A Valine-Derived Lithiated 3-Methylthiomethyl-1,3-oxazolidin-2-one for Enantioselective Nucleophilic Hydroxymethylation, Formylation, and Alkoxycarbonylation of Aldehydes

Article abstract of DOI:10.1021/ol0000410

(Equation Presented) The 3-methylthiomethyl-4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one (I, prepared in three steps from Boc-valine ester) is lithiated and added to aldehydes, with protecting in situ trapping of the primary adducts, to give the N,S-acet

Full text of DOI:10.1021/ol0000410

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1501-1504
A Valine-Derived Lithiated
3-Methylthiomethyl-1,3-oxazolidin-2-one
for Enantioselective Nucleophilic
Hydroxymethylation, Formylation, and
Alkoxycarbonylation of Aldehydes
Christoph Gaul1 and Dieter Seebach*
Laboratorium fu¨r Organische Chemie, Eidgeno¨ssische Technische Hochschule Zu¨rich
ETH-Zentrum, UniVersita¨tstrasse 16, CH-8092 Zu¨rich, Switzerland
seebach@org.chem.ethz.ch
Received February 23, 2000
ABSTRACT
The 3-methylthiomethyl-4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one (I, prepared in three steps from Boc-valine ester) is lithiated and added
to aldehydes, with protecting in situ trapping of the primary adducts, to give the N,S-acetal derivatives II of 2-hydroxy aldehydes in high yields
and diastereoselectivities. Cleavage (with ready recovery of the oxazolidinone auxiliary) is possible, to afford, for instance, enantiopure 1,2-
diols, selectively protected (OBn, OMOM, OTBS) in the 2-position.
Retrosynthetic analysis of molecules as simple as 1,2-diols
or 2-hydroxy aldehydes and esters reveals that organic
synthesis already provides an enormous number of possible
routes. If we focus on C,C bond-forming processes, of the
type indicated in the formulas A, B, and C (Figure 1), we
can possibly refer to in a preliminary communication such
as this.3 If we finally request that the process involves the
stoichiometric application with recycling of a chiral auxiliary,
there are only a few methods left, such as the use of
formaldehyde hydrazones4 and of lithiated heterocycles (cf.
the oxathianes5 or a 2-metalated N-Boc-oxazolidine in the
presence of sparteine6).
(1) Part of the projected Ph.D. Thesis of C.G., ETH Zu¨rich.
(2) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(3) Some synthetic equivalents of chiral formyl anions used for simple
carbonyl additions are deprotonated dithiane and dithiolane oxides (Sco-
lastico, Aggarwal) or certain lithiated R-heterosubstituted vinyllithium
compounds (Braun). (a) Colombo, L.; Gennari, C.; Scolastico, G.; Guanti,
G.; Narisano, E. J. Chem. Soc., Perkin Trans. 1 1981, 1278. (b) Aggarwal,
V. K.; Thomas, A.; Schade, S. Tetrahedron 1997, 53, 16213. (c) Aggarwal,
V. K.; Franklin, R.; Maddock, J.; Evans, G. R.; Thomas, A.; Mahon, M.
F.; Molloy, K. C.; Rice, M. J. J. Org. Chem. 1995, 60, 2174. (d) Aggarwal,
V. K.; Schade, S.; Adams, H. J. Org. Chem. 1997, 62, 1139. (e) Braun, M.
Angew. Chem., Int. Ed. 1998, 37, 430. (f) Mahler, H.; Braun, M. Chem.
Ber. 1991, 124, 1379.
Figure 1. C,C bond-forming preparation of 1,2-difunctionalized
hydroxy compounds.
realize that an umpolung of reactivity2 is required, and we
still find numerous methods in the literature. Even if we
narrow down our query further, to enantioselective versions
with C,C bond-formation, there are more solutions than we
(4) (a) Enders, D.; Bolkenius, M.; Vazquez, J.; Lassaletta, J. M.;
Fernandez, R. J. Prakt. Chem. 1998, 340, 281. (b) Pareja, C.; Martin-
Zamora, E.; Fernandez, R.; Lassaletta, J. M. J. Org. Chem. 1999, 64, 8846.
10.1021/ol0000410 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/03/2000

We present here a preliminary account of our work on
the application of an Evans auxiliary to the enantioselective
preparation of products of type A, B, and C with formation
of the central C,C bond.
adducts 4 in high yields and with good to excellent
stereoselectivities (Table 1).
When we first noticed7 the steric hindrance to nucleophilic
carbonyl addition caused by the geminal phenyl groups in
oxazolidinone 1,7-11 it occurred to us that we might be able
to directly lithiate a suitable derivative, such as methylthio-
methyl-substituted compound 2, by treatment with BuLi
(Figure 2).
Table 1. Addition of N,S-Acetal 2 to Aldehydes
products 4, 5
entry
RCHO
C6H5CHO
(pMeO)C6H4CHO
furfural
3-pyridinecarboxaldehyde
phenylpropargyl aldehyde
CH2dCMeCHO
yield [%]a
dr (4/5)b
1
2
3
4
5
6
7
a
b
c
d
e
f
90
92
90
72c
80d
88
93:7
91:9
90.5:9.5
96:4c (84:16)b
93:7
Figure 2. Oxazolidinones with nucleophilic reactivity in the 1′-
position.
85:15
iC3H7CHO
g
84 (61)d 71:29
a Combined yield of both isomers after FC. b Determined by H NMR
(300 MHz) of the crude product. c Yield/dr obtained after recrystallization
from MeOH. d Yield of the major isomer after FC.
1
Li reagent 3 is indeed generated in this way,12 and it can
be trapped by electrophiles. Chiral reagents of this general
type (with limited preparative usefulness) have been previ-
ously formed from tin compounds D by Sn/Li exchange in
work by Pearson and Nakai.13
Only two of the four possible diastereoisomers are formed.
Major isomers 4 and minor isomers 5 have the same
configuration at C(1′)-SMe and are epimeric at C(2′)-OH
(Table 1). Lithium compound 3 adds smoothly to aromatic,
heteroaromatic, and propargylic aldehydes (cf. entries 1-5)
with diastereoselectivities greater than 90%, while the
adducts with R,â-unsaturated aldehydes are usually formed
somewhat less selectively (cf. entry 6) (products resulting
from 1,4-addition are not observed). The addition of aliphatic
aldehydes (cf. entry 7) is also high yielding, but the
selectivities are lower. The diastereoisomeric products from
aliphatic, R,â-unsaturated, and propargylic aldehydes can
usually be separated by flash chromatography, with the major
isomer eluting first. In the case of aromatic aldehydes,
diastereoisomeric impurities are separated by recrystallization
from MeOH.14 Furthermore, simple trituration of the crude
addition products in hexane affords cleanly mixtures of 4
and 5 with enhanced diastereomer ratios.
N,S-Acetal 2 was prepared in high yield from oxazolidi-
none 1 by N-alkylation with chloromethyl methyl sulfide
(MTMCl) (Scheme 1).
Scheme 1
Treatment of 2 with BuLi in THF at -78 °C and
subsequent addition of an aldehyde at -100 °C afforded
We were able to obtain suitable single crystals of several
products of type 4/5 for the determination of the structure
(5) (a) Eliel, E. L.; Morris-Natschke, S. J. Am. Chem. Soc. 1984, 106,
2937. (b) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943. (c)
Ko, K. Y.; Frazee, W. J.; Eliel, E. L. Tetrahedron 1984, 40, 1333. (d)
Utimoto, K.; Nakamura, A.; Matsubara, S. J. Am. Chem. Soc. 1990, 112,
8189.
(6) Kise, N.; Urai, T.; Yoshida, J. Tetrahedron: Asymmetry 1998, 9,
3125.
(7) Hintermann, T.; Seebach, D. HelV. Chim. Acta 1998, 81, 2093.
(8) See also independent work with this oxazolidinone by two other
groups: (a) Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem.
Soc., Perkin Trans. 1 1999, 387. (b) Gibson, C. L.; Gillon, K.; Cook, S.
Tetrahedron Lett. 1998, 39, 6733.
(11) For reagents generated from carbonyl compounds with sterically
protected but electronically effectiVe CdO groups, see for instance: (a)
Ertas, M.; Seebach, D. HelV. Chim. Acta 1985, 68, 961. (b) Lubosch, W.;
Seebach, D. HelV. Chim. Acta 1980, 63, 102. (c) Schlecker, R.; Seebach,
D. HelV. Chim. Acta 1977, 60, 1459. (d) Seebach, D.; Lubosch, W.; Enders,
D. Chem. Ber. 1976, 109, 1309.
(12) The structure of 3 is drawn arbitrarily; the configuration of the
lithiated carbon is unknown. Cf. the X-ray crystal structure of a 1-bromo-
magnesio-2-pivaloyltetrahydroisoquinoline: Seebach, D.; Hansen, J.; Seiler,
P.; Gromek, J. M. J. Organomet. Chem. 1985, 285, 1.
(9) Oxazolidinone 1 and its enantiomer are commercially available as
(S)- and (R)-DIOZ: Shiratori Pharmaceutical Co., Ltd., Japan. Isobe, T.;
Fukuda, K. Japanese Patent JP 09143173, 1995; Chem. Abstr. 1997, 127,
50635.
(10) For a recent application in the synthesis of γ-amino acid derivatives,
see: Brenner, M.; Seebach, D. HelV. Chim. Acta 1999, 82, 2365.
(13) (a) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem.
Soc. 1993, 115, 2622 and earlier references therein. (b) Tomoyasu, T.;
Tomooka, K.; Nakai, T. Synlett 1998, 1147. (c) Tomoyasu, T.; Tomooka,
K.; Nakai, T. Tetrahedron Lett. 2000, 41, 345.
(14) All compounds were fully characterized by physical and chemical
data.
1502
Org. Lett., Vol. 2, No. 11, 2000

by X-ray crystallography. Thus, the X-ray crystal structure
of the major furfural adduct 4c is shown in Figure 3.
To extend the scope of the reaction, the in situ OH
protection of the addition products was examined (Scheme
2). Consecutive addition of benzaldehyde and chloromethyl
Scheme 2
Figure 3. X-ray crystal structure of addition product 4c. N: blue.
O: red. S: yellow.
Referring to the two newly created stereocenters, 4c has
(S,S)- or l-configuration. Hence, the new C,C bond is formed
with the relative topicity ul. X-ray crystal structure analysis
of several other aldehyde adducts revealed the same stereo-
chemical course for the formation of the major isomer
1
(C(2′)H usually at higher field in the H NMR spectra).
On the basis of the data obtained by X-ray crystallography,
a model for the stereochemical outcome of the reaction may
be suggested (Figure 4).15 The intermediate organolithium
methyl ether (MOMCl) to a solution of compound 3 afforded
MOM-protected benzaldehyde adduct 6 in 77% yield (dr
98.5:1.5).16
Similarly, the initially formed methacrolein adduct reacted
in situ with BnBr to give 7 in 55% yield (dr g99:1).
However, the use of N,N′-dimethylpropyleneurea (DMPU)
as a cosolvent is necessary for an efficient introduction of
the benzyl protecting group. In the case of isobutyraldehyde,
we were unable to perform the addition reaction and the
protecting step (with MOMCl, BnBr, and AcCl) in a one-
pot procedure. Therefore, the major isobutyraldehyde adduct
4g was first isolated and then treated with tert-butyldimeth-
ylsilyl triflate (TBSOTf) in CH2Cl2 to afford 8 in 53% overall
yield (dr g99:1) from sulfur compound 2.
Figure 4. Model for the stereochemical course of the addition
reaction (cf. refs 12 and 13b).
species may have a defined five-membered ring chelate
structure,12 with the iPr and the MeS substituents on opposite
sides of the bicyclic ring system. In the formation of the
major product, the aldehyde would then approach the C-Li
bond on its Re face to avoid steric repulsion between the R
and the MeS groups.
With compounds 6-8 in hand, the hydrolysis of the N,S-
acetals was envisaged. Several desulfurization reagents such
(17) For oxazolidinone-based hemiaminals, see: Bach, J.; Bull, S. D.;
Davies, S. G.; Nicholson, A. D. Tetrahedron Lett. 1999, 40, 6677.
(18) Representative experimental procedure: To a suspension of
benzaldehyde adduct 6 (450 mg, 0.915 mmol) in MeCN (3 mL), THF (3
mL), and H2O (1.5 mL) was added Hg(O2CCF3)2 (430 mg, 1.01 mmol) at
rt. After stirring for 5 min, the obtained clear solution was diluted with
H2O and Et2O. The organic layer was separated and the aqueous layer was
extracted with Et2O (2×). The combined organic layers were dried (MgSO4)
and concentrated under reduced pressure. The crude product (white solid)
was dissolved in THF (5 mL), and H2O (1.25 mL), NaBH4 (26 mg, 0.686
mmol), and DBU (69 µL, 0.458 mmol) were added consecutively at 0 °C.
Auxiliary 1 precipitated in the course of the reaction. After stirring for 15
min, a saturated aqueous NH4Cl solution was added and the precipitate
was filtered off. The precipitate was washed with saturated aqueous NH4-
Cl solution and Et2O and dried under high vacuum to yield 1 (184 mg,
71%) as a white solid. The filtrate was diluted with Et2O, the organic layer
(15) This model is consistent with observations made by Pearson and
Nakai (cf. ref 13).
(16) Representative experimental procedure: To a solution of N,S-
acetal 2 (500 mg, 1.46 mmol) in THF (8 mL) was added BuLi (1.20 mL,
1.76 mmol) at -78 °C. After stirring for 15 min, the reaction mixture was
cooled to -100 °C and freshly distilled benzaldehyde (192 µL, 1.90 mmol)
was added dropwise. The mixture was allowed to warm to -78 °C within
20 min and then MOMCl (189 µL, 2.49 mmol) was added. After stirring
for 4 h at rt, the white precipitate developing in the course of the reaction
was dissolved in CH2Cl2 and the reaction was quenched with a saturated
aqueous NH4Cl solution. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (2×). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The crude product
was triturated (boiling hexane, 2 × 5 mL) and recrystallized (MeOH/CH2-
Cl2) to give 6 (557 mg, 77%) as a 98.5:1.5 mixture with its C(2′)-OH epimer.
Org. Lett., Vol. 2, No. 11, 2000
1503

as HgCl2, AgNO3, CuCl2, NBS, MeI, or bis(trifluoroacetoxy)-
iodobenzene were tested, but all of them led to either
complex product mixtures or to no reaction at all. To our
surprise, treatment of the N,S-acetals 6-8 with Hg(O2CCF3)2
in MeCN/THF/H2O (2:2:1) at rt gave the corresponding
hemiaminals 9 (Scheme 3) within 5 min. Since these
The resulting selectively protected 1,2-diols 10 were isolated
in 82-90% yield.18 The enantiopurities of 10a and 10c were
determined by GC (Supelco γ-Dex 120), indicating that no
detectable racemization had occurred during the reduction.
Oxazolidinone 1 precipitated in the course of the reaction
and was recovered in 71-83% yield by simple filtration,
washing, and drying.
In conclusion, we have demonstrated that lithiated N,S-
acetal 3 undergoes diastereoselective addition reactions to
various types of aldehydes. Hydrolysis of the addition
products affords enantiomerically pure 2-hydroxy aldehydes
which are reduced in situ to selectively protected 1,2-diols.
Recovery of chiral auxiliary 1 is easy and proceeds in high
yields. Experiments to trap the 2-hydroxy aldehydes with
C-nucleophiles, such as Grignard or Wittig reagents, or to
oxidize to 2-hydroxy carboxylic acid derivatives (cf. 11),
are currently underway (Figure 5); also, preliminary results
Scheme 3
hemiaminals were rather sensitive to decomposition, they
were used without purification for further transformations.17
NMR experiments in CDCl3 provided evidence that hemi-
aminals 9 collapse instantaneously to the corresponding
2-hydroxy aldehyde and oxazolidinone 1 upon addition of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). As chiral 2-hy-
droxy aldehydes are fairly susceptible to racemization, it is
desirable to convert them in situ into chemically stable target
products such as 1,2-diols. Consequently, crude hemiaminals
9 were dissolved in THF/H2O (4:1) and were treated
consecutively with NaBH4 and DBU at 0 °C (Scheme 3).
Figure 5. An ester obtained (PCC) from a hemiaminal of type 9
and an adduct of 2 to a ketone.
indicate that addition to ketones (see 12) is possible (Figure
5). Thus, the method described here provides access to
selectively protected 1,2-diols, 2-hydroxy aldehydes (or
compounds derived thereof), and 2-hydroxy esters.
Acknowledgment. We thank P. Seiler for determination
of the X-ray crystal structure of compound 4c. We are also
grateful to Novartis Pharma AG for donation of 4-isopropyl-
5,5-diphenyl-1,3-oxazolidin-2-one and for continuing finan-
cial support.
was separated, and the aqueous layer was extracted with Et2O (2×). The
combined organic layers were dried (MgSO4) and concentrated under
reduced pressure. Purification by flash chromatography, eluting with
pentane/AcOEt (4:1), afforded 10a (151 mg, 90%) as a colorless oil.
OL0000410
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Org. Lett., Vol. 2, No. 11, 2000