Synthesis and absolute stereochemical assignment of (+)-miyakolide

Article abstract of DOI:10.1021/ja990789h

The first total synthesis of the marine macrolide miyakolide has been achieved, and its absolute stereochemistry has been determined. The carbon skeleton is assembled in a convergent fashion from three fragments via esterification, [3 + 2] dipolar cycload

Full text of DOI:10.1021/ja990789h

6816
J. Am. Chem. Soc. 1999, 121, 6816-6826
Synthesis and Absolute Stereochemical Assignment of
(+)-Miyakolide
David A. Evans,* David H. B. Ripin, David P. Halstead, and Kevin R. Campos
Contribution from the Department of Chemistry & Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
ReceiVed March 11, 1999
Abstract: The first total synthesis of the marine macrolide miyakolide has been achieved, and its absolute
stereochemistry has been determined. The carbon skeleton is assembled in a convergent fashion from three
fragments via esterification, [3 + 2] dipolar cycloaddition, and aldol addition. The utility of â-ketoimide aldol
reactions in fragment coupling was demonstrated on fully elaborated intermediates. The coupled material was
transformed into a 1,3,7-triketone-containing macrocycle that underwent a facile transannular aldol reaction
followed by hemiketalization to form the oxydecalin ring system of the natural product. Deprotection afforded
ent-miyakolide, which was produced in 6.8% overall yield and 29 linear steps.
The architecture of natural products has long provided the
Synthesis Plan.10 The premise underlying the synthesis plan
rested on the presumption that the C11-C19 oxydecalin subunit
in miyakolide might be assembled spontaneously through an
intramolecular aldol reaction (eq 1). If miyakolide is biosyn-
stimulus for the development of new reactions.1 Similarly,
postulated biosynthetic pathways to natural products have
focused attention on the laboratory simulation of these pivotal
events.2,3 We viewed miyakolide (1) as an ideal synthetic target
for these reasons (vide infra). Miyakolide was isolated in 1992
from a sponge of the genus Polyfibrospongia by Higa and co-
workers.4 Its relative stereochemistry was assigned by X-ray
crystallography and supported by detailed NMR spectroscopic
studies. Structurally, miyakolide displays a number of features
seen in several bioactive marine macrolides. The C1-C3
â-hemiketal ester/acid functionality is shared by natural products
such as aplasmomycin,5 aplysiatoxin,6 callipeltoside A,7 and
lonomycin A,8 while the C5 exocyclic unsaturated ester is a
structural element also found in the bryostatin class of natural
products.9
(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320-1367.
(b) Ireland, R. E. Aldrichim. Acta 1988, 21, 59-69. (c) Norcross, R. D.;
Paterson, I. Chem. ReV. 1995, 95, 2041-2114.
(2) Synthesis has been used as a tool to produce isotopically labeled
putative biosynthetic intermediates that are fed to the producing plant or
animal in order to study their incorporation into the biosynthetic pathway.
Some recent examples in the field of polyketide biosynthesis include: (a)
Cane, D. E.; Luo, G. J. Am. Chem. Soc. 1995, 117, 6633-6634. (b) Yue,
S.; Duncan, J. S.; Yamamoto, Y.; Hutchinson, C. R. J. Am. Chem. Soc.
1987, 109, 1253-1254.
(3) Proposed biosynthetic transformations have been reproduced in
laboratory syntheses of natural products in order to test their practicality
outside of the biological system and take advantage of the powerful
transformations. Some examples include: (a) Johnson, W. S.; Gravestock,
M. B.; McCarry, B. E. J. Am. Chem. Soc. 1971, 93, 4332-4334. (b)
Gravestock, M. B.; Johnson, W. S.; McCarry, B. E.; Parry, R. J.; Ratcliffe,
B. E. J. Am. Chem. Soc. 1978, 100, 4274-4282. (c) Chapman, O. L.; Engel,
M. R.; Springer, J. P.; Clardy, J. C. J. Am. Chem. Soc. 1971, 93, 6696-
6698. (d) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem. Soc.
1982, 104, 5560-5562. (e) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard,
G. S. J. Am. Chem. Soc. 1995, 117, 3448-3467. (f) Williams, D. R.;
Coleman, P. J.; Henry, S. S. J. Am. Chem. Soc. 1993, 115, 11654-11655.
(4) Higa, T.; Tanaka, J.; Komesu, M.; Gravalos, D. C.; Puentes, J. L.
F.; Bernardinelli, G.; Jefford, C. W. J. Am. Chem. Soc. 1992, 114, 7587-
7588.
thesized according to the standard polyketide model, an iterative
linear chain of subunits would be assembled, followed by
macrolactonization, cyclizations, and rearrangements.11 If mac-
(8) (a) Otake, N.; Koenuma, M.; Miyamae, H.; Sato, S.; Saito, Y.
Tetrahedron Lett. 1975, 4147-4150. (b) Omura, S.; Shibata, M.; Machida,
S.; Sawada, J.; Otake, N. J. Antibiot. 1976, 29, 15-20. (c) Riche, C.;
Pascard-Billy, C. J. Chem. Soc., Chem. Commun. 1975, 951-952.
(9) Petit, G. R.; Gao, F.; Sengupta, D.; Coll, J. C.; Herald, C. L.; Doubek,
D. L.; Schmidt, J. M.; Van Camp, J. R.; Rudloe, J. J.; Nieman, R. A.
Tetrahedron 1991, 47, 3601-3610.
(10) Progress toward the total synthesis of miyakolide has been
reported: Yoshimitsu, T.; Song, J. J.; Wang, G.-Q.; Masamune, S. J. Org.
Chem. 1997, 62, 8978-8979.
(5) Okazaki, T.; Kitahara, T.; Okami, Y. J. Antibiot. 1976, 29, 1019-
1025.
(6) Mynderse, J. S.; Moore, R. E. J. Org. Chem. 1978, 43, 2301-2303.
(7) Zampella, A.; D’Auria, M. D.; Minale L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc. 1996, 118, 11085-11088.
10.1021/ja990789h CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/14/1999

Synthesis of (+)-Miyakolide
J. Am. Chem. Soc., Vol. 121, No. 29, 1999 6817
Figure 1. Proposed miyakolide biosynthetic precursors 2a and 2b. The 2b-Model structure, less the metal ion M, minimized using the AMBER
forcefield.13 C1-C9 and C21-C27 not shown.
rolactonization indeed precedes the indicated intramolecular
aldol construction, macrocyclic precursors such as 2 (Figure 1)
could well be found along the biosynthetic pathway. If this
reaction is to be integrated into a synthesis plan, the desired
aldol adduct constitutes one of four possible product diastereo-
mers, and while this process might be enzymatically mediated,
it could also be simply controlled by the conformation of the
macrocycle.3ef,12,13 In implementing this strategy, it was felt that
macrocycle 2b might provide more conformational ordering in
the aldol step than its ring-chain tautomer 2a. To assess the
probability that the desired aldol macrocyclic stereocontrol might
be possible in 2b, a multiconformational search of the crucial
enol ketone intermediate was undertaken using the AMBER
force field, restricting the C18-C13 atom distance to a maximum
of 4.5 Å.14 Figure 1 depicts the lowest energy structure generated
by this search, wherein the C18 and C13 diastereofaces are
disposed to deliver the desired stereochemistry following an
intramolecular aldol reaction. While a generic metal ion, M,
has been incorporated into the 2b-Model illustration, this does
not imply that the metal ion was part of the calculation. In this
conformation, the chair transition state for the aldol addition is
accessible. The other low-energy conformation of 2b, differing
by only 0.1 kcal/mol, presents the C17-C19 (si) enol diastereo-
face opposite to that of the C13 carbonyl moiety; however, the
resulting aldol reaction must proceed via a boat transition state.
Since a spontaneous transannular aldol addition was antici-
pated when the three carbonyl groups at C13, C17, and C19 were
revealed, we felt it was important to also have the C11 alcohol
in its unprotected state prior to this bond construction. The aldol
adduct would thus undergo immediate hemiketalization, masking
the C17-C19 diketone moiety and suppressing elimination of
the C13 hydroxyl moiety. We then elected to mask the C17-C19
diketone as its derived isoxazole,15 which might undergo
spontaneous ring closure upon reduction of the N-O bond.16
While two possible isoxazole structures were entertained, we
chose to employ isoxazole 3 bearing nitrogen at C19 since the
reduction product of 3 might be easily hydrolyzed with
assistance of the C11 alcohol following the aldol reaction
(Scheme 1).17 In the event that the enaminone failed to
participate in oxydecalin formation, this functionality might be
hydrolyzed under conditions likely to effect the transannular
aldol step.18,19
(11) For recent reviews on the biosynthesis of polyketides, see: (a)
Cortes, J.; Haydock, S. F.; Roberts, G. A.; Bevitt, D. J.; Leadlay, P. F.
Nature 1990, 348, 176-178. (b) Donadio, S.; Staver, M. J.; McAlpine, J.
B.; Swanson, S. J.; Katz, L. Science 1991, 252, 675-679. (c) Malpartida,
F.; Hopwood, D. A. Nature 1984, 309, 462-464. (d) O’Hagan, D. Nat.
Prod. Rep. 1995, 1-33.
(12) Transannular reactions have been postulated in a number of
biosynthetic pathways. The dolabellanes are postulated to be biosynthetically
converted to the clavularanes and dolastanes via transannular ring-
contracting reactions: (a) Look, S. A.; Fenical, W. J. Org. Chem. 1982,
47, 4129-4134. Dactylol is postulated to be biosynthesized from humulene,
via a ring-contracting cationic olefin cyclization followed by cyclopropyl
cation rearrangement and solvolysis: (b) Schmitz, F. J.; Hollenbeak, K.
H.; Vanderah, D. J. Tetrahedron 1978, 34, 2719-2722. (c) Hayasaka, K.;
Ohtsuka, T.; Shirahama, H. Tetrahedron Lett. 1985, 26, 873-876. The
endiandric acids are postulated to be biosynthesized via a cascade of
electrocyclic reactions, including a ring-contracting cyclization: (d) Ban-
daranayake, W. M.; Banfield, J. E.; Black, D. St. C. J. Chem. Soc., Chem.
Commun. 1980, 902-903.
(13) Macrocyclic conformation has been employed as a control element
in synthesis in several instances: (a) Still, W. C.; Romero, A. G. J. Am.
Chem. Soc. 1986, 108, 2105-2106. (b) Schreiber, S. L.; Sammakia, T.;
Hulin, B.; Schulte, G. J. Am. Chem. Soc. 1986, 108, 2106-2108. (c) Vedejs,
E.; Gapinski, D. M. J. Am. Chem. Soc. 1983, 105, 5058-5061. Macrocyclic
ring contractions have been used with success to control diastereoselectivity
of the contracted ring-forming reaction. (d) Myers, A. G.; Condroski, K.
R. J. Am. Chem. Soc. 1993, 115, 7926-7927.
(15) For a review on the use of isoxazoles in synthesis, see: (a) Baraldi,
P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D. Synthesis 1987,
857-869. (b) Little, R. D. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5 pp 239-
270. (c) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH Publishers: New York, 1988. (d) Caramella, P.;
Grunanger, P. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
John Wiley & Sons: New York, 1984; Vol. 1, pp 291-392.
(16) Although deprotonation of an enaminone (NaOH) was required to
promote an aldol reaction (Yuste, F.; Sanchez-Obregon, R. J. Org. Chem.
1982, 47, 3665-3668), we hoped that the intramolecularity of our
transformation would force the reacting partners together and facilitate a
reaction under milder conditions.
(17) The regioisomeric isoxazole containing nitrogen at C17 was deemed
an inferior intermediate, as the aldol adduct would contain a C17 imine that
could tautomerize, epimerizing the C16 stereocenter.
(18) (a) Kato, N.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1984,
32, 1679-1682. (b) Eiden, F.; Patzelt, G. Arch. Pharm. (Weinheim, Ger.)
1986, 319, 242-251. (c) Auricchio, S.; Ricca, A.; DePava, O. V. Gazz.
Chim. Ital. 1980, 110, 567-570. (d) Kobuke, Y.; Kokubo, K.; Munakata,
M. J. Am. Chem. Soc. 1995, 117, 12751-12758. (e) Kashima, C.; Mukai,
N.; Tsuda, Y. Chem. Lett. 1973, 539-540.
(19) Mineral acids are most commonly employed to achieve this
transformation (see ref 18), but model studies on 3-amino-5-oxo-1-
phenyloct-3-ene demonstrated that this hydrolysis could be achieved under
milder conditions such as 4:4:1 AcOH/THF/water; PPTS in THF/water; or
CuX2 (X ) Cl, OTf, BF4) and water in a variety of organic solvents.
(14) All calculations were performed using the AMBER force field on
structures generated by a Monte Carlo multiconformer search using
MacroModel (Version 5.0) provided by Professor W. Clark Still, Columbia
University. The dielectric coefficient (ELE) in the force field was set at 60
to simulate a polar solvent. Only structures with a C18 to C13 atom distance
of 4.5 Å or less that were generated three or more times during the search
(out of 150, 000 structures generated) were considered. The AMBER force
field was selected because it generated a minimized structure of miyakolide
that more closely fit the X-ray crystal structure than structures generated
using the MM2 and MM3 force fields.

6818 J. Am. Chem. Soc., Vol. 121, No. 29, 1999
EVans et al.
Scheme 1
Scheme 2
on the pyranone precursor, relying on the steric and electronic
biases of the substrate for establishing the desired olefin
geometry. Unraveling the ketal to the open-chain tautomer
reveals keto alcohol 8. Although the methyl-bearing stereocenter
at C2 is prone to epimerization, the kinetic lability of this
functionality can be attenuated through the use of an oxazoli-
dinone auxiliary at the carboxyl terminus.21b,24 The 1,2-syn-diol
relationship at C7-C8 suggests a chelate-controlled aldol
addition of Chan’s diene25 (10) to aldehyde 9.
Isoxazole 3 was conveniently disconnected into three frag-
ments via [3 + 2] dipolar cycloaddition, C11-C12 aldol addition,
and esterification/lactonization transforms (Scheme 1). Of the
three fragment coupling processes, the C11-C12 aldol addition
was the most speculative. Neither the C12-C18 ketone fragment
nor the C1-C11 aldehyde bears a stereocenter sufficiently near
the reacting centers to provide reasonable diastereocontrol during
bond formation. Furthermore, regioselective enolization of the
C13 ketone was problematic. Both of these issues were addressed
through the incorporation of a removable substituent, X, at C14
that would serve both to direct enolization and to provide a
stereochemical control element for the aldol reaction. The
principal constraint on the selection of X was that it must be
removed under mild conditions on a multifunctional intermedi-
ate. The solution to this stereochemical issue is summarized in
Scheme 2.20 Using methodology developed in conjunction with
this project, syn and anti aldol adducts such as 5 are available
in high yield and diastereoselectivity from â-ketoimide 4.21
Conditions were developed to effect the illustrated hydrolysis
and decarboxylation of the (oxazolidinyl)carbonyl moiety (see
5 f 6). The mild reaction conditions (thiolate transesterification
of the imide followed by silver(I)-promoted hydrolysis of the
thioester) provide rapid access to aldol adducts such as 6.
Accordingly, the C14 (oxazolidinyl)carbonyl auxiliary was
employed as the chiral controller X.
Scheme 3
Addition of allylmagnesium bromide to (S)-O-trityl glycidol26
(THF, 0 °C) cleanly afforded the expected alcohol, which was
protected as the p-methoxybenzyl (PMB) ether 13 (Scheme 4).
Deprotection of the primary trityl ether (HCl, 93%) followed
by Swern oxidation27 under controlled conditions (DMSO,
(COCl)2, -78 °C; i-Pr2NEt, -30 °C)28 afforded aldehyde 9 of
sufficient purity for the subsequent aldol reaction. Complexation
of this aldehyde with TiCl2(O-i-Pr)2 (-78 °C),29 followed by
Results and Discussion
Synthesis of the C1-C11 Subunit. The synthesis plan for
the C1-C11 fragment is illustrated below (Scheme 3). We chose
to employ a fully elaborated synthon, despite the anticipated
sensitivity of the â,γ-unsaturated lactol moiety, rather than risk
late-stage manipulations on a complex, multifunctional system.
This approach confers the advantage of reducing the number
of orthogonal protecting groups required for masking the
reactive functionalities. We envisioned installing the C5 enoate
using a Horner-Wadsworth-Emmons22 or Peterson23 reaction
(23) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780-784. (b) Shimoji,
K.; Taguchi, H.; Oshima, K.; Yamamoto, H.; Nozaki, H. J. Am. Chem.
Soc. 1974, 96, 1620-1621.
(24) A â-ketoimide has been employed in an analogous intramolecular
ketalization without epimerization of the R-stereocenter in a synthesis of
lonomycin (ref 3e).
(25) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J. Can. J.
Chem. 1983, 61, 688-693.
(26) Hendrickson, H. S.; Hendrickson, E. K. Chem. Phys. Lipids 1990,
53, 115-120.
(20) Evans, D. A.; Ripin D. H. B.; Johnson, J. S.; Shaughnessy, E. A.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2119-2121.
(21) (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.;
Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866-868. (b) Evans, D. A.;
Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 2127-2142.
(22) For a review, see: Boutagy, J.; Thomas, R. Chem. ReV. 1974, 74,
87-99.
(27) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(28) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434-9453.
(29) (a) Izawa, T.; Mukaiyama, T. Chem. Lett. 1978, 409-412. (b)
Hagiwara, H.; Kimura, K.; Uda, H. J. Chem. Soc., Perkins Trans. 1 1992,
693-700.

Synthesis of (+)-Miyakolide
J. Am. Chem. Soc., Vol. 121, No. 29, 1999 6819
Scheme 4a
a Key: (a) CH2CHCH2MgBr, THF, 0 °C; (b) NaH, PMBBr, DMF/THF; (c) HCl, MeOH/Et2O, 0 °C; (d) (COCl)2, DMSO, i-Pr2NEt, -78 to -30
°C; (e) TiCl2(O-i-Pr)2, 10, CH2Cl2, -78 to 0 °C; (f) Et2BOMe, NaBH4, THF/MeOH, -78 °C; (g) Me2C(OMe)2, HCl ; (h) DIBAL-H, CH2Cl2, -78
°C, then MeOH, -78 °C; (i) 11, Bu2BOTf, i-Pr2NEt, CH2Cl2, 0 °C, then 16, -78 °C; (j) (COCl)2, DMSO, i-Pr2NEt, -78 f 0 °C; (k) TsOH,
MeCN/MeOH, -22 °C; (l) (COCl)2, DMSO, Et3N, -78f0 °C.
Table 1. Relevant NOEs
addition of Chan’s diene 10 (-78f0 °C), with presumed chelate
control, afforded ketoester 14 in 73% yield as an inseparable
20:1 mixture of isomers whose stereochemical proof will be
described below (eq 2). Syn reduction of keto alcohol 14
(Et2BOMe, NaBH4)30 cleanly produced syn-diol 15 as a >20:1
diastereomeric mixture in 99% yield.31 The unpurified diol,
protected as it derived acetonide, was treated with DIBAL-H
(CH2Cl2, -78 °C)32 to provide aldehyde 16 in 87% yield.
Dibutylboron triflate-mediated aldol addition of (4S)-3-pro-
pionyl-4-benzyloxazolidinone (11) to aldehyde 16 proceeded
in 84% yield to furnish the aldol adduct as a single diastereomer
as determined by 1H NMR spectroscopy.33 Swern oxidation gave
â-ketoimide 17 quantitatively. Cyclization of â-ketoimide 17
to the lactol methyl ether (TsOH, MeOH/MeCN, -22 °C)
proceeded in 71% yield (82% after re-submission of recovered
starting material).24 Finally, oxidation of the C5 alcohol to ketone
18 was accomplished quantitatively by the Swern procedure.27
The syn stereochemistry of the aldol addition step (9 f 14)
was confirmed by conversion to the illustrated bicyclic ortho
ester derivative (eq 2). Anti reduction of keto alcohol 14 with
Me4NBH(OAc)334 (10:1 diastereoselectivity, 90%) followed by
DDQ oxidation (70%)35 afforded the illustrated ortho ester.
NMR spectroscopic analysis of this ortho ester confirmed that
the desired stereochemical relationships had been established
(Table 1) and the addition process had indeed been chelate
controlled.
1H
NOE (%)
Hd (11)
Ha (4), He (3), Hd (4)
Hb (13)
Hb
Hc
Hd
Table 2. Selective Peterson Olefination of ketone 18
A number of strategies were investigated to stereoselectively
incorporate the C5 enoate (18 f 19-E) (eq 3, Table 2).
Conversion of 18 to exocyclic olefin 19-E (eq 3) under Horner-
Wadsworth-Emmons conditions22 (trimethyl phosphonoacetate,
NaHMDS, 0 °C, 2.5 h) afforded an 83% yield of a separable
1:1.8 mixture of isomers favoring the undesired Z isomer.
Alternatively, Peterson-Yamamoto23b olefination (LDA, methyl
(trimethylsilyl)acetate, -78 °C, 1 h) afforded a favorable 3:1
mixture of isomers (Table 2, entry 1), while the sodium enolate
(NaHMDS, methyl (trimethylsilyl)acetate, -78 °C, 1 h) was
entry
base
LDA
NaHMDS
LDA
solvent
E:Z
1
2
3
4
THS
THF
Et2O
PhMe
73:27
18:82
66:33
66:33
LDA
found to reverse the selectivity (Table 2, entry 2).36 Use of ether
or toluene as solvent attenuated the selectivity (Table 2, entries
3 and 4). On a large scale, it was optimal to run the olefination
at -110 °C, providing 73:27 selectivity in 99% yield. The
relative stereochemistry of the C5 enoate was assigned by
chemical shift analysis of 19-E (H4e δ 2.73, H6e δ 3.83).
Imide 19-E was hydrolyzed (LiO2H, DMF/THF/H2O)37 to
the derived carboxylic acid, which was transformed to its benzyl
ester 20 in 99% yield for the two steps (Scheme 5). Successive
osmium-catalyzed dihydroxylation and periodate cleavage af-
forded aldehyde 21 in 85% yield with no detectable cleavage
(30) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155-158.
(31) This reaction provided a higher yield and selectivity than the reaction
with Me4NBH(OAc)3, leading us to temporarily employ this configuration
at C5 to mask the exocyclic enoate.
(32) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 619-620.
(33) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127-2129. (b) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77-
82.
(34) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(35) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888.
(36) Trapping of the lithium and sodium enolates used for the olefinations
with TBSOTf gave identical silyl ketene acetals.

6820 J. Am. Chem. Soc., Vol. 121, No. 29, 1999
EVans et al.
Scheme 5a
Scheme 6a
a Key: (a) LiBH4, MeOH, THF, 0 °C; (b) (COCl)2, DMSO, Et3N,
-78 to 0 °C; (c) Ph3P, CBr4, CH2Cl2, 0 °C; (d) TFA/CH2Cl2; (e) n-BuLi,
THF, -78 °C; (f) (COCl)2, C6H6; ii) XpH (Xp ) (4S)-4-benzyloxazo-
lidinone), n-BuLi, THF, 0 °C; (g) Bu2BOTf, Et3N, CH2Cl2, 0 °C, then
EtCHO, -78 °C; (h) TMSCl, imidazole, CH2Cl2; (i) SO3‚pyr, i-Pr2NEt,
DMSO/CH2Cl2, -15 °C.
a Key: (a) LiOOH, THF/DMF/H2O, 0 f 23 °C; (b) BnBr, Cs2CO3,
DMF/CH2Cl2; (c) OsO4, NMO, THF/t-BuOH/H2O; (d) NaIO4, NaHCO3,
THF/t-BuOH/H2O; (e) TIPSCl, Et3N, then Et3NHOAc.
Paterson.42 The use of a heteroconjugate addition (31 f 30) of
the C25 alkoxide under conditions that allowed for equilibration
of the product diastereomers was the plan selected for the
construction of the pyran ring.
of the enoate. This fragment was thus prepared in 17 steps in
an overall yield of 24%. The analogous TIPS-protected ester
22, required for an alternate fragment assembly strategy (vide
infra), was prepared in four steps from 19-E (imide hydrolysis,
osmylation, periodate cleavage, and TIPS protection) without
purification of intermediates in 54% yield. This fragment is
available in 17 steps with an overall yield of 15%.
Scheme 7
Synthesis of the C12-C18 Subunit. The synthesis of the C12-
18 fragment began with intermediate 23, available in 88% yield
C
and >95:5 selectivity via Michael addition of the titanium
enolate of the propionyl oxazolidinone to tert-butyl acrylate
(Scheme 6).28,38 The imide was selectively reduced in the
presence of the tert-butyl ester using LiBH4,39 the primary
alcohol was oxidized,27 and the aldehyde was immediately
olefinated (Ph3P, CBr4)40 to afford dibromoolefin 24 (77%, three
steps). Cleavage of the tert-butyl ester (TFA/CH2Cl2, 99%)
followed by treatment with 4 equiv of n-butyllithium (THF, -78
°C) to effect elimination of the dibromoolefin delivered alkyne
25 in 83% yield. Acid chloride formation followed by imide
acylation with lithiated (4S)-4-benzyloxazolidinone formed
imide 26 in 86% yield. Following another boron aldol reaction
(26 f 27) and subsequent protection, 28, one of the two C12-
C18 fragments was constructed. The other C12-C18 synthon used
in an alternative assemblage sequence, 29, was prepared by
oxidiation of 27 (SO3‚pyridine, DMSO, i-Pr2NEt, -15 °C)41 in
95% yield. This sequence provided the two C12-C18 fragments
in nine steps and 31% and 32% overall yield, respectively, for
28 and 29 from Michael adduct 23.
The synthesis of this fragment began with the aldol addition
of ketone 32 to senecialdehyde (c-hex2BCl, Et3N, Et2O, -78
°C), which proceeded in 7.5:1 (98%) diastereoselectivity favor-
ing 1,4-syn product 33 (Scheme 8).42 While the two C25
diastereomers could not be separated at this point, after anti
reduction (Me4NBH(OAc)3, AcOH/CH3CN, -35 °C),34 the
desired diol 34a was purified by crystallization in 76% yield.
Successive protection of the diol as the bis-TES ether, benzyl
ether removal43 (LDBB, 96%), and oxidation41 of the derived
primary alcohol afforded aldehyde 35 in 85% overall yield.
Horner-Wadsworth-Emmons homologation (LiCl, Et3N,
(MeO)2P(O)CH2CO2Me, MeCN)44 afforded the E enoate (92%),
which was successively transformed to diol 36 and cyclized
under basic conditions (KOt-Bu, THF, -10 °C)45 to give an
apparent kinetic 1.5:1 mixture of tetrahydropyrans 37 and 38
in 96% yield. While it had been anticipated that this hetero-
conjugate addition would be reversible under these conditions,
this proved not to be the case; however, silyl protection of the
Synthesis of the C19-C27 Subunit. The plan for the synthesis
of the C19-C27 fragment is illustrated in Scheme 7. The origin
for the chirality in this subunit is the known methyl ketone 32
and its associated aldol reactions precedented in the work of
(37) (a) Jacobi, P. A.; Murphree, S.; Rupprecht, F.; Zheng, W. J. Org.
Chem. 1996, 61, 2413-2427. Attempted oxazolidinone cleavage under
standard conditions (LiOOH, THF/H2O, 0 °C) was sluggish; a large excess
of LiOOH at rt was required to achieve completion and competitive
hydrolysis of the unsaturated ester was observed. (b) Evans, D. A.; Britton,
T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141-6144.
(38) Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.; Cherry,
D.; Kato, Y. J. Org. Chem. 1991, 56, 5750-5752.
(39) (a) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 307-
312. (b) Kim, A. S. Ph.D. Thesis, Harvard University, 1996.
(40) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3972.
(41) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(42) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121-7124.
(43) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924-1930. (b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110,
854-860.
(44) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfield, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(45) Evans, D. A.; Carreira, E. M. Tetrahedron Lett. 1990, 31, 4703-
4706.

Synthesis of (+)-Miyakolide
J. Am. Chem. Soc., Vol. 121, No. 29, 1999 6821
Scheme 8
a Key: (a) c-hex2BCl, Et3N, Et2O, Me2CCHCHO, -78 °C; (b) Me4NBH(OAc)3, MeCN/AcOH, -35 °C; (c) TESCl, imidazole, CH2Cl2; (d)
LDBB, THF, -78 °C; (e) SO3‚pyridine, i-Pr2NEt, DMSO/CH2Cl2, -15 °C; (f) LiCl, Et3N, (MeO)2P(O)CH2CO2Me, MeCN, 0 f 23 °C; (g) TBAF,
H2O/THF; (h) KO-t-Bu, THF, -10 °C; (i) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C.
Scheme 9a
mixture (TBSOTf, 2,6-lutidine, 97%) followed by re-submission
of the mixture of silyl ethers to the basic cyclization conditions
afforded cis-tetrahydropyran 39 in >95:5 selectivity and 86%
yield. The structure of 39 was confirmed by NOE analysis and
subsequently an X-ray structure of tetrahydropyran 38.46
Two different approaches were explored for the conversion
of esters 38 or 39 to a functional nitrile oxide precursor. In the
first approach, the TES ether of methyl ester 38 was transformed
into oxime 40. Unfortunately, oxidation of 40 under a variety
of conditions to the desired chlorooxime (eq 4)47,48 failed due
a Key: (a) DIBAL-H, THF, -78 f 23 °C; (b) Ph3P, Br2, imidazole,
CH2Cl2/2-methyl-2-butene; (c) AgNO2, Et2O; (d) HF‚pyridine, pyr,
THF.
to unanticipated competitive chlorination of the trisubstituted
olefin. In an alternative approach, methyl ester 39 was trans-
formed in a conventional series of steps to the derived nitro
pyran 43 (Scheme 9). In the noteworthy step, bromide 41 was
path A. Aldol fragment coupling of the C12-C18 â-ketoimide
and the C1-C11 aldehyde should afford adduct 44. The
subsequent [3 + 2] dipolar cycloaddition to append the C19-
C27 nitrile oxide would then provide intermediate 45 containing
converted to nitro pyran 42 with silver nitrite49 in 78% yield
along with the corresponding nitrate ester in 17% yield. This
route provided access to the C19-C27 nitrile oxide precursors
42 and 43 in 13 and 14 steps, respectively, and 31% overall
yield from methyl ketone 32 (Scheme 8).
all of the carbon atoms present in miyakolide. Decarboxylation,
deprotection, and macrolactonization would provide the key
isoxazole-containing macrocycle 48. Alternatively, the [3 + 2]
coupling between the C12-C18 fragment and the C19-C27 nitrile
oxide cycloaddition to give adduct 46 (path B) could be followed
by a more complex â-ketoimide aldol coupling with the C1-
Fragment Coupling Strategies. The principal fragments of
the miyakolide skeleton were designed so that they might be
assembled in several different sequences (Scheme 10). The
assemblage strategy deemed most conservative is depicted as
C11 aldehyde to return to the common intermediate 45. A third
variation (path C) would involve the same C1-C18 aldol-coupled
intermediate 44 as in path A. After deprotection of the C1 ester,
the C19-C27 fragment would be incorporated via an esterifica-
tion reaction affording 47. Macrocyclization via [3 + 2]
cycloaddition followed by decarboxylation and deprotection
would again afford macrocycle 48. During the course of this
synthesis, all three assemblage strategies were evaluated (vide
infra).
Path A: Aldol f Cycloaddition f Esterification. While
â-ketoimide 4 has been utilized as a dipropionyl synthon for
the assemblage of a number of polypropionate targets,3e,28,39b,50
this methodology has not been previously used for the coupling
of complex fragments such as 29 or 46 (Scheme 10). In the
(46) Crystallographic data for 38: C13H22O4 Mw ) 242.3, orthorhombic,
colorless, P212121°, a ) 6.0062 (2) Å, b ) 11.4838 (5) Å, c ) 19.5391 (8)
Å, ν ) 1347.69 (9) Å3, Z ) 4, Dc ) 1.194 g cm-3, F(000) ) 528, µ(Mo
KR) ) 0.087 mm-1; R ) 0.0569, Rw ) 0.1340, GOF on F2 ) 1.124 for
2
5207 observed reflections. R ) ∑||Fo| - |Fc||/∑|Fo|. Rw ) (∑[w(Fo
-
Fc2)2]/∑[wFo ])1/2, where w ) q/σ2(Fo ) + (aP)2 + bP. See the Experimental
4
2
Section for details.
(47) Chlorinating agents tried included isocyanuric chloride, tert-butyl
hypochlorite at -78 °C (ref 48a), NCS (ref 48b, c), and NaOCl in a biphasic
system (ref 48d, e).
(48) (a) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.;
Takeda, T.; Waldner, A.; Williard, P. G.; Zutter, U. J. Am. Chem. Soc.
1986, 108, 1039-1049. (b) Stevens, R. V. Tetrahedron 1976, 32, 1599-
1612. (c) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916-3918. (d) Ponzio, G.; Busti, G. Gazz. Chim. Ital. II 1906, 36, 338.
(e) Grundmann, C.; Datta, S. K. J. Org. Chem. 1969, 34, 2016-2018.
(49) (a) Kornblum, N.; Taub, B.; Ungnade, H. E. J. Am. Chem. Soc.
1954, 76, 3209-3211. (b) Kornblum, N.; Ungnade, H. E. Organic Syntheses;
Wiley: New York, 1963; Collect. Vol. IV, pp 724-727.
(50) For examples, see: (a) Evans, D. A.; DiMare, M. J. Am. Chem.
Soc. 1986, 108, 2476-2478. (b) Evans, D. A.; Ng, H. P.; Rieger, D. L. J.
Am. Chem. Soc. 1993, 115, 11446-11459. (c) Evans, D. A.; Kim, A. S. J.
Am. Chem. Soc. 1996, 118, 11323-11324.

6822 J. Am. Chem. Soc., Vol. 121, No. 29, 1999
EVans et al.
Scheme 10
Scheme 11a
C11 was assigned on the basis of analogy to previous studies21b
and confirmed by NOE analysis of a later intermediate (vide
infra).
Theoretically, aldol adducts 49 or 50 could be decarboxylated
either preceding or following [3 + 2] cycloaddition. As the
conditions required to dehydrate the primary nitroalkane moiety
to its derived nitrile oxide51 (ArNCO, R3N, 90 °C) would likely
epimerize the R-center of a â-ketoimide, we initially chose to
examine a route that placed the decarboxylation step prior to
coupling. Treatment of aldol adduct 50 with potassium ethane-
thiolate (THF, 25 °C, 3 h) followed by purification provided a
mixture of C14-epimeric â-ketothioesters in quantitative yield
(Scheme 11).52,20 It was encouraging that the resident function-
ality in 50 emerged from these conditions unscathed. Unfortu-
nately, treatment of the resulting thioesters with silver nitrate
and 2,6-lutidine (5:1 THF/H2O, 48 h)53,20 failed to produce more
than a 38% yield of desired decarboxylated material 51. The
remainder of the isolated products lacked the alkyne functional-
ity, which was clearly interfering with the desired transforma-
tion.
The incompatibility of the alkyne functionality in 50 with
the Ag(I)-promoted hydrolysis/decarboxylation was easily over-
come by delaying the hydrolysis until after the nitrile oxide
cycloaddition step (Scheme 12). Alkyne 50 was premixed with
3-ClPhNCO and i-Pr2NEt in toluene at 90 °C51 followed by
addition of 2 equiv of nitroalkane 42 over 24 h.54 This procedure
afforded coupled isoxazole 52 in 96% yield. Surprisingly, almost
no epimerization (<5%) of the C14 stereocenter was observed,
presumably due to the steric congestion of the silyl-protected
a Key: (a) c-hex2BCl, Me2NEt, Et2O, 0 °C, then 21, -78 f 0 °C;
(b) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C; (c) EtSH, KH, THF; (d)
AgNO3, 2,6-lutidine, THF/H2O.
event, â-ketoimide 29 was transformed into its derived (E)-
boron enolate (1.3 equiv of c-hex2BCl, Me2NEt, ether, 0 °C)21b
to which was added 0.5 equiv of aldehyde 21 at -78 °C
(Scheme 11). The aldol adduct 49 was isolated in 90% yield
(based on aldehyde) in 92:8 diastereoselectivity along with good
recovery of the starting materials. It is noteworthy that the
standard isolation used for this reaction (NH4Cl quench followed
by IRA-743 resin, CH2Cl2) often resulted in product decomposi-
tion. Alternatively, if the reaction was quenched with 5%
NaHCO3 followed by immediate flash chromatography of the
partially concentrated organic layer, reproducible yields of the
aldol adduct could be obtained. The stereochemistry at C12 and
(51) Mukiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339-
5342.
(52) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31, 2849-
2852.
(53) (a) Corey, E. J.; Bock, M. C. Tetrahedron Lett. 1975, 3269-3270.
(b) Schwyzer, R.; Hurlimann, C. HelV. Chim. Acta 1954, 18, 155-166.
(54) Since nitrile oxides readily dimerize to furoxans (ref 15c), they must
be generated at low concentration in the presence of the efficient
dipolarophile.

Synthesis of (+)-Miyakolide
J. Am. Chem. Soc., Vol. 121, No. 29, 1999 6823
Scheme 12a
a Key: (a) 3-ClPhNCO, i-Pr2NEt, PhMe, 24 h addition of 42, 90 °C; (b) EtSH, KH, THF; (c) AgNO3, 2,6-lutidine, THF/H2O; (d) HF‚pyr,
2,6-lutidine; (e) 10% Pd/C, 1,4-cyclohexadiene, EtOH; (f) 2,4,6-Cl3PhCOCl, i-Pr2NEt, DMAP.
aldol adduct. The regiochemistry of the [3 + 2] cycloaddition
was confirmed by the characteristic 1H NMR chemical shift of
the C18 trigonal proton (δ ) 5.95) on the isoxazole nucleus.55
At this juncture, the hydrolysis/decarboxylation proceeded
uneventfully to afford a 95% yield of ketone 53.20 The
subsequent desilylation of the C11 and C23 TBS ethers in 53
(HF‚pyridine, 2,6-lutidine) proceeded in good yield;39b however,
cleavage of the terminal benzyl ester in the presence of the
trisubstituted olefin, enoate, and isoxazole proved challenging.
While transfer hydrosilylation56 afforded good yields (75-79%)
of the diol acid on a small (<10 mg) scale, this result was
irreproducible on scale-up.57 In the end, transfer hydrogenation
proved to be the more reliable method for removing the benzyl
ester (10% Pd/C, 1,4-cyclohexadiene, 100%),58 requiring only
filtration through Celite to deliver diol acid 54 in high purity.
No evidence of over-reduction was observed in this reaction.
Macrolactonization via the Yamaguchi procedure59 (2,4,6-
Cl3PhCOCl, i-Pr2NEt, DMAP, benzene) afforded 48 in 97%
yield, with no observable participation of the C11 alcohol. This
completed the synthesis of the macrocyclic precursor to the
miyakolide carbon skeleton.
supra), we presented the â-ketoimide fragment as the C13-
protected secondary alcohol 28 as a precaution against epimer-
ization of the C14 stereocenter. To a premixed solution of 1.4
equiv of 28, 3-ClPhNCO, and i-Pr2NEt in toluene at 90 °C51
was added nitroalkane 42 over 24 h, affording isoxazole 55 in
66% (Scheme 13). Deprotection of the C13 TMS ether and
Parikh-Doering oxidation41 delivered desired â-ketoimide 57
in 94% yield. Enolization of ketone 57 (1.4 equiv) followed by
addition of a solution of aldehyde 21 (1.0 equiv) provided a
50% yield of desired aldol adduct 58 in 90:10 selectivity. The
remainder of both the aldehyde and ketone starting materials
could be recovered in good yield (80% of unreacted 57, 48%
of 21). On the basis of the recovery of aldehyde component
21, this coupling process is quite viable. Nevertheless, despite
extensive reaction optimization, we were never able to raise
the yield of this reaction above the 50% level. Aldol adduct 58
was then converged with path A through the four-step sequence
outlined in Schemes 12 and 13 in 72% overall yield. One of
the attributes of the path A-path B strategy is the excellent
yield (96%) of the intramolecular macrolactonization step to
form 48 (Scheme 13).
Path B: Cycloaddition f Aldol f Esterification. In
principle, path B (Scheme 10) provides the shortest possible
linear route to miyakolide. Because of the conditions required
to generate the nitrile oxide for the [3 + 2] cycloaddition (vide
Path C: Aldol f Esterification f Cycloaddition. The third
assemblage strategy includes a penultimate macrocyclization via
[3 + 2] cycloaddition60 (path C, Scheme 10). This fragment
coupling requires that the C1 ester be deprotected in the presence
of the C17-C18 alkyne; accordingly, the TIPS-protected C1-
C11 aldehyde fragment 22 was utilized. Aldol fragment coupling
between â-ketoimide 29 and aldehyde 22 (c-hex2BCl, Me2NEt)
furnished the desired adduct 59 in 79% yield (Scheme 14).
Protection of the aldol adduct as its TES ether proceeded with
loss of the TIPS ester on workup (TESCl, imidazole; Et3NHOAc),
producing acid 60. Submission of this acid to modified
Yamaguchi conditions59 with alcohol 43 ((2,4,6-Cl3PhCO)2O,
i-Pr2NEt, DMAP, benzene) afforded ester 61 in 45% yield from
alcohol 59.61,62 Slow addition of nitroalkylalkyne 61 to
3-ClPhNCO and i-Pr2NEt in refluxing benzene furnished
(55) A regioisomeric isoxazole bearing substituents at the 3 and 4
positions, with a proton at the 5 position would have a singlet resonance
around δ 8.40. 3,5-Dimethylisoxazole has a C4 singlet resonance at δ 5.85,
and 3-methylisoxazole has a C4 resonance at δ 6.25 and a C5 resonance at
δ 8.40. The Aldrich Library of NMR Spectra, Edition II; Pouchert, C. J.,
Ed.; Aldrich Chemical Co.: Milwaukee, WI, 1983; Vol. 2, p 503.
(56) Sakaitani, M.; Kurokawa, N.; Ohfune, Y. Tetrahedron Lett. 1986,
27, 3753-3754.
(57) The breakdown of the intermediate triethylsilyl ester required
exposure to silica gel (chromatography) to reveal the highly polar diol acid.
Recovering the acid from silica gel was difficult, and the silyl ester
hydrolysis efficiency decreased as loading on silica gel increased. The
desired diol acid proved extremely acid sensitive, and an efficient alternative
cleavage of the TES ester was not found.
(58) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 43, 4194-4196.
(59) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(60) Macrolactonization via intramolecular [3 + 2] cycloaddition has
been demonstrated to be highly selective and efficient. Ko, S. S.; Confalone,
P. N. Tetrahedron 1985, 41, 3511-3518.

6824 J. Am. Chem. Soc., Vol. 121, No. 29, 1999
EVans et al.
Scheme 13a
a Key: (a) 3-ClPhNCO, i-Pr2NEt, PhMe, 24 h addition of 42, 90 °C; (b) PPTS, MeOH, 0 °C; (c) SO3‚pyr, i-Pr2NEt, DMSO/CH2Cl2, -15 °C;
(d) c-hex2BCl, Me2NEt, Et2O, 0 °C, then 21, -78 °C f 0 °C; (e) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C.
Scheme 14a
a Key: (a) c-hex2BCl, Me2NEt, Et2O, 0 °C; 22, -78f0 °C; (b) TESCl, imidazole, CH2Cl2, then Et3NHOAc; (c) (2,4,6-Cl3PhCO)2O, i-Pr2NEt,
DMAP, C6H6, 43; (d) 3-ClPhNCO, i-Pr2NEt, C6H6, 90 °C, 20 h addition of 61; (e) EtSH, NaHMDS, THF; (f) AgNO3, 2,6-lutidine, THF/H2O; (g)
HF‚pyr,THF.
macrocyclic isoxazole 62 in 68% yield. No regioisomeric
isoxazole was observed, and epimerization of the C14 stereo-
center was again minimal. Decarboxylation was effected via
sodium ethanethiolate transesterification of the imide followed
by hydrolysis with AgNO3 and 2,6-lutidine in 4:1 THF/water.20
Desilylation using HF‚pyridine buffered by excess pyridine
delivered macrocycle 48 in 70% yield from 62. The selectivity
of the hydrolysis procedure20 implemented on the advanced
intermediate 62 is noteworthy.
The Miyakolide Precursor. The high-risk portion of the
synthesis plan was contained in the final intramolecular aldol
step to construct the C11-C19 oxydecalin Miyakolide subunit.
To ensure the success of the terminal transformations, a number
of experiments were carried out on the isoxazole-containing
macrocycle 48 and its N-O reduction product 64 (Scheme 15).
Prior to isoxazole reduction, macrocycle 48 was used to model
the propensity of the C3 lactol methyl ether toward hydrolysis
and potential ring-chain tautomerism (65 f 66). If keto ester
66 is readily accessed under hydrolysis conditions, the integrity
of the C5 unsaturated ester would be placed in jeopardy as would
the stereochemistry of the C2 methyl group. In the event,
treatment of macrolactone 48 with TsOH (MeCN/water 5:1)
(61) Excess alcohol 43 was converted to its 2,4,6-trichlorobenzoate ester.
All other esterification conditions investigated (EDC (ref 62a-c), diiso-
propylcarbodiimide (ref 62a-c), PyBrOP (ref 62d), and BOP-Cl (ref 62e))
failed to deliver any esterified product.
(62) (a) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067-
1068. (b) Cruickshank, P. A.; Sheehan, J. C. J. Org. Chem. 1961, 26, 2525-
2528. (c) Hegarty, A. F.; Bruice, T. C. J. Am. Chem. Soc. 1970, 92, 6568-
6574. (d) Castro, B.; Coste, J. Fr. Patent 89-02-361. (e) Diago-Meseguer,
J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.; Zugaza-Bilbao, A.
Synthesis 1980, 547-551.

Synthesis of (+)-Miyakolide
J. Am. Chem. Soc., Vol. 121, No. 29, 1999 6825
Figure 2. Conformations of macrocycle 64 in benzene and in 5:1 dioxane/water. (arrows indicate observed NOEs).
Scheme 15a
experiments (Figure 2). Several conclusions were drawn from
this study. First, the correct diastereofaces of the C17-C19
enaminone and C13 carbonyl are properly oriented in both
solvents. Second, there seems to be a noticeable solvent effect
on the conformation. In benzene, the macrocycle appears to be
significantly compressed, as evidenced by transannular NOE
enhancements between protons on C12 and C16 and between the
PMB methylene and the C22 methyl group. In dioxane/water
the macrocycle appears to be in a more open conformation as
evidenced by NOE enhancements between the C3 methyl ketal
and the C22 methine and both C9 hydrogens. The C13 ketone is
pointing toward the exterior of the macrocycle.
Completion of the Synthesis. Treatment of enaminone 64
with Lewis acids such as Ti(O-i-Pr)4 or Et2BOMe in CH2Cl2
failed to effect any reaction from -78 °C to room temperature
(Scheme 16). The intent of these reactions was to activate the
C
13 ketone with the assistance of the C11 alcohol. Although no
reaction was observed, starting material was recovered un-
changed, allaying concern that the C3 mixed methyl ketal would
eliminate under Lewis acidic conditions. No reaction was
observed until the molecule was heated to 90 °C in dioxane/
pH 7 buffer. After 2 weeks, starting material had disappeared,
and a number of products were isolated, including an analogue
of the transannular aldol adduct 70 (Scheme 16) along with aldol
elimination products and a small amount of the transannular
aldol product still bearing nitrogen at C19. Although there are
only a few examples of enaminones participating in aldol
reactions,16 we had hoped that the forced proximity of the
reacting centers would facilitate such a reaction in this case.
As this did not seem to be the situation, we expected hydrolysis
of the enaminone to the corresponding 1,3-diketone would
provide a more reactive system. Given the success of the
hydrolysis of mixed methyl ketal 48, we decided to attempt the
simultaneous hydrolyses of the enaminone and mixed methyl
ketal. When enaminone 64 was treated with 1.5 equiV of TsOH
in 5:1 MeCN/water for 18 h, followed by addition of pH 10
buffer and stirring for an additional 15 min at room tempera-
ture, PMB-protected miyakolide 67 was obtained in 96% yield
for the one-pot, three-transformation process (Scheme 16).
a Key: (a) TsOH, MeCN/H2O; (b) 48 f 64: Mo(CO)6, H2O, MeCN,
reflux; (c) 63 f 65: W-2 Raney Ni, 1 atm H2, EtOH/AcOH.
delivered a 99% yield of hemiketal 63, which is stable for
several days at room temperature without significant isomer-
ization. Selective reduction of the N-O bond in isoxazoles 48
and 63 could be achieved using W-2 Raney nickel under 1 atm
of hydrogen (20:1 EtOH/AcOH) to afford lactol methyl ether
64 in 59% yield from 48 and hemiketal 65 in 74% yield from
63.63 A small amount of over-reduction of the C26 olefin was
also observed in this reaction. The Mo(CO)6 reduction procedure
of Nitta,64 (Mo(CO)6, MeCN-H2O, 70 °C) proved to be a better
reducing agent affording a 69% yield of enaminone 64, which
proved to be surprisingly stable. In contrast to expectation,
enaminone 64 failed to undergo the desired transannular aldol
reaction with the C13 ketone.
A closer examination of the details of the acid hydrolysis
step revealed that enaminone 64 could be selectively hydrolyzed
in the presence of the lactol methyl ether (AcOH/THF/water
4:4:1; or 0.95 equiv TsOH, MeCN/water 5:1),19 providing 1,3-
diketone 68 (enol/keto tautomer ratio 5:1). This triketone, which
The conformations of intermediate 64 in both benzene and
5:1 dioxane/water were examined through the use of NOESY
(63) Stagno D’Alcontres, G. Gazz. Chim. Ital. 1950, 80, 441.
(64) Nitta, M.; Kobayashi, T. J. Chem. Soc., Chem. Commun. 1982, 877-
878.

6826 J. Am. Chem. Soc., Vol. 121, No. 29, 1999
EVans et al.
Scheme 16a
a Key: (a) 1.5 equiv of TsOH, MeCN/H2O; (b) then pH 10 buffer; (c) DDQ, H2O, CH2Cl2.
does not cyclize under acidic conditions, could be isolated in
high purity. On treatment with pH 10 buffer (NaHCO3, Na2CO3)
in dioxane (15 min, 25 °C), the desired 3-methyl-8-OPMB-
miyakolide 70 was obtained in 95% yield for the two steps as
a single diastereomer. On the basis of these results, it appears
that in the one-pot, three-step process described earlier, enami-
none 64 is hydrolyzed to 68 first, followed by hydrolysis of
the mixed methyl ketal to 69, and finally cyclization to 67.
Subjecting enaminone 64 itself to pH 10 buffer in dioxane
resulted in no reaction; stronger bases such as NaH are generally
employed to deprotonate enaminones65 but would be incompat-
ible with this intermediate.
Final deprotection of the PMB group in 67 (DDQ, water,
CH2Cl2)35 produced (+)-miyakolide in 77% yield (Scheme 16).
The synthetic material displayed spectral characteristics identical
to those of the natural product (1H NMR, 13C NMR, IR, HRMS,
TLC) and an equal but opposite specific rotation (natural [R]23
D
Figure 3. X-ray structure of (+)-miyakolide with CCl4.
-24° (c ) 1.05, CHCl3),4 synthetic [R]23 +23° (c ) 0.4,
D
acylimides as R-keto chiral auxiliaries via the development of
the â-ketoimide decarboxylation reaction. In addition, the utility
and limitations of â-ketoimide aldol reactions as large fragment
coupling processes have been demonstrated. The large array of
functionality tolerated in the decarboxylation process validates
this as a viable two-step fragment coupling procedure. Finally,
the synthesis of a proposed biosynthetic intermediate and its
facile transformation into miyakolide demonstrate the validity
of this intermediate as a possible precursor to miyakolide.
CHCl3)). To further confirm that (+)-miyakolide had been
produced, crystals were grown from a mixture of CCl4, ethyl
acetate, and hexanes; (+)-miyakolide cocrystallized with CCl4,
allowing both the structure and absolute configuration to be
determined (Figure 3).66 This conclusively demonstrated that
the absolute configuration of natural miyakolide is enantiomeric
to that depicted in eq 1.
Conclusions
A total synthesis of the marine natural product miyakolide
has been achieved in a highly convergent manner from three
fragments in 29 linear steps and 6.8% overall yield, establishing
the absolute stereochemistry of the natural product. This
synthesis provided the impetus for the development of N-
Acknowledgment. Support has been provided by the
National Institutes of Health, Merck, and Pfizer. We thank Dr.
Andrew Tyler of the Harvard Mass Spectrometry Facility for
providing mass spectra and the NIH BRS Shared Instrumenta-
tion Grant Programs 1-S10-RR01748-01A1 and 1-S10-RR04870
and the NSF (CHE 88-14019) for providing NMR facilities.
(65) Kashima, C.; Katoh, A.; Yokota, Y.; Omote, Y. Synthesis 1983,
151-153.
(66) Crystallographic data for (+)-1: C36H54O12 (CCl4) Mw ) 678.9/
153.8, orthorhombic, colorless, P212121°, a ) 12.821(3) Å, b ) 14.992(3)
Å, c ) 21.088(4) Å, ν ) 4053.3(14) Å3, Z ) 4, Dc ) 1.364 g cm-3, F(000)
) 1760, µ(Mo KR) ) 0.087 mm-1; R ) 0.0694, Rw ) 0.1348, GOF on F2
Supporting Information Available: Full experimental
details and complete analytical data for all compounds reported
in this and X-ray crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
) 1.141 for 18549 observed reflections. R ) ∑||Fo| - |Fc||/∑|Fo|. Rw
)
2
2
4
2
(∑[w(Fo - Fc )2]/∑[wFo ])1/2, where w ) q/σ2(Fo ) + (aP)2 + bP. See
the Experimental Section (Supporting Information) for details.
JA990789H