Stereocontrolled entry to β-C-glycosides and bis-C,C-glycosides from C-glycals: preparation of a highly functionalized triene from D-mannose

Article abstract of DOI:10.1016/S0957-4166(01)00363-9

The C(3) hydroxyl group of C-glycals can be readily converted into mixed halo-acetals of 2-bromo-acetaldehyde. Radical reaction of the latter mediated by tri-n-butyltin hydride, with or without a radical acceptor, led diastereoselectively to either P-C-glycosides or bis-C,C-glycosides, respectively. The latter have been transformed into a highly functionalized triene, which is a potential precursor in a proposed synthesis of labdane type diterpenes from D-mannose.

Full text of DOI:10.1016/S0957-4166(01)00363-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2175–2183
Stereocontrolled entry to b-C-glycosides and bis-C,C-glycosides
from C-glycals: preparation of a highly functionalized triene
from
D-mannose
Ana M. Go´mez,* Marta Casillas, Seraf´ın Valverde and J. Cristo´bal Lo´pez*
Instituto de Qu´ımica Orga´nica General (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
Received 31 July 2001; accepted 7 August 2001
Abstract—The C(3) hydroxyl group of C-glycals can be readily converted into mixed halo-acetals of 2-bromo-acetaldehyde.
Radical reaction of the latter mediated by tri-n-butyltin hydride, with or without a radical acceptor, led diastereoselectively to
either b-C-glycosides or bis-C,C-glycosides, respectively. The latter have been transformed into a highly functionalized triene,
which is a potential precursor in a proposed synthesis of labdane type diterpenes from
All rights reserved.
D-mannose. © 2001 Elsevier Science Ltd.
1. Introduction
endowed with important biological properties,10 from
-glucose. Tsang and Fraser-Reid’s synthesis elegantly
D
The use of carbohydrates as starting materials in
organic synthesis has become a commonly used strategy
for more than two decades.1,2 Extension of the scope of
carbohydrates as suitable building blocks, thus, relies
on the development of convenient key intermediates,
which would comply with a series of requirements such
as easy stereocontrolled access, high degree of function-
alization and versatility. In this context, two areas of
special development in the chemistry of carbohydrates
have been the stereocontrolled preparation of branched
chain sugars3 and the synthesis of carbocyclic
compounds.4–6
combined the stereoselective preparation of a branched
chain C-glycoside derivative, 4, with the formation of a
carbocyclic decalin derivative, 3, readily obtained by
Diels–Alder cycloaddition of the former. The sequential
incorporation of the branches at C(1) and C(2) in
compound 4 required, however, multistep sequences.
The formation of the b-C-glycosidic bond (branch at
C(1)) was carried out via nucleophilic addition of an
organolithium reagent to a glucose-derived lactone, fol-
lowed by the stereoselective aldose reduction process
introduced independently by Gray11 and Kishi.12 The
introduction of the methyl group at C(2) also required
a multistep sequence (Scheme 1).7
In 1992, Tsang and Fraser-Reid7 reported the synthesis
of trans decalin 2,8 which had been used in Ziegler’s
total synthesis9 of Forskolin 1, a labdane-type diterpene
Based on this seminal contribution, we decided to
explore a novel approach to labdane-type diterpenes
OR
5
O
4
O
OR
O
HO HO
5
HO
1
O
O
4
4
1
1
HO
HO
O
O
10
8
2
2
OH
OH
O
5
1
2
O
1
OAc
2
H
H
H
OH
1
2
3
4
D-glucose
(terpene numbering)
(sugar numbering)
Scheme 1. Tsang and Fraser-Reid’s retrosynthesis of Forskolin from
D-glucose.
* Corresponding authors.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00363-9

2176
A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
from carbohydrates that would also involve the forma-
tion of a branched chain carbohydrate and a Diels–
Alder cycloaddition, but in which the number of steps
related to the installation of the branches will be mini-
mized. In this paper we disclose a novel, stereocon-
trolled, access to bis-C,C-glycosides,12,13 with an
additional branch at C(2), (e.g. 12b, Scheme 3), from
C-glycals (e.g. 10, Scheme 3). The synthetic utility of
this protocol has been illustrated with the preparation
of a monosaccharide-derived triene 18, which is a
potential intermediate in a proposed synthesis of lab-
dane type diterpenes.
2.2. Stereoselective installation of the branches at C(1)
and C(2)
In our designed synthesis we considered the rapid
assembly of the carbon branches at C(1) and C(2)
crucial. We have thus developed a method in which the
stereocontrolled construction of the quaternary carbon
at C(1) and the branch at C(2) occurs in just one
synthetic operation. The method, outlined in Scheme 3,
is an extension of previous work carried out by some of
us in Fraser-Reid’s laboratories.17 We had already
shown how a glycal could be correlated with a C-gly-
coside possessing a branch at C(2) (e.g. 10a“12a).
However, it remained to be established whether a sub-
stituent at C(1) would display any effect on such a
process.
2. Results and discussion
2.1. The approach
Our strategy,13 outlined in Scheme 2(a), features an
intramolecular Diels–Alder (IMDA) reaction14 of a
highly functionalized monosaccharide derivative (e.g.
Accordingly, C-methyl glycal 14 (Scheme 4), readily
prepared from glycosyl chloride 13 by treatment with
MeLi,18 was converted into mixed halo-acetals 15,19,20
and treated with HBu3Sn to afford in a stereoselective
manner b-C-methyl glycal 16.21 The stereochemistry at
C(1) in 16 was assigned on the basis of a NOE effect
between the C(7)-endo proton and the methyl group
protons at the anomeric position. Analogously, treat-
5), which is to be prepared from
D-mannose. The
relative stereochemistry for the branches at C(1) and
C(2) in the intermediate 5 was chosen by overlapping
with a substituted cyclohexane, 6, which had previously
been reported by Taber and Saleh15 to undergo a
stereoselective Diels–Alder cycloaddition to afford
trans-decalin 7 (Scheme 2(b)). Shortly after this project
was started, a similar approach, outlined in Scheme
2(c), was reported by Hanna et al.16 In Hanna’s
O
O
O
O
O
O R
1
O
O
R
O
O
X
1
2
R
X
Y
approach
D-galactal was stereoselectively correlated
Y
HBu3Sn
Br AIBN
O
O
with the intermediate triene 9 (Scheme 2(c)) by way of
consecutive C-Ferrier (branch at C(1)) and Claisen-Ire-
land (branch at C(2)) rearrangements. Our approach
differed from that of Hanna’s in which provisions for
the installation of a quaternary center at C(8) had been
made. In fact, the tetrasubstituted carbon atom at C(8)
in 1 was retrosynthetically correlated with the C(1)
anomeric center of bis-C,C-glycoside 5.
EtO
11
OEt
12
OEt
10
a R= H (ref 17)
b R= Me, this work
Scheme 3.
RO
RO
HO HO
HO
1
RO
HO
HO
O
10
8
O
OH
OH
1
O
5
a)
2
1
this
work
2
OAc
H
OH
D-mannose
5
1
(terpene numbering)
(sugar numbering)
ref 15
O
O
10
b)
c)
5
H
6
7
OR
OR
AcO
AcO
OAc
ref 16
O
1
O
1
O
2
O
O
D-galactal
8
9
Scheme 2.

A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
2177
O
O
O
O
O
O
O
O
O
Cl
MeLi
NEt3
O
O
O
Br
Br
ref 18
Br
HO
14
OEt
15
EtO
13
O
O
O
O
1
O
Bu3Sn
O
n.O.e
HBu3Sn
H
15
H7 endo
AIBN
75%
AIBN
64%
O
O
H7 exo
OEt
16
OEt
17
Scheme 4.
MeO
MeO
ment of 15 under Keck’s conditions with allyl
tributyltin22 in the presence of AIBN resulted in the
formation of the bis-C,C-glycoside 17.23
O
O
2.3. Elaboration of the triene moiety from 17
O
In our planned synthesis the diene had to be built on
the C-glycoside a-chain and the dienophile installed at
the C(2) branch. The allyl group, introduced at C(1),
was chosen because it provides the required number of
carbon atoms as well as the functionality to build the
pendant diene moiety by way of hydroboration, fol-
lowed by Wittig reaction.
18
O
O
O
ref 24
H
O
The substituent at C(2) was to be transformed in a
substituted dienophile, and we chose the exo-
methylenic lactone, 18, as our target since a similar
a-methylene lactone had been shown by Maier and
Pe´rez to undergo an efficient intramolecular Diels–
Alder reaction (IMDA) (Scheme 5).24
Scheme 5.
RO
RO
MeO
MeO
Exchange of the acid labile isopropylidene protecting
group in 17 by conversion to the more robust methyl
ethers led to compound 20 (two steps, 70 and 93%
yield) (Scheme 6), which upon Jones oxidation of the
ethyl acetal moiety led to lactone 21 (97% yield).
Hydroboration of the double bond furnished hydroxy
lactone 22 (76% yield), which upon Swern oxidation
(70% yield), followed by Wittig reaction with allyl-
triphenylphosphonium bromide (n-BuLi, THF) yielded
diene 23 in 20% yield as an (E)/(Z) mixture (ratio:
(E)/(Z)=1/1.7).
O
O
i
iii
17
O
O
97%
70%
OEt
O
21
19 R= OH
ii
93%
MeO
MeO
20 R= OMe
MeO
MeO
O
O
v, vi
iv
An alternative protocol in which the acetal“lactone
oxidation would be carried out after construction of the
diene moiety was also considered (Scheme 7). Accord-
ingly, hydroboration of 20 led to hydroxy compound 24
(82% yield), which was uneventfully oxidized to alde-
hyde 25 with PCC (80% yield). Wittig reaction of 25
with allyltriphenylphosphonium bromide, using n-BuLi
as a base, afforded diene 26 albeit in low yield (27%
yield, the use of different bases such as tert-BuOK,
O
O
20%
76%
HO
O
22
O
23
Scheme 6. (i) TsOH, EtOH; (ii) NaH, MeI; (iii) Jones
reagent; (iv) borane methyl sulfide, H2O2, NaOH; (v) (a)
Swern reagent, 70%; (b) BrPh3PCH2CHꢀCH2, BuLi, THF,
20%.

2178
A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
phenylselenylation of lactone 21 was carried out with
diphenyldiselenide in the presence of lithium hexa-
methyldisilazide and afforded selenolactone 27 in 42%
yield. However, we were unable to incorporate the
methyl group a to the lactone unit even in the presence
of different bases (LDA, (TMS)2NLi, (TMS)2NNa).
As a second alternative for the methylenation step, we
chose a method developed by Danishefsky,26 based on
the dimethylaminomethylenation of lactones followed
by amine quaternization and subsequent base-induced
elimination. Accordingly, lactone 21 was treated with
Eschenmoser’s salt in the presence of lithium hexa-
methyldisilazide in THF, followed by treatment with
MeI and DBU to afford the methylenic lactone 29 in
52% yield. The same protocol was also employed for
the synthesis of 18 when starting from lactone 23.
Initial attempts to effect IMDA on 18 under thermal
conditions have not yet succeeded, probably due to the
strain associated with the starting lactone; we are cur-
rently considering the preparation of novel trienes and
our results will be reported in due course.
Scheme 7. (i) Borane methyl sulfide, H2O2, NaOH; (ii) PCC;
(iii) BrPh3PCH2CHꢀCH2, BuLi, THF.
HMDSLi did not result in improved yields). Jones
oxidation of the latter did not lead to 23 and only
extensive decomposition was observed.
3. Summary
Installation of the exocyclic methylene moiety was next
attempted and model studies were carried out with
lactone 21 (Scheme 8). We first explored Grieco’s
methodology,25 based on the ready cis elimination of
selenoxides. According to this approach, the sequential
introduction of a phenlyselenyl group and a methyl
substituent on a g-butyrolactone, followed by elimina-
tion of the corresponding selenoxide would afford the
corresponding methylenic lactone. Accordingly,
In summary, we have described a completely stereose-
lective method for the efficient preparation of b-C-gly-
cosides (e.g. 16) and bis-C,C-glycosides (e.g. 17) from
readily available C-glycals.18 The stereochemical out-
come of the method is dictated by stereoelectronic
factors through the well-known preferred axial
approach of 1-glycopyranosyl radicals,27,28 which has
been termed radical anomeric effect,29 along with the
steric effects inferred from bicyclic nature of radical
11.17,19 This method when coupled with our recently
described protocol for the preparation of C-glycals
from glycosyl chlorides18 would allow the efficient
assembly of highly branched monosaccharide deriva-
tives (e.g. compound 17 was prepared from inexpensive
MeO
MeO
MeO
MeO
MeO
MeO
O
O
O
i
O
O
42%
O
SePh
SePh
O
O
D
-mannose in five steps).
O
28
27
21
4. Experimental
MeO
MeO
MeO
O
O
4.1. General procedures
ii
iii MeO
21
52%
O
O
All reactions were performed in dry flasks fitted with a
glass stopper or rubber septa under a positive pressure
of argon, unless otherwise noted. Air- and moisture-
sensitive liquids and solutions were transferred via
syringe or stainless steel cannula. Flash column chro-
matography was performed employing 230–400 mesh
silica gel. Thin-layer chromatography was conducted in
Kiesel gel 60 F254 (Merck). Detection was first by UV
(254 nm) then charring with a solution of 20% aqueous
sulfuric acid (200 mL) in acetic acid (800 mL). Anhy-
drous MgSO4 or NaSO4 was used to dry the organic
solutions during work-ups, and the removal of the
solvents was carried out under vacuum with a rotary
evaporator. Unless otherwise noted, materials were
obtained from commercially available sources and used
without further purification. Solvents were dried and
NMe2
O
O
29
I
MeO
MeO
MeO
MeO
O
O
ii, iii
34%
O
O
O
O
23
18
Scheme 8. (i) (TMS)2NLi, THF then PhSeSePh, HMPA; (ii)
LDA, THF, then Me2N+ꢀCH2 Br−; (iii) MeI, MeOH then
DBU.

A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
2179
purified using standard methods. 1H and 13C NMR
spectra were recorded in CDCl3 at 300, 400 or 500 and
75 or 50 MHz, respectively. Chemical shifts are
expressed in parts per million (l scale) downfield from
tetramethylsilane and are referenced to residual proton
in the NMR solvent. Proton NMR (1H NMR) are
presented in the following order: multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet and m, multiplet),
coupling constants in hertz, integration and assignment.
solution was kept at −78°C for 90 min and then was
allowed to warm to rt for about 60 min. A solution of
C-glycal 14 (1.05 g, 5.26 mmol) in triethylamine (10.5
mL) was added and the resulting mixture was stirred at
rt overnight. Concentration under reduced pressure and
flash chromatography (hexane/ethyl acetate; 95:5) led
to diastereomeric acetals 15 as a 1:1 mixture (1.42 g,
1
77%), 200 MHz; H NMR l (CDCl3) 4.85 (m, 1H),
4.76 (m, 1H), 4.65 (t, J=5.3 Hz, H-4, one isomer), 4.49
(m, 2H), 4.30 (t, J=6.8 Hz, H-4, other isomer), 3.93
(m, 1H), 4.10 (m, 1H), 3.60 (m, 2H, CH2
6 Br, one
4.2. 2,3:4,6-Di-O-isopropyliden-a-
D
-mannopyranoside
isomer), 3.31 (m, 2H, CH2Br, other isomer), 1.84 (t,
6
chloride 1330
3H, J=1.0 Hz, CH3, one isomer), 1.82 (t, 3H, J=1.0
Hz, CH3, other isomer), 1.42 (s, 3H, CH3, one isomer),
1.34 (s, 3H, CH3, other isomer), 1.21 (t, 3H, J=7.0 Hz,
CH3, one isomer), 1.20 (t, 3H, J=7.0 Hz, CH3, other
isomer); 13C NMR (50 MHz, CDCl3) l 161.1, 160.7,
108.8, 101.6, 99.2, 98.0, 96.7, 84.4, 83.9, 80.6, 77.4, 73.2,
72.6, 66.4, 65.4, 62.0, 61.0, 31.9, 31.5, 26.4, 26.3, 25.0,
15.0, 13.6.
To a solution of 2,3:4,6-di-O-isopropylidene-D-manno-
pyranoside31 (3.5 g, 13.5 mmol) and triphenylphosphine
(2 equiv.) in dry THF (27 mL) was added CCl4 (5
equiv.). The reaction was heated under reflux for 2 h,
then cooled, filtered through a small pad of Celite and
evaporated to give a residue, which was purified by
flash chromatography (n-hexane/EtOAc, 9:1) to yield
13 (3.57 g, 95%): [h]2D5=+52.9 (c=1.35, CHCl3). 1H
NMR (200 MHz, CDCl3): 1.31 (s, 3H, Me), 1.36 (s, 3H,
Me), 1.44 (s, 6H, 2×Me), 3.99 (dd, J5,6=4.4 Hz, J6,6%
=
4.5. (4aR,6R,6aS,9aR,9bS)-6-Allyl-2,2,6-trimethyloct-
ahydrofuro[2%,3%,4,5]pyrano[3,2-d][1,3]dioxin-8-yl ethyl
ether 17
8.8 Hz, 1H, H-6), 4.08 (dd, J5,6%=5.9 Hz, J6,6%=8.8 Hz,
1H, H-6%), 4.18 (dd, J3,4=3.5 Hz, J4,5=7.8 Hz, 1H,
H-4), 4.41 (ddd, J4,5=7.8 Hz, J5,6=4.4 Hz, J5,6%=5.9
Hz, 1H, H-5), 4.86 (dd, J2,3=5.8 Hz, J3,4=3.5 Hz, 1H,
H-3), 4.93 (d, J2,3=5.8 Hz, 1H, H-2), 6.05 (s, 1H, H-1);
13C NMR (50 MHz, CDCl3) l 113.3, 109.5, 97.7, 89.2,
82.4, 78.6, 72.3, 66.7, 26.9, 25.8, 25.2, 24.7
Bromo acetals 15 (1.42 g, 4.05 mmol), allyltributyltin
(3.75 mL, 12.15 mmol, 3 equiv.) and AIBN (0.4 mmol)
were heated in degassed toluene (80°C) for 48 h. Con-
centration in vacuo and the residue was purified by
flash chromatography (hexane/ethyl acetate; 95:5) to
afford 17 as a 1:1 mixture of epimers (808 mg, 64%): 1H
NMR (200 MHz, CDCl3) l 5.75 (m, 1H), 4.96–5.15 (m,
3H), 4.72 (m, 1H), 3.79–4.25 (m, 4H), 3.71 (m, 1H,
4.3. 2,6-Anhydro-1,3-dideoxy-5,7-O-(1-methylethylid-
ene)-D-arabino-hep-2-enitol 14
CH6 2CH3), 3.40 (m, 1H, CH6 2CH3), 2.84 (dd, J=7.6 Hz,
To a solution of glycosyl chloride 13 (250 mg, 0.89
mmol) in dry THF (3 mL) at room temperature was
added MeLi (1.5 M, 5 equiv.). After the starting mate-
rial had disappeared (3 h) the reaction mixture was
quenched with H2O. Et2O was then added and the
organic phase was washed with brine and dried
(Na2SO4). Evaporation of the organic layer followed by
flash chromatography (n-hexane/EtOAc, 9:1) afforded
14 (95 mg, 53%). [h]2D5=−4.5 (c=0.42, CHCl3). 1H
NMR (300 MHz, CDCl3): 1.28 (s, 3H, Me), 1.41 (s, 3H,
Me), 1.53 (s, 3H, Me), 4.05 (m, 2H, 2H-7), 4.14 (dd,
J=15.4 Hz, 1H), 2.60 (ddd, J=4.1 Hz, J=7.0 Hz,
J=15.4 Hz, 1H), 2.48 (m, 1H), 2.22 (m, 1H), 2.10 (dd,
J=7.0 Hz, J=14.5 Hz, 1H), 1.99 (m, 1H), 1.81 (m,
1H), 1.59 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.33 (s,
3H), 1.24 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.13 (t,
J=7.1 Hz, 3H), 1.09 (s, 3H); 13C NMR (50 MHz,
CDCl3) l 133.9, 133.5, 117.8, 117.7, 108.7, 108.5, 105.3,
105.3, 86.1, 83.5, 82.4, 80.3, 79.0, 74.0, 73.8, 67.6, 66.7,
63.3, 62.5, 50.2, 44.6, 43.8, 34.9, 34.7, 26.7, 26.6, 25.3,
23.2, 21.5, 17.3, 17.0, 14.9, 14.1. MS m/z 313.1 (M++1);
anal. calcd for C17H28O5: C, 65.36; H, 9.03. Found: C,
65.07; H, 8.89%.
J4,5=6.1 Hz, J5,6=7.4 Hz, 1H, H-5), 4.53 (dt, J5,6=6,7=
7.4 Hz, J6,7%=6.0 Hz, 1H, H-6), 4.68 (m, 1H, H-4), 4.69
(m, 1H, H-3; 13C NMR (50 MHz, C6D6) l 169.0, 105.9,
100.6, 86.3, 74.6, 74.0, 67.5, 27.4, 25.8, 25.3; anal. calcd
for C10H16O4: C, 59.98; H, 8.05. Found: C, 60.07; H,
7.82%.
4.6. (3aS,4R,6R,7S,7aR)-4-Allyl-2-ethoxy-7-methoxy-6-
(hydroxymethyl)-4-methylhexahydro-4H-furo[3,2-
c]pyran-7-ol 19
4.4. 2,6-Anhydro-4-O-(2-bromo-1-ethoxyethyl)-1,3-
dideoxy-5,7-O-(1-methylethylidene)-
D
-arabino-hep-2-eni-
To a 0.01 M solution of bis-C,C-glycoside 17 (550 mg,
1.76 mmol) (1:1 anomeric mixture at the acetal posi-
tion) in ethanol was added p-toluenesulfonic acid (3
equiv., 1.04 g). The resulting solution was stirred at rt
for 48 h after which time NEt3 was added. The result-
ing solution was concentrated under vacuum and sub-
jected to flash chromatography (n-hexane/EtOAc, 1:1)
tol 15
A solution of 1,2-dibromoethyl ether was prepared by
dropwise addition of bromine (2.17 mL, 8 equiv.) to a
stirred solution of ethyl vinyl ether (5.03 mL, 10 equiv.)
in dry CH2Cl2 (50 mL) maintained at −78°C. The

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A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
yielding diol 19 as a 10:1 anomeric mixture (335 mg,
70%). 1H NMR, l (200 MHz, CDCl3): 1.17 (s, 3H,
Me), 1.18 (t, J=7.1 Hz, CH3 major), 1.19 (t, J=7.1 Hz,
minor), 1.87 (m, 2H), 2.16 (m, 1H), 2.29 (m, 1H),
2.97–3.40 (m, 6 H), 4.56–4.89 (m, 1H), 5.03 (m, 1H),
5.12 (m, 1H), 5.21 (dd, J=1.2, 4.4 Hz, 1H), 5.68–5.82
(m, 1H). 13C NMR, l (50 MHz, CDCl3): 15.1, 21.3,
34.6, 43.9, 50.0, 62.9, 64.8, 71.5 (one isomer), 72.8
(other isomer), 78.5 (one isomer), 78.6 (other isomer),
83.0, 84.6, 105.8, 118.2, 133.4. M/e 273.2 (M++1), 267.3
(M+−15), 255.3, 249.3, 231.2, 228.2, 227.2, 209.2, 191.2,
185.2, 167.2, 145.3, 105.2, 85.3; anal. calcd for
C14H24O5: C, 61.74; H, 8.88. Found: C, 61.57; H,
8.54%.
4.9. (3aS,4R,6R,7S,7aR)-4-(3-Hydroxypropyl)-7-
methoxy-6-(methoxymethyl)-4-methylhexahydro-4H-
furo[3,2-c]pyran-2(3H)-one 22
A solution of lactone 21 (254 mg, 0.94 mmol) in dry
THF (15 mL) at 0°C was treated with borane methyl
sulfide (30 mL, 0.33 equiv., 0.313 mmol) and kept at this
temperature for 30 min. The reaction mixture was then
allowed to warm to rt and maintained at this tempera-
ture for 3 h, after which time the reaction was cooled to
0°C and treated with H2O2 (33%, 290 mL, 3 equiv., 2.82
mmol) and 2N NaOH (1 equiv., 0.94 mmol). The
reaction was then heated at 60°C for 45 min. Elimina-
tion of the solvent and flash chromatography (n-hex-
ane/EtOAc, 2:8) led to alcohol 22 (190 mg, 70%).
1
[h]2D5=−47.0 (c=0.61, CHCl3). H NMR, l (300 MHz,
4.7. (3aS,4R,6R,7S,7aR)-4-Allyl-2-ethoxy-7-methoxy-6-
(methoxymethyl)-4-methylhexahydro-4H-furo[3,2-
c]pyran 20
CDCl3): 1.20 (s, 3H, CH3), 1.40–1.80 (m, 4H), 2.04 (m,
1H), 2.62 (d, J=3.9 Hz, 1H), 2.65 (d, J=8.8 Hz, 1H),
2.79 (ddd, J=3.4, 6.2, 8.8 Hz, 1H), 3.41 (s, 3H, OMe),
3.47 (s, 3H, OMe), 3.48–3.51 (m, 1H), 3.53–3.74 (m,
4H), 4.00 (dd, J=3.4, 9.0 Hz, 1H), 5.11 (dd, J=3.4, 6.2
Hz, 1H). 13C NMR, l (50 MHz, CDCl3): 21.7 (Me),
27.1, 30.9, 35.8 (C-1¦, C-1%, C-2%), 47.6 (C-2), 57.8
(OMe), 59.3 (OMe), 62.1, 70.5 (C-6, C-3%), 76.5, 77.4,
85.3 (C-3, C-4, C-5), 83.7 (C-1), 176.4 (CꢀO); anal.
calcd for C14H24O6: C, 58.32; H, 8.39. Found: C, 58.63;
H, 8.52%.
To a solution of diol 19 (320 mg, 1.2 mmol) in dry
THF (12 mL) at 0°C was added sodium hydride (1.5
equiv. per OH, 3.6 mmol) and the suspension was
stirred for 1 h under argon, after which time tetra-n-
butylammonium iodide (2.4 mmol) and methyl iodide
(12 mmol) was added. The resulting mixture was stirred
for 3 h and quenched by careful addition of water. The
reaction was then extracted with dichloromethane (3×
10 mL) and the organic layer dried (MgSO4), filtered
and evaporated. The residue was chromatographed (n-
hexane/EtOAc, 75:25) to yield compound 20 (336 mg,
4.10. (3aS,4R,6R,7S,7aR)-4-[(3E/Z)-3,5-Hexadienyl)-7-
methoxy-6-(methoxymethyl)-4-methylhexahydro-4H-
furo[3,2-c]pyran-2(3H)-one 23
1
93%). H NMR, l (300 MHz, CDCl3) selected signals
for the major isomer: 1.18 (t, J=7.1 Hz, 3H, CH3), 1.25
(s, 3H, CH3), 1.89 (m, 2H), 2.09 (m, 1H), 2.30 (m, 1H),
2.78 (dt, J=6.8, 8.5 Hz, 1H), 3.38 (s, 3H, OMe), 3.49
(s, 3H, OMe), 3.38–3.72 (m, 5H), 3.80 (dd, J=4.1, 8.3
Hz, 1H), 4.72 (dd, J=6.7, 4.2 Hz, 1H), 5.04 (m, 2H),
5.16 (dd, J=2.3, 4.5 Hz, 1H), 5.71 (m, 1H). 13C NMR,
l (50 MHz, CDCl3): 15.2, 22.0, 35.0, 44.1, 50.1, 58.6,
59.3, 62.8, 73.1, 77.2, 78.1, 82.6, 83.9, 105.4, 118.0,
133.8.
Alcohol 22 (155 mg, 0.54 mmol) was oxidized with
PCC (350 mg, 3 equiv., 1.61 mmol) in dry CH2Cl2 (10
mL) in the presence of molecular sieves. Filtration of
the reaction mixture over a pad of Florisil® yielded the
corresponding aldehyde, which was used in the next
step without further purification. Data for the alde-
hyde: 1H NMR, l (200 MHz, CDCl3): 1.15 (s, 3H,
CH3), 1.30–1.78 (m, 4H), 2.40–2.62 (m, 2H), 2.80 (m,
1H), 3.39 (s, 3H, OMe), 3.47 (s, 3H, OMe), 3.40–3.68
(m, 4H), 3.90 (m, 1H), 5.12 (m, 1H), 9.76 (s, 1H, CHO).
4.8. (3aS,4R,6R,7S,7aR)-4-Allyl-7-methoxy-6-
(methoxymethyl)-4-methyltetrahydro-4H-furo[3,2-
c]pyran-2(3H)-one 21
A suspension of Ph3P+CH2CHꢀCH2 Br− (617 mg, 3
equiv., 1.61 mmol) in dry THF (10 mL) at 0°C under
argon, was treated with n-BuLi (1.6 M, 1 mL, 3 equiv.).
The resulting solution turned red and at this time the
above-mentioned aldehyde (0.54 mmol), in dry THF (7
mL), was added. The reaction mixture was allowed to
warm to rt and after 4 h was quenched by addition of
H2O, extracted with CH2Cl2 and the organic layer dried
(Na2SO4). Evaporation of the solvent and flash chro-
matography (n-hexane/EtOAc, 7:3) led to diene 23
Jones reagent was added dropwise to a solution of
acetal 20 (300 mg, 1 mmol) in acetone until the red
colour persisted. The reaction crude was treated with
isopropanol and triethylamine. Elimination of the sol-
vent and flash chromatography (n-hexane/EtOAc, 1:1)
yielded lactone 21 (254 mg, 95%). [h]2D5=−29.5 (c=0.74,
1
CHCl3). H NMR, l (300 MHz, CDCl3): 2.03 (s, 3H,
1
CH3), 2.15 (m, 1H), 2.32 (m, 1H), 2.56 (d, J=3.4 Hz,
1H), 2.60 (d, J=8.6 Hz, 1H), 2.83 (ddd, J=3.4, 6.3, 8.6
Hz, 1H), 3.39 (s, 3H, OMe), 3.40 (m, 1H,), 3.48 (s, 3H,
OMe), 3.50 (ddd, J=1.8, 8.5, 4.0 Hz, 1H), 3.73 (dd,
J=1.8, 10.2 Hz, 1H), 4.00 (dd, J=3.3, 8.8 Hz, 1H),
(33.6 mg, 20%) as a 1:1.7 (E):(Z) mixture. H NMR, l
(300 MHz, CDCl3): 1.17 (s, 3H, CH3 anomer from E),
1.25 (s, 3H, CH3 anomer from Z isomer), 1.40–1.60 (m,
2H), 2.05–2.40 (m, 2H), 2.57–2.65 (m, 2H), 2.75–2.78
(m, 1H), 3.39 (s, 3H, OMe from Z), 3.40 (s, 3H, OMe
from E), 3.43 (d, J=6.2 Hz, 1H), 3.48 (s, 3H, OMe
from E), 3.51 (s, 3H, OMe from Z), 3.55–3.58 (m, 1H),
3.73 (d, J=10.4 Hz, 1H), 3.92 (dd, J=3.4, 9.0 Hz, 1H),
4.97 (d, J5%,6%=10.3 Hz, 1H minor isomer), 5.07–5.12
(m, 2H), 5.20 (d, J5%,6%=17.1 Hz, 1H major isomer), 5.37
5.11 (m, 3H), 5.72 (m, 1H, CH6
ꢀCH2). 13C NMR, l (50
MHz, CDCl3): 22.6, 31.1, 44.7, 46.1, 58.1, 59.4, 71.2,
77.2, 77.6, 83.4, 85.6, 118.8, 132.9, 176.9; anal. calcd for
C14H22O5: C, 62.20; H, 8.20. Found: C, 62.12; H,
7.92%.

A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
2181
(ddd, J=5.6, 6.5, 11.7 Hz, 1H major isomer), 5.67 (dt,
Jt=7.2 Hz, Jd=14.4 Hz, 1H minor isomer), 5.96–6.09
(m, 1H), 6.28 (dt, Jt=10.2 Hz, Jd=17.0 Hz, 1H minor
isomer), 6.62 (dt, Jt=10.3 Hz, Jd=16.8 Hz, 1H major
isomer). 13C NMR, l (75 MHz, CDCl3): 22.0, 21.8
(Me), 29.7, 30.1, 30.7, 30.9, 39.4, 39.7, 47.0, 47.3, 58.1,
59.3, 59.5, 70.7, 71.1, 76.6, 77.6, 82.6, 83.2, 83.7, 85.4,
85.6, 115.4, 117.5, 129.7, 130.0, 131.3, 132.1, 134.0,
136.9, 176.6; anal. calcd for C17H26O5: C, 65.78; H,
8.44. Found: C, 66.01; H, 8.32%.
over Na2SO4. Elimination of the solvent and flash
chromatography (n-hexane/EtOAc, 8:2) led to diene 26
1
as a 45:55 (E):(Z) mixture (49.5 mg, 27%). H NMR, l
(300 MHz, CDCl3): 1.13 (s, 3H, CH3 anomeric from
E), 1.15 (s, 3H, CH3 anomeric from Z), 1.18 (t, J=7.0
Hz, 3H, CH3 from E), 1.19 (t, J=7.0 Hz, 3H, CH3
from Z), 1.40–1.50 (m, 4H), 1.87–1.93 (m, 4H), 2.07–
2.23 (m, 4H), 2.73–2.78 (m, 2H), 3.39 (s, 3H, OMe from
Z), 3.40 (s, 3H, OMe from E), 3.41–3.56 (m, 8H), 3.48
(s, 3H, OMe from E), 3.49 (s, 3H, OMe from Z),
3.71–3.76 (m, 4H), 4.73 (dd, J3,4=4.1 Hz, J2,3=6.7 Hz,
2H), 4.97 (d, J=10.3 Hz, 1H), 5.07–5.12 (m, 2H), 5.20
(d, J=17.1 Hz, 1H), 5.37 (ddd, J=5.6, 6.5, 11.7 Hz,
1H), 5.67 (dt, Jt=7.2 Hz, Jd=14.4 Hz), 5.94–6.08 (m,
1H), 6.28 (dt, Jt=10.2 Hz, Jd=17.0 Hz, 1H), 6.64 (dt,
Jt=10.3 Hz, Jd=16.8 Hz, 1H). 13C NMR, l (75 MHz,
CDCl3): 14.1, 15.2, 21.4, 22.7, 27.1, 29.4, 29.7, 31.9,
34.1, 35.0, 51.5, 51.9, 58.1, 58.5, 59.3, 59.5, 62.7, 63.5,
72.7, 76.6, 77.6, 78.2, 79.5, 79.9, 83.7, 83.9, 105.0, 105.4,
112.0, 113.5, 128.4, 128.6, 131.9, 132.0, 132.1, 132.2;
anal. calcd for C19H32O5: C, 67.03; H, 9.47. Found: C,
66.87.07; H, 9.23%.
4.11. 3-[(3aS,4R,6R,7S,7aR)-2-Ethoxy-7-methoxy-6-
(methoxymethyl)-4-methylhexahydro-4H-furo[3,2-
c]pyran-4-yl]-1-propanol 24
To a solution of bis-C,C-glycoside 20 (181 mg, 0.6
mmol) in dry THF (15 mL) at 0°C, under argon, was
added borane methyl sulfide (80 mL, 1.1 equiv., 0.66
mmol) and the resulting solution stirred for 30 min and
then allowed to warm to rt for 2 h. The reaction
mixture was then re-cooled to 0°C and treated with
H2O2 (33%, 100 mL, 3 equiv., 1.8 mmol) and 2N NaOH
(1 equiv., 0.6 mmol), the resulting mixture was then
heated at 60°C for 1 h. After evaporation of the solvent
the residue was chromatographed (n-hexane/EtOAc,
7:3) to yield hydroxy compound 24 (170 mg, 89%).
4.13. (3R,3aS,4R,6R,7S,7aR)-4-Allyl-7-methoxy-6-
(methoxymethyl)-4-methyl-3-(phenylselanyl)tetrahydro-
4H-furo[3,2-c]pyran-2(3H)-one 27
1
Selected data for the major isomer: H NMR, l (200
MHz, CDCl3): 1.15 (s, 3H, CH3), 1.19 (t, J=7.1 Hz,
3H, CH3), 1.40–1.80 (m, 4H), 1.92 (m, 2H), 2.73 (ddd,
To a solution of lactone 21 (150 mg, 0.55 mmol) in dry
THF at −78°C, under argon, was added (TMS)2NLi (1
M, 1.7 mL, 1.67 mmol), the temperature was allowed to
raise to 0°C and the reaction cooled again at −78°C.
PhSeSePh (520 mg, 1.67 mmol) and DMPU (210 mL,
1.67 mmol) were then added and the reaction tempera-
ture allowed to warm to rt for 5 h. The reaction was
quenched by the addition of an aqueous ammonium
chloride solution, extracted with CH2Cl2, and dried
(MgSO4). Elimination of the solvent and flash chro-
matography (n-hexane/EtOAc, 8:2) afforded seleno lac-
tone 27 (80 mg, 42% corrected yield based on recovered
lactone (10 mg)). [h]2D5=−16.1 (c=0.46, CHCl3). 1H
NMR, l (300 MHz, CDCl3): 1.17 (s, 3H, CH3), 2.11
(dd, J=8.0, 13.8 Hz, 1H), 2.25 (dd, J=6.8, 13.8 Hz,
1H), 2.79 (dd, J2,1¦=1.5 Hz, J2,3=6.0 Hz, 1H), 3.37 (s,
3H, OMe), 3.33–3.49 (m, 2H), 3.43 (s, 3H, OMe), 3.69
(dd, J=2.1, 10.6 Hz, 1H), 3.86 (d, J=1.5 Hz, 1H), 3.89
(dd, J3,4=3.0 Hz, J4,5=9.0 Hz, 1H), 4.74 (dd, J3,4=3.0
Hz, J2,3=6.0 Hz, 1H), 4.99–5.11 (m, 2H), 5.30–5.64 (m,
1H), 7.30–7.80 (m, 5H). 13C NMR, l (50 MHz,
CDCl3): 22.8, 31.6, 38.5, 45.0, 54.7, 58.1, 59.4, 71.1,
77.2, 83.9, 84.3, 119.1, 126.4, 129.5, 132.6, 136.3, 175.5.
J
2,1¦=3.4, 8.7 Hz, J2,3=6.8 Hz, 1H), 3.39 (s, 3H, OMe),
3.48 (s, 3H, OMe), 3.43–3.75 (m, 9H), 3.84 (dd, J3,4
=
=
4.1 Hz, J4,5=8.7 Hz, 1H), 4.74 (dd, J3,4=4.1 Hz, J2,3
6.8 Hz, 1H), 5.18 (dd, J=2.0, 4.6 Hz, 1H). 13C NMR,
l (50 MHz, CDCl3): 15.2, 21.3, 27.4, 35.0, 35.9, 51.6,
58.4, 59.3, 60.3, 62.3 72.6, 76.9, 77.1, 78.1, 83.7, 105.4;
anal. calcd for C16H30O6: C, 60.35; H, 9.50. Found: C,
60.07; H, 9.82%.
4.12. (3aS,4R,6R,7S,7aR)-2-Ethoxy-4(3Z/E)-3,5-hexa-
dienyl]-7-methoxy-6-(methoxymethyl)-4-methylhexahy-
dro-4H-furo[3,2-c]pyran 26
Alcohol 24 (170 mg, 0.54 mmol) was oxidized with
PCC (348 mg, 3 equiv., 1.61 mmol) in CH2Cl2 (15 mL)
in the presence of molecular sieves for 2 h. The reaction
mixture was then filtered through a pad of Florisil® and
the solvent evaporated to yield aldehyde 25, which was
used without further purification in the next step. Data
1
for 25: H NMR, l (200 MHz, CDCl3): 1.15 (s, 3H,
CH3), 1.21 (t, J=7.1 Hz, 3H, CH3), 1.36–1.78 (m, 4H),
2.22 (m, 2H), 2.80 (m, 1H), 3.38 (s, 3H), 3.47 (s, 3H),
3.36–3.55 (m, 4H), 3.76 (m, 1H), 4.73 (dd, J3,4=4.1 Hz,
4.14. (3aS,4R,6R,7S,7aR)-4-Allyl-7-methoxy-6-
(methoxymethyl)-4-methyl-3-methylentetrahydro-4H-
furo[3,2-c]pyran-2(3H)-one 29
J2,3=6.7 Hz, 1H), 5.16 (dd, J=2.5, 4.2 Hz, 1H), 9.74 (s,
1H, CHO).
To a suspension of Ph3P+CH2CH=CH2, Br− (621 mg,
3 equiv., 1.62 mmol) in dry THF (15 mL) at 0°C and
under argon, was added n-BuLi (1.6 M, 1.1 mL, 3
equiv.). After the solution turned red, aldehyde 25 (0.54
mmol) in THF (10 mL) was added. The reaction was
allowed to warm to rt and after 1 h the reaction was
quenched with H2O, extracted with CH2Cl2, and dried
To a solution of lactone 21 (76 mg, 0.28 mmol) in dry
THF (7 mL) at −78°C, under argon, was added
(TMS)2NLi (1 M, 840 mL, 0.84 mmol) and the temper-
ature was raised to −35°C. The reaction mixture was
cooled again to −78°C and DMPU (traces) and Eschen-
moser’s salt (156 mg, 3 equiv., 0.84 mmol) were added.
The temperature was allowed to raise to rt and after 5

2182
A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
h no more starting material was observed (TLC). The
reaction was then quenched by the addition of H2O,
extracted with CH2Cl2, dried (Na2SO4) and the solvent
evaporated. The resulting crude tertiary amine was
dissolved in methanol (1 mL) and MeI (0.5 mL) was
added. The resulting solution was kept in the dark at rt
for 48 h, after which time a white solid precipitate
appeared. Evaporation of the solvent under vacuum
yielded a residue which was taken up in 1,3 dioxolane
and treated with DBU (125 mL, 3 equiv., 0.84 mmol) at
rt for 4 h. Evaporation of the solvent and flash chro-
matography led to 29 (27.5 mg, 52% corrected yield).
from Z), 5.59 (d, J=1.7 Hz, 1H), 5.68 (dt, Jt=7.1 Hz,
Jd=14.3 Hz, 1H from E), 5.98–6.11 (m, 1H), 6.30 (dt,
Jt=10.3 Hz, Jd=17.0 Hz, 1H from E), 6.38 (d, J=1.9
Hz, 1H), 6.62 (dddd, J=1.1, 10.1, 11.2, 16.8 Hz, 1H
from Z).
13C NMR, l (75 MHz, CDCl3): 22.5, 22.7, 26.8, 29.7,
39.7, 42.4, 52.7, 53.0, 58.1, 59.4, 71.0, 71.6, 76.8, 77.2,
82.9, 83.1, 84.3, 84.7, 115.4, 124.5, 124.8, 125.1, 125.7,
131.2, 131.5, 133.9, 136.9, 135.5, 135.8, 170.7, 172.1;
anal. calcd for C17H24O5: C, 66.21; H, 7.84. Found: C,
66.07; H, 7.62%.
1
[h]2D5=−67.4 (c=0.69, CHCl3). H NMR, l (300 MHz,
CDCl3): 1.09 (s, 3H, CH3), 2.22 (dd, J=8.2, 13.7 Hz,
1H), 2.42 (dd, J=6.2, 13.8 Hz, 1H), 3.34 (ddd, J=1.7,
1.8 Hz, J2,3=6.5 Hz, 1H), 3.39 (s, 3H, OMe), 3.43 (dd,
Acknowledgements
J5,6=3.8 Hz, J6,6=10.6 Hz, 1H), 3.50 (s, 3H), 3.55
(ddd, J5,6=2.1, 3.8 Hz, J4,5=9.2 Hz, 1H), 3.74 (dd,
This research was supported with funds from the Direc-
cio´n General de Ensen˜anza Superior (Grant Nos. PB96-
0822, PB97-1244 and PPQ2000-1330). M.C. thanks the
Ministerio de Educacio´n y Cultura for a predoctoral
fellowship.
J
J
5,6=2.1 Hz, J6,6=10.6 Hz, 1H), 4.06 (dd, J3,4=3.2 Hz,
4,5=9.2 Hz, 1H), 5.07 (dd, J3,4=3.2 Hz, J2,3=6.5 Hz,
1H), 5.17 (m, 2H), 5.57 (d, J=1.8 Hz, 1H), 5.75 (m,
1H), 6.37 (d, J=1.8 Hz, 1H). 13C NMR, l (75 MHz,
CDCl3): 23.2, 44.5, 51.6, 58.0, 59.4, 70.9, 77.0, 77.3,
83.1, 84.4, 119.1, 124.7, 132.8, 135.7, 169.9; anal. calcd
for C15H22O5: C, 63.81; H, 7.85. Found: C, 63.90; H,
7.62%.
References
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4.15. (3aS,4R,6R,7S,7aR)-7-Methoxy-6-
(methoxymethyl)-4-methyl-3-methylen-4-[2Z/E-2,4-pen-
tadienyl]tetrahydro-4H-furo[3,2-c]pyran-2(3H)-one 18
(TMS)2NLi (1 M, 484 mL, 0.484 mmol) was added to a
solution of diene 23 (50 mg, 0.162 mmol) in dry THF (7
mL), under argon, at −78°C and the temperature
allowed to raise to −40°C for several minutes and then
cooled again at −78°C. DMPU (traces) and Eschen-
moser’s salt (90 mg, 3 equiv., 0.484 mmol) were then
added. The mixture was allowed to warm to rt and
stirred for 5 h, after which time H2O was added and the
reaction mixture was extracted (CH2Cl2), dried
(Na2SO4) and the solvent evaporated. The resulting
tertiary amine was then dissolved in anhydrous
methanol (1 mL) and treated with MeI (0.5 mL) and
kept at rt for 48 h. After a white precipitate was
observed, Et2O (2 mL) was added and the solvent was
evaporated under vacuum. The quaternary amine was
then taken up in 1,3 dioxolane and treated with DBU
(73 mL, 3 equiv., 0.486 mmol). After stirring the reac-
tion mixture for 4 h and evaporation of the solvents,
the residue was purified by flash chromatography (n-
hexane/EtOAc, 85:15) to yield triene 18 (10 mg, 34%
9. Ziegler, F. E.; Jaynes, B. H.; Saindane, M. T. J. Am.
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1
corrected yield) as a 1:1.7 (Z)/(E) mixture. H NMR, l
(300 MHz, CDCl3): 1.09 (s, 3H, CH3 from Z), 1.25 (s,
3H, CH3 from E), 1.50–1.80 (m, 2H), 2.05–2.30 (m,
2H), 3.27 (dt, Jt=1.7 Hz, Jd=6.5 Hz, 1H), 3.40 (s, 3H,
OMe from E), 3.41 (s, 3H, OMe from Z), 3.42–3.49 (m,
1H), 3.51 (s, 3H, OMe from Z and E), 3.53–3.58 (m,
1H), 3.74 (dd, J=1.95, 10.6 Hz, 1H), 3.99 (dd, J=3.2,
9.2 Hz, 1H), 4.98 (d, J=10.1 Hz, 1H from E), 5.06–
5.09 (m, 2H, from E), 5.12 (d, J=11.2 Hz, 1H from Z),
5.21 (d, J=16.8 Hz, 1H from Z), 5.39–5.47 (m, 1H

A. M. Go´mez et al. / Tetrahedron: Asymmetry 12 (2001) 2175–2183
2183
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