Synthetic approaches to the polycyclic alkaloid stemofoline

Article abstract of DOI:10.1039/b708910d

Preliminary studies of a synthetic approach to the alkaloid stemofoline 1 are reported. Stereoselective cyclisation of the ketoester 14 gave the 1-butyl-2,8-bis(methoxycarbonyl)-8-azabicyclo[3.2.1]octane 21 in which the 2-methoxycarbonyl group is in the a

Full text of DOI:10.1039/b708910d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthetic approaches to the polycyclic alkaloid stemofoline†‡
Alison M. Baylis, Michael. P. H. Davies and Eric J. Thomas*
Received 12th June 2007, Accepted 18th July 2007
First published as an Advance Article on the web 14th August 2007
DOI: 10.1039/b708910d
Preliminary studies of a synthetic approach to the alkaloid stemofoline 1 are reported. Stereoselective
cyclisation of the ketoester 14 gave the 1-butyl-2,8-bis(methoxycarbonyl)-8-azabicyclo[3.2.1]octane 21
in which the 2-methoxycarbonyl group is in the axial position. The analogous ketones 15, 18 and 19
were also cyclised to give the 8-azabicyclo[3.2.1]octanes 22–24 with axial electron-withdrawing
2-substituents. The structure of the bicyclic ketosulfone 22 was confirmed by X-ray diffraction.
Conversion of ester 21 into the tricyclic lactams 31 and 39, in which the amide fragments are
significantly distorted from planarity, was achieved by treatment of the iodides 29 and 38 with
tert-butyllithium. The structure of the deprotected tricyclic hydroxylactam 40 was confirmed by X-ray
diffraction, which showed the non-planar geometry of the lactam fragment and the distortion induced
into the bicyclo[3.2.1]octane by the additional two-carbon bridge. This meant that the endo hydrogen at
C9 was significantly closer to the 5-hydroxyl group than the endo hydrogen at C8. This structural
feature was utilised to direct a regioselective remote oxidation of the hydroxylactam 40 using lead
tetraacetate, which was accompanied by selective insertion into the closer endo C–H bond to give the
tetracyclic ether 41. Lactam 39 was converted into the tricyclic aminoketone 49 by reduction to the
aminol 44 using lithium aluminium hydride and reduction of the intermediate, possibly the chloride 46,
formed from aminol 44 using thionyl chloride, with more lithium aluminium hydride, followed by
O-deprotection and oxidation. The bicyclic ketoester 21 was also protected as its ketal 50, which was
taken through via the tricyclic lactam 54 into the ketoamine 49. Finally, allylation of the tricyclic lactam
42 and amine 49 gave the axial allylated products 60 and 58, but further elaboration for incorporation
of C10 and C11 (of stemofoline) was not straightforward. Alkylation of the protected hydroxyketone
64, which was prepared from the bicyclic ketoester 21, gave the axial alkylated products 65 and 69, and
the ketoester 69 was converted into the tricyclic hydroxylactone 73. However, the formation of a
tetracyclic lactam by treatment of the iodide 75 with tert-butyllithium was not successful.
have also been prepared for evaluation of their biological activity.11
Introduction
No biosynthetic studies have been carried out on Stemona
alkaloids but, on the basis of their structures, a biogenetic route
from spermidine and isoprenoid fragments, has been proposed.12
A possible strategy for the synthesis of stemofoline is outlined in
Scheme 1. 8-Azabicyclo[3.2.1]octanes, e.g. 6, should be available
via iminium ion cyclisations, such reactions having been widely
used for the synthesis of alkaloids.13 Construction of the third
ring of the stemofoline nucleus by regioselective alkylation would
provide a tricyclic intermediate, e.g. 5, and addition of the
remaining three-carbon fragment would deliver the ketolactam
4. At some point it will be necessary to introduce the oxygen
functionality which is to become the ethereal bridge between
C2 and C8 (stemofoline numbering). It may be necessary to
introduce this additional functionality earlier in the synthesis, but
an attractive strategy would be to use the ketoacid present in 4 to
effect a regioselective remote oxidation generating an intermediate
such as the pentacyclic acetal 3. Reduction of the lactam and
addition of the tetronic acid would then complete a synthesis of
stemofoline 1. We now report details of a synthesis of the tricyclic
hydroxylactam 40, which is analogous to 5, together with studies
of its regioselective remote oxidation and other functional group
interconversions that will underpin future attempts to complete a
synthesis of stemofoline.14,15
Extracts of the roots and leaves of several Stemonacea have been
widely used in traditional Chinese, Japanese and Thai medicine
to treat respiratory complaints and parasitic infections, and as
insecticides. More than twenty alkaloids have been isolated from
these species of which the most complex are stemofoline 1 and its
dehydro analogue, asparagamine A 2, which has also been isolated
from Asparagus racemosus.1 Because of their biological activities,
many synthetic studies have been carried out on the synthesis of the
stemona alkaloids including a synthesis of ( )-isostemofoline [the
(E)-isomer of stemofoline],2 and a synthesis of ( )-asparagamine
and its (E)-isomer,3 together with total syntheses of stenine,4
tuberostemonine,5 croomine,6 stemospironine,7 stemonamide8 and
stemoamide.9 Several other synthetic approaches to these alka-
loids have been reported,10 and simplified analogues of stemofoline
The School of Chemistry, The University of Manchester, Manchester, UK
M13 9PL. E-mail: e.j.thomas@manchester.ac.uk
† Electronic supplementary information (ESI) available: full experimental
details for the preparation of compounds 8–19 and 50–57. See DOI:
10.1039/b708910d
‡ CCDC reference number 650400. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b708910d
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Scheme 1 Outline of a possible synthesis of stemofoline.
Results and discussion
Assembly of the tropanone
Cyclisation precursors were prepared from 5-prop-2-enyl-
pyrrolidinone 7, as outlined in Scheme 2. Reaction of the
racemic§ pyrrolidinone N-tert-butoxycarbonyl derivative 816 with
butylmagnesium bromide17 gave ketone 9, which was protected as
its acetal 10. Ozonolysis gave the aldehyde 11, which was converted
into the ketoester 14 via an aldol condensation followed by oxida-
tion, and into the ketosulfone 18 by addition of lithiated methyl
phenyl sulfone followed by oxidation. The allylated analogues 15
and 19 were similarly prepared. In the nucleophilic additions to
aldehyde 11, it was found not to be necessary to allow for complete
deprotonation of the N-tert-butoxycarbonyl group, the use of ca.
25% of an excess of the lithiated esters and sulfones was generally
found to be sufficient.
Scheme 2 Synthesis of cyclisation precursors. Reagents and condi-
tions: i) (t-BuCO2)2O, DMAP, Et3N (76%); ii) n-BuMgBr, THF (91%);
iii) (CH2OH)2, pyH·OTs, benzene (81%); iv) O3, MeOH, then Ph3P (90%);
v) MeCO2Me, LDA, −78 ◦C (12, 95%) or ethyl pent-4-enoate, LDA,
−78 ◦C (13, 92%); vi) PDC (14, 73%) or Dess Martin (15, 59%; 18, 72%;
19, 66%); vii) PhSO2Me, LDA, −78 ◦C (16, 58%) or but-3-enyl phenyl
sulfone, LDA, −78 ◦C (17, 80%).
Treatment of the ketoester 14 with trifluoroacetic acid in
dichloromethane gave the imine 20, which was characterised by
a peak at tmax 1642 cm−1 in its IR spectrum corresponding to the
1
18,19
=
C N stretch, and by H NMR, see Scheme 3.
The imine was
unstable to chromatography, and so the crude imine was treated
with methyl chloroformate followed by an excess of triethylamine
at −78 ◦C, which gave a mixture of two products in the ratio 85 :
15. The major product was isolated (71% from 14) and identified
§ All of the work in this paper was carried out using racemic compounds.
However, the use of (S)-5-prop-2-enylpyrrolidinone would lead to an
asymmetric synthesis of stemofoline.
Scheme 3 Cyclisations of ketoesters.
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as the 8-azabicyclo[3.2.1]octane 21. The minor product could
not be isolated free of the major product and was not formally
identified, but may have been the C2-epimer of 21. The structure
of the tropanone 21 was consistent with its spectroscopic data,
but the configuration at C2 was not unequivocally assigned at
this point. The structure shown was assigned by analogy with the
stereoselectivities of analogous cyclisations and was subsequently
confirmed by later transformations, vide infra.
of these using trichloroethyl chloroformate each gave a single
product identified as the corresponding 8-azabicyclooctane 23
(42%) and 24 (40%). Neither of these cyclised products was
crystalline. However, the observation of an NOE enhancement
of H-4ax on irradiation of the phenyl ortho protons for the product
from cyclisation of the sulfone 19 indicated that the sulfone was
axial, as shown in structure 24. The ester 23 was identified by
analogy.
Cyclisation of the sulfone 18 was carried out in a similar
manner except using 2,2,2-trichloroethyl chloroformate to form
the iminium ion. This gave a 51% yield of a single crystalline
product shown to be the azabicyclooctane 22 with a chair
conformation for the six-membered ring and the phenylsulfonyl
group in the axial position, by X-ray crystallography, see Fig. 1. Of
interest was the broadening of the 1H NMR peaks assigned to the
diastereotopic methylene protons of the trichloroethyl ester, which
indicated hindered rotation about this fragment. On warming to
100 ◦C, these broad peaks were replaced by two doublets at d 5.24
and 5.02, each with J 11.5 Hz.
In these cyclisations, which are likely to be under thermody-
namic control, the electron-withdrawing group a to the ketone
seems to prefer the axial position in all cases, perhaps to avoid
unfavourable dipolar interactions with the ketone at C3. This
means that the allyl group at C2 in the bicyclic products 23 and 24
is unfavourably disposed for elaboration to form the third ring of
the stemofoline nucleus. Moreover, the hydrogen at C2 in products
21 and 22 is in the plane of the carbonyl group and so is not
particularly acidic. For these reasons, it was decided to study the
chemistry of the ketoester 21 with a view to modifying the axial 2-
methoxycarbonyl group to introduce the third ring of stemofoline.
Synthesis of a tetracyclic ether corresponding to the nucleus of
stemofoline
Reduction of the ketone 21 using sodium borohydride gave a
50 : 50 mixture of the epimeric alcohols 25 and 26. With zinc
borohydride, the reaction was 60 : 40 in favour of the axial alcohol
26, and with zinc cyanoborohydride, the selectivity improved to
75 : 25 in favour of alcohol 26, see Scheme 4. The configurations
of these alcohols were assigned on the basis of the diaxial 3,4-
coupling of 13 Hz observed for the equatorial alcohol 25. As
this equatorial alcohol could be re-oxidised back to the ketone
21 using pyridinium dichromate (87%), procedures with improved
stereoselectivitywere not investigated at this stage for thereduction
of ketone 21. Attempts to protect alcohol 26 using benzyl chloride
and sodium hydride led to mixtures of products, perhaps due
to a competing reverse aldol reaction, but the benzyl ether 27
was obtained in excellent yield using benzyl trichloroacetimidate
under acidic conditions. Reduction of the ester 27 into the primary
alcohol 28 using diisobutylaluminium hydride at 0 ◦C gave the
Fig. 1 ORTEP projection of the sulfone 22 as determined by X-ray
crystallography, ellipsoids shown at 30% probability.
The ester 15 and sulfone 19 had been prepared with a view to
using the allyl groups to introduce the third ring of the stemofoline
nucleus, cf. the conversion of 6 into 5. In the event, on cyclisation
Scheme 4 Synthesis of tricyclic lactam 31. Reagents and conditions: i) ZnCl2, NaBH3CN, Et2O (25 : 26 = 25 : 75, 91%); ii) benzyl trichloroacetimidate,
TfOH (99%); iii) DIBAL-H, hexane, 0 ◦C (28, 59%; 30, 18%) or DIBAL-H, hexane, −78 ◦C to rt (28, 75%); iv) I2, PPh3, imid. (81%); v) t-BuLi, −78 ◦
to rt (31, 71%) or t-BuLi, −78 ◦C (31, 20%; 32, 65%); vi) LiAlH4, ether, 0 ◦C (99%); vii) Ac2O, DMAP (cat.), Et3N (72%).
C
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tricyclic aminoacetal 30 as a side product, but the formation of this
aminoacetal, which confirmed the axial stereochemistry assigned
to the ester 21, could be avoided by carrying out the reduction
at a lower temperature. Aminoacetal 30 was of interest, however,
since its formation must have involved capture of an iminium
ion derived from the methyl carbamate by the primary alkoxide
formed on reduction of the ester. This observation suggested that
the carbonyl carbon of the carbamate could be incorporated into
the third ring of stemofoline. To investigate this possibility, the
alcohol 28 was converted into the iodide 29, and cyclisation of
the corresponding organolithium species formed by treatment
of 29 with tert-butyllithium was investigated. It was found that
reaction of the iodide 29 with an excess of tert-butyllithium with
an immediate quench gave a mixture of the aminoester 32 (65%)
and the tricyclic lactam 31 (20%). However, if after the addition of
the tert-butyllithium at −78 ◦C, the cooling bath was removed and
the reaction mixture stirred for 15 min, the aminoester 32 was not
formed and the tricyclic lactam 31 was isolated on work-up in a
good yield. These results were interpreted in terms of protonation
of the carbamate adduct 35 during an immediate quench or loss
of lithium methoxide on standing.
The geometry of the lactam 31 was determined by its tricyclic
structure, which required the lone-pair on nitrogen to be more or
less orthogonal to the P-orbitals of the carbonyl group.20 This
distortion from the usually planar amide geometry was reflected
in the IR spectrum of 31, which showed a carbonyl stretching
absorption at tmax 1747 cm−1, and in its chemistry. For example,
reduction using lithium aluminium hydride gave the aminol 33 as a
single diastereoisomer, characterised as its acetate 34, although the
configuration of the hydroxyl bearing carbon was not established.
The benzyl-protected hydroxylactam 31 was an oil, but the cor-
responding tert-butyldimethylsilyloxylactam 39 was crystalline.
This was prepared from the bicyclic aminoester 26 in a similar
fashion by O-silylation, reduction of the ester 36, conversion of the
alcohol 37 into the primary iodide 38, and treatment of the iodide
with tert-butyllithium, see Scheme 5. Lactam 39 was deprotected
to give the crystalline alcohol 40, the structure of which was
confirmed by X-ray crystallography, see Fig. 2.21 The N–C2 bond
Scheme 5 Synthesis of the pentacyclic lactam 41. Reagents and conditions:
i) TBSOTf, 2,6-lutidine (86%); ii) DIBAL-H, hexane, −78 ◦C to rt (78%);
iii) I2, PPh3, imid. (83%); iv) t-BuLi, −78 ◦C to rt (81%); v) TBAF, THF,
rt (99%); vi) Pb(OAc)4, benzene, reflux (40, 12%; 41, 35%; 42, 16%).
suggested that the hydroxyl oxygen could be used to discriminate
between these two endo hydrogens, providing a model for the
regioselective remote oxidation proposed for the conversion of
ketone 4 into acetal 3. Indeed, this was found to be the case, in that
oxidation of the alcohol 40 using an excess of lead(IV) acetate gave
the tetracyclic ether 41 as the major product (35%) together with
ketone 42 (16%) and unchanged starting material 40 (12%). The
structure of ether 41 was confirmed by 2D COSY 1H NMR studies.
In particular, H-7 showed vicinal couplings with the methylene
protons at both C6 and at C8 confirming the regioselectivity of
the oxidation.
The structure of ether 41 corresponds to the tetracyclic nucleus
of stemofoline. Indeed it has been suggested that an oxidation
akin to the conversion of alcohol 40 into ether 41 is involved in
the biosynthesis of stemofoline via protostemonine 43, another
alkaloid isolated from Stemonacea.12 Fig. 3 shows a comparison
of the structures of stemofoline 1 and protostemonine 43. It can be
˚
length of 1.432 A in the X-ray crystal structure of 40 confirmed
the single-bond character of this bond due to the non-planarity of
the lactam. It also revealed a twist in the azabicyclo[3.2.1]octane
fragment induced by the additional two-carbon bridge, which
˚
positioned the endo hydrogens at C8 and C9 2.97 and 2.32 A,
respectively, from the oxygen atom of the hydroxyl group. This
Fig. 2 ORTEP projection of the tricyclic lactam 40 as determined by
Fig.
3
A
comparison of the structures of stemofoline and
X-ray crystallography, ellipsoids shown at 30% probability.
protostemonine.
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seen that the polycyclic core components of these two structures
differ only by the extra oxygen in stemofoline between C2 and
C8, and the C–C bond between C3 and C7. The regioselective
introduction of the C5–C9 oxygen bridge in 41 could therefore be
regarded as mimicking the biosynthetic introduction of the oxygen
between C3 and C8 into stemofoline 1 albeit using very different
chemistry.
At this point, a procedure was developed to convert lactam 39
into the tricyclic ketoamine 49, see Scheme 6, since this conversion
will have to be carried out at some point in the synthesis of
stemofoline. As observed for the benzyl-protected lactam 31,
reduction of lactam 39 using lithium aluminium hydride gave the
aminol 44 (97%) as a single epimer, characterised as its acetate
45. After unsuccessful attempts to deoxygenate the aminol 44
using free-radical chemistry,22 it was converted into the amine
47 by treatment with thionyl chloride followed by reduction of
the intermediate so formed, possibly the chloride 46, with lithium
aluminium hydride (92% overall). Desilylation of the silyl ether 47
to the corresponding alcohol 48 was more efficient using boron
trifluoride diethyl etherate than with either aqueous acid or TBAF,
and the hydroxyamine 48 was oxidised to give the aminoketone 49
using Swern conditions.
This preparation of the aminoketone 49 had involved reduc-
tion of the ketoester 21, protection of the alcohol as its tert-
butyldimethylsilyl ether 36 and, following introduction of the
third ring, desilylation and reoxidation of alcohol 48 to the
ketone. To avoid the unnecessary steps of ketone reduction
and alcohol oxidation, an alternative sequence was investigated
with protection, rather than reduction, of the ketone 21, see
Scheme 7. Protection of the ketone 21 as its acetal 50 was best
achieved using 2-methoxy-1,3-dioxolane and toluene p-sulfonic
acid (cat.) in methanol–toluene. Reduction of the ester 50 into
the primary alcohol 52 required rather forceful conditions and
gave the aldehyde 51 as a side product, even with a large excess of
diisobutylaluminium hydride. Following conversion to the iodide
53, cyclisation using tert-butyllithium gave the tricyclic lactam 54
accompanied by small amounts of the bicyclic carbamate 55. The
lactam 54 was taken through via the aminol 56 to the acetal 57,
which was hydrolysed to the aminoketone 49 using dilute aqueous
acid. This second synthesis of the aminoketone 49 is slightly
shorter than the first but is, if anything, less efficient with a ca.
15% overall yield from the bicyclic ketone 21 as compared to a ca.
20% overall yield for the first route.
Alkylation of bi- and tricyclic ketones
It was now necessary to develop procedures for the incorporation
of the fragment corresponding to C10 and C11 of stemofoline to
complete an assembly of the intact pentacyclic nucleus of stemo-
foline. Initial studies were based on alkylation of the advanced
tricyclic ketoamine 49 and ketolactam 42 since the configuration
at C-4 in these compounds is fixed, see Scheme 8. Alkylation of the
amine using allyl iodide and potassium hexamethyldisilazide gave
a mixture of the axial and equatorial allylated products 58 and 59,
ratio 80 : 20, combined yield 56%. With lithium diisopropylamide,
a slightly lower yield, 42%, was obtained but only the axial product
58 was isolated. Treatment of 58 with potassium tert-butoxide led
to clean epimerisation to the equatorial product 59. Allylation
of the ketolactam 42 took place regioselectively a to the ketone,
with a mixture of the axial and equatorial products 60 and 61,
ratio 65 : 35, being obtained in modest yield using lithium
diisopropylamide and allyl bromide.
Scheme 6 Synthesis of the tricyclic aminoketone 49. Reagents and
conditions: i) LiAlH4, ether (97%); ii) Ac2O, py, DMAP (93%); iii) SOCl2,
then LiAlH4, ether (92%); iv) BF3·Et2O (85%); v) DMSO, (COCl)2, Et3N,
CH2Cl2 (85%).
Scheme 7 A second synthesis of aminoketone 49. Reagents and conditions: i) 2-methoxy-1,3-dioxolane, TsOH, MeOH, toluene, 50 ◦C (87%); ii) DIBAL-H
(51, 9%; 52, 55%); iii) I2, PPh3, imid. (78%); iv) t-BuLi, THF, −78 ◦C (54, 74%; 55, 4%); v) LiAlH4, Et2O (83%); vi) SOCl2 then LiAlH4 (75%); vii) 1%
aq. H2SO4 (90%).
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consistent with the structures assigned to 59 and 61. The equili-
bration of the axial isomer 58 into its equatorial epimer 59 is also
consistent with these structural assignments. However, oxidative
cleavage of the terminal double bond of the equatorial allylated
ketoamine 59 by ozonolysis or hydroxylation – periodate oxidation
was unsuccessful in our hands and alkylation of the aminoketone
49 using methyl bromoacetate was also unsuccessful. As the
allylation of the ketolactam 42 was less efficient than allylation
of the ketoamine 49, it was decided not to investigate alkylation of
the ketolactam 42 using methyl bromoacetate, but instead to inves-
tigate alkylation of more accessible bicyclic ketones earlier in the
synthesis.
Reduction of the bicyclic ester 26 using diisobutylaluminium
hydride gave the diol 62, which was converted into the ketone
64 by regioselective monoprotection and oxidation of the mono-
tert-butyldimethylsilyl ether 63, see Scheme 9. Allylation of the
ketone 64 using lithium hexamethyldisilazide and allyl iodide gave
the axially allylated product 65 in a moderate 55% yield, and
epimerisation to the equatorial epimer 66 was achieved using
potassium tert-butoxide in dichloromethane. The configuration
of epimers 65 and 66 at C4 was assigned on the basis of J4,5
Scheme 8 Allylation of tricyclic intermediates. Reagents and conditions:
i) KHMDS, allyl iodide, −78 ◦C (58 : 59 = 80 : 20, 56%) or LDA, allyl
iodide, −78 to rt (60, 42%); ii) KOt-Bu, CH2Cl2, methanol, rt (88%);
iii) LDA, allyl bromide, −78 ◦C to rt (60 : 61 = 65 : 35, 39%).
The structures of these allylated products were assigned on the
basis of spectroscopic data. Vicinal bond angles between the C–H
bond at C-7 and the methylene C–H bonds at C-6 and C-8 in the
X-ray structure of the tricyclic hydroxylactam 40 were 71◦ and
49◦ for the equatorial and axial hydrogens at C-6 and 85◦ and
28◦ for the endo and exo-hydrogens at C-8, respectively. For the
major products from the alkylation reactions, H-7 was observed as
a doublet with a coupling constant of ca. 7 Hz due to the coupling
with 8-Hexo, no coupling being observed between H-6eq and H-
7, and so these products were identified as the axially alkylated
products 58 and 60. For the epimeric products, H-7 was a triplet
with J ca. 7 Hz, due to coupling with both H-8exo and H-6axial
1
in their H NMR spectra with H-5 being observed as a doublet
(J 7 Hz) for the axially alkylated product 65, and as a double
doublet (J 4, 7.5 Hz) for the equatorially alkylated product 66
1
(cf. the H NMR data for 58–61). Their retained configuration
1
at C2 was provisionally assigned on the basis of unchanged H
NMR chemical shifts and coupling constants for H-2 and 2-
CH2. However, partial epimerisation at C2 was observed during
desilylation using tetrabutylammonium fluoride of both 65 and
66, which gave mixtures of the C2 epimers 67 and 68. For both 67
and 68, H-5 was a double doublet consistent with the allyl group
Scheme 9 Alkylation and further modification of bicyclic intermediates. Reagents and conditions: i) DIBAL-H, CH2Cl2, −78 ◦C, then NaBH4 (63%);
ii) TBSOTf, 2,6-lutidine, CH2Cl2 (94%); iii) PDC, CH2Cl2 (98%); iv) KHMDS, allyl iodide, −78 ◦C (63%); v) KOt-Bu, CH2Cl2, methanol (56%);
vi) TBAF, THF (67 : 68 = 60 : 40, 56% from 65; 67 : 68 = 50 : 50, 36%, from 66); vii) KHMDS, BrCH2CO2Me, −78 ◦C to rt (58%); viii) KOt-Bu, CH2Cl2,
methanol (70, 66%; 71, 9%); ix) ZnCl2, NaCNBH3, (74%); x) TBAF, THF (84%); xi) Ac2O, DMAP, Et3N (69%); xii) I2, PPh3, imid. (80%).
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being in the equatorial position at C4, i.e. 67 and 68 had to be
epimers at C2.
Experimental
Melting points were recorded on a Koffler heated stage mi-
croscope. Proton NMR spectra were recorded in deuterated
chloroform, unless otherwise indicated, on Bruker AC300, Varian
XL300 and Varian Unity 500 spectrometers; coupling constants
are given in Hz and chemical shifts relative to Me4Si. IR spectra
were recorded on a Perkin Elmer 1710FT spectrometer and were
run as evaporated films. Mass spectra were measured on a Kratos
MS20 and MS25 spectrometers.
In the case of the bicyclic ketone 64, alkylation using
methyl bromoacetate and potassium hexamethyldisilylazide was
successful, albeit only in a moderate 58% yield, and gave the
diaxial product 69. Epimerisation using potassium tert-butoxide
in dichloromethane–methanol gave the C4 epimer 70 (66%)
together with the doubly epimerised methyl ether 71 (9%). The
1
configuration of this methyl ether was established by H NMR
with an enhancement of H-4 on irradiation of H-2 and vice versa. It
may have been formed by elimination of tert-butyldimethylsilanol
from the b-silyloxyketone 69 followed by conjugate addition of
methanol with axial protonation at C2. For the silyl ether 70, an
NOE enhancement of H-4 was observed on irradiation of one of
the 2-CH protons and vice versa. For the compounds 69–71, the
configurations at C4 were also consistent with the coupling be-
tween H-4 and H-5 observed for the equatorially alkylated epimers
70 and 71 but not for the axially alkylated product 69. Reduction
of the silyloxyketone 70 using zinc borohydride gave the alcohol
72. As observed for the reduction of ketone 21, the reduction of
ketone 70 was stereoselective in favour of the axial alcohol, as
shown by the 1H NMR spectrum of 72 in which J2,3 = J3,4 = 4, i.e.
H-3 must be equatorial. Desilylation of 72 using either amberlite
resin or tetrabutylammonium fluoride in tetrahydrofuran was
accompanied by cyclisation and gave the hydroxylactone 73, the
structure of which was confirmed by conversion to its acetate
74. In particular the axial configuration at C2 was confirmed by
NOE. Finally, the iodide 75 was prepared from the hydroxylactone
73, but attempts to cyclise this via halogen–metal exchange using
tert-butyllithium were unsuccessful, complex mixtures of products
being obtained.
Chromatography refers to flash chromatography using Merck
silica gel 60 H (40–63 mm3, 230–400 mesh). Light petroleum refers
to the fraction boiling at 40–60 ◦C, and ether to diethyl ether.
All solvents and reagents were purified by standard techniques
before use. All non-aqueous reactions were performed under an
atmosphere of dry argon or nitrogen.
2-Butyl-5-(3-methoxycarbonyl-2-oxopropyl)pyrroline 20
Trifluoroacetic acid (36.0 cm3, 462 mmol) was added dropwise
to the ketoester 14 (12.4 g, 30.8 mmol) in dichloromethane
◦
(250 cm3) at 0 C, and the mixture allowed to warm to ambient
temperature, stirred for 5 h, then concentrated under reduced
pressure. The residue in ethyl acetate was washed with saturated
aqueous sodium hydrogen carbonate, water and brine, then dried
(MgSO4). Concentration under reduced pressure afforded the title
compound 20 as a bright yellow oil (7.36 g, ca.100%) used without
further purification. A small quantity was chromatographed
using dichloromethane–methanol–triethylamine (89 : 10 : 1) for
characterisation. Found: M+, 239.1521. C13H21NO3 requires M,
239.1521; tmax 1747, 1714, 1642, 1551, 1367, 1245, 1199 and
1169 cm−1; dH (300 MHz, CDCl3) 0.93 (3 H, t, J 9.5 Hz, CH3),
1.28–1.48 (3 H, m, 3ꢀ-H2 and 4-H), 1.50–1.62 (2 H, m, 2ꢀ-H2), 2.15
(l H, m, 4-Hꢀ), 2.30 (2 H, m, 1ꢀ-H2), 2.44–2.58 (2 H, m, 3-H2), 2.61
and 2.87 (each l H, dd, J 17 Hz, 9.5 Hz, 1ꢀ-H), 3.56 (2 H, s, 3ꢀ-H2),
3.73 (3 H, s, OCH3) and 4.28 (l H, m, 5-H); dC (50 MHz, CDCl3)
15.87, 24.62, 30.32, 30.54, 30.68, 35.22, 39.32, 50.72, 51.46, 54.42,
68.96, 169.51 and 184.14; m/z CI(NH3) 241 (15%), 240 (M+ + 1,
100).
Summary and conclusions
This work has provided a useful basis for a synthesis of stemo-
foline 1. Several 2-substituted-1-butyl-8-azabicyclo[3.2.1]octanes,
including the ester 21, in which the 2-substituents are in the axial
position ready for incorporation into the second pyrrolidine ring of
stemofoline, have been prepared stereoselectively. The tricyclic lac-
tams 31 and 39, in which the amides are significantly distorted from
planar geometry, have been prepared by cyclisation of the iodides
29 and 38 using tert-butyllithium, and lactam 39 was taken through
to the tetracyclic ether 41 by regioselective remote oxidation of the
alcohol 40, and to the tricyclic ketoamine 49 by reduction of the
lactam. However, although allylation of the tricyclic amide 42 and
amine 49 en route to appending the final ring of stemofoline was
successful, further elaboration of the products 59 and 61 proved
difficult. Although the bicyclic ester 21 could be converted into
the tricyclic lactone 73, this sequence was rather inefficient, and
preliminary studies on the conversion of the tricyclic iodide 75 into
a tetracyclic lactam were unsuccessful. At this point, rather than
incorporate the C(10)–C(11) fragment of stemofoline by alkylation
of cyclic intermediates, it was decided to study the synthesis and
cyclisation of more complex precursors analogous to the ketoester
14, which already contain this additional fragment, and which
could lead to an asymmetric synthesis of stemofoline. This work is
on-going.
(1RS,2RS,5SR)-l-Butyl-2,8-dimethoxycarbonyl-8-
azabicyclo[3.2.1]octan-3-one 21
Methyl chloroformate (3.58 cm3, 46.2 mmol) was added dropwise
to the imine 20 (7.36 g, 30.8 mmol) in dichloromethane (250 cm3)
at −78 ◦C and the mixture stirred for 15 min. Triethylamine
(26.0 cm3, 185 mmol) was added dropwise, maintaining the
reaction mixture below −70 ◦C, then the mixture was stirred at
−78 ◦C for 9 h and allowed to warm to ambient temperature over
3 h. Saturated aqueous ammonium chloride was added, and the
organic phase washed with water and brine, then dried (MgSO4).
After concentration under reduced pressure, chromatography
using light petroleum–ethyl acetate (80 : 20) as eluent gave the title
compound 21 as a colourless oil (6.51 g, 71% from 14). Found: M+,
297.1574. Cl5H23NO5 requires M, 297.1576; tmax 1740, 1713, 1369,
1279, 1235, 1195, 1157, 1126 and 1098 cm−1; dH (300 MHz, CDCl3)
0.97 (3 H, t, J 7.5, CH3), 1.20–1.75 (6 H, m, 2 × CH2, 6-H and
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7-H), 1.88–2.24 (4 H, m, CH2, 6-Hꢀ and 7-Hꢀ), 2.35 (1 H, d, J
17.5 Hz, 4-Heq), 3.24 (1 H, dd, J 17.5 Hz, 4 Hz, 4-Hax), 3.33 (1 H,
s, 2-H), 3.69 and 3.71 (each 3 H, s, OCH3) and 4.66 (1 H, m, 5-H);
m/z CI(NH3) 298 (M+ + 1, 100%).
Following the procedure outlined for the preparation of the
azabicyclooctane 21, 2,2,2-trichloroethyl chloroformate (0.5 cm3,
8.8 mmol) and the imine (644 mg) with triethylamine (1.85 cm3,
13.2 mmol) in dichloromethane (15 cm3), after chromatography
using light petroleum–ethyl acetate (98 : 2) as eluent, gave the
title compound 23 (436 mg, 42% from the ketoester 15), as a
colourless oil. Found: M+ + H, 467.1015. C20H2835Cl3NO5 requires
M, 467.1033; tmax 1717, 1639, 1397 and 1114 cm−1; dH (300 MHz,
CDCl3) 0.96 (3 H, t, J 7.5 Hz, CH3), 1.13–2.08 (9 H, m, 3 × CH2,
6-H2 and 7-H), 1.28 (3 H, t, J 8 Hz, OCH2CH3), 2.37 (1 H, d, J
17 Hz, 4-Heq), 2.49 (1 H, dd, J 13.5 Hz, 5.5 Hz, lꢀ-H), 2.60 (1 H,
dd, J 13.5 Hz, 9.5 Hz, lꢀ-Hꢀ), 2.99 (1 H, m, 7-Hꢀ), 3.50 (1 H, dd,
J 17 Hz, 5.5 Hz, 4-Hax), 3.97–4.19 (2 H, m, OCH2), 4.58 (1 H, d,
J 13 Hz, HCHCCl3), 4.73 (1 H, m, 5-H), 4.79 (1 H, d, J 13 Hz,
HCHCCl3), 4.99–5.17 (2 H, m, 3ꢀ-H2) and 5.87–6.03 (1 H, m, 2ꢀ-
H); dH (75 MHz, CDCl3) 13.84, 14.16, 23.13, 25.73, 28.36, 30.56,
30.84, 34.61, 48.37, 56.69, 61.58, 69.82, 71.13, 74.66, 95.50, 118.19,
134.48, 151.10 and 169.51; m/z (+FAB) 472 (2%), 470 (6) and 468
(M+ + 1, 8).
(1RS,2RS,5SR)-l-Butyl-2-phenylsulfonyl-8-(2,2,2-trichloro-
ethoxycarbonyl)-8-azabicyclo[3.2.1]-octan-3-one 22
Following the procedure outlined for the synthesis of pyrroline
20, trifluoroacetic acid (0.536 cm3, 7.35 mmol) and ketosulfone
18 (237 mg, 0.49 mmol) in dichloromethane (5.0 cm3) gave the
corresponding pyrroline as a yellow oil (156 mg, 99%) used without
further purification. Found: M+, 321.1398. C17H23NO3S requires
M, 321.1399; trnax 1719, 1641, 1448, 1323 and 1154 cm−1; dH
(300 MHz, CDCl3) 0.92 (3 H, t, J 9.5 Hz, CH3) 1.23–1.42 (2 H, m,
3ꢀ-H2), 1.40 (1 H, m, 4-H), 1.47–1.60 (2 H, m, 2ꢀ-H2), 2.14 (1 H,
m, 4-Hꢀ), 2.25–2.36 (2 H, br t, J 7.5 Hz, 1ꢀ-H2), 2.37–2.62 (2 H,
m, 3-H2), 2.83 (1 H, dd, J 17 Hz, 7.5 Hz, 1ꢀꢀ-H), 3.03 (1 H, dd,
J 17 Hz, 6.5 Hz, 1ꢀꢀ-Hꢀ), 4.29 (1 H, m, 5-H), 4.25 and 4.32 (each
1 H, d, J 15 Hz, 3ꢀꢀ-H), 7.58 (2 H, m, ArH), 7.67 (1 H, ArH)
and 7.90 (2 H, m, ArH); m/z CI(NH3) 322 (M+ + 1, 12%) and
182 (100).
Following the procedure outlined for the synthesis of az-
abicyclooctane 21, 2,2,2-trichloroethyl chloroformate (0.1 cm3,
0.98 mmol) and the pyrroline (156 mg, 0.49 mmol) in
dichloromethane (10.0 cm3), after chromatography using light
petroleum–ethyl acetate (85 : 15) as eluent, gave the title compound
22 as a white solid (124 mg, 51% from 18), recrystallised
from ethyl acetate–hexane to give colourless crystals, m.p. 144–
145 ◦C. Found: C, 48.4; H, 4.8; Cl, 21.2; N, 2.9; S, 6.6%.
C20H24Cl3NO5S requires C, 48.35; H, 4.85; Cl, 21.45; N, 2.8; S,
6.45%; tmax 1714, 1402, 1326, 1205 and 1145 cm−1; dH (300 MHz,
C6D6) 0.80–1.84 (11 H, m, CH2CH2CH2CH3, 6-Hexo and 7-Hexo),
2.13 (1 H, d, J 17 Hz, 4-Heq), 2.44 (1 H, m, 6-Hendo), 3.28 (1 H,
td, J 15 Hz, 5.5 Hz, 7-Hendo), 3.58 (1 H, dd, J 17 Hz, 5 Hz,
4-Hax), 3.87 (1 H, s, 2-H), 4.79 (1 H, m, 5-H), 4.90 and 5.67
(each 1 H, br s, OHCHCCl3), 6.92–7.08 (3 H, m, ArH) and 7.67–
7.86 (2 H, m, ArH); m/z CI(NH3) 500 (27%), 498 (74) and 496
(M+, 100).
(1RS,2RS,5SR)-l-Butyl-8-(2,2,2-trichloroethoxycarbonyl)-2-
phenylsulfonyl-2-prop-2ꢀ-enyl-8-azabicyclo[3.2.l]octan-3-one 24
Trifluoroacetic acid (0.428 cm3, 5.60 mmol) was added to a mixture
of the ketosulfones 19 (195 mg, 0.37 mmol) in dichloromethane
(5.0 cm3) at 0 ◦C. The mixture was stirred at ambient temperature
for 3 h then concentrated under reduced pressure. A solution of
the residue in ethyl acetate was washed with saturated aqueous
sodium hydrogen carbonate, water and brine, then dried (MgSO4).
Concentration under reduced pressure afforded a mixture of
diastereoisomers of the corresponding pyrroline (132 mg, 98%), a
mobile yellow oil used without further purification. Found: M+ +
H, 362.1788, C20H28NO3S requires M, 362.1790; tmax 1719, 1641,
1586, 1448, 1323, 1153 and 1086 cm−1; dH (300 MHz, CDCl3) 0.90
(3 H, t, J 8 Hz, CH3), 1.1–2.75 (12 H, m), 2.83 (0.5 H, dd, J 18.5 Hz,
9.5, 1ꢀ-H), 2.93 (0.5 H, dd, J 18.5 Hz, 11.5 Hz, 1ꢀ-H), 3.21 (0.5 H,
dd, J 18.5 Hz, 7.5 Hz, 1ꢀ-H), 3.30 (0.5 H, dd, J 18.5 Hz, 5.5 Hz,
1ꢀ-H), 4.21–4.44 (2 H, m, 5-H and 3ꢀ-H), 4.96–5.02 (2 H, m, 6ꢀ-H),
5.50–5.18 (1 H, m, 5ꢀ-H), 7.49–7.65 (2 H, m, ArH), 7.65–7.76 (1 H,
m, ArH) and 7.76–7.90 (2 H, m, ArH); m/z CI(NH3) 362 (M+ +
1, 100%) and 222 (95).
(1RS,2RS,5SR)-1-Butyl-2-ethoxycarbonyl-2-prop-2-enyl-8-(2,2,2-
trichloroethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-one 23
2,2,2-Trichloroethyl chloroformate (0.103 cm3, 0.75 mmol) was
added to the pyrroline (132 mg, 0.37 mmol) in dichloromethane
(5.0 cm3) at −78 ◦C. The mixture was stirred for 20 min then
triethylamine (0.314 cm3, 2.22 mmol) was added. After stirring
for 9 h, the mixture was allowed over 3 h to warm to ambient
temperature. Saturated aqueous ammonium chloride was added
and the mixture was stirred for 30 min. The organic phase was
washed with water and brine then dried (MgSO4). Concentration
under reduced pressure and flash chromatography of the residue,
using light petroleum–ethyl acetate (90 : 10) as eluent, gave the title
compound 24 (80 mg, 40%) as a colourless oil. Found: M+ + H,
536.0860. C23H2935Cl3NO5S requires M, 536.0832; tmax 1737, 1611,
1387, 1307, 1286, 1152 and 1127 cm−1; dH (200 MHz, C6D6) 0.95
(3 H, m, CH3), 1.16–1.87 (8 H, m), 2.28–2.47 (2 H, m), 2.92 (1 H,
br dd, J 17.5 Hz, 5, 4-Heq), 3.26 (1 H, ddd, J 15 Hz, 6.5 Hz, 2,
lꢀ-H), 3.40 (1 H, ddd, J 15 Hz, 7.5 Hz, 2.0 Hz, lꢀ-Hꢀ), 3.73 (1 H,
dd, J 17.5 Hz, 2.5 Hz, 4-Hax), 4.30 (1 H, m, 5-H), 4.30 and 4.59
Following the procedure outlined for the synthesis of the pyrroline
20, trifluoroacetic acid (1.6 cm3, 22.4 mmol) and the ketoester
15 (1.02 g, 2.24 mmol) in dichloromethane (20.0 cm3) gave the
corresponding pyrroline (644 mg, 99%) used without further pu-
rification. Found: M+, 293.1986. C17H27NO3 requires M, 293.1991;
tmax 1740, 1715, 1640, 1370, 1182 and 1030; dH (300 MHz, CDCl3)
0.85 (3 H, t, J 7.5 Hz, CH3), 1.18 (3 H, t, J 8 Hz, CH3), 1.21–1.37
(3 H, m, 4-H and CH2), 1.40–1.58 (2 H, m, CH2), 2.10 (1 H, m,
4-Hꢀ), 2.20–2.32 (2 H, m, CH2), 2.32–2.58 (5 H, m, 1ꢀꢀ-H, 3-H2,
4ꢀꢀ-H2), 2.97 and 3.06 (each 0.5 H, dd, J 17 Hz, 7.5 Hz, 1ꢀꢀ-H),
3.52 and 3.55 (each 0.5 H, t, J 7.5 Hz, 3ꢀꢀ-H), 4.11 (2 H, q, J
8 Hz, OCH2), 4.28 (1 H, m, 5-H), 4.93–5.09 (2 H, m, 6ꢀꢀ-H2) and
5.68 (1 H, m, 5ꢀꢀ-H); dC (75 MHz, CDCl3) 13.68, 13.96, 22.41,
28.42, 28.75, 31.87, 33.36, 37.09, 48.53, 48.82, 58.59, 61.24, 67.76,
117.26, 134.14, 169.31, 178.67 and 203.11; m/z (FAB) 402 (50%),
294 (M+ + 1, 34) and 124 (100).
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(each 1 H, d, J 12.5 Hz, HCHCCl3), 5.00 (1 H, dq, J 10 Hz, 2 Hz,
3ꢀ-H), 5.16 (1 H, dq, J 17 Hz, 2 Hz, 3ꢀ-Hꢀ), 5.98 (1 H, dddd, J
17 Hz, 10 Hz, 7.5 Hz, 6.5 Hz, 2ꢀ-H), 6.93–7.04 (3 H, m, ArH) and
7.82–7.94 (2 H, m, ArH); m/z (+FAB) 536 (M+ + 1, 24%), 394
(10) and 298 (15).
(5 H, m, ArH); m/z CI(NH3) 390 (M+ + 1, 100%), 300 (46) and
298 (37).
(1RS,2SR,3RS,5SR)-3-Benzyloxy-1-butyl-2-hydroxymethyl-8-
methoxycarbonyl-8-azabicyclo-[3.2.1]octane 28
Diisobutylaluminium hydride (0.55 cm3,
1 M in hexane,
Dimethyl (1RS,2RS,3SR,5SR)- and (1RS,2RS,3RS,5SR)-1-butyl-
0.55 mmol) was added t◦o the ester 27 (69 mg, 0.18 mmol) in
hexane (3.0 cm3) at −78 C. After 1 h, the mixture was allowed
to warm to ambient temperature, and celite (250 mg) and water
(0.25 cm3) were added. The slurry was diluted with ether (3.0 cm3),
and after 30 min, magnesium sulfate was added in small portions
until the mixture became granular. After a further 30 min, the
mixture was filtered and the filtrate washed with ethyl acetate
and concentrated under reduced pressure. Chromatography of the
residue using light petroleum–ethyl acetate (70 : 30) as eluent gave
the title compound 28 (48 mg, 75%) as a colourless oil. Found: M+,
361.2265. C21H31NO4 requires M, 361.2253; tmax 3442, 1705, 1684,
1453, 1382, 1098, 1066, 755 and 698 cm−1; dH (300 MHz, C6D6)
0.98 (3 H, t, J 8 Hz, 4ꢀ-H3), 1.25–1.50 (5 H, m), 1.63–1.87 (3 H,
m), 1.95–2.22 (4 H, m), 2.37–2.60 (2 H, m, 7-H and 2-H), 3.48
(3 H, s, OCH3), 3.65–3.86 (2 H, m, 2-CH2), 3.86 (1 H, d, J 6 Hz,
3-H), 4.31 (2 H, s, CH2Ph), 4.43 (1 H, m, 5-H) and 7.12–7.38
(5 H, m, ArH); m/z CI(NH3) 362 (M+ + 1, 35%), 331 (27) and
330 (100).
Reduction of the benzyloxyester 27 using diisobutylaluminium
hydride in hexane at 0◦C following the above procedure gave the al-
cohol 28 (59%) and (5SR,6RS,8SR,11RS)-6-benzyloxy-11-butyl-
l-aza-3-oxatricyclo[6.3.0.05.11]undecane 30 (18%). Found: M+,
315.2195. C20H29NO2 requires M, 315.2198; tmax 3029, 1384, 1210,
1145, 1092, 1070, 1043, 840, 734 and 697 cm−1; dH (200 MHz,
CDCl3) 0.94 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.16–1.50 (5 H, m), 1.57
(1 H, dt, J 4 Hz, 12.5 Hz, 9-H), 1.69–2.05 (4 H, m, 7-Heq, 9-H,
10-H and 5-H), 2.21 (1 H, m, 1ꢀ-H), 2.46–2.66 (2 H, m, 10-H and
7-Hax), 3.53–3.70 (2 H, m, 8-H and 4-H), 3.92 (1 H, d, J 6.3 Hz,
6-H), 4.19 (1 H, dd, J 11.5 Hz, 2.5 Hz, 4-H), 4.50 and 4.59 (each
1 H, d, J 12.5 Hz, HCHPh), 4.63 and 4.89 (each 1 H, d, J 11.5 Hz,
2-H) and 7.21–7.43 (5 H, m, ArH); m/z Cl(NH3) 316 (M+ + 1,
100%) and 208 (37).
3-hydroxy-8-azabicyclo[3.2.1]-octane-2,8-dicarboxylates 25 and 26
Zinc chloride (940 mg, 6.87 mmol) and sodium cyanoborohydride
(840 mg, 13.38 mmol) were added to the b-ketoester 21 (810 mg,
2.73 mmol) in ether (50 cm3) at ambient temperature. After
15 h, aqueous potassium iodate (80 cm3, 0.1 M) was added,
and the mixture extracted with ethyl acetate. The organic phase
was dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl acetate
(13 : 7) as eluent gave first the title compound 26 (555 mg, 68%),
as a colourless oil. Found: M+, 299.1742. Cl5H25NO5 requires M,
299.1733; tmax 3450, 1733, 1712, 1687, 1451, 1383 and 1193 cm−1;
dH (500 MHz, CD2Cl2) 0.96 (3 H, t, J 7 Hz, 4ꢀ-H3), 1.20–1.40
(4 H, m, 2ꢀ-H2 and 3ꢀ-H2), 1.45 (1 H, m, 1ꢀ-H), 1.59 (1 H, br d,
J 14.5 Hz, 4-Heq), 1.72–2.05 (4 H, m, 1ꢀ-Hꢀ, 6-H2 and 7-H), 2.20
(1 H, br s, OH), 2.35–2.46 (2 H, m, 4-Hax and 7-H), 2.72 (1 H, s,
2-H), 3.57 and 3.61 (each 3 H, s, OCH3), 4.15 (1 H, d, J 6 Hz,
3-H) and 4.64 (1 H, m, 5-H); m/z CI(NH3) 300 (M+ + 1, 100%).
The second eluted product was the title compound 25 (188 mg,
23%). Found: M+, 299.1734, Cl5H25NO5 requires M, 299.1733; tmax
3437, 1740, 1713, 1695, 1448, 1381 and 1169 cm−1; dH (500 MHz,
CD2Cl2) 0.92 (3 H, t, J 7 Hz, 4ꢀ-H3), 1.17–1.53 (6 H, m), 1.67–1.98
(5 H, m), 2.08 (1 H, s, OH), 2.21 (1 H, m, 4-Hax), 2.95 (1 H, d, J
6.5 Hz, 2-H), 3.57 and 3.64 (each 3 H, s, OCH3), 4.06 (1 H, dt, J
13 Hz, 6.5 Hz, 3-H) and 4.39 (1 H, m, 5-H); m/z (EI) 300 (M+ +
1, 28%), 299 (M+, 56), 282 (13), 268 (15), 257 (34), 240 (76), 197
(23) and 183 (100).
The equatorial hydroxyketone 25 (2.45 g, 8.36 mmol) was stirred
˚
with pyridinium dichromate (4.36 g, 12.5 mmol) and powdered 4 A
molecular sieves (2.5 g) in dichloromethane (40 cm3) at ambient
temperature for 12 h to give the ketone 21 (1.96 g, 87%) after
chromatography.
Dimethyl (1RS,2RS,3RS,5SR)-3-benzyloxy-l-butyl-8-
(1RS,2RS,3RS,5SR)-3-Benzyloxy-1-butyl-2-iodomethyl-8-
azabicyclo[3.2.1]octane-2,8-dicarboxylate 27
methoxycarbonyl-8-azabicyclo[3.2.1]-octane 29
Benzyl-2,2,2-trichloroacetimidate (0.09 cm3, 0.13 mmol) was
added to the alcohol 26 (121 mg, 0.11 mmol) in cyclohexane
and dichloromethane (3.0 cm3, 65:35) at ambient temperature.
Trifluoromethane sulfonic acid (0.006 cm3, 0.02 mmol) was added
and the mixture stirred for 12 h. The precipitate was removed
by filtration and the filtrate washed with saturated aqueous
sodium hydrogen carbonate, water and brine then dried (Na2SO4).
Concentration under reduced pressure and chromatography of
the residue using light petroleum–ethyl acetate (80 : 20) as eluent
afforded the title compound 27 (160 mg, 99%), as a colourless
oil. Found: M+ + H, 390.2269. C22H32NO5 requires M, 390.2280;
tmax 1733, 1709, 1444, 1377 and 1099 cm−1; dH (200 MHz, CDCl3)
0.94 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.16–1.58 (5 H, m), 1.74–2.03 (5 H,
m), 2.30–2.50 (2 H, m), 2.91 (1 H, s, 2-H), 3.62 and 3.68 (each
3 H, s, OCH3), 3.83 (1 H, d, J 6.5 Hz, 3-H), 4.40 (1 H, m, 5-H),
4.47 and 4.55 (each 1 H, d, J 11.5 Hz, HCHPh) and 7.22–7.42
The alcohol 28 (49 mg, 0.14 mmol), iodine (26 mg, 0.21 mmol),
imidazole (14 mg, 0.21 mmol) and triphenylphosphine (54 mg,
0.21 mmol) were stirred in dichloromethane (3.0 cm3) at ambient
temperature for 3 h. Saturated aqueous sodium thiosulfate was
added until the yellow colour disappeared then saturated aqueous
sodium hydrogen carbonate was added until the solids had
dissolved. The organic phase was washed with water and brine,
then dried (MgSO4) and concentrated under reduced pressure.
The residue was triturated with light petroleum–ethyl acetate
(90 : 10) and the mixture filtered. Concentration of the filtrate
under reduced pressure and chromatography of the residue using
light petroleum–ethyl acetate (94 : 6) as eluent gave the title
compound 29 (52 mg, 81%) as a colourless oil. Found: M+
−
I, 344.2230. C21H30NO3 requires M, 344.2226; tmax 1703, 1443,
1377 and 1098 cm−1; dH (200 MHz, C6D6) 0.92 (3 H, t, J 7.5 Hz,
4ꢀ-H3), 1.19–1.44 (4 H, m, 2ꢀ-H2 and 3ꢀ-H2), 1.50–2.10 (6 H, m,
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2-H, 4-Heq, 6-H, 7-H and 1ꢀ-H2), 2.32–2.50 (3 H, m, 6-H, 7-H and
4-Hax), 2.88 (1 H, t, J 11.5 Hz, 2-CH), 3.44 (3 H, s, OCH3), 3.91
(1 H, d, J 6.5 Hz, 3-H), 4.06 (1 H, dd, J 11.5 Hz, 2.5 Hz, 2-CHꢀ),
4.10 (1 H, m, 5-H), 4.40 and 4.51 (each 1 H, d, J 12.5 Hz, HCHPh)
and 7.13–7.40 (5 H, m, ArH); m/z (EI) 344 (M+ − 127, 13%) and
182 (22).
3.34–3.60 (3 H, m, 5-H, 7-H and OH), 4.44 and 4.55 (each 1 H, d,
J 16.5 Hz, HCHPh), 5.15 (1 H, m, 2-H) and 7.24–7.42 (5 H, m,
ArH); m/z CI(NH3) 316 (M+ + 1, 9%).
(4RS,5RS,7SR,10RS)-2-Acetoxy-5-benzyloxy-l0-butyl-l-
azatricyclo[5.3.0.04,10]decane 34
Triethylamine (0.045 cm3, 0.324 mmol) was added to the aminol
33 (8.5 mg, 0.027 mmol.), 4-N,N-dimethylaminopyridine (1 mg,
0.008 mmol) and acetic anhydride (0.016 cm3, 0.162 mmol) in
dichloromethane (1.5 cm3) at 0 ◦C, and the mixture was stirred
at ambient temperature for 12 h. Concentration under reduced
pressure and chromatography of the residue using light petroleum–
ethyl acetate (60 : 40) as eluent gave the title compound 34 (6.9 mg,
72%) as a colourless oil. Found: M+, 357.2284. C22H31NO3 requires
M, 357.2304; tmax 1736, 1650, 1366, 1244, 1122, 1099, 1021, 735
and 698 cm−1; dH (300 MHz, C6D6) 1.00 (3 H, t, J 7.5 Hz, 4ꢀ-H3),
1.25–1.88 (10 H, m, 3 × CH2, 3-H, 6-Heq, 8-Hexo and 9-Hexo), l.82
(3 H, s, CH3CO), 2.07–2.29 (3 H, m, 8-Hendo, 3-Hꢀ, 6-Hax), 2.35 (1 H,
dd, J 7.5 Hz, 2.5 Hz, 4-H), 2.97 (1 H, ddd, J 13 Hz, 9 Hz and 6 Hz,
9-Hendo), 3.18 (1 H, dd, J 5 Hz, 2.5 Hz, 5-H), 3.55 (1 H, m, 7-H), 4.22
and 4.28 (each 1 H, d, J 14 Hz, HCHPh), 6.14 (1 H, dd, J 7.5 Hz,
4 Hz, 2-H) and 7.15–7.48 (5 H, m, ArH); dC (50 MHz, CDCl3),
14.42, 21.77, 23.73, 27.14, 29.25, 30.14, 31.26, 38.58, 39.55, 45.71,
53.64, 61.67, 71.15, 79.61, 88.28, 127.25, 127.54, 128.51, 138.91
and 170.76; m/z CI(NH3) 358 (M+ + 1, 100%) and 298 (26).
(4RS,5RS,7SR,l0RS)-5-Benzyloxy-10-butyl-1-
azatricyclo[5.3.0.04,10]decan-2-one 31
tert-Butyllithium (0.195 cm3,1.6 M in hexanes, 0.31 mmol) was
added to the iodide 29 (52 mg, 0.11 mmol) in tetrahydrofuran
(1.5 cm3) at −78 ◦C. The cooling bath was removed and the
reaction mixture stirred for 5 min before the addition of water
(3 drops). The organic phase was diluted with ethyl acetate,
washed with saturated aqueous ammonium chloride and brine,
then dried (MgSO4). After concentration under reduced pressure,
chromatography of the residue using light petroleum–ethyl acetate
(80 : 20) as eluent gave the title compound 31 (25 mg, 71%) as
a colourless oil. Found: M+, 313.2034. C20H27NO2 requires M,
313.2042; trnax 1747, 1255, 1133, 1092, 1066, 736 and 697 cm−1; dH
(500 MHz, C6D6) 0.94 (3 H, t, J 8 Hz, 4ꢀ-H3), 1.18–1.30 (4 H, m,
2ꢀ-H2 and 3ꢀ-H2), 1.31 (1 H, d, J 16 Hz, 6-H), 1.36 and 1.47 (each
1 H, m, 1ꢀ-H), 1.65 (1 H, dt, J 3 Hz, 12.5 Hz, 9-Hexo), 1.75 (1 H, d,
J 18 Hz, 3-H), 1.79 (1 H, ddd, J 2.5 Hz, 9.5 Hz, 3 Hz, 8-Hexo), 2.10
(2 H, m, 6-Hax and 8-Hendo), 2.40 (1 H, dd, J 3 Hz, 2.5 Hz, 4-H),
2.66 (1 H, dd, J 18 Hz, 6.5 Hz, 3-Hꢀ), 3.03 (1 H, ddd, J 12.5 Hz,
9.5 Hz, 6.5 Hz, 9-Hendo), 3.20 (1 H, dd, J 5.5 Hz, 2.5 Hz, 5-H), 4.10
(1 H, m, 7-H), 4.23 (2 H, s, CH2Ph) and 7.17–7.35 (5 H, m, ArH);
dC (50 MHz, C6D6) 14.13, 23.41, 26.90, 30.23, 30.88, 31.42, 39.15,
41.56, 45.36, 65.76, 70.18, 71.02, 79.34 and 194.16; m/z CI(NH3)
314 (M+ + 1, 100%) and 206 (10).
(lRS,2RS,3RS,5SR)-1-Butyl-3-tert-butyldimethylsilyloxy-2,8-
dimethoxycarbonyl-8-azabicyclo-[3.2.1]octane 36
tert-Butyldimethylsilyl triflate (5.0 cm3, 22.3 mmol) was added to
the hydroxyester 26 (3.90 g, 13.1 mmol) and 2,6-lutidine (6.0 cm3,
◦
52.5 mmol) in dichloromethane (39 cm3) at 0 C. After 1 h, the
Addition of water immediately after the tert-butyllithium gave
rise to reduced yields of lactam 31 (ca. 20%). Filtration of the
residue after extraction into ethyl acetate through silica gel eluting
with methanol gave (1RS,2RS,3RS,5SR)-3-benzyloxy-1-butyl-2-
methoxycarbonylmethyl-8-azabicyclo-[3.2.1]octane 32 (65%); tmax
1736, 1563, 1455, 1435, 1403, 1198, 1175, 1095, 1065, 736 and
699 cm−1; dH (200 MHz, C6D6) 0.87 (3 H, t, J 7.5, 4ꢀ-H3), 1.04–
1.76 (11 H, m), 1.89–2.28 (3 H, m), 2.52 (l H, m, 7-H), 3.35 (3 H,
s, OCH3), 3.45 (1 H, d, J 5 Hz, 3-H), 3.68 (1 H, m, 5-H), 4.40 and
4.57 (each 1 H, d, J 13 Hz, HCHPh), 5.05 (1 H, br s, NH) and
7.08–7.39 (5 H, m, ArH); m/z CI(NH3) 346 (M+ + 1, 93%) and
100 (100).
reaction mixture was washed with saturated aqueous ammonium
chloride and water. The aqueous phase was washed with ethyl
acetate, and the combined organic phase was washed with brine
and dried (MgSO4). Concentration under reduced pressure and
chromatography of the residue using light petroleum–ethyl acetate
(90 : 10) as eluent gave the title compound 36 (4.7 g, 86%) as a
colourless oil. Found: M+, 413.2591. C21H39NO5Si requires M,
413.2597; tmax 1734, 1713, 1443, 1376, 1257, 1191, 1159, 1130,
1098, 1081, 836 and 776 cm−1; dH (300 MHz, C6D6) 0.00 and 0.02
(each 3 H, s, SiCH3), 0.96 (9 H, s, C(CH3)3), 1.03 (3 H, t, J 7 Hz,
4ꢀ-H3), 1.42–1.60 (5 H, m, 2ꢀ-H2, 3ꢀ-H2 and 4-Heq), 1.60–1.82 (2 H,
m, 6-Hendo and 4-Hax), 1.90 (1 H, dt, J 3 Hz, 12 Hz, 7-Hexo), 2.02
(1 H, dt, J 3 Hz, 9.5 Hz, 6-Hexo), 2.24 (1 H, m, 1ꢀ-H), 2.55 (1 H,
ddd, J 12 Hz, 9.5 Hz, 5 Hz, 7-Hendo), 2.80 (1 H, m, 1ꢀ-Hꢀ), 2.91
(1 H, s, 2-H), 3.55 (3 H, br s, OCH3), 3.60 (3 H, s, OCH3), 4.33
(l H, d, J 5 Hz, 3-H) and 4.53 (1 H, m, 5-H); dC (75 MHz, C6D6)
−5.35, −5.24, 14.22, 17.89, 23.69. 25.80, 26.01, 26.67, 35.4, 36.28,
37.32, 51.26, 51.52, 56.44, 56.63, 64.64, 68.20, 156.12 and 172.20;
m/z CI(NH3) 415 (100%) and 414 (M+ + 1, 99.5).
(4RS,5RS,7SR,10RS)-5-Benzyloxy-l0-butyl-l-
azatricyclo[5.3.0.04,10]decan-2-ol 33
Lithium aluminium hydride (6 mg, 0.16 mmol) was added to the
lactam 31 (25 mg, 0.08 mmol) in ether (1.0 cm3) at 0 ◦C. The
mixture was stirred for 30 min, then celite (25 mg) was added,
followedbywater(2drops). Stirringwascontinuedfor15min, then
small portions of magnesium sulfate were added until the solid
material became granular. Filtration and concentration under
reduced pressure afforded the title compound 33 (25 mg, 99%),
apparently a single diastereoisomer, as a colourless oil. Found: M+,
315.2223. C20H29NO2 requires M, 315.2198; tmax 3120, 1455, 1096,
1069, 733 and 697 cm−1; dH (200 MHz, CDCl3) 0.92 (3 H, m, 4ꢀ-
H3), 1.13–2.30 (13 H, m), 2.55 (1 H, m, 4-H), 2.80 (1 H, m, 9-H),
(1RS,2SR,3RS,5SR)-1-Butyl-3-tert-butyldimethylsilyloxy-2-
hydroxymethyl-8-methoxycarbonyl-8-azabicyclo[3.2.1]octane 37
Diisobutylaluminium hydride (25.0 cm3,1 M in pentane, 25 mmol)
was added to the ester 36 (4.7 g, 11.4 mmol) in hexane (90 cm3) at
−78 ◦C. The mixture was stirred for 1 h then allowed to warm to
ambient temperature over 1 h. Celite (5.0 g) was added, followed
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by water (3.0 cm3) and stirring was continued for 2 h. Magnesium
sulfate was added in small portions until the solid material
became granular. The solid material was removed by filtration
and washed with ethyl acetate. The combined organic phases
were concentrated under reduced pressure and chromatography
of the residue using light petroleum–ethyl acetate (75 : 25) as
eluent gave the title compound 37 (3.40 g, 78%) as a colourless oil.
Found: M+ + H, 386.2722. C20H40NO4Si requires M, 386.2726);
tmax 3463, 1710, 1685, 1451, 1382, 1255, 1098, 1056, 837 and
776 cm−1; dH (300 MHz, C6D6) 0.10 and 0.14 (each 3 H, s, SiCH3),
0.98 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.03 (9 H, s, C(CH3)3), 1.33–1.51
(4 H, m), 1.59 (1 H, m, 4-Heq), 1.67–1.92 (3 H, m), 2.05–2.26
(4 H, m), 2.44–2.61 (2H, m), 3.51 (3 H, s, OCH3), 3.69 (1 H, dd,
J 13 Hz, 7.5, 2-CH), 3.90 (1 H, dd, J 13 Hz, 3 Hz, 2-CHꢀ), 4.30
(1 H, d, J 4.8 Hz, 3-H) and 4.41–4.49 (1 H, m, 5-H); dC (75 MHz,
C6D6) −5.04, −4.89, 14.22, 17.93, 23.71, 25.88, 25.94, 26.61, 35.77,
36.40, 37.67, 51.62, 54.79, 56.62, 61.88, 64.81, 69.33 and 155.33;
m/z CI(NH3) 386 (M+ + 1, 7%), 355 (23) and 354 (100).
71 ◦C. Found: C, 67.9; H, 10.2; N, 4.3; M+, 337.2446. C19H35NO2Si
requires C, 67.7; H, 10.4; N, 4.15%; M, 337.2437; tmax 1749, 1254,
1192, 1133, 1091, 1060, 834 and 776 cm−1; dH (300 MHz, C6D6)
−0.02 and 0.01 (each 3 H, s, SiCH3), 0.89 (3 H, t, J 7.5 Hz, 4ꢀ-H3),
0.97 (9 H, s, C(CH3)3), 1.09 (1 H, d, J 15.5 Hz, 6-Heq), 1.17–1.54
(6 H, m), 1.65 (1 H, dt, J 3 Hz, 12.5 Hz), 1.80 (1 H, m), 1.78 (1 H,
d, J 17.5 Hz, 3-H), 2.03–2.24 (2 H, m), 2.24 (1 H, dd, J 5.5 Hz,
2.5 Hz, 4-H), 2.64 (1 H, dd, J 17.5 Hz, 5.5 Hz, 3-H), 3.10 (1 H,
ddd, J 12.5 Hz. 9.5 Hz, 6.5 Hz, 9-Hendo), 3.61 (1 H, dd, J 5.5 Hz,
2.5 Hz, 5-H) and 4.08 (1 H, m, 7-H); dC (75 MHz, C6D6) −5.12,
−5.07, 14.07, 17.96, 23.41, 25.83, 26.92, 30.17, 30.89, 35.40, 39.29,
41.51, 48.73, 66.22, 70.41, 72.72 and 194.16; m/z CI(NH3) 338
(M+ + 1, 100%).
(4RS,5RS,7SR,10RS)-10-Butyl-5-hydroxy-1-
azatricyclo[5.3.0.04,10]decan-2-one 40
Tetrabutylammonium fluoride (0.40 cm3, 1 M in tetrahydrofuran,
0.40 mmol) was added to the silyl ether 39 (68 mg, 0.2 mmol) in
tetrahydrofuran (2.0 cm3) at ambient temperature. The reaction
mixture was stirred for 12 h, then diluted with ethyl acetate and
washed with saturated aqueous ammonium chloride and water.
The combined aqueous phase was washed with ethyl acetate,
and the organic phase washed with brine and dried (MgSO4).
Concentration under reduced pressure and chromatography of
the residue using light petroleum–ethyl acetate (60 : 40) gave the
title compound 40 (45 mg, 99%) as a white solid recrystallised
from hexane–ethyl acetate to give colourless prismatic crystals,
(1RS,2SR,3RS,5SR)-1-Butyl-3-tert-butyldimethylsilyloxy-2-
iodomethyl-5-methoxycarbonyl-8-azabicyclo[3.2.1]octane 38
The alcohol 37 (3.40 g, 8.83 mmol), imidazole (0.89 g, 13.3 mmol),
triphenylphosphine (3.48 g, 13.3 mmol) and iodine (3.36 g,
13.7 mmol) were stirred in dichloromethane (100 cm3) for 12 h.
Saturated aqueous sodium thiosulfate and saturated aqueous
sodium hydrogen carbonate were added and the reaction mixture
stirred for 30 min. The organic phase was washed with water
and brine then dried. Concentration under reduced pressure and
chromatography of the residue using light petroleum–ethyl acetate
(95 : 5) as eluent gave the title compound 38 (3.64 g, 83%) as a
white amorphous, hygroscopic solid. Found: C, 48.4; H, 8.1; I,
25.7; N, 2.8. M+, 495.1634. C20H38INO3Si requires C, 48.5; H, 7.7;
I, 25.7; N, 2.8%; M, 495.1667; tmax 1707, 1444, 1376, 1256, 1150,
1098, 1050, 836 and 776 cm−1; dH (300 MHz, C6D6) 0.19 and 0.31
(each 3 H, s, SiCH3), 1.94 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.02 [9 H, s,
C(CH3)3], 1.29–1.49 (5 H, m), 1.58–1.80 (2 H, m), 1.85–2.10 (3 H,
m), 2.36 (1 H, d, J 11.5 Hz, 4-Hax), 2.44–2.65 (2 H, m), 2.82 (1 H,
t, J 11 Hz, 2-CH), 3.46 (3 H, s, OCH3), 4.03 (1 H, dd, J 11 Hz, 2,
2-CHꢀ), 4.31 (1 H, d, J 4.5 Hz, 3-H) and 4.31–4.40 (1 H, m, 5-H);
dC (75 MHz, C6D6) −4.69, −3.99, 6.64, 14.16, 17.88, 23.54, 25.92,
26.03, 26.78, 35.36, 35.44, 36.11, 51.54, 56.00, 56.52, 66.49, 70.60
and 154.59; m/z CI(NH3) 496 (M+ + 1, 36%), 495 (M+, 100) and
370 (71).
◦
m.p. 86–88 C. Found: M+, 223.1576. C13H21NO2 requires M,
223.1572; tmax 3426, 1746, 1724, 1460, 1133, 1017 and 941 cm−1;
dH (200 MHz, C6D6) 0.90 (3 H, t, J 8.7 Hz, 4ꢀ-H3), 0.96 (1 H,
d, J 19 Hz, 6-Heq), 1.06–1.50 (7 H, m, 3 × CH2 and OH), 1.50–
1.84 (3 H, m, 3-H, 8-Hexo and 9-Hexo), 2.06–2.24 (3 H, m, 4-H,
8-Hendo and 6-Hax), 2.60 (1 H, dd, J 17.5 Hz, 6.5 Hz, 3-Hꢀ), 3.04
(1 H, ddd, J 12.5 Hz, 10 Hz and 7 Hz, 9-Hendo), 3.32 (1 H, dd,
J 6.5 Hz, 4 Hz, 5-H) and 3.95–4.09 (1 H, m, 7-H); dC (75 MHz,
C6D6) 14.25, 23.63, 27.25, 30.25, 31.10, 35.13, 39.50, 41.88, 48.50,
66.25, 70.25, 71.88 and 194.50; m/z CI(NH3) 225 (13%) and 224
(M+ + 1, 100).
(4RS,5RS,7SR,9SR,10SR)-10-Butyl-1-aza-11-oxatetracyclo-
[5.3.0.04,10.15,9]undecan-2-one 41 and (4RS,7SR,10RS)-l0-butyl-1-
azatricyclo[5.3.0.04,10]decane-2,5-dione 42
The hydroxylactam 40 (17 mg, 0.08 mmo1) and lead(IV) acetate
(38 mg, 0.08 mmol) were heated under reflux in benzene (2.0 cm3)
for 12 h, more lead(IV) acetate (10 mg, 0.02 mmol) was added,
and the mixture heated for a further 6 h before being concentrated
under reduced pressure and diluted with ethyl acetate. The solution
was washed with saturated aqueous sodium thiosulfate, water, and
brine, then dried (MgSO4). Concentration under reduced pressure
and chromatography of the residue using hexane–ethyl acetate
(75 : 25) as eluent gave the title compound 41 (6 mg, 35%), as an
oil. Found: M+, 221.1414. Cl3Hl9NO2 requires M, 221.1416); tmax
1747, 1188, 1148, 1082, 1044, 1022, 993, 943, 864 and 848 cm−1;
dH (500 MHz, CDCl3) 0.88 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.21 (1 H, m,
1ꢀ-H), 1.32 (2 H, dq, J 9 Hz, 7.5 Hz, 3ꢀ-H2), 1.45 (1 H, m, 1ꢀ-Hꢀ),
1.55–1.63 (2 H, m, 2ꢀ-H2), 1.72 (1 H, dd, J 15 Hz, 3.5 Hz, 6-H), 1.84
(1 H, ddt, J 15 Hz, 4 Hz, 2 Hz, 6-H), 1.98 (1 H, dddt, J 12.5 Hz,
(4RS,5RS,7SR,10RS)-10-Butyl-5-tert-butyldimethylsilyloxy-1-
azabicyclo[5.3.0.04,10]decan-2-one 39
tert-Butyllithium (12.65 cm3,1.6 M in hexanes, 20.24 mmol) was
added to the iodide 38 (3.55 g, 7.17 mmol) in tetrahydrofuran
(100 cm3) at −78 ◦C. The mixture was stirred at −78 ◦C for
30 min, then at ambient temperature for 3 h. Saturated aqueous
ammonium chloride was added, and the organic phase diluted
with ether and washed with water. The combined aqueous phase
was washed with ethyl acetate, and the combined organic phase
washed with brine and dried (MgSO4). Concentration under
reduced pressure and chromatography of the residue using light
petroleum–ethyl acetate (85 : 15) as eluent gave the title compound
39 (1.94 g, 81%) as a white microcrystalline solid, m.p. 70–
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5.5 Hz, 3.5 Hz, 1.2 Hz, 8-H), 2.23 (1 H, dd, J 12.5 Hz, 1 Hz, 8-Hꢀ),
2.47 (1 H, dd, J 19 Hz, 1 Hz, 3-Hendo), 2.76 (1 H, t, J 6 Hz, 4-H),
2.87 (1 H, dd, J 19 Hz, 6 Hz, 3-Hexo), 4.02 (1 H, m, 7-H), 4.35 (1 H,
m, 5-H) and 4.46 (1 H, m, 9-H); dC (75 MHz, CDCl3) 13.96, 23.12,
27.15, 30.70, 33.54, 38.28, 40.01, 52.04, 63.42, 79.44, 80.00, 83.08
and 194.53; m/z (EI) 221 (M+, 57%), 192 (20), 179 (44) and 164
(22). The next product eluted was the title compound 42 (3 mg,
16%). Found: M+, 221.1421. Cl3Hl9NO2 requires M, 221.1416; tmax
1752, 1718 and 1132 cm−1; dH (200 MHz, CDCl3) 0.82 (3 H, t,
J 7.5 Hz, 4ꢀ-H3), 0.82–1.78 (10 H, m), 1.78 (1 H, d, J 16.5 Hz,
6-H), 1.87 (1 H, d, J 17.5 Hz, 3-Hendo), 2.45 (1 H, dd, J 16.5 Hz,
2 Hz, 6-Hꢀ), 2.47 (1 H, dd, J 17.5 Hz, 5 Hz, 3-Hexo), 2.74 (1 H, d, J
5 Hz, 4-H) and 3.75 (1 H, t, J 4.5 Hz, 7-H); dC (75 MHz, CDCl3)
13.9, 23.0, 26.6, 30.7, 32.4, 36.3, 40.9, 43.7, 61.0, 62.0, 72.2, 192.5,
208.5; m/z (EI) 221 (M+, 30%), 193 (47), 164 (31), 151 (26), 136
(37) and 123 (100). Finally, starting material 40 (2 mg, 12%) was
recovered.
(4RS,5RS,7SR,10RS)-10-Butyl-5-tert-butyldimethylsilyloxy-1-
azatricyclo[5.3.0.04,10]decane 47
Thionyl chloride (0.38 cm3, 5.21 mmol) was added dropwise to a
stirred solution of hydroxyamine 45 (515 mg, 1.52 mmol) in ether
(14.0 cm3). After 90 min, the solvent was removed under reduced
pressure, the residue was dissolved in ether (15 cm3), and the
solution added dropwise to lithium aluminium hydride (450 mg,
11.8 mmol) in ether (2 cm3) at 0 ◦C. The mixture was stirred
at ambient temperature for 3 h, then cooled to 0 ◦C, and water
(2 cm3) and celite (500 mg) were added. Stirring was continued for
30 min, then small portions of magnesium sulfate were added until
the solid material became granular. Filtration and concentration
under reduced pressure, after chromatography using ethyl acetate–
triethylamine (96 : 4) as eluent, gave the title compound 47 (450 mg,
92%), as a yellow oil. Found: M+, 323.2650. C19H37NOSi requires
M, 323.2644; tmax 1254, 1096, 1058, 863, 834 and 774 cm−1; dH
(300 MHz, CDCl3) 0.03 and 0.05 (each 3 H, s, SiCH3), 0.87–0.93
(12 H, m, 4ꢀ-H3 and C(CH3)3), 1.20–1.48 (8 H, m), 1.64 (1 H, td, J
14 Hz, 3 Hz), 1.90 (1 H, ddd, J 13 Hz, 10 Hz, 5.5 Hz), 1.95–2.14
(4 H, m), 2.90 (1 H, ddd, J 14 Hz, 10 Hz and 5.5 Hz, 9-H), 2.95–
3.03 (2 H, m, 2-H2), 3.31 (1 H, t, J 5.5 Hz, 7-H) and 3.76 (1 H,
br s, 5-H); m/z (EI) 324 (22%), 323 (M+, 72), 24 (45), 281 (29), 280
(37), 266 (27), 224 (38) and 192 (100).
Following the procedure outlined for the preparation of ketone
49, the alcohol 40 (160 mg, 0.717 mmol), after chromatography
using light petroleum–ethyl acetate (75 : 25) as eluent, gave the
ketone 42 (155 mg, 98%).
(4RS,5RS,7SR,10RS)-10-Butyl-5-tert-butyldimethylsilyloxy-1-
azatricyclo[5.3.0.04,10]decan-2-ol 44
(4RS,5RS,7SR,10RS)-10-Butyl-1-azatricyclo-
Lithium aluminium hydride (18 mg, 0.474 mmol) was added to
the lactam 39 (80 mg, 0.237 mmol) in ether (1.0 cm3) at 0 ◦C. The
mixture was stirred at ambient temperature for 30 min, then celite
(70 mg) was added, followed by 10 drops of water. Stirring was
continued for 45 min, then small portions of magnesium sulfate
were added until the solid material became granular. Filtration and
concentration under reduced pressure afforded the title compound
44 (78 mg, 97%) as a white solid, m.p. 148–149 ◦C. Found: M+ +
H, 340.2677. C19H38NO2Si requires M, 340.2672; tmax 3115, 1256,
1096, 1061, 1026, 861, 836 and 776 cm−1; dH (300 MHz, C6D6)
0.03 and 0.07 (each 3 H, s, SiCH3), 0.89–1.10 (12 H, m, 4ꢀ-H3 and
C(CH3)3), 1.15 (1 H, d, J 15.5 Hz, 6-Heq), 1.29–1.68 (5 H, m),
1.68–1.98 (4 H, m), 2.16–2.45 (4 H, m), 3.15 (1 H, m, 9-H), 3.47
(1 H, m, 7-H), 3.65 (1 H, m, 5-H) and 5.26 (1 H, m, 2-H); m/z
CI(NH3) 341 (27%) and 340 (M+ + 1, 100).
[5.3.0.04,10]decan-5-ol 48
Boron trifluoride diethyletherate (0.60 cm3, 4.78 mmol) was
added to the silyl ether 47 (450 mg, 1.39 mmol) in chloroform
(15 cm3) at ambient temperature. After 20 h, the solvent and
excess boron trifluoride diethyletherate were removed completely
under reduced pressure, and the mixture was taken up in aqueous
sodium hydroxide (10%) and extracted with chloroform. The
organic phase was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate–
triethylamine (90 : 10) as eluent gave the title compound 48
◦
(248 mg, 85%) as a white solid, m.p. 113–115 C. Found: M+,
209.1778. C13H23NO requires M, 209.1780; tmax 3300, 1461, 1096,
1027 and 954 cm−1; dH (500 MHz, CDCl3) 0.87 (3 H, t, J 6.5 Hz,
4ꢀ-H3), 1.10 (1 H, m, 2ꢀ-H), 1.20–1.43 (5 H, m), 1.36–1.43 (2 H,
m), 1.61 (1 H, td, J 13 Hz, 3 Hz), 1.81 (1 H, ddd, J 13 Hz, 10 Hz,
3 Hz), 1.95 (1 H, m, 3-H), 1.98–2.07 (4 H, m), 2.78 (1 H, ddd, J
15.5 Hz, 10 Hz, 6 Hz, 9-H), 2.88 (1 H, ddd, J 17 Hz, 10 Hz, 4.5 Hz,
2-H), 2.94 (1 H, ddd, J 17 Hz, 9 Hz, 5.5 Hz, 2-Hꢀ), 3.20 (1 H, t, J
5.5 Hz, 7-H) and 3.83 (1 H, t, J 3.5 Hz, 5-H); dC (75 MHz, CDCl3)
14.09, 23.49, 27.06, 28.89, 29.76, 30.23, 32.37, 37.46, 44.87, 45.92,
61.89, 72.13 and 73.06; m/z (EI) 209 (M+, 3%) and 192 (11).
(4RS,5RS,7SR,10RS)-2-Acetoxy-10-butyl-5-tert-butyldimethyl-
silyloxy-1-azatricyclo[5.3.0.04,10]-decane 45
Triethylamine (5 ll, 0.359 mmol) was added to the aminol 44
(10 mg, 0.029 mmol), DMAP (1 mg, 0.008 mmol) and acetic
anhydride (15 ll, 0.159 mmol) in dichloromethane (1.0 cm3) at
0
◦C. The mixture was stirred at ambient temperature for 15 h.
Concentration under reduced pressure and chromatography of
the residue using light petroleum–ethyl acetate (60 : 40) as eluent
gave the title compound 45 (10.5 mg, 93%) as a white solid, m.p.
(4RS,7SR,10RS)-10-Butyl-1-azatricyclo[5.3.0.04,10]decan-5-one 49
Dimethyl sulfoxide (1.50 cm3, 21.16 mmol) was added dropwise
to oxalyl chloride (1.08 cm3, 12.38 mmol) in dichloromethane
(15.0 cm3) at −50 ◦C. After 2 min, the aminol 48 (800 mg,
3.83 mmol) in dichloromethane (40 cm3) was added, and the
◦
40.5–42.5 C. Found: M+, 381.2693. C21H39NO3Si requires M,
381.2699); tmax 1737, 1250, 1112, 1065, 1021, 835 and 776 cm−1;
dH (300 MHz, C6D6) 0.01 and 0.05 (each 3 H, s, SiCH3), 0.94–1.04
(12 H, m, 4ꢀ-H3 and C(CH3)3), 1.08 (1 H, d, J 15.5 Hz, 6-Heq),
1.35–1.49 (3 H, m), 1.49–1.89 (7 H, m), 1.81 (3 H, s, CH3CO),
2.08–2.29 (3 H, m), 3.08 (1 H, m, 9-H), 3.53–3.63 (2 H, m, 5-H
and 7-H), 6.14 (1 H, dd, J 7 Hz, 4 Hz, 2-H); m/z (EI) 382 (M+ +
1, 12%) and 381 (34).
◦
reaction stirred at −50 C for 30 min. Triethylamine (5.60 cm3,
40.18 mmol) was added, and the mixture was allowed to warm to
ambient temperature. After concentration under reduced pressure,
the residue was dissolved in water and extracted with ethyl
acetate. The organic phase was dried (MgSO4) and concentrated
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under reduced pressure. Chromatography of the residue using
ethyl acetate–pyridine (99 : 1) as eluent gave the title compound
49 (670 mg, 85%) as a pale yellow oil. Found: M+, 207.1631.
C13H21NO requires M, 207.1623; tmax 1715 and 1103 cm−1; dH
(500 MHz, CDCl3) 0.86 (3 H, t, J 6.5 Hz, 4ꢀ-H3), 1.09–1.34 (5 H,
m, 1ꢀ-H, 2ꢀ-H2 and 3ꢀ-H2), 1.40–1.47 (1 H, m, 1ꢀ-Hꢀ), 1.57 (1 H, ddd,
J 3.5 Hz, 8 Hz, 11.5 Hz), 1.72 (1 H, ddd, J 3.5 Hz, 8.5 Hz, 13 Hz,
3-H), 1.76–1.80 (2 H, m), 1.97 (1 H, d, J 16 Hz, 6-Heq), 2.07 (1 H,
m, 8-H), 2.11 (1 H, m, 3-H), 2.50 (1 H, br dd, J 16 Hz, 5.5 Hz,
6-Hax), 2.58 (1 H, d, J 6 Hz, 4-H), 3.08 (1 H, ddd, J 14 Hz, 8.5 Hz,
5, 2-H), 3.16 (1 H, ddd, J 14 Hz, 9 Hz, 3.5 Hz, 2-Hꢀ) and 3.50 (1 H,
t, J 5.5 Hz, 7-H); dC (75 MHz, C6D6) 14.75, 24.03, 27.14, 29.50,
31.25, 31.50, 35.50, 42.85, 46.52, 60.22, 64.23, 76.70 and 209.81;
m/z (EI) 207 (M+, 11%).
(3 H, t, J 7 Hz, 4ꢀ-H3), 1.18–1.41 (5 H, m), 1.47 (1 H, m), 1.52–1.87
(6 H, m), 2.13 (1 H, m, 3-H), 2.49 (1 H, q, J 6.5 Hz, 8-H), 2.57 (1 H,
m), 2.62 (1 H, d, J 6.5 Hz, 4-H), 3.11–3.25 (2 H, m, 2-CH2), 3.43
(1 H, t, J 5 Hz, 7-H), 4.96–5.05 (2 H, m, 3ꢀ-H2) and 5.73 (1 H, m,
2ꢀ-H); dC (75 MHz, CDCl3) 14.00, 23.21, 25.02, 26.83, 28.85, 29.83,
30.99, 34.87, 45.71, 47.20, 58.20, 67.97, 77.02, 116.38, 135.98 and
211.06; m/z (CI) 265 (M+ + 18, 2%), 264 (11), 249 (22) and 248
(100).
(4RS,6SR,7SR,10RS)- and (4RS,6RS,7SR,10RS)-10-Butyl-6-
prop-2ꢀ-enyl-1-azatricyclo[5.3.0.04,10]decane-2,5-dione 60 and 61
n-Butyllithium (0.30 cm3, 1.6 M in hexanes, 0.48 mmol) was
added to diisopropylamine (70 ll, 0.50 mmol) in tetrahydrofuran
◦
(1.0 cm3) at 0 C. The solution was stirred for 20 min, cooled to
◦
−78 C and the ketolactam 42 (50 mg, 0.226 mmol) was added.
(4RS,6SR,7SR,10RS)- and (4RS,6RS,7SR,10RS)-10-Butyl-6-
◦
After 30 min, the mixture was allowed to warm to −35 C, then
prop-2ꢀ-enyl-1-azatricyclo[5.3.0.04,10]-decan-5-one 58 and 59
recooled to −78 ◦C, and allyl bromide (82 ll, 0.969 mmol) was
added. The mixture was allowed to warm to ambient temperature
over 2 h, then saturated aqueous ammonium chloride was added
and the mixture extracted with ethyl acetate. The organic phase
was washed with water, dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ethyl acetate (65 : 35) as eluent gave a mixture of the
title compounds 60 and 61 (23 mg, 39%) as a colourless oil, along
with some recovered ketoamide 42 (19 mg, 38%). HPLC using
acetonitrile–water (45 : 55) as eluent gave the title compound
60 (15 mg, 25%). Found: M+, 261.1725. C16H23NO2 requires M,
261.1729; tmax 1748, 1708 and 1136 cm−1; dH (300 MHz, C6D6)
0.84 (3 H, t, J 7 Hz, 4ꢀꢀ-H3), 0.86–1.24 (7 H, m), 1.40–1.48 (2 H,
m), 1.76 (1 H, m), 2.03 (1 H, dd, J 10.5 Hz, 6, 6-Heq), 2.09 (1 H,
d, J 18.5 Hz, 3-H), 2.36–2.57 (2 H, m, 1ꢀ-H2), 2.57 (1 H, dd, J
18.5 Hz, 5.5 Hz, 3-Hꢀ), 2.86 (1 H, d, J 5.5 Hz, 4-H), 4.08 (1 H,
d, J 5 Hz, 7-H), 5.05 and 5.20 (each 1 H, m, 3ꢀ-H) and 5.58
(1 H, m, 2ꢀ-H); m/z (EI) 262 (M+ + 1, 4%), 261 (19), 125 (38)
and 124 (100). The next eluted product was the title compound
61 (8 mg, 14%). Found: M+, 261.1720. C16H23NO2 requires M,
261.1729); tmax 1751, 1713 and 1132 cm−1; dH (300 MHz, C6D6)
0.84 (3 H, t, J 7 Hz, 4ꢀ-H3), 0.87–1.18 (4 H, m), 1.18–1.31, 1.36–
1.46, and 1.46–1.65 (each 2 H, m), 1.66–1.79 (1 H, m, 6-Hax),
1.89 (1 H, d, J 18.5 Hz, 3-H), 2.49 (1 H, dd, J 18.5 Hz, 5.5 Hz,
3-Hꢀ), 2.55–2.74 (2 H, m, 1ꢀ-H2), 2.77 (1 H, d, J 5.5 Hz, 4-H),
3.98 (1 H, t, J 5.5 Hz, 7-H), 4.91–5.01 (2 H, m, 3ꢀ-H2) and 5.55
(1 H, m, 2ꢀ-H); m/z (EI) 262 (M+ + 1, 3%), 261 (11), 125 (36) and
124 (100).
Potassium bis(trimethylsilyl)amide (0.7 cm3, 0.5 M in toluene,
0.35 mmol) was added to the ketone 49 (24 mg, 0.116 mmol)
in tetrahydrofuran (0.75 cm3) at −78 ◦C. After 30 min, allyl iodide
(86 ll, 0.94 mmol) was added, and the mixture was stirred for
75 min. Water was added, and the mixture was allowed to warm to
ambient temperature and extracted with chloroform. The organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using 1% pyridine in
light petroleum–ethyl acetate (50 : 50) as eluent gave a mixture of
the title compounds 58 and 59 (16 mg, 56%), 58 : 59 = 80 : 20, as
a pale yellow oil.
n-Butyllithium (0.45 cm3, 1.6 M in hexane, 0.72 mmol) was
added to diisopropylamine (92 ll, 0.656 mmol) in tetrahydrofuran
(3.5 cm3) at 0 ◦C, and the solution was stirred for 30 min. An
aliquot (1.7 cm3, 0.276 mmol) was added to the ketone 49 (20 mg,
0.097 mmol) in tetrahydrofuran (1.0 cm3) at −78 ◦C. After 1 h, allyl
iodide (70 ll, 0.766 mmol) was added and the mixture was allowed
to warm to ambient temperature. Water was added and the mixture
extracted with chloroform. The organic phase was dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using 1% pyridine in light petroleum–ethyl acetate (50 :
50) as eluent gave the title compound 58 (10 mg, 42%) as a pale
yellow oil. Found: M+, 247.1944. C16H25NO requires M, 247.1936;
tmax 1706, 1466, 1097 and 913 cm−1; dH (500 MHz, CDCl3) 0.87
(3 H, t, J 7 Hz, 4ꢀꢀ-H3), 1.18–1.36 (5 H, m), 1.41–1.52 (2 H, m),
1.71–1.86 (3 H, m), 2.04 (1 H, m, 8-H), 2.11 (1 H, dd, J 10.5 Hz,
7 Hz, 6-Heq), 2.19 (1 H, m, 3-H), 2.34 and 2.48 (each 1 H, m, 1ꢀ-H),
2.66 (1 H, d, J 7 Hz, 4-H), 3.15 (1 H, ddd, J 14 Hz, 10 Hz, 4.5 Hz,
2-H), 3.27 (1 H, ddd, J 14 Hz, 9 Hz, 5.5 Hz, 2-Hꢀ), 3.47 (1 H, d,
J 5.5 Hz, 7-H), 5.12–5.09 (2 H, m, 3ꢀ-H2) and 5.70 (1 H, m, 2ꢀ-H);
dC (75 MHz, C6D6) 14.25, 23.54, 26.54, 29.16, 30.16, 34.15, 34.63,
38.37, 45.57, 54.24, 60.10, 64.17, 74.53, 116.43, 136.95 and 211.47;
m/z (CI) 249 (19%) and 248 (M+ + 1, 100).
Methyl (1RS,2SR,3RS,5SR)-1-butyl-3-hydroxy-2-
hydroxymethyl-8-azabicyclo[3.2.1]octane-8-carboxylate 62
Diisobutylaluminium hydride (8.5 cm3, 1 M in dichloromethane,
8.5 mmol) was added to the b-hydroxyester 26 (695 mg, 2.32 mmol)
in dichloromethane (40 cm3) at −78 ◦C. After 90 min, water
(1 cm3) and celite (1.0 g) were added, and the mixture was
stirred at ambient temperature for 1 h. Magnesium sulfate was
added until the solid material became granular. The solid was
removed by filtration and washed with dichloromethane. The
organic phase was concentrated under reduced pressure, and the
residue was dissolved in ethanol (30 cm3). Sodium borohydride
(230 mg, 6.08 mmol) was added, and the mixture was stirred
Potassium t-butoxide (3.0 mg, 0.027 mmol) was added to ketone
58 (8 mg, 0.032 mmol) in a mixture of dichloromethane (1.0 cm3)
and methanol (0.5 cm3) at ambient temperature. After 15 h, water
was added and the mixture extracted with dichloromethane. The
organic phase was dried (MgSO4) and concentrated under reduced
pressure to yield the title compound 59 (7 mg, 88%) as a pale yellow
oil. Found: M+ + H, 248.2012. C16H26NO requires M, 248.2012;
tmax 1707, 1467, 1091 and 911 cm−1; dH (500 MHz, CDCl3) 0.88
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at ambient temperature for 2 h, then water (10 cm3) was added
and the mixture extracted with ethyl acetate. The organic extracts
were dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl acetate
(65 : 35) as eluent, yielded the title compound 62 (397 mg, 63%)
as a white solid, m.p. 121–122 ◦C. Found: C, 62.0; H, 9.4; N,
5.2; M+, 271.1789. C14H25NO4 requires C, 61.95; H, 9.3; N, 5.15%;
M, 271.1783); tmax 3401, 1679, 1452, 1385, 1096 and 1048 cm−1;
dH (500 MHz, CDCl3) 0.90 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.17–1.38
(4 H, m, 2ꢀ-H2 and 3ꢀ-H2), 1.59–1.67 (2 H, m, 4-Heq and 3-OH),
1.75 (1 H, ddd, J 16 Hz, 11.5 Hz, 4.5 Hz, 1ꢀ-H), 1.80–1.91 (3 H,
m), 1.97 (1 H, m), 2.12 (1 H, dt, J 14.5 Hz, 4.5 Hz, 4-Hax),
2.35–2.47 (3 H, m, 7-H, 1ꢀ-Hꢀ and OH), 3.61 (3 H, s, OCH3),
3.68 and 3.76 (each 1 H, m, 2-CH), 4.19 (1 H, d, J 4.5 Hz, 3-
H) and 4.35 (1 H, m, 5-H); dC (50 MHz, CDCl3) 14.63, 23.88,
26.26, 27.04, 36.04, 37.26, 37.71, 52.55, 53.87, 56.42, 62.36, 64.98,
68.97 and 155.84; m/z (EI) 271 (M+, 7%), 254 (23), 212 (84),
196 (26), 184 (30), 183 (100), 182 (68), 155 (32), 140 (66) and
126 (46).
2-CH), 3.96 (1 H, dd, J 10.5 Hz, 6 Hz, 2-CHꢀ) and 4.64 (1 H,
m, 5-H); dC (75 MHz, CDCl3) −5.69, −5.59, 14.04, 18.20, 23.18,
25.78, 26.41, 26.50, 34.39, 36.10, 47.77, 52.05, 55.85, 60.95, 64.98,
66.03, 154.56 and 209.26; m/z (CI) 384 (M+ + 1, 100%) and
326 (14).
Methyl (1RS,2SR,4SR,5SR)-1-butyl-4-prop-2ꢀ-enyl-2-tert-
butyldimethylsilyloxymethyl-3-oxo-8-azabicyclo[3.2.1]-
octane-8-carboxylate 65
Potassium bis(trimethylsilyl)amide (0.16 cm3, 15% in tetrahydro-
furan, 0.12 mmol) was added to the ketone 64 (23 mg, 0.06 mmol)
in tetrahydrofuran (1.0 cm3) at −78 ◦C. The mixture was allowed
to warm to −25 ◦C over 1 h, then recooled to −78 ◦C. Allyl iodide
(35 ll, 0.382 mmol) was added, and the mixture was warmed
to ambient temperature over 2 h. Saturated aqueous ammonium
chloride was added and the mixture extracted with ethyl acetate,
and the extracts dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue using light petroleum–
ethyl acetate (30 : 1) gave the title compound 65 (16 mg, 63%) as
a colourless oil. Found: M+ + H, 424.2870. C23H42NO4Si requires
M, 424.2883; tmax 1705, 1446, 1382, 1256, 1099, 839 and 778 cm−1;
dH (500 MHz, CDCl3) 0.00 and 0.03 (each 3 H, s, SiCH3), 0.84
(9 H, s, C(CH3)3), 0.89 (3 H, t, J 7 Hz, 4ꢀ-H3), 1.17 (1 H, m, 2ꢀ-H),
1.21–1.39 (3 H, m, 2ꢀ-Hꢀ and 3ꢀ-H2), 1.45–1.52 (1 H, m), 1.71 (1 H,
m), 1.87–2.00 (3 H, m), 2.14 (1 H, m, 1ꢀꢀ-H), 2.19–2.28 (2 H, m,
4-Heq and 1ꢀꢀ-Hꢀ), 2.39 (1 H, td, J 13, 3, 1ꢀ-H), 2.63 (1 H, t, J 7 Hz,
2-H), 3.67 (3 H, s, OCH3), 3.72 and 3.98 (each 1 H, dd, J 10.5 Hz,
7 Hz, 2-CH), 4.59 (1 H, d, J 7 Hz, 5-H), 5.02–5.09 (2 H, m, 3ꢀꢀ-H2)
and 5.76 (1 H, m, 2ꢀꢀ-H); dC (75 MHz, CDCl3) −5.50, 14.12, 18.20,
23.31, 25.85, 26.89, 27.76, 34.08, 34.60, 36.46, 51.94, 57.39, 59.52,
61.67, 65.20, 66.29, 117.25, 135.37, 154.78 and 211.39; m/z (CI)
424 (M++1, 100%) and 366 (13). Further elution yielded recovered
starting material 64 (6 mg, 26%).
Methyl (1RS,2SR,3RS,5SR)-1-butyl-2-tert-butyldimethylsilyloxy-
methyl-3-hydroxy-8-azabicyclo-[3.2.1]octane-8-carboxylate 63
tert-Butyldimethylsilyl triflate (0.35 cm3, 1.52 mmol) was added
to the diol 62 (397 mg, 1.46 mmol) and 2,6-lutidine (0.21 cm3,
1.80 mmol) in dichloromethane (40 cm3) at ambient temperature.
After 3 h, saturated aqueous ammonium chloride solution was
added, and the organic phase separated. The aqueous phase
was extracted with dichloromethane and the combined organic
phase dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl acetate
(90 : 10) as eluent gave the title compound 63 (530 mg, 94%)
as a colourless oil. Found: M+, 385.2651. C20H39NO4Si requires
M, 385.2648; tmax 3470, 1710, 1683, 1452, 1385, 1256, 1094 and
836 cm−1; dH (300 MHz, CDCl3) 0.04 and 0.05 (each 3 H, s, SiCH3),
0.86 (9 H, s, C(CH3)3), 0.90 (3 H, t, J 7 Hz, 4ꢀ-H3), 1.19–1.40 (4 H,
m, 2ꢀ-H2 and 3ꢀ-H2), 1.59 (1 H, d, J 15 Hz, 4-Heq), 1.65–1.98 (5 H,
m), 2.11 (1 H, dt, J 14.5 Hz, 4.5 Hz, 4-Hax), 2.30–2.48 (2 H, m),
3.26 (1 H, t, J 10.5 Hz, 2-CH), 3.59 (3 H, s, OCH3), 3.94 (1 H, dd,
J 10.5 Hz, 4 Hz, 2-CHꢀ), 4.24 (1 H, d, J 5 Hz, 3-H) and 4.32 (1 H,
m, 5-H); dC (75 MHz, CDCl3), −5.24, 14.24, 18.35, 23.48, 26.02,
26.26, 26.80, 35.51, 35.62, 36.61, 51.72, 54.72, 55.79, 61.73, 64.48,
67.27 and 154.47; m/z (EI) 386 (M+ + 1, 6,%), 328 (79), 326 (43),
184 (55), 183 (100) and 182 (94).
Methyl (1RS,2SR,4RS,5SR)-1-butyl-4-prop-2ꢀ-enyl-2-tert-
butyldimethylsilyloxymethyl-3-oxo-8-azabicyclo[3.2.1]-
octane-8-carboxylate 66
Potassium tert-butoxide (28 mg, 0.25 mmol) was added to
the tropanone 65 (32 mg, 0.076 mmol) in dichloromethane
(1.5 cm3) and methanol (0.75 cm3) at ambient temperature. After
36 h, saturated aqueous ammonium chloride was added, and
the mixture extracted with dichloromethane. The organic phase
was dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl acetate
(95 : 5) gave the title compound 66 (18 mg, 56%) as a colourless oil.
Found: M+ + H, 424.2884. C23H42NO4Si requires M, 424.2883);
tmax 1708, 1443, 1377, 1257, 1096, 839 and 779 cm−1; dH (500 MHz,
CDCl3) −0.03 and −0.01 (each 3H, s, SiCH3), 0.81 (9 H, s,
C(CH3)3), 0.89 (3 H, t, J 7 Hz, 4ꢀ-H3), 1.15–1.39 (4 H, m, 2ꢀ-
H2 and 3ꢀ-H2), 1.46 (1 H, m), 1.61–1.73 (2 H, m), 1.81–1.91 (2 H,
m), 1.95 and 2.12 (each 1 H, m, 1ꢀ-H), 2.55–2.66 (2 H, m, 2-H
and 1ꢀꢀ-H), 2.74 (1 H, dt, J 8.5 Hz, 4.5 Hz, 4-Hax), 3.70 (3 H, s,
OCH3), 3.77 (1 H, t, J 9.5 Hz, 2-CH), 3.92 (1 H, dd, J 10.5 Hz,
6.5 Hz, 2-CHꢀ), 4.46 (1 H, dd, J 7.5 Hz, 4 Hz, 5-H), 5.00–5.09
(2 H, m, 3ꢀꢀ-H2) and 5.78 (1 H, m, 2ꢀꢀ-H); m/z (CI) 424 (M+ + 1,
100%).
Methyl (1RS,2SR,5SR)-1-butyl-2-tert-butyldimethylsilyloxy-
methyl-3-oxo-8-azabicyclo[3.2.1]-octane-8-carboxylate 64
Following the procedure outlined for the oxidation of alcohol 12,
alcohol 63 (330 mg, 0.857 mmol), after chromatography using
light petroleum–ethyl acetate (93 : 7) gave the title compound 64
(322 mg, 98%) as a colourless oil. Found: M+ + H, 384.2570.
C20H37NO4Si requires M, 384.2570); tmax 1711, 1444, 1375, 1098
and 838 cm−1; dH (300 MHz, CDCl3) 0.01 and 0.03 (each 3 H,
s, SiCH3), 0.86 (9 H, s, C(CH3)3), 0.93 (3 H, t, J 7 Hz, 4ꢀ-H3),
1.19–1.45 (4 H, m, 2ꢀ-H2 and 3ꢀ-H2), 1.52 and 1.74 (each 1 H,
m), 1.84–2.09 (3 H, m), 2.22 (1 H, m), 2.27 (1 H, d, J 15 Hz,
4-Heq), 2.60 (1 H, t, J 6.5 Hz, 2-H), 2.74 (1 H, dd, J 15 Hz, 4,
4-Hax), 3.71 (3 H, s, OCH3), 3.79 (1 H, dd, J 10.5 Hz, 7.5 Hz,
3152 | Org. Biomol. Chem., 2007, 5, 3139–3155
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Methyl (1RS,2SR,4RS,5SR)- and (1RS,2RS,4RS,5SR)-1-butyl-
2-hydroxymethyl-4-prop-2ꢀ-enyl-3-oxo-8-azabicyclo[3.2.1]octane-
8-carboxylates 67 and 68
Methyl (1RS,2SR,4RS,5SR)-1-butyl-2-tert-butyldimethyl-
silyloxymethyl-4-methoxycarbonyl-methyl-3-oxo-8-azabicyclo-
[3.2.1]octane-8-carboxylate 70 and methyl (1RS,2RS,4RS,5SR)-
1-butyl-4-methoxycarbonylmethyl-2-methoxymethyl-3-oxo-8-
azabicyclo[3.2.1]octane-8-carboxylate 71
Following the procedure outlined for the synthesis of alcohol
40, tert-butyldimethylsilyl ether 65 (17 mg, 0.040 mmol), after
chromatography using light petroleum–ethyl acetate (75 : 25) as
eluent gave the title compound 68 (3 mg, 24%), as a colourless oil.
Found: M+ + H, 310.2015. C17H28NO4 requires M, 310.2018); tmax
3477, 1700, 1443, 1358, 1193 and 1103 cm−1; dH (300 MHz, CDCl3)
0.86 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.08–1.45 (5 H, m), 1.47–1.61 (2 H,
m), 1.68–1.94 (3 H, m), 2.29 (1 H, m), 2.58–2.69 (2 H, m), 2.88 (1 H,
m, 2-H), 3.74 (3 H, s, OCH3), 3.63–3.81 (2 H, m, 2-CH2), 4.41 (1 H,
dd, J 4.5 Hz, 6 Hz, 5-H), 5.01–5.12 (2 H, m, 3ꢀꢀ-H2) and 5.75 (1 H,
m, 2ꢀꢀ-H); m/z (CI) 327 (M+ + 18, 21%), 311 (20) and 310 (100).
The second eluted product was the title compound 67 (4 mg, 32%),
a colourless oil. Found: M+ + H, 310.2021. C17H28NO4 requires
M, 310.2018); tmax 3460, 1704, 1446 and 1379 cm−1; dH (300 MHz,
CDCl3) 0.91 (3 H, t, J 7, 4ꢀ-H3), 1.10–1.43 (4 H, m), 1.51 (1 H,
m), 1.62–1.93 (3 H, m), 1.94–2.06 (2 H, m), 2.30 (1 H, m), 2.45
(1 H, t, J 5 Hz, 2-H), 2.66–2.78 (2 H, m), 3.71 (3 H, s, OCH3),
3.82 (1 H, dd, J 12 Hz, 4, 2-CH), 3.94 (1 H, dd, J 12 Hz, 5.5 Hz,
2-CHꢀ), 4.50 (1 H, dd J 7.5 Hz, 3.5 Hz, 5-H), 5.02–5.11 (2 H, m,
3ꢀꢀ-H2) and 5.76 (1 H, m, 2ꢀꢀ-H); dC (75 MHz, CDCl3) 14.04, 21.74,
23.23, 26.47, 29.78, 33.95, 37.17, 52.54, 54.74, 58.38, 61.21, 63.57,
66.00, 116.72, 128.35, 135.26 and 156.53; m/z (CI) 327 (M++18,
3%), 311 (20) and 310 (100).
Potassium tert-butoxide (5 mg, 0.045 mmol) was added to the
ketoester 69 (29 mg, 0.064 mmol) in a mixture of dichloromethane
(1.0 cm3) and methanol (0.5 cm3) at ambient temperature. After
24 h, saturated aqueous ammonium chloride was added and the
mixture extracted with dichloromethane. The organic extracts
were dried (Na2SO4) and concentrated under reduced pressure.
Chromatography using light petroleum–ethyl acetate (90 : 10)
gave the title compound 70 (19 mg, 66%), as a colourless oil.
Found: M+ + H, 456.2784. C23H42NO6Si requires M, 456.2781);
tmax 1744, 1709, 1442, 1371, 1256, 1101, 839 and 778 cm−1; dH
(300 MHz, CDCl3) 0.04 and 0.06 (each 3 H, s, SiCH3), 0.87 (9 H,
s, C(CH3)3), 0.93 (3 H, t, J 7 Hz, 4ꢀ-H3), 1.15–1.50 (5 H, m), 1.61–
1.84 and 1.87–2.10 (each 2 H, m), 2.13 (1 H, dd, J 16 Hz, 6.5 Hz,
4-CH), 2.31 (1 H, m, 1ꢀ-H), 2.66 (1 H, t, J 7 Hz, 2-H), 2.80 (1 H,
dd, J 16.5 Hz, 7 Hz, 4-CHꢀ), 3.25 (1 H, m, 4-Hax), 3.69 and 3.73
(each 3 H, s, OCH3), 3.82 (1 H, dd, J 10.5 Hz, 8 Hz, 2-CH), 3.98
(1 H, dd, J 10.5 Hz, 6 Hz, 2-CHꢀ) and 4.49 (1 H, dd, J 7 Hz,
4.5 Hz, 5-H); dC (75 MHz, CDCl3) −5.58, −5.69, 14.09, 18.21,
22.27, 23.23, 25.82, 26.71, 30.82, 34.33, 36.17, 50.73, 51.83, 52.30,
59.50, 61.06, 64.49, 66.94, 154.57, 172.09 and 208.40; m/z (CI)
473 (M+ + 18, 3%) and 456 (100). The second eluted product was
the title compound 71 (2 mg, 9%), a colourless oil. Found: M+ +
H, 356.2076. C18H30NO6 requires M, 356.2073; tmax 1740, 1706,
1441, 1359 and 1119 cm−1; dH (300 MHz, CDCl3) 0.96 (3 H, t, J
7 Hz, 4ꢀ-H3), 1.23–1.61 (6 H, m), 1.76–1.96 (3 H, m), 2.13 (1 H,
dd, J 16.5 Hz, 5.5 Hz, 4-CH), 2.46 (1 H, m, 1ꢀ-H), 2.81 (1 H, dd,
J 16.5 Hz, 8 Hz, 4-CHꢀ), 2.95 (1 H, m, 2-H), 3.14–3.24 (1 H, m,
4-H), 3.34 (3 H, s, OCH3), 3.63 (1 H, dd, J 10 Hz, 3.5 Hz, 2-CH),
3.72 (1 H, m, 2-CHꢀ), 3.74 and 3.81 (each 3 H, s, CO2CH3) and
4.44 (1 H, t, J 5.5 Hz, 5-H); dC (75 MHz, CDCl3) 14.20, 23.12,
23.50, 25.27, 30.97, 31.12, 34.26, 51.22, 51.92, 52.59, 59.09, 60.78,
67.21, 67.84, 77.24, 155.11, 172.23 and 206.68; m/z (CI) 355 (M+,
1.5%), 182 (82) and 181 (100).
Following this procedure, tert-butyldimethylsilyl ether 66
(15 mg, 0.035 mmol) gave the alcohol 68 (2 mg, 18%) then the
more polar alcohol 67 (2 mg, 18%).
Methyl (1RS,2SR,4SR,5SR)-1-butyl-2-tert-butyldimethyl-
silyloxymethyl-4-methoxycarbonyl-methyl-3-oxo-8-
azabicyclo[3.2.1]octane-8-carboxylate 69
Potassium bis(trimethylsilyl)amide (6.5 cm3,15% in tetrahydrofu-
ran, 4.89 mmol) was added to the ketone 64 (350 mg, 0.914 mmol)
in tetrahydrofuran (11 cm3) at −78 ◦C. The mixture was allowed
◦
◦
to warm to 5 C over 90 min, then recooled to −78 C. Methyl
bromoacetate (1.4 cm3, 15.15 mmol) was added and the mixture
warmed to ambient temperature over 2 h. Saturated aqueous
ammonium chloride was added and the mixture extracted with
ethyl acetate. The organic phase was dried (Na2SO4) and con-
centrated under reduced pressure. Chromatography of the residue
using light petroleum–ethyl acetate (95 : 5) gave first recovered
starting material 64 (136 mg, 39%) and then the title compound
69 (244 mg, 58%), as a colourless oil. Found: M+ + H, 456.2774.
C23H42NO6Si requires M, 456.2781); tmax 1743, 1706, 1444, 1381,
1256, 1098 and 838 cm−1; dH (500 MHz, CDCl3) 0.01 and 0.04
(each 3 H, s, SiCH3), 0.84 (9 H, s, C(CH3)3), 0.90 (3 H, t, J 7.5 Hz,
4ꢀ-H3), 1.14–1.40 (4 H, m, 2ꢀ-C2 and 3ꢀ-C2), 1.54 and 1.72 (each
1 H, m), 1.88–2.05 (3 H, m), 2.32 (1 H, dd, J 17.5 Hz, 4 Hz, 4-CH),
2.35 (1 H, m, 1ꢀ-H), 2.56–2.63 (2 H, m, 2-H, 4-CHꢀ), 2.77 (1 H,
dd, J 11 Hz, 4 Hz, 4-Heq), 3.61 and 3.69 (each 3 H, s, OCH3), 3.79
(1 H, dd, J 10.5 Hz, 7 Hz, 2-CH), 3.94 (1 H, dd, J 10.5 Hz, 6.5 Hz,
2-CHꢀ) and 4.65 (1 H, d, J 7 Hz, 5-H); dC (75 MHz, CDCl3) −5.59,
−5.51, 14.10, 18.25, 23.28, 25.89, 26.87, 27.34, 33.19, 34.37, 36.50,
51.84, 54.63, 57.25, 61.76, 64.48, 66.14, 154.46, 171.57 and 210.87;
m/z (CI) 473 (M+ + 18, 4%), 457 (36) and 456 (100).
Methyl (1RS,2SR,3RS,4RS,5SR)-1-butyl-2-tert-butyldimethyl-
silyloxymethyl-3-hydroxy-4-methoxy-carbonylmethyl-
8-azabicyclo[3.2.1]octane-8-carboxylate 72
Following the procedure outlined for the reduction of ketone 21,
ketone 70 (65 mg, 0.143 mmol), after chromatography using light
petroleum–ethyl acetate (90:10) as eluent gave the title compound
72 (48 mg, 74%), as a colourless oil. Found: M+ + H, 458.2934.
C23H44NO6Si requires M, 458.2938; tmax 3471, 1741, 1710, 1684,
1448, 1385, 1254, 1100 and 838 cm−1; dH (500 MHz, CDCl3) 0.00
and 0.02 (each 3 H, s, SiCH3), 0.85 (9 H, s, C(CH3)3), 0.90 (3 H,
t, J 7 Hz, 4ꢀ-H3), 1.17–1.39 (4 H, m, 2ꢀ-H2 and 3ꢀ-H2), 1.61 (1 H,
m, 6-H), 1.70 (1 H, m, 1ꢀ-H), 1.76 (1 H, td, J 12.5 Hz, 3.5 Hz),
1.95–2.04 (2 H, m), 2.10 (1 H, d, J 4 Hz, OH), 2.27 (1 H, m, 4-H),
2.32–2.48 (3 H, m, 7-H, 1ꢀ-Hꢀ and 4-CH), 2.54 (1 H, dd, J 15,
11, 4-CHꢀ), 3.26 (1 H, t, J 10.5 Hz, 2-CH), 3.60 and 3.67 (each
3 H, s, OCH3), 3.91 (1 H, dd, J 11 Hz, 4 Hz, 2-CHꢀ), 4.07 (1 H,
dd, J 7.5 Hz, 2.5 Hz, 5-H) and 4.18 (1 H, t, J 4 Hz, 3-H); dC
(75 MHz, CDCl3) −5.42, −5.39, 14.14, 18.25, 21.82, 23.43, 25.92,
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26.93, 33.87, 35.44, 36.22, 38.14, 51.81, 53.44, 53.98, 59.61, 61.15,
64.67, 67.89, 154.49 and 173.27; m/z (CI) 475 (M+ + 18, 3%), 460
(7), 459 (26) and 458 (100).
Crystal data for 22‡
C20H24Cl3NO5S, colourless, acicular, m.p. 144–145 ◦C, crystal
dimensions 0.550 × 0.150 × 0.010 mm, monoclinic, a = 10.716(1),
◦
3
˚
˚
b = 20.066(2), c = 10.835(1) A, b = 91.767(9) , U = 2328.8(4) A ,
space group P21/c (No. 14), Z = 4, F(000) = 1032. x/2h scans
of (1.21 + 0.30 tanh)◦ were made at a speed of 16.0◦ min−1 at
296 1 K; 2963 reflections were collected with 0◦ < 2h < 120.2◦;
of these 2804 were unique and had I > 3.0r(I), and were used
in the analysis. The data were collected on a Rigaku AFC5R
diffractometer using graphite monochromated Cu Ka radiation.
Lorentz, polarisation and linear intensity drift (maximum 13.0%)
corrections were applied. The structure was solved by direct
methods. The refinement converged with R = 0.077, Rx = 0.078.
All calculations were performed using the TEXSAN crystallo-
graphic software package of the Molecular Structure Corporation
(1985). Atomic coordinates, bond lengths and angles, and thermal
parameters have been deposited at the CCDC‡.
Methyl (1RS,2SR,3RS,7RS,8RS)-1-butyl-2-hydroxymethyl-5-
oxo-4-oxa-11-azatricyclo[6.2.1.03,7]-undecane-11-carboxylate 73
Following the procedure outlined for deprotection of the silyl ether
39, silyl ether 72 (7 mg, 0.015 mmol), after chromatography using
light petroleum–ethyl acetate (50 : 50) as eluent, gave the title
compound 73 (4 mg, 84%) as a colourless oil. Found: M+ + H,
312.1808. C16H26NO5 requires M, 312.1811; tmax 3472, 1778, 1760,
1705, 1686, 1448, 1383, 1190, 1160 and 1042 cm−1; dH (500 MHz,
CDCl3) 0.92 (3 H, t, J 7.5 Hz, 4ꢀ-H3), 1.15–1.43 (4 H, m, 2ꢀ-H2 and
3ꢀ-H2), 1.54 (1 H, ddd, J 13.5 Hz, 10 Hz, 3.5 Hz), 1.75–1.89 (2 H,
m), 1.94–2.10 (2 H, m), 2.16 (1 H, t, J 3.5 Hz, 2-H), 2.25 (1 H, d,
J 18 Hz, 6-H), 2.40 (1 H, m, 1ꢀ-Hꢀ), 2.69–2.82 (3 H, m), 3.64 (3 H,
s, OCH3), 3.69 (1 H, m, 2-CH), 3.95 (1 H, dt, J 12.5 Hz, 4.5 Hz, 2-
CHꢀ), 4.28 (1 H, dd, J 8 Hz, 5.5 Hz, 8-H) and 4.73 (1 H, d, J 5.5 Hz,
3-H); dC (75 MHz, CDCl3) 14.08, 21.24, 23.28, 26.31, 33.41, 34.90,
36.22, 37.67, 47.51, 52.43, 58.09, 61.74, 63.78, 81.65, 155.30 and
176.23; m/z (EI) 311 (M+, 17%), 269 (45) and 182 (100).
Acknowledgements
We thank the EPSRC and Pfizer for CASE Awards (to A. M. B
and M. P. H. D.), Dr C. W. Greengrass (Pfizer) for helpful
discussions, and Dr M. Tute (Pfizer) for molecular modelling
studies.
Methyl (1RS,2SR,3RS,7RS,8RS)-2-acetoxymethyl-1-butyl-5-
oxo-4-oxa-11-azatricyclo[6.2.1.03,7]-undecane-11-carboxylate 74
Following the procedure outlined for the acetylation of alcohol
44, the alcohol 73 (4.5 mg, 0.014 mmol), after chromatography
using light petroleum–ethyl acetate (65 : 35) as eluent, gave the
title compound 74 (3.5 mg, 69%) as a colourless oil. Found: M+,
353.1829. C18H27NO6 requires M, 353.1838; tmax 1782, 1741, 1705,
1446, 1380, 1238, 1189, 1163 and 1038 cm−1; dH (500 MHz, CDCl3)
0.91 (3 H, t, J 7 Hz, 4ꢀ-H3), 1.21 (1 H, m, 2ꢀ-H), 1.30–1.39 (3 H, m,
2ꢀ-H and 3ꢀ-H2), 1.54 (1 H, m), 1.73–1.87 (2 H, m, 9-H and 1ꢀ-H),
1.95 (1 H, td, J 13 Hz, 3 Hz), 2.04 (3 H, s, CH3CO), 2.13 (1 H,
ddd, J 16 Hz, 9.5 Hz, 6.5 Hz), 2.29 (1 H, d, J 18 Hz, 6-H), 2.44
(1 H, dd, J 9 Hz, 3.5 Hz, 2-H), 2.43 (1 H, m, 1ꢀ-H), 2.72 (1 H, dd,
J 18 Hz, 8 Hz, 6-Hꢀ), 2.86 (1 H, m, 7-H), 3.63 (3 H, s, OCH3), 3.93
(1 H, dd, J 12 Hz, 9 Hz, 2-CH), 4.30 (1 H, t, J 6 Hz, 8-H), 4.43
(1 H, dd, J 12 Hz, 4 Hz, 2-CHꢀ) and 4.57 (1 H, d, J 5.5 Hz, 3-H);
m/z (EI) 354 (M+ + 1, 5%), 353 (9), 311 (17), 183 (19), 182 (100)
and 181 (85).
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The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3139–3155 | 3155
©