Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine

Article abstract of DOI:10.1016/j.tet.2016.09.006

The asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have been achieved using the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to α-alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the resultant enolates as the key stereodefining steps. The azabicyclic scaffolds were then efficiently constructed upon sequential oxidative cleavage of the olefinic units within the resultant β-amino esters and hydrogenolytic N-debenzylation of the corresponding dialdehydes, which occurs with concomitant double reductive cyclisation. Subsequent reduction of the ester moieties with LiAlH₄gave (+)-trachelanthamidine, (+)-tashiromine, (1S,8aR)-1-(hydroxymethyl)octahydroindolizine and (+)-epilupinine in 4.9, 4.1, 3.0 and 5.9% overall yield, respectively, in only six steps from commercially available starting materials.

Full text of DOI:10.1016/j.tet.2016.09.006

Accepted Manuscript
Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation
protocol: concise asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine
and (+)-epilupinine
Marta Brambilla, Stephen G. Davies, Ai M. Fletcher, Paul M. Roberts, James E.
Thomson, David Zimmer
PII:
S0040-4020(16)30900-0
10.1016/j.tet.2016.09.006
TET 28077
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 July 2016
Revised Date: 25 August 2016
Accepted Date: 5 September 2016
Please cite this article as: Brambilla M, Davies SG, Fletcher AM, Roberts PM, Thomson JE, Zimmer
D, Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise
asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.09.006.
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ACCEPTED MANUSCRIPT
Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise
asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine
Marta Brambilla, Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, James E. Thomson and David
Zimmer
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
OX1 3TA, U.K.
E-mail: steve.davies@chem.ox.ac.uk

ACCEPTED MANUSCRIPT
Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise
asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine
Marta Brambilla, Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, James E. Thomson and David
Zimmer
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
OX1 3TA, U.K.
E-mail: steve.davies@chem.ox.ac.uk
Abstract
The asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have been achieved
using the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to α-
alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the resultant enolates as the key
stereodefining steps. The azabicyclic scaffolds were then efficiently constructed upon sequential oxidative
cleavage of the olefinic units within the resultant β-amino esters and hydrogenolytic N-debenzylation of the
corresponding dialdehydes, which occurs with concomitant double reductive cyclisation. Subsequent
reduction of the ester moieties with LiAlH4 gave (+)-trachelanthamidine, (+)-tashiromine, (1S,8aR)-1-
(hydroxymethyl)octahydroindolizine and (+)-epilupinine in 4.9, 4.1, 3.0 and 5.9% overall yield, respectively,
in only six steps from commercially available starting materials.
Key words: (+)-trachelanthamidine, (+)-tashiromine, (+)-epilupinine, azabicyclic alkaloids, asymmetric
synthesis
1. Introduction
Azabicycles can be defined as systems exhibiting two fused aliphatic rings with an endocyclic nitrogen
atom. Pyrrolizidines 1, indolizidines 2 and quinolizidines 3 are sub-classes of [x.y.0]-azabicycles1 which
have the nitrogen atom located at a bridgehead position.2 Azabicyclic alkaloids of this type are prevalent in
Nature and display a broad array of different biological activity. For example, (+)-hyacinthacine A1 4 is a
potent glycosidase inhibitor,3 (–)-swainsonine 5 exhibits anti-cancer activity,4 and (–)-castanospermine 6 has
been used to treat Dengue virus (Fig. 1).5
1

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Fig. 1. The core structures of pyrrolizidines 1, indolizidines 2 and quinolizidines 3, and selected biologically active azabicyclic
alkaloids 4–6.
A fundamental step in the synthesis of these structures is the effective and stereoselective construction of the
azabicyclic scaffold. We have recently developed highly efficient routes to several pyrrolizidine alkaloids
employing a tandem hydrogenolytic N-debenzylation/double reductive cyclisation sequence to construct the
[3.3.0]-azabicyclic ring system.6 For example, conjugate addition7,8 of lithium amide (S)-7 to α,β-unsaturated
ester 8 followed by allylation of the resultant lithium (Z)-β-amino enolate9 gave 9 in 60% yield and 85:15 dr.
Ring-closing metathesis of 9, followed by treatment of 10 with KOtBu gave 11 in 34% yield (from 9) and
>99:1 dr. Olefinic oxidation10,11 of 11, reduction of the resultant lactone, and oxidative cleavage of the
corresponding 1,2-diol gave dialdehyde 12. Subsequent tandem hydrogenolytic N-debenzylation/double
reductive cyclisation of 12 gave (–)-isoretronecanol 13 in 52% yield (from 11) and >99:1 dr (Scheme 1).
Herein, we report a modification to this methodology and also expand its scope to encompass the
asymmetric syntheses of [4.3.0]- and [4.4.0]-azabicyclic targets (i.e., indolizidines and quinolizidines),
which culminates in the syntheses of (+)-trachelanthamidine12 (originally trachelantamidine13), (+)-
tashiromine, (1S,8aR)-1-(hydroxymethyl)octahydroindolizine and (+)-epilupinine.14
2

Ph
ACCEPTED MANUSCRIPT
Ph
Ph
N
Li
Ph
N
(S)-7
CO2tBu
CO2tBu
(i)
8, >99:1 dr
9, 60%, 85:15 dr
(ii)
Ph
Ph
Ph
N
Ph
N
CO2tBu
CO2tBu
(iii)
11, 80%, >99:1 dr
10, 43%, >99:1 dr
(iv) (vi)
Ph
Ph
N
OH
H
OH
(vii)
N
O
O
(
-isoretronecanol 13
12, not isolated
52% (from 11), >99:1 dr
Scheme 1. Reagents and conditions: (i) (S)-7, THF, –78 °C, 2 h then allyl bromide, –78 °C to rt, 12 h; (ii) Grubbs I, CH2Cl2, 35
t
°C, 16 h; (iii) KHMDS, BuOH, THF, rt, 16 h; (iv) HBF4, m-CPBA, CH2Cl2, rt, 48 h; (v) LiAlH4, THF, 0 °C, 2 h; (vi) NaIO4,
MeOH, rt, 1 h; (vii) H2 (5 atm), MeOH/AcOH (20:1), rt, 24 h.
2. Results and discussion
We initially set out to extend our existing methodology to the homologous substrates to access the target
indolizidines and quinolizidines. The requisite α,β-unsaturated esters were prepared from commercially
available alcohols 14 and 15 upon Swern oxidation and stereoselective Wittig reaction of the resultant
aldehydes 16 and 17, with tert-butyl 2-(triphenylphosphanylidene)acetate 21 (which was prepared in 68%
yield from tert-butyl bromoacetate and PPh3), which gave α,β-unsaturated esters 8 and 18 in 71 and 81%
isolated yield, respectively, and >99:1 dr [(E):(Z)] in each case. Conjugate addition7 of lithium (R)-N-benzyl-
N-(α-methylbenzyl)amide (R)-7 to α,β-unsaturated ester 8 (n = 1), followed by treatment of the resultant
lithium (Z)-β-amino enolate9 with satd aq NH4Cl, gave the known14l β-amino ester 19 in 89% yield and
>99:1 dr. Similarly, conjugate addition of lithium amide (R)-7 to α,β-unsaturated ester 18 (n = 2), followed
by protonation of the resultant lithium (Z)-β-amino enolate9 with satd aq NH4Cl, gave β-amino ester 20 as a
single diastereoisomer (>99:1 dr) in 97% yield (Scheme 2). The relative configuration within 20 was
assigned by reference to the transition state mnemonic8 which has been developed to correctly predict the
stereochemical outcome upon conjugate addition of lithium amide reagents to achiral α,β-unsaturated esters
(>200 examples), including the conjugate addition of (R)-7 to 8 (n = 1).
3

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Scheme 2. Reagents and conditions: (i) (COCl)2, DMSO, CH2Cl2, –78 °C, 1 h, then Et3N, –78 °C to rt, 10 min; (ii) 21, rt, 18 h;
(iii) (R)-7, THF, –78 °C, 2 h, then NH4Cl (satd aq).
By analogy to our established tandem conjugate addition/alkylation procedure, described above for 8
(n = 1),6a conjugate addition of lithium amide (R)-7 to α,β-unsaturated ester 18 (n = 2) followed by treatment
of the resultant lithium (Z)-β-amino enolate9 with allyl bromide gave a 65:35 mixture of C(2)-epimers 22
and 23, respectively. β-Amino esters 22 and 23 proved to be extremely difficult to separate, and the major
product 22 was isolated in only 5% yield as a single diastereoisomer (>99:1 dr) after exhaustive
chromatographic purification; a 65:35 mixed fraction of 22 and 23, respectively, was also isolated in 64%
combined yield. As complete diastereoselectivity was observed upon conjugate addition in the formation of
β-amino ester 20, compounds 22 and 23 were assigned as being C(2)-epimers. The 2,3-syn-relative
configuration within the major diastereoisomer 22 was tentatively assigned by analogy to the stereochemical
outcome observed upon tandem conjugate addition/alkylation of 8 (n = 1),6a and this assignment was later
unambiguously confirmed by chemical correlation to the target indolizidine (vide infra). We have previously
observed that the alkylation of lithium β-amino enolates with but-3-enyl bromide is a low yielding process;
however, alkylation with 1,4-diiodobutane followed by elimination of HI from the resultant α-alkyl-β-amino
ester can be an efficient method to introduce a but-3-enyl group at the C(2)-position. Indeed, conjugate
addition of lithium amide (R)-7 to α,β-unsaturated ester 8 (n = 1) followed by alkylation of the intermediate
lithium (Z)-β-amino enolate9 with 1,4-diiodobutane was found to yield a 60:40 partially separable mixture of
C(2)-epimers 24 and 25, which were isolated in 36 and 5% yield, respectively; a 50:50 mixed fraction of 24
and 25 was also obtained in 34% combined yield. Identical treatment of the homologous substrate 18 (n = 2)
gave a 63:37 mixture of C(2)-epimers 26 and 27, respectively. Although chromatographic purification of 26
and 27 proved difficult and various mixed fractions were obtained, 26 was isolated in 18% yield and 89:11
4

ACCEPTED MANUSCRIPT
dr, and 27 was isolated in 8% yield and 95:5 dr. The relative configurations within 24–27 were again
tentatively assigned by analogy to the outcome observed upon tandem conjugate addition/alkylation of 8
(n = 1).6a Elimination of HI from within both 24 (n = 1, >99:1 dr) and 25 (n = 1, >99:1 dr), upon treatment
with KOtBu, yielded a 65:35 mixture of 28 and 29, respectively, in both cases (Scheme 3). These results are
consistent with C(2)-epimerisation occurring as well as elimination of HI under the basic reaction
conditions.
Scheme 3. Reagents and conditions: (i) (R)-7, THF, –78 °C, 2 h, then allyl bromide, –78 °C to rt, 12 h; (ii) (R)-7, THF, –78 °C, 2
h, then 1,4-diiodobutane, –78 °C to rt, 12 h; (iii) KOtBu, THF, rt, 16 h. [a a 65:35 mixture of 22 and 23 was also isolated in 64%
b
c
combined yield; a 50:50 mixed fraction of 24 and 25 was also isolated in 34% combined yield; further mixed fractions were
also isolated in 20% total yield].
As C(2)-epimerisation was noted upon elimination of HI from within both 24 and 25, it was proposed that
reduction of the ester moiety should be performed first, removing the risk of epimerisation during the
subsequent elimination step. Following a literature procedure for the chemoselective reduction of an ester in
the presence of an ω-iodo substituent,15 both 24 (n = 1, >99:1 dr) and 26 (n = 2, 89:11 dr) were treated with
DIBAL-H in PhMe. After purification of the crude reaction mixtures, alcohols 30 (>99:1 dr) and 31 (89:11
dr) were isolated in 72 and 86% yield, respectively. Subsequent elimination of HI from within 30 and 31
upon treatment with KOtBu gave 32 in 56% yield and >99:1 dr, and 34 in 33% yield and 95:5 dr,
5

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respectively. In addition, α-allyl-β-amino ester 22 (>99:1 dr) was reduced with LiAlH4 to give the
corresponding alcohol 33 in 48% yield and >99:1 dr (Scheme 4).
Ph
Ph
Ph
N
Ph
N
(i)
CO2tBu
n
n
OH
I
I
24, n = 1, >99:1 dr
26, n = 2, 89:11 dr
30, n = 1, 72%, >99:1 dr
31, n = 2, 86%, 89:11 dr
n = 1, >99:1 dr
n = 2, 89:11 dr
(ii)
Ph
Ph
Ph
N
Ph
N
(iii)
CO2tBu
n
n
OH
m
22, n = 2, >99:1 dr
32, n = 1, m = 2, 56% (from 30), >99:1 dr
33, n = 2, m = 1, 48% (from 22), >99:1 dr
34, n = 2, m = 2, 33% (from 31), 95:5 dr
Scheme 4. Reagents and conditions: (i) DIBAL-H, PhMe, 0 °C, 4 h; (ii) KOtBu, THF, rt, 16 h; (iii) LiAlH4, THF, –78 °C to
rt, 18 h.
Attempts to optimise the overall yields of the requisite dienes via a strategy reliant on ring-closing
metathesis [i.e., an analogous approach to that which we used previously6a for the truncated analogue 9 (n =
1)] were thwarted by both poor conversion and low isolated yields. Instead, it was envisaged that oxidative
cleavage of the olefinic units within α-alkenyl-β-amino alcohols 32–34 would afford the requisite
dialdehydes, and application of the tandem hydrogenolytic N-debenzylation/double reductive cyclisation
protocol would then furnish the corresponding azabicycles. Initially, the efficacy of this route was evaluated
using mixtures of C(2)-epimeric alcohols 32–34 as these samples could easily be prepared on multigram
scales. Oxidative cleavage of the olefinic units within 32 (65:35 dr) via ozonolysis of the corresponding
hydrochloride salt 32·HCl (to circumvent N-oxidation) gave the corresponding dialdehyde 35. Subsequent
hydrogenolysis of 35 effected N-debenzylation and concomitant double reductive cyclisation, and following
purification of the crude reaction mixture on Dowex 50WX8 ion-exchange resin, (+)-tashiromine 38 was
isolated in 11% yield (from 32) and >99:1 dr. Similarly, ozonolysis of 33 (73:27 dr) followed by tandem
hydrogenolytic N-debenzylation/double reductive cyclisation of the resultant dialdehyde 36 gave, after
purification on Dowex 50WX8 ion-exchange resin, (1S,8aR)-1-(hydroxymethyl)indolizidine 40 as a single
diastereoisomer (>99:1 dr) in 17% isolated yield (from 33). In the homologous series, ozonolysis of 34
(74:26 dr) and tandem hydrogenolytic N-debenzylation/double reductive cyclisation of dialdehyde 37 gave a
79:21 mixture of quinolizidines 42 and 43, respectively. Sequential purification by ion-exchange
chromatography on Dowex 50WX8 resin followed by flash column chromatography on neutral alumina
6

ACCEPTED MANUSCRIPT
gave (+)-epilupinine 42 in 11% yield (from 34) and >99:1 dr (Scheme 5). In each case, the samples of the
azabicyclic targets 38, 40 and 42 were found to be contaminated with ~5% unidentified impurities, although
the specific rotations and spectroscopic data for these samples of (+)-tashiromine 38, (1S,8aR)-1-
(hydroxymethyl)indolizidine 40 and (+)-epilupinine 42 were all in reasonably good agreement with literature
data {for 38: [α]20 +30.0 (c 0.5 in CHCl3); lit.16 [α]20 +43.4 (c 0.53 in CHCl3); for 40: [α]20 +30.1 (c 0.42 in
D
D
D
EtOH); lit.14l [α]D20 +27.4 (c 1.0 in EtOH); for 42: [α]D20 +20.1 (c 0.33 in EtOH); lit.14j [α]2D0 +31.8 (c 0.6 in
EtOH)}. Despite the relatively low yields of 38, 40 and 42 obtained, these results established that the tandem
hydrogenolytic N-debenzylation/double reductive cyclisation protocol is indeed applicable to the synthesis
of indolizidines and quinolizidines. An alternative, higher yielding synthesis of diastereoisomerically pure
cyclisation precursors was therefore investigated via conjugate addition of lithium amide (R)-7 to the
corresponding α-alkenyl substituted α,β-unsaturated esters.
Ph
Ph
Ph
N
Ph
N
(i)
O
n
n
OH
OH
O
m
m
32, n = 1, m = 2, 65:35 dr
33, n = 2, m = 1, 73:27 dr
34, n = m = 2, 74:26 dr
35, n = 1, m = 2
36, n = 2, m = 1
37, n = m = 2
n = 1, m = 2, 65:35 dr [38:39]
n = 2, m = 1, 70:30 dr [40:41] (ii)
n = m = 2, 79:21 dr [42:43]
OH
OH
H
N
H
+
n
m
n
m
N
38, n = 1, m = 2, 11% (from 32),a >99:1 dr
40, n = 2, m =1, 17% (from 33),a,b >99:1 dr 41, n = 2, m =1
42, n = m = 2, 11% (from 34),a,c >99:1 dr
43, n = m = 2
39, n = 1, m = 2
Scheme 5. Reagents and conditions: (i) HCl/Et2O, rt, 5 min, then O3, CH2Cl2/MeOH (1:1), –78 °C, 1 h, then polymer supported
b
PPh3, –78 °C to rt, 2 h; (ii) H2, Pd(OH)2/C, MeOH/AcOH (25:1), 35 °C, 24 h. [a ~95% purity; an 86:14 mixture of 40 and 41,
c
respectively, was also isolated in 14% combined yield and ~95% purity; a 77:23 mixture of 42 and 43, respectively, was also
isolated in 8% combined yield and ~95% purity].
The requisite α-alkenyl substituted phosphonate reagents 45 and 46 were readily prepared from 44 upon
deprotonation with NaH and alkylation of the resultant anion with either allyl bromide or but-3-enyl
bromide, which gave 45 and 46 in 70 and 75% yield, respectively. Following a modified Wadsworth-
Emmons protocol17 deprotonation of the α-alkenyl phosphonate reagents 45 and 46 with MeMgBr and
ensuing reaction with aldehydes 16 and 17 gave α-alkenyl-α,β-unsaturated esters 47–50 in good yield and
moderately high [(E):(Z)] ratios (>70:30 dr); the presence of the (Z)-configured α,β-unsaturated esters was
not deemed to be a problem as it is known that lithium amides only undergo conjugate addition to (E)-
configured substrates.7 In accordance with our previous observations concerning conjugate additions of
7

ACCEPTED MANUSCRIPT
lithium amide (R)-7 to α,β-unsaturated esters bearing either methyl or benzyl substituents at the α-position,18
an alternative procedure was required for the conjugate addition of (R)-7 to α-alkenyl-α,β-unsaturated esters
47–50 due to poor diastereoselectivity and the formation of various side products under the standard
conditions for lithium amide conjugate addition (i.e., THF, –78 °C, 2 h). In order to overcome the issues
associated with both reactivity and diastereoselectivity, the conjugate addition was performed in PhMe prior
to dilution of the reaction medium with THF and subsequent addition of 2,6-di-tert-butyl phenol to the
resultant solution of the intermediate enolate.18 In each case, the α-alkenyl-β-amino esters ent-9, 28, 22 and
51 were prepared as single diastereoisomers (>99:1 dr) in 35–54% yield (Scheme 6). The configurations of
these β-amino ester products were assigned by analogy to the stereochemical outcome observed upon
conjugate addition of (R)-7 to the corresponding α-methyl- and α-benzyl-substituted α,β-unsaturated esters,
which was followed by diastereoselective protonation of the intermediate β-amino enolates with 2,6-di-tert-
butyl phenol;18 these assignments were later confirmed unambiguously by chemical correlation to the target
azabicycles (vide infra).
Scheme 6. Reagents and conditions: (i) NaH, THF, rt, 1 h then allyl bromide or but-3-enyl bromide, 70 °C, 36 h; (ii) MeMgBr,
THF, rt, 15 min then 16 (n = 1) or 17 (n = 2), 70 °C, 3 h; (iii) (R)-7, PhMe, –78 °C, 1 h then –30 °C, 2 h then THF, –78 °C, 30 min
then 2,6-di-tert-butylphenol, –78 °C to rt, 30 min.
Various attempts at the ozonolysis of these substrates (as the corresponding hydrochloride salts) were found
to be problematic. However, under optimised conditions, dialdehydes 52–55 were prepared upon treatment
of α-alkenyl-β-amino esters ent-9, 28, 22 and 51 with OsO4 and NaIO4 in the presence of 2,6-lutidine.19
Immediate subjection of dialdehydes 52–55 to the tandem hydrogenolytic N-debenzylation/double reductive
cyclisation conditions followed by reduction of the resultant azabicyclic esters 56–59 with LiAlH4 gave the
target hydroxymethyl bearing azabicycles 60, 38, 40 and 42 in >99:1 dr in each case. Purification of the
crude reaction mixtures gave (+)-trachelanthamidine 60, (+)-tashiromine 38, (1S,8aR)-1-(hydroxymethyl)-
octahydroindolizine 40 and (+)-epilupinine 42 as single diastereoisomers (>99:1 dr) in each case (Scheme 7).
8

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The specific rotations and spectroscopic data for these samples of 60, 38, 40 and 42 were in good agreement
+15.9 (c 1.0 in EtOH); lit.14g
+15.4 (c 1.2
25
[α]D
[α]2D0
[α]2D2
+41.9 (c 1.1 in EtOH); for
with literature values {for (+)-trachelanthamidine 60:
in EtOH); for (+)-tashiromine 38:
+39.0 (c 0.2 in EtOH); lit.20
[α]2D5
+39.8 (c 0.5 in EtOH); lit.14l
25
[α]D
[α]2D3
+27.4 (c 1.0 in
(1S,8aR)-1-(hydroxymethyl)octahydroindolizine 40:
+29.1 (c 0.3 in EtOH); lit.14k for ent-42
−29.2 (c 1.0 in EtOH)},
26
[α]2D5
[α]D
EtOH); for (+)-epilupinine 42:
thereby also confirming the assigned configurations within the synthetic precursors ent-9, 28, 22, 51 and 52–
59.
Scheme 7. Reagents and conditions: (i) OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane/H2O (3:1), rt, 40 min; (ii) H2 (5 atm), Pd(OH)2/C,
MeOH, rt, 120 h; (iii) LiAlH4, THF, –78 °C to rt, 2 h.
3. Conclusion
In conclusion, concise asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have
been achieved using the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-
methylbenzyl)amide to α-alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the
resultant enolates with 2,6-di-tert-butylphenol as the key stereodefining steps. The azabicyclic scaffolds
were then efficiently constructed upon sequential oxidative cleavage of the olefinic units and hydrogenolytic
N-debenzylation of the resultant dialdehydes, which occurs with concomitant double reductive cyclisation.
Subsequent reduction of the ester moieties with LiAlH4 gave the target hydroxymethyl bearing azabicycles.
Following this route, enantiopure samples of (+)-trachelanthamidine, (+)-tashiromine, (1S,8aR)-1-
(hydroxymethyl)octahydroindolizine and (+)-epilupinine were prepared as single diastereoisomers (>99:1
dr) in 4.9, 4.1, 3.0 and 5.9% overall yield, respectively, in only six steps from commercially available
starting materials.
9

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4. Experimental
4.1. General Experimental
Reactions involving organometallic or other moisture-sensitive reagents were carried out under a nitrogen or
argon atmosphere using standard vacuum line techniques and glassware that was flame dried and cooled
under nitrogen before use. BuLi was purchased from Sigma-Aldrich (as a solution in hexanes) and titrated
t
against diphenylacetic acid before use. BuOH was distilled from activated magnesium turnings. Allyl
bromide and but-3-enyl bromide were distilled from MgSO4. Solvents were dried according to the procedure
outlined by Grubbs and co-workers.21 Water was purified by an Elix® UV-10 system. All other reagents
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 phosphomolybdic acid.
Flash column chromatography was performed on Kieselgel 60 silica.
Melting points were recorded on a Gallenkamp Hot Stage apparatus. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm cell. Specific rotations are reported in 10−1 deg
cm2 g−1 and concentrations in g/100 mL. IR spectra were recorded on a Bruker Tensor 27 FT-IR
spectrometer using an ATR module. Selected characteristic peaks are reported in cm–1. NMR spectra were
recorded on Bruker Avance spectrometers in the deuterated solvent stated. Spectra were recorded at rt. The
field was locked by external referencing to the relevant deuteron resonance. 1H−1H COSY, 1H−13C HMQC,
1
and H−13C HMBC analyses were used to establish atom connectivity. Low-resolution mass spectra were
recorded on either a VG MassLab 20–250 or a Micromass Platform 1 spectrometer. Accurate mass
measurements were run on either a Bruker MicroTOF internally calibrated with polyalanine, or a Micromass
GCT instrument fitted with a Scientific Glass Instruments BPX5 column (15 m × 0.25 mm) using amyl
acetate as a lock mass.
tert-Butyl (E)-hepta-2,6-dienoate 8
A solution of (COCl)2 (2.38 mL, 28.4 mmol) in CH2Cl2 (40 mL) at –78 °C was treated with DMSO (2.20
mL, 31.0 mmol) in CH2Cl2 (40 mL). The resultant mixture was stirred at –78 °C for 10 min, then a solution
of 4-penten-1-ol 14 (2.00 g, 23.2 mmol) in CH2Cl2 (40 mL) was added. The resultant mixture was stirred at
–78 °C for 1 h, then Et3N (6.39 mL, 45.9 mmol) was added. The reaction mixture was allowed to warm to rt,
then 21 (8.74 g, 23.2 mmol) was added and the resultant mixture was stirred at rt for 18 h. Satd aq Na2CO3
10

ACCEPTED MANUSCRIPT
(40 mL) was then added and the reaction mixture was extracted with CH2Cl2 (3 × 25 mL). The combined
organic extracts were washed with brine (40 mL), then dried and concentrated in vacuo to give 8 in >99:1 dr
[(E):(Z)]. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave 8 as a
colourless oil (2.95 g, 71%, >99:1 dr [(E):(Z)]);22 δH (200 MHz, CDCl3) 1.49 (9H, s, CMe3), 2.14–2.36 (4H,
m, C(4)H2, C(5)H2), 5.00–5.16 (2H, m, C(7)H2), 5.77–5.95 (2H, m, C(2)H, C(6)H), 6.92 (1H, dt, J 15.7, 6.7,
C(3)H).
tert-Butyl (E)-octa-2,7-dienoate 18
A solution of (COCl)2 (2.37 mL, 28.0 mmol) in CH2Cl2 (40 mL) at –78 °C was treated with DMSO (2.15
mL, 30.3 mmol) in CH2Cl2 (40 mL). The resultant mixture was stirred at –78 °C for 10 min, then a solution
of 5-hexen-1-ol 15 (2.80 mL, 23.3 mmol) in CH2Cl2 (40 mL) was added. The resultant mixture was stirred at
–78 °C for 1 h, then Et3N (7.80 mL, 56.0 mmol) was then added. The reaction mixture was allowed to warm
to rt, then 21 (8.76 g, 23.3 mmol) was added and the resultant mixture was stirred at rt for 18 h. Satd aq
Na2CO3 (50 mL) was then added and the resultant mixture was extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were washed with brine (50 mL), then dried and concentrated in vacuo to give 18
in >99:1 dr [(E):(Z)]. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O, 100:1)
gave 18 as a colourless oil (3.72 g, 81%, >99:1 dr [(E):(Z)]); νmax (ATR) 1719 (C=O), 1653 (C=C); δH (400
MHz, CDCl3) 1.50 (9H, s, CMe3), 1.55–1.61 (2H, m, C(5)H2), 2.07–2.24 (4H, m, C(4)H2, C(6)H2), 4.98–
5.07 (2H, m, C(8)H2), 5.74–5.68 (2H, m, C(2)H, C(7)H), 6.88 (1H, dt, J 15.6, 7.0, C(3)H); δC (100 MHz,
CDCl3) 27.2 (C(5)), 28.1 (CMe3), 31.3 (C(4)), 33.1 (C(6)), 80.0 (CMe3), 115.0 (C(8)), 123.2 (C(2)), 138.1
+
(C(7)), 147.6 (C(3)), 166.1 (C(1)); m/z (ESI+) 219 ([M+Na]+, 100%); HRMS (ESI+) C12H20NaO2 ([M+Na]+)
requires 219.1356; found 219.1356.
tert-Butyl (R,R)-3-[N-benzyl-N-(α-methylbenzyl)amino]hept-6-enoate 19
BuLi (2.5 M in hexanes, 1.85 mL, 4.26 mmol) was added dropwise via syringe to a stirred solution of (R)-N-
benzyl-N-(α-methylbenzyl)amine (0.92 mL, 4.40 mmol, >99:1 er) in THF (10 mL) at –78 °C. After stirring
at –78 °C for 30 min, a solution of 8 (500 mg, 2.75 mmol, >99:1 dr [(E):(Z)]) in THF (10 mL) at –78 °C was
added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 2 h, then satd aq NH4Cl (10
mL) was added. The resultant mixture was allowed to warm to rt and stirred at rt for 15 min, then
concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 10% aq citric acid (10
11

ACCEPTED MANUSCRIPT
mL). The aqueous layer was extracted with CH2Cl2 (2 × 20 mL) and the combined organic extracts were
washed sequentially with satd aq NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), then dried and
concentrated in vacuo to give 19 in >99:1 dr. Purification via flash column chromatography (eluent 30−40
°C petrol/Et2O, 100:1) gave 19 as a pale yellow oil (959 mg, 89%, >99:1 dr);14l [α]20 +8.7 (c 1.0 in CHCl3);
D
{lit.14l [α ]D26 +8.1 (c 0.9 in CHCl3)}; δH (400 MHz, CDCl3) 1.25 (3H, d, J 7.0, C(α)Me), 1.28–1.39 (1H, m,
C(4)HA), 1.31 (9H, s, CMe3), 1.46 (1H, app dtd, J 14.9, 9.3, 5.0, C(4)HB), 1.74–1.82 (2H, m, C(2)H2), 2.00–
2.09 (1H, m, C(5)HA), 2.26–2.34 (1H, m, C(5)HB), 3.27 (1H, app tt, J 8.7, 4.4, C(3)H), 3.39 (1H, d, J 15.0,
NCHAHBPh), 3.67–3.75 (2H, m, C(α)H, NCHAHBPh), 4.83–4.94 (2H, m, C(7)H2), 5.70 (1H, app ddt, J 17.1,
10.3, 6.5, C(6)H), 7.12–7.35 (10H, m, Ph).
tert-Butyl (R,R)-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-enoate 20
BuLi (2.5 M in hexanes, 1.23 mL, 3.08 mmol) was added dropwise via syringe to a stirred solution of (R)-N-
benzyl-N-(α-methylbenzyl)amine (0.67 mL, 3.18 mmol, >99:1 er) in THF (8 mL) at –78 °C. After stirring at
–78 °C for 30 min, a solution of 18 (390 mg, 1.99 mmol, >99:1 dr [(E):(Z)]) in THF (8 mL) at –78 °C was
added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 2 h, then satd aq NH4Cl (10
mL) was added. The resultant mixture was allowed to warm to rt and stirred at rt for 15 min, then
concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 10% aq citric acid (10
mL). The aqueous layer was extracted with CH2Cl2 (2 × 20 mL) and the combined organic extracts were
washed sequentially with satd aq NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), then dried and
concentrated in vacuo to give 20 in >99:1 dr. Purification via flash column chromatography (eluent 30−40
°C petrol/Et2O, 20:1) gave 20 as a pale yellow oil (787 mg, 97%, >99:1 dr); [α]20 +6.5 (c 1.0 in CHCl3);
D
νmax (ATR) 1726 (C=O), 1640 (C=C); δH (400 MHz, CDCl3) 1.37 (3H, d, J 7.0, C(α)Me), 1.43 (9H, s,
CMe3), 1.46–1.63 (4H, m, C(4)H2, C(5)H2), 1.87−2.06 (4H, m, C(2)H2, C(6)H2), 3.31−3.38 (1H, m, C(3)H),
3.52 (1H, d, J 15.0, NCHAHBPh), 3.81−3.87 (2H, m, C(α)H, NCHAHBPh), 4.96−5.05 (2H, m, C(8)H2),
5.79−5.89 (1H, m, C(7)H), 7.25−7.47 (10H, m, Ph); δC (100 MHz, CDCl3) 20.5 (C(α)Me), 26.3 (C(5)), 28.1
(CMe3), 33.0 (C(4)), 33.7 (C(6)), 37.7 (C(2)), 50.1 (C(3)), 53.8 (NCH2Ph), 58.3 (C(α)), 80.0 (CMe3), 114.4
(C(8)), 126.6, 127.0, 128.0, 128.2, 128.3 (o,m,p-Ph), 139.1 (C(7)), 142.0, 140.7 (i-Ph), 172.2 (C(1)); m/z
+
(ESI+) 408 ([M+H]+, 100%); HRMS (ESI+) C27H38NO2 ([M+H]+) requires 408.2897; found 408.2898.
12

ACCEPTED MANUSCRIPT
tert-Butyl (2S,3R,αR)-2-allyl-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-enoate 22
Method A: BuLi (2.3 M in hexanes, 15.5 mL, 35.7 mmol) was added dropwise via syringe to a stirred
solution of (R)-N-benzyl-N-(α-methylbenzyl)amine (7.63 mL, 36.5 mmol, >99:1 er) in PhMe (15 mL) at –78
°C. After stirring at –78 °C for 30 min, a solution of 49 (2.39 g, 10.1 mmol, 73:27 dr [(E):(Z)]) in PhMe (8
mL) at –78 °C was added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 1 h and
then maintained at –30 °C for 2 h before being cooled to –78 °C. THF (80 mL) at –78 °C was added swiftly
via cannula and the resultant mixture was then stirred at –78 °C for 30 min. A solution of 2,6-di-tert-
butylphenol (8.26 g, 40.1 mmol) in THF (30 mL) was added dropwise via cannula and the resultant mixture
was allowed to warm to rt over 30 min then concentrated in vacuo. The residue was partitioned between
CH2Cl2 (60 mL) and 10% aq citric acid (60 mL). The aqueous layer was extracted with CH2Cl2 (2 × 60 mL)
and the combined organic extracts were washed sequentially with satd aq NaHCO3 (180 mL), H2O (180 mL)
and brine (180 mL), then dried and concentrated in vacuo. Purification via flash column chromatography
25
(eluent 30–40 °C petrol/Et O, 100:1) gave 22 as a colourless oil (1.58 g, 35%, >99:1 dr);
+40.4 (c 1.0
[α]D
2
in CHCl3); νmax (ATR) 1723 (C=O), 1641 (C=C); δH (400 MHz, CDCl3) 1.35 (3H, d, J 6.8, C(α)Me), 1.44
(9H, s, CMe3), 1.46–1.70 (4H, m, C(4)H2, C(5)H2), 1.94–2.03 (3H, m, C(6)H2, C(1')HA), 2.18–2.24 (1H, m,
C(1')HB), 2.22–2.28 (1H, m, C(2)H), 2.69–2.74 (1H, m, C(3)H), 3.84 (1H, d, J 15.0, NCHAHBPh), 3.96 (1H,
d, J 15.0, NCHAHBPh), 4.03 (1H, q, J 6.8, C(α)H), 4.91–5.04 (4H, m, C(8)H2, C(3')H2), 5.49–5.63 (1H, m,
C(7)H), 5.76–5.86 (1H, m, C(2')H), 7.24–7.50 (10H, m, Ph); δC (100 MHz, CDCl3) 19.7 (C(α)Me), 27.3
(C(5)), 28.1 (C(1')), 28.2 (CMe3), 30.1 (C(4)), 34.0 (C(6)), 49.7 (C(2)), 51.2 (NCH2Ph)), 59.3 (C(α)), 59.9
(C(3)), 80.3 (CMe3), 114.5 (C(3')), 116.0 (C(8)), 126.5, 126.9, 127.9, 128.0, 128.2, 128.3 (o,m,p-Ph), 136.0
(C(2')), 138.9 (i-Ph), 142.3 (C(7)), 144.8 (i-Ph), 174.4 (C(1)); m/z (ESI+) 448 ([M+H]+, 100%); HRMS
+
(ESI+) C30H42NO2 ([M+H]+) requires 448.3210; found 448.3212.
Method B: BuLi (2.5 M in hexanes, 6.87 mL, 15.8 mmol) was added dropwise via syringe to a stirred
solution of (R)-N-benzyl-N-(α-methylbenzyl)amine (3.40 mL, 16.3 mmol, >99:1 er) in THF (45 mL) at –78
°C. After stirring at –78 °C for 30 min, a solution of 18 (2.00 g, 10.2 mmol, >99:1 dr [(E):(Z)]) in THF (45
mL) at –78 °C was added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 2 h, then
freshly distilled allyl bromide (2.65 mL, 30.6 mmol) was added. The resultant mixture was allowed to warm
to rt and stirred at rt for 12 h, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (50
mL) and 10% aq citric acid (50 mL). The aqueous layer was extracted with CH2Cl2 (2 × 50 mL) and the
combined organic extracts were washed sequentially with satd aq NaHCO3 (50 mL), H2O (50 mL) and brine
13

ACCEPTED MANUSCRIPT
(50 mL), then dried and concentrated in vacuo to give a 65:35 mixture of 22 and 23, respectively.
Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave an inseparable
65:35 mixture of 22 and 23, respectively, as a colourless oil (2.90 g, 64%). Data for mixture: νmax (ATR)
+
1723 (C=O), 1641 (C=C); m/z (ESI+) 448 ([M+H]+, 100%); HRMS (ESI+) C30H42NO2 ([M+H]+) requires
448.3210; found 448.3212. Data for 23: δH (400 MHz, CDCl3) [selected peaks] 1.20 (3H, d, J 7.0, C(α)Me),
1.33 (9H, s, CMe3) 2.89–2.95 (1H, m, C(3)H), 3.68–3.72 (2H, m, NCH2Ph), 4.91–5.04 (4H, m, C(8)H2,
C(3')H2), 5.49–5.63 (1H, m, C(7)H), 5.76–5.86 (1H, m, C(2')H), 7.24–7.50 (10H, m, Ph); δC (100 MHz,
CDCl3) [selected peaks] 28.1 (CMe3), 79.8 (CMe3), 114.6 (C(3')), 115.4 (C(8)), 135.0 (C(2')), 137.9 (C(7)),
142.1, 144.6 (i-Ph), 174.0 (C(1)). Further elution gave 22 as a colourless oil (232 mg, 5%, >99:1 dr); [α]D20
+36.5 (c 1.0 in CHCl3).
tert-Butyl (2S,3R,αR) 2-(4-iodobut-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]hept-6-enoate 24 and
tert-butyl (R,R,R) 2-(4-iodobut-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]hept-6-enoate 25
BuLi (2.5 M in hexanes, 6.84 mL, 17.1 mmol) was added dropwise via syringe to a stirred solution of (R)-N-
benzyl-N-(α-methylbenzyl)amine (3.68 mL, 17.6 mmol, >99:1 er) in THF (40 mL) at –78 °C. After stirring
at –78 °C for 30 min, a solution of 8 (2.00 g, 11.0 mmol, >99:1 dr [(E):(Z)]) in THF (40 mL) at –78 °C was
added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 2 h, then 1,4-diiodobutane
(7.26 mL, 55.0 mmol) was added. The resultant mixture was allowed to warm to rt and stirred at rt for 12 h,
then concentrated in vacuo. The residue was partitioned between CH2Cl2 (50 mL) and 10% aq citric acid (50
mL). The aqueous layer was extracted with CH2Cl2 (2 × 50 mL) and the combined organic extracts were
washed sequentially with satd aq NaHCO3 (50 mL), H2O (50 mL) and brine (50 mL), then dried and
concentrated in vacuo to give a 60:40 mixture of 24 and 25, respectively. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave 24 as a pale yellow oil (2.30 g, 36%, >99:1 dr);
[α]20 +12.7 (c 1.0 in CHCl3); νmax (ATR) 1721 (C=O), 1640 (C=C); δH (400 MHz, CDCl3) 0.95–1.04 (1H,
D
m, C(2')HA), 1.06–1.21 (3H, m, C(1')H2, C(2')HB), 1.24 (3H, d, J 6.8, C(α)Me), 1.35 (9H, s, CMe3), 1.41–
1.49 (1H, m, C(4)HA), 1.54–1.63 (3H, m, C(4)HB, C(3')H2), 1.91–1.98 (1H, m, C(5)HA), 2.12–2.17 (1H, m,
C(2)H), 2.19–2.26 (1H, m, C(5)HB), 2.68–2.72 (1H, m, C(3)H), 3.00 (2H, t, J 6.9, C(4')H2), 3.74 (1H, d, J
14.9, NCHAHBPh), 3.84 (1H, d, J 14.9, NCHAHBPh), 3.91 (1H, q, J 6.8, C(α)H), 4.84–4.91 (2H, m, C(7)H2),
5.63–5.71 (1H, m, C(6)H), 7.15–7.29 (10H, m, Ph); δC (100 MHz, CDCl3) 6.9 (C(4')), 19.4 (C(α)Me), 28.1
(CMe3), 28.2 (C(2')), 29.8 (C(4)), 30.7 (C(1')), 32.1 (C(5)), 33.2 (C(3')), 49.8 (C(2)), 51.3 (NCH2Ph), 58.7
14

ACCEPTED MANUSCRIPT
(C(α)), 59.8 (C(3)), 80.3 (CMe3), 114.4 (C(7)), 138.9 (C(6)), 126.6, 126.7, 127.9, 128.2, 128.3 (o,m,p-Ph),
+
142.1, 144.6 (i-Ph), 174.9 (C(1)); m/z (ESI+) 576 ([M+H]+, 100%); HRMS (ESI+) C30H43INO2 ([M+H]+)
requires 576.2333; found 576.2333. Further elution gave an inseparable 50:50 mixture of 24 and 25 as a
colourless oil (2.13 g, 34%). Further elution gave 25 as a pale yellow oil (289 mg, 5%, >99:1 dr); [α]D20
+17.2 (c 1.0 in CHCl3); νmax (ATR) 1721 (C=O), 1640 (C=C); δH (400 MHz, CDCl3) 0.79–0.86 (1H, m,
C(2')HA), 0.90–0.99 (1H, m, C(2')HB), 1.10–1.19 (2H, m, C(1')H2), 1.23 (3H, d, J 6.9, C(α)Me), 1.35 (9H, s,
CMe3), 1.53–1.63 (4H, m, C(4)H2, C(3')H2), 1.99–2.10 (2H, m, C(5)H2), 2.19–2.23 (1H, m, C(2)H), 2.88–
2.23 (1H, m, C(3)H), 2.98 (2H, t, J 7.0, C(4')H2), 3.70 (1H, d, J 14.3 NCHAHBPh), 3.76 (1H, d, J 14.3
NCHAHBPh), 3.88 (1H, q, J 6.9, C(α)H), 4.86–4.98 (2H, m, C(7)H2), 5.65–5.80 (1H, m, C(6)H), 7.11–7.38
(10H, m, Ph); δC (100 MHz, CDCl3) 6.9 (C(4')), 16.8 (C(α)Me), 28.1 (CMe3), 28.2 (C(2')), 28.7 (C(4)), 29.1
(C(1')), 32.1 (C(5)), 33.4 (C(3')), 48.6 (C(2)), 50.9 (NCH2Ph), 58.4 (C(α)), 58.6 (C(3)), 80.3 (CMe3), 114.7
(C(7)), 138.6 (C(6)), 126.6, 126.9, 127.9, 128.2, 128.3 (o,m,p-Ph), 142.0, 144.4 (i-Ph), 174.4 (C(1)); m/z
(ESI+) 576 ([M+H]+, 100%); HRMS (ESI+) C30H43INO2 ([M+H]+) requires 576.2333; found 576.2333.
+
tert-Butyl (2S,3R,αR)-2-(4'-iodobut-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-enoate 26 and
tert-butyl (R,R,R)-2-(4'-iodobut-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-enoate 27
BuLi (2.5 M in hexanes, 6.09 mL, 14.0 mmol) was added dropwise via syringe to a stirred solution of (R)-N-
benzyl-N-(α-methylbenzyl)amine (3.01 mL, 14.4 mmol, >99:1 er) in THF (40 mL) at –78 °C. After stirring
at –78 °C for 30 min a solution of 18 (1.77 g, 9.00 mmol, >99:1 dr [(E):(Z)]) in THF (40 mL) at –78 °C was
added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 2 h, then 1,4-diiodobutane
(5.94 mL, 45.0 mmol) was added. The resultant mixture was allowed to warm to rt and stirred at rt for 12 h,
then concentrated in vacuo. The residue was partitioned between Et2O (60 mL) and 10% aq citric acid (60
mL). The aqueous layer was extracted with Et2O (2 × 80 mL) and the combined organic extracts were
washed sequentially with satd aq NaHCO3 (80 mL), H2O (80 mL) and brine (80 mL), then dried and
concentrated in vacuo to give a 63:37 mixture of 26 and 27, respectively. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave 27 as a colourless oil (425 mg, 8%, 95:5 dr);
[α]20 +15.9 (c 1.0 in CHCl3); νmax (ATR) 1722 (C=O), 1634 (C=C); δH (400 MHz, CDCl3) 0.87−0.90 (1H,
D
m, C(1')HA), 1.00−1.09 (1H, m, C(1')HB), 1.30 (3H, d, J 6.9, C(α)Me), 1.44 (9H, s, CMe3), 1.46−1.69 (8H,
m, C(4)H2, C(5)H2, C(2')H2, C(3')H2), 1.97−2.02 (2H, m, C(6)H2), 2.27−2.32 (1H, m, C(2)H), 2.92−2.95
(1H, m, C(3)H), 3.07 (2H, t, J 7.0, C(4')H2), 3.77 (1H, d, J 14.3, NCHAHBPh), 3.83 (1H, d, J 14.3,
15

ACCEPTED MANUSCRIPT
NCHAHBPh), 3.96 (1H, q, J 6.9, C(α)H), 4.97−5.04 (2H, m, C(8)H2), 5.76−5.86 (1H, m, C(7)H), 7.18−7.48
(10H, m, Ph); δC (100 MHz, CDCl3) 6.9 (C(4')), 16.8 (C(α)Me), 27.3 (C(1')), 28.2 (CMe3), 28.8 (C(2')), 29.7
(C(5)), 33.4 (C(4)), 34.0 (C(3')), 35.6 (C(6)), 48.9 (C(2)), 52.5 (NCH2Ph), 58.5 (C(α)), 59.2 (C(3)), 80.2
(CMe3), 114.5 (C(8)), 126.5, 126.7, 127.8, 128.0, 128.4, 128.7 (o,m,p-Ph), 138.7 (C(7)), 143.7, 144.4 (i-Ph),
+
174.5 (C(1)); m/z (ESI+) 590 ([M+H]+, 100%); HRMS (ESI+) C31H45INO2 ([M+H]+) requires 590.2489;
found 590.2473. Further elution gave various mixed fractions of 26 and 27 as colourless oils (1.08 g, 20%).
Further elution gave 26 as a colourless oil (962 mg, 18%, 89:11 dr); [α]2D0 +23.9 (c 1.0 in CHCl3); νmax
(ATR) 1722 (C=O), 1636 (C=C); δH (400 MHz, CDCl3) 1.04−1.29 (2H, m, C(1')H2), 1.32 (3H, d, J 6.9,
C(α)Me), 1.35−1.41 (1H, m, C(5)HA), 1.43 (9H, s, CMe3), 1.55−1.70 (7H, m, C(4)H2, C(5)HB, C(2')H2,
C(3')H2), 1.94−2.00 (2H, m, C(6)H2), 2.23 (1H, ddd, J 10.6, 7.0, 3.7, C(2)H), 2.76 (1H, td, J 7.0, 3.7,
C(3)H), 3.09 (2H, t, J 6.9, C(4')H2), 3.81 (1H, d, J 14.9, NCHAHBPh), 3.92 (1H, d, J 14.9, NCHAHBPh), 3.99
(1H, q, J 6.9, C(α)H), 4.94−5.02 (1H, m, C(8)H2), 5.74−5.84 (1H, m, C(7)H), 7.23−7.37 (10H, m, Ph); δC
(100 MHz, CDCl3) 6.9 (C(4')), 19.4 (C(α)Me), 27.3 (C(5)), 28.0 (CMe3), 28.2 (C(1')), 30.2 (C(2')), 30.6
(C(3')), 33.2 (C(4)), 34.1 (C(6)), 50.0 (C(2)), 51.3 (NCH2Ph), 58.8 (C(α)), 60.1 (C(3)), 80.2 (CMe3), 114.5
(C(8)), 126.5, 126.9, 127.8, 128.1, 128.2, 128.3 (o,m,p-Ph), 138.8 (C(7)), 142.2, 144.7 (i-Ph), 174.9 (C(1));
m/z (ESI+) 590 ([M+H]+, 100%); HRMS (ESI+) C31H45INO2 ([M+H]+) requires 590.2489; found 590.2474.
+
tert-Butyl (2S,3R,αR)-2-(but-3'-en-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]hept-6-enoate 28
Method A: BuLi (2.3 M in hexanes, 21.5 mL, 49.5 mmol) was added dropwise via syringe to a stirred
solution of (R)-N-benzyl-N-(α-methylbenzyl)amine (10.6 mL, 50.5 mmol, >99:1 er) in PhMe (21 mL) at –78
°C. After stirring at –78 °C for 30 min, a solution of 48 (3.40 g, 14.4 mmol, 71:29 dr [(E):(Z)]) in PhMe (11
mL) at –78 °C was added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 1 h and
then maintained at –30 °C for 2 h before being cooled to –78 °C. THF (110 mL) at –78 °C was added swiftly
via cannula and the reaction mixture was then stirred at –78 °C for 30 min. A solution of 2,6-di-tert-
butylphenol (11.5 g, 55.6 mmol) in THF (40 mL) was added dropwise via cannula and the resultant mixture
was allowed to warm to rt and stirred at rt for 30 min, then concentrated in vacuo. The residue was
partitioned between CH2Cl2 (80 mL) and 10% aq citric acid (80 mL). The aqueous layer was extracted with
CH2Cl2 (2 × 80 mL) and the combined organic extracts were washed sequentially with satd aq NaHCO3 (240
mL), H2O (240 mL) and brine (240 mL), then dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave 28 as a colourless oil (3.48 g, 54%, >99:1 dr);
16

ACCEPTED MANUSCRIPT
[α]2D5
+43.7 (c 1.0 in CHCl3); νmax (ATR) 1721 (C=O), 1640 (C=C); δH (400 MHz, CDCl3) 1.27 (3H, d, J
6.8, C(α)Me), 1.30–1.38 (2H, m, C(1')H2), 1.40 (9H, s, CMe3), 1.48–1.55 (1H, m, C(4)HA), 1.58–1.65 (1H,
m, C(4)HB), 1.66–1.73 (1H, m, C(2')HA), 1.83–1.89 (1H, m, C(2')HB), 1.95–2.01 (1H, m, C(5)HA), 2.24–
2.31 (2H, m, C(2)H, C(5)HB), 2.76 (1H, ddd, J 8.5, 6.0, 3.9, C(3)H), 3.78 (1H, d, J 15.1, NCHAHBPh), 3.90
(1H, d, J 15.1, NCHAHBPh), 3.97 (1H, q, J 6.8, C(α)H), 4.87–4.94 (4H, m, C(7)H2, C(4')H2), 5.61–5.74 (2H,
m, C(6)H, C(3')H), 7.18–7.35 (10H, m, Ph); δC (100 MHz, CDCl3) 20.0 (C(α)Me), 28.0 (CMe3), 29.7 (C(4)),
31.3 (C(1')), 31.6 (C(2')), 32.1 (C(5)), 49.0 (C(2)), 51.2 (NCH2Ph), 59.2 (C(α)), 60.2 (C(3)), 80.2 (CMe3),
114.3 (C(4')), 114.8 (C(7)), 126.5, 126.9, 127.9, 128.2 (o,m,p-Ph), 138.1 (C(3')), 138.9 (C(6)), 142.4, 144.6
+
(i-Ph), 174.9 (C(1)); m/z (ESI+) 448 ([M+H]+, 100%); HRMS (ESI+) C30H42NO2 ([M+H]+) requires
448.3210; found 448.3205.
Method B: KHMDS (0.7 M in PhMe, 24.9 mL, 17.4 mmol) was added to a solution of freshly distilled
tBuOH (1.66 mL, 17.4 mmol) in THF (75 mL) at rt. The resultant mixture was stirred at rt for 15 min, then a
solution of 24 (2.00 g, 3.48 mmol, >99:1 dr) in THF (75 mL) was added. The resultant mixture was left to
stir at rt for 16 h, then concentrated in vacuo. The residue was partitioned between satd aq NH4Cl (40 mL)
and Et2O (40 mL), and the aqueous layer was extracted with Et2O (2 × 30 mL). The combined organic
extracts were washed with satd aq NaHCO3 (40 mL) and brine (40 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave an
inseparable 65:35 mixture of 28 and 29, respectively, as a colourless oil (1.32 g, 85%). Data for mixture:
νmax(ATR) 1721 (C=O), 1639 (C=C); m/z (ESI+) 448 ([M+H]+, 100%); HRMS (ESI+) C30H42NO2 ([M+H]+)
+
requires 448.3210; found 448.3211. Data for 29: δH (400 MHz, CDCl3) [selected peaks] 1.21 (3H, d, J 7.0,
C(α)Me), 1.35 (9H, s, CMe3), 2.90–2.94 (1H, m, C(3)H), 3.64 (1H, d, J 14.4, NCHAHBPh), 3.78 (1H, d, J
14.4, NCHAHBPh), 4.81–4.94 (4H, m, C(7)H2, C(4')H2), 5.33–5.72 (2H, m, C(6)H, C(3')H), 7.11–7.38 (10H,
m, Ph); δC (100 MHz, CDCl3) [selected peaks] 28.1 (CMe3), 59.2 (C(3)), 80.1 (CMe3), 114.1 (C(4')), 114.6
(C(7)), 138.2 (C(3')), 138.7 (C(6)), 141.7, 144.0 (i-Ph), 174.7 (C(1)).
Method C: KHMDS (0.7 M in PhMe, 3.23 mL, 2.26 mmol) was added to a solution of freshly distilled
tBuOH (0.22 mL, 2.26 mmol) in THF (9 mL) at rt. The resultant mixture was stirred at rt for 15 min, then a
solution of 25 (260 mg, 0.45 mmol, >99:1 dr) in THF (9 mL) was added. The resultant mixture was left to
stir at rt for 16 h, then concentrated in vacuo. The residue was partitioned between satd aq NH4Cl (10 mL)
and Et2O (10 mL), and the aqueous layer was extracted with Et2O (2 × 10 mL). The combined organic
extracts were washed with satd aq NaHCO3 (10 mL) and brine (10 mL), then dried and concentrated in
17

ACCEPTED MANUSCRIPT
vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave an
inseparable 65:35 mixture of 28 and 29, respectively, as a colourless oil (162 mg, 80%).
(2S,3R,αR)-2-(4'-Iodobut-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]hept-6-en-1-ol 30
DIBAL-H (1.0 M in PhMe, 2.08 mL, 2.08 mmol) was added to a stirred solution of 24 (600 mg, 1.04 mmol,
>99:1 dr) in PhMe (18 mL) at 0 °C. The resultant mixture was allowed to stir at 0 °C for 4 h, then 2.0 M aq
NaOH (1.04 mL, 2.08 mmol) was added and the resultant mixture was allowed to warm to rt and stirred at rt
for 2 h. The reaction mixture was then filtered through Celite® (eluent THF), dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/EtOAc, 20:1) gave 30 as a
pale yellow oil (295 mg, 72%, >99:1 dr); [α]2D0 –13.1 (c 1.0 in CHCl3); νmax (ATR) 3416 (O–H), 1639
(C=C); δH (400 MHz, CDCl3) 1.17−1.37 (2H, m, C(2')H2), 1.41 (3H, d, 7.0, C(α)Me), 1.44−1.60 (2H, m,
C(1')H2), 1.75−1.85 (5H, m, C(4)HA, C(5)H2, C(3')H2), 2.00−2.18 (2H, m, C(2)H, C(4)HB), 2.80 (1H, br s,
OH), 2.92−2.94 (1H, m, C(3)H), 3.02−3.06 (1H, m, C(1)HA), 3.10−3.20 (2H, m, C(4')H2), 3.39−3.42 (1H,
m, C(1)HB), 3.76 (1H, d, J 13.6, NCHAHBPh), 3.89−3.95 (1H, m, C(α)H), 3.94 (1H, d, J 13.6, NCHAHBPh),
5.04−5.11 (2H, m, C(7)H2), 5.83−5.94 (1H, m, C(6)H), 7.23−7.45 (10H, m, Ph); δC (100 MHz, CDCl3) 6.9
(C(4')), 12.7 (C(1')), 23.9 (C(α)Me), 28.0 (C(2')), 29.2 (C(5)), 31.9 (C(4)), 33.7 (C(3')), 41.9 (C(2)), 52.5
(NCH2Ph), 57.0 (C(3)), 57.4 (C(α)), 63.4 (C(1)), 115.2 (C(7)), 127.2, 128.1, 128.5, 128.6, 128.9 (o,m,p-Ph),
138.2 (C(6)), 140.4, 143.1 (i-Ph); m/z (ESI+) 506 ([M+H]+, 100%); HRMS (ESI+) C26H37INO+ ([M+H]+)
requires 506.1914; found 506.1914.
(2S,3R,αR)-2-(4'-Iodobut-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-en-1-ol 31
DIBAL-H (1.0 M in PhMe, 4.66 mL, 4.66 mmol) was added to a stirred solution of 26 (920 mg, 1.55 mmol,
89:11 dr) in PhMe (30 mL) at 0 °C. The resultant mixture was allowed to stir at 0 °C for 4 h, then 2.0 M aq
NaOH (2.33 mL, 4.66 mmol) was added and the resultant mixture was allowed to warm to rt and stirred at rt
for 2 h. The reaction mixture was then filtered through Celite® (eluent THF), dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/EtOAc, 20:1) gave 31 as a
pale yellow oil (694 mg, 86%, 89:11 dr); [α]2D0 –28.0 (c 0.5 in CHCl3); νmax (ATR) 3412 (O–H), 1639
(C=C); δH (400 MHz, CDCl3) 1.16–1.23 (1H, m, C(2')HA), 1.34–1.38 (1H, m, C(2)H), 1.40 (3H, d, J 7.0,
C(α)Me), 1.43–1.59 (5H, m, C(1')H2, C(5)H2, C(2')HB), 1.64–1.73 (2H, m, C(4)H2), 1.74–1.85 (2H, m,
C(3')H2), 2.13 (2H, app q, J 7.1, C(6)H2), 2.94–3.00 (1H, m, C(3)H), 3.12–3.17 (2H, m, C(4')H2), 3.76 (1H,
18

ACCEPTED MANUSCRIPT
d, J 13.7, NCHAHBPh), 3.88–3.98 (2H, m, C(α)H, NCHAHBPh), 4.11–4.16 (2H, m, C(1)H2), 5.03–5.12 (2H,
m, C(8)H2), 5.87 (1H, app ddt, J 17.0, 10.2, 6.6, C(7)H), 7.24–7.46 (10H, m, Ph); δC (100 MHz, CDCl3)
7.00 (C(4')), 14.2 (C(α)Me), 21.1 (C(5)), 24.1 (C(1')), 28.1 (C(4)), 29.3 (C(2')), 33.8 (C(3')), 34.0 (C(6)),
42.2 (C(2)), 52.5 (NCH2Ph), 57.4 (C(α)), 57.8 (C(3)), 60.4 (C(1)), 114.9 (C(8)), 127.2, 127.3, 128.1, 128.5,
128.6, 129.0 (o,m,p-Ph), 138.6 (C(7)), 140.7, 143.3 (i-Ph); m/z (ESI+) 520 ([M+H]+, 100%); HRMS (ESI+)
C27H39INO+ ([M+H]+) requires 520.2071; found 520.2054.
(2S,3R,αR)-2-(But-3'-en-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]hept-6-en-1-ol 32
KHMDS (0.7 M PhMe, 3.54 mL, 2.48 mmol) was added to a stirred solution of freshly distilled tBuOH (0.24
mL, 2.48 mmol) in THF (12 mL) at rt. The resultant mixture was stirred at rt for 15 min, then a solution of
30 (250 mg, 0.50 mmol, >99:1 dr) in THF (12 mL) was added. The resultant mixture was left to stir at rt for
16 h, then concentrated in vacuo. The residue was partitioned between satd aq NH4Cl (20 mL) and Et2O (20
mL), and the aqueous layer was extracted with Et2O (2 × 20 mL). The combined organic extracts were
washed with satd aq NaHCO3 (20 mL) and brine (20 mL), then dried and concentrated in vacuo. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave 32 as a pale yellow oil (101 mg,
56%, >99:1 dr); [α]20 –17.2 (c 0.5 in CHCl3); νmax (ATR) 3420 (O–H), 1639 (C=C); δH (400 MHz, CDCl3)
D
1.18−1.27 (1H, m, C(2)H), 1.41 (3H, d, J 6.8, C(α)Me), 1.52−1.61 (2H, m, C(4)H2), 1.66−1.78 (1H, m,
C(1')HA), 1.79−1.91 (2H, m, C(1')HB, C(2')HA), 1.97−2.06 (1H, m, C(5)HA), 2.09−2.23 (2H, m, C(5)HB,
C(2')HB), 2.88–2.93 (1H, m, C(3)H), 3.05−3.13 (1H, m, C(1)HA), 3.40−3.51 (1H, m, C(1)HB), 3.71−3.98
(3H, m, C(α)H, NCH2Ph), 4.84−5.15 (4H, m, C(7)H2, C(4')H2), 5.53−6.01 (2H, m, C(6)H, C(3')H),
7.23−7.45 (10H, m, Ph); δC (100 MHz, CDCl3) 13.7 (C(α)Me), 24.0 (C(4)), 27.3 (C(1')), 31.8 (C(5)), 32.3
(C(2')), 40.9 (C(2)), 52.5 (NCH2Ph), 57.1 (C(α)), 57.3 (C(3)), 63.9 (C(1)), 114.9 (C(4')), 115.1 (C(7)), 127.2,
128.1, 128.4, 128.6, 129.0, 129.2 (o,m,p-Ph), 138.3 (C(3')), 138.7 (C(6)), 140.5, 143.2 (i-Ph); m/z (ESI+) 378
([M+H]+, 100%); HRMS (ESI+) C26H36NO+ ([M+H]+) requires 378.2791; found 378.2794.
(2S,3R,αR)-2-Allyl-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-en-1-ol 33
LiAlH4 (1.0 M in THF, 2.57 mL, 2.57 mmol) was added to a stirred solution of 22 (230 mg, 0.51 mmol,
>99:1 dr) in THF (7 mL) at –78 °C. The resultant mixture was allowed to warm to rt and stirred at rt for 18
h. 2.0 M aq NaOH (1.29 mL, 2.57 mmol) was then added and the resultant mixture was stirred at rt for 2 h.
The reaction mixture was filtered through Celite® (eluent THF), then dried and concentrated in vacuo.
19

ACCEPTED MANUSCRIPT
Purification via flash column chromatography (eluent 30–40 °C petrol/EtOAc, 20:1) gave 33 as a pale
yellow oil (93 mg, 48%, >99:1 dr); [α]20 –23.0 (c 0.5 in CHCl3); νmax (ATR) 3443, (O–H), 1640 (C=C); δH
D
(400 MHz, CDCl3) 1.30–1.33 (3H, m, C(α)Me), 1.36–1.55 (2H, m, C(4)H2), 1.59–1.77 (2H, m, C(5)H2),
1.89–2.26 (5H, m, C(2)H, C(6)H2, C(1')H2), 2.40 (1H, br s, OH), 2.86–2.94 (1H, m, C(1)HA), 3.25–3.37 (1H,
m, C(1)HB), 3.49–3.52 (1H, m, C(3)H), 3.66–3.70 (1H, m, NCHAHBPh), 3.81–3.85 (1H, m, NCHAHBPh),
3.90 (1H, q, J 6.9, C(α)H), 4.83–5.04 (4H, C(8)H2, C(3')H2), 5.48–5.61 (1H, m, C(7)H), 5.66–5.84 (1H, m,
C(2')H), 7.13–7.51 (10H, m, Ph); δC (100 MHz, CDCl3) 27.2 (C(α)Me), 28.3 (C(5)), 34.0 (C(1')), 34.4
(C(4)), 38.7 (C(6)), 42.4 (C(2)), 51.0 (C(1)), 52.3 (NCH2Ph), 56.8 (C(3)), 63.4 (C(α)), 114.9 (C(3')), 117.6
(C(8)), 127.1, 128.1, 128.4, 128.5, 128.8, 129.3 (o,m,p-Ph), 134.4 (C(2')), 137.9 (C(7)), 138.4, 138.5 (i-Ph);
m/z (ESI+) 378 ([M+H]+, 100%); HRMS (ESI+) C26H36NO+ ([M+H]+) requires 378.2791; found 378.2791.
(2S,3R,αR)-2-(But-3'-en-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-en-1-ol 34
t
KHMDS (0.5 M in PhMe, 12.9 mL, 6.45 mmol) was added to a stirred solution of freshly distilled BuOH
(0.62 mL, 6.5 mmol) in THF (25 mL) at rt. The resultant mixture was stirred at rt for 15 min, then a solution
of 31 (670 mg, 1.29 mmol, 89:11 dr) in THF (25 mL) was added. The resultant solution was left to stir at rt
for 16 h, then concentrated in vacuo. The residue was partitioned between satd aq NH4Cl (30 mL) and Et2O
(30 mL), and the aqueous layer was extracted with Et2O (2 × 30 mL). The combined organic extracts were
washed with satd aq NaHCO3 (30 mL) and brine (30 mL), then dried and concentrated in vacuo to give 34 in
95:5 dr. Purification via flash column chromatography (eluent 30–40 °C petrol/EtOAc, 20:1) gave 34 as a
colourless oil (167 mg, 33%, 95:5 dr); [α]20 –30.6 (c 0.5 in CHCl3); νmax (ATR) 3420 (O–H), 1640 (C=C);
D
δH (400 MHz, CDCl3) 1.35 (3H, d, J 6.9, C(α)Me), 1.39–1.45 (3H, m, C(2)H, C(5)H2), 1.47–1.54 (1H, m,
C(1')HA), 1.57–1.75 (3H, m, C(4)H2, C(1')HB), 1.83 (1H, app dq, J 14.7, 7.5, C(2')HA), 2.05–2.10 (2H, m,
C(6)H2), 2.12–2.19 (1H, m, C(2')HB), 2.85–2.88 (1H, m, C(1)HA), 2.94–2.97 (1H, m, C(3)H), 3.34–3.38
(1H, m, C(1)HB), 3.67–3.71 (1H, d, J 13.7, NCHAHBPh), 3.87–3.92 (2H, m, C(α)H, NCHAHBPh), 4.88–5.06
(4H, m, C(8)H2, C(4')H2), 5.66–5.86 (2H, m, C(7)H, C(3')H), 7.19–7.42 (10H, m, Ph); δC (100 MHz, CDCl3)
12.5 (C(α)Me), 24.0 (C(1')), 27.0 (C(5)), 27.9 (C(4)), 32.2 (C(2')), 33.4 (C(6)), 41.1 (C(2)), 52.4 (NCH2Ph),
57.1 (C(α)), 57.8 (C(3)), 63.3 (C(1)), 114.7 (C(8)), 114.8 (C(4')), 127.0, 127.2, 128.0, 128.5, 128.9 (o,m,p-
Ph), 138.5 (C(7)), 138.7 (C(3')), 140.5, 143.1 (i-Ph); m/z (ESI+) 392 ([M+H]+, 100%); HRMS (ESI+)
C27H38NO+ ([M+H]+) requires 392.2948; found 392.2936.
20

ACCEPTED MANUSCRIPT
tert-Butyl 2-(diethoxyphosphoryl)pent-4-enoate 45
A solution of 44 (20.0 g, 79.4 mmol) in THF (60 mL) was added dropwise via cannula to a stirred solution
of NaH (60% in mineral oil, 3.49 g, 87.3 mmol) in THF (530 mL) at rt. The resultant mixture was stirred at
rt for 1 h, then a solution of freshly distilled allyl bromide (3.40 mL, 39.7 mmol) in THF (60 mL) at rt was
added dropwise via cannula. The resultant mixture was heated at reflux for 36 h then allowed to cool to rt
before H2O (250 mL) was added. The aqueous layer was extracted with Et2O (2 × 350 mL) and the
combined organic extracts were dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/EtOAc, 1:1) gave 45 as a colourless oil (8.08 g, 70%); νmax (ATR)
1728 (C=O), 1643 (C=C); δH (400 MHz, CDCl3) 1.28–1.32 (6H, m, P(OCH2Me)2), 1.42 (9H, s, CMe3),
2.48–2.66 (2H, m, C(3)H2), 2.85–2.92 (1H, m, C(2)H), 4.08–4.15 (4H, m, P(OCH2Me)2), 4.99–5.09 (2H, m,
C(5)H2), 5.73 (1H, ddt, J 16.9, 10.2, 6.7, C(4)H); δC (100 MHz, CDCl3) 16.2 (d, J 1.9, P(OCH2Me)), 16.3 (d,
J 2.9, P(OCH2Me)), 27.8 (CMe3), 30.9 (d, J 4.8, C(3)), 46.1 (d, J 129.7, C(2)), 62.4 (d, J 7.6, P(OCH2Me)),
62.5 (d, J 5.7, P(OCH2Me)), 81.7 (CMe3), 116.8 (C(5)), 134.7 (d, J 17.2, C(4)), 167.5 (d, J 4.8, C(1)); m/z
(ESI+) 315 ([M+Na]+, 100%); HRMS (ESI+) C13H25NaO5P+ ([M+Na]+) requires 315.1332; found 315.1331.
tert-Butyl 2-(diethoxyphosphoryl)hex-5-enoate 46
A solution of 44 (20.0 g, 79.4 mmol) in THF (60 mL) was added dropwise via cannula to a stirred solution
of NaH (60% in mineral oil, 3.49 g, 87.3 mmol) in THF (530 mL) at rt. The resultant mixture was stirred at
rt for 1 h, then a solution of freshly distilled but-3-enyl bromide (4.03 mL, 39.7 mmol) in THF (60 mL) at
rt was added dropwise via cannula. The resultant mixture was heated at reflux for 36 h then allowed to cool
to rt before H2O (250 mL) was added. The aqueous layer was extracted with Et2O (2 × 350 mL) and the
combined organic extracts were dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/EtOAc, 1:1) gave 46 as a colourless oil (9.12 g, 75%); νmax (ATR)
1728 (C=O), 1642 (C=C); δH (400 MHz, CDCl3) 1.30–1.34 (6H, m, P(OCH2Me)2), 1.47 (9H, s, CMe3),
1.83–1.92 (1H, m, C(3)HA), 2.00–2.08 (2H, m, C(3)HB, C(4)HA), 2.14–2.19 (1H, m, C(4)HB), 2.83–2.90
(1H, m, C(2)H), 4.10–4.17 (4H, m, P(OCH2Me)2), 4.99–5.05 (2H, m, C(6)H2), 5.75 (1H, ddt, J 17.0, 10.3,
6.6, C(5)H); δC (100 MHz, CDCl3) 16.3 (d, J 2.9, P(OCH2Me)), 16.4 (d, J 2.9, P(OCH2Me)), 26.1 (d, J 4.8,
C(3)), 27.9 (CMe3), 32.2 (d, J 16.2, C(4)), 45.7 (d, J 130.7, C(2)), 62.4 (d, J 3.8, P(OCH2Me)), 62.5 (d, J 3.8,
P(OCH2Me)), 81.7 (CMe3), 116.0 (C(6)), 136.8 (C(5)), 168.1 (d, J 4.8, C(1)); m/z (ESI+) 329 ([M+Na]+,
100%); HRMS (ESI+) C14H27NaO5P+ ([M+Na]+) requires 329.1488; found 329.1487.
21

ACCEPTED MANUSCRIPT
tert-Butyl (E)-2-allyl-hepta-2,6-dienoate 47
MeMgBr (2.9 M in Et2O, 3.33 mL, 9.66 mmol) was added dropwise to a stirred solution of 45 (2.92 g, 10.0
mmol) in THF (130 mL) at rt. The resultant mixture was stirred at rt for 15 min, then 16 (1.10 mL, 11.2
mmol) was added. The resultant mixture was heated at reflux for 3 h, then the reaction mixture was allowed
to cool to rt and partitioned between satd aq NH4Cl (150 mL) and Et2O (150 mL). The aqueous layer was
extracted with EtOAc (2 × 150 mL), and the combined organic extracts were washed with brine, then dried
and concentrated in vacuo to give 47 in 76:24 dr [(E):(Z)]. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O, 100:1) gave 47 as a yellow oil (1.80 g, 81%, 76:24 dr [(E):(Z)]). Data for
mixture: νmax (ATR) 1710 (C=O), 1640 (C=C); m/z (ESI+) 245 ([M+Na]+, 100%); HRMS (ESI+)
+
C14H22NaO2 ([M+Na]+) requires 245.1512; found 245.1513. Data for major diastereoisomer: δH (400 MHz,
CDCl3) 1.45 (9H, s, CMe3), 2.13–2.18 (2H, m, C(5)H2), 2.21–2.26 (2H, m, C(4)H2), 3.00 (2H, d, J 5.9,
C(1')H2), 4.93–5.04 (4H, m, C(7)H2, C(3')H2), 5.72–5.83 (2H, m, C(6)H, C(2')H), 6.71 (1H, t, J 7.2, C(3)H);
δC (100 MHz, CDCl3) 27.8 (C(4)), 28.0 (CMe3), 30.9 (C(1')), 32.6 (C(5)), 80.0 (CMe3), 114.7 (C(3')), 115.2
(C(7)), 131.6 (C(2)), 135.6 (C(2')), 137.4 (C(6)), 141.4 (C(3)), 166.6 (C(1)). Data for minor diastereoisomer:
δH (400 MHz, CDCl3) 1.49 (9H, s, CMe3), 2.17 (2H, app q, J 7.0, C(5)H2), 2.52 (2H, app q, J 7.3, C(4)H2),
2.96 (2H, d, J 6.6, C(1')H2), 4.97–5.07 (4H, m, C(7)H2, C(3')H2), 5.77–5.87 (3H, m, C(3)H, C(6)H, C(2')H);
δC (100 MHz, CDCl3) 28.2 (CMe3), 28.7 (C(4)), 33.4 (C(5)), 38.9 (C(1')), 80.6 (CMe3), 114.9 (C(7)), 115.9
(C(3')), 132.1 (C(2)), 136.2 (C(2')), 137.9 (C(6)), 139.9 (C(3)), 167.1 (C(1)).
tert-Butyl (E)-2-(but-3'-en-1'-yl)hepta-2,6-dienoate 48
MeMgBr (2.9 M in Et2O, 3.33 mL, 9.66 mmol) was added dropwise to a stirred solution of 46 (2.92 g, 10.0
mmol) in THF (130 mL) at rt. The resultant mixture was stirred at rt for 15 min, then 16 (1.10 mL, 11.2
mmol) was added. The resultant mixture was heated at reflux for 3 h, then the reaction mixture was allowed
to cool to rt and partitioned between satd aq NH4Cl (150 mL) and Et2O (150 mL). The aqueous layer was
extracted with EtOAc (2 × 150 mL), and the combined organic extracts were washed with brine, then dried
and concentrated in vacuo to give 48 in 71:29 dr [(E):(Z)]. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O, 100:1) gave 48 as a pale yellow oil (1.51 g, 64%, 71:29 dr [(E):(Z)]). Data for
mixture: νmax (ATR) 1709 (C=O), 1641 (C=C); m/z (ESI+) 259 ([M+Na]+, 100%); HRMS (ESI+)
+
C15H24NaO2 ([M+Na]+) requires 259.1669; found 259.1670. Data for major diastereoisomer: δH (400 MHz,
22

ACCEPTED MANUSCRIPT
CDCl3) 1.49 (9H, s, CMe3), 2.12–2.21 (4H, m, C(4)H2, C(1')H2), 2.23–2.28 (2H, m, C(2')H2), 2.33–2.37
(2H, m, C(5)H2), 4.94–5.08 (4H, m, C(7)H2, C(4')H2), 5.77–5.86 (2H, m, C(6)H, C(3')H), 6.67 (1H, t, J 7.3,
C(3)H); δC (100 MHz, CDCl3) 26.5 (C(5)), 28.0 (C(2')), 28.1 (CMe3), 32.9 (C(4)), 33.5 (C(1')), 80.0 (CMe3),
114.8 (C(7)), 115.3 (C(4')), 133.4 (C(2)), 137.6 (C(3')), 138.1 (C(6)), 140.8 (C(3)), 167.1 (C(1)). Data for
minor diastereoisomer: δH (400 MHz, CDCl3) 1.51 (9H, s, CMe3), 2.14–2.20 (4H, m, C(1')H2, C(2')H2),
2.28–2.31 (2H, m, C(5)H2), 2.48 (2H, app q, J 7.4, C(4)H2), 4.95–5.06 (4H, m, C(7)H2, C(4')H2), 5.75–5.86
(3H, m, C(3)H, C(6)H, C(3')H); δC (100 MHz, CDCl3) 28.2 (CMe3), 28.6 (C(5)), 33.4 (C(1')), 33.5 (C(2')),
34.3 (C(4)), 80.5 (CMe3), 114.8 (C(4')), 114.9 (C(7)), 133.4 (C(2)), 138.0 (C(6)), 138.0 (C(3')), 139.0 (C(3)),
167.5 (C(1)).
tert-Butyl (E)-2-allyl-octa-2,7-dienoate 49
MeMgBr (2.9 M in Et2O, 1.34 mL, 3.84 mmol) was added dropwise to a stirred solution of 45 (1.18 g, 3.84
mmol) in THF (50 mL) at rt. The resultant mixture was stirred at rt for 15 min, then 17 (0.51 mL, 4.27
mmol) was added. The resultant mixture was heated at reflux for 3 h, then the reaction mixture was allowed
to cool to rt and partitioned between satd aq NH4Cl (60 mL) and Et2O (60 mL). The aqueous layer was
extracted with EtOAc (2 × 50 mL), and the combined organic extracts were washed with brine, then dried
and concentrated in vacuo to give 49 in 73:27 dr [(E):(Z)]. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O, 100:1) gave 49 as a pale yellow oil (737 mg, 81%, 73:27 dr [(E):(Z)]). Data
for mixture: νmax (ATR) 1712 (C=O), 1641 (C=C); m/z (ESI+) 259 ([M+Na]+, 100%); HRMS (ESI+)
+
C15H24NaO2 ([M+Na]+) requires 259.1669; found 259.1669. Data for major diastereoisomer: δH (400 MHz,
CDCl3) 1.48 (9H, s, CMe3), 1.50–1.58 (2H, m, C(5)H2), 2.08–2.11 (2H, m, C(6)H2), 2.15–2.20 (2H, m,
C(4)H2), 3.02 (2H, d, J 6.1, C(1')H2), 4.95–5.05 (4H, m, C(8)H2, C(3')H2), 5.75–5.85 (2H, m, C(7)H,
C(2')H), 6.74 (1H, t, J 7.5, C(3)H); δC (100 MHz, CDCl3) 27.8 (C(4)), 27.9 (C(5)), 28.1 (CMe3), 31.0 (C(1')),
33.4 (C(6)), 80.1 (CMe3), 114.8 (C(3')), 114.9 (C(8)), 131.5 (C(2)), 135.8 (C(2')), 138.2 (C(7)), 142.1 (C(3)),
166.9 (C(1)). Data for minor diastereoisomer: δH (400 MHz, CDCl3) 1.50 (9H, s, CMe3), 1.51–1.55 (2H, m,
C(5)H2), 2.06–2.11 (2H, m, C(6)H2), 2.40–2.45 (2H, m, C(4)H2), 2.96 (2H, d, J 6.6, C(1')H2), 4.94–5.08
(4H, m, C(8)H2, C(3')H2), 5.77–5.87 (3H, m, C(3)H, C(7)H, C(2')H); δC (100 MHz, CDCl3) 28.2 (CMe3),
28.7 (C(5)), 29.0 (C(4)), 33.4 (C(6)), 38.7 (C(1')), 80.5 (CMe3), 114.6 (C(8)), 115.9 (C(3')), 132.0 (C(2)),
136.3 (C(7)), 138.5 (C(2')), 140.4 (C(3)), 167.2 (C(1)).
23

ACCEPTED MANUSCRIPT
tert-Butyl (E)-2-(but-3'-en-1'-yl)octa-2,7-dienoate 50
MeMgBr (2.9 M in Et2O, 4.62 mL, 13.2 mmol) was added dropwise to a stirred solution of 46 (4.04 g, 13.2
mmol) in THF (50 mL) at rt. The resultant mixture was stirred at rt for 15 min, then 17 (1.76 mL, 14.7
mmol) was added. The resultant mixture was heated at reflux for 3 h, then the reaction mixture was allowed
to cool to rt and partitioned between satd aq NH4Cl (200 mL) and Et2O (200 mL). The aqueous layer was
extracted with EtOAc (2 × 200 mL), and the combined organic extracts were washed with brine, then dried
and concentrated in vacuo to give 50 in 75:25 dr [(E):(Z)]. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O, 100:1) gave 50 as a pale yellow oil (1.81 g, 55%, 75:25 dr [(E):(Z)]). Data for
mixture: νmax (ATR) 1711 (C=O), 1641 (C=C); m/z (ESI+) 273 ([M+Na]+, 100%); HRMS (ESI+)
+
C16H26NaO2 ([M+Na]+) requires 273.1825; found 273.1825. Data for major diastereoisomer: δH (400 MHz,
CDCl3) 1.49 (9H, s, CMe3), 1.50–1.57 (2H, m, C(5)H2), 2.06–2.19 (6H, m, C(4)H2, C(6)H2, C(2')H2), 2.31–
2.42 (2H, m, C(1')H2), 4.93–5.05 (4H, m, C(8)H2, C(4')H2), 5.73–5.86 (2H, m, C(7)H, C(3')H), 6.67 (1H, t, J
7.5, C(3)H); δC (100 MHz, CDCl3) 26.4 (C(1')), 27.9 (C(4)), 28.0 (C(5)), 28.1 (CMe3), 33.4 (C(2')), 33.5
(C(6)), 80.0 (CMe3), 114.7 (C(4')), 114.9 (C(8)), 133.2 (C(2)), 138.2 (C(3')), 138.2 (C(7)), 141.4 (C(3)),
167.1 (C(1)). Data for minor diastereoisomer: δH (400 MHz, CDCl3) 1.50 (9H, s, CMe3), 1.51–1.54 (2H, m,
C(5)H2), 2.05–2.11 (2H, m, C(6)H2), 2.15–2.21 (2H, m, C(2')H2), 2.28–2.32 (2H, m, C(1')H2), 2.36–2.42
(2H, m, C(4)H2), 4.95–5.04 (4H, m, C(8)H2, C(4')H2), 5.73–5.87 (3H, m, C(3)H, C(7)H, C(3')H); δC (100
MHz, CDCl3) 28.2 (CMe3), 28.8 (C(4)), 28.9 (C(5)), 33.4 (C(6)), 33.4 (C(2')), 34.4 (C(1')), 80.4 (CMe3),
114.6 (C(8)), 114.8 (C(4')), 133.2 (C(2)), 138.0 (C(7)), 138.6 (C(3')), 139.6 (C(3)), 167.6 (C(1)).
tert-Butyl (2S,3R,αR)-2-allyl-3-[N-benzyl-N-(α-methylbenzyl)amino]hept-6-enoate ent-9
Method A: BuLi (2.3 M in hexanes, 26.8 mL, 61.7 mmol) was added dropwise via syringe to a stirred
solution of (R)-N-benzyl-N-(α-methylbenzyl)amine (13.2 mL, 63.0 mmol, >99:1 er) in PhMe (27 mL) at –78
°C. After stirring at –78 °C for 30 min, a solution of 47 (4.00 g, 18.0 mmol, 76:24 dr [(E):(Z)]) in PhMe (13
mL) at –78 °C was added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 1 h and
then maintained at –30 °C for 2 h before being cooled to –78 °C. THF (140 mL) at –78 °C was added swiftly
via cannula and the resultant mixture was then stirred at –78 °C for 30 min. A solution of 2,6-di-tert-
butylphenol (14.3 g, 69.3 mmol) in THF (50 mL) was added dropwise via cannula and the resultant mixture
was allowed to warm to rt over 30 min, then concentrated in vacuo. The residue was partitioned between
CH2Cl2 (100 mL) and 10% aq citric acid (100 mL). The aqueous layer was extracted with CH2Cl2 (2 × 100
24

ACCEPTED MANUSCRIPT
mL) and the combined organic extracts were washed sequentially with satd aq NaHCO3 (300 mL), H2O (300
mL) and brine (300 mL), then dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O, 100:1) gave ent-9 as a colourless oil (3.20 g, 41%, >99:1 dr);
[α]2D5
+47.9 (c 1.0 in CHCl3); νmax (ATR) 1722 (C=O), 1640 (C=C); δH (400 MHz, CDCl3) 1.29 (3H, d, J
6.9, C(α)Me), 1.36 (9H, s, CMe3), 1.49–1.56 (1H, m, C(4)HA), 1.61–1.69 (1H, m, C(4)HB), 1.90–2.03 (2H,
m, C(5)HA, C(1')HA), 2.08–2.13 (1H, m, C(1')HB), 2.23–2.32 (2H, m, C(2)H, C(5)HB), 2.79 (1H, ddd, J 8.1,
6.5, 4.0, C(3)H), 3.79 (1H, d, J 15.0, NCHAHBPh), 3.90 (1H, d, J 15.0, NCHAHBPh), 3.97 (1H, q, J 6.9,
C(α)H), 4.85–4.96 (4H, m, C(7)H2, C(3')H2), 5.43–5.51 (1H, m, C(2')H), 5.71 (1H, ddt, J 17.0, 10.3, 6.6,
C(6)H), 7.18–7.34 (10H, m, Ph); δC (100 MHz, CDCl3) 19.6 (C(α)Me), 28.0 (CMe3), 29.7 (C(4)), 32.1
(C(5)), 36.2 (C(1')), 49.4 (C(2)), 51.2 (NCH2Ph), 59.1 (C(α)), 59.6 (C(3)), 80.3 (CMe3), 114.4 (C(7)), 116.0
(C(3')), 126.5, 126.9, 127.9, 128.2 (o,m,p-Ph), 135.9 (C(2')), 138.8 (C(6)), 142.2, 144.6 (i-Ph), 174.3 (C(1));
+
m/z (ESI+) 434 ([M+H]+, 100%); HRMS (ESI+) C29H40NO2 ([M+H]+) requires 434.3054; found 434.3049.
tert-Butyl (2S,3R,αR)-2-(but-3'-en-1'-yl)-3-[N-benzyl-N-(α-methylbenzyl)amino]oct-7-enoate 51
BuLi (2.3 M in hexanes, 7.10 mL, 16.3 mmol) was added dropwise via syringe to a stirred solution of (R)-N-
benzyl-N-(α-methylbenzyl)amine (3.47 mL, 16.6 mmol, >99:1 er) in PhMe (8 mL) at –78 °C. After stirring
at –78 °C for 30 min, a solution of 50 (1.17 g, 4.68 mmol, 75:25 dr [(E):(Z)]) in PhMe (4 mL) at –78 °C was
added dropwise via cannula. The reaction mixture was left to stir at –78 °C for 1 h and then maintained at
–30 °C for 2 h before being cooled to –78 °C. THF (36 mL) at –78 °C was added swiftly via cannula and the
resultant mixture was then stirred at –78 °C for 30 min. A solution of 2,6-di-tert-butylphenol (3.76 g, 18.3
mmol) in THF (15 mL) was added dropwise via cannula and the resultant mixture was allowed to warm to rt
over 30 min then concentrated in vacuo. The residue was partitioned between CH2Cl2 (30 mL) and 10% aq
citric acid (30 mL). The aqueous layer was extracted with CH2Cl2 (2 × 30 mL) and the combined organic
extracts were washed sequentially with satd aq NaHCO3 (90 mL), H2O (90 mL) and brine (90 mL), then
dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
25
petrol/Et O, 100:1) gave 51 as a colourless oil (992 mg, 46%, >99:1 dr);
+39.4 (c 0.5 in CHCl3); νmax
[α]D
2
(ATR) 1722 (C=O), 1640 (C=C); δH (400 MHz, CDCl3) 1.26 (3H, d, J 6.8, C(α)Me), 1.34–1.38 (3H, m,
C(5)HA, C(1')H2), 1.39 (9H, s, CMe3), 1.40–1.42 (1H, m, C(4)HA), 1.50–1.63 (2H, m, C(4)HB, C(5)HB),
1.65–1.73 (1H, m, C(2')HA), 1.82–1.94 (3H, m, C(6)H2, C(2')HB), 2.24–2.30 (1H, m, C(2)H), 2.73 (1H, ddd,
J 8.2, 6.3, 3.9, C(3)H), 3.76 (1H, d, J 15.1, NCHAHBPh), 3.89 (1H, d, J 15.1, NCHAHBPh), 3.96 (1H, q, J
25

ACCEPTED MANUSCRIPT
6.8, C(α)H), 4.89–4.96 (4H, m, C(8)H2, C(4')H2), 5.60–5.68 (1H, m, C(3')H), 5.73 (1H, ddt, J 17.0, 10.3,
6.7, C(7)H), 7.17–7.34 (10H, m, Ph); δC (100 MHz, CDCl3) 20.0 (C(α)Me), 27.3 (C(5)), 28.0 (CMe3), 30.1
(C(4)), 31.2 (C(1')), 31.6 (C(2')), 34.1 (C(6)), 49.2 (C(2)), 51.2 (NCH2Ph), 59.4 (C(α)), 60.5 (C(3)), 80.2
(CMe3), 114.4 (C(4')), 114.8 (C(8)), 126.4, 126.8, 127.9, 128.1, 128.2 (o,m,p-Ph), 138.2 (C(3')), 138.9
+
(C(7)), 142.5, 144.8 (i-Ph), 174.9 (C(1)); m/z (ESI+) 462 ([M+H]+, 100%); HRMS (ESI+) C31H44NO2
([M+H]+) requires 462.3367; found 462.3360.
(1S,7aR)-1-(Hydroxymethyl)hexahydro-1H-pyrrolizine [(+)-trachelanthamidine] 60
Step 1: 2,6-Lutidine (0.28 mL, 2.40 mmol), OsO4 (6.1 mg, 24.0 µmol) and NaIO4 (1.03 g, 4.82 mmol) were
sequentially added to a stirred solution of ent-9 (260 mg, 0.60 mmol, >99:1 dr) in 1,4-dioxane/H2O (3:1, 24
mL) at rt. The resultant mixture was stirred at rt for 40 min, then partitioned between CH2Cl2 (10 mL) and
10% aq citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and the combined
organic extracts were washed sequentially with satd aq NaHCO3 (30 mL) and brine (30 mL), then dried and
concentrated in vacuo to give 52.
Step 2: Pd(OH)2/C (260 mg, 100% w/w) was added to a stirred solution of the residue of 52 in MeOH (3
mL) at rt. The resultant mixture was degassed and saturated with H2 before being left to stir under an
atmosphere of H2 (5 atm) for 120 h. The reaction mixture was then filtered through a short plug of Celite®
(eluent MeOH) and concentrated in vacuo to give 56.
Step 3: LiAlH4 (2.4 M in THF, 1.50 mL, 3.60 mmol) was added to a stirred solution of the residue of 56 in
THF (5 mL) at –78 °C. The resultant mixture was allowed to warm to rt and stirred at rt for 2 h. 2.0 M aq
NaOH (1.8 mL, 3.6 mmol) was then added and the resultant mixture was stirred at rt for 2 h. The reaction
mixture was filtered through Celite® (eluent THF), then dried and concentrated in vacuo. Purification via ion
exchange chromatography on Dowex 50WX8 resin (hydrogen form, 100–200 mesh, eluent 18.0 M aq
NH4OH) gave 60 as a pale yellow oil (18 mg, 21% from ent-9, >99:1 dr);14g
+15.9 (c 1.0 in EtOH);
[α]2D5
{lit.14g
+15.4 (c 1.2 in EtOH)}; νmax (ATR) 3347 (O–H), 2932 (C–H);δH (400 MHz, CDCl3) 1.48–1.56
[α]2D0
(1H, m, C(7)HA), 1.56–1.68 (1H, m, C(2)HA), 1.69–1.77 (1H, m, C(6)HA), 1.78–1.86 (1H, m, C(6)HB),
1.88–2.01 (3H, m, C(1)H, C(2)HB, C(7)HB), 2.51 (1H, app td, J 9.9, 6.8, C(3)HA), 2.58 (1H, app dt, J 10.7,
6.6, C(5)HA), 2.94 (1H, dt, J 10.7, 6.3, C(5)HB), 3.11 (1H, ddd, J 9.9, 6.8, 3.2, C(3)HB), 3.20 (1H, app q, J
6.5, C(7a)H), 3.55–3.62 (2H, m, CH2OH), 3.72 (1H, br s, OH); δC (100 MHz, CDCl3) 25.7 (C(6)), 30.0
26

ACCEPTED MANUSCRIPT
(C(2)), 31.9 (C(7)), 48.4 (C(1)), 54.5 (C(3)), 54.7 (C(5)), 65.3 (CH2OH), 67.7 (C(7a)); m/z (ESI+) 142
([M+H]+, 100%); HRMS (ESI+) C8H16NO+ ([M+H]+) requires 142.1226; found 142.1229.
(8S,8aR)-8-(Hydroxymethyl)octahydro-8H-indolizine [(+)-tashiromine] 38
Method A – Step 1: 2,6-Lutidine (0.31 mL, 2.7 mmol), OsO4 (6.8 mg, 27 µmol) and NaIO4 (1.15 g, 5.37
mmol) were sequentially added to a stirred solution of 28 (300 mg, 0.67 mmol, >99:1 dr) in 1,4-dioxane/H2O
(3:1, 24 mL) at rt. The resultant mixture was stirred at rt for 40 min, then partitioned between CH2Cl2 (10
mL) and 10% aq citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and the
combined organic extracts were washed sequentially with satd aq NaHCO3 (30 mL) and brine (30 mL), then
dried and concentrated in vacuo to give 53.
Method A – Step 2: Pd(OH)2/C (300 mg, 100% w/w) was added to a stirred solution of the residue of 53 in
MeOH (3 mL) at rt. The resultant mixture was degassed and saturated with H2 before being left to stir under
an atmosphere of H2 (5 atm) for 120 h. The reaction mixture was then filtered through a short plug of Celite®
(eluent MeOH) and concentrated in vacuo to give 57.
Method A – Step 3: LiAlH4 (2.4 M in THF, 1.68 mL, 4.03 mmol) was added to a stirred solution of the
residue of 57 in THF (5 mL) at –78 °C. The resultant mixture was allowed to warm to rt and stirred at rt for
2 h. 2.0 M aq NaOH (2.02 mL, 4.03 mmol) was then added and the resultant mixture was stirred at rt for 2 h.
The reaction mixture was filtered through Celite® (eluent THF) then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 30:1:1) gave 38 as a pale
yellow oil (17 mg, 16% from 28, >99:1 dr);20
+39.0 (c 0.23 in EtOH); {lit.15
[α]2D5
[α]2D2
+41.9 (c 1.1 in
EtOH)}; νmax (ATR) 3341 (O−H), 2930 (C−H), 2794 (C−H); δH (400 MHz, CDCl3) 1.04 (1H, app qd, J 12.6,
4.4, C(7)HA), 1.44–1.98 (10H, m, C(1)H2, C(2)H2, C(5)HA, C(6)H2, C(7)HB, C(8)H, C(8a)H), 2.06 (1H, app
q, J 9.0, C(3)HA), 3.03–3.10 (2H, m, C(3)HB, C(5)HB), 3.46 (1H, dd, J 10.7, 6.7, CHAHBOH), 3.63 (1H, dd,
J 10.7, 4.6, CHAHBOH); δC (100 MHz, CDCl3) 20.7 (C(2)), 25.1 (C(6)), 27.6 (C(7)), 29.1 (C(1)), 44.6
(C(8)), 52.7 (C(5)), 54.1 (C(3)), 65.6 (CH2OH), 66.3 (C(8a)); m/z (ESI+) 156 ([M+H]+, 100%); HRMS
(ESI+) C9H18NO+ ([M+H]+) requires 156.1383; found 156.1383.
Method B – Step 1: A sample of 32 (370 mg, 1.10 mmol, 65:35 dr) was co-evaporated with HCl (3 × 2.0 mL,
2.0 M in Et2O), then the residue was dissolved in CH2Cl2/MeOH (1:1, 20 mL). The resultant mixture was
cooled to –78 °C and degassed with N2 and O2 before O3 was bubbled through the solution until a persistent
blue colour appeared. O2 was then bubbled through the solution until it became colourless. Polymer
27

ACCEPTED MANUSCRIPT
supported PPh3 (1.52 g, 3.30 mmol) was then added and the reaction mixture was allowed to warm to rt and
stirred at rt for 2 h. The reaction mixture was filtered through Celite® (eluent MeOH) then concentrated in
vacuo to give 35 (65:35 dr).
Method B – Step 2: Pd(OH)2/C (77 mg, 20% w/w) was then added to a stirred solution of the residue of 35 in
MeOH (5 mL), H2O (0.5 mL) and AcOH (0.2 mL) at 35 °C. The resultant mixture was degassed and
saturated with H2 before being left to stir under an atmosphere of H2 (5 atm) for 24 h. The reaction mixture
was then filtered through a short plug of Celite® (eluent MeOH) and concentrated in vacuo to give a 65:35
mixture of 38ꢀHOAc and 39ꢀHOAc, respectively, as a pale yellow oil. Purification via ion exchange
chromatography on Dowex 50WX8 resin (hydrogen form, 100–200 mesh, eluent 1.0 M aq NH4OH) gave 38
as a pale yellow oil (16 mg, 11%, >99:1 dr, ~95% purity);16 [α]D20 +30.0 (c 0.5 in CHCl3); {lit.16 [α ]D20 +43.4
(c 0.53 in CHCl3)}.
(1S,8aR)-1-(Hydroxymethyl)octahydro-1H-indolizine 40
Method A – Step 1: 2,6-Lutidine (0.31 mL, 2.68 mmol), OsO4 (6.8 mg, 26.8 µmol) and NaIO4 (1.15 g, 5.37
mmol) were sequentially added to a stirred solution of 22 (300 mg, 0.67 mmol, >99:1 dr) in 1,4-dioxane/H2O
(3:1, 24 mL) at rt. The resultant mixture was stirred at rt for 40 min, then partitioned between CH2Cl2 (10
mL) and 10% aq citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and the
combined organic extracts were washed sequentially with satd aq NaHCO3 (30 mL) and brine (30 mL), then
dried and concentrated in vacuo to give 54.
Method A – Step 2: Pd(OH)2/C (300 mg, 100% w/w) was added to a stirred solution of the residue of 54 in
MeOH (3 mL) at rt. The resultant mixture was degassed and saturated with H2 before being left to stir under
an atmosphere of H2 (5 atm) for 120 h. The reaction mixture was then filtered through a short plug of Celite®
(eluent MeOH) and concentrated in vacuo to give 58.
Method A – Step 3: LiAlH4 (2.4 M in THF, 1.68 mL, 4.03 mmol) was added to a stirred solution of the
residue of 58 in THF (5 mL) at –78 °C. The resultant mixture was allowed to warm to rt and stirred at rt for
2 h. 2.0 M aq NaOH (2.02 mL, 4.03 mmol) was then added and the resultant mixture was stirred at rt for 2 h.
The reaction mixture was filtered through Celite® (eluent THF) then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent CHCl3/MeOH/NH4OH, 30:1:1) gave 40 as a pale
yellow oil (15 mg, 15% from 22, >99:1 dr);14l
+39.8 (c 0.5 in EtOH); {lit.16
[α]2D5
[α]2D3
+27.4 (c 1.0 in
EtOH)}; νmax (ATR) 3353 (O−H), 2931 (C−H); δH (400 MHz, CDCl3) 1.18–1.31 (2H, m, C(7)HA, C(8)HA),
28