A synthesis of mycalamide B

Article abstract of DOI:10.1055/s-1998-1803

Mycalamide B, a potent antitumour agent, was synthesised from cheap, readily available starting materials: ethyl lactate, ethyl isobutyrate, 4-chlorobutanal, and 4-chlorobutanoyl chloride. The trioxabicyclo[4.4.0]decane ring system was created by reaction of a methoxymethyl ether with a silyloxyoxirane induced by phosphorus pentoxide.

Full text of DOI:10.1055/s-1998-1803

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A Synthesis of Mycalamide B
Philip J. Kocienski* , Robert Narquizian , Piotr Raubo Christopher Smith , F. Thomas Boyle
a
a
a
a
b
a
Department of Chemistry, Glasgow University, Glasgow G12 8QQ, UK
b
Zeneca Pharmaceuticals, Mereside, Macclesfield, Cheshire, SK10 4TG, UK
Received 16 May 1998
Abstract: Mycalamide B, a potent antitumour agent, was synthesised
from cheap, readily available starting materials: ethyl lactate, ethyl
isobutyrate, 4-chlorobutanal, and 4-chlorobutanoyl chloride. The
trioxabicyclo[4.4.0]decane ring system was created by reaction of a
methoxymethyl ether with a silyloxyoxirane induced by phosphorus
pentoxide.
yield. Conversion of lactone 17 to the stannane 18 was accomplished by
a 3-step sequence previously described in our synthesis of Pederin.
13
Mycalamides A 1 and B 2 were isolated from a sponge of the genus
Mycale and shown to be potent inhibitors of tumour proliferation in a
1,2
number of human tumour cell lines.
Total syntheses of mycalamides
A and B have been reported by Hong and Kishi and elegant approaches
3,4
to the various advanced fragments have been described by Nakata
,
5,6
7,8
Roush and Hoffmann . We now report a synthesis of mycalamide B
which shares the same fragment linkage strategy as our synthesis of 18-
O-methylmycalamide B (Scheme 1). However, the synthetic routes to
9
the fragments 5 and 6 have been completely redesigned to offer greater
flexibility, efficiency, and economy.
Scheme 1
The preparation of the 6-lithio-3,4-dihydro-2H-pyran 6 (Scheme 2)
began by
a
diastereoselective conjugate addition of lithium
dimethylcuprate to the ester 7 (Note 1) in the presence of TMSCl. The
10,11
adduct 8, obtained in 95% yield, revealed a dr of >15:1.
The final
C-C bond forming reaction in the sequence was also highly
diastereoselective. Alkylation of the potassium enolate of the ester 8
with allyl bromide gave the third contiguous stereogenic centre in 9 in
99% yield (dr > 20 :1). Routine transformations accomplished the
conversion of 9 to the alcohol 12 in preparation for the next critical step
in the sequence, the inversion of configuration at C-2 (mycalamide
numbering), which was plagued by competing elimination. However,
the combination of trityl as the protecting group and p-chlorobenzoic
acid as the nucleophile returned the nicely crystalline inverted ester 13
in 79% yield. Oxidative cleavage of the alkene followed by acid
treatment achieved simultaneous trityl deprotection and lactonisation to
give the second crystalline compound of the series, the lactone 15. The
phenylselenide group in 16 was introduced by nucleophilic substitution
Dihydropyranone 25, a critical intermediate in the synthesis of the
trioxabicyclo[4.4.0]decane ring system (Scheme 3), harbours a single
stereogenic centre at C-15 which was constructed efficiently by two
different routes. In the first route, the lithium enolate prepared from
ethyl isobutyrate was condensed with 4-chlorobutanoyl chloride to give
14-
the β-keto ester 18 in 93% yield. Catalytic asymmetric hydrogenation
16
of the β-keto ester using [(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl] chloro (p-cymene) ruthenium chloride installed the requisite
(R)-configured stereogenic centre in good yield and high enantiomeric
ratio (97:3). Alternatively, the same β-hydroxy ester intermediate 19
could be constructed with similar efficiency using an asymmetric
12
17,18
of the butyrolactone. Reductive cleavage of the p-chlorobenzoate in
directed aldol reaction mediated by the homochiral borane 21.
The
16 (Note 2) returned a hydroxy acid which lactonised to 17 in 72%
ring was constructed by Dieckmann cyclisation of the corresponding

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acetate 22 to give the β-keto lactone 23 which could be easily obtained
enantiopure by crystallisation. Simple O-methylation under phase
transfer catalysed conditions followed by reduction of the remaining
carbonyl with DIBALH returned the desired dihydropyranone 25 in 50-
52% overall yield from ethyl isobutyrate.
Synthesis of the trioxabicyclo[4.4.0]decane ring system (Scheme 4)
began with the Cu(I)-catalysed addition of vinylmagnesium chloride to
the dihydropyranone 25 (95%, dr = 95:5). A Sharpless asymmetric
19
dihydroxylation using hydroquinine 9-phenanthryl ether as ligand
converted alkene 26 to the diol 27 in 90% yield with a dr >10 :1. Minor
diastereoisomers accruing from the previous two steps were easily
separated by crystallisation of the monopivalate ester from which the
MOM ether derivative 28 was prepared. Conversion of 28 to its
enolsilane derivative followed by epoxidation with MCPBA gave the
oxirane 29 as a single diastereoisomer. Treatment of oxirane 29 with a
large excess of formaldehyde dimethylacetal and P O effected closure
2
5
of the 1,3-dioxane ring to form the trioxabicyclo[4.4.0]decane ring
system in 70% overall yield from ketone 28. After reduction of the
ketone followed by O-methylation of the resultant alcohol, the chloride
was displaced by phenylselenide whence selenoxide elimination
returned the terminal alkene 34. Attempts to prepare 34 by base-
catalysed elimination of the corresponding iodoalkane gave messy
reactions. A second Sharpless asymmetric dihydroxylation (Note 3)
using the same ligand as described above was then used to install
hydroxyl functions at C-17 and C-18 but the diastereoselectivity was
poor (dr = 3:2). After protection of the terminal hydroxyl in diol 35 as
its TBS ether, the remaining hydroxyl was O-methylated. Reductive
cleavage of the pivalate followed by oxidation of the liberated hydroxyl
using Sharpless conditions gave the carboxylic acid 37. The overall
yield for the 16-step sequence was 22.8% corresponding to 13.7% of the
desired diastereoisomer.
Scheme 3

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The carboxylic acid 37 was used to install the aminal nitrogen via a
Notes
Curtius rearrangement using the conditions of Shioiri (Scheme 5, Note
1.
Ester 7 was prepared from ethyl (S)-lactate in three steps in 69%
20
25
4).
Trapping the intermediate isocyanate with trimethylsilylethanol
overall yield : (a) TBSCl, NEt , DMAP, CH Cl ; (b) DIBALH,
3
2
2
gave the urethane 38 in 57% yield which was then acylated with methyl
oxalyl chloride to give imide 39. Cleavage of the trimethylsilylethyl
CH Cl ; and (c) NaH, (EtO) POCH CO Et, THF.
2
2
2
2
2
6
2.
3.
4.
Standard basic cleavage of the p-chlorobenzoate 16 gave up to 5%
of the C-2 epimer of 17.
urethane without detriment to the primary TBS group at C-18 was
accomplished by using TBAF buffered with acetic acid. The remainder
of the synthesis closely paralleled our previous synthesis of 18-O-
methylmycalamide—but with some unfortunate complications. The
bridge spanning the two ring systems was constructed via reaction of the
oxalamide 4 with the lithium derivative 6 (prepared by transmetallation
of stannane 18 with BuLi) to give the acyl dihydropyran 5 in 55% yield.
Reduction of the ketone function in 5 with L-Selectride followed by
acid-catalysed addition of MeOH gave 2 adducts (dr = 2:1) which were
esterified using p-nitrobenzoyl (PNB) chloride. This was a mistake
because the desired O-acylation was accompanied by substantial N-
acylation as well (Note 5) leading to a poor overall yield (15%) of the
desired ester 40. To complete the synthesis, the selenoxide derived from
40 was thermolysed briefly to generate the exocyclic alkene at C-4 and
both the PNB ester and the TBS group removed by treatment with
Low diastereoselectivity in similar Sharpless asymmetric
26
7
dihydroxylations was also observed by Kishi and Hoffmann .
The use of a Curtius rearrangement to construct the aminal
3
6
7
function was also a feature of the Nakata , Roush and Hoffmann
approaches.
5.
The p-nitrobenzoylation gave a total of 6 products which were
separated by column chromatography into three fractions
comprising 52% of the N,O-diacylated product; 25% of the O-
acylated product 40; and 23% of a triacylated product generated
by acylation of the C-18 hydroxyl following loss of the TBS
protecting group. Each of the fractions was a mixture of two
diastereoisomers at C-7 (dr 2:1 with the major isomer
corresponding to the desired stereochemistry). The epimers at C-7
were separable by preparative TLC.
TBAF•3H O in THF to give a mixture of Mycalamide B and 7-epi-
2
Mycalamide B with the latter predominating. Thus the PNB group
activates the C-7 position towards epimerisation.
Acknowledgements. We thank Zeneca Pharmaceuticals and the EPSRC
for financial support.
In conclusion, our new synthesis of Mycalamide B features much more
economical and shorter routes to the key fragments 5 and 6 and the
presence of the alkene function in dihydropyranone intermediate 25
References
(1) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K. J. Am.
Chem. Soc. 1988, 110, 4850.
21-23
enables our approach to be adapted to the onnamides
and
24
theopederins . The low level of diastereocontrol in the asymmetric
dihydroxylation remains an obstacle but the problems stemming from
acylation with p-nitrobenzoyl chloride which seriously marred the
closing stages of our synthesis should be easily circumvented by simply
switching to benzoyl chloride. Further improvements are under
investigation.
(2) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Thompson, A. M. J.
Org. Chem. 1990, 55, 223.
(3) Nakata, T.; Matsukura, H.; Jian, D. L.; Nagashima, H.
Tetrahedron Lett. 1994, 35, 8229.
(4) Nakata, T.; Fukui, H.; Nakagawa, T.; Matsukura, H. Heterocycles
1996, 42, 159.
(5) Roush, W. R.; Marron, T. G.; Pfeifer, L. A. J. Org. Chem. 1997,
62, 474.

872
LETTERS
SYNLETT
(6) Marron, T. G.; Roush, W. R. Tetrahedron Lett. 1995, 36, 1581.
(17) Kiyooka, S.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996, 37,
2597.
(7) Hoffmann, R. W.; Schlapbach, A. Tetrahedron Lett. 1993, 34,
7903.
(18) Kiyooka, S. J. Synth. Org.Chem. Jpn 1997, 55, 313.
(8) Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim. Acta
1996, 79, 346.
(19) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.;
Kawanami, Y.; Lübben, D.; Manoury, E.; Ogino, Y.; Shibata, T.;
Ukita, T. J. Org. Chem. 1991, 56, 4585.
(9) Kocienski, P.; Raubo, P.; Davis, J. K.; Boyle, F. T.; Davies, D. E.;
Richter, A. J. Chem. Soc., Perkin Trans. 1 1996, 1797.
(20) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(10) Yamamoto, Y.; Chouman, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J.
Am. Chem. Soc. 1992, 114, 7652.
(21) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T. J. Am.
Chem. Soc. 1988, 110, 4851.
(11) Hanessian, S.; Gai, Y.; Wang, W. Tetrahedron Lett. 1996, 37,
(22) Matsunaga, S.; Fusetani, N.; Nakao, Y. Tetrahedron 1992, 48,
7473.
8369.
(12) Liotta, D. Acc. Chem. Res. 1984, 17, 28.
(23) Kobayashi, J.; Itagaki, F.; Shigemori, H.; Sasaki, T. J. Natural
Products-Lloydia 1993, 56, 976.
(13) Kocienski, P.; Jarowicki, K.; Marczak, S. Synthesis 1991, 1191.
(14) Noyori, R.; Ohkima, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109,
5856.
(24) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1992, 57,
3828.
(25) Annunziata, R.; Cinquini, M.; Cozzi, F.; Dondio, G.; Raimondi, L.
(15) Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227.
Tetrahedron 1987, 43, 2369.
(16) King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J.
Org. Chem. 1992, 57, 6691.
(26) Hong, C. Y.; Kishi, Y. J. Org. Chem. 1990, 55, 4242.