Synthesis of the A/E/F sections of conaconitine, napelline and related diterpenoid alkaloids of the aconitine group

Article abstract of DOI:10.1039/a804664f

The tricyclic amines (±)-2; R = H and R = Me with five stereogenic centres, representing the A/E/F ring system of the title alkaloids, have been synthesised from penta-1,4-dien-3-ol in eight (overall yield 20%) and nine steps (overall yield 16%) respectively.

Full text of DOI:10.1039/a804664f

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Synthesis of the A/E/F sections of conaconitine, napelline and
related diterpenoid alkaloids of the aconitine group
Lynn C. Baillie,a Andrei Batsanov,a John R. Bearderb and Donald A. Whiting*a
a Department of Chemistry, The University, Nottingham, UK NG7 2RD
b Shell Research and Technology Centre, Thornton, PO Box 1, Chester, UK CH1 3SH
Received (in Cambridge) 19th June 1998, Accepted 27th August 1998
The tricyclic amines ( )-2; R = H and R = Me with five stereogenic centres, representing the A/E/F ring system of the
title alkaloids, have been synthesised from penta-1,4-dien-3-ol in eight (overall yield 20%) and nine steps (overall yield
16%) respectively.
The diterpenoid and norditerpenoid alkaloids1 comprise one of
the most interesting groups of natural products. Crude prepar-
ations from plants of the genera Aconitum, Delphinium and
a few others have long had a broad range of applications2
ranging from covert human poisons e.g. arrowhead dips and
(reputedly) agents for euthanasia, to traditional medical uses in
neuralgia, gout, hypertension, rheumatism etc., and they have
even been included as ingredients in intoxicating liquors. The
alkaloid constituents contain structurally complex pentacyclic
and hexacyclic systems which can be divided into four groups,
aconitines, lycoctonines, atisines and veatchines. A commonly
observed sub-unit is the A/E/F tricycle section as in e.g. the
aconitine skeleton 1, almost invariably functionalised by oxy-
genation. In connection with an interest in compounds contain-
ing sub-structures of aconitine and methyllycaconitine which
might display useful physiological activity, we selected several
target molecules comprising the nitrogen-containing A/E/F
unit with simple oxygenation patterns. In this paper we focus
on the target system 2, with a 1-hydroxy or methoxy group,
as found in conaconitine 33 (aconitine group), napelline 44
(veatchine group), karakolline, karasamine, liangshanine etc.1
The only reported synthesis5 of an A/E/F fragment is that of
compound 5, related to cardiopetaline. This tricycle was con-
structed using an intramolecular Diels–Alder reaction and an
imino-ene reaction to form the rings, in 11 steps and 2% overall
yield. A number of bicyclic analogues of methyllycaconitine
have been synthesised.6
In this paper we report the syntheses of the tricylic amines 2
(R = H) and 2 (R = Me) in a short sequence showing high
regio- and stereo-specificity, and which offers the potential for
enantioselectivity. The retrosynthetic analysis (Scheme 1)
involved an initial C–N bond disconnection from 2 to a cis-
fused 6,5-bicarbocycle 6, in which the N and ether O were
envisaged as relating to the oxazolidine 7. Heterocycle 7 could
then be viewed as the product of intramolecular 1,3-dipolar
cycloaddition of the nitrone 8, derivable in turn from a Diels–
Alder reaction.
H
H
RO
RO
NH
N
X
2
O–
N+
H
H
O
N
CHO
7
CHO
OR
8
C
E
A
D
A
RO
F
B
N
HN
R1
F
E
N
+
R2
1
2
9
OH
HO
Scheme 1 Retrosynthetic plan.
OMe
The starting point for such a route required a suitably func-
tionalised (E)-heptadiene 9. The orthoester Claisen extension
and rearrangement of penta-1,4-dienol 10 on heating with tri-
ethyl orthoacetate provided a very effective route7 to ethyl (E)-
hepta-4,6-dienoate 11a, and hence to the corresponding acid
11b (Scheme 2). In order to explore a range of Diels–Alder
variations we also prepared (E)-heptadienol 12a, and converted
it into the iodide 12b and the nitro compound 12c. Diels–Alder
reactions of dienes 11a, 11b and 12a–c with methyl meth-
acrylate and methacrolein were then explored using either
neat reagents or as solutions in organic solvents, with quinol as
additive, at various temperatures. The effects of aluminium tri-
chloride catalyst were also investigated. Although a fully com-
OMe
OH
OH
OH
N
N
OH
3
4
NH+
Cl–
5
J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478
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addition both methyl- and ethyl-hydroxylamines were required;
the latter was synthesised by ethylation of the bis-N,O-Boc
hydroxylamine 17, to afford the N-ethyl compound 18.9 Depro-
tection of the latter product provided ethylhydroxylammonium
trifluoroacetate 19, used directly in subsequent reactions.
i
CO2R
11a; R = Et (87%)
OH
10
ii
11b; R = H (89%)
iii
O
O
X
O
O
O
O
N
O
N
O
H
12a; X = OH (85%)
12b; X = I (76%)
O
O
iv
17
18
v
+
–
12c; X = NO2 (50%)
NH2OH CF3CO2
Scheme 2 Reagents and conditions: i, CH3C(OEt)3, EtCO2H, 142 ЊC,
3.5 h; ii, KOH, MeOH; iii, LiAlH4; iv, Ph3P, I2, imidazole; v, AgNO2.
19
The aldehyde 16 reacted with both methyl- and ethyl-
hydroxylamines in refluxing benzene to yield the isoxazolidines
20a and 20b respectively (Scheme 4). Efficient cleavage of the
prehensive and systematic series of trials was not attempted, the
results from a range of reaction conditions were disappointing;
reasonable yields could be obtained, and polymerisation of the
dienophile avoided, but the endo:exo ratios were unsatisfactory.
For example the dienol 12a reacted with methyl methacrylate at
220 ЊC over 6.5 h in the presence of quinol to afford the adduct
13 in 67% yield, but in an essentially non-stereospecific manner
(Scheme 3). We then resorted to the use of water as solvent for
R
R
HN
HO
N
O
H
ii
i
16
CH(OMe)2
CH(OMe)2
21a; R = H (94%)
21b; R = Me (92%)
i
20a; R = H (83%)
20b; R = Me (62%)
CO2Me
CH2OH
CO2Me
iii
13 (67%)
MeO
H
H
HO
H
H
H
H
iv
ii
MeO
N
H
N
H
CHO
CO2R
CHO
R
R
N
R
23a; R = H (47%)
23b; R = Me (67%)
22a; R = H (80%)
22b; R = Me (82%)
14a; R = H (92%)
iii
14b; R = Me (75%, 2 steps)
Scheme 4 Reagents and conditions: i, MeNHOHؒHCl or EtNHOHؒ
TFA, Et3N, benzene, reflux, 3.5 h; ii, NiCl2ؒ6 H2O, NaBH4, MeOH; iii,
a, 5 M HCl; b, buffer pH 5.5; c, NaCNBH3; iv, NaH, THF, MeI.
CHO
CO2Me
iv
v
14a
N–O bond was achieved using nickel chloride–sodium boro-
hydride. The heterocyclic ring was then closed by a one-pot
reductive amination procedure,10 in which the amines 21a and
21b were treated with 5 M hydrochloric acid to hydrolyse the
acetal, the resulting solution was buffered to pH 5.5, and reduc-
tion of the resulting cyclic imine intermediate was effected with
sodium cyanoborohydride, to afford the tricycles 22a and 22b in
excellent yield. Finally O-methylation was achieved by treat-
ment of the corresponding alkoxide with methyl iodide, to
afford the target compounds 23a and 23b. Molecular models
indicate that competing N-alkylation in this step is inhibited by
steric compression of the resulting quaternary ammonium salts,
and in agreement the yields of O-methyl ether were significantly
greater for the N-ethyl compound than for the N-methyl
relative.
The endo-stereochemistry of the adduct 14a is demonstrated
by the subsequent successful reductive amination, and the
remaining stereochemistry in the final product is controlled by
the nitrone cycloaddition. As an additional check, single crystal
X-ray analysis of the oxazolidine 20a was carried out, and
confirmed the assignments given here (see Fig. 1).
A related alternative strategy was also investigated, using a
nitrile oxide cycloaddition. Thus the aldehyde 16 was converted
into the oxime 24 (Scheme 5). Treatment of this oxime with
chloramine-T in refluxing methanol gave the isoxazole 25 (39%)
which could be reduced to the hydroxy amine 26 by nickel
chloride–sodium borohydride (45%). In view of the modest
yield obtained in the first attempts at these reactions, and the
CH(OMe)2
16 (91%)
CH(OMe)2
15 (80%)
Scheme 3 Reagents and conditions: i, 12a, quinol, 220 ЊC, 6.5 h; ii, 11b,
aq. NaHCO3, 45 ЊC, 24 h; iii, CH2N2; iv, HC(OMe)3, MeOH, PTSA;
v, DIBAL-H, toluene, Ϫ80 ЊC.
this reaction, following the work of Grieco and co-workers.8
Using reported literature conditions, an aqueous solution of
the sodium salt of acid 11b (4 equiv.) was treated with metha-
crolein (1 equiv.). The crude organic acid products containing
adduct 14a were methylated with diazomethane. Chroma-
tography of the esters afforded the desired endo-cyclohexene
14b with spectroscopic data in accord with the literature
report.8 The drawback of this approach was the use of excess
diene, the less accessible component. However, on running the
reaction in deuteriated water with varying ratios of diene:
dienophile concentrations and NMR monitoring it was ascer-
tained that there were no problems in using excess metha-
crolein. Thus reaction of the sodium salt of acid 11b (1 equiv.)
with methacrolein (4 equiv.) in water at 45 ЊC for 24 h gave the
endo-cyclohexene acid 14a as the major stereoisomer (15:1
endo:exo), in 92% yield.
Simultaneous acetalisation and esterification of acid 14a was
carried out by refluxing with trimethyl orthoformate and
methanol, with toluene-p-sulfonic acid catalyst, providing the
ester 15 which was reduced by diisobutylaluminium hydride
directly to the aldehyde 16. For the planned nitrone cyclo-
3472
J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478

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phenone), dichloromethane (calcium hydride), dimethoxy-
ethane (sodium). Organic extracts were dried over anhydrous
magnesium sulfate and the solvent was removed on a Buchi
rotary evaporator. Sodium hydride was handled as a 60%
suspension in mineral oil and was washed with petroleum ether
(bp 40–60 ЊC) prior to use.
The numberings used in systematic nomenclature and in
NMR assignments are shown below.
3
2
N
O
5'
2'
4
1
6'
1'
4'
3'
10
9
5
2
8
Fig. 1
1
O
7
6
3
O
N
N
OH
i
ii
16
HN
O
4
9
9
8
1
6
CH(OMe)2
25 (39%)
CH(OMe)2
24 (85%)
10
11
2
3
5
3 N
8
7
1
4
5
7
6
iii
2
OH
NH2
(E,E)-Ethyl hepta-4,6-dienoate 11a
A solution of penta-1,4-dien-3-ol 10 (5.00 g, 59.4 mmol) and
propionic acid (0.4 g, 5.4 mmol) in triethyl orthoacetate (70 ml)
was heated to reflux7a for 1 h. The mixture was cooled and
ethanol was removed by distillation [bp 68 ЊC (760 mmHg)].
The mixture was heated to reflux for 2 h, cooled and ethanol
was again removed by distillation. 2,6-Di-tert-butyl-4-methyl-
phenol (0.2 g, 0.9 mmol) was added and triethyl orthoacetate
was removed in vacuo [bp 45–50 ЊC (18 mmHg)]. The product
was subjected to column chromatography (solvent A, 4:1) to
yield the title compound as a colourless oil (7.97 g, 87%)
(Found: Mϩ, 154.097. C9H14O2 requires: 154.099); νmax(liquid
film)/cmϪ1 1737 (C᎐O), 1654, 1604 (C᎐C); δ (250 MHz, CDCl )
1.25 (3H, t, J 7.1, OCH2CH3), 2.41 (4H, m, 2-H2, 3-H2), 4.14
(2H, q, J 7.1, OCH2CH3), 4.99 (1H, dd, J 10.2, 1.5, 7-Ha), 5.11
(1H, dd, J 16.8, 1.5, 7-Hb), 5.63–5.75 (1H, m, 4-H), 6.09 (1H,
dd, J 15.0, 10.2, 5-H), 6.30 (1H, ddd, J 16.8, 10.2, 10.2, 6-H);
δC(67.8 MHz, CDCl3) 14.1 (OCH2CH3), 27.7 (CH2), 33.7
(CH2), 60.2 (OCH2CH3), 115.0 (C-7), 131.8 (CH), 132.5 (CH),
136.7 (CH), 172.7 (CO); m/z 154 (43%), 109 (29), 81 (100), 67
(90).
CH(OMe)2
26 (45%)
Scheme 5 Reagents and conditions: i, NH2OHؒHCl, pyridine; ii,
MeOH, chloramine-T, reflux, 4.5 h; iii, NiCl2, NaBH4, MeOH.
success of the nitrone cycloaddition route, this pathway was
explored no further.
Thus the synthesis of the desired tricyclic amines 2 (R = H)
and 2 (R = Me) containing five stereogenic centres, and model-
ling the A/E/F ring system of the title alkaloids, has been
effected in eight and nine steps respectively from the com-
mercially available penta-1,4-dien-3-ol, with overall yields 20
and 16%. Future work will focus on the extension of this route
to provide homochiral products through an enantioselective
cycloaddition process, and the introduction of further
oxygenation.
᎐
᎐
H
3
Experimental
Unless otherwise stated the following generalisations apply. All
melting points were determined on a Kofler hot-stage apparatus
and are uncorrected. IR spectra were obtained using a Perkin-
Elmer 1600 series FTIR or a Perkin-Elmer 1720-X FTIR
instrument as thin films (liquids) or chloroform solutions
(E,E)-Hepta-4,6-dienoic acid 11b
A solution of (E,E)-ethyl hepta-4,6-dienoate 11a (3.00 g, 19.5
mmol) and potassium hydroxide (5.0 g, 89 mmol) in dry meth-
anol (25 ml) was heated to reflux for 1.5 h.7b Methanol was
removed in vacuo and the residue partitioned between diethyl
ether and water. The aqueous layer was separated, acidified to
pH 3 with 2 M aqueous hydrochloric acid and extracted into
diethyl ether. The extracts were washed with brine, dried and
concentrated to yield the title compound as a yellow oil (2.18 g,
89%) (Found: C, 66.66, H, 8.39%; Mϩ, 126.065. C7H10O2
requires: C, 66.65, H, 7.99%; M, 126.068); νmax(liquid film)/cmϪ1
1
(solids). H NMR spectra were recorded on either a Bruker
AM 250 (250 MHz) or a Bruker 400 (400 MHz) instrument.
The spectra were recorded as dilute solutions in deuteriochloro-
form: the multiplicity of a signal is designated as: s, singlet; d,
doublet; t, triplet; q, quartet; sept., septet; br, broad; m, multi-
plet. Observed coupling constants, J, are reported in Hertz.
13C NMR spectra were recorded on either a JEOL EX 270 (67.8
MHz) or a Bruker AM400 (100.6 MHz) instrument, as dilute
solutions in deuteriochloroform. Multiplicities were obtained
using a DEPT sequence. Mass spectra were recorded on a VG
Autospec or a AEI MS902 or a VG 7070F instrument using
electron impact ionisation at 70 eV.
Column chromatography was performed using Merck silica
gel 60 and the following solvent systems were used: A,
petroleum ether (bp 40–60 ЊC)–diethyl ether; B, petroleum ether
(bp 40–60 ЊC)–ethyl acetate. Routinely, dry organic solvents
were stored under nitrogen. Benzene, toluene and diethyl
ether were dried over sodium wire. Other organic solvents were
dried by distillation from the following: THF (sodium, benzo-
1711 (C᎐O), 1654, 1604 (C᎐C); δ (250 MHz, CDCl ) 2.39–2.52
᎐
᎐
H
3
(4H, m, 2-H2, 3-H2), 5.01 (1H, d, J 10.2, 7-Ha), 5.14 (1H, d,
J 16.8, 7-Hb), 5.71 (1H, dt, J 15.1, 6.6, 4-H), 6.11 (1H, dd, J
15.1, 10.2, 5-H), 6.31 (1H, ddd, J 16.8, 10.2, 10.2, 6-H), 11.54
(1H, s, CO2H); δC(67.8 MHz, CDCl3) 27.1 (CH2), 33.3 (CH2),
115.5 (C-7), 131.9 (2 × CH), 136.6 (CH), 179.2 (CO); m/z 126
(63%), 81 (100), 67 (81).
(E,E)-Hepta-4,6-dienol 12a
To a suspension of lithium aluminium hydride (4.9 g, 130
mmol) in diethyl ether (75 ml) at 0 ЊC was added (E,E)-ethyl
hepta-4,6-dienoate 11a (5.0 g, 32 mmol) dropwise over 10 min.7a
J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478
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The mixture was allowed to warm to 25 ЊC and stirred for
1 h. The excess lithium aluminium hydride was cautiously
quenched sequentially with ethyl acetate, methanol and water.
1 M Aqueous hydrochloric acid was added to break up any
solid material and the mixture was extracted into diethyl ether.
The extracts were washed with sodium bicarbonate solution,
dried and concentrated. The product was subjected to column
chromatography (solvent A, 1:2) to yield the title compound as
a colourless oil (3.10 g, 85%) (Found: Mϩ, 112.084. C7H12O
requires: 112.089); νmax(liquid film)/cmϪ1 3339 (OH), 1652, 1603
m, 1-H2), 3.39, 3.40 (3H, 2 × s, OCH3), 5.21–5.48 (2H, m, 5-H,
6-H); δC(67.8 MHz, CDCl3) 15.1, 15.7 (2-CH3), 22.1, 22.3
(CH2), 25.6, 27.1 (CH2), 29.7, 30.0 (CH2), 30.4, 32.1 (CH2),
39.5, 42.2 (C-1Ј), 44.4, 44.6 (C-2Ј), 51.4, 51.8 (OCH3), 62.4, 62.7
(C-1), 125.2, 125.5 (CH), 128.0, 128.7 (CH), 178.0, 178.9 (CO);
m/z 152 (22%), 135 (49), 107 (69).
3-[(1S,2R)-2-Formyl-2-methylcyclohex-5-enyl]propionic acid
14a
To a solution of (E,E)-hepta-4,6-dienoic acid 11b (2.80 g, 22
mmol) in water (10 ml) at 25 ЊC was added sodium bicarbonate
(1.86 g, 22 mmol) portionwise over 5 min, and, after gas evolu-
tion had subsided, freshly distilled methacrolein (6.22 g, 89
mmol) was added. The mixture was warmed to 45 ЊC and
stirred for 24 h. The mixture was acidified to pH 3 with 2 M
aqueous hydrochloric acid and extracted into diethyl ether. The
extracts were washed with brine, dried and concentrated. The
product was subjected to column chromatography (solvent A,
2:1) to yield the title compound as a low melting solid (4.30 g,
92%); mp 25–28ЊC (Found: C, 67.48, H, 8.49%; Mϩ, 196.104.
C11H16O3 requires: C, 67.32, H, 8.22%; M, 196.110); νmax(liquid
(C᎐C); δ (250 MHz, CDCl ) 1.61–1.72 (2H, m, 2-H ), 2.12–
᎐
H
3
2
2.21 (2H, m, 3-H2), 3.64 (2H, t, J 6.5, 1-H2), 4.96 (1H, d, J 10.2,
7-Ha), 5.09 (1H, d, J 16.9, 7-Hb), 5.70 (1H, dt, J 14.9, 7.4, 4-H),
6.07 (1H, dd, J 14.9, 10.2, 5-H), 6.30 (1H, ddd, J 16.9, 10.2,
10.2, 6-H); δC(67.8 MHz, CDCl3) 28.7 (C-2), 31.9 (C-3), 60.0
(C-1), 115.0 (C-7), 131.3 (C-4), 134.3 (C-5), 137.0 (C-6); m/z 112
(16%), 94 (15).
(E,E)-1-Iodohepta-4,6-diene 12b
To a solution of triphenylphosphine (2.8 g, 11 mmol) and imid-
azole (0.73 g, 11 mmol) in acetonitrile (40 ml) at 25 ЊC under
argon was added iodine (2.7 g, 11 mmol). The solution turned
yellow and a white precipitate was observed. (E,E)-Hepta-4,6-
dienol 12a (1.0 g, 9 mmol) in acetonitrile (10 ml) was added
dropwise over 5 min. The mixture was stirred for 4 h, diluted
wth ethyl acetate and washed with aqueous sodium thiosulfate
and aqueous copper sulfate. The organic phase was dried and
concentrated. The product was subjected to column chrom-
atography (solvent A, 4:1) to yield the title compound as a
yellow oil (1.5 g, 76%) (Found: Mϩ, 221.992. C7H11I requires:
221.991); δH(250 MHz, CDCl3) 1.79–1.90 (2H, m, 2-H2), 2.09–
2.18 (2H, m, 3-H2), 3.12 (2H, t, J 6.9, 1-H2), 4.93 (1H, d, J 10.2,
7-Ha), 5.06 (1H, d, J 17.0, 7-Hb), 5.56 (1H, dt, J 15.0, 7.0, 4-H),
6.04 (1H, dd, J 15.0, 10.2, 5-H), 6.23 (1H, ddd, J 17.0, 10.2,
10.2, 6-H); δC(67.8 MHz, CDCl3) 6.7 (C-1), 33.0 (CH2), 33.4
(CH2), 115.9 (C-7), 132.6 (CH), 132.7 (CH), 137.2 (CH); m/z
222 (95%), 95 (70), 67 (100).
film)/cmϪ1 3181 (OH), 1717 (C᎐O); δ (250 MHz, CDCl ) 1.12
᎐
H
3
(3H, s, 2Ј-CH3), 1.50–1.60 (2H, m, 3-Ha, 3Ј-Ha), 1.82–1.92 (2H,
m, 3-Hb, 3Ј-Hb), 2.02–2.27 (3H, br m, 1Ј-H, 4Ј-H2), 2.39 (1H,
ddd, J 16.3, 8.6, 7.7, 2-Ha), 2.53 (1H, ddd, J 16.3, 8.8, 5.5,
2-Hb), 5.69–5.80 (2H, m, 5Ј-H, 6Ј-H), 9.66 (1H, s, 2Ј-CH);
δC(67.8 MHz, CDCl3) 19.9 (2Ј-CH3), 22.1 (C-4Ј), 26.6, 26.8
(C-3, C-3Ј), 31.7 (C-2), 36.8 (C-1Ј), 47.4 (C-2Ј), 126.7, 127.6
(C-5Ј, C-6Ј), 179.2 (C-1), 206.4 (CHO); m/z 196 (2%), 178 (25),
167 (10), 150 (21), 126 (17).
Methyl 3-[(1S,2R)-2-formyl-2-methylcyclohex-5-enyl]-
propionate 14b
To a solution of (E,E)-hepta-4,6-dienoic acid 11b (1.0 g, 7.9
mmol) in water (4 ml) was added sodium bicarbonate (0.63 g,
7.5 mmol) and freshly distilled methacrolein (0.14 g, 2.0 mmol)
at 25 ЊC.8a The mixture was stirred for 24 h and the mixture was
acidified to pH 3 with 2 M aqueous hydrochloric acid and
extracted into diethyl ether. The extracts were washed with
brine, dried and concentrated.
To a solution of diazomethane (1.01 g, 24 mmol) in diethyl
ether (60 ml) at 25 ЊC, formed by the standard procedure from
Diazald, was added the crude reaction mixture (1.70 g) drop-
wise over 10 min. The mixture was left for 1 h without stirring
and quenched with acetic acid. The mixture was basified to pH
9 with aqueous sodium bicarbonate and extracted into diethyl
ether. The extracts were dried and concentrated. The product
was subjected to column chromatography (solvent A, 4:1) to
yield methyl 3-[(1S,2R)-2-formyl-2-methylcyclohex-5-enyl]-
propionate8a (0.47 g, 75%) and methyl hepta-4,6-dienoate
(0.04 g, 5%).
(E,E)-1-Nitrohepta-4,6-diene 12c
To a suspension of silver nitrite (4.0 g, 26 mmol) in diethyl ether
(20 ml) at 0 ЊC in the dark was added (E,E)-1-iodohepta-4,6-
diene 12b (4.5 g, 20 mmol) in diethyl ether (30 ml) dropwise over
30 min. The mixture was stirred for 24 h at 0 ЊC, then at 25 ЊC
for 20 h. The mixture was filtered and the residue was washed
with diethyl ether. The filtrate was concentrated and the prod-
uct was subjected to column chromatography (solvent A, 5:1)
to yield the title compound as a yellow oil (1.4 g, 50%) along
with starting material (0.75 g, 17%) (Found: Mϩ, 141.082.
C7H11NO2 requires: 141.079); νmax(liquid film)/cmϪ1 1554 (NO);
δH(250 MHz, CDCl3) 2.10–2.22 (4H, m, 2-H2, 3-H2), 4.39 (2H,
t, J 6.7, 1-H2), 5.03 (1H, d, J 10.2, 7-Ha), 5.15 (1H, d, J 16.7,
7-Hb), 5.63 (1H, dt, J 15.0, 6.7, 4-H), 6.10 (1H, dd, J 15.0, 10.2,
5-H), 6.30 (1H, ddd, J 16.7, 10.2, 10.2, 6-H); δC(67.8 MHz,
CDCl3) 26.7 (CH2), 28.9 (CH2), 74.7 (C-1), 116.2 (C-7), 131.4
(CH), 132.9 (CH), 136.4 (CH); m/z 141 (3%), 95(21), 79 (100).
Methyl
3-[(1S,2R)-2-formyl-2-methylcyclohex-5-enyl]pro-
pionate; νmax(liquid film)/cmϪ1 1738 (C᎐O), 1653 (C᎐C); δ (270
᎐
᎐
H
MHz, CDCl3) 1.04 (3H, s, 2Ј-CH3), 1.06–1.11 (1H, m, 4Ј-Ha),
1.42–1.53 (2H, m, 3-Ha, 3Ј-Ha), 1.72–1.86 (2H, m, 3-Hb, 3Ј-Hb),
1.99–2.08 (2H, m, 1Ј-H, 4Ј-Hb), 2.20–2.47 (2H, m, 2-H2), 3.60
(3H, s, OCH3), 5.55–5.72 (2H, m, 5Ј-H, 6Ј-H), 9.59 (1H, s,
2Ј-CH); δC(67.8 MHz, CDCl3) 20.0 (2Ј-CH3), 22.2 (C-4Ј), 27.0,
27.1 (C-3, C-3Ј), 32.0 (C-2), 40.9 (C-1Ј), 47.5 (C-2Ј), 51.5
(OCH3), 127.0, 127.4 (C-5Ј, C-6Ј), 173.5 (C-1), 206.2 (CHO).
3-(2-Methoxycarbonyl-2-methylcyclohex-5-enyl)-1-hydroxy-
propane 13
A mixture of (E,E)-ethyl hepta-4,6-dienol 12a (0.10 g, 0.9
mmol), methyl methacrylate (0.05 g, 0.5 mmol) and quinol11
(1 mg, 9 × 10Ϫ3 mmol) was heated to 220 ЊC in a closed system
for 6.5 h. After cooling, the mixture was subjected to column
chromatography (solvent A, 1:1) to yield the title compound
as a mixture of diastereoisomers, as a colourless oil (0.06 g,
67%) (Found: (M Ϫ HCO2Me)ϩ, 152.120. C10H16O requires:
152.120); δH(250 MHz, CDCl3) 0.78, 0.92 (3H, 2 × s, 2Ј-H3),
1.08–1.63 (4H, m, 2 × CH2), 1.74 (2.5H, m, 0.5 × 1Ј-H, CH2),
2.11 (2H, m, CH2), 2.40 (0.5H, m, 0.5 × 1Ј-H), 3.28–3.38 (2H,
Methyl 3-[(1S,2R)-2-dimethoxymethyl-2-methylcyclohex-5-
enyl]propionate 15
To a solution of 3-[(1S,2R)-2-formyl-2-methylcyclohex-5-enyl]-
propionic acid 14a (1.50 g, 7.63 mmol) and toluene-p-sulfonic
acid (0.01 g, 0.05 mmol) in methanol (8 ml) heated to reflux was
added trimethyl orthoformate (0.88 g, 8.3 mmol) over 5 min.
The mixture was heated to reflux for 1 h and, after cooling, was
3474
J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478

View Article Online
quenched with sodium (0.25 g, 11 mmol) in methanol (2 ml).
The mixture was washed with water, dried and concentrated.
The product was subjected to column chromatography (solvent
B, 4:1) to yield the title compound as a pale orange oil (1.58 g,
80%) (Found: C, 65.95, H, 9.85. C14H24O4 requires: C, 65.60,
H, 9.44%; Found: (M Ϫ OMe)ϩ, 225.148. C13H21O3 requires:
225.149); νmax(liquid film)/cmϪ1 1741 (C᎐O), 1653 (C᎐C);
separated, washed with water, dried and concentrated to yield
the title compound 9 as a yellow oil (16.5 g, 99%); νmax(liquid
film)/cmϪ1 1785 (OC᎐O), 1717 (NC᎐O); δ (400 MHz, CDCl )
᎐
᎐
H
3
1.19 (3H, t, J 7.1, NCH2CH3), 1.49 (9H, s, C(CH3)3), 1.57 (9H,
s, C(CH3)3), 3.61 (2H, br q, NCH2CH3); δC(100.6 MHz, CDCl3)
11.8 (NCH2CH3), 27.4, 27.9 (2 × C(CH3)3), 44.9 (NCH2CH3),
81.9, 82.3 (2 × C(CH3)3), 153.6, 155.8 (2 × CO).
᎐
᎐
δH(250 MHz, CDCl3) 0.92 (3H, s, 2Ј-CH3), 1.36–1.51 (3H, m,
3-Ha, 3Ј-H2), 1.81–1.88 (1H, m, 1Ј-H), 1.89–1.97 (1H, m, 3-Hb),
2.00–2.03 (2H, m, 4Ј-H2), 2.28 (1H, ddd, J 15.6, 10.1, 5.3,
2-Ha), 2.46 (1H, ddd, J 15.6, 10.4, 5.3, 2-Hb), 3.47 (3H, s,
CH(OCH3)2), 3.56 (3H, s, CH(OCH3)2), 3.67 (3H, s, OCH3),
3.99 (1H, s, CH(OCH3)2), 5.59–5.67 (2H, m, 5Ј-H, 6Ј-H);
δC(67.8 MHz, CDCl3) 16.9 (2Ј-CH3), 22.2 (C-4Ј), 25.6 (C-3Ј),
27.1 (C-3), 32.2 (C-2), 40.6 (C-2Ј), 41.0 (C-1Ј), 51.4, 56.8
(CH(OCH3)2), 60.1 (OCH3), 111.8 (CH(OCH3)2), 126.4, 128.6
(C-5Ј, C-6Ј), 174.4 (C-1); m/z 225 (3%), 192 (13), 85 (40), 75
(100).
N-Ethylhydroxylammonium trifluoroacetate 19
To a solution of N,O-bis-tert-butoxycarbonyl-N-ethylhydrox-
ylamine 18 (12.0 g, 46 mmol) in dichloromethane (60 ml) at
25 ЊC was added trifluoroacetic acid (15.7 g, 140 mmol) drop-
wise over 10 min. The mixture was stirred for 1.5 h and the
solvent and excess trifluoroacetic acid were removed in vacuo to
yield the title compound as a crystalline solid (7.33 g, 91%), mp
89 ЊC; δH(400 MHz, CDCl3) 1.38 (3H, t, J 7.1, NCH2CH3), 3.40
(2H, t, J 7.1, NCH2CH3).
(1â,4â,7â,11â)-3-Methyl-8á-dimethoxymethyl-8â-methyl-3-aza-
2-oxatricyclo[5.3.1.04,11]undecane 20a†
3-[(1S,2R)-Dimethoxymethyl-2-methylcyclohex-5-enyl]propanal
16
A solution of 3-[(1S,2R)-dimethoxymethyl-2-methylcyclohex-
5-enyl]propanal 16 (0.20 g, 0.88 mmol), N-methylhydroxyl-
amine hydrochloride (0.16 g, 1.9 mmol) and triethylamine
(0.14 g, 1.9 mmol) in benzene (5 ml) was heated to reflux for
3.5 h. The solution was diluted with diethyl ether, filtered and
concentrated. The product was subjected to column chroma-
tography (solvent A, 2:3) to yield the title compound as white
needles (0.19 g, 83%); mp 75–81 ЊC (Found: C, 66.05; H, 10.20;
N, 5.40%; Mϩ, 255.183. C14H25NO3 requires: C, 65.85; H, 9.87;
N, 5.49%; M, 255.183); νmax(solution, CHCl3)/cmϪ1 2974, 2973
(CH2, CH); δH(270 MHz, CDCl3) 0.93 (3H, s, 8-CH3), 1.16–1.21
(1H, m, 9-Ha), 1.37–1.52 (4H, m, 5-Ha, 6-H2, 9-Hb), 1.61 (1H,
br m, 7-H), 1.80–1.85 (2H, m, 10-H2), 1.97 (1H, m, 5-Hb), 2.64
(3H, s, NCH3), 2.80 (1H, m, 11-H), 3.42 (1H, br m, 4-H), 3.42
(3H, s, CH(OCH3)2), 3.52 (3H, s, CH(OCH3)2), 3.81 (1H, s,
CH(OCH3)2), 4.22 (1H, br m, 1-H); δC(100.6 MHz, d6-DMSO,
80 ЊC) 17.2 (8-CH3), 20.3 (C-10), 21.4 (C-9), 25.7 (C-6), 33.3
(C-5), 40.2 (C-8), 43.8 (C-7), 44.0 (NCH3), 45.8 (C-11), 56.1,
58.2 (CH(OCH3)2), 70.4 (C-1), 71.8 (C-4), 112.2 (CH(OCH3)2);
m/z 255 (16%), 240 (69), 224 (12), 75 (100).
To a solution of methyl 3-[(1S,2R)-2-dimethoxymethyl-2-
methylcyclohexen-5-yl]propionate 15 (1.50 g, 5.8 mmol) in
toluene (30 ml) at Ϫ78 ЊC was added 1.5 M diisobutylalu-
minium hydride in toluene (4.70 ml, 7.05 mmol) dropwise over
5 min. After 1.5 h the solution was diluted with diethyl ether
and 2 M aqueous hydrochloric acid was added. The aqueous
layer was separated and extracted with diethyl ether. The com-
bined extracts were dried and concentrated. The product was
subjected to column chromatography (solvent A, 5:2) to yield
the title compound as a colourless solid (1.21 g, 91%); mp 18–
20 ЊC (Found: C, 68.52, H, 10.26. C13H22O3 requires: C, 68.99,
H, 9.80%; Found: (M Ϫ OMe)ϩ, 195. C12H19O2 requires: 195);
νmax(liquid film)/cmϪ1 1724 (C᎐O), 1652 (C᎐C); δ (250 MHz,
CDCl3) 0.93 (3H, s, 2Ј-CH3), 1.37–1.56 (3H, m, 3-Ha, 3Ј-H2),
1.85 (1H, br m, 1Ј-H), 1.91–1.99 (1H, m, 3-Hb), 2.03 (2H, m,
4Ј-H2), 2.42 (1H, dddd, J 17.1, 9.6, 5.8, 1.7, 2-Ha), 2.58 (1H,
dddd, J 17.1, 10.0, 5.6, 1.7, 2-Hb), 3.47 (3H, s, CH(OCH3)2),
3.57 (3H, s, CH(OCH3)2), 4.00 (1H, s, CH(OCH3)2), 5.58–5.68
(2H, m, 5Ј-H, 6Ј-H), 9.79 (1H, t, J 1.7, 1-H); δC(67.8 MHz,
CDCl3) 16.9 (2Ј-CH3), 21.9 (C-4Ј), 23.6 (C-3Ј), 25.1 (C-3), 40.3
(C-2Ј), 40.6 (C-1Ј), 41.7 (C-2), 56.4, 59.6 (CH(OCH3)2), 111.6
(CH(OCH3)2), 126.1, 128.3 (C-5Ј, C-6Ј), 202.3 (C-1); m/z (FAB
ϩve) 195 (15%), 163 (14).
᎐
᎐
H
(1â,4â,7â,11â)-3-Ethyl-8á-dimethoxymethyl-8â-methyl-3-aza-2-
oxatricyclo[5.3.1.04,11]undecane 20b†
A solution of 3-[(1S,2R)-2-dimethoxymethyl-2-methylcyclo-
hex-5-enyl]propanal 16 (0.12 g, 0.54 mmol), N-ethylhydroxyl-
amine trifluoroacetic acid (0.20 g, 1.1 mmol) and triethylamine
(0.12 g, 1.1 mmol) in benzene (5 ml) was heated to reflux for 4 h.
The solution was diluted with diethyl ether, filtered and concen-
trated. The product was subjected to column chromatography
(solvent A, 2:3) to yield the title compound as a colourless oil
which solidified on standing (0.09 g, 62%); mp 65–69 ЊC
(Found: C, 66.99; H, 10.49; N, 5.22. C15H27NO3 requires: C,
66.88; H, 10.10; N, 5.20%; Found: MHϩ, 269.197. C15H28NO3
requires: 269.199); νmax(solution, CHCl3)/cmϪ1 2943 (CH2, CH);
δH(400 MHz, CDCl3) 0.93 (3H, s, 8-CH3), 1.08 (3H, dd, J 7.1,
7.1, NCH2CH3), 1.17–1.25 (1H, m, 9-Ha), 1.38–1.56 (4H, m,
5-Ha, 6-H2, 9-Hb), 1.56–1.63 (1H, m, 7-H), 1.76–1.84 (2H, m,
10-H2), 1.96 (1H, m, 5-Hb), 2.76 (1H, m, 11-H), 2.60–2.67 (1H,
m, NCHaCH3), 2.85–2.94 (1H, m, NCHbCH3), 3.42–3.51 (1H,
m, 4-H), 3.43 (3H, s, CH(OCH3)2), 3.52 (3H, s, CH(OCH3)2),
3.82 (1H, s, CH(OCH3)2), 4.11 (1H, br m, 1-H); δC(100.6 MHz,
CDCl3) 13.1 (NCH2CH3), 17.0 (8-CH3), 21.0 (C-10), 22.0 (C-9),
26.4 (C-6), 34.9 (C-5), 40.2 (C-8), 44.4 (C-7), 46.2 (C-11), 51.4
N,O-Bis-tert-butoxycarbonylhydroxylamine 17
To a solution of N-hydroxylamine hydrochloride (10.4 g, 0.15
mol) and sodium carbonate (19.9 g, 0.19 mol) in water (75 ml)
at 35 ЊC was added di-tert-butyldicarbonate (68.8 g, 0.32 mol)
portionwise over 2.5 h. After 45 min, the solution was cooled to
25 ЊC and stirred for 16 h. The mixture was extracted into tolu-
ene and the extracts were dried and concentrated. The product
was recrystallised from hexane to yield the title compound as
white cubes (29.6 g, 85%); mp 67–71 ЊC (hexane) [lit.,9 mp 70–
72 ЊC (hexane)] (Found: C, 51.26, H, 8.50, N, 6.14. C10H19NO5
requires: C, 51.49, H, 8.21, N, 6.00%); νmax(KBr disc)/cmϪ1 3273
(NH), 1796 (OC᎐O), 1740 (NC᎐O); δ (400 MHz, CDCl ) 1.50
᎐
᎐
H
3
(9H, s, 3 × CH3), 1.52 (9H, s, 3 × CH3), 7.51 (1H, br s, NH);
δC(100.6 MHz, CDCl3) 27.7 (C(CH3)3), 28.0 (C(CH3)3), 83.0,
85.2 (2 × C), 153.6, 155.8 (2 × CO).
N,O-Bis-tert-butoxycarbonyl-N-ethylhydroxylamine 18
To a solution of N,O-bis-tert-butoxycarbonylhydroxylamine 17
(15.0 g, 64 mmol) in N,N-dimethylformamide (80 ml) at 25 ЊC
was added potassium carbonate (11.1 g, 80 mmol). To the
suspension at 30 ЊC was added ethyl iodide (11.1 g, 71 mmol)
dropwise over 45 min. After 2.5 h, the solution was cooled to
25 ЊC and diluted with water and toluene. The toluene layer was
† The correct IUPAC names for compounds 20a and 20b are
1β,4β,8β,11β-2-methyl-7α-dimethoxymethyl-7β-methyl-2-aza-3-oxatri-
cyclo[6.2.1.04,11]undecane and 1β,4β,8β,11β-2-ethyl-7α-dimethoxy-
methyl-7β-methyl-2-axa-3-oxatricyclo[6.2.1.o4,11]undecane respectively.
J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478
3475

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(NCH3), 56.9, 60.2 (CH(OCH3)2), 71.5, 71.7 (C-1, C-4), 113.4
(CH(OCH3)2); m/z 269 (12%), 238 (9), 222 (5), 75 (100).
in tetrahydrofuran (1.4 ml, 1.4 mmol) was added dropwise over
5 min.32 The mixture was stirred for a further 1.5 h, basified to
pH 12 with 2 M aqueous sodium hydroxide, and the product
was extracted into dichloromethane. The extracts were dried
and concentrated to yield the title compound as a yellow solid
(0.11 g, 80%); mp 82–86 ЊC (decomp.) (Found: Mϩ, 195.161.
C12H21NO requires: 195.162); νmax(solution, CHCl3)/cmϪ1 2792
(NCH); δH(400 MHz, CDCl3) 0.68 (3H, s, 1-CH3), 1.16–1.23
(1H, m, 5-Ha), 1.29 (1H, dddd, J 13.6, 13.6, 5.2, 2.6, 11-Ha),
1.48–1.57 (4H, m, 6-H2, 7-H, 11-Hb), 1.68–1.84 (3H, m, 5-Hb, 8-
H, 10-Ha), 1.87 (1H, dd, J 11.4, 2.6, 2-Ha), 2.03 (3H, s, NCH3),
2.22 (1H, d, J 11.4, 2-Hb), 2.39–2.50 (1H, m, 10-Hb), 3.16 (1H,
dd, J 4.5, 4.5, 4-H), 3.96 (1H, dd, J 10.5, 6.2, 9-H); δC(100.6
MHz, CDCl3) 20.3 (C-5), 24.4 (C-6), 25.9 (1-CH3), 31.1 (C-10),
32.1 (C-1), 38.6 (C-11), 42.4 (NCH3), 45.0 (C-7), 47.9 (C-8),
59.8 (C-2), 60.9 (C-4), 70.5 (C-9); m/z 195 (30%), 178 (85), 166
(100), 136 (17).
(1â,2á,6â,9á)-9-Methylamino-5á-dimethoxymethyl-5â-methyl-
bicyclo[4.3.0]nonan-2-ol 21a
To a stirred solution of 1β,4β,7β,11β-3-methyl-8α-dimethoxy-
methyl-8β-methyl-3-aza-2-oxatricyclo[5.3.1.04,11]undecane 20a
(0.50 g, 2.0 mmol) in methanol (40 ml) at 25 ЊC was added
nickel chloride hexahydrate (0.93 g, 3.9 mmol). Sodium
borohydride (0.46 g, 11.8 mmol) was added portionwise over
5 min, the mixture turned black and evolution of gas was
observed. The mixture was stirred for 2 h, the solvent was
removed in vacuo and the residue was dissolved in dichloro-
methane (50 ml) and conc. aqueous ammonia (50 ml). The
mixture was stirred for 1.5 h and the two layers were separated.
The aqueous layer was extracted with dichloromethane and
the combined organic phases were dried and concentrated to
yield the title compound as unstable orange crystals (0.48 g,
94%) (Found: (M Ϫ Me)ϩ, 242.175. C13H24NO3 requires:
242.176); νmax(solution, CHCl3)/cmϪ1 3343 (NH, OH); δH(400
MHz, CDCl3) 0.97 (3H, s, 5-CH3), 1.21–1.25 (1H, m, 4-Ha),
1.38–1.54 (2H, m, 7-Ha, 8-Ha), 1.62–1.83 (4H, m, 3-H2, 4-Hb,
6-H), 1.93–2.09 (3H, m, 1-H, 7-Hb, 8-Hb), 2.46 (3H, s, NCH3),
3.22 (9-H), 3.45 (3H, s, CH(OCH3)2), 3.56 (3H, s, CH(OCH3)2),
3.87 (1H, s, CH(OCH3)2), 4.01 (1H, br m, 2-H); δC(67.8 MHz,
CDCl3) 17.6 (5-CH3), 23.0 (C-4), 25.5 (C-7), 26.8 (C-3), 32.4
(NCH3), 36.4 (C-8), 40.6 (C-5), 42.6 (C-1), 45.6 (C-6), 57.0, 60.6
(CH(OCH3)2), 63.1 (C-9), 66.0 (C-2), 113.8 (CH(OCH3)2);
m/z 242 (20%), 225 (2), 210 (14), 194 (16).
(1â,4â,7â,8â,9á)-3-Ethyl-1-methyl-3-azatricyclo[5.4.0.04,8]-
undecan-9-ol 22b
1β,2α,6β,9α-9-Ethylamino-5α-dimethoxymethyl-5β-methyl-
bicyclo[4.3.0]nonan-2-ol 21b (0.35 g, 1.3 mmol) was treated
with 5 M aqueous hydrochloric acid (3.5 ml) and the mixture
was stirred at 25 ЊC for 1.75 h. 25% w/v Aqueous sodium
hydroxide (4 ml) was added and the mixture was buffered to
pH 5.5 with a freshly prepared citrate–phosphate buffer33
(20 ml). After 3.5 h 1 M sodium cyanoborohydride in THF
(2.58 ml, 2.58 mmol) was added dropwise over 5 min. The mix-
ture was stirred for a further 1.5 h, basified to pH 12 with 2 M
aqueous sodium hydroxide, and the product extracted into
dichloromethane. The extracts were dried and concentrated to
yield the title compound as a yellow solid (0.21 g, 82%); mp 58–
65 ЊC (decomp.) (Found: Mϩ, 209.178. C13H23NO requires:
209.178); νmax(solution, CHCl3)/mϪ1 2796 (NCH); δH(400
MHz, CDCl3) 0.69 (3H, s, 1-CH3), 0.99 (3H, dd, J 7.1, 7.1,
NCH2CH3), 1.21–1.36 (2H, m, 5-Ha, 11-Ha), 1.49–1.59 (4H, m,
6-H2, 7-H, 11-Hb), 1.66–1.81 (2H, m, 5-Hb, 10-Ha), 1.85 (1H, m,
8-H), 1.90 (1H, dd, J 11.5, 2.3, 2-Ha), 2.23 (1H, m, NCHaCH3),
2.32 (1H, m, NCHbCH3), 2.38–2.49 (1H, m, 10-Hb), 2.42 (1H,
d, J 11.5, 2-Hb), 3.36 (1H, dd, J 4.5, 4.5, 4-H), 3.96 (1H, ddd,
J 10.5, 6.3, 6.3, 9-H); δC(100.6 MHz, CDCl3) 12.7 (NCH2CH3),
21.2 (C-5), 24.2 (C-6), 25.8 (1-CH3), 30.9 (C-10), 32.1 (C-1),
38.2 (C-11), 45.2 (C-7), 47.6 (C-8), 49.0 (NCH2CH3), 57.3
(C-2), 59.1 (C-4), 70.0 (C-9); m/z 209 (31%), 194 (51), 180 (100),
164 (10), 122 (29).
(1â,2á,6â,9á)-9-Ethylamino-5á-dimethoxymethyl-5â-methyl-
bicyclo[4.3.0]nonan-2-ol 21b
To a solution of 1β,4β,7β,11β-3-ethyl-8α-dimethoxymethyl-8β-
methyl-3-aza-2-oxatricyclo[5.3.1.04,11]undecane 20b (0.50 g, 1.9
mmol) in methanol (40 ml) at 25 ЊC was added nickel chloride
hexahydrate (0.88 g, 3.7 mmol). Sodium borohydride (0.42 g, 11
mmol) was added portionwise over 5 min, the mixture turned
black and evolution of gas was observed. The mixture was
stirred for 2 h, the solvent was removed in vacuo and the residue
was dissolved in dichloromethane (50 ml) and conc. aqueous
ammonia (50 ml). The mixture was stirred for a further 1.5 h and
the two layers were separated. The aqueous layer was extracted
into dichloromethane and the combined extracts were dried and
concentrated to yield the title compound as a brown oil which
solidified on standing (0.46 g, 92%); mp 88–94 ЊC (Found: Mϩ,
271.211. C15H29NO3 requires: 271.215); νmax(solution, CHCl3)/
cmϪ1 3318 (br OH, NH); δH(400 MHz, CDCl3) 0.97 (3H, s,
5-CH3), 1.11 (3H, dd, J 7.1, 7.1, NCH2CH3), 1.18–1.64 (1H, m,
4-Ha), 1.38–1.52 (2H, m, 7-Ha, 8-Ha), 1.64–1.81 (4H, m, 3-H2,
4-Hb, 6-H), 1.94–2.06 (3H, m, 1-H, 7-Hb, 8-Hb), 2.65 (1H, dq,
J 14.7, 7.1, NCHaCH3), 2.66 (1H, dq, J 14.7, 7.1, NCHbCH3),
3.32 (1H, ddd, J 10.1, 7.1, 6.8, 9-H), 3.45 (3H, s, CH(OCH3)2),
3.56 (3H, s, CH(OCH3)2), 3.87 (1H, s, CH(OCH3)2), 3.99 (1H,
br m, 2-H); δC(100.6 MHz, CDCl3) 15.0 (NCH2CH3), 17.0
(5-CH3), 22.2 (C-4), 24.7 (C-7), 26.2 (C-3), 31.9 (C-8), 39.8
(C-5), 42.0 (C-1), 43.2 (NCH2CH3), 44.8 (C-6), 56.2, 59.6
(CH(OCH3)2), 60.3 (C-9), 65.2 (C-2), 113.0 (CH(OCH3)2); m/z
271 (0.5%), 256 (25), 224 (9), 208 (16), 75 (100).
(1â,4â,7â,8â,9á)-9-Methoxy-1,3-dimethyl-3-azatricyclo-
[5.4.0.04,8]undecane 23a
To a suspension of sodium hydride (0.10 g, 2.6 mmol) in
tetrahydrofuran (6 ml) at 25 ЊC was added (1β,4β,7β,8β,9α)-
1,3-dimethyl-3-azatricyclo[5.4.0.04,8]undecan-9-ol 22a (0.05 g,
0.26 mmol). The mixture was heated to reflux for 30 min and
methyl iodide (1.46 g, 10.2 mmol) was added cautiously. The
mixture was heated to reflux for a further 5.5 h. After cooling to
25 ЊC, the mixture was partitioned between water and diethyl
ether. The aqueous layer was separated and extracted with
diethyl ether. The combined extracts were dried and concen-
trated to yield the title compound as a yellow oil (25 mg, 47%)
(Found: Mϩ, 209.174. C13H23NO requires: 209.178); νmax(liquid
film)/cmϪ1 2785 (NCH); δH(400 MHz, CDCl3) 0.72 (3H, s, 1-
CH3), 1.17–1.42 (2H, m, 5-Ha, 11-Ha), 1.51, 1.65 (4H, m, 6-H2,
7-H, 11-Hb), 1.73–1.84 (2H, m, 5-Hb, 10-Ha), 1.89–1.93 (2H, m,
8-H, 2-Ha), 2.08 (3H, s, NCH3), 2.29 (1H, d, J 11.3, 2-Hb), 2.61
(1H, m, 10-Hb), 3.16 (1H, dd, J 4.3, 4.3, 4-H), 3.40 (3H, s,
OCH3), 3.58 (1H, ddd, J 11.0, 5.7, 5.7, 9-H); δC(100.6 MHz,
CDCl3) 20.5 (C-5), 24.2 (C-6), 25.8 (1-CH3), 27.0 (C-10), 32.3
(C-1), 38.8 (C-11), 42.5 (NCH3), 44.9, 45.2 (C-7, C-8), 56.1
(OCH3), 59.7 (C-2), 60.8 (C-4), 79.9 (C-9); m/z 209 (15%), 180
(36), 178 (100), 136 (11).
(1â,4â,7â,8â,9á)-1,3-Dimethyl-3-azatricyclo[5.4.0.04,8]undecan-
9-ol 22a
1β,2α,6β,9α-9-Methylamino-5α-dimethoxymethyl-5β-methyl-
bicyclo[4.3.0]nonan-2-ol 21a (0.19 g, 0.70 mmol) was treated
with 5 M hydrochloric acid (1.8 ml) and the mixture was stirred
at 25 ЊC for 1.5 h. 25% w/v Aqueous sodium hydroxide (2 ml)
was added and the mixture was buffered to pH 5.5 with a freshly
prepared citrate–phosphate buffer (10 ml). The mixture was
stirred for 3 h after which time 1 M sodium cyanoborohydride
3476
J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478

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(1â,4â,7â,8â,9á)-3-Ethyl-9-methoxy-1-methyl-3-azatricyclo-
[5.4.0.04,8]undecane 23b
CH), 2.08–2.34 (2H, m, CH2), 2.46 (1H, dd, J 6.4, 6.8, CH), 3.38
(3H, s, CH(OCH3)2), 3.46 (3H, s, CH(OCH3)2), 3.68 (1H, t,
J 11.1, 11-H), 3.79 (1H, s, CH(OCH3)2), 4.66 (1H, ddd, J 11.1,
7.4, 3.5, 1-H); δC(67.8 MHz, CDCl3) 19.6 (8-CH3), 23.2 (CH2),
23.3 (CH2), 24.1 (CH2), 27.4 (CH2), 36.1 (C-7), 37.8 (C-8), 50.5
(C-1), 57.0 (CH(OCH3)2), 59.8 (CH(OCH3)2), 77.0 (C-11),
111.5 (CH(OCH3)2), 167.3 (C-4); m/z 196 (2%), 178 (25), 167
(10), 150 (21), 126 (17), 75 (100).
To a suspension of sodium hydride (0.20 g, 5.1 mmol) in tetra-
hydrofuran (12 ml) at 25 ЊC was added (1β,4β,7β,8β,9α)-3-
ethyl-1-methyl-3-azatricyclo[5.4.0.04,8]undecan-9-ol 22b (0.10 g,
0.48 mmol). The mixture was heated to reflux for 30 min and
methyl iodide (1.46 g, 10.2 mmol) was added cautiously. The
mixture was heated to reflux for a further 5.5 h. After cooling to
25 ЊC, the mixture was partitioned between water and diethyl
ether. The aqueous layer was separated and extracted with
diethyl ether. The combined ether extracts were dried and con-
centrated to yield the title compound as an orange oil (0.072 g,
67%) (Found: (M Ϫ OCH3)ϩ, 192.174. C13H22N requires:
192.175); νmax(liquid film)/cmϪ1 2813 (NCH); δH(400 MHz,
CDCl3) 0.71 (3H, s, 1-CH3), 0.99 (3H, dd, J 7.1, 7.1,
NCH2CH3), 1.17–1.34 (2H, m, 5-Ha, 11-Ha), 1.49–1.63 (4H, m,
6-H2, 7-H, 11-Hb), 1.68–1.79 (2H, m, 5-Hb, 10-Ha), 1.82–1.89
(1H, m, 8-H), 1.84 (1H, dd, J 11.9, 2.8, 2-Ha), 2.12 (1H, dq,
J 11.9, 7.1, NCHaCH3), 2.30 (1H, dq, J 11.9, 7.1, NCHbCH3),
2.39 (1H, d, J 11.2, 2-Hb), 2.68–2.75 (1H, m, 10-Hb), 3.25 (1H,
dd, J 4.4, 4.4, 4-H), 3.38 (3H, s, OCH3), 3.57 (1H, m, 9-H);
δC(100.6 MHz, CDCl3) 13.2 (NCH2CH3), 21.6 (C-5), 24.4
(C-6), 26.0 (1-CH3), 27.2 (C-10), 32.3 (C-1), 39.0 (C-11), 45.0
(C-7), 46.1 (C-8), 49.0 (NCH2CH3), 56.1 (C-2), 57.2 (C-4), 59.5
(OCH3), 80.2 (C-9); m/z 192 (5%), 165 (6), 123 (15).
(1â,2á,6â,9á)-9-Amino-3á-dimethoxymethyl-3â-methylbicyclo-
[5.4.0]nonan-2-ol 26
To a solution of (1β,7β,11β)-8α-dimethoxymethyl-8β-methyl-3-
aza-2-oxatricyclo[5.3.1.04,11]undec-3-ene 25 (120 mg, 0.50
mmol) in methanol (10 ml) at 25 ЊC was added nickel chloride
hexahydrate (238 mg, 1.0 mmol). The mixture was cooled to
0 ЊC and sodium borohydride (95 mg, 2.5 mmol) was added
portionwise, the mixture turned black and evolution of gas was
observed. The mixture was stirred at 0 ЊC for 3 h, the solvent
was removed in vacuo and the residue was dissolved in dichloro-
methane (12 ml) and conc. aqueous ammonia (12 ml). The mix-
ture was stirred for a further 2 h and the two layers were separ-
ated. The aqueous layer was extracted with dichloromethane
and the combined dichloromethane extracts were dried and
concentrated to yield the title compound as unstable orange
crystals (54 mg, 45%) (Found: (M Ϫ Me)ϩ, 228.160. C12H22NO3
requires: 228.160); νmax(solution, CHCl3)/cmϪ1 3372 (OH, NH);
δH(250 MHz, CDCl3) 0.93 (3H, s, 5-CH3), 1.20 (1H, m, 4-Ha),
1.34–1.50 (2H, m, 7-Ha, 8-Ha), 1.63–1.76 (4H, m, 3-H2, 4-Hb,
6-H), 1.85–2.05 (3H, m, 1-H, 7-Hb, 8-Hb), 3.41 (3H, s,
CH(OCH3)2), 3.52 (3H, s, CH(OCH3)2), 3.58–3.62 (1H, m,
9-H), 3.84 (1H, s, CH(OCH3)2), 4.01 (1H, br m, 1-H); m/z 228
(3%), 212 (5), 211 (12), 75 (100).
3-[(1á,2â)-2-Dimethoxymethyl-2-methylcyclohex-5-enyl]prop-
anal oxime 24
To
a solution of 3-[(1S,2R)-2-dimethoxymethyl-2-methyl-
cyclohex-5-enyl]propanal 16 (400 mg, 1.76 mmol) in pyridine
(6 ml) at 25 ЊC was added N-hydroxylamine hydrochloride (488
mg, 7.04 mmol). After 2.5 h the mixture was concentrated in
vacuo and the residue was partitioned between diethyl ether and
water. The ether layer was separated and washed with aqueous
sodium hydroxide, dried and concentrated. The product was
subjected to column chromatography (solvent A, 4:1) to yield
the title compound as a colourless oil (353 mg, 85%); (Found:
(M Ϫ OMe Ϫ H2O)ϩ, 192.138. C12H18NO requires: 192.139);
νmax(liquid film)/cmϪ1 3338 (OH), 1652 (C᎐C). δ (250 MHz,
X-Ray study of compound 20a
Crystal data. Data were collected from a single crystal
(colourless plate, 0.37 × 0.21 × 0.06 mm) of the tricycle 20a,
using an Enraf-Nonius CAD4 diffractometer and Ni-filtered
Cu-Kα radiation. Crystal data: monoclinic, space group
P21/c, a = 9.397(1), b = 12.089(1), c = 13.052(2) Å, β =
᎐
H
CDCl3) 0.89, 0.90 (3H, 2 × s, 2Ј-CH3), 1.07–1.50 (2H, m, CH2),
1.66–1.90 (2H, m, CH2), 1.96–2.22 (3H, m, CH, CH2), 2.26–
2.45 (2H, m, 1Ј-H, CH2), 3.43, 3.44 (3H, 2 × s, CH(OCH3)2),
3.53, 3.54 (3H, 2 × s, CH(OCH3)2), 3.94, 3.95 (1H, 2 × s,
CH(OCH3)2), 5.58–5.74 (2H, m, 5Ј-H, 6Ј-H), 6.79 (0.4H, br s,
0.4 × OH), 7.41 (0.6H, t, J 6.0, 0.6 × OH); δC(67.8 MHz,
CDCl3) 17.0, 17.1 (2Ј-CH3), 22.1 (C-4Ј), 25.6, 25.7 (CH2), 27.5,
27.8 (CH2), 28.4 (CH2), 36.8 (C-4), 40.5, 41.0 (C-1Ј), 41.2
(C-2Ј), 56.7 (CH(OCH3)2), 59.9 (CH(OCH3)2), 111.9
(CH(OCH3)2), 126.0, 128.8, 128.9 (2 × CH), 151.9 (C-1); m/z
192 (6%), 160 (6), 93 (14), 75 (100).
105.40(1)Њ, U = 1429.5(3) Å3, Z = 4, Dx = 1.19
g ,
cmϪ3
λ = 1.54178 Å, µ = 6.6 cmϪ1. 2172 Reflections (1464 unique,
688 observed with I > 2σ(I)) were measured by 2θ/ω scan,
θ ≤ 50Њ, 27.4% loss of standard reflection intensities was noted
during the data collection.
¯
Solution and refinement. The structure was solved by direct
methods using SHELXS-8612a and refined by full-matrix least-
squares methods (9 outer non-H atoms anisotropic, the rest
isotropic, all H atoms ‘riding’) with SHELXL-9312b programs;
an empirical extinction correction was applied.13 The refine-
ment converged at R = 0.055; residual features in the difference
(1â,7â,11â)-8á-Dimethoxymethyl-8â-methyl-3-aza-2-oxatricyclo-
[5.3.1.04,11]undec-3-ene 25‡
Fourier map ranged from 0.22 to Ϫ0.19 e ÅϪ3
.
Full crystallographic details, excluding structure factor
tables, have been deposited at the Cambridge Crystallographic
Data Centre (CCDC). For details of the deposition scheme, see
‘Instructions for Authors’, J. Chem. Soc., Perkin Trans. 1, avail-
able via the RSC Web page (http://www.rsc.org/authors). Any
request to the CCDC for this material should quote the full
literature citation and the reference number 207/259.
To a solution of 3-[(1S,2R)-dimethoxymethyl-2-methylcyclo-
hex-5-enyl)propanal oxime 24 (346 mg, 1.43 mmol) in methanol
(12 ml) at 25 ЊC was added chloramine-T (359 mg, 1.58 mmol).
The mixture was refluxed for 4.5 h then concentrated in vacuo.
The residue was partitioned between diethyl ether and water.
The ether layer was separated and washed with aqueous sodium
hydroxide, dried and concentrated. The product was subjected
to column chromatography (solvent A, 2:3) to yield the title
compound as a yellow oil (132 mg, 39%); (Found: (M Ϫ
MeOH)ϩ, 207.127. C12H17NO2 requires: 207.126); δH(250 MHz,
CDCl3) 0.83 (3H, s, 8-CH3), 1.12–1.22 (1H, m, CH), 1.27–1.39
(1H, m, CH), 1.57–1.81 (3H, m, CH, CH2), 1.91–2.03 (1H, m,
References
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dimethoxymethyl-7β-methyl-2-aza-3-oxatricyclo[6.2.1.04,11]undec-1-ene.
J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478
3477

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J. Chem. Soc., Perkin Trans. 1, 1998, 3471–3478