Full and partial differentiation of tris-1,1,1-(hydroxymethyl)ethane via direct and indirect methodology

Article abstract of DOI:10.1016/j.tet.2004.02.056

Tris-1,1,1-(hydroxymethyl)ethane 1 was converted to a series of mono- and disubstituted derivatives. An indirect protocol for the differentiation of the alcohol groups was employed for the synthesis of partially and fully differentiated 1 containing a pro

Full text of DOI:10.1016/j.tet.2004.02.056

Tetrahedron 60 (2004) 3625–3636
Full and partial differentiation of
tris-1,1,1-(hydroxymethyl)ethane via direct and
indirect methodology
†
Philip Clarke, Martin J. Jeffery, A. James Boydell, Sally Whiting and Bruno Linclau
†
*
School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 12 December 2003; revised 2 February 2004; accepted 25 February 2004
Abstract—Tris-1,1,1-(hydroxymethyl)ethane 1 was converted to a series of mono- and disubstituted derivatives. An indirect protocol for the
differentiation of the alcohol groups was employed for the synthesis of partially and fully differentiated 1 containing a protected aldehyde
unit. Complete differentiation of the alcohol groups was also achieved using a direct strategy (two steps from 1). The first synthesis of 1,3-
dialdehydes derived from 1 is reported in two steps.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
group, leaving one hydroxyl group available for reaction. In
type B, only one hydroxyl group is functionalised, leaving
two hydroxyl groups available for further conversion. Type
C differs from type A in that different substituents were
introduced on two alcohol groups, resulting in the presence
of a chiral quaternary carbon atom.
Tris-1,1,1-(hydroxymethyl)ethane CH C(CH OH) 1 and
3
pentaerythritol C(CH OH) are very cheap bulk chemicals.
2
They are obtained on industrial scale via a mixed aldol
reaction of formaldehyde with, propanal and ethanal,
respectively, followed by a Cannizzarro reaction. Due to
3
2
4
1
the polyfunctional, symmetrical nature of these small
molecules, they are interesting and useful starting
materials/precursors for a range of applications, for
example, as low-molecular weight scaffolds for combina-
The traditional synthetic approach to obtain these three
differentiated forms of 1 is shown in Scheme 1. Acetal
formation of 1 leads directly to type A differentiated
molecules. Functionalisation of the remaining hydroxyl
group is now possible, leading to 2. Removal of the acetal
group then gives rise to type B differentiation. Following
this three-step method, monosilylated product 3 has been
2
torial chemistry purposes, as building blocks for dendrimer
3
4
synthesis, as initiators for polymerisation reactions, or for
5
a range of other purposes. In most cases, a chemical
differentiation of the alcohol groups needs to be achieved
prior to use in the aforementioned applications.
4
obtained. This differentiation method also has been applied
for the construction of dendrimers with 1 as a building block
(
where, in this context, P represents the attachment to the
3
Three typical differentiation levels, labelled A–C, that are
commonly found in the literature for 1 are shown in Figure 1.
In type A, two hydroxyl groups are protected as an acetal
dendrimer core in 2). Alternatively, type B monobenzylated
product 4 was directly obtained from type A benzylidene
acetal 5 by a reductive acetal-opening reaction with
5
f
LiAlH –BF .
4
3
When 2 is subjected to reductive acetal cleavage, then the
fully differentiated type C can be obtained in a three-step
sequence. Following this process, Gardiner reported the
synthesis of type C products 6 and 7 via cleavage of the
corresponding benzylidene or para-methoxy benzylidene
Figure 1. Differentiation levels of tris-1,1,1-(hydroxymethyl)ethane.
6
acetals.
Keywords: Scaffold; Building block; Alcohol differentiation;
Chemoselective acetal cleavage.
In an alternative indirect differentiation strategy, 1 was
converted to the oxetane-containing product 8 via a two-step
procedure. Acid-catalysed opening of the oxetane ring
with an alcohol leads to type B differentiated substrates in
*
Corresponding author. Tel.: þ44-23-8059-3816; fax: þ44-23-8059-6905;
5
e,7
e-mail address: bruno.linclau@soton.ac.uk
Southampton undergraduate project student.
†
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.056

3626
P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
Scheme 1. Indirect differentiation methods for tris-1,1,1-(hydroxymethyl)ethane.
three steps. Alternatively, the free alcohol group in 8 can be
functionalised to give 9. Acid-catalysed alcoholysis at this
stage gives rise to type C functionalisation in four steps. A
disadvantage of this method is that the alcohol is used as a
solvent in the oxetane opening reaction, which has obvious
implications to its scope. Hydrolysis of 9 leads to the type B
differentiated products.
The direct differentiation strategy is more appealing than the
indirect strategy in terms of number of steps. In addition, the
acetal formation of 1 is often reported to proceed in rather
moderate yield. Though the yield of this transformation is of
less importance due to the low cost of the starting materials,
it could complicate purification and isolation of the desired
acetals. In addition, lower yields generate additional waste,
which could be important on large scale. Nevertheless, the
indirect differentiation method remains important for
applications where initial monofunctionalisation is not
possible.
Another method for the synthesis of (alkylated) type B
differentiation products was achieved starting from diethyl
methyl malonate 10 (Scheme 2). Alkylation with chloro-
methyl methyl ether gives rise to 11, which subsequently is
5
a
reduced to give 12.
In this paper, we wish to describe an improved procedure for
the initial acetal protection in the synthesis of type A
compounds, leading to an efficient indirect differentiation
protocol to type B and type C products of tris-1,1,1-
(hydroxymethyl)ethane 1 that contain a protected aldehyde
group. This synthesis includes investigations concerning
selective reactions between two different acetal groups. We
report the first direct silyl monoprotection of 1 (TBDMS,
TBDPS, TIPS), leading to an efficient direct differentiation
protocol for type B and type C compounds containing
orthogonal protecting groups. The first type B 1,3-
dialdehyde structures derived from 1 in two steps are
described as well. Their straightforward synthesis of all
these derivatives should make these compounds readily
available as interesting building blocks for a range of
applications.
Scheme 2. Formation of type B molecule from diethyl methyl malonate.
A shorter, more efficient synthesis of type B and type C
differentiated tris-1,1,1-(hydroxymethyl)ethane could be
achieved via direct monofunctionalisation which, surpris-
ingly, has been only scarcely explored (Scheme 3). This
approach relies twice on a monofunctionalisation reaction,
of the triol and a diol, respectively. Type B structures were
obtained via monotritylation using 5.5 equiv. of 1, in 68%
8
yield. Monoalkylation of 1 via a Williamson alkylation was
9
reported in good yield as well (80%). With a weak base
(
K CO ) and a reactive alkylating agent (allyl bromide), a
3
2. Results and discussion
2
6
8
:1 ratio of mono- to diallylation product was achieved in
1
5% combined yield. Surprisingly, to the best of our
0
2.1. Indirect differentiation of tris-1,1,1-(hydroxy-
methyl)ethane
knowledge, no direct monosilylation of 1 has yet been
reported.
Our indirect differentiation protocol conventionally started
with reaction of tris-1,1,1-(hydroxymethyl)ethane 1 with
benzaldehyde (Scheme 4). Several conditions have been
described in the literature for this reaction (Table 1).
However, for large scale purposes, the use of large
quantities of ZnCl (entry 4) in conjunction with a workup
2
Scheme 3. Direct differentiation of tris-1,1,1-(hydroxymethyl)ethane.
5
f
which was described as difficult, was deemed impractical.
Benzaldehyde dimethyl acetal (entry 3), though still cheap,
is five times as expensive as benzaldehyde itself. When the
reaction was performed in aqueous medium (entry 1), the
acetal product was reported to precipitate from the reaction
mixture, albeit with a yield of only 60%.
Following this methodology, type C differentiation can be
obtained in two steps from 1. Type B structures have been
monoalkylated (allyl, benzyl) in moderate to good yields
4
a,10
(
C(O)CMe Br) was achieved in good yields (77–78%).
56 and 76%, respectively).
Monoesterification (Ac,
4
b,10
2

P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
3627
Scheme 4. Reagents and conditions: (a) ArCHO, PPTS, toluene, reflux (Dean and Stark), 1 h. (b) SO
3
·py, DMSO, Et
3
N, CH
2
Cl
2
, 0 8C, 3–6 h.
2 2 2 2 3 2 2 2
(c) TMSOCH CH OTMS, TMSOTf, CH Cl , 0 8C, 1 h. (d) BH ·SMe , TMSOTf, CH Cl , 278 8C, 3 h.
Table 1. Reaction of tris-1,1,1-(hydroxymethyl)ethane with benzaldehyde
Entry
PhCHO (equiv.)
Conditions
Yield (%)
c/t ratio
Reference
a
a
a
1
2
3
4
5
1.0
2.2
1.05
5.9
HCl (cat), H
2
O, 70–80 8C, 3 h
60
66
74
81
95
11
12
4
Toluene, pTSA (cat), Dean and Stark, 6 h
THF, pTSA (cat), room temperature, 3 h
ZnCl (0.9 equiv.), room temperature, 12 h
b
2
7:1
3.8:1
5f
This work
0.83
Toluene, PPTS (cat), Dean and Stark, 1 h
a
Not determined.
Benzaldehyde dimethyl acetal was used.
b
Hence, it was decided to optimise the acetal formation
reaction. Refluxing 1 and benzaldehyde (1.5 equiv.) in
would rely on selective acetal cleavage reactions. Treatment
of 16 with trimethylsilyl trifluoromethane sulfonate and
1
7
toluene with PPTS as catalyst and MgSO to bind the
4
borane dimethyl sulfide complex resulted in selective
reduction of the benzylidene acetal to give the correspond-
ing benzyl ether 18 in 81% yield. Similarly, selective
reductive cleavage of the para-methoxybenzylidene acetal
17 under the same conditions gave 19 in 78% yield. It has
been reported, based on competition experiments, that 1,3-
dioxane based acetals are more reactive towards reductive
ringopening than 1,3-dioxolane based acetals. However,
there are very few synthetic examples in the literature
that exploit this selectivity. While the selective
reductive cleavage of a para-methoxybenzylidene
acetal in the presence of a dimethyl acetal has been
reported, to the best of our knowledge no such selective
reaction has been reported involving the less reactive
1
3
liberated water only returned 43% of 5. When these
conditions were used in conjunction with a Dean and Stark
trap, a mixture of cis and trans 5 was formed. However, the
remaining primary alcohol subsequently reacted with excess
benzaldehyde to form the corresponding acyclic acetal
‘
dimer’ as a mixture of isomers, which could be separated
by preparative HPLC (see Section 4). Hence, when a
limiting amount of benzaldehyde was used, subsequent
acetal formation involving the free alcohol in 5 did not take
place, and a 95% yield of 5 was obtained, with a 3.8:1 ratio
of cis/trans isomers. Structural assignment of the isomers
was easily achieved based on the characteristic downfield
shift of the equatorial methyl group of the major isomer
compared to the upfield shift of the axial methyl group of the
1
8
benzylidene acetal.
1
4
minor isomer.
Unfortunately, in our hands, an attempted selective
oxidation of the para-methoxybenzylidene acetal 17 with
DDQ did not give a significant yield of the type C 20. As it is
Reaction of 1 with anisaldehyde under identical conditions
gave 13 as a mixture of cis/trans isomers in good yield as
well. The acetals 5 and 13 were subsequently oxidised under
known that cyclic acetals oxidise faster than acyclic
19a
1
5
Parikh–Doering conditions, leading to the corresponding
aldehydes 14 and 15 in excellent yield. The subsequent
protection of the aldehyde as 1,3-dioxolane proved difficult.
Reaction of 14 with 1,2-ethanediol in toluene or cyclo-
hexane with a range of acid-catalysts under Dean and Stark
conditions did not provide the desired product 16. However,
reaction of 14 with 1,2-ethanediol in toluene with pTSA at
room temperature gave 16 in 69% yield. In the event, the
acetals,
it was decided to change the 1,3-dioxolane
protecting group to an acyclic dimethyl acetal (Scheme 5).
Aldehyde 14 was subjected to Noyori conditions at 278 8C
with triflic acid as the catalyst. Surprisingly, this provided
the dimethyl acetal 21 as a single isomer, even though the
1
6
very mild Noyori-conditions using 1,2-bis-(trimethyl-
silyloxy)ethane and trimethylsilyltriflate as catalyst were
found to give the highest yield for the protection reaction
(
84%). The protection of 15, which contains a more acid-
sensitive para-methoxybenzylidene acetal group, was also
successfully achieved under Noyori conditions, leading to
1
7 in 92% yield.
With the acetals 16 and 17 in hand, the final transformation
to type C differentiated products was attempted, which
Scheme 5. Reagents and conditions: (a) TMSOCH
CH Cl , 278 8C, 3 h. (b) O , EtOAc, 278 8C, 1 h.
3 3 3
, CF SO H (cat),
2
2
3

3628
P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
starting material was a mixture of cis/trans isomers. A
similar result was achieved with 15 as starting material. The
structure of both 21 and 22 were elucidated by X-ray
crystallography, and determined to be the cis-isomer in
both cases.
recovered starting material. Attempted monobenzylation
2
3c
using silver oxide was not successful. Monoacetylation
was successfully achieved with Clarke’s CeCl -catalysed
3
2
0
23a
process
using 10 equiv. of acetic anhydride. Though
stirring the reaction mixture for 24 h as described mainly
returned diacetylated product (69%, with 29% of 29), close
monitoring of the reaction by TLC revealed an optimum
reaction time of 5 h, after which 89% of 29 was obtained.
Hence, the synthesis of fully differentiated tris-1,1,1-
(hydroxymethyl)ethane possessing orthogonal protecting
groups is easily obtained in a high-yielding two-step
operation.
1
9
Finally, ozone treatment of the diacetals 21 and 22 was
chemoselective, with the acyclic acetal left untouched. The
corresponding benzoate and para-methoxybenzoate esters
2
3 and 24 were obtained in 65 and 62% yield, respectively.
To the best of our knowledge, this is the first example of
such a selective oxidative cleavage between these two types
of acetals.
2.3. Synthesis of type B 1,3-dialdehydes derived from
tris-1,1,1-(hydroxymethyl)ethane
It can be noted that the selective acetal cleavage of the
benzylidene acetal occurs in similar yield compared to the
para-methoxybenzylidene acetal, which adds to the versa-
tility of the described indirect differentiation process, as a
range of protecting groups are made accessible.
Finally the synthesis towards type B 1,3-dialdehydes was
undertaken. To our surprise, there were only a handful
reported examples for the synthesis of 1,3-dialdehydes from
the corresponding 2,2-disubstituted 1,3-propanediol starting
materials, mostly from 2,2-dimethyl-1,3-propanediol. PCC
Hence, the fully differentiated compounds 18, 19, 23, and 24
are accessible from 1 in four steps.
2
4
was used as oxidant, though without mention of yields.
Under Swern conditions, very divergent results were
2
5
2.2. Synthesis of type C structures by direct
differentiation of tris-1,1,1-(hydroxymethyl)ethane
reported, ranging from very low to good yields. However,
Frigerio obtained a high yield for the oxidation of a 1,1-
bis(hydroxymethyl)cyclohexene derivative to the corre-
sponding 1,3-dialdehyde using o-iodoxybenzoic acid
The first direct preparation of monosilylated tris-1,1,1-
2
6
(
based on a similar protocol as reported for pentaerythritol.
hydroxymethyl)ethane was successfully accomplished,
2
(IBX) as oxidant.
1
An excess of 1 was used (Scheme 6), not only to reduce
polysilylation, but also for economic reasons, as 1 is vastly
cheaper than any silylating agent. By using a 5-fold excess
of 1, yields of the corresponding silyl ethers 25–27 ranged
from 73 to 90%. Any residual starting material was easily
removed during aqueous workup, and the small amounts of
disilylated compounds were separated in a straightforward
manner by column chromatography.
The 1,3-diol precursor, type B diol 30, was obtained in good
yields from the acetals 16 and 17 via hydrogenolysis
(Scheme 7). It is clear that 30 would be difficult to
synthesise in a direct differentiation protocol from 1.
Unfortunately, though a range of oxidants was explored,
we were not able to obtain 31 in good yields. IBX, Dess–
Martin periodinane (DMP) and TPAP/NMO, all returned
complex reaction mixtures, while with silver(I)carbonate
only starting material was recovered. Oxidation with PCC
and PDC gave complex reaction mixtures, though the use of
2
2
1
equiv. of PDC cleanly led to the corresponding mono-
2
7
aldehyde. Under Swern conditions, the monoaldehyde
was also isolated after a reaction time of 1 h, but when
longer reaction times were applied, again a complex mixture
was obtained.
3
Scheme 6. Reagents and conditions: (a) R SiCl, imidazole, DMF, room
temperature, 24 h. (b) NaH, BnBr, THF, reflux, 22 h. (c) Ac
room temperature, 5 h.
2 3
O, CeCl ,
With the monosilyl ethers in hand, further direct
differentiation was investigated. The selective mono-
functionalisation of meso and C -symmetric 1,3-diols,
2
including 2-substituted propanediols, has been the subject
2
3
of extensive research, yet is scarcely exploited for the
synthesis of type-B differentiated tris-1,1,1-(hydroxy-
4
,10
methyl)ethane.
with 1 equiv. of NaH in THF,
As shown in Scheme 6, deprotonation
2
3d
followed by benzyl
bromide addition at reflux temperature led to the formation
of type C product 28 in 81% yield, together with 8% of
2
Scheme 7. Reagents and conditions: (a) Pd(OH) /C, MeOH, room
temperature, 18 h. (b) IBX, EtOAc, room temperature, 3.5 h.

P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
3629
In the event, the oxidation was more successful starting
4. Experimental
from the type B monosilyl ethers 25 and 26. Though most
of the oxidation methods mentioned before gave complex
reaction mixtures as well, encouraging results were
obtained with PDC/AcOH(cat) and Dess–Martin period-
inane as oxidants, where, starting from 25, a mixture of
4.1. General
1,1,1-Tris(hydroxymethyl)ethane 1 was obtained from
commercial sources and used without further purification.
Reaction solvents were dried immediately prior to use as
follows: Et N and CH Cl were distilled from CaH . EtOAc
3
2 and 34 was obtained in 52 and 20% yield,
respectively. The side-product 34 is likely to arise from
a retro-aldol reaction at the intermediate mono-aldehyde
stage. When IBX was used, 32 was obtained in 58% yield
after chromatography. However, the procedure that was
used could not be scaled up. The reaction is conducted in
DMSO as solvent under dilute conditions in order to
dissolve the oxidant, and the workup procedure simply
consists of evaporating the solvent under vacuum,
followed by chromatography of the residue. Since 32 is
quite volatile, loss of material during evaporation of large
quantities of DMSO reduced the yield to 39% on 4 mmol
scale. A solution was found by using the higher-boiling
sulpholane as solvent. As IBX is not very soluble in
sulpholane, the reagent was used as a suspension.
Distillation of the 1,3-dialdehyde product from the
reaction mixture was now possible, leading to an isolated
yield of 69%. The yield could be raised to 76% when
DMSO was used as a co-solvent to obtain a homogeneous
reaction mixture. Finally, the best procedure was found to
use excess IBX reagent under heterogeneous conditions
3
2
2
2
was distilled from CaCl . MeOH was dried with Mg/I ,
2
2
followed by distillation. THF was distilled from Na/
benzophenone. Toluene was distilled from Na. DMSO
was distilled from CaH under reduced pressure and stored
2
over molecular sieves. Anhydrous DMF was purchased
from commercial sources and stored in a Schlenk flask. All
non-aqueous reactions were carried out under an
atmosphere of nitrogen. Chromatography refers to column
chromatography and was performed on 230–400 mesh
silica gel. Reactions were monitored by TLC (Merck) with
detection by UV illumination or through alkaline KMnO
1
4
oxidation. The melting points are reported uncorrected. H
1
3
NMR (400 MHz) and C NMR (100 MHz) were recorded
6
on a Bruker DPX400 spectrometer at 300K in either d -
acetone or CDCl referenced to residual solvent peaks;
3
chemical shifts are quoted in ppm. IR spectra were recorded
on a Nicolet Impact 400 spectrometer. The MS were run on
a Thermoquest 2000 spectrometer.
2
8
using ethyl acetate as solvent. This method allowed
simple filtration of excess IBX and its byproducts,
followed by evaporation of the solvent and isolation
after column chromatography. Hence, reaction of 25 or
4.1.1. (1-Methyl-4-phenyl-3,5-dioxanyl) methanol (5). To
a stirred solution of 1,1,1-tris(hydroxymethyl)ethane 1
(4.32 g, 36.0 mmol) in toluene (125 mL) was added PPTS
(86 mg). Benzaldehyde (3.1 mL, 30.0 mmol) was added
dropwise and the mixture was refluxed for 1 h using a Dean
2
6 in EtOAc at 80 8C for 3.5 h, followed by the
aforementioned workup protocol gave the corresponding
dialdehydes 32 and 33 in 83 and 71% isolated yields,
respectively.
and Stark apparatus. A 5% NaHCO (100 mL) solution was
3
added and the reaction was allowed to cool to room
temperature. The layers were separated and the aqueous
layer was extracted with CH Cl (2£100 mL). The organic
2
2
phases were combined, dried (Na SO ), and after filtration
2
4
the solvents were removed in vacuo. The crude product was
purified by chromatography (hexanes/acetone 8:2) to yield 5
as a white solid (5.95 g, 95%, 3.8:1 cis/trans). The isomers
were separated for identification purposes by preparative
HPLC (hexane/acetone 8:2).
3
. Conclusion
We have established a short, high-yielding, direct
differentiation strategy for the synthesis of fully differ-
entiated derivatives of tris-1,1,1-(hydroxymethyl)ethane
1
, possessing orthogonal functional groups. An indirect
differentiation strategy, based on the initial protection of
as a benzylidene acetal, was used to prepare fully
Compound cis-5. Mp 100–102 8C; IR (CH Cl -solution ca.
2
2
10 mg mL2 ): 3054 (m), 2978 (w), 2959 (w), 2850 (w),
1
1
1460 (m), 1420 (m), 1379 (m), 1195 (s), 1043 (s), 888
(m) cm2 ; H NMR (400 MHz, d -acetone): d 7.51–7.49
(2H, m, ArH); 7.38–7.36 (3H, m, ArH); 5.46 (1H, s, ArCH);
4.02 (2H, br d, J¼11.5 Hz, 2£CHHOCHAr); 3.93 (1H, t,
1
1
6
differentiated derivatives of 1 where one hydroxyl group
was converted to an acetal-protected aldehyde. A key
aspect in this synthesis was the selective oxidative or
reductive ring-opening of the benzylidene and para-
methoxybenzylidene acetal groups in the presence of,
respectively, a cyclic 1,3-dioxolane type acetal and an
acyclic dimethylacetal. These investigations resulted in
an extension of the scope of selective transformations
between different acetal groups which should be of use in
general synthetic organic chemistry. In addition, an
improved preparation of the benzylidene acetal of 1 is
reported. Finally, the first synthesis of a 1,3-dialdehyde
building block from 1 is reported in two high yielding
steps. The reactions involved are very straightforward and
this work should further extend the usefulness of the very
cheap building block 1 for a range of applications in
organic, combinatorial and polymer chemistry.
J¼5.3 Hz, OH); 3.84 (2H, d, J¼4.8 Hz, CH OH); 3.62 (2H,
2
dd, J¼10.3, 1.3 Hz, 2£CHHOCHAr); 0.79 (3H, s, CH );
3
1
3
6
C NMRþDEPT (100 MHz, d -acetone): d 140.8 (C),
129.4 (CH), 129.3 (2£CH), 127.8 (2£CH), 102.8 (CH) 74.2
(2£CH ), 65.6 (CH ), 36.2 (C), 18.0 (CH ); CIMS: m/z (%):
2
2
3
þ
209 ((MþH) , 100).
Compound trans-5. Mp 60–62 8C; IR (solution CH Cl ca.
2
2
2
1
10 mg mL ): 339 (m), 2950 (w), 2860 (w), 1451 (m), 1100
1
; H NMR (400 MHz, d -
(s), 1039 (s), 741 (m) cm2
1
6
acetone): d 7.52–7.49 (2H, m, ArH); 7.37–7.34 (3H, m,
ArH); 5.42 (1H, s, ArCH); 3.94 (2H, m, 2£CHHOCHAr);
3.87 (1H, m, OH); 3.78 (2H, m, 2£CHHOCHAr); 3.35 (2H,
1
3
m, CH OH); 1.25 (3H, m, CH ); C NMRþDEPT
2
3

3630
P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
6
(
(
(
1
100 MHz, d -acetone): d 141.0 (C), 130.0 (CH), 129.5
2£CH), 127.9 (2£CH), 103.0 (CH) 75.4 (2£CH ), 67.5
CHHOCHPh); 3.78 (1H, dd, J¼7.0, 2.3 Hz, ring
CHHOCHPh); 3.76 (1H, d, J¼9.0 Hz, CHHOCHPh); 3.69
(2H, d, J¼11.3 Hz, 2£ring CHHOCHPh); 3.34 (1H, d,
J¼9.5 Hz, CHHOCHPh); 3.28 (1H, d, J¼9.5 Hz,
2
þ
CH ), 36.7 (C), 19.9 (CH ); CIMS: m/z (%): 209 ((MþH) ,
2
3
00), 105 (10).
1
3
CHHOCHPh); 1.29 (3H, s, CH ); 0.89 (3H, s, CH );
C
3
3
6
Anal. (mixture of isomers) for C H O calcd C¼69.21;
NMRþDEPT (100 MHz, d -acetone): d 140.9 (C), 140.7
1
2 16 3
H¼7.74. Found C¼69.26; H¼7.80.
(C), 140.3 (C), 130.1 (CH), 130.0 (CH), 129.9 (CH), 129.8
(
2£CH), 129.5 (3£CH), 128.5 (2£CH), 127.9 (2£CH),
4.1.2. Synthesis of the ‘dimeric’ acetal isomers. To a
stirred solution of 1,1,1-tris(hydroxymethyl)ethane 1
127.8 (3£CH), 103.02 (CH), 130.00 (CH), 102.9 (CH),
75.48 (CH ), 75.45 (CH ), 74.56 (CH ), 74.54 (CH ), 70.1
2
2
2
2
(
(
1
8.93 g, 74.5 mmol) in toluene (250 mL) was added PPTS
86 mg) and MgSO4 (13.4 g). Benzaldehyde (11.3 mL,
11.7 mmol) was added dropwise and the mixture was
(CH ), 68.8 (CH ), 35.8 (C), 35.7 (C), 20.3 (CH ), 18.6
2 2 3
þ
5), 225 (100); HRMS (ES ) calcd for C H O Na
þ
(CH ); ESMS: m/z (%) 543 ((MþK) , 8), 527 ((MþNa) ,
3
þ
3
1
36
6
þ
refluxed overnight using a Dean and Stark trap. 5%
NaHCO (100 mL) solution was added and the reaction
(MþNa) 527.2404, found 527.2409.
3
was allowed to cool to room temperature. The layers were
separated and the aqueous layer extracted with CH Cl
2
2
(
(
2£100 mL). The organic phases were combined and dried
Na SO ). After filtration the solvents were removed in
2
4
vacuo. The crude product was purified by column
chromatography (95:5 hexanes/ethyl acetate) to yield the
acyclic acetals as a mixture of three ring isomers as a white
solid (7.30 g, 14.5 mmol, 39%, ratio 35/36/37 4.6:2.3:1).
The isomers were separated by HPLC (hexanes/ethyl
acetate 95:5).
Compound 37. Mp 104–106 8C; IR 2992 (w), 2972 (w),
2907 (w), 2869 (w), 1453 (m), 1382 (m), 1100 (s), 1038 (s),
2
1
1
1025 (s), 994 (s), 980 (s), 745 (s) cm
;
H NMR
6
(400 MHz, d -acetone): d 7.52–7.48 (6H, m, ArH); 7.46–
7.42 (2H, m, ArH); 7.39–7.34 (7H, m, ArH); 5.58 (1H, s,
CHPh); 5.46 (2H, s, 2£ring CHPh); 4.00 (2H, d, J¼10.8 Hz,
2
£ring CHHOCHPh); 3.97 (2H, d, J¼9.5 Hz, 2£ring
CHHOCHPh); 3.86 (2H, dd, J¼7.0, 2.5 Hz, 2£ring
CHHOCHPh); 3.84 (2H, dd, J¼7.0, 2.3 Hz, 2£ring
CHHOCHPh); 3.36 (2H, d, J¼9.5 Hz, 2£CHHOCHPh);
3
2
1
1
.29 (2H, d, J¼9.5 Hz, 2£CHHOCHPh); 1.34 (6H, s,
1
3
6
Compound 35. Mp 110–111 8C; IR 2950 (w), 2868 (w),
£CH ); C NMRþDEPT (100M Hz, d -acetone): d
3
1
9
7
7
454 (w), 1393 (m), 1205 (m), 1095 (s), 1045 (s), 1025 (s),
40.95 (2£C), 140.0 (C), 130.1 (2£CH), 129.9 (2£CH),
29.5 (5£CH), 128.3 (2£CH), 127.9 (4£CH), 103.3
2
1
1
6
67 (m) 756 (s) cm ; H NMR (400 MHz, d -acetone): d
.57–7.55 (2H, m, ArH); 7.45–7.39 (4H, m, ArH); 7.38–
.37 (2H, m, ArH); 7.35–7.32 (7H, m, ArH); 5.72 (1H, s,
(
(
(
2£CH), 103.2 (CH), 75.5 (2£CH ), 75.4 (2£CH ), 70.6
2
2
2£CH ), 35.9 (2£C), 20.4 (2£CH ); ESMS: m/z (%) 527
2 3
þ
þ
þ
CHPh); 5.46 (2H, s, 2£ring CHPh); 4.07–4.02 (4H, m,
(MþNa) , 100), 522 ((MþNH ) , 40); HRMS (ES ) calcd
4
þ
4
£ring CHHOCHPh); 3.89 (2H, d, J¼9.0 Hz, 2£
for C H O Na (MþNa) 527.2404, found 527.2399.
3
1 36 6
CHHOCHPh); 3.80 (2H, d, J¼8.9 Hz, 2£CHHOCHPh);
3
2
.65 (4H, d, J¼12.5 Hz, 4£ring CHHOCHPh); 0.95 (6H, s,
4
.1.3. [2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-
1
3
6
£CH ); C NMRþDEPT (100 MHz, d -acetone): d 140.8
3
5yl]methanol (13). An identical procedure was followed
as for the preparation of 5 (same scale). The crude product
was recrystallised (hexane/ethyl acetate 9:2) and the residue
purified by chromatography (hexanes/acetone 8:2) to yield
13 as a white solid (6.36 g, 89%, 2.9:1 cis/trans). The
isomers were separated for identification purposes by
preparative HPLC (hexanes/acetone 8:2).
(
(
1
(
2£C), 140.5 (C), 130.1 (2£CH), 129.7 (2£CH), 129.67
2£CH), 129.4 (2£CH), 128.3 (2£CH), 127.9 (5£CH),
03.3 (CH), 103.0 (CH), 74.8 (2£CH ), 74.4 (2£CH ), 69.0
2 3
2
2
2£CH ), 35.6 (2£C), 18.6 (2£CH ); ESMS: m/z (%) 543
þ þ
(
(MþK) , 30), 527 ((MþNa) , 35), 225 (100); HRMS
þ þ
31 36 6
(
ES ) calcd for C H O Na (MþNa) 527.2404, found
5
27.2399.
Compound cis-13. Mp 82–84 8C; IR (solution CH Cl ca.
2
2
1
1
1
(
0 mg mL2 ): 3290 (m), 2968 (m), 2935 (m), 2864 (m),
620 (w), 1502 (w), 1379 (m), 1247 (s), 1006 (s), 816
6
m) cm2 ; H NMR (400 MHz, d -acetone): d 7.39 (2H, d,
1
1
J¼8.5 Hz, ArH); 6.90 (2H, d, J¼8.7 Hz, ArH); 5.39 (1H, s,
ArCH); 3.89 (2H, m, 2£CHHOCHAr); 3.87 (1H, br s, OH);
3.81 (2H, s, CH OH); 3.77 (3H, s, OCH ); 3.59 (2H, m,
Compound 36. Mp 96–98 8C; IR 2950 (w), 2868 (w), 1454
2
3
3
1
(
(
7
w), 1393 (m), 1205 (m), 1095 (s), 1045 (s), 1025 (s), 968
6
2£CHHOCHAr); 0.77 (3H, s, CH ); C NMRþDEPT
3
2
1
1
6
m), 756 (s) cm ; H NMR (400 MHz, d -acetone): d
.47–7.31 (15H, m, ArH); 5.66 (1H, s, CHPh); 5.49 (1H, s,
(100 MHz, d -acetone): d 161.4 (C), 133.2 (C), 129.0
(2£CH), 114.7 (2£CH) 102.8 (CH), 74.2 (2£CH ), 65.6
2
CHPh); 5.30 (1H, s, CHPh); 4.09 (1H, dd, J¼6.0, 2.5 Hz,
ring CHHOCHPh); 4.07 (1H, dd, J¼6.0, 2.5 Hz, ring
CHHOCHPh); 3.92 (1H, d, J¼10.8 Hz, ring CHHOCHPh);
(CH ), 56.2 (CH ), 36.1 (C), 18.0 (CH ); CIMS: m/z (%):
3
2
3
þ
239 ((MþH) , 100), 137 (27), 121, (82).
3
.89 (1H, d, J¼10.5 Hz, ring CHHOCHPh); 3.86 (1H, d,
Compound trans-13. Mp 122–1238 C; IR (solution CH Cl
2
2
1
J¼9.0 Hz, CHHOCHPh); 3.80 (1H, dd, J¼7.3, 2.5 Hz, ring
ca. 10 mg mL2 ): 3465 (m), 2968 (w), 2907 (w), 2850 (w),

P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
3631
1
611 (m), 1516 (m), 1266 (s), 1062 (s), 987 (m), 835
2
(8:2 hexane/acetone) to yield a white solid (0.58 g, 98%).
The isomers were separated for identification purposes by
preparative HPLC (hexane/ethyl acetate 9:1).
1
1
6
(
s) cm ; H NMR (400 MHz, d -acetone): d 7.41 (2H, d,
J¼8.8 Hz, ArH); 6.91 (2H, d, J¼8.8 Hz, ArH); 5.35 (1H, s,
ArCH); 3.91 (2H, br d, J¼10.8 Hz, 2£CHHOCHAr); 3.83
(
1H, t, J¼5.3 Hz, OH); 3.78 (3H, s, ArOCH ); 3.75 (2H, dd,
Major isomer. Mp 102–104 8C; IR (solution CH Cl ca.
2
3
2
10 mg mL2 ): 2973 (m), 2940 (m), 2874 (m), 2836 (m),
1
J¼10.0, 1.0 Hz, 2£CHHOCHAr); 3.34 (2H, d, J¼5.3 Hz,
1
3
CH OH); 1.24 (3H, s, CH ); C NMRþDEPT (100 MHz,
1715 (s), 1611 (s), 1524 (s), 1393 (s), 1242 (s), 1001 (s), 821
2
3
6
21
1
6
d -acetone): d 161.5 (C), 133.5 (C), 129.2 (2£CH), 114.8
(s) cm ; H NMR (400 MHz, d -acetone): d 9.89 (1H, s,
CHO); 7.33 (2H, d, J¼8.3 Hz, ArH); 6.89 (2H, d, J¼9.0 Hz,
ArH); 5.48 (1H, s, ArCH); 4.47 (2H, d, J¼11.8 Hz,
2£CHHOCHAr); 3.83 (2H, dd, J¼11.8, 1.0 Hz, 2£
(
3
2£CH) 103.0 (CH), 75.4 (2£CH ), 67.5 (CH ), 56.3 (CH ),
2
2
3
þ
6.6 (C), 19.9 (CH ); CIMS: m/z (%): 239 ((MþH) , 20),
3
1
37 (52), 121, (100).
1
3
CHHOCHAr); 3.77 (3H, s, OCH ); 0.83 (3H, s, CH );
C
3
3
6
Anal. (mixture of isomers) for C H O calcd. C¼65.53;
NMRþDEPT (100 MHz, d -acetone): d 205.9 (CH), 161.6
1
3 18 4
H¼7.61. Found C¼65.69; H¼7.79.
(C), 132.6 (C), 129.1 (2£CH), 114.8 (2£CH), 102.6 (CH),
7
3.3 (2£CH ), 56.2 (CH ), 46.6 (C), 15.1 (CH ); EIMS: m/z
2
3
3
þ þ
4
.1.4. 2-Phenyl-5-methyl-1,3-dioxane-5-carbaldehyde
(%): 236 (M , 7), 235 (M2H , 12), 135 (100).
(
in CH Cl (50 mL) was dissolved in a mixture of DMSO
14). A suspension of SO ·pyridine (10.06 g, 63.3 mmol)
3
Minor isomer. Mp 108–110 8C; IR (solution CH Cl ca.
2
2
2
2
10 mg mL2 ): 3049 (w), 2959 (w), 2831 (w), 1720 (m),
21 1
1621 (m), 1516 (m), 1270 (w), 1171 (m), 736 (s) cm ; H
1
(
50 mL) and Et N (10.6 mL, 76.5 mmol). This solution was
3
immediately added dropwise to a stirred solution of 5
6.01 g, 28.8 mmol) in CH Cl (62 mL) at 0 8C, and the
6
(
NMR (400 MHz, d -acetone): d 9.59 (1H, s, CHO); 7.41
2
2
reaction mixture was stirred at 0 8C for 3 h. The reaction
mixture was poured into a mixture of saturated aqueous
NH Cl/water/Et O/pentane (1:1:1:1, 300 mL), and the
(2H, d, J¼8.8 Hz, ArH); 6.92 (2H, d, J¼8.8 Hz, ArH); 5.46
(1H, s, ArCH); 4.15 (2H, m, 2£CHHOCHAr); 3.94 (2H, m,
2£CHHOCHAr); 3.80 (3H, s, OCH ); 1.47 (3H, s, CH );
4
2
3
3
1
3
6
aqueous phase extracted with an Et O/pentane mixture
2
C NMRþDEPT (100 MHz, d -acetone): d 204.5 (CH),
(
over anhydrous Na SO . After removing the solvent in
1:1, 3£100 mL). The combined organic phases were dried
161.8 (C), 132.7 (C), 129.2 (2£CH), 114.9 (2£CH), 102.9
(CH), 72.1 (2£CH ), 56.3 (CH ), 47.5 (C), 17.4 (CH );
2
4
2
3
3
þ
vacuo, the pale yellow oil was purified by chromatography
hexane/ethyl acetate 9:1) to yield a white solid (5.34 g,
0%). The isomers were separated for identification
EIMS: m/z (%): 235 (M2H , 13), 152 (20), 135 (100).
(
9
Anal. (mixture of isomers) for C H O calcd C¼66.09;
1
3 16 4
purposes by preparative HPLC (hexane/ethyl acetate 9:1).
H¼6.83. Found C¼66.17; H¼6.89.
Major isomer. Mp 58–60 8C; IR (solution CH Cl ca.
2
4.1.6. 5-(1,3-Dioxalan-2-yl)-2-phenyl-5-methyl-1,3-diox-
ane (16). A solution of aldehyde 14 (0.78 g, 3.78 mmol) in
CH Cl (10 mL) was cooled to 0 8C. 1,2-Bis-(trimethyl-
2
0 mg mL2 ): 2968 (w), 2860 (w),1725 (s), 1460 (m), 1375
1
1
2
1
1
6
(
m), 1095 (s), 1015 (w) cm ; H NMR (400 MHz, d -
acetone): d 9.89 (1H, s, CHO); 7.44–7.41 (2H, m, ArH);
.37–7.32 (3H, m, ArH); 5.55 (1H, s, ArCH); 4.50 (2H, d,
2
2
silyloxy) ethane (1.4 mL, 5.7 mmol) was added and
trimethylsilyl trifluoromethane sulphonate (0.3 mL,
1.9 mmol) was added dropwise. The solution was stirred
at 0 8C for 1 h. Pyridine (3 mL) was added and the mixture
was poured into saturated aqueous NaHCO3 solution
(75 mL). The aqueous layer was extracted with CH Cl
7
J¼12.0 Hz, 2£CHHOCHAr); 3.86 (2H, d, J¼11.3 Hz,
1
3
2
£CHHOCHAr); 0.84 (3H, s, CH ); C NMRþDEPT
3
6
(
(
(
(
100 MHz, d -acetone): d 205.8 (CH), 140.2 (C), 130.2
CH), 129.5 (2£CH); 127.8 (2£CH), 102.7 (CH), 73.3
2£CH ), 46.7 (C), 15.1 (CH ); CIMS: m/z (%): 205
2
2
(2£90 mL) and the combined organic phases dried
2
3
þ
M2H , 15), 123 (25), 105 (100), 77 (53).
(Na SO ). After filtration the CH Cl was removed in
2
2
4
2
vacuo. The crude product was subjected to chromatography
(hexane/acetone 85:15) to yield the product as a mixture of
ring isomers (0.79 g, 3.18 mmol, 84%). The isomers were
separated for identification purposes by preparative HPLC,
both were isolated as white solids (hexanes/acetone 9.5:0.5).
Minor isomer. Mp 56–58 8C; IR (solution CH Cl ca.
2
2
0 mg mL2 ): 2954 (w), 2850 (w), 2727 (w), 1715 (s), 1455
1
1
2
1
1
(
(
(
m), 1379 (m), 1105 (w), 987 (m) cm
6
;
H NMR
400 MHz, d -acetone): d 9.56 (1H, s, CHO); 7.51–7.48
2H, m, ArH); 7.39–7.36 (3H, m, ArH); 5.52 (1H, s, ArCH);
4
.19 (2H, m, 2£CHHOCHAr); 3.97 (2H, m, 2£
Major isomer. Mp 104–106 8C; IR (CH Cl soln ca.
2
10 mg mL ) 3054 (w), 2988 (w), 2889 (w) 2865 (w),
1451 (w), 1385 (w), 1266 (s), 1214 (m), 1105 (m), 1015 (w),
2
1
3
21
CHHOCHAr); 1.48 (3H, s, CH ); C NMRþDEPT
3
6
(
100 MHz, d -acetone): d 204.5 (CH), 140.0 (C), 130.4
722 (s) cm2 ; H NMR (400 MHz, d -acetone): d 7.47–
7.44 (2H, m, ArH); 7.35–7.34 (3H, m, ArH); 5.50 (1H, s,
ArCH); 5.47 (1H, s, CH(OCH ) ); 4.20 (2H, m, 2£
1
1
6
(
(
3
CH), 129.6 (2£CH); 127.9 (2£CH), 103.0 (CH), 72.2
þ
2£CH ), 47.6 (C), 17.4 (CH ); EIMS: m/z (%): 206 (M ,
2
3
4), 205 (70), 123 (51), 105 (100), 77 (78).
2
2
CHHOCHAr); 3.93 (4H, m, CH(OCH ) ); 3.72 (2H, m,
2
2
1
3
Anal. (mixture of isomers) for C H O calcd C¼69.89;
2£CHHOCHAr); 0.67 (3H, s, CH ); C NMRþDEPT
1
2
14
3
3
6
H¼6.84. Found C¼69.77; H¼6.89.
(100 MHz, d -acetone): d 138.9 (C), 130.7 (CH), 129.5
(
2£CH) 127.9 (2£CH), 104.8 (CH), 103.0 (CH), 74.9
4
.1.5. 2-(4-Methoxyphenyl)-5-methyl-1,3dioxane-5-car-
(2£CH ), 66.9 (2£CH ), 38.1 (C), 13.1 (CH ); CIMS: m/z
2
2
3
þ
baldehyde (15). An identical procedure was followed as
for the preparation of 14 (2.50 mmol scale). The crude
product (pale yellow oil) was purified by chromatography
(%): 251 ((MþH) , 38), 105 (30), 73 (100).
Minor isomer. Mp 68–70 8C; IR (CH Cl soln ca.
2
2

3632
P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
1
1
0 mg mL2 ) 2964 (w), 2893 (w), 2845 (w), 1445 (m), 1384
s), 1328 (m), 1162 (w), 1082 (s), 1034 (m), 935 (m), 750
warmed to room temperature it was poured into a saturated
aqueous NaHCO solution (15 mL) and water (15 mL) and
(
(
(
3
m) cm2 ; H NMR (400 MHz, d -acetone): d 7.53–7.51
1
1
6
was extracted with CH Cl (3£30 mL). The organic phases
2
2
2H, m, ArH); 7.40–7.37 (3H, m, ArH); 5.54 (1H, s, ArCH);
.58 (1H, s, CH(OCH ) ); 4.03–3.96 (4H, m, 2£
were combined and dried (MgSO ). After filtration the
4
4
CH Cl was removed in vacuo. The crude product was
2
2
2
2
CHHOCHAr, CH(OCHH) ); 3.89–3.83 (4H, m, 2£
subjected to chromatography (hexane/ethyl acetate 6:4) to
yield the product as a colourless oil (0.202 g, 81%).
2
1
3
CHHOCHAr, CH(OCHH) ); 1.31 (3H, s, CH );
2
C
3
6
NMRþDEPT (100 MHz, d -acetone): d 140.9 (C), 130.1
(
(
CH), 129.5 (2£CH), 127.9 (2£CH), 107.1 (CH), 103.2
CH), 73.7 (2£CH ), 66.6 (2£CH ), 38.6 (C), 17.3 (CH );
IR (film) 3494 (m), 2983 (m), 2936 (m), 2874 (s), 1503 (w),
1451 (s), 1366 (m), 1101 (s), 1034 (s), 945 (s), 741 (s), 703
2
2
3
þ
21
1
6
CIMS: m/z (%): 251 ((MþH) , 100), 105 (20), 73 (80).
(s) cm ; H NMR (400 MHz, d -acetone): d 7.39–7.35
4H, m, ArH); 7.32 (1H, m, ArH); 4.88 (1H, s, CH(OCH ) );
4.55 (2H, s, CHHOCH Ar); 3.95–3.81 (4H, m,
(
2
2
Anal. (mixture of isomers) for C H O calcd C¼67.18;
1
4
18
4
2
H¼7.25. Found C¼67.38; H¼7.36.
CH(OCH ) ); 3.68 (1H, dd, J¼10.8, 4.5 Hz, CHHOH);
2
2
3
.64 (1H, m, CHHOH); 3.60 (1H, d, J¼8.7 Hz, CHHOCH -
2
4
.1.7. 5-(1,3-Dioxalan-2-yl)-2-(4-methoxyphenyl)-5-
Ar); 3.52 (1H, d, J¼8.8 Hz, CHHOCH Ar); 3.35 (1H, br s,
2
1
3
methyl-1,3-dioxane (17). An identical procedure was
followed as for the preparation of 16 (8.47 mmol scale).
The crude product was subjected to chromatography
CHHOH); 0.95 (3H, s, CH ); C NMRþDEPT (100 MHz,
3
6
d -acetone): d 140.7 (C), 129.8 (CH), 128.8 (4£CH), 107.1
(CH), 74.7 (CH ), 74.0 (CH ), 66.42 (CH ), 66.36 (CH ),
2
2
2
2
(
hexane/acetone 85:15) to yield the product as a mixture
65.8 (CH ), 44.9 (C), 15.1 (CH ); CIMS: m/z (%): 253
2 3
þ
calcd for C H O (M2H) 251.1283, found 251.1279.
of ring isomers (2.18 g, 92%). The isomers were separated
for identification purposes by preparative HPLC, both were
isolated as white solids (hexane/acetone 95:5).
((MþH) , 28), 205 (12), 115 (40), 73 (100): HRMS (EI)
þ
1
4 19 4
4
.1.9. 2-[1,3]Dioxolan-2-yl-3-(4-methoxy-benzyloxy)-2-
Major isomer. Mp 126–128 8C; IR (CH Cl soln ca.
2
methyl-propan-1-ol (19). Starting from 17, an identical
procedure was followed as for the preparation of 18 (same
scale). The crude product was subjected to chromatography
(hexane/ethyl acetate 6:4) to give the product as a colourless
oil (0.221 g, 78%).
2
0 mg mL2 ) 3054 (w), 2974 (m), 2889 (m), 2846 (m),
1
1
1
1
621 (m), 1512 (s), 1470 (m), 1389 (s), 1262 (s), 1186 (s),
2
1
1
6
087 (s), 826 (m), 727 (s) cm ; H NMR (400 MHz, d -
acetone): d 7.37 (2H, d, J¼7.8 Hz, ArH); 6.89 (2H, d,
J¼8.7 Hz, ArH); 5.47 (1H, s, ArCH); 5.44 (1H, s,
CH(CH ) ); 4.17 (2H, m, 2£CHHOCHAr); 3.87 (4H, m,
IR (film) 3489 (m), 2936 (s), 2988 (s), 2841 (s), 1621 (s),
1516 (s), 1465 (s), 1304 (s), 1034 (m), 1252 (s), 1105 (s),
2
2
CH(CH ) ); 3.71 (3H, s, OCH ); 3.69 (2H, m, 2£
2
2
3
1
3
21
1
6
CHHOCHAr); 0.66 (3H, s, CH ); C NMRþDEPT
1025 (s) cm ; H NMR (400 MHz, d -acetone): d 7.31
(2H, m, ArH); 6.93 (2H, m, ArH); 4.86 (1H, s, CH(OCH ) );
4.47 (2H, s, CHHOCH Ar); 3.94–3.81 (4H, m,
3
6
(
(
(
100 MHz, d -acetone): d 161.6 (C), 133.1 (C), 129.1
2£CH), 114.8 (2£CH), 104.9 (CH), 102.9 (CH), 74.9
2£CH ), 66.9 (2£CH ), 56.3 (CH ), 38.0 (C), 13.1 (CH );
2
2
2
CH(OCH ) ); 3.82 (3H, s, ArOCH ); 3.64 (1H, dd,
2 2
2
2
3
3
3
þ
CIMS: m/z (%): 281 (MþH) , 29), 151 (10), 133 (100).
J¼10.8, 5.5 Hz, CHHOH); 3.58 (1H, m, CHHOH); 3.55
(
1H, d, J¼8.8 Hz, CHHOCH Ar); 3.47 (1H, d, J¼9.0 Hz,
2
Minor isomer. Mp 116–118 8C; IR (CH Cl soln ca.
2
CHHOCH Ar); 3.29 (1H, t, J¼5.5 Hz, CHHOH); 0.93
2
2
1
1
1
0 mg mL2 ) 3045 (m), 2978 (m), 2931 (m), 2832 (m),
1
(3H, s, CH ); C NMRþDEPT (100 MHz, d -acetone): d
13
6
3
620 (m), 1522 (s), 1465 (m), 1389 (s), 1270 (s), 1176 (s),
1
160.8 (C), 132.6 (C), 130.5 (2£CH), 115.2 (2£CH), 107.2
2
1
086 (s), 1034 (m), 822 (m), 736 (s) cm
6
;
H NMR
(CH), 74.4 (CH ), 73.8 (CH ), 66.43 (CH ), 66.37 (CH ),
2
2
2
2
(
400 MHz, d -acetone): d 7.39 (2H, m, ArH); 6.91 (2H, m,
ArH); 5.36 (1H, s, ArCH); 4.53 (1H, s, CH(CH ) ); 3.96–
65.9 (CH ), 56.2 (CH ), 44.8 (C), 15.1 (CH ); EIMS: m/z
2 3 3
þ
HRMS (EI) calcd for C H O (M) 282.1467, found
282.1460.
(%): 281 ((M2H) , 4), 220 (12), 189 (27), 121 (100):
þ
2
2
3
.91 (4H, m, CH(CH ) ); 3.83–3.77 (7H, m, OCH þ2£
2
2
3
15 22 5
1
3
CHHOCHAr); 1.27 (3H, s, CH ); C NMRþDEPT
3
6
(
(
(
100 MHz, d -acetone): d 161.8 (C), 133.5 (C), 129.4
2£CH), 115.0 (2£CH), 107.3 (CH), 103.3 (CH), 73.8
2£CH ), 66.7 (2£CH ), 56.5 (CH ), 38.7 (C), 17.5 (CH );
4.1.10. cis-5-Dimethoxymethyl-5-methyl-2-phenyl-[1,3]-
dioxane (21). A solution of aldehyde 14 (2.99 g,
14.5 mmol) in CH Cl (58 mL) was cooled to 278 8C.
2
2
3
3
þ
CIMS: m/z (%): 281 (MþH) , 64), 136 (78), 73 (100).
2
2
Methoxytrimethylsilane (6.0 mL, 43.5 mmol) was added
followed by dropwise addition of triflic acid (0.76 mL,
4.2 mmol). The solution was stirred at 278 8C for 3 h.
Pyridine (7 mL) was added and the mixture poured on to
Anal. (mixture of isomers) for C H O calcd C¼64.27;
1
5 20 5
H¼7.19. Found C¼64.43; H¼7.31.
4
.1.8. 3-Benzyloxy-2-[1,3]dioxolan-2-yl-2-methyl-pro-
satd NaHCO solution (50 mL). The aqueous layer was
3
pan-1-ol (18). A solution of diacetal 16 (0.25 g, 1 mmol)
in CH Cl (5 mL) was cooled to 278 8C. Borane dimethyl
extracted with CH Cl (3£100 mL) and the organic phases
2
2
were combined and dried (Na SO ). After filtration, the
2
2
2
4
sulfide complex (0.19 mL, 2 mmol) was added followed by
dropwise addition of trimethylsilyl trifluoromethane sul-
fonate (0.36 mL, 2 mmol). The reaction mixture was stirred
at 278 8C for 3 h. After this time NaOMe (0.5 M solution in
MeOH, 16 mL) was added, followed by saturated aqueous
CH Cl was removed in vacuo. The crude product was
2 2
subjected to chromatography (hexane/acetone 9:1) to yield a
single isomer as a white solid (2.53 g, 69%).
2
1
Mp 108–112 8C; IR (CH Cl soln ca. 10 mg mL ) 3054
2
2
NaHCO solution (5 mL). When the reaction mixture had
3
(m), 2978 (m), 1393 (w), 1209 (w), 1167 (w), 1101 (m),

P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
3633
1
1
1
(
4
3
0
1
(
1
(
072 (m) cm2 ; H NMR (400 MHz, CDCl ): d 7.51–7.49
2H, m, ArH); 7.42–7.37 (3H, m, ArH); 5.47 (1H, s, ArCH);
IR (film) 3522 (br m), 2936 (m), 2841 (m), 1706 (s), 1606
(s), 1507 (s), 1469 (s), 1261 (s), 1167 (s), 1072 (s), 845 (m),
3
765 (m), 689 (m) cm2 ; H NMR (400 MHz, d -acetone): d
8.03 (2H, d, J¼9.0 Hz, ArH); 7.06 (2H, d, J¼8.8 Hz, ArH);
4.45 (1H, s, CH(OCH ) ); 4.29 (2H, s, CH OCOAr); 3.92
1 1
6
.89 (1H, s, CH(OCH ) ); 4.24 (2H, m, 2£CHHOCHAr);
3
2
.62 (6H, s, CH(OCH ) ); 3.59 (2H, m, 2£CHHOCHAr);
3 2
1
3
.74 (3H, s, CH ); C NMRþDEPT (100 MHz, CDCl ): d
3
3
3 2
2
38.4 (C), 128.9 (CH), 128.3 (2£CH), 126.1 (2£CH), 107.1
(3H, s, ArOCH ); 3.67–3.63 (3H, m, CH OH); 3.56 (3H, s,
3 2
1
3
CH), 102.0 (CH), 74.1 (2£CH ), 58.8 (2£CH ), 39.0 (C),
CHOCH ); 3.54 (3H, s, CHOCH ); 1.01 (3H, s, CH );
3
C
2
3
þ
3
3
6
2.2 (CH ); CIMS: m/z (%): 221 ((M2OMe) , 30), 105
3
NMRþDEPT (100 MHz, d -acetone): d 167.3 (C), 165.2
(C), 133.0 (2£CH), 124.5 (C), 115.4 (2£CH), 110.7 (CH),
67.5 (CH ), 65.2 (CH ), 59.6 (CH ), 59.3 (CH ), 56.7 (CH ),
35), 75 (100). Anal. for C H O calcd C¼66.65; H¼7.99.
1
4 20 4
Found C¼66.64; H¼8.03.
2
2
3
3
þ
3
46.7 (C), 15.4 (CH ); CIMS: m/z (%): 268 (M , 6), 267 (28),
135 (40), 85 (100); HRMS (ES ) calcd for C H O Na
3
þ
4
.1.11. cis-5-Dimethoxymethyl-2-(4-methoxy-phenyl)-5-
methyl-[1,3]dioxane (22). Starting from 15, an identical
procedure was followed as for the preparation of 21
1
5 22 6
þ
(MþNa) 321.1308, found 321.1311.
(
2.45 mmol scale). The crude product was subjected to
4.1.14. 2-(tert-Butyl-dimethyl-silanyloxymethyl)-2-
methyl-propane-1,3-diol (25). To 1,1,1-tris(hydroxy-
methyl)ethane 1 (2.39 g, 19.9 mmol) and imidazole
chromatography (hexane/acetone 9:1) to give a single
isomer as a white solid (0.601 g, 87%).
(0.903 g, 13.26 mmol) was added DMF (20 mL) and the
2
1
Mp 118–119 8C; IR (CH Cl soln ca. 10 mg mL ) 2964
2
reaction was stirred until complete dissolution occurred.
TBDMSCl (1.00 g, 6.63 mmol) was added dropwise and the
reaction mixture stirred at room temperature for 24 h. The
reaction was poured into water (10 mL) and the resultant
solution extracted with EtOAc (3£100 mL). The organic
phases were combined, dried over Na SO , filtered and
2
(
(
m), 2860 (m), 2827 (m), 1616, (m), 1497 (s), 1384 (s), 1261
2
1 1
s), 1152 (s), 1053 (s), 816 (m) cm ; H NMR (400 MHz,
6
d -acetone): d 7.43 (2H, d, J¼8.6 Hz, ArH); 6.94 (2H, d,
J¼8.8 Hz, ArH); 5.48 (1H, s, ArCH); 4.90 (1H, s,
CH(OCH ) ); 4.13 (2H, m, 2£CHHOCHAr); 3.82 (3H, s,
3
2
2
4
ArOCH ); 3.61 (2H, m, 2£CHHOCHAr); 3.59 (6H, s,
concentrated in vacuo. Chromatography (hexane/acetone
4:1) gave 25 as a colourless oil (1.13 g, 73%).
3
1
3
CH(OCH ) ); 0.68 (3H, s, CH ); C NMRþDEPT
3
2
3
6
(
(
(
100 MHz, d -acetone): d 161.7 (C), 133.3 (C), 129.1
2£CH), 114.9 (2£CH), 108.5 (CH), 103.2 (CH), 75.1
2£CH ), 59.4 (2£CH ), 56.3 (CH ), 40.3 (C), 13.3 (CH );
IR 3354 (w), 2952 (m), 2927 (m), 2881 (m), 2855 (m), 1470
1
(m), 1252 (m), 1092 (s), 1035 (s) cm2
;
1
H NMR
2
3
3
3
þ
CIMS: m/z (%): 283 ((MþH) , 4), 251 (6), 133 (100). Anal.
(400 MHz, CDCl ): d 3.70 (2H, dd, J¼11.0, 4.8 Hz,
3
for C H O calcd C¼63.81; H¼7.85. Found C¼64.06;
2£CHHOH); 3.59 (2H, s, CH OSi); 3.56 (2H, dd, J¼11.0,
1
5
22
5
2
H¼8.11.
6.6 Hz, 2£CHHOH); 2.83 (2H, dd, J¼7.0, 4.8 Hz,
2
0.07 (6H, s, Si(CH ) ); C NMR (100 MHz, CDCl ) d 68.8
£CH OH); 0.89 (9H, s, C(CH ) ); 0.79 (3H, s, CH );
3 2 3
2
3 3
3
1
3
4
.1.12. Benzoic acid 2-hydroxymethyl-3,3-dimethoxy-2-
methyl-propyl ester (23). A solution of diacetal 21
0.126 g, 0.5 mmol) in ethyl acetate (40 mL) was cooled
(CH ), 67.7 (2£CH ), 41.0 (C), 25.8 (3£CH ), 18.1 (C),
2
2
3
þ
100), 217 (6), 159 (57), 129 (9), 92 (26); HRMS (EI) calcd
(
16.8 (CH ), 25.7 (2£CH ); CIMS m/z (%) 235 ((MþH) ,
3
3
to 278 8C. Ozone was passed through the solution for 1 h.
After this time nitrogen was passed through the solution
until the blue colouration disappeared. The ethyl acetate was
removed in vacuo and the residue subjected to chromato-
graphy (hexane/acetone 8:2). The product 23 was obtained
as a colourless oil (0.087 g, 65%).
t
þ
for C H O Si (M2 Bu) 177.0947, found 177.0943.
7 17 2
4.1.15. 2-(tert-Butyl-diphenyl-silanyloxymethyl)-2-
methyl-propane-1,3-diol (26). To a stirred solution of
1,1,1-tris(hydroxymethyl)ethane 1 (1.31 g, 10.91 mmol)
and imidazole (0.49 g, 7.2 mmol) in dry DMF (20 mL),
TBDPSCl (1.0 g, 3.64 mmol) was added dropwise over
90 min. The reaction was then stirred at ambient tempera-
ture for 24 h. The reaction was poured into water (60 mL)
IR (film) 3503 (br s), 2936 (s), 2837 (s), 1725 (s), 1592 (s),
1
7
469 (w), 1445 (s), 1271 (s), 1176 (s), 1105 (s), 1067 (s),
1 1
03 (s) cm2 ; H NMR (400 MHz, d -acetone): d 8.09 (2H,
6
m, ArH); 7.66 (1H, m, ArH); 7.55 (2H, m, ArH); 4.47 (1H, s,
CH(OCH ) ); 4.33 (2H, s, CH OCOAr); 3.66 (3H, m,
and the aqueous solution extracted with Et O (2£50 mL).
2
The organic phases were combined, washed with H O
2
3
2
2
CH OH); 3.57 (3H, s, 1£CHOCH ); 3.55 (3H, s,
(50 mL), brine (50 mL), dried over Na SO , filtered and
2
2
3
4
1
3
1
£CHOCH ); 1.03 (3H, s, CH ); C NMRþDEPT
concentrated in vacuo. The resultant colourless oil was
purified by chromatography (hexane/acetone 75:25) to yield
26 as a colourless oil (1.18 g, 90%).
3
3
6
(
1
100 MHz, d -acetone): 167.5 (C), 134.6 (CH), 132.3 (C),
30.9 (2£CH), 130.2 (2£CH), 110.7 (CH), 67.8 (CH ), 65.2
2
(
m/z (%): 237 ((M2OCH ) , 54), 105 (62), 85 (72), 75
CH ), 59.5 (CH ), 59.2 (CH ), 46.6 (C), 15.4 (CH ); CIMS:
2
3
3
3
þ
IR 3394 (s), 3069 (m), 3049 (m), 2958 (s), 2929 (s), 2857
21 1
3
þ
91.1203, found 291.1204.
þ
(
2
100); HRMS (ES ) calcd for C H O Na (MþNa)
(s), 1589 (m), 1470 (s), 1427 (s),1049 (s) cm ; H NMR
(400 MHz, CDCl ): d 7.71–7.69 (4H, m, ArH); 7.49–7.40
1
4 20 5
3
(
6H, m, ArH); 3.75 (2H, d, J¼10.5 Hz, 2£CHHOH); 3.65
4
.1.13. 4-Methoxy-benzoic acid 2-hydroxymethyl-3,3-
(2H, s, CH OSi); 3.60 (2H, d, J¼11.0 Hz, 2£CHHOH); 2.84
2
dimethoxy-2-methyl-propyl ester (24). Starting from 22,
an identical procedure was followed as for the preparation
of 23 (0.47 mmol scale). The crude product was subjected to
chromatography (hexane/acetone 8:2) to give the product as
a colourless oil (0.092 g, 62%).
(2H, br s, 2£CH OH); 1.11 (9H, s, (C(CH ) ); 0.84 (3H, s,
2
3 3
1
3
CH ); C NMR (100 MHz, CDCl ) d 135.6 (4£CH), 132.9
3
3
(2£C), 129.8 (2£CH), 127.8 (4£CH), 68.4 (CH ), 67.6
2
(2£CH ), 41.5 (C), 26.8 (3£CH ), 19.2 (C), 16.7 (CH ); ES
2
3
3
þ
m/z (%) 739 ((2MþNa) , 100), 717 (53), 696 (12), 619 (21),

3634
P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
þ
4
60 (58), 381 (33), 127 (50); HRMS (ES ) calcd for
þ
was added a solution of 27 (1.00 g, 3.62 mmol) in THF
(15 mL) and the mixture was stirred for 5 min. Acetic
anhydride (3.4 mL, 36.2 mmol) was added and the reaction
mixture was stirred at ambient temperature for 5 h. The
C H O SiNa (MþNa) 381.1856, found 381.1857.
2
1 30 2
4
.1.16. 2-Methyl-2-triisopropylsilanyloxymethyl-
propane-1,3-diol (27). To a stirred solution of 1,1,1-
tris(hydroxymethyl)ethane 1 (5.61 g, 46.7 mmol) and
imidazole (1.27 g, 18.7 mmol) in dry DMF (25 mL),
TIPSCl (2.0 mL, 9.34 mmol) was added dropwise. The
reaction was stirred overnight at room temperature before
pouring into water (50 mL). The resultant solution was
extracted with EtOAc (3£20 mL), the organic phases were
combined, washed with water (20 mL), brine (20 mL), dried
over Na SO and then concentrated in vacuo. Chromato-
mixture was diluted with Et O (25 mL) and was then
2
washed with satd aq. NaHCO solution (2£20 mL), and
3
brine (20 mL). The organic layer was dried (Na SO ),
4
2
filtered and the solvent removed in vacuo. The residue was
subjected to chromatography (ethyl acetate/hexane 80:20)
to give 29 as a colourless oil (1.032 g, 89%).
IR 3469 (br w), 2943 (s), 2892 (m), 2867 (s), 1743 (s), 1725
2
1
(s), 1464 (m), 1382 (m), 1242 (s), 1103 (s), 1039 (s) cm
1
;
2
4
graphy of the crude product (hexane/acetone 4:1) yielded 27
as a colourless oil (1.44 g, 81%).
H NMR (400 MHz, CDCl ): d 4.12 (2H, s, CH OAc); 3.69
3 2
(1H, d, J¼9.5 Hz, CHHOSi); 3.65 (1H, d, J¼9.5 Hz,
CHHOSi); 3.56 (1H, dd, J¼11.0, 5.5 Hz, CHHOH); 3.52
(1H, dd, J¼11.0, 7.0 Hz, CHHOH); 2.73 (1H, dd, J¼6.5,
5.5 Hz, CH OH); 2.07 (3H, s, OCOCH ); 1.11–1.05 (21H,
IR 3385 (s), 2943 (s), 2893 (s), 2867 (s), 1464 (m), 1384
2
1 1
(
m), 1104 (s), 1105 (s), 882 (s) cm ; H NMR (400 MHz,
2
3
1
3
CDCl ): d 3.74 (2H, br d, J¼10.8 Hz, 2£CHHOH); 3.71
m, Si(CH(CH ) ) ); 0.87 (3H, s, CH ); C NMRþDEPT
(100 MHz, CDCl ): d 171.3 (C), 68.2 (CH ), 67.6 (CH ),
3 2 2
3
3 2 3
3
(
2H, s, CH OSi); 3.60 (2H, dd, J¼10.8, 5.0 Hz,
2
2
m, Si(CH(CH ) ) ); 0.82 (3H, s, CH ); C NMR (100 MHz,
£CHHOH); 2.68 (2H, br s, 2£CH OH); 1.15–1.06 (21H,
66.3 (CH ), 40.8 (C), 20.8 (CH ), 17.9 (6£CH ), 16.8
2
2
3
3
1
3
þ
301 ((M2H O) , 100), 275 ((M2 Pr) , 34), 173 (87), 145
(CH ), 11.8 (3£CH); CIMS: m/z (%) 319 ((MþH) , 79),
3
2 3
3
3
þ
((M2OTIPS) , 47); HRMS (ES ) calcd for C H O Si -
i
þ
CDCl ): d 69.5 (CH ), 67.8 (2£CH ), 41.3 (C), 17.9
3
2
2
2
þ
þ
þ
(
(
(
(
6£CH ), 16.9 (CH ), 11.8 (3£CH); CIMS m/z (%) 277
3
3
32 68
8
2
þ
34), 75 (100); HRMS (EI) calcd for C H O Si
(MþH) , 76), 259 (12), 233 (16), 215 (30), 173 (98), 119
Na (2MþNa) 659.4344, found 659.4348.
1
1
25
3
þ
M2C H ) 233.1573, found 233.1575.
3
4.1.19. 2-(1,3-Dioxolan-2yl)-2methyl-1,3-propanediol
30). To a stirred solution of 16 (0.76 g, 3.04 mmol) in
7
(
4
.1.17. 3-Benzyloxy-2-methyl-2-triisopropylsilanyloxy-
methanol (20 mL) was added 20% palladium hydroxide on
carbon (201 mg). The flask was evacuated and filled with
hydrogen gas three times and was then left under an
atmosphere of hydrogen (balloon) at room temperature for
18 h. The reaction mixture was then filtered through a plug
of Celite and was washed with methanol (2£25 mL). The
solvent was removed in vacuo and the residue chromato-
graphed on silica (hexane/acetone 6:4) to give the product
30 as a white solid (0.437 g, 89%).
methyl-propan-1-ol (28). To a suspension of sodium
hydride (0.22 g, 5.58 mmol, 60% dispersion in mineral
oil) in THF (8 mL) was added dropwise a solution of 27
(
1.50 g, 5.42 mmol) in THF (5 mL) over a period of 10 min.
The reaction mixture was then heated under reflux for 1 h
and then allowed to cool to room temperature. Benzyl
bromide (0.70 mL, 5.91 mmol) was then added dropwise
over a period of 10 min. The reaction mixture was then
heated under reflux for 22 h and then allowed to cool to
room temperature. Water (20 mL) was then added and the
layers separated. The aqueous layer was then extracted with
Starting from 17, using an identical procedure (3.57 mmol
scale) 30 was obtained (0.427 g, 74%) after a reaction time
of 48 h.
Et O (3£25 mL). The organic phases were then combined,
2
dried over MgSO , filtered and the solvent removed under
4
2
1
reduced pressure. The residue was subjected to chromato-
graphy (hexane/acetone 6:1) to give 28 as a colourless oil
Mp 48–52 8C; IR (CH Cl 10 mg mL ) 3380 (br s), 2959
2 2
(m), 2889 (s), 1696 (m), 1649 (m), 1394 (m), 1091 (s), 1044
(s), 727 (s) cm2 ; H NMR (400 MHz, d -acetone): d 4.83
1
1
6
(
1.599 g, 81%).
(
1H, s, (CH O) CH); 3.96–3.82 (4H, m, (CH O) CH); 3.66
2
2
2
2
IR 3447 (br m), 3089 (vw), 3065 (w), 3031 (w), 2943 (s),
(2H, d, J¼10.0 Hz, 2£CHHOH); 3.57 (2H, d, J¼11.0 Hz,
2
1
891 (m), 2866 (s), 1714 (w), 1497 (w), 1463 (s), 1455 (s),
384 (m), 1363 (m), 1248 (w), 1207 (w), 1098 (s) cm2 ; H
2£CHHOH); 3.54 (2H, br s, CHHOH); 0.89 (3H, s, CH );
3
1 1
13
6
C NMRþDEPT (100 MHz, d -acetone): d 107.7 (CH),
NMR (400 MHz, CDCl ): d 7.37–7.28 (5H, m, ArH); 4.52
3
66.4 (2£CH ), 66.3 (2£CH ), 44.8 (C), 14.9 (CH ); CIMS:
2
2
3
þ
(
(
(
2
0
1
2H, s, ArCH O); 3.76 (1H, d, J¼9.5 Hz, CHHOCH Ar); 3.72
m/z (%) 163 ((MþH) , 12), 115 (18), 73 (100). Anal. for
C H O calcd C¼51.84; H¼8.70. Found C¼51.40;
2
2
1H, d, J¼9.0 Hz, CHHOCH Ar); 3.63 (2H, s, CH OSi); 3.53
2
2
7
14
4
1H, d, J¼8.5 Hz, CHHOH);3.48 (1H, d, J¼8.5 Hz, CHHOH);
H¼8.63.
.99 (1H, br s, CH OH); 1.15–1.05 (21H, m, Si(CH(CH ) ) );
2 3 2 3
1
3
.89 (3H, s, CH3); C NMRþDEPT (100 MHz, CDCl ): d
4.1.20. 2-(tert-Butyl-dimethyl-silanyloxymethyl)-2-
methyl-malonaldehyde (32). To a solution of diol 25
(0.23 g, 1 mmol) in ethyl acetate (7 mL) was added
iodoxybenzoic acid (1.66 g, 6 mmol). The suspension was
then warmed in an oil bath at 80 8C for 3.5 h. After this time,
the reaction was cooled to room temperature and the IBX
removed by filtration. The filtrate was concentrated and
subjected to chromatography (hexane/ethyl acetate 95:5) to
give the product as a colourless oil (0.189 g, 83%).
3
38.3 (C), 128.3 (CH), 127.52 (2£CH), 127.48 (2£CH), 74.4
(
(
(
(
CH ), 73.5 (CH ), 69.6 (CH ), 68.1 (CH ), 41.3 (C), 18.0
2
2
2
2
þ
6£CH ), 17.3 (CH ), 11.8 (3£CH); ES MS: m/z (%) 389
3
3
þ
þ
þ
(MþNa) , 100); HRMS (ES ) calcd for C H O SiNa
21 38 3
MþNa) 389.2482, found 389.2485.
4.1.18. 3-Acetyl-2-methyl-2-triisopropylsilanyloxy-
methyl-propan-1-ol (29). To CeCl (88 mg, 0.36 mmol)
3

P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
3635
IR (film) 2954 (s), 2931 (s), 2860 (s), 2728 (w), 1706 (s),
Hegmann, T.; Tschierske, C.; Diele, S. Chem. Eur. J. 1999,
5, 1643–1660. (e) Dale, J.; Fredriksen, S. B. Acta Chem.
Scand. 1992, 46, 271–277. (f) Coxon, A. C.; Stoddart, J. F.
J. Chem. Soc., Perkin Trans. 1 1977, 767–785.
1
7
474 (m), 1379 (w), 1256 (m), 1096 (s), 1011 (w), 831 (s),
6
1 1
79 (s) cm2 ; H NMR (400 MHz, d -acetone): d 9.82 (2H,
s, 2£CHO); 4.16 (2H, s, CH ); 1.27 (3H, s, CH ); 0.92 (9H,
2
3
1
3
s, SiC(CH ) ); 0.13 (6H, s, Si(CH ) ); C NMRþDEPT
6. Gardiner, J. M.; Mather, P.; Morjan, R.; Pritchard, R. G.;
Warren, J. E.; Cooper, M. L.; Ferwanah, A. E.-R. S.; Abu-
Thiem, O. S. Tetrahedron Lett. 2002, 43, 2091–2094.
7. Pattison, D. B. J. Am. Chem. Soc. 1957, 79, 3455–3456.
8. Leznoff, C. C.; Marcuccio, S. M.; Greenberg, S.; Lever, A. B.
P.; Tomer, K. B. Can. J. Chem. 1985, 63, 623–631.
3
3
3 2
6
(
(
100 MHz, d -acetone): d 202.2 (2£CH), 66.0 (CH ), 65.5
2
C), 26.8 (CH ), 19.5 (C),13.4 (3£CH ), 24.8 (2£CH );
3
3
3
þ
t
EIMS: m/z (%) 201 ((M2CHO) , 4), 143 (M2 Bu–
þ þ
CH ) , 100), 57 (19). HRMS (ES ) calcd for C H O -
3 12 26 4
2
þ
SiNa (MþNaþMeOH) 285.1493, found 285.1496.
9
. Hisamoto, H.; Tani, M.; Mori, S.; Yamada, T.; Ishigaki, T.;
Tohma, H.; Suzuki, K. Anal. Chem. 1999, 71, 259–264.
4
.1.21. 2-(tert-Butyl-diphenyl-silanyloxymethyl)-2-
methyl-malonaldehyde (33). Starting from 26, an identical
procedure was followed as for the preparation of 32 (same
scale). The crude product was subjected to chromatography
(hexane/ethyl acetate 95:5) to give the product as a
colourless oil (0.248 g, 71%).
10. Omotowa, B. A.; Judd, M. R.; Twamley, B.; Shreeve, J. J. Org.
Chem. 2002, 67, 1588–1594.
11. Nassar, R. F.; Issidorides, C. H. J. Org. Chem. 1959, 24,
1832–1833.
12. Conrad, W. E.; Gesner, B. D.; Levasseur, L. A.; Murphy, R. F.;
Conrad, H. M. J. Org. Chem. 1961, 26, 3571–3574.
13. Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall,
J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483–7498.
14. This NMR-pattern is reversed in the methyl cyclohexane
system. For a discussion see: (a) Eliel, E. L.; Enanoza, R. M.
J. Am. Chem. Soc. 1972, 94, 8072–8081. (b) Ref. 5f.
15. Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89,
5505–5507.
IR (film) 3078 (w), 2955 (s), 2931 (s), 2869 (s), 2718 (w),
1
715 (s), 1474 (m), 1422 (s), 1384 (w), 1110 (s), 816 (s), 689
2
1
1
6
(
2
s) cm ; H NMR (400 MHz, d -acetone): d 9.90 (2H, s,
£CHO); 7.75–7.73 (4H, m, ArH); 7.50–7.47 (6H, m,
ArH); 4.21 (2H, s, CH ); 1.33 (3H, s, CH ); 1.09 (9H, s,
2
3
1
3
6
C(CH ) ); C NMRþDEPT (100 MHz, d -acetone): d
3
3
2
1
(
(
01.9 (2£CH), 137.1 (4£CH), 134.1 (2£C), 131.6 (2£CH),
29.5 (4£CH), 66.6 (CH ), 66.0 (C), 27.8 (3£CH ), 20.5
16. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1357–1358.
2
3
t
þ
C), 13.6 (CH ); EIMS: m/z (%) 297 ((M2 Bu) , 40), 267
3
t
þ
þ
409.1806, found
(M2 Bu–CHO) , 67), 199 (100). HRMS (ES ) calcd for
þ
17. Bartels, B.; Hunter, R. J. Org. Chem. 1993, 58, 6756–6765.
18. Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem.
Soc. 2000, 122, 10781–10787.
C H O SiNa (MþNaþMeOH)
2
2
30
4
4
09.1809.
1
9. (a) Delongchamps, P.; Moreau, C. Can. J. Chem. 1971, 49,
465–2467. (b) Delongchamps, P.; Moreau, C.; Frehel, D.;
Chenevert, R. Can. J. Chem. 1975, 53, 1204–1211.
2
Acknowledgements
2
0. Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic data Centre.
CCDC no. 224224 for 21 and CCDC no. 224223 for 22.
Copies of this information may be obtained from The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44-
We thank the University of Southampton, the EPSRC,
Pfizer, and the Royal Society for support. We are indebted to
Joan Street and Dr. Neil Wells for NMR support, and to Dr.
John Langley and Julie Herniman for MS support. We wish
to acknowledge the use of the EPSRC’s Chemical database
1
223-336-033; e-mail: deposit@ccdc.cam.ac.uk or www:
http://www.ccdc.cam.ac.uk).
2
9
service at Daresbury.
2
2
1. Hanessian, S.; Prabhanjan, H.; Qiu, D.; Nambiar, S. Can.
J. Chem. 1996, 74, 1731–1737.
2. The diastereotopic and enantiotopic relationships between the
1
protons in 25 lead to an interesting H NMR spectrum. The
References and notes
enantiotopic H
protons H and H
, hence appear as a doublet of doublets, as are the
enantiotopic) alcohol protons H and H
a
and H
a
0
appear as singlet. The diastereotopic
are enantiotopic respectively with H
0
b
and
1
2
. Vik, J.-E. Acta Chem. Scand. 1973, 27, 239–250.
b
c
Hc
0
. (a) Farcy, N.; De Muynck, H.; Madder, A.; Hosten, N.; De
Clercq, P. J. Org. Lett. 2001, 3, 4299–4301. (b) Heinonen, P.;
Virta, P.; L o¨ nnberg, H. Tetrahedron 1999, 55, 7613–7624.
(
d
0
d
(c) Hanessian, S.; Qiu, D.; Prabhanjan, H.; Reddy, G. V.; Lou,
B. Can. J. Chem. 1996, 74, 1738–1747.
3
4
. (a) Grayson, S. M.; Fr e´ chet, J. M. J. J. Am. Chem. Soc. 2000,
1
22, 10335–10344. (b) Grayson, S. M.; Jayaraman, M.;
Fr e´ chet, J. M. J. Chem. Commun. 1999, 1329–1330.
. (a) Glauser, T.; Stancik, C. M.; M o¨ ller, M.; Voytek, S.; Gast,
A. P.; Hedrick, J. L. Macromolecules 2002, 35, 5774–5781.
23. (a) Clarke, P. Tetrahedron Lett. 2002, 43, 4761–4763. (b) Yu,
C.; Liu, B.; Hu, L. Tetrahedron Lett. 2000, 41, 4281–4285.
(c) Bouzide, A.; Sauv e´ , G. Tetrahedron Lett. 1997, 38,
5945–5948. (d) Effenberger, F.; Eichhorn, J.; Roos, J.
Tetrahedron: Asymmetry 1995, 6, 271–282. (e) Nishiguchi,
T.; Fujisaka, S.; Ishii, Y.; Yano, Y.; Nishida, A. J. Org. Chem.
1994, 59, 1191–1195.
(
b) W u¨ rsch, A.; M o¨ ller, M.; Glauser, T.; Lim, L. S.; Voytek,
S.; Hedrick, J. L. Macromolecules 2001, 34, 6601–6615.
. (a) Doherty, S.; Robins, E. G.; Nieuwenhuyzen, M.;
Champkin, P. A.; Clegg, W. Organometallics 2002, 21,
5
4147–4158. (b) Liu, B.; Roy, R. Chem. Commun. 2002,
594–595. (c) Ueno, Y.; Takeba, M.; Mikawa, M.; Matsuda,
24. (a) Bassindale, M. J.; Hamley, P.; Leitner, A.; Harrity, J. P. A.
Tetrahedron Lett. 1999, 40, 3247–3250. (b) Ding, H.-J.;
J. Org. Chem. 1999, 64, 1211–1217. (d) Pegenau, A.;

3636
P. Clarke et al. / Tetrahedron 60 (2004) 3625–3636
Huang, Y.-F.; Tzeng, C.-C.; Wei, L.-M.; Yeh, S.-J. Bioorg.
Med. Chem. Lett. 1999, 9, 3199–3202.
5. (a) Appelhans, D.; Reichardt, C. Liebigs Ann.-Recl. 1997, 11,
385–2392. (b) Hayashi, N.; Mine, T.; Fujiwara, K.; Murai,
27. Examples of mono-oxidation of (primary) 1,3-diols: (a) Sung,
M. S.; Lee, H. I.; Lee, H. B.; Cha, J. K. J. Org. Chem. 2003, 68,
2205–2208. (b) Nakano, T.; Terada, T.; Ishui, Y.; Ogawa, M.
Synthesis 1986, 774–776.
2
2
A. Chem. Lett. 1994, 2143–2146. (c) Ziegler, F. E.; Sobolov,
S. B. J. Am. Chem. Soc. 1990, 112, 2749–2758.
6. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 43,
28. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003.
29. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. Chem. Inf.
Comput. Sci. 1996, 36, 746.
2
8019–8022. See also: Corey, E. J.; Palani, A. Tetrahedron
Lett. 1995, 44, 7945–7948.