Asymmetric synthesis of quaternary centers. Total synthesis of (-)-malyngolide.

Article abstract of DOI:10.1021/ol006599p

[structure] The deracemization of 3-nonyl-3,4-epoxybut-1-ene with Pd(0) in the presence of chiral ligands using p-methoxybenzyl alcohol as a nucleophile proceeds regio- and enantioselectively to form the monoprotected vinylglycidol in 99% ee. This chiral building block was converted in seven steps to (-)-malyngolide, an antibiotic showing significant activity against Mycobacterium smegmatis and Streptococcus pyogenes. An interesting aspect involves controlling the diastereoselectivity of protonation of an enolate via a distal hydroxyl group.

Full text of DOI:10.1021/ol006599p

ORGANIC
LETTERS
2000
Vol. 2, No. 25
4013-4015
Asymmetric Synthesis of Quaternary
Centers. Total Synthesis of
(−)-Malyngolide
Barry M. Trost,* Weiping Tang, and Jo1rg L. Schulte
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@leland.stanford.edu
Received September 15, 2000
ABSTRACT
The deracemization of 3-nonyl-3,4-epoxybut-1-ene with Pd(0) in the presence of chiral ligands using p-methoxybenzyl alcohol as a nucleophile
proceeds regio- and enantioselectively to form the monoprotected vinylglycidol in 99% ee. This chiral building block was converted in seven
steps to (−)-malyngolide, an antibiotic showing significant activity against Mycobacterium smegmatis and Streptococcus pyogenes. An interesting
aspect involves controlling the diastereoselectivity of protonation of an enolate via a distal hydroxyl group.
The regio- and enantioselective alkylation of vinyl epoxides
using the Pd-catalyzed asymmetric allylic alkylation (AAA)
offers a potentially powerful approach to vinylglycidols as
chiral building blocks.1 A particularly challenging task, the
stereocontrolled creation of quaternary centers, as shown in
eq 1, appears to be approachable by this strategy. Given the
the question of the geometry of the intermediate π-allylpal-
ladium complexes I and II. Since they lead to enantiomeric
products and the syn-anti isomerization involving the sub-
stituted terminus would not be expected to occur at ap-
preciable rates;2 if both are formed kinetically, only low ee’s
can be expected. We chose to explore this issue in the context
of a total synthesis of (-)-malyngolide (1) whose retrosyn-
thetic analysis is outlined in Scheme 1. The target should
Scheme 1. Retrosynthetic Analysis of (-)-Malyngolide
working model, a key question becomes the effect of the
size of the R group on the process both in terms of regio-
and enantioselectivity. A particularly nettlesome aspect is
(1) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 12702; Trost, B. M.; McEachern, E. J. J. Am. Chem. Soc. 1999, 121,
8649.
10.1021/ol006599p CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/18/2000

be accessible by chain extension of the primary alcohol of 2
with a propionate equivalent. Hydroboration-oxidation of 3
which could derive asymmetrically from racemic 4 would
constitute a short efficient synthesis. (-)-Malyngolide, an
antibiotic possessing significant activity against Mycobac-
terium smegmatis and Streptococcus pyogenes, was isolated
from the blue green alga Lyngbya Majuscula.3 The first
asymmetric synthesis by Mukaiyama involves use of a chiral
auxiliary.4a Most syntheses employ either chiral auxiliaries
or building blocks from the “chiral pool”.4-6 Few employ
asymmetric catalysis7 which allows equal access to either
enantiomer.
With the availability of the vinylglycidol 3 with high
enantiopurity, the stage is now set for the synthesis of either
enantiomer of malyngolide. The initial strategy examined
the introduction of the additional required propionate unit
in an intramolecular fashion. Thus, the silylated vinylglycidol
7 (see Scheme 2) was deprotected to the alcohol 8 (eq 3).
Scheme 2. Synthesis of (-)-Malyngolidea
An advantage of the deracemization of vinyl epoxides via
AAA is the ease of access of the substrate. The known
bromoketone 58 produced from 2-undecanone by the pro-
cedure of Zav’ylov9 reacts with vinylmagnesium bromide
to produce epoxide 410 directly in 65% yield (see eq 2).11
a (a) TIPSOSO2CF3, (C2H5)3N, CH2Cl2, 0 °C; (b) 9-BBN-H, 4
mol % of (Ph3P)3RhCl, THF, rt; H2O2, NaOH, THF, 50 °C; (c)
CH3SO2Cl, (C2H5)3N, CH2Cl2, -78 °C; (d) CH3CH(CO2C2H5)2,
NaH, PhCH3, 100 °C; (e) DDQ, CH2Cl2, H2O, rt; (f) NaOH, H2O,
C2H5OH, reflux; HOAc; PhCH3, reflux; (g) TBAF, THF, 0 °C; (h)
see text.
Exposure of a 1:1 mixture of racemic epoxide 4 and
p-methoxybenzyl alcohol to 1 mol % of a palladium(0)
catalyst and 3 mol % of ligand 6 in the presence of 1 mol %
of triethylboron gave PMB ether 310 as the exclusive
regioisomer. Chiral HPLC analysis established the ee as
97-99%. Alternatively, the enantiomeric ether ent-3 was
obtained by simply changing the ligand to ent-6.
Acylation of the magnesium alkoxide of 812 selectively
produced the tertiary propionate 9 uncomplicated by any silyl
migration. On the other hand, the migration of the propionate
(2) Faller, J. W.; Thomsen, M. E.; Mattina, M. J. J. Am. Chem. Soc.
1971, 93, 2642. Also see: Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
1998, 120, 9074.
(3) Cardllina, J. H., II; Moore, R. E.; Arnold, E. V.; Clardy, J. J. Org.
Chem. 1979, 44, 4039.
(6) Other asymmetric syntheses: (a) Noda, Y.; Kikuchi, M. Synth.
Commun. 1985, 15, 1245. (b) Giese, B.; Rupaner, R. Liebigs Ann. Chem.
1987, 231. (c) Asaoka, M.; Hayashibe, S.; Sonoda, S.; Takei, H. Tetrahedron
1991, 47, 6967. For enzymatic synthesis that permits access to single
enantiomers, see: (d) Sato, T.; Maeno, H.; Noro, T.; Fujisawa, T. Chem.
Lett. 1988, 1739. (e) Suemune, H.; Harabe, T.; Xie, Z.-F.; Sakai, K. Chem.
Pharm. Bull. 1988, 36, 4337.
(7) Catalytic asymmetric syntheses: (a) Flo¨rke, H.; Schaumann. E.
Liebigs Ann. 1996, 147. (b) Konno, H.; Hiroya, K.; Ogasawara, K.
Tetrahedron Lett. 1997, 38, 6023. (c) Kanada, R. M.; Taniguchi, T.;
Ogasawara, K. Tetrahedron Lett. 2000, 41, 3631.
(4) Chiral auxiliary syntheses: (a) Sakito, Y.; Tanaka, S.; Asami, M.;
Mukaiyama, T. Chem. Lett. 1980, 1223. (b) Mukaiyama, T. Tetrahedron
1981, 37, 4111. (c) Kogure, T.; Eliel, E. L. J. Org. Chem. 1984, 49, 576,
(d) Guingant, A. Tetrahedron: Asymmetry 1991, 2, 415. (e) Enders, D.;
Knopp, M. Tetrahedron 1996, 52, 5805. (f) Maezaki, N.; Matsumori, Y.;
Shogaki, T.; Soejima, M.; Tanaka, T.; Ohishi, H.; Iwata, C. Chem. Cammun.
1997, 1755. (g) Winter, E.; Hoppe, D. Tetrahedron 1998, 54, 10329. (h)
Maezaki, N.; Matsumori, Y.; Shogaki, T.; Soejima, M.; Ohishi, H.; Tanaka,
T.; Iwata, C. Tetrahedron 1998, 54, 13087.
(5) Chiral pool syntheses: (a) Pougny, J.-R.; Rollin, P.; Sinay, P.
Tetrahedron Lett. 1982, 23, 4929. (b) Ho, P.-T.; Wong, S. Can. J. Chem.
1985, 63, 2221. (c) Tokunaga, Y.; Nagano, H.; Shiota, M. J. Chem. Soc.,
Perkin Trans. 1 1986, 581. (d) Trinh, M.-C.; Florent, J.-C.; Monneret, C.
Tetrahedron 1988, 44, 6633. (e) Honda, T.; Imai, M.; Keino, K.; Tsubuki,
M. J. Chem. Soc., Perkin Trans. 1 1990, 2677. (f) Ichimoto, I.; Machiya,
K.; Kirihata, M.; Ueda, H. Agric. Biol. Chem. 1990, 54, 657. (g) Matsuo,
K.; Hasuike, Y.; Kado, H. Chem. Pharm. Bull. 1990, 38, 2847. (h) Nagano,
H.; Ohno, M.; Miyamae, Y. Bull Chem. Soc. Jpn. 1992, 65, 2814. (i) Ohira,
S.; Ida, T.; Moritani, M.; Hasegawa, T. J. Chem. Soc., Perkin Trans. 1
1998, 293. (j) Matsuo, K.; Matsumoto, T.; Nishiwaki, K. Heterocycles 1998,
48, 1213. (k) Carda, M.; Castillo, E.; Rodriguez, S.; Marco, J. A.
Tetrahedron Lett. 2000, 41, 5511.
(8) Bryant, M. W.; Smith, R. A. J.; Wong, L. Aust. J. Chem. 1982, 35,
2529.
(9) (a) Zav’yalov, S. I.; Kravchenko, N. E.; Ezhova, G. I.; Sitkareva, I.
V. Bull. Acad. Sci. USSR DiV. Chem. Sci. 1989, 38, 2152. (b) Zav’yalov,
S. I.; Ezhova, G. I.; Sitkareva, I. V.; Dorofeeva, O. V.; Zavozin, A. G.;
Rumyantseva, E. E. Bull. Acad. Sci. USSR DiV. Chem. Sci. 1989, 38, 2204.
(10) This compound has been satisfactorily characterized spectroscopi-
cally and the elemental composition has been established by combustion
analysis or high-resolution mass spectrometry.
(11) Sato, S.; Matsuda, I.; Izumi, Y. J. Organomet. Chem. 1989, 359,
255.
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Org. Lett., Vol. 2, No. 25, 2000

to internal delivery of the proton to form 1. In the event,
addition of 4 equiv of LDA in THF to the 1:1 mixture
followed by inverse quenching into a solution of PPTS in
acetonitrile gave a 3:1 mixture of 1:epi-1 from which pure
1 was isolated in 61% yield, pure epi-1 in 20% yield, and a
mixture of 1 and epi-1 in 5% yield. Recycling the latter
two fractions just once would raise the yield of pure 1 to
76%.
This nine-step route from bromoketone 5 provided enan-
tiomerically pure (-)-malyngolide in 12.5% overall yield
which can be improved to 16.5% overall yield with one
recycling. This strategy allows access to other interesting
targets. For example, tanikolides (18), recently isolated from
occurred in early attempts to form the alcohol 10. Use of
hydroboration catalyzed by Wilkinson’s catalyst13 with
sodium perborate as oxidant14 avoided the problem and
allowed clean formation of 10. However, attempts to activate
the alcohol toward displacement by making the sulfonate
11 led predominantly to the acyl-migrated product 12.
Switching to an intermolecular alkylation strategy avoided
the issue as shown in Scheme 2. Again, rhodium-catalyzed
hydroboration, to form alcohol 13,10 was preferred, but other-
wise the sequence to the mesylate 14 and subsequently the
alkylation product 1510 proceeded straightforwardly. After
oxidative removal of the PMB,15 hydrolysis of the hydroxy
diester 16 and acidification to effect decarboxylation, fol-
lowed by heating, gave the monosilyl derivative 17 as a 1:1
mixture of (-)-malyngolide 1 and its C-2 epimer quantita-
tively.
the marine cyanobacterium Lyngbya majuscula, shows
antifungal and brine-shrimp toxicity.16 Clearly, this target is
easily accessed by this strategy starting from 2-tridecanone
using ent-6 as the ligand for the dynamic kinetic asymmetric
transformation (DYKAT) and malonate for the chain exten-
sion.
The DYKAT of vinyl epoxides nicely accommodates
rather bulky groups. This observation strongly indicates that
the initial palladium-promoted ionization generates only one
geometric isomer, I or II, regardless of the length of R. These
results suggest a broad scope for this deracemization of
3-substituted vinyl epoxides.
Enhancement of the desired epimer 1 was envisioned to
be possible as outlined in eq 4. If the dianion 18 would adopt
Acknowledgment. We thank the General Medical Sci-
ences Institute of the National Institutes of Health and the
National Science Foundation for their generous support.
Generous financial support by the DAAD (NATO-/HSP III-
fellowship for J.L.S.) is gratefully acknowledged. Mass
spectra were provided by the Mass Spectrometry Facility,
University of San Francisco, supported by the NIH Division
of Research Resources.
Supporting Information Available: Characterization
data for 1, 3, 4, 7, 13, and 15. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL006599P
the conformation depicted, initial protonation of the more
basic alkoxide oxygen, to form alcohol 19, could then lead
(14) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem.
1989, 54, 5930.
(15) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(16) Singh, I. P.; Milligan, K. E.; Gerwick, W. H. J. Nat. Prod. 1999,
62, 1333.
(13) Ma¨nnig, D.; No¨th, H. Angew. Chem., Int. Ed. Engl. 1985, 24, 878.
Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992, 114,
6671.
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