Tetrahydropyran synthesis by intramolecular conjugate addition to enones: Synthesis of the clavosolide tetrahydropyran ring

Article abstract of DOI:10.1055/s-0030-1257890

The synthesis of a tetrahydropyran intermediate for clavosolide A is reported, employing a combination of cross-metathesis and intramolecular oxa-Michael addition. The intramolecular oxa-Michael addition to ,-unsaturated esters requires the use of strong bases and can result in either modest yields or stereoisomeric mixtures, and can be highly variable according to the substrate structure. In contrast, the corresponding ketones cyclise under very mild conditions to give the 2,6-cis-isomers directly. The use of appropriately substituted ketones allows efficient conversion into esters.

Full text of DOI:10.1055/s-0030-1257890

PAPER
2935
Tetrahydropyran Synthesis by Intramolecular Conjugate Addition to Enones:
Synthesis of the Clavosolide Tetrahydropyran Ring
Synthesis of
a
Te
o
trahydropyra
d
nIntermedit
e
ae Related
r
toClavo
i
solide ck W. Bates, Ping Song
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
Fax +65 67911961; E-mail: Roderick@ntu.edu.sg
Received 17 February 2010; revised 6 May 2010
cavernoside.5b We intended to synthesise this compound
Abstract: The synthesis of a tetrahydropyran intermediate for
by the cross-metathesis–intramolecular Michael strategy.
We initially carried out a model study in the racemic se-
ries lacking the ring methyl group (Scheme 1). The sub-
clavosolide A is reported, employing a combination of cross-
metathesis and intramolecular oxa-Michael addition. The intramo-
lecular oxa-Michael addition to a,b-unsaturated esters requires the
use of strong bases and can result in either modest yields or stereoi- strate was prepared by alkylation of the dianion of methyl
acetoacetate with BOMCl.6 Reduction of ketone 3 and
someric mixtures, and can be highly variable according to the sub-
strate structure. In contrast, the corresponding ketones cyclise under
conversion of the ester into a Weinreb amide 5 allowed
very mild conditions to give the 2,6-cis-isomers directly. The use of
addition of allylmagnesium bromide to give the b,g-unsat-
appropriately substituted ketones allows efficient conversion into
urated ketone 6. This material, which would rapidly isom-
esters.
erise on storage to the corresponding a,b-unsaturated
isomer, was stereoselectively reduced using tetramethyl-
Key words: Michael addition, tandem reaction, cyclisation
ammonium triacetoxyborohydride, according to the meth-
od of Evans,7 to give the anti-diol 7.8 Cross-metathesis
There are numerous examples of the synthesis of tetrahy-
with methyl acrylate proceeded smoothly in the presence
dropyrans by the intramolecular conjugate addition of an
of Grubbs’ second-generation catalyst to give the a,b-un-
oxygen nucleophile to a Michael acceptor, such as an a,b-
unsaturated ester or ketone.1 This method has recently
been made more convenient by the application of cross-
metathesis for the installation of the Michael acceptor.2
The structures of several natural products would indicate
that oxa-Michael addition to an a,b-unsaturated ester
would be the obvious procedure. One such natural product
is clavosolide A (1) (Figure 1). This marine natural prod-
uct, isolated from Myriastra clavosa, is a symmetrical di-
olide. Other members of the clavosolide family lack one
or more methyl groups and are not symmetrical.3,4 The
structure of clavosolide A was ultimately determined by
synthesis.4b,c Structural features include a methylated xy-
lose, a cyclopropane, and a tetrasubstituted tetrahydropy-
ran.
saturated ester 8, exclusively as the E-isomer, in good
yield, accompanied by dimethyl fumarate from self-met-
athesis of the acrylate. A better yield of 89% for the a,b-
unsaturated ester 8 was obtained by employing methyl
crotonate.9
OMe
MeO
O
OMe
O
O
H
OH
H
O
O
O
O
The use of the intramolecular oxa-Michael addition to
form the tetrahydropyran ring has been reported by Lee4b
and by Gurjar.4g In both cases, strong base was required to
obtain the tetrahydropyran as a single 2,6-cis-isomer and
the synthetic sequence was lengthened by the choice of
Wittig or Horner–Wadsworth–Emmons chemistry to in-
stall the Michael acceptor. The stereoselective synthesis
of the tetrahydropyran moiety under mild conditions in a
short and efficient reaction sequence is the subject of this
paper.
H
H
O
O
O
H
H
MeO2C
OBn
2
1
O
MeO
OMe
OMe
Figure 1 Clavosolide A
Tetrahydropyran 2 is an intermediate in Willis’ syntheses
of clavosolide4a and polycavernoside,5a and also, as its
TIPS ether, an intermediate in White’s synthesis of poly-
a,b-Unsaturated ester 8 was treated with several bases in
order to determine the mildest conditions for cyclisation.
No reaction was observed using potassium carbonate. The
use of sodium methoxide in methanol resulted in slow cy-
clisation to give the tetrahydropyran 9 as a mixture of ste-
reoisomers (ca 1:1). Treatment with a stronger base,
SYNTHESIS 2010, No. 17, pp 2935–2942
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1257890; Art ID: T03810SS
© Georg Thieme Verlag Stuttgart · New York

2936
R. W. Bates, P. Song
PAPER
NaBH4
MeOH, 0 °C
O
O
OH
O
O
O
1. NaH; n-BuLi, THF
2. BOMCl
OMe
BnO
X
BnO
OMe
70%
3
4 X = OMe
MeONHMe•HCl
i-PrMgCl, THF, –5 °C
75%
5 X = NMeOMe
MgBr
Me4NBH(OAc)3
AcOH, MeCN
0 °C to r.t.
OH OH
OH
O
Et2O, THF, 0 °C
81%
BnO
BnO
74%
7
6
CO2Me
Grubbs II (4 mol%)
OH
Me
t-BuOK
OH OH
CH2Cl2
THF, r.t.
CO2Me
BnO
89%
53%
O
H
H
8
CO2Me
9
BnO
Scheme 1 Model study for clavosolide THP synthesis
potassium tert-butoxide in THF, gave 9 exclusively as the use. Deprotection using Amberlyst 15 in methanol cleanly
2,6-cis isomer, but in moderate yield (53%).
removed the TBS group to give alcohol 14, but did not re-
sult in the oxa-Michael addition. In our synthesis of dio-
spongin A, it was possible to achieve deprotection–
cyclisation in tandem fashion.2b In that case the Michael
acceptor was an a,b-unsaturated ketone. The ester in the
present case is a less effective activator of the alkene. Ad-
dition of sodium methoxide to the deprotected material to
induce cyclisation resulted in the formation of the desired
tetrahydropyran 2 but, as in the model study, as a cis/trans
mixture (ca. 1.3:1).13 In contrast, use of potassium tert-bu-
toxide resulted in decomposition. It appears that the addi-
tional bulk provided by the methyl group promotes
fragmentation, possibly by some form of retro aldol pro-
cess.
With the model system completed, we turned to the real
system with the additional methyl group, employing the
sequence devised by White (Scheme 2), with minor mod-
ifications.5b Asymmetric reduction of the b-keto ester 3
using Genet’s convenient modification10 of Noyori’s sys-
tem gave the alcohol (R)-4 in excellent yield and an ee of
97%, as determined by chiral HPLC. This alcohol was
protected as its TBS ether and reduced to the aldehyde 11
using DIBAL-H. Crotylation was then achieved using the
Brown reagent derived from cis-but-2-ene and (+)-
Ipc2BOMe.11 The desired homoallylic alcohol 12 could be
obtained in up to 67% yield as a single stereoisomer after
chromatography. Cross-metathesis of this more hindered
alkene 12 with methyl acrylate gave the desired a,b-unsat- While the use of strong base with appropriate protection
urated ester in 89% yield, but required a high catalyst of functional groups could be a solution to this problem,
loading (20 mol%). A slightly better yield (95%) and a we sought a milder method. From experience with a,b-un-
much lower catalyst loading (5 mol%) could be achieved saturated ketones in the synthesis of diospongin A, it is
using the Hoveyda–Grubbs second-generation catalyst12 apparent that ketones are more effective electron-with-
(H–G2) in dichloroethane at reflux. The use of this higher drawing groups. With this in mind, the cross-metathesis
boiling solvent was found to be advantageous. Cross- between the alkene 12 and methyl vinyl ketone (MVK)
metathesis with methyl crotonate was too slow to be of was carried out to give the a,b-unsaturated ketone 15 in
H2
RuCl2•(R)-BINAP (2 mol%)
DIBAL-H
toluene, –78 °C
O
O
OR
O
EtOH, 50 °C
BnO
OMe
89%, 97% ee
BnO
OMe
88%
3
TBSOTf,
2,6-lutidine
96%
(R)-4 R = H
10 R = TBS
OH
O
OH
cis-but-2-ene, t-BuOK
n-BuLi, (+)-(Ipc)2BOMe
BF3•OEt2, THF
MeO2C
H–G2 (2.7 mol%)
DCE
t-BuOK, THF, r.t.
2
67%
O
TBSO
11
95%
O
R
TBS
MeO2C
12
OBn
OBn
OBn
13 R = TBS
SO3H
MeOH
14 R = H
88%
Scheme 2 Methyl acrylate metathesis–Michael chemistry
Synthesis 2010, No. 17, 2935–2942 © Thieme Stuttgart · New York

PAPER
Synthesis of a Tetrahydropyran Intermeditae Related to Clavosolide
2937
excellent yield (Scheme 3). Tandem deprotection–intra- Following the example of Heathcock, who employed a-
molecular Michael addition was then achieved upon treat- oxygenated ketones as ester surrogates in stereoselective
ment with Amberlyst 15 in methanol. The tetrahydropyr- aldol chemistry,16 treatment with periodic acid in reagent
an 16 was obtained exclusively as its 2,6-cis isomer. grade methanol yielded the desired ester 2 in 92% yield.
Cleavage of the methyl group by means of the haloform This material was spectroscopically identical to that re-
reaction was carried out using freshly prepared potassium ported by Willis and White.4a,5
hypochlorite in methanol.14 The desired methyl ester 2
The intramolecular oxa-Michael addition to a,b-unsatur-
was obtained in 50% yield, accompanied by a similar
ated esters is complicated by the need to use relatively
yield of the corresponding a,a-dichloro ester 17 due to
strong basic conditions to achieve both the addition and
conversion into the 2,6-cis-isomer. Intramolecular addi-
overhalogenation during the haloform reaction.
tion to a,b-unsaturated ketones proceeds highly efficient-
OH
OH
O
ly under very mild conditions to give the 2,6-cis-isomers
directly, and can be carried out in a tandem fashion with
O-desilylation. The use of a-oxygenated ketones allows
for subsequent facile, mild, and efficient cleavage to es-
ters. The synthesis of an intermediate for clavosolide
demonstrates the usefulness of this method.
H–G2 (2.5 mol%)
Cl(CH2)2Cl
O
O
94%
TBS
12
TBS
15
OBn
O
OBn
OH
THF was distilled from Na/benzophenone; CH2Cl2 and MeCN were
dried by distillation from CaH2 immediately prior to use. MeOH
was distilled from activated Mg. All other solvents and reagents
were used as received. IR spectra were recorded on a Bio-Rad FTS
165 spectrometer either neat or as Nujol mulls using NaCl plates. 1H
NMR spectra were recorded on a Bruker Avance DPX at 300, 400,
or 500 MHz with residual protic solvent as the reference. 13C NMR
spectra were recorded at 75, 100, or 125 MHz on the same instru-
ments. Chemical shifts (d) are in ppm and coupling constants (J) are
in Hz. Mass spectra were recorded on a Finnigan LCQ DECA XP
MAX Ultra instrument. High-resolution mass spectra were record-
ed on a Waters Q-Tof premier instrument or Finnigan MAT95XP
instrument. Specific rotations, [a]D, were recorded on an Jasco P-
1030 polarimeter and are given with units of 10–1 deg·cm2·g–1.
Enantiomeric excess was determined with chiral HPLC analysis,
performed on a Shimadzu HPLC and Daicel Chemical Industries
Chiralcel OD-H column, eluting with i-PrOH–hexane.
O
SO3H
KOCl
MeOH, r.t.
MeOH, r.t.
O
95%
H
H
OBn
16
OH
OH
O
MeO2C
MeO2C
Cl
O
H
+
H
H
H
Cl
OBn
OBn
2
17
46%
50%
Scheme 3 MVK metathesis-Michael chemistry
To solve this problem, an alternative strategy for the ke-
tone-into-ester conversion was adopted (Scheme 4). The
alkene 12 underwent cross-metathesis with the TBS ether
of 1-hydroxybut-3-en-2-one15 (18) to give the metathesis
Methyl ( )-5-(Benzyloxy)-3-hydroxypentanoate (4)
NaBH4 (9 mg, 0.25 mmol) was added to a solution of the b-keto es-
product 19 in excellent yield (91%), again employing the ter 3 (0.12 g, 0.50 mmol) in MeOH (3 mL) cooled in an ice bath.
The mixture was stirred for 1 h before sat. aq NH4Cl (5 mL) was
Hoveyda–Grubbs catalyst at 5 mol% loading in dichloro-
added at r.t. The volatiles were evaporated and the mixture was ex-
ethane. As anticipated, treatment of the metathesis prod-
tracted with EtOAc (2 × 8 mL). The combined organic layers were
uct 19 with Amberlyst 15 in methanol resulted in the
washed with H2O (5 mL) and brine (5 mL), and dried (MgSO4). The
removal of both protecting groups and cyclisation to yield
exclusively the 2,6-cis-isomer of the tetrahydropyran 20.
solvent was evaporated and the residue was purified by flash chro-
matography (85:15 hexane–EtOAc) on silica gel (5 g) to give 4 as a
colourless oil (0.09 g, 70%).
O
IR (neat): 3450, 2951, 2918, 2850, 1732, 1453, 1203, 1077, 1026,
735, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.77–1.84 (2 H, m), 2.50 (2 H, d,
J = 6.3 Hz), 3.5 (1 H, d, J = 3.3 Hz), 3.64–3.74 (5 H, m), 4.20–4.30
(1 H, m), 4.66 (1 H, d, J = 15.8 Hz), 4.74 (1 H, d, J = 15.8 Hz), 6.88
(1 H, dq, J = 15.5, 6.9 Hz), 7.28–7.38 (5 H, m).
TBSO
OH
OH
18
H–G2 (2.5 mol%)
DCE
O
91%
O
TBS
TBS
12
13C NMR (75 MHz, CDCl3): d = 172.7, 137.9, 128.3, 127.6, 127.5,
73.1, 67.8, 66.8, 51.6, 41.3, 35.9.
O
OBn
OBn
19
TBSO
MS (EI): m/z = 261 (M + Na), 239 (M + H).
OH
O
HRMS (EI): m/z calcd for C13H19O4 (M + H): 239.1283; found:
239.1280.
SO3H
HIO4, silica gel
MeOH, H2O, r.t.
O
MeOH, r.t.
2
91%
92%
H
H
( )-5-(Benzyloxy)-3-hydroxy-N-methoxy-N-methylpentan-
amide (5)
OH
OBn
20
i-PrMgCl (6.25 mL of a 2 M solution in THF, 13.5 mmol) was add-
ed slowly to a solution of the b-hydroxy ester 4 (0.60 g, 2.5 mmol)
Scheme 4 Completion of the formal synthesis
Synthesis 2010, No. 17, 2935–2942 © Thieme Stuttgart · New York

2938
R. W. Bates, P. Song
PAPER
and N,O-dimethylhydroxylamine hydrochloride (0.60 g, 6.3 mmol)
in THF (8 mL) at –5 °C under N2. The mixture was allowed to warm
to r.t. and stirred for 3 h., followed by the addition of sat. aq NH4Cl
(10 mL) at 0 °C. The volatiles were evaporated and the residue was
diluted with H2O (5 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed with brine (5 mL) and
dried (MgSO4). The solvent was evaporated and the residue was pu-
rified by flash chromatography (1:1.5 hexane–EtOAc) to give the
Weinreb amide 5 (0.59 g, 75%) as a colourless solid; mp 40–41 °C.
(2H , s), 5.12 (1 H, dd, J = 10.5, 1.4 Hz), 5.13 (1 H, dd, J = 16.9, 1.4
Hz), 5.82 (1 H, ddt, J = 16.9, 10.5, 7.1 Hz), 7.28–7.37 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 137.7, 134.7, 128.5, 127.8, 127.7,
117.8, 73.4, 72.4, 71.6, 68.8, 42.4, 42.3, 36.9.
MS (EI): m/z = 273 (M + Na), 251 (M + 1).
HRMS (EI): m/z calcd for C15H23O3 (M + H): 251.1647; found:
251.1649.
Methyl (5R*,7R*,E)-9-(Benzyloxy)-5,7-dihydroxynon-2-enoate
(8)
IR (neat): 3449, 2937, 2866, 1640, 1453, 1421, 1387, 1099, 998,
739, 698 cm–1.
Methyl crotonate (0.13 mL, 0.96 mmol) was added to a solution of
the diol 7 (0.10 g, 0.40 mmol) in CH2Cl2 (6 mL) under N2. Grubbs’
second-generation catalyst (12 mg, 0.016 mmol) dissolved in
CH2Cl2 (1 mL) and added to the mixture and the mixture was heated
at reflux for 3 h. The solvent was evaporated and the residue was pu-
rified by flash chromatography (85:15 hexane–EtOAc) on silica gel
(5 g) to give the a,b-unsaturated ester 8 (0.11 g, 89%) as a colour-
less oil.
1H NMR (300 MHz, CDCl3): d = 1.79–1.86 (2 H, m), 2.56 (1 H, dd,
J = 16.6, 8.7 Hz), 2.67 (1 H, dd, J = 16.6, 4.9 Hz), 3.19 (3 H, s),
3.66 (3 H, s), 3.68–3.90 (2 H, m), 3.89 (1 H, d, J = 2.8 Hz), 4.21–
4.28 (1 H, m), 4.52 (2 H, s), 7.27–7.32 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 173.5, 138.3, 128.3, 127.6, 127.6,
73.2, 67.7, 66.3, 61.2, 38.4, 36.3, 31.8.
MS (EI): m/z = 290 (M + Na), 268 (M + H).
IR (neat): 3411, 2915, 2866, 1657, 1436, 1275, 1168, 1092, 739,
676 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.62–1.69 (3 H, m), 1.91–1.99 (1
H, m), 2.33–2.47 (2 H, m), 3.73 (1 H, td, J = 4.6, 8.6 Hz), 3.69–3.77
(4 H, m), 4.06–4.19 (2 H, m), 4.52 (2 H, s), 5.90 (1 H, d, J = 15.6
Hz), 6.99 (1 H, dt, J = 15.6, 7.4 Hz), 7.28–7.37 (5 H, m).
HRMS (EI): m/z calcd for C14H22NO4 (M + H): 268.1549; found:
268.1542.
( )-8-(Benzyloxy)-6-hydroxyoct-1-en-4-one (6)
Freshly prepared allylmagnesium bromide (2.0 mL of a 0.45 M so-
lution in Et2O, 0.9 mmol) was added slowly to a solution of the
Weinreb amide 5 (0.20 g, 0.75 mmol) in THF (6 mL) under N2
cooled in an ice bath. The mixture was stirred at 0 °C for 2 h and
treated with sat. aq NH4Cl (5 mL). The THF was evaporated and the
mixture was extracted with EtOAc (3 × 6 mL). The combined or-
ganic layers were washed with brine (5 mL) and dried (MgSO4).
The solvent was evaporated to give the ketone 6 (0.15 g, 81%) as a
colourless oil, which was used directly in the next step.
13C NMR (75 MHz, CDCl3): d = 166.8, 145.6, 137.6, 128.5, 127.9,
127.7, 123.2, 73.4, 69.6, 69.5, 67.7, 51.4, 42.1, 40.2, 36.0.
MS (EI): m/z = 331 (M + Na), 309 (M + H), 223, 179.
HRMS (EI): m/z calcd for C18H27O5 (M + H): 309.1702; found:
309.1702.
Methyl (2R*,4R*,6S*)-[6-(2-Benzyloxyethyl)-4-hydroxytetra-
hydropyran-2-yl]acetate (9)
IR (neat): 3506, 2928, 2883, 1631, 1453, 1103, 1039, 917, 848, 739,
698 cm–1.
t-BuOK (10 mg, 0.098 mmol) was added to a solution of 8 (30 mg,
0.098 mmol) in THF (2 mL) under N2. The mixture was stirred
overnight at r.t. and quenched with sat. aq NH4Cl (2 mL). THF was
evaporated and the residue was extracted with EtOAc (6 mL). The
organic layer was washed with brine (5 mL) and dried (MgSO4).
The solvent was evaporated and the residue was purified by flash
chromatography (1:1 hexane–EtOAc) on silica gel (2 g) to give the
tetrahydropyran 9 (16 mg, 53%) as a colourless oil.
1H NMR (300 MHz, CDCl3): d = 1.73–1.83 (2 H, m), 2.60 (1 H, dd,
J = 16.6, 6.6 Hz), 2.65 (1 H, dd, J = 16.6, 10.65 Hz), 3.19 (2 H, d,
J = 8.9 Hz), 3.39 (1 H, d, J = 4.7 Hz), 3.62–3.70 (2 H, m), 4.24–4.30
(1 H, m), 4.51 (2 H, s), 5.13 (1 H, dd, J = 16.1, 2.1 Hz), 5.18 (1 H,
d, J = 9.7, 2.1 Hz), 5.92 (1 H, ddt, J = 16.1, 9.1, 7.4 Hz), 7.27–7.56
(5 H, m).
13C NMR (75 MHz, CDCl3): d = 207.0, 138.0, 130.0, 128.4, 127.7,
127.6, 119.2, 73.2, 67.9, 66.6, 48.8, 48.4, 36.0.
IR (neat): 3477, 2950, 2921, 2854, 1776, 1453, 1264, 1081, 1029,
700 cm–1.
MS (EI): m/z = 271 (M + H), 249 (M + H), 141.
HRMS (EI): m/z calcd for C15H21O3 (M + H): 249.1491; found:
249.1490.
1H NMR (300 MHz, CDCl3): d = 1.16 (1 H, ddd, J = 11.5, 11.5, 4.8
Hz), 1.20 (1 H, ddd, J = 11.5, 11.5, 4.8 Hz), 1.49 (1H, d, J = 4.2
Hz), 1.75–1.84 (2 H, m), 1.94 (1 H, ddt, J = 12.1, 4.5, 2.5 Hz), 2.01
(1 H, ddt, J = 12.1, 4.5, 2.5 Hz), 2.43 (1 H, dd, J = 15.1, 9.6 Hz),
2.58 (1 H, dd, J = 15.1, 7.8 Hz), 3.50–3.60 (3 H, m), 3.66 (3 H, s),
3.72–3.87 (2 H, m), 4.48 (2 H, s), 7.27–7.35 (5 H, m).
( )-(3R,5R)-1-(Benzyloxy)oct-7-ene-3,5-diol (7)
AcOH (1.7 mL) was added to a solution of Me4NBH(OAc)3 (0.80
g, 3.2 mmol) in MeCN (6 mL) at 0 °C under N2. The mixture was
stirred at r.t. for 30 min. A solution of 6 (80 mg, 0.40 mmol) in
MeCN (2 mL) was added to the solution. The mixture was stirred
for 3 h at r.t. and then neutralised with aq 2 M NaOH. The MeCN
was evaporated and the mixture was extracted with CH2Cl2 (3 × 4
mL). The combined organic layers were washed with brine (5 mL)
and dried (MgSO4). The solvent was evaporated and the residue was
purified by flash chromatography (1:1 hexane–EtOAc) on silica gel
(3 g) to give the diol 7 (60 mg, 74%) as a colourless oil.
13C NMR (75 MHz, CDCl3): d = 171.5, 138.5, 128.4, 127.7, 127.6,
73.1, 72.6, 72.0, 67.8, 66.6, 51.7, 41.0, 40.9, 40.7, 36.1.
MS (EI): m/z = 309 (M + H), 235.
HRMS (EI): m/z calcd for C17H24O5 + Na (M + Na): 331.1521;
found: 331.1520.
Methyl (R)-(–)-5-(Benzyloxy)-3-hydroxypentanoate [(R)-4]
(R)-BINAP (25 mg, 0.04 mmol) and bis(2-methylallyl)(1,5-cy-
clooctadiene)ruthenium(II) (12 mg, 0.04 mmol) were dissolved in
degassed anhyd acetone (6 mL) under N2. The solution was cooled
with an ice bath. HBr (0.33 mL, 29% in aq MeOH) was added to the
solution and the mixture was stirred at r.t. for 0.5 h. The solvent was
evaporated in vacuo. A solution of the b-keto ester 3 (0.47 g, 2
mmol) in EtOH (8 mL) was added to the freshly prepared catalyst
IR (neat): 3442, 2917, 2850, 1452, 1403, 1336, 1288, 915, 736, 698
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.66 (2 H, dt, J = 5.3, 3.0 Hz), 1.88
(1 H, ddd, J = 8.9, 8.7, 4.8 Hz), 1.92 (1 H, ddd, J = 9.2, 8.8, 5.4 Hz),
2.26 (2 H, t, J = 6.9 Hz), 3.66 (1 H, dt, J = 9.7, 4.1 Hz), 3.73 (1 H,
dt, J = 9.4, 5.0 Hz), 3.95–4.02 (1 H, m), 4.13–4.20 (1 H, m), 4.52
Synthesis 2010, No. 17, 2935–2942 © Thieme Stuttgart · New York

PAPER
Synthesis of a Tetrahydropyran Intermeditae Related to Clavosolide
2939
and the mixture was placed under H2 (balloon) and stirred overnight
at 50 °C. The solvent was evaporated and the residue was purified
by flash chromatography (85:15 hexane–EtOAc) on silica gel (12 g)
gel (12 g) to give 1217 (80 mg, 67%) as a colourless oil; [a]D25 –17.1
(c 0.43, CH2Cl2).
IR (neat): 3451, 2954, 2928, 2856, 1455, 1361, 1253, 1091, 834,
774, 697 cm–1.
25
to give the alcohol (R)-410 as a colourless oil (0.42 g, 89%); [a]D
–5.9 (c 1.55, CH2Cl2).
1H NMR (500 MHz, CDCl3): d = 0.07 (3 H, s), 0.10 (3 H, s), 0.88
(9 H, s), 1.06 (3 H, d, J = 6.8 Hz), 1.60 (2 H, t, J = 4.2 Hz), 1.85 (1
H, dq, J = 12.1, 6.7 Hz), 1.96 (1 H, dq, J = 12.1, 6.7 Hz), 2.19 (1 H,
m), 3.37 (1 H, d, J = 2.0 Hz), 3.50 (2 H, t, J = 6.5 Hz), 3.77 (1 H,
ddd, J = 6.9, 5.4, 2.0 Hz), 4.20 (1 H, ddt, J = 10.9, 6.2, 4.1 Hz), 4.45
(1 H, d, J = 11.2 Hz), 4.52 (1 H, d, J = 11.2 Hz), 4.98–5.05 (2 H, m),
5.72 (1 H, ddd, J = 17.6, 10.4, 7.6 Hz), 7.28–7.36 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 141.1, 138.2, 128.4, 127.7, 127.6,
114.8, 73.0, 71.6, 69.1, 66.8, 44.2, 38.9, 36.1, 25.8, 17.9, 15.1, –4.7,
–4.8.
Methyl (R)-5-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)pen-
tanoate [(R)-10]
2,6-Lutidine (0.13 mL, 1.3 mmol) and TBSOTf (0.28 mL, 1.2
mmol) were added sequentially to a solution of (R)-4 (0.24 g, 1
mmol) in CH2Cl2 (5 mL) at –78 °C under N2. The mixture was
stirred at –78 °C for 1 h and then the solvent was evaporated. Sat.
aq NH4Cl (5 mL) was added and the mixture was extracted with
CH2Cl2 (2 × 10 mL). The organic layer was washed with H2O
(5 mL) and brine (5 mL), and dried (MgSO4). The solvent was evap-
orated and the residue was purified by flash chromatography (95:5
hexane–EtOAc) on silica gel (10 g) to give 10 (0.33 g, 96%) as a co-
lourless oil, which was used directly in the next step.
MS (EI): m/z = 392 (M + Na), 379 (M + H), 288, 206.
HRMS (EI): m/z calcd for C22H39O3Si (M + H): 379.2668; found:
379.2668.
(R)-(+)-5-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)pentanal
(11)
(4R,5R,7S,E)-Methyl 9-(Benzyloxy)-7-(tert-butyldimethylsilyl-
oxy)-5-hydroxy-4-methylnon-2-enoate (13)
DIBAL-H (3.7 mL of a 1 M solution in hexane, 3.7 mmol) was add-
ed to a solution of 10 (1.0 g, 2.8 mmol) in toluene (18 mL) at –78 °C
under N2. The mixture was stirred for 30 min at –78 °C. A few drops
of H2O were added and the mixture was stirred for 30 min. Na2SO4
was added and the mixture was stirred until a crystalline precipitate
formed. The mixture was filtered through Celite and the solvent was
evaporated to give the aldehyde 1116 as a colourless oil (0.84 g,
92%), which was used in the next step without purification;
[a]D25 +9.8 (c 1.36, CH2Cl2).
Methyl acrylate (0.07 mL, 0.80 mmol) was added to a solution of 12
(0.10 g, 0.26 mmol) in DCE (8 mL) under N2. The second-genera-
tion Hoveyda–Grubbs catalyst (4 mg, 0.007 mmol) was dissolved in
DCE (1 mL) and added to the solution. The mixture was heated at
reflux for 12 h, and additional catalyst (4 mg, 0.007 mmol) in DCE
(1 mL) was added and the mixture was heated overnight at reflux.
The solvent was evaporated and the residue was purified by flash
chromatography (85:15 hexane–EtOAc) on silica gel (12 g) to give
13 (0.11 g, 95%) as a colourless oil; [a]D25 –11.0 (c 1.54, CH2Cl2).
IR (neat): 2952, 2923, 2851, 1725, 1493, 1264, 1097, 1041, 836,
735, 701 cm–1.
IR (neat): 3494, 2952, 2929, 2856, 1725, 1461, 1435, 1255, 1145,
808, 776, 735, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.06 (3 H, s), 0.07 (3 H, s), 0.86
(9 H, s), 1.82–1.90 (2 H, m), 2.50 (1 H, dd, J = 2.5, 6.0 Hz), 2.54 (1
H, dd, J = 2.9, 6.0 Hz), 3.52 (2 H, t, J = 6.0 Hz), 4.38 (1 H, quint,
J = 6.0 Hz), 4.45 (1 H, d, J = 12.2 Hz), 4.50 (1 H, d, J = 12.2 Hz),
7.26–7.37 (5 H, m), 9.79 (1 H, t, J = 2.3 Hz).
13C NMR (75 MHz, CDCl3): d = 202.1, 138.2, 128.4, 127.6, 127.6,
73.0, 66.3, 65.6, 51.0, 37.6, 25.7, 17.9, –4.7, –4.6.
1H NMR (500 MHz, CDCl3): d = 0.07 (3 H, s), 0.10 (3 H, s), 0.88
(9 H, s), 1.06 (3 H, d, J = 6.8 Hz), 1.53 (1 H, ddd, J = 14.6, 4.0, 2.0
Hz), 1.63 (1 H, ddd, J = 14.6, 10.7, 4.0 Hz), 1.84 (1 H, dq, J = 13.8,
6.7 Hz), 1.96 (1 H, dq, J = 11.7, 6.7 Hz), 2.37 (1 H, m), 3.49 (2 H,
t, J = 5.2 Hz), 3.68 (1 H, br), 3.72 (3 H, s), 3.89–3.91 (1 H, m), 4.18–
4.21 (1 H, m), 4.44 (1 H, d, J = 11.9 Hz), 4.50 (1 H, d, J = 11.9 Hz),
5.83 (1 H, d, J = 15.8 Hz), 6.94 (1 H, dd, J = 15.8, 7.8 Hz), 7.26–
7.35 (5 H, m).
MS (EI): m/z = 345 (M + Na), 322 (M), 214.
13C NMR (75 MHz, CDCl3): d = 167.0, 151.2, 138.2, 128.4, 127.7,
127.6, 121.0, 73.0, 71.2, 69.1, 66.6, 51.4, 42.9, 38.7, 35.8, 25.8,
17.9, 14.5, –4.7, –4.9.
HRMS (EI): m/z calcd for C18H31O3Si (M + H): 323.2042; found:
323.2043.
(3S,4S,6R)-(–)-8-(Benzyloxy)-6-(tert-butyldimethylsilyloxy)-3-
methyloct-1-en-4-ol (12)
MS (EI): m/z = 459 (M + Na), 437 (M + H).
HRMS (EI): m/z calcd for C24H40O4Si + Na (M + Na): 459.2594;
t-BuOK (0.31 mL of a 1 M solution in THF, 0.31 mmol) was added
dropwise to a solution of cis-but-2-ene (83 mL, 0.93 mmol) in THF
(2 mL) under N2 while maintaining the temperature below –65 °C.
n-BuLi (0.19 mL of a 1.6 M solution in hexane, 0.31 mmol) was
slowly added by a syringe pump maintaining the temperature below
–65 °C. The mixture was stirred at –78 °C for 0.5 h and then
warmed up to –25 °C and stirred for another 15 min. The orange
mixture was recooled to –78 °C. A solution of (+)-B-methoxydiiso-
pinocampheylborane (0.13 g, 0.40 mmol) in THF (2 mL) was added
dropwise to the reaction mixture by a syringe pump at –78 °C over
20 min. BF3·OEt2 (0.46 mL, 3.5 mmol) was added dropwise over 1
h. A solution of the aldehyde 11 (0.1 g, 0.31 mmol) in THF (3 mL)
was added to the Brown reagent and the mixture was stirred over-
night at –78 °C. H2O2 (8 mL, 30% aq) and aq 2 M NaOH (12 mL)
were added and the mixture was stirred at r.t. for 2 h. The volatiles
were evaporated and the mixture was extracted with Et2O (3 × 6
mL). The combined organic layers were washed with brine (5 mL)
and dried (MgSO4). The solvent was evaporated and the residue was
purified by flash chromatography (95:5 hexane–EtOAc) on silica
found: 459.2586.
Methyl (4R,5R,7S,E)-(–)-9-(Benzyloxy)-5,7-dihydroxy-4-meth-
ylnon-2-enoate (14)
The a,b-unsaturated ester 13 (0.22 g, 0.50 mmol) was dissolved in
MeOH (6 mL). Amberlyst 15 (0.15 g) was added and the mixture
was stirred overnight at r.t. The suspension was filtered through
Celite and the solvent was evaporated. The residue was purified by
flash chromatography (3:1 hexane–EtOAc) on silica gel (5 g) to af-
ford 14 (0.14 g, 88%) as a colourless oil that solidified during refrig-
eration; [a]D25 –35.2 (c 0.85, CH2Cl2).
IR (neat): 3494, 2952, 2929, 2856, 1725, 1461, 1435, 1255, 1145,
808, 776, 735, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.11 (3 H, d, J = 6.2 Hz), 1.57–
1.62 (2 H, m), 1.64–1.69 (1 H, m), 1.93 (1 H, ddt, J = 15.1, 8.0, 5.2
Hz), 2.46 (1 H, ddq, J = 10.0, 8.0, 5.0 Hz), 3.14 (1 H, d, J = 5.2 Hz),
3.58 (1 H, s), 3.67 (1 H, td, J = 3.6, 9.4 Hz), 3.72–3.77 (4 H, m),
3.83–3.89 (1 H, m), 4.13–4.2 (1 H, m), 4.5 (1 H, d, J = 11.9 Hz),
Synthesis 2010, No. 17, 2935–2942 © Thieme Stuttgart · New York

2940
R. W. Bates, P. Song
PAPER
4.52 (1 H, d, J = 11.9 Hz), 5.86 (1 H, d, J = 16.0 Hz), 6.94 (1 H, dd,
J = 17.0, 8.9 Hz), 7.29–7.37 (5 H, m).
Methyl (2S,3S,4S,6R)-(+)-[6-(2-Benzyloxyethyl)-4-hydroxy-3-
methyltetrahydropyran-2-yl]acetate (2) and Methyl
{(2S,3S,4S,6S)-(+)-6-[2-(Benzyloxy)ethyl]-4-hydroxy-3-meth-
yltetrahydro-2H-pyran-2-yl}-2,2-dichloroacetate (17)
Freshly prepared KOCl solution14 (1.5 mL) was added to a solution
of 16 (0.15 g, 0.49 mmol) in MeOH (3 mL). The mixture was stirred
for 30 min at r.t. The volatiles were evaporated and the mixture was
extracted with EtOAc (3 × 5 mL). The combined organic layers
were washed with brine and dried (MgSO4). The solvent was evap-
orated and the residue was purified by flash chromatography (85:15
hexane–EtOAc) on silica gel (6 g) to give 17 (89 mg, 46%) and 2
(80 mg, 50%) as colourless oils.
13C NMR (75 MHz, CDCl3): d = 167.0, 151.2, 137.6, 128.5, 127.9,
127.7, 121.1, 73.5, 71.6, 70.0, 69.7, 51.5, 42.8, 39.8, 35.9, 15.0.
MS (EI): m/z = 345 (M + Na), 323 (M + H).
HRMS (EI): m/z calcd for C18H27O5 (M + H): 323.1858; found:
323.1863.
(5R,6R,8S,E)-(–)-10-(Benzyloxy)-8-(tert-butyldimethylsilyloxy)-
6-hydroxy-5-methyldec-3-en-2-one (15)
Methyl vinyl ketone (0.20 mL, 2.4 mmol) was added to a solution
of the alcohol 14 (0.3 g, 0.80 mmol) in DCE (6 mL) under N2. The
second-generation Hoveyda–Grubbs catalyst (13 mg, 0.02 mmol)
was dissolved in DCE (1 mL) and added to the solution. The mix-
ture was heated at reflux for 14 h, and additional catalyst (4 mg,
0.007 mmol) in DCE (1 mL) was added and the mixture was heated
overnight at reflux. The solvent was evaporated and the residue was
purified by flash chromatography (85:15 hexane–EtOAc) on silica
gel (5 g) to give 15 (0.31 g, 94%) as a colourless oil; [a]D25 –17.4 (c
1.2, CH2Cl2).
Dichloroester 17
[a]D25 +33.7 (c 1.0, CH2Cl2).
IR (neat): 3405, 2951, 2919, 2864, 1765, 1454, 1365, 1245, 1075,
1019, 845, 738, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (3 H, d, J = 6.6 Hz), 1.36 (1
H, dt, J = 12.6, 11 Hz), 1.66 (1 H, d, J = 3.2 Hz), 1.74–1.88 (3 H,
m), 1.99 (1 H, ddd, J = 12.4, 4.9, 2.6 Hz), 3.46–3.50 (3 H, m), 3.64–
3.68 (1 H, m), 3.77 (1 H, d, J = 7.9 Hz), 3.81 (3 H, s), 4.46 (1 H, d,
J = 10.3 Hz), 4.49 (1 H, d, J = 10.3 Hz), 7.26–7.33 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 165.8, 138.3, 128.4, 127.6, 127.6,
85.1, 84.7, 73.4, 73.0, 72.6, 66.4, 54.2, 42.0, 40.8, 35.8, 12.5.
IR (neat): 3478, 2953, 2885, 2856, 1673, 1454, 1414, 1254, 1092,
984, 835, 775 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.07 (3 H, s), 0.09 (3 H, s), 0.88
(9 H, s), 1.05 (3 H, d, J = 6.8 Hz), 1.48–1.52 (1 H, m), 1.62 (1 H,
ddd, J = 12.4, 4.6, 4.0 Hz), 1.83–2.03 (2 H, m), 2.21 (3 H, s), 2.39–
2.48 (1 H, m), 3.49 (2 H, t, J = 5.9 Hz), 3.80 (1 H, d, J = 5.5 Hz),
3.94 (1 H, dd, J = 9.4, 5.3 Hz), 4.20–4.23 (1 H, m), 4.43 (1 H, d,
J = 11.9 Hz), 4.49 (1 H, d, J = 11.9 Hz), 6.05 (1 H, d, J = 16.2 Hz),
6.81 (1 H, dd, J = 16.2, 7.4 Hz), 7.26–7.35 (5 H, m).
MS (EI): m/z = 413 (M + Na), 391 (M + H), 332, 250.
HRMS (EI): m/z calcd for C18H25O535Cl2 (M + H): 391.1079; found:
391.1090.
Ester 2
For spectral data of 2, see below.
13C NMR (75 MHz, CDCl3): d = 198.8, 150.2, 138.1, 131.1, 128.3,
127.6, 73.0, 71.2, 69.2, 66.6, 42.8, 38.3, 35.7, 26.7, 25.7, 17.8, 14.2,
–4.8, –4.9.
1-(tert-Butyldimethylsilyloxy)but-3-en-2-one (18)
Dess–Martin periodinane (4.16 g, 9.80 mmol) was added to a solu-
tion of 1-(tert-butyldimethylsilyloxy)but-3-en-2-ol15 (1.0 g, 4.9
mmol) in CH2Cl2 (10 mL) cooled in an ice bath. The mixture was
stirred for 2 h at r.t., before filtration through Celite. The volatiles
were evaporated and the residue was purified by flash chromatogra-
phy (95:5 hexane–EtOAc) on silica gel (30 g) to give 18 (0.73 g,
75%) as a colourless oil.
MS (EI): m/z = 443 (M + Na), 421 (M + H), 403, 377.
HRMS (EI): m/z calcd for C24H40O4Si + Na (M + Na): 443.2594;
found: 443.2586.
1-{(2R,3S,4S,6S)-(+)-6-[2-(Benzyloxy)ethyl]-4-hydroxy-3-meth-
yltetrahydro-2H-pyran-2-yl}propan-2-one (16)
IR (neat): 2955, 2887, 1702, 1605, 1362, 1154, 990, 822, 775 cm–1.
Amberlyst 15 (70 mg) was added to a solution of 15 (0.10 g, 0.24
mmol) in MeOH (4 mL). The mixture was stirred overnight at r.t.
The suspension was filtered through Celite and the solvent was
evaporated. The residue was purified by flash chromatography (1:1
hexane–EtOAc) on silica gel (3 g) to give 16 (69 mg, 95%) as a co-
lourless oil; [a]D25 +23.1 (c 0.6, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 0.6 (6 H, s), 0.89 (9 H, s), 4.33 (2
H, s), 5.74 (1 H, d, J = 10.7 Hz), 6.30 (1 H, d, J = 17.6 Hz), 6.63 (1
H, dd, J = 17.6, 10.7 Hz).
13C NMR (75 MHz, CDCl3): d = 198.6, 131.6, 128.7, 68.5, 25.7,
18.3, –5.6.
IR (neat): 3049, 2953, 2919, 2849, 1642, 1529, 1249, 1040, 745 cm–1.
MS (EI): m/z = 223 (M + Na), 201 (M).
1H NMR (300 MHz, CDCl3): d = 0.97 (3 H, d, J = 6.5 Hz), 1.24–
1.32 (2 H, m), 1.55 (1 H, m,), 1.73–1.78 (2 H, m), 1.95 (1 H, ddd,
J = 12.4, 4.7, 1.8 Hz), 2.16 (3 H, s), 2.54 (1 H, dd, J = 14.7, 9.1 Hz),
2.59 (1 H, dd, J = 14.7, 3.6 Hz), 3.38 (1 H, ddd, J = 10.8, 10.4,
4.7Hz), 3.46 (1 H, td, J = 9.5, 3.7 Hz), 3.50–3.57 (3 H, m), 4.45 (1
H, d, J = 11.9 Hz), 4.49 (1 H, d, J = 11.9 Hz), 7.26–7.34 (5 H, m).
HRMS (EI): m/z calcd for C10H20O2Si + Na (M + Na): 223.1130;
found: 223.1127.
(5R,6R,8S,E)-(–)-10-Benzyloxy-6-hydroxy-5-methyl-1,8-
bis(tert-butyldimethylsilyloxy)dec-3-en-2-one (19)
A solution of the second-generation Hoveyda–Grubbs catalyst (13
mg, 0.020 mmol) in DCE (1 mL) was added to a solution of the al-
cohol 12 (0.3 g, 0.80 mmol) and ketone 18 (0.48 g, 2.4 mmol) in
DCE (10 mL) under N2. The mixture was heated at reflux for 12 h,
and additional catalyst (13 mg, 0.020 mmol) in DCE (1 mL) was
added and the mixture was heated overnight at reflux. The solvent
was evaporated and the residue was purified by flash chromatogra-
phy (85:15 hexane–EtOAc) on silica gel (10 g) to give 19 (0.40 g,
91%) as a colourless oil; [a]D25 –12.3 (c 1.0, CH2Cl2).
13C NMR (75 MHz, CDCl3): d = 207.8, 138.4, 128.4, 127.7, 127.6,
77.8, 73.2, 73.1, 72.4, 66.6, 47.4, 44.0, 41.2, 36.1, 30.9, 12.9.
MS (EI): m/z = 329 (M + Na), 307 (M + H), 251.
HRMS (EI): m/z calcd for C18H26O4 + Na (M + Na): 329.1729;
found: 329.1725.
IR (neat): 3475, 2954, 2929, 2884, 2856, 1719, 1621, 1461, 1253,
1097, 835, 776 cm–1.
Synthesis 2010, No. 17, 2935–2942 © Thieme Stuttgart · New York

PAPER
Synthesis of a Tetrahydropyran Intermeditae Related to Clavosolide
2941
1H NMR (300 MHz, CDCl3): d = 0.06–0.09 (12 H, m), 0.88 (9 H,
s), 0.92 (9 H, s), 1.06 (3 H, d, J = 6.8 Hz), 1.50–1.53 (1 H, m), 1.59–
1.62 (1 H, m), 1.81–1.97 (2 H, m), 2.38 (1 H, dd, J = 13.3, 6.7 Hz),
3.47–3.49 (2 H, m), 3.70 (1 H, s), 3.89–3.91 (1 H, m), 4.18–4.22 (1
H, m), 4.33 (2 H, s), 4.44 (1 H, d, J = 11.9 Hz), 4.50 (1 H, d, J = 11.9
Hz), 6.38 (1 H, d, J = 16.0 Hz), 6.94 (1 H, dd, J = 16.0, 7.6 Hz),
7.26–7.35 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 198.5, 149.7, 138.2, 128.4, 127.7,
127.6, 125.3, 73.0, 71.3, 69.1, 68.6, 66.6, 43.2, 38.6, 35.8, 25.8,
25.7, 18.4, 17.9, 14.5, –4.7, –4.9, –5.4, –5.5.
Acknowledgment
We thank the Singapore Minstry of Education Academic Research
Fund Tier 2 (grant T206B1220RS) and Nanyang Technological
University for generous support of this work.
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Tetrahedron Lett. 2006, 47, 3781. (h) Sedan, P. T.;
Charmant, J. P. H.; Willis, C. L. Org. Lett. 2008, 10, 1637.
(5) (a) Barry, C. S.; Bushby, N.; Harding, J. R.; Willis, C. L.
Org. Lett. 2005, 7, 2683. (b) Blakemore, P. R.; Browder, C.
C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L.
A.; Wardrop, D. J.; White, J. D. J. Org. Chem. 2005, 70,
5449.
MS (EI): m/z = 573 (M + Na), 419.
HRMS (EI): m/z calcd for C30H55O5Si2 (M + H): 551.3588; found:
551.3596.
1-{(2R,3S,4S,6S)-(+)-6-[2-(Benzyloxy)ethyl]-4-hydroxy-3-meth-
yltetrahydro-2H-pyran-2-yl}-3-hydroxypropan-2-one (20)
Amberlyst 15 (0.2 g) was added to a solution of 19 (0.30 g, 0.55
mmol) in MeOH (8 mL). The mixture was stirred overnight at r.t.
and filtered through Celite. The solvent was evaporated and the res-
idue was purified by flash chromatography (1:1 hexane–EtOAc) on
silica gel (9 g) to give 20 (0.16 g, 91%) as a colourless oil;
[a]D25 +3.9 (c 0.95, CH2Cl2).
IR (neat): 3402, 2954, 2864, 1760, 1454, 1232, 1076, 1014, 843,
732, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (3 H, d, J = 6.5 Hz), 1.12–
1.25 (2 H, m), 1.72 (2 H, quint, J = 6.2 Hz), 1.87 (1 H, ddd, J = 12.4,
4.6, 1.7 Hz), 2.50 (1 H, dd, J = 14.0, 8.8 Hz), 2.55 (1 H, dd, J = 14.7,
3.8 Hz), 3.08 (1 H, t, J = 3.7 Hz), 3.15 (1 H, d, J = 12.6 Hz), 3.33–
3.35 (1 H, m), 3.36 (1 H, ddd, J = 9.6, 10.4, 3.9 Hz), 3.42 (2 H, t,
J = 6.2 Hz), 3.48 (1 H, dt, J = 11.1, 6.1 Hz), 4.20 (1 H, d, J = 10.0
Hz), 4.23 (1 H, d, J = 10.0 Hz), 4.35 (1 H, d, J = 12.0 Hz), 4.46 (1
H, d, J = 12.0 Hz), 7.36–7.50 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 209.1, 138.4, 128.4, 127.8, 127.6,
77.9, 73.2, 73.0, 72.5, 69.5, 66.3, 43.9, 42.5, 41.0, 36.0, 12.8.
MS (EI): m/z = 345 (M + Na), 323 (M + H), 305, 251, 214.
HRMS (EI): m/z calcd for C18H26O5 + Na (M + Na): 345.1678;
found: 345.1677.
Methyl (2S,3S,4S,6R)-(+)-[6-(2-Benzyloxyethyl)-4-hydroxy-3-
methyltetrahydropyran-2-yl]acetate (2)
HIO4 (380 mg, 2.0 mmol), silica gel (1 g), and H2O (0.5 ml) were
added sequentially to a solution of hydroxyl ketone 20 (160 mg,
0.50 mmol) in MeOH (6 mL). The mixture was stirred overnight at
r.t. vigorously and then filtered through Celite. The filtrate was
dried (MgSO4) and evaporated and the residue was purified by flash
chromatography (1:1 hexane–EtOAc) on silica gel (5 g) to give 2
(150 mg, 92%) as a colourless oil; [a]D25 +8.5 (c 0.5, CHCl3).
IR (neat): 3054, 2952, 2926, 2855, 1714, 1434, 1315, 1200, 1177,
1098, 898 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.99 (3 H, d, J = 6.5 Hz), 1.19–
1.33 (2 H, m), 1.47 (1 H, d, J = 5.5 Hz), 1.72–1.83 (2 H, m), 1.95 (1
H, ddd, J = 12.4, 4.6, 1.6 Hz), 2.41 (1 H, dd, J = 14.7, 9.6 Hz), 2.64
(1 H, dd, J = 14.7, 3.3 Hz), 3.38 (1 H, ddd, J = 10.5, 9.5, 4.5 Hz),
3.46 (1 H, td, J = 9.5, 3.3 Hz), 3.52–3.57 (3 H, m, CH), 3.65 (3 H,
s), 4.45 (1 H, d, J = 11.9 Hz), 4.49 (1 H, d, J = 11.9 Hz), 7.26–7.36
(m, 5 H).
(6) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
(7) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(8) This anti-diol is an uncharacterised intermediate: Hassan,
A.; Lu, Y.; Krische, M. J. Org Lett. 2009, 11, 3112.
(9) Chaterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360.
13C NMR (75 MHz, CDCl3): d = 172.1, 138.5, 128.4, 127.6, 127.5,
77.8, 73.3, 73.1, 72.4, 66.7, 51.6, 43.9, 41.2, 39.1, 36.0, 12.8.
MS (EI): m/z = 345 (M + Na), 323 (M + H), 214.
HRMS (EI): m/z calcd for C18H27O5 (M + H): 323.1858; found:
323.1863.
Synthesis 2010, No. 17, 2935–2942 © Thieme Stuttgart · New York

2942
R. W. Bates, P. Song
PAPER
(10) (a) Genêt, J. P.; Ratovelomanana-Vidal, V.;
Caño de Andrade, M. C.; Pfister, X.; Guerreiro, P.; Lenoir,
J. Y. Tetrahedron Lett. 1995, 36, 4801. For other reports of
the asymmetric reduction of b-keto ester 3, see:
(b) Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler,
T. Tetrahedron 1995, 51, 3549. (c) Ali, S. M.; Georg, G. I.
Tetrahedron Lett. 1997, 38, 1703. (d) Eggar, M.; Mossman,
C. J.; Buck, S. B.; Nair, S. K.; Bhat, L.; Ali, S. M.; Reiff, S.
A.; Boge, T. C.; Georg, G. I. J. Org. Chem. 2000, 65, 7992.
(11) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108,
293. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986,
108, 5919. (c) Kim, Y.-J.; Wang, P.; Navarro-Villalobos,
M.; Rhode, B. D.; DerryBerry, J.; Gin, D. Y. J. Am. Chem.
Soc. 2006, 128, 11906.
ddd, J = 12.5, 4.3, 2.6 Hz), 2.44 (1 H, dd, J = 14.5, 4.4 Hz),
2.65 (1 H, dd, J = 14.5, 11.0 Hz), 3.48–3.62 (3 H, m), 3.66
(3 H, s), 3.85–3.89 (1 H, m), 4.43 (1 H, ddd, J = 10.8, 5.1,
4.9 Hz), 4.48 (1 H, d, J = 11.8 Hz), 4.54 (1 H, d, J = 11.8
Hz), 7.26–7.36 (5 H, m). 13C NMR (75 MHz, CDCl3): d =
172.0, 138.5, 128.4, 127.7, 127.5, 73.9, 73.1, 69.7, 66.9,
66.7, 51.7, 41.0, 40.4, 36.0, 33.4, 13.1. MS (EI): m/z = 345
(M + Na), 323 (M + H), 214. HRMS (EI): m/z calcd for
C18H27O5 (M + H): 323.1858; found: 323.1859.
(14) Tietze, L. F.; Eicher, T. Reactions and Syntheses in the
Organic Chemistry Laboratory; University Science Books:
Mill Valley California, 1989, 117.
(15) (a) Lu, K.; Huang, M. W.; Xiang, Z.; Liu, Y. X.; Chen, J. H.;
Yang, Z. Org. Lett. 2006, 8, 1193. (b) In our case, the
alcohol was prepared by the addition of vinylmagnesium
chloride to (tert-butyldimethylsilyloxy)acetaldehyde, which
in turn was prepared by ozonolysis of the bis-TBS ether of
cis-but-2-ene-1,4-diol.
(12) Song, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128,
3508.
(13) Data for the trans-isomer of tetrahydropyran 2: [a]D25 +90.6
(c 0.28, CH2Cl2). IR (neat): 3054, 2952, 2926, 2855, 1714,
1434, 1315, 1200, 1177, 1098, 898 cm–1. 1H NMR (300
MHz, CDCl3): d = 0.99 (3 H, d, J = 6.9 Hz), 1.20–1.32 (2 H,
m), 1.47 (1 H, d, J = 3.0 Hz), 1.75–1.91 (2 H, m), 1.99 (1 H,
(16) Mori, I.; Ishihara, K.; Heathcock, C. H. J. Org. Chem. 1990,
55, 1114.
(17) The enantiomer was prepared by White et al. (ref. 5b).
Synthesis 2010, No. 17, 2935–2942 © Thieme Stuttgart · New York