Unsaturated Oxo-Nitriles: Stereoselective, Chelation-Controlled Conjugate Additions

Article abstract of DOI:10.1021/jo9909709

Addition of Grignard reagents to the unsaturated oxo-nitrile 10 (4-hydroxy-4-methyl-6-oxocyclohex-1-enecarbonitrile) provides conjugate addition products with virtually complete stereocontrol. Mechanistic evidence supports a chelation-controlled conjugate addition via alkylmagnesium alkoxide intermediates. Diverse Grignard reagents having sp^3-, sp^2-, and sp-hybridized carbons react with comparable efficiency, with even sterically demanding nucleophiles adding with complete stereocontrol. Unsaturated oxo-nitriles that are incapable of chelation afford diastereomeric conjugate addition products through an unusual boatlike transition state. Collectively, these reactions illustrate the complementary stereoselectivity of chelation-controlled conjugate additions to hydroxylated, unsaturated oxo-nitriles and stereoelectronically controlled conjugate additions to enones.

Full text of DOI:10.1021/jo9909709

8568
J . Org. Chem. 1999, 64, 8568-8575
Un sa tu r a ted Oxo-Nitr iles: Ster eoselective, Ch ela tion -Con tr olled
Con ju ga te Ad d ition s
Fraser F. Fleming,*,1 J ianping Guo,1 Qunzhao Wang,1 and Douglas Weaver2
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282, and
Bristol-Myers Squibb Co., Syracuse, New York 13221-4755
Received J une 17, 1999
Addition of Grignard reagents to the unsaturated oxo-nitrile 10 (4-hydroxy-4-methyl-6-oxocyclohex-
1-enecarbonitrile) provides conjugate addition products with virtually complete stereocontrol.
Mechanistic evidence supports a chelation-controlled conjugate addition via alkylmagnesium
alkoxide intermediates. Diverse Grignard reagents having sp3-, sp2-, and sp-hybridized carbons
react with comparable efficiency, with even sterically demanding nucleophiles adding with complete
stereocontrol. Unsaturated oxo-nitriles that are incapable of chelation afford diastereomeric
conjugate addition products through an unusual boatlike transition state. Collectively, these
reactions illustrate the complementary stereoselectivity of chelation-controlled conjugate additions
to hydroxylated, unsaturated oxo-nitriles and stereoelectronically controlled conjugate additions
to enones.
In tr od u ction
have been most extensively investigated with quinol
alkoxides (2) that react with Grignard reagents to afford
conjugate addition products (3).9 Chelation between the
alkoxide and the Grignard reagent results in a transient
complex10 that delivers the nucleophile from the same
face and establishes the syn stereochemistry between the
alkyl and the hydroxyl groups.
Conjugate addition reactions are one of the most
important carbon-carbon bond-forming reactions in
organic synthesis.3 The central importance of conjugate
addition reactions results from the efficient, stereoselec-
tive, formation of a new bond two or more carbons
removed from an electron-withdrawing group. High ste-
reoselectivity is routinely achieved in conjugate additions
either through stereoelectronic control4 or by using
inherent structural features to bias the approach of the
nucleophile.5
Complementary stereoselectivity to the more hindered
face of a Michael acceptor is a significant synthetic
challenge. Excellent success in this area has been achieved
by chelating the nucleophile6 with an alcohol-derived
alkoxide7 or an ether oxygen,8 prior to the conjugate
addition reaction. Chelation-controlled addition reactions
The mechanism of chelation-controlled conjugate ad-
ditions is succinctly illustrated in a key step performed
during the synthesis of (()-euonyminol.11 Deprotonation
of 4 affords a lithium alkoxide that was sequentially
treated with 15-crown-5 and isopropenylmagnesium bro-
mide to ensure first a lithium-magnesium exchange,
followed by displacement of the Schlenk equilibrium from
the binary complex 5 toward the more reactive ternary
ate complex10 6. Nucleophilic addition from the ate
complex 6 is more favorable than from 510 and provides
the conjugate adduct 7 as the sole diastereomer. The
conversion of 4 f 7 underscores the complementary
stereoselectivity of chelation-controlled additions since 4
reacts with (CH2dCHMe)2CuCNLi2 to give the diaster-
eomeric conjugate addition product.11
(1) Duquesne University.
(2) Bristol-Myers Squibb Co.
(3) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Pergamon: New York, 1992.
(4) For cyclic systems see: (a) Deslongchamps, P. Stereoelectronic
Effects in Organic Chemistry; Pergamon: Exeter, U.K., 1983; pp 221-
242. For a leading reference to stereocontrol in acyclic systems, see:
(b) Yamamoto, K.; Ogura, H.; J ukuta, J .-i.; Inoue, H.; Hamada, K.;
Sugiyama, Y.; Yamada, S. J . Org. Chem. 1998, 63, 4449.
(5) Reference 3, pp 162-163.
(6) For a compilation of several examples see: Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(7) (a) Collins, P. W.; Dajani, E. Z.; Driskill, D. R.; Bruhn, M. S.;
J ung, C. J .; Pappo, R. J . Med. Chem. 1977, 20, 1152. (b) Pappo, R.;
Collins, P. W. Tetrahedron Lett., 1972, 2627. (c) Collins, P. W.; Dajani,
E. Z.; Bruhn, M. S.; Brown, C. H.; Palmer, J . R.; Pappo, R. Tetrahedron
Lett., 1975, 4217. (d) Metz, P.; Meiners, U.; Frohlich, R.; Grehl, M. J .
Org. Chem. 1994, 59, 3687. (e) Saddler, J . C.; Conrad, P. C.; Fuchs, P.
L. Tetrahedron Lett. 1978, 5079. (f) Sato, T.; Nakakita, M.; Kimura,
S.; Fujisawa, T. Tetrahedron Lett. 1989, 30, 977. (g) Vedejs, E.;
Buchanan, R. A.; Watanabe, Y. J . Am. Chem. Soc. 1989, 111, 8430.
(h) Hardinger, S. A.; Fuchs, P. L. J . Org. Chem. 1987, 52, 2739. (i)
Carreno, M. C.; Gonzalez, M. P.; Ribagorda, M.; Houk, K. N. J . Org.
Chem. 1998, 63, 3687.
(8) (a) Raczko, J . Tetrahedron Asymm. 1997, 8, 3821. (b) Klemeyer,
H. J .; Paquette, L. A. J . Org. Chem. 1994, 59, 7924. (c) Wipf, P.; Kim,
Y. J . Am. Chem. Soc. 1994, 116, 11678. (d) Stern, A. J .; Rohde, J . J .;
Swenton, J . S. J . Org. Chem. 1989, 54, 4413. (e) Leonard, J .; Ryan, G.
Tetrahedron Lett. 1987, 28, 2525. (f) Isobe, M.; Kitamura, M.; Goto, T.
Tetrahedron Lett. 1980, 21, 4727.
The chelation-controlled conjugate additions of 1 and
4 are typical in employing alcohols where dehydration
is not possible (1 f 3 and 4 f 7) or effectively prevented
(9) (a) Swiss, K. A.; Hinkley, W.; Maryanoff, C. A.; Liotta, D. C.
Synthesis 1992, 127. (b) Solomon, M.; J amison, W. C. L.; McCormick,
M.; Liotta, D.; Cherry, D. A.; Mills, J . E.; Shah, R. D.; Rodgers, J . D.;
Maryanoff, C. A. J . Am. Chem. Soc. 1988, 110, 3702.
(10) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J . Am. Chem. Soc.
1990, 112, 9393.
(11) (a) White, J . D. Pure Appl. Chem. 1994, 66, 2183. (b) White, J .
D.; Shin, H.; Kim, T.-S.; Cutshall, N. S. J . Am. Chem. Soc. 1997, 119,
2404.
10.1021/jo9909709 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/26/1999

Unsaturated Oxo-Nitriles
J . Org. Chem., Vol. 64, No. 23, 1999 8569
Sch em e 1
The synthesis of 10 efficiently provides a prototype
oxo-nitrile for probing chelation-controlled conjugate
addition reactions. Deprotonation of 10 under conven-
tional conditions10 (LDA16), followed by the addition of
15-crown-5 and MeMgCl, afforded none of the desired
conjugate addition product but resulted in exclusive
dehydration to give the aromatic nitrile 17 (Scheme 1).
We reasoned that the facile aromatization might result
from a competitive deprotonation of the more acidic
γ-protons of 10, in preference to the more accessible
hydroxyl proton. The resulting dehydration of 10 gener-
ates the relatively acidic dienone 15 allowing protonation
of the coformed alkoxide 13. Protonation of 13 regener-
ates 10 and allows a series of proton transfers to
equilibrate the desired alkoxide 13 to the more stable
aromatic nitrile 17.
because of geometrical constraints.12 We hoped to extend
this methodology to conjugate additions with unsaturated
aldols (8 f 9) since, although prone to dehydration, chiral
aldols are readily prepared in high optical purity13 and
the conjugate adducts 9 are potentially amenable to
further dehydration-conjugate addition reactions. We
envisaged minimizing the potential dehydration by using
an extremely reactive Michael acceptor to promote the
conjugate addition reaction (eq 1). We were specifically
We reasoned that aromatization might be avoided by
using an excess of base to preferentially deprotonate any
coformed dienone 15. Even with this precaution aroma-
tization is still conceivable since the subsequent metal-
alkoxide exchange of 13 (M ) Li to M ) Mg) generates a
relatively basic alkoxide. Self-deprotonation of 13 would
generate 10 and the alkoxide 14, providing another
equilibration route to the aromatic nitrile 17. We there-
fore chose to avoid formation of a “free” alkoxide by
directly generating the desired magnesium alkoxide with
an excess of methylmagnesium chloride.
interested in using R,â-unsaturated oxo-nitriles since
these are readily prepared14 and react conjugately even
with sterically hindered Grignard reagents.15 This ac-
count describes the successful chelation-controlled con-
jugate additions to the unsaturated oxo-nitrile 10,
diastereomeric conjugate additions to the corresponding
silyl ether, and a mechanistic discussion of the comple-
mentary stereoselectivity exhibited in these Michael
reactions.
We were pleased to find that simply adding an excess
of methylmagnesium chloride (2.5 equiv) to 10 provides
the desired conjugate addition product 19 in 51% yield
(Scheme 2). Characterization of 19 was particularly
difficult since oxo-nitriles readily enolize17 providing, in
this case, two equilibrating diastereomers. The stereo-
chemistry of the epimers was determined by silylating
the intermediate enolate with excess TBDMSCl (3 equiv),
resulting in two conjugate addition products (42% yield,
20a :21, 6.8:1 ratio) and the aromatic nitrile 22 (11%
yield). The diastereomers were separated by radial chro-
matography, providing pure samples of the major and
minor isomers resulting from chelation-controlled and
uncomplexed18 conjugate addition reactions, respectively
(vide infra).
Resu lts a n d Discu ssion
The prototype unsaturated oxo-nitrile 10 is readily
prepared using our domino ozonolysis-aldol cyclization
method14 (12 f 10). Addition of allylzinc bromide to 11
provides a tertiary alcohol that is treated with excess
lithioacetonitrile (3.5 equiv) to provide the desired nitrile
12 with essentially no dehydration being observed. Ap-
plying our domino ozonolysis-aldol methodology to 12
unmasks an aldehyde and triggers an intramolecular
aldol cyclization-dehydration sequence that affords 10 in
a single synthetic operation.
Determining the stereochemistry of the conjugate
addition products 20a and 21 proved particularly chal-
(14) Fleming, F. F.; Huang, A.; Sharief, V. Q.; Pu, Y. J . Org. Chem.
1999, 64, 2830.
(15) Fleming, F. F.; Tercek, F.; Pu, Y. J . Org. Chem. 1997, 62, 4883.
(16) Use of LiH, n-BuLi, or KH afforded only the aromatic nitrile
17.
(12) (a) Isobe, M.; Kitamura, M.; Goto, T. Tetrahedron Lett. 1979,
3465. (b) Ichikawa, Y.; Goto, T.; Bai, D.-L.; Isobe, M. Tetrahedron 1987,
43, 4737. (c) Isobe, M.; Ichikawa, Y.; Funabashi, Y.; Mio, S.; Goto, T.
Tetrahedron 1986, 42, 2863.
(17) Elnagdi, M.; Elmoghayar, M.; Elgemeie, G. Synthesis 1984, 1.
(18) In
a somewhat related system the conjugate addition of
(13) Heathcock, C. H. In Comprehensive Organic Synthesis; Fleming,
I., Trost, B. M., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 2, pp 181-
238.
prenylmagnesium bromide occurs without chelation control: Morales-
R´ıos, M. S.; Sua´rez-Castillo, O. R.; J oseph-Nathan, P. J . Org. Chem.
1999, 64, 1086.

8570 J . Org. Chem., Vol. 64, No. 23, 1999
Fleming et al.
Sch em e 2
and hydroxyl groups on the same face, as expected for a
chelation-controlled conjugate addition. The minor isomer
21 is therefore epimeric at C-6 and presumably arises
by a competitive uncomplexed conjugate addition.
Formation of 20a as the major product represents a
rewarding proof-of-principle for the chelation-controlled
addition to labile aldols. Initially the reaction was
optimized with more nucleophilic and less basic organo-
metallic reagents, having the potential to circumvent
formation of the aromatic nitrile 22. Screening a variety
of organometallic nucleophiles indicated that methyl-
magnesium chloride was the most effective reagent with
Me2Mg, MeCu, MeZnI (from Zn and MeI), and MeZnCl
(from ZnCl2 and MeMgCl) providing only the aromatic
nitrile 22 (eq 2). Of the organometallic reagents surveyed
lenging. A conformational analysis of the two diastere-
omers reveals that these isomers will preferentially adopt
different half-chair conformations. The major isomer,
tentatively assigned with the hydroxyl and secondary
methyl groups on the same side, will prefer conformation
I to avoid the 1,3 diaxial interaction between the methyl
and hydroxyl groups that exists in conformation II.19 The
minor isomer will prefer the alternative half-chair con-
formation IV to avoid the severe 1,3-diaxial interaction
that is present in conformation III. Initial support for
these complementary conformational preferences came
1
from the significant H NMR chemical shift differences
of the C-6 methine protons in 20a (m, δ ) 2.36-2.46)
and 21 (br s, δ ) 2.62), and was later substantiated from
an analysis of coupling constants and NOE experiments.
only MeLi, MeCeCl2, and LiCuMe2 provided conjugate
addition products, with a combination of MeMgCl and
LiCl being the most effective in terms of both yield and
stereoselectivity. Optimization therefore focused on the
use of Grignard reagents with lithium chloride, particu-
larly since this results in the exclusive isolation of
diastereomer 20a .
The role of lithium chloride in the conjugate addition
reaction is intriguing. The marked change in reactivity
suggests a shift in the solution composition of the
Grignard reagentsa speculation that is somewhat sup-
ported by our observation that LiCl is considerably more
soluble in THF solutions of MeMgCl than in THF alone.
Lithium chloride may associate with the Grignard re-
agent to form an ate complex [RMgXCl]-+Li21 in which
the increased charge density facilitates the subsequent
alkyl transfer to the magnesium alkoxide intermediate.
An accelerated alkyl transfer explains the formation of
one diastereomer, assuming that the alkyl transfer from
the ate complex for the subsequent chelation-controlled
reaction is faster than the uncomplexed conjugate addi-
tion. Similar alkyl transfers have been promoted with
DMPU9a although in the present case the efficiency with
DMPU is essentially the same as that obtained when
lithium chloride is omitted (Table 1, entries 2 and 3).
Further evidence for the role of the chloride ion is seen
in the lower yields obtained when lithium perchlorate is
substituted for lithium chloride (Table 1, entries 1 and
4, respectively), with 3 equiv of lithium chloride being
optimal (compare Table 1, entries 1 and 5).
1
The complete H NMR assignment of the two diaster-
eomers was facilitated by distinctive W-couplings be-
tween the equatorial protons at C-3 and C-5.20 Further-
more, in the major isomer the axial proton at C-5
appeared as a well-resolved dd with a large diaxial
coupling (J ) 11 Hz) to the C-6 proton, establishing I,
with the equatorially oriented methyl group, as the
preferred conformation. Determining the conformation
of the major isomer allowed the relative configurations
at C-4 and C-6 to be assigned through NOE experiments.
NOESY spectra of 20a were not well resolved, and
therefore, selective NOE experiments were performed in
benzene-d6, where the two methyl signals exhibit sig-
nificantly greater chemical shift differences than in
CDCl3. Irradiation of the quaternary methyl group in 20a
provided a small, but clear, enhancement of the proton
at C-6, confirming that the major isomer has the methyl
The chelation-controlled conjugate addition is ex-
tremely fast, being complete within 5 min at -78 °C. The
anion (18) resulting from the conjugate addition is best
silylated immediately with TBDMSCl and warmed to
room temperature, since this rather delicate silylation22
(19) The extremely small size of the nitrile group means that the
A12 interaction in I, between the methyl and nitrile groups, is
significantly less than 1,3-diaxial interaction in II. See: Eliel, E. L.;
Wilen, S. H.; Mander, L. N. In Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 696-7.
(21) Reike, R. D.; Bales, S. E. J . Am. Chem. Soc. 1974, 96, 1775.
(22) For example, anions of oxo-nitriles react efficiently with
t-BuMe2SiCl but not with t-BuPh2SiCl: Gonzalez, B.; Gonzalez, A. M.;
Pulido, F. J . Synth. Commun. 1995, 25, 1005.
(20) The proton assignments were fully corroborated by COSY and
selective proton decoupling experiments.

Unsaturated Oxo-Nitriles
Ta ble 1. Ad d ition of MeMgCl to 10
J . Org. Chem., Vol. 64, No. 23, 1999 8571
Ta ble 2. Ch ela tion -Con tr olled Ad d ition s to 10
yield (%)
entry
solvent
additive (equiv)
20a
22
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
DME
LiCl (3)
DMPU (5)
58
44
42
15
58
31
45
55
43
52
16
19
11
12
a
22
18
10
19
12
LiClO4 (5)
LiCl (5)
b
LiCl (5)c
LiCl (5)d
LiCl (3)
LiCl (3)
10
a
b
The yield was not determined. TBDMSCl was added at -78
°C, 3 h after the addition of MeMgCl. c The reaction mixture
temperature was kept at -78 °C for 6 h after the addition of TBSCl
and then allowed to warm to room temperature overnight.
d
Inverse addition.
is adversely affected by a delay in the addition of
TBDMSCl (Table 1, compare entry 3 with 6 and entry 1
with 7). Reversing the order of addition, with 10 being
added to the Grignard reagent, has essentially no effect
on the reaction (Table 1, entry 8). DME and THF are the
most suitable solvents with diethyl ether affording less
of the conjugate adduct (Table 1, entries 9 and 10).
With the chelation-controlled conjugate addition with
MeMgCl having been optimized, the generality of the
reaction was probed with several different Grignard
reagents. Diverse nucleophiles with sp, sp2, and sp3
hybridization react with comparable efficiency, providing
only one diastereomer and no detectable23 addition to the
ketone group (Table 2). Even sterically demanding nu-
cleophiles such as t-BuMgCl add relatively efficiently.
The modest yields result from the competitive formation
of the aromatic nitrile 22 and the formation of an
uncharacterized polymeric material.24 These modest
yields are partially offset by an excellent stereoselectivity,
with only one diastereomer being detected in each of
these reactions.
Sch em e 3
Two diverging mechanisms can be envisaged for these
chelation-controlled conjugate addition reactions (Scheme
3). The alkoxide 23, resulting from the deprotonation of
10, is thought to exchange with the Grignard reagent to
give the methylmagnesium alkoxide 24. On the basis of
the fact that Mg-O bonds are relatively strong,25 we
speculate that the Grignard reagents react with the
alkoxide 23 by a halogen-alkyl ligand exchange, rather
than a metal exchange (MgCl f MgR), although we
currently have no definitive information that allows
differentiation between these two sequences. Once formed,
the alkylmagnesium alkoxide 24 can react either with
an additional 1 equiv of the Grignard reagent to generate
the ate complex 25 or directly trigger the conjugate
addition reaction (24 f 18). Differentiating between
these mechanisms was possible by the incremental
addition of MeMgCl to 10.26 Sampling the reaction
mixture after the addition of 1 equiv of MeMgCl provided
mainly unreacted starting material, approximately 10%
of the aromatic nitrile 17, and a trace of the conjugate
addition product 19. Addition of a further 1 equiv of
MeMgCl generates the conjugate adduct 19 with no
change occurring with additional MeMgCl. This experi-
ment suggests an initial competitive proton abstraction
from the alcohol group affording primarily the alkoxide
23, with smaller amounts of γ-deprotonation leading
ultimately to the aromatic nitrile 17. Once formed, the
alkoxide 23 requires only one additional 1 equiv of
MeMgCl for the conjugate addition, implying that the
reactive species is the alkylmagnesium alkoxide 24 and
not the ate complex 25. Presumably the high reactivity
of unsaturated oxo-nitriles facilitates the chelation-
controlled addition with an alkylmagnesium alkoxide 24
(23) Based on 1H NMR spectra of the crude reaction mixture.
(24) Self-condensation of oxo-nitriles leads to trimers and higher
oligomers: Andresen, S.; Margaretha, P. J . Chem. Res., Synop. 1995,
455.
(26) Performed in the absence of LiCl to avoid potential complica-
tions through formation of additional ate complexes.
(25) Mader, M. M.; Edel, J . C. J . Org. Chem. 1998, 63, 2761.

8572 J . Org. Chem., Vol. 64, No. 23, 1999
Fleming et al.
Sch em e 4
Sch em e 5
allows for a chiral oxo-nitrile synthesis by reducing the
intermediate â-keto ester31 with a chiral reagent.32 As
expected, the oxo-nitriles 30a ,b cyclize smoothly upon
ozonolysis, providing the unsaturated oxo-nitriles 28a ,b
in 57% and 85% yield, respectively.
Cuprate additions to the unsaturated oxo-nitrile 28a
were both efficient and stereoselective. Addition of Me2-
CuLi provides an excellent yield (89%) of a single nitrile
diastereomer33 34a following silylation of the intermedi-
ate enolate 33 (Scheme 5). Formation of 34a is unusual
in proceeding through a boatlike transition state4a lead-
ing to the enolate 33, and is presumably a consequence
of the severe 1,3-diaxial interaction that would otherwise
occur in an attack cis to the TBDMS ether.34 The
n-butylcuprate reacts similarly, to provide the analogous
conjugate adduct 34b.
whereas less reactive enones (24, CN ) R) require the
more reactive ate complex for the conjugate addition.10
Further support for the addition proceeding through an
alkylmagnesium alkoxide (24) is implied from reactions
with DMPU. The addition of DMPU to ate complexes is
known10 to promote the reactions with enones, but DMPU
has essentially no effect with unsaturated oxo-nitriles,
implying that the reactive species is not the ate complex
but an alkylmagnesium alkoxide.
The diastereoselectivity of the chelation-controlled
conjugate additions to 10 complements most organocop-
per-based additions to C-5 substituted enones.27 Stereo-
selective additions to C-5 oxygenated enones have most
often employed cyclic acetals28 (26) in which the nucleo-
philic attack is sterically biased to one face of the enone,
although highly selective conjugate additions of organo-
copper reagents were recently achieved with the C-5
TBDMSO-substituted enone 27.29 We reasoned that
organocopper additions to silylated oxo-nitriles (28)
would provide conjugate adducts diastereomeric to those
obtained by chelation control, since the silyl group would
effectively bias the nucleophilic addition through the
combined influence of steric and stereoelectronic con-
straints. We therefore prepared two C-5 TBDMSO-oxo-
nitriles and evaluated the stereoselectivity of their
conjugate addition reactions.
We anticipated extending this stereoelectronically
controlled conjugate addition to the less-substituted oxo-
nitrile 28b.35 The TBDMS ether anchors the cyclohexane
ring36 so that nucleophilic attack is predisposed toward
an axial addition with stereoelectronic control (eq 3).
Addition of Me2CuLi occurs stereoselectively from the
axial direction (18:1)37 but the yield was unacceptably
low, presumably resulting from oligomerization of the
(31) Prepared using the procedure developed by Taber and Ruckle:
Taber, D. F.; Ruckle, R. E., J r. J . Am. Chem. Soc. 1986, 108, 7686.
(32) For leading references see: (a) Blanc, D.; Henry, J .-C.; Ra-
tovelomanana-Vidal, V.; Genet, J .-P. Tetrahedron Lett. 1997, 38, 6603.
(b) Taber, D. F.; Silverberg, L. J . Tetrahedron Lett. 1991, 32, 4227. (c)
Medson, C.; Smallridge, A. J .; Trewhella, M. A. Tetrahedron: Asym-
metry 1997, 8, 1049.
(33) The stereochemistry was determined by spectral comparison
of 34a with the hydroxyl analogue 21. Furthermore, the diastereomeric
silyl ether derived from 20a exhibits distinctly different spectral data
than that of 34a (see the Experimental Section for details).
(34) The discussion of facial selectivity assumes that the preferred
conformation has the smaller TBDMS ether in the axial orientation
as shown: Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry
of Organic Compounds; Wiley: New York, 1994; pp 696-7.
(35) Our aim was to access both conjugate addition diastereomers
through a stereoelectronically controlled conjugate addition to 28b and
a stereocomplementary chelation-controlled addition to the hydroxyl
analogue (28b, TBDMS ) H). The synthesis of the desired alcohol (28b,
TBDMS ) H) directly parallels Scheme 4 and provides the desired
oxo-nitrile (28b, TBDMS ) H) in good yield. Unfortunately this oxo-
nitrile decomposes readily on purification, preventing our efforts
toward implementing this stereochemical strategy.
The preparation of 28a ,b uses our one-pot, domino
ozonolysis-aldol synthesis14 of oxo-nitriles (Scheme 4).30
In each case the ozonolysis precursor 30 is obtained by
reacting lithioacetonitrile with the corresponding ester
29 or 32. Interestingly, the synthesis of 32 proceeds
without isomerization of the double bond and potentially
(27) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(28) (a) J eroncic, L. O.; Cabal, M.-P.; Danishefsky, S. J .; Shulte, G.
M. J . Org. Chem. 1991, 56, 387. (b) Marino, J . P.; Emonds, M. V. M.;
Stengel, P. J .; Oliveira, A. R. M.; Simonelli, F.; Ferreira, J . T. B.
Tetrahedron Lett. 1992, 33, 49. (c) Bhatt, R. K.; Ye, J .; Falck, J . R.
Tetrahedron Lett. 1996, 37, 3811. For related systems see: (d) Lin, J .;
Nikaido, M. M.; Clark, G. J . Org. Chem. 1987, 52, 3745. (e) Deruyttere,
X.; Dumortier, L.; Van der Eycken, J .; Vandewalle, M. Synlett 1992,
51.
(29) Hareau-Vittini, G.; Hikichi, S.; Sato, F. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2099.
(30) Direct treatment of 10 with various silylating reagents causes
dehydration to the aromatic nitrile 22.
(36) The conformational preference shown is based on the large axial
couplings of the methine proton (J ) 13 Hz for the peak width at half-
height).

Unsaturated Oxo-Nitriles
J . Org. Chem., Vol. 64, No. 23, 1999 8573
intermediate enolate.24 The high stereoselectivity of this
conjugate addition is one of the few examples where a
C-5-TBDMS enone controls the facial selectivity and
suggests that this strategy may be particularly useful
with less reactive enones.
In contrast to the sparse use of C-5 ether-substituted
enones,28,29 alkyl substituents are routinely employed in
stereoelectronically controlled conjugate additions.27 We
demonstrated the use of aldols in sequential conjugate
additions by eliminating 34a with n-Bu4NF, to provide
the C-5-substituted enone 36 (eq 4). Collectively, these
transformations illustrate the complementary stereo-
selectivity of conjugate additions to enones (stereoelec-
tronic control) and hydroxylated oxo-nitriles (chelation
control).
(s, 3H), 1.32 (d, J ) 6.3 Hz, 3H), 1.72 (br t, J ) 13.2 Hz, 1H),
1.83-2.16 (m, 3H), 2.56 (br d, J ) 13.2 Hz, 1H), 2.65 (dd, J )
13.3, 1.9 Hz, 1H), 3.21 (d, J ) 11.8 Hz, 1H); 13C NMR δ 20.7,
27.3, 33.1, 46.6, 50.1, 54.3, 71.9, 115.7, 198.0; MS m/e 168
(MH).
(()-(4S,6R )-4-H yd r oxy-4,6-d im e t h yl-2-(1,1,2,2-t e t r a -
m eth yl-1-sila p r op oxy)cycloh ex-1-en eca r bon itr ile (20a ).
The general procedure was employed with 10 (160 mg, 1.06
mmol in 6 mL THF), methylmagnesium chloride (2.9 M, 2.65
mmol), LiCl (137 mg, 3.23 mmol in 3 mL THF), and TBDMSCl
(400 mg, 2.65 mmol). Radial chromatography (1:3 EtOAc/
hexanes) of the crude product, followed by concentration of the
appropriate fractions, provided 42 mg of 22 (16%) and 172 mg
(58%) of 20a as an oil: IR (film) 3425, 2931, 2214, 1625 cm-1
;
1H NMR δ 0.24 (s, 3H), 0.25 (s, 3H), 0.98 (s, 9H), 1.23 (d, J )
6.7 Hz, 3H), 1.27 (s, 3H), 1.34 (dd, J ) 13,11 Hz, 1H), 1.60 (s,
1H), 1.80 (ddd, J ) 13, 6, 2 Hz, 1H), 2.23 (dt, J ) 17, 2 Hz,
1H), 2.36 (dd, J ) 17, 2 Hz, 1H), 2.36-2.46 (m, 1H); 13C NMR
δ -3.8, 18.1, 20.7, 25.5, 26.8, 29.0, 44.6, 45.5, 69.3, 95.0, 117.6,
163.0; MS m/e 282 (M + H).
(()-(4S ,6S )-4-H yd r oxy-4,6-d im e t h yl-2-(1,1,2,2-t e t r a -
m et h yl-1-sila p r op oxy)cycloh ex-1-en eca r bon it r ile (21).
The general procedure was employed with MeMgCl (2.9 M,
2.02 mmol), 10 (122 mg, 0.81 mmol), and TBDMSCl (207 mg,
1.37 mmol, but without the addition of LiCl. Chromatography
(1 mm plate, 1:3 EtOAc/hexanes) provided 89 mg (37%) of 20a
and 12 mg (5%) of 21 as an oil: IR (film) 3444, 2932, 2211,
1
1624 cm-1; H NMR δ 0.24 (s, 6H), 0.98 (s, 9H), 1.21 (d, J )
Con clu sion
6.8 Hz, 3H), 1.25-1.39 (m, 1H), 1.32 (s, 3H), 1.41-1.61 (m,
2H), 1.84 (ddd, J ) 13.7, 5.3, 3 Hz, 1H), 2.15 (d, J ) 18.2 Hz,
1H), 2.26 (dd, J ) 18.2, 3 Hz, 1H), 2.62 (br s, 1H); 13C NMR δ
-3.7, 18.1, 20.3, 25.5, 27.0, 30.1, 43.4, 44.5, 69.0, 95.8, 117.6,
162.4; MS m/e 281 (M).
Alkoxide-directed conjugate addition reactions provide
a highly stereoselective method of generating carbon-
carbon bonds. The alkoxide-directed additions to oxo-
nitrile 10 proceed with diverse Grignard reagents having
sp3-, sp2-, and sp-hybridized carbons, with even sterically
demanding nucleophiles adding with complete stereo-
control. The use of aldol-type enones demonstrates the
complementary stereoselectivity of chelation and stereo-
electronically controlled conjugate additions. Insights into
the mechanism of the chelation-controlled conjugate
addition, and the role of lithium chloride, provide the
understanding required for further chelation-controlled
reactions, particularly with aldol-type Michael acceptors.
(()-(4S,6S)-6-E t h yn yl-4-h yd r oxy-4-m et h yl-2-(1,1,2,2-
t et r a m et h yl-1-sila p r op oxy)cycloh ex-1-en eca r b on it r ile
(20b). The general procedure was employed with 10 (43 mg,
0.28 mmol in 3 mL of THF), ethynylmagnesium chloride (0.5
M, 0.71 mmol), LiCl (37 mg, 0.87 mmol in 2 mL of THF), and
TBDMSCl (108 mg, 0.72 mmol). Radial chromatography (1:4
EtOAc/hexanes) of the crude product, followed by concentration
of the appropriate fractions, provided 6 mg of 22 (9%) and 39
mg (47%) of 20b as an oil: IR (film) 3425, 3301, 2932, 2214,
1
1625 cm-1; H NMR δ 0.25 (s, 3H), 0.26 (s, 3H), 0.98 (s, 9H),
1.29 (s, 3H), 1.90-1.95 (m, 2H), 2.22 (d, J ) 18 Hz, 1H), 2.32
(d, J ) 2.6 Hz, 1H), 2.37 (d, J ) 18 Hz, 1H), 2.17-2.36 (br s,
1H), 3.38-3.49 (m, 1H); 13C NMR δ -3.7, 18.1, 25.4, 26.5, 28.2,
40.1, 44.7, 69.2, 71.5, 83.2, 90.2, 117.1, 164.0; MS m/e 292 (M
+ H).
Exp er im en ta l Section 38
Gen er a l Con ju ga te Ad d ition P r oced u r e. A THF solution
of the Grignard reagent (2.5 equiv) was added, by syringe, to
a THF solution of LiCl (3 equiv) at room temperature. The
resultant solution was stirred for 5 min and was then added
to a cold (-78 °C), stirred, THF solution (0.12 M) of 10 (1
equiv). The resultant solution was stirred for 5 min, and then
solid TBDMSCl (2.5 equiv) was added. The -78 °C bath was
removed, and the solution was allowed to warm to room
temperature, with stirring, overnight. Saturated, aqueous
ammonium chloride was then added to the reaction mixture,
the aqueous phase was extracted with EtOAc (3 × 2 mL), and
the extracts were combined and then dried over anhydrous
MgSO4. The crude material was concentrated under reduced
pressure and was then purified by radial chromatography.
(()-(4R,6R)-4-H yd r oxy-4,6-d im et h yl-2-(1,1,2,2-t et r a -
m et h yl-1-sila p r op oxy)cycloh ex-1-en eca r bon it r ile (19).
The general procedure was employed with MeMgCl (2.9 M,
1.09 mmol) and 10 (66 mg, 0.44 mmol) (without the addition
of LiCl) and was quenched by the addition of saturated,
aqueous NH4Cl (2 mL). Chromatography (1 mm plate, 1:3
EtOAc/hexanes) provided 11 mg (19%) of 17 and 37 mg (51%)
of 19 as an oily mixture of predominantly one diastereomer:
(()-(4S,6S)-4-Hyd r oxy-4-m eth yl-2-(1,1,2,2-tetr a m eth yl-
1-sila p r op oxy)-6-vin ylcycloh ex-1-en eca r bon itr ile (20c).
The general procedure was employed with 10 (80 mg, 0.53
mmol in 4 mL THF), vinylmagnesium bromide (1 M, 1.32
mmol), LiCl (114 mg, 2.69 mmol in 2 mL of THF), and
TBDMSCl (200 mg, 1.33 mmol). Radial chromatography (1:3
EtOAc/hexanes) of the crude product, followed by concentration
of the appropriate fractions, provided 19 mg of 22 (15%) and
76 mg (49%) of 20c as an oil: IR (film): 3425, 3082, 2931, 2212,
1
1623 cm-1; H NMR δ 0.25 (s, 3H), 0.26 (s, 3H), 0.98 (s, 9H),
1.29 (s, 3H), 1.55-1.86 (br s, 1H), 1.61 (dd, J ) 13, 8.3 Hz,
1H), 1.81 (ddd, J ) 13, 6, 1 Hz, 1H), 2.25 (dt, J ) 17.7, 1.6 Hz,
1H), 2.36 (dd, J ) 17.7, 2.4 Hz, 1H), 3.02 (br dd, J ) 14, 7 Hz,
1H), 5.18 (d, J ) 10 Hz, 1H), 5.23 (d, J ) 17 Hz, 1H), 5.74-
5.89 (ddd, J ) 17, 10, 7 Hz, 1H); 13C NMR δ -3.7, 18.1, 25.5,
27.7, 39.2, 41.6, 45.3, 69.6, 92.3, 116.8, 117.7, 139.1, 163.8; MS
m/e 294 (M + H).
(()-(4S,6S)-4-Hyd r oxy-4-m eth yl-6-p h en yl-2-(1,1,2,2-tet-
r am eth yl-1-silapr opoxy)cycloh ex-1-en ecar bon itr ile (20d).
The general procedure was employed with 10 (117 mg, 0.77
mmol in 6 mL THF), phenylmagnesium chloride (2 M, 1.94
mmol), LiCl (100 mg, 2.36 mmol in 3 mL of THF), and
TBDMSCl (292 mg, 1.94 mmol). Radial chromatography (1:4
EtOAc/hexanes) of the crude product, followed by concentration
of the appropriate fractions, provided 17 mg of 22 (9%) and
155 mg (58%) of 20d as an oil: IR (film) 3420, 3028, 2931,
2212, 1624 cm-1; 1H NMR δ 0.20 (s, 3H), 0.22 (s, 3H), 0.92 (s,
1
IR (film) 3427, 2970, 2251, 2204, 1728 cm-1; H NMR δ 1.26
(37) The inseparable diastereomers were assigned by spectral
comparison of the major diastereomer with 21 since 35 and 21 adopt
a common conformation and have identical spectral signatures.
(38) For general experimental procedures, see: Fleming, F. F.;
Hussain, Z.; Weaver, D.; Norman, R. E. J . Org. Chem. 1997, 62, 1305.

8574 J . Org. Chem., Vol. 64, No. 23, 1999
Fleming et al.
9H), 1.25 (s, 3H), 1.62 (dd, J ) 12.9, 10.5 Hz, 1H), 1.69 (br s,
1H), 1.88 (ddd, J ) 12.9, 6.0, 2 Hz, 1H), 2.23 (dt, J ) 17.6, 2
Hz, 1H), 2.40 (dd, J ) 17.6, 3 Hz, 1H), 3.42-3.52 (m, 1H),
7.08-7.31 (m, 5H); 13C NMR δ -3.7, 18.1, 25.5, 26.8, 41.7, 45.5,
46.0, 69.6, 93.5, 117.4, 127.2, 127.6, 128.8, 142.1, 164.4; MS
m/e 344 (M + H).
was allowed to warm to room temperature over 6 h. The
reaction mixture was then concentrated and purified by radial
chromatography (1 mm plate, 1:9 EtOAc/hexane) to afford 37
mg (57%) of 28a as a white waxy solid: mp 100.3-103.2 °C;
1
IR 2928, 2234, 1694, 1615 cm-1; H NMR δ 0.06 (s, 3H), 0.08
(s, 3H), 0.77 (s, 9H), 1.42 (s, 3H), 2.50-2.78 (m, 4H), 7.55-
7.59 (m, 1H); 13C NMR δ -2.5, -2.4, 17.8, 25.4, 29.2, 41.8,
52.0, 74.0, 113.9, 117.4, 158.5, 191.2; MS m/e 266 (M + H).
(()-(4S,6S)-6-(ter t-Bu tyl)-4-h yd r oxy-4-m eth yl-2-(1,1,2,2-
t et r a m et h yl-1-sila p r op oxy)cycloh ex-1-en eca r b on it r ile
(20e). The general procedure was employed with 10 (53 mg,
0.35 mmol in 3 mL of THF), tert-butylmagnesium chloride (1
M, 0.88 mmol), LiCl (73 mg, 1.72 mmol in 2 mL of THF), and
TBDMSCl (133 mg, 0.88 mmol). Radial chromatography (1:3
EtOAc/hexanes) of the crude product, followed by concentration
of the appropriate fractions, provided 13 mg of 22 (15%) and
49 mg (43%) of 20e as an oil: IR (film) 3418, 2960, 2208, 1606
(()-Eth yl (5E)-3-Hyd r oxyoct-5-en oa te (32). A hexanes
solution (4 mL) of trans-3-hexenoic acid (0.48 mL, 4.0 mmol),
containing 1 drop of dry DMF, was cooled to 0 °C, and then
neat oxalyl chloride (0.35 mL, 4.0 mmol) was slowly added.
The cooling bath was then removed, and after 1.5 h the solvent
was evaporated to provide trans-3-hexenoyl chloride as a
relatively pure oil. A THF solution (2 mL) of trans-3-hexenoyl
chloride was added to a cold (-78 °C), THF solution (15 mL)
of ethyl lithioacetate,39 prepared by the addition of neat ethyl
acetate (1.2 mL, 12.0 mmol) to a cold (-78 °C), THF solution
of LiHMDS (hexamethyldisilazane, 2.5 mL, 12.0 mmol; MeLi,
8.7 mL, 11.6 mmol) followed by stirring for 10 min. Following
the addition of trans-3-hexenoyl chloride, the solution was
allowed to stir at -78 °C for 5 min and then the cooling bath
was removed. After 1 h aqueous HCl (10% v/v, mL) was added
and the crude reaction mixture was extracted with EtOAc.
Purification of the crude material by radial chromatography
(4 mm plate, 1:19 EtOAc/hexane) provided 379.9 mg (52%) of
ethyl (5E)-3-oxooct-5-enoate as an oil: IR 2969, 1745, 1708,
1
cm-1; H NMR δ 0.22 (s, 3H), 0.25 (s, 3H), 0.98 (s, 9H), 1.05
(s, 9H), 1.23 (s, 3H), 1.30-1.45 (m, 1H), 1.72 (ddd, J ) 12.7, 6,
3 Hz, 1H), 1.72 (br s, 1H), 2.14-2.25 (m, 2H), 2.35 (dd, J )
16.9, 3.1 Hz, 1H); 13C NMR δ -3.7, 18.2, 25.6, 26.0, 28.0, 34.2,
39.1, 44.1, 45.8, 70.0, 92.3, 119.7, 166.1; MS m/e 324 (M + H).
4-Me t h yl-2-(1,1,2,2-t e t r a m e t h yl-1-sila p r op oxy)b e n -
zen eca r bon itr ile (22). In the conjugate addition reactions
of MeMgCl with 10, varying amounts of 22 were obtained as
an oil: IR (film) 2930, 2226, 1608 cm-1 1H NMR δ 0.27 (s,
;
6H), 1.04 (s, 9H), 2.35 (s, 3H), 6.69 (s, 1H), 6.81 (d, J ) 7.9
Hz, 1H), 7.38 (d, J ) 7.9 Hz, 1H); 13C NMR δ -4.4, 18.1, 21.9,
25.5, 102.3, 117.3, 120.5, 122.5, 133.1, 145.3, 157.9; MS m/e
248 (M + H).
1
1649 cm-1; H NMR δ 0.93 (t, J ) 7 Hz, 3H), 1.22 (t, J ) 7.1
(()-(5S)-5-Met h yl-3-oxo-5-(1,1,2,2-t et r a m et h yl-1-sila -
p r op oxy)oct-7-en en itr ile (30a ). Pyridine (2.37 mL, 29 mmol)
and TBDMSOTf (4.14 mL, 18 mmol) were added, sequentially,
to a stirred, cold (0 °C) CH2Cl2 solution (50 mL) of 2914 (2.072
g, 12 mmol). The resultant solution was stirred for 5 min, and
then the reaction mixture was allowed to warm to room
temperature overnight. The reaction mixture was poured into
a separatory funnel, washed with saturated NaHCO3 solution,
and extracted with EtOAc (3 × 3 mL) and was then dried over
MgSO4. The crude material was concentrated under reduced
pressure and purified by radial chromatography (4 mm plate,
1:6 EtOAc/hexane) to afford 2.53 g (73%) of ethyl (()-(3S)-3-
methyl-3-(1,1,2,2-tetramethyl-1-silapropoxy)hex-5-enoate as an
oil: IR (film) 3078, 2957, 1732, 1640 cm-1; 1H NMR δ 0.09 (s,
6H), 0.85 (s, 9H), 1.25 (t, J ) 7.1 Hz, 3H), 1.35 (s, 3H), 2.28-
2.48 (m, 4H), 4.09 (q, J ) 7.1 Hz, 2H), 5.03-5.10 (m, 2H), 5.78-
5.93 (m, 1H); 13C NMR δ -2.1, -2.0, 14.2, 18.1, 25.7, 27.7,
46.7, 47.4, 60.1, 74.4, 118.0, 134.5, 171.0; MS m/e 286 (M). Neat
CH3CN (60 mL, 1.15 mmol) was added dropwise to a cold (-78
°C), stirred, THF solution (1.5 mL) of n-BuLi (1.15 mmol). The
resultant solution was stirred for 5 min, and then a THF
solution (2 mL) of ethyl (()-(3S)-3-methyl-3-(1,1,2,2-tetram-
ethyl-1-silapropoxy)hex-5-enoate (133 mg, 0.47 mmol) was
added. The resultant solution was stirred for 30 min at -78
°C and then allowed to warm to room temperature overnight.
Aqueous HCl (2% v/v) was added until the reaction mixture
was acidic to litmus, and then the aqueous phase was extracted
with EtOAc (3 × 8 mL). The extracts were combined, washed
successively with saturated NaHCO3 solution and brine, and
then dried (MgSO4). The crude materials was concentrated and
then purified by radial chromatography (1 mm plate, 1:19
EtOAc/hexanes) to afford 124 mg (95%) of 30a as an oil: IR
Hz, 3H), 1.96-2.05 (m, 2H), 3.17 (d, J ) 6.5 Hz, 2H), 3.41 (s,
1H), 4.13 (q, J ) 7.1 Hz, 2H), 5.38-5.48 (m, 1H), 5.58 (ddd, J
) 15.3, 6.3, 6.0 Hz); 13C NMR δ 13.2, 13.9, 25.4, 46.6, 48.4,
61.1, 119.8, 137.5, 167.0, 201.3; MS m/e 184 (M). A cold (0 °C),
ethanol solution (1.5 mL) of ethyl (5E)-3-oxooct-5-enoate (556.0
mg, 3.0 mmol) was reduced by the slow addition of solid NaBH4
(56.7 mg, 1.5 mmol). After the vigorous reaction subsided, the
cooling bath was removed and the solution was then stirred
for a further 10 min. Aqueous HCl (3% v/v, mL) was added,
and the crude reaction mixture was then extracted with
EtOAc. Purification of the crude material by radial chroma-
tography (4 mm plate, 1:19 EtOAc/hexane) provided 495.5 mg
(88%) of 32 as an oil: IR 3509, 1731 cm-1; 1H NMR δ 0.97 (dd,
J ) 7.4, 6.2 Hz, 3H), 1.26 (td, J ) 7.1 Hz, 1.4 Hz, 3H), 2.02 (br
quintet, J ) 7 Hz, 2H), 2.13-2.26 (m 2H), 2.50 (dd, J ) 16, 4
Hz, 1H), 2.89 (s, 1H), 4.02 (br s, 1H), 4.15 (q, J ) 7.1 Hz, 2H),
5.34-5.44 (m, 1H), 5.56 (dt, J ) 15.3, 6 Hz, 1H); 13C NMR δ
13.7, 14.1, 25.6, 39.8, 40.7, 60.6, 67.8, 124.0, 136.2, 172.8; MS
m/e 187 (M + H).
(()-(7E )-(5R )-3-O x o -5-(1,1,2,2-t e t r a m e t h y l-1-s ila -
p r op oxy)d ec-7-en en it r ile (30b ). Treatment of 32 with
pyridine (0.62 mL, 7.4 mmol) and TBDMSOTf (1.1 mL, 4.5
mmol) as described for 30a provided 844.1 mg (92%) of ethyl
(7E)-3-(1,1,2,2-tetramethyl-1-silapropoxy)dec-7-enoate as an
1
oil: IR 2932, 1734 cm-1; H NMR δ 0.02 (s, 3H), 0.05 (s, 3H),
0.85 (s, 9H), 0.95 (dd, J ) 7.6, 7.4 Hz, 3H), 1.24 (t, J ) 7.2 Hz,
3H), 2.00 (br quintet, J ) 7 Hz, 2H), 2.17 (br t, J ) 6 Hz, 2H),
2.37 (dd, J ) 15, 7 Hz, 1H), 2.43 (dd, J ) 15, 5 Hz, 1H), 4.05-
4.18 (m, 3H), 5.31-5.41 (m, 1H), 5.50 (dt, J ) 15.3, 6 Hz, 1H);
13C NMR δ -4.9, -4.5, 13.7, 14.2, 18.0, 25.6, 25.7, 41.0, 42.3,
60.2, 69.5, 124.4, 135.3, 171.9; MS m/e 300 (M + H). Addition
of a THF solution of ethyl (7E)-3-(1,1,2,2-tetramethyl-1-sila-
propoxy)dec-7-enoate to lithioacetonitrile [from BuLi (1.19 mL,
1.57 mmol) and acetonitrile (82.1 mL, 1.57 mmol)], as described
for 30a , provided 226.8 mg (98%) of 30b as an oil: IR 2257,
1
(film) 3079, 2930, 2259, 1732, 1636 cm-1; H NMR δ 0.12 (s,
3H), 0.14 (s, 3H), 0.87 (s, 9H), 1.35 (s, 3H), 2.28 (dd, J ) 13.6,
7.9 Hz, 1H), 2.41 (dd, J ) 13.6, 6.7 Hz, 1H), 2.50 (d, J ) 14
Hz, 1H), 2.71 (d, J ) 14 Hz, 1H), 3.53 (d, J ) 19.5 Hz, 1H),
3.62 (d, J ) 19.5 Hz, 1H), 5.05-5.13 (m, 2H), 5.70-5.87 (m,
1H); 13C NMR δ -1.9, 18.1, 25.9, 27.7, 34.4, 47.5, 52.7, 75.6,
113.7, 119.0, 133.6, 196.6; MS m/e 266 (M - CH3).
(()-(4S)-4-Met h yl-6-oxo-4-(1,1,2,2-t et r a m et h yl-1-sila -
p r op oxy)cycloh ex-1-en eca r bon itr ile (28a ). A stream of
ozone was passed through a cold (-78 °C), dichloromethane
solution (3 mL) of 30a (69 mg, 0.25 mmol) until the distinctive
blue color of ozone was clearly observed. Ozonolysis was then
terminated, the excess ozone was displaced by passing a
stream of nitrogen through the solution, and then neat Me2S
(1 mL) was added dropwise at -78 °C. The resultant solution
1
1725 cm-1; H NMR δ 0.04 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H),
0.97 (t, J ) 7.4 Hz, 3H), 2.02 (br quintet, J ) 7 Hz, 2H), 2.11-
2.27 (m, 2H), 2.60 (dd, J ) 14.7, 4.6 Hz, 1H), 2.68 (dd, J )
14.7, 7.3 Hz, 1H), 3.15 (s, 2H), 4.17 (tt, J ) 7.2, 4.8 Hz, 1H),
5.32 (dtt, J ) 15.4, 7.0, 1 Hz, 1H), 5.52 (dt, J ) 15.4, 6 Hz);
13C NMR δ -4.9, -4.5, 13.6, 18.0, 25.6, 25.8, 33.9, 40.9, 48.5,
69.5, 113.5, 123.5, 136.3, 197.0; MS m/e 296 (M + H).
(4R)-6-Oxo-4-(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)cyclo-
h ex-1-en ecar bon itr ile (28b). Ozonolysis of a dichloromethane
(39) Rathke, M. W. J . Am. Chem. Soc. 1970, 92, 3222.

Unsaturated Oxo-Nitriles
J . Org. Chem., Vol. 64, No. 23, 1999 8575
solution (30 mL) of 30b (1.5 g, 5.1 mmol) using the same
procedure as described for 28a , provided, after reduction with
Me2S (60 mL), 1.09 g (85%) of 28b as an oil: IR 3025, 1684,
1608 cm-1; 1H NMR δ 0.07 (s, 6H), 0.86 (s, 9H), 2.56-2.84 (m,
mm plate, 1:99 EtOAc/hexane) to afford 76 mg (47%) of 34b
as an oil: IR (film) 2930, 2209, 1622 cm-1; 1H NMR δ 0.07 (s,
3H), 0.08 (s, 3H), 0.22 (s, 3H), 0.23 (s, 3H), 0.83 (s, 9H), 0.91
(t, J ) 7.0 Hz, 3H), 0.96-1.08 (m, 4H), 0.97 (s, 9H), 1.18-1.30
(m, 2H), 1.32 (s, 3H), 1.75-1.85 (m, 1H), 1.85 (dd, J ) 13, 5.2
Hz, 1H), 2.15 (d, J ) 2.1 Hz, 2H), 2.46-2.61 (m, 1H); 13C NMR
δ -3.7, -3.6, -2.2, 14.1, 18.1, 22.8, 25.5, 25.7, 28.3, 30.4, 32.2,
33.7, 41.5, 45.5, 71.4, 95.2, 118.1, 163.0; MS m/e 438 (M + H).
(4R,6R)-2,4-Bis(1,1,2,2-t et r a m et h yl-1-sila p r op oxy)-6-
m eth ylcycloh ex-1-en eca r bon itr ile (35). A THF solution of
Me2CuLi [1 mL, prepared from Me2S‚CuBr (138.8 mg, 0.68
mmol) and MeLi (0.95 mL, 1.35 mmol)] was added to a THF
solution (1 mL) of 28b (111.0 mg, 0.50 mmol) followed by
TBDMSCl (136.0 mg, 0.90 mmol) as described for the synthesis
of 34a . The crude product was purified by radial chromatog-
raphy (1 mm plate, 1:19 EtOAc/hexanes) to afford 50.9 mg
4H), 4.35 (dddd, J ) 10, 4, 3.6 Hz), 7.60 (t, J ) 4 Hz, 1H); 13
C
NMR δ -5.0, -4.9, 17.9, 25.6, 36.0, 46.8, 66.3, 113.8, 118.1,
158.4, 190.7; MS m/e 252 (M + H).
(()-(4R,6R)-2,4-Bis(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)-
4,6-d im eth ylcycloh ex-1-en eca r bon itr ile (34a ). A THF so-
lution of Me2CuLi [1 mL, prepared from Me2S‚CuBr (58 mg,
0.28 mmol) and MeLi (0.28 mmol)] was added, by syringe, to
a cold (-78 °C), stirred THF solution (1 mL) of 28a (49 mg,
0.18 mmol). After 30 min, TBDMSCl (55 mg, 0.36 mmol) was
added and then the resultant solution was allowed to warm
to room temperature overnight. Saturated, aqueous NH4Cl (2
mL, pH ) 8) was then added, the aqueous phase was extracted
with EtOAc (3 × 3 mL), and the extracts were combined and
then dried with anhydrous magnesium sulfate. The crude
material was concentrated under reduced pressure and puri-
fied by radial chromatography (1 mm plate, 1:99 EtOAc/
hexanes) to afford 65 mg (89%) of 34a as an oil: IR (film) 2931,
2210, 1634 cm-1; 1H NMR δ 0.07 (s, 3H), 0.08 (s, 3H), 0.23 (s,
6H), 0.83 (s, 9H), 0.97 (s, 9H), 1.16-1.24 (m, 1H), 1.17 (d, J )
6.9 Hz, 3H), 1.31 (s, 3H), 1.82 (dd, J ) 13.2, 5.0 Hz, 1H), 2.15
(br s, 2H), 2.54-2.71 (m, 1H); 13C NMR δ -3.8, -3.7, -2.3,
18.0, 20.1, 25.4, 25.7, 27.3, 30.1, 44.7, 45.3, 71.4, 95.5, 117.9,
162.7; MS m/e 396 (M + H).
1
(27%) of 35 as an oil: IR 2947, 2212, 1631 cm-1; H NMR δ
0.06 (s, 6H), 0.23 (s, 3H), 0.24 (s, 3H), 0.87 (s, 9H), 0.98 (s,
9H), 1.18 (d, J ) 7.1 Hz, 3H), 1.34 (dtt, J ) 13.2, 7.9, 2.3 Hz,
1H), 1.75 (ddd, J ) 13.2, 6.6, 1.0 Hz, 1 H), 2.10 (br ddt, J )
19, 4, 1 Hz, 1H), 2.35 (br ddd, J ) 19, 4, 2 Hz, 1H), 2.63 (br
quintet, J ) 7 Hz, 1H); 13C NMR δ -4.9, -4.7, -3.9, -3.8,
18.0, 18.1, 20.5, 20.9, 25.5, 25.7, 26.7, 38.0, 64.3, 96.1, 118.1,
162.2; MS m/e 382 (M + H).
(()-(6R )-4,6-Dim e t h yl-2-oxocycloh e x-3-e n e ca r b on i-
tr ile (36). A THF solution of tetrabutylammonium fluoride
(1 M, 0.39 mmol) was added to a THF solution of 34a (61 mg,
0.15 mmol). The resultant solution was refluxed for 2 h, diluted
with EtOAc (8 mL), and washed with saturated, aqueous
NaHCO3 and was then dried over MgSO4. The crude material
was concentrated under reduced pressure and was then
purified by radial chromatography (1 mm plate, 1:19 EtOAc/
hexanes) to afford 16 mg (70%) of 36 as an oil consisting of
two diastereomers (2:1 ratio): IR (film) 2932, 2248, 1682, 1634
(6S,4R)-2,4-Bis(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)-4,6-
d im eth ylcycloh ex-1-en eca r bon itr ile. Pyridine (20 mL, 0.25
mmol) and TBDMSOTf (45 mL, 0.20 mmol) were added,
sequentially, to a stirred, CH2Cl2 solution (1.5 mL) of 20a (37
mg, 0.13 mmol), and the resultant solution was stirred for 14
days at room temperature. Saturated aqueous NaHCO3 was
added, and the organic phase was then dried over MgSO4. The
crude material was concentrated under reduced pressure and
was then purified by radial chromatography (1 mm plate, 1:66
EtOAc/hexanes) to afford 5.5 mg (15%) of recovered 20a and
29 mg (56%) of (6S,4R)-2,4-bis(1,1,2,2-tetramethyl-1-sila-
propoxy)-4,6-dimethylcyclohex-1-enecarbonitrile as an oil: IR
(film): 2958, 2215, 1631 cm-1; 1H NMR δ 0.09 (s, 6H), 0.23 (s,
3H), 0.24 (s, 3H), 0.85 (s, 9H), 0.98 (s, 9H), 1.18-1.33 (m, 4H),
1.22 (s, 9H), 1.80 (br dd, J ) 11, 5 Hz, 1H), 2.17 (br d, J )
17.9 Hz, 1H), 2.28-2.36 (m, 2H); 13C NMR δ -3.8, -1.9, 17.8,
18.1, 20.7, 25.5, 25.7, 26.8, 28.9, 45.5, 46.8, 71.7, 95.1, 117.7,
163.1; MS m/e 396 (M + H).
1
cm-1; H NMR for major δ 1.32 (d, J ) 6.5 Hz, 3H), 2.01 (s,
3H), 2.32-2.52 (m, 3H), 3.18 (d, J ) 12.2 Hz, 1H), 5.98 (br s,
1H); 1H NMR for minor δ 1.23 (d, J ) 6.7 Hz, 3H), 2.02 (s,
3H), 2.09-2.24 (m, 3H), 3.44 (d, J ) 4.3 Hz, 1H), 5.94-5.97
(m, 1H); 13C NMR for major δ 20.0, 24.3, 33.7, 38.6, 47.2, 116.2,
124.6, 162.7, 188.2; 13C NMR for minor δ 17.5, 24.5, 32.0, 36.5,
44.7, 115.1, 124.2, 163.3, 188.2; MS m/e 150 (M + H).
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the NIH (Grant CA/GM 74355-
01) and helpful discussions with Drs. Peter Wipf and
Dennis Liotta.
(()-(4R,6R)-2,4-Bis(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)-
6-bu tyl-4-m eth ylcycloh ex-1-en eca r bon itr ile (34b). The
procedure for 34a was employed using n-Bu2CuLi [1 mL,
prepared from Me2S‚CuBr (115 mg, 0.56 mmol) and n-BuLi
(0.56 mmol)], 28a (99 mg, 0.37 mmol), and TBDMSCl (112.5
mg, 0.75 mmol). The crude material was concentrated under
reduced pressure and purified by radial chromatography (1
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9909709