A stereodivergent enantioselective approach to the C5-C8 segment of berkelic acid

Article abstract of DOI:10.1055/s-0029-1217546

A catalytic, asymmetric Gosteli-Claisen rearrangement (CAGC) has been utilized to provide the C5-C8 segment of berkelic acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217546

LETTER
2133
A Stereodivergent Enantioselective Approach to the C5–C8 Segment of
Berkelic Acid
Enantioselective
A
i
pproa
c
k
h
to the C5–
oC8 Segment
l
of Berk
a
e
lic Acid Stiasni, Martin Hiersemann*
Fakultät Chemie, Technische Universität Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
E-mail: martin.hiersemann@udo.edu
Received 15 April 2009
ic inflammatory and vascular diseases.6 Therefore, further
insights into the mechanism of action of selective MMP-
inhibitors could be of great value for future drug develop-
ment.
Abstract: A catalytic, asymmetric Gosteli–Claisen rearrangement
(CAGC) has been utilized to provide the C5–C8 segment of berkel-
ic acid.
Key words: allyl vinyl ether, asymmetric catalysis, berkelic acid,
Claisen rearrangement, dithiane
Our retrosynthetic strategy simplifies the tetracyclic core
of berkelic acid 2 to the known p-quinone methide pulvil-
loric acid (4)7 and the silyl enol ether 3. We envisioned
that pulvilloric acid could, due to its high reactivity and
electrophilic properties, react with a suitable nucleophile
such as the silyl enol ether 3 through a 1,6-conjugate ad-
dition as outlined in Scheme 1.8 Silyl enol ether 3 should
be available from the ketone 5, which could be accessible
from the a-keto ester 6 through a series of redox transfor-
mations. Further simplification leads to the achiral allyl
vinyl ether (Z,Z)-7, which is a substrate for the catalytic
asymmetric Gosteli–Claisen rearrangement9 (CAGC).
Berkelic acid (1) is an aromatic spiroketal isolated from a
Penicillium species growing in the highly acidic and
heavy-metal polluted Berkley Pit lake, a former open-pit
copper mine in Butte, Montana.1 It has drawn consider-
able attention among synthetic chemists due to its struc-
tural complexity and biological activity. The unique
carbon skeleton of 1 possesses an all-carbon quaternary
stereocenter (C-3) and two contiguous stereogenic centers
on an aliphatic chain – a structural feature also exhibited
by the natural product spicifernin.2 The relative configu-
ration of berkelic acid, apart from that at C-3, was origi-
nally assigned on the basis of NMR experiments,1 revised
by Fürstner,3 and the absolute configuration was finally
established through total synthesis by Snider (Figure 1).4
CO2H
HO2C
O
TPSO
O
O
O
OH
5
6
7
HO
8
9
OTMS
O
TPSO
7
HO2C
OH
6
8
5
9
O
O
O
O
3
2
4
8
7
10
3
6
4
2
MeO
9
5
O
1
O
8
O
8
1
TPSO
7
TPSO
7
6
6
CO2Me
CO2Me
Figure 1 Absolute configuration of (–)-berkelic acid (1) according
5
9
5
to Snider4
5, this letter
6
OTPS
5
CAGC
Berkelic acid (1) has shown selective activity against the
ovarian cancer cell line OVCAR-3 (GI50 = 91 nM) and ef-
fectively inhibited MMP-3 (GI50 = 1.87 mM) and caspase-
1 (GI50 = 0.098 mM).1 The family of matrix metallopro-
teinases (MMPs) include more than twenty zinc-depen-
dent enzymes capable of degrading most components of
the extracellular matrix (ECM). These enzymes are up-
regulated in almost all human tumors and promote tumor
progression by destroying matrix barriers surrounding the
tumor.5 The latest research suggests that selective MMP-
inhibitors could lead to new therapies for acute and chron-
8
6
(Z,Z)-7
7
O
Scheme 1 Initial retrosynthetic analysis of the tetracyclic core of
berkelic acid 2
(Z,Z)-7 was synthesized on a large scale (10 g) along with
(E,Z)-7 through a six-step sequence (Scheme 2).10 The
synthesis commenced with the selective protection of
commercially available (Z)-2-butene-1,4-diol (8), fol-
lowed by etherification and esterification to yield 10. Al-
dol addition of the enolate of the allyloxy-substituted
acetic acid ester 10 with acetaldehyde afforded b-hydroxy-
ester 11 in a moderate yield (67%) as a mixture of dia-
stereomers (7:3). Subsequent mesylation of 11 followed
SYNLETT 2009, No. 13, pp 2133–2136
x
x
.x
x
.2
0
0
9
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1217546; Art ID: G13209ST
© Georg Thieme Verlag Stuttgart · New York

2134
N. Stiasni, M. Hiersemann
LETTER
(S,S)-12 (8 mol%)
by DBU-mediated elimination, afforded allyl vinyl ether
7 as a mixture of diastereomers [(Z,Z)-7:(E,Z)-7 = 3:2],
which was conveniently separable by automated prepara-
tive HPLC.11 The pivotal CAGC of achiral (Z,Z)-7 was
performed in the presence of a catalytic amount (8 mol%)
of chiral Lewis acid [Cu{(S,S)-t-Bu-Box}(H2O)2](SbF6)2
1212 to furnish a-keto ester 6 in 96% yield as a single dia-
O
CH2Cl2, r.t., 24 h
(Z,Z)-7
TPSO
OMe
2
O
O
O
2 SbF6
N
N
6 96%, dr > 95:5, ee >90%
Cu
t-Bu
t-Bu
H2O OH2
(S,S)-12
LiAlH4, THF, 0 °C to r.t., 5 h
1
NaIO4, THF, H2O
r.t., 4 h
stereomer (dr >95:5, based on H NMR analysis) and
OH
O
enantiomer (>90% ee).13
TPSO
OH
TPSO
CO2H
14 90%
13 94%, dr = 4:1
1. TPSCl, Et3N, DMAP
OH
THF, 0 °C, 1 d
O
MeMgBr, THF, –78 °C, 1 h
2. n-BuLi, THF
HO
–78 °C to r.t., 30 min
8
DMP, pyridine
OH
ICH2CO2Na, r.t., 1 d
O
TPSO
CH2Cl2, r.t., 5 h
TPSO
TPSO
9 83%
MeI, K2CO3, DMF, r.t., 1 d
OH
15 88%, dr = 2:1
5 89%
LDA, THF
–78 °C, 15 min
MeCHO
CO2Me
CO2Me
Scheme 3 Synthesis of the ketone 5 in five steps and 64% yield
from (Z,Z)-7
–78 °C, 1 h
O
O
TPSO
11 67%, dr = 7:3
TPSO
6'
CO2H
O
10 91%
O
O
OH
8
1. MsCl, Et3N, CH2Cl2, 0 °C, 1 h
2. DBU, THF, 0 °C to r.t., 1 d
10
CO2Me
CO2H
HO
HO
OH
HPLC separation
O
TPSO
6'
(E,Z)-7 + (Z,Z)-7
TPSO
OMe
S
S
8
10
OMe
16
7
90%, (Z,Z)/(E,Z) = 3:2
17, this letter
Scheme 2 Synthesis of (E,Z)-7 and (Z,Z)-7 using an aldol conden-
18
sation to construct the stereogenic vinyl ether double bond
Scheme 4 Retrosynthetic analysis based on an oxa-Pictet–Spengler
transform
The completion of the synthesis of ketone 5 was achieved
through a series of redox reactions as illustrated in
Scheme 3. LiAlH4 reduction of the a-keto ester 6 yielded
the diol 13 as a 4:1 mixture of diastereomers. Subsequent
diol cleavage mediated by sodium periodate afforded the
aldehyde 14. Addition of MeMgBr to the aldehyde 14
yielded alcohol 15 (dr = 2:1), which was oxidized under
Dess–Martin conditions14 to provide the desired ketone 5.
TPSO
(S,S)-12 (8 mol%)
CH2Cl2, CF3CH2OH
r.t., 1 d
O
OMe
(E,Z)-7
O
19 95%, dr = 5:1, 90% ee
LiAlH4, THF, 0 °C to r.t.
To take advantage of the simultaneously formed allyl vi-
nyl ether (E,Z)-7, we reasoned that this compound could
be employed for the synthesis of the tetracyclic core (16)
of ent-berkelic acid (Scheme 4). Therefore, we decided to
prepare the building block 17, which could be advanced to
16 by an oxa-Pictet–Spengler reaction performed accord-
ing to Snider.15
TPSO
TPSO
NaIO4
O
OH
THF, H2O
r.t., 4 h
OH
21 82%
20 78%, dr = 4:1
HS(CH2)3SH, F3B⋅OEt2, r.t., 1 h
t-BuLi
THF–HMPA (10:1)
–78 °C, 10 min
ICH2CH(OMe)2, LiI
–78 °C, 30 min
In analogy to the CAGC of (Z,Z)-7, (E,Z)-7 was subjected
to (S,S)-12-catalyzed transformation to deliver the a-keto
ester 19 in excellent yield (95%), albeit with lower dia-
stereoselectivity and enantioselectivity (dr 5:1, 90% ee;
Scheme 5).13 a-Keto ester 19 was readily converted into
aldehyde 21 (64% over two steps), which, upon exposure
to 1,3-propanedithiol, yielded dithiane 22. To complete
the synthesis, we planned to alkylate the lithiated dithiane
22 with iodoacetaldehyde dimethyl acetal.16 However, all
TPSO
TPSO
OMe
S
S
S
S
OMe
22 97%
17 61%
Scheme 5 Synthesis of the acetal 17 in five steps and 36% yield
from (E,Z)-7
Synlett 2009, No. 13, 2133–2136 © Thieme Stuttgart · New York

LETTER
Enantioselective Approach to the C5–C8 Segment of Berkelic Acid
Hiersemann, M. Synlett 2007, 1683.
2135
attempts to effect this transformation using standard pro-
tocols were unsuccessful. Upon addition of lithium io-
dide, however, compound 17 was quickly formed in
moderate yield (61%). Unreacted dithiane 22 (19%) could
be reisolated.
(13) The relative and absolute configuration was assigned based
on the established stereochemical course of the CAGC. The
enantiomeric excess was determined by Mosher ester 1H
NMR analysis. To synthesize Mosher esters, aldehydes 14 or
18 were reduced to the corresponding primary alcohols with
NaBH4 in methanol, followed by esterification with
Mosher’s acid.17
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(15) Zhou, J.; Snider, B. B. Org. Lett. 2007, 9, 2071.
(16) Onoe, A.; Uemura, S.; Okano, M. Bull. Chem. Soc. Jpn.
1974, 47, 2818.
(17) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(18) a-Keto Ester 6: To a solution of [Cu{(S,S)-tert-Bu-
Box}(H2O)2](SbF6)2 (12; 81 mg, 0.094 mmol, 8 mol%) in
CH2Cl2 (3 mL, 3 mL/mmol 6) was added (Z,Z)-7 (0.5 g, 1.18
mmol, 1 equiv) in CH2Cl2 (3 mL, 3 mL/mmol 6) at r.t. The
solution was stirred for 24 h, then the solvent was evaporated
and the residue filtered through a short plug of silica gel
(cyclohexane–EtOAc, 1:1). Evaporation of the solvent and
purification by flash chromatography (cyclohexane–EtOAc,
50:1→20:1) furnished 6 (478 mg, 96%) as a clear oil.
Rf = 0.34 (cyclohexane–EtOAc, 10:1); 1H NMR (CDCl3,
400 MHz): d = 7.62–7.64 (m, 4 H), 7.36–7.45 (m, 6 H), 5.81
(ddd, J = 8.7, 10.3, 17.3 Hz, 1 H), 5.00–5.08 (m, 2 H), 3.80
(s, 3 H), 3.65–3.67 (m, 2 H), 3.56–3.63 (m, 1 H), 2.67–2.73
(m, 1 H), 1.11 (d, J = 6.8 Hz, 3 H), 1.04 (s, 9 H); 13C NMR
(CDCl3, 100 MHz): d = 196.7 (C), 161.8 (C), 136.8 (CH),
135.6 (4 × CH), 133.3 (C), 133.1 (C), 129.7 (2 × CH), 127.6
(4 × CH), 117.5 (CH2), 64.1 (CH2), 52.7 (CH3), 48.3 (CH),
42.6 (CH), 26.7 (3 × CH3), 19.2 (C), 12.5 (CH3); IR (neat):
2930, 2860, 1730, 1430 cm–1; Anal. Calcd for C25H32O4Si:
C, 70.72; H, 7.60. Found: C, 70.6; H, 7.6; [a]25D +38.1 (c 1.0,
CHCl3).
In summary, we have prepared diastereo- and enantiomer-
ically pure ketone 5, corresponding to the C5–C8 segment
of (–)-berkelic acid, using an eleven-step synthesis em-
ploying a catalytic asymmetric Gosteli–Claisen rear-
rangement as a key C–C connecting transformation.18 We
also prepared the C5–C10 segment 17, which could be
used to prepare the tetracyclic core of ent-berkelic acid 16
via an oxa-Pictet–Spengler reaction. We disclose our ob-
servation that a-substituted dithiane 22 does not react with
iodoacetaldehyde dimethyl acetal unless lithium iodide is
present.
Acknowledgment
Financial support by the DFG is gratefully acknowledged. N.S. is
the recipient of a DAAD fellowship.
References and Notes
(1) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006,
71, 5357.
(2) (a) Nakajima, H.; Hamasaki, T.; Maeta, S.; Kimura, Y.;
Takeuchi, Y. Phytochemistry 1990, 29, 1739. (b)Nakajima,
H.; Matsumoto, R.; Kimura, Y.; Hamasaki, T. J. Chem. Soc.,
Chem. Commun. 1992, 1654. (c) Nakajima, H.; Fujimoto,
H.; Matsumoto, R.; Hamasaki, T. J. Org. Chem. 1993, 58,
4526. (d) Nakajima, H.; Fukuyama, K.; Fujimoto, H.; Baba,
T.; Hamasaki, T. J. Chem. Soc., Perkin Trans. 1 1994, 1865.
(3) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.;
Goddard, R.; Fürstner, A. Angew. Chem. Int. Ed. 2008, 47,
8450.
(4) Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem. Int. Ed. 2009,
48, 1283.
(5) (a) Hoekstra, R.; Eskens, F. A. L. M.; Verweij, J. Oncologist
2001, 6, 415. (b) Coussens, L. M.; Fingleton, B.; Matrisian,
L. M. Science 2002, 295, 2387.
a-Keto Ester 19: To a solution of [Cu{(S,S)-tert-Bu-
Box}(H2O)2](SbF6)2 (12, 384 mg, 0.44 mmol, 8 mol%) in
CF3CH2OH (11 mL, 2 mL/mmol 7) was added (Z,Z)-7 (2.36
g, 5.55 mmol, 1 equiv) in CH2Cl2 (17 mL, 3 mL/mmol 7) at
r.t. The solution was stirred for 24 h, then the solvent was
evaporated and the residue filtered through a short plug of
silica gel (cyclohexane–EtOAc, 1:1). Evaporation of the
solvent and purification by flash chromatography
(cyclohexane–EtOAc, 50:1→20:1) furnished 19 (2.24 g,
95%) as a clear oil. Rf = 0.34 (cyclohexane–EtOAc, 10:1);
1H NMR (CDCl3, 400 MHz): d = 7.62–7.64 (m, 4 H), 7.36–
7.45 (m, 6 H), 5.54 (ddd, J = 17.1, 10.4, 9.3 Hz, 1 H), 4.98–
5.08 (m, 2 H), 3.80 (s, 3 H), 3.57–3.66 (m, 3 H), 2.75–2.83
(m, 1 H), 1.03–1.07 (m, 12 H); 13C NMR (CDCl3, 100
MHz): d = 196.6 (C), 161.7 (C), 135.5 (4 × CH), 135.0 (CH),
133.2 (C), 133.1 (C), 129.7 (2 × CH), 127.6 (4 × CH), 118.5
(CH2), 65.3 (CH2), 52.7 (CH3), 48.0 (CH), 42.4 (CH), 26.7
(3 × CH3), 19.2 (C), 12.4 (CH3); IR (neat): 2930, 2860, 1730,
1430 cm–1; Anal. Calcd for C25H32O4Si: C, 70.72; H, 7.60.
Found: C, 70.8; H, 7.5; [a]25D +4.3 (c 0.99, CHCl3).
Ketone 5: To a solution of 15 (1.1 g, 2.87 mmol, 1 equiv) in
CH2Cl2 (5.7 mL, 2 mL/mmol) was added pyridine (0.91 g,
11.5 mmol, 4.0 equiv) and Dess–Martin periodinane (1.6 g,
3.8 mmol, 1.3 equiv). The white suspension was stirred at r.t.
for 5 h before being quenched with sat. Na2S2O3. The phases
were separated, and the aqueous phase was washed with
CH2Cl2. The combined organic layers were dried (MgSO4),
concentrated under reduced pressure and the crude product
was purified by flash chromatography (cyclohexane–
EtOAc, 20:1) to yield 5 (0.98 g, 89%) as a colorless oil.
Rf = 0.27 (cyclohexane–EtOAc, 20:1); 1H NMR (CDCl3,
400 MHz): d = 7.64–7.66 (m, 4 H), 7.37–7.45 (m, 6 H),
5.77–5.86 (m, 1 H), 5.00–5.08 (m, 2 H), 3.67 (d, J = 5.2 Hz,
(6) Hu, J.; Van den Steen, P. E.; Sang, Q.-X. A.; Opdenakker, G.
Nat. Rev. Drug Discovery 2007, 6, 480.
(7) McOmie, J. F. W.; Turner, A. B.; Tute, M. S. J. Chem. Soc.
C 1966, 1608.
(8) (a) Inagaki, M.; Haga, N.; Kobayashi, M.; Ohta, N.; Kamata,
S.; Tsuri, T. J. Org. Chem. 2002, 67, 125. (b) Zjawiony,
J. K.; Bartyzel, P.; Hamann, M. T. J. Nat. Prod. 1998, 61,
1502.
(9) Hiersemann, M. Synthesis 2000, 1279.
(10) Preparative HPLC conditions: Nucleosil 50-5; 32 × 237
mm; heptane–EtOAc, 25:1; 26 mL/min; tR(Z,Z) = 31.5 min,
tR(E,Z) = 38.0 min; baseline separation with 200 mg/
injection.
(11) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.;
Tregay, S. W. J. Am. Chem. Soc. 1998, 120, 5824.
(12) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew.
Chem. Int. Ed. 2001, 40, 4700. (b) Abraham, L.; Körner,
M.; Schwab, P.; Hiersemann, M. Adv. Synth. Catal. 2004,
346, 1281. (c) Abraham, L.; Körner, M.; Hiersemann, M.
Tetrahedron Lett. 2004, 45, 3647. For applications of the
CAGC in total synthesis, see: (d) Pollex, A.; Hiersemann,
M. Org. Lett. 2005, 7, 5705. (e) Körner, M.; Hiersemann,
M. Org. Lett. 2007, 9, 4979. (f) Wang, Q.; Millet, A.;
Synlett 2009, No. 13, 2133–2136 © Thieme Stuttgart · New York

2136
N. Stiasni, M. Hiersemann
LETTER
2 H), 2.82 (m, 1 H), 2.43–2.49 (m, 1 H), 2.12 (s, 3 H), 1.04–
1.05 (m, 12 H); 13C NMR (CDCl3, 100 MHz): d = 211.8 (C),
137.7 (4 × CH), 135.6 (CH), 133.4 (2 × C), 129.7 (2 × CH),
127.6 (4 × CH), 116.9 (CH2), 64.3 (CH2), 48.6 (CH), 47.6
(CH), 29.4 (CH3), 26.8 (3 × CH3), 19.3 (C), 13.7 (CH3); IR
(neat): 2960, 2858, 1713, 1428 cm–1; Anal. Calcd for
dried (MgSO4) and concentrated under reduced pressure and
the crude product was purified by flash chromatography
(cyclohexane–EtOAc, 50:1→20:1) to afford unreacted 22
(20 mg, 19%) and 17 (77 mg, 61%). Rf = 0.20 (cyclohexane–
EtOAc, 20:1); 1H NMR (CDCl3, 400 MHz): d = 7.68–7.70
(m, 4 H), 7.38–7.45 (m, 6 H), 5.69–5.78 (m, 1 H), 5.06–5.17
(m, 2 H), 4.81 (t, J = 4.0 Hz, 1 H), 3.56–3.57 (m, 2 H), 3.30–
3.40 (m, 7 H), 2.72–3.03 (m, 3 H), 2.62–2.69 (m, 1 H), 2.51–
2.57 (m, 1 H), 2.18–2.22 (m, 1 H), 1.78–1.98 (m, 3 H), 1.05–
1.10 (m, 12 H). 13C NMR (CDCl3, 100 MHz): d = 136.7
(CH), 135.6 (4 × CH), 133.6 (C), 133.5 (C), 129.6 (2 × CH),
127.6 (4 × CH), 118.1 (CH2), 102.7 (CH), 66.8 (CH2), 57.2
(C), 53.5 (CH3), 52.5 (CH3), 46.0 (CH), 39.5 (CH2), 35.8
(CH), 26.9 (3 × CH3), 25.8 (CH2), 25.5 (CH2), 24.5 (CH2),
19.3 (C), 9.9 (CH3); IR (neat): 2930, 2900, 2860, 1430 cm–1;
Anal. Calcd for C30H44O3S2Si: C, 66.13; H, 8.14. Found: C,
66.2; H, 8.1; [a]25D +21.0 (c 1.01, CHCl3).
C24H32O2Si: C, 75.74; H, 8.47. Found: C, 75.6; H, 8.3; [a]25
D
+31.8 (c 0.97, CHCl3).
Acetal 17: To a solution of 22 (106 mg, 0.23 mmol, 1 equiv)
in THF (2 mL, 8.6 mL/mmol) and HMPA (0.3 mL), was
added t-BuLi (0.16 mL, 0.26 mmol, 1.1 equiv, 1.6 M in
pentane) at –78 °C. The solution was stirred at –78 °C for 15
min before a solution of iodoacetaldehyde dimethyl acetal
(150 mg, 0.69 mmol, 3.0 equiv) and LiI (109 mg, 0.81 mmol,
3.5 equiv) in THF (1 mL) was added. After stirring for 30
min, the reaction mixture was diluted with sat. NaHCO3 and
extracted with CH2Cl2. The combined organic layers were
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