Total synthesis of (+)-laurallene

Article abstract of DOI:10.1016/S0040-4039(03)00432-5

The stereoselective total synthesis of (+)-laurallene is described. The required key oxocene skeleton possessing trans-orientated alkyl substituents at the α,α′-positions was stereoselectively constructed via the cyclization of the corresponding hydroxy e

Full text of DOI:10.1016/S0040-4039(03)00432-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3175–3178
Total synthesis of (+)-laurallene
Toshikazu Saitoh,a Toshio Suzuki,b,* Masashi Sugimoto,a Hisahiro Hagiwaraa and Takashi Hoshib
aGraduate School of Science and Technology, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bFaculty of Engineering, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Received 31 January 2003; revised 13 February 2003; accepted 17 February 2003
Abstract—The stereoselective total synthesis of (+)-laurallene is described. The required key oxocene skeleton possessing
trans-orientated alkyl substituents at the a,a%-positions was stereoselectively constructed via the cyclization of the corresponding
hydroxy epoxide promoted by Eu(fod)3. © 2003 Elsevier Science Ltd. All rights reserved.
Red algae of the genus Laurencia, particularly Lauren-
cia nipponica, produce a wide variety of medium-sized
cyclic ethers as distinctive members of marine natural
products.1 Among them, eight-membered cyclic ethers
are abundant constituents, and are divided into two
subclasses, the lauthisan type and the laurenan type, in
view of the structural features arising from the bio-
genetic pathway.2 Much synthetic effort has been
directed towards the lauthisan structural class exem-
plified by (+)-laurencin.3,5a In contrast, there have been
few reports4,5 on synthetic studies of the laurenan com-
pounds, such as (+)-prelaureatin (1),6 (+)-laurallene
(2),7 (+)-(Z)-laureatin (3),8 and (+)-(Z)-isolaureatin (4)
(Fig. 1).8 This might be due to certain problems
incurred in assembling eight-membered cyclic ether sys-
tems and, moreover, the stereoselective introduction of
alkyl substituents into the a- and a%-positions of a cyclic
ether with trans-orientation.
oxocenes by cyclization of hydroxy cis-epoxides pro-
moted by Eu(fod)3.9 The method has a potential
advantage in that stereochemistry at the a- and a%-posi-
tions could be controlled stereospecifically since the
reaction proceeds via an SN2 process and exo mode
selectivity regardless of the configuration of the
hydroxyl and epoxide groups. In this communication,
we examined applicability of the methodology to the
synthesis of (+)-laurallene (2) as a part of our research
program. Recently, the first total synthesis of (+)-2 has
been reported by the Crimmins group.4b
Our synthetic plan is envisaged in Scheme 1. Hydroxy
epoxide 8, which could be obtained by coupling of
epoxide 9 with acetylene 10, was postulated as a key
precursor. Application of the foregoing protocol to 8
would result in the formation of a,a%-trans-oxocene 7
possessing the additional chiral centers at the C7 and
C13positions required for further manipulations. Dioxa-
bicyclic skeleton 5 would be accessible from epoxide 6,
derived from 7 including the Sharpless epoxidation
Recently, we reported an efficient method towards the
stereoselective construction of a,a%-cis- and a,a%-trans-
Figure 1.
Keywords: (+)-laurallene; oxocenes; medium-ring heterocycles; cyclization; hydroxy epoxides.
* Corresponding author. Tel./fax: +81-25-262-6780; e-mail: suzuki@eng.niigata-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00432-5

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T. Saitoh et al. / Tetrahedron Letters 44 (2003) 3175–3178
Scheme 1.
step.10 Stereoselective introduction of a bromoallene
moiety and a bromine functionality into 5 would com-
plete our synthesis.
obtained effectively by quenching after consumption of
nearly half of 14 and recycling the recovered 14. The
resulting hydroxy group was protected as a benzyl ether
to afford acetylene 10 in 97% yield.
According to the retro-synthetic scheme, the synthesis
of the acetylene 10 was investigated at the outset of this
Coupling of epoxide 9, derived from (−)-DET by our
reported procedure,12 with acetylene 10 was easily
achieved by the Yamaguchi method13 in 80% yield
(Scheme 3). Mesylation of the resulting hydroxy group
followed by cleavage of the TES ether gave the corre-
sponding alcohol, which was treated with a base to
afford epoxide 17 in high yield. Deprotection of the
MTM group of 17 (100%) followed by hydrogenation
in the presence of Lindlar catalyst provided hydroxy
epoxide 8 (98%). With the key precursor 8 for the
cyclization reaction in hand, the crucial step in this
synthesis was examined. The hydroxy epoxide 8 was
treated with Eu(fod)3 in refluxing toluene. The reaction
proceeded smoothly to afford the desired a,a%-trans-
oxeocene 7 in 70% yield as the sole cyclized product.
Next, we examined homologation of the side chain. The
exocene 7 was converted into diol 18 by a protection–
deprotection sequence. Selective tosylation of the pri-
research (Scheme 2). Diol 11, prepared from
D
-(+)-
ribonic g-lactone according to the Chen procedure,11
was successively protected with TBS (70%) and MTM
groups (81%), and subsequently treated with LiBH4 to
afford diol 12 (87%). Selective protection of the pri-
mary hydroxyl group as a TBDPS ether followed by
mesylation of the remaining secondary hydroxy group
provided compound 13 in 90% overall yield. Selective
cleavage of the TBS ether was conducted by exposure
to 1N HCl–MeOH–THF (78%). For this purpose,
TBAF or TBAF–AcOH conditions were not available
because of competitive deprotection of the TBDPS
group. The resulting hydroxy mesylate was treated with
K2CO3 in MeOH–CH2Cl2 to give epoxide 14 in 86%
yield. Next, the epoxide 14 was reacted with lithium
acetylide in DMSO. In the reaction, partial migration
of the TBDPS group of 14 and 15 into the acetylene
terminus of 15 was observed. Acetylene 15 was
Scheme 2. Reagents and conditions: (a) TBSCl, AgNO3, Py, CH3CN, 70%; (b) Ac2O, AcOH, DMSO, 70°C, 81%; (c) LiBH4, Et2O,
87%; (d) TBDPSCl, imidazole, DMF; (e) MsCl, Py, DMAP, CH2Cl2, 90% (two steps); (f) 1N HCl–MeOH–THF (1:10:4), 78%;
(g) K2CO3, MeOH–CH2Cl2 (1:1), 86%; (h) HCꢀCLi·EDA, DMSO–THF (6:1), 51% (recovered 14, 39%); (i) BnBr, NaH, Bu4NI,
THF, 97%.

T. Saitoh et al. / Tetrahedron Letters 44 (2003) 3175–3178
3177
Scheme 3. Reagents and conditions: (a) n-BuLi, BF3·OEt2, THF, −78°C, 80%; (b) MsCl, TEA, DMAP, CH2Cl2, 98%; (c) 80% aq.
AcOH–THF (5:2), 98%; (d) K2CO3, MeOH–CH2Cl2 (1:1), 99%; (e) MeI, NaHCO3, acetone–H2O (9:1), 40°C, 100%; (f) H2,
Lindlar cat., quinoline, AcOEt, 98%; (g) Eu(fod)3, toluene, 110°C, 70% (recovered 8, 21%); (h) Ac2O, TEA, DMAP, CH2Cl2, 99%;
(i) DDQ, CH2Cl2–phosphate buffer (pH 7.5) (9:1); (j) K2CO3, MeOH–CH2Cl2 (1:1), 77% (two steps); (k) (Bu3Sn)2O, toluene,
reflux, then TsCl, CH2Cl2, 97%; (l) K2CO3, MeOH–CH2Cl2 (1:1), 100%; (m) Me2CuLi, Et2O, −78°C, 100%; (n) TBSOTf,
2,6-lutidine, CH2Cl2, 0°C, 96%.
Scheme 4. Reagents and conditions: (a) NaH, propargyl alcohol, HMPA–THF (1:1), 0°C, 88%; (b) Dess–Martin periodinane,
CH2Cl2, 88%; (c) (EtO)2P(O)CH2CO2Et, NaH, THF, 0°C, 95%; (d) DIBAL, toluene, −78 to −30°C, 97%; (e) t-BuO2H, (+)-DET,
,
Ti(Oi-Pr)4, 4 A MS, CH2Cl2, −20°C, 62%, 91% de; (f) BzCl, TEA, DMAP, CH2Cl2, 97%; (g) DDQ, CH2ClCH2Cl, phosphate
buffer (pH 6.7) (9:1), 35°C, 61%; (h) TESOTf, 2,6-lutidine, CH2Cl2, −78 to 0°C, 97%; (i) DIBAL, toluene, −78°C, 88%; (j)
Dess–Martin periodinane, NaHCO3, CH2Cl2, 85%; (k) CBr4, HMPT, THF, 94%; (l) TBAF, THF, 0°C, 88%; (m) n-BuLi, THF,
−78 to −30°C, 97%; (n) 2,4,6-[(CH3)2CH]3C6H2SO2Cl, DMAP, CH2ClCH2Cl, 60°C, 93%; (o) LiCuBr2, THF, 80°C, 67%; (p) CSA,
MeOH, 50°C, 88%, (q) CBr4, (Oct)3P, 1-methyl-1-cyclohexene, toluene, 70°C, 87%.

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T. Saitoh et al. / Tetrahedron Letters 44 (2003) 3175–3178
mary hydroxy group of 18 via stannylene acetal14 fol-
lowed by treatment with K2CO3 in MeOH–CH2Cl2 led
to epoxide in high yield with retention of configuration.
Regioselective addition of Me2CuLi (100%), and subse-
quent protection of the resulting hydroxy group as a
TBS ether provided 19 (96%).
York, 1978; Vol. 1, pp. 43–121; (b) Erickson, K. L. In
Marine Natural Products; Scheuer, P. J., Ed.; Academic
Press: New York, 1983; Vol. 5, pp. 131–257; (c)
Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1–49. See also
his previous reviews in Nat. Prod. Rep.
2. Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.;
Fukuzawa, A.; Murai, A. Tetrahedron 1997, 53, 8371–
8382.
With 19 in hand, the stage was set for the construction
of the dioxabicyclic skeleton of (+)-2. Selective deprotec-
tion of the TBDPS group of 19 co-existing with the TBS
ether was carried out by the Shekhani method15 with the
following modifications: addition of propargyl alcohol
(10 equiv.) and use of THF–HMPA (1:1) as a solvent
system (Scheme 4). Under the conditions, high discrim-
ination between the TBDPS and TBS groups was
attained. Dess–Martin oxidation of the resulting alcohol
followed by Horner–Emmons reaction gave the
corresponding a,b-unsaturated ester, which was treated
with DIBAL to afford trans-allyl alcohol 20 in high
yield. Diastereoselective epoxidation of 20 by the Sharp-
less protocol10 provided the desired a-epoxide 6 (62%,
91% de). Protection of 6 with a benzoyl group (97%)
followed by cleavage of the benzyl ether with DDQ
resulted in the spontaneous formation of a tetra-
hydrofuran ring to provide dioxabicyclic skeleton 21
(61%). Next, we examined installation of the bromoal-
lene moiety. Conversion of 22, derived from 21 via a
protection–deprotection sequence, into 5 having a
propargyl alcohol moiety was achieved through the
following sequence involving the Corey method:16 (i)
oxidation of the primary hydroxy group with Dess–Mar-
tin periodinane; (ii) treatment with CBr4 and HMPT in
THF; (iii) deprotection of the TES group; (iv) treatment
with n-BuLi in THF. All steps proceeded in excellent
yields. According to the reported method,17 5 was
trisylated and subsequently treated with LiCuBr2 to
provide the desired 23 (67%), its bromoallene
diastereomer (5%), and the corresponding SN2 product
(12%). Bromoallene 23 separated by HPLC was desilyl-
ated under the acidic conditions. Finally, the resulting
hydroxy group was brominated with inversion of
configuration by the procedure of Murai3e with addition
of 1-methyl-1-cyclohexene18 to furnish (+)-2 in 87%
yield. The synthetic material was identical in all respects
(1H, 13C NMR, [h]D) to those reported for natural (+)-2.7
3. (a) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc.
1999, 121, 5653–5660; (b) Kru¨ger, J.; Hoffmann, R. W.
J. Am. Chem. Soc. 1997, 119, 7499–7504; (c) Burton, J.
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moto, T. J. Am. Chem. Soc. 1995, 117, 5958–5966; (e)
Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33,
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5. For the selective synthesis of a,a%-trans-eight-membered
cyclic ethers, see: (a) Mujica, M. T.; Afonso, M. M.;
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9728–9738; (b) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi,
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2797–2800.
8. Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron 1970, 26,
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In conclusion, the total synthesis of (+)-laurallene (2)
was accomplished with high stereoselectivity. This syn-
thetic study demonstrated that the cyclization of
hydroxy epoxides promoted by Eu(fod)3 is an efficient
approach to the stereoselective synthesis of highly func-
tionalized oxocenes. Further applications of this
methodology on the synthesis of related medium-sized
cyclic ethers are in progress in our laboratory.
References
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1. For reviews, see: (a) Moore, R. E. In Marine Natural
Products; Scheuer, P. J., Ed.; Academic Press: New