Highly diastereoselective lithium enolate aldol reactions of butane-2,3-diacetal desymmetrized glycolic acid and deprotection to enantiopure anti-2,3-dihydroxy esters.

Article abstract of DOI:10.1021/ol016707n

[reaction--see text] The butane-2,3-diacetal (BDA) desymmetrized glycolic acid building block 1 undergoes efficient and highly diastereoselective lithium enolate aldol reactions with both aromatic and aliphatic aldehydes to afford, after an acidic methano

Full text of DOI:10.1021/ol016707n

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3749-3752
Highly Diastereoselective Lithium
Enolate Aldol Reactions of
Butane-2,3-diacetal Desymmetrized
Glycolic Acid and Deprotection to
Enantiopure anti-2,3-Dihydroxy Esters
Darren J. Dixon, Steven V. Ley,* Alessandra Polara, and Tom Sheppard
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K.
sVl1000@cam.ac.uk
Received September 6, 2001
ABSTRACT
The butane-2,3-diacetal (BDA) desymmetrized glycolic acid building block 1 undergoes efficient and highly diastereoselective lithium enolate
aldol reactions with both aromatic and aliphatic aldehydes to afford, after an acidic methanolysis deprotection step, the enantiopure anti-
2,3-dihydroxy esters in good yield.
The aldol reaction continues to be a powerful and widely
used process in the construction of natural products.1 The
very nature of this reaction, where up to two stereogenic
centers are created in a single carbon-carbon bond forming
process, is clearly of great strategic importance in synthesis.
This is particularly true when the reactions proceed in both
enantioselective and diastereoselective fashion and when
additional functionality may be incorporated.
studies on the diastereoselective lithium enolate alkylation
reactions of the rigid R-hydoxy acid building block 1.3,4
Multigram quantities of the chiral butane-2,3-diacetal of
glyclolic acid 1 can be readily obtained, in either enantio-
meric form, in just three steps from commercially available
(S)- or (R)-3-chloropropan-1,2-diol 2.5 The synthesis relies
Here we describe further applications of a new cyclic,
chiral glycolate equivalent 1 in aldol coupling reactions2 and
in subsequent deprotections to afford enantiopure anti-2,3-
dihydroxyesters (Scheme 1). This work compliments our
Scheme 1. Overview: Synthesis of anti-2,3-Dihydroxy Esters
from Glycolate 1
(1) (a) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 181-
238.
(2) For related examples, see: (a) Andrus, M. B.; Meredith, E. L.; Soma
Sekhar, B. B. V. Org. Lett. 2001, 3, 259. (b) Andrus, M. B.; Soma Sekhar,
B. B. V.; Meredith, E. L.; Kent Dalley, N. Org. Lett. 2000, 2, 3035. (c)
Fujita, M.; Laine´, D.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1999, 1647.
(d) Pearson, W. H.; Hines, J. V. J. Org. Chem. 1989, 54, 4235. (e) D’Angelo,
J.; Page`s, O.; Maddaluno, J.; Dumas, F.; Revial, G. Tetrahedron Lett. 1983,
24, 5869.
10.1021/ol016707n CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/19/2001

on a chiral memory protocol; protection of the diol with the
butane-2,3-diacetal protecting group6 sets up two new
stereogenic centers in the diacetal backbone7 of 3. This
chirality is maintained throughout the subsequent HCl
elimination step and the oxidative cleavage of the enol ether
4 to afford the highly crystalline glycolate product 1.
These reactions could be performed on multigram scale
(>20 g) without the need to purify intermediate stages and,
following recrystallization of the final product, gave material
in greater than 99% ee (Scheme 2).8
of 1 at -78 °C. Stirring was maintained for 10 min before
1.1 equiv of aldehyde was added via syringe. The mixture
was stirred for a further 5 min before 2.0 equiv of acetic
acid was added in one portion to quench the reaction. On
warming to room temperature, diethyl ether was added, and
the precipitous mixture was filtered through a short (1-2
cm) plug of silica, eluting with diethyl ether. Evaporation
gave the crude product, which was purified by silica gel
chromatography or recrystallization.9 Table 1 summarizes
Table 1. Lithium Enolate Aldol Reactions of 1
Scheme 2. Synthesis of Building Block 1a
a Reagents and conditions: (i) CH3COCOCH3 (1.1 equiv), CSA
(0.1 equiv), CH(OCH3)3 (2.1 equiv), CH3OH, reflux, 2 h; (ii) tBuOK
(2.0 equiv), THF, reflux, 2 h; (iii) O3, CH2Cl2/MeOH (1:1, v/v),
-78 °C then DMS (2.0 equiv), -78 °C to room temperature.
Given the ready availability of 1 we now wish to report
the aldol reactions of the corresponding lithium enolate.
These reactions required little optimization.
In a typical example, 1.05 equiv of lithium hexamethyl-
disilazide (LHMDS) was added dropwise to a THF solution
a Relative stereochemistry unambiguously determined by single-crystal
X-ray diffraction. b Relative stereochemistry predicted by analogy.
(3) D´ıez, E.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2001, 40,
2906
(4) For related examples in the literature, see: (a) Yu, H.; Ballard, C.
E.; Wang, B. Tetrahedron Lett. 2001, 42, 1835. (b) Crimmins, M. T.;
Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2, 2165. (c) Jung, J. E.; Ho,
H.; Kim, H.-D. Tetrahedron Lett. 2000, 41, 1793. (d) Chang, J.-W.; Jang,
D.-P.; Uang, B.-J.; Liao, F.-L.; Wang, S.-L. Org. Lett. 1999, 1, 2061. (e)
Abazi, S.; Rapado, L. P.; Schenk, K.; Renauld, P. Eur. J. Org. Chem. 1999,
477. (f) Renauld, P.; Abazi, S. HelV. Chim. Acta 1996, 79, 1696. (g) Boons,
G.-J.; Downham, R.; Kim, K. S.; Ley, S. V.; Woods, M. Tetrahedron 1994,
50, 7157. (h) Downham, R.; Kim, K. S.; Ley, S. V.; Woods, M. Tetrahedron
Lett. 1994, 35, 769. (i) Mash, E. A.; Fryling, J. A. J. Org. Chem. 1991, 56,
1094. (j) Pearson, W. H.; Cheng, M.-C. J. Org. Chem. 1987, 52, 3176. (k)
Pearson, W. H.; Cheng, M.-C. J. Org. Chem. 1986, 51, 3746. (l) Seebach,
D. Modern Synthetic Methods; Scheffold, R., Ed.; Springer-Verlag: Berlin,
1986; pp 125-257. (m) Enomoto, M.; Ito, Y.; Katsuki, T.; Yamaguchi, M.
Tetrahedron Lett. 1985, 26, 1343. (n) Helmchen, G.; Wierzchowski, R.
Angew. Chem., Int. Ed. Engl. 1984, 23, 60. (o) Kelly, T. R.; Arvanitis, A.
Tetrahedron Lett 1984, 25, 39. (p) Seebach, D.; Naef, R. HelV. Chim. Acta
1981, 64, 2704.
the results obtained for some readily available aldehydes.
In all cases the diastereoselectivities in the reactions were
exceptional, with the worst case being for acetaldehyde (entry
1, 92% de). Reaction yields were invariably good to
excellent. Of the seven entries in Table 1, the relative
(9) Representative Procedure for the Synthesis of 10. To a stirred
solution of 1 (155 mg, 0.82 mmol) in tetrahydrofuran (2.5 mL) at -78 °C
was added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran
(1 M, 0.86 mL, 1.05 equiv). After 10 min p-anisaldehyde (0.10 mL, 1.1
equiv) was added, and the reaction mixture was stirred for a further 5 min.
The reaction was then quenched by addition of acetic acid (0.10 mL, 2
equiv) at -78 °C and warmed to room temperature. Diethyl ether was added
(2 mL), and the heterogeneous mixture was filtered through a short (2 cm)
plug of silica eluting with diethyl ether (15 mL). The filtrate was evaporated
in vacuo to leave a yellow oil. The reaction de was found to be >95% by
inspection of the 600 MHz proton NMR spectrum of the crude product.
Purification by flash column chromatography, eluting with 50% diethyl
ether/petroleum ether (bp 40-60 °C) gave 10 (250 mg, 96%) as white
(5) Available from Aldrich in both enantiomeric forms.
(6) For a recent and comprehensive review on 1,2-diacetals in synthesis,
see: Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53.
(7) For other examples of the BDA group acting as a chiral memory,
see: (a) Dixon, D. J.; Foster, A. C.; Ley, S. V.; Reynolds, D. J. J. Chem.
Soc., Perkin Trans. 1 1999, 1631. (b) Dixon, D. J.; Foster, A. C.; Ley, S.
V.; Reynolds, D. J. J. Chem. Soc., Perkin Trans. 1 1999, 1635. (c) Dixon,
D. J.; Foster A. C.; Ley, S. V. Org. Lett. 2000, 2, 123. (d) Dixon, D. J.;
Ley, S. V.; Reynolds, D. J. Angew. Chem., Int. Ed. 2000, 39, 3622.
(8) See the following: (a) Dixon, D. J.; Ley, S. V.; Rodriguez, F. Org.
Lett. 2001, 3, 3753. (b) Reference 3.
crystals: mp 67-69 °C (from Et2O); [R]31D +107.1 (c 1.37, CHCl3); νmax
-
(CHCl3) cm-1 3488 (OH), 1754 (CdO), 1150 (CO); 1H NMR δ (400 MHz,
CDCl3) 7.32 (2H, d, J 9, Ar), 6.87 (2H, d, J 9, Ar), 5.08 (1H, dd, J 2 and
4, CHOH), 4.31 (1H, d, J 4, COCH), 3.80 (3H, s, ArOCH3), 3.74 (1H, d,
J 2, OH), 3.32 (3H, s, OCH3), 3.28 (3H, s, OCH3), 1.47 (3H, s, CH3), 1.39
(3H, s, CH3); 13C NMR (CDCl3) δ 167.0, 159.3, 130.5, 128.1, 113.4, 105.0,
98.3, 75.4, 74.0, 55.2, 50.1, 49.3, 17.9, 16.8; m/z (+ESI) 349 (MNa+) (found
MNa+, 349.1274; C16H22O7Na requires M, 349.1258).
3750
Org. Lett., Vol. 3, No. 23, 2001

stereochemistries of five of the major diastereoisomeric
products were unambiguously proven by single crystal X-ray
diffraction, showing the highly crystalline nature of these
aldol products.
Table 2. Deprotection Reactions of Aldol Products 5-11
Using Methanolic HCl or CSA
We believe that the major diastereoisomeric product arises
through attack of the aldehyde to the re-face of the glycolate
enolate, avoiding the steric clash with the 1,3-related axial
methoxy group. Assuming chelation of the lithium cation
of the enolate to the aldehyde oxygen and a six-ring chairlike
transition state, placement of the R group of the aldehyde in
the equatorial position (away from the dioxane ring) rational-
izes the stereochemistry of the major product (Figure 1).10
Figure 1. Proposed transition state model leading to major
diastereoisomer.
a HCl in MeOH was the source of H+. b CSA (1.1 equiv) was the source
of H+. c Relative stereochemistry proven by single-crystal X-ray diffraction.
d Absolute stereochemistry confirmed by comparison of specific rotation
with literature values.
Deprotection of the major diastereoisomeric products was
possible by repeated dissolution of the compounds in
methanolic hydrochloric acid and evaporating in vacuo or
by overnight treatment with camphorsulfonic acid (1.1 equiv)
in anhydrous methanol (Table 2). The anti-1,2-diol methyl
esters 12-18 were produced in good yield. Comparison of
the specific rotation and spectroscopic data of 12 and 17
with the literature values allowed confirmation of the absolute
and relative stereochemistries11 (entries 1 and 6). Single-
crystal X-ray diffraction provided unambiguous determina-
tion of the relative stereochemistry of 17.
To illustrate the power of these reactions and to confirm
the relative and absolute stereochemistries in each case, the
aldol adducts from both the “mismatched” (20 and 21) and
“matched” (22) cases were subjected to an acidic metha-
nolysis reaction. Using 1.1 equiv of camphorsulfonic acid
Scheme 3. Lithium Enolate Aldol Reactions of (S,S)- and
(R,R)-1 with Chiral Aldehyde (S)-19a
The lithium enolate aldol addition of 1 to aldehydes
bearing a stereogenic center at the R-position was also
examined (Scheme 3).12 Treatment of (S,S)-1 with LHMDS
(1.05 equiv) followed by aldehyde (S)-19 (1.1 equiv) gave
the aldol products 20 and 21, as an inseparable mixture, in
82% yield and in a 52:48 ratio. When this reaction was
repeated using (R,R)-1, the major product was isolated in
87% yield and the reaction de was >95%. Assuming Felkin-
Anh control, these selectivities agree with the stereochemical
model described above; with the lithium enolate of glycolate
(R,R)-1 and (S)-19 providing the “matched” combination.
Clearly, these aldol reactions provide an easy and stereo-
selective route to contiguous triol motifs bearing the anti-
1,2-diol component.
(10) Boons, G.-J.; Downham, R.; Kim, K. S.; Ley, S. V.; Woods, M.
Tetrahedron 1994, 50, 7157.
(11) Specific rotations: 12 [R]31 -17.3 (c 0.585, CHCl3) ([R]20 -16
D
D
(c 1.1, MeOH) Achmad, S.; Hoeyer, A.; Kjaer, A.; Makmur, L.; Norrestam,
a Reagents and conditions: (i) LHMDS (1.1 equiv), THF, -78
°C, 10 min, then (S)-19, 5 min, then AcOH (2.0 equiv); (ii) MeOH,
(()-CSA (0.1 equiv), reflux, 30 min, then toluene added, reflux,
30 min.
R. Acta Chem. Scand. Ser. B 1987, 41, 599). 17: [R]31 -41.8 (c 0.54,
D
CHCl3) ([R]18D -43.9 (c 1.085, CHCl3) Matthews, B. R.; Jackson, W. R.;
Jacobs, H. A.; Watson, K. G. Aust. J. Chem. 1990, 43, 1195).
(12) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1.
Org. Lett., Vol. 3, No. 23, 2001
3751

in anhydrous boiling methanol, the inseparable mixture of
mismatched products 20 and 21 was converted into the
known, and separable, γ-lactones 23 and 24 in 45% and 34%
yield, respectively. Similarly, acidic methanolysis of 22
afforded γ-lactone 25 in 75% yield. Lactones 23-25 have
been reported previously, and the spectroscopic data as well
as the specific rotations of the lactones synthesized in our
work were in good agreement with the literature data.13
Additionally, our two-step synthesis of lactone 23 consti-
tutes a formal total synthesis of L-biopterin 26,14 a pterin
natural product that through its 5,6,7,8-tetrahydro form is
an essential enzyme cofactor in the conversion of phenyl-
alanine to tyrosine,15 tyrosine to DOPA,16 and in melanine
synthesis17 (Scheme 4).
Scheme 4. Previous Total Synthesis of L-Biopterin 26 from
Lactone 23
aromatic and aliphatic aldehydes to afford, after an acidic
methanolysis deprotection step, the enantiopure anti-1,2-diols
in good yield.
In summary, the butane-2,3-diacetal desymmetrized gly-
colic acid building block 1 undergoes efficient and highly
diastereoselective lithium enolate aldol reactions with both
Acknowledgment. We thank the EPSRC (D.J.D. and
T.S.), the Novartis Research Fellowship (S.V.L.), and Pfizer
Gobal Research and Development, Groton, U.S.A. for
financial support. We also thank Dr John E. Davies for the
X-ray structure determination.
(13) 23: [R]23D -29.4 (c 0.68, EtOH) ([R]21D -37.0 (c 1.1, EtOH), ref
12). 24: [R]22D -32.3 (c 0.34, MeOH) ([R]25D -34 (c 0.99, MeOH) Kaiser,
H.; Keller-Schierlein, W. HelV. Chim. Acta 1981, 407). 25: [R]23 -19.6
D
(c 1.02, MeOH) (enantiomer [R]D +17.0 (c 1.0, MeOH) Papageorgiou, C.;
Benezra, C. Tetrahedron Lett. 1984, 25, 6041).
Supporting Information Available: Experimental pro-
cedures for the acid promoted methanolysis and characteriza-
tion data for compounds 5-18. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Fernandez, A.-M.; Duhamel, L. J. Org. Chem. 1996, 61, 8698.
(15) Rembold, H.; Gyure, W. L. Angew. Chem., Int Ed Engl. 1972, 11,
1061.
(16) (a) Nagatsu, T.; Levitt, M.; Undenfriend, S. J. Biol. Chem. 1964,
239, 2910. (b) Lloyd, T.; Weiner, N. Mol. Pharm. 1971, 7, 569.
(17) (a) Ziegler, I. Z. Naturforsch. 1963, 18b, 551. (b) Kokolis, N.;
Ziegler, I. Z. Naturforsch. 1968, 23b, 860.
OL016707N
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Org. Lett., Vol. 3, No. 23, 2001