Total synthesis of the actin-depolymerizing agent (-)-mycalolide A: Application of chiral silane-based bond construction methodology

Article abstract of DOI:10.1021/ja002377a

A highly convergent asymmetric synthesis of the actin-depolymerizing agent (-)-mycalolide A has been achieved through the assembly and union of the C1-C19 trisoxazole fragment 2 and the C20-C35 aliphatic fragment 3, respectively. The C1-C19 fragment 2 was

Full text of DOI:10.1021/ja002377a

11090
J. Am. Chem. Soc. 2000, 122, 11090-11097
Total Synthesis of the Actin-Depolymerizing Agent (-)-Mycalolide
A: Application of Chiral Silane-Based Bond Construction
Methodology
James S. Panek* and Ping Liu
Contribution from the Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue, Boston, Massachusetts 02215
ReceiVed June 30, 2000
Abstract: A highly convergent asymmetric synthesis of the actin-depolymerizing agent (-)-mycalolide A has
been achieved through the assembly and union of the C1-C19 trisoxazole fragment 2 and the C20-C35
aliphatic fragment 3, respectively. The C1-C19 fragment 2 was constructed via a Kishi-Nozaki coupling
between the C1-C6 subunit 4 and the C7-C19 subunit 5, which in turn was obtained from a highly
stereoselective crotylation reaction of silane (S)-7 with trisoxazole aldehyde 8. The synthesis of the C20-C35
fragment 3 has been accomplished using chiral silane-based bond construction methodology for the introduction
of the stereochemical relationships. Union of the advanced intermediates 2 and 3 through a Schlosser-Wittig
protocol, macrocyclization utilizing Yamaguchi conditions, and subsequent functional group adjustments
completed the total synthesis of (-)-mycalolide A. The synthesis confirms the relative and absolute
stereochemistry of (-)-mycalolide A, as well as illustrates the application of chiral silane-based C-C bond
construction methodology to the asymmetric synthesis of complex molecules.
Introduction
During the course of a search for bioactive metabolites from
marine invertebrates, Fusetani and co-workers reported the
isolation and planar structure of (-)-mycalolide A (1), a new
secondary metabolite produced by a sponge of the genus
Mycale.1 This marine macrolide belongs to an emerging class
of trisoxazole-containing natural products, which include ul-
apualides,2 kabiramides,3 halichondramides,4 and jaspisamides.5
These natural products display a wide range of biological
activities, such as antifungal, antileukemic, and ichthyotoxic
properties. Mycalolide A exhibits potent antifungal activity
against a diverse array of pathogenic fungi and cytotoxicity
toward B-16 melanoma cells with IC50 values of 0.5-1.0 ng/
mL.1 Interest in mycalolide A was further heightened by its
reported ability to selectively inhibit the actomyosin Mg2+
-
ATPase.6 In that regard, it has been suggested that mycalolide
A acts as an actin-depolymerizing agent which may find
eventual applications in pharmacology as a probe of actin-
mediated cell functions, such as muscle contraction, cell motility,
and cell division.7 This activity profile is similar to that of
scytophycin B, a related natural product isolated from the
Figure 1. The mycalolide family.
cultures of a terrestial blue-green algae.8 Other natural products
exhibiting the same mechanism of action include latrunculins,9
swinholides,10 and aplyronins.11
Recently the relative and absolute stereochemistry of my-
calolides (Figure 1) has been determined through a combination
(1) Fusetani, N.; Yasumuro, K.; Matsunaga, S.; Hashimoto, K. Tetra-
hedron Lett. 1989, 30, 2809-2812.
(2) Roesener, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1986, 108, 846-
847.
1
of chemical degradation, extensive H and 13C NMR analysis,
and structural correlation experiments.12 Mycalolide A, as well
(3) (a) Matsunaga, S.; Fusetani, N.; Hashimoto, K. J. Am. Chem. Soc.
1986, 108, 847-849. (b) Matsunaga, S.; Fusetani, N.; Hashimoto, K.;
Koseki, K.; Noma, M.; Noguchi, H.; Sankawa, U. J. Org. Chem. 1989, 54,
1360-1363.
(8) Smith, C. D.; Carmeli, S.; Moore, R. E.; Patterson, G. M. L. Cancer
Res. 1993, 53, 1343-1347.
(9) Ayscough, K. R.; Stryker, J.; Pokala, N.; Sanders, M.; Crews, P.;
Drubin, D. G. J. Cell Biol. 1997, 137, 399-416 and references therein.
(10) Bubb, M. R.; Spector, I.; Bershadsky, A. D.; Korn, E. D. J. Biol.
Chem. 1995, 270, 3463-3466.
(11) Suenaga, K.; Kamei, N.; Okugawa, Y.; Takagi, M.; Akao, A.;
Kigoshi, H.; Yamada, K. Bioorg. Med. Chem. Lett. 1997, 7, 269-274 and
references therein.
(12) Matsunaga, S.; Liu, P.; Celatka, C. A.; Panek, J. S.; Fusetani, N. J.
Am. Chem. Soc. 1999, 121, 5605-5606.
(4) Kernan, M. R.; Molinski, T. F.; Faulkner, J. D. J. Org. Chem. 1988,
53, 5014-5020.
(5) Kobayashi, J.; Murata, O.; Shigemori, H. J. Nat. Prod. 1993, 56,
787-791.
(6) Hori, M.; Saito, S.; Shin, Y.; Ozaki, H.; Fusetani, N.; Karaki, H.
FEBS Lett. 1993, 322, 151-154.
(7) Saito, S.; Watabe, S.; Ozaki, H.; Fusetani, N.; Karaki, H. J. Biol.
Chem. 1994, 269, 29710-29714.
10.1021/ja002377a CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/01/2000

Synthesis of (-)-Mycalolide A
J. Am. Chem. Soc., Vol. 122, No. 45, 2000 11091
Figure 2. Retrosynthetic analysis of mycalolide A (1).
as other related marine macrolides, is constructed around a 28-
membered lactone which incorporates a trisoxazole subunit
linked by σ bonds, and an 11-carbon, polyketide side chain
terminating with an N-methyl-N-alkenylformamide moiety.
These unique structural features, together with their diverse
biological activities, have motivated a number of research groups
to develop synthetic strategies.13 In that regard, we viewed
mycalolide A as an ideal synthetic target for several reasons.
First, since a total synthesis had not yet been reported for any
member of the trisoxazole-containing natural products,14
a
synthesis would constitute a meaningful contribution. Second,
mycalolide A was identified as a suitably complex target to
expand the scope of our asymmetric crotylation methodology.
Finally, in view of the ambiguity over the stereochemical
assignment of mycalolides and other related trisoxazole-contain-
ing natural products (cf. ulapualides and kabiramides), a
definitive assignment of stereochemistry could be made. Herein
we report a detailed account of our efforts that culminated in
the first total synthesis of mycalolide A.15
Synthetic Plan
The synthetic plans developed for mycalolide A were guided
by the structural features of the molecule as well as our intention
to extend the utility of chiral silane-based bond construction
methodology. Through cleavage of the macrolide linkage and
the C19-C20 olefin bond, mycalolide A (1) was divided into
two primary fragments of comparable complexity (Figure 2).
These disconnections revealed the C1-C19 trisoxazole fragment
2 and the C20-C35 aliphatic fragment 3, union of which was
envisaged via a Schlosser-Wittig olefination16 followed by
macrocyclization to form the 28-membered lactone.
Figure 3. Retrosynthetic analysis of the C1-C19 fragment 2.
direction, this bond construction corresponds to a Stille-type
cross coupling17 or a CrCl2/NiCl2-mediated Kishi-Nozaki-type
coupling.18 We had envisioned that the stereogenic center in
subunit 4 could be accessed by a hydrolytic kinetic resolution
(HKR) of terminal epoxide 6,19 and the anti stereochemical
relationship at the C8 and C9 in subunit 5 would be established
with a chelation-controlled anti crotylation using a chiral silane
reagent.20,21
The retrosynthetic analysis of the C20-C35 aliphatic frag-
ment 3 is outlined in Figure 4. After functional group adjust-
ments, disconnection of 9 at C29-C30 was considered feasible,
since this operation would divide the molecule into two similar
segments, the C20-C29 subunit and the C30-C35 subunit.
These two advanced intermediates were desirable since the
stereochemical relationships could be installed by asymmetric
crotylation reactions.13f In particular, the two pairs of syn
stereogenic centers at C22/C23 and C26/C27 in subunit 10
would be established through two syn crotylation reactions,
while the remaining oxygenated stereogenic center would be
Further disconnection of fragment 2 at the C6-C7 σ bond
led to two smaller subunits, 4 and 5 (Figure 3). In the synthetic
(13) For earlier synthetic studies on related trisoxazoles, see (a) Knight,
D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 36-37. (b) Kiefel, M.
J.; Maddock, J.; Pattenden, G. Tetrahedron Lett. 1992, 33, 3227-3230. (c)
Pattenden, G. J. Heterocycl. Chem. 1992, 29, 607-618. (d) Yoo, S.-K.
Tetrahedron Lett. 1992, 33, 2159-2162. (e) Chattopadhyay, S. K.;
Pattenden, G. Tetrahedron Lett. 1995, 36, 5271-5274. (f) Panek, J. S.;
Beresis, R. T.; Celatka, C. A. J. Org. Chem. 1996, 61, 6494-6495. (g)
Panek, J. S.; Beresis, R. T. J. Org. Chem. 1996, 61, 6496-6497. (h) Liu,
P.; Celatka, C. A.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5445-5448. (i)
Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449-
5452. (j) Chattopadhyay, S. K.; Pattenden, G. Synlett 1997, 1342-1344.
(k) Chattopadhyay, S. K.; Pattenden, G. Synlett 1997, 1345-1348. (l) Liu,
P.; Panek, J. S. Tetrahedron Lett. 1998, 39, 6143-6146. (m) Liu, P.; Panek,
J. S. Tetrahedron Lett. 1998, 39, 6147-6150. (n) Kempson, J.; Pattenden,
G. Synlett 1999, 533-536.
(14) A total synthesis of one diastereomer of ulapualide A has been
reported; see: (a) Chattopadhyay, S. K.; Pattenden, G. Tetrahedron Lett.
1998, 39, 6095-6098. (b) Ulapualide: Chattopadhyay, S. K.; Pattenden,
G. J. Chem. Soc., Perkin Trans. 1, 2000, 15, 2429-2454. (c) Trisoxazole:
Rippon, D. E.; Waite, D. J. Chem. Soc., Perkin Trans. 1 2000, 15, 2415-
2428.
(15) Preliminary communication: Liu, P.; Panek, J. S. J. Am. Chem.
Soc. 2000, 122, 1235-1236.
(16) (a) Schlo¨sser, M.; Schaub, B. J. Am. Chem. Soc. 1982, 104, 5821-
5823. (b) For a review on Wittig reaction, see: Maryanoff, B. E.; Reitz, A.
B. Chem. ReV. 1989, 89, 863-927.
(17) (a) For a review, see: Stille, J. K. Angew. Chem., Int. Ed. Engl.
1986, 25, 508-524. (b) For a monograph on Stille coupling, see: Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
(18) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644-5646. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima,
K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048-6050.
(19) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936-938.
(20) For a review, see: Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95,
1293-1316.
(21) For literature precedent of anti crotylation, see: (a) Liu, P.; Panek,
J. S. Tetrahedron Lett. 1998, 39, 6143-6146. (b) Masse, C. E.; Panek, J.
S. Angew. Chem., Int. Ed. 1999, 38, 1093-1095.

11092 J. Am. Chem. Soc., Vol. 122, No. 45, 2000
Panek and Liu
Recently, an assortment of useful chiral synthons has been
made available as a result of advances in the area of asymmetric
catalysis.26 We were interested in the possibility of incorporating
the catalytic asymmetric strategies into our synthesis, and
envisioned that the stereogenic center in the C1-C6 subunit
could be established using Jacobsen’s HKR of terminal ep-
oxides.19 Bearing in mind the protecting group strategy, tert-
butyl 3,4-epoxybutanoate (6) was chosen as the starting point
of the new synthetic sequence (Scheme 2). Thus, the synthesis
of 4 was initiated by a HKR of the readily available racemic
epoxide 6,27 providing (R)-6 with 99% ee in 94% yield.28
Nucleophilic opening of the resolved epoxide using higher order
cuprate 1629 provided homoallylic alcohol 17 in 76% yield.
Protection of the free hydroxyl as its TBDPS ether followed
by stannane-iodine exchange completed the sequence to subunit
4 (four steps, 61% overall yield).
The advantage of this approach to 4 is that there are no
undesired stereochemical products. The C1 oxidation state is
set, since the product, after conversion of the tert-butyl ester to
the carboxylic acid, would be ready for macrolide formation.
Synthesis of the C7-C19 Subunit. The synthesis of this
subunit centers on the installation of the C8/C9 anti relationship
through a stereoselective crotylation reaction of silane (S)-7 and
trisoxazole aldehyde 8. Previous studies from our laboratory
concerning the reaction of the (E)-crotylsilanes with unfunc-
tionalized, achiral aldehydes have demonstrated universal syn
selectivity in the formation of homoallylic alcohols30 and
ethers.31 The stereochemical outcome of these crotylation
reactions can be explained by an anti-SE mechanism32 in which
the absolute stereochemistry of the newly formed methyl-bearing
center is controlled by the chirality of the silane reagent. In the
cases of double stereodifferentiating condensation reactions
between (E)-crotylsilane reagents and chiral, heterosubstituted
aldehydes, anti bond constructions could be achieved.22 Once
again, the chirality of the methyl-bearing center was determined
by the orientation of the C-SiR3 bond, while the configuration
of the hydroxy-bearing center can be rationalized through Felkin
induction33 or through Cram chelation.34
Figure 4. Retrosynthetic analysis of the C20-C35 fragment 3.
Scheme 1
constructed by substrate-controlled 1,3-anti induction. Inspection
of the C30-C35 subunit revealed an anti-anti stereochemical
triad which, we anticipated, could be installed through a double
stereodifferentiating anti crotylation reaction, a valuable exten-
sion of syn crotylation bond construction recently developed
in our laboratories.22 In the following discussion, the successful
implementation of our synthetic plan is detailed.
Results and Discussion
Synthesis of the C1-C6 Subunit. Our initial approach to
the C1-C6 subunit utilized commercially available (R)-1,2,4-
butanetriol as the source of C3 chirality (Scheme 1). Selective
Accordingly, the use of a bidentate Lewis acid (such as TiCl4)
and the condensation between trisoxazole aldehyde 813h and
silane (S)-7,35 in analogy with the reaction of monooxazole
aldehyde and the (S)-silane reagent,36 would provide a homoal-
t
protection of the 1,3-diol was cleanly achieved with Bu2Si-
(OTf)2/2,6-lutidine in CH2Cl2/DMF (1:1 v/v) and afforded the
primary alcohol 12 in 86% yield. This material was subjected
to a Swern oxidation (oxalyl chloride, DMSO, Et3N, -78 °C
to room temperature)23 to provide aldehyde 13. This aldehyde
was homologated to the five-carbon aldehyde 14 through a two-
step process: one-carbon homologation with (methoxymethyl)-
triphenylphosphonium ylide and hydrolysis of the resulting enol
ether with Hg(OAc)2.24 The C1-C6 subunit was completed
using Takai’s CrCl2-mediated olefination protocol,25 furnishing
(E)-vinyl iodide 15 (E:Z ) 6:1) in 74% yield.
Although the described approach to 15 was acceptable in
terms of overall yield, there were two drawbacks. First, the Takai
olefination provided modest selectivity (E:Z ) 6:1), and in our
hands the E/Z olefin isomers could not be separated by SiO2
chromatography. Second, the requirement of a carboxylate at
C1 necessitated a late-stage oxidation.
(26) (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. ComprehensiVe
Asymmetric Catalysis; Springer: New York, 1999; Vols. 1-3. (b) Ager,
D. J., Ed. Handbook of Chiral Chemicals; Marcel Dekker: New York, 1999.
(c) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH Publishers: New
York, 1993. (d) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1989.
(27) Racemic 6 was prepared by epoxidation of tert-butyl vinylacetate
with m-CPBA, which was in turn prepared according to the procedure
described in Ozeki, T.; Kusaka, M. Bull. Chem. Soc. Jpn. 1966, 39, 1995-
1998.
(28) The kinetic resolution yield is expressed as a percentage of the
theoretical maximum yield of 50%; the ee was determined by HPLC analysis
of the phenylthio derivatives of 6 with a Chiracel OD column.
(29) Behling, J. R.; Ng, J. S.; Babiak, K. A.; Campbell, A. L.; Elsworth,
E.; Lipshutz, B. H. Tetrahedron Lett. 1989, 30, 27-30.
(30) Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 294-296.
(31) Panek, J. S.; Beresis, R. T.; Xu, F.; Yang, M. J. Org. Chem. 1991,
56, 7341-7344.
(32) Hayashi, T.; Konishi, M.; Ito, H.; Kumada, M. J. Am. Chem. Soc.
1982, 104, 4962-4963.
(33) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199-2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61-
70.
(22) (a) Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996,
118, 12475-12476. (b) Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S.
Tetrahedron Lett. 1995, 36, 8727-8730. (c) Panek, J. S.; Beresis, R. T. J.
Org. Chem. 1993, 58, 809-811.
(23) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(24) Maercker, A. Org. React. 1965, 14, 270-490.
(25) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(34) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748-
2755. (b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468.
(35) For preparation of (S)-7, see: Panek, J. S.; Yang, M. G.; Solomon,
J. J. Org. Chem. 1993, 58, 1003-1010.
(36) Panek, J. S.; Liu, P. Tetrahedron Lett. 1998, 39, 6147-6150.

Synthesis of (-)-Mycalolide A
J. Am. Chem. Soc., Vol. 122, No. 45, 2000 11093
Scheme 2
Table 1. Lewis Acid Promoted Addition of Silane 7 to Aldehyde 8
dr of
yield of
yield of
entry
Lewis acid
conditionsa
18 and 19b
18c (%)
19c (%)
1
2
3
4
5
TiCl4
TiCl4
SbCl5
SnCl4
SnCl4
-78 to -50 °C, 12 h
>30:1
>30:1
>30:1
>30:1
>30:1
99
0
30
50
30
0
65
13
0
-78 °C to room temperature, 24 h
-78 to -50 °C, 12 h
-78 to -50 °C, 12 h
-78 °C to room temperature, 12 h
10
1
a All reactions were run in CH2Cl2. b Diastereoselection was determined by H NMR analysis of the crude products. c Yields refer to pure
materials isolated after chromatography on SiO2.
Scheme 3
lylic alcohol with an anti bond construction.36 The results of
these experiments are summarized in Table 1.37 At low
temperatures (<-50 °C), tetrahydrofuran 18 was the dominant
product formed; upon warming, the tetrahydrofuran underwent
ring opening to give anti homoallylic alcohol 19 (entries 1 and
2). Of the Lewis acids examined, freshly distilled TiCl4
performed the best. These reaction conditions allowed quantita-
tive formation of tetrahydrofuran at -50 °C and upon warming
to room temperature promoted ring opening to 19 in 65% yield.
Other less effective Lewis acids, such as SbCl5 and SnCl4, are
shown in Table 1 (entries 3-5).
Earlier reports from these laboratories have documented the
formation of tetrahydrofurans in reactions of chiral silane
reagents to aldehydes.38 For this process, we have postulated
that the initial asymmetric C-C bond construction occurs by
an anti-SE′ mode of addition and the emerging â-silyl carboca-
tion is stabilized through the σ f π conjugation of the adjacent
C-Si bond. A 1,2-cationic silyl group migration then proceeds
via a bridged cation, followed by heterocyclization, producing
tetrahydrofuran 18 (Scheme 3). The relative stereochemical
outcome of this condensation reaction could be accounted for
through a synclinal transition state, where a bidentate Lewis
acid coordinates to the aldehyde carbonyl and the oxazole
nitrogen to form a five-membered chelate, which results in a
turnover of the aldehyde π-facial selectivity to deliver an anti
stereochemical relationship.
Consequently, reaction conditions for the conversion of tet-
rahydrofuran 18 to homoallylic alcohol 19 were evaluated. For
the Lewis acids surveyed, BF3‚OEt2 was most effective,
affording clean furan opening. All other Lewis acids surveyed,
including TiCl4, SnCl4, and SbCl5, gave complex reaction
mixtures. Accordingly, BF3‚OEt2 was used to effect the conver-
sion of tetrahydrofuran 18 to homoallylic alcohol 19; however,
to obtain complete coversion to 19, the starting furan was
recycled three times. In this way, homoallylic alcohol 19 could
be obtained in a combined 90% yield.
With the C8/C9 anti stereochemical relationship established,
the synthesis of the C7-C19 subunit 5 was completed. A
straightforward three-step sequence was used: methylation of
alcohol 19 with Ag2O/MeI,39 dihydroxylation of olefin 20 with
OsO4/TMANO,40 and cleavage of the resulting diol with Pb-
(OAc)4 provided aldehyde 5 (Scheme 4).
Although tetrahydrofuran 18 was produced in nearly quantita-
tive yield in the presence of TiCl4, direct formation of the desired
homoallylic alcohol 19 could only be achieved in modest yield.
(37) The absolute stereochemistry of 18 and 19 was based on an anti-
SE′ addition mode. The relative stereochemistry of 18 was assigned in
correlation with 19, whose anti stereochemical relationship was secured by
Construction of the C6-C7 Bond. The carbon backbone
of the C1-C19 fragment was assembled by joining the C1-
3
measuring the JHa,Hb value (10.8 Hz) of the derived acetonide; see the
Supporting Information for experimental details.
(38) (a) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 26, 9868-
9870. (b) Beresis, R. T.; Panek, J. S. Bioorg. Med. Chem. Lett. 1993, 3,
1609-1613.
(39) Greene, A. E.; Drian, C. L.; Grabbe, P. J. Am. Chem. Soc. 1980,
102, 7583-7584.
(40) VanRheenen, V.; Kelley, R. C.; Cha, D. J. Org. Chem. 1978, 43,
2480-2482.

11094 J. Am. Chem. Soc., Vol. 122, No. 45, 2000
Panek and Liu
Scheme 4
Scheme 7
Scheme 5
Scheme 8
Scheme 6
and the C7-C19 subunit 5b, provided the desired allylic alcohol
24 in 80% yield, as a 1:1 mixture of the stereoisomers (Scheme
7). This material was oxidized to enone 29 using Dess-Martin
periodinane (Scheme 7).41 Selective deprotection of the primary
n
TBDPS ether with Bu4NF (1 equiv), followed by conversion
C6 and C7-C19 subunits (Scheme 5). In this reaction sequence,
however, the Pd-mediated cross coupling reaction of organotin
4a and acid chloride 5a turned out to be quite problematic. After
numerous experiments with different Pd sources, including Pd-
(PPh3)4, (PPh3)2PdCl2, Pd2(dba)3, and PhCH2Pd(Cl)(PPh3)2, it
was found only Pd2(dba)3 (toluene, Et3N, 35 °C) could deliver
the desired product 21, and in less than 10% yield. We then
turned our attention to a NiCl2/CrCl2-mediated coupling of
aldehydes and iodoolefins developed by Kishi and Nozaki.18
The nickel-chromium-mediated coupling between vinyl iodide
15 and aldehyde 5b was examined first to determine the precise
conditions for this transformation. As illustrated in Scheme 6,
the optimal procedure developed for this model system entailed
treatment of 15 and 5b in THF/DMF (3:1 v/v) with NiCl2/CrCl2
at room temperature, affording the coupling product 22 in 92%
yield, as roughly a 1:1 mixture of the allylic alcohol isomers.
Dess-Martin oxidation of alcohol 22 provided enone 23 in
nearly quantitative yield.41
of the resulting alcohol 25 to bromide 26 (CBr4/PPh3) and
hydrolysis of the tert-butyl ester with TFA, completed the
synthesis of the C1-C19 fragment 2.
Synthesis of the C20-C29 Subunit. In accord with a
previous report from this laboratory,13f the synthesis of the C20-
C29 subunit was initiated by a condensation reaction between
aldehyde 27 and (S)-silane 28 (2.0 equiv) in the presence of
TiCl4 (1.2 equiv, -78 °C, 8 h), affording homoallylic alcohol
29 in 88% yield (Scheme 8). O-Methylation of 29 with Me3-
OBF4 (6.0 equiv) and Proton Sponge (6.0 equiv) gave homo-
allylic ether 30 in 87% yield. Oxidative cleavage of the olefin
under standard ozonolysis conditions gave the expected alde-
hyde, which was immediately subjected to a Takai olefination25
to provide subunit 10 in 83% yield (two steps).
(41) (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.
For two improved procedures for the preparation of DMP, see: (c) Ireland,
R. E.; Liu, J. J. Org. Chem. 1993, 58, 2899. (d) Meyers, S. D.; Schreiber,
S. L. J. Org. Chem. 1994, 59, 7459-7552.
Under reaction conditions established for the model system,
the coupling of the actual intermediates, the C1-C6 subunit 4

Synthesis of (-)-Mycalolide A
J. Am. Chem. Soc., Vol. 122, No. 45, 2000 11095
Scheme 9
Scheme 10
Synthesis of the C30-C35 Subunit. The synthesis of the
C30-C35 subunit 11 centers on the installation of the anti-
anti stereochemical triad. This stereochemical relationship was
constructed with a double stereodifferentiating crotylation
reaction of (R)-3-(benzyloxy)-2-methylpropional (31) with silane
(S)-32 (Scheme 9).13f,22 In the presence of TiCl4 (1.2 equiv)
this anti-selective crotylation proceeded through a chelate-
controlled transition state to give homoallylic alcohol 33 (anti:
syn ) 15:1) in 79% yield, thus introducing the required
stereochemical relationship for subunit 11. Removal of the
benzyl group was effected by BCl3 (2 equiv), providing the 1,3-
diol 34 in 90% yield.42 Protection of the derived 1,3-diol
(PMBCHO, 1.3 equiv; catalytic p-TsOH) afforded the p-
methoxybenzylidine acetal 35 (89%), which was subjected to
nucleophilic opening (DIBAL-H, 5.0 equiv; CH2Cl2; -50 °C;
14 h) to give primary alcohol 36 in quantitative yield as a single
diastereomer. Oxidation of the alcohol using Dess-Martin
periodinane provided aldehyde 37 in 98% yield.41 A one-carbon
homologation with (methoxymethyl)triphenylphosphonium ylide
resulted in the formation of enol ether 38 (E:Z ) 1:1), which
was directly converted to the C35 acetal by 2,2-dimethyl-1,3-
propanediol and a catalytic amount of PPTS (74% from 37).
Cleavage of the trans-olefin under standard ozonolysis condi-
tions afforded aldehyde 11 in 77% yield, thus completing the
synthesis of the C30-C35 subunit.
Synthesis of the C20-C35 Fragment. After the C20-C29
and C30-C35 subunits were synthesized, their union would
assemble the backbone of fragment 3 (Scheme 10). This bond
construction was achieved through a Nid2-CrCl2-mediated
coupling reaction.18 We had learned that a successful outcome
of this coupling reaction was highly dependent on solvent
combination. During the course of these coupling experiments,
we learned that the combination THF/DMSO (3:1 v/v) gave
the best results. When subunits 10 and 11 were treated with
NiCl2-CrCl2 in THF/DMSO (3:1 v/v), coupling product 9 was
obtained in 88% yield as a 1:1 mixture of the alcohol
diastereomers. This mixture of alcohols was converted to
ketoaldehyde 40 by a three-step process: catalytic hydrogenation
of the olefin with PtO2/H2,43 removal of the pivaloate with
DIBAL-H,44 and oxidation of the resulting diol with Dess-
Martin periodinane.41 This three-step sequence provided 40 as
a single diastereomer in 90% yield. Completion of the synthesis
of fragment 3 was accomplished by deprotection of the PMB
group using DDQ45 and installation of an acetyl group at the
C32 hydroxyl.
(43) Rylander, P. N. Hydrogenation Methods; Academic Press: New
York, 1985; pp 41-44.
(44) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453-461.
(45) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888.
(46) (a) Zhao, Z.; Scarlato, G. R.; Armstrong, R. W. Tetrahedron Lett.
1991, 32, 1609-1612. (b) Ogawa, A. K.; DeMattei, J. A.; Scarlato, G. R.;
Tellew, J. E.; Chong, L. S.; Armstrong, R. W. J. Org. Chem. 1996, 61,
6153-6161.
(42) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc.
1989, 111, 1923-1925.

11096 J. Am. Chem. Soc., Vol. 122, No. 45, 2000
Panek and Liu
Table 2. Results of the Olefination Reaction between 26 and 40
entry
conditionsa
result
1
2
3
4
5
6
nBu3P/DMF; LDA (1.0 equiv)
<10%
<10%
decomposition
decomposition
no desired product
93%
nBu3P/DMF; KHMDS (1.0 equiv)
3P/DMF; KOtBu (1.0 equiv)
Et
(EtO)3P, reflux; KHMDS (1.0 equiv)b
(EtO)3P, reflux; LiCl (1.2 equiv); DBU (1.2 equiv)c
Et3P/DMF; DBU (1.0 equiv)
a All the reactions were run under an argon atmosphere. b Distilled THF was the reaction solvent. c The reaction was run in acetonitrile.
Scheme 11
Fragment Coupling. Having established viable routes to the
advanced intermediates 2 and 3, the critical fragment coupling
via a Schlo¨sser-Wittig16 protocol was investigated. During the
planning stages of this synthesis, the task of achieving a union
between 2 and 3 with a phosphorus-based olefination was not
regarded as a difficult one. We were optimistic however, given
the precedents set by Armstrong46 and Evans,47 who successfully
constructed an (E)-olefinated monooxazole in their calyculin
syntheses. We had also established precedence in model studies
of the construction of the trisoxazole (E)-olefin by a similar
protocol.13i However, this Wittig reaction proved to be extremely
challenging, and our results concerning the olefination reaction
between intermediates 26 and 40 are summarized in Table 2.
Conventional bases such as LDA, KHMDS, and KOtBu with
different solvent systems including DMF, THF, and their
combinations (not shown) failed to deliver a synthetically useful
yield of the desired product. Then recourse was made to a
Horner-Emmons olefination protocol48 (entries 4 and 5).
It has been well documented that mild organic bases such as
Et3N, Hu¨nig’s base, and DBU are effective for the formation
of carbonyl-stabilized ylides.49 In our case, the electron-deficient
heteroaromatic systems provided sufficient stabilization for an
ylide as effectively as a carbonyl. Therefore, tertiary amines
should be sufficiently basic to effect oxazole-stabilized ylide
formation, and the ylide thus formed would react with aldehydes
to form trans-olefins. Gratifyingly, when aldehyde 40 and the
in situ generated Wittig salt derived from 26 were treated with
DBU at 0 °C, the desired product 42 was formed as a single
olefin isomer in 93% yield (entry 6).
considerable problems. For instance, the use of catalytic TsOH
in refluxing benzene50 and TFA/CH2Cl2 at 0 °C51 decomposed
the starting material. In addition, the C24 TBS group was stable
toward HF/pyridine and TBAF/silica.52 However, PPTS (EtOH,
50 °C)53 was effective in this case. Finally, removal of the PMB
group using DDQ45 gave a low yield (<10%) of the desired
product as well as many byproducts which could not be
identified.
From the above experiments, we concluded that the C1
carboxyl protecting group and the PMB group needed to be
removed before fragment coupling. Therefore, the Schlosser-
Wittig olefination16 between carboxylic acid 2 and aldehyde 3
was carried out. Complete conversion to the ylide required 2.0
equiv of DBU, which delivered coupling product 43 as a single
isomer in 86% yield (Scheme 11).
Macrocyclization and Completion of the (-)-Mycalolide
A Synthesis. In preparation for macrocyclization, cleavage of
the C24 TBS protecting group was required to afford seco acid
44 (Scheme 12). Since PPTS (EtOH, 50 °C) could remove the
TBS group of intermediate 42, the same reaction conditions were
applied to coupling product 43, which provided 44 in 65% yield.
Macrolactonization of seco acid 44 was effected by modified
Yamaguchi conditions first reported by Yonemitsu (DMAP,
(47) Evans, D. A.; Gage, J. R.; Leighton J. L. J. Am. Chem. Soc. 1992,
114, 9434-9453.
(48) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733-1738.
(49) For a literature precedent of using Et3N (PhH, reflux) to generate a
carbonyl-stabilized ylide, see: Trippett, S.; Walker, D. M. J. Chem. Soc.
1961, 1266-1268.
At this crucial conjuncture, we needed to calibrate the
reactivity of advanced intermediate 42 to pursue the final stage
of the synthesis. The immediate subgoal was to prepare the seco
acid by defining appropriate conditions to remove the C1
carboxyl and C24 hydroxyl protecting groups. However, at-
tempts to reach the free carboxylic acid were met with
(50) Hermann, J. L.; Berger, M. H.; Schlessinger, R. H. J. Am. Chem.
Soc. 1973, 95, 7923.
(51) Wender, P. A.; Schaus, J. M.; White, A. W. J. Am. Chem. Soc.
1980, 102, 6157-6159.
(52) Clark, J. J. Chem. Soc., Chem. Commun. 1978, 789-791.
(53) White, J. D.; Kawasaki, M. J. Am. Chem. Soc. 1990, 112, 4991-
4993.

Synthesis of (-)-Mycalolide A
J. Am. Chem. Soc., Vol. 122, No. 45, 2000 11097
Scheme 12
Hu¨nig’s base, 2,4,6-Cl3PhCOCl, and the seco acid in PhH at
room temperature),54 which afforded the desired macrolactone
in 66% yield.
convergent and stereocontrolled strategy. The synthesis is
noteworthy in that nine of the eleven stereogenic centers within
the target molecule were established through asymmetric
crotylation reactions. Synthetic highlights featured in this work
include the use of DBU to effect the Schlosser-Wittig olefi-
nation, the Kishi-Nosaki coupling to construct the C6-C7 and
C29-C30 bonds, and the Jacobsen HKR to install the C3
stereogenic center. The completion of the total synthesis serves
to confirm the relative and absolute stereochemistry of (-)-
mycalolide A, as well as to illustrate the application of our chiral
silane-based C-C bond construction methodology to the
assembly of complex molecules. The synthetic plan presented
here offers a general approach to access the remaining members
of this class of natural products as well as other potentially
bioactive analogues.
Having successfully arrived at macrocycle 45, completion of
the synthesis of mycalolide A required installation of the
terminal N-methylformamide and removal of the TBDPS
hydroxyl protecting group at C3. This was accomplished by
hydrolysis of the acetal (PPTS/wet acetone, reflux),55 followed
by vinylformamide formation with PPTS/HCONHMe.13b The
final deprotection step proceeded cleanly with TBAF/AcOH,56
affording mycalolide A. The synthetic material was identical
with a natural sample,57 including 400 MHz 1H NMR, 75 MHz
13C NMR, IR, [R]D, and TLC Rf values in three different solvent
systems.58
Conclusion
The first total synthesis of the actin-depolymerizing agent
(-)-mycalolide A has been achieved by employing a highly
Acknowledgment. We are grateful to Dr. Richard T. Beresis
(Merck & Co., Inc.), Prof. Eric N. Jacobsen, Dr. Scott E. Schaus
(Harvard University), Prof. John A. Porco, Jr., and Ms.
Cassandra A. Celatka (Boston University) for helpful discus-
sions. Financial support was obtained from the NIH/NCI (Grant
R01CA56304).
(54) (a) Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu, O. Tetrahedron
Lett. 1990, 31, 6367-6370. (b) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu,
O. J. Org. Chem. 1990, 55, 7-9.
(55) Sterzycki, R. Synthesis 1979, 724-725.
(56) (a) All other reagents surveyed including HF/pyridine, TBAF, HF,
and LiBF4 led to decomposition of the starting material. (b) For a recent
example of using TBAF/AcOH to remove TBS, see: Smith, A. B., III;
Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935-3948.
Supporting Information Available: Complete experimental
procedures and physical and spectral data for all intermediates
and final products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(57) We are indebted to Professors S. Matsunaga and N. Fusetani of the
University of Tokyo for providing a reference sample of natural (-)-
mycalolide A.
(58) HCl-free CDCl3 (K2CO3-treated commercial CDCl3) was used for
measuring the NMR spectra of mycalolide A due to the acid-labile N-methyl-
N-alkenylformamide group in the natural product.
JA002377A