Direct, practical, and powerful crossed aldol additions between ketones and ketones or aldehydes utilizing environmentally benign TiCl4-Bu3N reagent

Article abstract of DOI:10.1016/S0040-4020(02)00977-8

An efficient TiCl₄-Bu₃N - (cat. TMSCl)-promoted aldol addition between ketones and ketones or aldehydes was performed. This environmentally benign method is advantageous from a green chemical viewpoint with regard to yield, substrate

Full text of DOI:10.1016/S0040-4020(02)00977-8

Tetrahedron 58 (2002) 8269–8280
Direct, practical, and powerful crossed aldol additions between
ketones and ketones or aldehydes utilizing environmentally
benign TiCl4–Bu3N reagent
*
Yoo Tanabe, Noriaki Matsumoto, Takahiro Higashi, Tomonori Misaki, Tomotaka Itoh,
Misako Yamamoto, Kumi Mitarai and Yoshinori Nishii
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen Sanda, Hyogo 669-1337, Japan
Received 9 May 2002; accepted 22 May 2002
Abstract—An efficient TiCl4–Bu3N—(cat. TMSCl)-promoted aldol addition between ketones and ketones or aldehydes was performed.
This environmentally benign method is advantageous from a green chemical viewpoint with regard to yield, substrates variation, reagent
availability, and simple procedures. This method was applied to a short step formal synthesis of (R)-muscone, a natural macrocyclic
musk. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
and powerful Ti-mediated aldol addition of ketones and
esters. We report here the direct and practical methods using
environmentally benign TiCl4 –Bu3N–(cat. TMSCl)
reagent for cross aldol additions between various ketones
and ketones (or aldehydes),5 and its application to the
formal synthesis of (R)-muscone, a representative macro-
cyclic musk ingredient.6
The crossed aldol addition of carbonyl compounds (or
carbonyl equivalents) is one of the most important reactions
in a large variety of organic syntheses due to its broad
utility.1 A number of methods have been explored, which
are generally classified into two categories: (a) carbonyl
substrates are converted to their metal enolates by treatment
with strong basic reagents (e.g. LDA and MHMDS)
followed by the addition of carbonyl acceptors, and (b)
carbonyl substrates are converted to enol silyl ethers, which
react with carbonyl acceptors promoted by Lewis acids or
other catalysts.
The present protocol of Ti-mediated reactions, including a
related aldol-type reaction of esters7 and Ti-(or Zr-)Claisen
condensation,8 demonstrates that the reactivity of C–C
bond formation rivals or surpasses numerous aldol additions
so far reported (Scheme 1). The salient features are as follows.
Ti-mediated aldol additions, originally called the
Mukaiyama and Narasaka aldol reaction, are regarded as
the pioneering and most powerful protocols conducting
cross-coupling between different ketones.2 From the recent
viewpoint of environmentally benign or green chemistry,
however, the indirect use of enol silyl ethers has
disadvantages because the preparation is slightly tedious
and atom-economy is poor. In 1989, we reported a related
direct Ti-Claisen condensation between carboxylic esters.3
Later, Evans and co-workers disclosed direct TiCl4–Et3N
(or i-Pr2NEt)-promoted stereoselective aldol additions
utilizing oxazolidines with aldehydes, which allow for to
its efficient asymmetric synthesis (the Evans’ protocol).4
These findings prompted us to explore a direct, practical,
(1) High reaction velocities and yields.
(2) Higher atom-economy and lower cost than the indirect
methods using enol silyl ethers and ketene silyl acetals.
(3) Use of readily available and very low toxic metal
reagents (e.g. TiCl4, ZrCl4), and use of practical amines
(Et3N, Bu3N) and solvents (toluene or CH2Cl2).
(4) Toleration against basic labile functionalities.
(5) Enhanced reactivity using catalytic TMSCl.
(6) Achievement of the related powerful Ti-(or Zr-)Claisen
condensation.
2. Results and discussion
Initially, we describe a direct crossed aldol reaction between
two different ketones utilizing TiCl4–Bu3N (Table 1). The
salient features of this method are as follows. (a) When
Et3N, i-Pr2NEt, TMEDA, pyridine, and DBU were used for
two reactions (entries 2 and 6), the conversion yields were
Keywords: aldol addition; titanium chloride; tributylamine;
chlorotrimethylsilane; muscone.
*
Corresponding author. Tel.: þ81-975-85-8394; fax: þ-81-975-85-9077;
e-mail: tanabe@kwansei.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00977-8

8270
Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
Scheme 1.
Table 1. Crossed Ti-aldol addition between two different ketones
Entry
1
Ketone
Ketone
Product
Yield (%)a,b
syn–antib,c
86
–
2
3
4
95(60)
86(60)
81(60)
,100:0 (,0:100)
–
–
5
6
7
91
84(45)
92
,100:0
84:16d (13:87)
72:28d
8e
60
82
60:40f
64:36
9
a
In CH2Cl2 at 2788C for 2–3 h unless otherwise noted. Molar ratio/ketone–TiCl4–Bu3N–ketone (acceptor)¼1.0:1.2:1.4:1.2.
Parentheses indicate the reported data using Sn(OTf)2–N-ethylpiperidine.9b
Determined by 1H NMR analyses of the crude products unless otherwise noted.
Determined by isolated yields.
Carried out at 2788C for 2 h and room temperature for 2 h.
syn and anti not assigned.
b
c
d
e
f

Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
Table 2. Crossed Ti-aldol addition between ketones and aldehydes
8271
Entry
1
Ketone
Aldehyde
Product
Yield (%)a,b
syn–antib,c
72
–
2
3
4
PhCHO
72 (71)
96 (74)
95 (80)
,100:0 (.95:5)
,100:0 (86:14)
96:4 (91:9)
5
Hept-CHO
92
92:8
6d
73 (73)
,100:0 (93:7)
7
83
,100:0
8
PhCHO
48 (41)
,100:0 (.95:5)
a
In CH2Cl2 at 2788C for 2–3 h unless otherwise noted. Molar ratio/ketone–TiCl4–Bu3N–aldehyde (acceptor)¼1.0:1.2:1.4:1.2.
Parentheses indicate the reported data using Sn(OTf)2–N-ethylpiperidine.9b
Determined by 1H NMR analyses.
Reported data using TiCl4-amine: i-Pr2NEt (95%, 92:2) and Et3N (73%, 87:13).4c
b
c
d
much lower (,20%) under identical conditions. (b) Among
catalytic TMSCl (0.05 equiv.) was an effective promoter.
Table 3 lists the results using a,a-dimethylketones. The
present method using TMSCl as a co-catalyst produced
higher yields for every example examined, compared with
same method without TMSCl (Method A) and with either
the original Mukaiyama aldol reaction (Method B; TiCl4 is
added into the mixture of enol silyl ethers and aldehydes)2a,b
or its related method (Method C; TiCl4 and aldehydes are
successively added into enol silyl ethers to generate TiCl3-
enolate)10 using enol silyl ethers with aldehydes, both of
which rank as the most powerful aldol addition systems. The
role of the TMSCl co-catalyst in the present system is not
clarified at present. We presume that TMSCl facilitates
enolate generation and/or activates the carbonyl oxygen of
acceptors. Related speculation was reported for the reaction
of enol silyl ether with some electrophiles.11
Lewis acid–amine reagents, Sn(OTf)2–N-ethylpiperidine is
the only agent known to conduct the cross-coupling between
aromatic ketones, but it fails to do so between lower reactive
aliphatic ketones,9 whereas TiCl4–Bu3N promoted the
desired reactions including aliphatic ketones (entries 8 and
9). (c) The yields were higher than those reported using
Sn(OTf)2. (d) In contrast to cases in which Sn(OTf)2 was
used, syn-selectivity was observed in each case. (e) Basic
labile a-chloroacetophenone functioned as an acceptor
(entry 5).
The reaction between ketones and aldehydes was then
examined (Table 2). Two important features are as follows.
(a) The yields were higher than those reported using
Sn(OTf)2.9 (b) Consistent and higher syn-selectivities were
observed, independent of the nature of the acceptors, due to
the rigid Ti-chelated six-membered transition state.
The TiCl4–Bu3N–cat. TMSCl reagent was also applied to
the preparation of important multi-functional a-chlorinated
aldols (Table 4). The salient features are follows. (a) TMSCl
For the reaction of sterically crowded unreactive substrates,

8272
Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
Table 3. Crossed Ti-aldol addition between sterically crowded ketones and aldehydes
Entry
1c
Ketone
Aldehyde or ketone
Product
Time (h)
0.5
Yield (%)a
87d
Yield (%)a (Methodb A, B, C)
(54, 71, 57)
2e
3c
4e
16.5
2.0
2.5
0.5
51
98
45
73
(44, trace, trace)
(81, 46, 75)
PhCHO
(35, trace, trace)
(59, 58, 44)
5c
a
In CH2Cl2 at 0–58C for 2–3 h unless otherwise noted.
(A) TiCl4–Bu3N method without TMSCl. (B) The Mukaiyama Ti-aldol reaction. (C) Related method of the Mukaiyama Ti-aldol reaction.
Molar ratio/ketone–TiCl4–Bu3N–aldehyde (acceptor)¼1.0:1.2:1.4:1.2.
b
c
d
e
In the place of Bu3N; Et3N (64%), i-Pr2NEt (53%), and TMEDA (trace).
Molar ratio/ketone–TiCl4–Bu3N–aldehyde or ketone (acceptor)¼1.0:1.5:2.0:1.2.
had a significant effect on this reaction with aldehydes. (b)
Use of equimolar TMSCl resulted in a somewhat reduced
yield (entry 1). (c) 13C NMR characterization supported the
speculation that TMSCl contributed slightly to the smooth
enolate formation of a-chloroacetophenone.12 The obtained
syn-a-chloroaldols are useful precursors for preparing the
normally non-accessible and thermodynamically unfavor-
able cis-a,b-epoxyketones,13 and are promising candidates
for radical type manuplation through reductive dechlorina-
tion.14
easily prepared by double alkylation of 1,10-dibromodecane
with 2 M amounts of methyl acetoacetate, followed by
hydrolysis and decarboxylation in 46% overall yield.
Radical coupling of 1,9-decadiene with 2 mol acetone is a
practical alternative route to diketone 33.16
The key intramolecular Ti-aldol addition of diketone 33
produced aldol adduct 34 in 52% yield under optimized
conditions (Table 6, entry 3). The salient features are as
follows. (a) Aldol adduct 34 was obtained for the first time,
in contrast to the result when Tsuji’s method was used for
the aldol condensation utilizing i-Bu2Al(OPh)–pyridine
reagent to give isomeric enone mixtures of E-, Z- and b,g-
35:17 the mixtures can be converted into racemic
muscone but are not a substrate for the synthesis of
(R)-muscone (36) (vide infra). (b) The reaction proceeded
with a higher concentration (10–50 mM) compared with
ring closing metathesis (ca. 4 mM), which is the key step of
the recent total synthesis of 36.18 (c) Although the
concentration was lower than the case of the related
intramolecular Ti-Claisen (Dieckmann) condensation of
dimethyl Z-octadecanedioate (100–300 mM), the slightly
smaller amounts of the present reagent were used
(Ti-Dieckmann reaction requires 2.8 equiv. of TiCl4 and
3.0 equiv. of Bu3N). Related 14- and 17-membered aldols
(39 and 40) were prepared from diketones 37 and 38,
respectively (entries 6 and 7).
Next, we investigated the aldol addition of several
a-oxygenated ketones (Table 5). Also in these cases,
TMSCl significantly enhance the yields. A basic labile
compound, phenacyl chloride, functioned as an acceptor
while suppressing a subsequent Darzen’s type reaction.1b
The present powerful Ti-aldol addition was successfully
applied to a formal synthesis of (R)-muscone (36). Practical
synthesis of natural macrocyclic musks, especially muscone
and civetone, is one of the most important topics in perfume
chemistry.15 We recently reported a couple of total
syntheses of civetone utilizing the related Ti-Claisen
condensation.8a,c These works prompted us to investigate
a short step synthesis of (R)-muscone (36) (Scheme 2).
The starting compound, 2,15-hexadecanedione (33), was

Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
Table 4. Crossed Ti-aldol addition between a-chloroketones and aldehydes
8273
Entry
1
Ketone
Aldehyde
syn-Product
Yield (%)a,b
81 (trace)d
syn–antic
PhCHO
89:11
2
3
63d,e
48d,f
91:9
88:12
4
5
6
71 (47)
63 (36)
72 (44)
58 (18)
94:6
92:8 (82:18)
83:17 (70:30)
80:20 (66:34)
PhCHO
7
a
In CH2Cl2 at 2788C for 2–3 h. Molar ratio/a-chloroketone–TiCl4–Bu3N–aldehyde (acceptor)¼1.0:1.2:1.4:1.2.
Parentheses indicate the cases without TMSCl.
Determined by 1H NMR analyses of the crude products.
Yields based on its TMS ethers.
Use of 1.0 equiv. of TMSCl.
Use of 0.05 equiv. of TMSOTf.
b
c
d
e
f
Stereoselective dehydration conditions of aldol 34 were
jasmone.21 As a notable recent application of the present
reagent (TiCl4–Bu3N), the Merck process group demon-
strated a multi-kilogram scale practical synthesis of the anti-
MRSA carbapenem intermediate utilizing the TiCl4–Bu3N
reagent as its key step (Scheme 3).22
screened (Table 7). Standard acid-catalyzed dehydrations
using PTS, H2SO4, CF3CO2H, SO2Cl2–Et3N, and MeSO2-
Cl–Et3N–Me3N·HCl19 afforded 35 in 57–97% with
moderate and consistent stereoselectivity (E–Z¼ca. 3:7)
and produced considerable amounts of undesirable isomer
b,g-35 (entries 1–5). Use of the Al(Oi-Bu)3 caused the
retro-aldol reaction (entry 6). In clear contrast, dehydrations
using Ti(Oi-Pr)4 and Ti(Oi-Bu)4 suppressed the formation
of b,g-35 and exhibited high yields and E-selectivity
(entries 7 and 8). Catalytic amounts (0.1 equiv) of NaSPh
rapidly isomerized the E-rich enone 35 (E–Z¼89:11) into
Z-rich enone 35 (E–Z¼27:73). These equilibrium ratios
indicate that the thermodynamic stability of E-35 and Z-35
are ca. 3:7, respectively. Accordingly, the present Ti(OR)4-
mediated dehydration proceeded in a kinetically controlled
manner.
In conclusion, we achieved an efficient, practical, and
environmentally benign alternative to the TiCl4-mediated
Mukaiyama aldol reaction. Further application to the
practical syntheses of perfumes and b-lactum antibiotics
are under investigation in our laboratory.
3. Experimental
3.1. General
Melting points were determined on a hot-stage microscope
apparatus (Yanagimoto) and are uncorrected. 1H NMR and
13C NMR Spectra were recorded on either JEOL a, Varian
300 or JEOL EX-90 spectrometer using TMS as internal
standard. IR Spectra were recorded on a JASCO FT/IR-
8000 spectrophotometer.
Takasago group documented that the (S)- and (R)-Ru-
BINAP asymmetric hydrogenation of both enones E-35 and
Z-35, respectively, afford R-muscone (36) with ca. 99% high
enantioselectivity.20 Consequently, jointed with this asym-
metric hydrogenation, a formal chiral synthesis of 36
(estimated, 80% ee) was preformed.
3.2. Typical procedure of the crossed aldol addition
between different ketones (Table 1, entry 2)
Finally, we developed the present protocol for the aldol-type
addition using simple phenyl esters7 and its application to a
short step synthesis of the lactone analog of dihydro-
TiCl4 (1 M CH2Cl2; 1.2 ml) and Bu3N (185 mg, 1.4 mmol)

8274
Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
Table 5. Crossed Ti-aldol addition between a-oxygenated ketones and aldehydes
Entry
1
Ketone
Aldehyde or ketone
PhCHO
Product
Yield (%)a,b
86 (68)
2
78 (45)
3
4
78 (23)
PhCHO
PhCHO
89c (66)
5
80 (58)
67d
a
In CH2Cl2 at 2788C for 2–3 h. Molar ratio/a-oxygenated ketone–TiCl4–Bu3N–ketone or aldehyde (acceptor)¼1.0:1.2:1.4:1.2.
b
c
d
Parentheses indicate the cases without TMSCl.
syn–anti¼92:8.
Et3N was used in the place of Bu3N.
Scheme 2.

Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
Table 6. Intramolecular Ti-aldol addition of dimethyl ketones
8275
stirred at 2788C for 2 h. The reaction mixture was quenched
with water and was extracted twice with ether. The organic
phase was washed with water, brine, dried (Na2SO4)
and concentrated. The obtained crude oil was purified by
SiO2-column chromatography (hexane–AcOEt¼9:1) to
give 3-hydroxy-2-methyl-1,3-diphenyl-1-butanone (2;
241 mg, 95%).
Entry Diketone
Equiv.
Concentration
(mM)
Product
Yield
(%)
3.2.1. 3-Hydroxy-1,3-diphenyl-1-pentanone (1). Pale
yellow crystals; mp 48.5–49.08C. IR (KBr): 3478, 2969,
TiCl4 Bu3N
1
2919, 2363, 2342, 1637, 1402, 1387, 1217, 983 cm21. H
NMR (400 MHz, CDCl3): d¼0.80 (3H, t, J¼7.2 Hz), 1.82–
1.97 (2H, m), 3.29 (1H, d, J¼17.6 Hz), 3.83 (1H, d,
J¼17.6 Hz), 7.16–7.58 (8H, m), 7.87–7.90 (2H, m). 13C
NMR (100 MHz, CDCl3): d¼7.75, 36.05, 47.32, 76.01,
124.96, 126.46, 128.01, 128.07, 128.63, 133.63, 137.00,
145.82, 201.69.
1
2
3
4
5
6
7
33 (n¼15) 1.5
3.0
10
10
10
10
50
10
10
34 (n¼15)
40
49
52
38
40
44
51
2.0
3.5
4.0
4.0
4.0
4.0
4.0
2.0
3.0
2.0
37 (n¼14) 2.0
39 (n¼14)
40 (n¼17)
38 (n¼17) 2.0
Table 7. Stereoselective dehydration of cyclic aldol 34
Entry
Reagent
PTS·H2O
Conc. H2SO4
CF3CO2H
SOCl2–Et3N
MsCl–Et3N–Me3N·HCl
Al(Oi-Bu)3
Ti(Oi-Pr)4
Ti(Oi-Bu)4
Equiv.
Temperature (8C)
Total yield (%)
Product ratioa, (E)-(35)–(Z)-35–b,g-35
1
2
3
4
5
6
7
8
0.4
0.4
50
87
76
83
57
97
22:60:18
29:64:7
23:65:12
18:43:39
25:57:18
20–25
20–25
20–25
240
20–25
20–25
20–25
Excess
10.0–10.0
2.0–2.0–0.5
2.0
Trace (retro aldol reaction)
2.0
2.0
85
88
89:11:0
91:9:0
a
Determined by 1H NMR analyses of the crude products.
Scheme 3.
were successively added to a stirred solution of propio-
phenone (134 mg, 1.0 mmol) in CH2Cl2 (2.0 ml) at 2788C
under an Ar atmosphere. After 30 min, acetophenone
(144 mg, 1.2 mmol) was added to the mixture, which was
3.2.2. 3-Hydroxy-2-methyl-1,3-diphenyl-1-butanone (2).
syn-Isomer; colorless oil. IR (neat): 3424, 1657, 1595, 1451,
1393, 1221, 970 cm21 1H NMR (400 MHz, CDCl3):
.
d¼1.01 (3H, d, J¼7.2 Hz), 1.56 (3H, s), 3.86 (1H, q,

8276
Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
J¼7.2 Hz), 4.73–4.85 (1H, br, –OH), 7.25–7.66 (8H, m),
8.02–8.04 (2H, m). 13C NMR (100 MHz, CDCl3): d¼13.73,
29.92, 48.58, 75.26, 124.78, 126.48, 128.03, 128.27, 128.81,
133.78, 136.55, 145.88, 207.75.
J¼7.2 Hz), 7.17–7.35 (5H, m). 13C NMR (100 MHz,
CDCl3): d¼6.95, 7.24, 11.65, 31.54, 37.28, 52.86, 76.66,
125.38, 126.42, 127.99, 145.61, 218.88.
3.2.8. 5-Ethyl-6-hydroxy-6-methyl-4-dodecanone (8).
syn- and anti-Mixture; pale yellow oil. IR (neat): 3505,
2961, 2934, 2874, 2361, 1701, 1458, 1375, 1142, 1040,
918 cm21. 1H NMR (400 MHz, CDCl3): d¼0.86–0.95 (9H,
m), 1.13 (3H, s), 1.19–1.63 (14H, m), 2.40–2.60 (3H, m).
13C NMR (100 MHz, CDCl3): d¼12.69, 12.89, 13.67,
14.06, 16.16, 16.21, 20.63, 21.11, 22.59, 23.64, 23.83,
26.37, 26.75, 29.80, 31.80, 39.45, 42.36, 44.69, 49.32,
49.48, 59.62, 60.06, 73.55, 74.24.
3.2.3. 3-Ethyl-3-hydroxy-2-methyl-1-phenyl-1-penta-
none (3). Colorless oil. IR (neat): 3483, 2959, 2936, 2361,
1
2342, 1665, 1456, 1212, 974 cm21. H NMR (400 MHz,
CDCl3): d¼0.83 (3H, t, J¼7.2 Hz), 0.89 (3H, t, J¼7.2 Hz),
1.25 (3H, d, J¼7.2 Hz), 1.44–1.57 (3H, m), 1.64–1.71 (1H,
m), 3.62 (1H, q, J¼7.2 Hz), 7.48–7.52 (2H, m), 7.60–7.63
(1H, m), 7.48–7.98 (2H, m). 13C NMR (100 MHz, CDCl3):
d¼7.71, 8.00, 12.57, 26.54, 29.86, 43.58, 76.00, 128.27,
128.82, 133.64, 136.82, 208.17.
3.2.9. 2-(1-Hydroxy-1-phenylethyl)cyclopentanone (9).
syn- and anti-Mixture; pale yellow oil. 1H NMR
(300 MHz, CDCl3): d¼1.57–2.00 (5H, m), 1.58 (1.1H, s),
1.73 (1.9H, s), 2.20 (1H, m), 2.48 (1H, m), 7.20–7.49 (5H,
m). 13C NMR (100 MHz, CDCl3): d¼19.97, 23.48, 28. 92,
39.73, 58.28, 75.35, 125.12, 126.67, 128.06, 145.47, 221.72.
3.2.4. 3-Hydroxy-2-methyl-1-phenyl-3-propyl-1-hexa-
none (4). Yellow oil. IR (neat): 3490, 2963, 2874, 1665,
1451, 1346, 1215, 974, 710 cm21 1H NMR (400 MHz,
.
CDCl3): d¼0.78 (3H, t, J¼7.2 Hz), 0.97 (3H, t, J¼7.2 Hz),
1.21–1.63 (8H, m), 1.25 (3H, d, J¼7.2 Hz), 3.58 (1H, q,
J¼7.2 Hz), 7.48–7.63 (3H, m), 7.94–7.96 (2H, m). 13C
NMR (100 MHz, CDCl3): d¼12.63, 14.56, 14.69, 16.67,
17.07, 37.29, 40.59, 44.36, 75.58, 128.25, 128.81, 133.60,
136.80, 208.11.
3.2.10. 3-Hydroxy-4-methyl-1-phenyl-1-pentanone (10).
Yellow oil. IR (neat): 3547, 2955, 2892, 1667, 1480, 1449,
.
1169, 1007, 752 cm21 1H NMR (400 MHz, CDCl3):
d¼1.00 (3H, d, J¼6.8 Hz), 1.02 (3H, d, J¼6.8 Hz), 1.77–
1.84 (1H, m), 2.54–2.77 (1H, br, –OH), 3.05 (1H, d,
J¼17.6 Hz), 3.18 (1H, d, J¼17.6 Hz), 3.98–4.02 (1H, m),
7.46–7.61 (3H, m), 7.96–7.98 (2H, m). 13C NMR
(100 MHz, CDCl3): d¼17.88, 18.52, 33.08, 41.91, 72.35,
128.05, 128.46, 128.64, 133.46, 136.87, 201.35.
3.2.5. 4-Chloro-3-hydroxy-2-methyl-1,3-diphenyl-1-
butanone (5). syn-Isomer; yellow oil. IR (neat) 3447,
1
3063, 2978, 1659, 1451, 1221, 760, 702 cm21. H NMR
(300 MHz; CDCl3): d¼1.09 (3H, d, J¼7.2 Hz), 3.73 (1H, d,
J¼11.1 Hz), 3.88 (1H, d, J¼11.1 Hz), 4.24 (1H, q,
J¼7.2 Hz), 7.28–7.67 (8H, m), 8.02–9.06 (2H, m). 13C
NMR (75 MHz; CDCl3): d¼14.01, 44.40, 52.25, 77.70,
125.42, 127.45, 128.18, 128.52, 128.90, 134.12, 135.91,
141.69, 207.09.
3.2.11. 3-Hydroxy-2-methyl-1,3-diphenyl-1-propanone
(11). syn-Isomer; pale yellow crystals; mp 72.5–73.08C.
IR (KBr): 3526, 1672, 1597, 1580, 1449, 1325, 1221,
1
974 cm21. H NMR (400 MHz, CDCl3): d¼1.21 (3H, d,
3.2.6. 5-Hydroxy-4-methyl-5-phenyl-3-hexanone (6). syn-
Isomer; colorless crystals; mp 45.5–46.08C. IR (neat):
J¼7.6 Hz), 1.39–1.71 (1H, br, –OH), 3.67–3.73 (1H, m),
5.25 (1H, d, J¼3.2 Hz), 7.24–7.61 (8H, m), 7.93–7.97 (2H,
m). 13C NMR (100 MHz, CDCl3): d¼11.13, 46.99, 73.03,
126.00, 127.29, 128.23, 128.45, 128.64, l28.77, 133.58,
135.58, 141.75, 205.78.
3449, 2982, 2938, 1690, 1449, 1393, 1373, 976, 700 cm21
.
1H NMR (400 MHz, CDCl3): d¼0.88 (3H, t, J¼7.2 Hz),
1.09 (3H, d, J¼7.2 Hz), 1.52 (3H, s), 2.48–2.67 (2H, m),
2.99 (1H, q, J¼7.2 Hz), 7.22–7.43 (5H, m). 13C NMR
(100 MHz, CDCl3): d¼7.40, 12.69, 29.60, 37.45, 53.83,
74.89, 124.68, 126.53, 128.06, 145.65, 219.21. anti-Isomer;
colorless oil. IR (neat): 3446, 2980, 2940, 1696, 1449, 1379,
1364, 763 cm21. 1H NMR (400 MHz CDCl3): d¼0.75 (3H,
t, J¼7.2 Hz), 1.27 (3H, d, J¼7.2 Hz), 1.45 (3H, s), 1.89–
1.95 (1H, m), 2.32–2.39 (1H, m), 3.15 (1H, q, J¼7.2 Hz),
7.18–7.39 (5H, m). 13C NMR (100 MHz, CDCl3): d¼6.98,
12.02, 27.00, 37.31, 53.29, 75.03, 124.53, 126.59, 128.15,
148.00, 218.76.
3.2.12. 3-Hydroxy-2-methyl-1-phenyl-1-hexanone (12).
syn-Isomer; yellow oil. IR (neat): 3447, 2961, 2936, 2361,
1
2342, 1672, 1456, 1213, 972 cm21. H NMR (300 MHz;
CDCl3): d¼0.95 (3H, d, J¼7.2 Hz), 1.26 (3H, d, J¼7.2 Hz),
1.33–1.67 (4H, m), 3.47 (1H, dq, J¼3.0, 7.2 Hz), 4.05 (syn;
1H, ddd, J¼3.0, 4.2, 8.4 Hz), 7.46–7.52 (2H, m), 7.57–7.63
(1H, m), 7.94–7.98 (2H, m). 13C NMR (75 MHz; CDCl3):
11.03, 14.02, 19.24, 36.42, 44.47, 71.00, 128.41, 128.73,
133.40, 135.83, 205.93.
3.2.7. 5-Hydroxy-4-methyl-5-phenyl-3-heptanone (7).
syn-Isomer; colorless oil. IR (neat): 3464, 2976, 2940,
3.2.13. 3-Hydroxy-2,4-dimethyl-1-phenyl-1-pentanone
(13). syn-Isomer; colorless oil. IR (neat): 3503, 2963,
1
1
2361, 2342, 1698, 1458, 1377, 1316, 968 cm21. H NMR
1678, 1451, 1215, 972, 710 cm21. H NMR (300 MHz;
(400 MHz, CDCl3): d¼0.64 (3H, t, J¼7.2 Hz), 0.85 (3H, d,
J¼7.6 Hz), 1.10 (3H, t, J¼7.2 Hz), 1.72–1.83 (2H, m),
2.52–2.69 (2H, m), 3.00 (1H, q, J¼7.2 Hz), 7.21–7.53 (5H,
m). 13C NMR (100 MHz, CDCl3): d¼7.37, 7.82, 12.71,
34.19, 37.72, 53.59, 78.09, 125.39, 126.30, 127.94, 128.35,
128.89, 143.07, 219.82. anti-Isomer; colorless oil. 1H NMR
(400 MHz, CDCl3): d¼0.63 (3H, t, J¼7.2 Hz), 0.73 (3H, t,
J¼7.2 Hz), 1.27 (3H, d, J¼7.2 Hz), 1.59–1.68 (1H, m),
1.85–1.98 (2H, m), 2.31–2.41 (1H, m), 3.18 (1H, q,
CDCl3): d¼0.96 (3H, d, J¼6.9 Hz), 1.04 (3H, d, J¼6.6 Hz),
1.25 (3H, d, J¼6.9 Hz), 1.78 (1H, dqq, J¼8.1, 6.6, 6.9 Hz),
3.64 (syn; 1H, dd, J¼2.7, 8.1 Hz), 3.68 (1H, dd, J¼2.7,
6.9 Hz), 7.46–7.52 (2H, m), 7.57–7.63 (1H, m), 7.93–7.99
(2H, m). 13C NMR (75 MHz; CDCl3): 10.72, 19.07, 19.13,
30.69, 41.76, 76.60, 128.40, 128.76, 133.40, 135.84, 205.89.
3.2.14. 5-Hydroxy-4-methyl-3-dodecanone (14). syn-
Isomer; colorless oil. IR (neat): 3455, 2930, 2857, 1703,

Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
8277
1460, 1377, 974 cm21
.
1H NMR (300 MHz; CDCl3):
(20). Pale yellow crystals; mp 76.0–77.08C. IR (KBr-disk):
3491, 2975, 2361, 2342, 1690, 1427, 1389, 1188, 1045,
d¼0.88 (3H, t, J¼6.9 Hz), 1.06 (3H, t, J¼7.2 Hz), 1.13
(3H, d, J¼7.2 Hz), 1.24–1.36 (10H, m), 1.41–1.55 (2H, m),
2.50 (1H, dq, J¼29.1, 7.2 Hz), 2.56 (1H, dq, J¼29.1,
7.2 Hz), 2.58 (1H, dq, J¼3.0, 7.2 Hz), 3.90 (1H, ddd, J¼3.0,
4.5, 8.4 Hz). 13C NMR (75 MHz; CDCl3): d¼7.60, 9.95,
14.05, 22.61, 26.02, 29.22, 29.53, 31.78, 34.01, 35.08,
49.70, 71.13, 216.69.
1
1018 cm21. H NMR (300 MHz; CDCl3): d¼1.04 (3H, s),
1.06 (3H, d, J¼6.9 Hz), 1.08 (3H, d, J¼6.9 Hz), 1.15 (3H,
s), 2.93–3.27 (1H, brs, –OH), 3.06–3.20 (1H, m), 4.95 (1H,
s), 7.22–7.36 (5H, m). 13C NMR (100 MHz; CDCl3):
d¼17.40, 19.75, 19.84, 22.50, 34.96, 52.51, 78.05, 127.42,
127.56, 127.81, 140.08, 221.85.
3.2.15. 5-Hydroxy-4,6-dimethyl-3-heptanone (15). syn-
Isomer; colorless oil. 1H NMR (300 MHz; CDCl3): d¼0.86
(3H, d, J¼6.6 Hz), 1.02 (3H, d, J¼6.6 Hz), 1.06 (3H, t,
J¼7.2 Hz), 1.12 (3H, d, J¼7.2 Hz), 1.66 (1H, dqq, J¼8.5,
6.6, 6.6 Hz), 2.43–2.66 (2H, m), 2.75 (1H, dq, J¼3.0,
7.2 Hz), 3.52 (syn; 1H, dd, J¼3.0, 8.5 Hz). 13C NMR
(75 MHz; CDCl3): 7.64, 9.47, 18.94, 19.06, 30.52, 34.84,
47.06, 76.25, 216.92.
3.2.20. 5-Hydroxy-2,4,4,5-tetramethyl-3-undecanone
(21). Colorless oil. IR (neat) 3484, 2959, 2932, 1686,
1470, 1379, 1231 cm21 1H NMR (400 MHz; CDCl3):
.
d¼0.88 (3H, t, J¼6.8 Hz), 1.05 (3H, d, J¼2.8 Hz), 1.07
(3H, d, J¼2.4 Hz), 1.09 (3H, s), 1.24 (3H, s), 1.25 (3H, s),
1.27–1.41 (10H, m), 3.13–3.20 (1H, m). 13C NMR
(100 MHz; CDCl3): d¼14.02, 19.48, 19.77, 20.62, 20.99,
21.40, 22.59, 23.31, 30.03, 31.89, 35.89, 37.21, 54.37,
76.11, 224.97.
3.2.16. 5-Ethyl-6-hydroxy-4-nonanone (16). syn-Isomer;
colorless oil. IR (neat) 3450, 2936, 2876, 1701, 1462, 1379,
3.2.21. 3-Hydroxy-2,2,4-trimethyl-1-phenyl-1-pentanone
(22). Pale yellow oil. IR (neat): 3490, 2965, 1669, 1470,
1260, 963 cm21. 1H NMR (300 MHz; CDCl3): d¼0.92 (3H,
d, J¼7.0 Hz), 0.97 (3H, d, J¼7.0 Hz), 1.34 (3H, s), 1.41
(3H, s), 1.82–1.97 (1H, m), 2.46–2.74 (1H, brs, –OH), 3.71
(1H, d, J¼4.0 Hz), 7.37–7.49 (3H, m), 7.60–7.65 (2H, m).
13C NMR (75 MHz; CDCl3): d¼17.72, 22.34, 23.12, 24.16,
30.13, 51.59, 82.16, 127.59, 128.05, 130.81, 139.49, 211.89.
1145, 1117, 1009 cm21 1H NMR (300 MHz; CDCl3)
.
d¼0.90 (3H, t, J¼7.5 Hz), 0.93 (6H, t, J¼7.5 Hz), 1.24–
1.40 (2H, m), 1.42–1.54 (2H, m), 1.57–1.82 (4H, m), 2.42
(1H, ddd, J¼7.2, 7.2, 17.7 Hz), 2.51 (1H, ddd, J¼4.2, 4.2,
9.3 Hz), 2.52 (1H, ddd, J¼7.2, 7.2, 17.7 Hz), 3.78 (1H, ddd,
J¼4.2, 4.2, 8.4 Hz). 13H NMR (75 MHz; CDCl3) d¼12.43,
13.70, 13.96, 16.63, 19.27, 19.58, 36.68, 46.57, 57.99,
71.22, 215.81.
3.2.22. 2-Chloro-3-trimetylsiloxy-1,3-diphenyl-1-propa-
none (TMS-ether of 23). Because a-chloroaldol (23)
adduct was relatively unstable, the yield was based on its
TMS-ether, which was obtained by nearly neutral trimethyl-
silylation using TMS-imidazole/catalytic TBAF.23 TiCl4
(1 M CH2Cl2; 1.2 ml) was added to a stirred solution of
phenacyl chloride (1a; 155 mg, 1.0 mmol) in CH2Cl2
(2.0 ml) at 2788C under an Ar atmosphere. TMSCl (6 ml,
0.05 mmol) and Bu3N (259 mg, 1.4 mmol) were succes-
sively added to the mixture, which was stirred for 30 min.
Then, benzaldehyde (127 mg, 1.2 mmol) was added to the
mixture followed by being stirred at 2788C for 2 h. The
mixture was quenched with water (10 ml), extracted twice
with ether. The combined organic phase was washed with
water, brine, dried (Na2SO4) and concentrated. To the
obtained crude oil (282 mg) in DMF (2.0 ml) was added
N-TMS-imidazole (281 mg, 2.0 mmol) and TBAF (1 M
THF; 0.02 ml). The mixture was allowed to stand for 10 min
at room temperature, then, was quenched with water
(10 ml). The combined organic phase was extracted twice
with ether, washed with water, brine, dried (Na2SO4)
and concentrated. The obtained crude oil was purified by
SiO2-column chromatography (hexane–AcOEt¼14:1) to
give 2-chloro-1,3-diphenyl-3-trimethylsiloxy-1-propanone
(268 mg, 81%).
3.2.17. 2-(1-Hydroxy-1-phenylethyl)cyclohexanone
(17).9b Typical procedure of the crossed aldol addition of
a,a-dimethylketones with aldehydes and 2-octanone pro-
moted by TiCl4–Bu3N–cat. TMSCl (Table 3, entry 1):
TiCl4 (1 M CH2Cl2; 1.2 ml), TMSCl (6 ml, 0.05 mmol), and
Bu3N (185 mg, 1.4 mmol) were successively added to a
stirred solution of diisopropyl ketone (114 mg, 1.0 mmol) in
CH2Cl2 (2.0 ml) at 0–58C under an Ar atmosphere. After
30 min, 2-methylpropanal (87 mg, 1.2 mmol) was added to
the mixture, which was stirred at 2788C for 30 min. The
reaction mixture was quenched with water and was
extracted twice with ether. The organic phase was washed
with water, brine, dried (Na2SO4) and concentrated. The
obtained crude oil was purified by SiO2-column chroma-
tography (hexane–AcOEt¼6:1) to give 5-hydroxy-2,4,4,6-
tetramethyl-3-heptanone (18; 241 mg, 87%). colorless oil.
IR (neat): 3526, 3506, 2971, 2361, 2340, 1698, 1472, 1385,
1015, 995 cm21. 1H NMR (400 MHz; CDCl3): d¼0.84 (3H,
d, J¼6.4 Hz), 0.99 (3H, d, J¼6.4 Hz), 1.06 (3H, d,
J¼5.6 Hz), 1.08 (3H, d, J¼5.6 Hz), 1.23 (6H, s), 1.79–
1.87 (1H, m), 2.95–3.06 (1H, brs, –OH), 3.07–3.17 (1H,
m), 3.49 (1H, d, J¼3.2 Hz). 13C NMR (100 MHz; CDCl3):
d¼17.18, 19.89, 20.19, 20.56, 22.55, 23.46, 29.67, 35.53,
51.63, 81.59, 222.74.
3.2.18. 5-Hydroxy-2,4,4,6,6-pentamethyl-3-octanone
(19). Orange crystals; mp 36.5–37.58C. 1H NMR
(400 MHz; CDCl3): d¼0.97 (9H, s), 1.06 (3H, d,
J¼5.8 Hz), 1.08 (3H, d, J¼5.8 Hz), 1.28 (3H, s), 1.30
(3H, s), 2.72–2.88 (1H, brs, –OH), 3.10–3.20 (1H, m), 3.58
(1H, s). 13C NMR (100 MHz; CDCl3): d¼20.25, 20.35,
22.96, 24.00, 28.55, 35.48, 36.92, 52.89, 83.50, 221.67.
syn-Isomer; pale yellow oil. IR (neat): 2361, 2341, 1690,
1
1252, 1100, 889, 843 cm21. H NMR (400 MHz; CDCl3):
d¼0.21 (9H, s), 5.22 (1H, d, J¼8.0 Hz), 5.26 (1H, d,
J¼8.0 Hz), 7.22–7.99 (10H, m). 13C NMR (100 MHz;
CDCl3): d¼0.04, 62.32, 75.54, 127.39, 128.25, 128.28,
128.54, 128.60, 133.56, 135.16, 140.09, 193.56. anti-
Isomer; pale yellow oil. 1H NMR (400 MHz; CDCl3):
d¼20.15 (9H, s), 5.08 (1H, d, J¼9.2 Hz), 5.16 (1H, d,
J¼9.2 Hz), 7.22–7.99 (10H, m).
3.2.19. 5-Hydroxy-2,4,4-trimethyl-5-phenyl-3-pentanone

8278
Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
3.2.23. 2-Chloro-3-hydroxy-1-phenyl-1-hexanone (24).
syn-Isomer; pale yellow oil. IR (neat): 3507, 2961, 2934,
(9H, s), 3.19 (1H, d, J¼16.8 Hz), 3.38 (1H, d, J¼16.8 Hz),
3.68 (1H, d, J¼20.2 Hz), 3.72 (1H, d, J¼20.2 Hz), 4.07 (2H,
s), 7.28–7.30 (1H, m), 7.33–7.37 (2H, m), 7.44–7.46 (2H,
m). 13C NMR (100 MHz; CDCl3): d¼25.65, 25.59, 18.34,
25.86, 44.63, 53.56, 70.34, 75.69, 125.84, 128.55, 129.18,
143.48, 242.71.
1
2363, 1686, 1597, 1451, 1302, 1213, 1078, 910 cm21. H
NMR (90 MHz; CDCl3): d¼0.78–1.14 (3H, t, J¼7.0 Hz),
1.36–1.88 (4H, m), 2.59–2.98 (1H, br, –OH), 4.11–4.38
(1H, m), 5.08 (1H, d, J¼4.3 Hz), 7.38–7.77 (3H, m), 7.91–
8.18 (2H, m). 13C NMR (100 MHz; CDCl3): d¼13.90,
18.86, 35.75, 60.70, 70.73, 128.93, 129.06, 134.26, 135.13,
194.68.
3.2.30. 1-t-(Butyldimethylsiloxy)-4-hydroxy-3-methyl-4-
phenyl-2-butanone (31). syn-Isomer; colorless crystals; mp
31.0–31.58C. IR (KBr): 3432, 2930, 2857, 2361, 1725,
1
3.2.24. 2-Chloro-2,4-dimethyl-3-hydroxy-1-phenyl-1-
pentanone (25). Colorless oil. IR (neat) 3486, 2965, 1678,
1447, 1254, 1020, 976 cm21. 1 H NMR (400 MHz; CDCl3):
d¼1.00 (3H, d, J¼6.8 Hz), 1.02 (3H, d, J¼7.2 Hz), 1.89
(3H, s), 2.02–2.10 (1H, m) 4.08 (1H, d, J¼5.2 Hz), 7.38–
7.48 (2H, m), 7.48–7.52 (1H, m), 7.98–8.01 (2H, m). 13C
NMR (100 MHz; CDCl3): d¼18.19, 22.22, 24.26, 30.48,
75.01, 79.60, 127.92, 129.40, 132.11, 135.73, 199.13.
1456, 1256, 1163, 1005, 837 cm21. H NMR (90 MHz;
CDCl3): d¼0.09 (6H, s), 0.90 (9H, s), 1.09 (3H, d,
J¼9.0 Hz), 3.02–3.28 (1H, m), 4.15 (2H, s), 5.07 (1H, d,
J¼5.0 Hz), 7.21–7.38 (5H, m). 13C NMR (100 MHz;
CDCl3): d¼25.73, 25.65, 10.65, 18.17, 25.64, 48.18,
68.67, 73.29, 125.95, 127.34, 128.18, 141.78, 213.78.
3.2.31. 4-Hydroxy-1,1-dimethoxy-4-phenyl-2-butanone
(32). Yellow oil. IR (neat): 3482, 2938, 2836, 1732, 1454,
.
1198, 1071, 986 cm21 1H NMR (90 MHz; CDCl3):
d¼2.90–3.20 (2H, m), 3.41 (6H, s), 4.47 (1H, s), 5.05–
5.30 (1H, m), 7.27–7.38 (5H, m). 13C NMR (100 MHz;
CDCl3): d¼46.47, 54.85, 69.62, 103.99, 125.70, 127.70,
128.52, 142.85, 205.45.
3.2.25. 4-Chloro-5-hydroxy-1,1-dimethyl-5-phenyl-3-
pentanone (26). Colorless crystals; mp 52.8–54.48C. IR
(KBr): 3320, 2975, 2934, 2361, 1711, 1476, 1456, 1370,
1323, 1211, 1067, 986 cm21. 1H NMR (400 MHz; CDCl3):
d¼0.88 (9H, s), 4.68 (1H, d, J¼7.6 Hz), 5.10 (1H, d,
J¼5.2 Hz), 7.29–7.42 (5H, m). 13C NMR (100 MHz;
CDCl3): d¼25.48, 55.00, 59.47, 74.14, 127.38, 128.43,
134.84, 138.12, 208.90.
3.2.32. 2,15-Hexadecanedione (33). Methyl acetoacetate
(0.92 g, 8.0 mmol) and DBU (1.22 g, 8.0 mmol) were
successively added to a stirred solution of NaI (0.66 g,
4.0 mmol) in DMF (2.0 ml) at room temperature. After
15 min, 1,10-dibromodecane (0.60 g, 2.0 mmol) was added
to the mixture during 30 min, followed by stirring for 2 h.
Water was added to the mixture, which was extracted with
ether. The organic phase was washed with water, brine,
dried (Na2SO4) and concentrated to give crude oil, which
was purified by SiO2-column chromatography (hexane–
AcOEt¼5:1) to give the intermediate (457 mg). This crude
product and 10% NaOH aqueous solution was stirred for
room temperature for 2 h and 608C for 3 h. To this mixture,
20% HCl aqueous solution was added (pH ,1). The mixture
was extracted with AcOEt and the organic phase was
washed with water, brine, dried (Na2SO4) and concentrated.
The obtained crude crystals were recrystallized from EtOH
to give the desired product. colorless crystals; mp 81.2–
3.2.26. 4-Chloro-2,2,6-trimethyl-5-hydroy-3-heptanone
(27). Colorless oil. IR (neat): 3505, 2969, 2936, 2361,
1
1703, 1476, 1370, 1084, 1007 cm21. H NMR (400 MHz;
CDCl3): d¼0.96 (3H, d, J¼6.4 Hz), 1.03 (3H, d, J¼6.4 Hz),
1.25 (9H, s), 1.80–1.88 (1H, m), 3.36–3.42 (1H, br, –OH),
3.54–3.60 (1H, m), 4.75 (1H, d, J¼3.9 Hz). 13C NMR
(100 MHz; CDCl3): d¼17.89, 19.21, 26.52, 30.59, 55.39,
75.90, 211.26.
3.2.27. 4-Hydroxy-2-oxo-4-phenybutyl benzoate (28).
Colorless crystals; mp 115–1188C. IR (KBr): 3482, 3061,
2924, 2897, 1718, 1277, 752, 696 cm21
.
1H NMR
(300 MHz; CDCl3): d¼2.84 (1H, dd, J¼3.3, 16.8 Hz),
2.99 (1H, dd, J¼9.3, 16.8 Hz), 4.92 (2H, s), 5.24 (1H, ddd,
J¼3.3, 3.3, 9.3 Hz), 7.26–7.40 (5H, m), 7.44–7.50 (2H,
m), 7.52–7.63 (1H, m), 8.07–8.11 (2H, m). 13C NMR
(75 MHz; CDCl3): d¼47.93, 68.88, 69.89, 125.59, 127.91,
128.52, 128.66, 129.01, 129.92, 133.54, 142.54, 165.91,
203.84.
1
82.58C. H NMR (300 MHz; CDCl3): d¼1.20–1.32 (16H,
m), 1.50–1.63 (4H, m), 2.13 (6H, s), 2.41 (4H, t, J¼7.4 Hz).
13C NMR (75 MHz; CDCl3): d¼23.87, 29.16, 29.36, 29.42,
29.52, 29.80, 43.80, 209.29.
3.2.28. 1-(1-Hydroxycyclohexyl)-2-oxo-2-phenylethyl
benzoate (29). Colorless crystals; mp 130–1328C. IR
(KBr): 3459, 2930, 2853, 1703, 1684, 1285, 716,
3.2.33. 2,14-Pentadecanedione (37). Colorless crystals; mp
1
77.5–78.58C. H NMR (300 MHz; CDCl3): d¼1.20–1.33
(14H, m), 1.49–1.62 (4H, m), 2.13 (6H, s), 2.41 (4H, t,
J¼7.4 Hz). 13C NMR (75 MHz; CDCl3): d¼23.84, 29.14,
29.34, 29.38, 29.47, 29.79, 43.78, 209.28.
687 cm21
.
1H NMR (300 MHz; CDCl3): d¼1.18–1.28
(1H, m), 1.50–1.67 (8H, m), 1.85–1.90 (1H, m), 6.03
(1H, s), 7.43–7.52 (4H, m), 7.56–7.62 (2H, m), 8.07–8.12
(4H, m). 13C NMR (75 MHz; CDCl3): d¼21.16,
21.25, 25.42, 34.26, 34.68, 72.86, 78.40, 128.47, 128.72,
128.81, 129.13, 129.89, 133.45, 133.60, 137.20, 166.09,
197.72.
3.2.34. 2,17-Octadecanedione (38). Colorless crystals; mp
1
92.0–93.58C. H NMR (300 MHz; CDCl3): d¼1.21–1.33
(20H, m), 1.50–1.62 (4H, m), 2.13 (6H, s), 2.41 (4H, t,
J¼7.4 Hz). 13C NMR (75 MHz; CDCl3): d¼23.87, 29.17,
29.37, 29.44, 29.56, 29.59, 29.80, 43.80, 209.29.
3.2.29. 1-(t-Butyldimethylsiloxy)-5-chloro-4-hydroxy-4-
phenyl-2-pentanone (30). Yellow oil. IR (neat) 3482,
3.2.35. 3-Hydroxy-3-methylcyclopentadecanone (34).
Two lots of solutions (A) and (B) were prepared; TiCl4
(110 ml, 1.00 mmol) diluted with CH2Cl2 (2.4 ml) under an
1
2955, 2932, 1717, 1256, 1109, 839 cm21
.
H NMR
(400 MHz; CDCl3): d¼0.04 (3H, s), 0.05 (3H, s), 0.90

Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
8279
argon atmosphere and (B) mixed solution of 2,15-hexa-
3.3. Isomerization of E-rich 3-methyl-2-cyclopenta-
decenone (35) using NaSPh
decanedione (33; 127 mg, 0.50 mmol) and Bu3N (370 mg,
2.00 mmol) in CH2Cl2 (1.7 ml). Solutions of (A) and (B)
were simultaneously and proportionally added to a stirred
CH2Cl2 solvent (45.0 ml) at 25–308C during 2 h under an
argon atmosphere, using a microfeeder apparatus equipped
with dual syringes (note: this procedure is critical). After
completion of the feed, the mixture was further stirred for
0.5 h at the same temperature. Then, water was added to the
stirring mixture, which was extracted with ether. The
organic phase was washed with water, brine, dried (Na2SO4)
and concentrated. The obtained crude oil was purified by
SiO2-column chromatography (hexane–AcOEt¼8:1) to
give the desired product (68 mg; 52%; purity 97% base on
1H NMR measurement). Colorless oil. IR (neat): 3484,
NaSPh (3 mg, 0.03 mmol) was added to the E-rich substrate
(35; E–Z¼ca. 9:1; 59 mg, 0.19 mmol) in hexane (0.5 ml) at
room temperature and the mixture was stirred for 1 h. Water
was added to the mixture and the similar work up to the
preparation of 35 gave the isomeric product (35; 56 mg,
95%, E–Z¼73:27 based on 1H NMR measurement).
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ and on Basic Areas (C)
from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, and by the Cosmetology
Foundation in Japan.
2930, 2855, 1703, 1460, 1408, 1372 cm21 1H NMR
.
(400 MHz; CDCl3): d¼1.09–1.57 (20H, m), 1.17 (3H, s),
1.61–1.72 (1H, m), 1.72–1.84 (1H, m), 2.33–2.40 (1H, m),
2.43 (1H, d, J¼16.8 Hz), 2.51 (0.5H, dd, J¼16.4, 5.6 Hz),
2.53 (0.5H, dd, J¼16.4, 5.6 Hz), 2.81 (1H, d, J¼16.8 Hz),
3.80–4.09 (1H, brs, –OH); 13C NMR (100 MHz; CDCl3):
d¼22.51, 23.68, 25.65, 26.11, 26.37, 26.50, 26.61, 26.67,
27.52, 27.70, 27.91, 41.17, 43.49, 50.70, 72.29, 213.94.
References
3.2.36. 3-Hydroxy-3-methylcyclobutadecanone (39).
1
Colorless crystals; mp 34.5–35.48C. H NMR (300 MHz;
1. (a) Heathcock, C. H. Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; 1991; Vol. 2, p 181. (b) Smith, M. B.;
March, J. March’s Advanced Organic Chemistry. 5th ed.;
Wiley: New York, 2001; p 1218.
CDCl3): d¼1.01–1.50 (18H, m), 1.16 (3H, s), 1.70–1.80
(1H, m), 1.83–1.97 (1H, m), 2.30–2.39 (1H, m), 2.57–2.67
(1H, m), 2.62 (2H, dd, J¼142.7, 17.7 Hz), 3.62–3.89 (1H,
brs); 13C NMR (75 MHz; CDCl3): d¼22.63, 22.80, 23.59,
24.05, 24.86, 25.33, 25.71, 26.11, 26.57, 27.73, 40.38,
42.29, 49.34, 72.41, 213.31.
2. (a) Mukaiyama, T.; Banno, K.; Narasaka, K. Chem. Lett. 1973,
1011. J. Am. Chem. Soc. 1974, 96, 7503. (b) Mukaiyama, T.
Organic Reactions; Wiley: New York, 1982; Vol. 28. p 203.
(c) Reetz, M. T. Organotitanium Reagents in Organic
Synthesis; Springer: New York, 1986. (d) Masamune, S.;
Choy, W.; Peterson, J. S.; Rita, L. R. Angew. Chem., Int. Ed.
Engl. 1985, 24, 1. (e) Bosnich, B. Aldrichim. Acta 1998, 31,
76. (f) Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321.
For recent representative works: (g) Saito, S.; Hatanaka, K.;
Kano, T.; Yamamoto, H. Angew. Chem. Int. Ed. 1998, 37,
3378. (h) Schmittel, M.; Ghorai, M. K.; Haeuseler, A.; Henn,
W.; Koy, T.; Soller, R. Eur. J. Org. Chem. 1999, 2007.
(i) Mahrwald, R.; Ziemer, B. Tetrahedron 1999, 55, 14005.
(j) Han, Z. F.; Yorimitsu, H.; Shinokubo, H.; Oshima, K.
Tetrahedron Lett. 2000, 41, 4415. (k) Ghosh, A. K.; Kim, J. H.
Tetrahedron Lett. 2001, 42, 1227.
3.2.37. 3-Hydroxy-3-methylcycloheptadecanone (40).
1
Colorless oil; H NMR (300 MHz; CDCl3): d¼1.11–1.39
(22H, m), 1.17 (3H, s), 1.43–1.79 (4H, m), 2.30–2.40 (1H,
m), 2.45–2.53 (1H, m), 2.46 (1H, d, J¼16.6 Hz), 2.78 (1H,
d, J¼17.2 Hz), 3.09–3.38 (1H, brs); 13C NMR (75 MHz;
CDCl3): d¼23.32, 24.22, 26.86, 26.90, 26.96, 27.01, 27.22,
27.27, 27.54, 27.62, 27.67, 28.12, 28.72, 41.14, 44.17,
50.79, 72.15, 213.89.
3.2.38. (E)- and (Z)-3-Methyl-2-cyclopentadecenone
(E-35 and Z-35). Ti(Oi-Bu)4 (103 ml, 0.30 mmol) was
added to a stirred solution of 3-hydroxy-3-methylcyclo-
pentadecanone (34; 37 mg, 0.15 mmol) at room tempera-
ture, followed by stirring for 24 h. The mixture was added to
cold water and Et2O, followed by Celite filtration. The
separated organic phase was washed with water, brine, dried
(Na2SO4) and concentrated. The obtained crude oil was
purified by SiO2-column chromatography (hexane–
Et2O¼8:1) to give the desired product (30 mg, 88%;
E-35–Z-35¼91:9). Colorless oil; IR (neat): 2930, 2859,
3. Tanabe, Y. Bull. Chem. Soc. Jpn 1989, 62, 1917.
4. (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.;
Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866. (b) Evans,
D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 113, 8215. (c) Evans, D. A.; Rieger,
D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 112,
1047. (d) Crimmis, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894.
5. A part of the preliminary results appeared in (a) Yoshida, Y.;
Hayashi, R.; Sumihara, H.; Tanabe, Y. Tetrahedron Lett. 1997,
38, 8727. (b) Yoshida, Y.; Matsumoto, N.; Hamasaki, R.;
Tanabe, Y. Tetrahedron Lett. 1999, 40, 4227.
1686, 1615, 1458, 1387, 1364, 1225 cm21 1H NMR
.
(400 MHz; CDCl3): d¼1.16–1.40 (15H, m), 1.44–1.70
(5H, m), 1.87 (E, 3H, d, J¼1.5 Hz), 2.14 (Z, 3H, d,
J¼1.2 Hz), 2.16–2.21 (Z, 2H, m), 2.34–2.43 (2H, m),
2.73–2.76 (E, 2H, m), 6.08–6.12 (E, 1H, m), 6.13–6.18 (Z,
1H, m); 13C NMR (75 MHz; CDCl3): d¼23.85, 23.94,
25.16, 25.16, 25.47, 25.48, 25.64, 26.19, 26.38, 26.38,
26.55, 26.63, 26.67, 26.70, 26.75, 26.80, 26.86, 26.95,
26.99, 27.05, 27.13, 31.76, 40.03, 43.60, 44.46, 123.72,
125.02, 158.63, 158.94, 202.06, 202.38.
6. Ruzicka, L. Helv. Chim. Acta 1926, 9, 715. Detailed references
is cited in Tanaka, K.; Ushio, H.; Kawabata, Y.; Suzuki, H.
J. Chem. Soc., Perkin Trans. 1 1991, 1445.
7. Tanabe, Y.; Matsumoto, N.; Funakoshi, S.; Manta, N. Synlett
2001, 1959.
8. Ref. 5a,b, and (a) Hamasaki, R.; Funakoshi, S.; Misaki, T.;
Tanabe, Y. Tetrahedron 2000, 56, 7423. (b) Tanabe, Y.;

8280
Y. Tanabe et al. / Tetrahedron 58 (2002) 8269–8280
Hamasaki, R.; Funakoshi, S. Chem. Commun. 2001, 1674.
(c) Tanabe, Y.; Makita, A.; Funakoshi, S.; Hamasaki, R.;
Kawakusu, T. Adv. Synth. Catal. 2002, 344, 507.
16. Abad, A.; Amo, M.; Pardo, J. R.; Sloane, E. Chem. Ind. 1985,
29.
17. Tsuji, J.; Yamada, T.; Kaito, M.; Mandai, T. Bull. Chem. Soc.
Jpn 1980, 53, 1417.
9. (a) Mukaiyama, T.; Stevens, R. W.; Iwasawa, N. Chem. Lett.
1982, 353. (b) Mukaiyama, T.; Iwasawa, N.; Stevens, R. W.;
Haga, T. Tetrahedron 1984, 40, 1381.
18. (a) Kamat, V. P.; Hagiwara, H.; Suzuki, T.; Ando, M. J. Chem.
Soc., Perkin Trans. 1 1998, 2253. (b) Louie, J.; Bielawski,
C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312.
(c) Fujimoto, S.; Yoshikawa, K.; Itoh, M.; Kitahara, T. Biosci.
Biotechnol. Biochem. 2002, 66, 1389.
10. Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1983, 24, 3341,
see also p 3343.
11. Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1987, 463.
12. 13C NMR (400 MHz) of three independent experiments with
three molar ratios (phenacyl chloride–TiCl4 –Bu3N–
TMSCl¼1.0:1.0:1.0:0.0, 0.5, and 1.0) in CD2Cl2 at 2788C
showed progressive appearance of enol carbon peak (d 135.85
and 151.20) of the titanium enolate.
19. Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183.
20. Ogura, S.; Yamamoto, T. JP 94192161. Chem. Abstr. 1995,
122, 132836.
21. Its synthesis and structure–activity relationship will be
reported in near future.
13. (a) Mukaiyama, T.; Haga, T.; Iwasawa, N. Chem. Lett. 1982,
1601. (b) Mukaiyama, T.; Yura, T.; Iwasawa, N. Chem. Lett.
1985, 809.
22. Humphrey, G. R.; Miller, R. A.; Pye, P. J.; Rossen, K.;
Reamer, R. A.; Maliakal, A.; Ceglia, S. S.; Grabowski, E. J. J.;
Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1999, 121,
11261.
14. Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH Publishers, Inc.: New York, 1996.
15. For recent reviews: (a) Williams, A. S. Synthesis 1999, 1707.
23. Tanabe, Y.; Murakami, M.; Kitaichi, K.; Yoshida, Y.
Tetrahedron Lett. 1994, 35, 8409.
´
(b) Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Frater, G. Angew.
Chem. Int. Ed. 2000, 39, 2980.