Asymmetric total syntheses of (+)-3-(Z)-laureatin and (+)-3-(Z)- isolaureatin by "lone pair-lone pair interaction-controlled" isomerization

Article abstract of DOI:10.1021/ja068346i

The first asymmetric total syntheses of the dihalogenated medium-sized dioxabicyclic marine natural products (+)-3-(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2) have been accomplished. Notable features of the highly stereo-, regio-, and chemoselective

Full text of DOI:10.1021/ja068346i

Published on Web 02/06/2007
Asymmetric Total Syntheses of (+)-3-(Z)-Laureatin and
(+)-3-(Z)-Isolaureatin by “Lone Pair-Lone Pair
Interaction-Controlled” Isomerization
Hyoungsu Kim, Hyunjoo Lee, Dongjoo Lee,† Sanghee Kim, and Deukjoon Kim*
Contribution from the Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National UniVersity, San 56-1, Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea
Received November 21, 2006; E-mail: deukjoon@snu.ac.kr
Abstract: The first asymmetric total syntheses of the dihalogenated medium-sized dioxabicyclic marine
natural products (+)-3-(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2) have been accomplished. Notable
features of the highly stereo-, regio-, and chemoselective syntheses of these R,R′-trans-oxocene natural
products include an intramolecular amide enolate alkylation to construct the R,R′-cis-oxocene, novel “lone
pair-lone pair interaction-controlled” epimerizations to the R,R′-trans-oxocenes, various strategies for
stereoselective introduction of halogen atoms, and novel olefin cross-metatheses for construction of the
(Z)-enyne systems.
Scheme 1. Enzymatic Transformation of (+)-Prelaureatin
Introduction
(+)-3-(Z)-Isolaureatin (1) and (+)-3-(Z)-laureatin (2) were
isolated from the red alga Laurencia nipponica by Irie and co-
workers in 1968.1 These marine natural products possess unique
structural features: a rare dioxabicyclic ring system that is
composed of a medium-sized oxocene moiety and a small ring,
either an oxolane or an oxetane. Furthermore, these R,R′-trans-
oxocene natural products contain six stereogenic centers in
addition to a (Z)-enyne system in their compact C15 framework.
The constitution as well as both the relative and absolute
configurations of these marine natural products were proposed
on the basis of spectroscopic studies, chemical correlations, and
biogenetic considerations.1 The proposed structures were firmly
established by Lewis acid catalyzed isomerization2 of (+)-3-
(Z)-laureatin (2) to (+)-3-(Z)-isolaureatin (1), albeit in low yield,
and by an X-ray crystallographic study3 of (+)-3-(Z)-isolaureatin
(1). In an enzymatic transformation4 shown in Scheme 1,
bromoperoxidase-catalyzed bromoetherification of (+)-prelau-
reatin by exposure to NaBr and H2O2 produced (+)-3-(Z)-
isolaureatin (0.07%) and (+)-3-(Z)-laureatin (0.05%). However,
monocyclic tetrahydrofurans 4a (0.9%) and 4b (0.3%) and a
mixture of three bromohydrins 3 (6%) were formed as the major
products. It is noteworthy that bromo oxolane 4a was produced
through transannular participation of the ring oxygen atom as
depicted in the scheme.
These dihalogenated C15 metabolites were shown to possess
strong activity as mosquito larvicides.5 Although these medium-
sized dioxabicyclic marine natural products have received a
significant amount of attention due to their interesting molecular
structure and potential as insecticides for mosquito vectors
transmitting malaria, no total synthesis has been reported.6-9
Our preliminary studies in this area suggested that successful
execution of a synthesis of these natural products hinges upon
stereoselective incorporation of halogen atoms into their oxocene
skeletons, which is recognized to be demanding (vide infra).7j,k
With this notion in mind, described herein are the first and
highly stereo-, regio-, and chemoselective syntheses of (+)-3-
† Current address: Department of Chemistry, University of Pennsylvania.
(1) (a) Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron Lett. 1968, 2091. (b)
Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron Lett. 1968, 2735. (c) Irie,
T.; Izawa, M.; Kurosawa, E. Tetrahedron 1970, 26, 851.
(2) Fukuzawa, A.; Kurosawa, E.; Irie, T. J. Org. Chem. 1972, 37, 680.
(3) Kurosawa, E.; Furusaki, A.; Izawa, M.; Fukuzawa, A.; Irie, T. Tetrahedron
Lett. 1973, 3857.
(4) (a) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.; Fukuzawa, A.; Murai,
A. Tetrahedron 1997, 53, 8371.(b) The substrate used in the enzymatic
transformation has deuterium at the alkyne terminus.
(5) (a) Watanabe, K.; Umeda, K.; Miyakado, M. Agric. Biol. Chem. 1989, 53,
2513. (b) For a recent review of prototypical insecticidal agents, see: El
Sayed, K. D.; Dunbar, D. C.; Perry, T. L.; Wilkins, S. P.; Hamann, M. T.
J. Agric. Food Chem. 1997, 45, 2765.
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J. AM. CHEM. SOC. 2007, 129, 2269-2274
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A R T I C L E S
Kim et al.
Scheme 2. Retrosynthetic Plan for (+)-3-(Z)-Isolaureatin (1) and
(+)-3-(Z)-Laureatin (2)
(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2), featuring an
intramolecular amide enolate alkylation (IAEA) to construct the
R,R′-cis-oxocene, novel “lone pair-lone pair interaction-
controlled” epimerizations to the R,R′-trans-oxocenes, various
strategies for stereoselective introduction of halogen atoms, and
novel olefin cross-metatheses for construction of the (Z)-enyne
systems as key transformations.
Results and Discussion
Our retrosynthetic plan, which includes a multitude of
halogenation steps, is shown in Scheme 2. We envisioned that
the two R,R′-trans-oxocene natural products,8 (+)-3-(Z)-iso-
laureatin (1) and (+)-3-(Z)-laureatin (2), could be elaborated
from R,R′-cis-oxolane 5 and R,R′-cis-oxetane 6, respectively,
by a novel “lone pair-lone pair interaction-controlled” isomer-
ization (vide infra). We further envisaged that chloro diol 7 could
serve as a common intermediate for the regioselective construc-
tion of the oxolane and oxetane rings present in these natural
products by an internal Williamson ether synthesis. It should
be emphasized that our R,R′-cis-oxocene-based strategy pos-
sesses a definite advantage, in particular, for synthesis of
Williamson substrate 7 (vide infra). Exploration of a direct route
to these natural products by way of a bromoetherification was
unsuccessful in our hands, probably due to the aforementioned
transannular participation of the oxocene ring oxygen atom.4
The requisite R,R′-cis-oxocene 8 in turn could be secured by
our intramolecular amide enolate alkylation7k,l of chloro amide
9. Further analysis indicated internal alkylation substrate 9 could
be prepared from the known glycolate oxazolidinone 10 and
allylic iodide 11 based on Evans methodology.10
(6) (a) Edwards, S. D.; Lewis, T.; Taylor, R. J. K. Tetrahedron Lett. 1999, 40,
4267. (b) Taylor, C. D.; Castillo, B. F., II; Howell, A. R. Abstracts of
Papers, 232nd National Meeting of the American Chemical Society, San
Francisco, CA, Sept 10-14, 2006; American Chemical Society: Wash-
ington, DC, 2006; ORGN-711. (c) Note added in proof: during the process
of publishing this article, Suzuki and coworkers reported a total synthesis
of (+)-3-(Z)-laureatin: Sugimoto, M.; Suzuki, T.; Hagiwara, H.; Hosi, T.
Tetrahedron Lett. 2007, 48, 1109.
(7) For total syntheses of R,R′-cis-oxocene Laurencia natural products, see:
(a) Murai, A.; Murase, H.; Matsue, H.; Masamune, T. Tetrahedron Lett.
1977, 2507. (b) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988,
110, 2248. (c) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345.
(d) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem.
Soc. 1995, 117, 5958. (e) Mujica, M. T.; Afonso, M. M.; Galindo, A.;
Palenzuela, J. A. Synlett 1996, 983. (f) Burton, J. W.; Clark, J. S.; Derrer,
S.; Stork, T. C.; Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997,
119, 7483. (g) Kru¨ger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119,
7499. (h) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029. (i)
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653. (j)
Boeckman, R. K., Jr.; Zhang, J.; Reeder, M. R. Org. Lett. 2002, 4, 3891.
(k) Kim, H.; Choi, W. J.; Jung, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.
2003, 125, 10238. (l) Baek, S.; Jo, H.; Kim, H.; Kim, H.; Kim, S.; Kim,
D. Org. Lett. 2005, 7, 75. (m) Fujiwara, K.; Yoshimoto, S.; Takizawa, A.;
Souma, S.; Mishima, H.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron
Lett. 2005, 46, 6819.
(8) For total synthesis of R,R′-trans-oxocene Laurencia natural products, see:
(a) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473. (b)
Fujiwara, K.; Souma, S.; Mishima, H.; Murai, A. Synlett 2002, 1493. (c)
Saitoh, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.; Hoshi, T. Tetrahedron
Lett. 2003, 44, 3175.
(9) For recent examples of C-C bond forming approaches to oxocene
construction, see: (a) Suh, Y.-G.; Koo, B.-A.; Kim, E.-N.; Choi, N.-S.
Tetrahedron Lett. 1995, 36, 2089. (b) Alvarez, E.; Delgado, M.; Diaz,
M. T.; Hanxing, L.; Perez, R.; Mart´ın, J. D. Tetrahedron Lett. 1996, 37,
2865. (c) Linderman, R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am.
Chem. Soc. 1997, 119, 6919. (d) Coster, M. J.; De Voss, J. J. Org. Lett.
2002, 4, 3047. (e) Cossy, J.; Taillier, C.; Bellosta, V. Tetrahedron Lett.
2002, 43, 7263. (f) Kadota, I.; Uyehara, H.; Yamamoto, Y. Tetrahedron
2004, 60, 7361. (g) Rhee, H. J.; Beom, H. Y.; Kim, H.-D. Tetrahedron
Lett. 2004, 45, 8019. (h) Clark, J. S.; Freeman, R. P.; Cacho, M.; Thomas,
A. W.; Swallow, S.; Wilson, C. Tetrahedron Lett. 2004, 45, 8639. (i) Ortega,
N.; Martin, T.; Martin, V. S. Org. Lett. 2006, 8, 871.
To commence the synthesis, key R,R′-cis-oxocene 8 was
prepared in an efficient manner by a seven-step sequence
identical to that employed for our synthesis of (+)-laurencin7l
(35% overall yield from readily available glycolate oxazolidi-
none 1011 and the known allylic iodide 1112). With R,R′-cis-
oxocene 8 available in multigram quantities, we directed our
attention to synthesis of key internal Williamson substrate 7
(Scheme 3). Chlorination of R,R′-cis-oxocene alcohol 12,
prepared by chemoselective removal of the PMB group in cis-
oxocene 8 with wet DDQ,13 by treatment with carbon tetra-
chloride and tri-n-octylphosphine in the presence of 1-methyl-
cyclohexene,14 efficiently furnished the desired chloride 13 with
inversion of configuration at C(7).15 Literature analogy7f,16 and
spectroscopic analysis suggest that R,R′-cis-oxocene alcohol 12
(11) Jones, T. K.; Mills, S. G.; Reamer, R. A.; Askin, D.; Desmond, R.; Volante,
R. P.; Shinkai, I. J. Am. Chem. Soc. 1989, 111, 1157.
(12) Holton, R. A.; Zoeller, J. R. J. Am. Chem. Soc. 1985, 107, 2124.
(13) Oikawa, Y.; Yochika, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
(14) (a) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345. (b)
Matsumura, R.; Suzuki, T.; Hagiwara, H.; Hoshi, T.; Ando, M. Tetrahedron
Lett. 2001, 42, 1543.
(15) We opted for the chloride instead of the corresponding bromide since the
yield of the chlorination (>77%) was significantly better than that of the
bromination (>60%) under comparable conditions.
(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) Norte, M.; Gonzalez, A. G.; Cataldo, F.;
Rodriguez, M. L.; Brito, I. Tetrahedron 1991, 45, 9411.
(10) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737. (b) Evans, D. A.; Cage, J. R.; Leighton, J. L.; Kim, A. S.
J. Org. Chem. 1992, 57, 1961. (c) Crimmins, M. T.; Emmitte, K. A.; Katz,
J. D. Org. Lett. 2000, 2, 2165.
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Lone Pair−Lone Pair Interaction-Controlled Isomerization
A R T I C L E S
Scheme 3. Synthesis of Internal Williamson Substrate 7a
a Reagents and conditions: (a) DDQ, CH2Cl2/pH 7.0 buffer (9:1), room temperature (rt), 2 h, 99%; (b) CCl4, Oct3P, 1-methylcyclohexene, toluene, 70 °C,
12 h; (c) OsO4, NMO, acetone/H2O (1:1), 0 °C, 4 h, 77% for two steps; (d) CCl4, Oct3P, 1-methylcyclohexene, toluene, 70 °C, 6 h; (e) OsO4, NMO,
acetone/H2O (1:1), 0 °C, 21% for two steps.
Scheme 4. Synthesis of Bicyclic Skeletons 5 and 6a
assumes conformation A, where the double bond and its ring
oxygen atom has an anti-relationship with respect to the best
plane through carbons C(7), C(8), C(11), and C(12). On the
other hand, the corresponding syn-conformation A′ is preferred
in the case of R,R′-trans-oxocene alcohol 12′.17 It is appropriate
at this point to delineate our rationale for adopting R,R′-cis-
oxocene 8 as our starting material. In contrast to R,R′-cis-
oxocene alcohol 12, our extensive experience in this field
suggested that halogenation of the corresponding R,R′-trans-
isomer 12′ might be quite problematic. In fact, attempted
chlorination of trans-oxocene alcohol 12′ yielded the eliminated
diene 14 as the major product (3:1) under the comparable
conditions.18 The difficulties encountered in the chlorination of
R,R′-trans-isomer 12′ in its preferred syn-conformation A′ can
be attributed to the â-dimethylamide group at C(12) which
sterically interferes with the incoming chloride. In addition, the
trans-periplanar relationship between the C(7) R-hydroxyl
function and the C(8) â-hydrogen atom in the syn-conformation
A′ might facilitate the observed elimination. Osmylation of R,R′-
cis-chloro olefin 13 then yielded the desired R-cis-diol 7
exclusively in good overall yield for the two steps (77% from
12) by electrophic attack from the sterically less congested
R-face of the molecule in its preferred anti-conformation B. It
is interesting to note that the corresponding R,R′-trans-chloro
olefin 13′ in its syn-conformation B′ undergoes electrophilic
attack from the sterically less hindered â-face to produce â-cis-
diol 7′ in a 3:1 â/R ratio under the comparable conditions, which
further substantiates our choice of an R,R′-cis-oxocene-based
strategy.
a Reagents and conditions: (a) NaH, THF, rt, 12 h, 98%; (b) (n-
Bu)2Sn(dO), toluene, reflux, then PMBCl, TBAI, 3 h, 80%; (c) DMF, NaH,
rt, 12 h, 90%.
With key Williamson substrate 7 in hand, we embarked on
the demanding task of installing the oxolane and oxetane
moieties in a regioselective fashion (Scheme 4). First, treatment
of chloro diol 7 with sodium hydride in THF afforded the desired
five-membered ether 5, a crucial intermediate for the synthesis
of (+)-isolaureatin (1), in a highly regioselective manner in
excellent yield (98%). With methodology for the regioselective
construction of the oxolane moiety of (+)-3-(Z)-isolaureatin (1)
secured, we focused our attention on the formation of the
oxetane unit of (+)-3-(Z)-laureatin (2). The tendency of chloro
diol 7 to form a five-membered ring under basic conditions thus
necessitated development of a method for monoprotection at
C(10) with a nonmigrating group19 under nonbasic conditions.
Unfortunately, an attempt to monoprotect chloro diol 7 under
(17) For the crystal structures of R,R′-trans-oxocene natural products, see: (a)
Kinnel, R. B.; Dieter, R. K.; Meinwald, J.; Engen, D. V.; Clardy, J.; Eisner,
T.; Stallard, M. O.; Fenical, W. Proc. Natl. Acad. Sci. U.S.A. 1979, 76,
3576. (b) Manzo, E.; Ciavatta, M. L.; Gavagnin, M.; Puliti, R.; Mollo, E.;
Guo, Y.-W.; Mattia, C. A.; Mazzarella, L.; Cimino, G. Tetrahedron 2005,
61, 7456.
(18) Addition of BnEt3NCl by Boeckman’s protocol7j afforded a 1:1 mixture
of 14 and 13′.
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A R T I C L E S
Kim et al.
Scheme 5. Introduction of Bromine at C(9) of (+)-Isolaureatin (1)a
Scheme 6. Epimerization of R,R′-cis-Ketone 20a
a Reagents and conditions: (a) EtMgBr, THF, rt, 1 h, 86%; (b) KOH,
THF/MeOH/H2O (3:2:1), rt, 48 h, 75% (93% BRSM), trans/cis ) 4:1.
successive treatment with Me3SnSnMe3 and Br2 by the Wulff
protocol.25 Finally, crucial diimide reduction26 of vinyl bromide
18 from the less hindered convex face, as shown in conformation
E, delivered the desired bromide 19 in a highly stereoselective
fashion.
a Reagents and conditions: (a) CBr4, Oct3P, toluene, rt to 80 °C, 4 h,
<10%; (b) TPAP, NMO, CH2Cl2, rt, 3 h, 92%; (c) KHMDS, THF,
-78 °C, 30 min, then PhNTf2, -78 °C, 1 h, 94%; (d) i. Me3SnSnMe3,
Pd(Ph3P)4, LiCl, THF, reflux, 3 h, ii. Br2, CH2Cl2, -20 °C, 1 h, 75%; (e)
p-toluenesulfonylhydrazide, xylenes, reflux, 2 h, 88%.
We next set out to tackle the formidable27 task of epimer-
ization at C(12), which constitutes a highlight of our synthetic
endeavor. After tactical exploitation of the 6,12-cis-stereochem-
istry of oxocene 8 to develop the chlorination at C(7) and the
osmylation step, it was imperative for us to find an opportune
moment for the pivotal isomerization. After considerable
experimentation, we elected to perform the epimerization on
R,R′-cis-ketone 20 by taking advantage of its unique dioxabi-
cyclic molecular structure. To this end, our direct ketone
synthesis protocol on R-alkoxy amide 19 with ethylmagnesium
bromide afforded R,R′-cis-ethyl ketone 20 in 86% yield (Scheme
6).7k,l We were delighted to find that, upon exposure to aqueous
potassium hydroxide, bicyclic R,R′-cis-ketone 20 underwent a
smooth isomerization to deliver the crucial R,R′-trans-ketone
21 in 75% isolated yield in a 4:1 trans/cis ratio, probably to
minimize the unfavorable electrostatic repulsion between the
oxygen lone pairs present in conformation F.28 This novel “lone
pair-lone pair interaction-controlled” isomerization is remark-
able since the equilibrium lies completely in favor of the R,R′-
cis-isomer in the case of monocyclic oxocene 20′.27
the acidic conditions of Iversen and Bundle20 was not regiose-
lective. After a considerable amount of experimentation, we
were pleased to find that the desired PMB ether 15 could be
obtained in a regioselective fashion by way of the corresponding
stannylene intermediate.21 The regioselectivity here can be
explained by invoking stannylene intermediate C, where the
C(10) group assumes an equatorial position. It is reasonable
that the sterically more exposed equatorial group undergoes
preferential alkylation. Treatment of chloro alcohol 15 with NaH
in DMF then provided oxetane 6, a key intermediate for the
synthesis of (+)-laureatin (2).22
With schemes for the regioselective syntheses of both 5 and
6 established, we next proceeded to address the remaining steps
of the synthesis of (+)-isolaureatin (1). As we anticipated,
introduction of bromine at C(9) with inversion of configuration
turned out to be a challenge since the bromine atom must be
incorporated from the sterically congested concave side of the
molecule in its preferred conformation D. In fact, attempts to
brominate secondary alcohol 5 under a variety of conditions
generally proceeded with retention of configuration in low
yields. To circumvent this problem, we were able to develop a
four-step sequence featuring a diimide reduction of vinyl
bromide 18 as a key step (Scheme 5). Thus, ketone 16, prepared
by TPAP oxidation23 of secondary alcohol 5, was converted to
the corresponding enol triflate 17 by exposure to KHMDS and
PhNTf2 in a chemoselective manner.24 Transformation of enol
triflate 17 to the desired vinyl bromide 18 was achieved by
After the correct configuration at C(12) was established, we
moved on to assembly of the C(12) and C(6) side-chain
appendages. For this purpose, highly stereoselective and efficient
L-Selectride reduction of ketone 21 in a Felkin-Ahn sense,
followed by side-chain bromination at C(13) of the resulting
(25) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.;
Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org.
Chem. 1986, 51, 277.
(26) (a) Dewey, R. S.; Van Tamelen, E. E. J. Am. Chem. Soc. 1961, 83, 3729.
(b) For an example of diimide reduction of a vinyl bromide, see: Chang,
K.-H.; Jenkins, M. N.; Wu, H.-R.; Li, W.-S. Tetrahedron Lett. 2003, 44,
1351.
(27) (a) Carling, R. W.; Curtis, N. R.; Holmes, A. B. Tetrahedron Lett. 1989,
30, 6081. (b) Carling, R. W.; Holmes, A. B. J. Chem. Soc., Chem. Commun.
1986, 565. (c) Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem. Soc.,
Perkin Trans. 1 1992, 83.
(28) For recent examples of controlling diastereoselectivity by the electrostatic
repulsion between various types of lone pairs, see: (a) 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. (b)
Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812.
(c) Lerchner, A.; Carreira, E. M. Chem. Eur. J. 2006, 12, 8208.
(19) The monoprotected chloro diol derivative of 7 with a silyl or acyl protecting
group at C(10) afforded the corresponding oxolane after migration of the
group upon exposure to base.
(20) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981, 1240.
(21) Hanessian, S.; David, S. Tetrahedron 1985, 41, 643.
(22) Use of THF instead of DMF as solvent produced a significant amount of
an elimination product.
(23) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc.,
Chem. Commun. 1987, 1625.
(24) (a) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14, 4607. (b)
McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979. (c) Scott,
W. J.; McMurry, J. E. Acc. Chem. Res. 1988, 21, 47.
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Scheme 7. Completion of Synthesis of (+)-Isolaureatin (1) by
Scheme 8. Epimerization of R,R′-cis-Ketone 29a
Olefin Cross-Metathesisa
a Reagents and conditions: (a) DDQ, CH2Cl2/pH 7.0 buffer (9:1), rt, 1
h, 96%; (b) CBr4, Oct3P, pyridine, toluene, rt to 80 °C, 12 h; (c) EtMgBr,
THF, rt, 1 h, 47% for two steps; (d) KOH, THF/MeOH/H2O (3:2:1), rt, 12
h, 78%; (e) EtMgBr, THF, rt, 1 h, 94%; (f) KOH, THF/MeOH/H2O (3:2:
1), rt, 12 h, 95%.
a Reagents and conditions: (a) L-Selectride, THF, -78 °C, 30 min, 94%;
(b) CBr4, Oct3P, toluene, rt to 80 °C, 4 h, 84%; (c) H2, Pd/C, EtOH/EtOAc
(1:1), 2 h, 97%; (d) o-nitrophenylselenocyanide, Oct3P, THF, rt, 2 h, then
m-CPBA, 0 °C to rt, 3 h, 88%; (e) enyne H, Grubbs’ catalyst I, benzene,
50 °C, 4 h, >76%, Z/E ) 7:1; (f) TBAF, THF, -20 °C, 1 h, 96%.
Scheme 9. Completion of Synthesis of (+)-Laureatin (2)a
secondary alcohol 22, furnished key dibromo compound 23 in
good yield (Scheme 7).
After functionalization of the C(12) side chain, we proceeded
to address assembly of the unsaturated C(6) appendage. Thus,
hydrogenolysis of the benzyl protecting group in 23, followed
by conversion of the resulting primary alcohol 24 into terminal
olefin 25 by Grieco’s protocol in a one-pot process,29 set up
the system for the crucial cross-metathesis for stereoselective
introduction of the (Z)-enyne unit. Cross-metathesis of alkene
25 with enyne H30 and Grubbs’ catalyst I31 using Lee’s
protocol32 furnished a 76% isolated yield of (Z)-enyne 26 with
a 7:1 Z/E stereoselectivity.33 To the best of our knowledge, this
constitutes the first application of the cross-metathesis protocol
of Lee to the construction of a terminal (Z)-enyne system in
natural product synthesis. It should be pointed out that (Z)-enyne
26 was found to be prone to ring opening under basic conditions
as depicted in J. In fact, observation of the same phenomenon
during a Wittig reaction to construct the (Z)-enyne unit in our
preliminary studies led us to resort to the alternative CM
strategy. Finally, careful removal of the TIPS group in 26 by
treatment with fluoride at -20 °C to avoid the above-mentioned
ring rupture furnished (+)-isolaureatin (1) in 96% yield. Spectral
and optical rotation data of synthetic (+)-isolaureatin were
identical to those of natural material.
a Reagents and conditions: (a) L-Selectride, THF, -78 °C, 30 min, 96%;
(b) DIAD, Ph3P, p-nitrobenzoic acid, THF, rt to 40 °C, 12 h, 90%; (c)
DDQ, CH2Cl2/pH 7.0 buffer (9:1), rt, 2 h, 95%; (d) CBr4, Oct3P, pyridine,
toluene, rt to 80 °C, 4 h, 81%; (e) LiAlH4, THF, 0 °C to rt, 1 h, 90%; (f)
CBr4, Oct3P, 1-methylcyclohexene, toluene, rt to 80 °C, 4 h, 82%; (g) H2,
Pd/C, EtOH/EtOAc (1:1), 1 h, 98%; (h) o-nitrophenylselenocyanide, Oct3P,
THF, rt, 2 h, then m-CPBA, 0 °C to rt, 1 h, 88%; (i) enyne H, Grubbs’
catalyst I, benzene, 50 °C, 4 h, >69%, Z/E ) 7:1; (j) TBAF, THF,
-20 °C, 1 h, 98%.
(29) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
(30) Enyne H was prepared in two steps from the commercially available (E)-
pent-2-en-4-yn-1-ol: (1) n-BuLi, THF, TIPSCl; (2) NaH, THF, allyl iodide.
(31) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2002, 41, 4035.
(32) (a) Kang, B.; Kim, D.-h.; Do, Y.; Chang, S. Org. Lett. 2003, 5, 3041. (b)
Hansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035. (c) Kang, B. K.; Lee,
J. M.; Kwak, J.; Lee, Y. S.; Chang, S. J. Org. Chem. 2004, 69, 7661.
(33) For recent representative reports on cross-metathesis, see: (a) Chatterjee,
A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 3171. (b) Chatterjee,
A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360. (c) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900.
With our synthesis of (+)-isolaureatin (1) accomplished, we
next turned to synthesis of (+)-laureatin (2) from the key
oxabicyclic R,R′-cis-oxetane 6 as depicted in Scheme 8.
Formation of cyclopropyl ketone 28 upon attempted base-
promoted isomerization of bromo ketone 27 forced us to defer
introduction of the bromine function at C(10) until after cis/
9
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A R T I C L E S
Kim et al.
trans isomerization. Once again, our direct ketone synthesis
protocol on R-alkoxy amide 6 with ethylmagnesium bromide
(94% yield), followed by pivotal “lone pair-lone pair interac-
tion-controlled” isomerization of the resultant R,R′-cis-ketone
29 (conformation K) by treatment with KOH in aqueous
methanol, afforded the more stable R,R′-trans-ketone 30
(conformation L) exclusively in excellent yield (95%). The
enhanced stereoselectivity here compared to bicyclic oxolane
ketone 21 (trans/cis ) 4:1) can be attributed to relief of
additional unfavorable steric interactions between the C(10) and
C(12) substituents in 29.
step CM protocol to give rise efficiently to (+)-laureatin (2) in
60% overall yield, whose spectral and optical rotation data were
in good agreement with those reported for the natural product.
Conclusion
In conclusion, the first and highly stereo-, regio-, and
chemoselective asymmetric total syntheses of (+)-3-(Z)-isolau-
reatin (1) and (+)-3-(Z)-laureatin (2), unique medium-sized
dioxabicyclic marine natural products with potent mosquito
larvicide activity, were accomplished in a completely substrate-
controlled manner. Our synthesis features a number of stereo-,
regio-, and chemoselective transformations including an in-
tramolecular amide enolate alkylation to construct the R,R′-cis-
oxocene skeleton, novel “lone pair-lone pair interaction-
controlled” epimerizations to the R,R′-trans-oxocenes, various
strategies for the demanding stereoselective introduction of
halogen atoms, and novel olefin cross-metatheses for construc-
tion of the (Z)-enyne systems.
To our great surprise, L-Selectride reduction of ketone 30
produced the undesired C(13)-(S) alcohol 31 exclusively in 96%
yield, probably due to the PMB group at C(10) which blocks
the Si-face of the carbonyl in Felkin-Ahn model M (Scheme
9). However, Mitsunobu inversion34 of secondary alcohol 31
provided the desired p-nitrobenzoate 32 in 90% yield, setting
the stage for the crucial sequential bromination at C(10) of the
bicylic oxocene and C(13) of the acyclic side chain. Our
experience dictated that ring bromination be carried out prior
to side-chain bromination.35 Thus, removal of the PMB protect-
ing group of 32 and ring bromination of the resulting alcohol
33 furnished bromide 34 in 78% yield for the two steps.
Reductive removal of the p-nitrobenzoate group in 34 with
LiAlH4, followed by side-chain bromination of the resulting
alcohol 35, yielded the requisite dibromide 36 in a satisfactory
yield (74%, two steps). As with the isolaureatin intermediate,
assembly of the C(6) side chain could be effected by the four-
Acknowledgment. We thank Professor J. Ishihara (Nagasaki
University) for providing spectra of (+)-3-(Z)-isolaureatin (1)
and (+)-3-(Z)-laureatin (2). This research was supported by the
Korea Research Foundation Grant (KRF-2004-015-C00272) and
the Brain Korea Project in 2005 and 2006.
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
1
spectra for 1, 2, 5-9, 12-38, 12′, and H NMR of 13-epi-
laureatin. This material is available free of charge via the Internet
at http://pubs.acs.org.
(34) Mitsunobu, O. Synthesis 1981, 1.
(35) Reversal of the order of halogenation steps led to partial epimerization of
the side-chain bromine.
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