Applications of the amino-cope rearrangement: Synthesis of tetrahydropyran, δ-lactone and piperidine targets

Article abstract of DOI:10.1039/b416179c

We report a novel approach to some chiral tetrahydropyran and δ-lactone targets that utilizes the asymmetric amino-Cope rearrangement as a key synthetic step. Products of amino-Cope rearrangement chemistry have also been applied to access piperidine targe

Full text of DOI:10.1039/b416179c

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A R T I C L E
Applications of the amino-Cope rearrangement: synthesis of
tetrahydropyran, d-lactone and piperidine targets
Steven M. Allin,*a Munira Essat,a Catarina Horro Pita,a Robert D. Baird,a Vickie McKee,a
Mark Elsegood,a Mark Edgar,a David M. Andrews,b Pritom Shah†b and Ian Aspinallc
a Department of Chemistry, Loughborough University, Loughborough, Leicestershire,
UK LE11 3TU. E-mail: s.m.allin@lboro.ac.uk
b GlaxoSmithKline, Gunnels Wood Road, Stevenage, UK SG1 2NY
c Syngenta, Jealott’s Hill Research Centre, Bracknell, UK RG42 6EY
Received 21st October 2004, Accepted 24th December 2004
First published as an Advance Article on the web 26th January 2005
We report a novel approach to some chiral tetrahydropyran and d-lactone targets that utilizes the asymmetric amino-
Cope rearrangement as a key synthetic step. Products of amino-Cope rearrangement chemistry have also been
applied to access piperidine targets, further demonstrating the potential of the methodology.
achieved at a chiral centre created during the rearrangement of
Introduction
a diastereoisomerically pure substrate.3
Asymmetric synthetic routes to tetrahydropyran and lactone
Although the precise mechanism of the amino-Cope re-
sub-units are of considerable interest since these heterocyclic
arrangement remains a matter for debate,4 we have demon-
components are found in many biologically active molecules
strated that the asymmetric amino-Cope rearrangement can
and natural products. In this paper we wish to demonstrate
have significant advantages over the analogous oxy-Cope re-
the synthetic utility of the asymmetric anionic amino-Cope
arrangement in terms of asymmetric induction.5 For example
rearrangement, and highlight its potential for future application
the axial/equatorial preference of an oxy-anion substituent
in natural product synthesis. The novel route described in this
in the proposed chair-like transition state of the oxy-Cope
paper delivers functionalized disubstituted tetrahydropyrans
rearrangement can be low, leading to a rearrangement product
and lactones in high enantiomeric excess from readily available
with a correspondingly low e.e.6
precursors. The key step in our synthetic protocol is the intro-
The preparation of the 3-amino-1,5-diene substrate required
duction of asymmetry by our recently developed asymmetric
for the asymmetric amino-Cope rearrangement has been de-
anionic amino-Cope methodology. To further demonstrate the
potential of this chemistry we have achieved the synthesis of
tailed elsewhere.5 Substrate 1 was readily isolated in diastereoiso-
merically pure form by recrystallization, and the relative stere-
a simple piperidine target from a product of an amino-Cope
ochemistry has now been confirmed by single crystal X-ray
rearrangement.
analysis (Fig. 1).
Discussion
There is growing interest in asymmetric variants of sigmatropic
rearrangements,1 and we are continuing to develop the amino-
Cope rearrangement as a new synthetic protocol. Scheme 1
summarizes our ultimate goal: the one-pot asymmetric synthesis
of acyclic targets containing (up to) three contiguous chiral
centres via amino-Cope rearrangement (step 1) and subsequent
(tandem) enamine derivatization and hydrolysis (step 2).
Scheme 1 Synthetic potential of the amino-Cope rearrangement.
Fig. 1 Crystal structure of amino-diene 1.
Our group has demonstrated the key steps of this pro-
tocol, including a successful tandem amino-Cope rearrange-
ment/enamine derivatization reaction.2 More recently we have
established that an anionic variant of the amino-Cope rear-
rangement is possible, and that asymmetric induction can be
Amino-Cope rearrangement of 1 was carried out by treating
the substrate with 2.5 equivalents of n-BuLi at −78 ◦C in THF,
the reaction mixture was subsequently allowed to reach room
temperature, and then heated under reflux for 2 h before an
aqueous quench (Scheme 2). The target aldehyde 3 was not ob-
served in the crude product mixture by 1H NMR spectroscopy,
but rather as the oxazolidine 2 resulting, presumably, from ring-
closure of the intermediate enamine on work-up. Liberation
† Present address: AstraZeneca R & D, Alderley Park, Macclesfield,
Cheshire, UK, SK10 4TF.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 0 9 – 8 1 5
8 0 9
©

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Scheme 2 Asymmetric amino-Cope rearrangement.
and purification of aldehyde 3 was effected simply by column
chromatography of the crude oxazolidine on silica gel.
The enantiomeric excess and absolute configuration of alde-
hyde 3 was determined by conversion to the corresponding di-
astereoisomeric oxazolidine derived from 1R, 2S-(−)-ephedrine,
as described by Agami.7 The absolute stereochemistry induced
on rearrangement of the 3-amino-1,5-diene substrates used in
all of our studies to date has been rationalized by invoking a
chair-like transition state model, 4, having the amine component
occupying a pseudo-equatorial orientation (Fig. 2), although
a model such as this is surely an over-simplification. Indeed,
as mentioned above, there is currently some debate over the
mechanism of the rearrangement, with certain 4-substituted 3-
amino-1,5-dienes having been shown4 to rearrange by a stepwise
mechanism. Nevertheless, model 4 provides a useful “rule of
thumb” in our studies.
Scheme 3 Electrophile-mediated cyclizations to access tetrahydropy-
ran targets.
Analysis of the separated diastereoisomers by chiral HPLC11
showed that THP 7a had an e.e. of 92%, again in good agreement
with the e.e. of the starting alcohol 5. The chromatogram
of THP 7b was not fully resolved, although the HPLC trace
clearly showed that the compound was highly enantiomerically
enriched.
One final class of tetrahydropyran was prepared through
epoxidation of the double bond followed by treatment with
catalytic CSA. The intermediate epoxides (a 2 : 1 mixture of
diastereoisomers 8a and 8b) were not separated, but directly
treated with CSA in dichloromethane at 0 ◦C to yield the target
THP 9 as a 2 : 1 mixture of diastereoisomers. We were able
to separate the diastereoisomers to yield 28% of the major
diastereoisomer 9a and 12% of 9b, and confirm the relative
stereochemistries by comparison with the 1H NMR spectra
of the iodotetrahydropyrans.10 In this case we were unable to
confirm the e.e. of either diastereoisomer by NMR or HPLC
techniques.
Based on the success of the approach described above, we then
investigated a similar electrophile-induced cyclization route to
access the target d-lactones, as described by others.12 We were
able to access the corresponding carboxylic acid derivative 10
from aldehyde 3 in 70% yield by sodium chlorite oxidation. We
then performed an iodine-induced cyclization at low tempera-
ture (I2, NaHCO3, THF, −78 ◦C) and isolated the target iodo-
lactone 11 in 70% overall yield (Scheme 4). 1H NMR analysis of
the crude reaction mixture revealed that the cyclization reaction
gave an excellent level of diastereoselectivity of 13 : 1, which was
confirmed by single crystal X-ray analysis of the isolated major
isomer to be in favour of the cis-diastereoisomer, 11a (Fig. 3).
The major diastereoisomer 11a, isolated by column chro-
matography, was shown to have an e.e. of 86% by chiral HPLC13
confirming minimal loss of stereochemical integrity during
derivatization and subsequent cyclization of the aldehyde.
Performing this cyclization under a range of alternative reac-
tion conditions gave variation in both the cis : trans isomer ratio
and the product yield, although all other conditions investigated
gave inferior diastereoisomeric ratios to the low temperature
cyclization described above (−78 ◦C, kinetic conditions). For
example, raising the reaction temperature in THF to room
temperature gave a 6 : 1 ratio in favour of the cis-diastereoisomer,
11a, with a slightly improved overall yield of 75%. Alternatively,
Fig. 2 Predictive model for amino-Cope rearrangement.
One useful method for the formation of oxygen heterocycles
involves the electrophile-induced cyclization of an unsaturated
alcohol precursor.8 We were able to access the corresponding
alcohol 5 from aldehyde 3 in 99% yield by sodium borohydride
reduction. Analysis of 5 by chiral HPLC9 showed essentially the
same level of e.e. for the alcohol product (92%) as was observed
for the aldehyde precursor by NMR determination.
With 5 in hand we performed an iodine-induced cyclization at
room temperature (I2, NaHCO3, MeCN) and achieved an almost
quantitative conversion to the target iodo-THP 6 (Scheme 3). 1H
NMR analysis of the crude reaction mixture revealed that the
cyclization had proceeded with a diastereoselectivity of 4 : 1 in
favour of the cis-diastereoisomer 6a.10
The major diastereoisomer 6a was isolated by column chro-
matography in 60% yield and further analysis by chiral HPLC11
showed this compound to have an e.e. of 92%, confirming no
loss of stereochemical integrity during cyclization.
After our success with iodine as the electrophile we chose
to investigate a variant of this cyclization methodology. The
phenylselenyl group is a useful handle that can allow further
molecular elaboration, and by applying a suitable selenium
electrophile, N-(phenylseleno)phthalimide (NPSP, 1.7 eq.), in
the presence of pyridinium p-toluenesulfonate (PPTS, 0.3 eq.) in
dichloromethane at −78 ◦C we were able to achieve cyclization
to the corresponding tetrahydropyran products. In this case,
1
however, a 1 : 1 diastereoisomeric ratio was observed by H
NMR analysis of the crude reaction mixture. We were able to
separate each component by column chromatography to yield
39% of 7a and 36% of 7b.
A significant reduction in the level of product diastereos-
electivity is observed on moving from the I+ to the PhSe+
electrophile; this has been noted previously by Greeves for
similar substrates and is referred to in more detail below.8c
8 1 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 0 9 – 8 1 5

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Scheme 5 Dehalogenation of lactone 11a.
Having achieved the asymmetric synthesis of tetrahydropyran
and lactone products we turned our attention to piperidine tar-
gets, and so were required to achieve a successful cyclization of
an aminated derivative of aldehyde 3. The starting point for this
study was the model secondary amine derivative 14, prepared in
73% yield by reductive amination of 3 with benzylamine. Despite
repeated attempts to access the corresponding piperidine targets
through application of known electrophile-induced cyclization
methodologies (Scheme 6), we were unable to induce formation
of the target heterocycle.
Scheme 4 Electrophile-mediated cyclizations to access lactone targets.
Scheme
6 Attempted electrophile-induced cyclizations to access
piperidines: E+ = (i) I2;16 (ii) Hg(OCOCF3)2;17 (iii) PdCl2;18 (iv) PhSeCl
Fig. 3 Crystal structure of 11a
and PhSeBr.19
use of acetonitrile as solvent at 0◦C gave a 6 : 1 ratio (cis : trans) in
70% overall yield, and at room temperature gave 4 : 1 (cis : trans)
in 73% overall yield.
Although the precise reason for the failure to observe cycliza-
tion of 14 is not known, it should be noted that in most cases the
substrates reported in literature were more heavily substituted
than 14, and consequently the resulting conformational effects
may perhaps lead to a more favourable arrangement of the
carbon backbone to allow for cyclization with other substrate
types.
Finally we decided to employ the oxidative cleavage-
cyclization route, described by Xue20 and highlighted in
Scheme 7, in order to access the corresponding 4-phenylpiper-
idine derivative 18.
Selective formation of cis-3,5-disubstituted lactones via
iodolactonization has been noted by others,14 and is consistent
with a chair-like transition state with attack onto a pseudo-
equatorial iodonium species during cyclization, as is also
suggested by our own X-ray crystal structure of 11a (Fig. 3).
By applying a selenium electrophile, phenylselenium chloride
(1.1 eq.), in the presence of pyridine (1.1 eq.) in dichloromethane
◦
at −78 C we were able to achieve cyclization of 10 to deliver
the corresponding d-lactone product 12 in 71% overall yield
(Scheme 4). In this case a 3 : 1 diastereoisomeric ratio, again
in favour of the cis-isomer 12a, was observed by 1H NMR
analysis of the crude reaction mixture.15 We were unable to
separate the diastereoisomeric components of this mixture by
column chromatography, and so were unable to determine
the e.e. of the major isomer. Based on the iodolactonization
result described above for the carboxylic acid, and also our
results detailing the synthesis of the enantiomerically enriched
tetrahydropyrans using a selenium-induced cyclization route, we
would not expect to observe any significant loss of e.e. during
this current derivatization procedure.
In the case of the seleno-lactonization procedure, variation of
the reaction conditions (kinetic vs. thermodynamic) had little
effect on the diastereoselectivity of the cyclization. For example,
use of dichloromethane solvent at room temperature gave a 2 : 1
ratio (cis : trans; 12a : 12b) in 58% yield. Use of THF solvent
at −78 ◦C gave 2 : 1 (cis : trans) in 67% yield, and at room
temperature only a 1.5 : 1 ratio in 55% yield.
Again a significant reduction in the level of product diastere-
oselectivity is observed on moving from the I+ to the PhSe+
electrophile. We believe that this may result from a reduced
preference by the PhSe+ electrophile to adopt the equatorial
orientation during cyclization via a chair-like transition state
that is clearly favoured by I+. Indeed, the work of Greeves shows
that PhSe+ favours an axial orientation during cyclization of d,e-
unsaturated hexenols to yield the corresponding tetrahydropy-
Scheme 7 Successful synthesis of a piperidine target. Reagents and con-
ditions: (i) N-(benzyloxycarbonyloxy)succinimide, NMM, DCM, RT,
18 h (79%); (ii) O3, PPh3, DCM, RT, 18 h, (85%); (iii) H2 (50 psi), Pd/C,
TFA, MeOH, RT, 18 h; (iv) N-(benzyloxycarbonyloxy)succinimide,
NMM, DCM, RT, 18 h (29%).
As noted in Scheme 7, protection of the secondary amine as its
Cbz-analogue, 15, was followed by ozonolysis to yield the amino-
aldehyde, 16. One-pot reductive removal of both benzyl and
Cbz-protecting groups induced in situ cyclization of the primary
amine product to generate the 4-phenyl piperidine derivative 17
that was initially isolated as its TFA salt but then used as crude
8c
ran products.
We were able to further manipulate lactone 11a by removing
the iodo-substituent using a radical induced method (Scheme 5)
to generate the methyl-substituted derivative, 13.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 0 9 – 8 1 5
8 1 1

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to access the Cbz-protected piperidine target 18, that was easier
to handle. Although this method generates an achiral piperidine
in this case (due to the centre of symmetry in 18), the importance
of having, eventually, discovered a suitable method to access the
important piperidine nucleus from simple products of amino-
Cope rearrangement should not be overlooked.
In summary, we have demonstrated the preparation of various
substituted tetrahydropyran, lactone and piperidine targets, with
high enantiomeric excess in the asymmetric series, representing
the first synthetic applications of the asymmetric amino-Cope
rearrangement.
(2R, 4S) and (2S, 4S)-2-(Iodomethyl)-4-phenyltetrahydro-
2H-pyran, 6a and 6b
A solution of alcohol 5 (0.08 g, 0.57 mmol) in acetonitrile
3
˚
(15 cm ) was stirred with 4 A MS and sodium hydrogencarbonate
(0.15 g, 1.8 mmol) at room temperature. Iodine (0.44 g,
1.7 mmol) was added in one portion and the mixture stirred
for 24 h before quenching with saturated aqueous sodium
thiosulfate solution (2 cm3). The acetonitrile was removed under
reduced pressure and the residue was partitioned between ethyl
acetate and water (40 cm3, 1 : 1). The organic layer was removed
and the aqueous portion extracted with a further 20 cm3 of ethyl
acetate. The combined organic layers were dried over anhydrous
sodium sulfate, filtered and the solvent removed under reduced
pressure to give a yellow oil which was shown to be a mixture of
diastereoisomers (4 : 1) by 1H NMR spectroscopy. Flash column
chromatography on silica gel, eluting with light petroleum
(bp range 40–60 ◦C)–ethyl acetate (10 : 1) gave the major
diastereoisomer 6a (0.08 g, 60%) as a colourless oil (the minor
diastereoisomer 6b was isolated using preparative TLC to
provide a 1H NMR reference thus enabling d.e. measurement).
6a: mmax (film)/cm−1 3060, 3026, 2934, 2828, 1602, 1494, 1452,
1378, 1254, 1193, 1125, 1084, 1029, 1012, 756 and 699; dH
(400 MHz; CDCl3) 1.39 (1 H, dt, J 12.3 and 11.1, C(3)HaxH),
1.77 (2 H, m, C(5)H2), 2.04 (1 H, m, C(3)HHeq), 2.82 (1 H, tt,
J 11.6 and 4.4, CHaxPh), 3.22 (1 H, dd, J 10.4 and 6.4, CHHI),
3.25 (1 H, dd, J 10.4 and 5.2, CHHI), 3.46 (1 H, m, C(2)Hax),
3.63 (1 H, m, CHaxHO), 4.19 (1 H, ddd, J 11.6, 4.4 and 1.8,
CHHeqO) and 7.21–7.34 (5 H, m, Ar-H); dC (100 MHz; CDCl3)
9.9 (CH2), 33.4 (CH2), 39.6 (CH2), 41.8 (CH), 68.9 (CH2), 77.4
(CH), 126.9 (CH), 127.1 (2 × CH), 129.1 (2 × CH) and 145.4
(q); m/z (EI) 302 (M+, 32%), 175 (33), 161 (100), 131 (28), 117
(23), 104 (25), 91 (43), 77 (12) and 43 (15). Found M+ 302.01672;
C12H15IO requires 302.01676.
Experimental
Where necessary, solvents were dried, distilled and stored over
˚
4 A molecular sieves prior to use. Reagent chemicals were
purchased from Lancaster Synthesis Ltd. and Aldrich Chemical
Co. Ltd, and were purified where necessary before use.
Flash-column chromatography was carried out using Merck
silica gel (70–230 Mesh ASTM). Analytical thin layer chro-
matography (TLC) was carried out using aluminium-backed
plates coated with 0.2 mm silica. Plates were visualised under
UV light (at 254 nm) or by staining with either potassium
permanganate solution or iodine. Yields quoted are for isolated,
purified products.
IR spectra were recorded in the range 4000–600 cm−1, using a
Perkin Elmer Paragon 100 FT-IR spectrometer as Nujol mulls
or as liquid films. 1H and 13C NMR spectra were recorded using
either a Bruker Avance 400 MHz Spectrometer or a Bruker
AC 250 MHz Spectrometer. NMR samples were made up in
deuterated solvents with all values quoted in ppm relative to
TMS as reference. Coupling constants (J values) are reported
in hertz (Hz). Diastereoisomer ratios were calculated from
the integration of suitable peaks in the proton NMR spectra.
Mass spectra were recorded using a Fisons VG Quattro II SQ
instrument and accurate-mass mass spectra were recorded using
a Kratos MS80 instrument. Melting points were determined on a
Gallenkamp Melting Point apparatus. Elemental analyses were
carried out on a Perkin Elmer 2400 CHN Elemental Analyser.
Optical rotations were performed using an Optical Activity AA-
10 Automatic Po◦larimeter and are reported in units of 10−1
deg cm2 g−1 at 20 C.
HPLC analysis (ChiralCel OD-H, hexanes–propan-2-ol
[99.5 : 0.5], 0.25 mL min−1) gave an e.e. of 92% that is in good
agreement with the e.e. of the starting alcohol.
6b: dH (400 MHz; CDCl3)1.91 (4 H, m, C(3)H2 and C(5)H2),
3.08 (1 H, m, CHaxPh), 3.41 (2 H, m, CH2I), 3.80 (2 H, t, CH2O),
3.95 (1 H, m, C(2)Heq) and 7.22–7.37 (5 H, m, Ar-H).
(2R,4S) and (2S,4S)-4-Phenyl-2-[(phenylseleno)methyl]-
tetrahydro-2H-pyran, 7a and 7b
A solution of alcohol 5 (0.068 g, 0.39 mmol) in dry
dichloromethane (20 cm3) was cooled to −78 ◦C. Pyridinium
p-toluenesulfonate (0.032 g, 0.12 mmol) was added and the
mixture was stirred for 10 min before addition of neat N-
phenylselenylphthalimide (0.208 g, 0.68 mmol) in one portion.
The reaction was stirred at −78 ◦C for 2 h then for a further 3 h
(3R)-3-Phenylhex-5-enol, 5 21
Aldehyde 3 (0.20 g, 1.2 mmol) was dissolved in methanol
(20 cm3) and cooled to 0 ◦C in an ice-bath. Sodium borohydride
(0.13 g, 3.5 mmol) was added neat in two portions and
the mixture stirred for 2 h whilst warming slowly to room
temperature. The solvent was removed under reduced pressure
and the gelatinous residue was dissolved in dichloromethane
(30 cm3), to which flash silica (0.50 g) was added and the solvent
removed again. Flash column chromatography on silica, eluting
with hexane–diethyl ether (4 : 1) gave alcohol 5 (0.20 g, 99%)
as a colourless oil: mmax (film)/cm−1 3334, 3076, 3027, 2928,
1640, 1602, 1494, 1452, 1440, 1047, 1028, 994, 913, 761 and
701; dH (400 MHz; CDCl3) 1.25 (1 H, br s, OH), 1.80 (1 H,
m, CHHCH2OH), 1.99 (1 H, m, CHHCH2OH), 2.38 (2 H, t,
◦
at 0 C. When the reaction was complete by TLC the solution
was filtered through Celite and the solvent then removed under
reduced pressure furnished a yellow oil which was shown to be
a mixture of diastereoisomers (1 : 1) by 1H NMR spectroscopy.
Flash column chromatography on silica gel, eluting with light
petroleum (bp range 40–60 ◦C)–ethyl acetate (7 : 1) gave 7a
(0.048 g, 39%) and 7b (0.045 g, 36%) as light yellow oils.
7a: mmax (film)/cm−1 3056, 3025, 2932, 2845, 1601, 1577, 1493,
1477, 1451, 1436, 1377, 1251, 1155, 1124, 1085, 1072, 1022,
1012, 756, 736, 691 and 669; dH (400 MHz; CDCl3) 1.51 (1 H, m,
C(3)HaxH), 1.77 (2 H, m, C(5)H2), 2.03 (1 H, m, C(3)HHeq), 2.77
(1 H, m, CHaxPh), 2.98 (1 H, dd, J 12.0 and 5.6, CHHSePh), 3.13
(1 H, dd, J 12.0 and 6.8, CHHSePh), 3.60 (2 H, m, C(2)Hax and
CHaxHO), 4.15 (1 H, m, CHHeqO) and 7.19–7.30 (8H, m, Ar-
H), 7.51–7.53 (2 H, m, Ar-H); dC (100 MHz; CDCl3) 33.3 (CH2),
33.5 (CH2), 39.2 (CH2), 41.6 (CH), 68.5 (CH2), 77.3 (CH), 126.4
(CH), 126.7 (CH), 126.8 (2 × CH), 128.6 (2 × CH), 129.1 (2 ×
CH), 130.6 (q), 132.5 (2 × CH) and 145.4 (q); m/z (EI) 332 (M+,
74%), 161 (99), 143 (23), 131 (31), 117 (38), 105 (46), 91 (100),
77 (32), 57 (19) and 43 (24). Found M+ 332.06827; C18H20OSe
requires 332.06793.
=
CH2CH CH2), 2.80 (1 H, m, CHPh), 3.46 (1 H, m, CHHOH),
=
3.54 (1 H, m, CHHOH), 4.96 (2 H, m, CH CH2), 5.67 (1 H,
=
m, CH CH2), 7.19 (3 H, m, Ar-H) and 7.30 (2 H, m, Ar-H);
dC (100 MHz; CDCl3) 39.0 (CH2), 41.7 (CH2), 42.7 (CH), 61.3
(CH2), 116.6 (CH2), 126.7 (CH), 128.0 (2 × CH), 128.8 (2 ×
CH), 137.1 (CH) and 144.9 (q); m/z (EI) 176 (M+, 3%), 158 (9),
135 (43), 131 (8), 117 (9), 105 (100), 91 (52) and 77 (6). Found M+
176.12008; C12H16O requires 176.12011.
HPLC analysis (ChiralCel OD, hexanes–propan-2-ol [95 : 5],
0.6 mL min−1) gave an e.e. of 92% which is in good agreement
with the e.e. of the starting aldehyde measured by 1H NMR.
8 1 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 0 9 – 8 1 5

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HPLC analysis (ChiralCel OD-H, hexanes–propan-2-ol
[99.5 : 0.5], 0.25 mL min−1) clearly showed that the sample
was greatly enantiomerically enriched when compared to an
authentic racemic sample, although full baseline separation was
not achieved.
9a: mmax (film)/cm−1 3421, 3027, 2934, 2849, 1602, 1495, 1452,
1381, 1259, 1131, 1086, 1069, 1040, 996, 758 and 700; dH
(400 MHz; CDCl3) 1.53 (1 H, m, C(3)HaxH), 1.84 (3 H, m,
C(3)HHeq and C(5)H2), 2.43 (1 H, br s, OH), 2.81 (1 H, m,
CHaxPh), 3.62 (4 H, m, CH2OH, C(2)Hax and CHaxHO), 4.19
(1 H, ddd, J 11.6, 6.0 and 3.6, CHHeqO) and 7.19–7.36 (5 H,
m, Ar-H); dC (100 MHz, CDCl3) 33.9 (CH2), 35.3 (CH2), 41.6
(CH), 66.6 (CH2), 68.4 (CH2), 78.5 (CH), 126.8 (CH), 127.1 (2 ×
CH), 128.9 (2 × CH) and 140.6 (q); m/z (EI) 192 (M+, 10%),
161 (100), 143 (14), 131 (12), 117 (24), 105 (25), 91 (27) and 77
(8). Found M+ 192.11503; C12H16O2 requires 192.11503.
9b: dH (400 MHz; CDCl3) 1.82 (1 H, m, C(3)HaxH), 2.00
(3 H, m, C(3)HHeq and C(5)H2), 2.43 (1 H, br s, OH), 3.08
(1 H, m, CHaxPh), 3.57 (1 H, m, C(2)Heq), 3.84 (4 H, CH2OH
and CHaxCHeqO) and 7.19–7.36 (5 H, m, Ar-H); dC (63 MHz,
CDCl3) 32.0 (CH2), 32.7 (CH2), 35.5 (CH), 62.7 (CH2), 63.6
(CH2), 73.7 (CH), 126.5 (CH), 127.6 (2 × CH), 128.9 (2 × CH)
and 140.5 (q).
7b: [a]2D5 −20.0 (c = 0.6, CHCl3); mmax (film)/cm−1 3056, 3025,
2932, 2845, 1601, 1577, 1493, 1477, 1451, 1436, 1377, 1251,
1155, 1124, 1085, 1072, 1022, 1012, 756, 736, 691 and 669; dH
(400 MHz; CDCl3) 1.91 (3 H, m, C(3)H2 and C(5)HHax), 2.09
(1 H, ddd, J 13.6, 9.2 and 4.4, C(5)HeqH), 3.01 (1 H, m, CHaxPh),
3.10 (1 H, dd, J 12.0 and 7.2, CHHSePh), 3.35 (1 H, dd, J 12.0
and 7.2, CHHSePh), 3.79 (2 H, m, C(2)Heq and CHaxHO), 4.06
(1 H, tt, J 7.2 and 4.8, CHHeqO), 7.18–7.32 (8H, m, Ar-H),
7.51–7.55 (2 H, m, Ar-H); dC (100 MHz; CDCl3) 30.5 (CH2),
32.1 (CH2), 35.2 (CH), 35.3 (CH2), 62.2 (CH2), 72.4 (CH), 126.2
(CH), 127.0 (CH), 127.1 (2 × CH), 128.5 (2 × CH), 129.1 (2 ×
CH), 130.1 (q), 132.9 (2 × CH), 144.6 (q); m/z (EI) 332 (M+,
40%), 161 (100), 143 (17), 131 (24), 117 (28), 105 (35), 91 (73),
77 (23), 57 (14) and 43 (18). Found M+ 332.06811; C18H20OSe
requires 332.06793.
(3R)-3-Phenyl-hex-5-enoic acid, 1022
The e.e. determined by HPLC analysis was in good agreement
with that of the starting alcohol (92%, ChiralCel OD-H,
hexanes–propan-2-ol [99.5 : 0.5], 0.25 mL min−1).
Aldehyde 3 (0.10 g, 0.57 mmol) was dissolved in aqueous buffer
(pH 4.0, 20 cm3) and cooled to 0 ◦C in an ice-bath. Sodium
chlorite (80% w/w, 0.195 g, 1.72 mmol) was added neat in
two portions followed by 2-methyl-2-butene (2.0 M, 0.86 cm3,
1.72 mmol) and the mixture was stirred vigorously for 3 h.
The aqueous solution was extracted with dichloromethane (3 ×
30 cm3), dried over anhydrous magnesium sulfate, filtered and
the solvent removed under reduced pressure to furnish an orange
oil. Flash column chromatography on silica gel, eluting with
hexanes-diethyl ether (4 : 1) gave carboxylic acid 10 (0.075 g,
70%) as a yellow oil: [a]2D5 = −20.0 (c = 1.27, CH2Cl2); mmax
(film)/cm−1 3357, 3063, 3028, 2924, 2855, 1706, 653, 1640,
1602, 1553, 1494, 1453, 1276, 1161, 1031, 911, 735 and 700;
dH (250 MHz; CDCl3) 2.41 (2H, t, J 7.0, CH2), 2.62 (1H, dd,
J 15.5 and 7.4, CHHC(O)OH), 2.75 (1H, dd, J 15.7 and 6.7,
(3S, 5R) and (3S, 5S)-4-Oxiranyl-3-phenylbutan-1-ol, 8a and 8b
Alcohol 5 (0.20 g, 1.1 mmol) was dissolved in dichloromethane
(20 cm3) and cooled to 0 ◦C in an ice-bath. Purified m-
chloroperbenzoic acid (0.49 g, 2.8 mmol) was added portion-
wise over 5 min to the stirred alcohol solution followed by
sodium hydrogencarbonate (0.27 g, 3.2 mmol). After 18 h the
crude reaction mixture was washed with saturated sodium sulfite
solution (2 × 20 cm3) to remove excess mCPBA and the organic
layer was dried over anhydrous sodium sulfate. Filtration and
evaporation of solvent under reduced pressure furnished the
crude epoxide. To prevent spontaneous cyclisation, flash column
chromatography on silica gel, eluting with diethyl ether–hexane
(2 : 1), had to be performed quickly and gave a mixture of
inseparable epoxides 8a and 8b (0.16 g, 73%) as a light yellow
oil with a diastereoisomeric ratio of 2 : 1.
=
CHHC(O)OH), 3.22 (1H, m, CHPh), 5.02 (2H, m, CH2), 5.65
=
(1H, m, CH ) and 7.19–7.33 (5H, m, ArH); dC (100 MHz;
CDCl3) 39.6 (CH2), 40.4 (CH2), 40.8 (CH), 116.0 (CH2), 126.9
(CH), 127.2 (2 × CH), 127.9 (2 × CH), 134.8 (CH), 142.9 (q),
and 177.2 (q); m/z (EI) 190 (M+, 15%), 149 (30), 107 (100),
91 (23) and 79 (24); Found M+ 190.09982; C12H14O2 requires
190.09938.
Analysis of mixture: mmax (film)/cm−1 3405, 3027, 2930, 1602,
1494, 1453, 1261, 1047, 847, 764 and 702; dH (400 MHz, CDCl3)
(* = minor isomer) 1.66–2.07 (4 H, m, CH2CH(Ph)CH2), 2.22
(1 H, br. s, OH), 2.29 (1 H, dd, J 4.9 and 2.8, CH(O)CHH),
2.44* (1 H, dd, J 4.9 and 2.8, CH(O)CHH), 2.58 (1 H, t,
J 4.9, CH(O)CHH), 2.60* (1 H, t, J 4.9, CH(O)CHH), 2.73
(1 H, m, CH(O)CH2), 2.80* (1 H, m, CH(O)CH2), 2.99 (1 H, m,
PhCH), 3.48 (2 H, m, CH2OH) and 7.19–7.32 (5 H, m, Ar-H);
dC (100 MHz, CDCl3) (* = minor isomer) 39.1* (CH2), 39.7
(CH2), 39.9* (CH2), 40.2* (CH), 40.4 (CH2), 40.5 (CH), 47.7*
(CH2), 47.9 (CH2), 51.2* (CH), 51.5 (CH), 60.9 (CH2), 126.9
(CH), 127.9* (CH), 128.0 (2 × CH), 129.0 (2 × CH), 144.4* (q)
and 144.5 (q); m/z (EI) 192 (M+, 5%), 161 (45), 156 (16), 143
(36), 129 (48), 117 (52), 105 (100), 91 (92), 77 (22) and 71 (16).
Found M+ 192.11486; C12H16O2 requires M+ 192.11503.
(4R, 6R)- and (4R, 6S)-6-Iodomethyl-4-phenyltetrahydro-
2H-pyran-2-one, 11a and 11b23
A solution of carboxylic acid 10 (0.090 g, 0.48 mmol) in THF
3
˚
(20 cm ) was stirred with 4A molecular sieves and sodium
hydrogencarbonate (0.394 g, 1.58 mmol) at room temperature.
Iodine (0.134 g, 1.58 mmol) was added and the mixture
stirred for 24 h before being quenched with saturated aqueous
sodium thiosulfate solution (2 cm3). Solvent was removed under
reduced pressure and the residue was partitioned between
dichloromethane and brine (40 cm 3, 1 : 1). The organic layer was
removed and the aqueous portion extracted with further 20 cm3
of dichloromethane. The combined organic layers were dried
over anhydrous magnesium sulfate, filtered and solvent removed
under reduced pressure to give orange oil which was shown to be
a mixture of diastereoisomers (4 : 1) by 1H NMR. Flash column
chromatography on silica gel, eluting with hexanes–diethyl ether
(1 : 1) gave the major diastereoisomer 11a (0.080 g, 53%) as a
light yellow solid. The minor diastereoisomer 11b (0.030 g, 20%)
as a colourless oil which was obtained using preparative TLC.
11a: mmax (film)/cm−1 1734, 1630, 1600, 1454, 1228, 1179, 1035
and 756; dH (400 MHz; CDCl3) 1.86 (1H, ddd, J 13.6, 12.4 and
11.6, C(5)Hax), 2.43 (1H, ddd, J 13.6, 5.2 and 3.2, C(5)Heq), 2.57
(1H, dd, J 18 and 12, C(3)Hax), 2.92 (1H, ddd, J 18, 5.6 and 2.0,
C(3)Heq), 3.21–3.25 (1H, m, CHPh), 3.38 (1H, dd, J 10.8 and
6.4, CHI), 3.44 (1H, dd, J 10.4 and 4.4, CHI), 4.37–4.42 (1H,
m, C(6)Hax) and 7.20–7.39 (5H, m, ArH); dC (100 MHz; CDCl3)
[(2R,4S) and (2S,4S)-4-Phenyltetrahydro-2H-pyran-2-yl]-
methanol, 9a and 9b
A solution of epoxides 8a and 8b (0.153 g, 0.80 mmol) in
dichloromethane (20 cm3) was stirred at room temperature
with a catalytic amount of camphorsulfonic acid (0.019 g,
0.08 mmol) for 20 h. The organic layer was washed once with
saturated aqueous sodium hydrogen carbonate solution, dried
over magnesium sulfate, filtered and the solvent removed under
reduced pressure to give a colourless oil which was shown to be
a mixture of diastereoisomers (2 : 1) by 1H NMR spectroscopy.
Flash column chromatography on silica gel, eluting with diethyl
ether–hexanes (2 : 1) gave tetrahydropyrans 9a (0.043 g, 28%)
and 9b (0.018 g, 12%) as colourless oils.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 0 9 – 8 1 5
8 1 3

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8.1 (CH2), 36.7 (CH2), 37.4 (CH), 37.6 (CH2), 78.8 (CH), 126.8
(2 × CH), 127.8 (CH), 129.5 (2 × CH), 142.5 (q) and 170.1 (q);
m/z (EI) 316 (M+, 20%), 189 (11), 175 (10), 131 (50), 129 (100),
104 (53), 91 (21), 77 (31) and 43 (13); Found M+ 315.99623;
C12H13O2I requires 315.99603.
with light petroleum (bp range 40–60 ◦C)–diethyl ether (10 : 1)
gave the lactone 13 (0.046 g, 83%) as a colourless oil: [a]D25
=
−17.2 (c = 1.00, CH2Cl2); mmax (film)/cm−1 2923, 2854, 1731,
1456, 1253, 1230, 757 and 700; dH(400 MHz; CDCl3) 1.45 (3H, d,
J 8.0, CH3), 1.69–1.76 (1H, m, C(5)Hax), 2.15 (1H, m, C(5)Heq),
2.53 (1H, dd, J 18.0 and 11.6, C(3)Hax), 2.92 (1H, ddd, J 17.6,
6 and 2.0 Hz, C(3)Heq), 3.15–3.23 (1H, m, CHPh), 4.53–4.61
(1H, m, CHCH3) and 7.19–7.35 (5H, m, ArH); dC (100 MHz;
CDCl3) 22.3 (CH3), 37.7 (CH2), 38.1 (CH2), 38.4 (CH2), 77.1
(CH), 126.8 (2 × CH), 127.6 (CH), 129.4 (2 × CH), 143.2 (q),
and 170.2 (q); m/z (EI) 190 (M+, 25%), 104 (100), 91 (15) and
78 (14); Found M+ 190.09938; C12H14O2 requires 190.09937.
HPLC analysis (ChiralCel OD-H, hexanes–propan-2-ol
[99 : 1], 0.25 mL min−1) gave an e.e. of 86%. Retention times:
major enantiomer = 16.96 min, minor = 14.57 min.
11b: mmax (film)/cm−1 1734, 1630, 1600, 1454, 1228, 1179, 1035
and 756; dH (400 MHz; CDCl3) 2.25 (2H, t, J 4.0, C(5)H2), 2.79–
2.87 (2H, m, C(3)H2), 3.31–3.43 (3H, m, CH2I and CHPh), 4.36
(1H, ddd, J 12.0, 8.0 and 4.0, C(6)Heq) and 7.20–7.39 (5H, m,
ArH); dC (100 MHz; CDCl3) 6.9 (CH2), 34.8 (CH), 35.4 (CH2),
35.9 (CH2), 76.2 (CH), 126.9 (2 × CH), 127.7 (CH), 129.5 (2 ×
CH), 142.6 (q) and 170.69 (q).
N-[(3R)-3-Phenylhex-5-enyl]-N-phenylmethylamine, 14
To a stirred solution of (R)-3-phenylhex-5-enal, 3, (3.35 g,
19.24 mmol) in dichloromethane (30 cm3) was added benzy-
lamine (2.1 cm3, 19.24 mmol) dropwise. The solution was stirred
for 30 min and MgSO4 was added. After 10 min, the mixture
was filtered and solvent was removed under reduced pressure.
The resultant light yellow oil was redissolved in dry MeOH
(40 cm3) and cooled to 0 ◦C. NaBH4 (2.4 g, 63.5 mmol) in
MeOH (10 cm3) was added and the solution was allowed to
warm to room temperature and stirred for 18 h. Solvent was
removed under reduced pressure and the crude was purified
by flash column chromatography (3 : 2 hexanes–EtOAc). The
product was isolated as a yellow oil (3.69 g, 73%). [a]2D5 −8.7
(c = 1.7, CHCl3) mmax (film/cm−1); 3027, 2922, 1640, 1602,
1494, 1453, 912, 734 and 700; dH (400 MHz; CDCl3) 1.40 (1H,
br, s, NH), 1.73–1.81 (1H, m, NHCH2CHH), 1.87–1.94 (1H,
(4R, 6R)- and (4R, 6S)-4-Phenyl-6-[(phenylseleno)methyl]-
tetrahydro-2H-pyran-2-one, 12a and 12b
To a magnetically stirred solution of carboxylic acid 10 (0.23 g,
1.21 mmol) in dry dichloromethane (5 cm3) under nitrogen,
pyridine (0.105 g, 1.33 mmol) was added and the solution
was stirred for 30 min at room temperature. The solution
was then cooled to −78 ◦C and phenylselenium chloride
(0.255 g, 1.33 mmol) was added. The reaction was stirred until
completion, which was indicated by the decoloration of the
red orange colour of phenylselenium chloride and confirmed
by TLC. The solvent was removed under reduced pressure to
give an orange solid, which was shown to be a mixture of
diastereoisomers (3 : 1) by 1H NMR spectroscopy. Purification
by flash column chromatography eluting with petroleum ether–
ethyl acetate (7 : 1) gave the inseparable isomeric lactones 12a
and 12b (305 mg, 71%) as orange oils.
=
m, NHCH2CHH), 2.36 (2H, t, J 7.2, CH2CH CH2), 2.44–2.53
(2H, m, NHCH2CH2), 2.66–2.74 (1H, m, PhCH), 3.63–3.72
=
(2H, m, PhCH2), 4.90–4.98 (2H, m, CH CH2), 5.60–5.68 (1H,
m, CH CH2), 7.14–7.29 (10H, m, ArH); dC (100 MHz; CDCl3)
12a: mmax (film)/cm−1 2923, 1732, 1578, 1495, 1477, 1381, 1227,
738 and 699; dH (400 MHz; CDCl3) 1.86 (1H, ddd, J 13.6, 12.0
and 10.4, C(5)Hax), 2.53 (1H, ddd, J 13.6, 5.2 and 3.2, C(5)Heq),
2.62 (1H, dd, J 18 and 11.6, C(3)Hax), 2.98 (1H, ddd, J 18.0, 6.0
and 2.0, C(3)Heq), 3.16 (1H, dd, J 13.0 and 7.7, CH2SePh), 3.21–
3.26 (1H, m, CHPh), 3.41 (1H, dd, J 12.87 and 4.67, CH2SePh),
4.63–4.69 (1H, m, C(6)Hax), 7.16–7.35 (8H, m, ArH) and 7.53–
7.54 (2H, m, ArH); dC (100 MHz; CDCl3) 32.9 (CH2), 36.1
(CH2), 37.8 (CH), 37.9 (CH2), 80.1 (CH), 126.8 (2 × CH), 129.4
(2 × CH), 129.4 (CH), 129.75 (CH), 129.76 (2 × CH), 133.4 (2 ×
CH), 142.9 (q) and 170.6 (2 × q); m/z (EI) 346 (M+, 54%), 189
(13), 175 (23), 157 (28), 143 (39), 131 (94), 117 (24), 105 (92),
91 (100) and 77 (69); Found M+ 346.04793; C18H18O2Se requires
346.04720.
12b: dH (400 MHz; CDCl3) 2.25–2.36 (2H, m, C(3)H2), 2.79
(1H, dd, J 17.1 and 8.70, C(5)H), 2.90 (1H, dd, J 17.1 and 6.4,
C(5)H), 3.13 (1H, dd, J 12.9 and 3.5, CHSePh), 3.37 (1H, dd,
J 12.9 and 4.7, CHSePh), 3.42 (1H, m, CHPh), 4.61 (1H, m,
C(6)Heq), 7.16–7.35 (8H, m, ArH) and 7.53–7.54 (2H, m, ArH);
dC (100 MHz; CDCl3) 32.1 (CH2), 34.5 (CH2), 34.8 (CH), 36.3
(CH2), 77.1 (CH), 126.9 (2 × CH), 127.6 (CH), 127.7 (2 × CH),
127.9 (2 × CH), 128.1 (CH), 133.8 (2 × CH), 142.9 (q) and 171.3
(2 × q).
=
36.2 (CH2), 41.5 (CH2), 43.9 (CH), 47.5 (CH2), 54.0 (CH2), 116.1
(CH2), 126.2 (CH), 126.9 (CH), 127.6 (2 × CH), 128.1 (2 × CH),
128.4 (4 × CH), 136.9 (CH), 140.4 (C), 144.8 (C); m/z (EI) 265
[M+, 14%] 91 (100), 120 (51); Found M+ 265.1832; C19H23N
requires 265.1831.
Phenylmethyl-N-[(3R)-3-phenylhex-5-enyl]-N-phenylmethyl-
carbamate, 15
To a solution of 14, (1.6 g, 6.03 mmol) in DMF (20 cm3)
was added N-(benzyloxycarbonyloxy)succinimide (1.65 g,
6.63 mmol) and NMM (2.7 cm3, 24.12 mmol). The reaction was
stirred for 18 h and EtOAc (20 cm3) was added. The solution was
acidified with aqueous 1 M HCl, washed with brine, dried over
anhydrous MgSO4 and concentrated under reduced pressure.
The crude was purified by flash column chromatography (9 : 1
◦
light petroleum (bp range 40–60 C)–EtOAc) and the product
was isolated as a yellow oil (1.90 g, 79%). [a]2D5 −1.4 (c = 1.5,
CHCl3); mmax (film/cm−1) 3027, 2924, 1700, 1494, 1472, 1452,
1421, 1228, 1214, 699; dH (400 MHz; CDCl3) 1.75–2.00 (2H,
=
m, NHCH2CH2), 2.25–2.32 (2H, m, CH2CH CH2), 2.48–2.58
(1H, m, PhCH), 3.00–3.22 (2H, m, NCH2CH2) 4.29–4.49 (2H,
=
m, PhCH2), 4.89–4.95 (2H, m, CH CH2), 5.11–5.18 (2H, m,
OCH2), 5.51–5.63 (1H, m, CH CH2), 6.97–7.35 (15H, m, ArH);
=
(4R, 6S)-6-Methyl-4-phenyltetrahydro-2H-pyran-2-one, 1324
dC (100 MHz; CDCl3) 33.4 (CH2), 41.5 (CH2), 43.4 (CH), 44.8
(CH2), 50.6 (CH2), 67.2 (CH2), 116.2 (CH2), 126.3 (2 × CH),
127.3 (CH), 127.5 (2 × CH), 127.9 (2 × CH), 128.4 (4 × CH),
128.5 (4 × CH), 136.5 (CH), 136.8 (2 × C), 137.8 (C), 144.1
(2 × C); MS (EI) m/z 399 [M+, 5%] 91 (100), 92 (16), 120 (14),
210 (17), 308 (11); Found: M+, 399.2195; C27H29NO2 requires
399.2198.
Tributyltin hydride (0.231 cm3, 0.873 mmol) dissolved in toluene
(2 cm3) was added to a solution of 11a (0.092 g, 0.29 mmol)
dissolved in dry toluene (5 cm3) under an inert atmosphere.
The mixture was heated to reflux, AIBN (0.005 g) was added
and the reaction was heated under reflux for a further 4 h.
AIBN (0.005 g) was added every 45 min until completion of
the reaction, confirmed by TLC. The solvent was removed
under reduced pressure and the residue was partitioned between
acetonitrile and hexane (20 cm3, 1 : 1) to remove excess tributyltin
hydride. The acetonitrile layer was further washed with hexane
(20 cm3) and solvent removed under reduced pressure furnishing
a yellow oil. Flash column chromatography on silica gel, eluting
Phenylmethyl-N-[(3S)-5-oxophenylpentyl]-N-phenylmethyl-
carbamate, 16
To a solution of 15, (1.55 g, 3.87 mmol) in DCM (30 cm3)
at −78 ◦C was bubbled O2 for 10 min followed by O3. The
solution turned blue after 5 min and bubbling was continued for
8 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 0 9 – 8 1 5

View Article Online
an additional 15 min. Triphenylphosphine (1.12 g, 4.26 mmol)
was added, the solution was stirred for 18 h at room temperature
and the reaction was quenched by addition of aqueous 1 M
HCl. The resultant mixture was washed with brine, dried over
anhydrous MgSO4 and concentrated under reduced pressure.
The crude was purified by flash column chromatography (4 : 1
hexanes–EtOAc) and the product was isolated as a transparent
oil (1.32 g, 85%). [a]2D5 −5.0 (c = 1.3, CHCl3); mmax (film/cm−1)
3028, 2932, 1721, 1698, 1494, 1471, 1452, 1422, 1231, 1215,
1120, 766, 736, 700; dH (400 MHz; CDCl3) 1.78–1.89 (2H, m,
NCH2CH2), 2.53–2.70 (2H, m, CH2CHO), 3.00–3.16 (3H, m,
PhCH & NCH2CH2), 4.31–4.47 (2H, m, PhCH2N), 5.10–5.18
(2H, m, OCH2), 6.99–7.63 (15H, m, ArH), 9.56 (1H, d, J 23.2,
CHO); dC (100 MHz; CDCl3) 34.1 (CH2), 37.6 (CH), 45.5 (CH2),
50.6 (2 × CH2), 67.3 (CH2), 126.9 (2 × CH), 127.4 (3 × CH),
128.0 (2 × CH), 128.6 (4 × CH), 128.8 (4 × CH), 136.7 (C),
137.7 (C), 142.7 (2 × C), 201.3 (CH). MS (EI) m/z 401 [M+, 6%]
49 (42), 84 (40), 91 (100), 92 (38), 120 (65), 164 (51), 266 (74);
Found: M+, 401.1997; C26H27NO3 requires 401.1991.
(joint studentship support to CHP) and the University of
Loughborough.
References
1 S. M. Allin and R. D. Baird, Curr. Org. Chem., 2001, 5, 395, and
references cited therein.
2 S. M. Allin, M. A. C. Button and S. J. Shuttleworth, Synlett, 1997,
725.
3 (a) S. M. Allin and M. A. C. Button, Tetrahedron Lett., 1998, 39,
3345; (b) S. M. Allin, M. A. C. Button and R. D. Baird, Synlett,
1998, 1117.
4 (a) S. M. Allin and M. A. C. Button, Tetrahedron Lett., 1999, 40,
3801; (b) H. K. Dobson, R. LeBlanc, H. Perrier, C. Stephenson,
T. R. Welch and D. Macdonald, Tetrahedron Lett., 1999, 40, 3119;
(c) H. Y. Yoo, K. N. Houk, J. K. Lee, M. A. Scialdone and A. I.
Meyers, J. Am. Chem. Soc., 1998, 120, 205; (d) T. J. Sprules, J. D.
Galpin and D. Macdonald, Tetrahedron Lett., 1993, 34, 247.
5 S. M. Allin, M. A. C. Button and R. D. Baird, Synlett, 1998, 1117.
6 E. Lee, Y. R. Lee, B. Moon, O. Kwon, M. S. Shim and J. S. Yun,
J. Org. Chem., 1994, 59, 1444.
7 C. Agami, F. Meynier, J. Berlan, Y. Besace and L. Brochard, J. Org.
Chem., 1986, 51, 73.
8 (a) T. C. Ting and P. A. Bartlett, J. Am. Chem. Soc., 1984, 106, 2668;
(b) F. Bennett, D. W. Knight and G. Fenton, J. Chem. Soc., Perkin
Trans. 1, 1991, 133; (c) N. Greeves and W.-M. Lee, Tetrahedron Lett.,
1997, 38, 6449.
9 Chiral HPLC study carried out using a Chiralcel-OD column
eluting with a 95% hexanes–5% propan-2-ol solvent mixture at
0.6 ml min−1. A racemic sample of the target under study was
prepared and investigated prior to the enantiomerically enriched
product. Retention times: major enantiomer = 18.9 min, minor =
22.2 min.
10 In all cases, the major (cis) diastereoisomers display a large diaxial
coupling of ca. 12 Hz between the C-2 proton at the chiral centre
created on electrophile-induced cyclisation and the axial C-3 proton.
For the minor (trans) diastereoisomers, the now equatorial C-2
proton displays a much weaker axial–equatorial coupling (ca. 4 Hz)
to the same C-3 proton.
Phenylmethyl 4-phenylhexahydropyridine-1-carboxylate, 18
To a solution of 16, (0.50 g, 1.25 mmol) in MeOH (100 cm3)
in a Parr bottle was added TFA (0.11 cm3, 1.4 mmol) and
10% palladium on carbon (0.05 g). The mixture was stirred
for 18 h under nitrogen at 50 psi. The catalyst was removed
by filtration through Celite and the solution was concentrated
under reduced pressure. The product was redissolved in DMF
(15 cm3) and N-(benzyloxycarbonyloxy)succinimide (0.50 g,
2.00 mmol) and NMM (0.88 cm3, 8.00 mmol) were added to
the solution. The reaction was stirred overnight and EtOAc
(20 cm3) was added. The mixture was acidified with aqueous 1 M
HCl, washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The crude was purified by flash column
chromatography (4 : 1 hexanes–EtOAc) and the product was
isolated as a light yellow oil (0.108 g, 29%).mmax (film/cm−1)
2936, 2850, 1700, 1696, 1452, 1429, 1221, 698; dH (400 MHz;
CDCl3) 1.63–1.77 (2H, m, 2 × (CHCHH)), 1.83–1.90 (2H, m,
2 × (CHCHH)), 2.66 (1H, tt, J 12.1, 3.5, CHPh), 2.88–2.94 (2H,
m, 2 × NCHH), 4.25–4.40 (2H, m, 2 × NCHH), 5.16 (2H, s,
OCH2), 7.18–7.38 (10H, m, ArH); dC (100 MHz; CDCl3) 33.1
(2 × CH2), 42.6 (CH), 44.7 (2 × CH2), 67.1 (CH2), 126.4 (CH),
126.8 (2 × CH), 127.9 (2 × CH), 128.0 (CH), 128.5 (2 × CH),
128.6 (2 × CH), 136.9 (C), 145.6 (C), 155.3 (C). MS (EI) m/z
296 [M+, 13%] 91(100); Found: (M + H)+, 296.1657; C19H21NO2
requires 296.1651.
11 Chiral HPLC study carried out using a Chiralcel-OD column
eluting with a 99.5% hexanes–0.5% propan-2-ol solvent mixture at
0.25 ml min−1. A racemic sample of the target under study was
prepared and investigated prior to the enantiomerically enriched
product. Retention times: 6a: major enantiomer = 46.9 min, minor =
42.5 min; 7a: major enantiomer = 51.2 min, minor = 60.1 min.
12 (a) P. A. Bartlett, D. P. Richardson and J. Myerson, Tetrahedron,
1984, 40, 2317; (b) F. Bennett, D. W. Knight and G. Fenton, J. Chem.
Soc., Perkin Trans. 1, 1991, 133; (c) N. Greeves and W.-M. Lee,
Tetrahedron Lett., 1997, 38, 6449.
13 Chiral HPLC study carried out using a Chiralcel-OD column eluting
with a 99 hexanes–1% propan-2-ol solvent mixture at 0.25 ml min−1
.
A racemic sample of the target under study was prepared and in-
vestigated prior to the enantiomerically enriched product. Retention
times: major enantiomer = 16.96 min, minor = 14.57 min.
14 (a) P. A. Bartlett, D. P. Richardson and J. Myerson, Tetrahedron,
1984, 40, 2317; (b) G. P. Lutz, H. Du, D. J. Gallagher and P.
Beak, J. Org. Chem., 1996, 61, 4542; (c) N. Greeves and W.-M. Lee,
Tetrahedron Lett., 1997, 38, 6449.
15 For the major (cis) diastereoisomers, the axial C-4 proton displays
large couplings of >11 Hz to both the C-3 and C-5 protons, therefore
strongly supporting a diaxial relationship of the C-4 proton to the
C-3 and C-5 protons.
Crystallography
Crystal data for 1. C21H25NO, M = 307.42, orthorhombic,
˚
P212121, a = 4.9818(5), b = 9.4157(10), c = 37.792(4) A, V =
3
˚
1772.7(3) A , Z = 4, wR2 = 0.1036 for all 4177 independent
reflections, R1 = 0.0432 for 3284 reflections with [I > 2r(I)].
Absolute structure not determined (Flack parameter −0.2(15)).
CCDC reference number 242655.
16 H. M. Hugel, A. B. Hughes and K. Khalil, Aust. J. Chem., 1998, 51,
Crystal data for 11a. C12H13IO2, M = 316.12, orthorhombic,
1149.
˚
P222121, a = 6.6491(4), b = 6.8227(4), c = 25.8973(14) A,
17 J. C. Sih and D. R. Graber, J. Org. Chem., 1982, 47, 4919.
18 P. Szolcsanyi, T. Gracza, M. Koman, N. Pronayova and T. Liptaj,
Tetrahedron: Asymmetry, 2000, 11, 2579.
19 M. A. Cooper and D. A. Ward, Tetrahedron Lett., 1994, 35, 5065.
20 C.-B. Xue, J. Roderick, R. L. Corbett and C. Decicco, J. Org. Chem.,
2002, 67, 865.
3
˚
V = 1174.83(12) A , Z = 4, wR = 0.0338 for all 2793 unique
data, R1 = 0.0150 for 2708 data with F2 ≥ 2r(F2). Absolute
structure parameter = 0.001(16), thus reliably determined.
CCDC reference number 206872.
21 H. Ahlbrecht, G. Bonnet, D. Enders and G. Zimmermann, Tetrahe-
dron Lett., 1980, 21, 3175.
22 C.-J. Chang, J.-M. Fang and L.-F. Liao, J. Org. Chem., 1993, 58,
1754.
See http://www.rsc.org/suppdata/ob/b4/b416179c/ for cry-
stallographic data in .cif or other electronic format.
23 G. P. Lutz, H. Du, D. J. Gallagher and P. Beak, J. Org. Chem., 1996,
Acknowledgements
61, 4542.
We thank the EPSRC (Quota studentship to R. D. B.), Glax-
oSmithKline (joint studentship support to M. E.), Syngenta
24 A. Barbero, D. C. Blakemore, I. Fleming and R. N. Wesley, J. Chem.
Soc., Perkin Trans. 1, 1997, 1329.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 0 9 – 8 1 5
8 1 5