The shortest (four-step) total synthesis of the eight-membered cyclic ether (rac)- and (-)-cis-lauthisan

Article abstract of DOI:10.1002/ejoc.201301042

Access to the eight-membered cyclic ether (rac)- and (-)-cis-lauthisan was achieved in two complementary ways in only four steps for the longest linear sequence by starting from commercially available materials. The sequence features a cis-stereoselective reductive cyclization as the key step. Copyright

Full text of DOI:10.1002/ejoc.201301042

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301042
The Shortest (Four-Step) Total Synthesis of the Eight-Membered Cyclic Ether
(rac)- and (–)-cis-Lauthisan
Gloria Hernández-Torres,[a] Julio Mateo,[a] Antonio Urbano,*[a] and M. Carmen Carreño*[a]
Keywords: Natural products / Total synthesis / Cyclization / Stereoselectivity / Cyclic ethers
Access to the eight-membered cyclic ether (rac)- and (–)-cis-
lauthisan was achieved in two complementary ways in only
four steps for the longest linear sequence by starting from
commercially available materials. The sequence features a
cis-stereoselective reductive cyclization as the key step.
them require multistep syntheses or take place with moder-
ate cis selectivities.
Introduction
Medium-ring ethers are present in a number of biolo-
gically active marine natural products, particularly from
Laurencia red algae.[1] Some compounds of this class con-
tain an eight-membered oxocane or oxocene ring, usually
with cis stereochemistry in the alkyl substituents at C-2 and
C-8. Among them, (+)-laurencin (1; Figure 1), isolated
from the extracts of Laurencia glandulifera,[2] is the most
representative example and has been the subject of signifi-
cant synthetic effort over the past years.[3] Regardless, the
formation of medium-sized rings remains a challenge be-
cause of their relative thermodynamic instability and the
unfavorable entropic factors contributing to difficult ring
formation.[4] Consequently, there continues to be a huge
interest in developing efficient and general processes that
allow access to such naturally occurring systems.
In recent years, we have described the syntheses of dif-
ferently sized cyclic ethers based on the Et3SiH/TMSOTf-
promoted (Tf = trifluoromethanesulfonyl) reductive cycliza-
tion of the corresponding hydroxy ketone.[7] The synthesis
of (–)-cis-2 we had previously reported[8] was accomplished
in seven steps and 20.5% overall yield by starting from
commercially available diethyl pimelate (3) and enantiopure
(–)-(S)-menthyl p-toluenesulfinate (4; Scheme 1). Key β-hy-
droxy sulfoxide intermediate (S)-5 in this synthesis was later
transformed into enantiopure hydroxy ketone (S)-6, the re-
ductive cyclization of which led to a 40% yield of (–)-2 in
a stereoselective manner.
Figure 1. Structures of eight-membered cyclic ethers (+)-laurencin
(1) and (+)-cis-lauthisan (2).
(+)-cis-Lauthisan (2; Figure 1) is the fully saturated core
of natural derivative 1 and has been often used as a target
to check the validity of a particular synthetic methodology
for efficient oxocane construction. Although several strate-
gies have been employed for the stereoselective preparation
of racemic[5] and enantioenriched[6] cis-lauthisan, most of
Scheme 1. Previous seven-step total synthesis of (–)-cis-lauthisan
(2) from diethyl pimelate (3) and (–)-menthyl p-toluenesulfinate (4).
To improve the yield of the cyclization step, we reasoned
to introduce a (Z)-substituted double bond in acyclic satu-
rated hydroxy ketone 6 to restrict its conformational mo-
bility, which would thus entropically favor the intramolecu-
lar process. We initially focused on (rac)-cis-2, as depicted
in the retrosynthesis (Scheme 2), via unsaturated hydroxy
ketone 8, with the hexyl and ethyl substituents exchanged
with respect to intermediate 6, as a complementary way to
access the cis-disubstituted eight-membered cyclic ether
framework.
[a] Departamento de Química Orgánica (Módulo 01),
Universidad Autónoma de Madrid,
Cantoblanco, 28049 Madrid, Spain
E-mail: antonio.urbano@uam.es
carmen.carrenno@uam.es
Homepage: http://www.uam.es/gruposinv/quinonso/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301042.
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G. Hernández-Torres, J. Mateo, A. Urbano, M. C. Carreño
SHORT COMMUNICATION
Scheme 2. Retrosynthesis towards (Ϯ)-cis-lauthisan (2) from vinyl
ketone (10) and (Ϯ)-1,2-epoxyoctane (13) through unsaturated in-
termediate 8.
Thus, (rac)-cis-2 could be synthesized from cyclic alkene
7 having a double bond at C4–C5 by proceeding from the
reductive cyclization of unsaturated hydroxy ketone 8,
which in turn could arise, in a controlled reduction, from
alkyne 9 (Scheme 2). This intermediate would be formed
from commercially available ethyl vinyl ketone (10) and
homopropargylic alcohol 11, which could proceed from the
opening of commercially available racemic 1,2-epoxyoctane
(13) with lithium acetylide 12.
Scheme 3. Four-step total synthesis of (Ϯ)-cis-lauthisan (2) from
ethyl vinyl ketone (10) and (Ϯ)-1,2-epoxyoctane (13) through satu-
rated intermediate (Ϯ)-16.
Results and Discussion
The synthesis of key unsaturated hydroxy ketone 8 began
with ring opening[9] of oxirane (Ϯ)-13 with the lithium acet- previous one[8] (seven steps, 20.5% yield), the overall yield is
ylide–ethylenediamine (EDA) complex (12) to provide car- not competitive owing to the low efficiency of the reductive
binol (Ϯ)-11 in 92% yield (Scheme 3). Conjugate addition cyclization step of (Z)-unsaturated hydroxy ketone (Ϯ)-8,
of homopropargylic alcohol 11 to ethyl vinyl ketone (10) which afforded the cyclized skeleton in only 25% yield.
was accomplished by using Rh(acac)(CO)2 (acac = acetyl-
Given that the presence of the double bond in (Ϯ)-8 did
acetonate) as the catalyst and tri(o-methoxyphenyl)phos- not improve this yield, we decided to focus again on the
phane as the ligand[10] (THF, 90 °C, 4 h) to give alkyne (Ϯ)- reductive cyclization of saturated acyclic precursor (Ϯ)-16
9 containing the entire carbon skeleton of (Ϯ)-cis-lauthisan (Scheme 3). Thus, hydroxy ketone (Ϯ)-16 was easily avail-
in 75% yield. Partial controlled hydrogenation of the triple able (88% isolated yield) by full hydrogenation of the triple
bond of 9 with Lindlar catalyst (DMF, r.t., 48 h) provided bond in alkyne (Ϯ)-9 (Scheme 3). Upon treatment with Et3-
desired hydroxy (Z)-alkenyl ketone (Ϯ)-8 in 80% yield. Re- SiH and TMSOTf, (Ϯ)-9 evolved into a mixture of (Ϯ)-cis-
ductive cyclization of (Ϯ)-(Z)-8 was performed with Et3SiH 2 and diastereomeric diols (Ϯ)-15, which were isolated in
(3 equiv.) and TMSOTf (1.5 equiv.) in CH2Cl2 at 0 °C. Un- 39 and 20% yield, respectively. The stereochemical course
der these conditions, a mixture of four compounds was of the reductive cyclization of (Ϯ)-16 was identical to that
formed. Separation by flash chromatography allowed cy- previously observed for isomeric derivative (S)-6
clized alkene isomers (Ϯ)-7a,b with the double bond at the (Scheme 1).[8] Thus, (Ϯ)-cis-2 was prepared in four steps in
C-4 or C-5 position to be isolated in 15 and 10% yield, 24% yield overall, which is the shortest total synthesis de-
respectively, in addition to open-chain diastereoisomeric di- scribed to date.
ols (Ϯ)-14, resulting from the direct reduction of the C=O
group of (Ϯ)-8, in 23% yield.
In agreement with the mechanism proposed for these re-
actions,[11,12] the formation of isomeric cyclic unsaturated
We confirmed the cyclic structures of (Ϯ)-7a and (Ϯ)-7b ethers (Ϯ)-7a,b could be explained as shown in Scheme 4.
and the acyclic structure of (Ϯ)-14 by hydrogenation of Initially, the Lewis acid (TMSOTf) must activate the carb-
each mixture in the presence of Pd(OH)2 (Scheme 3). Under onyl group of hydroxy ketone (Ϯ)-8 to give a species such
these conditions, isomers (Ϯ)-7a,b converged to (Ϯ)-cis-2 as A. Intramolecular nucleophilic attack of OH to the acti-
(90% yield), whereas compounds (Ϯ)-14 led to the corre- vated carbonyl group gives rise to unisolated mixed ketal
sponding open-chain saturated diastereoisomeric diols (Ϯ)- 17 (pathway a), precursor of cyclic oxocarbenium ion B, the
15 in 88% yield. The relative cis stereochemistry between formation of which is favored by the triflic acid present in
the substituents at C-2 and C-8 in cyclic unsaturated ethers the reaction medium. The stereoselective reaction of Et3SiH
(Ϯ)-7a,b was determined by NOESY experiments on hydro- with oxocarbenium ion B explains the formation of cyclic
genation product (Ϯ)-(2). Thus, the total synthesis of (Ϯ)- ether (Ϯ)-7a. A 1,3-hydride rearrangement of intermediate
cis-2 could be completed in five steps in 11% yield overall. B, which situates the deficiency at the carbon atom (i.e.,
Although this synthesis of cis-lauthisan is shorter than our BЈ), would lead to allylic carbenium ion C. Two resonance
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The Shortest Total Synthesis of (rac)- and (–)-cis-Lauthisan
forms, C and CЈ, can be written to stabilize the charge in hydroxy ketone (S)-6 in 99% yield. Reductive cyclization of
the allylic carbenium ion. Attack of Et3SiH to both C and (S)-6 under conditions similar to those shown in Scheme 3
CЈ justifies the observed formation of regioisomeric cyclic [Et3SiH (4 equiv.), TMSOTf (1.5 equiv.), CH2Cl2, 0 °C] af-
ethers (Ϯ)-7a,b with the rearranged double bond. Taking forded a mixture of (–)-cis-2 and diastereoisomeric diols 15,
into account the stereochemistry of hydrogenated product from which the former could be isolated in 45% yield. Thus,
(Ϯ)-2, which results from the mixture of unsaturated cyclic the shortest total synthesis of (–)-cis-2 reported to date was
ethers (Ϯ)-7a,b, the hydride rearrangement must be syn-fa- accomplished in 4+1 steps in 29% yield overall starting
cial from the pseudoaxial position. Direct attack of Et3SiH from commercially available precursors.
to the activated CO group of intermediate A (pathway b)
would explain the formation of open-chain diols (Ϯ)-14.
Scheme 5. (4+1)-Step total synthesis of (–)-cis-lauthisan (2) from
commercially available epoxide (S)-18 and allylic alcohol 20.
Conclusions
We have described two complementary ways to achieve
the shortest total syntheses of (rac)-cis-lauthisan (2) in 4
steps and 24% yield overall from commercially available
ethyl vinyl ketone and racemic 1,2-epoxyoctane and (–)-2 in
4+1 steps and 29% yield overall from commercially avail-
able 1-nonen-3-ol and enantiopure (S)-1,2-epoxybutane.
The heterocyclic system was formed from the stereoselective
Lewis acid catalyzed reductive cyclization of saturated iso-
Scheme 4. Mechanism of the TMSOTf/Et3SiH-promoted reaction
of (Ϯ)-8 and (Ϯ)-16 leading to cyclic regioisomers (Ϯ)-7 and (Ϯ)-
cis-lauthisan (2), respectively.
meric hydroxy ketone (rac)-16 and (S)-6, respectively. The
exchange of the position of the ethyl and hexyl substituents
in these open-chain precursors did not affect the stereose-
Considering these results and with the aim to shorten lectivity of the reductive cyclization step. We observed that
our previously reported synthesis of (–)-cis-2 on the basis this process is not applicable to unsaturated hydroxy
of the reductive cyclization of hydroxy ketone (S)-6 ketones such as 8, as the formation of intermediate carb-
(Scheme 1), we decided to synthesize this precursor, in a enium ions triggers undesired rearrangements, which de-
shorter way, from the chiral pool by following a retrosyn- crease the efficiency of the process.
thetic approach similar to that shown in Scheme 2 for rac-
Supporting Information (see footnote on the first page of this arti-
2 and by using commercially available enantiopure (S)-1,2-
epoxybutane (18) as the starting material. Thus, as shown
in Scheme 5, ring opening of oxirane (S)-18 with lithium
acetylide–EDA gave homopropargylic alcohol (S)-19 in
70% yield. 1-Nonen-3-one (21), needed to complete the car-
bon skeleton present in (–)-2, was obtained in 90% yield
after oxidation of commercially available 1-nonen-3-ol (20)
with Jones reagent, as described in the literature.[13] Rh-cat-
alyzed conjugate addition of terminal alkyne (S)-19 to en-
one 21 afforded enantiopure (S)-22 in 94% yield, after chro-
matographic purification. Full hydrogenation of the triple
bond in (S)-22 in the presence of Pd(OH)2 gave required
cle): Experimental procedures and copies of the NMR spectra.
Acknowledgments
The authors thank the Ministerio de Ciencia e Innovación (MIC-
INN) (grant number CTQ2011-24783), the Comunidad de Madrid,
and the European Social Fund (grant number SOLGEMAC-
S2009/ENE-1617) for financial support.
[1] J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro,
M. R. Prinsep, Nat. Prod. Rep. 2013, 30, 237, and earlier re-
views in the same series.
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[2] T. Irie, M. Suzuki, T. Masamune, Tetrahedron Lett. 1965, 6,
1091.
dron Lett. 2004, 45, 8019; e) Y. G. Suh, B. A. Koo, E. N. Kim,
N. S. Choi, Tetrahedron Lett. 1995, 36, 2089; f) H. Kim, Ch.
Ziani-Cherif, J. Oh, J. K. Cha, J. Org. Chem. 1995, 60, 792; g)
L. A. Paquette, T. J. Sweeney, Tetrahedron 1990, 46, 4487; h)
K. Tsushima, A. Murai, Chem. Lett. 1990, 761; i) L. A. Pa-
quette, T. J. Sweeney, J. Org. Chem. 1990, 55, 1703; j) H. Kot-
suki, Y. Ushio, I. Kadota, M. Ochi, J. Org. Chem. 1989, 54,
5153; k) R. W. Carling, A. B. Holmes, J. Chem. Soc., Chem.
Commun. 1986, 565.
a) M. C. Carreño, G. Hernández-Torres, A. Urbano, F. Colob-
ert, Chem. Eur. J. 2011, 17, 1283; b) F. Colobert, S. Choppin,
L. Ferreiro-Mederos, M. Obringer, S. Luengo Arratta, A. Ur-
bano, M. C. Carreño, Org. Lett. 2007, 9, 4451; c) M. C. Car-
reño, G. Hernández-Torres, A. Urbano, F. Colobert, Org. Lett.
2005, 7, 5517; d) M. C. Carreño, R. Des Mazery, A. Urbano,
F. Colobert, G. Solladié, Org. Lett. 2004, 6, 297; e) M. C. Car-
reño, R. Des Mazery, A. Urbano, F. Colobert, G. Solladié, J.
Org. Chem. 2003, 68, 7779; f) F. Colobert, R. Des Mazery, G.
Solladié, M. C. Carreño, Org. Lett. 2002, 4, 1723.
[3] a) N. Ortega, V. S. Martín, T. Martín, J. Org. Chem. 2010, 75,
6660; b) V. A. Adsool, S. V. Pansare, Org. Biomol. Chem. 2008,
6, 2011; c) K. Fujiwara, S. Yoshimoto, A. Takizawa, S. Souma,
H. Mishima, A. Murai, H. Kawai, T. Suzuki, Tetrahedron Lett.
2005, 46, 6819; d) S. Baek, H. Jo, H. Kim, H. Kim, S. Kim,
D. Kim, Org. Lett. 2005, 7, 75; e) I. Kadota, H. Uyehara, Y.
Yamamoto, Tetrahedron 2004, 60, 7361; f) M. T. Crimmins,
K. A. Emmitee, Org. Lett. 1999, 1, 2029; g) M. T. Crimmins,
A. L. Choy, J. Am. Chem. Soc. 1999, 121, 5653; h) M. T.
Mújica, M. M. Afonso, A. Galindo, J. A. Palenzuela, J. Org.
Chem. 1998, 63, 9728; i) J. W. Burton, J. S. Clark, S. Derrer,
T. C. Stork, J. G. Bendall, A. B. Holmes, J. Am. Chem. Soc.
1997, 119, 7483; j) J. Kreuger, R. W. Hoffman, J. Am. Chem.
Soc. 1997, 119, 7499; k) M. T. Mújica, M. M. Afonso, A. Gal-
indo, J. A. Palenzuela, Synlett 1996, 983; l) M. Bratz, W. H.
Bullock, L. E. Overman, T. Takemoto, J. Am. Chem. Soc. 1995,
117, 5958; m) K. Tsushima, A. Murai, Tetrahedron Lett. 1992,
33, 4345; n) T. Masamune, H. Murase, H. Matsue, A. Murai,
Bull. Chem. Soc. Jpn. 1979, 52, 135.
[7]
[8]
M. C. Carreño, F. Colobert, R. des Mazery, G. Solladié, A.
Urbano, Org. Lett. 2005, 7, 2039.
[4] G. Illuminati, L. Mandolini, Acc. Chem. Res. 1981, 14, 95.
[5] a) N. Miyakoshi, Y. Ohgaki, K. Masui, C. Mukai, Heterocycles
2007, 74, 185; b) M. J. Coster, J. J. De Voss, Org. Lett. 2002, 4,
3047; c) J. H. Udding, J. P. M. Giesselink, H. Hiemstra, W. N.
Speckamp, J. Org. Chem. 1994, 59, 6671; d) R. W. Carling, J. S.
Clark, A. B. Holmes, J. Chem. Soc. Perkin Trans. 1 1992, 83;
e) K. C. Nicolaou, D. G. McGarry, P. K. Somers, B. H. Kim,
W. W. Ogilvie, C. V. C. Prasad, C. A. Veale, R. R. Hark, J. Am.
Chem. Soc. 1990, 112, 6263; f) K. C. Nicolaou, D. G. McGarry,
P. K. Somers, C. A. Veale, G. T. Furst, J. Am. Chem. Soc. 1987,
109, 2504.
[9]
B. D. Schwartz, P. Y. Hayes, W. Kitching, J. J. De Voss, J. Org.
Chem. 2005, 70, 3054.
a) R. V. Lerum, J. D. Chisholm, Tetrahedron Lett. 2004, 45,
6591; b) S. Serron, J. Huang, S. P. Nolan, Organometallics 1998,
17, 534.
[10]
[11] C. H. Larsen, B. H. Ridgway, J. T. Shaw, D. M. Smith, K. A.
Woerpel, J. Am. Chem. Soc. 2005, 127, 10879, and references
cited therein.
[12] D. M. Smith, K. A. Woerpel, Org. Biomol. Chem. 2006, 4,
1195.
[13] L. A. Batory, C. E. McInnis, J. T. Njardarson, J. Am. Chem.
Soc. 2006, 128, 16054.
[6] a) D. Tripathi, S. K. Pandey, P. Kumar, Tetrahedron 2009, 65,
2226; b) N. Ortega, T. Martín, V. S. Martín, Eur. J. Org. Chem.
2009, 554; c) N. Ortega, T. Martín, V. S. Martín, Org. Lett.
2006, 8, 871; d) H. J. Rhee, H. Y. Beom, H. D. Kim, Tetrahe-
Received: July 12, 2013
Published Online: August 22, 2013
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