Chemoselectivity and unusual internal acetal formation in the synthesis of a glycosidation precursor

Article abstract of DOI:10.1055/s-2007-990910

Chemoselective deprotection of a tert-butyldimethyl (TBS) silyl ether group in the presence of an acetal moiety within an advanced iridoid precursor using scandium trifluoromethane-sulfonate at 25°C unexpectedly leads to internal acetal formation in high

Full text of DOI:10.1055/s-2007-990910

LETTER
3175
Chemoselectivity and Unusual Internal Acetal Formation in the Synthesis of a
Glycosidation Precursor
Synthesis of
a
Gly
n
cosidation
P
r
n
ecursor e T. Stevens,a James R. Bull,a Kelly Chibale*a,b
a
Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa
Fax +27(21)6897499; E-mail: Kelly.Chibale@uct.ac.za
b
Received 18 October 2007
cess. Transformation (c) comprises firstly acetal forma-
tion, followed by regioselective functionalisation of the
exocyclic olefin to install the requisite carbonyl group.
For process (d), opening of the heterocyclic moiety is re-
Abstract: Chemoselective deprotection of a tert-butyldimethyl
(TBS) silyl ether group in the presence of an acetal moiety within
an advanced iridoid precursor using scandium trifluoromethane-
sulfonate at 25 °C unexpectedly leads to internal acetal formation in
high yield (70%). The same reaction at 0 °C resulted in spontaneous quired first, to allow access to both termini. Homologative
lactonisation of the diol intermediate, which was further elaborated
to an iridoid glycosidation precursor.
olefination and oxidation of the ‘northern’ and ‘southern’
termini, respectively, complete this step.
Key words: iridoids, glycosidation, scandium triflate, chemoselec-
The starting material 2 was prepared according to a liter-
tive deprotection
ature procedure8 in which phthalic anhydride was directly
reduced with NaBH4 in cold N,N-dimethylformamide
(DMF) to give the lactone as a single product, which
The secoiridoid aglycone 1 is also the aglycone of more
could be purified by vacuum distillation (Scheme 2).
frequently reported secoiridoids including, sweroside.1
The next step was to conduct homologation studies on lac-
Most published syntheses of complex secoiridoids rely on
an advanced secoiridoid precursor as a starting point. This
tone 2. Both stepwise9 and one-pot procedures10 have
been described for the diisobutylaluminium hydride
(DIBAL-H) reduction of 2 to the corresponding lactol fol-
lowed by a Wittig reaction with a methylphosphorane to
give the homologated olefin. In the event, the reduction
procedure was found to be less selective than that de-
scribed and reduction of the product lactol to the corre-
sponding diol was observed prior to complete
consumption of starting lactone. The reaction of 2 with
1.5 equivalents of DIBAL-H showed complete consump-
tion of starting material and a 3:1 distribution of the re-
quired lactol 3 and the diol. It was later noted that very fast
addition of DIBAL-H to a rapidly stirring solution of 2
minimised over-reduction and amount of stoichiometric
hydride could be used to give 3 in 92% yield. Protection
of the hydroxyl group as a tert-butyldiphenylsilyl (TPS)
ether gave 4. Hydroboration–oxidation using 9-borabicy-
clononane (9-BBN-H) and hydrogen peroxide provided a
single product 5 with the expected chemo- and regioselec-
tivity (Scheme 2).
is exemplified by the synthesis of bakankosin2 and hunte-
reoside,3 which were both derived from the natural prod-
uct secologanin. The susceptibility of the hemiacetal in
sweroside aglycone 1 to epimerisation to give the thermo-
dynamically favoured trans-isomer has frequently been
reported, particularly upon de- and reglycosidation.4–7
This precluded the use of readily available sweroside or
secologanin as starting materials. Thus in view of the
aforementioned, we sought an alternative synthetic ap-
proach to sweroside aglycone 1, initially in racemic form.
We devised a retrosynthetic scheme as outlined in
Scheme 1. Transformation (a) consists of a series of func-
tional-group interconversions involving elimination, a
coupled oxidative endocyclic double-bond cleavage–ter-
mini reduction followed by lactonisation and deprotection
of the enolic and acetal moieties with concomitant ring
closure. An enolate-mediated process is reflected in the
C–C bond-formation step (b), so utilising the carbonyl
functionality available at this point. The aldehyde would
be protected as an enol ether after the homologation pro-
CO2R2
O
H
O
H
H
O
H
H
H
H
OR1
OR
OR
a
b
CHO
OR
c
d
O
O
CHO
H
H
H
OR
OH
2
1
Scheme 1 Synthetic plan for the racemic synthesis of sweroside aglycone
SYNLETT 2007, No. 20, pp 3175–3179
x
x
.x
x
.2
0
0
7
Advanced online publication: 21.11.2007
DOI: 10.1055/s-2007-990910; Art ID: D33207ST
© Georg Thieme Verlag Stuttgart · New York

3176
A. T. Stevens et al.
LETTER
H
H
H
H
O
H
OH
O
OR1
OR2
H
H
H
H
R
O
b
a
c
f
O
OTPS
O
H
5: R1 = H; R2 = TPS
6: R1 = Pv; R2 = TPS
7: R1 = Pv; R2 = H
2
3
4
d
e
8: R = CH2OPv
9: R = CH2OH
10: R = CO2H
g
Scheme 2 Reagents and conditions: (a) (i) DIBAL-H (1.5 mol equiv, slow addition), toluene, –78 °C, 72%; (ii) DIBAL-H (1.1 mol equiv, fast
addition), toluene, –78 °C, 92%; (b) (i) Ph3P+MeI–, n-BuLi, THF, 0–25 °C, 89%; (ii) TPSCl, imidazole, DMF, 99%; (c) 9-BBN, THF, then
NaOH (1 M), H2O2, 99%; (d) PvCl, DMAP, pyridine, 99%; (e) TBAF, THF, 96%; (f) (i) (COCl)2, DMSO, CH2Cl2, –78 °C, then Et3N, 0 °C;
(iv) TMSO(CH2)3OTMS, TMSOTf, –78 °C, 91% (over 2 steps); (g) (i) LAH, THF, 0 °C, 95%; (ii) CrO3 (8 M), acetone, 0 °C, 50%.
Treatment of 5 with pivaloyl chloride in pyridine afforded prepared in situ using catalytic ruthenium dioxide with so-
the pivaloate ester 6. The desilylation was chemoselec- dium periodate as the co-oxidant,12 gave a carboxylic acid
tive, leaving the pivaloate ester intact, to give 7. A TLC which was converted into its methyl ester 14 and then
monitoring of the Dess–Martin and Swern oxidations of 6 characterized (Scheme 3).13 When the oxidation was per-
indicated the formation of a single product. The NMR formed at ambient temperatures, as described, TLC anal-
spectra of the crude extracts from these reactions verified ysis showed evidence of numerous side reactions. The
the presence of a single diastereomer. Previous experience optimum reaction temperature was found to be 0 °C.
had highlighted the epimerisable nature of the aldehyde a- Spectroscopic and analytical data confirmed the assigned
proton to give a trans-ring junction, and crude aldehyde structure.
was thus protected without purification and further char-
Chemoselective deprotection of the silyl ethers was more
difficult than had been anticipated. Treatment of 14 with
acterisation. The mild acetal-formation procedure devel-
oped by Noyori11 was applied and provided the dioxane
TBAF at 0 °C showed a single polar product on TLC. The
derivative, 8 as a single diastereomer. Over two steps the
procedure using the Dess–Martin oxidation delivered
69% of 8, whilst the Swern oxidation afforded 91%.
Epimerisation was noted (by NMR) if the aldehyde pro-
tection reaction temperature exceeded –78 °C.
1H NMR spectrum of the product post chromatography
was dominated by four signals (d = ca. 0.96, 1.36, 1.65,
and 3.45 ppm) which indicated the presence of a tetrabu-
tylammonium species. The absence of a resonance relat-
ing to the ester methoxy protons indicated that hydrolysis
Treatment of 8 with an excess of LAH in THF at 0 °C de- of the ester may have accompanied silyl deprotection and
livered the alcohol 9. Oxidation of the alcohol to acid 10 that the resulting acid was isolated as an ammonium salt.
was achieved using a Jones oxidation at 0 °C, but was ac- Buffering the TBAF with an equimolar amount of acetic
companied by considerable decomposition, presumed to acid,14,15 gave the same result. Attempts to isolate a free
be due to hydrolysis of the acetal in the harshly acidic re- acid or a lactonised species resulted in decomposition.
action conditions. Ruthenium tetroxide oxidation also Deprotection using HF·pyridine gave multiple products.
produced mixtures, presumably due to interaction be- A procedure using trimethylsilyltrifluoromethane sul-
tween the reagent and the cyclohexenyl olefin. The oxida- fonate for the chemoselective desilylation of TBS ethers
tion was thus delayed until after cleavage of this olefin, under mild conditions has been reported.16 Application of
when chemoselective reaction could be assured.
those conditions to our system gave multiple products,
from which the major product 15 was isolated
(Scheme 3).
Ozonolysis of 8 in methanol at –78 °C followed by reduc-
tion with excess NaBH4 gave diol 11 (Scheme 3). The
high polarity of 11 made purification on silica gel difficult The 1H NMR spectrum of the product carried a signal im-
and the crude material was therefore silylated to give 12.
plying the presence of an acetal moiety (doublet, d = 5.12
ppm), but the absence of any methylene signals relating to
propanediol showed that the starting acetal was no longer
Pivaloate ester 12 underwent deprotection with LAH as
before to give 13. Oxidation with ruthenium tetroxide,
H
H
H
H
OPv
R1O
R1O
OR2
TBSO
TBSO
CO2Me
O
MeO2C
d
a
e
H
O
O
O
H
H
H
H
O
O
O
O
8
14
15
11: R1 = H; R2 = Pv
12: R1 = TBS; R2 = Pv
13: R1 = TBS; R2 = H
b
c
Scheme 3 Reagents and conditions: (a) O3, MeOH, –78 °C, then NaBH4, 25 °C; (b) TBSCl, imidazole, MeCN, 93%; (c) LAH, THF, 0 °C,
86%; (d) (i) RuO2 (cat.), NaIO4, CCl4–MeCN–H2O, 0 °C; (ii) MeI, K2CO3, DMF, MeCN, 91% (over 2 steps); (e) TMSOTf (3.0 mol equiv),
CH2Cl2, –78 °C, then MeOH (excess), –78 °C followed by NaHCO3 (aq), 27% or Sc(OTf)3, H2O, MeCN, 25 °C, 70%.
Synlett 2007, No. 20, 3175–3179 © Thieme Stuttgart · New York

LETTER
Synthesis of a Glycosidation Precursor
3177
1
present. The IR and H NMR spectra contained no evi- cleophilic silyloxy moiety. Following silyl exchange, a
dence of hydroxyl functionality and MS–FAB results further oxycarbenium intermediate intercepts the second
proposed a parent molecular ion with m/z = 200. All of silyloxy function, resulting in formation of the internal
these data confirm the assigned structure.17 The cis stereo- acetal.
chemistry at the ring junction is proposed on the basis of
the observed coupling of the acetal proton that (J = 3.6
Hz) implied a gauche relationship with its partner. In hy-
drindane-like systems, relationship of the bridgehead pro-
The mild, water-stable Lewis acid, scandium triflate, has
been used catalytically to cleave TBS ethers at ambient
temperatures.18 Treatment of 14 with 0.5 mol% Sc(OTf)3,
in the presence of an excess of water, in acetonitrile deliv-
tons in a trans system would be antiperiplanar and a larger
ered a 70% yield of 15. TLC monitoring of this reaction
coupling than that observed would be expected.
indicated that 15 was formed via a polar species assumed
Since 14 was treated with TMSOTf under aprotic condi- to be the desired diol with the acetal still intact. Under
tions, and the addition of methanol, followed by aqueous these reaction conditions, acetal hydrolysis catalysed by
sodium bicarbonate ten minutes later took place at –78 °C, the Lewis acid, followed by internal acetal formation with
a straightforward hydrolytic cleavage of the acetal moiety, the desilylated alcohols to give 15, is feasible.
followed by internal acetal formation was unlikely. In ad-
dition, examples cited in the original work showed isopro-
At 0 °C, complete reaction to the polar material could be
achieved prior to formation of 15. Spontaneous lactonisa-
tion of the diol intermediate provided 16, which was iso-
lated in 94% yield (Scheme 5).
pylidene ketal protecting groups to be stable to these
reagents at –40 °C.16 Although a difference in the rates of
hydrolysis of these moieties could be expected, this de-
gree of selectivity was unlikely. A mechanism for this re-
action is depicted in Scheme 4. The proposed reaction
mechanism invokes silylation of the acetal oxygen by
The structure of 16 was confirmed by reacting it with
TPSCl and imidazole in acetonitrile to give the product of
monosilylation, 17.19
TMSOTf, leading to an oxycarbenium intermediate. In
this form, the acetal is potentiated towards attack by a nu-
The primary alcohol 16 was converted into the selenide 18
by
reaction
with
phenylselenocyanate
and
CO2Me
H
H
H
TBSO
TBSO
TBSO
CO2Me
–
TfO
TMSOTf
+
O
TMS
14
TBSO
..
H
O
OTMS
:
O
+
TfO–
COMe
O+
COMe
H
H
..
H
H
H
TBSO
TBSO
TBSO
SiR3
CO2Me
TfO –
OTMS
O
OTMS
TfO–
SiR3
H
O
O
:
O
+
TfO –
+
H
TfO –
MeO2C
H2O
H
+O SiR3
15
H
O
Scheme 4 Proposed mechanism for internal acetal formation
O
H
O
O
H
O
H
O
O
H
O
O
TBSO
TBSO
CO2Me
O
a
d
f
OR
H
O
PhSe
O
R
PhSe
H
14
H
H
O
O
OH
16: R = OH
19: R = H
20: R = Bz (E-isomer)
21
b
c
e
17: R = TPS
18: R = PhSe
Scheme 5 Reagents and conditions: (a) Sc(OTf)3, H2O, MeCN, 0 °C, 94%; (b) TPSCl, imidazole, MeCN, 97%; (c) PhSeCN, n-Bu3P, THF,
72%; (d) Bredereck’s reagent, THF, reflux, 86%; (e) BzCl, pyridine, CH2Cl2, 87%; (f) CAN (0.1 mol equiv), MeCN, HCl–borate buffer
(pH 8), 60 °C, 65%.
Synlett 2007, No. 20, 3175–3179 © Thieme Stuttgart · New York

3178
A. T. Stevens et al.
LETTER
tributylphosphine20 (Scheme 5). The one-carbon homolo-
gation step was performed using tert-butoxybis(dimeth-
ylamino)methane, or Bredereck’s reagent, under mild
conditions. The formylated product 19 was present as a
mixture of tautomers for which the NMR spectra were too
complex to be easily assigned. The formation of 19 was,
however, confirmed by the detection of the parent molec-
ular ion in the mass spectrum. For complete characterisa-
tion, 19 was benzoylated to give the enoate ester 20
(11) Noyori, R.; Suzuki, M.; Tsunoda, T. Tetrahedron Lett. 1980,
21, 1357.
(12) Martin, V. S.; Carlsen, P. H. J.; Katsuki, T.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936.
(13) Methyl (3R*,4R*)-6-(tert-Butyldimethylsilanyloxy)-3-(2-
tert-butyldimethylsilanyloxyethyl)-4-(1,3-dioxan-2-
yl)hexanoate(14)
Sodium metaperiodate (10% solution in H2O, 100 mL) and
RuO2 (60 mg, 0.5 mmol) were added sequentially to a
vigorously stirred solution of 13 (21.32 g, 44.8 mmol) in
CCl4–MeCN (1:1, 100 mL) at 0 °C. Stirring was continued
at this temperature for 18 h. The resulting mixture was
poured into CH2Cl2–H2O (1:1, 1000 mL) and the aqueous
layer was extracted with CH2Cl2. The organic phase was
dried (MgSO4) and the solvent was removed under reduced
pressure to give the acid (27.21 g), which was dissolved in
MeCN (400 mL). N,N-Dimethylformamide (50 mL) was
added, followed by K2CO3 (12.36 g, 89.6 mmol) and IMe
(3.3 mL, 53.8 mmol). The mixture was stirred at 25 °C for
16 h. The mixture was concentrated under reduced pressure
and the residual aqueous slurry was added to EtOAc (800
mL). The organic phase was washed with H2O and brine,
dried (MgSO4), and the solvent was removed under reduced
pressure to give a residue (29.32 g), which was purified by
chromatography on silica gel (800 g) using EtOAc–hexane
(1:9) as eluent, to yield the ester 14 (20.54 g, 91%) as a gum.
IR (CHCl3): nmax = 1729 (CO) cm–1. 1H NMR (400 MHz,
CDCl3): d = 0.02 [6 H, s, Si(CH3)2], 0.04 [6 H, s, Si(CH3)2],
0.87 [9 H, s, SiC(CH3)3], 0.88 [9 H, s, SiC(CH3)3], 1.23–1.31
(1 H, m, 5¢¢-HA), 1.38–1.80 (5 H, m, 4-H, 5-H2, 1¢-H2), 1.93–
2.07 (1 H, m, 5¢¢-HB), 2.16 (1 H, dd, J = 15.6, 7.9 Hz, 2-HA),
2.25–2.37 (1 H, m, 3-H), 2.57 (1 H, dd, J = 15.6, 5.7 Hz, 2-
HB), 3.63 (3 H, s, OCH3), 3.55–3.79 (6 H, m, 6-H2, 2¢-H2, 4¢¢-
HA, 6¢¢-HA), 4.00–4.10 (2 H, m, 4¢¢-HB, 6¢¢-HB), 4.45 (1 H, d,
J = 3.9 Hz, 2¢¢-H). 13C NMR (100 MHz, CDCl3): d = –5.1 and
–5.1 [2 × Si(CH3)2], 18.4 and 18.5 [2 × SiC(CH3)3], 26.0 (C-
5¢¢), 26.1 and 26.2 [2 × SiC(CH3)3], 29.4 (C-1¢ or C-5), 32.6
(C-3), 35.7 (C-1¢ or C-5), 36.8 (C-2), 42.1 (C-4), 51.5
(OCH3), 61.8 and 62.9 (C-2¢, C-6), 66.9 and 67.0 (C-4¢¢, C-
6¢¢), 104.4 (C-2¢¢) and 174.2 (C-1). HRMS: m/z calcd for
C25H52O6Si2 [M]: 504.3303; found [M+]: 504.3268.
(14) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T.
J. Org. Chem. 1997, 62, 4721.
1
(Scheme 5). The H NMR chemical shift for 1¢-H (d =
8.36 ppm) was used to assign 2021 as the E-isomer on the
basis of the literature analogy.22
Deprotection of the acetal moiety in 19 accompanied by
the closure to the dihydropyran ring was required to pro-
vide the glycosidation precursor 21. Owing to the sensi-
tive nature of the chiral centre a to the carbonyl group to
be exposed, conventional acid hydrolysis was not consid-
ered for the deprotection reaction.23 Instead, a procedure
employing catalytic ceric ammonium nitrate in a buffered
medium24 was used. The major product from this reaction
proved to be unstable, and decomposition was observed
during chromatography on silica gel. However, the NMR
spectra of a sample obtained by flash chromatography al-
lowed it to be identified as 21, for which the connectivities
depicted were confirmed by 2D (COSY and HSQC) spec-
troscopy. The absence of signals associated with the me-
thylene groups of the dioxane moiety in both the 1H and 13
C spectra confirmed that deprotection had occurred.25
In conclusion, this study has unraveled an unusual acetal-
forming reaction mediated by TMSOTf and Sc(OTf)3 un-
der aprotic conditions. The usefulness of Sc(OTf)3 as a
mild Lewis acid at low temperature for the chemoselec-
tive cleavage of TBS ether in the presence of an acetal
moiety to deliver the desired lactone for further elabora-
tion into an advance iridoid glycosidation precursor has
also been demonstrated.
(15) Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. J. Org.
Acknowledgment
Chem. 1997, 62, 4591.
(16) Hunter, R.; Hinz, W.; Richards, P. Tetrahedron Lett. 1999,
40, 3643.
We thank the South African National Research Foundation for fi-
nancial support.
(17) Methyl (4¢S*,4¢aR*,7¢aR*)-{Hexahydrofuro[2,3-
b]pyran-4-yl}acetate (15)
Water (0.22 mL, 12.6 mmol) followed by a solution of
scandium trifluoromethanesufonate (6.2 mg, 0.013 mmol) in
MeCN (5 mL) were added to a stirred solution of 14 (1.27 g,
2.52 mmol) in MeCN (20 mL). The reaction was stirred for
40 min at 25 °C after which sat. aq NH4Cl was added. The
resulting mixture was extracted with CH2Cl2, dried
(MgSO4), and the solvent was removed in vacuo.
Chromatography of the residue (750 mg) on silica gel (70 g)
using EtOAc–hexane (3:7) as eluent, yielded the acetal 15
(354 mg, 70%) as an oil. IR (CHCl3): nmax = 1732 (CO)
cm–1. 1H NMR (300 MHz, CDCl3): d = 1.26 (1 H, dtd, J =
13.7, 2 × 8.3, 3.6 Hz, 3¢-HA), 1.70–1.91 (3 H, m, 3¢-HB, 4¢a-
H, 5¢-HA), 1.96 (1 H, dtd, J = 12.1, 8.3, 2 × 7.2 Hz, 5¢-HB),
2.04–2.16 (1 H, m, 4¢-H), 2.26 (1 H, dd, J = 15.1, 8.8 Hz, 2-
HA), 2.47 (1 H, dd, J = 15.1, 5.4 Hz, 2-HB), 3.60 (1 H, ddd,
J = 11.6, 6.2, 3.6 Hz, 2¢-HA), 3.65 (3 H, s, OCH3), 3.76 (1 H,
ddd, J = 11.6, 8.3, 3.5 Hz, 2¢-HB), 3.83 (1 H, td, J = 2 × 8.0,
5.2 Hz, 6¢-HA), 4.02 (1 H, q, J = 3 × 8.0 Hz, 6¢-HB), 5.12 (1
References and Notes
(1) Inouye, H.; Ueda, S.; Nakamura, Y. Tetrahedron Lett. 1966,
43, 5229.
(2) Tietze, L.-F.; Bärtels, C. Tetrahedron 1989, 45, 681.
(3) Ohmori, O.; Takayama, H.; Aimi, N. Tetrahedron Lett.
1999, 40, 5039.
(4) Hutchinson, C. R.; Mattes, K. C.; Nakane, M.; Partridge, J.
J.; Uskokovic, M. R. Helv. Chim. Acta 1978, 61, 1221.
(5) Hutchinson, C. R.; Ikeda, T. J. Org. Chem. 1984, 49, 2837.
(6) Drewes, S. E.; Horn, M. M.; Brown, N. J.; Munro, O. Q.;
Meyer, J. J. M.; Mathekga, A. D. M. Phytochemistry 2001,
57, 51.
(7) Ikeda, T.; Hutchinson, C. R. Tetrahedron Lett. 1984, 25,
2427.
(8) Belleau, B.; Puranen, J. Can. J. Chem. 1965, 43, 2551.
(9) Jaenicke, L.; Marner, F.-J. Chem. Ber. 1975, 108, 2202.
(10) Borland, D.; Getrest, H. F. Helv. Chim. Acta 1985, 68, 2063.
Synlett 2007, No. 20, 3175–3179 © Thieme Stuttgart · New York

LETTER
H, d, J = 3.6 Hz, 7¢a-H). 13C NMR (75 MHz, CDCl3): d =
Synthesis of a Glycosidation Precursor
3179
chromatography on silica gel (20 g) using EtOAc–hexane
(1:9) to elute excess benzoyl chloride followed by elution
with EtOAc–hexane (3:2) to yield the enol benzoate 20 (85
mg, 86%). IR (CHCl3): nmax = 1715, 1749 (CO) cm–1. 1H
NMR (400 MHz, CDCl3): d = 1.27–1.34 (1 H, m, 2¢¢¢-HA),
1.68–1.79 (1 H, m, 3¢¢-HA), 1.83–1.93 (1 H, m, 5-HA), 2.02
(1 H, qt, J = 3 × 12.4, 2 × 5.0 Hz, 2¢¢¢-HB), 2.09–2.24 (2 H,
m, 5-HB, 3¢¢-HB), 2.24–2.33 (1 H, m, 2¢¢-H), 2.98–3.13 (2 H,
m, 4¢¢-H2), 3.32–3.41 (1 H, m, 4-H), 3.63–3.74 (2 H, m, 1¢¢¢-
HA, 3¢¢¢-HA), 4.02–4.13 (3 H, m, 6-HA, 1¢¢¢-HB, 3¢¢¢-HB), 4.39
(1 H, ddd, J = 11.3, 6.2, 3.9 Hz, 6-HB), 4.57 (1 H, d, J = 3.3
Hz, 1¢¢-H), 7.16–8.14 (10 H, m, ArH), 8.36 (1 H, d, J = 1.7
Hz, 1¢-H). 13C NMR (100 MHz, CDCl3): d = 24.3 (C-5), 25.6
(C-2¢¢¢), 26.6 (C-4¢¢), 28.6 (C-3¢¢), 33.0 (C-4), 45.1 (C-2¢¢),
66.4 (C-6), 66.8 and 66.9 (C-1¢¢¢, C-3¢¢¢), 102.5 (C-1¢¢), 116.7
(C-3), 126.8, 127.8, 128.4, 128.8, 129.0, 130.1, 130.2, 130.3,
132.5, 133.5 and 134.2 (ArC), 144.1 (C-1¢), 162.0 (ArC=O),
167.4 (C-2). HRMS: m/z calcd for C26H28O680Se [M]:
516.1051; found [M+]: 516.1053.
27.4 (C-3¢), 27.8 (C-5¢), 31.2 (C-4¢), 39.2 (C-2), 41.1 (C-4¢a),
51.5 (OCH3), 60.2 (C-2¢), 65.6 (C-6¢), 100.2 (C-7¢), 172.1
(C-1). HRMS: m/z calcd for C10H16O4 [M]: 200.1049; found
[M+]: 200.1061.
(18) Oriyama, T.; Kobayashi, Y.; Noda, K. Synlett 1998, 1047.
(19) (2¢R*,4R*)-4-[4-tert-Butyldiphenylsilanyloxy-1-(propan-
1,3-dioxy)butan-2-yl]tetrahydropyran-2-one (17)
tert-Butyldiphenylsilyl chloride (0.13 mL, 0.49 mmol) and
imidazole (33 mg, 0.49 mmol) were added to a stirred
solution of 16 (40 mg, 0.16 mmol) in MeCN. The solution
was stirred for 2 h, diluted with CH2Cl2, washed with H2O,
dried (MgSO4), and the solvent was removed to give the
crude product (280 mg). Chromatography on silica gel (20 g)
using EtOAc–hexane (3:7) as eluent afforded the silyl ether
17 (75 mg, 97%). IR (CHCl3): nmax = 1731 (CO) cm–1. 1H
NMR (400 MHz, CDCl3): d = 1.05 [9 H, s, C(CH3)3], 1.24–
1.31 (1 H, m, 2¢¢-HA), 1.46–1.58 (1 H, m, 3¢-HA), 1.60–1.81
(4 H, m, 5-H2, 2¢-H, 3¢-HB), 1.97 (1 H, qt, J = 3 × 12.6,
2 × 4.9 Hz, 2¢¢-HB), 2.26–2.40 (2 H, m, 3-HA, 4-H), 2.61–
2.73 (1 H, m, 3-HB), 3.54–3.73 (3 H, m, 4¢-HA, 1¢¢-HA, 3¢¢-
HA), 3.74–3.83 (1 H, m, 4¢-HB), 3.98–4.07 (2 H, m, 1¢¢-HB,
3¢¢-HB), 4.15 (1 H, td, J = 2 × 11.1, 3.7 Hz, 6-HA), 4.32 (1 H,
ddd, J = 11.1, 4.8, 3.7 Hz, 6-HB), 4.43 (1 H, d, J = 3.5 Hz, 1¢-
(22) Mazal, C.; Jonas, J. Collect. Czech. Chem. Commun. 1993,
58, 1607.
(23) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; John Wiley and Sons: New York, 1999, 317.
(24) Marko, I. E.; Gautier, A.; Ates, A.; Leroy, B. Angew. Chem.
Int. Ed. 1999, 38, 3207.
H), 7.33–7.45 (6 H, m, ArH), 7.63–7.70 (4 H, m ArH). 13
C
NMR (100 MHz, CDCl3): d = 17.1 [C(CH3)3], 23.7 (C-2¢¢),
24.9 [C(CH3)3], 25.0 (C-3¢), 26.7 (C-5), 29.2 (C-4), 31.8 (C-
3), 40.9 (C-2¢), 60.5 (C-4¢), 64.9 and 64.9 (C-1¢¢ and C-3¢¢)
66.7 (C-6), 100.9 (C-1¢), 125.6 (0) and 125.6 (2), 127.6,
131.7 (6) and 131.8 (1), 133.5 (4) and 133.5 (9) (ArC), 170.0
(C-2). HRMS–FAB: m/z calcd for C12H19O5Na [M]:
505.2386; found [M+ + Na]: 505.2372.
(25) (4aS*,5R*,6R*)-6-Hydroxy-5-(2-phenylselanylethyl)-
4,4a,5,6-tetrahydro-3H-pyrano[3,4-c]-pyran-1-one (21)
Borate–HCl buffer (pH 8, 2 mL) followed by CAN (18 mg,
0.03 mmol) were added to a stirred solution of 19 (150 mg,
0.36 mmol) in MeCN (2 mL). The resulting mixture was
stirred at 60 °C for 24 h and then cooled and diluted with
CH2Cl2 (10 mL). The aqueous phase was extracted with
CH2Cl2, the combined organic phases were dried (MgSO4),
and the solvent was removed under reduced pressure to give
an oil (140 mg). Flash chromatography on silica gel (12 g)
using EtOAc–hexane (1:1) as eluent afforded the hemiacetal
21 (82 mg, 65%). 1H NMR (400 MHz, CDCl3): d = 1.34–
1.55 (1 H, m, 1¢-HA), 1.56–1.82 (3 H, m, 4-H2 and 1¢-HB),
2.06–2.18 (1 H, m, 5-H), 2.70–3.20 (3 H, m, 4a-H, 2¢-H2),
4.18–4.32 (1 H, m, 3-HA), 4.35–4.47 (1 H, m, 3-HB), 5.46 (1
H, d, J = 1.8 Hz, 6-H), 7.20–7.29 (3 H, m, ArH), 7.43–7.50
(2 H, m, ArH), 7.55 (1 H, d, J = 2.2 Hz, 8-H). 13C NMR (75
MHz, CDCl3): d = 24.2 (C-4), 25.1 (C-1¢), 25.6 (C-2¢), 27.8
(C-4a), 36.9 (C-5), 68.2 (C-3), 94.1 (C-6), 103.5 (C-8a)
127.2, 129.2 and 132.9 (ArC), 153.3 (C-8), 166.3 (C-1).
(20) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485.
(21) (2¢R*,3E,4S*)-4-[4-Phenylselanyl-1-(propan-1,3-
dioxy)butan-2-yl]-3-benzoyloxymethylenetetrahydro-
pyran-2-one (20)
Formyl lactone 19 (80 mg, 0.19 mmol) was dissolved in
CH2Cl2–pyridine (2:1, 3 mL). Benzoyl chloride (0.05 mL,
0.43 mmol) was added and the solution was stirred at 25 °C
for 90 min. The pyridine was removed under reduced
pressure by azeotrope formation with toluene (3 × 30 mL).
The resulting material was dissolved in CH2Cl2, washed with
brine, and the aqueous phase was extracted with CH2Cl2.
The organic extract was dried (MgSO4) to give the
benzoylated product (270 mg) which was purified by
Synlett 2007, No. 20, 3175–3179 © Thieme Stuttgart · New York

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