A simple route to enantiopure bis-lactones: synthesis of both enantiomers of epi-nor-canadensolide, nor-canadensolide, and canadensolide

Article abstract of DOI:10.1016/j.tet.2008.01.009

A simple strategy has been developed for the synthesis of both enantiomers of nor-canadensolide, epi-nor-canadensolide, and an intermediate to canadensolide. An orthoester Claisen rearrangement of an appropriately constructed allyl alcohol derivative prep

Full text of DOI:10.1016/j.tet.2008.01.009

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2359e2368
www.elsevier.com/locate/tet
A simple route to enantiopure bis-lactones: synthesis of both enantiomers
of epi-nor-canadensolide, nor-canadensolide, and canadensolide
*
Sujit Mondal, Subrata Ghosh
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, West Bengal, India
Received 26 September 2007; received in revised form 7 December 2007; accepted 3 January 2008
Available online 5 January 2008
Abstract
A simple strategy has been developed for the synthesis of both enantiomers of nor-canadensolide, epi-nor-canadensolide, and an intermediate
to canadensolide. An orthoester Claisen rearrangement of an appropriately constructed allyl alcohol derivative prepared from R-(þ)-2,3-di-O-
cyclohexylidine glyceraldehyde followed by epoxidation of the resulting unsaturated esters produced hydroxy-lactones, which on oxidation gave
keto-lactones. Stereoselective reduction of the keto-carbonyl using either a chelation controlled or a non-chelation controlled process led to the
natural or the epi-series, respectively. The interplay of the electronic effect between the polar groups and the steric effect of the b-substituent
during reduction of the keto-lactones turned out to be the key factors in deciding the stereochemical outcome. Regeneration of the aldehyde
functionality latent in the ketal moiety of the hydroxy-lactones provided the lactols, which on oxidation gave the bis-lactones.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Asymmetric synthesis; Bis-lactones; Chelation; Stereocontrol
1. Introduction
We envisaged the bicyclic lactols 2 with appropriate alkyl
chain (R) as the intermediates to the bis-lactones (Scheme
1). In a few earlier approaches to canadensolide, the lactol
2a has served as an intermediate. The lactol 2 would become
available from the keto-lactone 3. The ketal moiety in 3 would
provide the aldehyde functionality and a stereocontrolled hy-
dride reduction of the carbonyl group would deliver the hy-
droxyl group required for lactol formation. The keto-lactone
3 in principle should be available from the unsaturated ester
4 through lactonisation initiated by addition of an electrophile
to the carbonecarbon double bond. Hydride reduction of the
carbonyl group with a heteroatom at the a-chiral center gener-
ally proceeds with high diastereoselectivity especially when
the reaction proceeds through a metal chelated intermediate.
The keto-lactone 3 possesses a heteroatom (ring oxygen)
next to the carbonyl group. In addition, it has a bulky substit-
uent at b to the carbonyl group. Presumably, the stereoche-
mical outcome during reduction of the keto-carbonyl in 3
would be determined by the interplay of the electronic effect
exerted by the lactone oxygen and the steric hindrance posed
by the ketal substituent. During the present synthetic investiga-
tion we had the opportunity to explore the stereochemical
The bis-lactone represented by the general structure 1 is
found in a number of structurally related natural products
such as canadensolide 1a,1 sporothriolide 1b,2 and xylobovide
1c.3 They differ only in the length of the side chain. These
compounds exhibit important biological activities. For exam-
ple, canadensolide 1a, a mold metabolite formed by Penicil-
lium canadense, possesses an antigerminative activity against
fungi. Sporothriolide is an antibacterial, fungicidal, algicidal,
and herbicidal agent while xylobovide is a phytotoxic agent.
Due to the novel structure with three contiguous stereocenters
and interesting biological activities, considerable attention has
been focused on the development of new methodology for
their synthesis.4e21 As part of our interest in the synthesis of
natural products containing fused butyro-lactones,22 we initi-
ated a program for developing a general flexible route toward
the synthesis of these bis-lactones.
* Corresponding author. Tel.: þ91 33 2473 4971; fax: þ91 33 2473 2805.
E-mail address: ocsg@iacs.res.in (S. Ghosh).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.009

2360
S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
outcome in the reduction of the keto-lactone 3 along with its
other three possible diastereomers. This investigation has al-
lowed access to either the natural series or the epi-series of
the bis-lactones. In this paper the approach is illustrated by
a total synthesis of both enantiomers of nor-canadensolide,
epi-nor-canadensolide and a formal synthesis of (þ)-canaden-
solide and (ꢀ)-canadensolide.
The gross structure of the compounds 8 and 9 was
easily ascertained from spectroscopic data. Stereochemical
assignment to the compounds 8 and 9 followed from their
transformation to (þ)-nor-canadensolide 35 and (ꢀ)-nor-cana-
densolide (vide infra). Toward this end, the ester 8 was hydro-
lyzed with aqueous ethanolic KOH and the resulting acid was
treated with m-CPBA to produce the lactones 12 and 13 in
46% and 45% isolated yields, respectively (Scheme 3). The
lactone 12 was treated with 75% aqueous acetic acid and the
liberated vicinal diol was cleaved with NaIO4 to afford an
inseparable mixture of the lactols 14a and 14b in 1:2 ratio
as determined by integration of the proton attached to the
anomeric carbon at d 5.36 (s) for 14a and at d 5.54 (d,
J¼4.5 Hz) for 14b. The stereochemical assignment to 14a
and 14b is based on comparison of the observed coupling con-
stants to those reported in the literature.25 The mixture of the
lactols 14a and 14b on Jones oxidation produced the bis-lac-
tone 15, [a]2D6 þ25.03 (c 1.67, CHCl3). The spectral data of
the bis-lactone thus obtained were found to be comparable
with those reported18 for epi-nor-canadensolide. This con-
firmed the structure of the hydroxy-lactone as 12 and the inter-
mediate epoxide as 10. That the vicinal substituents in the
lactone 13 are trans to each other was confirmed by its failure
to undergo lactonisation when subjected to the reaction se-
quence for conversion of 12 to 15.
HO
O
H
H
O
O
O
O
R
O
O
H
H
R
1
2
R2
O
R2
R1
R1
O
O
O
H
CO2Et
O
O
O
H
R
R
3
4
a, R = n-Bu; b, R = n-Hex; c, R = Et
R1, R2 = -(CH2)5-
Scheme 1.
A similar protocol was employed to establish the structure
of the unsaturated ester 9. Thus, the acid obtained from the
2. Results and discussion
R2
O
R2
O
The unsaturated ester required for canadensolide was pre-
pared from the allylic alcohol 5 as delineated in Scheme 2.
The allylic alcohol 5 was obtained from R-(þ)-2,3-di-O-cyclo-
hexylidine glyceraldehyde according to the known proce-
dure.23 Oxidation of the alcohol 5 with DesseMartin
periodinane (DMP)24 afforded the aldehyde 6 in excellent
yield. Addition of n-BuLi to the aldehyde 6 followed by or-
thoester Claisen rearrangement of the resulting alcohol 7 led
to a 1:1 mixture of the two diastereomers 8 and 9 in 37%
and 35% yields, respectively.
R1
O
R1
O
H
H
O
O
i
+
8
O
O
83%
OH
OH
H
H
H
H
Bu
Bu
11
10
R2
R2
O
R1
R1
O
R2
O
R2
O
O
O
H
H
R1
O
R1
O
O
O
HO
Bu
12
HO
Bu
13
ii
O
O
Bu
R3
H
H
82%
HO
5, R3 = CH2OH
7
i
94%
ii 80%
6, R3 = CHO
R
R2
R1
O
R2
H
H
H
H
R1
iii
92%
O
O
O
O
O
O
O
O
H
H
O
O
iii
H
CO2Et
Bu
Bu
CO2Et
+
72%
14a, R = -OH
b, R = -OH
15
Bu
Bu
R1, R2 = -(CH2)5-
8
9
R1, R2 = -(CH2)5-
Scheme 3. (i) (a) KOHeEtOHeH2O, 85 ꢁC, 2 h; (b) m-CPBA, ClCH2CH2Cl,
0 ꢁC to rt, 6 h; (ii) (a) AcOHeH2O; (b) NaIO4, 80% (two steps); (iii) Jones
reagent, acetone, 0 ꢁC.
Scheme 2. (i) DMP, CH2Cl2, 2 h; (ii) n-BuLi, THF, ꢀ78 ꢁC; (iii) H3CC(OEt)3,
propionic acid (cat.), 140 ꢁC, 4 h.

S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
2361
ester 9 on treatment with m-CPBA afforded a mixture of the
hydroxy-lactones 16 and 17 in 35% and 44% yields, respec-
tively (Scheme 4). The hydroxy-lactone 16 was converted to
the bis-lactone 18 using the protocol for transformation of
the hydroxy-lactone 12 to the bis-lactone 15. The bis-lactone
18 has specific rotation [a]2D6 ꢀ28.73 (c 1.41, CHCl3) nearly
equal and opposite to that observed for 15. Thus, a synthesis
of (þ)-epi-nor-canadensolide and (ꢀ)-epi-nor-canadensolide
from an R-(þ)-glyceraldehyde derivative is achieved.
stereochemistry of the butyl group. This led us to investigate
the reduction of all the four possible diastereoisomers of the
keto-lactones 23, 25, 27, and 28. The keto-lactones 23, 25,
27, and 28 were obtained by oxidation of the hydroxy-lactones
12, 13, 16, and 17, respectively, with DMP in excellent yields.
Reduction of these ketones was carried out using NaBH4e
MeOH (condition A) as well as with NaBH4eMeOHeCeCl3
(condition B) (Scheme 5). The results are summarized in
Table 1.
Reduction of the ketone 23 with NaBH4 in MeOH gave
a mixture of the hydroxy-lactones 12 and 24 in1:1 ratio.
When the reduction was carried out in the presence of
CeCl3, the hydroxy-lactones 12 and 24 were obtained in a ratio
of 1:9 (entry 1, Table 1). The predominant formation of 24 in
the presence of CeCl3 dictates that the latter plays a significant
role in determining stereoselectivity and could be attributed to
hydride delivery from the convex face of the chelated interme-
diate 30 (Fig. 1). Chromatographic purification of this mixture
afforded the pure diastereomer 24 in 85% yield. Interestingly
reduction of the ketone 27 with NaBH4 alone or in the pres-
ence of CeCl3 produced exclusively the hydroxy-lactone 16
(entry 2, Table 1). Inspection of the Drieding model revealed
that of the two different conformers 31 and 32 of the keto-lac-
tone 27, the conformer 32 is preferred over 31 due to the pres-
ence of a steric interaction between the butyl residue and the
ketal group in the latter.
By analogy to the formation of the lactones 12 and 13 from
the ester 8, the hydroxy-lactone obtained along with 16 from
the ester 9 was assigned the structure 17. This assignment
was further corroborated by its transformation to the hy-
droxy-lactone 12 as delineated in Scheme 4.
The hydroxyl group in 17 was protected to afford the silyl
ether 19 in 87% yield. Reaction of lithium enolate of 19 with
PhSeBr afforded the lactone 20, which on treatment with hy-
drogen peroxide underwent selenoxide elimination to give the
butenolide 21. Hydrogenation of the butenolide 21 in the pres-
ence of PtO2 as catalyst afforded exclusively the cis-disubsti-
tuted lactone 22. Desilylation finally afforded 12, the structure
of which has already been established (Scheme 3).
After achieving the synthesis of both enantiomers of
nor-epi-canadensolide, we next focused our attention on the
synthesis of canadensolide. For this purpose it is necessary
to invert the stereochemistry of the butyl group in the cis-
hydroxy-lactones 12 and 16. An inversion of configuration
at C-4 and the stereocenter bearing the butyl group in 13
and 17 can also be considered toward this end. We decided
to pursue both this approach so that all the diastereomeric lac-
tones obtained above can be converted to canadensolide. We
thought that reduction of the keto-lactones derived from these
hydroxy-lactones would be the simplest way of inverting the
In order to delve into the matter, we have performed some
semi-empirical quantum mechanical calculations26 on the con-
formers 31 and 32 in regard to their minimum energies by
AM1 method developed by Dewar et al.27 The results indicate
that the conformer 32 (E¼ꢀ4796.8791 kcal/mol) in which the
butyl residue is away from the ketal is more stable than the
conformer 31 (E¼ꢀ4796.2877 kcal/mol) by ca. 0.6 kcal/mol.
R2
R2
R2
R1
R1
O
R1
O
O
O
O
SePh
O
O
H
H
H
i
iv
72%
O
O
9
+
HO
Bu
16
RO
Bu
TBDMSO
75%
O
O
O
H
H
H
Bu
20
17, R = H
iii 87%
v
100%
19, R = TBDMS
ii
R2
R2
O
R1
R1
O
O
O
H
O
H
vii
80%
vi
O
O
12
O
O
TBDMSO
Bu
22
TBDMSO
Bu
81%
O
O
O
H
H
H
Bu
18
21
For Structures 16-22 (except 18): R1, R2 = -(CH2)5-
Scheme 4. (i) (a) KOHeEtOHeH2O, 85 ꢁC, 2 h; (b) m-CPBA, ClCH2CH2Cl, 0 ꢁC to rt, 6 h; (ii) (a) AcOHeH2OeNaIO4, 82%; (b) Jones reagent, acetone, 0 ꢁC,
90%; (iii) TBDMSOTf, 2,6-lutidine, DCM, 0 ꢁC; (iv) LDA, THF, ꢀ78 ꢁC, HMPA, PhSeBr; (v) H2O2, Py, DCMeTHF (2:1), 8 h; (vi) H2ePtO2, MeOH, 5 h; (vii)
TBAF, THF, 0 ꢁCert.

2362
S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
R2
R2
O
16.The observed diastereoselectivity may also be attributed
R1
O
R1
O
by FelkineAnh model as depicted in structure 33. Reduction
of the ketone 25 with NaBH4 gave 1:1 mixture of the hy-
droxy-lactones 13 and 26. However, in the presence of CeCl3
the ratio of the hydroxy-lactones did not change significantly
producing 13 and 26 in 2:3 ratio (entry 3). The ketal unit and
the chain bearing the carbonyl group in the lactone 25 are
anti to each other ruling out the possibility of chelation.
Thus, no significant face selectivity was observed during re-
duction in the presence of CeCl3. The major diastereomer 26
was isolated in 50% yield through column chromatography.
The reduction of the ketone 28 (entry 4) with NaBH4 produced
the hydroxy-lactone 17 exclusively while with NaBH4eCeCl3
it gave the hydroxy-lactone 29 exclusively. Thus, a combination
of electronic factor and steric factor influences the reduction of
the carbonyl group in the keto-lactones 23, 25, 27, and 28.
The hydroxy-lactone 24 has the desired stereochemistry at
C-4 and the center bearing the butyl group for synthesis of nor-
canadensolide. Thus, treatment of the hydroxy-lactone 24 with
aqueous acetic acid followed by cleavage of the resulting diol
produced exclusively the lactol 34, [a]2D6 þ9.8 (c 1.64, CHCl3)
(Scheme 6). The stereochemical assignment to the lactol 34
follows from the coupling constant (J¼0) of the proton at-
tached to the anomeric center, which appeared as a singlet at
d 5.32. Notably, under identical conditions the ketal derivative
12 produced a mixture of the lactols 14a and 14b in 1:2 ratio
(Scheme 3). The contrasting behavior of the ketals toward the
formation of the bicycles is probably guided by the thermody-
namic stability of the products leading predominantly the lac-
tol 14b from 12 and exclusively 34 from 24. Jones oxidation of
the lactol 34 finally afforded (þ)-nor-canadensolide 35, [a]D24
þ24.50 (c 1.2, CHCl3); [lit.6 [a]D23 þ26.2 (c 0.50, CHCl3)].
The lactol 34 has already been converted to (þ)-
canadensolide.6
O
H
H
ii
i
O
O
O
O
O
12
13
16
HO
O
O
O
98%
85%
O
O
O
O
O
H
H
Bu
23
R2
Bu
24
R2
O
R1
O
R1
O
O
H
H
ii
i
HO
50%
97%
H
H
Bu
Bu
25
26
R2
R1
O
O
H
H
i
ii OR iii
16
95%
Bu
27
R2
R2
O
R1
O
R1
O
O
H
H
H
i, 95%
iii
ii
O
O
17
HO
O
50%
O
O
H
Bu
Bu
28
29
For structures 23-29: R1, R2 = -(CH2)5-
Scheme 5. (i) DMP, CH2Cl2, 2e2.5 h; (ii) NaBH4, MeOH, CeCl3$7H2O,
ꢀ20 ꢁC, 30 min; (iii) NaBH4, MeOH, 0 ꢁC, 30 min.
Table 1
Reduction of keto-lactones
HO
O
H
H
Entry
1
Keto-lactones
23
Hydroxy-lactones
Product ratio
i
ii
12þ24
50:50a
5:95b
100a,b
50:50a
40:60b
100a
O
O
O
O
24
80%
92%
O
O
H
H
n-Bu
n-Bu
2
3
27
25
16
13þ26
34
35
Scheme 6. (i) HOAceH2O then NaIO4; (ii) Jones reagent, acetone, 0 ꢁC.
4
28
17
29
100b
a
Finally, the hydroxy-lactone 26 obtained by reduction of
the ketone 25 was transformed to (ꢀ)-nor-canadensolide
(ꢀ)-35 as delineated in Scheme 7. To this end, the hydroxy
group in 26 was protected to give the silyl ether 36. The lac-
tone 36 was then converted to selenophenyl derivative 37 in
73% yield through alkylation of its lithium enolate with
Condition A.
Condition B.
b
Thus reduction of the carbonyl group under both the conditions
proceeds through the conformation 32 by addition of hydride
from the Re-face to produce exclusively the hydroxy-lactone
R1
O
R2
O
O
H
O
H
O
R1
R2
Ce3+
O
Bu
O
C
R1
O
O
O
O
O
H
H
O
O
R1
R2
O
O
O
H
O
R2
H
H
32
Bu
33
O
BH4
O
Bu
30
R1, R2 = -(CH2)5-
Bu
H
31
Figure 1.

S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
2363
R2
R2
lactones has been demonstrated to be influenced significantly
by steric and electronic effects imposed by the polar groups
present in the keto-lactones.
R1
O
R1
O
O
R4
O
H
iii
O
O
R3O
Bu
TBDMSO
O
O
4. Experimental section
H
H
Bu
4.1. General
26, R3 = R4 = H
i
97%
Melting points were taken in open capillaries in a sulfuric
acid bath. Petroleum ether refers to the fraction having bp
60e80 ꢁC. A usual workup of the reaction mixture consists
of extraction with ether, washing with brine, drying over
Na2SO4, and removal of the solvent in vacuo. Column chroma-
tography was carried out with silica gel (60e120 mesh). Peak
positions in 1H and 13C NMR spectra are indicated in parts per
million downfield from internal TMS in d units. NMR spectra
were taken in CDCl3 at 300 MHz for 1H and 75 MHz for 13C.
13C peak assignment is based on DEPT experiment. IR spectra
were recorded as neat for liquid and in KBr for solids. Unless
otherwise indicated, all reactions were carried out under blan-
ket of Ar.
36, R3 = TBDMS, R4 = H
ii 73%
37, R3 = TBDMS, R4 = SePh
R2
R1
O
O
HO
H
H
vi
vii
91%
iv
70%
(-)-35
O
O
O
78%
RO
O
O
H
H
Bu
Bu
41
39, R = TBDMS
40, R= H
v
82%
4.1.1. (1E)-1-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]hept-1-en-
3-ol 7
For structures 36-40: R1, R2 = -(CH2)5-
Scheme 7. (i) TBDMSOTf, 2,6-lutidine, DCM, 0 ꢁCert; (ii) LDA, THF,
ꢀ78 ꢁC, HMPA, PhSeBr; (iii) H2O2, Py, DCMeTHF (2:1), 8 h; (iv) H2e
PtO2, MeOH, 5 h; (v) TBAF, THF, 0 ꢁC to rt; (vi) HOAceH2O then NaIO4;
(vii) Jones reagent, acetone, 0 ꢁC.
To a magnetically stirred suspension of DesseMartin peri-
odinane (7.7 g, 18.2 mmol) in dichloromethane (30 mL) at
0 ꢁC, the allylic alcohol 5 (3.0 g, 15.2 mmol) in dichlorome-
thane (15 mL) was added drop-wise. The reaction mixture
was stirred for 30 min and was quenched with 10% Na2S2O3
solution (15 mL) doped with NaHCO3. The organic layer
was separated and the aqueous part extracted with diethyl
ether (2ꢂ100 mL). The combined organic layer was dried to
afford the enal 6 (2.8 g, 94%). Without further purification,
it was used in the next step. To a solution of the enal 6
(2.8 g, 14.2 mmol) in THF (40 mL) cooled to ꢀ78 ꢁC n-
BuLi (14.4 mL, 17.2 mmol, 1.5 M in hexane) was added
drop-wise. The reaction mixture was stirred for 30 min at
ꢀ78 ꢁC and then warmed to ꢀ30 ꢁC and quenched with satu-
rated aqueous NH4Cl (3 mL). Usual workup of the reaction
mixture with diethyl ether (2ꢂ80 mL) followed by column
chromatography (etherepetroleum ether 1:5) afforded the al-
lylic alcohol 7 (1.5 g, 82%) as a colorless liquid. IR 3419.6,
phenylselenyl bromide. Elimination of selenoxide from 37
afforded the butenolide 38 in near quantitative yield. Hydroge-
nation of the butenolide 38 over PtO2 afforded after chromato-
graphic purification the cis compound 39 (70%). Desilylation
of the lactone 39 gave the hydroxy-lactone 40. Treatment
of 40 with aqueous acetic acid followed by cleavage of the
resulting diol with periodate afforded the lactol 41, [a]D25
ꢀ10.0 (c 0.2, CHCl3) [lit.5 [a]D ꢀ14.9 (c 1.0, CHCl3) (for
an anomeric mixture of lactols)]. Jones oxidation of the lactol
41 gave (ꢀ)-nor-canadensolide (ꢀ)-35. The spectral data and
[a]D26 ꢀ21.5 (c 1.09, CHCl3) [lit. [a]D23 ꢀ18.9 (c 4.79, CHCl3)]
for the sample prepared by us were comparable with those
reported in the literature.10 The lactol 41 has already been con-
verted to (ꢀ)-canadensolide by earlier workers.4,5,10 Thus,
starting with R-(þ)-2,3-di-O-cyclohexylidine glyceraldehyde
a formal synthesis of both enantiomers of canadensolide is
achieved.
1448.4 cmꢀ1
;
1H NMR (of the diastereomeric mixture)
d 0.87 (3H, t, J¼6.5 Hz), 1.24e1.45 (6H, m), 1.47e1.60
(10H, m), 1.87 (1H, br s), 3.52e3.58 (1H, m), 4.03e4.10
(2H, m), 4.49 (1H, q, J¼6.8 Hz), 5.63 (1H, m), 5.77 (1H,
m); 13C NMR d 14.1, 14.2, 22.7, 23.9, 24.0, 24.1, 25.2,
27.7, 35.5, 35.6, 36.3, 36.6, 36.9, 69.2, 69.3, 72.0, 72.2,
76.3, 110.08, 110.12, 128.1, 128.3, 137.2, 137.3; HRMS
(ESI) calcd for C15H26O3Na (MþNa)þ, 277.1780; found,
277.1772.
3. Conclusion
We have developed a general strategy for synthesis of the
bis-lactone 1 in enantiomerically pure form. The strategy has
been illustrated by a formal synthesis of both enantiomers of
canadensolide starting from R-(þ)-2,3-di-O-cyclohexilidine
glyceraldehyde. Stereocontrolled reduction of the carbonyl
group in an appropriately constructed keto-lactone gave both
canadensolide and epi-canadensolide. The stereochemical out-
come during reduction of the carbonyl group in the keto-
4.1.2. Ethyl (3R,4E)-3-[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]hex-
4-enoate 8 and ethyl (3S,4E)-3-[(2S)-1,4-dioxaspiro[4.5]dec-
2-yl]hex-4-enoate 9
A mixture of the allylic alcohol 7 (1.26 g, 5.0 mmol), tri-
ethylorthoacetate (7.2 mL, 50.0 mmol), propionic acid (10 mg,

2364
S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
172.0 mmol), and xylene (20 mL) was heated at 140 ꢁC for 4 h.
The excess triethylorthoacetate and xylene was removed by dis-
tillation at reduced pressure. The residual mass was then purified
by flash chromatography (etherepetroleum ether 1:20) to afford
the ester 8 (570 mg, 37%): Rf¼0.6 (EtOAcepetroleum ether
110.8, 176.1; HRMS (ESI) calcd for C17H28O5Na (MþNa)þ,
335.1834; found, 335.1837 and the hydroxy-lactone 13
(800 mg, 45%): Rf¼0.4 (EtOAcepetroleum ether 1:1); IR
1
3446.6, 1774.4 cmꢀ1; [a]D25 ꢀ9.2 (c 1.75, CHCl3); H NMR
d 0.91 (3H, t, J¼6.9 Hz), 1.32e1.41 (6H, m), 1.46 (2H, m),
1.54 (4H, br s), 1.59 (4H, br s), 2.93 (1H, br s), 2.47e2.64
(2H, m), 2.72 (1H, m), 3.55 (1H, dd, J¼6.7, 8.1 Hz), 3.83
(1H, dt, J¼3.5, 8.2 Hz), 4.04 (1H, t, J¼7.5 Hz), 4.17 (1H,
dt, J¼3.8, 6.4 Hz), 4.29 (1H, t, J¼3.1 Hz); 13C NMR d 14.1,
22.7, 23.8, 24.0, 25.2, 27.9, 30.1, 32.2, 34.4, 36.1, 37.4,
66.9, 72.3, 75.9, 85.0, 110.3, 177.3; HRMS (ESI) calcd for
C17H28O5Na (MþNa)þ, 335.1834; found, 335.1832.
1
1:9); [a]2D4 þ7.20 (c 1.5, CHCl3); IR 1737.7 cmꢀ1; H NMR
d 0.84 (3H, t, J¼7.0 Hz), 1.21 (3H, t, J¼7.2 Hz), 1.25e1.29
(4H, m), 1.36 (2H, br s), 1.54 (4H, br s), 1.58 (4H, br s), 1.94
(2H, dt, J¼6.7, 6.6 Hz), 2.25 (1H, dd, J¼9.3, 14.5 Hz), 2.57
(1H, m), 2.69 (1H, dd, J¼4.5, 14.5 Hz), 3.63 (1H, dd, J¼5.7,
7.3 Hz), 3.87 (1H, dd, J¼4.8, 7.3 Hz), 3.91 (1H, q, J¼6.1 Hz),
4.09 (2H, q, J¼7.2 Hz), 5.14 (1H, dd, J¼8.8, 15.4 Hz), 5.52
(1H, td, J¼6.7, 15.4 Hz); 13C NMR d 13.9, 14.4, 22.1, 23.9,
24.1, 25.3, 31.5, 32.3, 35.2, 36.6, 37.6, 44.6, 60.3, 67.9, 77.8,
110.0, 128.0, 134.3, 172.6; HRMS (ESI) calcd for
C19H32O4Na (MþNa)þ, 347.2198; found, 347.2191 and the es-
ter 9 (550 mg, 35%): Rf¼0.5 (EtOAcepetroleum ether 1:9);
[a]D24 þ35.75 (c 1.6, CHCl3); IR 1737.7 cmꢀ1; 1H NMR d 0.84
(3H, t, J¼6.8 Hz), 1.20 (3H, t, J¼7.1 Hz), 1.27 (4H, m), 1.35
(2H, br s), 1.53 (4H, br s), 1.56 (4H, br s), 1.97 (2H, dt, J¼7.8,
7.8 Hz), 2.31 (1H, dd, J¼9.3, 15.0 Hz), 2.49 (1H, dd, J¼5.3,
15.0 Hz), 2.70 (1H, m), 3.60 (1H, t, J¼7.6 Hz), 3.90 (1H, t,
J¼7.6 Hz), 4.04e4.11 (3H, m), 5.26 (1H, dd, J¼8.5, 15.4 Hz),
5.48 (1H, td, J¼6.7, 15.4 Hz); 13C NMR d 14.0, 14.3, 22.1,
23.9, 24.0, 25.3, 31.5, 32.3, 34.9, 35.9, 36.5, 41.7, 60.4, 66.2,
77.2, 109.6, 127.4, 134.2, 172.6; HRMS (ESI) calcd for
C19H32O4Na (MþNa)þ, 347.2198; found, 347.2197.
4.1.4. (3aR,6R,6aS)-6-Butyl-4-hydroxytetrahydrofuro[3,4-b]
furan-2(3H)-one 14
A solution of the hydroxy-lactone 12 (110 mg, 0.35 mmol)
in CH3CN (0.5 mL) was treated with 75% aqueous AcOH
(2 mL) at rt for 6 h. To the resulting solution cooled to 0 ꢁC
NaIO4 (374 mg, 1.75 mmol) was added pinch-wise. After stir-
ring for 4 h at rt the reaction mixture was diluted with diethyl
ether (20 mL). The entire mass was transferred to a separatory
funnel and washed with saturated NaHCO3 solution (3ꢂ1 mL)
until alkaline. The organic layer was dried (Na2SO4) and con-
centrated to afford a mixture of the lactols 14a and 14b
(57 mg, 80%) as a low melting solid (mp 42e45 ꢁC). IR
3444.6, 1770.5 cmꢀ1 1H NMR (of the anomeric mixture)
;
d 0.91 (3H, t, J¼6.0 Hz), 1.37e1.49 (4H, m), 1.62e1.74
(2H, m), 2.50e2.60 (1H, m), 2.74e2.88 (1H, m), 2.96e3.06
(1H, m), 4.21 (1H, t, J¼7.7 Hz), 4.27e4.32 (1H, m), 4.60 (1H,
dd, J¼3.0, 7.8 Hz), 4.89 (1H, m), 5.36 (1H, s), 5.54 (1H, d,
J¼4.4 Hz); 13C NMR d 14.0, 14.1, 22.4, 22.6, 27.6, 28.0,
29.2, 32.0, 32.8, 34.2, 43.8, 46.3, 82.8, 85.6, 86.7, 87.4,
97.4, 104.7, 176.3, 177.3; HRMS (ESI) calcd for
C10H16O4Na (MþNa)þ, 223.0946; found, 223.0920.
4.1.3. (4S,5S)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-[(1R)-
1-hydroxypentyl]dihydrofuran-2(3H)-one 12 and (4S,5R)-4-
[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]-5-[(1S)-1-hydroxy-
pentyl]dihydrofuran-2(3H)-one 13
A solution of the ester 8 (1.8 g, 5.6 mmol) in EtOH (15 mL)
was heated under reflux with KOH (1.6 g, 28.0 mmol) and wa-
ter (4 mL) for 2.5 h. After removing ethanol under reduced
pressure the residual mass at ice-cold condition was diluted
with water (3 mL) and was acidified carefully with HCl
(5 mL, 4 N). The organic compound was then worked up to af-
ford the acid (1.5 g, 91%) as sticky yellowish liquid. To a mag-
netically stirred cooled (0 ꢁC) solution of the unsaturated acid
(1.7 g, 5.7 mmol) in 1,2-dichloroethane (25 mL) was added m-
CPBA (1.7 g, 7.6 mmol) portion-wise. Stirring was continued
for 6 h at rt. The precipitated white solid was filtered off and
washed thoroughly with diethyl ether. The combined filtrate
and washing was washed sequentially with saturated Na2SO3
(3ꢂ2 mL) and saturated NaHCO3 (3ꢂ2 mL), and dried
(Na2SO4). Evaporation of the solvent followed by column
chromatography of the residual mass afforded the hydroxy-
lactone 12 (810 mg, 46%): Rf¼0.3 (EtOAcepetroleum ether
1:1); IR 3419.6, 1766.7 cmꢀ1; [a]D26 þ7.56 (c 1.5, CHCl3);
1H NMR d 0.90 (3H, t, J¼6.8 Hz), 1.35 (6H, br s), 1.43e
1.60 (10H, m), 1.80 (1H, br s), 2.49 (1H, dd, J¼8.4,
17.1 Hz), 2.60 (1H, dd, J¼5.1, 17.1 Hz), 2.68e2.73 (1H, m),
3.58 (1H, t, J¼7.6 Hz), 3.88 (1H, dt, J¼2.0, 7.5 Hz), 4.10
(1H, t, J¼7.6 Hz), 4.23 (1H, t, J¼7.3 Hz), 4.60 (1H, dt,
J¼2.3, 6.7 Hz); 13C NMR d 14.1, 22.7, 23.9, 24.0, 25.1,
27.3, 29.8, 34.2, 34.3, 35.7, 40.0, 67.6, 70.0, 72.4, 83.4,
4.1.5. (3aR,6R,6aS)-6-Butyltetrahydrofuro[3,4-b]furan-2,
4-dione 15
The lactol 14 (50 mg, 2.5 mmol) in acetone (1 mL) as ob-
tained above was immediately treated with Jones reagent at
0 ꢁC until the color of the reagent persisted. Workup of the reac-
tion mixture with diethyl ether followed by column chromatog-
raphy (ethyl acetateepetroleum ether 1:3) afforded bis-lactone
15 (46 mg, 92%) as a white crystalline solid. Mp 85ꢀ86 ꢁC (lit.
(ꢃ)-15, mp 85e86 ꢁC); IR 1772.5 cmꢀ1; [a]2D6 þ25.03 (c 1.67,
CHCl3); 1H NMR d 0.92 (3H, t, J¼6.8 Hz), 1.44 (4H, m), 1.67
(2H, dt, J¼7.2, 7.2 Hz), 2.82e2.95 (2H, m), 3.45 (1H, ddd,
J¼3.4, 6.3, 9.2 Hz), 4.67 (1H, t, J¼7.0 Hz), 4.87 (1H, d,
J¼6.5 Hz); 13C NMR d 13.9, 22.3, 26.7, 31.0, 32.6, 39.8, 82.0,
84.2, 173.4, 175.4; HRMS (ESI) calcd for C10H14O4Na
(MþNa)þ, 221.0790; found, 221.0799.
4.1.6. (4R,5R)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-[(1S)-
1-hydroxypentyl]dihydrofuran-2(3H)-one 16 and (4R,5S)-4-
[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]-5-[(1R)-1-hydroxy-
pentyl]dihydrofuran-2(3H)-one 17
Following the procedure similar to the conversion of the
ester 8 to the hydroxy-lactones 12 and 13, the ester 9

S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
2365
(550 mg, 1.7 mmol) was converted to a diastereomeric mix-
ture of the hydroxy-lactone 16 (110 mg, 35%). Rf¼0.4
(EtOAcepetroleum ether 1:1); IR 3444.6, 1770.5 cmꢀ1
4.1.9. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(4R,5S)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]-3-
phenylselanyl-dihydro-furan-2-one 20
;
[a]2D4 ꢀ42.3 (c 1.2, CHCl3); 1H NMR d 0.90 (3H, t,
J¼6.9 Hz), 1.24e1.43 (6H, m), 1.47e1.60 (10H, m), 2.15
(1H, dd, J¼4.2, 17.7 Hz), 2.58 (1H, m), 2.76 (1H, dd,
J¼9.8, 17.7 Hz), 3.60 (1H, m), 3.82 (1H, m), 4.08 (2H, m),
4.41 (1H, t, J¼3.5 Hz); 13C NMR d 14.1, 22.7, 23.8,
24.0, 25.1, 27.7, 32.0, 32.4, 34.7, 36.4, 39.6, 67.5, 72.8,
76.8, 85.2, 110.7, 176.6; HRMS (ESI) calcd for C17H28O5Na
(MþNa)þ, 335.1834; found, 335.1832 and the hydroxy-
lactone 17 (140 mg, 44%): Rf¼0.5 (EtOAcepetroleum ether
1:1); IR 3431.1, 1780.2 cmꢀ1; [a]D24 ꢀ10.32 (c 2.0, CHCl3);
1H NMR d 0.91 (3H, t, J¼7.1 Hz), 1.33e1.43 (6H, m),
1.45e1.60 (8H, m), 1.75 (2H, m), 2.08 (1H, dd, J¼5.5,
21.0 Hz), 2.74 (1H, m), 2.76 (1H, dd, J¼8.1, 20.6 Hz),
3.60 (1H, t, J¼7.6 Hz), 3.87 (1H, dt, J¼2.6, 8.2 Hz),
4.15 (1H, t, J¼7.2 Hz), 4.18e4.28 (2H, m); 13C NMR
d 14.2, 22.9, 24.0, 24.1, 24.9, 27.3, 32.9, 33.6, 35.1,
36.2, 42.2, 68.6, 69.3, 73.1, 84.6, 111.6, 174.9; HRMS
(ESI) calcd for C17H28O5Na (MþNa)þ, 335.1834; found,
335.1831.
To a magnetically stirred solution of diisopropylamine
(0.16 mL, 1.08 mmol) in anhydrous THF (3 mL) cooled to
ꢀ20 ꢁC under argon atmosphere was added drop-wise n-
BuLi (0.57 mL, 0.85 mmol, 1.5 M in hexane), and stirred for
40 min. The solution was then cooled to ꢀ78 ꢁC and a solution
of the protected lactone 19 (180 mg, 0.42 mmol) in THF
(4 mL) was added drop-wise. The reaction mixture was then
slowly warmed to ꢀ30 ꢁC and stirred at that temperature for
30 min. The temperature of the reaction mixture was again
brought to ꢀ78 ꢁC and to it HMPA (0.1 mL) and phenylse-
lenyl bromide (120 mg, 0.50 mmol) in THF (3 mL) were
added sequentially. The reaction mixture was then allowed
to attain rt. After quenching with saturated NH4Cl solution,
the reaction mixture was worked up in the usual way with di-
ethyl ether (3ꢂ12 mL) to afford after column chromatography
(etherepetroleum ether 1:8) the lactone 20 (200 mg, 81%) as
1
a light yellow liquid. H NMR d 0.00 (3H, br s), 0.02 (3H, br
s), 0.80 (12H, m), 1.22 (4H, m), 1.40 (2H, br s), 1.51 (10H, br
s), 2.68 (1H, q, J¼7.5 Hz), 3.79 (1H, d, J¼7.7 Hz), 3.88 (2H,
m), 4.01 (1H, dd, J¼5.8, 8.7 Hz), 4.33 (1H, dd, J¼3.3,
7.3 Hz), 4.45 (1H, q, J¼7.0 Hz), 7.30 (3H, m), 7.62 (2H, d,
J¼6.6 Hz); 13C NMR d ꢀ4.3, ꢀ4.1, 14.5, 18.4, 23.2, 24.2,
24.3 25.5, 26.3 (3CH3), 27.9, 33.9, 35.4, 36.7, 40.9, 47.6,
67.6, 73.7, 74.5, 81.7, 109.4, 127.0, 129.6, 129.8 (2CH),
136.3 (2CH), 175.9; HRMS (ESI) calcd for C29H46O5SeSiNa
(MþNa)þ, 605.2180; found, 605.2188.
4.1.7. (3aS,6S,6aR)-6-Butyltetrahydrofuro[3,4-b]furan-2,4-
dione 18
Following the procedure for the conversion of the hydroxy-
lactone 12 to the bis-lactone 15, the hydroxy-lactone 16
(100 mg, 0.32 mmol) was first converted to a cyclic hemiace-
tal (52 mg, 82%) followed by Jones oxidation to afford the bis-
lactone 18 (46 mg, 90%), an enantiomer of the bis-lactone 15
as a white crystalline solid. [a]2D6 ꢀ28.73 (c 1.41, CHCl3);
HRMS (ESI) calcd for C10H14O4Na (MþNa)þ, 221.0790;
found, 221.0799.
4.1.10. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(5S)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]-5H-furan-2-one
21
To a solution of the lactone 20 (200 mg, 0.34 mmol) in di-
chloromethane (6 mL) and THF (3 mL), pyridine (0.05 mL, 0.
57 mmol) was added followed by addition of 30% H2O2
(5 mL) drop-wise. The reaction mixture was stirred at rt for
about 8 h. It was then worked up with diethyl ether to afford
after column chromatography (etherepetroleum ether 1:10)
the unsaturated lactone 21 (145 mg, 100%) as a light yellow
liquid. IR 1760.9 cmꢀ1; [a]D25 þ48.3 (c 1.0, CHCl3); 1H
NMR d 0.05 (3H, br s), 0.06 (3H, br s), 0.83e0.92 (12H,
m), 1.31 (4H, m), 1.41 (4H, m), 1.60 (8H, br s), 3.91 (1H,
dd, J¼6.6, 8.2 Hz), 4.12 (1H, t, J¼6.4 Hz), 4.28 (1H, dd,
J¼6.4, 8.2 Hz), 4.81 (1H, t, J¼6.2 Hz), 5.08 (1H, s), 5.92
(1H, s); 13C NMR d ꢀ4.7, ꢀ4.5, 14.1, 18.1, 22.7, 23.9,
24.0, 25.0, 25.9 (3CH3), 28.4, 32.7, 35.1, 36.0, 68.4, 71.8,
72.6, 86.6, 111.1, 117.6, 167.8, 172.4; HRMS (ESI) calcd
for C23H40O5SiNa (MþNa)þ, 447.2543; found, 447.2541.
4.1.8. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(4R,5S)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]dihydro-
furan-2-one 19
To a stirring solution of the secondary alcohol 17 (140 mg,
0.45 mmol) in dichloromethane (8 mL) 2,6-lutidine (0.1 mL,
0.90 mmol) was added drop-wise. After stirring for 5 min at
rt the reaction mixture was cooled to 0 ꢁC. TBDMSOTf
(0.14 mL, 0.58 mmol) was then added drop-wise and stirred
for 10 min at the same temperature. The solvent was removed
by blowing nitrogen and the residual organic material was
chromatographed (etherepetroleum ether 1:9) to afford the
lactone 19 (167 mg, 87%) as
a colorless liquid. IR
1782.1 cmꢀ1; [a]D25 ꢀ24.54 (c 2.07, CHCl3); H NMR d 0.00
(3H, br s), 0.03 (3H, br s), 0.82 (12H, br s), 1.20e1.32
(6H, m), 1.50e1.54 (10H, m), 2.23 (1H, dd, J¼9.1,
16.8 Hz), 2.42 (1H, dd, J¼11.3, 16.7 Hz), 2.72 (1H, m),
3.44 (1H, t, J¼7.7 Hz), 4.00 (2H, dd, J¼6.0, 7.9 Hz),
4.45e4.56 (2H, m); 13C NMR d ꢀ4.4, ꢀ4.3, 14.4, 18.3,
23.2, 24.2, 24.3, 25.5, 26.3 (3CH3), 28.5, 31.9, 33.9, 35.5,
36.9, 42.7, 68.6, 73.9, 76.0, 83.0, 110.5, 176.3; HRMS (ESI)
calcd for C23H42O5SiNa (MþNa)þ, 449.2699; found,
449.2671.
1
4.1.11. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(4S,5S)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]dihydro-
furan-2-one 22
To a solution of the unsaturated lactone 21 (110 mg,
0.26 mmol) in methanol (8 mL) at rt was added PtO2
(10 mg). The reaction mixture was stirred under hydrogen at-
mosphere for 5 h and then filtered through filter paper.

2366
S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
Removal of methanol under reduced pressure followed by col-
umn chromatography (etherepetroleum ether 1:9) gave the
t, J¼7.3 Hz), 4.37e4.43 (2H, m); 13C NMR d 14.1, 22.7,
23.9, 24.0, 25.0, 28.2, 29.1, 32.8, 34.8, 35.8, 40.4, 67.9,
71.0, 72.3, 82.8, 111.1, 176.2; HRMS (ESI) calcd for
C17H28O5Na (MþNa)þ, 335.1834; found, 335.1828.
lactone 22 (90 mg, 81%) as colorless oil. IR 1778.2 cmꢀ1
;
1
[a]2D5 þ14.56 (c 1.6, CHCl3); H NMR d 0.05 (3H, br s),
0.07 (3H, br s), 0.87 (12H, br s), 1.30e1.51 (8H, m), 1.56
(4H, br s), 1.60 (4H, br s), 2.46 (1H, dd, J¼3.8, 17.7 Hz),
2.61 (1H, dd, J¼9.8, 17.7 Hz), 2.75 (1H, m), 3.54 (1H, t,
J¼7.5 Hz), 3.89 (1H, m), 4.04 (1H, t, J¼7.3 Hz), 4.16 (1H,
dd, J¼4.5, 6.4 Hz), 4.36 (1H, t, J¼2.6 Hz); 13C NMR
d ꢀ4.6, ꢀ4.5, 14.1, 18.1, 23.0, 23.9, 24.0, 25.2, 26.0
(3CH3), 27.6, 30.4, 33.6, 34.5, 36.2, 36.5, 66.8, 73.4, 76.2,
83.9, 110.3, 176.7; HRMS (ESI) calcd for C23H42O5SiNa
(MþNa)þ, 449.2699; found, 449.2684.
4.1.15. (4S,5R)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
pentanoyldihydrofuran-2(3H)-one 25
Following the procedure for oxidation of the hydroxy-ace-
tone 12, the hydroxy-lactone 13 (500 mg, 1.6 mmol) was oxi-
dized with DesseMartin periodinane to afford the keto-lactone
25 (480 mg, 97%) as a crystalline white solid. Mp 68ꢀ69 ꢁC;
IR 1789.8, 1716.5 cmꢀ1; [a]D25 ꢀ93.9 (c 1.41, CHCl3); 1H
NMR d 0.90 (3H, t, J¼7.3 Hz), 1.24e1.40 (4H, m), 1.52e
1.62 (10H, m), 2.52e2.73 (5H, m), 3.58 (1H, dd, J¼6.4,
8.5 Hz), 4.10 (1H, dd, J¼6.9, 8.3 Hz), 4.33 (1H, dt, J¼3.4,
6.4 Hz), 4.68 (1H, d, J¼5.4 Hz); 13C NMR d 13.9, 22.3,
23.8, 24.0, 25.0, 25.2, 28.5, 34.4, 36.0, 39.0, 40.7, 67.0,
74.8, 83.8, 110.6, 175.2, 208.1; HRMS (ESI) calcd for
C17H26O5Na (MþNa)þ, 333.1678; found, 333.1674.
4.1.12. Deprotection of silyl group from the lactone 22
Deprotection of TBDMS group from the lactone 22 (70 mg,
0.16 mmol) in tetrahydrofuran (5 mL) was accomplished with
tetrabutylammonium fluoride (68 mg, 0.24 mmol). After stir-
ring the reaction mixture at rt for 4 h, it was worked up to af-
ford after column chromatography (ethyl acetateepetroleum
ether 1:3) the hydroxy-lactone 12 (41 mg, 80%). [a]2D6 þ7.6
(c 0.71, CHCl3).
4.1.16. (4S,5R)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
[(1R)-1-hydroxypentyl]dihydrofuran-2(3H)-one 26
Following the reduction condition A, the keto-lactone 25
(120 mg, 1.3 mmol) was reduced to a 1:1 diastereomeric mix-
ture of separable hydroxyl-lactones 13 (49 mg, 38%) and 26
(48 mg, 37%). IR 3444.6, 1778.2 cmꢀ1; [a]D25 ꢀ5.4 (c 0.8,
CHCl3); 1H NMR d 0.94 (3H, t, J¼6.7 Hz), 1.44 (6H, m), 1.59
(4H, br s), 1.63 (6H, br s), 2.64 (2H, dd, J¼3.6, 7.7 Hz), 2.75
(1H, m), 3.60 (2H, m), 4.08 (1H, t, J¼7.4 Hz), 4.22 (1H, dt,
J¼5.2, 6.4 Hz), 4.34 (1H, dd, J¼1.5, 5.0 Hz); 13C NMR
d 14.1, 22.6, 23.8, 24.0, 25.2, 28.0, 29.7, 33.7, 34.6, 36.0,
39.4, 67.0, 72.3, 74.8, 84.2, 110.4, 176.8; HRMS (ESI) calcd
for C17H28O5Na (MþNa)þ, 335.1834; found, 335.1838.
4.1.13. (4S,5S)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
pentanoyldihydrofuran-2(3H)-one 23
Following the procedure for oxidation of the alcohol 5 the
hydroxy-lactone 12 (150 mg, 0.48 mmol) in dichloromethane
(10 mL) was carried out with DesseMartin periodinane
(244 mg, 0.58 mmol) to afford after column chromatography
(etherepetroleum ether 1:4) the keto-lactone 23 (146 mg,
98%) as white crystalline solid. Mp 71e72 ꢁC; IR 1780.2,
1714.6 cmꢀ1; [a]D25 þ39.3 (c 1.8, CHCl3); H NMR d 0.90
1
(3H, t, J¼7.3 Hz), 1.29e1.63 (14H, m), 2.59e2.66 (2H, m),
2.69e2.79 (2H, m), 2.89 (1H, m), 3.53 (1H, dd, J¼6.3,
8.3 Hz), 4.04 (1H, t, J¼7.8 Hz), 4.24 (1H, t, J¼6.2 Hz), 4.81
(1H, d, J¼8.0 Hz); 13C NMR d 14.0, 22.3, 23.8, 24.1, 24.6,
25.2, 29.0, 33.8, 35.6, 40.0, 40.6, 67.0, 72.1, 84.0, 111.0,
175.5, 209.8; HRMS (ESI) calcd for C17H26O5Na (MþNa)þ,
333.1678; found, 333.1672.
4.1.17. (4R,5R)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
pentanoyldihydrofuran-2(3H)-one 27
Following the procedure for oxidation of the hydroxy-ace-
tone 12, the hydroxy-acetone 16 (200 mg, 0.64 mmol) was ox-
idized with DesseMartin periodinane to afford the keto-
lactone 27 (188 mg, 95%) as a crystalline white solid. Mp
1
4.1.14. General procedure for the reduction of the keto-
lactones with NaBH4eMeOH at 0 ꢁC (Condition A):
(4S,5S)-4-[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]-5-[(1S)-1-
hydroxypentyl]dihydrofuran-2(3H)-one 24
72e73 ꢁC; IR 1793.7, 1714.6 cmꢀ1; H NMR d 0.90 (3H, t,
J¼7.2 Hz), 1.25e1.37 (4H, m), 1.54e1.60 (10H, m), 2.32
(1H, m), 2.49e2.71 (4H, m), 3.70 (1H, dd, J¼4.7, 8.3 Hz),
4.06e4.16 (2H, m), 4.88 (1H, d, J¼2.8 Hz); 13C NMR
d 13.9, 22.3, 23.8, 24.1, 25.0, 25.1, 30.4, 34.3, 36.4, 39.2,
40.8, 61.5, 75.9, 82.8, 110.7, 175.2, 207.7; HRMS (ESI) calcd
for C17H26O5Na (MþNa)þ, 333.1678; found, 333.1693.
To a magnetically stirred solution of the keto-lactone 23
(150 mg, 0.48 mmol) in methanol (12 mL) at 0 ꢁC was added
NaBH4 (22 mg, 0.56 mmol) portion-wise. After stirring for
20 min at that temperature the reaction mixture was quenched
by addition of AcOH. Usual workup of the reaction mixture
afforded after column chromatography (ethyl acetateepetro-
leum ether 1: 3) a 1:1 diastereomeric mixture of hydroxyl-lac-
tones 12 (60 mg, 40%) and 24 (41 mg, 41%) as light yellow
viscous liquid. IR 3489.0, 1772.5 cmꢀ1; [a]D25 þ8.24 (c 0.93,
4.1.18. (4R,5S)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
pentanoyldihydrofuran-2(3H)-one 28
Following the procedure for oxidation of the hydroxy-ace-
tone 12, the hydroxy-acetone 17 (200 mg, 0.64 mmol) was ox-
idized with DesseMartin periodinane to afford the keto-
lactone 28 (190 mg, 96%) as a crystalline white solid. Mp
1
CHCl3); H NMR d 0.89 (3H, t, J¼6.7 Hz), 1.31e1.45 (6H,
1
m), 1.46e1.68 (10H, m), 2.43 (1H, dd, J¼7.8, 13.4 Hz),
2.77 (1H, dd, J¼9.8, 13.2 Hz), 2.82 (1H, m), 3.22 (1H, br
s), 3.58 (1H, t, J¼7.8 Hz), 3.78 (1H, t, J¼3.9 Hz), 4.12 (1H,
69e71 ꢁC; IR 1784.2, 1714.2 cmꢀ1; H NMR d 0.91 (3H, t,
J¼7.3 Hz), 1.30e1.40 (4H, m), 1.52e1.60 (10H, m), 2.39
(2H, m), 2.60 (1H, m), 2.80e2.90 (2H, m), 3.53 (1H, dd,

S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
2367
J¼6.1, 8.0 Hz), 3.90 (1H, m), 4.04 (1H, dd, J¼6.0, 8.0 Hz),
4.1.23. (3aR,6S,6aS)-6-Butyltetrahydrofuro[3,4-b]furan-
2,4-dione 35
5.04 (1H, d, J¼7.6 Hz); 13C NMR d 14.0, 22.3, 23.9, 24.1,
25.0, 25.1, 30.0, 34.9, 36.6, 42.0, 43.9, 68.1, 74.4, 81.4,
111.0, 175.0, 207.4; HRMS (ESI) calcd for C17H26O5Na
(MþNa)þ, 333.1678; found, 333.1676.
Following the procedure described for oxidation of the lac-
tol 14, the lactol 34 (35 mg, 0.18 mmol) in acetone (1 mL) was
oxidized with Jones reagent to afford after column chromato-
graphy bis-lactone 35 (32 mg, 92%) as a white crystalliꢀn1e
solid. Mp 84e86 ꢁC (lit. 85e85.5 ꢁC); IR 1770.5 cm
;
4.1.19. General procedure for the reduction of the keto-
lactones with NaBH4eCeCl3$7H2OeMeOH at ꢀ20 ꢁC
(Condition B): (4S,5S)-4-[(2S)-1,4-dioxaspiro[4.5]dec-2-
yl]-5-[(1S)-1-hydroxypentyl]dihydrofuran-2(3H)-one 24
To a magnetically stirred solution of the keto-lactone 23
(200 mg, 0.64 mmol) in methanol (15 mL) was added
CeCl3$H2O (169 mg, 0.64 mmol) and stirred for 5 min at rt.
The reaction mixture was then cooled to ꢀ20 ꢁC (iceesalt
bath) and to it NaBH4 (30 mg, 0.77 mmol) was added por-
tion-wise. After stirring for 30 min at ꢀ20 ꢁC the reaction
mixture was quenched by addition of AcOH. Usual workup
of the reaction mixture afforded after column chromatography
(ethyl acetateepetroleum ether 1:3) the hydroxyl-lactone 24
(172 mg, 85%) as a light yellow viscous liquid.
[a]D26 þ24.50 (c 1.3, CHCl3), [lit. [a]2D3 þ26.20 (c 0.50,
1
CHCl3)]; H NMR d 0.93 (3H, t, J¼7.0 Hz), 1.36e1.51 (4H,
m), 1.81e1.92 (2H, m), 2.91e2.95 (2H, m), 3.49 (1H, ddd,
J¼3.8, 6.1, 7.9 Hz), 4.58 (1H, ddd, J¼3.9, 6.5, 7.7 Hz), 5.10
(1H, dd, J¼3.9, 6.1 Hz); 13C NMR d 13.9, 22.5, 27.5, 28.6,
31.2, 41.9, 79.9, 82.5, 173.5, 175.3; HRMS (ESI) calcd for
C10H14O4Na (MþNa)þ, 221.0790; found, 221.0780.
4.1.24. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(4S,5R)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]dihydro-
furan-2-one 36
Following the procedure for the protection of the hydroxy-
lactone 17, the secondary alcohol 26 (160 mg, 0.51 mmol) was
protected as TBDMS ether using TBDMSOTf (0.14 mL,
0.61 mmol) and 2,6-lutidine (0.12 mL, 1.02 mmol) to afford
after column chromatography the lactone 36 (180 mg, 97%)
as a colorless liquid. IR 1778.6 cmꢀ1; [a]D27 ꢀ4.82 (c 1.1,
4.1.20. (4S,5R)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
[(1R)-1-hydroxypentyl]dihydrofuran-2(3H)-one 26
Following the reduction condition B, the keto-lactone 25
(400 mg, 1.3 mmol) was reduced to a 2:3 diastereomeric mix-
ture of alcohols 13 and 26. Separation of the major diastereo-
mer by flash chromatography on silica gel with 3:1 petroleum
ethereEtOAc for elution gave hydroxyl-lactone 26 (200 mg,
50%) as a colorless viscous liquid.
1
CHCl3); H NMR d 0.08 (3H, s), 0.09 (3H, s), 0.88 (12H, br
s), 1.25e1.33 (6H, m), 1.40 (2H, br s), 1.56 (4H, br s), 1.61
(4H, br s), 2.49e2.63 (3H, m), 3.56 (1H, dd, J¼6.7, 8.2 Hz),
3.72 (1H, dt, J¼2.6, 6.6 Hz), 4.05 (1H, dd, J¼6.7, 8.1 Hz),
4.20 (1H, dt, J¼3.5, 6.2 Hz), 4.39 (1H, t, J¼2.5 Hz); 13C
NMR d ꢀ4.3, ꢀ4.2, 14.1, 18.1, 22.9, 23.8, 24.0, 25.2, 25.9
(3CH3), 27.8, 30.0, 32.7, 34.6, 36.2, 39.0, 66.9, 73.7, 75.8,
82.8, 110.3, 176.6; HRMS (ESI) calcd for C23H42O5SiNa
(MþNa)þ, 449.2699; found, 449.2694.
4.1.21. (4R,5S)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
[(1S)-1-hydroxypentyl]dihydrofuran-2(3H)-one 29
Following the reduction condition B, the keto-lactone 28
(100 mg, 0.32 mmol) was reduced to afford exclusively the
4.1.25. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(4S,5R)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]-3-phenyl-
selanyl-dihydro-furan-2-one 37
hydroxyl-lactone 29 (85 mg, 86%). IR 3440.8, 1779.2 cmꢀ1
;
1H NMR d 0.90 (3H, t, J¼6.8 Hz), 1.27e1.40 (6H, m),
1.44e1.63 (10H, m), 1.93e2.20 (2H, m), 2.59e2.67 (1H,
m), 3.61e3.70 (2H, m), 4.00e4.12 (3H, m); 13C NMR
d 14.0, 22.7, 23.8, 24.1, 25.0, 26.6, 30.5, 31.5, 34.9, 36.2,
42.0, 67.5, 71.2, 79.2, 82.3, 111.2, 176.4; HRMS (ESI) calcd
for C17H28O5Na (MþNa)þ, 335.1834; found, 335.1836.
Following the procedure for the alkylation of the lactone 19
the lithium enolate of the lactone 36 (150 mg, 0.35 mmol) gen-
erated with LDA was alkylated with PhSeBr to afford the lac-
1
tone 37 (150 mg, 73%) as a light yellow liquid. H NMR (of
diastereomeric mixture) d 0.10 (6H, br s), 0.98 (12H, br s),
1.28 (12H, m), 1.57 (4H, br s), 2.70 (1H, m), 3.68 (1H, d,
J¼5.8 Hz), 3.94e4.08 (3H, m), 4.18e4.33 (2H, m), 7.28e
7.40 (3H, m), 7.58e7.75 (2H, m); 13C NMR d ꢀ4.3, ꢀ3.9,
14.1, 14.3, 18.1, 22.8, 23.0, 23.8, 24.0, 25.2, 26.0 (3CH3),
26.1 (3CH3), 29.5, 29.8, 29.9 (grease), 32.1, 33.5, 34.6, 36.2,
37.5, 44.3, 46.0, 65.8, 66.1, 72.6, 73.2, 74.7, 75.7, 81.9, 82.1,
110.3, 110.4, 127.9, 128.6, 129.0 (2CH), 129.6 (2CH), 131.7,
134.9, 135.3 (2CH), 136.2 (2CH), 176.4; HRMS (ESI) calcd
for C29H46O5SeSiNa (MþNa)þ, 605.2180; found, 605.2177.
4.1.22. (3aR,4R,6S,6aS)-6-Butyl-4-hydroxytetrahydrofuro
[3,4-b]furan-2(3H)-one 34
Following the procedure for conversion of the hydroxy-lac-
tone 12 to the lactol 14, the hydroxy-lactone 24 (100 mg,
0.32 mmol) was converted to the hemiacetal 34 (52 mg,
80%) as colorless sticky liquid. IR 3471.6, 1774.4 cmꢀ1
;
[a]2D6 þ9.8 (c 1.64, CHCl3); 1H NMR d 0.91 (3H, t,
J¼6.9 Hz), 1.33e1.45 (4H, m), 1.68 (2H, m), 2.50 (1H, dd
J¼3.5, 18.6 Hz), 2.83 (1H, dd, J¼11.2, 18.6 Hz), 3.07 (1H,
ddd, J¼3.5, 7.0, 11.0 Hz), 4.24 (1H, dt, J¼3.6, 6.9 Hz), 4.99
(1H, dd, J¼3.6, 6.9 Hz), 5.32 (1H, s); 13C NMR d 14.1,
22.8, 28.3, 28.5, 32.2, 46.3, 80.2, 83.7, 103.1, 176.3; HRMS
(ESI) calcd for C10H16O4Na (MþNa)þ, 223.0946; found,
223.0944.
4.1.26. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(5R)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]-5H-furan-2-
one 38
Following the procedure described above for the conversion
of lactone 20 to unsaturated lactone 21 the lactone 37 (150 mg,

2368
S. Mondal, S. Ghosh / Tetrahedron 64 (2008) 2359e2368
0.35 mmol) was converted to unsaturated lactone 38 (109 mg,
100%). IR 1764.7 cmꢀ1; [a]D25 þ63.4 (c 0.65, CHCl3); 1H
NMR d 0.07 (3H, br s), 0.09 (3H, br s), 0.84e0.91 (12H,
m), 1.25e1.49 (8H, m), 1.61 (8H, br s), 3.85 (1H, t,
J¼7.6 Hz), 4.16 (1H, m), 4.31 (1H, dd, J¼6.6, 8.0 Hz), 4.88
(1H, t, J¼6.5 Hz), 5.05 (1H, s), 6.00 (1H, s); 13C NMR
d ꢀ4.6, ꢀ4.5, 14.1, 18.1, 22.7, 23.9, 24.0, 25.1, 25.9
(3CH3), 28.4, 32.7, 35.1, 36.0, 68.4, 71.8, 72.6, 86.6, 111.1,
117.6, 167.8, 176.4; HRMS (ESI) calcd for C23H40O5SiNa
(MþNa)þ, 447.2543; found, 447.2542.
4.1.30. (3aS,6R,6aR)-6-Butyltetrahydrofuro[3,4-b]furan-
2,4-dione (ꢀ)-35
Jones oxidation of lactol 41 (20 mg, 0.1 mmol) in acetone
following the usual procedure afforded the bis-lactone (ꢀ)-
35 (18 mg, 91%) as white crystal. Mp 83e85 ꢁC [(lit. 85e
85.5 ꢁC)]; IR 1770.5 cmꢀ1; [a]D26 ꢀ21.5 (c 1.09, CHCl3) [lit.
[a]2D3 ꢀ18.9 (c 4.79, CHCl3)]; HRMS (ESI) calcd for
C10H14O4Na (MþNa)þ, 221.0790; found, 221.0778.
Acknowledgements
4.1.27. 5-[1(R)-1-(tert-Butyl-dimethyl-silanyloxy)-pentyl]-
(4R,5R)-4-[(2S)-1,4-dioxa-spiro[4.5]dec-2-yl]dihydro-
furan-2-one 39
S.G. thanks Department of Science and Technology, Gov-
ernment of India for Ramanna Fellowship. S.M. thanks
CSIR, New Delhi for Junior Research Fellowship. We are
thankful to Professor D. Datta of Inorganic Chemistry Depart-
ment of this Institute for AM1 calculations.
A solution of the unsaturated lactone 38 (100 mg,
0.24 mmol) in EtOH (6 mL) was hydrogenated using PtO2
as catalyst to afford after column chromatography (etherepe-
troleum ether 1:9) the lactone 39 (70 mg, 70%) as colorless
oil. IR 1780.2 cmꢀ1; [a]D27 þ31.63 (c 0.43, CHCl3); 1H
NMR d 0.07 (3H, br s), 0.10 (3H, br s), 0.87 (12H, br s),
1.24e1.47 (8H, m), 1.55 (4H, br s), 1.59 (4H, br s), 2.15
(1H, dd, J¼3.7, 17.7 Hz), 2.51 (1H, m), 2.68 (1H, dd,
J¼10.0, 17.7 Hz), 3.54 (1H, t, J¼4.4 Hz), 3.68 (1H, m),
4.06 (2H, m), 4.54 (1H, br s); 13C NMR d ꢀ4.4, ꢀ4.0, 14.1,
18.1, 22.8, 23.9, 24.1, 25.2, 25.9 (3CH3), 27.6, 31.6, 33.4,
34.7, 36.6, 40.2, 67.4, 74.4, 77.2, 82.8, 110.4, 176.5; HRMS
(ESI) calcd for C23H42O5SiNa (MþNa)þ, 449.2699; found,
449.2689.
References and notes
1. McCorkindale, N. J.; Wright, J. L. C.; Brian, P. W.; Clarke, S. M.; Hutch-
inson, S. A. Tetrahedron Lett. 1968, 6, 727.
2. Krohn, K.; Ludewig, K.; Aust, H. J.; Draeger, S.; Schulz, B. J. Antibiot.
1994, 47, 113.
3. Abate, D.; Abraham, W.-R.; Meyer, H. Phytochemistry 1997, 44, 1443.
4. Al-Abed, Y.; Naz, N.; Mootoo, D.; Voelter, W. Tetrahedron Lett. 1996, 37,
8641.
5. Honda, T.; Kobayashi, Y.; Tsubuki, M. Tetrahedron 1993, 49, 1211.
6. Nubbemeyer, U. Synthesis 1993, 1120.
7. Sharma, G. V. M.; Vepachedu, S. R. Tetrahedron Lett. 1991, 47, 519.
8. Honda, T.; Kobayashi, Y.; Tsubuki, M. Tetrahedron Lett. 1990, 31, 4891.
9. Tochtermann, W.; Schroeder, G. R.; Snatzke, G.; Peters, E. M.; Peters, K.;
Von Schnering, H. G. Chem. Ber. 1988, 121, 1625.
10. Anderson, R. C.; Fraser-Reid, B. J. Org. Chem. 1985, 50, 4786.
11. Sakai, T.; Yoshida, M.; Kohmoto, S.; Utaka, M.; Takeda, A. Tetrahedron
Lett. 1982, 23, 5185.
4.1.28. (4R,5R)-4-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-5-
[(1R)-1-hydroxypentyl]dihydrofuran-2(3H)-one 40
Following the procedure of deprotection of the silyl group
of the lactone 22, the protected lactone 39 (70 mg, 0.16 mmol)
in tetrahydrofuran (5 mL) at 0 ꢁC was deprotected using tetra-
butylammonium fluoride (68 mg, 0.24 mmol) to afford after
column chromatography (ethyl acetateepetroleum ether 1:3)
the hydroxy-lactone 40 (42 mg, 82%) as a colorless liquid.
IR 3458.1, 1770.5 cmꢀ1; [a]D26 þ8.93 (c 2.06, CHCl3); 1H
NMR d 0.91 (3H, t, J¼6.8 Hz), 1.38 (6H, m), 1.55 (6H, br
s), 1.60 (4H, br s), 2.21 (1H, m), 2.60e2.76 (2H, m), 3.56e
3.67 (2H, m), 4.07 (2H, m), 4.45 (1H, t, J¼2.2); 13C NMR
d 14.1, 22.6, 23.9, 24.1, 25.1, 28.0, 31.7, 33.7, 34.8, 36.5,
40.4, 67.5, 72.9, 77.2, 84.6, 110.6, 176.4; HRMS (ESI) calcd
for C17H28O5Na (MþNa)þ, 335.1834; found, 335.1830.
12. Ohrui, H.; Sueda, N.; Kuzuhara, H. Nippon Kagaku Kaishi 1981, 769.
13. Anderson, R. C.; Fraser-Reid, B. Tetrahedron Lett. 1978, 35, 3233.
14. Tsuboi, S.; Muranaka, K.; Sakai, T.; Takeda, A. J. Org. Chem. 1986, 51,
4944.
15. Tsuboi, S.; Fujita, H.; Muranaka, K.; Seko, K.; Takeda, A. Chem. Lett.
1982, 1909.
16. Kosugi, H.; Sekiguchi, S.; Sekita, R.; Uda, H. Bull. Chem. Soc. Jpn. 1976,
49, 520.
17. Carlson, R. M.; Oyler, A. R. J. Org. Chem. 1976, 41, 4065.
18. Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara, K.; Yoshikoshi, A.
J. Org. Chem. 1975, 40, 1932.
19. Kato, M.; Tanaka, R.; Yoshikoshi, A. J. Chem. Soc., Chem. Commun.
1971, 1561.
4.1.29. (3aS,4S,6R,6aR)-6-Butyl-4-hydroxytetrahydrofuro
[3,4-b]furan-2(3H)-one 41
20. Sharma, G. V. M.; Krishnudu, K. Tetrahedron Lett. 1995, 36, 2661.
21. Yu, M.; Lynch, V.; Pagenkopf, B. L. Org. Lett. 2001, 3, 2563.
22. Ghosh, S.; Sinha, S.; Drew, M. G. B. Org. Lett. 2006, 8, 3781.
23. Banerjee, S.; Ghosh, S.; Sinha, S.; Ghosh, S. J. Org. Chem. 2005, 70,
4199.
Following the similar protocol as used for the conversion of
the hydroxy-lactone 12 to lactols 14, the hydroxy-lactone 40
(40 mg, 0.13 mmol) was converted to the lactol 41 (20 mg,
78%). IR 3471.6, 1770.5 cmꢀ1; [a]D25 ꢀ10.0 (c 0.2, CHCl3)
[lit. (mixture of lactols) [a]D ꢀ14.9 (c 1.0, CHCl3)]; HRMS
(ESI) calcd for C10H16O4Na (MþNa)þ, 223.0946; found,
223.0942.
24. Dess, D. B.; Martin, J. C. J. J. Am. Chem. Soc. 1991, 113, 7277.
25. Panda, J.; Ghosh, S. Tetrahedron Lett. 1999, 40, 6693.
26. AM1 calculations were performed by using Hyper Chem (version 6.0).
27. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. J. Am. Chem.
Soc. 1985, 107, 3902.