Formal synthesis of (+)-crocacin C

Article abstract of DOI:10.1016/j.tetlet.2012.02.049

The formal synthesis of (+)-crocacin C is reported. The approach described takes advantage of a highly regioselective epoxide cuprate addition and a diastereoselective Overman rearrangement. The synthesis is practical and amenable to scale up.

Full text of DOI:10.1016/j.tetlet.2012.02.049

Tetrahedron Letters 53 (2012) 2114–2116
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Tetrahedron Letters
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Formal synthesis of (+)-crocacin C
Adele E. Pasqua a, Frank D. Ferrari a, James J. Crawford b, Rodolfo Marquez a,
⇑
,
a WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
b Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal synthesis of (+)-crocacin C is reported. The approach described takes advantage of a highly
regioselective epoxide cuprate addition and a diastereoselective Overman rearrangement. The synthesis
is practical and amenable to scale up.
Received 21 December 2011
Revised 1 February 2012
Accepted 10 February 2012
Available online 18 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Crocacins
Formal synthesis
Overman rearrangement
The crocacins are a family of four antifungal and cytotoxic anti-
biotics isolated by Höfle and co-workers from two different strains
of Chondromyces bacteria, which exhibit a wide range of biological
activities.1 Whilst crocacin A is only a moderate inhibitor of Gram
positive bacteria, it has shown remarkable activity as a growth
inhibitor of fungi and yeasts through inhibition of the electron flow
within the cytochrome bc1 segment (complex III) of the respiratory
chain.1 Additionally, crocacin D has shown a MIC of 1.4 ng/mL
noic acid, the nitrogen of which is protected by a complex polyke-
tide derived acyl residue. Crocacin C is the free carboxamide
common to all three of the other crocacins.
Crocacins A, B and D possess a highly reactive enamide unit,
which is crucial for their biological activity. Mechanistically, it has
been postulated that the enamide unit undergoes protonation and
the resulting N-acyliminium ion is then subjected to nucleophilic
attack to generate the enzyme conjugate required for activity.2
The promising biological activity of the crocacins together with
their low natural abundance and interesting structural features,
has made them attractive synthetic targets, and a number of for-
mal and total syntheses have been reported.3–8
As part of our efforts towards the synthesis of the crocacins, we
envisioned accessing crocacin, A, B and D via crocacin C, using the
imide olefination methodology recently developed in our group.9
In turn, crocacin C could be prepared using a modular approach
in which the dienoate ester and the phenyl substituted alkene
are incorporated by means of a Horner–Wadsworth–Emmons olef-
ination and an Overman rearrangement, respectively (Scheme 1).
Our synthesis of (+)-crocacin C began with Roche ester 1, which
was silylated and the resulting ester 2 converted into the corre-
sponding aldehyde 3 through a reduction-oxidation sequence.
Olefination of aldehyde 3 yielded the desired E-ethyl enoate 4 as
a single double bond isomer as determined by 1H NMR analysis
(Scheme 2).
against Saccharomyces cerevisiae and an IC50 of 60
lg/mL towards
L929 mouse fibroblast cell cultures.
NH
OR
O
O
N
H
OMe OMe
O
R = Me
R = H
crocacin A
crocacin B
NH2
O
crocacin C
OMe OMe
OMe OMe
NH
O
OMe
O
N
H
O
crocacin D
Reduction of ester 4 afforded alkenol 5 which was then epoxi-
dised under reagent-controlled conditions in excellent yield and
with high diastereoselectivity to yield the syn-epoxy-alcohol 6 as
an inseparable (95:5) mixture of diastereomers. Cuprate opening
of the epoxy-alcohol mixture under Nakamura’s conditions10
yielded the desired 1,3-diol 7 together with trace amounts of the
1,2-diol side product 8. Treatment of the diastereomeric mixture
Structurally, crocacins A, B and D are unusual linear dipeptides
incorporating glycine and a 6-aminohexenoic or 6-aminohexadie-
⇑
Corresponding author. Tel.: +44 141 330 5953; fax: +44 141 330 4888.
E-mail addresses: rudi.marquez@glasgow.ac.uk, r.marquez@chem.gla.ac.uk
(R. Marquez).
Ian Sword Reader of Organic Chemistry.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.049

A. E. Pasqua et al. / Tetrahedron Letters 53 (2012) 2114–2116
2115
MeI, NaH
BnBr, NaH
TBAI
TBDPSO
TBDPSO
OH
TBDPSO
HO
OBn
NH
OR
O
N
H
THF
75%
THF
96%
OH
7
OH
9
OMe OMe
O
O
crocacin A, B, D
(COCl)2,
DMSO, Et3N
Imide formation and olefination
TBAF
THF
82%
OBn
OBn
quant.
OMe
OMe
10
NH2
11
crocacin C
O
OMe OMe
O
Ph3P
13
OBn
Ph
OBn
OHC
PhH
39%
Horner-Wadsworth-Emmons
Overman rearrangement
OMe
12
O
OMe
14
R'O
OR
Scheme 3. Synthesis of enone 14.
OMe
Scheme 1. Crocacins’ retrosyntheses.
i) DIBAL-H, CH2Cl2;
(
S
)-Me-CBS
.
BH3 THF
OBn
THF
99%
O
ii) (COCl)2, DMSO, Et3N
OMe
14
HO
TBDPSCl
TBDPSO
CO2Me
CO2Me
Imid, DMF
quant.
99%
1
2
OBn
OBn
+
CO2Et
PhH, 80 oC
99%
Ph3P
DIBAL-H, Et2O
TBDPSO
TBDPSO
TBDPSO
OH
OMe
15a
OH
OMe
15b
CHO
CO2Et
quant.
1.1:1
separable by chromatography
3
4
(-)-DET, Ti(OiPr)4
Ac2O, Et3N
DMAP
OH
TBDPSO
OH
PdCl2(CH3CN)2
tBuOOH
93%, 90% d.e.
OBn
O
5
6
92%
THF
quant.
OAc
OMe
OH
16
MeLi, CuI
+
TBDPSO
NaIO4
OH
TBDPSO
OH
OH
OBn
7
8
DIBAL-H
CH2Cl2
99%
OH
OBn
OAc OMe
OH OMe
18
17
TBDPSO
65%
from 6
7
OH
MeI, NaH
TBAI
OBn
Scheme 2. Synthesis of mono-protected triol 7.
THF
93%
19
OMe OMe
with sodium periodate oxidised the 1,2-diol side product to the
corresponding aldehyde which could be separated by flash column
chromatography (Scheme 2).
The diastereomerically pure 1,3-diol 7 was selectively benzylat-
ed, and the resulting secondary alcohol 9 then methylated, to af-
ford the differentially protected triol 10. Desilylation of ether 10
yielded the free primary alcohol 11, which was oxidised to produce
aldehyde 12 in an excellent yield. Olefination of aldehyde 12 with
the stabilised phosphorane 1311 gave the desired enone 14 as a sin-
gle double bond isomer (Scheme 3).
With enone 14 in hand, the key Overman rearrangement was ex-
plored. Corey–Bakshi–Shibata reduction12 of enone 14 afforded a
1.1:1 mixture of diastereoisomers that was separable by flash col-
umn chromatography. The desired allylic alcohol 15a was acety-
lated to afford the rearrangement precursor 16, which upon
treatment with PdCl2(CH3CN)2 under Overman conditions13 cleanly
transposed the acetate group to generate the syn:anti:anti adduct 17
in quantitative yield and as a single diastereomer. Removal of the
acetate group followed by methylation of the resulting alcohol 18
afforded the core of (+)-crocacin C in an excellent yield (Scheme 4).
Selective hydrogenolysis of the benzyl group followed by oxida-
tion of the resulting primary alcohol afforded the corresponding
aldehyde intermediate. Stereoselective olefination under Horner–
Wadsworth–Emmons conditions using phosphonoacetate 2014
completed the formal synthesis of (+)-crocacin C. The spectral data
and optical rotation of dienoate ester 21 matched those reported
by Chakraborty and co-workers for the same advanced intermedi-
ate during their synthesis of (+)-crocacin C.4
i) AlCl3, PhNMe2, CH2Cl2;
ii) DMP, CH2Cl2;
iii) LDA, EtO2C
THF
PO(OEt)2
OEt
20
40% from 19
OMe OMe
21
O
Scheme 4. Formal synthesis of (+)-crocacin C.
In conclusion, we have completed a formal synthesis of (+)-
crocacin C,15 taking advantage of a highly regioselective epoxide
cuprate addition and of a diastereoselective Overman rearrange-
ment. The synthesis is practical and amenable to scale up. We
are currently in the process of expanding this approach to the syn-
thesis of new crocacin analogues.
Acknowledgements
We would like to thank Dr. Ian Sword for postgraduate support
(A.E.P.). The authors also thank Dr. Ian Sword and the EPSRC for
funding.
References and notes
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(100 MHz; CDCl3): dC 166.7, 152.8, 135.9, 133.6, 130.0, 127.9, 121.5, 67.6, 60.2,
39.1, 26.9, 19.2, 16.6, 14.3. IR (neat): 3416, 2961, 2859, 1717, 1653, 1472,
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m
1427, 1368, 1267, 1182, 1111, 1094, 1034, 982, 824, 802, 741, 700, 689,
613 cmꢀ1. HRMS (isobutane, CI+): found (M+H)+ 397.2203, C24H33O3Si requires
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397.2199. ½a 2D4
ꢀ10.40 (c 1.0, CHCl3).
ꢁ
{(2R,3R)-3-[(R)-1-(tert-Butyldiphenylsilyloxy)propan-2-yl]oxiran-2-yl}methanol,
(6). 1H NMR (400 MHz; CDCl3): dH 7.66–7.58 (4H, m), 7.42–7.28 (6H, m), 3.95
(1H, ddd, J = 17.8, 12.4, 5.3 Hz), 3.78–3.61 (3H, m), 3.19 (2H, d, J = 2.4 Hz), 1.81–
1.68 (2H, m), 1.10 (9H, s), 1.02 (3H, d, J = 6.0 Hz). 13C NMR (100 MHz; CDCl3): dC
135.6, 133.6, 129.8, 127.8, 65.9, 61.9, 57.5, 56.9, 37.8, 26.9, 19.4, 12.9. IR (neat):
m
3429, 2961, 2858, 1472, 1427, 1111, 1007, 824, 739, 699, 690, 614 cmꢀ1
.
HRMS (isobutane, CI+): found (M+H)+ 371.2052, C22H31O3Si requires 371.2042.
½ ꢁ ꢀ9.60 (c 0.125, CHCl3).
a 2D5
(2R,3R,4S)-5-(Benzyloxy)-3-methoxy-2,4-dimethylpentan-1-ol, (11). 1H NMR
(400 MHz; CDCl3): dH 7.41–7.32 (5H, m), 4.50 (2H, s), 3.75 (1H, dd, J = 9.6,
4.4 Hz), 3.65–3.45 (4H, m), 3.38 (3H, s), 2.93 (1H, t, J = 6.4 Hz), 2.05–1.82 (2H,
m), 0.80 (6H, m). 13C NMR (100 MHz; CDCl3): dC 138.6, 128.4, 127.9, 127.5,
7. Besßev, M.; Brehm, C.; Fürstner, A. Collect. Czech. Chem. Commun. 2005, 70, 1696–
1708.
89.1, 73.1, 72.2, 65.6, 61.1, 37.4, 36.4, 15.1, 14.6. IR (neat):
m 3433, 2924, 1458,
8. Candy, M.; Audran, G.; Bienayme, H.; Bressy, C.; Pons, J.-M. J. Org. Chem. 2010,
75, 1354–1359.
1366, 1088, 1026, 978, 903, 741, 694 cmꢀ1. HRMS (isobutane, CI+): found
(M+H)+ 253.1805, C15H25O3 requires 253.1804. ½a D25
ꢁ
+3.20 (c 1.0, CHCl3).
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7587–7588.
14. Mata, E. G.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1995, 785–799.
15. Spectroscopic data for representative compounds: (4S,2E)-Ethyl 5-(tert-
butyldiphenylsilyloxy)-4-methylpent-2-enoate, (4). 1H NMR (400 MHz; CDCl3):
dH 7.66–7.56 (4H, m), 7.43–7.30 (6H, m), 6.91 (1H, dd, J = 15.8, 7.5 Hz), 5.80
(1H, dd, J = 15.8, 1.5 Hz), 4.17 (2H, q, J = 7.1 Hz), 3.60–3.53 (2H, m), 2.61–2.42
(1H, m), 1.29 (3H, t, J = 7.0 Hz), 1.12 (3H, d, J = 6.7 Hz), 1.01 (9H, s). 13C NMR
(2S,3S,4R,5S,6E)-3,5-Dimethoxy-2,4-dimethyl-7-phenylhept-6-en-1-ol. 1H NMR
(500 MHz; CDCl3): dH 7.42–7.40 (2H, m), 7.36–7.31 (2H, m), 7.27–7.23 (1H,
m), 6.58 (1H, d, J = 15.9 Hz), 6.19 (1H, dd, J = 16.0, 7.3 Hz), 4.07 (1H, ddd, J = 7.3,
2.7, 0.9 Hz), 3.87–3.82 (1H, m), 3.56–3.52 (1H, m), 3.54 (3H, s), 3.32 (3H, s),
3.29 (1H, dd, J = 2.3, 9.0 Hz), 2.89 (1H, dd, J = 7.4, 2.4 Hz), 1.91–1.84 (2H, m),
1.21 (3H, d, J = 7.3 Hz), 0.91 (3H, d, J = 7.3 Hz). 13C NMR (125 MHz; CDCl3): dC
136.9, 132.4, 129.5, 128.8, 127.8, 126.6, 88.6, 81.3, 64.7, 61.8, 56.5, 42.5, 35.9,
16.4, 10.5. IR (neat)
m
3366, 2972, 2924, 2824, 1495, 1451, 1089 cmꢀ1. ½a D20
ꢁ
ꢀ4.28 (c 1.0, CHCl3).
(2E,4E,6S,7S,8R,9S,10E)-Ethyl
7,9-dimethoxy-3,6,8-trimethyl-11-phenylundeca-
2,4,10-trienoate, (21). 1H NMR (500 MHz; CDCl3): dH 7.32 (2H, d, J = 8.1 Hz),
7.24 (2H, dd, J = 8.3, 7.1 Hz), 7.16 (1H, m), 6.48 (1H, d, J = 16.1 Hz), 6.13–6.02
(2H, m), 6.08 (1H, d, J = 15.9 Hz), 5.60 (1H, s), 4.07 (2H, q, J = 6.9 Hz), 4.02–3.96
(1H, m), 3.46 (3H, s), 3.25 (3H, s), 3.12 (1H, dd, J = 9.9, 1.8 Hz), 2.54–2.46 (1H,
m), 2.17 (3H, d, J = 1.0 Hz), 1.56–1.45 (1H, m), 1.21 (3H, t, J = 6.8 Hz), 1.17 (3H,
d, J = 6.8 Hz), 0.88 (3H, d, J = 6.9 Hz). 13C NMR (125 MHz; CDCl3): dC 167.3,
152.2, 137.9, 136.7, 133.9, 132.7, 129.2, 128.4, 127.5, 125.5, 118.8, 87.1, 81.9,
61.5, 60.0, 56.6, 43.6, 40.9, 19.2, 14.4, 13.9, 10.2. ½a D19
ꢀ10.00 (c 0.2, CHCl3).
ꢁ