Rearrangement of ammonium ylides produced by intramolecular reaction of catalytically generated metal carbenoids. Part 2. Stereoselective synthesis of bicyclic amines

Article abstract of DOI:10.1039/b108182a

Ammonium ylides produced by intramolecular reaction of copper carbenoids tethered to cyclic allylic amines undergo [2,3]-rearrangement to deliver bicyclic amines. The reaction can be performed using a cyclic N-allylamine in which the diazo group is tethered adjacent to nitrogen, or a vinyl-substituted cyclic amine in which the diazo group is N-tethered to the ring. In the former type of reaction, stereoselective ylide formation and rearrangement usually delivers high levels of diastereocontrol. In the latter case, efficient 'chirality transfer' can be accomplished when the reaction is performed using an enantiomerically pure substrate. The reactions have been used to construct pyrrolizidine, indolizidine and quinolizidine systems, and the CE sub-unit found in the manzamine and ircinal alkaloids.

Full text of DOI:10.1039/b108182a

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Rearrangement of ammonium ylides produced by intramolecular
reaction of catalytically generated metal carbenoids. Part 2.
Stereoselective synthesis of bicyclic amines
1
J. Stephen Clark,*a Paul B. Hodgson,a Michael D. Goldsmith,a Alexander J. Blake,a
Paul A. Cookea and Leslie J. Streetb
a School of Chemistry, University of Nottingham, University Park, Nottingham, UK NG7 2RD
b Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park,
Harlow, Essex, UK CM20 2QR
Received (in Cambridge, UK) 10th September 2001, Accepted 1st November 2001
First published as an Advance Article on the web 26th November 2001
Ammonium ylides produced by intramolecular reaction of copper carbenoids tethered to cyclic allylic amines
undergo [2,3]-rearrangement to deliver bicyclic amines. The reaction can be performed using a cyclic N-allylamine in
which the diazo group is tethered adjacent to nitrogen, or a vinyl-substituted cyclic amine in which the diazo group
is N-tethered to the ring. In the former type of reaction, stereoselective ylide formation and rearrangement usually
delivers high levels of diastereocontrol. In the latter case, efficient ‘chirality transfer’ can be accomplished when
the reaction is performed using an enantiomerically pure substrate. The reactions have been used to construct
pyrrolizidine, indolizidine and quinolizidine systems, and the CE sub-unit found in the manzamine and
ircinal alkaloids.
an α-vinylic cyclic amine (Type II). For both types of substrate,
[2,3]-sigmatropic rearrangement of the intermediate ammo-
nium ylide should generate a bicyclic amine in which nitrogen is
Introduction
In the preceding paper,1 we demonstrated that simple five- to
eight-membered cyclic amines can be prepared by [2,3]-
positioned at the ring junction. However, in the first case (Type
sigmatropic rearrangement of cyclic allylic ammonium ylides
I), the pre-existing ring and stereogenic centre would be pre-
produced upon intramolecular reaction of amines with catalyt-
served and an additional stereogenic centre would be created
ically generated copper carbenoids.2,3 Although the yields of
upon ylide rearrangement. In contrast, the ylide generated from
cyclic amine products were generally very good, low levels of
the second class of substrate (Type II) should rearrange to give
diastereocontrol were obtained during the cyclisation of sub-
three-carbon ring-expansion of the original cyclic amine with
strates possessing a stereogenic centre on the tether connecting
concomitant loss of the original stereogenic centre and creation
of a new stereogenic centre at the carbon that was formerly part
of the ylide.
the diazo ketone to the allylic amine.1
In order to identify applications of the reaction and address
the issue of diastereocontrol, we investigated the intra-
molecular reaction of substrates in which the amine forms part
Results and discussion
of an existing ring (Scheme 1). Two classes of substrate were
Pyrrolizidine,4 indolizidine,5 and quinolizidine†5 alkaloids
are widely distributed in nature, and frequently possess potent
biological activity. In recent years, these natural products have
become popular synthetic targets as a consequence of their
bioactivity, moderate complexity and the diversity of possible
synthetic strategies for their construction.4,5
It was apparent that treatment of Type I substrates with a
suitable catalyst would result in tandem ammonium ylide
formation and rearrangement to give a potentially stereoselec-
tive entry into pyrrolizidine, indolizidine and quinolizidine
alkaloids, especially those bearing side chains of three-carbons
or longer (Fig. 1). In order to establish the feasibility of the
reaction and to determine the stereochemical outcome of these
reactions, four diazo ketone Type I precursors were prepared.
The first cyclisation precursor, diazo ketone 5, was prepared
from (S)-proline by the route shown in Scheme 2. Treatment of
(S)-proline with trifluoroacetic anhydride afforded the trifluoro-
acetamide 1, and the α-diazo ketone 2 was then obtained in
high yield by conversion of the N-protected amino acid 1 into
the corresponding acid chloride and subsequent treatment with
Scheme 1
studied: one in which the diazo ketone group is tethered to the
α-carbon of an N-allyl cyclic amine (Type I), and a second type
in which the diazo carbonyl unit is attached to the nitrogen of
† The IUPAC names for pyrrolizidine, indolizidine and quinolizidine
are hexahydropyrrolizine, octahydroindolizine and octahydroquino-
lizine, respectively.
DOI: 10.1039/b108182a
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ately treated with allyl bromide in the presence of potassium
carbonate to give the allylic amine 8 in 69% yield over two steps.
Although it was possible to purify the intermediate secondary
amine prior to alkylation, the yield over two steps was signifi-
cantly lower than that obtained when alkylation was performed
directly on unpurified amine.
The cyclisation precursor 14 was prepared from (S)-prolinol,
by the route shown in Scheme 4. (S)-Prolinol was first converted
Fig. 1
Scheme 2 Reagents and conditions: (i), (CF3CO)2O, 0 80 ЊC (31%);
(ii), (COCl)2, DMF (cat.), CH2Cl2, 0 ЊC; (iii), CH2N2, Et2O, 0 ЊC rt
(85%, 2 steps); (iv), PhCO2Ag, dioxane–H2O (2 : 1), 70 ЊC (84%); (v),
(COCl)2, DMF (cat.), CH2Cl2, 0 ЊC; (vi), CH2N2, Et2O, 0 ЊC rt (87%,
2 steps); (vii), Ba(OH)2 aq., rt; (viii), CH2CHCH2Br, K2CO3, THF, rt
(45%, 2 steps).
excess diazomethane. The homologated carboxylic acid 3 was
obtained in 84% yield by treatment of the α-diazo ketone 2 with
silver benzoate in aqueous dioxane to induce Wolff rearrange-
ment.6 The acid 3 was then converted into the α-diazo ketone 4
via the acid chloride in 87% yield over two steps. Subsequent
removal of the trifluoroacetyl group was accomplished by
hydrolysis of the amide 4 with a saturated aqueous solution of
barium hydroxide,1 and the resulting highly polar amine was
immediately alkylated with allyl bromide to give the cyclisation
precursor 5 in 45% yield over two steps.
Scheme 4 Reagents and conditions: (i), CF3CO2Et, Et3N, MeOH, rt
(84%); (ii), (COCl)2, Me2SO, CH2Cl2, Et3N, Ϫ78 ЊC; (iii),
ButO2CCH2P(O)(OEt)2, NaH, THF, 10 ЊC rt (29%, 2 steps); (iv),
Pd–C, H2, MeOH–H2O, rt (91%); (v), CF3CO2H, CH2Cl2, rt (91%); (vi),
(COCl)2, DMF (cat.), CH2Cl2, 0 ЊC; (vii), CH2N2, Et2O, 0 ЊC rt (93%,
2 steps); (viii), Ba(OH)2 aq., rt; (ix), CH2CHCH2Br, K2CO3, THF, rt
(32%, 2 steps).
into the N-protected amino alcohol 9 in high yield by treatment
with ethyl trifluoroacetate.8 Swern oxidation and Horner–
Emmons reaction of the resulting aldehyde with tert-butyl
diethylphosphonoacetate delivered the α,β-unsaturated ester 10
in modest yield over two steps. Hydrogenation of the alkene
using palladium on carbon at atmospheric pressure yielded the
saturated ester 11 in high yield, and subsequent cleavage of the
tert-butyl ester using trifluoroacetic acid gave the N-protected
amino acid 12 in 91% yield. Conversion of the carboxylic acid
12 into the α-diazo ketone 13 via the acid chloride was achieved
in an overall yield of 87%. The trifluoroacetyl group was then
removed using a saturated aqueous solution of barium hydrox-
ide, and the free amine was immediately alkylated with allyl
bromide to give the required cyclisation precursor 14 in a 32%
yield over two steps.
The synthesis of the cyclisation precursor 8 commenced
from piperidinylacetic acid (Scheme 3), which was prepared by
The final member of the Type I series of precursors was the
α-diazo ketone 17 (Scheme 5). The synthesis of this compound
commenced from the piperidine 7, which had been used as an
intermediate in the synthesis of the cyclisation precursor 8
(Scheme 3). Treatment of the α-diazo ketone 7 with silver()
benzoate delivered an 83% yield of the homologated N-pro-
tected amino acid 15 resulting from Wolff rearrangement,6 and
the carboxylic acid was then converted into the α-diazo ketone
16 via the acid chloride in 91% yield (Scheme 5). N-Depro-
tection using a saturated aqueous solution of barium hydroxide
proved to be unreliable and generally gave very low yields of the
required amine. Removal of the trifluoroacetyl group with an
aqueous solution of sodium hydroxide proved to be more satis-
factory, but the overall yield for the deprotection and alkylation
sequence was still modest. In spite of the rather low yield for
the final step of the sequence, the route provided the cyclis-
ation precursor 17 in sufficient quantities for study of the key
cyclisation reaction.
Scheme 3 Reagents and conditions: (i), (CF3CO)2O, 0 80 ЊC (62%);
(ii), (COCl)2, DMF (cat.), CH2Cl2, 0 ЊC; (iii), CH2N2, Et2O, 0 ЊC rt
(87%, 2 steps); (iv), K2CO3 aq., EtOH, rt; (v), CH2CHCH2Br, K2CO3,
THF, rt (69%, 2 steps).
Jones oxidation of commercially available piperidinylethanol.7
Treatment of the amino acid with trifluoroacetic anhydride
afforded the N-protected amino acid 6 in reasonable yield.
Conversion of the carboxylic acid 6 into the corresponding
acid chloride and subsequent reaction with a large excess of
diazomethane delivered the α-diazo ketone 7 in high yield.
Removal of the trifluoroacetyl group was accomplished by
hydrolysis with potassium carbonate in aqueous ethanol at
room temperature, and the resulting polar amine was immedi-
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that the isomer 19b was produced by partial epimerisation of
isomer 19a during purification. In order to confirm that epi-
merisation was occurring, a diethyl ether solution of a mixture
(4 : 1) of isomers 19a and 19b was exposed to silica gel. Com-
plete epimerisation of the indolizidinone 19a was observed
after 23 hours, and the isomeric compound 19b was obtained
as the sole product in 72% yield. This experiment confirmed
that the kinetically favoured indolizidinone 19a undergoes
epimerisation when exposed to silica gel and demonstrated
that the indolizidinone 19b is the thermodynamically favoured
epimer.
Cyclisation of the α-diazo ketone 14 was accomplished by
treatment with Cu(acac)2 in benzene at reflux (Scheme 6).
Analysis of the unpurified reaction product by 1H NMR
revealed that a mixture (3.5 : 1) of the indolizidinone diastereo-
isomers 20a and 20b had been produced. In this case, cyclis-
ation occurred to give mainly the ammonium ylide C (m = 1, n =
2), and this intermediate rearranged to deliver the indolizid-
inone 20a as the major product. However, upon purification of
the reaction mixture by chromatography on silica gel, the
indolizidinone 20b was obtained as the sole product in
66% yield. As in the previous case, the kinetically favoured
diastereoisomer 20a underwent complete epimerisation to
give the thermodynamically favoured diastereoisomer 20b upon
exposure to silica gel.
Scheme 5 Reagents and conditions: (i), PhCO2Ag, dioxane–H2O (2 : 1),
70 ЊC (83%); (ii), (COCl)2, DMF (cat.), CH2Cl2, 0 ЊC; (iii), CH2N2,
Et2O, 0 ЊC rt (91%, 2 steps); (iv), 2 M NaOH, rt; (v), CH2CHCH2Br,
K2CO3, THF, rt (18%, 2 steps).
Access to substantial quantities of the cyclisation precursors
5, 8, 14 and 17 by the routes outlined above allowed detailed
exploration of the ammonium ylide formation and rearrange-
ment reaction (Scheme 6). Treatment of the α-diazo ketone 5
Treatment of the final substrate in the series, diazo ketone 17,
with Cu(acac)2 in benzene at reflux afforded a mixture (6 : 1 or
1 : 6) of two diastereoisomeric quinolizidinones 21a and 21b in
a combined yield of 61%. Although the isomers were separable
by column chromatography on neutral alumina, it was not pos-
sible to deduce the relative configuration of the major or minor
isomer by 1H NMR or X-ray crystallography.
1
Overlapping signals in the H NMR spectra for compounds
18–21a–b precluded unambiguous stereochemical assignment
by analysis of coupling constant data or by NOE difference
spectroscopy. Consequently, it was necessary to employ X-ray
crystallography in order to establish the relative configurations
of the stereogenic centres in the cyclisation products.
The ketones 18–21a–b were liquids at room temperature and
so crystalline derivatives suitable for X-ray analysis were pre-
pared. Fortunately, stereoselective ketone reduction afforded a
solid alcohol in each case (Scheme 7). For example, reduction of
Scheme 6
with Cu(acac)2 in benzene at reflux gave the pyrrolizidine 18a in
65% yield with no evidence of formation of the diastereoiso-
meric product 18b. When Rh2(OAc)4 was employed as the cata-
lyst, the pyrrolizidine 18a was isolated as the sole identifiable
product, but in slightly lower yield (55%).
The exclusive formation of the isomer 18a can be explained
by preferential formation of the cis-fused bicyclic ammonium
ylide C (n = 1, m = 1) rather than the trans-fused bicyclic ylide
T (n = 1, m = 1). [2,3]-Sigmatropic rearrangement of the
ammonium ylide C (n = 1, m = 1) is stereospecific and delivers
the pyrrolizidine 18a exclusively. Clearly, it is not possible for
the intermediate ammonium ylide C (n = 1, m = 1) to adopt
the transition state geometry necessary for concerted [2,3]-
rearrangement to produce the isomer 18b.
Treatment of the α-diazo ketone 8 with Cu(acac)2 in ben-
zene at reflux delivered a mixture (4 : 1) of the diastereoiso-
meric products 19a and 19b in a combined yield of 62% after
purification by chromatography on silica gel. Analysis of the
unpurified reaction mixture by 1H NMR revealed that the
isomer 19a, derived from the ammonium ylide C (n = 2, m =
1), was produced exclusively during the reaction and suggested
Scheme 7
the pyrrolizidinone 18a using sodium borohydride gave the
crystalline amino alcohol 22 as a single isomer in 89% yield.
Crystals of the alcohol 22 were suitable for X-ray analysis,‡ and
the relative stereochemistry was determined unambiguously to
be that shown in Scheme 6. The result confirmed that the
pyrrolizidinone 18a is the product arising from cyclisation of
the α-diazo ketone 5.
‡ CCDC reference numbers for alcohols 22–24 172675–172677. See
http://www.rsc.org/suppdata/p1/b1/b108182a/ for crystallographic data
in .cif or other electronic format.
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L-Selectride® reduction of the indolizidinone 19b at low
temperature provided the crystalline alcohol 23 as the sole
product in 91% yield (Scheme 7). The relative stereochemistry
of the alcohol 23 was established by X-ray analysis,‡ which con-
firmed that the indolizidinone 19b is thermodynamically
favoured and the isomer 19a is produced upon cyclisation of
the α-diazo ketone 8.
Low temperature reduction of the indolizidinone 20b with
L-Selectride® provided the crystalline alcohol 24 as the sole
product in 69% yield, and the relative configuration was estab-
lished by X-ray crystallography.‡ In this case, cyclisation of the
α-diazo ketone 14 affords the indolizidinone 20a as the major
product and the indolizidinone 20b is the thermodynamically
favoured diastereoisomer.
complex 2913 in pentane afforded the same product (55% yield)
as obtained from copper-catalysed reaction of the diazo ketone
25. The lower reaction temperature required for the ring-closing
metathesis reaction probably accounts for the higher yield with
respect to the ring-expansion reaction. Interestingly, attempted
ring-closing metathesis of the diene 28 using the catalyst
Cl2Ru(PCy3)2CHPh failed to deliver any of the indolizidine 27,
a finding which is in accord with the known incompatibility of
the ruthenium metathesis catalyst with tertiary amines.14
The second Type II cyclisation reaction to be studied was that
of the diazo ketone 31. The precursor was prepared from the
N-protected vinylpyrrolidine 30 (Scheme 9), which was obtained
Attempts to determine the relative configuration of the
quinolizidinone 21a–b resulting from cyclisation of the α-diazo
ketone 17 proved to be unsuccessful. Reduction of the major
isomer with L-Selectride® afforded a single solid amino alcohol
in 70% yield, but all attempts to recrystallise this compound
failed to deliver crystals suitable for X-ray analysis. Con-
sequently, the relative stereochemistry of the major isomer
21a–b obtained upon cyclisation of the α-diazo ketone 17 was
not determined unambiguously.
The successful diastereoselective synthesis of pyrrolizidine,
indolizidine, and quinolizidine systems by copper-catalysed
reaction of Type I substrates, encouraged us to investigate the
complementary reactions of Type II substrates in which ring-
expansion of the original cyclic amine was expected to occur. A
vinylaziridine system was deemed to be a particularly attractive
precursor because ring-expansion would be facilitated by the
inherent ring strain. In fact, Coldham and Somfai had already
shown that vinylaziridines undergo efficient conversion into
substituted piperidines by a related base-promoted [2,3]-aza-
Wittig rearrangement reaction.9
Scheme
9
Reagents and conditions: (i), KOH, H2NNH2ؒH2O,
HO(CH2)2OH, reflux; (ii), Br(CH2)2COCHN2, Et3N, EtOAc, 60 ЊC
(55%, 2 steps); (iii), Cu(acac)2 (2 mol%), C6H6, reflux (56%); (iv),
L-Selectride®, THF, 0 ЊC rt (75%); (v), (R)-Ph(OMe)(CF3)CCOCl,
DMAP, Et3N, CH2Cl2, 0 ЊC.
The cyclisation precursor 25 was prepared from 2-
vinylaziridine by the route shown in Scheme 8. The starting
from (S)-prolinol by a literature route involving sequential car-
bamate formation, Parikh–Doering oxidation and methylen-
ation.15 Carbamate cleavage was accomplished by treatment of
the vinylpyrrolidine 30 with a mixture of potassium hydroxide
and hydrazine monohydrate in ethylene glycol at reflux (Scheme
9). The unpurified amine was then treated with 4-bromo-1-
diazobutan-2-one in the presence of triethylamine to deliver the
cyclisation precursor 31 in 55% yield over two steps. Exposure
of the α-diazo ketone 31 to Cu(acac)2 in benzene at reflux
afforded the bicyclic amine 33 as the sole isolable product in
56% yield.
At this stage, it was unclear whether rearrangement had
resulted in formation of an E- or Z-alkene. The alkene geo-
metry was determined by NMR analysis of the alcohol 34
obtained by stereoselective reduction of the ketone 33 using
L-Selectride®. The 1H NMR spectrum of the alcohol 34 in D6-
benzene contained two distinct alkene multiplets corresponding
to the vinylic hydrogens, and it was possible to extract the
alkene J value of 10 Hz. 1H NMR analysis of the crude product
from cyclisation reaction of the α-diazo ketone 31 indicated
that a very small amount of another alkene was produced
(vinylic multiplet at 5.90 ppm, J 17 Hz), suggesting that some of
the E-alkene product (E)-33 may be produced upon ammo-
nium ylide rearrangement. However, the minor product has
insufficient stability to survive chromatography. The isolation
of the Z-alkene as the sole product from our cyclisation reac-
tions is consistent with results reported by Vedejs for the ring
expansion of related ylides derived from ammonium salts of
vinylpyrrolidines.16
Scheme 8 Reagents and conditions: (i), Br(CH2)2COCHN2, Et3N,
EtOAc, 60 ЊC (53%); (ii), Cu(acac)2 (2 mol%), C6H6, reflux (24%); (iii),
29 (15 mol%), pentane, rt (55%).
material, 2-vinylaziridine, was obtained from butadiene mon-
oxide using the procedure of Stogryn and Brois,10 and reaction
of this with 4-bromo-1-diazobutan-2-one1,11 in the presence of
triethylamine afforded the cyclisation precursor 25 in 53% yield.
Treatment of the substrate with a sub-stoichiometric amount (2
mol%) of Cu(acac)2 in benzene at reflux afforded a 24% yield of
the indolizidine 27 resulting from [2,3]-rearrangement of the
presumed spirocyclic ammonium ylide 26. The modest yield of
the indolizidine 27 can be attributed to its instability (substan-
tial decomposition occurred within one day when it was stored
under argon at Ϫ30 ЊC).
The second stereochemical issue was whether efficient
transfer of stereochemical information had occurred during
rearrangement of the putative intermediate ammonium ylide
32.17 To eliminate the possibility of partial racemisation of
the bicyclic amine 33 prior to determination of enantiomeric
To confirm the identity of the cyclisation product, the
indolizidine 27 was prepared by ring-closing metathesis12 of the
diene 28.1 Treatment of the diene 28 with the molybdenum
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purity, the ketone was reduced with L-Selectride® prior to
purification. The enantiomeric excess of the resulting amino
alcohol 34 was then determined by NMR analysis of the ester
35 produced upon reaction with excess (R)-Mosher’s acid
1
chloride (Scheme 9). Although H NMR analysis of the crude
Mosher ester was inconclusive, complete separation of the sig-
nals corresponding to the two diastereoisomers was observed in
the 19F NMR spectrum. The 19F NMR analysis indicated the
presence of less than 1% of the minor diastereoisomer, indicat-
ing an ee of >98%. A diastereoisomeric mixture of Mosher
esters was also prepared from a racemic mixture of alcohol 34.
This confirmed that the observed peaks in the 19F NMR
spectrum corresponded to the two diastereoisomers and
demonstrated that kinetic resolution during esterification of
the alcohol 34 had not distorted the analysis.
Fig. 2
Remarkably, there is virtually complete transfer of stereo-
chemical information during rearrangement of the spiro-fused
ammonium ylide 32, even though the original stereogenic
centre is destroyed in the process. Although efficient transfer of
stereochemical information during the [2,3]-rearrangement of
ylides possessing an adjacent stereogenic centre or a stereogenic
heteroatom is known,17 the situation is complicated by the fact
that two diastereoisomeric ylides (A and B) can be produced by
reaction of the copper carbenoid with each nitrogen invertomer
(Scheme 10). The ylide B can undergo rearrangement to give the
found in many members of the manzamine and ircinal families
of alkaloids (e.g., manzamine A, Fig. 2).19 The manzamines and
ircinals are complex polycyclic natural products of marine
origin, which possess significant cytotoxic, antileukemic and
antibacterial activity.19 The formidable synthetic challenges
presented by the manzamines and ircinals coupled with their
significant biological activity has stimulated the development
of many approaches to these alkaloids.20 However, only recently
has this work culminated in total syntheses of some of these
alkaloids,21 and they remain important synthetic targets.
In summary, we have shown that ammonium ylides derived
from copper carbenoids generated from Type I and Type II
substrates undergo [2,3]-rearrangement to deliver bicyclic
amines in a stereoselective manner (Scheme 1). Reactions of
this type can be used to construct the core structures of pyr-
rolizidine, indolizidine and quinolizidine alkaloids, and a model
for the CE sub-unit found in many manzamine and ircinal
alkaloids.
Experimental
General
Air and/or moisture sensitive reactions were performed under
an atmosphere of nitrogen in oven or flame dried apparatus.
Organic solvents and reagents were dried and distilled using
standard methods: tetrahydrofuran (potassium–benzophen-
one ketyl), diethyl ether (sodium metal–benzophenone ketyl),
methanol (magnesium methoxide), ethyl trifluoroacetate
(anhydrous calcium chloride), allyl bromide (anhydrous mag-
nesium sulfate), benzene, dichloromethane and triethylamine
(calcium hydride). All other solvents and reagents were used
as received from commercial suppliers. All reactions were
monitored by thin layer chromatography using plastic- or
aluminium-backed silica gel 60 F254 plates. Thin layer chrom-
atography plates were viewed under UV light or were visualised
using either basic potassium permanganate solution or acidic
ethanolic anisaldehyde solution. Flash column chromatography
was performed using Merck 7734 grade silica gel or Fluka silica
gel 60 (220–440 mesh). Melting points were determined using
either Büchi 510 or Reichert hot-stage melting point apparatus.
IR spectra were recorded as potassium bromide disks, as liquid
films on sodium chloride plates, or as solutions in chloroform,
using either a Perkin-Elmer 1720X or 1600 series FTIR spectro-
meter. 1H NMR spectra were recorded using a Bruker DRX500
(500 MHz), AM400 (400 MHz) or WM250 (250 MHz) spectro-
Scheme 10
bicyclic compound 33 via a transition state in which the vinyl
group is positioned endo to the newly formed ring, or (E)-33 via
a transition state in which the vinyl group lies exo to the new
ring. The ylide A can rearrange to give only ent-(E)-33 because
geometric constraints preclude attainment of the transition
state required for formation of the Z-isomer (ent-33). The out-
come of the reaction suggests the bicyclic product 33 results
from endo rearrangement of the ylide (B) produced by reaction
of the carbenoid with the amine from the face of the pyrrol-
idine which presents the vinyl group. An analogous result was
obtained by Naidu and West during their synthesis of the
alkaloid (Ϫ)-epilupinine by [1,2]-rearrangement of an ammo-
nium ylide.3b3d In that case, a spiro-fused bicyclic ylide was
generated by attack of a carbenoid from the more hindered
side of the pyrrolidine. McMills and co-workers have shown
that a related enantiomerically pure α-diazo ester tethered
2-vinylpyrrolidine undergoes ammonium ylide formation and
[2,3]-rearrangement with ring-expansion to produce an oxaza-
bicyclo[6.4.0]dodecane in reasonable yield and with high ee.18
The six-step enantioselective synthesis of the azabicyclo-
[6.3.0]undecene 33 from (S)-prolinol constitutes a short, effi-
cient and novel chiral-pool route to a model for the CE sub-unit
1
meter. H NMR data are expressed as chemical shifts in ppm
from an internal standard of tetramethylsilane followed by the
number of protons, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; and br, broad), coupling constant(s)
J (Hz), and assignment. 13C NMR spectra were recorded using
a JEOL EX270 (67.5 MHz), Bruker AM400 (100 MHz) or
Bruker DRX500 (125 MHz) instrument and multiplicities were
obtained using a DEPT sequence. 13C NMR chemical shifts are
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337
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2
1
expressed in parts per million downfield from tetramethylsilane
or the sodium salt of 3-(trimethylsilyl)propanesulfonic acid.
High resolution mass spectra (HRMS) were obtained using
an AEI MS902 or VG Micromass 70E mass spectrometer,
using electron impact (EI), chemical ionisation (CI) or fast-
atom bombardment (FAB). Microanalysis was performed
by the microanalysis section of the School of Chemistry,
University of Nottingham. Optical rotations were recorded
using a JASCO DIP-370 digital polarimeter and are reported
(CO), 155.7 (CON, q, JFC 38), 116.0 (CF3, q, JFC 288), 64.1
(CH), 63.7 (CH), 53.9 (CH), 53.1 (CH), 48.2 (CH2), 47.3 (CH2),
31.7 (CH2), 28.3 (CH2), 24.7 (CH2), 20.8 (CH2); m/z (FAB)
236.0627 (Mϩ ϩ H. C8H8F3N3O2 requires 236.0647), 236
(Mϩ ϩ H, 23%), 208 (100).
(S)-(؉)-(1-Trifluoroacetylpyrrolidin-2-yl)ethanoic acid 3. Sil-
ver benzoate (0.19 g, 0.83 mmol) was added to a solution of the
α-diazo ketone 2 (4.0 g, 17 mmol) in a mixture of 1,4-dioxane
(165 cm3) and water (85 cm3). The mixture was heated at 70 ЊC
for 3 h and then concentrated in vacuo. The residue was dis-
solved in a saturated aqueous solution of sodium bicarbonate
(100 cm3) and extracted with diethyl ether (2 × 100 cm3). The
aqueous layer was acidified with 2 M hydrochloric acid then
extracted with diethyl ether (2 × 100 cm3), and the combined
organic extracts were dried over anhydrous magnesium sulfate
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (hexane–diethyl ether,
1 : 1) to give the carboxylic acid 3 (3.2 g, 84%) as a white solid;
mp 51–53 ЊC; [α]2D3 ϩ2.3 (c 1.0, CHCl3); νmax(CHCl3)/cmϪ1 3196,
2897, 1714, 1603; δH (500 MHz, CDCl3) 4.48–4.44 (1H, m,
NCHCH2CO), 3.70–3.66 (2H, m, NCH2), 3.05 (1H, dd, J 16.2
and 3.6, 1 × CH2CO), 2.51 (1H, dd, J 16.2 and 9.3, 1 ×
CH2CO), 2.23–2.15 (1H, m, 1 × NCH2CH2 or NCHCH2), 2.10–
1.95 (2H, m, 1 × NCH2CH2 and 1 × NCHCH2), 1.90–1.83 (1H,
m, 1 × NCH2CH2 or NCHCH2); δC (67.8 MHz, CDCl3) 176.4
(CO2H), 155.6 (CON, q, 2JFC 37), 116.0 (CF3, q, 1JFC 287), 55.7
(CH), 47.0 (CH2), 36.3 (CH2), 29.4 (CH2), 24.0 (CH2); m/z (EI)
225.0610 (Mϩ. C8H10F3NO3 requires 225.0613), 225 (Mϩ, 9%),
179 (36), 166 (100), 69 (31).
as [α]D expressed in 10Ϫ1 deg cm2 gϪ1 (concentration g cmϪ3
solvent, temperature ЊC).
,
General procedure for the preparation of ꢀ-diazo ketones
Oxalyl chloride was added dropwise to a solution of the carb-
oxylic acid in dry dichloromethane at room temperature or
0 ЊC. A few drops of dry dimethylformamide were added, and
the resulting mixture was stirred at room temperature or 0 ЊC
for the time indicated. The solvent was removed in vacuo and
the residue dissolved in dry diethyl ether. The ethereal solution
was added slowly to a solution of diazomethane in diethyl ether
at 0 ЊC, and the resulting solution was stirred at 0 ЊC and then at
room temperature. The remaining diazomethane was consumed
by dropwise addition of glacial acetic acid and the solution was
neutralised with a saturated aqueous solution of sodium
bicarbonate. The organic phase was separated and aqueous
phase extracted with diethyl ether. The combined organic
extracts were dried and the solvent removed in vacuo. The resi-
due was purified by flash column chromatography on silica gel
to give the α-diazo ketone.
(S)-(؊)-1-Trifluoroacetylpyrrolidine-2-carboxylic acid 1. Tri-
fluoroacetic anhydride (19.0 g, 90.5 mmol) was added dropwise
over 5 min to (S)-proline (8.0 g, 69 mmol) with vigorous stirring
at 0 ЊC. The mixture was stirred at 0 ЊC for 10 min then heated
at 80 ЊC for 2 h. The mixture was then diluted with 2 M
hydrochloric acid (100 cm3) and extracted with diethyl ether
(3 × 100 cm3). The combined organic extracts were dried over
anhydrous magnesium sulfate and the solvent removed in vacuo.
The residue purified by flash column chromatography on silica
gel (hexane–diethyl ether, 1 : 1) to give the amide 1 (4.6 g, 31%)
as colourless needles; mp 47–49 ЊC [lit.,22 46–48 ЊC]; [α]2D4 Ϫ1.6
(c 1.0, CHCl3); νmax(CHCl3)/cmϪ1 3159, 2898, 1764, 1726, 1693;
δH (400 MHz, CDCl3) δ 4.60–4.56 (1H, m, NCHCO), 3.83–3.73
(2H, m, NCH2), 2.33–1.95 (4H, m, NCH2CH2 and NCHCH2);
δC (67.8 MHz, CDCl3) 176.3 (CO2H), 156.2 (CON, q, 2JFC 38),
116.1 (CF3, q, 1JFC 287), 60.0 (CH), 59.2 (CH), 48.2 (CH2), 47.3
(CH2), 31.6 (CH2), 28.5 (CH2), 24.9 (CH2), 21.1 (CH2); m/z (EI)
211.0461 (Mϩ. C7H8F3NO3 requires 211.0456), 211 (Mϩ, 4%),
166 (100), 114 (3) (Found C, 39.8; H, 3.8; N, 6.5. C7H8F3NO3
requires C, 39.8; H, 3.8; N, 6.6%).
(S)-(؊)-1-Diazo-3-(1-trifluoroacetylpyrrolidin-2-yl)propan-
2-one 4. Following the general procedure, the acid chloride
was prepared by the reaction of the N-protected amino acid
3 (2.9 g, 13 mmol) with oxalyl chloride (4.5 cm3, 52 mmol) and
dry dimethylformamide (two drops) in dry dichloromethane
(60 cm3) at 0 ЊC. The mixture was warmed to room temperature
and stirred for 3 h. The acid chloride was dissolved in dry
dichloromethane (25 cm3) and added to a solution of diazo-
methane (∼48 mmol) in diethyl ether (200 cm3) at 0 ЊC, and the
mixture was allowed to warm to room temperature over 2 h.
The remaining diazomethane was consumed with glacial acetic
acid (2.80 cm3, 49.0 mmol). Purification by flash column chrom-
atography on silica gel (diethyl ether–hexane, 2 : 1) afforded the
α-diazo ketone 4 (2.8 g, 87%) as a yellow solid; mp 37–39 ЊC;
[α]2D4 Ϫ2.1 (c 1.0, CHCl3); νmax(CHCl3)/cmϪ1 3115, 2953, 2899,
2110, 1681, 1643; δH (250 MHz, CDCl3) 5.33 (1H, br s, CHN2),
4.37–4.30 (1H, m, NCHCH2CO), 3.58–3.46 (2H, m, NCH2),
2.90 (1H, m, 1 × CH2CO), 2.34 (1H, dd, J 14.7 and 9.5, 1 ×
CH2CO), 2.12–1.80 (4H, m, NCH2CH2 and NCHCH2); δC (67.8
MHz, CDCl3) 191.6 (CO), 190.6 (CO), 155.2 (CON, q, 2JFC 37),
1
115.9 (CON, q, JFC 288), 56.1 (CH), 55.0 (CH), 46.8 (CH2),
(S)-(؊)-2-(2-Diazoacetyl)-1-trifluoroacetylpyrrolidine 2. Fol-
lowing the general procedure, the acid chloride was prepared by
the reaction of the N-protected amino acid 1 (2.0 g, 9.5 mmol)
with oxalyl chloride (4.8 g, 38 mmol) and dry dimethylform-
amide (two drops) in dry dichloromethane (50 cm3) at 0 ЊC. The
mixture was warmed to room temperature and stirred for 3 h.
The acid chloride was dissolved in dry dichloromethane
(20 cm3) and added to a solution of diazomethane (∼40 mmol)
in diethyl ether (100 cm3) at 0 ЊC, and the mixture was allowed
to warm to room temperature over 2 h. The remaining diazo-
methane was consumed with glacial acetic acid (2.80 cm3,
49.0 mmol). Purification by flash column chromatography on
silica gel (diethyl ether–hexane, 2 : 1) afforded the α-diazo
ketone 2 (1.9 g, 85%) as a yellow solid; mp 42–44 ЊC; [α]2D4 Ϫ4.6
(c 1.0, CHCl3); νmax(CHCl3)/cmϪ1 3116, 2956, 2898, 2113, 1693,
1651; δH (400 MHz, CDCl3) 5.44 (1H, br s, CHN2), 4.62–4.53
(1H, m, NCHCO), 3.82–3.75 (2H, m, NCH2), 2.23–2.01 (4H,
m, NCH2CH2 and NCHCH2); δC (67.8 MHz, CDCl3) 191.1
46.7 (CH2), 42.2 (CH2), 30.9 (CH2), 29.1 (CH2), 24.0 (CH2),
19.9 (CH2); m/z (FAB) 250.0818 (Mϩ ϩ H. C9H11F3N3O2
requires 250.0803), 250 (Mϩ ϩ H, 73%), 222 (100), 180 (5), 166
(41), 83 (10) (Found C, 43.4; H, 4.0; N, 16.6. C9H10F3N3O2
requires C, 43.4; H, 4.0; N, 16.9%).
(S)-(؊)-1-(1-Allylpyrrolidin-2-yl)-3-diazopropan-2-one 5. The
α-diazo ketone 4 (1.0 g, 4.0 mmol) was dissolved in a saturated
aqueous solution of barium hydroxide (30 cm3) and stirred at
room temperature for 1 h. The solution was then extracted with
ethyl acetate (2 × 50 cm3). The aqueous phase was concentrated
to dryness in vacuo and the residue washed with ethyl acetate
(2 × 30 cm3). The combined organic extracts were dried over
anhydrous potassium carbonate and concentrated in vacuo. The
residue was dissolved in dry tetrahydrofuran (40 cm3) and
potassium carbonate (1.4 g, 10 mmol) was added followed by
allyl bromide (0.7 g, 6 mmol). The mixture was stirred at room
3330
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337

View Article Online
temperature for 24 h. The solvent was then removed in vacuo
and the residue diluted with a saturated aqueous solution of
sodium bicarbonate (30 cm3) and extracted with ethyl acetate
(3 × 30 cm3). The combined organic extracts were dried over
anhydrous potassium carbonate and concentrated in vacuo. The
residue was purified by flash column chromatography on silica
gel (1% triethylamine in diethyl ether) to give the amine 5
(0.35 g, 45%) as a yellow liquid; [α]2D4 Ϫ6.9 (c 1.05, CHCl3);
νmax(film)/cmϪ1 3079, 2967, 2875, 2805, 2104, 1634, 997, 921; δH
(400 MHz, CDCl3) 5.89 (1H, dddd, J 17.1, 10.2, 7.5 and 5.7,
1-Diazo-3-(1-trifluoroacetylpiperidin-2-yl)propan-2-one 7. Fol-
lowing the general procedure, the acid chloride was prepared
by the reaction of the N-protected amino acid 6 (1.59 g,
6.65 mmol) with oxalyl chloride (2.90 cm3, 33.2 mmol) and
dry dimethylformamide (two drops) in dry dichloromethane
(10 cm3) at 0 ЊC. The mixture was stirred at 0 ЊC for 50 min
and at room temperature for 45 min. The acid chloride was
dissolved in dry dichloromethane (10 cm3) and added to a sol-
ution of diazomethane (∼33 mmol) in diethyl ether (100 cm3) at
0 ЊC, and the mixture was allowed to warm to room temper-
ature over 16 h. The remaining diazomethane was consumed
with glacial acetic acid (2.80 cm3, 49.0 mmol). Purification by
flash column chromatography on silica gel (diethyl ether–
hexane, 2 : 1) afforded the α-diazo ketone 7 (1.52 g, 87%) as a
yellow solid (mixture of amide rotamers); mp 78–81 ЊC;
νmax(CHCl3)/cmϪ1 2947, 2862, 2112, 1682, 1643; δH (400 MHz,
CDCl3) 5.42 (0.75H, br s, CHN2), 5.29 (0.25H, br s, CHN2
rotamer), 5.10–4.95 (1H, m, NCHCH2CO), 4.70–4.40 (1H, m,
1 × NCH2), 3.92–3.76 (1H, m, 1 × NCH2), 3.27–3.15 (1H, m,
1 × CH2CO), 3.00–2.45 (3H, m, 1 × CH2CO, NCHCH2CH2),
1.90–1.40 (4H, m, NCH2CH2 and NCH2CH2CH2); δC (100
MHz, CDCl3) 191.0 (CO), 190.4 (CO), 155.6 (CON, q, J 35),
155.1 (CON, q, 2JFC 35), 116.5 (CF3, q, 1JFC 288), 116.3 (CF3, q,
J 288), 55.3 (CH), 55.0 (CH), 50.0 (CH), 47.6 (CH), 41.4 (CH2),
41.3 (CH2), 40.6 (CH2), 40.3 (CH2), 38.8 (CH2), 28.1 (CH2),
27.5 (CH2), 25.3 (CH2), 24.7 (CH2), 18.2 (CH2); m/z (EI)
235.0801 (Mϩ Ϫ N2. C10H12F3NO2 requires 235.0820).
CH᎐CH ), 5.36 (1H, br s, CHN ), 5.20 (1H, dd, J 17.1 and 1.0,
᎐
2
2
trans CH᎐CH ), 5.11 (1H, d, J 10.2, cis CH᎐CH ), 3.40 (1H, dd,
᎐
᎐
2
2
J 10.4 and 5.6, 1 × CH CH᎐CH ), 3.09–3.02 (1H, m, NCH-
᎐
2
2
CH CO), 2.88–2.77 (2H, m, 1 × NCH CH and 1 × CH CH᎐
᎐
2
2
2
2
CH2), 2.68–2.60 (1H, m, 1 × NCH2CH2), 2.34–2.17 (2H, m,
CH2CO), 2.08–1.98 (1H, m, 1 × NCH2CH2CH2), 1.82–1.68
(2H, m, 1 × NCH2CH2 and 1 × NCH2CH2CH2), 1.57, 1.43 (1H,
m, 1 × NCH2CH2); δC (67.8 MHz, CDCl3) 193.7 (CO), 135.9
(CH), 117.0 (CH2), 60.6 (CH), 57.3 (CH2), 55.1 (CH), 53.7
(CH2), 45.9 (CH2), 30.8 (CH2), 22.2 (CH2); m/z (CI, NH3)
194.1287 (Mϩ ϩ H. C10H16N3O requires 194.1293), 194 (Mϩ ϩ
H, 55%), 165 (20), 110 (100), 83 (16%).
2-(Piperidin-2-yl)ethanoic acid. 2-(Piperidin-2-yl)ethanol
(5.00 g, 38.7 mmol) was suspended in water (10 cm3) and the
mixture cooled to 0 ЊC. A solution of chromium trioxide
(10.0 g, 100 mmol) and concentrated sulfuric acid (20 g) in
water (150 cm3) was added dropwise over 1 h 15 min. The result-
ing solution was stirred at 0 ЊC for 2 h 15 min and at room
temperature for 13 h. After this time, the solution was diluted
with water and basified with solid barium hydroxide. Excess
barium hydroxide was converted to the carbonate by passage of
carbon dioxide and this was removed by filtration through
Celite. The aqueous solution was concentrated in vacuo, and
the residue recrystallised from methanol–diethyl ether to give
(piperidin-2-yl)ethanoic acid (3.77 g, 68%) as a white solid;
mp 217–219 ЊC [lit.,7 217–218 ЊC]; νmax(KBr)/cmϪ1 3424, 2954,
1644; δH (250 MHz, D2O) 3.46–3.30 (2H, m, 1 × NCH2 and
NCHCH2CO), 3.07–2.93 (1H, m, 1 × NCH2), 2.49 (2H, d,
J 6.7, CH2CO), 2.00–1.75 (3H, m, NCHCH2CH2 and 1 ×
NCH2CH2), 1.75–1.41 (3H, m, 1 × NCH2CH2 and NCH2-
CH2CH2); δC (67.8 MHz, D2O) 178.3 (CO2H), 55.3 (CH), 45.4
(CH2), 40.9 (CH2), 29.0 (CH2), 22.8 (CH2), 22.4 (CH2) (Found
C, 58.6; H, 9.3; N, 9.6. C7H13NO2 requires C, 58.7; H, 9.2;
N, 9.8%).
1-(Allylpiperidin-2-yl)-3-diazopropan-2-one 8. A 5% aqueous
solution of potassium carbonate (50 cm3) was added to a sol-
ution of the α-diazo ketone 7 (1.00 g, 3.80 mmol) in ethanol
(30 cm3). The resulting mixture was stirred at room temperature
for 20 h and then extracted with diethyl ether (3 × 75 cm3). The
combined organic extracts were dried over anhydrous potas-
sium carbonate and the solvent removed in vacuo. The residue
and potassium carbonate (1.36 g, 9.84 mmol) were suspended
in dry tetrahydrofuran (20 cm3) and allyl bromide (0.85 cm3,
9.8 mmol) was added dropwise over 1 min. The mixture was
stirred at room temperature for 22 h and the solvent then
removed in vacuo. The residue was diluted with a saturated
aqueous solution of sodium bicarbonate (50 cm3) and extracted
with diethyl ether (2 × 50 cm3). The combined organic extracts
were dried over anhydrous potassium carbonate and the solvent
removed in vacuo. The residue was purified by flash column
chromatography on silica gel (1% triethylamine in diethyl ether)
to give the allylic amine 8 (0.54 g, 69%) as a green liquid;
νmax(film)/cmϪ1 3078, 2934, 2857, 2795, 2104, 1636, 1000, 969,
920; δH (250 MHz, CDCl3) 5.78 (1H, dddd, J 17.2, 10.0, 7.3 and
2-(1-Trifluoroacetylpiperidin-2-yl)ethanoic acid 6. Trifluoro-
acetic anhydride (2.75 cm3, 19.5 mmol) was added dropwise
over 1 min to (piperidin-2-yl)ethanoic acid (2.53 g, 17.7 mmol)
at 0 ЊC with vigorous stirring. The mixture was stirred at 0 ЊC
for 5 min and a further portion of trifluoroacetic anhydride
(0.50 cm3, 3.5 mmol) was then added. The mixture was then
warmed to 85 ЊC and maintained at this temperature for 1 h
30 min, then diluted with a 1 M hydrochloric acid (50 cm3) and
extracted with diethyl ether (6 × 50 cm3). The combined organic
extracts were dried over anhydrous magnesium sulfate and the
solvent removed in vacuo. The residue was purified by flash
column chromatography on silica gel (diethyl ether–hexane,
1 : 1) to give the protected amino acid 6 (2.62 g, 62%) as a white
solid; mp 69–70 ЊC; νmax(CHCl3)/cmϪ1 3177, 2948, 2872, 1716,
1682; δH (400 MHz, [CD3]2SO, 393 K) 4.79–4.58 (1H, br m,
NCHCH2CO), 3.98–3.76 (1H, br m, 1 × NCH2), 3.24–3.02 (1H,
br m, 1 × NCH2), 2.74–2.46 (2H, m, CH2CO), 1.78–1.50 (5H,
m, NCH2CH2, NCHCH2CH2 and 1 × NCH2CH2CH2), 1.50–
1.38 (1H, m, 1 × NCH2CH2CH2); δC (100 MHz, [CD3]2SO,
393 K) 170.9 (CO), 154.8 (CON, q, 2JFC 35), 116.5 (CF3, q, 1JFC
289), 48.7 (CH), 39.9 (CH2), 34.8 (CH2), 27.6 (CH2), 24.7
(CH2), 17.8 (CH2); m/z (EI) 239 (Mϩ, 22%), 180 (100) (Found
C, 45.4; H, 5.25; N, 6.0. C9H12F3NO3 requires C, 45.2; H, 5.1;
N, 5.9%).
5.7, CH᎐CH ), 5.38 (1H, br s, CHN ), 5.18 (1H, dddd, J 17.2,
᎐
2
2
1.5, 1.0 and 0.7, trans CH᎐CH ), 5.17–5.11 (1H, m, cis CH᎐
᎐
᎐
2
CH ), 3.25 (1H, ddt, J 13.9, 5.7 and 1.5, CH CH᎐CH ), 2.96
᎐
2
2
2
(1H, ddt J 13.9, 7.3 and 1.0, NCH CH᎐CH ), 2.96–2.87 (1H, m,
᎐
2
2
NCH), 2.77–2.56 (2H, m, NCH2CH2), 2.39–2.23 (2H, m,
CH2CO), 1.77–1.31 (6H, m, NCH2CH2CH2, NCHCH2 and
NCH2CH2CH2); δC (67.8 MHz, CDCl3) 193.7 (CO), 135.1
(CH), 117.4 (CH2), 57.4 (CH2), 56.7 (CH), 55.0 (CH), 50.7
(CH2), 42.0 (CH2), 30.8 (CH2), 25.2 (CH2), 22.3 (CH2); m/z (EI)
179.1298 (Mϩ Ϫ N2. C11H17NO requires 179.1310).
(S)-(؊)-(1-Trifluoroacetylpyrrolidin-2-yl)methanol 9.8 (S)-
Pyrrolidinylmethanol (7.0 g, 69 mmol) and triethylamine
(10.1 cm3, 72.5 mmol) were dissolved in methanol (30 cm3) and
ethyl trifluoroacetate (12.4 cm3, 104 mmol) was added dropwise
to the mixture over a period of 30 min. The solution was stirred
at room temperature for 18 h then diluted with 2 M hydro-
chloric acid (100 cm3) and extracted with diethyl ether (3 ×
120 cm3). The aqueous phase was saturated with solid sodium
chloride and extracted with diethyl ether (100 cm3). The com-
bined organic extracts were dried over anhydrous magnesium
sulfate and concentrated in vacuo. The residue was purified by
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337
3331

View Article Online
flash column chromatography on silica gel (diethyl ether–
hexane, 2 : 1) to give the amide 9 (11.5 g, 84%) as a colourless
oil; [α]2D8 Ϫ64.6 (c 1.10, CHCl3); νmax(film)/cmϪ1 3425, 2979,
2889, 1791, 1686; δH (400 MHz, CDCl3) 4.27–4.21 (1H, m, 1 ×
CH2OH), 3.79–3.60 (4H, m, 1 × CH2OH, NCH2 and NCH-
CH2OH), 3.22 (1H, br s, OH), 2.13–1.86 (4H, m, NCH2CH2
and NCHCH2); δC (67.8 MHz, CDCl3) 156.6 (CON, q, 2JFC 37),
116.2 (CF3, q, 1JFC 287), 63.3 (CH2), 61.8 (CH), 59.3 (CH), 47.5
(CH2), 28.2 (CH2), 26.8 (CH2), 24.3 (CH2), 20.4 (CH2); m/z
(FAB) 198.0741 (Mϩ ϩ H. C7H11F3NO2 requires 198.0742).
(S)-(؊)-3-(1-Trifluoroacetylpyrrolidin-2-yl)propanoic acid 12.
Trifluoroacetic acid (1.3 cm3, 17 mmol) was added to a solution
of the ester 11 (1.0 g, 3.4 mmol) in dichloromethane (1 cm3) and
the mixture stirred at room temperature for 1 h. The solvent was
removed in vacuo and the residue purified by flash column
chromatography on silica gel (hexane–diethyl ether, 2 : 1) to
give the carboxylic acid 12 (0.74 g, 91%) as a white solid; mp
37–39 ЊC; [α]2D8 Ϫ2.27 (c 0.971, CHCl3); νmax(CHCl3)/cmϪ1 2979,
1729, 1690; δH (400 MHz, CDCl3) 4.27–4.20 (1H, m, CHCH2-
CH2CO2H), 3.72–3.60 (2H, m, NCH2), 2.49–2.35 (2H, m,
CH2CO2H), 2.18–1.90 (4H, m, CH2CH2CO2H and NCH2-
CH2CH2), 1.84–1.69 (2H, m, NCH2CH2); δC (67.8 MHz,
CDCl3) 178.0 (CO2H), 155.4 (CON, q, 2JFC 37), 115.9 (CF3, q,
1JFC 288), 58.2 (CH), 46.3 (CH2), 30.3 (CH2), 28.3 (CH2), 27.2
(CH2), 23.7 (CH2); m/z (FAB) 240.0829 (Mϩ ϩ H. C9H12F3NO3
requires 240.0848), 240 (Mϩ ϩ H, 60%), 222 (89), 194 (5), 166
(19).
tert-Butyl (S)-(؊)-3-(1-trifluoroacetylpyrrolidin-2-yl)propeno-
ate 10. Dimethyl sulfoxide (2.1 cm3, 30 mmol) was added drop-
wise to a solution of oxalyl chloride (1.25 cm3, 14.3 mmol)
in dichloromethane (75 cm3) at Ϫ78 ЊC over 15 min, and the
mixture was stirred at this temperature for a further 15 min. A
solution of the alcohol 9 (2.3 g, 12 mmol) in dichloromethane
(25 cm3) was then added over 30 min and the mixture was
stirred at Ϫ78 ЊC for 1 h 30 min. Triethylamine (7.9 cm3,
57 mmol) was added and the mixture was allowed to warm to
room temperature. The solution was diluted with dichloro-
methane (25 cm3) and washed with water (2 × 75 cm3). The
combined organic extracts were dried over anhydrous sodium
sulfate, and concentrated in vacuo. The resulting crude aldehyde
was used without further purification.
Sodium hydride (0.30 g, 13 mmol) was suspended in dry
tetrahydrofuran (10 cm3) at room temperature, and tert-butyl
diethylphosphonoacetate (3.0 g, 12 mmol) was added dropwise.
The mixture was stirred for 30 min and then cooled to 5 ЊC.
A solution of the aldehyde (2.0 g, 10 mmol) in dry tetrahydro-
furan (40 cm3) was added dropwise at such a rate as to keep the
temperature below 10 ЊC. The mixture was stirred at room
temperature for 4 h then concentrated in vacuo. The residue was
dissolved in dichloromethane (100 cm3) and washed succes-
sively with water (2 × 75 cm3), a 20% w/v aqueous solution of
sodium sulfite (75 cm3) and brine (75 cm3). The solvent was
removed in vacuo and the residue was purified by flash column
chromatography on silica gel (hexane–diethyl ether, 5 : 1) to give
the alkene 10 (1.0 g, 29%) as a white solid; mp 61–62 ЊC; [α]2D6
Ϫ1.00 (c 1.40, CHCl3); νmax(CHCl3)/cmϪ1 2980, 2904, 1694,
1658, 978; δH (400 MHz, CDCl3) 6.68 (1H, dd, J 15.6 and 5.8,
(S)-(؊)-1-Diazo-4-(1-trifluoroacetylpyrrolidin-2-yl)butan-
2-one 13. Following the general procedure, the acid chloride
was prepared by the reaction of the N-protected amino acid 12
(0.50 g, 2.1 mmol) with oxalyl chloride (0.73 cm3, 8.4 mmol)
and dry dimethylformamide (one drop) in dry dichloromethane
(15 cm3) at 0 ЊC. The mixture was warmed to room temperature
and stirred for 3 h. The acid chloride was dissolved in dry
dichloromethane (5 cm3) and added to a solution of diazo-
methane (∼10 mmol) in diethyl ether (50 cm3) at 0 ЊC, and the
mixture was allowed to warm to room temperature over 2 h.
The remaining diazomethane was consumed with glacial acetic
acid (0.6 cm3, 10 mmol). Purification by flash column chrom-
atography on silica gel (diethyl ether–hexane, 2 : 1) afforded the
α-diazo ketone 13 (0.51 g, 93%) as a yellow solid; mp 35–36 ЊC;
[α]2D6 Ϫ6.98 (c 1.29, CHCl3); νmax(CHCl3)/cmϪ1 3116, 2975, 2901,
2109, 1682, 1643; δH (400 MHz, CDCl3) 5.39 (1H, br s, CHN2),
4.25–4.12 (1H, m, CHCH2CH2CO), 3.68–3.60 (2H, m, NCH2),
2.45–2.30 (2H, m, CH2CO), 2.13–1.71 (6H, m, NCH2CH2CH2,
CHCH2CH2CO and NCH2CH2); δC (67.8 MHz, CDCl3) 194.0
2
1
(CO), 155.9 (CON, q, JFC 36), 116.4 (CF3, q, JFC 288), 58.8
(CH), 54.6 (CH), 46.6 (CH2), 37.6 (CH2), 29.1 (CH2), 28.2
(CH2), 24.2 (CH2); m/z (FAB) 235.0819 (Mϩ Ϫ N2. C10H12-
F3NO2 requires 235.0820), 264 (Mϩ ϩ H, 100%), 236 (95), 166
(32), 97 (6).
CHCH᎐CH), 5.75 (1H, dd, J 15.6 and 1.4, CHCH᎐CH), 4.82–
᎐
᎐
4.78, (1H, m, CHCH᎐CH), 3.79–3.64 (2H, m, NCH ), 2.16–
᎐
2
(S)-(؊)-1-(1-Allylpyrrolidin-2-yl)-4-diazobutan-3-one 14. The
α-diazo ketone 13 (1.2 g, 4.6 mmol) was dissolved in a saturated
aqueous solution of barium hydroxide (20 cm3) and stirred at
room temperature for 1 h. The solution was then extracted with
ethyl acetate (2 × 30 cm3). The aqueous phase was concentrated
to dryness in vacuo and the residue washed with ethyl acetate
(2 × 30 cm3). The combined organic extracts were dried over
anhydrous potassium carbonate and concentrated in vacuo. The
residue was dissolved in dry tetrahydrofuran (30 cm3), and
potassium carbonate (1.2 g, 8.7 mmol) and allyl bromide
(0.97 g, 8.0 mmol) were then added to the solution. The mixture
was stirred at room temperature for 24 h and the solvent was
then removed in vacuo. The residue was diluted with a saturated
aqueous solution of sodium bicarbonate (30 cm3) and extracted
with ethyl acetate (3 × 30 cm3). The combined organic extracts
were dried over anhydrous potassium carbonate and con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel (1% triethylamine in diethyl ether)
to give the allylic amine 14 (0.30 g, 32%) as a yellow liquid; [α]2D4
Ϫ6.44 (c 1.01, CHCl3); νmax(film)/cmϪ1 3077, 2960, 2873, 2794,
2101, 1641, 995, 918; δH (400 MHz, CDCl3) 5.90 (1H, dddd,
1.85 (4H, m, NCH-2CH2 and NCHCH2), 1.47 (9H, s, [CH3]3C);
2
δC (67.8 MHz, CDCl3) 164.8 (CO2), 155.1 (CON, q, JFC 37),
143.0 (CH), 123.1 (CH), 115.9 (CF3, q, 1JFC 288), 80.2 (C), 58.7
(CH), 46.5 (CH2), 29.3 (CH2), 27.6 (CH3), 23.7 (CH2); m/z
(FAB) 294.1313 (Mϩ ϩ H. C13H19F3NO3 requires 294.1317),
294 (Mϩ ϩ H, 12%), 236 (7), 220 (88).
tert-Butyl (S)-(؊)-3-(1-trifluoroacetylpyrrolidin-2-yl)propano-
ate 11. The alkene 10 (1.2 g, 4.1 mmol) and 10% palladium
on activated charcoal (0.2 g) were added to a mixture of meth-
anol (20 cm3) and water (2 cm3). The mixture was stirred at
room temperature under 1 atmosphere of hydrogen for 12 h.
The mixture was filtered through Celite and the solvent
removed in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane–diethyl ether, 3 : 1) to give
the ester 11 (1.1 g, 91%) as a colourless liquid; [α]2D6 Ϫ18.6
(c 1.30, CHCl3). νmax(film)/cmϪ1 2979, 1729, 1691; δH (250 MHz,
CDCl3) 4.24–4.16 (1H, m, CHCH2CH2CO), 3.69–3.60 (2H, m,
NCH2), 2.28–2.21 (2H, m, CH2CO), 2.20–1.91 (4H, m, CH2-
CH2CO and NCH2CH2CH2), 1.78–1.60 (2H, m, NCH2CH2),
1.45 (9H, s, [CH3]3C); δC (67.8 MHz, CDCl3) 171.9 (CO2), 155.4
(CON, q, 2JFC 36), 116.2 (CF3, q, 1JFC 288), 80.2 (C), 58.5 (CH),
46.3 (CH2), 46.3 (CH2), 32.2 (CH2), 28.6 (CH2), 27.8 (CH3),
24.0 (CH2); m/z (CI, CH4) 296.1473 (Mϩ ϩ H. C13H21F3NO3
requires 296.1474), 296 (Mϩ ϩ H, 100%), 239 (23), 222 (88), 166
(25).
J 17.1, 10.3, 7.6 and 5.5, CH᎐CH ), 5.25 (1H, br s, CHN ), 5.18
᎐
2
2
(1H, dq, J 17.1 and 1.5, trans CH᎐CH ), 5.11–5.07 (1H, m, cis
᎐
2
CH᎐CH ), 3.46 (1H, dddd, J 13.3, 5.5, 1.5 and 1.5, 1 ×
᎐
2
CH CH᎐CH ), 3.08 (1H, ddd, J 9.6, 7.2 and 2.8, 1 × NCH ),
᎐
2
2
2
2.75 (1H, dddd, J 13.3, 7.6, 0.9 and 0.9, 1 × CH CH᎐CH ),
᎐
2
2
2.47–2.25 (3H, m, CHCH2CH2CO and CH2CO), 2.15 (1H, td,
3332
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337

View Article Online
9.3 and 7.2, 1 × NCH2), 2.04–1.94 (1H, m, 1 × CH2CH2CO),
1.93–1.86 (1H, m, 1 × NCH2CH2CH2), 1.78–1.52 (3H, m,
NCH2CH2 and 1 × CH2CH2CO), 1.45 (1H, dddd, J 12.5,
10.0, 7.5 and 5.2, 1 × NCH2CH2CH2); δC (67.8 MHz, CD-
Cl3) 194.3 (CO), 135.4 (CH), 116.2 (CH2), 62.4 (CH), 56.6
(CH2), 53.6 (CH), 53.4 (CH2), 36.8 (CH2), 29.4 (CH2), 28.3
(CH2), 21.5 (CH2); m/z (CI, NH3) 208.1449 (Mϩ ϩ H. C11H18-
N3O requires 208.1450), 208 (Mϩ ϩ H, 95%), 207 (Mϩ, 9), 179
(19), 110 (100).
4-(1-Allylpiperidin-2-yl)-1-diazobutan-2-one 17. The α-diazo
ketone 16 (1.0 g, 3.6 mmol) was dissolved in a 2 M aqueous
solution of sodium hydroxide (30 cm3) and the mixture was
stirred at room temperature for 1 h. The solution was then
extracted with ethyl acetate (2 × 30 cm3). The aqueous phase
was concentrated in vacuo and the dry residue washed with
ethyl acetate (2 × 30 cm3). The combined organic extracts were
dried over anhydrous potassium carbonate and concentrated
in vacuo. The residue was dissolved in dry tetrahydrofuran
(30 cm3), and potassium carbonate (1.1 g, 8.0 mmol) and allyl
bromide (0.65 g, 5.4 mmol) were then added to the solution.
The mixture was stirred at room temperature for 24 h, and the
solvent was then removed in vacuo. The residue was diluted
with a saturated aqueous solution of sodium bicarbonate
(30 cm3) and extracted with ethyl acetate (3 × 30 cm3). The
combined organic extracts were dried over anhydrous potas-
sium carbonate and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (1% tri-
ethylamine in diethyl ether) to give the allylic amine 17 (0.14 g,
18%) as a yellow liquid; νmax(film)/cmϪ1 3077, 2934, 2856, 2791,
2102, 1641, 994, 918; δH (500 MHz, CDCl3) 5.91–5.82 (1H, m,
3-(1-Trifluoroacetylpiperidin-2-yl)propionic acid 15. Silver
benzoate (0.22 g, 0.96 mmol) was added to a solution of the
α-diazo ketone 7 (5.0 g, 19 mmol) in a mixture of 1,4-dioxane
(165 cm3) and water (85 cm3). The reaction mixture was heated
at 70 ЊC for 3 h and then concentrated in vacuo. The residue was
dissolved in a saturated aqueous solution of sodium bicarbon-
ate (150 cm3) and extracted with diethyl ether (2 × 100 cm3).
The aqueous layer was acidified with 2 M hydrochloric acid and
then extracted with diethyl ether (2 × 150 cm3). The combined
organic extracts were dried (magnesium sulfate) and concen-
trated in vacuo. The residue was purified by flash column chrom-
atography on silica gel (hexane–diethyl ether, 1 : 1) to give the
carboxylic acid 15 (4.0 g, 83%) as a white solid (mixture of
amide rotamers); mp 87–88 ЊC. νmax(CHCl3)/cmϪ1 3193, 2872,
2674, 1714; δH (400 MHz, CDCl3) 4.70–4.60 (0.8H, m,
CHCH2CH2CO), 4.36–4.32 (0.2H, m, 1 × NCH2), 4.01 (0.2H,
m, CHCH2CH2CO), 3.75–3.71 (0.8H, m, 1 × NCH2), 3.16–3.10
(0.8H, m, 1 × NCH2), 2.82–2.76 (0.2H, m, 1 × NCH2), 2.34–
2.10 (4H, m, CH2CO and CH2CH2CO), 1.90–1.64 (5H, m,
NCH2CH2, NCH2CH2CH2CH2, and 1 × NCH2CH2CH2), 1.50–
1.38 (1H, m, 1 × NCH2CH2CH2); δC (67.8 MHz, CDCl3) 178.9
(CO2H), 178.6 (CO2H), 156.4 (CON, q, 2JFC 34.3), 116.7 (CF3,
q, 1JFC 288), 116.7 (CF3, q, 1JFC 288), 52.9 (CH), 50.0 (CH), 41.2
(CH2), 38.4 (CH2), 30.7 (CH2), 30.3 (CH2), 29.2 (CH2), 28.6
(CH2), 26.0 (CH2), 25.2 (CH2), 24.6 (CH2), 24.4 (CH2), 18.8
(CH2), 18.6 (CH2); m/z (EI) 253.0923 (Mϩ. C10H14F3NO3
requires 253.0926), 254 (Mϩ ϩ H, 100%), 253 (Mϩ, 5), 208 (10),
180 (26), 73 (24) (Found C, 47.8; H, 5.7; N, 5.8. C10H14F3NO3
requires C, 47.4; H, 5.6; N, 5.5%).
CH᎐CH ), 5.25 (1H, br s, CHN ), 5.18 (1H, m, trans CH᎐CH ),
᎐
᎐
2
2
2
5.06 (1H, m, cis CH᎐CH ), 3.33 (1H, dd, J 14.0 and 5.7, 1 ×
᎐
2
CH2CH᎐CH2), 2.95 (1H, dd, J 14.0 and 7.4, 1 × CH2CH᎐CH2),
᎐
᎐
2.89 (1H, dt, J 11.7 and 4.1, 1 × NCH2), 2.43–2.27 (3H, m,
CHCH2CH2CO and CH2CO), 2.20–2.15 (1H, m, 1 × NCH2),
1.92–1.78 (2H, m, CH2CH2CO), 1.72–1.24 (6H, m, NCH2CH2,
NCH2CH2CH2 and NCH2CH2CH2CH2); δC (125 MHz, CDCl3)
195.2 (CO), 135.3 (CH), 117.5 (CH2), 59.2 (CH), 56.6 (CH2),
54.3 (CH), 51.9 (CH2), 36.6 (CH2), 30.1 (CH2), 26.4 (CH2), 25.3
(CH2), 23.7 (CH2); m/z (CI) 164 (3%), 124 (100).
General procedure for carbenoid generation, ylide formation and
rearrangement
A solution of the α-diazo ketone in dry solvent was added
dropwise from a pressure-equalising addition funnel through
the condenser to a solution of the appropriate copper() or
rhodium() complex in the same solvent at reflux. The resulting
solution was stirred at reflux and the solvent was then removed
in vacuo. The residue was purified by flash column chrom-
atography on silica gel to give the rearrangement product.
1-Diazo-4-(1-trifluoroacetylpiperidin-2-yl)butan-2-one 16. Fol-
lowing the general procedure, the acid chloride was prepared by
the reaction of the N-protected amino acid 15 (3.9 g, 15 mmol)
with oxalyl chloride (5.4 cm3, 62 mmol) and dry dimethyl-
formamide (two drops) in dry dichloromethane (75 cm3) at 0 ЊC.
The mixture was warmed to room temperature and stirred for
3 h. The acid chloride was dissolved in dry dichloromethane
(30 cm3) and added to a solution of diazomethane (∼60 mmol)
in diethyl ether (250 cm3) at 0 ЊC, and the mixture was allowed
to warm to room temperature over 2 h. The remaining
diazomethane was consumed with glacial acetic acid (3.9 g,
65 mmol). Purification by flash column chromatography on
silica gel (diethyl ether–hexane, 2 : 1) afforded the α-diazo
ketone 16 (3.9 g, 91%) as a yellow liquid (mixture of amide
rotamers); νmax(film)/cmϪ1 3090, 2944, 2868, 2104, 1682, 1642;
δH (400 MHz, CDCl3) 5.27 (1H, br s, CHN2), 4.70 (0.8H, m,
CHCH2CH2CO), 4.41–4.38 (0.2H, m, 1 × NCH2), 4.04 (0.2H,
m, CHCH2CH2CO), 3.77–3.73 (0.8H, m, 1 × NCH2), 3.25–3.17
(0.8H, m, 1 × NCH2), 2.88–2.82 (0.2H, m, 1 × NCH2), 2.38–
2.17 (4H, m, CH2CO and CH2CH2CO), 2.01–1.67 (5H, m,
NCH2CH2, NCH2CH2CH2CH2 and 1 × NCH2CH2CH2), 1.53–
1.43 (1H, m, 1 × NCH2CH2CH2); δC (67.8 MHz, CDCl3) 193.8
(CO), 193.3 (CO), 156.4 (CON, q, 2JFC 35), 155.8 (CON, q, 2JFC
(3S,8S)-3-Allyltetrahydropyrrolizin-2(3H)-one 18a. Accord-
ing to the general procedure, a solution of the α-diazo ketone
5 (0.12 g, 0.62 mmol) in dry benzene (60 cm3) was added to
a solution of Cu(acac)2 (3.2 mg, 0.012 mmol) in dry benzene
(10 cm3) at reflux, over a period of 30 min. The resulting sol-
ution was stirred at reflux for a further 15 min. Purification by
flash column chromatography on silica gel (diethyl ether) gave
the pyrrolizidinone 18a (67 mg, 65%) as a colourless liquid.
According to the general procedure, a solution of the α-diazo
ketone 5 (0.11 g, 0.57 mmol) in dry benzene (60 cm3) was added
to a solution of Rh2(OAc)4 (4.8 mg, 0.011 mmol) in dry benzene
(10 cm3) at reflux, over a period of 30 min. The resulting sol-
ution was stirred at reflux for a further 15 min. Purification by
flash column chromatography on silica gel (diethyl ether) gave
the pyrrolizidinone 18a (52 mg, 55%) as a colourless liquid; [α]2D4
Ϫ8.0 (c 0.85, CHCl3); νmax(film)/cmϪ1 2935, 2880, 1748, 1641,
997, 915; δH (500 MHz, CDCl3) 5.85 (1H, dddd, J 17.0, 10.2, 7.4
and 6.9, CH᎐CH ), 5.18–5.10 (1H, m, trans CH᎐H ), 5.09–5.05
᎐
᎐
2
2
(1H, m, cis CH᎐CH ), 3.67 (1H, dddd, J 8.0, 7.7, 7.7 and 4.0,
᎐
2
NCHCH2CO), 3.21–3.14 (1H, m, NCHCO), 2.90–2.81 (2H, m,
NCH ), 2.60 (1H, ddd, J 18.7, 8.0 and 0.6, 1 × CH CH᎐CH ),
᎐
2
2
2
1
1
35), 116.9 (CF3, q, JFC 288), 116.8 (CF3, q, JFC 288), 54.8
(CH), 53.3 (CH), 51.0 (CH), 50.6 (CH), 41.3 (CH2), 38.4 (CH2),
37.2 (CH2), 36.8 (CH2), 29.5 (CH2), 29.0 (CH2), 26.3 (CH2),
26.0 (CH2), 25.3 (CH2), 24.6 (CH2), 18.9 (CH2), 18.7 (CH2); m/z
(FAB) 278.1093 (Mϩ ϩ H. C11H15F3N3O2 requires 278.1116),
278 (Mϩ ϩ H, 55%), 250 (100), 180 (29).
2.50–2.43 (1H, m, 1 × CH CH᎐CH ), 2.36–2.24 (2H, m,
᎐
2 2
CH2CO), 2.12–2.05 (1H, m, 1 × NCH2CH2), 2.05–1.96 (1H, m,
1 × NCH2CH2), 1.90–1.81 (1H, m, 1 × NCH2CH2CH2), 1.48–
1.40 (1H, m, 1 × NCH2CH2CH2); δC (67.8 MHz, CDCl3) 217.6
(CO), 134.8 (CH), 117.4 (CH2), 69.5 (CH), 60.0 (CH), 54.5
(CH2), 42.2 (CH2), 36.7 (CH2), 31.6 (CH2), 25.1 (CH2); m/z (CI)
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337
3333

View Article Online
166.1231 (Mϩ ϩ H. C10H16NO requires 166.1232), 165 (Mϩ,
50%), 124 (100).
(CH), 52.5 (CH2), 38.8 (CH2), 32.8 (CH2), 30.1 (CH2), 29.1
(CH2), 22.2 (CH2); m/z (EI) 179.1316 (Mϩ. C11H17NO requires
179.1310), 180 (Mϩ ϩ H, 3%), 138 (53).
(3S*,8aS*)-3-Allylhexahydroindolizin-2(3H)-one 19a and
(3R*,8aS*)-3-allylhexahydroindolizin-2(3H)-one 19b. Accord-
ing to the general procedure, a solution of the α-diazo ketone 8
(198 mg, 0.955 mmol) in dry benzene (95 cm3) was added to a
solution of Cu(acac)2 (5.1 mg, 0.019 mmol) in dry benzene
(5 cm3) at reflux, over a period of 2 h. The resulting solution
was stirred at reflux for a further 10 min. Analysis of the crude
reaction mixture by 1H NMR indicated exclusive formation
of indolizidinone 19a. Purification by flash column chrom-
atography on silica gel (hexane–diethyl ether, 2 : 1) gave the
indolizidinone 19a (83.7 mg, 49%) and the indolizidinone 19b
(21.8 mg, 13%), resulting from partial epimerisation during
chromatography, as colourless liquids (combined yield of 62%).
Data for 19a; νmax(film)/cmϪ1 3077, 2932, 2854, 2801, 1755,
4-Allyloctahydroquinolizin-3-one 21a and 21b. According
to the general procedure, a solution of the α-diazo ketone 17
(0.14 g, 0.63 mmol) in dry benzene (50 cm3) was added to a
solution of Cu(acac)2 (3.3 mg, 0.013 mmol) in dry benzene
(10 cm3) at reflux, over a period of 30 min. The resulting
solution was stirred at reflux for a further 15 min. Purification
by flash column chromatography on neutral alumina (hexane–
diethyl ether, 4 : 1) gave the quinolizidinone 21a–b major (64 mg,
52%) and minor (11 mg, 9%) isomers as colourless liquids.
Major isomer; νmax(film)/cmϪ1 2936, 2860, 2790, 2733, 1716,
1639, 995, 908; δH (400 MHz, CDCl3) 5.67 (1H, dddd, J 16.7,
10.2, 8.0 and 6.6, CH᎐CH ), 5.30–5.00 (2H, m, CH᎐CH ), 3.25
᎐
᎐
2
2
(1H, dd, J 9.7 and 5.5, NCHCO), 2.86–2.79 (1H, m, NCH-
CH CH ), 2.68–2.59 (3H, m, NCH and 1 × CH CH᎐CH ),
1640, 997, 914; δH (250 MHz, CDCl ) 5.90–5.83 (1H, m, CH᎐
᎐
᎐
3
2
2
2
2
2
CH ), 5.14–5.04 (2H, m, CH᎐CH ), 3.36 (1H, t, J 5.7,
2.48–2.32 (3H, m, CH CO and 1 × CH CH᎐CH ), 1.97–
᎐
2 2 2
᎐
2
2
NCHCO), 3.25–3.14 (1H, m, NCHCH2CO), 3.13–3.03 (1H, m,
1 × NCH2), 2.77 (1H, ddd, J 12.6, 11.2 and 3.8, 1 × NCH2),
1.91 (1H, m, 1 × NCHCH2CH2CO), 1.75–1.22 (7H, m, 1 ×
NCHCH2CH2CO, NCHCH2CH2, NCH2CH2CH2 and NCH2-
CH2CH2); δC (125 MHz, CDCl3) 209.2 (CO), 134.2 (CH), 117.1
(CH2), 72.2 (CH), 51.9 (CH), 51.2 (CH2), 36.5 (CH2), 33.0
(CH2), 31.9 (CH2), 29.2 (CH2), 25.7 (CH2), 23.7 (CH2); m/z (EI)
152.1080 (Mϩ Ϫ C3H5. C9H14NO requires 152.1075). Minor
isomer; νmax(film)/cmϪ1 3083, 2942, 2880, 2798, 2740, 2710,
1716, 1640, 995, 913; δH (400 MHz, CDCl3) 5.85 (1H, dddd,
J 17.2, 10.2, 6.9 and 6.9, CH᎐CH ), 5.10 (1H, dd, J 17.2 and
2.56–2.21 (3H, m, 1 × CH CO and CH CH᎐CH ), 2.09 (1H,
᎐
2
2
2
dd, J 18.0 and 5.6, 1 × CH2CO), 1.88–1.80 (1H, m, 1 × NCH2-
CH2CH2), 1.68–1.17 (5H, m, NCH2CH2, NCHCH2CH2 and
1 × NCH2CH2CH2); δC (67.8 MHz, CDCl3) 215.8 (CO), 134.7
(CH), 117.3 (CH2), 64.8 (CH), 56.3 (CH), 46.6 (CH2), 44.2
(CH2), 32.0 (CH2), 29.7 (CH2), 24.2 (CH2), 21.7 (CH2). Data
for 19b; νmax(CHCl3)/cmϪ1 2940, 2787, 1753, 994, 916; δH
(250 MHz, CDCl3) 5.81 (1H, m, dddd, J 17.1, 10.2, 7.2 and 6.2,
᎐
2
1.6, trans CH᎐CH ), 5.05 (1H, br d, J 10.2, cis CH᎐CH ), 3.20–
᎐
᎐
2
2
CH᎐CH ), 5.12–4.99 (2H, m, CH᎐CH ), 3.19 (1H, dt, J 10.8
3.15 (1H, m, 1 × NCH2), 2.76 (1H, dd, J 5.3 and 3.0, NCHCO),
2.68–2.61 (1H, m, 1 × CH CH᎐CH ), 2.60–2.49 (2H, m, 1 ×
᎐
᎐
2
2
and 2.7, 1 × NCH2), 2.51–2.27 (5H, m, NCHCH2CO, NCHCO,
CH CH᎐CH , and 1 × CH CO), 2.11–1.60 (6H, m, 1 × NCH ,
᎐
2
2
NCH and 1 × CH CH᎐CH ), 2.40–2.30 (2H, m, 1 × NCH-
᎐
᎐
2
2
2
2
2
2
2
1 × CH2CO, NCH2CH2, 1 × NCHCH2CH2 and 1 × NCH2-
CH2CH2), 1.47–1.32 (2H, m, 1 × NCHCH2CH2 and 1 ×
NCH2CH2CH2); δC (67.8 MHz, CDCl3) 214.4 (CO), 134.9
(CH), 116.7 (CH2), 70.9 (CH), 60.8 (CH), 51.4 (CH2), 43.5
(CH2), 32.7 (CH2), 30.9 (CH2), 25.4 (CH2), 24.4 (CH2); m/z (EI)
138.0912 (Mϩ Ϫ C3H5. C8H12NO requires 138.0919).
CH2CH2CO and 1 × CH2CO), 1.97 (1H, dt, J 11.5 and 2.6, 1 ×
CH2CO), 1.92–1.86 (1H, m, 1 × COCH2CH2), 1.80–1.27 (7H,
m, 1 × COCH2CH2, NCH2CH2, NCH2CH2CH2 and NCH2-
CH2CH2CH2); δC (67.8 MHz, CDCl3) 208.1 (CO), 135.5 (CH),
116.3 (CH2), 71.9 (CH), 60.5 (CH), 52.5 (CH2), 39.2 (CH2), 33.2
(CH2), 31.9 (CH2), 31.2 (CH2), 25.6 (CH2), 23.9 (CH2).
(3R*,8aS*)-3-Allylhexahydroindolizin-2(3H)-one 19b. Silica
gel (1.0 g) was added to a solution of the indolizidinone 19a
(23.9 mg, 0.133 mmol) in diethyl ether (10 cm3) and the mixture
was stirred at room temperature for 15 h. Further silica gel
(1.0 g) was added and the mixture was stirred at room temper-
ature for an additional 8 h period. The mixture was filtered and
the silica gel washed with further diethyl ether (3 × 15 cm3). The
combined solution and washings were concentrated in vacuo,
and the crude product purified by flash column chrom-
atography on silica gel (hexane–diethyl ether, 4 : 1) to give the
indolizidinone 19b (17.1 mg, 72%) as a colourless liquid.
(2R,3S,8S)-3-Allylhexahydropyrrolizidin-2-ol 22. Sodium
borohydride (8 mg, 0.2 mmol) was added to a solution of the
indolizidinone 18a (50 mg, 0.30 mmol) in methanol (2 cm3) and
the mixture was stirred for 4 h at room temperature. The solvent
was removed in vacuo and the residue washed with ethyl acetate.
The organic washings were filtered, concentrated in vacuo and
the residue washed with several portions of hexane to give the
alcohol 22 (45 mg, 89%) as a white solid; mp 61–62 ЊC [α]2D8 Ϫ1.7
(c 0.49, CHCl3); νmax(CHCl3)/cmϪ1 3619, 2962, 2871, 1639,
1000, 915; δH (500 MHz, CDCl3) 6.02–5.94 (1H, dddd, J 17.1,
10.1, 7.3 and 7.3, CH᎐CH ), 5.22 (1H, d, J 17.1, trans CH᎐
᎐
᎐
2
CH ), 5.12 (1H, d, J 10.1, cis CH᎐CH ), 4.14–4.04 (1H, m,
᎐
2
2
(5R,9S)-5-Allylhexahydroindolizin-6(5H)-one 20b. Accord-
ing to the general procedure, a solution of the α-diazo ketone 14
(0.10 g, 0.48 mmol) in dry benzene (50 cm3) was added to a
solution of Cu(acac)2 (2.5 mg, 0.0096 mmol) in dry benzene
(10 cm3) at reflux, over a period of 30 min. The resulting sol-
ution was stirred at reflux for a further 15 min. Purification by
flash column chromatography on silica gel (hexane–diethyl
ether, 2 : 1) gave the indolizidinone 20b (57 mg, 66%) as a colour-
less liquid; [α]2D4 Ϫ1.2 (c 0.98, CHCl3); νmax(film)/cmϪ1 2943,
2880, 2797, 2739, 1716, 1640, 995, 913; δH (500 MHz, CDCl3)
CHOH), 3.56–3.45 (1H, m, 1 × NCH2), 3.02 (1H, ddd, J 12.0,
6.0 and 4.5, 1 × NCH ), 2.73–2.68 (1H, m, 1 × CH CH᎐CH ),
᎐
2
2
2
2.54 (m, 1H, 1 × CH CH᎐CH ), 2.42–2.33 (3H, m, NCHCH ,
᎐
2
2
2
NCHCHOH and 1 × CH2CHOH), 2.02–1.76 (4H, m, 1 ×
CH2CHOH, NCH2CH2CH2 and OH), 1.59–1.47 (2H, m,
NCH2CH2); δC (67.8 MHz, CDCl3) 136.3 (CH), 116.9 (CH2),
77.8 (CH), 71.9 (CH), 61.1 (CH), 54.7 (CH2), 40.3 (CH2), 39.3
(CH2), 33.1 (CH2), 25.9 (CH2); m/z (EI) 167.1312 (Mϩ.
C10H17NO requires 167.1310), 167 (Mϩ, 0.2%), 126 (100)
(Found C, 71.7; H, 10.35; N, 8.4. C10H17NO requires C, 71.8;
H, 10.2; N, 8.4%).
5.93–5.84 (1H, m, CH᎐CH ), 5.12 (1H, br d, J 17.2, trans CH᎐
᎐
᎐
2
CH ), 5.04 (1H, br d, J 10.1, cis, CH᎐CH ), 3.29–3.23 (1H, m,
᎐
2
2
NCHCO), 2.83–2.78 (1H, m, NCHCH2CH2), 2.65–2.59 (1H,
m, 1 × NCH ), 2.57–2.46 (3H, m, 1 × NCH and CH CH᎐
Crystal structure determination of alcohol 22.‡ Crystal data.
C10H17NO, M = 167.25, monoclinic, a = 8.536(2), b = 11.150(3),
c = 10.547(2) Å, β = 105.40(2)Њ, U = 967.8(4) Å3, T = 150(2) K,
space group P21/c (No. 14), Z = 4, Dc = 1.148 g cmϪ3, µ(Mo-
Kα) = 0.073 mmϪ1, 1702 unique reflections (Rint = 0.092) col-
lected and used in all calculations. Final R1 [1258 F > 4σ(F)] =
0.0570 and wR(all F 2) was 0.141.
᎐
2
2
2
CH2), 2.40–2.31 (1H, m, 1 × CH2CO), 2.21–2.07 (2H, m,
1 × CH2CO and 1 × NCH2CH2CH2), 2.03–1.80 (3H, m, 1 ×
NCH2CH2CH2 and CH2CH2CO), 1.75–1.66 (1H, m, 1 ×
NCH2CH2), 1.56–1.47 (1H, m, 1 × NCH2CH2); δC (67.8 MHz,
CDCl3) 207.5 (CO), 135.5 (CH), 116.5 (CH2), 72.2 (CH), 62.9
3334
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337

View Article Online
General procedure for reduction of cyclisation products with
L-Selectride®
reduced using L-Selectride® (0.70 cm3 of a 1.0 M solution in
tetrahydrofuran, 0.70 mmol) at Ϫ78 ЊC for 1 h. Purification
gave the alcohol (32 mg, 70%) as a colourless solid; mp 62–
64 ЊC; νmax(CHCl3)/cmϪ1 3616, 2933, 2857, 1636, 997, 908; δH
(400 MHz, CDCl3) 5.92–5.81 (1H, dddd, J 17.1, 10.1, 7.1
L-Selectride® was added dropwise to a solution of the ketone
in dry tetrahydrofuran at Ϫ78 ЊC over a period of 2 min. The
resulting solution was stirred at Ϫ78 ЊC and the solvent was
then removed in vacuo. The residue was stirred at room
temperature with a saturated aqueous solution of sodium
bicarbonate (5 cm3) for 3 h and the mixture was then extracted
with ethyl acetate (4 × 10 cm3). The combined organic extracts
were dried over anhydrous potassium carbonate and the solvent
removed in vacuo. The residue was purified by flash column
chromatography on silica gel (diethyl ether–methanol, 10 : 1) to
give the alcohol.
and 7.1, CH᎐CH ), 5.04–4.99 (1H, m, trans CH᎐CH ), 4.93–
᎐
᎐
2
2
4.90 (1H, m, cis CH᎐CH ), 3.89–3.84 (1H, m, CHOH), 2.95–
᎐
2
2.92 (1H, q, J 5.1, 1 × NCH2), 2.63–2.60 (1H, m, 1 × NCH2),
2.50 (1H, ddd, J 11.8, 11.8 and 3.0, 1 × CH CH᎐CH ), 2.35–
᎐
2
2
2.15 (3H, m, 1 × CH CH᎐CH , NCHCHOH, NCHCH CH ),
᎐
2
2
2
2
1.80 (1H, s, OH), 1.80–1.39 (6H, m, CH2CHOH, CH2CH2-
CHOH, NCH2CH2CH2CH2), 1.29–1.05 (4H, m, NCH2CH2,
NCH2CH2CH2); δC (67.8 MHz, CDCl3) 140.2 (CH), 115.7
(CH2), 71.6 (CH), 65.4 (CH), 53.4 (CH), 52.9 (CH2), 33.2
(CH2), 32.1 (CH2), 28.4 (CH2), 26.3 (CH2), 25.7 (CH2), 24.9
(CH2); m/z (FAB) 196.1705 (Mϩ ϩ H. C12H22NO requires
196.1701), 196 (Mϩ ϩ H, 18%), 154 (97).
(2R*,3R*,8aS*)-3-Allyloctahydroindolizin-2-ol 23. Following
the general procedure, the ketone 19b (51.1 mg, 0.285 mmol)
was reduced using L-Selectride® (0.85 cm3 of a 1 M solution in
dry tetrahydrofuran, 0.85 mmol) at Ϫ78 ЊC for 20 min. Purifi-
cation gave the alcohol 23 (47.1 mg, 91%) as a colourless solid;
mp 61–63 ЊC; νmax(CHCl3)/cm1 3180, 2933, 2851, 2800, 1636,
1000, 918; δH (250 MHz, CDCl3) 5.92 (1H, m, dddd, J 17.2,
1-Diazo-4-(2-vinylaziridin-1-yl)butan-2-one 25. A solution of
4-bromo-1-diazobutan-2-one1,12 (0.51 g, 2.9 mmol), 2-vinyl-
aziridine11 (0.20 g, 2.9 mmol) and triethylamine (0.44 g,
3.2 mmol) in ethyl acetate (30 cm3) was heated at 60 ЊC for 12 h.
The mixture was cooled and washed with water (2 × 10 cm3),
and the aqueous phase was then extracted with ethyl acetate
(2 × 15 cm3). The combined organic extracts were dried over
anhydrous potassium carbonate and concentrated in vacuo. The
residue was purified by flash column chromatography on silica
gel (dichloromethane–methanol 95 : 5) to give the α-diazo
ketone 25 (0.25 g, 53%) as a yellow liquid; νmax(film)/cmϪ1 3084,
2981, 2845, 2104, 1740, 1637, 990, 915; δH (250 MHz, CDCl3)
10.2, 6.9 and 6.6, CH᎐CH ), 5.17 (1H, dq, J 17.2 and 1.7, trans
᎐
2
CH᎐CH ), 5.11–5.04 (1H, m, cis CH᎐CH ), 4.12 (1H, ddd, J
᎐
᎐
2
2
7.8, 4.8 and 3.3, CHOH), 3.17–3.07 (1H, m, 1 × NCH2), 2.80
(1H, br s, OH), 2.40–2.29 (3H, m, 1 × NCHCH2CHOH and
CH CH᎐CH ), 2.03 (1H, dt, J 5.1 and 7.2, NCHCHOH), 1.84–
᎐
2
2
1.50 (6H, m, 1 × NCHCH2, 1 × NCH2, 1 × NCH2CH2CH2, 1 ×
NCH2CH2CH2CH2 and NCH2CH2), 1.38–1.18 (3H, m, 1 ×
NCHCH2CHOH 1 × NCHCH2CH2 and 1 × NCH2CH2CH2);
δC (67.8 MHz, CDCl3) 136.5 (CH), 116.8 (CH2), 70.9 (CH), 70.1
(CH), 64.4 (CH), 51.6 (CH2), 41.2 (CH2), 31.7 (CH2), 31.6
(CH2), 25.6 (CH2), 25.0 (CH2); m/z (EI) 181.1491 (Mϩ.
C11H19NO requires 181.1467).
5.51 (1H, ddd, J 17.2, 10.1 and 7.6, CH᎐CH ), 5.40 (1H, br s,
᎐
2
CHN ), 5.29 (1H, dd, J 17.2 and 1.6, trans CH᎐CH ), 5.10 (1H,
᎐
2
2
dd, J 10.1 and 1.6, cis CH᎐CH ), 2.73–2.50 (4H, m, CH CO
᎐
2
2
and CH CH CO), 1.90 (1H, ddd, J 7.6, 6.6 and 3.5, CHCH᎐
᎐
2
2
CH ), 1.76 (1H, d, J 3.5, 1 × CH CHCH᎐CH ), 1.53 (1H, d,
᎐
2
2
2
Crystal structure determination of alcohol 23.‡ Crystal data.
C11H19NO, M = 181.27, orthorhombic, a = 18.996(2), b =
8.413(3), c = 6.982(2) Å, U = 1115.8(5) Å3, T = 293(2) K, space
group Pca21(No. 29), Z = 4, Dc = 1.079 g cmϪ3, µ(Cu-Kα) =
0.530 mmϪ1, 637 unique reflections (Rint = 0.064) collected
and used in all calculations. Final R1 [543 F > 4σ(F)] = 0.0541
and wR(all F 2) was 0.141.
J 6.6, 1 × CH CHCH᎐CH ); δ (67.8 MHz, CDCl ) 193.5 (CO),
᎐
2
2
C
3
138.0 (CH), 116.1 (CH2), 56.2 (CH2), 55.3 (CH), 41.3, (CH),
40.9 (CH2), 35.2 (CH2); m/z (EI) 137 (Mϩ Ϫ N2, 5%), 69 (5), 41
(100).
2,3,8,8a-Tetrahydro-5H-indolizin-1-one 27. Ammonium ylide
formation and rearrangement. According to the general pro-
cedure, a solution of the α-diazo ketone 25 (50 mg, 0.30 mmol)
in dry benzene (25 cm3) was added to a solution of Cu(acac)2
(1.6 mg, 0.006 mmol) in dry benzene (5 cm3) at reflux, over a
period of 20 min. The resulting solution was stirred at reflux for
a further 15 min. Purification by flash column chromatography
on silica gel (diethyl ether–hexane, 2 : 1) gave the unstable
indolizidinone 27 (10 mg, 26%) as a colourless liquid.
(5R,6R,9S)-5-Allyloctahydroindolizin-6-ol 24. Following the
general procedure, the ketone 20b (40 mg, 0.22 mmol) was
reduced using L-Selectride® (0.67 cm3 of a 1.0 M solution in
tetrahydrofuran, 6.7 mmol) at Ϫ78 ЊC for 1 h. Purification gave
the alcohol 24 (28 mg, 69%) as a colourless solid; mp 62–64 ЊC;
νmax(CHCl3)/cmϪ1 3514, 2938, 2859, 2795, 1640, 996, 914; δH
(400 MHz, CDCl3) 5.82 (1H, dddd, J 17.2, 10.0, 7.2 and 7.2,
Ring-closing metathesis. The molybdenum complex 29 (83 mg,
1.1 mmol) was added to a solution of the diene 281 (0.10 g,
0.61 mmol) in degassed pentane (35 cm3) under an atmosphere
of argon and the mixture was stirred at room temperature for
4 h. The solvent was removed in vacuo and the residue purified
by flash column chromatography on silica gel (diethyl ether–
hexane, 2 : 1) to give the unstable indolizidinone 27 (46 mg, 55%)
as a colourless liquid; νmax(CHCl3)/cmϪ1 2798, 1750, 1000; δH
CH᎐CH ), 5.16–5.10 (1H, m, trans CH᎐CH ), 5.08–5.04 (1H,
᎐
᎐
2
2
m, cis CH᎐CH ), 3.73 (1H, br d, J 7.7, CHOH), 3.12 (1H, dt,
᎐
2
J 8.6 and 2.2, NCHCHOH), 2.45 (1H, d, J 9.0, NCHCH2CH2),
2.36–2.33 (2H, m, NCH ), 2.11–2.03 (2H, m, CH CH᎐CH ),
᎐
2
2
2
1.96–1.60 (6H, m, NCH2CH2, NCH2CH2CH2, CH2CHOH),
1.54–1.34 (3H, m, CH2CH2CHOH and OH); δC (67.8 MHz,
CDCl3) 135.5 (CH), 117.1 (CH2), 67.0 (CH), 65.6 (CH), 64.8
(CH), 51.1 (CH2), 35.2 (CH2), 31.8 (CH2), 30.7 (CH2), 25.7
(CH2), 20.6 (CH2); m/z (FAB) 182.1559 (Mϩ ϩ H. C11H20NO
requires 182.1545), 182 (Mϩ ϩ H, 15%), 164 (2), 140 (3).
(400 MHz, CDCl ) 5.82–5.72 (2H, m, CH᎐CH), 3.57–3.50 (1H,
᎐
3
m, 1 × NCH CH᎐CH), 3.48–3.44 (1H, m, NCHCO), 3.05–2.98
᎐
2
(1H, m, 1 × NCH CH᎐CH), 2.58–2.33 (5H, m, NCH CH CO,
᎐
2
2
2
CH᎐CHCH CH and 1 × CH CO), 2.20–2.09 (1H, m, 1 ×
Crystal structure determination of alcohol 24.‡ Crystal data.
C11H19NO, M = 181.27, monoclinic, a = 7.554(4), b = 7.161(3),
c = 19.49(2) Å, β = 100.12(8)Њ, U = 1037.9(13) Å3, T = 150(2) K,
space group P21/n (No. 14), Z = 4, Dc = 1.160 g cmϪ3, µ(Mo-
Kα) = 0.073 mmϪ1, 1355 reflections collected and used in all
calculations. Final R1 [850 F > 4σ(F)] = 0.0750 and wR(all F 2)
was 0.199.
᎐
2
2
CH2CO); δC (67.8 MHz, CDCl3) 214.4 (CO), 125.3 (CH), 124.4
(CH), 64.8 (CH), 53.0 (CH2), 50.2 (CH2), 36.1 (CH2), 26.5
(CH2).
(S)-(؊)-1-Diazo-4-(2-vinylpyrrolidin-1-yl)butan-2-one 31. The
N-protected vinylpyrrolidine 3016 (637 mg, 3.76 mmol) was
added to a mixture of potassium hydroxide (6.46 g, 115 mmol)
and hydrazine monohydrate (0.91 cm3, 19 mmol) in ethylene
glycol (9 cm3). The mixture was heated at reflux for 3 h 10 min,
4-Allyloctahydroquinolizin-3-ol. Following the general pro-
cedure, the ketone 21 (major isomer) (45 mg, 0.23 mmol) was
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337
3335

View Article Online
then cooled and extracted with ethyl acetate (4 × 15 cm3). The
ethyl acetate extracts were dried over anhydrous potassium
carbonate, and the solution added to a solution of 4-bromo-1-
diazobutan-2-one (803 mg, 4.54 mmol)1,12 in dry ethyl acetate
(5 cm3). Triethylamine (0.783 cm3, 5.62 mmol) was added to the
reaction, and the mixture heated at 60 ЊC for 14 h. After this
time, the reaction was washed with a saturated solution of
sodium bicarbonate (50 cm3), and the aqueous phase extracted
with ethyl acetate (3 × 50 cm3). The combined organic extracts
were dried over anhydrous potassium carbonate and the solvent
removed in vacuo. The residue was purified by flash column
chromatography on silica gel (1% triethylamine in diethyl
ether–hexane, 3 : 1) to give the α-diazo ketone 31 (399 mg, 55%)
as a green liquid; [α]2D7 = Ϫ48.5 (c 0.782, CHCl3); νmax(film)/cmϪ1
3079, 2966, 2876, 2796, 2104, 1641, 995, 920; δH (250 MHz,
(CH), 128.5 (CH), 75.7 (CH), 70.7 (CH), 55.9 (CH2), 52.4
(CH2), 33.5 (CH2), 28.1 (CH2), 27.6 (CH2), 24.0 (CH2); m/z (EI)
167.1306 (Mϩ. C10H17NO requires 167.1310).
Preparation of the Mosher’s ester 35. Triethylamine (0.45 µl,
0.32 mmol) was added dropwise to a solution of the amino
alcohol 34 (17.8 mg, 0.106 mmol) and 4-(N,N-dimethyl-
amino)pyridine (0.8 mg, 0.007 mmol) in dry dichloromethane
(3 cm3) at 0 ЊC. The mixture was stirred at 0 ЊC for 5 min and
then
a solution of (R)-(Ϫ)-α-methoxy-α-(trifluoromethyl)-
phenylacetic acid chloride (67.4 mg, 0.267 mmol) in dry dichloro-
methane (2 cm3) was added dropwise. The resulting solution
was stirred at 0 ЊC for 1 h and at room temperature for 53 h. The
reaction mixture was washed with saturated aqueous sodium
bicarbonate (5 cm3) and the aqueous phase extracted with
dichloromethane (2 × 5 cm3). The combined organic extracts
were dried over anhydrous potassium carbonate and the solvent
removed in vacuo. The residue was then analysed by 19F NMR
in CDCl3 referenced to CFCl3.
CDCl ) 5.67 (1H, ddd, J 17.1, 10.0 and 8.4, CH᎐CH ), 5.39
᎐
3
2
(1H, br s, CHN ), 5.20–5.06 (2H, m, CH᎐CH ), 3.18–3.00 (2H,
᎐
2
2
m, CHCH᎐CH and 1 × NCH CH CH ), 2.70 (1H, ddd, J 8.3,
᎐
2
2
2
2
8.0 and 7.9, 1 × NCH2CH2CO), 2.51–2.33 (3H, m, CH2CO and
1 × NCH2CH2CH2), 2.14 (1H, dt, J 8.7 and 8.6, 1 × NCH2-
CH2CO), 2.01–1.52 (4H, m, NCH2CH2CH2 and NCH2-
CH2CH2); δC (67.8 MHz, CDCl3) 193.8 (CO), 140.4 (CH), 116.6
(CH2), 68.8 (CH), 54.5 (CH), 53.3 (CH2), 49.2 (CH2), 40.1
(CH2), 31.4 (CH2), 22.0 (CH2); m/z (EI) 165.1147 (Mϩ Ϫ N2.
C10H15NO requires 165.1154).
Acknowledgements
We thank the EPSRC for providing studentship support (to
P. B. H. and M. G. D.), Dr R. Wheelhouse (University of
Nottingham) for performing 19F NMR spectroscopy, and Dr
J. Bordner (Pfizer, Groton) for assistance with the structure
determination of compound 23. We thank Professor F. G. West
(University of Utah) and Professor M. C. McMills (Ohio
University) for helpful discussions.
(8R)-(؉)-9-Oxo-1-azabicyclo[6.3.0]undec-5-ene 33. Accord-
ing to the general procedure, a solution of the α-diazo ketone 31
(151 mg, 0.783 mmol) in dry benzene (40 cm3) was added to a
solution of Cu(acac)2 (4.1 mg, 0.016 mmol) in dry benzene (8
cm3) at reflux, over a period of 1 h. The resulting solution was
stirred at reflux for a further 20 min. Purification by flash col-
umn chromatography on silica gel (hexane–diethyl ether, 3 : 1)
gave the bicyclic amine 33 (72.4 mg, 56%) as a colourless liquid;
[α]3D1 = ϩ2.58 (c 0.683, CHCl3); νmax(CHCl3)/cmϪ1 2930, 2850,
2800, 1750, 1600; δH (250 MHz, CDCl3) 5.78–5.64 (2H, m,
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14 G. C. Fu, S. T. Nguyen and R. H. Grubbs, J. Am. Chem. Soc., 1993,
115, 9856.
CHCH CH᎐CH and CHCH CH᎐CH), 3.34–3.27 (1H, m, 1 ×
᎐
᎐
2
2
CH2CH2CO), 2.82 (1H, ddd, J 14.1, 5.5 and 2.2, 1 × NCH2-
CH2CH2), 2.75–2.64 (1H, m, 1 × CH2CH2CO), 2.62–2.32 (6H,
m, NCHCO, CH2CO, 1 × NCHCH2, 1 × NCH2CH2CH2 and
1 × NCH2CH2CH2), 2.27–2.16 (1H, m, 1 × NCHCH2), 2.08–
1.97 (1H, m, 1 × NCH2CH2CH2), 1.91–1.75 (1H, m, 1 ×
NCH2CH2CH2), 1.47–1.32 (1H, m, 1 × NCH2CH2CH2); δC
(67.8 MHz, CDCl3) 215.7 (CO), 131.8 (CH), 127.3 (CH), 72.6
(CH), 53.8 (CH2), 52.1 (CH2), 37.4 (CH2), 29.0 (CH2), 28.5
(CH2), 24.2 (CH2); m/z (EI) 165.1154 (Mϩ. C10H15NO requires
165.1154).
(8R,9R)-9-Hydroxy-1-azabicyclo[6.3.0]undec-5-ene 34. L-
Selectride® (0.56 cm3 of a 1 M solution in tetrahydrofuran,
0.56 mmol) was added dropwise to a solution of the ketone 33
(30.8 mg, 0.186 mmol) in dry tetrahydrofuran (5 cm3) at 0 ЊC.
The resulting solution was stirred at 0 ЊC for 1 h and the solvent
was then removed in vacuo. The residue was stirred at room
temperature with a saturated aqueous solution of sodium
bicarbonate (5 cm3) for 20 h, and then extracted with ethyl
acetate (4 × 6 cm3). The combined organic extracts were dried
over anhydrous potassium carbonate and the solvent removed
in vacuo. The residue was purified by flash column chrom-
atography on silica gel (diethyl ether–methanol, 4 : 1) to give the
alcohol 34 (23.4 mg, 75%) as a colourless solid; mp 48–50 ЊC;
[α]2D6 = Ϫ95.2 (c 0.178, CHC13); νmax(CHCl3)/cmϪ1 3336, 2927,
2851, 1602, 1002, 908; δH (250 MHz, CDCl3) 5.82–5.59 (2H, m,
CHCH CH᎐CH and CHCH CH᎐CH), 4.09 (1H, m, ddd, J 7.2,
15 T. Sato, K. Tsujimoto, K. Matsubayashi, H. Ishibashi and M. Ikeda,
Chem. Pharm. Bull., 1992, 40, 2308.
16 E. Vedejs, J. P. Hagen, B. L. Roach and K. L. Spear, J. Org. Chem.,
1978, 43, 1185.
17 (a) R. K. Hill and T.-H. Chan, J. Am. Chem. Soc., 1966, 88, 866; (b)
R. K. Hill, Asymmetric Synthesis, J. D. Morrison, ed., Academic
Press, Orlando, 1984, vol. 3, ch. 8, 503; (c) K. W. Glaeske and F. G.
West, Org. Lett., 1999, 1, 31.
᎐
᎐
2
2
4.7 and 2.5, CHOH), 3.17 (1H, td, J 9.0 and 2.4, 1 × NCH2-
CH2CHOH), 2.76–2.67 (2H, m, NCH2CH2CH2), 2.54–1.96
(8H, m, NCHCHOH, 1 × NCH2CH2CHOH, NCHCH2,
NCH2CH2CH2, 1 × NCH2CH2CHOH and OH), 1.87–1.62
(2H, m, 1 × NCH2CH2CH2 and 1 × NCH2CH2CHOH), 1.45–
1.30 (1H, m, 1 × NCH2CH2CH2); δC (67.8 MHz, CDCl3) 130.1
3336
J. Chem. Soc., Perkin Trans. 1, 2001, 3325–3337

View Article Online
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