An enantioselective synthetic route to atractyligenin using the oxazaborolidine-catalyzed reduction of β-silyl- or β-stannyl-substituted α,β-enones as a key step

Article abstract of DOI:10.1021/ja973034o

In this paper, we describe a novel catalytic enantioselective synthetic route to the bicyclic tetraene ester 3, a key intermediate for the synthesis of the naturally occurring adenosine diphosphate transport inhibitor atractyligenin (2). The success of this route depended on the extension of the oxazaborolidine-catalyzed (CBS) reduction of an achiral β-stannyl-substituted α,β-enone (6c) to form a chiral allylic alcohol and further steps to effect simultaneous transfer of chirality, carbocycle formation, and quaternary stereocenter formation, which led to the triene acid 13. The conversion of 13 to 3 was carried out efficiently by a four-step sequence involving iodolactonization, double elimination, and esterification. The combined use of the CBS reduction of appropriate α,β-enones and Claisen rearrangement provides an important synthetic avenue to many types of natural products containing quaternary stereocenters embedded in cyclic networks.

Full text of DOI:10.1021/ja973034o

J. Am. Chem. Soc. 1997, 119, 11769-11776
11769
An Enantioselective Synthetic Route to Atractyligenin Using
the Oxazaborolidine-Catalyzed Reduction of â-Silyl- or
â-Stannyl-Substituted R,â-Enones as a Key Step
E. J. Corey,* Angel Guzman-Perez, and Scott E. Lazerwith
Contibution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
ReceiVed August 28, 1997X
Abstract: In this paper, we describe a novel catalytic enantioselective synthetic route to the bicyclic tetraene ester
3, a key intermediate for the synthesis of the naturally occurring adenosine diphosphate transport inhibitor atractyligenin
(2). The success of this route depended on the extension of the oxazaborolidine-catalyzed (CBS) reduction of an
achiral â-stannyl-substituted R,â-enone (6c) to form a chiral allylic alcohol and further steps to effect simultaneous
transfer of chirality, carbocycle formation, and quaternary stereocenter formation, which led to the triene acid 13.
The conversion of 13 to 3 was carried out efficiently by a four-step sequence involving iodolactonization, double
elimination, and esterification. The combined use of the CBS reduction of appropriate R,â-enones and Claisen
rearrangement provides an important synthetic avenue to many types of natural products containing quaternary
stereocenters embedded in cyclic networks.
Introduction
necessary to fully establish the detrimental effects of atractyl-
osides on the health of coffee consumers. The intriguing
biochemistry and the challenging structures of these compounds
have attracted the interest of our group, which reported the only
total synthesis of atractyligenin, as the racemate, to date.12 This
paper describes an enantioselective route to 3, the first chiral
intermediate in the synthesis of 2, and thus establishes the first
synthetic route to the natural form of 2. The enantioselective
synthesis of 3 demonstrates a new method for the generation
of quaternary stereocenters using the enantioselective ox-
azaborolidine-catalyzed (CBS) reduction of an enone followed
by chirality transfer via an Ireland-Claisen rearrangement,
which promises to be widely applicable.13
Atractyloside (1) and carboxyatractyloside are found in the
thistle Atractylis gummifera (Plunderer of Life), which has been
renowned since ancient times for its deadly toxicity.1 Atrac-
tyloside is highly poisonous by virtue of its strychnine-like
action, producing convulsions of a hypoglycemic type.2 It
functions as an inhibitor of oxidative phosphorylation by
blocking the translocation of adenosine diphosphate (ADP) into
mitochondria, and thus impairing the production of ATP.1,3
Atractyloside and other related compounds containing atrac-
tyligenin (2) as the aglycon are common in nature.4 Atractyl-
osides are present in Wedelia glauca,5 Iphinona aucheri,6 and
Drymaria arenariodes,7 and were implicated in the death of
cattle, camels, and other livestock that accidentally ingested
these plants. In addition, 1 is a component of Callilepis
laureola, which has been employed by the Zulus and other
African people as an herbal medicine. Many patients who have
used this remedy have suffered serious and often fatal liver
lesions.8 Unfortunately, atractylosides are also present in Coffea
beans (arabica and to a lesser extent robustica)9 and are
unwittingly ingested by coffee drinkers, as confirmed by the
detection of a metabolite of 2 in the urine of human coffee
consumers.9a,10 It has been suggested that atractylosides may
possibly be responsible for the statistical link between coffee
drinking and pancreatic cancer,11 although further work is clearly
X Abstract published in AdVance ACS Abstracts, December 1, 1997.
(1) Atractyloside: Chemistry, Biochemistry and Toxicology; Santi, R.,
Luciani, S., Eds.; Piccin Medical Books: Padova, Italy, 1978.
(2) The Merck Index, 12th ed.; Budavari, S., Ed.; Merck: Whitehouse
Station, NJ, 1996; p 902.
(3) Klingenberg, M. Trends Biochem. Sci. 1979, 4, 249.
(4) For the structural determination of 1 and 2, see: (a) Piozzi, F.; Quilico,
A.; Mondelli, R.; Ajello, T.; Sprio, V.; Malera, A. Tetrahedron 1966, Suppl
8, Part II, 515. (b) Piozzi, F.; Quilico, A.; Fuganti, C.; Ajello, T.; Sprio, V.
Gazz. Chim. Ital. 1967, 97, 935. (c) Reference 2.
(5) Schteingart, C. D.; Pomilio, A. B. J. Nat. Prod. 1984, 47, 1046.
(6) Roeder, E.; Bourauel, T.; Meier, U.; Wiedenfeld, H. Phytochemistry
1994, 37, 353.
(7) Vargas, D.; Dominguez, X. A.; Acun˜a-Askar, K.; Gutierrez, M.;
Hostettmann, K. Phytochemistry 1988, 27, 1532.
The CBS catalytic reduction of ketones using catalysts 4
(Scheme 1) is a remarkable transformation due to the high
enantioselectivities it provides, as well as the detailed mecha-
nistic understanding, broad scope, and predictability of the
(10) Obermann, H.; Spiteller, G.; Hoyer, G.-A. Chem. Ber. 1973, 106,
3506.
(11) Pegel, K. H. Chem. Eng. News 1981 (July 20), 4.
(12) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987,
109, 6187.
(13) For previous uses of the CBS reduction-Claisen rearrangement
sequence, see: (a) Kanematsu, K.; Nishizaki, A.; Sato, Y.; Shiro, M.
Tetrahedron Lett. 1992, 33, 4967. (b) Deng, W.; Jensen, M. S.; Overman,
L. E.; Rucker, P. V.; Vionnet, J.-P. J. Org. Chem. 1996, 61, 6760. (c)
Nicolaou, K. C.; Bertinato, P.; Piscopio, A. D.; Chakraborty, T. K.; Minowa,
N. J. Chem. Soc., Chem. Commun. 1993, 619. (d) Lo¨gers, M.; Overman,
L. E.; Welmaker, G. S. J. Am. Chem. Soc. 1995, 117, 9139. (e) Smith, D.
B.; Waltos, A. M.; Loughhead, D. G.; Weikert, R. J.; Morgans, D. J., Jr.;
Rohloff, J. C.; Link, J. O.; Zhu, R. J. Org. Chem. 1996, 61, 2236.
(8) Candy, H. A.; Pegel, K. H.; Brookes, B.; Rodwell, M. Phytochemistry
1977, 16, 1308.
(9) (a) Ludwig, H.: Obermann, H.; Spiteller, G. Chem. Ber. 1974, 107,
2409. (b) Obermann, H.; Spiteller, G. Chem. Ber. 1976, 109, 3450. (c)
Richter, H.; Spiteller, G. Chem. Ber. 1978, 111, 3506.
S0002-7863(97)03034-5 CCC: $14.00 © 1997 American Chemical Society

11770 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Corey et al.
Scheme 1. Enantioselective Oxaborolidine-Catalyzed
Reduction of Ketones
experiments were disappointing; the reduction proceeded in only
30% yield and 76% enantiomeric excess (ee).17 Careful
reaction.14 It represents a powerful tool for the synthesis of a
wide variety of simple and complex molecules.15 A summary
of the mechanistic model that has been presented for the
reduction of ketones catalyzed by oxazaborolidines 4 is depicted
in Scheme 1. The model has the following characteristics: (1)
coordination of the stoichiometric reducing agent R2BH to the
nitrogen atom of the catalyst, thereby activating one boron as a
hydride donor and the other as a Lewis acid; (2) coordination
of the prochiral ketone to the Lewis acidic catalyst at the R-face
of the boron in the oxazaborolidine ring and in an exo
arrangement, which minimizes unfavorable steric interactions
between ketone and catalyst while activating the carbonyl group,
as shown in 5; (3) preferential coordination of oxygen via the
electron lone pair syn to the ketone substituent with the smaller
effective steric bulk (RS), thereby placing the larger substituent
(RL) at a distance from the group on boron (R), as indicated in
5; and (4) stereoelectronically favorable hydride transfer from
the R2BH unit to the proximate ketone face. The rate accelera-
tion of this pathway relative to other modes is derived from (1)
the simultaneous activation of the reductant and ketone by the
catalyst and (2) the reduced entropic cost of the reaction when
the reagents are held in close proximity as in structure 5.14a,16
consideration of the aforementioned mechanistic model for the
CBS reduction suggested a reason for the low selectivity: the
ketone substituents of 6a are not sufficiently size-differentiated,
and consequently, the reaction proceeds with only a moderate
preference for complex 8a versus 8b (R ) H). In addition, the
model predicts that the use of a bulky and remoVable substituent
at the enone â-position, such as a â-trimethylsilyl (TMS) or
â-tri-n-butylstannyl (n-Bu3Sn) group, would significantly in-
crease the steric presence of the vinyl substituent so as to
discourage the pathway that proceeds via complex 8b. For
example, complex 8a (R ) TMS) should be more favorable
than 8b (R ) TMS) due to the unfavorable remote interactions
that exist between the TMS groups of the ketone and the
catalyst, in the latter structure.18 Furthermore, the â-substituent
should discourage the 1,4-addition or polymerization side
reactions that are probably responsible for the reduced yield
observed in the reduction of 6a. The CBS reductions of the
â-TMS and â-n-Bu3Sn enones (6b and 6c) were outstanding as
shown in Table 1. The use of dichloromethane as solvent
provided uniformly better results than toluene.19
Results and Discussion
Our synthetic plan for the asymmetric construction of key
intermediate 3 required the CBS reduction of ketone 6a. Initial
(14) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925. (c) Corey, E. J.; Shibata, S.;
Bakshi, R. K. J. Org. Chem. 1988, 53, 2861. (d) Corey, E. J. Proceedings
31st National Organic Chemistry Symposium of the American Chemical
Society; 1989; p 1. (e) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990,
31, 611. (f) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209. (g) Corey, E. J.;
Azimioara, M; Sarshar, S. Tetrahedron Lett. 1992, 33, 3429. For reviews,
see: (h) Singh, V. K. Synthesis 1992, 605. (i) Wallbaum, S.; Martens, J.
Tetrahedron: Asymmetry 1992, 3, 1475. (j) Deloux, L.; Srebnik, M. Chem.
ReV. 1993, 93, 763. (k) Link, J. O. Ph.D. Thesis, Harvard, University, July
1992.
(15) For applications of the CBS reduction from this group see: (a)
Corey, E. J.; Chen, C. P.; Parry, M. J. Tetrahedron Lett. 1988, 29, 2899
(PAF antagonists). (b) Corey, E. J.; Gavai, A. V. Tetrahedron Lett. 1988,
29, 3201 (ginkgolides A and B). (c) Corey, E. J.; Su, W.-g. Tetrahedron
Lett. 1988, 29, 3423. (d) Corey, E. J. Chem. Soc. ReV. 1988, 17, 111
(bilobalide). (e) Corey, E. J.; Jardine, P. D. S. Tetrahedron Lett. 1989, 30,
7297 (forskolin). (f) Corey, E. J.; Reichard, G. A. Tetrahedron Lett. 1989,
30, 5207 (fluoxetine). (g) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989,
30, 6275 (R-deutero alcohols). (h) Corey, E. J.; Link, J. O. Tetrahedron
Lett. 1990, 31, 601 (isoproteranol). (i) Corey, E. J.; Link, J. O. J. Org.
Chem. 1991, 56, 442 (denopamine). (j) Corey, E. J.; Chen, C.-P.; Reichard,
G. A. Tetrahedron Lett. 1989, 30, 5547 (chiral oxazaborolidines). (k) Corey,
E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906 (R-amino acids). (l)
Corey, E. J.; Kigoshi, H. Tetrahedron Lett. 1991, 32, 5025 (antheridic acid).
(m) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33, 3431 (R-hydroxy
acids). (n) Corey, E. J.; Yi, K. Y.; Matsuda, S. P. T. Tetrahedron Lett.
1992, 33, 2319 (2,3-oxidosqualene). (o) Corey, E. J.; Helal, C. J.
Tetrahedron Lett. 1993, 34, 5227 (terminal epoxides). (p) Corey, E. J.;
Cimprich, K. A. Tetrahedron Lett. 1992, 33, 4099 (chiral thiols). (q) Corey,
E. J.; Cheng, X.-M.; Cimprich, K. A.; Sarshar, S. Tetrahedron Lett. 1991,
32, 6835 (chiral controllers). (r) Corey, E. J.; Helal, C. J. Tetrahedron Lett.
1995, 36, 9153 (electronic effects). (s) Corey, E. J.; Helal, C. J. Tetrahedron
Lett. 1996, 37, 4837 (cetirizine hydrochloride). (t) Corey, E. J.; Helal, C. J.
Tetrahedron Lett. 1996, 37, 5675 (carbinoxamine). (u) Helal, C. J.;
Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996, 118, 10938
(propargylic alcohols). (v) Corey, E. J.; Helal, C. J. Tetrahedron Lett., in
press (cicaprost ω-side chain).
The choice of catalyst 4a15u deserves comment. The catalyst
bearing a bulky ((trimethylsilyl)methyl)boron substituent (4a)
was used in the expectation that this would maximize the remote
steric interactions present in complex 8b. As anticipated,
catalysts with smaller boron substituents, such as 4b (B-4-tert-
butylphenyl),20 4c (B-n-butyl), and 4d (B-methyl), resulted in
lower enantioselectivity for the reduction of enone 6b (Table
2).21
The removal of the olefinic substituent of compounds 7 was
more difficult than originally foreseen. The cleavage of the
TMS group of allylic alcohol 7b was low yielding (e15%) under
a number of conditions (HI, benzene, 65 °C; HBF4, acetonitrile,
55 °C; HF, acetonitrile, 23 °C; p-toluenesulfinic acid, acetoni-
(16) For an excellent discussion of the mechanism, see ref 14k.
(17) For the CBS reduction of acyclic enones, see: (a) Bach, J.;
Berenguer, R.; Farras, J.; Garcia, J.; Meseguer, J.; Vilarrasa, J. Tetrahe-
dron: Asymmetry 1995, 6, 2683. (b) Mulzer, J.; Dupre´, S.; Buschmann, J.;
Luger, P. Angew. Chem., Int. Ed. Engl. 1993, 32, 1452. (c) References 13d,e,
14b,e and 15r.
(18) For the use of remote steric interactions in the CBS reduction, see
ref 15u.
(19) In contrast, (E)-styryl methyl ketones gave rise to better enantiose-
lectivities in toluene than in CH2Cl2; see ref 15r.
(20) Catalyst 4b was developed by Mr. Christopher J. Helal of our group.
A report on the applications of this catalyst is forthcoming.
(21) The same tendency was observed in the reduction of ketone 6c
(catecholborane, CH2Cl2, -78 °C) using the following oxazaborolidine
catalysts (15 mol %): 4a (90% ee, 94% yield), 4b (79% ee, 57% yield),
and 4c (68% ee, 64% yield).

An EnantioselectiVe Synthetic Route to Atractyligenin
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11771
Scheme 2. Preparation of Lactone 9
Table 1. Effect of the â-Substituent on the Reduction of Enones
a Experiments were performed with catalyst (R)-4a to afford the (S)-
product. b Reaction temperature: -78 to -40 °C.
With optimized conditions for the CBS reduction in hand,
the synthesis of key fragment 3 via lactone 9 was accomplished
as follows. trans-Bis(tri-n-butylstannyl)ethylene23,25 was mono-
lithiated with n-butyllithium, and added over 5-10 min to
methyl 5-oxopentanoate26 in THF at -78 °C to afford racemic
7c in 82% yield, as shown in Scheme 2.23,25a Oxidation of the
allylic alcohol with pyridinium dichromate (PDC) provided
enone 6c.27 The large-scale CBS reduction of this enone was
best accomplished at -60 °C using freshly prepared catalyst
(S)-4a, which resulted in the formation of 7c of 88% ee.28 As
described above, fluoride-induced destannylation of optically
active 7c produced the hydroxy acid shown, which without
isolation was lactonized using 1-(3-(dimethylamino)propyl)-3-
ethylcarbodiimide hydrochloride and 4-(dimethylamino)pyridine,
to give 9 in 88% ee.
Table 2. Effect of the Catalyst on the Reduction of Enone 6b
As indicated in Scheme 3, lactone 9 was deprotonated using
lithium diisopropylamide, and alkylated with iodide 1012 in the
presence of hexamethylphosphoramide to provide compound
11 in 51% yield along with recovered starting material (25%).29
The Ireland-Claisen rearrangement of the corresponding silyl
ketene acetal 12 proceeded smoothly upon heating in toluene
to afford, after hydrolysis, carboxylic acid 13 in 94% yield from
lactone 11.30
a Experiment was performed with catalyst (S)-4a to afford the (R)-
product.
trile, reflux; p-toluenesulfonic acid, acetonitrile, reflux; and
n-Bu4NF, THF, reflux).22 Consequently, we investigated the
protodestannylation of alcohol 7c. The removal of the n-Bu3-
Sn group of 7c under mildly acidic conditions (silica gel,
benzene, reflux, 6 h, Dean-Stark trap with 4 Å molecular sieves,
82%)23 to afford lactone 9 was accompanied by partial racem-
ization. In contrast, destannylation under basic conditions (n-
Cyclohexenecarboxylic acid 13 was enantiospecifically con-
verted into the corresponding cyclohexadiene 16 by the fol-
(22) HI: (a) Ostwald, R.; Chavant, P.-Y.; Stadtmu¨ller, H.; Knochel, P.
J. Org. Chem. 1994, 59, 4143. HBF4: (b) Ireland, R. E.; Varney, M. D. J.
Am. Chem. Soc. 1984, 106, 3668. HF: (c) Danheiser, R. L.; Carini, D. J.;
Fink, D. M.; Basak, A. Tetrahedron 1983, 39, 935. p-TsH: (d) Bu¨chi, G.;
Wu¨est, H. Tetrahedron Lett. 1977, 49, 4305. p-TsOH: (e) Fujikura, S.;
Inoue, M.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 1999. n-Bu4-
NF: (f) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H.
Tetrahedron 1985, 41, 3257. For a review, see: (g) Fleming, I.; Dunogues,
J.; Smithers, R. In Organic Reactions; Kende, A. S., Ed.; Wiley: New York,
1989; Vol. 37, Chapter 2.
(23) Wollenberg, R. H. Ph.D. Thesis, Harvard University, December
1976.
(24) Utaka, M.; Watabu, H.; Takeda, A. J. Org. Chem. 1987, 52, 4363.
(25) (a) Corey, E. J.; Wollenberg, R. H. J. Am. Chem. Soc. 1974, 96,
5581. (b) Bottaro, J. C.; Hanson, R. N.; Seitz, D. E. J. Org. Chem. 1981,
46, 5221.
(26) Huckstep, M.; Taylor, R. J. K. Synthesis 1982, 881.
(27) Keck, G. E.; Burnett, D. A. J. Org. Chem. 1987, 52, 2958.
(28) Employment for large-scale experiments of catalyst that had been
stored for more than one day gave rise to a product of low enantiomeric
excess. Furthermore, the use of a reaction temperature of -78 °C at this
scale resulted in a sluggish reduction rate.
Bu4NF, THF), followed by lactonization, provided 9 in 83%
yield with no loss of optical purity. The absolute stereochem-
istry of 7c was established by hydrogenation of 9 (H2, Rh-C
(5%), ether, 0-23 °C, 2 h, 69%) to afford (S)-δ-heptanolactone,
followed by comparison of the specific rotation of the latter
compound with that of an authentic sample.24
(29) Herrmann, J. L.; Schlessinger, R. H. J. Chem. Soc., Chem. Commun.
1973, 711.

11772 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Scheme 3. Preparation of Acid 13
Corey et al.
Scheme 5. An Alternative Route to Key Intermediate 3
Scheme 4. Preparation of Acid 13
lowing sequence (Scheme 4): (1) iodolactonization in 79%
yield, (2) elimination of the resulting iodide 14 with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) to afford 15 of 88% ee
in 96% yield, and (3) position-selective elimination of lactone
15 using potassium hexamethyldisilazide in THF to provide acid
16 in 71% yield along with recovered starting material (25%).
The enantiomeric excess of intermediate 15 (88% ee) attests to
the complete chirality transfer that occurred via the Ireland-
Claisen rearrangement. The elimination of lactone 15 was not
driven to completion because this led to the concomitant
isomerization of 1,3-diene 16 to the corresponding achiral 1,4-
diene. The regioselectivity of the elimination is crucial; proton
abstraction must occur exclusively from the allylic position a
of 15, and not at all from the less acidic position b, because
competing deprotonation would result in racemization. The
reaction is very selective as is evidenced by the 88% ee of the
desired key intermediate 3, prepared in 90% yield by reaction
of acid 16 with diazomethane.
An alternative synthesis of compound 3, which was developed
using the allylic alcohol of higher optical purity 7b, is shown
in Scheme 5. 1-(Tri-n-butylstannyl)-2-(trimethylsilyl)ethylene31
underwent efficient Stille coupling32 with commercially available
methyl 4-(chloroformyl)butanoate at reflux to afford ketone 6b
in 92% yield. As described above, the CBS reduction of this
ketone using oxazaborolidine catalyst (R)-4a provided allylic
alcohol 7b of 94% ee in 96% yield; the absolute stereochemistry
of 7b was established by comparison of its specific rotation
with that of an authentic sample.33 Alcohol 7b was cyclized
under acidic conditions to give lactone 17. Compound 17 was
transformed to acid 20 by alkylation with 10, followed by
Ireland-Claisen rearrangement, as described for the compounds
lacking the TMS group. The corresponding ester 21 was treated
with N-bromosuccinimide in acetone-water at -25 °C to
provide allylic bromide 22 in 60% yield (with respect to
recovered starting material), which after elimination with DBU
gave the desired key intermediate 3 of 92-94% ee. While this
route to 3 is more direct than the stannyl route previously
described, the last two steps provided only modest yields. It
(30) For references on the Ireland-Claisen rearrangement of lactonic
silyl enolates, see: (a) Danishefsky, S.; Funk, R. L.; Kerwin, J. F., Jr. J.
Am .Chem. Soc. 1980, 102, 6889. (b) Danishefsky, S.; Tsuzuki, K. J. Am.
Chem. Soc., 1980, 102, 6891. (c) Danishefsky, S. J.; Audia, J. E. Tetrahedron
Lett. 1988, 29, 1371. (d) Danishefsky, S. J.; Simoneau, B. J. Am. Chem.
Soc. 1989, 111, 2599. (e) Turos, E.; Audia, J. E.; Danishefsky, S. J. J. Am.
Chem. Soc. 1989, 111, 8231. (f) Schreiber, S. L.; Smith, D. B. J. Org.
Chem. 1989, 54, 9. (g) Burke, S. D.; Piscopio, A. D.; Kort, M. E.;
Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; Shankaran, K. J. Org.
Chem. 1994, 59, 332. For a recent review on the Ireland-Claisen
rearrangement see: (h) Pereira, S.; Srebnik, M. Aldrichim. Acta 1993, 26,
17.
(31) Cunico, R. F.; Clayton, F. J. J. Org. Chem. 1976, 41, 1480.
(32) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48,
4634.
(33) Kitano, Y.; Matsumoto, T.; Sato, F. Tetrahedron 1988, 44, 4073.

An EnantioselectiVe Synthetic Route to Atractyligenin
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11773
over ca. 6 min. The reaction mixture was stirred for 45 min, quenched
by addition of NH4Cl (saturated aqueous solution) and ether, and
allowed to warm to 23 °C. The layers were separated. The organic
phase was washed twice with brine, dried over MgSO4(anhyd), and
concentrated in Vacuo. The residue was purified by flash chromatog-
raphy (hexanes-EtOAc, 75:25) to afford 4.39 g (82% yield) of racemic
7c as an oil. (For analytical data see 7c below.)
appears that the tetrasubstituted olefin in 21 competes for
bromination with the allylic silane functionality, and this results
in decreased yields. A number of experimental conditions were
investigated for the elimination of bromide 22 (e.g., pentaiso-
propylguanidine in acetonitrile at reflux for 12 h, or Pd(dba)2,
AgNO3, and dppp in acetonitrile at reflux for 6 h led mostly to
decomposition), and while DBU provided the highest yield, the
reaction was always plagued with competing decomposition
pathways. The enantiospecificities of the Claisen rearrangement
and the conversion of allylic silane 21 to diene 3 are evidenced
by the high enantiomeric purity of the final product.
Methyl 5-Oxo-7-(tri-n-butylstannyl)hept-6-enoate (6c). A solution
of racemic stannyl alcohol 7c (2.188 g, 4.89 mmol) in CH2Cl2 (52 mL)
at 23 °C was treated in one portion with pyridinium dichromate (2.76,
7.34 mmol). The resulting dark mixture was stirred for 18 h, diluted
with hexanes-ether (50:50), and filtered through a silica gel plug eluting
with hexanes-ether (50:50). The filtrate was concentrated in Vacuo.
The residue was purified by flash chromatography (hexanes-EtOAc,
85:15) to afford 1.817 g (83% yield) of product 6c as an oil: Rf )
0.25 (hexanes-EtOAc, 90:10); FTIR (film) 2957, 2928, 2873, 2852,
1742, 1696, 1675, 1460, 1439, 1375, 1250, 1203, 1177, 998 cm-1; 1H
NMR (500 MHz, C6D6) δ 7.60 (d, J ) 19.7 Hz, 1H), 6.69 (d, J ) 19.7
Hz, 1H), 3.29 (s, 3H), 2.35 (t, J ) 7.1 Hz, 2H), 2.12 (t, J ) 7.1 Hz,
2H), 1.91 (quintet, J ) 7.1 Hz, 2H), 1.50 (m, 6H), 1.30 (sextuplet, J
) 7.3 Hz, 6H), 0.99-0.85 (m, 15H); 13C NMR (100 MHz, C6D6) δ
196.7, 173.0, 147.8, 146.3, 50.9, 37.9, 33.1, 29.3, 27.6, 19.5, 13.8, 9.8;
CIMS (NH3) 464 [M + NH4]+, 462 [M + NH4 - 2]+, 460 [M + NH4
- 4]+, 447 [M + H]+, 428, 174, 157; HRMS calcd for [C20H38O3Sn +
NH4]+ 464.2187, found 464.2192.
Conclusions
In this paper, we report the CBS reductions of â-trimethylsilyl
and â-tri-n-butylstannyl acyclic enones, which give rise to higher
enantioselectivities than those obtained from the reduction of
unsubstituted acyclic enones. The enhanced enantioselectivities
are a result of remote steric interactions between the distal
trimethylsilyl or tri-n-butylstannyl groups on the enone â-posi-
tion and the (trimethylsilyl)methyl group on the boron atom of
catalyst 4a, which strongly disfavor the minor reduction
pathway. The tri-n-butylstannyl group can be removed from
the allylic alcohol product with no loss of optical purity using
tetra-n-butylammonium fluoride. These observations were
applied to the enantioselective synthesis of a key intermediate
in the preparation of the coffee bean-derived toxin atractyligenin.
An Ireland-Claisen rearrangement of a lactonic silyl enolate
was used for the complete transfer of chirality from the
secondary alcohol generated by CBS reduction to the quaternary
carbon stereocenter present in the key intermediate. The
regioselective-enantiospecific elimination of lactone 15 to acid
16 is also a noteworthy step of the synthesis. The CBS
reduction of enones and Ireland-Claisen rearrangement of
lactonic silyl enolates sequence presented herein affords sub-
stituted cyclohexenes reminiscent of Diels-Alder adducts. The
reliability and high enantioselectivity provided by the CBS
reduction and the stereospecificity of the Claisen rearrangement
should establish this sequence as a useful alternative to
asymmetric Diels-Alder reactions.
(S)-1-Aza-2-bora-2-((trimethylsilyl)methyl)-3-oxa-4,4-diphen-
ylbicyclo[3.3.0]octane ((S)-4a). A solution of (S)-(-)-R,R-diphenyl-
2-pyrrolidinemethanol34 (0.507 g, 2.0 mmol) and ((trimethylsilyl)-
methyl)boronic acid15u (0.317 g, 2.4 mmol) in toluene (20 mL) was
heated at reflux through a Dean-Stark apparatus (side arm filled with
4 Å molecular sieves and toluene) for 14 h. Most of the toluene was
then removed by distillation via the Dean-Stark side arm. The mixture
was cooled to 23 °C. The Dean-Stark apparatus was rapidly replaced
by a rubber septum. The flask was fitted with an additional rubber
septum. The remaining toluene was removed in Vacuo at 23 °C under
inert conditions. The residue was dissolved in toluene (20 mL) to
provide a 0.1 M solution of catalyst (S)-4a. An aliquot of this solution
1
was concentrated in Vacuo at 23 °C under inert conditions; H NMR
analysis of this sample in dry CDCl3 indicated that the catalyst formation
was complete. The catalyst solution was cooled to -78 °C under a
positive pressure of nitrogen. The nitrogen source was removed, and
the flask was stored at -20 °C in a closed jar containing Drierite.
Catalyst (R)-4a was prepared similarly. Data for 4a: 1H NMR (400
MHz, dry CDCl3) δ 7.52 (d, J ) 8.6 Hz, 2H), 7.38 (d, J ) 7.9 Hz,
2H), 7.17-7.35 (m, 6H), 4.28 (dd, J ) 5.6, 10.0 Hz, 1H), 3.34 (m,
1H), 3.04 (m, 1H), 1.76 (m, 2H), 1.58 (m, 1H), 0.79 (m, 1H), 0.08 (s,
3H), 0.05 (s, 6H); for additional analytical data see ref 15u.
Experimental Section
General Methods. All experiments involving moisture and/or air
sensitive compounds were performed in oven- or flame-dried glassware
equipped with rubber septa under a positive pressure of nitrogen or
argon. When necessary, solvents and reagents were distilled prior to
use and were transferred using a syringe or cannula. Reaction mixtures
were magnetically stirred, unless otherwise noted. Thin layer chro-
matography was performed on Merck precoated silica gel F-254 plates
(0.25 mm). Kugelrohr distillation temperatures are reported as oven
temperatures. Flash column chromatography was performed on Baker
230-400 mesh silica gel. Proton NMR spectra were recorded in parts
per million using the residual solvent signal as an internal standard:
CDCl3 (7.26 ppm) or C6D6 (7.15 ppm). Carbon NMR were recorded
in parts per million relative to the solvent signal: CDCl3 (77.07 ppm)
or C6D6 (128.0 ppm). Mass spectra and high-resolution mass spectra
(HRMS) were recorded on JEOL spectrometers and are reported in
units of mass to charge (m/e). The Chiralcel and Chiralpak HLPC
columns were obtained from Daicel Chemical Industries, Ltd., and the
(S,S)-Whelk-O1 column was obtained from Regis Chemical Co.
(()-Methyl 5-Hydroxy-7-(tri-n-butylstannyl)hept-6-enoate (Ra-
cemic 7c). A -78 °C solution of (E)-1,2-bis(tri-n-butylstannyl)-
ethylene23,25 (6.38 mL, 12.0 mmol) in THF (36 mL) was treated
dropwise with n-butyllithium in hexanes (2.44 M, 5.41 mL, 13.2 mmol).
The solution was allowed to slowly warm to -40 °C over 30 min, and
was then cooled to -78 °C. The resulting solution was added via dry-
ice-cooled cannula to a -78 °C solution of methyl 5-oxopentanoate26
(2.97 mL, 24.0 mmol) in THF (72 mL), down the side of the flask
(R)-Methyl 5-Hydroxy-7-(tri-n-butylstannyl)hept-6-enoate (7c).
Ketone 6c (0.111 g, 0.25 mmol) was azeotropically dried twice with
toluene (0.5 mL each) under inert conditions. The dry compound was
treated with a solution of catalyst (S)-4a in toluene (0.1 M, 0.380 mL,
0.038 mmol). The toluene was removed in Vacuo under inert
conditions, and replaced by CH2Cl2 (0.875 mL). The resulting solution
was cooled to -78 °C and treated dropwise over 10 min with a solution
of catecholborane (0.041 mL, 0.38 mmol) in CH2Cl2 (0.123 mL). The
reaction mixture was stirred at -78 °C for 20 h, quenched by slow
addition of MeOH (0.5 mL) down the side of the flask, warmed to 23
°C, and diluted with ether. The ethereal solution was washed repeatedly
with a 2:1 mixture of NaOH (1 M aqueous)-NaHCO3 (saturated
aqueous solution) until the washings were colorless, washed once with
brine, dried over MgSO4(anhyd), and concentrated in Vacuo. The
residue was purified by flash chromatography (hexanes-EtOAc, 75:
25) to afford 0.105 g (94% yield) of desired product 7c of 90% ee
(determined by chiral HPLC of the corresponding benzoate ester).
The above procedure can also be used for larger scale work if the
catalyst is prepared fresh, but for this scale it is more practical and
reproducible to perform the reaction at -60 °C as follows: A solution
of (S)-(-)-R,R-diphenyl-2-pyrrolidinemethanol34 (0.0633 g, 0.25 mmol)
and ((trimethylsilyl)methyl)boronic acid15u (0.0396 g, 0.30 mmol) in
toluene (5 mL) was heated at reflux through a Dean-Stark apparatus
(34) Kanth, J. V.; Periasamy, M. Tetrahedron 1993, 49, 5127.

11774 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Corey et al.
(side arm filled with 4 Å molecular sieves and toluene) for 14 h. Most
of the toluene was then removed by distillation via the Dean-Stark side
arm. The mixture was cooled to 23 °C. The Dean-Stark apparatus
was rapidly replaced by a rubber septum. The remaining toluene was
removed in Vacuo at 23 °C under inert conditions. The residue was
dissolved in CH2Cl2 (2.50 mL) to provide a 0.1 M solution of catalyst
(S)-4a. Ketone 6c (0.334 g, 0.75 mmol) was azeotropically dried twice
with toluene (1 mL each) under inert conditions. The dry compound
was treated with the freshly prepared solution of catalyst in CH2Cl2
(0.1 M, 1.13 mL, 0.113 mmol) and CH2Cl2 (0.29 mL). The resulting
homogeneous mixture was cooled to -60 °C and treated over ca. 11
min with a solution of catecholborane (0.120 mL, 1.13 mmol) in CH2-
Cl2 (0.72 mL) dropwise down the side of the flask. The reaction
mixture was stirred at -60 °C for 5 h, quenched by slow addition of
MeOH (1.0 mL) down the side of the flask, warmed to 23 °C, and
diluted with ether. The ethereal solution was washed repeatedly with
a 2:1 mixture of NaOH (1 M aqueous)-NaHCO3 (saturated aqueous
solution) until the washings were colorless, washed once with brine,
dried over MgSO4(anhyd), and concentrated in Vacuo. The residue
was purified by flash chromatography (hexanes-EtOAc, 75:25) to
afford 0.306 g (91% yield) of desired product 7c of 88% ee (determined
by chiral HPLC of the corresponding benzoate ester): Rf ) 0.45
(hexanes-EtOAc, 70:30); [R]23D +0.1° (c 1.26, benzene); FTIR (film)
3441, 2957, 2925, 2870, 2851, 1741, 1458, 1374, 1337, 1285, 1243,
1175, 1073, 1045, 991 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.15 (dd,
J ) 19.1, 0.9 Hz, 1H), 5.99 (dd, J ) 19.1, 5.5 Hz, 1H), 4.07 (m, 1H),
3.67 (s, 3H), 2.35 (t, J ) 7.4 Hz, 2H), 1.74-1.67 (m, 2H), 1.63 (br s,
1H), 1.59-1.53 (m, 2H), 1.52-1.45 (m, 6H), 1.30 (sextuplet, J ) 7.3
Hz, 6H), 0.94-0.82 (m, 15 H); 13C NMR (100 MHz, CDCl3) δ 174.1,
150.6, 128.1, 75.0, 51.5, 36.2, 33.9, 29.1, 27.3, 20.9, 13.7, 9.5; CIMS
(NH3) 466 [M + NH4]+, 464 [M + NH4 - 2]+, 462 [M + NH4 - 4]+,
431, 308 [Bu3SnNH3]+, 306, 176, 174; HRMS calcd for [C20H40O3-
Sn+NH4]+ 466.2343, found 466.2346; HPLC (chiral) of the corre-
sponding benzoate ester (Whelk-O1 at 23 °C; λ ) 254 nm; hexanes-
2-propanol, 97.5:2.5) retention times 12.3 (major), 14.9 (minor) min
at 1 mL/min flow rate.
15 min, treated with hexamethylphosphoramide (0.522 mL, 3.00 mmol),
and cooled to -78 °C. The resulting homogeneous mixture was treated
with a solution of lactone 9 (azeotropically dried with 0.25 mL of
benzene) (0.063 g, 0.50 mmol) in THF (1 mL) over 30 min using a
syringe pump, and stirred for an additional 30 min. The solution was
then treated dropwise with iodide 1012 (0.167 mL, 1.00 mmol), and
stirred for 5 min at -78 °C and 4.5 h at -50 °C. The reaction mixture
was quenched by addition of NH4Cl (saturated aqueous solution) and
extracted with ether. The organic phase was washed once with brine,
dried over MgSO4(anhyd), and concentrated in Vacuo. The residue
was purified by flash chromatography (hexanes-ether, 80:20 to 60:40
to 20:80) to afford (in this order) recovered iodide 10, dialkylated
lactone (0.006 g, 3%), desired product 11 (0.063 g, 51% yield, 68%
with respect to recovered starting material) as a ca. 1:1 mixture of
diastereomers (determined by 1H NMR), and recovered starting lactone
9 (0.016 g, 25%). Data for 11: Rf ) 0.40 (hexanes-EtOAc, 80:20);
FTIR (film) 2926, 2871, 2815, 1736, 1249, 1181, 1115, 1066, 1016,
992, 934 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.85 (m, 1H), 5.67 (m,
2H), 5.33 (m, 1H), 5.21 (m, 1H), 4.83-4.75 (m, 1H), 2.60 (m, 4H),
2.41 (m, 1H), 2.14-1.92 (m, 5H), 1.63 (s, 3H), 1.70-1.47 (m, 3H);
EIMS 246 [M]+, 178, 119, 106; HRMS calcd for [C16H22O2]+ 246.1620,
found 246.1623.
(R)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-3-cyclohexenecar-
boxylic acid (13). A solution of lactone 11 (0.072 g, 0.292 mmol) in
CH2Cl2 (3.0 mL) at -78 °C was treated with Et3N (0.122 mL, 0.876
mmol), followed by tert-butyldimethylsilyl trifluoromethanesulfonate
(0.101 mL, 0.438 mmol). The reaction mixture was warmed to 23 °C
over 30 min, and partitioned between pentane and ice-cold water. The
organic phase was rapidly washed with ice-cold water, dried over K2-
CO3(anhyd), and concentrated in Vacuo to provide silyl ketene acetal
12. A solution of the residue in toluene (5.0 mL) was heated at reflux
for 4.5 h, cooled to 23 °C, and concentrated in Vacuo. A solution of
the resulting oil in THF (3.0 mL) was treated with LiOH (1 M aqueous,
1.46 mL, 1.46 mmol) at 23 °C. The mixture was stirred for 15 min,
acidified by addition of HCl (1 M, 1.8 mL) to ca. pH 1, and extracted
with ether. The organic extract was washed twice with brine, dried
over MgSO4(anhyd), and concentrated in Vacuo. The residue was
purified by flash chromatography (hexanes-EtOAc-AcOH, 95:5:0.5
to 90:10:0.5) to afford 0.068 g (94% yield) of desired product 13 as an
oil: Rf ) 0.40 (hexanes-EtOAc-AcOH, 80:20:1, on an AcOH treated
plate); [R]23D +27° (c 1.4, CHCl3); FTIR (film) 3065, 3027, 2920, 2875,
2845, 2815, 1696, 1455, 1440, 1296, 1244, 1203 cm-1; 1H NMR (400
MHz, CDCl3) δ 5.67 (m, 4H), 2.59 (m, 4H), 2.54 (m, 1H), 2.17-1.93
(m, 6H), 1.61 (s, 3H), 1.76-1.56 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 183.7, 126.8, 126.4, 124.8, 124.7, 124.5, 124.1, 44.8, 36.4, 33.0, 32.6,
30.6, 29.5, 27.6, 22.7, 18.2; EIMS 246 [M]+, 126, 121, 106; HRMS
calcd for [C16H22O2]+ 246.1620, found 246.1627.
(R)-6-Hepteno-5-lactone (9). Stannyl alcohol 7c (0.459 g, 1.03
mmol) was treated with a solution of tetra-n-butylammonium fluoride
in THF (1 M, 5.15 mL, 5.15 mmol). The resulting mixture was heated
at reflux for 26 h, cooled to 23 °C, and treated with NaOH (1 M
aqueous, 30 mL). The mixture was washed twice with ether (30 mL
each). The aqueous layer was carefully acidified with HCl (4 M
aqueous, 10 mL) and extracted three times with EtOAc (100 mL each).
The combined organic extracts were washed once with brine (10 mL),
dried over MgSO4(anhyd), and concentrated in Vacuo. A solution of
the residue in CH2Cl2 (13.5 mL) at 0 °C was treated with 4-(dimethyl-
amino)pyridine (0.064 g, 0.52 mmol), followed by 1-(3-(dimethylami-
no)propyl)-3-ethylcarbodiimide hydrochloride (0.238 g, 1.24 mmol).
The mixture was stirred for 2 h at 23 °C, diluted with ether (ca. 55
mL), and filtered through a silica gel plug. The flask was rinsed
repeatedly with CH2Cl2-ether (4:1). The filtrate was concentrated in
Vacuo. The residue was purified by flash chromatography (hexanes-
ether, 30:70 to 20:80) to afford 0.108 g (83% yield) of product 9 of
88% ee (determined by chiral GC) as a fairly volatile oil: Rf ) 0.29
(1S,4S,5S)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-4-iodo-6-
oxa-7-oxobicyclo[3.2.1]octane (14). A solution of acid 13 (0.068 g,
0.276 mmol) in THF (0.6 mL) and water (0.6 mL) at 23 °C was slowly
treated with NaHCO3 (0.070 g, 0.828 mol). After the gas evolution
had subsided, the mixture was treated with potassium iodide (0.060 g,
0.359 mol), followed by iodine (0.091 g, 0.359 mol). The resulting
dark mixture was stirred in the dark for 3 h, quenched by addition of
Na2S2O3 (saturated aqueous solution) until the color disappeared, and
extracted with ether. The ethereal extracts were washed twice with
brine, dried over MgSO4(anhyd), and concentrated in Vacuo. The
residue was purified by flash chromatography (hexanes-EtOAc, 90:
10) to afford 0.081 g (79% yield) of colorless product 14 which
(hexanes-ether, 30:70); [R]23 -61.3° (c 1.65, CH2Cl2); FTIR (film)
D
2956, 1733, 1366, 1344, 1239, 1194, 1168, 1110, 1040, 988, 931 cm-1
;
1H NMR (500 MHz, CDCl3) δ 5.86 (ddd, J ) 17.2, 10.6, 5.4 Hz, 1H),
5.34 (d, J ) 17.1 Hz, 1H), 5.23 (d, J ) 10.6 Hz, 1H), 4.82 (m, 1H),
2.59 (m, 1H), 2.48 (m, 1H), 2.01-1.85 (m, 3H), 1.67 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 171.0, 136.1, 116.8, 80.2, 29.5, 27.8, 18.0;
CIMS (NH3) 144 [M + NH4]+, 127 [M + H]+; HRMS calcd for
[C7H10O2 + NH4]+ 144.1025, found 144.1027; GC (chiral) (G-TA
column at 100 °C (2 min), 1 °C/min ramp, 150 °C (30 min); FID;
injector temp ) detector temp ) 250 °C) retention times 21.6 (major),
24.0 (minor) min at 20.0 psi of helium. The absolute stereochemistry
was established by hydrogenation (H2, Rh-C (5%), ether, 0-23 °C, 2
h, 69% yield) to afford (S)-δ-heptanolactone: [R]23D -51° (c 0.69, THF)
(lit.24 for the (R)-enantiomer [R]D +55.0° (c 1.13, THF)).
solidified: mp 78-88 °C; Rf ) 0.31 (hexanes-EtOAc, 90:10); [R]23
D
-0.72° (c 2.76, CHCl3); FTIR (film) 2920, 2872, 2840, 2814, 1773,
1445, 1358, 1336, 1317, 1209, 1197, 1177, 1162, 1091, 1047, 1015,
994, 961, 912, 855 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.69 (m, 2H),
4.78 (dd, J ) 6.0, 4.2 Hz, 1H), 4.49 (t, J ) 4.5 Hz, 1H), 2.72 (d, J )
12.1 Hz, 1H), 2.61 (m, 4H), 2.43-2.30 (m, 2H), 2.15-2.05 (m, 2H),
1.92 (m, 1H), 1.84 (dd, J ) 13.1, 5.5 Hz, 1H), 1.65 (s, 3H), 1.67-
1.62 (m, 2H), 1.55 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 178.9,
126.3 (2C), 124.5, 124.4, 78.2, 46.2, 37.5, 32.9, 32.1, 30.5, 30.0, 29.3,
27.5, 23.7, 18.3; CIMS (NH3) 390 [M + NH4]+; HRMS calcd for
[C16H21O2I + NH4]+ 390.0930, found 390.0930.
(5R)-2-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-6-hepteno-5-lac-
tone (11). A solution of diisopropylamine (0.084 mL, 0.60 mmol) in
THF (5 mL) at 0 °C was treated dropwise with n-butyllithium in
hexanes (2.5 M, 0.240 mL, 0.60 mmol). The solution was stirred for

An EnantioselectiVe Synthetic Route to Atractyligenin
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11775
(1S,5S)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-6-oxa-7-oxo-
bicyclo[3.2.1]oct-3-ene (15). A solution of iodolactone 14 (0.078 g,
0.210 mmol) in benzene (1.0 mL) at 23 °C was treated with
1,8-diazabicyclo[5.4.0]undec-7-ene (0.047 mL, 0.315 mmol). The
solution was heated at reflux for 4 h. The resulting heterogeneous
mixture was allowed to cool to 23 °C, and partitioned between HCl (1
M aqueous) and ether. The ethereal layer were washed with brine,
NaHCO3 (saturated aqueous solution), and brine, dried over MgSO4
(anhyd), and concentrated in Vacuo. The residue was purified by flash
chromatography (hexanes-EtOAc, 85:15) to afford 0.049 g (96% yield)
of the desired product 15 of 88% ee (determined by chiral HPLC) as
a colorless solid: mp 60-63 °C (unrecrystallized); Rf ) 0.36 (hexanes-
(chiral) (Chiralcel OD at 23 °C; λ ) 254 nm; hexanes-2-propanol,
99.9:0.1), retention times: 19.6 (minor), 22.4 min (major) at 1 mL/
min flow rate.
Methyl 5-Oxo-7-(trimethylsilyl)hept-6-enoate (6b). A solution of
1-(tri-n-butylstannyl-2-(trimethylsilyl)ethylene31 (7.65 mL, 20.0 mmol)
and methyl 4-(chloroformyl)butanoate (Aldrich, 2.76 mL, 20.0 mmol)
in CHCl3 (20 mL) was treated at 23 °C with bis(triphenylphosphine)-
palladium(II) chloride (0.070 g, 0.10 mmol). The solution was heated
at reflux under a dry air atmosphere for 1 h. The resulting solution
was cooled to 23 °C, diluted with ether, and shaken with potassium
fluoride (half-saturated aqueous solution). The mixture was allowed
to stand for 10 min and filtered. The solid was washed with ether.
The organic layer of the filtrate was washed with potassium fluoride
(half-saturated aqueous solution) and filtered. The filtrate was washed
with brine, dried over MgSO4(anhyd), and concentrated in Vacuo. The
residue was purified by flash chromatography (hexanes-EtOAc, 85:
15) to afford 4.18 g (92% yield) of desired product 6b as a yellow oil:
Rf ) 0.36 (hexanes-EtOAc, 80:20); FTIR (film) 2956, 1739, 1698,
EtOAc, 80:20); [R]23 -69.5° (c 0.755, CHCl3); FTIR (film) 2916,
D
2873, 2815, 1769, 1427, 1381, 1308, 1265, 1130, 1104, 1053, 1016,
1
959, 947, 915 cm-1; H NMR (400 MHz, CDCl3) δ 6.23 (m, 1H),
5.89 (m, 1H), 5.68 (m, 2H), 4.74 (t, J ) 5.4 Hz, 1H), 2.61 (m, 4H),
2.43-2.30 (m, 3H), 2.16 (m, 1H), 2.02-1.94 (m, 2H), 1.76-1.67 (m,
2H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 180.3, 131.3, 129.2,
126.5 (2C), 124.5, 124.4, 71.6, 45.5, 37.9, 35.3, 32.9, 32.6, 30.5, 27.3,
18.2; CIMS (NH3) 262 [M + NH4]+, 245 [M + H]+; HRMS calcd for
[C16H20O2 + NH4]+ 262.1807, found 262.1806; HPLC (chiral) (Chiral-
cel OD at 23 °C; λ ) 225 nm; hexanes-2-propanol, 97.5:2.5) retention
times 16.8 (major), 20.7 (minor) min at 1 mL/min flow rate.
1
1679, 1437, 1251, 1206, 1175, 1150, 997, 865, 842 cm-1; H NMR
(400 MHz, CDCl3) δ 7.06 (d, J ) 19.3 Hz, 1H), 6.46 (d, J ) 19.3 Hz,
1H), 3.67 (s, 3H), 2.68 (t, J ) 7.2 Hz, 2H), 2.37 (t, J ) 7.2 Hz, 2H),
1.94 (quintet, J ) 7.2 Hz, 2H), 0.14 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 199.3, 173.5, 146.7 142.0, 51.4, 38.0, 33.0, 19.0, -2.0; CIMS
(NH3) 246 [M + NH4]+, 229 [M + H]+; HRMS calcd for [C11H20O3Si
+ NH4]+ 246.1525, found 246.1534.
(R)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)cyclohexa-2,4-di-
enecarboxylic Acid (16). A solution of lactone 15 (0.052 g, 0.214
mmol) in THF (1 mL) at -78 °C was treated with a solution of
potassium bis(trimethylsilyl)amide (0.047 g, 0.236 mmol) in THF (1
mL). The resulting solution was stirred at -30 °C for 4 h (at which
point the conversion was estimated to be 80% by TLC), and quenched
by addition of water. The mixture was partitioned between NaOH (0.1
M aqueous) and ether. The ethereal phase was washed twice with brine,
dried with MgSO4(anhyd), and concentrated in Vacuo. The residue
was filtered through a silica gel plug eluting with hexanes-EtOAc (80:
20) to provide 0.013 g (25%) of recovered starting material. The basic
aqueous phase was acidified to pH 0-1 with HCl (1 M aqueous) and
extracted with ether. The organic extracts were washed twice with
brine, dried over MgSO4(anhyd), and concentrated in Vacuo. The
residue was filtered through a silica gel plug eluting with hexanes-
EtOAc (80:20) to afford 0.037 g (71% yield, 95% with respect to
recovered starting material) of desired product 16 as a colorless solid:
mp 65-69 °C (unrecrystallized); Rf ) 0.48 (hexanes-EtOAc-AcOH,
80:20:1, on AcOH treated plates); [R]23D -80.3° (c 1.04, CHCl3); FTIR
(film) 3033, 2976, 2950, 2923, 2872, 2815, 1700, 1290, 1273, 1236
(S)-Methyl 5-Hydroxy-7-(trimethylsilyl)hept-6-enoate (7b). Ke-
toester 6b (0.514 g, 2.25 mmol) was azeotropically dried twice with
toluene (2 mL), treated with oxazaborolidine catalyst (R)-4a (0.1 M in
toluene, 2.25 mL, 0.225 mmol) at 23 °C, and concentrated in Vacuo
under inert conditions. The residue was dissolved in CH2Cl2 (8.10 mL).
The resulting solution was cooled to -78 °C, and treated dropwise
over 30 min with catecholborane (0.360 mL, 3.38 mmol) in CH2Cl2
(1.08 mL) via syringe pump directly into the solution. The reaction
mixture was stirred at -78 °C for 24 h, quenched by slow addition of
methanol (2 mL) down the side of the flask, warmed to 23 °C, and
diluted with ether. The solution was washed with a 2:1 mixture of
NaOH (1.0 M aqueous) and NaHCO3 (saturated aqueous solution) until
the washings were colorless, washed once with brine, dried over MgSO4
(anhyd), and concentrated in Vacuo. The residue was purified by flash
chromatography (hexanes-EtOAc, 70:30) to afford 0.500 g (96% yield)
of desired product 7b as a clear oil of 94% ee (determined by HPLC):
Rf ) 0.22 (CH2Cl2-EtOAc, 95:5); [R]22D +6.1° (c 0.80, CHCl3); FTIR
(film) 3448, 2955, 1741, 1621, 1438, 1420, 1365, 1308, 1248, 1201,
1
1175, 1101, 1065, 1042, 990, 867, 839 cm-1; H NMR (400 MHz,
1
cm-1; H NMR (500 MHz, CDCl3) δ 6.00 (dd, J ) 9.6, 5.1 Hz, 1H),
CDCl3) δ 6.02 (dd, J ) 18.7, 5.3 Hz, 1H), 5.85 (dd, J ) 18.7, 1.2 Hz,
1H), 4.09 (q, J ) 5.6 Hz, 1H), 3.67 (s, 3H), 2.35 (t, J ) 7.3 Hz, 2H),
1.8-1.5 (m, 4H), 0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.1,
148.2, 129.5, 74.1, 51.6, 36.1, 33.8, 20.8, -1.3; CIMS (NH3) 428 [2M
- CH3OH]+, 248 [M + NH4]+, 213 [M + H - H2O]+; HRMS calcd
for [C11H22O3Si + NH4]+ 248.1682, found 248.1682; HPLC (chiral)
(Regis Whelk-O1 at 23 °C; λ ) 250 nm; hexanes-2-propanol, 97.5:
2.5) retention times 12.3 (minor), 15.2 (major) min at 1 mL/min flow
rate. The absolute stereochemistry was established by comparison of
the optical rotation with that of an authentic sample: [R]25D +6.78° (c
1.15, CHCl3).33
5.89 (m, 1H), 5.85 (d, J ) 9.6 Hz, 1H), 5.78 (m, 1H), 5.66 (m, 2H),
2.77 (ddd, J ) 17.9, 3.9, 2.3 Hz, 1H), 2.58 (m, 4H), 2.35 (ddd, J )
17.9, 4.7, 1.4 Hz, 1H), 2.03-1.94 (m, 2H), 1.83 (td, J ) 12.2, 5.1 Hz,
1H), 1.70 (td, J ) 12.3, 5.4 Hz, 1H), 1.60 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 182.8, 128.2, 126.7, 125.1, 124.6, 124.5, 124.4, 124.3,
123.2, 45.8, 35.3, 32.9, 30.6, 30.5, 27.9, 18.2; CIMS (NH3) 262 [M +
NH4]+, 134, 96; HRMS calcd for [C16H20O2 + NH4]+ 262.1807, found
262.1798.
Methyl (R)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)cyclohexa-
2,4-dienecarboxylate (3). A solution of acid 16 (0.0280 g, 0.115
mmol) in CH2Cl2 (4 mL) at 23 °C was treated dropwise (over ca. 5
min) with a solution of CH2N2 in ether (ca. 0.45 M) until the solution
remained yellow. The resulting mixture was concentrated in Vacuo.
The residue was purified by flash chromatography (hexanes-EtOAc,
97.5:2.5) to afford 0.0267 g (90% yield) of desired product 3 of 88%
ee (determined by chiral HPLC) as an oil: Rf ) 0.45 (hexanes-EtOAc,
90:10); [R]23D -68.5° (c 1.02, CHCl3); FTIR (film) 2950, 2815, 1733,
(S)-7-(Trimethylsilyl)-6-hepteno-5-lactone (17). A solution of
allylic alcohol 7b (1.50 g, 6.51 mmol) in benzene (65 mL) was treated
with p-toluenesulfonic acid monohydrate (0.062 g, 0.326 mmol). The
flask was fitted with a pressure-equalizing funnel containing 4 Å
molecular sieves (25 mL), and above that a condenser. The reaction
mixture was heated at reflux for 1 h, cooled to 23 °C, and quenched
by addition of triethylamine (30 drops). The solution was passed
through a small silica gel plug eluting with ether and concentrated in
Vacuo. The product was purified by flash chromatography (CH2Cl2)
to afford 1.174 g (91% yield) of desired product 17 as a clear oil: Rf
) 0.50 (CH2Cl2-EtOAc, 95:5); [R]20D +22.0° (c 1.06, CHCl3); FTIR
1
1432, 1224, 1199, 1170 cm-1; H NMR (500 MHz, CDCl3) δ 5.96
(dd, J ) 9.6, 5.1 Hz, 1H), 5.87 (m, 1H), 5.84 (d, J ) 9.6 Hz, 1H), 5.77
(m, 1H), 5.76 (m, 2H), 3.70 (s, 3H), 2.76 (ddd, J ) 17.8, 3.9, 2.2 Hz,
1H), 2.57 (s, 4H), 2.33 (ddd, J ) 17.8, 4.6, 1.5 Hz, 1H), 1.98-1.86
(m, 2H), 1.78 (td, J ) 12.3, 5.1 Hz, 1H), 1.66 (td, J ) 12.6, 5.5 Hz,
1H), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 128.8, 126.8,
125.2, 124.6, 124.4, 124.1, 124.0, 123.1, 52.0, 45.9, 35.5, 32.9, 30.8,
30.6, 28.0, 18.2; EIMS 258 [M]+, 199 [M - CO2CH3]+, 140, 137,
105; HRMS calcd for [C17H22O2]+ 258.1620, found 258.1614; HPLC
1
(film) 2956, 1739, 1245, 1087, 1041, 990, 867, 839 cm-1; H NMR
(500 MHz, CDCl3) δ 5.99 (dd, J ) 18.3, 15.1 Hz, 2H), 4.80 (m, 1H),
2.56 (m, 1H), 2.49 (m, 1H), 2.01-1.83 (m, 3H), 1.65 (m, 1H), 0.05 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 142.7, 132.1, 81.6, 29.5,
27.7, 18.0, -1.6; CIMS (NH3) 216 [M + NH4]+, 199 [M + H]+; HRMS
calcd for [C10H18O2Si + NH4]+ 216.1420, found 216.1423.

11776 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Corey et al.
(5S)-2-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-7-(trimethylsilyl)-
6-hepteno-5-lactone (18). A solution of diisopropylamine (0.186, 1.33
mmol) in THF (11.0 mL) was treated with n-butyllithium (2.5 M in
hexanes, 0.532 mL, 1.33 mmol) at 0 °C, stirred for 15 min, and treated
with hexamethylphosphoramide (1.16 mL, 6.66 mmol). The resulting
solution was cooled to -78 °C and treated over 30 min (via syringe
pump) with lactone 17 (dried azeotropically with toluene, 2 × 1 mL)
(0.220 g, 1.11 mmol) in THF (1.5 mL). The reaction mixture was
stirred for 30 min, and treated dropwise with iodide 1012 (0.168 mL,
1.01 mmol). The solution was warmed to -50 °C, stirred for 3 h,
then cooled to -78 °C, and quenched by addition of NH4Cl (saturated
aqueous solution). The mixture was warmed to 23 °C, and partitioned
between ether and water. The aqueous layer was extracted with ether.
The combined organic extracts were washed with brine, dried over
MgSO4(anhyd), and concentrated in Vacuo. The residue was purified
by flash chromatography (hexanes eluted excess 10; hexanes-EtOAc,
95:5, eluted the product; hexanes-EtOAc, 70:30 eluted the remaining
starting material 17) to afford 0.055 g (25% yield) of starting lactone
17, and 0.158 g (45% yield, 60% with respect to recovered starting
material) of desired product 18 as a ca. 1:1 mixture of diastereomers
(determined by 1H NMR): Rf ) 0.45, 0.39 (hexanes-EtOAc, 80:20);
FTIR (film) 2954, 2871, 1736, 1459, 1371, 1248, 1215, 1178, 1095,
(0.049 g, 0.154 mmol) in ether (3 mL) was treated at 23 °C with
diazomethane (1.5 mL, 0.45 M in ether, 0.675 mmol) in three separate
portions (waiting 30 min between each) until the yellow color persisted.
The solution was quenched by addition of glacial acetic acid (1 drop).
The reaction mixture was partitioned between ether and NaHCO3
(saturated aqueous solution). The organic layer was washed with brine,
dried over MgSO4(anhyd), and concentrated in Vacuo to afford 0.050
g (98% yield) of desired product 21 as a colorless solid: mp 32-34
°C (not recrystallized); Rf ) 0.51 (hexanes-EtOAc, 90:10); [R]23
D
+198° (c 1.20, CHCl3); FTIR (film) 3025, 2952, 2923, 2916, 2874,
2839, 2815, 1731, 1249, 1189, 839 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.69-5.58 (m, 3H), 5.50 (m, 1H), 3.68 (s, 3H), 2.57 (s, 4H), 2.08-
1.82 (m, 6H), 1.72 (m, 3H), 1.59 (s, 3H), -0.01 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 177.6, 127.0, 126.8, 124.7, 124.5, 123.7, 122.8,
51.3, 46.1, 37.5, 34.3, 32.9, 30.6, 27.9, 23.7, 22.1, 18.1-1.2; CIMS
(NH3) 350 [M + NH4]+, 333 [M + H]+; HRMS calcd for [C20H32O2Si
+ NH4]+ 350.2515, found 350.2512.
Methyl (1R)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-4-bromo-
2-cyclohexenecarboxylate (22). A solution of ester 21 (0.0312 g,
0.0938 mmol) in acetone-water (4:1 mixture, 3.0 mL) at -25 °C was
treated dropwise with N-bromosuccinimide (0.0701 g/mL solution in
acetone, 0.298 mL, 0.1173 mmol). The resulting solution was stirred
at -25 °C in the dark for 1 h. The reaction mixture was quenched by
addition of Na2SO3 (saturated aqueous solution) and partitioned between
water and ether. The organic layer was washed with brine, dried over
MgSO4(anhyd), and concentrated in Vacuo. The residue was purified
by flash chromatography (hexanes-EtOAc, 95:5) to afford 0.0044 g
(14% yield) of starting material 21 and 0.0165 g (52% yield, 60% with
respect to recovered starting material) of 22 as a ca. 1:1 mixture of
1
1071, 989, 864, 839 cm-1; H NMR (500 MHz, CDCl3) δ 5.99 (m,
2H), 5.68 (m, 2H), 4.78 (m, 1H), 2.61 (m, 4H), 2.43 (m, 1H), 2.14-
1.93 (m, 6H), 1.75 (m, 1H), 1.65 (s, 3H), 1.6-1.4 (m, 1H), 0.07 (s,
9H); CIMS (NH3) 336 [M + NH4]+, 319 [M + H]+; HRMS calcd for
[C19H30O2Si + NH4]+ 336.2359, found 336.2357.
(1R,2S)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-2-(trimethyl-
silyl)-3-cyclohexenecarboxylic Acid (20). A solution of lactone 18
(0.327 g, 1.03 mmol) in CH2Cl2 (5 mL) at -78 °C was treated with
triethylamine (0.431 mL, 3.09 mmol), followed by tert-butyldimeth-
ylsilyl triflate (0.355 mL, 1.55 mmol). The resulting solution was
warmed to 23 °C over 30 min, and partitioned between pentane and
ice-cold water. The organic layer was washed with ice-cold water,
dried over K2CO3(anhyd), and concentrated in Vacuo to provide silyl
ketene acetal 19. A solution of the residue in toluene (15 mL) was
heated at reflux for 24 h. The solution was cooled to 23 °C and
concentrated in Vacuo. A solution of the residue in THF (10 mL) was
treated with lithium hydroxide (1 M aqueous, 2.1 mL, 2.1 mmol). The
reaction mixture was stirred at 23 °C for 15 min and treated with pH
4 buffer solution (30 mL), ether, and HCl (1 M aqueous, 2.1 mL, 2.1
mmol). The organic phase was separated. The aqueous layer was
extracted again with ether. The combined organic extracts were washed
three times with brine, dried over MgSO4(anhyd), and concentrated in
Vacuo. The residue was purified by flash chromatography (hexanes-
EtOAc, 90:10) to afford 0.259 g (79% yield) of desired product 20 as
a colorless solid: mp 88-92 °C (not recrystallized); Rf ) 0.38
(hexanes-EtOAc, 80:20); [R]20D +199° (c 0.640, CHCl3); FTIR (film)
1
diastereomers (determined by H NMR): Rf ) 0.45, 0.37 (hexanes-
EtOAc, 90:10); FTIR (film) 2950, 2926, 2871, 2814, 1732, 1445, 1435,
1
1267, 1227, 1201, 1171, 1130, 1057, 988, 806 cm-1; H NMR (400
MHz, CDCl3) δ 6.04-5.95 (m, 1H), 5.89 (d, J ) 10.2 Hz, 1/2H), 5.78
(d, J ) 9.8 Hz, 1/2H), 5.67 (m, 2H), 4.77 (m, 1/2H), 4.72 (m, 1/2H),
3.73 (s, 3/2H), 3.68 (s, 3/2H), 2.58 (m, 4H), 2.62-2.35 (m, 8H), 1.61
(s, 3/2H), 1.58 (s, 3/2H); CIMS (NH3) 358 [M + NH4 + 2]+, 356 [M
+ NH4]+; HRMS calcd for [C17H23O2Br + NH4]+ 356.1225, found
356.1216.
Methyl (R)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)cyclohexa-
2,4-dienecarboxylate (3). A solution of allylic bromide 22 (0.0057
g, 0.0168 mmol) in benzene (0.5 mL) was treated with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (0.025 mL, 0.168 mmol) and heated at reflux for 2
h. The reaction mixture was cooled to 23 °C, diluted with ether, washed
with brine, dried over MgSO4(anhyd), and concentrated in Vacuo. The
residue was purified by flash chromatography (hexanes-EtOAc, 95:
5) to afford 0.0015 g (35% yield) of desired product 3 of 92-94% ee
(determined by HPLC): [R]23D -71.4° (c 1.34, CHCl3); for additional
analytical data see 3 above.
1
2955, 2875, 1695, 1292, 1265, 1249, 838 cm-1; H NMR (400 MHz,
CDCl3) δ 5.70-5.53 (m, 4H), 2.59 (br s, 4H), 2.14-1.64 (m, 9H),
1.61 (s, 3H), 0.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 184.7, 127.0,
126.7, 124.8, 124.5, 123.9. 122.9, 46.1, 37.6, 34.2, 33.0, 30.7, 27.9,
23.3, 22.0, 18.2, -1.0; CIMS (NH3) 336 [M + NH4]+; HRMS calcd
for [C19H30O2 + NH4]+ 336.2359, found 336.2353.
Acknowledgment. This research was assisted financially by
grants from the National Science Foundation and the National
Institutes of Health.
Methyl (1R,2S)-1-(2-(2-Methyl-1,4-cyclohexadienyl)ethyl)-2-(tri-
methylsilyl)-3-cyclohexenecarboxylate (21). A solution of acid 20
JA973034O