A Formal Synthesis of (-)-Mycalamide A

Article abstract of DOI:10.1021/ja038787r

Novel strategies are developed for an efficient formal synthesis of (-)-mycalamide A. The left-hand side (-)-7-benzoylpederic acid is synthesized from (2S,3S)-2,3-epoxybutane. The key features include a highly regioselective Ru-catalyzed alkene-alkyne cou

Full text of DOI:10.1021/ja038787r

Published on Web 12/11/2003
A Formal Synthesis of (-)-Mycalamide A
Barry M. Trost,* Hanbiao Yang, and Gary D. Probst
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received September 29, 2003; E-mail: bmtrost@Stanford.edu
The mycalamides,1 onnamides,2 and theopederins3 are biologi-
Scheme 1. Retrosynthetic Analysis
cally and synthetically interesting natural products isolated from
marine sponges. Many of these compounds possess potent antiviral
and antitumor properties due to their ability to arrest protein
synthesis.4 The inhibition of protein synthesis is accomplished by
binding to the 80S ribosome and preventing the translocation of
the nascent peptide from the A site to the P site. One of the most
remarkable aspects of mycalamides A and B is their ability to
change the morphology of ras-transformed rat NRK-cells back to
normal cells by selectively inhibiting the biosynthesis of p21, a G
protein.5 These natural products have attracted a great deal of
attention from the synthetic cmmunity. Total synthesis of mycal-
amide A,6a,7,8 mycalamide B,6a,9 onnamide A,6b and theopederin D9
have been recorded. In addition, studies toward their total synthesis
have been reported by other groups.10 Since these molecules are
so complex, it is not surprising that the previous total syntheses
typically require around 30 linear steps to complete. Through the
use of synthetic methodologies developed in these laboratories, we
sought to streamline the synthesis.
Scheme 2. Synthesis of (-)-7-Benzoylpederic Acida
We focused our efforts on an asymmetric synthesis of (-)-7-
benzoylpederic acid 2 and the azide 3 since Nakata et al.7b reported
their conversion to mycalamide A in three steps (Scheme 1). By
envisioning alkene 4 as a flexible building block to several members
of these families including mycalamide A, a novel route for its
construction was developed that involves two Pd(0)-catalyzed O-π-
allyl cyclizations and a novel strategy to create 1,3-dioxan-4-ones.
All of the stereochemistry on the trioxadecalin ring derives from
either R- or S-pantolactone. Our strategy to synthesize acid 2 is
based on the recently developed Ru-catalyzed alkene-alkyne
coupling reaction.11 The stereochemistry of the pederic acid derives
from that of the initial chiral trans-2-butene epoxide, which is
commercially available. While our synthesis targeted the enanti-
omer, the natural series is equally accessible simply by using the
mirror-image starting materials.
The synthesis of 2 commenced with epoxide 10 (Scheme 2).
While the opening of 10 with the Yamaguchi protocol (lithium
trimethylsilylacetylide and BF3‚Et2O)12 gave capricious results, it
cleanly reacted with the corresponding alanate complex to afford
the alkyne 9.13 A regioselective Ru-catalyzed coupling reaction
between alkene 8 and alkyne 9 rapidly gave 7 with the carbon
skeleton present in 2. After protection with TBS-OTf, the less-
hindered olefin was chemoselectively dihydroxylated to furnish the
diol 11 as a 1:1 diastereomeric mixture. Monobenzoylation followed
by oxidative cyclization gave the desired pyran 15 in 18% yield
together with a mixture of 14 and 15 (63%) in 1:1 ratio after
chromatography on silica gel. Interestingly, diastereomer 14 was
in dynamic equilibrium with the desired isomer 15 on silica gel.
Subjecting the 1:1 mixture of 14 and 15 to silical gel column
chromatography for three cycles provided 15 in 53% yield together
with a 2:1 ratio of 14 and 15 (34%). The C(7) stereochemistry,
which has been difficult to control in many previous syntheses,14
is under substrate control. Thus, the stereochemical outcome in the
dihydroxylation step is inconsequential. Methylation without migra-
a Conditions: (a) TMS acetylene, n-BuLi, -78 °C, 20 min; then Me3Al,
-78 °C, 30 min, then -45 °C, 30 min; then 10, -78 °C, 15 min; then BF3
etherate, -78 °C, 1 h, quant. (b) 8, CpRu(CH3CN)3PF6 (10 mol %), acetone,
rt, 63%. (c) TBDMSOTi, Et3N, CH2Cl2, quant. (d) OsO4, NMO, acetone/
H2O, 2 °C, 96% (1/1 dr). (e) DMAP (5 mol %) Et3N, PhCOCl, CH2Cl2,
-78 to -40 °C, 70% (96% after f). (f) NaOCH3, MeOH, 0 °C to room
temperature. (g) Dess-Martin Periodianene, NaHCO3, CH2Cl2; then CSA
(10 mol %), MeOH, 81%, (h) silica gel. (i) CH3OTf, LHMDS, DME, -70
°C, 87%. (i) NIS, CH3CN, 0 °C, 91%. (k) (Ph3P)4Pd, Bu3SnH, 96%. (l)
n-PrSLi, HMPA, rt, 94%.
tion of the benzoyl group followed by removal of the vinyl TMS
afforded 17. The spectroscopic data (1HNMR, 13CNMR, [R]D) of
17 match those of Nakata.14a A dealkylative saponification of 17
with n-PrSLi15 completed the synthesis of the left-hand side 2,
common to the mycalamide, onnamide, and theopederin families.
The synthesis of the right-hand side azide 3 started from
commercially available (R)-pantolactone, which was methylated
with Ag2O and excess CH3I without racemization16 (Scheme 3).
After reduction with DIBAL-H, the resulting lactol was subjected
to mediated allylation reaction with 2-(chloromethyl)allyl acetate
in aqueous saturated NH4Cl17 to produce 6 with a 5:1 diastereomeric
ratio favoring 6. The stereochemistry was confirmed by X-ray
analysis. Surprisingly, Pd(0)-catalyzed cyclization exclusively
produced the eight-membered ring product 25 (79% yield) wherein
the primary alcohol served as the nucleophile (Scheme 4). In
contrast, the chemoselectivity was completely switched to form the
tetrahydrofuran 18 in 99% yield with the addition of Et3B. Moffat-
9
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J. AM. CHEM. SOC. 2004, 126, 48-49
10.1021/ja038787r CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of Azide 3a
to control the challenging C(7) stereocenter. The right-hand side 3
was synthesized from (R)-pantolactone. The novel features include
constructing the trioxadecalin core with two Pd(0)-mediated O-π-
allyl cyclizations. The first one is chemoselective, while the second
one is highly diastereoselective. Furthermore, a new strategy to
construct 1,3-dioxan-4-ones involving 4-methylene tetrahydro-
furans28 has been developed. Three additional steps would be
required to complete a total synthesis of mycalamide A.
Acknowledgment. We thank Professor Y. Kishi (Harvard
University) for sending us part of Dr. Hong C. Y.’s thesis, Professor
T. Nakata (RIKEN) for providing us the 1HNMR of 17, 18, and 3,
NIH General Medical Science (GM 13598) and NSF for their
generous financial support. Mass spectra were provided by the Mass
Spectrometry Regional Center of the UCSF Supported by the NIH
Division of Research Resources.
a Conditions: (a) Ag2O, MeI, CH3CN, 58 °C, 86%, 98% ee, (b) (i)
DIBAL-H, CH2Cl2, -78 °C; then 2-(chloromethyl)allyl acetate, In powder,
sat. aq NH4Cl, 62% (5/1 dr). (c) PdCl2(dppf), BEt3, Et3N, THF, reflux,
99%. (d) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °D, 90% (96% BRSM) (e)
vinyl magnesium bromide, MgBr2 diethyl ether complex, CH2Cl2, -78 °C
to rt, 96%. (f) n-BuLi, (Boc)2O, THF, 87% (95% BRSM). (g) (DHQD)2-
PHAL, K3Fe(CN)3, K2CO3, MeSO2NH2, t-BuOH/H2O; then NalO4, THF/
H2O, 91%. (h) m-CPBA, 30% Li2CO3, CH2Cl2, rt, 98%. (i) TBDMSOTf,
TEA, CH2Cl2, -78 °C, 30 min; then DMDO, acetone, CH2Cl2, molecular
sieves, -5 °C, 68%. (j) TBAT, benzoic acid, THF, 50 °C, 83%. (k) Tf2O,
pyridine, 0 °C; then NaNO2, DMF, rt, 75%. (I) Pd2(dba)3CHCl3, dppf, DCE,
70 °C, 58%. (m) DIBAL-H, -78 °C; then pyridine, DMAP, Ac2O, -78
°C to rt, 100% (1.6/1 dr). (n) 9-BBN, Wilkinson’s catalyst; then PCC, DCM,
45 °C. (o) Ph3PdCH2, toluene, -40 to -20 °C, 47% over two steps. (p)
(DHQD)2PYR, OsO4, K2CO3, K3Fe(CN)6, t-BuOH/H2O, for R-AcO 74%,
4.3/1 dr; for â-AcO quant., 9/1 dr. (q) Triphosgen, pyridine, DCM, -78
°C, R-AcO 73%, â-AcO 84%. (r) TMSOTf, TMSN3, CH3CN, 0 °C, 68%
(1.6/1 dr).
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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2,3-epoxybutane. The key features include a highly regioselective
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