C-Acylation of cyclopropanols: Preparation of functionalized 1,4-diketones

Article abstract of DOI:10.1021/ol400666x

A convenient method for preparing attractively functionalized 1,4-diketones has been devised by palladium-catalyzed cross-coupling of cyclopropanols and acyl chlorides. The utility of this method has been demonstrated in an enantioselective synthesis of (+)-myrmicarin 217.

Full text of DOI:10.1021/ol400666x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
C‑Acylation of Cyclopropanols:
Preparation of Functionalized
1,4-Diketones
Bibhuti Bhusan Parida, Pragna Pratic Das, Mathilde Niocel, and Jin Kun Cha*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit,
Michigan 48202, United States
jcha@chem.wayne.edu
Received March 12, 2013
ABSTRACT
A convenient method for preparing attractively functionalized 1,4-diketones has been devised by palladium-catalyzed cross-coupling of
cyclopropanols and acyl chlorides. The utility of this method has been demonstrated in an enantioselective synthesis of (þ)-myrmicarin 217.
As part of our research program directed at total synthe-
sis of bioactive natural products containing five- and six-
membered heterocycles, we required easy access to func-
tionalized 1,4-diketones. 1,4-Diketones have been shown
to be useful building blocks for the preparation of cyclo-
pentenones and five-membered hetereocycles.1 There are
various synthetic methods available, including (a) several
types of conjugate addition reactions of acyl radicals or
acyl anion equivalents to R,β-enones, in addition to car-
bonylative 1,4-addition,2 (b) addition of homoenolate
equivalents to acyl derivatives,3 (c) alkylation of enolates,4
(d) oxidative coupling of enolates,5 (e) one-carbon extension
of 1,3-diketones,6 and (f) other approaches (Scheme 1).7 A
wide variety of these known methods notwithstanding, a
practical and versatile coupling reaction of two functiona-
lized subunits (segment coupling) under mild conditions is
highly desirable. Taking advantage of the ready availabil-
ity of enantiopure cyclopropanols, we report herein the
palladium-catalyzed cross-coupling of cyclopropanols and
acyl chlorides for the convenient preparation of attrac-
tively functionalized 1,4-diketones.
(1) For reviews, see: (a) Piancatelli, G.; D’Auria, M.; D’Onofrio, F.
Synthesis 1994, 867. (b) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (c)
Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.;
Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411.
Inconjunctionwithourongoing studies onring-opening
reactions of cyclopropanols, we were particularly inter-
ested in approach b. One direct route to ketones involves
acylation of several types of organometallics with acyl
(2) (a) Corey, E. J.; Hegedus, L. S. J. Am. Chem. Soc. 1969, 91, 4926.
(b) Seyferth, D.; Hui, R. C. J. Am. Chem. Soc. 1985, 107, 4551. (c)
Lipshutz, B. H.; Elworthy, T. R. Tetrahedron Lett. 1990, 31, 477. (d)
Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (e) Harrington,
P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509. (f) Kerr, M. S.; de
Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (g) Mattson,
A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126,
2314. (h) Ryu, I.; Kusano, K.; Yamazaki, H.; Sonoda, N. J. Org. Chem.
1991, 56, 5003. (i) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem.
2004, 69, 908. (j) Custar, D. W.; Le, H.; Morken, J. P. Org. Lett. 2010,
12, 3760.
(3) (a) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I. Tetra-
hedron Lett. 1989, 30, 6541. (b) Fujimura, T.; Aoki, S.; Nakamura, E.
J. Org. Chem. 1991, 56, 2809. (c) Nomura, K.; Matsubara, S. Chem.;
Asian J. 2010, 5, 147. For indium homoenolates, see: (d) Shen, Z.-L.;
Goh, K. K. K.; Cheong, H.-L.; Wong, C. H. A.; Lia, Y.-C.; Yang, Y.-S.;
Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 15852. See also: (e) Ryu, I.;
Ikebe, M.; Sonoda, N.; Yamato, S.; Yamamura, G.; Komatsu, M.
Tetrahedron Lett. 2002, 43, 1257.
(4) Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc.
2002, 124, 7440 and references therein.
(5) (a) Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T. J. Am. Chem.
Soc. 1977, 99, 1487. (b) Narasaka, K.; Okauchi, T.; Tanaka, K.;
Murakami, M. Chem. Lett. 1992, 2099. (c) Jang, H. Y.; Hong, J.-B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004. (d) Clift, M. D.;
Taylor, C. N.; Thomson, R. J. Org. Lett. 2007, 9, 4667. (e) DeMartino,
M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546.
(6) (a) Xue, S.; Li, L.-Z.; Liu, Y.-K.; Guo, Q.-X. J. Org. Chem. 2006,
71, 215. (b) Ronsheim, M. D.; Hilgenkamp, R. K.; Zercher, C. K. Org.
Synth. 2004, Coll. Vol. 10, 526.
(7) (a) Pecunioso, A.; Menicagli, R. J. Org. Chem. 1988, 53, 2614. (b)
Bergman, R.; Nilsson, B.; Wickberg, B. TetrahedronLett. 1990, 31, 2783.
(c) Setzer, P.; Beauseigneur, A.; Pearson-Long, M. S. M.; Bertus, P.
Angew. Chem., Int. Ed. 2010, 49, 8691.
r
10.1021/ol400666x
XXXX American Chemical Society

Scheme 1. Synthetic Methods for 1,4-Diketones
Scheme 2. Acylation of Cyclopropanols and Silyl Ethers
chlorides or derivatives, and a useful method is the copper-
or palladium-catalyzed acylation of organozinc reagents.8,9
Despite pioneering studies on cyclopropanone hemiacetals
(R2 = alkoxy) as homoenolates by the Kuwajima group,
acylation met with limited success: preformed zinc ester
homoenolates were necessary for the preparation of 4-keto
esters via Pd(0)- or Cu(I)-catalyzed coupling.10 Extension
to the preparation of 1,4-diketones via keto homoenolates
was by no means straightforward due to their known
proclivity to cyclize to the corresponding cyclopropoxides
in contrast to the corresponding metal homoenolates of
weakly electrophilic esters and derivatives.11 Previous
methods involved the use of siloxycyclopropanes under
harsh conditions: this protocol was limited to aroyl chlor-
ides (Scheme 2).3 Aliphatic acyl chlorides gave no desired
product, and decarbonylation became problematic. We
hypothesized that the use of a suitable metal cycloprop-
oxide could offer a simple, yet effective solution to this
challenging problem.
As recently utilized in another transition-metal-mediated
CꢀC bond forming reaction of cyclopropanols,12 addition
of diethylzinc to a THF solution of (racemic) cyclopropa-
nol 7 gavethe corresponding zinc alkoxide 8. When a Pd(0)
catalyst13 and benzoyl chloride (R = Ph) were added in
one portion (fast addition), an ∼1:1 to 1:1.9 mixture of
O-acylation product 9 and C-acylation product 10 was
isolated (49ꢀ52%). On the other hand, slow (over 1 h via
syringe pump) addition of benzoyl chloride allowed clean
C-acylation to afford 10 in 71% yield, free from the
competing ethyl transfer. Also noteworthy is the regiospe-
cificity of the coupling reaction. In the absence of a
catalyst, treatment of 8 with benzoyl chloride resulted in
O-acylation (i.e., 9 in 35% yield), in addition to recovered 7
(∼25%).
Initial screening indicated that both THF and Et2O were
suitable as solvent, whereas significant amounts of starting
materials were recovered unreacted when 5:1 THFꢀDMA
was employed. In contrast, C-acylation of preformed zinc
ester homoenolates was reported to require the use of
HMPAꢀTMSCl in ether, whereas only O-acylation was
observed in CHCl3.10 We next examined the acylation re-
action of cyclopropanols 7, 11, and 12 with a bevy of acyl
chlorides to establish a broad substrate scope (Figure 1). A
full range of acyl chlorides gave satisfactory yields, and
substituents were well tolerated at R- or distal positions.
Small amounts of benzyl ethyl ketone (27) were isolated as
side products from the coupling reactions of cyclopropa-
nol 12 (R2 = H), whereas the corresponding ring-opened
ketones28were not foundfrom those of 7 and 11(R2 ¼ H).
Additional examples involving nonracemic substrates
underline the synthetic utility of the key methodology in
rapidly building up molecular complexity via segment
coupling (Figure 2, wherein the keto segments on the right
side are derived from acyl chlorides).14 As seen in the
preparation of 32, the coupling reaction is compatible with
(8) Negishi, E.-i.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J. A.;
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(9) For reviews, see: (a) Dieter, R. K. Tetrahedron 1999, 55, 4177. (b)
Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (c) Jana, R.;
Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(10) (a) Oshino, H.; Nakamura, E.; Kuwajima, I. J. Org. Chem. 1985,
50, 2802. See also: (b) Kuwajima, I.; Nakamura, E. Top. Curr. Chem.
1990, 155, 1. (c) Nakamura, E.; Kuwajima, I. Org. Synth. 1993, Coll. Vol.
8, 277.
(11) Crimmins, M. T.; Nantermet, P. G. Org. Prep. Proc. Int. 1993,
25, 41.
(12) Das, P. P.; Belmore, K.; Cha, J. K. Angew. Chem., Int. Ed. 2012,
51, 9517.
(13) A brief survey revealed that several Pd(0) catalysts [e.g., Pd(OAc)2/
Ph3P, Pd2(dba)3/4 Ph3P, or Pd(dba)2/4 Ph3P] were equally effective.
(14) Cyclopropanols were readily available by published methods:
(a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118,
291. (b) Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem.,
Int. Ed. 2002, 41, 2160. (c) Lee, H. G.; Lysenko, I. L.; Cha, J. K.
ARKIVOC 2008, 9, 133.
B
Org. Lett., Vol. XX, No. XX, XXXX

Figure 2. Cross-coupling of nonracemic substrates.
Scheme 3. Retrosynthetic Analysis and Total Synthesis
of (þ)-37
Figure 1. Cross-coupling of cyclopropanols and acyl chlorides.
the presence of a free hydroxyl group (2 equiv of Et2Zn
used) in the cyclopropanol partner.
As an initial foray into synthetic applications, (þ)-
myrmicarin 217 (37) was chosen as the first target
(Scheme 3).15ꢀ17 We envisioned an intramolecular
PaalꢀKnorr synthesis from 1,4-diketone 40 and sub-
sequent ring closing metathesis (RCM) of the resulting
pyrrole to afford tricycle 39. An enantioselective route
to the key intermediate 40 would be available by
€
(15) Schroder, F.; Franke, S.; Francke, W.; Baumann, H.; Kaib, M.;
Pasteels, J. M.; Daloze, D. Tetrahedron 1996, 52, 13539.
€
(16) racemic-37: (a) Schroder, F.; Francke, W. Tetrahedron 1998, 54,
ꢀ
ꢀ
5259. (R)-(þ)-37: (b) Sayah, B.; Pelloux-Leon, N.; Vallee, Y. J. Org.
Chem. 2000, 65, 2824. (c) Movassaghi, M.; Ondrus, A. E. Org. Lett.
2005, 7, 4423. See also: (d) Snyder, S. A.; ElSohly, A. M.; Kontes, F.
Angew. Chem., Int. Ed. 2010, 49, 9693. (e) Settambolo, R.; Guazzelli, G.;
Lazzaroni, R. Tetrahedron: Asymmetry 2003, 14, 1447. (f) Santarem, M.;
Vanucci-Bacque, C.; Lhommet, G. Heterocycles 2010, 81, 2523.
(17) For a review, see: Ondrus, A. E.; Movassaghi, M. Chem.
Commun. 2009, 4151.
(18) Prepared by the Kulinkovich cyclopropanation of γ-butyrolactone
with n-pentylmagnesium chloride, followed by straightforward functional
group manipulation: For reviews, see: (a) Kulinkovich, O. G.; de Meijere,
A. Chem. Rev. 2000, 100, 2789. (b) Kulinkovich, O. G. Chem. Rev. 2003,
103, 2597. (c) Cha, J. K.; Kulinkovich, O. G. Org. React. 2012, 77, 1.
cross-coupling between cyclopropanol 43 and crotonoyl
chloride. Our synthesis commenced with readily available
(()-41.18 Dess-Martin oxidation of alcohol 41 and asym-
metric allylation by Keck’s method19 [using (S)-BINOL)]
afforded homoallylic alcohol 42 as an inconsequential 1:1
mixture of two diastereomers. Azide 43 was next prepared
ꢀ
(19) Keck, G. E.;Krishnamurthy, D. Org. Synth. 2004, Coll. Vol. 10, 632.
Org. Lett., Vol. XX, No. XX, XXXX
C

in 81% overall yield by clean displacement of the second-
ary alcohol of 42 with diphenylphosphoryl azide,20 fol-
lowed by desilylation. The key cross-coupling reaction of
43 with crotonoyl chloride proceeded cleanly to provide 40
in 78% yield. Subsequent conversion of 40 to the corre-
sponding pyrrole started with initial treatment with triphe-
nylphosphine, followed by gentle heating of the resulting
intermediate 44 in tert-butanol (containing 5 equiv of
HOAc).21 Isolation of 44 (albeit fully characterized) was
unnecessary for the PaalꢀKnorr pyrrole synthesis. RCM of
the crude pyrrole product with Grubbs’ second-generation
catalysis delivered 39, which was converted by catalytic
hydrogenation to labile 38 (which was used immediately
for next step). Finally, VilsmeierꢀHaack acylation of 38
and subsequent LAH reduction according to literature
precedents completed an enantioselective synthesis of
(þ)-37.
In conclusion, a straightforward cross-coupling reaction
between cyclopropanols and acyl chlorides offers a versa-
tile method for preparing attractively functionalized
1,4-diketones. Segment coupling allows a rapid buildup
in molecular complexity due to an expedient bond con-
nection. In view of the ready availability of nonracemic
substrates, broad substrate scope, operational simplicity,
and mild reaction conditions, this method should find
use in natural product synthesis. Mechanistic and synthetic
studies are in progress.
Acknowledgment. We thank the NSF (CHE-1212879)
for generous financial support.
Supporting Information Available. Experimental de-
tails and spectroscopic data for key intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetra-
hedron Lett. 1977, 18, 1977.
(21) A protic solvent containing 3ꢀ5 equiv of HOAc (to promote the
imine to enamine tautomerization) was necessary for clean formation
(89ꢀ95%) of the pyrrole. With methanol as solvent, the Michael
reaction took place to afford the pyrrole bearing the corresponding
β-methoxy side chain in 95% yield.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX