Synthesis of an (R)-Garner-type aldehyde from L-serine: Useful building block for a (+)-furanomycin derivative

Article abstract of DOI:10.1055/s-0028-1087851

(+)-Furanomycin is an antibiotic that substitutes for L-isoleucine in bacterial protein translation. We propose here a new short synthesis of a useful intermediate, a 1,2-diprotected 2-aminopent-4-ene-1,3-diol, starting from the inexpensive natural amino acid L-serine, and via a Garner-type aldehyde. The (R)-α-amino aldehyde was obtained by the construction of an oxazoline ring between the N-protected amino group and the hydroxy group that resulted from reduction of the carboxylic acid functionality of L-serine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087851

PAPER
951
Synthesis of an (R)-Garner-type Aldehyde from L-Serine: Useful Building
Block for a (+)-Furanomycin Derivative
S
ynthesis of an (
R
)
i
-Garne
u
r-type
A
ldeh
s
yde from
e
L
-Serine ppe Bartoli,a Giustino Di Antonio,b Roberto Fiocchi,c Sandra Giuli,*c Enrico Marcantoni,*c Mauro Marcolinic
a
b
c
Department of Organic Chemistry ‘A. Mangini’, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Chemistry Research Centre, Boehringer-Ingelheim S.p.A., via Lorenzini 8, 20139 Milano, Italy
Department of Chemical Sciences, University of Camerino, via S. Agostino 1, 62032 Camerino (MC), Italy
Fax +39(737)402297; E-mail: enrico.marcantoni@unicam.it
Received 10 November 2008; revised 18 November 2008
OH
OH
Abstract: (+)-Furanomycin is an antibiotic that substitutes for L-
isoleucine in bacterial protein translation. We propose here a new
short synthesis of a useful intermediate, a 1,2-diprotected 2-amino-
pent-4-ene-1,3-diol, starting from the inexpensive natural amino
acid L-serine, and via a Garner-type aldehyde. The (R)-a-amino al-
dehyde was obtained by the construction of an oxazoline ring be-
tween the N-protected amino group and the hydroxy group that
resulted from reduction of the carboxylic acid functionality of L-
serine.
NH2
NH2
O
O
O
1
2
Figure 1
Key words: amino acids, diastereoselectivity, lanthanides, natural
products, protecting groups, Wittig reactions
a mercury-cation-promoted cyclization.8 These methods
involve the use of sugars, or similar hydroxy compounds,9
as the chiral pool.10 Two years later, however, Standaert
reported an alternative approach starting from the well-
studied and commercially available (R)-Garner aldehyde
as the chiral building block.11 Garner’s aldehyde repre-
sents an ideal chiral building block for the preparation of
many potentially useful chiral molecules in enantiomeri-
cally pure form.12 The major drawback of Standaert’s syn-
thesis lies in the use of the unnatural and expensive amino
acid D-serine as the starting material. However, although
the (S)-Garner aldehyde could be easily prepared from L-
serine, a unique method to synthesize the (R)-Garner alde-
hyde from a substantially cheaper and more readily avail-
able natural amino acid was developed by Datta using (S)-
methionine.13 To the best of our knowledge, the synthesis
of an (R)-Garner-type aldehyde starting from L-serine is
unprecedented, and it constitutes an attractive source of
chiral nonracemic starting material for many asymmetric
syntheses.14 In this paper, we describe a new method for
the synthesis of the (R)-Garner-type aldehyde 13, and for
the subsequent addition of a vinyl organocerium com-
pound to provide intermediate syn-14 for (+)-furanomy-
cin synthesis.
The increasing need for creating novel compounds that
contain functional and structural diversity continues to
give impetus to method development in synthetic chemis-
try. In this regard, our research interest has been focused
on the total synthesis of small biologically active mole-
cules and of useful building blocks for the synthesis of an-
tibiotics and natural products.1 Recently we have become
interested in the synthesis of olefinic 1,2-amino alcohols2
that are important intermediates for the preparation of
amino acid analogues such as (+)-furanomycin (1)
(Figure 1). First isolated in 1967 by Katagiri and co-
workers3 from the fermentation broth of Streptomyces
threomyceticus, it is one of very few natural amino acid
antibiotics containing a dihydrofuranyl ring system.4 This
non-proteinogenic a-amino acid is one of the smallest an-
tibacterial natural products reported. (+)-Furanomycin (1)
is accepted as a substrate by isoleucyl aminoacyl-tRNA
synthetase, and its antibacterial activity results from sub-
stitution for L-isoleucine (2) (Figure 1) during bacterial
protein translation.5 Several syntheses of (+)-furanomycin
(1) and derivatives have been disclosed, due to the interest
in its activity and its moderate chemical complexity.
Our investigations and studies for a convenient total syn-
thesis of 1 led us to the choice of natural amino acid L-
serine (Scheme 1) as an appropriate starting material for
the synthesis of the dihydrofuranylglycine ring system
present in our antibiotic target. Our retrosynthetic analysis
(Scheme 1) shows that the key step to build the 2,5-disub-
stituted dihydrofuran ring consists of ring-closing meta-
thesis (RCM)15 of 3. The formation of dihydrofuran rings
by RCM is a known procedure, and it is used to build un-
saturated five- or six-membered cyclic ethers.16 Hence,
our initial investigations focused on the stereoselective
synthesis of intermediate syn-14 by vinylation of the cor-
responding a-amino aldehyde 13. To this end, we required
The first total synthesis of a racemic mixture of ( )-fura-
nomycin (1) was published by Masamune and Ono in
1975.6 The first enantioselective synthesis of 1 appeared
five years later when Joullié and co-workers reported a
nine-step synthesis starting from D-glucose.7 In 1998,
Kang et al. proposed a 20-step synthesis, whereby the
trans-2,5-disubstituted dihydrofuran ring was obtained by
SYNTHESIS 2009, No. 6, pp 0951–0956
x
x
.
x
x
.2
0
0
9
Advanced online publication: 02.03.2009
DOI: 10.1055/s-0028-1087851; Art ID: Z24108SS
© Georg Thieme Verlag Stuttgart · New York

952
G. Bartoli et al.
PAPER
OH
O
a general route that would lead to the synthesis of the syn-
thetic equivalent of 4 and the desired (R)-aldehyde 5
(Scheme 1).
TBSO
O
a
OMe
OMe
NH2⋅HCl
NH2
7
8
b
O
O
O
OH
OH
OP
OP
TBSO
TBSO
NH2
NHP
NHP
c
OH
OH
1
3
4
NHBoc
10
NH2
9
OH
O
OH
O
Scheme 2 Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2,
r.t., 48 h; (b) NaBH4, EtOH, 35 °C, 5 h; (c) Boc2O, dioxane, 5 °C,
30 min, then r.t., 3.5 h.
OP
H
OP
OH
NHP
NHP
NH2
6
5
L-serine
TBSO
OH
Scheme 1
O
O
a
b
The retrosynthetic idea presented in Scheme 1 prompted
us to explore the methodology for obtaining the N,O-pro-
tected amino aldehyde 13, derived from L-serine, as the
source of chirality. In this strategy, the S-configuration at
the C2 position of L-serine is opposite to that required for
(+)-furanomycin (1). Thus, we formed an oxazoline ring
of the Garner-type aldehyde starting from compound 10
(see Scheme 2) by a cyclization involving the N-Boc-pro-
tected amino group and the hydroxy group resulting from
the reduced carboxylic moiety (see Scheme 3). Subse-
quent oxidation of the C3 hydroxy group of L-serine yield-
ed the aldehyde with the desired R-configuration, as
required for total synthesis of 1. The preparation of 10 in-
volved protection of the hydroxy group of L-serine as the
silyl ether 8 by treatment with tert-butyldimethylsilyl
chloride (Scheme 2). This protecting group was chosen
for its ease of introduction, and for the nonchelating na-
ture of the resulting silyl ether. In addition, by replacing L-
serine with the commercially available L-serine methyl
ester hydrochloride as starting material, protection of the
acid moiety of L-serine could be avoided. Reduction of 8
to the corresponding amino alcohol 9 was easily achieved
with sodium borohydride (Scheme 2).17 N-Boc protection
of this amino alcohol afforded the desired intermediate 10
in high yield.18
BocN
BocN
10
11
12
c
O
H
O
BocN
13
Scheme 3 Reagents and conditions: (a) cyclohexanone, PTSA, ben-
zene, reflux, 24 h; (b) TBAF, THF, r.t., 2 h; (c) Et3N, DMSO, CH2Cl2,
SO3·py, 0 °C, 15 min, then r.t., 2.5 h.
thesis of the corresponding aldehyde,21 was also unsuc-
cessful because of instability of the resulting aldehyde.
Therefore, in an effort to improve the stereochemical sta-
bility of the target (R)-Garner-type aldehyde, we looked at
increasing the steric bulk of the substituents on the oxazo-
lidine ring. We thus chose to cyclize compound 10 (see
Scheme 3) using a ketone more bulky than acetone, and 4-
tert-butylcyclohexanone was initially chosen based on the
known preference of a 4-tert-butyl group for the equatori-
al position. Oxidation by the sulfur trioxide–pyridine–
dimethyl sulfoxide complex22 resulted in a racemization-
free, but low-yielding procedure. The yield was, however,
satisfactory when cyclohexanone was used in the cycliza-
tion of precursor 10 to afford 11 (Scheme 3).
To form the oxazolidine ring from the resulting amino al-
cohol 10 (Scheme 3), compound 10 was then subjected to
reaction with 2,2-dimethoxypropane in acetone at room
temperature, with boron trifluoride–diethyl ether used as
the catalyst in the absence of solvent.19 However, subse-
quent attempts at oxidizing the thus formed N,O-oxazoli-
dine of 10 by treatment with oxidizing agents such as
pyridinium chlorochromate and the Dess–Martin periodi-
nane and by following the Parikh–Doering procedure
proved unsuccessful due to racemization of the aldehyde
product to various extents. Troublesome oxidations of de-
rivatives of serine have previously been noted.20
Cleavage of the silyl ether moiety in 11 by tetrabutylam-
monium fluoride led to alcohol 12 (Scheme 3). In con-
trast, with our cerium(III) chloride heptahydrate–sodium
iodide system for the deprotection of alkyl silyl ethers23 a
long reaction time was required and the N-Boc protecting
group was also removed.24 The subsequent oxidation of
12, carried out according to the Pfitzner–Moffatt proce-
The alternative protection of the amino group of 9 (see
Scheme 2) as the N-(9-phenylfluoren-9-yl) derivative,
which is known to prevent racemization during the syn-
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PAPER
Synthesis of an (R)-Garner-type Aldehyde from L-Serine
953
dure, afforded the desired stable aldehyde 13 in good yield The two diastereomers anti-14 and syn-14 were easily
(Scheme 3), and its optical rotation matched that found by separable by column chromatography, but because syn-14
Joullié.25 The 1H NMR spectrum of aldehyde 13 at room is necessary for the synthesis of (+)-furanomycin, we
temperature in chloroform-d solution displayed two broad were prompted to further investigate the diastereoselec-
but well-resolved singlets at 9.53 and 9.58 ppm (ratio 4:3) tive addition of the vinyl nucleophile to aldehyde 1. The
for the CHO group, while the 13C NMR spectrum consist- allylic alcohol anti-14 has interesting applications in or-
ed of two sets of resonances for the rotameric mixture. ganic synthesis,33 and the (R)-Garner-type aldehyde 13 is
Similar spectroscopic features have been described for N- a versatile reagent. For example, we found that a Wittig
(tert-butoxycarbonyl)-(S)-propinal by Pettit and co-work- reaction of aldehyde 13 in the presence of a strong base
ers.26 Attempts at improving the yield by using either such as n-butyllithium affords vinyl derivative 17 without
pyridinium chlorochromate or the Dess–Martin reagent epimerization at the stereogenic center (Scheme 5). It is
were again not successful.
known that Garner’s aldehyde can be methylenated with-
out epimerization only when Wittig–Horner conditions
are used.34 Our approach via aldehyde 13 thus provides an
alternative to the latter method in the preparation vinyl-
glycinol 18, a useful chiral building block,35 whose poten-
tial has thus far been limited by its relative inaccessibility.
The interest in this (R)-Garner-type aldehyde 13 as a
building block is due to its possible conversion into other
intermediates that are useful in the synthesis of numerous
compounds of biological interest.27 For instance, the addi-
tion of vinylmetal reagents to carbonyl compounds is rec-
ognized as a fundamental reaction for the preparation of
allylic alcohols. In view of this, we tried the addition of a
vinylcerium reagent, prepared from the corresponding vi-
nyl Grignard reagent and anhydrous cerium(III) chlo-
ride,28 to aldehyde 13 (Scheme 4). The ability of
cerium(III) chloride to mediate high-yielding and highly
diastereoselective transfer of carbon frameworks to alde-
hydes having base-epimerizable centers adjacent to a car-
bonyl group is well known.29 As illustrated in Scheme 4,
we obtained a mixture of allylic alcohols anti-14 and syn-
14, both widely used as building blocks in the syntheses
of naturally occurring and pharmacologically interesting
compounds.30 The anti configuration of the major prod-
uct, allylic alcohol anti-14 (anti-14/syn-14, 82:18), is in
complete agreement with the Felkin–Anh model that pre-
dicts the attack at the Si face.31 The anti diastereoselectiv-
ity was verified by conversion of anti-14 into 1,3-dioxane
16 (Scheme 4), for which the H4–H5 coupling constant
(JH4–H5 = 10 Hz) confirmed a trans relationship for these
two protons and, indirectly, the anti stereochemistry of
adduct anti-14.32
a
H
O
H
OH
NHBoc
13
BocN
17
18
Scheme 5 Reagents and conditions: (a) [Ph3PMe]Br, n-BuLi, THF,
–78 °C, 30 min, then 25 °C, 4 h.
In conclusion, we have presented an improved useful pro-
cedure for obtaining (R)-Garner-type aldehyde 13, an in-
termediate in a known synthesis of (+)-furanomycin (1).
We arrive at the correct absolute configuration without
use of the unnatural D-serine. The stereochemical stability
of our (R)-Garner-type aldehyde allowed us to effect its
methylenation to vinylglycinol derivative 17 without
epimerization by use of a classical Wittig reaction with n-
butyllithium as strong base. Thus, aldehyde 13 can be
used as a building block in the design of new complex
molecules with biological activity. Further studies aimed
at improving the diastereoselectivity of nucleophilic addi-
tions to aldehyde 13 are underway.
OH
OH
a
13
O
Most solvents and reagents were used without purification unless
mentioned otherwise. Solvents (EtOAc and hexane) for flash chro-
matography were distilled. Anhyd THF and Et2O were prepared by
distillation from sodium/benzophenone under a N2 atmosphere im-
mediately before use, while CH2Cl2 was freshly distilled from
CaH2. Et3N was distilled over CaH2 and stored under N2 until used.
Commercial L-serine was used as received. Melting points are un-
corrected. Reactions of compounds sensitive to air or moisture were
performed under N2. 1H and 13C NMR spectra were recorded on a
Varian Mercury 400 spectrometer and are referenced to the solvent
as internal standard. Mass spectra were recorded on a Hewlett-
Packard 6890N gas chromatograph with a mass-selective detector
MSD HP 5973N, utilizing electron ionization at an ionizing energy
of 70 eV. Microanalyses were performed on a Perkin-Elmer Ana-
lyzer 2400 CHN. IR spectra were recorded on a Perkin-Elmer FTIR
Paragon 500 spectrometer using thin films on NaCl plates. Only the
characteristic peaks are quoted. Analytical GC was performed with
a capillary-fused silica column (0.32 mm × 25 m), with stationary
phase OV1 (film thickness 0.40–0.45 mm). Solns were evaporated
under reduced pressure with a rotary evaporator and the residue was
O
BocN
BocN
syn-14
anti-14
82:18
b
O
O
OH
c
OH
NHBoc
15
NHBoc
16
Scheme 4 Reagents and conditions: (a) H2C=CHMgCl, CeCl3,
THF, –78 °C, 2 h, then –30 °C, 1 h; (b) BF3·OEt2, AcOH, MeOH, r.t.,
3 h; (c) (MeO)2CMe2, PPTS, CH2Cl2, r.t., 48 h.
Synthesis 2009, No. 6, 951–956 © Thieme Stuttgart · New York

954
G. Bartoli et al.
PAPER
tert-Butyl (3S)-3-(Hydroxymethyl)-1-oxa-4-azaspiro[4.5]dec-
chromatographed on a Baker silica gel (230–400 mesh) column us-
ing EtOAc–hexanes mixtures as eluent. Analytical TLC was per-
formed using precoated glass-backed plates (Merck Kieselgel 60
F254) and visualized by UV, Von’s reagent, KMnO4, or I2 stain.
ane-4-carboxylate (12)
A soln of 10 (2.00 g, 6.55 mmol) in anhyd benzene (60 mL), freshly
distilled cyclohexanone (65.5 mmol, 6.79 mL), and PTSA·H2O
(0.018 g, 0.098 mmol) were added to a three-necked, round-
bottomed flask, equipped with a magnetic stirring bar, Dean–
Stark trap, thermometer, and a reflux condenser with a CaSO4-filled
drying tube. The mixture was heated at reflux for 24 h. After evap-
oration of the benzene, the cooled amber soln was partitioned be-
tween sat. NaHCO3 soln (75 mL) and Et2O (3 × 150 mL). Then the
organic layer was washed with brine (2 × 30 mL) and dried
(MgSO4), filtered, and concentrated to give the crude product. The
crude was purified by chromatography (silica gel, cyclohexene–
EtOAc, 9:1) to give 11; yield: 1.79 g (71%).
(R)-2-Amino-3-(tert-butyldimethylsiloxy)propan-1-ol (9)
Imidazole (15.2 g, 0.22 mol) was added portionwise to a cooled soln
(0 °C) of L-(+)-serine methyl ester (7; 10 g, 0.064 mmol) and
TBSCl (20.34 g, 0.135 mol) in CH2Cl2 (75 mL) in a three-necked
round-bottomed flask under N2. Then the cooling bath was removed
and the mixture was stirred at r.t. for 48 h. After disappearance of
the starting material, a soln of 2 N HCl was added to the mixture un-
til the pH was 5. The product was extracted from the aqueous soln
with CH2Cl2 (6 × 100 mL). The combined organic layer was
washed with brine (2 × 40 mL) and dried (Na2SO4) and the solvent
was removed in vacuo; this gave 8 as a white solid; yield: 12.99 g
(87%). The compound was used without further purification.
A 1.0 M soln of TBAF in THF (4.67 mL, 4.67 mmol) was added to
a soln of 11 (1.50 g, 3.89 mmol) in anhyd THF (95 mL). After 2 h,
the resulting mixture was partitioned between H2O (2 × 50 mL) and
EtOAc (4 × 60 mL), and the phases were separated. The combined
organic layers were dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, cyclohexane–EtOAc, 7:3) to give compound 12.
The silyl serine methyl ester 8 (2 g, 8.58 mmol) was dissolved in ab-
solute EtOH (34 mL), and NaBH4 (1.30 g, 34.28 mmol) was added
at once. The mixture was warmed to 35 °C, and the reduction was
complete after 5 h. Then the mixture was treated with a pH 3 phos-
phate buffer and the hydrolysis was monitored by GC-MS. After 1.5
h, the mixture was concentrated and the silyl amino alcohol 9 was
extracted with CHCl3 (3 × 50 mL). Purification by chromatography
(silica gel, CHCl3–MeOH, 9:1) gave product 9.
Yield: 2.59 g (79%); colorless oil; [a]D25 +3.4 (c 1.60, CHCl3).
IR (neat): 3449, 3352, 1648, 1389, 1361 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.02 (s, 6 H), 0.90 (s, 9 H), 2.27
(br s, 3 H), 2.99 (t, J = 4.9 Hz, 1 H), 3.53 (dd, J = 10.7, 6.0 Hz, 1 H),
3.58–3.68 (m, 3 H).
Yield: 0.89 g (86%); white crystals; mp 104 °C.
IR (neat): 3477, 1667, 1376, 1295, 1276 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.00–1.80 (m, 17 H), 1.85–2.45
(m, 2 H), 2.74 (br s, OH, 1 H), 3.45–4.15 (m, 5 H)
13C NMR (100 MHz, CDCl3): d = 22.6, 23.6, 25.7, 28.6, 31.8, 35.8,
45.0, 63.3, 65.8, 95.7, 98.6, 155.0.
Anal. Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C,
61.95; H, 9.28; N, 5.10.
13C NMR (100 MHz, CDCl3): d = –5.7, 19.2, 24.3, 54.2, 64.2, 65.
MS (EI, 70 eV): m/z = 205 [M+], 174, 158, 148, 131, 119, 101, 75
tert-Butyl (3R)-3-Formyl-1-oxa-4-azaspiro[4.5]decane-4-car-
boxylate (13)
(100), 60.
Freshly distilled Et3N (1.84 mL, 13.24 mmol) was added to a soln
of alcohol 12 (0.50 g) in freshly distilled DMSO (1.85 mL) and
CH2Cl2 (15 mL) and the soln was stirred under argon at 0 °C.
SO3·py complex (1.184 g, 7.44 mmol) was added portionwise and
the reaction mixture was stirred at the same temperature for 15 min.
Then the mixture was allowed to warm to r.t., stirred for 2.5 h, di-
luted with CH2Cl2 (100 mL), and poured into ice water (100 mL).
The organic phase was separated, and the aqueous phase was ex-
tracted with CH2Cl2 (4 × 60 mL). The combined organic soln was
washed with H2O (2 × 35 mL) and brine (2 × 20 mL), dried
(MgSO4), and concentrated. This gave aldehyde 13 virtually pure
[GC-MS showed 1.67% of the (methylsulfanyl)methyl ether
formed by a Pummerer rearrangement], pure enough to be used in
the following step.
Anal. Calcd for C9H23NO2Si: C, 52.63; H, 11.29; N, 6.82. Found: C,
52.58; H, 11.28; N, 6.80.
tert-Butyl N-[(1R)-2-(tert-Butyldimethylsiloxy)-1-(hydroxy-
methyl)ethyl]carbamate (10)
A soln of (Boc)2O (1.76 g, 8.06 mmol) in dioxane (6.5 mL) was
added dropwise to an ice-cold, magnetically stirred soln of 9 in 1 N
aq NaOH (14 mL). The mixture (two-phase) was stirred at 5 °C for
30 min, then allowed to warm to r.t., and stirred overnight. The mix-
ture was concentrated to half its original volume by rotary evapora-
tion. It was then cooled in an ice–water bath, acidified to pH 2–3 by
the slow addition of 1 N aq KHSO4, and then extracted with EtOAc
(4 × 50 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated; this gave amino alcohol 10. The product
was used without further purification.
Yield: 0.427g (86%); colorless oil; [a]D25 +65.6 (c 1.57, CHCl3).
IR (neat): 2863, 1738, 1709, 1452, 1365 cm–1.
Yield: 3.45 g (93%); colorless oil.
IR (neat): 3449, 3360, 1714, 1694 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.01–1.78 (m, 17 H), 1.95–2.55
(m, 2 H) 3.92–4.35 (m, 3 H), 9.53 (s, 1 H), 9.58 (s, 10 H).
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 6 H), 0.89 (t, J = 2.7 Hz,
9 H), 1.45 (s, 9 H), 2.80 (br s, 1 H, OH), 3.51–3.71 (m, 2 H), 3.75–
3.85 (m, 3 H), 5.30 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = –4.8, 19.0, 25.7, 28.6, 54.0, 64.3,
79.0, 154.9.
13C NMR (100 MHz, CDCl3): d = 23.4, 24.7, 25.1, 28.5, 31.6, 32.4,
34.3, 35.3, 63.6, 64.1, 64.9, 81.3, 96.3, 151.3, 200.2.
MS (EI, 70 eV): m/z = 269 [M+], 240, 213, 196, 184, 140, 126, 96,
57 (100), 41, 29.
Anal. Calcd for C14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C,
62.42; H, 8.58; N, 5.18.
MS (EI, 70 eV): m/z = 274, 232, 218, 192, 174, 148, 131, 116, 100,
75, 57 (100), 41.
tert-Butyl (3R)-3-[(1R)-1-Hydroxyallyl]-1-oxa-4-aza-
spiro[4.5]decane-4-carboxylate (syn-14) and tert-Butyl (3R)-3-
[(1S)-1-Hydroxyallyl]-1-oxa-4-azaspiro[4.5]decane-4-carboxy-
late (anti-14)
Anal. Calcd for C14H31NO4Si: C, 55.04; H, 10.23; N, 4.59. Found:
C, 54.99; H, 10.20; N, 4.55.
CeCl3·7H2O (0.16 g, 0.43 mmol) was quickly and finely ground to
a powder in a mortar and placed in a 100-mL three-necked flask.
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PAPER
Synthesis of an (R)-Garner-type Aldehyde from L-Serine
955
The flask was immersed in an oil bath and heated gradually to 135–
140 °C under vacuum (<0.5 Torr). The powder was heated without
stirring for 1 h, and then the CeCl3 was stirred at the same tempera-
ture for another 1 h to be dried completely. While the flask was still
hot, N2 was introduced, and the powder was cooled in an ice bath.
Freshly distilled THF (10 mL) was added all at once with vigorous
stirring. The ice bath was removed and the suspension was well
stirred overnight under N2 at r.t. The flask was cooled at –78 °C and
a freshly prepared 0.87 M soln of vinylmagnesium bromide in THF
(0.49 mL, 0.43 mmol) was added slowly. The mixture was stirred at
–30 °C for 1 h, and then cooled at –78 °C while a soln of aldehyde
13 (0.40 g, 0.148 mmol) in THF (5 mL) was added dropwise to the
mixture. The reaction mixture was stirred for 2 h at –78 °C and for
1 h at –30 °C. The reaction was monitored by TLC and GC-MS. To
the mixture was added a sat. soln of NH4Cl (15 mL) and the flask
was allowed to warm to r.t. Then the aqueous phase was extracted
with Et2O (4 × 40 mL) and the combined organic extract was
washed with sat. NaHCO3 soln (20 mL) and brine (20 mL) and dried
(MgSO4). The crude mixture of diastereomers 14 was purified by
chromatography (silica gel, cyclohexane–EtOAc, 8:2).
mL, 0.61 mmol) was added dropwise. The mixture was stirred for
0.5 h, allowing the temperature to reach 0 °C, at which point it was
stirred for an additional 1 h. The resulting dark red soln was used for
the Wittig reaction with aldehyde 13. The soln was cooled (–78 °C)
and compound 13 (0.165 g, 0.612 mmol) in THF (5 mL) was added
dropwise over 10 min. The reaction mixture was stirred under N2;
the temperature was allowed to reach 25 °C and then the mixture
was stirred for 4 h. After the reaction was quenched by the addition
of sat. aq NH4Cl (30 mL), the THF was evaporated under reduced
pressure and the residue was extracted with EtOAc (4 × 40 mL).
The combined organic phases were washed with H2O (25 mL) and
brine (15 mL) and dried (MgSO4). After evaporation of the solvent
under reduced pressure, the residue was purified by flash chroma-
tography (cyclohexane–EtOAc, 9:1).
Yield: 0.115 g (75%); colorless oil; [a]D –10.9 (c 1.46, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.80–1.85 (m, 17 H), 2.00–2.57
(m, 2 H), 3.72 (dd, J = 8.8, 2.0 Hz, 1 H), 3.98 (dd, J = 8.8, 5.9 Hz,
1 H), 4.18–4.45 (m, 1 H), 5.05–5.30 (m, 1 H), 5.69–5.90 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.6, 24.8, 28.6, 30.9, 35.1, 59.8,
68.1, 79.9, 95.6, 115.8, 137.8, 152.8.
MS (EI, 70 eV): m/z = 267 [M+], 211, 168, 124, 111, 70, 57 (100),
41.
Yield: 0.10 g (86%); anti-14/syn-14 (82:18).
IR (neat): 3418, 3078, 1694, 1455, 1392 cm–1.
1H NMR (400 MHz, CDCl3): d (anti-14) = 0.95–1.70 (m, 17 H),
1.82–2.45 (m, 2 H), 3.65–4.25 (m, 4 H), 5.17 (dt, J = 10.4, 1.65 Hz,
1 H), 5.33 (d, J = 17.2 Hz, 1 H), 5.76–5.90 (m, 1 H).
1H NMR (400 MHz, CDCl3): d (syn-14) = 0.95–1.75 (m, 17 H),
1.85–2.65 (s, 2 H), 3.65–4.42 (m, 4 H), 5.20 (d, J = 10.4 Hz, 1 H),
5.31 (d, J = 17.1 Hz, 1 H), 5.72–5.84 (m, 1 H).
13C NMR (100 MHz, CDCl3): d (anti-14) = 23.5, 25.1, 28.5, 29.8,
31.5, 34.9, 61.7, 64.5, 74.3, 81.4, 96.0, 116.3, 137.1, 154.4.
13C NMR (100 MHz, CDCl3): d (syn-14) = 23.6, 25.1, 28.5, 29.9,
31.2, 35.7, 61.7, 64.2, 75.7, 81.8, 96.0, 118.0, 137.6, 152.3.
Acknowledgment
This work was carried out in the framework of the National Project
‘Studio degli Aspetti Teorici ed Applicativi degli Aggregati di
Molecole Target su Siti Catalitici Stereoselettivi’ supported by the
MIUR, Rome, and by the University of Camerino. G.D.A. grate-
fully acknowledges Boehringer Ingelheim for a doctoral fellowship.
We thank Pfizer Italia Ascoli Piceno Plant and GoldenPlast Potenza
Picena for granting doctoral fellowships to M.M. and R.F., respec-
tively. Special thanks are due to Dr. Riccardo Giovannini of
Boehringer-Ingelheim, Milan, for helpful discussions.
MS (EI, 70 eV): m/z = 297 [M+], 240, 184, 154, 140, 123, 96, 81,
69, 57(100), 41, 29.
Anal. Calcd for C16H27NO4: C, 64.62; H, 9.15; N, 4.71. Found: C,
64.55; H, 9.08; N, 4.70.
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IR (neat): 3079, 1703, 1368, 1160, 1066 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.43 (s, 9 H), 1.49 (s, 6 H) 3.45–
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Synthesis 2009, No. 6, 951–956 © Thieme Stuttgart · New York