Cyclic sulfamidates as lactam precursors. An efficient asymmetric synthesis of (-)-aphanorphine

Article abstract of DOI:10.1039/b510761j

A short and efficient enantioselective synthesis of (-)-aphanorphine is described based on the use of a cyclic sulfamidate to provide a suitably functionalised lactam that allows for construction of the tricyclic 3-benzazepine scaffold. The Royal Society

Full text of DOI:10.1039/b510761j

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Cyclic sulfamidates as lactam precursors. An efficient asymmetric
synthesis of (-)-aphanorphine{
John F. Bower,a Peter Szetob and Timothy Gallagher*a
Received (in Cambridge, UK) 27th July 2005, Accepted 26th September 2005
First published as an Advance Article on the web 20th October 2005
DOI: 10.1039/b510761j
A short and efficient enantioselective synthesis of (2)-aphanor-
phine is described based on the use of a cyclic sulfamidate to
provide a suitably functionalised lactam that allows for
construction of the tricyclic 3-benzazepine scaffold.
We have recently reported synthetic entries to enantiomerically
pure 5- and 6-ring nitrogen heterocycles, including lactams, based
on exploiting the availability and reactivity of 1,2- and 1,3-cyclic
sulfamidates towards functionalised nucleophiles.1a,b In particular,
enolates show a high degree of flexibility providing a-functiona-
lised lactams in good yield (Scheme 1).1b
using a Rh-DuPHOS-based8 catalyst system to give 7 in essentially
quantitative yield and in 99% ee (as judged by chiral HPLC). Our
aim was to use 7 to provide the requisite 1,2-cyclic sulfamidate via
the corresponding N-methylated amino alcohol 10. Attempts to
reduce both the ester as well as the N-Boc moiety (to N-Me) of 7
failed because of competing debromination, but this problem was
Scheme 1
solved in an efficient manner. Reduction of 7 with LiAlH4 gave
alcohol 8 in 96% yield. This intermediate was then treated with
It is important to define the scope and robustness of this
NaH to effect cyclisation to the cyclic carbamate 9, which was then
sulfamidate-based chemistry in a broader sense, and in this paper
methylated in situ with no need for isolation." Once the alkylation
we report on the application of this lactam methodology to a
step was judged to be complete (TLC), NaOH and MeOH were
highly efficient and direct synthesis of (2)-aphanorphine 1.
added and the intermediate carbamate was cleaved hydrolytically.
Aphanorphine, first isolated from the fresh-water blue-green alga
This allowed us to convert 8 to 10 in 92% overall yield and in a
Aphanizomenon flos-aquae,2 incorporates a 3-benzazepine scaffold,
single pot operation. The key cyclic sulfamidate 4 was then
prepared in two steps (81% overall)9 and the enantiomeric purity
was confirmed as 99% ee by chiral HPLC.
which is closely related to the synthetic analgesic pentazocine 2.3{
This structural feature makes aphanorphine an interesting target
for synthesis and a number of groups have reported routes to both
racemic and enantiomerically pure 1.4,5
Exposure of 4 to the enolate derived from triethyl phospho-
noacetate served to cleave efficiently the cyclic sulfamidate and
following an acidic workup, lactam 11 was isolated in 84% yield as
an inconsequential mixture of diastereoisomers. Exposure of 11 to
HCHO gave the desired exo-methylene lactam 3 in 74% yield. This
intermediate is set up to establish the key C(1)–C(9a) bond of 1
under radical or (reductive) Heck reaction conditions. Both
processes were studied in detail, but under a range of Heck
conditions, no cyclisation occurred.10 Pd-mediated oxidative
addition did occur but we only observed the product of C–Br
reduction. Consequently it is unclear whether the Heck cyclisation
takes place, or if it does occur this step may be reversible. The
alternative aryl radical pathway was, however, successfully
implemented. Exposure of 3 to Bu3SnH (PhH, AIBN, reflux)
resulted in cyclisation to give 12I in 62% yield (see below).
Reduction of the lactam moiety of 12 gave (+)-O-methyl
aphanorphine 13 ([a]D20 + 8.3 (c 0.5, CHCl3); lit. [a]2D8 + 8.1 (c 1.2,
CHCl3),5h [a]D20 + 9.4 (c 0.3, CHCl3),5j [a]D20 + 8.7 (c 1.06, CHCl3)5n),
which constitutes a formal synthesis of (2)-aphanorphine 1.
Our approach to aphanorphine relied on an ability to generate
the C(1)–C(9a) bond to complete the 3-benzazepine array. This
focussed our attention on a suitable precursor, which was the exo-
methylene lactam 3, available in turn from an enantiomerically
pure 1,2-cyclic sulfamidate 4.
The implementation of this strategy is outlined in Scheme 2.
2-Bromo-4-methoxybenzaldehyde 5§ was condensed with com-
mercially available N-Boc-a-phosphonoglycine trimethyl ester7 to
give the corresponding dehydroamino ester 6 in 99% yield and
.99% Z isomer. Asymmetric reduction of 6 was accomplished
aSchool of Chemistry, University of Bristol, Bristol, UK BS8 1TS.
E-mail: t.gallagher@bristol.ac.uk; Fax: +44 117 9298611;
Tel: +44 117 9288260
bChemical Development, GlaxoSmithKline, Medicines Research Centre,
Stevenage, UK SG1 2NY
{ Electronic Supplementary Information (ESI) available: Full experi-
mental details and spectroscopic data. See DOI: 10.1039/b510761j
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Scheme 2 Reagents and conditions: i, BocNHCH(PO(OMe2))CO2Me, N,N,N9,N9-tetramethylguanidine, CH2Cl2 (99%); ii, [((R,R)-Et-
DuPHOS)Rh(COD)]BF4 (1.5 mol%), H2 (5 bar), MeOH (100%); iii, LiAlH4, THF, 0 uC (96%); iv, NaH, THF; v, NaH, MeI, THF; vi, NaOH,
MeOH, reflux, 2 h (92% from 8); vii, SOCl2, imidazole, Et3N, CH2Cl2, 0 uC; viii, RuCl3 (0.15 mol%), NaIO4, H2O, EtOAc, 0 uC (81% from 10); ix,
(EtO)2OPCH2CO2Et, KOt-Bu, THF, 40 uC then 5 M HCl (84%); x, NaH, paraformaldehyde, THF (74%); xi, Bu3SnH–AIBN (added over 1.5 h), PhH,
reflux (62% + 18% of 16); xii, LiAlH4, THF (93%).
The radical-mediated cyclisation of 3 to give 12 merits comment
(Scheme 3). Previously, Ishibashi5j,m described a related approach
to 1 based on construction of the C(1)–C(9a) bond. However, this
required the presence of a thio-substituted radical acceptor (as in
14) to promote the radical cyclisation step. In the absence of this
thio residue, although this was only reported in the desmethoxy
series, a major pathway observed corresponded to intramolecular
1,5-hydrogen atom abstraction i.e. leading to 15. In our approach,
there is no requirement for additional activation of the exo-
methylene moiety to achieve an efficient cyclisation. We do,
however, also observe the product (16) of a formal 1,5-hydrogen
atom abstraction. Interestingly, the amount of 16 does increase if
the Bu3SnH–AIBN component is added over a shorter period.**
This suggests that 16 could also arise via a direct isomerisation of
the exo-alkene to the endo-isomer.
In summary, we have described a novel entry to (2)-aphanor-
phine 1 based on exploiting the reactivity of cyclic sulfamidates as
progenitors of substituted, a-functionalised lactams. The route
outlined in Scheme 2 is highly efficient, and the conversion of 5 to
O-methyl aphanorphine 13 proceeds in an overall yield of 25.4%,
which compares very favourably with existing synthetic
approaches to (2)-aphanorphine 1.
We acknowledge EPSRC and GSK for financial support of
this research programme, and Dow Pharma for providing the
Rh-DuPHOS catalyst.
Notes and references
{ Pentazocine and naloxone (Talwin nX1) are prescribed together, with
naloxone reducing the dependence and morphine-like side effects of
pentazocine. Interestingly, and despite the co-occurrence of saxitoxin and
neosaxitoxin with aphanorphine in Aphanizomenon flos-aquae, this plant
material is also marketed as a food supplement and nutraceutical.
§ 2-Bromo-4-methoxybenzaldehyde 5 was prepared as described by Durst6a
using Comins’ methodology6b for directed ortho-lithiation of aryl
aldehydes.
" The intermediacy of the cyclic carbamate 9 is inferred, but this species
has not been isolated.
I Intermediate 12 was reported in racemic form by Funk, who also
described the lactam reduction and O-demethylation. Spectroscopic data
obtained for lactam 12 matched that reported by Funk (see ESI).4b We
converted 12 to (+)-O-methyl aphanorphine 13, which constitutes a formal
synthesis of (2)-aphanorphine 1; the O-demethylation step has been
reported by a number of groups in yields ranging from 57–86%.
** This observation does not exclude participation of the 1,5-hydrogen
atom abstraction pathway, but the ratio of 12 to 16 would not be expected
to depend on the concentration of Bu3SnH if intramolecular abstraction
was the only source of 16. In our hands, exo-methylene lactams related to 3
Scheme 3
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