Two-directional elaboration of hydroxyacetone under thermodynamically controlled conditions: Allylation or 2-propynylation and aldol reaction

Article abstract of DOI:10.1021/jo0618573

Enolate generated from O-(tetrahydropyran-2-yl)hydroxyacetone under thermodynamically controlled conditions (1.3 equiv of NaH, THF, 0 °C to rt) was allylated at the carbon bearing the protected hydroxy group with very high regioselectively. When tert-BuOH, equivalent to the excessive portion of initially added NaH, was introduced into the mixture followed by addition of aldehyde, aldol reaction took place on the methyl group to give 1-substituted 4-hydroxy-(1E),6-heptadien-3-one in acceptable yields after acidic treatment of the mixture for dehydration and deprotection. Introducing a chiral auxiliary protecting group into hydroxyacetone led to asymmetric allylation though stereoselectivity was around 50% ee. Thus, the hidden aspect of the chemoselective nature of protected hydroxy acetone-derived enolate generated under thermodynamically controlled conditions has opened a new avenue for two-directional elaboration of hydroxyacetone that should be potentially useful in organic synthesis.

Full text of DOI:10.1021/jo0618573

Two-Directional Elaboration of Hydroxyacetone under
Thermodynamically Controlled Conditions: Allylation or
2-Propynylation and Aldol Reaction
Teruhiko Ishikawa,* Toshiaki Aikawa, Eiko Ohata, Takako Iseki, Satoshi Maeda,
Takashi Matsuo, Tatsuo Fujino, and Seiki Saito*
Department of Medical and Bioengineering Science, Graduate School of Natural Science and Technology;
Okayama UniVersity, Tsushima, Okayama, Japan 700-8530
seisaito@biotech.okayama-u.ac.jp
ReceiVed September 7, 2006
Enolate generated from O-(tetrahydropyran-2-yl)hydroxyacetone under thermodynamically controlled
conditions (1.3 equiv of NaH, THF, 0 °C to rt) was allylated at the carbon bearing the protected hydroxy
group with very high regioselectively. When tert-BuOH, equivalent to the excessive portion of initially
added NaH, was introduced into the mixture followed by addition of aldehyde, aldol reaction took place
on the methyl group to give 1-substituted 4-hydroxy-(1E),6-heptadien-3-one in acceptable yields after
acidic treatment of the mixture for dehydration and deprotection. Introducing a chiral auxiliary protecting
group into hydroxyacetone led to asymmetric allylation though stereoselectivity was around 50 % ee.
Thus, the hidden aspect of the chemoselective nature of protected hydroxyacetone-derived enolate generated
under thermodynamically controlled conditions has opened a new avenue for two-directional elaboration
of hydroxyacetone that should be potentially useful in organic synthesis.
Introduction
metrical simple ketones (tert-BuOK, THF, 0 °C to rt) we
recognized that the more substituted enolates served as a Michael
donor attacking R,â-unsaturated esters as illustrated in Scheme
1 for isopropyl methyl ketone as a representative case. Ad-
ditionally, in separate experiments the less substituted enolate
reacted with aldehydes or esters again in a highly regioselective
manner to give R,â-unsaturated ketone or 1,3-diketone
(Scheme 1).2
Since then we have been intrigued by the potential of
regioselective functionalization of simple unsymmetrical ketones
as an efficient synthetic method under thermodynamically
controlled conditions. Eventually, we found that hydroxyacetone
can lead to ketones bearing 1-hydroxy-3-butenyl (or 3-butynyl)
segments in one side and 2-substituted ethenyl segments in the
other via sequential allylation (or propargylation) and aldol
condensation3 as illustrated in Scheme 2. We also found that
these processes could be performed as one-pot transformations
if so desired and the former processes as asymmetric allylations.
Since domino processes deserve consideration in terms of
synthetic efficiency, environmental benignity, or, more impor-
tantly, reaction processing, a great deal of efforts have been
paid for developing such processes.1 In accordance with this
issue, we have been involved in developing domino processes
such as Michael addition and Claisen reactions leading to a
variety of cyclohexane-1,3-dione derivatives.2 In this transfor-
mation employing equilibrated enolates produced from unsym-
(1) Tietze, L. F.; Haunert, F. In Stimulating Concepts in Chemistry;
Shibasaki, M., Stoddart, J. F., Vo¨gtle, F., Eds.; Wiley-VCE: Weinheim,
Germany, 2000; pp 39-64. See also: Pellissier, H. Tetrahedron 2006, 62,
1619-1665 and 2143-2173.
(2) (a) Ishikawa, T.; Kadoya, R.; Arai, M.; Takahashi, H.; Kaishi, Y.;
Mizuta, T.; Yoshikai, K.; Saito, S. J. Org. Chem. 2001, 66, 8000-8009.
See also: Ishikawa, T.; Miyahara, T.; Asakura, M.; Higuchi, S.; Miyauchi,
Y.; Saito, S. Org. Lett. 2005, 7, 1211-121. We succeeded in achieving
domino processes leading to benzofurans from cyclohexane-1,3-diones in
one pot in which 13 elementary processes were operating.
10.1021/jo0618573 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/15/2006
J. Org. Chem. 2007, 72, 435-441
435

Ishikawa et al.
TABLE 1. Preliminary Experiments for Allylation of 1a
SCHEME 1. Observed Chemoselective Aspect of Ketone
Enolate Generated under Thermodynamically Controlled
Conditions
product:
yield %a
entry
1
allyl-Br equiv base (equiv)
solvent
THF
THF/DMFb
1
2
3
4
5
6c
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1.2
1.2
1.5
2.0
2.0
2.0
2.0
2.0
NaH (1.1)
NaH (1.1)
NaH (1.1)
NaH (1.3)
3a: 35 (50)
3a: 12
THF/DMSOb 3a: 37
THF
3a: 52 (62)
t-BuOK (1.3) THF
3a: 61
3b: 53
LDA (1.1)
NaH (1.3)
NaH (1.3)
THF
THF
THF
a For isolated products, yields in parentheses are corrected for recovered
1a. b 1:1 ratio. c LDA was prepared at -78 °C: alkylation was conducted
at 0 °C to rt.
SCHEME 2
Results and Discussion
Two-Directional Elaboration of Hydroxyacetone. Alkyla-
tion of enolates generated from simple dissymmetric ketones
under thermodynamically controlled conditions is difficult to
control in terms of the regiochemistry of the alkylation when
the ketones bear methyl and methylene groups or methylene
groups at both sides of the carbonyl group. Furthermore, these
carbons can be dialkylated if alkylating agent and base are
employed in an excessive amount. Hydroxyacetone (1a) is not
an exceptional molecule in that context, and we thought that
1a may fall into such a category. Contrary to this negative
assumption, however, the unexpected allylation of O-(tetrahy-
dropyran-2-yl)hydroxyacetone (1a) was realized in a preliminary
experiment as shown in Table 1 (entry 1). Thus, treatment of a
mixture of 1a and allyl bromide (2a, 1.2 equiv) in THF with
sodium hydride (NaH, 1.1 equiv) at 0 °C to rt furnished
O-(tetrahydropyran-2-yl)-2-oxo-5-hexen-3-ol (3a) in 35% yield
(50%, corrected for recovered 1a, entry 1) although accompanied
by highly polar, unidentifiable byproducts. Closer inspection
paying strong attention to finding the regioisomeric allylation
product was in vain. These results clearly indicated for the first
time that the allylation reaction of this class proceeded at the
carbon bearing the protected hydroxy group with very high
regioselectivity (>99%).
When the amounts of both bases (NaH) and allyl bromide
were increased (1.3 and 2.0 equiv, respectively), a much better
yield as 52% (62% corrected for recovered 1a, entry 4) resulted,
although undesired polyalkylation or formation of regioisomers
was expected. Alkoxide base such as potassium tert-butoxide
(tert-BuOK, 1.3 equiv) led to almost the same yield of 3a
(entry 5).
Although a possible Williamson process between the base
and reactive allyl bromide employed in a 1.3:2.0 ratio was
considered to be unavoidable, the desired allylation indeed
Four representative strategies have been available for syn-
thesizing hydroxyacetone derivatives which involve direct
oxidations of enolates or enol ethers,4 reactions of enamines or
enolates with nitroso compounds,5 aldol reactions of hydroxy-
acetones,6 and traditional acyloin ester condensation.7 However,
by inspection of the literature pertinent to this field it turned
out that regioselective allylation (or propargylation) of prototype
hydroxyacetones under thermodynamically controlled conditions
has no precedence. Here we will disclose the first example of
regioselective allylation (or propargylation) of the hydroxy-
acetone enolates on the oxygen-centered carbon followed by
aldol reaction on the methyl carbon under thermodynamically
controlled conditions.
(3) Since domino reactions are defined as processes of making two or
more bonds in which the subsequent reactions take place at the function-
alities obtained in the former step, the processes presented in this work are
not necessarily the domino processes. For the definition of the domino
processes, see ref 1.
(4) For review, see: Jones, A. B. In ComprehensiVe Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, Chapter
2.3.
(5) For review, see: Merino, P.; Tejero, T. Angew. Chem., Int. Ed. 2004,
43, 2995-2997.
(6) For recent examples, see: (a) Hoffmann, T.; Zhong, G.; List, B.;
Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R.; Barbas, C. F., III
J. Am. Chem. Soc. 1998, 120, 2768-2779. (b) List, B.; Shabat, D.; Barbas,
C. F., III; Lerner, R. Chem. Eur. J. 1998, 4, 881-885. (c) Notz, W.; List,
B. J. Am. Chem. Soc. 2000, 122, 7386-7387. (d) Yoshikawa, N.; Kumagai,
N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M.
J. Am. Chem. Soc. 2001, 123, 2466-2467. (e) Trost, B. M.; Ito, H.; Silcoff,
E. R. J. Am. Chem. Soc. 2001, 123, 3367-3368. (f) Tang, Z.; Yang, Z.-H.;
Cun, L.-Z.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285-
2287. Evans, D. A.; Glorius, F.; Burch, J. D. Org. Lett. 2005, 7, 3331-
3333. For reviews, see: (g) Hassner, A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
1, Chapter 2.4. (h) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326-
1328.
(7) (a) Freund, A. Justus Liebigs Ann. Chem. 1861, 118, 33-34. (b)
McElvain, Org. React. 1948, 4, 256-268. (c) Bloomfield, J. J.; Owsley,
D. C.; Nelke, J. M. Org. React. 1976, 23, 259-403. (d) Finley, K. T. Chem.
ReV. 1964, 64, 573-589. (e) Ru¨hlmann, K. Synthesis 1971, 236-253. (f)
Cram, D. J.; Antar, M. F. J. Am. Chem. Soc. 1958, 80, 3109-3114. (g)
Wasserman, E. J. Am. Chem. Soc. 1960, 82, 4433-4434. (h) Sauvage,
J.-P. Acc. Chem. Res. 1990, 23, 319-327.
436 J. Org. Chem., Vol. 72, No. 2, 2007

Allylation or 2-Propynylation and Aldol Reaction
TABLE 2. Regioselective Allylation and Propargylation of
(2-Tetrahydropyranyl)oxyacetone
SCHEME 3
proceeded. No significant improvement in chemical yields was
attained when changing solvent (THF) to mixed solvent systems
such as THF-DMF (entry 2) or THF-DMSO (entry 3) and
protecting group to a benzyl group (1b, entry 7). It should be
mentioned that the reaction was deteriorated to only result in
decomposition of 1c and formation of highly polar unidentifiable
mixtures for LDA as a base (entry 6).8 Such was also the case
for a TBDMS protecting group (1c, entry 8).9 On the basis of
these preliminary results we decided to use the NaH/THF system
for allylation of protected hydroxyacetone in this work.
SCHEME 4a
In Table 2 are summarized the results for allylations of 1a
with other allylic bromides plus benzyl bromide and 2-propynyl
bromide (NaH in THF, 0 °C to rt). Almost the same level of
chemical yields as that for the prototype allylic bromide (entry
1) resulted for those electrophiles. Very careful diagnosis of
the products (3a, 4-7) by means of NMR spectroscopy in terms
of the site of carbon-carbon bond formation revealed that an
extremely high level of regioselectivity was again achieved.
Since the protected hydroxyacetone 1a is considered to surely
lead to thermodynamically controlled enolates under the given
reaction conditions (NaH or tert-BuOK, THF, 0 °C to rt), the
cause of the observed regiochemical outcome should be ascribed
to the intrinsic reactivity difference between the two types of
enolates A (or B) and C (Scheme 3) toward electrophiles. In
addition to this interesting aspects of the reaction, 3a provided
the additional significant result that only type-C’ enolates react
with furfural on treatment of 3a with tert-BuOK (20 mol %) in
THF in the presence of the aldehyde (1.5 equiv) to give 8 in
64% yield after acidic treatment with complete reverse regi-
a Conditions: (a) (1) tert-BuOK (20 mol %), THF, 0 °C, 5 min, then
Fu-CHO (1.5 equiv), 0 °C, 1 h, (2) TsOH (0.1 equiv), EtOH, rt, 5 h. (b) (1)
tert-BuOK (20 mol %), THF, 0 °C, 5 min, then PhCHO or i-PrCHO (1.5
equiv), 0 °C, 1.5 h, (2) TsOH (0.1 equiv), EtOH, rt, 5 h. (c) (1) tert-BuOK
(20 mol %), THF, 0 °C, 5 min, then Fu-CHO (1.5 equiv), 0 °C, 1.5 h, (2)
TsOH (0.1 equiv), EtOH, rt, 17 h.
oselectivity (Scheme 4). Acyloins 4 or 5 also gave aldol
condensation products 9-11 exclusively on treatment with base
in the presence of aldehydes such as benzaldehyde, 2-methyl-
propanal, or furfural (Scheme 4). These facts clearly indicate
the generality of the regioselective aldol reaction of this class
taking place on less substituted acyloin enolate even if the
enolate is equilibrated with the more substituted one.
The two processes indicated in Table 1 and Scheme 4 can
be conducted in one pot. For instance, after treating 1a in THF
with NaH (1.3 equiv) in the presence of prenyl bromide (1.2
equiv) (18 h, rt), tert-BuOH (0.3 equiv, corresponding to the
excessive portion of NaH employed initially) was added to the
mixture followed by addition of benzaldehyde (2.0 equiv), and
the resulting mixture was stirred at rt for 13 h. Then 2 N HCl
(aqueous solution, 2 equiv) was added to the mixture for
dehydration and deprotection (rt, 12 h) to give 9 in 44% yield
based on 1a. Since the whole process consists of four individual
(8) It was reported that when LDA was employed for generating chiral
enolates from N-(benzyloxyacetyl)- or N-(tert-butyldimethylsilyloxyacetyl)-
oxazolidinone followed by addition of neryl bromide, no alkylation
proceeded at all for the TBDMS-protection case and only 20% yield of
alkylated product was obtained for the benzyl-protection case. However,
when other chiral auxiliary such as (-)-ephedrine-derived imidazolidinone
was employed, its N-(benzyloxyacetyl) derivative led to 49% yield of
alkylated product (LDA, neryl bromide), see: Cardillo, G.; Orena, M.;
Romero, M.; Sandri, S. Tetrahedron 1989, 45, 1501-1508.
(9) As indicated in ref 8, Evans substrate such as N-(tert-butyldimeth-
ylsilyloxyacetyl)oxazolidinone did not lead to any alkylation product at all
(LDA, neryl bromide, THF). Our observation for 1c similar to that previous
case may be ascribed to the same cause, which is not completely clear at
present. We must await future systematic studies for elucidating the exact
nature of the hydroxyacetone enolates concerned.
J. Org. Chem, Vol. 72, No. 2, 2007 437

Ishikawa et al.
TABLE 3. One-Pot Two-Directional Elaboraton of 1a
CHART 1
SCHEME 5
a RBr (1.2 equiv), NaH (1.3 equiv), THF, t-BuOH (0.6 equiv), ZCHO
(2.0 equiv). b RBr (2.0 equiv), NaH (1.3 equiv), THF, t-BuOH (0.3 equiv),
ZCHO (2.0 equiv). c RBr (2.0 equiv), NaH (1.3 equiv), THF, t-BuOH (0.3
equiv), ZCHO (2.0 equiv). d RBr (1.2 equiv), NaH (1.2 equiv), THF,
t-BuOH (0.2 equiv), ZCHO (2.0 equiv).
reactions such as allylation, aldol reaction, dehydration, and
deprotection, the average chemical yield for each step can be
estimated to be ca. 82%. Other results pertinent to this two-
directional elaboration of 1a in one pot are summarized in Table
3. The one-pot process required much longer for the aldol
reaction (6-16 h, Table 3), whereas 1-1.5 h was enough for
the separate experiments (Scheme 4). This is probably because
most of the generated tert-BuONa by addition of tert-BuOH
can be used as a nucleophile in Williamson ether synthesis with
unchanged halides during process II.
Thus, two-directional chain synthesis of simple acyloins such
as 1a has been realized by means of unveiled chemoselective
nature of acyloin-based enolates generated under thermody-
namically controlled conditions. It may make sense that genera-
tion of enolates under kinetically controlled conditions including
amide bases at -78 °C is not necessarily needed when we
contemplate bringing about aldol reaction at terminal methyl
groups of acyloin derivatives. This outcome is quite consistent
with the previous results outlined in Scheme 1.
Asymmetric Allylation: Preliminary Results. The regi-
oselective construction of allylated acyloin frameworks shown
so far is concerned with introduction of oxygen-centered
stereogenic carbons. To realize asymmetric allylation reactions
of prototype acyloin, replacement of the THP protecting group
in 1a with an appropriate chiral auxiliary capable of performing
its easy introduction and recycling may be desirable. This idea
led us to develop pantolactone-based acetal-type chiral auxiliary
as depicted in Chart 1. Each enantiomer of pantolactone is
commercially available, and the (S)-isomer, for example, was
converted to 16 (63% in three steps) by DIBAL-H reduction
(toluene, -78 °C) after protecting the hydroxy group with a
tert-butyldiphenylsilyl group (TBDPSCl, imidazole, THF, 15)
followed by acetylation (Ac2O, Et3N, DMAP, THF). A mixture
of 16 and hydroxyacetone in CH2Cl2 in the presence of Lewis
acid such as BF3‚OEt2 (-50 °C, 1 h to 0 °C, 3 h) exclusively
gave substrate 17 (72%) ready for examining asymmetric
allylation. Nucleophilic attack of hydroxyacetone biased by the
neighboring TBDPSO-centered stereogenic center may probably
take place from the convex face of intermediate 18 produced
through Lewis-acid-promoted deacetoxylation.
In Scheme 5 is summarized the reaction of 17 with allyl
bromide under the reaction conditions developed in this work
(2.0 equiv of NaH, THF, 2.0 equiv of CH2dCHCH2Br, 0 °C to
rt) to give a mixture of diastereoisomers (19 and 20, 69% in a
ratio of 1:3), which were able to be separated by column
chromatography over silica gel. In order to confirm absolute
configurations for newly developed stereogenic centers, the
major component 20 was correlated with known derivatives 24
or 25. Wadsworth-Emmons reaction of 20 with diethyl
thiazolylmethylphosphonate 2110 (NaHDMS, THF) gave the (E)-
trisubstituted olefin derivative (22) in quantitative yield (99%),
which was treated with trifluoroacetic acid in CH2Cl2 at 0 °C
for 1.5 h to afford 24 (71%) with [R]D -18.6 (c 1.0) together
with recovered chiral auxiliary (23, 33%)11 for recycling: the
(10) Schinzer, D.; Limberg, A.; Bo¨hm, O. M. Chem. Eur. J. 1996, 2,
1477-1482.
(11) Acid-promoted dehydrative dimerization of liberated 23 took place
under the given reaction conditions (CF3CO2H, CH2Cl2, 0 °C) to give bis-
[(2S,3S)-3-tert-butyldiphenylsiloxy-4,4-dimethyl]oxolan-2-yl ether. We are
now trying to convert this dimer (hemiacetal anhydride) to 23.
(12) (a) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He,
Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119,
7974-7991. (b) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka,
T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073-
10092. (c) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 523-524. (d) Schinzer, D.; Bauer,
A.; Bo¨hm, O. M.; Limherg, A.; Cordes, M. Chem. Eur. J. 1999, 5, 2483-
2491. (e) Storer, R. I.; Takemoto, T.; Jackson, P. S.; Brown, D. S.;
Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2004, 10, 2529-2547.
438 J. Org. Chem., Vol. 72, No. 2, 2007

Allylation or 2-Propynylation and Aldol Reaction
TABLE 4. Alkylations of 1a with Iodoalkanesa
SCHEME 6
sign of the optical rotation of 24 was the same as that reported
for 24.12 Routine acetylation of 24 gave the corresponding
acetate (25, 90%) exhibiting [R]D -41.8 (c 1.1), which is fully
consistent with that reported.12b
The asymmetric allylation developed here was applied to
reaction of 17 with neryl chloride (26),13 which is shown in
Scheme 6. The reaction resulted in nearly the same level of
chemical yield (73%) and diastereoselectivity (2.3:1) as that for
prototype allylation (Scheme 5). Separation of the major isomer
(27) by silica gel column chromatography was also successful
in this case, which is a useful synthetic block in the total
synthesis of epothilone families.13
Alkylation: Preliminary Results. The feasibility of alky-
lations under the reaction conditions used for the allylations of
1a should be examined because it would be of benefit to organic
synthesis. Although we attempted alkylation using bromoal-
kanes, more reactive iodomethane, iodoeethane, and 1-iodobu-
tane were needed for expected alkylation to be realized [1.2
equiv of NaH, 1.3 equiv of iodoalkane, THF (32 mL/g 1a), 0
°C to rt, 17 h]. Contrary to the case of allylations, alkylations
resulted in formation of regioisomers except for methylation
and polyalkylation in every case examined. In addition, separa-
tions of these products by column chromatography over silica
gel were successful only partly, and hence, usually structure
determinations were forced to be done for such mixtures. The
results are shown in Table 4.
Separation of product mixtures obtained from entry 1 by
column chromatography over silica gel afforded, apart from
unchanged 1a (14%), three parts X, Y, and Z in order of
decreasing polarity. X (14 wt % based on the total weight of
the products mixture) was an inseparable mixture and estimated
to contain at least three polyalkylated products judging from
the presence of three NMR signals for protons attached to the
THP-based acetal carbon as well as the increasing amounts of
methylene protons (9 × CH2) and teminal methyl protons (2 ×
CH3).14 On the contrary, NMR analysis for Y unambiguously
indicated that Y is a single diastereoisomer of 28 produced via
a Conditions: 1.2 equiv of NaH, 1.3 equiv of iodoalkane, THF (32 mL/g
1a), 0 °C to rt, 17 h. For entries 1 and 2, polyalkylation products were
isolated as the least polar fractions in chromatographic separation: 2.5%
and 6% yield, respectively. For entry 3, polyalkylation products (33) were
detected in a very small amount (>1%). b Corrected for recovered 1a.
c Minor diastereomer could be separated, major diastereomer and 29 were
obtained as a mixture, and their ratio was determined by NMR. d Diaste-
reoisomers were difficult to separate. e Diastereoisomeric mixture (31), 32,
and 33 were difficult to separate; yields and diastereoisomeric ratio were
determined by NMR.
alkylation at the more substituted carbon of 1a (8% yield
corrected for recovered 1a). Since the NMR spectra of Z
exhibited both an AB quartet due to THPO-attached methylene
group and a sharp singlet due to an acyl methyl group, Z was
determined to be a mixture of another diastereoisomer of 28
(10% yield corrected for recovered 1a) and constitutional isomer
29 (5% yield corrected for recovered 1a) produced via alkylation
at the methyl carbon of 1a. Thus, the regioselectivity for
monobutylation of 1a was 3.6:1 in preference of alkylation
proceeding at the more substituted site of 1a though the chemical
yield was unacceptable (18%).
In contrast to those disappointing results for butylation,
alkylation using iodomethane (entry 2) provided more hopeful
results: 30 as a diastereoisomeric mixture (1.2:1) produced from
alkylation at the more substituted carbon of 1a was obtained in
60% yield (corrected for recovered 1a)15 as a monomethylation
product. Although a mixture of less polar polyalkylation
products was separable (6% yield, corrected for recovered 1a),16
(13) For synthesis of the epothilone D segment from neryl halide, see:
Scheid, G.; Ruijter, E.; Konarzycka-Bessler, M.; Bornscheuer, U. T.;
Wessjohann, L. A. Tetrahedron: Asymmetry 2004, 15, 2861-2869.
(14) Even very careful flash column chromatography was not successful
for separation of the mixture. In addition to NMR information described in
the text, other significant NMR signals were observed indicating the presence
of acyl CH3 (singlet), OdC-CH2R (triplet), or THPO-CH2 (AB quartet)
for X, which tentatively led us to conclude that X contains polyalkylated
products such as 34, 35, or 36, though a final decision must await further
reliable structural analyses. On the basis of these considerations, the yield
of the polyalkylated products was calculated to be 2.5%.
(15) Because of the higher volatility of 30, significant loss of products
during evaporative workup was unavoidable. Accordingly, the yield
indicated in the text was determined by NMR for a sample containing EtOAc
stemmed from column chromatographic separation.
(16) Structures of difficult to separate polyalkylation products (three
components) were estimated to be 37 (two diastereoisomers) and 38 on the
basis of NMR analysis of the mixture. Chemical yield was calculated based
on these structures.
J. Org. Chem, Vol. 72, No. 2, 2007 439

Ishikawa et al.
no signal for the AB quartet due to THPO-based acetal proton
was observed by NMR diagnosis, and accordingly, only
polyalkylation16 of the initial alkylation products 30 was
troublesome; thus, highly regioselective methylation indeed
proceeded under the same reaction conditions as those for the
allylations of 1a. Ethylation (entry 3), much less reactive than
the methylation, afforded a mixture of 31 (two diastereoisomers),
regioisomeric 32 (29%, 14:1), and very small amount of 33
(>1%).
Regioselectivity. The results listed in Table 4 clearly suggest
that the regioselectivity of alkylation may be correlated to the
reactivity of each alkylation: the more reactive the alkylation
becomes, the higher the regioselectivity results in terms of a
ratio of alkylation at a THPO-centered carbon to that at a methyl
carbon. Since the reactivity of this class (SN2) should be partly
controlled by steric reason of iodoalkanes (electrophiles), we
must estimate the stability difference between more substituted
enolate (A or B) and less substituted enolate (C) shown in
Scheme 3 in order to evaluate the transition-state energy
difference between the alkylation at a THPO-centered carbon
and that at a methyl carbon of 1a. Future systematic studies
including calculations for energy levels of components involved
in alkylation pathways as well as allylation pathways need to
be performed.
Experimental Section
General Procedure for Allylation or 2-Propynylation. The
following procedure for the synthesis of 3a is representative. To a
solution of ketone 1a (77 mg, 0.49 mmol) in THF (4 mL) was
added NaH (2.5 mg, 60% in oil, 0.63 mmol, 1.3 equiv), and the
mixture was stirred at 0 °C for 5 min followed by addition of allyl
bromide (0.082 mL, 0.97 mmol, 2 equiv) at 0 °C. The reaction
was stirred at room temperature for 15 h and quenched by addition
of a saturated aqueous solution of NH4Cl (1 mL) and water at
0 °C. The mixture was extracted with ethyl acetate-hexane mixed
solvent (1:1). The combined organic layers were dried over Na2-
SO4 and concentrated to give an oil, which was purified by column
chromatography over silica gel to provide 3a as a mixture of two
diastereoisomers (1.2:1) [50 mg, 0.25 mmol, 52% (62%: corrected
for unchanged 1a)] and 1a (12 mg, 16% recovered). 3a: IR
(neat): 2942, 1716 cm-1. H NMR δ 1.46-1.90 (m, ring-(CH2)3,
1
6H), 2.13 and 2.21 (s for each, CH3CdO, 3H), 2.39 and 2.46 (ddt
for each, J ) 7.2, 6.3, 1.0 Hz, dC-CHH and dC-CHH, 2H),
3.37-3.53 (m, ring-CHH-O, 1H), 3.77-3.90 (m, ring-CHH-O,
1H), 3.95 and 4.22 (t for each, J ) 6.3 Hz, CH-OTHP, 1H), 4.54
and 4.55 (dd for each, J ) 6.1, 2.8 Hz and 6.7, 3.7 Hz, ring-O-
CH-O, 1H), 5.03-5.16 (m, H2Cd, 2H), 5.74 and 5.83 (ddt for
each, J ) 17.0, 10.2, 7.1 Hz, dCH-, 1H). 13C NMR δ (19.1, 20.3),
(25.2, 25.3), (26.3, 26.4), (30.5, 30.7), (36.1, 36.9), (62.4, 63.9),
(80.7, 82.7), (97.7, 100.1), (117.9, 118.0), (132.9, 133.1), (210.0,
210.4). Anal. Calcd for C11H18O3: C, 66.64; H, 9.15; O, 24.21.
Found: C, 66.78; H, 9.02. Exact mass, m/z 198.125112 (calcd for
C11H18O3 m/z 198.12560).
Concluding Remarks
General Procedure for Aldol Condensation Followed by
Deprotection. The following procedure for the synthesis of 9 is
representative.
The present stage for the asymmetric allylation of protected
hydroxy acetone (17), though novel, seems to be short of the
modern level of stereoselectivity requirement. A breakthrough
in this context is now one of our major concerns. Nevertheless,
the thermodynamically controlled enolates generated from
protected hydroxyacetones have proven useful for two-
directional carbon chain elongation involving allylation on the
oxygen-centered carbon and aldol condensation on the methyl
carbon. This shows the hidden potential of acyloins in synthetic
organic chemistry. With respect to R-oxygen carbanions of other
types developed so far, almost all of them have additional
stabilization systems such as allylic or benzylic conjugation,
electron-withdrawing cyano conjugation (protected cyanohy-
drins), R-silicon effect (R,â-epoxyalkylsilanes), or phosphorus
conjugation.17 Furthermore, it should be noted that no regio-
chemical issue exists for these cases. Therefore, the acyloin
chemistry developed here would provide a conceptually novel
bias or clue about synthetic planning of carbon chains involving
an acyloin unit which may serve as an efficient strategy in
synthesizing targeting molecules for natural18 or unnatural
products.
To a solution of 4 (0.24 g, 1.0 mmol) in THF (10 mL) was added
tert-BuOK (0.022 g, 0.20 mmol) at 0 °C. After stirring at 0 °C for
5 min, benzaldehyde (0.15 mL, 1.5 mmol) was added to the mixture
at 0 °C. The reaction was stirred at 0 °C for 1.5 h and quenched by
addition of water at 0 °C. The mixture was extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4 and
concentrated to give an oil, which was purified by column
chromatography on silica gel to provide an enone (0.233 g, 0.74
mmol, 74%). To a solution of this enone in EtOH (7 mL) was added
TsOH (0.014 g, 0.074 mmol) at 0 °C. The reaction was stirred at
room temperature for 5 h and quenched by addition of NEt3 (0.021
mL, 0.15 mmol) and water. The mixture was extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4 and
concentrated to give an oil, which was purified by column
chromatography over silica gel to provide 9 (0.15 g, 0.64 mmol,
64% from 4): 1H NMR δ 1.61 (s, trans-CH3Cd, 3H), 1.71 (d,
J ) 1.3 Hz, cis-CH3Cd, 3H), 2.43 (m, dC-CHH, 1H), 2.60 (m,
dC-CHH, 1H), 3.61 (bd, J ) 5.5 Hz, OH, 1H), 4.51 (bq, J ) 5.5
Hz, CH-OH, 1H), 5.18 (tq, J ) 7.3, 1.3, dCH, 1H), 6.88 (d, J )
15.9 Hz, OdC-CHd, 1H), 7.34-7.43 (m, 3H), 7.53-7.62 (m,
2H), 7.74 (d, J ) 15.9 Hz, OdC-CdCH, 1H). 13C NMR δ 18.0,
25.8, 33.3, 75.1, 118.1, 120.7, 128.2, 128.5, 129.0, 129.9, 131.0,
134.1, 135.5, 144.4, 200.4. Anal. Calcd for C15H18O2: C, 78.23;
H, 7.88; O, 13.89. Found: C, 78.01; H, 7.79. Exact mass, m/z
230.13108 (calcd for C15H18O2 m/z 230.13068).
(17) For a review on alkylations of heteroatom-stabilized carbanions other
than acyloins, see: Cheshire, D. R. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, Chapter
1.4. In this series of outstanding comprehensive surveys, no description of
the alkylation or allylation of acyloins is presented, see also: Evans,
D. A.; Sacks, C. E.; Kleschick, W. A.; Taber, T. R. J. Am. Chem. Soc.
1979, 101, 6789-6791 in which regioselective alkylation of 2-butanone-
based 3-PhS-substituted N,N-dimethylhydrazone under thermodynamically
controlled conditions [KH, tert-BuOK (0.03 equiv), THF, reflux, then
iodoalkane, 0 °C to rt) is described.
(18) The acyloin framework is a key structural unit of many natural
products, and chiral R-hydroxy ketones (acyloins) are versatile synthetic
intermediates for diversified bioactive compounds, see: (a) Bel-Rhlid, R.;
Fauve, A.; Veschambre, H. J. Org. Chem. 1989, 54, 3221-3223. (b) Awano,
K.; Yanai, T.; Watanabe, I.; Takagi, Y.; Kitahara, T.; Mori, K. Biosci.
Biotechnol. Biochem. 1995, 59, 1251-1254. (c) Shi, X.; Leal, W. S.;
Meinwald, J. Bioorg. Med. Chem. 1996, 4, 297-303 (d) Scheid, G.; Huit,
W.; Ruijter, E.; Orru, R. V. A.; Henke, E.; Bornscheuer, U.; Wessjohann,
L. A. Eur. J. Org. Chem. 2004, 1063-1074.
General Procedure for One-Pot Chemoselective Transforma-
tion of 1a. The following procedure for the synthesis of 9 is
representative.
To a solution of ketone 1a (100 mg, 0.66 mmol) in THF (3 mL)
was added NaH (3.4 mg 60% in oil, 0.85 mmol, 1.3 equiv) at 0
°C. After stirring at 0 °C for 5 min, prenyl bromide (0.092 mL,
0.79 mmol, 1.2 equiv) was added to the mixture at 0 °C. The
reaction was stirred at room temperature for 18 h, tert-BuOH (0.04
mL, 0.39 mmol, 0.6 equiv) and benzaldehyde (0.15 mL, 1.31 mmol,
2.0 equiv) were added to the reaction mixture at 0 °C, and the
resulting mixture was stirred at room temperature for 13 h, followed
by addition of 2 N HCl (aqueous solution 0.65 mL, 2.0 equiv),
440 J. Org. Chem., Vol. 72, No. 2, 2007

Allylation or 2-Propynylation and Aldol Reaction
stirring being continued at room temperature for 12 h. The reaction
was quenched by addition of a saturated aqueous solution of
NaHCO3 and water at 0 °C. The mixture was extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4 and
concentrated by a rotary evaporator to give an oil, which was
purified by column chromatography to provide 9.
addition of water at 0 °C. The mixture was extracted with ethyl
acetate-hexane mixed solvent (1:1). The combined organic layers
were dried over Na2SO4 and concentrated to give an oil, which
was purified by column chromatography over silica gel to provide
22 (0.455 g, 0.809 mmol, 99%); [R]25 +5.3 (c 1.0, CHCl3). IR
D
1
(neat): 2931, 2858, 1427 cm-1. H NMR δ 0.88 (s, 3H), 1.11 (s,
1-[(2R,3S)-3-tert-Butyldiphenylsiloxy-4,4-dimethyloxolan-2-yloxyl-
propan-2-one (17). To a solution of 16 (17.9 g, 43.4 mmol) and
hydroxyacetone (3.6 mL, 52.1 mmol) in CH2Cl2 (200 mL) was
slowly added BF3‚OEt2 (1.10 mL, 8.68 mmol) at -78 °C. The
mixture was stirred at -78 to -10 °C for 4.5 h and quenched by
addition of Et3N (1.20 mL, 8.68 mmol) at -10 °C, and to the thus-
obtained mixture were added CH2Cl2 and water. The aqueous
solution was extracted with CH2Cl2, and the combined organic
layers were dried over Na2SO4 and concentrated to give an oil,
which was purified by column chromatography over silica gel to
3H), 1.12 (s, 9H), 1.90 (s, 3H), 2.10 (t, J ) 7.1 Hz, 2H), 2.69 (s,
3H), 3.54-3.62 (m, 3H), 3.94 (d, J ) 1.9 Hz, 1H), 4.85-4.91 (m,
2H), 4.94 (d, J ) 2.2 Hz, 1H), 5.38-5.53 (m, 1H), 6.32 (s, 1H),
6.90 (s, 1H), 7.36-7.48 (m, 6H), 7.67-7.77 (m, 4H). 13C NMR δ
14.0, 19.1, 19.4, 21.0, 23.7, 27.0, 37.6, 42.3, 78.6, 84.4, 85.8, 109.5,
115.2, 116.4, 120.1, 127.5, 127.6, 129.6, 129.7, 133.3, 134.1, 134.4,
135.9, 136.1, 140.2, 152.9, 164.0.
(3S)-2-Methyl-1-(2-methyl-1,3-thiazol-4-yl)-(1E,5)-hexadien-3-
ol (24). To a solution of 22 (54 mg, 0.097 mmol) in CH2Cl2 (4.4
mL) was added trifluoroacetic acid (0.44 mL) at 0 °C, and the
mixture was stirred at 0 °C for 1.5 h and quenched by addition of
a saturated aqueous solution of NaHCO3 at 0 °C. The mixture was
extracted with ethyl acetate, and the combined organic layers were
dried over Na2SO4 and concentrated to give an oil, which was
purified by column chromatography over silica gel to provide 24
(14.5 mg, 0.069 mmol, 71%) and 23 (11.7 mg, 0.032 mmol, 33%).
24: [R]17 -18.6 (c 1.00, CHCl3) (Lit.13 [R]22 -20.2 (c 1.0,
provide 17 (13.5 g, 73%); [R]17 +18.4 (c 1.00, CHCl3). IR
D
1
(film): 2960, 2858, 1722 cm-1. H NMR δ 0.92 (s, 3H), 1.11 (s,
9H), 1.18 (s, 3H), 1.94 (s, 3H), 3.45 and 3.87 (ABq, J ) 16.5 Hz,
ring-CH2O, 2H), 3.63 (s, OdC-CH2, 2H), 3.98 (d, J ) 2.5 Hz,
ring-CH-OSi, 1H), 4.78 (d, J ) 2.5 Hz, ring-OCH(O), 1H), 7.30-
7.50 (m, Ar-H, 6H), 7.65-7.71 (m, Ar-H, 4H). 13C NMR δ 19.3,
20.7, 23.3, 26.5, 26.9, 42.6, 73.4, 78.8, 84.9, 110.1, 127.4, 127.6,
129.7, 129.8, 133.1, 133.7, 135.9, 135.9, 206.8.
D
D
CHCl3). IR (neat): 3350, 2945, 1643 cm-1. H NMR δ 2.01 (d,
J ) 1.4 Hz, CH3Cd, 3H), 2.30-2.47 (m, dC-CH2, 2H), 2.61 (b,
OH, 1H), 2.68 (s, NdC-CH3, 3H), 4.19 (b three lines, CH-O,
1H), 5.06-5.17 (m, 2H), 5.81 (ddt, J ) 17.1, 10.1, 7.1 Hz, Cd
CH-C, 1H), 6.53 (bs, MeCdCH, 1H), 6.91 (s, ring-CdCH-S,
1H). 13C NMR δ 14.3, 19.1, 40.0, 76.4, 115.4, 117.7, 118.9, 134.6,
141.5, 152.7, 164.5.
1
(3S)-3-[(2R,3S)-3-tert-Butyldiphenylsiloxy-4,4-dimethyloxolan-
2-yl]oxy-5-hexen-2-one (20). To a solution of 17 (0.834 g, 1.95
mmol) in THF (12 mL) was added NaH (0.094 g, 60%, 2.34 mmol),
and the mixture was stirred at 0 °C for 5 min followed by addition
of allyl bromide (0.20 mL, 2.34 mmol) at 0 °C. The reaction was
stirred at room temperature for 15 h and quenched by addition of
a saturated aqueous solution of NH4Cl (1 mL) and water at 0 °C.
The mixture was extracted with ethyl acetate-hexane mixed solvent
(1:1), and the combined organic layers were dried over Na2SO4
and concentrated to give an oil, which was purified by column
chromatography over silica gel to provided 19 (0.15 g, 0.33 mmol,
17%) and 20 (0.47 g, 1.01 mmol, 52%). Data of 20 (major
isomer): [R]20D +7.5 (c 1.0, CHCl3). IR (film): 2931, 2858, 1716,
(1S)-[(1E)-Methyl-2-(2-methyl-1,3-thiazol-4-yl)ethynyl]-3-bute-
nyl Acetate (25). To a solution of 24 (17.1 mg, 0.081 mmol) in
CH2Cl2 (1 mL) were added Et3N (0.030 mL, 0.20 mmol), Ac2O
(0.015 mL, 0.15 mmol), and 4-(N,N-dimethylamino)pyridine (2.1
mg, 0.016 mmol) at 0 °C, and the mixture was stirred at room
temperature for 2 h and quenched by addition of water at 0 °C.
The mixture was extracted with ethyl acetate, and the combined
organic layers were dried over Na2SO4 and concentrated to give
an oil, which was purified by column chromatography over silica
1
1427 cm-1. H NMR δ 0.88 (s, 3H), 1.11 (s, 9H), 1.12 (s, 3H),
2.04 (s, 3H), 2.10 (tt, )C-CH2, J ) 6.6, 1.1 Hz, 2H), 3.57 and
3.61 (ABq, J ) 8.3 Hz, ring-OCH2, 2H), 3.57 (t, J ) 6.6 Hz, CH-
OR*, 1H), 3.95 (d, J ) 2.5 Hz, ring-CHOSi, 1H), 4.92 (d, J ) 2.5
Hz, ring-OCH(O), 1H), 4.95-5.02 (m, CH2dC, 2H), 5.58-5.75
(m, dCH-, 1H), 7.34-7.48 (m, 6H), 7.63-7.75 (m, 4H). 13C NMR
δ 19.6, 21.0, 23.5, 26.0, 27.2, 36.1, 43.0, 78.9, 83.7, 85.3, 110.4,
117.5, 127.3, 127.4, 129.5, 129.6, 132.3, 132.9, 133.6, 135.6, 209.3.
Data of 19 (minor isomer): [R]22D +26.3 (c 1.00, CHCl3). 1H NMR
δ 0.90 (s, 3H), 1.10 (s, 9H), 1.13 (s, 3H), 1.76 (s, 3H), 2.30-2.43
(m, 2H), 3.68 and 3.64 (ABq, J ) 8.5 Hz, 2H), 3.76 (t, J ) 5.8
Hz, 1H), 3.96 (d, J ) 1.8 Hz, 1H), 4.94 (d, J ) 1.8 Hz, 1H), 4.96-
5.04 (m, 2H), 5.58-5.74 (m, 1H), 7.32-7.49 (m, 6H), 7.62-7.74
(m, 4H). 13C NMR δ 19.7, 21.5, 24.2, 26.4, 27.2, 37.2, 42.5, 79.3,
82.2, 85.2, 109.7, 117.5, 127.4, 127.5, 129.6, 129.7, 132.8, 133.0,
133.5, 135.6, 135.8, 208.8.
gel to provide 25 (18.6 mg, 96%); [R]20 -41.8 (c 1.10, CHCl3)
D
(Lit.13b [R]D -40.0 (c 7.3, CHCl3). IR (film): 2944, 1740 cm-1
.
1H NMR δ 2.07 (s, CH3C) + CH3CO, 6H), 2.48 (t, J ) 6.9 Hz,
dC-CH2-C-OAc, 2H), 2.70 (s, NdC-CH3, 3H), 5.05 (ddt,
J ) 10.1, 1.9, 1.1 Hz, cis-HHCdCH-C, 1H), 5.10 (ddd, J ) 17.1,
3.3, 1.4 Hz, trans-HHCdCH-C, 1H), 5.32 (t, J ) 6.9 Hz, CH-
OAc, 1H), 6.51 (bs, MeCdCH, 1H), 6.94 (s, ring-CdCH-S, 1H).
13C NMR δ 14.8, 19.2, 21.2, 37.6, 78.1, 116.2, 117.7, 120.7, 133.4,
137.2, 152.5, 164.6, 170.1.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
(3S)-3-[(2R,3S)-3-tert-Butyldiphenylsiloxy-4,4-dimethyloxolan-
2-yloxy]-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)hexa-(1E,5)-diene (22).
To a solution of 21 (0.505 g, 2.03 mmol) in THF (2 mL) was added
NaHMDS (2.0 mL, 1.0 M, 2.0 mmol) at -78 °C, and the mixture
was stirred at -78 °C for 30 min followed by addition of a solution
of 20 (0.379 g, 0.812 mmol) in THF (3.5 mL) at -78 °C. The
reaction was stirred at room temperature for 15 h and quenched by
Supporting Information Available: Representative experi-
mental procedures, physical properties, and NMR charts. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO0618573
J. Org. Chem, Vol. 72, No. 2, 2007 441