Diastereoselective total synthesis of both enantiomers of epolactaene

Article abstract of DOI:10.1021/jo025641m

A stereocontrolled total synthesis of both the (+)- and (-)-epolactaene ((+)- and (-)-1) enantiomers from tetrahydropyran-2-ol is described. The following reactions in this synthesis are particularly noteworthy: (1) the stereoselective construction of the conjugated (E,E,E)-triene by a combination of kinetic deprotonation and thermodynamic equilibration, (2) the E-selective Knoevenagel condensation of β-ketonitrile 33 with a chiral 2-alkoxyaldehyde, (3) a diastereoselective epoxidation achieved using a bulky nucleophile (TrOOLi) and an appropriate protecting group, (4) the mild hydrolysis of an α-epoxy nitrile by silica gel on TLC facilitated by hydroxyl-mediated, intramolecular assistance.

Full text of DOI:10.1021/jo025641m

Dia ster eoselective Tota l Syn th esis of Both En a n tiom er s of
Ep ola cta en e
Yujiro Hayashi,*,†,‡ J un Kanayama,† J unichiro Yamaguchi,† and Mitsuru Shoji†
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, J apan, and Department of Chemistry, Graduate School of
Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, J apan
hayashi@ci.kagu.tus.ac.jp
Received February 21, 2002
A stereocontrolled total synthesis of both the (+)- and (-)-epolactaene ((+)- and (-)-1) enantiomers
from tetrahydropyran-2-ol is described. The following reactions in this synthesis are particularly
noteworthy: (1) the stereoselective construction of the conjugated (E,E,E)-triene by a combination
of kinetic deprotonation and thermodynamic equilibration, (2) the E-selective Knoevenagel
condensation of â-ketonitrile 33 with a chiral 2-alkoxyaldehyde, (3) a diastereoselective epoxidation
achieved using a bulky nucleophile (TrOOLi) and an appropriate protecting group, (4) the mild
hydrolysis of an R-epoxy nitrile by silica gel on TLC facilitated by hydroxyl-mediated, intramolecular
assistance.
In tr od u ction
structure and interesting biological properties and the
scarcity of natural material, epolactaene has been an
attractive target for organic chemists, and several re-
search groups have undertaken its total synthesis. The
first total syntheses of 1, published by our8 and Kogen’s9
laboratories in 1998, established its absolute stereochem-
istry to be 13R,14R. Kobayashi et al. also described a
synthesis in 1999.10
Epolactaene (1) is a microbial metabolite isolated by
Kakeya, Osada, et al. from the fungal strain Penicillium
sp. BM 1689-P.1 As it is effective in promoting neurite
Ou r P r eviou s Syn th esis of Ep ola cta en e
Epolactaene contains an epoxylactam and a conjugated
triene, both of which are thought to be labile, as the epoxy
group of the former is activated by two adjacent electron-
withdrawing groups, while the latter can be decomposed
by acid, base, light, and oxidizing conditions. We planned
to construct the triene first, and then to assemble the
epoxylactam rapidly under mild reaction conditions. As
the absolute stereochemistry was initially unknown, our
synthetic route should provide easy access to both enan-
tiomers. We succeeded in achieving these goals, and in
determining the absolute stereochemistry, the key steps
of our synthesis being summarized in Scheme 1. Tetra-
hydropyran-2-ol (2) was converted to (E,E)-dienecarboxy-
lic acid derivative 3 stereoselectively by Wittig and
Horner-Emmons reactions. After aldol reaction of ester
3 with acetaldehyde to afford (E,E)-diene derivative 4,
dehydration and isomerization reactions afforded conju-
outgrowth and arresting the cell cycle at the G1 phase
in a human neuroblastoma cell line, it is regarded as a
potential treatment for various neurodegenerative dis-
eases such as dementia.2 Recently, epolactaene was found
to inhibit the activities of mammalian DNA polymerases
and human DNA topoisomerase II.3 Structurally, epo-
lactaene contains a labile (E,E,E)-triene and a novel
3-alkenoyl-3,4-epoxy-2-pyrrolidinone moiety. The 3-alk-
enoyl-2-pyrrolidinone group has been found in several
natural products including pramanici,4 L-755,807,5 PI-
091,6 and fusarin C.7 Because of its highly unusual
* To whom correspondence should be addressed at the Tokyo
University of Science.
† Tokyo University of Science.
‡ The University of Tokyo.
(1) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada, H. J .
Antibiot. 1995, 48, 733.
(2) (a) Kakeya, H.; Onozawa, C.; Sato, M.; Arai, K.; Osada, H. J .
Med. Chem. 1997, 40, 391. (b) Vantini, G,; Skaper, S. D. Pharmacol.
Res. 1992, 26, 1. (c) Dicicco-Bloom, E.; Friedman, W. J .; Black, I. B.
Neuron 1993, 11, 1101.
(3) Mizushima, Y.; Kobayashi, S.; Kuramochi, K.; Nagata, S.;
Sugawara, F.; Sakaguchi, K. Biochem. Biophys. Res. Commun. 2000,
273, 784.
(6) Kawashima, A.; Yoshimura, Y.; Sakai, N.; Kamigoori, K.; Mi-
zutani, T.; Omura, S. (Heisei). J pn. Kokai Tokkyo Koho J P 02062859
A2 19900302, 1990.
(7) Eilbert, F.; Thines, E.; Arendholz, W. R.; Sterner, O.; Anke, H.
J . Antibiot. 1997, 50, 443.
(4) Schwartz, R. E.; Helms, G. L.; Bolessa, E. A.; Wilson, K. E.;
Giacobbe, R. A.; Tkacz, J . S.; Bills, G. F.; Liesch, J . M.; Zink, D. L.;
Curotto, J . E.; Pramanik, B.; Onishi, J . C. Tetrahedron 1994, 50, 1675.
(5) Lam, Y. K. T.; Hensens, O. D.; Ransom, R.; Giacobbe, R. A.;
Polishook, J .; Zink, D. Tetrahedron 1996, 52, 1481.
(8) Hayashi, Y.; Narasaka, K. Chem. Lett. 1998, 313.
(9) Marumoto, S.; Kogen. H.; Naruto, S. J . Org. Chem. 1998, 63,
2068. Tetrahedron 1999, 55, 7129, 7145.
(10) Kuramochi, K.; Nagata, S.; Itaya, H.; Takano, K.; Kobayashi
S. Tetrahedron Lett. 1999, 40, 7371.
10.1021/jo025641m CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/05/2002
J . Org. Chem. 2002, 67, 9443-9448
9443

Hayashi et al.
SCHEME 1. Th e F ir st Tota l Syn th esis of (+)-1
gated (E,E,E)-triene 5, which was converted to triene
aldehyde 6. Horner-Emmons reaction of the newly
developed â-ketothioester diethyl phosphonate derivative
7 and 6 proceeded smoothly to afford γ,δ-unsaturated
â-ketothioester 8. After transformation of the thioester
to amide 9, Knoevenagel condensation11 with (R)-2-(tert-
butyldimethylsiloxymethoxy)propanal (10), which was
readily prepared from (R)-methyl lactate, afforded R,â-
unsaturated amide 11. Epoxidation of 11 gave epoxide
12. Deprotection of the protecting group, followed by the
oxidation, afforded (+)-1 for the first time.
Thus, the first total synthesis of epolactaene had been
accomplished, and its absolute stereochemistry deter-
mined.8 However, two steps had proved unsatisfactory
in terms of stereoselectivity and/or yield: One was the
Knoevenagel condensation between â-ketoamide 9 and
the chiral alkoxyaldehyde 10, which afforded addition
product 11 in low yield, and with low E/ Z-selectivity. The
other was the epoxidation reaction of 11 to give epoxide
12, for which diastereoselectivity was low (ca. 3:1). For
epolactaene and various analogues to be prepared in
quantity, these two steps needed to be improved. In this
paper, we describe the optimization of these steps, as well
as full details of the stereocontrolled total synthesis of
(+)-epolactaene by the application of these modifications.
E-isomer is the thermodynamic product; neither an
increase in catalyst loading nor an increase in reaction
time increased the yield of the desired Z-isomer. Altering
the hydroxyl protecting group of the aldehyde partner
does not improve the yield: Knoevenagel condensation
of ketoamide 9 with an aldehyde containing the more
bulky triethylsilyl protecting group proceeds slower in
reduced yield (Table 1, entry 2). We turned to the
possibility of using other â-ketoamide synthetic equiva-
lents such as â-ketoester, â-ketothioester, and â-ketoni-
trile. Initial model studies centered on the reaction of
substrates having a phenyl group instead of the triene
moiety, with an R-alkoxypropanal, in the presence of a
catalytic amount of ethylenediammonium diacetate.12
The results for model substrates 13a -c are summarized
in Table 1. â-Ketoester 13a did not react, and neither
possible condensation product was formed (entry 3).
Though the reactions of â-ketothioester 13b with 2-(tert-
butyldimethylsiloxymethoxy)propanal and with 2-trieth-
ylsiloxypropanal both proceeded, the undesired E-isomers
14′a and 14′b were exclusively formed in 84% and 48%
yield, respectively13 (entries 4 and 5, for the determina-
tion of the stereochemistry of Knoevenagel adducts of
14′a and 14′b vide infra). The difference in yield for these
two aldehydes is due to the bulkiness of their protecting
groups. The smaller this is, the better the yield. The high
E-selectivity is a result of the ready isomerization of
Z-isomer to E-isomer. â-Ketonitrile 13c, however, reacted
smoothly with both 2-(tert-butyldimethylsiloxymethoxy)-
propanal and 2-triethylsiloxypropanal in a much shorter
time than did â-ketothioester, to give the desired E-
Mod el Stu d ies
Because of the problems encountered in the Knoev-
enagel condensation of â-ketoamide 9 outlined above, we
examined the reaction conditions in detail and found that
the desired Z-isomer 11 is kinetically favored, while the
(12) Tietze, L.-F.; Kiedrowski, G. v. Tetrahedron Lett. 1981, 219;
Tietze, L.-F.; Bachmann, J .; Wichmann, J .; Burkhardt, O. Synthesis
1994, 1185.
(13) Hayashi, Y.; Miyamoto, Y.; Shoji, M. Tetrahedron Lett. 2002,
43, 4079.
(11) For reviews, see: J ones, G. Org. React. (N.Y.) 1967, 15, 204.
Tietze, L. F.; Beifuss, U. In Comprehensive Organic Synthesis; Trost,
B. M., Editor-in-Chief; Pergamon Press: Oxford, 1991; Vol. 2, p 341.
9444 J . Org. Chem., Vol. 67, No. 26, 2002

Diastereoselective Total Synthesis of Epolactaene
TABLE 1. Kn oeven a gel Rea ction of 9 a n d 13
a
Isolated yield. The character in parentheses indicates the geometry of the olefin.
adducts14 14c and 14d without formation of the Z-isomer
(note the change in priority) in good yield (entries 6 and
7). It is noteworthy that Knoevenagel condensations of
â-ketonitrile 13c and of â-ketothioester 13b selectively
afford the completely opposite stereoisomers. This high
E-selectivity for the cyano derivative can be attributed
to the thermodynamic stability of this isomer, for which
owing to the linear structure of the cyano group there is
no increased steric repulsion in the E-olefin. This high
E-selectivity with a â-ketonitrile is general to alde-
hydes: Not only the reaction with R-alkoxyaldehydes
such as 10, but also reactions with aromatic and aliphatic
aldehydes such as benzaldehyde and isobutyraldehyde
afford the E Knoevenagel condensation products stereo-
selectively.15 The high chemical yields and short reaction
time of the Knoevenagel reactions of the â-ketonitrile
with aldehyde derivatives such as 2-(tert-butyldimethyl-
siloxymethoxy)propanal and 2-triethylsiloxypropanal, re-
gardless of the relative bulkiness of their protecting
groups, indicate that the â-ketonitrile is highly reactive
as a Knoevenagel donor. This high reactivity of â-keto-
nitrile 13c is due to the strong electron-withdrawing
ability of the cyano group.
Next the stereoselectivity of the epoxidation was
investigated (Table 2). Though the reaction of 14c having
the tert-butyldimethylsiloxymethyl protecting group with
TrOOLi (Tr ) Ph3C) generated from TrOOH16 and
n-BuLi proceeded, the diastereoselectivity was very low
(59:41). On the other hand, nearly perfect stereoselection
was realized in the reaction of 14d , having the triethylsilyl
protecting group with TrOOLi, in which the nucleophile
attacks from the opposite face of the triethylsilyl protecting
group at -78 °C, affording â-epoxide 15d in 81% yield
TABLE 2. Ep oxid a tion Rea ction of 14
yielda
(%)
entry
R
15:15′
59:41
>99 (15d ):<1
1
2
CH2OSi-t-BuMe2 (14c)
SiEt3 (14d )
70
81
a
Isolated yield.
(for determination of the stereochemistry vide infra). The
bulky triethylsilyl protecting group is essential for this
high selectivity because only low selectivity was observed
in the reaction using the tert-butyldimethylsiloxymethyl-
containing substrate. Chelation of the tert-butyldimeth-
ylsiloxymethoxy moiety with lithium ion would reduce
the diastereoselectivity. The bulky nucleophile (TrOOLi)
is also necessary for high selectivity, as lower diastereo-
selectivity (5:1) was observed when the less bulky t-
BuOOLi was employed.
The remaining conceivable difficulty inherited with
this â-ketonitrile methodology is that the cyano group
must be hydrolyzed to an amide17 under reaction condi-
tions mild enough to be compatible with the conjugated
triene. However, we happened to find a neat solution to
(14) Because of the instability of the condensation products, rough
purification was performed by rapid column chromatography on florisil
gel.
(15) The Knoevenagel reaction of â-ketonitrile 13c with benzalde-
hyde and isobutyraldehyde afforded E-olefins selectively in 89% and
95% yields, respectively.
(16) Bissing, D. E.; Matuszak, C. A.; McEwen, W. E. J . Am. Chem.
Soc. 1964, 86, 3824.
(17) RuH2(PPh3)4-mediated hydration of nitriles has been reported
to proceed under neutral conditions at 120 °C, but our nitrile 16 was
decomposed under the literature conditions. Murahashi, S.; Sasao, S.;
Saito, E.; Naota, T. J . Am. Chem. Soc. 1992, 57, 2521 and references
therein.
J . Org. Chem, Vol. 67, No. 26, 2002 9445

Hayashi et al.
SCHEME 2. Mod el Syn th esis of th e Ep oxyla cta m Moiety 19 of Ep ola cta en e
SCHEME 3. Deter m in a tion of th e Geom etr y of 14′a
this problem. During purification of alcohol 16 by thin-
layer chromatography (TLC) on silica gel after removal
of the TES protecting group, hydrolysis of the nitrile
occurred via intramolecular hydroxy group assistance,
affording epoxylactone 17 and epoxyamide 18 (Scheme
2). The former was successfully transformed to the latter
by treatment with NH4OH in MeOH at 0 °C for 30 min
to give 18 in 74% yield over three steps from 15d .
Treatment of nitrile 16 with silica gel on TLC is crucial
for this transformation: Stirring the nitrile 16 in several
solvents in the presence of silica gel does not transform
it to the hydroxy amide 18. Other acidic conditions such
as p-TsOH in MeOH, acetic acid, and trifluoroacetic acid
are ineffective, generating several byproducts. Oxidation
of 18 with SO3‚pyridine,18 DMSO, and NEt3 proceeded
well, affording 3-alkenoyl-3,4-epoxy-2-pyrrolidinone 19 in
73% yield.
F IGURE 1. NOEs observed for lactones 17 and 17′.
between Mea and Ha was observed for 17, but not
detected for isomer 17′. This establishes the stereochem-
istry of 17 and 17′ to be as depicted in Figure 1.
Tota l Syn th esis of Ep ola cta en e by th e New
Meth od
Having established an improved synthetic route to the
3-alkenoyl-3,4-epoxy-2-pyrrolidinone, this methodology
was next applied to the total synthesis of epolactaene.
As the difference between this synthetic route and the
previous one is in the construction of the epoxylactam,
synthetic procedures for the triene part are essentially
the same, with only a few minor modifications. That is,
methyl 9-(tert-butyldimethylsiloxy)-2-ethylidene-4-meth-
ylnona-3,5-dienoate (5) was the key triene intermediate
in our first synthesis,8 while the corresponding tert-butyl
ester derivative 27 is required for the new route to
discriminate between the two ester groups in the reaction
of advanced intermediate 30 with LiCH2CN (vide infra,
Scheme 4).
Assign m en t of Ster eoch em istr y
The stereochemistry of Knoevenagel condensation
products 14′a and 14d was determined as follows: As
14′a could be converted to epoxyhydrofuran 20,19 by
epoxidation and deprotection (Scheme 3), the geometry
of 14′a was determined to be E. On the other hand, as
epoxylactone 17 was obtained from 14d as shown in
Scheme 2, the geometry of olefin 14d was assigned to be
E (note the change of priority).
The stereochemistry of epoxide 15d was determined
by an NOE study of the epoxylactone 17, the other
diastereomer of which, 17′, had already been obtained
in our previous synthesis of epolactaene.8 An NOE
Wittig coupling of 2 with (ethoxycarbonylethylidene)-
triphenylphosphorane in toluene at 90 °C for 1 h afforded
E-unsaturated ester 21 stereoselectively (E:Z ) >95:<5)
in 98% yield, the hydroxy group of which was protected
by treatment with tert-butyldimethylsilyl chloride (TB-
(18) Parikh, J . R.; Doering, W. v. E. J . Am. Chem. Soc. 1967, 89,
5505.
(19) The stereochemistry of epoxyhydrofuran 20 was not determined.
9446 J . Org. Chem., Vol. 67, No. 26, 2002

Diastereoselective Total Synthesis of Epolactaene
SCHEME 4
SCl) and imidazole in CH2Cl2 to give TBS ether 22 in
99% yield. Conversion of 22 to tert-butyl (E,E)-2,4-
nonadienoate 25 was accomplished stereoselectively by
the following sequence: (1) reduction of ester 22 to allylic
alcohol 23 by diisobutylaluminum hydride (DIBAL-H) in
CH2Cl2 from -78 to 0 °C; (2) oxidation of the allylic
alcohol 23 to aldehyde 24 by SO3‚pyridine,18 DMSO, and
NEt3 in CH2Cl2, 94% yield over two steps;20 (3) Horner-
Emmons reaction of 24 with tert-butyl dimethylphos-
phonoacetate and NaH in THF at 0 °C to afford 25 in
96% yield. Aldol condensation of the lithium enolate
generated from 25 and lithium diisopropylamide (LDA)
in THF-HMPA at -78 °C with acetaldehyde at -78 °C
for 3 h gave syn- and anti-aldols 26 in 96% yield in a
1:1.7 ratio, which could be separated by column chroma-
tography but were used as a mixture in the next step.
The diene moiety of these aldol isomers has the E,E-
geometry, with no other isomers being formed. This high
E,E-selectivity can be attributed to the selective, kinetic
deprotonation of proton Ha from the most stable confor-
mation, in which repulsion between the methyl and R
groups is minimized, as shown in Figure 2.
nonadienoate derivative 27 as follows: The aldols 26
were transformed into their mesylates by reaction with
methanesulfonyl chloride, NEt3, and a catalytic amount
of 4-(N,N-dimethylamino)pyridine (DMAP) in CH2Cl2.
Elimination of methanesulfonic acid from the crude
mesylates and isomerization using 1,4-diazabicyclo[2.2.2]-
octane (DABCO)21 in MeOH at reflux for 120 h22 afforded
a 15:1 mixture of (E)- and (Z)-ethylidene derivatives 27
in 86% yield. The following points about this transforma-
tion are noteworthy: (1) The (E)-ethylidene derivative
27 was stereoselectively formed from the syn-aldol at rt
by treatment with DABCO, while a mixture of Z- and
E-isomers was obtained from the anti-aldol. (2) Isomer-
ization of the Z-isomer to the E-isomer 27 proceeded
gradually in MeOH under reflux in the presence of
DABCO.
Since stereoselective preparation of diene 27 had been
achieved, the construction of the 3-alkenoyl-3,4-epoxy-
2-pyrrolidinone was next examined. Deprotection of the
silyl ether using n-Bu4NF in THF at rt for 2 h afforded
alcohol 28 quantitatively, and then SO3‚pyridine18 oxida-
tion gave aldehyde 29, also quantitatively. The Horner-
Emmons reaction of 29 with methyl 2-(diethylphosphono)-
The mixture of syn- and anti-aldols 26 was converted
to tert-butyl (3E,5E)-2-[(E)-ethylidene]-4-methyl-3,5-
(20) Griffith-Ley oxidation with 4-methylmorpholine N-oxide and
catalytic amount of tetrapropylammonium perruthenate in the
a
presence of molecular sieves 4A was employed in our previous synthesis
of epolactaene.8 Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23,
13.
(21) DABCO is more effective than DBU, which was used in our
8
previous synthesis of epolactaene.
(22) The isomerization of tert-butyl ester (Z)-27 was slower than that
of the corresponding methyl ester, which was used in our previous
synthesis of epolactaene.8
F IGURE 2. Kinetic deprotonation of Ha with LDA.
J . Org. Chem, Vol. 67, No. 26, 2002 9447

Hayashi et al.
propanate and n-BuLi in DME23 at rt afforded E-
R,â-unsaturated ester 30 quantitatively with high E-
selectivity. The reaction of methyl ester 30 with LiCH2-
CN (2 equiv) proceeded in 1 min at -88 °C, affording
â-ketonitrile 31 in 93% yield, while over-reaction at the
tert-butyl ester moiety was observed at higher temper-
atures and longer reaction times. After cleavage of the
tert-butyl ester with CF3CO2H, the resulting carboxylic
acid 32 was reacted with diazomethane at -78 °C,
affording methyl ester 33 in 92% yield over two steps.
Low temperature is again a key to the success of this
transformation, because a â-methoxy-R,â-unsaturated
nitrile is formed at 0 °C.
The critical Knoevenagel condensation between â-ke-
tonitrile 33 and (S)-2-triethylsiloxypropanal proceeded in
the presence of a catalytic amount of ethylenediammo-
nium diacetate, affording the addition product 34. Owing
to the instability of 34 and the next intermediate 35,
isolation was not performed until the purification of 38.
After short column chromatography on florisil gel, the
crude material 34 was treated with TrOOLi at -78 °C,
affording the epoxide 35. The following three reactions,
deprotection of the TES group with AcOH and NH4F in
aq THF, hydrolysis of the nitrile by silica gel on TLC,
and ammonolysis of the lactone-formed 37 by NH4OH in
MeOH, were carried out to afford hydroxyamide 38 in
22% yield over five steps (average 74% per step) after
purification on TLC. These five steps proceeded as
efficiently as in the model series, generating the func-
tionalized compound stereoselectively. The final oxidation
could be achieved using SO3‚pyridine,18 DMSO, and NEt3
in CH2Cl2, affording (+)-1 in 78% yield.
2-triethylsiloxypropanal revealed that no racemization
had in fact occurred under the present reaction condi-
tions.
Synthetic (+)-1 exhibited spectral data identical to
those reported for the natural substance (1H NMR, 13C
NMR, and mass spectroscopies), as well as a very similar
26
optical rotation (synthetic epolactaene, [R]D +31 (c )
26
0.12, MeOH); natural epolactaene, [R]D +32 (c ) 0.1,
MeOH)1). In addition, synthetic (+)-1 shows almost the
same biological activity as natural (+)-1 in SH-SY5Y
cells. The enantiomer of epolactaene was also synthesized
by the same route using (R)-2-triethylsiloxypropanal as
the Knoevenagel condensation partner with â-ketonitrile
33. Detailed biological studies on both enantiomers of
epolactaene and several analogues are now under way,
the results of which will be reported in due course.
In summary, both enantiomers of epolactaene have
been synthesized in an enantio- and diastereoselective
manner. This synthesis has several noteworthy fea-
tures: (1) the stereoselective formation of a substituted
conjugated (E,E,E)-triene, the diene unit of which was
stereoselectively synthesized by kinetic deprotonation,
with the final olefin being prepared selectively by ther-
modynamic equilibration, (2) the complementary stereo-
selective Knoevenagel reactions of â-ketonitriles and
â-ketothioesters, which afforded opposite stereoisomers,
(3) stereoselective epoxidation by a combination of a
suitable protecting group and a bulky hydroperoxide, (4)
the mild hydrolysis of a nitrile by silica gel during TLC
involving intramolecular assistance by a hydroxyl group.
Though we had succeeded in developing an improved
total synthesis of (+)-1, there remains the possibility of
racemization having occurred at the chiral center. That
is, the chiral 2-siloxypropanal may racemize during the
Knoevenagel reaction, not only because it has an acidic
R-hydrogen but also because an easily enolizable imine
may readily be formed by reaction with ethylenediam-
monium diacetate.24 The Knoevenagel adduct 34 may
also racemize under the basic epoxidation conditions,
because the allylic proton of 34 is likely to be acidic due
to the neighboring vinylogous â-ketonitrile structure.
However, the NMR spectra of the MTPA esters25 of
epoxides 36 prepared from optically active and racemic
Ack n ow led gm en t. This work was supported by the
Sumitomo Foundation and Grants-in-Aid for Scientific
Research from the Ministry of Education, Culture,
Sports, Science and Technology, Government of J apan.
Y.H. thanks Professor K. Narasaka, The University
of Tokyo, for helpful discussion and encouragement
throughout the course of this work. We also thank Drs.
H. Osada and H. Kakeya, Institute of Physical and
Chemical Research (RIKEN), for the biological tests and
helpful discussion.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
1
mental procedures, full characterization, and copies of the H
and 13C NMR and IR spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(23) Thompson, S. K.; Heathcook, C. H. J . Org. Chem. 1990, 55,
3386.
(24) A probable mechanism for the Knoevenagel reaction is as
follows: an ammonium salt reacts with an aldehyde to afford an imine,
which then reacts with a nucleophile. The isomerization of imine and
enamine is a well-known process, which leads to the racemic imine.
For the above reaction mechanism, see the reviews in ref 11.
J O025641M
(25) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543. Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
9448 J . Org. Chem., Vol. 67, No. 26, 2002