) cm 3361, 2864,
ꢀ
1724, 1612,1511. HRMSꢀESI: calcd. C24
H26NO
3
[M ꢀ Cl ]: 376.1907, found 376.1917.
To a solution of the above amine salt (854 mg, 2.08 mmol) and Nꢀmethyl
carbamoylimidazole (520 mg, 4.16 mmol) in THF was added trimethylamine (0.58 ml, 4.16
22
mmol). The solution was stirred at room temperature for 18 h before being concentrated and
subjected to silica gel column chromatography to afford the title compound as a white solid
1
(
299 mg, 33%). M.P. > 250°C. H NMR (400 MHz, CDCl
3
) δ: 7.43ꢀ7.31 (m, 5H), 7.20 (d,
= 6.97 Hz, 2H), 6.83 (d, = 7.7 Hz, 2H),
.87 (br s, 1H), 5.03 (s, 2H), 3.85 (s, 2H), 3.79 (s, 5H), 3.06 (s, 3H). C NMR (100 MHz,
CDCl ) δ: 158.8, 157.9, 137.1, 129.7, 129.0, 128.7, 128.3, 128.1, 127.6, 121.0, 119.9, 115.4,
J
= 7.7 Hz, 2H), 6.97 (d,
J
= 8.7 Hz, 2H), 6.90 (d,
J
J
13
5
3
ꢀ1
114.5, 70.0, 55.47, 29.52, 28.5, 28.2. νmax (ATRꢀIR) cm 3033, 2833, 1676, 1609, 1509.
+
HRMSꢀESI: calcd. C26
H
26
N
2
NaO
3
[M + Na ]: 437.1836, found 437.1833.
tert-Butyl 4-benzyl-5-(4-(benzyloxy)benzyl)-3-methyl-2-oxo-imidazolone-1-carboxylate (20)
Compound 20 was prepared according to general procedure 2 from compound 18 (92 mg,
1
0
.226 mmol). The title compound was obtained as light brown oil (88 mg, 76%). H NMR
(400 MHz, CDCl
3
) δ: 7.42ꢀ7.21 (m, 12H), 7.13 (d, J = 7 Hz, 2H), 7.02 (d, J = 8 Hz, 2H), 6.87
13
(
d, = 8 Hz, 2H), 5.04 (s, 2H), 4.06 (s, 2H), 3.82 (s, 2H), 2.99 (s, 3H), 1.38 (s, 9H). C NMR
J
(100 MHz, CDCl ) δ: 157.3, 151.9, 148.5, 137.1, 136.8, 131.2, 128.9, 128.9, 128.6, 128.6,
3
128.0, 127.95, 127.5, 127.1 120.8, 116.4, 114.9, 84.1, 70.1, 29.3, 29.1, 27.74, 27.7. νmax
ꢀ1
+
(
ATRꢀIR) cm 3061, 1771, 1720, 1508. HRMSꢀESI: calcd. C30
32 2 4
H N NaO [M + Na ]:
507.2254, found 507.2232.
tert-Butyl
5-(4-(benzyloxy)benzyl)-4-(4-methoxybenzyl)-3-methyl-2-oxo-imidazolone-1-
carboxylate (21)
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Compound 21 was prepared according to general procedure 2 from compound 19 (266 mg,
1
0
.642 mmol). The title compound was obtained as a light brown oil (248 mg, 72%). H NMR
(
400 MHz, CDCl
3
) δ: 7.42ꢀ7.30 (m, 5H), 7.03 (d,
= 8.9 Hz, 2H), 6.81 (d, = 8.9 Hz, 2H), 5.03 (s, 2H), 4.05 (s, 2H), 3.77 (s, 3H),
) δ: 158.6, 157.3, 151.9, 148.3, 137.1,
31.3, 128.9, 128.87, 128.6, 128.0, 127.4, 121.2, 116.2, 115.0, 114.3, 84.0, 70.1, 55.4, 29.3,
J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H),
6.86 (d,
J
J
13
3
1
.75 (s, 2H), 1.37 (s, 9H). C NMR (100 MHz, CDCl
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
28.2, 27.7. νmax (ATRꢀIR) cm 2980, 1770, 1658, 1454. HRMSꢀESI: calcd. C31
34 2 5
H N NaO
+
[
M + Na ]: 537.2360, found 537.2364.
tert-Butyl 4-benzyl-5-(4-hydroxybenzyl)-3-methyl-2-oxo-imidazole-1-carboxylate (22)
Compound 22 was prepared according to general procedure 6 starting from compound 20 (26
1
mg, 0.0513 mmol). The title compound was obtained as a colourless foam (19 mg, 90%). H
NMR (400 MHz, CDCl ) δ: 7.32ꢀ7.17 (m, 3H), 7.11 (d,
J
=7.22, 2H), 6.93 (s, 1H), 6.91 (d,
J
3
= 8.5 Hz, 2H), 6.74 (d,
J = 8.5 Hz, 2H), 4.04 (s, 2H), 3.81 (s, 2H), 2.99 (s, 3H), 1.34 (s, 9H).
1
3
C NMR (100 MHz, CDCl
3
) δ: 155.0, 152.2, 148.2, 136.7, 130.1, 129.0, 128.8, 127.1, 121.0,
ꢀ1
1
16.9, 115.5, 84.5, 29.3, 29.1, 27.9, 27.7. νmax (ATRꢀIR) cm 3266, 2980, 1766, 1694, 1594.
+
HRMSꢀESI: calcd. C H N NaO [M + Na ]: 417.1785; found 417.1759.
23
26
2
4
tert-Butyl
5-(4-hydroxybenzyl)-4-(4-methoxybenzyl)-3-methyl-2-oxo-2,3-imidazole-1-
carboxylate (23)
Phenol 23 was prepared according to general procedure 6 from compound 21 (10 mg, 0.0186
1
mmol) scale in MeOH. The title compound was obtained as a white film (7 mg, 87%). H
NMR (400 MHz, CDCl ) δ: 7.02 (d,
J
= 8.7 Hz, 2H), 6.92 (d,
= 8.7 Hz, 2H), 4.04 (s, 2H), 3.77 (s, 3H), 3.72 (s, 2H), 2.99 (s, 3H),
.34 (s, 9H). C NMR (100 MHz, CDCl ) δ: 158.7, 155.1, 152.2, 148.4, 130.7, 130.0, 129.7,
29.0, 128.7, 128.6, 121.3, 116.7, 115.5, 114.4, 84.6, 55.4, 29.3, 28.3, 27.9, 27.8, 27.7. νmax
J = 8.7 Hz, 2H), 6.81 (d, J =
3
8.7 Hz, 2H), 6.74 (d,
J
1
3
1
1
3
ꢀ1
+
(ATRꢀIR) cm 3277, 2980, 1768, 1697, 1594. HRMSꢀESI: calcd. C H N NaO [M + Na ]:
2
4
28
2
5
447.1890, found 447.1903.
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tert-Butyl
5-(4-(benzyloxy)benzyl)-5-hydroxy-3-methyl-2,4-dioxoimidazolidine-1-
carboxylate (25) and tert-butyl 4-benzoyl-5-(4-(benzyloxy)benzyl)-4,5-dihydroxy-3-methyl-
-oxoimidazolidine-1-carboxylate (26)
2
To a solution of 20 (100 mg, 0.206 mmol) in acetone (2 mL) was added mCPBA (55% with
41% water and 4% mꢀClꢀbenzoic acid) (64 mg, 0.206 mmol) at 0°C. The reaction was stirred
for 1h, and was quenched with sat. NaHCO3(aq). The mixture was partitioned between EtOAc
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(5 mL) and water (5 mL) and the aqueous layer was extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with brine (5 mL), dried over MgSO and concentrated
4
in vacuo. The crude NMR showed starting material still present in the mixture. The crude
mixture was taken up in acetone (2 mL) to which was added mCPBA (55% with 41% water
and 4% mꢀClꢀbenzoic acid) (172 mg, 0.618 mmol) at 0 °C and the reaction was stirred for 3h
and quenched with sat. NaHCO3(aq). The mixture was partitioned between EtOAc (5 mL) and
water (5 mL) and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined
organic layers were washed with brine (5 mL), dried over MgSO
4
and concentrated in vacuo
.
Column chromatography yielded 25 (14 mg, 15%) and 26 (9 mg, 8%) as colourless oils.
1
2
5: H NMR (400 MHz, CDCl
3
) δ: 7.42ꢀ7.30 (m, 5H), 6.96 (d,
J
= 8.7 Hz, 2H), 6.84 (d,
J
=
8.7 Hz, 2H), 5.01 (ABq, ꢁδAB = 7.1 Hz,
J
AB = 11.6 Hz, 2H), 3.59 and 3.40 (ABq, J = 13.6
1
3
Hz, 2H), 2.79 (s, 3H), 1.63 (s, 9H). C NMR (100 MHz, CDCl
3
) δ: 169.4, 158.5, 150.6,
149.7, 136.9, 130.5, 128.7, 128.2, 127.7, 125.1, 115.3, 88.9, 85.4, 70.1, 41.2, 28.3, 24.7. νmax
ꢀ1
26 2 6
(ATRꢀIR) cm 3415, 2852, 1810, 1740, 1611, 1511. HRMSꢀESI: calcd. C23H N NaO [M +
+
Na ]: 449.1683; found 449.1649.
1
2
6: H NMR (400 MHz, CDCl ) δ: 7.45ꢀ7.30 (m, 10H), 7.20 (d,
J
= 7.6 Hz, 2H), 6.95 (d,
= 17.1 Hz, 2H), 3.95 (s, 1H),
) δ: 205.3, 158.2, 153.0, 150.2, 138.4,
37.1, 133.7, 131.8, 131.0, 130.8, 130.3, 130.0, 129.9, 129.5, 128.73, 128.68, 128.7, 128.4,
J =
3
7.6 Hz, 2H), 5.06 (s, 2H), 4.22 (s, 1H), 4.24 and 3.85 (ABq,
J
13
2
1
1
2
.65 (s, 3H), 1.65 (s, 9H). C NMR (100 MHz, CDCl
3
ꢀ1
28.1, 127.9, 127.6, 126.1, 115.1, 93.1, 91.0, 70.2, 44.3, 28.0, 26.4. νmax (ATRꢀIR) cm 3392,
+
980, 2324, 1725, 1610, 1511. HRMSꢀESI: calcd. for C30
H
32
N
2
NaO
7
[M + Na ] 555.2107;
found 555.2129.
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tert-Butyl
(E)-4-benzylidene-5-(4-(benzyloxy)benzyl)-5-hydroxy-3-methyl-2-
oxoimidazolidine-1-carboxylate
(24a)
and
tert-butyl
(Z)-4-benzylidene-5-(4-
(benzyloxy)benzyl)-5-hydroxy-3-methyl-2-oxoimidazolidine-1-carboxylate (24b)
To a solution of 20 (60 mg, 0.111 mmol) in wet acetone (1.1 mL) was added Davis
oxaziridine (29 mg, 0.111 mmol) and the reaction was monitored by TLC analysis. Upon
consumption of the starting material, the mixture was concentrated in vacuo and the title
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
compounds 24a:24b were isolated as a 1:1.3 mixture (23 mg, 40%). H NMR are reported
1
3
separately, C NMR, IR and HRMS are reported as a mixture due to isomerization.
Individual yields not reported due to difficulty separating the compounds using column
chromatography.
1
2
4a: H NMR (400 MHz, CDCl
3
) δ: 7.78 (d,
= 8.8 Hz), 5.82 (s, 1H), 5.09 (s, 1H), 4.99 (s, 2H), 3.47 and 3.23 (ABq,
= 13.5 Hz, 2H), 2.83 (s, 3H), 1.62 (s, 9H).
J = 7.6 Hz, 2H), 7.43ꢀ7.25 (m, 8H), 6.84 (d, J =
8.8 Hz, 2H), 6.77 (d,
J
J
1
24b: H NMR (400 MHz, CDCl
.2 Hz, 2H), 6.86 (d, = 8.2 Hz, 2H), 6.03 (s, 1H), 5.01 (ABq, ∆δAB = 9.17 Hz,
Hz, 2H), 6.63 (s, 1H), 3.75 and 3.12 (ABq, = 14.0 Hz, 2H), 2.37 (s, 3H), 1.63 (s, 9H).
3
) δ: 7.41ꢀ7.21 (m, 8H), 7.17 (d, J = 7.1 Hz, 2H), 7.07 (d, J =
8
J
JAB = 11.6
J
1
3
24a/b (mixture): C NMR (100 MHz, CDCl
3
) δ: 158.1, 157.9, 151.5, 151.1, 151.0, 151.0,
138.2, 137.3, 137.0, 136.92, 136.9, 134.6, 134.4, 130.7, 130.4, 129.6, 129.4, 128.5, 127.8,
127.5, 126.9, 126.81, 126.8, 126.5, 114.7, 114.6, 104.8, 102.3, 90.1, 89.6, 84.2, 69.9, 45.4,
ꢀ1
39.6, 30.6, 28.2, 26.6. νmax (ATRꢀIR) cm 3399, 3063, 2979, 1747, 1599. HRMSꢀESI: calcd.
+
for C30
H
32
N
2
NaO
5
[M + Na ]: 523.2203; found 523.2229.
1'-(4-Methoxybenzyl)-2'-methyl-2',8'-dihydro-3'H,5'H-spiro[cyclohexane-1,7'-imidazo[1,5-
c][1,3]oxazine]-2,5-diene-3',4,5'-trione (29)
To a solution of 23 (54 mg, 0.121 mmol) in wet 2,2,2ꢀtrifluoroethanol (1.20 mL) was added
PIDA (39 mg, 0.121 mmol) and the solution immediately turned black. The reaction was
monitored by TLC and upon consumption of starting material, was quenched with NaS
M). The mixture was partitioned between EtOAc (5 mL) and H O (5 mL) and the aqueous
layer was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with
2 3
O (1
2
brine (5 mL), dried over MgSO
4
and concentrated in vacuo. The title compound was obtained
1
as a brown oil following column chromatography using EtOAc as eluent (16 mg, 34%). H
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NMR (400 MHz, CDCl
.7 Hz, 2H), 6.32 (d, = 10.2 Hz, 2H), 3.78 (s, 3H), 3.68 (2H), 3.07 (s, 3H), 2.88 (s, 2H). C
NMR (100 MHz, CDCl ) δ: 183.5, 159.3, 150.2, 143.6, 143.2, 136.7, 130.4, 129.2, 126.9,
3
) δ: 7.01 (d, J = 8.7Hz, 2H), 6.87 (d, J = 10.2 Hz, 2H), 6.85 (d, J =
1
3
8
J
3
ꢀ1
121.1, 114.7, 108.4, 76.5, 55.5, 29.7, 28.8, 27.8. νmax (ATRꢀIR) cm 2933, 1786, 1674, 1611,
+
1511. HRMSꢀESI: calcd. for C20
H
18
N
2
NaO
5
[M + Na ]: 389.1113, found 389.1108.
0
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4-(4-(Benzyloxy)benzyl)-5-(4-methoxybenzyl)-1,3-dimethyl-imidazol-2-one (31)
To a solution of imidazolone 19 (149 mg 0.340 mmol) and iodomethane (57 ꢀL, 0.902
mmol) in THF (6.8 mL) at 0°C was added NaH 60% dispersion in mineral oil (14 mg, 0.340
mmol). The reaction was monitored by TLC analysis and upon completion was quenched
with sat. NH
and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine (10 mL), dried over MgSO and concentrated in vacuo. The title
4 2
Cl(aq). The mixture was partitioned between EtOAc (10 mL) and H O (10 mL)
4
compound was obtained as a colourless oil following purification by column chromatography
1
using EtOAc as eluent (106 mg, 69%). H NMR (400 MHz, CDCl
3
) δ: 7.44ꢀ7.28 (m, 5H),
= 8.7 Hz, 2H), 5.03 (s, 2H), 3.79
) δ: 158.4, 157.7, 153.8, 137.0, 130.6,
7.04 (d,
J
= 8.0 Hz, 4H), 6.90 (d, J = 8.7 Hz, 2H), 6.82 (d, J
13
(
s, 7H), 3.04 (s, 6H). C NMR (100 MHz, CDCl
3
130.2, 129.9, 128.7, 128.1, 127.5, 117.7, 115.4, 115.2, 114.2, 80.2, 55.4, 28.4, 27.9. νmax
ꢀ1
+
(
ATRꢀIR) cm 2908, 1673, 1582. HRMSꢀESI: calcd. for C27
29 2 3
H N O [M + H ]: 429.2173;
found 429.2154.
4-(4-Hydroxybenzyl)-5-(4-methoxybenzyl)-1,3-dimethyl-imidazol-2-one (32)
Compound 32 was prepared according to general procedure 6 starting from 31 (106 mg,
1
0
.247 mmol). The title compound was obtained as a colourless oil (63 mg, 76%). H NMR
(
400 MHz, CDCl ) δ: 8.50 (s, 1H), 7.01 (d,
J
= 8.4 Hz, 2H), 6.89 (d,
= 8.4 Hz, 2H), 3.78 (s, 2H), 3.77 (s, 5H), 3.05 (s, 3H), 3.05 (s,
) δ: 158.5, 156.1, 153.7, 129.7, 129.0, 128.8, 128.2, 118.4,
J = 8.4 Hz, 2H), 6.80 (d,
3
J
3
1
= 8.4 Hz, 2H), 6.72 (d, J
1
3
H). C NMR (100 MHz, CDCl
3
ꢀ1
14.3, 55.4, 28.4, 28.1. νmax (ATRꢀIR) cm 3171, 2834, 1642. HRMSꢀESI: calcd. for
+
C H N NaO [M + Na ]: 361.1532; found 361.1513.
20
22
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5-(4-(Benzyloxy)benzyl)-3-methylimidazolidine-2,4-dione (39)
Et N (1.73 mL, 12.4 mmol) was added to a suspension of HCl salt of 38 (3.32 g, 10.3 mmol)
3
in THF (35 mL), followed by
reaction was heated to reflux overnight. The solution was cooled to room temperature, and
partitioned between H O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with
EtOAc (3 × 50 mL) and the combined organic phases were washed with brine (50 mL), dried
over MgSO and concentrated in vacuo
Nꢀmethylcarbamoyl imidazole (1.551 g, 12.4 mmol) and the
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.
The crude residue was dissolved in EtOH (50 mL) and Na (284 mg, 12.4 mmol) was added to
the solution and a white precipitate appeared. Upon consumption of starting material as
determined by TLC, the reaction was concentrated in vacuo. The crude residue was taken up
2
in EtOAc/isopropanol (4:1) (100 mL) and washed with H O (50 mL). The aqueous layer was
extracted with EtOAc/isopropanol (4:1) (3 × 50 mL) and the combined organic phases were
washed with brine (50 mL), dried over MgSO and concentrated in vacuo. The crude product
4
was washed with cold EtOH and used without further purification. The title compound was
1
obtained as a white crystalline solid (2.84 g, 74 % over two steps). M.P. 166ꢀ167 °C H NMR
(
400 MHz, CDCl
3
) δ: 7.43ꢀ7.31 (m, 5H), 7.11 (d,
J
= 8.7 Hz, 2H), 6.93 (d,
= 14.0 Hz, 3.7 Hz, 1H) and
= 14 Hz, 9 Hz, 1H), 2.97 (s, 3H). C NMR (100 MHz, CDCl ) δ: 173.4,
J = 8.7 Hz, 2H),
5
.47 (s, 1H), 5.05 (s, 2H), 4.19 (dd, = 8.9, 3.7), 3.23 (AMXdd, J
J
13
2.77 (AMXdd,
J
3
158.0, 157.4, 136.8, 130.3, 128.6, 128.0, 127.4, 127.4, 151.1, 70.0, 59.6, 37.0, 24.4. νmax
ꢀ1
(
18 2 3
ATRꢀIR) cm 3316, 2924, 1774, 1708, 1600, 1511. HRMSꢀESI: calcd. C18H N NaO [M +
+
Na ]: 333.1210, found 333.1180.
tert-Butyl 5-(4-(benzyloxy)benzyl)-3-methyl-2,4-dioxoimidazolidine-1-carboxylate (40)
To a solution of 39 (200 mg, 0.665 mmol) in THF (2 mL) was added Boc O (168 mg, 0.774
2
mmol) followed by DMAP (8 mg, 0.0664 mmol). Upon consumption of starting material as
indicated by TLC analysis, the reaction was diluted with EtOAc (6 mL) and quenched with
sat NH
was extracted with EtOAc (3 × 5 mL) and the combined organic layers were washed with
brine (10 mL), dried over MgSO and concentrated in vacuo. The title compound was
4
Cl(aq) and partitioned between EtOAc (5 mL) and water (5 mL). The aqueous layer
4
obtained as a white crystalline solid that was used without further purification (233 mg,
1
86%). M.P. 114ꢀ116°C H NMR (400 MHz, CDCl
3
) δ: 7.42ꢀ7.30 (m, 5H), 6.95 (d,
J
= 8.6
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