Unusual reagent control of diastereoselectivity in the 1,2-addition of hard carbon nucleophiles to C(6)-heteroatom substituted cyclohexenones.

Article abstract of DOI:10.1021/ol016673j

[reaction: see text] A surprising and synthetically useful counterion-dependent reversal of diastereoselectivity was found in 1,2-additions of hard carbon nucleophiles to C(6)-heterosubstituted cyclohexenones. In general, Grignard reagents added syn to th

Full text of DOI:10.1021/ol016673j

ORGANIC
LETTERS
2
001
Vol. 3, No. 25
007-4010
Unusual Reagent Control of
Diastereoselectivity in the 1,2-Addition
of Hard Carbon Nucleophiles to
C6-Heteroatom Substituted
Cyclohexenones
4
†
Harriet A. Lindsay, Catherine L. Salisbury, Wally Cordes, and
Matthias C. McIntosh*
Department of Chemistry and Biochemistry, UniVersity of Arkansas,
FayetteVille, Arkansas 72701
mcintosh@uark.edu
Received August 30, 2001 (Revised Manuscript Received October 30, 2001)
ABSTRACT
A surprising and synthetically useful counterion-dependent reversal of diastereoselectivity was found in 1,2-additions of hard carbon nucleophiles
to C -heterosubstituted cyclohexenones. In general, Grignard reagents added syn to the C -substituent and Li reagents added anti, although
some exceptions were found. Selectivities could be increased in some cases by appropriate choice of solvent and/or cosolvent.
6
6
4
-9
The addition of carbon nucleophiles to aldehydes and ketones
is one of the fundamental reactions in organic synthesis.
have been demonstrated both experimentally
and com-
1
5
putationally. However, it is clear from results in our
laboratories that these simple guidelines do not generally
predict the stereochemical outcome in additions to C -
6
Such additions to cyclohexenones afford tertiary allylic
cyclohexenols, which are common functional groups in
2
10,11
natural products (Figure 1) as well as useful intermediates
heteroatom substituted cyclohexenones.
in a variety of reactions.3
In the context of ongoing studies in our laboratories, we
required stereoselective syntheses of a series of vinyl and
In 1,2-additions to cyclohexanones and cyclohexenones,
the intrinsic stereoelectronic preference for axial addition of
small nucleophiles and the propensity of larger nucleophiles
to give higher proportions of equatorial addition products
†
Author to whom correspondence regarding X-ray crystallographic
analyses should be addressed.
(
1) (a) Ashby, E. C.; Laemmle, J. T. Chem. ReV. 1975, 75, 521-546.
(
b) Eliel, E. L. in Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1983; Vol. 2, pp 125-155. (c) Holm, T.; Crossland, I.
in Grignard Reagents: New DeVelopments; Richey, H. G., Ed.; Wiley: New
York, 2000, pp 1-26. (d) Wakefield, B. J. Organomagnesium Methods in
Organic Synthesis; Academic Press: San Diego, 1995. (e) Eicher, T. In
The Chemistry of the Carbonyl Group; Patai, S., Ed.; Interscience: New
York, 1991; Vol. 1, pp 621-693. (f) Huryn, D. M. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 1,
pp 49-75 and references therein.
Figure 1. Natural products containing tertiary allylic alcohols or
derivatives thereof.
1
0.1021/ol016673j CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

2
5:1 diastereoselectivity with either alkynyl- or vinyl-Li or
-
MgBr. The reactions presumably proceeded via a Felkin-
Table 1. 1,2 Additions to 6-chlorocyclohexenone
13
Anh transition state with addition occurring anti to the axial
C
1
4
6
-chloro substituent (vide infra).
By contrast, vinylmetal additions to trans-6-chlorocarvone
12
3
a demonstrated an unusual counterion-dependent reversal
of diastereoselectivity (Table 2, entries 1 and 2). VinylMgBr
Table 2. Vinyl Additions to trans-6-Halocarvone
a
Yield after desilylation. b 10% 1,4-addition products also isolated.
entry
compd
X
M
4:5
yielda
alkynyl cyclohexenols such as 2a,b (Table 1). Additions of
1
2
3
4
a
a
b
b
Cl
Cl
F
MgBr
Li
MgBr
Li
4:1
1:5
2:1
1:3
65
70
36
56
vinyl and ethynyl nucleophiles to 6-chlorocyclohexenone
3b,12
(1)
gave the expected anti alcohols 2a,b with greater than
F
(2) For examples of natural products containing tertiary allylic alcohols,
a
see: (a) Sakai, R.; Higa, T. J. Am. Chem. Soc. 1986, 108, 6404-6405. (b)
Macias, F. A.; Varela, R. M.; Simonet, A. M.; Cutler, H. G.; Cutler, S. J.;
Dugan, F. M.; Hill, R. A. J. Org. Chem. 2000, 65, 9039-9046. (c) Fraga,
B. M.; Terrero, D.; Gutierrez, C.; Gonzalez-Coloma, A. Phytochemistry
Isolated yield of major isomer.
2
001, 56, 315-320. (d) Collins, D. O.; Gallimore, W. A.; Reynolds, W.
produced predominately equatorial alcohol 4a via addition
syn to the C -chloride. VinylLi addition produced axial
alcohol 5a as the major product via anti addition. The relative
stereochemistry of alcohols 4a and 5a was determined by
F.; Williams, L. A. D.; Reese, P. B. J. Nat. Prod. 2000, 63, 1515-1518.
(
e) Ahmed. A. A. J. Nat. Prod. 2000, 63, 989-991. (f) Cinel, B.; Roberge,
6
M.; Behrisch, H.; van Ofwegen, L.; Castro, C. B.; Andersen, R. J. Org.
Lett. 2000, 2, 257-260.
(3) See, for example: (a) Still, W. C. J. Am. Chem. Soc. 1977, 99, 4186-
1
3
15
4
1
7
187. (b) Paquette, L. A.; Ross, R. J.; Shi, Y.-J. J. Org. Chem. 1990, 55,
589-1598. (c) Zhang, X.; McIntosh, M. C. Tetrahedron Lett. 1998, 39,
043-7046. (d) Trost, B. M.; Haffner, C. D.; Jebaratnam, D. J.; Krische,
C NMR analysis of the two diastereomers. A few
scattered examples of counterion-dependent reversal of
1
6
M. J.; Thomas, A. P. J. Am. Chem. Soc. 1999, 121, 6183-6192.
selectivity have appeared in the literature, although to our
knowledge no systematic investigation of this phenomenon
has been conducted.
(4) (a) Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am. Chem. Soc.
1
1
987, 109, 613-615. (b) Trost, B. M.; Florez, J.; Haller, K. J. J. Org. Chem.
988, 53, 2394-2396.
(5) (a) Wu, Y.-D.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 908-910.
In an effort to probe steric versus electronic effects of the
(
5
b) Wu, Y.-D.; Houk, K. N.; Trost, B. M. J. Am. Chem. Soc. 1987, 109,
560-5561. (c) Wu, Y.-D.; Houk, K. N.; Florez, J.; Trost, B. M. J. Org.
6
C -heteroatom on diastereoselection, vinylmetal additions to
1
7
Chem. 1991, 56, 3656-3664. (d) Ando, K.; Houk, K. N.; Busch, J.;
Menasse, A.; Sequin, U. J. Org. Chem. 1998, 63, 1761-1766.
trans-6-fluorocarvone 3b were examined (Table 2, entries
1
8
3
and 4). In the case of vinylmetal additions to fluoro-
(6) (a) Stork, G.; Stryker, J. M. Tetrahedron Lett. 1983, 24, 4887-4890.
(
b) Stork, G.; West, F.; Lee, H. Y.; Isaacs, R. C. A.; Manabe, S. J. Am.
Chem. Soc. 1996, 118, 10660-10661.
7) Buckwalter, B. L.; Burfitt, I. R.; Felkin, H.; Joly-Goudket, M.;
carvone 3b, we again observed a reversal of diastereoselec-
(
Naemura, K.; Salomon, M. F.; Wenkert, E.; Wovkulich, P. M. J. Am. Chem.
Soc. 1978, 100, 6445-6450.
(13) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205-
2208. (c) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-161.
(14) Although we were unable to rigorously determine the relative
stereochemistries of alcohols 2a and 2b, the assignments are based on ample
precedent: (a) Hussey, A. S.; Herr, R. R. J. Org. Chem. 1959, 24, 843-
845. (b) Gilchrist, T. L.; Stanford, J. E. J. Chem. Soc., Perkin Trans. 1
1987, 225-230. See also refs 3b and 22.
(8) (a) Tanis, S. P.; McMills, M. C.; Herrinton, P. M. J. Org. Chem.
1
985, 50, 5887-5889. (b) Harnett, J. J.; Alcaraz, L.; Mioskowski, C.; Martel,
J. P.; Le Gall, T.; Shin, D.-S.; Falck, J. R. Tetrahedron Lett. 1994, 35,
009-2012.
9) Trost, B. M.; Keeley, D. E.; Arndt, H. C.; Rigby, J. H.; Bogdanowicz,
M. J. J. Am. Chem. Soc. 1977, 99, 3080-3087.
10) For examples of 1,2-additions to epoxyquinones and epoxyquinone
monoketals, see: Wipf, P.; Coish, P. D. G. J. Org. Chem. 1999, 64, 5053-
061. Alcaraz, L.; Macdonald, G.; Ragot, J.; Lewis, N. J.; Taylor, R. J. K.
Tetrahedron 1999, 55, 3707-3716 and references therein.
11) A recent issue of Chemical ReViews was devoted to diastereo-
selection: (a) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1224.
b) Dannenberg, J. J. Chem. ReV. 1999, 99, 1225-1242. (c) Tomoda, S.
Chem. ReV. 1999, 99, 1243-1264. (d) Cieplak, A. S. Chem. ReV. 1999,
9, 1265-1336. (e) Ohwada, T. Chem. ReV. 1999, 99, 1337-1376. (f) Gung,
2
(
(
(15) The 13C NMR shifts for the tertiary carbinol carbon and the terminal
carbon of the vinyl substituent of equatorial alcohols 4a,b were downfield
relative to those of axial alcohols 5a,b, whereas the shift of the internal
carbon of the vinyl substituent of 4a,b was upfield relative to that of 5a,b.
See Supporting Information for shift assignments and refs 4a and 7 for
relevant examples.
5
(
(
(16) (a) Miyashita, K.; Tanaka, A.; Shintaku, H.; Iwata, C. Tetrahedron
1998, 54, 1395-1406. (b) Ireland, R. E.; Courtney, L.; Fitzsimmons, B. J.
J. Org. Chem. 1983, 48, 5189-5198. (c) See also Tagamose, T. M.; Bols,
M. Chem. Eur. J. 1997, 3, 456-462. Nicotra, F.; Panza, L.; Ronchetti, F.;
Russo, G. Gazz. Chim. Ital. 1989, 119, 577-579. (d) There was apparently
no reversal of diastereoselectivity in 1,2-additions of vinylMgBr and vinylLi
to 2-chlorocyclohexanone: Holt, D. A. Tetrahedron Lett. 1981, 22, 2243-
2246.
9
B. W. Chem. ReV. 1999, 99, 1377-1386. (g) Kaselj, M.; Chung, W.-S.; le
Noble, W. J. Chem. ReV. 1999, 99, 1387-1414. (h) Adcock, W.; Trout, N.
A. Chem. ReV. 1999, 99, 1415-1436. (i) Mehta, G.; Chandrasekhar, J.
Chem. ReV. 1999, 99, 1437-1468. (j) Wipf, P.; Jung, J.-K. Chem. ReV.
1
999, 99, 1469-1480.
(
12) (a) Wender, P. A.; Holt, D. A. J. Am. Chem. Soc. 1985, 107, 7771-
(17) trans-6-Fluorocarvone 3b was prepared by fluorination of the Li
enolate of (S)-(+)-carvone using the procedure of Davis: Davis, F. A.;
Han, W. Tetrahedron Lett. 1992, 33, 1153-1156.
7
772. (b) Brummond, K. M.; Gesenberg, K. D. Tetrahedron Lett. 1999,
4
0, 2231-2234.
4008
Org. Lett., Vol. 3, No. 25, 2001

tivity,15 although the magnitude decreased slightly in both
additions.
tions to methoxyethoxymethyl (MEM) protected 6-hydroxy-
cyclohexenone 10. A reversal of diastereoselectivity was
2
3
The diastereoselectivity of additions of several other hard
carbon nucleophiles to trans-6-chlorocarvone 3a was inves-
tigated (Table 3). Counterion-dependent reversal of selectiv-
again observed as a function of the counterion (entries 1 and
3, Table 4). Some notable solvent effects were observed
2
4
Table 4. Solvent Effects in Alkyl MgBr and Alkyl Li
Additions to 6-OMEM-cyclohexenone
Table 3. Diastereoselectivity in Additions to
trans-6-Chlorocarvone
entrya
R
M
solvent
compd
6:7b
yieldc
1
2
3
4
5
6
HCC
TBSCC
nBu
MgBr
Li
MgBr
Li
MgBr
Li
THF
ether
ether
THF
ether
ether
a
a
b
b
c
c
5:1
1:6
25:1
1:619
12:1
1:720
78
71d
59
58e
52
nBu
Ph
Ph
51
a
All additions except entry 2 were performed on substrates derived from
b
1
the (R)-enantiomer of carvone. Ratio determined by H NMR integration
of C6-protons. Isolated yield of major isomer. Yield after desilylation.
Inseparable mixture of diastereomers.
c
d
e
ity was evident for all sets of nucleophiles, with Grignard
reagents giving good to excellent syn selectivity (entries 1,
3
, and 5) and alkynyl, alkyl, and aryllithium reagents all
1
5
exhibiting good anti selectivity (entries 2, 4, and 6).
However, when cis-6-chlorocarvone 8, was treated with
either vinylMgBr or vinylLi, anti diastereomer 9 was
21
a
1
Isolated yield of major isomer.
produced as the sole detectable product by H NMR analysis
(
Scheme 1).22
in the additions. When DMPU was used in the Grignard
additions (entries 2 and 7), selectivity increased from 2:1 to
Scheme 1. Vinyl Additions to cis-6-Chlorocarvone
3
:1 for ethynylMgBr and from 2:1 to 4:1 for vinylMgBr. In
the Li acetylide additions, changing the solvent from THF
to ether improved selectivity from 1:3 to 1:7 (entries 3 and
4
3
). Adding NEt as a cosolvent further improved the
2
5
selectivity to 1:13 (entry 5). No such solvent-related
improvements were found for the addition of vinyllithium,
(20) X-ray crystallographic analysis of alcohol 7c confirmed stereo-
chemical assignments. See Supporting Information for details.
(21) Kinetic epimerization of trans-6-chlorocarvone 3a was achieved by
adding 3a to a solution of LDA at -78 °C followed by addition of a THF
solution of camphor sulfonic acid. A 3:1 ratio of 8:3a was obtained with
cis-6-chlorocarvone 8 isolated in 64% yield.
(22) X-ray crystallographic analysis of an (S)-O-benzyl lactate ester
derived from 9 confirmed stereochemical assignments. See Supporting
Information for details.
(23) MEM-protected 6-hydroxycyclohexenone 11 was available from
Rubottom oxidation and protection of 2-cyclohexen-1-one. (a) Oxidation:
Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599-1602. (b)
Protection: Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett. 1976,
809-812.
(24) Relative stereochemistries for alcohols 11 and 12 were assigned by
correlation to the free diol derived from propargyl alcohol 11a. The structure
of the diol was unambiguously determined by X-ray crystallography (see
Supporting Information for full details).
To determine whether these findings were generalizable
to other C -substituted cyclohexenones, we examined addi-
6
(
18) It has been reported that the proportion of equatorial reduction of
cis-2-fluoro-4-tert-butyl-cyclohexanone increased slightly relative to the
-chloro analog: Rosenberg, R. E.; Abel, R. L.; Drake, M. D.; Fox, D. J.;
Ignatz, A. K.; Kwiat, D. M.; Schaal, K. M.; Virkler, P. R. J. Org. Chem.
001, 66, 1694-1700.
2
2
n
(
19) BuLi addition to 3a was performed at room temperature, and the
reaction mixture was quenched with HOAc after 5 min. In the absence of
an HOAc quench, selective decomposition of the minor product 6b occurred
upon prolonged (ca. 90 min) stirring of the reaction mixture at room
temperature. Presumably the minor isomer 6b, in which the alkoxide is
trans to the chloride, decomposed via formation of the corresponding
epoxide. In this case, an apparent selectivity of >1:20 was observed. See
Supporting Information for details.
(25) Carreira, E. M.; Du Bois, J. Tetrahedon Lett. 1995, 36, 1209-1212.
Org. Lett., Vol. 3, No. 25, 2001
4009

with the highest selectivity being only 1:2 in THF (entry
diastereoselection (e.g., from 1:5 to 5:1), extricating the
6
individual contributions of solvent, metal, R-group, and C -
2
6
8).
Several models for carbonyl addition have been proposed
to rationalize diastereoselectivity in the addition of nucleo-
philes to cyclohexanones and cyclohexenones. These include
heteroatom substituent may prove challenging.31 Further
efforts toward optimizing the diastereoselectivity, probing
the generality of the reversal and examining a wider variety
of counterions are underway.
In summary, we have found that diastereoselectivity in
6
the addition of hard carbon nucleophiles to C -substituted
1
a,27,28
13
18
Cram chelation,
Felkin-Anh, electrostatic repulsion,
and delivery28,29 models. In the examples reported herein,
four reaction pathways are in principle possible: axial or
equatorial addition to either half-chair conformation of the
cyclohexenone substrate (i or ii, Figure 2). In the case of
cyclohexenones may in some cases be controlled by the
counterion of the nucleophile, with Grignard reagents gener-
6
ally adding syn and lithium reagents adding anti to the C -
substituent. Further, this selectivity may be optimized by use
of an appropriate solvent and/or cosolvent in the addition
reaction.
Acknowledgment. Support for this work was provided
by the National Institutes of Health (GM-59406). M.C.M.
is a Cottrell Scholar of Research Corporation. We thank
Frank R. Fronczek, Louisiana State University, for assistance
with X-ray crystallographic analysis. Thanks to Andrew Poss,
Honeywell International, Inc., for a generous gift of N-
fluorobenzenesulfonimide.
6
Figure 2. Four possible reaction pathways for additions to C -
substituted cyclohexenones.
Supporting Information Available: Representative ex-
perimental procedures, characterization data for compounds
2
-9, 11a,c, and 12b,c; lactate ester of 9, ORTEPs of 7c,
6
1
-chlorocyclohexenone and cis-6-chlorocarvone, (cf. Table
and Scheme 1), excellent diastereoselectivity was observed
the (S)-O-benzyl lactate ester of 9, and the free diol derived
from 11a; structure proof of alcohols 11a and 11c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
and the same product was formed regardless of the nucleo-
phile counterion. These results imply the operation of a single
Felkin-Anh pathway, in which axial attack of the nucleo-
phile occurs via the half-chair conformation i.
OL016673J
However, the observation of counterion-dependent reversal
of diastereoselectivity is indicative of the operation of at least
two reaction pathways.30 Similarly, the modest diastereo-
selectivities observed in additions to 6-OMEM cyclo-
hexenone imply that Cram chelation and/or Felkin-Anh
pathways are not the sole modes of addition. Given the
relatively modest energy differences necessary to reverse the
(30) Computational studies have examined the role of polar substituents
in diastereoselective carbonyl addition reactions: (a) Wong, S. S.; Paddon-
Row, M. N. J. Chem. Soc., Chem. Commun. 1990, 456-458. (b) Wu, Y.-
D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5018-5027.
(
c) Shi, Z.; Boyd, R. J. J. Am. Chem. Soc. 1993, 115, 9614-9619. Other
theoretical studies have investigated selectivity in additions involving
Grignard, organolithium, organoaluminum and/or organopotassium re-
agents: Yadav, V. K.; Sriramurthy, V. Tetrahedron 2001, 57, 3987-3995.
See also refs 5c-d.
(31) A further complicating factor is the aggregation state of the
nucleophile. A number of studies indicate that the molecular aggregation
of organolithium and Grignard reagents is dependent upon solvent and the
R group and that aggregation affects the reactivity of the nucleophile as
well as the mechanism and the stereoselectivity of the addition. (a)
Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.;
Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028-2038.
(b) McGarrity, J. F.; Ogle, C. A. J. Am. Chem. Soc. 1984, 107, 1805-
1815. (c) Haeffner, F.; Sun, C.; Williard, P. G. J. Am. Chem. Soc. 2000,
122, 12342-12348. See also refs 1a, c, d.
(
26) Ancillary studies using various protecting groups for the C6 alcohol
yielded similar results.
27) Still, W. C.; McDonald, J. H. Tetrahedron Lett. 1980, 21, 1031-
034.
(
1
1
3
(
28) Paquette, L. A.; Lobben, P. C. J. Am. Chem. Soc. 1996, 118, 1917-
930.
(
52.
29) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351-
4010
Org. Lett., Vol. 3, No. 25, 2001