A concise synthesis of berkelic acid inspired by combining the natural products spicifernin and pulvilloric acid

Article abstract of DOI:10.1021/ja905387r

(Chemical Equation Presented) We describe a concise synthesis of the structurally novel fungal extremophile metabolite berkelic acid, an effort leading to an unambiguous assignment of C22 stereochemistry. Our synthetic approach was inspired by the recogni

Full text of DOI:10.1021/ja905387r

Published on Web 07/24/2009
A Concise Synthesis of Berkelic Acid Inspired by Combining the Natural
Products Spicifernin and Pulvilloric Acid
Christopher F. Bender, Francis K. Yoshimoto, Christopher L. Paradise, and Jef K. De Brabander*
Department of Biochemistry and Simmons ComprehensiVe Cancer Center, The UniVersity of Texas Southwestern
Medical Center at Dallas, Dallas, Texas 75390-9038
Received June 30, 2009; E-mail: jef.debrabander@utsouthwestern.edu
Scheme 1. Synthetic Strategy
Berkeley Pit Lake in Montana, a 30 billion gallon flooded copper
mine and the largest superfund cleanup site in the United States, is
an unlikely source of structurally novel natural products. Yet, this
highly acidic, heavy-metal contaminated poisonous broth harbors
microbial life, including an extremophilic Penicilium fungus that
produces the unique tetracyclic chroman/isochroman spiroketal
berkelic acid (Figure 1). This compound, isolated by Stierle et al.
in 2006, was found to possess selective activity against the human
ovarian cancer cell line OVCAR-3 (GI50 91 nM) and moderate
inhibitory activity against the matrix metalloproteinase MMP-3
(1.87 µM) and the cysteine protease caspase-1 (98 µM).1
Scheme 2. Synthesis of Alkyne Fragmenta
Figure 1. Original and revised structures of berkelic acid.
The stereochemistry of berkelic acid was originally assigned as
shown in structure 1 on the basis of NMR experiments, although
the configuration at the quaternary stereocenter C22 and absolute
configuration were left undetermined. Recently, the Fu¨rstner group
reported studies leading to a revision of the relative stereochemistry
of berkelic acid as shown in structure 2 through total synthesis of
the corresponding methyl ester.2 Through elegant synthetic, NMR,
and crystallographic studies, they further revealed that the originally
proposed relative stereochemistry does not represent a thermody-
namic minimum because of a key syn-periplanar interaction between
the C25 methyl substituent and C16 methylene group.3 Subse-
quently, Snider and co-workers reported their total synthesis of
berkelic acid, which established its absolute configuration as shown
in 2, and putatively assigned the stereochemistry at the quaternary
center as C22-S.4,5 Herein, we wish to report a concise synthesis
of the two C22 epimers of berkelic acid (2) that fully corroborates
the revised stereochemistry and unambiguously resolves the
remaining issue of C22 stereochemistry.
Our approach was inspired by the recognition that the original
assigned berkelic acid structure 1 represents a formal combination
of the natural products spicifernin6 (3) and pulvilloric acid7
(4, Scheme 1).8 Based on this notion, we developed a strategy that
would emulate this hypothetical combination and designed a suitable
spicifernin-like synthon such as enolether 7,9 available via metal-
catalyzed cycloisomerization.10 Participation of this material in a
[4+2] cycloaddition with the ortho-quinone methide tautomer 5
of pulvilloric acid (4) would deliver spiroketal 1. It did not escape
our attention that this chemistry could potentially be implemented
with minimal oxidation state adjustments.11
a Reagents and conditions: (a) L-tBu-Val-NH2, BF3 ·Et2O, PhH, reflux
(82-88%); (b) LDA, PhMe, -78 °C, 1 h, THF (2.5 equiv), -78 °C, 3 h,
MeI, -78 °C, 17 h; (c) 1 M aq. HCl/THF (1:1), rt, 1 h; (d) TiCl4, THF, 4
Å MS, 0 °C, 30 min, NEt3, -78 °C, 1 h, PMBOCH2CHO, -78 °C, 1.5 h,
rt 1.5 h (42-45%, 3 steps); (e) 1-trimethylsilyl-1-butyne, sBuLi, THF, -78
°C, 2 h, CuBr ·SMe2, -78 °C, 1 h, then add 12, -78 °C, 24 h; (f) K2CO3,
MeOH, rt, 2 h; (g) DDQ, CH2Cl2/H2O (7:1), rt (70%, 3 steps); (h) 4-Br-
2-NO2PhNHNH2 ·HCl, EtOH, reflux, 2 d (40%, 2 steps).
Given the ambiguity related to the absolute stereochemistry at
C22, we opted for a synthesis that would enable access to the two
C22 epimers of fragment 6 (Scheme 2). Starting with commercially
available methyl 2-ethyl-3-oxobutanoate (8), the corresponding (L)-
tBu valinate-derived enamine 9 was prepared (82-88% yield) and
alkylated with methyl iodide to afford the R-quaternary substituted
imine derivative 10 with high stereoselectivity (>15:1 dr).12 The
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11350 J. AM. CHEM. SOC. 2009, 131, 11350–11352
10.1021/ja905387r CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of Aromatic Fragmenta
efficiently effected the desired conjugate propargylation.16 Although
the anti-selectivity was acceptable, the stereogenic quaternary center
did not impart any facial selectivity, leading to an inseparable
equimolar mixture of R,S- and S,R-diastereomers 13a and 13b.17
As such, this crude mixture was carried forward by treatment with
methanolic potassium carbonate, followed by oxidative deprotection
to yield compounds 14a,b. Proton NMR analysis of chromato-
graphically homogeneous material (with correct elemental analy-
sis),13 isolated in 70% yield from enone 12, indicated a complex
mixture of equilibrating lactols and open-chain isomers. The
corresponding mixture of enantiomers ent-14a,b was prepared from
the (D)-tBu valinate-derived enamine ent-9, or cheaper, by switching
the additive from THF to HMPA during the alkylation of (L)-tBu
valinate-derived enamine 9.12
A concise enantioconvergent synthesis of the precursor to
pulvilloric acid 4 begins with a cross-coupling of triflate 16,
obtained from commercially available methyl 2,4,6-trihydroxy-
benzoate 15 in 91% yield, with 1-heptenylboronic acid to afford
styrene derivative 17 (91% yield, Scheme 3). Installation of the
homobenzylic alcohol was best achieved via oxidation with
mCPBA of the MOM protected derivative of 17, followed by
benzylic epoxide reduction. Racemic alcohol 18 was thus
obtained in 76% yield for the three-step sequence. Screening of
a set of enzymes to mediate a kinetic resolution identified a
lyophilized formulation of a lipase from Alcaligenes sp. to effect
the transesterification (vinyl acetate) with high enantioselectivity
at ∼50% conversion.18 Alcohol 19 and acetate 20 were isolated
in 51% and 46% isolated yield and 93% and 95% ee, respec-
tively. Alcohol 19 was easily recycled to the desired acetate 20
via Mitsunobu esterification (78% yield). Simultaneous removal
of the protecting groups was achieved Via stirring in acidic
methanol (quant.). Condensation of the resulting triol 21 with
triethyl orthoformate according to an adapted procedure de-
scribed for the synthesis of pulvilloric acid (4) yielded isoch-
roman acetal 22 (99% yield), the precursor to pulvilloric acid
methyl ester. Although it has been reported that the carboxylic
acid corresponding to 22 will yield pulvilloric acid (4) upon
removal of ethanol under ultrahigh vacuum,7d we opted to
explore Lewis acid promoted in situ dearomatization of 22 as
described below.
a Reagents and conditions: (a) Tf2O, lutidine, CH2Cl2, 0 °C, 16 h (91%);
(b) nC5H11CHCHB(OH)2, 5% Pd(dppf)Cl2, K2CO3, THF/H2O (10:1), ∆,
i
2.5 h (91%); (c) MOMCl, Pr2NEt, CH2Cl2, 0 °C f rt, 18 h; (d) mCPBA,
CH2Cl2, rt, 5 h (84%, 2 steps); (e) Pd/CaCO3, H2, MeOH, rt, 20 h (90%);
(f) Lipase (Alcaligenes sp., lyophilized), MTBE, 4 ÅMS, vinyl acetate, rt,
7 d; (g) 0.25 M HCl in MeOH, rt, 15 h (100%); (h) (EtO)3CH, TFA, rt,
15 h (99%); (i) PPh3, DEAD, HOAc, PhMe, rt, 7 h (78%).
absolute stereochemistry at C22 was determined by a single crystal
X-ray diffraction analysis of the cyclic 4-bromo-2-nitrophenylhy-
drazone derivative 11.13 Continuing with the synthesis, hydrolysis
of crude imine 10 was followed by a titanium tetrachloride-mediated
dehydrative aldol reaction with (4-methoxybenzyloxy)ethanal yield-
ing enone 12 in 42-45% yield (3 steps) from enamine 9. We
explored various options to introduce the R-methyl-substituted
propargyl unit and settled on an approach that entails a conjugate
addition of a metalated propargyl/allenyl species to enone 12.
Although the stereoselective propargylation of aldehydes is well
precedented, we could find only one example of the corresponding
conjugate addition in the literature.15 After substantial experimenta-
tion, we found that addition of enone 12 to a cold (-78 °C) dark
red solution of a cuprate derived from adding (4-(trimethylsilyl)but-
3-yn-2-yl)lithium to a suspension of CuBr ·SMe2 in THF (-78 °C)
Scheme 4. Synthesis of Berkelic Acid (2) and C22-R Diastereomer 27a
a Reagents and conditions: (a) 14a,b or ent-14a,b (2.6 equiv), 22 (1 equiv), Et2O, rt, 2 h; (b) (Bu3Sn)2O (35 equiv), PhMe, ∆, 8 h for 2, 14 h for 27.
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C O M M U N I C A T I O N S
As noted above, we were intrigued by the possibility to effect
in situ dearomatization of lactol 22 to pulvilloric acid methyl ester
under conditions that would allow tandem C-C bond formation
with spicifernin-like fragment 14. We speculated that Ag+ would
have a proper balance of hard Lewis acidic properties to induce
removal of ethanol from 22 and sufficient alkynophilic character
to induce cycloisomerization of alkynol 14 to enolether 23 (Scheme
4).19 Gratifyingly, stirring a solution of lactol 22 (1 equiv) and
AgSbF6 (3.5 equiv) in the presence of alkynols 14a,b (2.6 equiv)
resulted in the formation of methyl berkelate 26 (from 14a) and
four additional diastereomeric berkelates 25 (from 14b)20 in a ratio
of ∼6:4, indicating a slight kinetic preference for the formation of
26. We hypothesize that AgSbF6 instigated a reaction cascade
involving (1) in situ formation of ortho-quinone methide 24,21 (2)
cycloisomerization of 14 to enolether 23, and (3) coupling Via [4+2]
cycloaddition.22
Because the methyl berkelate diastereomers were not separable
by chromatography, they were carried forward as a crude
mixture. Although Fu¨rstner and co-workers disclosed that they
could not identify conditions for the selective deprotection of
the methyl benzoate in the presence of the aliphatic methyl ester,2
we found that (Bu3Sn)2O in toluene accomplished the task when
the reaction was interrupted at partial conversion.23 Berkelic acid
2 was thus isolated in 35% isolated yield (from lactol 22) at
70% conversion and 46% yield after one recycling (77% based
on theoretical maximum yield). Prolonged reaction times resulted
in the formation of decarboxylated product 28 (∼4:1 mixture
of C22 diastereomers). The corresponding C22-R diastereomer
27 was prepared via an identical sequence from ent-14a,b and
lactol 22 in 26% yield. Only C22-S diastereomer 2 displayed
spectral data fully congruent with natural berkelic acid,1 thus
establishing the complete stereostructure of this unique natural
Supporting Information Available: Experimental procedures and
characterization data for new compounds (PDF, CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Sierle, A. A.; Sierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357–5360.
(2) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.; Goddard, R.;
Fu¨rstner, A. Angew. Chem., Int. Ed. 2008, 47, 8450–8454.
(3) Huang and Pettus reached a similar conclusion on the basis of a model
study; see: Huang, Y.; Pettus, T. R. R. Synlett 2008, 1353–1356.
(4) Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem., Int. Ed. 2009, 48, 1283–
1286.
(5) Fu¨rstner and coworkers prepared both C22 diastereomers of berkelic acid
methyl ester, but close spectral similarity and lack of an authentic sample
precluded confident assignment. The Snider assignment is based on
correlation to model compounds and thus remains to be confirmed.
(6) (a) Nakajima, H.; Hamasaki, T.; Maeta, S.; Kimura, Y.; Takeuchi, Y.
Phytochemistry 1990, 29, 1739–1743. (b) Nakajima, H.; Fukuyama, K.;
Fujimoto, H.; Baba, T.; Hamasaki, T. J. Chem. Soc., Perkin Trans. 1 1994,
1865–1869.
(7) (a) McOmie, J. F. W.; Turner, A. B.; Tute, M. S. J. Chem. Soc. C 1966,
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Ann./Recl. 1997, 213–216.
(8) This notion may or may not have biosynthetic relevance, a question that
remains to be answered. It is interesting to note that spiciferone A was
isolated alongside berkelic acid.1 Spiciferone A was also isolated together
with spicifernin from the phytopathogenic fungus Cochliobolus spicifer
Nelson,6 and both were shown to derive from a common hexaketide
precursor. Hence, the genetic machinery to produce the common precursor
to spiciferone A and spicifernin is also present in the penicilium species
that produces berkelic acid. For the biosynthesis of spiciferone A and
spicifernin, see: Nakajima, H.; Fujimoto, H.; Matsumoto, R.; Hamasaki,
T. J. Org. Chem. 1993, 58, 4526–4528.
(9) Note that enolether 7, required for berkelic acid synthesis, is at a lower
oxidation state than spicifernin 3.
(10) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907–4910.
(11) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed. 2009,
48, 2854–2867.
(12) Ando, K.; Takemasa, Y.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49,
15-79-1588.
(13) See Supporting Information.
(14) For a review on the propargylation of aldehydes, see: Marshall, J. A. J.
Org. Chem. 2007, 8153–8166.
product for the first time. The rotation of synthetic 2 ([R]D
)
(15) Song, Y.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 3543–3545.
(16) For an example of 1,2-additions to aldehydes with similarly prepared
cuprates, see: Alouane, N.; Vrancken, E.; Mangeney, P. Synthesis 2007,
1261–1264.
-76.7, c ) 0.06 in MeOH) agreed with those for natural ([R]D
) -83.5, c ) 0.0113 in MeOH)1 and Snider’s synthetic berkelic
acid ([R]D ) -115.5, c ) 0.55 in MeOH).4
(17) We are currently exploring this potentially useful transformation. Model
studies with the corresponding gem-dimethyl substituted conjugated ꢀ-ke-
toesters indicate that a γ-protected alcohol is required for high anti-
selectivity. We are also exploring the possibility to impart facial selectivity
with homochiral Marshall-type allenyl organometallic species.14 Results
of these studies will be reported in due course.
In conclusion, we have achieved a highly convergent and
efficient synthesis of berkelic acid that fully establishes the
stereochemistry at C22 in 10 steps and 11-27% overall yield
from commercially available starting materials. Notably, we
identified a unique Ag-catalyzed cascade dearomatization-
cycloisomerization-cycloaddition sequence to couple two natural
product inspired fragments and a potentially useful anti-selective
conjugate propargylation reaction.
(18) For the use of this enzyme for the resolution of benzylic and homobenzylic
alcohols, see: Naemura, K.; Murata, M.; Tanaka, R.; Yano, M.; Hirose,
K.; Tobe, Y. Tetrahedron: Asymmetry 1996, 3285–3294.
(19) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817–8152.
(20) Reaction of 14b leads to a berkelate with the original assigned stereo-
chemistry, which exists in equilibrium with C15, C17, and C18 epimers.2
(21) A silver concentration-dependent equilibrium between pulvilloric acid
methyl ester and 22 was observed by NMR (22, AgSbF6, CD2Cl2).
(22) For a review on o-quinone methides, see: Van De Water, R. W.; Pettus,
T. R. R. Tetrahedron 2002, 58, 5367–5405. For an application, see ref 3.
(23) Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett. 1988, 29, 6893–6896.
Acknowledgment. This work was supported by the NIH
(CA90349) and the Robert A. Welch Foundation. C.F.B. thanks
the NIH for a postdoctoral fellowship (T32CA12433401). We thank
Dr. Vincent Lynch (UT Austin) for X-ray analysis.
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