Stereoselective synthesis of syn-α-methyl-β-hydroxy esters

Article abstract of DOI:10.1016/S0957-4166(00)00274-3

Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2-syn/1,3-syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O-formylated syn-α-me

Full text of DOI:10.1016/S0957-4166(00)00274-3

Tetrahedron: Asymmetry 11 (2000) 3211±3220
Stereoselective synthesis of syn-a-methyl-b-hydroxy esters
Miguel Carda,a,* Juan Murga,a Eva Falomir,a Florenci Gonzaleza
and J. Alberto Marcob,*
a
Â
Â
Â
Â
Departamento de Quimica Inorganica y Organica, Universidad Jaume I, Castellon, E-12080 Castellon, Spain
b
Â
Departamento de Quimica Organica, Universidad de Valencia, E-46100 Burjassot, Valencia, Spain
Received 29 June 2000; accepted 12 July 2000
Abstract
Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a
highly stereoselective fashion to yield 1,2-syn/1,3-syn stereoisomers. Oxidative cleavage of the aldol adducts
yields enantiopure O-formylated syn-a-methyl-b-hydroxy esters, easily cleaved to the corresponding
hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate
equivalent. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Among the biologically active, naturally occurring molecules known to date, macrolide and
polyether antibiotics have been the object of particular interest.1 For the stereoselective synthesis
of such molecules, a number of strategies have been developed, the aldol reaction being particularly
worthy of mention.2 In connection with our current interest in the development of erythrulose as
a C4 chiral building block,3 we have recently described the formation of boron enolates of protected
erythrulose derivatives and their subsequent addition to aldehydes.4 We have subsequently shown
that oxidative cleavage of these aldols yields selectively protected a,b-dihydroxy esters.5 In the
present communication, we show that the structurally related ethyl ketone (R)- or (S)-1 (Scheme 1)
behaves in the same way and provides aldols of general structure 2, precursors in turn of
a-methyl-b-hydroxy esters 3 via oxidative cleavage of bond a. Ketone 1 is thus a chiral equivalent
of the d2 synthon propionic acid enolate, a key chiral building block in the synthesis of natural
polypropionates.1 Furthermore, alternative functional manipulations of aldols 2 (e.g. cleavage of
bond b or no C±C bond cleavage) should lead to polyhydroxy derivatives such as 4 or 5, which
constitute structural units present in natural macrolides and polyethers. Ketone 1 may thus be an
equivalent of the hitherto undescribed d3 and d4 chirons depicted below.
* Corresponding authors. Fax: +34-964-728214; e-mails: mcarda@qio.uji.es, alberto.marco@uv.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00274-3

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M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
Scheme 1.
2. Results and discussion
Ethyl ketone (S)-1 was prepared as shown in Scheme 2 from the corresponding l-erythrulose
acetal.6,7 Similarly to that observed in erythrulose acetals, (S)-1 was amenable to transformation
into boron enolates by means of Brown's dicyclohexylboron chloride (Chx2BCl)/tertiary amine
system.8a In contrast to the ketones above, however, (S)-1 gave boron enolates also with
Mukaiyama's nBu2BOTf/tertiary amine system.8b Aldol reactions promoted by either of these
reagents led to the same syn aldol adducts 6 in good chemical yields as essentially single
1
diastereoisomers (diastereomeric ratio, d.r. >95:5, as determined by H and 13C NMR). The
sterically hindered pivaldehyde was the only aldehyde tested which did not react under the
conditions described.9
Scheme 2. Reagents and conditions: (a) LiAlH4, THF; (b) NaIO4/MeOH; (c) EtMgBr; (d) PCC/CH2Cl2, 45% overall;
(e) L2BX, Et3N, Et2O, ^78ꢀC, then RCHO, ^78ꢀC, 77±85%, d.r. >95:5 (L2BX=nBu2BOTf or Chx2BCl)

M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
3213
The 2,4-syn/4,5-syn relative as well as the absolute con®guration of aldol adducts 6 was
assumed on the basis of the observations on structurally related erythrulose derivatives. The
relatively small values of the coupling constants J4,5=2.9±4.5 Hz supported this conclusion,10
later con®rmed as described below. We show here that ketone (S)-1 behaves as an e€ective chiral
equivalent of the d2 propionic acid enolate synthon.
Suitable conditions for acetonide cleavage were adapted from our recent report.5 Thus,
compounds 6 were treated with periodic acid hydrate in ethyl acetate11 under carefully controlled
conditions (see Experimental). The acids formed were isolated as their methyl esters and assigned
structure 7 (Scheme 3) on the basis of spectroscopic ®ndings and the subsequent synthetic
manipulations. Hydrolysis of the formyl group in 7 took place under mild basic conditions to
yield the a-methyl-b-hydroxy esters 8. A particular case was the formylated ester 7a which, due to
its volatility, was isolated in low yields. For this reason, aldol 6a was silylated with t-butyldi-
methylsilyl tri¯ate (TBSOTf) to 9, which was then oxidatively cleaved to 10. Desilylation of 10
a€orded hydroxy ester 8a. This compound, as well as its enantiomer and 8c, has already been
described.10 Its physical and spectral properties are completely coincident with those found by us,
therefore con®rming our stereochemical assignment. Esters 8 should be amenable to conversion,
via nucleophilic substitution of the hydroxyl group or other synthetic processes, into compounds
of pharmacological interest such as, for example, b-amino acids.12 Furthermore, since ketone (R)-1
is also easily available through the corresponding d-glyceraldehyde derivative,13 the preparation
of compounds of the antipodal series is also feasible. E€orts in these directions are presently
underway in our group.
The stereochemical outcome of the aldol reactions with ketone 1 is worth mentioning. Whether
the reaction was promoted by Chx2BCl or by nBu2BOTf, the same syn aldols 6 were obtained.
This strongly suggests that Z enolates are key intermediates in both types of processes, which is
expected for the latter reagent but not for the former.14 Ethyl ketone 1 therefore shares the same
stereochemical preferences displayed by erythrulose acetals, and perhaps for the same
reasons.4,15 Computational calculations by our group16,17 support the idea that aldol adducts are
formed through the Z boron enolate participating in a chair-like transition state of the Zimmerman±
Traxler type.18 The formation of a Z boron enolate with Chx2BCl, rather than the expected E
enolate, thus remains to be explained and is the object of current theoretical and experimental
work in our group.17
Scheme 3. Reagents and conditions: (a) H5IO6, EtOAc, then CH2N2, 84±90%; (b) KHCO3/MeOH, 82±85%;
(c) TBSOTf, 2,6-lutidine, 79%; (d) HF, aq. MeCN, 80%

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M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
3. Experimental
3.1. General methods
NMR spectra were measured in CDCl3 solution at 25ꢀC (Varian Unity 500 and 400 NMR
spectrometers). Mass spectra were run either by the electron impact (EIMS, 70 eV), chemical
ionization (CIMS, CH4) or fast atom bombardment mode (FABMS, m-nitrobenzyl alcohol
matrix) on a VG AutoSpec mass spectrometer. IR spectra were recorded as oily ®lms on NaCl
plates (oils) or as KBr pellets (solids). Optical rotations were measured at 22ꢀC. Commercial
reagents (Aldrich or Fluka) were used as received. Hexane solutions of Chx2BCl were generated
by hydroboration of cyclohexene with monochloroborane as reported in the literature.19
Reactions which required an inert atmosphere were performed under dry Ar in ¯ame-dried
glassware. Et2O and THF were freshly distilled under Ar from sodium±benzophenone ketyl.
Dichloromethane was distilled from P2O5 and stored over 4 A molecular sieves. Tertiary amines were
distilled from CaH2. Column chromatography was performed on silica gel Sud-Chemie AG (60±200
mm) with the indicated eluent. All new compounds gave satisfactory combustion analyses (þ0.4%).
3.2. (2S)-1,2-O-Cyclohexylidene-1,2-dihydroxypentan-3-one (S)-1 (The following procedure can
be scaled up ten times without noticeable changes in the yields.)
A solution of 3,4-O-cyclohexylidene-l-erythrulose6 (2 g, ca. 10 mmol) in dry THF (100 mL)
was added dropwise under Ar to a cooled suspension (0ꢀC) of LiAlH4 (380 mg, 10 mmol) in the
same solvent (50 mL). The mixture was then stirred for 4 h at room temperature. After recooling
to 0ꢀC, the excess of reducing agent was destroyed by careful addition of water (3 mL), 5% aq.
NaOH (15 mL) and again water (20 mL). The mixture was then stirred for a further 30 min,
®ltered through Celite and concentrated in vacuo. This furnished an oil which was submitted
without puri®cation to oxidative cleavage with NaIO4.
A solution of NaIO4 (3.9 g, 18.2 mmol) in water (25 mL) was added dropwise at room
temperature to a solution of the crude product above in MeOH (40 mL). After stirring for 1 h,
the mixture was concentrated in vacuo to dryness, the residue was diluted with CH2Cl2 and washed
with brine. The organic layer was dried on anhydrous Na2SO4 and concentrated in vacuo. This
gave crude cyclohexylidene glyceraldehyde as a colourless oil, which was used directly in the next step.
The product obtained above was dissolved in dry Et2O (25 mL), cooled to 0ꢀC and treated
dropwise under Ar with EtMgBr (6.7 mL of a 3 M solution in Et2O, ca. 20 mmol). After stirring
for 1 h at the same temperature, the reaction was quenched with satd. aq. NH4Cl (1 mL) and poured
onto brine. The mixture was extracted with EtOAc, and the organic layer was dried on anhydrous
Na2SO4 and evaporated in vacuo to a€ord a colourless oil, which was used as such in the last step.
The crude mixture of epimeric alcohols obtained in the previous step was dissolved in dry
CH2Cl2 (10 mL) and treated at room temperature under Ar with NaOAc (1.5 g, 18.3 mmol) and
PCC (3.2 g, 14.8 mmol). The reaction mixture was stirred overnight at room temperature and
then ®ltered. The residue was evaporated in vacuo and chromatographed on silica gel (hexane
EtOAc, 9:1) to yield (S)-1 (891 mg, 45% overall yield from 3,4-O-cyclohexylidene-l-erythrulose):
oil, [ꢀ]D ^62 (CHCl3, c 3.1); IR ꢁmax cm^1: 3019, 2941, 1716 (ketone CˆO), 1450, 1370, 1216,
1161, 1110, 1095, 1042, 924, 763; EIMS, m/z (rel. int.) 198.1248 M+ (11), 155 (66), 141 (100), 81
1
(22), 57 (38). Calcd for C11H18O3, M=198.1256; H NMR (500 MHz): ꢂ 4.42 (1H, dd, J=7.5, 6
Hz, H-2), 4.18 (1H, dd, J=8.5, 7.5 Hz, H-1a), 3.97 (1H, dd, J=8.5, 6 Hz, H-1b), 2.64 (2H, q, J=7

M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
3215
Hz, H-4), 1.75±1.40 (10H, m, cyclohexane protons), 1.05 (3H, t, J=7 Hz, H-5); 13C NMR (125
MHz): ꢂ 211.7 (C-3), 111.5 (acetal Cq), 79.9 (C-2), 66.2 (C-1), 35.7, 34.5, 31.8, 25.1, 23.9, 23.7
(cyclohexane ring carbons+C-4), 7.0 (C-5).
3.3. General procedure for aldol additions of ketone (S)-1
Reactions were performed under an inert atmosphere: to a stirred solution of Chx2BCl (1.8 mL
of a 1 M hexane solution, 1.8 mmol) and Et3N (278 mL, 2 mmol) in anhydrous Et2O (6 mL) at
^78ꢀC was added (S)-1 (198 mg, ca. 1 mmol) in anhydrous ether (6 mL). A solution of the
aldehyde (4 mmol) in ether (6 mL) was then added, and the reaction mixture was stirred at ^78ꢀC
for 2 h. The mixture was then heated to 0ꢀC and treated with pH 7 phosphate bu€er (6 mL) and
MeOH (6 mL), followed by a 30% aq. H2O2 solution (3 mL). After stirring for 1 h at room
temperature, the mixture was poured into satd. aq. NaHCO3 and extracted with Et2O. The
organic layer was washed with brine and dried on anhydrous Na2SO4. Solvent removal in vacuo
and column chromatography of the residue on silica gel (hexane:Et2O, 9:1, then 4:1) a€orded the
aldol addition product 6 as essentially one diastereoisomer. Chemical yields: 6a (85%), 6b (80%),
6c (77%), 6d (85%). When Chx2BCl was replaced by nBu2BOTf, analogous results were observed.
3.4. (2S,4R,5S)-1,2-O-Cyclohexylidene-1,2,5-trihydroxy-4,6-dimethylheptan-3-one 6a
Colourless needles, mp 65±66ꢀC (hexane±CH2Cl2), [ꢀ]D ^60.5 (CHCl3, c 1); IR ꢁmax cm^1: 3450
(br, OH), 3055, 2941, 1709 (ketone CˆO), 1421, 1266, 1096, 896, 739; EIMS, m/z (rel. int.)
1
270.1837 M+ (5), 227 (5), 155 (20), 141 (100). Calcd for C15H26O4, M=270.1831; H NMR (400
MHz): ꢂ 4.52 (1H, dd, J=7.8, 5.7 Hz, H-2), 4.17 (1H, dd, J=8.6, 7.8 Hz, H-1a), 3.98 (1H, dd,
J=8.6, 5.7 Hz, H-1b), 3.64 (1H, dd, J=8.2, 3 Hz, H-5), 3.31 (1H, dq, J=7, 3 Hz, H-4), 2.30 (1H,
br s, OH), 1.70±1.50 (9H, m, H-6+cyclohexane protons), 1.40 (2H, m, cyclohexane protons), 1.04
(3H, d, J=7 Hz, Me-C4), 1.00, 0.88 (2Â3H, 2Âd, J=6.5 Hz, H-7/Me-C6); 13C NMR (100 MHz):
ꢂ 214.6 (C-3), 111.6 (acetal Cq), 79.2 (C-2), 76.2 (C-5), 66.3 (C-1), 43.8 (C-4), 35.6, 34.3, 25.0, 23.9,
23.7 (cyclohexane carbons), 31.2 (C-6), 19.1, 19.0 (C-7/Me-C6), 8.4 (Me-C4).
3.5. (2S,4R,5S)-1,2-O-Cyclohexylidene-1,2,5-trihydroxy-5-cyclohexyl-4-methylpentan-3-one 6b
Oil, [ꢀ]D ^59.9 (CHCl3, c 1); IR ꢁmax cm^1: 3480 (br, OH), 2928, 2854, 1713 (ketone CˆO),
1450, 1369, 1267, 1161, 1095, 923, 910, 736; CIMS, m/z (rel. int.) 293.2119 [M+H+^H2O] (60), 195
1
(90), 151 (100). Calcd for C18H31O4^H2O, M=293.2117; H NMR (500 MHz): ꢂ 4.52 (1H, dd,
J=7.8, 5.7 Hz, H-2), 4.16 (1H, dd, J=8.6, 7.8 Hz, H-1a), 3.98 (1H, dd, J=8.6, 5.7 Hz, H-1b), 3.71
(1H, dd, J=8.5, 2.9 Hz, H-5), 3.30 (1H, dq, J=7, 2.9 Hz, H-4), 2.02 (1H, br d, J=13 Hz, cyclo-
hexane proton), 1.80±1.50 (12H, m, cyclohexane protons), 1.40±1.10 (7H, m, H-6+cyclohexane
protons), 1.04 (3H, d, J=7 Hz, Me-C4), 1.00 (2H, m, cyclohexane protons); 13C NMR (125
MHz): ꢂ 214.5 (C-3), 111.6 (acetal Cq), 79.2 (C-2), 74.9 (C-5), 66.3 (C-1), 43.5 (C-4), 40.6 (C-6),
35.6, 34.4, 29.3, 29.1, 26.3, 26.0, 25.8, 25.0, 23.9, 23.8 (cyclohexane carbons), 8.3 (Me-C4).
3.6. (2S,4R,5R)-1,2-O-Cyclohexylidene-1,2,5-trihydroxy-4-methyl-5-phenylpentan-3-one 6c
Oil, [ꢀ]D ^71.2 (CHCl3, c 0.25); IR ꢁmax cm^1: 3470 (br, OH), 3019, 2939, 1712 (ketone CˆO),
1451, 1370, 1216, 1161, 1095, 923, 764; EIMS, m/z (rel. int.) 304.1670 M+ (6), 141 (100). Calcd for

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M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
C18H24O4, M=304.1674; 1H NMR (500 MHz): ꢂ 7.35±7.20 (5H, m, aromatic), 5.12 (1H, d, J=4.5
Hz, H-5), 4.35 (1H, dd, J=7.5, 5 Hz, H-2), 4.07 (1H, dd, J=8.5, 7.5 Hz, H-1a), 3.85 (1H, dd,
J=8.5, 5 Hz, H-1b), 3.40 (1H, dq, J=4.5, 7 Hz, H-4), 1.70±1.50 (8H, m, cyclohexane protons),
1.40 (2H, m, cyclohexane protons), 1.03 (3H, d, J=7 Hz, Me-C4); 13C NMR (125 MHz): ꢂ 213.4
(C-3), 141.9, 128.2, 127.5, 126.0 (aromatic), 111.6 (acetal Cq), 79.4 (C-2), 73.3 (C-5), 65.8 (C-1),
48.9 (C-4), 35.6, 34.3, 24.9, 23.9, 23.7 (cyclohexane carbons), 10.0 (Me-C4).
3.7. (2S,4R,5R)-1,2-O-Cyclohexylidene-1,2,5-trihydroxy-4-methyl-5-(4-chlorophenyl)pentan-3-
one 6d
Oil, [ꢀ]D ^63.1 (CHCl3, c 0.25); IR ꢁmax cm^1: 3470 (br, OH), 3019, 2936, 1714 (ketone CˆO),
1491, 1450, 1370, 1161, 1092, 923, 847, 829; EIMS, m/z (rel. int.) 338.1281 M+ (3), 141 (100).
Calcd for C18H2335ClO4, M=338.1285; 1H NMR (500 MHz): ꢂ 7.35±7.25 (4H, m, aromatic), 5.12
(1H, br d, J=4 Hz, H-5), 4.42 (1H, dd, J=8, 5.5 Hz, H-2), 4.17 (1H, dd, J=8.5, 8 Hz, H-1a), 3.92
(1H, dd, J=8.5, 5.5 Hz, H-1b), 3.38 (1H, dq, J=4, 7 Hz, H-4), 2.90 (1H, br s, OH), 1.70±1.50 (8H,
m, cyclohexane protons), 1.40 (2H, m, cyclohexane protons), 1.02 (3H, d, J=7 Hz, Me-C4); 13C
NMR (125 MHz): ꢂ 214.1 (C-3), 140.2, 133.3, 128.5, 127.5 (aromatic), 111.9 (acetal Cq), 79.5 (C-2),
72.6 (C-5), 66.3 (C-1), 48.3 (C-4), 35.7, 34.3, 25.0, 24.0, 23.7 (cyclohexane carbons), 9.7 (Me-C4).
3.8. (2S,4R,5S)-1,2-O-Cyclohexylidene-5-O-t-butyldimethylsilyl-1,2,5-trihydroxy-4,6-dimethyl-
heptan-3-one 9
Compound 6a (270 mg, ca. 1 mmol) was dissolved in dry CH2Cl2 (10 mL), cooled to 0ꢀC and
treated with 2,6-lutidine (350 mL, ca. 3 mmol) and TBSOTf (460 mL, ca. 2 mmol). After stirring for
2 h at room temperature, the reaction mixture was poured onto brine and extracted with CH2Cl2.
The organic layer was then dried on anhydrous Na2SO4, ®ltered and evaporated in vacuo. Col-
umn chromatography of the residue on silica gel (hexane:Et2O, 9:1) a€orded 9 (303 mg, 79%):
oil, [ꢀ]D ^79.5 (CHCl3, c 0.5); IR ꢁmax cm^1: 2935, 1713 (ketone CˆO), 1463, 1252, 1094, 835, 774;
EIMS, m/z (rel. int.) 384.2685 M+ (1), 341 (7), 255 (32), 157 (100). Calcd for C21H40O4Si,
M=384.2696; 1H NMR (500 MHz): ꢂ 4.51 (1H, dd, J=7.7, 5.8 Hz, H-2), 4.17 (1H, dd, J=8.5, 7.7
Hz, H-1a), 3.98 (1H, dd, J=8.5, 5.8 Hz, H-1b), 3.89 (1H, t, J=5 Hz, H-5), 3.33 (1H, dq, J=5, 7
Hz, H-4), 1.75±1.55 (9H, m, H-6+cyclohexane protons), 1.40 (2H, m, cyclohexane protons), 1.06
(3H, d, J=7 Hz, Me-C4), 0.94, 0.89 (2Â3H, 2Âd, J=6.5 Hz, H-7/Me-C6), 0.90 (9H, s, SiCMe3),
0.06, 0.00 (2Â3H, 2Âs, SiMe2); 13C NMR (100 MHz): ꢂ 213.2 (C-3), 111.4 (acetal Cq), 79.7 (C-2),
76.8 (C-5), 66.4 (C-1), 45.3 (C-4), 35.7, 34.4, 25.1, 23.9, 23.8 (cyclohexane carbons), 33.4 (C-6),
26.1 (SiCMe3), 19.7, 18.2 (C-7/Me-C6), 18.4 (SiCMe3), 11.8 (Me-C4), ^3.8, ^3.9 (SiMe2).
3.9. Periodic acid cleavage of aldols 6
The aldol (1 mmol) was dissolved in EtOAc (10 mL) and treated with H5IO6 (800 mg, ca. 3.5
mmol). After stirring at room temperature until consumption of 6 (ca. 2 h, TLC monitoring!),
solid sodium thiosulfate (320 mg, ca. 2 mmol) was added. The reaction mixture was stirred for 5 min,
®ltered through Celite (the Celite was washed with an additional amount of EtOAc) and evaporated
in vacuo. The oily residue was treated with ethereal diazomethane. Column chromatography on
silica gel (hexane:Et2O, 9:1) a€orded 7. Chemical yields: 7b (84%), 7c (90%), 7d (86%). Oxidative
cleavage of the silylated aldol 9 was performed under the same conditions to furnish 10 in 88% yield.

M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
3217
3.10. Methyl (2R,3S)-3-O-formyl-3-cyclohexyl-3-hydroxy-2-methylpropanoate 7b
Oil, [ꢀ]D ^1 (CHCl3, c 0.3); IR ꢁmax cm^1: 3025, 2932, 2855, 1732 (ester CˆO), 1450, 1168, 1076,
757; CIMS, m/z 183.1388 [M+H+^HCOOH] (82), 151 (100). Calcd for C12H21O4^HCOOH,
1
M=183.1385; H NMR (500 MHz): ꢂ 8.11 (1H, s, OCHO), 5.16 (1H, dd, J=6.5, 5.5 Hz, H-3),
3.68 (3H, s, OMe), 2.80 (1H, dq, J=5.5, 7 Hz, H-2), 1.80±1.50 (6H, m, cyclohexane protons),
1.30±1.00 (5H, m, cyclohexane protons), 1.18 (3H, d, J=7 Hz, Me-C2); 13C NMR (125 MHz): ꢂ
174.4 (C-1), 160.6 (CHO), 77.6 (C-3), 51.9 (OMe), 40.5 (C-2), 39.3 (C-4), 29.3, 28.3, 26.1, 25.9,
25.7 (cyclohexane carbons), 11.1 (Me-C2).
3.11. Methyl (2R,3R)-3-O-formyl-3-hydroxy-2-methyl-3-phenylpropanoate 7c
Oil, [ꢀ]D +50.6 (CHCl3, c 2.8); IR ꢁmax cm^1: 1732 (br, ester CˆO), 1455, 1263, 1161, 913, 760;
EIMS, m/z (rel. int.) 222.0899 M+ (20), 194 (11), 162 (22), 107 (100). Calcd for C12H14O4,
1
M=222.0892; H NMR (500 MHz): ꢂ 8.09 (1H, s, OCHO), 7.35±7.25 (5H, m, aromatic), 6.18
(1H, d, J=7 Hz, H-3), 3.55 (3H, s, OMe), 2.98 (1H, quint, J=7 Hz, H-2), 1.23 (3H, d, J=7 Hz,
Me-C2); 13C NMR (125 MHz): ꢂ 173.0 (C-1), 159.6 (CHO), 137.7, 128.2, 128.1, 126.4 (aromatic),
75.5 (C-3), 51.6 (OMe), 45.5 (C-2), 12.2 (Me-C2).
3.12. Methyl (2R,3R)-3-O-formyl-3-hydroxy-2-methyl-3-(4-chlorophenyl)propanoate 7d
Oil, [ꢀ]D +61.5 (CHCl3, c 1.7); IR ꢁmax cm^1: 1735 (br, ester CˆO), 1493, 1459, 1266, 1215,
1160, 1092, 1015, 822, 756; EIMS, m/z (rel. int.) 256.0503 M+ (27), 196 (45), 141 (100), 88 (82).
1
Calcd for C12H1335ClO4, M=256.0502; H NMR (500 MHz): ꢂ 8.08 (1H, s, OCHO), 7.35±7.25
(4H, m, aromatic), 6.10 (1H, d, J=7 Hz, H-3), 3.57 (3H, s, OMe), 2.93 (1H, quint, J=7 Hz, H-2),
1.23 (3H, d, J=7 Hz, Me-C2); 13C NMR (125 MHz): ꢂ 173.0 (C-1), 159.7 (CHO), 136.5, 134.3,
128.7, 128.2 (aromatic), 75.2 (C-3), 51.9 (OMe), 45.6 (C-2), 12.7 (Me-C2).
3.13. Methyl (2R,3S)-3-O-t-butyldimethylsilyl-3-hydroxy-2,4-dimethylpentanoate 10
Oil, [ꢀ]D ^30.3 (CHCl3, c 0.8); IR ꢁmax cm^1: 1720 (ester CˆO), 1463, 1257, 1113, 835, 773;
EIMS, m/z (rel. int.) 259.1724 [M+^Me] (4), 231 (22), 217 (100), 187 (24). Calcd for C14H30O3Si^CH3,
1
M=259.1729; H NMR (500 MHz): ꢂ 3.81 (1H, t, J=5 Hz, H-3), 3.67 (3H, s, OMe), 2.60 (1H,
dq, J=5, 7.5 Hz, H-2), 1.70 (1H, dqq, J=5, 7, 7 Hz, H-4), 1.15 (3H, d, J=7.5 Hz, Me-C2), 0.91,
0.89 (2Â3H, 2Âd, J=7 Hz, H-5/Me-C4), 0.90 (9H, s, SiCMe3), 0.06, 0.00 (2Â3H, 2Âs, SiMe2);
13C NMR (125 MHz): ꢂ 176.1 (C-1), 77.8 (C-3), 51.5 (OMe), 43.1 (C-2), 33.1 (C-4), 26.1
(SiCMe3), 19.3, 18.1 (C-5/Me-C4), 18.4 (SiCMe3), 12.4 (Me-C2), ^4.1, ^4.2 (SiMe2).
3.14. Alkaline deformylation of esters 7
The ester (1 mmol) was dissolved in dry MeOH (5 mL) and treated with solid KHCO3 (110 mg,
ca. 1.1 mmol). After stirring at room temperature for ca. 1 h (TLC monitoring!), the mixture was
®ltered and evaporated in vacuo. Column chromatography of the residue on silica gel (hex-
ane:EtOAc, 4:1) a€orded 8. Chemical yields: 8b (85%), 8c (82%), 8d (83%).

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M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
3.15. Desilylation of 10
The silylated ester (137 mg, 0.5 mmol) was dissolved in acetonitrile (5 mL) and treated with
48% aqueous HF (180 ml, ca. 5 mmol). The reaction mixture was stirred at room temp. for 1 h,
poured onto 5% aq. NaHCO3 and worked up. Column chromatography of the residue on silica
gel (hexane:EtOAc, 4:1) followed by bulb-to-bulb distillation provided ester 8a (80%).
3.16. Methyl (2R,3S)-3-hydroxy-2,4-dimethylpentanoate 8a
Oil, [ꢀ]D +7.4 (CH2Cl2, c 0.2), lit.10c [ꢀ]D +7.8 (CH2Cl2, c 0.2); IR ꢁmax cm^1: 3500 (br, OH),
3019, 2930, 2854, 1728 (ester CˆO), 1450, 1437, 1216; CIMS, m/z (rel. int.) 161.1170 [M+H+]
1
(12), 143 [M+H+^H2O] (100). Calcd for C8H17O3, M=161.1177; H NMR (400 MHz): ꢂ 3.65
(3H, s, OMe), 3.53 (1H, dd, J=8, 3.8 Hz, H-3), 2.62 (1H, dq, J=3.8, 7.1 Hz, H-2), 2.55 (1H, br s,
OH), 1.61 (1H, dqq, J=8, 6.5, 6.5 Hz, H-4), 1.13 (3H, d, J=7.1 Hz, Me-C2), 0.95, 0.83 (2Â3H,
2Âd, J=6.5 Hz, Me-C4/H-5); 13C NMR (100 MHz): ꢂ 176.9 (C-1), 76.8 (C-3), 51.8 (OMe), 41.8
(C-2), 30.6 (C-4), 19.1, 18.5 (C-5, Me-C4), 10.2 (Me-C2).
3.17. Methyl (2R,3S)-3-cyclohexyl-3-hydroxy-2-methylpropanoate 8b
Oil, [ꢀ]D ^5.5 (CHCl3, c 0.3); IR ꢁmax cm^1: 3500 (br, OH), 2928, 2853, 1728 (ester CˆO), 1450,
1262, 1204, 991, 757; CIMS, m/z 201.1488 [M+H+] (8), 183 [M+H+^H2O] (100). Calcd for
C11H21O3, M=201.1490; 1H NMR (500 MHz): ꢂ 3.71 (3H, s, OMe), 3.63 (1H, dd, J=8.2, 3.3 Hz,
H-3), 2.68 (1H, dq, J=3.3, 7 Hz, H-2), 2.05 (1H, br d, J=13 Hz, cyclohexane proton), 1.80±1.55
(4H, m, cyclohexane protons), 1.40±1.10 (4H, m, cyclohexane protons), 1.17 (3H, d, J=7 Hz, Me-
C2), 1.00 (2H, qd, J=13, 3 Hz, cyclohexane protons); 13C NMR (125 MHz): ꢂ 177.1 (C-1), 75.7
(C-3), 51.8 (OMe), 41.3 (C-2), 40.2 (cyclohexane CH), 29.1, 29.0, 26.4, 26.1, 25.9 (cyclohexane
CH2), 10.0 (Me-C2).
3.18. Methyl (2R,3R)-3-hydroxy-2-methyl-3-phenylpropanoate 8c
Oil, [ꢀ]D +23.2 (CHCl3, c 1), lit.10b [ꢀ]D +23.1 (CHCl3, c 1.5); IR ꢁmax cm^1: 3450 (br, OH), 1721
(ester CˆO), 1453, 1436, 1349, 1256, 1198, 1170, 1060, 1035, 900, 770, 745; EIMS, m/z (rel.
1
int.) 194.0940 M+ (12), 107 (88), 88 (100). Calcd for C11H14O3, M=194.0943; H NMR (500
MHz): ꢂ 7.35±7.25 (5H, m, aromatic), 5.12 (1H, d, J=4 Hz, H-3), 3.68 (3H, s, OMe), 2.90 (1H,
br s, OH), 2.80 (1H, dq, J=4, 7 Hz, H-2), 1.14 (3H, d, J=7 Hz, Me-C2); 13C NMR (125 MHz):
ꢂ 176.2 (C-1), 141.4, 128.2, 127.5, 126.0 (aromatic), 73.6 (C-3), 51.8 (OMe), 46.4 (C-2), 10.7
(Me-C2).
3.19. Methyl (2R,3R)-3-hydroxy-2-methyl-3-(4-chlorophenyl)-propanoate 8d
Oil, [ꢀ]D +17.2 (CHCl3, c 1.8); IR ꢁmax cm^1: 3460 (br, OH), 1722 (br, ester CˆO), 1493, 1458,
1437, 1349, 1201, 1091, 1063, 1014, 812; EIMS, m/z (rel. int.) 228.0561 M+ (2), 141 (60), 88 (100).
Calcd for C11H1335ClO3, M=228.0553; 1H NMR (500 MHz): ꢂ 7.35±7.25 (4H, m, aromatic), 5.04
(1H, d, J=4.4 Hz, H-3), 3.66 (3H, s, OMe), 3.20 (1H, br s, OH), 2.74 (1H, dq, J=4.4, 7 Hz, H-2),
1.10 (3H, d, J=7 Hz, Me-C2); 13C NMR (125 MHz): ꢂ 175.8 (C-1), 140.0, 133.1, 128.3, 127.3
(aromatic), 72.9 (C-3), 51.8 (OMe), 46.3 (C-2), 10.7 (Me-C2).

M. Carda et al. / Tetrahedron: Asymmetry 11 (2000) 3211±3220
3219
Acknowledgements
The authors acknowledge ®nancial support by the DGICYT (project PB98-1438) and by
BANCAIXA (project P1B99-18). E.F. thanks the Conselleria de Cultura de la Generalitat
Valenciana for a pre-doctoral fellowship. We further thank Professor E. Domõnguez and her
co-workers for sending detailed physical data of compound 8a prior to publication.
References
1. (a) Recent Progress in the Chemical Synthesis of Antibiotics; Lukacs, G.; Ohno. M., Eds.; Springer: Berlin, 1990.
(b) Tatsuta, K. ibid. pp. 1±38. (c) Blizzard, T.; Fisher, M.; Mrozik, H.; Shih, T. ibid. pp. 65±102. (d) Isobe, M. ibid.
pp. 103±134. (e) Beau, J.-M. ibid. pp. 135±182. (f) Yonemitsu, O.; Horita, K. ibid. pp. 447±466. (g) Norcross, R. D.;
Paterson, I. Chem. Rev. 1995, 95, 2041±2114.
2. (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1±115. (b) Mukaiyama, T. Org. React.
1982, 28, 203±331. (c) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York,
1984; Vol. 3, pp. 1±110. (d) Heathcock, C. H. ibid. pp. 111±212. (e) Heathcock, C. H. Aldrichimica Acta 1990, 23,
99±111. (f) Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.; Winterfeldt, E., Eds.; Pergamon Press:
Oxford, 1993; Vol. 2. (g) Mekelburger, H. B.; Wilcox, C. S. ibid. pp. 99±131. (h) Heathcock, C.H. ibid. pp. 133±179
and 181±238. (i) Kim, B. M.; Williams, S. F.; Masamune, S. ibid. pp. 239±275. (j) Rathke, M. W.; Weipert, P. ibid.
pp. 277±299. (k) Paterson, I. ibid. pp. 301±319. (l) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317±
338. (m) Braun, M. In Houben-Weyl's Methods of Organic Chemistry, Stereoselective Synthesis; Helmchen, G.,
Ho€mann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1996; Vol. 3, pp. 1603±1666,
1713±1735.
3. Marco, J. A.; Carda, M.; Gonzalez, F.; Rodrõguez, S.; Castillo, E.; Murga, J. J. Org. Chem. 1998, 63, 698±707, and
references cited therein.
4. (a) Marco, J. A.; Carda, M.; Falomir, E.; Palomo, C.; Oiarbide, M.; Ortiz, J. A.; Linden, A. Tetrahedron Lett.
1999, 1065±1068. (b) Carda, M.; Falomir, E.; Murga, J.; Castillo, E.; Gonzalez, F.; Marco, J. A. Tetrahedron Lett.
1999, 6845±6848.
5. Carda, M.; Murga, J.; Falomir, E.; Gonzalez, F.; Marco, J. A. Tetrahedron 2000, 56, 677±683.
6. Carda, M.; Rodrõguez, S.; Murga, J.; Falomir, E.; Marco, J. A.; Roper, H. Synth. Commun. 1999, 29, 2601±2610.
7. The acetonide corresponding to (S)-1 can also be used in aldol reactions with good results (E. Falomir, PhD
Thesis, University of Castellon, 1998). Ketone (S)-1, however, is obtained with a better yield from l-erythrulose.
The acetonide corresponding to (R)-1 is known; see, for example: Ziegler, F. E.; Tung, J. S. J. Org. Chem. 1991,
56, 6530±6537.
8. (a) Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993, 58, 147±153. (b) Mukaiyama, T.; Inoue, T. Bull.
Chem. Soc. Jpn. 1980, 53, 174±178. For a general review on boron aldol additions, see: Cowden, C. J.; Paterson, I.
Org. React. 1997, 51, 1±200.
9. Other enolization systems which did not lead to success were: (a) TiCl4/iPr2NEt: Evans, D. A.; Clark, J. S.;
Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866±868 (decomposition). (b) SnCl4/
iPr2NEt: Rossi, T.; Marchioro, C.; Paio, A.; Thomas, R. J.; Zarantonello, P. J. Org. Chem. 1997, 62, 1653±1661
(decomposition). (c) n-BuBCl2/tertiary amine: Ramachandran, P. V.; Xu, W.-C.; Brown, H. C. Tetrahedron Lett.
1997, 769±772 (no reaction).
10. (a) Meyers, A. I.; Yamamoto, Y. Tetrahedron 1984, 40, 2309±2315. (b) Gennari, C.; Colombo, L.; Bertolini, G.;
Schimperna, G. J. Org. Chem. 1987, 52, 2754±2760. (c) Vicario, J. L.; Badõa, D.; Domõnguez, E.; Rodrõguez, M.;
Carrillo, L. J. Org. Chem. 2000, 65, 3754±3760.
11. (a) Wu, W.-L.; Wu, Y.-L. J. Org. Chem. 1993, 58, 3586±3588. (b) Xie, M.; Berges, D. A.; Robins, M. J. J. Org.
Chem. 1996, 61, 5178±5179.
12. (a) Cole, D. C. Tetrahedron 1994, 50, 9517±9582. (b) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichimica Acta
1994, 27, 3±11. (c) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117±128.
13. Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60, 585±587.
14. For the enolization of ketones with Chx2BCl/tertiary amine to yield E boron enolates, see Ref. 8a and: (a) Brown,
H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441±3442.

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(b) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57, 2716±2721. (c) Brown, H. C.;
Ganesan, K.; Dhar, R. K. J. Org. Chem. 1992, 57, 3767±3772. (d) Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993,
58, 4182±4184. (e) Paterson, I.; Nowak, T. Tetrahedron Lett. 1996, 8243±8246.
15. Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett. 1994, 9083±9086. These authors suggested that
initial formation of a ®ve-membered chelate involving the boron, the carbonyl oxygen and the a oxygen atoms,
followed by stereoselective deprotonation by the tertiary amine, explains the formation of a Z enolate. This and
other alternative explanations are now being studied by us at both the theoretical and experimental level.
16. For recent theoretical studies on boron aldol reactions, see: (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org.
Chem. 1990, 55, 481±493. (b) Bernardi, A.; Capelli, A. M.; Comotti, A.; Gennari, C.; Gardner, M.; Goodman,
J. M.; Paterson, I. Tetrahedron 1991, 47, 3471±3484. (c) Gennari, C.; Vieth, S.; Comotti, A.; Vulpetti, A.;
Goodman, J. M.; Paterson, I. Tetrahedron 1992, 48, 4439±4458. (d) Vulpetti, A.; Bernardi, A.; Gennari, C.;
Goodman, J. M.; Paterson, I. Tetrahedron 1993, 49, 685±696.
17. Computational ab initio calculations on enolization and aldolization processes are being performed by Dr. J.
Murga and will be disclosed in due time.
18. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920±1923.
19. Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116, 11287±11314.