A formal total synthesis of crocacin C

Article abstract of DOI:10.1016/j.tetlet.2006.10.141

An efficient total synthesis of a potent antifungal and moderate cytotoxic agent crocacin C is described. The synthesis involves the generation of four contiguous stereogenic centres via desymmetrization of a meso bicyclic dihydrofuran using asymmetric hy

Full text of DOI:10.1016/j.tetlet.2006.10.141

Tetrahedron Letters 48 (2007) 145–148
A formal total synthesis of crocacin C
J. S. Yadav,* P. Venkatram Reddy and L. Chandraiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 August 2006; revised 19 October 2006; accepted 26 October 2006
Available online 17 November 2006
Abstract—An efficient total synthesis of a potent antifungal and moderate cytotoxic agent crocacin C is described. The synthesis
involves the generation of four contiguous stereogenic centres via desymmetrization of a meso bicyclic dihydrofuran using asymmet-
ric hydroboration.
Ó 2006 Published by Elsevier Ltd.
Crocacins A–D (1–4) are a group of compounds found
in the extracts of Chondromyces crocatus and Chondro-
myces pediculatus.1 The crocacins moderately inhibit
Gram-positive bacteria and are potent inhibitors of ani-
mal cell cultures, several yeasts and fungi. Crocacin D
possesses the highest activity against Saccharomyces
cerevisiae as well as higher toxicity in L929 mouse fibro-
blast cell culture.2
A retrosynthetic analysis of 1 is shown in Figure 1,
which illustrates that crocacin C could be constructed
by coupling aldehyde 5 and 2-benzothiazolyl-sulfone 6
via a modified Julia olefination reaction. Intermediate
5 could in turn be prepared by cross-metathesis of
styrene and olefin 7, which could be synthesized from
lactone 8.7
The synthesis of fragment 5 began with bicyclic lactone
8. Benzyl and p-methoxybenzyl ether analogues of
lactone 8 have been synthesized earlier by our group
and successfully employed for the synthesis of fragments
of rifamycin,8 discodermolide,9 scytoficin10 as well as
the total syntheses of prelactone B11 and membrenone
C.12
The crocacins are polyketide-derived dipeptides with
four contiguous stereocentres, consisting of a 6-amino-
hexenoic or hexadienoic acid and up to five double
bonds. The relative configurations of these compounds
were deduced using 2D NMR experiments and molecu-
lar modelling studies, 2 and their absolute configurations
were confirmed by total synthesis.3–5 The interesting
biological profile and structural features of crocacins
have attracted several synthetic chemists worldwide to-
wards stereoselective total syntheses as well as construc-
tion of intermediates.6
Acid catalyzed methanolysis of the bicyclic lactone 8
proceeded smoothly to furnish ester 10 in 80% yield.
Lithium aluminum hydride mediated reduction of the
ester afforded the primary alcohol in 92% yield, which
was subsequently converted into iodide 11 using I2,
PPh3 and imidazole.13 Base catalyzed elimination14 of
iodide resulted inolefin 7, which was converted to
aldehyde 12 via dihydroxylation and sodium periodate
promoted cleavage. An attempt was made towards the
synthesis of compound 14 by modified Julia olefin-
ation15 of aldehyde 12 with benzothiazol-2-benzyl sul-
fone 13 but this resulted in poor and inconsistent
yields (50% from 7). This prompted us to modify the
synthetic strategy, by employing olefin 7 in cross-
metathesis reaction16 with styrene to obtain 14. Accord-
ingly, olefin 7 was treated with styrene using Grubbs’ II
generation catalyst (10 mol %) in benzene17 at 55 °C to
furnish the trans-styrene derivative 14 in 81% (98:2/
E:Z) yield (see Scheme 1).
In continuation of our ongoing programme of synthesiz-
ing polyketide natural products by applying a desym-
metrization strategy, we embarked on the total
synthesis of crocacins. Herein, we describe the stereo-
convergent synthesis of an advanced intermediate, a
linear trienoate, for the synthesis of crocacin C utilizing
asymmetric hydroboration, cross-metathesis and modi-
fied Julia olefination reactions.
Keywords: Crocacin; Desymmetrization; Cross-metathesis; Modified
Julia olefination.
*
Corresponding author. Fax: +91 40 27160512; e-mail: yadavpub@
iict.res.in
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.10.141

146
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 145–148
Me Me
R
NH
OMe
O
N
H
Me
O
O
OMe OMe
2
1: R=H; Crocacin C
R = fragment 2: Crocacin A
R = fragment 3: Crocacin B
R = fragment 4: Crocacin D
OH
O
O
N
H
O
O
3
Me Me
OMe
N
Me
O
O O
S
N
S
H
+
CHO
4
OEt
OMe OMe
5
6
O
O
MeO
Me
O
O
O
Me
OMe
OMe
OMe
7
9
8
Figure 1.
O
O
O
MeO
O
t-BuOK,
H2SO4, MeOH
oC-rt, 80%
1. LAH, THF,
0 oC-r.t, 92%
MeO
O
I
CO2Me
THF
0
0 oC, 83%
2. I2, Ph3P, Imid,
CH3CN/Et2O (1:3)
0 oC, 85%
OMe
OMe
OMe
8
10
11
N
O
MeO
O
1.OsO4, NMO,
acetone/H2O
13, LiHMDS
THF, -78 oC,
MeO
O
CHO
S
S
14
O
2.NaIO4,
THF/H2O
then, 12
(50% from 7)
OMe
OMe
7
12
Styrene, Grubbs II gen.cat.
(10 mol%) benzene 55 oC, 81%
13
MeO
O
1. AcOH/H2O (2:1)
55 oC
Me Me
1. TBSCl, Imid,
CH2Cl2, 90%
OH
2.NaBH4, MeOH
64%
OMe
OH
OMe
2.NaH, MeI, THF,
0 oC, 94%
15
14
Me Me
Me Me
1. Dess-Martin
reagent
OTBS
Bu4NF
THF, 90%
OH
5
OMe OMe
CH2Cl2, rt, 88%
OMe OMe
16
17
Scheme 1.
Aqueous acetic acid induced hydrolysis18 of lactol-ether
of the resultant lactol yielded 1,5-diol 15 in 64% yield.
14 followed by sodium borohydride mediated reduction
Selective protection of the primary hydroxyl group as

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 145–148
147
N
N
S
Me
O
Chloroacetone
Ph3P=CHCO2Et,
N
S
SH
S
S
O
S
OEt
Et3N, THF, 97%
benzene, reflux, 68%
19
18
Me
O
LiHMDS, -78 oC
O O
S
N
Me Me
Oxone,
OEt
OEt
S
THF:MeOH:H2O
(4:2:4), 92%
then 5, -78 oC,
THF, 56%
6
Me
O
OMe OMe
20
ref. 3
Me Me
NH2
Me
O
OMe OMe
crocacin C
Scheme 2.
T. K.; Jayaprakash, S.; Laxman, P. Tetrahedron 2001, 57,
9467.
its TBS ether was effected by TBSCl and imidazole, and
then methylation of the secondary hydroxyl group using
NaH and MeI furnished dimethyl ether 16. Desilylation
gave the known alcohol 1719 in 76% yield (from 15),
which upon Dess–Martin oxidation20 furnished alde-
hyde 5.
4. (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett.
2002, 4, 525; (b) Chakraborthy, T. K.; Laxman, P.
Tetrahedron Lett. 2002, 43, 2645; (c) Crowely, P. J.;
Aspinall, I. H.; Gillen, K.; Godfrey, C. R. A.; Devillers, I.
M.; Munns, G. R.; Sageot, O. A.; Swanborough, J.;
Worthington, P.; Williams, A. J. Chim. 2003, 57, 685; (d)
Dias, L. C.; de Oleveira, L. G.; Vilcachagua, J. D.;
Florian, N. J. Org. Chem. 2005, 70, 2225.
5. (a) Chakraborthy, T. K.; Laxman, P. Tetrahedron Lett.
2003, 44, 4989; (b) Feutrill, J. T.; Rizzacasa, M. A. Aust. J.
Chem. 2003, 56, 783.
6. (a) Gurjar, M. K.; Khaladkar, T. P.; Borhade, R. G.;
Murugan, A. Tetrahedron Lett. 2003, 44, 5183; (b)
Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2004, 45,
5593.
Sulfone 6 was synthesized from mercaptobenzothiazole
(MBT) and chloroacetone in the presence of triethyl-
amine shown in Scheme 2. Thus, treatment of mercapto-
benzothiazole with chloroacetone furnished 18.
Subsequent Wittig reaction with the stabilized ylide
(Ph3P = CHCO2Et) gave a,b-unsaturated ester 19.
Selective oxidation of the sulfide of 19 with oxone affor-
ded sulfone 6 (61% yield from MBT).
7. The synthesis of lactone 8 is similar to the preparation of
its benzyl and p-methoxybenzyl analogues; see Ref. 9,
Finally, fragments 5 and 6 were coupled via modified
Julia olefination.15 Accordingly, pre-lithiated sulfone 6
was treated with aldehyde 5 at ꢀ78 °C to furnish trieno-
ate 20, a known intermediate19 for the synthesis of
crocacins A–D,3 in 56% yield.
O
O
O
HO
NaH, MeI
(+)-IPC2BH
7 days
THF,
0 oC-r.t
9
OMe
I
OH
In conclusion, the formal total synthesis of crocacin C
has been achieved in a stereocontrolled manner by the
creation of four contiguous chiral centres via desymmet-
rization, a trans-styrene derivative by Grubbs cross-
metathesis and a linear trienoate via modified Julia
olefination.
OMe
O
O
O
O
O
PCC
m-CPBA
CH2Cl2
NaHCO3
CH2Cl2
8
II
OMe
OMe
8. Yadav, J. S.; Rao, C. S.; Chandrasekhar, S.; Ramarao, A.
V. Tetrahedron Lett. 1995, 36, 7717.
References and notes
9. Yadav, J. S.; Abraham, S.; Reddy, M. M.; Sabitha, G.;
Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett. 2001, 42,
4713.
10. Yadav, J. S.; Ahmed, M. Tetrahedron Lett. 2002, 43, 7147.
11. Yadav, J. S.; Reddy, K. B.; Sabitha, G. Tetrahedron Lett.
2004, 45, 6475.
1. Kunze, B.; Jansen, R.; Ho¨fle, G.; Reichennach, H. J.
Antibiot. 1994, 47, 881.
2. (a) Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 1999, 1085; (b) Kunze,
B.; Jansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075.
12. Yadav, J. S.; Srinivas, R.; Sathaiah, K. Tetrahedron Lett.
2006, 47, 1603.
13. Garegg, P. J.; Samuelson, B. J. Chem. Soc., Perkin Trans.
1 1980, 2866.
14. Sylvestre, I.; Olliver, J.; Salaun, J. Tetrahedron Lett. 2001,
42, 4991.
3. (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett.
2000, 2, 3365; (b) Chakraborthy, T. K.; Jayaprakash, S.
Tetrahedron Lett. 2001, 42, 497; (c) Dias, L. C.; de
Oleveira, L. G. Org. Lett. 2001, 3, 3951; (d) Chakraborthy,

148
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 145–148
15. (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563; (b) Harris, J. M.; O’Doherty, G. A. Tetrahedron
2001, 57, 5161; (c) Blakemore, P. R.; Cole, W. J.;
Kocienski, P. J.; Morley, A. Synlett 1998, 26.
16. For reviews on olefin metathesis, see: (a) Grubbs, R. H.;
Trnka, T. M. Acc. Chem. Res. 2001, 34, 18; (b) Connon, S.
J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900; (c)
Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360.
2H), 1.00 (d, 3H, J = 7.5 Hz), 0.87 (d, 3H, J = 6.7 Hz);
13C NMR (50 MHz, CDCl3): d 136.6, 115.2, 103.5, 77.6,
71.4, 56.0, 54.6, 36.4, 35.9, 12.8, 8.9; HRESIMS: Calcd for
C11H20O3Na [M+Na+]: 223.1310. Found: 223.1300. Com-
20
pound 14: light yellowish oil; ½aꢁD ꢀ64.7 (c 1.90, CHCl3);
1H NMR (300 MHz, CDCl3): d 7.36–7.15 (m, 5H), 6.60 (d,
1H, J = 15.9 Hz), 6.20 (dd, 1H, J = 15.9, 6.6 Hz), 4.58 (s,
1H), 4.45 (m, 1H), 3.60 (t, 1H, J = 5.1 Hz), 3.34 (s, 3H),
3.33 (s, 3H), 2.17–2.05 (m, 2H), 1.04 (d, 3H, J = 7.9 Hz),
0.92 (d, 3H, J = 7.9 Hz); 13C NMR (75 MHz, CDCl3): d
132.1, 130.4, 128.5, 128.3, 127.4, 126.4, 103.6, 77.9, 77.0,
71.5, 56.2, 54.2, 36.6, 12.9, 9.3; mass (ESI): m/z 299
[M+Na+]. HRESIMS: Calcd for C17H24O3Na [M+Na+]:
299.1273. Found: 299.1261. Compound 6: white solid; mp:
68–70 °C; IR mmax (film): 2994, 2951, 1769, 1699, 1438,
17. Quinn, K. J.; Isaacs, A. K.; Christopher, B. A. D.; Szklarz,
S. C.; Arvary, R. A. Org. Lett. 2005, 7, 1243.
18. Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817.
19. The spectral and physical data of alcohol 17 and ester 20
matched in all respect with reported data (Ref. 3). Selected
physical data for compound 17: clear oil; Rf 0.3 (EtOAc/
20
hexane 25:75); ½aꢁD ꢀ3.8 (c 1.80, CH2Cl2). Compound 20:
1333, 1285, 1154, 1035, 861 cmꢀ1 1H NMR (300 MHz,
;
20
light yellowish oil, ½aꢁD ꢀ6.7 (c 0.2 CHCl3). Compound 7:
CDCl3): d 8.20 (d, 1H, J = 9.2 Hz), 8.00 (d, 1H, J =
6.9 Hz), 7.55–7.68 (m, 2H), 5.78 (s, 1H), 4.26 (s, 2H), 4.08
(q, 2H, J = 13.8, 6.9 Hz), 2.33 (s, 3H), 1.24 (t, 3H, J =
6.9 Hz); mass (ESIMS): m/z 348 [M+Na+], 326 [M+H+].
20. Dess, D. B.; Martin, J. C. J. J. Am. Chem. Soc. 1991, 113,
7277.
20
colorless oil. Rf 0.5 (EtOAc/hexane 10:90); ½aꢁD ꢀ94.7 (c
1
0.87, CHCl3); H NMR (300 MHz, CDCl3): d 5.87–5.76
(m, 1H), 5.28 (dt, 1H, J = 17.3, 1.5 Hz), 5.25 (dt, 1H,
J = 10.5, 1.5 Hz), 4.52 (s, 1H), 3.57 (t, 1H, J = 5.2 Hz),
4.27–4.25 (m, 1H), 3.31 (s, 3H), 3.29 (s, 3H), 2.11–1.98 (m,