Total synthesis of manzamine A and related alkaloids

Article abstract of DOI:10.1021/ja308826x

Total syntheses of three structurally complex marine natural products, manzamine A, ircinol A, and ircinal A, are reported. The route pivoted on the construction of a late-stage protecting-group-free pentacyclic enol triflate coupling partner, from which all three family members were accessed divergently via palladium-catalyzed reactions. The rapid synthesis of this key pentacyclic enol triflate was achieved by a highly convergent union of five fragments through a stereoselective Michael addition, a three-component nitro-Mannich lactamization cascade, an unprecedented and highly stereoselective reductive nitro-Mannich cyclization cascade, a stereoselective organometallic addition, and a Z-selective alkene ring-closing metathesis. Altogether this chemistry has allowed the shortest synthetic route to date for manzamine A (18-step longest linear sequence) via a late-stage diversification point that is ideal for future manzamine A analogue synthesis.

Full text of DOI:10.1021/ja308826x

Communication
pubs.acs.org/JACS
Total Synthesis of Manzamine A and Related Alkaloids
Pavol Jakubec, Alison Hawkins, Wolfgang Felzmann, and Darren J. Dixon*
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: Total syntheses of three structurally com-
plex marine natural products, manzamine A, ircinol A, and
ircinal A, are reported. The route pivoted on the
construction of a late-stage protecting-group-free pentacy-
clic enol triflate coupling partner, from which all three
family members were accessed divergently via palladium-
catalyzed reactions. The rapid synthesis of this key
pentacyclic enol triflate was achieved by a highly
convergent union of five fragments through a stereo-
selective Michael addition, a three-component nitro-
Mannich lactamization cascade, an unprecedented and
highly stereoselective reductive nitro-Mannich cyclization
cascade, a stereoselective organometallic addition, and a Z-
selective alkene ring-closing metathesis. Altogether this
chemistry has allowed the shortest synthetic route to date
for manzamine A (18-step longest linear sequence) via a
Figure 1. Retrosynthetic analysis of manzamine A.
late-stage diversification point that is ideal for future
manzamine A analogue synthesis.
would be primed for annulation via a nitro-Mannich/
lactamization cascade (to provide the A ring) and suitably
equipped for further elaboration into the B ring, provided a new
annulation method to unite the terminal carbon of Michael
acceptor 6 with the carbonyl carbon of the pyrrolidinone ring
could be developed. For this we planned to employ nitroalkane
4 as an intermediate. The nitro group would play dual roles in
allowing an intramolecular Mannich type reaction to occur on
an in situ-generated iminium ion (following full reduction of
the piperidinone carbonyl group and partial reduction of the
pyrrolidinone carbonyl group) and a subsequent oxidation via a
Nef reaction to cyclohexanone 3. A stereoselective addition of a
3-butenyl anion equivalent to the resulting carbonyl group,
followed by enol triflate formation and a Z-selective ring-closing
metathesis (RCM), would provide the key late-stage inter-
mediate 2.
Key to the multigram preparation of the nitro olefin coupling
partner 6 (Scheme 1) was the synthesis of homoallylic alcohol
10 from commercial starting materials using scalable synthetic
procedures.
Nucleophilic substitution of the hindered neopentylic
bromide 8 by acetate was nontrivial but was achieved using
neat Aliquat 336 and potassium acetate at 120 °C.6
Methanolysis of the resulting ester 9 occurred smoothly using
potassium carbonate in methanol at room temperature. Alcohol
10 was obtained in 49% yield (84% based on recovered starting
material). Oxidation of alcohol 10 using the Swern protocol
occurred without incident, and the crude aldehyde 11 reacted
with nitromethane under basic conditions to give Henry
anzamine A (1) is a marine alkaloid first isolated by
M
Higa et al. in 1986 from a sponge in the Okinawa Sea. It
exhibits a range of potent biological properties, including
insecticidal, anti-bacterial, anti-inflammatory, anti-cancer, and
anti-malarial activity.1 Manzamine A (1) has a pentacyclic
(ABCDE) core comprising 6-, 6-, 5-, 13-, and 8-membered
rings, two Z-olefins, two tertiary amines, and five stereocenters
including four contiguous and two quaternary centers. Attached
to the B ring is a β-carboline heteroaromatic ring system. The
unique biological profile of manzamine A (1) and its complex
structure make it a highly desirable target for synthesis.
To date, there have been many papers describing synthetic
efforts toward the core2 and three published total syntheses by
Winkler,3 Martin,4 and Fukuyama.5 The shortest route, that of
Martin, was completed in 23 steps from commercial material,
but the average step count still remains high at ∼28. All three of
these elegant routes converged on ircinal A as the precursor to
manzamine A, and demonstrably this is a successful strategy.
However, our analysis identified enol triflate 2 (Figure 1) as a
synthetically valuable late-stage intermediate. From the outset
our aim was to synthesize enol triflate 2 on scale, via the
shortest route possible, and then diversify from this point using
metal-catalyzed coupling reactions, thus providing access to
manzamine A and other family members such as ircinol A and
ircinal A. Herein we report our findings.
To access enol triflate 2, our aim was to develop a short route
founded on a key stereoselective Michael addition of 8,5-
pronucleophile 7 to a nitro olefin coupling partner 6, possessing
protected enone functionality. The nitro ester Michael adduct 5
Received: September 5, 2012
Published: October 7, 2012
© 2012 American Chemical Society
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Communication
a
Scheme 1. Synthesis of Electrophile 6
Scheme 3. Synthesis of the Pentacyclic Core of Manzamine
Alkaloids
a
a
Reagents and conditions: (a) KOAc, Aliquat 336, 120 °C, 16 h; (b)
K2CO3, MeOH, RT, 1 h, 49% (84% brs) (over two steps); (c) COCl2,
DMSO, Et3N, CH2Cl2, −78 °C to RT, 0.5 h; (d) CH3NO2, EtOH,
0 °C, 2 h, 90% (over two steps); (e) MsCl, Et3N, CH2Cl2, −15 °C to
RT, 15 min, 90%.
product 12 in 90% over two steps. Dehydration with
methanesulfonyl chloride and triethylamine gave the desired
nitro olefin 6 in 90% yield. All of the five steps of this route
were reproducible, and multigram quantities of 6 were
obtained.
With Michael acceptor 6 in hand, its diastereoselective union
with known 8,5-pronucleophile 77 was investigated. Dissimilar
to our previous study, the organocatalyzed Michael addition7−9
was not viable, presumably owing to the steric hindrance of the
adjacent acetal and vinyl group in 6. Nonetheless, desirable
reactivity was witnessed when stoichiometric potassium
hexamethyldisilazide was used as the base in conjunction with
a mole equivalent of 18-crown-6. The naked enolate imparted
moderate diastereoselectivity toward the desired diaster-
eoisomer 5 (dr ∼73:27:0:0 in the crude mixture). Fortunately,
the diastereomers were readily separated via flash column
chromatography, and the isolated 65% yield of the pure major
diasteromer was respectable for such a key chemical union. The
stereochemistry of 5 was unambiguously determined by single-
crystal X-ray diffraction (Scheme 2) and is consistent with our
previous findings.7,9
a
Reagents and conditions: (a) CH2O (13), hex-5-en-1-amine (14),
MeOH, reflux, 10 h, 88%; (b) AIBN, Bu3SnH, toluene, reflux, 30 min,
77%; (c) TMSCl, KI, 4 Å MS, MeCN, RT, 50 min, 81%; (d) AgNO2,
Et2O, RT, 48 h, 63%; (e) DIBAL, toluene, −78 to −20 °C, 1 h, 74% of
18 and 7% of 19 (dr 83:17); (f) Ti(OiPr)4, Ph2SiH2, hexane, 0 °C, 2 h,
81% (dr 83:17); (g) TiCl3, THF, water, RT, 5 h, 56% of 3, 21% of 20;
(h) 3-butenylmagnesium bromide (24), THF, CeCl3, 0 °C, 0.5 h then
HCl, 40 h, RT, 91%; (i) TMSOTf, Et3N, Et2O, RT, 30 min, 72%; (j)
Commins’ reagent (25), KHMDS, THF, −78 °C, 20 min, 90%; (k)
Grubbs’ first-generation catalyst (20 mol %), CH2Cl2, reflux, 3 h, 73%,
70:30 Z/E.
63% yield. Conversion of 4 to nitro amine 19 was without
precedent and required a series of precise and controlled
chemoselective reductions, followed by an intramolecular
Mannich reaction. Our initial concerns about the tolerance of
the nitro group to fairly harsh reducing conditions were
unfounded; the piperidinone carbonyl could be selectively
reduced with DIBAL, and the piperidine 18 was isolated in 74%
yield. Importantly, alongside piperidine 18, tetracyclic product
19 was isolated in 7% yield, thus validating the concept of our
reductive nitro-Mannich cyclization cascade.13 Following this
chemoselective reduction, a range of reducing agents with the
potential to deliver hydride to the pyrrolidinone carbonyl of 18,
but without causing over-reduction to the pyrrolidine or
reduction of either double bond, the acetal, or the nitro group,
were systematically explored. Pleasingly, the titanium tetraiso-
propoxide/diphenylsilane reducing agent system introduced by
Buchwald14 provided the necessary chemoselectivity and
reactivity profile. Reaction with pyrrolidinone 18 halted after
the first hydride addition and gave, after a silica gel workup, the
desired intramolecular nitro-Mannich product 19 as two of the
possible four diastereomers, epimeric at the carbon atom
bearing the nitro group, in a 83:17 ratio, in 81% yield.
Presumably, the high diastereofacial selectivity arises from
preferred attack of the tethered nitronate nucleophile to the
Scheme 2. Stereoselective Michael Addition of Key Building
Blocks
a
a
Reagents and conditions: (a) KHMDS, 18-crown-6, −94 °C, THF, 1
h, 65% of 5, 21% of minor isomer 5′.
Following the development of a nitro-Mannich/lactamization
cascade10 nitro ester Michael adduct 5 was reacted with
formaldehyde (13) and hex-5-en-1-amine (14) in refluxing
methanol to afford 4-nitro-piperidin-2-one 15 as a single
diastereoisomer in high yield (Scheme 3). Nitro group removal
under modified Ono’s conditions11 gave the functionalized
tricyclic core 16 ready for further elaboration. Conversion of
alkene 16 to nitroalkane 4 was made possible by the
intermediacy of iodide 17 generated by anti-Markovnikov
addition of HI to the double bond.12 Reaction of iodide 17 with
silver nitrite gave the substitution product, nitro alkane 4, in
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Journal of the American Chemical Society
Communication
proximal Si face of the spirocyclic iminium ion intermediate.
With the suitably configured nitro-Mannich product 19/19′ in
hand, our attention turned to its transformation into ketone 3.
Although the Nef reaction has been well-studied and a
plethora of reagents is available,15 such transformations are
rarely attempted on complex tertiary amine-containing
substrates.16 The presence of the acid-labile acetal functionality,
the retro-Mannich-prone skeleton, and the oxidizable tertiary
amine moieties of 19 complicated our study. However, after
considerable screening, the use of the McMurry modification of
a reductive Nef reaction15 employing titanium trichloride in
THF/water at low pH gave the key tetracyclic ketone 3 in 56%
isolated yield (together with 21% yield of intermediate oxime
20). Transformation of ketone 3 into TMS-protected enol
triflate 23 required three steps and was relatively straightfor-
ward. Thus, a highly stereoselective addition of a 3-
butenylcerium-derived organometallic followed by acetal
hydrolysis on workup gave hydroxy ketone 21 in nearly
quantitative yield. TMS ether protection under standard
conditions efficiently gave 22 which on treatment with
Commins’ reagent (25) then KHMDS gave the TMS-protected
enol triflate 23 in 90% yield. To complete the synthesis of the
key late-stage coupling intermediate 2, a Z-selective RCM was
required. From our screening of commonly employed,
commercially available Ru-based catalysts for alkene RCM,
only the Grubbs’ first-generation catalyst tolerated the labile
TMS protecting group on 23 during the reaction. Acidic
workup and silica gel chromatography gave the separable
pentacyclic deprotected products 2 and 2′ in 73% yield as a
70:30 Z:E mixture of diastereomers.
With access to the key late-stage intermediate 2 established,
the cross-coupling of the β-carboline moiety was investigated.
Pleasingly, the synthesis of tributylstannylated β-carboline 29
was possible (see Supporting Information) and its coupling
under palladium(0) catalysis successful, and manzamine A (1)
was afforded in 52% yield (Scheme 4). The spectroscopic data
(1H NMR, 13C NMR), high-resolution mass spectrometric
data, and specific rotation of our synthetic material were in
excellent agreement with published data.
Having demonstrated the utility of 2 for the preparation of
manzamine A (1), we then explored its utility for the
preparation of other family members. Thus, an alkoxycarbony-
lation reaction17 with methanol and carbon monoxide under
palladium catalysis gave methyl ircinate (26) in 78% yield
(Scheme 4). This compound was readily reduced to ircinol A18
(27) using excess DIBAL at low temperature. Finally a
reductive carbonylation19 with carbon monoxide and tributyltin
hydride under palladium(0) catalysis gave ircinal A20 (28) in
58% yield. The spectroscopic data of synthetic 27 and 28 were
in excellent agreement with the published values.
Scheme 4. Completion of the Total Syntheses of Manzamine
A, Ircinol A, and Ircinal A
a
a
Reagents and conditions: (a) Pd(PPh3)4 (12 mol %), 29, DMF,
60 °C, 1 h, 52%; (b) Pd(OAc)2 (18 mol %), PPh3 (40 mol %), CO,
Et3N, MeOH, DMF, 60 °C, 1 h, 78%; (c) DIBAL, toluene, −78 °C,
2 h, 82%; (d) Pd(PPh3)4 (10 mol %), CO, LiCl, Bu3SnH, toluene,
50 °C, 30 min, 58%.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures; spectroscopic and analytical data for
1
all new compounds including H and 13C NMR spectra; X-ray
crystallographic data (CIF) for 5 and 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Darren.dixon@chem.ox.ac.uk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC (Leadership Fellowship to D.J.D.,
Studentship to A.H., and Post-Doctoral Fellowship to P.J.),
GlaxoSmithKline (studentship to A.H.), and the Austrian
In conclusion, we have developed a short and stereoselective
synthesis (18-step longest linear sequence) of manzamine A
(1). Not only is this the shortest to date, but it is distinguished
from other synthetic routes by the adoption of a cross-coupling
strategy to attach the β-carboline, important for its biological
activity,21 to key late-stage intermediate enol triflate 2. This
approach allowed us to synthesize ircinal A (28) and methyl
ircinate (26) via alternative coupling reactions and is ideally
suited for future manzamine A analogue synthesis. Inves-
tigations to this end are ongoing, and the results will be
disclosed in due course.
Science Fund (FWF) (Erwin-Schrodinger Fellowship to W.F.).
̈
We also thank Andrew F. Kyle and David M. Barber for X-ray
structure determination and the Oxford Chemical Crystallog-
raphy Service for use of the instrumentation.
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