A convergent regiospecific synthesis of zirconium enolates

Article abstract of DOI:10.1016/j.tet.2003.09.022

α-Lithiated phenylsulphonyloxiranes insert into alkenylzirconocene chlorides with loss of phenylsulphinate to give zirconyloxiranes which smoothly rearrange by either α- or β- C-O cleavage to afford regiodefined zirconium enolates which may be further elaborated.

Full text of DOI:10.1016/j.tet.2003.09.022

Tetrahedron 59 (2003) 9857–9864
A convergent regiospecific synthesis of zirconium enolates
*
Aleksandra Kasatkin and Richard J. Whitby
Department of Chemistry, Southampton University, Highfield, Southampton, SO17 1BJ, UK
Received 2 July 2003; revised 1 August 2003; accepted 5 September 2003
Abstract—a-Lithiated phenylsulphonyloxiranes insert into alkenylzirconocene chlorides with loss of phenylsulphinate to give
zirconyloxiranes which smoothly rearrange by either a- or b- C–O cleavage to afford regiodefined zirconium enolates which may be
further elaborated.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
ð1Þ
Metallated oxiranes are widely used as nucleophiles, and as
sources of carbenes, but their use as carbenoids is much less
studied.1 The term ‘carbenoid’ was initially used for 1-halo-
1-metallo (usually lithio) species.2 The ring-strain present in
metallated oxiranes renders the alkoxide a sufficiently good
leaving group that carbenoid properties may be observed.1
We are interested in the insertion of carbenoids into
carbon–metal bonds to afford new organometallic
species—an inherently iterative reaction ideally suited to
ð2Þ
We have developed the insertion of a wide variety of
the development of novel multi component couplings.
carbenoids into zirconacycles and acyclic organozircono-
Lithiated oxiranes react with excess organolithium reagent
cene chlorides to provide useful multi component coupling
to give products formally derived by such an insertion,
methods.8–11 As part of this work we have demonstrated the
although the reaction is normally drawn as occurring via a
insertion of lithiated oxiranes into zirconacycles10 and
free carbene formed by a-elimination.1,3 A ‘carbenoid’
mechanism for the addition is via nucleophilic4 ring opening
acyclic organozirconocene chlorides.11 For example we
recently reported the addition of lithiated cyanooxiranes to
of the oxirane, probably best drawn as occurring via 1,2-
organozirconocene chlorides with opening of the oxirane
rearrangement of a ‘lithium-ate’ intermediate5 (Eq. (1),
ring to afford a,b-unsaturated nitriles after elimination of
M¼Li). The reaction of lithiated oxiranes with organo-
zirconocene oxide (Scheme 1).11 We now report the
aluminium compounds almost certainly occurs via such a
1,2-metallate rearrangement of an ‘ate’ complex (Eq. (1),
M¼AlR2).6 Negishi has demonstrated the insertion of
a-lithio-a-halo species into a variety of transition metal
species.7 Insertion into organozirconocenes was particularly
facile, probably because these exist as co-ordinatively
unsaturated ‘16 electron’ complexes which readily add the
carbenoid to afford an 18 electron ‘ate’ complex which may
undergo a 1,2-metallate rearrangement to afford the product
(Eq. (2)).
Keywords: zirconium enolate; carbenoid; lithiated oxirane; multi-
component; rearrangement.
*
Scheme 1. Insertion of lithiated cyanooxiranes into organozirconocene
chlorides.
Corresponding author. Tel.: þ44-23-8059-2777; fax: þ44-23-8059-3781;
e-mail: rjw1@soton.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.022

9858
A. Kasatkin, R. J. Whitby / Tetrahedron 59 (2003) 9857–9864
remarkably different course taken by the insertion when
lithiated phenylsulphonyloxiranes are used.
reaction of a metallated oxirane with a nucleophile which
does not directly cleave the oxirane ring. Presumably the
difference in behaviour compared with cyanooxiranes
(Scheme 1) is due to the much greater stability of the
phenylsulphinate anion compared with cyanide (pKa values
of phenylsulphinic acid and hydrogen cyanide in water are
2.1 and 9.2, respectively). The presence of the oxirane
oxygen is essential for sulphinate to act as a leaving group in
the 1,2-metallate rearrangement. For example lithiated
alkylsulphones do not insert into alkenylzirconocene
chlorides, but lithiated methoxymethylenesulphone does.9
Rearrangement of the zirconyloxirane 5 then affords the
zirconium enolate 6 which may be protonated to afford the
ketone 7.
2. Results and discussion
2.1. Insertion of b,b-disubstituted a-lithiated
phenylsulphonyloxiranes
Hydrozirconation of 1-octyne gave the alkenylzirconium
species 1a. After cooling to 2788C addition of the
b-disubstituted phenylsulphonyloxirane 2a followed by
lithium diisopropylamide (LDA) to generate the lithiated
oxirane 312 in situ, warming to 2608C, then quenching by
pouring into aqueous sodium bicarbonate solution gave a
mixture of the ketone 7a and a-hydroxyketone 8a in 13 and
63% isolated yields, respectively. The formation of 7a and
8a implies the intermediate formation of the zirconium
enolate 6a.13 A reasonable mechanism is attack of the
lithiated phenylsuphonyloxirane 3 on the alkenylzircono-
cene chloride 1 to form an ‘ate’ complex 4 which undergoes
a 1,2-metallate rearrangement with loss of phenylsulphinate
to afford the zirconyloxirane 5. This is the first example of
Rearrangements of lithiated oxiranes to carbonyl com-
pounds are known but these generally occur by cleavage of
the a-C–O bond and a mechanism involving a carbene
intermediate is usually postulated.1,14 Often yields and
selectivity are poor, and there are few examples of the
proposed intermediate enolates being productively
trapped.15 The only rearrangements of metallated oxiranes
to enolates which unambiguously involve cleavage of the b
Scheme 2. Formation and reactions of zirconium dienolates derived from b,b-disubstituted a-lithiated phenylsulphonyloxiranes.
Table 1. Formation and reaction of zirconium enolates derived from b,b-disubstituted phenylsulphonyloxiranes
Entry
Zirconocene 1
Phenylsulphonyloxirane 2
Ketone 7
Yield (%)a
a-Hydroxyketone 8
R1
R2
R3
Yield (%)a
1
2
3
4
5
6
7
n-C6H13
n-C6H13
(CH2)2OBn
(CH2)2OSitBuMe2
SiMe3
1a
1a
1b
1c
1d
1a
1a
Me
Me
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
2a
2b
2b
2b
2b
2c
2d
87
84
40
79
50
77
77
7a
7b
7c
7d
7e
7f
63
60
8a
8b
51
38
8c
8d
n-C6H13
n-C6H13
–(CH2)2C(O(CH2)2O)(CH2)2–
Me Bu
7g
a
Isolated yields based on phenylsulphonyloxirane.

A. Kasatkin, R. J. Whitby / Tetrahedron 59 (2003) 9857–9864
9859
C–O bond of which we are aware is of terminally
lithiated monosubstituted oxiranes, and lithiated oxazolinyl
oxiranes.16 The mechanism of b C–O bond cleavage of
lithiated oxiranes to afford an enolate may be viewed as an
electrocyclic ring opening,1,14,16 but for 5 to 6 we believe a
1,2-elimination more reasonable. The very poor overlap
between the s* orbital of the breaking C–O bond and C–Zr
s-bond in the starting oxirane implies that substantial
electron donation from the latter can only occur late on the
reaction pathway i.e. when the C–O bond is largely/
completely cleaved. A very similar mechanism is suggested
for Lewis acid catalysed rearrangements of b,b-disubsti-
tuted silyloxiranes.17a,b With the 1,2-elimination mechanism
formation of the enolate should be stereospecific, though we
have not yet investigated this aspect of the reaction.
reasonable yield (Table 1). Formation of the b-silylenones
7d and 8c are notable.
We further demonstrated the utility of the enolate 6
derived from zirconocene 1a and phenylsulphonyloxirane
2a by quenching the reaction with benzaldehyde and
butanal to afford aldol products 10a and 10b in reasonable
overall yields for a three component coupling reaction
(Scheme 2).
2.2. Insertion of b-monosubstituted a-lithiated
phenylsulphonyloxiranes
The reaction of a-lithiated b-monosubstituted-(E)-phenyl-
sulphonyloxiranes 11 with (E)-1-octenylzirconocene
chloride followed by aqueous quench gave the b,g-
unsaturated ketones 15 implying the enolates 14 as
intermediates (Scheme 3). The reaction thus follows a
similar course to that shown in Scheme 2 as far as the
zirconyloxirane 12, but then opening of the oxirane occurs
with cleavage of the bond between oxygen and the
metallated carbon (a-cleavage). There are several ways to
describe the mechanism for the rearrangement of 12 to 14.
Initial a-elimination of zirconium alkoxide to afford the
carbene 13 which inserts into the b C–H bond to afford the
enolate 14 (Scheme 3) is favoured by the strong affinity of
zirconium for oxygen. It is also the mechanism usually
drawn for rearrangement of lithiated oxiranes to enolates.1,14
Alternatively cleavage of the a C–O bond accompanied by
1,2-hydride migration to afford the a-zirconylketone 18,
which may rearrange to the enolate 14 (Eq. (3)) has
precedent in the Lewis acid catalysed rearrangement of
many oxiranes,19 in particular of silyloxiranes to b-silyl-
ketones.17a,c The above are two extreme forms of a
mechanism in which a-elimination of zirconium alkoxide
is concerted with migration of the b-hydride to afford 14
directly (Eq. (4)). The transition state 19 for this process
The remarkably facile oxidation of the enolate 6 to afford
the alcohol 8 on aqueous quench in air is notable.18
Quenching with deoxygenated water under argon gave only
the ketone 7. Quenching the reaction mixture under an
oxygen atmosphere slightly improved the selectivity for 8
over 7, but also gave a little (5–10%) of the hydroperoxide
9. The small amounts of hydroperoxide 9 formed could be
converted to the alcohol 8 in situ by addition of
dimethylsulphide. Stirring the enolate 6 under an oxygen
atmosphere for 30 min followed by careful purging (via
freeze/evacuate/thaw cycles) of all the oxygen before
quenching with oxygen free aqueous sodium bicarbonate
solution gave only the ketone 7. The simultaneous presence
of oxygen and aqueous sodium bicarbonate is thus
necessary for the formation of 8 and 9. The predominant
formation of the alcohol 8 rather than hydroperoxide 9 in the
reaction has some precedent,18 but could also be due to the
presence of phenylsulphinic acid, a competent reducing
agent, from the initial elimination. By variation of the
starting alkyne, and phenylsulphonyloxirane, a range of
ketones 7 and a-hydroxyketones 8 were formed in
Scheme 3. Formation and reactions of zirconium dienolates derived from b-monosubstituted a-lithiated phenylsulphonyloxiranes.

9860
A. Kasatkin, R. J. Whitby / Tetrahedron 59 (2003) 9857–9864
resembles that well established for Simmons Smith
cyclopropanation,20 however, initial orbital alignment is
very poor implying a late transition state with much of the
character of 13. Cope demonstrated that in rearrangements
of lithiated oxiranes via a C–O bond cleavage to afford
carbonyl compounds it is the group cis to the metal which
migrates.21 The Lewis acid induced rearrangement of
silyloxiranes to b-silyl ketones has also been shown to
involve selective 1,2-migration of the group cis to the
silicon.17a,c It is thus surprising that we found that the yield
of ketone 15c from (Z)-b-phenyl phenylsulphonyloxirane
was higher than from the (E)-isomer 11 (R2¼Ph), though
both were poor.
shows the same regiochemical preference.17 In 12 breaking
of the b C–O bond is disfavoured as positive charge build-up
would be on a secondary centre, and the observed 1,2-shift
favoured by the good migrating group ability of hydride.
3. Conclusions
Reaction of in situ generated a-lithio phenylsulphonyl-
oxiranes with alkenylzirconocene chlorides derived by
hydrozirconation of alkynes affords zirconyloxiranes
which incorporate the alkenyl fragment via a 1,2-metallate
rearrangement with loss of phenylsulphinate. Subsequent
rearrangement to zirconium enolates through cleavage of
either a- or b-oxirane C–O bonds is facile, probably due to
promotion by the Lewis acidity of the zirconium. The
enolates so formed may be further elaborated by aldol
reaction to provide a novel one-pot three component
coupling reaction. The exceptionally facile oxidation of
1,1-disubstututed-2-(chloro(biscyclopentadienyl)zirconyl)-
oxydienes with air to afford a-hydroxyketones is also notable.
ð3Þ
ð4Þ
4. Experimental
It is interesting that even when the aqueous quench of
enolates 14 was carried out in an atmosphere of oxygen
there was no formation of a-hydroxyketones analogous to 8.
Work-up of the enolates with aldehydes gave the aldol
products 16 in good overall yield but poor diastereo-
selectivity. Alkyl aldehydes required the addition of
BF3·Et2O for clean reaction. Although the aldol products
could be separated by column chromatography they were
rather unstable and elimination to the a,b-unsaturated
ketones 17 was used to provide more stable derivatives. The
E/Z composition of the products 17 was influenced by the
diastereoisomer of the aldol product 16 used, but was not
stereospecific.
4.1. General techniques
1H and 13C NMR spectra were recorded on a Bruker AC300
spectrometer (300 MHz proton, 75 MHz carbon) in CDCl3.
Chemical shifts are reported as values in ppm relative to
tetramethylsilane, referenced to solvent (CHCl3/CDCl3).
The following abbreviations are used in proton spectra to
denote multiplicity and shape of signal and may be
compounded: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, br¼broad. 13C spectra were proton
decoupled. Atmospheric pressure chemical ionisation
(APCI) mass spectra were recorded on a VG Platform
spectrometer in acetonitrile. m/z signals are reported as
values in atomic mass units followed by the peak intensity
relative to the base peak. High Resolution Mass Spectra
(HRMS) were recorded on a VG Analytical 70-250-SE
double focusing mass spectrometer using either electron
impact (EI) (70 eV) or chemical ionisation (CI) (using
ammonia as the reagent gas) as indicated. Infra-red spectra
were recorded on a Perkin–Elmer 1600 FT-IR spectrometer
as films between sodium chloride plates. Elemental analyses
were performed by the University College London
Microanalysis Service. Organometallic reactions were
performed under argon using standard Schlenk techniques.
Boiling points (bp) refer to oven temperatures in Kugelrohr
distillation at the pressure specified.
2.3. Explanation of reactivity and regioselectivity
The remarkably facile rearrangement of a-zirconyl oxiranes
to zirconium enolates, and the difference in behaviour of
b-monosubstititued and b,b-disubstituted phenylsulphonyl-
oxiranes in giving regioisomeric dienolates 6 and 14,
respectively requires explanation. We believe that action of
the zirconium as a Lewis acid towards the oxirane oxygen
during these rearrangements is important. The structure of
Cp2Zr(Cl)(CH2OMe) shows strong bonding between the
oxygen and zirconium, and its reactivity is consistent with
an ‘oxonium ion’ depiction.22 The rearrangements of
zirconyloxiranes to enolates could thus be considered to
be both ‘pushed’ by the anionic character of the carbon to
which zirconium is attached, and ‘pulled’ by Lewis acid
interaction of the zirconium with the oxirane oxygen.
4.2. Materials
Cp2Zr(H)Cl (Schwartz reagent) was purchased from
Aldrich and weighed out in a glovebag under nitrogen.
The phenylsulphonyloxiranes were prepared by the reaction
of phenyl chloromethyl sulphone with acetone, cyclo-
hexanone, 1,4-cyclohexanedione mono-ethylene ketal,
methyl pentyl ketone, butanal, and isobutanal, respectively,
in 50% aq. NaOH–triethylbenzylammonium chloride (cat.)
system.23,24 Trans- and cis-2-phenyl-1-phenylsulphonyl-
oxiranes were prepared by stereoselective epoxidation of
The transition state for rearrangement of the zirconyl
oxiranes 5 to enolates 6 (b-C–O cleavage) must involve
substantial positive charge build-up on the carbon b to the
zirconium since the zirconium-carbon bond is initially close
to orthogonal to the breaking C–O bond’s s* orbital. The
b-C–O bond cleavage will thus be strongly favoured when
the b-position is tertiary, as in 5 (cf. secondary as in 12).
The Lewis acid catalysed rearrangement of silyloxiranes

A. Kasatkin, R. J. Whitby / Tetrahedron 59 (2003) 9857–9864
9861
trans- and cis-b-styryl phenyl sulphones with lithium tert-
butyl hydroperoxide.25 Tetrahydrofuran was freshly
distilled from sodium/benzophenone. Petrol refers to the
fraction of petroleum ether that has a boiling range 40–608C
and was distilled before use.
1H), 3.68 (t, J¼6.4 Hz, 2H), 6.14 (d, J¼15.8 Hz, 1H), 6.80
(dt, J1¼15.8 Hz, J2¼7.0 Hz, 1H). 13C NMR: d 18.42, 25.89,
26.00, 28.86, 36.07, 48.53, 61.77, 130.37, 143.76, 203.46.
IR: 1694, 1669, 1629, 1253, 1102, 835, 776 cm21. Anal.
calcd for C17H32O2Si: C 68.86, H 10.88; found: C 68.77, H
10.89.
4.3. General procedure for the formation of zirconium
enolates
4.4.5. (E)-1-Cyclohexyl-3-trimethylsilyl-2-propen-1-one
(7e). 1H NMR: d 20.02 (s, 9H), 1.05–1.70 (m, 10H),
2.53 (m, 1H), 6.40 (d, J¼19.1 Hz, 1H), 6.95 (d, J¼19.1 Hz,
1H). 13C NMR: d 21.62, 25.88, 26.03, 28.82, 47.91, 140.91,
146.47, 203.15. IR: 1682, 1249, 1219, 1101, 987, 868, 843,
750 cm21. Anal. calcd for C12H22OSi: C 68.51, H 10.54, Si
13.35; found: C 68.40, H 10.51, Si 13.53.
To a stirred suspension of Cp2Zr(H)Cl (0.297 g, 1.15 mmol)
in THF (9.0 mL) was added 1-octyne (0.110 g, 1.00 mmol).
The mixture was stirred at 208C for 1 h to give a clear
yellow solution of (E)-octenylzirconocene chloride. After
cooling to 2908C a solution of the phenylsulphonyloxirane
2a (0.163 g, 0.77 mmol) in THF (2.5 mL) was added
followed by a solution of LDA (1.00 mmol, 0.50 mL,
2.0 M in heptane/THF/ethylbenzene). The reaction
mixture was stirred at 290 to 2608C for 1 h to afford a
solution of the zirconium enolate ready for the next
reactions.
4.4.6. (E)-1-(1.4-Dioxaspiro[4.5]dec-8-yl)-2-nonen-1-one
(7f). Bp 180–1858C/0.5 mm Hg. 1H NMR: d 0.88 (m, 3H),
1.20–1.85 (m, 16H), 2.20 (m, 2H), 2.58 (m, 1H), 3.92 (s,
4H), 6.17 (d, J¼15.8 Hz, 1H), 6.88 (dt, J1¼15.8 Hz,
J2¼7.0 Hz, 1H). 13C NMR: d 14.20, 22.68, 26.23, 28.21,
29.01, 31.72, 32.63, 34.15, 47.23, 64.44, 108.31, 128.29,
147.71, 202.52. IR: 1692, 1666, 1625, 1458, 1364, 1102,
1035, 929 cm21. Anal. calcd for C17H28O3: C 72.82, H
10.06; found: 72.47, H 10.17.
4.4. Protonation of enolates
To the solution of the zirconium enolate prepared above was
added degassed saturated NaHCO3 aq. (6 mL) at 2608C.
The cooling bath was immediately removed, and the
mixture was stirred at 208C for 1 h. After extraction with
ether (2£6 mL) the organic layer washed with 2 M HCl aq.
(5 mL), brine (2£10 mL), dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by
column chromatography on silica gel (40–60 petrol
ether/EtOAc mixtures) to give the product a,b- or b,g-
unsaturated ketone as colourless to very pale yellow oils in
the yields given in the tables.
4.4.7. (E)-6-Methyl-8-pentadecen-7-one (7g). Bp 140–
1458C/0.5 mm Hg. 1H NMR: d 0.82 (m, 6H), 1.00 (d,
J¼7.0 Hz, 3H), 1.15–1.65 (m, 16H), 2.15 (m, 2H), 2.68 (tq,
J1¼J2¼7.0 Hz, 1H), 6.07 (d, J¼15.8 Hz, 1H), 6.80 (dt,
J1¼15.8 Hz, J2¼7.0 Hz, 1H). 13C NMR: d 14.17, 16.74,
22.66, 27.13, 28.24, 28.99, 31.73, 32.04, 32.62, 33.39,
43.94, 129.03, 147.49, 204.38. IR: 1696, 1670, 1627, 1459,
1377, 977, 737 cm21. Anal. calcd for C16H30O: C 80.61, H
12.68; found: C 80.38, H 12.76.
4.4.1. (E)-2-Methyl-4-undecen-3-one (7a). Bp 110–
1158C/0.5 mm Hg). Proton and carbon NMR, and IR data
consistent with the literature.26 Anal. calcd for C12H22O: C
79.06, H 12.16; found: C 78.82, H 12.37.
4.4.8. (E)-6-Tridecen-4-one (15a). Bp 95–1008C/
0.5 mm Hg. 1H NMR: d 0.82 (m, 6H), 1.10–1.35 (m,
10H), 1.52 (tq, J1¼J2¼7.0 Hz, 2H), 1.97 (m, 2H), 2.35 (t,
J¼7.0 Hz, 2H), 3.02 (d, J¼5.2 Hz, 2H), 5.45 (m, 2H). 13C
NMR: d 13.85, 14.21, 17.28, 22.75, 28.95, 29.32, 31.83,
32.72, 44.14, 47.00, 121.99, 135.32, 209.81. IR: 1714, 1464,
1408, 1366, 1124, 967, 725 cm21. Anal. calcd for C13H24O:
C 79.53, H 12.32; found: C 79.15, H 12.28.
4.4.2. (E)-1-Cyclohexyl-2-nonen-1-one (7b). Bp 140–
1
1458C/0.5 mm Hg. H NMR: d 0.80 (m, 3H), 1.10–1.45
and 1.55–1.80 (m, 18H), 2.11 (m, 2H), 2.46 (m, 1H), 6.07
(d, J¼15.8 Hz, 1H), 6.78 (dt, J1¼15.8 Hz, J2¼7.0 Hz, 1H).
13C NMR: d 14.18, 22.68, 25.90, 26.04, 28.24, 28.86, 29.01,
31.73, 32.62, 48.66, 128.70, 147.31, 203.62, IR: 1692, 1665,
1626, 1450, 977, 756 cm21. Anal. calcd for C15H26O: C
81.02, H 11.79; found: C 81.10, H 11.95.
4.4.9. (E)-2-Methyl-5-dodecen-3-one (15b). Bp 90–938C/
1
0.5 mm Hg. H NMR: d 0.88 (m, 3H), 1.10 (d, J¼7.0 Hz,
6H), 1.20–1.40 (m, 8H), 2.02 (m, 2H), 2.67 (qq,
J1¼J2¼7.0 Hz, 1H), 3.12 (d, J¼5.2 Hz, 2H), 5.52 (m,
2H). 13C NMR: d 14.07, 18.18, 22.60, 28.80, 29.19, 31.69,
32.58, 40.15, 44.47, 121.99, 134.90, 213.18. IR: 1714, 1466,
1382, 967 cm21. Anal. calcd for C13H24O: C 79.53, H
12.32; found: C 79.44, H 12.30.
4.4.3. (E)-1-Cyclohexyl-5-benzyloxy-2-penten-1-one (7c).
1H NMR: d 1.10–1.40 and 1.55–1.80 (m, 10H), 2.46 (m,
3H), 3.52 (t, J¼6.4 Hz, 2H), 4.45 (s, 2H), 6.13 (d,
J¼15.8 Hz, 1H), 6.80 (dt, J1¼15.8 Hz, J2¼7.0 Hz, 1H),
7.24 (m, 5H). 13C NMR: d 25.90, 26.05, 28.83, 33.02, 48.65,
68.52, 73.21, 127.86, 128.58, 130.25, 138.24, 143.39,
203.43. IR: 1738, 1692, 1664, 1626, 1451, 1365, 1100,
735, 698 cm21. MS (APCI) 273 (MþH, 51%), 272 (62), 165
(100), 145 (69), 132 (36). HRMS (EI) calcd for C18H24O2
(M): 272.1776, found: 272.1783.
4.4.10. (E)-1-Phenyl-3-decen-1-one (15c). 1H NMR: d 0.88
(m, 3H), 1.20–1.40 (m, 8H), 2.05 (m, 2H), 3.70 (d,
J¼5.1 Hz, 2H), 5.65 (m, 2H), 7.42–7.60 and 7.98 (m 5H).
IR: 1686, 1448, 1207, 967, 754, 690 cm21. MS (APCI) 231
(MþH, 100%). HRMS (CI) calcd for C16H23O (MþH):
231.1749, found: 231.1728.
4.4.4. (E)-1-Cyclohexyl-5-tert-butyldimethylsilyloxy-2-
1
4.5. Oxidation of enolates
penten-1-one (7d). H NMR: d 0.00 (s, 6H), 0.85 (s, 9H),
1.15–1.40 and 1.55–1.80 (m, 10H), 2.37 (m, 2H), 2.52 (m,
The solution of the zirconium enolate prepared above was

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A. Kasatkin, R. J. Whitby / Tetrahedron 59 (2003) 9857–9864
added dropwise to saturated NaHCO3 aq. (20 mL) at 208C
with vigorous stirring under an oxygen atmosphere. The
resulting mixture was stirred at 208C for 1 h and extracted
with ether (2£6 mL). The organic layer was washed with
brine (2£10 mL), then Me2S (0.095 g, 1.54 mmol) was
added and the mixture was kept at 208C overnight. After
drying over MgSO4 and concentration under reduced
pressure the residue was purified by column chromato-
graphy on silica gel (40–60 petrol ether/EtOAc, mixtures)
to give the product a-hydroxyketones as colourless oils in
the yields given in Table 1.
4.6.1. (E)-1-Phenyl-1-hydroxy-2,2-dimethyl-4-undecen-
1
3-one (10a). H NMR: d 0.91 (m, 3H), 1.07 (s, 3H), 1.17
(s, 3H), 1.25–1.55 (m, 8H), 2.25 (m, 2H), 3.37 (br s, 0H),
4.96 (s, 1H), 6.56 (d, J¼15.4 Hz, 1H), 7.04 (dt, J1¼15.4 Hz,
J2¼7.0 Hz, 1H), 7.33 (m, 5H). 13C NMR: d 14.23, 18.19,
22.71, 22.80, 28.24, 29.04, 31.74, 32.78, 51.01, 78.38,
124.87, 127.70, 127.83, 128.10, 140.28, 149.32, 205.65. IR:
3450 br, 1738, 1681, 1619, 1365, 1228, 1217, 703 cm21
.
MS (APCI) 287 (MþH, 9%), 271 (8), 224 (100), 183 (71),
139 (37). HRMS (EI) calcd for C19H28O2 (M): 288.2089,
found: 288.2093.
1
4.5.1. (E)-2-Methyl-2-hydroxy-4-undecen-3-one (8a). H
4.6.2. (E)-4-Hydroxy-5,5-dimethyl-7-tetradecen-6-one
1
(10b). H NMR: d 0.93 (m, 6H), 1.15 (s, 3H), 1.20 (s,
NMR: d 0.79 (m, 3H), 1.15–1.45 (m, 8H), 1.30 (s, 6H), 2.20
(m, 2H), 3.95 (br s, 0H), 6.35 (d, J¼15.4 Hz, 1H), 7.07 (dt,
J1¼15.4 Hz, J2¼7.0 Hz, 1H). 13C NMR: d 14.44, 22.93,
26.72, 28.34, 29.25, 31.95, 33.18, 75.51, 122.54, 151.66,
202.78. IR: 3450 br, 1688, 1625, 1465, 1362, 1163, 1081,
971 cm21. MS (APCI) 199 (MþH, 100%), 181 (14), 153
(30). HRMS (CI) calcd for C12H23O2 (MþH): 199.1698,
found: 199.1693.
3H), 1.25–1.70 (m, 12H), 2.23 (m, 2H), 2.57 (br s, 0H), 3.70
(m, 1H), 6.50 (d, J¼15.4 Hz, 1H), 6.98 (dt, J1¼15.4 Hz,
J2¼7.0 Hz, 1H). 13C NMR: d 14.19, 19.55, 20.07, 21.61,
22.69, 28.23, 29.01, 31.72, 32.73, 33.72, 50.60, 76.19,
124.87, 148.96, 205.45. IR: 3450 br, 1682, 1620, 1466,
977 cm21. MS (APCI) 255 (MþH, 100), 224 (61), 183 (45),
139 (28). HRMS calcd for C16H31O2 (MþH): 255.2324,
found: 255.2326.
4.5.2. (E)-1-(1-Hydroxycyclohexyl)-2-nonen-1-one (8b).
1H NMR: d 0.90 (m, 3H), 1.20–1.80 (m, 18H), 2.25 (m,
2H), 3.87 (br s, 0H), 6.50 (d, J¼15.4 Hz, 1H), 7.16 (dt,
J1¼15.4 Hz, J2¼7.0 Hz). 13C NMR: d 14.19, 21.25, 22.67,
25.49, 28.13, 29.01, 31.71, 32.95, 33.76, 77.03, 122.56,
4.6.3. (E)-5-[Hydroxy(phenyl)methyl]-6-tridecen-4-one
1
(16a). H NMR: d 0.70 (t, J¼6.8 Hz, 3H), 0.80 (m, 3H),
1.00–1.55 (m, 10H), 1.97 (m, 2H), 2.05 and 2.30 (two m,
2H), 3.07 (br s, 0H), 3.25 (dd, J1¼8.5 Hz, J2¼5.9 Hz, 1H),
4.90 (d, J¼5.9 Hz, 1H), 5.40–5.55 (m, 2H), 7.20 (m, 5H)
(main isomer); 0.80 (m, 6H), 1.00–1.55 (m, 10H), 1.80 (m,
2H), 2.22–2.48 (m, 2H), 3.07 (br s, 0H), 3.38 (dd,
J1¼9.2 Hz, J2¼8.5 Hz, 1H), 4.85 (d, J¼8.5 Hz, 1H), 5.11
(dd, J1¼15.4 Hz, J2¼9.2 Hz, 1H), 5.30 (dt, J1¼15.4 Hz,
J2¼6.6 Hz, 1H), 7.20 (m, 5H) (minor isomer). 13C NMR: d
13.67, 14.23, 16.78, 22.74, 28.85, 29.16, 31.79, 32.80,
44.79, 64.09, 73.70, 123.44, 126.63, 127.67, 128.28, 138.48,
141.45, 212.43 (main isomer).
151.07, 202.63. IR: 3450 br, 1682, 1622, 985 cm21
.
MS (APCI) 239 (MþH, 100), 221 (12), 139 (32).
HRMS (EI) calcd for C15H27O2 (MþH): 239.2011, found:
239.2011.
4.5.3. (E)-1-(1-Hydroxycyclohexyl)-5-tert-butyldimethyl-
silyloxy-2-penten-1-one (8c). 1H NMR: d 0.02 (s, 6H), 0.85
(s, 9H), 1.20–1.75 (m, 10H) 2.43 (m, 2H), 3.74 (t,
J¼6.4 Hz, 2H), 3.80 (br s, 0H), 6.53 (d, J¼15.4 Hz, 1H),
7.08 (dt, J1¼15.4 Hz, J2¼7.0 Hz, 1H). 13C NMR: 18.38,
21.22, 25.47, 25.98, 33.70, 36.30, 61.43, 77.05, 124.25,
147.51, 202.40. IR: 3450 br, 1684, 1626, 1255, 1096, 984,
835, 776 cm21. MS (APCI) 313 (MþH, 100), 295 (8), 213
(16). HRMS (EI) calcd for C17H33O3Si (MþH): 313.2199,
found: 313.2204.
4.6.4. 1-Phenyl-2-(1-octenyl)-1-hexen-3-one (17a). To a
solution of 16a (0.151 g, 0.50 mmol) in CH2Cl2 (3.0 mL)
was added triethylamine (0.101 g, 1.00 mmol) and MsCl
(0.074 g, 0.65 mmol) at 08C. The reaction mixture was
stirred at 0 to 208C for 3 h, then diluted with ether (6 mL)
and washed with 2 M HCl aq. (5 mL) followed by saturated
NaHCO3 aq. (5 mL). After drying over MgSO4 and
concentration under reduced pressure the crude mesylate
was dissolved in CH2Cl2 (3.0 mL). DABCO (0.084 g,
0.75 mmol) was added, the mixture was stirred at 208C for
18 h and diluted with ether (6 mL). After washing with 2 M
HCl aq. (5 mL) the organic layer was dried over MgSO4 and
concentrated under reduced pressure. The crude diene was
purified by column chromatography on silica gel (40–60
petrol ether/EtOAc, 20:1) to afford the title dienone 17a
(0.081 g, 57% yield) as a mixture of Z,E- and E,E-isomers.
1H NMR: d 0.82 (m, 3H), 0.91 (t, J¼6.8 Hz, 3H), 1.15–1.40
(m, 8H), 1.62 (tq, J1¼J2¼6.8 Hz, 2H), 2.08 (m, 2H), 2.65 (t,
J¼7.4 Hz, 2H), 5.88 (dt, J1¼16.2 Hz, J2¼7.0 Hz, 1H), 6.20
(d, J¼16.2 Hz, 1H), 6.93 (s, 1H), 7.10–7.40 (m, 5H) (Z,
E-isomer); 0.77 (m, 3H), 0.91 (t, J¼6, 8 Hz, 3H), 1.15–1.40
(m, 8H), 1.52 (tq, J1¼J2¼6.8 Hz, 2H), 2.04 (m, 2H), 2.32 (t,
J¼7.4 Hz, 2H), 5.56 (dt, J1¼15.8 Hz, J2¼7.0 Hz, 1H), 6.02
(d, J¼15.8 Hz, 1H), 6.36 (s, 1H), 7.10–7.40 (m, 5H) (E,E-
isomer). 13C NMR: d 14.01, 14.26, 18.19, 22.75, 29.08,
31.85, 33.73, 42.64, 123.61, 128.42, 128.67, 130.24, 133.86,
4.5.4. (E)-1-(1-Hydroxycyclohexyl)-3-trimethylsilyl-2-
1
propen-1-one (8d). H NMR: d 0.03 (s, 9H), 1.10–1.65
(m, 10H), 3.52 (s, 0H), 6.76 (d, J¼19.1 Hz, 1H), 7.25 (d,
J¼19.1 Hz, 1H). 13C NMR: d 21.68, 21.16, 25.41, 33.65,
77.17, 134.35, 151.10, 201.81. IR: 3400 br, 1681, 1249,
1219, 987, 868, 844, 750 cm21. HRMS (CI) calcd for
C12H23O2Si (MþH): 227.1467, found: 227.1455.
4.6. Reaction of enolates with aldehydes
To the solution of the zirconium enolate prepared above was
added the aldehyde (1.16 mmol) at 2608C. The mixture was
allowed to warm to 208C over 2 h, stirred at 208C for 1 h and
hydrolysed with NaHCO3 aq. (6 mL). After extraction with
ether (2£6 mL) the organic layer was washed with 2 M HCl
aq. (5 mL), brine (2£10 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (40–60
petrol ether/EtOAc mixtures) to give the aldol products in
the yields given in the Schemes and Tables.

A. Kasatkin, R. J. Whitby / Tetrahedron 59 (2003) 9857–9864
9863
1
135.93, 138.47, 139.90, 204.67 (Z,E-isomer); 13.76, 17.03,
29.19, 33.31, 45.58, 127.95, 128.12, 129.37, 134.27, 143.25,
210.20 (E,E-isomer). IR: 1682, 1640, 1593, 1491, 1465,
1378, 963, 756, 696 cm21. HRMS (EI) calcd for C20H28O
(M): 284.2140, found: 284.2132.
(17c). H NMR: d 0.84 (m, 3H), 1.09 (d, J¼7.3 Hz, 6H),
1.10–1.40 (m, 8H), 2.05 (m, 2H), 3.17 (qq, J1¼J2¼7.3 Hz,
1H), 5.81 (dt, J1¼16.2 Hz, J2¼7.0 Hz, 1H), 6.28 (d,
J¼16.2 Hz, 1H), 6.82 (s, 1H), 7.10–7.40 (m, 5H) (Z,E-
isomer); 0.84 (m, 3H), 0.94 (d, J¼7.3 Hz, 6H), 1.10–1.40
(m, 8H), 2.05 (m, 2H), 2.44 (qq, J1¼J2¼7.3 Hz, 1H), 5.55
(dt, J1¼16.2 Hz, J2¼7.0 Hz, 1H), 6.07 (d, J¼16.2 Hz, 1H),
6.48 (s, 1H), 7.10–7.40 (m, 5H) (E,E-isomer). 13C NMR: d
14.25, 18.91, 22.79, 29.05, 31.84, 33.66, 37.78, 124.04,
128.30, 128.43, 130.13, 132.35, 135.99, 138.21, 139.98,
209.33 (Z,E-isomer). IR: 3023, 2930, 2851, 1680, 1642,
4.6.5. (E)-5-(1-Hydroxybutyl)-6-tridecen-4-one (16b).
Method as for 16a, except that 1 equiv. BF3·Et2O was
added dropwise directly after the butanal. 1H NMR: d 0.83
(m, 6H), 1.15–1.55 (m, 14H), 2.02 (m, 2H), 2.27–2.53 (m,
2H), 2.95 (br s, 0H), 2.99 (m, 1H), 3.87 (m, 1H), 5.38 (dd,
J1¼15.4 Hz, J2¼9.2 Hz, 1H), 5.60 (dt, J1¼15.4 Hz,
J2¼6.6 Hz, 1H) (main isomer); 0.85 (m, 6H), 1.15–1.55
(m, 14H), 1.97 (m, 2H), 2.25–2.50 (m, 2H), 2.58 (d,
J¼5.9 Hz, 0H), 3.05 (dd, J1¼J2¼9.2 Hz, 1H), 3.80 (m, 1H),
5.17 (dd, J1¼15.4 Hz, J2¼9.2 Hz, 1H), 5.56 (dt,
J1¼15.4 Hz, J2¼6.6 Hz, 1H) (minor isomer). 13C NMR: d
13.80, 14.15, 17.02, 18.97, 22.76, 28.91, 29.28, 31.79,
32.87, 36.44, 44.17, 61.19, 70.61, 123.21, 138.22, 213.87
(main isomer); 13.81, 14.20, 17.04, 18.75, 22.76, 28.88,
29.16, 31.78, 32.77, 36.58, 44.52, 62.99, 71.99, 124.87,
136.94, 213.32 (minor isomer). The product 16b was
converted into the 1,3-diene 17b (mixture of Z,E- and
E,E-isomers) as described for 17a.
1600, 1490, 1465, 1375, 1180, 1025, 960, 922, 754 cm21
HRMS (EI) calcd for C20H28O (M): 284.2140, found:
284.2138.
.
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council (EPSRC) for a postdoctoral award (GR/N00647).
R. J. W. thanks Pfizer for generous uncommitted support.
4.6.6. 5-(1-Octenyl)-5-nonen-4-one (17b). 1H NMR: d
0.75–0.92 (m, 9H), 1.15–1.65 (m, 12H), 2.08 (m, 2H), 2.21
(m, 2H), 2.55 (t, J¼7.4 Hz, 2H), 5.74 (dt, J1¼15.8 Hz,
J2¼7.0 Hz, 1H), 6.03 (d, J¼15.8 Hz, 1H), 6.28 (t,
J¼7.4 Hz, 1H) (Z,E-isomer); 0.75–0.92 (m, 9H), 1.15–
1.65 (m, 12H), 1.98 (m, 4H), 2.48 (t, J¼7.4 Hz, 2H), 5.30
(dt, J1¼15.8 Hz, J2¼7.0 Hz, 1H), 5.38 (t, J¼7.4 Hz, 1H),
5.89 (d, J¼15.8 Hz, 1H) (E,E-isomer). 13C NMR: d 14.07,
14.22, 18.20, 22.59, 22.76, 29.03, 29.33, 31.00, 31.84,
41.64, 122.64, 136.97, 139.66, 139.79, 203.43 (Z,E-isomer);
13.90, 13.99, 17.08, 22.92, 28.98, 29.24, 31.36, 33.10,
45.83, 128.62, 130.91, 132.12, 142.98, 209.00 (E,E-isomer).
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