Straightforward and efficient synthesis of (4R,6S)-4-(tert-butyldimethyl- siloxy)-6-(hydroxymethyl)tetrahydropyran-2-one

Article abstract of DOI:10.1055/s-2008-1077957

A novel synthetic approach to (4R,6S)-4-(tert-butyldimethylsiloxy)-6- (hydroxymethyl)tetrahydropyran-2-one, a key precursor of statin side chain, is described. A prime feature of the presented strategy is the transformation of (4R,6S)-4-(tert-butyldimethylsiloxy)-6-(iodomethyl)tetrahydropyran-2-one to an acetate ester derivative and subsequent cleavage of an acetate protection by applying homogeneous tin catalysis. Iodolactone used in the study is accessible by a new route in five steps from (S)-ethyl 4-chloro-3-hydroxybutanoate. This method overcomes many of the drawbacks associated with previously reported approaches. It gives the title compound in 21% over seven steps, which is the highest attained overall yield yet. The disclosed approach was realized in convenient and economical manner suitable for industrial use.

Full text of DOI:10.1055/s-2008-1077957

2036
LETTER
Straightforward and Efficient Synthesis of (4R,6S)-4-(tert-Butyldimethyl-
siloxy)-6-(hydroxymethyl)tetrahydropyran-2-one
Synthesis of
a
6
d
-Hydroxyme
e
thyl-Lacton
n
ized Statin
S
k
ide-Chain
P
r
o
ecursor Časar*
Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27, 1234
Mengeš, Slovenia
Fax +386(1)7237382; E-mail: zdenko.casar@sandoz.com
Received 29 April 2008
This paper is dedicated in memoriam to Assist. Prof. Dr. Viktor Menart (1951–2007)
OH
Abstract: A novel synthetic approach to (4R,6S)-4-(tert-butyldi-
methylsiloxy)-6-(hydroxymethyl)tetrahydropyran-2-one, a key pre-
cursor of statin side chain, is described. A prime feature of the
presented strategy is the transformation of (4R,6S)-4-(tert-bu-
tyldimethylsiloxy)-6-(iodomethyl)tetrahydropyran-2-one to an ace-
tate ester derivative and subsequent cleavage of an acetate
protection by applying homogeneous tin catalysis. Iodolactone used
in the study is accessible by a new route in five steps from (S)-ethyl
4-chloro-3-hydroxybutanoate. This method overcomes many of the
drawbacks associated with previously reported approaches. It gives
the title compound in 21% over seven steps, which is the highest at-
tained overall yield yet. The disclosed approach was realized in con-
venient and economical manner suitable for industrial use.
OH
OH
O
R
Het
OM
O
O
R = substituted decalin ring
microbially derived statins
M = H, Na, Ca
synthetic statins
Het = heterocyclic core;
Figure 1 General structure of fungal and synthetic statins
OH
O
X = Cl, Br, I
Cl
statins
OP
P = protecting group
OEt
4
Key words: drugs, lactones, stereoselective synthesis, homoge-
neous catalysis, tin
OH
OP
X
HO
X
Statins are a group of compounds which share the ability
to inhibit hydroxymethylglutaryl coenzyme A (HMG-
CoA) reductase, the enzyme that controls the rate-limiting
step of cholesterol synthesis.1,2 Statins have become the
most effective hypolipidemic drugs available.3 Among
the currently available statins, pravastatin, simvastatin,
and lovastatin are fungal in origin, while the so-called su-
perstatins fluvastatin, atorvastatin, and rouvastatin are
synthetic.4 Statins are chemically and pharmacologically
a diverse group of drugs that share some common struc-
tural features. For example, they all share a 3,5-dihydroxy
acid side chain, which may be present in an inactive lac-
tone form (b-hydroxy lactone moiety). In vivo, these d-
lactone prodrugs are enzymatically hydrolyzed to their ac-
tive hydroxy acid forms.5 Statins share rigid, hydrophobic
groups that are covalently linked to the 3,5-dihydroxy
acid chain. The structure of these groups differs signifi-
cantly between microbially derived and synthetic statins.
While microbially-derived statins contain the structurally
complex substituted chiral hexahydronaphthalene ring
system, synthetic statins possess simple substituted het-
eroaromatic motifs (Figure 1).
O
OH
O
O
O
O
3
2
1
Scheme 1 Retrosynthetic analysis of statins’ synthesis via 6-(halo-
methyl)lactone derivatives 2
Nevertheless, the b-hydroxy lactone moiety has proven to
be essential for biological activity of these compounds.6
Lactonized statin side chain 1 (P = H) has been prepared
before.7,8 Recently, efficient and highly stereoselective
approaches to chiral halolactole derivatives 3 (X = Cl)
emerged by using an enzymatically catalyzed aldol con-
densation. Subsequent oxidation of lactoles 3 afforded the
corresponding 6-(halometyl)lactonized side-chain precur-
sors 2 (X = Cl, P = H). This methodology has opened a
short, efficient, and cheap pathway to statins with high
stereochemical purity.9 However, precursors 2 have not
been coupled directly, without ring opening, with hydro-
phobic portions to produce statins. Therefore, a challenge
for direct transformation of halolactone precursor 2 of sta-
tin side chain, without ring opening, to functionalized de-
rivative that could be coupled with heterocyclic core
appeared. These facts stimulated us to evaluate this chal-
lenging approach for statin formation. Since we did not
possess an enzymatically derived lactole precursor 3 in or-
der to pursue our idea, we were stimulated to prepare a
halolactone 2 synthetically. Thus, in the first part of our
investigation we focused on development of an efficient
synthetic strategy to a protected halolactone 2. After-
wards, in the second part, we studied different possibili-
ties of its transformation to the appropriate precursor 1
SYNLETT 2008, No. 13, pp 2036–2040
x
x
.x
x
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077957; Art ID: G13308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of a 6-Hydroxymethyl-Lactonized Statin Side-Chain Precursor
2037
CuI, DMPU, P(OEt)3
CH2=CHMgCl
TBSCl
imidazole
OH
O
OH
O
OTBS O
OTBS O
NaI
Cl
I
I
THF
–40 °C to r.t., 3 h
OEt
4 99.3% ee
OEt
OEt
OEt
acetone
reflux, 60 h
DMF
0 °C to r.t., 12 h
85%
5
90%
6
68–74%
7
crystallization
OTBS
OTBS
OTBS
I2
or
OTBS O
NaHCO3
chromatography
KOH
+
MeOH
40 °C, 2 h
MeCN
0 °C, 4 h
OH
I
I
43–65%
I
O
O
O
O
O
O
93%
90%
99.3% de
2
9
8
2
Scheme 2 Synthetic approach to 6-(iodomethyl)lactone 2 from butanoate 4; yields refer to isolated products 5, 6, 7, and 8, at least 96% pure
by GC analysis
which would be suitable for further transformation (e.g., acidification to produce (R)-3-(tert-butyldimethyl-
oxidation) to produce the corresponding coupling partner siloxy)hex-5-enoic acid (8)18 in excellent yield (93%).
for Wittig reaction (Scheme 1).
The acid 8 was lactonized in the presence of iodine and
NaHCO3 in MeCN at 0 °C to afford a mixture of diaste-
reomeric iodolactones 2 and 9 in 90% yield and ratio
77:23 as determined by HPLC. The desired (4R,6S)-io-
dolactone 2 was isolated either by successive crystalliza-
tions from pentane in 43% yield with 99.3% de as
We have expected that (4R,6S)-4-(tert-butyldimethyl-
siloxy)-6-(iodomethyl)-tetrahydropyran-2-one (2, X = I,
P = TBS) would suit our needs. This molecule was pre-
pared by Knight and Bennett from alkyl 2-cyanoacetate in
five steps in poor 4% overall yield.10 Latter on, a formal
synthesis of the TBS-protected lactone 2 was successfully
completed in twelve steps.11 We anticipated that 6-(io-
domethyl)lactone 2 could be transformed to (4R,6S)-4-
(tert-butyldimethylsiloxy)-6-(hydroxymethyl)tetrahydro-
pyran-2-one (1, P = TBS) which would allow possibility
for transformation to an aldehyde derivative. Although
20
determined by HPLC {[a]D –16.8 (c 1, CHCl3)}, in
quantities up to 250 g or by chromatographic separation
on silica with hexane–t-BuMeO = 8:2 mobile phase with
yields up to 65% and 99.8% de. The overall yield of 23%
(crystallization) or 34% (chromatography) was achieved
for the five-step sequence (Scheme 2).
four different approaches12–15 to lactone 1 (P = TBS) have With iodolactone 2 in hands we pursued our strategy for
been reported until now, it has never been obtained via its transformation to an appropriate derivative for cou-
halolactone 2. Moreover, reported approaches either give pling reaction. Direct oxidation19 of lactone 2 to an alde-
poor overall yields of lactone 1 (P = TBS),12 apply envi- hyde derivative proved to be impossible. Since
ronmentally unacceptable reagents (Hg salts),13 require iodolactones are sensitive to basic conditions20 we consid-
many synthetic steps,13,14 or use industrially uncommon ered to introduce an oxygen nucleophile at exocyclic io-
starting materials and multiple expensive reagents.14,15
domethyl position by applying mild reaction conditions.
Therefore, direct conversion of iodolactone 2 to (hy-
droxymethyl)lactone 1 was attempted with water as a mild
source of oxygen nucleophile in polar aprotic solvents.21
Unfortunately, this approach gave only decomposition
products. These results prompted us to consider an acetate
anion, which is considered as one of the least basic oxy-
gen nucleophiles with fair nucleophilicity (Scheme 3 and
Table 1). The first experiment was performed in acetone
with 10 equivalents NaOAc at reflux (entry 1);22 however,
under these conditions reaction did not take place. Next,
we changed the solvent to MeCN and increased the reac-
tion temperature to 82 °C (entry 2). Similarly, no product
was detected. Then, we replaced the solvent by AcOH and
tested the reaction at 118 °C (entry 3). Even at these con-
ditions only starting material 2 was recovered. Finally,
conducting the reaction in DMF23 (entries 4–6) resulted in
the formation of the desired acetate 11 for the first time.
The acetate 11 was isolated in ca. 30% yield. However,
acetate 11 was accompanied with the significant amount
of unknown product, which proved, after isolation and
careful NMR and MS analysis, to be alkene derivative
10.24 This suggested that NaOAc is basic enough to pro-
mote the elimination reaction as well. We observed that at
Our synthetic pathway to lactone 2 starts with transforma-
tion of (S)-ethyl 4-chloro-3-hydroxybutanoate (4), an in-
dustrially produced chiral starting material with high
stereochemical purity (>99% ee), to a (R)-ethyl 3-(tert-
butyldimethylsiloxy)hex-5-enoate (7) according to the
three-step sequence which was reported recently by Sato
et al. for the R-enantiomer of 416 and later by Numata et
al. for the S-enantiomer of 4.17 In the first step butanoate
4 was transformed with NaI in acetone into (S)-ethyl 3-hy-
droxy-4-iodobutanoate (5) in 85% yield. Subsequent TBS
protection was achieved with TBSCl in DMF in the pres-
ence of imidazole to produce (S)-ethyl 3-(tert-butyldi-
methylsiloxy)-4-iodobutanoate (6) in 90% yield. We
conveniently isolated products of the first two steps by
vacuum distillation instead of chromatography16 to facili-
tate a large-scale preparation. We modified the third reac-
tion step of this sequence where we used vinylmagnesium
chloride, which is an industrially produced and less haz-
ardous chemical in comparison to vinylmagnesium bro-
mide. Hex-5-enoate
7 was isolated in 74% by
chromatographic isolation or in 68% yield by using distil-
lation purification in quantities of up to 500 g. Ester 7 was
hydrolyzed with KOH in MeOH at 40 °C followed by
Synlett 2008, No. 13, 2036–2040 © Thieme Stuttgart · New York

2038
Z. Časar
LETTER
OTBS
O
OTBS
O
OTBS
power and is less toxic than DMF (entries 8–10). At 40 °C
the reaction was very slow (entry 8) and the crude product
contained 1.32 equivalents of starting lactone 2. At 60 °C
(entry 9) the reaction was completed in 16 hours with a ra-
tio of 0.70:1 of products 10 and 11. The increase of the re-
action temperature to 80 °C resulted in a completed
reaction in five hours, but with unfavorable product distri-
bution (entry 10). Exchange of NaOAc for the less basic
LiOAc completed the reaction in DMF in 17.5 hours for
one equivalent of acetate (entry 11). Nevertheless, the
product distribution did not improve compared to entry 6.
When Ca(OAc)2 was used in DMA (entry 12), the reac-
tion was very slow. The use of NH4OAc in DMF (entry
13) afforded only decomposition products. To reduce the
extent of the elimination reaction we considered the use of
acetates that would not allow the equilibration of reaction
products and reactants in the reaction mixture. Therefore,
acetates that would form insoluble iodides in the reaction
media were considered. When Pb(OAc)2 was used in
AcOH at 120 °C only decomposition products were ob-
served, and PbI2 precipitated from the media (entry 14).
MOAc
+
I
O
solvent
35–93%
O
O
O
O
O
2
10
11
Scheme 3 Reaction of 6-(iodomethyl)lactone 2 with acetates
60 °C the reaction was very slow (entry 4) and there was
still 0.24 equivalents of unreacted 2 present in the crude
product. In five hours at 80 °C the amount of unreacted 2
decreased to 0.13 equivalents (entry 5). In 64.5 hours re-
action was completed, for the first time only with one
equivalent of NaOAc, with products 10 and 11 in a ratio
of 1:0.78 in favor of the desired product (entry 6). In order
to diminish the extent of the undesired reaction we added
some AcOH to the reaction medium.25 However, 10 was
present in the crude product in even a slightly higher
quantity (entry 7). We also considered the use of N,N-
dimethylacetamide (DMA) which has excellent solvent
Table 1 Transformation of Iodolactone 2 with Acetate Nucleophile
Entry
Reaction conditions
Solvent
Composition of producta
Time (h)
14
Temp (°C)
60
MOAc (equiv)
NaOAc (10)
NaOAc (10)
NaOAc (10)
NaOAc (10)
NaOAc (10)
NaOAc (1)
2
1
–
1
10
11
1
2
Me2CO
MeCN
AcOH
DMF
0
0
b
b
b
17
82
–
–
3
16.3
18.5
5
118
60
0
0
1
1
1
1
1
1
1
1
1
4
0.24
0.13
0
0.89
0.90
0.78
0.88
0.96
0.70
1.06
0.77
1.00
5
DMF
80
6
DMF
64.5
18.5
16
80
7
DMF–AcOH
DMA
DMA
DMA
DMF
80
NaOAc (10)
NaOAc (10)
NaOAc (10)
NaOAc (10)
LiOAc (1)
0
8
40
1.32
0
9
16
60
10
11
12
13
14
15
16
17
18
19
20
5
80
0
17.5
16
80
0
DMA
DMF
80
Ca(OAc)2 (10)
NH4OAc (10)
Pb(OAc)2 (1)
LiOAc (2) + AgBF4 (2)
LiOAc (2) + AgBF4 (2.1)
AgOAc (3)
2.43
b
b
b
5
80
–
–
–
b
b
b
AcOH
DMF
4
120
80
–
–
–
b
b
b
16
–
–
–
AcOH
DMF
16
120
80
0
0
1
1
1
1
1
16.5
2.5
4
0
0.85
AcOH
AcOH
AcOH
120
120
120
AgOAc (3)
0.06
0
0
0
0
AgOAc (2)
6
AgOAc (1.1)
0
a Ratio between compounds 2, 10, and 11 determined by 1H NMR integral.
b Only decomposition products were present (none of 2, 10, or 11 were observed in the product).
Synlett 2008, No. 13, 2036–2040 © Thieme Stuttgart · New York

LETTER
Synthesis of a 6-Hydroxymethyl-Lactonized Statin Side-Chain Precursor
2039
Next, we considered the LiOAc/AgBF4 couple (entries 15 ran-2-one (1) in 21% overall yield from the industrial
and 16), which should precipitate the AgI from the mix- starting material 4, which represents the highest efficiency
ture after the substitution reaction would have taken place yet known. For this purpose a new synthetic route to io-
and NaI released. In DMF this approach did not improve dolactone 2 was developed, which is an improvement on
the results. Instead, only decomposition products were ob- the previously described methods regarding yield as well
tained (entry 15). A breakthrough was achieved when two as simplicity. The strategy disclosed herein provides an
equivalents of LiOAc were used in the presence of 2.1 efficient methodology for the synthesis of statins.
equivalents AgBF4 in AcOH at 120 °C (entry 16). For the
first time a clean reaction took place giving only the de-
sired product 11 after 16 hours. This result induced us to
Acknowledgment
The author gratefully acknowledges Mr. P. Drnovšek for support of
this project, Dr. M. Vodopivec and Dr. S. Andrenšek for mass spec-
tra, Mr. M. Uštar for HPLC and GC analysis, Mr. S. Borišek for ac-
quisition of NMR spectra, and Mrs. A. Jeriha for technical
assistance.
simplify the applied system. Therefore, LiOAc/AgBF4
couple was replaced by AgOAc (entries 17–20). Interest-
ingly, when the reaction with three equivalents of AgOAc
was performed in DMF at 80 °C a mixture of 10 and 11
was obtained (entry 17) with similar product distribution
as in entry 7. After the exchange of solvent for AcOH and
short optimization of the reaction time and quantity of
AgOAc (entries 18 and 19) the ultimate conditions were
found (entry 20): a reaction in AcOH at 120 °C for six
hours with 1.1 equivalents of AgOAc. By applying these
conditions, 11 could be prepared in 93% yield26 in quanti-
ties of up to 500 g.
References and Notes
(1) Tobert, J. A. Nat. Rev. Drug Discov. 2003, 2, 517.
(2) Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibiot. 1976, 29,
1346.
(3) Lahera, V.; Goicoechea, M.; de Vinuesa, S. G.; Miana, M.;
de las Heras, N.; Cachofeiro, V.; Luno, J. Curr. Med. Chem.
2007, 14, 243.
Successful introduction of an oxygen nucleophile into io-
dolactone 2 has led us to another challenging task: selec-
tive cleavage of the acetate ester in the presence of the
lactone ester moiety in 11.
(4) Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160.
(5) Grabarkiewicz, T.; Grobelny, P.; Hoffmann, M.; Mielcarek,
J. Org. Biomol. Chem. 2006, 4, 4299.
(6) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.;
Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.;
Thompson, M. D.; Wright, J. J. J. Med. Chem. 1990, 33,
2982.
(7) For examples of synthesis, see: Fernandes, R. A.; Kumar, P.
Eur. J. Org. Chem. 2002, 2921; and references cited therein.
(8) (a) Reddy, M. V. R.; Brown, H. C.; Ramachandran, P. V.
J. Organomet. Chem. 2001, 624, 239. (b) Ghosh, A. K.; Le,
H. J. Org. Chem. 2002, 67, 8783.
(9) Greenberg, W.; Varvak, A.; Hanson, S. R.; Wong, K.;
Huang, H.; Chen, P.; Burk, M. J. Proc. Natl. Acad. Sci. U. S.
A. 2004, 101, 5788; and references cited therein.
(10) Bennett, F.; Knight, D. W.; Fenton, G. J. Chem. Soc., Perkin
Trans. 1 1991, 133; and references cited therein.
(11) Maddrell, S. J.; Turner, N. J.; Kerridge, A.; Willetts, A. J.;
Crosby, J. Tetrahedron Lett. 1996, 37, 6001.
(12) Lactone 1 (P = TBS) with mp 74–75 °C was obtained in
seven steps from (S)-malic acid ester via (S)-butane-1,2,4-
triol in an overall yield of 2%: Rosen, T.; Taschner, M. J.;
Heathcock, C. H. J. Org. Chem. 1984, 49, 3994.
(13) Enantiomerically pure lactone 1 with [a]D –7.5 and mp 72–
74 °C was accessed in 10% overall yield by an eight-step
convergent synthesis based on diastereoselective aldol
condensation between enzymatically derived chiral
sulfoxide auxiliary prepared in two steps and chiral building
block derived from (S)-butane-1,2,4-triol: Tang, J.;
Brackenridge, I.; Roberts, S. M.; Beecher, J.; Willetts, A. J.
Tetrahedron 1995, 51, 13217.
(14) Method utilizes an enzymatically derived chiral
3-hydroxycyclohexane acetate derivative obtained from
phloroglucitol which was then transformed via Baeyer–
Villiger oxidation to lactone 1 (P = TBS) with [a]D +1.9 and
mp 95 °C in nine steps and in 13% overall yield:
(a) Ghorpade, S. R.; Kalkote, U. R.; Chavan, S. P.; Bhide, S.
R.; Ravindranathan, T.; Puranik, V. G. J. Org. Chem. 2001,
66, 6803. (b) Kalkote, U. R.; Ghorpade, S. R.; Chavan, S. P.;
Ravindranathan, T. J. Org. Chem. 2001, 66, 8277.
Although the cleavage of acetate protection is a very well-
described topic even in the case of selective cleavage in
the presence of other esters such as formate, benzoate, and
trichloroacetate, there are few methods describing cleav-
age of acetate in the presence of another alkyl ester.27 Re-
cently, Otera et al. reported a neutral organotin catalyst [t-
Bu2SnOH(Cl)]2 for mild and efficient deacetylations.28
We considered this catalyst for deacetylation of 11 which
would give the desired lactone 1 (P = TBS, Scheme 4). In-
deed, treatment of 11 in THF–MeOH (1:1) at room tem-
perature in the presence of 5–10 mol% of [t-
Bu2SnOH(Cl)]2 for 24 hours brought the reaction to com-
pletion. After evaporation of the solvent, removal of cata-
lyst by filtration through a thin pad of silica and
recrystallization from hexane, lactone 1 (P = TBS) was
isolated as white needles in 66% yield in quantities up to
20
100 g. The determined [a]D of –0.2 (c 1, CHCl3) and
melting point of 102 °C (DSC onset) for lactone 1 pre-
pared by our approach are close to observations of
Tararov et al.15
OTBS
OTBS
[t-Bu2SnOH(Cl)]2
(5–10 mol%)
O
HO
MeOH–THF (1:1)
r.t., 24 h
O
O
O
O
66%
O
11
1
Scheme 4 Catalytic cleavage of acetate protection with tin catalyst
In conclusion, we have developed a straightforward, effi-
cient, and scalable seven-step approach to (4R,6S)-4-(tert-
butyldimethylsiloxy)-6-(hydroxymethyl)tetrahydropy-
Synlett 2008, No. 13, 2036–2040 © Thieme Stuttgart · New York

2040
Z. Časar
LETTER
(15) The most efficient (S)-malic acid based approach provided
lactone 1 (P = TBS) with [a]D +0.33, mp 96–98 °C in seven
steps in 16% overall yield: Tararov, V. I.; Andrushko, N.;
Andrushko, V.; König, G.; Spannenberg, A.; Börner, A. Eur.
J. Org. Chem. 2006, 5543; and references cited therein.
(16) Hareau, G. P.-J.; Koiwa, M.; Hikichi, S.; Sato, F. J. Am.
Chem. Soc. 1999, 121, 3640.
(17) Yamada, T.; Iritani, M.; Minoura, K.; Numata, A.;
Kobayashi, Y.; Wang, Y.-G. J. Antibiot. 2002, 55, 147.
(18) A hint for the preparation of acid 8 from ester 7 with LiOH
in 70% yield was given in: Kobayashi, Y.; Wang, Y.-G.
Tetrahedron Lett. 2002, 43, 4381.
(19) (a) Epstein, W. W.; Sweat, F. W. Chem. Rev. 1967, 67, 247;
and references cited therein. (b) Chandrasekhar, S.; Sridhar,
M. Tetrahedron Lett. 2000, 41, 5423; and references cited
therein. (c) Das, S.; Panigrahi, A. K.; Maikap, G. C.
Tetrahedron Lett. 2003, 44, 1375.
(20) (a) Bedford, S. B.; Fenton, G.; Knight, D. W.; Shaw, D.
Tetrahedron Lett. 1992, 33, 6505. (b) Allevi, P.; Anastasia,
M. Tetrahedron: Asymmetry 2000, 11, 3151.
(25) Cowley, B. R.; Humber, D. C.; Laundon, B.; Long, A. G.;
Lynd, A. L. Tetrahedron 1983, 39, 461.
(26) Procedure for the Preparation of [(2S,4R)-4-(tert-
Butyldimethylsiloxy)-6-oxotetrahydro-2H-pyran-2-
yl]methyl Acetate (11)
To the solution of (4R,6S)-4-(tert-butyldimethylsiloxy)-6-
(iodomethyl)-tetrahydropyran-2-one (2, 40.00 g, 108.0
mmol) in AcOH (660 mL) was added AgOAc (20.03 g,
118.8 mmol). The resultant mixture was then heated at 120–
125 °C for 6 h. The reaction mixture was filtered through
diatomite filter medium (Celite®). The obtained filtrate was
evaporated to afford the residue. To this residue EtOAc (500
mL) and H2O (600 mL) were added. The organic layer was
separated and the aqueous layer was washed again with
EtOAc (5 × 150 mL). The combined organic layers were
washed with H2O (4 × 300 mL), brine (5 × 300 mL) and
dried over anhyd MgSO4, filtered, and concentrated under
reduced pressure to afford 30.28 g (92.6%) of [(2S,4R)-4-
(tert-butyldimethylsiloxy)-6-oxotetrahydro-2H-pyran-2-
yl]methyl acetate (11) as a pale yellow oil (HPLC purity
98%). IR (liquid film): 2955, 2930, 2897, 2857, 1742, 1226,
1089 cm–1. 1H NMR (300 MHz, CDCl3): d = 4.93 (m, 1 H),
4.37 (m, 1 H), 4.30 (dd, J = 12, 3 Hz, 1 H), 4.21 (dd, J = 12,
5 Hz, 1 H), 2.62 (d, J = 4 Hz, 2 H), 2.11 (s, 3 H), 1.84–1.80
(m, 2 H), 0.89 (s, 9 H), 0.09, 0.09 (2 s, 6 H). 13C NMR (75
MHz, CDCl3): d = 170.4, 169.1, 73.3, 65.5, 63.0, 38.9, 32.2,
20.5, 17.7, –5.1, –5.2. HRMS (EI): m/z calcd for C14H27O5Si
[M + H]+: 303.1628; found: 303.1629. [a]D20 +11.0 (c 1,
CHCl3).
(21) Hutchins, R. D.; Taffer, I. M. J. Org. Chem. 1983, 48, 1360.
(22) Gammill, R. B. J. Org. Chem. 1984, 49, 5035.
(23) Williams, R. M.; Im, M. N. J. Am. Chem. Soc. 1991, 113,
9276.
(24) Data for (R)-4-(tert-Butyldimethylsiloxy)-6-methylene-
tetrahydro-2H-pyran-2-one (10)
IR (KBr): 2956, 2930, 2897, 2857, 1760, 1663, 1210, 1130,
1089 cm–1. 1H NMR (300 MHz, CDCl3): d = 4.75 (s, 1 H),
4.33 (s, 1 H), 4.21 (m, 1 H), 2.78–2.52 (m, 4 H), 0.87 (s, 9
H), 0.08, 0.08 (2 s, 6 H). 13C NMR (75 MHz, CDCl3): d =
166.9, 152.2, 95.6, 62.7, 39.5, 35.6, 25.5, 17.7, –5.0. HRMS
(EI): m/z calcd for C12H23O3Si [M + H]+: 243.1416; found:
243.1414. [a]D20 –3.0 (c 1, CHCl3).
(27) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups
in Organic Synthesis, 4th ed.; John Wiley and Sons: New
York, 2007, 223–239; and references cited therein.
(28) Orita, A.; Hamada, Y.; Nakano, T.; Toyoshima, S.; Otera, J.
Chem. Eur. J. 2001, 7, 3321.
Synlett 2008, No. 13, 2036–2040 © Thieme Stuttgart · New York