Concise formal synthesis of (-)-7-deoxyloganin via N-heterocyclic carbene catalysed rearrangement of α,β-unsaturated enol esters

Article abstract of DOI:10.1039/c1ob05953j

NHC catalysed rearrangement of α,β-unsaturated enol esters derived from formyl acetates and cyclopentyl annulated α,β- unsaturated acids provides the cyclopentapyranone core of (-)-7-deoxyloganin (1) with diastereo- and chemoselectivity in 6 steps startin

Full text of DOI:10.1039/c1ob05953j

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PAPER
Concise formal synthesis of (-)-7-deoxyloganin via N-heterocyclic carbene
catalysed rearrangement of a,b-unsaturated enol esters†
Lisa Candish and David W. Lupton*
Received 13th June 2011, Accepted 14th September 2011
DOI: 10.1039/c1ob05953j
NHC catalysed rearrangement of a,b-unsaturated enol esters derived from formyl acetates and
cyclopentyl annulated a,b-unsaturated acids provides the cyclopentapyranone core of (-)-7-deoxy-
loganin (1) with diastereo- and chemoselectivity in 6 steps starting from (-)-citronellal. The elaboration
to the natural product has been investigated using two new approaches. The most successful intercepts
our previous work on (-)-7-deoxyloganin (1) allowing completion of a formal total synthesis in 10-steps.
should provide access to the cyclopentapyran core of (-)-7-
deoxyloganin (1), and ultimately the natural product itself. This
was realised with the total synthesis of (-)-7-deoxyloganin (1)
completed last year.6b While these studies were successful they
suffered from a number of limitations, resulting in an 18-step linear
sequence and concomitant low overall yield. To demonstrate the
enabling role of reaction discovery on target oriented synthesis,
we chose to re-examine this sequence, to improve the step count
and overall yield. Herein we provide a full-account of our studies
on the synthesis of (-)-7-deoxyloganin, with optimisation of
the key NHC catalysed rearrangement, improved preparation
of the rearrangement precursor (S)-3c and alternate end-game
strategies. These refinements allow a formal total synthesis of (-)-
7-deoxyloganin (1) to be completed in 10-steps.
Introduction
Iridoids are a diverse family of natural products with over
250 members of marine and terrestrial origins.1 Structurally a
cyclopentapyran core of type I or II, with a cis relationship
between H-5 and H-9 is common (Scheme 1), although stereoiso-
meric examples, and seco derivatives, are known. Their role
in biosynthesis has been extensively investigated, with pivotal
involvement as the non-nitrogeous component in alkaloid biosyn-
thesis established.2 In addition iridoids have received attention
as bioactive entities, with recent studies demonstrating that, for
example, 9-deoxygelsemide (2) and catalpol derivatives have anti-
cancer activity.1d,e,3 The compact and structurally rich nature of
iridoids, together with their numerous biological roles, continue to
stimulate investigations focused on their chemical synthesis.4
Results and discussion
The use of NHCs as organocatalysts for non-carbonyl umpolung
reactions has received limited attention.6,7 In 2009 we found
that NHCs catalyse the rearrangement of a,b-unsaturated enol
esters to dihydropyranones (Scheme 2) via normal polarity
intermediates.6a
To investigate the utility of this transformation studies into the
chemical synthesis of (-)-7-deoxyloganin (1) were undertaken,
with the key transformation involving isomerisation of enol
ester 3 to the cyclopentapyranone 4. The chemoselectivity of
such a transformation was identified as a potential challenge,
since NHC catalysed transesterification has been reported.8 In
addition the reaction must tolerate annulation across the a-
and b-positions of the a,b-unsaturated motif. Finally, substrate
directed diastereoselectivity, to deliver the cis arrangement of
H5, H9 and the methyl at C-8, would need to be realised
(Scheme 2).
Scheme 1 Iridoid natural products.
While investigating Lewis base mediated reaction cascades, we
recently discovered a N-heterocyclic carbene (NHC) catalysed
dihydropyranone synthesis.5,6 We postulated that this reaction
Monash University, Clayton 3800, Melbourne, Australia. E-mail: david.
lupton@monash.edu; Fax: +61 2 9905 4597; Tel: +61 3 99020327
Optimisation of the NHC catalysed isomerisation
† Electronic supplementary information (ESI) available: 1H- and 13C-
NMR spectra of all reported compounds as well as additional experimental
procedures. See DOI: 10.1039/c1ob05953j
Since the key challenges associated with the synthesis of 1
relate to the proposed NHC catalysed isomerisation of 3→4
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Scheme 2 Synthetic strategy and potential reaction mechanism.
model studies were undertaken to establish the viability of this
event. Investigations commenced with the preparation of diesters
t
8a and 8b (R = Bu or Et) from formyl acetates 6a–b9 and
cinnamoyl chloride. Their rearrangements to lactone 9a and 9b,
were undertaken to examine the impact, if any, of the type of ester
on the reaction. The methyl ester was not prepared due to reported
difficulties in the synthesis of methyl formyl acetate 6c (R = Me)10
(vide infra). When the ethyl ester 8b (R = Et) was rearranged forcing
conditions were required, and only a modest yield of lactone 9b
was obtained (Table 1, entry 1◦b). In contrast the t-butyl ester 8a
gave lactone 9a after 1 h at 0 C and in excellent yield (Table 1,
entry 1a).
Scheme 3 Cross-over studies of enol ester 12a and b.
Having demonstrated the viability of diester containing sub-
strates in the rearrangement, cyclopentyl ester 10 was prepared, to
examine substrates bearing annulation across the a,b-unsaturated
portion. In this case an acceptable yield, albeit with modest
stereoselectivity, was achieved only when the reaction was heated
in toluene at reflux for 14 h (Table 1, entry 2a). The diastereose-
lectivity could be moderately improved by employing homochiral
triazolium derived carbene B, however this catalyst provided only
a trace of the desired product (Table 1, entry 2b). Unfortunately,
and as observed with other NHC catalysed reactions exploiting
substrates in the carboxylic acid oxidation state, triazolium derived
NHCs display modest reactivity.6,11
The lack of reactivity with annulated a,b-unsaturated com-
pounds was attributed to difficulties accessing hemiacetal I. To
facilitate its formation the smaller, but comparably nucleophilic13
tetramethyl imidazol-2-ylidene carbene C1 was trialled. To our
satisfaction when using this catalyst 4a formed in 40% isolated
yield (Table 1, entry 3b). While this catalyst gave the most
useful result it is difficult to handle, and can provide unreliable
results. Changing to the more stable, albeit slightly more hindered,
diisopropyl dimethyl (IPrMe) NHC C2 provided lactone 4a in 74%
yield and with an improved 3 : 1 diastereoselectivity (Table 1, entry
3c). Switching the solvent to toluene increased the stereoselectivity
(4.4 : 1), although the yield suffered (Table 1, entry 3d).
The rearrangement of ethyl ester 3b (R = Et), and methyl ester 3c
(R = Me) using IPrMe C2 was trialled. In these cases comparable
yields to those obtained using t-butyl ester 3a were achieved (Table
1, entry 3c cf. e and f). This result allows greater flexibility in the
end-game of the synthesis (vide infra).
While these studies demonstrate the viability of assembling
(-)-7-deoxyloganin (1) using the NHC catalysed rearrangement
of 3→4, in addition they highlight potential difficulties with
substrates annulated across the a,b-unsaturation.
Based on the greater yields obtained with 8a compared to 8b t-
t
butyl ester 3a (R = Bu) was identified as the most suitable subtarget
for the total synthesis. Unfortunately, when this substrate was
For the optimisation studies detailed above cyclopentyl sub-
strates 3a–c were assembled from 2,5-dimethoxytetrahydrofuran
(14) in seven to nine steps via the t-butyl ester 3a (Scheme 4,
steps (i)→(ix)).6b In the first generation total synthesis lipase-based
resolution of cyclopentanol 1514 followed by TBS protection was
employed to provide homochiral allylic alcohol 18 in 99% ee, which
was elaborated in 10-steps to the rearrangement precursor (S)-3c
(Scheme 4). The laborious assembly of (S)-3c is due to a number of
factors, specifically, the requirement of a TBS group in alcohol 18
to ensure good stereochemical relay in the methylation reaction,
use of a kinetic resolution, and indirect formation of the methyl
ester (S)-3c via the t-butyl ester (S)-3a. To increase the efficiency
exposed to NHC A in refluxing toluene for 14 h none of the desired
t
cyclopentapyran 4a (R = Bu) formed (Table 1, entry 3a). The lack
of reactivity mirrored the results observed with other annulated
substrates (i.e. 10).
For the rearrangement to occur formation of hemiacetal I must
occur and be followed by formation of acyl azolium II/enolate III
ion pair or a Claisen rearrangement (Scheme 2).12 To clarify which
mechanism is operative in this reaction a cross-over study with
substrates 12a and b was undertaken (Scheme 3). This reaction
provided 13a and b with none of the crossed-product, thereby
implicating the Claisen pathway.
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Table 1 Development of the NHC catalysed rearrangement of a,b-unsaturated enol esters
Entry
1a
Catalyst
Temperature
0 ◦Cd
Solvent
Toluene
Starting material/product
R
dra
Yieldb
84
10 mol% Ac
a, tBu
—
b
2a
10 mol% Ac
10 mol% Ac
Reflux
Reflux
Toluene
Toluene
b, Et
—
—
33
64
2 : 1e
b
3a
10 mol% Bc
10 mol% Ac
Reflux
Reflux
Toluene
Toluene
—
3 : 1e
—
Trace
—
a, tBu
b
c
d
e
f
40 mol% C1f
30 mol% C2f
30 mol% C2f
20 mol% C2f
20 mol% C2f
-78 ◦C→rt
-78 ◦C→rt
-78 ◦C→rt
-78 ◦C→rt
-78 ◦C→rt
THF
THF
Toluene
THF
THF
a, tBu
a, tBu
a, tBu
b, Et
2 : 1
3 : 1
4.4 : 1
3.2 : 1
3.4 : 1
40
74
38
78
82
c, Me
a Stereoisomeric ratio determined by 1H-NMR. b Isolated yield following flash column chromatography. c Carbene generated using 20 mol% KOtBu. d One
hour reaction time. e Prepared as an inseparable mixture of diastereoisomers. f Carbene generated by reduction of the thiourea and isolated.
Scheme 4 First generation synthesis of (S)-3c.
of the synthesis of (-)-7-deoxyloganin (1), either improved access
to (S)-3c, or an alternate end-game exploiting the more easily
accessed (S)-3a or (S)-3b were required. These approaches are
discussed in the following section.
produce the lactols 20a and b, then acetylated to provide 7a
and b (Scheme 5). For these studies the racemic materials were
exploited.
Modified end-game, late stage transesterification
Initial studies focused on employing the more accessible (S)-
3a or (S)-3b, and exploiting a late-stage transesterification to
access the natural product. To examine this strategy lactones
t
15
4a (R = Bu) and b (R = Et) were reduced using NaBH4 to
Scheme 5 Reduction and acetylation of 4a and 4b.
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Direct glycosylation of lactol 21 has been reported using
pentaacetoxyl trichloroacetimidate 22 by Krische in a synthesis
of geniposide4e (Scheme 6). When the related transformation of
20a was attempted using the reported conditions, or with alternate
Lewis acids, no reaction was observed. The origin of this difference
in reactivity is not obvious, although it may relate to subtle
stereoelectronic differences due to the pivaloyl protected alcohol
within 21.
Scheme 7 Glycosylation studies of lactol acetates 7a and 7b.
been developed.4b Building upon these results it would simply
be a matter of oxidizing this material to deliver enantioenriched
acid (S)-17. Finally, it should be possible to eliminate two further
operations by acylating methyl formyl acetate 6c rather than t-
butyl formyl acetate 6a.
To execute this synthesis we commenced with exo methylenation
of (S)-citronellal (27) to provide 28 in excellent yield (Scheme 8).17
Ring closing metathesis proceeded in good yield when conducted
at high dilution to afford the somewhat volatile cyclopentenal
26. Oxidation using silver nitrate furnished the acid, which was
immediately converted to the acid chloride (S)-5. Esterification
with methyl formyl acetate 6c proved challenging due to difficulties
accessing the required starting material. While the preparation of
t-butyl formyl acetate 6a and ethyl formyl acetate 6b is readily
achieved from Meldrum’s acid,9 attempts to prepare the methyl
ester 6c using this approach led to polymerisation. By ozonolysing
methyl butenoate, as reported by Cossy,10 it was possible to access
methyl formyl acetate 6c, which following partial purification,
could be converted to the methyl ester (S)-3c in 78% isolated yield.
Thus in 5-steps it is possible to intercept an intermediate, that in
our first generation synthesis of 7-deoxyloganin,6b was elaborated
to the natural product in a further 5-steps.
Scheme 6 Attempted glycosylation of lactol 20a.
The lack of reactivity with lactol 20a directed attentions to
the more commonly used lactol acetates, i.e 7, as substrates
for glycosylation. Using procedures developed by Tietze,16 and
modified by MacMillan for the synthesis of brasoside and
littoralisone,4d the glycosylation of t-butyl lactol acetate 7a was
attempted. Unfortunately, cleavage of the t-butyl ester gave acid
23 which failed to undergo glycosylation (Scheme 7). Screening
a number of Lewis acids failed to improve this situation. By
changing to ethyl ester 7b ester cleavage was eliminated and
glycone 24 could be prepared. Unfortunately, while the subsequent
deacetylation proceeded smoothly, the ethyl group proved resistant
to transesterification, thereby providing the undesired ethyl ester
variant of the natural product 25. The use of extended reaction
times, more forcing reaction conditions, and alternate transesteri-
fication catalysts, failed to address this lack of reactivity, and led to
decomposition of the substrate. Due to these difficulties attention
was directed to improving access to methyl ester (S)-3c.
Conclusions
We have examined two new approaches to the synthesis of (-)-7-
deoxyloganin (1). In the first, and ultimately unsuccessful strategy,
a transesterification was investigated to convert the ethyl ester of
24 to the required methyl ester during final acetate deprotection.
Synthesis of cyclopentapyrans 4 from citronellal (18)
In studies by Jacobsen on the synthesis of type I iridolactones
the preparation of aldehyde 26 in two steps from citronellal has
Scheme 8 Improved 10-step synthesis of 7-doxyloganin 1.
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This transformation proved impossible to achieve, thus prompting
the development of a strategy in which the required methyl
ester was installed at the beginning of the synthesis. Using this
approach a number of transformations can be removed from
our first generation synthesis allowing a 10-steps formal total
synthesis of (-)-7-deoxyloganin (1) to be achieved in 5-steps. This
shortened synthesis highlights the potential reaction discovery has
on enhancing efficiency in multistep synthesis. Furthermore, its
short nature in principle allows the preparation of alternate type
II iridoids using modified strategies.
13C-NMR (125 MHz, CDCl3) d 28.2, 80.8, 107.7, 115.5, 128.5,
129.0, 131.2, 133.7, 148.3, 149.0, 162.8, 165.5; HRMS Found
(M+NH4)+ 292.1549, C16H18O4 requires (M+NH4)+ 292.1549.
(E)-3-Ethoxy-3-oxoprop-1-enyl cinnamate (8b)
Compound 8b was prepared as a clear and colourless oil from
ethyl formyl acetate 6b using the procedure for the synthesis of
8a (0.615 g, 50%). Rf 0.3 (1 : 9, v/v EtOAc:hexane); IR nmax 3066,
1
2981, 1738, 1702, 1629, 1450, 1367, 1141 cm-1; H-NMR (500
MHz, CDCl3) d 1.31 (t, J = 7.0 Hz, 3H), 4.23 (q, J = 7.0 Hz, 2H),
5.81 (d, J = 12.5 Hz, 1H), 6.47 (d, J = 16.0 Hz, 1H), 7.42–7.44 (m,
3H), 7.57–7.56 (m, 2H), 7.86 (d, J = 16.0 Hz, 1H), 8.45 (d, J =
12.5 Hz, 1H); 13C-NMR (125 MHz, CDCl3) d 14.2, 60.5, 105.9,
115.3, 128.5, 129.0, 131.2, 133.7, 148.5, 149.7, 162.7, 166.3; HRMS
Found (M+H)+ 247.0964, C14H14O4 requires (M+H)+ 247.0965.
Experimental
General Experimental
Proton (1H) and carbon (13C) NMR spectra were recorded on a
Bruker DRX400 operating at 400 MHz for proton and 100 MHz
for carbon nuclei. Infrared spectra (nmax) were recorded on a
Perkin-Elmer RXI FTIR Spectrometer. Low resolution mass
spectrometry (ESI) was performed on a Micromass Platform
QMS spectrometer. High resolution mass spectra (HRMS) were
recorded on a Bruker BioApex 47e FTMS fitted with an Analytical
electrospray source using NaI for accurate mass calibration.
Melting points were measured on a Stuart hot-stage microscope
apparatus. Flash column chromatography was performed on silica
gel (Davisil LC60A, 40–63 mm silica media) using compressed air
or nitrogen. Thin layer chromatography (TLC) was performed
using aluminum-backed plates coated with 0.2 mm silica (Merck,
DC-Platten, Kieselgel; 60 F254 plates). Eluted plates were visualized
using a 254 nm UV lamp and/or by treatment with a suitable
stain followed by heating. Starting materials and reagents were
purchased from Sigma-Aldrich and were used as supplied or, in the
case of some liquids, distilled. Tetrahydrofuran (THF) was distilled
from sodium benzophenone ketyl. Ethanol and dichloromethane
were distilled from calcium hydride. Acetonitrile, t-butanol (t-
BuOH), and toluene was purified using SPS (Alumina column
using an mBraun system) and degassed. Trimethylsilyl trifluo-
romethanesulfonate was distilled twice from CaH2 immediately
prior to use. Imidazolium salt from which NHC A was prepared
was prepared using the procedure of Arduengo.18 Carbene C1
was prepared using the procedure of Kuhn,19 and C2 using the
procedure of Yamaguchi.20
(S/R)-tert-Butyl 2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-
carboxylate (9a)
To a stirring solution of IMes·HCl (17 mg, 0.05 mmol) in
toluene (2 ml) was added tBuOK (11 mg, 0.1 mmol). The cloudy
suspension was stirred at rt for 1 h resulting in a clear yellow
solution of NHC A. This was cooled to 0 ◦C and a solution of enol
ester 8a in toluene (1 ml) was added dropwise. The reaction was
allowed to slowly warm to rt and was stirred for a further 1 h. The
mixture was concentrated and the crude residue purified by flash
column chromatography (3 : 7, v/v EtOAc:hexane) to provide the
title compound 9a as a white solid (0.144 g, 84%). Rf 0.2 (3 : 7, v/v
EtOAc:hexane); IR nmax 3112, 2978, 1786, 1693, 1651, 1453, 1368,
1159 cm-1; 1H-NMR (500 MHz, CDCl3) d 1.42 (s, 9H), 2.86 (dd,
J = 16.0, 1.5 Hz, 1H), 3.05 (dd, J = 16.0, 7.5 Hz, 1H), 4.15 (dd, J =
7.5, 1.5 Hz, 1H), 7.16–7.32 (m, 5H), 7.67 (s, 1H) 13C-NMR (125
MHz, CDCl3) d 28.0, 36.0, 36.5, 81.7, 115.7, 126.5, 127.6, 129.1,
140.2, 150.2, 164.0, 165.9; EI-LRMS Found (M-(CH3)3)+ 217.1,
C16H18O4 requires (M-(CH3)3)+ 217.1.
(S/R)-Ethyl 2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-carboxylate
(9b)
Lactone 9b was prepared following the procedure for the synthesis
of 9a, however the reaction was heated at reflux for 16 h to afford
the title compound as a pale yellow oil (0.041 g, 33%). Rf 0.3
(1 : 5, v/v EtOAc:hexane); IR nmax 3108, 2986, 1790, 1713, 1650,
1
1453, 1382, 1160 cm-1; H-NMR (500 MHz, CDCl3) d 1.27 (t, J
(E)-3-(tert-Butoxy)-3-oxoprop-1-enyl cinnamate (8a)
= 7.0 Hz, 3H), 2.90 (dd, J = 16.0, 1.5 Hz, 1H), 3.05 (dd, J = 16.0,
8.0 Hz, 1H), 4.19–4.25 (m, 3H), 7.20–7.36 (m, 5H), 7.79 (s, 1H);
13C-NMR (125 MHz, CDCl3) d 14.1, 35.9, 36.3, 61.0, 114.4, 126.5,
127.7, 129.1, 139.9, 150.7, 164.8, 165.6; HRMS Found (M+H)+
247.0969, C14H14O4 requires (M+H)+ 247.0965.
To a stirring solution of cinnamoyl chloride (0.916 g, 5.5 mmol)
and DMAP (1.5 mmol, 0.183 g) in THF (10 ml) was added
tert-butyl formyl acetate 6a (0.720 g, 5 mmol) in THF (5 ml).
The reaction was stirred at rt for 1 h, and then diluted with
CH2Cl2 (40 ml) and washed with H2O (5 ml), HCl (5 ml
of a 1 M aqueous solution), NaHCO3 (5 ml of a saturated
aqueous solution), and H2O (5 ml). The organic phase was dried
(MgSO4) and concentrated. The crude material was purified by
flash chromatography (1 : 9, v/v EtOAc:hexane) to yield the pure
enol ester as a white solid (0.617 g, 45%). Rf 0.3 (1 : 9, v/v
EtOAc:hexane); IR nmax 3069, 2979, 1763, 1699, 1630, 1451, 1370,
1128 cm-1; 1H-NMR (500 MHz, CDCl3) d 1.51 (s, 9H), 5.73 (d, J =
12.5 Hz, 1H), 6.47 (d, J = 16.0 Hz, 1H), 7.43–7.42 (m, 3H), 7.58–
7.56 (m, 2H), 7.85 (d, J = 16.0 Hz, 1H), 8.34 (d, J = 12.5 Hz, 1H);
(S/R)-3-Oxocyclohex-1-enyl 5-methylcyclopent-1-enecarboxylate
(10)
To a stirring solution of 1,3-cyclohexanedione (0.11 g, 1 mmol)
and pyridine (0.082 ml, 1 mmol) in CH2Cl2 (5 ml) was added
acid chloride 5 (0.16 g, 1.1 mmol) in CH2Cl2 (1 ml). The mixture
was stirred at rt for 2 h then diluted with CH2Cl2 (40 ml) and
washed with H2O (5 ml), HCl (5 ml of a 1 M aqueous solution),
NaHCO3 (5 ml of a saturated aqueous solution), and H2O
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(5 ml). The organic phase was dried (MgSO4) and concentrated.
The crude material was purified by flash chromatography (1 : 4, v/v
EtOAc:hexane) to yield the enol ester 10 as a clear and colourless
oil (0.125 g, 57%). Rf 0.3 (3 : 7, v/v EtOAc:hexane); IR nmax 2871,
(4aS,7S,7aR)-Ethyl 7-methyl-1-oxo-1,4a,5,6,7,7a hexahydrocyclo
penta[c]pyran-4-carboxylate and (4aR,7R,7aS)-Ethyl 7-methyl-
1-oxo-1,4a,5,6,7,7a hexahydrocyclo penta[c]pyran-4-carboxylate
(4b)
1
1734, 1678, 1644, 1618, 1456, 1125 cm-1; H-NMR (500 MHz,
Using the procedure reported for the synthesis of 4c6b the
title compound 4b was prepared as a clear and colourless
oil (0.175 g, 78%). Rf 0.5 (1 : 4, v/v EtOAc:hexane) IR nmax
CDCl3) d 1.14 (d, J = 6.5 Hz, 3H), 1.59 (oct, J = 4.0 Hz, 1H), 2.05
(quint, J = 6.5 Hz, 2H), 2.18–2.24 (m, 1H), 2.37–2.42 (m, 2H),
2.42–2.48 (m, 1H), 2.52–2.60 (m, 3H), 2.99–3.04 (m, 1H), 5.92 (s,
1H), 6.89–6.91 (m, 1H); 13C-NMR (125 MHz, CDCl3) d 19.7, 21.3,
28.4, 31.7, 32.0, 36.7, 38.6, 117.3, 139.7, 147.3, 161.2, 170.1, 199.6;
HRMS Found (M+H)+ 221.1166, C13H16O3 requires (M+H)+
221.1179.
1
2967, 1778, 1715, 1657, 1465, 1333, 1274, 1156 cm-1; H-NMR
(300 MHz, CDCl3) d 1.16 (d, J = 6.6 Hz, 3H), 1.26 (t, J =
7.2 Hz, 3H), 1.30–1.44 (m, 2H), 1.86–1.95 (m, 1H), 2.21–2.31
(m, 1H), 2.44–2.53 (m, 2H), 3.07–3.15 (m, 1H), 4.15–4.23 (m,
2H), 7.38 (s, 1H); 13C-NMR (75 MHz, CDCl3) d 14.1, 20.4,
33.1, 33.2, 35.9, 39.3, 48.3, 60.6, 113.6, 147.8, 165.6, 169.0;
HRMS Found (M+H)+ 225.1120, C12H16O4 requires (M+H)+
225.1121.
(3S,3aR,9bS)-3-Methyl-1,3,3a,7,8,9b-hexahydrocyclopenta[c]-
chromene-4,9(2H,6H)-dione and (3R,3aS,9bR)-3-methyl-
1,3,3a,7,8,9b-hexahydrocyclopenta[c]chromene-4,9(2H,6H)-dione
(3S,3aS,9bR)-3-Methyl-1,3,3a,7,8,9b-hexahydrocyclopenta[c]-
chromene-4,9(2H,6H)-dione and (3R,3aR,9bS)-3-methyl-1,3,3a,
7,8,9b-hexahydrocyclopenta[c]chromene-4,9(2H,6H)-dione (11)
(E)-3-Oxocyclohex-1-en-1-yl 3-(2-methoxyphenyl)acrylate 12a
Using the procedure reported for the synthesis of 12b6a the title
compound 12a was prepared as a white solid (0.424 g, 78%). Rf 0.3
(1 : 3, v/v EtOAc:hexane); IR nmax 2951, 1735, 1673, 1624, 1598,
1466, 1118 cm-1; 1H-NMR (500 MHz, CDCl3) d 2.08 (p, J = 6.0
Hz, 2H), 2.43 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 6.0 Hz, 2H), 3.90 (s,
3H), 6.00 (s, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H),
6.98 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0
Hz, 1H), 8.07 (d, J = 16.0 Hz, 1H); 13C-NMR (125 MHz, CDCl3)
d 21.3, 28.4, 36.7, 55.5, 111.2, 116.7, 117.2, 120.7, 122.6, 129.4,
132.3, 143.3, 158.6, 163.8, 170.3, 199.7; HRMS Found (M+H)+
273.1121, C16H16O4 requires (M+H)+ 273.1121.
Lactone 11 was prepared as an inseparable mixture of diastereoiso-
mers using the procedure reported for the synthesis of 9a as a clear
and colourless oil (0.050 g, 45%). Rf 0.2 (1 : 4, v/v EtOAc : hexane);
1
IR nmax 2959, 1773, 1654, 1457, 1375, 1168 cm-1; H-NMR (400
MHz, CDCl3) d (major) 1.07 (d, J = 6.8 Hz, 3H), 1.20–1.24 (m,
1H), 1.38–1.43 (m, 1H), 1.80 (dq, J = 12.4, 6.8 Hz, 2H), 1.96–2.18
(m, 2H), 2.15–2.34 (m, 1H), 2.37–2.43 (m, 2H), 2.48–2.54 (m, 2H),
2.60 (q, J = 6.8 Hz, 1H), 3.17–3.20 (m, 1H) (minor) 1.18 (d, J = 6.8
Hz, 3H), 1.57–1.66 (m, 2H), 1.89–1.95 (m, 1H), 1.96–2.18 (m, 2H),
2.25–2.34 (m, 1H), 2.35–2.41 (m, 2H), 2.48–2.54 (m, 2H), 2.52–
2.54 (m, 1H), 3.15–3.23 (m, 2H); 13C-NMR (100 MHz, CDCl3) d
16.4, 20.5, 20.6, 20.8, 27.3, 27.4, 32.6, 32.7, 33.4, 33.5, 34.4, 34.5,
36.9, 37.1, 39.0, 39.6, 46.3, 49.1, 117.5, 117.6, 164.6, 164.7, 167.7,
167.9, 197.4, 197.6; HRMS Found (M+H)+ 221.1171, C13H16O3
requires (M+H)+ 221.1172.
Crossover experiment
To a stirring solution of IMes·HCl (17 mg, 0.05 mmol) in
toluene (2 ml) was added tBuOK (11 mg, 0.1 mmol). The cloudy
suspension was stirred at rt for 1 h resulting in a clear yellow
solution of NHC A. This was cooled to 0 ◦C and a solution of
enol esters 12a (61 mg, 0.25 mmol) and 12b (68 mg, 0.25 mmol) as
a 1 : 1 mixture in toluene (1 ml) was added dropwise. The reaction
was allowed to slowly warm to rt and was stirred for a further 1
h. The mixture was concentrated and the crude residue purified
by flash column chromatography (3 : 7, v/v EtOAc : hexane) to
provide the title compounds 13a and 13b6a as white solids (46
mg, 75%) and (56 mg, 82%) respectively. 4-(2-Methoxyphenyl)-
3,4,7,8-tetrahydro-2H-chromene-2,5(6H)-dione 13a. Rf 0.2 (1 : 3,
v/v EtOAc:hexane); IR nmax 2952, 1783, 1651, 1492, 1374, 1112
cm-1; 1H-NMR (500 MHz, CDCl3) d 2.03–2.08 (m, 2H), 2.39 (t, J =
6.5 Hz, 2H), 2.60–2.65 (m, 2H), 2.85–2.86 (m, 2H), 3.76 (s, 3H),
4.37–4.39 (m, 1H), 6.81–6.86 (m, 2H), 7.12 (dd, J = 8.0, 2.0 Hz,
1H), 7.19 (dt, J = 8.0, 1.5 Hz, 1H); 13C-NMR (125 MHz, CDCl3) d
20.6, 27.4, 31.3, 34.4, 36.8, 54.4, 110.6, 114.8, 120.5, 128.2, 128.6,
129.2, 156.9, 165.8, 167.1, 196.4; HRMS Found (M+H)+ 273.1119,
C16H16O4 requires (M+H)+ 273.1121.
(E)-3-Ethoxy-3-oxoprop-1-en-1-yl 5-methylcyclopent-1-
enecarboxylate (3b)
A magnetically stirred solution of acid chloride 5 (1.08 g,
7.5 mmol) in CH2Cl2 (5 ml) was cooled to 0 ◦C then treated
dropwise with Hu¨nig’s base (1.6 ml 9 mmol) followed by ethyl
formyl acetate (6b) (5 ml of a 1.4 M solution in CH2Cl2, 7 mmol).
◦
The reaction was stirred at 0 C for 1 h then diluted with Et2O
(15 ml) and washed with H2O (5 ml), HCl (5 ml of a 1 M
aqueous solution) and NaHCO3 (5 ml of a saturated aqueous
solution). The organic phase was dried (MgSO4), concentrated
in vacuo and purified via flash column chomatography (1 : 5, v/v
EtOAc:hexane) to furnish the title compound 3b as a clear and
colourless oil (1.53 g, 91%). Rf 0.3 (1 : 5, v/v EtOAc:hexane)
IR nmax 2953, 1741, 1442, 1651, 1620, 1436, 1110 cm-1; 1H-
NMR (300 MHz, CDCl3) d 1.13 (d, J = 6.9 Hz, 3H), 1.28
(t, J = 7.2 Hz, 3H), 1.53–1.63 (m, 1H), 2.13–2.26 (m, 1H),
2.37–2.64 (m, 2H), 2.99–3.09 (m, 1H), 4.19 (q, J = 7.2 Hz,
2H), 5.71 (d, J = 12.6 Hz, 1H), 6.96–6.98 (m, 1H), 8.36 (d,
J = 12.6 Hz, 1H); 13C-NMR (75 MHz, CDCl3) d 14.2, 19.6,
31.8, 31.9, 38.6, 60.3, 105.3, 138.8, 148.1, 149.7, 160.3, 166.3;
HRMS Found (M+Na)+ 247.0942, C12H16O4 requires (M+Na)+
247.0941.
(S)-5-Methylcyclopent-1-enecarboxylic acid ((S)-17)
To a stirring solution of silver nitrate (0.24 g, 1.4 mmol) in H2O
(0.5 ml) was added sodium hydroxide (0.5 ml of a 5.6 M aqueous
solution, 2.8 mmol). After stirring for 5 min, aldehyde 26 (0.11
g, 1 mmol) was added in one portion. The solution had stirred
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for 14 h at rt then filtered and the residue was washed with
H2O (2 ¥ 2 ml). The comb◦ined aqueous layer was washed with
Et2O and then cooled to 0 C and acidified with HCl (3 ml of a
2 M aqueous solution). The aqueous layer was then extracted
with Et2O (3 ¥ 5 ml), dried (MgSO4) and concentrated. The
crude material was purified by flash column chromatography
(3 : 10, v/v EtOAc : hexane) to afford (S)-17 as a white solid
(0.066 g, 63%) whose spectral data matched that re-
ported.6b
(4aS,7S,7aR)-1-acetoxy-7-methyl-1,4a,5,6,7,7a-
hexahydrocyclopenta[c]pyran-4-carboxylic acid and
(4aR,7R,7aS)-1-acetoxy-7-methyl-1,4a,5,6,7,7a-
hexahydrocyclopenta[c]pyran-4-carboxylic acid (23)
A solution of acetate 7a (0.020 g, 0.067 mmol) in benzene was
transferred to a Schlenk flask containing 1-O-(trimethylsilyl)-
2,3,4,6-tetra-O-acetyl-b-D-glucopyranose (0.086 g, 0.2 mmol, pre-
pared following the method of Allevi).21 The solution was frozen
and benzene removed by sublimation. The remaining solid was
◦
dissolved in CH3CN (0.5 ml) and the mixture cooled to -30 C.
(1R,4aS,7S,7aR)-tert-Butyl 1-hydroxy-7-methyl-1,4a,5,6,7,7a-
hexahydrocyclopenta [c]pyran-4-carboxylate and (1S,4aR,7R,
7aS)-tert-Butyl 1-hydroxy-7-methyl-1,4a,5,6,7,7a-hexahydro-
cyclopenta [c]pyran-4-carboxylate (20a)
TMSOTf (0.14 ml of a 5% solution in CH3CN, 0.039 mmol) was
then added dropwise. The reaction was stirred at -30 ◦C for 3
days after which time phosphate buffer (2 ml of a 0.1 M pH 7
solution) was added and the mixture extracted with ether (3 ¥ 3
ml). The combined organics were dried (MgSO4) and concentrated
in vacuo. Purification of the crude material via flash column
chromatography (3 : 7, v/v EtOAc : hexane) provided the title acid
23 as a yellow oil (9 mg, 57%). Rf 0.2 (3 : 7, v/v EtOAc : hexane)
1H-NMR (300 MHz, CDCl3) d 1.08 (d, J = 6.0 Hz, 3H), 1.17–1.22
(m, 1H), 1.42–1.53 (m, 1H), 1.76–1.93 (m, 3H), 2.12 (s, 3H) 2.18–
2.28 (m, 1H), 2.92 (q, J = 7.2 Hz, 1H), 5.97 (d, J = 5.1 Hz, 1H),
7.45 (s, 1H); HRMS Found (M+H)+ 241.1070, C12H16O5 requires
(M+H)+ 241.1071.
Using the procedure reported for the synthesis of 20c6b the title
compound 20a was prepared as a clear and colourless oil (0.069 g,
54%). Rf 0.2 (1 : 3, v/v EtOAc : hexane) IR nmax 3409, 2957, 1704,
1631, 1434, 1096 cm-1; 1H-NMR (300 MHz, CDCl3) d 1.08 (d, J =
6.9 Hz, 3H), 1.33–1.54 (m, 2H), 1.47 (s, 9H), 1.58–1.78 (m, 1H),
1.82–2.00 (m, 2H), 2.22–2.31 (m, 1H), 2.79–2.87 (m, 1H), 3.82 (s,
1H), 4.88 (d, J = 6.9 Hz, 1H), 7.32 (s, 1H); 13C-NMR (75 MHz,
CDCl3) d 20.8, 28.3, 33.0, 33.2, 34.6, 35.7, 49.1, 79.9, 95.5, 112.5,
150.9, 167.1; HRMS Found (M+H)+ 255.1587, C14H22O4 requires
(M+H)+ 255.1591.
(1S,4aS,7S,7aR)-Ethyl 7-methyl-1-(((2S,3R,4S,5S,6R)-3,4,5-
trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-
1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-4-carboxylate (25)
(1S,4aS,7S,7aR)-tert-butyl 1-Acetoxy-7-methyl-1,4a,5,6,7,7a-
hexahydrocyclo penta[c]pyran-4-carboxylate and (1R,4aR,7R,
7aS)-tert-butyl 1-Acetoxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclo
penta[c]pyran-4-carboxylate (7a)
Using the procedure reported for the synthesis of 16b the title com-
pound 25 was prepared by glycosylation followed by deacetylation
as a gum which was separable from the alternate diastereoisomer (9
mg, 34%). Rf 0.1 (20 : 1 v/v EtOAc : MeOH) 1H-NMR (300 MHz,
CDCl3) d 1.01 (d, J = 6.3 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.24–
1.29 (m, 1H), 1.38–1.50 (m, 1H), 1.86–1.99 (m, 3H), 2.16–2.25
(m, 1H) 2.97 (q, J = 7.8 Hz, 1H), 3.36 (dd, J = 9.3, 8.1 Hz, 1H),
3.44–3.65 (m, 3H), 3.50 (dd, J = 12.3, 5.6 Hz, 1H), 3.96, (dd, J
= 12.3, 2.1 Hz, 1H), 4.22–4.29 (m, 2H), 4.91 (q, J = 8.1 Hz, 2H),
5.38 (d, J = 4.5 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H); HRMS Found
(M+Na)+ 411.1624, C18H28O9 requires (M+Na)+ 411.1626.
Using the procedure reported for the synthesis of 7c6b the title
compound 7a was prepared as a clear and colourless oil (8
mg, 61%). Rf 0.5 (1 : 3, v/v EtOAc : hexane) IR nmax 2978, 1745,
1721, 1666, 1495, 1120 cm-1; 1H-NMR (300 MHz, CDCl3) d
1.07 (d, J = 6.3 Hz, 3H), 1.11–1.23 (m, 1H), 1.41–1.54 (m,
1H), 1.47 (s, 9H), 1.68–1.90 (m, 2H), 2.12 (s, 3H), 2.16–2.27
(m, 2H), 2.85–2.94 (m, 1H), 5.95 (d, J = 4.5 Hz, 1H), 7.24 (d,
J = 1.5 Hz, 1H); 13C-NMR (75 MHz, CDCl3) d 19.8, 20.2, 28.1,
31.8, 32.0, 33.1, 34.8, 47.7, 81.1, 91.0, 112.3, 150.9, 167.6, 169.0;
HRMS Found (M+H)+ 297.1699, C16H24O5 requires (M+H)+
297.1697.
Acknowledgements
The authors thank the ARC (DP0881137), Monash University
Research Accelerator Program and the Cancer CRC (for a partial
scholarship to LC) for financial support.
(1S,4aS,7S,7aR)-Ethyl 1-acetoxy-7-methyl-1,4a,5,6,7,7a-
hexahydrocyclopenta[c]pyran-4-carboxylate and (1R,4aR,-
7R,7aS)-Ethyl 1-acetoxy-7-methyl-1,4a,5,6,7,7a-
hexahydrocyclopenta[c]pyran-4-carboxylate (7b)
Notes and references
Using the procedure reported for the synthesis of 7a6b the title
compound 7b was prepared in two steps from lactone 4b without
purification following the reduction (19 mg, 46%). Rf 0.5 (1 : 3,
v/v EtOAc : hexane) 1H-NMR (300 MHz, CDCl3) d 1.07 (d, J =
6.0 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.18–1.27 (m, 1H), 1.41–
1.51 (m, 1H), 1.72–1.91 (m, 2H), 2.10 (s, 3H), 2.16–2.17 (m, 2H),
2.89–2.96 (m, 1H), 4.11–4.23 (m, 2H), 5.94 (d, J = 4.8 Hz, 1H),
7.33 (s, 1H); 13C-NMR (75 MHz, CDCl3) d 14.2, 19.9, 20.9,
31.8, 33.0, 33.1, 35.2, 47.2, 59.9, 91.5, 112.2, 150.2, 167.0, 169.6;
HRMS Found (M+H)+ 269.1382, C14H20O5 requires (M+H)+
269.1384.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8182–8189 | 8189
©