Synthesis of the tricyclic core of the marine natural product labiatin A

Article abstract of DOI:10.1055/s-2005-918485

A synthetic route to a model of the tricyclic core of labiatin A is described. Two catalytic metal carbenoid reactions, C-H insertion and oxonium ylide generation with subsequent [2,3]-sigmatropic rearrangement, have been used to assemble the tricyclic sy

Full text of DOI:10.1055/s-2005-918485

3398
PAPER
Synthesis of the Tricyclic Core of the Marine Natural Product Labiatin A
S
ynthesis
.of the
T
ricyc
S
lic Core of La
t
biatin Aephen Clark,*a Carl A. Baxter,a José L. Castrob
a
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
Fax +44(115)9513564; E-mail: j.s.clark@nottingham.ac.uk
b
Received 9 September 2005
Dedicated to Professor Steven V. Ley, FRS, on the occasion of his 60th birthday
The unusual tricyclic framework of labiatin A coupled
Abstract: A synthetic route to a model of the tricyclic core of labi-
atin A is described. Two catalytic metal carbenoid reactions, C–H
insertion and oxonium ylide generation with subsequent [2,3]-sig-
matropic rearrangement, have been used to assemble the tricyclic
system in an efficient and stereoselective manner.
with the dense array of oxygen-containing functionality
and multiple stereogenic centres make it an attractive but
challenging synthetic target. In other work, we have de-
veloped a powerful strategy for the synthesis of the
bridged ether core of the structurally related terrestrial
natural product neoliacinic acid (Figure 1), by sequential
use of a carbenoid C–H insertion reaction and tandem ox-
onium ylide generation and rearrangement.3 The retrosyn-
thetic analysis of labiatin A incorporating this strategy is
shown in Scheme 1. Simple functional group interconver-
sion and dehydration leads to the diketone i. Disconnec-
Key words: carbenoid, ylide, rearrangement, stereoselective syn-
thesis, natural product
Labiatin A, a highly oxygenated natural product belong-
ing to the eunicellin (cladiellin) family of diterpenoids,
was isolated from a sample of the gorgonian coral Euni-
cella labiata collected off the coast of Senegal (Figure 1).1
Four other eunicellin diterpenoids (labiatins B and C, and
labiatamides A and B) were later isolated from the same
coral and were found to possess the C-2–C-9 ether linkage
which is characteristic of this class of natural product (e.g.
labiatins B and C, Figure 1).2 In contrast, labiatin A has an
unusual C-2–C-6 ether bridge and is structurally unique
with regard to marine natural products.
tion via
a
retrosynthetic ylide formation and
rearrangement sequence gives the diazo ketone ii, and fur-
ther simplification produces the dihydro-3(2H)-furanone
iii. A retrosynthetic carbenoid C–H insertion reaction then
reveals the diazo ketone iv.
OAc
H
O
OMe
H
H
AcO
Me
AcO
Me
H
O
OAc
H
O
Me
HO
OMe
O
H
H
H
Me
Me
Me
Me
Me
O
CO2H
H
AcO
Me
OAc
i
H
O
Me
O
O
H
H
H
H
Me
Me
Me
AcO
Me
O
RO
O
O
OAc
OH
neoliacinic acid
labiatin A
O
H
O
H
H
H
AcO
AcO
N2
ii
RO
O
O
Me
Me
Me
Me
Me
Me
AcO
Me
AcO
Me
iii
Me
Me
H
H
H
H
H
H
H
H
OR
N2
OAc
OAc
O
O
Me
Me
O
H
O
HO
labiatin C
RO
Me
Me
iv
labiatin B
Scheme 1 Retrosynthetic analysis of labiatin A
Figure 1 The labiatin family of marine natural products and neoli-
acinic acid
In order to test the viability of the synthetic strategy im-
plied by the retrosynthetic analysis shown above, we pre-
pared the diazo ketone 5 (Scheme 2). The synthesis
commenced with the alcohol 1, which we have prepared
previously3 by chelation-controlled addition of an organo-
copper reagent to the chiral pool derived compound (R)-
isopropylideneglyceraldehyde (Scheme 2).4 The alcohol
SYNTHESIS 2005, No. 19, pp 3398–3404
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918485; Art ID: C06705SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

PAPER
Synthesis of the Tricyclic Core of Labiatin A
3399
1 was converted into the ether 2 by standard Williamson Reaction of the diazo ketone 5 with rhodium(II)
coupling with 1-(bromomethyl)cyclohexene (prepared trifluoroacetamide7 in THF at reflux resulted in rhodium
from a commercially available ester in two steps).5 Re- carbenoid formation and subsequent intramolecular C–H
moval of the acetonide protecting group afforded the cor- insertion to give the required dihydro-3(2H)-furanone 6 as
responding 1,2-diol and treatment of the diol with sodium an inseparable mixture of diastereoisomers (ca. 2:1,
periodate delivered the aldehyde 3. Subsequent chlorite cis:trans) in 60% yield (Scheme 3 and Table 1, entry 1).
oxidation6 provided the carboxylic acid 4 and this was Diastereoisomeric mixtures of the acetal 7, arising from
then converted into the diazo ketone 5 by reaction with anomalous C–H insertion,8 and the intramolecular cyclo-
isobutylchloroformate and treatment of the resulting propanation product 8 were also isolated. The inseparable
mixed anhydride with a large excess of ethereal diazo- 2:1 mixture of diastereoisomers of dihydro-3(2H)-fura-
methane.
none 6 was used in the next step of the synthesis
(Scheme 4).
Me
Me
Me
Me
Br
H
H
O
O
O
O
H
X
O
Y
a
H
+
Rh2L4 cat.,
OH
O
5
O
+
O
H
H
H
H
H
solvent, r.t./reflux
PMBO
1
PMBO
O
2
PMBO
6 X = O, Y = CH2
7 X = CH2, Y = O
8
PMBO
b, c
Scheme 3
O
OH
O
H
O
d
In subsequent studies, the carbenoid C–H insertion reac-
tion was explored in detail and several rhodium catalysts
and reaction conditions were investigated (Scheme 3,
Table 1). The catalysts were selected based on data ob-
tained during our work concerning the synthesis of neoli-
acinic acid.3 The results obtained using rhodium(II)
trifluoroacetamide dimer as catalyst under various reac-
tion conditions are shown (Table 1, entries 1–4). CH2Cl2
proved to be an unsuitable solvent because it tended to
promote alkene cyclopropanation at the expense of C–H
insertion. Lowering the reaction temperature from reflux
H
H
PMBO
O
PMBO
4
3
e
N2
O
H
PMBO
5
Scheme 2 Preparation of the diazo ketone 5, the precursor required to ambient temperature resulted in an improvement in the
for the carbenoid C–H insertion reaction. Reagents and conditions:
(a) NaH, THF, r.t. → reflux, then 1-(bromomethyl)cyclohexene,
THF, r.t. → reflux, 91% (based on recovered starting material); (b)
tate dimer as the catalyst (Table 1, entries 5 and 6) result-
PPTS (0.2 equiv), HO(CH2)2OH–THF–CH2Cl2 (2:1:1), reflux; (c)
ratio of cis:trans isomers (2:1 → 6:1) of the (2H)-furanone
6 without altering the yield. The use of rhodium(II) ace-
ed in a decrease in the yield of the required C–H insertion
product 6. In studies concerning the synthesis of neolia-
cinic acid, the bulky catalyst rhodium(II) triphenylacetate
NaIO4 (4 equiv), THF–H2O, r.t., 96% over 2 steps; (d) NaClO2 (7.5
equiv), NaH2PO4 (6.5 equiv), 2-methyl-2-butene (8.1 equiv), t-
BuOH, H2O, r.t.; (e) i-BuOCOCl (1 equiv), Et3N, Et2O, r.t. then
CH2N2, Et2O, 0 °C → r.t., 76% over 2 steps.
Table 1 The Influence of Catalyst and Conditions on the Reaction of the Diazo Ketone 5 (Scheme 3)
Entry
L
Solvent
THF
Temp
reflux
r.t.
Yield of 6 (%) (cis:trans)a Yield of 7, 8 (%)
1
2
3
4
5
6
7
HNCOCF3
HNCOCF3
HNCOCF3
HNCOCF3
O2CCH3
O2CCH3
O2CCPh3
60 (2:1)
59 (6:1)
21 (2:1)
33 (3:1)
26 (7:1)
16 (4:1)
32 (2:3)
7 (13), 8 (16)
8 (13)
THF
CH2Cl2
CH2Cl2
THF
reflux
r.t.
8 (35)
8 (27)
reflux
r.t.
7 (2), 8 (36)
8 (21)
THF
CH2Cl2
r.t.
7 (7), 8 (16)
a Diastereomeric ratio determined by NMR.
Synthesis 2005, No. 19, 3398–3404 © Thieme Stuttgart · New York

3400
J. S. Clark et al.
PAPER
dimer had given good results,3a but low yields were ob- investigated, but the optimum conditions were those used
tained when this catalyst was employed, and in one case during our work concerning the synthesis of the core of
only starting material was isolated. The unstable acetal 7, neoliacinic acid (Table 2, entry 1).3 Treatment of the a-di-
arising by anomalous C–H insertion, was also isolated in azo ketone 13 with copper(II) hexafluoroacetylacetonate
low yield from several of the reactions (entries 1, 5 and 7).8 [Cu(hfacac)2] in CH2Cl2 at reflux afforded the ether-
bridged compounds 15 and 16 in a combined yield of 83%
Conversion of the (2H)-furanone 6 into the key cyclisa-
with the required [2,3]-rearrangement product 15 (3:2,
tion precursor 13 was accomplished using the route shown
E:Z isomer mixture) predominating. It proved difficult to
in Scheme 4. The methyl group was installed by treatment
separate the oxabicyclo[3.3.1]nonane 16, arising from a
[1,2]-shift of the oxonium ylide intermediate, from the re-
of the ketone 6 with methyllithium. At this stage, 1H NMR
NOE experiments performed on the tertiary alcohol 9 con-
firmed that the required cis relationship had been estab-
lished upon carbenoid C–H insertion, and that
nucleophilic addition of methyllithium had given the ex-
quired [2,3]-rearrangement product 15 and so the mixture
was subjected to isomerisation,10 giving the thermody-
namically favoured (Z)-15 (Scheme 5).
pected diastereoisomer. Acetylation of the tertiary alcohol
Me
AcO
Me
AcO
to give the ester 10 was achieved using standard tech-
niques and removal of the p-methoxybenzyl protecting
group using CAN9 gave the alcohol 11. Oxidation of the
free hydroxyl group to give the aldehyde 12 was per-
formed using Dess–Martin periodinane, and subsequent
chlorite oxidation delivered the corresponding carboxylic
acid.6 The diazo ketone 13 was then obtained by conver-
sion of the carboxylic acid into the corresponding acid
chloride followed by treatment with diazomethane.
MLn, solvent
reflux
O
O
H
H
H
H
N2
13
O
O
14
[2,3]
[1,2]
Ha
Hb
AcO
Me
H
J = 12.6 Hz
AcO
H
AcO
AIBN,
Me
HO
O
O
H
O
Me
H
O
+
H
Me
H
O
EtSH,
C6H6, reflux
O
a
O
H
O
O
(Z)-15 64% (E:Z, 3:2)
15
H
H
H
H
16
Scheme 5 Construction of the tricyclic core of labiatin A
PMBO
6
PMBO
9
b
Table 2 The Influence of Catalyst and Conditions on the Reaction
of Diazo Ketone 13 (Scheme 5)
Me
AcO
Me
AcO
Entry
MLn
Solvent
Yield 15 + 16 Ratioa 15
c
(%), Ratioa
(E:Z)
O
O
H
H
H
H
15:16
1
2
3
4
Cu(hfacac)2
Cu(hfacac)2
Cu(acac)2
CH2Cl2
C6H6
83, 2:1
52, 6:1
35, 2:1
22, 3:1
3:2
4:1
1:1
1:6
HO
11
PMBO
10
d
Me
AcO
Me
AcO
CH2Cl2
b
e-g
Rh2(O2CCH3)4
CH2Cl2
O
O
H
H
H
H
a Product and diastereomeric ratio determined by NMR.
b Reaction performed at r.t.
N2
13
O
O
12
It was important to establish that the relative configuration
of the stereogenic centre in the cyclohexyl ring of the tri-
cyclic product (Z)-15 corresponded to that in labiatin A.
The 1H NMR data for compound (Z)-15 proved to be con-
clusive: the signal for the proton Hb is a doublet with J =
12.6 Hz as a consequence of the coupling between Ha and
Hb. The magnitude of the coupling constant is indicative
of a large dihedral angle and that the relationship between
Ha and Hb is anti. The 1H NMR NOE data also provided
strong evidence that the relative configurations of the ste-
reogenic centres in the tricyclic compound (Z)-15 are the
same as the corresponding stereogenic centres in labiatin
A.
Scheme 4 Preparation of the diazo ketone 13, the precursor required
for the tandem oxonium ylide formation and rearrangement. Reagents
and conditions: (a) MeLi (2 equiv), PhMe, –78 °C → r.t., 60%; (b)
Ac2O (5 equiv), DMAP (3 equiv), Et3N, Et2O, r.t., 77%; (c) CAN (2
equiv), MeCN–H2O (9:1), r.t., 86%; (d) Dess–Martin periodinane
(1.5 equiv), CH2Cl2, 0 °C → r.t., 83%; (e) NaClO2 (7.5 equiv),
NaH2PO4 (6.5 equiv), 2-methyl-2-butene (8 equiv), t-BuOH, H2O,
r.t.; (f) NaOMe (1 equiv), MeOH, r.t.; (g) (COCl)2 (5 equiv), C6H6, r.t.
then CH2N2, Et2O, 0 °C, 77% over 3 steps.
It was now possible to explore the pivotal model reaction
that would deliver the fused tricyclic framework found in
labiatin A (Scheme 5). Several reaction conditions were
Synthesis 2005, No. 19, 3398–3404 © Thieme Stuttgart · New York

PAPER
Synthesis of the Tricyclic Core of Labiatin A
3401
CH2CH2CH2CH2, OCHCH2CH2), 1.37–1.48 (m,
OCHCH2CH2), 1.41 [s, 3 H, C(CH3)2], 1.35 [s, 3 H, C(CH3)2].
1
H,
In summary, we have assembled the core of labiatin A in
an efficient manner using metal carbenoid transforma-
tions. Intramolecular C–H insertion was used to construct 13C NMR (100 MHz, CDCl3): d = 159.1 (C), 135.3 (C), 130.7 (C),
129.2 (CH), 125.1 (CH), 113.7 (CH), 109.2 (C), 78.9 (CH), 78.0
a dihydro-3(2H)-furanone and subsequent elaboration by
(CH), 75.8 (CH2), 72.5 (CH2), 69.9 (CH2), 65.8 (CH2), 55.2 (CH3),
a sequence involving tandem oxonium ylide formation
27.1 (CH2), 26.5 (CH3), 26.1 (CH2), 25.9 (CH2), 25.4 (CH3), 25.0
and [2,3]-rearrangement delivered the complete tricyclic
(CH2), 22.5 (CH2), 22.4 (CH2).
system.
HRMS (CI; CH4): m/z [M+ + H] calcd for C24H37O5: 405.2641;
found: 405.2624.
We are currently exploiting carbenoid methodology to
synthesise labiatin A. Results of this work will be reported
in due course.
Anal. Calcd for C24H36O5 (404.55): C, 71.26; H, 8.97. Found: C,
71.26; H, 9.02.
(2R)-5-(Benzyloxy)-2-(cyclohex-1-en-1-ylmethoxy)pentanal (3)
Pyridinium p-toluene sulfonate (656 mg, 2.61 mmol) was added to
a solution of 2 (5.28 g, 13.1 mmol) in ethylene glycol (184 mL),
THF (92 mL) and CH2Cl2 (92 mL) and heated at reflux for 20 h. The
reaction was allowed to cool to r.t. and was neutralised with concd
NH3 solution (ca. 2 mL). The mixture was diluted with water (200
mL) and extracted with CH2Cl2 (3 × 100 mL). The organic extracts
were combined and washed with water (150 mL) and brine (100
mL), dried (MgSO4) and concentrated in vacuo to give a yellow oil.
The crude diol was dissolved in THF (153 mL) and then water (61
mL) and sodium periodate (11.17 g, 52.22 mmol) were added at r.t.
over 10 min. The mixture was allowed to stir for 90 min, quenched
with water (150 mL), and then extracted with Et2O (3 × 100 mL).
The Et2O extracts were combined and washed with water (150 mL)
and brine (100 mL), then dried (MgSO4) and concentrated in vacuo
to give a yellow oil. Flash column chromatography on silica gel
(PE–EtOAc, 9:1 → 4:1) gave the aldehyde 3 (4.15 g, 96%) as a co-
lourless oil; [a]D23 +4.6 (c = 0.82, CHCl3).
Solvents were distilled prior to use: THF by distillation from sodi-
um and benzophenone, Et2O by distillation from sodium and ben-
zophenone, CH2Cl2 by distillation from CaH2. Reagents were used
as supplied unless otherwise stated. Petroleum ether (PE) used had
the boiling point in the range 40–60 °C. TLC was performed using
Merck Kiesegel 60 F254 plates and visualisation was by UV light
and staining with ethanolic anisaldehyde or ceric ammonium mo-
lybdate with heat. Flash column chromatography was performed us-
ing Merck Kiesegel silica gel. 1H NMR spectra were recorded on a
Bruker DRX 500 or Bruker AV 400 FT spectrometer at ambient
temperature. Data are reported as chemical shifts in ppm relative to
residual CHCl3 or TMS on the d scale, multiplicity (br = broad, s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, or combi-
nations thereof), coupling constant (J), integration, and assignment.
13C NMR spectra were recorded on a Bruker DRX 500 (125 MHz)
or a Bruker AV 400 (100 MHz) FT spectrometer at ambient temper-
ature. Data are reported as chemical shifts in ppm relative to resid-
ual CHCl3 on the d scale and assignment. Assignments were made
using DEPT 135 and DEPT 90 pulse experiments and HMQC ex-
periments. IR spectra were recorded in the range 600–4000 cm–1 on
a Perkin–Elmer 1600 FT-IR instrument at ambient temperature.
HRMS data were obtained using chemical ionisation on a Fisons
VG autospec instrument. Elemental analyses were carried out on an
Exeter Analytical Inc. CE-440 elemental analyser. Optical rotations
were obtained using a Jasco DIP 370 digital polarimeter.
IR (CHCl3): 2936, 2861, 2838, 1722, 1612, 995, 908, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.61 (d, J = 2.2 Hz, 1 H, CHO),
7.24 (d, J = 8.7 Hz, 2 H, ArH), 6.87 (d, J = 8.7 Hz, 2 H, ArH), 5.67
(br, 1 H, C=CH), 4.41 (s, 2 H, OCH2Ar), 3.95 (d, J = 11.1 Hz, 1 H,
OCH2C=CH), 3.84 (d, J = 11.1 Hz, 1 H, OCH2C=CH), 3.79 (s, 3 H,
OCH3), 3.64–3.68 (m, 1 H, OCHCH2CH2), 3.40–3.48 (m, 2 H,
CH2OPMB), 2.00–2.03 (m, 4 H, CH2C=CHCH2), 1.53–1.80 (m, 8
H, OCHCH2CH2, CH2CH2CH2CH2).
13C NMR (100 MHz, CDCl3): d = 204.2 (CH), 159.2 (C), 134.2 (C),
130.5 (C), 129.3 (CH), 126.6 (CH), 113.8 (CH), 82.7 (CH), 75.6
(CH2), 72.6 (CH2), 69.4 (CH2), 55.3 (CH3), 26.9 (CH2), 26.1 (CH2),
25.1 (CH2), 25.0 (CH2), 22.4 (CH2), 22.3 (CH2).
4-O-(Cyclohex-1-en-1-ylmethyl)-2,3-dideoxy-1-O-(4-methoxy-
benzyl)-5,6-O-(1-methylethylidene)-D-threo-hexitol (2)
A solution of the alcohol 1 (5.80 g, 18.7 mmol) in anhyd THF (31
mL) was added to a stirred suspension of NaH (539 mg, 24.3 mmol)
in anhyd THF (196 mL) at r.t. under N2. The mixture was heated at
reflux for 1 h under N2, then a solution of 1-(bromomethyl)cyclo-
hexene (4.26 g, 22.4 mmol) in anhyd THF (78 mL) was added by
cannula under N2. The reaction was heated at reflux for 24 h and
then allowed to cool to r.t. The reaction was quenched by the addi-
tion of sat. NH4Cl solution (50 mL) and water (200 mL). The reac-
tion mixture was then extracted with Et2O (3 × 150 mL). The Et2O
extracts were combined and washed with water (200 mL) and brine
(100 mL), then dried (MgSO4) and concentrated in vacuo to give a
brown oil. Flash column chromatography on silica gel (PE–EtOAc,
HRMS (CI; CH4): m/z [M+] calcd for C20H28O4: 332.1988; found:
332.1985.
(3R)-3-(Cyclohex-1-en-1-ylmethoxy)-1-diazo-6-[(4-methoxy-
benzyl)oxy]hexan-2-one (5)
A solution of sodium chlorite (80%, 8.73 g, 96.6 mmol) and sodium
dihydrogenorthophosphate dihydrate (13.04 g, 83.60 mmol) in wa-
ter (129 mL) was added dropwise over 10 min at r.t. to a solution of
the aldehyde 3 (4.15 g, 12.9 mmol) and 2-methyl-2-butene (11.0
mL of 90% solution, 104 mmol) in t-BuOH (65 mL). The mixture
was left to stir for 90 min at r.t., then the volatile compounds were
removed in vacuo and the mixture was extracted with Et2O (3 × 100
mL). The Et2O extracts were combined and washed with water (100
mL) and brine (80 mL), dried (MgSO4) and concentrated in vacuo.
22
19:1 → 1:1) gave the ether 2 (5.92 g, 78%) as a clear oil; [a]D
+20.5 (c = 1.9, CHCl3).
IR (CHCl3): 2934, 2860, 2838, 1681, 1612, 999, 861, 840 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.25 (d, J = 8.6 Hz, 2 H, ArH),
6.87 (d, J = 8.6 Hz, 2 H, ArH), 5.67 (br, 1 H, C=CH), 4.42 (s, 2 H,
OCH2Ar), 4.16 (ddd, J = 6.3, 6.6, 7.4 Hz, 1 H, OCH2CHO), 4.02 (d,
J = 11.3 Hz, 1 H, OCH2C=CH), 3.96 (dd, J = 6.6, 8.2 Hz, 1 H,
OCH2CHO), 3.88 (d, J = 11.3 Hz, 1 H, OCH2C=CH), 3.79 (s, 3 H,
OCH3), 3.68 (dd, J = 7.4, 8.2 Hz, 1 H, OCH2CHO), 3.40–3.48 (m,
2 H, CH2OPMB), 3.33 (ddd, J = 3.6, 6.3, 8.7 Hz, 1 H, OCHCHO),
The unpurified acid was dissolved in anhyd Et2O (84 mL), stirred at
r.t. under Ar and Et3N (1.97 mL, 14.2 mmol) and isobutylchlorofor-
mate (1.84 mL, 14.2 mmol) were added sequentially. The mixture
was stirred for 3 h, then filtered and added dropwise over 20 min to
a solution of diazomethane (ca. 129 mmol in 161 mL of Et2O) at 0
°C. The resulting solution was stirred overnight and the excess dia-
zomethane was then quenched with AcOH (3 mL). After 30 min the
solution was diluted with Et2O (100 mL) and washed with sat.
1.98–2.05 (m,
4
H, CH2C=CHCH2), 1.85–1.75 (m,
1 H,
OCHCH2CH2),
1.71–1.49 (m, H, OCHCH2CH2,
6
Synthesis 2005, No. 19, 3398–3404 © Thieme Stuttgart · New York

3402
J. S. Clark et al.
PAPER
NaHCO3 solution (100 mL) and brine (80 mL). The ethereal solu-
tion was then dried (MgSO4) and concentrated in vacuo. The result-
ing yellow oil was purified by flash column chromatography on
silica gel (PE–EtOAc, 10:1 → 7:1) to afford the diazo ketone 5
(3.67 g, 76%) as a yellow oil; [a]D21 +49.8 (c = 1.28, CHCl3).
Compound 7
Mixture of isomers (4:1).
IR (CHCl3): 2928, 2862, 1684, 1614, 983, 899 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.7 Hz, 2 H, ArH),
6.88 (d, J = 8.7 Hz, 2 H, ArH), 5.97–5.99 [m, 1 H, C=CH (minor)],
5.91–5.94 [m, 1 H, C=CH (major)], 5.51 [s, 1 H, OCHO (major)],
5.37 [s, 1 H, OCHO (minor)], 4.62–4.65 [m, 1 H, OCHCH2 (ma-
jor)], 4.48–4.53 [m, 1 H, OCHCH2 (minor)], 4.44 (s, 2 H, OCH2Ar),
4.31 [t, J = 2.0 Hz, 1 H, CH2=C (major)], 4.29 [t, J = 2.2 Hz, 1 H,
CH2=C (minor)], 3.83 [dd, J = 1.3, 2.2 Hz, 1 H, CH2=C (major)],
3.80–3.81 [m, 1 H, CH2=C (minor)], 3.81 (s, 3 H, OCH3), 3.45–3.54
(m, 2 H, CH2OCH2Ar), 1.98–2.09 (m, 4 H, CH2C=CHCH2), 1.71–
IR (CHCl3): 2934, 2860, 2838, 2109, 1634, 1000, 878, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 8.6 Hz, 2 H, ArH),
6.87 (d, J = 8.6 Hz, 2 H, ArH), 5.72 (s, 1 H, CHN2), 5.67 (br, 1 H,
C=CH), 4.41 (s, 2 H, OCH2Ar), 3.91 (d, J = 11.4 Hz, 1 H,
OCH2C=CH), 3.80 (s, 3 H, OCH3), 3.74 (d, J = 11.4 Hz, 1 H,
OCH2C=CH), 3.72–3.78 (m, 1 H, OCHCH2CH2), 3.44 (t, J = 5.6
Hz, 2 H, CH2OPMB), 1.96–2.04 (m, 4 H, CH2C=CHCH2), 1.53–
1.80 (m, 8 H, OCHCH2CH2, CH2CH2CH2CH2).
13C NMR (100 MHz, CDCl3): d = 197.9 (C), 159.2 (C), 134.1 (C),
130.7 (C), 129.3 (CH), 126.1 (CH), 113.8 (CH), 83.0 (CH), 75.4
(CH2), 72.6 (CH2), 69.7 (CH2), 55.3 (CH3), 52.3 (CH), 30.1 (CH2),
26.2 (CH2), 25.5 (CH2), 25.0 (CH2), 22.5 (CH2), 22.3 (CH2).
1.85 (m,
4 H, OCHCH2CH2CH2O), 1.58–1.68 (m, 4 H,
CH2CH2CH2CH2).
13C NMR (100 MHz, CDCl3): d = 160.2 (C), 160.0 (C), 159.2 (C),
134.6 (C), 133.9 (C), 130.7 (C), 130.6 (CH), 129.4 (CH), 129.3
(CH), 113.9 (CH), 107.3 (CH), 107.1 (CH), 78.1 (CH), 78.1 (CH2),
77.8 (CH2), 72.7 (CH2), 72.6 (CH2), 69.6 (CH2), 69.4 (CH2), 55.4
(CH3), 32.0 (CH2), 31.1 (CH2), 26.6 (CH2), 25.8 (CH2), 25.2 (CH2),
25.0 (CH2), 22.3 (CH2), 22.0 (CH2), 21.5 (CH2), 21.4 (CH2).
HRMS (CI, CH4): m/z [M+ + H] calcd for C21H29N2O4: 373.2127;
found: 373.2143.
Anal. Calcd for C21H28O4N2 (372.47): C, 67.72; H, 7.58; N, 7.52.
Found: C, 67.52; H, 7.57; N, 7.52.
HRMS (CI, NH3): m/z [M+] calcd for C21H28O4: 344.1988; found:
344.1992.
(2R,5R)-5-Cyclohex-1-en-1-yl-2-{3-[(4-methoxybenzyl)oxy]pro-
pyl}dihydrofuran-3(2H)-one (6), (2R,4R)-2-Cyclohex-1-en-1-yl-
4-{3-[(4-methoxybenzyl)oxy]propyl}-5-methylene-1,3-dioxo-
lane (7) and (3R)-3-{3-[(4-Methoxybenzyl)oxy]propyl}hexa-
hydrobenzo[1,3]cyclopropa[1,2-c]pyran-4(3H)-one (8)
A solution of diazo ketone 5 (130 mg, 0.349 mmol) in anhyd THF
(15 mL) was added dropwise over 40 min to a solution of rhodi-
um(II) trifluoroacetamide dimer (2 mg) in anhyd THF (2 mL) under
N2 at reflux. The reaction was stirred at reflux for a further 10 min,
allowed to cool to r.t. and concentrated in vacuo. Flash column
chromatography on silica gel (hexane–EtOAc, 9:1 → 4:1) gave the
dihydro-3(2H)-furanone 6 (67.5 mg, 60%, 2:1 mixture of diaste-
reoisomers), the enol ether acetal 7 (16 mg, 13%, 4:1 mixture of dia-
stereoisomers) and the cyclopropane 8 (18.5 mg, 16%, 2:1 mixture
of diastereoisomers) as colourless oils.
Compound 8
Mixture of isomers (2:1).
IR (CHCl3): 2935, 2859, 1679, 1613, 999, 867 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.23–7.26 (m, 2 H, ArH), 6.84–
6.88 (m, 2 H, ArH), 4.42 [s, 2 H, OCH2Ar (minor)], 4.41 [s, 2 H,
OCH2Ar (major)], 3.87–3.91 (m, 1 H, OCHCH2), 3.85 [d, J = 11.3
Hz, 1 H, OCH2 (major)], 3.79 (s, 3 H, OCH3), 3.68 [d, J = 11.6 Hz,
1 H, OCH2 (minor)], 3.58–3.61 (m, 1 H, OCHCH2), 3.59 (d, J =
11.6 Hz, 1 H, OCH2), 3.54 (d, J = 11.3 Hz, 1 H, CH2), 3.40–3.47 (m,
2 H, CH2OCH2Ar), 2.35 (m, 1 H, O=CCHCH), 1.84–1.97 (m, 2 H,
CH2CH2CH2CH2, OCHCH2CH2), 1.55–1.78 (m,
OCHCH2CH2, OCHCH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2,
O=CCHCH), 1.25–1.38 (m, 4 H, CH2CH2CH2CH2).
13C NMR (100 MHz, CDCl3): d = 207.8 (C), 207.4 (C), 159.1 (C),
130.7 (C), 129.2 (CH), 113.7 (CH), 82.1 (CH), 78.7 (CH), 72.5
(CH2), 72.4 (CH2), 69.7 (CH2), 69.4 (CH2), 67.8 (CH2), 62.1 (CH2),
55.3 (CH3), 39.0 (CH), 37.9 (CH), 29.0 (CH2), 28.7 (C), 28.6 (CH2),
25.9 (CH2), 25.7 (CH2), 25.5 (CH2), 24.6 (CH), 24.3 (CH2), 23.2
(CH), 23.1 (CH2), 21.1 (CH2), 20.4 (CH2).
7
H,
Compound 6
Mixture of isomers (2:1).
IR (CHCl3): 2934, 2860, 2838, 1754, 1613, 894, 838 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 8.6 Hz, 2 H, ArH),
6.87 (d, J = 8.6 Hz, 2 H, ArH), 5.83 [s, 1 H, C=CH (cis)], 5.74 [s, 1
H, C=CH (trans)], 4.66 [t, J = 7.2 Hz, 1 H, OCHC=CH (trans)],
4.45 [dd, J = 5.8, 10.8 Hz, 1 H, OCHC=CH (cis)], 4.42 (s, 2 H,
OCH2Ar), 3.96 [dd, J = 3.8, 8.0 Hz, 1 H, OCHCH2CH2 (trans)],
3.75–3.85 [m, 1 H, OCHCH2CH2 (cis)], 3.80 (s, 3 H, OCH3), 3.43–
3.48 (m, 2 H, CH2OCH2Ar), 2.54 [dd, J = 7.2, 18.0 Hz, 1 H,
CH2C=O (trans)], 2.48 [dd, J = 5.7, 18.0 Hz, 1 H, CH2C=O (cis)],
2.45 [dd, J = 7.2, 18.0 Hz, 1 H, CH2C=O (trans)], 2.34 [dd, J = 10.8,
18.0 Hz, 1 H, CH2C=O (cis)], 2.11–1.96 (m, 4 H, CH2C=CHCH2),
HRMS (CI, CH4): m/z [M+] calcd for C21H28O4: 344.1988; found:
344.1985.
(2R,5R)-2-[3-(Benzyloxy)propyl]-5-cyclohex-1-en-1-yl-3-meth-
yltetrahydrofuran-3-ol (9)
Methyllithium (1.60 M solution in Et2O, 345 mL, 0.552 mmol) was
added dropwise over 5 min to a solution of the ketone 6 (95 mg, 0.28
mmol, 2:1 mixture of diastereoisomers) in anhyd toluene (4 mL) at
–78 °C under Ar. The reaction was stirred for 16 h, being allowed
to warm to r.t. during this period. The reaction was quenched with
water (5 mL) at 0 °C and the mixture was extracted with Et2O (3 ×
10 mL). The combined Et2O extracts were washed with water (10
mL) and brine (8 mL), and then dried (MgSO4) and concentrated in
vacuo to give an oil. Flash column chromatography on silica gel
(hexane–EtOAc, 9:1 → 1:1) gave the alcohol 9 (59 mg, 60%, ca.
90% based on isomer composition of ketone 6) as a colourless oil;
[a]D21 +10.5 (c = 1.0, CHCl3).
1.53–1.92
(m,
8
H,
OCHCH2CH2,
OCHCH2CH2,
CH2CH2CH2CH2).
13C NMR (125 MHz, CDCl3): d = 216.7 (C), 216.4 (C), 159.1 (C),
136.2 (C), 135.6 (C), 130.6 (C), 129.3 (CH), 125.6 (CH), 124.6
(CH), 113.8 (CH), 81.1 (CH), 79.4 (CH), 79.3 (CH), 78.6 (CH),
72.5 (CH2), 69.7 (CH2), 69.5 (CH2), 55.3 (CH3), 41.5 (CH2), 40.6
(CH2), 27.8 (CH2), 27.7 (CH2), 25.7 (CH2), 25.4 (CH2), 25.0 (CH2),
25.0 (CH2), 24.0 (CH2), 23.5 (CH2), 22.4 (CH2), 22.4 (CH2).
HRMS (CI, NH3): m/z [M+] calcd for C21H28O4: 344.1988; found:
344.1984.
IR (CHCl3): 2936, 2860, 2838, 1612, 996, 914 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.6 Hz, 2 H, ArH),
6.87 (d, J = 8.6 Hz, 2 H, ArH), 5.82 (br, 1 H, C=CH), 4.44 (s, 2 H,
OCH2Ar), 4.17–4.20 (m, 1 H, OCHC=CH), 3.80 (s, 3 H, OCH3),
Anal. Calcd for C21H28O4 (344.45): C, 73.23; H, 8.19. Found: C,
72.84; H, 8.36.
Synthesis 2005, No. 19, 3398–3404 © Thieme Stuttgart · New York

PAPER
Synthesis of the Tricyclic Core of Labiatin A
3403
3.44–3.56 (m, 2 H, CH2OPMB), 3.41 (dd, J = 3.7, 8.8 Hz, 1 H,
OCHCH2CH2), 2.10 (dd, J = 9.0, 13.4 Hz, 1 H, CH2CHC=CH),
2.01–2.04 (m, 2 H, C=CHCH2), 1.87–1.96 (m, 2 H, CH2C=CH),
1.89 (dd, J = 5.6, 13.4 Hz, 1 H, CH2CHC=CH), 1.82 (br, 1 H, OH),
1.53–1.75 (m, 8 H, OCHCH2CH2, CH2CH2CH2CH2), 1.26 (s, 3 H,
CCH3).
13C NMR (125 MHz, CDCl3): d = 159.1 (C), 138.7 (C), 130.8 (C),
129.3 (CH), 121.8 (CH), 113.8 (CH), 86.4 (CH), 79.5 (CH), 78.5
(C), 72.6 (CH2), 70.1 (CH2), 55.3 (CH3), 46.0 (CH2), 27.1 (CH2),
25.1 (CH2), 24.9 (CH2), 24.6 (CH2), 23.1 (CH3), 22.6 (CH2), 22.5
(CH2).
1H NMR (400 MHz, CDCl3): d = 5.70 (br, 1 H, C=CH), 4.18 (dd,
J = 7.7, 7.8 Hz, 1 H, OCHC=CH), 3.64–3.72 (m, 2 H, CH2OH),
3.41–3.45 (m, 1 H, OCHCH2CH2), 2.54 (br, 1 H, OH), 2.40 (dd, J =
7.8, 14.3 Hz, 1 H, CH2CHC=CH), 2.23 (dd, J = 7.7, 14.3 Hz, 1 H,
CH2CHC=CH), 1.94–1.99 (m, 2 H, C=CHCH2), 1.97 (s, 3 H,
CH3C=O), 1.80–1.94 (m, 2 H, CH2C=CH), 1.71–1.77 (m, 4 H,
OCHCH2CH2), 1.50–1.65 (m, 4 H, CH2CH2CH2CH2), 1.52 (s, 3 H,
CCH3).
13C NMR (100 MHz, CDCl3): d = 170.6 (C), 136.6 (C), 123.5 (CH),
87.7 (CH), 86.5 (C), 80.9 (CH), 63.0 (CH2), 42.5 (CH2), 30.5 (CH2),
26.0 (CH2), 25.0 (CH2), 23.9 (CH2), 22.5 (CH2), 22.5 (CH2), 22.1
(CH3), 21.6 (CH3).
HRMS (CI, CH4): m/z [M+] calcd for C22H32O4: 360.2301; found:
360.2315.
HRMS (CI, NH3): m/z [M+ + H] calcd for C16H27O4: 283.1909;
found: 283.1901.
Anal. Calcd for C22H32O4 (360.49): C, 73.30; H, 8.95. Found: C,
73.15; H, 8.87.
3-[(2R,3S,5R)-3-(Acetyloxy)-5-cyclohex-1-en-1-yl-3-methyl-
tetrahydrofuran-2-yl]propanal (12)
(2R,3S,5R)-5-Cyclohex-1-en-1-yl-2-[3-(4-methoxybenzyl)oxy-
propyl]-3-methyltetrahydrofuran-3-yl Acetate (10)
Dess–Martin periodinane (771 mg, 1.82 mmol) was added in 3 por-
tions at 30 min intervals to a solution of the alcohol 11 (342 mg,
1.21 mmol) in anhyd CH2Cl2 (17 mL) at 0 °C under Ar. The mixture
was stirred for a further 1 h at r.t. and then quenched by the addition
of sat. sodium thiosulfate solution (10 mL). The mixture was ex-
tracted with CH2Cl2 (3 × 30 mL) and the combined extracts were
washed with sat. NaHCO3 solution (20 mL), water (20 mL) and
brine (20 mL). The extracts were dried (MgSO4) and concentrated
in vacuo to give a cloudy oil. Flash column chromatography on sil-
ica gel (PE–EtOAc, 9:1 → 4:1) gave the aldehyde 12 (282 mg, 83%)
as a colourless oil; [a]D21 –9.6 (c = 1.08, CHCl3).
Ac2O (864 mL, 9.15 mmol) was added to a solution of the alcohol 9
(660 mg, 1.83 mmol), DMAP (671 mg, 5.49 mmol) and Et3N (2.04
mL, 14.6 mmol) in anhyd Et2O (24 mL) at r.t. under Ar and the re-
sulting solution was stirred for 20 h. Water (30 mL) was added and
the mixture was extracted with Et2O (3 × 50 mL). The Et2O extracts
were combined and washed with water (50 mL) and brine (30 mL),
then dried (MgSO4) and concentrated in vacuo to give an oil. Flash
column chromatography on silica gel (PE–EtOAc, 19:1 → 4:1)
21
gave the acetate 10 (570 mg, 77%) as a colourless oil; [a]D –9.7
(c = 1.01, CHCl3).
IR (CHCl3): 2933, 2860, 2838, 1725, 996, 950, 892 cm–1.
IR (CHCl3): 2935, 2860, 2839, 1727, 1612, 997, 950, 909 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.83 (t, J = 1.3 Hz, 1 H, CHO),
5.71 (br, 1 H, C=CH), 4.16 (dd, J = 7.6, 8.0 Hz, 1 H, OCHC=CH),
3.47 (dd, J = 4.4, 8.3 Hz, 1 H, OCHCH2CH2), 2.73 (dddd, J = 1.3,
6.5, 7.8, 18.1 Hz, 1 H, OCHCH2CH2), 2.61 (dddd, J = 1.3, 7.2, 7.7,
18.1 Hz, 1 H, OCHCH2CH2), 2.37 (dd, J = 8.0, 14.2 Hz, 1 H,
CH2CHC=CH), 2.26 (dd, J = 7.6, 14.2 Hz, 1 H, CH2CHC=CH),
1.90–2.04 (m, 5 H, OCHCH2CH2, CH2C=CH, C=CHCH2), 2.00 (s,
3 H, CH3C=O), 1.81–1.88 (m, 1 H, CH2C=CH), 1.50–1.66 (m, 4 H,
CH2CH2CH2CH2), 1.55 (s, 3 H, CCH3).
13C NMR (100 MHz, CDCl3): d = 202.3 (CH), 170.4 (C), 136.7 (C),
123.4 (CH), 86.3 (CH), 86.2 (C), 80.8 (CH), 42.5 (CH2), 41.1
(CH2), 24.9 (CH2), 23.7 (CH2), 22.5 (CH2), 22.5 (CH2), 22.0 (CH3),
21.7 (CH3), 21.6 (CH2).
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.7 Hz, 2 H, ArH),
6.87 (d, J = 8.7 Hz, 2 H, ArH), 5.72 (br, 1 H, C=CH), 4.46 (d, J =
11.6 Hz, 1 H, OCH2Ar), 4.43 (d, J = 11.6 Hz, 1 H, OCH2Ar), 4.14
(t, J = 7.7 Hz, 1 H, OCHC=CH), 3.80 (s, 3 H, OCH3), 3.45–3.56 (m,
2 H, CH2OPMB), 3.42 (dd, J = 4.5, 6.1 Hz, 1 H, OCHCH2CH2),
2.36 (dd, J = 7.9, 14.2 Hz, 1 H, CH2CHC=CH), 2.23 (dd, J = 7.6,
14.2 Hz, 1 H, CH2CHC=CH), 1.93–2.03 (m, 3 H, C=CHCH2,
CH2C=CH), 1.98 (s, 3 H, CH3C=O), 1.80–1.92 (m, 2 H,
OCHCH2CH2, OCHCH2CH2), 1.48–1.76 (m, 7 H, OCHCH2CH2,
OCHCH2CH2, CH2C=CH, CH2CH2CH2CH2), 1.52 (s, 3 H, CCH3).
13C NMR (125 MHz, CDCl3): d = 170.6 (C), 159.1 (C), 137.0 (C),
130.8 (C), 129.2 (CH), 123.3 (CH), 113.8 (CH), 87.2 (CH), 86.5
(C), 80.7 (CH), 72.5 (CH2), 70.0 (CH2), 55.3 (CH3), 42.7 (CH2),
27.0 (CH2), 25.7 (CH2), 25.0 (CH2), 23.8 (CH2), 22.5 (CH2), 22.5
(CH2), 22.1 (CH3), 21.8 (CH3).
HRMS (CI, CH4): m/z [M+] calcd for C16H24O4: 280.1675; found:
280.1675.
HRMS (CI, CH4): m/z [M+] calcd for C24H34O5: 402.2406; found:
402.2388.
(2R,3S,5R)-5-Cyclohex-1-en-1-yl-2-(4-diazo-3-oxo-butyl)-3-
methyltetrahydrofuran-3-yl Acetate (13)
Anal. Calcd for C24H34O5 (402.53): C, 71.61; H, 8.51. Found: C,
71.55; H, 8.43.
A solution of sodium chlorite (80%, 380 mg, 4.20 mmol) and sodi-
um dihydrogenorthophosphate dihydrate (567 mg, 3.63 mmol) in
water (5.6 mL) was added dropwise over 10 min to a solution of the
aldehyde 12 (157 mg, 0.560 mmol) and 2-methyl-2-butene (475 mL,
4.48 mmol) in t-BuOH (2.8 mL). The reaction was stirred at r.t. for
90 min and then the volatile compounds were removed in vacuo.
The mixture was diluted with water (10 mL) and the mixture was
extracted with Et2O (3 × 20 mL). The Et2O extracts were combined
and washed with water (20 mL) and brine (20 mL), and then dried
(MgSO4) and concentrated in vacuo to give the carboxylic acid as
an oil.
(2R,3S,5R)-5-Cyclohex-1-en-1-yl-2-(3-hydroxypropyl)-3-meth-
yltetrahydrofuran-3-yl Acetate (11)
CAN (1.55 g, 2.83 mmol) was added to a solution of the PMB ether
10 (570 mg, 1.42 mmol) in MeCN (29 mL) and water (3.2 mL) at
r.t. The resulting mixture was stirred at r.t. for 30 min, then diluted
with water (30 mL) and EtOAc (30 mL). The aqueous layer was
separated and extracted with EtOAc (3 × 50 mL). The EtOAc ex-
tracts were combined and washed with water (20 mL) and brine (20
mL), then dried (MgSO4) and concentrated in vacuo to give an oil.
Flash column chromatography on silica gel (PE–EtOAc, 3:1 → 2:1)
gave the alcohol 11 (342 mg, 86%) as a colourless oil; [a]D21 –10.3
(c = 0.68, CHCl3).
The crude acid was dissolved in anhyd MeOH (6.5 mL) under Ar
and MeONa (32 mg, 0.59 mmol) was added in one portion. The
mixture was stirred for 15 min, concentrated in vacuo and dried for
1 h under high vacuum. The white solid was dissolved in anhyd ben-
zene (6.5 mL) and oxalyl chloride (244 mL, 2.80 mmol) was added
dropwise over 10 min at r.t. under Ar. The mixture was stirred for 2
h, concentrated in vacuo and diluted with CH2Cl2 (50 mL). The so-
IR (CHCl3): 3425, 2933, 2860, 2839, 1728, 1000, 871 cm–1.
Synthesis 2005, No. 19, 3398–3404 © Thieme Stuttgart · New York

3404
J. S. Clark et al.
PAPER
lution was then added dropwise over 30 min to an ethereal solution
of diazomethane (ca. 2.8 mmol in 16 mL of Et2O) at 0 °C. The re-
sulting mixture was stirred for 2 h and the excess diazomethane was
then quenched with AcOH (2 mL). After 30 min the reaction mix-
ture was diluted with Et2O (50 mL) and washed with sat. NaHCO3
solution (80 mL). The aqueous washings were extracted with Et2O
(2 × 10 mL) and the Et2O extracts were combined and washed with
water (80 mL) and brine (50 mL). The Et2O extracts were dried
(MgSO4) and concentrated in vacuo to give an oil. Flash column
chromatography (PE–EtOAc, 9:1 → 4:1) gave the diazo ketone 13
(138 mg, 77%) as a yellow oil; [a]D21 –12.4 (c = 1.0, CHCl3).
13C NMR (125 MHz, CDCl3): d = 210.5 (C), 170.0 (C), 139.5 (C),
121.7 (CH), 87.4 (C), 79.8 (CH), 77.8 (CH), 39.9 (CH), 34.6 (CH2),
31.8 (CH2), 30.7 (CH2), 25.9 (CH2), 24.4 (CH2), 22.6 (CH3), 22.3
(CH3), 21.1 (CH2), 19.7 (CH2).
HRMS (CI, NH3): m/z [M+ + H] calcd for C17H25O4: 293.1753;
found: 293.1743.
Compound 16
[a]D20 –23.2 (c = 0.65, CHCl3).
IR (CHCl3): 2934, 1728, 1602, 876 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.33–5.37 (m, 1 H, C=CH), 4.47–
4.50 (m, 1 H, OCHCH2CH2), 4.21 (d, J = 5.9 Hz, 1 H, OCHC=O),
2.55–2.65 (m, 2 H, OCHCH, CH2C=O), 1.95–2.33 (m, 7 H,
CH2C=O, OCHCH2CH2, OCHCHCH2, CH2C=CH, C=CHCH2),
2.02 (s, 3 H, CH3C=O), 1.85 (t, J = 13.6 Hz, 1 H, OCHCHCH2),
1.77 (s, 3 H, CCH3), 1.76–1.79 (m, 1 H, CH2C=CH), 1.66–1.73 (m,
1 H, CH2CH2CH2CH2), 1.51–1.62 (m, 3 H, CH2CH2CH2CH2,
CH2CH2CH2CH2).
13C NMR (100 MHz, CDCl3): d = 209.1 (C), 170.1 (C), 134.7 (C),
122.1 (CH), 81.3 (C), 79.1 (CH), 71.4 (CH), 42.8 (CH), 35.7 (CH2),
33.5 (CH2), 28.4 (CH2), 25.3 (CH2), 23.0 (CH2), 22.9 (CH3), 22.4
(CH2), 22.2 (CH3), 21.7 (CH2).
IR (CHCl3): 2936, 2860, 2108, 1729, 1640, 1000, 952, 877 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.73 (br, 1 H, C=CH), 5.28 (br, 1
H, CHN2), 4.17 (dd, J = 7.7, 7.9 Hz, 1 H, OCHC=CH), 3.45 (dd, J =
3.1, 9.6 Hz, 1 H, OCHCH2CH2), 2.52–2.63 (m, 1 H, OCHCH2CH2),
2.48–2.52 (m, 1 H, OCHCH2CH2), 2.38 (dd, J = 7.9, 14.2 Hz, 1 H,
CH2CHC=CH), 2.25 (dd, J = 7.7, 14.2 Hz, 1 H, CH2CHC=CH),
1.91–2.06 (m, 5 H, OCHCH2CH2, CH2C=CH, C=CHCH2), 1.99 (s,
3 H, CH3C=O), 1.90–1.82 (m, 1 H, CH2C=CH), 1.65–1.52 (m, 4 H,
CH2CH2CH2CH2), 1.55 (s, 3 H, CCH3).
13C NMR (100 MHz, CDCl3): d = 194.9 (C), 170.5 (C), 136.9 (C),
123.6 (CH), 86.4 (CH), 86.3 (C), 80.9 (CH), 54.5 (CH), 42.5 (CH2),
37.8 (CH2), 25.0 (CH2), 24.3 (CH2), 23.8 (CH2), 22.6 (CH2), 22.6
(CH2), 22.1 (CH3), 21.7 (CH3).
HRMS (CI, CH4): m/z [M+] calcd for C17H24O4: 292.1675; found:
292.1662.
HRMS (CI, CH4): m/z [M+ + H] calcd for C17H25N2O4: 321.1814;
found: 321.1827.
Acknowledgment
(4aR,5R,9R,10R,12Z)-10-Methyl-6-oxo-
We thank the EPSRC and Merck Sharp and Dohme for financial
support.
1,2,3,4,4a,5,6,7,8,9,10,11-dodecahydro-5,9-epoxybenzo[10]an-
nulen-10-yl Acetate [(Z)-15] and (1R,2R,4R,5R)-4-Cyclohex-1-
en-1-yl-2-methyl-6-oxo-9-oxabicyclo[3.3.1]non-2-yl Acetate
(16)
A solution of diazo ketone 13 (20 mg, 0.062 mmol) in anhyd
CH2Cl2 (4 mL) was added dropwise over 5 min to a solution of cop-
per(II) hexafluoroacetylacetonate (1.5 mg, 0.0031 mmol, 5.0
mol%) in anhyd CH2Cl2 (1 mL) at reflux under N2. The reaction was
stirred at reflux for 30 min, cooled to r.t. and concentrated in vacuo
to give an oil. Flash column chromatography on silica gel (hexane–
EtOAc, 4:1) gave the [1,2]-shift product 16 and the [2,3]-rearrange-
ment product 15 (3:2, E:Z isomers) as an inseparable mixture of 15
and 16 (3:1, overall yield 15 mg, 83%).
References
(1) Roussis, V.; Fenical, W.; Vagias, C.; Kornprobst, J.-M.;
Miralles, J. Tetrahedron 1996, 52, 2735.
(2) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531.
(3) (a) Clark, J. S.; Dossetter, A. G.; Whittingham, W. G.
Tetrahedron Lett. 1996, 37, 5605. (b) Clark, J. S.; Dossetter,
A. G.; Blake, A. J.; Li, W. S.; Whittingham, W. G. Chem.
Commun. 1999, 749.
(4) (a) Jackson, D. Y. Synth. Commun. 1988, 18, 337. (b) Sato,
F.; Kobayashi, Y.; Takahashi, O.; Chiba, T.; Takeda, Y.;
Kusakabe, M. J. Chem. Soc., Chem. Commun. 1985, 1636.
(5) Lythgoe, B.; Trippett, S.; Watkins, J. C. J. Chem. Soc. 1956,
4060.
(6) Bal, B. S.; Childers, W. E. Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091.
AIBN (4.5 mg, 0.027 mmol) was added in 4 portions, over 4 h, to a
solution of the alkene 15 (15 mg, 0.055 mmol) and ethanethiol (0.2
mL) in anhyd benzene (3 mL) at reflux under Ar. After this time the
solution was cooled and concentrated in vacuo to give an oil. Flash
column chromatography on silica gel (hexane–EtOAc, 4:1) gave a
mixture of the [1,2]-shift product 16 (4 mg) and the fused tricyclic
compound (Z)-15 (7 mg, 64%). The products (oils) were separable
by column chromatography (10% AgNO3 absorbed on silica).
(7) Dennis, A. M.; Korp, J. D.; Bernal, I.; Howard, R. A.; Bear,
J. L. Inorg. Chem. 1983, 22, 1522.
(8) Similar anomalous C–H insertion products have been
isolated from metal carbenoid reactions previously:
(a) Mander, L. N.; Owen, D. J. Tetrahedron Lett. 1996, 37,
723. (b) Clark, J. S.; Dossetter, A. G.; Russell, C. A.;
Whittingham, W. G. J. Org. Chem. 1997, 62, 4910.
(c) Clark, J. S.; Wong, Y.-S.; Townsend, R. J. Tetrahedron
Lett. 2001, 42, 6187. (d) Clark, J. S.; Dossetter, A. G.;
Wong, Y.-S.; Townsend, R. J.; Whittingham, W. G.;
Russell, C. A. J. Org. Chem. 2004, 69, 3886.
Compound (Z)-15
[a]D20 +21.3 (c = 0.60, CHCl3).
IR (CHCl3): 2935, 1722, 1601, 874 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.49 (ddd, J = 2.3, 8.2, 8.4 Hz, 1
H, CH=C), 4.36 (dd, J = 6.9, 11.9 Hz, 1 H, OCHCH2CH2), 3.90 (d,
J = 12.6 Hz, 1 H, OCHC=O), 2.72 (dd, J = 3.3, 12.6 Hz, 1 H,
OCHCH), 2.54–2.65 (m, 3 H, CH2CH=C, CH2C=O), 2.46 (ddd, J =
6.3, 13.5, 17.7 Hz, 1 H, CH2C=O), 1.90–2.26 (m, 5 H,
OCHCH2CH2, CH=CCH2, OCHCHCH2), 1.97 (s, 3 H, CH3C=O),
1.72–1.74 (m, 1 H, CH=CCH2CH2), 1.71 (s, 3 H, CCH3), 1.55–1.58
(m, 1 H, OCHCHCH2CH2), 1.40–1.48 (m, 2 H, OCHCHCH2,
OCHCHCH2CH2), 1.26–1.32 (m, 1 H, CH=CCH2CH2).
(9) (a) Johansson, R.; Samuelsson, B. J. Chem. Soc., Chem.
Commun. 1984, 201. (b) Johansson, R.; Samuelsson, B. J.
Chem. Soc., Perkin Trans. 1 1984, 2371.
(10) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gennari, C.;
Raimondi, L. J. Org. Chem. 1987, 52, 4674.
Synthesis 2005, No. 19, 3398–3404 © Thieme Stuttgart · New York