A concise enantioselective synthesis of the AB ring system of the manzamine alkaloids by ring-closing enyne metathesis

Article abstract of DOI:10.1016/S0040-4039(01)00404-X

The AB ring system found in the manzamine A and related alkaloids has been prepared from (-)-quinine by a short enantioselective route. The key step in the sequence is a ruthenium-catalysed ring-closing enyne metathesis re action which delivers a bicyclic diene in good yield. The functionality required for further elaboration of the AB system has been installed by sequential regioselective hydroboration and stereoselective catalytic aminohydroxylation.

Full text of DOI:10.1016/S0040-4039(01)00404-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3235–3238
A concise enantioselective synthesis of the AB ring system of the
manzamine alkaloids by ring-closing enyne metathesis
J. Stephen Clark,a,* Robert J. Townsend,a Alexander J. Blake,a Simon J. Teatb and Amanda Johnsc
aSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
bCLRC Daresbury Laboratory, Daresbury, Warrington, Cheshire WA4 4AD, UK
cDepartment of Medicinal Chemistry, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex CM19 5AW, UK
Received 23 February 2001; accepted 8 March 2001
Abstract—The AB ring system found in the manzamine A and related alkaloids has been prepared from (−)-quinine by a short
enantioselective route. The key step in the sequence is a ruthenium-catalysed ring-closing enyne metathesis re action which delivers
a bicyclic diene in good yield. The functionality required for further elaboration of the AB system has been installed by sequential
regioselective hydroboration and stereoselective catalytic aminohydroxylation. © 2001 Elsevier Science Ltd. All rights reserved.
Over the past 15 years, members of the manzamine
family of alkaloids have been the focus of an unprece-
dented level of synthetic interest.1 Since the discovery of
manzamine A in 19862 and the subsequent isolation of
structurally related alkaloids from marine sponges of
the Haliclona, Pellina and Xestospongia genera,3 the
unique structures of these compounds coupled with
their potent anti-tumour and anti-microbial activities
has made them alluring synthetic targets.2–4 The com-
plex pentacyclic core found in most of the manzamines,
ircinals and ircinols contains interlocking 5-, 6-, 8- and
13-membered rings and is one of the most challenging
naturally occurring ring systems known. In recent years
an ever increasing number of new strategies and reac-
tions have been developed for the assembly of sub-units
found in the pentacyclic core of these alkaloids.5 This
intense synthetic activity has culminated in two recent
landmark syntheses of members of the manzamine fam-
ily of natural products, completed by the groups of
Winkler and Martin.6,7
In previous studies, we have prepared the CE ring
system of manzamine A in enantiomerically pure form.8
Simultaneous construction of both rings was accom-
R
OH
N
H
N
H
N
R
N
N
N
H
H
H
H
OH
OH
OH
A
B
N
N
N
C
D
N
N
N
O
E
O
manzamine A R = H
R = OH
manzamine E R = H
manzamine X
manzamine F R = OH
manzamine Y
Keywords: manzamine; alkaloids; ring-closing; enyne; metathesis.
* Corresponding author. Tel.: +44 (0)115 9513542; fax: +44 (0)115 9513564; e-mail: j.s.clark@nottingham.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00404-X

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J. S. Clark et al. / Tetrahedron Letters 42 (2001) 3235–3238
H
N
H
H
H
O
a, b
c, d
e, f
N
N
Oi-Pr
N
OH
N
H
N
H
Boc
Boc
H
H
H
2
3
1
HO
H
g
j
OH
MeO
Boc
OBn
OBn
H
H
H
6
NHTs
h, i
N
N
Boc
Boc
H
H
H
k
5
OBn
4
OH
N
Boc
H
OH
7
Scheme 1. Reagents: (a) t-BuOK, Ph2CO, PhMe, reflux, 6 h (100%); (b) t-BuOK, O2, i-PrOH, THF, 0“20°C, 3 h (89%); (c)
(t-BuOCO)2O, Et3N, DMAP, CH2Cl2, 0°C“rt, 18 h (77%); (d) LiAlH4, THF, 0°C“rt, 1.5 h (95%); (e) TsCl, Et3N, CH2Cl2, rt,
16 h; (f) HCCLi·(NH2CH2)2, DMSO, THF, rt (55%, 2 steps); (g) Cl2(PCy3)2RuCHPh (10 mol%), CH2CH2, CH2Cl2, rt (96%); (h)
(i) Sia2BH, THF, −10“4°C, 6 h, (ii) NaOH aq., 30% H2O2, THF, −10°C“rt, 18 h (70%); (i) NaH, BnBr, n-Bu4NI, 18-c-6, THF,
0°C“rt, 19 h (92%); (j) K2OsO2(OH)4 (8 mol%), (DHQD)2PHAL (10 mol%), TsNClNa (6 equiv.), MeCN, H2O, rt, 72 h (76%);
(k) K2OsO2(OH)4 (8 mol%), (DHQD)2PHAL (10 mol%), MsNClNa (6 equiv.), n-PrOH, H2O, rt, 17 h (83%).
ruthenium catalyst [Cl2(PCy3)2RuCHPh] which resulted
in efficient ring-closing enyne metathesis and delivered
the diene 4 in 96% yield.12 Regioselective hydroboration
at the terminal position of the diene was accomplished
using disiamylborane, and the resulting homoallylic
alcohol was alkylated to provide the benzylic ether 5.
The required amino and hydroxyl groups were then
introduced simultaneously by employing a highly
diastereoselective and regioselective Sharpless aminohy-
droxylation reaction.13,14 The highest yield (76%) of the
required amino alcohol 6 was obtained by using a large
excess of Chloramine-T and sub-stoichiometric
amounts of potassium osmate(VI) dihydrate and the
phthalazine ligand (DHQD)2PHAL in degassed
aqueous acetonitrile at room temperature.13a,d The
phthalazine was required to accelerate the reaction, but
even in the presence of this ligand the reaction was
rather sluggish and took 3 days to proceed to comple-
tion. The diastereoselective aminohydroxylation reac-
tion is noteworthy because there are relatively few
plished by treatment of a diazo-substituted vinyl pyrro-
lidine with copper(II) acetylacetonate. During this key
reaction, cyclisation of the intermediate copper car-
benoid generated a spirocyclic ammonium ylide which
underwent immediate [2,3] rearrangement to deliver the
required ring system. We now disclose a short enan-
tioselective synthesis of the AB ring system present in
manzamine A and other alkaloids of the manzamine
family.
In most published syntheses of sub-units containing the
AB ring system, Diels–Alder reactions have been used
to construct the reduced isoquinoline core.9 In our
synthesis of this system, sequential ruthenium-catalysed
ring-closing enyne metathesis and catalytic aminohy-
droxylation reactions are employed to construct the
functionalised B ring. Although ring-closing diene
metathesis reactions have been used by others to pre-
pare the 13-membered D ring and the 8-membered E
ring,7,9n,o,10 preparation of the AB ring system using a
ring-closing enyne metathesis reaction has not been
explored.
The synthesis commenced with the efficient conversion
of (−)-quinine into the meroquinene ester 1 following
the procedure of Martinelli et al.11 Thus, oxidation of
(−)-quinine to quininone and subsequent ring cleavage
afforded the ester 1. Protection of the amine as the
t-butyl carbamate and subsequent ester reduction with
lithium aluminium hydride afforded the alcohol 2 in
good yield. Conversion of the primary alcohol into the
tosylate and subsequent displacement with lithium
acetylide ethylene diamine complex delivered the alkyne
3 in 55% yield over two steps. The enyne 3 was then
treated with a sub-stoichiometric amount of the Grubbs
Figure 1. The X-ray crystal structure of amino alcohol 6.

J. S. Clark et al. / Tetrahedron Letters 42 (2001) 3235–3238
3237
H
OAc
OAc
N
N
Boc
Boc
H
H
H
H
10a
H
OH
OR
a, b
c
d
N
OH
N
N
Boc
Boc
Boc
H
H
H
2
8
9
H
10b
Scheme 2. Reagents: (a) (i) DMSO, (COCl)2, CH2Cl2, −78°C, (ii) Et3N, −78°C“rt (91%); (b) HCCMgBr, THF, 0°C“rt, 26 h
(86%); (c) Ac2O, DMAP, Et3N, CH2Cl2, rt, 1 h (98%); (d) Cl2(PCy3)2RuCHPh (10 mol%), CH2CH2, PhMe, 80°C (46%).
closure reaction. Although it was not possible to deter-
mine unambiguously which diastereoisomer had under-
gone cyclisation, it is clear that a highly stereoselective
synthesis of one of the diastereoisomeric acetates 9 will
be required in order to ensure that the subsequent
ring-closing enyne metathesis reaction proceeds in high
yield.
published examples in which trisubstituted cyclic alke-
nes have been used as substrates.15 Although the highly
diastereoselective aminohydroxylation reaction is
largely substrate controlled, the (DHQD)2PHAL ligand
was selected with the expectation that reagent control
and substrate control would be matched. The choice of
(DHQD)2PHAL was based on results from analogous
asymmetric dihydroxylation reactions performed in the
presence of this ligand.16
In summary, we have prepared the AB ring system of
manzamine A in enantiomerically pure form by a short
and efficient route which commences from (−)-quinine,
an inexpensive and readily available chiral pool starting
material. The AB system possesses most of the func-
tionality required for further elaboration to an
advanced intermediate in the synthesis of manzamine
A, and we are currently exploring the construction of
the other rings found in the pentacyclic core of the
natural product.
The crystalline amino alcohol 6, which possesses appro-
priate amino functionality for introduction of ring C
and part of the side-chain necessary for construction of
the D ring, was obtained in good yield as a single
diastereoisomer. Crystals suitable for X-ray crystallog-
raphy were obtained by recrystallisation of the amino
alcohol 6 from diethyl ether. X-ray analysis using syn-
chrotron radiation confirmed both the structure of this
compound and the relative configuration of the four
contiguous stereogenic centres (Fig. 1).17
Acknowledgements
Further investigation of the aminohydroxylation reac-
tion revealed that the nature of the chloramine reagent
is critical to the success of this transformation.13d When
Chloramine-M was used instead of Chloramine-T,13b
stereoselective dihydroxylation occurred instead of
aminohydroxylation; the 1,2-diol 7 was obtained in
good yield and none of the required amino alcohol 6
was isolated (Scheme 1).16
We are grateful to the EPSRC for the award of an
Industrial Studentship (to R.J.T). We thank CLRC
Daresbury Laboratory for access to Station 9.8 on the
Synchrotron Radiation Source, and Mr. Neil R. Brooks
for experimental assistance.
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