Novel cyclic 1,2-diacetals derived from (2R,3R)-(+)-tartaric acid: Synthesis and application as N,O ligands for the enantioselective alkylation of benzaldehyde by diethylzinc

Article abstract of DOI:10.1002/ejoc.200300750

A chiral cyclic 1,2-diacetal derived from tartaric acid was used as the basic structural unit for novel ligands. Monooxazoline carbinols in which the degree of substitution of the alcohol and the nature of the stereocentre in the oxazoline ring were varied were synthesized in moderate to good yields. The influence of these structural factors on asymmetric induction was examined in the enantioselective addition of diethylzinc to benzaldehyde. Up to 60% ee was observed with a secondary or a tertiary alcohol as the metal-chelating group. Wiley-VCH Verlag GmbH & Co, KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300750

FULL PAPER
Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(؉)-Tartaric Acid: Synthesis
and Application as N,O Ligands for the Enantioselective Alkylation of
Benzaldehyde by Diethylzinc
[a]
[b]
[a]
´
M. Teresa Barros,* Christopher D. Maycock, and Ana Maria Faısca Phillips
Keywords: Alkylation / Asymmetric catalysis / Diacetals / Zinc / N,O ligands
A chiral cyclic 1,2-diacetal derived from tartaric acid was
ric induction was examined in the enantioselective addition
used as the basic structural unit for novel ligands. Monoox- of diethylzinc to benzaldehyde. Up to 60% ee was observed
azoline carbinols in which the degree of substitution of the
alcohol and the nature of the stereocentre in the oxazoline
ring were varied were synthesized in moderate to good
yields. The influence of these structural factors on asymmet-
with a secondary or a tertiary alcohol as the metal-chelat-
ing group.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Some derivatives of the cyclic 1,2-diacetal 1 made by
other researchers have already found applications in enanti-
oselective synthesis: as bis(oxazolines) in cyclopropanation
1,2-Diacetals have been known for many years, but their reactions,[3] as diphosphanes in the hydrogenation of acry-
chemistry still remains largely unexplored.[1] Cyclic 1,2-di- late derivatives[4] and enamides,[5] as thioethers in the
acetals such as 1, derived from tartaric acid, have been the hydrogenation of enamides,[5] and as phosphonites in ke-
subject of several studies during the last few years.[1] They tone hydrosilylation.[6] All the chiral ligands based on the
have a rigid 1,4-dioxane ring in which two methoxy groups 1,4-dioxane skeleton reported so far have C2 symmetry.
are stabilized in a trans-diaxial relationship by a double an- This symmetry was long believed to be the most efficient
omeric effect, and four chiral centres, which make them feature for ligand-induced multiplication of chirality, but re-
good templates for chirality transfer. They are structurally cently more complex structures bearing different chelating
related to TADDOL 2, which is also prepared from tartaric groups and more than one element of chirality have proved
acid, contains a 1,3-dioxolane ring, and whose derivatives to be very useful.[7] We decided to do away with C2 sym-
have many applications in catalysis.[2]
metry, and to synthesize ligands with oxazoline and
hydroxy units, i.e. with two different donor atoms, N and
O, capable of chelating to metals. It is a well-known fact
that in homogeneous catalysis there is an almost complete
lack of useful structureϪactivity relationship.[8] Since most
catalytic cycles consist of several consecutive discrete steps,
intermediates may be quite different and hence it is difficult
to predict which structural factors may be best suited to a
particular reaction. We synthesized a series of ligands with
different structural features which could influence the in-
duction of chirality, such as hydroxy group substitution and
the nature of the chiral substituent in the oxazoline ring,
aiming to have a useful series to add to the chiral pool.
In order to assess the ability of our new catalysts to in-
duce asymmetry in catalytic reactions we decided to study
the enantioselective addition of diethylzinc to benzaldehyde
to produce 1-phenylpropanol, commonly used as a chiral
building block. This reaction has been widely studied since
its discovery by Oguni and Omi in 1984,[9] and it has been
reviewed recently.[10] Amino alcohols constitute an import-
ant part of the chiral ligands studied, and oxazoline-con-
[a]
´
Departamento de Quımica, REQUIMTE, Faculdade de
ˆ
Ciencias e Tecnologia, Universidade Nova de Lisboa,
2825 Monte de Caparica, Portugal
Fax: (internat.) ϩ 351-212948550
E-mail: amfp@dq.fct.unl.pt
[b]
´
´
Instituto de Tecnologia Quımica e Biologica, Universidade
Nova de Lisboa,
Rua da Quinta Grande 6, Apartado 127, 2780 Oeiras, Portugal
Fax: (internat.) ϩ 351-214469789
1820
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300750
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Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(ϩ)-Tartaric Acid
FULL PAPER
taining catalysts have also received some attention. Simple way (vide infra), and heating to higher temperatures (deca-
hydroxymethyloxazolines,[11] pyridyloxazoline alcohols,[12] lin reflux) was necessary. The amides could, however, be
ferrocene-based systems[13] and a TADDOL analog[14] have readily converted into oxazolines by activation of the
been tried with success, but a systematic investigation of the hydroxy group as a tosylate and in situ ring closure in the
effect of altering the degree of substitution of the alcohol presence of excess triethylamine. This method works well
chelating group has not been made. The present study when there are other secondary or tertiary hydroxy groups
aimed to fill this gap as well as to explore further the chem- in a molecule.[19] Novel oxazolines 6aϪc were synthesized
istry of 1,2-diacetals.
in this manner. They were the only product of the reaction
and were obtained in good to high yields (65Ϫ79% from
the acid) after column chromatography.
Results and Discussion
B. Synthesis of the Catalyst Containing a Secondary
Hydroxy Group
A. Synthesis of TADDOL Analogs
The C2-symmetric diester 1 used as starting material for
Catalysts containing a primary or a secondary hydroxy
the preparation of all the catalysts was obtained from group required a different synthetic strategy. In these cases
(2R,3R)-(ϩ)-tartaric acid by an acetal exchange reaction it was necessary to protect the carboxylic acid function
with 2,2,3,3-tetramethoxybutane and p-toluenesulfonic acid before transforming the ester into an alcohol (Scheme 2).
as catalyst as reported previously.[15] The diester was con- Corey’s orthoester protecting group was used to protect the
verted into unsymmetrical derivatives via the half-ester 3, acid against the attack of organometallic reagents (Grig-
obtained in good yield (85%) by partial hydrolysis with nard reagents, LiAlH4)[20] as its oxabicyclo[2,2,2]octyl or-
methanolic KOH[16] (Scheme 1). Reaction of the half-ester thoester (OBO ester 9). This strategy could be used success-
with an excess of Grignard reagent produced the tertiary fully because the base-stable cyclic orthoester is much more
alcohol directly, a strategy which has already been used with sensitive to acid than the cyclic 1,2-diacetal, and deprotec-
the TADDOL analogues.[17] Oxazolines 6aϪc could be re- tion could be achieved under very mild conditions in which
adily obtained from the acid in good to high yields the cyclic acetal was not affected.
(65Ϫ79%) in a two-step process: amidation and dehydrative
The OBO ester was prepared in two steps; acid 3 was
cyclization. Heating the acid in the presence of an amino initially esterified with 3-(hydroxymethyl)-3-methyloxetane
alcohol to 150 °C with concomitant azeotropic removal of and DCC/DMAP; higher yields of product 8 were obtained
the water formed with a DeanϪStark trap, produced am- (77%) when an excess (two-fold) of oxetane alcohol was
ides 5aϪc.
used. The ester was subsequently converted into the OBO
The products were pure enough to be used in the next ester 9 by a rearrangement reaction catalyzed by BF3·Et2O.
step without prior purification. When the activation energy The reaction was complete in 1 hour at room temperature,
for this process is low enough, oxazolines may form directly and the OBO ester was obtained as the only product in high
in this fashion by removal of another molecule of water,[18] yield (82%). Direct reduction of protected ester 9 to the
but in our case only one oxazoline was synthesized in this aldehyde was tried, but attempts with DIBAL-H or LiAlH4/
Scheme 1. Reagents and conditions: i) 1.2 equiv. KOH, MeOH, reflux; ii) 3 equiv. PhMgBr, THF, reflux; iii) amino alcohol, xylene,
reflux; iv) pTsCl, Et3N, CH2Cl2, reflux
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M. T. Barros, C. D. Maycock, A. M. Faısca Phillips
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Scheme 2. Reagents and conditions: i) DCC, DMAP, CH2Cl2, 0 °C, 4 h; ii) BF3·Et2O, CH2Cl2, room temp., 1 h; iii) LiAlH4, THF, reflux;
iv) (COCl)2, DMSO, Et3N, CH2Cl2, Ϫ60 °C; v) PhMgBr, THF, reflux, 1 h 30; vi) 1  HCl, pH 1, 0 °C, 40 min, then 1  LiOH, pH 11,
reflux; vii) amino alcohol, xylene, reflux, 17 h; viii) pTsCl, Et3N, CH2Cl2, reflux, 17 h
Et2NH were unsuccessful. Hence the ester was first reduced
C. Synthesis of the Catalyst Containing a Primary
Hydroxy Group
[21]
with LiAlH4
to alcohol 10 in good yield (68%), and 10
was then converted into the aldehyde 11 (in 87% yield) by
Swern oxidation under standard conditions.[22] The product
The approach used for the synthesis of this catalyst is
was pure enough to be used in the next step without further shown in Scheme 3. Acid 3 was protected as the OBO ester,
purification. Grignard addition proceeded smoothly, and and the ester function was reduced to the alcohol. Depro-
the alcohol was obtained in 72% yield after chromatogra- tection was carried out as described for 12, to give 16 in
phy. There was no duplication of signals in spectra (1H good yield (88%). The oxazoline synthesis, however, re-
NMR, 13C NMR), suggesting that the product formed with quired a method different from that used for the other cata-
either full or very high stereocontrol.[23] The acid was then lysts. After the amidation of 16, there are two primary
deprotected[24] in a sequence of two one-pot reactions. hydroxy groups present in the molecule which can compete
Acidifying a THF/H2O solution of 12 at 0 °C with HCl to in the tosylation step, and mixtures can be produced. Hence
pH 1 and stirring for 30 min caused complete rearrange- a direct approach was used. Dehydration at 135 °C in xy-
ment of the OBO ester to an intermediate ester. Only one lene produced amide 17 together with small amounts of the
product formed in this step, as indicated by TLC. This ester oxazoline; even after long periods of heating the reaction
may be isolated if wished. Normally it was not isolated, but did not go to completion, and eventually other (unidenti-
the solution was treated with aqueous LiOH solution and fied) products formed. When the acid and the amino al-
the pH raised to 11. After a period of reflux (4:30 h), the cohol were heated to a higher temperature in decalin (bath
hydrolysis was complete and acid 13 could be obtained in temperature 210 °C) oxazoline 18 formed. The reaction
high yield (88%) by acidification and extraction. The amid- goes via the amide, which is the major component of the
ation and subsequent oxazoline formation were carried out reaction mixture after 17 h of reflux. If the amide is not
as described for catalysts 6a؊c to give 15 in 63% yield.
isolated but the mixture is refluxed for 3Ϫ4 days, about 75%
1822
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Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(ϩ)-Tartaric Acid
FULL PAPER
of the starting material is converted into product. Refluxing
the mixture longer (i.e. 6 days) does not increase the conver-
sion, even though some amide is still present in the reaction
mixture after this time, as indicated by 1H NMR spec-
troscopy.
Scheme 3. Reagents and conditions: i) 1  HCl, pH 1, 0 °C, 30 min,
then 1  LiOH, pH 11, reflux; ii) amino alcohol, decalin, reflux
Figure 1. Variation of the ee as a function of the reaction con-
ditions in the addition of diethylzinc to benzaldehyde catalyzed by
6a: a) the effect of the catalyst concentration on ee and on conver-
sion after 24 h; b) the effect of temperature observed after 24 h.[26]
D. Catalysis
The potential of the novel chiral oxazoline carbinols to
catalyze the asymmetric addition of Et2Zn to benzaldehyde Figure 1 (see a and b) illustrate some of the results. The
was investigated. Preliminary experiments showed that 2 reaction was slow; after 24 h at 12 °C there was more than
mol equivalents of Et2Zn were necessary, otherwise the re- 80% conversion, but small amounts of aldehyde remained
action would not go further than half-way, irrespective of unchanged. This also happened at room temperature, with
the length of time used. The addition was tried with 6a 9% unchanged aldehyde remaining even after 47 h, as deter-
as catalyst, at different temperatures and different catalyst mined by 1H NMR spectroscopy. It seems that the alkoxide
concentrations, to establish the best reaction conditions. formed inhibits the reaction, as reported to occur in some
Table 1. Enantioselective addition of diethylzinc to benzaldehyde catalyzed by various oxazoline carbinols
Entry[a]
Catalyst
R1
R2
R3
Substrate[b] [%]
BzOH[b] [%]
Conversion[c] [%]
ee[d] [%]
1
2
3
4
5
6a
6b
6c
16
18
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
H
Ph
iPr
Me
Ph
Ph
16
11
20
nf[f]
2
Ͻ 9
Ͻ 5
Ͻ 5
Ͻ 5
Ͻ 10
67
54
46
20
49
11
nd[e]
66
79
58
H
[a]
Reactions were carried out under argon, and a molar ratio of Et2Zn/benzaldehyde/catalyst ϭ 2.1:1:0.1. Additions took place at 0 °C
[b]
1
[c]
and the mixtures were afterwards stirred for 24 h at 12Ϫ15 °C.
Determined from the H NMR spectrum. Determined by HPLC
analysis, using 1-phenylethanol as internal standard. [d] Determined by HPLC analysis, on a Chiralcel OB-H column from Daicel. [e] Not
[f]
determined. Not found.
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´
M. T. Barros, C. D. Maycock, A. M. Faısca Phillips
FULL PAPER
cases by other researchers. The highest enantiomeric excess change from the diphenylhydroxymethyl to the phenyl-
was obtained when the reaction was carried out at 0 °C hydroxymethyl group had little influence on induction de-
(61%), but at this temperature the reaction was even slower; spite an increase in the reaction rate, but a change from the
a benzaldehyde to alcohol ratio of 1:3.7 was obtained after diphenylhydroxymethyl to the hydroxymethyl group had a
42 h, and propiophenone also formed in large amounts large influence on induction. In the oxazoline unit, the nat-
(20%) as a by-product. Propiophenone results from a slow ure of the chiral substituent as well as steric effects had a
disproportionation reaction between the ethylation product strong influence on induction, which decreased in the order
ethylzinc 1-phenyl-1-propoxide and benzaldehyde.[25]
Ph Ͼ iPr Ͼ Me.
At higher temperatures, i.e. 12Ϫ15 °C, no propiophenone
1
formed, as determined by H NMR spectroscopy, and the
enantiomeric excess was 54%. Raising the temperature
speeded up the reaction more, but the ee dropped slightly
(41% was obtained after 24 h). Varying the catalyst concen-
tration had a small effect on the enantioselectivity of the
reaction, but a large effect on the rate. Hence changing the
catalyst concentration from 3.7 to 11.0 mmol equivalents
increased the ee from 44 to 55%, whereas the conversion
changed from 63 to 97% in 24 h. When the final reaction
conditions were selected, a compromise between these fac-
Experimental Section
General Remarks: All reactions were carried out under argon. Sol-
vents were purified by standard procedures and distilled before use.
2,2,3,3-Tetramethoxybutane,[27] dioxane dimethyl ester 1,[1] and the
hydroxymethyloxetane 7,[20a] were prepared according to literature
procedures. Column chromatography was carried out on
MachereyϪNagel silica gel (230Ϫ400 mesh). Melting points were
measured with an Electrothermal Melting Point apparatus or with
tors was made, so that a good conversion could be reached a Reichert Thermovar apparatus, and are uncorrected. Elemental
analyses (C, H, N) were performed by the Laboratory for External
Services of CQFB-Lab Associado/REQUIMTE, of the Depart-
ment of Chemistry, FCT, UNL, Monte de Caparica. NMR spectra
were obtained with a Bruker AR X400 NMR spectrometer. Chemi-
cal shifts are reported relative to TMS. Signals in 13C NMR spectra
were assigned with the aid of DEPT spectra. Two-dimensional
spectra (COSY 45, HMQC, SECSY) were recorded whenever
necessary for structure elucidation. IR spectra were obtained with
a Mattson Instruments Satellite FTIR spectrometer. Optical ro-
tations (0.5-dm cell, 1-mL capacity) were measured with an
at a low catalyst concentration. All the catalysts prepared
were then assessed under identical conditions, and the re-
sults are presented in Table 1.
Benzyl alcohol, which forms by β-hydride reduction, is
sometimes obtained as a major by-product of the reaction
between benzaldehyde and diethylzinc. In our reactions un-
der optimized conditions it was present as less than 10% of
the crude reaction mixtures. The (R)-isomer was the pre-
dominant product in all cases. The highest enantiomeric ex-
cess was obtained with catalyst 6a, the catalyst containing AAϪ1000 Polarimeter from Optical Activity Ltd. HPLC analyses
were carried out with a Merck Hitachi instrument equipped with
a Chiralcel OB-H column, with hexane/iPrOH as eluent (flow
0.9 mL/min), and a MerckϪHitachi -4250 UVϪVIS detector.
a tertiary alcohol group (54%), and the lowest (11%) with
18, containing a primary hydroxy group. Catalyst 4 (con-
taining a secondary hydroxy group, and hence another chi-
ral centre near the active reaction centre) provided nearly
the same induction as 6a (49%), but it also gave the largest
enhancement in rate (all the substrate had reacted after
24 h). A separate experiment showed that after 16 h only Ͻ
(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-di-
carboxylic Acid Monomethyl Ester (3): The diester (5.33 g, 0.018
mol) was suspended in dry MeOH (12 mL). Potassium hydroxide
(1.25 g, 0. 022 mol) in MeOH (10 mL) was added dropwise, at room
2% of the starting material remained unchanged. These re- temperature, over a period of 1 h. The solution was afterwards re-
fluxed for 2 h 30. The solvent was then evaporated off, and the
mixture was distributed between CHCl3 and water. The aqueous
layer was extracted twice more with CHCl3. The combined chloro-
form fractions were dried with anhydrous magnesium sulfate and
the solvent evaporated off. The residue was checked for the pres-
ence of unchanged diester. The diester obtained (0.349 g) was later
recycled. The remaining aqueous phase was acidified with HCl
solution (2 ) to pH 1 and extracted with diethyl ether. The pH
was adjusted with HCl before each extraction. After drying, the
solvent was evaporated off to give the product as a viscous colour-
sults suggest that steric effects play an important role in
reducing the number of conformations possible in the tran-
sition state, and hence the catalyst containing a tertiary al-
cohol group gave the best induction.
Conclusion
In the course of this work methods for the synthesis of
novel chiral oxazoline carbinols were developed. They were less liquid (4.34 g, 86%). [α]2D1 ϭ Ϫ132 (c ϭ 2.03, CHCl3). 1H NMR
(400.1 MHz, CDCl3): δ ϭ 1.36 (s, 3 H, CH3), 1.37 (s, 3 H, 2 ϫ
CH3), 3.32 (s, 3 H, OCH3), 3.33 (s, 3 H, OCH3), 3.78 (s, 3 H,
COOCH3), 4.49 (d, J ϭ 5 Hz, 1 H, dioxane CH), 4.60 (d, J ϭ
5 Hz, 1 H, dioxane CH), 9.00Ϫ9.25 (br. s, COOH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ ϭ 17.3 (2 ϫ CH3), 48.6 (2 ϫ OCH3), 52.6
(CH3), 68.3 (CH), 68.7 (CH), 99.2 (acetal C), 99.6 (acetal C), 168.2
(CO), 171.7 (CO) ppm. IR (CHCl3): ν˜ ϭ 3668, 3483, 3028, 3001,
2954, 2908, 2839, 2613, 2556, 1744, 1440, 1380, 1354, 1292, 1231,
1202, 1178, 1143, 1114, 1040, 898, 889, 855, 772, 664, 579, 428
cmϪ1. C11H18O8 (278.26): calcd. C 47.48, H 6.52; found C 47.57,
obtained in good to moderate yields from a cyclic 1,2-diace-
tal derived from tartaric acid. Structural features such as
the degree of substitution of the alcohol as well as the nat-
ure of the chiral substituent in the oxazoline ring were va-
ried. The effect of these modifications on the ability of these
ligands to induce chirality was investigated in a model reac-
tion, the enantioselective addition of diethylzinc to benzal-
dehyde. Steric effects near the hydroxy group seemed to be
more important than the presence of an extra stereogenic
centre near the coordination sphere of the metal. Thus, a H 6.87.
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Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(ϩ)-Tartaric Acid
(2R,3R,5R,6R)-3-(Hydroxydiphenylmethyl)-5,6-dimethoxy-5,6-di-
FULL PAPER
1529, 1495, 1450, 1378, 1201, 1143, 1132, 1121, 1039, 911, 701
cmϪ1. C30H35NO7 (521.61): calcd. C 69.08, H 6.76, N 2.69; found
C 69.25, H 6.75, N 2.68.
methyl-1,4-dioxane-2-carboxylic Acid (4):
A flame-dried two-
necked flask was charged with a phenylmagnesium bromide solu-
tion (21.5 mL of a 1  solution in THF, 21.5 mmol). Half-ester 3
(1.99 g, 0.716 mmol) in dry THF (2.9 mL) was added dropwise at
room temperature over 1 h while the solution was stirred under
argon. Afterwards the mixture was refluxed for 17 h. The reaction
mixture was then cooled in an ice bath, and ice (3 g) was added.
The pH was lowered to 1 with 1  HCl and the product was ex-
tracted with diethyl ether. The combined extracts were washed with
a saturated salt solution, filtered through anhydrous sodium sulfate
and the solvent was removed using a rotary evaporator. The sample
was dried. The product was purified by column chromatography
on silica gel treated with 1% Et3N in hexane (EtOAc/MeOH, 8:2).
Some product eluted as a salt, which was converted into the free
acid after dissolution in water, acidification to pH ഠ 1 with 2 
HCl and extraction with diethyl ether. The product was obtained
(2R,3R,5R,6R)-N-[(S)-1-Hydroxymethylisopropyl]-3-(hydroxy-
diphenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-
oxamide (5b): Prepared from (S)-(ϩ)-2-amino-3-methyl-1-butanol
(0.103 g, 0.989 mmol) and acid 4 (0.398 g, 0.989 mmol), as de-
scribed under the general procedure for amidation. It may be puri-
fied by chromatography on silica gel (EtOAc/hexane, 6:4). M.p.
149Ϫ150 °C. [α]2D2 ϭ ϩ28.9 (c ϭ 0.52, CHCl3). The assignments of
the NMR signals were made by HMBC. 1H NMR (400.1 MHz,
CDCl3): δ ϭ 0.89 [d, J ϭ 6.8 Hz, 3 H, CH(CH3)2], 0.93 [d, J ϭ
6.4 Hz, 3 H, CH(CH3)2], 1.13 (s, 3 H, CH3), 1.30 (s, 3 H, CH3),
1.88Ϫ1.97 [m, 1 H, CH(CH3)2], 2.19 (t, J ϭ 5.6 Hz, 1 H, CH2OH),
2.64 (s, 3 H, OCH3), 3.20 (s, 3 H, OCH3), 3.65Ϫ3.78 (m, 3 H, CHN
ϩ CH2), 4.10 (d, J ϭ 9.2 Hz, 1 H, dioxane CH), 4.58 (d, J ϭ 9.2
Hz, 1 H, dioxane CH), 6.01 (s, 1 H, OH), 7.14 (t, J ϭ 7.2 Hz, 2
H, Ph-H), 7.21 (t, J ϭ 7.2 Hz, 2 H, Ph-H), 7.29 (t, J ϭ 7.2 Hz, 2
H, Ph-H), 7.36Ϫ7.40 (m, 3 H, 2 H of Ph ϩ NH), 8.00 (d, J ϭ 7.6
Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3, DEPT): δ ϭ
17.3 (2 ϫ CH3), 18.6 [CH3, CH(CH3)2], 19.5 [CH3, CH(CH3)2],
28.7 [CH, CH(CH3)2], 48.0 (CH3 of OCH3), 48.2 (CH3 of OCH3),
57.1 (CHN), 63.3 (CH2), 70.0 (dioxane CH), 76.4 (dioxane CH),
126.6 (CH, Ph), 127.1 (4 ϫ CH, Ph), 127.6 (CH, Ph), 127.8 (4 ϫ
CH, Ph), 143.6 (Cquat, Ph), 146.0 (Cquat, Ph), 166.7 (CONH), 172.3
(CONH) ppm. IR (CHCl3): ν˜ ϭ 3409, 3062, 2995, 2965, 2898,
2836, 1648, 1531, 1493, 1449, 1377, 1265, 1205, 1143, 1131, 1122,
1044, 925, 908, 745, 722, 702 cmϪ1. C27H37NO7 (487.59): calcd. C
66.51, H 7.65, N 2.87; found C 66.38, H 7.67, N 2.95.
as a white solid. Total yield: 1.16 g, 40%. M.p. 163Ϫ164 °C. [α]2D7
ϭ
Ϫ26.6 (c ϭ 2.00, CHCl3). 1H NMR (400.1 MHz, CDCl3): δ ϭ 1.18
(s, 3 H, CH3), 1.33 (s, 3 H, CH3), 3.13 (s, 3 H, OCH3), 3.29 (s, 3
H, OCH3), 4.46 (d, J ϭ 9.0 Hz, 1 H, CH), 4.84 (d, J ϭ 9.0 Hz, 1
H, CH), 7.10 (t, J ϭ 7.3 Hz, 1 H, Ph), 7.18 (t, J ϭ 7.8 Hz, 2 ϫ H,
Ph-H), 7.25 (t, J ϭ 7.3 Hz, 1 H, Ph-H), 7.35 (t, J ϭ 7.8 Hz, 2 ϫ
H, Ph-H), 7.42 (d, J ϭ 7.5 Hz, 2 ϫ H, Ph-H), 7.72 (d, J ϭ 7.5 Hz,
2 ϫ H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 17.3
(CH3), 17.4 (CH3), 48.5 (OCH3), 48.9 (OCH3), 68.8 (CH), 72.7
(CH), 78.1 (COH), 98.6 (acetal C), 99.1 (acetal C), 126.6 (4 ϫ CH,
Ph), 126.9 (4 ϫ CH, Ph), 127.0 (2 ϫ CH, Ph), 127.4 (CH, Ph),
127.6 (4 ϫ CH, Ph), 127.9 (4 ϫ CH, Ph), 142.1 (CH, Ph), 144.5 (2
ϫ CH, Ph), 173.2 (CO) ppm. IR (CHCl3): ν˜ ϭ 3671, 3550, 3415,
3062, 3027, 3010, 2950, 2837, 1727, 1600, 1493, 1450, 1377, 1144,
(2R,3R,5R,6R)-N-[(S)-2-Hydroxy-1-methylethyl]-3-(hydroxy-
diphenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-
oxamide (5c): Prepared from (S)-(ϩ)-2-amino-1-propanol (0.053 g,
0.692 mmol) and acid 4 (0.281 g, 0.699 mmol), as described in the
1128, 1119, 1038, 977, 912, 891, 876, 703, 664 cmϪ1
.
C22H26O7·MeOH (434.49): calcd. C 63.58, H 6.96; found C 63.80,
H 6.90.
1
general procedure for amidation. H NMR (400.1 MHz, CHCl3):
General Procedure for Amidation: A reaction flask topped with a
DeanϪStark apparatus and a condenser was charged with acid 4
(1.00 mmol), the amino alcohol (1.00 mmol) and xylene (4.60 mL).
The mixture was refluxed for 17 h under argon. The solvent was
then removed in vacuo, and the product was dried. Amides 5aϪc
were prepared in this way and were obtained as solids which were
used in the next step without further purification.
δ ϭ 1.12 (s, 3 H, CH3), 1.17 (d, J ϭ 6.8 Hz, 3 H, CH3), 1.31 (s, 3
H, CH3), 2.66 (s, 3 H, OCH3), 3.20 (s, 3 H, OCH3), 3.58 (dd, J ϭ
4.8, 10.8 Hz, 1 H, CHaHbOH), 3.69 (dd, J ϭ 4.0, 11.2 Hz, 1 H,
CHaHbOH), 4.02 (m, 1 H, CHN), 4.10 (d, J ϭ 9.2 Hz. Hz, 1 H,
CH), 4.53 (d, J ϭ 9.6 Hz, 1 H, CH), 6.20 (br. s, 1 H, OH), 7.16 (t,
2 H, Ph), 7.21 (t, 2 H, Ph), 7.29 (t, 1 H, Ph), 7.39 (t, 3 H, Ph), 8.00
(d, J ϭ 7.6 Hz, 2 H, Ph) ppm. 13C NMR (100.6 MHz, CDCl3,
DEPT): δ ϭ 16.8 (CH3), 17.3 (2 ϫ CH3), 47.5 (CHCH3), 48.0
(OCH3), 48.4 (OCH3), 65.9 (CH2OH), 69.8 (CH), 76.2 (CH), 78.3
(CquatOH), 98.8 (acetal C), 99.1 (acetal C), 126.6 (CH, Ph), 127.1
(CH, Ph), 127.6 (CH, Ph), 127.8 (CH, Ph), 128.9 (CH, Ph), 143.5
(Cquat, Ph), 145.2 (Cquat, Ph), 171.7 (CONH) ppm. IR (CHCl3):
ν˜ ϭ 3690, 3409, 3061, 3010, 2950, 2837, 1647, 1602, 1534, 1493,
(2R,3R,5R,6R)-N-[(S)-2-Hydroxyl-1-phenylethyl]-3-(hydroxy-
diphenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-
oxamide (5a): Prepared from (S)-(ϩ)-2-amino-2-phenylethanol
(0.200 g, 1.41 mmol) and acid 4 (0.569 g, 1.41 mmol) as described
under the general procedure for amidation. It may be purified by
chromatography on silica gel (EtOAc/hexane, 7.4:2.6) and recrys-
tallized from EtOAc/hexane to give white crystals. M.p. 166 °C.
1450, 1378, 1214, 1143, 1131, 1043, 913, 774, 744, 702, 665 cmϪ1
.
1
[α]2D1 ϭ ϩ63.9 (c ϭ 0.26, CHCl3). H NMR (400.1 MHz, CHCl3):
General Procedure for Oxazoline Synthesis: The oxazolines 6aϪc
were prepared from the corresponding amides 5aϪc as follows: the
amide (1.00 mmol) was dissolved in CH2Cl2 (3.0 mL). Dry triethyl-
amine (4.99 mmol) and p-toluenesulfonyl chloride (1.06 mmol)
were added, and the mixture was refluxed under argon for 17 h.
After cooling to room temp. water (1.00 mmol) was added, and the
mixture was refluxed for 40 min. It was then cooled and extracted
four times with water. The organic layer was dried through anhy-
drous sodium sulfate, and the product was obtained as a solid after
evaporation of the solvent.
δ ϭ 1.06 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 2.60 (s, 3 H, OCH3),
3.12 (s, 3 H, OCH3), 3.80 (dd, Jvic ϭ 5.6, Jgem ϭ 11.2 Hz,
CHaCHb), 3.86 (dd, Jvic ϭ 4.0, Jgem ϭ 11.2 Hz, 1 H, CHaCHb),
4.10 (d, J ϭ 9.6 Hz, 1 H, dioxane CH), 4.51 (d, J 10 Hz, 1 H,
dioxane CH), 4.98 (m, 1 H, CHN), 7.06Ϫ7.32 (m, 14 H, Ph-H),
7.64 (d, J 8 Hz, 1 H, CONH), 7.92 (d, J ϭ 7.2 Hz, 2 H, Ph-H)
ppm. 13C NMR (100.6 MHz, CDCl3; DEPT): δ ϭ 17.3 (2 ϫ CH3),
48.0 (OCH3), 48.3 (OCH3), 55.2 (CH or NHCH), 65.8 (CH2), 69.9
(CH or NHCH), 76.1 (CH or NHCH), 78.3 (Ph2COH), 98.9 (acetal
C), 99.1 (acetal C), 126.5 (CH, Ph), 126.6 (CH, Ph), 127.1 (CH,
Ph), 127.5 (CH, Ph), 127.8 (CH, Ph), 128.9 (CH, Ph), 138.4 (Cquat
Ph), 143.4 (Cquat, Ph), 145.1 (Cquat, Ph), 171.8 (CONH) ppm. IR
(CHCl3): ν˜ ϭ 3666, 3597, 3408, 3301, 3065, 3010, 2950, 2837, 1650,
,
{(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-[(S)-4-phenyl-4,5-
dihydrooxazol-2-yl]-1,4-dioxan-2-yl}diphenylmethanol (6a): White
solid (76% based on the amide); purification by chromatography
Eur. J. Org. Chem. 2004, 1820Ϫ1829
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1825

´
M. T. Barros, C. D. Maycock, A. M. Faısca Phillips
FULL PAPER
on silica gel (CH2Cl2/EtOAc, 8:2). M.p. 79Ϫ80 °C (sublimes).
[α]3D2 ϭ Ϫ99.0 (c ϭ 2.00, CHCl3). The assignments of the NMR
ν˜ ϭ 3556, 3061, 3009, 2970, 2953, 2905, 2837, 1676, 1600, 1492,
1473, 1450, 1377, 1143, 1129, 1036, 986, 946. C25H31NO6 (441.52):
signals were made by HMBC. 1H NMR (400.1 MHz, CDCl3): δ ϭ calcd. C 68.01, H 7.08, N 3.17; found C 68.06, H 7.18, N 3.16.
1.07 (s, 3 H, CH3), 1.26 (s, 3 H, CH3), 3.00 (s, 3 H, OCH3), 3.22
3-Methyl (2-Methyloxetan-2-yl)methyl (2R,3R,5R,6R)-5,6-Dimeth-
(s, 3 H, OCH3), 3.85 (t, J ϭ 8.3 Hz, 1 H, OCHaHb), 4.27 (t, J ϭ
oxy-5,6-dimethyl-1,4-dioxane-2,3-dicarboxylate (8): Half-ester
3
10.3 Hz, 1 H, OCHaHb), 4.60 (t, J 9 Hz, 1 H, CHN), 4.80 (AB
system, J ഠ 0 Hz, 2 H, 2 ϫ dioxane CH), 6.95 (d, J ϭ 7.0 Hz, 2
H, Ph-H), 7.07 (t, J ϭ 7.2 Hz, 1 H, Ph-H), 7.17 (m, 6 H, Ph-H),
7.22 (t, J ϭ 7.4 Hz, 2 H, Ph-H), 7.46 (d, J ϭ 7.7 Hz, 2 H Hz, Ph-
H), 7.70 (d, J ϭ 7.7 Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz,
CDCl3, DEPT): δ ϭ 17.2 (CH3), 17.4 (CH3), 48.3 (OCH3), 48.8
(OCH3), 65.6 (CH), 68.3 (NCHPh), 73.3 (CH), 74.4 (CH2), 78.0
(CPh2OH), 98.7 (acetal C), 99.3 (acetal C), 126.5 (CH, Ph), 126.7
(CH, Ph), 126.8 (2 ϫ CH, Ph), 127.1 (CH, Ph), 127.3 (CH, Ph),
127.5 (CH, Ph), 127.7 (CH, Ph), 128.5 (CH, Ph), 141.0 (Cquat, Ph),
143.3 (Cquat, Ph), 144.6 (Cquat, Ph), 165.4 (OCN) ppm. IR (CHCl3):
ν˜ ϭ 3676, 3559, 3089, 3066, 3034, 3026, 3010, 2964, 2951, 2907,
2837, 1753, 1673, 1600, 1494, 1471, 1450, 1377, 1262, 1217, 1176,
1165, 1217, 1176, 1165, 1143, 1129, 1118, 1035, 987, 786, 767, 749,
737, 701, 670, 664 cmϪ1. C30H33NO6 (503.60): calcd. C 71.55, H
6.61, N 2.78; found C 71.27, H 6.64, N 2.73.
(0.664 g, 2.39 mmol), 3-hydroxymethyl-3-methyloxetane (0.526 g,
5.15 mmol) and 4-dimethylaminopyridine (0.032 g, 0.262 mmol)
were dissolved in CH2Cl2 (4.6 mL), and the solution was cooled to
0 °C. 1,3-Dicyclohexylcarbodiimide (0.592 g, 2.87 mmol) dissolved
in CH2Cl2 (2.3 mL) was added dropwise. The urea started to pre-
cipitate within a few minutes. The solution was then stirred at 0 °C
under argon for 4 h. The precipitated urea was filtered off with the
aid of CH2Cl2. The solvent was removed using a rotary evaporator,
the solid residue was redissolved in CH2Cl2 and filtered. The solu-
tion was then washed successively with water, HCl (0.2 ) and satu-
rated sodium hydrogencarbonate solution. The solvent was re-
moved using a rotary evaporator. The crude product was purified
by flash chromatography on silica gel pre-treated with 1% Et3N in
hexane (hexane/EtOAc, 1:1) to give a viscous liquid (0.593 g, 77%).
[α]2D7 ϭ Ϫ111.1 (c ϭ 2.01, CHCl3). 1H NMR (400.1 MHz, CDCl3):
δ ϭ 1.34 (s, 3 H, CH3), 1.35 (s, 6 H, 2 ϫ CH3), 3.33 (s, 6 H, 2 ϫ
OCH3), 3.77 (s, 3 H, CO2CH3), 4.25 (virtual q, J ϭ 8 Hz, 2 H,
CH2OCO), 4.37 (d, J ϭ 6 Hz, 2 H, CH2O), 4.52 (d, J ϭ 6 Hz, 2
H, CH2O), 4.55 (s, 1 H, CH), 4.56 (s, 1 H, CH) ppm. 13C NMR
(100.6 MHz, CDCl3, DEPT): δ ϭ 17.1 (CH3, 2 ϫ CH3), 20.9
(CH3), 38.9 (Cquat, CϪCH3), 48.1 (CH3, 2 ϫ OMe), 52.3 (CH3, 2
ϫ CO2Me), 68.1 (CH), 68.2 (CH), 69.2 (CH2, CH2OCO), 79.0
(CH2, 2 ϫ CH2O), 98.9 (Cquat, 2 ϫ acetal C), 167.6 (Cquat, CO2),
168.0 (Cquat, CO2) ppm. IR (CHCl3): ν˜ ϭ 3010, 2956, 2879, 2838,
1749, 1460, 1440, 1380, 1289, 1230, 1178, 1144, 1113, 1039, 984,
890, 755, 664. C16H26O9 (362.38): calcd. C 53.03, H 7.23; found C
53.28, H 7.17.
{(3R,3R,5R,6R)-3-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-5,6-
dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl}diphenylmethanol
White solid (79% based on acid 4); purification by chromatography
on silica gel (CH2Cl2/EtOAc, 8.5:1.5). M.p. 58Ϫ59 °C. [α]2D5
(6b):
ϭ
Ϫ84.7 (c ϭ 2.02, CHCl3). 1H NMR (400.1 MHz, CDCl3): δ ϭ 0.77
(d, J ϭ 6.8 Hz, 3 H, CH3 of iPr), 0.84 (d, J ϭ 7.2 Hz, 3 H, CH3
of iPr), 1.10 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 1.58 [m, 1 H,
CH(CH3)2], 2.96 (s, 3 H, OCH3), 3.25 (s, 3 H, OCH3), 3.61 (m, 1
H, CHN), 3.83 (t, J ϭ 8.0 Hz, 1 H, CHaHbO), 4.07 (dd, J ϭ 8.4
Hz, 1 H, CHaHbO), 4.67 (AB system, J ഠ 0 Hz, 2 H, 2 ϫ dioxane
CH), 7.13 (t, J ϭ 7.2 Hz, 1 H, Ph-H), 7.23 (m, 3 H, Ph-H), 7.34
(t, J ϭ 7.2 Hz, 2 H, Ph-H), 7.48 (d, J ϭ 8.4 Hz, 2 H, Ph-H), 7.86
(d, J ϭ 7.2 Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3,
DEPT): δ ϭ 17.1 (CH3), 17.3 (CH3), 18.0 (CH3 of iPr), 18.4 (CH3
of iPr), 32.1 (CH of iPr), 48.2 (OCH3), 48.6 (OCH3), 65.7 (dioxane
CH), 70.3 (CH2), 70.8 (CHN), 74.1 (dioxane CH), 77.9 (CPh2OH),
98.7 (acetal C), 99.2 (acetal C), 126.6 (CH, Ph), 126.8 (CH, Ph),
127.2 (CH, Ph), 127.4 (CH, Ph), 127.6 (CH, Ph), 144.1 (Cquat, Ph),
164.7 (OCN) ppm. IR (CHCl3): ν˜ ϭ 3558, 3090, 3062, 3009, 2964,
2908, 2875, 2837, 1676, 1600, 1492, 1464, 1449, 1375, 1212, 1202,
1142, 1129, 1120, 1035, 987, 946, 911, 892, 881 cmϪ1. C27H35NO6
(469.56): calcd. C 69.06, H 7.51, N 2.98; found C 69.12, H 7.51,
N 2.95.
Methyl
(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-
2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxane-2-carboxylate (9): A
suspension of the oxetanyl ester 8 (3.50 g, 9.61 mmol) in dry
CH2Cl2 (12.4 mL) was stirred at room temp. under argon. Boron
trifluorideϪetherate (0.307 mL, 2.48 mmol) was added dropwise.
The resulting solution changed from colourless to yellow brown in
less than 10 min. One hour later Et3N (1.4 mL) was added, the
solution was stirred for 5Ϫ10 min and diethyl ether was added to
precipitate the boron trifluorideϪtriethylamine complex. After stir-
ring for about 10 min, the precipitate was filtered off and the sol-
vent was removed using a rotary evaporator. The product was puri-
fied by column chromatography on silica gel pre-treated with 1%
Et3N in hexane[28] (EtOAc) to give a white solid (2.87 g, 82%). M.p.
{(2R,3R,5R,6R)-5,6-Dimethoxy-3-[(S)-4-methyl-4,5-dihydrooxazol-
2-yl]-5,6-dimethyl-1,4-dioxan-2-yl}diphenylmethanol (6c): White
solid (65% based on acid 4); purification by chromatography on
1
78 °C. [α]3D1 ϭ Ϫ131.9 (c ϭ 0.81, CHCl3). H NMR (400.1 MHz,
CDCl3): δ ϭ 0.79 (s, 3 H, CH3), 1.32 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3), 3.29 (s, 3 H, OCH3), 3.31 (s, 3 H, OCH3), 3.73 (s, 3 H,
CO2CH3), 3.89 (s, 6 H, 3 ϫ CH2), 4.06 (d, J ϭ 10 Hz, 1 H, CH),
4.44 (d, J ϭ 10 Hz, 1 H, CH) ppm. 13C NMR (100.6 MHz, CDCl3):
δ ϭ 14.3 (CH3), 17.3 (CH3), 17.5 (CH3), 30.5 (Cquat-CH3), 48.1 (2
ϫ OCH3), 53.2 (CO2CH3), 69.5 (CH), 69.9 (CH), 72.4 (3 ϫ CH2O),
98.5 (acetal C), 99.1 (acetal C), 106.5 (orthoester C), 169.0 (CO2)
ppm. IR (CHCl3): ν˜ ϭ 3009, 2952, 2885, 2837, 1746, 1471, 1460,
1439, 1404, 1379, 1353, 1289, 1199, 1141, 1119, 1076, 1043, 993,
892, 854, 821, 767, 739, 664, 562, 540, 440 cmϪ1. C16H26O9
(362.19): calcd. C 53.06, H 7.18; found C 52.84, H 7.24.
silica gel (EtOAc/CH2Cl2, 1:1). M.p. 124 °C (sublimes). [α]2D7
ϭ
Ϫ88.9 (c ϭ 2.01, CHCl3). 1H NMR (CDCl3): δ ϭ 1.08 (d, J ϭ 6.6
Hz, 3 H, oxazoline CH3), 1.13 (s, 3 H, CH3), 1.30 (s, 3 H, CH3),
3.08 (s, 3 H, OCH3), 3.26 (s, 3 H, OCH3), 3.59 (t, J ϭ 7.9 Hz, 1
H, CHaHb), 3.69 (m, 1 H, CHCH3), 4.06 (t, J ϭ 8.7 Hz, 1 H,
CHaHb), 4.67 (d, J ϭ 9.7 Hz, 1 H, dioxane CH), 4.82 (d, J ϭ 9.7
Hz, 1 H, dioxane CH), 5.69 (br. s, 1 H, OH), 7.12 (t, J ϭ 7.2 Hz,
1 H, Ph-H), 7.23 (q, J ϭ 7.7 Hz, 1 H, CH, Ph-H), 7.33 (t, J ϭ 7.4
Hz, 2 H, Ph-H), 7.51 (d, J ϭ 7.7 Hz, 2 H, Ph-H), 7.77 (d, J ϭ 7.7
Hz, 2 H, Ph-H) ppm. 13C NMR (CDCl3, DEPT): δ ϭ 17.2 (CH3),
17.4 (CH3), 20.7 (oxazoline CH3), 48.2 (OCH3), 48.8 (OCH3), 60.5 [(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-2,6,7-
(CHN), 65.5 (dioxane CH), 73.3 (dioxane CH), 73.6 (CH2), 78.0 trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxan-2-yl]methanol (10): A two-
(Cquat-OH), 98.6 (acetal C), 99.2 (acetal C), 126.7 (CH, Ph), 126.8
necked round-bottom flask was flame dried and charged with Li-
(CH, Ph), 127.1 (CH, Ph), 127.3 (CH, Ph), 127.6 (CH, Ph), 143.4 AlH4 (51.0 mg, 1.34 mmol) and dry THF (0.48 mL). Protected
(Cquat, Ph), 144.7 (Cquat, Ph), 163.8 (OϪCϭN) ppm. IR (CHCl3): half-ester 9 (0.396 g, 1.09 mmol) dissolved in dry THF (2.6 mL)
1826
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1820Ϫ1829

Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(ϩ)-Tartaric Acid
FULL PAPER
was added dropwise at room temperature. The resulting suspension in an ice bath, and stirred under argon. Aldehyde 11 (0.214 g,
was refluxed for 3 h or until a TLC plate showed that the starting 0.521 mmol) dissolved in dry THF (1.75 mL), was added dropwise
material had all been consumed. The mixture was then warmed to
room temperature and an aqueous solution of KOH (10%) was
over a period of 40 min. The solution was then placed in a oil bath
and heated to reflux. After 1 h 20 it was cooled to room tempera-
added dropwise. The flask was stirred vigorously after each ad- ture, ammonium chloride solution (5%) was added, and the prod-
dition until the mixture turned white. Refluxing was continued for
another hour. The solution was filtered and the product extracted
a few times with boiling THF. The pooled extracts were dried with
anhydrous sodium sulfate, and the solvent removed using a rotary
evaporator. The solid obtained was purified by column chromatog-
raphy on silica gel pre-treated with 1% Et3N in hexane[28] (EtOAc/
uct extracted three times with diethyl ether. The combined extracts
were dried with anhydrous sodium sulfate, and the solvent removed
using a rotary evaporator. The product was purified by column
chromatography on silica gel pre-treated with 1% Et3N in hexane
EtOAc/hexane, 1:1) to give a white solid (0.153 g, 72%). M.p.
161Ϫ162 °C. [α]2D7 ϭ Ϫ141.0 (c ϭ 0.58, CHCl3). The assignments
1
hexane, 8:2) to give the product as a white hygroscopic solid of the NMR signals were made by COSY. H NMR (400.1 MHz,
(0.250 g, 68%). [α]2D2 ϭ Ϫ112.2 (c ϭ 2.00, CHCl3). 1H NMR CDCl3): δ ϭ 0.85 (s, 3 H, orthoester CH3), 1.14 (s, 3 H, CH3), 1.30
(400.1 MHz, CDCl3): δ ϭ 0.82 (s, 3 H, CH3 of OBO ester), 1.30
(s, 3 H, CH3), 1.36 (s, 3 H, CH3), 2.27 (br. s, OH), 3.25 (s, 3 H,
(s, 3 H, CH3), 2.60 (s, 3 H, OCH3), 2.94 (d, J ϭ 8 Hz, 1 H, CHϪC,
orthoester), 3.28 (s, 3 H, OCH3), 3.99 (s, 6 H, 3 ϫ orthoester CH2),
OCH3), 3.28 (s, 3 H, OCH3), 3.76 (m, 3 H, 1 CH ϩ CH2OH), 3.92 4.06 (m, 1 H, CHOH), 5.22 (d, J ϭ 8.4 Hz, 1 H, dioxane CHCPh),
(br. s, 7 H, 3 ϫ orthoester CH2 ϩ CH) ppm. 13C NMR
7.21 (t, J ϭ 7.2 Hz, 1 H, Ph), 7.30 (t, J ϭ 7.4 Hz, 2 H, Ph-H), 7.39
(100.6 MHz, CDCl3; DEPT): δ ϭ 12.9 (CH3), 17.4 (2 ϫ CH3), 30.4 (d, J ϭ 7.5 Hz, 2 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3,
(Cquat Cquat-CH3), 47.8 (OCH3), 48.0 (OCH3), 62.7 (CH2, DEPT): δ ϭ 14.4 (orthoester Me), 17.3 (CH3), 17.4 (CH3), 30.6
CH2OH), 69.0 (CH), 69.8 (CH), 72.4 (CH2, 3 ϫ CH2O of OBO (orthoester Cquat), 47.3 (OCH3), 47.9 (OCH3), 69.5 (CH), 71.4
ester), 98.6 (Cquat, acetal C), 99.1 (Cquat, acetal C), 107.1 (orthoes- (CH), 72.1 (CH), 72.5 (3 ϫ CH2), 98.9 (acetal C), 99.2 (acetal C),
ter C) ppm. IR (KBr): ν˜ ϭ 3574, 3487, 2983, 2939, 2833, 1617, 107.4 (orthoester Cquat), 126.0 (CH, Ph), 126.6 (CH, Ph), 127.6
1474, 1459, 1404, 1316, 1299, 1285, 1256, 1198, 1123, 1038, 979, (CH, Ph), 141.8 (Cquat, Ph) ppm. IR (KBr): ν˜ ϭ 3557.1, 3436.0,
940, 912, 888, 863, 752, 745, 736, 643, 660, 607 cmϪ1. C15H25O8 3083, 3057, 3031, 2991.3, 2947.5, 2882.9, 2832.7, 1495.7, 1469.0,
,
(333.36): calcd. C 54.05, H 7.56; found C 53.81, H 7.66.
1453.1, 1403.7, 1377.3, 1282.8, 1197.2, 1133.2, 1071.7, 1052.0,
1022.5, 993.0, 903.9, 887.1, 853.2, 828.3, 753.8, 738.6, 753.8, 738.8,
701.4, 571.2 cmϪ1. C21H30O8 (410.46): calcd. C 61.45, H 7.37;
found C 61.23, H 7.40.
(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-2,6,7-
trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxane-2-carbaldehyde (11): A re-
action vessel was purged with argon, flame-dried and charged with
dry CH2Cl2 (3.2 mL) and (COCl)2 (0.152 mL, 1.75 mmol). The
solution was cooled to Ϫ60 °C. Dry DMSO (0.264 mL, 3.72 mol)
dissolved in dry CH2Cl2 (0.77 mL) was added dropwise at a good
rate. The temperature was kept between Ϫ50 and Ϫ60 °C. Five
minutes later alcohol 10 (0.513 g, 1.53 mmol) dissolved in dry
CH2Cl2 (2.2 mL) was added over 10 min. The mixture was stirred
for 40 min at Ϫ50 to Ϫ60 °C, then Et3N (1.1 mL) was added drop-
wise. The mixture was stirred for 5 min at this temperature, then it
was placed in an iceϪNaCl bath and stirred for 30 min at 0 °C.
CH2Cl2 was added to the cold solution, and the mixture was
washed successively with ice-cold NH4Cl (5% solution) and a satu-
rated NaCl solution. It was filtered through anhydrous magnesium
sulfate and the solvent was evaporated to give a solid (0.374 g,
87%), which was used in the next reaction without purification.
For analytical determinations the product was purified by column
chromatography on silica gel treated with 1% Et3N in hexane
(EtOAc/hexane, 8:2). M.p. 73Ϫ74 °C. [α]3D0 ϭ Ϫ117.0 (c ϭ 2.04,
(2R,3R,5R,6R)-3-(Hydroxyphenylmethyl)-5,6-dimethoxy-5,6-
dimethyl-1,4-dioxane-2-carboxylic Acid (13): Monoalcohol 12
(0.491 g, 1.20 mmol) was dissolved in THF/H2O (40:1, 6.16 mL).
The solution was cooled to 0 °C and the pH was adjusted to 1 with
HCl (2 ). The mixture was then stirred at this temperature for
40 min, by which time the OBO ester had been fully converted into
the ester as indicated by a TLC plate. The pH was then raised to
11 with LiOH solution (1 ) and the mixture was heated and re-
fluxed for 4 h 40, or until the ester could no longer be detected by
TLC. During this time the pH was checked two or three times, and
adjusted again with LiOH to pH 11 if the solution was found to
have become neutral. After cooling, the pH of the solution was
adjusted to 1 and the product was extracted four times with diethyl
ether. The combined diethyl ether extracts were filtered through
anhydrous sodium sulfate and the solvent was removed using a
rotary evaporator to give a white crystalline product (0.343 g, 88%),
which was used as it was in the next step. The product may be
recrystallized from diethyl ether/hexane to give white crystals. M.p.
142Ϫ143 °C. [α]2D2 ϭ Ϫ148.0 (c ϭ 2.01, CHCl3). 1H NMR
(400.1 MHz, CDCl3): δ ϭ 1.23 (s, 3 H, CH3), 1.34 (s, 3 H, CH3),
2.78 (s, 3 H, OCH3), 3.32 (s, 3 H, OCH3), 3.98 (dd, J ϭ 1.6, 10.0
Hz, CH), 4.66 (d, ABX system, J ϭ 10.0 Hz, 1 H, CHOH), 5.20
(AB system, 1 H, CHCOO), 7.26 (d, J ϭ 7.2 Hz, 1 H, Ph-H), 7.33
(t, J ϭ 6.4 Hz, 2 H, Ph-H), 7.40 (d, J ϭ 7.2 Hz, 2 H, Ph-H) ppm.
13C NMR (100.6 MHz, CDCl3, DEPT): δ ϭ 17.3 (2 ϫ CH3), 47.8
(OCH3), 48.6 (OCH3), 68.4 (CHOH or dioxane CH), 71.6 (CHOH
or dioxane CH), 71.8 (CHOH or dioxane CH), 98.9 (acetal C),
99.4 (acetal C), 126.1 (CH, Ph), 127.4 (CH, Ph), 128.0 (CH, Ph),
140.8 (Cquat, Ph), 171.2 (COOH) ppm. IR (CHCl3): ν˜ ϭ 3674, 3556,
3426, 3026, 3012, 2951, 2837, 1772, 1739, 1604, 1453, 1378, 1230,
1198, 1143, 1130, 1037, 907, 890, 855, 826, 781, 778, 770, 766, 760,
755, 750, 746, 742, 734, 701, 666, 634 cmϪ1. C16H22O7 (326.35):
calcd. C 58.89, H 6.80; found C 58.99, H 6.88.
1
CHCl3). H NMR (400.1 MHz, CDCl3): δ ϭ 0.81 (s, 3 H, CH3 of
OBO ester), 1.33 (s, 3 H, CH3), 1.38 (s, 3 H, CH3), 3.26 (s, 3 H,
OCH3), 3.30 (s, 3 H, OCH3), 3.91 (s, 6 H, 3 ϫ orthoester CH2),
4.01 (d, J ϭ 10 Hz, 1 H, CH), 4.32 (dd, J ϭ 3.2, 9.6 Hz, 1 H, CH),
9.53 (d, J ϭ 3.2 Hz, 1 H, CHO) ppm. 13C NMR (100.6 MHz,
CDCl3): δ ϭ 14.3 (orthoester CH3), 17.3 (CH3), 17.4 (CH3), 30.6
(orthoester C-CH3), 48.1 (2 ϫ OCH3), 69.1 (CH), 72.4 (3 ϫ ortho-
ester CH2), 72.9 (CH-CHO), 98.6 (acetal C), 99.2 (acetal C), 106.4
(orthoester C), 195.2 (CHO) ppm. IR (CHCl3): ν˜ ϭ 3010, 2960,
2949, 2885, 2837, 1735, 1472, 1459, 1403, 1460, 1403, 1378, 1353,
1241, 1139, 1122, 1072, 1049, 1024, 999, 932, 889, 875, 756, 741,
593, 563 cmϪ1. C15H24O8 (332.35): calcd. C 54.21, H 7.28; found
C 54.17, H 7.45.
[(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-(4-methyl-2,6,7-
trioxabicyclo[2.2.2]oct-1-yl)-1,4-dioxan-2-yl]phenylmethanol
(12):
Phenylmagnesium bromide (0.78 mL, 0.78 mmol of a 1  solution
(2R,3R,5R,6R)-N-[(S)-2-Hydroxy-1-phenylethyl]-3-(hydroxy-
in hexanes) was added to a round-bottom two-necked flask, cooled
phenylmethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carb-
Eur. J. Org. Chem. 2004, 1820Ϫ1829
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1827

´
M. T. Barros, C. D. Maycock, A. M. Faısca Phillips
FULL PAPER
oxamide
(14):
(S)-(ϩ)-2-Amino-2-phenylethanol
(0.064 g,
a rotary evaporator to give a white crystalline product (1.01 g,
88%), used in the next reaction without further purification. It may
0.457 mmol), acid 13 (0.149 g, 0.457 mmol) and xylene (2.1 mL)
were heated to reflux and treated as described for amides 5aϪc. be recrystallized from diethyl ether/hexane mixtures. M.p. 132 °C.
The product obtained was purified by column chromatography on
silica gel (CH2Cl2/EtOAc, 3:2) to give a white solid (0.087 g, 43%).
M.p. 153 °C. [α]2D1 ϭ Ϫ67.2 (c ϭ 1.75, CHCl3). The assignments of
the NMR signals were made by HMBC. 1H NMR (400.1 MHz,
[α]2D8 ϭ Ϫ148.7 (c ϭ 1.95, MeOH). 1H NMR (400.1 MHz, CDCl3):
δ ϭ 1.32 (s, 3 H, CH3), 1.39 (s, 3 H, CH3), 3.27 (s, 3 H, OCH3),
3.30 (s, 3 H, OCH3), 3.81Ϫ3.93 (m, 3 H, 2 ϫ H of CH2 ϩ CH),
4.44 (d, J ϭ 9.9 Hz, 6 Hz, 1 H, CH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ ϭ 1.23 (s, 3 H, CH3), 1.31 (s, 3 H, CH3), 1.67 (br. s, CDCl3): δ ϭ 17.3 (CH3), 17.4 (CH3), 48.2 (OCH3), 48.6 (OCH3),
OH), 2.49 (br. s, OH), 2.82 (s, 3 H, OCH3), 3.21 (s, 3 H, OCH3), 62.2 (CH2OH), 68.5 (CH), 68.9 (CH), 98.8 (acetal C), 99.5 (acetal
3.90 (dd, J ϭ 1.6 Hz, 1 H, 10 Hz, 1 H, dioxane CH), 3.94 (m, 2
C), 170.6 (COOH) ppm. IR (KBr): ν˜ ϭ 3401, 2996, 2959, 2841,
H, 2 ϫ H of CH2), 4.50 (d, J ϭ 10 Hz, dioxane CH), 5.13 (m, 1 2685, 1755, 1458, 1405, 1382, 1354, 1336, 1312, 1210, 1130, 1069,
H, CHN), 5.26 (br. s, CHOH), 7.23 (t, J ϭ 7.2 Hz, 2 H, Ph-H),
7.31 (m, 5 H, Ph-H), 7.38 (d, J ϭ 7.2 Hz, 1 H, CONH), 7.43 (m,
3 H, Ph-H) ppm. 13C NMR (100.6 MHz, CDCl3, DEPT): δ ϭ 17.3
(CH3), 17.4 (CH3), 47.9 (OCH3), 48.4 (OCH3), 55.5 (CH, CHPh),
66.5 (CH2), 69.3 (CH, dioxane CHCON), 72.0 (CH, CHPh(OH),
73.0 (CH, dioxane CH), 98.9 (acetal C), 99.3 (acetal C), 126.4 (2
ϫ CH, Ph), 126.6 (2 ϫ CH, Ph), 127.0 (CH), 127.8 (2 ϫ CH, Ph),
1046, 966, 946, 890, 866, 773, 739, 670, 650 cmϪ1. C10H18O7
(250.25): calcd. C 48.00, H 7.25; found C 48.20, H 7.41.
(2R,3R,5R,6R)-N-[(S)-2-Hydroxy-1-phenylethyl]-3-(hydroxy-
methyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carboxamide
(17): A two-necked round-bottom flask was charged with acid 16
(0.253 g, 1.00 mmol), (S)-(ϩ)-2-amino-2-phenylethanol (0.134 g,
0.098 mmol) and xylene (0.32 mL). The resulting suspension was
stirred and refluxed under argon for 17 h. The solvent was removed
under reduced pressure and the product was dried to give the crude
amide. The assignments of the NMR signals were made by decoup-
128.1 (CH), 129.0 (2 ϫ CH, Ph), 138.5 (Cquat, Ph), 141.1 ( Cquat
,
Ph), 170.0 (CONH) ppm. IR (CHCl3): ν˜ ϭ 3676, 3412, 3066, 3012,
2951, 2837, 1668, 1522, 1496, 1454, 1378, 1233, 1197, 1143, 1132,
1037, 948, 908, 891, 827, 782, 778, 774, 768, 764, 755, 750, 744,
738, 702 cmϪ1. C24H31NO7 (445.51): calcd. C 64.70, H 7.01, N
3.14; found C 64.47, H 6.73, N 3.04.
1
ling. H NMR (400.1 MHz, CDCl3): δ ϭ 1.31 (s, 3 H, CH3), 1.37
(s, 3 H, CH3), 2.62 (br. s, OH), 3.25 (s, 3 H, OCH3), 3.28 (s, 3 H,
OCH3), 3.71 (s, 1 H, OH), 3.71Ϫ3.81 (m, 3 H, dioxane CH ϩ
CH2), 3.89Ϫ3.93 (m, 2 H, PhCHCH2), 4.30 (d, J ϭ 9.2 Hz, 1 H,
CHCO), 5.07Ϫ5.11 (m, 1 H, CHN), 7.21Ϫ7.33 (m, 5 H, Ph-H),
7.54 (d, J ϭ 7.2 Hz, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3,
DEPT): δ ϭ 17.40 (2 ϫ CH3), 48.1 (OCH3), 48.3 (OCH3), 55.1
[(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-[(S)-4-phenyl-4,5-
dihydrooxazol-2-yl)-1,4-dioxan-2-yl]phenylmethanol (15): Amide 14
(0.263 mmol) was dissolved in CH2Cl2 (0.80 mL) and p-toluenesul-
fonyl chloride (0.051 g, 0.269 mmol) and dry triethylamine
(0.18 mL, 5.00 mmol) were added. The mixture was refluxed for
17 h and treated as described for oxazolines 6a؊c. The product
was purified by chromatography on silica gel (EtOAc/hexane, 7:3)
to give a white solid (0.071 g, 63%). M.p. 47Ϫ48 °C. [α]2D2 ϭ Ϫ129.0
(c ϭ 0.77, CHCl3). The assignments of the NMR signals were made
by COSY and HMBC. 1H NMR (400.1 MHz, CDCl3): δ ϭ 1.32
(s, 3 H, CH3), 1.35 (s, 3 H, CH3), 3.07 (s, 3 H, OCH3), 3.31 (s, 3
H, OCH3), 4.05 (d, J ϭ 8 Hz, 1 H, OH, exchanges with D2O), 4.07
(t, J ϭ 8.8 Hz, 1 H, CHaHb), 4.30 (dd, J ϭ 3.2, 9.6 Hz, 1 H,
CHCOH), 4.44 (dd, J ϭ 8.4 Hz, 10 Hz, 1 H, CHaHb), 4.61 (d, J ϭ
10 Hz, 1 H, CH), 4.92 (dd, J ϭ 2.8, 7.6 Hz, 1 H, CHPhOH), 5.03
(app. t, J ϭ 10 Hz, 1 H, NCHPh), 7.20 (d, J ϭ 6.8 Hz, 2 H, Ph-
H), 7.33 (m, 6 H, Ph-H), 7.42 (d, J ϭ 7.2 Hz, 2 H, Ph-H) ppm.
13C NMR (100.6 MHz, CDCl3): δ ϭ 17.3 (CH3), 17.5 (CH3), 48.01
(OCH3), 48.3 (OCH3), 65.3 (dioxane CH), 69.2 (CHPhN), 72.5
(CHCPh), 72.6 (CHPhOH), 74.6 (CH2), 99.08 (acetal C), 99.09
(acetal C), 126.7 (2 ϫ CH, Ph), 127.4 (CH, Ph), 127.8 (CH, Ph),
(CH), 63.0 (CH2), 65.5 (CH2), 70.1 (CH), 70.9 (CH), 98.7 (Cquat
,
acetal C), 99.3 (Cquat, acetal C), 126.5 (2 ϫ CH, Ph), 127.7 (CH,
Ph), 128.7 (2 ϫ CH, Ph), 138.8 (Cquat, Ph), 169.8 (CONH) ppm.
[(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-[(S)-4-phenyl-4,5-
dihydrooxazol-2-yl]-1,4-dioxan-2-yl]methanol (18): Acid 16 (0.253 g,
1.00 mmol) and (S)-(ϩ)-2-amino-2-phenylethanol (0.144 g,
1.02 mmol) were mixed in decalin (2.98 mL) and refluxed for 94 h
with a DeanϪStark trap, under argon, using a sand bath kept at
210 °C. After this time the solvent was removed under reduced
pressure to give a crude mixture consisting of oxazoline, starting
material and one unidentified product, with the oxazoline being
the major component. Refluxing the mixture longer did not im-
prove the outcome. The solid was stirred in EtOH with charcoal
and filtered through Celite. After column chromatography on silica
gel (CHCl3/EtOAc, 1:5) the product was obtained as a pale-yellow
solid (0.046 g, 15%). [α]1D9 ϭ Ϫ107.4 (c ϭ 0.51, CHCl3). The assign-
ments of the NMR signals were made by HMBC. 1H NMR
(400.1 MHz, CDCl3): δ ؍ 1.33 (s, 3 H, Me), 1.39 (s, 3 H, Me), 3.30
(s, 3 H, OMe), 3.35 (s, 3 H, OMe), 3.75 (dd, J ϭ 4.4, 12.4 Hz, 1
H, CHaHbOH), 3.82 (dd, J ϭ 4.8, 12.4 Hz, 1 H, CHaHbOH), 4.16
(m, oxazoline H of CH2 ϩ dioxane CH), 4.59 (d, J ϭ 10 Hz, diox-
ane CH), 4.70 (dd, J ϭ 8.8 Hz, 10 Hz, 1 H, oxazoline H of CH2),
5.24 (t, J ϭ 10 Hz, 1 H, oxazoline NCH), 7.21 (d, J ϭ 6.8 Hz, 1 H,
Ar-H), 7.37Ϫ7.27 (m, Ar-H) ppm. 13C NMR (100.6 MHz, CDCl3,
DEPT): δ ϭ 17.4 (CH3), 17.5 (CH3), 48.1 (CH3), 48.4 (CH3), 62.9
(CH2OH), 66.0 (CHN), 69.3 (dioxane CH), 69.8 (dioxane CH),
74.8 (oxazoline CH2), 98.9 (acetal C), 99.1 (acetal C), 126.5 (2 ϫ
CH, Ph), 127.8 (CH, Ph), 128.8 (2 ϫ CH, Ph), 141.3 (Cquat, Ph),
165.1 (OϪCϭN) ppm. IR (CHCl3): ν˜ ϭ 3671, 3587, 3406, 3010,
2964, 2949, 2837, 1667, 1604, 1495, 1455, 1378, 1232, 1142, 1132,
1120, 1036, 924, 890, 869, 700, 664 cmϪ1. C18H25NO6 (351.40):
calcd. C 61.52, H 7.17, N 3.99; found C 61.51, H 6.97, N 4.18.
127.9 (CH, Ph), 128.7 (CH, Ph), 140.8 (Cquat, Ph), 141.4 (Cquat
,
Ph), 164.6 (OϪCϭN) ppm. IR (KBr): ν˜ ϭ 3542, 3431, 3087, 3062,
3029, 2993, 2950, 2834, 1668, 1495, 1454, 1377, 1199, 1183, 1142,
1128, 1037, 922, 857, 759, 746, 701 cmϪ1. C24H29NO6 (427.50):
calcd. C 67.43, H 6.84, N 3.28; found C 67.16, H 6.86, N 3.24.
(2R,3R,5R,6R)-3-(Hydroxymethyl)-5,6-dimethoxy-5,6-dimethyl-1,4-
dioxane-2-carboxylic Acid (16): Monoalcohol 10 (1.519 g,
4.54 mmol) was dissolved in THF/H2O (40:1, 23.6 mL). The solu-
tion was cooled to 0 °C and the pH was adjusted to 1 with HCl (2
). The mixture was then stirred at this temperature for 30 min, by
which time the OBO ester had been fully converted into the acid
as indicated by a TLC plate. The pH was then raised to 11 with a
solution of LiOH (1 ) and the mixture was heated and refluxed
for 2 h, or until the ester could no longer be detected by TLC. After
cooling, the pH of the solution was adjusted to 1 and the product
was extracted four times with diethyl ether. The sample was dried
with anhydrous sodium sulfate and the solvent was removed using
General Procedure for the Catalyzed Enantioselective Addition of
Diethylzinc to Benzaldehyde: A Schlenk flask was flame-dried in
1828
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1820Ϫ1829

Novel Cyclic 1,2-Diacetals Derived from (2R,3R)-(ϩ)-Tartaric Acid
FULL PAPER
C. Bolm, K. Mun˜iz-Fernandez, A. Seger, G. Raabe, K.
[13] [13a]
´
vacuo and filled with argon when cool. The catalyst was added (10
mol %) and then dry distilled toluene (0.96 mL). The solution was
degassed three times by freezeϪpumpϪthaw, it was returned to an
argon line and the flask was refilled with argon. The solution was
cooled to 0 °C and a solution of diethylzinc in hexane (2.16 mL,
1.0 , 2.2 equiv.) was added dropwise. The mixture was stirred for
10 min and freshly distilled benzaldehyde (0.100 mL, 0.984 mmol)
was added dropwise. The flask was then closed, placed in a covered
bath at the temperature required, and stirred for the period indi-
cated in each experiment. Afterwards 1  HCl solution was added
dropwise, the product was extracted with CH2Cl2, dried with anhy-
drous MgSO4 and the solvent removed using a rotary evaporator.
Günther, J. Org. Chem. 1998, 63, 7860Ϫ7867. [13b] W.-P. Deng,
X.-L. Hou, L.-X. Dai, Tetrahedron: Asymmetry 1999, 10,
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Nakatsuji, I. Ikeda, Synlett 2000, 10, 1512Ϫ1514.
D. Seebach, A. Pichota, A. K. Beck, A. B. Pinkerton, T. Litz,
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M. T. Barros, A. J. Burke, C. D. Maycock, Tetrahedron Lett.
1999, 40, 1583Ϫ1586.
[14]
[15]
[16]
For a related method used in the synthesis of 2,3-O-isopro-
pylidene see: J. A. Musich, H. Rapoport, J. Am. Chem. Soc.
1978, 100, 4865Ϫ4872.
D. A. Seebach, E. Devaquet, A. Ernst, M. Hayakawa, F. N.
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[17]
[18]
Determination of Enantiomeric Excesses: HPLC analysis on a chiral
column was used under the following conditions: column, Daicel
Co. CHIRALCEL OB-H; eluent, hexane/2-propanol 85.5:1.5;
flow-rate, 0.9 mL/min; detection, 254 nm. Under these conditions
racemic 1-phenyl-1-propanol exhibited baseline separation of
peaks: (S) isomer tR 13 min, (R) isomer tR 16 min.[29] Peaks were
assigned on the basis of the known order of elution of the enanti-
omers on this column. For quantitative determinations, racemic 1-
phenylethanol was used as internal standard.
See, for instance, ref.[11]
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eses of oxazolines, see: C. Giordano, S. Caviocchioli, S. Levi,
M. Villa, Tetrahedron Lett. 1988, 29, 5561Ϫ5564. [19b] M. Peer,
J. C. De Jong, M. Kiefer, T. Langer, H. Rieck, H. Schell, P.
Sennhenn, J. Sprinz, H. Steinhagen, B. Wiese, G. Helmchen,
Tetrahedron 1996, 52, 7547Ϫ7583.
[20] [20a]
E. J. Corey, N. Raju, Tetrahedron Lett. 1983, 24,
[20b]
5571Ϫ5574.
H. Kunz, H. Walman, in Comprehensive Or-
ganic Synthesis (Eds.: B. M. Trost, I. Fleming, L. A. Paquette),
Pergamon Press, 1991, vol. III, p. 673.
See, for example: D. Haag, H.-D. Scharf, J. Org. Chem. 1996,
[21]
[22]
[23]
Acknowledgments
61, 6127Ϫ6135.
E. J. Leopold, Org. Synth. Coll. Vol. VII, John Wiley & Sons,
New York, 1990, p. 258Ϫ263.
An attempt was made to determine the configuration of the
newly created chiral centre by MosherЈs method, but this was
unsuccessful. The determination will be attempted at a later
stage when more material is available.
ˆ
The financial support given by Fundac¸a˜o para a Ciencia e Tecnolo-
gia to A. M. F. P. is gratefully acknowledged.
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53Ϫ80.
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2001, 40, 92Ϫ138.
M. T. Barros, A. J. Burke, C. D. Maycock, C. R. Santos, Tenth
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[24b]
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[4]
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[27]
2055Ϫ2064.
The result at 0 °C was obtained after a reaction time of 42 h.
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[28]
The OBO esters prepared in this study were very sensitive to
acid. For example, treated silica gel was necessary in all cases
and samples for NMR spectroscopy were prepared routinely
just prior to recording spectra, because it was found that the
OBO ester rearranged easily to an ester if left standing in
CDCl3 solution for prolonged periods. Similar findings have
been reported by others, i.e.: M. A. Blaskovich, G. A. Lajoie,
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Received November 28, 2003
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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