Concise total synthesis of (+)-crocacin C

Article abstract of DOI:10.1021/jo800906p

(Chemical Equation Presented) The cytotoxic natural product (+)-crocacin C (1) has been synthesized in 10 linear steps from commercially available Evans' chiral propionimide in 5% overall yield (8 steps from Evans' chiral dipropionate synthon). No protect

Full text of DOI:10.1021/jo800906p

Concise Total Synthesis of (+)-Crocacin C
Gopal Sirasani, Tapas Paul, and Rodrigo B. Andrade*
Department of Chemistry, Temple UniVersity, Philadelphia,
PennsylVania 19122
randrade@temple.edu
ReceiVed April 26, 2008
FIGURE 1. Structures of crocacins A-D (1-4).
SCHEME 1. Retrosynthesis of Crocacin C (1)
The cytotoxic natural product (+)-crocacin C (1) has been
synthesized in 10 linear steps from commercially available
Evans’ chiral propionimide in 5% overall yield (8 steps from
Evans’ chiral dipropionate synthon). No protecting groups
were utilized.
In 1999, Jansen and co-workers reported the structures of
crocacin C (1) and its congeners crocacins A (2), B (3), and D
(4), which were isolated from various strains of the myxobac-
terium Chondromyces crocatus (Figure 1).1
These natural products moderately inhibit Gram-positive
bacterial growth and possess antifungal and cytotoxic activity.2
Recently, the crocacins have been identified as novel agricultural
pesticide leads.3 By inspection, crocacin C (1) is composed of
a polyketide fragment possessing the challenging anti-anti-syn
stereotetrad (C16-C19) in addition to a conjugated (E,E)-
dienamide system (C11-C15). Crocacins A (2), B (3), and D
(4) are further characterized by an acid-sensitive (Z)-N-acyle-
namine motif (C7-C11) tethered to a glycine residue. These
structural features coupled with an interesting bioactivity profile
have made these natural products attractive targets for synthesis.
To date, there have been three reported asymmetric total
syntheses4–7 and four asymmetric formal syntheses8–12 of
crocacin C (1). As 1 represents the common structural feature
among all congeners, we sought to prepare this natural product
in the most efficient manner possible. Toward this end, we began
with a retrosynthetic analysis that maximized convergence and
avoided protecting groups altogether (Scheme 1).13
(1) Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach, H.; Hofle, G. Eur.
J. Org. Chem. 1999, 1085–1089.
A disconnection at the C14-C15 olefinic bond yields
aldehyde 6 and vinylogous phosphonate 5,14 which will be
assembled in a forward sense by a vinylogous HWE reaction.
Aldehyde 6 is fashioned in turn from an Evans dipropionate
aldol reaction between ketoimide 7 and trans-cinnamaldehyde
(2) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot. 1994, 47,
881–886.
(3) Crowley, P. J.; Aspinall, I. H.; Gillen, K.; Godfrey, C. R. A.; Devillers,
I. M.; Munns, G. R.; Sageot, O. A.; Swanborough, J.; Worthington, P. A.;
Williams, J. Chimia 2003, 57, 685–691.
(4) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett. 2000, 2, 3365–
3367.
(5) Chakraborty, T. K.; Jayaprakash, S. Tetrahedron Lett. 2001, 42, 497–
499.
(10) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synlett 2007,
(6) Chakraborty, T. K.; Jayaprakash, S.; Laxman, P. Tetrahedron 2001, 57,
9461–9467.
2049–2052.
(11) Yadav, J. S.; Reddy, P. V.; Chandraiah, L. Tetrahedron Lett. 2007, 48,
145–148.
(7) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2001, 3, 3951–3954.
(8) Gurjar, M. K.; Khaladkar, T. P.; Borhade, R. G.; Murugan, A. Tetrahedron
Lett. 2003, 44, 5183–5187.
(12) Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2004, 45, 5593–5595.
(13) Hoffmann, R. W. Synthesis 2006, 3531–3541.
(14) Mata, E. G.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1995, 785–
799.
(9) Besev, M.; Brehm, C.; Furstner, A. Collect. Czech. Chem. Commun. 2005,
70, 1696–1708.
6386 J. Org. Chem. 2008, 73, 6386–6388
10.1021/jo800906p CCC: $40.75 2008 American Chemical Society
Published on Web 07/16/2008

SCHEME 2. Evans Dipropionate Aldol Reaction
SCHEME 3. Reduction of 11 and 13C NMR Acetonide
Analysis
SCHEME 4. Completion of the Synthesis
(8).15 An obvious strength of this method lies in the ability to
(1) exert stereocontrol in the aldol reaction to access either syn
aldol diastereomer and (2) utilize the newly formed hydroxyl
to direct the stereochemical course of the reduction by proper
reagent selection, leading to either a 1,3-syn or 1,3-anti diol.16
The synthesis commenced with the preparation of ketoimide
7 by an Evans aldol reaction17 of oxazolidinone 9 and
propionaldehyde (dr >20:1) followed by Parikh-Doering
oxidation,18 which proceeded in 71% overall yield. Enolization
of 7 with TiCl4 and i-Pr2NEt and subsequent addition of trans-
cinnamaldehyde (8) furnished the desired syn-syn aldol 11 (dr
>20:1) in 75% yield (Scheme 2).
With aldol 11 in hand, attention was placed on the stereo-
selective, directed reduction of the C17 ketone with
NMe4BH(OAc)3 to furnish the desired 1,3-anti diol.16 In the
event, reduction of 11 in MeCN/AcOH at -40 °C smoothly
afforded diol 12 as a single diastereomer. To confirm the relative
1,3-anti stereochemistry, diol 12 was converted into an acetonide
following standard conditions and subjected to 13C NMR
analysis. Resonances from the acetonide NMR (23.5 and 25.8
ppm for the methyls; 100.8 ppm for the ketal carbon) were
consistent with those found in a twist-boat conformation, which
is indicative of a 1,3-anti diol disposition (Scheme 3).19,20 This
analysis is consistent with previous synthetic studies on crocacin
C (1).7,21
At this point, various methylation protocols were screened
to install both requisite methyl ethers.22 Ultimately, the com-
bination of MeOTf and 2,6-di-tert-butyl-4-methylpyridine at 0
°C provided 14 in 49% yield with unproductive elimination
accounting for the remaining mass balance (Scheme 4).
Reductive removal of the chiral auxiliary with LiBH4 afforded
a known intermediary alcohol, which has been previously
converted into crocacin C (1) by a number of routes.4–7 The
remainder of the synthesis followed known literature protocols.
Oxidation of the alcohol with the Dess-Martin periodinane23
provided aldehyde 6 in 59% yield from 14. Endgame began
with a stereoselective, vinylogous Horner-Wadsworth-Emmons
reaction to prepare conjugated E,E-dienoate 15 in 57% yield
as one diastereomer. Saponification of the ester, activation of
the intermediary acid with methyl chloroformate, and treatment
with aqueous ammonia delivered crocacin C (1) in 63% yield
from 6.6
In summary, the asymmetric total synthesis of 1 has been
accomplished in 10 steps from commercially available Evans’
propionimide 9 in 5% overall yield without recourse to
protecting groups.
Experimental Section
(15) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866–868.
(16) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560–3578.
Aldol 11. To a solution of dipropionimide 7 (1.38 g, 4.77 mmol)
in CH2Cl2 (19 mL) at -10 °C was added TiCl4 (1.00 g, 5.25 mmol)
then freshly distilled i-Pr2NEt (0.68 g, 5.25 mmol). After being
stirred for 1 h, the reaction mixture was cooled to -78 °C and
freshly distilled aldehyde 8 (0.69 g, 5.25 mmol) was added
dropwise. The reaction mixture was stirred at -78 °C for 30 min
then warmed to -40 °C over a period of 1 h. The reaction mixture
was warmed to 0 °C and quenched by the addition of phosphate
buffer (7.6 mL, pH 7) and stirred an additional 5 min. The reaction
mixture was extracted with CH2Cl2 (2 × 20 mL). The combined
(17) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127–2129.
(18) Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992,
48, 2127–2142.
(19) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945–
948.
(20) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31,
7099–7100.
(21) A similar argument was made in support of the stereochemical
assignment by Dias and co-workers on a similar intermediate (ref 7).
(22) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. Tetrahedron
Lett. 1994, 35, 7171–7172.
(23) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
J. Org. Chem. Vol. 73, No. 16, 2008 6387

organic layers were washed with aqueous NaHCO3 (15 mL) and
brine solution (15 mL), dried (Na2SO4), and filtered. The solvent
was concentrated under reduced pressure, and the residue was
purified by flash chromatography eluting with EtOAc/hexanes (1:
5) to afford 1.50 g (75%) of aldol 11 as a yellow oil.
[R]20D -165.0 (c 1.0, CH2Cl2); IR (neat) 3524, 2252, 1774, 1713,
1391, 1358, 1215, 909, 731 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.35-7.13 (m, 10H), 6.63 (dd, J ) 16.0, 1.2 Hz, 1H), 6.13 (dd, J
) 16.0, 5.6 Hz, 1H), 4.84 (q, J ) 7.2 Hz, 1H), 4.78 (br s, 1H),
4.73-4.68 (m, 1H), 4.22-4.12 (m, 2H), 3.24 (dd, J ) 13.6, 3.2
Hz, 1H), 3.02-3.00 (m, 2H), 2.74 (dd, J ) 13.6, 9.6 Hz, 1H),
1.45 (d, J ) 7.6 Hz, 3H), 1.13 (d, J ) 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 211.1, 170.0, 153.9, 136.7, 134.9, 130.9, 129.3,
128.9, 128.5, 127.5, 127.4, 126.5, 71.9, 66.6, 55.3, 52.3, 49.7, 37.8,
13.0, 10.5. HRMS (FAB) calcd for C25H27NO5 + Na+ 444.1786,
found 444.1778.
purified by flash chromatography eluting with EtOAc/hexanes
(1:4) to afford 65.0 mg (73%) of acetonide 13 as a yellow oil.
[R]20D -50.2 (c 1.0, CH2Cl2); IR (neat) 3154, 3029, 2986, 2253,
1780, 1698, 1455, 1383, 1263, 1222, 1107, 1022, 969, 909, 650
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.34-7.14 (m, 10H), 6.54
(dd, J ) 15.8, 0.8 Hz, 1H), 6.09 (dd, J ) 15.8, 6.0 Hz, 1H),
4.66-4.54 (m, 1H), 4.57-4.54 (m, 1H), 4.12-4.11 (m, 2H),
4.04-3.96 (m, 1H), 3.67 (dd, J ) 9.2, 6.8 Hz, 1H), 3.20 (dd, J )
13.2, 3.2 Hz, 1H), 2.74 (dd, J ) 13.2, 9.6 Hz, 1H), 1.93-1.85 (m,
1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.18 (d, J ) 6.8 Hz, 3H), 0.95 (d,
J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.1, 153.2,
137.0, 135.3, 130.5, 129.5, 129.0,128.5, 127.4, 127.3, 127.2, 126.4,
100.8, 76.2, 70.0, 66.0, 55.4, 42.9, 38.9, 38.0, 25.8, 23.5, 14.0, 12.8.
HRMS (FAB) calcd for C28H33NO5 + Na+ 486.2256, found
486.2254.
Imide 14. To a stirred solution of the diol 12 (70.0 mg, 0.17
mmol) in CHCl3 (1.5 mL) at 0 °C was added 2,6-di-tert-butyl-4-
methylpyridine (1.19 g, 5.81 mmol) followed by the addition of
MeOTf (0.82 g, 4.98 mmol). The reaction mixture was stirred for
28 h at 0 °C, quenched with MeOH (2 mL), extracted with CH2Cl2
(3 × 5 mL), washed with brine solution (5 mL), dried (Na2SO4)
and filtered. The solvent was concentrated under reduced pressure,
and the residue was purified by flash chromatography eluting with
EtOAc/hexanes (1:4) to afford 37.0 mg (49%) of imide 14 as a
yellow oil.
Diol 12. To a stirred solution of Me4NBH(OAc)3 (5.63 g, 21.40
mmol) in MeCN (10 mL) was added glacial AcOH (10 mL). After
being stirred for 30 min, the reaction mixture was cooled to -40
°C and a solution of 11 (1.50 g, 3.57 mmol) in MeCN (10 mL)
was added via cannula. After being stirred for 6 h at this same
temperature, the reaction mixture was transferred to a refrigerator
and allowed to age for 16 h at -20 °C. Aqueous sodium tartrate
(0.5 M, 25 mL) was added. The reaction mixture was warmed to
rt over 1 h then diluted with additional sodium tartrate (0.5 M, 25
mL) and CH2Cl2 (50 mL). The organic layer was separated, and
the aqueous layer was back-extracted with CH2Cl2 (2 × 25 mL).
The combined organic layers were washed with aqueous NaHCO3
(30 mL) and brine solution (30 mL), dried (Na2SO4), and filtered.
The solvent was concentrated under reduced pressure, and the
residue was purified by flash chromatography eluting with EtOAc/
hexanes (2:3) to afford 1.32 g (88%) of diol 12 as a yellow oil.
[R]20D -74.5 (c 1.0, CH2Cl2); IR (neat) 3154, 2983, 2253, 1780,
1698, 1470, 1383, 1264, 1094, 907, 733, 650 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.36-7.14 (m, 10H), 6.50 (d, J ) 21.2, Hz, 1H),
6.08 (dd, J ) 21.2, 9.6 Hz, 1H), 4.57-4.56 (m, 1H), 4.13-4.08
(m, 3H), 3.94 (dd, J ) 9.6, 4.8 Hz, 1H), 3.41-3.36 (m, 4H),
3.25-3.20 (m, 4H), 2.69 (dd, J ) 17.6, 13.0 Hz, 1H), 1.90-1.88
(m, 1H), 1.20 (d, J ) 6.4 Hz, 3H), 0.90 (d, J ) 9.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 175.2, 153.1, 136.8, 135.4, 132.3, 129.5,
129.2, 128.9, 128.6, 127.6, 127.3, 126.5, 84.9, 81.8, 66.0, 60.1,
56.5, 55.7, 41.6, 40.7, 37.9, 14.1, 11.0. HRMS (FAB) calcd for
C27H33NO5 + Na+ 474.2256, found 474.2228.
[R]20D -80.8 (c 1.0, CH2Cl2); IR (neat) 3460, 3028, 2976, 2360,
1
2341, 2252, 1779, 1698, 1455, 1385, 1209, 908, 732; H NMR
(400 MHz, CDCl3) δ 7.40-7.20 (m, 10H), 6.64 (dd, J ) 16.0, 1.2
Hz, 1H), 6.26 (dd, J ) 16.0, 5.6 Hz, 1H), 4.77-4.75 (m, 2H),
4.26-4.16 (m, 3H), 3.98 (d, J ) 8.4 Hz, 1H), 3.73 (q, J ) 6.9 Hz,
1H), 3.31 (br s, 1H), 3.25 (dd, J ) 13.2, 3.4 Hz, 1H), 2.81 (dd, J
) 13.2, 9.6 Hz, 1H), 1.97-1.90 (m, 1H), 1.31 (d, J ) 7.2 Hz,
3H), 1.04 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
177.1, 153.3, 136.8, 135.0, 130.5, 130.3, 129.4, 129.0, 128.5, 127.5,
127.4, 126.4, 78.4, 72.8, 66.2, 55.5, 40.3, 39.8, 37.9,15.0, 11.6.
HRMS (FAB) calcd for C25H29 NO5 + Na+ 446.1943, found
446.1945.
Acknowledgment. Financial support of this work by the
Department of Chemistry at Temple University is gratefully
acknowledged. We also kindly thank Profs. Chris Schafmeister
for access to LCMS instrumentation and Scott McN. Sieburth
for helpful discussions.
Supporting Information Available: Experimental proce-
dures for 1, 6, and 15, NMR spectra (1H and 13C NMR spectra)
for 1 and 11-14, and LCMS trace of 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acetonide 13. To a stirred solution of diol 12 (80.0 mg, 0.19
mmol) in dimethoxypropane (19 mL) was added a catalytic amount
of PPTS. The reaction mixture was stirred for 3 h. The solvent
was concentrated under reduced pressure, and the residue was
JO800906P
6388 J. Org. Chem. Vol. 73, No. 16, 2008