Enantioselective synthesis of 2-allyl and 2-(3- trimethylsilylpropargyl)-2-hydroxycyclohexanone using osmium-catalyzed asymmetric dihydroxylation

Article abstract of DOI:10.1016/S0957-4166(98)00144-X

The catalytic asymmetric dihydroxylation of (1-cyclohexenyl) or (1- cyclopentenyl) acetonitrile 5 and 15 with AD-mix-β occurred with good enantiofacial selectivity (87 to 94.7% ee after recrystallization) giving (R,R)-diols in agreement with the mnemonic

Full text of DOI:10.1016/S0957-4166(98)00144-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1619–1626
Enantioselective synthesis of 2-allyl and 2-(3-trimethyl-
silylpropargyl)-2-hydroxycyclohexanone using osmium-catalyzed
asymmetric dihydroxylation
Jean-Michel Devaux, Jacques Goré and Jean-Michel Vatèle ∗
Laboratoire de Chimie Organique 1, associé au CNRS, Université Claude Bernard, CPE, 43 Bd du 11 Novembre 1918, 69622
Villeurbanne, France
Received 19 March 1998; accepted 7 April 1998
Abstract
The catalytic asymmetric dihydroxylation of (1-cyclohexenyl) or (1-cyclopentenyl) acetonitrile 5 and 15 with
AD-mix-β occurred with good enantiofacial selectivity (87 to 94.7% ee after recrystallization) giving (R,R)-diols
in agreement with the mnemonic device. The 6-membered ring diol nitrile was easily transformed, via standard
functional group manipulations, to 2-allyl and 2-(3-trimethylsilylprop-2-ynyl)-2-hydroxycyclohexanone in about
35% overall yield. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
In pursuit of the total synthesis of histrionicotoxin 1, a potent noncompetitive blocker of neuromuscular
nicotinic channels,1,2 we recently reported an efficient method to prepare enantioenriched α-allyl or
propargyl-α-aminocyclohexanone 2a and 2b, good candidates for the elaboration of the 2-substituted-
1-azaspiro[5.5]undecane ring system of 1.3 This methodology involves a benzilic-type rearrangement
of tertiary α-hydroxyimines 3a and 3b and proceeds by a 1,2-suprafacial shift and complete chiral
transmission (Scheme 1).3c,d The potential of this process was demonstrated by the concise formal
synthesis of (−)-perhydrohistrionicotoxin,3d a hydrogenation product of 1, which like 1 is an important
biochemical tool for the study of the mechanism of action of cholinergic agonists in the neuromuscular
system.4
As shown in Scheme 2, we first developed a synthesis of (R)-α-ketols 4a and 4b, precursors of
compounds 3a and 3b involving a flash-chromatography resolution of diastereomeric ketals for 4a or
esters for 4b.3e Depending of the substrate, this method presents several drawbacks: (1) in the case
∗
Corresponding author. E-mail: vatele@univ-lyon1.fr
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00144-X

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J.-M. Devaux et al. / Tetrahedron: Asymmetry 9 (1998) 1619–1626
Scheme 1.
of 4a, the efficiency of the chromatographic separation was low (∆Rf=0.05) and partial racemization
occurred during acid deketalization via 1,2-migration of the allyl group5; (2) formation of (ꢀ)-4b from
1,2-cyclohexanedione is a low-yielding process.3e For these reasons, we searched for a more convenient
and practical asymmetric synthesis of α-ketols 4a and 4b.
Scheme 2.
Herein, we report the synthesis of enantioenriched α-ketols 4a and 4b based on a reagent-control
strategy of the stereochemistry. Because α-ketols 4a and 4b can obviously arise from their corresponding
1,2-diols, the Sharpless catalytic asymmetric dihydroxylation (AD)6 of a substituted cyclohexene was
used to introduce enantioselectively the quaternary stereogenic center of 4a and 4b. If a large number
of examples of the AD reaction have appeared in the literature6,7 only very few concern 1-substituted
cyclohexene derivatives. Enantioselectivity in the AD reaction of this type of cycloolefin is quite variable
ranging from 14 to 48% ee with those bearing bulky substituents8 to near 100% with 1-phenyl or 1-[(p-
methoxybenzoyloxy)methyl]-1-cyclohexene.6,9
Compound 5 bearing a nitrile function, commercially available and cheap, was identified by us as a
perfect precursor for α-ketols 4a and 4b.
2. Results and discussion
The AD reaction of the unsaturated nitrile 5 using AD-mix-β was rather sluggish giving the diol 6
in 65% yield after three days at room temperature. However, addition of 0.4 mol% of osmium tetroxide
and 1 equivalent of methanesulfonamide to the reaction mixture increased dramatically the rate of the
reaction (8 h, 0°C) and improved the yield.10 The diol 6 was thus obtained in 94% yield and 71% ee
(determined by chiral GC after protection as an acetonide). The acetonide 7 could be obtained in almost
pure enantiomeric form after two recrystallizations in hexane (94.7% ee, 70% yield). Reduction of the
nitrile 7 took place smoothly at room temperature, in the presence of an excess of DIBAL-H to give the
aldehyde 8 in 89% yield (Scheme 3).

J.-M. Devaux et al. / Tetrahedron: Asymmetry 9 (1998) 1619–1626
1621
Scheme 3. Reagents and conditions: (a) AD-mix-β, OsO4 (0.4 mol%), MeSO2NH2 (1 equiv.), t-BuOH:H2O (1:1), 0°C, 8 h; (b)
2-methoxypropene, camphorsulfonic acid, THF, RT, 90 min; (c) DIBAL-H, THF, RT, 14 h; (d) CH2I2 (10 equiv.), Zn (30 equiv.),
Zn (30 equiv.), Me3Al (2 equiv.), THF, RT, 20 min then 8, −20°C-→RT; (e) 2 N HCl:MeOH (4:1), RT, 4 h; (f) o-iodoxybenzoic
acid (IBX) (2.5 equiv.), DMSO, RT, 6 h; (g) PPh3 (3 equiv.), 8 then CBr4 (1.5 equiv.), CH2Cl2, −20°C-→RT, 1 h; (h) n-BuLi (2
equiv.), Me3SiCl, THF, −78°C-→RT (3 h)
At this stage, our goal became the introduction of the terminal olefinic and silylated acetylenic
functionalities. A Wittig reaction between aldehyde 8 and methylene triphenylphosphorane afforded the
olefin 9 in 43–52% yield. The yield of the methylenation reaction was greatly increased by means of
the CH2I2–Zn–AlMe3 system11 (79% yield). Acid hydrolysis of the acetonide protecting group followed
by oxidation with o-iodoxybenzoic acid (IBX) in methyl sulfoxide12 yielded the desired (R)-ketol 4a in
77% yield for the two steps. The absolute configuration of 4a13 confirmed the enantiofacial selectivity
of the AD reaction of 5 predicted by a mnemonic device proposed by Sharpless et al.10a We next
focussed our attention on the formation of α-ketol 4b bearing a 3-trimethylsilylpropargyl grouping. To
this goal, aldehyde 8 was converted to the dibromo-olefin 11 by the Corey–Fuchs reaction14 in 78% yield.
Treatment of 11 with 2 equivalents of n-BuLi followed by an excess of chlorotrimethylsilane afforded the
alkynylsilane 12 in 89% yield. Acid-catalyzed removal of the isopropylidene group followed by oxidation
with IBX in methyl sulfoxide completed the synthesis of α-ketol 4b in 78% yield.13
As an extension of the above described methodology, we studied the asymmetric dihydroxylation of
commercially available (1-cyclopentyl) acetonitrile 15. Under the same reaction conditions as for the
corresponding 6-membered ring olefin 5, the enantiofacial selectivity of the AD reaction on 15 slightly
decreased in comparison to that of compound 5 (61% ee versus 71% ee). Moreover, the sense of π-facial
discrimination of the AD reaction on 15 is very likely the same as for its corresponding 6-membered ring
analog 5. Recrystallization of the diol 16 in dichloromethane–hexane increased its enantiomeric purity
to 87% (conditions not optimized). The diol 16 is potentially a valuable intermediate of spirolactam 19,
a precursor of cephalotaxin 20,15 via the homopropargylic alcohol 18 (Scheme 4).16
In summary, the AD reaction allowed a simple and practical preparation of enantioenriched α-ketols
4a and 4b. Starting from cheap 1-(cyclohexenyl)acetonitrile 5, α-ketols 4a and 4b were respectively
obtained in 35 and 31% yield. Further studies directed towards the synthesis of the precursor of
cephalotaxin, lactam 19, are currently underway.

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J.-M. Devaux et al. / Tetrahedron: Asymmetry 9 (1998) 1619–1626
Scheme 4.
3. Experimental
3.1. General procedures
1H NMR spectra were recorded in CDCl3 (δH=7.25) at ambient probe temperature on a Bruker AC
200 (200 MHz) spectrometer. Data are presented as follows: chemical shift (in ppm on the δ scale relative
to δTMS=0), multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet, br=broad), integration, coupling
constant and interpretation. 13C NMR spectra were recorded at ambient probe temperature on a Brucker
AC 200 (50.3 MHz) in CDCl3 used as the reference (δc=77.0). IR were recorded on a Perkin–Elmer
298 spectrophotometer. Optical rotations were measured on a Perkin–Elmer 141 polarimeter at the
sodium D line (589 nm). Melting points were determined on a Büchi 530 apparatus and are uncorrected.
Enantiomeric excesses were determined by GC using a Shimadzu GC.14A apparatus on a Lipodex E.MN
column (25 m×0.25 mm). Combustion analyses were performed by the Service Central de Microanalyse,
CNRS, Solaize.
Reagents and solvents were purified by standard means. Tetrahydrofuran was distilled from sodium
wire/benzophenone and stored under a nitrogen atmosphere. Dichloromethane and methyl sulfoxide were
distilled from calcium hydride. Methanol was distilled from magnesium metal. All other chemicals were
used as received. Unless otherwise stated, all experiments were performed under anhydrous conditions
in an atmosphere of nitrogen.
3.2. (1R,2R)-(1,2-Dihydroxycyclohexyl) acetonitrile 6
A mixture of tert-butyl alcohol (70 ml), water (70 ml), AD-mix-β (20 g) and methane sulfonamide
(1.36 g, 14.3 mmol) was stirred for a few minutes at room temperature until two clear phases were
produced. After addition of osmium tetroxide (4 wt% in water, 0.36 ml, 0.06 mmol), the mixture was
cooled to 0°C and (1-cyclohexenyl) acetonitrile (1.73 g, 14.3 mmol) was added. The mixture was stirred
for 8 h at 0°C. Sodium metabisulfite (14 g) was added and after stirring the mixture for 1 h at 0°C,
dichloromethane (120 ml) was added. The aqueous phase was extracted twice with dichloromethane
(120 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness. The residue
was purified by flash-chromatography on silica gel (Et2O:petroleum ether, 3:2) to give 6 as a white solid
20
(2.1 g, 94% yield). M.p. 95–101°C; [α]D −1.6 (c 1, CHCl3) (66% ee); IR (KBr) 2980, 2930, 2860,
1
2240 cm−1; H NMR: 1.3–1.8 (m, 7H), 2.0 (m, 1H), 2.58 (d+brs, 2H, J=17 Hz, CH2CN, OH), 2.73
(d+brs, 2H, J=17 Hz, CH2CN, OH), 3.52 (dd 1H, J=4.4 and 10.3 Hz, CHOH); 13C NMR: 20.6, 23.7,
28.8, 30.4, 34.6, 72.1, 72.7, 117.9; anal. calcd for C8H13NO2: C, 61.91; H, 8.44; N, 9.02. Found: C,
61.79; H, 8.64; N, 9.02.

J.-M. Devaux et al. / Tetrahedron: Asymmetry 9 (1998) 1619–1626
1623
3.3. (1R,2R)-[(1,2-Isopropylidenedioxy)cyclohexyl]acetonitrile 7
To a solution of the diol 6 (1.95 g, 12.56 mmol) in tetrahydrofuran (40 ml) was successively added
camphorsulfonic acid (0.04 g) and 2-methoxypropene (2.72 ml, 25.1 mmol). The reaction was stirred for
90 min. at room temperature. After concentration in vacuo, the residue was chromatographed on silica
gel (Et2O:petroleum ether, 1:3) to afford 7 as a white solid (2.37 g, 97% yield). The enantiomeric excess
(71%) was determined by GC analysis: nitrogen (carrier gas); temp. 80–150°C (5°C/min); retention
time (min): 19.25 for (S)-7 and 19.69 for (R)-7. Two recrystallizations in hexane gave 7 (1.68 g) with
20
an enantiomeric excess of 94.7%. M.p. 55–60°C; [α]D −27.6 (c 0.7, CHCl3) (94.7% ee); IR (KBr)
2980, 2930, 2860, 2240, 1360, 1340 cm−1; 1H NMR: 1.32 (s, 3H, CH3), 1.5 (s, 3H, CH3), 1.1–1.7 (m,
7H), 2.1–2.2 (m, 1H), 2.58 (d, 1H, J=17 Hz, CH2CN), 2.67 (d, 1H, J=17 Hz, CH2CN), 4.1 (brs, 1H,
CHOCMe2); 13C NMR: 19.5, 22.6, 25.5, 26.2, 26.8, 28.3, 34.6, 76.0, 77.2, 108.3, 116.9; anal. calcd for
C11H17NO2: C, 67.66; H, 8.77. Found: C, 67.17; H, 8.82.
3.4. (1R,2R)-[(1,2-Isopropylidenedioxy)cyclohexyl]acetaldehyde 8
To a solution of the nitrile 7 (1 g, 5.1 mmol) in tetrahydrofuran (20 ml), cooled to −78°C, was
added dropwise DIBAL-H (1 M in hexane, 14.4 ml). The reaction mixture was stirred for 14 h at room
temperature, cooled to 0°C and 2 N HCl solution (5 ml) was added. After stirring for 20 min, the solution
was filtered on a pad of silica gel (Et2O:petroleum ether, 3:7). The filtrate was concentrated under reduced
pressure to give the aldehyde 8 as an oil (0.895 g, 89% yield), which was used for the next step without
further purification. IR (neat) 2980, 2930, 2860, 2730, 1730, 1360, 1340 cm−1.
3.5. (1R,5R)-1-Allyl-3,3-dimethyl-2,4-dioxabicyclo[4,3,0]nonane 9
A tetrahydrofuran solution (15 ml) of diiodomethane (1.2 ml, 14.9 mmol), zinc (3 g, 45.8 mmol)
and trimethylaluminium (2 M in THF, 1.51 ml, 3 mmol) was stirred at room temperature for 20 min.
The solution was then cooled down to −20°C and the aldehyde 8 (0.3 g, 1.51 mmol) in tetrahydrofuran
(2 ml) was added. The reaction mixture was slowly warmed up to room temperature (2 h), cooled to
0°C and quenched with a saturated NH4Cl solution (5 ml). Extraction with ether, drying (MgSO4) and
evaporation of the organic extracts gave a residue which was purified by column chromatography on
20
silica gel (Et2O:petroleum ether, 3:97) to afford the olefin 9 as an oil (0.23 g, 79% yield). [α]D −19.5
1
(c 2, CHCl3); IR (neat) 3060, 2990, 2980, 2930, 1640, 1360 cm−1; H NMR: 1.3 (s, 3H, CH3), 1.5 (s,
3H, CH3), 1.1–1.7 (m, 7H), 2–2.1 (m, 1H), 2.32 (dd, J=6.8 and 16 Hz, CH2–CH_CH2), 2.40 (dd, J=6.8
and 16 Hz, CH2–CH_CH2), 3.9 (brs, 1H, CHOCMe2), 5.0–5.13 (m, 2H, CH_CH2), 5.9 (ddt, 1H, J=6.8,
10.5 and 17 Hz, CH_CH2); 13C NMR: 19.8, 22.7, 26.2, 27.0, 28.5, 34.3, 40.2, 76.3, 80.1, 106.8, 117.7,
133.9.
3.6. (1R,2R)-1-Allyl-1,2-cyclohexanediol 10
A solution of the acetonide 9 (0.2 g, 1 mmol) in methanol:2 N HCl (4:1) was stirred for 4 h at
room temperature. The solution was concentrated under reduced pressure and the residue was purified
by chromatography on silica gel (Et2O:petroleum ether, 3:2) to yield the diol 10 (0.152 g, 96% yield)
obtained as a white solid. M.p. 70–72°C; [α]D20 +2.9 (c 1.6, CHCl3); IR (KBr) 3400, 2980, 2930, 2860,
1640 cm−1; 1H NMR: 1.4–1.8 (m, 8H, 4CH2), 2.38 (dd, 1H, J=6.7 and 15.5 Hz, CH2–CH_CH2), 2.51
(dd, J=6.7 and 15.5 Hz, CH2–CH_CH2), 3.7 (brt, 1H, J=5.7 Hz, CHOH), 5.1–5.3 (m, 2H, CH_CH2),

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J.-M. Devaux et al. / Tetrahedron: Asymmetry 9 (1998) 1619–1626
5.9 (ddt, 1H, J=6.7, 10.5, 17 Hz, CH_CH2); 13C NMR: 21.1, 23.3, 30.4, 34.4, 43.7, 73.4, 118.8, 133.9;
anal. calcd for C9H16O2: C, 69.19; H, 10.32. Found: C, 68.75; H, 10.30.
3.7. (2R)-2-Allyl-2-hydroxycyclohexanone 4a
To a solution of o-iodoxybenzoic acid (IBX)12a,b (0.46 g, 2.5 equiv.) in methyl sulfoxide (6 ml)
was added the diol 10 (0.1 g, 0.64 mmol) in methyl sulfoxide (3 ml). The solution was stirred for 6
h at room temperature, cooled to 0°C and quenched by water (20 ml). The precipitate (iodosobenzoic
acid) was filtered and the filtrate was extracted with dichloromethane (3×20 ml). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel
20
(Et2O:petroleum ether, 1:4) to give the α-ketol 4a as a yellow oil (0.079 g, 80% yield). [α]D −146.8
(c 1.1, CHCl3), [lit. −139.2 (c 1.2, CHCl3), 89% ee].3c Its spectroscopic data were identical to those
reported in the literature.3e
3.8. (1R,5R)-1-(3,3-Dibromo)allyl-3,3-dimethyl-2,4-dioxabicyclo[4.3.0]nonane 11
To a dichloromethane solution (10 ml) containing triphenylphosphine (1.63 g, 6.23 mmol) and the
aldehyde 8 (0.41 g, 2.1 mmol), cooled to −20°C, was added carbon tetrabromide (1.03 g, 3.12 mmol)
in dichloromethane (5 ml). After stirring the reaction mixture for 1 h at room temperature, a mixture
of ether:petroleum ether (10 ml, 1:9) was added. The suspension (PPh3O) was filtered on silica gel
20
(Et2O:petroleum ether, 1:9) to afford the dibromo-olefin 11 (0.58 g, 78%) as an oil. [α]D −16.9 (c 1.6,
1
CHCl3); IR (neat) 3030, 2980, 2930, 2860, 1630, 1360, 1340 cm−1; H NMR: 1.3 (s, 3H, CH3), 1.5
(s, 3H, CH3), 1.1–1.8 (m, 7H), 2.05–2.2 (m, 1H), 2.4 (d, 2H, J=7.3 Hz, CH2CH_CBr2), 3.85 (brs, 1H,
CHOCMe2), 6.58 (t, 1H, J=7.3 Hz, CH_CBr2); 13C NMR: 19.8, 22.8, 26.4, 26.8, 28.4, 34.5, 39.0, 76.3,
79.8, 90.4, 107.3, 134.9; anal. calcd for C12H18Br2O2: C, 40.7; H, 5.12. Found: C, 40.98; H, 5.14.
3.9. (1R,5R)-3,3-Dimethyl-1-(3-trimethylsilylprop-2-ynyl)-2,4-dioxabicyclo[4,3,0]nonane 12
To a cooled solution (−78°C) of the dibromo-olefin 11 (0.51 g, 1.44 mmol) in tetrahydrofuran
(7 ml) was added n-BuLi (2.3 M in hexanes, 1.24 ml, 2 equiv.). After stirring for 1 h at −78°C,
chlorotrimethylsilane was added (0.55 ml, 4.3 mmol). The reaction mixture was stirred for 3 h at room
temperature, concentrated in vacuo and the residue purified by flash column chromatography on silica
20
gel (Et2O:petroleum ether, 1:9) to give 12 as a yellow oil (0.34 g, 89% yield). [α]D −30.9 (c 1.6,
CHCl3); IR (neat) 2990, 2940, 2860, 2180, 1360, 1340 cm−1; 1H NMR: 0.15 (s, 9H, SiMe3), 1.37 (s, 3H,
CH3), 1.45 (s, 3H, CH3), 1.5–1.7 (m, 7H), 2–2.15 (m, 1H), 2.5 (s, 2H, CH2–C^CSiMe3), 4.2 (brs, 1H,
CHOCMe2); 13C NMR: 0.1, 19.6, 22.8, 26.3, 26.9, 28.0, 28.3, 35.3, 75.6, 79.0, 87.3, 103.4, 107.8.
3.10. (1R,2R)-1-(3-Trimethylsilylprop-2-ynyl)-1,2-cyclohexanediol 13
The acetonide hydrolysis of compound 12 (0.23 g) was effected according to the protocol used for 9.
20
The diol 13 was obtained as a white solid in 96% yield. M.p. 94–96°C; [α]D −26.4 (c 0.9, CHCl3); IR
(KBr) 3400, 2980, 2930, 2860, 2180 cm−1; 1H NMR: 0.15 (s, 9H, SiMe3), 1.1–1.9 (m, 8H, 4CH2), 2.4
(brs, 2H, OH), 2.48 (d, 1H, J=17 Hz, CH2C^CSiMe3), 2.6 (d, 1H, J=17 Hz, CH2C≡CSiMe3), 3.6 (dd,
1H, 4 and 9.7 Hz, CHOH); 13C NMR: 0.15, 21.1, 23.8, 30.4, 31.4, 34.8, 72.7, 73.0, 88.5, 103.4; anal.
calcd for C12H22O2Si: C, 63.6; H, 9.79. Found: C, 63.1; H, 9.75.

J.-M. Devaux et al. / Tetrahedron: Asymmetry 9 (1998) 1619–1626
1625
3.11. (2R)-2-(3-Trimethylsilylprop-2-ynyl)-2-hydroxycyclohexanone 4b
The diol 13 (0.123 g) was oxidized by IBX by the same protocol as for 10. Compound 4b was obtained
as a yellow oil in 81% yield. [α]D −92.3 (c 1, CHCl3), [lit. [α]D −93 (c 1.3, CHCl3) >96% ee].3e Its
20
20
spectroscopic data were found to be identical to those reported in the literature.3e
3.12. (1R,2R)-(1,2-Dihydroxycyclopentyl)acetonitrile 16
The AD reaction on 15 (0.53 g, 4.94 mmol) was effected according to the protocol described for
compound 5. The diol 16 was obtained as a white solid in 97% yield (87% ee after two recrystallizations
20
from dichloromethane–hexane). M.p. 70–72°C; [α]D −15 (c 1, CHCl3) (87% ee); IR (KBr), 3400,
3020, 2920, 2240 cm−1; 1H NMR: 1.4–2.1 (m, 6H), 2.56 (d, 1H, J=17 Hz, CH2CN); 2.66 (d, 1H, J=17
Hz, CH2CN), 3.95 (t, 1H, J=7.3 Hz, CHOH). 13C NMR: 19.0, 27.7, 31.7, 35.7, 76.4, 76.7, 117.8.
3.13. (1R,2R)-[(1,2-Isopropylidenedioxy)cyclopentyl]acetonitrile 17
The diol 16 (0.7 g) was protected as an acetonide by the same procedure as for compound 6. The
20
acetonide 17 (0.76 g) was obtained as an oil in 87% yield. [α]D +45 (c 1.2, CHCl3) (61% ee). The
enantiomeric excess was determined by chiral GC analysis: nitrogen (gas carrier); temp. 80–150°C
(4°C/min); retention time (min): 13.03 for (S)-17 and 13.37 for (R)-17. 1H NMR: 1.37 (s, 3H, CH3), 1.42
(s, 3H, CH3), 1.5–2.0 (m, 6H, 3CH2), 2.68 (d, 1H, J=16 Hz, CH2CN), 2.73 (d, 1H, J=16 Hz, CH2CN),
4.47 (d, 1H, J=4.5 Hz, CHOCMe2); 13C NMR: 23.2, 26.4, 27.2, 28.2, 33.3, 38.6, 85.3, 88.3, 110.7, 117.2.
Acknowledgements
We wish to thank the Ministere de l’Enseignement et de la Recherche for fellowship to JMD.
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10. For improvements of the AD reaction see: (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.;
Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D. and Zhang, X. L. J. Org. Chem. 1992, 57, 2768–2771;
(b) Bennani, Y. L. and Sharpless, K. B. Tetrahedron Lett. 1993, 34, 2079–2082.

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11. Takai, K.; Hotta, Y.; Oshima, K. and Nozaki, H. Tetrahedron Lett. 1978, 2417–2420.
12. (a) Frigerio, M. and Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–8022; (b) Frigerio, M.; Santagostino, M.; Sputore,
S. and Palmisano, G. J. Org. Chem. 1995, 60, 7272–7276.
13. The absolute configuration of α-ketols 4a and 4b was determined by comparison of their specific rotations with literature
values.3e
14. Corey, E. J. and Fuchs, P. L. Tetrahedron Lett. 1972, 3769–3772.
15. Nagasaka, T.; Sato, H. and Saeki, S. I. Tetrahedron: Asymmetry 1997, 8, 191–194.
16. Indeed, the acetonide 17 can be transformed by the same reaction sequence as for 7 to the analog of the α-aminoketone
2b, which by palladium-promoted endo-azacyclization, unpublished method developed in our laboratory, will furnish the
lactam 19.