A useful synthetic equivalent of a hydroxyacetone enolate

Article abstract of DOI:10.1021/ol2019357

Indium promoted allylation of carbonyl compounds with 4-(bromomethyl)-1,3- dioxol-2-one diastereoselectively affords anti-α,β-dihydroxyketones, protected as enol carbonates. These initial products can be deprotected to free dihydroxyketones or transformed

Full text of DOI:10.1021/ol2019357

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4720–4723
A Useful Synthetic Equivalent of a
Hydroxyacetone Enolate
Miljan Bigovic,† Veselin Maslak,† Zorana Tokic-Vujosevic,‡ Vladimir Divjakovic,§ and
Radomir N. Saicic*,†
Faculty of Chemistry, University of Belgrade, Studentski Trg 16, P. O. B. 51, 11158
Belgrade, Serbia, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, P. O.
B. 146, 11000 Belgrade, Serbia, and Faculty of Science, University of Novi Sad, Trg
Dositeja Obradovica 3, 21000 Novi Sad, Serbia
rsaicic@chem.bg.ac.rs
Received July 18, 2011
ABSTRACT
Indium promoted allylation of carbonyl compounds with 4-(bromomethyl)-1,3-dioxol-2-one diastereoselectively affords anti-R,β-dihydroxyketones,
protected as enol carbonates. These initial products can be deprotected to free dihydroxyketones or transformed under mild conditions into the
corresponding cyclic carbonates, which constitutes a useful approach to hydroxyacetone aldols.
Initially regarded as a mechanistic curiosity,1 metal
mediated allylations in aqueous media have rapidly
evolved into a highly useful synthetic method. Among
several metals that may promote such a type of trans-
formation,2 indium and zinc have found widespread
application.3 Although the allyl group is in principle
amenable to various oxidative transformations, which
makes it a synthetic equivalent of other nucleophiles,
it would be highly desirable to extend the scope of allylation
under aqueous conditions to the introduction of more
highly functionalized structural subunits into organic
compounds. To this aim, allylic halides with an additional
halogen,4 or sulfur,5 substituent have been employed.
Oxygen-substituted allylic halides, such as 3-bromopropenyl
benzoate,6 acetate,7 or methyl carbonate,8 have been
used as d1-hydroxyallyl synthons (synthetic equivalents
of 1-hydroxyallyl anion). Recently, we introduced 2-
(methoxymethyl)allyl bromide as a synthetic equivalent
of an acetone enolate.9
† Faculty of Chemistry, University of Belgrade.
‡ Faculty of Pharmacy, University of Belgrade.
§ Faculty of Science, University of Novi Sad.
(1) (a) Petrier, C.; Einhorn, C.; Luche, J. L. Tetrahedron Lett. 1985,
26, 1449. (b) Petrier, C.; Luche, L. J. J. Org. Chem. 1987, 50, 910.
(2) Review article on allylations with allylmetals: Roush, W. R. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2, p 1.
(5) Marquez, F.; Montoro, R.; Llebaria, A.; Lago, E.; Molins, E.;
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Org. Lett. 2006, 8, 3303.
(9) (a) Maslak, V.; Tokic-Vujosevic, Z.; Ferjancic, Z.; Saicic, R. N.
Tetrahedron Lett. 2009, 50, 6709. (b) For the extension of this concept to
other 2-(alkoxy)allyl bromides, see: Dhanjee, H.; Minehan, T. G. Tetra-
hedron Lett. 2010, 51, 5609. See also:(c) 2-acetoxy-3-chloropropene:
Mandai, T.; Nokami, J.; Yano, T.; Yoshinaga, Y.; Otera, J. J. Org.
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synthesis of natural products, see: Lee, K.-C.; Loh, T.-P. Chem. Com-
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(4) (a) 2,3-Dichloropropene: Oda, Y.; Matsuo, S.; Saito, K. Tetra-
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r
10.1021/ol2019357
Published on Web 08/04/2011
2011 American Chemical Society

We set out to further enhance the synthetic potential of
this method, by increasing the level of functionalization of
the allylic reagent, thus making it a synthetic equivalent of
more highly functionalized nucleophilic species. To this
end, wespeculated that 4-(bromomethyl)-1,3-dioxol-2-one
1 would be a reagent of choice, for several reasons: (a) two
oxygen substituents make it a synthetic equivalent of an
hydroxyacetone enolate; (b) the cyclic structure of the
reagent contributes to stereodifferentiation in the transi-
tion state, which should result in a diastereoselective
allylation reaction; (c) the reaction products are obtained
in a protected form, suitable for further synthetic trans-
formations. Literaturesearching revealedthatWender had
reported the allylation with 4-(bromomethyl)-1,3-dioxol-
2-one as early as 1990;10 however, the reaction was only
performed with an organochromium reagent and a mix-
ture of regioisomers was obtained. The expected reaction
product is a protected form of an R,β-dihydroxy ketone,
i.e. a hydroxyacetone aldol À a common structural motif
of many natural products and biologically active mole-
cules. It should be noted that, within the past decade, a
significant breakthrough in the stereoselective aldol addi-
tion of hydroxyacetone has been achieved through orga-
nocatalysis. Extensive studies in this field have recently
brought about organocatalysts that efficiently promote the
formation of hydroxyacetone syn-aldols;11 aldolase anti-
body 38C2 has also been used for this purpose, with
excellent enantioselectivity, but modest diastereoselectivity.12
Anti-isomersseemtobesomewhatmoredifficulttoobtain:
while proline,13 DMTC,13b and proline derived14 organo-
catalysts usually afford anti-aldols in high yields and with
excellent enantioselectivities, the diastereoselectivities of
the reaction are often moderate. Therefore, it would be
desirable to have an alternative, mechanistically com-
plementary method for the synthesis of anti-configured
R,β-dihydroxy ketones and the derivatives thereof.
Table 1. Allylation of Aromatic Aldehydes with 1
In our first experiment, 4-(bromomethyl)-1,3-dioxol-2-
one 115 was submitted to the reaction with benzaldehyde,
in the presence of indium, in aqueous THF. Gratifyingly,
within 15 min, TLC indicated full conversion of the
starting material into a single product, which was isolated
in 96% yield. Spectroscopic characterization showed this
a Zn was used instead of In. The reaction time was 45 min.
(10) Wender, P. A.; Wisniewski Grissom, J.; Hoffman, U.; Mah, R.
Tetrahedron Lett. 1990, 46, 6605.
(11) (a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2007, 129, 288. (b) Li, J.; Luo, S.; Cheng, J.-P.
J. Org. Chem. 2009, 74, 1747. (c) Wu, X.; Ma, Z.; Ye, Z.; Qian, S.; Zhao,
G. Adv. Synth. Catal. 2009, 351, 158. (d) DBU-catalyzed aldolisation of
hydroxyacetone gives aldols in syn/anti ratios which vary from 9/1 to
7/3: Market, M.; Mulzer, M.; Schetter, B.; Mehrwald, R. J. Am. Chem.
Soc. 2007, 129, 7258.
(12) List, B.; Shabat, D.; Barbas, C. F., III; Lerner, R. A. Chem.;
Eur. J. 1998, 4, 881.
(13) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc.
2001, 123, 5260.
product to be, as expected, 4-(hydroxy(phenyl)methyl)-5-
methylene-1,3-dioxolan-2-one 2a, with a diastereomeric
ratio of anti/syn = 11:1. The generality of the procedure
was tested with a series of aromatic aldehydes, which all
afforded the desired products in excellent yields; the results
of these experiments are represented in Table 1. The
relative stereochemistry of the products was confirmed
by X-ray crystallographic analysis of the compound 2e,
which is represented in Figure 1. A drop in diastereoselec-
tivity was observed when there was a proximal oxygen
substituent, capable of coordinating the indium ion in the
transition state (entries 2 and 10). These reactions could
also be performed with zinc, instead of indium. Under
(14) Lombardo, M.; Pasi, F.; Easwar, S.; Trombini, C. Adv. Synth.
Catal. 2007, 349, 2061.
(15) This compound was obtained according to the modified litera-
ture procedure, in two steps, from hydroxyacetone, according to the
procedure described for the 4,5-dimethyl derivative: (a) Alexander, J. U.
S. Patent 5,466,811, 1995; Chem. Abstr. 1995, 124, 176148x. (b) Saka-
moto, F.; Ikeda, S.; Tsukamoto, G. Chem. Pharm. Bull. 1984, 32, 2241.
See the Supporting Information for details.
Org. Lett., Vol. 13, No. 17, 2011
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Table 2. Allylations of Aliphatic Carbonyl Compounds with 1
Figure 1. ORTEP diagram for 2e.
pyruvate, the diastereomerically pure reaction product 2p
contained 15% of the rearranged carbonate 2q. The
relative stereochemistry of this compound (2q) was deter-
mined by a NOESY experiment, which allowed us to
deduce the stereochemistry of 2p, as well.16 Allylation of
2,3,4,5-tetra-O-acetyl-D-arabinose proceeded with asym-
metric induction, providing a single anti isomer 2m (entry7),
as confirmed by X-ray crystallographic analysis (Figure 2).
Surprisingly, no asymmetric induction was observed in the
reaction with the Garner aldehyde, which furnished equi-
molar amounts of both anti isomers (entry 8).17
Figure 2. Ortep diagram for 2m. Hydrogen atoms are omitted
for clarity.
The advantage of our method is that the aldol-like
products are obtained in a protected form 2, suitable for
further synthetic manipulation. If, however, free R,β-dihy-
droxy ketones 3 are needed, the initial products can be
deprotected. While the acid- or base-catalyzed hydrolysis
a Zn was used instead of In. The reaction time was 45 min. b Re-
presented are the absolute configurations of the reactant and the
product. c obtained as an equimolar mixture of (S,R,R) and (S,S,S)
isomers (only the (S,R,R)-isomer is represented).
Scheme 1. Deprotection of the Initial Products 2 into
R,β-Dihydroxyketones 3
these conditions, however, the yields and diastereoselec-
tivities decreased (Table 1, entries 3, 6, and 8).
Next, we examined the reaction with aliphatic carbonyl
compounds. In all cases, the desired products were ob-
tained in good/excellent yields (Table 2). The lack of
diastereoselectivity was observed with conjugated enals
(entries 3, 4, and 5), again, when there was a coordinating
oxygen in the R-position (entry 6). In the case of methyl
4722
Org. Lett., Vol. 13, No. 17, 2011

The initial products of type 2 can also be converted into
cyclic carbonates 4 À another protected form of anti-R,β-
dihydroxy ketones 3. This transformation was effected
under very mild conditions, by the treatment of 2 with a
catalytic amount of DIPEA in chloroform at room tem-
perature. As represented by Scheme 2, the generality of the
procedure was tested on a series of compounds, which all
gave cis products 4 stereoselectively, with the exception of
unsaturatedderivatives2jand 2k, whichgavehighyields of
diastereoisomeric mixtures. Interestingly, treatment of 2d
(or 2e) with 5 equiv of the same reagent furnished trans
isomer 5d (or 5e). This finding raised the hope of develop-
ing a diastereodivergent synthesis where, starting from
carbonyl compounds, either syn or anti aldols of hydro-
xyacetone could be obtained at will, protected as cyclic
carbonates. Unfortunately, the procedure lacked general-
ity, as other substrates of type 2 gave mixtures of 4, 5, and
the elimination product 6.18
Scheme 2. Base-Promoted Rearrangement and Isomerization
Reactions of Enol Carbonates 2
To summarize, indium mediated allylation of carbonyl
compounds with 4-(bromomethyl)-1,3-dioxol-2-one 1 al-
lows for the synthesis of anti-R,β-hydroxy ketones, in
either protected or free form. Research oriented toward
the development of a catalytic asymmetric variant of this
method is underway.
Acknowledgment. Financial support of the Ministry of
Science and Technological Development of the Republic
of Serbia is acknowledged (Project No. 172027).
aTrans/cis = 1.3:1. bTrans/cis = 1:1.
Supporting Information Available. Experimental pro-
1
was not successful for this purpose, treatment of 2 with
aqueous mercuric nitrate resulted in instantaneous forma-
tion of the free aldol products 3, which retained the initial
anti configuration (Scheme 1).
cedures; copies of H NMR, 13C NMR, and other rele-
vant spectra of all new compounds; crystal data for 2e,
2m, and 2n (cif files). This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) 2q is formed from 2p by a rearrangement which occurs with the
retention of stereochemistry; see below.
(17) Their structures were confirmed by X-ray crystallography; see
the Supporting Information for details.
(18) (a) Julia, M.; Binet du Jassonneix, C. Bull. Soc. Chim. Fr. 1975,
751. (b) Mors, W.; Gottliee, O. R.; Djerassi, C. J. Am. Chem. Soc. 1957,
79, 4507.
Org. Lett., Vol. 13, No. 17, 2011
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