Optically active allenes from β-lactone templates: Asymmetric total synthesis of (-)-malyngolide [11]

Full text of DOI:10.1021/ja002783u

10470
J. Am. Chem. Soc. 2000, 122, 10470-10471
terminus would be subject to the well-established stereoelectronic
requirements for SN2′ addition and, therefore, proceed with
rigorous translation of the lactone stereogenic center to the chiral
allene reaction product.7 To evaluate this hypothesis, a series of
optically active alkynyl-substituted â-lactones were prepared from
asymmetric AAC reactions catalyzed by the Al(III) catalyst 1
using either acetyl or propionyl bromide and the requisite
propargylic aldehyde (eq 1).6 The resulting enantiomerically
enriched â-lactones 2 participated in efficient SN2′ ring opening
using alkyl Grignard reagents and a Cu(I) reaction catalyst (10
mol %), providing access to a variety of structurally diverse
optically active allenes 3 (eq 2).8
Optically Active Allenes from â-Lactone Templates:
Asymmetric Total Synthesis of (-)-Malyngolide
Zhonghui Wan and Scott G. Nelson*
Department of Chemistry
UniVersity of Pittsburgh
Pittsburgh, PennsylVania 15260
ReceiVed July 31, 2000
Allenes have emerged as increasingly popular intermediates
for asymmetric organic synthesis due largely to the potential for
relaying the associated axial chirality to ensuing bond construc-
tions.1,2 The SN2′ addition of nucleophiles to suitably derivatized,
optically active propargylic ethers is among the most direct route
to the enantiomerically enriched allenes required for asymmetric
synthesis.3,4 Alkyne-substituted â-lactones are subject to SN2′
nucleophilic addition analogous to that observed for activated
propargylic alcohols, rendering these lactones as complimentary
precursors to allene derivatives.5 Our recent success in preparing
optically active alkynyl-substituted â-lactones via catalytic asym-
metric acyl halide-aldehyde cyclocondensation (AAC) reactions
prompted us to explore the union of the asymmetric AAC
reactions and ensuing SN2′ ring opening as a general strategy for
preparing optically active allene derivatives (eq 1).6 This report
details the successful implementation of this strategy to the
asymmetric synthesis of structurally diverse di- and trisubstituted
allenes via an operationally simple two-step procedure from
propargylic aldehydes. The utility of this reaction technology to
asymmetric organic synthesis is demonstrated in a concise and
efficient asymmetric synthesis of the naturally occurring antibiotic
(-)-malyngolide.
Copper-catalyzed additions of various organometallic nucleo-
philes to the â-lactone electrophiles uniformly proceed in high
yields and with consistent chirality transfer from the â-lactones
2 to the derived â-allenic acids 3 (Table 1). Nucleophilic addition
appears insensitive to the steric environment about the nucleophilic
carbon atom; straight-chain, branched, and aryl Grignard reagents
promote equally efficient ring opening to the optically active
allenic acids 3 (entries a-g). Addition of unbranched nucleophiles
can be accompanied by variable amounts (0-6%) of SN2 lactone
ring opening leading to â-disubstituted carboxylic acids 4 (entries
c, i, j).9 Using CuCN‚2LiBr as the reaction catalyst (10 mol %)
affords substantially improved regioselectivity in these examples
relative to CuBr‚DMS. Ring opening of sterically hindered alkynyl
lactones is also possible with MeMgBr addition to the trimeth-
ylsilyl-substituted alkynyl lactone 2 (R1 ) Bn, R2 ) SiMe3)
providing the optically active trisubstituted allene 3h in 80% yield
(entry h). Variation in the electronic properties of the requisite
nucleophiles is also tolerated in this allene synthesis with zinc
ester enolates (entry i) and the magnesium anion of acetonitrile
(entry j) affording the optically active trisubstituted allenes. The
attenuated reactivity of zinc enolates relative to alkyl Grignard
reagents necessitated higher reaction temperatures (22 °C) for
complete reaction; this temperature requirement is believed to
be responsible for the modest erosion of allene enantiomeric purity
relative to the lactone precursor that is observed in this one
example.10 The stereochemical outcome of these reactions pro-
(4) Synthesis of optically active allene acetic acid derivatives via Johnson
ortho ester Claisen rearrangement of propargylic alcohols: (a) Mori, K.;
Nukada, T.; Ebata, T. Tetrahedron 1981, 37, 1343-1347. (b) Cooper, G. F.;
Wren, D. L.; Jackson D. Y.; Beard C. C.; Galeazzi, E.; Van Horn, A. R.; Li,
T. T. J. Org. Chem. 1993, 58, 4280-4286.
Alkynyl-substituted â-lactones can be considered a subset of
activated propargylic ethers in which ring strain imparts the
necessary activation of the ether functional group to allow SN2′
nucleophilic addition. On the basis of this premise, we anticipated
that nucleophilic addition to the â-lactone’s remote alkyne
(5) (a) Sato, T.; Kawashima, M.; Fujisawa, T. Tetrahedron Lett. 1981, 22,
2375-2378. (b) Sato, T.; Takeuchi, M.; Itoh, T.; Kawashima, M.; Fujisawa,
T. Tetrahedron Lett. 1981, 22, 1817-1820.
(6) (a) Nelson, S. G.; Peelen, T. J.; Wan. Z. J. Am. Chem. Soc. 1999, 121,
9742-9743. (b) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883-1886.
(7) (a) Claesson, A.; Olsson, L.-I. J. Am. Chem. Soc. 1979, 101, 7302-
7311. (b) Olsson, L.-I.; Claesson, A. Acta Chem. Scand. B 1979, 33, 679. (c)
Marek, I.; Mangeney, P.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1986,
27, 5499-5502. (d) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54,
3726-3730. (e) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. J.
Am. Chem. Soc. 1990, 112, 8042-8047.
(8) Either CuCN‚2LiBr or CuBr‚DMS were used as reaction catalysts.
Stoichiometric Gilman cuprates were considerably less reactive toward SN2′
ring opening relative to the Cu(I)-catalyzed alkyl Grignard additions.
(9) For the competing modes of nucleophilic ring opening available to
â-lactone electrophiles, see: Pommier, A.; Pons, J.-M. Synthesis 1993, 441-
459.
(1) Optically active allene reagents in asymmetric synthesis: (a) Marshall,
J. A. Chem. ReV. 1996, 96, 31-48 and references therein. (b) Marshall, J. A.
Chem. ReV. 2000, 100, 3163-3186 and references therein.
(2) Representative applications of chiral allene intermediates in natural
product synthesis: (a) Shepard, M. S.; Carreira, E. M. J. Am. Chem. Soc.
1997, 119, 2597-2605. (b) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998,
63, 7885-7892. (c) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T.
J. J. Am. Chem. Soc. 1999, 121, 3633-3639. (d) Ha, J. D.; Cha, J. K. J. Am.
Chem. Soc. 1999, 121, 10012-10020. (e) VanBrunt, M. P.; Standaert, R. F.
Org. Lett. 2000, 2, 705-708. (f) Brummond, K. M.; Lu, J.; Petersen J. J. Am.
Chem. Soc. 2000, 122, 4915-4920.
(3) (a) Rona, P.; Crabbe´, P. J. Am. Chem. Soc. 1969, 91, 3289-3292. For
reviews, see: (b) Pasto, D. J. Tetrahedron 1984, 40, 2804-2827. (c) Schuster,
H. F.; Coppola, G. M. Allenes in Organic Synthesis; John Wiley & Sons:
New York, 1984. (d) Bruneau, C.; Dixneuf, P. H. In ComprehensiVe Organic
Functional Group Transformations; Katritzky, A. P.; Meth-Cohn, O.; Rees,
C. W., Eds.; Pergamon Press: New York, 1997; Vol. 1, Ch 1.20, 953-995.
(10) Enantiomeric purity of the allene derivatives 3 was assayed by Ag-
(I)-catalyzed cyclization of the carboxylic acid or allenic alcohol (obtained
from the LAH reduction of the carboxylic acid) and separation of the δ-lactone
or dihydropyran enantiomers, respectively, by chiral GC or HPLC. See
Supporting Information for details.
10.1021/ja002783u CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/05/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10471
Table 1. SN2′ Ring Opening of Alkynyl-Substituted â-Lactones 2
lactone 2 (% ee)
allene (3) (% ee)
% yield 3
R1
R2
R3
(% ee)a
a
b
c
d
e
f
g
h
i
H
CH2OBn (93)
CH2OBn (93)
CH2OBn (93)
CH2OBn (93)
CH2OBn (93)
CH2OBn (93)
CHMe2 (3a)
CH2CH2CHCH2 (3b)
(CH2)10CH3 (3c)
C6H5 (3d)
CH3 (3e)
CMe3 (3f)
92 (92)
H
H
H
H
H
94 (93)b
90 (92)c
93 (nd)d
92 (93)b
93 (nd)d
88 (90)e
80 (nd)d
84 (83)b,f
79 (90)g
Figure 1. Malyngolide retrosynthesis.
CH3 (CH2)2OPMB (90) CH3 (3g)
Scheme 1a
Bn
H
H
SiMe3 (93)
CH2OBn (93)
CH2OBn (93)
CH3 (3h)
CH2CO2CMe3 (3i)
CH2CN (3j)
j
a See ref 10 for determination of stereoisomer ratios. b CuCN‚2LiBr
was used as the reaction catalyst. Unless otherwise noted, CuBr‚DMS
was used as the reaction catalyst. c Isolated with 2.8% of regioisomer
4. d Not determined. All related examples provided complete translation
of lactone chirality. e Value represents diastereomeric excess. f Isolated
with 6% of regioisomer 4. g Isolated with 1.6% of regioisomer 4.
vides the first evidence that 4-alkynyl-2-oxetanones belong to the
class of propargylic ethers that undergo stereospecific anti-1,3-
substitution reactions.11
a (a) 10 mol % 1, EtCOBr, iPr2NEt, CH2Cl2, -50 °C. (b) nC9H19MgBr,
10 mol % CuBr, THF, -78 °C. (c) 10 mol%, AgNO3, 5 mol % iPr2NEt,
80 °C, CH3CN. (d) H2, Pd-C.
Optically active 1,3-disubstituted allenes are also conveniently
obtained from the â-lactone templates. 4-Ethynyl-2-oxetanone 5,
obtained in 93% ee from cyclocondensation of 3-trimethylsilyl-
propynal and subsequent silyl group cleavage, provides a common
platform for preparing a variety of disubstituted allenic acids (eq
3). Copper-catalyzed Grignard addition to 5 affords the 1,3-
disubstituted allenes 6 bearing straight chain, branched, or aryl
substituents as the exclusive reaction products in high yields and
with consistent chirality transfer.
The malyngolide synthesis was initiated with the asymmetric
AAC reaction of propionyl bromide and 4-benzyloxybuynal (10)15
catalyzed by the Al(triamine) complex 1 (10 mol %) to provide
the cis-3,4-disubstituted-2-oxetanone 9 in 85% yield (94% ee,
91:9 cis:trans) (Scheme 1).6b Copper-catalyzed ring opening of
9 with nonyl Grignard delivered the optically active trisubstituted
allene 8 (92%). Electrophilic activation of the trisubstituted allene
was expected to engage the carboxylic acid in a 6-endo-trig
cyclization in preference to the competitive 5-exo-dig pathway
owing to the enhanced stabilization provided to the developing
positive charge at the disubstituted allene terminus in the transition
state leading to the δ-lactone.16 Consistent with this expectation,
Ag(I)-catalyzed cyclization of allenic acid 8, accelerated by a
substoichiometric quantity of soluble amine base (5 mol % iPr2-
NEt), resulted in rapid formation of the δ-lactone 11 (80%),
thereby establishing the requisite tertiary carbinol stereocenter.
Ensuing Pd(0)-catalyzed alkene dihydrogenation proceeded with
concomitant hydrogenolysis of the benzyl ether to afford synthetic
(-)-malyngolide (7) in 87% yield (94% ee, 100% de) in four
steps and 54% overall yield from the aldehyde 10.17,18
The â-allenic acids emerging from the AAC-SN2′ ring opening
sequence provide versatile precursors to optically active oxygen
heterocycles by exploiting the annulative addition of the car-
boxylate terminus onto the allene unit.12 To highlight this utility,
â-lactones and the derived allenic acids were examined as conduits
for a concise, fully stereocontrolled synthesis of the naturally
occurring antibiotic (-)-malyngolide (7).13,14 The synthesis was
predicated on establishing the δ-lactone core of malyngolide by
the cyclization of the trisusbstituted allenic acid 8 that would be,
in turn, obtained from â-lactone 9 (Figure 1). Following this
synthesis strategy, both stereogenic centers present in malyngolide
would be established in the initial asymmetric AAC reaction with
the lactone â-stereocenter ultimately being relayed to the requisite
tertiary carbinol stereocenter via the intermediacy of the chiral
allene 8.
The asymmetric AAC-SN2′ ring opening sequence provides an
efficient and operationally simple enantioselective synthesis di-
and trisubstituted allene derivatives. The optically active allenes
provided the cornerstone for a highly efficient enantioselective
synthesis of the naturally occurring antibiotic malyngolide, an
investigation that highlights the utility of these allene derivatives
in asymmetric organic synthesis.
Acknowledgment. The American Cancer Society (RPG CCD-99301)
and the Merck Research Laboratories are gratefully acknowledged for
support of this work.
(11) Stereoselection in SN2′ nucleophilic additions to activated propargylic
electrophiles can vary depending on leaving group structure. See ref 7.
(12) (a) Grimaldi, J.; Normant, M. H. C. R. Ser. C 1978, 286, 593-594.
(b) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997, 62,
367-371. (c) Grimaldi, J.; Cormons, A. Tetrahedron Lett. 1985, 26, 825-
828.
Supporting Information Available: Experimental procedures and
1
representative H and 13C spectra (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Cardllina, J. H. II; Moore, R. E.; Arnold, E. V.; Clardy, J. J. Org.
Chem. 1979, 44, 4039-4042.
JA002783U
(14) Recent asymmetric syntheses of (-)-malyngolide: (a) Flo¨rke, H.;
Schaumann, E. Liebigs Ann. 1996, 147-151. (b) Enders, D.; Knopp, M.
Tetrahedron. 1996, 52, 5805-5818. (c) Konno, H.; Hiroya, K.; Ogasawara,
K. Tetrahedron Lett. 1997, 38, 6023-6026. (d) Maezaki, N.; Matsumori, Y.;
Shogaki, T.; Soejima, M.; Ohnishi, H.; Tanaka, Y.; Iwata, C. J. Chem. Soc.,
Chem. Commun. 1997, 1755-1756. (e) Ohira, S.; Ida, T.; Moritani, M.;
Hasegawa, T. J. Chem. Soc., Perkin Trans. 1 1998, 293-294. (f) Matsuo, K.;
Matsumoto, T.; Nishiwaki, K. Heterocycles 1998, 48, 1213-1220. (g) Winter,
E.; Hoppe, D. Tetrahedron 1998, 54, 10329-10338. (h) Maezaki, N.;
Matsumori, Y.; Shogaki, T.; Soejima, M.; Ohnishi, H.; Tanaka, Y.; Iwata, C.
Tetrahedron 1998, 54, 13087-13104 and ref 13 therein for a comprehensive
listing of previous malyngolide syntheses. (i) Kanada, R. M.; Taniguchi, T.;
Ogasawara, K. Tetrahedron Lett. 2000, 54, 3631-3635.
(15) Journet, M.; Cai, D.; DiMichele, L. M.; Larsen, R. D. Tetrahedron
Lett. 1998, 39, 6427-6428.
(16) Marshall, J. A.; Bartley, G. S. J. Org. Chem. 1994, 59, 7169-7171.
See also ref 12.
(17) The minor diastereomer introduced during the initial AAC reaction
was removed at this stage by column chromatography.
(18) The structure of (+)-tanikolide, a close structural relative to malyn-
golide, has recently been reported, see: Singh, I. P.; Milligan, K. E.; Gerwick,
W. H. J. Nat. Prod. 1999, 62, 1333-1335. An asymmetric synthesis of (-)-
tanikolide from allenic acid 3c was completed via a two-step procedure
analogous to that used in preparing (-)-malyngolide. See Supporting
Information for full procedural details.