Enantioselective synthesis of (+)-(2R,3S,6R)-decarestrictine L

Article abstract of DOI:10.1021/jo972187r

A convergent enantioselective synthesis of (+)-(2R,3S,6R)- decarestrictine L (1), a natural inhibitor of cholesterol biosynthesis, is described from commercially available (S)-malic acid and (R)-isobutyl lactate. The third chiral center was created by stereoselective reduction of a chiral α-hydroxy ketone, and an intramolecular S(N)2-type reaction allowed the stereocontrolled formation of the tetrahydropyranyl ring.

Full text of DOI:10.1021/jo972187r

2332
J . Org. Chem. 1998, 63, 2332-2337
En a n tioselective Syn th esis of (+)-(2R,3S,6R)-Deca r estr ictin e L
Guy Solladie´,*,† Eva Arce,† Claude Bauder,† and M. Carmen Carren˜o*,‡
Universite´ Louis Pasteur (ECPM), Laboratoire de Ste´re´ochimie associe´ au CNRS, 1, rue Blaise Pascal,
67008 Strasbourg, France, and Departamento de Qu´ımica Orga´nica (C-I), Universidad Auto´noma,
Cantoblanco, 28049 Madrid, Spain
Received December 2, 1997
A convergent enantioselective synthesis of (+)-(2R,3S,6R)-decarestrictine L (1), a natural inhibitor
of cholesterol biosynthesis, is described from commercially available (S)-malic acid and (R)-isobutyl
lactate. The third chiral center was created by stereoselective reduction of a chiral R-hydroxy ketone,
and an intramolecular SN2-type reaction allowed the stereocontrolled formation of the tetrahydro-
pyranyl ring.
Decarestrictine L, first isolated in 1992 in the research
laboratories of Hoechst AG1 from a culture of Penicillium
simplicissimum, is a minor component of the decarestric-
tine family, a growing class of natural products with
remarkable potential as new inhibitors of cholesterol
biosynthesis.2,3 Its biological activity as an inhibitor of
the HMG-CoA reductase, involved in the first steps of
the biosynthesis of cholesterol, was demonstrated by 13C-
and 18O-labeling experiments.3a,b The major components
of this family show a 10-membered lactone ring system,
while decarestrictine L 1 has a tetrahydropyranic struc-
ture (Figure 1).1,3,4 Some of these compounds share the
common feature of a methyl carbinol moiety in the
lactone or heterocyclic ring in the R configuration and
different oxygenated chiral centers. The relative config-
uration of natural (+)-decarestrictine L was established
by NMR,1 and its absolute configuration (+)-(2R,3S,6R)
was later confirmed by Kibayashi,5 who reported the first
total synthesis of the natural isomer.
The macrolactone derivatives of the decarestrictine
family have been the subject of major synthetic efforts,4,6
whereas decarestrictine L has received less attention. To
our knowledge, only three total syntheses of this molecule
have already been reported. One of them, due to Clark
et al.,7 corresponds to the racemic derivative, and the
strategy used for the construction of the heterocyclic ring
is based on a tandem intramolecular carbenoid insertion
and ylide rearrangement reaction. The enantioselective
synthesis reported by Kibayashi5 stems from the previ-
ously known transformation of D-mannitol into 1,2:5,6-
diepoxyhexane8 and the stereoselective formation of the
F igu r e 1.
tetrahydropyranyl nucleus through an intramolecular
1,4-conjugate addition. A similar cyclization strategy was
used by Nokami,9 who introduced the methyl carbinol
moiety from optically active propylene oxide. Both ap-
proaches suffer from low yields in the cyclization step.
In connection with our research devoted to asymmetric
synthesis of polyhydroxylated natural products,10 we
focused on derivatives bearing a chiral tetrahydropyran
moiety, with the aim of finding a general approach to
efficiently create the heterocycle from a polyhydroxylated
skeleton. We report in this paper an enantioselective and
convergent synthesis of the natural isomer of decarestric-
tine L from commercially available (S)-malic acid and (R)-
isobutyl lactate, using a stereocontrolled intramolecular
substitution to generate the tetrahydropyran ring.
As shown in the retrosynthetic approach (Scheme 1),
the polyhydroxylated derivative 12 can be considered as
a suitable precursor of the tetrahydropyranyl ring by
stereoselective intramolecular cyclization between the
OH at C-7 and the mesylate at C-3. The synthesis of 12
could be achieved from 7 through a stereoselective
† Universite´ Louis Pasteur.
‡ Universidad Auto´noma.
(1) Grabley, S.; Hammann, P.; Huetter, K.; Kirsch, R.; Kluge, H.;
Thiericke, R.; Mayer, M.; Zeeck, A. J . Antibiot. 1992, 45, 1176.
(2) Grabley, S.; Granzer, E.; Hu¨etter, K.; Ludwig, D.; Mayer, M.;
Thiericke, R.; Till, G.; Winck, J .; Phillips, S.; Zeeck, A. J . Antibiot. 1992,
45, 56.
(3) (a) Go¨hrt, A.; Zeeck, A.; Hu¨etter, K.; Kirsch, R.; Kluge, H.;
Thiericke, R.; Mayer, M. J . Antibiot. 1992, 45, 66. (b) Mayer, M.;
Thiericke, R. J . Antibiot., 1993, 46, 1372. (c) Mayer, M.; Thiericke, R.
J . Chem. Soc., Perkin Trans. 1 1993, 495.
(4) Andrus, M. B.; Shih, T. L. J . Org. Chem. 1996, 61, 8780.
(5) Machinaga, N.; Kibayashi, C. Tetrahedron Lett. 1993, 34, 5739.
(6) For a total synthesis of racemic derivatives see ref 4. For more
recent asymmetric syntheses see: (a) Nagumo, S.; Suemune, H.; Sakai,
K. Tetrahedron 1992, 48, 8667. (b) J ones, G. B.; Chapman, B. J .; Huber,
R. S.; Beaty, R. Tetrahedron: Asymmetry 1994, 5, 1199. (c) Enders,
D.; Plant, A.; Dreckel, K.; Prokopenko, O. F. Liebigs Ann. Chem. 1995,
1127.
(8) (a) Machinaga, N.; Kibayashi, C. Synthesis 1992, 989. (b)
Machinaga, N.; Kibayashi, C. J . Org. Chem. 1992, 57, 5178. (c) Corey,
E. J .; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 1979.
(9) Nokami, J .; Taniguchi, T.; Ogawa, Y. Chem. Lett. 1995, 43.
(10) (a) Solladie´, G.; Almario, A. Tetrahedron Lett. 1994, 35, 1937.
(b) Solladie´, G.; Huser, N.; Garc´ıa-Ruano, J . L.; Adrio, J .; Carren˜o, M.
C.; Tito, A. Tetrahedron Lett. 1994, 35, 5297. (c) Solladie´, G.; Hanquet,
G.; Rolland, C. Tetrahedron Lett. 1997, 38, 5847. (d) Carren˜o, M. C.;
Urbano, A.; Fischer, J . Angew. Chem., Int. Ed. Engl. 1997, 36, 1621.
(7) Clark, J . S.; Whitlock, G. A. Tetrahedron Lett. 1994, 35, 6381.
S0022-3263(97)02187-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/19/1998

Synthesis of (+)-(2R,3S,6R)-Decarestrictine L
J . Org. Chem., Vol. 63, No. 7, 1998 2333
Sch em e 1
Sch em e 3
the resulting crude diol was protected with dimethoxy-
propane in dimethylformamide.15 The purification of the
corresponding 1,3-acetonide 3 by chromatography on
silica gel produced different degradated byproducts. We
finally found that addition of Et3N (1%) to the eluent
prevented opening of the acetonide.16 Under these condi-
tions, compound 3 was isolated pure in 60% yield.
Reaction of 3 with lithium dimethyl methylphospho-
nate17,18 at -78 °C afforded the â-ketophosphonate 4 in
95% yield. All attempts to purify compound 4 by flash
column chromatography were unsuccessful, probably due
to the high polarity of this material. Therefore, 4 was
employed in the next Horner-Wadsworth-Emmons step
without further purification.
On the other hand, the aldehyde 6, necessary for
coupling with fragment 4, was synthesized from (R)-
isobutyl lactate, which was first benzylated with Ag2O19,20
to get the derivative 5 (85% yield) in enantiomerically
pure form (Scheme 3). This benzylation procedure was
used instead of the more conventional NaH/BnBr method
to avoid the strong racemization that is known20 to occur
under these conditions. DIBAL reduction of the ester
group in ether/pentane (1:9) afforded the aldehyde (+)-
(R)-6 in 96% isolated yield.
reduction of the R-hydroxy ketone moiety. Finally, the
C5-C6 disconnection of the keto derivative 7 could give
two fragments: the ketophosphonate 4 and the aldehyde
6 that could be assembled by a Horner-Wadsworth-
Emmons olefination. The compound 4 could be synthe-
sized from malic acid and the aldehyde 6 from the readily
available isobutyl lactate.
Sch em e 2
The phosphonate 4 was then coupled, in the presence
of 1 equiv of NaH in THF, with the aldehyde 6, giving 7
in 90% yield (Scheme 4). We noticed that this experi-
mental procedure was very critical since the reaction
temperature must be maintained at -40 °C during the
addition of the aldehyde to the phosphonate anion, and
a slow rate for the addition was required to achieve such
excellent yield. Moreover, this reaction was difficult to
scale up. After several experiments, we determined that
optimal results were obtained when the amount of
phosphonate was limited to ∼0.5 g to avoid byproducts
and get high yield.
To obtain the syn-1,2-diol derivative 8, a highly dias-
tereoselective reduction of the carbonyl group in com-
pound 7 was required. Treatment of 7 with a variety of
reducing agents provided mixtures of anti and syn
isomers. The anti derivative was preferentially formed
by reducing the carbonyl group of 7 with DIBAL/ZnBr2
(90% yield and 60% de). We finally found that L-
Selectride (Aldrich) at -78 °C afforded the syn isomer 8
The synthesis of fragment 4 began with transformation
of (S)-malic acid into the methyl ester 2 in quantitative
yield by the known one-pot chemoselective monoesteri-
fication with MeOH via the corresponding anhydride
made with trifluoroacetic anhydride11,12 (Scheme 2). The
carboxylic acid function was then reduced at low tem-
perature (-15 °C) with borane dimethyl sulfide,13,14 and
(14) The selective reduction of the carboxylic acid function could also
be achieved with borane in THF at 0 °C to afford the free 1,3-diol as
a colorless oil: [R]D ) -26 (c 1.56, CHCl3).12
(15) Mori, K.; Maemoto, S. Liebigs Ann. Chem. 1987, 863.
(16) The structure of the byproduct was tentatively assigned as the
2-O-(methoxyisopropyl)-2-hydroxy-γ-lactone on the base of its 1H NMR
spectrum.
(17) (a) Wadsworth, W. S.; Emmons, W. D. J . Am. Chem. Soc. 1961,
83, 1733. (b) Mikolajczyk, M.; Balczewski, P. Synthesis 1984, 691. (c)
Karanewsky, D. S.; Malley, M. F.; Gougoutas, J . Z. J . Org. Chem. 1991,
56, 3744.
(18) (a) Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa,
Y. J . Am. Chem. Soc. 1988, 110, 4685. (b) Yamanoi, T.; Akiyama, T.;
Ishida, E.; Abe, H.; Amemiya, M.; Inazu, T. Chem. Lett. 1989, 335.
(19) (a) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima,
S. Tetrahedron 1989, 45, 5767. (b) Hammerschmidt, F. Monatsh. Chem.
1991, 122, 389.
(11) (a) Miller, M. J .; Bajwa, J . S.; Mattingly, P. G.; Peterson, K. J .
Org. Chem. 1982, 47, 4928. (b) Gong, B.; Lynn, D. G. J . Org. Chem.
1990, 55, 4763. (c) Danielmeier, K.; Steckhan, E. Tetrahedron: Asym-
metry 1995, 6, 1181. (d) Maeda, H.; Suzuki, M.; Sugano, H.; Matsu-
moto, K. Synthesis 1988, 401.
(12) Wu¨nsch, B.; Diekmann, H.; Ho¨fner, G. Liebigs Ann. Chem.
1993, 1273.
(13) Cohen, N.; Lopresti, R. J .; Saucy, G. J . Am. Chem. Soc. 1979,
101, 6710.
(20) Takai, K.; Heathcock, C. H. J . Org. Chem. 1985, 50, 3247.

2334 J . Org. Chem., Vol. 63, No. 7, 1998
Solladie´ et al.
Sch em e 4
in 95% yield in a highly diastereoslective manner
(>97:3). A similar diastereoselectivity with this reagent
was reported by Nicolaou in the synthesis of the poly-
hydroxylated chain of amphotericin B18a and in the
synthesis of sphingosine.18b Our results could be ex-
plained on the basis of the Felkin-Anh model assuming
a favored approach of the reducing agent from the less
hindered face in a conformation of 7 in which the vicinal
oxygen is perpendicular to the plane of the carbonyl
group. The relative and absolute configurations of
compound 8 were further confirmed by chemical correla-
tion with natural decarestrictine L.
benzene. This reaction gave compound 14 in 90% yield
with complete inversion of configuration at C-3.
After deprotection of the silylated group in 14, the
primary hydroxy group of 15 was submitted to Swern
oxidation to obtain the corresponding aldehyde that,
without purification, was reacted with methylmagnesium
bromide. The resulting secondary carbinol was oxidized
with PDC in DMF to the methyl ketone 16 with an
overall yield of 61% from 14.
Deprotection of the MOM group was not as straight-
forward as we could expect due to the C-2 epimerization
observed in the presence of HCl. After several experi-
ments we could obtain (+)-(2R,3S,6R)-decarestrictine L
(1) without epimerization by treating the MOM deriva-
tive 16 with TiCl4 in CH2Cl2 at 0 °C.22 The resulting
decarestrictine L was isolated in 80% yield and was
shown to have all the characteristics described in the
literature for the natural product.1 The fact that the
natural enantiomer was obtained confirmed the configu-
rational assignment of all the precursors and that of the
compound 8 obtained by stereoselective reduction of the
ketone 7.
Once the stereogenic center at C-4 was generated, the
next few steps for the transformation of compound 8 into
the mesylate 13 (Scheme 4) involved the selective and
differential protection of the hydroxy groups: protection
of the OH at C-4 with MOMCl/i-Pr2NEt, cleavage of the
acetonide with PPTS/MeOH, selective protection of the
primary terminal OH with TBDMSCl/imidazole, and
finally mesylation of the OH at C-3 to introduce the
adequate leaving group for the cyclization. These four
steps occurred with an overall yield of 78%. Debenzyla-
tion and reduction of the double bond of 12 were ac-
complished in a single step by hydrogenation over
palladium on charcoal (8 h at 1 bar to reduce the double
bond and then 10 h at 5 bars for the debenzylation step)
to obtain the compound 13 in 95% overall yield. This
sequential procedure is critical; the debenzylation has to
be done after reducing the double bond to avoid the
formation of degradated products of the allylic alcohol
in the reduction conditions.
Con clu sion
We have reported an alternative source of decarestric-
tine L (1) from readily available and inexpensive starting
materials, (S)-malic acid and (R)-isobutyl lactate, in a
28% overall yield. An interesting stereochemical feature
was the preparation of the intermediate (3S,4S,7R)-8
The cyclization step to form the pyran ring was carried
out under standard conditions21 with NaH in refluxing
(21) Lee, H. W.; Lee, I. Y. C. Synlett 1991, 871.
(22) Corey, E. J .; Gras, J . L.; Ulrich, P. Tetrahedron Lett. 1976, 809.

Synthesis of (+)-(2R,3S,6R)-Decarestrictine L
J . Org. Chem., Vol. 63, No. 7, 1998 2335
over MgSO4, and concentrated in vacuo. The crude product
was purified by chromatography (hexane/Et2O 80:20) to give
7.88 g (96%) of 6 as a colorless oil: [R]20D ) +38.5 (c 1, CHCl3);
1H NMR (CDCl3) δ 9.67 (d, J ) 1.8 Hz, 1H), 7.34 (m, 5H), 4.67
and 4.59 (AB syst, J ) 12.0 Hz, ∆ν ) 10 Hz, 2H), 3.89 (dq, J
) 7.0, 1.8 Hz, 1H), 1.34 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3)
δ 200.0, 137.0, 128.5 × 2, 128.0 × 3, 75.5, 72.0, 15.0; IR (CHCl3)
1720. Anal. Calcd for C10H12O2: C, 73.14; H, 7.36. Found:
C, 72.87; H, 7.64.
(+)-(3S,7R)-7-O-Ben zyl 1,3-O-Isop r op ylid en e-1,3,7-tr i-
h yd r oxy-5-octen -4-on e (7). A solution of phosphonate 4 (583
mg, 2.19 mmol) in 30 mL of dry THF was added to a
suspension of NaH (53 mg, 2.19 mmol) in 30 mL of dry THF
at -40 °C, and the mixture was stirred for 40 min. A solution
of aldehyde 6 (300 mg, 1.83 mmol) in 50 mL of dry THF was
added dropwise for 1 h, and the temperature was allowed to
rise to room temperature. After the mixture was stirred for
20 h, 30 mL of saturated aqueous NH4Cl was added, the
resulting mixture was extracted with Et2O, washed with
saturated aqueous NaCl, and dried over MgSO4, and the
solvent was evaporated. The product was purified by chro-
matography (hexane/Et2O 75:25) to give 500 mg (90%) of 7 as
a colorless liquid: [R]20D ) +7.0 (c 1, CHCl3); 1H NMR (CDCl3)
δ 7.32 (m, 5H), 6.95 (dd, J ) 15.8, 5.6 Hz, 1H), 6.74 (dd, J )
15.8, 1.0 Hz, 1H), 4.50 (m, 3H), 4.20-3.86 (m, 3H), 1.75 (m,
2H), 1.49 (s, 3H), 1.48 (s, 3H), 1.33 (d, J ) 6.5 Hz, 3H); 13C
NMR (CDCl3) δ 197.9, 149.1, 138.1, 128.3 × 2, 127.6 × 3, 123.4,
98.6, 74.2, 73.9, 70.7, 59.4, 29.5, 27.1, 20.5, 19.0; IR (CHCl3)
3020, 1675, 1620, 1210.
using the highly diastereoselective L-Selectride reduction
of the R-hydroxy ketone 7.
Exp er im en ta l Section
Meth yl (-)-(S)-2,4-O-Isop r op ylid en e-2,4-d ih yd r oxybu -
ta n oa te (3). BH3‚Me2S 97% (6.42 mL, 67.8 mmol) was added
dropwise to a solution of (-)-(S)-methyl malate11,12 2 (5 g, 33.9
mmol) in 100 mL of dry THF at -15 °C under argon. The
mixture was allowed to warm to room temperature and stirred
for 24 h. The reaction was cautiously hydrolyzed by dropwise
addition of 20 mL of H2O and concentrated. The residue was
diluted with AcOEt and filtered. The solid was washed with
AcOEt, and the organic phases were combined and concen-
trated in vacuo to give the diol precursor of 3, which was used
in the next step without further purification: 1H NMR (CDCl3)
δ 4.66 (dd, J ) 6.7, 4.5 Hz, 1H), 4.03 (t, J ) 5.6 Hz, 2H), 3.80
(s, 3H), 2.24 (m, 1H), 2.04 (m, 1H).
The crude diol (4.5 g, 33.9 mmol) was dissolved in 50 mL of
dry DMF and 150 mL of 2,2-dimethoxypropane, and PPTS (375
mg, 1.5 mmol) was added. The mixture was stirred for 24 h
at room temperature and washed with saturated aqueous
NaHCO3, extracted with CHCl3, dried over MgSO4, and
evaporated. The excess of DMF was eliminated by azeotropic
distillation with diethyl ether. Chromatography (hexane/
AcOEt 75:25 + 1% Et3N) yielded, after washing with saturated
NH4Cl, 3.9 g (60%) of 3 as a yellow oil: [R]20 ) -17.0 (c 1,
D
1
CHCl3); H NMR (CDCl3) δ 4.52 (m, 1H), 3.95 (m, 2H), 3.76
(s, 3H), 2.03-1.74 (m, 2H), 1.48 (s, 6H); 13C NMR (CDCl3) δ
171.0, 98.7, 68.3, 59.1, 51.9, 29.2, 27.2, 19.7; IR (CHCl3) 3150,
2940, 2860, 2300, 1730, 1635. Anal. Calcd for C8H14O4: C,
55.16; H, 8.10. Found: C, 55.54; H, 7.88.
(+)-(3S,4S,7R)-7-O-Ben zyl-1,3-O-isop r op ylid en e-1,3,4,7-
tetr ol-5-octen e (8). To a solution of 7 (3 g, 10 mmol) in 150
mL of dry THF was added a suspension of L-Selectride (1 M
in THF, 19.8 mL, 19.8 mmol) at -78 °C. The mixture was
stirred for 1 h, quenched with saturated aqueous NH4Cl (150
mL), and extracted with Et2O and the solvent evaporated. The
residue was dissolved in AcOEt and washed with a 5% solution
of H2O2 for 2 h. The organic phase was washed with H2O and
dried over MgSO4 and the solvent evaporated to give 2.88 g
(95%) of 8 as a colorless liquid. The product was used without
further purification, but a sample was purified by chromatog-
(-)-(S)-3,5-O-Isopr opyliden e-1-(dim eth oxyph osph on yl)-
3,5-d ih yd r oxyp en ta n -2-on e (4). A solution of n-BuLi (1.6
M in hexane, 13.1 mL, 21 mmol) was added to dimethyl
methylphosphonate (2.27 mL, 21 mmol) dissolved in 40 mL of
dry THF and stirred at -78 °C for 15 min. A solution of 3
(1.75 g, 10 mmol) in 30 mL of dry THF was added dropwise
and stirred for 3 h at -78 °C. The mixture was quenched with
saturated aqueous NH4Cl, extracted with AcOEt, washed with
saturated aqueous NaCl, and dried over MgSO4, and the
solvent was evaporated to give 2.53 g (95%) of 4 as a yellow
raphy (Et2O/hexane 50:50) for analysis: [R]20 ) +32.0 (c 1,
D
CHCl3); 1H NMR (C6D6) δ 7.37-7.05 (m, 5H), 5.80 (dd, J )
15.7, 7.0 Hz, 1H), 5.57 (dd, J ) 15.7, 7.0 Hz, 1H), 4.54 and
4.33 (AB syst, J ) 12.0 Hz, ∆ν ) 42 Hz, 2H), 3.92 (t, J ) 6.0
Hz, 1H), 3.83 (qn, J ) 6.5 Hz, 1H), 3.53 (m, 3H), 2.65 (br s,
1H), 1.40 (s, 3H), 1.24 (d, J ) 6.5 Hz, 3H), 1.20 (s, 3H), 0.90
(m, 2H); 13C NMR (C6D6) δ 139.8, 135.3, 130.2, 127.8 × 5, 98.7,
75.2 × 2, 72.5, 70.1, 59.2, 30.0, 27.2, 21.8, 19.3; IR (CHCl3)
3560, 2950, 2870, 1715, 1515. Anal. Calcd for C18H26O4: C,
70.56; H, 8.55. Found: C, 70.20; H, 8.34.
oil. The product was used without further purification: [R]20
D
1
) -50.0 (c 1, CHCl3); H NMR (CDCl3) δ 4.37 (m, 1H), 3.90
(m, 2H), 3.77 (d, J H-P ) 11.4 Hz, 6H), 3.47 (dd, J ) 22.7 and
14.2 Hz, 1H), 3.15 (dd, J ) 22.0 and 14.2 Hz, 1H), 1.73 (m,
2H), 1.46 (s, 3H), 1.43 (s, 3H); 13C NMR (CDCl3) δ 201.8, 99.0,
73.9, 59.4, 52.9, 52.7, 35.4, 29.5, 26.4, 18.8; IR (CHCl3) 3000,
2950, 2870, 2850, 1725, 1390. Anal. Calcd for C10H19O6P: C,
45.11; H, 7.19. Found: C, 44.88; H, 7.08.
Isobu tyl (+)-(R)-2-(Ben zyloxy)p r op ion a te (5). Ag2O
(11.6 g, 50 mmol) was added to a mixture of (R)-isobutyl lactate
(7.5 mL, 50 mmol) and BnBr (6.6 mL, 55 mmol) in 75 mL of
dry Et2O. The suspension was refluxed overnight, filtered, and
concentrated. The crude product was purified by chromatog-
(+)-(3S,4S,7R)-7-O-Ben zyl-1,3-O-Isop r op ylid en e-4-O-
(m eth oxym eth yl)-1,3,4,7-tetr ol-5-octen e (9). To a solution
of 8 (1.53 g, 5 mmol) in 75 mL of dry CH2Cl2 at 0 °C were
added i-Pr2NEt (8.6 mL, 50 mmol) and MOMCl (2.5 mL, 50
mmol). After the mixture was stirred at room temperature
for 10 h, a saturated aqueous NaHCO3 solution was added.
The resulting mixture was extracted with CH2Cl2, washed with
saturated aqueous NaCl, and dried over MgSO4 and the
solvent evaporated. Chromatography (hexane/Et2O 65:35)
raphy (hexane/Et2O 90:10) to give 8.8 g (85%) of 5 as a colorless
1
oil: [R]20 ) +84.5 (c 1, CHCl3); H NMR (CDCl3) δ 7.35 (m,
D
5H), 4.72 and 4.45 (AB syst, J ) 11.5 Hz, ∆ν ) 52 Hz, 2H),
4.07 (q, J ) 6.8 Hz, 1H), 3.95 (dd, J ) 6.7 and 2.4 Hz, 2H),
1.97 (m, 1H), 1.45 (d, J ) 6.8 Hz, 3H), 0.95 (d, J ) 6.7 Hz,
6H); 13C NMR (CDCl3) δ 173.4, 136.7, 128.4 × 2, 127.9 × 2,
127.8, 74.0, 71.9, 70.8, 27.7, 19.0, 18.8; IR (CHCl3) 3000, 1740,
1520, 1425. Anal. Calcd for C14H20O3: C, 71.14; H, 8.54.
Found: C, 71.04; H, 8.46.
gave 1.58 g (90%) of 9 as a colorless oil: [R]20 ) +61.0 (c 1,
D
1
CHCl3); H NMR (CDCl3) δ 7.31 (m, 5H), 5.72 (dd, J ) 15.8,
6.8 Hz, 1H), 5.57 (dd, J ) 15.8, 6.6 Hz, 1H), 4.72 and 4.64 (AB
syst, J ) 6.7 Hz, ∆ν ) 13 Hz, 2H), 4.57 and 4.38 (AB syst, J
) 12.0 Hz, ∆ν) 36 Hz, 2H), 4.04-3.83 (m, 5H), 3.40 (s, 3H),
1.70 (m, 2H), 1.46 (s, 3H), 1.39 (s, 3H), 1.28 (d, J ) 6.5 Hz,
3H); 13C NMR (CDCl3) δ 138.6, 136.8, 128.3, 127.7, 127.6 × 2,
127.4 × 2, 98.3, 94.3, 78.5, 75.0, 71.0, 70.0, 59.6, 55.3, 29.8,
27.0, 21.6, 19.2; IR (CHCl3) 2990, 2400, 1720, 1450, 1385, 1375.
Anal. Calcd for C20H30O5: C, 68.54; H, 8.62. Found: C, 68.26;
H, 8.42.
(+)-(R)-2-(Ben zyloxy)p r op a n a l (6). A solution of DIBAL
(1 M in hexane, 67 mL, 67 mmol) was dropwise added to ester
5 (11.8 g, 50 mmol) dissolved in 300 mL of a mixture of Et2O/
pentane 1/9 at -78 °C. After the solution was stirred for 30
min, 30 mL of MeOH and 150 mL of saturated aqueous sodium
tartrate were added, and the organic phase was diluted with
150 mL of AcOEt. The mixture was stirred for 30-40 min at
0 °C and evaporated. The residue was dissolved in AcOEt,
and saturated aqueous sodium tartrate was added. The
mixture was stirred for 30 min, extracted with AcOEt, dried
(+)-(3S,4S,7R)-7-O-Ben zyl-4-O-(m eth oxym eth yl)-1,3,4,7-
tetr ol-5-octen e (10). To a solution of 9 (1.76 g, 5 mmol) in
300 mL of dry MeOH was added PPTS (630 mg, 2.53 mmol).
The solution was stirred at room temperature for 3 h and
neutralized with saturated aqueous NaHCO3 and the solvent

2336 J . Org. Chem., Vol. 63, No. 7, 1998
Solladie´ et al.
evaporated. The residue was dissolved in CH2Cl2 (100 mL)
and H2O (100 mL), extracted with CH2Cl2, and dried over
MgSO4 and the solvent evaporated to give 1.53 g (99%) of 10
as a colorless oil. The product was used without further
purification, but a sample was purified by chromatography
mL of benzene were added NaH (50 mg) and dry DMSO (5-6
drops). After the mixture was stirred at reflux overnight,
saturated aqueous NH4Cl (15 mL) was added. The mixture
was extracted with Et2O, washed with saturated aqueous
NaCl, dried over MgSO4, and concentrated in vacuo to give
344 mg (90%) of 14 as a colorless oil. The product was used
without further purification, but a sample was purified by
(hexane/Et2O 8:92) for analysis: [R]20 ) +72.0 (c 1, CHCl3);
D
1H NMR (CDCl3) δ 7.30 (m, 5H), 5.73 (dd, J ) 15.8 and 7.0
Hz, 1H), 5.51 (dd, J ) 15.8 and 7.6 Hz, 1H), 4.74 and 4.60
(AB syst, J ) 6.7 Hz, ∆ν ) 27 Hz, 2H), 4.54 and 4.38 (AB syst,
J ) 11.8 Hz, ∆ν ) 31 Hz, 2H), 3.88 (m, 5H), 3.38 (s, 3H), 3.10
(br s, 2H), 1.68 (m, 2H), 1.27 (d, J ) 6.4 Hz, 3H); 13C NMR
(CDCl3) δ 138.3, 138.0, 128.3, 127.7, 127.5 × 2, 127.4 × 2, 94.0,
80.4, 74.8, 73.1, 70.1, 60.7, 55.6, 34.3, 21.3; IR (CHCl3) 2990,
2880, 1710, 1520, 1420. Anal. Calcd for C17H26O5: C, 65.78;
H, 8.44. Found: C, 65.33; H, 8.57.
chromatography (hexane/Et2O 85:15) for analysis: [R]20
)
D
1
+25.0 (c 1, CHCl3); H NMR (C6D6) δ 4.58 and 4.53 (AB syst,
J ) 6.9 Hz, ∆ν ) 6 Hz, 2H), 4.03 (dt, J ) 9.1, 4.8 Hz, 1H),
3.80 (m, 2H), 3.68 (ddq, J ) 10.4, 6.4, 4.1 Hz, 1H), 3.32 (q, J
) 5.0 Hz, 1H), 3.20 (s, 3H), 1.82 (m, 2H), 1.68-1.29 (m, 4H),
1.10 (d, J ) 6.4 Hz, 3H), 1.00 (s, 9H), 0.11 (s, 3H), 0.10 (s,
3H); 13C NMR (C6D6) δ 95.1, 74.5, 70.9, 66.1, 60.1, 55.1, 34.4,
28.6, 26.2 × 3, 25.0, 19.7, 18.6, -5.2 × 2; IR (CHCl3) 3000,
2950, 2930, 2860, 1515, 1470. Anal. Calcd for C16H34O4Si: C,
60.33; H, 10.76. Found: C, 60.19; H, 10.77.
(+)-(3S,4S,7R)-7-O-Ben zyl-1-O-(ter t-bu tyldim eth ylsilyl)-
4-O-(m eth oxym eth yl)-1,3,4,7-tetr ol-5-octen e (11). To a
solution of 10 (1.56 g, 5 mmol) in 50 mL of dry DMF were
added TBDMSCl (910 mg, 6 mmol) and imidazole (823 mg,
12 mmol). After being stirred at room temperature for 4 h,
the mixture was quenched with H2O (30 mL) and Et2O (75
mL), extracted with Et2O, washed with saturated aqueous
NH4Cl and saturated aqueous NaCl, and dried over MgSO4
and the solvent evaporated. Chromatography (hexane/Et2O
(+)-(2R,3S,6R)-3-O-[(Meth oxym eth yl)oxy]-6-m eth yl-2-
(2-h yd r oxyeth yl)tetr a h yd r op yr a n (15). To a solution of
14 (375 mg, 1.2 mmol) in 30 mL of dry THF at 0 °C under
argon was added TBAF 1 M in THF (1.8 mL, 1.8 mmol), and
the reaction was stirred at 0 °C for 4 h. SiO2 (1 g) was added,
and the mixture was stirred for 30 min. The solvent was
removed and the product adsorbed on silica gel was chromato-
graphed (hexane/Et2O 20:80) to give 235 mg (95%) of 15 as a
60:40) yielded 2.0 g (94%) of 11 as a colorless oil: [R]20
)
D
+63.0 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.31 (m, 5H), 5.65 (ddd,
J ) 15.7, 7.2, 6.8 Hz, 2H), 4.76 and 4.62 (AB syst, J ) 6.6 Hz,
∆ν ) 28 Hz, 2H), 4.57 and 4.38 (AB syst, J ) 11.8 Hz, ∆ν )
36 Hz, 2H), 3.89 (m, 5H), 3.40 (s, 3H), 3.18 (br s, 1H), 1.68 (m,
2H), 1.28 (d, J ) 6.5 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C
NMR (CDCl3) δ 138.6, 137.4, 128.4, 128.3, 127.6 × 2, 127.4 ×
2, 94.0, 80.0, 75.0, 72.3, 70.1, 61.1, 55.6, 35.0, 25.9 × 3, 21.5,
18.2, -5.5 × 2; IR (CHCl3) 3590, 3480, 3000, 2950, 1720, 1610.
Anal. Calcd for C23H40O5Si: C, 65.05; H, 9.49. Found: C,
65.20; H, 9.42.
yellow oil: [R]20 ) +44.5 (c 1, CHCl3); 1H NMR (C6D6) δ 4.54
D
and 4.48 (AB syst, J ) 6.8 Hz, ∆ν ) 10 Hz, 2H), 3.91 (ddd, J
) 9.1, 5.1, 4.4 Hz, 1H), 3.76 (m, 2H), 3.63 (ddq, J ) 10.7, 6.4,
4.6 Hz, 1H), 3.24 (dt, J ) 5.6, 5.1 Hz, 1H), 3.17 (s, 3H), 3.13
(br s, 1H), 1.75 (m, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 1.02 (d, J
) 6.4 Hz, 3H); 13C NMR (C6D6) δ 95.0, 74.4, 73.2, 66.6, 60.5,
55.2, 33.6, 28.4, 24.8, 19.2; IR (CHCl3) 3620, 3490, 2940, 2400,
1525, 1425. Anal. Calcd for C10H20O4: C, 58.80; H, 9.87.
Found: C, 58.45; H, 9.56.
(+)-(2R,3S,6R)-3-[(Meth oxym eth yl)oxy]-6-m eth yl-2-(2-
oxop r op yl)tetr a h yd r op yr a n (16). To a solution of oxalyl
chloride (210 µL, 2.45 mmol) in 8 mL of dry CH2Cl2 at -78 °C
under argon was added DMSO (315 µL, 4.40 mmol). The
mixture was stirred for 1 h at -78 °C, and a solution of 15
(200 mg, 0.98 mmol) in 6 mL of dry CH2Cl2 was cannulated.
After 3 h at -78 °C, Et3N (890 mL, 6.36 mmol) was added,
and the reaction was allowed to warm to room temperature.
The mixture was quenched with saturated aqueous NH4Cl (10
mL), neutralized with HCl 10% until pH ) 6, extracted with
CH2Cl2, washed with saturated aqueous NaCl, dried over
MgSO4, and concentrated in vacuo. The residue was triturated
with Et2O and filtered to give 200 mg (100%) of the corre-
sponding aldehyde as a yellow oil. The product was used
without further purification: 1H NMR (C6D6) δ 9.53 (dd, J )
3.1, 1.9 Hz, 1H), 4.47 and 4.38 (AB syst, J ) 6.8 Hz, ∆ν ) 10
Hz, 2H), 4.08 (ddd, J ) 8.3, 6.6, 5.0 Hz, 1H), 3.64 (m, 1H),
3.12 (s, 3H), 3.06 (m, 1H), 2.43-2.17 (m, 2H), 1.60-1.18 (m,
4H), 0.97 (d, J ) 6.5 Hz, 3H); 13C NMR (C6D6) δ 199.6, 95.0,
74.5, 69.3, 67.2, 55.2, 46.0, 28.4, 24.7, 18.2. To a solution of
this aldehyde (0.98 mmol) in 8 mL of dry THF at 0 °C under
argon was added MeMgBr (3 M in Et2O, 590 µL, 1.76 mmol).
After the mixture was stirred for 4 h, saturated aqueous NH4-
Cl (8 mL) was added, extracted with CH2Cl2, dried over
MgSO4, and concentrated in vacuo. The residue was dissolved
in 15 mL of DMF, and PDC (1.84 g, 4.89 mmol) was added at
room temperature. After 5 h, the mixture was quenched with
Et2O (20 mL) and H2O (15 mL). The aqueous layer was
saturated with NaCl before extraction with Et2O. The com-
bined organic layers were dried over MgSO4 and evaporated.
(+)-(3S,4S,7R)-7-O-Ben zyl-1-O-(ter t-bu tyldim eth ylsilyl)-
3-O-(m eth an esu lfon yl)-4-O-(m eth oxym eth yl)-1,3,4,7-tetr ol-
5-octen e (12). Triethylamine (13.8 mL, 100 mmol) was added
to a solution of 11 (2.13 g, 5 mmol) in 100 mL of dry CH2Cl2
at 0 °C. After 15 min, MsCl (3.88 mL, 50 mmol) was added.
The mixture was stirred for 40 min at 0 °C, quenched with
saturated aqueous NH4Cl (75 mL), extracted with CH2Cl2,
washed with saturated aqueous NaCl, and dried over MgSO4
and the solvent evaporated. Chromatography (hexane/Et2O
65:35) yielded 2.34 g (93%) of 12 as a colorless oil: [R]20
)
D
+30.0 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.32 (m, 5H), 5.87-
5.52 (m, 2H), 4.85 (m, 1H), 4.73 and 4.61 (AB syst, J ) 6.6
Hz, ∆ν ) 22 Hz, 2H), 4.56 and 4.39 (AB syst, J ) 11.8 Hz, ∆ν
) 32 Hz, 2H), 4.32 (t, J ) 6.8 Hz, 1H), 4.00 (qn, J ) 6.5 Hz,
1H), 3.75 (m, 2H), 3.39 (s, 3H), 3.06 (s, 3H), 2.09-1.76 (m, 2H),
1.29 (d, J ) 6.5 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR
(CDCl3) δ 138.5 × 2, 128.3 × 2, 127.5 × 2, 127.4, 126.3, 94.1,
80.7, 76.5, 74.7, 70.1, 58.2, 55.7, 38.1, 33.5, 25.7 × 3, 21.3, 18.1,
-5.5 × 2; IR (CHCl3) 3000, 2950, 2400, 1715, 1440, 1360.
Anal. Calcd for C24H42O7SSi: C, 57.34; H, 8.42. Found: C,
57.58; H, 8.34.
(-)-(3S,4S,7R)-1-O-(ter t-Bu tyld im eth ylsilyl)-3-O-(m eth -
a n esu lfon yl)-4-O-(m eth oxym eth yl)-1,3,4,7-tetr a h yd r oxy-
octa n e (13). To a solution of 12 (620 mg, 1.2 mmol) in 30
mL of AcOEt was added Pd/C 10% (10% weight), and the
mixture was stirred for 8 h under 1-2 bars of hydrogen
pressure and then overnight under 5 bars. The suspension
was filtered on Celite and washed with AcOEt and the solvent
evaporated. Chromatography (hexane/Et2O 40:60) yielded 475
mg (95%) of 13 as a colorless oil: [R]20 ) -30.0 (c 1, CHCl3);
Chromatography (hexane/Et2O 50:50) yielded 135 mg (64%)
D
1
1H NMR (CDCl3) δ 4.92 (m, 1H), 4.69 and 4.65 (AB syst, J )
6.9 Hz, ∆ν ) 6 Hz, 2H), 3.76 (m, 4H), 3.38 (s, 3H), 3.04 (s,
3H), 2.05-1.48 (m, 6H), 1.18 (d, J ) 6.2 Hz, 3H), 0.88 (s, 9H),
0.05 (s, 6H); 13C NMR (CDCl3) δ 96.9, 79.7, 78.1, 67.4, 58.3,
56.0, 38.0, 34.5, 32.2, 25.8 × 3, 25.4, 23.5, 18.1, -5.5 × 2; IR
(CHCl3) 3680, 3620, 2940, 2920, 2390, 1460. Anal. Calcd for
of 16 as a colorless oil: [R]20 ) +43.0 (c 1, CHCl3); H NMR
D
(CDCl3) δ 4.72 and 4.63 (AB syst, J ) 6.8 Hz, ∆ν ) 15 Hz,
2H), 4.16 (dt, J ) 7.7, 5.9 Hz, 1H), 3.85 (m, 1H), 3.37 (s, 3H),
3.34 (m, 1H), 2.68 (m, 2H), 2.19 (s, 3H), 1.96-1.51 (m, 4H)
and 1.21 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3) δ 206.8, 94.7,
73.5, 70.5, 67.2, 55.4, 45.8, 30.1, 28.0, 24.1, 18.6; IR (CHCl3)
3010, 2970, 2940, 2400, 1720, 1525, 1425.
C
17H38O7SSi: C, 49.24; H, 9.24. Found: C, 49.37; H, 9.04.
(+)-(2R,3S,6R)-3-O-[(Meth oxym eth yl)oxy]-6-m eth yl-2-
[2-O-(ter t-b u t yld im et h ylsilyl)-2-h yd r oxyet h yl]t et r a h y-
d r op yr a n (14). To a solution of 13 (500 mg, 1.2 mmol) in 60
(+)-(2R,3S,6R)-6-Meth yl-2-(2-oxop r op yl)tetr a h yd r op y-
r a n -3-ol [Deca r estr ictin e L (1)]. To a solution of 16 (100
mg, 0.46 mmol) in 15 mL of dry CH2Cl2 under argon at 0 °C

Synthesis of (+)-(2R,3S,6R)-Decarestrictine L
J . Org. Chem., Vol. 63, No. 7, 1998 2337
was added TiCl4 (1 M in CH2Cl2, 2.8 mL, 2.77 mmol). The
mixture was stirred for 30 min, hydrolyzed with saturated
aqueous NaHCO3 (8 mL) until pH ) 7, extracted with CH2-
Cl2, and dried over MgSO4. Evaporation and chromatography
(CHCl3/MeOH 92:8) yielded 64 mg (80%) of 1 as a colorless
oil: [R]20 ) +26.0 (c 0.7, MeOH) [lit.1 [R]20 ) +21.8 (c 0.5,
NMR (CDCl3) δ 207.6, 72.0, 69.3, 67.4, 46.3, 30.5, 28.2, 27.0,
18.4. Anal. Calcd for C9H16O3: C, 62.77; H, 9.36. Found: C,
62.69; H, 9.38.
Ack n ow led gm en t. We gratefully acknowledge the
French Embassy in Madrid for financial support (fel-
lowship to E.A.).
D
D
MeOH)]; 1H NMR (CDCl3) δ 4.01 (q, J ) 6.5 Hz, 1H), 3.95 (m,
1H), 3.40 (m, 1H), 2.73 (d, J ) 6.5 Hz, 2H), 2.21 (s, 3H), 2.12
(br s, 1H), 1.92-1.50 (m, 4H), 1.22 (d, J ) 6.5 Hz, 3H); 13C
J O972187R