Construction of substituted cyclohexanones by reductive cyclization of 7-oxo-2,8-alkadienyl esters

Article abstract of DOI:10.1021/ol0169325

(matrix presented) Cyclization of 7-oxo-2,8-alkadienyl esters upon reaction with triphenylphosphinecopper hydride hexamer stereoselectively yields substituted cyclohexanones having a cis relationship of carbon side chains at C2 and C3. This cyclohexanone

Full text of DOI:10.1021/ol0169325

ORGANIC
LETTERS
2002
Vol. 4, No. 1
79-82
Construction of Substituted
Cyclohexanones by Reductive
Cyclization of 7-Oxo-2,8-alkadienyl
Esters
Theodore M. Kamenecka,† Larry E. Overman,* and Sylvie K. Ly Sakata‡
Department of Chemistry, UniVersity of California, IrVine, 516 Rowland Hall,
IrVine, California 92697-2025
leoVerma@uci.edu
Received October 18, 2001
ABSTRACT
Cyclization of 7-oxo-2,8-alkadienyl esters upon reaction with triphenylphosphinecopper hydride hexamer stereoselectively yields substituted
cyclohexanones having a cis relationship of carbon side chains at C2 and C3. This cyclohexanone construction is particularly useful for
preparing 4-alkoxy- or 4-siloxy-2,3-disubstituted cyclohexanones, in which instance stereoselection is g20:1.
The preparation of six-membered carbocyclic rings is a
fundamental process of organic synthesis. One useful method
is to assemble such rings from acyclic precursors by
sequential conjugate addition reactions.1 In one widely
investigated variant of this strategy, a 2,7-nonadienyldicar-
boxylic diester is cyclized by reaction with an external
carbon,2 nitrogen,3 or hydride4 nucleophile (eq 1). For
ongoing synthesis efforts directed at members of the man-
zamine alkaloid family, we required an efficient way to
prepare cyclohexanones having carbon side chains at C2 and
C3 and an oxygen substituent at C4. To achieve this
objective, we examined a new tandem Michael sequence in
which cyclization of a 7-oxo-2,8-alkadienyl ester would be
Y. J. Org. Chem. 1992, 57, 3139-3145. (g) Shida, N.; Uyehara, T.;
Yamamoto, Y. J. Org. Chem. 1992, 57, 5049-5051. (h) Urones, J. G.;
Garrido, N. M.; D´ıez, D.; Dominguez, S. H.; Davies, S. G. Tetrahedron:
Asymmetry 1999, 10, 1637-1641.
(4) LiR3BH: (a) Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura,
K.; Yoshii, E. J. Org. Chem. 1992, 57, 2888-2902. (b) Hori, K.; Kazumo,
H.; Nomura, K.; Yoshii, E. Tetrahedron Lett. 1993, 34, 2183-2186. (c)
Yoshii, E.; Hori, K.; Nomura, K.; Yamaguchi, K. Synlett 1995, 568-570.
(d) Yoshizaki, H.; Tanaka, T.; Yoshii, E.; Koizumi, T.; Takeda, K.
Tetrahedron Lett. 1998, 39, 47-50. (e) Takeda, K.; Ohkawa, N.; Hori, K.;
Koizumi, T.; Yoshii, E. Heterocycles 1998, 47, 277-282. n-Bu3SnH: (f)
Suwa, T.; Nishino, K.; Miyatake, M.; Shibata, I.; Baba, A. Tetrahedron
Lett. 2000, 41, 3403-3406. PhSiH3: (g) Baik, T.-G.; Luis, A. L.; Wang,
L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112-5113.
(5) (a) Brief review: Daeuble, J. F.; Stryker, J. M. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L., Ed.; Wiley: New York, 1996;
p 2651. (b) Brestensky, D. M.; Huseland, D. E.; McGettigan, C.; Stryker,
J. M. Tetrahedron Lett. 1988, 29, 3749-3752.
* To whom correspondence should be addressed.
† Current address: Merck Research Laboratories, MRLSDB2-1204, 3535
General Atomics Court, La Jolla, CA 92121.
‡ Current address: Pfizer Global Research & Development, La Jolla,
3565 General Atomics Court, La Jolla, CA, 92121.
(1) (a) Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin,
J. I. Org. React. 1995, 47, 315-552. (b) Ho, T. L. Tandem Organic
Reactions; John Wiley: New York, 1992. (c) Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. Engl. 1993, 32, 131-163.
(2) (a) Saito, S.; Hirohara, Y.; Narahara, O.; Moriwake, T. J. Am. Chem.
Soc. 1989, 111, 4533-4535. (b) Klimko, P. G.; Singleton, D. A. J. Org.
Chem. 1992, 57, 1733-1740. (c) Savchenko, A. V.; Montgomery, J. J.
Org. Chem. 1996, 61, 1562-1563.
(3) Typically a lithium amide: (a) Uyehara, T.; Asao, N.; Yamamoto,
Y. J. Chem. Soc., Chem. Commun. 1987, 1410-1411. (b) Uyehara, T.;
Asao, N.; Yamamoto, Y. Tetrahedron 1988, 44, 4173-4180. (c) Uyehara,
T.; Shida, N.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1989, 113-
114. (d) Uyehara, T.; Asao, N.; Yamamoto, Y. J. Chem. Soc. Chem.
Commun. 1989, 753-754. (e) Asao, N.; Uyehara, T.; Yamamoto, Y.
Tetrahedron 1990, 46, 4563-4572. (f) Uyehara, T.; Shida, N.; Yamamoto,
(6) A small portion of these studies were disclosed in a 1996 presentation;
see: Kamenecka, T. M.; Ly, S. K.; Overman, L. E. Abstracts of Papers,
212th National Meeting of the American Chemical Society, Orlando, FL.;
American Chemical Society: Washington, DC, 1996: ORGN 010.
(7) For other sequential reactions that are initiated by conjugate reduction
with Stryker’s reagent, see: (a) Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng,
K.-F. Org. Lett. 2001, 3, 1901-1903. (b) Lipshutz, B. H.; Chrisman, W.;
Noson, K.; Papa, P.; Sclafani, J. A.; Vivian, R. W.; Keith, J. M. Tetrahedron
2000, 56, 2779-2788. (c) Chiu, P.; Chen, B.; Cheng, K.-F. Tetrahedron
Lett. 1998, 39, 9229-9232. (d) Kiyooka, S.; Shimizu, A.; Torii, S.
Tetrahedron Lett. 1998, 39, 5237-5240. (e) ref 5a.
10.1021/ol0169325 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/12/2001

promoted by an external hydride reagent. Commercially
available triphenylphosphinecopper hydride hexamer [Ph3-
PCuH]6 (5), Stryker’s reagent, was found to be the reagent
of choice for this process (eq 2).5 The scope and limitations
of this new stereocontrolled synthesis of substituted cyclo-
hexanones is the subject of this report.6,7
An issue of chemoselectivity, not involved in reductive
cyclizations of dienyl diesters, would be critical for the
success of the cyclohexanone construction depicted in eq 2:
conjugate reduction of the R,â-unsaturated ketone functional
array must be the initial event. Salient results of our
investigation of this issue with 7-oxo-2,8-alkadienoic ester
8a are summarized in Scheme 2. Not surprisingly, attempted
Scheme 2
Simple 7-oxo-2,8-alkadienoic esters and analogous nitriles
were employed in our exploratory studies. They were
prepared from δ-valerolactone as summarized in Scheme 1.
Scheme 1a
cyclization of 8a with lithium tri(sec-butyl)borohydride, the
reagent utilized extensively by Yoshii in tandem Michael
cyclizations of dienyl diesters 1,4a-e resulted largely in 1,2-
reduction of the enone group to yield allylic alcohol 12.
Stryker’s reagent 5, which is known to reduce both R,â-
unsaturated esters and R,â-ketones in conjugate fashion,5
exhibited the requisite chemoselectivity, converting 8a in
good yield to cyclohexanones 13a and 14a. The relative
configuration of these stereoisomeric products was ascer-
tained by their individual equilibration (DBU, PhH, 60 °C)
to give a 3:1 equilibrium mixture of trans (14a) and cis (13a)
stereoisomers.
a Reagents and yields: (a) LiCH2PO(OEt)2; (b) RCHO, K2CO3;
(c) TPAP, NMO; (d) Ph3PdCHCO2Me, 8a: 50% overall from 6,
8b: 60% overall from 6; (e) (CF3CH2O)2P(O)CH2CO2Me, KH-
MDS, 18-C-6, 9: 56% overall from 6; (f) (Ph3PCH2I)+I-, NaH-
MDS, HMPA; (g) KCN, (Ph3P)4Pd, 18-C-6; (h) CHI3, CrCl2, 10:
22% overall from 6, 11: 43% overall from 6.
The yield (80%) and stereoselectivity (13a:14a ) 17:1)
of the reductive cyclization of 8a were optimal when the
reaction was carried out in toluene at -50 °C using 0.2 equiv
(1.2 hydride equiv) of 5 (Table 1). Carrying out the reduction
at room temperature reduced the yield and stereoselection
only slightly. However, stereoselection was solvent depend-
ent, decreasing markedly with increasing solvent polarity
(Table 1, entries 3-5). The purity of [Ph3PCuH]6 (5) was
also important for realizing high cis stereoselectivity, as
stereoselection was reduced if 5 was contaminated with
excess Ph3P.12
(E,E)-Oxoalkadienyl esters 8 were obtained from keto
aldehydes 78 by reaction with methyl (triphenylphosphora-
nylidene)acetate, whereas the 2Z,8E stereoisomer 9 was
formed from 7a by the method of Still and Gennari.9
Related oxodienyl nitriles were obtained from their cor-
responding vinyl iodide precursors10 by palladium-catalyzed
coupling with KCN.11 After purification by column chro-
matography, the isomeric purity of 8-11 was judged to be
1
g95% by H NMR analysis.
To pursue the origin of the solvent effect on cyclization
stereoselectivity, oxoalkadienyl ester 8a was allowed to react
(8) Prepared by a general method: (a) Ditrich, K.; Hoffmann, R. W.
Tetrahedron Lett. 1985, 26, 6325-6328. (b) Altenbach, H.-J.; Holzapfel,
W.; Smerat, G.; Finkler, S. H. Tetrahedron Lett. 1985, 26, 6329-6332.
(9) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(10) E isomer: (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30,
2173-2174. (b) Z isomer: Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem.
Soc. 1986, 108, 7408-7410.
(12) (a) The purity of commercial samples of 5, which is readily assayed
by 1H NMR analysis, differs widely.5,7b Stryker’s one-pot preparation of
55b reliably produces material of high purity. (b) Using Schlenk equipment,
excess Ph3P can be removed from 5 by slurrying the reagent with hexane
or benzene under an argon or nitrogen atmosphere and filtering and drying
residual 5 under vacuum.
(11) Yamamura, K.; Murahashi, S.-I. Tetrahedron Lett. 1977, 50, 4429-
4430.
80
Org. Lett., Vol. 4, No. 1, 2002

product 13b, (Z)-enoate 9 cyclized stereorandomly under
identical conditions. Also cyclizing with low stereoselectivity
were the (Z)- and (E)-7-oxo-2,8-alkadienyl nitriles 10 and
11. Substitution on the double bonds, even at the R-position
of the enoate Michael acceptor, appears not to be tolerated.
For example, 18 did not cyclize but upon workup yielded
only the product of enone-1,4-reduction 19 in reactions
carried out over a range of temperatures (-50 to 50 °C).15,16
This cyclohexanone construction is particularly useful for
the stereocontrolled synthesis of 4-alkoxy- or 4-siloxy-2,3-
disubstituted cyclohexanones (eq 2, X ) OR). The acyclic
precursors for these reactions can be assembled in a variety
of ways, in both racemic and enantiopure form.16,17 For
example, racemic 24 (>15:1 E:Z by 1H NMR analysis) was
prepared in 43% overall yield from cyclopentenone phos-
phonate 2018 using a series of standard transformations
(Scheme 4).19-21
Table 1. Reductive Cyclization of 8a
products
temp
°C
15
Z:Ec
entry
solvent (ꢀ)b
yield %
13a :14a c
1d
2
3
4
5
PhH (2.3)
23
23
-50
-50
-50
70
74
80f
10:1
17:1
17:1e
7:1e
PhMe (2.4)
PhMe (2.4)
PhCl (5.6)
CH2Cl2 (8.9)
20:1e
8:1e
3:1e
86
1:1e
a Conditions: 0.2 equiv (1.2 hydride equiv) of [Ph3PCuH]6, [8a] ) 0.1
M. b Dielectric constant. c By 1H NMR analysis. d [8a] ) 0.4 M. e Mean
values from duplicate experiments. f When [8a] ) 0.07 or 0.2 M, the ratio
13a:14a was unchanged; however, the yield was reduced slightly (72-
74%).
with 5 in various solvents in the presence of TMSCl and
Et3N.5a,13 Enoxysilane stereoisomers (Z)- and (E)-15 were
produced in high yield in these experiments.14 As sum-
marized in Table 1, stereoselection in forming the (Z)-
enoxysilane stereoisomer in trapping experiments correlates
directly with stereoselection in forming the 2,3-cis-cyclo-
hexanone product 13a.
Scheme 4
Additional definition of the scope and some insight into
the mechanism of this new synthesis of substituted cyclo-
hexanones were provided by the experiments summarized
in Scheme 3. Although (E)-7-oxo-9-phenyl-2,8-alkadienoic
Scheme 3
A variety of (E)-4-alkoxy- and (E)-4-siloxy-7-oxo-2,8-
alkadienyl esters cyclize upon reaction with 0.2-0.3 equiv
of [Ph3PCuH]6 (5) to provide a single cyclohexanone product
in high yield (Scheme 5). Diastereoselection in forming 30-
34 was judged to be g20:1 in reactions carried out either at
-50 °C or at room temperature.22 Yields are slightly higher
in reactions conducted at room temperature with 0.3 equiv
of 5. A variety of substituents can be incorporated in the
CH2R1 side chain.17 For example, the high-yielding cycliza-
tion of enantiopure 28 to give enantiopure 34 demonstrates
that even a highly bulky tritylamino group is tolerated at
the γ-position of the enoate. High stereoselection was not
(14) Diagnostic chemical shifts of the C8 vinylic hydrogens of (Z)- and
(E)-15 readily defined their configurations; see: Saunders, W. H.; Xie, L.
F. J. Am. Chem. Soc. 1991, 113, 3123-3130.
(15) Substitution at the R-position of the enone is also not tolerated.16
(16) Ly, S. K. Ph.D. Dissertation, University of California, Irvine, CA,
1998.
(17) Kamenecka, T. M. Ph.D. Dissertation, University of California,
Irvine, CA, 1996.
(18) Available in one step and high yield from dimethyl glutarate; see:
Wenkert, E.; Schorp, M. K. J. Org. Chem. 1994, 59, 1943-1944.
(19) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
(20) Claus, R. E.; Schreiber, S. L. Org. Synth., Coll. Vol. 7 1990, 168-
171.
ester 8b cyclized in the presence of 0.2 equiv of [Ph3PCuH]6
(5) to provide largely the cis-2,3-disubstituted cyclohexanone
(21) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267-
(13) The high stereoselectivity seen in toluene in reductive silylation of
8a with Stryker’s reagent suggests the use of this reagent and solvent for
stereocontrolled synthesis of other acyclic (Z)-enoxysilanes.
277.
(22) Diagnostic signals for other stereoisomers were not apparent in 1H
and 13C NMR spectra of crude reaction products.
Org. Lett., Vol. 4, No. 1, 2002
81

Scheme 5
Figure 1. Possible rationale for forming the less stable 2,3 cis
stereoisomer.
selection seen when 13a and 14a are formed by reaction of
enoxysilane (Z)-15 with tetrabutylammonium fluoride.25,26
Preferential formation of the trans-2,3-disubstituted cyclo-
hexanone stereoisomer 17 from the (E)-R,â-unsaturated
nitrile analogue 11 (see Scheme 3) suggests that coordination
with the copper enolate in the (E)-enoate series might involve
the carbonyl oxygen, rather than the C-C π-bond, of the
Michael acceptor.
In summary, reaction of (E,E)-7-oxo-2,8-alkadienyl esters
with Stryker’s reagent gives the less stable cis stereoisomer
of 2,3-disubstituted cyclohexanones in high yield and ste-
reoselectivity. This cyclohexanone construction is particularly
useful for preparing 4-alkoxy- or 4-siloxy-2,3-disubstituted
cyclohexanones (eq 2, X ) OR), in which instance stereo-
selection is g20:1. Cyclohexanones of this latter type are
readily assembled in high enantiopurity because many
convenient methods are available for preparing the allylic
alcohol precursors in enantioenriched form.16,17,27 Although
not addressed in this investigation, recent disclosures suggest
that the reactions reported herein might well be carried out
using catalytic quantities of [Ph3PCuH]6.7b,28
seen in cyclizations of acyclic precursors having alkyl
substituents γ to the ester. For example, 29 cyclized under
identical conditions to provide a 4:1 mixture of stereo-
isomeric products 35.
Cyclohexanones 30-34 showed diagnostic narrow mul-
tiplets for their C4 methine hydrogens, suggesting an axial
orientation for the alkoxy or siloxy substituents. The broad
signal observed for the C2 hydrogen of 30-32 established
that the C2 side chains of these products are equatorial. These
data suggest the configurations of 30-34 that are depicted
in Scheme 5. Evidence for this conclusion was secured by
hydrolysis of 32 to give acid 36,23 whose dicyclohexylamine
salt 37 was amenable to single-crystal X-ray analysis.17 As
suggested by the NMR data, 37 adopts a chair conformation
that places the C3 alkyl and C4 siloxy substituents axial.
A distinctive feature of the reductive cyclizations of (E,E)-
7-oxo-2,8-alkadienyl esters reported herein is preferential
formation of cyclohexanone products having a cis relation-
ship of the C2 and C3 side chains. In contrast, cyclizations
of (E,E)-2,7-nonadienyldicarboxylic diesters typically provide
trans products (eq 1), an outcome rationalized by chair
transition state topographies in which the emerging C2 and
C3 side chains adopt quasi-equatorial orientations.2-4 Al-
though detailed mechanistic analysis is beyond the scope of
this initial disclosure, we suggest that chelation between the
copper of a (Z)-copper enolate intermediate and the enoate
is responsible for the stereoselection seen in cyclizations of
(E,E)-7-oxo-2,8-alkadienyl esters (Figure 1). The observed
erosion of stereoselectivity when excess Ph3P is present is
consistent with this suggestion,24 as is the lack of stereo-
Acknowledgment. We thank the NSF (CHE-9726471)
for financial support, Drs. J. Greaves and J. Mudd for mass
spectrometric analyses, and Dr. J. Ziller for X-ray analyses.
NMR and mass spectra were determined at UCI with
instruments purchased with the assistance of the NSF and
HIH.
Supporting Information Available: Representative ex-
perimental procedures: preparation of 24 and its cyclization
to 30 and trapping of the initially formed acyclic enolate
derived from 8a to form (Z)-15. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0169325
(25) Several other observations made during this investigation are
consistent with this analysis. For example, a cyclization topography related
to A should be less favorable when the C4 substituent is methyl than when
the substituent is alkoxy or siloxy due to the larger A value of the former.26
As a result of destabilizing steric interactions between C5 and a Z ester
group, (Z)-enoate 9 should also have a reduced propensity to cyclize in the
fashion depicted in Figure 1.
(26) Eliel, E. L.; Satici, H. J. Org. Chem. 1994, 59, 688-689 and related
references therein.
(27) Methoden Org. Chem. (Houben-Weyl, Workbook Edition), 4th ed.;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.;
Thieme: Stuttgart, 1995.
(28) (a) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett.
1998, 39, 4627-4630. (b) Mori, A.; Fujita, A.; Kajiro, H.; Nishihara, Y.;
Hiyama, T. Tetrahedron 1999, 55, 4573-4582. (c) Chen, J.-X.; Daeuble,
J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron 2000, 56, 2153-2166.
(d) Chen, J.-X.; Daeuble, J. F.; Stryker, J. M. Tetrahedron 2000, 56, 2789-
2798. See also: (e) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 6797-6798.
(23) That epimerization of the carboxyl substituent did not occur under
the basic hydrolysis conditions was confirmed by reaction of acid 36 with
diazomethane to return 32.
(24) In the presence of 2.5 equiv of Ph3P, cyclization of 8b by the
conditions reported in Scheme 3 gave 13b and 14b in a 1:1 ratio.
82
Org. Lett., Vol. 4, No. 1, 2002