Total synthesis of berkelic acid

Article abstract of DOI:10.1002/chem.201001133

A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route. Queue up: Three deprotection and three bond-forming reactions, all of which are effected just by a trace of HCl, zip an easily attained enone to the polycyclic core of berkelic acid in diastereomerically pure form and essentially quantitative yield. This cascade process paves the way to a concise and effective total synthesis of this alleged metalloproteinase-3 inhibitor and cytotoxic metabolite derived from an extremophilic fungus.

Full text of DOI:10.1002/chem.201001133

FULL PAPER
DOI: 10.1002/chem.201001133
Total Synthesis of Berkelic Acid
Thomas N. Snaddon, Philipp Buchgraber, Saskia Schulthoff, Conny Wirtz,
Richard Mynott, and Alois Fꢀrstner*[a]
Abstract: A productive total synthesis
aldol condensation, in which the acetyl
residue in 20 transforms from a passive
protecting group into an active partici-
pant. Access to fragment 25 takes ad-
vantage of the Collum–Godenschwager
variant of the ester enolate Claisen re-
arrangement, which clearly surpasses
the classical Ireland–Claisen procedure
in terms of diastereoselectivity. Al-
though it is possible to elaborate 32
into the target without any additional
manipulations of protecting groups, a
short detour consisting in the conver-
of both enantiomers of berkelic acid
(1) is outlined that takes the structure
revision of this bioactive fungal meta-
ꢁ
sion of the phenolic OH into the cor-
bolite previously proposed by our
responding TBS-ether is beneficial. It
tempers the sensitivity of the com-
pound toward oxidation and hence im-
proves the efficiency and reliability of
the final stages. Orthogonal ester
groups for the benzoate and the ali-
phatic carboxylate terminus of the side
chain secure an efficient liberation of
free berkelic acid in the final step of
the route.
group into account. The successful
route relies on a fully optimized triple-
deprotection/1,4-addition/spiroacetali-
zation cascade reaction sequence,
which delivers the tetracyclic core 32
of the target as a single isomer in ex-
cellent yield. The required cyclization
precursor 31 is assembled from the
polysubstituted benzaldehyde deriva-
tive 20 and methyl ketone 25 by an
Keywords: Anticancer agents · en-
zyme inhibitors · natural products ·
spiro compounds · total synthesis
Introduction
vide strategic advantages over compounds derived from
more technology-based approaches to drug discovery,[1,2] in
particular since natureꢀs bounty remains relatively untap-
ped.[3]
Natural products have a prestigious history in human medi-
cine as drugs or drug precursors. As such, they continue to
play an overly important role in particular for the treatment
of chronic ailments, infectious diseases, and cancers, as well
as for the modulation of the immune system. Changing
paradigms in the pharmaceutical industry, however, have
disfavored natural product chemistry during the last de-
cades. The slow rate of discovery of relevant new hits from
natural sources, difficulties in purification and structure as-
signment, undesirable levels of (stereochemical) complexity,
as well as serious supply problems are often considered non-
competitive. Yet, the evolutionary wisdom encoded in the
structure of a small molecule natural product lead may pro-
Berkelic acid (1) is a good example that illustrates both
sides of the coin of contemporary natural product chemistry.
This stereochemically dense secondary metabolite was iso-
lated from an extremophilic Penicillium species harvested
from the surface waters of Berkeley Pit Lake, a flooded
former copper mine in Butte, Montana.[4,5] The environment
of this lake is very hostile, with highly acidic waters (pH
ꢀ2.5) rich in a plethora of heavy metal salts. Whereas the
role of berkelic acid in the producing fungus is currently un-
known, this compound was reported to display selective ac-
tivity against the human ovarian cancer cell line OVCAR-3
(GI50 = 91 nm).[4] Moreover, it was reported to be a pro-
nounced inhibitor of the cysteine protease caspase-1 (98 mm)
as well as the matrix metalloproteinase MMP-3 (1.87 mm).[4]
As emphasized by the isolation team, MMP-3 is upregulated
in OVCAR-3 but not in other ovarian cancer cell lines,[4]
even though it remains speculative at this point whether the
reported inhibition of this particular enzyme and the cyto-
toxicity profile of berkelic acid are directly correlated or
not.
[a] Dr. T. N. Snaddon, Dr. P. Buchgraber, S. Schulthoff, C. Wirtz,
Dr. R. Mynott, Prof. Dr. A. Fꢁrstner
Max-Planck-Institut fꢁr Kohlenforschung
45470 Mꢁlheim/Ruhr (Germany)
Fax : (+49) 208 306 2994
E-mail: fuerstner@kofo.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001133.
Chem. Eur. J. 2010, 16, 12133 – 12140
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12133

Matrix metalloproteinases (MMPs) are a family of zinc-
dependent endopeptidases that play a key role in the degra-
dation of the extracellular matrix.[6] Collectively, they are in-
volved in various physiological and pathological processes
responsible for, amongst others, osteoarthritis, rheumatoid
arthritis, multiple sclerosis, cirrhosis and tumor metastasis.[7]
The biological importance of this family of enzymes has led
to significant interest in the development of small-molecule
inhibitors of specific MMPs, which could lead to novel and
effective therapeutic agents.[8] Most of the existing synthetic
MMP inhibitors are peptide-derived and/or contain a func-
tional group capable of bidentate chelation of the catalytic
zinc ion within the MMP active site.[8,9] Since berkelic acid
features neither of these structural elements, it may consti-
tute an alternative starting point in the quest for pharma-
ceutically relevant MMP-3 inhibitors.
Results and Discussion
Structural issues and strategic considerations: Our original
retrosynthesis was directed at structure 3 proposed by
Stierle et al.[4] and had to take the then unknown stereo-
chemistry of the all-carbon-quarternary center at C22 into
account (Scheme 2). To this end, a convergent approach was
pursued that would allow for the incorporation of either
enantiomer of aldehyde A at a late stage. The suitably pro-
tected core structure B would be assembled by a Michael
addition/spiroacetalization cascade from the linear precursor
C, which would itself derive from aldehyde D and methyl
ketone E by an aldol condensation.[10,14,15]
Attracted by the distinctive architecture of berkelic acid
and intrigued by its promising biological properties, we initi-
ated a program aiming at a secured access to this fungal me-
tabolite and analogues thereof via total synthesis. In a pre-
liminary Communication, we reported our route to berkelic
acid methyl ester (2), which entailed a major reassignment
of the stereostructure of the tetracyclic core of the target
(Scheme 1).[10,11] Herein we present an account of further
Scheme 2. Retrosynthetic analysis of the originally proposed but incor-
rect structure 3 of berkelic acid.
Much to our surprise, however, treatment of 4 as the syn-
thetic equivalent of the envisaged cyclization precursor C
with dilute HCl furnished an almost statistical mixture of
the diastereomeric spiroacetal products 5–8 (Scheme 3).[10]
In contrast to a previous model study by Snider,[11a] attempts
to equilibrate the crude mixture by exposure to various
acids were futile. Similarly, treatment of any of the pure iso-
mers with PPTS rapidly regenerated the original product
distribution. The structure of all four isomers could be es-
tablished beyond doubt by extensive NMR studies and inde-
pendently confirmed by a crystal structure analysis of 5, the
stereoisomer corresponding to the originally proposed core
structure of berkelic acid.[10] However, the 13C NMR of 5 re-
vealed several significant deviations from the chemical shifts
reported for the natural product that could not be attributed
to the truncated side chain (Table 1). Most importantly, the
shift of the C25 methyl group (d = 14.38 ppm) differed con-
siderably from the corresponding signal in berkelic acid (d
= 11.9 ppm). NOESY analyses and the solid-state structure
of 5 revealed an unfavorable syn-periplanar arrangement of
this C25 methyl branch and the C16 methylene group of the
adjacent tetrahydropyran ring. Although isomers 6–8 avoid
Scheme 1. Proposed and revised structures of berkelic acid. The all-
carbon quarternary stereocenter at C22 remained unassigned in the origi-
nal publication.[4]
synthetic efforts that address the deficiencies in our initial
synthesis and allowed us to obtain both enantiomers of the
free acid 1 itself. While this work was in progress, Snider
and co-workers completed a synthesis of (ꢁ)-1, which con-
firmed our structural revision, established the absolute con-
figuration and tentatively designated the stereochemistry of
the C22-quaternary center.[12] Shortly thereafter, De
Brabander and co-workers also reached (ꢁ)-1 by emulating
a conceivable biosynthesis route, and in so doing conclusive-
ly assigned the C22-(S) stereochemistry.[13]
12134
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12133 – 12140

Total Synthesis of Berkelic Acid
FULL PAPER
such an eclipsing interaction, their spectral data did not
match those of berkelic acid either (see Table 1).[10]
These results made clear that the original structure 3[4]
must be incorrect.[10,16,17] Based on the comprehensive data
set and the inspection of molecular models we concluded
that 1 or its antipode ent-1 might describe this natural prod-
uct correctly. In excellent agreement with this notion, treat-
ment of compound 9 (which is nothing but the C9-epimer of
4) with dilute HCl provided only one major product 10, the
NMR data and NOESY correlations of which nicely corre-
sponded to those reported for the natural product
(Scheme 4 and Table 1).[10] The stereostructure was con-
Scheme 3. Key experiment suggesting that the originally proposed stereo-
structure of berkelic acid needed major revision: a) acetyl chloride,
MeOH/CH2Cl2, 08C!RT, 91 % (5/6/7/8 0.9:1:0.8:1.3), cf. ref. [10].
Table 1. Comparison of relevant 13C NMR data of 5–8 and 10 with those
of berkelic acid reported in the literature; numbering scheme as shown
for 5 in Scheme 3. In this comparison, one must keep in mind that the
synthetic samples are aromatic methyl esters, whereas the natural prod-
uct has a free carboxylic acid at C1. Characteristic deviations within the
chromane spiroacetal segment are highlighted in bold.
Position
Ref.[a]
5[b]
6[b]
7[b]
8[b]
10[b]
1
2
3
4
5
6
7
8
173.6
101.0
163.4
109.4
142.3
113.7
153.0
35.4
76.5
37.4
26.2
33.0
23.7
14.4
69.4
35.0
110.7
49.2
11.9
171.83
103.31
161.20
109.08
141.29
114.20
152.69
35.41
76.69
37.49
26.19
33.03
23.70
14.39
69.77
34.16
112.38
50.98
14.38
72.42
171.61
103.82
160.67
108.94
140.86
114.08
152.35
35.38
76.61
37.47
26.23
33.06
23.73
14.43
69.73
35.84
110.53
47.15
10.56
74.06
172.04
103.68
162.04
109.84
141.47
117.02
153.81
35.03
76.12
37.22
26.22
33.07
23.70
14.41
69.66
39.41
111.69
51.99
11.98
72.94
172.30
102.44
162.52
108.62
143.22
114.23
152.72
35.08
73.56
36.41
26.32
33.04
23.76
14.43
63.29
35.46
110.62
50.12
11.36
73.14
172.20
102.18
162.06
108.97
141.78
113.98
152.91
35.41
76.57
37.44
26.21
33.06
23.73
14.43
69.58
35.19
110.49
50.06
11.23
73.12
Scheme 4. Synthesis-driven structure revision for berkelic acid methyl
ester exemplified for the 22R isomer. This synthesis had been performed
before the absolute configuration of the natural product was known and
led to what turned out to be the non-natural enantiomer: a) acetyl chlo-
ride, MeOH/CH2Cl2, 08C ! RT, 94% (d.r. ꢃ12.5:1), cf. ref. [10].
9
10
11
12
13
14
15
16
17
18
25
26
firmed by X-ray analysis of the derived iodide 11
(Figure 1).[18] This compound could then be converted into
both C22 diastereoisomers of berkelic acid methyl ester, but
the oxidation of the intermediate alcohol 12 containing an
electron-rich phenol core was plagued by undesirable side
reactions and was therefore rather low yielding.[10]
Even though the NMR spectra of the two C22 isomers of
ent-2 recorded at 600 MHz were subtly different, an unam-
biguous assignment of the rogue C22 quaternary center was
not possible since no authentic sample of 2 could be made
available for direct comparison. On the other hand, our at-
tempt to form the free acid ent-1 by selective cleavage of
the methyl benzoate function in the presence of the aliphat-
74.1
[a] Ref. [4]; in CD3OD at 125 MHz. [b] In CD3OD at 150.9 MHz. The
solvent signal was used as reference and the chemical shifts are given rel-
ative to TMS (dC ꢂ 49.0 ppm). The samples were all measured under the
same experimental conditions and the chemical shifts in the Table are
given to two decimal places for the sake of better internal comparison.
Chem. Eur. J. 2010, 16, 12133 – 12140
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12135

A. Fꢁrstner et al.
Figure 1. Structure of one of the two crystallographically independent
molecules of 11 in the solid state. The anisotropic displacement parame-
ter ellipsoids are drawn at the 50% probability level.[18]
ic methyl ester in the side chain remained unsuccessful
(Scheme 4).[10] De Brabander and co-workers later found
that (Bu3Sn)2O in toluene accomplished this task, but in
their case the reaction had to be stopped at partial conver-
sion.[13]
Scheme 5. a) BBr3, CH2Cl2, ꢁ788C ! RT, 95%; b) BnBr, K2CO3, DMF,
91%; c) [CuCl
(cod)] (10 mol%), (R)-2-pentyloxirane, ꢁ508C ! RT,
74%; d) H2, Pd/C (10% w/w), MeOH, quant.; e) CO2 (1 atm), KHCO3,
glycerin, 1508C; f) NEt3, BnBr, DMF, RT, 59% (over both steps);
g) TBSCl, imidazole, CH2Cl2, 89%; h) K2CO3, MeOH, 458C, 72%; i) N-
iodosuccinimide, CH2Cl2, 85%; j) 1) MeLi, Et2O, ꢁ1058C; 2) tBuLi,
ꢁ1008C; 3) DMF, ꢁ105 ! ꢁ358C; 4) AcCl, ꢁ55 ! ꢁ258C, 75%. Bn =
benzyl, cod = 1,5-cyclooctadiene, TBS = tert-butyldimethylsilyl.
The lessons learnt during our own synthesis-driven struc-
ture revision campaign, together with the additional infor-
mation gathered by the Snider and De Brabander groups,
defined the following objectives for the second phase of our
project: First and foremost, the two esters must be distin-
guished by an orthogonal protecting group regimen to
enable an effective release of free berkelic acid in the final
step of the sequence. Moreover, the sensitivity of the elec-
tron-rich pentasubstituted aromatic ring in 1, which plagued
the efficiency of our initial effort, has to be tempered
through adequate late-stage manipulations. If successful,
these modifications should enable a convergent assembly of
the target from relatively simple building blocks, while
taking advantage of an efficient cascade reaction sequence
for the formation of the complex polycyclic skeleton.[19] In
combination with optimized fragment syntheses, this strat-
egy should result in a productive, scalable and flexible
second generation total synthesis of this promising target,
which was realized as outlined below.
reaction of the highly functionalized aryl–lithium intermedi-
ate thus formed with DMF, followed by quenching the reac-
tion with acetyl chloride resulted in formylation of the
arene[23] and acylation of the phenol to give product 20.
That attempts to acylate the phenol in a separate event met
with failure suggests that the presence of two ortho carbonyl
functions largely reduces its nucleophilicity. The presence of
an acetyl group, however, was desirable as it would take an
active role in the projected aldol condensation (see below).
A suitable synthesis of fragment E hinges on the efficient
installation of the vicinal stereocenters (Scheme 6). Mindful
of the prowess of the Claisen rearrangement[24] and recog-
nizing that E should be accessible from a g,d-unsaturated
carboxylic acid motif, ester 23 was prepared by Mitsunobu
esterification[25] of known lactate-derived alcohol 22[26] with
propionic acid. Whilst this reaction proceeded well under a
Preparation of the building blocks: The preparation of the
key building blocks followed similar lines to our initial Com-
munication[10] but was fully optimized for larger material
throughput. Each route is concise and scalable and gives
ready access to either enantiomer.
Specifically, the preparation of building block D began
with CuI-catalyzed ring opening of (R)-pentyloxirane (>
99% ee)[20] by the Grignard reagent derived from 3,5-bis(-
benzyloxy)-1-bromobenzene (14)[21] giving 15 (Scheme 5).
Subsequent hydrogenolysis of the benzyl ethers and Kolbe–
Schmitt carboxylation[22] of bis-phenol 16 afforded the corre-
sponding carboxylic acid, which was converted into benzyl
ester 17. This group is orthogonal to the methyl ester in the
side chain yet to be installed and can be cleaved under con-
ditions that should not endanger the oxidation-sensitive
phenol in the late stages of the synthesis. Global silylation
of 17 followed by selective mono-desilylation and regiose-
lective iodination gave 19. Finally, lithium–iodine exchange,
Scheme 6. a) Ref. [26] (96% ee); b) propionic acid, PPh3, DIAD, toluene,
59% (93% ee); c) 1) LiHMDS, NEt3, toluene, ꢁ788C
!
RT; 2)
TMSCHN2, MeOH, 77–81% (over both steps anti/syn 96:4); d) Me-
A
08C, 92%. DIAD = diisopropyl azodicarboxylate, LiHMDS = lithium
hexamethyldisilazide.
12136
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12133 – 12140

Total Synthesis of Berkelic Acid
FULL PAPER
variety of conditions, a significant erosion of enantiopurity
was observed when conducted in THF (96 ! 83% ee).
However, switching to the less polar toluene gave 23 in an
acceptable 93% ee.
All attempts to further improve this procedure or to effect
the same transformation using chemical oxidants (i.e., NIS
or NBS)[32] largely met with failure. While, in principle, ent-
30 could be accessed from the same starting material simply
by reversing the order of the alkylation steps (i.e., ethylation
prior to methylation), such a process resulted in significantly
reduced enolate reactivity towards the second electrophilic
partner and poorer levels of diastereoselection. Thus, we
chose to prepare the antipode ent-30 by the existing proce-
dure beginning from dimethyl-l-malate (ent-26).
In our initial Communication, a standard Ireland–Claisen
rearrangement of the silylketene acetal derived from ent-23
(KHMDS, TMSCl, toluene)[27,28] provided, upon methyla-
tion, anti-24 in good yield and acceptable diastereoselectiv-
ity (d.r. 10.2:1).[10] Whilst the minor diastereomer could be
removed at a later stage, we were keen to find a more effi-
cient method. Collum and Godenschwager have recently re-
ported intriguing conditions for the enolization of acyclic
ketones and esters.[29] As part of a sustained and comprehen-
sive investigation of the nature and reactivity of lithium
bases and enolates, these authors recognized that deprotona-
tions of esters mediated by a combination of LiHMDS and
NEt3 in toluene are extremely fast and occur with unprece-
dented E/Z selectivity. Furthermore, the resultant lithium
ester enolates themselves undergo Claisen rearrangement
with outstanding levels of diastereoselection (E/Z >30:1)
without needing to form the corresponding silylketene ace-
tals in situ.[29] The fact that enolization occurs up to 20 times
faster in the absence of THF and, in any event, the corre-
sponding THF-ligated enolates fail to undergo efficient rear-
rangement renders this one of the most significant modern
developments in Claisen chemistry. Indeed, rearrangement
of 23 under the Collum–Godenschwager conditions afforded
ester 24 in good yield and vastly improved diastereoselectiv-
ity (d.r. 96:4) on a gram scale after methylation of the crude
acid. Subsequent transformation of 24 into the correspond-
ing Weinreb amide[30] and addition of MeMgBr at low tem-
perature readily gave the desired fragment 25.
Fragment linkage and core assemblage: In analogy to our
initial report, but now working in the correct stereochemical
series,[10] fragments D and E were joined together by an
aldol condensation. Specifically, the kinetic enolate of
Fragment A containing the all-carbon quarternary center
was prepared in either enantiomeric form by following a lit-
erature procedure (Scheme 7).[31] Thus, treatment of dimeth-
Scheme 7. a) 1) LDA, THF, ꢁ788C; 2. MeI, ꢁ708C, 50%; b) 1. LDA,
THF, ꢁ788C; 2. EtI, ꢁ78 ! 48C, 60%; c) KOH, MeOH/H2O (9:1), 94–
99%; d) NEt3, MeOH, Pt-electrodes, 24 V, 55–59%. LDA = lithium di-
ACHTUNGTRENNUNGisopropylamide.
Scheme 8. a) 25, LDA, THF, ꢁ788C ! RT, 65%; b) acetyl chloride,
MeOH/CH2Cl2, 08C ! RT, 92%; c) TBSCl, imidazole, CH2Cl2, RT,
98%; d) 1. OsO4 (2 mol%), N-methylmorpholine-N-oxide, acetone; 2.
yl-d-malate (26) with LDA (2.1 equiv) followed by C-alkyla-
tion of the resulting dianion with methyl iodide gave 27. A
second alkylation using ethyl iodide as the electrophilic
partner furnished 28 (d.r. 95:5), which was selectively sapo-
nified to the corresponding a-hydroxy acid 29. Electrochem-
ical oxidative decarboxylation of 29 occurred in well repro-
ducible 55–59% yield to give the required aldehyde 30.[31]
Pb
G
steps); e) I2, PPh3, imidazole, CH2Cl2, 94%; f) 1. tBuLi, Et2O, ꢁ1058C,
then 30; 2. DMP, K2CO3, CH2Cl2, 08C, 74% (over two steps); g) Bu4NF,
THF, 95%; h) H2, Pd(OH)2 (10% w/w), EtOAc, RT, 88%. LDA = lithi-
um diisopropylamide, TBS
Martin periodinane.
=
tert-butyldimethylsilyl, DMP
=
Dess–
Chem. Eur. J. 2010, 16, 12133 – 12140
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12137

A. Fꢁrstner et al.
methyl ketone 25 was reacted with aldehyde 20 to provide
product 31 (Scheme 8). This transformation takes advantage
of the acetyl group in the substrate, which migrates from the
phenolic site in 20 to the more basic alkoxide generated in
the initial step. The released phenoxide then promotes elim-
ination of the resulting acetate ester to give the required
enone 31. Subsequent treatment with HCl/MeOH provided
compound 32 as a single isomer in 92% yield through an
obviously well-orchestrated triple-deprotection/1,4-addition/
spirocyclization cascade; no sign of trans-esterification was
observed.
Scheme 9. a) OsO4 (5 mol%), NMO, acetone; b) PbACHTNUGRTNE(UGN OAc)4, CH2Cl2; c)
NaClO2, NaH2PO4, tBuOH/H2O 2:1, (2E)-butene; d) TMSCHN2,
MeOH, 08C, 96% (over four steps); e) Bu4NF, THF; f) H2 (1 atm),
Pd(OH)2 cat., EtOAc, 85% (over both steps).
At this juncture we considered a minor diversion from
our initial synthesis, the latter stages of which had suffered
from the fact that the free phenol in the assembled core was
highly susceptible to oxidation.[33] As such, protection of the
phenol as its TBS ether 33 resulted in a vast improvement,
with the three-stage conversion to 34 proceeding in high
yield. Despite the advantages offered by the new protecting
group, its lability required some optimization of the reaction
conditions. Specifically, during the oxidative cleavage of the
intermediate diol formed by OsO4-catalyzed dihydroxylation
of 33, the TBS group could be completely retained only if
the stoichiometry of the oxidant was rigorously controlled.
was easily attained by subjecting the crude aldehyde formed
by the oxidative cleavage of the olefinic terminus in 33 to
Pinnick oxidation[36] and esterification with trimethylsilyl di-
azomethane. Subsequent cleavage of the silyl group in 37
and hydrogenolysis of the remaining benzyl ester gave the
truncated congener 38 for biological testing. With this mate-
rial and our synthetic samples of analytically pure (ꢁ)-1,
(+)-1 and the 22S-diastereomer thereof in hand (cf. Experi-
mental Section), we hope to resolve a puzzle resulting from
contradictory reports from the groups of Stierle and Snider.
Whereas the isolation team claimed highly selective cytotox-
icity for berkelic acid against the OVCAR-3 tumor cells, as
outlined in the Introduction,[4] the latter group found that
their synthetic material did not show significant activity at
10ꢁ5 m concentration when profiled in the NCI 60 cancer
cell-line assay.[12b] The results of our investigation will be re-
ported in a separate publication in due time.
To this end, one equivalent of a stock solution of PbACTHNUTRGNEUNG(OAc)4
in CH2Cl2 was added dropwise and the reaction monitored
closely by TLC. Reduction of the resulting crude aldehyde
with NaBH4 in MeOH also led to partial deprotection; how-
ever, employing a milder mixed-phase THF/H2O system left
the TBS ether untouched. Conversion of alcohol 34 thus
formed into iodide 35 again occurred with partial TBS de-
protection, which was attributed to residual hydrogen iodide
in the commercial iodine and/or to impurities in the imida-
zole. Gratifyingly, the use of freshly sublimed and recrystal-
lized reagents allowed for full retention of the protective
group.
Conclusion
A concise and productive total synthesis of berkelic acid (1)
has been accomplished that takes the structure revision pre-
viously proposed by our group into account and remedies
the shortcomings of the original route.[10] Specifically, the
tetracyclic core 32 of the target was assembled as a single
diastereomer by a triple-deprotection/1,4-addition/spiroace-
talization cascade, which proceeded with remarkable effi-
ciency. The required cyclization precursor 31 was obtained
from segments 20 and 25 by an aldol condensation, in which
the phenolic acetate moiety adjacent to the aldehyde in 20
not only serves as a passive protecting group but also takes
an active and productive role. The preparation of the
methyl ketone 25 benefits from the Collum–Godenschwager
modification of the ester enolate Claisen rearrangement,
which proved superior to the classical Ireland–Claisen pro-
cess in terms of diastereoselectivity. Although our previous
work had shown that the elaboration of 32 into the target
can be accomplished without any extra protecting group ma-
nipulation, the short detour of blocking the free phenolic
site as a TBS-ether was found to be highly beneficial. Whilst
this tactic added two extra steps to the longest linear se-
quence, it tempered the sensitivity of the pentasubstituted
arene ring toward oxidation and hence greatly improved the
For the final fragment coupling, the pre-nucleophile 35
was subjected to halogen–metal exchange at low tempera-
ture followed by the addition of aldehyde 30. Oxidation of
the resulting secondary alcohol with Dess–Martin periodin-
ACHTUNGTRENNUNG
ane[34] afforded fully protected berkelic acid 36. Fluoride-in-
duced desilylation followed by hydrogenolysis of the benzyl
ester over Pearlmanꢀs catalyst[35] proceeded uneventfully to
provide berkelic acid (ꢁ)-1. The recorded spectra for the
synthetic samples were fully consistent with the published
data, and the optical rotation of 1 was also in good agree-
ment with those for natural and synthetic berkelic acid re-
ported in the literature.[4,12,13] It should be noted, however,
that we encountered problems in the purification, handling
and storage of berkelic acid such that oxidative degradation
was a common frustration. Only the use of carefully de-
gassed solvents and storage in a matrix of frozen and de-
gassed benzene resolved these issues. Suffice it to mention
that the synthesis of non-natural berkelic acid (+)-1 has
also been accomplished by the same route (see the Experi-
mental Section).
Finally, we prepared an analogue deprived of the side
chain carrying the quaternary center (Scheme 9). This goal
12138
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12133 – 12140

Total Synthesis of Berkelic Acid
FULL PAPER
Chem. 2009, 52, 6347–6361; c) S. M. Marques, E. Nuti, A. Rossello,
C. T. Supuran, T. Tuccinardi, A. Martinelli, M. A. Santos J. Med.
Chem. 2008, 51, 7968–7979 and references therein.
productivity and reproducibility of the route. The choice of
orthogonal ester groups for the benzoate and the aliphatic
carboxylate terminus of the side chain ensured an efficient
release of free berkelic acid in the final step. Collectively,
the modifications allowed us to obtain (ꢁ)-1 in ꢀ5% yield
over the 19 steps in the longest linear sequence. Moreover,
the flexibility inherent to the successful blueprint qualifies it
as a basis for a future synthesis-driven molecular editing of
this interesting fungal metabolite.[37]
[10] P. Buchgraber, T. N. Snaddon, C. Wirtz, R. Mynott, R. Goddard, A.
Fꢁrstner, Angew. Chem. 2008, 120, 8578–8582; Angew. Chem. Int.
Ed. 2008, 47, 8450–8454.
[11] For studies toward berkelic acid and simplified model compounds,
see: a) J. Zhou, B. B. Snider, Org. Lett. 2007, 9, 2071–2074; b) M.
A. Marsini, Y. Huang, C. C. Lindsey, K.-L. Wu, T. R. R. Pettus, Org.
Lett. 2008, 10, 1477–1480; c) Y. Huang, T. R. R. Pettus, Synlett 2008,
1353–1356; d) N. Stiasni, M. Hiersemann, Synlett 2009, 2133–2136;
e) Z. E. Wilson, M. A. Brimble, Org. Biomol. Chem. 2010, 8, 1284–
1286.
[12] a) X. Wu, J. Zhou, B. B. Snider, Angew. Chem. 2009, 121, 1309–
1312; Angew. Chem. Int. Ed. 2009, 48, 1283–1286; b) X. Wu, J.
Zhou, B. B. Snider, J. Org. Chem. 2009, 74, 6245–6252.
[13] C. F. Bender, F. K. Yoshimoto, C. L. Paradise, J. K. De Brabander, J.
Am. Chem. Soc. 2009, 131, 11350–11352.
Experimental Section
The entire experimental section can be found in the Supporting Informa-
tion, including compound characterization data and copies of NMR spec-
tra.
[14] For a recent example of a deprotection/spiroketalization cascade as
a key step of a total synthesis from this laboratory, see: a) G. W.
O’Neil, J. Ceccon, S. Benson, M.-P. Collin, B. Fasching, A. Fꢁrstner,
Angew. Chem. 2009, 121, 10124–10129; Angew. Chem. Int. Ed.
2009, 48, 9940–9945; b) S. Benson, M.-P. Collin, G. W. O’Neil, J.
Ceccon, B. Fasching, M. D. B. Fenster, C. Godbout, K. Radkowski,
R. Goddard, A. Fꢁrstner, Angew. Chem. 2009, 121, 10130–10134;
Angew. Chem. Int. Ed. 2009, 48, 9946–9950.
[15] For reviews on spiroacetals, see: a) F. Perron, K. F. Albizati, Chem.
Rev. 1989, 89, 1617–1661; b) J. E. Aho, P. M. Pihko, T. K. Rissa,
Chem. Rev. 2005, 105, 4406–4440.
[16] For a review on natural products of mistaken identity, see: K. C.
Nicolaou, S. A. Snyder, Angew. Chem. 2005, 117, 1036–1069;
Angew. Chem. Int. Ed. 2005, 44, 1012–1044.
Acknowledgements
Generous financial support by the MPG, the Chemical Genomics Center
(CGC) Initiative of the MPG, and the Fonds der Chemischen Industrie is
gratefully acknowledged. We thank Professor A. A. Stierle and Professor
D. B. Stierle, Montana Tech of the University of Montana, for providing
copies of spectra, Dr. Richard Goddard for solving the crystal structure
of compound 11, and the chromatography department of our Institute for
excellent support.
[17] For other total syntheses from this laboratory which led to the revi-
sion of the originally proposed structures of bioactive natural prod-
ucts or the clarification of previously unknown structural details,
see: a) A. Fꢁrstner, K. Radkowski, C. Wirtz, R. Goddard, C. W.
Lehmann, R. Mynott, J. Am. Chem. Soc. 2002, 124, 7061–7069;
b) A. Fꢁrstner, M. Albert, J. Mlynarski, M. Matheu, E. DeClercq, J.
Am. Chem. Soc. 2003, 125, 13132–13142; c) A. Fꢁrstner, J. Ruiz-
Caro, H. Prinz, H. Waldmann, J. Org. Chem. 2004, 69, 459–467;
d) A. Fꢁrstner, K. Radkowski, H. Peters, Angew. Chem. 2005, 117,
2837–2841; Angew. Chem. Int. Ed. 2005, 44, 2777–2781; e) A. Fꢁrst-
ner, K. Radkowski, H. Peters, G. Seidel, C. Wirtz, R. Mynott, C. W.
Lehmann, Chem. Eur. J. 2007, 13, 1929–1945; f) A. Fꢁrstner, E. K.
Heilmann, P. W. Davies, Angew. Chem. 2007, 119, 4844–4847;
Angew. Chem. Int. Ed. 2007, 46, 4760–4763; g) A. Fꢁrstner, O. Lar-
ionov, S. Flꢁgge, Angew. Chem. 2007, 119, 5641–5644; Angew.
Chem. Int. Ed. 2007, 46, 5545–5548; h) A. Fꢁrstner, L. C. Bouchez,
L. Morency, J.-A. Funel, V. Liepins, F.-H. Porꢃe, R. Gilmour, D.
Laurich, F. Beaufils, M. Tamiya, Chem. Eur. J. 2009, 15, 3983–4010.
[18] Figure 2 in our original communication erroneously displayed com-
pound 5 rather than iodide 11 as stated in the legend. Although the
structure of the iodide was contained in the Supporting Information
and had been deposited at the Cambridge Crystallographic Data
Centre, we present it here again to avoid any doubts or ambiguities.
CCDC 693829 (11) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[1] For a discussion, see the following references and literature cited
therein: a) K. Kumar, H. Waldmann, Angew. Chem. 2009, 121,
3272–3290; Angew. Chem. Int. Ed. 2009, 48, 3224–3242; b) I. Pater-
son, E. A. Anderson, Science 2005, 310, 451–453; c) J. Mann, Nat.
Rev. Cancer 2002, 2, 143–148.
[2] For a detailed analysis of how many drugs introduced to the market
over the last decades derive from natural products, see: a) D. J.
Newman, G. M. Cragg, K. M. Snader, J. Nat. Prod. 2003, 66, 1022–
1037; b) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2007, 70, 461–
477; c) G. M. Cragg, P. G. Grothaus, D. J. Newman, Chem. Rev. 2009,
109, 3012–3043.
[3] For example, it has been estimated that less than 1% of all bacteria
has been cultured. This gives some indication of the enormous task
and unexploited potential that lies ahead, cf.: J. Clardy, C. Walsh,
Nature 2004, 432, 829–837.
[4] A. A. Stierle, D. B. Stierle, K. Kelly, J. Org. Chem. 2006, 71, 5357–
5360.
[5] A. A. Stierle, D. B. Stierle, in Bioactive Natural Products (Part L)
(Ed.: Atta-ur-Rahman), Stud. Nat. Prod. Chem., Vol. 32, Part 12,
Elsevier, Amsterdam, 2005, pp. 1123–1175.
[6] C. E. Brinckerhoff, L. M. Matrisian, Nat. Rev. Mol. Cell Biol. 2002,
3, 207–214.
[7] G. Murphy, H. Nagase, Mol. Aspects Med. 2008, 29, 290–308.
[8] a) Inhibition of Matrix Metalloproteinases: Therapeutic Applications
(Eds.: R. A. Greenwald, S. Zucker, L. M. Golub), Ann. N. Y. Acad.
Sci., Vol. 878, 1999; b) H. Matter, M. Schudok, Curr. Opin. Drug
Discovery Dev. 2004, 7, 513–535; c) M. Whittaker, C. D. Floyd, P.
Brown, A. J. H. Gearing, Chem. Rev. 1999, 99, 2735–2776; d) C. M.
Overall, O. Kleifeld, Nat. Rev. Cancer 2006, 6, 227–239.
[9] a) Marimastat is one such molecule; however, poor performance in
clinical trials led to its withdrawal, see: J. A. Sparano, P. Bernardo,
P. Stephenson, W. P. Gradishar, J. N. Ingle, S. Zucker, N. E. David-
son, J. Clin. Oncol. 2004, 22, 4683–4690; b) for further investiga-
tions, see: E. Nuti, L. Panelli, F. Casalini, S. I. Avramova, E. Orlan-
dini, S. Santamaria, S. Nencetti, T. Tuccinardi, A. Martinelli, G. Cer-
cignani, N. D’Amelio, A. Maiocchi, F. Uggeri, A. Rossello, J. Med.
[19] For cascade-, domino- and tandem reaction sequences, see the fol-
lowing for leading reviews and references therein: a) L. F. Tietze, U.
Beifuss, Angew. Chem. 1993, 105, 137–170; Angew. Chem. Int. Ed.
Engl. 1993, 32, 131–163; b) K. C. Nicolaou, D. J. Edmonds, P. G.
Bulger, Angew. Chem. 2006, 118, 7292–7344; Angew. Chem. Int. Ed.
2006, 45, 7134–7186; c) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev.
2009, 38, 2993–3009.
[20] Prepared by hydrolytic kinetic resolution (HKR), see: S. E. Schaus,
B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E.
Chem. Eur. J. 2010, 16, 12133 – 12140
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12139

A. Fꢁrstner et al.
Gould, M. E. Furrow, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124,
1307–1315.
[32] T. R. Beebe, R. L. Adkins, A. I. Belcher, T. Choy, A. E. Fuller, V. L.
Morgan, B. B. Sencherey, L. J. Russell, S. W. Yates, J. Org. Chem.
1982, 47, 3006–3008.
[21] T. Rçdel, H. Gerlach, Liebigs Ann. Chem. 1997, 213–216.
[22] A. S. Lindsey, H. Jeskey, Chem. Rev. 1957, 57, 583–620.
[23] An attempt to circumvent the iodination/lithiation by direct ortho-
formylation of the phenol according to the following literature pro-
cedure was unrewarding, cf., T. V. Hansen, L. Skattebøl, Org. Synth.
2005, 82, 64–67.
[24] a) A. M. Martꢄn Castro, Chem. Rev. 2004, 104, 2939–3002; b) Y.
Chai, S. Hong, H. A. Lindsay, C. McFarland, M. C. McIntosh, Tetra-
hedron 2002, 58, 2905–2928; c) The Claisen Rearrangement. Meth-
ods and Applications (Eds.: M. Hiersemann, U. Nubbemeyer),
Wiley-VCH, Weinheim, 2007.
[25] K. C. Kumara Swamy, N. N. Bhuvan Kumar, E. Balaraman, K. V. P.
Pavan Kumar, Chem. Rev. 2009, 109, 2551–2651.
[26] Y. Ichikawa, K. Tsuboi, M. Isobe, J. Chem. Soc. Perkin Trans. 1
1994, 2791–2796.
[27] a) R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897–
5898; b) R. E. Ireland, P. Wipf, J.-N. Xiang, J. Org. Chem. 1991, 56,
3572–3582.
[33] Oxidation under Swern conditions gave the required ketone in a 1:1
ratio together with a methylthiomethyl adduct in 69% combined
yield; other oxidants degraded the electron-rich arene, cf. ref. [10].
[34] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156;
b) S. D. Meyer, S. L. Schreiber, J. Org. Chem. 1994, 59, 7549–7552.
[35] W. M. Pearlman, Tetrahedron Lett. 1967, 8, 1663–1664.
[36] B. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron 1981, 37,
2091–2096.
[37] For representative projects of this type from our laboratory, see:
a) A. Fꢁrstner, D. Kirk, M. D. B. Fenster, C. Aꢅssa, D. De Souza, O.
Mꢁller, Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 8103–8108; b) A.
Fꢁrstner, D. De Souza, L. Turet, M. D. B. Fenster, L. Parra-Rapado,
C. Wirtz, R. Mynott, C. W. Lehmann, Chem. Eur. J. 2007, 13, 115–
134; c) A. Fꢁrstner, D. Kirk, M. D. B. Fenster, C. Aꢅssa, D. De Sou-
za, C. Nevado, T. Tuttle, W. Thiel, O. Mꢁller, Chem. Eur. J. 2007, 13,
135–149; d) A. Fꢁrstner, C. Nevado, M. Waser, M. Tremblay, C.
´
Chevrier, F. Teply, C. Aissa, E. Moulin, O. Mꢁller, J. Am. Chem.
[28] a) A. Francais, O. Bedel, W. Picoul, A. Meddour, J. Courtieu, A.
Haudrechy, Tetrahedron: Asymmetry 2005, 16, 1141–1155; b) W.
Picoul, R. Urchegui, A. Haudrechy, Y. Langlois, Tetrahedron Lett.
1999, 40, 4797–4800.
[29] a) P. F. Godenschwager, D. B. Collum, J. Am. Chem. Soc. 2008, 130,
8726–8732; b) see also: P. F. Godenschwager, D. B. Collum, J. Am.
Chem. Soc. 2007, 129, 12023–12031.
Soc. 2007, 129, 9150–9161; e) A. Fꢁrstner, S. Flꢁgge, O. Larionov, Y.
Takahashi, T. Kubota, J. Kobayashi, Chem. Eur. J. 2009, 15, 4011–
4029; f) A. Fꢁrstner, E. Kattnig, G. Kelter, H.-H. Fiebig, Chem. Eur.
J. 2009, 15, 4030–4043; g) P. Buchgraber, M. M. Domostoj, B.
Scheiper, C. Wirtz, R. Mynott, J. Rust, A. Fꢁrstner, Tetrahedron
2009, 65, 6519–6534; h) A. Fꢁrstner, F. Feyen, H. Prinz, H. Wald-
mann, Tetrahedron 2004, 60, 9543–9558.
[30] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–3818.
[31] P. Renaud, M. Hꢁrzeler, D. Seebach, Helv. Chim. Acta 1987, 70,
292–298.
Received: June 17, 2010
Published online: September 17, 2010
12140
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12133 – 12140