Pd-catalyzed regioselective acylation of α,β-unsaturated ketone derivatives by acylzirconocene chloride as an acyl group donor

Article abstract of DOI:10.1016/S0040-4020(02)00857-8

Acylzirconocene chlorides reacted with α,β-unsaturated ketones (α,β-enone or -ynone) to give regioselectively 1,2- or 1,4-products under Pd-catalyzed conditions. In the reactions of α,β-enones, excellent regioselectivity was attained by the choice of the

Full text of DOI:10.1016/S0040-4020(02)00857-8

Tetrahedron 58 (2002) 7559–7571
Pd-catalyzed regioselective acylation of a,b-unsaturated ketone
derivatives by acylzirconocene chloride as an acyl group donor
*
Yuji Hanzawa, Nobuhito Tabuchi, Kensuke Narita, Akito Kakuuchi, Masaya Yabe
*
and Takeo Taguchi
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 11 June 2002; accepted 19 July 2002
Abstract—Acylzirconocene chlorides reacted with a,b-unsaturated ketones (a,b-enone or -ynone) to give regioselectively 1,2- or
1,4-products under Pd-catalyzed conditions. In the reactions of a,b-enones, excellent regioselectivity was attained by the choice of the Pd(II)
catalyst system. Thus, the 1,2- or 1,4-products were selectively prepared by choosing PdCl2(PPh3)2 or Pd(OAc)2–BF3·OEt2, respectively.
The presence of a monodentate phosphine ligand brought about a 1,2-addition product, selectively. In these Pd-catalyzed reactions, the Pd(0)
species was considered to be an active catalyst, which was generated in situ through transmetalation of acyl groups from zirconium to Pd(II)
followed by reductive elimination of Pd(0). a,b-Ynones also reacted with acylzirconocene chloride to give regioselectively 1,4-products
under the Pd-catalyzed conditions. In contrast to the reactions of a,b-enones, the presence of a triphenylphosphine ligand brought about the
selective formation of 1,4-adduct. By virtue of the phosphine ligand-effect in the addition of an acyl anion to a,b-enones, enantioselective
1,2-addition of acylzirconocene chloride to cyclic a,b-enones was carried out in modest optical purity (,66% ee) by the use of 5 mol%
Pd(OAc)2-(R )-MOP (Pd/P¼1:2) catalyst. The origin of the enantioselectivity was deduced by considering an (R)-MOP coordinated p-allylic
acyl Pd complex. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
reactivity toward organometallic reagents have been
reported,7 no report as a donor of an unmasked acyl anion
had been made until we published the Lewis acid-mediated
reactions of acylzirconocene chloride derivatives with
aldehydes giving a-ketol derivatives.8 In these reactions, a
salient feature of the acylzirconocene chloride as an
unmasked acyl anion donor was revealed for the first time
(Scheme 1). During the study of the carbon–carbon bond
formation by the use of acylzirconocene chloride with an
electrophile, we revealed the regiochemically tunable
nucleophilic acylation of a,b-enones under Pd-catalyzed
conditions. We describe herein a full account of the
Pd-catalyzed reactions of the acylzirconocene chlorides
with a,b-unsaturated ketones (enones and ynones) and
the enantioselective 1,2-addition of an acyl anion to
a,b-enones.9,10
The generation and reactions of acyl metals [RC(O)M] as an
‘unmasked’ acyl anion donor are an intensive research
field.1 In particular, the acyl metal species in which the
metal is a main group metal (M¼Li, Zn, etc.) has been
extensively studied by many research groups.2 However,
their use as an unmasked acyl anion donor for organic
synthesis encountered difficulties due to the limited stability
and/or the extreme reaction conditions of the acyl metal
species. As well as the acyl-main group metal complexes,
acyl-transition metal complexes have also long attracted our
attention because of their intrinsic usefulness as an acyl
anion equivalent.3 Several stable acyl-transition metal
complexes such as nickel,4 iron,5 and cobalt6 complexes
have been developed and reported as an unmasked acyl
anion donor. These complexes also suffer severe limitations
due to the use of highly toxic metal carbonyls as the starting
materials. Acylzirconocene chlorides, however, are stable
and easily accessible through the hydrozirconation of
alkenes or alkynes with the Schwartz reagent (Cp2ZrHCl)
followed by the insertion of carbon monoxide. Although the
conversion of acylzirconocene complexes to carboxylic acid
derivatives by a hydrolysis–oxidation procedure and the
Keywords: regioselectivity; acylzirconocene; Pd catalyst; acyl anion.
*
Corresponding authors. Tel.: þ81-426-76-3274; fax: þ81-426-76-3257;
e-mail: hanzaway@ps.toyaku.ac.jp
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00857-8

7560
Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
Scheme 2.
Table 1. Pd-catalyzed reaction of 2-cyclohexen-1-one with 1a
Entry
Pd catalysta
2 Yieldb %
3 Yieldb %
1
2
3
4
5
6
7
8
Pd(PPh3)4
34
29
31
81
49
13
20
–
–
–
17
–
c
Pd2(dba)·CHCl3–PPh3
PdCl2(dppe)
PdCl2(PPh3)2
c
Pd(OAc)2–PPh3
Pd(OAc)2
18
45
60
d
Pd(OAc)2
Pd(OAc)2–BF3·OEt2
Figure 1. Yields of 1,2-addition products of a,b-enones by 1a (numbers in
bold type indicate 1,2-adducts).
d,e
Reaction conditions; ambient temperature, toluene, 20 h.
a
5 mol% catalyst.
Isolated yield.
b
PdCl2(PPh3)2 (5 mol%) in toluene and Pd(OAc)2
(10 mol%)–BF3·OEt2 in Et2O–THF (2:1) are shown in
Figs. 1 and 2, respectively.
c
Pd/P¼1:2.
d
10 mol% catalyst.
Solvent; ether/THF¼2:1.
e
2. Results and discussion
Under the respective reaction conditions, the 1,2- or
1,4-products are obtained in mostly good to excellent
yields. However, the reaction of cyclopentenone gave a
complex mixture under the 1,2-addition conditions (Fig. 1),
while the 1,4-product 12 was obtained in good yield under
1,4-addition conditions (Fig. 2).
2.1. Regioselective acylation of a,b-enones
Michael-type addition of an unmasked acyl anion to
a,b-enones by utilizing acyl metals is a practical procedure
for the preparation of 1,4-dicarbonyl compounds.4,11
Acylzirconocene chloride complex 1 is an unreactive
species toward a,b-enones even if a Lewis acid or silver
salt was employed as an additive.12 In the presence of
a palladium catalyst, however, the reactions of 1 with
a,b-enones did proceed efficiently to give acylated products
and the regioselectivity could be controlled efficiently by
the choice of the catalytic system. Thus, examination of the
catalytic system by the reaction of n-nonanoylzirconocene
chloride (1a) with cyclohexenone revealed that the presence
of a triphenylphosphine ligand tends to yield selectively
1,2-adducts 2, and the presence of an equivalent amount of
a Lewis acid yields 1,4-adduct 3 (Scheme 2, Table 1).
Among the palladium catalysts examined, PdCl2[P(C6H5)3]2
and Pd(OAc)2–BF3·OEt2 were the catalyst of choice for
the regioselective formation of 1,2- and 1,4-adducts,
respectively (entries 4 and 8, Table 1). Other Lewis acids,
such as ZnCl2 or MgBr2·OEt2, can be used for BF3·OEt2 in
1,4-selective addition. It is worth mentioning that Pd(OAc)2
showed an interesting feature because the regioselectivity
of the reaction was completely reversed by the additive
(entries 5 and 8, Table 1). Nickel catalysts such as,
Ni(acac)2 showed a similar efficiency to Pd(OAc)2. Other
Ni complexes [NiCl2(dppf), NiCl2(PPh3)2 and Ni(PPh3)4]
were ineffective. Addition of BF3·OEt2 to the PdCl2(PPh3)2-
catalyst did not alter the 1,2-regioselectivity. The results of
the reactions of 1a with a,b-enones by the use of
Figure 2. Yields of 1,4-addition products of a,b-enones by 1a (numbers in
bold type indicate 1,4-adducts).

Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
7561
Figure 5. Pd-catalyzed 1,2- or 1,4-selective addition of 1b (numbers in bold
type indicate products).
tunable regioselectivity of 1 toward a,b-enones indicates
that the complex 1 is a very useful reagent as a donor of an
unmasked acyl anion.
Figure 3. A catalytic cycle for the formation of 2 or 3.
Bis-substitution at the b-position of acyclic a,b-enone
retards not only the formation of the 1,4-adduct but also the
formation of the 1,2-adduct. It should be mentioned that
concomitant formation (,5%) of a diketone derived from
the self-coupling of 1a under both reaction conditions
suggests the participation of the Pd(0) complex as an actual
catalyst (Fig. 3), and a similar observation has been made in
the Pd-catalyzed coupling reactions of acylzirconocene
chloride and organic halide.13
2.2. Regioselective acylation of a,b-ynones
Because a,b-ynone 24 is a good Michael acceptor toward
organometallic reagents, we examined the reactions of 1
with 24 on the assumption that the Pd-catalyzed reaction
conditions employed for a,b-enones would proceed as well.
It turned out that the reactions proceed efficiently to give the
acyl addition products as we expected. The regioselectivity
of the reaction, however, was contrastive with that of the
reactions of a,b-enones; that is, the presence of a phosphine
ligand exerted influence on the regioselectivity to afford
1,4-product 25. Thus, the reaction of 1a with 4-phenyl-but-
3-yn-2-one (24a) (Scheme 3) in the presence of PdCl2-
(PPh3)2 or Pd(PPh3)4-catalyst gave 1,4-acylation product
25a in a slight preference of Z-isomers (E/Z¼1:2.4) in 65 or
45% yield, respectively, together with a trace amount
(,5%) of a diketone as in the cases of a,b-enones. On the
other hand, use of Pd(acac)2 or PdCl2(CH3CN)2 as a catalyst
under otherwise identical conditions rendered the reaction
slow (by TLC), and a 1,2-adduct 26a was obtained in
40–47% yield together with a small amount (5–15%) of
1,4-adduct 25a. Formation of 25 by the PdCl2(PPh3)2 or
Pd(PPh3)4-catalyzed 1,4-selective addition of acylzircono-
cene chlorides 1 to a,b-ynone derivatives 24 is listed in
Table 2.
Non-reactivity of an a,b-conjugated ester, g,d-unsaturated
ketone and saturated ketone, and formation of a complex
mixture in the reaction of an a,b-enal imply that an
a,b-enone skeleton is essential in the present reaction.
Based on these observations and the mechanism, which is
reported for the Ni or Pd-catalyzed 1,4-addition of
alkenylzirconocene chloride to a,b-enones,10 an electron
transfer from Pd(0) to the a,b-enone skeleton would take
part in the reaction as a crucial process (Fig. 3).14
Thus, an electron transfer from Pd(0) to cyclohexenone, for
example, formation of acylpalladium p-allylic complex
19 and reductive elimination of Pd(0), would give either a
1,2- or 1,4-acylation product (2 or 3). The role of the
triphenylphosphine ligand in the regioselective formation of
1,2-acylation product 2 could be explained by the preferred
formation of stereochemically less crowded intermediate
complex 19A (L¼PPh3) compared to 19B (L¼PPh3) and
subsequent reductive elimination of Pd(0) from 19A
(L¼PPh3) (Fig. 4).
In all cases examined, the reaction proceeds with high
1,4-regioselectivity and efficiency, albeit the stereoselectiv-
ity is low. It is notable that the regioselectivity was
unaffected even in the reactions of 24 which possesses
a bulky substituent at the sp carbon (entries 2, 4 and 5,
Table 2). Other catalysts [PdCl2dppe, (dba)3Pd2·CHCl3,
NiCl2(PPh3)2, Ni(PPh3)4, Ni(acac)2 and Ni(COD)2] ended
with recovery of the starting material or formation of a
Although the mechanism involved in the reversal of
regioselectivity by changing the palladium catalyst from
PdCl2(PPh3)2 to Pd(OAc)2 –BF3·OEt2 remains to be
clarified, an addition of a Lewis acid might exert an
electronic or a steric effect by coordinating to the assumed
acyl p-allyl complex 19 (L¼solvent) intermediate. The
described regioselective addition was also carried out by the
use of a,b-unsaturated acylzirconocene chloride 1b, albeit
the yield was lower than that of 1a (Fig. 5). In any event, the
Figure 4. Isomeric complexes 19A and B.
Scheme 3.

7562
Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
Table 2. PdCl2(PPh3)2- and/or Pd(PPh3)4-catalyzed reactions of 24 with saturated acylzirconocene chloride 1
Entry
1, R
24
Pd catalysta
25
R1
R2
Yield (%)b
(E/Z )c
1
2
3
4
5
6
7
n-C8H17
1a
Ph
CH3
nBu
t Bu
A
B
A
B
A
B
A
B
A
B
A
B
A
B
85
68
71
77
59
83
82
95
73
73
95
95
70
51
(1/2.4)
(1/2.4)
(1/3)
(1/2)
(1/2)
(1/1)
(1/1)
(1/2.5)
(1/3.5)
(1/3)
25b
24b
25c
25d
25e
25f
25g
Ph
BnO(CH2)2
t Bu
Ph
tBu
nBu
2-Naphthyl
Ph
nBu
(1/2.3)
(1/2.5)
(1/3)
nBu
25h
25i
(1/3)
8
A
B
78
71
(1/3.6)
(1/3)
a
Catalyst A: PdCl2(PPh3)2, catalyst B: Pd(PPh3)4.
Isolated yield.
Determined by 1H NMR.
b
c
complex mixture. It is worth noting that ethyl phenyl-
propiolate and oct-4-yne did not react with 1a under the
same reaction conditions, and the starting materials were
recovered unchanged. a,b-Ynone, which possesses alkynyl
hydrogen, e.g. 1-phenyl propynone, ended with formation of
a complex mixture. Thus, the activation of the triple bond by
an electron-withdrawing ketone-carbonyl and the absence
of alkynyl-hydrogen are requisite for bringing about the
reaction. According to the facts that (i) either PdCl2(PPh3)2
or Pd(PPh3)4 can be used as a catalyst, and (ii) a trace
amount of diketone derived from the self-coupling of 1 is
formed by the use of PdCl2(PPh3)2 catalyst, a mechanism
which is analogous to the Pd(0)-catalyzed reactions of
a,b-enones with 1 was assumed (Fig. 6). Thus, a catalytic
process; (i) an electron transfer from Pd(0) to a,b-ynone
24, (ii) formation of Pd-allenyl complex 27, (iii) trans-
metalation and (iv) reductive elimination of Pd(0) would
be involved. Although the quite different effect of the
triphenylphosphine ligand on the regioselectivity compared
to the reaction of a,b-enones is puzzling, steric or electronic
difference between the intermediate Pd-allenyl complexes
27 might exert influence on the regioselectivity. It should
be mentioned that the isomerization of a,b-ynone to
conjugated dienone via allenyl ketone by Pd(0) or PPh3
has been reported.15 In the present reactions, however,
this isomerization was scarcely involved since t Bu or
phenyl-substituted a,b-ynone, which has no isomerizable
hydrogen, gave 25.
PdCl2(PPh3)2-catalyzed reactions of a,b-unsaturated acyl-
zirconocene chloride with a,b-ynone turned out to be a
one-pot procedure for the preparation of cyclopentenone
derivatives 28 (Scheme 4). The reaction of 24a with 1b in
THF for 12 h at ambient temperature, cyclopentenone
derivative 28a were isolated in 21% yield together with
the 1,4-addition products 29a (27% yield). Formation of 28
was increased by prolonged treatment (48 h) of the reaction
mixture. Thus, the reaction of 1b with 24b and the reaction
of 1c with 24b in THF at ambient temperature for 48 h gave
28b and 28c in 47 and 63% yields, respectively.
The formation of 28 was a result of the secondary process
Figure 6. A catalytic cycle for the formation of 25 or 26.
Scheme 4.

Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
7563
Table 3. Enantioselective formation of 2
Entry
Pd catalysta
Phosphineb
Yield (%)c ee (%)d
1
2
3
4
5
6
7
8
PdCl2[(R )-BINAP]
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
Pd(OAc)2
–
19
14
81
90
88
89
92
48
–
–
–
12
66
61
62
56
(R,R)-CHIRAPHOS
(þ)-NMDPP
(R)-MOP
(R)-MOP
(R)-MOP
Figure 8. Enantioselective complexation of (R)-MOP-Pd.
As can be deduced from the previously discussed results,
the use of a chiral bidentate phosphine ligand, (R)-BINAP17
or (R,R )-CHIRAPHOS18 was ineffective in the reaction
(entries 1 and 2, Table 3). However, a chiral monodentate
phosphine ligand, (þ)-NMDPP19 or (R )-MOP,20 enhanced
the reaction rate compared to triphenylphosphin ligand, and
(R )-MOP, which was developed by Hayashi et al.20 shows
considerable efficiency in the chiral induction into the
product (R)-2, [a ]2D4¼242.1 (c¼1.04 in CHCl3), (66% ee,
88% yield) (entry 5). No significant difference between
(R )-MOP and its derivatives (BnO-, i PrO- or TBDMSO-
(R )-MOP)20c,d was observed in the chiral induction. It is
worth mentioning that the utilization of the (R )-MOP ligand
brought about a significant increment of yields and the
reaction rate compared to the case of the triphenylphosphine
ligand. This ligand effect of (R)-MOP enables us to isolate a
1,2-acylation product 31 (67% ee, 36% yield, Fig. 7) from
cyclopentenone, which gave a complex mixture under the
Pd(OAc)2–PPh3 conditions (Fig. 1). The present enantio-
selective reaction is less efficient for acyclic a,b-enones,
albeit excellent chemical yields and regioselectivity are
attained (Fig. 7).
PdCl2(PhCN)2
Pd(acac)2
(R)-MOP
(R)-MOP
9
10
PdCl2(CH3CN)2
Pd2(dba)3·CHCl3
(R)-MOP
(R)-MOP
86
70
64
64
Reaction conditions, see Section 5.
a
5 mol% catalyst.
Pd/P¼1:2.
b
c
Isolated yield.
Determined by chiralcel AD HPLC after being derivatized to benzoyl
ester.
d
of the enolate intermediate 30 through either the Nazarov
reaction or by an intramolecular conjugated addition
reaction of the enolate 30.16 In any event, an access to
highly substituted cyclopentenone derivatives 28 in one-pot
procedure from ynone 24 under mild conditions would
render the present procedure useful.
3. Enantioselective 1,2-addition of acylzirconocene
chloride to a,b-enones
Based on the discussed acylpalladium p-allylic complex
19A (L¼PPh3) (Fig. 4) and the reported X-ray structure of
the (R )-MOP-Pd p-allylic complex,21 the acylpalladium-
(R )-MOP p-allylic complex 32 and 33 would be respon-
sible for the formation of (R)-2 and (S )-2, respectively
(Fig. 8).
The effect of the triphenylphosphine ligand in the p-allyl
complex intermediate 19 upon the regioselective formation
of the 1,2-adduct (Fig. 3) led us to examine an enantio-
selective version of the 1,2-acylation by utilizing a chiral
phosphine ligand. The Pd(II)-chiral phosphine-catalyzed
reactions of 1a with cyclohexenone in toluene were carried
out and the results are listed in Table 3. All reactions were
carried out by utilizing 5 mol% palladium catalyst and a
chiral phosphine ligand (Pd/P¼1:2).
Complex 33, which would give (S)-2, suffers from steric
Figure 7. Enantioselective 1,2-addition of 1a to a,b-enones (numbers in
bold type indicate 1,2-adduct).
Scheme 5.

7564
Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
compression between the MeO-naphthyl ring and the acyl
group, while there is no such steric interaction in complex
32. Thus, reductive elimination of Pd(0) from 32 would
yield (R )-2, preferentially. The result of the enantioselective
reaction would further support the legitimacy of the
proposed complex 19A in the regioselective 1,2-acylation
reactions. The absolute stereochemistry of (R )-2 was
confirmed by the following synthesis of (S )-2 from the
easily accessible allylic alcohol 34 (Scheme 5). Kinetic
resolution22,23 of 34 with (þ)-DIPT, Ti(O-i Pr)4 and
t BuOOH gave optically active (R)-allylic alcohol (R)-34
(90% ee, 45% yield).24 Epoxidation of (R )-34 with
Ti(O-i Pr)4, t BuOOH and (2)-DIPT gave epoxy alcohol
35 (90% yield, .95% ee).25 Treatment of 35 with sodium
phenylselenide gave vic-diol 36, which was protected as
cyclic orthoformate 37. Oxidation of 37 with sodium
periodate at 08C, deprotection of the vic-diol protective
group (DIBAL-H) followed by oxidation (Swern oxidation)
of the secondary alcohol gave (S)-2 (.95% ee), [a ]2D6¼45.5
(c¼0.57, CHCl3), which was identical in every respect with
the product (R )-2 derived from the enantioselective
acylation, except for the sign of specific rotation.
commercial suppliers and used without further purification
unless otherwise noted. NMR spectra were measured at 300
1
or 400 MHz for H and 75.5 or 100.6 MHz for 13C. Fuji
silysia silica gel BW-80S (60–200 mesh) was used for
column chromatography and prepacked column CPS-223L-
1 was used for medium-pressure liquid chromatography
(MPLC). An enantiomeric excess of the optically active
product was determined by HPLC-analysis using chiralcel
AD or OD column with 254 nm UV detector after being
derivatized to benzoate.
5.1. Preparation of a solution of acylzirconocene chloride
To a suspension of Cp2Zr(H)Cl (2.0 mmol) in CH2Cl2
(8 mL) was added alkene or alkyne (4 mmol) at ambient
temperature and the mixture was stirred for 0.5 h under Ar
atmosphere. After the mixture was stirred for 2 h under CO
(1 atm), the solvent was evaporated in vacuo to give a pale
yellow solid, and toluene (15 mL) or THF (5 mL) was added
to the solid.
5.2. 1,2-Regioselective acylations of a,b-enones: general
procedure
To a toluene solution (15 mL) of acylzirconocene chloride
(2.0 mmol) were added a,b-unsaturated ketone (1 mmol)
and PdCl2(PPh3)3 (5 mol%) at ambient temperature. After
the reaction mixture was stirred for 20 h at the same
temperature, the mixture was treated with aq. NaHCO3 and
extracted with ether. The combined organic layer was
washed with brine, dried over MgSO4, filtered and
concentrated. The crude product was purified by column
chromatography (hexane/ethyl acetate¼50:1) to give pure
1,2-acylation product.
4. Conclusion
Stable and easily accessible acylzirconocene chlorides
proved to be an excellent donor of an unmasked acyl
anion to a,b-unsaturated ketones under the palladium-
catalyzed conditions. The highly tunable regioselectivity of
an acylzirconocene chloride complex in the acylation
reactions of a,b-enone and a,b-ynone was dependent
upon the presence of a monodentate phosphine ligand.
However, the effect of the phosphine ligand was quite
contrary in a,b-enone and a,b-ynone compounds; that is,
1,2-selectivity in the former and 1,4-selectivity in the latter
are observed. In these reactions, an electron transfer from
the low-valent Pd-catalyst to a,b-unsaturated ketone is
involved at the initial step. A facile access to cyclo-
pentenone derivatives by the Pd-catalyzed reaction of
a,b-unsaturated acylzirconocene chlorides with the
a,b-ynone system has added a new and simple way for
the preparation of cyclopentenone compounds, which
constitute an important portion of biologically active
molecules. Furthermore, the enantioselective 1,2-addition
of an acyl anion to cyclic a,b-enones reveals the new
potentiality of the acylzirconocene chloride complex as an
unmasked acyl anion donor. The stable acylzirconocene
species can be enrolled as a very handy substitute for the
reported toxic acyl metal complexes, and we are now
continuing our efforts to explore further the reactivity of the
acylzirconocene chloride derivatives.
5.2.1. 1-(Hydroxy-2-cyclohexen-1-yl)-1-nonanone (2).
1
Colorless oil, H NMR (400 MHz, CDCl3) d 0.87 (t, J¼
6.8 Hz, 3H), 1.26–1.31 (m, 10H), 1.57–1.66 (m, 3H),
1.77–1.88 (m, 3H), 2.03–2.21 (m, 2H), 2.50 (dt, J¼1.3,
8.3 Hz, 2H), 4.03 (s, 1H), 5.47 (qd, J¼1.3, 9.9 Hz, 1H),
6.12–6.15 (m, 1H); 13C NMR (100.6 MHz, CDCl3) d 14.1,
18.1, 22.6, 24.0, 24.8, 29.1, 29.2, 29.3, 31.8, 33.3, 36.3,
76.0, 126.1, 133.6, 213.8; IR (neat) n 3467, 1709 cm21
;
EIMS m/z 238 (Mþ). Anal. calcd for C15H26O2: C, 75.58; H,
10.99. Found: C, 75.28; H, 10.92.
5.2.2. 1-(Hydroxy-3-methyl-2-cyclohexen-1-yl)-1-nona-
none (4). Colorless oil, 1H NMR (400 MHz, CDCl3) d
0.87 (t, J¼6.9 Hz, 3H), 1.26–1.31 (m, 10H), 1.53–1.61 (m,
3H), 1.69–1.90 (m, 6H), 2.02–2.10 (m, 2H), 2.48 (t,
J¼7.3 Hz, 2H), 4.00 (s, 1H), 5.20 (s, 1H); 13C NMR
(100.6 MHz, CDCl3) d 14.1, 18.6, 22.6, 24.1, 24.2, 29.1,
29.2, 29.3, 29.9, 31.8, 32.9, 36.3, 76.7, 120.5, 141.9, 214.3;
IR (neat) n 3468, 1708 cm21; EIMS m/z 252 (Mþ). Anal.
calcd for C16H28O2: C, 76.14; H, 11.18. Found: C, 76.04; H,
11.01.
5. Experimental
All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous
conditions. Tetrahydrofuran (THF), diethyl ether (Et2O)
were distilled from sodium benzophenone ketyl. Dichloro-
methane (CH2Cl2) was distilled from calcium hydride.
Zirconocenehydrochloride (Cp2ZrHCl) was prepared by the
method of Buchwald.26 Materials were obtained from
5.2.3. 1-(Hydroxy-2-cyclohepten-1-yl)-1-nonanone (5).
1
Colorless oil, H NMR (400 MHz, CDCl3) d 0.87 (t, J¼
6.9 Hz, 3H), 1.26–1.31 (m, 10H), 1.53–1.89 (m, 6H),
1.96–2.03 (m, 2H), 2.28 (qd, J¼1.3, 5.8 Hz, 2H), 2.56 (m,
2H), 3.86 (s, 1H), 5.36 (qd, J¼1.3, 11.5 Hz, 1H), 6.01 (m,
1H); 13C NMR (100.6 MHz, CDCl3) d 14.1, 22.6, 23.0,

Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
7565
23.9, 27.1, 27.2, 29.1, 29.2, 29.3, 31.8, 35.4, 36.3, 81.0,
130.4, 135.9, 213.1; IR (neat) n 3464, 2927, 1711 cm21
J¼6.9 Hz, 3H), 1.27–1.32 (m, 10H), 1.53–1.61 (m, 2H),
1.65 (s, 3H), 2.18–2.34 (m, 3H), 2.41 (dt, J¼7.4, 17.7 Hz,
1H), 2.57 (dt, J¼7.4, 17.7 Hz, 1H), 2.75–2.82 (m, 1H), 4.28
(s, 1H), 5.15 (s, 1H), 5.22 (s, 1H), 7.17–7.31 (m, 5H); 13C
NMR (100.6 MHz, CDCl3) d 14.0, 18.8, 22.6, 23.7, 29.1,
29.2, 29.3, 29.8, 31.8, 35.0, 37.4, 83.3, 114.1, 126.0, 128.4,
;
EIMS m/z 252 (Mþ); HRMS calcd for C16H28O2: 252.2089.
Found: 252.2073.
5.2.4. (E )-4-n-Butyl-2-tridecen-4-ol-5-one (6). Colorless
oil, 1H NMR (400 MHz, CDCl3) d 0.85–0.92 (m, 6H),
0.95–1.05 (m, 1H), 1.24–1.43 (m, 13H), 1.53–1.60 (m,
2H), 1.66–1.76 (m, 5H), 2.38–2.58 (m, 2H), 4.07 (s, 1H),
5.51 (dq, J¼1.5, 15.3 Hz, 1H), 5.86 (dq, J¼6.7, 15.3 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) d 13.9, 14.1, 17.8,
22.6, 22.9, 23.8, 25.3, 29.1, 29.2, 29.3, 31.8, 36.1, 37.8,
128.5, 141.8, 145.3, 212.4; IR (neat) n 3462, 1706 cm21
;
EIMS m/z 316 (Mþ). Anal. calcd for C21H32O2: C, 79.70; H,
10.19. Found: C, 79.74; H, 10.07.
5.2.10. (E )-1-(Hydroxy-2-cyclohexen-1-yl)-2-hepten-1-
one (20). Colorless oil, 1H NMR (400 MHz, CDCl3) d
0.91 (t, J¼7.2 Hz, 3H), 1.31–1.47 (m, 4H), 1.57–1.65 (m,
2H), 1.76–1.85 (m, 3H), 2.00–2.10 (m, 1H), 2.19- 2.27 (m,
2H), 4.20 (s, 1H), 5.50 (dq, J¼1.5, 8.7 Hz, 1H), 6.14–6.18
(m, 1H), 6.34 (td, J¼1.5, 15.4 Hz, 1H), 7.14 (td, J¼7.1,
15.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) d 13.8, 18.0,
22.3, 25.0, 30.1, 32.5, 33.7, 74.9, 123.3, 126.0, 133.7, 151.0,
201.4; IR (neat) n 3455, 1689 cm21; EIMS m/z 208 (Mþ);
HRMS calcd for C13H20O2: 208.14633. Found: 208.14641.
81.4, 127.5, 131.4, 212.0; IR (neat) n 3471, 1707 cm21
;
EIMS m/z 268 (Mþ). Anal. calcd for C17H32O2: C, 76.06; H,
12.02. Found: C, 76.05; H, 11.85.
5.2.5. (E )-3-Methyl-1-phenyl-1-dodecen-3-ol-4-one (7).
Colorless oil, 1H NMR (400 MHz, CDCl3) d 0.85
(t, J¼6.9 Hz, 3H), 1.22–1.25 (m, 10H), 1.54 (s, 3H),
1.59–1.64 (m, 2H), 2.59 (t, J¼7.3 Hz, 2H), 4.21 (s, 1H),
6.23 (d, J¼15.9 Hz, 1H), 6.77 (d, J¼15.9 Hz, 1H), 7.24–
7.38 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d 14.1, 22.6,
23.9, 25.0, 29.0, 29.1, 29.3, 31.8, 36.1, 79.0, 126.7, 128.0,
128.6, 130.0, 131.1, 136.3, 211.6; IR (neat) n 3466,
1710 cm21; EIMS m/z 288 (Mþ). Anal. calcd for
C19H28O2: C, 79.12; H, 9.79. Found: C, 79.13; H, 9.65.
5.2.11. (1E,5E )-3-Methyl-1-phenyl-1,5-decadien-3-ol-4-
one (22). Colorless oil, 1H NMR (400 MHz, CDCl3) d
0.92 (t, J¼7.2 Hz, 3H), 1.31–1.51 (m, 4H), 1.58 (s, 3H),
2.26 (dq, J¼1.4, 7.0 Hz, 2H), 4.43 (s, 1H), 6.27 (d, J¼
15.9 Hz, 1H), 6.46 (td, J¼1.4, 15.3 Hz, 1H), 6.80 (d, J¼
15.9 Hz, 1H), 7.18 (td, J¼7.0, 15.3 Hz, 1H), 7.24–7.42 (m,
5H); 13C NMR (100.6 MHz, CDCl3) d 13.7, 22.2, 24.8,
30.0, 32.5, 77.8, 122.7, 126.7, 127.9, 128.5, 129.9, 131.2,
136.4, 151.6, 199.0; IR (neat) n 3452, 1689 cm21; EIMS m/z
258 (Mþ); HRMS calcd for C17H22O2: 258.16198. Found:
258.16122.
5.2.6. (E)-4-Phenyl-2-tridecen-4-ol-5-one (8). Colorless
1
oil, H NMR (400 MHz, CDCl3) d 0.86 (t, J¼6.9 Hz, 3H),
1.15–1.28 (m, 10H), 1.40–1.58 (m, 2H), 1.84 (dd, J¼1.0,
6.2 Hz, 3H), 2.30–2.50 (m, 2H), 4.68 (s, 1H), 6.06 (dq,
J¼6.2, 15.2 Hz, 1H), 6.15 (dd, J¼1.0, 15.2 Hz, 1H), 7.30–
7.41 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d 14.0, 18.0,
22.6, 24.1, 28.9, 29.0, 29.1, 31.7, 36.8, 82.6, 126.8, 128.0,
128.6, 128.8, 129.2, 141.3, 209.9; IR (neat) n 3456,
1711 cm21; EIMS m/z 288 (Mþ); HRMS calcd for
C19H28O2: 288.20893. Found: 288.20833.
5.3. 1,4-Regioselective acylation of a,b-enones: general
procedure
To a THF solution (5 mL) of acylzirconocene chloride
(2 mmol) were added a solution of a,b-unsaturated ketone
(1 mmol) in ether (10 mL), Pd(OAc)2 (10 mol%) and
BF3·OEt2 (1 mmol) at 08C. After the reaction mixture was
stirred for 20 h at the same temperature, the mixture was
treated with aq. NaHCO3 and extracted with ether. The
combined organic layer was washed with brine, dried over
MgSO4, filtered and concentrated. The crude product was
purified by column chromatography (hexane/ethyl
acetate¼20:1) to give pure 1,4-acylation product.
5.3.1. 3-n-Nonanoylcyclopentanone (12). Colorless oil, 1H
NMR (400 MHz, CDCl3) d 0.87 (t, J¼6.8 Hz, 3H), 1.20–
1.30 (m, 10H), 1.57–1.61 (m, 2H), 1.95–2.02 (m, 1H),
2.16–2.57 (m, 7H), 3.20–3.25 (m, 1H); 13C NMR
(100.6 MHz, CDCl3) d 14.0, 22.6, 23.6, 26.0, 29.1,
29.2, 29.3, 31.8, 37.5, 40.1, 41.7, 47.7, 210.8, 216.7; IR
(neat) n 1747, 1713 cm21; EIMS m/z 224 (Mþ). Anal. calcd
for C14H24O2: C, 74.95; H, 10.78. Found: C, 74.82; H,
10.66.
5.2.7. 3-(2-Phenylethyl)-1-dodecen-3-ol-4-one (9). Color-
1
less oil, H NMR (400 MHz, CDCl3) d 0.88 (t, J¼6.9 Hz,
3H), 1.22–1.31 (m, 10H), 1.55–1.62 (m, 2H), 2.00–2.13
(m, 2H), 2.40–2.61 (m, 3H), 2.71–2.79 (m, 1H), 4.17 (s,
1H), 5.28 (dd, J¼1.1, 10.6 Hz, 1H), 5.53 (dd, J¼1.1,
17.0 Hz, 1H), 5.96 (dd, J¼10.6, 17.0 Hz, 1H), 7.16–7.30
(m, 5H); 13C NMR (100.6 MHz, CDCl3) d 14.1, 22.6 23.7,
29.1, 29.2, 29.3, 29.6, 31.8, 36.3, 39.7, 82.0, 116.8, 126.0,
128.4, 128.5, 137.9, 141.5, 211.1; IR (neat) n 3468,
1709 cm21; EIMS m/z 302 (Mþ). Anal. calcd for
C20H30O2: C, 79.42; H, 10.00. Found: C, 79.16; H, 10.01.
5.2.8. 1-Phenyl-3,6-tetradecanedione (10). Colorless
1
crystals, mp 31.0–33.58C; H NMR (400 MHz, CDCl3) d
0.88 (t, J¼6.9 Hz, 3H), 1.27–1.32 (m, 10H), 1.50–1.60 (m,
2H), 2.44 (t, J¼7.5 Hz, 2H), 2.63–2.69 (m, 4H), 2.77–2.81
(m, 2H), 2.87–2.92 (m, 2H), 7.17–7.29 (m, 5H); 13C NMR
(100.6 MHz, CDCl3) d 14.1, 22.6 23.9, 29.1, 29.2, 29.4,
29.7, 31.8, 36.0, 36.2, 42.9, 44.3, 126.1, 128.3, 128.5, 141.0,
208.5, 209.7; IR (neat) n 1701 cm21; EIMS m/z 302 (Mþ).
Anal. calcd for C20H30O2: C, 79.42; H, 10.00. Found: C,
79.23; H, 10.06.
1
5.3.2. 3-n-Nonanoylcyclohexanone (3). Colorless oil, H
NMR (400 MHz, CDCl3) d 0.86 (t, J¼6.8 Hz, 3H), 1.20–
1.29 (m, 10H), 1.54–1.78 (m, 4H), 2.00–2.11 (m, 2H),
2.25–2.53 (m, 6H), 2.82–2.89 (m, 1H); 13C NMR
(100.6 MHz, CDCl3) d 14.0, 22.6, 23.6, 25.0, 27.4, 29.1,
29.2, 29.3, 31.8, 41.0, 41.2, 42.6, 50.2, 210.1, 210.8; IR
5.2.9. 2-Methyl-3-(2-phenylethyl)-1-dodecen-3-ol-4-one
1
(11). Colorless oil, H NMR (400 MHz, CDCl3) d 0.89 (t,

7566
Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
(neat) n 1712 cm21; EIMS m/z 238 (Mþ). Anal. calcd
for C15H26O2: C, 75.58; H, 10.99. Found: C, 75.36; H,
10.88.
42.8, 42.9, 45.6, 126.0, 128.3, 128.4, 141.3, 209.7, 212.5;
IR (neat) n 1711 cm21; EIMS m/z 316 (Mþ). Anal. calcd
for C21H32O2: C, 79.70; H, 10.19. Found: C, 79.63; H,
10.11.
5.3.3. 3-Methyl-3-n-nonanoylcyclohexanone (13). Color-
1
less oil, H NMR (400 MHz, CDCl3) d 0.86 (t, J¼6.9 Hz,
5.3.9. 3-[(E )-Heptenoyl]cyclohexanone (21). Colorless
oil, 1H NMR (400 MHz, CDCl3) d 0.90 (t, J¼7.3 Hz,
3H), 1.29–1.48 (m, 4H), 1.67–1.77 (m, 2H), 1.99–2.11 (m,
2H), 2.20–2.40 (m, 5H), 2.52–2.59 (m, 1H), 3.06–3.13 (m,
1H), 6.12 (td, J¼1.4, 15.7 Hz, 1H), 6.91 (td, J¼7.0, 15.7 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) d 13.8, 22.2, 24.9,
27.7, 30.1, 32.2, 41.0, 42.8, 47.8, 128.1, 149.0, 199.8, 210.3;
IR (neat) n 1714, 1666 cm21; EIMS m/z 208 (Mþ); HRMS
calcd for C13H20O2: 208.14633. Found: 208.14677.
3H), 1.19 (s, 3H), 1.20–1.31 (m, 10H), 1.50–1.57 (m, 2H),
1.67–1.77 (m, 2H), 1.83–1.92 (m, 1H), 1.97–2.04 (m, 1H),
2.09 (d, J¼14.4 Hz, 1H), 2.19–2.34 (m, 2H), 2.37–2.51 (m,
2H), 2.68 (d, J¼14.4 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3) d 14.0, 21.8, 22.6, 23.3, 23.6, 29.1, 29.2, 29.4, 31.8,
33.4, 36.5, 40.2, 49.3, 51.9, 209.7, 213.3; IR (neat) n
1707 cm21; EIMS m/z 252 (Mþ); HRMS calcd for
C16H28O2: 252.20893. Found: 252.20745.
5.3.4. 3-n-Nonanoylcycloheptanone (14). Colorless oil, 1H
NMR (400 MHz, CDCl3) d 0.87 (t, J¼6.9 Hz, 3H), 1.26 (m,
10H), 1.44–1.68 (m, 5H), 1.83–2.03 (m, 3H), 2.39–2.58
(m, 5H), 2.68–2.78 (m, 2H); 13C NMR (100.6 MHz,
CDCl3) d 14.1, 22.6, 23.7, 28.2, 29.1, 29.2, 29.3, 31.8,
32.7, 40.9, 43.8, 44.7, 48.2, 211.7, 212.7; IR (neat) n
1706 cm21; EIMS m/z 252 (Mþ); HRMS calcd for
C16H28O2: 252.20893. Found: 252.20943.
5.3.10. (E)-4-Phenyl-6-undecen-2,5-dione (23). Colorless
1
oil, H NMR (400 MHz, CDCl3) d 0.84 (t, J¼7.3 Hz, 3H),
1.19–1.39 (m, 4H), 2.10 (dq, J¼1.4, 7.0 Hz, 2H), 2.16 (s,
3H), 2.59 (dd, J¼4.2, 17.8 Hz, 1H), 3.44 (dd, J¼9.8,
17.8 Hz, 1H), 4.40 (dd, J¼4.2, 9.8 Hz, 1H), 6.06 (td, J¼1.4,
15.7 Hz, 1H), 6.80 (td, J¼7.0, 15.7 Hz, 1H), 7.17–7.32 (m,
5H); 13C NMR (100.6 MHz, CDCl3) d 13.7, 22.1, 30.0,
30.1, 32.1, 46.6, 51.6, 127.3, 128.3, 128.5, 129.0, 138.4,
148.5, 197.9, 206.8; IR (neat) n 1718, 1670 cm21; EIMS m/z
258 (Mþ). Anal. calcd for C17H22O2: C, 79.03; H, 8.58.
Found: C, 79.00; H, 8.54.
5.3.5. 7-Methyl-5,8-hexadecanedione (15). Colorless oil,
1H NMR (400 MHz, CDCl3) d 0.85–0.90 (m, 6H), 1.06 (m,
J¼7.1 Hz, 3H), 1.26–1.33 (m, 12H), 1.49–1.57 (m, 4H),
2.30–2.45 (m, 3H), 2.52 (t, J¼7.4 Hz, 2H), 2.93 (dd, J¼9.1,
17.5 Hz, 1H), 2.99–3.07 (m, 1H); 13C NMR (100.6 MHz,
CDCl3) d 13.8, 14.1, 16.8, 22.3, 22.6, 23.6, 25.9, 29.1, 29.3,
29.4, 31.8, 40.9, 41.3, 42.6, 45.6, 209.8, 213.8; IR (neat) n
1712 cm21; EIMS m/z 268 (Mþ). Anal. calcd for C17H32O2:
C, 76.06, H, 12.02. Found: C, 75.76, H, 11.92.
5.4. 1,4-Regioselective acylation of a,b-ynones 24:
general procedure
To a THF solution (5 mL) of acylzirconocene chloride 1
were added a solution of a,b-ynone 24 (1 mmol) in ether
(10 mL) and PdCl2(PPh3)2 (10 mol%) at 08C. After the
reaction mixture was stirred for 12 h at ambient tempera-
ture, the mixture was treated with aq. NaHCO3 and
extracted with ether. The combined organic layer was
washed with brine, dried over MgSO4, filtered and
concentrated. The crude product was purified by column
chromatography (hexane/ethyl acetate¼40:1) to give pure
1,4-acylation product 25 as each stereoisomer.
1
5.3.6. 4-Phenyl-2,5-tridecanedione (16). Colorless oil, H
NMR (400 MHz, CDCl3) d 0.89 (t, J¼6.9 Hz, 3H), 1.20–
1.34 (m, 10H), 1.47–1.63 (m, 2H), 2.22 (s, 3H), 2.38–2.61
(m, 2H), 2.63 (dd, J¼3.8, 17.9 Hz, 1H), 3.51 (dd, J¼10.3,
17.9 Hz, 1H), 4.27 (dd, J¼3.8, 10.3 Hz, 1H), 7.24–7.40 (m,
5H); 13C NMR (100.6 MHz, CDCl3) d 14.0, 22.6, 23.6,
28.9, 29.0, 29.2, 30.0, 31.4, 41.5, 46.5, 53.3, 127.4, 128.2,
129.0, 138.0, 206.8, 209.4; IR (neat) n 1715 cm21; EIMS
m/z 288 (Mþ). Anal. calcd for C19H28O2: C, 79.12, H, 9.79.
Found: C, 78.98, H, 9.72.
5.4.1. (E )-3-Butyl-1-phenyl-2-dodecene-1,4-dione
[(E )-25b]. 1H NMR (400 MHz, CDCl3) d 0.86 (t, J¼
7.1 Hz, 3H), 0.88 (t, J¼6.9 Hz, 3H), 1.30–1.39 (m,14H),
1.66–1.70 (quint, J¼7.2 Hz, 2H), 2.58 (t, J¼7.6 Hz, 2H),
2.75 (t, J¼7.4 Hz, 2H), 7.32 (s, 1H), 7.47–7.94 (m, 5H); 13C
NMR (100.6 MHz, CDCl3) d 13.7, 14.0, 22.6, 22.9, 24.4,
27.6, 29.1, 29.2, 29.4, 31.4, 31.8, 38.6, 128.5, 128.8, 129.8,
133.5, 137.5, 152.5, 193.0, 202.9; IR (neat) n 2927, 1668,
1607 cm21; EIMS m/z 328 (Mþ); HRMS calcd for
C22H32O2 328.24023. Found 328.24006.
5.3.7. 3-Methyl-1-phenyl-1,4-dodecanedione (17). Color-
1
less oil, H NMR (400 MHz, CDCl3) d 0.88 (t, J¼6.9 Hz,
3H), 1.18 (d, J¼7.3 Hz, 3H), 1.27–1.30 (m, 10H), 1.57–
1.62 (m, 2H), 2.55–2.70 (m, 2H), 2.91 (dd, J¼4.5, 17.9 Hz,
1H), 3.18–3.27 (m, 1H), 3.54 (dd, J¼8.9, 17.9 Hz, 1H),
7.43–7.57 (m, 3H), 7.94–7.96 (m, 2H); 13C NMR
(100.6 MHz, CDCl3) d 14.1, 17.0, 22.7, 23.6, 29.1, 29.3,
29.4, 31.9, 41.1, 41.5, 41.9, 128.0, 128.6, 133.1, 136.7,
198.7, 213.8; IR (neat) n 1714, 1686 cm21; EIMS m/z 288
(Mþ); HRMS calcd for C19H28O2: 288.20893. Found:
288.20847.
5.4.2. (Z )-3-Butyl-1-phenyl-2-dodecene-1,4-dione
[(Z )-25b]. 1H NMR (400 MHz, CDCl3) d 0.87 (t, J¼
6.9 Hz, 3H), 0.95 (t, J¼7.3 Hz, 3H), 1.26–1.35 (m, 10H),
1.38–1.44 (m, 2H), 1.52–1.59 (m, 2H), 1.68–1.76 (quint,
J¼7.42 Hz, 2H), 2.35–2.40 (m, 2H), 2.55 (t, J¼7.58 Hz,
2H), 6.77 (t, J¼1.43 Hz, 1H), 7.44–7.94 (m, 5H); 13C NMR
(100.6 MHz, CDCl3) d 13.7, 14.0, 22.3, 22.6, 23.3, 29.0,
29.1, 29.2, 29.4, 31.8, 34.5, 41.5, 120.2, 128.5, 128.6,
133.1, 137.2, 162.5, 189.1, 209.2; IR (neat) n 2927, 1662,
1605 cm21; EIMS m/z 328 (Mþ); HRMS calcd for
C22H32O2 328.24023. Found 328.24195.
5.3.8. 4-Methyl-1-phenyl-3,6-tetradecanedione (18).
1
Colorless oil, H NMR (400 MHz, CDCl3) d 0.88 (t, J¼
6.9 Hz, 3H), 1.04 (d, J¼7.0 Hz, 3H), 1.20–1.31 (m, 10H),
1.50–1.58 (m, 2H), 2.31–2.45 (m, 2H), 2.84–3.05 (m, 7H),
7.16–7.29 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d
14.1, 16.5, 22.6, 23.7, 29.1, 29.2, 29.3, 29.6, 31.8, 41.0,

Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
7567
5.4.3. (E )-4-(1,1-Dimethylethyl)-3-tridecene-2,5-dione
1
406 (Mþ); HRMS calcd for C27H34O3 406.25079. Found
406.24908.
[(E )-25c]. H NMR (400 MHz, CDCl3) d 0.84 (dd, J¼6.9,
6.0 Hz, 3H), 1.18 (d, J¼6.58 Hz, 9H), 1.23–1.25 (m, 10H),
1.54–1.57 (quint, J¼6.8 Hz, 2H), 2.24 (d, J¼0.5 Hz, 1H),
2.50–2.53 (t, J¼7.3 Hz, 2H), 5.85 (s, 1H), 4.40 (s, 2H);
13C NMR (100.6 MHz, CDCl3) d 14.0, 22.5, 23.4,
29.0, 29.3, 29.6, 31.7, 31.8, 35.4, 42.9, 126.3, 160.9,
201.1, 207.3; IR (neat) n 2930, 1706, 1636 cm21; EIMS m/z
266 (Mþ); HRMS calcd for C17H30O2 266.22458. Found
266.22514.
5.4.9. (E )-3-(1,1-Dimethylethyl)-1-phenyl-2-dodecene-
1
1,4-dione [(E )-25e]. H NMR (400 MHz, CDCl3) d 0.86
(t, J¼6.8 Hz, 3H), 1.14 (s, 9H), 1.21–1.31 (m, 10H), 1.62–
1.77 (quint, J¼7.2 Hz, 2H), 2.70 (t, J¼7.3 Hz, 2H), 6.33 (s,
1H), 7.44 (t, J¼7.4 Hz, 2H), 7.57–7.96 (m, 3H); 13C NMR
(100.6 MHz, CDCl3) d 14.1, 22.6, 23.8, 29.1, 29.2, 29.4,
30.1, 31.8, 36.2, 43.1, 126.3, 128.7, 129.0, 133.7, 136.9,
159.3, 195.7, 207.2; IR (neat) n 2926, 1670 cm21; EIMS m/z
328 (Mþ). Anal. calcd for C22H32O2: C, 80.44; H, 9.82.
Found: C, 80.17; H, 9.80.
5.4.4. (Z )-4-(1,1-Dimethylethyl)-3-tridecene-2,5-dione
[(Z )-25c]. 1H NMR (400 MHz, CDCl3) d 0.86 (t, J¼
6.9 Hz, 3H), 1.15 (s, 9H), 1.26–1.29 (m, 10H), 1.67–1.75
(quint, J¼7.4 Hz, 2H), 2.20 (s, J¼6.4 Hz, 3H), 2.42 (t, J¼
7.6 Hz, 2H), 6.12 (s, 1H); 13C NMR (100.6 MHz, CDCl3) d
14.0, 22.6, 23.2, 29.1, 29.2, 29.3, 29.4, 30.5, 31.8, 35.4,
43.7, 121.1, 169.0, 197.1, 209.0; IR (neat) n 2925, 1696,
1598 cm21; EIMS m/z 266 (Mþ); HRMS calcd for
C17H30O2 266.22458. Found 266.22511.
5.4.10. (Z )-3-(1,1-Dimethylethyl)-1-phenyl-2-dodecene-
1
1,4-dione [(Z )-25e]. H NMR (400 MHz, CDCl3) d 0.87
(t, J¼7.0 Hz, 3H), 1.25–1.36 (m, 19H), 1.73–1.81 (quint,
J¼7.4 Hz, 2H), 2.52 (t, J¼7.6 Hz, 2H), 6.90 (s, 1H), 7.45–
7.94 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d 14.0,
22.6, 23.3, 29.1, 29.2, 29.4, 31.8, 36.1, 43.8, 118.0,
128.4, 128.6, 133.3, 137.7, 170.9, 189.4, 209.1; IR (neat)
n 2926, 1698, 1662, 1599 cm21; EIMS m/z 328 (Mþ). Anal.
calcd for C22H32O2: C, 80.44; H, 9.82. Found: C, 80.35; H,
9.78.
1
5.4.5. (E )-4-Phenyl-3-tridecene-2,5-dione [(E)-25a]. H
NMR (400 MHz, CDCl3) d 0.86 (t, J¼6.9 Hz, 3H), 1.23–
1.29 (m, 10H), 1.56–1.58 (m, 2H), 1.87 (s, 2H), 2.56 (t,
J¼7.3 Hz, 2H), 6.79 (s, 1H), 7.16–7.41 (m, 5H); 13C NMR
(100.6 MHz, CDCl3) d 14.1, 22.6, 24.0, 29.0, 29.2, 30.5,
31.7, 40.2, 128.6, 128.9, 129.0, 133.9, 134.5, 147.8, 201.2,
202.2; IR (neat) n 2925, 2854, 1687 cm21; EIMS m/z 286
(Mþ); HRMS calcd for C19H26O2 286.19328. Found
286.19249.
5.4.11. (E )-5-Butyl-2,2-dimethyl-4-tetradecene-3,6-
dione [(E )-25f]. 1H NMR (400 MHz, CDCl3) d 0.87
(t, J¼7.1 Hz, 3H), 0.89 (t, J¼7.1 Hz, 3H), 1.18 (s, 9H),
1.27–1.36 (m, 14H), 1.58–1.64 (m, 2H), 2.57 (t, J¼7.3 Hz,
2H), 2.66 (t, J¼7.4 Hz, 2H), 7.00 (s, 1H); 13C NMR
(100.6 MHz, CDCl3) d 13.8, 14.0, 22.6, 22.9, 24.4, 26.2,
27.2, 29.1, 29.2, 29.3, 31.5, 31.8, 38.7, 44.3, 127.4, 152.8,
203.3, 207.4; IR (neat) n 3000, 1685, 1608 cm21; EIMS m/z
308 (Mþ); HRMS calcd for C20H36O2 308.27153. Found
308.26984.
5.4.6. (Z )-4-Phenyl-3-tridecene-2,5-dione [(Z)-25a]. 1H
NMR (400 MHz, CDCl3) d 0.86 (t, J¼6.9 Hz, 3H), 1.18–
1.32 (m, 10H), 1.70 (quint, J¼7.4 Hz, 2H), 2.31 (s, 3H),
2.56 (t, J¼7.6 Hz, 2H), 6.50 (s, 1H), 7.38–7.41 (m, 5H); 13C
NMR (100.6 MHz, CDCl3) d 14.1, 22.6, 23.4, 29.0, 29.1,
29.3, 30.5, 31.8, 42.3, 122.2, 126.9, 129.0, 130.5, 133.2,
156.8, 196.6, 207.4; IR (neat) n 2925, 1686 cm21; EIMS m/z
286 (Mþ); HRMS calcd for C19H26O2 286.19328. Found
286.19420.
5.4.12. (Z )-5-Butyl-2,2-dimethyl-4-tetradecene-3,6-dione
[(Z)-25f]. 1H NMR (400 MHz, CDCl3) d 0.87 (t, J¼6.9 Hz,
3H), 0.92 (t, J¼7.3 Hz, 3H), 1.15 (s, 9H), 1.27–1.40 (m,
12H), 1.47 (quint, J¼7.4 Hz, 2H), 1.66 (m, 2H), 2.23–2.27
(m, 2H), 2.45 (t, J¼7.6 Hz, 2H), 6.26 (t, J¼1.3 Hz, 1H); 13C
NMR (100.6 MHz, CDCl3) d 13.7, 14.0, 22.2, 22.6, 23.3,
26.1, 29.11, 29.17, 29.2, 29.4, 31.8, 34.2, 41.3, 42.9, 119.2,
5.4.7. (E )-1-Phenyl-3-{2-[(phenylmethyl)oxy]ethyl}-2-
dodecene-1,4-dione [(E)-25d]. 1H NMR (400 MHz,
CDCl3) d 0.89 (t, J¼6.3 Hz, 3H), 1.27–1.32 (m, 12H),
1.60–1.65 (quint, J¼7.2 Hz, 2H), 2.76 (t, J¼7.4 Hz, 2H),
2.99 (t, J¼6.4 Hz, 2H), 3.60 (t, J¼6.4 Hz, 2H), 4.40 (s, 2H),
7.19–7.93 (m, 9H); 13C NMR (100.6 MHz, CDCl3) d 14.4,
23.0, 24.6, 28.5, 29.5, 29.6, 29.8, 32.2, 39.1, 69.6, 73.0,
127.7, 127.8, 128.6, 129.0, 129.1, 131.3, 133.9, 137.8,
138.7, 150.0, 193.1, 203.1; IR (neat) n 2924, 2854,
1666 cm21; EIMS m/z 406 (Mþ); HRMS calcd for
C27H34O3 406.25079. Found 406.25227.
161.2, 203.9, 209.6; IR (neat) n 2928, 1760, 1608 cm21
;
EIMS m/z 308 (Mþ); HRMS calcd for C20H36O2 308.27153.
Found 308.27088.
5.4.13. (E )-3-Butyl-1-(2-naphthalenyl)-2-dodecene-1,4-
1
dione [(E )-25g]. H NMR (400 MHz, CDCl3) d 0.85 (t,
J¼7.2 Hz, 3H), 0.89 (t, J¼6.8 Hz, 3H), 1.29–1.40 (m,
14H), 1.71 (quint, J¼7.3 Hz, 2H), 2.61 (t, J¼7.7 Hz, 2H),
2.81 (t, J¼7.4 Hz, 2H), 7.46 (s, 1H), 7.56–8.48 (m, 7H); 13C
NMR (100.6 MHz, CDCl3) d 13.7, 14.0, 22.6, 22.8, 24.4,
27.7, 29.1, 29.3, 29.4, 31.4, 31.8, 38.7, 123.8, 126.9, 127.8,
128.8, 129.6, 130.0, 130.6, 132.4, 134.8, 135.8, 152.3,
5.4.8. (Z )-1-Phenyl-3-{2-[(phenylmethyl)oxy]ethyl}-2-
dodecene-1,4-dione [(Z)-25d]. 1H NMR (400 MHz,
CDCl3) d 0.87 (t, J¼6.9 Hz, 3H), 1.19–1.26 (m, 10H),
1.64–1.69 (quint, J¼7.2 Hz, 2H), 2.54 (t, J¼7.6 Hz,
2H), 2.67–2.70 (dt, J¼1.2, 6.2 Hz, 2H), 3.69 (t, J¼
6.2 Hz, 2H), 4.54 (s, 2H), 6.88 (t, J¼1.2 Hz, 1H), 7.27–
7.92 (m, 10H); 13C NMR (100.6 MHz, CDCl3) d 13.1, 21.6,
22.3, 28.1, 28.4, 28.6, 30.8, 34.1, 40.6, 66.3, 72.2, 121.7,
126.8, 127.4, 127.5, 127.6, 132.2, 136.1, 136.8, 157.1,
188.3, 207.7; IR (neat) n 2917, 2850, 1698 cm21; EIMS m/z
192.9, 203.0; IR (neat) n 2926, 2856, 1662, 1626 cm21
;
EIMS m/z 378 (Mþ); HRMS calcd for C26H34O2 378.25588.
Found 378.25516.
5.4.14. (Z )-3-Butyl-1-(2-naphthalenyl)-2-dodecene-1,4-
1
dione [(Z )-25g]. H NMR (400 MHz, CDCl3) d 0.85 (t,
J¼7.0 Hz, 3H), 0.98 (t, J¼7.3 Hz, 3H), 1.25–1.31 (m,
10H), 1.43–1.48 (m, 2H), 1.59–1.62 (m, 2H), 1.75 (quint,

7568
Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
J¼7.4 Hz, 2H), 2.40–2.45 (m, 2H), 2.59 (t, J¼7.6 Hz, 2H),
6.93 (t, J¼1.4 Hz, 1H), 7.55–8.45 (m, 7H); 13C NMR
(100.6 MHz, CDCl3) d 13.8, 14.0, 22.4, 22.6, 23.4, 29.1,
29.2, 29.3, 29.4, 31.8, 34.6, 41.6, 120.4, 124.2, 126.8, 127.8,
128.6, 129.6, 130.1, 132.5, 134.6, 135.6, 162.4, 189.0,
209.2; IR (neat) n 2926, 1658, 1602 cm21; EIMS m/z 378
(Mþ); HRMS calcd for C26H34O2 378.25588. Found
378.25458.
5.4.20. 2,4-Dibutyl-3-(phenylcarbonyl)-2-cyclopenten-1-
one (28b). 1H NMR (400 MHz, CDCl3) d 0.72 (t, J¼7.3 Hz,
3H), 0.79 (t, J¼6.8 Hz, 3H), 1.22–1.30 (m, 9H), 1.58 (m,
1H), 2.01–2.10 (m, 2H), 2.19–2.24 (dd, J¼2.2, 18.9 Hz,
1H), 2.68–2.74 (dd, J¼6.5, 18.9 Hz, 1H), 3.23 (s, 1H), 7.49
(t, J¼7.8 Hz, 2H), 7.63 (t, J¼7.4 Hz, 1H), 7.84 (d, J¼
7.1 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) d 13.5, 13.8,
22.4, 22.5, 23.7, 29.8, 30.1, 33.5, 40.9, 41.0, 128.9, 129.0,
134.2, 135.9, 143.7, 168.7, 197.0, 208.0; IR (neat) n 1709,
1662 cm21; EIMS m/z 398 (Mþ); HRMS calcd for
C20H26O2 298.19328. Found: 298.19327.
5.4.15. (E )-3-Butyl-5-cyclohexyl-1-phenyl-2-pentene-
1
1,4-dione [(E)-25h]. H NMR (400 MHz, CDCl3) d 0.81
(t, J¼7.1 Hz, 3H), 1.09–1.72 (m, 12H), 1.80–1.85 (dd,
J¼1.2, 14.2 Hz, 2H), 1.95–2.05 (m, 1H), 2.34–2.38 (quint,
J¼8.2 Hz, 2H), 2.48 (d, J¼6.5 Hz, 2H), 6.75 (s, 1H), 7.42–
7.98 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d 13.8, 22.3,
26.2, 26.4, 29.3, 32.7, 33.3, 34.3, 48.6, 120.5, 128.5, 128.7,
133.1, 137.4, 162.1, 189.2, 208.1; IR (neat) n 2924,
1668 cm21; EIMS m/z 312 (Mþ); HRMS calcd for
C21H28O2 312.20893. Found: 312.20893.
5.4.21. 2-Butyl-4-(2-{[(1,1-dimethylethyl)(diphenyl)-silyl-
oxy]}ethyl)-3-(phenylcarbonyl)-2-cyclopenten-1-one
1
(28c). H NMR (400 MHz, CDCl3) d 0.72 (t, J¼7.6 Hz,
3H), 0.97 (s, 9H), 1.06–1.43 (m, 5H), 1.85–1.89 (m, 1H),
2.02–2.13 (m, 2H), 2.21–2.27 (dd, J¼2.2, 19.0 Hz, 1H),
2.63–2.69 (dd, J¼6.5, 19.0 Hz, 1H), 3.45–3.69 (m, 3H),
7.30–7.86 (m, 15H); 13C NMR (100.6 MHz, CDCl3) d 13.9,
19.4, 22.9, 24.2, 27.1, 27.3, 30.6, 36.9, 38.4, 41.5, 62.4,
128.0, 128.1, 129.4, 129.5, 130.0, 133.7, 133.8, 134.6,
135.8, 135.9, 136.2, 144.4, 169.1, 197.2, 208.3; IR (neat) n
1688 cm21; EIMS m/z 524 (Mþ); HRMS calcd for
C34H40O3Si 524.27467. Found: 524.27468.
5.4.16. (Z )-3-Butyl-5-cyclohexyl-1-phenyl-2-pentene-
1
1,4-dione [(Z)-25h]. H NMR (400 MHz, CDCl3) d 0.95
(t, J¼7.3 Hz, 3H), 1.09–1.72 (m, 12H), 1.80–1.85 (dd,
J¼1.2, 14.2 Hz, 2H), 1.95–2.05 (m, 1H), 2.34–2.38 (quint,
J¼8.2 Hz, 2H), 2.48 (d, J¼6.5 Hz, 2H), 6.75 (s, 1H), 7.42
(m, 5H); 13C NMR (100.6 MHz, CDCl3) d 13.8, 22.3, 26.2,
26.4, 29.3, 32.7, 33.3, 34.4, 48.6, 120.5, 128.5, 128.7, 133.1,
5.5. Enantioselective 1,2-acylation: general procedure
137.4, 162.1, 189.2, 208.1; IR (neat) n 2926, 1690 cm21
;
To a toluene solution of acylzirconocene chloride, which
was generated from alkene or alkyne (2.0 mmol) and
Cp2Zr(H)Cl (1.0 mmol) in CH2Cl2 (8 mL) as described
before, were added a,b-unsaturated ketone (1 mmol),
Pd(OAc)2 (5 mol%) and (R )-MeO-MOP (10 mol%) at
08C. After the reaction mixture was stirred for 20 h at
ambient temperature, the mixture was treated with aq.
NaHCO3 and extracted with ether. The combined organic
layer was washed with brine, dried over MgSO4, filtered and
concentrated. The crude product was purified by column
chromatography (hexane/ethyl acetate) to give pure
1,2-acylation product.
EIMS m/z 312 (Mþ); HRMS calcd for C21H28O2 312.20893.
Found: 312.20894.
5.4.17. (E )-3-Butyl-7,7-dimethyl-1-phenyl-2-octene-1,4-
dione [(E )-25i]. 1H NMR (400 MHz, CDCl3) d 0.88
(t, J¼7.0 Hz, 3H), 0.95 (s, 9H), 1.23–1.56 (m, 6H), 2.57
(t, J¼8.0 Hz, 2H), 2.68–2.77 (m, 2H), 7.33 (s, 1H), 7.45–
7.97 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d 13.8, 22.9,
27.6, 29.2, 30.2, 31.4, 34.4, 38.1, 128.6, 128.9, 129.8, 133.5,
152.4, 193.1, 203.3; IR (neat) n 2930, 1690 cm21; EIMS m/z
300 (Mþ); HRMS calcd for C20H28O2 300.20893. Found:
300.20892.
5.5.1. 1-(1-Hydroxy-2-cyclopenten-1-yl)-1-nonanone
(31). Colorless oil, 67% ee, [a ]2D5.0¼þ36.32 (c 1.02,
5.4.18. (Z )-3-Butyl-7,7-dimethyl-1-phenyl-2-octene-1,4-
1
dione [(Z )-25i]. H NMR (400 MHz, CDCl3) d 0.90 (s,
1
CHCl3). H NMR (400 MHz, CDCl3) d 0.87 (t, J¼6.8 Hz,
9H), 0.94 (t, J¼7.0 Hz, 3H), 1.41 (quint, J¼7.2 Hz, 2H),
1.54–1.58 (m, 2H), 1.65–1.69 (m, 2H), 2.30–2.41 (dt,
J¼1.4, 8.3 Hz, 2H), 2.51–2.54 (m, 2H), 6.78 (t, J¼1.3 Hz,
1H), 7.44 (t, J¼7.8 Hz, 2H), 7.56 (t, J¼7.0 Hz, 1H), (d,
J¼7.1 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) d 13.7, 22.3,
29.1, 29.2, 30.0, 34.6, 37.0, 37.2, 120.2, 128.5, 128.6, 133.1,
3H), 1.17–1.30 (m, 10H), 1.37–1.44 (m, 1H), 1.52–1.65
(m, 3H), 1.97 (td, J¼8.7, 13.7 Hz, 1H), 2.17–2.23 (m, 1H),
2.44–2.48 (m, 2H), 3.65 (s, 1H), 6.03 (td, J¼2.0, 10.0 Hz,
1H), 6.90–9.94 (m, 1H); 13C NMR (100.6 MHz, CDCl3) d
14.1, 22.6, 23.0, 25.3, 29.2, 29.5, 29.9, 31.8, 33.9, 36.0,
75.4, 126.5, 150.8, 202.9; IR (neat) n 3496, 1681 cm21
;
137.3, 162.5, 189.2, 209.7; IR (neat) n 2900, 1688 cm21
;
EIMS m/z 224 (Mþ); HRMS calcd for C14H24O2:
224.17763. Found: 224.17808.
EIMS m/z 300 (Mþ); HRMS calcd for C20H28O2 300.20893.
Found: 300.20895.
5.5.2. 1-[(1R )-1-Hydroxy-2-cyclohexen-1-yl]-1-nona-
none [(R )-2]. Colorless oil, 66% ee, [a ]2D4.0¼242.11 (c
1.04, CHCl3). 1H NMR spectrum was identical to racemic 2.
5.4.19. 3-Acetyl-4-butyl-2-phenyl-2-cyclopenten-1-one
1
(28a). H NMR (400 MHz, CDCl3) d 0.86 (t, J¼6.9 Hz,
3H), 1.17–1.28 (m, 5H), 1.70–1.73 (m, 1H), 2.05
(s, 3H), 2.30–2.35 (dd, J¼2.1, 1.9 Hz, 1H), 2.72–2.78
(dd, J¼6.7, 19.1 Hz, 1H), 3.28 (s, 1H), 7.23–7.40 (m, 5H);
13C NMR (100.6 MHz, CDCl3) d 14.0, 27.4, 29.0, 29.2,
30.6, 31.6, 39.4, 41.2, 128.6, 128.8, 129.1, 130.2, 142.2,
169.8, 203.4, 206.6; IR (neat) n 3389, 1700 cm21; EIMS m/z
256 (Mþ); HRMS calcd for C17H20O2 256.14633. Found:
256.14635.
5.5.3. 1-[(1R )-1-Hydroxy-2-cyclohepten-1-yl]-1-nona-
none (ent-5). Colorless oil, 38% ee, [a ]2D3.0¼235.65 (c
0.92, CHCl3). 1H NMR spectrum was identical to recemic 5.
5.5.4. (E )-3-Methyl-1-phenyl-1-dodecene-3-ol-4-one
(ent-7). Colorless oil 17% ee, [a ]2D4.8¼237.96 (c 1.11,
1
CHCl3). H NMR spectrum was identical to racemic 7.

Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
7569
5.5.5. (E )-4-Phenyl-2-tridecene-4-ol-5-one (ent-8). Color-
less oil 6% ee.27 1H NMR spectrum was identical to racemic
8.
solution of 35 (400 mg, 1.7 mmol) in ethanol (3 mL) at 08C
and the mixture was stirred at ambient temperature over-
night. After addition of aq. NaHCO3, the mixture was
extracted with ether and the combined ether layer was
washed with brine before drying (MgSO4). Concentration of
the filtrate to dryness and purification by silica gel column
chromatography (hexane/ethyl acetate¼60:1) gave 36
(661 mg, 95%) as colorless crystals. 36; [a ]2D6.0¼þ43.24
5.6. Preparation of (S )-2
5.6.1. 1-(1-Cyclohexen-1-yl)-1-nonanol (34). Under an
argon atmosphere, to a cold (2788C) suspension of cyclo-
hexanone-p-toluenesulfonylhydrazone (5 g, 18.8 mmol) and
TMEDA (50 mL) in hexane (600 mL) was slowly added a
n-BuLi (1.46 M in hexane, 28.8 mL). The mixture was
stirred at the same temperature for 0.5 and 8 h at ambient
temperature. After the mixture was chilled at 2788C, a
solution of 1-n-nonanal (2.9 mL, 17.1 mmol) in TMEDA
(10 mL) was added and the mixture was stirred for 2 h at
2788C and 8 h at ambient temperature. The reaction
mixture was treated with H2O and extracted with ether.
The combined ether layer was washed with brine, dried over
MgSO4 and filtered. Concentration of the filtrate gave a
crude residue which was purified by column chroma-
tography (hexane/ethyl acetate¼20:1) gave pure oil 34
1
(c 0.60, CHCl3), mp 91.0–92.58C; H NMR (400 MHz,
CDCl3) d 0.88 (t, J¼6.9 Hz, 3H), 1.24–1.36 (m, 11H),
1.46–1.63 (m, 7H), 1.70–1.94 (m, 4H), 2.10 (brs 1H),
2.17–2.24 (m, 1H), 3.32 (d, J¼2.1 Hz, 1H), 3.74 (d, J¼
10.5 Hz, 1H), 7.23–7.26 (m, 3H), 7.51–7.53 (m, 2H); 13C
NMR (100.6 MHz, CDCl3) d 14.1, 20.9, 21.5, 22.7, 26.0,
28.4, 28.9, 29.3, 29.6, 31.5, 31.9, 50.2, 75.2, 76.6, 127.5,
129.1, 130.2, 133.9; IR (neat) n 3388 cm21; EIMS m/z 398
(Mþ). Anal. calcd for C21H34O2Se: C, 63.46; H,8.66.
Found: C, 63.48; H, 8.58.
5.6.5. (4R,5R,6S )-2-Methoxy-4-octyl-6-(phenylselanyl)-
1,3-dioxaspiro[4,5]decane (37). To a solution of 36
(300 mg, 0.75 mmol) in DMF (3 mL) were added trimethyl
orthoformate (3 mL) and a catalytic amount of PPTS, and
the mixture was stirred for 4 h at ambient temperature. After
pouring the mixture into aq. NaHCO3, the mixture was
extracted with ether. The combined ether layer was washed
with brine, dried over MgSO4 and filtered. Concentration of
the filtrate gave crude oil which was purified by silica gel
column chromatography (hexane/ethyl acetate¼40:1) to
give 37 (330 mg, quant). 37; [a ]2D7.0¼þ41.13 (c 0.50,
1
(1.83 g, 48%). 34; H NMR (400 MHz, CDCl3) d 0.88 (t,
J¼6.7 Hz, 3H), 1.20–1.37 (m, 14H), 1.49–1.65 (m, 5H),
1.88–2.08 (m, 4H), 3.94 (t, J¼6.7 Hz, 1H), 5.64 (s, 1H); 13C
NMR (100.6 MHz, CDCl3) d 14.1, 22.7, 23.3, 24.0, 25.8,
29.3, 29.6, 29.7, 31.9, 34.8, 76.7, 123.0, 140.1; IR (neat) n
3346 cm21; EIMS m/z 224 (Mþ). Anal. calcd for C15H28O:
C, 80.29; H,12.58. Found: C, 80.32; H, 12.31.
5.6.2. (1R )-1-(1-Cyclohexen-1-yl)-1-nonanol [(R )-34]. To
a solution of rac-34 (1.69 g, 7.5 mmol) in CH2Cl2 (100 mL)
were added Ti(O-i Pr)4 (2.2 mL, 7.5 mmol) and L-(þ)-DIPT
(2.1 g, 9 mmol). After the mixture was chilled at 2208C,
t BuOOH was added and the mixture was stood overnight at
the same temperature. The mixture was poured into
H2O/acetone (1:10, 30 mL) and stirred for 1 h. After
addition of sat. aq. NaCl–30% NaOH solution, the mixture
was extracted with CH2Cl2. The combined organic layer
was dried over MgSO4, filtered and concentrated. Purifi-
cation of the reaction product by silica gel column
chromatography (hexane/ethyl acetate¼50:1) gave (R )-34
(90% ee, 756 mg, 45%) and epoxy alcohol (49% ee,
767 mg, 43%). (R )-34: colorless oil, [a]2D3.0¼þ6.6 (c 0.50,
CHCl3).
1
CHCl3), H NMR (400 MHz, CDCl3) d 0.88 (t, J¼6.9 Hz,
3H), 1.25–1.47 (m, 14H), 1.55–1.98 (m, 9H), 3.36 (s, 3H),
3.81 (dd, J¼2.1, 11.2 Hz, 1H), 5.65 (s, 1H), 7.24–7.27, (m,
3H), 7.47–7.50 (m, 2H); 13C NMR (100.6 MHz, CDCl3) d
14.1, 20.9, 21.2, 22.7, 25.7, 28.7, 29.2, 29.3, 29.4, 31.9,
31.9, 47.4, 52.6, 83.0, 85.4, 116.0, 127.3, 129.2, 130.6,
132.9; EIMS m/z 440 (Mþ). Anal. calcd for C23H36O3Se: C,
62.86; H, 8.26. Found: C, 62.85; H, 8.21.
5.6.6. 1-[(1S)-1-Hydroxy-2-cyclohexen-1-yl]-1-nonanone
[(S)-2]. (1) Elimination of PhSe-group and deprotection of
37. To an aq. THF (85%) solution (8 mL) of 37 (302 mg,
0.7 mmol) was added NaIO4 (1.5 g, 7 mmol) and the
mixture was stirred overnight at ambient temperature.
After the addition of aq. NaHCO3, the mixture was extracted
with ether. The ether solution was washed with brine, dried
and filtered before concentration. Purification of the crude
product by silica gel column chromatography (hexane/ethyl
acetate¼60:1) gave an elimination product (85 mg), whose
CH2Cl2 solution (85 mg in 5 mL) was treated with DIBAL-
H at 2788C and the solution was stirred at 08C for 10 min.
After adding 2 M solution of NaOH, the mixture was
extracted with ether. The ether solution was washed with
brine, dried over MgSO4 and filtered before concentration.
Purification by silica gel column chromatography (hexane/
ethyl acetate¼7:1) gave (1S)-1-[(1R )-1-hydroxynonyl]-2-
cyclohexen-1-ol (56 mg, 35% yield from 37). (1S)-1-[(1R)-
1-hydroxynonyl]-2-cyclohexen-1-ol: [a ]2D4.0¼þ40.15 (c
0.50, CHCl3), 1H NMR (400 MHz, CDCl3) d 0.88 (t,
J¼6.9 Hz, 3H), 1.27–1.36 (m, 12H), 1.43–1.49 (m, 1H),
1.56–1.65 (m, 2H), 1.67–1.76 (m, 3H), 1.91–2.10 (m, 3H),
2.67 (s, 1H), 3.46, (d, J¼9.0 Hz, 1H), 5.73 (d, J¼10.2 Hz,
1H), 5.93–5.97 (m, 1H); 13C NMR (100.6 MHz, CDCl3) d
5.6.3. (1R)-1-[(6R)-7-Oxabicyclo[4.1.0]hept-1-yl]-1-nona-
nol (35). According to the same procedure described for the
kinetic resolution of 34, The epoxidation of (R )-34 was
carried out by utilizing D-(2)-DIPT to give 35 (.95% ee,
1
692 mg, 90%). 35; [a ]2D6.0¼þ26.12 (c 1.38, CHCl3), H
NMR (400 MHz, CDCl3) d 0.88 (t, J¼6.9 Hz, 3H), 1.22–
1.61 (m, 18H), 1.70–1.84 (m, 3H), 1.96–2.04 (m, 1H), 2.13
(s, 1H), 3.20 (d, J¼2.5 Hz, 1H), 3.54 (d, J¼7.0 Hz, 1H); 13C
NMR (100.6 MHz, CDCl3) d 14.1, 19.7, 20.4, 22.7, 24.5,
25.1, 25.8, 29.3, 29.5, 29.8, 31.9, 32.8, 55.4, 62.3, 71.7; IR
(neat) n 3449, 2928, 2856, 1723 cm21; EIMS m/z 240 (Mþ).
Anal. calcd for C15H28O2: C, 74.95; H,11.74. Found: C,
74.77; H, 11.42.
5.6.4. (1R,2S )-1-[(1R )-1-Hydroxynonyl]-2-(phenylsela-
nyl)-cyclohexanol (36). To a solution of PhSeNa, which
was prepared from PhSeSePh (346 mg, 1.1 mmol) and
NaBH4 (87 mg, 2.3 mmol) in ethanol (10 mL), was added a

7570
Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
(t) Devasagayaraj, A.; Knochel, P. Tetrahedron Lett. 1995, 36,
8411.
14.1, 18.6, 22.7, 25.4, 26.7, 29.3, 29.6 29.7, 31.1, 31.9, 32.0,
72.2, 76.8, 128.3, 132.4; IR (neat) n 3396, 2924 cm21
;
EIMS m/z 223 (Mþ2OH); HRMS calcd for C15H27O
(Mþ2OH): 223.20619. Found: 223.20717.
3. For reviews, see; (a) Collman, J. P. Acc. Chem. Res. 1975, 342.
(b) Durfee, L. D.; Rothwell, I. P. Chem. Rev. 1988, 88,
1059.
4. (a) Corey, E. J.; Hegedus, L. S. J. Am. Chem. Soc. 1969, 91,
4926. (b) Myeong, S. K.; Sawa, Y.; Ryang, M.; Tsutsumi, S.
Bull. Chem. Soc. Jpn 1965, 38, 330. (c) Sawa, Y.; Hashimoto,
I.; Ryang, M.; Tsutsumi, S. J. Org. Chem. 1968, 33, 2159.
(d) Hermanson, J. R.; Hershberger, J. W.; Pinhas, A. R.
Organometallics 1995, 14, 5426. (e) Hegedus, L. S.; Tamura,
R. Organometallics 1982, 1, 1188.
(2) Swern oxidation. To a solution of (COCl)2 (0.03 mL,
023 mmol) in CH2Cl2 (7 mL) was added DMSO (0.05 mL,
0.69 mmol) at 2608C and the mixture was stirred for 0.5 h
at the same temperature. To the reaction mixture was added
a solution of (1S)-1-[(1R)-1-hydroxynonyl]-2-cyclohexen-
1-ol (56 mg, 0.23 mmol) in CH2Cl2 (2 mL) at 2608C and
the mixture was stirred for 15 min at the same temperature.
After addition of (C2H5)3N (0.1 mL, 0.74 mmol), the
mixture was stirred 5 min at 2608C and 1 h at ambient
temperature. After being added H2O, the mixture was
extracted with ether. The combined ether layer was washed
with brine, dried over MgSO4, filtered and concentrated.
The crude oil was purified by column chromatography
(hexane/ethyl acetate¼50:1) to give (S )-2 (41 mg, 75%
yield). (S )-2: [a ]2D6.6¼þ45.56 (c 0.57, CHCl3). 1H and 13C
NMR spectra were identical to those of rac-2.
5. (a) Collman, J. P.; Winter, S. R.; Clark, D. R. J. Am. Chem.
Soc. 1972, 94, 1788. (b) Yamashita, M.; Miyoshi, K.;
Nakazono, Y.; Suemitsu, R. Bull. Chem. Soc. Jpn 1982, 55,
1663. (c) McMurry, J. E.; Andrus, A. Tetrahedron Lett. 1980,
21, 4687. (d) Yamashita, M.; Yamamura, S.; Kurimoto, M.;
Suemitsu, R. Chem. Lett. 1979, 1067. (e) Alper, H.; Marchand,
B.; Tanaka, M. Can. J. Chem. 1979, 57, 598. (f) Yamashita,
M.; Tashika, H.; Uchida, M. Bull. Chem. Soc. Jpn 1992, 65,
1257. (g) Cooke, M. P., Jr.; Parlman, R. M. J. Am. Chem. Soc.
1977, 99, 5222.
6. (a) Hegedus, L. S.; Inoue, Y. J. Am. Chem. Soc. 1982, 104,
4917. (b) Hegedus, L. S.; Perry, R. J. J. Org. Chem. 1985, 50,
4955.
Acknowledgments
7. (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
(b) Schwartz, J.; Labinger, J. A. Angew. Chem. Int. Ed.
Engl. 1976, 15, 333. (c) Bertelo, C. A.; Schwartz, J. J. Am.
Chem. Soc. 1975, 97, 228. (d) Takacs, J. M. Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12, p 39.
(e) Labinger, J. A. Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, p
667. Reactions of acylzirconocene complex with alkyl-
aluminum reagents; (f) Waymouth, R. M.; Clauser, K. R.;
Grubbs, R. H. J. Am. Chem. Soc. 1986, 108, 6385.
(g) Waymouth, R. M.; Santarsiero, B. D.; Coots, R. J.;
Bronikowski, M. J.; Grubbs, R. H. J. Am. Chem. Soc. 1986,
108, 1427. (h) Waymouth, R. M.; Grubbs, R. H.
Organometallics 1988, 7, 1631. and the references cited
therein.
This research was supported by the Ministry of Education,
Science and Culture, Japan (no. C2 10672000).
References
1. (a) For reviews on unmasked acyl anion: see, Saalfrank, R. W.
Acyl Anionen und daren Derivate; Methoden der Organishen
Chemie; 1993; Houben-Weyl 4th ed. E-19d, p 567.
(b) Narayana, C.; Periasamy, M. Synthesis 1985, 253.
2. (a) Seyferth, D.; Hui, R. C.; Wang, W.-L. J. Org. Chem. 1993,
58, 5843. (b) Seyferth, D.; Weinstein, R. M.; Hui, R. C.;
Wang, W.-L.; Archer, C. M. J. Org. Chem. 1992, 57, 5620.
(c) Seyferth, D.; Weinstein, R. M.; Hui, R. C.; Wang, W.-L.;
Archer, C. M. J. Org. Chem. 1991, 56, 5768. (d) Hui, R.;
Seyferth, D. Org. Synth. 1990, 69, 114. (e) Seyferth, D.; Hui,
R. C.; Weinstein, R. M.; Wang, W.-L. Nova Acta Leopold.
1985, 59, 335. (f) Ryu, I.; Yamamoto, H.; Sonoda, N.; Murai,
S. Organometallics 1996, 15, 5459. (g) Kai, H.; Iwamoto, K.;
Chatani, N.; Murai, S. J. Am. Chem. Soc. 1996, 118, 7634.
(h) Orita, A.; Ohe, K.; Murai, S. Organometallics 1994, 13,
1533. (i) Orita, A.; Fukudome, M.; Ohe, K.; Murai, S. J. Org.
Chem. 1994, 59, 477. (j) Ryu, I.; Hayama, Y.; Hirai, A.;
Sonoda, N.; Orita, A.; Ohe, K.; Murai, S. J. Am. Chem. Soc.
1990, 112, 7061. (k) Hiiro, T.; Morita, Y.; Inoue, T.; Kambe,
N.; Ogawa, A.; Ryu, I.; Sonoda, N. J. Am. Chem. Soc. 1990,
112, 455. (l) Murai, S.; Ryu, I.; Iriguchi, J.; Sonoda, N. J. Am.
Chem. Soc. 1984, 106, 2440. (m) Kabalka, G. W.; Li, N.-S.;
Yu, S. Organometallics 1995, 14, 1565. (n) Li, N.-S.; Yu, S.;
Kabalka, G. W. J. Org. Chem. 1995, 60, 5973. (o) Kabalka,
G. W.; Gotsick, J. T.; Pace, R. D.; Li, N.-S. Organometallics
1994, 13, 5163. (p) Smith, K.; Pritchard, G. J. Angew. Chem.
Int. Ed. Engl. 1990, 29, 282. (q) Chemla, F.; Normant, J. F.
Tetrahedron 1997, 53, 17265. (r) Rathke, M. W.; Yu, H.
J. Org. Chem. 1972, 37, 1732. (s) Jackson, R. F. W.; Turner,
D.; Block, M. H. J. Chem. Soc., Perkin Trans. 1 1997, 865.
8. (a) Harada, S.; Taguchi, T.; Tabuchi, N.; Narita, K.; Hanzawa,
Y. Angew. Chem. Int. Ed. Engl. 1998, 37, 1696. Kagan et al.
has reported a similar reaction by utilizing acylsamarium
complexes. (b) Machrouhi, F.; Namy, J.-L.; Kagan, H. B.
Tetrahedron Lett. 1997, 38, 7183. (c) Namy, J.-L.; Colomb,
M.; Kagan, H. B. Tetrahedron Lett. 1994, 35, 1723. (d) Collin,
J.; Namy, J. L.; Dallemer, F.; Kagan, H. B. J. Org. Chem.
1991, 56, 3118. (e) Collin, J.; Dallemer, F.; Namy, J. L.;
Kagan, H. B. Tetrahedron Lett. 1989, 30, 7407. (f) Collin, J.;
Kagan, H. B. Tetrahedron Lett. 1988, 29, 6097.
9. (a) Hanzawa, Y.; Tabuchi, N.; Taguchi, T. Tetrahedron Lett.
1998, 39, 8141. (b) Hanzawa, Y.; Tabuchi, N.; Saito, K.;
Noguchi, S.; Taguchi, T. Angew. Chem. Int. Ed. Engl. 1999,
38, 2395.
10. It should be mentioned that the metal-catalyzed conjugate
addition of an alkenyl or alkylzirconocene chloride to a,
b-enones has been reported. (a) Loots, M. J.; Schwartz, J.
J. Am. Chem. Soc. 1977, 99, 8045. (b) Schwartz, J.; Loots,
M. J.; Kosugi, H. J. Am. Chem. Soc. 1980, 102, 1333.
(c) Dayrit, F. M.; Schwartz, J. J. Am. Chem. Soc. 1981, 103,
4466. (d) Lipshutz, B. H.; Wood, M. R. J. Am. Chem. Soc.
1994, 116, 11698. (e) Wipf, P.; Smitrovich, J. H. J. Org. Chem.

Y. Hanzawa et al. / Tetrahedron 58 (2002) 7559–7571
7571
1991, 56, 6494. (f) Wipf, P.; Xu, W.; Smitrovich, J. H.;
Lehmann, R.; Venanzi, L. M. Tetrahedron 1994, 50, 1935.
(g) Wipf, P.; Takahashi, H. Chem. Commun. 1996, 2675.
11. (a) Seyferth, D.; Hui, R. C. J. Am. Chem. Soc. 1985, 107, 4551.
(b) Seyferth, D.; Hui, R. C. Tetrahedron Lett. 1986, 27, 1473.
(c) Lipshutz, B. H.; Elworthy, T. R. Tetrahedron Lett. 1990,
31, 477. (d) Li, N.-S.; Yu, S.; Kabalka, G. W. Organometallics
1998, 17, 3815. and the references cited therein.
the Pd–CHIRAPHOS complex, see Yamaguchi, M.; Shima,
T.; Yamagishi, T.; Hida, M. Tetrahedron Lett. 1990, 31, 5049.
19. (þ)-NMDPP: (þ)-Neomenthyldiphenylphosphine.
20. (R )-MOP: (R )-2-(diphenylphosphino)-20-methoxy-1,10-
binaphthyl; (a) Hayashi, T. J. Synth. Org. Chem. Jpn 1994,
52, 900. (b) Uozumi, Y.; Hayashi, T. Pure Appl. Chem. 1992,
64, 1911. (c) Uozumi, Y.; Suzuki, N.; Ogiwara, A.; Hayashi,
T. Tetrahedron 1994, 50, 4293. (d) Uozumi, Y.; Tanahashi,
A.; Lee, S.-Y.; Hayashi, T. J. Org. Chem. 1993, 58, 1945.
21. Hayashi, T.; Iwamura, H.; Naito, M.; Matsumoto, Y.; Uozumi,
Y. J. Am. Chem. Soc. 1994, 116, 775.
12. Reactions of a,b-unsaturated aldehydes with acylzirconocene
chloride gave 1,2-adducts under Lewis acid- or silver salt-
mediated conditions. See, Ref. 8a.
13. Hanzawa, Y.; Tabuchi, N.; Taguchi, T. Tetrahedron Lett.
1998, 39, 6249.
22. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
14. Although the capture of the zirconocene enolate intermediate
with a carbon nucleophile was unsuccessful, we found an
efficient trapping of the enolate through an intramolecular
aldol reaction. For examples of conjugate addition–enolate
trapping reactions of organozirconocenes to a,b-enones, see
Refs. 10d,g.
23. (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.;
Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765.
24. A similar system to 34 has been reported to give the resolved
(R )-alcohol efficiently by the use of L-(þ)-DIPT under the
Sharpless kinetic resolution. See, Ref. 23.
15. (a) Trost, B. M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110,
2301. (b) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992,
114, 7933.
25. Although the highly diastereoselective epoxidation of (R )-34
is possible without adding chiral tartrate, we added
(2)-tartrate, whose chirality matches kinetically for (R )-34,
to improve the optical purity of epoxy alcohol 35.
26. Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.;
King, S. M. Org. Synth. 1993, 71, 77.
16. Denmark, S. E. Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford,
1991; Vol. 5, p 751.
17. (R )-BINAP: (R )-2,20-bis(diphenylphosphino)-1,10-binaphthyl
Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.;
Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori, R.
J. Org. Chem. 1986, 51, 629.
27. We could not determine the exact [a ]D value due to the nearly
racemic nature. The ee value was determined by chiral HPLC
analysis.
18. (R,R )-CHIRAPHOS: (2R,3R)-bis(diphenylphosphino)butane;