Synthesis of diverse acyclic precursors to pyrroles for studies of prebiotic routes to tetrapyrrole macrocycles

Article abstract of DOI:10.1039/c6nj02048h

A chemical model for the origin of tetrapyrrole macrocycles under prebiotic conditions entails the condensation of acyclic dicarbonyl compounds and α-aminoketones to form pyrroles that are equipped for subsequent self-condensation. Development and exploration of the scope of the chemical model (including combinatorial reactions, studies of the effects of structurally defective substrates, and reactions in aqueous or organic media) have relied on the availability of diverse starting materials prepared by traditional chemical synthesis methods. Here the synthesis of all acyclic dicarbonyl compounds and α-aminoketones used in the prior prebiotic model studies is described. There are five sets of acyclic dicarbonyl compounds including (i) β-ketoesters bearing diverse 4-substituents, (ii) levulinic acid derivatives bearing selected 5-substituents (i.e., analogues of δ-aminolevulinic acid, ALA), (iii) meso-substituted β-ketoesters, (iv) meso-substituted β-diketones that contain one 4-substituent, and (v) hybrid molecules that contain both the β-ketoacyl unit and the levulinic acid skeleton (or homologue thereof). A variety of α-aminoketones (homologues of ALA) also have been prepared. Altogether, the synthesis of 53 compounds is described, encompassing 28 new compounds as well as 25 known compounds that have been more fully characterized or prepared via alternative routes. The ability to convert selected acyclic compounds directly via pyrroles to porphyrinogens in a single-flask process may also prove useful in mainstream syntheses of diverse tetrapyrroles regardless of possible prebiotic relevance.

Full text of DOI:10.1039/c6nj02048h

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Synthesis of diverse acyclic precursors to pyrroles
for studies of prebiotic routes to tetrapyrrole
macrocycles†
Cite this:DOI: 10.1039/c6nj02048h
Vanampally Chandrashaker, Marcin Ptaszek,‡ Masahiko Taniguchi and
Jonathan S. Lindsey*
A chemical model for the origin of tetrapyrrole macrocycles under prebiotic conditions entails the
condensation of acyclic dicarbonyl compounds and a-aminoketones to form pyrroles that are equipped
for subsequent self-condensation. Development and exploration of the scope of the chemical model
(including combinatorial reactions, studies of the effects of structurally defective substrates, and
reactions in aqueous or organic media) have relied on the availability of diverse starting materials
prepared by traditional chemical synthesis methods. Here the synthesis of all acyclic dicarbonyl
compounds and a-aminoketones used in the prior prebiotic model studies is described. There are
five sets of acyclic dicarbonyl compounds including (i) b-ketoesters bearing diverse 4-substituents,
(ii) levulinic acid derivatives bearing selected 5-substituents (i.e., analogues of d-aminolevulinic acid,
ALA), (iii) meso-substituted b-ketoesters, (iv) meso-substituted b-diketones that contain one
4-substituent, and (v) hybrid molecules that contain both the b-ketoacyl unit and the levulinic acid
skeleton (or homologue thereof). A variety of a-aminoketones (homologues of ALA) also have been
prepared. Altogether, the synthesis of 53 compounds is described, encompassing 28 new
compounds as well as 25 known compounds that have been more fully characterized or prepared
via alternative routes. The ability to convert selected acyclic compounds directly via pyrroles to
porphyrinogens in a single-flask process may also prove useful in mainstream syntheses of diverse
tetrapyrroles regardless of possible prebiotic relevance.
Received (in Montpellier, France)
1st July 2016,
Accepted 31st August 2016
DOI: 10.1039/c6nj02048h
www.rsc.org/njc
plausible prebiotic conditions (i.e., aqueous solution, near
neutral pH, modest temperatures).
Introduction
As part of a program aimed at developing a chemical model for
Two hybrid reaction processes were initially identified: (1) the
the prebiotic origin of tetrapyrrole macrocycles, we have been b-ketoester methyl 4-methoxyacetoacetate (MeO-1-Me) undergoes
investigating routes that broadly mirror certain aspects of the condensation with ALA to give the corresponding pyrrole
modern biosynthesis of tetrapyrrole macrocycles yet proceed in (MeO-1P) upon reaction in dilute aqueous solution;1 and (2) a
the absence of enzymes.1–18 The routes entail alternatives to the b-diketone bearing an acetic acid substituent at the meso
deceptively simple self-condensation of ALA to form PBG, carbon and methoxy groups at the terminal carbons (2-AcOH)
which largely if not completely fails in solution in the absence undergoes condensation with ALA to give the corresponding
of enzymes or a macromolecular catalyst (Scheme 1).9,15,19–21 pyrrole MeO-2P.2 Both pyrroles are equipped for self-condensation
The failure has been referred to as the Achilles heel of pre- and thus react further to form the corresponding porphyrino-
biogenesis of tetrapyrrole macrocycles.21,22 The alternative gen (Scheme 1). The term ‘‘equipped for self-condensation’’
routes to PBG analogues from acyclic substrates proceed under implies no substituent at one pyrrole a-position, and the presence
of XCH2 – at the other a-position, where X is a good leaving
group.18 Pyrrole MeO-1P affords an abiotic porphyrinogen
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204,
USA. E-mail: jlindsey@ncsu.edu; Fax: +1-9195132830; Tel: +1-9195156406
† Electronic supplementary information (ESI) available: NMR spectra for new
compounds, known compounds reported previously with limited data, and known
compounds prepared by new routes. CCDC 1488933–1488936. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c6nj02048h
‡ Present address: Department of Chemistry and Biochemistry, University of
Maryland, Baltimore County, Baltimore, Maryland 21250-0001, USA.
(1-Pogen, not known in modern biochemistry), whereas MeO-2P
affords uroporphyrinogens I–IV, of which uroporphyrinogen III is
Nature’s last universal precursor to all extant tetrapyrroles.23 Both
the biotic and abiotic porphyrinogens are valuable as part of a
chemical model for understanding how tetrapyrrole macrocycles
can form under simple conditions.
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Scheme 1 Non-enzymic routes to porphyrinogens from acyclic reactants via PBG or analogues.
Combinatorial processes leading to tetrapyrroles also have regard to date include four diketones 2-R (where R = methyl,
been examined for the reaction of pools of diketones 2-R and hexyl, acetic acid, pentanoic acid) and four aminoketones AK-R
aminoketones AK-R (Scheme 1). A tandem combinatorial (where R = ethyl, propyl, propanoic acid (i.e., ALA), butanoic
process ensues, where a small set of acyclic reactants affords acid). An additional diketone 2-R (R = ethyl) and an amino-
a collection of pyrroles, which upon self-condensation afford ketone AK-R (R = methyl) have been prepared but were not
diverse b-substituted tetrapyrrole macrocycles (porphyrinogens examined in combinatorial processes to avoid mass degeneracy
leading to porphyrins).4,5,10 The substrates examined in this of substituents.3,6,7
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The initial study of the reactions shown in Scheme 1 to form
Paper
tetrapyrrole macrocycles prompted investigation of a wider
variety of acyclic carbonyl compounds in condensations with
aminoketones. Our objectives were multi-fold: first, to under-
stand the nature of suitable XCH2 substituents, which must
afford stable acyclic carbonyl species and remain innocent
toward (if not guide) pyrrole formation, yet constitute viable
leaving groups at the pyrrole a-methylene site upon subsequent
self-condensation leading to tetrapyrrole macrocycles. Second,
to understand the scope of the Ri and Rj substituents, which are
destined to become tetrapyrrole b-substituents. The Ri,j sub-
stituents have a large effect on the polarity and hence aqueous/
membrane partitioning of the resulting tetrapyrrole macrocycles.11
And third, to have at hand a collection of substrates (both carbonyl-
containing compounds and a-aminoketones) for the examination
of combinatorial reactions,4,10 thereby forming tetrapyrrole macro-
cycles that bear diverse b-pyrrole substituents.
The acyclic carbonyl substrates of interest fall into five
families (Chart 1): (1) b-ketoester analogues of MeO-1-Me that
contain a variety of XCH2 and R substituents. The b-ketoesters
are examined as esters rather than the free acid (because the
free acid is expected to decarboxylate spontaneously in solution).24
(2) Analogues of ALA that contain the same 4-oxopentanoic acid
skeleton but differ in the nature of the 5-substituent. The
5-substituents were chosen to examine the factors that affect
reactivity at the 5- versus 3-position. (3) b-Ketoesters that contain a
meso-substituent and require loss of the ester unit to form the
pyrrole. (4) b-Diketones that are defective in some manner (e.g.,
X = H) such that the pyrrole is not equipped for self-condensation,
thereby enabling the role of defective substrates to be examined in
structure-directed reactions. (5) Hybrid molecules that incorporate
a b-diketone in a levulinic acid skeleton (or homologue thereof), of
which 2-AcOH is the prototypical member, yet contain a variety of
substituents at the meso sites.
In this paper, we report the synthesis of 450 such compounds.
The syntheses employed herein are not meant to be prebiotic in
nature; mainstream methods of chemical synthesis are employed
to access compounds for developing a chemical model of pyrrole
formation possibly relevant to the prebiogenesis of tetrapyrrole
macrocycles. The b-dicarbonyl compounds and a-aminoketones
have been employed in a variety of studies of porphyrinogen
formation.1,2,4,5,8–10,12,13,15–18 While our chief interests have con-
cerned possible prebiotic syntheses, the ability to convert acyclic
reactants to diverse porphyrins in one-flask reactions may have utility
in a variety of domains. In both regards, the collected syntheses of the
450 acyclic compounds should facilitate further studies of routes to
pyrroles and subsequent pyrrole-containing products.
Chart 1 Classes of target compounds.
A variety of synthetic routes were required to create the set of 450
acyclic compounds. The preparation of a number of the new target
compounds proved challenging owing to (i) the presence of several
reactive functional groups, (ii) water solubility, and (iii) limited
methods of purification, given that many were oils and were not
amenable to vacuum distillation. For clarity, the Experimental section
delineates the known and new compounds, extent of characterization
data for the known compounds, and reliance on established versus
new synthetic routes to prepare known and new compounds.
Results and discussion
The chemistry of carbonyl and b-dicarbonyl compounds has been
an area of active interest for over a century,25,26 and numerous
a-aminoketones also have been prepared.27 Indeed, about half of
b-Ketoesters bearing diverse 4-substituents
the target compounds herein have been prepared and described in The target acetoacetate derivatives include oxygen-, sulfur-, and
the literature, but often with limited or no characterization data. nitrogen-centered substituents at the 4-position. b-Ketoesters
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are well known and versatile substrates containing both electron- Reaction of Cl-1 with pyridine or morpholine gave the pyridinium
rich and electron-deficient substituents.25 Two distinct approaches chloride salt (Pyr-1)40,41 or the N-morpholino product, respectively
were examined to obtain the desired b-ketoesters. The first (Mor-1) (entries 8 and 9). Reaction of Cl-1 with sodium iodide
approach relied on the derivatization of ethyl 4-chloroaceto- under microwave irradiation gave ethyl 4-iodo-3-oxobutanoate
acetate (Cl-1) with the appropriate nucleophile. In the second (I-1)37 in 80% yield (entry 10) accompanied by 1-dimer in 4% yield.
approach, the b-ketoester moiety was constructed using Claisen Indeed, 1-dimer was a frequent byproduct in a number of the
condensation of an a-functionalized acetone derivative and above reactions but was not isolated.
diethyl carbonate. The former approach employs readily available
Modification of 4-substituted b-ketoesters. Several derivatives
starting materials and would appear to provide a straightforward of the 4-substituted b-ketoesters shown in Table 1 were sought.
route to the various derivatives, particularly given the long history Compound MeO-1 has been prepared previously by nucleophilic
of development of b-ketoester chemistry.25 However, the reactivity substitution of ethyl 4-bromoacetoacetate,42 but we had difficulty
of the b-ketoester system imposes limitations for the reagents and in reproducing this method. Instead, transesterification43 with
conditions used, and therefore makes some transformations 4-(N,N-dimethylamino)pyridine (DMAP) in refluxing ethanol was
difficult and inefficient. For example, treatment of Cl-1 with nucleo- used to convert methyl 4-methoxyacetoacetate to the ethyl ester
philes that also are strong bases affords the cyclohexanedione MeO-1 (Scheme 3). Similar reaction in toluene containing hexanol
derivative 1-dimer (Scheme 2). Indeed, we isolated 1-dimer as the gave the hexyl ester MeO-1-Hex.
major product upon reaction of Cl-1 with potassium phthalimide
Attempts to prepare ethyl 4-amino-3-oxobutanoate (H2N-1)
in a failed attempt to obtain the corresponding amine. Compound by Staudinger reaction of N3-1 with triphenylphosphine were
1-dimer is trivially termed succinyl succinate owing to its known unsuccessful. Attempts to synthesize ethyl 4-dimethylamino-3-
formation by the two-fold Claisen–Dieckmann condensation of oxobutanoate (Me2N-1) by direct amination of Cl-1 also were
dialkyl succinates.28 We obtained the X-ray structure of 1-dimer unsuccessful. Therefore, Me2N-1 was prepared by Claisen con-
and found this to agree with the prior report.29 Other unwanted densation of N,N-dimethylaminoacetone and diethyl carbonate,
reactions are also possible.30 In such cases more elaborate appro- following a modified literature procedure (Scheme 4).44
aches were required, or the second approach was pursued.
Phosphorylation of 4-hydroxy b-ketoesters. A b-ketoester
Substitution at the 4-position of b-ketoesters. The commer- bearing a 4-phosphoester substituent was a key target compound
cially available ethyl 4-chloroacetoacetate (Cl-1) was used as given the expected water solubility and facile nucleofugacity of the
a key substrate for elaboration. Thus, treatment of Cl-1 with phosphate moiety. While the introduction of the phosphoester
sodium formate in DMF at 50 1C using a literature procedure31 moiety is a straightforward matter with simple haloalkyl or hydroxy-
with modification gave the known31 ethyl 4-formyloxy-3-oxo- alkyl substrates, or even with b-diketones,45 the b-ketoester frame-
butanoate (HCO2-1) in 28% yield (entry 1, Table 1). The reaction work presented a number of challenges. Initially, we planned to
with sodium acetate in acetic acid at 95 1C gave 4-acetoxy-3- convert ethyl 4-chloroacetoacetate (Cl-1) to the dibenzyl ester
oxobutanoate32,33 AcO-1 in 27% yield (entry 2). Treatment of Cl-1 BnPiO-1 in a one-step procedure, to be followed by deprotection
with sodium thioacetate or potassium thiocyanate in acetonitrile to give the sodium phosphate salt PiO-1. However, attempts to
at room temperature gave ethyl 3-oxo-4-S-(acetylthio)butanoate obtain the corresponding benzyl ester upon reaction of Cl-1 with
(AcS-1)34 in 43% yield or ethyl 3-oxo-4-thiocyanatobutanoate dibenzyl phosphate tetramethylammonium salt46 or the reaction of
(NCS-1)30 in 94% yield, respectively (entries 3 and 4). Treatment HO-1 with dibenzyl chlorophosphate47 were unsuccessful.
of 11 with sodium thiomethoxide gave the known thioether35
MeS-1 in 62% yield (entry 5).
The synthesis of the disodium salt of phosphoester PiO-1 is
outlined in Scheme 5. Hydrogenolysis of the benzyl ether BnO-1
The 4-hydroxy analogue was pursued via the intermediacy of gave the 4-hydroxy-3-oxobutanoate31,36,37,48 HO-1 in 91% yield.
the benzyl ether. Hence, treatment of Cl-1 with excess sodium Handling of the hydroxyketone proved difficult regardless
benzoxide (prepared in situ by treatment of benzyl alcohol with of the reaction conditions and duration. In many cases the
sodium hydride) at 0 1C gave the known30,36,37 ethyl 4-benzyloxy-3- product was observed by 1H NMR spectroscopy of the crude reaction
oxobutanoate (BnO-1) upon column chromatography in 62% yield mixture; however, extensive decomposition was observed during
(B95% purity; entry 6).
work-up.
Treatment of HO-1 with dibenzyl N,N-diisopropylphosphor-
Reaction of Cl-1 with sodium azide gave known compound
ethyl 4-azido-3-oxobutanoate (N3-1)38 in 59% yield (entry 7). The amidite in the presence of 1H-tetrazole converted the alcohol
azide is a potential precursor for various amino derivatives.39 to the corresponding phosphotriester, as confirmed by 1H NMR
spectroscopy of the crude reaction mixture. Subsequent treatment49
of the crude triester with 30% aqueous H2O2 afforded phos-
photriester BnPiO-1 in 21% yield. Hydrogenolysis and treatment
of the resulting acid with 2 equiv. of NaOH afforded disodium
salt PiO-1 in 81% yield (purity B 85%). The synthesis of PiO-1
proved to be challenging owing to the unstable nature of
compounds HO-1 through PiO-1; indeed, the series was beset
with incomplete characterization yet the resulting crude PiO-1
Scheme 2 Undesired self-condensation of Cl-1.
was suitable for exploratory studies. Almost all of the target
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Table 1 Synthesis of 4-substituted b-ketoesters
Entry
XM
Conditions
X
Product
Yield (%)
1
2
3
4
5
6
7
8
9
HCO2Na
AcONa
AcSNa
DMF, 50 1C, 5 h
HCO2-
AcO-
AcS-
NCS-
MeS
PhCH2O-
N3-
Pyridine
C4H8NO
I-
HCO2-1
AcO-1
AcS-1
NCS-1
MeS-1
BnO-1
N3-1
28
27
43
94
62
62
59
78
37
80
AcOH, 95 1C, 16 h
MeCN, rt,a overnight
MeCN, rt, overnight
DMF, rt, overnight
THF, 0 1C - rt, 2 h
MeCN, 50 1C, 4 h
Neat, rt, 2 h
NCSK
MeSNa
BnONa
N3Na
Pyridine
Morpholine
INa
Pyr-1b
Mor-1
I-1
CH2Cl2, rt, 2 h
Acetone, 65 1C, 0.5 h, microwave
10
a
b
Room temperature. Pyridinium chloride salt.
Scheme 3 Synthesis of b-ketoesters via transesterification.
Scheme 4 Synthesis of an amino-b-ketoester.
compounds in this section (Cl-1, AcO-1, AcS-1, NCS-1, MeS-1,
Pyr-1, Mor-1, HO-1, MeO-1, and PiO-1) have been examined in
prebiotic model reactions with ALA.18
Scheme 5 Phosphoester derivatives of b-ketoesters.
5-Substituted levulinates
The target levulinates HO-3-Me, PiO-3-Me, PiO-3, and EtOCO2-3 avoid the 5-hydroxy species owing to facile bis-hemiketal for-
are presented in Chart 2. In general, the synthesis of the mation. Two phosphoesters of 5-hydroxylevulinic acid were
levulinate derivatives proved far simpler than the corre- sought, the free carboxylic acid or carboxylate (PiO-3) and
sponding b-ketoester compounds. The synthesis begins with the methyl carboxylate (PiO-3-Me). The routes to both target
levulinic acid (3), which is commercially available in large molecules (Scheme 6) begin with methyl 5-bromolevulinate
quantities. A large number of derivatives of ALA have been (Br-3-Me), prepared by bromination of levulinic acid in methanol
prepared in recent years for use in studies of photodynamic containing bromine,54,55 and proceed via the 5-hydroxylevulinic
therapy; however, such compounds typically preserve the 5-amino acid protected as the new benzyl carboxylate (HO-3-Bn) and the
substituent and are modified at the carboxylic acid unit.27,50–52
5-Hydroxylevulinic acid, a secondary metabolite that has been
known56 methyl carboxylate (HO-3-Me).
Our attempts to convert Br-3-Me directly into the corre-
prepared synthetically,53 could be employed but we preferred to sponding phosphotriester by reaction with tetramethyl-
work with carboxylic acid esters (for solubility purposes) and to ammonium dibenzylphosphate46 or silver dibenzylphosphate57
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BnPiO-3-Me in 69% yield. Hydrogenolysis and treatment of
the resulting acid with two equiv. of sodium hydroxide afforded
the desired disodium salt of the methyl ester PiO-3-Me in
91% yield.
To prepare the free carboxylic acid (or carboxylate) PiO-3, the
bromoester Br-3-Me was subjected to transesterification to give
the benzyl ester Br-3-Bn followed by sodium formate to give the
Chart 2 Diverse levulinic acid derivatives.
were unsuccessful. Therefore, the bromoester Br-3-Me was con- formate ester. Hydrolysis upon chromatography on activated
verted to HO-3-Me upon reaction with sodium formate in aqueous alumina60 gave the desired benzyl 5-hydroxylevulinate (HO-3-Bn).
ethanol.56 The reported yield for this simple transformation is 95%, The synthesis of compound Br-3-Bn was recently reported by
but in our hands the yield was more typically B20%. Compound opening of succinic anhydride with benzyl alcohol followed by
HO-3-Me was relatively unstable; upon standing on the benchtop Arndt–Eistert a-bromo homologation, which involves the use of
the clear liquid formed crystals. Upon X-ray diffraction the crystal diazomethane.61 Attempts to prepare Br-3-Bn via bromination
was found to be altaicadispirolactone,58 a natural compound that has of benzyl levulinate62 afforded a mixture of products. The
been characterized previously by X-ray diffraction.59 Reaction of phosphorylation of HO-3-Bn to give tribenzyl ester BnPiO-3-Bn
HO-3-Me (prior to spiro-lactone formation) with dibenzyl N,N- followed by hydrogenolysis afforded PiO-3 in 95% yield. Other
diisopropyl phosphoramidite followed by in situ oxidation with derivatives of 5-hydroxylevulinic acid also were prepared. The
m-CPBA and column chromatography afforded phosphotriester reaction of benzyl 5-hydroxylevulinic acid (HO-3-Bn) with ethyl
Scheme 6 Synthesis of a phosphoester and carbonate analogues of ALA.
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chloroformate afforded the corresponding ethyl carbonate EtOCO2- ester with TFA also failed to yield pure 5-AcOH. Alkylation with
3-Bn, which upon hydrogenolysis gave the target ethyl carbonate bromoacetic acid (using sodium methoxide/methanol), as done for
derivative of levulinic acid EtOCO2-3 as shown in Scheme 6 (right ethyl acetoacetate,64 also was unsuccessful. On the other hand, the
side). Model prebiotic reactions of PiO-3-Me with ALA have been benzyl ester 5-AcOBn upon hydrogenolysis gave the desired target
carried out.15
compound 5-AcOH as the major product along with the intra-
molecular anhydride 5-AcOH0 and some other minor products that
could not be identified by either mass spectrometry or NMR
spectroscopy. The failure to obtain a pure compound prompted
examination of related b-dicarbonyl compounds. Known meso-
alkylated b-ketoesters 5-Me65 and 5-Me-lactone66 were prepared
as described in the literature and examined in reactions with
ALA.18
b-Ketoesters with meso-substituents
The first b-ketoacyl compound examined that gave a self-
assembling pyrrole upon reaction with ALA was the b-ketoester
methyl 4-methoxyacetoacetate (MeO-1-Me, Scheme 1).1 Here we
examined compounds that are a hybrid of methyl 4-methoxy-
acetoacetate (MeO-1-Me) and 5-methoxylevulinic acid. The hybrid
b-ketoester-levulinate 5-AcOH is the target shown in Scheme 7.
More generally, we sought b-diketones alkylated with acetic acid
for a broad study of reactivity (vide infra).
b-Diketones with meso-alkylation
A broader set of meso-alkylated b-diketone (rather than b-ketoester)
compounds is shown in Chart 3. The rationale here was that the
cleavage of the keto group would be more facile than that of the
ester upon pyrrole formation with an a-aminoketone such as ALA.
The target compounds contain zero, one, or two reactive groups at
the terminal 1- and 5-positions. In the case of methoxy as the
reactive group, the resulting pyrrole should be equipped with an
a-(methoxymethyl) unit. On the other hand, the diketone lacking a
terminal leaving group at the 1- and 5-positions affords reaction
with an a-aminoketone that is arrested at the pyrrole stage.13,17
The reaction of pentane-2,4-dione (AcAc) with ethyl bromo-
aetate or benzyl bromoacetate in the presence of NaH afforded
the corresponding hybrid b-ketoacyl-levulinate 6-AcOEt67 or
6-AcOBn, respectively (Scheme 8). Such compounds are 3-acetyl
derivatives of levulinate esters. Attempted hydrolysis of 6-AcOEt
under basic conditions afforded levulinic acid, in which case we
pursued 6-AcOH via hydrogenolysis of 6-AcOBn. During the course
of our work, a report appeared concerning the identical synthesis
of (but incomplete data for) 6-AcOBn68 and the synthesis of
6-AcOH via acidolysis of the parent tert-butyl ester.69 Hydrogeno-
lysis of 6-AcOBn under standard conditions gave the free acid
6-AcOH. Compound 6-AcOH has been prepared70 by acylation of
a-angelica lactone using acetic anhydride and BF3ꢀetherate, albeit
without sufficient data. Reaction of 6-AcOH with an a-amino-
ketone leads to a pyrrole that lacks the a-XCH2 unit necessary
for subsequent self-condensation.13,17 Accordingly, 6-AcOH was
The synthesis of 5-AcOH was challenging owing to the
conflicting reaction requirements posed by the ketone, ester,
and carboxylic acid groups in close proximity. Synthesis of
5-AcOH was envisaged by alkylation of MeO-1-Me with a
2-bromoacetate with subsequent conversion of the ester to the
free acid. A number of alkylations were performed with 2-bromo-
acetates to find a viable route to 5-AcOH. Alkylation of MeO-1-Me
with 2-(trimethylsilyl)ethyl bromoacetate (4-EtTMS)63 in toluene
in the presence of NaH successfully gave the alkylated product
5-AcOEtTMS. Surprisingly, attempts to cleave the trimethylsilyl-
ethyl group of 5-AcOEtTMS upon treatment with TBAF (under
mild basic conditions) in THF failed to provide pure 5-AcOH.
Treatment of the analogous ethyl ester with LiOH or the tert-butyl
Scheme 7 Synthesis of a b-ketoester/levulinic acid hybrid.
Chart 3 b-Diketone/levulinic acid hybrids with 0–2 terminal substituents.
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Scheme 8 Synthesis of b-diketone/levulinic hybrid with
0 terminal
substituents.
used2 in studies of Knorr versus Fischer–Fink pyrrole formation9 as
well as studies of the effects of impurities in prebiotic model
reactions, wherein small quantities of defective pyrroles interfere
in a combinatorial manner with reactions of normal pyrroles
leading to porphyrinogens.16,17
Scheme 9 Synthesis of b-diketone/levulinic hybrid with one terminal
substituent.
was reported to be quite unstable.77 The known routes to 2 include
the following: (I) Cram’s approach with 1,3-dithianyl-protected
malonaldehyde;72,74 (II) self-condensation of 1,3-dimethoxyacetone
via morpholine catalysis;75 and (III) Claisen condensation of methyl
methoxyacetate and methoxyacetone.72
1-Methoxy b-diketones with meso-alkylation
A b-diketone bearing a single reactive terminal group was
prepared as shown in Scheme 9. Reaction of ethyl methoxy-
acetate with acetone in the presence of sodium metal afforded
4-methoxyacetoacetate (7), a known compound71 prepared
prior to the advent of modern characterization methods; the
only prior data available were boiling point and elemental
analysis. Alkylation of 7 with benzyl bromoacetate in the same
manner as for acetylacetone (to prepare analogue 6-AcOBn)
gave 7-AcOBn in 20% yield. Subsequent hydrogenolysis gave the
free acid 7-AcOH in 80% yield. In studies of the limits of
structure-directed chemistry, compound 7-AcOH was found to
react with ALA at one or the other of the carbonyl groups,
leading to production of two pyrroles; one pyrrole is defective
and the other is normal, yet the former thwarts the reaction of the
latter in a combinatorial manner thereby blocking porphyrinogen
formation.17
We first examined route I, where 1,5-diacetoxyacetylacetone
(2-OAc) was chosen as a target compound to access the b-diketone
2 bearing two reactive termini (Scheme 11). 2,20-Methylenebis(1,3-
dithiane) (8), which contains 1,3-dithiacyclohexane moieties to
mask the aldehyde groups, was adopted as a starting material.
Formaldehyde (gas) was previously used as the hydroxymethyl-
ation source for the synthesis of 8-OH and 8-(OH)2,74,78 requiring
the unwieldy treatment of the ꢁ50 1C reaction mixture with
gaseous formaldehyde (generated from paraformaldehyde at
4150 1C). Recently, N-methoxy-N-methylformamide (Weinreb
formamide), a stable liquid at room temperature, was developed
as a versatile formylating reagent.79,80 Thus, 8 was treated with
n-butyllithium and N-methoxy-N-methylformamide to obtain the
mono-formylated 2,20-methylenebis(1,3-dithiane) instead of the
desired bis-formylated product (structures not shown). Reduction
of the crude mono formylated product with sodium borohydride
gave mono-hydroxymethyl compound 8-OH in 85% yield.
1,5-Dimethoxy b-diketones with meso-alkylation
The b-diketone bearing two reactive terminal groups and a Attempted synthesis of bis(hydroxymethyl) compound 8-(OH)2
central meso substituent was a key target. In this regard, the from 8-OH under similar conditions (without reduction by
symmetric 1,5-dimethoxyacetylacetone (2) is a critical inter- NaBH4) resulted in cyclization to give the di-spiro compound
mediate; 2 has been prepared (albeit with limited characteriza- 8-OH/O in 73% yield. The latter was fully characterized and the
tion data) via three methods72–75 as shown in Scheme 10. structure was verified by single crystal X-ray diffraction. To
Alternative routes to 2 might entail alkylation of 1,5-dihydroxy- avoid intramolecular cyclization, the tert-butyldimethylsilyl
acetylacetone (unknown and likely unstable) or substitution of group was introduced as a protecting group for the hydroxy-
a 1,5-dihaloacetylacetone. In the latter regard, 1,5-dibromo- methyl compound 8-OH to afford 8-OTBS in 65% yield. The
acetylacetone was used in the preparation of pyrazole,76 but second installation of the hydroxymethyl group in 8-OTBS
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4-methoxyacetoacetate (MeO-1-tBu, prepared from methyl methoxy-
acetate and tert-butyl acetate)83 or benzyl 4-methoxyacetoacetate
(MeO-1-Bn,84 prepared from methyl methoxyacetate and benzyl
acetate). Acylation of MeO-1-tBu or MeO-1-Bn was carried out
with methoxyacetyl chloride in the presence of sodium hydride.
Treatment of the crude product to acidolysis or hydrogenolysis
(both accompanied by decarboxylation) afforded 2 in 33% or
24% yield, respectively. Purification by column chromatography
was relatively straightforward in the case of MeO-1-Bn (Scheme 12,
left side). Compound 2 provided the building block for preparation
of a variety of substrates for studies of pyrrole formation, and was
used in condensations with ALA to give the corresponding
porphyrinogens.16
Scheme 10 Known routes to a versatile b-diketone substrate.
Alkylation of 2 with benzyl bromoacetate under the mild
conditions of potassium carbonate in acetone at room tempera-
ture gave the corresponding ester 2-AcOBn in 64% yield
afforded 8-OTBS/OH in 20% yield (with recovery of 8-OTBS in (Scheme 12, center). Subsequent hydrogenolysis gave the free
34% yield). Deprotection of the tert-butyldimethylsilyl group of acid 2-AcOH in 69% yield. Alkylation of 2 with benzyl 5-iodo-
8-OTBS/OH smoothly afforded the desired bis(hydroxymethyl) pentanoate85 in the presence of DBU in benzene (an approach
compound 8-(OH)2 in 70% yield. Acetylation of 8-(OH)2 with that has been reported to afford higher yields with long-chain
acetyl chloride afforded 8-(OAc)2 in 97% yield. The latter also alkyl halides86) gave the corresponding ester 2-PnOBn but in
was characterized by single crystal X-ray diffraction. In the last only 17% yield. Subsequent hydrogenolysis gave the free acid
step, deprotection of the 1,3-dithiane protecting group was 2-PnOH, a homologue of 2-AcOH, in 38% yield.
attempted under various conditions [HgCl2, HgCl2 with HgO
The methylene protons of 2 are sufficiently acidic that meso
(red or yellow), Hg(ClO4)2, or Dess–Martin periodinane], which alkylation could be achieved with a very mild base such as
did not provide the desired compound 1,5-diacetoxyacetyl- K2CO3 at room temperature (Scheme 12, right side). Alkylation
acetone (2-OAc).
of 2 with an alkyl iodide afforded the corresponding meso-alkyl
Route II was not examined given the limited literature product 2-Me, 2-Et, or 2-Hex. As expected, dialkylation and
precedent. We turned to route III, where acylation of a tert- O-alkylation were competitive side reactions, and multiple
butyl b-ketoester or benzyl b-ketoester with an a-halo ester products were obtained on the basis of TLC and 1H NMR analysis.
followed by acidolysis or hydrogenolysis, respectively, a general Each target compound was obtained by column chromato-
approach to g-keto esters.81,82 Thus, route III began with tert-butyl graphy. The target compounds are hydrophobic analogues of
Scheme 11 Exploration of route I to a versatile b-diketone substrate.
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Scheme 12 Synthesis of b-diketone/levulinic (or ketoalkanoic) hybrids with two terminal substituents.
the b-diketone/levulinic (or ketoalkanoic) hybrid compounds solution pH of B2–3.1 Accordingly, we have prepared each
described above. The series-2 compounds (2-AcOH, 2-Me, 2-Et, a-aminoketone as the hydrochloride salt.
2-Hex, 2-PnOH) have been employed with diverse a-aminoketones
1-Aminoacetone (AK-Me) was prepared as described in the
literature.89 The synthesis of 1-aminobutan-2-one (AK-Et) has
been reported by the same method for the synthesis of 1-amino-
acetone (i.e., phthalimide reaction with the corresponding,
in a wide variety of model prebiotic reactions.2,4,5,8–10,12,13,16–18
a-Aminoketones
Aminocarbonyl compounds are versatile starting materials in commercially available 1-bromobutanone, via Phth-AK-Et) but
synthetic chemistry and undergo a variety of reactions.87 ALA no characterization data were provided.90 We have employed
and methyl 5-aminolevulinate are commercially available. the same method and herein provide full characterization data
Diverse esters of ALA have been prepared, chiefly for studies (Scheme 13, left panel).
in photodynamic therapy.27 ALA analogues that were of interest
The 1-amino-2-pentanone analogue of ALA wherein the
to us for prebiotic studies are shown in Chart 4. We prepared carboxylic acid is reduced to the hydrocarbon (AK-Pr) was pre-
hexyl and decyl esters of ALA (ALA-R where R = hexyl or decyl) as pared in a straightforward manner (Scheme 13, center panel).
described in the literature50–52 for studies of model prebiotic Reaction of propylmagnesium chloride with the a-chloromethyl
reactions in micellar media.18
Weinreb amide afforded the 5-chloropentan-4-one,91 which upon
The stability of a-aminoketones has received considerable treatment with potassium phthalimide gave the N-phthalyl deriva-
attention given the use of such compounds in photodynamic tive of the aminoketone Phth-AK-Pr in 33% yield. Subsequent
therapeutic studies and clinical applications.88 a-Aminoketones are hydrolysis gave the target aminoketone AK-Pr. Both intermediate
prone to self-condensation leading to the dihydropyrazine.9,15,19,20 and target are known but with incomplete characterization data.92,93
The self-condensation is strongly pH-dependent and is effectively
The homologue of ALA containing one additional methylene
suppressed at low pH where the amine is protonated. Indeed, group, AK-BuOH, was prepared previously (Scheme 13, right
dissolution of the hydrochloride salt of ALA in water affords a panel) but with insufficient data.94 The a-acylation of the enolate
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derivatives by chromatography in some cases was accompanied
by a substantial loss in overall yield. All compounds reported
here were characterized by 1H and 13C NMR spectroscopy,
ESI-MS, and, in the case of compounds containing phosphorous,
by 31P NMR spectroscopy. While most of the compounds
reported here are soluble in organic solvents (CHCl3, CH2Cl2),
phosphoesters PiO-1, PiO-3, and PiO-3-Me were not soluble in
organic solvents, and their NMR spectra were recorded in D2O.
Phosphoesters PiO-1, PiO-3, and PiO-3-Me in the form of free
acids (rather than sodium salts) were soluble in DMSO.
The presence of keto–enol tautomerism in b-dicarbonyl com-
pounds complicates reporting of the NMR spectral peaks, especially
given that the ratio of keto to enol form varies depending on
1
conditions (e.g., concentration, solvent). In addition, the H NMR
Chart 4 Aminolevulinic acid (R = H) and analogues (HCl salts).
signals of mono and dialkylated products of the compounds pre-
paredhereinoftenoverlappedwitheachother. Ingeneral, eachofthe
b-dicarbonyl compounds characterized herein exhibited a mixture of
keto and enol forms. The NMR spectral peaks are reported for the
dominant species, which in general was the keto form. In those cases
where the enol form was dominant, the data are so indicated.
Four single-crystal X-ray structures were determined. ORTEP
drawings of 1-dimer, altaicadispirolactone, 8-OH/O, and 8-(OAc)2
are shown in Fig. 1. The X-ray structures of 1-dimer and altaica-
dispirolactone have been reported previously.29,59,95 The space
group and the cell size of 1-dimer were essentially identical to
those in the prior reports.29,95 On the other hand, the space group
and the cell size of altaicadispirolactone were distinct for the
of ethyl hippurate with glutaric anhydride in the presence of
N,N,N0N0-tetramethylethylenediamine (TMEDA) afforded the
corresponding b-ketoester Bz-AK-BuOH-CEt, which in hot aqueous
acid underwent amide hydrolysis, ester hydrolysis, and decarboxyl-
ation to afford the target AK-BuOH. In model prebiotic reactions,
the a-aminoketone AK-Et has been employed in a variety of studies
with various diketones,4,5,8–10,16 AK-Pr and AK-BuOH were examined
in expanded combinatorial studies,10 and AK-Me was used with
2-AcOH to afford a homologue of coproporphyrinogen.18
Characterization
Each b-ketoester and b-diketone typically was obtained as an previous report (P21/n)59 and our result (P21/c); in particular, the
oil, and was purified by column chromatography. The alkyl- ruffle of the rings and torsion angles were slightly different.
ation of b-dicarbonyl compounds typically afforded monoalkyl Monoclinic P21/n and P21/c are equivalent space groups;96
and dialkyl derivatives, which have similar polarities to that of however, transformation of our result to P21/n did not provide
the target compound. The removal of the unwanted dialkyl the same cell size as in the previous report. Bis-dithianes 8-OH/O
Scheme 13 Synthesis of ALA analogues.
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Fig. 1 ORTEP drawings of (1) 1-dimer, (2) altaicadispirolactone, (3) 8-OH/O and (4) 8-(OAc)2. The thermal ellipsoids are drawn at the 50% probability level.
and 8-(OAc)2 are novel compounds. Compound 8-OH/O bears a mineral oil. The Pd(OH)2/C was 20% containing 50% water,
dispiro bis-dithiane in a framework composed of a distinctive whereas the Pd/C was 10%. THF was distilled from NaH/
dispiro[5,1,58,36]hexadecane. X-ray structures of similar dispiro benzophenone as required. Anhydrous CH3CN, CH2Cl2 and
bis-dithiane derivatives97 and a trispiro bis-dithiane98 have been DMF were used as received from commercial sources. Melting
reported. X-ray structures of bis-dithianes such as 8-(OAc)2 have points are uncorrected. Electrospray ionization mass spectrometry
been extensively studied.99–102 The crystallographic data for the (ESI-MS) data are reported for the molecule ion or cationized
four structures are listed in Table 2.
molecule ion. Column chromatography was performed with flash
silica gel unless noted otherwise.
All 1H NMR (300 MHz) spectra were obtained in CDCl3
unless noted otherwise, and the chemical shift was calibrated
with respect to the TMS signal at 0.0 ppm. In some cases, the
chemical shift also was calibrated with respect to the residual
solvent signal (7.24 ppm for CHCl3, 2.50 ppm for DMSO, 4.80 ppm
for HDO). All 13C NMR (75 MHz) spectra were obtained in CDCl3
unless noted otherwise, and the chemical shift was calibrated with
respect to the CHCl3 signal at 77.23 ppm. 31P NMR (161.978 MHz)
spectra were recorded in D2O (unless noted otherwise) in a
double-layer NMR tube. Chemical shifts are reported with respect
to H3PO4 (85% in H2O) as an internal standard placed in an
insert NMR tube.
Gas chromatography was carried out using an HP-GCD,
G-1800A equipped with an electron ionization detector and a
fused silica capillary column (J & W Scientific DB-5MS, 30 m ꢂ
0.25 mm ꢂ 0.25 mM). The method used was 60 1C initial tem-
perature (3 min), increase 15 1C minꢁ1, plateau at 200 1C. Relative
yields were determined by integration of the peak areas.
Microwave experiments were performed using a CEM Discover
Summary
The carbonyl and aminoketone compounds described herein
provide substrates for examination of pyrrole formation as part
of a chemical model for the prebiogenesis of tetrapyrrole macro-
cycles. The dearth of knowledge concerning simple routes to
pyrroles equipped for self-condensation has crimped exploration
of alternatives to the canonical ALA - PBG - uroporphyrinogen
pathway, the first step of which constitutes the Achilles heel of a
proposed overall prebiotic (non-enzymic) route to tetrapyrrole
macrocycles.15,18,21,22 Regardless of possible prebiotic relevance,
each of the precursors is available to probe the scope, limitations,
and course of complex reaction processes leading to pyrroles and
potentially via subsequent oligomerizations to porphyrinogens.
Experimental
General methods
All commercially available materials were used as received unless Synthesis Unit equipped with an infrared sensor for temperature
noted otherwise. The NaH employed was 60% dispersion in monitoring. The contents of each vessel were stirred magnetically
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Table 2 Crystallographic data for 1-dimer, altaicadispirolactone, 8-OH/O, and 8-(OAc)2
Compound
1-Dimer
Altaicadispirolactone
8-OH/O
8-(OAc)2
Formula
C12H16N9
256.25
Triclinic
%
P1
4.1534(8)
7.3467(10)
10.0543(14)
103.074(13)
94.848(14)
98.213(16)
293.60(8)
1
C10H12O6
228.20
Monoclinic
P21/c
10.5040(4)
7.8964(3)
6.3078(3)
90.00
105.0813(19)
90.00
505.17(4)
2
C11H18O2S4
310.49
Monoclinic
C2/c
18.0071(8)
6.3969(3)
23.9129(11)
90.00
91.280(2)
90.00
2753.8(2)
8
C15H24O4S4
396.58
Monoclinic
P21/c
10.0126(2)
13.6578(3)
13.4101(3)
90.00
95.186(1)
90.00
Formula weight (g molꢁ1
)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
a (1)
b (1)
g (1)
V (Å3)
Z
1828.73(3)
4
0.535
m (cmꢁ1
)
0.992
0.126
0.677
2Fmax (1)
140.48
963
0.0569
0.1434
0.0715
0.1542
79.1
2899
0.0412
0.1106
0.0540
0.1201
86.42
9496
0.0387
0.0808
0.0526
0.0846
70.3
8114
0.0248
0.0642
0.0311
0.0673
Unique reflections
a
R1
b
wR2
R1 (all data)a
wR2 (all data)b
P
P
P
P
a
b
2
R1
=
(|FO| ꢁ |FC|)/ FO. wR2 = [ (w(FO ꢁ FC2)2)/ (wFO4)]1.
and subjected to microwave irradiation at 50 W. The protocol was known, have full characterization data, and were prepared as
as follows: (1) heat from room temperature to 50 1C (ramp time described in the literature.
1 min), (2) hold at 50 1C and irradiate for 30 min in an open vessel
Commercially available compounds. Ethyl 4-chloroaceto-
reflux, (3) allow to cool to room temperature (B2 min), (4) check acetate (Cl-1), methyl 4-methoxyacetoacetate (MeO-1-Me), levulinic
the reaction mixture by TLC analysis.
acid (3), and 6-AcOEt were obtained from commercial sources.
Delineation of intermediate and target compounds
Synthesis procedures
New compounds. To our knowledge, syntheses of compounds
Ethyl 4-iodoacetoacetate (I-1). A solution of Cl-1 (8.24 g,
Mor-1, MeO-1-Hex, PiO-1, BnPiO-1, 2-AcOBn, 2-AcOH, 2-PnOH, 50.0 mmol) in acetone (75 mL) was treated with NaI (11.2 g,
2-PnOBn, 2-Me, 2-Et, 2-Hex, PiO-3-Me, BnPiO-3-Me, HO-3-Bn, 75.0 mmol), and the resulting solution was subjected to micro-
BnPiO-3-Bn, PiO-3, EtOCO2-3-Bn, EtOCO2-3, 5-AcOEtTMS, 5-AcOBn, wave irradiation at 50 W for 30 min in an open vessel at reflux.
5-AcOH, 5-AcOH0, 7-AcOBn, 7-AcOH, 8-OTBS, 8-OTBS/OH, 8-OH/O, The reaction mixture was diluted with water (50 mL) and
and 8-(OAc)2 are reported here for the first time. Full characterization extracted with ethyl acetate (2 ꢂ 100 mL). The organic layer
is reported for each compound with the exception of PiO-1 and was dried (Na2SO4) and concentrated. Column chromatography
BnPiO-1, which proved to be somewhat unstable, and for 5-AcOH0, [silica, hexanes/ethyl acetate (100 : 0 to 90 : 10)] afforded the less
which was inseparable from 5-AcOH.
polar fluorescent compound 1-dimer (500 mg, 4%) followed by
Known compounds with limited or no data. Compounds the title compound as a colorless viscous oil (10.2 g, 80%):
I-1,37 HCO2-1,31 AcO-1,32,33 NCS-1,30 MeS-1,35 Me2N-1,44 Pyr-1,40,41 1H NMR d 1.28 (t, J = 5.1 Hz, 3H), 3.71 (s, 2H), 3.98 (s, 2H), 4.20
HO-1,31,36,37,48 BnO-1,36,37,48 6-AcOBn,68 7,71 8-OH,78 8-(OH)2,73,74 (q, J = 5.1 Hz, 2H); 13C NMR (100 MHz) d 6.06, 14.30, 45.70, 61.9,
Phth-AK-Et,90 Phth-AK-Pr,92 AK-Et,90 AL(CH2)A,94 Bz-AK-BuOH- 167.0, 195.6; ESI-MS obsd 278.9489, calcd 278.9489 [(M + Na)+,
CEt94 have been reported. The synthesis of each of these M = C6H9IO3].
compounds has been carried out here with report of full charac-
terization data, except for Me2N-1 and HO-1, which proved to be sodium formate (1.70 g, 40.0 mmol) in anhydrous DMF (80 mL)
unstable.
was treated with Cl-1 (3.28 g, 2.72 mL, d = 1.21 g mLꢁ1
Ethyl 4-formyloxyacetoacetate (HCO2-1). A suspension of
,
Known compounds with incomplete data made here by a 20.0 mmol). The resulting mixture was stirred at 50 1C for 5 h.
new route. Compounds AcS-1,34 MeO-1,42 MeO-1-Bn,84 2,72–75 The reaction mixture was diluted with ethyl acetate, washed (water
and AK-Pr93 have been reported but full characterization data and brine), dried (Na2SO4) and concentrated. Column chromato-
have not been reported. We employed a new route and have graphy (silica, CH2Cl2) afforded a yellow oil (1.035 g, 28%):
provided full characterization.
1H NMR d 1.26 (t, J = 7.1 Hz, 3H), 3.50 (s, 2H), 4.19 (q, J =
Known compounds with full data made here by a new route. 7.1 Hz, 2H), 4.88 (s, 2H), 8.12 (s, 1H); 13C NMR d 14.2, 46.2, 62.0,
Compounds Br-3-Bn61 and 6-AcOH69 are known and have been 67.2, 90.1, 159.8, 166.4, 195.8; ESI-MS obsd 197.04216, calcd
fully characterized previously. We employed new routes and have 197.04204 [(M + Na)+, M = C7H10O5].
also provided full characterization.
Ethyl 4-acetoxyacetoacetate (AcO-1). Following a reported
Known compounds with full characterization. Compounds procedure32,33 with modification, a solution of Cl-1 (16.4 g,
N3-1,38 MeO-1-tBu,83 HO-3-Me,56 Br-3-Me,54,55 4-EtTMS,63 benzyl 100 mmol) in glacial acetic acid (100 mL) was treated with
5-iodopentanoate,85 ALA-R (R = hexyl, decyl),50,52 and AK-Me89 are anhydrous sodium acetate (24.0 g, 300 mmol). The resulting
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mixture was stirred for 16 h at 95 1C. Acetic acid was removed dropwise to the mixture at 110 1C, and the resulting mixture
by distillation under reduced pressure. The reaction mixture was refluxed for 4 h. The reaction mixture was acidified by the
was diluted with CH2Cl2 (150 mL), stirred for 1 h, and cooled addition of acetic acid (B2 mL), diluted with water, and washed
to 0 1C for 1 h. The solid thus precipitated was removed by with ethyl acetate. The organic extract was discarded. The pH of
filtration. The filtrate was washed with water (2 ꢂ 100 mL) and the aqueous phase was adjusted to B9–10 with 2 M NaOH, and
brine (100 mL), dried (Na2SO4) and concentrated. The resulting then the aqueous phase was extracted with ethyl acetate. The
residue was subjected to fractional distillation under reduced organic extract was washed with brine, dried and concentrated.
pressure. The first fraction was the unreacted starting material Column chromatography [silica, CH2Cl2/ethyl acetate (1 : 1) -
followed by the product as a clear oil (5.1 g, 27%): 13C NMR CH2Cl2/MeOH (10 : 1)] afforded a dark-brown viscous oil (0.260 g,
(100 MHz) d 14.0, 20.3, 46.0, 61.6, 67.8, 166.4, 167.0, 196.7; 30%), which decomposed over B6 months at ꢁ15 1C. Characteri-
ESI-MS obsd 211.0576, calcd 211.0577 [(M + Na)+, M = C8H12O5]. zation data (1H NMR) were consistent with those reported in the
1
The H NMR spectrum matched that reported.32
literature.44
Ethyl 4-(S-acetylthio)acetoacetate (AcS-1). A suspension of
Ethyl 4-(N-pyridinium)acetoacetate chloride (Pyr-1). Following
sodium thioacetate (1.37 g, 12.0 mmol) in anhydrous CH3CN a known procedure,40,41 the reaction of Cl-1 (8.23 g, 50.0 mmol)
(20 mL) was treated with Cl-1 (1.64 g, 10.0 mmol). The resulting with distilled pyridine (4.03 mL, 50.0 mmol) instantaneously
mixture was stirred overnight at room temperature. The reaction formed a salt in quantitative yield. Recrystallization [ethanol/
mixture was diluted with CH2Cl2, washed (water and brine), dried diethyl ether (1: 1)] of 3.15 g of the salt afforded colorless crystals
(Na2SO4) and concentrated. Column chromatography (silica, (2.45 g, 78%): 1H NMR (400 MHz) d 1.26 (t, J = 6.8 Hz, 3H), 4.03
CH2Cl2) provided an unidentified side product (first fraction) (s, 2H), 4.17 (q, J = 6.8 Hz, 2H), 6.72 (s, 2H), 8.07–8.16 (m, 2H),
followed by the title compound as an orange oil (0.886 g, 43%): 8.53 (t, J = 8.4 Hz, 1H), 9.41–9.50 (m, 2H); 13C NMR (100 MHz)
1H NMR d 1.25 (t, J = 7.1 Hz, 3H), 2.36 (s, 3H), 3.56 (s, 2H), 3.84 d 13.6, 46.5, 61.23, 67.7, 127.4, 145.5, 146.0, 166.0, 194.5; ESI-MS
(s, 2H), 4.17 (q, J = 7.1 Hz, 2H); 13C NMR d 14.2, 30.2, 39.2, 48.2, obsd 208.0970, calcd 208.0968 [M+, M = C11H14NO3].
61.7, 91.0, 166.8, 194.2, 196.7; ESI-MS obsd 227.03494, calcd
227.03485 [(M + Na)+, M = C8H12O4S].
Ethyl 4-(N-morpholino)acetoacetate (Mor-1). A solution of
Cl-1 (1.64 g, 10.0 mmol) in CH2Cl2 (20 mL) was treated with
Ethyl 4-(thiocyanato)acetoacetate (NCS-1). A suspension of morpholine (4.35 mL, 50.0 mmol). After a few minutes, preci-
potassium thiocyanate (0.972 g, 10.0 mmol) in CH3CN (10 mL) pitation started. The mixture was stirred for 2 h. The reaction
was treated with Cl-1 (1.64 g, 10.0 mmol). The resulting mixture mixture was filtered. The isolated precipitate was found to be
was stirred overnight at room temperature. The reaction mix- morpholine hydrochloride (1H NMR analysis). The filtrate was
ture was diluted with ethyl acetate, washed (water and brine), washed with aqueous NaOH solution (10 mL, 2.0 M). The
dried (Na2SO4) and concentrated. Column chromatography organic layer was washed with water (20 mL), dried (Na2SO4)
(silica, CH2Cl2) afforded a colorless oil, which turned light- and concentrated. The unreacted morpholine was evaporated
yellow upon standing (1.76 g, 94%): 1H NMR d 1.26 (t, J = 7.1 Hz, under reduced pressure. Column chromatography (hexanes/
3H), 3.60 (s, 2H), 4.17 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H); 13C NMR ethyl acetate 9 : 1 to 6 : 4) afforded a dark yellow oil (800 mg,
d 14.2, 36.4, 43.6, 47.6, 61.1, 62.2, 93.0, 111.3, 166.3, 168.2, 37%): 1H NMR d 1.28 (t, J = 7.2 Hz, 3H), 2.51 (t, J = 4.8 Hz, 4H),
171.9, 194.3; ESI-MS obsd 188.03764, calcd 188.03759 [(M + H)+, 3.28 (s, 2H), 3.50 (s, 2H), 3.73 (t, J = 4.8 Hz, 4H), 4.19 (q, J =
M = C7H9NO3S].
7.2 Hz, 2H); 13C NMR (100 MHz) d 14.1, 46.8, 53.6, 61.3, 66.7,
Ethyl 4-(S-methylthio)acetoacetate (MeS-1). A suspension of 67.7, 167.2, 201.6; ESI-MS obsd 216.1230, calcd 216.1230 [(M + H)+,
sodium thiomethoxide (0.841 g, 12.0 mmol) in anhydrous DMF M = C10H17NO4].
(10 mL) was treated with Cl-1 (1.64 g, 10.0 mmol). The resulting
Ethyl 4-methoxyacetoacetate (MeO-1). Following a procedure
solution of
mixture was stirred overnight at room temperature. The reaction for transesterification43 with modification,
a
mixture was diluted with CH2Cl2, washed (water and brine), dried MeO-1-Me (8.50 g, 58.2 mmol) in ethanol (150 mL) was treated
(Na2SO4) and concentrated. Column chromatography (silica, with DMAP (7.32 g, 60.0 mmol). The reaction mixture was
CH2Cl2) provided a highly fluorescent, unidentified side product refluxed in a flask equipped with a 30 cm distilling head
(first fraction, colorless) and the title compound (second fraction) (Hennion design, filled with glass beads). The solvent level
as a light-yellow oil (1.10 g, 62%); 1H NMR d 1.28 (t, J = 7.1 Hz, 3H), was maintained throughout the reaction, with continuous
2.06 (s, 3H), 3.31 (s, 2H), 3.66 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H); 13
NMR d 14.3, 15.8, 43.3, 46.3, 61.7, 167.4, 197.6; ESI-MS obsd methyl ester was monitored using GC-MS till there was no
177.0576, calcd 177.0580 [(M + H)+, M = C7H12O3S].
change. The reaction mixture was concentrated, diluted with
C
removal of solvent at the receiving end. The ratio of ethyl versus
Ethyl 4-(N,N-dimethylamino)acetoacetate (Me2N-1). The title diethyl ether (200 mL), and washed with 1 N HCl (100 mL). The
compound was prepared by slight modification of a reported organic layer was washed with brine (100 mL), dried (Na2SO4)
procedure,44 given that in our hands the reported procedure and concentrated. The residue thus obtained was subjected to
did not afford the desired product. A suspension of NaH (0.220 g, fractional distillation under reduced pressure to obtain the
60% in oil, 5.50 mmol) in dry toluene (10 mL) was treated product as a clear oil (3.81 g, 41%, the ratio of ethyl ester versus
all-at-once with N,N-dimethylaminoacetone (0.500 g, 0.566 mL, methyl ester was 95 : 5 upon GC analysis): 1H NMR d 1.28
4.95 mmol), and the resulting mixture was refluxed for 2 h. (t, J = 7.2 Hz, 3H), 3.42 (s, 3H), 3.50 (s, 2H), 4.09 (s, 2H), 4.20
Then, diethyl carbonate (1.21 g, 1.25 mL, 10.2 mmol) was added (q, J = 7.2 Hz, 2H); 13C NMR d 14.1, 45.9, 59.4, 61.4, 77.4, 167.0,
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201.7; ESI-MS obsd 161.0812, calcd 161.0808 [(M + H)+, 1H NMR spectrum showed the presence of B5% of unidenti-
M = C7H12O4].
fied impurities): 1H NMR d 1.25 (t, J = 7.2 Hz, 3H), 3.44 (s, 2H),
Ethyl 4-(benzyloxy)acetoacetate (BnO-1). The title compound 4.16 (q, J = 7.2 Hz, 2H), 4.55 (d, J = 8.8 Hz, 2H), 5.03–5.12
was obtained upon modification of reported procedures.36,37,48 (m, 4H), 7.33–7.37 (m, 10H); ESI-MS obsd 407.1256, calcd
A suspension of NaH (1.60 g, 40.0 mmol, 60% in mineral oil) in 407.1254 [(M + H)+, M = C20H23O7P].
THF (10 mL) was treated (dropwise over B10 min) with a
(4-Ethoxy-2,4-dioxobutyl)phosphate disodium salt (PiO-1). A
solution of benzyl alcohol (4.32 g, 40.0 mmol) in THF (4 mL) solution of BnPiO-1 (0.429 g, 1.06 mmol) in methanol (15 mL)
at 0 1C. The resulting reaction mixture was allowed to warm to was treated with 10% Pd/C (0.147 g) and stirred under a balloon
room temperature, was then stirred for 30 min, and was then pressure of H2 for 6 h. The mixture was filtered through Celite
cooled to 0 1C. A solution of Cl-1 (3.28 g, 20.0 mmol) in THF (methanol) and concentrated to a light-yellow, viscous oil
1
(4 mL) was added dropwise to the mixture at 0 1C over 30 min. (0.221 g, 92%): H NMR (DMSO-d6) d 1.19 (t, J = 7.0 Hz, 3H),
The resulting mixture was stirred at 0 1C for 30 min, and then at 3.64 (s, 2H), 4.09 (q, J = 7.0 Hz, 2H), 4.53 (d, J = 8.4 Hz, 2H). The
room temperature for 1 h. The reaction mixture was acidified resulting oil was dissolved in methanol (5 mL) and treated
by the slow addition of 1 M HCl, and extracted with diethyl dropwise with NaOH (68 mg, 1.7 mmol) in methanol (10 mL).
ether. The organic phase was washed (water and brine), dried The solution was stirred for 5 min. Concentration afforded
(Na2SO4) and concentrated. Column chromatography (silica, a light-yellow solid as the disodium salt (0.233 g, 81%
1
CH2Cl2) afforded a light-yellow oil (2.91 g, 62%): ESI-MS obsd from BnPiO-1): H NMR (D2O) d 1.26 (t, J = 7.0 Hz, 3H), 3.75
259.0942, calcd 259.0941 [(M + Na)+, M = C13H16O4]; the (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 4.50 (d, J = 6.4 Hz, 2H);
1H NMR spectrum was consistent with that reported previously;37 31P NMR d 3.86; ESI-MS obsd 225.0172, calcd 225.0170
13C NMR (100 MHz) d 13.9, 45.8, 61.2, 73.2, 74.6, 127.7, 127.9, [(M ꢁ H)ꢁ, M = C6H11O7P]; ESI-MS obsd 249.0135, calcd
128.4, 136.9, 166.9, 201.5. Reaction at a 40.0 mmol scale under 249.0135 [(M + Na)+].
identical conditions provided 6.22 g (66%) of the title compound
albeit in lower purity.
Hexyl 4-methoxyacetoacetate (MeO-1-Hex). A solution of
MeO-1-Me (4.10 g, 28.0 mmol) in toluene (100 mL) was treated
Ethyl 4-hydroxyacetoacetate (HO-1). Following a reported with hexanol (17 mL, 140 mmol) and DMAP (3.41 g, 28.0 mmol).
procedure31,37,48 with modification, a solution of BnO-1 (2.10 g, The reaction mixture was refluxed at 130 1C for 20 h with a
8.90 mmol) in methanol (60 mmol) was treated with 10% Pd/C 15 cm fractionating column equipped with a condenser. The
(0.230 g), and a balloon with H2 was attached to the flask. The methanol produced in the reaction was collected. The reaction
1
reaction mixture was stirred at room temperature for 4 h and then was monitored using H NMR spectroscopy. The reaction was
filtered. (Caution! Allowing the filter cake to dry on filter paper can quenched by the addition of saturated aqueous NH4Cl (50 mL).
cause a fire. On the other hand, filtration of the reaction mixture The mixture was diluted with diethyl ether (100 mL) and then
through Celite usually resulted in extensive decomposition of washed with 1 N HCl (50 mL) followed by brine (100 mL). The
product.) The filtrate was concentrated to afford a colorless oil organic layer was dried (Na2SO4) and concentrated. The residue
(1.19 g, 91%): ESI-MS obsd 147.0653, calcd 147.0652 [(M + H)+, was subjected to distillation to remove excess hexanol. Column
1
M = C6H10O4]; the H NMR spectrum was consistent with that chromatography [silica, hexanes/ethyl acetate (9 : 1 to 7 : 3)]
reported previously.31,37 The title compound was handled with afforded a colorless oil (5.21 g, 86%): 1H NMR d 0.89 (t, J =
difficulty given the apparent propensity to self-condensation and 6.6 Hz, 3H), 1.22–1.42 (m, 6H), 1.58–1.72 (m, 2H), 3.42 (s, 3H),
was used directly in subsequent reactions.
3.51 (s, 2H), 4.09 (s, 2H), 4.13 (t, J = 6.9 Hz, 2H); 13C NMR
Dibenzyl(4-ethoxy-2,4-dioxobutyl)phosphate (BnPiO-1). Follow- (100 MHz) d 14.1, 22.6, 25.6, 28.5, 31.5, 45.9, 59.4, 65.7, 77.4,
ing a reported procedure for the a-hydroxyketone,49 a solution of 167.2, 201.7; ESI-MS obsd 239.1257, calcd 239.1254 [(M + Na)+,
HO-1 (0.730 g, 5.00 mmol) in anhydrous CH2Cl2 (50 mL) was M = C11H20O4].
treated with 1H-tetrazole (17.8 mL, B0.45 mM in CH3CN,
Benzyl 4-methoxyacetoacetate (MeO-1-Bn). A solution of LDA
8 mmol). The resulting mixture was stirred at room temperature (52 mL, 104 mmol, 2.0 M solution) in THF (150 mL) at ꢁ78 1C
for 20 min and then treated with dibenzyl N,N-diisopropyl phos- was treated with benzyl acetate (15.0 g, 100 mmol) via addition
phoramidite (2.92 mL, 8.00 mmol). The resulting mixture was funnel over 20 min. The mixture turned yellow at the end of
stirred at room temperature for 3 h, whereupon 1H NMR spectro- addition, and was further stirred for 15 min. Then, a-methoxy-
scopy showed complete consumption of starting material. methyl acetate (10.4 g, 100 mmol) was added to this yellow
A sample of 30% aqueous H2O2 (1.5 mL, 30% aqueous solution) mixture via addition funnel over 15 min. The resulting mixture
was added, and the resulting mixture was stirred for 3 h. was stirred for 2 h at ꢁ78 1C. The reaction mixture was allowed
A second batch of H2O2 was added, and the resulting mixture to warm to room temperature and then quenched by the
was stirred for an additional 3 h. The excess H2O2 was addition of 2 N HCl (100 mL). The mixture was extracted with
quenched by the addition of saturated aqueous sodium hydro- ethyl acetate (2 ꢂ 200 mL). The organic layer was dried (Na2SO4)
sulfite (B20 mL). The organic layer was separated, and the and concentrated under high vacuum to obtain a light yellow
aqueous phase was washed with CH2Cl2. The combined organic oil (20.4 g, 92% yield): 1H NMR d 3.36 (s, 3H), 3.56 (s, 2H),
phase was washed (water and brine), dried (Na2SO4) and 4.05 (s, 2H), 5.17 (s, 2H), 7.35–7.41 (m, 5H); 13C NMR (100 MHz)
concentrated. Column chromatography [twice, silica, CH2Cl2/ d 45.6, 59.1, 66.9, 77.1, 128.2, 128.3, 128.5, 135.3, 166.8, 201.4;
ethyl acetate (5 : 1)] afforded a colorless oil (0.429 g, 21%; the ESI-MS obsd 245.0784, calcd 245.0784 [(M + Na)+, M = C12H14O4].
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Reaction leading to 1-dimer. Undesired compound 1-dimer acetate (100 : 0 to 95 : 5)] afforded a pale yellow oil (1.32 g, 24%)
was isolated from the reaction of potassium phthalimide with with characterization data as that obtained via acidolysis of the
Cl-1. A solution of potassium phthalimide (5.56 g, 30.0 mmol) tert-butyl ester described above.
in dry DMF (20 mL) was treated with Cl-1 (3.28 g, 20.0 mmol).
Benzyl 5-methoxy-3-(2-methoxyacetyl)levulinic acid (2-AcOBn).
The resulting mixture was stirred at 80 1C for 4 h. The reaction A solution of 2 (3.85 g, 24.0 mmol) in anhydrous acetone (50 mL)
mixture was quenched by the addition of saturated aqueous was treated with anhydrous K2CO3 (4.80 g, 34.7 mmol). The
NH4Cl. The resulting mixture was extracted with CH2Cl2. The mixture was stirred for 30 min followed by the addition of 4-Bn
organic extract was washed (water and brine), dried (Na2SO4) (4.91 mL, 31.2 mmol). The mixture was stirred at room tempera-
and concentrated. A portion of the resulting yellow solid was ture for 16 h, then water (50 mL) was added. The aqueous reaction
chromatographed [silica, hexanes/CH2Cl2 (1 : 1)] to afford a mixture was further treated with 1 N HCl till the effervescence
yellow crystalline solid. The yield was not determined, given ceased. The mixture was extracted with diethyl ether (2 ꢂ 100 mL).
that this reaction was initially intended to explore the reactivity The organic layer was dried (Na2SO4) and concentrated. Column
of ethyl 4-chloroacetoacetate. Crystals suitable for X-ray analysis chromatography [silica, hexanes/ethyl acetate (9 : 1 to 7 : 3)]
1
were grown by slow evaporation of a CH2Cl2/cyclohexane afforded a colorless viscous oil (4.80 g, 64%): H NMR d 2.85 (d,
solution: mp 129–130 1C; 1H NMR d 1.31 (t, J = 7.1 Hz, 6H), J = 6.9 Hz, 2H), 3.40 (s, 6H), 4.10 (dd, J = 17.1 and 20.7 Hz, 4H), 4.49
3.18 (s, 4H), 4.23 (q, J = 7.1 Hz, 4H), 12.19 (s, 2H); 13C NMR d (t, J = 6.9 Hz, 1H), 5.11 (s, 2H), 7.28–7.42 (m, 5H); 13C NMR
14.5, 28.8, 61.0, 93.5, 168.7, 171.6; ESI-MS obsd 257.1021, calcd (100 MHz) d 31.6, 54.0, 59.4, 67.0, 77.0, 128.3, 128.5, 128.7, 135.6,
257.1020 [(M + H)+, M = C12H16O6]; anal. calcd for C12H16O6: C, 171.1, 203.1; ESI-MS obsd 331.1156, calcd 331.1152 [(M + Na)+,
56.24; H, 6.29; O, 37.46. Found: C, 56.28; H, 6.26; O, 37.59.
M = C16H20O6].
1,5-Dimethoxy-2,4-pentanedione (2), from MeO-1-tBu. A
5-Methoxy-3-(2-methoxyacetyl)levulinic acid (2-AcOH). A
solution of MeO-1-tBu (13.9 g, 73.9 mmol) in toluene (100 mL) solution of 2-AcOBn (4.70 g, 15.2 mmol) in methanol and water
was treated with NaH (4.10 g, 102 mmol). The mixture was (2 : 1, 20 mL) was treated with Pd(OH)2/C (100 mg). The mixture
stirred for 30 min. The mixture was cooled to 0 1C followed by was stirred overnight (16 h) under a hydrogen atmosphere
treatment with methoxyacetyl chloride (7.35 mL, 80.0 mmol). (balloon pressure). The mixture was filtered through a small
The mixture was allowed to warm to room temperature and pad of Celite. The Celite pad was further washed with methanol
stirred for 4 h. The reaction was quenched by the addition of (20 mL). The combined filtrate was concentrated followed by
saturated aqueous NH4Cl solution followed by the addition of column chromatography [silica, CH2Cl2/methanol (100 : 0 to
1
1 N HCl (50 mL). The mixture was extracted with diethyl ether 98 : 2)] to obtain a colorless viscous oil (2.32 g, 69%): H NMR
(2 ꢂ 200 mL). The organic layer was dried (Na2SO4) and d 2.70–2.91 (br, 2H), 3.42 (s, 6H), 3.98–4.20 (br, 4H), 4.38–4.60
concentrated. For acidolysis, the residue was diluted with (br, 1H); 13C NMR (100 MHz) d 31.2, 53.7, 59.4, 76.9, 175.7,
CH2Cl2 (50 mL) and treated with TFA (3 mL) with stirring for 203.4; ESI-MS obsd 241.0681, calcd 241.0683 (M + Na)+, obsd
2 h at room temperature. The reaction mixture was concen- 219.0859, calcd 219.0863 [(M + H)+, M = C9H14O6]. Note: the
trated and subjected to Kugelrohr distillation. Further purification proton signals (other than for methoxy), and the carbon signals
(to remove UV-inactive impurities) was carried out by column corresponding to methylene and carbonyl groups, were broad
chromatography [silica, hexanes/ethyl acetate (10 : 0 to 9 : 1), due to rapid keto–enol tautomerization.
column length of 28 cm ꢂ width of 5 cm, flow rate 20 mL minꢁ1
;
Benzyl 8-methoxy-7-oxo-6-(2-methoxyacetyl)octanoic acid
10 h duration] to remove the less polar and more polar (2-PnOBn). Following the alkylation procedure of Ono86 with
impurities from the title compound, which was isolated as a slight modification, a solution of 2 (2.79 g, 17.4 mmol) in
pale yellow oil (3.92 g, 33%): 1H NMR enold 3.44 (s, 6H), anhydrous benzene (200 mL) was treated with DBU (3.8 g,
4.03 (s, 4H), 6.24 (s, 1H); 13C NMR (100 MHz) enold 59.4, 73.4, 25 mmol). The mixture was stirred for 30 min followed by the
94.3, 191.5; ESI-MS obsd 161.0809, calcd 161.0808 [(M + H)+, addition of benzyl 5-iodopentanoate (5.53 g, 17.4 mmol). The
M = C7H12O4].
mixture was stirred for 6 h and then diluted with water (50 mL).
1,5-Dimethoxy-2,4-pentanedione (2), from MeO-1-Bn.
solution of MeO-1-Bn (7.52 g, 34.3 mmol) in toluene (50 mL) organic layer was dried (Na2SO4) and concentrated. Column
A
The mixture was extracted with diethyl ether (2 ꢂ 100 mL). The
was treated with NaH (1.44 g, 60.0 mmol). The mixture was chromatography [silica, hexanes/ethyl acetate (9 : 1 to 7 : 3)]
1
stirred for 30 min. The mixture was cooled to 0 1C followed by afforded a colorless viscous oil (1.04 g, 17%): H NMR d 1.24–
treatment with methoxyacetyl chloride (3.63 mL, 40.0 mmol). 1.40 (m, 2H), 1.58–1.84 (m, 4H), 2.35 (t, J = 7.5 Hz, 2H), 3.39
The mixture was allowed to warm to room temperature and (s, 6H), 3.93 (t, J = 6.9 Hz, 1H), 4.03 (dd, J = 4.8 and 21.9 Hz, 4H),
stirred for 4 h. The reaction was quenched by the addition of 5.10 (s, 2H), 7.28–7.42 (m, 5H); 13C NMR (100 MHz) d 24.7, 26.6,
2 N HCl (50 mL). The mixture was extracted with diethyl ether 26.9, 33.8, 57.8, 59.2, 66.2, 77.0, 128.19, 128.23, 128.6, 135.1,
(2 ꢂ 100 mL). The organic layer was dried (Na2SO4) and 173.2, 204.2; ESI-MS obsd 373.1616, calcd 373.1622 [(M + Na)+,
concentrated. For hydrogenolysis, the residue was diluted with M = C19H26O6].
THF (50 mL) and treated with Pd(OH)2/C and a hydrogen atmo-
8-Methoxy-7-oxo-6-(2-methoxyacetyl)octanoic acid (2-PnOH).
sphere under balloon pressure for 2 days at room temperature. A solution of 2-PnOBn (1.04 g, 2.90 mmol) in THF (20 mL) was
The reaction was monitored by TLC accompanied by a balloon treated with Pd(OH)2/C (20 mg). The mixture was stirred under
refill each time. Column chromatography [silica, hexanes/ethyl a hydrogen atmosphere (balloon pressure) for one day. The mixture
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was filtered through a small pad of Celite. The Celite pad was
(5-Methoxy-2,5-dioxopentyl)phosphate disodium salt (PiO-3-
washed with THF (20 mL). The THF eluant was concentrated Me). A solution of BnPiO-3-Me (1.38 g, 3.39 mmol) in methanol
followed by column chromatography [silica, CH2Cl2/methanol (45 mL) was treated with 10% Pd/C (0.474 g) and stirred under a
(100 : 0 to 98 : 2)] to obtain a colorless viscous oil (300 mg, 38%): balloon pressure of H2 for 6 h. The mixture was filtered through
1H NMR d 1.26–1.42 (m, 2H), 1.56–1.86 (m, 4H), 2.35 (t, J = Celite (methanol). The filtrate was concentrated to afford a
1
7.5 Hz, 2H), 3.40 (s, 6H), 3.96 (t, J = 6.6 Hz, 1H), 4.04 (dd, J = 4.8 colorless viscous oil (0.757 g, 99%): H NMR (DMSO-d6) d 2.51
and 21.9 Hz, 4H); 13C NMR d 24.5, 26.6, 26.9, 33.6, 57.91, 59.3, (t, J = 6.6 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 3.58 (s, 3H), 4.46 (d, J =
77.0, 179.0, 204.3; ESI-MS obsd 283.1143, calcd 283.1152 8.4 Hz, 2H). The oil was dissolved in methanol (5 mL), treated
[(M + Na)+, M = C12H20O6].
dropwise with NaOH (0.267 g, 6.68 mmol) in methanol (10 mL),
1,5-Dimethoxy-3-hexyl-2,4-pentanedione (2-Hex). Following and stirred for 5 min. Concentration afforded a white solid,
the alkylation procedure of Ono86 with slight modification, a which was dried under high vacuum over KOH (0.840 g, 91%):
solution of 2 (1.80 g, 11.2 mmol) in anhydrous benzene (50 mL) 1H NMR (D2O) d 2.66 (t, J = 6.3 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H),
was treated with DBU (2.28 g, 15.0 mmol). The mixture was 3.69 (s, 3H), 4.47 (d, J = 5.9 Hz, 2H); 13C NMR (D2O) d 27.7, 33.6,
stirred for 30 min followed by the addition of 1-iodohexane 52.6, 69.3, 176.2, 211.9; 31P NMR d 4.27; ESI-MS obsd 225.0173,
(2.37 g, 11.2 mmol). The mixture was stirred at room temperature calcd 225.0170 [(M ꢁ H)ꢁ, M = C6H11O7P]; ESI-MS obsd
for 6 h and then diluted with water (50 mL). The mixture was 249.0135, calcd 249.0135 [(M + Na)+].
extracted with diethyl ether (2 ꢂ 50 mL). The organic layer
Dibenzyl(5-methoxy-2,5-dioxopentyl)phosphate (BnPiO-3-Me).
was dried (Na2SO4) and concentrated. The resulting residue was A solution of 1H-tetrazole (25 mL, 11 mmol, 0.45 M in aceto-
distilled (Kugelrohr apparatus) to remove the volatile constitu- nitrile) was treated with dibenzyl N,N-diisopropylphosphoramidite
ents (unreacted 2 and 1-iodohexane). Column chromatography (3.28 mL, 10.0 mmol) and stirred for 10 min. The resulting mixture
[silica, hexanes/ethyl acetate (10 : 0 to 9 : 1)] afforded a colorless was treated with a solution of HO-3-Me (1.31 g, 8.97 mmol) in
1
viscous oil (880 mg, 32%): H NMR d 0.87 (t, J = 6.6 Hz, 2H), CH2Cl2 (10 mL) and stirred for 3 h. The reaction mixture was
1.18–1.38 (m, 8H), 1.70–1.82 (m, 2H), 3.41 (s, 6H), 3.91 (t, J = 6.6 Hz, cooled to ꢁ78 1C, treated with m-CPBA (3.0 g), and stirred for 1 h.
1H), 4.05 (dd, J = 6.0 and 22.8 Hz, 4H); 13C NMR (100 MHz) d 14.0, The reaction mixture was allowed to warm to rt and stirred for 1 h.
22.5, 27.1, 27.5, 29.2, 31.5, 58.3, 59.2, 77.1, 204.3; ESI-MS obsd The mixture was diluted with CH2Cl2 (100 mL) and then washed
267.1569, calcd 267.1567 [(M + Na)+, M = C13H24O4].
with saturated aqueous Na2SO3 (2 ꢂ 50 mL), saturated aqueous
1,5-Dimethoxy-3-methyl-2,4-pentanedione (2-Me). A solution NaHCO3 (2 ꢂ 50 mL), and water (100 mL). The organic fraction
of 2 (753 mg, 4.70 mmol) in anhydrous acetone (15 mL) was was dried (Na2SO4) and concentrated. Column chromatography
treated with anhydrous K2CO3 (690 mg, 5.00 mmol). The [silica, CH2Cl2/ethyl acetate (10 : 0 to 8 : 2)] afforded a colorless oil
mixture was stirred for 30 min followed by the addition of (2.54 g, 69%): 1H NMR d 2.55–2.63 (m, 2H), 2.64–2.72 (m, 2H), 3.66
iodomethane (0.50 mL, 8.2 mmol). The mixture was stirred at (s, 3H), 4.50 (d, J = 9.0 Hz, 2H), 5.03–5.17 (m, 4H), 7.63–7.82
room temperature for 16 h. The reaction was quenched by the (m, 10H); 13C NMR d 27.1, 33.1, 51.8, 69.7 (d, J = 5.7 Hz), 70.4
addition of water (20 mL). The aqueous mixture was treated (d, J = 5.9 Hz) 128.1, 128.6, 128.6, 135.5 (d, J = 6.8 Hz), 172.6, 203.3
with 1 N HCl until the effervescence ceased. The mixture was (d, J = 6.2 Hz); 31P NMR d ꢁ0.71; ESI-MS obsd 429.1071, calcd
extracted with diethyl ether (2 ꢂ 50 mL). The organic layer was 429.1074 [(M + Na)+, M = C20H23O7P].
dried (Na2SO4) and concentrated. Column chromatography
Benzyl 5-bromolevulinate (Br-3-Bn). A solution of Br-3-Me
[silica, hexanes/ethyl acetate (10 : 0 to 9 : 1)] afforded a colorless (14.8 g, 70.8 mmol) in toluene (200 mL) was treated with benzyl
1
viscous oil (491 mg, 60%): H NMR d 1.25 (d, J = 7.2 Hz, 3H), alcohol (50 mL, 482 mmol) and p-TsOHꢀH2O (2.0 g, 10 mmol).
3.41 (s, 6H), 3.97 (q, J = 7.2 Hz, 1H), 4.06 (d, J = 1.5 Hz, 4H); 13
C
The reaction mixture was refluxed at 130 1C for 4 h with a 10 cm
NMR (100 MHz) d 11.7, 52.4, 59.4, 76.7, 205.5; ESI-MS obsd fractionating column fitted with a condenser. The methanol
175.0965, calcd 175.0964 [(M + H)+, M = C8H14O4].
produced in the reaction was collected. The reaction was moni-
1
1,5-Dimethoxy-3-ethyl-2,4-pentanedione (2-Et). A solution of tored using H NMR spectroscopy. The reaction was quenched
2 (570 mg, 3.57 mmol) in anhydrous acetone (15 mL) was by the addition of saturated aqueous NaHCO3 (50 mL). The
treated with anhydrous K2CO3 (620 mg, 4.50 mmol). The mixture mixture was diluted with diethyl ether (200 mL) and washed
was stirred for 30 min followed by the addition of iodoethane with brine (100 mL). The organic layer was dried (Na2SO4),
(400 mL, 5.00 mmol). The mixture was refluxed for 12 h. The concentrated, and subjected to Kugelrohr distillation to remove
reaction was quenched by the addition of water (20 mL). The excess benzyl alcohol. The undistilled residue was further
aqueous reaction mixture was further treated with 1 N HCl until purified by column chromatography [silica, hexanes/ethyl acetate
the effervescence ceased. The mixture was extracted with diethyl (10 : 0 to 9 : 1)] to obtain a colorless oil (14.0 g, 69%): 1H NMR
ether (2 ꢂ 50 mL). The organic layer was dried (Na2SO4) and d 2.70 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 3.94 (s, 2H), 5.11
concentrated. Column chromatography [silica, hexanes/ethyl (s, 2H), 7.27–7.41 (m, 5H); 13C NMR d 28.3, 34.35, 34.40, 66.7,
acetate (100 : 0 to 95 : 05)] afforded a colorless viscous oil (240 mg, 128.3, 128.4, 128.6, 135.7, 172.2, 200.5; ESI-MS obsd 306.9944,
1
36%): H NMR d 0.94 (t, J = 7.2 Hz, 3H), 1.78–1.88 (m, 2H), 3.41 calcd 306.9940 [(M + Na)+, M = C12H13O3Br].
(s, 6H), 3.85 (t, J = 6.8 Hz, 1H), 4.05 (dd, J = 17.1 & 23.1 Hz, 4H);
13C NMR (100 MHz) d 12.2, 20.7, 59.4, 59.8, 77.2, 204.4; ESI-MS (9.26 g, 32.4 mmol) in DMF (100 mL) was treated with sodium
obsd 211.0938, calcd 211.0941 [(M + Na)+, M = C9H16O4].
formate (4.42 g, 65.0 mmol) and stirred overnight at room
Benzyl 5-hydroxylevulinate (HO-3-Bn). A solution of Br-3-Bn
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temperature. The reaction mixture was diluted with water for 3 h. The mixture was added to an ice-cold solution of 2 N
(150 mL) and extracted using diethyl ether (2 ꢂ 150 mL). The HCl (100 mL) and then extracted with diethyl ether (2 ꢂ 100 mL).
organic fraction was concentrated to obtain the corresponding The organic fraction was dried (Na2SO4) and concentrated to
formate in pure form [1H NMR d 2.68–2.81 (m, 4H), 4.80 (s, 2H), obtain a colorless oil (1.29 g, 87%): 1H NMR d 1.33 (t, J =
5.12 (s, 2H), 7.30–7.42 (m, 5H), 8.15 (s, 1H)]. The formate so 7.2 Hz, 3H), 2.70–2.81 (m, 4H), 4.24 (q, J = 7.2 Hz, 2H) 4.71
obtained was diluted with CH2Cl2 (50 mL) and passed through (s, 2H), 5.11 (s, 2H), 7.32–7.42 (m, 5H); 13C NMR d 14.3, 27.6, 33.3,
an activated alumina column (2.5 ꢂ 10 cm), eluting with 40% 64.8, 66.7, 70.5, 128.32, 128.39, 128.7, 135.8, 154.8, 172.2, 202.4;
methanol in CH2Cl2 according to a reported procedure.60 The ESI-MS obsd 317.100, calcd 317.0996 [(M + Na)+, M = C15H18O6].
fractions containing the title compound were concentrated to
5-[(Ethoxycarbonyl)oxy]levulinic acid (EtOCO2-3). A solution
afford a colorless oil, which solidified under high vacuum to of EtOCO2-3-Bn (1.28 g, 4.37 mmol) in methanol (15 mL) was
give a colorless low melting solid (6.17 g, 85%): 1H NMR d 2.67– treated with Pd(OH)2/C (20% Pd on carbon with 50% water wet,
2.80 (m, 4H), 3.00 (t, J = 4.5 Hz, 1H), 4.30 (d, J = 4.5 Hz, 2H), 5.12 100 mg). The mixture was stirred overnight (16 h) under an
(s, 2H), 7.30–7.42 (m, 5H); 13C NMR d 27.9, 32.9, 66.9, 68.4, atmosphere of hydrogen (balloon pressure). The mixture was
128.40, 128.52, 128.8, 135.7, 172.3, 208.2; ESI-MS obsd filtered through a small pad of Celite. The Celite pad was
245.0787, calcd 245.0784 [(M + Na)+, M = C12H14O4].
washed with methanol (20 mL). The filtrate was concentrated
1
Benzyl 5-dibenzylphospholevulinate (BnPiO-3-Bn). A solution to obtain a white solid (804 mg, 90%): mp 75–76 1C; H NMR
of 1H-tetrazole (25 mL, 11 mmol, 0.45 M in acetonitrile) was (D2O) d 1.27 (t, J = 7.2 Hz, 3H), 2.67 (t, J = 6.0 Hz, 2H), 2.71–2.89
treated with dibenzyl N,N-diisopropylphosphoramidite (3.61 mL, (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 4.88–4.96 (br, 2H); 13C NMR
11.0 mmol) and stirred for 10 min. The resulting mixture was (100 MHz, D2O) d 13.5, 27.4, 33.1, 65.9, 70.7, 155.3, 176.9, 206.6;
treated with a solution of HO-3-Bn (2.22 g, 10.0 mmol) in CH2Cl2 ESI-MS obsd 227.0522, calcd 227.0526 [(M + Na)+, M = C8H12O6];
(10 mL) and stirred for 3 h. The reaction mixture was cooled to anal. calcd for C8H12O6: C, 47.06; H, 5.92; O, 47.02. Found: C,
ꢁ78 1C, treated with m-CPBA (3.0 g), and then stirred for 1 h. The 47.02; H, 5.94; O, 47.07.
reaction mixture was allowed to warm to rt and stirred for another
2-(Trimethylsilyl)ethyl 5-methoxy-3-(methoxycarbonyl)levulinate
1 h. The mixture was diluted with CH2Cl2 (100 mL) and washed (5-AcOEtTMS). A sample of MeO-1-Me (1.29 mL, 10.0 mmol) was
with Na2SO3 (2 ꢂ 50 mL), Na2CO3 (2 ꢂ 50 mL), and water (100 mL). added dropwise (over 1–2 min) to a suspension of NaH (0.422 g,
The organic fraction was dried (Na2SO4) and concentrated. Column 11.0 mmol, 60% in mineral oil) in dry toluene (20 mL). The
chromatography [silica, hexanes/ethyl acetate (10 : 0 to 9 : 1)] resulting mixture was stirred at room temperature for 10 min,
afforded a colorless oil (3.70 g, 76%): 1H NMR d 2.60–2.75 whereupon a sample of 4-EtTMS (3.58 g, 15.0 mmol) was added.
(m, 4H), 4.48 (d, J = 9.0 Hz, 2H), 5.03–5.15 (m, 4H), 5.10 (s, 2H) The resulting mixture was stirred overnight at 60 1C. The
is merged with the multiplet, 7.30–7.42 (m, 15H); 13C NMR reaction mixture was acidified with 10% HCl and extracted
(100 MHz) d 27.6, 32.3, 66.8, 69.9 (d, J = 6.1 Hz), 70.6 (d, J = with diethyl ether. The organic layer was washed (water and
6.1 Hz) 128.28, 128.38, 128.48, 128.75, 128.82, 128.87, 135.68, brine), dried (Na2SO4) and concentrated. Column chromato-
135.75, 135.87, 172.3, 203.3 (d, J = 6.8 Hz); 31P NMR ꢁ0.654; graphy (silica, CH2Cl2) afforded a light-yellow oil (1.95 g, 64%):
ESI-MS obsd 483.1559, calcd 483.1567 [(M + H)+], obsd 505.1376, 1H NMR d 0.02 (s, 9H), 0.93–1.00 (m, 2H), 2.81 (dd, 3J = 5.4 Hz,
3
2
calcd 505.1387 [(M + Na)+ M = C26H27O7P].
2J = 17.5 Hz, 1H), 3.01 (dd, J = 9.1 Hz, J = 17.5 Hz, 1H), 3.43
5-Phosphonatolevulinic acid disodium salt (PiO-3). A turbid (s, 3H), 3.72 (s, 3H), 4.17–4.18 (m, 2 + 1H), 4.25 (app d, J = 3.9
suspension of BnPiO-3-Bn (926 mg, 1.92 mmol) in THF/water Hz, 2H); 13C NMR d ꢁ1.3, 17.5, 32.5, 49.9, 53.0, 59.7, 63.7,
(10 mL, 1 : 2) was treated with Pd(OH)2/C (300 mg). The mixture 77.6, 168.8, 171.6, 202.8; ESI-MS obsd 327.1237, calcd 327.1234
was stirred for 24 h under an atmosphere of hydrogen (balloon [(M + Na)+, M = C13H24O6Si].
pressure). The mixture was filtered (0.2 mm filter), and the
Benzyl 5-methoxy-3-(methoxycarbonyl)levulinate (5-AcOBn).
filtered material was washed with water (10 mL). Concentration A suspension of NaH (670 mg, 16.7 mmol, 60% in mineral oil) in
1
of the filtrate afforded a colorless oil (387 mg, 95%): H NMR toluene (50 mL) was treated with MeO-1-Me (2.22 g, 15.2 mmol).
(DMSO-d6) d 2.43 (t, J = 6.3 Hz, 2H), 2.66 (t, J = 6.3 Hz, 2H), 4.45 The mixture was stirred for 30 min. The mixture was treated with
(d, J = 8.4 Hz, 2H); 13C NMR (DMSO-d6) d 27.3, 33.1, 69.3 (d, J = benzyl 2-bromoacetate (2.66 mL, 17.0 mmol). The reaction mixture
4.8 Hz), 173.8, 205.0 (d, J = 7.1 Hz); 31P NMR d ꢁ 0.277. The oil was stirred at 60 1C for 12 h. The reaction mixture was quenched by
was dissolved in water (10 mL) containing 160 mg of NaOH to the addition of saturated aqueous NH4Cl (10 mL) and then
make the salt. Lyophilization gave a white solid (460 mg, 98%), acidified with 2 N HCl (15 mL). The resulting mixture was extracted
which appeared to be the disodium salt: 1H NMR (300 MHz, with diethyl ether (2 ꢂ 100 mL). The organic phase was washed
D2O) d 2.51 (t, J = 6.6 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 4.53 (d, J = (water), dried (Na2SO4) and concentrated. Column chromatography
7.5 Hz, 2H); 13C NMR (75 MHz, D2O) d 29.5, 34.0, 69.4 (d, J = [silica, hexanes/ethyl acetate (9 : 1 to 8 : 2)] afforded a colorless oil
4.8 Hz), 128.7 (d, J = 43.2 Hz), 179.8; 31P NMR d 0.901; ESI-MS (4.02 g, 89%): 1H NMR d 2.91 (dd, J = 5.7 & 17.4 Hz, 1H), 3.31 (dd,
obsd 256.9791, calcd 256.9798 [(M + H)+, M = C5H7Na2O7P].
J = 9.0 & 17.4 Hz, 1H), 3.42 (s, 3H), 3.71 (s, 3H), 4.08–4.19 (m, 1H),
Benzyl 5-[(ethoxycarbonyl)oxy]levulinate (EtOCO2-3-Bn). 4.24 (d, J = 5.7 Hz, 2H), 5.11 (dd, J = 6.3 & 12.6 Hz, 2H), 7.29–7.42
A solution of HO-3-Bn (1.15 g, 5.01 mmol) in pyridine (20 mL) (m, 5H); 13C NMR (100 MHz) d 32.2, 49.7, 52.8, 59.4, 66.9, 77.3,
was treated with ethyl chloroformate at 0 1C. The reaction 128.29, 128.42, 128.6, 135.5, 168.5, 171.0, 202.4; ESI-MS obsd
mixture was allowed to warm to room temperature and stirred 317.0993, calcd 317.0996 [(M + Na)+, M = C15H18O6].
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Benzyl 5-methoxy-3-(methoxycarbonyl)levulinic acid (5-AcOH).
Paper
Benzyl-1-methoxy-3-acetyllevulinate (7-AcOBn). A suspension
A solution of 5-AcOBn (1.07 g, 3.63 mmol) in methanol (10 mL) of NaH (650 mg, 16.3 mmol, 60% in mineral oil) in toluene
with an added drop of water was treated with Pd(OH)2/C (120 mg). (40 mL) was treated with 7 (2.10 g, 16.1 mmol) whereupon the
The mixture was stirred overnight (16 h) under an atmosphere of mixture turned a turbid white. The mixture was stirred for
hydrogen (balloon pressure). The mixture was filtered through a 30 min. The mixture was treated with 4-Bn (2.77 mL, 17.7 mmol)
small pad of Celite. The Celite pad was washed with methanol and stirred at 60 1C for 16 h. The reaction mixture was quenched
(20 mL). The filtrate was concentrated to obtain a mixture containing by the addition of saturated aqueous NH4Cl (10 mL) and then
the title compound (600 mg). Repeated attempts at purification acidified with 2 N HCl (8 mL). The mixture was extracted with
by column chromatography were unsuccessful. The mixture was diethyl ether (2 ꢂ 100 mL). The organic phase was washed
treated with NaOH (30 mL, 1 N) and washed with diethyl ether (water), dried (Na2SO4) and concentrated. Column chromato-
(2 ꢂ 50 mL) to remove impurities. The mixture was acidified graphy [silica, hexanes/ethyl acetate (9: 1 to 8 : 2)] afforded the
(to pH B 1 using aqueous HCl) and extracted with diethyl ether title compound as a colorless oil (900 mg, 20%) followed by a
(2 ꢂ 100 mL). The latter extract was concentrated to afford the mixture containing the product with some impurity (600 mg).
title compound in B65% purity. A minor constituent in the Data for the title compound: 1H NMR d 2.27 (s, 3H), 2.79 (dd, J =
mixture was assigned to a cyclized species (5-AcOH0) on the basis 6.0 & 17.4 Hz, 1H), 3.00 (dd, J = 8.4 & 17.4 Hz, 1H), 3.40 (s, 3H),
of mass spectrometric analysis: ESI-MS obsd 171.0316, calcd 4.05 (s, 2H), 4.37 (dd, J = 6.0 & 8.4 Hz, 1H), 5.11 (t, J = 10.2 Hz,
171.0299 [(M ꢁ H)+, M = C7H8O5]. Data from the mixture 2H), 7.30–7.42 (m, 5H); 13C NMR (100 MHz) d 29.8, 32.0, 58.2,
1
assigned to the title compound: H NMR d 2.92 (dd, J = 5.4 & 59.3, 66.9, 77.1, 128.3, 128.4, 128.6, 135.5, 171.1, 202.3, 203.5;
17.0 Hz, 1H), 3.10 (dd, J = 8.7 & 17.0 Hz, 1H), 3.44 (s, 3H), 3.75 ESI-MS obsd 301.1048, calcd 301.1046 [(M + Na)+, M = C15H18O5].
(s, 3H), 4.05–4.10 (m, 1H), 4.25 (dd, J = 17.4 & 23.4 Hz, 2H);
1-Methoxy-3-acetyllevulinic acid (7-AcOH). A solution of
13C NMR (100 MHz) d 31.9, 49.7, 53.1, 59.5, 77.3, 168.5, 176.5, 7-AcOBn (792 mg, 2.84 mmol) in methanol (15 mL) was treated
202.4; ESI-MS obsd 227.0526, calcd 227.0526 [(M + Na)+, with Pd(OH)2/C (50 mg). The mixture was stirred for 12 h under
M = C8H12O6].
an atmosphere of hydrogen (balloon pressure). The mixture
Benzyl 3-acetyllevulinate (6-AcOBn). A suspension of NaH was filtered through a small pad of Celite. The Celite pad was
(1.27 g, 31.8 mmol, 60% in mineral oil) in toluene (100 mL) was washed with methanol (20 mL). The filtrate was concentrated
treated with 2,4-pentanedione (2.80 g, 28.0 mmol). The mixture and purified by column chromatography [silica, CH2Cl2/MeOH
was stirred for 15 min. The mixture was treated with 4-Bn (100 : 0 to 97 : 3)] to obtain a colorless viscous oil (433 mg, 80%):
(5.17 mL, 33.0 mmol). The reaction mixture was stirred at 60 1C 1H NMR d 2.30 (s, 3H), 2.78 (dd, J = 6.9 & 17.7 Hz, 1H), 3.03
for 16 h. The reaction mixture was quenched by the addition of (dd, J = 8.1 & 17.7 Hz, 1H), 3.43 (s, 3H), 3.98 (br, 2H), 4.10–4.30
saturated aqueous NH4Cl (10 mL) and then acidified with 2 N (br, 1H); 13C NMR d 30.1, 31.7, 59.5, 73.4, 103.3, 177.2, 191.4,
HCl (15 mL). The mixture was extracted with diethyl ether 202.9; ESI-MS obsd 189.0753, calcd 189.0757 [(M + H)+, obsd
(2 ꢂ 100 mL). The organic phase was washed (water), dried 211.0574, calcd 211.0577 [(M + Na)+, M = C8H12O5].
(Na2SO4) and concentrated. Column chromatography [silica,
Methylene-2-(1,3-dithianyl)-20-(1,3-dithianyl-2-hydroxymethyl)
hexanes/ethyl acetate (9 : 1 to 8 : 2)] afforded a colorless oil (8-OH). A solution of 8 (17.2 g, 76.7 mmol) in THF (200 mL) was
1
(4.81 g, 69%): H NMR d 2.25 (s, 6H), 2.93 (d, J = 7.5 Hz, 2H), treated dropwise (addition funnel) with n-butyllithium (34.0 mL,
4.15 (t, J = 7.5 Hz, 1H), 5.10 (s, 2H), 7.30–7.41 (m, 5H); 13C NMR (100 85.0 mmol, 2.5 M solution in hexanes) at ꢁ15 1C for 2 h. The
MHz) d 29.7, 32.7, 63.3, 67.0, 128.4, 128.5, 128.7, 135.5, 171.1, 202.5; reaction mixture was treated dropwise (addition funnel, 20 min)
ESI-MS obsd 249.1122, calcd 249.1121 [(M + H)+, M = C14H16O4].
with N-methoxy-N-methylformamide79,80 (85.0 mL, 85.0 mmol,
3-Acetyllevulinic acid (6-AcOH). A solution of 6-AcOBn (1.59 g, 1.00 M solution in THF) at room temperature for 2 h. The reaction
6.39 mmol) in methanol (10 mL) with an added drop of water was mixture was washed with saturated aqueous NH4Cl (200 mL) and
treated with Pd(OH)2/C (100 mg). The mixture was stirred over- extracted with ethyl acetate (2 ꢂ 200 mL). The organic extract was
night (16 h) under an atmosphere of hydrogen (balloon pressure). dried (Na2SO4) and concentrated to dryness. The resulting solid
The mixture was filtered through a small pad of Celite. The Celite was dissolved in methanol (100 mL), and the resulting solution
pad was washed with methanol (20 mL). The filtrate was con- was treated with NaBH4 (5.00 g, 132 mmol) at room temperature
centrated to obtain a colorless oil (1.00 g, 99%): mp 71–72 1C; for 1 h. The reaction mixture was concentrated (B30 mL), diluted
1H NMR d 2.26 (s, 6H), 2.94 (d, J = 7.2 Hz, 2H), 4.09 (t, J = 7.2 Hz, with ethyl acetate (200 mL), and washed with water (2 ꢂ 100 mL).
1H); 13C NMR (100 MHz) d 29.8, 32.4, 63.1, 177.8, 192.2; ESI-MS The organic extract was dried (Na2SO4) and concentrated to afford
obsd 159.0650, calcd 159.0652 [(M + H)+, 181.0469, calcd 181.0471 a viscous pale yellow oil (18.6 g, 86%): 1H NMR d 1.78–2.15
[(M + Na)+, M = C7H10O4].
(m, 4H), 2.23 (d, J = 5.1 Hz, 2H), 2.35 (t, J = 7.2 Hz, 1H), 2.68
1-Methoxy-2,4-pentanedione (7). Following a known procedure,71 (q, J = 3.3 Hz, 1H), 2.73 (q, J = 3.3 Hz, 1H), 2.79–3.04 (m, 6H), 3.83
reaction of ethyl methoxyacetate (10.0 g, 84.6 mmol), sodium (2.3 g, (d, J = 7.2 Hz, 2H), 4.34 (t, J = 5.1 Hz, 1H); 13C NMR d 24.4, 24.9,
100 mmol) and acetone (4.94 mL, 85.0 mmol) afforded the title 25.8, 30.7, 41.7, 43.9, 54.4, 64.4; ESI-MS obsd 305.0128, calcd
compound (3.12 g, 28%): H NMR enold 2.09 (s, 3H), 3.42 (s, 3H), 305.0133 [(M + Na)+, M = C10H18OS4]. 8-OH was synthesized
1
3.98 (s, 2H), 5.79 (s, 1H); 13C NMR (100 MHz) enold 24.6, 59.2, 73.6, previously but without reported characterization data.74,78
97.1, 192.1, 201.8; ESI-MS obsd 153.0520, calcd 153.0522 [(M + Na)+,
M = C6H10O3].
15-Oxa-1,5,9,13-tetrathiadispiro[5.1.58.36]hexadecan-14-ol
(8-OH/O). Following the procedure described above for the
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hydroxymethylation of 8, a solution of 8-OH (260 mg, 1.02 mmol)
2,20-Methylenebis(1,3-dithianyl-2-hydroxymethyl) (8-(OH)2).
in THF (5 mL) was treated with n-butyllithium (1.87 mL, A solution of 8-OTBS/OH (1.70 g, 3.98 mmol) in THF (5 mL)
2.99 mmol, 1.6 M solution in hexanes) at ꢁ20 1C for 2 h. The was treated with tetra-n-butylammonium fluoride (5.00 mL,
reaction mixture was treated with N-methoxy-N-methylformamide 5.00 mmol, 1.0 M in THF) at room temperature for 2 h. The
(3.50 mL, 3.50 mmol, 1.00 M solution in THF) at room tempera- reaction mixture was treated with ethyl acetate (100 mL) and
ture for 2 h. The reaction mixture was washed with saturated then washed with brine (2 ꢂ 20 mL). The organic extract was
aqueous NH4Cl (10 mL) and extracted with ethyl acetate (2 ꢂ dried (Na2SO4) and concentrated to afford a colorless solid
20 mL). The organic extract was dried (Na2SO4) and concen- (871 mg, 70%): mp 128–129 1C; 1H NMR d 1.83–2.10 (m, 4H), 2.52
trated to afford a colorless solid (210 mg, 73%): mp 158–160 1C; (s, 2H), 2.67–2.78 (m, 4H), 2.88–3.02 (m, 6H), 4.01 (d, J = 6.0 Hz,
1H NMR d 1.82–2.14 (m, 4H), 2.29 (d, J = 15.3 Hz, 1H), 2.56–2.82 4H); 13C NMR d 24.5, 26.6, 44.5, 54.6, 64.3; ESI-MS obsd 335.0238,
(m, 5H), 2.90–3.02 (m, 2H), 3.09–3.25 (m, 1H), 3.17 (d, J = calcd 335.0238 [(M + Na)+, M = C11H20O2S4]. 8-(OH)2 was synthe-
15.3 Hz, 1H), 3.61 (d, J = 5.4 Hz, 1H), 3.85 (d, J = 12.3 Hz, 1H), sized previously but only melting point data (112–114 1C) were
4.37 (dd, J = 1.8 and 12.3 Hz, 1H), 5.13 (d, J = 5.4 Hz, 1H); reported.74
13C NMR d 24.1, 24.9, 26.87, 27.03, 27.51, 27.61, 46.5, 46.9, 51.2,
2,20-Methylenebis(2-acetoxymethyl-1,3-dithianyl) (8-(OAc)2).
69.4, 99.8; ESI-MS obsd 333.0082, calcd 333.0082 [(M + Na)+, A solution of 8-(OH)2 (2.21 g, 7.08 mmol) in anhydrous
M = C11H18O2S4]; anal. calcd for C11H18O2S4: C, 42.55; H, 5.84; dichloromethane (25 mL) was treated with pyridine (4.00 mL,
S, 41.30. Found: C, 42.58; H, 5.83; S, 41.37.
49.4 mmol) at room temperature for 10 min. Acetyl chloride
Methylene-2-(1,3-dithianyl)-20-[2-[tert-butyl(dimethyl)silyl]- (1.70 mL, 23.9 mmol) was added to the reaction mixture, which
oxymethyl]-1,3-dithianyl] (8-OTBS). A solution of 8-OH (3.56 g, was then stirred overnight. Water (50 mL) was added, where-
13.9 mmol) in anhydrous dichloromethane (50 mL) was treated upon the mixture was extracted with ethyl acetate (2 ꢂ 100 mL).
with imidazole (2.31 g, 33.9 mmol) at room temperature for 5 min, The organic extract was dried (Na2SO4) and concentrated
followed by treatment with tert-butyldimethylsilyl chloride (2.56 g, to afford a light yellow solid (2.72 g, 97%): mp 102–103 1C;
16.9 mmol) at room temperature for 2 h. The reaction mixture was 1H NMR d 1.80–1.93 (m, 2H), 2.01–2.10 (m, 2H), 2.14 (s, 6H),
concentrated to dryness, dissolved in ethyl acetate (100 mL), and 2.46 (s, 2H), 2.60–2.69 (m, 4H), 3.00–3.10 (m, 4H), 4.68 (s, 4H);
washed with water (2 ꢂ 50 mL). The organic extract was dried 13C NMR d 21.3, 24.4, 27.1, 45.9, 51.9, 64.7, 107.6; ESI-MS obsd
(Na2SO4) and concentrated to afford a colorless oil (3.29 g, 66%): 419.0444, calcd 419.0450 [(M + Na)+, M = C15H24O4S4]; anal.
1H NMR d 0.06 (s, 6H), 0.89 (s, 9H), 1.72–2.10 (m, 4H), 2.30 (d, J = calcd for C15H24O4S4: C, 45.43; H, 6.10; S, 32.34. Found: C,
5.4 Hz, 2H), 2.73–2.83 (m, 6H), 2.86–2.98 (m, 2H), 3.85 (s, 2H), 4.30 45.45; H, 6.24; S, 32.32.
(t, J = 5.4 Hz, 1H); 13C NMR d ꢁ5.1, 18.6, 25.32, 25.47, 26.1, 26.3,
N-(2-Oxobutyl)phthalimide (Phth-AK-Et). Following a procedure
31.1, 42.3, 42.9, 54.7, 64.7; ESI-MS obsd 419.1000, calcd 419.0998 for the homologous 1-aminoacetone,89 a solution of 1-bromo-2-
[(M + Na)+, M = C16H32OS4Si].
butanone (4.87 g, 32.2 mmol) in anhydrous DMF (100 mL) was
Methylene-2-(1,3-dithianyl-2-hydroxymethyl)-20-[2-[tert-butyl- treated with potassium phthalimide (6.48 g, 35.0 mmol) at
(dimethyl)silyl]oxymethyl]-1,3-dithianyl] (8-OTBS/OH). Following room temperature for 16 h. The reaction mixture was poured
the procedure described above for the hydroxymethylation of 8, into water (250 mL) and stirred for 30 min. The precipitate thus
a solution of 8-OTBS (3.36 g, 9.17 mmol) in THF (50 mL) was formed was removed by filtration of the mixture under suction.
treated with n-butyllithium (12.0 mL, 19.2 mmol, 1.6 M solution The filtered material was washed with water (3 ꢂ 50 mL) and
in hexanes) at ꢁ15 1C for 2 h. The reaction mixture was treated dried under vacuum over P2O5 to obtain fine white needles
with N-methoxy-N-methylformamide (10.0 mL, 15.0 mmol, (4.20 g, 71%): mp 108–109 1C; 1H NMR d 1.14 (t, J = 7.5 Hz, 3H),
1.50 M solution in THF) at room temperature for 2 h. The 2.56 (q, J = 7.5 Hz, 2H), 4.49 (s, 2H), 7.72–7.79 (m, 2H), 7.84–7.92
reaction mixture was washed with saturated aqueous NH4Cl (m, 2H); 13C NMR (100 MHz) d 7.6, 33.4, 46.4, 123.7, 132.3,
(50 mL) and extracted with ethyl acetate (2 ꢂ 50 mL). The 134.3, 167.9, 202.8; ESI-MS obsd 218.0807, calcd 218.0812
organic extract was dried (Na2SO4) and concentrated to dryness. [(M + H)+, M = C12H11NO3].
The resulting solid was dissolved in methanol (25 mL), and the
1-Amino-2-butanone hydrochloride (AK-Et). Following a
resulting solution was treated with NaBH4 (1.22 g, 33.1 mmol) at procedure for the homologous 1-aminoacetone,89 a suspension
room temperature for 1 h. The reaction mixture was concen- of Phth-AK-Et (4.20 g, 19.35 mmol) in 6 N HCl (40 mL) was
trated (B10 mL), diluted with ethyl acetate (100 mL), and refluxed for 10 h. The reaction mixture was cooled to 0 1C. The
washed with water (2 ꢂ 50 mL). The organic extract was dried precipitated phthalic acid was removed by filtration of the
(Na2SO4), concentrated and chromatographed [silica, hexanes to mixture and washed with ice-cold water (10 mL). The filtrate
hexanes/ethyl acetate (4: 1)] to afford unreacted starting material was concentrated and lyophilized to obtain a white solid (2.02 g,
1
(1.10 g 34%) and the title compound (726 mg, 20%) as a colorless 85%), which upon H NMR analysis was found to contain 10%
1
viscous material: H NMR d 0.14 (s, 6H), 0.94 (s, 9H), 1.85–2.07 phthalic acid as an impurity: 1H NMR (D2O) d 1.05 (t, J = 7.5 Hz,
(m, 4H), 2.59–2.75 (m, 2H), 2.64 (s, 2H), 2.79–2.99 (m, 6H), 3.21 3H), 2.61 (q, J = 7.5 Hz, 2H), 4.07 (s, 2H); 13C NMR (100 MHz, D2O)
(t, J = 7.2 Hz, 1H), 4.03 (d, J = 7.2 Hz, 2H), 4.07 (s, 2H); 13C NMR d d 6.7, 33.3, 47.0, 207.1; ESI-MS obsd 88.0760, calcd 88.0757
–5.0, 18.6, 24.87, 24.93, 26.1, 26.66, 26.82, 43.5, 54.5, 55.1, [(M + H)+, M = C4H9ON].
64.2, 68.0; ESI-MS obsd 449.1094, calcd 449.1103 [(M + Na)+,
M = C17H32O2S4Si].
7-Ethoxycarbonyl-6-benzoylamide-5-oxohexanoic acid (Bz-AK-
BuOH-CEt). Following a reported procedure94 with slight
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Paper
modification, a three-neck flask equipped with two addition refluxed for 12 h. Upon cooling, the precipitate (phthalic acid)
funnels was charged with THF (50 mL) and LDA solution (17 mL, was removed by filtration of the mixture and was washed with
34 mmol, 2.0 M solution in THF) at ꢁ78 1C. TMEDA (3.95 g, ice-cold 6 N HCl (20 mL). The filtrate was concentrated and
34.0 mmol) was added. The mixture was stirred for 30 min. Ethyl dried under vacuum over P2O5 to obtain a white hygroscopic
1
hippurate was dried overnight (over P2O5). The resulting ethyl solid (720 mg, 64%): H NMR (D2O) d 0.90 (t, J = 7.5 Hz, 3H),
hippurate (3.15 g, 15.2 mmol) in THF (50 mL) was placed in one 1.52–1.74 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 4.07 (s, 2H); 13C NMR
addition funnel and added dropwise to the LDA solution at (100 MHz, D2O) d 13.0, 16.6, 41.7, 47.3, 206.7; ESI-MS obsd
ꢁ78 1C. The resulting yellow suspension was stirred for 1 h at 102.0915, calcd 102.0913 (M+, M = C5H12ClNO).
ꢁ78 1C. Glutaric anhydride (1.73 g, 15.2 mmol) in THF (50 mL)
was slowly added from the second addition funnel to the yellow
suspension. The mixture was further stirred for 1 h at ꢁ78 1C.
The reaction mixture was allowed to warm to 0 1C, and then
quenched by the addition of 1 N HCl (100 mL). The mixture was
extracted with ethyl acetate (3 ꢂ 50 mL). The extract was dried
(Na2SO4) and concentrated. Column chromatography [silica,
CH2Cl2/MeOH (100: 0 to 98: 02)] afforded a colorless viscous
X-ray crystallographic analysis
X-ray measurements were preformed on a Bruker-Nonius Kappa
Axis X8 Apex2 diffractometer at 110 K. In each case, the frame
integration was performed using SAINT.103 The resulting raw data
were scaled and absorption-corrected using a multi-scan aver-
aging of symmetry equivalent data using SADABS.104 Each struc-
ture was solved by direct methods using the XS program.105 All
non-hydrogen atoms were obtained from the initial solution. The
hydrogen atoms were introduced at idealized positions and were
allowed to refine isotropically. Each structure was refined using
the XL program from SHELXTL.106 CCDC: 1-dimer, 1488933;
8-(OAc)2, 1488934; 8-OH/O, 1488935; altaicadispirolactone, 1488936.
1
oil (3.51 g, 72%): H NMR (400 MHz) d 1.13 (t, J = 7.6 Hz, 3H),
1.92–2.08 (m, 2H), 2.42 (t, J = 7.6 Hz, 2H), 2.80–3.04 (m, 2H), 4.30
(q, J = 7.6 Hz, 2H), 5.43 (d, J = 6.0 Hz, 1H), 7.30–7.60 (m, 4H),
7.78–7.92 (m, 2H); 13C NMR (100 MHz) d 14.1, 18.4, 32.7,
40.0, 62.91, 62.97, 127.4, 128.8, 132.3, 132.9, 166.3, 167.2,
178.1, 200.9; ESI-MS obsd 344.1097, calcd 344.1105 [(M + Na)+,
M = C16H19NO6].
6-Amino-5-oxohexanoic acid hydrochloride (AK-BuOH).
Following a reported procedure94 with slight modification, a
suspension of the carbamate Bz-AK-BuOH-CEt (4.4 g, 13.7 mmol)
in 6 N HCl (30 mL) was refluxed for 12 h. Upon cooling, the
precipitate (benzoic acid) was removed by filtration and washed
with ice-cold 6 N HCl (20 mL). The filtrate was concentrated and
dried over P2O5 to obtain a light brown hygroscopic solid (1.60 g,
80%): 1H NMR (D2O) d 1.80–1.98 (m, 2H), 2.42 (t, J = 7.2 Hz, 2H),
2.67 (t, J = 7.2 Hz, 2H), 4.06 (s, 2H); 13C NMR (D2O) d 20.5, 35.3,
41.1, 49.7, 180.6, 207.8; ESI-MS obsd 146.0808, calcd 146.0812
[M+, M = C6H12ClNO3].
N-(2-oxopentyl)phthalimide (Phth-AK-Pr). Following a known
procedure,91 a solution of 2-chloro-N-methoxy-N-methylacetamide
(3.42 g, 25.0 mmol) in THF (75 mL) at 0 1C was treated dropwise
with n-propylmagnesium chloride (2.0 M in diethyl ether, 15 mL,
30 mmol). The reaction mixture was allowed to warm to room
temperature. The resulting white suspension was stirred for 2 h.
The mixture was poured into ice-cold 1 N HCl and extracted with
diethyl ether (3 ꢂ 50 mL). The organic layer was dried (Na2SO4),
concentrated and diluted with DMF (100 mL). The resulting
solution was treated with potassium phthalimide (4.63 g,
25 mmol) and stirred for 16 h. The precipitate thus formed
was removed by filtration of the mixture over a fritted-glass
filter. The filtered precipitate was washed with water (500 mL)
and dried under vacuum over P2O5 for a few hours to obtain
white needles (1.91 g, 33%): mp 85–86 1C (lit.92 83–84 1C);
1H NMR d 0.97 (t, J = 7.2 Hz, 3H), 1.61–1.77 (m, 2H), 2.51 (t, J =
7.2 Hz, 2H), 4.48 (s, 2H), 7.69–7.78 (m, 2H), 7.83–7.92 (m, 2H);
13C NMR d 13.8, 17.3, 42.0, 46.8, 123.7, 132.3, 134.3, 167.9,
202.4; ESI-MS obsd 232.0966, calcd 232.0968 [(M + H)+,
M = C13H13NO3].
Acknowledgements
This research was supported by the NSF Chemistry of Life
Processes Program (CHE-0953010). We thank Ms Deborah
Garcia and Mr Elias Nieves-Bernier for technical assistance in
the preparation of several compounds. Mass spectra were
obtained at the Mass Spectrometry Laboratory for Biotechno-
logy at North Carolina State University. Partial funding for the
facility was obtained from the North Carolina Biotechnology
Center and the National Science Foundation. X-ray structure
characterization was provided by Dr Paul D. Boyle and Dr Roger
D. Sommer at the North Carolina State University X-ray Structure
Facility.
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