β-Hydroxy-γ-lactones as nucleophiles in the Nicholas reaction for the synthesis of oxepene rings. Enantioselective formal synthesis of (-)-isolaurepinnacin and (+)-rogioloxepane A

Article abstract of DOI:10.1039/c4cc00389f

The enantioselective formal synthesis of (-)-isolaurepinnacin and (+)-rogioloxepane A has been achieved. The key steps are an intermolecular Nicholas reaction with a β-hydroxy-γ-lactone as the nucleophile, to form branched linear ethers, and an olefin ring-closing metathesis to obtain the oxepene core. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00389f

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b-Hydroxy-c-lactones as nucleophiles in the
Nicholas reaction for the synthesis of oxepene
rings. Enantioselective formal synthesis of
(ꢀ)-isolaurepinnacin and (+)-rogioloxepane A†
Cite this: Chem. Commun., 2014,
50, 3685
Received 16th January 2014,
Accepted 11th February 2014
Julio Rodrıguez-Lopez,a Nuria Ortega,a Victor S. Martın*a and Tomas Martın*ab
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DOI: 10.1039/c4cc00389f
www.rsc.org/chemcomm
The enantioselective formal synthesis of (ꢀ)-isolaurepinnacin and
(+)-rogioloxepane A has been achieved. The key steps are an
intermolecular Nicholas reaction with a b-hydroxy-c-lactone as
the nucleophile, to form branched linear ethers, and an olefin
ring-closing metathesis to obtain the oxepene core.
Fig. 1 Representative examples of lauroxepanes.
Medium-ring oxacycles are a common structural feature present in
many ladder ether marine toxins, which have important implica-
tions with regard to their biological impact. Furthermore, medium- a,a0-cis-disubstitution oxepene ring and a conjugate trans-enyne unit,
ring ethers are the structural skeletons of an important group of while rogioloxepane A (2) has an a,a0-trans-disubstitution pattern and
marine natural products, called lauroxanes. Lauroxanes are a series a conjugate cis-enyne unit, both compounds having four stereogenic
of nonterpenoid C15-metabolites derived from fatty acid metabo- centers (Fig. 1). To date there is only one enantioselective synthesis
lism (acetogenins) that have been isolated from the Laurencia and one stereoselective synthesis reported for each one of these
species of red algae, and those marine organisms which feed on natural products.5 As part of our continuing program directed at
them. These compounds display a wide range of biological activity the synthesis of biologically active substances of marine origin6 and
including antitumor, antimicrobial, antifeedant, immunosuppressant, the development of new synthetic methodologies for the construction
and pesticide activity.1 Their fascinating structures and bio- of medium-ring ethers,7 we embarked on the enantioselective formal
logical activities have stimulated the imagination and have been a synthesis of (ꢀ)-isolaurepinnacin (ent-1) and (+)-rogioloxepane A (2).
challenge for synthetic chemists.2 Seven-membered cyclic ethers Recently, we developed a new strategy for the synthesis of medium-
are less common in lauroxanes and therefore synthetic approaches ring oxacycles based on an intermolecular Nicholas reaction8
to them have been limited. The most representative examples of (interNR) to form unsaturated branched linear ethers and a ring
lauroxanes containing the oxepene ring are (+)-isolaurepinnacin (1) closing olefin metathesis (RCM) to obtain the cobalt complex cyclic
and (+)-rogioloxepane A (2) (Fig. 1).
ethers. Using this approach we were able to obtain saturated cyclic
Isolaurepinnacin (1) was isolated from Laurencia pinnata Yamada ethers of seven, eight and nine members such as (+)-cis- and (ꢀ)-trans-
collected at Motsuta point, Hokkaido (Japan) in 1981 by Fukuzawa lauthisan and (+)-cis- and (+)-trans-obtusan, whose structures represent
and Masamune.3 Rogioloxepane A (2) was isolated from Laurencia the basic skeletons present in a number of these naturally occurring
microcladia Yamada off the torrent II Rogiolo in the Mediterranean non-terpenoid seven-, eight-, and nine-membered ring ethers.9 Addi-
in 1992 by Pietra’s group.4 Isolaurepinnacin (1) contains an tionally, the methodology was exemplified by the formal synthesis of
(+)-laurencin, a lauroxane with an eight-membered cyclic ether.9c
Our initial synthetic approach is envisaged in Scheme 1. The key
a
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Instituto Universitario de Bio-Organica ‘‘Antonio Gonzalez’’, CIBICAN,
features of the route included: first, the synthesis of the branched
linear ethers by an interNR using the acetylenic cobalt complex 9 as
the electrophile and the enantioenriched monoprotected diol 8 as the
nucleophile. It should be mentioned that bromide 9 is a very
convenient synthetic equivalent of enyne 7 during the interNR
coupling to avoid elimination of the alcohol.9c Afterwards, we planned
that the unsaturated branched ethers 6 would be obtained through a
simple reaction sequence: decomplexation and elimination of
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Departamento de Quımica Organica, Universidad de La Laguna (ULL),
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Avda. Francisco Sanchez 2, 38206 La Laguna, Tenerife, Spain.
E-mail: vmartin@ull.es
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Instituto de Productos Naturales y Agrobiologıa, Consejo Superior de
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Investigaciones Cientıficas (CSIC), Avda. Francisco Sanchez 3,
38206 La Laguna, Tenerife, Spain. E-mail: tmartin@ipna.csic.es
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and copies of 1H and 13C NMR spectra of all compounds. See DOI:
10.1039/c4cc00389f
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Scheme 2 Reagents and conditions: (a) Oxone, K2CO3, CH3CN/buffer
pH = 10.5 (1 : 1), 11, 0 1C; (b) 3% H2SO4 (aq), 81% after 2 steps; (c) BF3ꢁOEt2,
CH2Cl2, 0 1C, dr 1.0 : 1.0, 70%; (d) CAN, acetone, 0 1C, 97%; (e) (1) o-NO2PhSeCN,
NaBH4, EtOH, rt, (2) 30% H2O2, 0 1C, quantitative; (f) DIBAL-H (1 equiv.),
THF, ꢀ78 1C; (g) CH3PPh3+Brꢀ, n-BuLi, THF, ꢀ78 1C - ꢀ20 1C, 3 h, 89%
after 2 steps; (h) Co2(CO)8, CH2Cl2, rt; (i) 2nd generation Grubbs’ catalyst,
CH2Cl2, 40 1C, 84% after 2 steps; (j) BF3ꢁOEt2, CH2Cl2, 0 1C, 94%; (k) CAN,
acetone, 0 1C, 95%.
Scheme 1 Retrosynthetic analysis.
the bromide. Second, the RCM would provide the oxepenes 5,
which can be used as precursor for the synthesis of the com-
pounds 3 and 4. Oxepene 3 is the enantiomer of an advanced the terminal alkenes in one of the branches.13 The syntheses of the
intermediate in the formal synthesis of (+)-isolaurepinnacin (1) dienes syn-6 (PQH) and anti-6 (PQH) were accomplished by two
reported by Suzuki and coworkers.5b Furthermore, oxepene 4 is an consecutive steps: reduction with one equivalent of DIBAL-H and
advanced intermediate in the total synthesis of (+)-rogioloxepane one-carbon homologation by the Wittig-olefination of the lactol
A (2) developed by Crimmins and coworkers.5d
After several fruitless attempts to achieve the interNR using reaction the TMS group was removed from the terminal alkyne.
monoprotected diol 8, we pondered the use of b-hydroxy-g-lactone Before the cyclization step by RCM, the complexation of the
obtained. Interestingly, when water was used to quench the Wittig
10 as its synthetic equivalent.10 Our thoughts were based on the alkyne groups were carried out with Co2(CO)8, affording the cobalt-
hypothesis that 10 introduces the correct stereochemistry in two complexes. This complexation generated a series of advantages:
stereocenters and would be a less sterically hindered and more first, the cobalt complex should avoid the undesirable participation
conformationally constrained nucleophile. The synthesis began of the triple bond in the metathesis process,14 and second, the
with the commercially available methyl trans-3-hexenoate, which Co2(CO)6-alkyne can be used as a stereochemical control agent for
was subjected to a Shi asymmetric epoxidation.11 Then, the an isomerization process. With the diene complexes in hand,
obtained epoxide was treated with acid aqueous solution to afford closure of the oxepenes with the second-generation Grubbs’ catalyst
the g-lactone 10 in good yield, albeit with an enantiomeric ratio (er) was performed. Thus, exposure of diene cobalt-complexes to
of 87 : 13 (Scheme 2).12 From the synthetic standpoint, the relatively 30 mol% of the catalyst in dichloromethane (0.004 M) at reflux,
low er of the compound 10 does not represent a major problem for cleanly produced the desired and easily separable cycle-complexes
the enantiomeric purity of the final products, because another cis-13 and trans-13 in excellent yields. Cleavage of the hexacarbonyl
asymmetric epoxidation has been planned at a later stage of the dicobalt from complexes cis-13 and trans-13 provided the oxepenes
synthetic route (vide infra). The next step was the interNR between cis-5 (PQH) and trans-5 (PQH), which were used to establish the
the g-lactone 10 and the cobalt complex 99c to afford in good yields stereochemistry of both isomers by NOE studies.15 At this stage of
the doubly branched ethers syn-12 and anti-12, as an equimolecular the synthesis, we also pondered the possibility of performing an
epimeric mixture in the newly created stereocenter. These hexa- isomerization of the trans-isomer to the cis-isomer considering that
carbonyl dicobalt complexes were easily separated by column such a stereoisomer is thermodynamically more stable. It was
chromatography on silica gel. At this point of the synthesis, we successfully performed under acidic conditions using boron
were unable to determine which one was the syn complex, and trifluoride diethyl etherate as the acid.16
which one was the anti. Therefore, the stereochemistry determina-
The next step was the protection of the secondary alcohol with
tion was postponed to more advanced intermediates. Decomplexa- the same protective groups present in the target molecules 3 and 4,
tion of the Co2(CO)6-complexes of syn-12 and anti-12 and further i.e. t-butyldimethylsilyl (TBS) and benzyl (Bn), obtaining the
bromide elimination using a variant of the Grieco reaction provided oxepenes 14 and 15, respectively (Scheme 3). Once we had
3686 | Chem. Commun., 2014, 50, 3685--3688
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Using this strategy we performed, in few steps, the
enantioselective formal synthesis of (ꢀ)-isolaurepinnacin and
(+)-rogioloxepane A, two of the most representative lauroxanes
with a seven-membered cyclic ether.
We thank the Spanish MINECO, cofinanced by the European
Regional Development Fund (ERDF) (CTQ2011-28417-C02-01 and
CTQ2011-22653) and the IMBRAIN project (FP7-REGPOT-2012-
CT2012-31637-IMBRAIN), funded under the 7th Framework
Programme (CAPACITIES) for financial support.
Notes and references
1 (a) D. J. Faulkner, Nat. Prod. Rep., 2002, 19, 1–48, and preceding
issues; (b) J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. Munro and
M. R. Prinsep, Nat. Prod. Rep., 2013, 30, 237–323 and previous issues
in the series; (c) B.-G. Wang, J. B. Gloer, N.-Y. Ji and J.-C. Zhao,
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2 For reviews, see: (a) A. Deiters and S. F. Martin, Chem. Rev., 2004,
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(c) T. Martın, J. I. Padron and V. S. Martın, Synlett, 2014, 12–32;
(d) D. Kim, Synlett, 2014, 33–57; For selected synthesis, see: (e) M. T.
Crimmins and E. A. Tabet, J. Am. Chem. Soc., 2000, 122, 5473–5476;
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Scheme 3 Reagents and conditions: (a) TBSOTf, imidazole, CH2Cl2, rt,
92%; (b) NaH, BnBr, TBAI (cat), THF, 87%; (c) n-BuLi, THF, 15 min, then
(CH2O)n, ꢀ40 1C to rt, 2 h, 93% for 14, 94% for 15; (d) LiAlH4, THF, rt, 92%
for 14, 95% for 15; (e) (+)-DET, Ti(OPr-i)4, t-BuOOH, 4 Å MS, CH2Cl2,
ꢀ20 1C, 84%; (f) RedAl, THF, rt, 90% for 16, 93% for 17; (g) (ꢀ)-DET, Ti(OPr-i)4,
t-BuOOH, 4 Å MS, CH2Cl2, ꢀ20 1C, 84%; (h) TsCl, Et3N, CH2Cl2, DMAP (cat),
rt, quantitative; (i) NaI, NaCN, CH3CN, 80 1C, 80%; (j) TBSOTf, imidazole, Et3N,
rt; (k) TFA, THF:H2O, 0 1C, 86% after 2 steps.
3 A. Fukuzawa and T. Masamune, Tetrahedron Lett., 1981, 22, 4081–4084.
4 G. Guella, I. Mancini, G. Chiasera and F. Pietra, Helv. Chim. Acta,
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5 For the enantioselective total synthesis of Isolaurepinnacin (1) see:
(a) D. Berger, L. E. Overman and P. A. Renhowe, J. Am. Chem. Soc.,
1997, 119, 2446–2452. For the stereoselective formal synthesis of
Isolaurepinnacin (1) see: (b) T. Suzuki, R. Matsamura, K. Oku,
K. Taguchi, H. Hagiwara, T. Hoshi and M. Ando, Tetrahedron Lett.,
2001, 42, 65–67. For the stereoselective total synthesis of rogioloxepane A
(2) see: (c) R. Matsamura, T. Suzuki, H. Hagiwara, T. Hoshi and M. Ando,
Tetrahedron Lett., 2001, 42, 1543–1546. For the enantioselective total
synthesis of rogioloxepane A (2) see: (d) M. T. Crimmins and A. C.
DeBaillie, Org. Lett., 2003, 5, 3009–3011.
successfully built the left part of the advanced intermediates 3
and 4, we focused our attention on the conversion of the
terminal alkynes into the right side chains. The best approach
found was the transformation of the terminal alkynes to the
allylic alcohols 16 and 17 by coupling of the lithium salts of
the alkynes with paraformaldehyde followed by reduction of the
propargylic alcohols with LiAlH4. In order to introduce the
secondary alcohol adjacent to the oxepene rings, Katsuki–
Sharpless asymmetric epoxidations17 were performed with the
allylic alcohols 16 and 17 using as chiral auxiliary (+)-diethyl
tartrate18 and (ꢀ)-diethyl tartrate,18 respectively. Regioselective
opening of the 2,3-epoxy-alcohols with Red-Al provided the two
1,3-diols 18 and 19 in excellent yields. The completion of the
enantioselective formal synthesis of (ꢀ)-isolaurepinnacin (ent-1)
from diol 18 dealt with the transformation of the primary alcohol
into a cyano group. To achieve this goal, a one-carbon homo-
logation of the primary alcohol was performed by a simple two-
step sequence: selective tosylation and NaCN nucleophilic
substitution. Finally, to achieve the enantioselective formal
synthesis of (+)-rogioloxepane A (2) the diol 19 was protected,
as the bis-silyl ethers, followed by selective deprotection of the
silyl ether of the primary alcohol with trifluoroacetic acid.
The iterative use of the Co2(CO)6 acetylenic complex provides
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6 (a) T. Martın, M. A. Soler, J. M. Betancort and V. S. Martın, J. Org.
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Chem., 1997, 62, 1570–1571; (b) T. Martın and V. S. Martın, Tetrahedron
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9 (a) N. Ortega, T. Martın and V. S. Martın, Org. Lett., 2006, 8, 871–873;
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10 This compound has been previously synthesized via an enzymatic
kinetic resolution of racemic trans-methyl 3,4-epoxyhexanoate
(96% ee, 31% yield): S. Y. F. Mak, N. R. Curtis, A. N. Payne, M. S.
Congreve, A. J. Wildsmith, C. L. Francis, J. E. Davies, S. I. Pascu,
J. W. Burton and A. B. Holmes, Chem.–Eur. J., 2008, 14, 2867–2885.
11 O. A. Wong and Y. Shi, Chem. Rev., 2008, 108, 3958–3987.
a powerful synthetic methodology to address the synthesis of 12 The enantiomeric excess was determinate by Mosher’s ester analysis.
See ESI†.
seven-membered cyclic ethers. The strategy is based on two key
steps: intermolecular Nicholas reaction using a b-hydroxy-
13 S. D. Burke and E. A. Voight, Org. Lett., 2001, 3, 237–240.
14 S. T. Diver and A. J. Giessert, Chem. Rev., 2004, 104, 1317–1382.
g-lactone as the nucleophile and a ring closing metathesis. 15 See ESI†.
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16 Milder acids such as montmorillonite K-10 were fruitless. F. R. P. 18 The asymmetric epoxidation of the allylic alcohol provided two
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Crisostomo, R. Carrillo, T. Martın and V. S. Martın, Tetrahedron
Lett., 2005, 46, 2829–2832.
diastereoisomers, which were easily separated by column chromato-
graphy on silica gel. The major diastereomer (84% yield) has the
correct configuration of all the stereocenters, and the other
(E12% yield) displays the correct configuration on the 2,3-epoxide,
but the other three stereogenic centers are inverted, this is because
the g-lactone 10 is not optically pure. See ESI†.
17 (a) T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102,
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5974–5976; (b) T. Katsuki and V. S. Martın, in Organic Reactions,
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pp. 1–299.
3688 | Chem. Commun., 2014, 50, 3685--3688
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