Asymmetric crotylation reactions in synthesis of polypropionate-derived macrolides: Application to total synthesis of oleandolide

Article abstract of DOI:10.1021/ja020853m

Complete details of a convergent asymmetric synthesis of oleandolide (1), the aglycon of the macrolide antibiotic oleandomycin, is described. The synthesis has been achieved through the assembly and coupling of the left- and right-hand subunits 12 and 38,

Full text of DOI:10.1021/ja020853m

Published on Web 10/04/2002
Asymmetric Crotylation Reactions in Synthesis of
Polypropionate-Derived Macrolides: Application to Total
Synthesis of Oleandolide
Tao Hu, Norito Takenaka, and James S. Panek*,†
Contribution from the Department of Chemistry and Center for Molecular Library Design,
Metcalf Center for Science and Engineering, 590 Commonwealth AVenue, Boston UniVersity,
Boston, Massachusetts 02215
Received June 18, 2002
Abstract: Complete details of a convergent asymmetric synthesis of oleandolide (1), the aglycon of the
macrolide antibiotic oleandomycin, is described. The synthesis has been achieved through the assembly
and coupling of the left- and right-hand subunits 12 and 38, respectively. These subunits were prepared
from chiral silane-based asymmetric crotylation reactions to control the stereochemical relationships. The
left- and right-hand subunits (C1-C7 and C8-C14) were brought together through a Pd(0)-catalyzed sp3-
sp2 cross-coupling reaction between the zinc intermediate 40 and vinyl triflate 38 to give 27. This product
was converted to seco acid 42a and cyclized to lactone 35 under Yamaguchi conditions. This material was
then epoxidized with m-chloroperbenzoic acid (m-CPBA) to install the correct C8 epoxide as a single
diastereomer, which after a short deprotection sequence completed the synthesis of oleandolide.
Introduction
Oleandomycin is representative of the 14-membered polypro-
pionate-derived macrolide antibiotics.1 This natural product
contains a number of structurally complex elements, including
10 stereocenters and an unusual exocyclic epoxide at C8 (Figure
1). The compound is produced by the actinomycete Streptomyces
antibioticus and was originally reported by Sobin et al. in 1955.2
It was first characterized in 1958 as an epoxide containing a
polyhydroxy and polymethyl macrocyclic lactone with two
appended sugars, desosamine and L-oleandrose, which permitted
partial structure assignment.3 The complete structure of olean-
domycin was established in 1960 by Celmer, Woodward, and
co-workers.4 Its relative configuration was assigned by NMR
techniques in 1965 by Celmer5 and later confirmed by X-ray
crystallography of the 11,4′′-bis[O-(p-bromobenzoyl)] derivative
by Ogura et al.6
Figure 1. Representative 14-membered macrolides.
(TAO) derivatives, has been used widely in clinical and
veterinary areas. Particularly good responses were achieved
against Gram-positive bacteria and mycoplasma.7 Concerning
the mechanism of action of these agents, they are believed to
inhibit bacterial RNA-dependent protein synthesis by binding
to the P site of the bacterial 50S ribosomal subunit, blocking
either transpeptidation and/or translocation reactions.8 These
compounds have found nonantibiotic utilities as well. For
instance, TAO is currently used in conjunction with a corticos-
teroid, providing frontline therapy in cases of refractory asthma.9
Oleandomycin possesses similar breadth of therapeutic activ-
ity to the well-known erythromycins. It exhibits activity against
Gram-positive and some Gram-negative bacteria, possessing a
bacteriostatic rather than a bactericidal action. As a result of its
low toxicity and high antibacterial potency, oleandomycin, as
well as its phosphate (matromycin) and triacetyloleandomycin
* Corresponding author: e-mail Panek@chem.bu.edu.
† Recipient of a 2002 Arthur C. Cope Scholar Award.
(1) Macrolide Antibiotics, Chemistry, Biology and Practice; Omura, S., Ed.;
Academic Press: Orlando, FL, 1984.
(7) (a) For a review of macrolides in clinical use, see Nakayama, I. In Macrolide
Antibiotics, Chemistry, Biology and Practice; Omura, S., Ed.; Academic
Press: Orlando, FL, 1984; pp 261-230. For a review on veterinary practice,
see Wilson, R. C. In Macrolide Antibiotics, Chemistry, Biology and
Practice; Omura, S., Ed.; Academic Press: Orlando, FL, 1984; pp 301-
338.
(8) Corcoran, J. W. In Macrolide Antibiotics, Chemistry, Biology and Practice;
Omura, S., Ed.; Academic Press: Orlando, FL, 1984; pp 232-259.
(9) Drug EValuations Annual 1995; Bennett, D. R., Ed.; American Medical
Association: Chicago, 1995; p 536.
(2) Sobin, B. A.; English, R. A.; Celmer, W. D. Antibiot. Annu. 1955, 2, 827-
830.
(3) Els, H.; Celmer, W. D.; Murai, K. J. Am. Chem. Soc. 1958, 80, 3777-
3782.
(4) Hochstein, F. A.; Els, H.; Celmer, W. D.; Shapiro, B. L.; Woodward, R.
B. J. Am. Chem. Soc. 1960, 82, 3225-3227.
(5) Celmer, W. D. J. Am. Chem. Soc. 1965, 87, 1797-1799.
(6) Ogura, H.; Furuhata, K.; Harada, Y.; Iitaka, Y. J. Am. Chem. Soc. 1978,
100, 6733-6737.
9
12806
J. AM. CHEM. SOC. 2002, 124, 12806-12815
10.1021/ja020853m CCC: $22.00 © 2002 American Chemical Society

Asymmetric Crotylation in Oleandolide Synthesis
A R T I C L E S
Scheme 1. Identification of the Polypropionate Backbone
Scheme 2. Retrosynthetic Analysis of Oleandolide
The macrolide antibiotics encompass a biologically active
class of molecules sharing the characteristics of a macrocyclic
lactone and an amino sugar appendage. Despite the wide variety
of stereochemical and oxidation-state permutations represented
in these molecules, the aglycon precursors to these compounds
are structurally homologous with other polyketide antibiotics,
indicative of their common biosynthetic origins.10 Indeed, each
seco acid of the corresponding aglycon precursors bears
evidence of the individual propionate, acetate, and occasionally
other small carboxylates that are iteratively incorporated into
their respective structures during biosynthesis.11 For instance,
the aglycon of oleandomycin, oleandolide (1), is a macrocyclic
lactone whose polypropionate backbone comprises six propi-
onate subunits and one acetate (Scheme 1). Biosynthetically,
these simple building blocks are assembled in an iterative
fashion through the enzymatic functions performed by polyketide
syntheses and various reductases.12
To the chemical community, the stereochemical and func-
tional group complexity of the polypropionate-derived macrolide
antibiotics poses a formidable challenge for chemical synthesis.
Studies toward the asymmetric synthesis of these natural
products have stimulated the development of a host of new
reactions and concepts for C-C bond construction in the context
of acyclic stereocontrol.13 To date, four syntheses of oleandolide
(1) have been reported independently from Tatsuta’s,14 Pater-
son’s,15 Evans’,16 and our laboratories.17 The first synthesis of
1 by Tatsuta and co-workers was reported in 1990 and employed
a carbohydrate-based approach, and the later two syntheses from
Paterson and Evans both relied on chiral enolate-based bond
construction technology to establish the stereochemical relation-
ships. In 1988 Tatsuta accomplished the bisglycosidation of
oleandolide (1) to provide the natural product oleandomycin,
and thus a synthesis of 1 constitutes a formal total synthesis of
oleandomycin.18 We elected to pursue the synthesis of olean-
dolide to expand the scope and the utility of the double-
stereodifferentiating crotylation methodology recently developed
in our laboratory.19 It was our intention to design a highly
convergent and efficient pathway that could address the selective
installation of the stereogenic centers utilizing our chiral
organosilane reagents.20 The use of these reagents, which bear
C-centered chirality, represents a mechanistically different
approach from the chiral enolate and enolate surrogate meth-
odology often used in the preparation of stereochemically
complex molecules.
Results and Discussion
Synthesis Plan. Our retrosynthetic analysis of oleandolide
(1) is outlined in Scheme 2. Opening of the lactone results in
the generation of an acyclic C1-C14 seco acid. Studies on the
related macrolide antibiotic erythromycin have shown that the
stereochemistry at C9 is critical in determining the efficiency
of macrolactonization reactions used to close the 14-membered
ring: changing the configuration at C9 has a pronounced effect
on the conformations available to the seco acid and hence on
the success of the macrolactonization.13 Although the C9
(10) (a) Hopwood, D. A.; Sherman, D. H. Annu. ReV. Genet. 1990, 24, 37-66.
(b) Hutchinson, C. R.; Fujii, I. Annu. ReV. Microbiol. 1995, 49, 201-238.
(11) Woodward, R. B. Angew. Chem. 1956, 68, 13-20.
(12) (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.
(13) (a) For a review of synthetic efforts in this field see Paterson, I.; Mansuri,
M. M. Tetrahedron 1985, 41, 3569-3624. (b) Mulzer, J. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1452-1454. (c) Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products; Lukas, G., Ed.;
Springer-Verlag: Berlin, 1993; Vol. 2.
(18) Tatsuta, K.; Kobayashi, W.; Gunji, H.; Masuda, H. Tetrahedron Lett. 1988,
29, 3975-3978.
(14) Tatsuta, K.; Ishiyama, T.; Tajima, S.; Xoguchi, Y.; Gunji, H. Tetrahedron
Lett. 1990, 31, 709-712.
(19) (a) Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118,
12475-12476. (b) Panek, J. S.; Cirillo, P. F. J. Org. Chem. Soc. 1993, 58,
294-296. (c) Panek, J. S.; Beresis, R. T. J. Org. Chem. 1993, 58, 809-
811. (d) Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S. Tetrahedron
Lett. 1995, 36, 8727-8730.
(15) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M. A. J.
Am. Chem. Soc. 1994, 116, 11287-11314.
(16) Evans, D. A.; Kim, A. N.; Metternich, R.; Novack, V. J. J. Am. Chem.
Soc. 1998, 120, 5921-5942.
(17) Hu, T.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229-
9230.
(20) For a review, see Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-
1316.
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A R T I C L E S
Hu et al.
Scheme 3. Synthesis of the C1-C7 Subunit
stereocenter would eventually be lost through oxidation to a
ketone, this center, bearing an S configuration, has proved
instrumental in achieving efficient conversion in the macrocy-
clization.15,16 Consequently, the C9 stereocenter was installed
as 9S configuration prior to macrocycle formation.
The exocyclic epoxide at C8 is a unique structual feature of
oleandolide not found in any of the other known macrolide
antibiotics; accordingly, it was envisaged that this sensitive
functionality might be introduced after the macrocyclization.
We reasoned that the re (R) face (bottom) of the exocyclic olefin
might become sterically hindered and resistant to electrophilic
addition if the allylic (9S)-hydroxy is protected by a large
protecting group. Conventional epoxidation with m-CPBA
should provide the desired diastereoisomer by delivering the
electrophile predominantly from the si (â) face of the exocyclic
alkene. Accordingly, the 9S configuration may play a crucial
role not only in efficient macrolactonization but also in the late-
stage substrate-controlled epoxidation. Planning a highly con-
vergent synthesis, C-C bond disconnection of seco acid at C7-
C8 would divide the molecule into two advanced subunits of
similar complexity. The crucial carbon bond formation was
based on a nucleophilic addition of an alkylmetal intermediate
to the C8 aldehyde of the C8-C14 subunit. The required C8
olefin, precursor to the epoxide, will be installed by a phosphorus-
based olefination methodology of the corresponding ketone.
and 2,6-lutidine in CH2Cl2 at -78 °C, followed by (iii)
ozonolysis of the E double bond, successfully afforded 7 in 81%
overall yield (Scheme 3). In the presence of TiCl4, the
condensation between aldehyde 7 and (S)-silane 3 produced the
anti homoallylic alcohol 8 (dr > 30:1 5,6-anti/5,6-syn) with
excellent levels of Felkin induction. In this double stereodif-
ferentiating crotylation reaction, the formation of compound 8
can be rationalized by addition of silane 3 to the si face of the
aldehyde 7 via the normally favored Felkin orientation in the
transition state. The configuration of the silane, and the
stereoelectronic preference for anti SE′ addition, determines the
facial selectivity of the silane reagent, which is translated into
the stereochemistry of the C5 methyl substituent of the product.
Compound 8 was converted to diol 9 in two steps: depro-
tection of the 1,3-diol (HF‚Py) followed by selective protection
of the primary hydroxyl as its tert-butyldiphenylsilyl (TBDPS)
ether gave diol 9 in 92% overall yield. Acetonide formation
between the C3-C5 diol of 9 provided acetonide 10 in nearly
quantitative yield (Scheme 4). Analysis of the three-bond
Having defined a fragment coupling strategy, we focused on
the stereoselective installation of stereogenic centers in the C1-
C14 acyclic polypropionate backbone. The array of alternating
methyl and oxygen groups on the carbon backbone suggested
to us that eight of the stereocenters of oleandolide might be
constructed through four double stereodifferentiating crotylation
using three different chiral silanes.21 The remaining stereocenter
(C13-hydroxy) will be established by a heteroatom-directed
hydride reduction of the corresponding â-hydroxy ketone. The
Lewis acid promoted asymmetric crotylation between these
chiral organosilanes and the requisite chiral aldehydes will be
conducted for the introduction of the required stereogenic
centers.
Synthesis of the C1-C7 Subunit. By employment of chiral
organosilanes, the majority of the stereochemical relationships
were introduced with high levels of selectivity. The synthesis
of the C1-C7 subunit utilized two asymmetric crotylation
reactions for the introduction of the C3-C4 and C5-C6
stereogenic centers. The construction began with an asymmetric
crotylation between the R-methyl aldehyde 5 and silane reagent
(R)-2,21a generating the 3,4-syn homoallylic alcohol 6 in 90%
yield (dr > 30:1 syn:anti; Scheme 3). This syn-selective
crotylation is consistent with an anti-SE′ mechanism.19a,20 The
use of Lewis acids such as TiCl4 (1.2 equiv), in combination
with a silicon-based protecting-group strategy, prevents chelate
formation and helps direct the (R)-silane approach to the si face
of the aldehyde, where the aldehyde adopts the preferred Felkin
rotamer.
1
coupling constants correlating C3-C4 and C4-C5 in the H
NMR spectrum of acetonide 10 revealed small vicinal coupling
values (JH3,H4 ) 1.8 Hz, JH4,H5 ) 2.1 Hz), which is consistent
with syn stereochemistry between C3-C4 and C4-C5 stereo-
genic centers.
Further evidence for this assignment was obtained from the
13C NMR chemical shifts of ketal and methyl groups of the
acetonide carbons of 10 (99.7, 30.0, and 19.5 ppm respectively),
which are in excellent agreement with the values commonly
observed for syn-1,3-diol acetonides (methyl groups resonating
at 19 and 30 ppm). The NMR experiment indicated a lack of
resonance in the regions expected for an anti-1,3-diol acetonide
(25.0 ppm).22 Synthesis of the C1-C7 subunit 12 was completed
Homoallylic alcohol 6 was converted to aldehyde 7 in a three-
step sequence: (i) desilylation with 2% aqueous HCl/MeOH at
room temperature afforded the corresponding diol, and (ii)
t
(22) Rychnovsky and Evans have independently reported reliable 13C NMR
correlation experiments where ppm values of the quaternary carbon atom
of acetonides can be correlated to 1,3-syn or 1,3-anti stereochemical
relationships. (a) Rychnovsky, S. D.; Roger, B.; Yang, G. J. Org. Chem.
1993, 58, 3511-3515 (b) Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 31, 7099-7103.
protection of the resulting diol with Bu2Si(OTf)2 (1.1 equiv)
(21) (a) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N. F.; Panek, J. S.
Org. Synth. 1997, 75, 78-88. (b) Jain, N. F.; Cirillo, P. F.; Schaus, J. V.;
Panek, J. S. Tetrahedron Lett. 1995, 36, 8723-8726.
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Asymmetric Crotylation in Oleandolide Synthesis
A R T I C L E S
Scheme 4. Synthesis and Stereochemistry of the C1-C7 Subunit
Scheme 5. Synthesis of the C8-C14 Subunit
by oxidative cleavage [O3/dimethyl sulfide (DMS)] of the E
double of 10, followed by reduction of the crude aldehyde
(NaBH4), which gave primary alcohol 11 in 92% yield.
Subsequent treatment of this material with PPh3/I2/imidazole23
produced the primary alkyl iodide 12, completing the C1-C7
subunit.
Synthesis of the C8-C14 Subunit. The synthesis of this
subunit began with the syn-selective crotylation of R-silyloxy
acetaldehyde 13 with silane (R)-2. This BF3‚OEt2-promoted
reaction gave diol 14 with high levels of selectivity and installed
the C9 stereocenter (Scheme 5).24 Deprotection of the primary
tert-butyldimethylsilyl ether occurred while the reaction was
warmed from -78 to 0 °C,25 which led to the isolation of diol
14 in 80-82% yield. This diol was protected as its di-TBS ether;
subsequent oxidative cleavage of the double bond (O3/Me2S)
afforded R-methyl aldehyde 15 in 93% yield. This material was
used in a second double stereodifferentiating crotylation reaction
with â-methyl-substituted silane (S)-4.21b Use of a TiCl4-
promoted reaction (CH2Cl2 at -50 °C) produced the 11,12-
anti-homoallylic alcohol 16 (88% yield; dr > 30:1 anti/syn)
with Felkin induction.19a The use of chiral silane 4 permitted
the introduction of a trans-trisubstituted olefin, which was
cleaved under standard ozonolysis conditions to afford the
â-hydroxyketone 17. To confirm the anti stereochemistry
between the newly installed methyl and hydroxyl groups in
compound 16, the â-hydroxyketone 17 was converted to
acetonide 19 in two steps: (i) directed reduction utilizing
catecholborane26 gave syn diol 18, followed by (ii) conversion
of the diol 18 to acetonide 19 by use of 2,2-dimethoxypropane
constant (J ) 10.4 Hz) between H11 and H12, which confirmed
the anti relationship between C11-C12 stereocenters. The 13
C
chemical shifts of the acetonide carbons of 19 are 97.5, 30.4,
and 19.7 ppm, indicative of a syn-diol-derived acetonide.22
The desired anti-diol 20 was obtained by a heteroatom-
directed hydride reduction of â-hydroxyketone 17 with Me4-
NBH(OAc)3.27 This directed reduction afforded the anti-1,3-
diol 20 in 89% yield as a single diastereomer. The C11-C13
anti stereochemical relationship of diol 20 was verified by ana-
lysis of the 13C NMR spectrum of the corresponding acetonide
21. The chemical shifts of the two acetonide methyl groups were
observed at 25.5 and 23.9 ppm, in agreement with values
commonly observed for an anti-1,3-diol acetonide (25.0 ppm).22
With the installation of all the requisite stereogenic centers
of the C8-C14 subunit, we elected to protect the C11,C13 anti-
diol as its benzylidene acetal to achieve an orthogonal protection
(Scheme 6). Accordingly, a thermodynamically controlled
acetalization of the C11,C13 anti-diol 20 with benzaldehyde
dimethyl acetal in the presence of a catalytic amount of CSA
gave, after 12 h, compound 22 as a single stereoisomer. The
primary TBS silyl ether was selectively deprotected with HF‚
Py/pyridine/tetrahydrofuran (THF) [1:2:5 v/v/v; room temper-
ature, 3 h, 96% yield], and the resulting primary alcohol 23
1
with a catalytic amount of p-TsOH. Analysis of the H NMR
spectrum of this acetonide revealed a large vicinal coupling
(23) Corey, E. J.; Pyne, S. G.; Su, W. G. Tetrahedron Lett. 1983, 24, 4883-
4886.
(24) The 9S isomer has been shown to be crucial in the success of the
macrocyclization reaction; see refs 15 and 16 for further discussion.
(25) Due to the low reactivity profile of this reaction, a higher reaction
temperature was required to drive the reaction into completion.
(26) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190-5192.
(27) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560-3578.
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A R T I C L E S
Hu et al.
Scheme 6. Completion of the C8-C14 Subunit
Scheme 7. C7-C8 Bond Formation through Alkyllithium Addition
was converted to chiral aldehyde 24 by oxidation with the
Dess-Martin reagent,28 completing the synthesis of the C8-
C14 subunit.
selective removal of the primary TBDPS protecting group in
the presence of the secondary TBS ether at C9, which presented
potential problems given the complexity and acid liability of
the molecule.31,32 Gratifyingly, the TBDPS group could be
cleanly removed by 1.0 equiv of tetrabutylammonium fluoride
(TBAF) and provided the primary alcohol 28 in 98% yield with
the C9 TBS ether left intact. In the next important reaction
sequence, the benzylidene acetal of 28 was opened regioselec-
tively in the presence of excess diisobutylaluminum hydride
(DIBAL)33 to afford diol 29 in ∼70% yield, which liberated
the C13 secondary hydroxy.
C7-C8 Bond Formation. With the C1-C7 and C8-C14
subunits in hand, the stage was set to explore conditions to
merge the two subunits. Our first experiments centered on the
direct addition of an organometallic species derived from iodide
12 to aldehyde 24. This option would construct the C7-C8
carbon bond while convergently providing the fully function-
alized C1-C14 polypropionate backbone of the macrolide.
Preliminary experiments revealed that simple nucleophiles,
alkyllithium (MeLi), or Grignard reagents (EtMgBr, n-BuMgCl)
cleanly added to substrate 24 at low temperature. However,
attempts to convert 12 into such species were unsuccessful. The
organolithium derived from 12 by halogen-metal exchange with
tBuLi (2.0 equiv) was itself short-lived and operationally difficult
to handle.29 A diethyl ether or THF solution of the organolithium
intermediate could be maintained at low temperature and added
to aldehyde 24, although low yields (15-20%) of the product
were observed. Attempts to transmetalate the organolithium
derived from 12 with MgBr2, CuCN, or CeCl3 prior to addition
of aldehyde 24 led to poor isolated yields, formation of
byproducts, or decomposition of the starting aldehyde.
After considerable effort, we found that in the solvent system
of Bailey and Punzalan30 (pentane/diethyl ether, 3:2 v/v), the
derived alkyllithium intermediate of 12 condensed with aldehyde
24 at -78 °C and gave 25 as a mixture of diastereomeric
alcohols in 50-60% modest yield. This mixture of secondary
alcohols 25 was oxidized to the ketone by use of the Dess-
Martin reagent, providing 26 in 52% yield (two steps from
aldehyde 24; Scheme 7). Having prepared the C1-C14 carbon
backbone of the natural product, further elaboration to the seco
acid was next pursued.
The conversion of diol 29 to seco acid 33 necessarily required
the selective oxidation of the C1-hydroxy to a carboxylic acid
in the presence of the secondary C13 OH group. Recent
literature precedent had indicated that the use of hindered
chlorooxoammonium salts should be ideal for this process.34
The use of stoichiometric oxoammonium chloride salt 30 for
selective oxidation of compound 29 resulted in a complicated
mixture of products. However, in situ generation of the unstable
salt derived from 4-methoxy-2,2,6,6,tetramethylpiperidine-1-
oxyl (4-methoxy-TEMPO) 31 by a catalytic process proved to
be efficient and produced the desired hydroxy aldehyde 32 in
quantitative yield.35 This material was further oxidized by
sodium chlorite to deliver the seco acid 33 in 99% yield.36
Cyclization and Elaboration of the Macrocycle. Macro-
lactonization of the (9S)-TBS ether 33 was effected under
modified Yamaguchi conditions37 to afford macrolide 34 in
(31) For an excellent review on selective deprotection of silyl ethers, see Nelson,
T. D.; Crouch, R. D. Synthesis, 1996, 1031-1069.
(32) For review on protecting-group strategies in organic synthesis, see
Schelhaas, M.; Waldmann H. Angew. Chem., Int. Ed. Engl. 1996, 35, 2056-
2083.
(33) (a) Yamamoto, H.; Maruoka, K. Tetrahedron 1988, 44, 5001-5032. (b)
Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593-
1596.
(34) For recent review, see DeNooy, A. E. J.; Basemer A. C.; VanBekkum, H.
Synthesis 1996, 1153-1174.
(35) (a) Anelli, P. L.; Biffi, C.; Montanarie, F.; Quici, S. J. Org. Chem. 1987,
52, 2559-2562. (b) Ireland, R. E.; Gleason, J. L.; Gegnas, L. D.; Highsmith,
T. K. J. Org. Chem. 1996, 61, 6856-6872.
(36) Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574-5576.
(37) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993. (b) Hikota, M.; Sakurai, Y.; Horita,
K.; Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367-6370. (c) Hikota,
M.; Tone, H.; Horita, K.; Yonemitsu, O. J. Org. Chem. 1990, 55, 7-9.
Synthesis of the Seco Acid. Olefination of ketone 26 was
undertaken to establish the C8 terminal olefin that would serve
as the precursor to the epoxide. Accordingly, Wittig olefination
with triphenylphosphonium methylide (Ph3PdCH2) cleanly
produced the desired alkene 27 in 95% yield (Scheme 8).
Transformation of the C1-alcohol to a carboxylic acid required
(28) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
t
(29) For a review on the halogen-lithium exchange using BuLi, see Bailey,
W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1-23.
(30) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5400-5406.
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Asymmetric Crotylation in Oleandolide Synthesis
A R T I C L E S
Scheme 8. Preparation of Seco Acid
9).39 Higher energy conformations (up to 8 kJ mol-1 above the
ground state) showed a similar local conformation about the
C8 olefin. Furthermore, attempts to introduce the C8-epoxide
on 34 prior the C11-benzyl group removal proved unsuccess-
ful.40 The results of those experiments indicated that, to obtain
a stereoselective epoxidation, the C11 benzyl group of macro-
cycle 34 needed to be removed in order to expose the si face of
the C8 olefin. Unfortunately, all attempts at the debenzylation
of macrocycle 34 failed. The presence of the C8 double bond
in 34 precluded the use of standard hydrogenolysis conditions
for benzyl ether deprotection; while debenzylation via a
dissolving metal reduction (Li or Na/liquid NH3, THF, -78 °C)
reduced the lactone. Furthermore, by use of Freeman’s lithium
di-tert-butylbiphenyl radical anion (LDBB) reagent41 in THF
at -78 °C, the desired alcohol 35 was obtained in modest yields
ranging between 20% and 30%.
Scheme 9. Macrocyclization
At this stage of the synthesis, it became apparent that although
a convergent, stereoselective synthesis of the macrolide 34 had
been developed, the elaboration of this intermediate to complete
the synthesis of oleandolide was likely to be difficult resulting
from late-stage protecting-group manipulations. In addition,
modest yield obtained during the fragment coupling [12 + 24
f 25] and the benzyl ether removal [34 f 35] placed us in a
difficult position to complete the synthesis in seamless manner.
Accordingly, we concluded that a more effective fragment
coupling protocol and protecting-group strategy was necessary
to achieve an efficient synthesis of oleandolide.
quantitative yield (Scheme 9). This cyclization was performed
as a two-step, one-pot procedure whereby an intermediate mixed
anhydride was formed from 2,4,6-trichlorobenzoyl chloride
before treatment with excess N,N-dimethyl-4-aminopyridine
(DMAP).37 This highly efficient cyclization may be attributed
to the preferential closure of the seco acid in which the large
C-9S substituent ultimately can achieve the thermodynamically
more stable pseudoequatorial position on the macrocycle 34.38
Revised Retrosynthetic Analysis. In the revised approach,
the crucial C7-C8 bond formation relied on a Pd(0)-catalyzed
sp3-sp2 cross-coupling reaction between an alkylmetal species
and a vinyl triflate fragment (Scheme 10). The new approach
retains the same C1-C7 subunit 12, and the vinyl triflate 38
would be readily accessible from aldehyde 24.
With the assembly of the macrocycle complete, the synthesis
was nearing the stage for introduction of the last stereogenic
center, the C8 exocyclic epoxide. Depicted as one of the low-
energy conformers of 34, the re (bottom) face of C8 olefin is
illustrated as being blocked by the C9-OTBS group, whereas
the si (top) face was obstructed by the C11-benzyl ether (Scheme
(39) A Monte Carlo MM2 energy minimization protocol was used for these
calculations.
(38) Previous work on the related macrolide antibiotic erythromycin has shown
that the stereochemistry at C9 is critical for the efficiency of macrocy-
clization; see Woodward, R. B., et al. J. Am. Chem. Soc. 1981, 103, 3213-
3215. Also see refs 15 and 16.
(40) When compound 34 was subjected to standard epoxidation conditions (such
as m-CPBA or H2O2/KHCO3), no epoxidation product was detected and
only unchanged starting material was recovered. Also see Table 1.
(41) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924-1930.
9
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A R T I C L E S
Hu et al.
Scheme 10. Revised Synthetic Plan
Scheme 12. Pd(0)-Mediated sp3-sp2 Suzuki Coupling
was oxidized with the Dess-Martin reagent to afford ketone
37 in excellent yield (98% over two steps). The methyl ketone
was then converted to vinyl triflate 38 in 88% yield by trapping
of the potassium enolate with N-phenyltriflimide (PhNTf2,
2.0 equiv), thereby completing the assembly of the C8-C14
subunit.
Scheme 11. Revised Synthesis of the C8-C14 Subunit
Pd(0)-Mediated Fragment Coupling. With the revised
synthesis of the C8-C14 subunit completed, we were in a
position to probe the feasibility of a palladium-catalyzed cross-
coupling reaction between primary iodide 12 and vinyl triflate
38 to effect C7-C8 bond formation. Recently, Suzuki and co-
workers43 have documented the scope and limitations of the
palladium-catalyzed alkyl boronate coupling reactions with
triflates and their synthetic applications. We envisioned that a
Suzuki coupling sequence may be ideally suited for our fragment
coupling, as the required sp3-hybridized organoboron can be
conveniently generated from an alkyllithium (derived from 12)
through Li f B transmetalation.44,45
The cross-coupling process was initiated by an iodine f
t
lithium exchange with BuLi (2.1 equiv, 30 min) followed by
addition of B-methoxy-9-BBN to generate the ate complex 39.45a
Subsequent coupling with vinyl triflate 38 in the presence of
the PdCl2(dppf) catalyst and LiCl additive (3.0 equiv) gave the
desired coupling product 27 in a disappointing 12% isolated
yield, with a large amount of starting vinyl triflate 38 (∼40%)
and homocoupling product (25-30%) also isolated (Scheme
12). In efforts to enhance the reaction efficiency, several
different combinations of bases, palladium sources, and solvent
systems were evaluated; however, only low yields (5-15%) of
product could be obtained.46 The use of higher reaction
temperature or longer reaction times did not improve the yield
of desired coupling product but produced significant decomposi-
tion and increased amount of homocoupling product. Current
mechanistic understanding concerning these cross-coupling
reactions suggest that the low reaction yields obtained from these
Particularly compelling were the mild characteristics of the
palladium-mediated coupling reaction compatible for highly
functionalized cases. Although less structurally complex alkyl-
metal species are known to undergo cross-coupling reactions
with vinyl triflates, the highly functionalized R,â-branched
alkylmetal intermediates have received little attention in complex
molecule and natural product synthesis.42 In that context, the
use of such a modified Negishi-like coupling would allow for
an efficient and highly convergent approach to oleandolide. In
addition, the benzylidene functionality between the C9 and C11
hydroxyls would be manipulated prior to macrocyclization.
Revised Synthesis of the C8-C14 Subunit. Synthesis of
the C8-C14 vinyl triflate fragment began with aldehyde 24
(Scheme 11). The one-carbon homologation of aldehyde 24 to
compound 36 was accomplished by the addition of MeMgBr
(3.0 equiv) at low temperature (-78 °C), which produced
alcohol 36 as a ∼3:1 mixture of diastereomers. The mixture
(43) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-2208.
(44) For recent review on Suzuki coupling, see Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457-2483.
(45) For selected recent synthetic applications of sp3-sp2-type Suzuki coupling
reactions, see (a) Marshall, J.; Johns, B. J. Org. Chem. 1998, 63, 7885-
7892. (b) Meng, D.; Bertinato, P.; Balog, A.; Su, D.; Kamenecka, T.;
Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073-
10092. (c) Johnson, C. R.; Braun M. J. Am. Chem. Soc. 1993, 115, 11014-
11015.
(46) It is worth pointing out that the presence of a stoichiometric amount of
water was necessary for successful cross-coupling reactions. This observa-
tion is consistent with studies previously reported by Johnson and Braun;
see ref 45c.
(42) For reviews on vinyl or aryl triflate chemistry, see (a) Ritter, K. Synthesis
1993, 735-762. (b) Scott, W. J.; McMurry, J. E. Acc. Chem. Res. 1988,
21, 47-54.
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Asymmetric Crotylation in Oleandolide Synthesis
A R T I C L E S
Scheme 13. Pd(0)-Mediated sp3-sp2 Negishi-type Coupling
experiments may be attributed to the slow rate of transmetalation
between the alkyl boronate and the Pd(II) intermediate.44 The
weak σ-donor ligand triphenylarsine (AsPh3) was used to
increase the electrophilicity of the Pd(II) intermediate (there-
fore accelerating the rate-determining transmetalation step);
however, only a slight improvement of the yield (∼20%) was
achieved.47
The poor efficiency of the Suzuki coupling reaction in our
hands prompted us to turn our efforts toward a Negishi-type
coupling, in which an alkylzinc intermediate would be used as
the nucleophilic reaction partner in the sp2-sp3 cross-coupling
reaction.48 The rationale was that the transmetalation of Zn f
Pd would be much faster than the corresponding B f Pd
transformation;49 therefore, higher catalytic turnover and a
cleaner reaction might be achieved. Examination of the literature
precedents indicated that certain unfunctionalized alkylzinc
species can undergo coupling reactions with vinyl triflates;50
however, the palladium(0)-mediated cross coupling between a
functionalized, R,â-branched alkylzinc intermediate and vinyl
triflate had not been documented.
As illustrated in Scheme 13, the alkyllithium reagent derived
from 12 (via I f Li exchange) was transmetalated in situ with
a solution of anhydrous ZnCl2 (3.0 equiv) in THF at -78 °C
for 15 min to afford the sp3-hybridized alkylzinc species 40.
Since this intermediate was not stable at temperatures above 0
°C, it was crucial to use this material directly in the palladium-
catalyzed coupling with vinyl triflate 38 while the reaction
temperature was maintained between -20 and 0 °C. In contrast
to the Suzuki-like reaction, this one-pot sequence involving an
organozinc intermediate sp3-sp2 C-C bond formation afforded
the C1-C14 carbon backbone 27 in 82% yield.51 The remark-
able efficiency of this cross-coupling reaction appears to be a
consequence of the higher reactivity of the alkylzinc species
compared to the organoboronate adduct used in the Suzuki
reaction.
be addressed. The primary C1-TBDPS protecting group of 27
was selectively removed, and the resulting primary alcohol was
oxidized to the corresponding carboxylic acid by use of PDC
(10 equiv, DMF, room temperature),52 affording 41 in 90% yield
(Scheme 13). Selective removal of the benzylidene acetal from
the C11 and C13 oxygens proved to be quite challenging.
Conditions for deprotection (BCl3, FeCl3‚SiO2, FeCl3‚6H2O, I2/
MeOH) were unselective as competing deprotection of the C9-
OTBS and/or C3-C5 acetonide were observed. Furthermore,
reduction by use of dissolving metal (Na/NH3, Li/EtNH2/EtOH)
gave complicated reaction mixtures, and catalytic phase-transfer
hydrogenolysis, with 20% Pd(OH)2 on carbon and cyclohexene
as the hydrogen donor at reflux, did provide the desired product
in a modest 41% yield.53 Under the best conditions identified
thus far, the desired seco acid 42a could be obtained in 83%
yield by use of EtSH/Zn(OTf)2 in CH2Cl2 buffered with
NaHCO3 powder.54 During the course of this reaction, ap-
proximately 8% triol acid 42b was also isolated as a side
product.
Macrocyclization and Epoxidation of C8 Exocyclic Olefin.
The seco acid 42a, bearing the C11-C13 diol, was cyclized
under modified Yamaguchi conditions40 to afford the 14-
membered macrolide 35 in excellent yield. No trace of the
1
undesired 12-membered lactone was detectable by H NMR
spectroscopy (Scheme 14).55 It was postulated that the strong
conformational preference of the seco acid containing a large
substituent at 9S predisposes the dihydroxy acid to cyclize
efficiently. In this case, the 9S-OTBS group eventually achieved
a thermodynamically favored pseudoequatorial position.
The elaboration of macrocycle 35 to oleandolide required the
stereoselective introduction of an epoxide at C8. In this regard,
molecular modeling39 studies suggested that good levels of si
(â) face selectivity could be expected in electrophilic additions
to the C8 alkene of the macrolide, as the bulky allylic TBS
ether blocks the re (R) face of the alkene. Indeed, the crucial
epoxidation with m-CPBA (CH2Cl2, room temperature, 4 h)
turned out to be remarkably selective, affording the â-epoxide
With an efficient approach to the advanced intermediate 27
being established, the final stages of the synthesis could now
(47) The benefits of AsPh3 in the Stille reaction have been well documented;
see Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.
(48) Negishi, E. Acc. Chem. Res. 1982, 15, 340-348.
(52) Corey, E. J.; Schmidt, G.; Tetrahedron Lett. 1978, 5, 399-402.
(53) Hanessian, S.; Liak, T. J.; Vanasse, B. Synthesis 1981, 396-397.
(54) Nicolaou, K. C.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.; Prasad, C.
V. C.; Ogilvie, W. W. Angew. Chem., Int. Ed. Engl. 1990, 30, 300-303.
(55) Although triol acid 42 was isolated as a side product during the de-
protection of the benzylidene, the amount obtained was sufficient to
attempt macrocyclization. When this material was subjected to the identical
macrocyclization conditions used before, a complicated mixture of mono-
lides and diolides was obtained.
(49) Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N.; J.
Am. Chem. Soc. 1987, 109, 2393-2401.
(50) For reviews on organozinc reagents in organic synthesis, see (a) Knochel,
P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188. (b) Erdik, E.
Tetrahedron 1992, 48, 9577-9648.
(51) Although this cross-coupling reaction proceeded well with THF as solvent,
the same reaction in diethyl ether or THF/Et2O was much more sluggish.
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A R T I C L E S
Hu et al.
Table 1. Substrate-Controlled Epoxidation of the C8 Exocyclic Olefin
R
reagent
m-CPBA
m-CPBA
CF3CO3H/NaHCO3
m-CPBA
CF3CO3H/NaHCO3
m-CPBA
CF3CO3H/NaHCO3
solvent
43:8-epi-43a
yieldb (%)
H
CH2Cl2
Et2O
100:0
100:0
100:0
100:0
96:4
89
58
82
28
31
0
benzene
CH2Cl2
benzene
CH2Cl2
benzene
Me
Bn
0
1
a Ratio determined by H NMR analysis of crude sample. b Isolated yield after SiO2 column chromatography.
Scheme 14. Stereoselective Epoxidation
on methoxy-directed cyclopropanations of allylic and homoal-
lylic cyclohexenols. Finally, our attempts to introduce the C8-
epoxide on the C11-benzyl ether of 35 (Scheme 9, substrate
34) were unsuccessful, as no trace of epoxide was detected under
several different epoxidation conditions. These experimental
results are consistent with a steric control approach and
underscore the important role of the remote C11-hydroxy
(methyl ether) as a heteroatom directing group in substrate-
controlled epoxidation.59
At this juncture, the completion of the oleandolide synthesis
required two deprotection steps and the oxidation of the C9-
hydroxyl to the corresponding ketone. The C9 silyl ether of 43
was cleanly removed by use of TBAF (1.5 equiv, THF, room
temperature, 30 min), affording diol 44 in 98% yield. Taking
advantage of the steric nature of tetrapropylammonium perru-
thenate (TPAP),60 the selective oxidation of diol 44 at the C9
hydroxy was accomplished with TPAP/NMO in CH2Cl2 at 0
°C, giving the epoxy ketone 45 in 98% yield (Scheme 15). The
selectivity of this TPAP oxidation is believed to originate from
the positioning of the C11 pseudoequatorial hydrogen into the
center of the macrocycle making it inaccessible in the oxidative
addition step involving the R-C-H bond to the oxo metal
bond.61,62 Finally, deprotection of the C3-C5 acetonide by use
of PPTS in acetone/water (10:1 v/v) under reflux for 30 min
cleanly produced oleandolide 1 in 95% yield,63 which was
obtained as an expected 1:3 mixture of 9-keto and 5,9-hemiacetal
tautomers (Scheme 15). The spectral data and physical properties
[1H and 13C NMR, IR, [R]D, Rf , and high-resolution mass
spectrometry (HRMS)] were identical with the published
data.15,16 As further confirmation of structure, the triacetate
derivative 46 was prepared and its properties proved to be
identical to the published analytical data as well.15,16
43 as a single diastereomer in excellent yield (Table 1).56 This
reaction is perhaps a nice illustration of the Henbest principle
as it translates to a 14-membered macrolide in a transannular
epoxidation reaction.57 Interestingly, in the absence of the
directing influence of the hydroxy group, the epoxidation of
the methyl ether version of 35 proceeded at a much slower rate
(room temperature, 24 h) and only ∼30% yield could be
achieved. As suggested by a reviewer, the reduced reaction rate
and efficiency observed in the epoxidation of the methyl ether
version may simply reflect the branched nature of the methyl
ether relative to a hydroxyl group. This notion is supported by
the early work of Chan and Rickborn58 concerning their results
(58) (a) Chan, J. H.-H.;.; Rickborn, B.. J. Am. Chem. Soc. 1968, 90, 6406-
6411. (b) Staroscik, J. A.; Rickborn, B. J. Org. Chem. 1972, 37, 738-740.
(59) For a review on heteroatom substrate-directed reactions, see Hoveyda, A.
H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(60) For a review on TPAP/NMO oxidation protocol, see Ley, S. V.; Norman,
J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639-666.
(61) For a mechanistic discussion of the TPAP-catalyzed oxidation, see Lee,
D. G.; Congson, L. N. Can. J. Chem. 1990, 68, 1774-1779.
(62) For the first selective oxidation with chromic acid on a related erythrolide
B analogue, see Corey, E. J.; Melvin, L. S. Tetrahedron Lett. 1975, 929-
932.
(56) The stereochemical assignment of epoxide 43 was made by measurement
and analysis of 1H NMR three-bond coupling constants and analysis and
nuclear Overhauser effect (NOE) experiments.
(63) Other reaction conditions (5% Rh on carbon/H2/EtOH; FeCl3‚6H2O) proved
unsuccessful as the C8 epoxide opening and/or decomposed products were
obtained.
(57) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1959, 1968-1965.
9
12814 J. AM. CHEM. SOC. VOL. 124, NO. 43, 2002

Asymmetric Crotylation in Oleandolide Synthesis
A R T I C L E S
Scheme 15. Completion of the Total Synthesis of Oleandolide
Conclusion
of the carbon backbone of oleandolide. On balance, the
asymmetric crotylation methodology offers a promising and
mechanistic complementary alternative to aldol- and aldol
surrogate-based approaches to these natural products.
A convergent enantioselective synthesis of oleandolide has
been achieved in 32 steps (20 steps longest linear sequence)
and 16.3% overall yield. Since the two sugar units have been
previously introduced onto oleandolide by Tatsuta’s group,14
this work also constitutes a formal total synthesis of oleando-
mycin.
Key features of the synthesis include high levels of selectivity
in the crotylation reactions used to establish seven out of 10
stereogenic centers. An apparent transannular heteroatom-
directed epoxidation reaction of the C8 olefin, assisted by the
C11-â-OH, was used for the introduction of the 8R epoxide.
Also of note is the use of a underdeveloped Negishi-type sp3-
sp2 fragment coupling reaction between a functionalized alkyl-
zinc intermediate 40 and vinyl triflate 38 for the construction
Acknowledgment. We are grateful to Professor David A.
Evans and Dr. Annette S. Kim (Harvard University) and to Dr.
Nareshkumar F. Jain (R. W. Johnson PRI) for helpful discus-
sions. Financial support was obtained from NIH (GM55740).
Supporting Information Available: Complete experimental
procedures and spectral characterization of all intermediates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA020853M
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J. AM. CHEM. SOC. VOL. 124, NO. 43, 2002 12815