An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards 'clickable' biodegradable polylactide

Article abstract of DOI:10.3762/bjoc.10.139

2-Hydroxy-4-pentynoic acid (1) is a key intermediate towards 'clickable' polylactide which allows for efficient introduction of a broad range of pendant functional groups onto polymers from a single monomer via convenient 'click' chemistry with organic az

Full text of DOI:10.3762/bjoc.10.139

An economical and safe procedure to synthesize
2-hydroxy-4-pentynoic acid: A precursor towards
‘clickable’ biodegradable polylactide
Quanxuan Zhang*1, Hong Ren2,3 and Gregory L. Baker1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1365–1371.
1Department of Chemistry, Michigan State University, East Lansing,
Michigan 48824, USA, 2Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts 02138, USA
and 3Athinoula A. Martinos Center for Biomedical Imaging,
Department of Radiology, Massachusetts General Hospital, Harvard
Medical School, Charlestown, Massachusetts 02129, USA
doi:10.3762/bjoc.10.139
Received: 26 March 2014
Accepted: 17 May 2014
Published: 17 June 2014
Associate Editor: D. Y.-K. Chen
Email:
Quanxuan Zhang* - zhangqua@msu.edu
© 2014 Zhang et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
alkylation; ‘click’ chemistry; ‘clickable’ polylactide; decomposition;
diethyl 2-acetamidomalonate; 2-hydroxy-4-pentynoic acid; one-pot;
optimization; propargyl bromide; propargyl tosylate; safe and
economical
Abstract
2-Hydroxy-4-pentynoic acid (1) is a key intermediate towards ‘clickable’ polylactide which allows for efficient introduction of a
broad range of pendant functional groups onto polymers from a single monomer via convenient ‘click’ chemistry with organic
azides. The incorporation of various pendant functional groups could effectively tailor the physicochemical properties of polylac-
tide. The reported synthesis of 1 started from propargyl bromide and ethyl glyoxylate. However, both of starting materials are
expensive and unstable; especially, propargyl bromide is shock-sensitive and subjected to thermal explosive decomposition, which
makes the preparation of 1 impractical with high cost and high risk of explosion. Herein, we report a simple, economical and safe
synthetic route to prepare 1 using cheap and commercially available diethyl 2-acetamidomalonate (4) and propargyl alcohol. The
desired product 1 was obtained via alkylation of malonate 4 with propargyl tosylate followed by a one-pot four-step sequence of
hydrolysis, decarboxylation, diazotization and hydroxylation of propargylic malonate 5 without work-up of any intermediate.
Introduction
Aliphatic polyesters, in particular polylactide (PLA), are now biocompatibility, biodegradability and mechanical properties.
widely used for biomedical applications, such as surgery sutures However, due to low solubility of PLA in water, applications of
[1], implants for bone fixation [2], drug delivery vehicles [3,4] PLA in an aqueous environment have been greatly restricted. In
and tissue engineering scaffolds [5] because of their excellent addition, the lack of functional group diversity in the back-
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bones and side chains of PLA makes further modification diffi- (Scheme 1) and studied ‘click’ modification of acetylene func-
cult. Therefore, the introduction of a variety of functional tionalized PLA [17]. One new family of water-soluble and
groups to PLA is highly desirable to modulate the physico- temperature responsive biodegradable PLA material with
chemical properties of the resulting polymers, such as tunable lower critical solution temperature (LCST) in a range
hydrophilicity.
from 25 to 65 °C was obtained after ‘click’ grafting with a mix-
ture of alkyl and PEG azides. Starting from the same precursor
Recently, numerous α,ω-chain end functionalized PLAs have 1 [18], Yu and coworkers have prepared a novel graft polymer-
been reported through ring-opening polymerization of lactide drug conjugate (GPDC) with potent cancer inhibitor paclitaxel
by judicious choice of initiating alcohols and further post-poly- linked to PLA backbones. The GPC results indicated that
merization modification of ω-chain end hydroxy groups [6-8]. GPDC released paclitaxel moieties from polymer complexes in
Moreover, the appending functionalities along PLA backbones phosphate buffer solutions under physiological pH of 5.5 and
provide great opportunities for altering physical and/or chem- 7.4, suggesting its potential clinical application. More recently,
ical properties of PLAs. PLA with pendent functional groups Coumes and coworkers have prepared acetylene functionalized
can be achieved by ring-opening polymerization of functional PLAs from precursor 1 and ‘click’ modification of the resulting
lactide monomers, post-polymerization modification, or a PLAs with PEG azides provided amphiphilic graft copolymers
combination of these two approaches. The appending hydroxy which form nanorod aggregates in water [19].
[9], carboxyl [10], poly(ethylene glycol) (PEG) [11-14], allyl
[15], azido [16] and acetylene [17] functionalities on PLA back- The results discussed above indicate the great power to tune
bones have been reported and offered great opportunities for physicochemical properties of PLA by ‘click’ modification of
covalent post-polymerization modification of PLAs.
acetylene functionalized PLA. Precursor 1 is the key intermedi-
ate in the preparation of these ‘clickable’ PLAs. It was synthe-
Among various functional groups, acetylene functionalized sized in 40% overall yield via hydrolysis of ester 2 which was
PLA has attracted much attention [17-19]. By having a single generated by Reformatsky-type reaction of propargyl bromide
functional lactide monomer, it allows for facile placement of a with fresh distilled ethyl glyoxylate in the presence of activated
broad range of pendant functional groups onto polymers via zinc (Scheme 1) [17]. However, the synthesis of precursor 1
convenient ‘click’ reaction with organic azido molecules used propargyl bromide and ethyl glyoxylate as starting ma-
without PLA backbone degradation [17]. ‘Click’ chemistry terials, both of which are expensive and unstable. These starting
[20], which is copper(I)-catalyzed 1,3-dipolar cycloaddition of materials must be stabilized by toluene and purified before reac-
azides and alkynes, has been developed and utilized in recent tion. Flash column chromatography is also required in the
years as a powerful synthetic strategy because of its high selec- process. Besides its high cost, propargyl bromide is shock-
tivity and excellent tolerance to different functional groups and sensitive and subjected to thermal explosive decomposition [21-
reaction conditions. Our group has prepared the first ‘clickable’ 23], which makes the preparation of 1 via this method imprac-
PLA using 2-hydroxy-4-pentynoic acid (1) as a precursor tical with high risk of explosion.
Scheme 1: Synthesis of 2-hydroxy-4-pentynoic acid (1).
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Thus, efforts were taken to develop a safe and practical syn- Scheme 3 were determined not to be feasible probably due to
thetic route for precursor 1. Our first successful effort in the the interruption of the ethynyl proton in the presence of
synthesis of 1 gave a good overall yield (50%) after removal of organometallic reagents [29].
the trimethylsilyl protecting group and hydrolysis of ester 3,
generated from diethylaluminum(trimethylsilyl)acetylide and As discussed above, there are two important factors that should
methyl glycidate (Scheme 2) [24]. Although it does not involve be taken into account in order to achieve a safe and economical
explosive propargyl bromide, this method requires an excess route resulting in precursor 1: 1) a non-explosive and cheap
(2 equivalents) of expensive trimethylsilylacetylene [25-28] and source of acetylene building moiety; and 2) basic reaction
highly flammable chemicals (butyllithium and diethylalu- conditions involving a low pKa (<24) to avoid the interruption
minum chloride) which makes this route even more costly and of the ethynyl proton (pKa ~24) while introducing the acety-
less attractive. Therefore, in order to provide sufficient 1 for lene moiety. Propargyl tosylate, prepared from propargyl
preparing ‘clickable’ PLA and expand its application scope via alcohol and tosyl chloride, is a safe analogue of propargyl bro-
‘click’ modification in biomedical fields, an economical and mide with low cost. Malonate has a low pKa of ~13 and can be
safe procedure to synthesize 1 with good yield is highly desir- easily deprotonated and alkylated by mild bases such as
able using simple and cheap starting materials.
sodium/potassium alkoxides without deprotonating a terminal
alkyne. Conveniently, both malonate and propargyl alcohol are
Several other promising synthetic routes to precursor 1 were commercially available in bulk quantities. Herein, we report one
also proposed and examined in our group in order to find a safe economical and safe procedure using diethyl 2-acetamido-
and affordable procedure without using propargyl bromide. malonate (4) and propargyl alcohol as starting materials to
However, all attempted synthetic routes to 1 indicated in synthesize 1. The synthesis was completed via alkylation of
Scheme 2: Synthesis of 1 via epoxide ring opening with organoalane.
Scheme 3: Attempted synthetic routes for compound 1.
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malonate 4 with propargyl tosylate followed by a one-pot four- with a mechanical stirrer, which resulted in a messy mixture of
step sequence of hydrolysis, decarboxylation, diazotization and product observed from the 1H NMR spectrum of the crude reac-
hydroxylation of propargylic malonate 5 without work-up of tion mixture. The C-alkylation of 4 in a more common solvent,
any intermediates.
THF, was found to be not suitable due to the low conversion
with even a much longer reaction time (entry 3, Table 1) [31].
Under the conditions indicated in Scheme 4 and Table 1,
Results and Discussion
The synthesis of the desired precursor 1 was straightforward propargylic derivative 5 was obtained in quantitative yield and
and outlined in Scheme 4. Propargyl alcohol, a cheap source of with high purity after optimization, and it is not necessary to
an acetylene moiety, was tosylated with tosyl chloride further purify 5.
following a modified procedure [30] to provide propargyl tosy-
late in high yield as a dark liquid after drying under vacuum. Reflux of 5 in a 2 M aqueous solution of H2SO4 enabled the
Diethyl 2-acetamidomalonate (4), deprotonated by potassium one-pot synthesis of intermediate 6 via sequential hydrolysis of
tert-butoxide, was alkylated in dioxane by a conventional amide and esters, and decarboxylation of the resulting malonic
C-alkylation method [31-34] with propargyl tosylate to give acid. The resulting intermediate 6 was not isolated and used
propargylic derivative 5. The alkylation step was optimized and directly for the subsequent reaction. Notably, basic treatment of
it can be conducted with an enolate concentration of 4 up to 5 as discussed in literature [31,33] would not allow conversion
0.25 M in dioxane (Table 1). The attempt with higher enolate of 5 to 6 in a convenient one-pot manner, since more harsh
concentration was not smooth due to the increased viscosity of basic conditions are required for carrying out amide hydrolysis
the reaction mixture and thus low efficiency of stirring, even of 5. Because the following diazotization of 6 requires strong
Scheme 4: Synthesis of 2-hydroxy-4-pentynoic acid (1) from diethyl 2-acetamidomalonate.
Table 1: Optimization of alkylation of 4.a
Solvent
volume/mL
Concentration
Entry
4/mmol
Solvent
t/h
Conversionb
Yield
of 4/M
1
2
3
47.5
95
dioxane
dioxane
THF
475
375
475
0.1
0.25
0.1
20
24
98%
99%
55%
96.0%
99.0%
–c
47.5
120
aPotassium tert-butoxide was dissolved in solvent (half volume of total solvent) and transferred to a solution of 4 via cannula, then propargyl tosylate
was added dropwise. bEstimated by 1H NMR. cProduct was not isolated.
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acidic conditions, the proper choice of acidic hydrolysis and decomposition of 1, since the addition of either salt compli-
decarboxylation of 5 in H2SO4 thus also further facilitated the cated the following work-up and purification procedure.
one-pot conversion of intermediate 6 to 1 via diazotization and However, intact product 1 was readily obtained as a slight
hydroxylation without additional work-up or isolation of 6 [35- yellow solid in 49% yield by adding Na2S2O5 solid to an ether
40]. In addition, proper choice of H2SO4 instead of HCl [41,42] solution of acid 1, followed by simple filtration, concentration
for one-pot conversion of 5 to 6 could avoid the formation of and sublimation under vacuum (Table 2). The spectroscopic
the possible side product 2-chloro-4-pentynoic acid [43,44], if data of 1 were in good agreement with both authentic samples
chloride anions are present in the solution during the synthesis of 1 previously prepared in our lab and literature reports [17-
of 1 from 6 via diazotization and hydroxylation.
19]. This indicates that solid Na2S2O5 removes possible
oxidants and simply enables the formation of undecomposed
However, 2-hydroxy-4-pentynoic acid (1) rapidly decomposes solid product 1 after drying in vacuo. Despite the moderate
while drying under high vacuum after continuous extraction yield, this procedure represents a simple, economical and safe
from aqueous solution with diethyl ether (Table 2). This was approach to synthesize precursor 1.
not expected since acid 1 prepared by other methods did not
decompose upon isolation (Scheme 2) [17]. The possible reason Conclusion
for this decomposition is that there might be certain oxidants One simple, economical and safe procedure to prepare
present in ether phase after continuous extraction (for example, 2-hydroxy-4-pentynoic acid (1) was developed and optimized
HNO2 and HNO3, verified by a rapid color change of KI-starch using cheap and commercially available starting materials –
test paper), which destroy product 1 during concentration and diethyl 2-acetamidomalonate (4) and propargyl alcohol.
drying under vacuum. And neither addition of urea (reacting C-Alkylation of malonate 4 with propargyl tosylate in dioxane
with HNO2 to release N2, CO2 and H2O) nor passing of crude afforded propargyl derivative 5 quantitatively. The proper
product 1 through a short silica gel column can stop its decom- choice of acidic hydrolysis and decarboxylation of 5 in 2 M
position. So three reductants were examined which presumably H2SO4 enabled the synthesis of precursor 1 via a one-pot four-
would remove any residual oxidants. Product 1 was not detected step sequence of hydrolysis, decarboxylation, diazotization and
in ether filtrate after addition of solid Na2SO3 to an ether solu- hydroxylation of propargylic malonate 5 without work-up of
tion of 1 and filtration to remove Na2SO3 solid. However, acid any intermediates. Solid Na2S2O5 was effective to remove any
1 can be recovered in lower yield after extracting the acidified possible oxidants (like HNO2 and HNO3) to prevent decompo-
aqueous solution of Na2SO3 with ether (Table 2). Apparently, sition of product 1 while drying under vacuum. Overall, this
acid 1 precipitated as its sodium salt from ether via an procedure represents a practical and economical approach to
acid–base reaction with Na2SO3 (pKa of 1: ~3.8 [45]; pKa of conveniently synthesize precursor 1 for preparation of ‘click-
H2SO3: 1.9, 7.2). When reductant Na2S2O3 was added to an able’ polylactide biomaterials.
ether solution of acid 1, a yellow solid mixture containing both
Experimental
acid 1 and sulfur was obtained after removal of ether under
vacuum (Table 2). It is known that sodium thiosulfate decom- General methods
poses to give sulfur as a solid product under acidic conditions All reactions, if not stated otherwise, were performed in oven-
[46]. Dissolution of this solid mixture in water, filtration to dried glassware under nitrogen atmosphere. THF and dioxane
remove sulfur and subsequent removal of water in vacuo gave were dried over sodium/benzophenone and distilled before use.
pure acid product 1 in 30% yield. These results indicate that it is All other reagents and solvents were ACS grade and used as
not convenient to use solid Na2SO3 or Na2S2O3 to prevent the received unless specified. Melting points were measured on an
Table 2: 2-Hydroxy-4-pentynoic acid (1) after treatment with different reductants.
Reductanta
None
Na2SO3
Na2S2O3
Na2S2O5
Compounds in ether phaseb
1
No 1
Sulfur + 1
1
Appearance of dry 1c
Decomposition black
Light yellow solidd
Yellow solid
Light yellow solid
aSolid reductants were added into ether extract containing 1 and the resulting mixture was stirred. bCompounds in ether extract after treatment with
reductants. cProduct 1 was obtained upon removal of ether after treatment with reductants and followed by filtration. dProduct 1 was recovered with
low yield after extracting the acidified aqueous solution of solid Na2SO3 with ether.
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Beilstein J. Org. Chem. 2014, 10, 1365–1371.
Electrothermo® melting point apparatus. 1H NMR and heated to reflux until full conversion of 5 to 2-amino-4-
13C NMR were recorded on a VXR-500 MHz instrument in pentynoic acid (6, ~36 h). The reaction mixture was used
CDCl3 unless otherwise noted. CDCl3 was used as the internal directly without further isolation. A solution of NaNO2
standard for both 1H NMR (δ = 7.24) and 13C NMR (δ = 77.0). (5 equiv, 40%) in water was added dropwise to the aqueous
solution of amino acid 6 at 0 °C followed by the addition of
Synthesis of propargyl tosylate
another 3 equiv of NaNO2 in water (40%). The resulting mix-
A 2 L round bottom flask equipped with a mechanical stirrer ture was stirred for 40 h at room temperature, and urea in
was charged with 58 mL (1.0 mol) of propargyl alcohol, 250 g diluted HCl (1 M) was added dropwise until the mixture did not
(1.30 mol) of tosyl chloride and 1000 mL of diethyl ether under make potassium iodide starch test paper blue or purple. The
nitrogen. The resulting reaction mixture was cooled in an ice resulting product 1 was extracted with ether using a continuous
bath, and NaOH pellets (200 g, 5.00 mol) were added to the extraction apparatus. Solid Na2S2O5 was added to ether layer
solution in 6 portions at 0 °C under vigorous stirring. The and the resulting mixture was stirred until it did not turn potas-
resulting mixture was continually stirred overnight at room sium iodide starch test paper to purple. After removal of
temperature. The suspension was poured into cold water and the Na2S2O5 via filtration, the ether layer was concentrated, dried
resulting aqueous layer was extracted with ether (2 × 250 mL). and sublimated under vacuum to give 24.1 g of acid 1 in 49.0%
The ether layer was combined, dried over anhydrous Na2SO4 yield [17]. 1H NMR (500 MHz, CDCl3) δ 4.35 (t, J = 4.5 Hz,
and concentrated. Pure propargyl tosylate was obtained as a 1H), 2.68 (m, 2H), 2.08 (t, J = 2.5 Hz, 1H); 13C NMR
dark liquid [30,47] in 84.0% yield (185 g) by drying under high (125 MHz, CDCl3) δ 177.5, 77.7, 71.9, 68.5, 24.4.
vacuum (Caution: gloves are required when handling propargyl
tosylate). 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8 Hz, 2H), Acknowledgements
7.30 (d, J = 8.5 Hz, 2H), 4.65 (d, J = 2.5 Hz, 2H), 2. 49 (t, J = This manuscript is in memory of our friend and colleague, Prof.
2.5 Hz, 1H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ Gregory L. Baker, who passed away unexpectedly while this
145.3, 133.1, 130.0, 128.2, 77.4, 75.4, 57.44, 21.8.
paper was under preparation. The authors are grateful to Prof.
William D. Wulff at Michigan State University for his invalu-
able guidance, discussions and assistance during preparation of
this manuscript.
Synthesis of diethyl α-propargyl-α-acetamido-
malonate (5)
To a solution of 105 g (0.483 mol) of diethyl 2-acetamido-
malonate (4) in 1.35 L of dioxane was added a slurry of 61 g
(0.54 mol) of potassium tert-butoxide in 550 mL of dioxane
dropwise via cannula over 2 h while stirring with a mechanical
stirrer at room temperature. The resulting suspension was
heated to 50 °C and stirred for another 2 h. A solution of
propargyl tosylate (83 mL, 0.49 mol) in 150 mL of dioxane was
added dropwise at 50 °C over 1 h and the resulting mixture was
brought to reflux overnight. The reaction mixture was cooled to
room temperature and filtered to remove the solid. The filtrate
was concentrated on rotavap and the crude product was
dissolved in 1 L of dichloromethane. The organic layer was
washed with water (2 × 500 mL), decolorized with activated
charcoal and dried over anhydrous Na2SO4. The desired prod-
uct diethyl α-propargyl-α-acetamidomalonate (5) was obtained
as a light yellow solid [31] in 99.0% yield (122 g) by solvent
evaporation and drying under vacuum. Mp 85–88 °C; 1H NMR
(500 MHz, CDCl3) δ 6.91 (s, 1H), 4.24 (dd, J = 3, 7.5 Hz, 4H),
3.26 (d, J = 2.5 Hz, 2H), 2.04 (s, 3H), 1.94 (t, J = 2.5 Hz, 1H),
1.24 (t, J = 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 169.6,
166.8, 78.7, 71.9, 65.5, 63.3, 24.1, 23.3, 14.2.
References
1. Dechy-Cabaret, O.; Martin-Vaca, B.; Bourissou, D. Chem. Rev. 2004,
104, 6147–6176. doi:10.1021/cr040002s
2. Claes, L. E.; Ignatius, A. A.; Rehm, K. E.; Scholz, C. Biomaterials 1996,
17, 1621–1626. doi:10.1016/0142-9612(95)00327-4
3. Jiang, W.; Gupta, R. K.; Deshpande, M. C.; Schwendeman, S. P.
Adv. Drug Delivery Rev. 2005, 57, 391–410.
doi:10.1016/j.addr.2004.09.003
4. Rancan, F.; Papakostas, D.; Hadam, S.; Hackbarth, S.; Delair, T.;
Primard, C.; Verrier, B.; Sterry, W.; Blume-Peytavi, U.; Vogt, A.
Pharm. Res. 2009, 26, 2027–2036. doi:10.1007/s11095-009-9919-x
5. Pan, Z.; Ding, J. Interface Focus 2012, 2, 366–377.
doi:10.1098/rsfs.2011.0123
6. Mizutani, M.; Arnold, S. C.; Matsuda, T. Biomacromolecules 2002, 3,
668–675. doi:10.1021/bm0101670
7. Nederberg, F.; Bowden, T.; Hilborn, J. Macromolecules 2004, 37,
954–965. doi:10.1021/ma035433b
8. Stanford, M. J.; Dove, A. P. Macromolecules 2009, 42, 141–147.
doi:10.1021/ma801977e
9. Trollsås, M.; Lee, V. Y.; Mecerreyes, D.; Löwenhielm, P.; Möller, M.;
Miller, R. D.; Hedrick, J. L. Macromolecules 2000, 33, 4619–4627.
doi:10.1021/ma992161x
10.Kimura, Y.; Shirotani, K.; Yamane, H.; Kitao, T. Macromolecules 1988,
21, 3338–3340. doi:10.1021/ma00189a037
11.Lutz, J.-F.; Hoth, A. Macromolecules 2006, 39, 893–896.
doi:10.1021/ma0517042
Synthesis of 2-hydroxy-4-pentynoic acid (1)
A 3 L round bottom flask was charged with 110 g (0.431 mol)
of 5 and 1.2 L of 2 M H2SO4 and the resulting mixture was
12.Jiang, X.; Smith, M. R., III; Baker, G. L. Macromolecules 2008, 41,
318–324. doi:10.1021/ma070775t
1370

Beilstein J. Org. Chem. 2014, 10, 1365–1371.
13.Jiang, X.; Vogel, E. B.; Smith, M. R., III; Baker, G. L.
J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 5227–5236.
doi:10.1002/pola.22268
37.Dragovich, P. S.; Prins, T. J.; Zhou, R.; Johnson, T. O.; Hua, Y.;
Luu, H. T.; Sakata, S. K.; Brown, E. L.; Maldonado, F. C.; Tuntland, T.;
Lee, C. A.; Fuhrman, S. A.; Zalman, L. S.; Patick, A. K.;
Matthews, D. A.; Wu, E. Y.; Guo, M.; Borer, B. C.; Nayyar, N. K.;
Moran, T.; Chen, L.; Rejto, P. A.; Rose, P. W.; Guzman, M. C.;
Dovalsantos, E. Z.; Lee, S.; McGee, K.; Mohajeri, M.; Liese, A.; Tao, J.;
Kosa, M. B.; Liu, B.; Batugo, M. R.; Gleeson, J.-P. R.; Wu, Z. P.; Liu, J.;
Meador, J. W., III; Ferre, R. A. J. Med. Chem. 2003, 46, 4572–4585.
doi:10.1021/jm030166l
14.Castillo, J. A.; Borchmann, D. E.; Cheng, A. Y.; Wang, Y.; Hu, C.;
García, A. J.; Weck, M. Macromolecules 2012, 45, 62–69.
doi:10.1021/ma2016387
15.Mecerreyes, D.; Miller, R. D.; Hedrick, J. L.; Detrembleur, C.;
Jerome, R. J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 870–875.
doi:10.1002/(SICI)1099-0518(20000301)38:5<870::AID-POLA11>3.0.C
O;2-7
38.Feifel, S. C.; Schmiederer, T.; Hornbogen, T.; Berg, H.;
Süssmuth, R. D.; Zocher, R. ChemBioChem 2007, 8, 1767–1770.
doi:10.1002/cbic.200700377
16.Rubinshtein, M.; James, C. R.; Young, J. L.; Ma, Y. J.; Kobayashi, Y.;
Gianneschi, N. C.; Yang, J. Org. Lett. 2010, 12, 3560–3563.
doi:10.1021/ol101433v
39.Müller, J.; Feifel, S. C.; Schmiederer, T.; Zocher, R.; Süssmuth, R. D.
ChemBioChem 2009, 10, 323–328. doi:10.1002/cbic.200800539
40.Matthes, D.; Richter, L.; Müller, J.; Denisiuk, A.; Feifel, S. C.; Xu, Y.;
Espinosa-Artiles, P.; Süssmuth, R. D.; Molnár, I. Chem. Commun.
2012, 48, 5674–5676. doi:10.1039/c2cc31669b
17.Jiang, X.; Vogel, E. B.; Smith, M. R., III; Baker, G. L. Macromolecules
2008, 41, 1937–1944. doi:10.1021/ma7027962
18.Yu, Y.; Zou, J.; Yu, L.; Ji, W.; Li, Y.; Law, W.-C.; Cheng, C.
Macromolecules 2011, 44, 4793–4800. doi:10.1021/ma2005102
19.Coumes, F.; Darcos, V.; Domurado, D.; Li, S.; Coudane, J.
Polym. Chem. 2013, 4, 3705–3713. doi:10.1039/c3py00375b
20.Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. 2001, 113,
2056–2075.
41.Cali, P.; Begtrup, M. Synthesis 2002, 63–66.
doi:10.1055/s-2002-19301
42.Nejman, M.; Śliwińska, A.; Zwierzak, A. Tetrahedron 2005, 61,
8536–8541. doi:10.1016/j.tet.2005.04.077
doi:10.1002/1521-3757(20010601)113:11<2056::AID-ANGE2056>3.0.
CO;2-W
43.Fu, S.-C. J.; Birnbaum, S. M.; Greenstein, J. P. J. Am. Chem. Soc.
1954, 76, 6054–6058. doi:10.1021/ja01652a057
Angew. Chem., Int. Ed. 2001, 40, 2004–2021.
44.Koppenhoefer, B.; Schurig, V. Org. Synth. 1993, Coll. Vol. 8, 119;
1988, 66, 151.
doi:10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO
;2-5
45.Deprez, P. Alpha-hydroxy acids: chemistry, pH and pKa, and
mechanism of action. Textbook of Chemical Peels. Superficial,
Medium, and Deep Peels in Cosmetic Practice, 1st ed.; Informa UK:
London, U.K., 2007.
21.Forshey, D. R.; Cooper, J. C.; Martindill, G. H.; Kuchta, J. M.
Fire Technol. 1969, 5, 100–111. doi:10.1007/BF02591588
22.Nwokogu, G. C. Propargylmagnesium Bromide. e-EROS Encyclopedia
of Reagents for Organic Synthesis; Wiley, 2001.
46.Kerker, M. J. Chem. Phys. 1951, 19, 1324–1325.
doi:10.1063/1.1748044
23.Wuts, P. G. M.; Greene, T. W. Protection for the Hydroxyl Group,
Including 1,2- and 1,3-Diols. Greene's Protective Groups in Organic
Synthesis, 4th ed.; John Wiley & Sons: Hoboken, NJ, 2006; pp 99 ff.
doi:10.1002/9780470053485.ch2
47.Asano, K.; Matsubara, S. Org. Lett. 2009, 11, 1757–1759.
doi:10.1021/ol900125y
24.Roush, W. R.; Blizzard, T. A.; Basha, F. Z. Tetrahedron Lett. 1982, 23,
2331–2334. doi:10.1016/S0040-4039(00)87334-7
25.Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1982, 23, 3597–3600.
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Creative Commons Attribution License
doi:10.1016/S0040-4039(00)87680-7
26.Akita, H.; Matsukura, H.; Oishil, T. Tetrahedron Lett. 1986, 27,
5397–5400. doi:10.1016/S0040-4039(00)85221-1
27.Larcheveque, M.; Peit, Y. Bull. Soc. Chim. Fr. 1986, 130–139.
28.Murray, T. F.; Samsel, E. G.; Varma, V.; Norton, J. R.
J. Am. Chem. Soc. 1981, 103, 7520–7528. doi:10.1021/ja00415a020
29.The routes shown in Scheme 3 are unpublished and will not be
presented in this paper.
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
30.Srinivasan, R.; Uttamchandani, M.; Yao, S. Q. Org. Lett. 2006, 8,
713–716. doi:10.1021/ol052895w
(http://www.beilstein-journals.org/bjoc)
31.Brea, R. J.; López-Deber, M. P.; Castedo, L.; Granja, J. R.
J. Org. Chem. 2006, 71, 7870–7873. doi:10.1021/jo061300n
32.Baldwin, J. E.; Bradley, M.; Abbott, S. D.; Adlington, R. M. Tetrahedron
1991, 47, 5309–5328. doi:10.1016/S0040-4020(01)87142-8
33.van Hest, J. C. M.; Kiick, K. L.; Tirrell, D. A. J. Am. Chem. Soc. 2000,
122, 1282–1288. doi:10.1021/ja992749j
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.10.139
34.Young, D. D.; Torres-Kolbus, J.; Deiters, A. Bioorg. Med. Chem. Lett.
2008, 18, 5478–5480. doi:10.1016/j.bmcl.2008.09.025
35.Pettit, G. R.; Hu, S.; Knight, J. C.; Chapuis, J.-C. J. Nat. Prod. 2009,
72, 372–379. doi:10.1021/np800607x
36.Cahiez, G.; Metais, E. Tetrahedron Lett. 1995, 36, 6449–6452.
doi:10.1016/0040-4039(95)01289-T
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