Stereoelectronic effects in the reactions of conformationally restricted, substituted cyclohexane-1,2-diones with 1,2-diols

Article abstract of DOI:10.1016/S0957-4166(98)00227-4

The asymmetric synthesis of a C₂-symmetric cyclic 1,2-diketone is reported along with investigations into its properties as a potential asymmetric protecting group for 1,2-diols as the corresponding 1,2-diacetal.

Full text of DOI:10.1016/S0957-4166(98)00227-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2471–2480
Stereoelectronic effects in the reactions of conformationally
restricted, substituted cyclohexane-1,2-diones with 1,2-diols
Roman Lenz, Steven V. Ley,∗ Dafydd R. Owen and Stuart L. Warriner
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 18 May 1998; accepted 9 June 1998
Abstract
The asymmetric synthesis of a C2-symmetric cyclic 1,2-diketone is reported along with investigations into its
properties as a potential asymmetric protecting group for 1,2-diols as the corresponding 1,2-diacetal. © 1998
Elsevier Science Ltd. All rights reserved.
1. Introduction
We have recently introduced the concept of 1,2-diacetals as a highly effective protecting group for
trans-vicinal diols (Fig. 1).1,2 In line with the progress achieved with chiral dispiroketal protection of
diols,3 it was felt that an asymmetric version of the cyclohexane-1,2-diacetal (CDA) procedure would
represent an attractive advance.
In order to develop a suitable chiral diacetal, it was reasoned that introduction of substituents onto
the initial cyclohexane-1,2-dione reagent would provide the opportunity for further chirality control
upon reaction with a 1,2-diol. It was anticipated that any substituents on the reagent ring should have
a preference for equatorial orientation in the corresponding 1,2-diacetal products. Incorporation of
these substituents in an asymmetric fashion, in combination with the preference for their equatorial
arrangement of the 1,2-diol, should control the absolute stereochemistry of each acetal centre formed.
The other selectivity control elements operating during acetal formation, precedented in the achiral
Fig. 1.
∗
Corresponding author. E-mail: svl1000@cus.cam.ac.uk
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00227-4

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R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
Fig. 2.
reagent series, of full anomeric stabilisation and the formation of an all-chair array, should lead to the
formation of a single diastereomeric diacetal product on reaction with the 1,2-diol.
2. Results and discussion
The potential availability of both enantiomers of the 1,2-diketone 1 fulfils the reagent criteria for this
study (Fig. 2). Substitution at the 4- and 5-positions of the cyclohexane in a trans-relationship maintains
the C2-symmetry of the reagent and avoids functionalisation at the potentially epimerisable 3- and 6-
sites. The methyl control substituents also allow characteristic doublets to appear well away from the key
structural diagnostic area of the 1H NMR spectrum between 3 and 5 ppm.
The reagent is synthesised using an asymmetric Diels–Alder reaction as the important step, leading to
diol 2.4,5 The synthesis of this reagent yields optically pure material (as judged by chiral GC) and may
be applied to furnish diketones (S,S)-1 and (R,R)-1 as both enantiomers of the menthol chiral auxiliary
are readily available (Scheme 1).
Scheme 1. Reagents and conditions: i. MsCl, pyridine; ii. LiAlH4, Et2O, THF; iii. cat. OsO4, NMO, t-BuOH, THF, H2O; iv.
TFAA, DMSO, DCM, Et3N6
The potential resolution of (ꢀ)-cyclohexane-1,2-diol 6 was selected as the initial application for the
new reagent. It was anticipated that the chirality of the reagent 1,2-diketone would match that of a single
enantiomer of the racemic diol mixture, employing the control elements discussed earlier. The reagent
1 was therefore expected to effect a resolution of the diol material by selective formation of a single
diacetal diastereoisomer.
However, reaction of diketone (S,S)-1 with (ꢀ)-cyclohexane-1,2-diol 6 under the standard CDA
forming conditions7 yielded four major diacetal-like products 7–10 and a minor aromatic compound
11 (Scheme 2).
The relative amounts of these compounds on isolation depended greatly as to when the reaction was
terminated. The desired chirality matched CDA-like product 7, incorporating the (S,S)-enantiomer of
the diol, was isolated along with three mismatched diol adducts. These were a double addition product
8 of exclusively the (R,R)-diol into the asymmetric diketone, a monoaddition of the (R,R)-diol to yield
the non-symmetric dimethoxydiacetal 9 and a monoaddition of the (R,R)-diol to give a symmetrical
dimethoxydiacetal 10. A fifth, aromatised compound 11 was also observed in small quantities from the
reaction. This product was thought to have been formed by double elimination of methanol from the
diacetal followed by a series of hydride shifts to gain aromaticity.

R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
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Scheme 2. Reagents and conditions: i. cat. CSA, CH(OMe)3, MeOH, reflux
Structural assignment of the products could be made on a crude level, regarding whether the diacetal
product had C2-symmetry or not, by 13C NMR analysis. Although it was possible to isolate all of the
adducts from reaction of the racemic diol with the homochiral diketone by chromatography, the adducts
were also synthesised in crossover experiments by reaction of the homochiral diol with the homochiral
diketone. In separate experiments, both the matched and mismatched enantiomers of the homochiral diol
were reacted with the homochiral diketone to confirm the enantiomer of the diol incorporated in the
observed products. Extensive efforts to try and equilibrate the racemic diol reaction mixture to a single
diacetal product indicated that mixtures of these competing dione adducts would always be obtained
over the timescales employed. As these experiments did not lead substantially to any of the desired CDA
reactivity, it remained to explain the observed product outcome in Scheme 2, particularly relating to the
diacetal adducts 8, 9 and 10 featuring the mismatched enantiomer of the diol.
The low molecular weight of the monoaddition compounds involved allowed the progress of the
reaction to be readily followed by GC. The reaction of homochiral diketone 1 with racemic cyclohexane-
1,2-diol 6, yielding the mixture of diacetal compounds, was analysed at regular intervals by GC using
18-crown-6 as an internal standard. It was possible to observe the changes in the relative diacetal product
distribution with time by this method. The results of the study were encouraging as they indicated that
the fully stabilised matched CDA adduct 7 appeared to be the thermodynamically favoured course for the
reaction. The amount of the matched CDA product 7 continued to rise with time. In contrast to this trend,
the amounts of mismatched monoadducts 9 and 10 fell, over the timescale of the reaction, suggesting
that these were kinetic adducts and thermodynamically less favoured (Fig. 3).
Confident in the status of the fully stabilised CDA product 7 as the thermodynamically most stable
diacetal product from the GC data meant that sealed tube reactions with the dimethyl reagent, to force
the thermodynamic course of the process, was a sensible option. It was hoped that high temperature
conditions would overcome the formation of the kinetic mismatched diol adducts and effect the desired
resolution by exclusive formation of the thermodynamically favoured matched CDA 7. The failure of
this approach however was hinted at earlier as the aromatic byproduct 11 had been observed. The most
thermodynamically favourable and totally non-reversible pathway was aromatisation and this was indeed
the course followed by the reaction under these harsh conditions. Reaction in a sealed tube therefore at
150°C for 22 hours lead to exclusive formation of the aromatised product 11.
Structural variants on the diketone reagent 1 were also synthesised. Both the dimethyl and dibenzyl
ethers of diol 2 (Scheme 1) were synthesised and progressed through to give the corresponding diketone
reagents 12 and 13 (Fig. 4). The GC experiments were repeated using these diketones and similar trends
in product distribution were observed. Reaction of these diketones was slower than with the dimethyl
diketone 1. These diketones also showed a greater tendency to aromatise when incorporated in diacetal
structures. A small amount of a second symmetrical diacetal 14, formed by reaction of the matched (S,S)-

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R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
Fig. 3.
Fig. 4.
Fig. 5.
diol with the dimethylated diketone 12 was observed in this series of reactions (Fig. 4). This was not seen
in the first series using diketone 1.
The clearest way of addressing the explanation for the formation of the products observed is to
consider the fates of the two enantiomers of the diol racemate separately, on reaction with the homochiral
diketone reagent. These theories are governed by a number of assumptions concerning the reactivity of
the system, the most important being the ubiquitous presence of equatorially orientated control groups
on the reagent ring. Considering the case of the mismatched diol first, the assumption has been made
that initial equatorial attack is made on a planar methoxonium ion by the first alcohol of the 1,2-diol
to give 15. The second alcohol group of the 1,2-diol then takes part in a tethered ring closure onto
the vicinal methoxonium ion 16. The six membered tether enforces an axial orientation of attack for
the hydroxyl group. Initial attack of the alcohol, whether it be axial or equatorial, leads to the same
product 9 on tethered ring closure. This chair dioxane-fused product 9 is observed and isolated from
the reaction mixture (Fig. 5). The dioxane ring formed by this process adopts a chair conformation very
easily. However, despite its all-chair conformation it is lacking an anomeric effect at one of the formed
acetal centres.
Had the central dioxane ring been able to flip its conformation at this stage, the non-fully anomerically

R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
2475
Fig. 6.
Fig. 7.
stabilised acetal centre indicated in 9 (Fig. 5) would have been able to invert and lead to a fully
anomerically stabilised CDA. However, the required simultaneous ring flip of the reagent ring on
inversion of the dioxane would have forced the conformationally restricting methyl groups into a diaxial
orientation. This breaks the fundamental assumption for the explanation of this reactivity — diequatorial
control groups must be retained. Therefore, the indicated oxygen lone pair of 9 (Fig. 6) cannot assume
an antiperiplanar orientation with the methoxy leaving group, thus preventing assisted oxonium ion
formation.
It is proposed that both symmetrical fused product 10 and double addition product 8 are formed from
the initial chair fused adduct 9. Of the three potential oxonium ions that can be formed from 9, only
17, where the central dioxane is not cleaved, offers a route to the symmetrical product 10. Trapping of
oxonium ion 17 with methanol from the opposite face to the methoxy group at the vicinal acetal centre
leads to the symmetrical mismatched diol addition product 10 (Fig. 7).
The double addition product 8 must come about by initial cleavage of the equatorial dioxane bond in 9
to give oxonium ion 18. Attack on oxonium ion 18 from the least hindered face by a second equivalent of
mismatched diol gives the trans-diaxial intermediate 19. Sequential oxonium ion formation and tethered
ring-closure gives the mismatched diol double addition product 8, which is C2-symmetric (Fig. 8). These
proposals, within the stated parameters, account for the formation of the three observed mismatched diol
adducts. The theory depends on the formation of the non-symmetrical chair fused product 9 as the initial
intermediate for the formation of the other two mismatched compounds observed.
Considering the fate of the matched diol, two products containing the matched diol enantiomer have
been observed. Assuming the fixed conformation of the reagent cyclohexane ring, the stereochemistry of
the matched diol now enforces a tethered ring closure that can only take place to yield a boat dioxane 20
(Fig. 9). This is in contrast to the mismatched diol case (Fig. 5) which could close to a more favourable
chair conformation in the formation of non-symmetrical 9. Any attempt to join the matched diol onto the
diketone reagent to give a chair dioxane fusion would demand a ring flip of the reagent cyclohexane ring
leading to disfavoured diaxial control groups. This boat fused dioxane 20 was not however observed as
an intermediate in the reaction.
The most probable mechanism for the formation of the matched CDA product 7 invokes the unsym-
metrical boat fusion product of type 20 as a disfavoured but highly reactive intermediate (Fig. 10). The
lone pairs in 20 are aligned for oxonium ion formation at each acetal centre, unlike in 9 in the mismatched
diol case (Fig. 6). If the matched diol boat fusion product 20 could be formed initially, its pathway to
the matched CDA adduct 7 should be rapid and facile as the lone pair orientations always appear to be

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R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
Fig. 8.
Fig. 9.
Fig. 10.
favourable. Evidently the formation of this boat fused precursor is not facile and this is illustrated in the
low amounts of matched diol adducts formed relative to mismatched adducts 8, 9 and 10.
In summary, the initial reaction of the mismatched diol kinetically consumes the asymmetric diketone
reagent. Reaction of the matched diol is slow and initially disfavoured due to the energetic penalty of
forming boat fused 20. Therefore, the thermodynamic CDA product 7 only forms via a slow equilibration
process. By this time, a competing, irreversible degradation process is also taking place through an
aromatisation reaction.
Studies in the deprotection of the separated diacetal adducts 7, 8 and 9, using TFA:water (9:1) at 40°C,
yielded the expected enantiomer of diol in each case. The diols, derivatised as their diacetates for analysis
were recovered in greater than 95% e.e. as judged by chiral GC.
In conclusion, the synthesis of an asymmetric 1,2-diketone variant for the CDA procedure has
illustrated some interesting constraints on the use of such cyclic 1,2-diketones in procedures that had
previously enjoyed success in the asymmetric application of dispiroketal chemistry. (ꢀ)-Cyclohexane-
1,2-diol has served as an excellent model in the elucidation of the mechanistic aspects of the CDA
reaction. These observations have added to our understanding of the CDA process and have clarified
the implications for this type of asymmetric cyclic diketone reagent in synthesis.

R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
2477
3. Experimental
1H NMR spectra were recorded on a Bruker DRX-600, a Bruker DRX-500, a Bruker AM-400, a
Bruker AC-250 or a Bruker AC-200 spectrometer as solutions in deuteriochloroform (CDCl3) using
the residual CHCl3 as a reference (7.26 ppm) unless otherwise stated. 13C spectra were recorded on
a Bruker AC-200, a Bruker AC-250 or Bruker AM-400 spectrometer and chemical shifts are quoted
relative to the middle peak of CDCl3 (77 ppm). Coupling constants are quoted in hertz. Mass spectra
were obtained on a Kratos MS890MS spectrometer at the Department of Chemistry, University of
Cambridge. Microanalyses were performed in the University of Cambridge microanalyses laboratory.
Optical rotations were measured using an Optical Activity AA-1000 polarimeter and are quoted in
units of 10−1 deg cm2 g−1. Melting points were determined on a Reichert hot stage apparatus and
are uncorrected. Ether refers to diethyl ether and petrol refers to light petroleum ether (b.p. 40–60°C).
All solvents were purified before use: petroleum ether was redistilled, dichloromethane was distilled
from calcium hydride, ether and terahydrofuran were distilled from sodium–benzophenone ketyl and
methanol was distilled from magnesium. Unless otherwise stated, reactions were carried out under an
argon atmosphere in oven dried glassware (150°C overnight). Reagents were either dried by standard
procedures or used as purchased. Flash chromatography was carried out using Merck Kieselgel 60
(0.040–0.063 mm) under pressure. Thin layer chromatography was visualised with UV light (254 nm)
and acidified ammonium molybdate(IV) as appropriate.
3.1. (1S,2S)-1,2-Di-(methanesulfonyloxymethyl)-cyclohex-4-ene 3
A solution of (1S,2S)-cyclohex-4-ene-1,2-dimethanol 2 (12.58 g, 88.5 mmol) in pyridine (100 ml) was
stirred at 0°C. Methanesulfonyl chloride (27.44 ml, 354 mmol) was added to the mixture dropwise over
a period of 40 minutes. The mixture was stirred at room temperature for a further 17 hours. Ice water (ca.
100 ml) was added and the mixture was extracted with DCM (3×75 ml). The combined organic fractions
were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column
chromatography (eluent: ether:petrol=4:1) to give the dimesylate 3 as a white solid (21.4 g, 81%). Found:
C 40.55, H 6.05. C10H18O6S2 requires C 40.26, H 6.08%; m.p. 55°C; [α]D22 +59.4 (c 1.0, CHCl3); νmax
(film)/cm−1 1758, 1655, 1462, 1336, 1174, 1070, 981, 849, 785, 747; δH (400 MHz; CDCl3), [1.98–1.99
(2H, m), 2.14–2.17 (4H, m), H-1, H-2, H-3, H-6], 3.03 (6H, s, 2×OSO2CH3), 4.21 (2H, dd, J=5.0, 10.0,
2×CHaHbOSO2Me), 4.27 (2H, dd, J=5.0, 10.0, 2×CHaHbOSO2Me), 5.63 (2H, s, vinyl-H); δC (100
MHz; CDCl3) 25.9 (C-3, C-6), 33.7 (C-1, C-2), 37.4 (2×SO2CH3), 70.8 (2×CH2OSO2Me), 124.8 (C-
+
4, C-5); m/z (EI) 202 (7%, M−HOSO2CH3 ), 106 (83), 91 (100), 78 (61); found: [M−HOSO2CH3]+
202.0644. C9H14O3S requires M−HOSO2CH3 202.0644.
3.2. (1S,2S)-Dimethyl cyclohex-4-ene 4
To a solution of lithium aluminium hydride (493 mg, 13.0 mmol) in ether (16.5 ml) heated to reflux
was added (1S,2S)-cyclohex-4-ene-1,2-dimethanol dimethanesulfonate 3 (822 mg, 2.76 mmol) in the
minimum amount of THF (2.5 ml). The reaction was left at reflux for 15 hours. On cooling, careful
addition of saturated aqueous ammonium chloride solution (5 ml) was followed by stirring for 1 hour.
The organic phase was then dried (Na2SO4). Evaporation of the solvent was carried out with care due to
the volatilty of the product 4 using a rotary evaporator with the water bath set to 50°C and no vacuum
applied. This allowed the solvent to be distilled off leaving the product oil still slightly contaminated with
THF. δH (500 MHz; CDCl3) 0.94 (6H, d, J=7.5, 2×CH3), 5.62 (2H, d, J=2.5, vinyl-H).

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R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
3.3. (1R,2S,4S,5S)-4,5-Dimethyl cyclohexane-1,2-diol 5
Osmium tetroxide (2.5% wt. solution in t-butanol, 2.4 ml, 0.24 mmol) was added to a biphasic solution
of (1S,2S)-dimethylcyclohex-4-ene 4 (ca. 2.4 g), N-methylmorpholine-N-oxide (2.5 ml, 24.0 mmol) in
THF (15 ml), t-BuOH (9 ml) and water (2 ml). The mixture was stirred for 17 hours. Sodium sulfite
(3 g) was added to the mixture followed by water (10 ml). The mixture was extracted once with ethyl
acetate (15 ml). The organic phase was then extracted with n-BuOH (3×15 ml). The combined organic
portions were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash
column chromatography (eluent: ether:methanol=99:1) to yield the diol 5 (2.0 g, 65% over 2 steps from
(1S,2S)-cyclohex-4-ene-1,2-dimethanol dimethanesulfonate) as a white solid. Found: C 66.76, H 11.39.
C8H16O2 requires C 66.63, H 11.19%; m.p. 88–89°C; [α]D +34.3 (c 1.0, CHCl3); νmax (film)/cm−1
22
3329, 3022, 2892, 1436, 1069, 1023, 957, 661; δH (400 MHz; CDCl3), 0.85 (3H, d, J=6.5, 4-CH3), 0.92
(3H, d, J=6.5, 5-CH3), 0.97–1.10 (1H, m, H-5), 1.16 (1H, ddd, J=2.5, 12.5, 14.0, H-3ax), 1.28–1.39 (1H,
m, H-4), 1.39 (1H, dd J=12.0, 24.0, H-6ax), 1.61 (1H, dddd, 1.0, 3.5, 4.5, 12.0, H-6eq), 1.87 (1H, dt,
J=3.5, 14.0, H-3eq), [2.11 (1H, br s) and 2.29 (1H, br s), 2×OH], 3.61 (1H, m, H-1), 3.91 (1H, d, J=2.5,
H-2); δC (100 MHz; CDCl3), [19.1 and 19.8 (2×CH3)], [31.3 and 37.0 (C-4, C-5)], [37.4 and 39.7 (C-3,
C-6)], [69.9 and 71.7 (C-1, C-2)]; m/z (EI) 143 (4%, M−H+), 124 (20), 106 (46), 93 (100), 79 (66), 67
(29), 57 (22), 53 (20); found; [M−H]+ 143.1066. C8H15O2 requires M−H 143.1072.
3.4. (4S,5S)-2-Hydroxy-4,5-dimethyl-cyclohex-2-enone [(4S,5S)-4,5-dimethyl-cyclohexane-1,2-dione]
1
Trifluoroacetic anhydride (0.89 ml, 6.30 mmol) was added dropwise over a period of 20 minutes to
a solution of DMSO (0.49 ml, 6.95 mmol) in DCM (30 ml) at −60°C. The solution was allowed to
stir for a further 20 minutes. A solution of (1R,2S,4S,5S)-4,5-dimethyl-1,2-cyclohexanediol 5 in DCM
(4 ml) was added via cannula and the solution left stirring at −60°C for 1.5 hours. Triethylamine (2
ml, 14.3 mmol) was added dropwise and the yellow solution left at −60°C for 1 hour. The solution
was then allowed to reach room temperature. The reaction was poured into 10% aqueous HCl (30 ml)
which was extracted with DCM (2×10 ml). The combined organic fractions were dried (MgSO4) and
evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent:
ether:petrol=1:9) to yield an off-white solid 1 (273 mg, 90%) of highly characteristic smell. Found:
21
C 68.27, H 8.61. C8H12O2 requires C 68.55, H 8.63%; m.p. 35°C; [α]D +100 (c 1.0, DCM); νmax
(film)/cm−1 3420, 2964, 2877, 1676, 1452, 1407, 1279, 1223, 1170; δH (200 MHz; CDCl3), [1.05 (3H,
d, J=6.5) and 1.13 (3H, d, J=7.0), 2×CH3], [1.71–1.94 (1H, m) and 2.15–2.36 (1H, m), H-4, H-5], 2.52
(1H, dd, J=12.5, 16.5, H-6ax), 2.57 (1H, dd, J=4.0, 16.5, H-6eq), 5.75 (1H, br s, OH), 5.90 (1H, d, J=3.0,
H-3); δC (400 MHz; CDCl3), [19.1 and 19.5 (2×CH3)], [37.0 and 37.7 (C-4, C-5)], 43.8 (C-6), 124.1
(C-3), 146.1 (C-2), 195.7 (C-1); m/z (EI) 140 (23%, M+), 125 (21), 111 (5), 98 (29), 91 (12), 81 (24), 70
(68), 55 (16), 50 (42), 41 (23); found; [M]+ 140.0831. C8H12O2 requires M 140.0837.
3.5. Attempted resolution of trans-cyclohexane-1,2-diol
(4S,5S)-4,5-Dimethyl-cyclohexane-1,2-dione 1 (110 mg, 0.79 mmol), (ꢀ)-CSA (23 mg, 0.01 mmol),
(ꢀ)-trans-cyclohexane-1,2-diol 6 (220 mg, 1.89 mmol) and trimethylorthoformate (0.35 ml, 3.2 mmol)
were heated at reflux for 36 hours in dry methanol (13 ml). The reaction was neutralised with triethyl-
amine (0.1 ml) and the solvents removed under reduced pressure. The residue was purified by flash

R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
2479
column chromatography (gradient elution: ether:petrol=1:9 to ether:petrol=2:3) to allow the separation
of the following four diacetal compounds as white solids.
3.5.1. (1R,2R,10R,20S,40S,50S)-(10,20-Dimethoxy-40,50-dimethyl-cyclohexan-10 ,20-diyl) cyclohexane-
1,2-diol 9
22
Found: C 67.55, H 9.95. C16H28O4 requires C 67.57, H 9.92%; m.p. 91–93°C; [α]D +58.0 (c 1.0,
DCM); νmax (film)/cm−1 2921, 1454, 1375, 1225, 1193, 1114, 1072, 1053, 1026, 975; δH (400 MHz;
CDCl3), [0.86 (3H, d, J=6.0) and 0.92 (3H, d, J=6.0), 2×CH3], [1.16–1.34 (5H, m), 1.40–1.48 (1H, m),
1.68–1.75 (2H, m) and 1.77–1.85 (2H, m), H-3, H-4, H-5, H-6, H-40, H-50], 1.41 (1H, dd, J=12.5, 13.0,
H-30ax/H-60ax), 1.69 (1H, dd, J=3.5, 14.0, H-30eq/H-60eq), 1.90 (1H, dd, J=3.5, 13.0, H-30eq/H-60eq), 1.98
(1H, dd, J=12.0, 14.0, H-30ax/H-60ax), [3.25 (3H, s) and 3.33 (3H, s), 2×OCH3], 3.42–3.54 (2H, m, H-1,
H-2); δC (100 MHz; CDCl3), [19.0 and 19.2 (2×CH3)], [24.2, 24.5, 29.6, 30.3, 34.3, 34.5, 35.0 and 39.6
(C-3, C-4, C-5, C-6, C-30, C-40, C-50, C-60)], [47.5 and 48.7 (2×OCH3)], [72.0 and 75.5 (C-1, C-2)],
[98.1 and 98.8 (C-10, C-20)]; m/z (EI) 284 (4%, M+), 269 (13), 171 (83), 155 (9), 139 (100), 111 (10), 95
(13), 82 (20), 67 (35); found; [M]+ 284.1986. C16H28O4 requires M 284.1987.
3.5.2. (1R,2R,10R,20R,40S,50S)-(10,20-Dimethoxy-40,50-dimethyl-cyclohexan-10 ,20-diyl) cyclohexane-
1,2-diol 10
19
Found: C 67.45, H 9.89. C16H28O4 requires C 67.56, H 9.93%; m.p. 108–109°C; [α]D −18.4 (c 1.0,
DCM); νmax (film)/cm−1 2865, 2823, 2805, 1410, 1245, 1180, 1148, 1129, 1107, 1089, 1035, 1010, 975,
936, 840, 802; δH (600 MHz; CDCl3) 0.89 (6H, d, J=6.0, 2×CH3), 1.14–1.29 (6H, m, H-4, H-5, H-40,
H-50), 1.44 (2H, dd, J=12.0, 13.5, H-30ax, H-60ax), 1.65–1.68 (2H, m, H-3ax, H-6ax), 1.86 (2H, dd, J=3.0,
13.5, H-30eq, H-60eq), 1.95–1.99 (2H, m, H-3eq, H-6eq), 3.26 (6H, s, 2×OCH3), 3.94–4.01 (2H, m, H-1,
H-2); δC (100 MHz; CDCl3) 19.1 (2×CH3), [24.0, 31.9 and 37.1 (C-3, C-4, C-5, C-6, C-30, C-60)], 34.6
(C-40, C-50), 47.0 (2×OCH3), 75.2 (C-1, C-2), 99.7 (C-10, C-20); m/z (EI) 269 (20), 222 (8), 171 (97),
139 (100), 95 (23); found; [M−Me]+ 269.1758. C15H25O4 requires M 269.1753.
3.5.3. (1S,2S,10R,20R,40S,50S)-(10,20-Dimethoxy-40,50-dimethyl-cyclohexan-10 ,20-diyl) cyclohexane-
1,2-diol 7
22
Found: C 67.36, H 9.99. C16H28O4 requires C 67.56, H 9.93%; m.p. 112–114°C; [α]D −96.4 (c 1.0,
DCM); νmax (film)/cm−1 2930, 1453, 1200, 1108, 1072, 1045, 1012; δH (400 MHz; CDCl3) 0.89 (6H,
d, J=6.0, 2×CH3), 1.16–1.31 (4H, m, H-4ax, H-5ax, H-40, H-50), 1.31–1.43 (2H, m, H-3ax/eq, H-6ax/eq),
1.51 (2H, dd, J=12.0, 13.5, H-30ax, H-60ax), 1.69–1.75 (4H, m, H-4eq, H-5eq, H-30eq, H-60eq), 1.75–1.82
(2H, m, H-3ax/eq, H-6ax/eq), 3.18 (6H, s, 2×OCH3), 3.57–3.61 (2H, m, H-1, H-2); δC (100 MHz; CDCl3)
19.3 (2×CH3), [24.6, 30.0 and 35.6 (C-3, C-4, C-5, C-6, C-30, C-60)], 34.6 (C-40, C-50), 46.8 (2×OCH3),
72.5 (C-1, C-2), 98.1 (C-10, C-20); m/z (EI) 284 (3%, M+), 269 (57), 253 (28), 220 (23), 171 (84), 139
(100), 95 (24), 67 (36); found; [M]+ 284.1993. C16H28O4 requires M 284.1987.
3.5.4. (4aR,5aR,6aR,10aR,11aR,12aR,14S,15S)-14,15-Dimethyl-5a,11a-butano-5,6,11,12-tetraoxa-
perhydrotetracene 8
22
Found: C 71.33, H 9.74. C20H32O4 requires C 71.30, H 9.59%; m.p. 208°C; [α]D +85.1 (c 1.0,
DCM); νmax (Nujol)/cm−1 1450, 1376, 1228, 1194, 1108, 1069, 1029, 991, 858; δH (200 MHz; CDCl3),
0.90 (6H, d, J=6.0, 2×CH3) [1.28–1.49 (12H, m) and 1.71–2.09 (10H, m), H-1, H-2, H-3, H-4, H-7, H-8,
H-9, H-10, H-13, H-14, H-15, H-16], [3.54 (2H, ap dt, J=4.0, 10.0) and 3.89 (2H, ap dt, J=4.0, 10.0),
H-4a, H-6a, H-10a, H-12a]; δC (100 MHz; CDCl3) 18.7 (2×CH3), [24.2, 24.4, 29.6, 30.1 and 40.6 (C-1,
C-2, C-3, C-4, C-7, C-8, C-9, C-10, C-13, C-16)], 34.8 (C-14, C-15), [71.5 and 76.0 (C-4a, C-6a, C-10a,

2480
R. Lenz et al. / Tetrahedron: Asymmetry 9 (1998) 2471–2480
C-12a)], 96.1 (C-5a, C-11a); m/z (EI) 336 (9%, M+), 222 (100), 139 (13), 95 (7), 81 (13); found; [M]+
336.2303. C20H32O4 requires M−Me 336.2300.
Acknowledgements
We thank the Swiss National Science Foundation (RL), the LINK Asymmetric Synthesis Programme
(DRO), SmithKline Beecham (SLW) and the Novartis Research Fellowship (to SVL) for funding this
work.
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