Exploiting orthogonally reactive functionality: Synthesis and stereochemical assignment of (-)-ushikulide A

Article abstract of DOI:10.1021/ja807127s

In spite of the tremendous advances in modern spectroscopic methods, organic synthesis continues to play a pivotal role in elucidating the full structures of complex natural products. This method has the advantage that, even in the absence of a firm structural assignment, a combination of logic and spectroscopic comparison can arrive at the correct structure. Herein, we report execution of this strategy with respect to ushikulide A, a newly isolated and previously stereochemically undefined member of the oligomycin-rutamycin family. To maximize synthetic efficiency, we envisioned chemoselective manipulation of orthogonally reactive functional groups, notably alkenes and alkynes as surrogates for certain carbonyl and hydroxyl functionalities. This approach has the dual effect of minimizing the number of steps and protecting groups required for our synthetic route. This strategy culminated in the efficient synthesis and stereochemical assignment of ushikulide A. Copyright

Full text of DOI:10.1021/ja807127s

Published on Web 11/07/2008
Exploiting Orthogonally Reactive Functionality: Synthesis and
Stereochemical Assignment of (-)-Ushikulide A
Barry M. Trost* and Brendan M. O’Boyle
Department of Chemistry, Stanford UniVersity, Stanford, California, 94305-5080
Received September 26, 2008; E-mail: bmtrost@stanford.edu
In 2005, Takahashi and co-workers reported the isolation of
nections with less utilized but orthogonally reactive alkene and
alkyne chemistry. Furthermore, these operations appear feasible in
either order, allowing either the Suzuki coupling or a macrolac-
tonization to close the 22-membered ring.
ushikulide A (1) from a culture broth of Streptomyces sp. IUK-
102 (Figure 1).1 This compound exhibits potent activity against
murine splenic lymphocyte proliferation (IC50 ) 70 nM), rivaling
that of the well-known cyclosporin A2 and FK506,3 which
revolutionized organ transplant therapy by suppressing rejection.
Takahashi’s structural assignment dealt with connectivity, not
stereochemistry, as analysis of 1 by X-ray diffraction proved
untenable in this particular case.4 Thus the complete structure
remains unknown, along with several other members of this
family.5,6 Interestingly, while some family members have potent
antibiotic activity (cytovaricin), others exhibit immunosuppressant
activity (ushikulide A, dunaimycin D2S). The exact cause of this
divergent activity and in some cases the full structure of the
bioactive natural product (e.g. dunaimycin D2S, Figure 1) remains
unknown. Therefore, development of an effective and versatile
synthetic strategy to such compounds would have the dual objective
of establishing the full three-dimensional structures of these natural
products, while also providing a mechanism to explore the
relationship of structure and function. To embark upon an ushikulide
A synthesis, we made a tentative assignment based on analogy to
cytovaricin,6 a structurally similar compound whose full structure
is well established.
The desired spiroketal fragment (2) is rapidly assembled by
utilizing two alkynes, which serve as functional equivalents to
groups typically accessed via alcohols or ketones (e.g., the spiroketal
and C-14, C-15 olefin, Scheme 1). Specifically, the alkyne 4 serves
as a stabilized anion, which undergoes addition to aldehyde 5. The
alkyne contained in 6 then functions as an electrophile in a metal
catalyzed spiroketalization reaction. Utilization of the alkyne in this
manner achieves efficiency by functioning as a carbonyl surrogate,
which chemoselectively unveils the desired spiroketal (2). A novel
aspect of this strategy is the recognition that the inherent polarization
of the alkyne (6) would lead to the desired regioselectivity in the
spirocyclization. By having an inductively electron-withdrawing
benzoyloxy group at C-21, a positive charge at the neighboring
acetylenic carbon (C-22) should be destabilized, directing the initial
cyclization onto C-23 and leading to the desired spiroketal.10
A
second alkyne building block (7) serves as a propargyl nucleophile
under conditions developed by Tamaru11 and extended by Mar-
shall,12 thus completing the spiroketal fragment (2).
Scheme 1. Retrosynthesis of Ushikulide A
Figure 1. Tentative assignment of ushikulide A.
We envision that the aliphatic fragment (3) could be accessed
in a convergent manner via disconnection of the C-8, C-9 bond,
furnishing an aldol donor (8) and an acceptor (9). Given the similar
size of the methyl and allyl groups at C-10, such a process is not
expected to give acceptable diastereoselectivity. However, recent
advances in our zinc aldol methodology13 cause us to envision that
such a reaction could be made diastereoselective through catalyst
control.
While sp2-sp2 Suzuki coupling and esterification are well-
established in several related natural product syntheses,7,8 we
envisioned a less common sp3-sp2 Suzuki coupling9 and esteri-
fication to be an attractive alternative to access the C-14, C-15 olefin
with geometric control (Scheme 1), thereby simplifying the synthetic
problem to preparation of a spiroketal fragment (2) and an aliphatic
fragment (3). By utilizing the reactivity of a carboxyl group in the
former step, and then the reactivities of two C-C π-systems, we
sequentially utilize more common carbonyl and hydroxyl discon-
Preparation of the spiroketal (2) begins with the known reduction
of methyl 3-oxopentanoate,14 followed by protection of the second-
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ary alcohol as a p-methoxybenzyl ether and monoreduction with
DIBAL-H to yield aldehyde 10 in good yield and excellent optical
activity (Scheme 2). A brief survey of crotylations led us to the
method of Brown,15 which after TBS protection provides the alkene
11 as a pure diastereomer (d.r. > 20:1). Hydroboration/iodination
is followed by nucleophilic substitution yielding the desired alkyne
4 in seven linear steps.
desired spiroketal fragment (2) in a total of 16 linear steps from
methyl 3-oxopentanoate.
Scheme 3. Completion of the Spiroketal Fragmenta
Scheme 2. Toward the Synthesis of the Spiroketal Fragmenta
a Conditions: (a) n-BuLi, THF, 90%, 1.5:1 syn/anti; (b) for syn: DEAD,
PhCOOH, PPh3, toluene, 92%, for anti: BzCl, pyridine, 95%; (c) HCl, H2O,
THF; (d) 10 mol % AuCl, PPTS, THF, 63%; (e) MeI, NaHCO3, CH3CN,
H2O, 80%; (f) 10 mol% Pd(OAc)2, ZnEt2, PPh3, THF, 7, 90%, 3.8:1 d.r.;
(g) TBSOTf, 2,6-lutidine, CH2Cl2 (h) K2CO3, MeOH (i) Bu3SnH, 5 mol%
PdCl2(PPh3)2, THF, then I2, 90% over 3 steps.
Our approach toward the aliphatic fragment (3) begins with the
known homoallyl alcohol 18 (Scheme 4).25 Wacker oxidation10
unveils the desired ketone 19. Preparation of the aldehyde partner
9 utilizes a tartrate modified SnII mediated addition of allyl bromide
to benzyl pyruvate, as described by Mukaiyama,26 to give tertiary
alcohol 20 in excellent chemical yield and optical purity. Protection
and DIBAL-H reduction affords the aldehyde 9.
a Conditions: (a) 0.1 mol% (R)-BINAP, 0.05 mol% [RuCl2(C6H6)]2,
MeOH, H2 1800 psi, 92%, 99% ee; (b) PMBO(CdNH)CCl3, 1 mol%
Cu(OTf)2, toluene, 85%; (c) DIBAL-H, CH2Cl2, 82%; (d) (i) cis-2-butene,
n-BuLi, KOt-Bu, THF, (ii) (+) Ipc2BOMe, (iii) BF3 ·OEt2 then 10, >20:1
d.r.; (e) TBSCl, imid., DMF, 87% over 2 steps; (f) 9-BBN, THF then I2,
NaOCH3, MeOH, 85%; (g) THF, DMPU, LiCCTMS, then KOH, MeOH,
81%; (h) TiCl4, EtN(i-Pr)2, NMP, CH2Cl2, single diastereomer, 90%; (i)
TBSOTf, 2,6-lutidine, CH2Cl2, 96%; (j) DIBAL-H, CH2Cl2, 87%; (k) 10
mol% (S,S) ProPhenol, Me2Zn, toluene, 88%, 95% ee; (l) LiOH, THF, H2O
then CuCl, CH3CN, 75%; (m) MsCl, Et3N, CH2Cl2, 95%.
Scheme 4. Synthesis of the Aliphatic Fragmenta
The known aldehyde 1216 participates in an aldol reaction under
the conditions of Crimmins17 yielding the aldol adduct 13 in
excellent yield as a single diastereomer. Protection and DIBAL-H
reduction affords the aldehyde 5.
For synthesis of propargyl mesylate 7, we turned to our
ProPhenol zinc alkynylation methodology,18 which affords the
adduct of isovaleraldehyde and methyl propiolate in good yield and
excellent stereoselectivity (Scheme 2). Following saponification of
the methyl ester, exposure of the crude acid to cuprous chloride
induces decarboxylation,19 leaving only mesylation of the secondary
propargyl alcohol to complete the propargyl mesylate (7).
a Conditions: (a) PMBO(CdNH)CCl3, 0.5 mol% Sc(OTf)3, toluene, 88%;
(b) 10 mol% PdCl2, CuCl, O2, DMF, H2O, 60%; (c) allyl bromide, tin(II)
catecholate, DBU, CuI, (-)-diisopropyl tartrate, CH2Cl2, 92%, 99% ee; (d)
PMBO(CdNH)CCl3, 1 mol% Sc(OTf)3, toluene, 85%; (e) DIBAL-H,
CH2Cl2, 90%; (f) 60 mol% Et2Zn, t-BuOH, dioxane, 30 mol% (S,S)
ProPhenol, 65% b.r.s.m.; (g) NaBH4, MeOBEt2, MeOH, THF; (h) p-TsOH,
CH2Cl2, 2,2-dimethoxypropane, 71% over 2 steps; (i) n-Bu4NF, THF; (j)
Dess-Martin reagent, CH2Cl2; (k) n-BuLi, (EtO)2P(O)CH2CO2TMS, THF,
92% over 3 steps.
Union of aldehyde 5 and alkyne 4 (Scheme 3) by metalation of
alkyne (n-BuLi, -78 °C), followed by addition of the aldehyde,
affords a mixture of diastereomers at C-21 (∼1.5:1 d.r.). Addition
of bidentate Lewis acids (Et2AlCl, MgBr2 ·OEt2, or Ti(Oi-Pr)Cl3)
to favor the desired anti 1,3 diol is unsuccessful due to low
conversion and modest stereoselectivity. However, these epimers
(not shown) are easily separable on silica gel, and both epimers
converge to the desired diol 14, one via ester formation by
Mitsunobu inversion and the other via standard esterification (BzCl,
pyridine). Utilization of a PdII catalyzed spiroketalization20-22
results in low conversion in this case. On the other hand, warming
a THF solution containing diol 14, gold(I) chloride, and PPTS23,24
proceeds smoothly to yield spiroketal 15. Hydrolysis of the 1,3
dithiane in the presence of methyl iodide yields the aldehyde 16,
which is successfully propargylated under the conditions of
Marshall12 furnishing a 3.8:1 distribution of separable C-17 epimers.
As this center will be oxidized, both epimers are of equal value in
our synthesis; however for practical reasons, we continue forward
with the major compound 17. Three additional steps produce the
Enolate formation (19, LiN(i-Pr)2, -78 °C) prior to addition of
aldehyde 9 reveals the expected low stereoselectivity (∼1:1 d.r.)
for the direct aldol reaction. Addition of chelating Lewis acids (e.g.,
ZnCl2) failed to increase this selectivity. Worse, separation of the
resulting C-9 aldol epimers is prohibitively difficult on a preparative
scale. An attempted Mukaiyama aldol reaction after formation of
the silyl enol ether (19, LiN(i-Pr)2, Me3SiCl, -78 °C) with several
bidentate Lewis acids (ZnCl2, MgBr2 ·OEt2, GaCl3 TiCl4, or Ti(Oi-
Pr)2Cl2) results in only slow hydrolysis of the silyl enol ether.
Therefore, our attention turned to catalyst control as a means to
overcome this stereochemical quandary. Gratifyingly, the (S,S)
ProPhenol dinuclear zinc complex promotes the aldol process,
wherein the desired diastereomer is formed with >20:1 d.r.13
A
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syn reduction of the aldol 21 is followed by formation of acetonide
22. The aliphatic fragment (3) is completed in three additional steps
and a total of 11 linear steps from the (S)-Roche ester.
Suzuki coupling9 unites the spiroketal and aliphatic fragments
yielding seco-acid 23 directly (Scheme 5). Yonemitsu’s modification
of the Yamaguchi esterification7 fails to give any product when
applied to seco-acid 23. Applying the Wasserman-Kita esterifi-
cation to macrolaconization27 affords the desired macrocycle 24
in ∼30% yield. However, the method of Shiina28 improves this
yield to 65%.
and alkynes as orthogonally reactive surrogates for hydroxyl and
carbonyl functionalities. Further novel features of this synthesis
include a new and highly regioselective gold catalyzed spiroket-
alization reaction, utilization of (S,S) ProPhenol in enantio- and
diastereoselective alkynylation and aldol reactions, and establish-
ment of the full structure of ushikulide A via total synthesis. Further
efforts to optimize this route and apply it to other members of the
family are underway and will be reported in due course.
Acknowledgment. We gratefully acknowledge K. Takahashi
for providing an authentic sample of ushikulide A and also S. Lynch
for his invaluable help in the acquisition of 2-D NMR data. We
thank the Stanford Graduate Fellowship Program and NIH (GM
13598) for their financial support of our program, Johnson Matthey
for their supply of precious metal salts, and Aldrich for ProPhenol.
Scheme 5. Completion of the Synthesisa
Supporting Information Available: Detailed experimental proce-
dures, full characterization of all products, and comparison NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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a Conditions: (a) 3, 9-BBN, THF; then 2, DMF, H2O, 10 mol%
PdCl2(dppf), 10 mol% Ph3As, Cs2CO3, 67%; (b) 2-methyl-6-nitrobenzoic
anhydride, 4-DMAP, DCE, 65%; (c) HF·pyridine, pyridine, THF; (d)
Dess-Martin reagent, CH2Cl2; (e) DDQ, H2O, CH2Cl2 then dilute with
3:2 AcOH/H2O, 52% over 3 steps.
Deprotection of the C-17 TBS group of 24 is accomplished under
buffered HF ·pyridine conditions (Scheme 5). Dess-Martin oxida-
tion unveils the sensitive ꢀ, γ unsaturated ketone, which is cleanly
deprotected of its three p-methoxylbenzyl ethers upon exposure to
DDQ. The resulting triol (not shown) is dissolved in a 3:2 mixture
of acetic acid and water to remove the acetonide. As the reaction
progresses, TLC analysis shows the formation of a more polar spot
of indistinguishable Rf compared to an authentic sample of
ushikulide A. Upon isolation, this compound exhibits identical 1H,
13C, IR, HRMS, and HPLC properties when compared to the same
authentic sample. Measurement of the optical rotation {[R]24
)
D
-12° (c 0.28, MeOH)} confirms that the absolute stereochemistry
also matches that of natural ushikulide A1 {[R]25D ) -13° (c 0.50,
MeOH)}. In total, these data prove our tentative assignment to be
correct and lead us to assign the complete structure of (-)-
ushikulide A as depicted below.
In summary, we report the first synthesis of (-)-ushikulide A
which establishes its relative and absolute stereochemistry. Our route
requires 21 linear and 41 total steps (2.2% yield over the linear
sequence), which is gratifying given the complexity of our target
(40 carbon atoms and 14 stereogenic centers). The efficiency of
this strategy is in no small measure due to the utilization of alkenes
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