Desymmetrisation of dialdehydes: (+)-(S) and (-)-(R) nor-methyl mevaldate as versatile synthetic intermediates

Article abstract of DOI:10.1016/S0040-4039(02)00533-6

Desymmetrisation of 3-(t-butyldimethylsilyloxy)pentanedial 2 may be carried out by monoacetalisation with (R)- or (S)-2-phenylethanol. The products may be elaborated to nor-methyl mevaldate derivatives.

Full text of DOI:10.1016/S0040-4039(02)00533-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3593–3596
Desymmetrisation of dialdehydes: (+)-(S) and (−)-(R) nor-methyl
mevaldate as versatile synthetic intermediates
Shirley L. J. Buckley, Michael G. B. Drew, Laurence M. Harwood* and Antonio J. Mac´ıas-Sa´nchez
Department of Chemistry, University of Reading, Whiteknights, Reading, Berkshire RG6 6AD, UK
Received 17 January 2002; revised 5 March 2002; accepted 15 March 2002
Abstract—Desymmetrisation of 3-(t-butyldimethylsilyloxy)pentanedial 2 may be carried out by monoacetalisation with (R)- or
(S)-2-phenylethanol. The products may be elaborated to nor-methyl mevaldate derivatives. © 2002 Elsevier Science Ltd. All rights
reserved.
The synthetic versatility of 1,3,5 trioxygenated sub-
strates has led to much interest in their enantiocon-
trolled construction and such derivatives have been
obtained through desymmetrisation of anhydrides,1
enzymatic reductions2a and ester hydrolysis,3 enantiose-
lective catalytic hydrogenation,4 stereoselective aldol
condensation,4 Sharpless asymmetric epoxidation,5 and
by transformation of other enantiopure precursors.2b
Desymmetrisation is proving to be a powerful synthetic
tool,6 and dialdehydes have been the focus of a number
of studies.7 We decided to explore the potential for
desymmetrisation of dialdehyde 2 via diastereocon-
trolled acetal formation with chiral alcohols.
Although several approaches to analogues of dialde-
hyde 2 have been reported,7b,8 we found it to be conve-
niently prepared through a six-step sequence from
cyclopentadiene. The known alcohol 4 was obtained
from cyclopentadiene via epoxide 3 in 20% overall yield
following the procedure of Crandall.9 Alcohol 4 was
protected as its t-butyldimethylsilyl ether 5 in 95% yield
(TBDMSCl–imidazole, THF, 0°C) and this was trans-
formed into a 12:1 mixture of diasteroisomeric diols 6
by the method of Matteson, employing catalytic
osmium tetroxide in t-butanol at reflux with trimethyl-
amine-N-oxide as the reoxidant.10 Cleavage of 6 with
sodium periodate in 8:2 dioxane:water, followed by
exhaustive extraction with ethyl acetate furnished dial
2, which forms the cyclic hydrate 7 on standing. In
order to achieve reproducible results in the subsequent
desymmetrisation step, it was imperative to transform
the hydrate back to the dialdehyde by treating with
In this paper we present the synthesis of (+)-(S) and
(−)-(R) methyl (t-butyldimethylsilyl)mevaldate (R)- and
(S)-1 via desymmetrisation of dialdehyde 2, readily
obtained from cyclopentadiene (Scheme 1). Procedures
for obtaining enantiomerically enriched (R)-1 have
been reported previously.2b,3a,5
,
powdered 4 A molecular sieves in refluxing THF for 2
h (Scheme 2).
A range of chiral alcohols was investigated with 2-
phenylethanol showing the highest diastereoselectivity.
After refluxing 1.5 equiv. of chiral alcohol with dialde-
Scheme 1.
,
hyde 2 and 4 A molecular sieves in THF for 18 h,
analysis indicated a mixture of monoacetals and start-
ing material.11 Although these could be isolated and
characterised, it was found most convenient to filter the
slurry through a pad of Celite®, remove the solvent and
Keywords: desymmetrisation; 3-(t-butyldimethylsilyloxy)pentanedial;
nor-methyl mevaldate.
* Corresponding author. Tel.: +44 (0)118 9318 449; fax: +44 (0)118
9316 782; e-mail: l.m.harwood@reading.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00533-6

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S. L. J. Buckley et al. / Tetrahedron Letters 43 (2002) 3593–3596
With the assignment of the absolute configuration at
C-3 on lactones 10 and ent-10 as (R) and (S), respec-
tively, the relative stereochemistry on compounds 10
and 11 could be established by combination of NOE
difference studies and 1H NMR coupling constants
(Fig. 2).
In conclusion, we have shown that dialdehyde 2 may be
desymmetrised using chiral alcohols by diastereocon-
trolled monoacetal formation and the products con-
verted to useful chiral intermediates. Although the
conversion in the acetalistion step is not high, the
overall procedure constitutes an experimentally expedi-
ent means of accessing (S)-1 and (R)-1.
Scheme 2. Reagents and conditions: (a) CH3CO3H,
CH3CO2Na, Na2CO3, CH2Cl2, T<10°C; (b) LiAlH4, Et2O,
0°C; (c) TBDMSCl, imidazole, THF, 0°C; (d) OsO4,
(CH3)3NO, pyr, t-BuOH, H2O, reflux; (e) NaIO4, dioxane/
,
H2O (8:2), rt; (f) 4 A mol. sieves, THF, reflux.
treat the residue with PCC in CH2Cl2 overnight.12 By
this means (R)-2-phenylethanol furnished the readily
separable lactones 10 and 11 in 9 and 1% overall
isolated yields, respectively.13 (S)-2-Phenylethanol like-
wise gave ent-10 and ent-11 in the same yields (Scheme
3). Treatment of lactones 10 and ent-10 with MeONa in
MeOH at −35°C for 18 h, yielded (R)-1 and (S)-1 in
76% yield, possessing specific rotations of −10.5 (c=
1.5, CHCl3), and +10.7 (c=0.475, CHCl3), respec-
tively,14 together with (R)-2-phenylethanol and
(S)-2-phenylethanol, recovered in 64% yield and pos-
sessing the same specific rotations as the starting mate-
rials (Scheme 4).15,16
Scheme 3. Reagents and conditions: (a) (+)-(R)-1-
,
phenylethanol, 4 A mol. sieves, THF, reflux, 24 h; (b) PCC, 4
,
,
A mol. sieves, CH2Cl2, 18 h; (c) (−)-(S)-1-phenylethanol, 4 A
mol. sieves, THF, reflux, 24 h.
Confirmation of the absolute stereochemistries of (R)-1
and (S)-1 and those of the parent compounds 10 and
ent-10, at C-3, was achieved via lactones 12 and 13,
obtained from treatment of compound 2 with (S)-
methyl mandelate in THF under reflux, followed by
oxidation of the crude mixture with PCC. Compounds
12 and 13 furnished crystals suitable for X-ray crystal-
lographic analysis, establishing the absolute configura-
tion at C-3 in lactones 12 and 13 as (R) and (S),
respectively (Fig. 1).17 Subsequent treatment of lactone
12 with MeOH/MeONa yielded (R)-1; whereas lactone
13 gave (S)-1 (Scheme 4).
Scheme 4. Reagents and conditions: (a) (+)-(S) methyl mande-
,
,
late, 4 A mol. sieves, THF, reflux, 24 h; (b) PCC, 4 A mol.
sieves, CH2Cl2, 18 h; (c) MeONa, MeOH, −35°C.

S. L. J. Buckley et al. / Tetrahedron Letters 43 (2002) 3593–3596
3595
Figure 1. X-Ray for compounds 12 (upper) and 13 (lower) (ORTEP projections).
Acknowledgements
We thank Mr A. W. Jahans for technical assistance.
S.L.J.B. thanks the University of Reading for a
research studentship. A.J.M.-S. thanks the Secretaria de
Estado de Universidades, Investigacion y desarrollo
(SEUID; Spanish funding body) for a postdoctoral
fellowship and University of Cadiz (Spain) for financial
support for this project.
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Figure 2. Selected NOE for compounds 10 (upper) and 11
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3596
S. L. J. Buckley et al. / Tetrahedron Letters 43 (2002) 3593–3596
purification by column chromatography yielded 10 (79
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13. Data for compound 10: [h]2D5 +157 (c=1.02, CHCl3); lH
(400 MHz; CDCl3) 0.03 (3H, s, SiCH3
SiCH3), 0.76 (9H, s, SiC(CH3)3), 1.46 (3H, d, J 6.8,
CHCH3), 1.85 (1H, ddd, J 3.6, 6.8, 13.8, H-4b), 1.94 (1H,
6 ), 0.02 (3H, s,
6
6
6
ddd, J 3.6, 5.6, 13.8, H-4a), 2.47 (1H, dd, J 5.6, 17.2,
H-2), 2.76 (1H, dd, J 4.8, 17.2, H-2%), 4.33 (1H, m, H-3a),
4.99 (1H, q, J 6.4, H-1%), 5.25 (1H, dd, J 3.6, 5.6, H-5b),
7.36–7.27 (5H, C6H6 5); selected NOE H-3alH-4a (4%),
H-4alH-4b (23%), H-4blH-5b (7%), H-5blH-1% (7%);
lC (100 MHz; CDCl3) −4.79, −4.93, 17.87 23.92, 25.57,
37.05, 39.95, 62.51, 75.78, 97.92, 126.46, 127.97, 128.56,
141.79, 169.64.
4. Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler,
T. Tetrahedron 1995, 51, 3549.
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Tullis, J. S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T.
J. Org. Chem. 1998, 53, 8284; (c) Vares, L.; Rein, T. Org.
Lett. 2000, 2, 2611; (d) BouzBouz, S.; Popkin, M. E.;
Cossy, J. Org. Lett. 2000, 2, 3449; (e) Tanaka, K.; Ohta,
Y.; Fuji, K. Tetrahedron Lett. 1993, 34, 4071; (f)
Oppolzer, W.; De Brabander, J.; Walther, E.; Bernar-
dinelli, G. Tetrahedron Lett. 1995, 36, 4413; (g) Oppolzer,
W.; Walter, E.; Perez Balado, C.; De Brabander, J.
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Y.; Honda, A.; Nakao, S.; Noguchi, I.; Iwata, C.;
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hedron Lett. 1996, 37, 3345; (j) Roush, W. R.; Park, J. C.
Tetrahedron Lett. 1990, 31, 4707.
Data for compound 11: [h]2D5+144 (c=0.37, CHCl3); lH
(400 MHz; CDCl3) 0.03 (6H, s, Si(CH3 2
6 ) ), 0.86 (9H, s,
SiC(CH3)3), 1.47 (3H, d, J 6.6, CHCH3), 1.82 (1H, ddd,
6
6
J 7.7, 9.2, 14.0, H-4a), 2.22 (1H, dddd, J 1.8, 4.4, 5.4,
14.0, H-4b), 2.51 (1H, dd, J 9.2, 16.8, H-2a), 2.69 (1H,
ddd, J 1.8, 5.4, 16.8, H-2b), 3.98 (1H, tt, J 5.4, 9.2, H-3b),
5.08 (1H, q, J 6.6, H-1%), 5.04 (1H, dd, J 4.4, 7.7, H-5b),
7.28–7.38 (5H, C6H6 5); selected NOE H-3blH-2b (4%),
H-3blH-5b (5%), H-3blH-4b (5%), H-2blH-2a
(18%), H-4blH-4a (23%), H-4a“H-2a (3%), H-4blH-
5b (10%); lC (100 MHz; CDCl3) −4.81, −4.75, 17.89
24.04, 25.61, 38.69, 40.13, 62.62, 75.81, 97.86, 126.56,
128.06, 128.70, 141.98, 169.53.
14. [h]2D5 −9.6 (c=1.2, CHCl3), Ref. 2b; [h]2D5 −9.83 (c=5.38,
CHCl3), Ref. 5.
15. (−)-(R) Methyl (t-butyldimethylsilyl) mevaldate (R)-(1).
Sodium methoxide (18 mg) was added to a solution of
lactone 8 (23 mg) in dry MeOH (3 mL) at −35°C. The
reaction was stirred at −35°C for 24 h, then quenched
with saturated NH4Cl (3.5 mL). The reaction was then
warmed to room temperature and diethyl ether (10 mL)
and brine (2 mL) were added. The layers were separated
and the aqueous layer was then extracted with diethyl
ether (3×20 mL). The combined organic layers were
washed with brine (2×5 mL), dried over Na2SO4 and the
solvent was removed under reduced pressure to give a
crude reaction product (25 mg), which was purified by
column chromatography to give (R)-1 (13 mg, 76%) and
(R)-2-phenylethanol (5 mg, 64%).
8. Harada, T.; Kagamihara, Y.; Tanaka, S.; Sakamoto, K.;
Oku, A. J. Org. Chem. 1989, 54, 3816.
9. Crandall, J. K.; Banks, D. B.; Colyer, R. A.; Watkins, R.
J.; Arrington, J. P. J. Org. Chem. 1968, 33, 423.
10. Ray, R.; Matteson, D. S. Tetrahedron Lett. 1980, 21, 449.
11. Leaving the reaction for longer times led to no increase in
conversion, but the diastereoisomeric ratios on the iso-
lated products are lower.
12. Desymmetrisation of 3-(t-butyldimethylsilyloxy)pentandial
(2)/PCC oxidation procedure. (3R,5S,1%R)-3-(t-Butyl-
dimethylsilyloxy)-5-hydroxy-5-(1%-phenylethoxy) pentanoic
acid lactone (10), (3S,5S,1%R)-3-(t-butyl dimethylsilyloxy)-
5-hydroxy-5-(1%-phenylethoxy)pentanoic acid lactone (11).
1-Phenyl-ethanol (325 mg) was added to a suspension of
16. Data for compound 1: (R)-(1) [h]2D5 −10.5 (c=1.5,
CHCl3), lit.;2b (S)–(1) [h]D25 +10.7 (c=0.475, CHCl3); lH
(200 MHz; CDCl3) 0.01 (6H, s, Si(CH3 2
SiC(CH3)3), 2.49 (2H, dd, J 1.6, 5.9, H-2, H-2%), 2.58 (1H,
m, H-4, H-4%), 3.61 (3H, s, COOCH3), 4.56 (1H, q, J 5.9,
H-3), 9.73 (1H, t, J 1.9, CHO); lC (50 MHz; CDCl3)
6 ) ), 0.86 (9H, s,
,
dial 2 (576 mg) and 4 A powdered molecular sieves (2.5
6
g) in dry THF (10 mL). The slurry was refluxed for 24 h,
filtered through Celite® and the THF was removed under
reduced pressure to yield 757 mg of crude product. This
oil was dissolved in DCM (12 mL) and then added
dropwise to a suspension of PCC (2.0 g) and powdered 4
6
6
−4.48, −4.40, 17.81 25.56, 42.30, 50.84, 51.37, 64.99,
170.95, 200.35.
17. Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 168527 and 168528.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: +44(0)-1223-336033; e-mail: deposit@
ccdc.cam.ac.uk).
,
A molecular sieves (3.0 g) in DCM (15 mL) at room
temperature. The reaction was stirred vigorously at room
temperature for 18 h, diethyl ether was then added and
the mixture was stirred for a further 1 h. The suspension
was filtered over a pad of silica gel, and washed through
with further ether. The ether was removed under reduced
pressure to give a crude mixture of lactones. Further