Cis and trans selective 1,4-addition of a lithium dithioester enolate to 4-O-TBS-2-cyclohexenone

Article abstract of DOI:10.1021/ol0611090

The 1,4-addition of the lithium enolate of methyldithioacetate (LMDTA) to (±)-4-O-TBS-2-cyclohexenone (3) can be varied from being highly 3,4-trans selective to being highly 3,4-cis selective simply by varying the reaction temperature. This stereodivergen

Full text of DOI:10.1021/ol0611090

ORGANIC
LETTERS
2
006
Vol. 8, No. 18
891-3894
Cis and Trans Selective 1,4-Addition of
a Lithium Dithioester Enolate to
3
4-O-TBS-2-cyclohexenone
Alan C. Spivey,*,† Laetitia J. Martin, Damian M. Grainger, Jo
Andrew J. P. White
†
†
1
rg Ortner, and
‡
†
Department of Chemistry, South Kensington Campus, Imperial College, London SW7
AZ, United Kingdom, and Department of Chemistry, UniVersity of Sheffield,
2
Brook Hill, Sheffield S3 7HF, United Kingdom
a.c.spiVey@imperial.ac.uk
Received May 5, 2006
ABSTRACT
The 1,4-addition of the lithium enolate of methyldithioacetate (LMDTA) to (±)-4-O-TBS-2-cyclohexenone (3) can be varied from being highly
3,4-trans selective to being highly 3,4-cis selective simply by varying the reaction temperature. This stereodivergency allows expedient syntheses
of the corresponding trans and cis methyl esters 6t and 6c and derived bicyclic ketolactones 7t and 7c.
3
The 1,4-addition of carbon-based nucleophiles to 2,3-
unsaturated carbonyl compounds constitutes a powerful
CsC bond forming reaction for synthesis. 4-Substituted
enones. The origin of the trans selectivity has been attributed
to initial reversible formation of diastereomeric d-π* Cu-
(III) complexes followed by preferential insertion by the trans
complex on steric grounds. The enolates formed from
1
4
2-cyclohexenones are a particularly well-studied class of
substrates because the enolates generated by these reactions
have found widespread use in target orientated synthesis.
Control of the relative stereochemistry between C3 and C4
and the ability to trap the enolates with electrophiles at
oxygen or stereoselectively at C2 is critical for maximum
versatility.
3
organocopper additions (e.g., using RCu‚BF ) are rather
2
5
unreactive toward electrophile trapping reactions, but the
enolates resulting from HO and LO cuprate additions
6
generally participate efficiently.
(3) The situation for substrates containing a quaternary C- and O-
substituted 4-stereocenter is more complex: 1,4-addition of Me2CuLi/Et2-
CuLi to cyclohexenone γ-spiroacetal gave cis selectivity relative to the
O-substituent in the absence of TMSCl but trans selectivity in the presence
of TMSCl. See ref 4a and Jameleddine, K.; Yakdhan, K.; Jamil, K.; Bechir,
B. H.; Denis, G. Synth. Commun. 2002, 32, 2719-2722.
The most widely studied classes of C nucleophiles are
organocopper, higher order (HO) cuprate, and lower order
1
(
LO) cuprate reagents. These reagents all react with high
(
4) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015-
levels of 3,4-trans selectivity for 4-substituted 2-cyclohex-
6
018. (b) Hareau-Vittini, G.; Hikichi, S.; Sato, F. Angew. Chem., Int. Ed.
1
998, 37, 2099-2101.
†
Imperial College.
University of Sheffield.
(5) William, A. D.; Kobayashi, Y. Org. Lett. 2001, 3, 2017-2020.
(6) (a) McMurray, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-
‡
(
1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, U.K., 1992.
2) Lopez-Pelegrin, J. A.; Janda, K. D. Chem.sEur. J. 2000, 6, 1917-
922 and references therein.
982. (b) Polniaszek, R. P.; Dillard, L. W. J. Org. Chem. 1992, 57, 4103-
4110. (c) Comins, D. L.; Dehghani, A. Tetahedron Lett. 1992, 33, 6299-
6302. (d) Comins, D. L.; Al-awar, R. S. J. Org. Chem. 1995, 60, 711-
716.
(
1
1
0.1021/ol0611090 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/12/2006

By contrast, just two cis selective 1,4-addition protocols
for 4-substituted 2-cyclohexenones have been developed.
might result in cis selective addition to 4-alkoxy enones by
analogy with the proposed role of Al in some cis selective
additions of alkynyl and trialkyl aluminum reagents to
7
2
The first was Danishefsky et al.’s HgI catalyzed cis addition
8
15
of silyl ketene acetals to 4-O-siloxy-2-cyclohexenones, and
the second was Liotta et al.’s Mg-alkoxide promoted cis-
3-alkoxy-2-cyclopentenones.
Preliminary experiments established that the lithium eno-
late of methyldithioacetate (LMDTA) underwent smooth 1,4-
addition to 2-cyclohexenone (1) in THF at -78 °C and that
the resulting enolate could be trapped using Comins’ reagent
to give the vinyl triflate 2 in 83% yield (Scheme 2).
addition of alkyl and aryl Grignard reagents to 4-hydroxy-
9
2
-cyclohexenones. The Liotta method was originally de-
veloped for substrates having a tert-hydroxyl directing group
but has subsequently been used by White with a sec-hydroxyl
directing group10 (Scheme 1).
Scheme 2. 1,4-Addition of LMDTA to 2-Cyclohenenone (1)
Scheme 1. Stereoselective Conjugate Addition Reactions to
and Trapping with Comins’ Reagent
Cyclic 4-Alkoxy Enones
Applying the same conditions but using (()-4-O-TBS-2-
cyclohexenone (3) as the substrate and initially quenching
4
with aqueous NH Cl we were intrigued to find that two
Danishefsky et al. ascribed the cis selectivity in their silyl
ketene acetal additions to stereoelectronically controlled
isomeric products 4 and 5 were formed exclusively depend-
ing on whether the reactions were quenched at -78 °C or
after warming to room temperature, respectively (Scheme
8
c,11
attack anti to the best σ donor (i.e., σCH not σCO).
Swiss
and Liotta proposed association of the nucleophile with
hydroxy function then intramolecular delivery in their
3
).
9
b
protocol.
In connection with a total synthesis program directed
Scheme 3. 1,4-Addition of LMDTA to
12
toward the synthesis of Amaryllidaceae alkaloids we were
interested in developing a method for cis selective 1,4-
addition of a functionalized 2-carbon nucleophile to a 4-O-
TBS-2-cyclohexenone under conditions which would allow
for the trapping of the resulting enolate at oxygen as the
vinyl triflate. Neither of the aforementioned methods proved
suitable so we sought to develop a new protocol.
(
()-4-O-TBS-2-cyclohexenone (3)sNH
4
Cl Quench at -78 °C
and after Warming to Room Temperature
Metzner has shown that lithium dithioester enolates
13
undergo smooth 1,4-addition to a range of enones including
trans selective 1,4-addition (dr 94:6) to 4-methyl-2-cyclo-
hexenone.14 We envisaged that the high oxaphilicity of Li
(7) More recently, Yamazaki reported that 1,4-addition of the potassium
enolate of cyanoethyl acetate to enone 3 proceeded with moderate cis
selectivity (dr 73:22); no rationale was proposed: Yamazaki, N.; Kusangagi,
T.; Kibayashi, C. Tetahedron Lett. 2004, 45, 6509-6512.
As we were unable to establish the relative stereochem-
istries between C3 and C4 in the products 4 and 5 by NOE
measurements, the stereochemical assignments for these
products were established by conversion to the novel trans
ketolactone 7t and the known cis ketolactone 7c, respectively.
(8) (a) Danishefsky, S. J.; Simoneau, B. Pure Appl. Chem. 1988, 60,
1
555-1562. (b) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989,
1
11, 2599-2604. (c) Jeroncic, L. O.; Cabal, M. P.; Danishefsky, S. J. J.
Org. Chem. 1991, 56, 387-395.
(9) (a) Solomon, M.; Jamison, W. C. L.; McCormick, M.; Liotta, D.;
16
This involved HgO-mediated conversion to the isomeric
Cherry, D. A.; Mills, J. E.; Shah, R. D.; Rodgers, J. D.; Maryanoff, C. A.
J. Am. Chem. Soc. 1988, 110, 3702-3704. (b) Swiss, K. A.; Liotta, D. C.
J. Am. Chem. Soc. 1990, 112, 9393-9394. (c) Swiss, K. A.; Hinkley, W.;
Maryanoff, C. A.; Liotta, D. C. Synthesis 1992, 127-131. (d) Booker-
Milburn, K. I.; Jenkins, H.; Charmant, J. P. H.; Mohr, P. Org. Lett. 2003,
(14) Berrada, S.; Metzner, P. Bull. Soc. Chim. Fr. 1986, 817-821.
(15) (a) Pappo, R.; Collins, P. W. Tetahedron Lett. 1972, 2627-2630.
(b) Collins, P. W.; Dajani, E. Z.; Bruhn, M. S.; Brown, C. H.; Palmer, J.
R.; Pappo, R. Terahedron Lett. 1975, 4217-4220. (c) Collins, P. W.; Dajani,
E. Z.; Driskill, D. R.; Bruhn, M. S.; Jung, C. J.; Pappo, R. J. Med. Chem.
1977, 20, 1152-1159. (d) Caddick, S.; Delisser, V. M. Terahedron Lett.
1997, 38, 2355-2358. (e) Yakura, T.; Tanaka, K.; Iwamoto, M.; Nameki,
M.; Ikeda, M. Synlett 1999, 1313-1315. (f) Yakura, T.; Tanaka, K.; Kitano,
T.; Uenishi, J.; Ikeda, M. Tetrahedron 2000, 56, 7715-7721.
5
, 3309-3312.
(10) White, J. D. Pure Appl. Chem. 1994, 2183-2188.
(11) Cieplak, A. S. Chem. ReV. 1999, 99, 1265-1336.
(12) Rinner, U.; Hudlicky, T. Synlett 2005, 365-387.
(13) (a) Metzner, P. Synthesis 1992, 1185-1199. (b) Berrada, S.; Desert,
S.; Metzner, P. Tetrahedron 1988, 44, 3575-3586. (c) Berrada, S.; Metzner,
P.; Rakotonirina, R. Bull. Soc. Chim. Fr. 1985, 881-890.
(16) Jung, M. E.; Parker, M. H. J. Org. Chem. 1997, 62, 7094-7095.
3892
Org. Lett., Vol. 8, No. 18, 2006

methyl esters 6t and 6c17 and then acid mediated TBS
deprotection/lactonization18 (Scheme 4).
Scheme 4. Confirmation of Relative Stereochemistry (at C3
and C4) for Products 4 and 5
Figure 2. Molecular structure of one (I) of the two independent
1
9
molecules present in the crystals of cis 1,4-addition product 5.
Variation of the temperature at which the conjugate
addition reactions were quenched with NH Cl revealed that
4
trans product 4 is obtained exclusively when the reaction is
quenched at below ca. -45 °C but that on warming above
this temperature the cis product 5 is increasingly formed.
Quenching with Comins’ reagent at -78 °C allowed the
isolation of trans vinyl triflate 9 in 72% yield, but quenching
with this reagent at room temperature resulted in the
formation of cis product 5 (40%) along with some labile
products that we were unable to isolate (Scheme 5).
The identity of trans ketolactone 7t was secured with a
single-crystal X-ray structure determination (Figure 1 and
Scheme 5. 1,4-Addition of LMDTA to
a
(
()-4-O-TBS-2-cyclohexenone (3) sTrapping with Comins’
Reagent at -78 °C and Attempted Trapping after Warming to
Room Temperature
Figure 1. Molecular structure of trans ketolactone 7t.
Supporting Information) whereas the identity of cis keto-
lactone 7c was confirmed by re-synthesis according to the
19
method of Danishefsky (3 f 8 f 6c f 7c) and also
comparison with Danishefsky’s published data.8
Additionally, the relative stereochemistry and identity of
cis addition product 5 was unambiguously established by a
single-crystal X-ray structure determination (Figure 2 and
Supporting Information).20
c
These results are inconsistent with our original idea that
coordination between the lithium of the dithioester enolate
and the 4-siloxy group would direct cis addition; the
mechanistic situation is clearly more complex. A possible
mechanism is outlined below (Scheme 6).
(17) Interestingly, trans TBS ether 6t is very prone to desilylation on
silica to give the corresponding alcohol whereas cis TBS ether 6c is not.
The trans alcohol can, however, also be readily cyclized to trans lactone 7t
Thus, the trans product 4 is probably formed by direct
protonation of the kinetic trans enolate 10t at low temper-
ature. The cis product 5 may be formed by isomerization of
this initially formed trans enolate 10t, on warming, to the
(
68%); see Supporting Information.
18) TBS ether deprotection/lactonization was performed essentially as
in ref 8c but using HCl in place of HF.
19) We used CH2C(OMe)OTBS rather than CH2C(OEt)OTBS and,
therefore, obtained the Me ester (cf. Et ester in ref 8c).
20) Compound 5 crystallized with two independent molecules (I and
(
(
1
cis enolate 10c via retro-1,4-addition/re-addition and then
(
irreversible intramolecular ketone to dithioester enolate
exchange (10cψax-eq f 11). Intramolecular ketone enolate
to dithioester enolate exchange has been proposed previously
by Metzner who also noted that it occurs at about -45 °C
II) in the asymmetric unit; molecule I is shown in Figure 2, and molecule
II is shown in Figure S2 in the Supporting Information. The two molecules
have essentially identical geometries (excluding the disorder in molecule
IIssee the Supporting Information) as can be seen by comparing the two
images.
Org. Lett., Vol. 8, No. 18, 2006
3893

cyclization (12 f 13), and then isomerization of the
tetrahydropyran-2-thione 14 formed on protonation to the
1-methylsulfanyl-2-thiabicyclo[3.3.1]nonan-3-one product 5.
Irrespective of the mechanistic nuances, the thermally
stereodivergent behavior of LMDTA toward 1,4-addition to
Scheme 6. Possible Pathway for the Formation of trans and
cis Isomers 4 and 5
4
-O-TBS-2-cyclohexenone (3) provides expedient access to
the trans and cis 3,4-functionalized cyclohexanone esters 6t
and 6c and the corresponding ketolactones 7t and 7c from a
common precursor. The generality of this stereodivergent
behavior with respect to the nature of the C4 substituent is
2
2
under current investigation in our laboratories.
The rare syn selective addition process is synthetically
complementary to that of Danishefsky which provides silyl
enol ether products from the same 4-O-TBS ether substrates
and to that of Liotta which requires the use of 4-hydroxy-
2
-enones, which in our experience are often labile species.23
Although using the current method only the anti vinyl triflate
could be trapped-out as originally envisaged, the cis
9
addition protocol has proved uniquely suited to our approach
to Amaryllidaceae alkaloids as will be reported in due course.
Acknowledgment. Grateful acknowledgment is made to
Imperial College London, the EPSRC, F.Hoffmann-La
Roche, Basel, and Sanofi-aventis, Alnwick, for financial
support of this work.
following 1,4-addition of dithioester enolates to acyclic
1
3b
enones. It appears that that in our case the cis enolate
conformer 10cψax-eq required for intramolecular exchange to
the dithioester 11 is lower in energy by a sufficient amount
relative to the corresponding trans enolate conformer 10tψax-ax
to allow selective bleeding of the cis enolate from the
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 2-9 and
crystallographic data for compounds 5 and 7t. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0611090
21
equilibrium. The subsequent steps could involve thioketene
formation (11 f 12), methyl thiolate triggered 6-exo-dig
(22) Cyclization to the 1-methylsulfanyl-2-thiabicyclo[3.3.1]nonan-3-one
ring system (cf. 5) on warming does not require the presence of a
4-substituent; using 2-cyclohexenone itself cyclization also ensues (Spivey,
A. C.; Martin, L. J. Unpublished).
(23) Spivey, A. C.; Gir o´ Ma n˜ as, C.; Mann, I. Chem. Commun. 2005,
4426-4428.
(
21) Enolates 10cψax-eq and 10tψax-ax differ in the orientation of their
respective 4-O-TBS substituents (equatorial vs axial); an O-TMS substituent
has an A value of 3.1 kJ mol ; see Stereochemistry of Organic Compounds;
Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1994; p 696.
-1
3894
Org. Lett., Vol. 8, No. 18, 2006