An approach to an asymmetric synthesis of stemofoline

Article abstract of DOI:10.1016/j.tetasy.2009.03.002

A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbony

Full text of DOI:10.1016/j.tetasy.2009.03.002

Tetrahedron: Asymmetry 20 (2009) 970–979
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An approach to an asymmetric synthesis of stemofoline
*
Eric J. Thomas , Clare F. Vickers
The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-
methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-
2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbonylamino-6-methylenedecanoate. This was taken
through to methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-butoxycarbonylamino-3,8-dioxod-
odecanoate which on treatment with trifluoroacetic acid cyclised stereoselectively to give
(1R,2S,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-
3-oxo-8-azabicyclo[3.2.1]octane, a potential precursor of stemofoline. Reduction and N-deprotection
of this ketone gave (1R,2S,3R,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-
8-azabicyclo[3.2.1]octan-3-ol the structure of which was confirmed by X-ray diffraction.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 March 2009
Accepted 5 March 2009
Available online 15 April 2009
This paper is dedicated to Professor George
Fleet, on the occasion of his 65th birthday.
1. Introduction
which was converted into ether 6, which has the tetracyclic core
structure of stemofoline, by regioselective remote oxidation. How-
The Stemona alkaloids have been isolated from extracts
obtained from the roots and leaves of several Stemonacea used in
traditional medicine in China, Japan and Thailand to treat respira-
tory illnesses and parasitic infections.1 The more complex Stemona
alkaloids include stemofoline 1 and asparagamine A 2, which has
also been isolated from Asparagus racemosus.2 Many synthetic
approaches to the Stemona alkaloids have been described includ-
ing total syntheses of ( )-isostemofoline3 [the (E)-isomer of
stemofoline] and ( )-asparagamine together with its (E)-isomer.4,5
No biosynthetic work has been reported for these alkaloids but a
biogenetic route has been proposed.1
ever, attempts to introduce fragments corresponding to the C(10)–
C(11) side chain of stemofoline into bi- and tricyclic intermediates
prepared from 4 and 5 were relatively low yielding.6 Therefore, it
was decided to study the synthesis and cyclisation of open-chain
intermediates corresponding to the keto-ester 3 to which the
C(10)-C(11) fragment had already been attached.
BocNH
O
CO2Me
CO2Me
N
i. TFA
n-Bu
n-Bu
2
ii. ClCO2Me,
Et3N
O
O
O
H
MeO2C
3
4
steps
Me
O
5
O
N
6
O
OMe
H
O
Me
10
9a
N
R
4
9
11
N
Pb(OAc)4
O
7
3
H
8
n-Bu
n-Bu
H
H
1
O
2
OH
O
6
1
R=(CH2)3CH3
2 R = CH=CHCH2CH3
5
Keto-ester 7 which has three stereogenic centres corresponding
to those at C(9a), C(9) and C(10) in stemofoline, was identified as
the initial target and syntheses based on an asymmetric Mannich
strategy were considered. The titanium(IV)-mediated addition of
ester enolate anions to N-tert-butylsulfinimines developed by Ell-
man has proven to be a very useful asymmetric synthesis of b-ami-
no-esters.7 For the synthesis of the keto-ester 7 this would involve
the reaction of ester 9 with the chiral sulfinimine 8 followed by
further elaboration to develop the keto-ester functionality. In his
case, both the sulfinimine and the ester are chiral, and so the
Studies have been carried out on a synthetic approach to
stemofoline, based on the modification of tropinone 4 prepared
by a stereoselective cyclisation of a cyclic iminium ion generated
from the racemic open-chain amido-ketone 3.6 Subsequent modi-
fication of the tropinone 4 gave the tricyclic hydroxylactam 5,
* Corresponding author. Tel.: +44 (0) 161 275 4613; fax: +44 (0) 161 275 4939
(E.J.T.).
E-mail address: e.j.thomas@manchester.ac.uk (E.J. Thomas).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.002

E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
971
overall stereoselectivity would be affected by both the ester and
the imine. Herein, we report preliminary studies into the use of
the Ellman reaction to prepare intermediates analogous to keto-es-
ter 7 and the stereoselective cyclisations of these to give 8-azabicy-
clo[3.2.1]octanes which may have use in an asymmetric synthesis
of stemofoline.
dibromoketone 11, which was converted into ester 9 by treatment
with lithium hexamethyldisilazide and butyllithium.8 Alterna-
tively, ester 10 was taken through to iodide 12 by reduction and
reaction of the resulting alcohol with iodine and triphenylphos-
phine. Iodide 12 was then converted into the required ester 9 by
halogen–metal exchange using tert-butyllithium followed by the
addition of methyl chloroformate (Scheme 1).
O
BocNH
H
Non-1-en-5-ol 139 was oxidised to the corresponding ketone
which was protected as its acetal 14. Ozonolysis gave the aldehyde
15 which was immediately converted into the sulfinimine 8 by
treatment with (S)-tert-butyl sulfinamide, see Scheme 2.10 The
reaction of the titanium enolate of ester 9 with the sulfinimine 8
was then carried out at 60 °C and gave a mixture of two products
which were isolated in yields of 66% and 11%. The major product
was identified as the required diastereoisomer 17 on the basis of
Ellman’s mnemonic7 and by comparison with similar products
prepared later, vide infra. The minor product was identified as a
diastereoisomer of the major product from spectroscopic data
but its stereochemistry was not established.
CO2Me
n-Bu
H
O
O
Me
OBn
7
O
O
S
N
tBu
OMe
+
n-Bu
Me
O
O
9
8
OBn
At this point it was necessary to convert the ester 16 into a keto-
ester analogous to 7. However, the aldehyde 18 prepared from
ester 16 by reduction followed by oxidation, was found to be
unstable, and attempts to effect an aldol condensation with methyl
acetate were thwarted by competing elimination to the a,b-unsat-
urated aldehyde 19.
2. Results and discussion
Two procedures were used to prepare methyl (S)-4-benzyloxy-
3-methylbutanoate 9 from methyl (R)-3-benzyloxy-2-methylpro-
panoate 10. The addition of lithiated dibromomethane gave
It would appear that the elimination of the sulfinamide group
from the aldehyde is relatively facile. Attempts were made to
remove the sulfinyl group from the Mannich product 16 under
acidic conditions in methanol, but competing loss of the acetal
was observed and complex mixtures of products were obtained.
It appeared necessary to use intermediates with a different
functional group precursor for the ketone. 4-Methylene-octanal11
was prepared from the alcohol 20 and condensed with (S)-tert-bu-
tyl sulfinamide to give the sulfinimine 21, see Scheme 3. Reaction
of the titanium(IV) enolate of ester 9 with the sulfinimine 21 gave
mainly the required product 22, 72% isolated yield, together with a
mixture of other minor diastereoisomers which were not separated
or formally characterised. The structure shown for the major Man-
nich product was assigned by analogy with Ellman’s work and was
confirmed by X-ray diffraction later in the synthesis.
Br
CO2Me
O
Br
i
Me
Me
OBn
OBn
11
10
iii
ii
O
I
iv
OMe
Me
Me
OBn
OBn
12
9
The tert-butylsulfinyl auxiliary could now be removed under
acidic conditions and the amine protected as its tert-butoxycar-
bonyl derivative 23. This was taken through to aldehyde 25 by
reduction followed by oxidation and condensation with methyl
acetate to give keto-ester 26 after oxidation of the mixture of epi-
Scheme 1. Reagents and conditions: (i) CH2Br2, LiTMP, ꢀ78 °C, 30 min (50%); (ii)
LiHMDS, ꢀ78 °C, 1 h, then nBuLi, ꢀ78 °C, 1 h, followed by AcCl, MeOH, 0 °C (52%);
(iii) (a) DIBAL-H, hexanes, ꢀ78 °C, 1 h, rt 3 h (91%) (b) Ph3P, imid., I2, THF, 0 °C then
rt, 3 h (93%); (iv) tBuLi, pentane, Et2O, ꢀ78 °C, 5 min to rt, then MeCO2Cl, ꢀ78 °C,
5 min (60%).
O
S
O
S
tBu
O
H
tBu
NH
n-Bu
N
n-Bu
H
i, ii
iv
iii
X
n-Bu
n-Bu
+ minor diastereoisomer
O
O
OH
13
OMe
O
O
O
O
Me
14 X =CH2
15 X =O
8
16
OBn
v
O
S
O
O
S
tBu
NH
tBu
NH
H
O
H
H
n-Bu
n-Bu
n-Bu
H
vii
vi
OH
H
O
O
H
O
O
O
O
Me
Me
Me
OBn
OBn
OBn
18
19
17
Scheme 2. Reagents and conditions: (i) (a) CrO3, H2SO4, H2O (71%), (b) (CH2OH)2, benzene, TsOH (cat.), heat under reflux, 18 h (98%); (ii) O3, MeOH, ꢀ78 °C, 30 min, Me2S, rt,
2 h; (iii) (S)-tert-butyl sulfinamide, CH2Cl2, CuSO4, rt, 18 h (45% from 14); (iv) LDA, 9, ꢀ78 °C, 1 h, TiCl(OiPr)3, ꢀ78 °C, 1 h, 8, ꢀ60 °C, 48 h (66% plus 11% of a second
diastereoisomer); (v), LiAlH4, 0 °C, 40 min, rt, 2 h (92%); (vi), Dess Martin periodinane, py., CH2Cl2, 0 °C, 3.5 h (70%); (vii) LDA, methyl acetate, ꢀ78 °C, 1 h (28%).

972
E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
O
S
O
H
tBu
NH
O
H
BocNH
O
S
H
H
n-Bu
n-Bu
n-Bu
iii
i
OMe
OMe
N
tBu
ii
OH
n-Bu
Me
23
Me
22
OBn
20
21
OBn
+ minor diastereoisomer
iv
O
H
O
O
O
O
BocNH
H
BocNH
BocNH
H
BocNH
H
H
n-Bu
n-Bu
n-Bu
n-Bu
H
OH
OMe vii
vi
OMe
v
H
H
H
O
Me
Me
24
Me
27
Me
26
OBn
OBn
OBn
OBn
25
Scheme 3. Reagents and conditions: (i) (a) PDC, CH2Cl2, rt, 24 h (60%) (b) (S)-tert-butyl sulfinamide, CuSO4, CH2Cl2, rt, 24 h (93%); (ii) LDA, 9, ꢀ78 °C, 1 h, TiCl(OiPr)3, ꢀ78 °C,
21, ꢀ90 °C, 18 h (22, 72% plus 18% of a mixture of three other diastereoisomers); (iii) (a) HCl, dioxane, H2O, MeOH, rt, 1 h (b) Et3N, Boc-anhydride, THF, rt, 1 h (93% fom 22);
(iv) DIBAL-H, hexanes, THF, ꢀ78 °C, 1 h, rt, 20 min (85%); (v) Dess Martin periodinane, py., CH2Cl2, 0 °C, 3.5 h (81%); (vi) (a) LDA, methyl acetate, ꢀ78 °C, 1 h, add 25, ꢀ78 °C,
2 h (82%) (b) PDC, 4 Å molecular sieves, CH2Cl2, rt, 24 h (86%); (vii) OsO4, 4-methylmorpholine N-oxide, THF, tBuOH, H2O, 0 °C, rt, 24 h (b) NaIO4, MeOH, pH 7 phosphate
buffer, rt, 1 h (75% from 26).
meric aldol products. The double-bond was then cleaved by
hydroxylation12 followed by cleavage of the diol using sodium per-
iodate to give diketo-ester 27, the potential iminium ion cyclisa-
tion precursor (Scheme 3).
these data did not unambigously reveal the configuration at C(2),
it was noticed that H(2) for the new compound, at d 3.7, was signif-
icantly deshielded relative to H(2), in 4 which was observed at d
3.33, and was observed as a broadened singlet, possibly due to hin-
dered rotation involving the Boc-group. Reduction of ketone 28
using sodium borohydride was highly stereoselective and gave a
single alcohol subsequently shown to be the axial alcohol 29.
Structural and stereochemical assignments in this series were
confirmed when the amine prepared by treatment of the Boc-pro-
tected amino-alcohol 29 with tert-butyldimethylsilyl triflate and
2,6-lutidine13 was shown to have the structure 30 by X-ray diffrac-
tion. Figure 1 shows a projection of the amine which establishes its
structure confirming both the proposed stereoselectivity of the
Ellman reaction and the equatorial orientation of the 2-methoxy-
carbonyl substituent.
In the original work, acetal 3 had been treated with trifluoroace-
tic acid to remove the acetal and tert-butoxycarbonyl-protecting
groups. This gave a cyclic imine which was induced to undergo fur-
ther cyclisation to give the 8-azabicyclo[3.2.1]octanone 4 by treat-
ment with methyl chloroformate and triethylamine. Of interest
was the stereoselectivity of this process since the methoxycarbonyl
group ended up in the axial position at C(2), probably due to ther-
modynamic control. However, when the Boc-protected amino-ke-
tone 27 was treated with trifluoroacetic acid in dichloromethane
at 0 °C, a relatively non-polar product, subsequently identified as
the 8-azabicyclo[3.2.1]octanone 28, started to appear within
5 min and was isolated in an 82% yield after 1 h, (Scheme 4).
H
O
O
BocNH
H
CO2tBu
H
H
Me
N
n-Bu
n-Bu
i
OMe
H
BnO
2
O
O
Me
CO2Me
OBn
28
27
iv
ii
nBu
H
H
O
O
N
CO2tBu
H
H
Me
N
n-Bu
OMe
H
BnO
H
HO
Me
CO Me
2
Figure 1. An ORTEP projection of the structure of amino-alcohol 30 as determined
by X-ray diffraction.
OBn
31
29
iii
v
The formation of tropinone 28, in which the 2-methoxycarbonyl
group is equatorial, contrasts with the formation of the axial epimer
4 in the cyclisation of keto-ester 3. To probe the reasons for this
dichotomy, the Boc-protected amino-ketone 27 was treated with
neat trifluoroacetic acid at room temperature. Under these condi-
tions, the loss of the tert-butoxycarbonyl group was observed and
the cyclic imine 31 was isolated and characterised. This was now
treated with methyl chloroformate and triethylamine. A fairly com-
plex mixture of products was obtained from this reaction but the
major product, which was isolated in a 41% yield, was identified as
the tropinone 32 in which the 2-methoxycarbonyl group is axial, this
assignment being made on the basis of spectroscopic data, for exam-
ple, the chemical shift of H(2) at d 3.35.
H
H
CO2Me
H
CO2Me
H
Me
Me
N
NH
n-Bu
n-Bu
BnO
2
BnO
H
O
H
CO Me
HO
2
32
30
Scheme 4. Reagents and conditions: (i) TFA, CH2Cl2, 0 °C, 1 h (82%); (ii) NaBH4,
MeOH, 0 °C, 30 min (99%); (iii) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 24 h (57%); (iv) TFA,
0 °C, rt, 20 min (79%); (v) MeCO2Cl, CH2Cl2, ꢀ78 °C, Et3N, ꢀ78 °C, 18 h (41%).
The product from this cyclisation reaction was identified as an
8-azabicyclo[3.2.1]octanone from its spectroscopic data. Although

E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
973
The formation of the equatorial product 28 from keto-ester 27
4. Experimental
may be due to kinetic control, possibly involving the addition of
the (Z)-enol of the keto-ester to the iminium ion formed by an
acid-catalysed reaction of the Boc-protected amine and the 8-ke-
tone functionality. The formation of the cyclic imine 31 must fol-
low loss of the tert-butoxycarbonyl group either from the
intermediate iminium ion or from the tropinone 28. As the conver-
sion of imine 31 into the tropinone 32 is carried out under more
vigorous conditions than those used to prepare 28, it may be that
thermodynamic control is involved in this case.
The efficient formation of tropinone 28 with the equatorial 2-
methoxycarbonyl group, and a side-chain corresponding to C(10)
and C(11) of stemofoline, makes this an attractive intermediate
for a synthesis of stemofoline. However, a new protocol is required
for the introduction of the third ring incorporating C(5) and C(6) of
stemofoline, (see structure 1) since in the original work, the axial
methoxycarbonyl group was used directly to form a bridge with
the N-methoxycarbonyl group. Allylation of the tropinone 28
formed cleanly product 33 with the prop-2-enyl substituent in
the axial position, see Scheme 5. Oxidative cleavage of the alkene
then gave aldehyde 34 but attempts to remove the tert-butoxycar-
bonyl group from this keto-aldehyde led to an acid-catalysed intra-
molecular aldol condensation forming the hydroxy-ketone 35. This
was obtained as a single epimer at the hydroxyl bearing carbon,
the configuration shown being tentatively assigned since in this
epimer the hydroxy group should be able to undergo intramolecu-
lar hydrogen bonding with the carbamate.
4.1. General procedures
Flash column chromatography was performed using Merck sil-
ica gel (60H; 40–60
, 230–240 mesh). Petrol refers to light petro-
l
leum which was redistilled before use and refers to the fraction
boiling between 40 and 60 °C. Tetrahydrofuran was dried over
sodium-benzophenone and was distilled prior to use. Dichloro-
methane was dried over CaH2 and distilled before use. Ether refers
to diethyl ether. Reactions under non-aqueous conditions were
carried out under an atmosphere of nitrogen or argon.
Electron impact (EI) or chemical ionisation using ammonia (CI)
mass spectra were recorded using a Micromass Trio 200 spectrom-
eter and high resolution mass spectra on a Kratos Concept IS spec-
trometer. Infra-red spectra were measured using a Genesis FTIR
spectrometer on NaBr plates, either neat or as evaporated films
unless otherwise stated. Nuclear magnetic resonance spectra were
recorded in deuteriated chloroform unless otherwise indicated on
either
a Varian Unity 500 (500 MHz), Varian INOVA 400
(300 MHz), or a Varian INOVA 300 (300 MHz) spectrometer. Cou-
pling constants (J) are given in hertz (Hz) and chemical shifts are
relative to tetramethylsilane.
4.2. (R)-4-Benzyloxy-1,1-dibromo-3-methylbutan-2-one 118
Lithium 2,2,6,6-tetramethylpiperidine (173.49 mmol) in THF
(300 mL), prepared by treating 2,2,6,6-tetramethylpiperidine
(35.5 mL, 208.2 mmol) in THF (300 mL) with nBuLi (1.6 M in hex-
anes, 108.43 mL, 173.49 mmol) at 0 °C, was added to methyl (R)-
3-benzyloxy-2-methylpropanoate 10 (18.04 g, 86.74 mmol) and
dibromomethane (12.3 mL, 173.49 mmol) in THF (290 mL) at
ꢀ78 °C. After 30 min at – 78 °C, the solution was added to aqueous
hydrogen chloride (1.2 M, 600 mL, 720 mmol) and the mixture was
concentrated under reduced pressure. The residue was extracted
with Et2O (2 ꢁ 600 mL) and the organic extracts were dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using Et2O (5%) in light petroleum gave the title compound
11 (15.18 g, 43.37 mmol, 50%), as a pale yellow oil, Rf = 0.62 in 10%
Et2O/light petroleum (Found: M++NH4, 365.9697. C12H18NO2Br2 re-
H
H
t
H
CO2tBu
H
CO2 Bu
Me
Me
N
n-Bu
N
i
n-Bu
BnO
BnO
2
2
O
O
CO2Me
33
CO2Me
28
ii
H
OH
H
t
O
CO2 Bu
t
Me
H
CO2 Bu
N
Me
iii
N
quires M, 365.9699); ½a D22
ꢂ
¼ ꢀ109:25 (c 6.7, CHCl3); mmax 2957,
n-Bu
BnO
n-Bu
BnO
O
2934, 2861, 1740, 1455, 1436, 1369, 1250, 1194, 1176, 1095 and
702 cmꢀ1; dH (500 MHz, CDCl3) 7.30–7.19 (5H, m, ArH), 6.02 (1H,
s, 1-H), 4.42 and 4.40 (each 1H, d, J 12, HCHPh), 3.51–3.39 (3H, m,
4-H2, 3-H) and 1.15 (3H, d, J 6.5, 3-CH3); dC (125 Hz, CDCl3)
198.39, 137.50, 128.49, 127.88, 127.65, 73.45, 73.18, 44.42, 41.67
and 14.62; m/z (ESꢀ) 347 (50%), 349 (100) and 351 (50).
CO2Me
34
O
CO2Me
35
Scheme 5. Reagents and conditions: (i) NaH, DMF, rt, 30 min, then TBAI, allyl
bromide, THF, reflux, 24 h (83%); (ii) OsO4, 2,6-lutidine, THF, H2O, NaIO4, rt, 5 h
(80%); (iii) TFA, rt, 2 min (40%).
4.3. Methyl (S)-4-benzyloxy-3-methylbutanoate 9
3. Conclusions
(a) Lithium hexamethyldisilazide (1
M in THF, 52.05 mL,
52.05 mmol) was added to the dibromoketone 11 (15.18 g,
43.37 mmol) in THF (430 mL) at ꢀ78 °C and the solution stirred
at ꢀ78 °C for 1 h. n-Butyllithium (1.6 M in hexanes, 59.63 mL,
95.41 mmol) was added dropwise and the dark red solution stirred
at ꢀ78 °C for 1 h then allowed to warm to 0 °C and stirred for
30 min before being added to acetyl chloride (75 mL) in anhydrous
methanol (350 mL) at 0 °C. The mixture was concentrated under
reduced pressure and the brown residue was diluted with Et2O
(200 mL) and washed with water (200 mL), saturated aqueous
sodium hydrogen carbonate (200 mL) and brine (200 mL). After
drying (MgSO4) and concentration under reduced pressure, chro-
matography using Et2O (20%) in light petroleum gave the title com-
pound 9 (4.98 g, 22.43 mmol, 52%), as a colourless oil, Rf = 0.38 in
20% Et2O/light petroleum {Found: M++H, 223.1327. C13H19O3
This work has provided examples of Mannich reactions
involving a chiral ester as well as a chiral sulfinimine. Although
aspects of matching and mismatching of the chiral reagent and
chiral substrate were not investigated, the combination used
gave useful stereoselectivity in the context of an asymmetric
approach to stemofoline. The observation of different stereose-
lectivities in the iminium ion-induced cyclisations of the keto-es-
ter 27 depending on the reaction conditions, possibly due to
kinetic and thermodynamic control, is also of interest, and will
be studied further. Finally, the C(10)–C(11) side-chain of stemof-
oline is present in both tropinones 28 and 32 which may prove
to be useful stemofoline precursors. The completion of a total
synthesis of stemofoline from these and related tropinones is
currently under investigation.

974
E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
requires M, 223.1329); ½a D22
ꢂ
¼ ꢀ7:3 (c 7.1, CHCl3)}; mmax 2954,
114 mmol) was added dropwise at ꢀ78 °C and the solution was
allowed to warm to room temperature and was stirred for 2 h.
After concentration under reduced pressure, the residue was taken
up in Et2O (100 mL) and the solution was washed with water
(100 mL). The aqueous phase was extracted with Et2O
(3 ꢁ 100 mL) and the organic extracts were dried (MgSO4) and con-
centrated under reduced pressure to give the aldehyde 15 as a
colourless oil, dH (500 MHz, CDCl3) 9.62 (1H, t, J 1.5, 1-H), which
was azeotroped with benzene.
2858, 1737, 1454, 1437, 1364, 1251, 1194, 1176, 1098, 738 and
699 cmꢀ1; dH (300 MHz, CDCl3) 7.35–7.40 (5H, m, ArH), 4.55 (2H,
s, CH2Ph), 3.70 (3H, s, OMe), 3.43 (1H, dd, J 5.5, 9, 4-H), 3.35 (1H,
dd, J 7, 9, 4-H0), 2.55 (1H, dd, J 6, 15, 2-H), 2.38 (1H, m, 3-H), 2.23
(1H, dd, J 7.5, 15, 2-H0) and 1.03 (3H, d, J 6.5, 3-CH3); dC (75 Hz,
CDCl3) 173.78, 138.77, 128.61, 127.82, 127.79, 75.06, 73.24,
57.71, 38.77, 31.14 and 17.27; m/z (CI+) 223 (M++1, 100%).
(b) tert-Butyllithium (1.7 M in pentane, 116.54 mL,
198.11 mmol) was added to the iodide 1214 (27.36 g, 94 mmol)
in Et2O (940 mL) at ꢀ78 °C. The yellow solution was stirred at
ꢀ78 °C for 5 min, allowed to warm to room temperature over 1 h
and then re-cooled to ꢀ78 °C. Methyl chloroformate (29.5 mL,
377 mmol) in Et2O (470 mL) was added and the mixture stirred
for 5 min before saturated aqueous ammonium chloride (1 L) was
added. The aqueous phase was extracted with Et2O (1 L) and the
organic extracts were washed with water (2 L) and brine (2 L),
and dried (MgSO4). After concentration under reduced pressure,
chromatography of the residue using 20% Et2O in light petroleum
gave the ester 9 (12.5 g, 56.4 mmol, 60%) as a colourless oil.
Coppersulfateandthealdehyde15(2 g, 10.87 mmol)wereadded
to (S)-(ꢀ)-tert-butanesulfinamide (1.45 g, 11.96 mmol) in CH2Cl2
(24 mL) at room temperature and the suspension stirred for 18 h.
The mixture was filtered through a pad of Celite and concentrated
under reduced pressure. Chromatography of the residue using 50%
Et2O in light petroleum gave the title compound 8 (1.41 g,
4.89 mmol, 45% from 14) as a colourless oil, Rf = 0.15 in 50% Et2O/
light petroleum (Found: M+H+, 290.1790. C14H28NO3S requires M,
290.1784); ½a 2D7
¼ þ127:8 (c 10.3, CHCl3); mmax 2957, 2873, 1733,
ꢂ
1624, 1458, 1364, 1182, 1143, 1085 and 949 cmꢀ1; dH (300 MHz,
CDCl3) 8.01 (1H, t, J 4.5, 1-H), 3.86–3.67 [4H, m, O(CH2)2O], 2.52
(2H, m, 2-H2), 1.90 (2H, m, 3-H2), 1.55 (2H, m, 5-H2), 1.26 (4H, m,
6-H2, 7-H2), 1.12 (9H, s, tBu) and 0.83 (3H, t, J 7.5, 8-H3); dC (75 Hz,
CDCl3) 169.50, 110.90, 65.00, 56.75, 56.57, 37.16, 33.90, 32.30,
26.97, 22.95, 22.33 and 13.85; m/z (CI+) 290 (M++1, 100%).
4.4. Non-1-en-5-one ethylene acetal 14
Chromic oxide (3.76 g, 37.65 mmol), concentrated sulfuric acid
(3 mL) and water (11 mL) were added dropwise to non-1-en-5-ol
13 (4.86 g, 34.23 mmol) in acetone (13 mL) at 0 °C and the mixture
was stirred for 30 min at 0 °C. Water (100 mL) was added and the
mixture extracted with Et2O (3 ꢁ 200 mL). The organic extracts
were dried (MgSO4) and concentrated under reduced pressure to
give a brown oil which was distilled to give non-1-en-5-one
(3.41 g, 24.4 mmol, 71%) as a colourless oil, bp 75 °C at 15 mmHg,
Rf = 0.75 in 20% Et2O/light petroleum (Found: M+H+, 140.1200.
C9H16O, requires M, 140.1196); mmax 2959, 2933, 2873, 1715,
1641, 1412, 1370, 1128, 996, 913 and 744 cmꢀ1; dH (300 MHz,
CDCl3) 5.74 (1H, ddt, J 10, 17, 6.5, 2-H), 4.95 (1H, ddt, J 3, 17, 1.5,
1-H), 4.90 (1H, ddt, J 3, 10, 1.5, 1-H0), 2.44 (2H, t, J 7.5, 4-H2),
2.34 (2H, t, J 7.5, 6-H2), 2.27 (2H, m, 3-H2), 1.47 (2H, tt, J 7.5, 8,
7-H2), 1.25 (2H, tq, J 7.5, 8, 8-H2) and 0.83 (3H, t, J 7.5, 9-H3); dC
(75 Hz, CDCl3) 210.61, 137.20, 115.14, 42.63, 41.74, 27.78, 25.90,
22.35 and 13.86; m/z (CI+) 158 (M++18, 100%) and 141 (M++1, 20).
Ethylene glycol (1.5 mL, 26.80 mmol) followed by toluene
p-sulfonic acid (5 mg) was added to non-1-en-5-one (3.41 g,
24.36 mmol) in benzene (34 mL) and the mixture heated under
reflux for 18 h using a Dean Stark trap. After cooling to room tem-
perature and concentrating under reduced pressure, Et2O (100 mL)
was added and the solution was washed with saturated aqueous
sodium hydrogen carbonate (150 mL). The aqueous phase was
extracted with Et2O (100 mL) and the organic extracts were dried
(MgSO4) and concentrated under reduced pressure to give the title
compound 14 (4.4 g, 23.9 mmol, 98%) as a colourless oil, Rf = 0.75
in 20% Et2O/light petroleum (Found: M++H, 185.1531. C11H21O2
requires M, 185.1536); mmax 2955, 2875, 1642, 1453, 1213, 1155,
1079, 1043 and 910 cmꢀ1; dH (500 MHz, CDCl3) 5.76 (1H, ddt, J
10, 17, 6.5, 2-H), 4.97 (1H, ddd, J 1.5, 3.5, 17, 1-H), 4.87 (1H, ddd,
J 1.5, 3.5, 10, 1-H0), 3.87 [4H, s, O(CH2)2O], 2.05 (2H, m, 3-H2),
1.64 (2H, m, 4-H2), 1.54 (2H, m, 6-H2), 1.25 (4H, m, 7-H2 and 8-
H2) and 0.83 (3H, t, J 7.5, 9-H3); dC (125 Hz, CDCl3) 138.63,
114.18, 111.51, 64.96, 37.02, 36.24, 28.13, 26.00, 23.00 and
14.08; m/z (CI+) 185 (M++1, 100%).
4.6. Methyl (2R,3S)-2-[(S)-2-Benzyloxy-1-methylethyl]-3-[(SS)-
tert-butylsulfinylamino]-6-oxodecanoate ethylene acetal 16
n-Butyllithium (1.6 M in hexanes, 5.2 mL, 8.37 mmol) was added
to di-isopropylamine (1.3 mL, 9.13 mmol) in THF (45 mL) at 0 °C and
the solution stirred at 0 °C for 30 min before being cooled to ꢀ78 °C.
The ester 9 (1.69 g, 7.61 mmol) in THF (40 mL) was added and the
solution stirred at ꢀ78 °C for 1 h before chlorotitanium tri-isoprop-
oxide (3.83 mL, 15.22 mmol) in THF (15 mL) was added. The bright
yellowsolutionwasstirredat ꢀ78 °Cfor1 handthenthesulfinimine
8 (771 mg, 2.67 mmol) in THF (0.5 mL) was added. The reaction mix-
ture was stirred at ꢀ60 °C for 48 h and saturated aqueous ammo-
nium chloride (50 mL) was added. The mixture was diluted with
water (50 mL) and extracted with Et2O (3 ꢁ 100 mL). The organic
extractswerewashedwithwater(300 mL)andbrine(300 mL), dried
(Na2SO4) and concentrated under reduced pressure. Chromatogra-
phy of the residue using 80% Et2O in light petroleum gave the minor
diastereomer (148 mg, 0.29 mmol, 10%) as a colourless oil, Rf = 0.35
in 80% Et2O/light petroleum (Found: M++H, 512.3035. C27H46NO6S
requires M, 512.3040); ½a D26
¼ þ14:7 (c 1.9, CHCl3); mmax 2956,
ꢂ
1718, 1455, 1362, 1170, 1071 and 736 cmꢀ1; dH (500 MHz, CDCl3)
7.26 (5H, m, ArH), 4.82 (1H, d, J 8, NH), 4.47 and 4.40 (each 1H, d, J
12.5, HCHPh), 3.81 [4H, m, O(CH2)2O], 3.65 (1H, dd, J 4, 10, 20-H),
3.62 (3H, s, OMe), 3.35 (1H, dd, J 3.5, 10, 20-H0), 3.23 (1H, m, 3-H),
2.70 (1H, dd, J 3.5, 10, 2-H), 2.28 (1H, m, 10-H), 1.61 (1H, m, 7-H),
1.53–1.46 (4H, m), 1.37 (2H, m, 5-H2), 1.26–1.19 (3H, m), 1.16 (9H,
t
s, Bu), 0.90 (3H, d, J 7, 10-CH3) and 0.82 (3H, t, J 6.5, 10-H3); dC
(75 Hz, CDCl3) 176.13, 138.89, 128.56, 127.89, 127.73, 111.70,
73.24, 71.72, 65.29, 65.15, 56.54, 56.14, 51.70, 50.74, 37.17, 33.92,
32.83, 31.25, 26.24, 23.22, 16.39 and 14.34; m/z (CI+) 512 (M++1,
100%).
The second fraction was the title compound 16 (900 mg,
1.76 mmol, 66%) as a colourless oil, Rf = 0.24 in 80% Et2O/light petro-
leum, ½a 2D6
ꢂ
¼ þ7:2 (c 8.3, CHCl3);
mmax 3436, 2872, 1733, 1455, 1364,
1261, 1196 and 1168 cmꢀ1; dH (500 MHz, CDCl3) 7.24 (5H, m, ArH),
4.41 and 4.36 (each 1H, d, J 12, HCHPh), 4.00 (1H, d, J 8, NH), 3.83
[4H, m, O(CH2)2O], 3.56 (3H, s, OMe), 3.46 (1H, m, 3-H), 3.37 (1H,
dd, J 5.5, 9.5, 20-H), 3.23 (1H, dd, J 6.5, 9.5, 20-H0), 2.76 (1H, dd, J 4.5,
9, 2-H), 2.24 (1H, m, 10-H), 1.77 and 1.60 (each 1H, m, 5-H), 1.50
(3H, m, 4-H, 7-H2), 1.23 (5H, m, 4-H0, 8-H2, 9-H2), 1.15 (9H, s, tBu),
0.98 (3H, d, J 7, 10-CH3) and 0.82 (3H, t, J 7, 10-H3); dC (125 Hz, CDCl3)
4.5. (SS)-N-(tert-Butylsulfinyl)-4-oxo-octanimine ethylene
acetal 8
Ozonised air was bubbled through a solution of the alkene 14
(2 g, 10.87 mmol) in methanol (42 mL) at ꢀ78 °C for ca. 30 min
until a pale blue colour persisted. Dimethyl sulfide (8.6 mL,

E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
975
173.46, 138.33, 128.28, 127.76, 127.47, 111.48, 74.10, 73.01, 64.93,
64.86, 56.46, 56.10, 53.93, 51.57, 36.93, 33.78, 32.68, 26.20, 26.05,
22.93, 22.77, 15.31 and 14.21.
ꢀ78 °C. Methyl acetate (0.26 mL, 0.32 mmol) in THF (0.8 mL) was
added, followed, after 1 h at ꢀ78 °C, by the aldehyde 18 (120 mg,
0.25 mmol) in THF (0.5 mL). The solution was stirred for 1 h and
then warmed to rt before saturated aqueous ammonium chloride
(10 mL) was added. The mixture was diluted with Et2O (10 mL)
and the aqueous phase extracted with Et2O (3 ꢁ 10 mL). The organ-
ic extracts were washed with brine (30 mL), dried (MgSO4), filtered
and concentrated under reduced pressure. Chromatography of the
residue using 25% Et2O in light petroleum gave the title compound
19 (25 mg, 0.069 mmol, 28%) as a colourless oil, Rf = 0.92 in 90%
Et2O/light petroleum; mmax 3400, 2958, 2935, 2873, 2714, 1714,
1686, 1635, 1455, 1373, 1261, 1206, 1091, 1039, 949, 739 and
699 cmꢀ1; dH (300 MHz, CDCl3) 9.26 (1H, d, J 1.5, 1-H), 7.26–7.20
(5H, m, ArH), 6.43 (1H, t, J 7.5, 3-H), 4.40 (2H, s, CH2Ph), 3.85
[4H, m, O(CH2)2O], 3.61 (1H, dd, J 8, 9, 20-H), 3.53 (1H, dd, J 7, 9,
20-H0), 2.99 (1H, m, 10-H), 2.38 (2H, m, 4-H2), 1.72 (2H, m, 5-H2),
1.52 (2H, m, 7-H2), 1.27–1.22 (4H, m, 8-H2 and 9-H2), 1.09 (3H,
d, J 7.5, 10-CH3) and 0.83 (3H, t, J 7.5, 10-H3); dC (75 Hz, CDCl3)
194.47, 156.16, 143.33, 137.55, 127.24, 126.55, 126.40, 110.09,
71.96, 63.99, 62.67, 36.11, 31.44, 24.94, 22.46, 21.93, 21.29, 14.44
and 13.04; m/z (CI+) 361 (M++1, 10%), 350 (25), 322 (50), 242
(20), 160 (65), 143 (95) and 106 (100).
4.7. (2R,3S)-2-[(S)-2-Benzyloxy-1-methylethyl]-3-[(SS)-tert-
butylsulfinylamino]-6-oxodecan-1-ol ethylene acetal 17
Lithium aluminium hydride (140 mg, 3.5 mmol) was added at
0 °C to the ester 16 (900 mg, 1.76 mmol) in THF (7 mL). The sus-
pension was stirred at 0 °C for 40 min, allowed to warm to room
temperature and stirred for a further 2 h. Ethyl acetate (30 mL)
was added dropwise at 0 °C followed by water (30 mL). The aque-
ous layer was extracted with ethyl acetate (2 ꢁ 30 mL) and the
organic extracts washed with brine (60 mL), dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the res-
idue using 2% methanol in Et2O gave the title compound 17
(780 mg, 1.61 mmol, 91.5%) as a colourless oil, Rf = 0.25 in Et2O
(Found: M+H+, 484.3102. C26H46NO5S requires M, 484.3091);
½
a 2D6
ꢂ
¼ þ17:9 (c 9.6, CHCl3); mmax 3370, 3259, 2956, 2873, 1455,
1365, 1073, 1043, 737 and 699 cmꢀ1; dH (500 MHz, CDCl3) 7.26
(5H, m, ArH), 5.02 (1H, d, J 8.5, NH), 4.46 (2H, s, CH2Ph), 3.86
[4H, m, O(CH2)2O], 3.74 (1H, t, J 11, 1-H), 3.64 (1H, dd, J 3.5, 11,
1-H0), 3.40 (1H, m, 3-H), 3.28 (1H, t, J 9.5, 20-H), 3.16 (1H, dd, J
4.5, 9.5, 20-H0), 2.05 (1H, m, 10-H), 1.83 (1H, m, 2-H), 1.76 (1H, m,
t
4.10. (SS)-N-(tert-Butylsulfinyl)-4-methylene-octanimine 21
5-H), 1.58–1.43 (6H, m), 1.26 (3H, m), 1.05 (9H, s, Bu), 0.90 (3H,
d, J 7.5, 10-CH3) and 0.83 (3H, t, J 6.5, 10-H3); dC (125 Hz, CDCl3)
137.52, 128.51, 127.87, 127.69, 111.64, 73.44, 72.73, 64.89, 59.06,
57.51, 48.73, 34.41, 34.23, 30.77, 30.31, 28.72, 26.02, 22.97,
22.81, 18.08 and 14.13; m/z (CI+) 484 (M++1, 30%), 422 (15), 365
(20), 129 (70) and 91 (100).
4-Methylene-octanol 20 (3.25 g, 22.89 mmol) in CH2Cl2
(100 mL) was added to a suspension of pyridinium dichromate
(21.97 g, 57.23 mmol) in CH2Cl2 (100 mL) and the resultant mix-
ture stirred at room temperature for 24 h. Et2O (200 mL) was
added and the suspension filtered through a short column of silica
gel (200 mL). The column was washed with Et2O (5 ꢁ 200 mL) and
the filtrate concentrated under reduced pressure. Chromatography
of the residue using 5% Et2O in light petroleum gave 4-methylene-
octanal (1.83 g, 13.07 mmol, 60%) as a colourless oil, Rf = 0.82 in
40% Et2O/light petroleum; mmax 2930, 1730, 1646, 1454, 1262,
1138, 889 and 800 cmꢀ1; dH (500 MHz, CDCl3) 9.71 (1H, t, J 1.5,
1-H), 4.71 and 4.63 (each 1H, d, J 1, 4-CH), 2.57 (2H, td, J 7.5, 1.5,
2-H2), 2.28 (2H, t, J 7.5, 3-H2), 1.96 (2H, t, J 8, 5-H2), 1.35 (2H, m,
6-H2), 1.24 (2H, m, 7-H2) and 0.84 (3H, t, J 7.5, 8-H3); dC (125 Hz,
CDCl3) 202.33, 147.88, 109.45, 41.87, 36.02, 29.87, 28.07, 22.38
and 13.95.
4.8. (2R,3S)-2-[(S)-2-Benzyloxy-1-methylethyl]-3-[(S)-tert-
butylsulfinylamino)-6-oxodecanal ethylene acetal 18
Pyridine (5.8 mL, 17.71 mmol) and the Dess Martin periodinane
(1.4 g, 3.28 mmol) were added at 0 °C to the alcohol 17 (780 mg,
1.61 mmol) in CH2Cl2 (11.5 mL). The solution was stirred at 0 °C
for 3.5 h and then the mixture was diluted with Et2O (100 mL) and
poured into a mixture of sodium thiosulfite (25 g) and saturated
aqueous sodium hydrogen carbonate (100 mL). The mixture was
stirred at rt until all the solid had dissolved. The aqueous phase
was extracted with Et2O (2 ꢁ 100 mL) and the organic extracts
washed with water (4 ꢁ 300 mL), brine (300 mL) and dried (MgSO4).
After concentration under reduced pressure, chromatography of the
residue using Et2O gave the title compound 18 (546 mg, 70%) as a
colourless oil, Rf = 0.43 in Et2O (Found: M+H+, 482.2925. C26H44NO5S
Copper sulfate (3.58 g, 22.4 mmol) and 4-methylene-octanal
(1.57 g, 11.2 mmol) in CH2Cl2 (30 mL) were added to (S)-(ꢀ)-tert-
butanesulfinamide (1.5 g, 12.34 mmol) in CH2Cl2 (30 mL) at room
temperature and the suspension stirred for 18 h. The mixture
was filtered through a pad of Celite and concentrated under
reduced pressure. Chromatography of the residue using 40% Et2O
in light petroleum gave the title compound 21 (2.53 g, 10.41 mmol,
93%) as a colourless oil (Found: M+H+, 244.1739. C13H26NOS
requires M, 482.2935); ½a D24
ꢂ
¼ þ12:8 (c 5.3, CHCl3);
mmax 3419, 3236,
2957, 2872, 1714, 1455, 1364, 1070, 739 and 699 cmꢀ1; dH
(300 MHz, CDCl3) 9.71 (1H, d, J 3, 1-H), 7.28–7.19 (5H, m, ArH),
4.40 and 4.34 (each 1H, d, J 12, HCHPh), 4.01 (1H, d, J 9, NH), 3.83
[4H, m, O(CH2)2O], 3.45 (1H, dd, J 4.5, 9, 20-H), 3.42 (1H, m, 3-H),
3.28 (1H, dd, J 8, 9, 200-H0), 2.56 (1H, m, 2-H), 2.33 (1H, m, 10-H),
1.78 (1H, ddd, J 4, 11, 13.5, 4-H), 1.63 (1H, m, 4-H0), 1.50–1.46 (3H,
m, 7-H2, 5-H), 1.36 (1H, ddd, J 4.5, 11, 15, 5-H00), 1.23–1.18 (4H, m,
9-H2, 8-H2), 1.15 (9H, s, tBu), 0.99 (3H, d, J 7, 10-CH3) and 0.82 (3H,
t, J 6.5, 10-H3); dC (75 Hz, CDCl3) 206.01, 137.17, 128.41, 128.32,
127.70, 111.49, 74.18, 73.27, 64.87, 64.85, 60.13, 57.13, 56.22,
55.67, 36.86, 34.01, 32.83, 26.38, 25.95, 22.78, 15.25 and 14.08; m/
z (CI+) 482 (M++1, 10%), 290 (80) and 85 (100).
requires M, 244.1730); ½a D26
¼ þ230 (c 11.5, CHCl3) mmax 2958,
ꢂ
2929, 1645, 1622, 1456, 1363, 1088 and 889 cmꢀ1; dH (500 MHz,
CDCl3) 8.01 (1H, t, J 4.5, 1-H), 4.71 and 4.67 both (1H, m, 4-CH),
2.60 (2H, m, 2-H2), 2.27 (2H, t, J 7.5, 3-H2), 1.97 (2H, t, J 7.5, 5-
t
H2), 1.35 (2H, m, 6-H2), 1.25 (2H, m, 7-H2), 1.12 (9H, s, Bu) and
0.84 (3H, t, J 7.5, 8-H3); dC (125 Hz, CDCl3) 169.19, 147.89,
109.69, 56.54, 35.88, 34.22, 31.41, 29.86, 22.41, 22.34 and 13.97;
m/z (CI+) 244 (M++1, 100%).
4.11. Methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-[(SS)-
tert-butylsulfinylamino]-6-methylenedecanoate 22
4.9. (E)-2-[(S)-2-Benzyloxy-1-methylethyl]-6-oxodecan-2-enal
ethylene acetal 19
n-Butyllithium (1.6 M in hexanes, 32.78 mL, 52.45 mmol) was
added to di-isopropylamine (7.5 mL, 53.48 mmol) in THF
(250 mL) at 0 °C and the solution stirred for 30 min then cooled
to ꢀ78 °C. The ester 9 (11.42 g, 51.4 mmol) in THF (250 mL) was
n-Butyllithium (1.6 M in hexane, 0.2 mL, 0.35 mmol) was added
to di-isopropylamine (0.05 mL, 0.38 mmol) in THF (1 mL) at 0 °C
and the solution stirred at 0 °C for 30 min before being cooled to

976
E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
added and the mixture stirred for 1 h Chlorotitanium triisopropox-
ide (25.86 mL, 102.85 mmol) in THF (100 mL) was added and the
solution was stirred at ꢀ78 °C for 1 h. The sulfinylimine 21 (5.0 g,
20.57 mmol) in THF (4 mL) was then added and, after 18 h at
ꢀ90 °C, saturated aqueous ammonium chloride (500 mL) was
added at ꢀ78 °C and the mixture allowed to warm to room tem-
perature before being diluted with water (100 mL) and extracted
with Et2O (2 ꢁ 600 mL). The organic extracts were washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using hexane–acetonitrile–CH2Cl2
(25:3:7 to 20:3:7) gave a mixture of minor products (1.72 g,
3.7 mmol, 18%), Rf = 0.59 in 80% Et2O/light petroleum, followed
by the title compound 22 (6.89 g, 14.81 mmol, 72%) as a colourless
oil, Rf = 0.36 in 80% Et2O/light petroleum (Found: M+H+, 466.2992.
and at room temperature for 20 min. Saturated aqueous potassium
sodium tartrate (150 mL) was added dropwise at 0 °C and the mix-
ture was diluted with Et2O (200 mL) then stirred for 18 h at room
temperature. The aqueous phase was extracted with Et2O
(3 ꢁ 200 mL) and the organic extracts washed with water
(800 mL) and brine (800 mL) then dried (Na2SO4). After concentra-
tion under reduced pressure, chromatography of the residue using
50% Et2O in light petroleum gave the title compound 24 (5.07 g,
11.70 mmol, 85%) as a colourless oil, Rf = 0.18 in 30% Et2O/light
petroleum (Found: M+H+, 434.3271. C26H44NO4 requires M,
434.3265) ½a 2D3
¼ ꢀ23:2 (c 12.4, CHCl3) mmax 3407, 2959, 2929,
ꢂ
1688, 1511, 1454, 1365, 1249, 1172, 1092, 1075, 1043, 887 and
737; dH (500 MHz, CDCl3) 7.27 (5H, m, ArH), 5.36 (1H, d, J 10, NH),
4.64 and 4.62 (each 1H, s, 6-CH), 4.45 and 4.41 (each 1H, d, J 11.5,
HCHPh), 3.82 (1H, m, 3-H), 3.66 (1H, dd, J 4.5, 9.5, OH), 3.54 (1H,
ddd, J 4.5, 9.5, 12, 1-H), 3.48 (1H, ddd, J 4.5, 9, 12, 1-H0), 3.22 (2H,
m, 20-H2), 2.05 (1H, m, 10-H), 2.01–1.89 (4H, m, 7-H2, 5-H2), 1.62
(1H, m, 2-H), 1.54 (2H, dd, J 8, 15, 4-H2), 1.37 (9H, s, tBu), 1.31 (2H,
m, 8-H2), 1.23 (2H, m, 9-H2), 0.93 (3H, d, J 7.5, 10-CH3) and 0.83
(3H, t, J 7.5, 10-H3); dC (125 Hz, CDCl3) 157.32, 149.50, 137.47,
128.51, 127.90,127.85, 108.96, 79.24, 73.47, 72.27, 65.87 58.98,
49.10, 48.95, 35.81, 33.04, 31.03, 29.96, 28.43, 22.45, 18.12 and
14.02; m/z (ES+) 456 (M+ + 23, 50%) and 434 (M++1, 100).
C26H44NO4S requires M, 466.2986); ½a D23
¼ þ6:8 (c 4.7, CHCl3) mmax
ꢂ
3311, 2955, 1733, 1644, 1455, 1364, 1194, 1168, 1074, 889, 737
and 698 cmꢀ1; dH (500 MHz, CDCl3) 7.27–7.18 (5H, m, ArH), 4.67
(1H, d, J 1, 6-CH), 4.62 (1H, s, 6-CH0), 4.41 and 4.37 (each 1H, d, J
12, HCHPh), 3.98 (1H, d, J 9, NH), 3.56 (3H, s, OMe), 3.47 (1H, dddd,
J 2.5, 4.5, 7, 9, 3-H), 3.36 (1H, dd, J 5.5, 9, 20-H), 3.22 (1H, dd, J 4.5, 9,
20-H0), 2.78 (1H, dd, J 4.5, 9, 2-H), 2.22 (1H, m, 100-H), 2.13 (1H, ddd,
J 4.5, 9.5, 14.5, 5-H), 1.92 (3H, m, 5-H0, 7-H2), 1.61 (1H, dddd, J 2.5,
7, 9.5, 12, 4-H), 1.34–1.18 (5H, m, 4-H0, 8-H2, 9-H2), 1.16 (9H, s,
tBu), 0.97 (3H, d, J 7, 100-CH3) and 0.83 (3H, t, J 7, 10-H3); dC
(125 Hz, CDCl3) 173.55, 148.94, 138.33, 128.27, 127.62, 127.45,
109.68, 74.15, 73.01, 56.12, 55.73, 53.89, 51.53, 35.69, 32.70,
32.54, 30.17, 29.92, 22.77, 22.40, 15.27 and 13.99; m/z (CI+) 466
(M++1, 80%) and 91 (100).
4.14. (2R,3S)-2-[(S)-2-Benzyloxy-1-methylethyl]-3-tert-
butoxycarbonylamino-6-methylenedecanal 25
Pyridine (10.42 mL, 128.7 mmol) and the Dess Martin period-
inane (10.42 g, 24.57 mmol) were added to the alcohol 24 (5.07 g,
11.70 mmol) in CH2Cl2 (84 mL) at 0 °C and the solution stirred at
0 °C for 3.5 h before being poured into a solution of sodium thiosul-
fate (25 g) in saturated aqueous sodium hydrogen carbonate
(100 mL). The mixture was stirred at room temperature until all
the solid had dissolved. The aqueous phase was then extracted with
CH2Cl2 (2 ꢁ 100 mL) and the organic extracts were washed with
water (4 ꢁ 300 mL) and brine (300 mL) and dried (MgSO4). After
concentration under reduced pressure, chromatography of the resi-
due using 30% Et2O in light petroleum gave the title compound 25
(4.08 g, 9.48 mmol, 81%) as a colourless oil, Rf = 0.58 in 50% Et2O/
light petroleum (Found: M+H+, 432.3104. C26H42NO4 requires M,
4.12. Methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-
butoxycarbonylamino-6-methylenedecanoate 23
Hydrogen chloride (4 M in dioxane, 18.51 mL, 74 mmol) was
added to the sulfinamide 22 (6.89 g, 14.81 mmol) in methanol
(150 mL) at room temperature and the solution stirred at room tem-
perature for 1 h before being concentrated under reduced pressure.
The residue was taken up in water (10 mL) and the solution cooled to
0 °C before triethylamine (4.75 mL, 34.1 mmol) and di-tert-butyl
dicarboxylate (4.33 g, 19.25 mmol) in THF (7.4 mL) were added.
The mixture was stirred at room temperature for 1 h, diluted with
CH2Cl2 (100 mL) and washed with saturated aqueous sodium hydro-
gen sulfate (100 mL), water (100 mL) and brine (100 mL) then dried
(MgSO4). After concentration under reduced pressure, chromatogra-
phy of the residue using 30% Et2O in light petroleum gave the title
432.3108); ½a 2D5
¼ ꢀ20:95 (c 6.3, CHCl3) mmax 3367, 2959, 1712,
ꢂ
1510, 1453, 1365, 1247, 1170, 1097 and 736 cmꢀ1; dH (500 MHz,
CDCl3) 9.64 (1H, d, J 3.5, 1-H), 7.29–7.19 (5H, m, ArH), 4.74 (1H, d, J
9.5, NH), 4.66 and 4.62 (each, 1H, s, 6-CH), 4.38 (2H, s, CH2Ph), 3.95
(1H, ddd, J 3, 6, 9.5, 3-H), 3.44 (1H, dd, J 4.5, 9.5, 20-H), 3.33 (1H, dd,
J 7, 9.5, 20-H0), 2.32 (1H, ddd, J 3.5, 6, 9.5, 2-H), 2.25 (1H, m, 10-H),
2.04 (1H, ddd, J 4.5, 10, 15, 5-H), 1.95 (1H, dd, J 7, 10, 5-H0), 1.91
compound 23 (6.35 g, 13.77 mmol, 93%) as
a colourless oil,
Rf = 0.20 in 15% Et2O/light petroleum (Found: M+H+, 462.3205.
C27H44NO5 requires M, 462.3214); ½a D23
¼ ꢀ24:8 (c 11.6, CHCl3) mmax
ꢂ
t
3364, 2958, 1713, 1645, 1513, 1454, 1366, 1170, 1099, 889, 737 and
698 cmꢀ1; dH (500 MHz, CDCl3); 7.27–7.18 (5H, m, ArH), 4.65 and
4.63 (each 1H, s, 6-CH), 4.55 (1H, d, J 9.5, NH), 4.41 and 4.36 (each
1H, d, J 12, HCHPh), 3.84 (1H, m, 3-H), 3.53 (3H, s, OMe), 3.43 and
3.25 (each, 1H, dd, J 6, 9.5, 20-H), 2.58 (1H, dd, J 6.5, 7.5, 2-H), 2.17
(1H, m, 10-H), 2.03 (1H, ddd, J 4.5, 10, 14.5, 5-H), 1.92 (3H, m, 5-H0,
(2H, t, J 7.5, 7-H2), 1.63 (2H, m, 8-H and 4-H), 1.36 (9H, s, Bu),
1.34–1.19 (4H, m, 4-H0, 8-H0, 9-H2), 0.99 (3H, d, J 7, 10-CH3) and
0.83 (3H, t, J 7, 10-H3); dC (75 Hz, CDCl3) 204.63, 155.52, 148.94,
137.89, 128.41, 128.34, 127.66, 109.31, 79.35, 73.44, 73.18, 59.55,
49.42, 35.85, 32.66, 32.63, 30.38, 29.93, 28.38, 22.45, 15.66 and
14.00; m/z (ES+) 432 (M++1, 100%).
t
7-H2), 1.59 (1H, m, 4-H), 1.37 (9H, s, Bu), 1.32 (1H, m, 4-H0), 1.30
(2H, m, 8-H2), 1.22 (2H, m, 9-H2), 0.96 (3H, d, J 7, 10-CH3) and 0.82
(3H, t, J 7, 10-H3); dC (125 Hz, CDCl3) 173.82, 155.43, 149.15,
138.40, 128.29, 127.61, 127.47, 109.19, 79.22, 73.81, 73.01, 52.90,
51.37, 49.79, 35.85, 32.89, 32.57, 29.94, 29.77, 28.39, 22.45, 15.48
and 14.00; m/z (ES+) 462 (M++1, 100%).
4.15. Methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-
butoxycarbonylamino-8-methylene-3-oxododecanoate 26
n-Butyllithium (1.6 M in hexanes, 15.08 mL, 24.17 mmol) was
added to di-isopropylamine (3.45 mL, 24.65 mmol) in THF
(140 mL) at 0 °C and the solution stirred for 30 min then cooled
to ꢀ78 °C. Methyl acetate (1.89 mL, 23.7 mmol) was added and
the mixture stirred for 1 h. The aldehyde 25 (4.08 g, 9.48 mmol)
in THF (19 mL) was added and the solution stirred at ꢀ78 °C for
2 h. Saturated aqueous ammonium chloride (200 mL) was added
and the mixture extracted with Et2O (3 ꢁ 200 mL). The organic
extracts were washed with water (600 mL) and brine (600 mL),
4.13. (2R,3S)-2-[(S)-2-Benzyloxy-1-methylethyl]-3-tert-
butoxycarbonylamino-6-methylenedecan-1-ol 24
Di-isobutylaluminium hydride (1 M in hexanes, 82.62 mL,
82.62 mmol) was added to the ester 23 (6.35 g, 13.77 mmol) in
THF (51 mL) at ꢀ78 °C and the solution stirred at ꢀ78 °C for 1 h

E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
977
dried (Na2SO4) and concentrated under reduced pressure. Chroma-
tography of the residue using 40% Et2O in light petroleum gave the
aldol products (3.93 g, 7.77 mmol, 82%) as a 2:1 mixture of diaste-
reomers, Rf = 0.33 (major) and 0.22 (minor) in 40% Et2O/light petro-
leum (Found: M+H+, 506.3464. C29H48NO6, requires M, 506.3476);
mmax 3367, 2957, 1710, 1517, 1454, 1366, 1251, 1172, 1089, 887
and 736 cmꢀ1; dH (500 MHz, CDCl3) major diastereomer 7.29–
7.27 (5H, m, ArH), 5.86 (1H, d, J 9.5, NH), 4.65 (2H, s, 8-CH2), 4.48
(2H, s, CH2Ph), 4.02 (1H, m, 3-H), 3.61 (3H, s, OMe), 3.58 (1H, d, J
9, 20-H), 3.55 (1H, m, 5-H), 3.30 (1H, dd, J 3.5, 9, 20-H0), 3.21 (1H,
br s, OH), 2.64 (1H, dd, J 1.5, 16.5, 2-H), 2.42 (1H, dd, J 9, 16.5, 2-
H0), 2.12 (1H, m, 10-H), 1.94 (4H, m, 7-H2, 9-H2), 1.62–1.51 (3H,
suspension was stirred for 1 h then diluted with water (60 mL) and
extracted with Et2O (3 ꢁ 50 mL). The organic extracts were washed
with brine (150 mL) and dried (Na2SO4). After concentration under
reduced pressure, chromatography of the residue using 50% Et2O in
light petroleum gave the title compound 27 (2.53 g, 5.01 mmol,
75% from 26) as a colourless oil, Rf = 0.16 in 50% Et2O/light petro-
leum (Found: M+H+, 506.3105. C28H44NO7 requires M, 506.3112);
½
a 2D5
ꢂ
¼ ꢀ123:5 (c 3.4, CHCl3) mmax 3368, 2960, 1747, 1710, 1512,
1453, 1367, 1245, 1165, 737 and 698 cmꢀ1; dH (500 MHz, C6D6)
keto-tautomer 7.36–7.19 (5H, m, ArH), 5.04 (1H, d, J 9.5, NH),
4.32 and 4.30 (each 1H, d, J 12, HCHPh), 4.17 (1H, m, 5-H), 3.56
and 3.52 (each 1H, d, J 16, 2-H), 3.45 (3H, s, OMe), 3.36 (1H, dd, J
2, 9.5, 20-H), 3.26 (1H, dd, J 5, 9.5, 20-H0), 3.07 (1H, dd, J 6.5, 7.5,
4-H), 2.38 (1H, m, 9-H), 2.31 (1H, m, 10-H), 2.24 (1H, dd, J 7, 14,
9-H0), 2.18 (1H, t, J 7, 7-H), 2.05 (2H, m, 6-H, 7-H0), 1.74 (1H, m,
t
m, 4-H, 6-H2), 1.32 (9H, s, Bu), 1.28–1.20 (4H, m, 10-H2, 11-H2),
1.03 (3H, d, J 7.5, 10-CH3) and 0.83 (3H, t, J 7.5, 11-H3); minor
diastereomer 7.25–7.20 (5H, m, ArH), 5.30 (1H, d, J 10, NH), 4.63
(2H, s, 8-CH2), 4.49 and 4.42 (each 1H, d, J 12, HCHPh), 4.15 (1H,
m, 3-H), 3.62 (3H, s, OMe), 3.50 (1H, dd, J 8.5, 16.5, 20-H), 3.35
(1H, m, 5-H), 3.26 (1H, m, 20-H0), 3.21 (1H, br s, OH), 2.55–2.48
(2H, m, 2-H2), 2.12 (1H, 10-H), 2.06–1.97 (4H, m, 7-H2, 9-H2),
1.71–1.63 (3H, m, 4-H, 6-H2), 1.46–1.38 (4H, m, 10-H2, 11-H2),
t
6-H0), 1.54 (9H, s, Bu), 1.25 (4H, m, 10-H2, 11-H2), 1.09 (3H, d, J
7, 10-CH3) and 0.91 (3H, t, J 7.5, 12-H3); minor peaks attributed
to the enol tautomer (ca. 25%) 12.80 (1H, s, OH), 5.19 (1H, s, 2-H)
and 3.41 (3H, s, OMe); dC (75 Hz, CDCl3) 208.92, 204.79, 167.72,
155.69, 138.73, 128.48, 128.28, 127.38, 78.80, 73.99, 72.88, 58.73,
51.83, 51.61, 50.81, 42.42, 38.94, 33.76, 28.38, 25.99, 24.80,
22.49, 15.28 and 13.98; m/z (ES+) 528 (M+23, 100%) and 506 (20).
t
1.35 (9H, s, Bu), 0.91 (3H, d, J 7, 10-CH3), 0.85 (3H, m, 12-H3); m/
z (CI+) 506 (M++1, 50%) and 406 (100).
The aldol products (3.93 g, 7.77 mmol) in CH2Cl2 (32 mL) were
added to
a
suspension of pyridinium dichromate (7.46 g,
4.17. (1R,2S,4R,5S)-4-[(S)-2-Benzyloxy-1-methylethyl]-1-butyl-
2-methoxycarbonyl-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]
octan-3-one 28
19.4 mmol) and molecular sieves (8 g) in CH2Cl2 (33 mL) at room
temperature and the suspension was stirred at room temperature
for 24 h then filtered through a pad of silica and concentrated
under reduced pressure. Chromatography of the residue using
50% Et2O in light petroleum gave the title compound 26 (3.36 g,
6.68 mmol, 86%) as a colourless oil, Rf = 0.5 in 50% Et2O/light petro-
leum (Found: M+H+, 504.3322. C29H46NO6, requires M, 504.3320);
Trifluoroacetic acid (0.25 mL, 3.24 mmol) was added to the
diketo-ester 27 (820 mg, 1.62 mmol) in CH2Cl2 (30 mL) at 0 °C
and the mixture stirred at 0 °C for 1 h before saturated aqueous
sodium hydrogen carbonate (30 mL) was added. The aqueous
phase was extracted with CH2Cl2 (2 ꢁ 30 mL) and the organic
extracts were washed with water (90 mL) and brine (90 mL) before
being dried (MgSO4). After concentration under reduced pressure,
chromatography of the residue using 5% Et2O in light petroleum
gave the title compound 28 (648 mg, 1.33 mmol, 82%) as a colour-
less oil which solidified upon standing to give a white amorphous
solid, Rf = 0.37 in 20% Et2O/light petroleum, mp = 55.9–58.3 °C
(Found: M+Na+, 510.2826. C28H41NO6Na requires M, 510.2826);
½
a 2D6
ꢂ
¼ ꢀ50 (c 6.4, CHCl3)
mmax 3375, 2958, 1747, 1710, 1648, 1628,
1510, 1451, 1366, 1242, 1168, 1097, 890 and 738 cmꢀ1; dH
(500 MHz, CDCl3) keto-tautomer 7.29–7.21 (5H, m, ArH), 4.66
and 4.63 (each 1H, s, 8-CH), 4.63 (1H, d, J 10, NH), 4.37 and 4.33
(each 1H, d, J 12, HCHPh), 3.81 (1H, m, 5-H), 3.62 (3H, s, OMe),
3.45 and 3.38 (each, 1H, d, J 16, 2-H), 3.31 and 3.27 (each 1H, dd,
J 9, 5, 20-H), 2.98 (1H, dd, J 5.5, 8.5, 4-H), 2.18 (1H, m, 10-H), 2.01
(1H, m, 7-H), 1.94–1.85 (3H, m, 7-H0, 9-H2), 1.64 and 1.40 (each
1H, m, 6-H), 1.37 (9H, s, tBu), 1.33–1.30 (2H, m, 10-H2), 1.26–
1.18 (2H, m, 11-H2), 0.91 (3H, d, J 7, 10-CH3) and 0.83 (3H, t, J 7,
12-H3); minor peaks attributed to the enol tautomer (ca. 25%)
12.0 (1H, s, OH), 4.88 (1H, s, 2-H) and 3.66 (3H, s, OMe); dC
(125 Hz, CDCl3) 204.52, 171.69, 154.48, 147.82, 137.01, 127.34,
126.71, 126.39, 108.45, 78.43, 73.02, 72.70, 71.84, 57.05, 51.10,
50.18, 35.04, 34.72, 28.90, 28.03, 27.35, 21.60, 21.42, 13.94 and
12.97; m/z (ES+) 526 (M+23, 100%) and 504 (40).
½
a 2D2
ꢂ
¼ ꢀ16:5 (c 17, CHCl3) mmax 2959, 1748, 1703, 1456, 1358,
1318, 1259, 1161 and 739 cmꢀ1; dH (500 MHz, C6D6) 7.20–6.82
(5H, m, ArH), 4.34 (1H, m, 5-H), 4.10 and 4.06 (each 1H, d, J 12,
HCHPh), 4.00 (1H, br s, 2-H), 3.41 (1H, m, 200-H), 3.25 (1H, m, 200-
H0), 3.25 (3H, s, OMe), 2.73 (1H, br d, J 5.5, 4-H), 2.62 (1H, ddd, J
6, 10, 14.5, 7-H), 2.11 (1H, m, 100-H), 1.71 (2H, m, 7-H0, 10-H), 1.50
(1H, m, 6-H), 1.35–1.05 (6H, m, 6-H0, 10-H0, 20-H2, 30-H2), 1.22
t
(9H, s, Bu), 0.83–0.74 (3H, d, J 7, 100-CH3) and 0.78 (3H, t, J 7, 40-
H3); dC (75 Hz, CDCl3) 204.65, 168.97, 154.22, 139.00, 128.49,
127.75, 127.63, 80.94, 74.30, 73.18, 68.02, 65.74, 59.94, 55.20,
52.08, 34.38, 30.33, 28.53, 25.46, 23.20, 23.19, 22.91, 14.85 and
14.48; m/z (ES+) 511 (M+23, 25%), 510 (100) and 488 (20).
4.16. Methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-
butoxycarbonylamino-3,8-dioxododecanoate 27
4-Methylmorpholine N-oxide (1.66 g, 13.76 mmol) and osmium
tetroxide (85 mg, 0.33 mmol) were added to the alkene 26 (3.36 g,
6.68 mmol) in THF–tBuOH–H2O (44 mL; 20:20:4) at 0 °C and the
reaction stirred at room temperature for 24 h. Sodium metabisul-
fite (2 g, 10.5 mmol) was added and the suspension was stirred
for 4 h at room temperature then filtered through Celite which
was washed with ethyl acetate (200 mL). The filtrate was washed
with saturated aqueous sodium metabisulfite (200 mL), water
(200 mL) and brine (200 mL) and dried (Na2SO4). Concentration
under reduced pressure and chromatography of the residue using
4.18. (1R,2S,3R,4R,5S)-4-[(S)-2-Benzyloxy-1-methyl-ethyl]-1-
butyl-2-methoxycarbonyl-8-tert-butoxycarbon-yl-8-azabicyclo
[3.2.1]octan-3-ol 29
Sodium borohydride (88 mg, 2.3 mmol) was added to the trop-
inone 28 (110 mg, 0.23 mmol) in methanol (13.3 mL) at 0 °C and
the suspension was stirred at 0 °C for 30 min. After concentration
under reduced pressure, the residue was taken up in ethyl acetate
(20 mL) and the solution washed with water (20 mL) and brine
(20 mL) and dried (Na2SO4). After concentration under reduced
pressure, chromatography of the residue using 30% Et2O in light
petroleum gave the title compound 29 (110 mg, 0.22 mmol,
99.9%) as a colourless oil, Rf = 0.35 in 30% Et2O/light petroleum
(Found: M+Na+, 512.2979. C28H43NO6Na, requires M, 512.2983);
10% ethyl acetate in Et2O gave
a mixture of diols (2.69 g,
5.01 mmol) (Found: M++Na, 560.3201. C29H47NO8Na requires M,
560.3194); m/z (ES+) 560 (M++23, 100%). These were dissolved in
a mixture of methanol (20 mL) and pH 7 aqueous phosphate buffer
(10 mL). Sodium periodate (2.14 g, 10.02 mmol) was added and the

978
E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
½
a 2D2
ꢂ
¼ ꢀ48:05 (c 35.3, CHCl3); mmax 3469, 2920, 1747, 1699, 1460,
4.21. (1R,2R,4R,5S)-4-[(S)-2-Benzyloxy-1-methylethyl]-1-butyl-
2,8-dimethoxycarbonyl-8-azabicyclo[3.2.1]octan-3-one 32
1365 and 1171 cmꢀ1; dH (500 MHz, C6D6) 7.28–7.19 (5H, m, ArH),
4.43 and 4.40 (each 1H, d, J 11.5, HCHPh), 4.24 (1H, m, 3-H), 4.14
(1H, br d, J 5.5, 5-H), 3.88 (1H, d, J 3.5, OH), 3.63 (3H, s, OMe),
3.45 (1H, dd, J 3, 9, 200-H), 3.37 (1H, dd, J 8, 8.5, 200-H0), 2.95 (1H,
br s, 2-H), 2.57 (1H, m, 4-H), 1.96 (3H, m, 100-H, 6-H2), 1.82 (1H,
m, 7-H), 1.74 (1H, m, 7-H0), 1.63 and 1.46 (each, 1H, m, 10-H),
Methyl chloroformate (6 lL, 0.075 mmol) was added to the
imine 31 (20 mg, 0.05 mmol) in CH2Cl2 (1 mL) at ꢀ78 °C and the
solution stirred at ꢀ78 °C for 30 min. Triethylamine (0.04 mL,
0.3 mmol) was added and reaction stirred at ꢀ78 °C for 18 h before
being allowed to warm to room temperature. Saturated aqueous
ammonium chloride (10 mL) was added and the mixture extracted
with CH2Cl2 (3 ꢁ 10 mL). The organic extracts were washed with
water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using 20%
Et2O in light petroleum gave the title compound 32 (8 mg,
0.02 mmol, 41%) as a colourless oil, Rf = 0.50 in 50% Et2O/light
petroleum (Found: M+Na+, 468.2355. C25H35NO6Na requires M,
t
1.37 (9H, s, Bu), 1.23 (4H, m, 20-H2, 30-H2), 0.92 (3H, d, J 7, 100-
CH3) and 0.82 (3H, t, J 7, 40-H3); dC (75 Hz, CDCl3) 173.19, 154.32,
137.68, 128.75, 128.21, 128.16, 79.60, 76.30, 73.95, 68.40, 64.37,
58.72, 51.60, 49.58, 34.69, 31.79, 30.32, 28.74, 28.74, 25.21,
23.43, 22.28, 16.15 and 14.63; m/z (ES+) 512 (100%).
4.19. (1R,2S,3R,4R,5S)-4-[(S)-2-Benzyloxy-1-methyl-ethyl]-1-
butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]-octan-3-ol 30
468.2357); ½a 2D9
¼ ꢀ37:7 (c 5.1, CHCl3) mmax 2956, 1735, 1708,
ꢂ
2,6-Lutidine (0.03 mL, 0.28 mmol) and tert-butyldimethylsilyl
trifluoromethanesulfonate (0.03 mL, 0.12 mmol) were added to
the tert-butoxycarbamate 29 (34 mg, 0.07 mmol) in CH2Cl2
(0.23 mL) at 0 °C and the solution was allowed to warm to room
temperature and stirred for 24 h. The reaction mixture was washed
with saturated aqueous ammonium chloride (1 mL), dried
(Na2SO4) and concentrated under reduced pressure. Chromatogra-
phy of the residue using 1% methanol in CH2Cl2 gave the title com-
pound 30 (16 mg, 0.04 mmol, 57%) as a white crystalline solid,
mp = 74.2–75.5 °C, Rf = 0.43 in 10% MeOH/CH2Cl2 (Found: C, 70.4;
H, 9.25; N, 3.4. C23H35O4N requires C, 70.9; H, 9.05; N, 3.6. Found:
1442, 1364, 1327, 1233, 1196, 1169, 1100, 738 and 698 cmꢀ1; dH
(500 MHz, C6D6) 7.24 (2H, d, J 7, ArH), 7.10 (2H, m, ArH), 7.00
(1H, dd, J 7, 7.5, ArH), 4.56 (1H, br m, 5-H), 4.31 and 4.25 (each
1H, d, J 12, HCHPh), 3.60 (1H, dd, J 3, 10, 200-H), 3.58 (1H, dd, J 4,
10, 200-H0), 3.38 (6H, s, 2 ꢁ OMe), 3.35 (1H, m, 2-H), 2.32 (1H, m,
100-H), 2.18 (2H, br m, 7-H, 4-H), 1.47 (1H, td, J 12.5, 3.5, 7-H0),
1.28–1.08 (8H, m, 6-H2, 10-H2, 20-H2 and 30-H2), 0.99 (3H, d, J 7,
100-CH3) and 0.83 (3H, t, J 7.5, 40-H3); dC (75 Hz, C6D6) 204.73,
168.22, 154.22, 139.55, 128.37, 127.52, 127.35, 74.57, 73.07,
67.68, 67.16, 58.81, 54.49, 51.95, 51.74, 35.48, 30.82, 30.11,
26.70, 23.41, 22.42, 14.64 and 14.17; m/z (ES+) 468 (M++23, 100%).
M++H, 390.2638. C23H36O4N, requires M, 390.2639); ½a D26
¼ ꢀ48 (c
ꢂ
0.5, CHCl3); mmax 3482, 2954, 2923, 2861, 1744, 1456, 1434, 1361,
1303, 1262, 1192, 1177, 1139, 1090, 1075, 745 and 699 cmꢀ1; dH
(500 MHz, C6D6) 7.29–7.18 (5H, m, ArH), 4.43 and 4.40 (each 1H,
d, J 11.5, HCHPh), 4.26 (1H, m, 3-H), 3.70 (1H, d, J 3.5, OH), 3.64
(3H, s, OMe), 3.44 (1H, dd, J 2.5, 10, 200-H), 3.40 (1H, br d, J 5.5, 5-
H), 3.37 (1H, dd, J 7.5, 10, 200-H0), 2.70 (1H, d, J 4.5, 2-H), 2.57
(1H, ddd, J 4.5, 9.5, 13, 7-H), 2.13 (1H, ddd, J 4, 9.5, 13, 7-H0),
1.98 (1H, m, 100-H), 1.85 (1H, m, 10-H), 1.58 (3H, m), 1.35 (2H, m),
1.21 (4H, m, 20-H2, 30-H2), 0.90 (3H, d, J 7, 100-CH3) and 0.81 (3H,
d, J 7, 40-H3); dC (75 Hz, CDCl3) 173.16, 137.39, 128.48, 127.98,
127.94, 76.32, 73.10, 67.91, 62.86, 56.34, 54.07, 51.26, 38.30,
32.50, 31.84, 26.83, 26.38, 23.32, 23.32, 16.19 and 14.08; m/z
(ES+) 412 (M++23, 20%) and 390 (100).
4.22. (1R,2S,4R,5S)-4-[(S)-2-Benzyloxy-1-methylethyl]-1-butyl-
2-methoxycarbonyl-8-tert-butoxycarbonyl-2-prop-2-enyl-8-
azabicyclo[3.2.1]octan-3-one 33
The tropinone 28 (200 mg, 0.41 mmol) in THF (1.4 mL) was
added to a suspension of sodium hydride (18 mg, 0.45 mmol) in
dimethylformamide (1.5 mL) at room temperature and the mixture
stirred for 30 min. Tetrabutylammonium iodide (15 mg,
0.04 mmol) and allyl bromide (0.37 mL, 4.1 mmol) in THF (3 mL)
were added and reaction mixture was heated under reflux for
24 h. Saturated aqueous ammonium chloride (6 mL) was added
and the organic phase washed with water (6 mL) and brine
(6 mL) and dried (MgSO4). After concentration under reduced pres-
sure, chromatography using 10% Et2O in light petroleum gave the
title compound 33 (180 mg, 0.34 mmol, 83%) as a colourless vis-
cous oil, Rf = 0.40 in 20% Et2O/light petroleum (Found: M+Na+,
4.20. Methyl (4R,5S)-6-(benzyloxy)-4-[(S)-5-butyl-3,4-dihydro-
2H-pyrrolin-2-yl]-5-methyl-3-oxohexanoate 31
550.3149. C31H45NO6Na, requires 550.3139); ½a D26
¼ ꢀ56 (c 75.1,
ꢂ
Trifluoroacetic acid (0.126 mL, 1.62 mmol) was added to the
diketone 27 (50 mg, 0.01 mmol) at 0 °C and the solution allowed
to warm to room temperature then stirred for 20 min. Saturated
aqueous sodium hydrogen carbonate (5 mL) was added and the
mixture extracted with CH2Cl2 (3 ꢁ 5 mL). The organic extracts
were washed with water (15 mL) and brine (15 mL), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using 50% Et2O in light petroleum gave the title compound
31 (30 mg, 0.078 mmol, 79%) as a colourless oil, Rf = 0.13 in 50%
Et2O/light petroleum (Found: M+H+, 388.2481. C23H34NO4 requires
CHCl3) mmax 2960, 1730, 1702, 1456, 1367, 1218, 1158, 1091, 994,
919, 736 and 698 cmꢀ1; dH (500 MHz, C6D6) 7.38 (2H, d, J 7.5,
ArH), 7.28 (2H, m, ArH), 7.20 (1H, dd, J 7, 7.5, ArH), 6.12 (1H, dtd,
J 4, 10, 17, 200-H), 5.18 (1H, d, J 17, 300-H), 5.07 (1H, d, J 10, 300-H0),
4.71 (1H, m, 5-H), 4.39 (2H, s, CH2Ph), 3.57 (2H, m, 2000-H2), 3.50
(2H, m, 100-H2), 3.47 (3H, s, OMe), 3.11 (1H, ddd, J 4.5, 10, 14),
3.06 (1H, dd, J 4, 9, 4-H), 2.90 (1H, br m), 2.44 (1H, m, 1000-H),
t
2.01 (1H, dt, J 5, 13.5), 1.80–1.48 (3H, m), 1.52 (9H, s, Bu), 1.43–
1.37 (4H, m), 1.11 (3H, d, J 7, 1000-CH3), 1.03 (3H, t, J 7, 40-H3); dC
(75 Hz, CDCl3) 206.16, 170.48, 153.50, 139.16, 133.94, 128.46,
127.57, 127.53, 118.35, 74.51, 72.93, 72.67, 72.65, 58.63, 55.88,
52.37, 36.55, 31.82, 29.98, 29.97, 29.19, 28.63, 26.45, 23.42,
22.67, 14.76 and 14.52; m/z (ES+) 550 (M++23, 100%) and 518 (20).
M, 388.2482); ½a D26
¼ ꢀ18:4 (c 6.3, CHCl3); mmax 2957, 1747, 1707,
ꢂ
1644, 1455, 1261, 1168, 1097, 1026, 801, 738 and 699 cmꢀ1; dH
(500 MHz, CDCl3) 7.36–7.33 (5H, m, ArH), 4.50 and 4.44 (each
1H, d, J 12, HCHPh), 4.36 (1H, m, 20-H), 3.74 (1H, d, J 14, 2-H),
3.67 (3H, s, OMe), 3.55 (1H, d, J 14, 2-H0), 3.37 (2H, m, 6-H2),
2.35 (2H, m), 2.22 (2H, m), 2.04–1.77 (2H, m), 1.68–1.33 (6H, m,
100-H2, 200-H2, 300-H2), 1.07 (3H, d, J 7, 5-CH3) and 0.95 (3H, t, J 7.5,
400-H3); dC (75 Hz, CDCl3) 207.06, 179.79, 167.97, 138.67, 128.57,
127.82, 127.67, 74.53, 73.25, 73.05, 57.08, 52.51, 52.09, 37.83,
33.99, 33.76, 28.68, 23.03, 22.93, 15.42 and 14.17; m/z (ES+) 410
(M + 23, 90%) and 388 (100).
4.23. (1R,2S,4R,5S)-4-[(S)-2-Benzyloxy-1-methylethyl]-1-butyl-
2-formylmethyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-8-
azabicyclo[3.2.1]octan-3-one 34
2,6-Lutidine (0.03 mL) followed by osmium tetroxide (0.6 mg,
0.0025 mmol) and sodium periodate (107 mg, 0.5 mmol) was
added to the tropinone 33 (65 mg, 0.123 mmol) in THF (2.25 mL)

E. J. Thomas, C. F. Vickers / Tetrahedron: Asymmetry 20 (2009) 970–979
979
containing water (0.75 mL). The suspension was stirred for 5 h,
diluted with water (7 mL) and extracted with CH2Cl2 (3 ꢁ 10 mL).
The organic extracts were washed with brine (30 mL), dried
(Na2SO4) and concentrated under reduced pressure. Chromatogra-
phy of the residue using 20% Et2O in light petroleum gave the title
compound 34 (51 mg, 0.098 mmol, 80%) as a colourless oil,
Rf = 0.13 in 20% Et2O/light petroleum (Found: M+NH4þ, 547.3369.
31.61, 31.06, 28.34, 27.29, 21.90, 19.55, 14.28 and 13.18; m/z
(ES+) 530 (M++1, 10%) and 547 (M++18, 30).
4.25. Crystal data for tropinone 30
C23H35NO4, MW 389.52, monoclinic, space group C2,
a = 28.621(4), b = 8.2096(11), c = 9.3660(13) Å, b = 96.940(2)°,
C30H47N2O7, requires M, 547.3378); ½a D29
ꢂ
¼ ꢀ25:5 (c 12.4, CHCl3)
V = 2184.6(5) Å3, Z = 4, Dc = 1.184 g cmꢀ3 ) = 0.080 mmꢀ1
, l(Mo Ka ,
mmax 2964, 2854, 1728, 1698, 1455, 1369, 1261, 1204, 1157,
1094, 889, 802 and 698 cmꢀ1; dH (500 MHz, C6D6) 9.46 (1H, t, J
1.5, 200-H), 7.20 (2H, d, J 7.5, ArH), 7.08 (2H, t, J 7.5, ArH), 6.98
(1H, t, J 7.5, ArH), 4.53 (1H, m, 5-H), 4.35 and 4.24 (each 1H, d, J
12.5, HCHPh), 3.54 (1H, br m, 2000-H), 3.48 (1H, dd, J 2.5, 8.5, 2000-
H0), 3.17 (3H, s, OMe), 3.12 (1H, m, 100-H), 3.09 (1H, m, 4-H),
2.87–2.77 (2H, m), 2.25 (1H, m, 1000-H), 1.84 (1H, dt, J 5, 13), 1.60
F(000) = 848, T = 100 K. Crystal dimensions were 0.3 ꢁ 0.25 ꢁ
0.05 mm. 8829 reflections measured, 2431 independent reflections
(Rint = 0.054), R1 = 0.054 for the 2122 reflections with I > 2r(I),
wR(F2) = 0.125 (all data). Atomic coordinates, bond lengths and an-
gles and thermal parameters have been deposited with the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, CCDC number 721348.
t
and 1.47 (each 1H, m, 10-H), 1.40 (1H, m), 1.26 (9H, s, Bu), 1.23–
1.16 (5H, m), 0.90 (3H, d, J 7, 1000-CH3) and 0.84 (3H, t, J 7.5, 40-
H3); dC (125 Hz, CDCl3) 204.65, 200.20, 168.94, 168.09, 137.96,
127.19, 126.41, 126.26, 72.69, 71.79, 70.12, 58.45, 51.63, 51.57,
43.48, 31.72, 31.67, 27.48, 27.47, 25.09, 25.0, 22.06, 21.56, 20.82,
13.41 and 13.24; m/z (ES+) 552 (M++23, 100%).
Acknowledgements
We thank the EPSRC for a studentship (to C.F.V.) and Dr. M.
Helliwell for the X-ray crystal structure determination.
References
4.24. (1R,2S,5S,6S)-5-[(S)-2-Benzyloxy-1-methyl-ethyl]1-butyl-
4-hydroxy-2-methoxycarbonyl-9-tert-butoxy-carbonyl-9-
azatricyclo[4.2.1.12,5]decan-10-one 35
1. Seger, C.; Mereiter, K.; Kaltenegger, E.; Pacher, T.; Greger, H.; Hofer, O. Chem.
Biodivers. 2004, 1, 265.
2. (a) Irie, H.; Masaki, N.; Ohno, K.; Osaki, K.; Taga, T.; Uyeo, S. J. Chem. Soc., Chem.
Commun. 1970, 1066; (b) Sakata, K.; Aoki, K.; Chang, C.-F.; Sakurai, A.; Tamura,
S.; Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457; (c) Pilli, R. A.; de Oliveira, M.
daC. F. Nat. Prod. Rep 2000, 17, 117.
3. Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431.
4. Brüggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.;
Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284.
5. (a) Epperson, M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41, 1778;; (b) Alibés,
R.; Blanco, P.; Casa, E.; Closa, M.; de March, P.; Figueredo, M.; Font, J.; Sanfeliu,
E.; Álvarez-Larena, Á. J. Org. Chem. 2005, 70, 3157; (c) Smith, S. C.; Bentley, P. D.
Tetrahedron Lett. 2002, 43, 899; (d) Ye, Y.; Velten, R. F. Tetrahedron Lett. 2003,
44, 7171.
6. Baylis, A. M.; Davies, M. P. H.; Thomas, E. J. Org. Biomol. Chem. 2007, 5,
3139.
7. (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819; (b) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984; (c) Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8868.
8. Kowalski, C. J.; Reddy, R. E. J. Org. Chem. 1992, 57, 7194.
9. Janza, B.; Studer, A. J. Org. Chem. 2005, 70, 6991.
10. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64,
1278.
The aldehyde 34 (10 mg, 0.019 mmol) was stirred in trifluoro-
acetic acid (4 lL) at room temperature for 2 min. Saturated aque-
ous ammonium bicarbonate (5 mL) was added and the mixture
extracted with CH2Cl2 (3 ꢁ 5 mL). The organic extracts were
washed with brine (15 mL), dried (Na2SO4), filtered and concen-
trated under reduced pressure. Chromatography of the residue
using 50% Et2O in light petroleum and then neat Et2O gave the title
compound 35 (4 mg, 0.008 mmol, 40%) as a colourless oil, Rf = 0.3
in 100% Et2O; mmax 3479, 2958, 1738, 1700, 1687, 1454, 1384,
1252, 1205, 1162, 1102, 1033, 734 and 699 cmꢀ1; dH (500 MHz,
C6D6) 7.10 (2H, d, J 7, ArH), 7.05 (2H, m, ArH), 6.96 (1H, dd, J 7,
8, ArH), 4.79 (1H, d, J 12, OH), 4.56 (1H, m, 4-H), 4.39 (1H, dt, J 4,
8, 6-H), 4.15 (2H, s, CH2Ph), 3.58 (1H, dd, J 4.5, 9, 200-H), 3.36 (1H,
dd, J 4, 9, 200-H0), 3.45 (1H, m), 3.10 (3H, s, OMe), 3.06 (1H, dd, J
7, 12.5, 3-H), 2.85 (1H, dd, J 4, 7.5), 2.21 (1H, m, 100-H), 2.02 (1H,
ddd, J 2.5, 6.5, 9), 1.86 (1H, dd, J 8.5, 12.5, 3-H0), 1.67 (1H, m),
11. Taura, Y.; Tanaka, M.; Wu, X.-M.; Funakoshi, K.; Sakai, K. Tetrahedron 1991, 47,
4879; Taura, Y.; Tanaka, M.; Funakoshi, K.; Sakai, K. Tetrahedron Lett. 1989, 30,
6349.
12. (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973; (b)
Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217.
13. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
14. White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292.
t
1.46 (1H, m), 1.40–1.18 (5H, m), 1.17 (9H, s, Bu), 0.81 (3H, d, J
7.5, 100-CH3), 0.78 (3H, t, J 7, 40-H3); dC (100 Hz, CDCl3) 208.24,
170.40, 152.32, 137.60, 127.26, 126.51, 126.44, 80.11, 73.44,
72.94, 71.98, 71.01, 54.50, 52.48, 51.42, 48.57, 41.74, 34.12,