Formal synthesis of (+)-nakadomarin A

Article abstract of DOI:10.1021/ol100412f

The formal synthesis of (+)-nakadomarin A was completed. The significant points of this synthesis are the highly stereoselective formation of the diazatricyclo[6.4.0.0^1,5]dodecane skeleton (A, B, and D rings) based on the Pauson-Khand reaction and novel furan ring (C ring) formation, using the vinyl residue of the Pauson-Khand product.

Full text of DOI:10.1021/ol100412f

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1800-1803
Formal Synthesis of (+)-Nakadomarin A
Fuyuhiko Inagaki, Masahiko Kinebuchi, Naoki Miyakoshi, and Chisato Mukai*
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received February 17, 2010
ABSTRACT
The formal synthesis of (+)-nakadomarin A was completed. The significant points of this synthesis are the highly stereoselective formation
of the diazatricyclo[6.4.0.01,5]dodecane skeleton (A, B, and D rings) based on the Pauson-Khand reaction and novel furan ring (C ring)
formation, using the vinyl residue of the Pauson-Khand product.
Nakadomarin A is a representative manzamine-related
alkaloid that was isolated from the Okinawan marine sponge
Amphimedon sp. (SS-264) by Kobayashi in 1997 (Figure 1).1
Nakadomarin A exhibited a cytotoxicity against murine
lymphoma L1210 cells (IC50 1.3 µg/mL), inhibitory activity
against cyclin dependent kinase 4 (IC50 9.9 µg/mL), anti-
microbial activity against a fungus (Trichophyton menta-
grophytes, MIC 23 µg/mL), and a Gram-positive bacterium
(Corynebacterium xerosis, MIC 11 µg/mL). This marine
natural product has a unique fused-hexacyclic framework
consisting of A through F rings (6-5-5-5-8-15 mem-
bered rings). Four total syntheses2 of both the (-)- and (+)-
nakadomarin A have so far been recorded besides several
synthetic studies of nakadomarin A.3 The first and second
total syntheses of (+)-nakadomarin A (unnatural form) and
(-)-nakadomarin A (natural form), respectively, were con-
secutively accomplished by Nishida in 20032a and 2004.2b
In addition, Kerr recently reported the total synthesis of (+)-
nakadomarin A in 2007,2c and in the last year, the total
synthesis of (-)-nakadomarin A was completed by Dixon.2d
Figure 1. Structure of (-)-nakadomarin A.
We have recently been involved in the investigation of
not only the stereoselective Co2(CO)8-mediated intramolecu-
(3) (a) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc.
1999, 121, 11108–11113. (b) Fu¨rstner, A.; Guth, O.; Du¨ffels, A.; Seidel,
G.; Liebl, M.; Gabor, B.; Mynott, R. Chem.sEur. J. 2001, 7, 4811–4820.
(c) Nagata, T.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42,
8345–8349. (d) Magnus, P.; Fielding, M. R.; Wells, C.; Lynch, V.
Tetrahedron Lett. 2002, 43, 947–950. (e) Ahrendt, K. A.; Williams, R. M.
Org. Lett. 2004, 6, 4539–4541. (f) Young, I. S.; Williams, J. L.; Kerr, M. A.
Org. Lett. 2005, 7, 953–955. (g) Nilson, M. G.; Funk, R. L. Org. Lett.
2006, 8, 3833–3836. (h) Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H.
Org. Lett. 2008, 10, 1791–1793.
(1) (a) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org.
Chem. 1997, 62, 9236–9239. (b) Kobayashi, J.; Tsuda, M.; Ishibashi, M.
Pure Appl. Chem. 1991, 71, 1123–1126.
(2) (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003,
125, 7484–7485. (b) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem.,
Int. Ed. 2004, 43, 2020–2023. (c) Young, I. S.; Kerr, M. A. J. Am. Chem.
Soc. 2007, 129, 1465–1469. (d) Jakubec, P.; Cockfield, D. M.; Dixon, D. J.
J. Am. Chem. Soc. 2009, 131, 16632–16633.
10.1021/ol100412f  2010 American Chemical Society
Published on Web 03/16/2010

lar Pauson-Khand reaction (PKR) of enynes leading to the
construction of bicyclo[m.3.0] skeletons (m ) 3, 4),4 but also
the Rh(I)-catalyzed intramolecular Pauson-Khand type
reaction of allene-alkyne substrates5 and bis(allene)s6 which
successfully provided the larger-sized bicyclo[m.3.0] frame-
works (m ) 4, 5, 6). Thus, the Pauson-Khand (type)
reactions unambiguously emerged as a powerful tool for
constructing bicyclo[m.3.0] structures (m ) 3-6). We now
report the novel synthesis of (+)-nakadomarin A by taking
advantage of the carbonylative [2+2+1] cycloaddition of
the enyne derivative, which provides the central tricyclic
framework (rings A, B, and D) in one operation. Our simple
retrosynthetic analysis of (+)-nakadomarin A (1) is depicted
in Scheme 1. The primary target molecule would be assumed
simpler enyne derivative 4b, which has a 2-benzyloxyethyl
group at the triple bond terminus (Table 1, entry 2). Although
Table 1. Pauson-Khand Reaction of 4
Scheme 1. Retrosynthesis of (+)-Nakadomarin A
a This result was reported by Magnus. See ref 3d.
4b was exposed to various Pauson-Khand conditions,
unexpectedly, no desired ring-closed products could be
obtained. This observation is in sharp contrast to the result
reported by Magnus,3d in which the intramolecular PKR of
the much simpler enyne analogue 4a (without a substituent
at the triple bond terminus) produced the carbonylative
[2+2+1] cycloaddition product 5a in 69% yield (entry 1).
We tentatively assumed that if a suitable π-electron donating
component, such as an olefin, is present at the proper position
to the alkyne-Co2(CO)6 complex moiety, it might anchi-
merically not only assist in the liberation of CO from the
cobalt atom, but also accelerate the coordination of an
internal olefin counterpart with the cobalt atom thus ending
up with a favorable result.7 Thus, an additional substrate 4c
having a vinyl group at the triple bond terminus was
prepared. Compound 4c was then treated with Co2(CO)8 to
afford the corresponding Co2(CO)6 complex, which was
subsequently exposed to several Pauson-Khand conditions,
and we found that the most standard condition, namely
heating in toluene at 110 °C under a CO atmosphere, effected
the ring-closing step to produce the desired product 5c in
52% yield (entry 3).
With the fact that the introduction of the vinyl group to
the triple bond terminus provided the favorable result in the
PKR of the alkyne-dihydropyrrole substrate in mind, the
synthesis of (+)-nakadomarin A was initiated according to
the protocol shown in Scheme 2. By taking the construction
of both the furan and 15-membered rings at the latter stages
into account, the homopropargyl amine 7 possessing a
pentenyl residue at the triple bond terminus was prepared
as follows. The Sonogashira coupling of the known vinylio-
to be the 6-5-5-5 tetracyclic compound 2, because the
compounds similar to 2 have already been transformed into
(+)-nakadomarin A2a,c by the two ring-closing olefin met-
atheses. The key synthetic intermediate, a tetracyclic com-
pound 2, might be assembled from the carbonylative
[2+2+1] cycloaddition product 3 via the furan ring formation
by taking advantage of the proper carbon tether (R5) at the
position R to the carbonyl functionality of 3. Therefore, our
tactical feature involves the PKR of the enyne derivative 4
as the most significant step in the synthesis of (+)-
nakadomarin A (1).
Prior to examining the PKR of 4 with suitable substituents,
we initially investigated the ring-closing reaction using a
(4) (a) Mukai, C.; Kobayashi, M.; Kim, I. J.; Hanaoka, M. Tetrahedron
2002, 58, 5225–5230. (b) Nomura, I.; Mukai, C. Org. Lett. 2002, 4, 4301–
4304. (c) Nomura, I.; Mukai, C. J. Org. Chem. 2004, 69, 1803–1812. (d)
Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 10147–
10154.
(5) (a) Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett.
2002, 4, 1755–1758. (b) Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem.
2003, 68, 1376–1385. (c) Mukai, C.; Inagaki, F.; Yoshida, T.; Kitagaki, S.
Tetrahedron Lett. 2004, 45, 4117–4121. (d) Mukai, C.; Inagaki, F.; Yoshida,
T.; Yoshitani, K.; Hara, Y.; Kitagaki, S. J. Org. Chem. 2005, 70, 7159–
7171. (e) Mukai, C.; Hirose, T.; Teramoto, S.; Kitagaki, S. Tetrahedron
2005, 61, 10983–10994. (f) Inagaki, F.; Kawamura, T.; Mukai, C.
Tetrahedron 2007, 63, 5154–5160.
(7) (a) Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibelmann, S.; Van
Pelt, C. E. J. Am. Chem. Soc. 1993, 115, 7199–7207. (b) Wender, P. A.;
Croatt, M. P.; Deschamps, N. M. J. Am. Chem. Soc. 2004, 126, 5948–
5949. (c) Croatt, M. P.; Wender, P. A. Eur. J. Org. Chem. 2010, 19–32.
(d) Brusey, S. A.; Banide, E. V.; Do¨rrich, S.; O’Donohue, P.; Ortin, Y.;
Mu¨ller-Bunz, H.; Long, C.; Evans, P.; McGlinchey, M. J. Organometallics
2009, 28, 6308–6319.
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Chem., Int. Ed. 2009, 48, 2007–2011.
Org. Lett., Vol. 12, No. 8, 2010
1801

reached the condition that involves consecutive treatment of
4d with Co2(CO)8 in Et2O and heating of the resulting cobalt
Scheme 2
.
Synthesis of Dienyne 4d
10
n
complex in toluene at 110 °C in the presence of BuSMe
providing 5d in 60% yield in a highly stereoselective
manner.11 The stereoselective formation of 5d must be
attributed to the preferential approach of the Co2(CO)6
complex to the olefin moiety of the dihydropyrrole ring from
the opposite side of the siloxymethyl group in order to avoid
any serious nonbonding interaction.
The efficient construction of the fused furan ring (C ring)
was the next subject for our synthesis (Scheme 4). The
Scheme 4. Synthesis of Tetracyclic Compound 11a
dide 6, prepared from 4-pentyn-1-ol according to the
literature,8 with 3-butyn-1-ol to furnish the homoallylic
alcohol derivative in 84% yield, was subsequently converted
to the primary amine derivative 7 in 84% yield by the
standard methods. Meanwhile, preparation of another alde-
hyde fragment 9 commenced with the introduction of an ester
group at the R position to the carbonyl functionality of the
known (R)-8,9 derived from L-pyroglutamic acid, to produce
the ketoester derivative. Reduction of the resulting 1,3-
dicarbonyl compound was followed by acid treatment to
afford the aldehyde 9 in a 59% overall yield. The reductive
amination of the aldehyde 9 with the primary amine 7 in
the presence of NaBH4 furnished the secondary amine
derivative, which was subsequently converted into the
corresponding tosyl amide 4d in 69% yield (2 steps).
Our endeavor then focused on the stereoselective PKR of
the dienyne 4d having suitable substituents. According to a
preliminary experiment, 4d was exposed to specific condi-
tions (treatment with Co2(CO)8 in Et2O and heating in toluene
at 110 °C under CO) to afford the desired tricyclic compound
5d (Scheme 3). However, the yield was much lower (23%)
protecting group on the primary hydroxyl group of 5d was
first changed from the PMB group to the benzoyl group under
the standard conditions to furnish 10. On the basis of the
literature precedent,12 hydroxylation of the isolated double
bond of the R-pentenyl-R,ꢀ-cyclopentenone framework of
10 was examined expecting the formation of the correspond-
ing furan derivative, but no desired furan derivatives could
be formed. Alternatively, successive treatment of 10 with
OsO4 and acid treatment (CSA in toluene at 110 °C)
underwent efficient dihydroxylation and furan ring formation
to give the tetracyclic furan derivative 11a in 80% yield
accompanied by loss of the Boc protecting group. Easy furan
ring formation could be achieved, but 11a has an undesired
double bond on ring A.
Judging from the literature precedents,3c,h the selective
reduction of the double bond of 11a by direct hydrogenation
seemed to be less hopeful due to the high reactivity of the
strained furan ring. Indeed, only a trace amount of the desired
12a was obtained when the NH compound was exposed to
the hydrogenation conditions along with the production of
fairly high amounts of the over-reduced products (Table 2,
Scheme 3. Pauson-Khand Reaction of 4d
(8) Mandal, A. K.; Schneekloth, J. S., Jr.; Crews, C. M. Org. Lett. 2005,
7, 3645–3648.
(9) (a) Zanardi, F.; Sartori, A.; Curti, C.; Battistini, L.; Rassu, G.;
Nicastro, G.; Casiraghi, G. J. Org. Chem. 2007, 72, 1814–1817. (b) Shinada,
T.; Hamada, M.; Kawasaki, M.; Ohfune, Y. Heterocycles 2005, 66, 511–
525.
(10) Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett
1999, 771–773.
(11) The stereochemistry of 5d was determined based on a NOE
experiment of the amine compound, which was derived from 5d by
removing of the Boc group.
(12) (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.;
Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955–2020. (b) Maiti,
S.; Sengupta, S.; Giri, C.; Achari, B.; Banerjee, A. K. Tetrahedron Lett.
2001, 42, 2389–2391. (c) Boto, A.; Herna´ndez, D.; Herna´ndez, R. Org.
Lett. 2007, 9, 1721–1724.
compared to that of the preliminary experiment (52%). After
screening several Pauson-Khand conditions again, we finally
1802
Org. Lett., Vol. 12, No. 8, 2010

Table 2. Stereo- and Regioselective Hydrogenation of 11
Scheme 5. Formal Synthesis of (+)-Nakadomarin A
entry
Substrate
R
time (h)
product
yield (%)
1
11a
11b
11c
H
Boc
Fmoc
24
24
6
12a
12b
12c
trace
32
51
2
3a
a 20% Pd/C was used.
entry 1). Introduction of the Boc group on the secondary
amine of 11b, however, significantly improved the yield. In
fact, the hydrogenation of 11b proceeded under 10 atm of
H2 in the presence of 10% Pd/C in AcOEt to furnish the
desired hydrogenated product 12b in 32% yield (entry 2).
Furthermore, compound 11c with a bulkier Fmoc group on
the secondary amine produced 12a in 51% yield under
similar conditions (20% Pd/C /10 atm of H2/AcOEt, entry
3) by removing the protecting group.13 Thus, the direct
transformation of 11c into 12a was realized by a simple
hydrogenation and deprotection.
The amine compound 12a was acylated with 5-hexenoyl
chloride to afford the amide, which was subsequently treated
with TBAF to give 13 in 55% yield (Scheme 5). The
formation of the 8-membered ring was performed by
successive oxidation with Dess-Martin reagent, Wittig
reaction, and ring-closing olefin metathesis with Grubbs
second (generation) catalyst to furnish 14 in 84%. The
remaining manipulation before completion of synthesis of
the (+)-nakadamarin A is the construction of the 15-
membered ring. Therefore, the introduction of both hexenyl
and butenyl residues on rings A and C, respectively, was
our next objective. The terminal alkyne derivative 15 was
prepared in a 73% overall yield by the debenzoylation of
14, oxidation, and treatment with Ohira-Bestmann reagent.14
Removal of the Ts group of 15 proceeded upon exposure to
sodium naphthalenide producing the secondary amine, which
was condensed with 5-hexenoic acid to give 16 in 69% yield.
Hydrogenation of 16 in the presence of the Lindlar catalyst
provided 17 in 83% yield. The synthetic 17 was identical
with the previously synthesized ones by comparison of their
spectral data. Since Nishida2a and Kerr2c have already
completed their total syntheses of (+)-nakadomarin A from
17, the present synthesis of 17 amounts to the formal
synthesis of (+)-nakadomarin A.
In summary, we have completed the formal synthesis of
(+)-nakadomarin A from the commercially available L-
pyroglutamic acid. The most significant feature of this
synthesis involves (i) the PKR of an alkyne-dihydropyrrole
derivative having a vinyl functionality at the triple bond
terminus, which enabled us to stereoselectivley construct the
desired 6-5-5 tricyclic ring system with suitable substit-
uents, and (ii) novel furan ring formation and selective
hydrogenation.
Acknowledgment. This work was supported in part by a
Grant-in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan,
for which we are thankful.
Supporting Information Available: Preparation and
characterization data for compounds 4d, 5c, 5d, 7, 9, 10,
11a, 11c, 12a, 13-16, and 17 and 1H and 13C NMR spectra
for compounds 4d, 5c, 5d, 7, 9, 10, 11a, 11c, 12a, 13-16,
and 17. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) The stereochemistry of 12a was confirmed by the NOESY
experiment.
(14) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Mu¨ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522.
OL100412F
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1803