Total synthesis of mycalamide A

Article abstract of DOI:10.1021/ja050728l

This communication describes a concise and efficient total synthesis of mycalamide A by the convergent coupling of pederic acid unit with the mycalamine unit. The left-half, (+)-7-benzoylpederic acid, was synthesized from (2R,3R)-3-methylpent-4-en-2-ol in

Full text of DOI:10.1021/ja050728l

Published on Web 05/04/2005
Total Synthesis of Mycalamide A
Jeong-Hun Sohn, Nobuaki Waizumi,† H. Marlon Zhong,‡ and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received February 3, 2005; E-mail: vrawal@uchiago.edu
Mycalamides A-D,1 onnamides A-F,2 and theopederins A-L3
Scheme 1. Retrosynthetic Analysis
belong to a class of structurally related natural products. These com-
pounds possess strong antitumor and antiviral activities, and some
members display potencies at subnanomolar concentrations in cells
as a consequence of protein synthesis inhibition.4 In particular, mycal-
amideA(1), isolatedfromaNewZealandmarinespongeofthegenus
Mycale, also exhibits immunosuppressive action by blocking T-cell
activation in mice and is significantly more potent than FK-506
and cyclosporine A.5 The combination of intriguing biological
profile, structural complexity, and scarce supply of these natural
products has stimulated intense research efforts by synthetic chem-
ists, and total, formal, or partial syntheses of several members of
this family of compounds have been reported.6-9 We report here a
convergent synthesis of mycalamide A, wherein the two major parts
of the target are synthesized through concise, stereocontrolled routes.
Our plan for the preparation of mycalamide A entailed linking
of the pederic acid half (2), which is found in all members of the
above family of compounds, with the mycalamine half (3) through
an amide bond (Scheme 1).6 Diastereoselective formation of this
bond has proven challenging, since the aminal group in mycalamine
is configurationally unstable under acidic, neutral, or basic
conditions.6a,b We devised a palladium-catalyzed tandem cyclization
sequence to construct the pederic acid framework. The exocyclic
double bond containing pyran ring 4 was expected to arise from
an intramolecular Heck reaction of σ-alkylpalladium species 5,
which, in turn, was the expected product of a Wacker-type reaction
of enolether 6.11 Since Pd(0) is produced at the end of the cascade,
a secondary oxidant would be required to complete the catalytic
cycle. In the challenging trioxadecalin part, five out of the seven
carbons in this bicyclic ring system are stereogenic. Further analysis
revealed that the oxygenated four-carbon fragment was derivable
from the abundant C2 symmetric compound, tartaric acid.
Scheme 2 summarizes the tandem Wacker/Heck route to pederic
acid, the left-half of mycalamide A. Esterification of benzylidene-
protected glyceric acid12 with the known homoallylic alcohol 7,13
using EDC, followed by Petasis methylenation14 produced enolether
14, possessing the carbons necessary for pederic acid and poised
for the Pd-catalyzed cyclization sequence. Syringe pump addition
of 14 to a mixture containing MeOH, HC(OMe)3, propylene oxide,
benzoquinone as the stoichiometric oxidant, and 0.15 equiv of PdCl2
in THF-DMF (20/1) at ambient temperature provided the desired
tetrahydropyran 15 in 78% yield as a 5.7:1 mixture of diastereomers.
Removal of the benzylidene group and selective TES protection of
the primary alcohol followed by benzoylation of the secondary hy-
droxyl gave 16 in excellent yield. Slow addition of 16 to a mixture
of PDC in DMF converted the TES-protected hydroxyl directly to
the corresponding acid 17 (83%). For the purpose of characteriza-
tion, the acid was converted to the corresponding methyl ester (18).15
The synthesis of the right-half of mycalamide A commenced
with diethyl D-tartrate (12), which was desymmetrized through a
Scheme 2. Synthesis of (+)-7-Benzoylpederic Acida
a Conditions: (a) EDC, DMAP, CH2Cl2, 91%. (b) Cp2TiMe2, PhCH3,
80 °C, 85%. (c) PdCl2 (0.15 equiv), benzoquinone, MeOH, HC(OMe)3,
propylene oxide, THF/DMF (20/1), 78%. (d) Na, liq. NH3, EtOH, 93%.
(e) TESCl, DIPEA, CH2Cl2, 93%. (f) BzCl, DMAP, DIPEA, CH2Cl2, 94%.
(g) PDC, DMF, 83%. (h) CH2N2, Et2O, quant.
four-step sequence to give the aldehyde 11 in 77% overall yield.
(Scheme 3) Chelation-controlled addition of tri-n-butylprenylstan-
nane to aldehyde 11 using ZnBr2 introduced the next stereocenter
with >50:1 diastereoselectivity.9c,16 Methylation of 10 (98%) was
followed by a new protocol devised to remove both MOM groups
under mild conditions. Treatment with ZnBr2 and n-BuSH in
methylene chloride for a few minutes at room temperature removed
both MOM groups and gave diol 19 in 98% yield.17 Selective
benzoylation of C(11)-OH followed by MOM protection of the
remaining OH and removal of the benzoyl group afforded alcohol
20 in good yield. Ozonolysis of 20 followed by acetylation produced
a lactol acetate, which on treatment with BF3‚OEt2 and allyltrim-
ethylsilane in methylene chloride furnished 9 as a single diastere-
omer in 66% yield from 20.8,9c,d,18
In preparation for the dioxane formation, the TBDPS group was
removed, and the resulting alcohol was oxidized under Swern
conditions. Treatment of the resulting aldehyde with paraformal-
† Present address: Pfizer Inc., Nagoya Laboratories, Taketoyo, Aiichi, Japan.
‡ Present address: Johnson & Johnson Pharmaceuticals Research and Develop-
ment, L.L.C., Spring House, PA.
9
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J. AM. CHEM. SOC. 2005, 127, 7290-7291
10.1021/ja050728l CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of Mycalaminea
were developed for the preparation of either mycalamide A (1) or
C(10)-epi-mycalamide A (26).
Acknowledgment. Generous financial support from the National
Cancer Institute of the NIH (R01 CA101438) is gratefully
acknowledged. We thank Pfizer Inc. (Japan) for postdoctoral
fellowship support to N.W.
1
Supporting Information Available: Experimental details and H
and 13C NMR spectra of key intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
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a Conditions: (a) (MeO)2CH2, P2O5, CH2Cl2 (quant). (b) LAH, Et2O
(86%). (c) n-BuLi, TBDPSCl, THF (quant). (d) (COCl)2, DMSO, Et3N
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O3, Me2S, CH2Cl2; Ac2O, DMAP, pyr; BF3‚OEt2, CH2CHCH2TMS, CH2Cl2,
66%. (l) TBAF, THF, 91%. (m) (COCl)2, DMSO, NEt3, CH2Cl2. (n)
(CHO)n, concd HCl, THF; Ac2O, DMAP, pyr, 63%, dr 5.4:1. (o) OsO4,
(DHQ)2PYR, K2CO3, K3Fe(CN)6, t-BuOH/H2O, -3 °C (R-AcO 83%, dr
5.0:1; â-OAc 85%, dr 5.9:1). (p) Ac2O, DIPEA, DMAP, CH2Cl2, 92%. (q)
TMSN3, TMSOTf, CH3CN, -78 to 0 °C (quant). (r) H2, Pd/C, EtOAc, 90%.
Scheme 4. Synthesis of Mycalamide A
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dehyde and concentrated HCl in THF at -15 to -10 °C directly
yielded the 4-hydroxy-1,3-dioxane, which upon acetylation afforded
trioxadecalin 21 (57% yield from 9). After asymmetric dihydroxy-
lation19 of 21, the diacetate of diol 22 was treated with TMSN3
and TMSOTf to transform the anomeric acetate to an azide, which
on hydrogenation gave the desired mycalamine unit, 23.
For coupling the two partners, an extensive examination of
methods6a,b revealed that the reaction proceeded cleanly and in good
yield (61%) using PyAOP and i-Pr2NEt in (Scheme 4). However,
deprotection of the coupled product with 1 N LiOH in THF gave
only C(10)-epi-mycalamide A 264c (75%),20 which could not be
epimerized to mycalamide A.6a Gratifyingly, when the coupling of
17 and 23 was carried out using DCC and DMAP in dichlo-
romethane, the predominant product was the desired mycalamide
diastereomer, 24, obtained in a 5:1 ratio along with 25. Finally,
the three esters were removed through hydrolysis using 1 N LiOH
in THF to afford mycalamide A in 78% yield.20
In conclusion, we have completed a concise and efficient total
synthesis of mycalamide A by the convergent coupling of pederic
acid piece 17 with mycalamine unit 23. The left half, (+)-7-
benzoylpederic acid, was synthesized in seven steps and 34.6%
overall yield from homoallylic alcohol 7 through a route that
featured a one-step Pd(II)-catalyzed tandem Wacker/Heck cycliza-
tion reaction to prepare the tetrahydropyran ring system. The right
half unit, 23, was synthesized from diethyl D-tartrate (12) in 21
steps and 10.5% overall yield. Effective, stereoselective methods
(19) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless,
K. B. J. Org. Chem. 1993, 58, 3785.
(20) The NMR spectra of our synthetic mycalamide A and epi-mycalamide A
matched to those of the naturally derived materials. We thank Prof. J. W.
Blunt (University of Canterbury, New Zealand) for kindly providing the
spectra.
JA050728L
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