Studies on the Origin of 1,5-anti Induction in Boron-Mediated Aldol Reactions

Article abstract of DOI:10.1002/ejoc.200300592

A model for the origin of selectivity in boron-mediated 1,5-anti-aldols is presented. This model involves π-stacking between the boron enolate and a remote aromatic ring. A short, facile method for the synthesis of the C-12 to C-22 segment of peloruside A and its 1,5-anti-aldol coupling using the proposed model is also presented. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300592

FULL PAPER
Studies on the Origin of 1,5-anti Induction in Boron-Mediated Aldol Reactions
Bridget L. Stocker,[a] Paul Teesdale-Spittle,[b] and John O. Hoberg*[a][‡]
Keywords: Boron / Aldol reactions / 1,5-anti induction / Peloruside A
A model for the origin of selectivity in boron-mediated 1,5-
anti-aldols is presented. This model involves π-stacking be-
tween the boron enolate and a remote aromatic ring. A short,
of peloruside A and its 1,5-anti-aldol coupling using the pro-
posed model is also presented.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
facile method for the synthesis of the C-12 to C-22 segment Germany, 2004)
Introduction
conditions used. For example, Evans has reported high 1,5-
syn selectivities when using the syn-selective chloro(phenyl)-
boryl enolates,[5] and Paterson has reported two examples
of anti induction when using (Ϫ)-Ipc2BCl derived enola-
tes.[4a] In this latter situation however, stereochemical con-
trol was only achieved by using the chiral Ipc ligand as the
stereocontrolling moiety, as use of the achiral dibutyl li-
gands gave almost no selectivity.
The selectivity in these reactions has long been speculated
to be an electrostatic effect exerted by the β-alkoxy substitu-
ent,[3a,6] and that the nature of the β-oxygen protecting
group is critical in determining the level of induction.[4]
However to date, no studies or models have been reported
for this surprising process. In view of this, we have designed
and conducted experiments that provide insight into the na-
ture of this reaction.
The aldol reaction is one of the fundamental methods for
carbonϪcarbon bond formation and is an extremely power-
ful method for the assembly of 1,3-polyols.[1] A controlling
element that influences the stereochemical outcome of this
process is the β-heteroatom substituent (Scheme 1). For ex-
ample, in the addition of enol silanes to β-alkoxy aldehydes
excellent levels of 1,3-anti induction are observed.[2]
Alternatively, Evans[3] and Paterson[4] pioneered the area of
remote 1,5-induction, in which a β-alkoxy substituent on
the enolate nucleophile provides for the aldehyde π-facial
selectivity. In this latter system, high selectivities are almost
always obtained when the β-hydroxy protecting group is
benzylic or a benzylidene acetal,[3a,4] and as a result these
protecting groups are used almost exclusively. The selectivit-
ies with tert-butylsilyl protecting groups depends on the
Results and Discussion
This investigation started as a result of our efforts
towards a synthesis of peloruside A (1),[7] in which we
sought to take advantage of a boron-mediated 1,5-anti-al-
dol reaction for the coupling of fragments 2 and 3,
Scheme 2. Coupling of these two would require efficient
anti induction between C-11 and C-15 in which the stereo-
chemical controlling element is the silyl-protected β-alkoxy
substituent in 2. Our working model for this coupling was
based on enolate A, in which orbital interaction between
the enolate and a phenyl group on the silyl produces alde-
hyde π-facial discrimination through a twist-boat transition
state.[8] In this transition state, the large alkyl group on the
aldehyde adopts a geometry away from the phenyl ring and
the aldehyde proton is orientated towards the phenyl ring,
thus producing minimum steric interactions and leading to
the desired 1,5-anti product. Potentially, this model also ex-
plains the previously reported results in which β-meth-
oxybenzyl ethers interact with the boron enolate. We have
Scheme 1. Stereochemical outcomes for 1,3- and 1,5-aldols
[a]
School of Chemical and Physical Sciences, Victoria University
of Wellington,
Wellington, New Zealand
[b]
School of Biological Sciences, Victoria University of
Wellington,
Wellington, New Zealand
E-mail: john.hoberg@vuw.ac.nz
[‡]
Current address: Department of Chemistry, University of
Wyoming,
Laramie, WY 82071, USA
E-mail: Hoberg@uwyo.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
330
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300592
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Origin of 1,5-anti Induction in Boron-Mediated Aldol Reactions
FULL PAPER
Scheme 2. Aldol coupling reaction towards the synthesis of
peloruside A, see Table 1 for R1 and R2
Scheme 3. Synthesis of fragment 2; reagents: (a) acetone/LDA,
THF; (b) acetone, DMSO, 20 % -proline, 38 % for 4a; (c) 3-but-
enol, Et3N, CH2Cl2, (d) Et3N, CH2Cl2; (e) 9Ϫ12 mol % B, CH2Cl2
therefore constructed a series of derivatives to test this
model’s validity.
a Schock/Hovedya molybdenum catalyst,[18] but this gave
only unmodified starting material.[19]
Synthesis of fragment 2 began with an initial formation
of racemic 4a and 4b[9] using the enolate of acetone, but we
subsequently adopted List’s direct aldol procedure[10] for
the enantioselective formation of 4a, obtaining 4a in 74 %
ee, Scheme 3.[11] Although low yielding, this is an extremely
facile and inexpensive step, which is easily performed on a
gram scale. For simplicity, we coupled 3-butenol to silanes
5 using standard procedures[12] to give 6 in modest to good
yields. It should be noted that both (R)- and (S)-2-ethyl-3-
butenol are available in one step using a Zr-catalyzed ethyl-
magnesation of 2,5-dihydrofuran, thus making this strategy
adaptable to peloruside A.[13] Subsequent coupling of 4 and
6 occurs without difficulty providing derivatives of 7 in high
yields, Table 1, Entries 1Ϫ5. For Entries 1 and 2, crude 6a
is used without purification, thus the overall yield in Table 1
is from 5. In attempts to improve the yields, we reversed
this sequence by silylation of the larger 4 with 5, however
decomposition of 4 resulted. Cyclization of 7 was carried
out using Grubbs catalyst B,[14] which gave derivatives of 2
in good yields, Entries 6Ϫ10.[15,16] The cyclizations did re-
quire the use of 9Ϫ12 mol % of the catalyst at room tem-
perature, as heating the reaction mixture resulted in de-
With the required substrates in hand, we turned our at-
tention towards the aldol reaction of 2 and the comparison
of an aromatic vs. nonaromatic participating group. Given
that the dimethylsilane derivatives gave consistently low
yields, we abandoned the use of these and focused on the
higher yielding diphenyl and diisopropyl derivatives. We in-
itially tested both 2c and 7c using a variety of boron-me-
diated aldol reactions to ascertain the inherent selectivity of
the diisopropyl silyl group (Scheme 4). Although excellent
composition of the diene.[17] We also investigated the use of Scheme 4. Aldol reaction of silyl-protected enolates
Table 1. Synthesis of ketone 2
Entry
7 (isolated yield)
Entry
2 (isolated yield)
1
2
3
4
5
7a R1 ϭ Ph, R2 ϭ Me (61 %)[a][b]
7b R1 ϭ Ph, R2 ϭ H (65 %)[b][c]
7c R1 ϭ iPr, R2 ϭ Me (86 %)[a][d]
7d R1 ϭ iPr, R2 ϭ H (82 %)[b] [d]
7e R1 ϭ Me, R2 ϭ H (77 %)[b]
6
7
8
9
2a R1 ϭ Ph, R2 ϭ Me (54 %)[a]
2b R1 ϭ Ph, R2 ϭ H (81 %)[c]
2c R1 ϭ iPr, R2 ϭ Me (60 %)[a]
2d R1 ϭ iPr, R2 ϭ H (74 %)[b]
2e R1 ϭ Me, R2 ϭ H (42 %)[b]
10
[a]
[b]
[c]
[d]
Formed using nonracemic 4a. Overall yield from Ph2SiCl2. Formed using racemic 4b. Catalytic DMAP used.
Eur. J. Org. Chem. 2004, 330Ϫ336
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331

B. L. Stocker, P. Teesdale-Spittle, J. O. Hoberg
FULL PAPER
aldol reaction using 7b with Cy2BOTf and tBuCHO gave a
2:1 ratio. Molecular mechanics calculations of 12aϪc con-
firm the ease of rotation in conformation C. Importantly
though, this does indicate that the selectivities observed
with 2aϪb are not due to an electrostatic effect exerted by
the β-alkoxy moiety but are likely a result of the enolate
fixed into a conformation conducive to interaction with a
single phenyl ring. However, in the previously reported p-
methoxybenzyl-protected β-hydroxy ketones (Scheme 1),
these enolates are able to adopt a geometry as depicted
in D.
Table 2. Comparison of aldol reactions
Entry
Substrate/R2BX[a]
Yield
Ratio
1
2
3
4
5
6
7
2c R1 ϭ iPr/(Ϫ)-Ipc2BCl
2c R1 ϭ iPr/Cy2BOTf
7c R1 ϭ iPr/(Ϫ)-Ipc2BCl
7c R1 ϭ iPr/Cy2BOTf
2a R1 ϭ Ph/(Ϫ)-Ipc2BCl
2a R1 ϭ Ph/Cy2BOTf
2b R1 ϭ Ph/(Ϫ)-Ipc2BCl
88 %
95 %
93 %
97 %
8/9 (1.5:1)
8/9 (1.2:1)
10/11 (2.2:1)
10/11 (1.2:1)
8/9 (Ͼ 99:1)
8/9 (Ͼ 99:1)
8/9 (Ͼ 99:1)
94 %
68 %[b]
60 %[b]
[a]
[b]
Performed in Et2O with Et3N at Ϫ78 °C. Unoptimised.
yields were obtained for the aldol reaction, as expected
poor selectivities were obtained (Table 2 Entries 1Ϫ4). To
our delight, however, the aldol with the diphenylsilyl group
reacted with excellent diastereoselectivity (Entries 5Ϫ7), il-
lustrating that a phenylsilyl protecting group does provide
excellent anti induction. It is also apparent that the use of
the chiral Ipc ligand is not responsible for the high selec-
tivity by comparison of Entries 5 and 6. Given that the size
of the silyl substituents are comparable, we maintain that
an orbital interaction between the phenyl group and the
enolate is responsible for the observed induction. Modelling
studies on fragment 2 of peloruside A using a methyl enol
ether in replace of the boron enolate further support this
proposal (Figure 1). As seen, excellent overlap between the
enol ether and a phenyl ring is occurring (II), while with
the isopropylsilane I no interaction is available and the enol
ether adopts an open geometry.
Scheme 5. Aldol reactions of acyclic tert-butydiphenylsilyl-
protected enolates
Conclusion
In conclusion, experimental evidence points to a model in
which orbital interaction between the enolate and a remote
phenyl substituent is a plausible component in controlling
the stereochemistry in 1,5-anti-aldols. Furthermore, we have
developed a short, facile method for the synthesis of the C-
12 to C-22 segment of peloruside, and have established a
protocol for its desired coupling.
Experimental Section
General: All reagents were of commercial quality and solvents were
dried using standard procedures. Standard syringe techniques were
used and all reactions were carried out under argon unless other-
wise noted. Reaction progress was monitored using aluminium-
backed TLC plates pre-coated with silica UV254 and visualised by
either UV radiation (254 nm) or ceric ammonium molybdate dip.
Flash chromatography was performed using silica gel 60 (220Ϫ240
mesh) with the solvent systems as indicated. 1H and 13C NMR
spectra were recorded with a Varian Inova at 300 and 75 MHz,
respectively; and referenced to solvent peaks (1H: residual CHCl3;
13C: CDCl3). Accurate masses were recorded with a Mariner time
of flight spectrometer. For the modelling studies, energy-minimized
low-energy conformations were obtained using the MM3 forcefield
and a Monte Carlo Molecular Mechanics conformational search
routine as implemented in Macromodel v7.2 using the Maestro
v4.1 interface, and the lowest energy structures retained. The global
minimum energy structure obtained was additionally validated by
minimization in Mopac with the AM1 Hamiltonian. AM1- and
MM3-minimized structures showed no significant differences.
Figure 1. Molecular modelling of iPr2Si and Ph2Si enol ethers
We next investigated acyclic, tert-butyldiphenylsilyl
ethers.
Theoretically,
these
also
could
involve
aromaticϪenolate interactions; however, as there are two
phenyl moieties incorporated in a flexible system, two dif-
ferent conformations could arise as depicted in
C
(Scheme 5). To test this, aldol reactions of the model ke-
tones 12aϪc were performed and as expected resulted in a
4-Hydroxy-5-methyl-5-hexen-2-one (4a): To a solution of diisopro-
relatively nonselective process. Analogously, the attempted pylamine (1.37 mL, 9.81 mmol) in dry THF (40 mL), cooled to
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Eur. J. Org. Chem. 2004, 330Ϫ336

Origin of 1,5-anti Induction in Boron-Mediated Aldol Reactions
FULL PAPER
Ϫ78 °C, was added a solution of 2  butyllithium in hexanes
(4.90 mL, 9.81 mmol). After stirring at Ϫ78 °C for 10 min, a solu-
tion of acetone (600 µL, 8.17 mmol) in THF (4 mL) was slowly
added over 5 min. Stirring was continued at Ϫ78 °C for 50 min and
then a solution of methacrolein (811 µL, 9.81 mmol) in THF
(4 mL) was added. The mixture was stirred at Ϫ78 °C for a further
10 min, followed by addition of saturated ammonium chloride
solution. The mixture was then extracted twice with diethyl ether
and the organic extracts washed with brine, dried with MgSO4 and
the solvent removed under reduced pressure. The residual product
was purified by bulb-to-bulb distillation (58Ϫ60 °C, 0.4 Torr) to
give 4a as a colourless oil (882 mg, 84 %). Spectral data match that
previously reported.[11]
reaction mixture was stirred at room temperature before being
heated at reflux for 36 h. The solution was then cooled to room
temperature and concentrated under reduced pressure. The result-
ant oil was dissolved in diethyl ether/pentane (1:1, 10 mL), suction-
filtered, and reconcentrated to afford an oil, which was used with-
out further purification.
General Procedure for the Formation of Diphenylsilyl Ethers 7a and
7b: To a cold (0 °C), stirred solution of the crude of (3-butenoxy)di-
phenylsilyl chloride (2.0 mmol) and β-hydroxy ketone (1.73 mmol)
in CH2Cl2 (5 mL) was added triethylamine (241 µL, 1.73 mmol)
dropwise. The ice bath was then removed and the solution stirred at
room temparature for 2.5 h before being quenched with saturated
sodium hydrogencarbonate, extracted twice with diethyl ether, and
the organic extracts washed with water, brine, and dried with
MgSO4. Filtration and concentration gave a residue oil, which was
purified by flash chromatography on silica gel (hexanes/EtOAc,
20:1) to give the diphenylsilyl ether as a clear oil. Yields are re-
ported for the total conversion from dichlorodiphenylsilyl chlo-
ride (5).
(R)-4-Hydroxy-5-methyl-5-hexen-2-one (4a): -proline (438 mg,
3.76 mmol) was added to 125 mL of DMSO/acetone (4:1) and the
resulting suspension stirred at room temperature for 15 min.
Freshly distilled methacrolein (1.04 mL, 12.5 mmol) was then ad-
ded. After being stirred at room temperature overnight, the re-
sulting yellow solution was quenched with saturated ammonium
chloride, extracted twice with diethyl ether and the organic extracts
washed with brine, dried with MgSO4 and filtered. The solvent was
removed under reduced pressure and the residual oil purified by
flash chromatography on a neutralised silica gel column (hexanes/
EtOAc, 3:1). The resulting oil (611 mg, 38 %) was then used im-
mediately. The ee was determined by silylation followed by chiral
GC analysis as follows: To a solution of the β-hydroxy ketone
(200 mg, 1.56 mmol) in DMF (3 mL) was added tert-butyldimeth-
ylsilyl chloride (259 mg, 1.72 mmol) and imidazole (212 mg,
3.12 mmol). After stirring at room temparture for 24 h, the solution
was quenched with saturated ammonium chloride, extracted twice
with diethyl ether, and the organic extracts were washed with brine,
dried with MgSO4, filtered and the solvents removed under reduced
pressure. The residual oil was then purified by flash chromatogra-
phy (hexanes/EtOAc, 50:1) to give 202 mg of pure hydroxy ether;
74 % ee; determined using a 60 m ϫ 0.25 mm Cyclodex-B column.
1H NMR (300 MHz, CDCl3): δ ϭ 4.95 (s, 1 H), 4.78 (s, 1 H), 4.54
(dd, J ϭ 3.9, 8.4 Hz, 1 H), 2.74 (dd, J ϭ 8.7, 14.7 Hz, 1 H), 2.39
(dd, J ϭ 3.9, 18.3 Hz, 1 H), 2.16 (s, 3 H), 1.69 (s, 3 H), 0.85 (s, 9
H), 0.02 (s, 3 H), 0.00, (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 207.8, 147.0, 111.5, 73.7, 50.6, 32.0, 26.0, 18.3, 17.46, Ϫ4.6,
Ϫ5.1 ppm. IR (neat): ν˜ ϭ 2930 cmϪ1, 2857, 1360, 1718, 1251, 1074,
835, 776. HRMS (ESI) calcd. for C13H26O2Si [M ϩ Hϩ] 243.1774,
found 243.1780.
4-[(3-Butenoxy)diphenylsilyloxy]-5-methyl-5-hexen-2-one
(7a):
Dichlorodiphenylsilane (330 µL, 1.57 mmol) produced 7a (335 mg,
0.95 mmol) in an overall yield of 61 %. 1H NMR (300 MHz,
CDCl3): δ ϭ 7.65 (m, 4 H), 7.41 (m, 6 H), 5.84 (m, 1 H), 5.07 (m,
2 H), 4.93 (s, 1 H), 4.80 (m, 2 H), 3.80 (t, J ϭ 6.9 Hz, 2 H), 2.82
(dd, J ϭ 7.5, 15 Hz, 1 H), 2.58 (dd, J ϭ 5.4, 15 Hz, 1 H), 2.35 (dt,
J ϭ 6.6, 13.2 Hz, 2 H), 2.10 (s, 3 H), 1.73 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 206.9, 145.7, 135.4, 135.3, 132.9, 130.6,
130.5, 128.0, 116.8, 112.5, 73.5, 62.9, 50.5, 37.1, 31.2, 17.6, ppm.
IR (neat): ν˜ ϭ 3079 cmϪ1, 2924, 2878, 1714, 1087, 719. HRMS
(ESI) calcd. for C23H28O3Si [M ϩ Naϩ] 403.1680, found 403.1699.
4-[(3-Butenoxy)diphenylsilyloxy]-5-hexen-2-one (7b): Dichlorodi-
phenylsilane (330 µL, 1.57 mmol) produced 7b (374 mg,
1.02 mmol) in an overall yield of 65 %. 1H NMR (300 MHz,
CDCl3): δ ϭ 7.65 (m, 4 H), 7.41 (m, 6 H), 5.50 (m, 2 H), 5.09 (m,
4 H), 4.84 (dt, J ϭ 6.0, 12.9 Hz, 1 H), 3.81 (t, J ϭ 6.9 Hz, 2 H),
2.79 (dd, J ϭ 6.6, 15 Hz, 1 H), 2.61 (dd, J ϭ 5.7, 15.4 Hz, 1 H),
2.35, (dt, J ϭ 6.9, 13.8 Hz, 2 H), 2.11 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 206.7, 139.5, 135.4, 135.3, 130.6, 128.1,
128.0, 116.8, 115.5, 70.8, 63.0, 51.8, 37.1, 31.3 ppm. IR (neat): ν˜ ϭ
3071 cmϪ1, 3003, 2874, 1715, 1115, 1079, 914, 717. HRMS (ESI)
calcd. for C22H26O3Si [M ϩ Naϩ] 389.1542, found 389.1543.
General Procedure for the Formation of Diisopropylsilyl Ethers 7c
and 7d: To a stirred solution of (3-butenoxy)diisopropylsilyl chlo-
ride (1.2 mmol), β-hydroxy ketone (1 mmol), and DMAP
(0.05 mmol) in CH2Cl2 (5 mL) was added triethylamine (1.2 mmol)
dropwise The resulting solution was stirred at reflux for 18 h,
cooled to room temperature, quenched with saturated sodium hy-
drogencarbonate, and extracted twice with diethyl ether. The or-
ganic extracts were washed with water, brine, dried with MgSO4,
filtered and concentrated under reduced pressure. The residual oil
was purified by flash chromatography (hexanes/EtOAc, 20:1).
(3-Butenoxy)diisopropylsilyl Chloride (6b): To a stirred mixture of
diisopropylsilyl dichloride (4 mL, 22.2 mmol) and triethylamine
(3.4 mL, 24.4 mmol) in CH2Cl2 (85 mL) at 0 °C was added a solu-
tion of 3-buten-1-ol (1.91 mL, 22.2 mmol) in CH2Cl2 (20 mL) over
30 min. The reaction mixture was then stirred at room temperature
before being heated at reflux for 48 h. After cooling to room tem-
perature and concentrating under reduced pressure, the resultant
oil was dissolved in diethyl ether/pentane (1:1, 100 mL), suction-
filtered and reconcentrated to afford an oil. Fractional distillation
of the crude material gave 6b as a colourless oil (58Ϫ60 °C, 1 Torr,
2.64 g, 54 %). 1H NMR (300 MHz, CDCl3): δ ϭ 5.82 (m, 1 H),
5.06 (m, 2 H), 3.83 (t, J ϭ 6.6 Hz, 2 H), 2.32 (dt, J ϭ 6.9, 13.5 Hz,
2 H) 1.07 (m, 14 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 135.1,
4-[(3-Butenoxy)diisopropylsilyloxy]-5-methyl-5-hexen-2-one (7c): β-
Hydroxy ketone (4a) (329 mg, 2.57 mmol) gave 7c as a colourless
oil in 86 % (687 mg). 1H NMR (300 MHz, CDCl3): δ ϭ 5.84 (m, 1
H), 5.04 (m, 2 H), 4.81 (s, 1 H), 4.76 (t, J ϭ 6.3 Hz, 1 H), 3.74 (t,
J ϭ 6.9 Hz, 2 H), 2.74 (dd, J ϭ 7.2, 15 Hz, 1 H), 2.57 (dd, J ϭ
5.4, 14 Hz, 1 H), 2.30, (dt, J ϭ 6.6, 13.8 Hz, 2 H), 2.17 (s, 3 H),
117.0, 63.6, 37.0, 17.0, 16.9, 15.2 ppm. IR (neat): ν˜ ϭ 2954 cmϪ1
,
2876, 1109, 994, 922, 886.
(3-Butenoxy)diphenylsilyl Chloride (6a): To a stirred mixture of di-
phenylylsilyl dichloride (330 µL, 1.57 mmol) and triethylamine (241 1.73 (s, 3 H), 1.02 (m, 14 H) ppm. 13C NMR (75 MHz, CDCl3):
µL, 1.73 mmol) in CH2Cl2 (6 mL) at 0 °C was added a solution of
3-buten-1-ol (135 µL, 1.57 mmol) in CH2Cl2 (1 mL) dropwise. The
δ ϭ 207.4, 146.5, 135.6, 116.6, 111.8, 73.0, 62.8, 50.9, 37.5, 31.7,
17.6, 17.5, 12.5, 12.4 ppm. IR (neat): ν˜ ϭ 2945 cmϪ1, 2867, 1716,
Eur. J. Org. Chem. 2004, 330Ϫ336
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333

B. L. Stocker, P. Teesdale-Spittle, J. O. Hoberg
FULL PAPER
1085, 1060, 999, 883, 688. HRMS (ESI) calcd. for C17H32O3Si [M 4.8, 14.7 Hz, 1 H), 2.40 (m, 1 H), 2.23 (s, 3 H), 1.02 (m, 14 H)
ϩ Naϩ] 335.2012, found 335.2013.
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 207.9, 135.3, 129.4, 66.9,
63.8, 51.5, 31.7, 31.1, 17.7, 17.6, 17.5, 12.8, 12.5 ppm. IR (neat):
ν˜ ϭ 2944, 2867, 1715, 1120, 1011, 732 cmϪ1. HRMS (ESI) calcd.
for C14H27O3Si [M ϩ Hϩ] 271.1717, found 271.1724.
4-[(3-Butenoxy)diisopropylsilyloxy]-5-hexen-2-one (7d): β-Hydroxy
ketone (4b) (243 mg, 2.13 mmol) gave 7d as a colourless oil in 82 %
(521 mg). 1H NMR (300 MHz, CDCl3): δ ϭ 5.84 (m, 2 H), 5.20
(m, 4 H), 4.78 (dt, J ϭ 6.3, 12.3 Hz, 1 H), 3.75 (t, J ϭ 6.9 Hz, 2 Representative Procedure for Aldol Reactions: To a stirred solution
H), 2.74 (dd, J ϭ 6.6, 15.3 Hz, 1 H), 2.57 (dd, J ϭ 6.3, 15.3 Hz, 1
H), 2.29 (dt, J ϭ 6.6, 13.5 Hz, 2 H), 2.16 (s, 3 H), 1.01 (m, 14 H)
of Cy2OBTf or (Ϫ)-Ipc2BCl (1.5 mmol) in anhydrous diethyl ether
(4 mL) at Ϫ78 °C (for Cy2OBTf) or 0 °C (for (Ϫ)-Ipc2BCl) was
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 207.2, 140.3, 135.6, 116.6, slowly added triethylamine (1.7 mmol). A solution of the ketone
114.8, 70.2, 62.8, 52.2, 37.5, 31.7, 17.6, 17.5, 12.5, 12.4 ppm. IR (1 mmol) in CH2Cl2 (4 mL) was then added through a cannula.
(neat): ν˜ ϭ 2944 cmϪ1, 2867, 1717, 1087, 990, 883, 689. HRMS
The reaction mixture was stirred at Ϫ78 °C for 30 min or 0 °C,
(ESI) calcd. for C16H30O3Si [M ϩ Naϩ] 321.1847, found 321.1856. respectively, before being cooled to Ϫ78 °C, at which point pival-
dehyde (2 mmol) was added dropwise. The solution was stirred at
Ϫ78 °C for 3 h then at Ϫ20 °C for 10 h, then quenched at Ϫ20 °C
by addition of a pH ϭ 7 buffer solution (30 % methanol, hydrogen
peroxide solution). The solution was then stirred at room tempera-
ture for 3 h and extracted twice with diethyl ether. The organic
extracts were washed with water, brine, dried with MgSO4, filtered
General Procedure for RCM: To a solution of the diene (1 mmol)
in CH2Cl2 (100 mL) was added (benzylidene)[1,3-bis(2,4,6-trimeth-
ylphenyl)-4,5-dihydroimidazol-2-ylidene](tricyclohexylphosphane)-
ruthenium() dichloride (0.09 mmol for R2 ϭ H, 0.12 mmol for
R2 ϭ Me). The reaction mixture was stirred at room temperature
for 8Ϫ12 h, the solvent was removed under reduced pressure and
and concentrated under reduced pressure. Purification of the crude
the dark residue filtered through a short pad of silica gel (hexanes/
material by flash chromatography (hexanes/EtOAc, gradient 50:1
EtOAc, 10:1). The filtered solution was then stirred with activated
to 10:1) gave the aldol adducts as colorless oils.
charcoal (8.5 g) for 24 h. The mixture was filtered, concentrated
in vacuo and purified by careful gradient flash chromatography
(hexanes/EtOAc, 50:1 to 20:1) to provide the cyclic olefin as a
colourless oil.
7,11-O-Diisopropylsilanediyl-7,11-dihydroxy-2,2,8-trimethyl-8-
undecen-5-one: Reaction of 2c (106 mg, 0.37 mmol) with (Ϫ)-
Ipc2BCl gave a mixture of 8 and 9 in 88 % yield (120 mg), ds ϭ
1.5:1. Spectral data reported for one diastereomer, separated by
flash chromatography. 1H NMR (300 MHz, CDCl3): δ ϭ 5.43 (t,
J ϭ 8.7 Hz, 1 H), 4.89 (dd, J ϭ 3.3, 9.6 Hz, 1 H), 3.85 (m, 2 H),
3.00Ϫ2.48 (m, 5 H), 2.22 (m, 1 H), 1.75 (s, 3 H), 1.02 (m, 14 H),
0.93 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 211.9, 140.5,
125.0, 74.7, 71.2, 64.3, 49.5, 46.4, 34.3, 30.8, 25.9, 21.2, 17.7, 17.6,
17.5, 17.4, 12.8, 12.5 ppm. IR (neat): ν˜ ϭ 3479 cmϪ1, 2954, 2868,
1709, 1114, 1006, 940, 733, 696. HRMS (ESI) calcd. for
C20H38O4Si [M ϩ Hϩ] 371.2602, found 371.2612.
(4R)-4,8-O-Diphenylsilanediyl-4,8-dihydroxy-5-methyl-5-octen-2-
one ((AUthor: Nomenclature affords inclusion of "4,8-dihydroxy"!
)) (2a): Diene 7a (270 mg, 0.71 mmol) gave 2a in 54 % (135 mg).
1H NMR (300 MHz, CDCl3): δ ϭ 7.64 (m, 4 H), 7.39 (m, 6 H),
5.44 (t, J ϭ 8.1 Hz, 1 H), 4.90 (dd, J ϭ 3.9, 9.6 Hz, 1 H), 4.05 (m,
2 H), 2.94 (dd, J ϭ 9.9, 15.3 Hz, 1 H), 2.93 (m, 1 H), 2.62 (dd, J ϭ
3.6, 15.3 Hz, 1 H), 2.26 (m, 1 H), 2.25 (s, 3 H), 1.60 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 207.6, 140.8, 134.8, 133.8, 133.5,
130.5, 130.4, 128.1, 125.1, 71.7, 64.4, 49.6, 31.2, 30.9, 21.5 ppm. IR
(neat): ν˜ ϭ 3070 cmϪ1, 2919, 2876, 1713, 1115, 1083, 716, 699. Aldol Reaction with 2c Using Cy2BOTf: Reaction of 2c (30 mg,
HRMS (ESI) calcd. for C21H24O3Si [M ϩ Hϩ] 353.1568, found
0.11 mmol) with Cy2BOTf gave a mixture of 8 and 9 in 95 %
(37 mg), ds ϭ 1.2:1.
353.1565.
4,8-O-Diphenylsilanediyl-4,8-dihydroxy-5-octen-2-one (2b): Diene
3-[(3-Butenoxy)diisopropylsilyloxy]-7-hydroxy-2,8,8-trimethyl-1-
7b (80 mg, 0.22 mmol) gave 2b in 81 % (60 mg). 1H NMR nonen-5-one (10 and 11): Reaction of 7c (50 mg, 0.16 mmol) with
(300 MHz, CDCl3): δ ϭ 7.65 (m, 4 H), 7.39 (m, 6 H), 5.73 (m, 2
(Ϫ)-Ipc2BCl gave 10 and 11 in 93 % yield (59 mg), ds ϭ 2.2:1. Spec-
H), 5.13 (m, 1 H), 4.09 (m, 1 H), 3.94 (m, 1 H), 2.96 (dd, J ϭ 8.1, tral data is reported for the combined diastereomers. 1H NMR
15 Hz, 1 H), 2.64 (dd, J ϭ 4.5, 15 Hz, 1 H), 2.63 (m, 1 H), 2.42 (300 MHz, CDCl3): δ ϭ 5.86 (m, 1 H), 5.06 (m, 2 H), 5.00 (s, 1
(m, 1 H), 2.22 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
H), 4.84 (s, 1 H), 4.78 (t, J ϭ 6.3 Hz, 1 H), 3.74 (m, 2 H), 2.79Ϫ2.44
(m, 4 H), 2.31 (dt, J ϭ 6.9, 13.5 Hz, 2 H), 1.75 (s, 3 H), 1.03 (m,
207.3, 135.2, 135.0, 134.8, 133.7, 130.5, 130.4, 129.3, 128.2, 128.1,
67.4, 63.7, 51.5, 31.3, 31.1 ppm. IR (neat): ν˜ ϭ 3067 cmϪ1, 3013, 14 H), 0.92 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 211.2,
2955, 2926, 2878, 1715, 1128, 1082, 720, 700. HRMS (ESI) calcd. 211.1, 146.4, 135.5, 116.6, 112.0, 111.9, 74.9, 74.8, 72.9, 62.9, 50.8,
for C20H22O3Si [M ϩ Hϩ] 339.1408, found 339.1411.
50.7, 46.2, 46.1, 37.5, 34.3, 26.0, 25.9, 17.6, 17.5, 17.3, 12.5,
12.4 ppm. IR (neat): ν˜ ϭ 3530 cmϪ1, 2948, 2868, 1709, 1101, 909.
HRMS (ESI) calcd. for C22H42O4Si [M ϩ Naϩ] 421.2734, found
421.2744.
(4R)-4,8-O-Diisopropylsilanediyl-4,8-dihydroxy-5-methyl-5-octen-2-
one (2c): Diene 7c (110 mg, 0.35 mmol) gave 2c in 60 % (60 mg).
1H NMR (300 MHz, CDCl3): δ ϭ 5.42 (m, 1 H), 4.89 (dd, J ϭ
3.6, 9.6 Hz, 1 H), 3.9 (m, 2 H), 2.82 (dd, J ϭ 9.6, 14.4 Hz, 1 H), Aldol Reaction with 7c Using Cy2BOTf: Ketone 7c (50 mg,
2.72 (m, 1 H), 2.50 (dd, J ϭ 3.6, 14.7 Hz, 1 H), 2.25 (s, 3 H), 2.24 0.16 mmol) gave 10 and 11 in 97 % yield (61 mg), ds ϭ 1.2:1.
(m. 1 H), 1.74 (s, 3 H), 1.00 (m, 14 H) ppm. 13C NMR (75 MHz,
(3R,7R)-7,11-O-Diphenylsilanediyl-7,11-dihydroxy-2,2,8-trimethyl-
CDCl3): δ ϭ 208.1, 140.6, 125.0, 71.0, 64.3, 49.6, 31.6, 30.8, 21.1,
8-undecen-5-one: Reaction of 2a (100 mg, 0.28 mmol) with (Ϫ)-
17.6, 17.5, 12.8, 12.5 ppm. IR (neat): ν˜ ϭ 2943, 2866, 1715, 1112,
Ipc2BCl gave 8a in 94 % yield (115 mg), ds Ͼ 99:1. 1H NMR
1036, 883, 693 cmϪ1. HRMS (ESI). Calcd. for C15H28O3Si [M ϩ
(300 MHz, CDCl3): δ ϭ 7.61 (m, 4 H), 7.38 (m, 6 H), 5.44 (t, J ϭ
9.6 Hz, 1 H), 4.90 (dd, J ϭ 3.3, 9.6 Hz, 1 H), 4.06 (m, 2 H), 3.76
Hϩ] 285.1891, found 285.1881.
4,8-O-Diisopropylsilanediyl-4,8-dihydroxy-5-octen-2-one (2d): Diene
(dd, J ϭ 1.8, 10.5 Hz, 1 H), 2.99 (dd, J ϭ 9.8, 14.9 Hz, 1 H), 2.91
7d (340 mg, 1.14 mmol) gave 2d in 74 % (229 mg). 1H NMR (m, 1 H), 2.76 (dd, J ϭ 1.8, 17.8 Hz, 1 H), 2.62 (dd, J ϭ 3.6,
(300 MHz, CDCl3): δ ϭ 5.72 (m, 2 H), 4.93 (m, 1 H), 3.91 (m, 2
H), 2.80 (dd, J ϭ 8.4, 14.7 Hz, 1 H), 2.56 (m, 1 H), 2.54 (dd, J ϭ
14.7 Hz, 1 H), 2.58 (dd, J ϭ 10.2, 17.7 Hz, 1 H), 2.28 (m, 1 H),
1.61 (s, 3 H), 0.89 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
334
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 330Ϫ336

Origin of 1,5-anti Induction in Boron-Mediated Aldol Reactions
211.5, 140.7, 134.8, 134.7, 133.6, 133.3, 130.5, 130.4, 128.1, 74.8, 33.7, 27.3, 25.9, 19.7, 17.9, 17.6 ppm. IR (neat): ν˜ ϭ 3502 cmϪ1
FULL PAPER
,
71.9, 64.3, 49.5, 46.1, 34.3, 30.9, 25.9, 21.5 ppm. IR (neat): ν˜ ϭ
3072, 2957, 2858, 1709, 1110, 1057, 823, 702. HRMS (ESI) calcd.
3480 cmϪ1, 3070, 2955, 2873, 2247, 1706, 1116, 1073, 909, 730, for C28H42O3Si [M ϩ Naϩ] 477.2854, found 477.2796.
716, 699. HRMS (ESI) calcd. for C26H34O4Si [M ϩ Naϩ] 461.2120,
found 461.2119.
7-(tert-Butyldiphenylsiloxy)-3-hydroxy-2,8-dimethylnonan-5-one
(13b): Aldol reaction of 12b (119 mg, 0.32 mmol) and isobutylal-
dehyde gave 13b in 86 % yield (125 mg), ds ϭ 2.5:1. Spectral data
(3R,7R)-7,11-O-Diphenylsilanediyl-7,11-dihydroxy-2,2-dimethyl-8-
undecen-5-one: Reaction of 2b (114 mg, 0.34 mmol) with (Ϫ)-
Ipc2BCl gave 8b in 60 % (86 mg, not optimised) ds Ͼ 99:1. 1H
NMR (300 MHz, CDCl3): δ ϭ 7.64 (m, 4 H), 7.40 (m, 6 H), 5.74
(m, 2 H), 5.14 (m, 1 H), 4.09 (m, 1 H), 3.94 (m, 1 H), 3.74 (d, J ϭ
10.2 Hz, 1 H), 3.03Ϫ2.39 (m, 6 H), 0.88 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 211.2, 135.0, 134.7, 133.5, 133.4, 130.6,
130.4, 129.4, 128.2, 128.1, 74.8, 67.6, 63.7, 51.3, 46.1, 34.3, 31.0,
25.9 ppm. IR (neat): ν˜ ϭ 3509 cmϪ1, 3019, 2959, 2873, 1709, 1125,
1070, 723. HRMS (ESI) calcd. for C25H32O4Si [M ϩ Naϩ]
447.1961, found 447.1962.
1
reported for one diastereomer. H NMR (300 MHz, CDCl3): δ ϭ
7.69 (dd, J ϭ 1.5, 7.8 Hz, 2 H), 7.63 (dd, J ϭ 1.5, 7.8 Hz, 2 H),
7.37 (m, 6 H), 4.16 (m, 1 H), 3.55 (dt, J ϭ 6.0, 11.7 Hz, 1 H), 2.79
(br. s, 1 H), 2.55Ϫ2.24 (m, 4 H), 1.68 (m, 1 H), 1.54 (m, 1 H), 1.02
(s, 9 H), 0.90 (d, J ϭ 6.9 Hz, 3 H), 0.84 (d, J ϭ 6.9 Hz, 3 H), 0.81
(d, J ϭ 6.9 Hz, 3 H), 0.77 (d, J ϭ 6.9 Hz) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 211.2, 136.3, 136.2, 134.6, 134.1, 130.0,
129.8, 127.8, 127.7, 73.6, 72.0, 47.6, 47.1, 33.7, 33.0, 27.3, 19.7,
18.6, 18.0, 17.9, 17.6 ppm. IR (neat): ν˜ ϭ 3478 cmϪ1, 3072, 2929,
2932, 2859, 1707, 1109, 1006, 760, 701. HRMS (ESI) calcd. for
C27H40O3Si [M ϩ Naϩ] 463.2653, found 463.2638.
Representative Procedure for the Synthesis of tert-Butyldiphenylsilyl
Ethers 12aϪc: To a solution of the β-hydroxy ketone (1 mmol) in
DMF (1.5 mL) was added dimethyl(phenyl)silyl chloride
(1.1 mmol) and imidazole (2 mmol). After stirring at room tem-
perature for 24 h, the solution was quenched with saturated am-
monium chloride, extracted twice with diethyl ether. The organic
extracts were washed with brine, dried with MgSO4, filtered and
the solvents removed under reduced pressure. The residual oil was
purified by flash chromatography.
7-(tert-Butyldiphenylsiloxy)-3-hydroxy-2,8-dimethyl-2,8-nonadien-5-
one (13c): Aldol reaction of 12c (453 mg, 1.23 mmol) with methac-
rolein gave 13c in 89 % yield (505 mg), ds ϭ 1.2:1. Spectral data
reported for the combined diastereomers. 1H NMR (300 MHz,
CDCl3): δ ϭ 7.67 (m, 4 H), 7.40 (m, 6 H), 4.95 (s, 1 H), 4.83 (br.
s, 2 H), 4.77 (s, 1 H), 4.61 (m, 1 H), 4.32 (m, 1 H), 3.90 (br. s, 1
H), 2.73Ϫ2.2.40 (m, 4 H), 1.70 (s, 3 H), 1.68 (s, 3 H), 1.07 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 209.5, 145.7, 136.2, 136.1,
134.1, 133.5, 130.1, 130.0, 127.9, 127.8, 112.7, 111.4, 73.8, 73.7,
70.9, 50.5, 49.0, 48.8, 27.2, 19.6, 18.6, 18.5, 17.5 ppm. IR (neat):
ν˜ ϭ 3450 cmϪ1, 3073, 2932, 2858, 1709, 1111, 1072, 822, 702, 612.
HRMS (ESI) calcd. for C27H36O3Si [M ϩ Hϩ] 437.2528, found
437.2507.
(R)-4-(tert-Butyldiphenylsiloxy)-5-methylhexan-2-one (12a): 4-
Hydroxy-5-methylhexane-2-one (646 mg, 5.0 mmol) produced 12a
(1.27 g, 3.44 mmol) in an overall yield of 69 % after purification
by flash chromatography (hexanes/ethyl acetate, 50:1). 1H NMR
(300 MHz, CDCl3): δ ϭ 7.70 (m, 4 H), 7.42 (m, 6 H), 4.18 (m,1
H), 2.56 (dd, J ϭ 6.6, 15.9 Hz, 1 H), 2.42 (dd, J ϭ 5.4, 15.9 Hz, 1
H), 1.88 (s, 3 H), 1.72 (m, 1 H), 1.06 (s, 9 H), 0.94 (d, J ϭ 6.6 Hz),
0.81 (d, J ϭ 6.9 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 207.6,
136.3, 1362, 134.5, 134.3, 129.9, 127.8, 127.7, 73.9, 47.8, 33.7, 30.8,
27.3, 19.8, 18.0, 17.5 ppm. IR (neat): ν˜ ϭ 3072 cmϪ1, 2960, 2932,
2857, 1715, 1660, 1110, 1068, 740, 703. HRMS (ESI) calcd. for
C23H32O2Si [M ϩ Hϩ] 369.2305, found 369.2245.
Acknowledgments
Financial support was provided by the New Zealand Cancer
Society, the Public Good Science Fund and the Foundation for
Research Science and Tecnology (fellowship to B. S.). Dr. Peter
Northcote’s assistance in determination of relative stereochemistry
is also greatly acknowledged.
(R)-4-(tert-Butyldiphenylsiloxy)-5-methyl-5-hexen-2-one (12c): 4-
Hydroxy-5-methyl-5-hexen-2-one[20] (546 mg, 4.2 mmol) produced
12b (1.15 g, 3.14 mmol) in an overall yield of 75 % after purifi-
cation by flash chromatography (hexanes/ethyl acetate, 50:1). 1H
NMR (300 MHz, CDCl3): δ ϭ 7.65 (m, 4 H), 7.38 (m, 6 H), 4.78
(s, 1 H), 4.72 (s, 1 H), 4.59 (t, J ϭ 6 Hz, 1 H), 2.61 (dd, J ϭ 6.0,
14.7 Hz,1 H), 2.52 (dd, J ϭ 6.6, 14.7 Hz, 1 H), 2.10 (s, 3 H), 1.68
(s, 3 H), 1.06 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 206.8,
145.8, 136.2, 134.1, 133.7, 130.0, 128.0, 127.8, 127.7, 112.6, 74.1,
50.8, 31.1, 27.2, 19.6, 17.4 ppm. IR (neat): ν˜ ϭ 3072 cmϪ1, 2931,
2857, 1713, 1427, 1360, 1162, 1106, 1063, 739, 700. HRMS (ESI)
calcd. for C23H30O2Si [M ϩ Naϩ] 389.1922, found 389.1907.
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1
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I. Paterson, M. Emilia
J ϭ 1.2, 7.2 Hz, 2 H), 7.68 (dd, J ϭ 1.2, 7.5 Hz, 2 H), 7.42 (m, 6
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16.2 Hz, 1 H), 2.43 (dd, J ϭ 4.8, 16.2 Hz, 1 H), 2.28 (m, 2 H), 1.73
(m, 1 H), 1.06 (s, 9 H), 0.95 (d, J ϭ 6.3 Hz, 3 H), 0.86 (br. s, 6 H),
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136.3, 136.2, 134.6, 134.1, 129.9, 127.8, 74.7, 73.6, 47.7, 45.2, 34.2,
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Eur. J. Org. Chem. 2004, 330Ϫ336
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
335

B. L. Stocker, P. Teesdale-Spittle, J. O. Hoberg
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Blechert has reported a modified ruthenium catalyst that
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atsu, S. Blechert, Angew. Chem. Int. Ed. 2002, 41, 2403Ϫ2404.
Synthesized by adaptation of ref.[9]
[10b]
[16]
[17]
2000, 122, 2395Ϫ2396.
B. List, P. Pojarliev, C. Castello,
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C. F. Barbas, J. Am. Chem. Soc. 2001, 123, 5260Ϫ5267.
ee determined by chiral GC using the tert-butyldimethylsilyl
derivative. Alternatively, this can be synthesized in 60 % yield
and 73 % ee using the Ipc boron enolate of acetone: I. Pater-
son, J. M. Goodman, M. A. Lister, R. C. Schumann, C. K.
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[11]
[18]
[19]
[12] [12a]
J. W. Gillard, R. Fortin, H. E. Morton, C. Yoakim, C. A.
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[12b]
2602Ϫ2608.
5667Ϫ5670.
S. Rover, P. Wipf, Tetrahedron Lett. 1999, 40,
C. Colombier, T. Skrydstrup, J.-M. Beau,
[12c]
[20]
Tetrahedron Lett. 1994, 35, 8167Ϫ8170.
Received September 23, 2003
336
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 330Ϫ336