Synthesis of the tricyclic core of the marine alkaloid lepadiformine

Article abstract of DOI:10.1055/s-2003-36782

A stereoselective synthesis of the tricyclic core in racemic form of the marine alkaloid Lepadiformine is described from 4-methoxy-3-pyrrolin-2-one (methyl tetramate). Key steps involve 5,5-dialkylation of the tetramate, metathesis closure to an A/C 1-aza

Full text of DOI:10.1055/s-2003-36782

LETTER
271
Synthesis of the Tricyclic Core of the Marine Alkaloid Lepadiformine
Synthesis of the
T
o
ricyclic Cor
g
e
of the Mar
i
ne
A
lkaloid
r
Lepadiformin
H
e
unter,* Philip Richards
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax +27(21)6897499; E-mail: Roger@science.uct.ac.za
Received 6 December 2002
Abstract: A stereoselective synthesis of the tricyclic core in ra-
cemic form of the marine alkaloid Lepadiformine is described from
4-methoxy-3-pyrrolin-2-one (methyl tetramate). Key steps involve
5,5-dialkylation of the tetramate, metathesis closure to an A/C 1-
azaspirocycle and stereoselective hydrogenation for the trans A/B
1-azadecalin system.
Key words: marine alkaloid, metathesis, silyloxypyrrole alkyl-
ation, tetramate reduction, 1-azaspiro[4.5]decane
Considerable interest has been shown recently in the syn-
thesis of the marine alkaloid Lepadiformine 1, a tricyclic
perhydropyrrolo[2,1-j]quinoline isolated1 from the tuni-
cate Clavelina lepadiformis and reported to have moder-
ate in vitro cytotoxic activity against certain tumour cell
lines,1 as well as various cardiovascular effects in vivo
and in vitro.2 The early syntheses3 utilised cycloaddition
methodology for construction of the pivotal tertiaryaza
stereogenic centre of the trans-1-azadecalin A/B ring
junction. More recently, Weinreb has demonstrated the
application of an intramolecular spirocyclisation of an N-
acyliminium ion with an allylsilane to accomplish the first
enantioselective synthesis4 of the alkaloid, thus establish-
ing its absolute configuration. A key intermediate in
Weinreb’s synthesis was a 1-azaspiro[4.5]decyl unit used
as an A/C ring-system template. Recent publications on
the construction of the natural products FR9014835 and
(–)-TAN1251A6 have highlighted the use of substituted 1-
azaspiro[4.5]decanes, and in this communication we dis-
close a novel strategy for accessing this ring system as a
6-ketone7 with subsequent conversion of it in moderate
stereoselectivity to the tricyclic core of Lepadiformine in
racemic form (Figure 1).
Figure 1 Lepadiformine and other azaspirocyclic natural products
phy. Phase transfer9 protection of the lactam nitrogen of
3a produced the N-protected derivative 3b in excellent
yield setting the stage for construction of the pivotal ter-
tiaryaza centre (Scheme 1).
Scheme 1 Reagents and conditions: (a) n-BuLi (2 equiv), THF, –78
°C, allyl bromide (1 equiv), 79%; (b) KOH, Bu4NHSO4, THF, 88%.
Given the poor regioselectivity of alkylation of the tetra-
mate lithium dienolate, we opted to investigate the use of
the much softer silyl dienol ether (2-silyloxypyrrole). Al-
though N-Boc-2-tert-butyldimethylsilyloxypyrrole from
N-Boc-3-pyrrolin-2-one has been demonstrated by
Casiraghi10 to be a versatile building block in natural
product synthesis for 5-regioselective alkylation reac-
tions, no equivalent studies have been carried out on the
silyl dienol ether from an appropriately N-protected 4-
methoxy-3-pyrrolin-2-one. Jones reported11 preparing the
trimethylsilyl dienol ether of 4-methoxy-1-methyl-3-pyr-
rolin-2-one, but carried out no dissociative reactions on it.
We rationalised that the 4-methoxy group enhancing the
5-coefficient in the HOMO would offset the increased
steric factor caused by the 5-allyl substituent. Further-
more, we were interested in developing one-pot method-
ology using the cheaper chlorotrimethylsilane rather than
trapping and isolating the more expensive tert-butyldime-
thylsilyl dienol ether used in Casiraghi’s system. Thus we
were gratified to find that sequential treatment of 3b with
Our strategy centred around a sequence involving 5,5-di-
alkylation of a tetramate derivative, followed by chain ex-
tension and metathesis to the substituted azaspirocycle. 5-
Alkylation of the lithium dienolate of N-protected tetra-
mates with primary alkylating agents is well established in
the literature,8 however in our hands allylation of 1-ben-
zyl-4-methoxy-3-pyrrolin-2-one produced significant
quantities of the a-alkylation product. Thus we resorted to
using a procedure reported by Jones8a involving allylation
of the dianion of 4-methoxy-3-pyrrolin-2-one 2 with one
equivalent of allyl bromide. 5-Allyltetramate 3a was ob-
tained in 79% isolated yield after column chromatogra-
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2003,0,02,0271,0273,ftx,en;D22202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

272
R. Hunter, P. Richards
LETTER
n-BuLi, TMSCl, CH(OMe)3 and BF3⋅OEt2 furnished ex- before olefination resulted in no improvement. By com-
clusively the crystalline 5,5-disubstituted product 4 in parison, Grignard addition with BrMg(CH2)3OBn17 (3
88% isolated yield after chromatography (Scheme 2).12
equiv) gratifyingly resulted in an efficient addition to
form the tertiary alcohol 9 as a mixture of diastereomers
(4:3). Dehydration of 9 could be accomplished using a va-
riety of conventional reagents (e.g. POCl3 or SOCl2, pyri-
dine), but the best method18 proved to be using anhydrous
CuSO4 in refluxing p-xylene, which returned a 91% yield
of a mixture of endocyclic and exocyclic alkenes 10 (4:1)
without formation of any rearrangement products. Hydro-
genation of the double bonds of 10 with concomitant hy-
drogenolysis of the benzyl protecting group, mesylation
and ring closure using sodium hydride to generate the lac-
tam anion19 resulted in a 2:1 mixture of diastereomeric tri-
cycles 11a,b, separable by chromatography. The major
product 11a was assigned as the desired trans-1-azadeca-
lin ring system on the basis that the minor product 11b had
identical spectroscopic data to the known cis-1-azadecalin
synthesised by Aube’s group20 via an intramolecular
Schmidt reaction. The observed diastereoselectivity may
be rationalised via hydrogenation of the least hindered
face of the alkene(s) 10 (Scheme 4).
Scheme 2 Reagents and conditions: (a) n-BuLi (1.2 equiv), THF,
–78 °C, TMSCl (1.5 equiv); (b) HC(OMe)3, BF3⋅OEt2, 88%.
For development of the metathesis chemistry required to
generate the azaspirocycle, 4 was chemoselectively hy-
drolysed in quantitative yield to the aldehyde using over-
night treatment with trifluoroacetic acid (1% H2O).
Subsequent addition of allyl Grignard gave homoallylic
alcohol 5 in 76% yield (3:1), which was cleanly and rap-
idly metathesised with Grubb’s catalyst13 (2–5 mol%) to
the 5,5-spirotetramate 6 in 92% yield. Given the scope of
substitution in the metathesis reaction, a range of substitu-
tion patterns for the cyclohexane ring of the azaspirocycle
may be envisaged. Derivatives of the 5,5-spirotetramate
template of 6 have found use as potent herbicides,14 but in
the context of Lepadiformine it was desirable to reduce15
the vinyl ether of the tetramate ring to afford the saturated
C-ring. This was efficiently accomplished by sodium in
refluxing liquid ammonia to afford 7 in which both the
enol ether and benzyl groups had been completely re-
duced. Compound 7 was hydrogenated and oxidised to the
saturated keto-γ-lactam 87 (Scheme 3).
Scheme 4 Reagents and conditions: (a) BrMg(CH2)3OBn (3 equiv),
THF, 0 °C, 85%, (4:3); (b) CuSO4, p-xylene, ∆, 91%; (c) H2, Pd-C,
85% (2:1); (d) (i) MsCl, Et3N, THF; (ii) NaH, DMF, 80% (2:1).
In conclusion, we have developed some new methodology
for synthesising 5,5-spirotetramates and demonstrated a
sequence for elaboration to the tricyclic core of Lepadi-
formine in moderate stereoselectivity. The strategy de-
scribed herein augurs well21 for the possibility of
refinement into an enantioselective synthesis of the al-
kaloid as well as being able to furnish derivatives for
structure-activity anti-cancer studies.
Scheme 3 Reagents and conditions: (a) CF3CO2H (1% H2O), 35 °C,
95%; (b) allylMgCl, THF, –78 °C to 0 °C, 76% (3:1); (c)
RhCl2(PCy3)2=CHPh, CH2Cl2, 40 °C, 2 h; (d) Na, NH3 (l), –33 °C,
85%; (e) H2, Pd-C; (f) TPAP (5 mol%), NMO, CH3CN, powdered
mol. sieves, 78% over 2 steps.
Acknowledgement
We thank the South African NRF (National Research Foundation)
Annulation of 8 to construct the B ring of the Lepadifor- for financial support.
mine tricyclic core was explored in a number of ways.
Horner–Wittig olefination16 with the carbanion of
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Synlett 2003, No. 2, 271–273 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of the Tricyclic Core of the Marine Alkaloid Lepadiformine
273
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(CH2Cl2) = 3019, 1669, 1640, 1346 cm–1. Found: M+ (+ H),
318.17144. C18H24NO4 requires M+: 318.17053. 1H NMR
(400 MHz, CDCl3): δ = 2.37 (1 H, ddt, J = 1.1, 7.7, 14.7 Hz,
CH2), 2.54 (1 H, dd, J = 6.6, 14.7 Hz, CH2), 3.27 (3 H, s,
OCH3), 3.32 (3 H, s, OCH3), 3.75 (3 H, s, OCH3), 4.21 (1 H,
s, OCHO), 4.61 (2 H, s, PhCH2), 4.84 (2 H, m, CH=CH2),
5.12 (1 H, s, H-3), 5.18 (1 H, m, CH=CH2), 7.15–7.38 (5 H,
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43.6 (PhCH2), 57.8, 57.9 and 58.0 (3 × OCH3), 71.8 (C-5),
95.2 (C-3), 107.6 (OCHO), 118.6 (CH=CH2), 126.6, 128.0
and 128.5 (aromatic), 130.9 (CH=CH2), 139.6 (aromatic),
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(12) The following experimental procedure for conversion of
3b to 4 applies: The substrate 3b (0.73g, 3mmol) was
dissolved in anhyd THF (30 mL) under N2 and cooled to –78
°C. A solution of n-BuLi in hexane (2.25 mL of a 1.6 M
solution, 3.6 mmol, 1.2 equiv) was added dropwise. After
stirring for 30 min at –78 °C TMSCl (0.57 mL, 4.5 mmol, 1.5
equiv) was added dropwise and the solution was stirred for a
further 30 min at –78 °C. Trimethyl orthoformate (1.00 mL,
9.0 mmol, 3 equiv) was then added, followed by BF3⋅OEt2
(0.57 mL, 4.5 mmol, 1.5 equiv). The reaction was allowed to
slowly warm to –20 °C over 2 h. Sat. NaHCO3 solution was
then added and the THF was removed by evaporation. The
remaining aqueous layer was extracted with 3 portions of
EtOAc. The organic layers were combined, dried and
concentrated to give an oily residue. The product was
Synlett 2003, No. 2, 271–273 ISSN 0936-5214 © Thieme Stuttgart · New York