Ring-construction/stereoselective functionalization cascade: Total synthesis of pachastrissamine (jaspine B) through palladium-catalyzed bis-cyclization of bromoallenes

Article abstract of DOI:10.1021/ol901904w

Palladium(0)-catalyzed cyclization of bromoallenes bearing hydroxyl and benzamide groups as internal nucleophiles stereoselectively provides functlonallzed tetrahydrofuran. With this bis-cyclizatlon as the key step, a short total synthesis of pachastrissa

Full text of DOI:10.1021/ol901904w

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4478-4481
Ring-Construction/Stereoselective
Functionalization Cascade: Total
Synthesis of Pachastrissamine (Jaspine B)
through Palladium-Catalyzed
Bis-cyclization of Bromoallenes
Shinsuke Inuki, Yuji Yoshimitsu, Shinya Oishi, Nobutaka Fujii,* and
Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received August 17, 2009
ABSTRACT
Palladium(0)-catalyzed cyclization of bromoallenes bearing hydroxyl and benzamide groups as internal nucleophiles stereoselectively provides
functionalized tetrahydrofuran. With this bis-cyclization as the key step, a short total synthesis of pachastrissamine, a biologically active
marine natural product, was achieved.
Bromoallenes have attracted much attention due to their
interesting chemical properties associated with cumulated
double bonds and a bromine atom.1 Recently, we have
developed a novel synthesis of medium-sized heterocycles
3 containing one or two heteroatoms via cyclization of
bromoallenes 1 bearing an oxygen, nitrogen, or carbon
nucleophile in the presence of a palladium(0) catalyst and
alcohol (Scheme 1, eq 1).2 The first intramolecular nucleo-
philic attack by NuA at the central carbon atom of the allenic
moiety of 1, followed by protonation, gives π-allylpalladium
intermediate 2. Then the second intermolecular reaction with
NuB proceeds to give the monocyclization products 3 along
with their regioisomers 4 in some cases. Namely, bromoal-
lenes 5 can act as allyl dication equivalents 6 (Scheme 1, eq
2). More recently, we expanded this chemistry to cascade
cyclization of bromoallenes 7 bearing a dual nucleophilic
moiety leading to bicyclic products 9 (Scheme 1, eq 3).3
Unfortunately, this reaction is limited to highly nucleophilic
sulfamides (NuA-NuB ) NSO2N), presumably due to the
restricted conformation in the endo-type second cyclization.
The competing external nucleophilic attack by an alkoxide
derived from alcohol, which is a highly effective solvent for
this type of transformation, is also problematic.
We turned our attention to cascade cyclization of bro-
moallenes of type 10 bearing nucleophilic groups at both
ends of a branched alkyl group. This would lead to bicyclic
products such as 13 (Scheme 2). This reaction could facilitate
stereoselective functionalization on the exo-type second
cyclization, utilizing the chiral center at the branched
position. Apparently, the key to success of this cascade
(1) Ma, S. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 614-619.
(2) (a) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew. Chem.,
Int. Ed. 2003, 42, 1749–1753. (b) Ohno, H.; Hamaguchi, H.; Ohata, M.;
Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744–8754.
(3) (a) Hamaguchi, H.; Kosaka, S.; Ohno, H.; Tanaka, T. Angew. Chem.,
Int. Ed. 2005, 44, 1513–1517. (b) Hamaguchi, H.; Kosaka, S.; Ohno, H.;
Fujii, N.; Tanaka, T. Chem.sEur. J. 2007, 13, 1692–1708.
10.1021/ol901904w CCC: $40.75
Published on Web 09/09/2009
 2009 American Chemical Society

including jaspine A and 2-epi-jaspine B. Pachastrissamine
(jaspine B) 17 exhibits cytotoxic activity against various
tumor cell lines at nanomolar level.4,5 In 2009, Delgado and
co-workers reported that DHCer-mediated autophagy might
be involved in the cytotoxicity.6 Owing to its biological
importance, pachastrissamine has been the target of many
synthetic studies.7 Stereoselective construction of the trisub-
stituted tetrahydrofuran ring is a major issue in the total
synthesis.
Scheme 1. Palladium(0)-Catalyzed Cyclization of Bromoallenes
Figure 1. Structures of naturally occurring jaspines.
reaction is controlled successive nucleophilic attacks by NuA
and NuB in the desired order, as well as inhibition of the
external reaction with alkoxide; first cyclization by NuA or
NuB will produce intermediate 11 or 12, respectively, which
would be converted to the cyclic products 13/14 or 15/16,
by the intra- or intermolecular reaction. We chose pachas-
trissamine (jaspine B), which bears three contiguous stereo-
genic centers on its tetrahydrofuran core structure, for the
model study to evaluate this working hypothesis on the ring-
construction/stereoselective functionalization cascade.
We expected that palladium(0)-catalyzed cyclization of
bromoallenes 19 bearing hydroxy and benzamide groups8
as internal nucleophiles could regio- and stereoselectively
provide appropriately functionalized tetrahydrofuran 18 for
synthesis of pachastrissamine 17 (Scheme 3). The bicyclic
structure of 18 including the exo-olefin would be useful for
stereoselective construction of a C-2 stereogenic center as
well as carbon homologation. Herein, we describe an
efficient, short, total synthesis of pachastrissamine (jaspine
B) utilizing cascade cyclization of a bromoallene of type 19,
which has two internal nucleophiles at both ends of a
branched alkyl group.
Scheme 2. Construction of Bicyclic Structures by
Palladium(0)-Catalyzed Cascade Cyclization of Bromoallenes 10
(6) Canals, D.; Mormeneo, D.; Fabria`s, G.; Llebaria, A.; Casas, J.;
Delgado, A. Bioorg. Med. Chem. 2009, 17, 235–241.
(7) For previous syntheses, see: (a) Sudhakar, N.; Kumar, A. R.;
Prabhakar, A.; Jagadeesh, B.; Rao, B. V. Tetrahedron Lett. 2005, 46, 325–
327. (b) Bhaket, P.; Morris, K.; Stauffer, C. S.; Datta, A. Org. Lett. 2005,
7, 875–876. (c) van den Berg, R.; Boltje, T.; Verhagen, C.; Litjens, R.;
Vander Marel, G.; Overkleeft, H. J. Org. Chem. 2006, 71, 836–839. (d)
Du, Y.; Liu, J.; Linhardt, R. J. J. Org. Chem. 2006, 71, 1251–1253. (e)
Liu, J.; Du, Y.; Dong, X.; Meng, S.; Xiao, J.; Cheng, L. Carbohydr. Res.
2006, 341, 2653–2657. (f) Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A.
Tetrahedron 2006, 62, 5421–5425. (g) Lee, T.; Lee, S.; Kwak, Y. S.; Kim,
D.; Kim, S. Org. Lett. 2007, 9, 429–432. (h) Reddy, L. V. R.; Reddy, P. V.;
Shaw, A. K. Tetrahedron: Asymmetry 2007, 18, 542–546. (i) Ramana, C. V.;
Giri, A. G.; Suryawanshi, S. B.; Gonnade, R. G. Tetrahedron Lett. 2007,
48, 265–268. (j) Prasad, K. R.; Chandrakumar, A. J. Org. Chem. 2007, 72,
6312–6315. (k) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Snchez-Fernndez, E. M.;
Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18, 2510–
2513. (l) Yakura, T.; Sato, S.; Yoshimoto, Y. Chem. Pharm. Bull. 2007,
55, 1284–1286. (m) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies,
S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell,
A. J.; Snchez-Fernndez, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2008, 6, 1665–1673. (n) Passiniemi, M.; Koskinen,
A. M. P. Tetrahedron Lett. 2008, 49, 980–983. (o) Venkatesan, K.;
Srinivasan, K. V. Tetrahedron: Asymmetry 2008, 19, 209–215. (p) Enders,
D.; Terteryan, V.; Palecek, J. Synthesis 2008, 2278–2282. (q) Ichikawa,
Y.; Matsunaga, K.; Masuda, T.; Kotsuki, H.; Nakano, K. Tetrahedron 2008,
64, 11313–11318. For a review, see: (r) Abraham, E.; Davies, S. G.; Roberts,
P. M.; Russell, A. J.; Thomson, J. E. Tetrahedron: Asymmetry 2008, 19,
1027–1047.
The structure of pachastrissamine 17 (Figure 1), an
anhydrophytosphingosine derivative isolated from a marine
sponge Pachastrissa sp., was reported by Higa and co-
workers in 2002.4 Shortly thereafter, Debitus and co-workers
isolated the same compound from a different marine sponge,
Jaspis sp., and named jaspine B.5 Other structurally related
analogues have also been isolated from the same species,
(4) Kuroda, I.; Musman, M.; Ohtani, I.; Ichiba, T.; Tanaka, J.; Garcia-
Gravalos, D.; Higa, T. J. Nat. Prod. 2002, 65, 1505–1506.
(5) Ledroit, V.; Debitus, C.; Lavaud, C.; Massoit, G. Tetrahedron Lett.
2003, 44, 225–228.
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3408. (b) Cook, G. R.; Shanker, P. S. Tetrahedron Lett. 1998, 39, 4991–
4994. (c) Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Oh, C.-Y.; Ham, W.-H. J.
Org. Chem. 1999, 64, 9450–9458.
Org. Lett., Vol. 11, No. 19, 2009
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We next investigated cascade cyclization of bromoallene
19a in the presence of palladium(0) (Table 1). Treatment of
19a with Pd(PPh3)4 (5 mol %) and NaH (2.0 equiv) in MeOH
at 50 °C (standard conditions for cyclization of bromoal-
lenes2) successfully produced the desired bicyclic tetrahy-
drofuran 18 in 50% yield (entry 1). The undesired cyclization
initiated by the first cyclization by the benzamide group
(Scheme 2) was not promoted. However, the anticipated side
products dihydrofuran 23a (formed by the intermolecular
reaction with methoxide) and a small amount of furan 24
were observed. Formation of the furan 24 can be rationalized
by ꢀ-hydride elimination of the π-allylpalladium intermediate
(e.g., 11 or 12, Scheme 2) followed by aromatization.13 To
suppress the intermolecular reaction with the external alkox-
ide, the reaction was examined under other conditions,
including the use of a mixed solvent. Reaction in THF/MeOH
(4:1) decreased yields of both 18 and 23a (40% and 15%,
respectively), while the amount of furan 24 increased (10%
yield, entry 2). Of the several bases investigated, Cs2CO3
(1.2 equiv) most effectively produced the desired product
18 and suppressed formation of furan 24 (entries 2-5). The
best result was obtained using a mixed solvent of THF/
MeOH (10:1) in the presence of 1.2 equiv of Cs2CO3 (89%,
entry 6). It should be noted that the use of solely THF
resulted in low yield of 18 (12%, entry 7) and recovery of
the starting material, which suggests that an alcoholic solvent
plays an important role in this type of transformation.
Interestingly, use of CF3CH2OH, a more acidic solvent which
might facilitate the protonation step, only gave the undesired
compound 23b bearing a trifluoroethoxy group in high yield
(93%, entry 8). Moreover, use of t-BuOH was not effective
(entry 9). These results indicate that pKa values and bulkiness
of the alcohol solvent have significant effects on the reaction,
i.e., the intramolecular vs intermolecular reaction in the
Scheme 3. Retrosynthetic Analysis of Pachastrissamine 17
Preparation of the required bromoallene 19a is outlined
in Scheme 4. The erythro-alkynol 21a was easily prepared
from (S)-Garner’s aldehyde 209 following the literature
procedure.10 Treatment of 21a with MsCl and Et3N gave
the corresponding mesylate, which was then allowed to react
with CuBr·DMS/LiBr11 (DMS ) Me2S) to afford the (S,aR)-
bromoallene 22a.12 Removal of the Boc and acetal groups
with TFA followed by acylation with BzCl/Et3N afforded
the benzamide 19a.
Scheme 4. Synthesis of Bromoallene 19a
Table 1. Palladium-Catalyzed Cascade Cyclization of Bromoallene 19aa
yield (%)b
entry
base (equiv)
solvent
MeOH
THF/MeOH (4:1)
THF/MeOH (4:1)
THF/MeOH (4:1)
THF/MeOH (4:1)
THF/MeOH (10:1)
THF
time (h)
18
23
24
recoveryc (%)
41
1
2
3
4
5
6
7
8
9
NaH (2.0)
NaH (2.0)
2.0
1.0
4.0
2.5
2.5
2.5
5.5
2.5
2.5
50
40
43
67
78
89
12
45
15
trace
10
K2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
26
20
trace
64
60
THF/TFE (4:1)
THF/t-BuOH (4:1)
93
12
a All reactions were performed with 5 mol % of Pd(PPh3)4 at 0.1 M in the solvent indicated. b Yield of isolated products. c Recovery of starting material.
TFE ) 2,2,2-trifluoroethanol.
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Org. Lett., Vol. 11, No. 19, 2009

second nucleophilic attack and reactivity of the bromoallene
with a palladium catalyst.
ment with a cuprate derived from C13H27MgBr/CuI provided
the tetrahydrofuran 26 bearing all the requisite functional-
ities.15 Finally, pachastrissamine 17 was obtained by hy-
drolysis of 26 with 20% aqueous H2SO4.16 The spectroscopic
data and optical rotation of synthetic pachastrissamine 17
were in agreement with those reported for the natural and
To investigate the difference in reactivity between the
diastereomeric bromoallenes 19a and 19b, we next synthe-
sized (S,aS)-bromoallene 19b, also starting from Garner’s
aldehyde 20 (Scheme 5). The threo-alkynol 21b, stereose-
lectively obtained following Taddei’s protocol,12 was con-
verted into the desired bromoallene 19b in the same manner
as described above (Scheme 4). Bromoallene 19b was then
subjected to the optimized reaction conditions shown in entry
6 (Table 1) to give the desired bicyclic product 18 in 88%
yield. These results show both bromoallene 19a and 19b
equally undergo the cascade cyclization to give the same
product 18. This means that a diastereomeric mixture of
bromoallenes can be directly employed for preparation of
18.
synthetic substance [1H/13C NMR, IR, melting point, [R]25
D
19.7 (EtOH)].4,5,7
Scheme 6. Total Synthesis of Pachastrissamine (17)
Scheme 5. Synthesis and Palladium-Catalyzed Cascade
Cyclization of the Epimeric Bromoallene 19b
In conclusion, we have developed a novel ring-construc-
tion/stereoselective functionalization cascade by palladium(0)-
catalyzed bis-cyclization of bromoallenes. Using bromoal-
lenes bearing hydroxy and benzamide groups as internal
nucleophiles allows the sequential nucleophilic reactions to
selectively proceed in the desired order to form a function-
alized tetrahydrofuran ring. This strategy provides an efficient
synthetic route to pachastrissamine 17 bearing three contigu-
ous stereogenic centers from Garner’s aldehyde as the sole
chiral source in 11 steps and 11% overall yield.
With the functionalized tetrahydrofuran 18 prepared, the
final stage was to complete the total synthesis of pachas-
trissamine 17 (Scheme 6). This required introduction of a
C-2 side chain with an all-cis configuration and hydrolysis
of the oxazoline ring. Hydroboration-oxidation of the exo-
olefin of 18 with 9-BBN provided the primary alcohol 25
with the desired configuration as the sole diastereomer.14
Treatment of 25 with Tf2O and Et3N followed by displace-
Acknowledgment. This work was supported by a Grant-
in-Aid for Encouragement of Young Scientists (A) (H.O.)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, and Targeted Proteins Research
Program. S.I. is grateful for Research Fellowships from the
Japan Society for the Promotion of Science (JSPS) for Young
Scientists. Appreciation is expressed to Fundamental Studies
in Health Sciences of the National Institute of Biomedical
Innovation (NIBIO).
(9) (a) Garner, P. Tetrahedron Lett. 1984, 25, 5855–5858. (b) Campbell,
A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998, 1707–1709.
(10) Herold, P. HelV. Chim. Acta 1988, 71, 354–362.
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Elsevier, C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.;
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Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Preparation of 22 was previously reported: (a) D’Aniello, F.; Mann,
A.; Taddei, M.; Wermuth, C.-G. Tetrahedron Lett. 1994, 35, 7775–7778.
(b) D’Aniello, F.; Mann, A.; Schoenfelder, A.; Taddei, M. Tetrahedron
1997, 53, 1447–1456. For improvement of the yield of 22, a slightly
modified bromination protocol was used (3 equiv of the copper reagent, 65
°C; see the Supporting Information).
OL901904W
(13) A related furan formation as a byproduct in the cascade cyclization
of propargylic bromides was recently reported; see: Ohno, H.; Okano, A.;
Kosaka, S.; Tsukamoto, K.; Ohata, M.; Ishihara, K.; Maeda, H.; Tanaka,
T.; Fujii, N. Org. Lett. 2008, 10, 1171–1174.
(15) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-
R. J. Am. Chem. Soc. 2003, 125, 14702–14703.
(16) Lehr, P.; Billich, A.; Charpiot, B.; Ettmayer, P.; Scholz, D.;
Rosenwirth, B.; Gstach, H. J. Med. Chem. 1996, 39, 2060–2067.
(14) Ghosh, A. K.; Xi, K. Org. Lett. 2007, 9, 4013–4016.
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