Asymmetric synthesis of Sedum alkaloids via lithium amide conjugate addition

Article abstract of DOI:10.1016/j.tet.2009.09.104

Conjugate addition of lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-but-3-enyl-N-(α-methylbenzyl)amide to an alkyl hexa-2,4-dienoate or alkyl hepta-2,6-dienoate, followed by ring-closing metathesis of the olefin functionalities within the resultant β-amino ester, generates a range of diastereoisomerically pure azacycles in good yield. These homochiral templates are readily transformed to a range of piperidine alkaloids of the Sedum family, and the corresponding five-, seven- and eight-membered ring homologues.

Full text of DOI:10.1016/j.tet.2009.09.104

Tetrahedron 65 (2009) 10192–10213
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of Sedum alkaloids via lithium amide conjugate addition
*
Stephen G. Davies , Ai M. Fletcher, Paul M. Roberts, Andrew D. Smith
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Conjugate addition of lithium (R)-N-allyl-N-(a-methylbenzyl)amide or lithium (R)-N-but-3-enyl-N-(a-
Received 26 August 2009
Received in revised form
18 September 2009
Accepted 24 September 2009
Available online 30 September 2009
methylbenzyl)amide to an alkyl hexa-2,4-dienoate or alkyl hepta-2,6-dienoate, followed by ring-closing
metathesis of the olefin functionalities within the resultant -amino ester, generates a range of dia-
stereoisomerically pure azacycles in good yield. These homochiral templates are readily transformed to
a range of piperidine alkaloids of the Sedum family, and the corresponding five-, seven- and eight-
membered ring homologues.
b
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Lithium amides
Asymmetric synthesis
Ring-closing metathesis
Sedum alkaloids
Sedamine
1. Introduction
enantiomers have subsequently been found in many other Sedum
species,1 and the C(1)-epimeric compound allosedamine 4 has been
The Sedum alkaloids have been isolated from some 60 species of
the genus Sedum.1 The most commonly occurring members of this
alkaloid family are 2-substituted piperidines,2 e.g., norsedamine 1,
allosedridine 2, sedamine 3 and allosedamine 4, which differ in the
presence or absence of a methyl group on the piperidine nitrogen
atom, the relative stereochemistry of the amino-alcohol moiety and
the identity of the alcohol-containing side chain. Pyrrolidine mem-
bers of the family have also been isolated, e.g., pyrrolsedamine 5,1
pseudohygroline 63 and pyrrolallosedamine 7,1 along with the less
commonly occurring ketone derivatives, e.g., pelletierine 8 (Fig. 1).
Sedamine 3 is perhaps the best known Sedum alkaloid: it was the first
member of the family to be isolated from the Sedum acre.4 Both
isolated from the Indian tobacco plant Lobelia inflate.5 Sedamine 3 and
allosedamine 4 have been shown to exhibit interesting and desirable
biological properties: sedamine 3 may be of use for cognitive disor-
ders6 and allosedamine 4 is useful for the treatment of various re-
spiratory illnesses, including asthma, bronchitis and pneumonia.7 The
synthesis of a variety of Sedum alkaloids, both in racemic and homo-
chiral form, has been actively pursued over the past 50 years: strat-
egies based upon manipulation of chiral pool starting materials, as
well as asymmetric methods, have been reported.8
Previous investigations from this laboratory have shown
extensively that the conjugate addition of a homochiral, sec-
ondary lithium amide derived from
a-methylbenzylamine to an
Me Me
NH
NH
OH
OH
N
OH
N
OH
Ph
Me
Ph
Me
(+)-allosedamine 4
(+)-norsedamine 1
(+)-allosedridine 2
(+)-sedamine 3
Me
Me
Me
NH
O
N
OH
N
OH
N
OH
Me
Ph
Me
Ph
pyrrolallosedamine 7
pelletierine 8
(+)-pyrrolsedamine 5 (+)-pseudohygroline 6
Figure 1. Structures of representative Sedum alkaloids 1–8.
* Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.104

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10193
a
,b
-unsaturated ester represents an efficient strategy for the syn-
thesis of acyclic and cyclic
-amino esters and derivatives.9 We have
reported that the conjugate addition of lithium (S)-N-allyl-N-(
methylbenzyl)amide10 to a suitable
-unsaturated ester can be
coupled with subsequent ring-closing metathesis to generate
homochiral pyrrolidine and piperidine scaffolds, as exemplified
through the synthesis of homoproline 14 (Scheme 1).11 Herein the
further application of this lithium amide conjugate addition/ring-
closing metathesis protocol to facilitate a general strategy towards
the asymmetric synthesis of a range of Sedum alkaloids and de-
rivatives employing the highly diastereoselective conjugate addi-
b
(i)
CO2R
CO2R
+
a
-
Ph
N
Me
a,b
CO2R
Me
9, R = tBu
16, R = tBu, 82%, 97:3 dr
17, R = tBu, 2%
15, R = Me
18, R = Me, 76%, 97:3 dr
(ii)
tion of lithium (R)-N-but-3-enyl-N-(a-methylbenzyl)amide is
delineated.
N
Ph
CO2R
19, R = tBu, 78%, >99:1 dr
20, R = Me, 75%, >99:1 dr
(i)
t
CO2 Bu
Ph
N
Me
Scheme 2. Reagents and conditions: (i) lithium (R)-N-but-3-enyl-N-(a-methyl-
t
CO2 Bu
benzyl)amide, THF, ꢀ78 ꢂC, 2 h; (ii) Grubbs I (4 mol %), CH2Cl2, rt, 12 h, then P(CH2OH)3,
Me
Et3N, SiO2, CH2Cl2, rt, 2 h; (iii) H2 (4 atm), RhCl(PPh3)3 (5 mol %), EtOAc, rt, 12 h.
9
10, 78%
97:3 dr
Deprotection of tetrahydropyridine 19 to the corresponding
cyclic
b-amino acid, homopipecolic acid 23, was next probed.
(ii)
Tandem hydrogenation/hydrogenolysis of 19 gave piperidine 21 in
93% isolated yield, which was shown to be of 99:1 er by chiral GC
analysis of the corresponding N-acetate 22 and comparison with an
authentic racemic standard.17 Hydrolysis of the tert-butyl ester
within 21 was achieved upon treatment with TFA, giving, after ion-
exchange chromatography, homopipecolic acid 2311,18 in 72% yield,
43% overall from tert-butyl hexa-2,4-dienoate 9. The spectroscopic
properties of 23 were in excellent agreement with those previously
(iii)
N
Ph
N
Ph
t
t
CO2 Bu
CO2 Bu
11, 77%
12, 86%
97:3 dr, 98:2 er
97:3 dr
24
26
reported {[
a]
ꢀ23.4 (c 0.5 in H2O); lit.11 for enantiomer [
a]
D
(iv)
D
þ24.0 (c 0.9 in H2O)} (Scheme 3).
(v)
NH
NH
t
CO2 Bu
CO2H
14, 96%
(i)
NH
N
Ph
13, 92%
t
CO2 Bu
t
CO2 Bu
Scheme 1. Reagents and conditions: (i) lithium (S)-N-allyl-N-(
a-methylbenzyl)amide,
THF, ꢀ78 ꢂC, 2 h; (ii) Grubbs I (4 mol %), CH2Cl2, 30 ꢂC, 6 h; (iii) H2 (2 atm), RhCl(PPh3)3
(5 mol %), C6H6, rt, 12 h; (iv) H2 (5 atm), Pd(OH)2/C (50% w/w), MeOH, rt, 12 h; (v) TFA,
CH2Cl2, rt, 12 h, then HCl (6 M, aq), then Dowex 50WX8-200.
19, >99:1 dr
21, 93%
(ii)
(iii)
2. Results and discussion
Ac
N
NH
2.1. Asymmetric synthesis of cyclic b-amino acids
t
CO2H
CO2 Bu
Conjugate addition of lithium (R)-N-but-3-enyl-N-(
benzyl)amide12 to tert-butyl and methyl hexa-2,4-dienoate 9 and
15 gave the corresponding -amino esters (3S, R)-16 and (3S, R)-
17 in 97:3 dr in each case.13 Conjugate addition to 9 was accom-
panied by small amounts of competing -deprotonation (6%)
resulting in the formation of -unsaturated ester 17 upon
protonation.14 Chromatography furnished the desired
-amino es-
ter 16 in 82% yield and 97:3 dr, and -unsaturated ester 17 in
a-methyl-
22, 90%
99:1 er
23, 72%
b
a
a
Scheme 3. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C (50% w/w), EtOAc, rt,
12 h; (ii) Ac2O, DMAP, pyridine, rt, 12 h; (iii) TFA, CH2Cl2, rt, 12 h, then HCl (6 M, aq),
then Dowex 50WX8-200.
3
b,g,d,3
b
Having demonstrated that this protocol represents an efficient
procedure for the synthesis of functionalised piperidine scaffolds,
application to the corresponding seven- and eight-membered skel-
etons was investigated. Olefination of 4-pentenal upon treatment
with either tert-butyl or methyl diethylphosphonoacetate 24 and 25
b,g,d,3
2% yield. Addition to 15 also resulted in the formation of several
minor, unidentified side-products, with chromatographic purifica-
tion giving
(3S)-stereochemistry within
from the known (R)-configuration of the
b
-amino ester 18 in 76% yield and 97:3 dr. The absolute
-amino esters 16 and 18 was assigned
-methylbenzyl stereo-
b
and MeMgBr19 gave the corresponding (E)-
a,b-unsaturated esters 26
a
and 27 in good yields and with total control of the geometry of
the olefin [(E):(Z) >99:1]. Subsequent conjugate additions of lithium
centre by reference to the transition state mnemonic that was de-
veloped by us to rationalise the exceptional facial bias of this class
of lithium amide.15 Ring-closing metathesis of the olefin function-
(R)-N-allyl-N-(
N-( -methylbenzyl)amide to
ceeded, in each case, to give the corresponding (3R,
esters 28–31 in ꢁ97:3 dr, which were isolated in good yield. The
a
-methylbenzyl)amide and lithium (R)-N-but-3-enyl-
-unsaturated esters 26 and 27 pro-
R)- -amino
a
a,b
alities within
b-amino esters 16 and 18 was achieved upon treat-
a
b
ment with Grubbs I, followed by removal of the spent catalyst with
tris(hydroxymethyl)phosphine16 and purification by chromatogra-
phy giving tetrahydropyridines 19 and 20 in 78 and 75% yield,
respectively, and in >99:1 dr in each case (Scheme 2).
absolute stereochemistry within b-amino esters 28–31 was assigned
by reference to the transition state mnemonic previously described15
(Scheme 4).

10194
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
(i)
achieved after treatment with 8 mol % Grubbs I over 12 h at 30 ꢂC,
O
CO2R
with 38 and 39 being isolated in good yield and >99:1 dr. Hydro-
genation of hexahydroazocine 38 promoted by Wilkinson’s catalyst
was followed by hydrogenolysis in the presence of Pearlman’s cat-
alyst, giving azocane 41 in 82% yield over two steps, which was
shown to be of 98:2 er by chiral GC analysis of the corresponding N-
acetate 42 and comparison with an authentic racemic standard.17
Hydrolysis of the tert-butyl ester and ion-exchange chromatography
(EtO)2P
CO2R
24, R = tBu
25, R = Me
26, R=tBu, 91%, (E):(Z) >99:1
27, R=Me, 92%, (E):(Z) >99:1
(ii)
(iii)
gave cyclic
b
-amino acid 43 in 87% yield (Scheme 6).
Ph
N
Ph
N
CO2R
CO2R
(i)
N
Ph
Ph
N
28, R=tBu, 94%, 98:2 dr
29, R = Me, 79%, 98:2 dr
30, R = tBu, 98%, 97:3 dr
31, R=Me, 88%, 97:3 dr
CO2R
CO2R
Scheme 4. Reagents and conditions: (i) MeMgBr, THF, ꢀ78 ꢂC, then 4-pentenal, THF,
30, R = tBu, 97:3 dr
31, R = Me, 97:3 dr
38, R=tBu, 84%, >99:1 dr
39, R = Me, 85%, >99:1 dr
ꢀ78 ꢂC to rt, 4 h; (ii) lithium (R)-N-allyl-N-(
a
-methylbenzyl)amide, THF, ꢀ78 ꢂC, 2 h;
(iii) lithium (R)-N-but-3-enyl-N-(
a
-methylbenzyl)amide, THF, ꢀ78 ꢂC, 2 h.
(ii)
R = tBu
The ring-closing metathesis reactions of 28 and 29 required
treatment with 8 mol % Grubbs I over 12 h at room temperature to
achieve quantitative conversion to the corresponding tetrahy-
droazepines 32 and 33, which were isolated in good yield and
>99:1 dr. Attempted tandem hydrogenation/hydrogenolysis of 32
upon treatment with Pearlman’s catalyst under a hydrogen atmo-
sphere resulted in the formation of a complex mixture of products
from which the desired azepane 35 was isolated in only 34% yield. A
two-step protocol was therefore implemented. Treatment of tet-
rahydroazepine 32 with Wilkinson’s catalyst in EtOAc gave azepane
34 in 85% yield and >99:1 dr; subsequent hydrogenolysis mediated
by Pearlman’s catalyst gave the desired azepane 35 in 90% yield,
which was shown to be of 99:1 er by chiral GC analysis of the
corresponding N-acetate 36 and comparison with an authentic
racemic standard.17 Hydrolysis of the tert-butyl ester within 35 and
(iii)
(v)
NH
N
Ph
CO2tBu
CO2tBu
41, 86%
(iv)
40, 95%, >99:1 dr
Ac
N
NH
CO2tBu
CO2H
42, 96%, 98:2 er
43, 87%
Scheme 6. Reagents and conditions: (i) Grubbs I (8 mol %), CH2Cl2, 30 ꢂC, 12 h, then
P(CH2OH)3, Et3N, SiO2, CH2Cl2, rt, 2 h; (ii) H2 (4 atm), RhCl(PPh3)3 (5 mol %), EtOAc, rt,
12 h; (iii) H2 (5 atm), Pd(OH)2/C (50% w/w), EtOAc, rt, 12 h; (iv) Ac2O, DMAP, pyridine,
rt, 12 h; (v) TFA, CH2Cl2, rt, 12 h, then HCl (6 M, aq), then Dowex 50WX8-200.
ion-exchange chromatography gave cyclic
yield (Scheme 5).
b-amino acid 37 in 92%
(i)
2.2. Synthetic application: asymmetric synthesis of a range of
N
Ph
Ph
N
Sedum alkaloids and homologues
CO2R
CO2R
Having shown that this lithium amide conjugate addition/ring-
closing metathesis protocol allows the rapid assembly of azocyclic
structures comprising six-, seven- and eight-membered rings, the
utility of this methodology for the synthesis of a family of Sedum
alkaloid natural products and homologues was next demon-
strated. Tandem hydrogenation/hydrogenolysis of tetrahydropyr-
idine 20 in the presence of Boc2O gave N-Boc piperidine 4420 in
91% yield. Conversion to Weinreb amide 4521 was effected upon
treatment with N,O-dimethylhydroxylamine hydrochloride and
isopropylmagnesium chloride,22 giving 45 in 89% isolated yield.
Subsequent addition of phenylmagnesium bromide or methyl-
magnesium bromide gave the corresponding ketones 4623 and 47
in good yields (Scheme 7).
28, R = tBu, 98:2 dr
29, R = Me, 98:2 dr
32, R=tBu, 91%, >99:1 dr
33, R = Me, 89%, >99:1 dr
(ii)
R = tBu
(iii
)
NH
N
Ph
CO2 Bu
t
CO2 Bu
t
35, 90%
34, 85%, >99:1 dr
(v)
(iv)
The reduction of a range of N-protected
a
-(piperidin-20-yl)-
Ac
N
ketones with various reducing agents has been the subject of sev-
eral investigations, with the observed levels of selectivity varying
widely from poor (w50:50) to very good (>90:10).24 Reduction of
ketone 46 with various hydride sources (e.g., LiAlH4, LiBH4, NaBH4,
NH
t
CO2H
CO2 Bu
36, 90%, 99:1 er
37, 92%
DIBAL-H, L-Selectride) was investigated although in general poor
Scheme 5. Reagents and conditions: (i) Grubbs
I (8 mol %), CH2Cl2, rt, 12 h, then
levels of selectivity, resulting in near 50:50 mixtures of di-
astereoisomers, were observed.25 Employing LiAl(OtBu)3H,24d,g,i,j
however, gave the known amino-alcohol syn-4921,24e,26 in >99:1 dr,
which was isolated in 94% yield and >99:1 dr. Application to ketone
47 gave a 96:4 mixture of the corresponding syn- and anti-dia-
stereoisomers 50 and 51, with purification furnishing syn-50 in
P(CH2OH)3, Et3N, SiO2, CH2Cl2, rt, 2 h; (ii) H2 (4 atm), RhCl(PPh3)3 (5 mol %), EtOAc, rt,
12 h; (iii) H2 (5 atm), Pd(OH)2/C (50% w/w), EtOAc, rt, 12 h; (iv) Ac2O, DMAP, pyridine,
rt, 12 h; (v) TFA, CH2Cl2, rt, 12 h, then HCl (6 M, aq), then Dowex 50WX8-200.
In the eight-membered ring series, formation of hexahydro-
azocines 38 and 39 from the b-amino ester precursors 30 and 31 was

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10195
Boc
OH
Boc
Boc
Boc
(i)
N
N
N
O
OH
(i)
N
+
N
Ph
Ph
CO2Me
Ph
Ph
CO2Me
46
syn-49
anti-52
Crude dr
syn-49a
anti-52a
20, >99:1 dr
44, 91%
Hydride Source
syn-49:anti-52
Yield %
Yield %
(ii)
BH3·THF
56:44
-
-
(S)-B-Me-CBS/BH3·THF
(R)-B-Me-CBS/BH3·THF
92:8
25:75
82
19
3
67
Boc
Boc
N
O
Scheme 9. Reagents and conditions: (i) (R)-B-Me-CBS (5 mol %), BH3$THF, THF, 0 ꢂC,
2 h; (ii) (S)-B-Me-CBS (5 mol %), BH3$THF, THF, 0 ꢂC, 2 h; (iii) BH3$THF, THF, 0 ꢂC, 2 h.
[aIsolated yields refer to single diastereoisomers (>99:1 dr).]
(iii)
N
O
Me
N
R
OMe
46, R = Ph, 72%
47, R = Me, 82%
45, 89%
Removal of the tert-butoxycarbonyl protecting group from anti-
22
52 gave (ꢀ)-norallosedamine 53 in 89% yield and >99:1 dr {[
a]
D
21
ꢀ23.0 (c 2.0 in EtOH); lit. for enantiomer30
[
a]
þ37.2 (c 3.0 in
Scheme 7. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C (50% w/w), Boc2O, EtOAc,
D
i
rt, 12 h; (ii) (MeO)(Me)NH$HCl, PrMgCl, THF, ꢀ20 to 0 ꢂC, 6 h; (iii) RMgBr, Et2O, 6 h.
EtOH)}, and reduction of 52 with LiAlH4 gave (þ)-allosedamine 4 in
22
21
77% yield and 98:2 dr {[
a
]
þ29.7 (c 1.0 in MeOH); lit.30
[a
]
þ32.0
D
D
92% yield and >99:1 dr, and anti-51 in 2% yield and >99:1 dr. The
configurations within syn-50 and anti-51 could not be assigned
a priori; they were subsequently determined through conversion of
syn-50 to (þ)-allosedridine 2. The very high levels of stereo-
selectivity arising upon reduction of ketones 46 and 47 with
LiAl(OtBu)3H may be explained by invoking transition state 48, in
which chelation of the aluminium atom between the carbamate
and ketone carbonyls directs hydride delivery to the least hindered
face of the ketone (Si face of 46, Re face of 47).27 Removal of the tert-
(c 2.0 in MeOH)} (Scheme 10).
Boc
(i)
NH
OH
N
OH
Ph
53, 89%, >99:1 dr
Ph
anti-52, >99:1 dr
(ii)
butoxycarbonyl protecting group from syn-50 gave (þ)-allose-
Me
25
dridine 2 in 87% yield and >99:1 dr {[
a
]
þ20.1 (c 1.0 in MeOH);
þ17.1 (c 1.55 in MeOH)}.
N
OH
D
29
25
lit.28
[
a
]
þ16.2 (c 4.0 in MeOH); lit.29
[a]
D
D
Ph
4, 77%, >97:3 dr
Under identical conditions, hydrolysis of syn-49 gave (þ)-norsed-
23
amine 1 in 90% yield and >99:1 dr {[
a]
þ24.6 (c 1.0 in MeOH);
D
17
lit.30
[
a
]
þ33.2 (c 2.0 in MeOH)}, with carbamate reduction upon
D
Scheme 10. Reagents and conditions: (i) HCl (3 M, aq), MeOH, 50 ꢂC, 3 h; (ii) LiAlH4,
22
treatment with LiAlH4 giving (þ)-sedamine 3 {[
a
]
þ81.5 (c 1.1 in
21
D
THF, reflux, 6 h.
25
MeOH); [
a
]
þ82.1 (c 1.0 in EtOH); lit. for enantiomer30
[
a
]
D
ꢀ81.7
D
32
(c 3.0 in MeOH); lit.31
>99:1 dr (Scheme 8).
[
a
]
þ87.0 (c 1.1 in EtOH)} in 86% yield and
The application of this strategy to the synthesis of pyrrolidine
D
members of the Sedum alkaloid family1 was explored. Conjugate
addition of lithium (R)-N-allyl-N-(
unsaturated ester 15 proceeded in 97:3 dr, furnishing
(3S, R)-54 in 83% isolated yield and 97:3 dr after purification. The
absolute (3S, R)-configuration within -amino ester 54 was
assigned by reference to the transition state mnemonic for the
lithium amide conjugate addition reaction.15 Subsequent ring-
closing metathesis with Grubbs I furnished dihydropyrrole 55 in
80% yield. Hydrogenation of 55 in benzene furnished pyrrolidine 56
and pyrrole 57 in a 96:4 ratio, respectively, which were separated
via flash column chromatography, giving pyrrolidine 56 in 87%
yield and >99:1 dr, and pyrrole 57 in 4% yield (Scheme 11).
a
-methylbenzyl)amide to
a,b-
Boc
Boc
(i)
Boc
N OH
b-amino ester
N
OH
N
O
a
+
a
b
R
R
R
46, R = Ph
47, R = Me
syn-49, R = Ph, 94%
syn-50, R = Me, 92%
anti-51, R = Me, 2%
(ii)
(iii)
R = Ph
R
O
OtBu
O
Me
NH
OH
N
OH
N
H
Al
R
48
Ph
3, 86%
1, R = Ph, 90%
2, R = Me, 87%
(i)
Scheme 8. Reagents and conditions: (i) LiAl(OtBu)3H, THF, 0 ꢂC, 6 h; (ii) HCl (3 M, aq),
MeOH, 50 ꢂC, 3 h; (iii) LiAlH4, THF, reflux, 6 h. [All compounds were isolated as single
diastereoisomers (>99:1 dr).].
CO2Me
Ph
N
Me
CO2Me
Me
15
54, 83%, 97:3 dr
In order to access the corresponding anti-diastereoisomers, an
alternative reduction protocol employing the homochiral CBS re-
agent32 was probed. Reduction of phenyl ketone 46 with BH3$THF
gave a 56:44 mixture of syn-49:anti-52,21,24e,26 indicating a slight
substrate preference for formation of the syn-diastereoisomer 49.
In the doubly diastereoselectively ‘matched’ case,33 reduction
promoted by (S)-B-Me-CBS gave a 92:8 mixture of syn-49:anti-52.
In the ‘mismatched’ case, the homochiral (R)-B-Me-CBS reagent
exerted the dominant stereocontrol to furnish a 25:75 mixture of
syn-49:anti-52, from which syn-49 and anti-52 were isolated in 19
and 67% yield, respectively, and as single diastereoisomers in both
cases (Scheme 9).
(ii)
(iii)
+
N
Ph
CO2Me
57, 4%
N
Ph
N
Ph
56:57
CO2Me
CO2Me
96:4
56, 87% >99:1 dr
55, 80%, >99:1 dr
-methylbenzyl)amide
Scheme 11. Reagents and conditions: (i) lithium (R)-N-allyl-N-(
a
(1.6 equiv), THF, ꢀ78 ꢂC, 2 h; (ii) Grubbs I (4 mol %), CH2Cl2, rt, 12 h, then P(CH2OH)3,
Et3N, SiO2, CH2Cl2, rt, 2 h; (iii) H2 (4 atm), RhCl(PPh3)3 (5 mol %), C6H6, rt, 12 h.

10196
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
Hydrogenolysis of 56 in the presence of Boc2O gave N-Boc pyr-
Boc
OH
(i)
NH
OH
N
rolidine 58,34 with subsequent treatment with (MeO)(Me)NH$HCl
and iPrMgCl22 giving Weinreb amide 59. Conversion to the phenyl
and methyl ketones 60 and 61, respectively, was achieved upon
reaction with the requisite Grignard reagent (Scheme 12).
R
R
syn-62, R = Ph
66, R = Ph, 81%
67, R = Me, 93%
syn-64, R = Me
(ii)
Boc
(i)
N
Me
N
Ph
CO2Me
58, 78%
(ii)
N
OH
CO2Me
R
56, >99:1 dr
5, R = Ph, 56%
6, R = Me, 80%
Scheme 14. Reagents and conditions: (i) HCl (3 M, aq), MeOH, 50 ꢂC, 3 h; (ii) LiAlH4,
THF, reflux, 6 h. [All compounds are single diastereoisomers (>99:1 dr).]
Boc
Boc
N
O
(iii)
N
O
Me
(i)
N
N
Ph
N
Ph
R
OMe
CO2Me
CO2Me
60, R = Ph, 81%
59, 92%
61, R = Me, 89%
68, 87%
33, >99:1 dr
Scheme 12. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C (50% w/w), Boc2O,
EtOAc, rt, 12 h; (ii) (MeO)(Me)NH$HCl, iPrMgCl, THF, ꢀ20 to 0 ꢂC, 6 h; (iii) RMgBr, Et2O,
ꢀ78 to 0 ꢂC, 6 h.
>99:1 dr
(ii)
Boc
Boc
Reduction of both ketones with LiAl(OtBu)3H proceeded to give
the corresponding syn-diastereoisomer as the major product in each
case (syn:anti >99:1 for 60, R¼Ph; syn:anti 97:3 for 61, R¼Me). The
stereoselectivity of these reductions was subsequently established
by chemical correlation of syn-62 and syn-64 with pyrrolsedamine 5
and (þ)-pseudohygroline 6, and is consistent with a transition state
similar to 48, invoked to rationalise the selectivity observed in the
analogous six-membered ring compounds 46 and 47. In an effort to
form the corresponding anti-diastereoisomers stereoselectively in
the five-membered ring system, reduction promoted by the CBS
reagent was investigated. In these investigations, treatment of
phenyl ketone 60 with (R)-B-Me-CBS proceeded to give a 15:85 ratio
of syn-62:anti-63, and reduction of methyl ketone 61 with (S)-B-Me-
CBS gave a 24:76 ratio of syn-64:anti-65. The desired anti-di-
astereoisomers 63 and 65 were isolated in 71 and 68% yield,
respectively, after chromatographic purification (Scheme 13).
N
O
(iii)
N
Me
N
CO2Me
70, 90%
OMe
69, 88%
(iv)
Boc
Boc
(v)
N
O
N
OH
C3H7
C3H7
72, 95%
71, 73%
>99:1 dr
Scheme 15. Reagents and conditions: (i) H2 (4 atm), RhCl(PPh3)3 (5 mol %), EtOAc,
rt, 12 h; (ii) H2 (5 atm), Pd(OH)2/C (50% w/w), Boc2O, EtOAc, rt, 12 h; (iii)
(MeO)(Me)NH$HCl, PrMgCl, THF, ꢀ20 to 0 ꢂC, 6 h; (iv) C3H7MgCl, Et2O, ꢀ78 to
i
0
ꢂC, 6 h; (v) LiAl(OtBu)3H, THF, 0 ꢂC, 6 h.
(i) or (ii)
Boc
Boc
OH
Boc
N OH
or (iii) or (iv)
N
N
O
+
R
R
R
60, R = Ph
61, R = Me
syn-62, R = Ph
anti-63, R = Ph
anti-65, R = Me
syn-64, R = Me
Ratio
syn
anti
a
a
Ketone
Hydride Source
LiAl(OtBu)3H
syn:anti
Yield %
Yield %
60, R = Ph
60, R = Ph
60, R = Ph
60, R = Ph
61, R = Me
61, R = Me
61, R = Me
61, R = Me
>99:1
50:50
88:12
15:85
97:3
96
-
0
-
BH3·THF
(S)-B-Me-CBS/BH3·THF
(R)-B-Me-CBS/BH3·THF
LiAl(OtBu)3H
BH3·THF
(S)-B-Me-CBS/BH3·THF
(R)-B-Me-CBS/BH3·THF
78
12
94
-
10
71
1
50:50*
24:76
84:16
-
68
18
70
12
Scheme 13. Reagents and conditions: (i) LiAl(OtBu)3H, THF, 0 ꢂC, 6 h; (ii) BH3$THF, THF, 0 ꢂC, 2 h; (iii) (S)-B-Me-CBS, BH3$THF, THF, 0 ꢂC, 2 h; (iv) (R)-B-Me-CBS, BH3$THF, THF, 0 ꢂC,
2 h. [*50% conversion. aIsolated yields refer to single diastereoisomers (>99:1 dr).]
Hydrolysis of syn-62 and syn-64 gave the corresponding pyrroli-
The generality of this protocol to medium ring systems was also
demonstrated. In the seven-membered azepine system, tetrahy-
droazepine 33 was derivatised to the corresponding n-propyl ke-
tone 71 in four steps. Reduction of 71 with LiAl(OtBu)3H proceeded
to give 72 as a single diastereoisomer with high levels of selectivity
(Scheme 15). An analogous sequence of reactions applied to hex-
ahydroazocine 39 resulted in the highly selective formation of syn-
dines 6635 and 67, whilst carbamate reduction upon treatment with
22
LiAlH4 gave pyrrolsedamine 51 and (þ)-pseudohygroline 63 {[
a]
D
20
25
þ105.2 (c 1.0 in EtOH); lit.3 [
a]
þ84.4 (c 3.4 in EtOH); lit.36
[
a
]
þ97.0
D
(c 1.0 in EtOH); lit.37
[
a
]
þD78.8 (c 0.9 in EtOH)}, respectively. The
20
D
23
specific rotation of pyrrolsedamine 5 {[
a
]
þ73.7 (c 2.0 in EtOH)}
D
allowedassignmentof(1R,20R)-5as the (þ)-enantiomer38 (Scheme14).

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10197
77 (Scheme 16). In both of these ring systems the syn-configura-
tions within 72 and 77 resulting from LiAl(OtBu)3H reduction were
assigned by analogy to those unambiguously proven in the pyrro-
lidine and piperidine systems.
Elmer 241 polarimeter with a water-jacketed 10 cm cell. Specific
rotations are reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/
100 mL. IR spectra were recorded on a Bruker Tensor 27 FT-IR
spectrometer as either a thin film on NaCl plates (film) or a KBr disc
(KBr), as stated. Selected characteristic peaks are reported in cmꢀ1
.
NMR spectra were recorded on Bruker Avance spectrometers in the
deuterated solvent stated. Spectra were recorded at rt unless oth-
erwise stated. The field was locked by external referencing to the
relevant deuteron resonance. In cases where methylene carbon
atoms of ring systems could not be unambiguously assigned, the
descriptor ‘CH2’ is employed throughout. Low-resolution mass
spectra were recorded on either a VG MassLab 20-250 or a Micro-
mass Platform 1 spectrometer. Accurate mass measurements were
run on either a Bruker MicroTOF internally calibrated with poly-
alanine, or a Micromass GCT instrument fitted with a Scientific
Glass Instruments BPX5 column (15 mꢃ0.25 mm) using amyl
acetate as a lock mass.
(i)
N
Ph
N
Ph
CO2Me
CO2Me
39, >99:1 dr
73, 94%
>99:1 dr
(ii)
Boc
N
O
Boc
N
(iii)
(v)
Me
N
CO2Me
75, 93%
OMe
4.2. General procedure 1: lithium amide conjugate addition
74, 85%
(iv)
BuLi (2.5 M in hexanes, 1.55 equiv) was added dropwise via
syringe to a stirred solution of the requisite amine (1.6 equiv) in THF
at ꢀ78 ꢂC under nitrogen. After stirring for 30 min, a solution of the
Boc
Boc
OH
N
O
N
requisite
a,
b
-unsaturated ester (1.0 equiv) in THF at ꢀ78 ꢂC was
Ph
Ph
added dropwise via cannula. After stirring for a further 2 h at
ꢀ78 ꢂC the reaction mixture was quenched with satd aq NH4Cl.
After warming to rt over 15 min the reaction mixture was con-
centrated in vacuo. The residue was partitioned between CH2Cl2
and 10% aq citric acid. The organic layer was separated and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were washed sequentially with satd aq NaHCO3 and
brine, before being dried and concentrated in vacuo to give the
crude reaction mixture.
77, 91%
>99:1 dr
76, 76%
Scheme 16. Reagents and conditions: (i) H2 (4 atm), RhCl(PPh3)3 (5 mol %), EtOAc,
rt, 12 h; (ii) H2 (5 atm), Pd(OH)2/C (50% w/w), Boc2O, EtOAc, rt, 12 h; (iii)
(MeO)(Me)NH$HCl, PrMgCl, THF, ꢀ20 to 0 ꢂC, 6 h; (iv) PhMgBr, Et2O, ꢀ78 to 0 ꢂC,
i
6 h; (v) LiAl(OtBu)3H, THF, 0 ꢂC, 6 h.
3. Conclusion
In conclusion, conjugate addition of lithium (R)-N-allyl-N-(
a-
4.3. General procedure 2: ring-closing metathesis
methylbenzyl)amide or lithium (R)-N-but-3-enyl-N-( -methylbenzyl)
a
amide to an alkyl hexa-2,4-dienoate or alkyl hepta-2,6-dienoate,
followed by ring-closing metathesis of the olefin functionalities
Grubbs I (4 mol % or 8 mol %) was added to a stirred solution of
the substrate (1.0 equiv) in dry, degassed CH2Cl2 at rt. After stirring
at the temperature stated for 12 h the reaction mixture was con-
centrated in vacuo. The residue was redissolved in CH2Cl2, stirred,
and tris(hydroxymethyl)phosphine (100 equiv w.r.t. Grubbs I) and
Et3N (2.0 equiv) were added sequentially. After stirring for 10 min,
excess silica (>10 equiv) was added and stirring continued for
a further 2 h. The mixture was then filtered and concentrated in
vacuo to give the crude reaction mixture.
within the resultant
b-amino ester, generates a range of dia-
stereoisomerically pure azacycles in good yield. These homo-
chiral templates are readily transformed to a range of piperidine
alkaloids of the Sedum family, and the corresponding five-,
seven- and eight-membered ring homologues.
4. Experimental
4.1. General experimental
4.4. General procedure 3: hydrogenation with Wilkinson’s
catalyst
All reactions involving organometallic or other moisture-sen-
sitive reagents were carried out under a nitrogen or argon at-
mosphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.39 Water was purified by an ElixÒ UV-10 system.
All other solvents were used as supplied (analytical or HPLC
grade) without prior purification. Organic layers were dried over
MgSO4. Thin layer chromatography was performed on aluminium
plates coated with 60 F254 silica. Plates were visualised using UV
light (254 nm), iodine, 1% aq KMnO4, or 10% ethanolic phospho-
molybdic acid. Flash column chromatography was performed on
Kieselgel 60 silica.
Wilkinson’s catalyst (5 mol %) was added to a vigorously stirred
solution of the substrate in the solvent stated and placed under
a hydrogen atmosphere (4 atm). Stirring continued for 12 h, after
which time the reaction mixture was concentrated in vacuo to give
the crude reaction mixture.
4.5. General procedure 4: hydrogenation/hydrogenolysis with
Pearlman’s catalyst
Pearlman’s catalyst (50% w/w of substrate) was added to a vig-
orously stirred solution of the requisite substrate in the solvent
stated and placed under a hydrogen atmosphere (5 atm). Stirring
continued for 12 h, after which time the reaction mixture was fil-
tered through CeliteÒ (eluent EtOAc) and concentrated in vacuo to
give the crude reaction mixture.
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford, UK.
Melting points were recorded on a Gallenkamp Hot Stage apparatus
and are uncorrected. Optical rotations were recorded on a Perkin–

10198
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
4.6. General procedure 5: cleavage of esters with TFA
Boc2O (1.3 equiv) in EtOAc and placed under a hydrogen atmo-
sphere (5 atm). Stirring continued for 12 h, after which time the
reaction mixture was filtered through CeliteÒ (eluent EtOAc) and
concentrated in vacuo.
TFA was added dropwise to a stirred solution of the requisite
tert-butyl ester in CH2Cl2 at rt and the reaction mixture was stirred
for 12 h. After this time the reaction mixture was concentrated in
vacuo and the residue was co-evaporated with 6 M aq HCl. The
residue was then further co-evaporated with 6 M aq HCl solution to
give the crude reaction mixture.
4.12. Generalprocedure11:ketonereductionwithB-methylCBS
B-Methyl CBS reagent (1.0 M in PhMe, 5 mol %) was added via
syringe to a stirred solution of BH3$THF complex (1.0 M in THF,
1.0 equiv) in THF at 0 ꢂC. After stirring for 5 min, a solution of the
requisite ketone (1.0 equiv) in THF at 0 ꢂC was added dropwise via
cannula. Stirring was continued at 0 ꢂC for 2 h. The reaction was
quenched with a few drops of MeOH and concentrated in vacuo to
give the crude reaction mixture.
4.7. General procedure 6: Wadsworth–Emmons reaction
The requisite base was added dropwise via syringe to a stirred
solution of the requisite phosphonate in THF at ꢀ78 ꢂC and stir-
ring continued for 30 min. A solution of the requisite aldehyde in
THF at ꢀ78 ꢂC was added dropwise via cannula, and stirring
continued for a further 30 min at ꢀ78 ꢂC before the reaction
mixture was allowed to warm to rt over the stated amount of
time. After this time, the reaction mixture was quenched with
satd aq NH4Cl and allowed to warm to rt over 15 min. Brine was
added, the organic layer was separated and the aqueous layer was
extracted twice with Et2O. The combined organic layers were
dried and concentrated in vacuo to give the crude reaction
mixture.
4.13. General procedure 12: N-Boc deprotection with HCl
3 M aq HCl was added to a stirred solution of the requisite
substrate in MeOH and heated at 50 ꢂC for 3 h. After cooling to rt
the reaction mixture was concentrated in vacuo. The residue was
partitioned between CH2Cl2 and satd aq NaHCO3. The organic layer
was separated and the aqueous layer was extracted twice with
CH2Cl2. The combined organic layers were dried and concentrated
in vacuo to give the crude reaction mixture.
4.8. General procedure 7: hydride reduction
4.14. General procedure 13: N-Boc reduction with LiAlH4
A solution of the requisite hydride reagent was added to a so-
lution of the requisite substrate in the stated solvent at the stated
temperature under nitrogen and allowed to stir for the stated
amount of time. The reaction was quenched by addition of a few
drops of ice-cold water. EtOAc was added and the mixture stirred
for a further hour. After this time, the reaction mixture was filtered
through CeliteÒ (eluent EtOAc) and the filtrate was concentrated in
vacuo to give the crude reaction mixture.
LiAlH4 powder (5.0 equiv) was added portionwise to a stirred
solution of the requisite substrate in THF at 0 ꢂC. The reaction
mixture was heated at 65 ꢂC for 6 h and then cooled to 0 ꢂC. The
mixture was quenched by sequential addition of 10% aq NaOH and
H2O. The mixture was extracted with CH2Cl2 and the combined
organic layers were dried, filtered and concentrated in vacuo to give
the crude reaction mixture.
4.9. General procedure 8: preparation of Weinreb amides
from methyl esters
4.14.1. tert-Butyl (E,E)-hexa-2,4-dienaote 9.
t
CO2 Bu
iPrMgCl (2.0 M in THF, 3.0 equiv) was added dropwise via
syringe to a vigorously stirred slurry of the requisite methyl ester
(1.0 equiv) and N,O-dimethylhydroxylamine hydrochloride
(1.55 equiv) in THF at ꢀ20 ꢂC. The reaction mixture was allowed
to warm to 0 ꢂC and stirring continued at 0 ꢂC for 4 h. The re-
action was quenched with a few drops of water and EtOAc was
added. The slurry was filtered through CeliteÒ (eluent EtOAc)
and the filtrate was concentrated in vacuo to give the crude
reaction mixture.
Me
Condensed isobutylene gas (125 g, 2.23 mol) at ꢀ78 ꢂC was
added to a stirred solution of (E,E)-hexa-2,4-dienoic acid (25.0 g,
223 mmol), and a catalytic amount of 10 M aq H2SO4 (w1 mL), in
CH2Cl2 (1 L) at 0 ꢂC. The reaction mixture was allowed to warm to rt
over 48 h. The reaction mixture was washed with satd aq NaHCO3
(5ꢃ200 mL), and the combined aqueous washings were then
extracted with CH2Cl2 (2ꢃ200 mL). The combined organic extracts
were washed with brine (200 mL), dried and concentrated in vacuo.
Purification of the residue via flash column chromatography (elu-
ent pentane/Et2O, 100:1) gave 9 as a colourless oil (27.8 g, 74%); dH
(400 MHz, CDCl3) 1.49 (9H, s, CMe3), 1.85 (3H, d, J 6.2, C(6)H3), 5.71
(1H, d, J 15.4, C(2)H), 6.07–6.21 (2H, m, C(4)H, C(5)H), 7.14 (1H, dd,
J 15.4, 10.0, C(3)H).
4.10. General procedure 9: preparation of ketones from
Weinreb amides
The requisite Grignard reagent (2.0 equiv as a solution in Et2O
at the molarity stated) was added dropwise via syringe to
a vigorously stirred solution of the requisite Weinreb amide
(1.0 equiv) in Et2O at ꢀ78 ꢂC. The reaction mixture was allowed
to warm to 0 ꢂC and stirring continued at 0 ꢂC for 6 h. The re-
action was quenched with a few drops of water and EtOAc was
added. The slurry was filtered through CeliteÒ (eluent EtOAc)
and the filtrate was concentrated in vacuo to give the crude
reaction mixture.
4.14.2. Methyl (E,E)-hexa-2,4-dienoate 15.
CO2Me
Me
4.11. General procedure 10: tandem hydrogenation/
hydrogenolysis and N-Boc protection
SOCl2 (4.23 mL, 58.0 mmol) was added dropwise to MeOH
(50 mL) stirring at ꢀ10 ꢂC. (E,E)-Hexa-2,4-dienoic acid (5.00 g,
44.6 mmol) was then added in one portion and the reaction mix-
ture was refluxed for 2 h before being concentrated in vacuo. The
residue was dissolved in CH2Cl2 (50 mL) and the resultant solution
Pearlman’s catalyst (50% w/w of substrate) was added to a vig-
orously stirred solution of the requisite substrate (1.0 equiv) and

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10199
washed with satd aq NaHCO3 (5ꢃ50 mL), dried and concentrated in
vacuo. Purification via flash column chromatography (eluent pen-
tane/Et2O, 100:1) gave 15 as a colourless oil (4.78 g, 85%); dH
(400 MHz, CDCl3) 1.77 (3H, d, J 5.4, C(6)H3), 3.66 (3H, s, OMe), 5.72
(1H, d, J 15.2, C(2)H), 6.03–6.16 (2H, m, C(4)H, C(5)H), 7.17–7.26 (1H,
m, C(3)H).
(400 MHz, CDCl3) 1.38 (3H, d, J 6.8, C(
C(6)H3), 2.05–2.09 (2H, m, NCH2CH2), 2.37 (1H, dd, J 14.3, 7.6,
C(2)HA), 2.48–2.62 (3H, m, C(2)HB, NCH2), 3.59 (3H, s, OMe), 3.80–
3.85 (1H, m, C(3)H), 3.98 (1H, q, J 6.8, C(a)H), 4.90–4.98 (2H, m,
CH]CH2), 5.52–5.54 (2H, m, C(4)H, C(5)H), 5.58–5.73 (1H, m,
CH]CH2), 7.19–7.38 (5H, m, Ph); dC (100 MHz, CDCl3) 18.0 (C(6),
a
)Me), 1.70–1.71 (3H, m,
C(
a
)Me), 34.7 (NCH2CH2), 38.9 (C(2)), 46.3 (NCH2), 51.3 (OMe), 57.1
4.14.3. tert-Butyl (3S,4E,
a
R)-3-[N-but-30-enyl-N-(
a
-methylbenzyl)-
(C(3)), 57.6 (C(a
)), 115.1 (CH]CH2), 126.5, 126.9, 127.7, 127.9, 130.6
amino]hex-4-enoate 16.
(C(4), C(5), p-Ph, m-Ph, o-Ph), 137.1 (CH]CH2), 145.3 (i-Ph), 172.4
(C(1)); m/z (ESIþ) 302 ([MþH]þ, 100%); HRMS (ESIþ) C19H28NOþ2
([MþH]þ) requires 302.2120; found 302.2120.
4.14.5. tert-Butyl (20S, R)-2-[N(10)-( -methylbenzyl)-10,20,50,60-tetra-
a a
hydropyridin-20-yl]ethanoate 19.
Ph
N
t
CO2 Bu
Me
N
Ph
Following General Procedure 1, BuLi (2.5 M in hexanes,
t
CO2 Bu
3.69 mL, 9.21 mmol), N-but-3-enyl-N-(a-methylbenzyl)amine
(1.67 g, 9.51 mmol) in THF (20 mL) at ꢀ78 ꢂC, and 9 (1.00 g,
5.94 mmol) in THF (20 mL) at ꢀ78 ꢂC gave a 96:4 mixture of 16:17.
Purification via flash column chromatography (eluent pentane/
Following General Procedure 2, Grubbs I (95.8 mg, 0.116 mmol)
and 16 (1.00 g, 2.91 mmol) in CH2Cl2 (300 mL) at rt gave the crude
reaction mixture. Purification by treatment with P(CH2OH)3
(1.44 g, 11.6 mmol), Et3N (0.81 mL, 5.82 mmol) and silica in CH2Cl2
(w30 mL) followed by filtration through a short plug of silica gel
(eluent pentane/Et2O, 20:1) gave 19 as a colourless oil (683 mg,
Et2O, 50:1) gave 17 as a colourless oil (23 mg, 2%)40
; nmax (film)
2978, 2931 (C–H), 1733 (C]O); dH (400 MHz, CDCl3) 1.46 (9H, s,
CMe3), 3.04 (2H, d, J 7.2, C(2)H2), 5.04–5.18 (2H, m, C(6)H2), 5.78
(1H, dt, J 15.4, 7.2, C(3)H), 6.10–6.16 (1H, m, C(4)H), 6.35 (1H, app
dt, J 17.1, 10.2, C(5)H); dC (100 MHz, CDCl3) 28.5 (CMe3), 39.5 (C(2)),
80.9 (CMe3), 116.8 (C(6)), 126.7 (C(3)), 134.4 (C(4)), 136.9 (C(5)),
170.9 (C(1)); m/z (CIþ) 169 ([MþH]þ, 100%); HRMS (CIþ) C10H17O2þ
([MþH]þ) requires 169.1229; found 169.1230. Further elution gave
78%, >99:1 dr); C19H27NO2 requires C, 75.7; H, 9.0; N, 4.65%;
found C, 75.5; H, 9.0; N, 4.6%; [
25
a]
þ41.8 (c 1.5 in CHCl3); nmax
D
(film) 2931 (C–H), 1731 (C]O); dH (400 MHz, CDCl3) 1.39 (3H, d, J
6.6, C(a
)Me), 1.49 (9H, s, CMe3), 1.68–1.75 (1H, m, C(50)HA), 2.07–
16 as a colourless oil (1.67 g, 82%, 97:3 dr); C22H33NO2 requires C,
24
2.15 (1H, m, C(50)HB), 2.38 (1H, dd, J 14.2, 6.9, C(2)HA), 2.45–2.51
(1H, m, C(60)HA), 2.60 (1H, dd, J 14.2, 7.3, C(2)HB), 2.86 (1H, ddd, J
13.3, 9.5, 4.8, C(60)HB), 3.73–3.76 (1H, m, C(20)H), 3.90 (1H, q, J 6.6,
76.9; H, 9.7; N, 4.1%; found C, 76.4; H, 9.9; N, 4.0%; [
a
]
ꢀ11.3 (c
D
2.5 in CHCl3); nmax (film) 2977 (C–H), 1733 (C]O); dH (400 MHz,
CDCl3) 1.37 (3H, d, J 6.8, C( )Me), 1.41 (9H, s, CMe3), 1.70–1.72 (3H,
a
a
)H), 5.64–5.68 (1H, m, C(30)H), 5.80–5.85 (1H, m, C(40)H), 7.21–
m, C(6)H3), 2.00–2.07 (2H, m, NCH2CH2), 2.29 (1H, dd, J 14.1, 8.4,
C(2)HA), 2.42 (1H, dd, J 14.1, 6.6, C(2)HB), 2.48–2.57 (2H, m, NCH2),
3.76–3.82 (1H, m, C(3)H), 3.94 (1H, q, J 6.8, C(a)H), 4.88–4.94 (2H,
m, CH]CH2), 5.46–5.57 (2H, m, C(4)H, C(5)H), 5.60–5.70 (1H, m,
CH]CH2), 7.19–7.39 (5H, m, Ph); dC (100 MHz, CDCl3) 17.9 (C(6)),
C(
7.35 (5H, m, Ph); dC (100 MHz, CDCl3) 21.8 (C(
28.2 (CMe3), 40.0 (C(60)), 40.5 (C(2)), 52.1 (C(20)), 57.9 (C(
a
)Me), 22.0 (C(50)),
)), 80.1
a
(CMe3), 126.3, 126.8, 127.6, 128.1, 128.9 (C(30), C(40), p-Ph, m-Ph, o-
Ph), 144.5 (i-Ph), 171.4 (C(1)); m/z (ESIþ) 302 ([MþH]þ, 100%);
HRMS (ESIþ) C19H28NOþ2 ([MþH]þ) requires 302.2120; found
302.2115.
18.6 (C(
a)Me), 28.1 (CMe3), 35.0 (NCH2CH2), 40.1 (C(2)), 46.5
(NCH2), 57.6 (C(3)), 58.0 (C(a)), 80.0 (CMe3), 115.0 (CH]CH2),
126.5, 126.7, 127.7, 127.9, 130.7 (C(4), C(5), p-Ph, m-Ph, o-Ph), 137.1
(CH]CH2), 145.6 (i-Ph), 171.4 (C(1)); m/z (ESIþ) 344 ([MþH]þ,
100%); HRMS (ESIþ) C22H34NOþ2 ([MþH]þ) requires 344.2590;
found 344.2592.
4.14.6. (20S, R)-Methyl 2-[N(10)-( -methylbenzyl)-10,20,50,60-tetra-
a a
hydropyridin-20-yl]ethanoate 20.
4.14.4. Methyl (3S,4E,a a-methylbenzyl)amino]
R)-3-[N-but-30-enyl-N-(
hex-4-enoate 18.
N
Ph
CO2Me
Ph
N
Following General Procedure 2, Grubbs I (109 mg, 0.133 mmol)
and 18 (1.00 g, 3.32 mmol) in CH2Cl2 (300 mL) at rt gave the crude
reaction mixture. Purification by treatment with P(CH2OH)3
(1.65 g, 13.3 mmol), Et3N (0.92 mL, 6.64 mmol) and silica in CH2Cl2
(w30 mL) followed by filtration through a short plug of silica gel
(eluent pentane/Et2O, 20:1) gave 20 as a colourless oil (647 mg,
CO2Me
Me
Following General Procedure 1, BuLi (2.5 M in hexanes, 4.91 mL,
12.3 mmol),
N-but-3-enyl-N-(
a
-methylbenzyl)amine
(2.22 g,
75%, >99:1 dr); C16H21NO2 requires C, 74.1; H, 8.2; N, 5.4%; found
16
12.7 mmol) in THF (20 mL) at ꢀ78 ꢂC, and 15 (1.00 g, 7.93 mmol) in
THF (20 mL) at ꢀ78 ꢂC gave 18 in 97:3 dr. Purification via flash
column chromatography (eluent pentane/Et2O, 50:1) gave 18 as
C, 73.9; H, 8.0; N, 5.3%; [
a
]
þ42.1 (c 1.0 in CHCl3); nmax (film) 2972
D
(C–H), 1738 (C]O); dH (400 MHz, CDCl3) 1.36 (3H, d, J 6.6, C(a)Me),
1.65–1.72 (1H, m, C(50)HA), 2.08–2.18 (1H, m, C(50)HB), 2.49 (1H, dd,
J 14.4, 6.3, C(2)HA), 2.49–2.55 (1H, m, C(60)HA), 2.69 (1H, dd, J 14.4,
7.8, C(2)HB), 2.84 (1H, ddd, J 13.6, 10.1, 4.5, C(60)HB), 3.65 (3H, s,
a colourless oil (1.81 g, 76%, 97:3 dr); C19H27NO2 requires C, 75.7; H,
9.0; N, 4.65%; found C, 75.6; H, 9.0; N, 4.4%; [
CHCl3); nmax (film) 2973 (C–H), 1741 (C]O), 1640 (C]C); dH
24
a]
ꢀ20.7 (c 1.0 in
D
OMe), 3.83–3.87 (1H, m, C(20)H), 3.88 (1H, q, J 6.6, C(
a)H), 5.65–

10200
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
5.69 (1H, m, C(30)H), 5.84–5.88 (1H, m, C(40)H), 7.21–7.33 (5H, m,
Ph); dC (100 MHz, CDCl3) 21.5 (C(50)), 22.0 (C(
)Me), 39.3 (C(2)),
40.0 (C(60)), 51.5 (OMe), 51.7 (C(20)), 58.0 (C( )), 126.8 (C(40), p-Ph),
130 ꢂC, 120 min; (R)-22 tR¼156.2 min; (S)-22 tR¼159.2 min). (R)-22
a
was therefore assessed to be 99:1 er.
a
127.4, 128.2 (o-Ph, m-Ph), 128.6 (C(30)), 144.9 (i-Ph), 172.6 (C(1));
m/z (ESIþ) 260 ([MþH]þ, 100%); HRMS (ESIþ) C16H22NOþ2 ([MþH]þ)
requires 260.1651; found 260.1649.
4.14.9. (R)-2-(Piperidin-20-yl)ethanoic acid 23.
NH
4.14.7. tert-Butyl (R)-2-(piperidin-20–yl)ethanoate 21.
CO2H
NH
Following General Procedure 5, TFA (0.1 mL) and (R)-21
(100 mg) in CH2Cl2 (1 mL) at rt gave the crude reaction mixture. Co-
evaporation with 6 M aq HCl and purification of the residue via ion-
exchange chromatography on Dowex 50WX8-200 resin (eluent
t
CO2 Bu
1 M aq NH4OH) gave 23 as a white solid (52 mg, 72%)18; mp 215–
Following General Procedure 4, Pearlman’s catalyst (250 mg)
and 19 (500 mg) in EtOAc (5 mL) under H2 (5 atm) at rt gave the
crude reaction mixture. Purification via flash column chromatog-
24
217 ꢂC; {lit.18 mp 218–221 ꢂC}; [
a]
ꢀ23.4 (c 0.5 in H2O); {lit.11 for
D
26
enantiomer [
a
]
þ24.0 (c 0.9 in H2O)}; dH (400 MHz, D2O) 1.39–
D
1.85 (6H, m, C(30)H2, C(40)H2, C(50)H2), 2.45 (2H, app d, J 6.6, C(2)H2),
2.88–2.90 (1H, m, C(60)HA), 3.25–3.39 (2H, m, C(20)H, C(60)HB).
raphy (eluent pentane/Et2O/Et3N, 80:20:1) gave 21 as a colourless
25
oil (307 mg, 93%)41; [
a
]
ꢀ6.8 (c 1.5 in CH2Cl2); lit. for enantiomer
D
24
[
a]
þ8.3 (c 1.4 in CH2Cl2); dH (400 MHz, CDCl3) 1.13–1.51 (3H, m,
D
C(30)HA, C(40)HA, C(50)HA) overlapping 1.45 (9H, s, CMe3), 1.58–1.62
(2H, m, C(30)HB, C(50)HB), 1.75–1.79 (1H, m, C(40)HB), 2.11 (1H, br s,
NH), 2.30 (2H, app d, J 6.4, C(2)H2), 2.64–2.70 (1H, m, C(60)HA), 2.84–
2.91 (1H, m, C(20)H), 3.04–3.07 (1H, m, C(60)HB).
4.14.10. tert-Butyl diethylphosphonoacetate 24.
O
t
CO2 Bu
(EtO)2P
4.14.8. tert-Butyl (RS)- and (R)-[N(10)-acetylpiperidin-20-yl]ethanoate
22.
A stirred mixture of tert-butyl bromoacetate (10.0 g, 51.3 mmol)
and triethylphosphite (8.79 mL, 51.3 mmol) was heated at 50 ꢂC for
2 h. After this time volatiles were removed in vacuo to give 24 as
a colourless liquid (12.9 g, quant); dH (200 MHz, CDCl3) 1.24 (6H, t, J
7.2, P(OCH2CH3)2), 1.37 (9H, s, CMe3), 2.77 (2H, d, J 21.5, PCH2), 4.02–
4.08 (4H, m, P(OCH2CH3)2).
Ac
N
t
CO2 Bu
4.14.11. Methyl diethylphosphonoacetate 25.
Ac2O (0.14 mL, 1.51 mmol) was added dropwise to a stirred
solution of (R)-21 (100 mg, 0.50 mmol) and DMAP (cat, 2 mg) in
pyridine (2 mL) and the reaction mixture stirred at rt for 12 h. The
reaction mixture was quenched with H2O (1 mL) and Et2O was
added (2 mL). The organic layer was separated and the aqueous
layer extracted with Et2O (2ꢃ2 mL). The combined organic ex-
tracts were washed sequentially with satd aq CuSO4 (5 mL) and
H2O (2ꢃ5 mL) before being dried, and concentrated in vacuo.
O
(EtO)2P
CO2Me
A stirred mixture of methyl bromoacetate (10.0 g, 65.4 mmol)
and triethylphosphite (11.2 mL, 65.4 mmol) was heated at 50 ꢂC for
2 h. After this time volatiles were removed in vacuo to give 25 as
a colourless liquid (13.7 g, quantitative); dH (200 MHz, CDCl3) 1.31
(6H, t, J 7.0, P(OCH2CH3)2), 2.95 (2H, d, J 21.5, PCH2), 3.71 (3H, s,
OMe), 4.07–4.21 (4H, m, P(OCH2CH3)2).
Purification via flash column chromatography (eluent pentane/
22
EtOAc, 4:1) gave (R)-22 as a colourless oil (107 mg, 88%); [a]
D
þ4.3 (c 1.0 in CHCl3); nmax (film) 2936 (C–H), 1725 (C]O, ester),
1646 (C]O, amide); dH (400 MHz, CDCl3) [58:42 mixture of
rotamers] 1.32–1.73 (m, C(30)H2, C(40)H2, C(50)H2), 1.42 (s, CMe3),
1.43 (s, CMe3), 2.06 (s, COMe), 2.15 (s, COMe), 2.42 (dd, J 13.9, 7.9,
C(2)HA), 2.48 (dd, J 14.6, 6.8, C(2)HA), 2.52 (dd, J 13.9, 8.0, C(2)HB),
2.56–2.64 (m, C(60)HA), 2.68 (dd, J 14.6, 8.2, C(2)HB), 3.11–3.20 (m,
C(60)HA), 3.57–3.65 (m, C(60)HB), 4.38–4.45 (m, C(20)H), 4.52–4.59
(m, C(60)HB), 5.17–5.23 (m, C(20)H); dH (500 MHz, DMSO-d6, 373 K)
1.32–1.65 (6H, m, C(30)H2, C(40)H2, C(50)H2) overlapping 1.41 (9H, s,
C(CH3)3), 2.01 (3H, s, COCH3), 2.45–2.58 (2H, m, C(2)H2), 3.02 (1H,
br s, C(60)HA), 3.5–5.0 (2H, br, C(20)H, C(60)HB); dC (125 MHz,
DMSO-d6, 373 K) [resonances attributable to C(20) and C(60) were
not observed] 19.0 (CH2), 21.6 (COMe), 25.7 (CH2), 27.6 (CH2), 28.2
(CMe3), 36.9 (C(2)), 80.4 (CMe3), 168.5 (NCO), 170.6 (C(1)); m/z
(ESIþ) 300 ([Mþ59]þ, 100%); HRMS (ESIþ) C13H24NOþ3 ([MþH]þ)
requires 242.1756; found 242.1760. An analogous procedure ap-
plied to (RS)-2117 (100 mg) gave (RS)-22 as a colourless oil
(109 mg, 90%).
4.14.12. tert-Butyl (E)-hepta-2,6-dienoate 26.
t
CO2 Bu
4.14.12.1. Olefination promoted by MeMgBr. Following General
Procedure 6, MeMgBr (3.0 M in Et2O, 5.94 mL, 17.8 mmol), 24
(4.50 g, 17.8 mmol) in THF (20 mL), and pent-4-enal (1.00 g,
11.9 mmol) in THF (10 mL) gave, after 4 h, (E)-26 in >99:1 dr.
Purification via flash column chromatography (eluent pentane/
Et2O, 100:1) gave (E)-26 as a colourless oil (1.98 g, 91%, >99:1 dr);
nmax (film) 2975 (C–H), 1718 (C]O), 1652 (C]C); dH (400 MHz,
(RS)-22 was analysed by chiral GC, giving complete resolution of
enantiomers (run conditions: 70 ꢂC, 60 min; 4.0 ꢂC/min ramp;

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10201
CDCl3) 1.48 (9H, s, CMe3), 2.18–2.30 (4H, m, C(4)H2, C(5)H2), 4.99–
54.2 (C(3)), 58.4 (C(a)),79.9 (CMe3),114.3,115.3 (C(7), NCH2CH]CH2),
5.07 (2H, m, C(7)H2), 5.74–5.86 (2H, m, C(2)H, C(6)H), 6.87 (1H, dt,
J 15.5, 6.5, C(3)H); dC (100 MHz, CDCl3) 28.1 (CMe3), 31.3 (C(5)),
32.1 (C(4)), 79.9 (CMe3), 115.4 (C(7)), 123.3 (C(6)), 137.1 (C(3)),
146.9 (C(2)), 165.9 (C(1)); m/z (CIþ) 183 ([MþH]þ, 72%), 127 (100);
HRMS (CIþ) C11H19Oþ2 ([MþH]þ) requires 183.1385; found
183.1382.
126.8 (p-Ph), 127.8, 128.1 (m-Ph, o-Ph), 139.0, 139.2 (C(6),
NCH2CH]CH2), 144.0 (i-Ph), 172.1 (C(1)); m/z (ESIþ) 344 ([MþH]þ,
100%); HRMS (ESIþ) C22H34NO2þ ([MþH]þ) requires 344.2590; found
344.2593.
4.14.15. Methyl (3R,aR)-3-[N-allyl-N-(a-methylbenzyl)amino]hept-
6-enoate 29.
4.14.12.2. Olefination promoted by BuLi. Following General
Procedure 6, BuLi (2.5 M in hexanes, 26.1 mL, 65.4 mmol), 24
(16.5 g, 65.4 mmol) in THF (50 mL), and pent-4-enal (5.00 g,
59.4 mmol) in THF (25 mL) gave, after 2 h, a 90:10 mixture of
(E)-26:(Z)-26. Purification via flash column chromatography
(eluent pentane/Et2O, 100:1) gave (Z)-26 as a colourless oil
(214 mg, 2%, >99:1 dr); nmax (film) 2977 (C–H), 1716 (C]O), 1645
(C]C); dH (400 MHz, CDCl3) 1.48 (9H, s, CMe3), 2.16–2.21 (2H, m,
C(5)H2), 2.69–2.74 (2H, m, C(4)H2), 4.97–5.06 (2H, m, C(7)H2),
5.67–5.70 (1H, m, C(2)H), 5.76–5.86 (1H, m, C(6)H), 6.10 (1H, dt, J
11.6, 7.2, C(3)H); dC (100 MHz, CDCl3) 27.8 (C(4)), 28.1 (CMe3), 33.0
(C(5)), 80.0 (CMe3), 115.2 (C(7)), 121.8 (C(6)), 137.5 (C(2)), 147.7
(C(3)), 165.8 (C(1)); m/z (CIþ) 183 ([MþH]þ, 45%), 127 (100);
HRMS (CIþ) C11H19Oþ2 ([MþH]þ) requires 183.1385; found
183.1380. Further elution gave (E)-26 as a colourless oil (8.93 g,
83%, >99:1 dr).42
Ph
N
CO2Me
Following General Procedure 1, BuLi (2.5 M in hexanes,
4.42 mL, 11.1 mmol), (R)-N-allyl-N-(a-methylbenzyl)amine (1.84 g,
11.4 mmol) in THF (20 mL) at ꢀ78 ꢂC, and 27 (1.00 g, 7.13 mmol) in
THF (20 mL) at ꢀ78 ꢂC gave 29 in 98:2 dr. Purification via flash
column chromatography (eluent pentane/Et2O, 50:1) gave 29 as
25
a colourless oil (1.69 g, 79%, 98:2 dr); [
nmax (film) 2975 (C–H), 1737 (C]O), 1640 (C]C); dH (400 MHz,
CDCl3) 1.32–1.43 (1H, m, C(4)HA) overlapping 1.40 (3H, d, J 6.8,
a]
ꢀ15.4 (c 1.5 in CHCl3);
D
C(a)Me), 1.52–1.61 (1H, m, C(4)HB), 1.97–2.18 (3H, m, C(2)H2,
C(5)HA), 2.20–2.35 (1H, m, C(5)HB), 3.10 (1H, dd, J 15.4, 6.8, NCHA),
3.22–3.35 (2H, m, C(3)H, NCHB), 3.58 (3H, s, OMe), 3.96 (1H, q, J 6.8,
4.14.13. Methyl (E)-hepta-2,6-dienoate 27.
CO2Me
C(
C(6)H, NCH2CH]CH2), 7.20–7.31 (5H, m, Ph); dC (100 MHz, CDCl3)
20.3 (C( )Me), 31.1 (C(5)), 32.4 (C(4)), 36.7 (C(2)), 48.7 (NCH2), 51.3
(OMe), 54.3 (C(3)), 58.2 (C( )), 114.3, 115.5 (C(7), NCH2CH]CH2),
a)H), 4.94–5.23 (4H, m, C(7)H2, NCH2CH]CH2), 5.76–5.92 (2H, m,
a
a
Following General Procedure 6, MeMgBr (3.0 M in Et2O, 5.94 mL,
17.8 mmol), 25 (3.75 g, 17.8 mmol) in THF (20 mL), and pent-4-enal
(1.00 g, 11.9 mmol) in THF (10 mL) gave, after 4 h, (E)-27 in >99:1
dr. Purification via flash column chromatography (eluent pentane/
126.8 (p-Ph), 127.6, 128.1 (m-Ph, o-Ph), 138.7, 139.0 (C(6),
NCH2CH]CH2), 144.1 (i-Ph), 173.1 (C(1)); m/z (ESIþ) 302 ([MþH]þ,
100%); HRMS (ESIþ) C19H28NO2þ ([MþH]þ) requires 302.2120; found
302.2122.
Et2O, 100:1) gave (E)-27 as a colourless oil (1.54 g, 92%, >99:1 dr)43
;
dH (400 MHz, CDCl3) 2.19–2.35 (4H, m, C(4)H2, C(5)H2), 3.73 (3H, s,
OMe), 5.01–5.08 (2H, m, C(7)H2), 5.75–5.87 (2H, m, C(2)H, C(6)H),
6.97 (1H, dt, J 15.7, 6.8, C(3)H).
4.14.16. tert-Butyl (3R,a a-methylbenzyl)ami-
R)-3-[N-but-30-enyl-N-(
no]hept-6-enoate 30.
4.14.14. tert-Butyl (3R,aR)-3-[N-allyl-N-(a-methylbenzyl)amino]hept-
6-enoate 28.
Ph
N
t
CO2 Bu
Ph
N
t
CO2 Bu
Following General Procedure 1, BuLi (2.5 M in hexanes, 3.40 mL,
8.50 mmol), (R)-N-but-3-enyl-N-(a-methylbenzyl)amine (1.54 g,
8.78 mmol) in THF (20 mL) at ꢀ78 ꢂC, and 26 (1.00 g, 5.49 mmol) in
THF (20 mL) at ꢀ78 ꢂC gave 30 in 97:3 dr. Purification via flash
column chromatography (eluent pentane/Et2O, 50:1) gave 30 as
Following General Procedure 1, BuLi (2.5 M in hexanes, 3.35 mL,
8.50 mmol), (R)-N-allyl-N-(a-methylbenzyl)amine (1.42 g, 8.78
a colourless oil (1.93 g, 98%, 97:3 dr)44; C23H35NO2 requires C, 77.3;
mmol) in THF (20 mL) at ꢀ78 ꢂC, and 26 (1.00 g, 5.49 mmol) in THF
25
(20 mL) at ꢀ78 ꢂC gave 28 in 98:2 dr. Purification via flash column
H, 9.9; N, 3.9%; found C, 77.6; H, 9.7; N, 3.8%; [
a
]
D
ꢀ16.1 (c 1.0 in
chromatography (eluent pentane/Et2O, 50:1) gave 28 as a colourless
CHCl3); nmax (film) 2976 (C–H), 1727 (C]O), 1640 (C]C); dH
(400 MHz, CDCl3) 1.31–1.42 (1H, m, C(4)HA) overlapping 1.40 (9H, s,
25
oil (1.76 g, 94%, 98:2 dr); [
a
]
ꢀ20.7 (c 1.0 in CHCl3); nmax (film) 2977
D
(C–H), 1727 (C]O), 1641 (C]C); dH (400 MHz, CDCl3) 1.32–1.42 (1H,
m, C(4)HA) overlapping 1.40 (9H, s, CMe3) and 1.41 (3H, d, J 6.8,
CMe3) and 1.42 (3H, d, J 6.8, C(a)Me), 1.46–1.56 (1H, m, C(4)HB),
1.94–2.08 (3H, m, C(2)H2, C(5)HA), 2.11–2.30 (3H, m, C(5)HB,
NCH2CH2), 2.51–2.56 (2H, m, NCH2), 3.15–3.22 (1H, m, C(3)H), 3.88
C(a)Me), 1.46–1.57 (1H, m, C(4)HB), 1.94 (1H, dd, J 14.5, 8.8, C(2)HA),
1.99–2.08 (1H, m, C(5)HA) overlapping 2.03 (1H, dd, J 14.5, 4.4,
C(2)HB), 2.17–2.34 (1H, m, C(5)HB), 3.05 (1H, dd, J 15.3, 6.9, NCHA),
3.20–3.31 (2H, m, C(3)H, NCHB), 3.93 (1H, q, J 6.8, C(a)H), 4.92–5.23
(4H, m, C(7)H2, NCH2CH]CH2), 5.75–5.91 (2H, m, C(6)H,
NCH2CH]CH2), 7.20–7.34 (5H, m, Ph); dC (100 MHz, CDCl3) 20.8
(C(a)Me), 28.1 (CMe3), 31.0 (C(5)), 32.4 (C(4)), 37.8 (C(2)), 48.7 (NCH2),
(1H, q, J 6.8, C(
5.71–5.84 (2H, m, C(6)H, NCH2CH2CH]CH2), 7.21–7.38 (5H, m, Ph);
dC (100 MHz, CDCl3) 21.0 (C( )Me), 28.0 (CMe3), 31.0 (C(5)), 32.2
(C(4)), 35.4 (NCH2CH2), 37.7 (C(2)), 45.7 (NCH2), 54.8 (C(3)), 58.9
(C( )), 79.9 (CMe3), 114.2, 115.3 (C(7), NCH2CH2CH]CH2), 126.8 (p-
Ph), 127.7, 128.1 (m-Ph, o-Ph), 137.1, 139.0 (C(6), NCH2CH2CH]CH2),
a)H), 4.92–5.03 (4H, m, C(7)H2, NCH2CH2CH]CH2),
a
a

10202
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
144.6 (i-Ph), 172.2 (C(1)); m/z (ESIþ) 358 ([MþH]þ, 78%), 302 (100);
HRMS (ESIþ) C23H36NOþ2 ([MþH]þ) requires 358.2746; found
358.2749.
(100); HRMS (ESIþ) C20H30NO2þ ([MþH]þ) requires 316.2277; found
316.2274.
4.14.19. Methyl (20R,
a
R)-2-[N(10)-(
a
-methylbenzyl)-20,30,40,70-tetra-
4.14.17. Methyl (3R,
a
R)-3-[N-but-30-enyl-N-(
a-methylbenzyl)amino]-
hydro-1H-azepin-20-yl]ethanoate 33.
hept-6-enoate 31.
N
Ph
CO2Me
Ph
N
CO2Me
Following General Procedure 2, Grubbs I (218 mg, 0.265 mmol)
and 29 (1.00 g, 3.32 mmol) in CH2Cl2 (300 mL) at rt gave the crude
reaction mixture. Purification by treatment with P(CH2OH)3 (3.29 g,
26.5 mmol), Et3N (0.92 mL, 6.64 mmol) and silica in CH2Cl2
(w30 mL) followed by filtration through a short plug of silica gel
Following General Procedure 1, BuLi (2.5 M in hexanes, 4.42 mL,
11.1 mmol), (R)-N-but-3-enyl-N-(a-methylbenzyl)amine (2.00 g,
11.4 mmol) in THF (20 mL) at ꢀ78 ꢂC, and 27 (1.00 g, 7.13 mmol) in
(eluent pentane/Et2O, 20:1) gave 33 as a colourless oil (806 mg, 89%,
THF (20 mL) at ꢀ78 ꢂC gave 31 in 97:3 dr. Purification via flash
22
>99:1 dr); [
a
]
ꢀ31.5 (c 1.0 in CHCl3); nmax (film) 2929 (C–H), 1739
D
column chromatography (eluent pentane/Et2O, 50:1) gave 31 as
(C]O); dH (400 MHz, CDCl3) 1.38 (3H, d, J 6.7, C(a)Me), 1.70–1.79
25
a colourless oil (1.99 g, 88%, 97:3 dr); [
a
]
D
ꢀ16.5 (c 1.5 in CHCl3);
(1H, m, C(30)HA), 1.92–1.96 (1H, m, C(30)HB), 2.15–2.28 (2H, m,
C(40)H2), 2.42 (1H, dd, J 14.0, 5.8, C(2)HA), 2.60 (1H, dd, J 14.0, 8.9,
C(2)HB), 2.82 (1H, dd, J 17.4, 6.1, C(70)HA), 3.38–3.45 (1H, m, C(70)HB),
nmax (film) 2976 (C–H), 1737 (C]O), 1640 (C]C); dH (400 MHz,
CDCl3) 1.31–1.44 (1H, m, C(4)HA) overlapping 1.41 (3H, d, J 6.8,
C(
C(5)H2, NCH2CH2), 2.53–2.62 (2H, m, NCH2), 3.20–3.26 (1H, m,
C(3)H), 3.57 (3H, s, OMe), 3.91 (1H, q, J 6.8, C( )H), 4.94–5.09 (4H, m,
C(7)H2, NCH2CH2CH]CH2), 5.72–5.88 (2H, m, C(6)H,
NCH2CH2CH]CH2), 7.21–7.36 (5H, m, Ph); dC (100 MHz, CDCl3) 20.5
(C( )Me), 31.3 (C(5)), 32.4 (C(4)), 35.2 (NCH2CH2), 36.6 (C(2)), 45.5
(NCH2), 51.3 (OMe), 54.8 (C(3)), 58.6 (C( )), 114.3, 115.4 (C(7),
a)Me), 1.51–1.60 (1H, m, C(4)HB), 1.96–2.35 (5H, m, C(2)H2,
3.74 (3H, s, OMe), 3.85–3.92 (1H, m, C(20)H), 4.06 (1H, q, J 6.7, C(
a
)H),
5.26–5.31 (1H, m, C(60)H), 5.77–5.83 (1H, m, C(50)H), 7.18–7.29 (5H,
m, Ph); dC (100 MHz, CDCl3) 22.2 (C(
)Me), 26.6 (C(40)), 33.4 (C(30)),
40.2 (C(2)), 43.1 (C(70)), 51.4 (OMe), 54.6 (C(20)), 59.1 (C(
)),126.5 (p-
a
a
a
Ph), 127.1, 128.1 (m-Ph, o-Ph), 128.9 (C(60)), 131.8 (C(50)), 146.9 (i-Ph),
173.0 (C(1)); m/z (ESIþ) 274 ([MþH]þ, 100%); HRMS (ESIþ)
C17H24NOþ2 ([MþH]þ) requires 274.1807; found 274.1802.
a
a
NCH2CH2CH]CH2), 126.7 (p-Ph), 127.7, 128.1 (m-Ph, o-Ph), 137.0,
138.7 (C(6), NCH2CH2CH]CH2), 144.6 (i-Ph), 173.2 (C(1)); m/z (ESIþ)
316 ([MþH]þ, 100%); HRMS (ESIþ) C20H30NOþ2 ([MþH]þ) requires
316.2277; found 316.2276.
4.14.20. tert-Butyl (20R,
a
R)-2-[N(10)-(
a
-methylbenzyl)azepan-20-yl]-
ethanoate 34.
4.14.18. tert-Butyl (20R, R)-2-[N(10)-( -methylbenzyl)-20,30,40,70-tetra-
a a
hydro-1H-azepin-20-yl]ethanoate 32.
Ph
N
t
CO2 Bu
Following General Procedure 3, Wilkinson’s catalyst (14.7 mg,
0.016 mmol) and 32 (100 mg, 0.32 mmol) in EtOAc (5 mL) under H2
(4 atm) at rt gave the crude reaction mixture. Purification via flash
Ph
CO2 Bu
N
t
column chromatography (eluent pentane/Et2O, 10:1) gave 34 as
22
a colourless oil (86.2 mg, 85%, >99:1 dr); [
a]
ꢀ2.8 (c 1.0 in CHCl3);
D
nmax (film) 2927 (C–H), 1725 (C]O); dH (400 MHz, CDCl3) 1.32–1.50
(3H, m, CH2) overlapping 1.38 (3H, d, J 6.7, C( )Me) and 1.41 (9H, s,
a
Following General Procedure 2, Grubbs I (192 mg, 0.233 mmol)
and 28 (1.00 g, 2.91 mmol) in CH2Cl2 (300 mL) at rt gave the crude
reaction mixture. Purification by treatment with P(CH2OH)3
(23.3 mmol, 2.89 g), Et3N (5.82 mmol, 0.81 mL) and silica in CH2Cl2
(w30 mL) followed by filtration through a short plug of silica gel
(eluent pentane/Et2O, 20:1) gave 32 as a colourless oil, which so-
lidified on standing to a white solid (835 mg, 91%, >99:1 dr);
CMe3), 1.51–1.69 (4H, m, CH2), 1.80–1.88 (1H, m, CH2), 2.15 (1H, dd, J
13.5, 8.9, C(2)HA), 2.44 (1H, dd, J 13.5, 5.1, C(2)HB), 2.67–2.70 (2H, m,
C(70)H2), 3.29–3.53 (1H, m, C(20)H), 3.97 (1H, q, J 6.7, C(
a
)H), 7.19–
)Me), 24.3 (CH2), 28.1
(CMe3), 29.1, 29.4, 34.2 (CH2), 39.6 (C(2)), 43.8 (C(70)), 55.4 (C(20)),
7.35 (5H, m Ph); dC (100 MHz, CDCl3) 21.7 (C(
a
59.9 (C(a)), 79.8 (CMe3), 126.5 (p-Ph), 127.4, 128.1 (m-Ph, o-Ph),
145.7 (i-Ph), 172.4 (C(1)); m/z (ESIþ) 318 ([MþH]þ, 100%); HRMS
C20H29NO2 requires C, 76.15; H, 9.3; N, 4.4%; found C, 76.4; H, 9.5; N,
(ESIþ) C20H32NO2þ ([MþH]þ) requires 318.2433; found 318.2430.
25
4.3%; mp 38–40 ꢂC; [
a]
þ33.2 (c 1.5 in CHCl3); nmax (KBr) 2976 (C–
D
H), 1729 (C]O); dH (400 MHz, CDCl3) 1.42 (3H, d, J 6.6, C(a)Me), 1.51
4.14.21. tert-Butyl (R)-2-(azepan-20-yl)ethanoate 35.
(9H, s, CMe3), 1.66–1.75 (1H, m, C(30)HA), 1.91–1.98 (1H, m, C(30)HB),
2.16–2.27 (2H, m, C(40)H2), 2.32 (1H, dd, J 14.1, 6.3, C(2)HA), 2.55 (1H,
dd, J 14.1, 8.2, C(2)HB), 2.85 (1H, dd, J 17.4, 6.3, C(70)HA), 3.40–3.44
NH
(1H, m, C(70)HB), 3.81–3.88 (1H, m, C(20)H), 4.06 (1H, q, J 6.6, C(
a
)H),
5.29–5.33 (1H, m, C(60)H), 5.78–5.84 (1H, m, C(50)H), 7.19–7.31 (5H,
m, Ph); dC (100 MHz, CDCl3) 22.2 (C(
)Me), 26.4 (C(40)), 28.2 (CMe3),
)), 80.0
t
CO2 Bu
a
32.4 (C(30)), 41.1 (C(2)), 43.3 (C(70)), 54.6 (C(20)), 59.1 (C(
a
(CMe3), 126.5 (p-Ph), 127.2, 128.0 (m-Ph, o-Ph), 129.1 (C(60)), 131.9
(C(50)), 146.8 (i-Ph), 172.0 (C(1)); m/z (ESIþ) 316 ([MþH]þ, 90%), 260
Following General Procedure 4, Pearlman’s catalyst (250 mg)
and 34 (500 mg) in EtOAc (5 mL) under H2 (5 atm) at rt gave the

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10203
crude reaction mixture. Purification via flash column chromatog-
C(30)H2, C(40)H2, C(50)H2, C(60)H2), 2.36–2.43 (2H, m, C(2)H2), 3.09
(1H, ddd, J 13.7, 7.6, 4.0, C(70)HA), 3.20 (1H, ddd, J 13.7, 7.3, 4.1 C(70)HB),
3.40–3.47 (1H, m, C(20)H); dC (100 MHz, D2O) 24.6, 25.0, 26.1, 31.2
(C(30), C(40), C(50), C(60)), 40.3 (C(2)), 45.4 (C(70)), 56.9 C(20), 178.3
(C(1)); m/z (ESIꢀ) 156 ([MꢀH]ꢀ, 100%); HRMS (ESIꢀ) C8H14NOꢀ2
([MꢀH]ꢀ) requires 156.1025; found 156.1022.
raphy on silica gel (eluent pentane/Et2O/Et3N, 80:20:1) gave 35 as
20
a colourless oil (301 mg, 90%); [
a
]
ꢀ3.9 (c 1.5 in CHCl3); nmax (film)
D
3352 (N–H), 2927 (C–H), 1728 (C]O); dH (400 MHz, CDCl3) 1.25–
1.78 (8H, m, C(30)H2, C(40)H2, C(50)H2, C(60)H2), overlapping 1.42
(9H, s, CMe3), 1.96 (1H, br s, NH), 2.27–2.30 (2H, m, C(2)H2), 2.67–
2.73 (1H, m, C(70)HA), 2.92–2.97 (1H, m, C(70)HB), 3.00–3.08 (1H, m,
C(20)H); dC (100 MHz, CDCl3) 25.5, 27.1 (CH2), 28.1 (CMe3), 31.1, 36.4
(CH2), 43.5 (C(2)), 47.1 (C(70)), 56.0 C(20), 80.3 (CMe3), 171.9 (C(1));
m/z (ESIþ) 214 ([MþH]þ, 100%); HRMS (ESIþ) C12H24NOþ2 ([MþH]þ)
requires 214.1807; found 214.1817.
4.14.24. tert-Butyl (20R, R)-2-[N(10)-( -methylbenzyl)-10,20,30,40,70,80-
a a
hexahydroazocin-20-yl]ethanoate 38.
4.14.22. tert-Butyl (R)- and (RS)-2-[N(10)-acetlyazepan-20-yl]etha-
noate (R)- and (RS)-36.
N
Ph
CO2 Bu
t
Ac
N
t
Following General Procedure 2, Grubbs I (184 mg, 0.224 mmol)
and 30 (1.00 g, 2.80 mmol) in CH2Cl2 (300 mL) at 30 ꢂC gave the
crude reaction mixture. Purification by treatment with P(CH2OH)3
(22.4 mmol, 2.78 g), Et3N (5.59 mmol, 0.78 mL) and silica in CH2Cl2
(w30 mL) followed by filtration through a short plug of silica gel
(eluent pentane/Et2O, 20:1) gave 38 as a white solid (812 mg, 88%,
CO2 Bu
Ac2O (0.13 mL, 1.41 mmol) was added dropwise to a stirred so-
lution of (R)-35 (100 mg, 0.47 mmol) and DMAP (cat, 2 mg) in
pyridine (2 mL) and the reaction mixture stirred at rt for 12 h. The
reaction mixture was quenched with H2O (1 mL) and Et2O was
added (2 mL). The organic layer was separated and the aqueous
layer extracted with Et2O (2ꢃ2 mL). The combined organic extracts
were washed sequentially with satd aq CuSO4 (5 mL) and H2O
(2ꢃ5 mL) before being dried and concentrated in vacuo. Purifica-
>99:1 dr); C21H31NO2 requires C, 76.55; H, 9.5; N, 4.25%; found C,
25
76.5; H, 9.4; N, 4.2%; mp 50–52 ꢂC; [
a
]
þ49.5 (c 1.0 in CHCl3);
D
nmax (KBr) 2922 (C–H), 1721 (C]O); dH (400 MHz, CDCl3) 1.39 (9H,
s, CMe3), 1.40–1.48 (1H, m, C(30)HA), 1.49 (3H, d, J 7.1, C(
)Me), 1.80–
a
1.88 (1H, m, C(30)HB), 1.91–1.99 (1H, m, C(70)HA) overlapping 1.98
(1H, dd, J 15.4, 7.1, C(2)HA), 2.02–2.09 (1H, m, C(40)HA), 2.24 (1H,
dd, J 15.4, 7.1, C(2)HB), 2.36–2.48 (2H, m, C(40)HB, C(70)HB), 2.87–
2.94 (1H, m, C(80)HA), 3.24–3.30 (1H, m, C(80)HB), 3.52–3.59 (1H,
tion via flash column chromatography (eluent pentane/EtOAc, 4:1)
20
gave (R)-36 as a colourless oil (114 mg, 95%); [
a]
þ65.9 (c 1.0 in
D
m, C(20)H), 4.08 (1H, q, J 7.1, C(
5.79–5.85 (1H, m, C(60)H), 7.16–7.35 (5H, m, Ph); dC (100 MHz,
CDCl3) 22.7 (C(
)Me), 25.1 (C(40)), 28.0 (CMe3), 30.2 (C(70)), 33.8
(C(30)), 40.5 (C(2)), 49.2 (C(80)), 55.4 (C( )), 56.2 (C(20)), 79.8
a
)H), 5.67–5.73 (1H, m, C(50)H),
CHCl3); nmax (film) 2930 (C–H), 1727 (C]O, ester), 1644 (C]O,
amide); dH (400 MHz, CDCl3) [50:50 mixture of rotamers] 1.15–1.48
(m, CH2) overlapping 1.43 (s, CMe3) and 1.44 (s, CMe3), 1.56–1.67 (m,
CH2), 1.75–1.83 (m, CH2), 2.09–2.22 (m, CH2) overlapping 2.12 (s,
COMe) and 2.29 (s, COMe), 2.29 (dd, J 14.1, 7.7, C(2)HA), 2.34 (dd, J
14.3, J 7.8, C(2)HA), 2.41–2.46 (m, C(2)HB), 2.56–2.61 (m, C(70)HA),
3.08–3.13 (m, C(70)HA), 3.50–3.54 (m, C(70)HB), 4.08–4.15 (m, C(20)H,
C(70)HB), 4.67–4.73 (m, C(20)H); dC (125 MHz, CDCl3) 21.8 (COMe),
21.9 (NCOMe), 24.5, 25.0, 27.3 (CH2), 27.9 (CMe3), 29.1, 29.7, 30.1,
32.5, 34.5 (CH2), 40.2, 40.5, 41.7, 43.9 (C(2), C(70)), 51.3, 54.6 (C(20)),
80.3, 81.0 (CMe3), 170.1, 170.2, 170.4, 170.5 (C(1), NCO); m/z (ESIþ)
314 ([Mþ59]þ, 100%); HRMS (ESIþ) C14H26NOþ3 ([MþH]þ) requires
256.1913; found 256.1911. An analogous procedure applied to (RS)-
3517 (100 mg) gave (RS)-36 (108 mg, 90%).
a
a
(CMe3), 126.1 (p-Ph), 126.8, 128.1 (m-Ph, o-Ph), 129.8 (C(60)), 130.7
(C(50)), 148.0 (i-Ph), 172.2 (C(1)); m/z (ESIþ) 330 ([MþH]þ, 78%),
274 (100); HRMS (ESIþ) C21H32NOþ2 ([MþH]þ) requires 330.2433;
found 330.2434.
4.14.25. Methyl(20R,
a
R)-2-[N(10)-(
a
-methylbenzyl)-10,20,30,40,70,80-hexa-
hydroazocin-20-yl]ethanoate 39.
N
Ph
(RS)-36 was analysed by chiral GC, giving complete resolution of
enantiomers (run conditions: 70 ꢂC, 60 min; 4.0 ꢂC/min ramp;
130 ꢂC, 180 min; (R)-36 tR¼204.3 min; (S)-36 tR¼210.9 min). (R)-36
was therefore assessed to be 99:1 er.
CO2Me
4.14.23. (R)-2-(Azepan-20-yl)ethanoic acid 37.
Following General Procedure 2, Grubbs I (209 mg, 0.254 mmol)
and 31 (1.00 g, 3.17 mmol) in CH2Cl2 (300 mL) at 30 ꢂC gave the
crude reaction mixture. Purification by treatment with P(CH2OH)3
(3.15 g, 25.4 mmol), Et3N (0.88 mL, 6.34 mmol) and silica in CH2Cl2
(w30 mL) followed by filtration through a short plug of silica gel
NH
CO2H
(eluent pentane/Et2O, 20:1) gave 39 as a white solid (778 mg, 85%,
22
>99:1 dr); mp 40–42 ꢂC; [
a
]
ꢀ45.5 (c 1.0 in CHCl3); nmax (KBr)
D
2920 (C–H), 1736 (C]O); dH (400 MHz, CDCl3) 1.35–1.44 (1H, m,
C(30)HA), 1.49 (3H, d, J 7.2, C( )Me), 1.81–1.90 (1H, m, C(30)HB), 1.93–
Following General Procedure 5, TFA (0.2 mL) and (R)-35 (250 mg)
in CH2Cl2 (2 mL) at rt gave the crude reaction mixture. Co-evapora-
tion with 6 M aq HCl and purification via ion-exchange chroma-
a
2.00 (1H, m, C(70)HA), 2.00–2.08 (1H, m, C(40)HA) overlapping 1.98
(1H, dd, J 15.7, 6.5, C(2)HA), 2.28 (1H, dd, J 15.7, 8.2, C(2)HB), 2.34–
2.46 (2H, m, C(40)HB, C(70)HB), 2.91–2.98 (1H, m, C(80)HA), 3.34–3.40
(1H, m, C(80)HB), 3.49 (3H, s, OMe), 3.54–3.65 (1H, m, C(20)H), 4.08
tography on Dowex 50WX8-200 resin (eluent 1 M aq NH4OH) gave
20
37 as a white solid (169 mg, 92%); mp 180–182 ꢂC; [
a]
D
ꢀ42.4 (c 2.0
in H2O); nmax (KBr) 3388 (NHþ2 , br), 2937 (C–H), 1584 (COꢀ2 asym-
metric),1397 (COꢀ2 symmetric); dH (400 MHz, D2O) 1.40–1.86 (8H, m,
(1H, q, J 7.2, C(
a
)H), 5.65–5.72 (1H, m, C(50)H), 5.80–5.87 (1H, m,
)Me),
C(60)H), 7.15–7.34 (5H, m, Ph); dC (100 MHz, CDCl3) 22.9 (C(
a

10204
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
25.0 (C(40)), 30.4 (C(70)), 33.8 (C(30)), 39.1 (C(2)), 49.4 (C(80)), 51.2
pyridine (2 mL) and the reaction mixture stirred at rt for 12 h. The
reaction mixture was quenched with H2O (1 mL) and Et2O was
added (2 mL). The organic layer was separated and the aqueous
layer extracted with Et2O (2ꢃ2 mL). The combined organic extracts
were washed sequentially with satd aq CuSO4 (5 mL) and H2O
(2ꢃ5 mL) before being dried and concentrated in vacuo. Purifica-
(OMe), 55.1 (C(20)), 56.2 (C(
a)), 126.1 (p-Ph), 126.5, 128.0 (m-Ph, o-
Ph), 130.0 (C(60)), 130.6 (C(50)), 148.4 (i-Ph), 173.1 (C(1)); m/z (ESIþ)
288 ([MþH]þ, 100%); HRMS (ESIþ) C18H26NOþ2 ([MþH]þ) requires
288.1964; found 288.1955.
4.14.26. tert-Butyl (20R,
a
R)-2-[N(10)-(
a
-methylbenzyl)azocan-20-yl]-
tion via flash column chromatography (eluent pentane/EtOAc, 4:1)
22
ethanoate 40.
gave (R)-42 as a colourless oil (109 mg, 92%); [
a
]
ꢀ9.1 (c 1.0 in
D
CHCl3); nmax (film) 2930 (C–H), 1727 (C]O, ester), 1644 (C]O,
amide); dH (400 MHz, CDCl3) [65:35 mixture of rotamers] 1.32–1.93
(m, C(30)H2, C(40)H2, C(50)H2, C(60)H2, C(70)H2) overlapping 1.43 (s,
CMe3), 1.98–2.12 (m, C(70)HB) overlapping 2.10 (s, COMe), 2.17 (s,
COMe), 2.30–2.41 (m, C(2)H2), 2.54–2.65 (m, C(2)HB), 2.72–2.80 (m,
C(80)HA), 3.28–3.43 (m, C(80)H2), 3.81–3.87 (m, C(80)HB), 4.07–4.15
(m, C(20)H), 4.47–4.58 (m, C(20)H); dC (125 MHz, CDCl3) 22.1
(COMe), 22.4 (COMe), 24.2, 24.8, 25.4, 25.9, 26.0, 26.1, 26.4 (CH2),
27.9, 28.0 (CMe3), 28.3, 29.4, 29.9 (CH2), 40.1 (C(2)), 40.6 (C(80)), 41.4
(C(2), C(80)), 55.6 (C(20)), 80.3, 81.1 (CMe3), 170.3, 170.4 (NCO), 170.8,
170.9 (C(1)); m/z (ESIþ) 328 ([Mþ59]þ, 100%); HRMS (ESIþ)
C15H28NOþ3 ([MþH]þ) requires 270.2069; found 270.2074. An
analogous procedure applied to (RS)-4117 (100 mg) gave (RS)-42
(113 mg, 96%).
N
Ph
t
CO2 Bu
Following General Procedure 3, Wilkinson’s catalyst (14.0 mg,
0.015 mmol) and 38 (100 mg, 0.30 mmol) in EtOAc (5 mL) under
H2 (4 atm) at rt gave the crude reaction mixture. Purification via
flash column chromatography (eluent pentane/Et2O, 10:1) gave 40
as a colourless oil (96 mg, 95%, >99:1 dr); [
CHCl3); nmax (film) 2975 (C–H), 1724 (C]O); dH (400 MHz, CDCl3)
1.30–1.47 (4H, m, CH2) overlapping 1.32 (9H, s, CMe3) and 1.38
(3H, d, J 6.9, C(a)Me), 1.52–1.69 (4H, m, CH2), 1.83–1.95 (2H, m,
22
a
]
þ4.2 (c 1.0 in
D
(RS)-42 was analysed by chiral GC, giving complete resolution of
enantiomers (run conditions: 70 ꢂC, 90 min; 4.0 ꢂC/min ramp;
130 ꢂC, 240 min; (R)-42 tR¼319.6 min; (S)-42 tR¼324.3 min). (R)-42
was therefore assessed to be 98:2 er.
C(2)HA, CH2), 1.99–2.13 (1H, m, CH2), 2.42 (1H, dd, J 13.2, 3.1,
C(2)HB), 2.53–2.61 (1H, m, C(80)HA), 2.70–2.77 (1H, m, C(80)HB),
2.87–2.96 (1H, m, C(20)H), 3.72 (1H, q, J 6.9, C(
a
)H), 7.20–7.36 (5H,
)Me), 25.8, 26.5 (CH2), 28.0
(CMe3), 28.8, 31.4, 32.8 (CH2), 34.8 (C(2)), 43.3 (C(80)), 56.3 (C(20)),
4.14.29. (R)-2-(Azocan-20-yl)ethanoic acid 43.
m Ph); dC (100 MHz, CDCl3) 23.5 (C(
a
61.8 (C(a)), 79.6 (CMe3), 126.7 (p-Ph), 127.4, 128.3 (m-Ph, o-Ph),
146.0 (i-Ph), 172.7 (C(1)); m/z (ESIþ) 332 ([MþH]þ, 100%); HRMS
NH
(ESIþ) C21H34NO2þ ([MþH]þ) requires 332.2590; found 330.2590.
CO2H
4.14.27. tert-Butyl (R)-2-(azocan-20-yl)ethanoate 41.
Following General Procedure 5, TFA (0.2 mL) and (R)-41
(250 mg) in CH2Cl2 (2 mL) at rt gave the crude reaction mixture. Co-
evaporation with 6 M aq HCl and purification via ion-exchange
chromatography on Dowex 50WX8-200 resin (eluent 1 M aq
NH
t
CO2 Bu
NH4OH) gave 43 as a white solid (163 mg, 87%); mp 197–199 ꢂC;
20
[a
]
ꢀ13.3 (c 1.0 in H2O); nmax (KBr) 3367 (NHþ2 , br), 2933 (C–H),
D
1582 (COꢀ2 asymmetric), 1402 (CO2ꢀ symmetric); dH (400 MHz, D2O)
1.45–1.84 (10H, m, C(30)H2, C(40)H2, C(50)H2, C(60)H2, C(70)H2), 2.50–
2.55 (2H, m C(2)H2), 3.13 (1H, ddd, J 14.0, 7.8, 3.8, C(80)HA), 3.28 (1H,
ddd, J 14.0, 7.5, 4.1, C(80)HA), 3.52–3.60 (1H, m, C(20)H); dC (100 MHz,
D2O) 23.5, 24.2, 24.3, 25.0, 29.5 (C(30), C(40), C(50), C(60), C(70)), 40.3
(C(2)), 45.1 (C(80)), 55.3 (C(20)), 178.5 (C(1)); m/z (ESIþ) 172
([MþH]þ, 100%); HRMS (ESIþ) C9H18NOþ2 ([MþH]þ) requires
172.1338; found 172.1334.
Following General Procedure 4, Pearlman’s catalyst (250 mg) and
40 (500 mg) in EtOAc (5 mL) under H2 (5 atm) at rt gave the crude
reaction mixture. Purification via flash column chromatography
(eluent pentane/Et2O/Et3N, 80:20:1) gave (R)-41 as a colourless oil
22
(294 mg, 86%); [
a
]
ꢀ1.6 (c 1.0 in CHCl3); nmax (film) 3364 (N–H),
D
2920 (C–H), 1727 (C]O); dH (400 MHz, CDCl3) 1.28–1.74 (11H, m,
C(30)H2, C(40)H2, C(50)H2, C(60)H2, C(70)H2, NH) overlapping 1.44 (9H,
s, CMe3), 2.21–2.30 (2H, m, C(2)H2), 2.66–2.73 (1H, m, C(80)HA),
2.92–2.99 (1H, m, C(80)HB), 3.06–3.13 (1H, m, C(20)H); dC (100 MHz,
CDCl3) 23.4, 25.3, 27.8 (CH2), 28.1 (CMe3), 29.5, 33.8 (CH2), 43.8
(C(2)), 47.0 (C(80)), 54.4 (C(20)), 80.2 (CMe3), 172.1 (C(1)); m/z (ESIþ)
228 ([MþH]þ, 100%); HRMS (ESIþ) C13H26NOþ2 ([MþH]þ) requires
228.1964; found 228.1965.
4.14.30. Methyl (R)-[N(10)-(tert-butoxycarbonyl)piperidin-20-yl]etha-
noate 44.
Boc
N
4.14.28. tert-Butyl (R)- and (RS)-2-(N-acetylazocan-20-yl)ethanoate
CO2Me
42.
Ac
N
Following General Procedure 10, Pearlman’s catalyst (250 mg),
20 (500 mg, 1.93 mmol) and Boc2O (547 mg, 2.51 mmol) in EtOAc
(5 mL) under H2 (5 atm) at rt gave the crude reaction mixture.
Purification via flash column chromatography (eluent pentane/
t
CO2 Bu
Et2O, 20:1; increased to pentane/Et2O, 10:1) gave 44 as a colourless
22
oil (450 mg, 91%)20; [
a
]
þ8.1 (c 2.0 in CHCl3); {lit.20 for enantio-
Ac2O (0.12 mL, 1.32 mmol) was added dropwise to a stirred so-
lution of (R)-41 (100 mg, 0.44 mmol) and DMAP (cat, 2 mg) in
D
20
mer [
a]
ꢀ8.3 (c 4.5 in CHCl3)}; dH (400 MHz, CDCl3) 1.37–1.70 (6H,
D

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10205
m, C(30)H2, C(40)H2, C(50)H2) overlapping 1.44 (9H, s, CMe3), 2.51
(1H, dd, J 14.2, 7.8, C(2)HA), 2.62 (1H, dd, J 14.2, 7.3, C(2)HB), 2.74–
2.77 (1H, m, C(60)HA), 3.65 (3H, s, OMe), 3.97–3.99 (1H, m, C(60)HB),
4.66–4.68 (1H, m, C(20)H).
207.1 (C(2)); m/z (ESIþ) 300 ([Mþ59]þ, 100%); HRMS (ESIþ)
C13H24NOþ3 requires 242.1756; found 242.1761.
4.14.34. (1R,20R)-1-Phenyl-2-[N(10)-(tert-butoxycarbonyl)piperidin-
20-yl]ethanol syn-49.
4.14.31. N-Methoxy-N-methyl (R)-[N(10)-(tert-butoxycarbonyl)piper-
idin-20-yl]ethanamide 45.
Boc
N
OH
Boc
Ph
N
O
Me
N
Following General Procedure 7, LiAl(OtBu3)H (210 mg,
0.82 mmol) and 46 (100 mg, 0.33 mmol) in THF (5 mL) at 0 ꢂC for
6 h gave syn-49 in >99:1 dr. Purification via flash column chro-
OMe
matography (eluent pentane/EtOAc, 10:1) gave syn-49 as a colour-
22
less oil (95 mg, 94%, >99:1 dr)21,24e,26; [
a
]
þ48.6 (c 1.0 in EtOH);
Following General Procedure 8, iPrMgCl (2.0 M in THF, 0.58 mL,
1.17 mmol), N,O-dimethylhydroxylamine hydrochloride (59 mg,
0.60 mmol) and 44 (100 mg, 0.39 mmol) in THF (5 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
D
25
{lit.26
[
a]
þ44.8 (c 0.6 in EtOH)}; dH (400 MHz, CDCl3) 1.37–1.71
D
(6H, m, C(30)H2, C(40)H2, C(50)H2) overlapping 1.46 (9H, s, CMe3),
1.85–1.91 (1H, m, C(2)HA), 2.06–2.15 (1H, m, C(2)HB), 2.74–2.82 (1H,
m, C(60)HA), 3.81–3.99 (1H, app br s, C(60)HB), 4.35–4.46 (1H, app br
s, C(20)H), 4.76–4.80 (1H, app br s, C(1)H), 7.25–7.39 (5H, m, Ph).
raphy (eluent pentane/EtOAc, 5:1) gave 45 as a colourless oil
22
(99 mg, 89%)21; [
a
]
D
þ3.3 (c 1.0 in CHCl3); dH (400 MHz, CDCl3)
1.38–1.65 (6H, m, C(30)H2, C(40)H2, C(50)H2) overlapping 1.44 (9H, s,
CMe3), 2.59–2.72 (2H, m, C(2)H2), 2.79–2.86 (1H, m, C(60)HA), 3.13
(3H, s, NMe), 3.70 (3H, s, OMe), 3.98–4.01 (1H, m, C(60)HB), 4.71–
4.73 (1H, m, C(20)H).
4.14.35. (2S,20R)- and (2R,20R)-1-[N(10)-(tert-butoxycarbonyl)piperidin-
20-yl]propan-2-ol syn-50 and anti-51.
Boc
OH
Boc
OH
N
N
4.14.32. (R)-1-Phenyl-2-[N(10)-(tert-butoxycarbonyl)piperidin-20-
yl]ethanone 46.
+
Me
Me
syn-50
anti-51
Boc
N
O
Following General Procedure 7, LiAl(OtBu)3H (211 mg,
0.83 mmol) and 47 (100 mg, 0.41 mmol) in THF (5 mL) at 0 ꢂC for 6 h
gave a 96:4 mixture of syn-50:anti-51. Purification via flash column
Ph
chromatography (eluent pentane/EtOAc, 10:1) gave anti-51 as
23
a colourless oil (2 mg, 2%, >99:1 dr); [
a
]
þ25.6 (c 0.6 in CHCl3);
D
Following General Procedure 9, PhMgBr (3.0 M in Et2O, 0.23 mL,
0.70 mmol) and 45 (100 mg, 0.35 mmol) in Et2O (2 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
raphy (eluent pentane/Et2O, 10:1) gave 46 as a colourless oil, which
nmax (film) 3446 (O–H), 2934 (C–H), 1688, 1659 (carbamate); dH
(400 MHz, CDCl3) 1.14–1.76 (7H, m, C(1)H2, C(30)HA, C(40)H2, C(50)H2)
overlapping 1.20 (3H, d, J 6.3, C(3)H3) and 1.45 (9H, s, CMe3),1.99 (1H,
t, J 13.4, C(30)HB), 2.68 (1H, t, J 12.7, C(60)HA), 3.52 (1H, br s, C(2)H),
3.90–4.00 (1H, m, C(60)HB), 4.35 (1H, br s, OH), 4.46 (1H, m, C(20)H);
dC (100 MHz, CDCl3) 19.2 (CH2), 22.5 (C(3)), 25.5 (CH2), 28.4 (CMe3),
29.3, 39.4, 39.6 (CH2), 46.5 (C(20)), 63.3 (C(2)), 80.1 (CMe3), 156.2
(NCO); m/z (ESIþ) 302 ([Mþ59]þ, 100%); HRMS (ESIþ) C13H26NOþ3
solidified on standing to a white solid (81 mg, 76%)23; mp 52–54 ꢂC;
22
[
a]
ꢀ17.8 (c 1.0 in CHCl3); dH (400 MHz, CDCl3) 1.22–1.68 (6H, m,
D
C(30)H2, C(40)H2, C(50)H2) overlapping 1.37 (9H, s, CMe3), 2.86–2.93
(1H, m, C(60)HA), 3.15 (1H, dd, J 14.3, 6.1, C(2)HA), 3.24 (1H, dd, J 14.3,
8.5, C(2)HB), 4.04–4.08 (1H, m, C(60)HB), 4.83–4.86 (1H, m, C(20)H).
requires 244.1913; found 244.1911. Further elution gave syn-50 as
23
4.14.33. (R)-[N(10)-(tert-butoxycarbonyl)piperidin-20-yl]propanone
47.
a colourless oil (93 mg, 92%, >99:1 dr); [
a]
þ35.5 (c 0.8 in CHCl3);
D
nmax (film) 3431 (O–H), 2933 (C–H), 1690, 1667 (carbamate); dH
(400 MHz, CDCl3) 1.21 (3H, d, J 6.3, C(3)H3),1.32–1.92 (8H, m, C(1)H2,
C(30)H2, C(40)H2, C(50)H2) overlapping 1.46 (9H, s, CMe3), 2.83 (1H, t, J
12.7, C(60)HA), 3.79–3.88 (1H, m, C(2)H), 3.90–4.03 (1H, m, C(60)HB),
4.28–4.37 (1H, m, C(20)H); dC (100 MHz, CDCl3) 19.1 (CH2), 23.5
(C(3)), 25.5 (CH2), 28.5 (CMe3), 30.9, 39.8, 40.0 (CH2), 48.6 (C(20)),
66.6 (C(2)), 79.8 (CMe3), 155.8 (NCO); m/z (ESIþ) 302 ([Mþ59]þ,
100%); HRMS (ESIþ) C13H26NO3þ requires 244.1913; found 244.1913.
Boc
N
O
Me
Following General Procedure 9, MeMgBr (3.0 M in Et2O, 0.23 mL,
0.70 mmol) and 45 (100 mg, 0.35 mmol) in Et2O (2 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
4.14.36. (1S,20R)-1-Phenyl-2-[N-(tert-butoxycarbonyl)piperidin-20-yl]-
ethanol anti-52.
raphy (eluent pentane/Et2O,10:1) gave 47 as a colourless oil (69 mg,
23
Boc
82%); [
a]
þ8.2 (c 2.0 in CHCl3); nmax (film) 2935 (C–H), 1713 (C]O,
D
N
OH
ketone), 1694 (C]O, carbamate); dH (400 MHz, CDCl3) 1.34–1.68
(6H, m, C(30)H2, C(40)H2, C(50)H2) overlapping 1.43 (9H, s, CMe3),
2.17 (3H, s, C(3)H3), 2.58–2.68 (2H, m, C(1)H2), 2.72–2.82 (1H, m,
C(60)HA), 3.88–4.03 (1H, m, C(60)HB), 4.68–4.77 (1H, m, C(20)H); dC
(100 MHz, CDCl3) 18.9, 25.3 (CH2), 28.4 (CMe3), 28.5 (CH2), 30.0
(C(3)), 39.5 (C(60)), 44.3 (C(1)), 47.3 (C(20)), 79.6 (CMe3),154.7 (NCO),
Ph
Following General Procedure 11, BH3$THF complex (1.0 M in
THF, 0.33 mL, 0.33 mmol), (R)-B-Me-CBS (1.0 M in PhMe, 0.02 mL,

10206
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
0.016 mmol) in THF (2 mL) at 0 ꢂC, and 46 (100 mg, 0.33 mmol) in
THF (2 mL) at 0 ꢂC gave a 25:75 ratio of syn-49:anti-52. Purifica-
tion via flash column chromatography (eluent pentane/EtOAc,
concentrated in vacuo to give 1 as a colourless crystalline solid
23
(151 mg, 90%, >99:1 dr); mp 82–84 ꢂC; [
a
]
þ24.6 (c 1.0 in MeOH);
D
17
{lit.30
[
a]
þ33.2 (c 2.0 in MeOH)}; nmax (KBr) 3363 (O–H, N–H, br),
D
10:1) gave anti-52 as a colourless oil, which solidified on standing
2934 (C–H), 1450, 1061; dH (400 MHz, CDCl3) 1.31–1.40 (3H, m,
C(30)HA, C(40)HA, C(50)HA), 1.54–1.61 (2H, m, C(30)HB, C(40)HB), 1.69–
1.75 (1H, m, C(2)HA), 1.79–1.88 (2H, m, C(2)HB, C(50)HB), 2.52–2.58
(1H, m, C(60)HA), 2.75–2.80 (1H, m, C(20)H), 3.03–3.07 (1H, m,
C(60)HB), 3.70–3.85 (2H, br s, NH, OH), 5.03 (1H, dd, J 7.5, 4.1, C(1)H),
7.22–7.40 (5H, m Ph); dC (100 MHz, CDCl3) 21.5 (C(50)), 26.4, 32.0
(C(30), C(40),), 44.1 (C(2)), 46.6 (C(60)), 54.4 (C(20)), 71.8 (C(10)), 125.7,
126.7, 128.2 (p-, m-, o-Ph), 145.5 (i-Ph); m/z (ESIþ) 206 ([MþH]þ,
100%); HRMS (ESIþ) C13H20NOþ ([MþH]þ) requires 206.1539; found
206.1536.
22
to a white solid (68 mg, 67%, >99:1 dr)21,24e,26; mp 58–60 ꢂC; [
a]
D
25
þ30.1 (c 1.0 in EtOH); {lit.26
[
a
]
D
þ26.5 (c 0.6 in EtOH)}; dH
(400 MHz, CDCl3) 1.30–1.68 (6H, m, C(30)H2, C(40)H2, C(50)H2)
overlapping 1.50 (9H, s, CMe3), 1.71–1.83 (1H, m, C(2)HA), 2.17–2.27
(1H, m, C(2)HB), 2.73–2.86 (1H, m, C(60)HA), 3.95–4.11 (1H, m,
C(60)HB), 4.35–4.50 (1H, m, C(20)H), 4.54–4.66 (1H, m, C(1)H), 7.24–
7.39 (5H, m Ph). Further elution gave syn-49 as a colourless oil
(19 mg, 19%, >99:1 dr).
Under identical conditions, reduction of 46 (100 mg) with
BH3$THF complex alone gave a 56:44 mixture of syn-49:anti-52,
and reduction with BH3$THF complex in the presence of (S)-B-Me-
CBS gave a 92:8 mixture of syn-49:anti-52. This crude reaction
mixture was purified via flash column chromatography to give syn-
49 (83 mg, 82%, >99:1 dr) and anti-52 (4 mg, 3%, >99:1 dr).
4.14.39. (2S,20R)-1-(Piperidin-20-yl)propan-2-ol [(þ)-allosedridine] 2.
NH
OH
4.14.37. (1S,20R)-1-Phenyl-2-(piperidine-20-yl)ethanol [(ꢀ)-norallosed-
amine] 53.
Me
Following General Procedure 12, 3 M aq HCl (0.5 mL) and syn-
50 (50 mg, 0.21 mmol) in MeOH (2 mL) at 50 ꢂC gave the crude
reaction mixture. Basification and purification via flash column
NH
OH
Ph
chromatography (eluent CHCl3/MeOH/Et3N, 98:2:1) gave 2 as
25
a colourless crystalline solid (26 mg, 87%); mp 79–81 ꢂC; [
a]
D
29
þ20.1 (c 1.0 in MeOH); {lit.28
[
a
]
þ16.2 (c 4.0 in MeOH); lit.29
D
25
[
a
]
þ17.1 (c 1.55 in MeOH)}; nmax (KBr) 3284 (O–H, N–H, br),
D
Following General Procedure 12, 3 M aq HCl (1 mL) and anti-52
(100 mg, 0.33 mmol) in MeOH (5 mL) at 50 ꢂC gave the crude re-
action mixture. The crude mixture was dissolved in 1 M aq HCl
(10 mL), and washed with CH2Cl2 (2ꢃ10 mL). The aqueous layer
was basified with 1 M aq. NaOH and extracted with CH2Cl2
(5ꢃ10 mL). The combined organics were dried, filtered and con-
2932 (C–H); dH (400 MHz, CDCl3) 1.07–1.20 (1H, m, C(30)HA)
overlapping 1.13 (3H, d, J 6.3, C(3)H3), 1.24–1.39 (2H, m, C(1)HA,
C(50)HA), 1.43–1.55 (2H, m, C(1)HB, C(40)HA), 1.57–1.68 (2H, m,
C(30)HB, C(50)HB), 1.76–1.85 (1H, m, C(40)HB), 2.55–2.65 (1H, m,
C(60)HA), 2.70–2.78 (1H, m, C(20)HA), 3.02–3.09 (1H, m, C(60)HB),
3.42 (2H, br s, OH, NH), 3.95–4.03 (1H, m, C(2)H); dC (100 MHz,
CDCl3) 23.9 (C(3)), 24.4 (C(40)), 27.0 (C(50)), 34.0 (C(30)), 44.1
(C(1)), 45.9 (C(60)), 58.2 (C(20)), 69.0 (C(2)); m/z (ESIþ) 143
([MþH]þ, 100%); HRMS (ESIþ) C8H18NOþ ([MþH]þ) requires
143.1388; found 143.1391.
centrated in vacuo to give 53 as white solid (60 mg, 89%, >99:1 dr);
23
mp 80–81 ꢂC; [
a
]
ꢀ23.0 (c 2.0 in EtOH); {lit.30 for enantiomer
D
21
[
a]
þ37.2 (c 3.0 in EtOH)}; nmax (KBr) 3258 (O–H, N–H, br), 2924
D
(C–H), 1472; dH (400 MHz, CDCl3) 1.05–1.16 (1H, m, C(30)HA), 1.25–
1.57 (1H, m, C(50)HA), 1.50–1.75 (5H, m, C(2)H2, C(30)HB, C(40)HA,
C(50)HB), 1.79–1.86 (1H, m, C(40)HB), 2.65–2.72 (1H, ddd, J 3.0, 11.8,
13.6, C(60)HA), 2.98 (1H, app. tt, J 10.8, 2.8, C(20)H), 3.04–3.10 (1H, m,
C(60)HB), 3.80–4.10 (2H, br s, OH and NH), 4.93 (1H, dd, J 8.1, 2.5,
C(1)H), 7.22–7.40 (5H, m Ph); dC (100 MHz, CDCl3) 24.5 (C(40)), 27.2
(C(50)), 37.2 (C(30)), 45.1 (C(2)), 46.0 (C(60)), 58.2 (C(20)), 75.4 (C(1)),
125.6, 126.9, 128.2, 128.3, (m-, p-, o-Ph), 145.3 (i-Ph); m/z (ESIþ) 206
([MþH]þ, 100%); HRMS (ESIþ) C13H20NOþ ([MþH]þ) requires
206.1539; found 206.1542.
4.14.40. (1R,20R)-1-Phenyl-2-[N(10)methylpiperidin-20-yl]ethanol
[(þ)-sedamine] 3.
Me
N
OH
Ph
4.14.38. (1R,20R)-1-Phenyl-2-(piperidin-20-yl)ethanol [(þ)-norsed-
amine] 1.
Following General Procedure 13, syn-49 (280 mg, 0.91 mmol),
lithium aluminium hydride (175 mg, 4.5 mmol) in THF (13 mL) gave
the crude reaction mixture. The crude mixture was dissolved in 1 M
aq HCl (10 mL), and washed with CH2Cl2 (2ꢃ10 mL). The aqueous
layer was basified with 1 M aq NaOH and extracted with CH2Cl2
(5ꢃ10 mL). The combined organics were dried, filtered and con-
NH
OH
Ph
centrated in vacuo to give 3 as a colourless oil, which solidified on
22
standing to a white solid (171 mg, 86%, >99:1 dr); [
a
]
D
þ81.5 (c 1.1
21
25
in MeOH); [
a]
þ82.1 (c 1.0 in EtOH); {lit. for enantiomer30
[a]
D
D
32
Following General Procedure 12, 3 M aq HCl (2 mL) and syn-49
(250 mg, 0.82 mmol) in MeOH (8 mL) at 50 ꢂC gave the crude re-
action mixture. The crude mixture was dissolved in 1 M aq HCl
(20 mL), and washed with CH2Cl2 (2ꢃ20 mL). The aqueous layer
was basified with 1 M aq NaOH and extracted with CH2Cl2
(5ꢃ20 mL). The combined organic layers were dried, filtered and
ꢀ81.7 (c 3.0 in MeOH); lit.31
[
a
]
D
þ87.0 (c 1.1 in EtOH)}; nmax (film)
3356 (O–H, N–H, br), 2934 (C–H), 1451; dH (400 MHz, CDCl3) 1.30–
1.37 (1H, m, C(30)HA), 1.46–1.50 (3H, m, C(2)HA, C(40)HA, C(50)HA),
1.55–1.68 (2H, m, C(40)HB, C(50)HB),1.75–1.80 (1H, m, C(30)HB), 2.09–
2.17 (1H, m, C(2)HB), 2.49 (3H, s, NCH3), 2.53–2.58 (1H, m, C(60)HA),
2.83–2.87 (1H, m, C(20)HB) and 3.05–3.09 (1H, m, C(60)HB), 4.90 (1H,

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10207
dd, J 2.8, 10.7, C(1)H), 7.23–7.27 (1H, m Ph), 7.32–7.40 (4H, m, Ph); dC
(100 MHz, CDCl3) 20.6 (C(50)), 22.4 (C(40)), 25.9 (C(30)), 39.8 (C(2)),
40.0 (NCH3), 51.5 (C(60)), 60.9 (C(20)), 74.5 (C(1)), 125.6 (p-Ph), 127.0,
128.3 (m-Ph, o-Ph), 145.6 (i-Ph); m/z (ESIþ) 220 ([MþH]þ, 100%);
HRMS (ESIþ) C14H21NOþ ([MþH]þ) requires 220.1696; found
220.1702.
([MþH]þ, 100%); HRMS (ESIþ) C18H26NOþ2 ([MþH]þ) requires
288.1964; found 288.1959.
4.14.43. Methyl
1H-pyrrol-20-yl]ethanoate 55.
(20S, R)-2-[N(10)-( -methylbenzyl)-20,50-dihydro-
a a
4.14.41. (1S,20R)-1-Phenyl-2-[N(10)-methylpiperidin-20-yl]ethanol
[(þ)-allosedamine] 4.
N
Ph
CO2Me
Me
N
OH
Following General Procedure 2, Grubbs I (115 mg, 0.139 mmol)
and 54 (1.00 g, 3.48 mmol) in CH2Cl2 (300 mL) gave the crude re-
action mixture. Purification by treatment with P(CH2OH)3 (1.73 g,
13.9 mmol), Et3N (0.97 mL, 6.96 mmol) and silica in CH2Cl2
(w30 mL) and filtration through a short plug of silica gel (eluent
Ph
Following General Procedure 13, anti-52 (200 mg, 0.65 mmol),
lithium aluminium hydride (124 mg, 3.3 mmol) in THF (9.5 mL)
gave the crude reaction mixture. The crude mixture was dissolved
in 1 M aq HCl (10 mL), and washed with CH2Cl2 (2ꢃ10 mL). The
aqueous layer was basified with 1 M aq NaOH and extracted with
CH2Cl2 (5ꢃ10 mL). The combined organics were dried, filtered and
concentrated in vacuo to give 4 as a colourless oil, which solidified
on standing to a white solid (110 mg, 77%, 98:2 dr); mp 76–78 ꢂC;
pentane/Et2O, 20:1) gave 55 as a colourless oil (685 mg, 80%, >99:1
20
dr); [
a]
þ142.1 (c 0.7 in CHCl3); nmax (film) 2953 (C–H), 1738
D
(C]O); dH (400 MHz, CDCl3) 1.45 (3H, d, J 6.8, C(a)Me), 2.46 (1H, dd,
J 14.9, 8.8, C(2)HA), 2.69 (1H, dd, J 14.9, 4.3, C(2)HB), 3.38–3.44 (1H,
m, C(50)HA), 3.60–3.65 (1H, m, C(50)HB), 3.68 (3H, s, OMe), 3.86 (1H,
q, J 6.8, C(
C(40)H), 7.21–7.35 (5H, m, Ph); dC (100 MHz, CDCl3) 22.8 (C(
41.6 (C(2)), 51.4 (OMe), 58.5 (C(50)), 62.2 (C( )), 64.5 (C(20)),126.8 (p-
a
)H), 4.18–4.24 (1H, m, C(20)H), 5.72–5.78 (2H, m, C(30)H,
a
)Me),
a
22
21
[
a]
þ29.7 (c 1.0 in MeOH); {lit.30
[
a]
þ32.0 (c 2.0 in MeOH)}; nmax
D
D
Ph), 127.4, 128.3, 130.5 (C(30), C(40), m-Ph, o-Ph), 145.1 (i-Ph), 172.4
(C(1)); m/z (ESIþ) 246 ([MþH]þ, 100%); HRMS (ESIþ) C15H20NOþ2
([MþH]þ) requires 246.1494; found 244.1499.
(KBr) 3319 (O–H, N–H, br), 2934 (C–H), 1451; dH (400 MHz, CDCl3)
1.26–1.36 (1H, m, C(40)HA), 1.60–1.70 (4H, m, C(2)HA, C(30)HA,
C(50)H2), 1.79–1.89 (2H, m, C(30)HB, C(40)HB), 2.09–2.18 (2H, m,
C(2)HB, C(60)HA), 2.40–2.43 (1H, m, C(20)H), 2.46 (3H, s, NCH3), 2.96–
3.01 (1H, m, C(60)HB), 5.07 (1H, dd, J 10.6, 3.5, C(1)H), 7.23–7.38 (5H,
m Ph); dC (100 MHz, CDCl3) 23.8 (C(40)), 24.6 (C(50)), 28.9(C(30)),
39.6 (C(2)), 42.8 (NCH3), 56.6 (C(60)), 62.4 (C(20)), 71.3 (C(1)), 125.6
(p-Ph), 126.9, 128.2 (m-Ph, o-Ph), 145.2 (i-Ph); m/z (ESIþ) 220
([MþH]þ, 100%); HRMS (ESIþ) C14H22NOþ ([MþH]þ) requires
220.1696; found 220.1703.
4.14.44. Methyl (20R,
a
R)-2-[N(10)-( -methylbenzyl)pyrrolidin-20-yl]-
a
ethanoate 56.
N
Ph
CO2Me
4.14.42. Methyl (3S,4E,
a
R)-3-[N-allyl-N-(
a
-methylbenzyl)amino]hex-
4-enoate 54.
Following General Procedure 3, Wilkinson’s catalyst (94.2 mg,
0.102 mmol) and 55 (500 mg, 2.04 mmol) in benzene (5 mL) under
H2 (4 atm) at rt gave a 96:4 mixture of 56:57. Purification via flash
column chromatography on silica gel (eluent pentane/Et2O, 10:1)
Ph
N
21
gave 57 as a colourless oil (20 mg, 4%); [
a
]
þ20.8 (c 0.5 in CHCl3);
D
CO2Me
nmax (film) 2934 (C–H), 1739 (C]O); dH (400 MHz, CDCl3) 1.83 (3H,
d, J 7.0, C( )Me), 3.53 (2H, AB system, JAB 16.4, C(2)H2), 3.57 (3H, s,
OMe), 5.42 (1H, q, J 7.0, C( )H), 6.12–6.15 (1H, m, Ar), 6.21 (1H, app t,
J 3.3, Ar), 6.87–6.88 (1H, m, Ar), 7.00–7.02 (2H, m, Ph), 7.22–7.33 (3H,
m, Ph); dC (100 MHz, CDCl3) 22.6 (C( )Me), 32.5 (C(2)), 52.0 (OMe),
55.0 (C(
Me
a
a
Following General Procedure 1, BuLi (2.5 M in hexanes,
a
4.91 mL, 12.3 mmol), (R)-N-allyl-N-(
a
-methylbenzyl)amine (2.05 g,
a)), 107.4, 109.3, 118.4 (Ar), 124.9 (i-Ar), 125.7 (p-Ph), 127.2,
12.7 mmol) in THF (10 mL) at ꢀ78 ꢂC, and 15 (1.00 g, 7.93 mmol)
128.7 (m-Ph, o-Ph), 143.4 (i-Ph), 171.0 (C(1)); m/z (ESIþ) 302
([Mþ59]þ, 100%); HRMS (ESIþ) C15H18NOþ2 ([MþH]þ) requires
in THF (10 mL) at ꢀ78 ꢂC gave 54 in 97:3 dr. Purification via flash
column chromatography (eluent pentane/Et2O, 50:1) gave 54 as
244.1338; found 244.1339. Further elution gave 56 as a colourless
13
21
a colourless oil (1.89 g, 83%, 97:3 dr); [
nmax (film) 2958 (C–H), 1740 (C]O), 1640 (C]C); dH (400 MHz,
CDCl3) 1.38 (3H, d, J 6.8, C( )Me), 1.72 (3H, d, J 5.3, C(6)H3), 2.37
(1H, dd, J 14.3, 7.6, C(2)HA), 2.53 (1H, dd, J 14.3, 7.6, C(2)HB), 3.11–
3.23 (2H, m, NCH2), 3.58 (3H, s, OMe), 3.84–3.90 (1H, m, C(3)H),
a
]
ꢀ2.4 (c 1.0 in CHCl3);
oil (440 mg, 87%, >99:1 dr); [
a]
þ65.2 (c 3.0 in CHCl3); nmax (film)
D
D
2971 (C–H), 1737 (C]O); dH (400 MHz, CDCl3) 1.44 (3H, d, J 6.8,
a
C(a
)Me), 1.54–1.66 (2H, m, C(30)HA, C(40)HA), 1.69–1.76 (1H, m,
C(40)HB), 1.83–1.93 (1H, m, C(30)HB), 2.32 (1H, dd, J 14.6, 9.8, C(2)HA),
2.39–2.45 (1H, m, C(50)HA), 2.66 (1H, dd, J 14.6, 3.6, C(2)HB), 2.78–
2.83 (1H, m, C(50)HB), 3.12–3.18 (1H, m, C(20)H), 3.66 (3H, s, OMe),
4.05 (1H, q, J 6.8, C(
(2H, m, C(4)H, C(5)H), 5.80–5.87 (1H, m, CH]CH2), 7.20–7.37 (5H,
m, Ph); dC (100 MHz, CDCl3) 17.9, 18.0 (C(6), C( )Me), 38.8 (C(2)),
49.4 (NCH2), 51.3 (OMe), 56.7, 56.7 (C(3), C( )), 115.7 (CH]CH2),
a)H), 5.02–5.15 (2H, m, CH]CH2), 5.48–5.56
3.76 (1H, q, J 6.8, C(
22.2 (C(
)Me), 22.8 (C(40)), 30.9 (C(30)), 40.1 (C(2)), 50.1 (C(50)), 51.4
(OMe), 56.8 (C(20)), 60.8 (C(
a)), 126.9 (p-Ph), 127.8, 128.1 (m-Ph, o-
a)H), 7.22–7.34 (5H, m, Ph); dC (100 MHz, CDCl3)
a
a
a
126.5 (p-Ph), 127.0, 127.6, 128.0, 130.6 (C(4), C(5), m-Ph, o-Ph),
Ph), 143.1 (i-Ph), 172.9 (C(1)); m/z (ESIþ) 248 ([MþH]þ, 100%); HRMS
138.8 (CH]CH2), 145.1 (i-Ph), 172.4 (C(1)); m/z (ESIþ) 288
(ESIþ) C15H22NO2þ ([MþH]þ) requires 248.1651; found 248.1648.

10208
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
4.14.45. Methyl (R)-2-[N(10)-(tert-butoxycarbonyl)pyrrolidin-20-yl]-
gave the crude reaction mixture. Purification via flash column
ethanoate 58.
chromatography (eluent pentane/Et2O, 10:1) gave 60 as a colour-
23
less oil (85 mg, 81%); [
a
]
D
þ20.7 (c 3.0 in CHCl3); nmax (film) 2975
Boc
N
(C–H), 1692 (C]O, carbamate), 1683 (C]O, ketone); dH (400 MHz,
CDCl3) 1.46 (9H, s, CMe3), 1.72–1.91 (3H, m, C(30)HA, C(40)H2), 1.98–
2.14 (1H, br m, C(30)HB), 2.75–2.91 (1H, br m, C(2)HA), 3.26–3.45
(2H, br m, C(50)H2), 3.51–3.76 (1H, m, C(2)HB), 4.30–4.36 (1H, m,
C(20)H), 7.42–7.50 (2H, br m, Ph), 7.50–7.60 (1H, br m, Ph), 7.94–
8.07 (2H, br m, Ph); dH (500 MHz, DMSO-d6, 373 K) 1.39 (9H, s,
CMe3), 1.66–1.71 (1H, m, C(30)HA), 1.76–1.82 (1H, m, C(40)HA), 1.85–
1.94 (1H, m, C(40)HB), 1.98–2.06 (1H, m, C(30)HB), 3.03 (1H, dd, J
15.5, 8.9, C(2)HA), 3.27–3.35 (2H, m, C(50)H2), 3.43 (1H, dd, J 15.5,
3.5, C(2)HB), 4.19–4.24 (1H, m, C(20)H), 7.51–7.54 (2H, m, Ph), 7.61–
7.65 (1H, m, Ph), 7.97–7.99 (2H, m, Ph); dC (125 MHz, DMSO-d6,
373 K) 23.2 (C(30)), 28.7 (CMe3), 31.2 (C(40)), 43.5 (C(2)), 46.5
(C(50)), 54.5 (C(20)), 79.0 (CMe3), 128.4, 128.9, 133.4 (p-Ph, m-Ph, o-
Ph), 137.6 (i-Ph), 153.9 (NCO), 199.0 (C(1)); m/z (ESIþ) 312
([MþNa]þ, 100%); HRMS (ESIþ) C17H24NOþ3 ([MþH]þ) requires
290.1756; found 290.1756.
CO2Me
Following General Procedure 10, Pearlman’s catalyst (250 mg), 56
(500 mg, 2.02 mmol) and Boc2O (574 mg, 2.63 mmol) in EtOAc
(5 mL) under H2 (5 atm) at rt gave the crude reaction mixture. Pu-
rification via flash column chromatography (eluent pentane/Et2O,
20:1; increased to pentane/Et2O, 10:1) gave 58 as a colourless oil
22
(385 mg, 78%)34; [
a]
þ31.5 (c 2.0 in CHCl3); nmax (film) 2975 (C–H),
D
1740 (C]O, ester),1695 (C]O, carbamate);dH (400 MHz, CDCl3)1.44
(9H, s, CMe3), 1.72–1.90 (3H, m, C(30)H2, C(40)HA), 1.90–2.11 (1H, m,
C(40)HB), 2.35 (1H, dd, J 15.0, 9.7, C(2)HA), 2.80 and 2.92 (1H, br d, J
15.0, C(2)HB), 3.25–3.40 (2H, m, C(50)H2), 3.65 (3H, s, OMe), 4.08–4.22
(1H, m, C(20)H); dH (500 MHz, DMSO-d6, 373 K) 1.43 (9H, s, CMe3),
1.69–1.85 (3H, m, C(30)H2, C(40)HA), 1.99–2.03 (1H, m, C(40)HB), 2.39
(1H, dd, J 14.8, 8.8, C(2)HA), 2.72 (1H, dd, J 14.8, 3.8, C(2)HB), 3.21–3.31
(2H, m, C(50)H2), 3.62 (3H, s, OMe), 4.00–4.03 (1H, m, C(20)H); dC
(125 MHz, DMSO-d6, 373 K) 23.1 (C(30)), 28.6 (CMe3), 31.0 (C(40)),
39.0 (C(2)), 46.5 (C(50)), 51.5 (OMe), 54.3 (C(20)), 79.0 (CMe3), 153.9
(NCO), 171.6 (C(1)); m/z (ESIþ) 302 ([Mþ59]þ, 100%); HRMS (ESIþ)
C12H22NOþ4 ([MþH]þ) requires 244.1549; found 244.1541.
4.14.48. (R)-[N(10)-(tert-butoxycarbonyl)pyrrolidin-20-yl]propanone
61.
Boc
N
O
4.14.46. N-Methoxy-N-methyl (R)-2-[N(10)-(tert-butoxycarbonyl)-
pyrrolidin-20-yl]ethanamide 59.
Me
Boc
N
O
Following General Procedure 9, MeMgBr (3.0 M in Et2O, 0.24 mL,
0.73 mmol) and 59 (100 mg, 0.37 mmol) in Et2O (2 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
Me
N
OMe
raphy (eluent pentane/Et2O,10:1) gave 61 as a colourless oil (74 mg,
23
89%); [
a]
þ31.6 (c 2.5 in CHCl3); nmax (film) 2974 (C–H), 1713
D
(C]O, ketone), 1693 (C]O, carbamate); dH (400 MHz, CDCl3) 1.43
(9H, s, CMe3), 1.57–1.64 (1H, m, C(30)HA), 1.76–1.82 (2H, m, C(40)H2),
2.00–2.09 (1H, m, C(30)HB), 2.12 (3H, s, C(3)H3), 2.32–2.42 (1H, m,
C(1)HA), 2.89–3.10 (1H, m, C(1)HB), 3.26–3.35 (2H, m, C(50)H2),
4.06–4.16 (1H, m, C(20)H); dH (500 MHz, DMSO-d6, 373 K) 1.42 (9H,
s, CMe3), 1.55–1.61 (1H, m, C(30)HA), 1.72–1.86 (2H, m, C(40)H2),
1.95–2.03 (1H, m, C(30)HB), 2.10 (3H, s, C(3)H3), 2.50 (1H, dd, J 15.8,
9.1, C(1)HA), 2.84 (1H, dd, J 15.8, 4.0, C(1)HB), 3.21–3.31 (2H, m,
C(50)H2), 4.01–4.06 (1H, m, C(20)H); dC (125 MHz, DMSO-d6, 373 K)
23.2 (C(30)), 28.7 (CMe3), 30.6 (C(3)), 31.3 (C(40)), 46.4 (C(50)), 48.2
(C(1)), 53.7 (C(20)), 78.9 (CMe3), 153.9 (NCO), 206.9 (C(2)); m/z
(ESIþ) 250 ([MþNa]þ, 100%); HRMS (ESIþ) C12H22NOþ3 ([MþH]þ)
requires 228.1600; found 228.1606.
i
Following General Procedure 8, PrMgCl (2.0 M in THF, 1.23 mL,
2.47 mmol), N,O-dimethylhydroxylamine hydrochloride (124 mg,
1.27 mmol) and 58 (200 mg, 0.82 mmol) in THF (5 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
raphy (eluent pentane/EtOAc, 5:1) gave 59 as a colourless oil
22
(205 mg, 92%); [
a
]
þ42.5 (c 4.5, in CHCl3); nmax (film) 2973 (C–H),
D
1694 (C]O, carbamate), 1667 (C]O, amide); dH (400 MHz, CDCl3)
1.47 (9H, s, CMe3), 1.73–1.90 (3H, m, C(30)HA, C(40)H2), 2.02–2.12
(1H, m, C(30)HB), 2.40–2.48 (1H, m, C(2)HA), 2.96 (1H, app br s,
C(2)HB), 3.17 (3H, s, NMe), 3.30–3.40 (2H, app br s, C(50)H2), 3.69
(3H, s, OMe), 4.17–4.25 (1H, br m, C(20)H); dH (500 MHz, DMSO-d6,
373 K) 1.42 (9H, s, CMe3), 1.67–1.89 (3H, m, C(30)HA, C(40)H2), 1.94–
2.01 (1H, m, C(30)HB), 2.44 (1H, dd, J 15.1, 9.5, C(2)HA), 2.83 (1H, dd, J
15.1, 3.8, C(2)HB), 3.06 (3H, s, NMe), 3.24–3.32 (2H, m, C(50)H2), 3.67
(3H, s, OMe), 4.04–4.09 (1H, br m, C(20)H); dC (125 MHz, DMSO-d6,
373 K) 23.1 (C(30)), 28.7 (CMe3), 31.1 (C(40)), 32.6 (NMe), 36.6 (C(2)),
46.5 (C(50)), 54.3 (C(20)), 61.4 (OMe), 78.8 (CMe3), 153.9 (N0CO), 171.7
(C(1)); m/z (ESIþ) 331 ([Mþ59]þ, 100%); HRMS (ESIþ)
C13H24N2NaOþ4 ([MþNa]þ) requires 295.1634; found 295.1648.
4.14.49. (1R,20R)-1-Phenyl-2-[N(10)-(tert-butoxycarbonyl)pyrrolidin-
20-yl]ethanol syn-62.
Boc
N
OH
Ph
4.14.47. (R)-1-Phenyl-2-[N(10)-(tert-butoxycarbonyl)pyrrolidin-20-
yl]ethanone 60.
Boc
N
O
Following General Procedure 7, LiAl(OtBu)3H (220 mg,
0.86 mmol) and 60 (100 mg, 0.35 mmol) in THF (5 mL) at 0 ꢂC for
6 h gave syn-62 in >99:1 dr. Purification via flash column chro-
Ph
matography (eluent pentane/EtOAc, 10:1) gave syn-62 as a colour-
23
less oil (97 mg, 96%, >99:1 dr); [
a]
þ87.1 (c 1.0 in CHCl3); nmax
Following General Procedure 9, PhMgBr (3.0 M in Et2O,
0.24 mL, 0.73 mmol) and 59 (100 mg, 0.37 mmol) in Et2O (2 mL)
D
(film) 3412 (O–H), 2974 (C–H), 1692, 1668 (carbamate); dH

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10209
(400 MHz, CDCl3) 1.46 (9H, s, CMe3), 1.63–2.23 (6H, m, C(2)H2,
C(30)H2, C(40)H2), 3.30–3.38 (2H, m, C(50)H2), 4.05–4.15 (1H, m,
C(20)H), 4.72–4.83 (1H, m, C(1)H), 7.22–7.39 (5H, m, Ph); dC
(100 MHz, CDCl3) 23.8 (C(30)), 28.5 (CMe3), 32.4 (C(40)), 46.3, 46.4
(C(2), C(50)), 55.7 (C(20)), 72.7 (C(1)), 79.8 (CMe3),125.6 (p-Ph),127.0,
128.3 (m-Ph, o-Ph), 144.3 (i-Ph), 155.3 (NCO); m/z (ESIþ) 350
([Mþ59]þ, 100%); HRMS (ESIþ) C17H25NNaOþ3 ([MþNa]þ) requires
314.1732; found 314.1734.
28.5 (CMe3), 32.5 (C(40)), 45.8, 46.4 (C(1), C(50)), 55.7 (C(20)), 66.5
(C(2)), 79.7 (CMe3), 155.6 (NCO); m/z (ESIþ) 288 ([Mþ59]þ, 100%);
HRMS (ESIþ) C12H24NOþ3 ([MþH]þ) requires 230.1756; found
230.1750.
4.14.52. (2R,20R)-1-[N(10)-(tert-butoxycarbonyl)pyrrolidin-20-yl]pro-
pan-2-ol anti-65.
4.14.50. (1S,20R)-1-Phenyl-2-[N(10)-(tert-butoxycarbonyl)pyrrolidin-
20-yl]ethanol anti-63.
Boc
N
OH
Me
Boc
N
OH
Ph
Following General Procedure 11, BH3$THF complex (1.0 M in
THF, 0.44 mL, 0.44 mmol), (S)-B-Me-CBS (1.0 M in PhMe, 0.02 mL,
0.022 mmol) in THF (2 mL) at 0 ꢂC, and 61 (100 mg, 0.44 mmol) in
THF (2 mL) at 0 ꢂC, gave a 24:76 mixture of syn-64:anti-65. Purifi-
Following General Procedure 11, BH3$THF complex (1.0 M in
THF, 0.35 mL, 0.35 mmol), (R)-B-Me-CBS (1.0 M in PhMe, 0.02 mL,
0.017 mmol) in THF (2 mL) at 0 ꢂC, and 60 (100 mg, 0.35 mmol) in
THF (2 mL) at 0 ꢂC, gave a 15:85 mixture of syn-62:anti-63. Pu-
rification via flash column chromatography (eluent pentane/
EtOAc, 10:1) gave anti-63 as a colourless oil, which solidified on
cation via flash column chromatography (eluent pentane/EtOAc,
23
10:1) gave anti-65 as a colourless oil (68 mg, 68%, >99:1 dr); [a]
D
þ10.9 (c 0.7 in CHCl3); nmax (film) 3440 (O–H), 2971 (C–H), 1694,
1669 (carbamate); dH (400 MHz, CDCl3) 1.17 (3H, d, J 6.3, C(3)H3),
1.32–2.01 (6H, m, C(1)H2, C(30)H2, C(40)H2) overlapping 1.46 (9H, s,
CMe3), 3.26–3.37 (2H, m, C(50)H2), 3.65–3.76 (1H, m, C(2)H), 4.13–
4.22 (1H, m, C(20)H), 5.01 (1H, br s, OH); dC (100 MHz, CDCl3) 22.6
(C(30)), 23.5 (C(3)), 28.5 (CMe3), 31.1 (C(40)), 45.6, 46.5 (C(1), C(50)),
53.8 (C(20)), 63.6 (C(2)), 79.8 (CMe3), 156.6 (NCO); m/z (ESIþ) 288
([Mþ59]þ, 100%); HRMS (ESIþ) C12H24NOþ3 ([MþH]þ) requires
230.1756; found 230.1761. Further elution gave syn-64 as a colour-
less oil (18 mg, 18%, >99:1 dr).
Under identical conditions, reduction of 61 (100 mg) with
BH3$THF complex alone gave 50% conversion to a 50:50 mixture of
syn-64:anti-65, and reduction with BH3$THF complex in the pres-
ence of (R)-B-Me-CBS gave an 84:16 mixture of syn-64:anti-65. This
crude reaction mixture was purified via flash column chromatog-
raphy to give syn-64 (71 mg, 70%, >99:1 dr) and anti-65 (12 mg,
12%, >99:1 dr).
standing to a colourless solid (72 mg, 71%, >99:1 dr); mp 70–
23
72 ꢂC; [
a
]
þ23.6 (c 0.6 in CHCl3); nmax (film) 3366 (O–H), 2975
D
(C–H), 1682, 1659 (carbamate); dH (400 MHz, CDCl3) 1.50 (9H, s,
CMe3), 1.55–2.07 (6H, m, C(2)H2, C(30)H2, C(40)H2), 3.34–3.45 (2H,
m, C(50)H2), 4.27–4.35 (1H, m, C(20)H), 4.59–4.68 (1H, m, C(1)H),
5.47 (1H, br s, OH), 7.22–7.39 (5H, m, Ph); dC (100 MHz, CDCl3)
23.6 (C(30)), 28.5 (CMe3), 31.2 (C(40)), 46.4, 46.7 (C(2), C(50)), 53.9
(C(20)), 70.0 (C(1)), 80.1 (CMe3), 125.7 (p-Ph), 126.8, 128.2 (m-Ph,
o-Ph), 144.3 (i-Ph), 156.8 (NCO); m/z (ESIþ) 350 ([Mþ59]þ, 100%);
HRMS (ESIþ) C17H26NOþ3 ([MþH]þ) requires 292.1913; found
292.1915. Further elution gave syn-62 as a colourless oil (12 mg,
12%, >99:1 dr).
Under identical conditions, reduction of 60 (100 mg) with
BH3$THF complex alone gave a 50:50 mixture of syn-62:anti-63,
and reduction with BH3$THF complex in the presence of (S)-B-Me-
CBS gave an 88:12 mixture of syn-62:anti-63. This crude reaction
mixture was purified via flash column chromatography to give syn-
62 (79 mg, 78%, >99:1 dr) and anti-63 (11 mg, 10%, >99:1 dr).
4.14.53. (1R,20R)-1-Phenyl-2-(pyrrolidin-20-yl)ethanol 66.
NH
OH
4.14.51. (2S,20R)-1-[N(10)-(tert-butoxycarbonyl)pyrrolidin-20-yl]pro-
pan-2-ol syn-64.
Ph
Boc
N
OH
Following General Procedure 12, 3 M aq HCl (2 mL) and syn-62
(280 mg, 0.96 mmol) in MeOH (8 mL) at 50 ꢂC gave the crude re-
action mixture. The crude mixture was dissolved in 1 M aq HCl
(20 mL), and washed with CH2Cl2 (2ꢃ20 mL). The aqueous layer
was basified with 1 M aq NaOH and extracted with CH2Cl2
(5ꢃ20 mL). The combined organics were dried, filtered and con-
centrated in vacuo to give 66 as pale yellow oil (149 mg, 81%, >99:1
Me
Following General Procedure 7, LiAl(OtBu)3H (280 mg,
1.10 mmol) and 61 (100 mg, 0.35 mmol) in THF (2 mL) at 0 ꢂC for
6 h gave a 97:3 mixture of syn-64:anti-65. Purification via flash
column chromatography (eluent pentane/EtOAc, 10:1) gave anti-
65 as a colourless oil (1 mg, 1%, >99:1 dr). Further elution gave
syn-64 as a colourless oil (95 mg, 94%, >99:1 dr); [
1.0 in CHCl3); nmax (film) 3426 (O–H), 2971 (C–H), 1694, 1673
(carbamate); dH (400 MHz, CDCl3) 1.18 (3H, d, J 5.3, C(3)H3), 1.40–
2.02 (6H, m, C(1)H2, C(30)H2, C(40)H2) overlapping 1.46 (9H, s,
CMe3), 3.27–3.39 (2H, m, C(50)H2), 3.87 (1H, br s, C(2)H), 3.98
(1H, br s, C(20)H); dC (100 MHz, CDCl3) 23.8 (C(30)), 23.9 (C(3)),
23
25
dr); [
a]
þ40.0 (c 1.1 in MeOH); {lit.35
[
a
]
D
þ36.8 (c 0.9 in MeOH)};
D
nmax (film) 3258 (O–H, N–H, br), 2924 (C–H), 1472; dH (400 MHz,
CDCl3) 1.05–1.35 (1H, m, C(30)HA), 1.54–1.70 (3H, m, C(2)H2,
C(40)HA), 1.79–1.85 (1H, m, C(40)HB), 1.90–1.97 (1H, m, C(30)HB), 2.85
(1H, dt, J 12.0, 7.5, C(50)HA), 2.97–3.02 (1H, m, C(50)HB), 3.53–3.58
(1H, m, C(20)H), 4.79–4.80 (2H, br s, OH and NH), 4.86 (1H, dd, J 10.4,
2.2, C(1)H), 7.22–7.39 (5H, m Ph); dC (100 MHz, CDCl3) 25.7 (C(40)),
32.7 (C(30)), 43.3 (C(2)), 45.6 (C(50)), 59.2 (C(20)), 74.7 (C(1)), 125.6,
126.9, 128.2 (m-, p-, o-Ph), 145.4 (i-Ph); m/z (ESIþ) 192 ([MþH]þ,
23
a
]
þ78.5 (c
D

10210
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
100%); HRMS (ESIþ) C12H18NOþ ([MþH]þ) requires 192.1310; found
gave the crude reaction mixture. The crude mixture was dissolved
in 1 M aq HCl (10 mL), and washed with CH2Cl2 (2ꢃ10 mL). The
aqueous layer was basified with 1 M aq NaOH and extracted with
CH2Cl2 (5ꢃ10 mL). The combined organics were dried, filtered and
concentrated in vacuo to give 6 as a colourless oil (142 mg, 80%,
192.1314.
4.14.54. (2S,20R)-1-(Pyrrolidin-20-yl)propan-2-ol 67.
22
20
>99:1 dr)3; [
EtOH); lit.36
a
]
]
þ105.2 (c 1.0 in EtOH); {lit.3
[
a
]
þ84.4 (c 3.4 in
D
D
NH
OH
25
20
[a
þ97.0 (c 1.0 in EtOH); lit.37
[a]
D
þ78.8 (c 0.9 in
D
Me
EtOH)}; nmax (film) 3362 (O–H, N–H, br), 2964 (C–H), 1418; dH
(400 MHz, CDCl3) 1.14 (2H, d, J 6.3, C(3)H3), 1.32–1.49 (3H,
m, C(1)H2, C(30)HA), 1.72–1.78 (2H, m, C(40)H2), 1.97–2.03 (1H, m,
C(30)HB), 2.31–2.36 (4H, m, NCH3, C(50)HA), 2.67–2.69 (1H, m,
C(20)H), 3.02 (1H, dt, J 10.4, 6.6, C(50)HB), 3.88–3.92 (1H, m, C(2)H);
dC (100 MHz, CDCl3) 22.8 (C(40)), 24.3 (CH3), 30.5 (C(30)), 42.9
(NCH3), 43.0 (C(1)), 55.5 (C(50)), 65.7 (C(20)), 67.4 (C(2)); m/z (ESIþ)
144 ([MþH]þ, 100%); HRMS (ESIþ) C8H18NOþ ([MþH]þ) requires
144.1383; found 144.1386.
Following General Procedure 12, 3 M aq HCl (2 mL) and syn-64
(230 mg, 1.00 mmol) in MeOH (8 mL) at 50 ꢂC gave the crude re-
action mixture. The crude mixture was dissolved in 1 M aq HCl
(20 mL), and washed with CH2Cl2 (2ꢃ20 mL). The aqueous layer
was basified with 1 M aq NaOH and extracted with CH2Cl2
(5ꢃ20 mL). The combined organics were dried, filtered and con-
centrated in vacuo to give 67 as pale yellow oil (120 mg, 93%, >99:1
4.14.57. Methyl (20R,
a
R)-2-[N-(
a
-methylbenzyl)azepan-20-yl]etha-
23
dr); [
a
]
þ36.2 (c 2.6 EtOH); nmax (film) 3258 (O–H, N–H, br), 2924
D
noate 68.
(C–H), 1472; dH (400 MHz, CDCl3) 1.10 (3H, d, J 6.0, CH3), 1.22–1.24
(1H, m, C(1)HA), 1.29–1.34 (1H, m, C(30)HA), 1.42–1.44 (1H, m,
C(1)HB), 1.56–1.59 (1H, m, C(40)HA), 1.76–1.78 (1H, m, C(40)HB), 1.83–
1.90 (1H, m, C(30)HB), 2.75 (1H, dt, J 11.7, 7.5, C(50)HA), 2.94–2.97 (1H,
m, C(50)HB), 3.32–3.37 (1H, m, C(20)H), 3.88–3.92 (1H, m, C(2)H),
4.10–4.25 (2H, br s, OH and NH); dC (100 MHz, CDCl3) 23.7 (CH3),
25.7 (C(40)), 32.8 (C(30)), 42.4 (C(1)), 45.6 (C(50)), 59.2 (C(20)), 68.3
(C(2)); m/z (ESIþ) 130 ([MþH]þ, 100%); HRMS (ESIþ) C7H16NOþ
([MþH]þ) requires 130.1226; found 130.1229.
N
Ph
CO2Me
Following General Procedure 3, Wilkinson’s catalyst (84.6 mg,
0.091 mmol) and 33 (500 mg, 1.83 mmol) in EtOAc (5 mL) under H2
(4 atm) at rt gave the crude reaction mixture. Purification via flash
4.14.55. (1R,20R)-1-Phenyl-2-[N-(10)methylpyrrolidin-20-yl]ethanol
[(þ)-pyrrolsedamine] 5.
column chromatography (eluent pentane/Et2O, 10:1) gave 68 as
21
a colourless oil (437 mg, 87%, >99:1 dr); [
a]
ꢀ3.3 (c 0.8 in CHCl3);
D
Me
N
OH
nmax (film) 2927 (C–H), 1737 (C]O); dH (400 MHz, CDCl3) 1.27–1.72
(7H, m, C(30)HA, C(40)H2, C(50)H2, C(60)H2) overlapping 1.38 (3H, d, J
6.7, C(
C(2)HA), 2.53 (1H, dd, J 13.8, 5.8, C(2)HB), 2.65–2.76 (2H, m, C(70)H2),
3.45–3.53 (1H, m, C(20)H), 3.64 (3H, s, OMe), 4.01 (1H, q, J 6.7, C(
)H),
7.20–7.34 (5H, m, Ph); dC (100 MHz, CDCl3) 21.9 (C( )Me), 24.2, 28.5,
29.4 (C(40), C(50), C(60)), 34.6 (C(30)), 38.4 (C(2)), 43.8 (C(70)), 51.3
a
)Me), 1.82–1.90 (1H, m, C(30)HB), 2.28 (1H, dd, J 13.8, 8.0,
Ph
a
Following General Procedure 13, syn-62 (260 mg, 0.89 mmol),
lithium aluminium hydride (165 mg, 4.5 mmol) in THF (13 mL) gave
the crude reaction mixture. The crude mixture was dissolved in 1 M
aq HCl (10 mL), and washed with CH2Cl2 (2ꢃ10 mL). The aqueous
layer was basified with 1 M aq NaOH and extracted with CH2Cl2
(5ꢃ10 mL). The combined organics were dried, filtered and con-
centrated in vacuo. Recrystallisation from CH2Cl2/heptane (v:v 1:1)
a
(OMe), 55.1 (C(20)), 59.9 (C(
a)),126.6 (p-Ph),127.3,128.2 (m-Ph, o-Ph),
145.8 (i-Ph), 173.4 (C(1)); m/z (ESIþ) 276 ([MþH]þ, 100%); HRMS
(ESIþ) C17H26NO2þ ([MþH]þ) requires 276.1964; found 276.1960.
4.14.58. Methyl (R)-2-[N-(tert-butoxycarbonyl)azepan-20-yl]etha-
noate 69.
gave 5 as a white solid (102 mg, 56%, >99:1 dr)1; mp 88–90 ꢂC;
23
[
a]
þ73.7 (c 2.0 in EtOH); nmax (KBr) 3355 (O–H, N–H, br), 3085,
D
2949 (C–H), 1493; dH (400 MHz, CDCl3) 1.39–1.45 (1H, m, C(30)HA),
1.62 (1H, ddd, J 13.4, 6.0, 2.5, C(2)HA), 1.75–1.81 (3H, m, C(2)HB,
C(40)H2), 1.99–2.04 (1H, m, C(30)HB), 2.37–2.42 (4H, m, NCH3,
C(50)HA), 2.83–2.87 (1H, m, C(20)H), 3.08–3.12 (1H, m, C(50)HB), 4.81
(1H, dd, J 13.4, 2.5, C(1)H), 7.22–7.36 (5H, m, Ph); dC (100 MHz,
CDCl3) 22.7 (C(40)), 30.4 (C(30)), 40. 0 (C(2)), 42.7 (NCH3), 55.5
(C(50)), 65.9 (C(20)), 73.6 (C(1)), 125.4, 127.0, 128.2 (m-, p-, o-Ph),
145.5 (i-Ph); m/z (ESIþ) 206 ([MþH]þ, 100%); HRMS (ESIþ)
C13H20NOþ ([MþH]þ) requires 206.1539; found 206.1542.
Boc
N
CO2Me
Following General Procedure 10, Pearlman’s catalyst (250 mg),
68 (500 mg, 1.82 mmol) and Boc2O (515 mg, 2.36 mmol) in EtOAc
(5 mL) under H2 (5 atm) at rt gave the crude reaction mixture.
Purification via flash column chromatography (eluent pentane/
4.14.56. (2S,20R)-1-[N(10)-Methylpyrrolidin-20-yl]propan-2-ol [(þ)-
pseudohygroline] 6.
Et2O, 20:1; increased to pentane/Et2O, 10:1) gave 69 as a colourless
22
oil (435 mg, 88%); [
a
]
þ33.0 (c 1.5 in CHCl3); nmax (film) 2929 (C–
D
H), 1740 (C]O, ester),1691 (C]O, carbamate); dH (400 MHz, CDCl3)
[56:44 mixture of rotamers] 1.12–1.73 (m, C(30)HA, C(40)H2, C(50)H2,
C(60)H2) overlapping 1.38 (s, CMe3) and 1.39 (s, CMe3), 1.94–2.05 (m,
C(30)HB), 2.27 (dd, J 14.2, 7.6, C(2)HA), 2.28 (dd, J 13.9, 7.1, C(2)HA),
2.41 (dd, J 13.9, 6.6, C(2)HB), 2.43 (dd, J 14.2, 5.8, C(2)HB), 2.63–2.73
(m, C(70)HA), 3.52–3.62 (m, C(70)HB) overlapping 3.57 (s, OMe) and
3.59 (s, OMe), 3.64–3.71 (m, C(70)HB), 4.14–4.22 (m, C(20)H), 4.29–
4.37 (m, C(20)H); dH (500 MHz, DMSO-d6, 373 K) 1.15–1.50 (4H, m,
Me
N
OH
Me
Following General Procedure 13, syn-64 (200 mg, 0.87 mmol),
lithium aluminium hydride (165 mg, 4.37 mmol) in THF (13 mL)

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10211
CH2) overlapping 1.42 (9H, s, CMe3), 1.59–1.75 (3H, m, CH2), 1.97–
2.02 (1H, m, CH2), 2.38–2.47 (2H, m, C(2)H2), 2.87 (1H, ddd, J 14.5,
11.0, 2.0, C(70)HA), 3.50–3.64 (1H, br m, C(70)HB) overlapping 3.60
(3H, s, OMe), 4.23 (1H, br s, C(20)H); dC (125 MHz, DMSO-d6, 373 K)
25.4 (CH2), 28.6 (CMe3), 28.9, 29.0 (CH2), 33.5 (C(30)), 39.6 (C(2)),
42.2 (C(70)), 51.5 (OMe), 53.0 (C(20)), 78.9 (CMe3), 155.1 (NCO), 171.5
(C(1)); m/z (ESIþ) 330 ([Mþ59]þ, 100%); HRMS (ESIþ) C14H26NOþ4
([MþH]þ) requires 272.1862; found 272.1875.
([MþNa]þ, 100%); HRMS (ESIþ) C16H30NOþ3 ([MþH]þ) requires
284.2226; found 284.2233.
4.14.61. (2S,20R)-1-[N-(tert-Butoxycarbonyl)azepan-20-yl]pentan-2-
ol syn-72.
Boc
N
OH
C3H7
4.14.59. (R)-N-Methoxy-N-methyl-2-[N0-(tert-butoxycarbonyl)azepan-
20-yl]ethanoate 70.
Following General Procedure 7, LiAl(OtBu)3H (224 mg,
0.88 mmol) and 71 (100 mg, 0.35 mmol) in THF (5 mL) at 0 ꢂC for
6 h gave the crude reaction mixture. Analysis by 400 MHz 1H NMR
spectroscopy revealed the presence of syn-72 in >99:1 dr. Purifi-
cation of the residue via flash column chromatography on silica gel
Boc
N
O
Me
N
OMe
(eluent pentane/EtOAc 10:1) gave syn-72 as a colourless oil (95 mg,
22
95%, >99:1 dr); [
a
]
þ87.2 (c 0.5 in CHCl3); nmax (film) 3418 (O–H),
D
i
Following General Procedure 8, PrMgCl (2.0 M in THF, 1.11 mL,
2.21 mmol), N,O-dimethylhydroxylamine hydrochloride (111 mg,
1.14 mmol) and 69 (200 mg, 0.74 mmol) in THF (5 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
2929 (C–H), 1690, 1662 (carbamate); dH (500 MHz, CDCl3) 0.93 (3H,
t, J 7.0, C(5)H3), 1.23–1.90 (13H, m, C(1)H2, C(3)H2, C(4)H2, C(30)HA,
C(40)H2, C(50)H2, C(60)H2) overlapping 1.52 (9H, s, C(CH3)3), 2.09–
2.14 (1H, m, C(30)HB), 2.75 (1H, t, J 13.2, C(70)HA), 3.62–3.68 (1H, m,
C(70)HB), 3.70–3.76 (1H, m, C(2)H), 4.13–4.19 (1H, m, C(20)H); dC
(125 MHz, CDCl3) 14.1 (C(5)), 19.2 (CH2), 25.0 (CH2), 28.5 (C(CH3)3),
28.9 (CH2), 29.7 (CH2), 35.8 (CH2), 39.6 (CH2), 41.9 (C(70)), 42.9
(C(1)), 53.4 (C(20)), 70.2 (C(2)), 79.7 (C(CH3)3), 157.0 (NCO); m/z
(ESIþ) 344 ([Mþ59]þ, 100%); HRMS (ESIþ) C16H32NOþ3 ([MþH]þ)
requires 286.2382; found 286.2381.
raphy (eluent pentane/EtOAc, 5:1) gave 70 as a colourless oil
22
(200 mg, 90%); [
a
]
þ35.3 (c 3.5 in CHCl3); nmax (film) 2929 (C–H),
D
1689 (C]O, carbamate, amide); dH (400 MHz, CDCl3) [59:41 mix-
ture of rotamers] 1.18–1.78 (m, C(30)HA, C(40)H2, C(50)H2, C(60)H2)
overlapping 1.42 (s, CMe3) and 1.44 (s, CMe3), 2.04–2.11 (m,
C(30)HB), 2.44 (dd, J 14.3, 7.8, C(2)HA), 2.53 (d, J 6.3, C(2)H2), 2.61 (dd,
J 14.3, 5.8, C(2)HB), 2.74–2.85 (m, C(70)HA), 3.12 (s, NMe), 3.15 (s,
NMe), 3.54–3.62 (br m, C(70)HB), 3.64 (s, OMe), 3.66 (s, OMe), 3.69–
3.75 (m, C(70)HB), 4.27–4.35 (m, C(20)H), 4.40 (app br s, C(20)H); dH
(500 MHz, DMSO-d6, 373 K) 1.14–1.50 (4H, m, CH2) overlapping
1.42 (9H, s, CMe3), 1.60–1.74 (3H, m, CH2), 1.97–2.04 (1H, m, CH2),
2.50–2.53 (2H, m, C(2)H2), 2.91 (1H, ddd, J 14.2, 11.0, 1.9, C(70)HA),
3.09 (3H, s, NMe), 3.51–3.58 (1H, br m, C(70)HB), 3.67 (3H, s, OMe),
4.26 (1H, app br s, C(20)H); dC (125 MHz, DMSO-d6, 373 K) 25.5
(CH2), 28.7 (CMe3), 29.0, 29.4 (CH2), 31.0 (NMe), 33.6 (C(30)), 37.4
(C(2)), 42.6 (C(70)), 53.0 (C(20)), 61.4 (OMe), 78.8 (CMe3), 155.1
(N0CO), 171.5 (C(1)); m/z (ESIþ) 359 ([Mþ59]þ, 100%); HRMS (ESIþ)
C15H29N2Oþ4 ([MþH]þ) requires 301.2127; found 301.2120.
4.14.62. Methyl (20R, -methylbenzyl)azocan-20-yl]ethanoate
aR)-2-[N-(a
73.
N
Ph
CO2Me
Following General Procedure 3, Wilkinson’s catalyst (80.5 mg,
0.087 mmol) and 39 (500 mg, 1.74 mmol) in EtOAc (5 mL) under H2
(4 atm) at rt gave the crude reaction mixture. Purification via flash
4.14.60. (R)-1-[N-(tert-butoxycarbonyl)azepan-20-yl]pentan-2-one
71.
column chromatography (eluent pentane/Et2O, 10:1) gave 73 as
22
a colourless oil (474 mg, 94%, >99:1 dr); [
nmax (film) 2923 (C–H), 1735 (C]O); dH (400 MHz, CDCl3) 1.28–1.66
(8H, m, CH2) overlapping 1.37 (3H, d, J 6.6, C( )Me), 1.82–1.91 (1H,
a
]
þ7.3 (c 0.8 in CHCl3);
D
a
Boc
N
O
m, CH2), 2.03–2.09 (2H, m, C(2)HA, CH2), 2.46 (1H, dd, J 13.4, 3.7,
C(2)HB), 2.56–2.62 (1H, m, C(80)HA), 2.70–2.78 (1H, m, C(80)HB),
2.93–3.00 (1H, m, C(20)H), 3.53 (3H, s, OMe), 3.74 (1H, q, J 6.6,
C3H7
C(
a)H), 7.21–7.36 (5H, m Ph); dC (100 MHz, CDCl3) 23.6 (C(a)Me),
25.8, 26.4, 28.7, 31.3, 33.0 (C(30), C(40), C(50), C(60), C(70)), 33.6 (C(2)),
43.2 (C(80)), 51.3 (OMe), 56.2 (C(20)), 61.8 (C(
a)), 126.8 (p-Ph), 127.4,
Following General Procedure 9, C3H7MgCl (2.0 M in Et2O,
0.33 mL, 0.67 mmol) 70 (100 mg, 0.33 mmol) in Et2O (2 mL) gave
the crude reaction mixture. Purification of the residue via flash
column chromatography on silica gel (eluent pentane/Et2O 10:1)
128.3 (m-Ph, o-Ph), 145.9 (i-Ph), 173.1 (C(1)); m/z (ESIþ) 290
([MþH]þ, 100%); HRMS (ESIþ) C18H28NOþ2 ([MþH]þ) requires
290.2120; found 290.2118.
gave 71 as a colourless oil, a 59:41 mixture of rotamers (59:41,
23
4.14.63. Methyl
noate 74.
(R)-2-[N-(tert-butoxycarbonyl)azocan-20-yl]etha-
68.6 mg, 73%); [
a]
þ28.2 (c 2.1 in CHCl3); nmax (film) 2930 (C–H),
D
1712 (C]O, ketone), 1689 (C]O, carbamate); dH (500 MHz, DMSO-
d6, 373 K) 0.87 (3H, t, J 7.3, C(5)H3), 1.15–1.73 (9H, m, C(4)H2,
C(30)HA, C(40)H2, C(50)H2, C(60)H2) overlapping 1.42 (9H, s, C(CH3)3),
1.93–2.01 (1H, m, C(30)HB), 2.34–2.45 (2H, m, C(3)H2), 2.53 (2H, br d,
J 6.6, C(1)H2), 2.89 (1H, ddd, J 14.5, 10.7, 2.2, C(70)HA), 3.48–3.58 (1H,
br m, C(70)HB), 4.25 (1H, app br s, C(20)H); dC (125 MHz, DMSO-d6,
373 K) 13.9 (C(5)), 17.1 (C(4)), 25.4 (CH2), 28.7 (C(CH3)3), 28.9 (CH2),
29.2 (CH2), 33.9 (C(30)), 42.4 (C(70)), 44.8 (C(3)), 47.9 (C(1)), 52.6
(C(20)), 78.9 (C(CH3)3), 155.1 (NCO), 208.8 (C(2)); m/z (ESIþ) 306
Boc
N
CO2Me
Following General Procedure 10, Pearlman’s catalyst (250 mg),
73 (500 mg, 1.73 mmol) and Boc2O (490 mg, 2.25 mmol) in EtOAc

10212
S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
(5 mL) under H2 (5 atm) rt gave the crude reaction mixture. Puri-
fication via flash column chromatography (eluent pentane/Et2O,
1688 (C]O, carbamate), 1652 (C]O, ketone); dH (400 MHz, CDCl3)
1.38–1.93 (10H, m, C(30)H2, C(40)H2, C(50)H2, C(60)H2, C(70)H2)
overlapping 1.43 (9H, s, CMe3), 2.93–3.01 (1H, m, C(2)HA), 3.11–3.43
(3H, m, C(2)HB, C(80)H2), 4.30–4.47 (1H, m, C(20)H), 7.32–7.59 (3H,
m, Ph), 7.94–8.00 (2H, m, Ph); dC (100 MHz, CDCl3) [rotameric] 25.3,
26.4, 26.8, 27.7 (CH2), 28.4, 28.5 (CMe3), 30.0 (CH2), 43.7, 44.1 (C(2),
C(8)), 53.8 (C(20)), 79.1, 79.5 (CMe3), 128.2, 128.4, 128.5, 128.6, 128.7
(p-Ph, m-Ph, o-Ph), 133.0, 133.2 (i-Ph), 155.0, 155.4 (NCO), 198.5,
199.2 (C(1)); m/z (ESIþ) 390 ([Mþ59]þ, 100%); HRMS (ESIþ)
C20H30NOþ3 ([MþH]þ) requires 332.2226; found 332.2214.
20:1; increased to pentane/Et2O, 10:1) gave 74 as a colourless oil
22
(418 mg, 85%); [
a]
ꢀ5.0 (c 1.0 in CHCl3); nmax (film) 2928 (C–H),
D
1741 (C]O, ester), 1692 (C]O, carbamate); dH (400 MHz, CDCl3)
[57:43 mixture of rotamers] 1.38–1.93 (m, C(30)H2, C(40)H2, C(50)H2,
C(60)H2, C(70)H2) overlapping 1.46 (s, CMe3) and 1.47 (s, CMe3),
2.32–2.39 (m, C(2)HA), 2.49 (dd, J 14.0, 7.6, C(2)HB), 2.53–2.65 (m,
C(2)HB), 2.92–3.01 (m, C(80)HA), 3.18–3.39 (m, C(80)H2), 3.64 (s,
OMe), 3.66 (s, OMe), 4.08–4.20 (m, C(20)H), 4.31–4.41 (m, C(20)H); dH
(500 MHz, DMSO-d6, 373 K) 1.32–1.81 (10H, m, C(30)H2, C(40)H2,
C(50)H2, C(60)H2, C(70)H2) overlapping 1.39 (9H, s, CMe3), 2.31–2.53
(2H, m, C(2)H2), 2.96–3.35 (2H, m, C(80)H2), 3.56 (3H, s, OMe), 3.95–
4.23 (1H, m, C(20)H); dC (125 MHz, DMSO-d6, 373 K) 24.9, 25.8, 26.2,
26.7 (CH2), 28.6 (CMe3), 30.8 (CH2), 41.2 (C(80)), 51.6 (C(20)), 53.4
(OMe), 79.2 (CMe3), 155.3 (NCO), 172.0 (C(1)); m/z (ESIþ) 344
([Mþ59]þ, 100%); HRMS (ESIþ) C15H28NOþ4 ([MþH]þ) requires
286.2018; found 286.2007.
4.14.66. (1R,20R)-1-Phenyl-2-[N-(tert-butoxycarbonyl)azocan-20-
yl]ethanol syn-77.
Boc
N
OH
Ph
4.14.64. N-Methoxy-N-methyl (R)-2-[N0-(tert-butoxycarbonyl)azocan-
20-yl]ethanoamide 75.
Following General Procedure 7, LiAl(OtBu)3H (192 mg,
0.75 mmol) and 76 (100 mg, 0.30 mmol) in THF (2 mL) at 0 ꢂC for
6 h gave syn-77 in >99:1 dr. Purification via flash column chro-
Boc
N
O
matography (eluent pentane/EtOAc, 10:1) gave syn-77 as a colour-
23
Me
less oil (92 mg, 91%, >99:1 dr); [
a]
þ77.4 (c 0.8, in CHCl3); nmax
D
N
(film) 3411 (O–H), 2927 (C–H), 1687, 1662 (carbamate); dH
(400 MHz, CDCl3) 1.32–1.92 (12H, m, C(2)H2, C(30)H2, C(40)H2,
C(50)H2, C(60)H2, C(70)H2) overlapping 1.46 (9H, s, CMe3), 2.72–2.80
(1H, m, C(80)HA), 3.00–3.06 (1H, m, C(80)HB), 4.15–4.22 (1H, m,
C(20)H), 4.74–4.79 (1H, m, C(1)H), 7.20–7.37 (5H, m, Ph); dC
(100 MHz, CDCl3) 24.5, 26.1, 27.0, 27.7 (CH2), 28.6 (CMe3), 30.5
(CH2), 41.4 (C(80)), 44.3 (C(2)), 53.1 (C(20)), 71.8 (C(1)), 79.7 (CMe3),
125.4, 126.8, 128.2 (p-Ph, m-Ph, o-Ph), 144.9 (i-Ph), 156.8 (NCO); m/z
(ESIþ) 356 ([MþNa]þ, 100%); HRMS (ESIþ) C20H31NNaOþ3 ([MþNa]þ)
requires 356.2196; found 356.2195.
OMe
Following General Procedure 8, iPrMgCl (2.0 M in THF, 2.63 mL,
5.26 mmol), N,O-dimethylhydroxylamine hydrochloride (265 mg,
2.72 mmol) and 74 (500 mg, 1.75 mmol) in THF (10 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
raphy (eluent pentane/EtOAc, 5:1) gave 75 as a colourless oil
22
(112 mg, 93%); [
a]
ꢀ11.0 (c 2.5 in CHCl3); nmax (film) 2929 (C–H),
D
1689 (C]O, carbamate, amide); dH (400 MHz, CDCl3) [54:46 mix-
ture of rotamers] 1.32–1.82 (m, C(30)H2, C(40)H2, C(50)H2, C(60)H2,
C(70)H2) overlapping 1.42 (s, CMe3) and 1.44 (s, CMe3), 2.42–2.79 (m,
C(2)H2), 3.00–3.18 (m, C(80)HA) overlapping 3.11 (s, NMe) and 3.14
(s, NMe), 3.20–3.36 (m, C(80)HB), 3.64 (s, OMe), 3.66 (s, OMe), 4.11–
4.23 (m, C(20)H), 4.24–4.38 (m, C(20)H); dH (500 MHz, DMSO-d6,
373 K) 1.35–1.84 (m, C(30)H2, C(40)H2, C(50)H2, C(60)H2, C(70)H2)
overlapping 1.43 (s, CMe3), 2.47–2.65 (2H, m, C(2)H2), 3.07–3.18
(1H, m, C(80)HA) overlapping 3.09 (3H, s, NMe), 3.19–3.30 (1H, m,
C(80)HB), 3.67 (3H, s, OMe), 4.08–4.27 (1H, m, C(20)H); dC (125 MHz,
DMSO-d6, 373 K) 25.3, 26.5, 26.8, 26.7 (CH2), 28.7 (CMe3), 30.0
(CH2), 32.7 (NMe), 37.1 (C(2)), 43.2 (C(80)), 53.5 (C(20)), 61.4 (OMe),
78.7 (CMe3), 155.0 (N0CO), 171.7 (C(1)); m/z (ESIþ) 373 ([Mþ59]þ,
100%); HRMS (ESIþ) C16H31N2Oþ4 ([MþH]þ) requires 315.2284;
found 315.2278.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.09.104.
References and notes
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4.14.65. (R)-1-Phenyl-2-[N-(tert-butoxycarbonyl)azocan-20-yl]etha-
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N
O
8. For a review, see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
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Ph
Following General Procedure 9, PhMgBr (3.0 M in Et2O, 0.21 mL,
0.64 mmol) and 75 (100 mg, 0.32 mmol) in Et2O (2 mL) gave the
crude reaction mixture. Purification via flash column chromatog-
10. Davies, S. G.; Fenwick, D. R. J. Chem. Soc., Chem. Commun. 1995, 109; Davies, S. G.;
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raphy (eluent pentane/Et2O, 10:1) gave 76 as a colourless oil
23
(80.2 mg, 76%); [
a
]
ꢀ32.3 (c 1.0 in CHCl3); nmax (film) 2928 (C–H),
D

S.G. Davies et al. / Tetrahedron 65 (2009) 10192–10213
10213
Davies, S. G.; Fenwick, D. R. Chem. Commun.1997, 565; Davies, S. G.; Fenwick, D. R.;
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25. Reduction with L-Selectride resulted in a 76:24 mixture of diastereoisomers.
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27. A similar transition state was proposed by Pasarella et al. to rationalise the
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12. Attempted preparation of (R)-N-but-3-enyl-N-(
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a-methylbenzyl)amine by
a
a
bromobut-1-ene (1 equiv) in the presence of K2CO3 proved to be an effective
and operationally simple procedure for the preparation of (R)-N-but-3-enyl-
28. Schopf, C.; Gams, E.; Koppernock, F.; Raush, R.; Wallbe, R. Liebigs Ann. Chem.
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N-(
enyl-N-(
a
-methylbenzyl)amine on multigram scale. Deprotonation of (R)-N-but-3-
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a
-methylbenzyl)amine in THF at ꢀ78 ꢂC using BuLi gave a pale yel-
low solution of the requisite lithium amide.
13. The reaction diastereoselectivity was assessed by peak integration of the 1H
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14. For examples of the analogous
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17. Full details are contained in the ESI.
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40. Repetition of this experiment led, on occasion, to isolation of
a small
amount (<1%) of (RS)-tert-butyl 3-butylhex-5-enoate as colourless oil
a
(first to elute); nmax (film) 2928 (C–H), 1732 (C]O); dH (400 MHz, CDCl3) 0.
86–0.90 (3H, m, C(40) H3), 1.15–1.37 (6H, m, C(10) H2, C(20) H2, C(30) H2), 1.43
(9H, s, C Me3), 1.65 (1H, dd, J 6.5, 1.4, C(6) H3), 2.11 (1H, dd, J 14.3, 8.6, C(2)
HA), 2.24 (1H, dd, J 14.3, 6.1, C(2) HB), 2.32–2.49 (1H, m, C(3) H), 5.21 (1H,
ddd, J 15.0, 8.5, 1.4, C(4) H), 5.43 (1H, dq, J 15.0, 6.5, C(5) H); dC (100 MHz,
CDCl3) 14.1 (C(40)), 17.8 (C(6)), 22.7 (CH2), 28.1 (C Me3), 29.3, 34.7 (CH2), 39.8
(C(3)), 41.9 (C(2)), 79.3 (CMe3), 125.2, 134.0 (C(4), C(5)); m/z (CIþ
) 227
([MþH]þ, 32%), 171(100); HRMS (CIþ) C14H27Oþ2 ([MþH]þ) requires 227.2011;
found 227.2003.
23. Dias, L. C.; Pilli, R. A. Synth. Commun. 1991, 21, 2213.
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metry 2000, 11, 2231.
42. A fraction containing both double bond isomers was also obtained (538 mg, 5%).
43. Bruckner, R.; Harcken, C.; Rank, E. Chem.dEur. J. 1998, 4, 2342; Alcon, M.;
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44. Repetition of this experiment led, on occasion, to isolation of a small amount
(<1% conversion of starting material) of (RS)- tert-butyl 3-butylhept-6-enoate
as a colourless oil (first to elute); nmax (film) 2929 (C–H), 1731 (C]O), 1641
(C]C); dH (400 MHz, CDCl3) 0.88–0.91 (3H, m, C(40) H3), 1.26–1.49 (8H, m,
C(4) H2, C(10) H2, C(20) H2, C(30) H2) overlapping 1.45 (9H, s, C Me3), 1.82–1.86
(1H, m, C(3) H), 2.06 (2H, app q, J 7.9, C(5) H2), 2.16 (2H, app d, J 6.8, C(2) H2),
4.93–5.04 (2H, m, C(7) H2), 5.76–5.86 (1H, m, C(6) H); dC (100 MHz, CDCl3) 14.
1 (C(40)), 22.9 (CH2), 28.1 (C Me3), 28.7, 30.8, 33.1, 33.4 (CH2), 34.6 (C(3)), 40.3
(C(2)), 80.0 (CMe3), 114.3 (C(7)), 138.9 (C(6)), 172.9 (C(1)); m/z (CIþ) 241
([MþH]þ, 100%); HRMS (CIþ) C15H29O2þ ([MþH]þ) requires 241.2168; found
241.2173.
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