A sterically-encumbered, C2-symmetric chiral acetal for enhanced asymmetric induction in the Pauson-Khand reaction

Article abstract of DOI:10.1021/jo0263667

High levels of diastereoselection were achieved in the PKR, of 1,6- and 1,7-cyclopropylidenynes bearing a bulky propargylic C₂-symmetric acetal.

Full text of DOI:10.1021/jo0263667

ethers of Oppolzer’s 3-(neopentyloxy)isoborneol also in-
duced a highly diastereoselective PKR,7 as shown in the
syntheses of angular triquinane ring systems10 and (+)-
15-norpentalenene.11 The technology later evolved to the
use of sulfur-containing chiral auxiliaries, where the first
generation of this type, N-(2-alkynoyl) derivatives of
chiral oxazolidinones and sultams, e.g., Oppolzer’s 10,2-
camphorsultam, promoted exceptionally high levels of
regio- and stereoselective intermolecular PKR.12 A sulfi-
nyl group, when bound to the alkene, induced complete
stereoselectivity in the intramolecular variant,13 and a
phenylsulfonyl group in 3-oxygenated 1,6-enynes ren-
dered endo stereochemical control.14 Optically pure alkyn-
yl p-tolyl sulfoxides resulted only in moderate yields and
low selectivities in intermolecular PKRs.15 Similarly,
chiral acetylene thioethers provided low selectivity in
both inter- and intramolecular cyclizations.16 Finally, a
new generation of chelating auxiliaries derived from
camphor has emerged that combines the advantages of
strategies (a) and (b) and benefits from the directed (or
chelated)-PKR technology.11,17,18
Meanwhile, de Meijere and co-workers reported the
construction of an enantiopure spiro(cyclopropane-1,4′-
bicyclo[3.3.0]oct-1-en-3-one), 4, derived from a diastereo-
selective PKR of a 1,6-cyclopropylidenyne bearing a
propargylic C2-symmetric chiral acetal (Scheme 1).19,20 It
was conceived that a larger alkyl group (R ) C(CH3)2-
OCH3)21 in a tartrate-derived chiral auxiliary, as in diol
5, should improve the diastereoselectivity of the cycload-
dition. Herein, we disclose our studies toward this end,
including its scope, limitations, and implications.
A Ster ica lly-En cu m ber ed , C2-Sym m etr ic
Ch ir a l Aceta l for En h a n ced Asym m etr ic
In d u ction in th e P a u son -Kh a n d Rea ction
Marie E. Krafft,* Llorente V. R. Bon˜aga,
Andrew S. Felts, Chitaru Hirosawa, and Sean Kerrigan
Department of Chemistry and Biochemistry, The Florida
State University, Tallahassee, Florida 32306-4390
mek@chem.fsu.edu
Received August 28, 2002
Abstr a ct: High levels of diastereoselection were achieved
in the PKR of 1,6- and 1,7-cyclopropylidenynes bearing a
bulky propargylic C2-symmetric acetal.
Asymmetric induction to generate optically active
cyclopentenones is an ongoing challenge in the Pauson-
Khand reaction (PKR).1,2 Undeniably, realization of this
goal augments the already high synthetic value of this
method. Approaches envisaged in achieving varying
degrees of asymmetry in the cobalt-mediated PKR in-
clude (a) utility of a chiral auxiliary bound to either
reacting units, (b) generation of cobalt complexes pos-
sessing a disymmetric C2Co2 core,3 (c) addition of a chiral
promoter or coordinating ligand,4 and (d) a combination
of the first two strategies.5
Our study relies on the first strategy in which a chiral
auxiliary is incorporated as a control element adjacent
to the alkyne moiety. Used in early studies on stereo-
selective PKRs, chiral trans-2-phenylcyclohexanol6,7 was
successfully applied to the syntheses of (+)-hirsutene,6
(+)-â-cuparenone,8 and (+)-brefeldin A.9 Enol and ynol
The chiral diol 5 was prepared directly from (+)-
dimethyl-L-tartrate, 1.21 Synthesis of the (cyclopropy-
lidenepropyl)ethynyl dioxolanes parallels the route de-
scribed by de Meijere (Scheme 2). Benzyl 4-cyclopropyli-
denebutanoate 7 was best prepared from the Wittig
reaction of benzyl 4-oxobutanoate ester and cyclopropy-
(1) For recent reviews on the PKR, see: (a) Brummond, K. M.; Kent,
J . L. Tetrahedron 2000, 56, 3263. (b) Fletcher, A. J .; Christie, S. D. R.
J . Chem. Soc., Perkin Trans. 1 2000, 1657. For leading references on
asymmetric PKR, see: (c) Ingate, S. T.; Marco-Contelles, J . Org. Prep.
Proced. Int. 1998, 30, 123. (d) Kennedy, A. R.; Kerr, W. J .; Lindsay, D.
M.; Scott, J . S.; Watson, S. P. J . Chem. Soc., Perkin Trans. 1 2000,
4366. (e) Isamu, M. Organomet. News 2001, 1, 16.
(2) For references on asymmetric PK-type reactions of enynes, see:
(a) Buchwald, S. L.; Hicks, F. A. In Comprehensive Asymmetric
Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlag, 1999; Vol. II, p 491. (b) Shibata, T.; Takagi, K. J . Am.
Chem. Soc. 2000, 122, 9852. (c) J eong, N.; Sung, B. K.; Choi, K. Y. J .
Am. Chem. Soc. 2000, 122, 6771.
(3) (a) Carbery, D. R.; Kerr, W. J .; Lindsay, D. M.; Scott, J . S.;
Watson, S. P. Tetrahedron Lett. 2000, 41, 3235. (b) Balsells, J .;
Vazquez, J .; Moyano, A.; Pericas, M. A.; Riera, A. J . Org. Chem. 2000,
65, 7291. (c) Gimbert, Y.; Robert, F.; Durif, A.; Averbuch, M.-T.; Kann,
N.; Greene, A. E. J . Org. Chem. 1999, 64, 3492. (d) Hiroi, K.; Watanabe,
T. Tetrahedron Lett. 2000, 41, 3935. (e) Fletcher, A. J .; Rutherford, D.
T.; Christie, S. D. R. Synlett 2000, 1040.
(4) Chiral amine-N-oxide, see: (a) Kerr, W. J .; Lindsay, D. M.;
Rankin, E. M.; Scott, J . S.; Watson, S. P. Tetrahedron Lett. 2000, 41,
3229. (b) Derdau, V.; Laschat, S. J . Organomet. Chem. 2002, 642, 131.
Chiral phosphine in the catalytic enantioselective PKR using Co2(CO)8,
see: (c) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron:
Asymmetry 2000, 11, 797. For references on cobalt phosphite asym-
metric PKR, see: (d) Sturla, S.; Buchwald, S. J . Org. Chem. 2002, 67,
3398.
(8) Castro, J .; Moyano, A.; Pericas, M. A.; Riera, A.; Greene, A. E.;
Alvarez-Larena, A.; Piniella, J . F. J . Org. Chem. 1996, 61, 9016.
(9) Bernardes, V.; Kann, N.; Riera, A.; Moyano, A.; Pericas, M. A.;
Greene, A. E. J . Org. Chem. 1995, 60, 6670.
(10) Tormo, J .; Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron 1996, 52, 14021.
(11) Tormo, J .; Moyano, A.; Pericas, M. A.; Riera, A. J . Org. Chem.
1997, 62, 4851.
(12) Fonquerna, S.; Rios, R.; Moyano, A.; Pericas, M. A.; Riera, A.
Eur. J . Org. Chem. 1999, 3459, 9.
(13) Carretero, J . C.; Adrio, J . Synthesis 2001, 12, 1888.
(14) Carretero, J . C.; Adrio, J . Angew. Chem., Int. Ed. 2000, 39, 2906.
(15) Montenegro, E.; Moyano, A.; Pericas, M. A.; Riera, A.; Alvarez-
Larena, A.; Piniella, J . Tetrahedron: Asymmetry 1999, 10, 457.
(16) Montenegro, E.; Poch, M.; Moyano, A.; Pericas, M. A.; Riera,
A. Tetrahedron 1997, 53, 8651.
(17) Krafft, M. E.; J uliano, C. A.; Scott, I. L.; Wright. C. J . Am.
Chem. Soc. 1991, 113, 1693.
(18) (a) Montenegro, E.; Poch, M.; Moyano, A.; Pericas, M. A.; Riera,
A. Tetrahedron Lett. 1998, 39, 335. (b) Verdaguer, X.; Vazquez, J .;
Fuster, G.; Bernardes-Genisson, V.; Greene, A. E.; Moyano, A.; Pericas,
M. A.; Riera, A. J . Org. Chem. 1998, 63, 7037.
(5) Marchueta, I.; Montenegro, E.; Panov, D.; Poch, M.; Verdaguer,
X.; Moyano, A.; Pericas, M. A.; Riera, A. J . Org. Chem. 2001, 66, 6400.
(6) Castro, J .; Sorensen, H.; Riera, A.; Morin, C.; Moyano, A.; Pericas,
M. A.; Greene, A. E. J . Am. Chem. Soc. 1990, 112, 9388.
(7) Less asymmetric influence was observed when appended to the
alkyne moiety of a 1,6-enyne. Verdaguer, X.; Moyano, A.; Pericas, M.
A.; Riera, A.; Greene, A. E.; Piniella, J . F.; Alvarez-Larena, A. J .
Organomet. Chem. 1992, 433, 305.
(19) (a) Stolle, A.; Becker, H.; Salaun, J .; de Meijere, A. Tetrahedron
Lett. 1994, 35, 3521. (b) Becker, H. Ph.D. Dissertation, Institut fur
Organische Chemie, Georg-August-Universitat Gottingen, 1996.
(20) (a) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990,
1, 477. (b) Whitesell, J . K. Chem. Rev. 1989, 89, 1581.
(21) (a) Mash, E. A.; Hemperly, S. B.; Nelson, K. A.; Heidt, P. C.;
Van Deusen, S. J . Org. Chem. 1990, 55, 2045. (b) Chikashita, H.;
Yuasa, T.; Itoh, K. Chem. Lett. 1992, 1457.
10.1021/jo0263667 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/26/2003
J . Org. Chem. 2003, 68, 6039-6042
6039

SCHEME 1a
TABLE 1
% yield
(diastereomer
ratio)c
NMO-mediated cyclization
conditionsa
entry
79 (1:10)d
b
1
2
3
4
5 equiv of NMO (solid), 0.03 M CH2Cl2
5 equiv of NMO, 0.03 M CH2Cl2
5 equiv of NMO, 0.003 M CH2Cl2
1 equiv of NMO (5×), 1.5 h interval,
0.03 M CH2Cl2
68 (1:15-20)e
65 (1:10-13)e
58 (1:11)f
a
Key: (i) Co2(CO)8; (ii) CH2Cl2, rt, 6 equiv of NMO (Ar, 10 h)
5
1.5 equiv of NMO (5×), 1.5 h interval,
64 (1:9)
or 5 equiv of Me3NO (O2, 12-16 h).
0.03 M CH2Cl2, 0 °C to rt
SCHEME 2a
a
All reactions were conducted under an Ar atmosphere at rt
unless specified. Reaction conditions as reported by de Meijere.6
b
c Determined from 300 MHz 1H NMR spectroscopy. Average
d
chromatographed yields of the major diastereomer from three
trials. e four trials. f two trials.
SCHEME 36,a
a
Reagents and conditions: (a) benzyl alcohol, benzene, reflux,
99%; (b) (i) O3, CH2Cl2, -78 °C, (ii) Me2S, Et3N, -78 °C to rt, 80%
to quant; (c) cyclopropyltriphenylphosphonium bromide, NaH, cat.
TDA-1, THF, reflux, 68%; (d) (i) 8 or 9, n-BuLi, THF, -78 °C, (ii)
7 and then BF3‚Et2O, -78 °C to rt, 10: 71%; 11: 78%; (e) 5 or 12,
i-PrOTMS, catalytic TMSOTf, CH2Cl2, -30 °C to rt, 13: 74%; 15:
98%; 16: 30%; (f) HF/pyridine, acetonitrile, 14, 85%.
a
Reagents and conditions: (a) Me2CuLi, Et2O, 0 °C, 92%; (b)
25 mol % pTSA, acetone, rt, 85%; (c) 60 mol % pTSA, acetone, 65
°C, 45%.
a more sterically hindered chiral auxiliary from diol 5.
Despite its high degree of substitution, the dicobalt-
hexacarbonyl complex of enyne 13 cyclized quite well
providing 58-79% yields of the major diastereomer.
Results indicated higher diastereomeric ratios of the
products (1:15-20) when NMO was added as a solution
in CH2Cl2 rather than as a solid (entry 2 vs 1). Dilution
of the reaction mixture resulted in a slight erosion of
selectivity (entry 2 vs 3). Incremental addition of NMO
as a solution in CH2Cl2 at ambient temperature (entry
4), and at 0 °C with subsequent warming to ambient
temperature (entry 5) gave lower selectivities and yields.
Several important observations were made in these
studies. First, addition of the oxidant (NMO) as a solid
resulted in a lower selectivity compared to addition as a
solution (Table 1, entry 1 vs 2). Second, using our best
reaction conditions (Table 1, entry 2), cyclization of enyne
15 occurred with lower diastereoselectivity (1:10) than
cyclization of enyne 13. In our hands, cyclization of 15
under de Meijere’s conditions19 gave the major diastere-
omer in 68% yield (1:5 dr), which is in agreement with
their findings. Third, only 42% of the major diastereomer
was isolated from a mixture of two diastereomers and
decomplexed starting material (3:1:1) obtained after
thermal reactions (0.02 M in toluene, 105 °C, N2).
To ascertain the absolute configuration of the newly
generated asymmetric center, the major diastereomer 17
was subjected to a series of transformations as previously
described (Scheme 3).19 De Meijere observed that direct
hydrolysis of the acetal in 18 resulted in not only an
lidene triphenylphosphorane, in the presence of tris[2-
(2-methoxyethoxy)ethyl]amine (TDA-1) as a phase-
transfer catalyst.22 For optimal results in the Wittig
reaction, we determined that a large excess of dry Wittig
salt (6-10 equiv), generation of the phosphorane under
refluxing conditions for an extended period of time (8-
10 h), and use of a phase-transfer catalyst, TDA-1, were
required. 6-Cyclopropylidene-1-hexyne-3-ones 10 and 11
were synthesized by reactions of ester 7 with the corre-
sponding lithium alkynyltrifluoroborates of 8 and 9,
prepared in situ by addition of BF3‚Et2O to the corre-
sponding lithium acetylides at -78 °C in THF.23
A
modified Noyori acetal formation of 10 and 11 with diols
5 or 12 using iPrOTMS and catalytic amounts of TMSOTf
afforded the appropriate acetals 13, 15, and 16.24 Com-
pound 14 bearing a terminal alkyne moiety was easily
obtained from desilylation of enyne 13.
A series of N-methylmorpholine-N-oxide (NMO)-pro-
moted PK reactions with the preformed dicobalthexa-
carbonyl complex of chiral (cyclopropylidenepropyl)eth-
ynyldioxolane 13 was carried out to survey the optimal
reaction conditions for diastereoselection (Table 1). Re-
sults show the reproducibility and high diastereoselec-
tivity in the PK reactions of 13 indicating marked
improvement over the previous report as a result of using
(22) Stafford, J . A.; McMurry, J . E. Tetrahedron Lett. 1988, 29, 2531.
(23) Yamaguchi, M.; Shibato, K.; Fujiwara, S.; Hirao, I. Synthesis
1986, 421.
(24) Kurihara, M.; Miyata, N. Chem. Lett. 1995, 263.
6040 J . Org. Chem., Vol. 68, No. 15, 2003

SCHEME 4
acetal cleavage but also double bond isomerization to give
the bicyclo[3.3.0]octenedione (eq 1).19 In our case, at-
tempted hydrolysis of the acetal moiety25 in enone 17
under the following reaction conditions only gave the
unreacted enone 17: (a) 5 mol % pTSA, acetone, ambient
temperature to reflux; (b) 25 mol % pTSA, acetone, reflux;
(c) 2 N HCl, THF, ambient temperature; and (d) acetone/
H2O/60% HClO4 (10:1:1), ambient temperature. Thus, 17
was functionalized as previously reported.19 Lithium
dimethylcuprate addition and followed by protiodesily-
lation of R-keto silane 19 furnished ketone 20 in high
yield. Subsequent acid-catalyzed hydrolysis of dioxolane
20 gave a good yield of dione 21 whose optical rotation
[R]20D ) -143 is consistent with the reported value.19 The
C-5 position in the cycloadduct generated in this fashion
was reported to have an R absolute configuration. As
indicated earlier the origin of this diastereoselectivity is
determined at the metallacycle-forming step in the
proposed mechanism of the PK reaction.19a
conditions, although de Meijere obtained the cycloadduct
of enyne 26 in 32% yield upon heating its cobalt complex
in acetonitrile at 80 °C. These results suggest that the
steric requirements imposed by the bulky auxiliary are
not the only factor contributing to its lack of reactivity,
as is also evident from the lack of reactivity of enyne 28.
In contrast, enyne 13 (vide supra) and keto enyne 10 (eq
3), both possessing the methylenecyclopropane moiety
furnished the cyclopentenone in good yields under the
NMO-promoted conditions. Meanwhile, the lack of reac-
tivity of an analogous isopropylidene moiety (R2 ) H,
R3 ) R4 ) CH3) is well precedented in the literature.29
Use of the activated methylenecyclopropane end group
as in enyne 13 provides an access to the dimethyl-
substituted bicyclopentenone ring upon reduction of the
spirocyclopropyl moiety in enone 17 or 29.30
We proceeded to investigate the effect of alkyl substi-
tution on the alkene and alkyne moieties on the stereo-
chemical outcome of the cyclization. As shown in Table
1 and eq 2, variation of the alkyne substituents (R′ ) H,
Ph, TMS) revealed the necessity of a bulky group, such
as TMS on the alkyne component to induce asymmetry.26
Enyne 14, bearing a terminal acetylene, cyclized non-
selectively, a result consistent with de Meijere’s findings
with the analogous desilylated 15.19 A marked improve-
ment in diastereoselection was observed when the alkyl
group was modified from R′ ) H (14) to the largest R′ )
TMS (13). These results indicate that the TMS group
could serve as a “pro-H” taking advantage of its high
diastereoselective influence in the PKR.27
We also investigated the cyclizations of the homologous
7-cyclopropylidene-1-heptyne-3-ones bearing the propar-
gylic acetal derived from diol 5. The chiral acetals of
7-cyclopropylidene-1-heptyne-3-ones 36 and 37 were
prepared in a straightforward manner from 5-hexen-1-
ol (Scheme 5), and the corresponding dicobalthexacar-
bonyl complexes were subjected to various PKR condi-
1
tions (Table 2). As is evident from the H NMR spectra
of the crude reaction mixtures using 36, only one dia-
stereomer could apparently be detected from all of the
conditions used. Similar results were also observed from
reaction of the analogous enyne 37, which was derived
from the less hindered chiral diol 12. Under the condi-
tions used in Table 2, we were not able to obtain the other
diastereomeric product in either case for spectral com-
parison. Enone 39 and its diastereomer, as prepared by
de Meijere,19 although indistinguishable by 1H NMR
spectroscopy and TLC, showed different resonances in
the 13C NMR spectrum. They ultimately determined the
structure of enone 39 by crystallographic separation and
X-ray crystallography.19 Enones 38 and 39 obtained using
our reaction conditions did not show any isomeric impu-
Changing the alkene substitution in these systems
further confirmed the enhanced reactivity observed from
methylenecyclopropane terminators in the PK reaction
(Scheme 4).28 It was noted by de Meijere’s studies that
enynes without this end group reacted poorly and only
under more drastic conditions (hexanes, 110 °C) to
provide the same selectivity. NMO-promoted or thermally
mediated cyclizations (with or without an additive) of the
dicobalthexacarbonyl complexes of enynes 24 and 25 gave
only decomplexed starting materials. Their corresponding
propargylic ketones 26 and 27 did not cyclize under these
1
rities in both the H and 13C NMR spectra.
(28) (a) Stolle, A.; Becker, H.; Salaun, J .; de Meijere, A. Tetrahedron
Lett. 1994, 35, 3517. See also: (b) Brase, S.; Schomenauer, S.;
McGaffin, G.; Stolle, A.; de Meijere, A. Chem. Eur. J . 1996, 2, 545. (c)
Zorn, C.; Anichini, B.; Goti, A.; Brandi, A.; Kozhushkov, S. I.; de
Meijere, A.; Citti, L. J . Org. Chem. 1999, 64, 7846. (d) Corlay, H.;
Fouquet, E.; Magnier, E.; Motherwell, W. B. J . Chem. Soc., Chem.
Commun. 1999, 183.
(25) Greene, T. W.; Wutts, P. G. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley and Sons: New York, 1999.
(26) Reported yields in eq 2 correspond to the mixture of diastere-
omers, and dr was determined by 300 MHz 1H NMR spectroscopy.
(27) Krafft, M. E.; Wright, C. Tetrahedron Lett. 1992, 33, 151.
(29) (a) Sugihara, T.; Yamaguchi, M. J . Am. Chem. Soc. 1998, 120,
10782. (b) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J . Am. Chem.
Soc. 1999, 121, 5881.
(30) Piers, E.; Karunaratne, V. J . Chem. Soc., Chem. Commun. 1984,
959.
J . Org. Chem, Vol. 68, No. 15, 2003 6041

i
SCHEME 5a
mL) were added successively PrOTMS (0.15 mL, 0.84 mmol)
and TMSOTf (4 drops). After being stirred for 14 h, with the
bath warming to ambient temperature, the mixture was quenched
with pyridine and poured into a solution of saturated NaHCO3.
It was then extracted with CH2Cl2 (3 × 15 mL), and the
combined organic layer was washed with brine, dried (MgSO4),
and plugged through a short pad of coarse silica gel. Concentra-
tion in vacuo and purification by flash chromatography (SiO2,
3% and then 2% EtOAc in hexanes) provided 40 mg of acetal 13
1
(74%). H NMR (CDCl3, 500 MHz): δ 5.82 (tdt, J ) 6.4, 4.1, 2.0
Hz, 1H), 4.14 (d, J ) 5.2 Hz, 1H), 4.00 (d, J ) 5.0 Hz, 1H), 3.22
(s, 3H), 3.21 (s, 3H), 2.43 (apparent dtm, J ) 6.2, 6.2 Hz, 2H),
2.04 (m, 2H), 1.29 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H), 1.17 (s, 3H),
1.02 (m, 4H). 13C NMR (CDCl3, 75 MHz): δ 120.87, 117.61,
105.22, 104.87, 88.16, 84.27, 83.90, 75.75, 75.38, 49.00, 48.78,
41.11, 26.81, 22.14, 21.75, 20.46, 19.92, 1.65, 1.58, -0.58. MS
[CI, m/z (rel intensity)]: 363.3 (100), 395.6 (M+ + 1, 24). Anal.
Calcd for C22H38O4Si: C, 66.96; H, 9.71. Found: C, 67.04; H,
a
Reagents and conditions: (a) TBSCl, Et3N, catalytic DMAP,
CH2Cl2, 97%; (b) (i) O3, CH2Cl2, (ii) Me2S, Et3N, 77%; (c) NaH,
cyclopropyltriphenylphosphonium bromide, catalytic TDA-1, THF,
reflux, 35%; (d) TBAF, THF, 80%; (e) PCC, CH2Cl2, 90%; (f)
TMSCCH, n-BuLi, THF, -78 °C to rt, 55%; (g) PCC, CH2Cl2, 83%;
(h) 5 or 12, i-PrOTMS, cat. TMSOTf, CH2Cl2, -30 °C to rt, 36,
65%; 37, 89%.
9.67. [R]20 -4.5 (c ) 1, CHCl3).
D
Rep r esen ta tive Exp er im en ta l P r oced u r es. In all of the
procedures described below, the dicobalthexacarbonyl complexed
enynes were prepared just prior to the reactions. A typical
procedure involved reaction of the enyne with the commercially
available Co2(CO)8 in petroleum ether (0.2 M) at ambient
temperature for 30 min or upon completion as determined by
TLC. The complex was then filtered through a short plug of
Celite (petroleum ether as solvent) and the solvent was removed
in vacuo at ambient temperature.
TABLE 2
Gen er a l P r oced u r es Used in Ta ble 1. In entry 1, to a
solution of the dicobalthexacarbonyl complex of enyne 13 (20
mg, 0.03 mmol) in CH2Cl2 (1.0 mL) was added NMO‚H2O (21
mg, 0.16 mmol) and the solution stirred at ambient temperature
for 18 h. It was then diluted with EtOAc (10 mL) and plugged
through a short pad of coarse silica gel. Concentration in vacuo
and purification by flash chromatography (SiO2, 3% EtOAc in
hexanes) afforded 10 mg of enone 17 (83%). In entries 2 and 3,
5 equiv of NMO‚H2O in CH2Cl2 (0.50 M) was added in one
portion to the reaction mixture (substrate concentration of 0.03
and 0.003 M, respectively). In entry 4, 1 equiv of a NMO-CH2-
Cl2 solution (0.50 M) was added five times to the reaction
mixture (0.03 M substrate concentration) at 1.5 h intervals at
ambient temperature. In entry 5, 1 equiv of a NMO-CH2Cl2
solution (0.50 M) was added five times to the reaction mixture
(0.03 M substrate concentration) at 1.5 h intervals at 0 °C and
the mixture warmed to ambient temperature. These reactions
were typically worked up after 15-20 h.
% yielda
entry
cyclization conditionsa
5 equiv of NMO (solid), 0.03 M CH2Cl2, rt, 18 h 41 ND
5 equiv of NMO, 0.03 M CH2Cl2, rt, 18 h 94 85
38 39
1
2
3
4
5
5 equiv of Me3NO, 0.03 M CH2Cl2, -78 °C, 18 h 88 91
0.02 M toluene, 90-105 °C, N2 1 h
9 equiv of CyNH2, 0.01 M DCE reflux, N2,
30 min
63 89
ND 73
a
Average of two or three trials. ND ) not determined.
Comparison of the cyclizations of 6-cyclopropylidene-
1-trimethylsilyl-3-one acetal and the 7-cyclopropylidene
analogue shows better diastereoselectivity in the latter
system, as was noted by de Meijere (Scheme 1).19b In our
case, when we subjected enynes 13 and 36 to de Meijere’s
reaction conditions (cf. Table 1, entries 1 and 2, and Table
2, entries 1 and 2) we also observed higher ratios of dia-
stereomeric enones in both ring sizes using the more hin-
dered acetal. Other reaction conditions used for the cycli-
zation of 36 also gave high yields of one diastereomer.
In summary, as first reported by de Meijere, diaste-
reoselective cyclizations of 1,6- and 1,7-cyclopropylide-
nynones bearing chiral C2-symmetric acetals of propar-
gylic ketones could be achieved in the PKR. We, on the
other hand, have further shown that more sterically
demanding substituents on the tartrate-derived auxiliary
enhanced the stereoselection without loss of efficiency.
In addition to the bulky substituent on the alkyne moiety,
it was also demonstrated that the methylenecyclopropyl
group in the precursor enyne is essential to reactivity of
this system in the PKR. We have also provided modified
reaction conditions to the ones originally reported that
achieved optimal diastereoselection in the cyclizations.
En on e 17 was prepared according to the procedures described
above and obtained as the major diastereomer. 1H NMR (CDCl3,
500 MHz): δ 4.14 (d, J ) 5.0 Hz, 1H, CHO), 4.09 (d, J ) 5.0 Hz,
1H, CHO), 3.22 (s, 3H, OCH3), 3.17 (s, 3H, OCH3), 3.13 (t, J )
9.6 Hz, 1H, CHCH2), 2.18 (ddd, J ) 14.9, 9.6, 5.3 Hz, 1H, O2-
CCHH), 2.05 (br dddd, J ) 14.0, 11.2, 5.3, 0.9 Hz, 1H, O2CCHH),
1.88 (dtd, J ) 12.4, 9.6, 5.3 Hz, 1H, CHHCH), 1.31-1.25 (m,
2H, 1 Cpr H, CHHCH), 1.23 (s, 3H, C(CH3)O), 1.17 (s, 6H, 2
C(CH3)O), 1.14 (s, 3H, C(CH3)O), 0.88-0.99 (m, 3H, 3 Cpr-H),
0.24 (s, 9H, Si(CH3)3). 13C NMR (CDCl3, 75 MHz): δ 214.00,
190.21, 133.93, 114.27, 85.39, 82.12, 75.66, 75.46, 49.13, 49.04,
47.44, 38.38, 34.40, 23.36, 22.19, 21.71, 20.76, 20.09, 15.18, 14.15,
-0.12. MS [CI, m/z (rel intensity)]: 171.1 (44), 423.3 (100, M+
+ 1). Anal. Calcd for C23H38O5Si‚0.5 H2O: C, 64.00; H, 8.87.
Found: C, 64.07; H, 8.87. [R]20 -115 (c ) 1, CHCl3).
D
Ack n ow led gm en t. Support for this work was pro-
vided by the National Science Foundation and by the
donors to the Krafft Research Fund. We also would like
to acknowledge Prof. A. de Meijere for graciously
providing us a copy of Dr. H. Becker’s dissertation and
spectra of dione 21.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 16, 23, 27, and 38 and experimental data for all
other compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Exp er im en ta l Section
Aceta l 13. To a cooled solution (-20 °C) of keto enyne 10 (28
mg, 0.14 mmol) and diol 5 (60 mg, 0.29 mmol) in CH2Cl2 (2.2
J O0263667
6042 J . Org. Chem., Vol. 68, No. 15, 2003