Chelation-controlled reduction: stereoselective formation of syn-1,3-diols and synthesis of compactin and mevinolin lactone.

Article abstract of DOI:10.1021/jo020402k

Chelation-controlled reduction of chiral beta-alkoxy ketones containing a competing beta'-oxygen functionality has been investigated. Various syn-1,3-diols were prepared conveniently by reduction of beta-alkoxy ketones with LiI/LiAlH(4) (syn:anti selectivity up to >99:1). The corresponding beta-alkoxy ketones were derived from nitro-aldol reactions of chiral alkoxy aldehydes with a series of nitro compounds. This methodology is utilized in a short and efficient synthesis of the delta-lactone moiety of the HMG-CoA reductase inhibitors compactin and mevinolin.

Full text of DOI:10.1021/jo020402k

Ch ela tion -Con tr olled Red u ction : Ster eoselective F or m a tion of
syn -1,3-Diols a n d Syn th esis of Com p a ctin a n d Mevin olin La cton e
Arun K. Ghosh* and Hui Lei
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received J une 12, 2002
Chelation-controlled reduction of chiral â-alkoxy ketones containing a competing â′-oxygen
functionality has been investigated. Various syn-1,3-diols were prepared conveniently by reduction
of â-alkoxy ketones with LiI/LiAlH4 (syn:anti selectivity up to >99:1). The corresponding â-alkoxy
ketones were derived from nitro-aldol reactions of chiral alkoxy aldehydes with a series of nitro
compounds. This methodology is utilized in a short and efficient synthesis of the δ-lactone moiety
of the HMG-CoA reductase inhibitors compactin and mevinolin.
syn-1,3-Diol subunits are common structural features
imbedded in numerous biologically important natural
products.1 Among known methodologies, stereoselective
reductions directed by preexisting chiral â-alkoxy or
hydroxy centers are particularly useful. In this context,
asymmetric reductions of â-hydroxy ketones2 and δ-hy-
droxy-â-keto esters3 have been reported. Although di-
rected reductions of acyclic â-hydroxy ketones are known
to provide excellent syn-diastereoselectivities, the corre-
sponding reduction of â-alkoxy ketones generally provides
lower stereochemical control. Reductions of acyclic â-alkoxy
ketones with LiAlH4 in the presence of LiI, however, has
been shown to proceed with high diastereoselectivities
by Mori, Suzuki, and co-workers.4 In connection with our
synthetic studies toward madumycin and griseoviridin,
we investigated the stereoselective reduction of acyclic
chiral â-alkoxy ketones containing a competing â′-oxygen
functionality.5 Herein, we report a useful synthetic route
to a variety of functionalized optically active syn-1,3-diols
by chelation-controlled reduction of chiral â-alkoxy ke-
tones using Mori and Suzuki’s LiAlH4-LiI protocol.4 The
syntheses of various chiral â-alkoxy ketones involve nitro-
aldol reaction of chiral R-alkoxy aldehydes and conversion
of the aldolates to the corresponding nitro alkene deriva-
tives and then to chiral â-alkoxy ketones. This methodol-
ogy has been utilized in a short and efficient synthesis
of the (4R,6S)-tetrahydro-2-pyrone moiety of the HMG-
CoA reductase inhibitors compactin and mevinolin, which
is essential for their biological properties.6
Reaction steps leading to various â-alkoxy ketones from
chiral R-alkoxy aldehydes are described in Scheme 1.
Henry reaction of (+)-2,3-O-isopropylidene-D-glyceralde-
hyde 1a 7 with 3-nitropropanol triisopropylsilyl ether 2c8
in the presence of a catalytic amount of DBU (0.1 equiv)
in CH3CN provided the nitro-aldol product (3) as a
diastereomeric mixture in 83% yield. The nitro-aldol
product was dehydrated using copper chloride and dicy-
clohexylcarbodiimide (DCC) as described by Seebach and
co-workers.9 Treatment of the above mixture of nitro-
aldols with DCC (2.2 equiv) and CuCl (1.5 equiv) in CH3-
CN followed by heating the resulting mixture at 60 °C
for 15 h afforded nitro alkene 4d as a mixture (3.6:1 by
1H NMR analysis) of Z/E isomers in 87% yield. Reduction
of the nitro alkene mixture with zinc (3 equiv) and 4 N
aqueous HOAc in THF at 0 °C for 15 min provided the
corresponding oxime.10 Heating the oxime with NaHSO3
(5 equiv) in a mixture of H2O and EtOH (1:2) at reflux
furnished ketone 5d 11 in 90% yield for two steps. Fol-
lowing the above procedures, aldehyde 1a and other nitro
derivatives (2a , 2b, and 2d ) afforded various â-alkoxy
ketones 5a -c and 5f.12 Other chiral alkoxy aldehydes
1b-e were prepared from the corresponding known13
alcohols by Swern oxidation. Reaction of the resulting
aldehydes with nitro alkane 2c provided the correspond-
ing nitro aldols, which were converted to ketones 5e and
5g-i following the reaction sequence described above. Of
particular note, various protecting group compatibility
(1) (a) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T.
K. J . Am. Chem. Soc. 1988, 110, 4696. (b) Rychnovsky, S. D.;
Griesegraber, G.; Kim, J . J . Am. Chem.. Soc. 1994, 116, 2621 and
references therein.
(2) Narasaka, K.; Pai, F. Tetrahedron 1984, 40, 2223.
(3) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. Tetrahedron Lett. 1987, 28, 155.
(4) (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron
Lett. 1988, 29, 5419. (b) Mori, Y.; Takeuchi, A.; Kageyama, H.; Suzuki,
M. Tetrahedron Lett. 1988, 29, 5423. (c) Mori, Y.; Suzuki, M. Tetra-
hedron Lett. 1989, 30, 4383. (d) Mori, Y.; Suzuki, M. Tetrahedron Lett.
1989, 30, 4387. (e) Mori, Y.; Furukawa, H. Chem. Pharm. Bull. 1994,
42, 2161.
(6) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J .;
Deana, A. A.; Gilfilan, J . L.; Huff, J . W.; Novello, F. C.; Prugh, J . D.;
Smith, R. L.; Willard, A. K. J . Med. Chem. 1985, 28, 347.
(7) J ackson, D. Synth. Commun. 1988, 18, 337
(8) Prepared by protection of 3-nitro propanol with TIPSOTf and
2,6-lutidine. Please see: O¨ hrlein, R.; Schwab, W.; Ehrler, R.; J a¨ger,
V. Synthesis 1986, 535.
(9) Knochel, P.; Seebach, D. Synthesis 1982, 1017.
(5) (a) Ghosh, A. K.; Liu, W.-M. J . Org. Chem. 1997, 62, 7908. (b)
Ghosh, A. K.; Lei, H. Synthesis 2002, 371.
(10) Baer, H. H.; Rank, W. Can. J . Chem. 1969, 47, 145.
(11) Arau´jo, H. C.; Mahajan, J . R. Synthesis 1981, 49.
10.1021/jo020402k CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002
J . Org. Chem. 2002, 67, 8783-8788
8783

Ghosh and Lei
SCHEME 1a
SCHEME 2a
a
Reagents and conditions: (a) LiI, LiAlH4, Et2O, -78 °C, 83%.
The reason for this lower selectivity is presumably the
presence of a competing chelating substitutent at the â′-
position as shown in stereochemical model 8. On the basis
of this model, it appeared that the competing â′-chelation
could be minimized by incorporating sterically demand-
ing protecting groups for the â′-hydroxy position. Indeed,
as shown in Table 1, protection of the â′-hydroxyl group
with sterically more hindered diphenylmethyl and tri-
phenlymethyl groups resulted in significant improvement
in syn-diastereoselectivities with increasing bulkiness of
the protective group (entries 2 and 3). Furthermore,
reduction of the â-alkoxy ketone with a bulky TIPS group
at the â′-alkoxy position (ketone 5d , entry 4) provided a
a
Reagents and conditions: (a) DBU, CH3CN, 15 h; (b) CuCl,
DCC, CH3CN, 60 °C, 15 h; (c) Zn, HOAc, THF, 0 °C, 15 min; (d)
NaHSO3, EtOH-H2O, reflux.
1
single syn-1,3-diol derivative (6d ) by H and 13C NMR
in both aldehyde and nitroalkane substrates is evident
in Scheme 1.
analysis.14 Similarly, reduction of the corresponding
â-alkoxy ketone with γ- and δ-alkoxy substituents (ketone
5e, entry 5) also provided syn-1,3-diol derivative 6e
exclusively. We have also examined reduction of a
â-alkoxy ketone with OTIPS in the R′-position. However,
the selectivity is reduced significantly (4:1) as a result of
the stronger chelation of the R′-oxygen compared to that
of the â′-oxygen (entries 4 and 6). Initial stereochemical
assignment of the major syn-isomer 6a was based upon
its conversion to syn-1,3-diol derivative 6d .15 The stereo-
chemistry of 6d was conclusively established after its
conversion to the δ-lactone of HMG-CoA reductase in-
hibitors mevinolin and comparison of spectroscopic prop-
erties.16
Various â-alkoxy ketones thus obtained from conve-
nient transposition of R-alkoxy aldehydes were subjected
to LAH reduction in the presence of LiI following the
procedure of Mori and Suzuki.4 As shown in Scheme 2,
reduction of ketone 5a with LiAlH4 (10 equiv) and LiI
(10 equiv) at -78 °C in ether resulted in the formation
of a mixture (diastereomeric ratio 2.4:1) of syn- and anti-
1,3-diol derivatives 6a and 7a , respectively, in 83%
combined yield after silica gel chromatography.14 Inter-
estingly, the observed diastereoselectivity is modest
compared to that of the reduction of a â-alkoxy ketone
with â′-alkyl substituents reported by Mori and Suzuki.4
(12) Compound 5c was prepared as follows:
We subsequently examined the stereochemical influ-
ence of various substituents at the â-oxygen. As shown,
with decreasing size from benzylidene to ethylidene to
methylene (5g-i), the syn-selectivities improved from
3.7:1 to 7:1 (entries 7-9). These results are consistent
with the fact that a smaller substituent on the 1,3-
dioxane ring leads to better metal chelation between the
â-oxygen and ketone carbonyl oxygen, which translates
into better reduction stereoselectivities. Stereochemical
assignment of 6g was established after its conversion to
isopropylidene derivative 10 and analysis of its 13C NMR
chemical shifts based upon the report of Rychnovsky and
(13) (a) Pawlak, J . Nakanishi, K. J . Org. Chem. 1987, 52, 2896. (b)
Rychnovshy, S. D.; Plzak, K.; Pickering, D. Tetrahedron Lett. 1994,
35, 6799. (c) Gras, J .; Nouguier, R.; Mchich, M. Tetrahedron Lett. 1987,
28, 6601. (d) Hungerbu¨hler, E.; Seebach, D. Helv. Chim. Acta. 1981,
64, 687.
(14) Diastereomeric ratios (syn/anti) were calculated based upon the
relative intensity of the stereogenic proton or carbon (by 1H or 13C NMR
in C6D6 or CDCl3) on the dioxane or dioxolane ring.
(15) Catalytic hydrogenation of 6a in ethyl acetate over Pearlman’s
catalyst followed by TIPS protection with TIPSCl and imidazole in
DMF provided 6d .
(16) Ghosh, A. K.; Lei, H. J . Org. Chem., 2000, 65, 4779.
8784 J . Org. Chem., Vol. 67, No. 25, 2002

Chelation-Controlled Reduction
SCHEME 3a
TABLE 1. Ster eoselective Red u ction of â-Alk oxy
Keton es
a
Reagents and conditions: (a) H2, 10% Pd-C, EtOAC; (b) TBSCl,
Et3N, DMAP, CH2Cl2 (c) Me2C(OMe)2, p-TsOH, CH2Cl2; (d) TBAF,
THF; (e) MOMCl, iPr2NEt, DMAP, CH2Cl2; (f) BF3‚OEt2, CH2Cl2.
SCHEME 4a
a
Reagents and conditions: (a) (i) NaH, BnBr, TBAI, THF,
reflux; (ii) TBAF, THF, 76% two steps; (b) NaIO4, RuCl3‚3H2O,
CCl4-CH3CN-H2O; (c) p-TsOH, CH2Cl2, 65% two steps; (d) H2,
Pd(OH)2, EtOAc, 85%.
diagnostic of a syn-1,3-diol derivative. Interestingly,
isopropylidene derivative 10 provides access to an opti-
cally active syn-1,3-diol derivative containing differential
protecting groups at the left and right sides. As expected,
removal of the silyl group in 10 by treatment with
tetrabutylammonium fluoride in THF provided known
meso-diol 11.18 The stereochemistry of diol derivative 6i
derived from 5i was confirmed by correlation with 6g.
The primary hydroxy group in triol 9 was protected as a
MOM ether with MOMCl and iPr2NEt in the presence
of a catalytic amount of DMAP in CH2Cl2. The MOM
group was converted to formal derivative 6i by treatment
with BF3‚OEt2 in CH2Cl2. The resulting compound was
identical (by 1H and 13C NMR) to the major product
obtained from reduction of ketone 5i.
The synthetic application of this methodology was
demonstrated in a short and efficient synthesis of lactone
15, which is the key structural feature of compactin and
mevinolin for their potent HMG-CoA reductase inhibitory
properties.6 As shown in Scheme 4, protection of alcohol
6d as a benzyl ether by treatment with NaH and benzyl
bromide in the presence of tetrabutylammonium iodide
(catalytic) in THF for 5 h followed by removal of TIPS
by treatment with tetrabutylammonium fluoride afforded
a
Ratios determined by 1H and 13C NMR after chromatography.
b
Mixture yield after chromatography.
co-workers.17 As depicted in Scheme 3, removal of the
benzylidene protecting group in 6g by catalytic hydro-
genation provided triol 9. Selective protection of the
primary hydroxyl group as a TBS ether with TBSCl and
triethylamine in the presence of a catalytic amount of
DMAP followed by protection of the 1,3-diol as an
acetonide with 2,2-dimethoxy propane and a catalytic
amount of p-TsOH in CH2Cl2 furnished isopropylidene
derivative 10. The 18-31 ppm region of the 13C NMR of
10 revealed the presence of two peaks corresponding to
the two methyl groups of the acetonide: one being at 19.8
ppm and the other being at 30.2 ppm. Based upon the
report of Rychnovsky, these chemical shift values are
(17) Rychnovsky, S. D.; Skalitzky, D. J . Tetrahedron Lett. 1990, 31,
945.
(18) Bonini, A.; Racioppi, R.; Viggiani, L.; Righi, G.; Rossi, L.
Tetrahedron: Asymmetry 1993, 4, 793.
J . Org. Chem, Vol. 67, No. 25, 2002 8785

Ghosh and Lei
3-Nitr o-O-tr iisop r op ylsilyl-1-p r op a n ol 2c. To a stirred
solution of 3-nitropropanol (1.55 g, 14.7 mmol) in CH2Cl2 (40
mL) was added TIPSOTf (5.9 mL, 22.1 mmol) and 2,6-lutidine
(3.4 mL, 29.4 mmol). The resulting mixture was stirred for
1.5 h and quenched with saturated aqueous NaHCO3. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed with
brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by silica gel chromatogra-
phy (2% EtOAc in hexanes) to give the title compound (3.51
g, 91%) as an yellow oil: IR (film) 2944, 2867, 1554, 1463, 1381,
alcohol 12 (76% yield for 2 steps). Oxidation of alcohol
12 according to Sharpless’s procedure19 using NaIO4 and
RuCl3‚H2O (catalytic) in a mixture of CCl4, CH3CN, and
water at 23 °C for 30 min provided carboxylic acid 13.
Treatment of acid 13 with a catalytic amount of p-TsOH
resulted in concomitant deprotection of the acetonide and
lactonization (65% yield for two steps) to provide lactone
14. Removal of the benzyl protection in 14 by catalytic
hydrogenation using Pearlman’s catalyst furnished com-
pactin lactone 15 ([R]23 +2.2, c 2.5, MeOH; lit.20 [R]23
D
D
1
1115 cm-1; H NMR (300 MHz, CDCl3) δ 1.0-1.07 (m, 21H),
+1.81, c 0.992, MeOH) in 85% yield after silica gel
chromatography. The synthesis of lactone 15 thus pro-
vided evidence of the absolute configuration of alcohol
6d .
2.18-2.26 (m, 2H), 3.81 (t, 2H, J ) 5.7 Hz), 4.54 (t, 2H, J )
7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 11.7, 17.9, 30.2, 59.5,
72.4.
2-Nitr o-O-tr iisop r op ylsily-1-eth a n ol 2d . To a stirred
solution of 2-nitroethanol (355.7 mg, 3.91 mmol) in CH2Cl2 (10
mL) was added TIPSOTf (1.5 mL, 5.8 mmol) and 2,6-lutidine
(0.91 mL, 7.8 mmol). The resulting mixture was stirred for
1.5 h and quenched with saturated aqueous NaHCO3. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed with
brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by silica gel chromatogra-
phy (5% EtOAc in hexanes) to give the title compound (941.2
mg, 97%) as a yellow oil: IR (film) 2945, 2868, 1561, 1463,
1367, 1127 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.96-1.05 (m,
21H), 4.21 (t, 2H, J ) 5.2 Hz), 4.45 (t, 2H, J ) 5.2 Hz); 13C
NMR (75 MHz, CDCl3) δ 11.7, 17.7, 59.9, 77.7.
In conclusion, a nitro aldol reaction combined with
chelation-controlled LiAlH4 reduction provided stereo-
controlled access to functionalized syn-1,3-diol deriva-
tives. The overall protocol is practical and quite efficient.
Further studies of these reactions are currently under
investigation.
Exp er im en ta l Section
Anhydrous solvents and reagents were obtained as follows:
tetrahydrofuran and diethyl ether, distillation from sodium
and benzophenone; methylene chloride, distillation from CaH2;
diisopropylethylamine and triethylamine, distillation from
CaH2. All other solvents were HPLC grade. Analytical HPLC
analysis was performed on a reverse phase column (4.6 mm
× 25 cm) with 60%CH3CN/H2O as the solvent, flow rate 1.0
mL/min, λ 185 nm). Column chromatography was performed
with 240-400 mesh silica gel under low pressure of 5-10 psi.
Thin-layer chromatography (TLC) was carried out with silica
gel plates.
Rep r esen ta tive P r oced u r e for Nitr o Ald ol Rea ction
a n d Su bsequ en t Deh yd r a tion . Nitr oa lk en e 4d . To a
stirred solution of nitro compound 2c (2.82 g, 10.8 mmol) in
dry CH3CN (40 mL) was added DBU (0.15 mL, 1.0 mmol)
dropwise. The reaction mixture was stirred for 5 min, aldehyde
1a (1.40 g, 10.7 mmol) was added, and the resulting solution
was stirred for 15 h. The reaction was quenched with saturated
aqueous NH4Cl. The layers were separated, and the aqueous
layer was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by silica gel chromatography (10% EtOAc in hexanes) to give
nitro alcohol 3d (3.77 g, 83%) as a mixture of isomers. To a
stirred solution of the above nitro alcohols in CH3CN were
added DCC (4.85 g, 23.5 mmol) and CuCl (1.59 g. 16.1 mmol),
and the resulting solution was heated at 60 °C for 15 h. After
this period, the reaction was cooled to room temperature,
diluted with ethyl acetate, and quenched with oxalic acid (6
g) in methanol. The suspension was filtered through a Celite
pad, and the filtrate was washed with saturated aqueous
NaHCO3 and brine and dried over Na2SO4. After evaporation
of the solvent under reduced pressure, the residue was purified
by column chromatography (5% EtOAc in hexanes) to afford
the nitro alkene (4d , 2.88 g 87%) as a yellow oil in a mixture
Syn th esis of n itr o Com p ou n d s 2a-d . 3-Nitr o-O-ben zyl-
1-p r op a n ol 2a .21 To a stirred solution of 3-nitropropanol (1.57
g, 14.9 mmol) and trichlorobenzyloxyacetimide (4.2 mL, 22.4
mmol) in CH2Cl2 (80 mL) at 0 °C was added TFA (0.2 mL, 2.2
mmol) dropwise, and the resulting mixture turned cloudy. The
resulting mixture was stirred for 1.5 h, and the solvent was
removed under reduced pressure. The residue was dissolved
in hexane and ether (6:1), washed with NaHCO3 and brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by silica gel chromatography (3%
EtOAc in hexanes) to give the title compound (2.55 g, 88%) as
1
a yellow oil: IR (film) 2932, 2865, 1552, 1453, 1098 cm-1; H
NMR (300 MHz, CDCl3) δ 2.26-2.34 (m, 2H), 3.57 (t, 2H, J )
5.7 Hz), 4.51-4.57 (m, 4H), 7.31-7.37 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 27.3, 65.8, 72.5, 72.9, 127.4, 127.5, 128.2, 137.5.
3-Nitr o-O-d ip h en lym eth yl-1-p r op a n ol 2b. To a stirred
solution of 3-nitropropanol (119.9 mg, 1.1 mmol) and benzhy-
drol (251.2 mg, 1.3 mmol) in CH2Cl2 (10 mL) was added TsOH
(216.9 mg, 1.1 mmol). The resulting mixture was stirred for
15 h and was quenched by saturated aqueous NaHCO3. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed with
brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by silica gel chromatogra-
phy (5% EtOAc in hexanes) to give the title compound (209.8
mg, 81%) as a yellow oil: IR (film) 3028, 2869, 1551, 1452,
1382, 1095 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.31-2.35 (m,
2H), 3.56 (t, 2H, J ) 5.7 Hz), 4.55 (t, 2H, J ) 6.9 Hz), 5.38 (s,
1H), 7.30-7.39 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 26.4,
64.7, 72.6, 83.8, 126.5, 127.4, 128.2, 141.5.
1
of E/Z isomers. Major isomer: H NMR (300 MHz, CDCl3) δ
0.99-1.01 (m, 21H), 1.38 (s, 3H), 1.45 (s, 3H), 2.85-2.91 (m,
2H), 3.75 (dd, 1H, J ) 6.6, 8.1 Hz), 3.80-3.85 (m, 2H), 4.18
(dd, 1H, J ) 6.6, 9.0 Hz), 4.85 (q, 1H, J ) 8.7 Hz), 7.10 (d, 1H,
J ) 8.7 Hz); 13C NMR (75 MHz, CDCl3) δ 11.8, 17.9, 25.6, 26.6,
30.6, 60.7, 68.8, 71.8, 110.6, 134.6, 151.0.
Rep r esen ta tive P r oced u r e for Keton es 5a -i. Keton e
5d . To a stirred solution of nitro alkene 4d (1.96 g, 5.26 mmol)
in THF (80 mL) at 0 °C was added freshly activated zinc dust
(1.02 g, 15.8 mmol) and 4 N acetic acid (7.9 mL, 31.6 mmol).
After 15 min, the suspension was filtered, and the filter cake
was washed with ethyl acetate. Saturated NaHCO3 was added
to the filtrate, and this was extracted with ethyl acetate. The
combined organic layers were washed with brine and dried
over Na2SO4. After evaporation of the solvent under reduced
pressure, the oxime was used directly for the next step without
further purification. To a stirred solution of the above oxime
in ethanol (20 mL) and H2O (10 mL) was added NaHSO3 (2.74
g, 26.3 mmol). The resulting solution was heated to reflux for
(19) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(20) Takano, S.; Sekiguchi, Y.; Ogasawara, K. Synthesis 1989, 539.
(21) Yamada, K.; Moll, G.; Shibasaki, M. Synlett 2001, S1, 980.
8786 J . Org. Chem., Vol. 67, No. 25, 2002

Chelation-Controlled Reduction
5 h. After this period, the reaction was cooled to room
temperature and concentrated under reduced pressure. The
residue was diluted with H2O and extracted with ethyl acetate
(2 × 20 mL). The combined organic layers were washed with
brine and dried over Na2SO4. After evaporation of the solvent
under reduced pressure, the residue was purified by column
chromatography (10% EtOAc in hexanes) on silica gel to
provide ketone 5d (1.56 g, 86% 2 steps) as an oil: [R]23D +7.65
(c 4.72, CHCl3); IR (film) 2942, 2866, 1713, 1463, 1379, 1100,
1066 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.02-1.07 (m, 21H),
1.34 (s, 3H), 1.39 (s, 3H), 2.62-2.70 (m, 3H), 2.98 (dd, 1H, J )
5.8, 17.4 Hz), 3.52 (dd, 1H, J ) 6.9, 8.5 Hz), 3.97 (t, 2H, J )
4.06 (m, 1H), 4.10 (dd, 1H, J ) 4.9, 11.4 Hz), 4.72 (d,1H, J )
6.2 Hz), 5.05 (d, 1H, J ) 6.2 Hz); 13C NMR (100 MHz, CDCl3)
δ 11.7, 17.9, 31.9, 38.9, 43.1, 62.5, 66.6, 69.1, 75.4, 93.7; MS
(EI) m/z 153.3, 333.2.
(3S,5R)-1-O-(ter t-Bu t yld im et h ylsilyl)-7-O-(t r iisop r o-
p ylsilyl)-3,5-O-isop r op ylid en e-h ep ta n e 10. To a stirred
solution of compound 9 (48.6 mg, 0.15 mmol) in CH2Cl2 (5 mL)
were added DMAP (1.8 mg, 0.01 mmol), TBSCl (22.6 mg, 0.15
mmol), and Et3N (23 µL, 0.17 mmol). The resulting solution
was stirred at room temperature for 15 h and quenched with
aqueous NH4Cl. The layers were separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over Na2SO4, and evaporated
under reduced pressure. The residue was dissolved in CH2Cl2
(10 mL), and p-TsOH (3 mg, 0.015 mmol) was added. The
resulting solution was stirred for 30 min and quenched with
aqueous NaHCO3. The layers were separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers
were washed with brine and dried over Na2SO4. After evapo-
ration of the solvent under reduced pressure, the residue oil
was purified by column chromatography (5% EtOAc in hex-
anes) on silica gel to provide compound 10 (58.5 mg, 82% 2
steps) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.04 (s,
6H), 0.88 (s, 9H), 1.04-1.07 (m, 21H), 1.18 (m 1H), 1.36 (s,
3H), 1.42 (s, 3H), 1.52 (td, 1H, J ) 2.5, 13 Hz), 1.58-1.71 (m,
4H), 3.62-3.75 (m, 3H), 3.80 (m, 1H), 4.0-4.10 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ -5.3, 11.9, 18.0, 19.8, 25.9, 29.7,
30.2, 37.4, 39.5, 39.7, 58.9, 59.1, 65.6 (2C), 98.4; HRMS (EI)
m/z calcd for C25H54O4NaSi2 (M+ + Na) 497.3458, found
497.3460.
6.4 Hz), 4.19 (dd, 1H, J ) 5.8, 8.5 Hz), 4.44-4.48 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 11.8, 17.9, 25.4, 26.8, 46.3, 48.0,
59.1, 69.4, 71.5, 108.6, 207.7; HRMS (EI) m/z calcd for
C
18H36O4NaSi (M+ + Na) 367.2281, found 367.2295.
Rep r esen ta tive P r oced u r e for LiI/LiAlH4 Red u ction .
syn -1,3-Diol 6d . To a stirred solution of ketone 5d (287 mg,
0.8 mmol) in ether (20 mL) was added LiI (1.11 g, 8.3 mmol),
and the resulting mixture was stirred at -40 °C for 5 min.
After this period, the mixture was cooled to -78 °C, and LiAlH4
(315.0 mg, 8.3 mmol) was added. The reaction was stirred for
30 min and quenched with aqueous 10% potassium sodium
tartrate solution. The layers were separated, and the aqueous
layer was extracted with ether. The combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography
(20% EtOAc in hexanes) on silica gel to provide alcohol 6d
(273.3 mg, 95%) as a colorless oil: [R]23D +8.89 (c 0.98, CHCl3);
IR (film) 3500, 2941, 2866, 1463, 1098 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.03-1.07 (m, 21H), 1.36 (s, 3H), 1.41 (s, 3H),
1.63-1.85 (m, 4H), 3.57 (t, 1H, J ) 7.7 Hz), 3.77 (d, 1H, H )
1.6 Hz), 3.87-4.01 (m, 3H), 4.11 (dd, 1H, J ) 5.87, 8.07 Hz),
4.27-4.51 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 11.7, 17.9,
25.7, 26.9, 38.8, 40.6, 62.4, 69.6, 69.7, 74.3, 108.8; HRMS (EI)
m eso-3,5-O-Isop r op ylid en e-1,7-h ep ta d iol 11. To a stirred
solution of 10 (13.0 mg, 0.03 mmol) in THF (5 mL) was added
1 M tetrabutylammonium flouride in THF (0.12 mL, 0.12
mmol), and the reaction mixture was stirred for 2 h. The
reaction was quenched with aqueous NH4Cl. The layers were
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine
and dried over Na2SO4. After evaporation of solvent under
reduced pressure, the residue was purified by column chro-
matography (80% EtOAc in hexanes) on silica gel to provide
alcohol 11 (5.3 mg, 87%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 1.36-1.40 (m, 1H), 1.39 (s, 3H), 1.44-1.46 (m, 1H),
1.49 (s, 3H), 1.67-1.77 (m, 4H), 2.41 (br, 2H), 3.63-3.82 (m,
4H), 4.08-4.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.8,
30.2, 36.4 38.0, 60.7, 69.2, 98.7.
(2S,4S)-1,2-O-Isop r op ylid en e-4-O-ben zyl-6-h exa n ol 12.
To a stirred solution of NaH (81.6 mg, 2.0 mmol) and alcohol
6d (190 mg, 0.5 mmol) in THF (20 mL) were added tetrabu-
tylammonium iodide (19 mg, 0.05 mmol) and benzyl bromide
(0.12 mL, 2 mmol). The resulting mixture was heated to reflux
for 5 h. After this period, the solution was cooled to room
temperature and quenched by aqueous NH4Cl. The layers were
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine
and dried over Na2SO4. Evaporation of the solvent under
reduced pressure provided a residue, which was used for next
step without further purification. To a stirred solution of the
above residue in THF (10 mL) was added tetrabutylammonium
flouride (1.0 M solution in THF) (1.53 mL, 1.5 mmol), and the
reaction mixture was stirred for an additional 5 h. The reaction
was quenched with aqueous NH4Cl. The layers were separated,
and the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with brine and dried
over Na2SO4. After evaporation of the solvent under reduced
pressure, the residue was purified by column chromatography
(50% EtOAc in hexanes) on silica gel to provide alcohol 12
(119.3 mg, 76% 2 steps) as a colorless oil: [R]23D -18.6 (c 2.20,
CHCl3); IR 3422, 2984, 2936, 2874, 1370, 1214, 1055 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.34 (s, 3H), 1.41 (s, 3H), 1.72-
1.90 (m, 3H), 1.99-2.07 (m, 1H), 2.31 (br, 1H), 3.52 (t, 1H, J
) 7.8 Hz), 3.72-3.83 (m, 3H), 4.01 (dd, 1H, J ) 6.0, 8.1 Hz),
4.15-4.24 (m, 1H), 4.54 (ABq, 2H, J ) 11.7, ∆ν ) 22.8 Hz),
m/z calcd for
369.2425.
C
18H38O4NaSi (M+ + Na) 369.2437, found
1-O-(Tr iisop r op ylsilyl)-3,5,7-h ep ta tr iol 9. To a stirred
solution of 6g (102 mg, 0.25 mmol) in ethyl acetate (10 mL)
and methanol (3 mL) was added Pd(OH)2 (25 mg), and the
resulting solution was placed under a H2 balloon and stirred
for 15 h at room temperature. The mixture was filtered, and
the filtrate was evaporated under reduced pressure to provide
compound 9 (79.6 mg, 99%) as a colorless oil. The purity of 9
was determined to be >98% by HPLC (retention time 9.12
min): [R]23D -11.4 (c 0.92, CHCl3); IR (film) 3356, 2942, 2866,
1462, 1099 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.04-1.10 (m,
21H), 1.50 (td, 1H, J ) 14.1, 2.2 Hz), 1.60-1.65 (m, 1H), 1.68-
1.79 (m, 4H), 3.79-3.86 (m, 2H), 3.93 (dt, 1H, J ) 9.6, 3.3
Hz), 4.00 (td, 1H, J ) 10.1, 4.5 Hz), 4.14-4.20 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 12.0, 18.3, 38.9, 39.0, 43.6, 61.9,
63.8, 73.2, 74.4.
1,3-O-Meth ylen e-7-O-(tr iisop r op ylsilyl)-5-h ep ta n ol 6i
(fr om 9). To a stirred solution of 9 (7.8 mg, 0.024 mmol) and
DMAP (1 mg) in CH2Cl2 (5 mL) was added iPr2NEt (42 µL,
0.24 mmol). The resulting solution was cooled to 0 °C, and
MOMCl (3 µL, 0.04 mmol) was added. The reaction was stirred
for 12 h and quenched with NH4Cl. The layers were separated,
and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The residue
was dissolved in CH2Cl2 (3 mL), and the mixture was cooled
to 0 °C. BF3‚OEt2 (3 µL, 0.02 mmol) in CH2Cl2 (1 mL) was
added. After 5 min, the reaction was quenched with NaHCO3.
The layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by column chro-
matography (20% EtOAc in hexanes) on silica gel to provide
6i (3 mg): IR (film) 3503, 2944, 2924, 2866, 1099 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 1.05-1.10 (m, 21H), 1.53-1.88 (m,
6H), 3.73 (dt, 2H, J ) 2.5, 11.9 Hz), 3.84-3.98 (m, 3H), 4.00-
J . Org. Chem, Vol. 67, No. 25, 2002 8787

Ghosh and Lei
7.32-7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 25.7, 27.0,
36.1, 37.3, 60.1, 69.6, 70.9, 72.8, 75.2, 108.7, 127.8, 127.9, 128.4,
138.0.
(4R,6S)-4-Hyd r oxy-6-h yd r oxym eth yltetr a h yd r o-2-p y-
r on e 15. To a stirred solution of 7 (28 mg, 0.1 mmol) in ethyl
acetate (3 mL) was added Pd(OH)2 (3.5 mg), and the resulting
solution was placed under a H2 balloon and stirred for 5 h at
room temperature. The mixture was filtered, and the filtrate
was evaporated under reduced pressure. The residue oil was
purified by column chromatography (EtOAc) on silica gel to
(4R,6S)-4-Ben zyloxy-6-h yd r oxym et h ylt et r a h yd r o-2-
p yr on e 14. To a stirred solution of alcohol 12 (87 mg, 0.28
mmol) and NaIO4 (181.8 mg, 0.84 mmol) in CCl4 (1 mL), CH3-
CN (1 mL), and H2O (0.6 mL) was added ruthemium trichlo-
ride hydrate (5.8 mg, 0.03 mmol), and the mixture was stirred
for 30 min at room temperature. After this period, CH2Cl2 (5
mL) was added, and the layers were separated. The aqueous
layer was extracted with CH2Cl2. The combined organic layers
were dried over Na2SO4 and filtered. To the solution was added
p-TsOH (5.3 mg, 0.03 mmol). The resulting mixture was stirred
for 1 h at room temperature and quenched with aqueous
NaHCO3. The layers were separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chro-
matography (80% EtOAc in hexanes) on silica gel to provide
provide title compound 15 (15 mg, 85%) as a colorless oil: [R]23
D
+2.2 (c 2.5, MeOH); lit.20 [R]23 +1.81 (c 0.992, MeOH); IR
D
(film) 3377, 2930, 1712 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.90-2.04 (m, 4H), 2.68-2.76 (m, 2H), 3.68 (dd, 1H, J ) 12.4,
4.6 Hz), 3.93 (dd, 1H, J ) 12.4, 2.8 Hz), 4.48 (m, 1H), 4.83 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 31.3, 38.5, 62.7, 64.5, 76.2,
169.6; MS (CI) m/z 147 (M++H); HRMS (EI) m/z calcd for
C6H9O3 (M+ - OH) 129.0552, found 129.0545.
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health (GM 53386) is
gratefully acknowledged. We thank Dr. Geoffrey Bilcer
for helpful discussions.
alcohol 14 (43 mg, 65% 2 steps) as a colorless oil: [R]23 +0.9
D
(c 1.71, CHCl3); IR (film) 3409, 2924, 1727, 1254, 1072 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.93 (ddd, 1H, J ) 3.0, 11.5, 14.3
Hz), 2.07-2.07 (m, 1H), 2.57 (br, 1H), 2.64 (dd, 1H, J ) 4.7,
17.6 Hz), 2.80 (ddd, 1H, J ) 2.0, 3.0, 17.6 Hz), 3.63 (dd, 1H, J
) 4.4, 12.4 Hz), 3.88 (dd, 1H, J ) 3.0, 12.4 Hz), 4.03-4.07 (m,
1H), 4.54 (ABq, 2H, J ) 12.0 Hz, ∆ν ) 13.7 Hz), 4.71-4.77
(m, 1H), 7.29-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 28.7,
35.8, 64.4, 69.2, 70.5, 77.3, 127.5, 127.9, 128.5, 137.5, 170.0;
HRMS (EI) m/z calcd for C13H17O4 (M+ + H) 237.1127, found
237.1137.
Su p p or tin g In for m a tion Ava ila ble: Reaction yields and
spectral and analytical data for compounds 4a ,b,e-i, 5a -c,e-
1
i; spectral data for 6a -c,e-i; and copies of H and 13C NMR
spectra for compounds 2, 5, 6, 9-12, 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O020402K
8788 J . Org. Chem., Vol. 67, No. 25, 2002