Total synthesis of (-)-nakadomarin A

Article abstract of DOI:10.1039/c1cc13665h

A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereosele

Full text of DOI:10.1039/c1cc13665h

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 10037–10039
www.rsc.org/chemcomm
COMMUNICATION
Total synthesis of (À)-nakadomarin Aw
Andrew F. Kyle, Pavol Jakubec, Dane M. Cockfield, Ed Cleator, John Skidmore and
a
a
b
c
d
a
Darren J. Dixon*
Received 20th June 2011, Accepted 21st July 2011
DOI: 10.1039/c1cc13665h
1
1,12
A highly diastereoselective bifunctional organocatalyst controlled
Michael addition, a nitro-Mannich/lactamization cascade, a
furan N-acyliminium cyclisation, a sequential alkyne RCM/
syn-reduction and an alkene RCM has allowed a 19 step, highly
stereoselective synthesis of (À)-nakadomarin A.
syn-selective hydrogenation.
Herein we wish to report a
new highly Z-selective route to (À)-nakadomarin A employing
an alkyne RCM as a key macrocyclic ring-forming step.
Our retrosynthetic plan (Scheme 1) pivoted on the stereo-
selective synthesis of late stage tetracyclic intermediate 2 which
would be suitably poised for a sequential alkyne RCM to
construct the 15-membered ring and an alkene RCM to
construct the 8-membered ring. We envisaged this product
would be accessible from the nitro ester 7 through our
(
À)-Nakadomarin A is a marine alkaloid of the manzamine
family first isolated by Kobayashi and co-workers in 1997
from the Haplosclerid sponge Amphimedon sp., collected off
the coast of the Kerama Islands, Okinawa. This hexacyclic
alkaloid contains an 8/5/5/5/15/6 ring system incorporating
four stereogenic centres, including one quaternary carbon.
7
documented nitro-Mannich/lactamization cascade chemistry
and
a subsequent stereoselective intramolecular furanyl
N-acyliminium cyclisation. Nitro ester 7 would be formed from
a diastereoselective Michael addition of pronucleophile 9 with
nitro olefin 8 controlled by a bifunctional organocatalyst.
Pronucleophile 9 was constructed on multigram scale through
Cytotoxic activity against murine lymphoma L1210 cells
À1
(
IC50 = 1.3 mg mL ), inhibition of cyclin dependent kinase
À1
4
(IC50 = 9.9 mg mL ) and antimicrobial activity against the
À1
13
fungus Trichophyton mentagrophytes (MIC = 23 mg mL
and the gram-positive bacterium Corynebacterium xerosis
)
a two step protocol starting from pyroglutamol (see ESIw).
Nitro olefin 8 was synthesized from dimethyl (2-oxopropyl)-
À1
(MIC = 11 mg mL ) have all been exhibited by this molecule
in biological screens.
phosphonate in a route analogous to that previously reported
7
1
,2
(see ESIw).
The biological activity and intriguing structural complexity
has resulted in significant interest from the synthesis community.
To date there have been nine papers describing the construction
Pivotal to the success of our synthesis was the stereoselective
construction of the C–C bond linking the quaternary stereo-
centre to the tertiary stereocentre bearing the functionalized
furan heterocycle. Preliminary investigations (Scheme 2) into
the levels of diastereocontrol that could be achieved using a
nitro olefin Michael addition reaction were carried out using 9
and model nitro olefin 10. Treatment of 9 and 10 with achiral
base 1,4-diazabicyclo[2.2.2.]octane (DABCO) 15 in toluene led
to the formation of two of the possible four diastereoisomers,
3
4–8
of the tetracyclic core, five total syntheses and two formal
9
,10
syntheses.
8
With the exception of a recent synthesis by
Funk, all of the other total synthesis papers, including the
one from our group, used alkene ring closing metathesis
(
RCM) to construct the 15-membered ring and E/Z isomeric
mixtures were obtained.
With the general failure of the routes to deliver high
Z-selectivity in the alkene RCM we recognized that a solution
was to employ an alkyne RCM combined with a concomitant
a
Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford, OX1 3TA, United
Kingdom. E-mail: darren.dixon@chem.ox.ac.uk;
Tel: +44 1865 275648
School of Chemistry, The University of Manchester, Manchester,
United Kingdom
Merck Sharp Dohme Research Laboratories, Global Process
Research, Hoddesdon, Hertfordshire, EN11 9BU, United Kingdom
GlaxoSmithKline, Neurosciences Centre of Excellence for Drug
Discovery, New Frontiers Science Park, Harlow, CM19 5AW,
United Kingdom
b
c
d
w Electronic supplementary information (ESI) available: Experimental
procedures, ‘matched’ and ‘mismatched’ substrate and catalyst control
studies and spectral data for all new compounds. CCDC reference
numbers 805604, 805605. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc13665h
Scheme 1 Retrosynthetic analysis of (À)-nakadomarin A.
Chem. Commun., 2011, 47, 10037–10039 10037
This journal is c The Royal Society of Chemistry 2011

View Article Online
treatment with hept-5-yn-1-amine 5 and formaldehyde (6) in
refluxing methanol afforded nitro piperidin-2-one 4 as a single
1
5
diastereomer in 52% yield. Reductive removal of the nitro
group occurred smoothly using tributyltin hydride and
1
6
AIBN. To construct the tetracyclic core via an N-acylimi-
nium ion cyclisation, selective delivery of one hydride to 3 was
required. This was readily achieved after a protecting group
switch: acid catalyzed methanolysis of the isopropylidene
protecting group of 18 allowed exhaustive Boc protection of
NH and OH functionality. Treatment of this compound with
s
Superhydride at low temperature afforded 19. Subjecting this
substrate to neat formic acid for 15 h followed by an alkaline
hydrolytic work-up afforded the tetracyclic core of (À)-naka-
3b,4
domarin A 20 as a single diastereoisomer (Scheme 3).
Dissolution in formic acid facilitated the desired N-acyliminium
ion formation/cyclisation and double Boc deprotection but also
afforded hydrolysable formic acid derived side products.
Aware of the compatibility of alkyne ring closing metathesis
with alkene functionality but the known incompatibility of
Scheme 2 Preliminary nitro olefin Michael addition studies.
a) Catalyst 15 (10 mol%), toluene, 30 1C, 7 days, 4.3:1:0:0 crude dr,
8% yield (mixture of diastereoisomers); (b) Catalyst 16 (10 mol%),
1
7
some catalysts to amine functionality, the most attractive
alkyne RCM precursor was 2. Transformation of 20 to 2 was
readily achieved in three standard transformations; a selective
hexenoylation of the pyrrolidine nitrogen atom was followed
by an IBX oxidation and Wittig olefination (Scheme 4). With
alkyne RCM precursor in hand a range of commercial and
literature reported alkyne RCM catalysts were screened and in
(
3
toluene, 30 1C, 48 h, 15 : 1 : 0 : 0 crude dr, 80% yield (single diastereo-
isomer 11); (c) Catalyst 17 (10 mol%), toluene, 30 1C, 5 days,
4
: 12 : 1 : 1 crude dr, 61% yield [mixture of diastereoisomers
(6 : 19 : 1 : 1 dr)].
1
8
1
1 and 12, in a 4.3 : 1 ratio respectively. The relative stereo-
our hands the Schrock tungsten neopentylidyne catalyst was
by far the best producing the desired product in 69% yield
when the reaction was performed at moderate dilution in
chlorobenzene at 80 1C (largest scale: 36 mg of diyne 2). The
best stereo- and chemoselectivity in the alkyne hydrogenation
was found using nickel boride in the presence of excess
chemistries of the major diastereoisomer 11 and the minor
diastereoisomer 12 were unambiguously determined by single
crystal X-ray analysis (see ESIw). Epimeric at the newly
formed tertiary stereocentre these diastereoisomers resulted
from exclusive addition to the convex face of the enolized
bicyclic pronucleophile, however, facial selectivity on addition
to the nitro olefin was only poorly imparted by the chiral
pronucleophile. To improve diastereoselection, bifunctional
organocatalysts introduced by our group and others were
1
9
ethylenediamine. Hydrogenation in the absence of ethylene-
diamine and when using Lindlar conditions rapidly resulted in
a complex mixture of products attributed to reduction of the
alkene functionalities in the molecule. To complete the
total synthesis two steps remained; the alkene ring-closing
metathesis to construct the 8-membered ring and the
1
4
investigated. Pleasingly using cinchonine derived urea 16 as
catalyst at 10 mol% a significantly improved diastereo-
selectivity was observed; after 48 h 11 and 12 were formed in
a ratio of 15 : 1 and the isolated yield of pure 11 after flash
column chromatography and a recrystallization was 80%.
Interestingly use of pseudoenantiomeric cinchonidine derived
urea 17 resulted in a reduced reaction rate (5 days), as well as
a
4
poor and reversed diastereoselection (11 : 12 : 13 : 14,
: 12 : 1 : 1 dr). These data confirm that bifunctional organo-
catalyst stereocontrol dominates the inherent substrate stereo-
control and that pronucleophile 9 and cinchonine derived
organocatalyst 16 are matched for the production of 11,
whereas 17 and 9 are mismatched.
Applying the findings of the model system, pronucleophile 9
(
2 eq.) was reacted with furanyl nitro olefin 8 in toluene at 30
C in the presence of 10 mol% 16. The reaction was complete
1
after 52 h, was highly diastereoselective (dr 18 : 1 : 0 : 0) and the
desired Michael adduct 7 was isolated as a single diastereomer
in 81% yield [1.99 g of 7 (largest single batch)]. The good
reactivity and high selectivity achieved in this key C–C bond
forming transformation using pronucleophile 9 represents a
Scheme 3 Synthesis of tetracyclic core 20. Reaction conditions:
(
a) organocatalyst 16 (10 mol%), toluene, 30 1C, 52 h, 81%, single
diastereoisomer; (b) hept-5-yn-1-amine 5, CH QO (6), MeOH, reflux, 8
h, 52%; (c) AIBN, Bu SnH, mesitylene, 165 1C, 2.5 h, 65%; (d) PTSA,
MeOH, reflux, 5 h, 87%; (e) di-tert-butyl dicarbonate, DMAP, Et N,
2
3
3
significant improvement from our previously reported route to
7
CH Cl , rt, 15 h, 88%; (f) lithium triethylborohydride, THF, À78 1C, 2 h,
2
2
(
À)-nakadomarin A. With gram quantities of 7 in hand,
79%; (g) HCOOH, rt, 15 h, then LiOH, MeOH, 50 1C, 5 h, 86%.
1
0038 Chem. Commun., 2011, 47, 10037–10039
This journal is c The Royal Society of Chemistry 2011

View Article Online
2
3
For a review of the isolation of the related compound manzamine
A, see: (a) E. Magnier and Y. Langlois, Tetrahedron, 1998,
5
4, 6201; For syntheses see: (b) J. D. Winkler and J. M. Axten,
J. Am. Chem. Soc., 1998, 120, 6425; (c) J. M. Humphrey, Y. Liao,
A. Ali, T. Rein, Y.-L. Wong, H.-J. Chen, A. K. Courtney and
S. F. Martin, J. Am. Chem. Soc., 2002, 124, 8584; (d) T. Toma,
Y. Kita and T. Fukuyama, J. Am. Chem. Soc., 2010, 132, 10233.
(a) A. Furstner, O. Guth, A. Duffels, G. Seidel, M. Liebl, B. Gabor
¨ ¨
and R. Mynott, Chem.–Eur. J., 2001, 7, 4811; (b) T. Nagata,
A. Nishida and M. Nakagawa, Tetrahedron Lett., 2001, 42, 8345;
(c) P. Magnus, M. R. Fielding, C. Wells and V. Lynch, Tetrahedron
Lett., 2002, 43, 947; (d) E. Leclerc and M. A. Tius, Org. Lett., 2003,
5, 1171; (e) K. A. Ahrendt and R. M. Williams, Org. Lett., 2004,
6, 4539; (f) I. S. Young, J. L. Williams and M. A. Kerr, Org. Lett.,
2005, 7, 953; (g) M. G. Nilson and R. L. Funk, Org. Lett., 2006,
8, 3833; (h) H. Deng, X. Yang, Z. Tong, Z. Li and H. Zhai, Org.
Lett., 2008, 10, 1791; (i) T. Haimowitz, M. E. Fitzgerald and
J. D. Winkler, Tetrahedron Lett., 2011, 52, 2162.
T. Nagata, M. Nakagawa and A. Nishida, J. Am. Chem. Soc.,
2003, 125, 7484.
K. Ono, M. Nakagawa and A. Nishida, Angew. Chem., Int. Ed.,
2004, 43, 2054.
4
5
Scheme 4 Synthesis of (À)-nakadomarin A 1. Reaction conditions:
a) hex-5-enoyl chloride, Et N, CH Cl
, À20 1C to rt, 3 h, 89%;
b) IBX, DMSO, rt, 24 h; (c) MePPh Br, KO Bu, THF/toluene, rt, 15 min,
WRC–C(CH , chlorobenzene, 80 1C,
, Ni(OAc) O, NH CH CH NH , EtOH,
Á4H
(
3
2
2
t
(
3
6
7
I. S. Young and M. A. Kerr, J. Am. Chem. Soc., 2007, 129, 1465.
P. Jakubec, D. M. Cockfield and D. J. Dixon, J. Am. Chem. Soc.,
7
4% (2 steps); (d) [(CH
h, 69%; (e) H , NaBH
3
)
3
CO]
3
3 3
)
2
2
4
2
2
2
2
2
2
2
009, 131, 16632.
rt, 1.3 h, 87%; (f) DIBAL-H, toluene, 0 1C to rt, 6 h, 59%;
g) Grubbs’ 1st generation catalyst, (+)-CSA, CH Cl , reflux, 8 h, 70%.
8 M. G. Nilson and R. L. Funk, Org. Lett., 2010, 12, 4912.
9 R. A. Stockman, P. J. McDermott, A. F. Newton and P. Magnus,
Synlett, 2010, 4, 559.
(
2
2
exhaustive amide/lactam functional group reduction to the
diamine. Owing to difficulties in our hands closing the 8-mem-
bered ring directly on 22, the amide and lactam functional groups
were first reduced using an excess of DIBAL-H at 0 1C in
toluene. Subsequent treatment of diamine 23 with Grubbs’ first
generation catalyst in the presence of (+)-CSA afforded (À)-
nakadomarin A 1 in 70% yield (6.5 mg). The structure of synthetic
10 F. Inagaki, M. Kinebuchi, N. Miyakoshi and C. Mukai, Org. Lett.,
2
010, 12, 1800.
1 This approach has been adopted previously in a number of
natural product syntheses. For a review see: (a) A. Furstner and
1
¨
P. W. Davies, Chem. Commun., 2005, 2307; For selected recent
examples see: (b) V. V. Vintonyak and M. E. Maier, Angew.
Chem., Int. Ed., 2007, 46, 5209; (c) B. J. Smith and
G. A. Sulikowski, Angew. Chem., Int. Ed., 2010, 49, 1599;
(
d) V. Hickmann, M. Alcarazo and A. Fu
Soc., 2010, 132, 11042.
2 For an example of alkyne ring closing metathesisin a model
system of the nakadomarin macrocycle see: A. Furstner,
O. Guth, A. Rumbo and G. Seidel, J. Am. Chem. Soc., 1999,
21, 11108.
13 (a) S. Saijo, M. Wada, J. Himiza and A. Ishida, Chem. Pharm. Bull.,
980, 28, 1449; (b) S. G. Davies, D. J. Dixon, G. J.-M. Doisneau,
J. C. Prodger and H. J. Sanganee, Tetrahedron: Asymmetry, 2002,
3, 647.
14 (a) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun., 2005,
¨
rstner, J. Am. Chem.
(
–)-nakadomarin A 1 was confirmed by comparison of the spectral
4
–8
1
data and specific rotation with those of the literature.
¨
In summary, a 19 step route (longest linear sequence) to
(
À)-nakadomarin A 1 employing an alkyne ring-closing
1
metathesis to enable the stereoselective construction of the
Z-configured alkene in the 15-membered ring has been
achieved. Furthermore ‘matched’ catalyst and substrate control
facilitated a highly diastereoselective nitro olefin Michael
addition to fix two of the four stereogenic centres in one key
step. While longer than our first reported route to (À)-nakado-
marin A [12 steps (longest linear sequence)] significant improve-
ments have been made. This second generation route compares
favourably to all of the other total syntheses reported including
1
1
4
2
481; (b) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed.,
005, 44, 6367; (c) T. Okino, Y. Hoashi and Y. Takemoto, J. Am.
Chem. Soc., 2003, 125, 12672.
¨
¨
5 For seminal work see: (a) M. Muhlstadt and B. Schulze, J. Prakt.
Chem., 1975, 317, 919; (b) H. Bhagwatheeswaran, S. P. Gaur and
P. C. Jain, Synthesis, 1976, 9, 615; For recent applications see:
(c) P. Jakubec, M. Halliwell and D. J. Dixon, Org. Lett., 2008,
1
1
8
the synthesis of Funk [21 steps (longest linear sequence)] which
1
0, 4267; (d) P. Hynes, P. A. Stupple and D. J. Dixon, Org. Lett.,
also employed an alkyne ring closing metathesis step.
2008, 10, 1389; (e) S. M.-C. Pelletier, P. C. Ray and D. J. Dixon,
Org. Lett., 2009, 11, 4512.
We gratefully acknowledge the EPSRC for a postdoctoral
fellowship (to PJ) and Leadership Fellowship (to DJD). We
also thank the EPSRC and GlaxoSmithKline for an EPSRC-
Pharma Synthesis Studentship (to AFK), Merck, Sharp and
Dohme (Hoddesdon, UK) for a CASE award (to DMC) and
The University of Manchester for a studentship (to DMC). We
thank Prof. Andrew Weller and Dr Adrian Chaplin for the use
of a glovebox. We also thank the Oxford Chemical Crystal-
lography Service for the use of their instrumentation.
6 For seminal work see: (a) N. Ono, H. Miyake, R. Tamura and
A. Kaji, Tetrahedron Lett., 1981, 22, 1705; (b) D. D. Tanner,
E. V. Blackburn and G. E. Diaz, J. Am. Chem. Soc., 1981,
103, 1557; For more recent examples see: (c) J. Tormo,
D. S. Hays and G. C. Fu, J. Org. Chem., 1998, 63, 5296;
(
d) B. Shen and J. N. Johnston, Org. Lett., 2008, 10, 4397.
7 For a review see: (a) W. Zhang and J. S. Moore, Adv. Synth. Catal.,
007, 349, 93; (b) K. C. Nicolaou, P. G. Bulger and D. Sarlah,
Angew. Chem., Int. Ed., 2005, 44, 4490.
8 (a) R. R. Schrock, D. N. Clark, J. Sancho, J. H. Wengrovius,
S. M. Rocklage and S. F. Pedersen, Organometallics, 1982, 1, 1645;
1
1
2
(
b) J. H. Freudenberger, R. R. Schrock, M. R. Churchill,
A. L. Rheingold and J. W. Ziller, Organometallics, 1984, 3, 1563;
c) M. L. Listemann and R. R. Schrock, Organometallics, 1985,
, 74; (d) R. R. Schrock, Polyhedron, 1995, 14, 3177.
9 C. A. Brown and V. K. Ahuja, J. Chem. Soc., Chem. Commun.,
973, 553.
Notes and references
(
4
1
For isolation and biological properties of (–)-nakadomarin A, see:
a) J. Kobayashi, D. Watanabe, N. Kawasaki and M. Tsuda,
J. Org. Chem., 1997, 62, 9236; (b) J. Kobayashi, M. Tsuda and
M. Ishibashi, Pure Appl. Chem., 1999, 71, 1123.
(
1
1
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10037–10039 10039