Biomimetic asymmetric total synthesis of (-)-laurefucin via an organoselenium-mediated intramolecular hydroxyetherification

Article abstract of DOI:10.1021/ja806304s

The first asymmetric total synthesis of (-)-laurefucin (1), a unique C-15 acetogenin with a 2,8-dioxabicyclo[5.2.1]decane skeleton, has been accomplished in nine steps in 31% overall yield from known oxocene 10. Highlights of the highly stereoselective synthesis include a novel organoselenium-mediated biomimetic hydroxyetherification.

Full text of DOI:10.1021/ja806304s

Published on Web 11/17/2008
Biomimetic Asymmetric Total Synthesis of (-)-Laurefucin via
an Organoselenium-Mediated Intramolecular
Hydroxyetherification
Byungsook Kim,† Miseon Lee,† Mi Jung Kim,† Hyunjoo Lee,† Sanghee Kim,†
Deukjoon Kim,*,† Minseob Koh,‡ Seung Bum Park,‡ and Kye Jung Shin§
The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National
UniVersity, Seoul 151-742, Korea, Department of Chemistry, Seoul National UniVersity, Seoul
151-747, Korea, and Life Sciences Research DiVision, Center for Chemoinformatics Research,
Korea Institute of Science and Technology,
Seoul 130-650, Korea
Received August 9, 2008; E-mail: deukjoon@snu.ac.kr
Abstract: The first asymmetric total synthesis of (-)-laurefucin (1), a unique C-15 acetogenin with a 2,8-
dioxabicyclo[5.2.1]decane skeleton, has been accomplished in nine steps in 31% overall yield from known
oxocene 10. Highlights of the highly stereoselective synthesis include a novel organoselenium-mediated
biomimetic hydroxyetherification.
Scheme 1. Proposed Biogenetic Pathway of (-)-Laurefucin (1)
Introduction
(-)-Laurefucin (1), the first C-15 acetogenin with a unique
2,8-dioxabicyclo[5.2.1]decane skeleton, was isolated by Irie and
co-workers in 1972 from the red alga Laurencia nipponica.1
Since then, a considerable number of congeners have been
isolated from various marine sources.2 The structure and
absolute configuration of the R,R′-cis disubstituted medium ring
marine natural product 1 were firmly established by X-ray
crystallography.3 Laurefucin (1) is reported to possess an
interesting inhibitory activity for drug metabolism.4
On the basis of enzymatic and chemical considerations, it
was proposed that (-)-laurefucin (1) might be biogenetically
derived from deacetyllaurencin (2) through the intermediacy of
bromoether 3, which is designated as prelaurefucin.2b,5 Dis-
placement of the C-10 bromide functionality in 3 by transannular
participation of the ring oxygen and subsequent nucleophilic
attack by H2O at the C-10 position in the resultant oxonium
ion 4 with retention of configuration would lead to laurefucin
as depicted in Scheme 1. It has been demonstrated that
deacetyllaurencin (2) is transformed to laurefucin (1) by action
of lactoperoxidase5a or bromoperoxidase.5b In addition, the
possible involvement of prelaurefucin (3) in the biosynthetic
pathway was supported by a facile conversion of hexahydro-
prelaurefucin, synthesized from natural laurefucin by a catalytic
hydrogenation-bromination sequence, to hexahydrolaurefucin
in aqueous solvents.5a
We have been involved in development of an efficient
synthetic method for generation of the pivotal dioxatricyclic
oxonium core in 4 in view of its possible involvement in the
biosynthesis of other natural products such as notoryne (5)2b,5a
and ocellenyne (6)6 as well as laurefucin. As shown in Scheme
2, nucleophilic attack at C-7 in dioxatricyclic oxonium ion 4
by chloride would lead to notoryne, an adjacent bis-tetrahydro-
furanoid marine natural product. Likewise, attack of bromide
† The Research Institute of Pharmaceutical Sciences, College of Pharmacy.
‡ Department of Chemistry, Seoul National University.
§ Center for Chemoinformatics Research, Korea Institute of Science and
Technology.
(1) Fukuzawa, A.; Kurosawa, E.; Irie, T. Tetrahedron Lett. 1972, 13, 3.
(2) (a) Wratten, S. J.; Faulkner, D. J. J. Org. Chem. 1977, 42, 3343. (b)
Kikuchi, H.; Suzuki, T.; Kurosawa, E.; Suzuki, M. Bull. Chem. Soc.
Jpn. 1991, 64, 1763. (c) Ko¨nig, G. M.; Wright, A. D. J. Nat. Prod.
1994, 57, 477.
ion at C-13 would produce ocellenyne with
a 2,5-
dioxabicyclo[2.2.1]heptane skeleton. Described herein is a
highly stereoselective, substrate-controlled asymmetric total
synthesis of (-)-laurefucin (1), featuring a novel highly efficient
(3) Furusaki, A.; Kurosawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron Lett.
1973, 14, 4579.
(4) Kaul, P. N.; Kulkarni, S. K.; Kurosawa, E. J. Pharm. Pharmacol. 1978,
30, 589.
(5) (a) Fukuzawa, A.; Aye, M.; Nakamura, N.; Tamura, M.; Murai, A.
Tetrahedron Lett. 1990, 31, 4895. (b) Fukuzawa, A.; Aye, M.;
Takasugi, Y.; Nakamura, M.; Tamura, M.; Murai, A. Chem. Lett. 1994,
2307.
(6) (a) Schulte, G. R.; Chung, M. C. H.; Scheuer, P. J. J. Org. Chem.
1981, 46, 3870. (b) The stereochemistry of the 12,13-dibromo moiety
and of the side chains of the bicyclic system was not firmly established.
9
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Kim et al.
Scheme 2. Proposed Biogenetic Role of Oxonium Ion 4
Scheme 4. Preparation of Key Etherification Substrate 9a
a Reagents and conditions: (a) DDQ, ClCH2CH2Cl/pH 7.4 buffer (9:1),
50 °C, 5 h, 96%; (b) CBr4, Oct3P, pyridine, toluene, 70 °C, 2 h, 78%; (c)
BnO(CH2)3MgBr, THF, room temperature (rt), 1 h, 70%; (d) L-Selectride,
THF, -78 °C, 1 h, 96%.
Scheme 3. Retrosynthetic Plan for (-)-Laurefucin (1)
dioxabicyclo[5.2.1]decane skeleton, which would be problematic
(vide infra).9 Further retrosynthetic analysis suggested that key
etherification substrate 9 should be accessible in an efficient
manner from known oxocene amide 10, which was prepared
via our previously reported intramolecular amide enolate
alkylation (IAEA) of chloro amide 11.10
Our synthesis commenced with the preparation of key
cyclization substrate 9 from oxocene 10 (Scheme 4). Thus,
oxidative cleavage of the benzyl group in oxocene 10 by the
Yonemitsu method11 and subsequent bromination of the result-
ing alcohol 12 by exposure to CBr4 and Oct3P12 with inversion
of configuration furnished bromo oxocene 13 in 75% overall
yield for the two steps. Application of our direct ketone synthesis
protocol13 to R-alkoxy amide 13 with 3-benzyloxypropylmag-
nesium bromide, followed by Felkin–Ahn L-Selectride reduc-
tion12a,14 of the resultant ketone 14, provided the requisite
secondary alcohol 9 as a single isomer (67%, two steps). The
key NOE interactions observed for 9 as well as literature
organoselenium-mediated hydroxyetherification that mimics the
proposed biogenetic pathway.
Results and Discussion
(9) For examples of electrophilic transannular cyclization to form oxonium
ion intermediates by a ring oxygen atom in ∆4-oxocenes with halogen
electrophiles, see: (a) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi,
Y.; Fukuzawa, A.; Murai, A. Tetrahedron 1997, 53, 8371. (b)
Sugimoto, M.; Suzuki, T.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett.
2007, 48, 1109. With selenium electrophiles, see: (c) Clark, J. S.;
Wong, Y.-S. Chem. Commun. 2000, 1079. With Lewis acids, see: (d)
Paquette, L. A.; Scott, M. K. J. Am. Chem. Soc. 1972, 94, 6751, and
references therein. (e) Blumenkopf, T. A.; Bratz, M.; Castan˜eda, A.;
Look, G. C.; Overman, L. E.; Rodriguez, D.; Thompson, A. S. J. Am.
Chem. Soc. 1990, 112, 4386. (f) While our manuscript was undergoing
review, Mascal and coworkers reported synthesis of an oxatriquinane
oxonium ion: Mascal, M.; Hafezi, N.; Meher, N. K.; Fettinger, J. C.
J. Am. Chem. Soc. 2008, 130, 13532.
As shown in Scheme 3, we envisioned that (-)-laurefucin
(1) could be secured from alkene 7 by incorporation of the (E)-
enyne moiety via an olefin cross-metathesis (CM)/Colvin alkyne
synthesis strategy.7 Terminal alkene 7 could in turn be readily
elaborated from protected primary alcohol derivative 8 using
Grieco’s method.8 Furthermore, we were intrigued by the
possibility of implementing a biomimetic hydroxyetherification
of γ,δ-unsaturated alcohol 9 for the synthesis of key intermediate
8 by a sequential intramolecular etherification-transannular
cyclization process. However, we were concerned about po-
tential transannular participation by the oxocene ring oxygen
in 9 prior to the crucial internal etherification to form the 2,8-
(10) Baek, S.; Jo, H.; Kim, H.; Kim, H.; Kim, S.; Kim, D. Org. Lett. 2005,
7, 75.
(11) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23,
885.
(7) (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973,
151. (b) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem.
Commun. 1992, 721. (c) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett
1994, 107.
(12) (a) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345. (b)
Suzuki, T.; Matsumura, R.; Oku, K.; Taguchi, K.; Hagiwara, H.; Hoshi,
T.; Ando, M. Tetrahedron Lett. 2001, 42, 65.
(13) Kim, H.; Choi, W. J.; Jung, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.
2003, 125, 10238.
(8) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.
(14) Clark, J. S.; Holmes, A. B. Tetrahedron Lett. 1988, 29, 4333.
9
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Asymmetric Total Synthesis of (-)-Laurefucin
A R T I C L E S
Scheme 5. Attempts to Synthesize Key Dioxabicyclic Intermediate 8
sterically hindered ꢀ-face of the molecule in its preferred anti-
conformation 9a, which precluded the desired intramolecular
epoxide-opening route to 8.18 The observed NOE interactions
for 15, as depicted in the scheme, were consistent with a
ꢀ-epoxide.
Likewise, oxidative mercuriocyclization of γ,δ-unsaturated
alcohol 9 furnished the undesired C(10)-ꢀ-alcohol 8′ as the
major product in 63% isolated yield in a 10:1 ꢀ/R ratio.19,20 It
is worthwhile mentioning at this point that only R-mercuronium
ion 16, produced from 9 in its syn-conformation 9b, can undergo
intramolecular etherification. The stereochemical nature of the
desired minor isomer 8 was established by the NOESY studies
illustrated in the scheme and further corroborated by crystal-
lographic analysis of the final product (vide infra). It is
interesting to note that, as suggested by careful analysis of the
NOESY spectra, the undesired major ꢀ-alcohol 8′ adopts
conformation 8′b to alleviate the unfavorable nonbonding steric
interactions between the C-6 benzyloxypropyl group and the
C-10 ꢀ-hydroxyl function that are present in 8′a. In this
connection, our calculation predicted that 8′b was more stable
than 8′a by 8.26 kcal/mol.17 In addition, oxidation of the two
alcohols 8 and 8′ gave the same ketone, confirming that they
are epimeric at C-10.
Particularly disappointing was that treatment of γ,δ-unsatur-
ated alcohol 9 with NBS in an attempt to synthesize the pivotal
bromoether 19 produced a roughly 1:2 mixture of tetrahydro-
furans 21 and 22 in 81% total yield (Scheme 6). It is of note
that both the hydroxyl group and ring oxygen atom are properly
situated to interact with R-bromonium ion 18. Unlike the
proposed biogenetic events, bromonium ion 18 undergoes
transannular cyclization9 via attack by the ring oxygen atom
prior to the desired bromoetherification by the hydroxyl func-
tion to generate the unwanted oxonium ion 20. Cationic
rearrangement9b of 20 or intramolecular attack at the C-7
position by the benzyloxy oxygen then would yield tetrahydro-
furanyl ketone 21 or tetrahydropyranyl tetrahydrofuran 22,
respectively. Although our attempt to obtain a crystalline
derivative of 22 for an X-ray study was unsuccessful, the NOE
interactions observed for the tetrahydrofuran moiety of 22 and
the large vicinal coupling constant (J ) 10.4 Hz) between
hydrogens Ha and Hb in the corresponding p-bromobenzoate
22′, indicative of a trans-diaxial relationship, are consistent with
the proposed structure.
analogy15,16 suggested that R,R′-cis-oxocene 9 assumes the anti-
conformation 9a. This was further supported by computational
analysis with structural optimizations of the two conformers (in
truncated form), which predicted anti-conformer 9a to be more
stable than syn-conformer 9b by 2.6 kcal/mol.17
With the key cyclization substrate 9 in hand, we proceeded
to address construction of the 2,8-dioxabicyclo[5.2.1]decane
skeleton of (-)-laurefucin (1). Examination of several conven-
tional protocols for achieving the hydroxyetherification proved
to be problematic as illustrated in Scheme 5. For instance,
exposure of hydroxy oxocene 9 to m-CPBA led to exclusive
formation of ꢀ-epoxide 15 by electrophilic attack from the less
(18) One of the reviewers pointed out that ꢀ-epoxide 15 might also arise
from syn-conformation 9b via a Henbest-like hydrogen-bonding
interaction. Although this possibility cannot be ruled out completely,
our rationalization of the stereochemical outcome of the epoxidation
is strongly supported by the observations that the TBS ether of 9
produced the corresponding ꢀ-epoxide under comparable conditions.
In addition, osmylation of a similar R,R′-cis-oxocene produced a ꢀ-cis-
diol (see ref 15b).
(19) (a) Broka, C. A.; Lin, Y.-T. J. Org. Chem. 1988, 53, 5876. (b)
Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.;
Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. J. Am. Chem.
Soc. 2001, 123, 9021. (c) Kang, S.; Lee, S. Chem. Commun. 1998, 7,
761. (d) Kang, S.; Lee, J.; Lee, S. Tetrahedron Lett. 1998, 39, 59.
(20) (a) The oxidative mercuriocyclization proved to be somewhat capri-
cious in our hands due to simple reductive demercuration and reversion
to the starting material of the organomercurial intermediate. (b) Our
preliminary attempts to convert C(10)-ꢀ-alcohol 8′ to the desired
R-alcohol 8 in a stereoselective fashion by either an oxidation-
reduction sequence or a Mitsunobu inversion were unsatisfactory.
However, extensive efforts were not made for this purpose simply
because the far more efficient organoselenium-based protocol was
developed.
(15) (a) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.;
Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483. (b) Kim, H.; Lee,
H.; Lee, D.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2007, 129, 2269.
(16) For the crystal structures of R,R′-cis-oxocene natural products, see:
(a) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M.
J. Chem. Soc., Chem. Commun. 1965, 638. (b) Cameron, A. F.;
Cheung, K. K.; Ferguson, G.; Robertson, J. M. J. Chem. Soc. (B) 1969,
559. (c) Gonzalez, A. G.; Martin, J. D.; Martin, V. S.; Norte, M.;
Perez, R.; Ruano, J. Z. Tetrahedron 1982, 38, 1009. (d) Cardellina II,
J. H.; Horseley, S. B.; Clardy, J.; Leftow, S. R.; Meinwald, J. Can.
J. Chem. 1982, 60, 2675. (e) Norte, M.; Gonzalez, A. G.; Cataldo, F.;
Rodriguez, M. L.; Brito, I. Tetrahedron 1991, 45, 9411.
(17) See the Supporting Information for the optimized molecular geometries
of 9a, 9b, 15, 8, 8′a, and 8′b. The energy-minimized conformations
(Materials Studio 4.2, Systematic grid scan) were further optimized
by the density functional theory method (PBE-GGA) at the DND level
(Materials Studio 4.2, DMol3). Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
Note that, in this approach, the benzyloxypropyl and ethyl substituents
were replaced by methyl groups to expedite the PBE-GGA/DND
optimizations.
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Kim et al.
Scheme 6. Attempted Biomimetic Bromoetherification of 9
Scheme 8. Completion of the Synthesisa
a Reagents and conditions: (a) H2, 10% Pd/C, EtOH, rt, 30 min, 100%;
(b) o-nitrophenylselenocyanide, Oct3P, THF, rt, 30 min, then 30% H2O2, 0
°C to rt, 21 h, 72%; (c) crotonaldehyde, (H2IMes)(Cy3P)Cl2RudCHPh,
CH2Cl2, 40 °C, 1.5 h, then DMSO, rt, 12 h; (d) TMSCH2N2, LDA, THF,
-78 to 0 °C, 2 h, 85% (two steps).
Scheme 7. Organoselenium-Mediated Biomimetic
Hydroxyetherificationa
participation2b,5a,9 by the ring oxygen in the resultant adduct
25, would generate the pivotal putative biogenetic intermediate
26 as depicted in the scheme. It is worth noting that adduct 25
is expected to have a conformation similar to that of 8, and
would be favorably disposed for transannular cyclization through
intramolecular attack by the oxocane oxygen atom. Ensuing
nucleophilic attack by the water at C-10 in oxonium ion 26
would then lead to hydroxyether 8 with an overall double
inversion. Several observations support this rationalization: (1)
premature interruption of the reaction produced phenylseleno-
ether 24 along with the desired hydroxyetherification product
8; (2) resubjection of 24 to the reaction conditions produced
hydroxyether 8; (3) selenoether 24 did not undergo the tran-
sannular cyclization in the absence of N-PSP.
Significantly, while R-bromonium ion 18 apparently proceeds
with transannular participation by the ring oxygen atom prior
to cyclic ether formation (Scheme 6), the corresponding
intermediates R-mercuronium ion 16 (Scheme 5) and R-sele-
nonium ion 23 (Scheme 7) appear to undergo preferential
nucleophilic attack by the side-chain hydroxyl group to produce
organomercury species 17 and selenoether 24, respectively. It
is reasonable to assume that this divergence in reaction pathways
(attack by the ring oxygen atom vs the hydroxyl) might be due
to conformational differences between reactive intermediates
18 vs 16 and 23. In addition, we note that these reactions take
a Reagents and conditions: (a) N-PSP (3 equiv), PTSA (0.2 equiv),
CH3CN/H2O (9:1), 0.005 M, rt, 2.5 h, 100%.
After extensive experimentation, we were delighted to find
that, upon exposure to an excess amount of N-phenylselenoph-
thalimide (N-PSP)21 in the presence of PTSA in CH3CN/H2O
(9:1) at room temperature for 2.5 h, γ,δ-unsaturated alcohol 9
gave rise directly to the desired dioxabicyclic hydroxyether 8
in quantitative yield (Scheme 7).22 We rationalize that intramo-
lecular etherification of R-selenonium ion 23, generated from 9
in its syn-conformation 9b upon exposure to N-PSP, produces
selenoether 24.23 Subsequent activation of the phenylselenyl
group24 in selenoether 24 by N-PSP, followed by transannular
(22) (a) When PhSeBr or PhSeCl was used instead of N-PSP and PTSA
under otherwise comparable conditions, the reaction proceeded more
slowly to give the desired hydroxyether 8 in somewhat lower yields
(rt, 24 h, 85% and rt, 48 h, 86%, respectively). (b) In the absence of
water, bromoether 19 (45%) and the chloroether corresponding to 19
(76%) were obtained, respectively. The low yields observed in these
organoselenium-mediated haloetherifications might be due to the
instability of the corresponding haloethers, in particular bromoether
19, towards water during chromatography.
(23) (a) Nicolaou, K. C. Tetrahedron 1981, 37, 4097, and references therein.
(b) Brimble, M. A.; Pavia, G. S.; Stevenson, R. J. Tetrahedron Lett.
2002, 43, 1735, and references therein.
(21) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J. Am.
Chem. Soc. 1979, 101, 3704.
(24) Morella, A. M.; Ward, A. D. Tetrahedron Lett. 1984, 25, 1197.
9
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Asymmetric Total Synthesis of (-)-Laurefucin
A R T I C L E S
place in different solvents, but the precise nature of these
differences is unclear at the present time.
dioxabicyclo[5.2.1]decane skeleton, has been accomplished in
nine steps in 31% yield from known oxocene 10.26 The highly
stereoselective synthesis features a novel, highly efficient
organoselenium-mediated biomimetic-type intramolecular hy-
droxyetherification as a key step. Application of our organose-
lenium-based one-pot protocol for generating the pivotal
dioxatricyclic oxonium intermediate to the synthesis of other
natural products is under investigation in our laboratories.
After construction of the requisite dioxabicyclic skeleton, we
directed our attention to assembly of the (E)-enyne moiety to
complete the synthesis (Scheme 8). To this end, we developed
a protection-free four-step sequence based on a CM/Colvin-Ohira
homologation protocol, which complements our recently re-
ported CM-based (Z)-enyne synthesis.15b Thus, hydrogenolysis
of the benzyl protecting group in 8, followed by chemoselective
conversion of the resulting diol 27 into terminal olefin 7 by
Grieco’s method,8 set up the system for stereoselective introduc-
tion of the (E)-enyne unit. Cross-metathesis of alkene 7 with
crotonaldehyde25 using the Grubbs second-generation catalyst,
followed by exposure of the resulting trans-R,ꢀ-unsaturated
aldehyde 28 to lithio TMS-diazomethane,7 delivered (-)-
laurefucin (1) in 85% yield for the two steps. The spectral and
optical rotation data for our synthetic material were in good
agreement with those of the natural product.2c The structure of
oursyntheticlaurefucinwasfurtherverifiedbyX-raycrystallography.
Acknowledgment. This work was supported by the SRC/ERC
program of MOST/KOSEF (R11-2007-107-02001-0).
Supporting Information Available: General experimental
procedures including spectroscopic and analytical data for all
1
new compounds along with copies of the H and 13C NMR
spectra for 1, 7, 8, 8′, 9, 12-15, 21-22, 22′, 24, 27-28, X-ray
crystallographic data for 1, detailed experimental procedure of
computational study, and the outcome of conformational
optimization and energy minimization. This material is available
free of charge via the Internet at http://pubs.acs.org.
Conclusion
In summary, the first asymmetric total synthesis of (-)-
laurefucin (1), the first C-15 acetogenin containing a 2,8-
JA806304S
(25) For examples of olefin cross-metathesis with crotonaldehyde, see: (a)
Morgan, J. P.; Morrill, C.; Grubbs, R. H. Org. Lett. 2002, 4, 67. (b)
Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem.
Soc. 2002, 124, 10396.
(26) The asymmetric synthesis of (-)-laurefucin (1) has been accomplished
in a completely substrate-controlled manner in 16 steps in 11% overall
yield from the known (S)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone:
Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029.
9
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