Conformational analysis of axially substituted 4,4′-bi-1,3-dioxanyls

Article abstract of DOI:10.1002/ejoc.200400504

In contrast to the simple 4,4′-bi-1,3-dioxanyl derivative 6, which has no conformational preference at the inter-ring bond, the derivatives 9 and 10, which have two strategically placed axial methyl groups, show conformational preferences exceeding 95 %.

Full text of DOI:10.1002/ejoc.200400504

FULL PAPER
Conformational Analysis of Axially Substituted 4,4Ј-Bi-1,3-dioxanyls[‡]
Trixi Brandl[a] and Reinhard W. Hoffmann*[a]
Keywords: Conformational analysis / Oxygen heterocycles
In contrast to the simple 4,4Ј-bi-1,3-dioxanyl derivative 6,
which has no conformational preference at the inter-ring
bond, the derivatives 9 and 10, which have two strategically
placed axial methyl groups, show conformational prefer-
ences exceeding 95 %. This is related to the conformational
preference found in one of the substructures of the natural
product prymnesin.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
The constitution of a molecule does not necessarily de-
fine its shape because rotation about single bonds generates
a multitude of different possible conformations. However,
the shape of a molecule will be defined when, for certain
reasons, only a single conformation at each rotateable bond
is populated. The structural element of bicyclohexyl (1) is
seemingly unspectacular in this respect, although Biali[2]
has shown that certain bicylohexyl derivatives, such as 2,
populate preferred conformations not only in the six-mem-
bered rings, but also at the inter-ring bonds, in order to
avoid syn-pentane interactions.[3]
Ͼ 90%.[5] The effect of the equatorial methyl groups on the
conformational preference becomes evident when compar-
ing these coupling constants with those of compound 6.
The absence of the conformation-controlling methyl groups
renders conformation 6a as just one of several low energy
conformations.
In 2 it is the axial substituents R on the central ring that
control the conformations at the inter-ring bonds. Related
bi-tetrahydropyranyl systems of the type 3 have been stud-
ied by W. C. Still.[4] In that case, methyl substituents are
placed in equatorial positions and, considering the inter-
ring bond, they destabilize the conformers 3b and 3c by
syn-pentane interactions such that conformer 3a is popu-
lated almost exclusively.
With the intention of designing flexible molecules with
defined shape we prepared the acetals 4 and 5 related to the
3
compound 3. Determination of the JH,H coupling con-
stants across the inter-ring bond revealed that these
compounds populate a single conformation 4a or 5a to
[‡]
Flexible Molecules with Defined Shape, XX. Part XIX: Ref.[1]
Fachbereich Chemie der Philipps Universität,
[a]
Hans Meerwein Str., 35032 Marburg, Germany
Fax: (internat.) ϩ 49-(0)6421-2825677
E-mail: rwho@chemie.uni-marburg.de
Eur. J. Org. Chem. 2004, 4373Ϫ4378
DOI: 10.1002/ejoc.200400504
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4373

T. Brandl, R. W. Hoffmann
FULL PAPER
we carried out on 4,4Ј-bi-1,3-dioxolan-4-yl compounds 9
and 10, which contain axial methyl groups.
In compounds 3 to 5 the conformational restriction is
imposed by a methyl group placed equatorially on the ring.
As compound 2 illustrates, a similar conformational restric-
tion should be possible also by a substituent in an axial
position. This was demonstrated[6] recently in a study deal-
ing with the structure of prymnesin. In that study, model
compounds 7 and 8 were prepared.
3
The JH,H coupling constants across the inter-ring bond
demonstrate a distinct conformational preference for 7a in
the case of compound 7 and an even higher conformational
preference for 8a in the case of the diastereomeric com-
pound 8. Prymnesin (not shown), which contains substruc-
3
ture 8, has a JH,H coupling constant of 8.5 Hz.
Clearly the single axial methyl group is capable of con-
trolling the conformation at the inter-ring bonds of 7, 8,
and of prymnesin to favour a single distinct conformation.
This must be essential for the biological function of prym-
nesin (which has not been established), because this methyl
group is the only methyl branch in this huge (C90) natural
product with a linear carbon chain probably derived from
a polyketide of biogenetic origin. The exchange of a single
gene cassette (propionate for acetate) at this position must
have imparted a significant advantage for the modified mol-
ecule during evolution. The introduction of this methyl
group controls the folding at a flexible hinge of prymnesin
to give the molecule a distinct shape, optimal for its biologi-
cal function.
According to the considerations delineated above, we
were convinced that compounds 9 and 10 should display a
high preference for population of the conformations 9a and
10a, respectively.
The synthesis of 9 commenced with the commercially
available methyl (R)-(Ϫ)-hydroxyisobutyrate (11). Silylation
and reduction following literature precedent[7] gave the al-
cohol 12.
The latter was converted into the phenyltetrazolyl sulfide
13, which was subsequently oxidised to the sulfone 14 in
order to initiate a Julia/Lythgoe olefination using the Koci-
enski variant.[8] Consequently, the alcohol 12 was oxidized
to the aldehyde 15.[9]
The study of compounds 7 and 8 demonstrated the con-
trol of conformation at an inter-ring bond between two
tetrahydropyran rings by an axial methyl substituent.[6] This
stimulated us to perform and report related studies which
4374
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4373Ϫ4378

Conformational Analysis of Axially Substituted 4,4Ј-Bi-1,3-dioxanyls
FULL PAPER
dominant according to the 13C NMR chemical shifts. The
presence of the (Z) diastereomer was neglected since only
the (E) isomer reacted[16] to give the diol 24 in the sub-
sequent asymmetric dihydroxylation,[12] in 73% yield. In the
event of an unexpected dihydroxylation at the other face of
the double bond, the reaction sequence would have led to
the known[5] compound 5 instead of 10. The reaction se-
quence was completed by a DDQ oxidation,[17] which pro-
vided directly the desired bi-1,3-dioxanyl 10.
Olefination gave 16 in 69% yield. 16 was obtained as the
pure (E) diastereomer. This followed from the coupling con-
stant of 15.7 Hz between the olefinic hydrogen atoms.[10]
At this stage, the two remaining stereogenic centres were
introduced by an asymmetric dihydroxylation[11] using the
(DHQ)2PHAL ligand[12] and 2 mol% osmate. The reaction
provided the diol 17 as a single diastereomer in 84% yield.
If the dihydroxylation had unexpectedly occurred at the
other face of the double bond, the reaction sequence would
have led to the known compound 4[5] instead of 9. The tert-
butyldimethylsilyl groups of 17 could be readily removed by
treatment with Dowex 50 in MeOH. However, acetonis-
ation of the resulting tetraol 18 was problematic. There is a
strong tendency for formation of a mono-acetonide at the
two internal hydroxy groups under equilibrating conditions.
We therefore resorted to a kinetically controlled acetonis-
ation with methoxypropene.[13] This furnished the desired
4,4Ј-bi-1,3-dioxolanyl 9 in moderate yield.
The corresponding p-methoxyphenyl derivative 10 was
prepared using similar methods. Given the difficulties en-
countered in converting the tetraol 18 into a bi-1,3-diox-
anyl, we wanted to introduce the p-methoxybenzyl group at
an early stage. Thus, our synthesis started from the known
alcohol 19 and aldehyde 22.[14] First, the alcohol 19 was
converted into the sulfone 21 via the iodo compound 20.[15]
On JuliaϪLythgoe olefination with the aldehyde 22, the sul-
fone 21 gave the alkene 23 as a 13:1 (1H NMR) mixture of
geometric isomers, in 68% yield. The (E) isomer was pre-
Next, we turned to the conformational analysis of 9 and
10. Initial force field calculations with the MM3* force field
implemented in the MACROMODEL program package[18]
indicated a 96% preference for 9 to populate conformation
9a and a 99% preference for conformation 10a in the case
of compound 10.[19] We wanted to substantiate this by de-
3
termination of the JH,H coupling constants across the in-
ter-ring bond. Due to the C2 symmetry of 9 and 10 the
relevant hydrogen atoms at the ring junction are homo-
topic. In order to measure the coupling constants the sym-
metry had to be broken in a SELINCOR experiment.[20]
This revealed coupling constants of 8.6 Hz and 9.2 Hz for
compounds 9 and 10, respectively, indicating that the con-
formers 9a and 10a are indeed populated to a Ͼ 90% ex-
tent. In fact, the conformational preference is more marked
in the case of 10 in line with the predictions made on the
basis of the force field calculations. The high confor-
mational preference for a single conformation at the inter-
ring bond demonstrates the effect that can be attained by
Eur. J. Org. Chem. 2004, 4373Ϫ4378
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4375

T. Brandl, R. W. Hoffmann
FULL PAPER
solution was stirred for 1 h at this temp. Aldehyde 15 (241 mg,
1.19 mmol) was added and the mixture was allowed to reach room
temperature over 12 h. Water (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 (10 mL), dried (Na2SO4) and concentrated.
Flash chromatography of the residue with pentane/tert-butyl
methyl ether, 9:1, furnished the product 16 (307 mg, 69%) as a
colourless oil. In addition, some (150 mg, 0.38 mmol) of the sulfone
14 was recovered. 16: [α]2D0 ϭ Ϫ4.4 (c ϭ 3.30, CHCl3). 1H NMR
(200 MHz, CDCl3) δ ϭ 0.15 (s, 12 H), 0.86 (s, 18 H), 0.93 (d, J ϭ
6.8 Hz, 6 H), 2.20Ϫ2.26 (m, 2 H), 3.32 (dd, J ϭ 9.8, 7.2 Hz, 2 H),
3.45 (dd, J ϭ 9.8, 6.0 Hz, 2 H), 5.24Ϫ5.40 (mc, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ ϭ Ϫ5.6 (4 C), 16.7 (2 C), 18.3 (2 C),
25.9 (6 C), 39.4 (2 C), 68.3 (2 C), 132.4 (2 C) ppm. HRMS (ESI)
[Mϩ ϩ Na] (C20H44O2Si2Na): calcd. 395.2778; found 395.2827.
(two) axially placed methyl groups. This underscores the
interpretation regarding the conformation controlling effect
of the axial methyl group in prymnesin,[6] alluded to above.
Experimental Section
General Remarks: All temperatures quoted are uncorrected. 1H
NMR, 13C NMR: Bruker ARX-200, AC-300, WH-400, AM-400,
AMX-500. Boiling range of petroleum ether: 40Ϫ60 °C. Flash
chromatography: Silica gel SI 60, E. Merck KGaA, Darmstadt,
40Ϫ63 µm. pH7-buffer: NaH2PO4·2 H2O (56.2 g) and Na2HPO4·4
H2O (213.6 g) made up to 1  using water. Conformer populations
were estimated on the basis of force field calculations using the
MM3* force field implemented in the MACROMODEL[18] pro-
gram, version ‘‘maestro 4.1’’. 5000 starting structures were gener-
ated with a Monte Carlo procedure and energy minimized (CHCl3
environment). Conformers having energies of Ͻ 6 kcal·molϪ1 above
the minimum energy conformer were subjected to a Boltzmann av-
eraging for 298 K to predict the conformer population.
(2R,3S,4S,5R)-1,6-Bis(tert-butyldimethylsilyloxy)-2,5-dimethylhex-
ane-3,4-diol (17): The alkene 16 (363 mg, 0.97 mmol) was added to
a mixture of potassium osmate(VI) dihydrate (7.0 mg, 0.02 mmol),
(DHQ)2PHAL[12] (40 mg, 0.05 mmol), potassium hexacyanoferrat-
e(III) (958 mg, 2.91 mmol), potassium carbonate (402 mg,
2.91 mmol), and methanesulfonamide (92 mg, 0.97 mmol) in water/
tert-butyl alcohol (1:1, 8 mL). After stirring at room temperature
for 12 h, sodium sulfite (3.5 g) was added and stirring was con-
tinued for 1 h. Water (20 mL) was added, the layers were separated
and the aqueous layer was extracted with tert-butyl methyl ether (6
ϫ 10 mL). The combined organic layers were washed with aqueous
KOH (0.5 , 10 mL), dried (Na2SO4) and concentrated. Flash chro-
matography of the residue with pentane/tert-butyl methyl ether,
9:1Ǟ 5:1, furnished the product 17 (329 mg, 84%) as a colourless
oil, which crystallised upon storage in a refrigerator. M.p. 48 °C.
[α]2D0 ϭ Ϫ4.8 (c ϭ 2.49, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
0.06 (s, 12 H), 0.83 (s, 18 H), 0.87 (d, J ϭ 7.0 Hz, 6 H), 1.66Ϫ1.72
(m, 2 H), 3.12 (d, J ϭ 3.5 Hz, 2 H), 3.54 (dd, J ϭ 10.0, 6.0 Hz, 2
H), 3.62 (dd, J ϭ 10.0, 4.2 Hz, 2 H), 3.65Ϫ3.68 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ Ϫ5.9 (4 C), 11.2 (2 C), 18.2 (2 C),
25.9 (6 C), 37.6 (2 C), 66.4 (2 C), 72.9 (2 C) ppm. C20H46O4Si2
(406.75): calcd. C 59.06, H 11.40; found C 58.85, H 11.58.
(2R)-5-[3-(tert-Butyldimethylsilyloxy)-2-methylpropylsulfanyl]-1-
phenyl-1H-tetrazole (13): Diethyl azodicarboxylate (1.045 g,
6.00 mmol) was added dropwise at 0 °C to a solution of (2R)-3-
(tert-butyldimethylsilyloxy)-2-methylpropanol[7]
(12,
1.022 g,
5.00 mmol) and triphenylphosphane (1.574 g, 6.00 mmol) in THF
(20 mL). After stirring at room temperature for 1.5 h silica gel (ca.
5 g) was added and the solvent was removed in vacuo. Flash chro-
matography of the residue with pentane/tert-butyl methyl ether,
30:1, furnished the product 13 (1.725 g, 95%) as a colourless oil.
[α]2D0 ϭ ϩ2.2 (c ϭ 3.43, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
Ϫ0.02 (s, 6 H), 0.85 (s, 9 H), 1.01 (d, J ϭ 6.8 Hz, 3 H), 2.06Ϫ2.16
(m, 1 H), 3.34 (dd, J ϭ 12.8, 6.6 Hz, 1 H), 3.47 (dd, J ϭ 12.8,
6.7 Hz, 1 H), 3.49 (dd, J ϭ 10.0, 5.6 Hz, 1 H), 3.61 (dd, J ϭ 10.0,
4.8 Hz, 1 H), 7.50Ϫ7.57 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ5.3 (2 C), 16.2, 18.3, 25.9 (3 C), 35.7, 37.0, 66.4,
123.9 (2 C), 129.7 (2 C), 130.0, 133.2, 157.4 ppm. C17H28N4OSSi
(364.58): calcd. C 56.00, H 7.74, N 15.37; found C 55.95, H 7.65,
N 15.47.
(4S,5R,4SЈ,5RЈ)-2,2,5,2Ј,2Ј,5Ј-Hexamethyl-4,4Ј-bi-1,3-dioxanyl (9):
Dowex 50 ion exchange resin (ca 20 mg) was added to a solution
of the diol 17 (107 mg, 0.26 mmol) in MeOH (2 mL) and the mix-
ture was stirred for 18 h at room temp. The mixture was filtered,
the resin was washed with MeOH (2 mL) and the combined fil-
trates were concentrated. The residue was taken up in THF
(1.5 mL). 2-Methoxypropene (75 mg, 1.04 mmol) and pyridinium
p-toluenesulfonate (ca 20 mg) were added at 0 °C. After stirring for
1 h at this temperature, saturated aqueous NaHCO3 solution
(2 mL) was added. The mixture was extracted with tert-butyl
methyl 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, 3:1 containing 1% of triethyl-
amine, furnished the product 9 (26 mg, 40%) as a colourless solid
of m.p. 98 °C. [α]2D0 ϭ Ϫ7.3 (c ϭ 1.23, CHCl3). 1H NMR (500 MHz,
CDCl3): δ ϭ 1.10 (d, J ϭ 6.8 Hz, 6 H), 1.41 (s, 6 H), 1.43 (s, 6 H),
1.48Ϫ1.53 (m, 2 H), 3.55 (dd, J ϭ 11.5, 1.5 Hz, 2 H), 3.82 (ps, 2
H), 4.10 (dd, J ϭ 11.5, 2.3 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 11.5 (2 C), 19.0 (2 C), 28.3 (2 C), 29.7 (2 C), 67.0 (2
C), 72.1 (2 C), 98.9 (2 C) ppm. C14H26O4 (258.36): calcd. C 65.09,
H 10.14; found C 64.94, H 10.03.
(2R)-5-[3-(tert-Butyldimethylsilyloxy)-2-methylpropane-1-sulfonyl]-
1-phenyl-1H-tetrazole (14): m-Chloroperbenzoic acid (3.357 g,
13.62 mmol) was added in small portions at 0 °C to a solution of
the sulfide 13 (826 mg, 2.27 mmol) in dichloromethane (20 mL).
The resulting white suspension was stirred for 18 h at room temp.
Aqueous NaOH (10%, 30 mL) was added, the layers were sepa-
rated and the aqueous layer was extracted with tert-butyl methyl
ether (4 ϫ 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated. Flash chromatography of the residue
with pentane/tert-butyl methyl ether, 4:1, furnished the product 14
(886 mg, 98%) as a colourless oil. [α]2D0 ϭ Ϫ5.5 (c ϭ 6.23, CHCl3).
1H NMR (300 MHz, CDCl3): δ ϭ Ϫ0.10 (s, 6 H), 0.84 (s, 9 H),
1.10 (d, J ϭ 6.9 Hz, 3 H), 2.37Ϫ2.47 (m, 1 H), 3.45 (dd, J ϭ 10.0,
5.6 Hz, 1 H), 3.50 (dd, J ϭ 14.7, 7.7 Hz, 1 H), 3.67 (dd, J ϭ 10.0,
4.6 Hz, 1 H), 3.99 (dd, J ϭ 14.7, 4.9 Hz, 1 H), 7.50Ϫ7.55 (m, 3 H),
7.61Ϫ7.65 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.7,
Ϫ5.6, 18.7, 18.2, 25.8 (3 C), 31.2, 58.6, 66.1, 125.1 (2 C), 129.6 (2
C), 131.3, 133.1, 154.0 ppm. C17H28N4O3SSi (396.58): calcd. C
51.49, H 7.36, N 14.14; found C 51.63, H 7.36, N 13.86.
(2S,5S,3E)-1,6-Bis(tert-butyldimethylsilyloxy)-2,5-dimethyl-3-
hexene (16): A solution of KHMDS (0.50  in DME, 3.40 mL,
1.7 mmol) was added at Ϫ55 °C to a solution of the sulfone 14[7]
(2R)-1-Methoxy-4-[2-methyl-3-(phenylsulfonyl)propoxymethyl]-
benzene (21): A mixture of (2R)-1-iodo-3-(4-methoxybenzyloxy)-2-
(674 mg, 1.70 mmol) in DME (7 mL). The resulting yellow-orange methylpropane[15] (20) (1.456 g, 4.55 mmol) and sodium benzene-
4376
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4373Ϫ4378

Conformational Analysis of Axially Substituted 4,4Ј-Bi-1,3-dioxanyls
FULL PAPER
sulfinate (2.595 g, 15.81 mmol) in DMF (15 mL) was heated for separated and the aqueous layer was extracted with dichlorometh-
12 h to 60 °C. Water (100 mL) was added and the mixture was ane (6 ϫ 2 mL). The combined organic layers were washed with
extracted with tert-butyl methyl ether (4 ϫ 20 mL). The combined
organic layers were dried (Na2SO4) and concentrated. Flash chro-
matography of the residue with pentane/tert-butyl methyl ether,
1.5:1Ǟ 1:1, furnished the product 20 (1.259 g, 83%) as a colourless
oil. [α]2D0 ϭ Ϫ5.2 (c ϭ 1.15, CHCl3). 1H NMR (300 MHz,
CDCl3):[21] δ ϭ 1.10 (d, 3J ϭ 6.9 Hz, 3 H), 2.32Ϫ2.42 (m, 1 H),
2.91 (dd, 3J ϭ 7.9, 2J ϭ 14.2 Hz, 1 H), 3.27 (dd, 3J ϭ 6.5, 2J ϭ
9.4 Hz, 1 H), 3.35Ϫ3.42 (m, 2 H), 3.79 (s, 3 H), 4.32 (d, 2J ϭ
11.7 Hz, 1 H), 4.36 (d, 2J ϭ 11.7 Hz, 1 H), 6.84Ϫ6.88 (m, 2 H),
7.16Ϫ7.20 (m, 2 H), 7.52Ϫ7.57 (m, 2 H), 7.61Ϫ7.67 (m, 1 H),
7.90Ϫ7.92 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 17.1,
29.3, 55.2, 59.3, 72.5, 73.2, 113.7 (2 C), 127.8 (2 C), 129.1 (2 C),
129.2 (2 C), 130.1, 133.4, 140.1, 159.2 ppm. C18H22O4S (334.12):
calcd. C 64.65, H 6.63; found C 64.38, H 6.72.
aqueous KOH (0.5 , 5 mL), dried (Na2SO4) and concentrated.
Flash chromatography of the residue with pentane/tert-butyl
methyl ether, 1:1Ǟ 0:1, furnished the diastereomerically pure prod-
uct 24 (46 mg, 73%) as a colourless oil together with (2S,3Z,5S)-
1,6-bis(4-methoxybenzyloxy)-2,5-dimethyl-3-hexene (4 mg, 0.01
mmol, 7%).
24: [α]2D0 ϭ ϩ13.5 (c ϭ 1.52, CHCl3). 1H NMR (300 MHz, CDCl3):
3
δ ϭ 0.96 (d, J ϭ 7.0 Hz, 6 H), 1.84Ϫ2.02 (m, 2 H), 3.07 (br. s, 2
H), 3.41Ϫ3.50 (m, 2 H), 3.60Ϫ3.64 (m, 4 H), 3.79 (s, 6 H), 4.43 (s,
4 H), 6.84Ϫ6.99 (m, 4 H), 7.22Ϫ7.28 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 11.9 (2 C), 36.1 (2 C), 55.2 (2 C), 72.9 (2
C), 73.1 (2 C), 73.2 (2 C), 113.8 (4 C), 129.2 (4 C), 130.2 (2 C),
159.9 (2 C) ppm.
(2S,3Z,5S)-1,6-Bis(4-methoxybenzyloxy)-2,5-dimethyl-3-hexene
(2S,3E,5S)-1,6-Bis(4-methoxybenzyloxy)-2,5-dimethyl-3-hexene
(23): A solution of nBuLi (1.55  in hexane, 1.30 mL, 2.00 mmol)
was added dropwise at Ϫ78 °C to a solution of the sulfone 20
(758 mg, 2.27 mmol) in anhydrous THF (10 mL). After stirring for
1 h a solution of the aldehyde 22[14] (218 mg, 1.05 mmol) in THF
(2 mL) was added dropwise. Stirring was continued for 2 h at Ϫ78
°C. The reaction was quenched by addition of saturated aqueous
NH4Cl solution (10 mL). The layers were separated and the aque-
ous layer was extracted with tert-butyl methyl ether (4 ϫ 5 mL).
The combined organic layers were dried (Na2SO4) and concen-
trated. Flash chromatography of the residue with pentane/tert-butyl
methyl ether, 1.5:1, furnished a diastereomeric mixture of hydroxy-
sulfones (548 mg, 96%) as a colourless oil (together with recovered
sulfone 20 (415 mg, 1.24 mmol)). 1H NMR (300 MHz, CDCl3): δ ϭ
1
3
(Z-23): H NMR (400 MHz, CDCl3): δ ϭ 1.00 (d, J ϭ 6.7 Hz, 6
H), 2.78Ϫ2.82 (m, 2 H), 3.18Ϫ3.32 (m, 4 H), 3.80 (s, 6 H),
4.40Ϫ4.47 (m, 4 H), 5.16Ϫ5.23 (m, 4 H), 7.22Ϫ7.26 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 18.1 (2 C), 32.8 (2 C), 55.2 (2
C), 72.5 (2 C), 75.0 (2 C), 113.7 (4 C), 129.0 (4 C), 133.0 (2 C),
158.7 (2 C) ppm.
(2S,2ЈS,5R,5ЈR)-2,2Ј-Bis(4-methoxyphenyl)-5,5Ј-dimethyl-4,4Ј-bi-
1,3-dioxanyl (10): The diol 24 (262 mg, 0.63 mmol) and molecular
˚
sieves (3 A, 600 mg, freshly powdered) were stirred in dichloro-
methane (10 mL) for 1 h and the suspension was cooled to Ϫ30
°C. Dichlorodicyanoquinone (316 mg, 1.39 mmol) was added and
stirring was continued while the temperature increased to 0 °C over
5 h. The colour changed from green over deep red to pink. The
mixture was filtered and saturated aqueous NaHCO3 solution
(10 mL) was added to the filtrate. The layers were separated and
the aqueous layer was extracted with dichloromethane (4 ϫ
10 mL). The combined organic layers were washed with brine
(10 mL), dried (Na2SO4) and concentrated. Flash chromatography
of the residue with pentane/tert-butyl methyl ether, 2:1, containing
1% of triethylamine, furnished the product 10 (128 mg, 49%) as a
colourless solid of m.p. 178 °C. [α]2D0 ϭ ϩ68.5 (c ϭ 0.73, CHCl3).
1H NMR (500 MHz, CDCl3): δ ϭ 1.25 (d, 3J ϭ 6.8 Hz, 6 H), 1.68
(pq, J ϭ 6.9 Hz, 2 H), 3.80 (s, 6 H), 3.99Ϫ4.02 (m, 4 H), 4.08Ϫ4.11
3
3
0.73 (d, J ϭ 7.1 Hz, 3 H), 0.77 (d, J ϭ 6.8 Hz, 3 H), 1.87Ϫ2.32
(m, 2 H), 2.46 (br. s, 1 H), 3.26Ϫ3.37 (m, 1 H), 3.42Ϫ3.50 (m, 2
H), 3.67 (s, 6 H), 3.73Ϫ3.81 (m, 2 H), 4.08Ϫ4.16 (m, 1 H),
4.23Ϫ4.35 (m, 4 H), 6.75Ϫ6.79 (m, 5 H), 7.05Ϫ7.19 (m, 3 H),
7.29Ϫ7.53 (m, 3 H), 7.74Ϫ7.84 (m, 1 H), 7.65Ϫ7.70 (m, 1 H) ppm.
Na2HPO4 (903 mg, 6.36 mmol) and Na/Hg (6%, 4.6 g, ca.
12 mmol) were added at Ϫ35 °C to a solution of the hydroxy-sul-
fones (486 mg, 0.90 mmol) in MeOH/EtOAc (2:1, 12 mL). After
stirring for 1 h at this temperature, water (10 mL) was added and
the liquid was decanted from the residual mercury. The solution
was extracted with tert-butyl methyl ether (4 ϫ 10 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated. Flash
chromatography of the residue with pentane/tert-butyl methyl
3
(dd, J ϭ 2.3, 2J ϭ 11.2 Hz, 2 H), 5.51 (s, 2 H) 6.86Ϫ6.89 (m, 4
H), 7.42Ϫ7.45 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
12.0 (2 C), 28.4 (2 C), 55.3 (2 C), 77.6 (2 C), 79.7 (2 C), 101.6 (2
C), 113.5 (4 C), 127.4 (4 C), 131.3 (2 C), 159.9 (2 C) ppm. Com-
pound 10 was characterized by the spectroscopic data only.
ether, 9:1Ǟ 2:1, furnished the alkene 23 as a colourless oil. [α]2D0
ϭ
ϩ3.7 (c ϭ 1.91, CHCl3). 1H NMR (500 MHz, CDCl3): δ ϭ 1.00
(d, 3J ϭ 6.8 Hz, 6 H), 2.41Ϫ2.46 (m, 2 H), 3.22 (dd, 3J ϭ 7.3, 2J ϭ
3
2
9.1 Hz, 2 H), 3.33 (dd, J ϭ 6.2, J ϭ 9.1 Hz, 2 H), 3.76 (s, 6 H),
4.42 (s, 4 H), 5.37Ϫ5.44 (m, 2 H), 6.86 (d, J ϭ 8.7 Hz, 4 H), 7.24
(d, J ϭ 8.7 Hz, 4 H) ppm. Integration of the olefinic proton signals
revealed an E/Z-ratio of 13:1. 13C NMR (50 MHz, CDCl3): δ ϭ
17.2 (2 C), 36.8 (2 C), 55.2 (2 C), 72.5 (2 C), 75.2 (2 C), 113.7 (4
C), 129.1 (4 C), 130.8 (2 C), 132.4 (2 C), 159.0 (2 C) ppm. C24H32O4
(384.51): calcd. C 74.97, H 8.39; found C 75.04, H 8.21.
Acknowledgments
Essential support for this study came from the Deutsche For-
schungsgemeinschaft (Ho 274/28Ϫ1 and the Graduiertenkolleg
‘‘Metallorganische Chemie’’) and the Volkswagenstiftung. Special
thanks go to the Fonds der Chemischen Industrie for granting a
fellowship to T. B.
(2R,3S,4S,5R)-1,6-Bis(4-methoxybenzyloxy)-2,5-dimethylhexane-
3,4-diol (24): The alkene 23 (58 mg, 0.15 mmol) was added to a
mixture of potassium osmate() dihydrate (0.7 mg, 2.7 µmol),
(DHQ)2PHAL[12] (5.0 mg, 6.4 µmol), potassium hexacyanoferrate-
() (148 mg, 0.45 mmol), potassium carbonate (62 mg, 0.45
mmol), and methanesulfonamide (14 mg, 0.15 mmol) in water/tert-
butyl alcohol (1:1, 1.5 mL). After stirring at room temperature for
16 h, sodium sulfite (113 mg, 0.90 mmol) was added and stirring
was continued for 1 h. Water (2 mL) was added, the layers were
[1]
R. W. Hoffmann, G. Mas, T. Brandl, Eur. J. Org. Chem.
2002, 3455Ϫ3464.
[2]
[2a] I. Columbus, S. Cohen, S. E. Biali, J. Am. Chem. Soc. 1994,
[2b]
116, 10306Ϫ10307.
I. Columbus, R. E. Hoffman, S. E.
Biali, J. Am. Chem. Soc. 1996, 118, 6890Ϫ6896.
R. W. Hoffmann, Angew. Chem. 2000, 112, 2134Ϫ2150; Angew.
Chem. Int. Ed. 2000, 39, 2054Ϫ2070.
[3]
Eur. J. Org. Chem. 2004, 4373Ϫ4378
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4377

T. Brandl, R. W. Hoffmann
FULL PAPER
[4] [4a]
[11b]
T. Iimori, S. D. Erickson, A. L. Rheingold, W. C. Still,
1991, 2, 973Ϫ976.
G. Oddon, D. Uguen, A. De Clan, J.
[4b]
Tetrahedron Lett. 1989, 30, 6947Ϫ6950.
J. Org. Chem. 1991, 56, 6964Ϫ6966.
G. Li, W. C. Still,
X. Wang, S. D. Erick-
Fischer, Tetrahedron Lett. 1998, 39, 1149Ϫ1152.
K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J.
Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M.
Wang, D. Xu, X.-L. Zhang, J. Org. Chem. 1992, 57,
2769Ϫ2771.
[4c]
[12]
[13]
son, T. Iimori, W. C. Still, J. Am. Chem. Soc. 1992, 114,
4128Ϫ4137. [4d] S. D. Erickson, M. H. J. Ohlmeyer, W. C. Still,
[4e]
Tetrahedron Lett. 1992, 33, 5925Ϫ5928.
Tetrahedron Lett. 1992, 33, 5929Ϫ5932.
Tetrahedron Lett. 1993, 34, 919Ϫ922.
Tetrahedron Lett. 1993, 34, 6701Ϫ6704.
G. Li, W. C. Still,
G. Li, W. C. Still,
[4f]
[4g]
M. L. Wolfrom, A. B. Diwadkar, J. Gelas, D. Horton, Car-
bohydr. Res. 1974, 35, 87Ϫ96.
S. Tang, W. C. Still,
[4h]
M. T. Burger, A.
[14] [14a] R. D. Walkup, J. D. Kahl, R. R. Kane, J. Org. Chem. 1998,
63, 9113Ϫ9116. [14b] M. G. Organ, J. Wang, J. Org. Chem. 2003,
68, 5568Ϫ5574.
Armstrong, F. Guarnieri, D. Q. McDonald, W. C. Still, J. Am.
Chem. Soc. 1994, 116, 3593Ϫ3594.
T. Brandl, R. W. Hoffmann, Eur. J. Org. Chem. 2002,
2613Ϫ2623.
M. Sasaki, M. Ebine, H. Takagi, H. Takakura, T. Shida, M.
Satake, Y. Oshima, T. Igarashi, T. Yasumoto, Org. Lett. 2004,
6, 1501Ϫ1504.
K. Mori, K. Koseki, Tetrahedron 1988, 44, 6013Ϫ6020.
P. R. Blakemore, W. J. Cole, P. J. Kocienski, A. Morely, Synlett
1998, 26Ϫ28.
S. D. Burke, J. E. Cobb, K. Takeuchi, J. Org. Chem. 1990, 55,
2138Ϫ2151.
[15]
[5]
[6]
T. Heckrodt, J. Mulzer, Synthesis 2002, 1857Ϫ1866.
D. Xu, G. A. Crispino, K. B. Sharpless, J. Am. Chem. Soc.
[16]
1992, 114, 7570Ϫ7572.
[17]
Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tetrahedron Lett. 1982,
23, 885Ϫ888.
[18]
F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp,
M. Lipton, C. Caufield, G. Chang, T. Hendrickson, W. C. Still,
[7]
[8]
J. Comput. Chem. 1990, 11, 440Ϫ467.
[19]
For the bis(acetonide) corresponding to 9 (having only one ax-
[9]
ial methyl group) the preference to populate a conformation
corresponding to 9a was calculated to be 88%.
[10]
[20]
As the olefinic hydrogen atoms in 16 are homotopic due to the
C2 symmetry of the molecule, this value had to be determined
T. Fäcke, S. Berger, Magn. Reson. Chem. 1995, 33, 144Ϫ148.
[21]
cf. the data in: P. M. Smith, E. J. Thomas, J. Chem. Soc., Perkin
by a SELINCOR experiment.[20]
Trans. 1 1998, 3541Ϫ3566.
[11]
[11a]
Cf.:
L. Sun, W. Zhou, X. Pan, Tetrahedron: Asymmetry
Received July 19, 2004
4378
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4373Ϫ4378