Ti-direct, powerful, stereoselective aldol-type additions of esters and thioesters to carbonyl compounds: Application to the synthesis and evaluation of lactone analogs of jasmone perfumes

Article abstract of DOI:10.1039/b613544g

An efficient TiCl₄-Et₃N or Bu₃N-promoted aldol-type addition of phenyl and thiophenyl esters or thioaryl esters with aldehydes and ketones was performed (total 46 examples). The present method is advantageous from atom-economical and cost-effective viewpoints; good to excellent yields, moderate to good syn-selectivity, substrate variations, reagent availability, and simple procedures. Utilizing the present reaction as the key step, an efficient short synthesis of three lactone [2(5H)-furanone] analogs of jasmine perfumes was performed. Among them, the lactone analog of cis-jasmone had a unique perfume property (tabac). The Royal Society of Chemistry.

Full text of DOI:10.1039/b613544g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Ti-direct, powerful, stereoselective aldol-type additions of esters and thioesters
to carbonyl compounds: application to the synthesis and evaluation of lactone
analogs of jasmone perfumes†
Ryohei Nagase, Noriaki Matsumoto, Kohei Hosomi, Takahiro Higashi, Syunsuke Funakoshi, Tomonori Misaki
and Yoo Tanabe*
Received 18th September 2006, Accepted 23rd October 2006
First published as an Advance Article on the web 20th November 2006
DOI: 10.1039/b613544g
An efficient TiCl4–Et3N or Bu3N-promoted aldol-type addition of phenyl and thiophenyl esters or
thioaryl esters with aldehydes and ketones was performed (total 46 examples). The present method is
advantageous from atom-economical and cost-effective viewpoints; good to excellent yields, moderate
to good syn-selectivity, substrate variations, reagent availability, and simple procedures. Utilizing the
present reaction as the key step, an efficient short synthesis of three lactone [2(5H)-furanone] analogs of
jasmine perfumes was performed. Among them, the lactone analog of cis-jasmone had a unique
perfume property (tabac).
and stereoselective aldol-type additions of esters and thioesters
Introduction
to aldehydes and ketones promoted by a TiCl4-amine reagent.7
The aldol-type addition of simple esters with aldehydes and
This paper also describes an application for the short and efficient
ketones (carbonyl acceptor) has attained an important position in
organic syntheses due to its broad utility, that is, a straightforward
method to access useful b-hydroxy esters.1 In general, this reaction
synthesis of three lactone analogs for dihydrojasmone (known),
cis- and trans-jasmone (novel), with an evaluation of their perfume
property.
is categorizedintotwotypes:(i)the directmethod of metal enolates
generated by strong basic reagents [e.g., LDA and MHMDS (M =
Results and discussion
Li, Na, K) (metal exchanged enolates are also employable)] to
react with the carbonyl acceptor, and (ii) the indirect method of
The salient features of these Ti-mediated reactions are as follows.
ketene silyl acetals derived from carboxylic esters to react with the
(i) High reaction velocities and yields. (ii) Higher atom-economy
carbonyl acceptor promoted by Lewis acids or other catalysts (the
and lower cost than the indirect methods using enol silyl ethers and
Mukaiyama protocol).
ketene silyl acetals. (iii) Use of readily available and low toxic metal
reagents (e.g., TiCl4, ZrCl4), and use of practical amines (Et3N,
Bu3N) and solvents (toluene, CH2Cl2). (iv) Toleration against
basic labile functionalities. (v) Enhanced reactivity using catalytic
TMSCl in rare cases.
Direct aldol-type addition of simple esters with carbonyl accep-
tors using Lewis acids combined with tertiary amines possesses
several advantages because of its simple and atom-economical
procedure, high regio- and stereoselectivity, and tolerance to basic
(A) Basic investigation of Ti-direct aldol-type addition of methyl
propanoate to aldehydes
The initial attempt was guided by the reaction between methyl
propanoate (CH3CH2CO2CH3) and PhCHO or t-BuCHO uti-
lizing a TiCl4–Bu3N reagent (Scheme 1). The desired b-hydroxy
methyl esters 1a, 1b were obtained in 75% and 82% yield,
respectively. This result is in clear contrast to the method
using a TiCl2(OTf)2–Et3N reagent, which resists the aldol-type
addition and promotes a competitive Ti-Claisen condensation of
labile functionalities. Due to the lower enolization ability of esters
(pKa ∼ 25) than that of ketones or aldehydes (pKa ∼ 19–21),
however, there have been only three successful methods to this
objective; the use of diazabromoborane (Corey’s group),2 dicyclo-
hexyliodoborane (Brown’s group),3 and boron triflate (Masamune
and Abiko’s group).4 From the recently recognized standpoint
of process chemistry, readily available, atom-economical, and
cost-effective synthetic reagents are increasingly required for the
production of fine chemicals. Consistent with our continued
studies on Ti-Claisen condensation5 and relevant Ti-direct aldol-
type additions,6 we report herein the full details of direct, powerful,
Department of Chemistry, School of Science and Technology, Kwansei
Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan. E-mail:
tanabe@kwansei.ac.jp; Fax: +81-79-565-9077; Tel: +81-79-565-8394
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b613544g
Scheme
aldehydes.
1
Ti-direct aldol-type addition of methyl propanoate to
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Table 1 Ti-direct aldol-type addition of phenyl esters 2 to aldehydes and ketones
Entry
R1
R2
H
H
R3
R4
H
H
Product
Yield (%)
Syn–antib
1
2c
3
Me
Me
Ph
3a
3a
3b
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
80
75
84
76
79
83
77
86d
76
87
87
80
80
81
73
79
82 : 18
85 : 15
84 : 16
84 : 16
89 : 11
64 : 36
—
68 : 32
84 : 16
65 : 35
—
n-Pr
4c
5
Me
Me
Me
Me
Bu
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
i-Pr
Ph
Et
H
Et
Et
CH2Cl
H
Et
H
H
H
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
n-Pr
i-Pr
Ph
Et
Bu
Me
Me
Me
Me
Me
Me
—
—
—
—
Et
Et
CH2Cl
3m
3n
Ph
—
a Carried out in CH2Cl2 at −78 ◦C (entries 1–10) and at 0–5 ◦C (entries 11–16). Molar ratio 2–ketone or aldehyde–TiCl4–Et3N = 1 : 1.2 : 1.2 : 1.4 (entries
1–10) and 2–ketone or aldehyde–TiCl4–Et3N = 1 : 1.2 : 1.5 : 2.0 (entries 11–16). b Determined by 1H NMR of the crude product. c Use of Bu3N instead
of Et3N. d Yield based on its TMS ether.
CH3CH2CO2CH3, supported by careful cross-over experiments.5a
Unfortunately, the carbonyl acceptor was limited to aldehydes
Table 2 Ti-direct aldol-type addition of 2-chloro and 2-mesyloxy-
propanoates to aldehydes and ketonesa
lacking a-protons, that is, an undesirable side self-aldol addition
predominated between two aldehydes such as i-PrCHO, which has
a-protons.
To overcome the problem, we planned to use slightly acidic
phenyl esters 2, because of the higher acidity of phenyl esters
than that of alkyl esters.8 Phenyl esters are readily prepared by
several methods and are easily hydrolyzed under milder conditions
compared with alkyl esters.9
Entry
X
R1
R2 Product
Yield (%)
Drb,c
1
2
3
4
5
6
Cl
Cl
Cl
Cl
OMs
OMs
Ph
i-Pr
Et
Ph
Ph
Et
H
H
5a
5b
88
86
69
75
89
60
(70 : 30)
(74 : 26)
—
(74 : 26)
(89 : 11)
—
Et 5c
Et 5d
H
Et
5e
5f
(B) Ti-direct aldol-type addition of phenyl ester to aldehydes and
ketones
a Carried out in CH2Cl2 at 0–5 ◦C (entries 1–4) and at −78 ◦C (entries
5, 6). Molar ratio 4–ketone or aldehyde–TiCl4–Et3N = 1 : 1.2 : 1.2 :
1
1.4. b Determined by H NMR of the crude product. c Syn/anti was not
The aldol-type reaction of phenyl esters 2 with various aldehydes
or ketones utilizing TiCl4–Et3N was examined. Table 1 lists the
successful results. The salient features are as follows. (i) Because
of the specific character of titanium enolate,10 the present method
is powerful enough to conduct the addition not only to aldehydes
but also to less reactive ketones, giving the desired b-hydroxy esters
3. (ii) Et3N is somewhat superior to Bu3N with regard to yield
(entries 1–4) in contrast to the Ti-crossed aldol additions6b between
two different ketones.11 (iii) Moderate to good syn-selectivity was
obtained. (iv) This method is applicable to the reaction of less
reactive phenyl 2-methylpropanoate under practical temperatures
(0–5 ◦C) (entries 11–16).
assigned.
Note that the reaction using CH3ClCHCO2CH3 instead of
the corresponding phenyl esters 4 resulted in oxidative self-
coupling addition at the a-carbon to give dimeric product 6
(Scheme 2), as described by the Kise, Matsumura, and Periasamy
groups.13 Accordingly, from the synthetic view, especially for aldol
chemistry, the use of phenyl esters has an advantage over that of
methyl esters.
Encouraged by this result, we next investigated the aldol-
type addition of readily available phenyl 2-chloro and 2-
mesyloxypropanoates (4; CH3XCHCO2Ph, X = Cl, OMs) with
aldehydes or ketones. Table 2 lists the successful results. a-
Halogenated esters are labile under basic conditions and generally
undergo further Darzens-type reactions to form a,b-epoxyesters.12
Scheme 2 Ti-promoted oxidative coupling of methyl 2-chloropropanoate.
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Table 3 Ti-direct aldol-type addition of phenylthio esters 7 to aldehydes and ketonesa
Entry
R1
R2
H
R3
Ph
R4
H
Product
Yield (%)
Syn–antib
1
2c
3
4
5
6
6
7
8
Me
8a
8a
8b
8c
8d
8e
8f
8g
8h
8i
99
94
98
96
99
77
98
98
78
80
76
97
86
86 : 14
86 : 14
82 : 18
81 : 19
83 : 17
—
77 : 23
77 : 23
—
Me
Me
Me
Me
Me
Bu
H
H
H
H
H
H
H
Me
Me
Cl
Cl
n-Pr
i-Pr
CH2CH2Ph
Et
Ph
Ph
Et
Ph
n-Pr
Ph
H
H
H
Et
Et
H
Et
H
H
H
H
Bu
9
Me
Me
Me
Me
—
—
10
11
12
8j
8k
8l
(70 : 30)d
(80 : 20)d
n-Pr
a Carried out in CH2Cl2 at −78 ◦C (entries 1–8) and at 0–5 ◦C (entries 9–12). Molar ratio 7–aldehyde (ketone)–TiCl4–Bu3N = 1 : 1.2 (1.5) : 1.2 : 1.4.
b Determined by 1H NMR of the crude product. c Use of Et3N instead of Bu3N. d Syn/anti was not assigned.
Table 4 Ti-direct aldol-type addition of arylthio esters 9 to aldehydes and
(C) Ti-direct aldol-type addition of phenylthio esters to aldehydes
and ketones
ketones using TiCl4–Bu3Na
The use of phenylthio esters 7 instead of phenyl esters 2 has a no-
table advantage, because of inherently feasible enolate formation.14
Table 3 lists the successful results. As anticipated, Ti-enolates
of 7 were smoothly generated because of the higher acidity of
the a-proton of 7 than that of 2. The salient features are as
follows. (i) With the exception of only a few cases, these reactions
proceeded smoothly in excellent yields to afford the desired b-
hydroxyl thioesters 8. (ii) In contrast to the case using phenyl
esters 2, Bu3N was slightly superior to Et3N with regard to yield
(entries 1, 2). (iii) a,a-Disubstituted phenylthio esters successfully
underwent the reaction at 0–5 ◦C (entries 9–12).
The substituent effect was investigated to improve the yield
and stereoselectivity. Table 4 lists the results. Among the aryl
thioesters screened, 4-nitrophenyl propanethioate 9 produced
better results than phenylthio ester 8a with PhCHO regarding
the syn-selectivity (entry 7). The use of n-PrCHO, i-PrCHO, and
PhCOEt as electrophiles, however, did not notably improve the
results (entries 9–12).
Entry
Ar
R1
Ph
R2
H
Product Yield (%)
Syn–antib
1
2
3
4
5
6
7
8
9
Ph
8a
99
95
99
92
95
96
99
97
92
90
86 : 14
80 : 20
82 : 18
90 : 10
86 : 14
86 : 14
94 : 6
74 : 26
67 : 33
79 : 21
(4-OMe)Ph
(4-t-Bu)Ph
(2-Cl)Ph
(3-Cl)Ph
(4-Cl)Ph
(4-NO2)Ph
10a
10b
10c
10d
10e
10f
10g
10h
10i
n-Pr
i-Pr
Ph
H
H
Et
10
a Carried out in CH2Cl2 at −78 ◦C. Molar ratio 9–aldehyde (ketone)–
TiCl4–Bu3N = 1 : 1.2 (1.5) : 1.2 : 1.4. b Determined by H NMR of the
1
crude product.
(D) Synthesis of lactone [2(5H)-furanone] analogs for three
jasmone perfumes
The present Ti-direct aldol-type addition was successfully applied
to the synthesis of three lactone [2(5H)-furanone] analogs 11–
13 of jasmone, which is a typical jasmine perfume (Fig. 1).
Lactone analog 12 of cis-jasmone is a particularly promising
candidate for the synthetic isoster. The Givordan group reported
the synthesis of lactone analog 11 of dihydrojasmone utilizing the
Reformatsky reaction as the key step.15 This method, however, is
difficult to apply for the synthesis of 12 bearing a double bond in
R. Our interest in the practical short synthesis of useful natural
perfumes such as cis-jasmone and (R)-muscone,5h (Z)-civetone,5d,f
(R)-mintlactone and (R)-menthofuran,6c utilizing Ti-mediated
Fig. 1 Three lactone analogs 11–13 of jasmone perfume.
C–C bond forming reactions led us to investigate the general
synthesis for lactone analogs 11–13.
The synthesis of dihydrojasmone lactone analog 11 is shown
in Scheme 3. Ti-direct aldol-type addition of phenyl heptanoate
with commercially available 1-acetoxy-2-propanone proceeded
smoothly to give aldol adduct 14 in 72% yield. The final step
was performed through a convenient one-pot deprotection and
intramolecular cyclization with dehydration to give 11 in 70%
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Table 5 Results of odour evaluations of the synthetic compounds
Compounds
Odour description
Floral, green, jasmine,
spicy, fruity
Floral, green, fruity, fatty,
lactonic
Scheme 3 Synthesis of dihydrojasmone lactone analog 11. Reagents and
conditions: (i) 1.0 M aq KOH, MeOH–THF = 2 : 1, then 1.0 M HCl,
20–25 ◦C (70%).
yield. The total yield was increased compared with the reported
method15 utilizing the Reformatsky reaction (34–40% → 50%).
Scheme 4 shows the synthesis of 12 and 13. Readily available
cis- and trans-2-pentenols (Aoba alcohol analog) 15 and 16 were
converted to mesylates 17 and 18, respectively, using either a
conventional method (CH3SO2Cl–Et3N) or an alternative safe
and practical sulfonylation for allylic alcohols (CH3SO2Cl–Et3N–
Me3N·HCl).16 Alkylation using dimethyl malonate with 17 and
18 gave 19 and 20, which were subjected to hydrolysis and
decarboxylation to give acids 21 and 22, respectively. Acids 21
and 22 were converted to phenyl esters 23 and 24, by conventional
esterification.17 The key direct Ti-aldol-type addition of 23 and
24 with AcOCH2COCH3 gave adducts 25 (83%) and 26 (70%),
respectively. In a similar one-pot procedure, novel cis- and
trans-lactone analogs 12 (67%) and 13 (65%) was successfully
synthesized.
Floral, green, tuberose,
fruity, tabac, lactonic
Floral, green, fruity,
jasmine, lactonic
property. The present method will provide a new avenue for the
aldol-type reaction using esters to obtain a variety of b-hydroxy
esters and lactones [2(5H)-furanones].
The perfume properties of the lactone analogs 11, 12, and 13
were evaluated by the Takasago International Corporation. The
results are listed in Table 5. Note that the perfume of 12 showed a
unique property for men’s fragrance (tabac).
Experimental
In conclusion, we achieved a simple and efficient Ti-direct aldol-
type addition of phenyl and thiophenyl esters with aldehydes and
ketones. Application of the present method for synthesizing three
lactone analogs 11, 12, and 13 was performed. Evaluation of these
analogs revealed that cis-jasmone analog 12 has a notable perfume
Melting points were determined on a hot stage microscope
apparatus (Yanagimoto) and were uncorrected. NMR spectra
were recorded on a JEOL DELTA 300 spectrometer, operating at
300 MHz for 1H NMR and 75 MHz for 13C NMR. Chemical shifts
(d ppm) in CDCl3 were reported downfield from TMS (=0) for 1H
Scheme 4 Synthesis of cis- and trans-jasmone lactone analogs 12 and 13. Reagents and conditions: (i) MsCl, Et3N, Et2O, 0–5 ◦C or MsCl, Et3N–cat.
Me3N·HCl, toluene, 0–5 ◦C. (ii) Dimethyl malonate, NaH, DMF, 20–25 ◦C. (iii) 5 M KOH aq, MeOH–THF = 2 : 1, reflux. (iv) Heat at ca. 150 ◦C.
(v) SOCl2, cat. DMF, hexane, reflux. (vi) PhOH, Et3N, MeCN, 0–5 ◦C. (vii) TiCl4, Et3N, CH2Cl2, then AcOCH2COCH3, −78 ◦C. (viii) 1.0 M aq KOH,
MeOH–THF = 2 : 1, then 1.0 M aq HCl, 20–25 ◦C.
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NMR. For 13C NMR, chemical shifts were reported on a scale
relative to CDCl3 (77.00 ppm) as an internal reference. IR spectra
were recorded on a JASCO FT/IR-5300 spectrophotometer.
Data of known and new compounds 1a,18 1b,19 3a,20 3b,20 3c,20
3h, 3i,22 3k, 3m, 5d, 8a,23 8b,24 8c,23 8d,23 8f, 8h, 8i,25 8l, 10a, 10b,
10c, 10d, 10e, 10f, 10g, 10h, 10i, 11,15 20,25 22, 24, 19, 2125 and 23
are described in the electronic supporting information.†
0.96 (3H, t, J = 7.6 Hz), 1.35 (3H, d, J = 7.2 Hz), 1.45–1.58 (1H,
m), 1.59–1.75 (3H, m), 2.56 (1H br s), 2.85 (1H, q, J = 7.2 Hz),
7.04–7.12 (2H, m), 7.21–7.29 (1H, m), 7.34–7.44 (2H, m); 13C
NMR (75 MHz, CDCl3) d 7.59, 7.78, 11.91, 26.63, 29.75, 45.20,
74.99, 121.42, 126.10, 129.49, 150.25, 175.80; IR (neat) 3532, 2973,
1736, 1493, 1458, 1194, 1165 cm−1. Anal. Calcd for C14H20O3: C,
71.16; H, 8.53, found: C, 70.9; H, 8.2%.
Phenyl 4-chloro-2-methyl-3-phenyl-3-trimethylsiloxybutanoate
(3f). Because the aldol adduct between phenyl 2-chloropro-
panoate and phenacyl chloride was relatively unstable, the yield
and diastereoselectivity were based on its TMS-ether. This TMS-
ether was obtained by nearly neutral trimethylsilylation using
BSA–PyH+·OTf−.21 BSA (494 lL, 2.0 mmol) was added to a
stirred solution of the obtained crude aldol adduct (334 mg)
and PyH+·OTf− (69 mg, 0.3 mmol) in THF (2.0 mL) at 20–
25 ◦C followed by being stirred at the same temp. for 12 h.
Water was added to the mixture, which was extracted twice with
Et2O. The combined organic phase was washed water, brine,
dried (Na2SO4) and concentrated. The obtained crude product
was purified by SiO2-column chromatography to give the desired
product 3f (323 mg, 86%, syn–anti = 68 : 32).
Ti-direct aldol-type addition of methyl propanoate to PhCHO or
t-BuCHO (Scheme 1)
Bu3N (475 lL, 2.0 mmol) and TiCl4 (165 lL, 1.5 mmol) were
successively added to a stirred solution of methyl propanoate
(88 mg, 1.0 mmol) and an aldehyde (PhCHO; 127 mg or t-BuCHO;
103 mg, 1.2 mmol) in CH2Cl2 (2.0 mL) at 0–5 ◦C under an Ar
atmosphere, followed by being stirred at the same temp. for 2 h. The
mixture was poured into ice water, which was extracted twice with
Et2O. The combined organic phase was washed with water, brine,
dried (Na2SO4) and concentrated. The obtained crude product
was purified by SiO2-column chromatography to give the desired
b-hydroxy ester 1a (146 mg, 75%, syn–anti = 65 : 35) or 1b (143 mg,
82%, syn–anti = 81 : 19).
syn- and anti-Mixture; colorless oil; 1H NMR (300 MHz,
CDCl3) d 0.18 (anti, 9H × 1/3, s), 0.22 (syn, 9H × 2/3, s), 1.13
(syn, 3H × 2/3, d, J = 7.2 Hz), 1.18 (anti, 3H × 1/3, d, J = 7.2 Hz),
3.17 (syn, 1H × 2/3, q, J = 7.2 Hz), 3.30 (anti, 1H × 1/3, q, J =
7.2 Hz), 4.10 (syn, 1H × 2/3, d, Jgem = 12.0 Hz), 4.13 (anti, 1H ×
1/3, d, Jgem = 12.0 Hz), 4.26 (syn, 1H × 2/3, d, Jgem = 12.0 Hz),
4.35 (anti, 1H × 1/3, d, Jgem = 12.0 Hz), 6.80–6.96 (2H, m), 7.09–
7.53 (8H, m); 13C NMR (75 MHz, CDCl3) d 2.33, 12.37, 12.87,
49.92, 50.56, 50.61, 50.92, 81.19, 81.40, 121.34, 125.70, 125.80,
126.16, 126.66, 127.44, 127.65, 127.86, 127.96, 129.28, 129.37,
141.32, 142.15, 150.43, 150.46, 171.77, 171.86; IR (neat) 2957,
1759, 1493, 1252, 1192, 1161, 1084, 845 cm−1. Anal. Calcd for
C17H17ClO3: C, 67.00; H, 5.62, found: C, 66.7; H, 5.5%.
General procedure of Ti-direct aldol-type addition of
a-monoalkylated phenyl esters to aldehydes or ketones (Table 1,
entries 1–10)
TiCl4 (132 lL, 1.2 mmol) and Et3N (142 mg, 1.4 mmol) in
CH2Cl2 (0.5 mL) were successively added to a stirred solution
of a phenyl ester (1.0 mmol) in CH2Cl2 (1.5 mL) at −78 ◦C under
an Ar atmosphere. After stirring at the same temp. for 30 min,
an aldehyde or a ketone (1.2 mmol) was added to the mixture,
followed by being stirred at the same temp. for 2 h. The mixture
was poured into ice water (reverse quench), which was extracted
twice with Et2O. The combined organic phase was washed with
water, brine, dried (Na2SO4) and concentrated. The obtained crude
product was purified by SiO2-column chromatography to give
desired b-hydroxy phenyl esters 3a–3h.
Phenyl
2-butyl-3-hydroxy-3-phenylpropanoate
(3g). syn-
Isomer; yellow crystals; mp 44–46 ◦C; 1H NMR (300 MHz,
CDCl3) d 0.91 (3H, t, J = 6.9 Hz), 1.22–1.53 (4H, m), 1.86–1.93
(2H, m), 2.49 (1H, br s), 2.98 (1H, q, J = 6.9 Hz), 4.98 (1H, d,
J = 6.9 Hz), 6.69–6.77 (2H, m), 7.13–7.47 (8H, m); 13C NMR
(75 MHz, CDCl3) d 13.92, 22.60, 27.99, 29.77, 53.56, 74.93,
121.40, 125.89, 126.58, 128.13, 128.51, 129.33, 141.61, 150.27,
173.14; IR (KBr) 3426, 2955, 1748, 1493, 1356, 1190, 1144, 1042,
760, 702 cm−1. Anal. Calcd for C19H22O3: C, 76.48; H, 7.43, found:
C, 76.5; H, 7.2%.
Phenyl 2-methyl-3-hydroxy-3-phenyl-pentanoate (3d). syn-
◦
1
Isomer; colorless crystals; mp 77–78 C; H NMR (300 MHz,
CDCl3) d 0.73 (3H, t, J = 7.2 Hz), 1.11 (3H, d, J = 7.2 Hz), 1.93
(1H, dq, J = 7.2 Hz, Jgem = 13.8 Hz), 2.07 (1H, dq, J = 7.2 Hz,
Jgem = 13.8 Hz), 3.12 (1H, q, J = 7.2 Hz), 3.46 (1H, br s), 7.05–
7.13 (2H, m), 7.22–7.30 (2H, m), 7.32–7.48 (6H, m); 13C NMR
(75 MHz, CDCl3) d 7.86, 12.83, 34.46, 49.12, 77.42, 121.40, 125.57,
126.20, 126.60, 128.07, 129.51, 142.26, 150.20, 176.09; IR (KBr)
3555, 1728, 1493, 1190, 1167, 1136, 1111, 1074, 750, 700 cm−1.
anti-Isomer; colorless crystals; mp 74–75 ◦C; 1H NMR
(300 MHz, CDCl3) d 0.70 (3H, t, J = 7.2 Hz), 1.51 (3H, d, J =
7.2 Hz), 1.73 (1H, dq, J = 7.2 Hz, Jgem = 13.8 Hz), 2.02 (1H,
dq, J = 7.2 Hz, Jgem = 13.8 Hz), 3.32 (1H, q, J = 7.2 Hz), 3.74
(1H, br s), 6.42–6.53 (2H, m), 7.07–7.16 (1H, m), 7.18–7.32 (3H,
m), 7.33–7.42 (2H, m), 7.45–7.53 (2H, m); 13C NMR (75 MHz,
CDCl3) d 7.53, 11.99, 31.59, 47.92, 77.19, 121.17, 125.72, 125.99,
126.89, 128.09, 129.28, 145.00, 149.85, 175.74; IR (KBr) 3532,
2973, 1725, 1352, 1192, 1154, 1098, 959, 764, 704 cm−1. Anal.
Calcd for C18H20O3: C, 76.03; H, 7.09, found: C, 75.8; H, 6.8%.
General procedure of Ti-direct aldol-type addition of
a,a-dimethylated phenyl esters to aldehydes or ketones (Table 1,
entries 11–16)
TiCl4 (165 lL, 1.5 mmol) was added to a stirred solution of
a,a-disubstituted phenyl esters (1.0 mmol) and Et3N (202 mg,
2.0 mmol) in CH2Cl2 (1.5 mL) at 0–5 ◦C under an Ar atmosphere.
After stirring at the same temp. for 30 min, an aldehyde or
ketone (1.2 mmol) was added to the mixture, followed by being
stirred at 0–5 ◦C for 2 h. The mixture was poured into ice
water, which was extracted twice with Et2O. The combined
organic phase was washed with water, brine, dried (Na2SO4)
and concentrated. The obtained crude product was purified by
Phenyl 3-ethyl-3-hydroxy-2-methylpentanoate (3e). Pale yel-
low oil; 1H NMR (300 MHz, CDCl3) d 0.89 (3H, t, J = 7.6 Hz),
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SiO2-column chromatography to give desired b-hydroxy phenyl
esters 3i–3n.
(1H, m), 2.22 (1H, br s), 3.96 (1H, d, J = 4.8 Hz), 7.07–7.16 (2H,
m), 7.22–7.30 (1H, m), 7.35–7.46 (2H, m); 13C NMR (75 MHz,
CDCl3) d 17.74, 21.66, 24.68, 30.82, 71.82, 79.96, 121.04, 126.33,
129.56, 150.44, 169.78; IR (neat) 3532, 2965, 1752, 1593, 1493,
1238, 1194, 750 cm−1.
Phenyl 3-hydroxy-2,2-dimethylhexanoate (3j). Pale yellow oil;
1H NMR (300 MHz, CDCl3) d 0.97 (3H, t, J = 7.2 Hz), 1.31–1.73
(4H, m), 1.33 (3H, s), 1.35 (3H, s), 3.79 (1H, dd, J = 2.4, 10.0 Hz),
7.02–7.08 (2H, m), 7.20–7.27 (1H, m), 7.34–7.42 (2H, m); 13C
NMR (75 MHz, CDCl3) d 14.01, 19.82, 20.34, 22.01, 33.96, 47.59,
76.37, 121.46, 125.85, 129.43, 150.71, 176.32; IR (neat) 3526, 2961,
1744, 1595, 1493, 1196, 1109 cm−1. Anal. Calcd for C14H20O3: C,
71.16; H, 8.53, found: C, 70.9; H, 8.4%.
Minor product; colorless crystals; mp 40–41 ◦C; 1H NMR
(300 MHz, CDCl3) d 1.05 (3H d, J = 6.9 Hz), 1.10 (3H, d, J =
6.9 Hz), 1.87 (3H, s), 1.89–2.01 (1H, m), 2.43 (1H br s), 4.02 (1H,
d, J = 5.9 Hz), 7.09–7.16 (2H, m), 7.23–7.31 (1H, m), 7.37–7.46
(2H, m); 13C NMR (75 MHz, CDCl3) d 18.62, 20.88, 21.97, 30.76,
74.13, 79.43, 120.98, 126.33, 129.56, 150.44, 169.32; IR (KBr)
3541, 2971, 1745, 1487, 1250, 1194, 1161, 1098, 1046, 752 cm−1.
Anal. Calcd for C13H17ClO3: C, 60.82; H, 6.67, found: C, 60.6; H,
6.64%.
Phenyl 3-hydroxy-2,2-dimethyl-3-phenylpentanoate (3l). Col-
orless oil; 1H NMR (300 MHz, CDCl3) d 0.78 (3H, t, J = 7.2 Hz),
1.31 (3H, s), 1.35 (3H, s), 1.87 (1H, dq, J = 7.2 Hz, Jgem = 14.1 Hz),
2.40 (1H, dq, J = 7.2 Hz, Jgem = 14.1 Hz), 4.06 (1H, br s), 6.90–
6.98 (2H, m), 7.18–7.42 (6H, m), 7.44–7.53 (2H, m); 13C NMR
(75 MHz, CDCl3) d 8.01, 21.80, 21.99, 28.24, 51.00, 80.00, 121.38,
126.08, 126.87, 127.40, 128.02, 129.43, 140.20, 150.37, 177.58; IR
(neat) 3501, 2980, 2940, 1719, 1593, 1493, 1186, 1115, 706 cm−1.
Anal. Calcd for C19H22O3: C, 76.48; H, 7.43, found: C, 76.4; H,
7.4%.
Phenyl 2-chloro-3-ethyl-3-hydroxy-2-methylpentanoate (5c).
1
Pale yellow oil; H NMR (300 MHz, CDCl3) d 1.03 (3H, t, J =
7.6 Hz), 1.04 (3H, t, J = 7.6 Hz), 1.78–1.98 (4H, m), 1.95 (3H,
s), 2.97 (1H, br s), 7.09–7.14 (2H, m), 7.24–7.30 (1H, m), 7.37–
7.45 (2H, m); 13C NMR (75 MHz, CDCl3) d 8.76, 8.95, 24.76,
27.92, 28.16, 76.75, 77.73, 121.11, 126.45, 129.60, 150.41, 170.62;
IR (neat) 3542, 2975, 2946, 1738, 1593, 1491, 1458, 1231, 1090,
756, 727, 689 cm−1. Anal. Calcd for C14H19ClO3: C, 62.10; H, 7.07,
found: C, 61.9; H, 6.8%.
Phenyl 4-chloro-3-hydroxy-2,2-dimethyl-3-phenylbutanoate (3n).
Brown oil; 1H NMR (300 MHz, CDCl3) d 1.32 (3H, s), 1.37 (3H,
s), 3.56 (1H, br s), 4.36 (1H, d, Jgem = 11.7 Hz), 4.51 (1H, d,
Jgem = 11.7 Hz); 13C NMR (75 MHz, CDCl3) d 21.38, 22.71,
50.54, 51.13, 79.29, 121.34, 125.99, 127.16, 127.81, 127.88, 129.41,
139.76, 150.58, 175.09; IR (neat) 3549, 2984, 1736, 1593, 1493,
1190, 1121, 706 cm−1. Anal. Calcd for C18H19ClO3: C, 67.82; H,
6.01, found: C, 67.6; H, 5.8%.
Phenyl
3-hydroxy-2-mesyloxy-2-methyl-3-phenylpropanoate
(5e). Diastereomixture; brown crystals; mp 78–80 ◦C; 1H NMR
(300 MHz, CDCl3) d 1.87 (3H × 1/9, s), 1.90 (3H × 8/9, s), 2.92
(1H br s), 3.13 (3H × 1/9, s), 3.19 (3H × 8/9, s), 5.13 (1H ×
1/9, s), 5.16 (1H × 8/9, s), 6.92–6.99 (2H, m), 7.20–7.28 (1H,
m), 7.32–7.47 (7H, m); 13C NMR (75 MHz, CDCl3) d 17.76,
40.80, 78.22, 91.57, 121.17, 126.43, 127.77, 128.46, 129.09, 129.51,
136.03, 150.08, 168.46; IR (KBr) 3555, 1752, 1348, 1265, 1181,
1113, 1094, 1055, 918, 725 cm−1. Anal. Calcd for C17H18O6S: C,
58.27; H, 5.18, found: C, 58.1; H, 5.2%.
General procedure of Ti-direct aldol-type addition of a-chloro or
a-mesyloxy phenyl esters to aldehydes or ketones (Table 2)
TiCl4 (132 lL, 1.2 mmol) and Et3N (142 mg, 1.4 mmol) in CH2Cl2
(0.5 mL) were successively added to a stirred solution of a-chloro
or a-mesyloxy phenyl esters (1.0 mmol) in CH2Cl2 (1.5 mL) at
0–5 ◦C (entries 1–4) or −78 ◦C (entries 5 and 6) under an Ar
atmosphere. After stirring at the same temp. for 30 min, an
aldehyde or ketone (1.2 mmol) was added to the mixture, followed
by being stirred at the same temp. for 2 h. The mixture was poured
into ice water, which was extracted twice with Et2O. The combined
organic phase was washed with water, brine, dried (Na2SO4) and
concentrated. The obtained crude product was purified by SiO2-
column chromatography to give desired b-hydroxy phenyl esters
5a–5f.
Phenyl 3-ethyl-3-hydroxy-2-mesyloxy-2-methylpentanoate (5f).
1
Colorless oil; N NMR (300 MHz, CDCl3) d 1.01 (3H, t, J =
7.6 Hz), 1.02 (3H, t, J = 7.6 Hz), 1.70–1.87 (4H, m), 2.04 (3H,
s), 2.27 (1H br s), 3.15 (3H, s), 7.09–7.18 (2H, m), 7.23–7.31 (1H,
m), 7.36–7.45 (2H, m); 13C NMR (75 MHz, CDCl3) d 8.34, 19.85,
26.86, 26.98, 40.57, 77.75, 93.35, 121.27, 126.47, 129.60, 150.27,
169.26; IR (neat) 3528, 2976, 1757, 1348, 1250, 1192, 1086, 976,
937, 914 cm−1. Anal. Calcd for C15H22O6S: C, 54.53; H, 6.71, found:
C, 54.6; H, 6.8%.
Dimethyl 2,3-dichloro-2,3-dimethylbutanedioate (6). To
a
Phenyl 2-chloro-3-hydroxy-2-methyl-3-phenylpropanoate (5a).
Diastereomixture; pale yellow oil; H NMR (300 MHz, CDCl3)
stirred solution of methyl 2-chloropropanoate (123 mg, 1.0 mmol)
in CH2Cl2 (1.0 mL), TiCl4 (139 lL, 1.2 mmol), Bu3N (259 mg,
1.4 mmol) in CH2Cl2 (0.5 mL), and benzaldehyde (122 lL,
1.2 mmol) were successively added at 0–5 ◦C under an Ar
atmosphere and the mixture was stirred at the same temp. for
2 h. Water was added to the mixture, which was extracted twice
with Et2O. The combined organic phase was washed with water,
brine, dried (Na2SO4) and concentrated. The obtained crude oil
was purified by SiO2-column chromatography to give the desired
product 6 (129 mg, 53%).
1
d 1.76 (3H × 3/10, s), 1.78 (3H × 7/10, s), 2.86 (1H, br s), 5.36
(1H × 7/10, s), 5.37 (1H × 3/10, s), 7.04–7.14 (2H, m), 7.22–7.30
(1H, m), 7.34–7.55 (7H, m); 13C NMR (75 MHz, CDCl3) d 21.68,
22.50, 65.81, 69.49, 73.56, 77.75, 121.06, 121.11, 126.31, 126.37,
127.88, 127.94, 128.17, 128.30, 128.63, 128.82, 129.55, 136.96,
137.29, 150.56, 169.51; IR (neat) 3517, 3065, 3036, 1759, 1593,
1493, 1233, 1192, 910, 739 cm−1. Anal. Calcd for C16H15ClO3: C,
66.10; H, 5.20, found: C, 65.9; H, 4.9%.
Phenyl 2-chloro-3-hydroxy-2,4-dimethylpentanoate (5b). Ma-
jor product; yellow oil; 1H NMR (300 MHz, CDCl3) d 1.06 (3H,
d, J = 6.9 Hz), 1.10 (3H, d, J = 6.9 Hz), 1.93 (3H, s), 2.01–2.15
Diastereomixture; colorless oil; 1H NMR (300 MHz, CDCl3) d
1.99 (3H × 1/2, s), 2.07 (3H × 1/2, s), 3.81 (3H × 1/2, s), 3.83
(3H × 1/2, s); 13C NMR (75 MHz, CDCl3) d 26.11, 26.61, 53.49,
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53.57, 73.31, 73.44, 169.03, 169.12; IR (neat) 3005, 2957, 1744,
1449, 1383, 1258, 1094, 976 cm−1.
702, 687 cm−1. Anal. Calcd for C16H15ClO2S: C, 62.64; H, 4.93,
found: C, 62.4; H, 4.8%.
General procedure of Ti-direct aldol-type addition of arylthio
esters with aldehydes or ketones (Table 4)
General procedure of Ti-direct aldol-type addition of phenylthio
esters to aldehydes or ketones (Table 3)
TiCl4 (132 mL, 1.2 mmol) and Bu3N (259 mg, 1.4 mmol) in
CH2Cl2 (0.5 mL) were successively added to a stirred solution
of arylthio esters (1.0 mmol) in CH2Cl2 (1.5 mL) at −78 ◦C under
an Ar atmosphere. After stirring at the same temp. for 30 min,
an aldehyde (1.2 mmol) or ketone (1.5 mmol) was added to the
mixture, followed by being stirred at the same temp. for 2 h. The
mixture was poured into ice water, which was extracted twice with
Et2O. The combined organic phase was washed with water, brine,
dried (Na2SO4) and concentrated. The obtained crude product
was purified by Si2O-column chromatography to give desired b-
hydroxy arylthio esters 10a–10i.
TiCl4 (132 lL, 1.2 mmol) and Bu3N (259 mg, 1.4 mmol) in
CH2Cl2 (0.5 mL) were successively added to a stirred solution
of phenylthio esters (1.0 mmol) in CH2Cl2 (1.5 mL) at −78 ◦C
(entries 1–8) or 0–5 ◦C (entries 9–12) under an Ar atmosphere.
After stirring at the same temp. for 30 min, an aldehyde (1.2 mmol)
or ketone (1.5 mmol) was added to the mixture, followed by being
stirred at the same temp. for 2 h. The mixture was poured into
ice water, which was extracted twice with Et2O. The combined
organic phase was washed with water, brine, dried (Na2SO4) and
concentrated. The obtained crude product was purified by SiO2-
column chromatography to give desired b-hydroxy phenylthio
esters 8a–8l.
Phenyl 4-acetoxy-3-hydroxy-3-methylheptanoate (14). TiCl4
(396 lL, 3.6 mmol) and Et3N (425 mg, 4.2 mmol) in CH2Cl2
(1.0 mL) were successively added to a stirred solution of phenyl
S-Phenyl 3-ethyl-3-hydroxy-2-methylpentanethioate (8e). Col-
orless crystals; mp 38–40 ◦C; 1H NMR (300 MHz, CDCl3) d 0.84
(3H, t, J = 7.6 Hz), 0.93 (3H, t, J = 7.6 Hz), 1.31 (3H, d, J =
6.9 Hz), 1.36–1.51 (1H, m), 1.54–1.71 (3H, m), 2.88 (1H, q, J =
6.9 Hz), 2.90 (1H, br s), 7.36–7.48 (5H, m); 13C NMR (75 MHz,
CDCl3) d 7.59, 7.90, 12.64, 26.46, 29.71, 53.00, 75.99, 127.21,
129.24, 129.62, 134.34, 204.35; IR (KBr) 3532, 2969, 1680, 1445,
1329, 1132, 953, 901, 747, 687 cm−1. Anal. Calcd for C14H20O2S:
C, 66.63; H, 7.99, found: C, 66.8; H, 8.05%.
◦
heptanoate (619 mg, 3.0 mmol) in CH2Cl2 (10.0 mL) at −78 C
under an Ar atmosphere. After stirring at the same temp. for
30 min, a solution of acetoxy-2-propanone (418 mg, 3.6 mmol)
in CH2Cl2 (1.0 mL) was added to the mixture, followed by being
stirred at the same temp. for 2 h. The mixture was poured into ice
water (reverse quench), which was extracted twice with AcOEt.
The combined organic phase was washed with water, brine, dried
(Na2SO4) and concentrated. Obtained crude product was purified
by SiO2-column chromatography (hexane–AcOEt = 10 : 1) to give
the desired product 14 (701 mg, 72%).
S-Phenyl 2-butyl-3-hydroxy-3-phenylpropanethioate (8g). syn-
1
and anti-Mixture; pale yellow oil; H NMR (300 MHz, CDCl3)
1
Diastereomixture; colorless oil; H NMR (300 MHz, CDCl3)
d 0.86 (3H, t, J = 6.9 Hz), 1.19–1.47 (4H, m), 1.59–1.93 (2H,
m), 2.72 (syn, 1H × 7/9, br s), 2.81 (anti, 1H × 2/9, bt d, J =
5.2 Hz), 2.96 (syn, 1H × 7/9, ddd, J = 3.8, 5.9, 10.0 Hz), 3.00–3.07
(anti, 1H × 2/9, m), 4.83 (anti, 1H × 2/9, dd, J = 5.2, 6.9 Hz),
4.94 (syn, 1H × 7/9, d, J = 5.9 Hz), 7.19–7.42 (10H, m); 13C
NMR (75 MHz, CDCl3) d 13.73, 13.79, 22.49, 22.66, 27.29, 29.10,
29.58, 29.87, 60.71, 61.32, 74.44, 75.72, 126.31, 127.27, 127.46,
127.73, 127.98, 128.26, 128.44, 129.09, 129.43, 134.25, 134.29,
141.27, 141.86, 201.00, 201.54; IR (neat) 3453, 2957, 2930, 2861,
1698, 1024, 924, 747, 702, 691 cm−1. Anal. Calcd for C19H22O2S:
C, 72.57; H, 7.05, found: C, 72.3; H, 7.01%.
d 0.84–0.97 (3H, m), 1.25–1.54 (6H, m), 1.33 (3H × 7/10, s),
1.37 (3H × 3/10, s), 1.57–1.79 (1H, m), 1.80–1.96 (1H, m), 2.10
(3H × 7/10, s), 2.12 (3H × 3/10, s), 2.38 (1H, br s), 2.82 (1H ×
7/10, dd, J = 3.4, 11.7 Hz), 2.83 (1H × 3/10, dd, J = 3.4,
11.7 Hz), 4.09 (1H × 7/10, d, J = 11.4 Hz), 4.10 (1H × 3/10,
d, J = 11.4 Hz), 4.13 (1H × 7/10, d, J = 11.4 Hz), 4.20 (1H ×
3/10, d, J = 11.4 Hz), 7.05–7.12 (2H, m), 7.21–7.29 (1H, m),
7.35–7.43 (2H, m); 13C NMR (75 MHz, CDCl3) d 13.96, 20.84,
21.49, 22.43, 23.25, 27.00, 27.59, 27.67, 31.57, 51.66, 52.62, 68.95,
70.00, 72.39, 72.64, 121.44, 121.48, 126.08, 126.12, 129.49, 150.27,
150.33, 170.81, 173.68; IR (neat) 3495, 2957, 1748, 1493, 1373,
1233, 1196, 1163, 1113, 1044 cm−1. Anal. Calcd for C18H26O5: C,
67.06; H, 8.13, found: C, 66.8; H, 8.0%.
S-Phenyl 3-hydroxy-2,2-dimethylhexanethioate (8j). Pale yel-
low oil; 1H NMR (300 MHz, CDCl3) d 0.94 (3H, t, J = 7.2 Hz),
1.25–1.69 (4H, m), 1.32 (3H, s), 1.34 (3H, s), 2.07 (1H, br s), 3.65–
3.77 (1H, m), 7.34–7.46 (5H, m); 13C NMR (75 MHz, CDCl3)
d 13.96, 19.81, 20.97, 22.45, 33.92, 54.84, 76.89, 127.46, 129.16,
129.35, 134.92, 205.59; IR (neat) 3472, 2961, 1690, 1466, 1441,
959, 928, 747, 689 cm−1. Anal. Calcd for C14H20O2S: C, 66.63; H,
7.99, found: C, 66.5; H, 7.7%.
Phenyl 4-acetoxy-3-hydroxy-3-methyl-2-[(Z)-pent-2-enyl]but-
anoate (25). Following the procedure of aldol-type addition of
phenyl esters to aldehydes or ketones (Table 1, entries 1–10), the
reaction of (Z)-phenyl hept-4-enoate (23; 613 mg, 3.0 mmol) with
acetoxy-2-propanone (418 mg, 3.6 mmol) using TiCl4 (396 lL,
3.6 mmol) and Et3N (425 mg, 4.2 mmol) gave the desired product
25 (798 mg, 83%).
S-Phenyl 2-chloro-3-hydroxy-2-methyl-3-phenylpropanethioate
(8k). Diastereomixture; colorless crystals; mp 81–82 ◦C; 1H
NMR (300 MHz, CDCl3) d 1.63 (3H × 7/10, s), 1.85 (3H × 3/10),
2.93 (1H br s), 5.12 (1H × 3/10, s), 5.17 (1H × 7/10, s), 7.25–
7.47 (10H, m); 13C NMR (75 MHz, CDCl3) d 24.49, 25.99, 77.96,
78.34, 78.95, 80.88, 127.44, 127.75, 127.88, 128.09, 128.19, 128.51,
128.65, 129.26, 129.72, 134.59, 134.65, 137.44, 137.54, 200.07,
200.37; IR (KBr) 3484, 1676, 1441, 1038, 1024, 970, 951, 747,
1
Diastereomixture; yellow oil; H NMR (300 MHz, CDCl3) d
0.97 (3H, t, J = 7.6 Hz), 1.35 (3H × 7/10, s), 1.40 (3H × 3/10, s),
2.03–2.15 (2H, m), 2.09 (3H × 7/10, s), 2.12 (3H × 3/10, s), 2.34–
2.52 (1H, m), 2.63–2.77 (1H, m), 2.82 (1H, br s), 2.87 (1H × 7/10,
dd, J = 4.1, 11.0 Hz), 2.89 (1H × 3/10, dd, J = 4.1, 11.4 Hz), 4.09
(1H × 7/10, d, Jgem = 11.4 Hz), 4.11 (1H × 3/10, d, Jgem = 11.4 Hz),
4.15 (1H × 7/10, d, Jgem = 11.4 Hz), 4.20 (1H × 3/10, d, Jgem
=
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11.4 Hz), 5.34–5.47 (1H, m), 5.50–5.62 (1H, m), 7.01–7.10 (2H,
m), 7.19–7.28 (1H, m), 7.33–7.42 (2H, m); 13C NMR (75 MHz,
CDCl3) d 14.11, 20.55, 20.84, 21.74, 23.27, 24.98, 25.47, 51.51,
52.39, 68.89, 70.04, 72.26, 72.41, 121.51, 124.59, 124.82, 126.08,
129.43, 134.69, 134.78, 150.31, 150.35, 170.73, 173.37; IR (neat)
3491, 2967, 1748, 1493, 1373, 1236, 1194, 1163, 1119, 1046 cm−1.
Anal. Calcd for C18H24O5: C, 67.48; H, 7.55, found: C, 67.2; H,
7.5%.
174.69; IR (neat) 3418, 2973, 1740, 1676, 1443, 1389, 1343, 1188,
1101, 1038 cm−1.
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Scientific Research on Basic Areas (B) “18350056”, Priority
Areas (A) “17035087” and “18037068”, and Exploratory Research
“17655045” from MEXT. We appreciate the Takasago Interna-
tional Corporation for the evaluation of the lactone analogs.
4-Methyl-3-[(Z)-pent-2-enyl]-2(5H)-furanone (12). 1.0 M KOH
aqueous solution (2.5 mL) was added to
a stirred so-
lution of phenyl 4-acetoxy-3-hydroxy-3-methyl-2-[(Z)-pent-2-
enyl]butanoate (25; 320 mg, 1.0 mmol) in MeOH–THF (7.8 mL,
v/v = 2/1) at 20–25 ◦C, and the mixture was stirred at the same
temp. for 10 h. 1.0 M HCl aqueous solution (3.0 mL) was added
to the mixture, followed by being stirred at the same temp. for 2 h.
The mixture was concentrated under reduced pressure, which was
extracted twice with Et2O. The obtained organic phase was washed
with water, brine, dried (Na2SO4), and concentrated. The obtained
crude product was purified by SiO2-column chromatography
(hexane–AcOEt = 8 : 1) to give the desired product 12 (109 mg,
67%).
Pale yellow oil; 1H NMR (300 MHz,CDCl3) d 1.00 (3H, t, J =
7.6 Hz), 2.04 (3H, s), 2.16 (2H, dq, J = 6.9, 7.6 Hz), 3.03 (2H, d,
J = 7.2 Hz), 4.61 (2H, d, J = 1.0 Hz), 5.28–5.39 (1H, m), 5.41–5.52
(1H, m); 13C NMR (75 MHz, CDCl3) d 12.24, 14.03, 20.54, 21.53,
72.43, 123.58, 126.08, 133.41, 156.54, 174.71; IR (neat) 2961, 1740,
1437, 1341, 1231, 1155, 1028, 970 cm−1. Anal. Calcd for C10H14O2:
C, 72.26; H, 8.49; O, 19.25, found: C, 72.1; H, 8.3%.
References
1 (a) C. H. Heathcock, Comprehensive Organic Synthesis, ed. B. M. Trost
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R. Hayashi, H. Sumihara and Y. Tanabe, Tetrahedron Lett., 1997, 38,
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Misaki and Y. Tanabe, Tetrahedron, 2000, 56, 7423; (e) Y. Tanabe,
R. Hamasaki and S. Funakoshi, Chem. Commun., 2001, 1674; (f) Y.
Tanabe, A. Makita, S. Funakoshi, R. Hamasaki and T. Kawakusu,
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T. Misaki, Y. Nishii, M. Sunagawa and A. Sasaki, Adv. Synth. Catal.,
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Phenyl
4-acetoxy-3-hydroxy-3-methyl-2-[(E)-pent-2-enyl]-
butanoate (26). Following the procedure for the preparation
of 24, the reaction of (E)-phenyl hept-4-enoate (24; 613 mg,
3.0 mmol) with acetoxy-2-acetone (418 mg, 3.6 mmol) using TiCl4
(396 lL, 3.6 mmol) and Et3N (425 mg, 4.2 mmol) gave the desired
product 26 (677 mg, 70%).
6 (a) Y. Tanabe, N. Matsumoto, S. Funakoshi and N. Manta, Synlett,
2001, 1959; (b) Y. Tanabe, N. Matsumoto, T. Higashi, T. Misaki, T.
Itoh, M. Yamamoto, K. Mitarai and Y. Nishii, Tetrahedron, 2002, 58,
8269; (c) Y. Tanabe, K. Mitarai, T. Higashi, T. Misaki and Y. Nishii,
Chem. Commun., 2002, 2542.
Diastereomixture; pale yellow oil; 1H NMR (300 MHz, CDCl3)
d 0.99 (3H, t, J = 7.2 Hz), 1.34 (3H × 7/10, s), 1.38 (3H × 3/10, s),
2.05 (2H, quint., J = 7.2 Hz), 2.10 (3H × 7/10, s) 2.13 (3H × 3/10,
s), 2.37–2.61 (2H, m), 2.88 (1H × 7/10, dd, J = 4.5, 11.01 Hz),
2.90 (1H × 3/10, dd, J = 4.8, 9.6 Hz), 3.11 (1H, br s), 4.08 (1H ×
7/10, d, Jgem = 11.4 Hz), 4.10 (1H × 3/10, d, Jgem = 11.4 Hz), 4.14
(1H × 7/10, d, Jgem = 11.4 Hz), 4.19 (1H × 3/10, Jgem = 11.4 Hz),
5.39–5.53 (1H, m), 5.65 (1H, dt, J = 6.2, 15.5 Hz), 6.99–7.11 (2H,
m), 7.19–7.28 (1H, m), 7.32–7.43 (2H, m); 13C NMR (75 MHz,
CDCl3) d 13.57, 20.84, 21.74, 23.14, 25.53, 30.32, 30.86, 51.74,
52.62, 68.95, 70.02, 72.20, 72.35, 121.44, 121.48, 124.80, 125.07,
126.07, 129.43, 135.32, 135.45, 150.29, 170.73, 173.20; IR (neat)
3497, 2965, 1734, 1493, 1373, 1238, 1194, 1163, 1047, 970 cm−1.
7 A part of the preliminary result appeared in ref. 6a.
8
1H NMR shifts (ppm) of a-position of two methyl esters and two phenyl
esters are as follows. Methyl hexanoate (2.30), phenyl hexanoate (2.55),
methyl 2-methyl propanoate (2.56), phenyl 2-methyl propanoate (2.80).
This result indicates higher reactivity of phenyl esters.
9 T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis,
Wiley, New York, 3rd edn, 1999, p. 414.
10 For recent selected works: (a) M. Periasamy, G. Srinivas, G. V.
Karunaker and P. Bharathi, Tetrahedron Lett., 1999, 40, 7577; (b) J. C.
Adrian, J. L. Barkin, R. J. Fox, J. F. Chick, A. D. Hunter and R. A.
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Bull. Chem. Soc. Jpn., 2000, 73, 2579.
11 The use of other amines, i-Pr2NEt (∼30%), pyridine (trace), PhNMe2
(trace), and Ph2NMe (trace) produced disappointing results.
4-Methyl-3-[(E)-pent-2-enyl]-2(5H)-furanone (13). Following
the procedure for the preparation of 12, the reaction of phenyl
4-acetoxy-3-hydroxy-3-methyl-2-[(E)-pent-2-enyl]butanoate (26;
320 mg, 1.0 mmol) gave 4-methyl-3-[(E)-pent-2-enyl]-2(5H)-
furanone (13; 108 mg, 65%).
´
12 (a) Ref. 1b, p. 1230; (b) P. Bako, A. Szo¨llo˜sy, P. Bombicz and L. To˜ke,
Synlett, 1997, 291.
13 (a) N. Kise, K. Tokioka, Y. Aoyama and Y. Matsumura, J. Org. Chem.,
1995, 60, 1100; (b) Y. Matsumura, M. Nishimura, H. Hiu, M. Watanabe
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Terao and N. Ueda, Tetrahedron, 1998, 54, 2697; (d) V. D. Rao and M.
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1
Yellow oil; H NMR (300 MHz, CDCl3) d 0.96 (3H, t, J =
14 For example: (a) S. Tamai, H. Ushiroguchi, S. Sano and Y. Nagao,
Chem. Lett., 1995, 295; (b) J. M. Yost, G. Zhou and D. M. Coltart, Org.
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7.2 Hz), 1.94–2.06 (2H, m), 2.03 (3H, s), 2.97 (2H, d, J = 6.2 Hz),
4.62 (2H, d, J = 1.0 Hz), 5.41 (1H, dtt, J = 1.4, 6.2, 15.1 Hz),
5.55 (1H, dtt, J = 1.4, 6.2, 15.1 Hz); 13C NMR (75 MHz, CDCl3)
d 12.14, 13.46, 25.26, 26.39, 72.37, 123.60, 125.68, 133.96, 157.04,
158 | Org. Biomol. Chem., 2007, 5, 151–159
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17 A direct esterification method using p-TsCl–N-methylimidazole also
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