Cyclic alkenenitriles: Synthesis, conjugate addition, and stereoselective annulation

Article abstract of DOI:10.1021/jo0345291

O-Alkylation of unsaturated silyl cyanohydrins with DMSO-Ac₂O triggers a rearrangement to methylthiomethyl-protected hydroxyalkenenitriles that are easily hydrolyzed for subsequent annulations with ω-chloroalkyl Grignard reagents. Deprotonating the γ-hydroxyalkenenitriles with t-BuMgCl followed by addition of ω-chloroalkyl Grignard reagents triggers a conjugate addition-alkylation sequence leading exclusively to cis-octalins, hydrindanes, and decalins. Stereoelectronic control favors an axial conjugate addition leading to a particularly reactive conformer that rapidly cyclizes to cis-fused bicyclic nitriles, whereas generating the ring-flipped conformer, through a stepwise sequence, allows access to the diastereomeric trans-decalin. Collectively, the rearrangement-annulation sequence represents the first general annulation of alkenenitriles to assemble diverse bicyclic nitriles with complete control over the two newly installed stereocenters.

Full text of DOI:10.1021/jo0345291

Cyclic Alk en en itr iles: Syn th esis, Con ju ga te Ad d ition , a n d
Ster eoselective An n u la tion
Fraser F. Fleming,* Zhiyu Zhang, Qunzhao Wang, and Omar W. Steward
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530
flemingf@duq.edu
Received April 25, 2003
O-Alkylation of unsaturated silyl cyanohydrins with DMSO-Ac2O triggers a rearrangement to
methylthiomethyl-protected hydroxyalkenenitriles that are easily hydrolyzed for subsequent
annulations with ω-chloroalkyl Grignard reagents. Deprotonating the γ-hydroxyalkenenitriles with
t-BuMgCl followed by addition of ω-chloroalkyl Grignard reagents triggers a conjugate addition-
alkylation sequence leading exclusively to cis-octalins, hydrindanes, and decalins. Stereoelectronic
control favors an axial conjugate addition leading to a particularly reactive conformer that rapidly
cyclizes to cis-fused bicyclic nitriles, whereas generating the ring-flipped conformer, through a
stepwise sequence, allows access to the diastereomeric trans-decalin. Collectively, the rearrange-
ment-annulation sequence represents the first general annulation of alkenenitriles to assemble
diverse bicyclic nitriles with complete control over the two newly installed stereocenters.
SCHEME 1. Ch ela tion -Con tr olled Con ju ga te
In tr od u ction
Ad d ition -Alk yla tion of Alk en en itr iles
Annulations feature prominently as key bond-forming
reactions in natural product syntheses.1 The centrality
of annulation reactions stems from numerous reliable
strategies for elaborating monocyclic precursors into
complex, biologically active, multicyclic targets.2 Origi-
nally, the power of annulation-based synthesis was first
demonstrated in Robinson annulation routes to steroids,3
initiating an enduring search for annulations of increas-
ing complexity, stereoselectivity, and efficiency.4 Fulfill-
ing these criteria has inspired syntheses of several
exceptionally versatile bifunctional reagents, containing
nucleophilic and electrophilic centers, for sequential
conjugate addition-alkylation annulations to unsatur-
ated carbonyl compounds.5
effective method for promoting conjugate additions to
alkenenitriles8 is to temporarily chelate Grignard re-
agents to γ-hydroxy unsaturated nitriles,9 effectively
harnessing the inherent entropic advantages10 of in-
tramolecular reactions in promoting a formal intermo-
lecular conjugate addition (Scheme 1). Mechanistically,
sequential deprotonation of hydroxyalkenenitriles 1 fol-
lowed by alkyl exchange11 from a modest excess of a
Annulation reactions with unsaturated nitriles are
inherently more difficult than analogous annulations
with unsaturated carbonyl compounds. The challenge
stems from the paucity of anionic conjugate additions to
unsaturated nitriles which, despite being highly polar-
ized,6 are recalcitrant Michael acceptors that react poorly
with many conventional nucleophiles.7 A particularly
* Corresponding author.
(1) (a) Tokoroyama, T. Synthesis 2000, 611. (b) Vandewalle, M.; De
Clercq, P. Tetrahedron 1985, 41, 1767.
(8) (a) J amison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S.
L. J . Am. Chem. Soc. 1997, 119, 4353. (b) Molander, G. A.; Harris, C.
R. J . Org. Chem. 1997, 62, 7418. (c) Fleming, F. F.; Hussain, Z.;
Weaver, D.; Norman, R. E. J . Org. Chem. 1997, 62, 1305. (d) Cooke,
M. P., J r.; Parlman, R. M. J . Am. Chem. Soc. 1977, 99, 5222. (e)
Brattesani, D. N.; Heathcock, C. H. J . Org. Chem. 1975, 40, 2165.
(9) For hydroxy alkenenitriles, see: (a) Fleming, F. F.; Wang, Q.;
Zhang, Z.; Steward, O. W. J . Org. Chem. 2002, 67, 5953. For hydroxy
alkynenitriles, see: (b) Fleming, F. F.; Gudipati, V.; Steward, O. W.
Tetrahedron 2003, 59, 5585.
(2) Varner, M. A.; Grossman, R. B. Tetrahedron 1999, 55, 13867.
(3) (a) Gawley, R. E. Synthesis 1976, 777. (b) J ung, M. E. Tetrahe-
dron 1976, 32, 3.
(4) For recent annulation reviews, see: (a) Reference 1. (b) McCar-
roll, A. J .; Walton, J . C. J . Chem. Soc., Perkin Trans. 1 2001, 3215. (c)
Grossman, R. B. Synlett 2001, 13. (c) Larock, R. C. J . Organomet.
Chem. 1999, 576, 111. (d) Davies, H. M. L. Adv. Cycloaddition 1999,
5, 119.
(5) Piers, E. Pure Appl. Chem. 1988, 60, 107.
(6) Reddy, G. S.; Mandell, L.; Goldstein, J . H. J . Am. Chem. Soc.
1961, 83, 3, 1300.
(10) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; Wiley: New York, 1994; pp 676-682.
(11) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J . Am. Chem. Soc.
1990, 112, 9393.
(7) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.
10.1021/jo0345291 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/29/2003
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J . Org. Chem. 2003, 68, 7646-7650

Cyclic Alkenenitriles
second Grignard reagent generates the alkylmagnesium
alkoxide 2 that triggers a stereoselective conjugate ad-
dition. Alkylating the resulting magnesiated nitrile 3
with electrophiles installs two new stereocenters in one
synthetic operation.12
insight into the stereoelectronically controlled conju-
gate addition and cyclization reactions.
Resu lts a n d Discu ssion
A key lead for O-alkylating the trimethylsiloxyl group
of enone-derived17 cyanohydrins stems from two O-
alkylations of trimethylsilyl cyanohydrins with ClCH2-
OCH3.18 Presuming the alkylation to require a particu-
larly reactive electrophile, the cyanohydrin 5a 17a,b was
treated with the sulfonium ylide 9a 19 to directly generate
the methylthiomethyl cyanohydrin 6a (Scheme 3). The
trimethylsilyl-methylthiomethyl interchange proceeds
by an O-alkylation of 5a with ylide 9a ,20 formed in situ
from DMSO and acetic anhydride,19 followed by desilyl-
ation to generate 6a . Unfortunately, chlorination of 6a
with SO2Cl221 followed by numerous metalation strategies
failed to promote the desired Wittig rearrangement22 of
11a but rather caused significant degradation and for-
mation of ketone-containing ethers arising from attack
on the nitrile group.23 Attempts to deprotonate and
rearrange the corresponding nitrile (11a , CNdCl),24 were
similarly fruitless despite close precedent in the rear-
rangement of cyanomethyl enamines.25
Conceptually, the sequential conjugate addition-alkyl-
ation of ω-chloroalkyl Grignard reagents5,13 to cyclic
hydroxyalkenenitriles provides an annulation route to
bicyclic nitriles. Developing this annulation strategy
requires an expedient synthesis of cyclic hydroxyal-
kenenitriles for which few syntheses currently exist.14
Addressing this deficiency suggested accessing the req-
uisite cyclic hydroxyalkenenitriles from an unsaturated
silyl cyanohydrin since chiral silyl cyanohydrins are
readily available in high enantiomeric ratios.15 The stra-
tegy envisages conversion of an unsaturated trimethyl-
silyl cyanohydrin to the corresponding methylthiometh-
yl ether followed by halogen-SMe exchange and [2,3]
Wittig rearrangement (Scheme 2). The 2-fold appeal of
this sequence lies in transposing the cyanohydrin chiral-
ity into the hydroxyalkenenitrile16 for stereoselective
chelation-controlled conjugate additions and in concur-
rently expanding the versatility of silyl cyanohydrins
through an oxygen functional group interchange rather
than the more typical addition to, or hydrolysis of, the
nitrile group.15
SCHEME 3. O-Alk yla tion of Silylcya n oh yd r in 5a
SCHEME 2. Cya n oh yd r in -Alk en en itr ile
Rea r r a n gem en t Str a tegy
Although the [2,3] Wittig strategy proved unmanage-
able, concurrent alkylations of the methyl-substituted
Pursuing this strategy identified an unusual silyl cy-
anohydrin rearrangement for synthesizing several cyclic
alkenenitriles. Chelation-controlled conjugate addition of
ω-chloroalkyl Grignard reagents to the resulting cyclic
hydroxyalkenenitriles generates intermediate magnesi-
ated nitriles that cyclize to cis-octalins, hydrindanes, and
decalins in the first general annulation of alkenenitriles.
Collectively, the rearrangement-annulation reactions
generate a diverse array of bicyclic nitriles providing
(17) (a) Higuchi, K.; Onaka, M.; Izumi, Y. Bull. Chem. Soc. J . 1993,
66, 2016. (b) Wada, M.; Takahashi, T.; Domae, T.; Fukuma, T.; Miyoshi,
N.; Smith, K. Tetrahedron: Asymmetry 1997, 8, 3939. (c) Agami, C.;
Fadlallah, M. Tetrahedron 1983, 39, 777.
(18) Kabalka, G. W.; Mathur, S. B.; Gai, Y. Z. Org. Prep. Proc. Intl.
1990, 22, 87.
(19) (a) Lee, T. V. In Comprehensive Organic Synthesis; Fleming,
I., Trost, B. M., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 291-303.
(b) Yamada, K.; Kato, K.; Nagase, H.; Hirata, Y. Tetrahedron Lett.
1976, 17, 65.
(20) O-Alkylation of the TMS cyanohydrin by the sulfonium ylide,
rather than Ac2O, is required by the recovery of unreacted 5c from
refluxing Ac2O.
(21) Okada, Y.; Wang, J .; Yamamoto, T.; Mu, Y.; Yokoi, T. J . Chem.
Soc., Perkin Trans. 1 1996, 2139.
(22) Davidsen, S. K. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, U.K., 1995; pp
5005-5006.
(12) Fleming, F. F.; Wang, Q.; Steward, O. W. J . Org. Chem. 2003,
68, 4235.
(13) (a) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 4415. (b) Bernady, K. F.; Poletto, J . F.;
Nocera, J .; Mirando, P.; Schaub, R. E.; Weiss, M. J . J . Org. Chem. 1980,
45, 4702.
(14) (a) Fleming, F. F.; Wang, Q.; Steward, O. W. J . Org. Chem.
2001, 66, 2171. (b) Kurihara, T.; Miki, M.; Yoneda, R.; Harusawa, S.
Chem. Pharm. Bull. 1986, 34, 2747. (c) Nokami, J .; Mandai, T.
Nishimura, A.; Takeda, T.; Wakabayashi, S.; Kunieda, N. Tetrahedron
Lett. 1986, 27, 5109. (d) Nokami, J .; Mandai, T.; Imakura, Y.;
Nishiuchi, K.; Kawada, M.; Wakabayashi, S. Tetrahedron Lett. 1981,
22, 4489.
(15) (a) Gregory, R. J . H. Chem. Rev. 1999, 99, 3649. (b) Effenberger,
F. Enantiomer 1996, 1, 359. (c) North, M. Synlett 1993, 807.
(16) Schrader, T.; Kirsten, C.; Herm, M. Phosp. Sulf. Silicon 1999,
144-146, 161.
(23) The poor electrophilicity of the nitrile functionality and the
viability of several nitrile-containing alkyllithiuma,b and Grignardc-h
reagents implied the viability of forming and rearranging the metalated
cyanohydrin 7a . (a) Tucker, C. E.; Majid, T. N.; Knochel, P. J . Am.
Chem. Soc. 1992, 114, 3983. (b) Parham, W. E.; J ones, L. D. J . Org.
Chem. 1976, 41, 1187. (c) Inoue, A.; Kitagawa, K.; Shinokubo, H.;
Oshima, K. J . Org. Chem. 2001, 66, 4333. (d) Lee, J .-s.; Velarde-Ortiz,
R.; Guijarro, A.; Wurst, J . R.; Rieke, R. D. J . Org. Chem. 2000, 65,
5428. (e) Abarbri, M.; Thibonnet, J .; Be´rillon, L.; Dehmel, F.; Rot-
tla¨nder, M.; Knochel, P. J . Org. Chem. 2000, 65, 4618. (f) Thibonnet,
J .; Knochel, P. Tetrahedron Lett. 2000, 41, 3319. (g) Kitagawa, K.;
Inoue, A.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 2000,
39, 2481. (h) Burns, T. P.; Rieke, R. D. J . Org. Chem. 1987, 52, 3674.
J . Org. Chem, Vol. 68, No. 20, 2003 7647

Fleming et al.
SCHEME 4. Rea r r a n gem en t of Tr im eth ylsilyl Cya n oh yd r in s to Cyclic Alk en en itr iles
TABLE 1. Hyd r oxya lk en en itr ile An n u la tion s w ith
ω-Ch lor oa lk yl Gr ign a r d Rea gen ts
analogue 5c were rewarded with an unanticipated rear-
rangement to the synthetically valuable cyclic alkeneni-
trile 14c (Scheme 4). Mechanistically, alkylation of 5c
with the sulfonium salt 9a affords the oxonium ion 10c26
that, unlike 10a , fragments to the more stable methyl-
substituted carbocation27 12c (Scheme 4). Subsequent
DMSO attack28 on carbocation 12c generates the sulfon-
ium nitrile29 13c that suffers a Pummerer-type rear-
rangement30 to afford the rearranged nitrile 14c (55%
yield). The relatively facile rearrangement of 5c contrasts
with the significantly less efficient rearrangement of the
cyanohydrins 5b and 5d (24% and 20% yield, respec-
tively)31 that rearrange more slowly32 allowing the ini-
tially formed alkenenitriles to react further, as implied
by concurrent formation of the unusual ester-nitrile 16d
with 14d .30e
Mercury-assisted hydrolyses33 of 14b-d efficiently
provides a series of γ-hydroxyalkenenitriles for chelation-
controlled conjugate addition-alkylations (Table 1).34
t-BuMgCl-initiated deprotonation of the 5-membered
nitrile 1a and addition of a slight excess of the chloroalkyl
(24) Soli, E. D.; Manoso, A. S.; Patterson, M. C.; DeShong, P.; Favor,
D. A.; Hirschmann, R.; Smith, A. B., III. J . Org. Chem. 1999, 64, 3171.
(25) Mander, L. N.; Turner, J . V. J . Org. Chem. 1973, 38, 2915.
(26) Prior cleavage of the TMS group to the corresponding cyano-
hydrin (5c, Me3SidH), by adventitious acetic acid, appears unlikely
since subjecting the cyanohydrin (5c, Me3SidH) to the reaction
conditions affords 14c in only 7% yield.
(27) Stabilization of carbocations by nitriles rests on dramatically
enhanced ionization rates in generating carbocations adjacent to
nitriles, relative to trifluoromethyl groups,a although recent evidence
suggests that the rate differences are due to ground state effects and
that nitriles do not significantly stabilize adjacent carbocations.b The
divergent reactivity between 5a and 5c is more consistent with
formation of a carbocation, rather than a concerted displacement, with
modest stabilization from the nitrile and a greater inductive stabiliza-
tion from the methyl group for 5c. (a) Creary, X. Chem. Rev. 1991, 91,
1625. (b) Tekeuchi, K.; Kitagawa, T.; Ohga, Y.; Nakakimura, A.;
Munakata, M. Tetrahedron 1997, 53, 8155.
(28) Addition of sodium acetate suppresses the yield for the analog-
ous 5-membered ring cyanohydrin implying that DMSO is the nuleo-
phile rather that acetate.
(29) For a comprehensive analysis of carbocation interception by
DMSO, see: Creary, X.; Burtch, E. A.; J iang, Z. J . Org. Chem. 2003,
68, 1117.
a
One equivalent of t-BuLi is added after addition of 17a to
(30) (a) Kennedy, M.; McKervey, M. A. In Comprehensive Organic
Synthesis; Fleming, I., Trost, B. M., Eds.; Pergamon: Oxford, 1991;
Vol. 7, pp 193-216. (b) Abe, H.; Fujii, H.; Masunari, C.; Itani, J .;
Kashino, S.; Shibaike, K.; Harayama, T. Chem. Pharm. Bull. 1997,
45, 778. (c) Williams, D. R.; Klingler, F. D.; Dabral, V. Tetrahedron
Lett. 1988, 29, 3415. (d) Hendrickson, J . B.; Schwartzman, S. M.
Tetrahedron Lett. 1975, 16, 273. (e) Corey, E. J .; Kim, C. U. J . Am.
Chem. Soc. 1972, 94, 7586. (f) J ohnson, C. R.; Phillips, W. G. J . Am.
Chem. Soc. 1969, 91, 682. (g) Pfitzner, K. E.; Moffatt, J . G. J . Am.
Chem. Soc. 1965, 87, 5670.
promote conjugate addition through the ate complex (Scheme 5).
b
1d was synthesized by ring opening of the corresponding
epoxide.14a
Grignard reagents 17a -c trigger sequential conjugate
addition-alkylations generating the octaline- and hy-
drindane-substituted nitriles 18a -c (Table 1, entries
7648 J . Org. Chem., Vol. 68, No. 20, 2003

Cyclic Alkenenitriles
SCHEME 5. Ster eoelectr on ic Con tr ol in Ch ela tion -Con tr olled Con ju ga te Ad d ition -Alk yla tion s
1-3). An analogous annulation of 1b with 17a generates
the hydrindane 18d with a complementary substitution
pattern (compare Table 1, entries 2 and 3 with 4) whereas
the annulations of 1b-d with 17b,c afford decalin-
containing nitriles (Table 1, entries 5-8). In each in-
stance, the chelation-controlled conjugate addition of
ω-haloalkyl Grignard reagents rapidly assembles the
corresponding bicyclic nitriles with complete control over
the two newly installed stereocenters.
for the conjugate additions is the pyramidalization of the
â-carbon during the alkyl transfer, creating two potential
addition modes for the more flexible 6-membered al-
kenenitriles: axial delivery of the alkyl group through a
stereoelectronically favored chairlike transition state
21ba or equatorial alkyl delivery through a less favor-
able, boatlike transition state 21bb.35 An analogous
pyramidalization of the â-carbon in the 5-membered
alkenenitrile requires a more significant distortion of the
bicyclo[3.3.0] transition state 21a potentially explaining
the requirement for conjugate addition through the more
nucleophilic ate complex 19a .36
Preferential formation of the cis-decalins 18e-h (Table
1, entries 5-8) is highly unusual since analogous meta-
lated nitriles preferentially cyclize to trans-decalins.37 An
extensive series of cyclizations with 23 reveals that
pyramidalization of the metalated nitrile in THF directs
cyclization to the trans-decalin 25 through the least
sterically congested transition state 24 (Scheme 6). The
Several fascinating mechanistic details emerge by
comparing the annulations of the chloroalkyl Grignard
17a with the 5- and 6-membered alkenenitriles 1a and
1b (Table 1, entries 1 and 4, respectively). In each case,
sequential deprotonation of the alkenenitriles with t-
BuMgCl, and halogen-alkyl exchange11 with 17a , gener-
ates the key alkylmagnesium alkoxides 2a and 2b
(Scheme 5). Intramolecular delivery of the chloroalkyl
group is facile from 2b, and for every other conjugate
addition (Table 1, entries 2-8), whereas 2a requires the
addition of t-BuLi to coax conjugate addition through the
more nucleophilic ate complex9a 19a (Scheme 5). Critical
SCHEME 6. Tr a n s-Selective Nitr ile An ion
Cycliza tion s
(31) No rearrangement of the trimethylsilyl cyanohydrin i (R ) Me3-
Si)17c occurs under identical conditions whereas exposure of the
cyanohydrin ii (R
dehydration to the corresponding diene iv, hydrolysis to 4-cholesten-
3-one v, and recovery of unreacted cyanohydrin ii (48%).
) H) to TsOH causes rearrangement to iii,
contrasting annulations to cis-decalins suggests that the
conjugate addition generates particularly reactive di-
magnesiated nitriles, such as 22e, poised for a rapid
cyclization from the conformation directly ensuing from
an axial conjugate addition (Scheme 7)sassuming that
internal alkylation is faster38 than equilibration to the
more stable chair conformation and subsequent cycliza-
tion to a trans-decalin.
(35) An excellent stereoelectronic analysis rationalizes the prefer-
ence for axial conjugate addition of endocyclic enones,a whereas the
stereoelectronic analysis for an exocyclic electron-withdrawing group
does not appear to have been examined previously. (a) Deslongchamps,
P. Stereoelectronic Effects in Organic Chemistry; Pergamon: Exeter,
1983; pp 221-242. Consistent with a stereoelectonically favored axial
addition is the inability to react 17c with the steroidal nitrile ii31 where
the rigid steroidal trans-ring junction enforces the more difficult
equatorial conjugate addition from an axially oriented alkylmagnesium
alkoxide.
(32) Only 60% conversion of 5d occurs in 40 h, the time required
for complete conversion of 5c to 14c.
(33) Corey, E. J .; Bock, M. G. Tetrahedron Lett. 1975, 16, 3269.
(34) For a preliminary communication, see: Fleming, F. F.; Zhang,
Z.; Wang, Q.; Steward, O. W. Org. Lett. 2002, 4, 2493.
J . Org. Chem, Vol. 68, No. 20, 2003 7649

Fleming et al.
SCHEME 7. Cis-Selective Nitr ile An ion
An n u la tion s
tonating 26 with excess LiHMDS generates the confor-
mationally biased dilithiated nitrile 22ea 40 that cyclizes
exclusively to the trans-decalin 27. Exclusive cyclization
to the trans-decalin is consistent with alkylation through
the less sterically congested conformer 22ea , strongly
implying41 that the cis-selective annulations of 18e-h
result from a rapid cyclization of the axial conformation
formed directly following the conjugate addition (22e,
Scheme 7).
Mechanistically the annulations of chloroalkyl Grig-
nard reagents with 6-membered hydroxyalkenenitriles
exhibit a high degree of stereoelectronic control. The
initial formation of an equatorially oriented alkylmag-
nesium alkoxide, generated by t-BuMgCl deprotonation
and halogen-alkyl exchange (20bb, Scheme 5), preferen-
tially triggers an axial conjugate addition to alkeneni-
triles through a chairlike transition state (21ba , Scheme
5). Conjugate addition installs an axially oriented chlo-
robutyl side chain that is rapidly alkylated by the
particularly reactive dimagnesiated nitrile, irreversibly
establishing the cis-ring junction stereochemistry in
decalins 18e-h .
Key evidence supporting the rapid cyclization of 22e
rests on cyclizing the analogous dilithiated nitrile to a
trans-decalin (Scheme 8). Accessing the desired equato-
SCHEME 8. Tr a n s-Selective Nitr ile An ion
“An n u la tion ”
Con clu sion
ω-Haloalkyl Grignard reagents trigger chelation-
controlled annulations with 5- and 6-membered cyclic
alkenenitriles that are derived from an unusual rear-
rangement of unsaturated silyl cyanohydrins. The an-
nulation generates cis-fused octalins, hydrindanes, and
decalins with complete control over the two newly
installed stereocenters. Collectively, the conjugate addi-
tion-alkylation provides the first general annulation of
alkenenitriles, affording substituted bicyclic nitriles that
are ideal precursors for terpenoid syntheses.
rial precursor 26 was achieved through the conjugate
addition of a TBDPS-containing Grignard reagent to 1b
where the TBDPSO-substituent allows a conformational
equilibration after the conjugate addition without pre-
mature cyclization.39 Subsequent silyl ether cleavage and
chlorination provides the chloride 26 with the chlorobutyl
group in the requisite equatorial conformation. Depro-
Ack n ow led gm en t. Financial support of this re-
search from NIH and travel funds from NSF are
gratefully acknowledged.
(36) Presumably addition of the homologous Grignard 17b to 1a does
not require conjugate addition through the ate complex since 17b is
more reactive than 17a . The greater nucleophilicity of 17b could stem
from better internal chelationa with the pendant chloride that increases
the electron density on magnesiumb that is relayed into a greater
nucleophilicity of the adjacent carbon-magnesium bond. (a) For
internal chelation of Grignard reagents, see: Bickelhaupt, F. In
Grignard Reagents: New Developments; Richey, H. G., J r., Ed.;
Wiley: Chichester, 2000; Chapter 9. (b) For an analogous activation
of dialkylzincs by ligation, see: Reddy, C. K.; Devasagayaraj. A.;
Knochel, P. Tetrahedron Lett. 1996, 37, 4495.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, 1H NMR and 13C NMR spectra for all new compounds,
and an ORTEP for 18f. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0345291
(37) Fleming, F. F.; Shook, B. C. J . Org. Chem. 2002, 67, 2885.
(38) Attempts to intercept 22e by premature protonation afforded
only recovered 1b and decalin 18e.
(40) Fleming, F. F.; Shook, B. C.; J iang, T.; Steward, O. W.
Tetrahedron 2003, 59,737.
(41) Cyclization of the experimentally more accessible dilithiated
nitrile 22e, rather than the dimagnesiated nitrile 22e (Li ) MgX), does
not rule out the possible influence of different aggregation effects that
may influence the stereoselectivity.
(39) The stereochemical assignment is based on a 1H NMR coupling
constant analysis and by analogy to the conformational preferences of
closely related nitriles.9a
7650 J . Org. Chem., Vol. 68, No. 20, 2003