Free radical 5-exo-dig cyclization as the key step in the synthesis of bis-butyrolactone natural products: Experimental and theoretical studies

Article abstract of DOI:10.1039/c1ob00019e

Radical cyclization reactions were performed by 5-exo-dig mode to yield cis-fused bicyclic systems, leading to the synthesis of bis-butyrolactone class of natural products. The study was aimed at understanding the impact of alkyl side chains of furanoside

Full text of DOI:10.1039/c1ob00019e

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PAPER
Free radical 5-exo-dig cyclization as the key step in the synthesis of
bis-butyrolactone natural products: experimental and theoretical studies†‡
Gangavaram V. M. Sharma,*a Devoju Harinada Chary,a Nagula Chandramouli,a Florian Achrainer,b
Sateesh Patrudub and Hendrik Zipse*b
Received 5th January 2011, Accepted 5th April 2011
DOI: 10.1039/c1ob00019e
Radical cyclization reactions were performed by 5-exo-dig mode to yield cis-fused bicyclic systems,
leading to the synthesis of bis-butyrolactone class of natural products. The study was aimed at
understanding the impact of alkyl side chains of furanoside ring systems in L-ara configuration on the
radical cyclization. It was amply demonstrated by experimental studies that the increase in the length of
the alkyl side chain has an effect on the cyclization: while efficient cyclization reactions could be
realized with methyl and ethyl side chains, the yields were significantly reduced in the case of n-pentyl
side chain. Theoretical studies using DFT and (RO)MP2 methods were carried out to analyze the
influence of the substitution pattern on the cyclization barriers.
Introduction
Radical cyclization reactions1 for the synthesis of cyclic carbon
frameworks, particularly the cis-fused bicyclic system, is a simple
and prominent protocol. Utilization of a 5-exo-dig2 mode of
cyclization of a suitably substituted 5-hexynyl radical onto the
alkyne is usually a highly regioselective reaction and efficient
at introducing an exo-methylene group. Application of radical
cyclization on carbohydrate derived precursors has found wide
utility, while the above strategies were successfully adopted by
our group for the synthesis of natural products containing
bis-butyrolactone moieties. In our earlier studies, a 5-exo-dig
radical cyclization approach was efficiently utilized for the syn-
thesis of avenaciolide3 (1), 4-epi-ethisolide4 (2), discosiolide5 (3),
canadensolide6,7 (4) and sporothriolide4 (5), besides xylobovide.8
For the synthesis of 1–5 (Scheme 1), the corresponding radical
intermediates 6 and 7 were derived from diacetone glucose (DAG)
8. The cyclization was found to be successful in giving the cis-
Scheme 1 Retrosynthetic analysis of 1–5 and 9.
fused bicyclic systems along with the concomitant introduction
of the exo-methylene group. In further studies, a similar strategy
was used for the synthesis of iso-avenaciolide9 (9), a structurally
related natural product, wherein the attempt at the cyclization
of the radical intermediate 10, generated from 8 or L-arabinose
derivative 11,9c met with failure and the synthesis of 9 could not
be achieved by the above protocol.
Results and discussion
aOrganic Chemistry Division III, Indian Institute of Chemical Technology
(CSIR), Hyderabad, India. E-mail: esmvee@iict.res.in
The successful synthesis of 1–5 (Scheme 1), and failure to attain
9 inferred that: (a) the systems with D-xylo configuration undergo
a facile cyclization and (b) the systems with L-ara configuration
resisted doing so. The above observations on the resistance of 10
to undergo radical cyclization prompted us to study the impact
of the side chain on radical cyclization reactions. Based on the
retrosynthetic analysis (Scheme 2), synthesis of cis-fused bicyclic
systems 12a–12c and 13a–13c could be achieved through the
bDepartment of Chemistry, LMU Mu¨nchen, Butenandtstrasse 5-13, D-
81377 Mu¨nchen, Germany. E-mail: zipse@cup.lmu.de
† This work is dedicated to the memory of Athel Beckwith, a great teacher
and a true pioneer in the area of radical chemistry.
‡ Electronic supplementary information (ESI) available: Analytical data
and synthetic details for all synthesized compounds, energies and
structures obtained in DFT and ab initio calculations. See DOI:
10.1039/c1ob00019e
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the successful synthesis of cis-fused bicyclic systems 12b (71%)
and 13b (60%) respectively. A similar study was conducted on the
radical precursors 14c (b-) and 15c (a-). Unlike in the case of
14a–b and 15a–b, the b-anomer 14c underwent radical cyclization
reaction to give cis-fused bicyclic system albeit in a very poor yield
(14%), while 15c totally resisted undergoing cyclization. Thus, it is
pertinent to mention that cyclization products with methyl or ethyl
side chains were obtained in better yields from the b-anomers over
the a-anomers. In the case of n-pentyl side chain, the a-anomer
failed to give the cyclization product and the b-anomer gave the
product in very poor yield. These results on the n-pentyl side chain
very well complement the results obtained earlier with an n-octyl
side chain. Thus, it is evident to mention that the side chain in
L-ara configuration has a role to play in the 5-exo-dig radical
cyclizations.
Scheme 2 Retrosynthetic analysis of 12 and 13.
xanthates 14a–14c and 15a–15c, which in turn could be derived
from 11.
Anomeric mixtures of 23a, 23b and 23c (Scheme 3), prepared
from L-arabinose (see ESI‡),10 independently on reaction with
propargyl bromide in the presence of NaH in dry THF furnished
the required propargyl derivatives 24a–c and 25a–c respectively.
Both the b-anomers 24a–c and a-anomers 25a–c were indepen-
dently subjected to oxidative deprotection of the PMB group
with DDQ in wet CH2Cl2 to give alcohols 26a–c and 27a–c
respectively. The alcohols 26a–c and 27a–c on reaction with NaH
and carbon disulfide followed by methyl iodide were converted into
the corresponding xanthate esters 14a–c and 15a–c respectively.
Synthesis of ethisolide
Ethisolide (28), iso-avenaciolide (9) and avenaciolide (1) are three
bis-lactone secondary mold metabolites isolated from broths of
Aspergillus and Penicillium species, and have been reported to
possess antifungal and antibacterial activities. Ethisolide (28) has
similar structural features to iso-avenaciolide (9), except for an
ethyl side chain. However, it differs from avenaciolide (1) and 4-
epi-ethisolide (2) in being a positional isomer. During the studies,
the radical reactions with different side chains, synthesis of 12b and
13b (Scheme 3) has been achieved successfully. The conversion of
12b into ethisolide (28) has already been reported11 in the literature,
and this study thus formally concludes the total synthesis of
ethisolide 28.
Theoretical studies on 5-exo-dig cyclizations in selected systems
derived from the tetrahydrofuran skeleton
In order to shed some light on the influence of the substituents
present in precursor 15 on the efficiency of the subsequent 5-exo-
dig cyclization processes, theoretical studies were undertaken for
a series of radicals in which the a-configuration of the methoxy
group at C-5 was kept constant, while the stereochemistry and
the substitution pattern at the C-2 position was allowed to
vary (Scheme 4). The influence of the configuration at the C-2
position on the reaction barrier and reaction enthalpy for the
cyclization step was first studied for R = CH3 (Table 1). As
Scheme 3 Synthesis of intermediates 12 and 13.
Having prepared the radical precursors, the stage was set for
radical cyclization reactions. Accordingly, 14a and 15a (Scheme 3),
with a methyl side chain were subjected to radical reaction with
n-Bu3SnH in the presence of catalytic amounts of AIBN in dry
benzene at reflux for 12 h. Interestingly, unlike 10 with the n-
octyl side chain, both 14a and 15a underwent cyclization to
give the respective cyclized products 12a (69%) and 13a (57%)
(Scheme 3). Further, radical cyclization was next attempted on
14b (b-) and 15b (a-) with an ethyl side chain, which resulted in
Scheme 4 5-Exo-dig cyclizations in selected systems derived from the
tetrahydrofuran skeleton.
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Table 1 Boltzmann-averaged activation and reaction enthalpies for the
equal intermolecular trapping rates for radicals 31a and 34a with
hydrogen donors, this indicates that cyclization of 29a may be low
yielding under conditions optimized for the reaction of 32a.
In Fig. 1 the most stable conformers of 29a and 32a are
shown together with the respective transition states and reaction
products. Only one low energy conformation could be found for
the orientation of the methoxy group at C5 due to the presence
of a strong exo-anomeric effect. For the cyclized product radicals
two configurations at the newly formed double bond are possible.
For both products 31a and 34a we find that the Z-configuration
is more favourable than the E-configuration (see ESI‡ for further
details).
In order to explore possible reasons for the unusual chain length
dependence observed in radical cyclization reactions involving
precursor 15a–15c, the reaction pathways of all-cis substituted
tetrahydrofuran models 29a–d were examined varying the size
of the side chain from methyl, ethyl, n-propyl to n-butyl. At
the UB3LYP/6-311+G(d,p)//UB3LYP/6-31G(d) level of theory
we find that extending the side chain from R = Me to R = Et
leads to marginally lower barriers, in full agreement with the
experimental studies. However, further extension of the sidechain
to R = n-propyl or n-butyl led to only marginally higher barriers.
These largely similar reaction barriers are accompanied by equally
similar reaction energies (Table 1).
Since the DFT hybrid functional UB3LYP does not take dis-
persion effects into account properly we also performed restricted
open-shell MP2 ((RO)MP2) single point calculations using the
large G3MP2large basis set.12 Reaction barriers calculated at
(RO)MP2 level are uniformly lower than UB3LYP barriers by
approx. 10 kJ mol-1 and reaction energies are larger by approx.
14 kJ mol-1 in all cases. However, also at ROMP2 level the barrier
differences for cyclization of radicals 29a–d remain quite small.
Thus, while the calculated reaction barriers and reaction energies
for cyclization of radicals 29a and 32a clearly respond to the
stereochemistry selected at C2, the calculations performed for
cyclization of radicals 29a–d do not provide an answer for the
systems described in Scheme 4 (in kJ mol-1)
DH‡298(30-29) DH298(31-29) DH‡298(33-32) DH298(34-32)
a: R = CH3
UB3LYPa
ROMP2b
+33.51
+25.60
-64.90
-78.86
+29.10
+22.63
-74.02
-86.03
b: R = C2H5
UB3LYPa
ROMP2b
c: R = n-C3H7
UB3LYPa
ROMP2b
d: R = n-C4H9
UB3LYPa
ROMP2b
+32.30
+23.83
-64.82
-78.81
n/a
n/a
n/a
n/a
+33.15
+24.44
-64.24
-78.75
n/a
n/a
n/a
n/a
+33.72
-63.81
-78.66
n/a
n/a
n/a
n/a
+24.79
a UB3LYP/6-311+G(d,p)//UB3LYP/6-31G(d).
b (RO)MP2(FC)/G3MP2large//UB3LYP/6-31G(d).
previously anticipated we find here that the reaction barrier for
cyclization of radical 29a is somewhat larger at DH‡298(30a-29a) =
+33.51 kJ mol-1 as compared to the barrier for cyclization of
radical 32a with DH‡298(33a-32a) = +29.10 kJ mol-1 at UB3LYP/6-
311+G(d,p) level of theory. The higher barrier for cyclization
of 29a is undoubtedly due to the all-cis stereochemistry in
this system, which is also reflected in the reaction energy for
formation of product 31a. Comparing the differences in barriers
of DDH‡298(30a-33a) = +4.41 kJ mol-1 with differences in reaction
energies of DDH298(31a-34a) = +9.12 kJ mol-1 we may also
conclude that approx. 50% of the strain energy present in the
product radicals is already present in the respective transition
states. According to the Eyring equation, the cyclization rates
depend on the activation energies in an exponential manner.
Assuming identical activation entropies for both processes we
can use the expression k34a/k31a = exp((DH‡ - DH‡31a)/RT) =
34a
5.8 to predict that the cyclization rate for 32a will be 5.8 times
faster than that for 29a at a temperature of 298.15 K. Assuming
Fig. 1 Structures of the most stable conformers of 29a and 32a together with the corresponding transition states and reaction products as obtained at
UB3LYP/6-31G(d) level of theory (distances are given in pm).
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largely reduced yields in cyclization reactions of radicals 29 with
longer alkyl substituents at C2 position. These may, of course, not
only be due to problems with the actual cyclization step, but may
also reflect problems with other steps of the radical chain reaction.
0.93 mmol) was added to the reaction mixture at 0 ◦C and stirred
at room temperature for 4 h. Reaction mixture was quenched with
aq. NH4Cl solution (3 mL) and extracted with ethyl acetate (2 ¥
10 mL). Organic layer was washed with water (5 mL), brine (5 mL),
dried (Na2SO4), evaporated andthe residue was purified by column
chromatography. First eluted (60–120 Silica gel; ethyl acetate–n-
hexane, 1.2 : 8.8) was 24a (0.13 g, 45%) as a liquid; [a]D = -218.2
(c 0.66, chloroform); IR (neat): nmax 3451, 3282, 2924, 1720, 1611,
Conclusion
The manuscript describes theoretical and experimental studies on
the impact of the side chains at the C2 and C5 positions on 5-
exo-dig radical cyclization reactions in radicals derived from L-
arabinose. While the stereochemistry at the anomeric C5 position
remains without much consequence in the cyclization reactions,
the length of the substituent at the C2 position has a marked effect
on cyclization yields: while extension of the C2 substituent from
methyl to ethyl leads to slightly increased yields, the cyclization
becomes much more difficult for the n-pentyl substituted system.
Theoretical studies of cyclization reactions indicate that the
stereochemistry at the C2 position has a significant impact on
the cyclization barriers. The theoretical studies also indicate
that variation of the substituent from methyl to ethyl leads to
a minor reduction in reaction barriers, in full agreement with
experiment. Further extension of the C2 substituent to n-propyl
and n-butyl does not lead to drastically altered cyclization barriers
and suggests that the largely reduced reaction yields observed
experimentally are due to other factors in the overall chain
reaction.
1513, 1248, 1100, 1065, 1050, 943, 771 cm-1 1H NMR (300 MHz,
;
CDCl3): d 1.25 (d, 3H, J = 6.0 Hz, CH3), 2.42 (t, 1H, J = 2.2 Hz,
acetylenic), 3.33 (s, 3H, OCH3), 3.42–3.46 (q, 1H, J = 3.7, 7.5 Hz,
H-3), 3.77 (s, 3H, Ar–OCH3), 3.94–4.19 (m, 4H, H-2, H-4 and
OCH2), 4.43–4.62 (dd, 2H, J = 11.7 Hz, Ar–OCH2), 4.77 (s, 1H,
H-5), 6.82 (d, 2H, J = 8.3 Hz, Ar–H), 7.22 (d, 2H, J = 8.6 Hz,
Ar–H); 13C NMR (CDCl3, 100 MHz): d 159.1, 129.8, 129.3 (2C),
113.7 (2C), 106.5, 88.4, 87.9, 76.6, 74.9, 71.8, 57.2, 54.6, 54.5, 18.6;
HRMS (ESI): m/z calculated for C17H22NaO5(M++Na) 329.1364,
found 329.1354.
Second eluted (60–120 Silica gel; ethyl acetate–n-hexane,
1.2 : 8.8) was 25a (0.09 g, 31%) as colourless liquid; [a]D = +129.0
(c 0.36, chloroform); IR (neat): nmax 3448, 3282, 1720, 1636, 771,
600 cm-1 1H NMR (300 MHz, CDCl3): d 1.28 (d, 3H, J = 6.4 Hz,
;
CH3), 2.42 (t, 1H, J = 2.2 Hz, acetylenic), 3.38 (s, 3H, OCH3), 3.78
(s, 3H, Ar–OCH3), 3.85 (t, 1H, J = 6.4 Hz, H-3), 3.95 (p, 1H, J =
6.0, 12.4 Hz, H-2), 4.15–4.31 (m, 3H, H-4, OCH2), 4.45–4.64 (dd,
2H, J = 11.3 Hz, Ar–OCH2), 4.83 (d, 1H, J = 4.1 Hz, H-5), 6.82
(d, 2H, J = 8.3 Hz, Ar–H), 7.22 (d, 2H, J = 8.6 Hz, Ar–H). 13C
NMR (CDCl3, 75 MHz): d 159.2, 130.1, 129.4 (2C), 113.8 (2C),
101.2, 86.4, 83.7, 77.6, 75.1, 72.0, 57.5, 55.2, 54.7, 22.1; HRMS
(ESI): m/z calculated for C17H22NaO5(M++Na) 329.1364, found
329.1367.
Experimental part
General experimental details
Solvents were dried over standard drying agents and freshly dis-
tilled prior to use. All commercially available chemicals were used
without further purification. All reactions were performed under
Nitrogen. 1H NMR (200 MHz, 300 MHz, 400 MHz and 500 MHz)
and 13C NMR (75 MHz) spectra were measured with a Varian
Gemini FT-200 MHz spectrometer, Bruker Avance 300 MHz,
Unity 400 MHz and Inova-500 MHz with tetramethylsilane as
internal standard for solutions in deuteriochloroform. J values
are given in Hz. Chemical shifts were reported in ppm relative
to the solvent signal. Multiplicities are indicated as follows: s
(singlet); d (doublet); t (triplet); q (quartet); m (multiplet); dd
(doublet of doublets); quin (quintet). All column chromatographic
separations were performed using silica gel (Acme’s, 60–120
mesh). Organic solutions were dried over anhydrous Na2SO4 and
concentrated below 40 ◦C in vacuo. IR spectra were recorded
on a Perkin–Elmer IR-683 spectrophotometer with NaCl optics.
Optical rotations were measured with JASCO DIP 300 digital
polarimeter at 25 ◦C. Mass spectra were recorded on CEC-21-
11013 or Fannigan Mat 1210 double focusing mass spectrometers
operating at a direct inlet system or LC/MSD Trap SL (Agilent
Technologies).
(2S,3S,4R,5R)-Tetrahydro-5-methoxy-2-methyl-4-(prop-2-nylo-
xy)furan-3-ol (26a). A solution of 24a (0.22 g, 0.71 mmol) in
aq. CH2Cl2 (1 : 19, H2O–CH2Cl2, 10 mL) was treated with DDQ
(0.32 g, 1.43 mmol) at 0 ◦C and stirred for 2 h. The reaction
mixture was quenched with aq. NaHCO3 solution (7 mL) and
extracted with CH2Cl2 (2 ¥ 15 mL). Organic layer was washed
with aq. NaHCO3 solution (10 mL), water (10 mL), brine (10 mL)
and dried (Na2SO4). Evaporation of the solvent and purification
of residue obtained by chromatography (60–120 Silica gel; ethyl
acetate–n-hexane, 1 : 4) afforded 26a (0.12 g, 94%) as a liquid;
[a]D = -65.2 (c 1.53, CDCl3); IR (neat): nmax 3447, 2925, 2854,
1741, 1219, 771 cm-1 1H NMR (200 MHz, CDCl3): d 1.29 (d, 3H,
;
J = 6.2 Hz, CH3), 2.44 (t, 1H, J = 2.5 Hz, acetylenic), 2.66 (bd,
1H, OH), 3.36 (s, 3H, OCH3), 3.69 (bs, 1H, H-3), 3.90 (d, 1H, J =
2.9 Hz, H-2), 3.99 (t, 1H, J = 5.8 Hz, H-4), 4.22 (t, 2H, J = 2.5 Hz,
OCH2), 4.84 (s, 1H, H-5); 13C NMR (CDCl3, 75 MHz): d 106.4,
88.8, 80.5, 80.1, 75.0, 57.4, 54.7, 29.6, 18.6; HRMS (ESI): m/z
calculated for C9H14NaO4(M++Na) 209.0789, found 209.0793.
(2S,3S,4R,5S)-Tetrahydro-5-methoxy-2-methyl-4-(prop-2-yny-
loxy)furan-3-ol (27a). A solution of 25a (0.39 g, 1.27 mmol) in
aq. CH2Cl2 (1 : 19, H2O–CH2Cl2, 10 mL) was treated with DDQ
(0.58 g, 2.54 mmol) at 0 ◦C as described for 26a. Work up and
purification by column chromatography (60–120 Silica gel; ethyl
acetate–n-hexane, 1 : 4) afforded 27a (0.21 g, 89%) as a liquid;
[a]D = +284.1 (c 0.44, CDCl3); IR (neat): nmax 3437, 2926, 2856,
(2S,3S,4R,5R)-3-(4-Methoxybenzyloxy)-tetrahydro-5-metho-
xy-2-methyl-4-(prop-2-ynyloxy)furan (24a) and (2S,3S,4R,5S)-3-
(4-methoxybenzyloxy)-tetrahydro-5-methoxy-2-methyl-4-(prop-2-
ynyloxy)furan (25a). A stirred suspension of sodium hydride
(0.04 g, 2.14 mmol) in dry THF (5 mL) under N2 atmosphere
was treated with a solution of 23a (0.25 g, 0.93 mmol) in THF
(3 mL) at 0 ◦C and stirred for 15 min. Propargyl bromide (0.08 mL,
1737, 1219, 1051, 769 cm-1 1H NMR (300 MHz, CDCl3): d 1.33
;
(d, 3H, J = 6.4 Hz, CH3), 2.45 (t, 1H, J = 2.2 Hz, acetylenic), 3.38
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(s, 3H, OCH3), 3.87 (p, 1H, J = 6.42, 12.8 Hz, H-3), 4.07–3.95 (m,
2H, H-2, H-4), 4.16–4.38 (ddd, 2H, J = 2.2, 16.2 Hz, OCH2), 4.81
(d, 1H, J = 3.8 Hz, H-5); 13C NMR (CDCl3, 75 MHz): d 100.7,
84.1, 79.2, 77.9, 75.2, 57.6, 54.6, 31.5, 21.0; HRMS (ESI): m/z
calculated for C9H14NaO4(M++Na) 209.0789, found 209.0797.
1H NMR (400 MHz, CDCl3): d 1.25 (d, 3H, J = 9.0 Hz, CH3), 3.18
(t, 1H, J = 6.8 Hz, H-3a), 3.31–3.40 (m, 4H, H-4, OCH3), 4.19–4.30
(m, 2H, OCH2), 4.53 (d, 1H, J = 3.8 Hz, H-6a), 4.81 (s, 1H, H-6),
4.90 (d, 1H, J = 1.5 Hz, olefinic), 5.08 (d, 1H, J = 2.2 Hz, olefinic);
13C NMR (CDCl3, 75 MHz): d 146.3, 107.5, 106.2, 85.2, 74.5, 73.0,
54.7, 52.8, 29.6; HRMS (ESI): m/z calculated for C9H15O3(M++H)
171.1021, found 171.1023.
O-(2S,3S,4R,5R)-Tetrahydro-5-methoxy-2-methyl-4-(prop-2-
ynyloxy)furan-3-yl-S-methyl carbonodithioate (14a). A stirred
suspension of NaH (0.05 g, 2.25 mmol) in dry THF (3 mL)
under N2 atmosphere was treated with a solution of 26a (0.14 g,
0.75 mmol) in THF (3 mL) at 0 ◦C and stirred at room temperature
fo◦r 30 min. Carbon disulfide (0.07 mL, 1.12 mmol) was added at
0 C and stirred at room temperature for 30 min. Methyl iodide
(0.07 mL, 1.12 mmol) was added at 0 ◦C and stirred at room
temperature for 2 h. The reaction mixture was quenched with aq.
NH4Cl solution (4 mL) and extracted with ethyl acetate (3 ¥ 5 mL).
Organic layer was washed with water (6 mL), brine (6 mL), dried
(Na2SO4) and evaporated. Purification of the residue by column
chromatography (60–120 Silica gel; ethyl acetate–n-hexane, 1 : 9)
afforded 14a (0.18 g, 89%) as light yellow liquid; [a]D = -304.2
(c 1.04, CDCl3); IR (neat): nmax 3448, 2921, 2851, 1724, 1460,
(3aR,4S,6R,6aR)-Hexahydro-6-methoxy-4-methyl-3-methyle-
nefuro[3,4-b]furan (13a). A solution of 15a (0.85 g, 3.07 mmol)
in dry benzene (25 mL) under N2 atmosphere was treated with
n-Bu3SnH (1.65 mL, 6.15 mmol) as described for 12a. Work up
and column chromatographic purification (60–120 Silica gel, ethyl
acetate–n-hexane, 0.7 : 9.3) gave 13a (0.30 g, 57%) as a colorless
liquid; [a]D = -2.44 (c 0.33, CDCl3); IR (neat): nmax 2923, 2853,
1732, 1654, 1461, 1261, 1029, 869, 723 cm-1 1H NMR (400 MHz,
;
CDCl3): d 1.23 (d, 3H, J = 6.5 Hz, CH3), 3.23 (t, 1H, J = 5.8 Hz,
H-3a), 3.50 (s, 3H, OCH3), 4.06 (m, 1H, H-4), 4.28–4.38 (m, 2H,
OCH2), 4.61 (q, 1H, H-6a), 4.67 (d, 1H, J = 3.6 Hz, H-6), 4.89 (d,
1H, J = 2.1 Hz, olefinic), 5.08 (d, 1H, J = 2.1 Hz, olefinic); 13C NMR
(CDCl3, 75 MHz): d 146.3, 108.0, 105.2, 83.7, 73.9, 73.7, 57.7,
50.5, 29.4; HRMS (ESI): m/z calculated for C9H14NaO3(M++Na)
193.0840, found 193.0839.
1250, 1071, 771 cm-1 1H NMR (400 MHz, CDCl3): d 1.43 (d,
;
3H, J = 6.2 Hz, CH3), 2.47 (t, 1H, J = 2.2 Hz, acetylenic), 2.57
(s, 3H, SCH3), 3.38 (s, 4H, H-2, OCH3), 4.19 (s, 1H, H-4), 4.30
(s, 2H, OCH2), 5.0 (s, 1H, H-5), 5.61 (d, 1H, J = 3.3 Hz, H-
3); 13C NMR (CDCl3, 75 MHz): d 214.7, 107.3, 96.3, 86.3, 84.5,
76.3, 75.3, 57.8, 55.2, 18.9, 15.8; HRMS (ESI): m/z calculated for
C11H16NaO4S2(M++Na) 299.0387, found 299.0391.
(3aR,4S,6R,6aR)-4-Ethyl-hexahydro-6-methoxy-3-methyle-
nefuro[3,4-b]furan (12b). A solution of 14b (0.10 g, 0.34 mmol)
in dry benzene (25 mL) on reaction with n-Bu3SnH (0.18 mL,
0.68 mmol) and catalytic amount of AIBN as described for 12a.
Work up and column chromatographic purification (60–120 Silica
gel, ethyl acetate–n-hexane, 0.7 : 9.3) gave 12b (0.04 g, 71%) as a
colorless liquid; [a]D = -49.2 (c 0.23, CDCl3); IR (neat): nmax 3437,
O-(2S,3S,4R,5S)-Tetrahydro-5-methoxy-2-methyl-4-(prop-2-
ynyloxy)furan-3-yl-S-methyl carbonodithioate (15a). A stirred
suspension of NaH (0.05 g, 2.25 mmol) in dry THF (5 mL)
under N2 atmosphere was treated with a solution of 27a (0.14 g,
0.75 mmol) in THF (4 mL) at 0 ◦C and stirred at room temperature
fo◦r 30 min. Carbon disulfide (0.07 mL, 1.12 mmol) was added at
0 C and stirred at room temperature for 30 min. Methyl iodide
(0.07 mL, 1.12 mmol) was added at 0 ◦C work up as described for
14a and purification of the residue by column chromatography
(60–120 Silica gel; ethyl acetate–n-hexane, 1 : 9) afforded 15a
(0.18 g, 86%) as light yellow liquid; [a]D = +285.1 (c 0.44, CDCl3);
IR (neat): nmax 3285, 2924, 2858, 2120, 1712, 1446, 1210, 1064,
2926, 2856, 1737, 1219, 1051, 769 cm-1 1H NMR (300 MHz,
;
CDCl3): d 1.01 (t, 3H, J = 7.3 Hz, CH3), 1.49 (m, 2H, CH2), 3.19
(t, 1H, J = 7.1 Hz, H-3a), 3.29 (s, 3H, OCH3), 3.94 (m, 1H, H-4),
4.16 (m, 2H, J = 1.7, 3.5 Hz, OCH2), 4.53 (d, 1H, J = 6.4 Hz,
H-6a), 4.81 (s, 1H, H-6), 4.92 (q, 1H, J = 1.7 Hz, olefinic) 5.06 (q,
1H, J = 1.5 Hz, olefinic); 13C NMR (CDCl3, 75 MHz): d 147.1,
107.7, 96.2, 88.5, 80.9, 72.6, 54.1, 50.0, 24.3, 11.4; HRMS (ESI):
m/z calculated for C10H17O3(M++H) 185.1177, found 185.1170.
(3aR,4S,6S,6aR)-4-Ethyl-hexahydro-6-methoxy-3-methylene-
furo[3,4-b]furan (13b). A solution of 15b (0.10 g, 0.34 mmol)
in dry benzene (25 mL) on reaction with n-Bu3SnH (0.18 mL,
0.68 mmol) and catalytic amount of AIBN as described for 13a.
Work up and column chromatographic purification (60–120 Silica
gel, ethyl acetate–n-hexane, 0.9 : 9.1) gave 13b (0.03 g, 60%) as
a colorless liquid; [a]D = -285.8 (c 0.23, CDCl3); IR (neat): nmax
669 cm-1 1H NMR (300 MHz, CDCl3): d 1.50 (d, 3H, J = 6.4 Hz,
;
CH3), 2.42 (t, 1H, J = 2.2 Hz, acetylenic), 2.58 (s, 3H, SCH3), 3.44
(s, 3H, OCH3), 4.06 (m, 1H, H-2), 4.25 (t, 2H, J = 2.2 Hz, OCH2),
4.45 (t, 1H, J = 5.2 Hz, H-4), 4.95 (d, 1H, J = 4.5 Hz, H-5), 5.90 (q,
1H, J = 4.1 Hz, H-3); 13C NMR (CDCl3, 100 MHz): d 214.9, 106.9,
88.7, 86.3, 78.7, 78.3, 75.3, 57.7, 54.6, 19.1 (2C); HRMS(ESI): m/z
calculated for C11H16NaO4S2(M++Na) 299.0387, found 299.0389.
3412, 2891, 2797, 1764, 1176, 1083, 804 cm-1 1H NMR (400 MHz,
;
CDCl3): d 1.02 (t, 3H, J = 7.3 Hz, CH3), 1.55 (m, 2H, CH2), 3.26
(t, 1H, J = 7.3 Hz, H-3a), 3.51 (s, 3H, OCH3), 3.74 (m, 1H, H-
4), 4.25–4.35 (q, 2H, J = 12.1 Hz, OCH2), 4.60 (m, 1H, H-6a),
4.67 (d, 1H, J = 3.6 Hz, H-6), 4.91 (s, 1H, olefinic), 5.06 (s, 1H,
olefinic); 13C NMR (CDCl3, 75 MHz): d 146.6, 107.8, 105.1, 83.5,
78.6, 74.0, 57.5, 50.1, 24.9, 11.2; HRMS (ESI): m/z calculated for
C10H17O3(M++H) 185.1177, found 185.1175.
(3aR,4S,6S,6aR)-Hexahydro-6-methoxy-4-methyl-3-methyl-
enefuro[3,4-b]furan (12a). A solution of 14a (0.18 g, 0.67 mmol)
in dry benzene (25 mL) under N2 atmosphere was treated with
n-Bu3SnH (0.36 mL, 1.34 mmol) at room temperature and heated
at reflux for 30 min. After 30 min, a catalytic amount of AIBN was
added at reflux and continued the reflux for 12 h. The reaction mix-
ture was cooled to room temperature, benzene evaporated under
reduced pressure and residue purified by column chromatography
(60–120 Silica gel; ethyl acetate–n-hexane, 1.2 : 8.8) to afford 12a
(0.08 g, 69%) as a colorless liquid; [a]D = -21.70 (c 0.41, CDCl3);
(3aR,4S,6R,6aR)-Hexahydro-6-methoxy-3-methylene-4-pentyl-
furo[3,4-b]furan (12c). A solution of 14c (0.08 g, 0.24 mmol)
in dry benzene (25 mL) on reaction with n-Bu3SnH (0.13 mL,
0.48 mmol) and catalytic amount of AIBN as described for 12a.
Work up and column chromatographic purification (60–120 Silica
IR (neat): nmax 2925, 2852, 1731, 1654, 1463, 1265, 1100, 771 cm-1
;
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gel, ethyl acetate–n-hexane, 0.5 : 9.5) gave 12c (0.008 g, 14%) as a
colorless liquid; [a]D = -249.7 (c 0.26, CDCl3); IR (neat): nmax3367,
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2832, 2165, 1167, 762 cm-1 1H NMR (300 MHz, CDCl3): 0.89 (t,
;
3H, J = 6.6 Hz, CH3), 1.28–1.58 (m, 8H, alkyl chain), 3.23 (t, 1H,
J = 6.2 Hz, H-3a), 3.33 (s, 3H, OCH3), 4.08 (m, 1H, H-4), 4.21 (q,
2H, J = 12.3 Hz, OCH2), 4.59 (d, 1H, J = 6.1 Hz, H-6a), 4.89 (s,
1H, H-6), 4.95 (s, 1H, olefinic), d 5.09 (s, 1H, olefinic); 13C NMR
(CDCl3, 150 MHz): d 146.5, 108.0, 107.6, 88.3, 79.3, 72.5, 54.1,
49.8, 31.8, 31.0, 26.5, 22.6, 14.0; HRMS (ESI): m/z calculated for
C13H22NaO3(M++Na) 249.1466, found 249.1456.
Theoretical methods
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In order to study the intramolecular 5-exo-dig-cyclization reaction
in propargyloxy-substituted radicals 29 and 32 for each stage along
the reaction pathway the conformational space has been searched
extensively with the MM3* force field13 and the systematic search
routine implemented in MACROMODEL 9.714 in order to identify
all possible low energy conformations. Geometry optimizations
have then been performed at the UB3LYP/6-31G(d) level of
theory. Thermal corrections to enthalpies at 298.15 K have been
calculated at the same level using the rigid rotor/harmonic
oscillator model. Single point energies have subsequently been
calculated at the UB3LYP/6-311+G(d,p) level of theory. Combi-
nation of these total energies with thermal corrections calculated
at UB3LYP/6-31G(d) level yield the enthalpies “H298” discussed
in the text. Single point calculations have also been performed
at the (RO)MP2(FC)/G3MP2large level and combined with
thermochemical corrections to 298.15 K obtained at UB3LYP/6-
31G(d) level using a scaling factor of 0.9806. These results are
termed as “ROMP2” in the text. The G3MP2large basis set is a
large triple-zeta basis set used in the G3(MP2) compound energy
scheme.12 All calculations have been performed with Gaussian 03.15
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cyclisation routes on carbohydrate derived 5-hexenyl and 5-hexynyl
systems: synthesis of natural and non-natural Products”, Ph. D. Thesis,
by T. Gopinath, (Kakatiya University, Warangal, India, November
2004).
10 See ESI‡ for the synthetic details (17 to 23a–c) and experimental details
(17 to 23a–c, 24b–c to 27b–c, 14b–c, 15b–c).
11 J. Cossy, J.-L. Ranaivosata and V. Bellosta, Tetrahedron Lett., 1994, 35,
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12 L. A. Curtiss, P. C. Redfern, K. Raghavachari, V. Rassolov and J. A.
Pople, J. Chem. Phys., 1999, 110, 4703.
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111, 8551; (b) J. H. Lii and N. L. Allinger, J. Am. Chem. Soc., 1989,
111, 8566; (c) J. H. Lii and N. L. Allinger, J. Am. Chem. Soc., 1989,
111, 8576.
14 Schro¨dinger, LLC., MacroModel 9.7, 2009.
15 Gaussian 03, Revision E.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr.,
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G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R.
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G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M.
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Acknowledgements
H. C. thanks CSIR, New Delhi for financial support.
Notes and References
1 (a) B. Giese, B. Kopping, T. Gobel, J. Dickhaut, G. Thoma, K. J.
Kulicke and F. Trach, Radical Cyclization Reaction in Organic Reaction,
L. A. Paquette, Ed.; Wiley: New York, 1996, 48, 301; (b) B. Giese,
4084 | Org. Biomol. Chem., 2011, 9, 4079–4084
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The Royal Society of Chemistry 2011
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