Polyhydroxylated pyrrolizidine alkaloids from transannular iodoaminations: Application to the asymmetric syntheses of (-)-hyacinthacine A1, (-)-7a-epi-hyacinthacine A1, (-)-hyacinthacine A2, and (-)-1-epi-alexine

Article abstract of DOI:10.1039/c3ob40205c

The transannular iodoamination of substituted 1,2,3,4,7,8-hexahydroazocine scaffolds has been developed into a versatile, diastereodivergent route to enable the synthesis of a range of pyrrolizidine alkaloids, as demonstrated by the syntheses of (-)-hyacinthacine A1, (-)-7a-epi-hyacinthacine A1, (-)-hyacinthacine A2, and (-)-1-epi-alexine. The requisite 1,2,3,4,7,8- hexahydroazocines (bearing either an N-α-methyl-p-methoxybenzyl group or no N-substituent) were readily prepared via conjugate addition of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to either tert-butyl (4S,5R,E)-4,5-dihydroxy-4,5-O-isopropylidene-2,7-dienoate (derived from d-ribose) or tert-butyl (S,S,E)-4,5-dihydroxy-4,5-O-isopropylidene-2,7-dienoate (derived from l-tartaric acid) coupled with in situ enolate oxidation with (-)-camphorsulfonyloxaziridine, followed by ring-closing metathesis with Grubbs I catalyst. Subsequent reaction with I₂ resulted in transannular iodoamination (accompanied by concomitant loss of the N-α-methyl-p- methoxybenzyl group for tertiary amine substrates) to give the corresponding pyrrolizidine scaffolds. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40205c

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PAPER
Polyhydroxylated pyrrolizidine alkaloids from
transannular iodoaminations: application to the
asymmetric syntheses of (−)-hyacinthacine A1,
(−)-7a-epi-hyacinthacine A1, (−)-hyacinthacine A2,
and (−)-1-epi-alexine†‡
Cite this: Org. Biomol. Chem., 2013, 11,
3187
E. Anne Brock, Stephen G. Davies,* James A. Lee, Paul M. Roberts and
James E. Thomson
The transannular iodoamination of substituted 1,2,3,4,7,8-hexahydroazocine scaffolds has been deve-
loped into a versatile, diastereodivergent route to enable the synthesis of a range of pyrrolizidine alka-
loids, as demonstrated by the syntheses of (−)-hyacinthacine A1, (−)-7a-epi-hyacinthacine A1,
(−)-hyacinthacine A2, and (−)-1-epi-alexine. The requisite 1,2,3,4,7,8-hexahydroazocines (bearing either
an N-α-methyl-p-methoxybenzyl group or no N-substituent) were readily prepared via conjugate addition
of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to either tert-butyl (4S,5R,E)-4,5-di-
hydroxy-4,5-O-isopropylidene-2,7-dienoate (derived from D-ribose) or tert-butyl (S,S,E)-4,5-dihydroxy-4,5-O-
isopropylidene-2,7-dienoate (derived from L-tartaric acid) coupled with in situ enolate oxidation with
(−)-camphorsulfonyloxaziridine, followed by ring-closing metathesis with Grubbs I catalyst. Subsequent
reaction with I2 resulted in transannular iodoamination (accompanied by concomitant loss of the
N-α-methyl-p-methoxybenzyl group for tertiary amine substrates) to give the corresponding pyrrolizidine
scaffolds.
Received 30th January 2013,
Accepted 14th March 2013
DOI: 10.1039/c3ob40205c
www.rsc.org/obc
as specific sugar mimics, the nitrogen atom becoming proto-
nated within the enzyme pocket thereby mimicking the postu-
Introduction
Polyhydroxylated pyrrolizidine (hexahydro-1H-pyrrolizine) alka- lated oxo-carbenium ion intermediate of glycosidic bond
loids are characterized by an azabicyclic core bedecked with cleavage.1,6
dense oxygen (hydroxyl) functionality,1 as exemplified by the
We have recently developed efficient asymmetric syntheses
structures of (+)-hyacinthacine A1,2 (+)-alexine3 and (+)- of both pyrrolizidine7 and tropane8 molecular architectures
casuarine4 (Fig. 1). A considerable amount of effort has been which are reliant on transannular9 iodoamination as a key
put into the isolation, structural elucidation, and synthesis of step. For example, conjugate addition of lithium (R)-N-but-
polyhydroxylated pyrrolizidine alkaloids, with Fleet et al. being 3-enyl-N-(α-methyl-p-methoxybenzyl)amide 1 (>99% ee)10 to
lead exponents within this field.2–5 The burgeoning interest in α,β,ε,ζ-diunsaturated ester 2 (derived from D-ribose) and in situ
this type of compound stems mainly from the often potent bio- enolate oxidation
with (−)-camphorsulfonyloxaziridine
logical activities exhibited, in particular specific glycosidase [(−)-CSO] gave α-hydroxy-β-amino-ε,ζ-unsaturated ester 3 in
inhibition.1,6 The distribution and orientation of hydroxyl 50% yield and >99 : 1 dr. Subsequent treatment of 3 with
groups around the bicyclic core enables these alkaloids to act Grubbs I catalyst gave hexahydroazocine11 4 in 73% yield.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, UK. E-mail: steve.davies@chem.ox.ac.uk
†This article is part of the RSC journal web theme issue commemorating the
60th birthday of Professor Andrew Hamilton.
‡Electronic supplementary information (ESI) available: Full experimental
details, copies of 1H and 13C NMR spectra, and crystallographic data. CCDC
922276 and 922277. For ESI and crystallographic data in CIF format see DOI:
10.1039/c3ob40205c
Fig. 1 Structures of (+)-hyacinthacine A1, (+)-alexine, and (+)-casuarine.
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Under optimised conditions, transannular iodoamination of
412 in CH2Cl2 (EtOH-stabilised) gave a 1 : 1 mixture of iodopyr-
rolizidine 7·HI and α-methyl-p-methoxybenzyl ethyl ether 8,
from which 7·HI could be isolated in 79% yield (>99 : 1 dr) by
crystallisation from 30–40 °C petrol. Chromatographic purifi-
cation of the residue from the mother liquors gave 8 in 95%
yield and 3% ee.13 The stereochemical outcome of this reac-
tion is consistent with initial reversible iodonium ion for-
mation being followed by preferential ring-opening of
intermediate iodonium ion 5 upon transannular attack of the
nitrogen atom to give 6. Subsequent loss of the α-methyl-p-
methoxybenzyl group as the corresponding cation (SN1-type
process) followed by salt formation with in situ generated HI
gives iodopyrrolizidine 7·HI, and trapping of the α-methyl-p-
methoxybenzyl cation by the EtOH stabiliser present in the
reaction solvent gives ether 8; the isolation of essentially
racemic ether 8 supports the intermediacy of a cation in this
process. Elaboration of iodopyrrolizidine 7 to the correspond-
ing 1,2-dihydroxy-3-hydroxymethyl pyrrolizidine scaffold [in
this case (−)-7a-epi-hyacinthacine A1 10, a known (synthetic)
diastereoisomer14 of the pyrrolizidine alkaloid hyacinthacine
A1] was next accomplished in four further steps and 64%
yield, or 10% yield over nine steps from D-ribose (Scheme 1).7
In order to exploit this approach for the synthesis of poly-
hydroxylated pyrrolizidine alkaloids, several structural ana-
logues of hexahydroazocine 4, which encompass systematic
removal of the N-substituent and O-isopropylidene group, pres-
ence of an α-branch within the C(2′)-substituent, and variation
of the relative configuration of the C(4′)-stereogenic centre,
were prepared. It was anticipated that subjection of these ana-
logues to the previously optimised conditions for transannular
iodoamination may give some insight into the origin of the
diastereoselectivity of the process, as well as providing further
iodopyrrolizidines for elaboration to polyhydroxylated pyrroli-
zidine alkaloids. Herein we report our investigations within
this area, which culminate in the asymmetric syntheses of
(−)-hyacinthacine A1, (−)-hyacinthacine A2, and (−)-1-epi-
alexine, and an alternative synthesis of (−)-7a-epi-hyacintha-
cine A1.
Scheme 1 Reagents and conditions: (i) (R)-1, THF, −78 °C, 2 h then (−)-CSO,
−78 °C to rt, 12 h; (ii) Grubbs I, CH2Cl2, rt, 12 h then P(CH2OH)3, Et3N, SiO2,
CH2Cl2, rt, 12 h; (iii) I2, NaHCO3, CH2Cl2 (EtOH-stabilised), rt, 12 h; (iv) LiAlH4,
THF, −78 °C to rt, 12 h; (v) NaIO4, MeOH, H2O, rt, 4 h then NaBH4, rt, 12 h; (vi)
HCl (3.0 M aq.), MeOH, reflux, 2 h. PMP = p-methoxyphenyl.
Results and discussion
The significance of the α-branch within the C(2′)-substituent
of 4 on the diastereoselectivity of the transannular iodoamina-
tion reaction was investigated first. Thus, treatment of 4 with
LiAlH4 resulted in the reduction of the ester to give diol 11 in
89% yield and >99 : 1 dr. Oxidative cleavage of this diol upon
treatment with NaIO4 and then reduction with NaBH4 proved
to be somewhat problematic, producing a white solid which
under 1 atm H2 in the presence of Et3N and 10% Pd/C (to
effect reduction of the C–I bond) was followed by acid-cata-
lysed hydrolysis on treatment with 6.0 M aq. HCl. Purification
via ion exchange chromatography gave (−)-7a-epi-hyacinthacine
A1 10 in 75% yield and >99 : 1 dr. In addition, given the known
enantiomeric purity of the lithium (R)-N-but-3-enyl-N-
(α-methyl-p-methoxybenzyl)amide 1 (i.e., >99% ee)10 employed
for the conjugate addition to α,β,ε,ζ-diunsaturated ester 2
(itself prepared from D-ribose), from which 10 is ultimately
derived, the enantiomeric purity of 10 (as well as those of 4
1
gave an intractable H NMR spectrum in an range of solvents.
However, chromatographic purification allowed the isolation
of 12 in >99 : 1 dr, albeit in only 15% yield. Transannular
iodoamination of hexahydroazocine 12 under our optimised
conditions7 gave a single compound, subsequently assigned as
iodopyrrolizidine 14·HI. Immediate hydrogenolysis of 14·HI
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and 11–14) can be confidently assigned as >99% ee. The iden- chromatography (Scheme 3). The structure and relative con-
tity of 10 as the product in this case was established by com- figuration of 15 were confirmed by single crystal X-ray diffrac-
parison of its 1H and 13C NMR spectra and specific rotation tion analysis15 (Fig. 2). Due to the inherent insolubility of
{[α]2D0 −39.5 (c 0.3 in H2O)} with our sample prepared pre- hexahydroazocine triol 15 in CH2Cl2 the transannular iodoami-
viously {[α]2D5 −45.9 (c 0.2 in H2O)} from transannular iodoami- nation was performed in MeOH. In order to avoid partial dis-
nation of hexahydroazocine 4.7 These data were in good solution of NaHCO3 or Na2S2O3 (used during work-up), a new
agreement with those previously reported for (+)-7a-epi-hya- procedure was designed whereby no NaHCO3 was used and
cinthacine A1 10 {[α]D27 +47.0 (c 0.65 in H2O)} by Izquierdo only 1.0 equiv. of I2 was employed to ensure that there was no
et al.,14a (−)-7a-epi-hyacinthacine A1 10 {[α]2D2 −45.3 (c 1.5 in excess reagent left to quench at the end of the reaction. After
H2O)} by Clapés et al.,14c and ( )-7a-epi-hyacinthacine A1 10 by stirring the reaction mixture for 12 h at rt the solvent was
Affolter et al.14d The stereochemical outcome of this transan- removed in vacuo to give a single product, subsequently
nular iodoamination is therefore in accordance with that for 4, assigned as iodopyrrolizidine 17·HI. Hydrogenolysis of 17·HI
and indicates that the presence of the α-branch within the and purification of the resultant product by ion exchange
C(2′)-substituent is not crucial for determining the diastereo- chromatography gave a single polyhydroxylated pyrrolizidine,
selectivity of the reaction. Assuming, in both cases, that analo- which was isolated in 94% yield and >99 : 1 dr, and identified
1
gous mechanisms operate (i.e., via reversible iodonium ion as (−)-hyacinthacine A1 182,14b,16 by comparison of its H and
formation and subsequent attack by the nitrogen atom), the
configuration within iodopyrrolizidine 14 was assigned from
that of 10. In turn, 14 would result from transannular cyclisa-
tion of iodonium ion 13 (Scheme 2).
Next, the effect of removing both the (acid labile)
N-α-methyl-p-methoxybenzyl and O-isopropylidene groups on
the outcome of the transannular iodoamination reaction was
investigated. Thus, treatment of hexahydroazocine 12 with
3.0 M aq. HCl in MeOH gave the fully deprotected hexahydro-
azocine triol 15 in 69% yield after purification by ion-exchange
Scheme 3 Reagents and conditions: (i) HCl (3.0 M aq.), MeOH, reflux, 2 h; (ii)
I2, MeOH, rt, 12 h; (ii) H2, Pd/C, Et3N, MeOH, rt, 18 h.
Scheme 2 Reagents and conditions: (i) LiAlH4, THF, −78 °C to rt, 12 h; (ii)
NaIO4, MeOH, rt, 4 h then NaBH4, rt, 4 h; (iii) I2, NaHCO3, CH2Cl2 (EtOH-stabil-
ised), rt, 12 h; (iv) H2, Pd/C, Et3N, MeOH, rt, 18 h then HCl (6.0 M aq.), MeOH.
Fig. 2 Chem 3D representation of the single crystal X-ray diffraction structure
of 15 (selected H atoms are omitted for clarity).
PMP = p-methoxyphenyl.
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13C NMR spectra and specific rotation {[α]2D0 −34.1 (c 0.4 in
H2O); [α]2D0 −32.0 (c 0.6 in MeOH)} with those previously
reported by Asano et al. for a sample of (+)-hyacinthacine A1
18 isolated from Muscari armeniacum {[α]2D0 +38.2 (c 0.23 in
H2O)},2 and those reported for synthetic samples of
(+)-hyacinthacine A1 18 {[α]2D4 +35.6 (c 0.32 in H2O);14b [α]2D0
+45.0 (c 0.23 in H2O);16a [α]D25 +33.5 (c 0.2 in MeOH);16b [α]D21
+43.9 (c 0.29 in H2O);16c [α]D22 +43.5 (c 0.23 in H2O)}16d and
(−)-hyacinthacine A1 18 {[α]2D0 −20.0 (c 1.0 in MeOH)}.16e As
before, by invoking a mechanism which involves reversible
iodonium ion formation and subsequent attack of the nitrogen
atom, the isolation of 18 from this sequence of reactions
suggested that the transannular cyclisation of hexahydroazo-
cine triol 15 had occurred via iodonium ion 16 to give iodopyr-
rolizidine 17, indicating that this reaction proceeds with
complementary diastereocontrol to that observed for hexa-
hydroazocines 4 and 12 (Scheme 3).
To increase further the synthetic value of the transannular
iodoamination approach to polyhydroxylated pyrrolizidines, it
was desirable to be able to access the corresponding 1,2-anti-
configured pyrrolizidine diastereoisomers. Since these stereo-
centres are derived from the α,β,ε,ζ-diunsaturated ester, it was
proposed that this could be achieved if α,β,ε,ζ-diunsaturated
ester 26 was employed in the conjugate addition/ring-closing
metathesis/transannular iodoamination approach7 in the
place of 2. The optimum procedure for the preparation of 26
on scale involved initial acetonide protection of dimethyl L-tar-
trate 19 followed by treatment with LiAlH4 to give diol 2017,18
in 90% yield. Selective mono-O-TBDMS protection of one of
the hydroxyl groups within 20 on treatment with 1.0 equiv.
TBDMSCl and 1.0 equiv. NaH gave 2118,19 in 83% yield. This
was followed by Swern oxidation of the remaining (free)
hydroxyl group within 21 to give the corresponding aldehyde
22,19 which was immediately subjected to Wittig reaction with
the ylide derived from triphenylmethylphosphonium iodide
and KOtBu to give alkene 2320 in 92% yield. Removal of the
O-TBDMS group within 23 upon treatment with TBAF gave
alcohol 2421 in 74% yield. Finally, ‘one-pot’ Swern/Wittig reac-
tion22 (which circumvented the need to isolate the volatile,
intermediate aldehyde 25)21 gave 2623 (in 98 : 2 dr), which was
isolated in 63% yield and >99 : 1 dr after chromatographic
purification (Scheme 4).
Scheme 4 Reagents and conditions: (i) (MeO)2CMe2, TsOH, PhMe, reflux, 16 h;
(ii) LiAlH4, THF, reflux, 16 h; (iii) NaH, THF, 0 °C to rt, 45 min then TBDMSCl, rt,
16 h; (iv) (COCl)2, DMSO, CH2Cl2, −78 °C, 1 h then Et3N, −78 °C to rt, 30 min;
(v) KOtBu, [Ph3PMe]+[I]−, THF, rt,
1 h; (vi) TBAF, THF, 0 °C, 2.5 h;
(vii) Ph3PvCHCO2tBu, CH2Cl2, rt, 12 h.
the C(3′) and C(4′)-stereocentres (derived from dimethyl L-tar-
trate), and the known (R)-configuration of the N-α-methyl-p-
methoxybenzyl group. This analysis also allowed the absolute
(3S,4S,5S,αR)-configuration within β-amino ester 27 and the
absolute (2R,3S,4S,5S,αR)-configuration within α-hydroxy-
β-amino ester 28 to be unambiguously assigned. These stereo-
chemical outcomes are not only consistent with our previous
observations in closely related systems,25 but also with our
transition state mnemonic for conjugate addition of this class
of lithium amide to achiral α,β-unsaturated esters28 and
with the well-established anti-stereochemical outcome of our
aminohydroxylation procedure.26
Conjugate addition of (R)-1 to 2624,25 resulted in formation
of a single β-amino ester 27, which was isolated in 65% yield.
The synthesis of the corresponding α-hydroxy-β-amino ester 28
was next achieved upon conjugate addition of (R)-1 to 26 in
THF at −78 °C followed by the addition of (−)-CSO,26 which
gave 28 in 58% isolated yield and >99 : 1 dr (and 27 in 9% iso-
lated yield and >99 : 1 dr). Subsequent ring-closing meta-
thesis27 of 28 required treatment with 10 mol% Grubbs I
catalyst in CH2Cl2 at 30 °C to effect complete conversion to
hexahydroazocine 29, which was isolated in 91% yield and
>99 : 1 dr (Scheme 5). The relative configuration within 29 was
unambiguously established by single crystal X-ray diffraction
analysis (Fig. 3),15 with the absolute (2R,2′S,3′S,4′S,αR)-con-
figuration being assigned from the known configurations of
As transannular iodoamination of hexahydroazocine 29
would result in concomitant formation of a trans-5,5-fused
bicyclic system it was envisaged that this would not be a feas-
ible process. Indeed, treatment of 29 under the previously
optimised conditions to effect transannular iodoamination
of hexahydroazocine 47 resulted in the formation of
a
68 : 32 mixture of secondary amine 32 and tricyclic hemi-
aminal ether 33, with no evidence of pyrrolizidine products.
Chromatographic purification gave 32 in 40% yield and >99 : 1
dr, and 33 in 24% yield and >99 : 1 dr. The structure of 33 was
established by extensive NMR spectroscopic analysis, including
1H–1H 2D COSY and HMBC; in particular the 1H and 13C NMR
chemical shifts corresponding to C(7)H (δH 5.10 ppm and δC
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Scheme 6 Reagents and conditions: (i) I2, NaHCO3, CH2Cl2 (EtOH-stabilised), rt,
12 h. PMP = p-methoxyphenyl.
Scheme 5 Reagents and conditions: (i) (R)-1, THF, −78 °C, 2 h then (−)-CSO,
−78 °C to rt, 12 h; (ii) (R)-1, THF, −78 °C, 2 h; (iii) Grubbs I, CH2Cl2, 30 °C, 12 h
then P(CH2OH)3, Et3N, SiO2, CH2Cl2, rt, 12 h. PMP = p-methoxyphenyl.
formation of the least substituted imine 31 followed by trap-
ping upon attack of the C(2)-hydroxyl group gives tricyclic
hemiaminal ether 33. These results are entirely consistent with
previous observations made by Deno and Fruit Jr., who
studied the oxidative N-dealkylation of a range of acyclic,
unsymmetrical amines with bromine.29
Given the expected difficulties encountered with effecting
transannular iodoamination of 29, preparation of a derivative
which lacked the O-isopropylidene group and its subsequent
transannular cyclisation was examined. Following the pro-
cedure developed for the synthesis of hexahydroazocine triol
15, initial reduction of hexahydroazocine 29 with LiAlH4 gave
diol 35 in 77% yield. Subsequent oxidative cleavage of the 1,2-
diol unit within 35 upon treatment with NaIO4 and immediate
reduction of the resultant aldehyde with NaBH4 gave the
required C(3)-hydroxymethyl substituted hexahydroazocine 36
in 57% yield. Acid-catalysed hydrolysis of the acetonide group
within 36 proceeded with simultaneous N-debenzylation to
give hexahydroazocine triol 37 in 70% yield after purification
by ion exchange chromatography (Scheme 7).
Treatment of hexahydroazocine triol 37 with 1.0 equiv. of I2
in MeOH for 12 h at rt followed by removal of the solvent
in vacuo gave a single compound, which was subsequently
assigned as iodopyrrolizidine 39·HI, in >99 : 1 dr. As before,
hydrogenolysis of 39·HI and purification of the resultant
product by ion exchange chromatography gave a single poly-
hydroxylated pyrrolizidine, which was isolated in 95% yield
and >99 : 1 dr, and identified as (−)-hyacinthacine A2 40 by
comparison of its 1H and 13C NMR spectra with those
Fig. 3 Chem 3D representation of the single crystal X-ray diffraction structure
of 29 (selected H atoms are omitted for clarity).
94.5 ppm) were characteristic of the formation of an N–O
acetal (Scheme 6). The mechanism for halogen promoted
N-dealkylation of tertiary amines has been proposed to involve
initial N-oxidation followed by the formation of an iminium
ion, which undergoes hydrolysis upon aqueous work-up to
give a secondary amine and the corresponding aldehyde or
ketone.29 Iodine-promoted oxidation of hexahydroazocine 29
and subsequent formation of the most substituted/stable
imine 30 followed by hydrolysis would result in the formation
of secondary amine 32 and ketone 34. Although 34 was not iso-
lated, it was tentatively assigned as being present in the 1H
NMR spectrum of the crude reaction mixture. Meanwhile,
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their synthesis of (+)-hyacinthacine A2 40, Martin et al.,30a
reported [α]D +12.5 (c 0.4 in H2O) for their synthetic sample of
(+)-40 but noted that “a small sample purified by Professor
Asano under the same conditions as the natural product gave
[α]D +23 (c 0.04 in H2O)”.
The configuration within iodopyrrolizidine 39 was assigned
from that of 40 on the basis of a cyclisation mechanism invol-
ving attack of the nitrogen atom onto an iodonium ion, in this
case 38. The stereochemical outcomes of the highly diastereo-
selective and diastereodivergent transannular iodoaminations
of hexahydroazocines 4, 12, 15 and 37 can, in all cases, be
rationalised by invoking a mechanism involving the reversible
formation of two diastereoisomeric iodonium ions. In the
cases of hexahydroazocines 15 and 37, transannular strain
present in iodonium ions 43 and 44 may disfavour their cycli-
sation and hence the reaction proceeds via iodonium ions 16
and 38 to give pyrrolizidines 17 and 39, respectively. In con-
trast, for the cases of 4 and 12, cyclisation of iodonium ions 41
and 42 is presumably disfavoured due to the large 1,2-strain
now present between the N-α-methyl-p-methoxybenzyl group
and the C(2′)-substituent (rather than due to the presence of
the O-isopropylidene group). The reaction thus preferentially
proceeds via iodonium ions 5 and 13 (the transannular strain
between the C(2′)-substituent and the distal ring hydrogen
atoms being less significant than 1,2-strain in this case) to give
pyrrolizidines 7 and 14, respectively (Fig. 4).
Scheme 7 Reagents and conditions: (i) LiAlH4, THF, −78 °C to rt, 12 h;
(ii) NaIO4, MeOH, H2O, rt, 4 h then NaBH4, rt, 12 h; (iii) HCl (3.0 M aq.), MeOH,
reflux, 2 h. PMP = p-methoxyphenyl.
The successful preparation of the 1,2-dihydroxy-3-(hydroxy-
methyl)pyrrolizidines (−)-7a-epi-hyacinthacine A1 10, (−)-hya-
cinthacine A1 18 and (−)-hyacinthacine A2 40 instigated a
study into the synthesis of other, more densely hydroxylated
pyrrolizidine scaffolds. As a representative example, it was
envisaged that substitution of the C(7)-iodo functionality
within pyrrolizidine 7 for a hydroxyl group would allow the
synthesis of the 1,2,7-trihydroxy-3-hydroxymethyl substitution
pattern to access diastereoisomers of the naturally occurring
pyrrolizidine alkaloid alexine.3 Using a range of conditions to
attempt SN2-type reaction delivered either returned starting
material or a complex mixture of products. A radical-mediated
substitution was therefore investigated.31,32 Treatment of 7·HI
with Bu3SnH in the presence of TEMPO gave a 75 : 25 mixture
of diastereoisomeric pyrrolizidines 45 and 46. Chromato-
graphic purification on silica doped with 10% KF33 gave 45 in
69% yield, and an impure sample of 46 in 19% yield, as single
Scheme 8 Reagents and conditions: (i) I2, MeOH, rt, 12 h; (ii) H2, Pd/C, Et3N,
MeOH, rt, 18 h.
previously reported by Asano et al. for a sample of (+)-
hyacinthacine A2 40 isolated from Muscari armeniacum,2 and
those reported for synthetic samples16e,30 (Scheme 8).
It is noteworthy that although the sign of the specific
rotation for our sample of (−)-hyacinthacine A2 40 {[α]2D5 −11.0
(c 0.43 in H2O); [α]2D5 −11.2 (c 0.83 in MeOH)} was, as expected, diastereoisomers in both cases. Given the known absolute con-
opposite to that reported for the sample of (+)-hyacinthacine
figuration within pyrrolizidine 7, pyrrolizidines 45 and 46
were assigned as being epimers at C(7). The absolute
A2 40 isolated from the natural source {[α]2D5 +20.1 (c 0.44 in
H2O)},2 their magnitudes differed significantly. However, com- (1R,2S,3S,7R,7aS,1′R)-configuration within 45 was sub-
parison with data reported for other synthetic samples of
sequently established unambiguously by chemical correlation
(vide infra), and therefore the absolute (1R,2S,3S,7S,7aS,1′R)-
(+)-hyacinthacine A2 40 {[α]D +12.5 (c 0.4 in H2O);30a [α]D24 +12.7
(c 0.13 in H2O);30b [α]D25 +10.5 (c 0.6 in H2O);30c [α]2D0 +19.9 configuration within 46 could also be assigned (Scheme 9).
(c 0.97 in MeOH);30d [α]D20 +11.2 (c 0.52 in H2O);30e [α]D +12.1 (c
Cleavage of the N–O bond within 45 was achieved by reac-
0.3 in H2O);30f [α]D26 +12 (c 0.4 in H2O);30g [α]2D0 +12.6 (c 1.64 in
tion with activated Zn in AcOH32 to give the corresponding
H2O);30h [α]2D4 +12.4 (c 0.2 in H2O);30i [α]2D0 +10.6 (c 1.2 in hydroxypyrrolizidine 47 in 61% yield and >99 : 1 dr. Reduction
H2O)};30j [α]D +12 (c 0.4 in H2O)}30k and (−)-hyacinthacine A2
of 47 with LiAlH4 gave 48 in 46% yield and >99 : 1 dr. Acid-cata-
40 {[α]2D0 −11.0 (c 1.0 in MeOH)}16e revealed good agreement
lysed hydrolysis of the acetonide group within 48 allowed the
within a range of values (10 < [α]D < 13) in all but one case. In isolation of polyhydroxylated pyrrolizidine 49 in 84% yield as a
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Fig. 4 Postulated mechanistic rationale for the observed stereochemical outcomes of transannular iodoamination of hexahydroazocines 4, 12, 15 and 37 [R = (R)-
α-methyl-p-methoxybenzyl].
(c 0.58 in H2O);34a [α]D25 +53.4 (c 0.43 in H2O)},34b and those
reported for a synthetic sample of (+)-1-epi-alexine 51 {[α]D20
+34.8 (c 0.5 in H2O)} by Ikota et al.35a and for a synthetic
sample of (−)-1-epi-alexine 51 {[α]2D0 −51 (c 0.51 in H2O)} by
Donohoe et al.,16d showed good agreement and therefore
allowed for its unambiguous structural and stereochemical
assignment and, hence, those of 45–50 (Scheme 10).
Conclusion
In conclusion, a range of substituted 1,2,3,4,7,8-hexahydroazo-
cines (bearing either an N-α-methyl-p-methoxybenzyl group or
no N-substituent) were prepared via conjugate addition of
lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide
to either tert-butyl (4S,5R,E)-4,5-dihydroxy-4,5-O-isopropyli-
dene-2,7-dienoate (derived from D-ribose) or tert-butyl (S,S,E)-
Scheme 9 Reagents and conditions: (i) Bu3SnH, TEMPO, PhMe, 70 °C, 1.5 h.
4,5-dihydroxy-4,5-O-isopropylidene-2,7-dienoate (derived from
L-tartaric acid) coupled with in situ enolate oxidation with
(−)-camphorsulfonyloxaziridine, followed by ring-closing
single diastereoisomer. Treatment of pyrrolizidine 48 with
NaIO4 and immediate reduction of the resultant aldehyde with
NaBH4 proved problematic and resulted in a crude reaction
metathesis with Grubbs I catalyst as the key steps. Subsequent
reaction with I2 resulted in highly diastereoselective and dia-
stereodivergent transannular iodoaminations (accompanied by
concomitant loss of the N-α-methyl-p-methoxybenzyl group for
tertiary amine substrates) to give the corresponding pyrrolizi-
dine scaffolds. The stereochemical outcomes of these reactions
can be rationalised by invoking reversible iodonium ion for-
mation and subsequent cyclisation upon attack of the nitrogen
atom, with the delicate interplay between 1,2-strain and trans-
annular strain in the intermediate iodonium ions being
responsible for the diastereoselectivity observed. The utility of
this approach for pyrrolizidine alkaloid synthesis has been
demonstrated by the preparation of (−)-hyacinthacine A1,
(−)-7a-epi-hyacinthacine A1, (−)-hyacinthacine A2, and (−)-1-
epi-alexine.
mixture that produced
a
complex 1H NMR spectrum.
Attempted chromatographic purification did not allow the iso-
lation of any identifiable species, although subjection of the
crude reaction mixture to 3.0 M aq. HCl and subsequent ion-
exchange chromatography, initially on DOWEX 1X8-200 (OH−
form) followed by DOWEX 50WX8 (H+ form), allowed the iso-
lation of (−)-1-epi-alexine 51 [also called (−)-2,3,7-tri-epi-austra-
line]34,35 in 29% yield from 48. A comparison of the 1H and
13C NMR spectroscopic data, and specific rotation, of our syn-
thetic sample of (−)-1-epi-alexine 51 {[α]2D0 −48 (c 0.03 in H2O);
[α]2D0 −60 (c 0.03 in MeOH)} with those reported for (+)-1-epi-
alexine 51 isolated from Castanospermum australe {[α]D +59.7
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0.10 mmol) in CH2Cl2 (EtOH-stabilised, 3 mL). The resultant
mixture was left to stir at rt for 12 h then concentrated
in vacuo. The residue was dissolved in degassed MeOH (3 mL)
and 10% Pd/C (18 mg, 50% w/w) and Et3N (0.03 mL,
0.20 mmol) were added. The reaction mixture was stirred at rt
under 1 atm H2 for 18 h then filtered through Celite® (eluent
MeOH) and concentrated in vacuo. The residue was dissolved
in MeOH (2 mL) and co-evaporated with 6.0 M aq. HCl (2 mL),
the process repeated, and the residue was dissolved in H2O
(2 mL) and purified on DOWEX 1X8-200 (OH− form) ion
exchange resin to give 10 as a colourless oil (13 mg, 75%,
>99 : 1 dr);7,14 [α]D20 −39.5 (c 0.3 in H2O) {lit. for (+)-10 [α]D27
+47.0 (c 0.65 in H2O);14a lit. for (−)-10 [α]2D5 −45.9 (c 0.2 in
H2O);7 [α]2D2 −45.3 (c 1.5 in H2O)};14b δH (500 MHz, MeOH-d4)
1.50–1.58 (1H, m, C(7)HA), 1.69–1.70 (1H, m, C(6)HA),
1.89–1.95 (1H, m, C(6)HB), 2.16–2.22 (1H, m, C(7)HB), 2.86 (1H,
td, J 10.1, 6.0, C(5)HA), 2.97–3.01 (1H, m, C(5)HB), 3.29 (1H, td,
J 8.8, 4.1, C(3)H), 3.47 (1H, td, J 8.2, 2.3, C(7a)H), 3.81 (1H, dd,
J 5.3, 2.3, C(1)H), 3.84–3.91 (2H, m, C(1′)H2), 3.93 (1H, dd,
J 8.8, 5.3, C(2)H); δH (500 MHz, D2O) 1.39–1.47 (1H, m, C(7)-
HA), 1.53–1.62 (1H, m, C(6)HA), 1.78–1.84 (1H, m, C(6)HB),
2.07–2.13 (1H, m, C(7)HB), 2.64 (1H, td, J 10.4, 5.7, C(5)HA),
2.82–2.85 (1H, m, C(5)HB), 3.14 (1H, dt, 6.3, 9.5, C(3)H), 3.31
(1H, td, 7.9, 2.2, C(7a)H), 3.79 (2H, d, J 6.3, C(1′)H2), 3.82 (1H,
dd, J 5.0, 2.2, C(1)H), 3.92 (1H, dd, J 9.5, 5.0, C(2)H); δH
(500 MHz, D2O [TSP])37 1.49–1.57 (1H, m, C(7)HA), 1.63–1.73
(1H, m, C(6)HA), 1.89–1.94 (1H, m, C(6)HB), 2.17–2.23 (1H, m,
C(7)HB), 2.76 (1H, td, J 10.4, 5.7, C(5)HA), 2.94–2.97 (1H, m,
C(5)HB), 3.25 (1H, app dd, 9.5, 6.6, C(3)H), 3.43 (1H, app dd,
8.2, 2.3, C(7a)H), 3.89 (2H, d, J 6.6, C(1′)H2), 3.82 (1H, dd, J 5.0,
2.3, C(1)H), 3.92 (1H, dd, J 9.5, 5.0, C(2)H); δC (125 MHz,
MeOH-d4) 27.3 (C(6)), 30.9 (C(7)), 46.5 (C(5)), 60.9 (C(1′)), 66.9
(C(3)), 71.7 (C(7a)), 72.4 (C(2)), 77.0 (C(1)); δC (125 MHz, D2O)
Scheme 10 Reagents and conditions: (i) Zn, AcOH, THF, H2O, 70 °C, 2 h; (ii)
LiAlH4, THF, −78 °C to rt, 12 h; (iii) NaIO4, MeOH, H2O, rt, 4 h then NaBH4, rt,
12 h; (iv) HCl (3.0 M aq.), MeOH, reflux, 2 h.
Experimental
General experimental details
Reactions involving moisture-sensitive reagents were carried 25.7 (C(6)), 29.3 (C(7)), 47.2 (C(5)), 59.4 (C(1′), 64.4 (C(3)), 69.5
out under a nitrogen atmosphere using standard vacuum line (C(7a)), 70.8 (C(2)), 75.4 (C(1)); δC (125 MHz, D2O [TSP])37 28.6
techniques and glassware that was flame dried and cooled (C(6)), 32.2 (C(7)), 50.1 (C(5)), 62.3 (C(1′), 67.3 (C(3)), 72.6
under nitrogen before use. Solvents were dried according to (C(7a)), 73.8 (C(2)), 78.2 (C(1)); m/z (ESI)+ 174 ([M + H]+, 100%);
the procedure outlined by Grubbs and co-workers.36 Organic HRMS (ESI+) C8H16NO3 ([M + H]+) requires 174.1125; found
+
layers were dried over MgSO4. Thin layer chromatography was 174.1129.
performed on aluminium plates coated with 60 F254 silica.
Flash column chromatography was performed on Kieselgel 60 dihydroxyethyl)-3,4-dihydroxy-3,4-O-isopropylidine-1,2,3,4,7,8-
silica.
hexahydroazocine 11. LiAlH4 (1.0 in THF, 0.52 mL,
(2S,3S,4R,1′R,αR,Z)-N(1)-(α-Methyl-p-methoxybenzyl)-2-(1′,2′-
M
Melting points are uncorrected. Specific rotations are 0.52 mmol) was added to a stirred solution of 4 (118 mg,
reported in 10−1 deg cm2 g−1 and concentrations in g per 0.26 mmol) in THF (10 mL) at −78 °C. The resultant mixture
100 mL. IR spectra were recorded as a thin film on NaCl plates was allowed to warm to rt over 12 h before 2.0 M aq. NaOH
(film), or using an ATR module (ATR), as stated. Selected (1 mL) was added. The resultant mixture was stirred at rt for
characteristic peaks are reported in cm−1. NMR spectra were 1 h then filtered through Celite® (eluent EtOAc), dried and
recorded in the deuterated solvent stated. The field was locked concentrated in vacuo. Purification via flash column chromato-
by external referencing to the relevant deuteron resonance. graphy (eluent CH2Cl2–MeOH, 20 : 1) gave 11 as a white oil
1
1H–1H COSY and H–13C HMQC analyses were used to estab- (91 mg, 89%, >99 : 1 dr); [α]2D5 +44.9 (c 0.2 in MeOH); νmax
lish atom connectivity. Accurate mass measurements were run (film) 3356 (O–H), 2933 (C–H), 1609 (CvC); δH (400 MHz,
on
a
MicroTOF instrument internally calibrated with CDCl3) 1.46 (3H, s, MeCMe), 1.49 (3H, d, J 6.8, C(α)Me), 1.53
(3H, s, MeCMe), 1.66 (1H, br s, OH), 2.01–2.08 (1H, m, C(7)HA),
polyalanine.
(1R,2S,3S,7aR)-1,2-Dihydroxy-3-hydroxymethylhexahydro-1H- 2.21–2.29 (1H, m, C(7)HB), 2.33 (1H, br s, OH), 2.77 (1H, app
pyrrolizidine [(−)-7a-epi-hyacinthacine A1] 10. I2 (77 mg, dd, J 14.9, 11.1, C(8)HA), 3.29–3.35 (2H, m, C(2)H, C(8)HB),
0.30 mmol) was added to a stirred solution of 12 (35 mg, 3.49–3.54 (2H, m, C(2′)H2), 3.80 (3H, s, OMe), 3.80–3.84 (1H,
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m, C(1′)H), 4.33 (1H, q, J 6.8, C(α)H), 4.63 (1H, dd, J 10.4, 5.3, X-Ray crystal structure determination for 15‡
C(3)H), 5.24–5.27 (1H, m, C(4)H), 5.59–5.64 (1H, m, C(5)H),
5.89–5.96 (1H, m, C(6)H), 6.85 (2H, d, J 8.6, Ar), 7.20 (2H, d, Data were collected using an Oxford Diffraction SuperNova diffr-
J 8.6, Ar); δC (100 MHz, CDCl3) 23.0 (C(α)Me), 26.7, 28.1 (CMe2), actometer with graphite monochromated Cu-Kα radiation using
31.1 (C(7)), 48.4 (C(8)), 55.0 (C(α)), 55.2 (OMe), 61.2 (C(2)), 64.8 standard procedures at 150 K. The structure was solved by direct
(C(2′)), 73.9 (C(1′)), 77.8 (C(4)), 80.8 (C(3)), 110.2 (CMe2), 113.7, methods (SIR92); all non-hydrogen atoms were refined with an-
127.9 (Ar), 131.2 (C(6)), 132.7 (C(5)), 137.7, 158.2 (Ar); m/z (ESI+) isotropic thermal parameters. Hydrogen atoms were added at
777 ([2M + Na]+, 100%), 400 ([M + Na]+, 30%); HRMS (ESI+) idealised positions. The structure was refined using CRYSTALS.38
C21H31NNaO5+ ([M + Na]+) requires 400.2094; found 400.2094.
X-ray crystal structure data for 15 [C8H15NO3]: M = 173.21,
(2S,3S,4R,αR,Z)-N(1)-(α-Methyl-p-methoxybenzyl)-2-(hydroxy- orthorhombic, space group P212121, a = 6.9174(2) Å, b = 9.4363(3)
methyl)-3,4-dihydroxy-3,4-O-isopropylidine-1,2,3,4,7,8-hexa- Å, c = 14.0634(4) Å, V = 917.99(5) Å3, Z = 4, μ = 0.790 mm−1, col-
hydroazocine 12. NaIO4 (2.63 g, 12.3 mmol) was added to a ourless plate, crystal dimensions = 0.03 × 0.13 × 0.20 mm. A
solution of 11 (464 mg, 1.23 mmol) in MeOH (10 mL). The total of 1119 unique reflections were measured for 6 < θ < 76
resultant mixture was stirred at rt for 4 h then filtered through and 2676 reflections were used in the refinement. The final
Celite® (eluent MeOH). NaBH4 (465 mg, 12.3 mmol) was then parameters were wR2 = 0.086 and R1 = 0.038 [I > 0.0σ(I)], with
added to the filtrate and the reaction mixture was allowed to Flack enantiopole = 0.1(2).39 CCDC 922276.
stir at rt for 4 h before satd aq. NH4Cl (1 mL) was added. The
(1R,2S,3S,4R,7R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-7-iodo-
resultant mixture was concentrated in vacuo and the residue hexahydropyrrolizidinium iodide 17·HI. I2 (21 mg, 0.08 mmol)
was partitioned between CH2Cl2 (10 mL) and H2O (10 mL). was added to a stirred solution of 15 (14 mg, 0.08 mmol) in
The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and MeOH (1.5 mL). The resultant mixture was stirred at rt for 12 h
the combined organic extracts were dried and concentrated then concentrated in vacuo to give 17·HI as a brown oil (35 mg,
in vacuo. Purification via flash column chromatography gave quant, >99 : 1 dr); δH (500 MHz, MeOH-d4) 2.44–2.49 (1H, m,
12 as a colourless oil (66 mg, 15%, >99 : 1 dr); [α]2D5 +2.81 (c C(6)HA), 2.76–2.85 (1H, m, C(6)HB), 3.44–3.48 (1H, m, C(5)HA),
0.96 in MeOH); νmax (film) 3463 (O–H), 2970, 2937 (C–H), 1609 3.54 (1H, td, J 12.0, 6.9, C(5)HB), 3.63–3.67 (1H, m, C(3)H), 3.85
(CvC); δH (400 MHz, CDCl3) 1.40 (3H, s, MeCMe), 1.49 (3H, s, (1H, dd, J 12.1, 5.0, C(1′)HA), 4.01 (1H, dd, J 12.1, 2.8, C(1′)HB),
MeCMe), 1.50 (3H, d, J 6.8, C(α)Me), 2.03–2.09 (1H, m, C(7)HA), 4.18 (1H, dd, J 10.4, 3.3, C(2)H), 4.26–4.32 (2H, m, C(7)H, C(7a)
2.22–2.30 (1H, m, C(7)HB), 2.36 (1H, br s, OH), 2.73 (1H, app H), 4.41 (1H, app t, J 2.8, C(1)H); δC (125 MHz, MeOH-d4)
dd, J 14.4, 11.4, C(8)HA), 3.31–3.45 (3H, m, C(1′)HA, C(2)H, C(8) 9.3 (C(7)), 36.8 (C(6)), 57.5 (C(5)), 58.5 (C(1′)), 71.8 (C(7a)), 73.3
HB), 3.65 (1H, dd, J 10.9, 5.1, C(1′)HB), 3.80 (3H, s, OMe), 4.24 (C(2)), 74.7, 74.8 (C(1), C(3)); m/z (ESI+) 322 ([M + Na]+, 10%),
(1H, q, J 6.8, C(α)H), 4.34 (1H, dd, J 10.1, 5.6, C(3)H), 5.15–5.18 300 ([M + H]+, 100%); HRMS (ESI+) C8H15INO3 ([M + H]+)
+
(1H, m, C(4)H), 5.64 (1H, dd, J 11.1, 5.8, C(5)H), 5.83–5.91 (1H, requires 300.0091; found 300.0086.
m, C(6)H), 6.87 (2H, d, J 8.7, Ar), 7.25 (2H, d, J 8.7, Ar); δC
(1R,2S,3S,7aR)-1,2-Dihydroxy-3-hydroxymethylhexahydro-1H-
(100 MHz, CDCl3) 22.2 (C(α)Me), 26.4, 28.0 (CMe2), 30.6 (C(7)), pyrrolizidine [(−)-hyacinthacine A1] 18. 10% Pd/C (17 mg,
48.9 (C(8)), 53.5 (C(α)), 55.2 (OMe), 62.0 (C(1′)), 62.1 (C(2)), 77.0 50% w/w) was added to a solution of 17·HI (35 mg, 0.08 mmol)
(C(4)), 80.9 (C(3)), 109.2 (CMe2), 113.9, 127.6 (Ar), 130.6 (C(6)), and Et3N (0.08 mL, 0.58 mmol) in degassed MeOH (2 mL). The
133.4 (C(5)), 137.9, 158.4 (Ar); m/z (ESI+) 717 ([2M + Na]+, resultant mixture was stirred at rt under 1 atm H2 for 18 h
100%), 370 ([M + Na]+, 80%), 348 ([M + H]+, 30%); HRMS (ESI+) then filtered through Celite® (eluent MeOH) and concentrated
C20H29NNaO4+ ([M + Na]+) requires 370.1989; found 370.1983.
in vacuo. The residue was dissolved in HCl (1.25 M in MeOH,
(2S,3S,4R,Z)-2-(Hydroxymethyl)-3,4-dihydroxy-1,2,3,4,7,8-hexa- 2 mL). The resultant solution was stirred at rt for 5 min then
hydroazocine 15. 3.0 M aq. HCl (0.5 mL) was added to a concentrated in vacuo. This process was repeated and the
stirred solution of 12 (53 mg, 0.15 mmol) in MeOH (1 mL). residue was dissolved in H2O (2 mL) and purified on DOWEX
The reaction mixture was heated at reflux for 2 h then concen- 1X8-200 (OH− form) ion exchange resin to give 18 as a colour-
trated in vacuo. The residue was dissolved in H2O (1.5 mL) less oil (13 mg, 94%, >99 : 1 dr);2,14b,16 [α]D20 −34.1 (c 0.4 in
and purified on DOWEX 1X8-200 (OH− form) ion exchange H2O); [α]D20 −32.0 (c 0.64 in MeOH); {lit. for (+)-18 [α]2D0 +38.2
resin to give 15 as a white solid (18 mg, 69%, >99 : 1 dr); (c 0.23 in H2O);2 [α]D24 +35.6 (c 0.32 in H2O);14b [α]D20 +45.0
mp 194–198 °C; [α]D20 −8.1 (c 0.27 in H2O); δH (500 MHz, D2O) (c 0.23 in H2O);16a [α]D25 +33.5 (c 0.2 in MeOH);16b [α]2D1 +43.9
2.09–2.22 (2H, m, C(7)H2), 2.35–2.39 (1H, m, C(2)H), 2.46–2.52 (c 0.29 in H2O);16c [α]D22 +43.5 (c 0.23 in H2O);16d lit. for (−)-18
(1H, m, C(8)HA), 3.02 (1H, ddd, J 13.2, 4.4, 3.2, C(8)HB), [α]2D0 −20.0 (c 1.0 in MeOH)};16e δH (500 MHz, MeOH-d4)
3.38 (1H, dd, J 11.5, 7.9, C(1′)HA), 3.54 (1H, dd, J 9.5, 3.2, 1.66–1.72 (1H, m, C(7)HA), 1.75–1.82 (1H, m, C(6)HA),
C(3)H), 3.78 (1H, dd, J 11.5, 3.2, C(1′)HB), 4.79 (1H, app ddd, 1.92–1.99 (1H, m, C(6)HB), 2.06–2.13 (1H, m, C(7)HB),
J 8.2, 3.2, 1.3, C(4)H), 5.54–5.58 (1H, m, CH), 5.89–5.95 (1H, m, 2.63–2.68 (1H, m, C(5)HA), 2.75–2.79 (1H, m, C(3)H), 3.05–3.09
CH); δC (125 MHz, D2O) 29.4, (C(7)), 50.4 (C(8)), 63.5 (C(1′)), (1H, m, C(5)HB), 3.46 (1H, td, J 7.6, 3.8, C(7a)H), 3.60 (1H, dd,
64.2, (C(2)), 69.2 (C(4)), 75.9 (C(3)), 131.2, 131.3 (C(5), C(6)); J 11.0, 6.6, C(1′)HA), 3.81 (1H, dd, J 11.0, 3.5, C(1′)HB),
m/z (ESI+) 196 ([M + Na]+, 100%), 174 ([M + H]+, 75%); HRMS 3.87–3.90 (2H, m, C(1)H, C(2)H); δC (125 MHz, MeOH-d4) 25.2
(ESI+) C8H15NNaO3 ([M + Na]+) requires 196.0944; found (C(7)), 28.1 (C(6)), 56.8 (C(5)), 64.7 (C(1′)), 66.9 (C(7a)), 71.1
+
196.0950.
(C(3)), 72.9 (C(1)), 76.8 (C(2)); m/z (ESI+) 196 ([M + Na]+, 15%),
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174 ([M + H]+, 100%); HRMS (ESI+) C8H16NO3 ([M + H]+) (63.3 g, 156 mmol) and KOtBu (17.5 g, 156 mmol) in THF
requires 174.1125; found 174.1123. (100 mL) that had been stirring at rt for 2 h. The resultant
+
(S,S)-2,2-Dimethyl-4,5-dihydroxymethyl-1,3-dioxolane 20. Step 1: mixture was stirred at rt for 1 h before H2O (100 mL) was
(MeO)2CMe2 (12.0 mL, 96.9 mmol) and TsOH (128 mg, added. The aqueous layer was extracted with Et2O (2 × 100 mL)
0.65 mmol) were added to a solution of dimethyl L-tartrate 19 and the combined organic extracts were washed sequentially
(11.5 g, 64.6 mmol) in PhMe (75 mL). The reaction mixture with H2O (150 mL) and brine (150 mL), then dried and con-
was fitted with a Dean-Stark apparatus and heated at reflux for centrated in vacuo. The residue was passed through a plug of
16 h, then allowed to cool to rt before satd aq. NaHCO3 silica (eluent 30–40 °C petrol–EtOAc, 50 : 1) to give 23 as a col-
(50 mL) was added. The resultant mixture was stirred at rt for ourless oil (13.0 g, 92%, >99 : 1 dr);20 [α]D20 −6.1 (c 0.2 in
15 min then the aqueous layer was extracted with EtOAc (2 × CHCl3); δH (400 MHz, CDCl3) 0.07 (3H, s, MeSiMe), 0.08 (3H, s,
30 mL). The combined organic extracts were washed with H2O MeSiMe), 0.90 (9H, s, SiCMe3), 1.43 (3H, s, MeCMe), 1.44 (3H,
(40 mL) and brine (40 mL), then dried and concentrated s, MeCMe), 3.74–3.78 (3H, m, CH, CH2OSi), 4.32–4.37 (1H, m,
in vacuo to give a yellow oil (13.5 g).
Step 2: LiAlH4 (1.0 M in THF, 100 mL, 100 mmol) was dt, J 17.2, 1.4, CHvCHAHB), 5.82–5.91 (1H, m, CHvCH2).
added dropwise to a stirred solution of the residue (10.0 g) in (S,S)-2,2-Dimethyl-4-[(tert-butyldimethylsilyloxy)methyl]-
CH), 5.24 (1H, app dt, J 10.2, 1.4, CHvCHAHB), 5.37 (1H, app
THF (160 mL) at 0 °C. The reaction mixture was heated at 5-vinyl-1,3-dioxolane 24. TBAF (1.0 M in THF, 57.3 mL,
reflux for 16 h then allowed to cool to rt before 10% aq. NaOH 57.3 mmol) was added to a stirred solution of 23 (13.0 g,
(150 mL), H2O (70 mL) and EtOAc (150 mL) were added sequen- 47.7 mmol) in THF (500 mL) at 0 °C. The resultant mixture
tially. The resultant mixture was stirred at rt for 1 h then filtered was stirred at 0 °C for 2.5 h before satd aq. NH4Cl (15 mL) was
through Celite® (eluent EtOAc), dried and concentrated in vacuo added. The resultant mixture was partitioned between Et2O
to give 20 as a pale yellow oil (7.00 g, 90% from 19, >99 : 1 (200 mL) and H2O (300 mL) and the aqueous layer was
dr);17,18 δH (400 MHz, CDCl3) 1.44 (6H, s, CMe2), 2.52 (2H, br s, extracted with Et2O (2 × 200 mL). The combined organic
OH), 3.67–3.74 (2H, m, 2 × CHAHBOH), 3.81–3.87 (2H, m, 2 × extracts were washed with brine (500 mL), then dried and con-
CHAHBOH), 4.02–4.05 (2H, m, C(4)H, C(5)H).
centrated in vacuo. Purification via flash column chromato-
(S,S)-2,2-Dimethyl-4-(tert-butyldimethylsilyloxy)methyl- graphy gave 24 as a colourless oil (5.57 g, 74%, >99 : 1 dr);21
5-hydroxymethyl-1,3-dioxolane 21. A solution of 20 (10.7 g, [α]2D0 −3.6 (c 1.1 in CHCl3); δH (400 MHz, CDCl3) 1.45 (6H, s,
66.0 mmol) in THF (50 mL) was added dropwise to a stirred CMe2), 1.99 (1H, br s, OH), 3.58–3.64 (1H, m, CHAHBOH),
slurry of NaH (60% dispersion in mineral oil, 2.61 g, 3.79–3.87 (2H, m, CHAHBOH, CH), 4.33 (1H, app t, J 7.5, CH),
66.0 mmol) in THF (50 mL) at 0 °C. The reaction mixture was 5.28 (1H, app dt, J 10.2, 1.0, CHvCHAHB), 5.40 (1H, app dt,
allowed to warm to for 45 min before TBDMSCl (9.84 g, J 17.1, 1.0, CHvCHAHB), 5.80–5.89 (1H, m, CHvCH2).
66.0 mmol) was added. The resultant mixture was stirred at rt
tert-Butyl (S,S,E)-4,5-dihydroxy-4,5-O-isopropylidenehepta-
for 16 h then diluted with Et2O (50 mL) and satd aq. NaHCO3 2,6-dienoate 26. DMSO (3.25 mL, 45.7 mmol) was added drop-
(2 × 50 mL). The aqueous layer was extracted with Et2O (2 × wise to a stirred solution of (COCl)2 (3.63 mL, 42.3 mmol) in
50 mL) and the combined organic extracts were dried and con- CH2Cl2 (50 mL) at −78 °C. The resultant mixture was left to
centrated in vacuo. Purification via flash column chromato- stir at −78 °C for 15 min before 24 (5.57 g, 35.2 mmol) in
graphy (eluent 30–40 °C petrol–EtOAc, 5 : 1) gave 21 as a pale CH2Cl2 (50 mL) was added. The reaction was stirred for 1 h at
yellow oil (15.3 g, 83%, >99 : 1 dr);18,19 [α]D24 +14.5 (c 1.0 in −78 °C then Et3N (9.82 mL, 70.4 mmol) was added and the
CHCl3); δH (400 MHz, CDCl3) 0.09 (6H, s, SiMe2), 0.91 (9H, s, reaction mixture was allowed to warm to rt over 30 min. After
t
SiCMe3), 1.41 (3H, s, MeCMe), 1.42 (3H, s, MeCMe), 2.38 (1H, this time Ph3PvCHCO2 Bu (13.3 g, 35.2 mmol) was added and
dd, J 8.3, 4.4, OH), 3.64–3.81 (3H, m, CH2OH, CHAHBOSi), the resultant mixture was left to stir for 12 h at rt then concen-
3.86–3.92 (2H, m, CH, CHAHBOSi), 4.00 (1H, dt, J 7.5, 4.6, CH).
trated in vacuo to give (S,S,E)-26 in 98 : 2 dr. Purification via
(S,S)-2,2-Dimethyl-4-(tert-butyldimethylsilyloxy)methyl- flash column chromatography (eluent 30–40 °C petrol–Et2O,
5-hydroxymethyl-1,3-dioxolane 23. DMSO (14.8 mL, 208 mmol) 25 : 1) gave (S,S,E)-26 as a colourless oil (5.64 g, 63%, >99 : 1
was added dropwise to a stirred solution of (COCl)2 (8.92 mL, dr);23 [α]D25 +7.1 (c 0.4 in CHCl3); δH (400 MHz, CDCl3) 1.46 (3H,
104 mmol) in CH2Cl2 (100 mL) at −78 °C. The reaction s, MeCMe), 1.47 (3H, s, MeCMe), 1.49 (9H, s, CMe3), 4.14 (1H,
mixture was left to stir for 15 min before a solution of 21 app t, J 7.7, C(5)H), 4.21–4.25 (1H, m, C(4)H), 5.31 (1H, app d,
(14.4 g, 51.9 mmol) in CH2Cl2 (50 mL) was added. The resul- J 9.6, C(7)HA), 5.41 (1H, app d, J 17.1, C(7)HB), 5.78–5.88 (1H,
tant mixture was stirred at −78 °C for 1 h, then Et3N (43.4 mL, m, C(6)H), 6.04 (1H, app dd, J 15.7, 1.5, C(2)H), 6.76 (1H, dd,
312 mmol) was added and the reaction mixture was allowed to J 15.7, 5.5, C(3)H).
warm to rt over 30 min. The reaction mixture was then diluted
tert-Butyl (3S,4S,5S,αR)-3-[N-but-3′-enyl-N-(α-methyl-p-
with CH2Cl2 (50 mL) and the resultant solution washed methoxybenzyl)amino]-4,5-dihydroxy-4,5-O-isopropylidenehept-
sequentially with H2O (100 mL) and brine (100 mL). The 6-enoate 27. BuLi (2.5 M in hexanes, 0.47 mL, 1.18 mmol) was
aqueous layer was extracted with CH2Cl2 (2 × 100 mL) and the added dropwise to a stirred solution of (R)-N-but-3-enyl-
combined organic extracts dried and concentrated in vacuo. N-(α-methyl-p-methoxybenzyl)amine10 (258 mg, 1.26 mmol) in
The residue was dissolved in THF (50 mL) and the resultant THF (5 mL) at −78 °C. After stirring at −78 °C for 30 min a
solution was added dropwise to a solution of [Ph3PMe]+[I]− solution of (S,S,E)-26 (200 mg, 0.79 mmol) in THF (5 mL) at
3196 | Org. Biomol. Chem., 2013, 11, 3187–3202
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−78 °C was added dropwise via cannula. The reaction mixture (C(3)), 70.4 (C(2)), 78.1 (C(4)), 81.4 (C(5)), 82.2 (CMe3), 108.4
was left to stir for 2 h, before satd aq. NH4Cl (2 mL) was (CMe2), 113.4 (Ar), 115.4 (C(4′)), 116.3 (C(7)), 129.2, 134.4 (Ar),
added. The resultant mixture was allowed to warm to rt over 136.9, 137.3 (C(6), C(3′)), 158.7 (Ar), 173.3 (C(1)); m/z (ESI+) 498
15 min then concentrated in vacuo. The residue was then parti- ([M + Na]+, 95%), 476 ([M + H]+, 100%); HRMS (ESI+)
tioned between CH2Cl2 (10 mL) and 10% aq. citric acid solu- C27H41NNaO6+ ([M + Na]+) requires 498.2826; found 498.2824.
tion (10 mL). The aqueous layer was extracted with CH2Cl2 (2 ×
10 mL) and the combined organic extracts were washed p-methoxybenzyl)-3′,4′-dihydroxy-3′,4′-O-isopropylidine-1′,2′,3′,4′,7′,8′-
sequentially with satd aq. NaHCO3 (20 mL), H2O (20 mL) and hexahydroazocin-2′-yl]ethanoate 29. Grubbs (625 mg,
tert-Butyl (2R,2′S,3′S,4′S,αR,Z)-2-hydroxy-2-[N(1′)-(α-methyl-
I
brine (20 mL), then dried and concentrated in vacuo to give 27 0.76 mmol) was added to a stirred solution of 28 (3.40 g,
in >99 : 1 dr. Purification via flash column chromatography 7.15 mmol) in CH2Cl2 (300 mL) at 30 °C. The resultant mixture
(eluent 30–40 °C petrol–EtOAc, 10 : 1) gave 27 as a yellow oil was stirred at 30 °C for 12 h then concentrated in vacuo. The
(230 mg, 65%, >99 : 1 dr); [α]2D5 −23.6 (c 0.6 in CHCl3); νmax residue was dissolved in CH2Cl2 (50 mL) and tris(hydroxy-
(film) 2979, 2933, 2835 (C–H), 1726 (CvO), 1640, 1610 (CvC); methyl)phosphine (17.7 g, 143 mmol), Et3N (2.0 mL,
δH (400 MHz, CDCl3) 1.38 (9H, app d, J 7.3, C(α)Me, CMe2), 14.3 mmol) and excess silica were added sequentially. The
1.44 (9H, s, CMe3), 2.10–2.17 (2H, m, C(2′)H2), 2.20 (1H, dd, resultant mixture was left to stir at rt for 12 h, then concen-
J 15.7, 5.8, C(2)HA), 2.31 (1H, dd, J 15.7, 6.3, C(2)HB), 2.48–2.61 trated in vacuo. Purification via flash column chromatography
(2H, m, C(1′)H2), 3.54 (1H, app q, J 5.8, C(3)H), 3.79 (3H, s, (eluent 30–40 °C petrol–EtOAc, 5 : 1) gave 29 as a yellow crystal-
OMe), 3.84 (1H, dd, J 8.3, 4.3, C(4)H), 3.93 (1H, q, J 6.8, C(α)H), line solid (2.91 g, 91%, >99 : 1 dr); mp 60–63 °C; [α]2D5 +17.9
4.09 (1H, app t, J 7.8, C(5)H), 4.91–5.00 (2H, m, C(4′)H2), 5.24 (c 1.6 in CHCl3); νmax (ATR) 3482 (O–H), 2980, 2934, 2836
(1H, app d, J 10.6, C(7)HA), 5.39 (1H, app d, J 17.2, C(7)HB), (C–H), 1723 (CvO), 1611 (CvC); δH (400 MHz, CDCl3) 1.11 (3H,
5.64–5.75 (1H, m, C(3′)H), 5.83–5.93 (1H, m, C(6)H), 6.82 (2H, d, s, MeCMe), 1.29 (3H, s, MeCMe), 1.35 (9H, s, CMe3), 1.40 (3H, d,
J 8.7, Ar), 7.25 (2H, d, J 8.7, Ar); δC (100 MHz, CDCl3) 19.4 J 6.7, C(α)Me), 2.02–2.12 (1H, m, C(7′)HA), 2.34–2.45 (1H, m,
(C(α)Me), 27.0 (MeCMe), 28.1 (MeCMe, CMe3), 34.3, 34.5 (C(2), C(7′)HB), 2.83–2.91 (1H, m, C(8′)HA), 3.11–3.16 (1H, m, C(8′)HB),
C(2′)), 46.3 (C(1′)), 55.2 (C(3), OMe), 57.0 (C(α)), 80.0 (CMe3), 3.17 (1H, app d, J 8.8, C(2′)H), 3.21 (1H, d, J 4.6, OH), 3.77 (3H,
81.0 (C(5)), 82.1 (C(4)), 109.0 (CMe2), 113.3 (Ar), 115.2 (C(4′)), s, OMe), 3.94 (1H, q, J 6.7, C(α)H), 4.27–4.33 (2H, m, C(2)H,
118.0 (C(7)), 128.8 (Ar), 136.1 (C(6)), 136.2 (Ar), 137.0 (C(3′), C(3′)H), 4.66–4.70 (1H, m, C(4′)H), 5.65–5.73 (1H, m, C(6′)H),
158.4 (Ar), 172.0 (C(1)); m/z (ESI)+ 482 ([M + Na]+, 100%); HRMS 5.79–5.84 (1H, m, C(5′)H), 6.84 (2H, d, J 8.7, Ar), 7.25 (2H, d,
(ESI+) C27H42NO5+ ([M + H]+) requires 460.3057; found 460.3041. J 8.7, Ar); δC (100 MHz, CDCl3) 22.3 (C(α)Me), 26.1, 27.0 (CMe2),
tert-Butyl (2R,3S,4S,5S,αR)-2,4,5-trihydroxy-3-[N-but-3′-enyl- 27.9 (CMe3), 30.5 (C(7′)), 46.5 (C(8′)), 55.2 (OMe), 61.3 (C(α)),
N-(α-methyl-p-methoxybenzyl)amino]-4,5-O-isopropylidenehept- 63.3 (C(2′)), 68.6, 78.0, 78.4 (C(2), C(3′), C(4′)), 82.3 (CMe3), 108.1
6-enoate 28. BuLi (2.3 M in hexanes, 8.35 mL, 19.4 mmol) was (CMe2), 113.8 (Ar), 128.5, 128.6 (C(6′), Ar), 130.6 (C(5′)), 137.1,
added dropwise to a stirred solution of (R)-N-but-3-enyl- 158.5 (Ar), 173.6 (C(1)); m/z (ESI+) 917 ([2M + Na]+, 100%), 470
N-(α-methyl-p-methoxybenzyl)amine10 (4.12 g, 20.0 mmol) in ([M
+ +
Na]+, 65%), 448 ([M H]+, 90%); HRMS (ESI+)
THF (10 mL) at −78 °C. After stirring at −78 °C for 30 min a C25H37NNaO6+ ([M + Na]+) requires 470.2513; found 470.2500.
solution of (S,S,E)-26 (3.19 g, 12.5 mmol) in THF (5 mL) at
X-Ray crystal structure determination for 29‡
−78 °C was added dropwise via cannula. The reaction mixture
was left to stir for 2 h, before (−)-CSO (5.75 g, 25.0 mmol) was Data were collected using a Nonius κ-CCD diffractometer with
added. The resultant mixture was allowed to warm to rt over graphite monochromated Mo-Kα radiation using standard pro-
12 h then concentrated in vacuo. Purification via flash column cedures at 150 K. The structure was solved by direct methods
chromatography (eluent 30–40 °C petrol–EtOAc, 30 : 1) gave 27 (SIR92); all non-hydrogen atoms were refined with anisotropic
as a colourless oil (520 mg, 9%, >99 : 1 dr). Further elution thermal parameters. Hydrogen atoms were added at idealised
gave 28 as a yellow oil (3.47 g, 58%, >99 : 1 dr); [α]D25 −57.8 positions. The structure was refined using CRYSTALS.38
(c 0.6 in CHCl3); νmax (film) 3491 (O–H), 2980, 2934, 2836
X-ray crystal structure data for 29 [C25H37NO6]: M = 447.57,
(C–H), 1726 (CvO), 1640, 1610 (CvC); δH (400 MHz, CDCl3) orthorhombic, space group P212121, a = 9.0523(1) Å, b =
1.30 (3H, s, MeCMe), 1.34 (3H, s, MeCMe), 1.44 (3H, d, J 6.8, 11.9795(2) Å, c = 22.5183(4) Å, V = 2441.93(7) Å3, Z = 4, μ =
C(α)Me), 1.49 (9H, s, CMe3), 2.21–2.31 (1H, m, C(2′)HA), 0.086 mm−1, colourless block, crystal dimensions = 0.23 × 0.29
2.33–2.42 (1H, m, C(2′)HB), 2.60–2.67 (1H, m, C(1′)HA), × 0.34 mm. A total of 3145 unique reflections were measured
2.98–3.06 (1H, m, C(1′)HB) overlapping 3.04 (1H, d, J 6.2, OH), for 5 < θ < 27 and 2332 reflections were used in the refinement.
3.50 (1H, app d, J 9.4, C(3)H), 3.74 (1H, app d, J 6.2, C(2)H), The final parameters were wR2 = 0.068 and R1 = 0.032 [I >
3.80 (3H, s, OMe), 3.99 (1H, q, J 6.8, C(α)H), 4.06 (1H, app t, −3.0σ(I)]. CCDC 922277.
J 9.4, C(4)H), 4.22 (1H, app t, J 7.8, C(5)H), 4.98–5.01 (1H, m,
tert-Butyl (2R,2′S,3′S,4′S,Z)-2-hydroxy-2-[3′,4′-dihydroxy-3′,4′-
C(4′)HA), 5.07–5.09 (1H, m, C(4′)HB), 5.21–5.24 (1H, m, C(7)HA), O-isopropylidine-1′,2′,3′,4′,7′,8′-hexahydroazocin-2′-yl]ethanoate
5.40–5.45 (1H, m, C(7)HB), 5.74–5.85 (1H, m, C(3′)H), 5.98–6.06 32 and (1R,2S,3S,7S,9R,αR,Z)-2,3-dihydroxy-2,3-O-isopropyli-
(1H, m, C(6)H), 6.83 (2H, d, J 8.4, Ar), 7.26 (2H, d, J 8.4, Ar); δC dene-9-(tert-butoxycarbonyl)-N(10)-(α-methyl-p-methoxybenzyl)-
(100 MHz, CDCl3) 20.4 (C(α)Me), 26.7, 27.1 (CMe2), 28.1 8-oxa-10-azabicyclo[5.2.1]dec-4-ene 33. I2 (340 mg, 1.34 mmol)
(CMe3), 33.6 (C(2′)), 46.5 (C(1′)), 55.2 (OMe), 57.4 (C(α)), 61.9 and NaHCO3 (113 mg, 1.34 mmol) were added sequentially to
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a stirred solution of 29 (200 mg, 0.45 mmol) in CH2Cl2 (EtOH- m, C(6)H), 5.80–5.86 (1H, m, C(5)H), 6.85 (2H, d, J 8.7, Ar), 7.19
stabilised, 20 mL). The reaction mixture was stirred at rt for (2H, d, J 8.7, Ar); δC (100 MHz, CDCl3) 22.5 (C(α)Me), 26.4, 27.0
12 h before Na2S2O3 (excess) was added. After stirring for 1 h (CMe2), 29.9 (C(7)), 46.3 (C(8)), 55.3 (OMe), 60.9 (C(α)), 63.0
the reaction mixture was filtered and concentrated in vacuo to (C(2)), 65.1 (C(2′)), 69.7 (C(1′)), 79.1, 79.2 (C(3), C(4)), 108.6
give a 68 : 32 mixture of 32 and 33. Purification via flash (CMe2), 113.9, 128.3 (Ar), 128.7 (C(6)), 129.9 (C(5)), 137.4, 158.6
column chromatography (eluent 30–40 °C petrol–EtOAc, 5 : 1) (Ar); m/z (ESI+) 400 ([M
gave 33 as a colourless oil (48 mg, 24%, >99 : 1 dr); [α]2D5 −26.0 C21H31NNaO5+ ([M + Na]+) requires 400.2094; found 400.2082.
(c 0.52 in CHCl3); νmax (ATR) 2980, 2932 (C–H), 1731 (CvO), (2S,3S,4S,αR,Z)-N(1)-(α-Methyl-p-methoxybenzyl)-2-(hydroxy-
+
Na]+, 100%); HRMS (ESI+)
1611 (CvC); δH (400 MHz, CDCl3) 1.32 (3H, s, MeCMe), 1.42 methyl)-3,4-dihydroxy-3,4-O-isopropylidine-1,2,3,4,7,8-hexa-
(3H, s, MeCMe), 1.43–1.45 (12H, m, CMe3, C(α)Me), 2.26–2.31 hydroazocine 36. NaIO4 (9.41 g, 44.0 mmol) was added to a
(1H, m, C(6)HA), 2.64–2.71 (1H, m, C(6)HB), 3.44 (1H, dd, J 8.6, solution of 35 (1.66 g, 4.40 mmol) in MeOH–H2O (v/v 5 : 1,
1.15, C(2)H), 3.69 (1H, dd, 6.3, 1.15, C(1)H), 3.81 (3H, s, OMe), 40 mL). The resultant mixture was left to stir at rt for 4 h then
3.95 (1H, q, J 6.6, C(α)H), 3.99 (1H, d, J 6.3, C(9)H), 4.81–4.85 filtered through Celite® (eluent MeOH). NaBH4 (1.66 g,
(1H, m, C(3)H), 5.10 (1H, d, J 4.3, C(7)H), 5.59–5.65 (1H, m, 44.0 mmol) was then added to the filtrate and the reaction
C(5)H), 5.77–5.82 (1H, m, C(4)H), 6.87 (2H, d, J 8.6, Ar), 7.28 mixture was allowed to stir at rt for 12 h before satd aq. NH4Cl
(2H, d, J 8.6, Ar); δC (100 MHz, CDCl3) 21.5 (C(α)Me), 27.0, 27.1 (2 mL) was added. The resultant mixture was filtered through
(CMe2), 28.0 (CMe3), 34.8 (C(6)), 55.2 (OMe), 61.3, 61.6 (C(1), Celite® (eluent CHCl3–MeOH, 3 : 1) and concentrated in vacuo.
C(α)), 77.5, 77.8 (C(9), C(3)), 81.5 (C(2)), 82.0 (CMe3), 94.5 Purification via flash column chromatography (eluent
(C(7)), 108.1 (CMe2), 113.9 (Ar), 125.4 (C(5)), 128.8 (Ar), 129.6 30–40 °C petrol–EtOAc, 5 : 1) gave 36 as a yellow oil (877 mg,
(C(4)), 134.9, 159.0 (Ar), 168.0 (CO2 Bu); m/z (ESI+) 913 ([2M + 57%, >99 : 1 dr); [α]2D5 +38.7 (c 0.38 in CHCl3); νmax (ATR) 3469
t
Na]+, 100%), 446 ([M + H]+, 80%); HRMS (ESI+) C25H36NO6
(O–H), 2980, 2933 (C–H), 1610 (CvC); δH (400 MHz, CDCl3)
+
([M + H]+) requires 446.2573; found 446.2542. Further elution 1.29 (3H, s, MeCMe), 1.33 (3H, d, J 6.8, C(α)Me), 1.39 (3H, s,
gave 32 as a colourless oil (57 mg, 40%, >99 : 1 dr); [α]D25 −1.65 MeCMe), 2.05–2.24 (3H, m, C(7)H2, OH), 2.88–3.01 (3H, m,
(c 1.03 in CHCl3); νmax (ATR) 3493 (O–H), 2982, 2933, 2867 C(2)H, C(8)H2), 3.65 (1H, dd, J 11.1, 6.3, C(1′)HA), 3.72 (1H, dd,
(C–H), 1727 (CvO), 1611 (CvC); δH (400 MHz, CDCl3) 1.40 J 11.1, 6.6, C(1′)HB), 3.77 (3H, s, OMe), 3.84 (1H, app t, J 8.6,
(6H, s, CMe2), 1.48 (CMe3), 2.03–2.09 (1H, m, C(7′)HA), 2.29–2.40 C(3)H), 4.06 (1H, q, J 6.8, C(α)H), 4.61–4.66 (1H, m, C(4)H),
(1H, m, C(7′)HB), 2.79 (1H, ddd, J 14.4, 12.6, 4.6, C(8′)HA), 2.85 5.64–5.71 (1H, m, C(6)H), 5.84 (1H, dd, J 11.6, 3.8, C(5)H), 6.84
(1H, dd, J 9.8, 3.5, C(2′)H), 2.93–2.98 (1H, m, C(8′)HB), 3.38 (1H, (2H, d, J 8.6, Ar), 7.22 (2H, d, J 8.6, Ar); δC (100 MHz, CDCl3)
app t, J 9.8, C(3′)H), 4.19 (1H, app d, J 3.5, C(2)H), 4.49 (1H, br t, 22.4 (C(α)Me), 26.6, 27.0 (CMe2), 29.9 (C(7)), 46.0 (C(8)), 55.2
J 7.3, C(4′)H), 5.55–5.62 (1H, m, C(6′)H), 5.86–5.90 (1H, m, (OMe), 58.9 (C(α)), 61.8, 62.0 (C(2), C(1′)), 79.1 (C(4)), 82.3
C(5′)H); δC (100 MHz, CDCl3) 26.9, 27.0 (CMe2), 28.1 (CMe3), (C(3)), 108.8 (CMe2), 113.9, 127.8 (Ar), 128.5 (C(6)), 130.3 (C(5)),
28.7 (C(7′)), 46.8 (C(8′)), 59.9 (C(2′)), 72.8 (C(2)), 78.5 (C(4′)), 81.2 138.2, 158.4 (Ar); m/z (ESI+) 717 ([2M + Na]+, 100%); HRMS
(C(3′)), 81.9 (CMe3), 109.1 (CMe2), 127.4 (C(6′)), 130.4 (C(5′)), (ESI+) C20H29NNaO4 ([M + Na]+) requires 370.1989; found
+
171.7 (C(1)); m/z (ESI+) 649 ([2M + Na]+, 100%), 336 ([M + Na]+, 370.1983.
85%), 314 ([M + H]+, 90%); HRMS (ESI+) C16H27NNaO5
([M + Na]+) requires 336.1781; found 336.1787.
(S,S,S,Z)-2-(Hydroxymethyl)-3,4-dihydroxy-1,2,3,4,7,8-hexa-
hydroazocine 37. 3.0 M aq. HCl (2 mL) was added to a stirred
+
(2S,3S,4S,1′R,αR,Z)-N(1)-(α-Methyl-p-methoxybenzyl)-2- solution of 36 (656 mg, 1.89 mmol) in MeOH (6 mL). The reac-
(dihydroxyethyl)-3,4-dihydroxy-3,4-O-isopropylidine-1,2,3,4,7,8- tion mixture was heated at reflux for 2 h then concentrated
hexahydroazocine 35. LiAlH4 (1.0
M in THF, 11.4 mL, in vacuo. The residue was dissolved in H2O (2 mL) and purified
11.4 mmol) was added to a stirred solution of 29 (2.56 g, on DOWEX 1X8–200 (OH− form) ion exchange resin to give 37
5.72 mmol) in THF (100 mL) at −78 °C. The reaction mixture as a colourless oil (229 mg, 70%, >99 : 1 dr); [α]2D5 −1.23 (c 1.06
was allowed to warm to rt over 12 h before 2.0 M aq. NaOH in MeOH); νmax (ATR) 3340 (O–H), 2939 (C–H), 1648 (CvC);
(10 mL) was added. The resultant mixture was stirred for 1 h δH (500 MHz, MeOH-d4) 2.13–2.18 (1H, m, C(7)HA), 2.26–2.35
then filtered through Celite® (eluent EtOAc), dried and con- (1H, m, C(7)HB), 2.42–2.47 (1H, m, C(2)H), 2.64 (1H, ddd,
centrated in vacuo. Purification via flash column chromato- J 13.6, 12.3, 4.7, C(8)HA), 2.82 (1H, ddd, J 13.6, 6.0, 1.9, C(8)HB),
graphy (eluent 30–40 °C petrol–EtOAc, 10 : 1 increased to 2 : 1) 3.13 (1H, app t, J 9.5, C(3)H), 3.41 (1H, dd, J 10.6, 7.3, C(1′)HA),
gave 35 as a pale brown oil (1.65 g, 77%, >99 : 1 dr); [α]2D5 +53.3 3.81 (1H, dd, J 10.6, 4.7, C(1′)HB), 4.16–4.19 (1H, m, C(4)H),
(c 0.29 in CHCl3); νmax (ATR) 3425 (O–H), 2982, 2934, 2836 5.51–5.57 (1H, m, C(6)H), 5.74–5.77 (1H, m, C(5)H);
(C–H), 1610 (CvC); δH (400 MHz, CDCl3) 1.21 (3H, s, MeCMe), δC (125 MHz, MeOH-d4) 28.8 (C(7)), 46.1 (C(8)), 61.4 (C(2)), 65.5
1.37 (3H, d, J 6.8, C(α)Me), 1.31 (3H, s, MeCMe), 2.08–2.18 (1H, (C(1′)), 74.0 (C(4)), 76.2 (C(3)), 127.0 (C(6)), 136.0 (C(5)); m/z
m, C(7)HA), 2.32–2.42 (1H, m, C(7)HB), 2.71 (1H, dd, J 8.6, 3.0, (ESI+) 196 ([M + Na]+, 30%), 174 ([M + H]+, 55%); HRMS (ESI+)
C(2)H), 2.81–3.05 (2H, m, 2 × OH) overlapping 2.87–2.91 (1H, C8H15NNaO3+ ([M + Na]+) requires 196.0944; found 196.0945.
m, C(8)HA), 3.05–3.13 (1H, m, C(8)HB), 3.39 (1H, dd, J 11.6, 3.5,
(1S,2S,3S,4R,7R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-7-iodo-
C(2′)HA), 3.51 (1H, dd, J 11.6, 4.3, C(2′)HB), 3.80 (3H, s, OMe), hexahydropyrrolizidinium iodide 39·HI. I2 (74 mg, 0.29 mmol)
3.92 (1H, q, J 6.8, C(α)H), 3.94–3.98 (1H, m, C(1′)H), 4.28 (1H, was added to a stirred solution of 37 (50 mg, 0.29 mmol) in
app t, J 8.6, C(3)H), 4.68–4.72 (1H, m, C(4)H), 5.69–5.76 (1H, MeOH (5 mL). The resultant mixture was stirred at rt for 12 h
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then concentrated in vacuo to give 39·HI as a brown oil added in three portions to a stirred solution of 7·HI (100 mg,
(124 mg, quant, >99 : 1 dr); δH (400 MHz, MeOH-d4) 2.52–2.61 0.18 mmol) and TEMPO (140 mg, 0.88 mmol) in PhMe (5 mL)
(1H, m, C(6)HA), 2.64–2.74 (1H, m, C(6)HB), 3.39–3.43 (1H, m, at 70 °C. The reaction mixture was heated at 70 °C for 1.5 h
C(3)H), 3.50–3.61 (2H, m, C(5)H2), 3.68 (1H, app t, J 7.3, C(7a) then cooled to rt and concentrated in vacuo to give a
H), 3.87 (1H, dd, J 12.4, 4.55, C(1′)HA), 3.97 (1H, dd, J 12.4, 3.0, 75 : 25 mixture of 45 and 46. Purification via flash column
C(1′)HB), 4.06 (1H, dd, J 10.1, 7.3, C(2)H), 4.19 (1H, app t, J 7.3, chromatography (silica doped with 10% KF,33 eluent 30–40 °C
C(1)H), 4.73 (1H, app q, J 5.8, C(7)H); δC (100 MHz, MeOH-d4) petrol–acetone, 50 : 1 increased to 10 : 1) gave 45 as a yellow oil
19.0 (C(7)), 37.5 (C(6)), 54.1 (C(5)), 56.5 (C(1′)), 71.0, 71.1 (C(3), (57 mg, 69%, >99 : 1 dr); [α]2D0 −6.3 (c 2.4 in CHCl3); νmax (ATR)
C(7a)), 75.0 (C(2)), 81.1 (C(1)); m/z (ESI+) 300 ([M + H]+, 100%); 3484 (O–H), 2977, 2833, 2871 (C–H), 1732 (CvO);
+
HRMS (ESI+) C8H15INO3 ([M + H]+) requires 300.0091; found δH (400 MHz, CDCl3) 1.07 (3H, s, MeCMe), 1.09 (3H, s,
300.0087.
MeCMe), 1.16 (3H, s, MeCMe), 1.22–1.27 (1H, m, CHA) overlap-
(S,S,S,S)-1,2-Dihydroxy-3-hydroxymethylhexahydro-1H-pyrro- ping 1.22 (3H, s, MeCMe) and 1.26 (3H, s, MeCMe), 1.28–1.34
lizidine [(−)-hyacinthacine A2] 40. 10% Pd/C (43 mg, 50% (1H, m, CHB), 1.40–1.47 (4H, m, 2 × CH2) 1.47 (3H, s, MeCMe),
w/w) was added to a solution of 39·HI (86 mg, 0.20 mmol) and 1.49 (9H, s, CMe3), 1.88–1.97 (1H, m, C(6)HA), 2.26–2.33 (1H,
Et3N (0.08 mL, 0.58 mmol) in degassed MeOH (2 mL). The m, C(6)HB), 2.67 (1H, td, J 10.1, 6.3, C(5)HA), 2.92–2.95 (1H, m,
resultant mixture was stirred at rt under 1 atm H2 for 18 h C(5)HB), 3.22 (1H, d, J 4.3, OH), 3.40 (1H, app d, J 5.8, C(3)H),
then filtered through Celite® (eluent MeOH) and concentrated 3.55–3.58 (1H, m, C(7a)H), 4.36 (1H, td, J 7.6, 4.3, C(7)H),
in vacuo. The residue was dissolved in MeOH (2 mL) and co- 4.41–4.43 (1H, m, C(1′)H), 4.54 (1H, dd, J 6.8, 3.5, C(1)H), 4.73
evaporated with 6.0 M aq. HCl (2 mL), the process repeated, (1H, app t, J 6.8, C(2)H); δC (100 MHz, CDCl3) 17.2 (CH2), 20.2
and the residue was dissolved in H2O (2 mL) and purified on (2 × MeCMe), 25.4 (MeCMe), 27.7 (MeCMe), 27.9 (CMe3), 34.2,
DOWEX 1X8-200 (OH− form) ion exchange resin to give 40 as a 34.3 (MeCMe), 34.8 (C(6)), 40.2 (2 × CH2), 47.7 (C(5)), 59.4, 59.8
colourless oil (33 mg, 95%, >99 : 1 dr);2,16e,30 [α]2D5 −11.0 (c 0.43 (CMe2), 68.8 (C(3), C(1′)), 75.6 (C(7a)), 78.9 (C(2)), 83.4 (CMe3),
in H2O); [α]2D5 −11.2 (c 0.83 in MeOH); lit. for (+)-40 [α]2D5 +20.1 85.4 (C(1)), 89.7 (C(7)), 113.5 (CMe2), 172.9 (C(2′)); m/z (ESI+)
(c 0.44 in H2O);2 [α]2D4 +12.5 (c 0.4 in H2O);30a [α]D24 +12.7 (c 0.13 469 ([M + H]+, 100%); HRMS (ESI+) C25H45N2O6 ([M + H]+)
+
in H2O);30b [α]D25 +10.5 (c 0.6 in H2O);30c [α]2D0 +19.9 (c 0.97 in requires 469.3272; found 469.3275. Further elution gave an
MeOH);30d [α]2D0 +11.2 (c 0.52 in H2O);30e [α]D +12.1 (c 0.3 impure sample of 46 as a brown oil (16 mg, 19%, >99 : 1 dr);
in H2O);30f [α]D26 +12 (c 0.4 in H2O);30g [α]D20 +12.6 (c 1.64 in δH (400 MHz, CDCl3) 1.16 (6H, s, 2 × MeCMe), 1.24–1.33 (2H,
H2O);30h [α]2D4 +12.4 (c 0.2 in H2O);30i [α]D20 +10.6 (c 1.2 in m, CH2) overlapping 1.26 (6H, s, 2 × MeCMe) and 1.32 (3H, s,
H2O);30j lit. for (−)-40 [α]D20 −11.0 (c 1.0 in MeOH)};16e δH MeCMe), 1.43–1.49 (4H, m, 2 × CH2), 1.49 (3H, s, MeCMe), 1.50
(400 MHz, MeOH-d4); 1.71–1.80 (2H, m, C(6)HA, C(7)HA), (9H, s, CMe3), 2.08 (2H, app q, J 7.1, C(6)H2), 2.63–2.69 (1H, m,
1.81–1.88 (1H, m, C(6)HB), 1.92–1.99 (1H, m, C(7)HB), C(5)HA), 3.00–3.06 (1H, m, C(5)HB), 3.27 (1H, d, J 3.8, OH), 3.38
2.58–2.62 (1H, m, C(3)H), 2.76–2.82 (1H, m, C(5)HA), 2.90–2.96 (1H, dd, J 6.1, 1.5, C(3)H), 3.53–3.58 (1H, m, C(7a)H), 4.39–4.42
(1H, m, C(5)HB), 3.15–3.20 (1H, m, C(7a)H), 3.56–3.61 (2H, m, (1H, m, C(1′)H), 4.56 (1H, app q, J 6.1, C(7)H), 4.76 (1H, app t,
C(1)H, C(1′)HA), 3.71–3.77 (2H, m, C(2)H, C(1′)HB); δH J 6.6, C(2)H), 4.91 (1H, dd, J 6.8, 4.3, C(1)H); δC (100 MHz,
(500 MHz, D2O) 1.61–1.70 (2H, m, C(6)HA, C(7)HA), 1.73–1.80 CDCl3) [selected peaks] 17.2 (CH2), 25.4, 27.7 (CMe2), 28.0
(1H, m, C(6)HB), 1.81–1.88 (1H, m, C(7)HB), 2.59–2.62 (1H, m, (CMe3), 29.7 (CH2), 33.2 (C(6)), 40.4 (CH2), 45.5 (C(5)), 69.1
C(3)H), 2.62–2.67 (1H, m, C(5)HA), 2.77–2.82 (1H, m, C(5)HB), (C(3), C(1′)), 73.3 (C(7a)), 78.8 (C(1)), 80.1 (C(2)), 83.1 (CMe3),
3.05 (1H, app td, J 7.6, 4.4, C(7a)H), 3.54 (1H, dd, J 11.7, 6.6, 83.6 (C(7)), 113.4 (CMe2), 172.5 (C(2′)); m/z (ESI+) 469 ([M + H]+,
C(1′)HA), 3.63–3.70 (3H, m, C(1)H, C(2)H, C(1′)HB); δH 100%); HRMS (ESI+) C25H45N2O6+ ([M + H]+) requires 469.3272;
(500 MHz, D2O [TSP])37 1.73–1.81 (2H, m, C(6)HA, C(7)HA), found 469.3263.
1.84–1.91 (1H, m, C(6)HB), 1.93–1.99 (1H, m, C(7)HB),
(1R,2S,3S,7R,7aS,1′R)-1,2,7-Trihydroxy-1,2-O-isopropylidene-3-
2.71–2.74 (1H, m, C(3)H), 2.75–2.79 (1H, m, C(5)HA), 2.89–2.94 (1′-hydroxy-2′-tert-butoxy-2′-oxoethyl)hexahydro-1H-pyrrolizidine
(1H, m, C(5)HB), 3.17 (1H, app td, J 7.9, 4.7, C(7a)H), 3.65 (1H, 47. Activated Zn dust (1.12 g, 17.1 mmol) was added to a
dd, J 12.0, 6.6, C(1′)HA), 3.72–3.81 (3H, m, C(1)H, C(2)H, stirred solution of 45 (200 mg, 0.43 mmol) in AcOH–THF–H2O
C(1′)HB); δC (100 MHz, MeOH-d4) 24.8 (C(6)), 30.6 (C(7)), 55.2 (v/v 3 : 1 : 1, 35 mL). The reaction mixture was heated at 70 °C
(C(5)), 63.4 (C(1′)), 67.5 (C(7a)), 70.9 (C(3)), 77.9 (C(2)), 81.6 for 2 h then cooled to rt and filtered through Celite® (eluent
(C(1)); δC (125 MHz, D2O) 24.5 (C(6)), 29.8 (C(7)), 54.8 (C(5)), EtOAc), dried and concentrated in vacuo. The residue was
63.1 (C(1′)), 66.0 (C(7a)), 69.1 (C(3)), 77.2 (C(2)), 80.2 (C(1)); redissolved in EtOAc (20 mL) and filtered through Celite®
δC (125 MHz, D2O [TSP])37 27.4 (C(6)), 32.6 (C(7)), 57.7 (C(5)), (eluent EtOAc). Purification via flash column chromatography
65.7 (C(1′)), 69.0 (C(7a)), 72.1 (C(3)), 80.0 (C(2)), 83.0 (C(1)); m/z (eluent 30–40 °C petrol–acetone, 2 : 1) gave 47 as a yellow oil
(ESI+) 174 ([M + H]+, 100%); HRMS (ESI+) C8H16NO3+ ([M + H]+) (86 mg, 61%, >99 : 1 dr); [α]2D0 +3.4 (c 1.3 in MeOH); νmax (ATR)
requires 174.1125; found 174.1131.
3313 (O–H), 2981 (C–H), 1732 (CvO); δH (300 MHz, MeOH-d4)
(1R,2S,3S,7R,7aS,1′R)- and (1R,2S,3S,7S,7aS,1′R)-1,2-Di- 1.30 (3H, s, MeCMe), 1.50 (3H, s, MeCMe), 1.51 (9H, s, CMe3),
hydroxy-1,2-O-isopropylidene-3-(1′-hydroxy-2′-tert-butoxy-2′-oxoethyl)- 1.68–1.79 (1H, m, C(6)HA), 2.17–2.26 (1H, m, C(6)HB),
7-{[2′′,2′′,6′′,6′′-tetramethylpiperidin-N(1′′)-yl]oxy}hexahydro-1H- 2.90–2.97 (1H, m, C(5)HA), 3.03–3.11 (1H, m, C(5)HB), 3.27 (1H,
pyrrolizidine 45 and 46. Bu3SnH (0.15 mL, 0.53 mmol) was dd, J 5.1, 3.1, C(7a)H), 3.47–3.49 (1H, m, C(3)H), 4.19 (1H, app q,
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J 6.9, C(7)H), 4.39 (1H, d, J 2.1, C(1′)H), 4.54 (1H, dd, J 6.3, 3.1, 3 : 1) and concentrated in vacuo. Purification via flash column
C(1)H), 4.77–4.81 (1H, m, C(2)H); δC (75 MHz, MeOH-d4) 25.6, chromatography (eluent CH2Cl2–MeOH, 10 : 1) gave 50. 3.0 M
27.9 (CMe2), 28.3 (CMe3), 36.4 (C(6)), 47.1 (C(5)), 69.6 (C(1′)), aq. HCl (0.5 mL) was added to a stirred solution of 50 in
70.1 (C(3)), 75.4 (C(7)), 79.7 (C(7a)), 82.4 (C(2)), 83.5 (CMe3), MeOH (1 mL). The reaction mixture was heated at reflux for
84.2 (C(1)), 114.0 (CMe2), 173.7 (C(2′)); m/z (ESI+) 330 ([M + H]+, 2 h then concentrated in vacuo. The residue was dissolved in
+
100%); HRMS (ESI+) C16H28NO6 ([M + H]+) requires 330.1911; H2O (0.5 mL) and purified on DOWEX 1X8-200 (OH− form) ion
found 330.1907.
(1R,2S,3S,7R,7aR,1′R)-1,2,7-Trihydroxy-1,2-O-isopropylidene-3- 51 as a colourless oil (4 mg, 29%, >99 : 1 dr);34,35 [α]D20 −48
(1′,2′-dihydroxyethyl)hexahydro-1H-pyrrolizidine
48. LiAlH4 (c 0.03 in H2O); [α]2D0 −60 (c 0.03 in MeOH); {lit. for (+)-51 [α]D
exchange resin, and then on DOWEX 50WX8 (H+ form) to give
(1.0 M in THF, 0.91 mL, 0.91 mmol) was added to a stirred +59.7 (c 0.58 in H2O);34a [α]D25 +53.4 (c 0.43 in H2O);34b [α]2D0
solution of 47 (75 mg, 0.23 mmol) in THF (5 mL) at −78 °C. +34.8 (c 0.5 in H2O);35a lit. for (−)-51 [α]D20 −51.0 (c 0.51 in
The resultant mixture was allowed to warm to rt over 12 h H2O)};16d δH (500 MHz, D2O) 1.62–1.70 (1H, m, C(6)HA),
before 2.0 M aq. NaOH (1 mL) was added. The resultant 2.02–2.07 (1H, m, C(6)HB), 2.80 (1H, td, J 10.5, 5.8, C(5)HA),
mixture was left to stir at rt for a further 1 h, then filtered 2.88–2.91 (1H, m, C(5)HB), 3.07–3.12 (2H, m, C(3)H, C(7a)H),
through Celite® (eluent EtOAc), dried and concentrated 3.76 (1H, s, C(1′)HA), 3.78 (1H, d, J 1.9, C(1′)HB), 3.85 (1H, dd,
in vacuo. Purification via flash column chromatography (eluent J 9.8, 5.2, C(2)H), 3.96 (1H, dd, J 5.2, 2.2, C(1)H), 4.02–4.06 (1H,
CH2Cl2–MeOH–Et3N, 10 : 1 : 0.1) gave 48 as a pale yellow oil m, C(7)H); δH (500 MHz, D2O [TSP])37 1.71–1.78 (1H, m,
(27 mg, 46%, >99 : 1 dr); [α]2D0 −19.1 (c 1.1 in MeOH); νmax C(6)HA), 2.09–2.16 (1H, m, C(6)HB), 2.85 (1H, td, J 10.4, 5.7,
(ATR) 3367 (O–H), 2983, 2933 (C–H); δH (300 MHz, MeOH-d4) C(5)HA), 2.96 (1H, ddd, J 10.1, 6.9, 3.2, C(5)HB), 3.13 (1H, dd,
1.22 (3H, s, MeCMe), 1.38 (3H, s, MeCMe), 1.57–1.68 (1H, m, J 5.7, 2.4, C(7a)H), 3.15–3.18 (1H, m, C(3)H), 3.86 (1H, d, J 1.6,
C(6)HA), 2.05–2.15 (1H, m, C(6)HB), 2.79–2.84 (2H, m, C(5)H2), C(1′)HA), 3.87 (1H, d, J 4.1, C(1′)HB), 3.93 (1H, dd, J 9.5, 5.4,
2.96–3.00 (1H, m, C(3)H), 3.17 (1H, app t, J 3.8, C(7a)H), C(2)H), 4.05 (1H, dd, J 5.4, 2.4, C(1)H), 4.12 (1H, ddd, J 8.2, 6.3,
3.39–3.54 (2H, m, C(2′)H2), 3.76–3.82 (1H, m, C(1′)H), 6.0, C(7)H); δC (125 MHz, D2O) 33.4 (C(6)), 44.7 (C(5)), 58.9
4.13–4.18 (1H, m, C(7)H), 4.42 (1H, dd, J 6.6, 3.8, C(1)H), (C(1′)), 64.4 (C(3)), 70.9 (C(2)), 73.6 (C(1)), 74.2 (C(7)), 75.7
4.73–4.77 (1H, m, C(2)H); δC (75 MHz, MeOH-d4) 25.5, 27.8 (C(7a); δC (125 MHz, D2O [TSP])37 36.4 (C(6)), 47.5 (C(5)), 62.0
(CMe2), 36.0 (C(6)), 47.6 (C(5)), 65.9 (C(2′)), 69.4 (C(3)), 71.3 (C(1′)), 67.3 (C(3)), 73.9 (C(2)), 76.7 (C(1)), 77.2 (C(7)), 78.5
(C(1′)), 75.5 (C(7)), 79.2 (C(7a)), 82.3 (C(2)), 85.1 (C(1)); m/z (C(7a); m/z (ESI+) 190 ([M
+
H]+, 100%); HRMS (ESI+)
(ESI+) 282 ([M + Na]+, 30%), 260 ([M + H]+, 100%); HRMS (ESI+) C8H16NO4+ ([M + H]+) requires 190.1074; found 190.1076.
C12H22NO5+ ([M + H]+) requires 260.1492; found 260.1489.
(1R,2S,3S,7R,7aR,1′R)-1,2,7-Trihydroxy-3-(1′,2′-dihydroxyethyl)-
hexahydro-1H-pyrrolizidine 49. 3.0 M aq. HCl (0.5 mL) was
added to a stirred solution of 48 (7 mg, 0.03 mmol) in MeOH
Notes and references
(1 mL). The reaction mixture was heated at reflux for 2 h then
concentrated in vacuo. The residue was dissolved in H2O
(0.5 mL) and purified on DOWEX 1X8-200 (OH− form) ion
exchange resin to give 49 as a colourless oil (5 mg, 84%, >99 : 1
dr); [α]2D0 −22.0 (c 0.3 in MeOH); δH (500 MHz, MeOH-d4)
1.71–1.78 (1H, m, C(6)HA), 2.07–2.13 (1H, m, C(6)HB), 2.92 (1H,
ddd, J 10.4, 6.9, 3.5, C(5)HA), 3.06–3.11 (2H, m, C(3)H, C(5)HB),
3.17 (1H, dd, J 5.4, 3.0, C(7a)H), 3.63 (1H, dd, J 11.4, 6.6,
C(2′)HA), 3.69 (1H, dd, J 11.4, 6.6, C(2′)HB), 3.91 (1H, dd, J 5.6,
3.0, C(1)H), 4.00–4.07 (2H, m, C(7)H, C(1′)H), 4.17 (1H, dd,
J 8.5, 5.6, C(2)H); δC (125 MHz, MeOH-d4) 35.7 (C(6)), 47.0
(C(5)), 66.1 (C(3)), 66.5 (C(2′)), 71.4 (C(1′)), 71.9 (C(2)), 75.3
(C(1)), 75.9 (C(7)), 78.4 (C(7a)); m/z (ESI+) 220 ([M + H]+, 100%);
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M. R. Wormald, P. M. de Q. Lilley and D. J. Watkin, Tetrahe-
dron Lett., 1994, 35, 7849.
5 B. G. Davis, Tetrahedron: Asymmetry, 2009, 20, 652.
6 N. Asano, R. J. Nash, R. J. Molyneux and G. W. J. Fleet,
Tetrahedron: Asymmetry, 2000, 11, 1645.
HRMS (ESI+) C9H18NO5 ([M + H]+) requires 220.1179; found
+
220.1188.
7 E. A. Brock, S. G. Davies, J. A. Lee, P. M. Roberts and
J. E. Thomson, Org. Lett., 2011, 13, 1594.
(1R,2S,3S,7R,7aR)-1,2,7-Trihydroxy-3-hydroxymethylhexa-
hydro-1H-pyrrolizidine [(−)-1-epi-alexine] 51. NaIO4 (165 mg,
0.77 mmol) was added to a solution of 49 (19 mg, 0.08 mmol)
in MeOH–H2O (v/v 2 : 1, 1.5 mL). The resultant mixture was left
to stir at rt for 4 h then filtered through Celite® (eluent
MeOH). NaBH4 (29 mg, 0.77 mmol) was then added to the fil-
trate and the resultant mixture was allowed to stir at rt for 12 h
before satd aq. NH4Cl (0.5 mL) was added. The resultant
mixture was filtered through Celite® (eluent EtOAc–MeOH,
8 (a) E. A. Brock, S. G. Davies, J. A. Lee, P. M. Roberts and
J. E. Thomson, Org. Lett., 2012, 14, 4278. For examples of
the use of iodoamination for the preparation of pyrroli-
dines, see: S. G. Davies, R. L. Nicholson, P. D. Price,
P. M. Roberts and A. D. Smith, Synlett, 2004, 901;
(b) S. G. Davies, R. L. Nicholson, P. D. Price, P. M. Roberts,
E. D. Savory, A. D. Smith and J. E. Thomson, Tetrahedron:
Asymmetry, 2009, 20, 758; (c) S. G. Davies, J. A. Lee,
3200 | Org. Biomol. Chem., 2013, 11, 3187–3202
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Paper
P. M. Roberts, J. E. Thomson and C. J. West, Tetrahedron 15 Crystallographic data (excluding structure factors) have
Lett., 2011, 52, 6477; (d) S. G. Davies, J. A. Lee,
P. M. Roberts, J. E. Thomson and C. J. West, Tetrahedron,
2012, 68, 4302.
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
922276 (15) and 922277 (29).
9 The phrase “a transannulation effect” was coined by Cope in 16 For previous syntheses of (+)-hyacinthacine A1 18, see ref.
1952; see: A. C. Cope, S. W. Fenton and C. F. Spencer, J. Am.
Chem. Soc., 1952, 74, 5884. Prelog also reported a similar
“chemical transannular effect”; see: V. Prelog and
K. Schenker, Helv. Chim. Acta, 1952, 2044. Prior to 1952,
reactions had been reported which occurred in a transan-
nular manner but which were not referenced as such; for
example, see: R. Willstätter, Liebigs Ann. Chem., 1903, 326,
23.
14b and: (a) L. Chabaud, Y. Landais and P. Renaud, Org.
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(d) T. J. Donohoe, R. E. Thomas, M. D. Cheeseman,
C. L. Rigby, I. D. Linney and G. Bhalay, Org. Lett., 2008, 10,
3615. For a previous synthesis of (−)-hyacinthacine A1 18,
see: (e) J. Calveras, J. Casas, T. Parella, J. Joglar and
P. Clapés, Adv. Synth. Catal., 2007, 349, 1661. For a previous
synthesis of ( )-hyacinthacine A1 18, see: (f) T. J. Donohoe,
H. O. Sintim and J. Hollinshead, J. Org. Chem., 2005, 70,
2005.
10 Enantiopure (R)-α-methyl-p-methoxybenzylamine (>99% ee)
is commercially available. Alkylation of (R)-α-methyl-p-
methoxybenzylamine upon treatment with 4-bromobut-1-
ene in the presence of K2CO3 gave (R)-N-but-3-enyl-N-
(α-methyl-p-methoxybenzyl)amine; subsequent deprotona-
tion with BuLi in THF generated a yellow solution 17 E. A. Mash, K. A. Nelson, S. Van Deusen, S. B. Hemperly,
of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)-
amide 1.
11 Throughout this manuscript, “hexahydroazocine” specifi-
cally refers to 1,2,3,4,7,8-hexahydroazocine.
P. D. Theisen and C. H. Heathcock, Org. Synth., 1990, 68, 92.
18 S. G. Davies, E. M. Foster, A. B. Frost, J. A. Lee,
P. M. Roberts and J. E. Thomson, Org. Biomol. Chem., 2012,
10, 6186.
12 For other transannular cyclisation processes of hexahydro- 19 H. Iida, N. Yamakazi and C. Kibayashi, J. Org. Chem., 1987,
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dron, 2007, 63, 10059.
65, 9129. See also: A. Lauritsen and R. Madsen, Org. 22 S. G. Davies, J. A. Lee, P. M. Roberts, J. E. Thomson and
Biomol. Chem., 2006, 4, 2898. For selected recent examples J. Yin, Org. Lett., 2012, 14, 218.
of transannular cyclisation processes of scaffolds other 23 T. D. W. Claridge, S. G. Davies, J. A. Lee, R. L. Nicholson,
than hexahydroazocine, see: D. C. Beshore and A. B. Smith
P. M. Roberts, A. J. Russell, A. D. Smith and S. M. Toms,
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C. B. Pipper and R. Madsen, Eur. J. Org. Chem., 2009, 3387; 24 S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron: Asym-
M. Marc, F. Outurquin, P.-Y. Renard, C. Creminion and
X. Franck, Tetrahedron Lett., 2009, 50, 4554; S.-M. Paek,
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13, 3538.
metry, 2005, 16, 2833; S. G. Davies, N. M. Garrido,
D. Kruchinin, O. Ichihara, L. J. Kotchie, P. D. Price,
A. J. Price Mortimer, A. J. Russell and A. D. Smith, Tetra-
hedron: Asymmetry, 2006, 17, 1793; S. G. Davies,
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hedron: Asymmetry, 2012, 23, 1111.
13 The enantiomeric purity of 8 was determined by Chiral GC 25 We have previously established that the doubly diastereo-
analysis for which the authors would like to thank Carole
J. R. Bataille.
selective conjugate addition of lithium (S)-N-benzyl-N-
(α-methylbenzyl)amide to α,β-unsaturated ester (R,R,E)-26
represents the doubly diastereoselective “matched” case;
see: S. G. Davies, M. J. Durbin, E. C. Goddard, P. M. Kelly,
W. Kurosawa, J. A. Lee, R. L. Nicholson, P. D. Price,
P. M. Roberts, A. J. Russell, P. M. Scott and A. D. Smith,
Org. Biomol. Chem., 2009, 7, 761. On this basis it was
expected that conjugate addition of lithium amide (R)-1 to
(S,S,E)-26 would represent the “matched” reaction. The
assumed “mismatched” conjugate addition of (S)-1 to (S,S,E)-
26 was not attempted.
14 For previous syntheses of (+)-7a-epi-hyacinthacine A1 10,
see: (a) I. Izquierdo, M. T. Plaza, J. A. Tamayo, F. Franco
and F. Sánchez-Cantalejo, Tetrahedron, 2010, 66, 3788;
(b) G. D’Adamio, A. Goti, C. Parmeggiani, E. Moren-Clavijo,
I. Robina and F. Cardona, Eur. J. Org. Chem., 2011, 17,
7155. For a previous synthesis of (−)-7a-epi-hyacinthacine
A1 10, see: (c) X. Garrabou, L. Gomez, J. Joglar, S. Gil,
T. Parella, J. Bujons and P. Clapés, Chem.–Eur. J., 2010, 16,
10691. For a previous synthesis of ( )-7a-epi-hyacinthacine
A1 10, see: (d) O. Affolter, A. Baro, W. Frey and S. Laschat, 26 For development of this methodology, see: M. E. Bunnage,
Tetrahedron, 2009, 65, 6626.
S. G. Davies and C. J. Goodwin, J. Chem. Soc., Perkin Trans.
This journal is © The Royal Society of Chemistry 2013
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Paper
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P. M. Roberts, A. D. Smith, H. Rodríguez-Solla,
J. E. Thomson and S. M. Toms, Org. Biomol. Chem., 2007, 5, 31 A. G. M. Barrett, B. C. B. Bezuidenhoudt and
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and H. Rodríguez-Solla, Synlett, 2002, 1146;
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(a) N. Ikota, H. Nakagawa, S. Ohno, K. Noguchi and
K. Okuyama, Tetrahedron, 1998, 54, 8985. For a previous
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37 Chemical shift values reported downfield from sodium
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This journal is © The Royal Society of Chemistry 2013