Synthesis and conformational analysis of meso-ter(1,3-dioxan-4-yls)

Article abstract of DOI:10.1002/1099-0690(200210)2002:20<3455::AID-EJOC3455>3.0.CO;2-V

A convergent synthesis of the meso-ter(1,3-dioxanyls) 8-11 has been achieved, starting from two enantiomeric building blocks in each case. The stereogenic centres in the central linkage region were set up by stereocontrolled aldol additions. Structure ass

Full text of DOI:10.1002/1099-0690(200210)2002:20<3455::AID-EJOC3455>3.0.CO;2-V

FULL PAPER
Synthesis and Conformational Analysis of meso-Ter(1,3-dioxan-4-yls)[‡]
Reinhard W. Hoffmann,*[a] Gemma Mas,[a] and Trixi Brandl[a]
Keywords: meso Compounds / Conformational analysis / Force-field calculations
3
A convergent synthesis of the meso-ter(1,3-dioxanyls) 8−11
has been achieved, starting from two enantiomeric building coupling constants, which reflect distinct conformer popula-
blocks in each case. The stereogenic centres in the central tions.
linkage region were set up by stereocontrolled aldol addi- ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
on comparisons between experimental and calculated JH,H
tions. Structure assignment of the final products was based
2002)
Certain di(1,3-dioxan-4-yls) 1 have a preferred conforma-
The synthesis of meso compounds with more than four
tion at the inter-ring bond when properly substituted in the stereocentres (e.g., of 6) in turn requires totally different
5,5Ј-positions.[1,2] This also holds for the inter-ring bonds approaches. There are two options for an efficient synthesis
in the ter(1,3-dioxan-4-yls) 3 and 4.[3] Our previous syn- of such compounds: one is to start from a central achiral
thesis of 3 and 4 was rather ineffective and did not capitalise (meso) building block (e.g., 5[4]) and to create the additional
on the symmetry (meso) of these compounds. As we wanted stereogenic centres by bidirectional synthesis.[5,6]
to study the conformational preferences of additional
(meso) symmetric ter-dioxanyls 2, a different synthetic ap-
proach to this class of meso compounds appeared necessary.
The difficulty in this approach is that only substrate-
based asymmetric induction can be applied, since identic-
ally substituted stereogenic centres of opposite configura-
tion have to be created in a single step. We have recently
utilised that approach successfully for the synthesis of other
meso compounds with more than four stereogenic
centres.[7,8]
The second approach is based on two enantiomeric build-
ing blocks (e.g., 7 and ent-7), which constitute the ‘‘outer
wings’’ of the target structure. This approach appears unat-
tractive at first, because both enantiomers of the building
blocks have to be prepared. This disadvantage may be bal-
anced by the convergency of the approach. The joining of
these building blocks is easy if the linkage region is devoid
of stereogenic centres. In the case of meso derivatives of 2,
such as 6, however, there are further stereocentres in the
linkage region, the control of which constitutes an addi-
tional challenge. This control is difficult to master, as asym-
metric induction may originate from either building block,
The synthesis of open-chain meso compounds with up
to four contiguous stereocentres can be addressed by, for
example, the DielsϪAlder or related cycloaddition reac-
tions, as long as they are inherently symmetric. The cyclic
adducts then have to be subjected to a ring-opening process,
as shown in the following generalised example.
[‡]
Flexible Molecules with Defined Shape, XIX. Part XVIII: Ref.[1]
Fachbereich Chemie der Philipps-Universiät,
[a]
Hans Meerwein-Str. 35032 Marburg, Germany
Fax: (internat.) ϩ 49-(0)6421/2828917
E-mail: rwho@chemie.uni-marburg.de
Eur. J. Org. Chem. 2002, 3455Ϫ3464  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1020Ϫ3455 $ 20.00ϩ.50/0
3455

R. W. Hoffmann, G. Mas, T. Brandl
FULL PAPER
resulting in matched or mismatched situations. Again, product was obtained. The diols were then converted into
chiral reagents or chiral auxiliaries are less likely to be ap- the ter-dioxanes 8 and 9 by acetalization.
plicable to such a problem. We nevertheless hoped that the
techniques of 1,2- and 1,4-asymmetric induction, highly de-
veloped in the field of aldol additions[9] might provide a
solution to this problem. We discuss in this paper how a
convergent approach can indeed be used in conjunction
with the aldol addition for a quick synthesis of the meso
compounds 8؊11.
Assignment of the relative configuration was not obvious
either at the stage of 17/18, or at the stages of 19/20 or 8/
9. A tentative assignment was achieved by considering the
conformational properties of the ter-dioxanes 8 and 9. The
conformer population can be analysed by force-field
(MM3*) calculations with the program MACROMO-
DEL.[16] Compound 8 is calculated to populate several con-
formations at the inter-ring bond, resulting in a predicted
3JH,H coupling constant of 5.0 Hz for the protons at the
As a prelude to the synthesis of more complex meso com-
inter-ring bonds of compound 8.
pounds of type 2, we tested the convergent approach in a
synthesis of the ter(1,3-dioxanyl)s 8 and 9. To this end, both
-malic acid (12) and -malic acid were converted into 13
and ent-13 by literature procedures.[10] Reduction of 12 with
boraneϪmethyl sulfide complex[11] was followed by per-
silylation of the resulting triol (69%). Subsequent Noyori
acetalisation[12] regioselectively furnished the dioxane 13
(97%).
DessϪMartin oxidation[13] provided the aldehyde 14
(70%), which was converted via the alcohol 15 (71%) into
the ketone 16 (91%). To initiate the aldol addition, the ke-
tone 16 was deprotonated with lithium diisopropylamide
and the resulting enolate was added to the aldehyde ent-14.
This afforded a mixture of the two aldol products 17 and
18 (92%) in a 1:1 ratio. A boron-mediated aldol addition
A similar analysis for compound 9 predicts a value of
6.1 Hz. This difference is clearly too small to allow a reli-
able assignment. Nevertheless, the almost perfect match to
the experimentally determined values of 5.1 and 6.4 Hz en-
couraged us to make a tentative assignment as given in the
formula scheme.
With the synthesis of 8 and 9 we were able to demon-
(chlorodicyclohexylborane, triethylamine)[9,14] likewise fur- strate that a convergent route to meso compounds by use
nished the two aldols in a 1:1 ratio. The aldol products of the aldol addition is feasible and concise. However, con-
could be separated by chromatography and were subjected trol of the stereogenic centres in the linkage region clearly
individually to syn-selective DIBAL reduction.[15] In each needs further attention, for example by turning to
case, according to the 13C NMR spectra, a symmetrical (ipc)2boron-enolates.[9]
3456
Eur. J. Org. Chem. 2002, 3455Ϫ3464

meso-Ter(1,3-dioxan-4-yls)
FULL PAPER
In the synthesis of the ter-dioxanes 10 and 11, the addi- of 24 was generated with Li-tetramethylpiperidide, a re-
tional methyl groups might aid in attaining higher stereo- agent that usually generates an E enolate. The formation of
selectivity in the aldol addition step. The building blocks a syn-aldol on addition to ent-22 is therefore noteworthy.
required for a convergent synthesis of the meso compounds At this stage, however, it is not clear whether the syn-aldol
10 and 11 are the alcohols 21 and ent-21. These were again 25 or 26 was obtained.
elaborated from - and -malic acid by following literature
precedent, with a Frater alkylation,[17Ϫ20] followed by bor-
ane reduction and regioselective acetalization.[21,22]
The aldol product was carried forward by reduction with
DIBAL to form a syn-diol (27 or 28, NMR spectra show
the product to be symmetrical), which was converted into
the acetonide (11 or 29).
The central dioxane ring in 11 or 29 was clearly derived
from a syn-1,3-diol (13C NMR signals at 19.4, 29.4, and
98.5 ppm[28,29]) with an axial methyl group (13C NMR sig-
nal at 6.2 ppm).[26,27] As before, no obvious distinction be-
tween 11 or 29 was available. We therefore again resorted
to conformational analysis for both 11 and 29, regarding
the conformer population at the inter-ring bonds. MM3*
calculations showed that 11 has a ca. 99% preference to
populate conformation 11a, reflected in a predicted coup-
ling constant of 8.7 Hz between 3-H and 4-H. Diastereomer
29 is calculated to have a sizeable preference (77%) for con-
formation 29a, giving a predicted coupling constant of
3.0 Hz between 3-H and 4-H.
DessϪMartin oxidation[13] of 21 provided the aldehyde
22, which on treatment with ethylmagnesium bromide fur-
nished a 2:1 mixture of the alcohols 23. Ley oxidation[23,24]
provided the ketone 24 in 90% yield. The methyl and pro-
pionyl substituents are in equatorial positions, as indicated
by the 10.5 Hz coupling displayed by 4-H.
The compound obtained had a 3-H/4-H coupling con-
stant of 8.3 Hz and should therefore be the diastereomer
11. This suggests that, in the aldol addition between the
The aldol addition between the lithium enolate of 24 and
the aldehyde ent-22 furnished a single aldol product in 64%
yield. The 2-H/3-H coupling constant of 2.9 Hz and the
chemical shift of the methyl carbon at C-2 of δ ϭ 6.0 ppm
indicate the formation of a syn-aldol.[25] The lithium enolate
lithium enolate of 24 and the aldehyde ent-22,
a
FelkinϪAnh preference on the side of the aldehyde[30] (che-
lation control should not be favoured, due to the low basi-
city of acetals) was working in concert with a 1,3-anti in-
duction across the enolate moiety. The latter result is sur-
prising (cf. the usual transition state models[9,31]), given the
fact that the lithium enolate of 24 was probably a Z enolate.
The aldol addition between 24 and ent-22 produced a
syn-aldol, indicating an unexpected formation of a Z li-
thium enolate from 24. In order to generate an anti aldol,
we converted the ketone 24 into its E enolborinate by treat-
ment with chlorodicyclohexylborane and triethylamine.[9,14]
Subsequent addition to ent-22 furnished a single aldol
product (89%), which was clearly different from 24. The 2-
H/3-H coupling of 10.3 Hz and the methyl signal at δ ϭ
12 ppm suggested[25] it to be an anti aldol (either 30 or 31).
Since, once again, no obvious means of distinction be-
tween 30 and 31 was available, we converted the aldol into
the ter-dioxane (10 or 34). The central dioxane ring in the
product is derived from a syn-1,3-diol (δC at 19.0, 29.9, and
98.0 ppm)[28,29] with an equatorial methyl group (δC at
13.6 ppm).[26,27]
In order to make a distinction between 10 and 34, we
resorted as before to conformational analysis of the pre-
Eur. J. Org. Chem. 2002, 3455Ϫ3464
3457

R. W. Hoffmann, G. Mas, T. Brandl
FULL PAPER
Conversion of the aldehyde 38 into the ketone 40 was
effected as described for the generation of the ketone 24.
The Z lithium enolate of the ketone 40 was generated by
deprotonation with lithium diisopropylamide and then ad-
ded to the aldehyde ent-38, resulting in a single aldol 41 or
42 in 62% yield. The fact that neither ketone 40 nor the
aldehyde 38 were enantiomerically pure was not a problem
in the coupling reaction, because due to the principle of
Horeau[35] the ee of the coupling product should have in-
creased in our case to 97%, if a somewhat lower yield were
accepted. The resulting aldol is a syn aldol, on the basis of
a 3JH,H coupling constant of 4.0 Hz and a 13C NMR chem-
ical shift of the methyl group of δ ϭ 8 ppm. As before,
however, we could not determine the relative configurations
(41 or 42) of the newly formed stereogenic centres with re-
spect to the resident stereocentres in the aldehyde and ke-
tone, respectively. The intended conversion of the aldol
(presumably 42) into the diol 43 could not, however, be
achieved. Repeated attempts at reduction with DIBAH re-
sulted in a product that lacked any plane of symmetry. One
of the (labile) p-methoxybenzylidene acetals was probably
reductively opened in parallel with the formation of the 1,3-
diol unit. Thus, our approach to compound 44 was aban-
doned at this point.
ferred conformation at the inter-ring bond. MM3* predicts
10 to exist in an essentially monoconformational situation,
with conformer 10a being populated to 90%. This should
give a predicted H/H-coupling constant of 1.9 Hz across
the inter-ring bond. Compound 34 should, in turn, have no
marked conformational preference at the inter-ring bonds.
In line with this, force-field calculations predict the H/H-
coupling constant across the inter-ring bond of 34 to be
4.5 Hz.
The product obtained had a H/H-coupling constant of
1.3 Hz (cf. the values of 2.4 and 2.5 Hz for the previously
described[3] compounds 3 and 4). We therefore conclude
that the product is compound 10 and not 34. Thus, the
aldol addition between the aldehyde ent-22 and the boron
E enolate of 24 was dominated by the usual[9,31] 1,3-anti
induction across the enolate moiety, but entailing an unex-
pected anti Felkin addition to the aldehyde ent-22.
In a continued attempt to access meso compounds of the
type 2, we targeted compound 43, which was calculated to
have a high (98%) conformational preference at the inter-
ring bonds as well. We therefore investigated the aldol addi-
tion between the ketone 40 and the aldehyde ent-38.
The synthesis started from the known[32] epoxide 35, ob-
tained by a Sharpless epoxidation. The material obtained
by us had an optical purity of only ca. 75%, but this is not
detrimental in a synthesis of a meso compound. To obtain
the 1,3-diol 36, of several methods tested,[33] a copper(I)-
catalysed Grignard addition[34] gave the highest (7:1) select-
ivity towards the formation of a 1,3- over a 1,2-diol. The
diol 36 was then converted into the p-methoxybenzylidene
acetal 37 (92%). DessϪMartin oxidation[13] furnished the
aldehyde 38 (73%), in which 4-H showed a 2.7 Hz coupling
to 5-H. Together with an NOE contact between 2-H and 4-
H, this indicates an equatorial placement of the aryl and
aldehyde groups and an axial arrangement of the methyl
group. The enantiomeric aldehyde ent-38 was obtained by
a corresponding sequence of reactions.
3458
Eur. J. Org. Chem. 2002, 3455Ϫ3464

meso-Ter(1,3-dioxan-4-yls)
FULL PAPER
Overall, these results demonstrate that a highly efficient destabilising than the corresponding CH/O syn-pentane in-
and stereoselective construction of meso compounds such teractions.[40]
as 10 or 11 is possible by use of the convergent approach
starting from the two enantiomeric ‘‘ends’’ of the molecule.
The high levels of asymmetric induction inherent to various
Experimental Section
variants[9,31] of the aldol addition were certainly a key to
General Remarks: All temperatures quoted are uncorrected. 1H
the success of this approach.
NMR, 13C NMR: Bruker ARX 200, AC 300, WH 400, AM 400,
While the main emphasis of this paper rests on the con-
vergent synthesis of meso compounds with multiple ste-
reogenic centres, the conformational preferences of the
compounds 8؊11 nevertheless merit some comments:
3
AMX 500. JH,H coupling constants were taken directly from the
500 MHz NMR spectra, 3JC,H coupling constants were determined
by Bax’s method.[41] Boiling range of petroleum ether: 40Ϫ60 °C.
Flash chromatography: Silica gel SI 60, E. Merck KGaA, Darm-
stadt, 40Ϫ63 µm. pH7-buffer: NaH2PO4·2H2O (56.2 g) and
Na2HPO4·4H2O (213.6 g), made up to 1 L with water. Conformer
populations were estimated by force-field calculations with the
MM3* force-field implemented in the MACROMODEL[16] pro-
gram, versions 4.5 and 6.5. 1500 starting structures were generated
with a Monte Carlo procedure and energy-minimised (gas phase
environment). Conformers with energies of less than 6 kcal·molϪ1
above the minimum energy conformer were subjected to Boltzmann
averaging for 298 K to predict the conformer population.
3
The JH,H coupling constants of 5.1 and 6.4 Hz at the
inter-ring bonds of 8 and 9 show that these compounds
display no conformational preference whatsoever. The ef-
fect of the methyl groups in the corresponding compounds
10 and 11 becomes increasingly evident: compound 10, for
instance, has a coupling constant of 1.3 Hz at the inter-ring
bond. This does not by itself prove a high conformational
preference, though, because both low-energy conformers
3
10a and 10b should have small JH,H coupling constants at
1. (2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxane-4-carbaldehyde (14):
DessϪMartin periodinane[13] (4.05 g, 9.54 mmol) and pyridine (823
µL, 10.2 mmol) were added to a solution of the alcohol 13 (1.43 g,
6.36 mmol) in dichloromethane (60 mL). After the mixture had
been stirred for 4 h at room temperature it was poured into satur-
ated aqueous K2CO3/Na2S2O3 (100 mL). After stirring for 10 min
the layers were separated and the aqueous layer was extracted with
tert-butyl methyl ether (2 ϫ 20 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated. This provided the alde-
hyde 14 (989 mg, 70%), which was used immediately, due to its
their inter-ring bonds, as both conformers have the relevant
hydrogen atoms in a gauche arrangement. Evidence that 10a
is indeed the predominant conformer (as predicted by the
force-field calculations) is provided by the determination of
3
the indicated JC,H coupling constant to 3.0 Hz, character-
istic[36] of a CϪCϪCϪH gauche arrangement. The behavi-
our of compound 10 is thus in line with the analogues 3
and 4;[3] that is, with expectations and calculations.
tendency to polymerise. 1H NMR (200 MHz, C6D6):
δ ϭ
1.45Ϫ2.00 (m, 2 H), 3.47Ϫ3.60 (m, 3 H), 5.45 (s, 1 H), 6.72Ϫ6.76
(m, 2 H), 7.19Ϫ7.25 (m, 2 H), 9.89 (s, 1 H) ppm.
2. (1RS)-1-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-1-ethanol
(15): A solution of ethylmagnesium bromide (2.5  in ether,
4.0 mL, 10 mmol) was added dropwise at 0 °C to a solution of the
aldehyde 14 (1.35 g, 6.05 mmol) in ether (60 mL). After stirring for
2 h the mixture was poured onto ice and was neutralised with aque-
ous 2  hydrochloric acid. The mixture was extracted with tert-
butyl methyl ether (3 ϫ 10 mL). The combined extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated.
Flash chromatography with pentane/tert-butyl methyl ether, 1:1
(containing 1% of triethylamine) furnished a 1.5:1-diastereomeric
mixture (1.03 g, 71%) of the alcohol 15 as a colourless oil. 1H
NMR (200 MHz, C6D6): δ ϭ 0.90 (d, J ϭ 6.5 Hz, 3 H), 0.92 (d,
J ϭ 6.5 Hz, 3 H), 0.90Ϫ0.99 (m, 2 H), 1.40 (tdd, J ϭ 13.3, 11.5,
5.2 Hz, 1 H), 1.70 (tdd, J ϭ 13.0, 11.5, and 5.0 Hz, 1 H), 3.14 (s,
6 H), 3.19Ϫ3.29 (m, 3 H), 3.35 (td, J ϭ 11.5, 2.7 Hz, 1 H), 3.50
(quin, J ϭ 6.5 Hz, 1 H), 3.59 (qd, J ϭ 6.5, 4.4 Hz, 1 H), 3.80 (ddd,
J ϭ 11.4, 5.2, 1.3 Hz, 1 H), 3.88 (ddd, J ϭ 11.5, 5.3, and 1.3 Hz,
1 H), 5.18 (s, 1 H), 5.24 (s, 1 H), 6.66Ϫ6.74 (m, 4 H), 7.37Ϫ7.48
(m, 4 H) ppm. 13C NMR (75 MHz, C6D6): major isomer δ ϭ 18.3,
25.6, 54.9, 66.9, 69.4, 80.9, 101.5, 113.8, 128.1, 132.3, 160.5 ppm;
minor isomer δ ϭ 18.2, 27.3, 54.9, 66.6, 70.3, 81.8, 101.6, 113.9,
128.3, 132.1, 160.6 ppm. C13H18O4: calcd. 238.1205; found.
(HRMS EI) 238.1199.
General considerations would not, however, have given
rise to the expectation that compound 11 should show a
significant conformer preference at all, because each of the
diamond-lattice type conformations should suffer from
some kind of a syn-pentane interaction.[37] We were there-
fore surprised that the MM3* calculations predicted a 99%
preference for conformer 11a, despite the presence of two
CH/O syn-pentane interactions and two anti OϪCϪCϪO
arrangements, which are energetically less favourable than
gauche OϪCϪCϪO arrangements.[38,39] An explanation for
the preference of conformation 11a has to take into account
that any rotation at one of the inter-ring bonds of 11 creates
3. 1-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-1-ethanone (16):
˚
Powdered molecular sieves (4 A, 100 mg), N-methylmorpholine N-
two CH/CH syn-pentane interactions, which are much more oxide (62 mg, 0.53 mmol) and tetrapropylammonium perruthenate
Eur. J. Org. Chem. 2002, 3455Ϫ3464 3459

R. W. Hoffmann, G. Mas, T. Brandl
FULL PAPER
(7 mg, 0.02 mmol) were added to a solution of the alcohol 15
(83 mg, 0.35 mmol) in dichloromethane (1.5 mL). After stirring for
methyl ether, 1:9, (containing 1% of triethylamine) furnished the
diol 20 (194 mg, 98%) as a colourless solid (m.p. 164 °C). 1H NMR
30 min at room temperature the mixture was separated by flash (500 MHz, CDCl3): δ ϭ 1.53 (q, J ϭ 13.7 Hz, 1 H), 1.61 (dq, J ϭ
chromatography with pentane/tert-butyl methyl ether, 2:1 (con-
taining 1% of triethylamine) to give the ketone 16 (76 mg, 91%) as
a colourless oil, which later solidified (m.p. 74 °C). [α]2D0 ϭ Ϫ55.6
13.3, 1.2 Hz, 2 H), 1.95 (qd, J ϭ 12.1, 4.9 Hz, 2 H), 2.00 (dt, J ϭ
14.5, 2.2 Hz, 1 H), 3.42 (br. s, 2 H), 3.74 (ddd, J ϭ 11.3, 5.2, and
2.3 Hz, 2 H), 3.79 (s, 6 H), 3.90Ϫ3.94 (m, 2 H), 4.29 (ddd, J ϭ
(c ϭ 1.08, CHCl3). 1H NMR (200 MHz, C6D6): δ ϭ 1.31 (dtd, J ϭ 11.6, 4.0, and 1.0 Hz, 2 H), 5.47 (s, 2 H), 6.86Ϫ6.91 (m, 4 H),
13.4, 2.8, and 1.4 Hz, 1 H), 1.57 (dtd, J ϭ 13.4, 11.8, and 5.0 Hz,
7.37Ϫ7.43 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 25.9,
1 H), 1.91 (s, 3 H), 3.21 (s, 3 H), 3.30 (td, J ϭ 11.8, 2.8 Hz, 1 H), 33.3, 55.2, 66.7, 74.2, 79.4, 100.9, 113.5, 127.3, 130.9, 159.9 ppm.
3.66 (dd, J ϭ 11.8, 2.8 Hz, 1 H), 3.78 (ddd, J ϭ 11.8, 5.0, and
The diol 20 (40 mg, 90 µmol) was dissolved in THF (1 mL). 2-
Methoxypropene (17 µL, 0.174 mmol) and p-toluenesulfonic acid
(ca. 5 mg) were added. The mixture was stirred for 30 min and
poured into saturated aqueous NaHCO3 (2 mL). The layers were
separated and the aqueous layer was extracted with ether (4 ϫ
2 mL). The combined organic layers were dried (Na2SO4) and con-
centrated. Flash chromatography of the residue with pentane/tert-
butyl methyl ether, 2:1 (containing 1% of triethylamine) furnished
the product 9 (32 mg, 72%) as a colourless solid of m.p. 191 °C.
1H NMR (200 MHz, C6D6): δ ϭ 1.26 (s, 3 H), 1.43 (dq, J ϭ 13.3,
1.4 Hz, 2 H), 1.51 (s, 3 H), 1.58 (q, J ϭ 11.6 Hz, 1 H), 1.75 (qd,
J ϭ 12.7, 4.9 Hz, 2 H), 2.14 (dt, J ϭ 13.0, 2.5 Hz, 1 H), 3.24 (s, 6
H), 3.58 (td, J ϭ 11.5 2.5 Hz, 2 H), 3.62 (ddd, J ϭ 11.2, 6.4, and
2.4 Hz, 2 H), 3.76 (ddd, J ϭ 11.5, 6.4, and 2.5 Hz, 2 H), 4.04 (ddd,
J ϭ 11.3, 4.9, and 1.3 Hz, 2 H), 5.39 (s, 2 H), 6.77Ϫ6.79 (m, 4 H),
7.57Ϫ7.62 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 19.8,
28.0, 29.9, 30.2, 55.3, 66.9, 71.5, 79.8, 98.8, 101.0, 113.6, 127.4,
131.3, 159.9 ppm. C28H36O8: calcd. 500.2410; found (HRMS EI)
500.2410.
1.4 Hz, 1 H), 5.13 (s, 1 H), 6.73Ϫ6.80 (m, 2 H), 7.42Ϫ7.49 (m, 2
H) ppm. 13C NMR (75 MHz, C6D6): δ ϭ 25.5, 27.6, 54.9, 66.7,
81.8, 101.2, 113.9, 128.0, 131.7, 160.7, 206.7 ppm. C13H16O4
(236.2): calcd. C 66.06, H 6.83; found C 66.06, H 6.92.
4. (3RS)-3-Hydroxy-3-[(2R,4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-
yl]-1-[(2S,4S)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-1-propanone
(17,18): n-Butyllithium (1.53  in hexane, 1.96 mL, 3.00 mmol) was
added dropwise at 0 °C to a solution of diisopropylamine (492 mg,
3.00 mmol) in THF (10 mL). After stirring for 15 min, the solution
was cooled to Ϫ78 °C and a solution of the ketone 16 (588 mg,
2.50 mmol) in THF (3 mL) was added dropwise. After the mixture
had been stirred for a further 20 min, a solution of the aldehyde
ent-14 (444 mg, 2.00 mmol) in THF (3 mL) was added dropwise.
After stirring for 40 min at Ϫ78 °C, the mixture was poured onto
pH7 buffer solution (20 mL). The layers were separated and the
aqueous layer was extracted with ether (4 ϫ 10 mL). The combined
organic layers were dried (Na2SO4) and concentrated. Flash chro-
matography of the residue with pentane/tert-butyl methyl ether, 1:1
(ϩ 1% of triethylamine) furnished the aldol 17 (420 mg, 46%) and
the aldol 18 (123 mg, 46%) as colourless oils.
6. (4R,6S)-4-[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-6-
[(2S,4S)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-2,2-dimethyl-1,3-
dioxane (8): A solution of the aldol 17 (51 mg, 0.11 mmol) was
converted into the ter-dioxane 8 (67%) as described under 5. m.p.
180 °C. 1H NMR (500 MHz, C6D6): δ ϭ 1.03 (dq, J ϭ 13.1, 1.4 Hz,
2 H), 1.32 (s, 3 H), 1.38 (dt, J ϭ 12.5, 2.5 Hz, 1 H), 1.53 (s, 3 H),
1.58 (q, J ϭ 12.1 Hz, 1 H), 1.81 (qd, J ϭ 12.5, J ϭ 5.0 Hz, 2 H),
3.24 (s, 6 H), 3.56 (td, J ϭ 11.2, 2.3 Hz, 2 H), 3.73 (ddd, J ϭ 11.2,
5.1, and 2.2 Hz, 2 H), 3.93 (ddd, J ϭ 11.2, 5.1, and 2.3 Hz, 2 H),
4.03 (ddd, J ϭ 11.4, 4.0, 0.9 Hz, 2 H), 5.43 (s, 2 H), 6.78Ϫ6.80 (m,
4 H), 7.60Ϫ7.65 (m, 4 H) ppm. 13C NMR (50 MHz, C6D6): δ ϭ
19.7, 26.0, 26.9, 30.4, 54.8, 66.9, 71.1, 80.3, 98.7, 101.9, 113.8,
128.5, 132.2, 160.4 ppm. C28H36O8, [M ϩ H]: calcd. 501.2488,
found (HRMS ESI) 501.2538.
1
Aldol 17: [α]2D0 ϭ Ϫ62.1 (c ϭ 0.98, CHCl3). H NMR (500 MHz,
C6D6): δ ϭ 1.26 (d, J ϭ 12.5 Hz, 1 H), 1.38 (d, J ϭ 12.2 Hz, 1 H),
1.65Ϫ1.76 (m, 4 H), 2.73 (br. s, 1 H), 3.27 (s, 6 H), 3.34 (td, J ϭ
12.4, 1.9 Hz, 1 H), 3.46 (td, J ϭ 12.2, 2.3 Hz, 1 H), 3.55 (ddd, J ϭ
11.2, 6.0, and 2.2 Hz, 1 H), 3.80Ϫ3.86 (m, 2 H), 3.96 (dd, J ϭ 11.6,
4.9 Hz, 1 H), 4.18Ϫ4.22 (m, 1 H), 5.20 (s, 1 H), 5.31 (s, 1 H),
6.80Ϫ6.84 (m, 4 H), 7.52Ϫ7.54 (m, 4 H) ppm. 13C NMR
(125 MHz, C6D6): δ ϭ 27.3, 27.4, 41.2, 54.8, 66.6, 66.7, 70.2, 79.4,
81.6, 101.2, 101.3, 113.7, 113.9, 127.9, 128.0, 131.4, 132.0, 160.4,
160.5, 209.0 ppm. C25H30O8, [M ϩ Na]: calcd. 481.1838; found
(HRMS ESI) 481.1842.
1
Aldol 18: [α]2D0 ϭ Ϫ43.6 (c ϭ 1.12, CHCl3). H NMR (500 MHz,
C6D6): δ ϭ 1.18Ϫ1.22 (m, 1 H), 1.24Ϫ1.27 (m, 1 H), 1.33Ϫ1.37
(m, 1 H), 1.70Ϫ1.82 (m, 3 H), 2.64 (s, 1 H), 3.27Ϫ3.29 (m, 1 H),
3.28 (s, 3 H), 3.29 (s, 3 H), 3.36 (td, J ϭ 12.2, 2.5 Hz, 1 H), 3.49
(td, J ϭ 11.9, 2.5 Hz, 1 H), 3.72 (dd, J ϭ 11.5, 2.3 Hz, 1 H),
3.81Ϫ3.85 (m, 2 H), 4.00 (ddd, J ϭ 11.1, 4.9, and 1.1 Hz, 1 H),
5.20 (s, 1 H), 5.33 (s, 1 H), 6.75Ϫ6.81 (m, 4 H), 7.50Ϫ7.54 (m, 4
H) ppm. 13C NMR (125 MHz, C6D6): δ ϭ 23.2, 25.4, 44.6, 54.8,
66.0, 66.9, 73.3, 81.9, 82.6, 101.2, 101.4, 113.7, 113.9, 127.8, 127.9,
131.2, 132.0, 160.3, 160.5, 210.6 ppm.
7.
(1RS)-1-[(2S,4S,5S)-5-Methyl-2-phenyl-1,3-dioxan-4-yl]-1-pro-
panol (23): Pyridine (194 µL, 2.40 mmol) and DessϪMartin
periodinane[13] (1.02 g, 2.40 mmol) were added at room temper-
ature to a solution of (2S,4S,5S)-5-methyl-2-phenyl-1,3-dioxan-4-
ylmethanol[21] (312 mg, 1.50 mmol) in dichloromethane (10 mL).
After stirring for 3 h the mixture was poured into a solution of
potassium carbonate (4 g) in saturated aqueous Na2S2O3 (20 mL).
After the mixture had been stirred for 10 min, the layers were sep-
arated and the aqueous layer was extracted with tert-butyl methyl
5. (4S,6R)-4-[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-6- ether (2 ϫ 10 mL). The combined organic layers were washed with
[(2S,4S)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-2,2-dimethyl-1,3-
dioxane (9): A solution of DIBAH (1  in petroleum ether,
1.29 mL, 1.3 mmol) was added at Ϫ100 °C to a solution of the
aldol 18 (196 mg, 0.43 mmol) in THF (7 mL). After stirring for 5 h,
the mixture was poured into saturated aqueous sodium potassium
tartrate solution (20 mL) and stirred for 1 h. The layers were separ-
ated and the aqueous layer was extracted with ether (5 ϫ 10 mL).
saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried
(Na2SO4), and concentrated. The resulting crude aldehyde 22
(271 mg, 87%) was used as obtained for the next step. [α]2D0 ϭ Ϫ43.1
(c ϭ 1.37, CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 0.92 (d, J ϭ
6.7 Hz, 3 H), 2.08Ϫ2.19 (m, 1 H), 3.56 (t, J ϭ 11.3 Hz, 1 H), 3.89
(d, J ϭ 10.8 Hz, 1 H), 4.20 (dd, J ϭ 11.3, 4.9 Hz, 1 H), 5.55 (s, 1
H), 7.37Ϫ7.42 (m, 3 H), 7.48Ϫ7.52 (m, 2 H), 9.67 (s, 1 H) ppm.
The combined organic layers were dried (Na2SO4) and concen- 13C NMR (50 MHz, CDCl3): δ ϭ 11.4, 29.4, 72.5, 85.5, 100.5,
trated. Flash chromatography of the residue with pentane/tert-butyl
126.1, 128.3, 129.1, 137.5, 199.5 ppm.
3460
Eur. J. Org. Chem. 2002, 3455Ϫ3464

meso-Ter(1,3-dioxan-4-yls)
FULL PAPER
A solution of ethylmagnesium bromide (2.5  in ether, 1.60 mL,
3.90 mmol) was added at 0 °C to a solution of the aldehyde 22
centrated. Flash chromatography of the residue with pentane/tert-
butyl methyl ether, 4:1 (containing 1% of triethylamine) furnished
(538 mg, 2.61 mmol) in ether (15 mL) After stirring for 2 h the mix- the aldol 25 (single stereoisomer, 366 mg, 64%) as a colourless oil.
ture was poured onto ice and neutralised by addition of hydro-
chloric acid (2N). The layers were separated and the aqueous layer
was extracted with tert-butyl methyl ether (3 ϫ 10 mL). The com-
[α]2D0 ϭ Ϫ45.8 (c ϭ 1.04, CHCl3). 1H NMR (300 MHz, CDCl3):
δ ϭ0.70 (d, J ϭ 6.8 Hz, 3 H), 0.80 (d, J ϭ 6.6 Hz, 3 H), 1.15 (d,
J ϭ 7.1 Hz, 3 H), 1.83Ϫ1.91 (m, 1 H), 2.10Ϫ2.21 (m, 1 H), 2.79
bined organic layers were washed with brine (10 mL), dried (d, J ϭ 6.1 Hz, 1 H), 3.48 (t, J ϭ 11.5 Hz, 1 H), 3.55 (t, J ϭ
(Na2SO4), and concentrated. Flash chromatography of the residue
with pentane/tert-butyl methyl ether, 3:1 (containing 1% of triethyl-
11.5 Hz, 1 H), 3.57 (dd, J ϭ 10.0, 5.9 Hz, 1 H), 3.63 (qd, J ϭ 7.1,
2.9 Hz, 1 H), 3.97 (d, J ϭ 10.2 Hz, 1 H), 3.98 (dd, J ϭ 11.5, 4.7 Hz,
amine) furnished a 2:1 diastereomer mixture of alcohols 23 1 H), 4.10 (dd, J ϭ 11.5, 4.9 Hz, 1 H), 4.26 (td, J ϭ 6.1, 2.9 Hz, 1
(441 mg, 72%) as a colourless oil. A small sample was rechromato-
graphed to give the pure diastereomers.
H), 5.36 (s, 1 H), 5.46 (s, 1 H), 7.23Ϫ7.25 (m, 6 H), 7.34Ϫ7.40 (m,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 10.0, 12.3, 12.4, 30.7,
32.8, 42.6, 71.8, 72.8, 73.1, 83.5, 86.2, 101.0, 101.2, 125.9 (2 C),
126.0 (2 C), 128.1 (2 C), 128.2 (2 C), 128.7, 128.9, 137.4, 138.1,
211.6 ppm. C26H32O6: calcd. 440.2199; found (HRMS EI)
440.2218.
Major Diastereomer: [α]2D0 ϭ ϩ4.2 (c ϭ 1.67, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 0.83 (d, J ϭ 6.7 Hz, 3 H), 1.00 (t, J ϭ
7.4 Hz, 3 H), 1.45Ϫ1.60 (m, 2 H), 2.10Ϫ2.34 (m, 1 H), 3.39 (dd,
J ϭ 10.0, 1.2 Hz, 1 H), 3.52 (t, J ϭ 11.2 Hz, 1 H), 3.53Ϫ3.57 (m,
1 H), 4.18 (dd, J ϭ 11.2, 4.9 Hz, 1 H), 5.56 (s, 1 H), 7.25Ϫ7.37 (m,
3 H), 7.45Ϫ7.50 (m, 2 H) ppm, the OH signal was obscured. 13C
NMR (50 MHz, CDCl3): δ ϭ 10.4, 12.1, 27.2, 29.4, 71.4, 72.9, 84.0,
100.7, 126.0, 128.2, 128.7, 138.5 ppm. C14H20O3 (236.3): calcd. C
71.16, H 8.53; found C 71.02, H 8.75.
10. (4S,5R,6R)-2,2,5-Trimethyl-4-[(2R,4R,5R)-5-methyl-2-phenyl-
1,3-dioxan-4-yl]-6-[(2S,4S,5S)-5-methyl-2-phenyl-1,3-dioxan-4-yl]-
1,3-dioxane (11): A solution of DIBAH (1.0  in petroleum ether,
1.0 mL, 1.0 mmol) was added dropwise at Ϫ100 °C to a solution
of the aldol 25 (129 mg, 0.29 mmol) in THF (5 mL). After stirring
for 3 h the mixture was poured into saturated aqueous potassium
sodium tartrate (10 mL). After this mixture had been stirred for a
further 1 h, the layers were separated and the aqueous layer was
extracted with tert-butyl methyl ether (5 ϫ 5 mL). The combined
organic layers were washed with brine (5 mL), dried (Na2SO4), and
concentrated. Flash chromatography of the residue with pentane/
tert-butyl methyl ether, 2:1 (containing 1% of triethylamine) fur-
Minor diastereomer: [α]2D0 ϭ ϩ10.3 (c ϭ 1.15 in CHCl3). H NMR
1
(200 MHz, CDCl3): δ ϭ 0.80 (d, J ϭ 6.5 Hz, 3 H), 1.04 (t, J ϭ
7.2 Hz, 3 H), 1.51Ϫ1.76 (m, 2 H), 1.92Ϫ2.01 (m, 1 H), 3.50 (t, J ϭ
11.3 Hz, 1 H), 3.53Ϫ3.58 (m, 3 H), 4.10 (dd, J ϭ 11.3, 4.8 Hz, 1
H), 5.48 (s, 1 H), 7.34Ϫ7.40 (m, 3 H), 7.45Ϫ7.50 (m, 2 H) ppm,
the OH signal was obscured. 13C NMR (50 MHz, CDCl3): δ ϭ
10.6, 12.0, 24.0, 30.5, 71.4, 72.6, 85.6, 101.5, 126.2, 128.0, 128.6,
138.4 ppm. C14H20O3: calcd. 236.1412; (HRMS EI) found
236.1404.
1
nished the syn-diol 27 (93 mg, 71%) as a colourless oil. H NMR
(300 MHz, CDCl3): δ ϭ 0.90 (d, J ϭ 6.8 Hz, 6 H), 1.16 (d, J ϭ
6.8 Hz, 3 H), 1.96Ϫ2.10 (m, 2 H), 2.39Ϫ2.46 (m, 1 H), 3.23 (d, J ϭ
4.4 Hz, 2 H), 3.52 (t, J ϭ 11.2 Hz, 2 H), 3.59 (dd, J ϭ 10.0, 6.1 Hz,
2 H), 4.04Ϫ4.08 (m, 2 H), 4.10 (dd, J ϭ 11.3, 4.6 Hz, 2 H), 5.45
(s, 2 H), 7.34Ϫ7.36 (m, 6 H), 7.43Ϫ7.47 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 6.4, 12.5, 32.8, 33.2, 73.1, 78.1, 83.6, 101.4,
125.9, 128.2, 128.8, 138.3 ppm.
8.
1-[(2S,4S,5S)-5-Methyl-2-phenyl-1,3-dioxan-4-yl]-1-propanone
˚
(24): Powdered molecular sieves (4 A, 2.4 g), N-methylmorpholine
N-oxide (829 mg, 7.08 mmol) and tetrapropylammonium perruth-
enate (84 mg, 0.24 mmol) were added to a solution of the alcohols
obtained under 7. (1.115 g, 4.72 mmol) in dichloromethane
(20 mL). After stirring for 2 h at room temperature, the mixture
was concentrated. Flash chromatography of the residue with pent-
ane/tert-butyl methyl ether, 4:1 (containing 1% of triethylamine)
furnished the ketone 24 (989 mg, 90%) as a colourless oil, which
solidified on storage at 5 °C. M.p.: 33 °C. [α]2D0 ϭ Ϫ57.4 (c ϭ 1.29,
2-Methoxypropene (31 µL, 0.32 mmol) and p-toluenesulfonic acid
(ca 5 mg) were added to a solution of the diol 27 (72 mg,
0.16 mmol) in THF (1 mL). After the mixture had been stirred for
2 h at room temperature, saturated aqueous NaHCO3 (2 mL) was
added. The layers were separated and the aqueous layer was ex-
tracted with ether (4 ϫ 2 mL). The combined organic layers were
dried (Na2SO4) and concentrated. Flash chromatography of the
residue with pentane/tert-butyl methyl ether, 7:1 (containing 1% of
triethylamine) furnished the acetonide 11 (51 mg, 69%) as a colour-
less solid of m.p. 190 °C. 1H NMR (500 MHz, C6D6): δ ϭ 0.85 (d,
J ϭ 6.7 Hz, 6 H), 1.28 (s, 3 H), 1.40 (d, J ϭ 6.7 Hz, 3 H), 1.50 (s,
3 H), 1.95Ϫ2.02 (m, 2 H), 2.56 (qt, J ϭ 6.7, 2.2 Hz, 1 H), 3.35 (t,
J ϭ 11.2 Hz, 2 H), 3.50 (dd, J ϭ 9.3, 8.3 Hz, 2 H), 3.96 (dd, J ϭ
8.3, 2.3 Hz, 2 H), 4.05 (dd, J ϭ 11.3, 4.7 Hz, 2 H), 5.46 (s, 2 H),
7.30Ϫ7.32 (m, 2 H), 7.37Ϫ7.41 (m, 4 H), 7.81Ϫ7.84 (m, 4 H) ppm.
13C NMR (75 MHz, C6D6): δ ϭ 6.2, 13.0, 19.4, 29.1, 29.9, 35.4,
73.0, 77.1, 80.2, 98.5, 100.2, 126.0, 128.4, 128.9, 139.5 ppm.
C29H38O6: calcd. 482.2668; found (HRMS EI) 482.2662.
1
CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 0.86 (d, J ϭ 6.6 Hz, 3
H), 1.07 (t, J ϭ 7.5 Hz, 3 H), 1.97Ϫ2.19 (m, 1 H), 2.74 (q, J ϭ
7.4 Hz, 2 H), 3.54 (t, J ϭ 11.3 Hz, 1 H), 3.92 (d, J ϭ 10.5 Hz, 1
H), 4.16 (dd, J ϭ 11.3, 4.8 Hz, 1 H), 5.53 (s, 1 H), 7.35Ϫ7.40 (m,
3 H), 7.49Ϫ7.52 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ
6.9, 12.0, 30.9, 31.2, 72.8, 87.4, 100.6, 125.9, 128.2, 128.9, 152.8,
208.8 ppm. C14H18O3 (234.3): calcd. C 71.77, H 7.74; found C
71.64, H 7.52.
9. (2S,3S)-3-Hydroxy-2-methyl-3-[(2R,4R,5R)-5-methyl-2-phenyl-
1,3-dioxan-4-yl]-1-[(2S,4S,5S)-5-methyl-2-phenyl-1,3-dioxan-4-
yl]propan-1-one (25): A solution of n-butyllithium (1.53  in hex-
ane, 915 µL, 1.40 mmol) was added at 0 °C to a solution of 2,2,6,6-
tetramethylpiperidine (253 µL, 1.50 mmol) in THF (3 mL). After
stirring for 15 min the mixture was cooled to Ϫ78 °C and a solution
of the ketone 24 (327 mg, 1.40 mmol) in THF (3 mL) was added.
11. (2S,3R)-3-Hydroxy-2-methyl-3-[(2R,4R,5R)-5-methyl-2-phenyl-
1,3-dioxan-4-yl]-1-[(2S,4S,5S)-5-methyl-2-phenyl-1,3-dioxan-4-
After stirring for 20 min a solution of the aldehyde ent-22 (280 mg, yl]propan-1-one (30): Triethylamine (904 µL, 6.52 mmol) was added
1.30 mmol) in THF (2 mL) was added and stirring was continued
for 1 h. The mixture was poured into aqueous buffer (pH 7, 15 mL)
and the layers were separated. The aqueous layer was extracted
with tert-butyl methyl ether (3 ϫ 10 mL). The combined organic
layers were washed with brine (10 mL), dried (Na2SO4), and con-
at 0 °C to a solution of chlorodicyclohexylborane (1.26 mL,
5.83 mmol) in ether (13 mL). After the mixture had been stirred
for 5 min, a solution of the ketone 24 (801 mg, 3.43 mmol) in ether
(3 mL) was added, resulting in the formation of a white precipitate.
After stirring for further 2 h the mixture was cooled to Ϫ78 °C. A
Eur. J. Org. Chem. 2002, 3455Ϫ3464
3461

R. W. Hoffmann, G. Mas, T. Brandl
solution of the aldehyde ent-22 (541 mg, 2.62 mmol) in ether (Na2SO4), and concentrated. Flash chromatography of the residue
FULL PAPER
(3 mL) was added slowly. The mixture was kept for 48 h at Ϫ18 °C
and was subsequently poured into a combination of buffer solution
(pH7, 10 mL), water (10 mL) and methanol (10 mL). The layers
were separated and the aqueous layer was extracted with ether (3
ϫ 10 mL). The combined extracts were concentrated and the res-
idue was taken up in a mixture of buffer solution (pH7, 10 mL)
and methanol (20 mL). Aqueous hydrogen peroxide (30%, 5 mL)
was added slowly and the mixture was stirred for 1 h. The mixture
was extracted with ether (5 ϫ 15 mL). The combined organic layers
were washed with brine (10 mL), dried (Na2SO4), and concen-
trated. Flash chromatography of the residue with pentane/tert-butyl
methyl ether, 3:1 (containing 1% of triethylamine) furnished the
aldol 30 (1.032 g, 89%) as a single diastereomer. [α]2D0 ϭ Ϫ54.7 (c ϭ
1.54, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 0.59 (d, J ϭ
6.8 Hz, 3 H), 0.72 (d, J ϭ 6.8 Hz, 3 H), 1.22 (d, J ϭ 7.1 Hz, 3 H),
1.63 (br. s, 1 H), 1.75Ϫ1.79 (m, 1 H), 1.82Ϫ1.94 (m, 2 H), 3.16 (t,
J ϭ 11.2 Hz, 1 H), 3.37 (t, J ϭ 11.3 Hz, 1 H), 3.53 (d, J ϭ 10.5 Hz,
1 H), 3.54 (dd, J ϭ 10.3, 3.4 Hz, 1 H), 3.71 (dt, J ϭ 10.3, 3.2 Hz,
1 H), 3.91 (dd, J ϭ 11.3, 4.9 Hz, 1 H), 3.94 (dd, J ϭ 11.3, 4.9 Hz,
1 H), 5.15 (s, 1 H), 5.35 (s, 1 H), 7.21Ϫ7.23 (m, 4 H), 7.26Ϫ7.30
(m, 2 H), 7.33Ϫ7.36 (m, 2 H), 7.42Ϫ7.45 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 12.0, 12.2, 16.0, 31.1, 31.4, 37.9, 72.7, 72.8,
76.9, 86.0, 86.1, 100.6, 100.7, 125.9, 126.0, 127.9, 128.0, 128.6,
128.7, 137.9, 138.2, 214.5 ppm. C26H32O6: calcd. 440.2199; found
(HRMS EI) 440.2220.
with pentane/tert-butyl methyl ether, 1:1 furnished the 1,3-diol 36
(405 mg, 70%) as well as the 1,2-diol (56 mg, 10%) as colourless
oils.
Compound 36: [α]2D0 ϭ Ϫ17.2 (c ϭ 2.47, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 0.03 (s, 6 H), 0.83 (s, 9 H), 0.88 (d, J ϭ
7.0 Hz, 3 H), 1.76Ϫ1.82 (m, 1 H), 3.02 (d, J ϭ 3.4 Hz, 1 H),
3.22Ϫ3.30 (m, 1 H), 3.54Ϫ3.60 (m, 4 H), 3.73Ϫ3.77 (m, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ Ϫ5.3, 11.1, 18.3, 25.9, 37.2, 65.1,
66.1, 73.8 ppm. C11H26O3Si (234.4): calcd. C 56.36, H 11.18; found
C 56.06, H 11.40.
The 1,2-diol: [α]2D0 ϭ Ϫ25.7 (c ϭ 1.50, CHCl3). 1H NMR (200 MHz,
CDCl3): δ ϭ 0.01 (s, 6 H), 0.83 (s, 9 H), 0.86 (d, J ϭ 7.2 Hz, 3 H),
1.70Ϫ1.74 (m, 1 H), 3.51Ϫ3.69 (m, 5 H). The signal of the OH
groups was obscured. 13C NMR (50 MHz, CDCl3): δ ϭ Ϫ5.4, 11.6,
18.0, 25.7, 37.6, 64.4, 66.3, 74.4.
15. (2S,4S,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-ylme-
thanol (37): A solution of the diol 36 (954 mg, 4.07 mmol), anisal-
dehyde diethyl acetal (1.03 g, 4.88 mmol), and camphorsulfonic
acid (ca. 5 mg) in dichloromethane (5 mL) was heated at 15 mbar
to 40 °C for 30 min in a rotary evaporator. THF (20 mL) and a
solution of tetrabutylammonium fluoride (1  in THF, 5.0 mL,
5.0 mmol) were added and the mixture was stirred for 20 min. The
mixture was concentrated in vacuo. Flash chromatography of the
residue with pentane/ether, 1:1 furnished the acetal 37 as a colour-
less oil; [α]2D0 ϭ Ϫ18.9 (c ϭ 1.72, CHCl3). 1H NMR (300 MHz,
C6D6): δ ϭ 1.04 (d, J ϭ 7.0 Hz, 3 H), 1.22Ϫ1.29 (m, 1 H), 1.85
(br. s, 1 H), 3.26 (s, 3 H), 3.30 (dd, J ϭ 11.4, 4.4 Hz, 1 H), 3.59
(dd, J ϭ 11.4, 8.0 Hz, 1 H), 3.64 (dd, J ϭ 11.2, 2.0 Hz, 1 H), 3.68
(dd, J ϭ 11.2, 1.0 Hz, 1 H), 3.76 (ddd, J ϭ 8.0, 4.4, and 2.0 Hz, 1
H), 5.35 (s, 1 H), 6.81Ϫ6.84 (m, 2 H), 7.53Ϫ7.56 (m, 2 H) ppm.
13C NMR (75 MHz, C6D6): δ ϭ 11.6, 30.2, 54.8, 63.9, 73.6, 80.5,
102.1, 113.8, 128.1, 132.1, 160.5 ppm. C13H18O4 (238.1): calcd. C
65.53, H 7.61; found C 65.14, H 7.48.
12. (1R,2r,3S)-2-Methyl-1-[(2R,4R,5R)-5-methyl-2-phenyl-1,3-di-
oxan-4-yl]-3-[(2S,4S,5S)-5-methyl-2-phenyl-1,3-dioxan-4-yl]propane-
1,3-diol (32): The ketone 30 (187 mg, 0.425 mmol) was reduced as
described under 10. to give the syn-diol 32 (128 mg, 73%) as a col-
1
ourless oil. H NMR (300 MHz, C6D6): δ ϭ 0.83 (d, J ϭ 6.8 Hz,
6 H), 1.48 (d, J ϭ 7.1 Hz, 3 H), 2.21Ϫ2.37 (m, 2 H), 2.79Ϫ2.84
(m, 1 H), 3.42 (t, J ϭ 11.2 Hz, 2 H), 3.87 (dd, J ϭ 10.0, 3.7 Hz, 2
H), 4.15 (dd, J ϭ 11.2, 4.7 Hz, 4 H), 4.22 (br. s, 2 H), 5.65 (s, 2
H), 7.42Ϫ7.56 (m, 6 H), 7.91Ϫ7.99 (m, 4 H). 13C NMR (50 MHz,
CDCl3): δ ϭ 12.6, 19.2, 31.1, 34.6, 73.0, 76.6, 86.4, 101.3, 126.0,
128.1, 128.8, 138.0 ppm. C26H34O6: calcd. 442.2355; found (HRMS
EI) 442.2353.
16. (1RS)-1-[(2S,4S,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-
4-yl]-1-propanol (39): DessϪMartin periodinane[13] (1.10 g,
2.60 mmol) was added to a solution of the alcohol 37 (310 mg,
1.30 mmol) in dichloromethane (6 mL). The mixture was stirred for
4 h and concentrated. Flash chromatography of the residue with
pentane/tert-butyl methyl ether, 1:1 (containing 1% of triethylam-
ine) furnished the aldehyde 38 (225 mg, 73%) as a colourless oil.
[α]2D0 ϭ Ϫ52.8 (c ϭ 1.04, CHCl3). 1H NMR (300 MHz, C6D6): δ ϭ
1.03 (d, J ϭ 6.8 Hz, 3 H), 1.49Ϫ1.55 (m, 1 H), 3.27 (s, 3 H), 3.43
(dd, J ϭ 11.2, 2.5 Hz, 1 H), 3.55 (dd, J ϭ 11.2, 1.2 Hz, 1 H), 3.66
(d, J ϭ 2.7 Hz, 1 H), 5.23 (s, 1 H), 6.82Ϫ6.94 (m, 2 H), 7.49Ϫ7.56
(m, 2 H), 9.46 (s, 1 H) ppm. 13C NMR (50 MHz, C6D6): δ ϭ 11.9,
30.7, 54.8, 72.8, 83.5, 101.8, 113.9, 128.4, 131.3, 160.7, 201.5 ppm.
13. (4R,5R,6S)-2,2,5-Trimethyl-4-[(2R,4R,5R)-5-methyl-2-phenyl-
1,3-dioxan-4-yl]-6-[(2S,4S,5S)-5-methyl-2-phenyl-1,3-dioxan-4-yl]-
1,3-dioxane (10): The diol 32 (102 mg, 0.230 mmol) was converted
into the acetonide as described under 10. to give 10 (86 mg, 78%)
1
as a colourless solid of m.p. 100 °C. H NMR (500 MHz, CDCl3):
δ ϭ 0.89 (d, J ϭ 6.6 Hz, 6 H), 1.09 (d, J ϭ 6.3 Hz, 3 H), 1.41 (s,
3 H), 1.46 (s, 3 H), 2.07 (tq, J ϭ 10.7, 6.3 Hz, 1 H), 2.21Ϫ2.32 (m,
2 H), 3.52 (t, J ϭ 11.2 Hz, 2 H), 3.57 (dd, J ϭ 12.3, 1.3 Hz, 2 H),
3.77 (dd, J ϭ 10.7, 1.3 Hz, 2 H), 4.11 (dd, J ϭ 11.2, 4.8 Hz, 2 H),
5.48 (s, 2 H), 7.34Ϫ7.39 (m, 6 H), 7.49Ϫ7.52 (m, 4 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 12.8, 13.6, 19.0, 29.9, 31.6, 31.8, 73.3,
76.4, 85.2, 98.0, 101.0, 126.0, 128.0, 128.7, 138.6 ppm. C29H38O6:
calcd. 482.2668; found (HRMS EI) 482.2695.
A solution of ethylmagnesium bromide (2.5  in ether, 1.0 mL,
2.5 mmol) was added at Ϫ10 °C to a solution of the aldehyde 38
(556 mg, 2.09 mmol) in ether (10 mL). After the mixture had been
stirred for 30 min, saturated aqueous NH4Cl (15 mL) was added.
The layers were separated and the aqueous layer was extracted with
tert-butyl methyl ether (4 ϫ 10 mL). The combined organic layers
were washed with brine (25 mL), dried (Na2SO4), and concen-
trated. Flash chromatography of the residue with pentane/tert-butyl
methyl ether, 1:1 (containing 1% of triethylamine) furnished a 4:1
mixture of the diastereomeric alcohols 39. A small sample was
rechromatographed to give the pure diastereomers.
14. (2R,3S)-4-(tert-Butyldimethylsilyloxy)-2-methylbutane-1,3-diol
(36): A solution of methylmagnesium bromide (2.7  in THF,
2.70 mL, 7.4 mmol) was added dropwise at Ϫ20 °C to a suspension
of copper(I) iodide (141 mg, 0.74 mmol) in THF/ether (5:1 v/v,
25 mL) The resulting suspension was cooled to Ϫ40 °C and a solu-
tion of the epoxide 35[32] (539 mg, 2.47 mmol) in ether (3 mL) was
added. After the mixture had been stirred for 3.5 h, saturated aque-
ous NH4Cl (20 mL) and aqueous ammonia (32%, 5 mL) were ad-
ded. The layers were separated and the aqueous layer was extracted
with tert-butyl methyl ether (3 ϫ 15 mL). The combined organic
layers were washed with water (10 mL) and brine (10 mL), dried
Major Diastereomer: [α]2D0 ϭ Ϫ15.7 (c ϭ 2.13, CHCl3). H NMR
1
(300 MHz, C6D6): δ ϭ 0.95 (t, J ϭ 7.3 Hz, 3 H), 1.28 (d, J ϭ
3462
Eur. J. Org. Chem. 2002, 3455Ϫ3464

meso-Ter(1,3-dioxan-4-yls)
FULL PAPER
6.8 Hz, 3 H), 1.33Ϫ1.45 (m, 1 H), 1.63Ϫ1.65 (m, 1 H), 1.67Ϫ1.70
(m, 1 H), 3.29 (s, 3 H), 3.48Ϫ3.50 (m, 2 H), 3.77 (dd, J ϭ 11.0,
2.4 Hz, 1 H), 3.87 (dd, J ϭ 11.0, 1.2 Hz, 1 H), 5.38 (s, 1 H),
6.80Ϫ6.85 (m, 2 H), 7.54Ϫ7.56 (m, 2 H) ppm. The OH signal was
obscured. 13C NMR (75 MHz, C6D6): δ ϭ 9.9, 12.0, 27.2, 29.7,
54.9, 71.9, 74.1, 82.2, 102.1, 113.8, 128.0, 132.4, 160.5 ppm.
C15H22O4: calcd. 266.1518; found (HRMS EI) 266.1516.
thanks go to the Fonds der Chemischen Industrie for providing a
fellowship to T. B.
[1]
R. W. Hoffmann, Angew. Chem. 2000, 112, 2134Ϫ2150; Angew.
Chem. Int. Ed. 2000, 39, 2054Ϫ2070.
[2]
T: Brandl, Dissertation, University of Marburg, 2001.
1
Minor Diastereomer: [α]2D0 ϭ Ϫ17.2 (c ϭ 1.43, CHCl3). H NMR
[3]
T. Brandl, R. W. Hoffmann, Eur. J. Org. Chem. 2002,
(300 MHz, C6D6): δ ϭ 1.04 (d, J ϭ 6.8 Hz, 3 H), 1.11 (t, J ϭ
7.6 Hz, 3 H), 1.20Ϫ1.27 (m, 3 H), 3.30 (s, 3 H), 3.28Ϫ3.35 (m, 1
H), 3.68 (dd, J ϭ 8.6, 2.0 Hz, 1 H), 3.55 (dd, J ϭ 8.6, 2.9 Hz, 1
H), 3.60 (q, J ϭ 2.2 Hz, 1 H), 3.68 (dd, J ϭ 11.2, 0.7 Hz, 1 H),
5.33 (s, 1 H), 6.82Ϫ6.86 (m, 2 H), 7.61Ϫ7.70 (m, 2 H) ppm. 13C
NMR (75 MHz, C6D6): δ ϭ 10.1, 11.7, 24.2, 29.9, 54.9, 72.4, 73.7,
83.6, 102.4, 113.9, 128.1, 132.1, 160.7 ppm.
2613Ϫ2623.
[4]
For a related building block see: A. B. Jones, A. Villalobos, R.
L. Linde II, S. J. Danishefsky, J. Org. Chem. 1990, 55,
2786Ϫ2797.
[5]
C. S. Poss, S. L. Schreiber, Acc. Chem. Res. 1994, 27, 9Ϫ17.
[6]
S. R. Magnuson, Tetrahedron 1995, 51, 2167Ϫ2213.
[7]
R. W. Hoffmann, K. Menzel, Eur. J. Org. Chem. 2001,
2749Ϫ2755.
[8]
T. Trieselmann, R. W. Hoffmann, K. Menzel, Eur. J. Org.
17. 1-[(2S,4S,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-1-
propanone (40): The mixture of alcohols 39 (208 mg, 0.782 mmol)
was oxidized as described under 8. Flash chromatography with
pentane/tert-butyl methyl ether, 2:1 (containing 1% of triethylam-
ine) furnished the ketone 40 (174 mg, 85%) as a colourless oil.
[α]2D0 ϭ Ϫ44.1 (c ϭ 2.01, CHCl3). 1H NMR (400 MHz, C6D6): δ ϭ
1.09 (t, J ϭ 7.3 Hz, 3 H), 1.14 (d, J ϭ 7.1 Hz, 3 H), 1.90Ϫ1.95 (m,
1 H), 2.43Ϫ2.56 (m, 2 H), 3.41 (s, 3 H), 3.67 (dd, J ϭ 11.2, 2.4 Hz,
1 H), 3.74 (dd, J ϭ 11.2, 1.5 Hz, 1 H), 4.01 (d, J ϭ 2.7 Hz, 1 H),
5.32 (s, 1 H), 6.93Ϫ6.98 (m, 2 H), 7.62Ϫ7.67 (m, 2 H) ppm. 13C
NMR (75 MHz, C6D6): δ ϭ 6.9, 12.9, 31.2, 32.9, 54.8, 73.0, 84.4,
101.6, 113.8, 128.3, 131.7, 160.6, 210.0 ppm. C15H20O4: calcd.
264.1362; found (HRMS EI) 264.1370.
Chem. 2002, 1292Ϫ1304.
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C. J. Cowden, I. Paterson, Org. React. 1997, 51, 1Ϫ200.
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J. D. Kendall, P. D. Woodgate, Aust. J. Chem. 1998, 51,
1083Ϫ1096.
S. Hanessian, A. Ugolini, D. Dube, A. Glamyan, Can. J. Chem.
[11]
´
1984, 62, 2146Ϫ2147.
[12]
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T. Tsunoda, M. Suzuki, R. Noyori, Tetrahedron Lett. 1980,
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D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113,
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18. Aldol Addition between 40 and ent-38: n-Butyllithium (1.53  in
hexane, 1.40 mL, 2.15 mmol) was added at 0 °C to a solution of
diisopropylamine (302 µL, 2.15 mmol) in THF (3 mL). The mix-
ture was stirred for 15 min and cooled to Ϫ78 °C. A solution of
the ketone 40 (378 mg, 1.43 mmol) in THF (3 mL) was added, fol-
lowed by 15 min stirring. A solution of the aldehyde ent-38
(549 mg, 2.32 mmol) in THF (3 mL) was added dropwise at Ϫ78
°C. After the mixture had been stirred for 30 min, buffer solution
(pH 7, 10 mL) was added, the layers were separated, and the aque-
ous layer was extracted with ether (4 ϫ 7 mL). The combined or-
ganic layers were washed with brine (5 mL), dried (Na2SO4) and
concentrated. Flash chromatography of the residue with pentane/
tert-butyl methyl ether, 1:1 (containing 1% of triethylamine) fur-
nished an aldol (446 mg, 62%) as a colourless oil. [α]2D0 ϭ Ϫ10.3
(c ϭ 1.70, CHCl3). 1H NMR (500 MHz, CDCl3): δ ϭ 1.10 (d, J ϭ
6.9 Hz, 3 H), 1.15 (d, J ϭ 7.1 Hz, 3 H), 1.23 (d, J ϭ 6.9 Hz, 3 H),
1.88Ϫ1.91 (m, 1 H), 2.05Ϫ2.09 (m, 1 H), 3.49 (qd, J ϭ 7.0, 4.1 Hz,
1 H), 3.76 (dd, J ϭ 9.2, 2.2 Hz, 1 H), 3.78 (s, 6 H), 3.89 (dd, J ϭ
11.2, 2.1 Hz, 1 H), 3.96 (d, J ϭ 11.1 Hz, 1 H), 4.02Ϫ4.04 (m, 2 H),
4.05 (dd, J ϭ 9.5, 4.0 Hz, 1 H), 4.23 (d, J ϭ 2.8 Hz, 1 H), 5.33 (s,
1 H), 5.42 (s, 1 H), 6.87Ϫ6.90 (m, 4 H), 7.35Ϫ7.38 (m, 2 H),
7.44Ϫ7.46 (m, 2 H) ppm. The OH signal was obscured. 13C NMR
(75 MHz, C6D6): δ ϭ 8.0, 9.3, 11.7, 29.6, 31.0, 43.3, 54.8, 70.2,
73.2, 74.0, 80.2, 84.0, 102.0, 102.4, 114.1, 114.2, 128.3, 128.4, 131.2,
132.4, 160.8, 213.9 ppm. C28H36O8: calcd. 500.2410; found (HRMS
EI) 500.2424.
[17]
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D. Seebach, D. Wasmuth, Helv. Chim. Acta 1980, 63, 197Ϫ200.
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Acknowledgments
We thank Michael Rommel for carrying out exploratory experi-
ments. We acknowledge generous support from the Deutsche For-
schungsgemeinschaft (Ho 274/28-1 and Graduierten-Kolleg
‘‘Metallorganische Chemie’’) and the Volkswagen-Stiftung. Special
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Eur. J. Org. Chem. 2002, 3455Ϫ3464
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R. W. Hoffmann, G. Mas, T. Brandl
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[O02246]
[39]
3464
Eur. J. Org. Chem. 2002, 3455Ϫ3464