Efficient access to novel furanofurone compounds from quinic acid: Studies of inter-and intramolecular Wittig reactions on lactones

Article abstract of DOI:10.1055/s-2007-992356

(-)-Quinic acid has been converted into derivatives of a furo[3,2-b]furan-2-one system using Wittig olefination reactions of lactones. Studies for this transformation included the use of microwave-assisted reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992356

LETTER
3045
Efficient Access to Novel Furanofurone Compounds from Quinic Acid:
Studies of Inter-and Intramolecular Wittig Reactions on Lactones
I
nter-and Intram
ú
olecular
W
i
c
ttig Reactio
i
ns on L
a
actones Helena Brito Baptistella,* André de Carvalho Jorge
Instituto de Química, UNICAMP, CP 6154, 13084-971 Campinas, SP, Brazil
Fax +55(19)35213023; E-mail: lhbb@iqm.unicamp.br
Received 23 May 2007
So, with these premises in mind and envisaging the prep-
aration of new compounds with this core structure, we
proceeded to synthesize some derivatives like 4 from the
acetal quinide 3, a readily available derivative of quinic
acid (Scheme 1). For the preparation of the furone ring of
4, a Wittig olefination on the lactone system of 3, which
could occur, in principle, via an inter- or intramolecular
reaction, was explored.
Abstract: (–)-Quinic acid has been converted into derivatives of a
furo[3,2-b]furan-2-one system using Wittig olefination reactions of
lactones. Studies for this transformation included the use of micro-
wave-assisted reactions.
Key words: quinic acid, furanofurone systems, Wittig olefination
reactions on lactones, microwave-assisted reactions, heterocycles
The low reactivity of carboxylic acid derivatives towards
phosphoranylidenes is well known, but it is also known
that under forcing conditions, such as higher
temperatures11 or the use of microwave-assisted reac-
tions,12 some of these substrates may lead to heterosubsti-
tuted olefinic linkages in good yields. Treating the g-
lactone 33 with ethoxycarbonylmethylene(triphenyl)
phosphorane 5, either using reflux in toluene11a or using
long periods of heating in sealed vessels,11b the reactions
failed completely. The lactone was recovered and the
phosphorane did not withstand the applied conditions. In
a microwave-assisted reaction13 without solvents, as de-
scribed by Sabitha for other esters and amides,12 the start-
ing material 3 was also recovered intact. On the other
hand, using microwave irradiation in reactions in toluene
or more polar solvents such as chlorobenzene or diethyl-
ene glycol dimethyl ether, better results were obtained
(Scheme 2). With chlorobenzene as solvent and tempera-
tures varying in the range from 150–180 °C (reached in
about 15 min), it was possible to isolate two major prod-
ucts after one hour, the Z-olefin 6 (39%) and the unsatur-
ated furanofurone system 8 (46%), besides some
unchanged lactone 3 (10%).14
(–)-Quinic acid (1, Figure 1) is a very attractive starting
material for the synthesis of naturally occurring substanc-
es and related compounds,1 but, even considering its ver-
satile structure, only a few reports describe its use for the
preparation of oxygenated heterocycles.2–4 In the scope of
our ongoing work related to this utilization of quinic acid,3
we turned our attention to some fused oxyheterocycles,
especially to the furo[3,2-b]furan-2-one system 2
(Figure 1), present in a great number of interesting natural
products. These skeletons, also referred to as furanofu-
rones (or furano-furones), may be found, for example,
among styryl lactones,5 nortriterpenoids,6 iridoids7 and al-
kaloids,8 among others,9,10 and a great number of these
compounds present impressive pharmacological activity.
HOOC
OH
1
O
4
7
2
5
3
O
O 1
5
HO
OH
4
OH
1
2
Figure 1
Wittig reaction/
cyclization
O
H
O
OH
HOOC
HO
OH
R1
O
O
O
O
R2
OH
O
OH
R1 = R2 = CHO or derivatives
1
3
4
deprotection and
oxidative cleavage
Scheme 1
SYNLETT 2007, No. 19, pp 3045–3049
x
x
.x
x
.2
0
0
7
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-992356; Art ID: S03707ST
© Georg Thieme Verlag Stuttgart · New York

3046
L. H. B. Baptistella, A. de C. Jorge
LETTER
NaH, THF,
reflux, 3 h,
44%
O
O
O
OEt
OH
O
O
O
EtO
OH
OR
OH
Ph3P=CHCOOEt
5
O
O
O
O
O
+
+
+
O
O
O
O
O
MW
O
O
O
O
O
3
6
7*
8
9* R = Ac 1%
10* R = Et 4%
7%
* isolated under special conditions15
Scheme 2
From these results, our first consideration was a nonselec- 10, respectively, from 3 (Scheme 3). Previously reported
tive Wittig olefination of 3, with the furanofurone deriva- alkylation and acylation of amines by this Wittig reagent
tive 8 arising from a spontaneous cyclization of an E- in hydroxylic solvents17 supports this proposition.
olefin. However, when some minor products, isolated un-
It is not possible, with these results, to assert that 8 arose
der special conditions,15 were identified as the E-olefin 7,
only by an intramolecular Wittig reaction from 3; howev-
the ester 9, and the ether 10, and,16 additionally, the E-ole-
er, to test the ease of this transformation, the lactone 3 was
fin 7 was revealed to be very resistant to intramolecular
transesterification (see Scheme 2 – reflux of 7 with Et3N
or DBU in THF or toluene, or even microwave-assisted
treatment of 7 with the Wittig reagent 5, failed), we rea-
soned that two mechanistic routes might be occurring at
the same time: on the one hand, a microwave-assisted
Wittig olefination of the carbonyl group, leading to a mix-
ture of Z- and E-olefins 6 and 7, and on the other hand, an
initial transesterification of the phosphoranylidene re-
agent by 3, followed by an intramolecular Wittig reaction,
leading to 8 (Scheme 3). In this case, the ethanol released
in the first step would be involved in a sequence of proto-
nation and dissociation reactions, producing a ketene and
a phosphonium salt, reagents for the formation of 9 and
sequentially treated18 with bromoacetyl bromide, triphen-
ylphosphine, and DBU (Scheme 4). All steps were per-
formed without purification of the intermediates.19 Even
considering the steric hindrance of the tertiary hydroxyl
group of 3, this sequence provided 8 in very good yield
(Scheme 4 – 82% overall yield from 3), better than those
obtained under microwave-assisted olefination condi-
tions. The ease of the conversion [12 → 8] also supports
the transient formation of the ylide 11 under microwave-
assisted olefination of 3, as proposed in Scheme 3.
Concerning the stereoselectivity of the intermolecular mi-
crowave-assisted Wittig reaction of 3, it is also not possi-
ble to assert, with the results shown in Scheme 2, that the
PPh3
O
O
O
O
O
intramolecular
Wittig reaction
O
O
O
O
O
11
OAc
O
O
O
8
OH
Ph3P=CHCOOEt
O
3
5
O
H2C=C=O
O
+
O
MW
O
9
Ph3P=CHCOOEt
EtO–
O
transesterification
3
+
5
OEt
EtOH
+
Ph3P
O
O
OEt
+
3
–
EtO-PPh3 OEt
O
O
10
O
Scheme 3 Proposition for the synthesis of 8, 9, and 10 from 3
Synlett 2007, No. 19, 3045–3049 © Thieme Stuttgart · New York

LETTER
Inter-and Intramolecular Wittig Reactions on Lactones
3047
In a continuation of our synthesis, compound 8 was sub-
jected to a catalytic hydrogenation to give, after a slow re-
action (5 h), the saturated furanofurone 16 in quantitative
yield (Scheme 6). The deprotection of the diol system was
accomplished by a microwave-activated reaction with
aqueous acetic acid, giving 17 in 98% yield. Finally, with
the desired functionality on the cyclohexane system, an
oxidative cleavage was applied. After a slow reaction (24
h) with sodium periodate, the unstable dialdehyde 18 was
isolated in 81% yield. Reduction with sodium borohy-
dride gave the furanofurone diol 19 in 50% yield, which
was revealed to be a very polar compound. Better results
were achieved when 16 was treated with periodic acid,
followed by reduction of the crude aldehyde with sodium
borohydride. The desired diol 19 was isolated in 45%
yield.20 Additionally, a less polar furanofurone derivative
was also prepared from 18 (Scheme 6), using a Wittig re-
action with the ylide obtained from benzyltriphenylphos-
phonium bromide. By catalytic hydrogenation of the
resulting olefins 20, the branched furanofurone 21 was
isolated in 56% overall yield.21 A 1D NOESY experiment
on 21 did not show correlations between H4 and H7, and
presented sufficient characteristic NOE (between H7–
H6endo and H7–H3endo) to allow for the confirmation that
the C7 substituent was kept as exo.
Br
O
O
O
O
OH
BrCOCH2Br,
Et2O, pyridine,
0 °C to r.t., 2 h
O
O
O
O
89%
O
O
3
12
O
i. Ph3P, MeCN, r.t. to
50 °C, 2 h
ii. DBU, MeCN, –15 °C
to 50 °C, 15 min
O
O
92%
O
8
O
Scheme 4
ratio Z/E is 5.6:1 (as observed for 6:7), but applying the
same treatment on compound 13 (Scheme 5) with the ter-
tiary hydroxyl group protected, the ratio of Z/E tetrahy-
drofurylidene acetates 14:15 was 5:1 – almost the same.
Thus, this ratio may be considered as a good indication of
stereoselectivity of these lactones under microwave-as-
sisted Wittig olefination conditions.
O
O
EtO
OEt
O
OMe
OMe
OMe
5, chlorobenzene,
MW
O
O
O
+
55%
O
O
O
5 : 1
O
O
O
13
14
15
Scheme 5
i. H5IO6, EtOAc, r.t., 3 h
ii. NaBH4, EtOH, r.t., 30 min
45%
O
O
O
O
H
O
O
AcOH (75%),
MW, 95 °C, 15 min
O
H
2 (2.5 atm), Pd/C,
EtOAc, 5 h
H
H
O
HO
O
O
O
O
98%
O
quantitative
O
OH
HO
19
8
16
O
17
H
NaBH4, MeOH,
r.t., 30 min
O
O
OH
4
3
O
O
7
50%
NaIO4, MeOH,
r.t., 24 h
81%
H
O
6
H
18
O
64%
O
Ph
Br–Ph3P+CH2Ph
Ph3P
H
H
Ph
n-BuLi, THF
4
3
Ph
O
O
H2 (2.5 atm), Pd/C,
EtOAc, r.t., 5 h
7
O
O
O
6
87%
21
20
Ph
Ph
Scheme 6
Synlett 2007, No. 19, 3045–3049 © Thieme Stuttgart · New York

3048
L. H. B. Baptistella, A. de C. Jorge
LETTER
(11) (a) Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1;
and references cited therein. (b) Lakhrissi, M.; Chapleur, Y.
Angew. Chem., Int. Ed. Engl. 1996, 35, 750. (c) Lakhrissi,
Y.; Taillefumier, C.; Lakhrissi, M.; Chapleur, Y.
Tetrahedron: Asymmetry 2000, 11, 417.
In summary, investigation of microwave-assisted reac-
tions in the quinide system 3 permitted us to establish vi-
able routes to disubstituted derivatives of furanofurone
compounds from quinic acid. A direct microwave-assist-
ed treatment of 3 and stabilized phosphoranylidenes allow
us a better understanding of the possible pathways con-
cerning the Wittig olefinations of these a-hydroxy lactone
skeletons, but the best results concerning the desired prep-
arations were obtained when intramolecular Wittig reac-
tions were performed. The furanofurone dialdehyde 18
and some of its derivatives, such as the diol 19, the styryl
lactones 20, and the dialkylated compound 21 have been
prepared in good overall yields, and their cytotoxic activ-
ities, as well as those of their intermediates, are under in-
(12) Sabitha, G.; Reddy, M. M.; Srinivas, D.; Yadov, J. S.
Tetrahedron Lett. 1999, 40, 165.
(13) Microwave labstation MicroSYNTH (Millestone) operating
at 2.45 GHz, dual magnetron system with delivered
microwave power of 1000 W (pulsed irradiation), equipped
with a thermocouple temperature control system. All
experiments were conduced in sealed vessels (20 mL – the
volume of the reactions were no more than 10% of this) with
magnetic stirring.
(14) The lactone 3 was recovered intact when treated, with or
without the assistance of microwaves, with
diethylphosphonoacetate and bases (Horner–Wadsworth–
Emmons olefinations).
(15) Batches of several reaction mixtures were combined for
chromatographic purification.
vestigation.
Further
synthetic
applications
of
tetrahydrofurylidene 6 are also in progress in our labora-
tory.
(16) Reaction of Lactone 3 with Ph3PCHCOOEt under
Microwave Irradiation
Acknowledgment
A 20 mL microwave vessel (for reactions up to 4 bar)
containing a mixture of 3 (200 mg, 0.93 mmol), freshly
distilled chlorobenzene (2 mL), and ethoxycarbonyl-
methylene(triphenyl) phosphorane (5, 500 mg, 1.43 mmol)
was connected to a temperature sensor, and the apparatus
was irradiated for 1 h in a microwave equipment
programmed for temperature control: 15 min to reach
180 °C and then 1 h at this temperature. After cooling, the
mixture was evaporated. The residue was purified by silica
gel column chromatography (hexane–EtOAc 15%) to give 6
(39%) and 8 (46%), besides unchanged lactone 3 (10%).
When batches of several reaction mixtures were combined
for chromatographic purification, compounds 7 (7%), 9
(1%), and 10 (4%) were also isolated.
We are grateful to Prof. Paulo M. Imamura for his helpful discussi-
ons and Prof. Carol H. Collins for revising this manuscript. A.C.J.
thanks CNPq for a fellowship and we gratefully acknowledge FA-
PESP for financial support.
References and Notes
(1) (a) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini,
G. P.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515.
(b) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem.
Soc. 2005, 127, 5970. (c) Hanessian, S.; Wang, J.;
Montgomery, D.; Stoll, V.; Stewart, K. D.; Kati, W.; Maring,
C.; Kempf, D.; Hutchins, C.; Laver, W. G. Bioorg. Med.
Chem. Lett. 2002, 12, 3425.
(2) (a) Matsuo, K.; Matsumoto, T.; Nishiwaki, K. Heterocycles
1998, 48, 1213. (b) Matsuo, K.; Sugimura, W.; Shimizu, Y.;
Nishiwaki, K.; Kuwajima, H. Heterocycles 2000, 53, 1505.
(3) Baptistella, L. H. B.; Cerchiaro, G. Carbohydr. Res. 2004,
339, 665.
(4) Barnwell, M. G.; Hungerford, N. L.; Jolliffe, K. A. Org. Lett.
2004, 6, 2737.
(5) Cytotoxic compounds isolated from plants of Goniothala
mus species. See: (a) Ruiz, P.; Murga, J.; Carda, M.; Marco,
J. A. J. Org. Chem. 2005, 70, 713. (b) Lopez-Lazaro, M.;
Martin-Cordero, C.; Bermejo, A.; Cortés, D.; Ayuso, M. J.
Anticancer Res. 2001, 21, 3493.
(6) Found in plants of Schisandraceae family, used in Chinese
traditional medicine. See: Li, R.-T.; Li, S.-H.; Zhao, Q.-S.;
Lin, Z.-W.; Sun, H.-D.; Lu, Y.; Wang, C.; Zheng, Q.-T.
Tetrahedron Lett. 2003, 44, 3531.
(7) Isolated from plants of Scrophularia species and used in
Asian herbal medicine. See: Han, J. S.; Lowary, T. L. J. Org.
Chem. 2003, 68, 4116.
(8) Isolated from Stemona species, which present insecticidal
activities. See: Kaltenegger, E.; Brem, B.; Mereiter, K.;
Kalchhauser, H.; Kählig, H.; Hofer, O.; Vajrodaya, S.;
Greger, H. Phytochemistry 2003, 63, 803.
(9) A potent enzyme activator used for cardiac irregularities,
isolated from Caribbean sponges of the genus Plakortis. See:
Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124,
9718.
Compound 6: [a]D20 47.6 (c 0.58, CHCl3). IR (film): nmax
=
3392, 1687, 1650 cm–1. 1H NMR (500 MHz, CDCl3): d =
1.24 (t, 3 H, J = 7.0 Hz), 1.28 and 1.48 (2 × s, 2 × 3 H), 2.08
(dd, 1 H, J = 4.3, 13.7 Hz), 2.11 (dddd, 1 H, J = 1.0, 2.6, 6.1,
11.5 Hz), 2.27 (ddd, 1 H, J = 2.6, 8.2, 13.7 Hz), 2.38 (d, 1 H,
J = 11.5 Hz), 3.35 (br s, 1 H), 4.11 (q, 2 H, J = 7.0 Hz), 4.28
(ddd, 1 H, J = 1.0, 2.9, 6.2 Hz), 4.38 (ddd, 1 H, J = 4.3, 6.2,
8.2 Hz), 4.82 (dd, 1 H, J = 2.9, 6.1 Hz), 5.05 (s, 1 H). 13
C
NMR (125 MHz, CDCl3): d = 14.2, 24.7, 27.3, 36.0, 42.0,
59.8, 71.7, 72.6, 76.2, 79.8, 86.7, 110.0, 166.4, 174.6.
HRMS (EI): m/z calcd for C14H20O6: 284.12598; found:
284.12726.
Compound 8: mp 77.5–78.1 °C. [a]D20 –135.5 (c 0.34,
CHCl3). IR (KBr): nmax = 1767, 1664 cm–1. 1H NMR (500
MHz, CDCl3): d = 1.32 and 1.51 (2 × s, 2 × 3 H), 2.10 (ddd,
1 H, J = 2.1, 7.1, 15.1 Hz), 2.18 (dddd, 1 H, J = 1.9, 2.1, 6.3,
11.4 Hz), 2.59 (dd, 1 H, J = 1.6, 15.1 Hz), 2.74 (d, 1 H,
J = 11.4 Hz), 4.36 (dt, 1 H, J = 1.9, 7.1 Hz), 4.61 (tdd, 1 H,
J = 1.0, 1.6, 7.1 Hz), 4.87 (s, 1 H) 5.03 (ddd, 1 H, J = 1.0,
1.9, 6.3 Hz). 13C NMR (125 MHz, CDCl3): d = 24.0, 26.8,
32.7, 35.9, 71.8, 73.1, 82.4, 84.0, 89.2, 109.7, 173.4, 187.7.
HRMS (EI): m/z calcd for C12H14O5: 238.08412; found:
238.08394.
Compound 7: [a]D20 –47.7 (c 0.28, CHCl3). IR (film): nmax
=
3268, 1685, 1676 cm–1. 1H NMR (500 MHz, CDCl3): d =
1.29 (t, 3 H, J = 7.1 Hz), 1.32 and 1.51 (2 × s, 2 × 3 H), 2.09
(dd, 1 H, J = 4.9, 13.4 Hz), 2.27 (dddd, 1 H, J = 1.2, 2.5, 6.0,
11.7 Hz), 2.46 (d, 1 H, J = 11.7 Hz), 2.60 (ddd, 1 H, J = 2.5,
8.2, 13.4 Hz), 4.18 (m, 2 H), 4.21 (m, 1 H), 4.35 (ddd, 1 H,
J = 4.9, 6.3, 8.2 Hz), 4.78 (dd, 1 H, J = 3.0, 6.0 Hz), 5.30 (s,
1 H), 7.03 (s, 1 H). 13C NMR (125 MHz, CDCl3): d = 14.1,
(10) Compounds found in braconid wasps. See: Mereyala, H. B.;
Gadikota, R. R. Tetrahedron: Asymmetry 2000, 11, 743.
Synlett 2007, No. 19, 3045–3049 © Thieme Stuttgart · New York

LETTER
24.9, 27.3, 37.1, 41.6, 60.6, 71.9, 73.0, 76.3, 79.6, 90.5,
Inter-and Intramolecular Wittig Reactions on Lactones
3049
crystals; mp 85.0–87.5 °C. [a]D20 1.69 (c 1.4, CHCl3). IR
(KBr): nmax = 2809, 1759 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.34 and 1.53 (2 × s, 2 × 3 H), 2.37 (dd, 1 H, J = 3.3, 14.6
Hz), 2.50 (ddd, 1 H, J = 2.4, 7.2, 14.6 Hz), 2.63 (d, 1 H,
J = 11.4 Hz), 3.02 (dddd, 1 H, J = 1.3, 2.4, 6.2, 11.4 Hz),
3.88 (s, 2 H) 4.33 (ddd, 1 H, J = 1.3, 2.5, 7.2 Hz), 4.55 (td, 1
H, J = 3.3, 7.2 Hz), 4.80 (dd, 1 H, J = 2.5, 6.2 Hz). 13C NMR
(75 MHz, CDCl3): d = 24.3, 25.2, 26.9, 30.3, 35.3, 71.0,
72.3, 75.4, 77.6, 110.1, 165.4, 172.6. HRMS (EI): m/z calcd
for C12H15BrO6: 335.00862; found: 320.9851 [M – CH3]. 2)
Triphenylphosphine (188 mg, 0.72 mmol) was added to a
solution of 12 (200 mg, 0.6 mmol) in anhyd MeCN (2 mL)
at r.t.; and the resulting mixture was warmed to 50 °C and
maintained for 2 h. After cooling (–15 °C), DBU (73 mg,
0.48 mmol) was slowly added. The mixture was stirred at
this temperature for 10 min and then warmed to 50 °C for 15
min. The reaction was then cooled (0 °C), diluted with Et2O
(30 mL), and filtered through a short silica column, which
was washed with further Et2O. Evaporation of the solvent
and flash chromatography (hexane–EtOAc 15%) of the
crude residue gave 8 as a white crystalline solid in 92% yield
(131 mg).
110.0, 170.2, 180.2. HRMS (EI): m/z calcd for C14H20O6:
284.12598; found: 284.12315.
Compound 9: IR (film): nmax = 1802, 1748 cm–1. 1H NMR
(500 MHz, CDCl3): d = 1.33 and 1.52 (2 × s, 2 × 3 H), 2.12
(s, 3 H) 2.31 (dd, 1 H, J = 3.0, 14.5 Hz), 2.45 (ddd, 1 H,
J = 2.1, 7.3, 14.5 Hz), 2.54 (d, 1 H, J = 11.3 Hz), 3.05 (dddd,
1 H, J = 1.2, 2.1, 6.2, 11.3 Hz), 4.32 (ddd, 1 H, J = 1.2, 2.4,
7.3 Hz), 4.53 (td, 1 H, J = 3.0, 7.3 Hz), 4.78 (dd, 1 H, J = 2.4,
6.2 Hz). 13C NMR (125 MHz, CDCl3): d = 24.3, 26.9, 30.3,
35.5, 71.0, 72.4, 75.3, 76.0, 109.9, 169.2, 173.5. HRMS (EI):
m/z calcd for C12H16O6: 256.09468; found: 256.09362.
Compound 10: IR (film): nmax = 1791 cm–1. 1H NMR (500
MHz, CDCl3): d = 1.24 (t, 1 H, J = 7 Hz) 1.32 and 1.51
(2 × s, 2 × 3 H), 2.17 (m, 1 H), 2.39 (dd, 1 H, J = 1.8, 13.0
Hz), 2.42 (m, 2 H), 3.57 and 3.63 (2 × m, 2 × 1 H), 4.28 (dd,
1 H, J = 1.8, 6.8 Hz), 4.51 (td, 1 H, J = 2.5, 6.8 Hz), 4.67 (dd,
1 H, J = 2.5, 5.5 Hz). 13C NMR (125 MHz, CDCl3): d = 15.5,
24.3, 27.0, 30.3, 36.0, 60.2, 71.4, 72.3, 74.9, 76.5, 109.6,
175.9. HRMS (EI): m/z calcd for C12H18O5: 242.11543;
found: 242.11399.
(17) Desmaële, D. Tetrahedron Lett. 1996, 37, 1233.
(18) Bittner, C.; Burgo, A.; Murphy, P. J.; Sung, C. H.; Thornhill,
A. J. Tetrahedron Lett. 1999, 40, 3455.
(20) Small signals, always presented on the spectral data of crude
19, were attributed to the C7-epimer of 19 (less than 8%
yield). This compound probably arises from a minor C7-
epimer of the dialdehyde 18. A seven-membered lactone,
possible by intramolecular transesterification reaction of 19,
was not observed..
(21) Data for Compound 21 – [(4S,5S,7S)-7-(2-Phenylethyl)-
5-(3-phenylpropyl)tetrahydrofuro[3,2-b]furan-2 (3H)-
one]
(19) Preparation of 8 via the Bromoacetyl Derivative 12
1) A solution of 3 (200 mg, 0.93 mmol) in anhyd Et2O (15
mL), under argon atmosphere, was stirred at 0 °C, and anhyd
pyridine (100 mL, 1.2 mmol) was added, followed by
bromoacetyl bromide (100 mL, 1.15 mmol). The solution
was slowly warmed to r.t., in the absence of light, and the
stirring was maintained for 2 h. Then, H2O (15 mL) was
added and the aqueous layer was separated and extracted two
more times with Et2O (15 mL). The combined organic layers
were washed sequentially with H2O (25 mL), sat. CuSO4
solution (25 mL), H2O (25 mL) and brine (25 mL),
separated, and dried (MgSO4). After filtration, the solvent
was concentrated to give crude 12 in 89% yield (278 mg),
used without purification in the next step. For
[a]D20 –14.5 (c 0.27, CHCl3). IR (film): nmax = 1779 cm–1. 1H
NMR (500 MHz, CDCl3): d = 1.59 (dd, 1 H, J = 10.3, 13.4
Hz), 1.70–1.97 (m, 6 H), 2.37 (dd, 1 H, J = 4.6, 13.4 Hz),
2.61–2.79 (m, 4 H), 2.65 (d, 1 H, J = 18.8 Hz), 2.79 (dd, 1 H,
J = 6.2, 18.8 Hz), 4.46 (d, 1 H, J = 6.2 Hz), 4.73 (m, 1 H),
7.16–7.34 (m, 10 H). 13C NMR (125 MHz, CDCl3): d = 26.0,
32.2, 35.6, 36.2, 36.3, 37.0, 42.8, 77.7, 80.7, 96.5, 125.9,
126.0, 128.2, 128.3, 128.4, 141.2, 141.3, 175.5. HRMS (EI):
m/z calcd for C23H26O3: 350.45094; found: 350.45186.
characterization, a small sample was purified by flash
chromatography (hexane–EtOAc 20%), to give 12 as white
Synlett 2007, No. 19, 3045–3049 © Thieme Stuttgart · New York

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