General enantioselective synthesis of butyrolactone natural products via ruthenium-SYNPHOS-catalyzed hydrogenation reactions

Article abstract of DOI:10.1002/adsc.200600504

Enantioselective syntheses of several paraconic acids have been achieved using catalyzed asymmetric hydrogenation of β-keto esters with SYNPHOS as a ligand. This strategy allowed the short synthesis of biologically active (-)-methylenolactocin 1, (-)-protolichesterinic acid 2, (-)-phaseolinic acid 3 and (+)-roccellaric acid 4.

Full text of DOI:10.1002/adsc.200600504

FULL PAPERS
DOI: 10.1002/adsc.200600504
General Enantioselective Synthesis of Butyrolactone Natural
Products via Ruthenium-SYNPHOSꢀ-Catalyzed Hydrogenation
Reactions
Delphine Blanc,a Jonathan Madec,a Florence Popowyck,a Tahar Ayad,a
Phannarath Phansavath,a,* Virginie Ratovelomanana-Vidal,a,*
and Jean-Pierre GenÞta,*
a
Laboratoire de Synth›se SØlective Organique et Produits Naturels, Ecole Nationale SupØrieure de Chimie de Paris, UMR
7573 CNRS, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax : (+33)-1-4407-1062; e-mail: jean-pierre-genet@enscp.fr, virginie-vidal@enscp.fr or phannarath-phansavath@enscp.fr
Received: October 4, 2006
Abstract: Enantioselective syntheses of several para- lactocin 1, (À)-protolichesterinic acid 2, (À)-phaseo-
conic acids have been achieved using catalyzed linic acid 3 and (+)-roccellaric acid 4.
asymmetric hydrogenation of b-keto esters with
SYNPHOSꢀ as a ligand. This strategy allowed the Keywords: asymmetric catalysis; atropisomerism; hy-
short synthesis of biologically active (À)-methyleno- drogenation; ruthenium; total synthesis
Introduction
Paraconic acids (3-carboxylic acid substituted g-butyr-
olactones) are a class of trisubstituted g-butyrolac-
tones of biological significance exhibiting antibiotic
and antitumor properties.[1] Their structural units fre-
quently occur in natural products such as alkaloids,
macrocyclic antibiotics and pheromones.[2] Conse-
quently, they have attracted considerable interest
over the years.[3] Characteristic features of this class
of compounds are the C-4 carboxyl functionality as
well as an alkyl chain at C-5, ranging in length from
five to fifteen carbon atoms. The C-3 center, bearing
Scheme 1. Structures of paraconic acids 1–4.
a methylene or a methyl group, plays a vital role in
the biological activity of the molecule (Scheme 1).
Due to their interesting biological properties, nu-
merous syntheses of compounds 1–4 have been re- SYNPHOSꢀ towards the synthesis of key intermedi-
ported in both racemic and enantioselective versions, ates for the preparation of target molecules of syn-
using the chiral pool,[4] chiral auxiliaries,[5] catalytic thetic interest.[8] As part of our continuing interest in
asymmetric methodologies,[6] or enzymatic routes.[7] the homogeneous ruthenium-promoted hydrogenation
However, many of these syntheses suffer from poor reactions,[10] we report in this paper, a new application
overall yields, large number of steps, and lack of gen- of SYNPHOSꢀ ligand for a general route to paraconic
erality. Our interest in the use of ruthenium-mediated acids using an Ru-SYNPHOSꢀ-catalyzed asymmetric
asymmetric hydrogenation for the preparation of bio- hydrogenation reaction as key step.
logically relevant molecules[8] led us to study the de-
Our retrosynthetic analysis is based on ruthenium-
velopment of a general strategy for the stereoselective catalyzed asymmetric hydrogenation of b-keto esters
synthesis of the paraconic acids 1–4. Recently, we suc- 6 or 13 to install the C-5 hydroxy-bearing stereocen-
ceeded in designing and developing a new atropiso- ter, followed by diastereoselective alkylation, lactoni-
meric diphosphine named SYNPHOSꢀ.[9] Our group zation, and finally methylation or methylenation at
has focused on expanding the versatile applications of the C-3 center to give the desired paraconic acids 1–4
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Delphine Blanc et al.
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(Scheme 2). Thus, cis-g-butyrolactone 9 (R=C5H11)
would serve as the common intermediate for the syn-
thesis of (À)-methylenolactocin 1 and (À)-phaseolinic
Scheme 2. Retrosynthetic analysis of paraconic acids 1-4.
acid 3, while (À)-protolichesterinic acid 2 would
result from cis-g-butyrolactone 17 (R=C13H27). Final-
ly, (+)-roccellaric acid 4 would be obtained by meth-
ylation of cis-g-butyrolactone (ent)-17, which would
easily result from b-keto ester 13. One relevant fea-
ture of this approach is that both enantiomers of lac-
tones 9 and 17 could be synthesized with high enan-
tio-and diastereoselectivities starting from the same
b-keto esters 6 and 13, respectively, using an asym-
metric Ru-SYNPHOSꢀ-mediated hydrogenation as
the key step.
Scheme 3. Total synthesis of (À)-methylenolactocin 1.
Results and Discussion
The synthesis of (À)-methylenolactocin 1 began with 67% yield as a single diastereomer after flash chro-
commercially available hexanoyl chloride 5 which was matographic separation. Oxidation-lactonization of 8
converted into the corresponding b-keto ester 6 using was accomplished by ozonolysis in CH2Cl2/MeOH (9/
Wempleꢂs procedure[11] (Scheme 3). Thus, treatment 1) followed by treatment with a catalytic amount of
of 5 with monomethyl monopotassium malonate, p-toluenesulfonic acid in toluene which gave the de-
magnesium chloride and triethylamine in acetonitrile, sired lactone 9 in 64% yield. The trans-lactone 10, re-
afforded 6 in 94% yield. The asymmetric hydrogena- quired for the synthesis of (À)-methylenolactocin 1
tion of 6 was carried out under a low hydrogen pres- was prepared by treatment of 9 with DBU at room
sure of 5 bar in methanol at S/C=200 by using the in temperature to effect smooth equilibration into the
situ generated {RuBr2[(S)-SYNPHOS]ꢀ} complex[9e] C-4 epimeric lactone 10. Subsequent hydrolysis of
prepared from a mixture of commercially available compound 10 yielded quantitatively the correspond-
(COD)Ru(2-methylallyl)2 and the diphosphine by ad- ing carboxylic acid 11. For the introduction of the
dition of 2.2 equivs. of HBr according to our conven- exo-methylene group at the C-3 center, we followed
ient procedure.[12] Under the above conditions, (S)- the procedure reported by Greene et al.[5h] Thus, com-
methyl 3-hydroxyoctanoate 7 was obtained in 96% pound 11 was treated with Stiles reagent[14] (magne-
yield and with excellent enantioselectivity (ee sium methylcarbonate in DMF) at 1358C for 69 h,
>99.5%).
then with a solution of aqueous formaldehyde and N-
Alkylation of 7 with allyl bromide using the Frµter– methylaniline in the presence of sodium acetate to
Seebach conditions[13] then afforded compound 8 in afford 1 in 51% yield. We have thus completed a
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short synthesis of (À)-methylenolactocin 1 (seven method. Then, asymmetric hydrogenation of 13 was
steps from commercially available hexanoyl chloride) performed in methanol at 508C under 5 bar of hydro-
using ruthenium-SYNPHOSꢀ-mediated hydrogenation gen and using either (S)-or ( R)-SYNPHOSꢀ as a
as a key step to install the C-5 stereocenter with high ligand to afford respectively the corresponding b-hy-
enantioselectivity.
droxy esters 14 and (ent)-14 in 94% yield and with
In an analogous way, (À)-protolichesterinic acid 2 excellent enantioselectivity (ee >99.5%). Diastereo-
and (+)-roccellaric acid 4 were synthesized starting selective alkylation of 14 and (ent)-14 with allyl bro-
from commercially available tetradecanoyl chloride mide readily furnished respectively 15 and (ent)-15 as
12 as depicted in Scheme 4. b-Keto ester 13 was first single diastereomers after flash chromatographic sep-
prepared in high yield from 12 by using Wempleꢂs aration. Ozonolysis of 15 was then performed using
the same conditions as for the parent compound 8.
However, several attempts at ozonolysis resulted only
in recovery of the starting material. Therefore, we de-
cided to use the RuCl3/NaIO4 system for the oxida-
tion of compound 15. The oxidation-lactonization se-
quence was carried out after protection of 15 as its
tert-butyldimethylsilyl ether 16. Thus, exposure of 16
and (ent)-16 to sodium periodate and catalytic ruthe-
nium chloride in carbon tetrachloride/acetonitrile/
water (1/1/1), followed by treatment with para-tolue-
nesulfonic acid in methanol, afforded respectively g-
butyrolactones 17 and (ent)-17, which underwent
smooth equilibration into trans-lactones 18 and (ent)-
18 in the presence of DBU.
Subsequent hydrolysis of compound 18 furnished
the corresponding carboxylic acid 19 in 98% yield.
This compound has been previously converted into
(À)-protolichesterinic acid 2 by Greene et al.[5h] in
68% yield. We have thus completed a formal total
synthesis of 2 in good overall yield (32%) and with
very high enantio-and diastereoselectivities. A total
synthesis of (+)-roccellaric acid 4 was achieved as
well starting from (ent)-18. Diastereoselective methyl-
ation of lactone (ent)-18 proceeded in very low
yield.[17] Hydrolysis of the methylated compound fi-
nally afforded the natural product in 60% yield.
(À)-Phaseolinic acid 3 was prepared from the previ-
ously synthesized syn-lactone 9 (Scheme 5) following
the two-step sequence already used for the prepara-
tion of compound 4. Thus, the methyl group at the
C-3 stereocenter was set in good yield and in a highly
Scheme 4. Total synthesis of (À)-protolichesterinic acid 2
and (+)-roccellaric acid 4.
Scheme 5. Synthesis of (À)-phaseolinic acid 3.
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Delphine Blanc et al.
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tube, degassed by three vacuum/argon cycles at room tem-
perature, and dissolved in degassed acetone (1 mL). To this
suspension was added at room temperature a 0.15 N metha-
nolic HBr solution (147 mL, 0.022 mmol) and the mixture
was stirred at 258C for 30 min. After evaporation of the sol-
vent under vacuum, a solution of b-keto ester (2 mmol) in
MeOH (2 mL) was added to the ruthenium catalyst. The re-
sulting mixture was placed under the desired hydrogen pres-
sure and temperature for 24 h. After removal of the solvent,
the residue was purified by flash chromatography on silica
gel to afford the b-hydroxy ester.
diastereoselective manner by treatment with
NaHMDS/methyl iodide, and subsequent hydrolysis
finally delivered (À)-phaseolinic acid 3 in 91% yield.
Conclusions
In summary, we have developed a concise and effi-
cient enantioselective synthesis towards a variety of
paraconic acids using catalytic asymmetric hydrogena-
tion of achiral b-keto esters as the key step to set the
hydroxy function at the C-5 stereocenter. We have
shown that the SYNPHOSꢀ ligand can be efficiently
used in these transformations, providing the develop-
ment of a general route to trisubstituted g-butyrolac-
tones. This flexible method allowed the synthesis of
four members of the paraconic acids class, which were
obtained in seven to nine steps starting from inexpen-
sive acid chlorides (for comparison, the other report-
ed syntheses generally involve up to fourteen steps,
and only four steps for the shortest one).
Methyl 3-Oxooctanoate (6)
To a suspension of potassium methyl malonate (14.3 g,
92.0 mmol) in CH3CN (125 mL) at 58C was added Et3N
(12.4 mL, 88.7 mmol) followed by anhydrous MgCl2 (10.6 g,
111.4 mmol). The mixture was stirred at room temperature
for 3 h, then cooled to 08C and hexanoyl chloride (5.7 g,
42.0 mmol) was added dropwise followed by the addition of
more Et3N (1.38 mL, 9.8 mmol). The mixture was allowed to
stir for 20 h at room temperature and concentrated. Et2O
(100 mL) was added to the resulting solid followed by 6 N
HCl until complete dissolution of the precipitate. The aque-
ous layer was separated and extracted with Et2O. The com-
bined organic layers were washed with saturated Na2CO3
followed by brine, dried (MgSO4) and concentrated under
vacuum. The residue was purified by Kugelrohr distillation
(bp 888C/0.4 torr) to give 6 as a colorless oil; yield: 6.8 g
Experimental Section
General Remarks
1
(94%); IR (neat): n=1750, 1720 cmÀ1; H NMR (200 MHz,
All solvents were reagent grade and distilled under positive
pressure of argon prior to use. Amines and CH2Cl2 were dis-
tilled from calcium hydride. THF was distilled from sodium-
benzophenone. Unless specially mentioned, all reactions
were carried out under an argon atmosphere. All commer-
cially available reagents were used without further purifica-
tion unless otherwise indicated. Nuclear magnetic reso-
nance: 1H-and 13C NMR spectra were recorded either at
200 MHz and 50 MHz, respectively, on an AC200 Brüker
spectrometer, or at 400 MHz and 100 MHz, respectively, on
an ARX400 Brüker spectrometer. Infrared spectra (IR)
were recorded on either a Perkin–Elmer 783G spectrometer
or an IRFT Nicolet 205 spectrometer. Mass spectra (MS)
were measured on a Hewlett–Packard 5989 A (70 eV) mass
spectrometer. Flash column chromatography was performed
on Merck silica gel (0.040–0.063 mesh). Thin layer chroma-
tography (TLC) analysis was performed on Merck silica gel
60 PF 254 and revealed either by UV light at 254 nm or by
a potassium permanganate solution. Melting points (mp)
were determined on a Kofler melting point apparatus and
are uncorrected. Optical rotation values were measured
with a Perkin–Elmer 241 polarimeter. High performance
liquid chromatography analyses (HPLC) were performed on
a Waters instrument (Waters 486 detector, 717 autosampler).
Elemental analysis was performed by the Service RØgional
de Microanalyse de l’UniversitØ Pierre et Marie Curie.
CDCl3): d=11.94 (s, 1H, enol form), 4.90 (s, 1H, enol
form), 3.64 (s, 3H), 3.37 (s, 2H), 2.45 (t, 2H, J=7.3 Hz),
1.50 (m, 2H), 1.21 (m, 4H), 0.80 (t, 3H, J=6.7 Hz);
13C NMR (50 MHz, CDCl3): d=202.6, 167.5, 51.9, 48.7, 42.7,
30.9, 22.9, 22.2, 13.6; MS (EI): m/z=172 [M+·].
(S)-Methyl 3-Hydroxyoctanoate (7)
Methyl 3-oxooctanoate 6 (10.0 g, 58.1 mmol) was hydrogen-
ated according to the general procedure for hydrogenation,
using 0.5 mol% of the catalyst [Ru((S)-SYNPHOS)Br2] in
MeOH (5 mL) at 508C under 5 bar of hydrogen for 24 h.
The reaction mixture was concentrated and the residue was
purified by Kugelrohr distillation (bp 1408C/2 torr) to afford
7 as a colorless oil; yield: 9.7 g (96%); [a]2D0: +22.4 (c 2.0,
CHCl3), lit.[15] [a]D24: +24 (c 1.0, CHCl3); IR (neat): n=3400
(broad), 1735 cmÀ1 1H NMR (200 MHz, CDCl3): d=4.03
;
(m, 1H), 4.74 (s, 3H), 2.92 (d, 1H, J=4.0 Hz), 2.55 (dd, 1H,
J=16.4 and 3.6 Hz), 2.42 (dd, 1H, J=16.4 and 8.5 Hz),
1.60–1.25 (m, 8H), 0.91 (t, 3H, J=6.4 Hz); 13C NMR
(50 MHz, CDCl3): d=173.3, 67.8, 51.5, 41.1, 36.4, 31.5, 25.0,
22.4, 13.8; MS (EI): m/z=175 [M+ +1]; anal. calcd. for
C9H18O3 (174.24): C 62.04, H 10.41; found: C 61.96, H 10.44.
HPLC analysis (of the corresponding acetate): column, Chir-
alcel AS-H; eluent, hexane/propan-2-ol, 98/2; flow rate:
1.0 mLminÀ1; detection: 215 nm, tR: 6.78 min, (S)-7, tR:
7.32 min, (R)-7.
General Procedure for the Asymmetric
Hydrogenation of b-Keto Esters
A
(R)- or (S)-SYNPHOSꢀ (7.7 mg, 0.012 mmol) and
(COD)Ru(2-methylallyl)2 (3.2 mg, 0.01 mmol, commercially
available from Acros), were placed in a round-bottomed
To a solution of LDA (70.4 mmol) in THF was added drop-
wise at À788C a solution of 7 (5.0 g, 28.7 mmol) in THF
(68 mL). The mixture was stirred at À788C for 1 h and allyl
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bromide (6.3 mL, 71.8 mmol) was added followed by HMPA
(9.3 mL, 51.7 mmol). After being stirred for 1 h at À788C,
the reaction mixture was slowly warmed to À208C, stirred
at this temperature for 1 h and saturated NaHCO3 was
added at 08C followed by Et2O. A 10% HCl solution was
slowly added until pH 2 and the aqueous layer was extracted
with Et2O. The combined organic layers were washed with
water and brine, dried (MgSO4) and concentrated under
vacuum. Purification of the residue by flash chromatography
(1 to 10% AcOEt in cyclohexane) afforded 8 as a colorless
oil; yield: 4.1 g (67%); [a]20: À4.2 (c 1.05, CHCl3); IR
AHCTREUNG
To a solution of 10 (126 mg, 0.59 mmol) in dioxane (6.3 mL)
was added 6 N HCl (3.6 mL) at room temperature. The mix-
ture was refluxed for 2 h and concentrated under vacuum.
An acid/base treatment then furnished 11 as a white solid;
yield: 114 mg (97%); [a]2D0: À52 (c 0.5, CHCl3), lit.[5i] [a]2D0:
À54 (c 0.5, CHCl3); IR (CH2Cl2): n=1760, 1725 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.96 (br s, 1H), 4.62 (q,
1H, J=7.0 Hz), 3.05 (m, 1H), 2.93 (dd, 1H, J=17.9 and
8.4 Hz), 2.82 (dd, 1H, J=17.9 and 9.6 Hz), 1.90–1.20 (m,
8H), 0.89 (m, 3H); 13C NMR (100 MHz, CDCl3): d=176.6,
174.8, 82.2, 45.8, 35.7, 32.3, 31.7, 25.2, 22.8, 14.3; MS (CI,
NH3): m/z=218 [M+ +NH4].
(neat): n=3400 (broad), D1740, 1660 cmÀ1
;
1H NMR
(200 MHz, CDCl3): d=5.76 (ddt, 1H, J=17.0, 10.1 and
7.0 Hz), 5.05 (m, 2H), 3.73 (s, 3H), 3.75–3.60 (m, 1H), 2.62–
2.38 (m, 4H), 1.50–1.20 (m, 8H), 0.91 (t, 3H, J=6.4 Hz);
13C NMR (50 MHz, CDCl3): d=175.1, 134.7, 117.0, 71.6,
51.4, 50.4, 35.3, 33.6, 31.5, 25.2, 22.4, 13.8; MS (EI): m/z=
215 [M+ +1].
(À)-Methylenolactocin (1)
A 2M solution of methoxymagnesium methyl carbonate in
DMF (3.7 mL, 7.16 mmol) was added to 11 (42 mg,
0.21 mmol) and the mixture was stirred at 1358C for 69 h,
hydrolyzed with 10N HCl and extracted with CH2Cl2. The
combined organic layers were dried (MgSO4) and concen-
trated under vacuum. To the crude product was added an
aqueous solution (330 mL) of formaldehyde and N-methyla-
niline [prepared by mixing acetic acid (5.0 mL), a solution
of 30% formaldehyde in H2O (4.6 mL), N-methylaniline
(1.3 mL) and sodium acetate (150 mg)] and the mixture was
stirred at room temperature for 2 h, diluted with CH2Cl2,
washed with brine, dried (MgSO4) and concentrated. Purifi-
cation of the residue by flash chromatography (CHCl3/
AcOEt/AcOH: 90/8/2) furnished 1 as a white solid; yield:
23 mg (51%); [a]D20: À10 (c 0.5, MeOH), lit.[5i] [a]2D0: À6.8 (c
(3S,4S)-3-Methoxycarbonyl-4-pentyl-g-butyrolactone
(9)
At À788C, a stream of ozone was bubbled through a solu-
tion of 8 (500 mg, 2.33 mmol) in CH2Cl2/MeOH (9/1 mL)
until a persistent blue color was perceived. The excess of
ozone was then chased away by bubbling argon through the
solution to give a colorless mixture which was concentrated.
The crude residue was dissolved in toluene and a catalytic
amount of PTSA was added. The reaction mixture was stir-
red at 808C for 1 h and concentrated. Purification of the res-
idue by flash chromatography (10% to 40% AcOEt in cy-
clohexane, water deactivated silica gel) afforded 9 as a
yellow solid; yield: 319 mg (64%); [a]2D0: À81 (c 0.97,
CHCl3), lit.[5h] [a]D21: À78 (c 1.0, CHCl3); IR (CH2Cl2): n=
0.5, MeOH); IR (CH2Cl2): n=1760, 1710 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=8.95 (br s, 1H), 6.46 (d, 1H, J=
2.9 Hz), 6.02 (d, 1H, J=2.6 Hz), 4.81 (m, 1H), 3.62 (td, 1H,
J=5.7 and 2.8 Hz), 1.80–1.65 (m, 2H), 1.60–1.22 (m, 6H),
0.90 (t, 3H, J=6.6 Hz); 13C NMR (100 MHz, CDCl3): d=
172.4, 168.2, 132.6, 125.8, 78.9, 49.4, 35.8, 31.4, 24.5, 22.5,
14.0; MS (EI): m/z=213 [M+ +1].
1790, 1745 cmÀ1 1H NMR (200 MHz, CDCl3): d=4.63 (m,
;
1H), 3.76 (s, 3H), 3.45 (ddd, 1H, J=8.6, 7.3 and 5.6 Hz),
2.91 (dd, 1H, J=17.6 and 5.6 Hz), 2.67 (dd, 1H, J=17.6 and
8.6 Hz), 1.70–1.20 (m, 8H), 0.91 (m, 3H); 13C NMR
(50 MHz, CDCl3): d=174.8, 170.7, 80.4, 52.2, 44.2, 31.7
(2C), 31.3, 25.4, 22.4, 13.9; MS (EI): m/z=215 [M+ +1];
anal. calcd. for C11H18O4 (214.26): C 61.66, H 8.47; found: C
61.76, H 8.37.
Methyl 3-Oxohexadecanoate (13)
Starting from tetradecanoyl chloride (4.8 g, 19.6 mmol) and
following the procedure described for the preparation of
compound 6, ester 13 was obtained after flash chromatogra-
phy (10% AcOEt in cyclohexane) as a white solid; yield:
A
(10)
5.3 g (94%); mp 39–408C; IR (KBr): n=1750, 1725 cmÀ1
;
1H NMR (200 MHz, CDCl3): d=3.77 (s, 3H), 3.47 (s, 2H),
2.55 (t, 2H, J=7.2 Hz), 1.59 (m, 2H), 1.45 (m, 20H), 0.91 (t,
3H, J=6.7 Hz); 13C NMR (50 MHz, CDCl3): d=202.1,
173.6, 52.2, 48.9, 42.9, 31.8, 29.2 (8C), 23.4, 22.6, 14.0; MS
(EI): m/z=285 [M+ +1]; anal. calcd. for C17H32O3 (284.44):
C 71.79, H 11.34; found: C 71.96, H 11.25.
To a solution of 9 (154 mg, 0.72 mmol) in CH2Cl2 (10 mL)
was added DBU (258 mL, 1.72 mmol) and the resulting mix-
ture was stirred at room temperature for 72 h, diluted with
AcOEt and washed with saturated NH4Cl. The organic layer
was separated, washed with brine, dried (MgSO4) and con-
centrated under vacuum. The crude product was purified by
flash chromatography (10% to 20% AcOEt in cyclohexane)
to afford 10 as a white solid; yield: 129 mg (84%); [a]2D0:
À55 (c 1.1, CHCl3), lit.[5i] [a]D20: À56 (c 1.0, CHCl3); IR
(S)-Methyl 3-Hydroxyhexadecanoate (14) and (R)-
Methyl 3-Hydroxyhexadecanoate [(ent)-14]
1
(CH2Cl2): n=1790, 1740 cmÀ1; H NMR (400 MHz, CDCl3):
d=4.58 (q, 1H, J=7.1 Hz), 3.77 (s, 3H), 3.03 (m, 1H), 2.92
(dd, 1H, J=17.7 and 8.8 Hz), 2.77 (dd, 1H, J=17.7 and
9.5 Hz), 1.81–1.70 (m, 2H), 1.50–1.28 (m, 6H), 0.90 (t, 3H,
J=6.4 Hz); 13C NMR (100 MHz, CDCl3): d=174.5, 171.5,
82.0, 52.8, 45.8, 35.4, 32.3, 31.4, 24.9, 22.5, 14.0; MS (CI,
NH3): m/z=232 [M+ +NH4].
Methyl 3-oxohexadecanoate 13 (4.0 g, 14.0 mmol) was hy-
drogenated according to the general procedure for hydroge-
nation, using 0.5 mol% of [Ru((S)-SYNPHOS)Br2] in
MeOH (15 mL) at 508C under 5 bar of hydrogen for 24 h.
The reaction mixture was concentrated and the residue was
purified by flash chromatography (15 to 25% AcOEt in cy-
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Delphine Blanc et al.
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clohexane) to afford 14 as a white solid; yield: 3.8 g (94%);
mp 528C; [a]D20: +6.1 (c 1.1, CHCl3), lit.[16] [a]2D0: +13.5 (c
2.09, CHCl3).
AHCTREUNG
Compound (ent)-14: white solid, mp 51–538C; [a]2D0: À6.0
(c 1.0, CHCl3), lit.[8e] [a]D25: À16.6 (c 1.0, CHCl3); IR (KBr): n
To a suspension of 16 (1.76 g, 4.0 mmol) and sodium period-
ate (3.4 g, 16 mmol) in a 1/1/1 mixture of CCl4/MeCN/H2O
(60 mL) was added ruthenium trichloride hydrate (70 mg,
0.26 mmol) and the mixture was stirred vigorously for 20 h
at room temperature. After extraction with Et2O, the com-
bined organic layers were washed with brine, dried (MgSO4)
and concentrated under vacuum. The crude product was dis-
solved in MeOH (100 mL) and p-toluenesulfonic acid
(190 mg, 1 mmol) was added. The mixture was stirred at
room temperature for 20 h and concentrated. The residue
was purified by flash chromatography (10 to 40% AcOEt in
cyclohexane) to afford 17 as a white solid; yield: 782 mg
(60%); mp 68–708C; [a]2D0: À58 (c 1.0, CHCl3).
1
=3300 (broad), 1750 cmÀ1; H NMR (200 MHz, CDCl3): d=
4.04 (m, 1H), 3.74 (s, 3H), 2.89 (d, 1H, J=4.0 Hz), 2.55 (dd,
1H, J=16.4 and 3.6 Hz), 2.42 (dd, 1H, J=16.4 and 8.6 Hz),
1.45 (m, 2H),1.28 (m, 22H), 0.91 (t, 3H, J=6.6 Hz);
13C NMR (50 MHz, CDCl3): d=173.6, 68.1, 51.8, 41.2, 36.6,
32.0, 29.7 (8C), 25.6, 22.8, 14.2; MS (CI, NH3): m/z=304
[M+ +NH4], 287 [M+ +1]; anal. calcd. for C17H34O3 (286.45):
C 71.28, H 11.96; found: C 71.23, H 11.84. HPLC analysis
(of the corresponding benzoate): column, Chiralcel OD-H;
eluent, hexane/propan-2-ol 99/1; flow rate: 1.0 mLminÀ1; de-
tection: 215 nm; tR: 7.30 min, 14, tR: 8.05 min, (ent)-14.
Compound (ent)-17: white solid; mp 70–728C; [a]2D0: +59
A
(c 1.2, CHCl3); IR (KBr): n=1775, 1730 cmÀ1 1H NMR
;
and (2R,3R)-Methyl 2-Allyl 3-hydroxyhexadecanoate
[(ent)-15]
(200 MHz, CDCl3): d=4.64 (m, 1H), 3.77 (s, 3H), 3.46 (ddt,
1H, J=8.6, 7.3 and 5.6 Hz), 2.93 (dd, 1H, J=17.6 and
5.6 Hz), 2.68 (dd, 1H, J=17.6 and 8.6 Hz), 1.57 (m, 2H),
1.27 (m, 22H), 0.90 (t, 3H, J=6.6 Hz); 13C NMR (50 MHz,
CDCl3): d=174.8, 170.7, 80.3, 52.1, 44.2, 31.8, 31.7, 31.3, 29.5
(6C), 29.2, 29.1, 25.7, 22.6, 14.0; MS (CI, NH3): m/z=344
[M+ +NH4], 327 [M+ +1]; anal. calcd. for C19H34O4 (326.47):
C 69.90, H 10.50; found: C 69.99, H 10.51.
Starting from (S)-methyl 3-hydroxy-hexadecanoate 14 (5.7 g,
20 mmol) and following the procedure described for the
preparation of compound 8, ester 15 was obtained after
flash chromatography (5% AcOEt in cyclohexane) as a
white solid; yield: 5.2 g (80%); mp 36–388C; [a]2D0: À2 (c
1.2, CHCl3).
Compound (ent)-15: white solid; mp 38–408C; [a]2D0: +4
(c 1.1, CHCl3). IR (KBr): n=3400 (broad), 1725, 1650 cmÀ1
;
(2S,3R)-Methyl 5-Oxo-2-tridecyltetrahydrofuran-3-
carboxylate (18) and (2R,3S)-Methyl 5-Oxo-2-
tridecyltetrahydrofuran-3-carboxylate [(ent)-18]
1H NMR (200 MHz, CDCl3): d=5.78 (ddt, 1H, J=17.0, 10.1
and 6.9 Hz), 5.10 (m, 2H), 3.73 (s, 3H), 3.70 (m, 1H), 2.65–
2.40 (m, 4H), 1.48 (m, 2H), 1.28 (m, 22H), 0.91 (t, 3H, J=
6.3 Hz); 13C NMR (50 MHz, CDCl3): d=175.2, 134.8, 116.9,
71.8, 51.4, 50.5, 35.3, 33.6, 31.6, 29.6 (5C), 29.5, 29.4, 29.1,
25.2, 22.4, 13.9; MS (EI): m/z=327 [M+ +1]; anal. calcd. for
C20H38O3 (326.52): C 73.57, H 11.73; found: C 73.76, H
11.65.
Starting from (3S,4S)-3-methoxycarbonyl-4-tridecyl-g-butyr-
olactone 17 (751 mg, 2.3 mmol) and following the procedure
described for the preparation of compound 10, ester 18 was
obtained after flash chromatography (10 to 30% AcOEt in
cyclohexane) as a white solid; yield: 533 mg (71%); mp
448C; [a]2D0: À78 (c 1.0, CHCl3).
Compound (ent)-18: white solid; mp 458C; [a]2D0: +80 (c
(2S,3S)-Methyl 2-Allyl-3-tert-
butyldimethylsiloxyhexadecanoate (16)
1.08, CHCl3); IR (KBr): n=1775, 1735 cmÀ1
;
1H NMR
(200 MHz, CDCl3): d=4.58 (m, 1H), 3.77 (s, 3H), 3.05 (m,
1H), 2.92 (dd, 1H, J=18.0 and 8.6 Hz), 2.78 (dd, 1H, J=
18.0 and 9.5 Hz), 1.74 (m, 2H), 1.50–1.28 (m, 22H), 0.90 (t,
3H, J=6.8 Hz); 13C NMR (50 MHz, CDCl3): d=174.2,
171.4, 81.8, 52.5, 45.5, 35.2, 32.0, 31.7, 29.5 (6C), 29.2, 29.1,
25.0, 22.5, 14.0; MS (CI, NH3): m/z=344 [M+ +NH4]; 327
[M+ +1]; anal. calcd. for C19H34O4 (326.47): C 69.90, H
10.50; found: C 70.0, H 10.5.
To a solution of 15 (326 mg, 1.0 mmol) in CH2Cl2 (1 mL)
were added tert-butyldimethylsilyl trifluoromethanesulfo-
nate (345 mL, 1.5 mmol) and 2,6-lutidine (235 mL, 2.0 mmol).
The mixture was stirred at room temperature for 2 h,
quenched with brine and extracted with AcOEt. The com-
bined organic layers were washed with brine, dried (MgSO4)
and concentrated under vacuum. The crude product was pu-
rified by flash chromatography (5% AcOEt in cyclohexane)
to afford 16 as a pale yellow oil; yield: 431 mg (98%); [a]2D0:
+11.7 (c 1.07, CHCl3); IR (thin film): n=1742, 1650, 1254,
(2S,3R)-5-Oxo-2-tridecyltetrahydrofuran-3-carboxylic
Acid (19)
835 cmÀ1 1H NMR (200 MHz, CDCl3): d=5.75 (ddt, 1H,
;
Starting from (2S,3R)-methyl 5-oxo 2-tridecyltetrahydrfur-
an-3-carboxylate 18 (440 mg, 1.3 mmol) and following the
procedure described for the preparation of compound 11,
acid 19 was obtained as a white solid; yield: 413 mg (98%);
mp 109–1108C; [a]2D0: À40 (c 0.5, CHCl3); IR (KBr): n=
J=16.8, 10.0 and 7.0 Hz), 5.78 (m, 2H), 3.90 (m, 1H), 3.63
(s, 3H), 2.70–2.20 (m, 3H), 1.48 (m, 24H), 0.89–0.83 (m,
12H), 0.02 (s, 6H); 13C NMR (50 MHz, CDCl3): d=173.9,
135.8, 116.1, 72.6, 51.2, 51.1, 33.5, 31.8, 31.5, 29.6 (9C), 29.5,
29.4, 29.1, 25.6, 24.0, 22.5, 17.8, 13.9; MS (CI, NH3): m/z=
441 [M+ +1]; anal. calcd. for C26H52O3Si (440.79): C 70.8, H
11.9; found: C 70.66, H 12.05.
1775, 1730 cmÀ1 1H NMR (200 MHz, CDCl3): d=4.64 (q,
;
1H, J=7.0 Hz), 3.15 (m, 1H), 2.92 (dd, 1H, J=18.0 and
8.5 Hz), 2.78 (dd, 1H, J=18.0 and 9.5 Hz), 1.60 (m, 2H),
1.50–1.20 (m, 22H), 0.90 (t, 3H, J=6.8 Hz); 13C NMR
(50 MHz, CDCl3): d=176.5, 174.5, 81.8, 45.5, 35.5, 31.8,
31.3, 29.5 (6C), 29.2, 29.1, 25.7, 22.5, 14.0; MS (CI, NH3):
948
www.asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 943 – 950

Enantioselective Synthesis of Butyrolactone Natural Products
FULL PAPERS
m/z=330 [M+ +NH4], 313 [M+ +1]; anal. calcd. for
C18H32O4 (312.45): C 69.15, H 10.32; found: C 69.08, H
10.23.
Acknowledgements
This work was partially supported by a grant from the CPER
(2000–2006 action 10040 “Pôle Chimie du vivant“).
(+)-Roccellaric Acid (4)
To a 1 M solution of NaHMDS in THF (6.4 mL, 6.4 mmol)
was added at À788C a solution of ent-18 (979 mg, 3 mmol)
in THF (6 mL). The mixture was stirred at À788C for 1 h
then methyl iodide (1.7 mL, 27 mmol) was added dropwise.
After being stirred for 2 h, the reaction mixture was warmed
to À208C, hydrolyzed with 1 N HCl, and extracted with
Et2O. The combined organic layers were washed with brine,
dried (MgSO4) and concentrated under vacuum. The crude
product was purified by flash chromatography (5% to 20%
AcOEt in cyclohexane) to afford (2S,3S,4S)-methyl 4-methyl
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A
butyrolactone (20)
Starting from 9 (30 mg, 0.14 mmol) and following the proce-
dure described above for the preparation of (2S,3S,4S)-
methyl 4-methyl 5-oxo 2-tridecyltetrahydrofuran-3-carboxyl-
ate, lactone 20 was obtained after flash chromatography
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26 mg (82%); [a]D20: À89 (c 0.75, CH3CN), lit.[1c] [a]2D0: À82 (c
0.3, CH3CN); 1H NMR (400 MHz, CDCl3): d=4.65 (m,
1H), 3.77 (s, 3H), 3.25–3.00 (m, 2H), 1.30 (d, 3H, J=
6.8 Hz), 1.60–1.26 (m, 8H), 0.85 (t, 3H, J=6.3 Hz);
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51.8, 36.4, 31.4, 31.3, 25.3, 22.5, 14.5, 14.0; MS (CI, NH3):
m/z=246 [M+ +NH4], 229 [M+ +1].
(À)-Phaseolinic Acid (3)
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1.43–1.24 (m, 6H), 0.90 (m, 3H); 13C NMR (100 MHz,
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ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 943 – 950