Palladium-catalyzed medium-ring formation for construction of the core structure of laurencia oxacycles: Synthetic study of laurendecumallene B

Article abstract of DOI:10.1021/ol401231y

Palladium-catalyzed medium-ring formation from a cyclic propargyl carbonate via a ring-opening and -closing cascade proceeded at the central carbon atom of the propargyl unit to provide a tetrahydro-2H-oxocine derivative bearing the core structure of laurencia oxacycle. The synthetic application of this reaction to a possible laurendecumallene B precursor is also presented.

Full text of DOI:10.1021/ol401231y

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Palladium-Catalyzed Medium-Ring
Formation for Construction of the Core
Structure of Laurencia Oxacycles:
Synthetic Study of Laurendecumallene B
Yuji Yoshimitsu, Shinsuke Inuki, 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 May 2, 2013
ABSTRACT
Palladium-catalyzed medium-ring formation from a cyclic propargyl carbonate via a ring-opening and -closing cascade proceeded at the central
carbon atom of the propargyl unit to provide a tetrahydro-2H-oxocine derivative bearing the core structure of laurencia oxacycle. The synthetic
application of this reaction to a possible laurendecumallene B precursor is also presented.
The marine genus Laurencia specifically produces a
significant subset of medium-ring haloethers as secondary
metabolites; these typically consist of a C15 carbon skele-
ton with an enyne or bromoallene side chain.1 Since the
first report of the isolation of (þ)-laurencin (1) from
Laurencia glandulifera by Irie et al. in 1965,2 numerous
medium-ring haloethers have been isolated from Lauren-
cia red algae. Laurendecumallene B (2), a C15 acetogenin
isolated from the marine red alga Laurencia decumbens,
was first reported by Wang et al. in 2007 (Figure 1).3
Another structurally related laurendecumallene, known
as laurendecumallene A (3), was also isolated from the
same species. To date, the total synthesis of laurendecu-
mallene B has not been reported in the literature. The
relative configuration of laurendecumallene B has been
partly determined, but the configurations of the axial
chirality of bromoallene and the substituent at the C-13
position, and the absolute configuration of the molecule,
have not yet been elucidated.
The development of synthetic strategies for the construc-
tion of these Laurencia oxacycles have been extensively
investigated in recent years.4ꢀ6 However, for the syntheses
of diverse collections of medium-ring natural products and
(4) For reviews, see: (a) Yeung, K. S.; Paterson, I. Chem. Rev. 2005,
105, 4237–4313. (b) Fujiwara, K. In Topics in Heterocyclic Chemistry,
Vol. 5; Kiyota, H., Ed.; Springer-Verlag: Berlin, 2006; pp 97ꢀ148. (c)
Blunt, J. W.; Copp, B. R.; Hu, W. P.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2007, 24, 31–86. (d) Morris, J. C.;
Nicholas, G. M.; Phillips, A. J. Nat. Prod. Rep. 2007, 24, 87–108.
(5) For selected recent syntheses based on ring-closing metathesis,
see: (a) Park, J.; Kim, B.; Kim, H.; Kim, S.; Kim, D. Angew. Chem., Int.
Ed. 2007, 46, 4726–4728. (b) Adsool, V. A.; Pansare, S. V. Org. Biomol.
Chem. 2008, 6, 2011–2015. (c) Sasaki, M.; Hashimoto, A.; Tanaka, K.;
Kawahata, M.; Yamaguchi, K.; Takeda, K. Org. Lett. 2008, 10, 1803–
1806. (d) Ortega, N.; Martın, V. S.; Martın, T. J. Org. Chem. 2010, 75,
´ ´
6660–6672. (e) Kim, M. J.; Sohn, T.; Kim, D.; Paton, R. S. J. Am. Chem.
Soc. 2012, 134, 20178–20188.
(1) (a) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141–152. (b)
Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48. (c) Suzuki, M.;
Vairappan, C. S. Curr. Top. Phytochem. 2005, 7, 1–34.
(2) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 6,
1091–1099.
(6) For selected recent syntheses without using ring-closing metathe-
sis, see: (a) Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D. J. Am. Chem.
Soc. 2007, 129, 2269–2274. (b) Li, J.; Suh, J. M.; Chin, E. Org. Lett. 2010,
12, 4712–4715. (c) Snyder, S. A.; Treitler, D. S.; Brucks, A. P.; Sattler, W.
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(3) Ji, N. Y.; Li, X. M.; Li, K.; Wang, B. G. J. Nat. Prod. 2007, 70,
1499–1502.
r
10.1021/ol401231y
XXXX American Chemical Society

as their antipodes (ent-2c/d) from the common intermediate
for the synthesis of 2a/b at a later stage of the synthesis.
In 2003, the author’s group reported that bromoallenes
such as 7, which are synthetic equivalents of propargylic
compounds, were extremely useful for the synthesis of
medium-sized rings 8 (Scheme 1, eq 1).9 We have also
shown that cyclization through ring opening and closing is
a convenient strategy for the construction of bicyclic
structures.10 In 2001, Yoshida, Ihara, and co-workers
developed a methodology for the synthesis of cyclic carbo-
nates, based on a Pd-catalyzed cascade reaction involving
a CO2 eliminationꢀfixation process.11 Inthe current work,
we tried to apply these chemistries to the synthesis of
Laurencia oxacycles (eq 2), in which a cyclic propargyl
carbonate 9 possessing a strategically positioned hydroxy
functionality could undergo Pd-mediated medium-ring
formation through ring-opening and -closing reactions
via an η3-allylpalladium complex B. These compounds
could then be trapped by the pendant carbonate, providing
medium-sized ethers 10.
Figure 1. Structures of naturally occurring haloethers from
Laurencia species.
their derivatives, the development of efficient approaches
for the construction of medium-ring ethers, not only those
based on ring-closing metathesis,5 remains important.6
Because of the interesting activities of eight-membered
Laurencia oxacycles,7 attempts were made in this study to
complete the first total synthesis of laurendecumallene B.
Despite the presence of several stereogenic centers, the
configuration of the axial chirality of the bromoallene
moiety in Laurencia oxacycles can be predicted from their
strong optical rotation values, which are in good agreement
with Lowe’s rule.8 Based on the positive value of the optical
Scheme 1. Cyclization of Propargylic/Allenic Compounds
rotation of laurendecumallene B ([R]18 = þ60.6 in
D
CHCl3), its axial chirality was assumed to be (S). The target
structures were therefore identified as compounds 2aꢀd
(Figure 2). The decision was taken to develop a synthetic
route to compounds 2a/b based on the absolute configura-
tion of the core structures of the related bromoallenes
from Laurencia species, such as (þ)-laurallene (4), (þ)-
pannosallene (5), and (þ)-itomanallene A (6) (Figure 1). If
necessary, the other possible isomers 2c/d could be formed
The retrosynthetic analysis of the possible stereoisomers
2a/b is shown in Scheme 2. It was envisaged that 2a/b could
be derived from 12 by deoxygenation at the C-5 position,
followed by the introduction of a bromoallene side chain
and a Br-atom at the C-13 position. The fused tetrahy-
drofuran 12couldbeconstructedfrom the cycliccarbonate
13 via a sequence of hydroborationꢀoxidation and cycli-
zation by intramolecular SN2 displacement reactions,
which would use the resulting hydroxy group as a leaving
group. The eight-membered ring in 13 could in turn be
constructed via the Pd-catalyzed cyclization of the cyclic
propargyl carbonate 14, which could be synthesized via a
(9) (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.
(10) Okano, A.; Oishi, S.; Tanaka, T.; Fujii, N.; Ohno, H. J. Org.
Chem. 2010, 75, 3396–3400.
Figure 2. Possible structures of laurendecumallene B.
(11) (a) Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616–
619. (b) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc.
2003, 125, 4874–4881.
(7) Watanabe, K.; Umeda, K.; Miyakado, M. Agric. Biol. Chem.
1989, 53, 2513–2515.
(8) (a) Lowe, G. Chem. Commun. 1965, 411–413. The absolute con-
figurations of the bromoallene moiety can be sometimes predicted by
their optical rotation values, even if the molecules have several chiral
centers. For example, see: (b) Ohno, H.; Ando, K.; Hamaguchi, H.;
Takeoka, Y.; Tanaka, T. J. Am. Chem. Soc. 2002, 124, 15255–15266.
(12) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179–3181. (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y.
J. Am. Chem. Soc. 1986, 108, 5644–5646. (c) Takai, K.; Tagashira, M.;
Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc.
1986, 108, 6048–6050.
B
Org. Lett., Vol. XX, No. XX, XXXX

was converted to alkyne 20 in 69% yield by treatment
with lithiated TMS-diazomethane. The hydroxy group
was then protected as the corresponding p-methoxyphenyl
ether, using Mitsunobu conditions, to give 21 in 66%
yield.16 The conversion of the acetonide to the correspond-
ing carbonate group was conducted by exposure of 21 to
Scheme 2. Retrosynthetic Analysis of Possible Isomers 2a/b
TsOH H2O in MeOH, followed by treatment with tri-
3
phosgene in the presence of pyridine to give cyclic carbo-
nate 22 in 67% yield. The iodoalkyne 16 was obtained by
iodination of the terminal alkyne in 22 using NIS/AgNO3
in 79% yield.17
Scheme 4. Synthesis of Alkyne 16
NozakiꢀHiyamaꢀKishi (NHK) coupling reaction12 be-
tween aldehyde 15 and alkyne 16, and several subsequent
functional group manipulations. It was envisaged that the
known L-arabinose-derived hemiacetal 1713 could be used
as a common intermediate for the syntheses of 15 and 16.
We started our synthesis by preparing 19, the precursor
of aldehyde 15 (Scheme 3). The addition of lithium acet-
ylide (prepared from but-1-yne) to the known hemiacetal
17 was quenched with ClCO2Me to furnish the corre-
sponding methyl carbonate, which was subsequently trea-
ted with Pd(OAc)2/dppb/ammonium formate to give the
deoxygenated product 18.14 Subsequent Birch reduction of
the alkyne moiety occurred, with concomitant carbonate
cleavage, to afford 19.
The synthesis and cyclization of carbonate 14 is illu-
strated in Scheme 5. DessꢀMartin oxidation of the pri-
mary alcohol 19 and subsequent NozakiꢀHiyamaꢀKishi
coupling12 with alkyne 16 gave a propargyl alcohol, which
was transformed into thiocarbonate 23. This material was
then immediately subjected to a Sharpless asymmetric
dihydroxylation, followed by sequential selective mono-
silylation and deoxygenation reactions because the thio-
carbonates of this series are relatively labile. We then
Scheme 5. Synthesis and Pd-Catalyzed Cyclization of 14a
Scheme 3. Synthesis of Alkene 19 (Precursor of 15)a
a dppb = 1,4-bis(diphenylphosphino)butane.
We then proceeded toward the synthesis of alkyne 16
(Scheme 4). Using the method reported by Myers,15 17
(13) Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem.;
Eur. J. 2003, 9, 3397–3414.
(14) (a) Mandai, T.; Matsumoto, T.; Tsujiguchi, Y.; Matsuoka, S.;
Tsuji, J. J. Organomet. Chem. 1994, 473, 343–352. (b) Sawada, D.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521–10532. (c)
Ohmiya, H.; Yang, M.; Yamauchi, Y.; Ohtsuka, Y.; Sawamura, M. Org.
Lett. 2010, 12, 1796–1799.
a DMP = Dess-Martin periodinane; (DHQ)2PHAL = hydroquinine
1,4-phthalazinediyl diether.
(16) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291–6292.
(17) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew.
(15) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000, 39,
2732–2735.
Chem., Int. Ed. Engl. 1984, 23, 727–729.
Org. Lett., Vol. XX, No. XX, XXXX
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investigated the cyclization of 14 using Pd(0). Treatment of
14with Pd2(dba)3 CHCl3 and dppfin MeOHat50 °C only
3
Scheme 6. Construction of THF Ring and Bromoallene Moietya
afforded the solvolysis product. However, the reaction in
DMF produced the desired oxocine derivative 13, albeit in
14% yield. The best result was obtained using 30 mol % of
Pd2(dba)3 and 80 mol % of dppf in the presence of 3 equiv
of H2O in DMF (58% yield) (for details, see Supporting
Information).
The investigation proceeded toward the construction of
the tetrahydrofuran ring (Scheme 6). Unfortunately, initial
attempts to introduce the required hydroxy group into
acetonide 13 via a hydroborationꢀoxidation sequence
proved unsuccessful. In contrast, application of hydrobor-
ationꢀoxidation to the deprotected enol ether 24 proceeded
smoothly with high levels of regio- and stereoselectivity to
give triol 25 as a single diastereomer. Reinstallation of the
acetonide group, followed by sequential mesylation and
methanolysis of the cyclic carbonate, promoted the facile
formation of the tetrahydrofuran ring to give 12 bearing the
requisite bicyclic core structure. Xanthate formation was
followed by CAN-mediated deprotection18 and Bartonꢀ
McCombie deoxygenation19 to give the primary alcohol 27.
The construction of the bromoallene moiety was accom-
plished using the well-established strategy developed by
Overman and Kim.20 DessꢀMartin oxidation of 27 gave
the corresponding aldehyde, which was treated with ethyny-
ltitanium triisopropoxide and then desilylated to give
the propargyl alcohol 28 as the sole stereoisomer.20,21 The
trysilate 29 was converted to bromoallene 30 via the estab-
lished anti SN20 substitution using the bromocuprate
reagent.22 The optical rotation value of the bromoallene
a Tris = 2,4,6-triisopropylbenzenesulfonyl.
30 ([R]25 = þ68.4) supports the (S)-axial chirality.
D
Exposure of 30 to the dppe-mediated bromination
conditions23 followed by cleavage of the acetonide with
AcOH led to detection of the bromination product, which
corresponded well with natural laurendecumallene B (2)
In conclusion, we demonstrated that Pd-catalyzed
medium-ring formation is useful for construction of the
core structure of Laurencia oxacycles. Further studies to
achieve the total synthesis of laurendecumallene B, includ-
ing optimization of bromination conditions and the appro-
priate protecting group for the vicinal diol moiety, are now
underway.
1
by H NMR and optical rotation values (see Supporting
Information). However, further investigations are necessary
to achieve the total synthesis elucidating the C-13
stereochemistry.
Acknowledgment. ThisworkwassupportedbyaGrant-
in-Aid for the Encouragement of Young Scientists (A)
(H.O.) and Platform for Drug Design, Discovery, and
Development from the MEXT, Japan. Y.Y. and S.I. are
grateful for Research Fellowships from the Japan Society
for the Promotion of Science (JSPS) for Young Scientists.
(18) For removal of a PMP group under buffered conditions, see:
Floreancig, P. E.; Swalley, S. E.; Trauger, J. W.; Dervan, P. B. J. Am.
Chem. Soc. 2000, 122, 6342–6350.
(19) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574–1585.
(20) (a) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org.
Chem. 1993, 58, 2468–2477. (b) Jeong, W.; Kim, M. J.; Kim, H.; Kim, S.;
Kim, D.; Shin, K. J. Angew. Chem., Int. Ed. 2010, 49, 752–756.
(21) For determination of the relative configuration at the pro-
pargylic position, see Supporting Information.
Supporting Information Available. Our attemptstoward
total synthesis, detailed results of the Pd-catalyzed cycliza-
tion, experimental procedures, and characterization data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
ꢀ
(22) (a) Montury, M.; Gore, J. Synth. Commun. 1980, 10, 873–879.
(b) Elsevier, C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos,
H. J. T.; Vermeer, P.; Runge, W. J. Org. Chem. 1982, 47, 2194–2196.
(23) (a) Fujiwara, K.; Kobayashi, M.; Awakura, D.; Murai, A.
Synlett 2000, 1187–1189. See also: (b) Bratz, M.; Bullock, W. H.;
Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995, 117, 5958–
5966. (c) Fujiwara, K.; Tsunashima, M.; Awakura, D.; Murai, A.
Tetrahedron Lett. 1995, 36, 8263–8266.
The authors declare no competing financial interest.
D
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