Total syntheses of (±) and (-)-stemoamide

Article abstract of DOI:10.1021/ja994214w

(±)-Stemoamide (1) was prepared in seven steps beginning with y- chlorobutryl chloride (20) and succinimide (15), which were efficiently converted to the key alkyne oxazole 17 on a multigram scale. Intramolecular (Diels-Alder)-(retro-Diels-Alder) reaction of 17 then gave butenolide 12b directly upon aqueous workup. The remaining two stereocenters in 1 were established in a single step by a highly selective reduction of 12b (NaBH₄/NiCl₂), followed by equilibration to the thermodynamically favored natural configuration. In analogous fashion (-)-stemoamide (1) was prepared beginning with L-pyroglutamic acid (S-35).

Full text of DOI:10.1021/ja994214w

J. Am. Chem. Soc. 2000, 122, 4295-4303
4295
Total Syntheses of (()- and (-)-Stemoamide
Peter A. Jacobi*,† and Kyungae Lee
Contribution from the Hall-Atwater Laboratories, Wesleyan UniVersity,
Middletown, Connecticut 06459-0180, and Burke Chemical Laboratory,
Dartmouth College, HanoVer, New Hampshire 03755
ReceiVed December 2, 1999
Abstract: (()-Stemoamide (1) was prepared in seven steps beginning with γ-chlorobutryl chloride (20) and
succinimide (15), which were efficiently converted to the key alkyne oxazole 17 on a multigram scale.
Intramolecular (Diels-Alder)-(retro-Diels-Alder) reaction of 17 then gave butenolide 12b directly upon
aqueous workup. The remaining two stereocenters in 1 were established in a single step by a highly selective
reduction of 12b (NaBH4/NiCl2), followed by equilibration to the thermodynamically favored natural
configuration. In analogous fashion (-)-stemoamide (1) was prepared beginning with L-pyroglutamic acid
(S-35).
Introduction
a number of pure constituents have been isolated and character-
ized, utilizing X-ray crystallography in combination with
degradation studies and spectroscopy.3 In addition to 1, members
of the stemona class include stenine (2), croomine (3), tuberos-
temonine (4), and stemonine (5). A distinguishing feature of
this group is the presence of a perhydroazaazulene ring (cf. 6),
and most members also contain an R-methyl-γ-butryolactone
functionality.
Stemoamide (1) is a member of the stemona class of alkaloids
that was isolated in 1992 from Stemona tuberosa, and whose
structure was elucidated by an extensive series of 2D NMR
experiments together with IR spectroscopy (Figure 1).1a Extracts
Not surprisingly, members of this class have attracted
considerable attention, and several partial and total syntheses
have appeared in the past few years. These include syntheses
of (()-stenine (1990)4a and (-)-stenine (1995),4b (+)-croomine
(1989, 1996),4c,d and the tricyclic core of tuberostemonine
(1996).4e In addition, four syntheses of stemoamide (1) have
been reported,4f-i making this compound the most sought after
target of the group. The first of these was carried out by
Williams et al. (1994),4f who prepared (-)-1 in ∼25 steps
beginning with (R)-(-)-methyl 3-hydroxy-2-methylpropionate.
Subsequently, Narasaka et al. reported a synthesis of (()-1
featuring sequential oxidative couplings of appropriately sub-
stituted organostannanes with ketone silyl enol ethers (1996).4g
Also in 1996, Mori et al. described a novel synthesis of (-)-1
(3) For leading references see: (a) Ye, Y.; Qin, G.; Xu, R.-S. Phy-
tochemistry 1994, 37, 1201, 1205. (b) Cheng, D.; Guo, J.; Chu, T. T.; Ro¨der,
E. J. Nat. Prod. 1988, 51, 202. (c) Xu, R.-S.; Lu, Y.-J.; Chu, J.-H.; Iwashita,
T.; Naoki, H.; Naya, Y.; Nakanishi, K. Tetrahedron 1982, 38, 2667. See
also ref 1.
(4) (a) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236. Chen,
C.-Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840. (b) Wipf, P.; Kim, Y.;
Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106. (c) Williams, D. R.;
Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923. (d) Martin,
S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299. (e) Goldstein, D. M.;
Wipf, P. Tetrahedron Lett. 1996, 37, 739. (f) Williams, D. R.; Reddy, J.
P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417 (g) Kohno, Y.; Narasaka,
K. Bull. Chem. Soc. Jpn. 1996, 69, 2063. (h) Kinoshita, A.; Mori, M. J.
Org. Chem. 1996, 61, 8356. Kinoshita, A.; Mori, M. J. Org. Chem.
Heterocycles 1997, 46 287. See also: Ivin, K. J. J. Mol. Catal. A: Chem.
1998, 133, 1. (i) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119, 3409.
Related synthetic efforts: (j) Morimoto, Y.; Nishida, K.; Hayashi, Y.;
Shirahama, H. Tetrahedron Lett. 1993, 34, 5773. (k) Martin, S. F.; Corbett,
J. W. Synthesis 1992, 55. (l) Beddoes, R. L.; Davies, M. P. H.; Thomas, E.
J. J. Chem. Soc., Chem. Commun. 1992, 538. (m) Wipf, P.; Kim, Y.
Tetrahedron Lett. 1992, 33, 5477. (n) Xiang, L. I.; Kozikowski, A. P. Synlett
1990, 2, 279. (o) Unless otherwise indicated all structures refer to racemic
compounds.
Figure 1. Stemona alkaloids.
of the Stemona species (and the closely related Croomiacea)
have been employed in Chinese traditional medicine for many
years, both in managing certain respiratory disorders (bronchitis,
pertussis, and tuberculosis) and also as anthelmintics (i.e.,
antiparasitic agents).2 However, it is only relatively recently that
† Current address: Department of Chemistry, Dartmouth College,
Hanover, NH 03755.
(1) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
(2) For leading references, see: (a) Goetz, M.; Edwards, O. E. In The
Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1976; Vol.
IX, pp 545-551. (b) Nakanishi, K.; Goto, T.; Ito, S.; Natori, S.; Nozoe, S.
In Natural Products Chemistry; Academic Press: New York, 1975; Vol.
2, pp 292-93. See also ref 1.
10.1021/ja994214w CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/19/2000

4296 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Jacobi and Lee
utilizing a Ru-catalyzed enyne metathesis reaction.4h In this
paper we provide experimental details for a conceptually new
synthesis of (()-stemoamide, which affords (()-1 in seven
steps beginning with γ-chlorobutryl chloride.4i In addition,
we describe a concise synthesis of enantiomerically pure
(-)-stemoamide (1).
operations carried out sequentially, so long as the stereogenic
centers were introduced in proper order. One strategy for
realizing this goal is outlined below.
We first addressed the issue of stereochemical control at the
noncontiguous C8 and C9a stereocenters. In stemoamide (1) these
centers are not epimerizable, and they are too far apart for
effective control by asymmetric induction (cf. Figure 3).
However, this situation changes markedly upon introduction of
a double bond at C9-C10 (Figure 4). Now both C8 and C9a are
Background
Our synthetic plan took advantage of the exceptional reactivity
of alkyne oxazoles 7 in intramolecular Diels-Alder cyclizations
(Figure 2).5a Transformations of this type lead directly to highly
Figure 4. Sequential epimerization.
epimerizable, and they are able to directly interact with each
other. On this basis we chose butenolide 12b as the key
intermediate for establishing the trans relative stereochemistry
of 1 at C8 and C9a under thermodynamic control. Models show
that the isomeric cis-butenolide 12a suffers from severe steric
crowding. Mainly this is due to the fact that the C10 methyl
group is forced into close proximity to the C1 methylene
hydrogens. In this arrangement, the C10 methyl bond and the
C1-C9a pyrrolidinone bond have a dihedral angle close to 0°
(pseudoeclipsed). Assuming free equilibration, epimerization at
C8 in 12a has the effect of increasing this dihedral angle to
∼60° (pseudostaggered), thereby greatly reducing steric interac-
tions. This relationship, which is qualitatively apparent with
models, was quantified with molecular mechanics calculations
(MM2*), which gave ∆Ha,b ) 3.9 kcal/mol for the strain energy
difference between 12a and 12b.6 Epimerization at C9a in 12a,
while having the same effect, was viewed as less likely due to
the lower pKa of H8 (the validity of this assumption was later
demonstrated with enantiomerically pure (-)-12b, vide infra).
Once in hand, cis reduction of 12b from the least hindered â-face
would afford the methyl lactone 13, which again suffers from
van der Waal’s repulsion between Me10 and C1. However,
inversion at the now epimerizable C10-position would relieve
this interaction, and produce stemoamide (1) as the thermody-
namically most stable product (MM2* ∆H13,1 ) 4.6 kcal/mol).6
Figure 2. Synthetic strategy.
substituted furans 9, via intermediate adducts 8 that suffer rapid
loss of RCN. When A ) alkoxy, mild acid hydrolysis of 9
affords butenolides 10, a conversion that we have previously
employed in syntheses of paniculide A and norsecurinine.5b,c
Finally, reduction of 10 provides a versatile route to lactones
11.5a This approach seemed well suited for constructing the
carbon skeleton of 1.
A potentially more difficult task pertained to stereochemical
control at C8-C10, but here nature greatly simplified our task
(Figure 3). Inspection of models indicates that each of the
Figure 3. Energy minimum.
stereogenic centers in 1 is in the thermodynamically most
favored configuration (i.e., 1 is the most stable of eight possible
diastereomers). In principle, then, equilibration at each of these
centers should lead ultimately to the “natural” relative stereo-
chemistry, an iteration that is readily achieved computationally.
Experimentally, such a “global” minimization is not possible,
since only C10 in 1 represents an epimerizable site. In practice,
however, the same result would obtain were each of these
Discussion and Results
(()-Stemoamide (1). Our initial goal was the synthesis of
the alkyne oxazole 17, which we believed to be only two steps
removed from the key butenolide 12b (Scheme 1).4o These steps
involved thermolysis of 17 to afford the methoxyfuran 19,
followed by mild acid hydrolysis.5 It was uncertain whether 12b
might be produced directly from 19 via a kinetically controlled
(5) (a) Jacobi, P. A. In AdVances in Heterocyclic Natural Product
Synthesis; Pearson, W. H., Ed.; Jai Press Inc.: Greenwich, CT, 1992; Vol.
II, pp 251-98 and references therein. (b) Jacobi, P. A.; Kaczmarek, C. S.
R.; Udodong, U. E. S. Tetrahedron 1987, 43, 5475. (c) Jacobi, P. A.; Blum,
C. A.; DeSimone, R. W.; Udodong, U. E. S. J. Am. Chem. Soc. 1991, 113,
5384.
(6) (a) Calculations were carried out using MacroModel V5.5, employing
the MM2* force field, and using Monte Carlo simulations to locate global
minima (>1000 MC steps).6b (b) Chang, G.; Guida, W. C.; Still, W. C. J.
Am. Chem. Soc. 1989, 111, 4379. See also: (c) Mohamadi, F.; Richards,
N. G. J.; Guida, W. C.; Liskamp, R.; Caufield, C.; Chang, G.; Hendrickson,
T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.

Total Syntheses of Stemoamide
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4297
Scheme 1
intermediate amide 21, which was formed in a high state of
purity (cf. Experimental Section). Our initial alkylation experi-
ments were then carried out with succinimide (15), which gave
a 97% yield of the oxazole imide 22 upon treatment at 0 °C
with NaH/DMF. These conditions turned out to be general for
alkylation of 14 with a range of imide/lactam nucleophiles (vide
infra). A number of routes were explored for converting the
oxazole imide 22 to the desired alkyne oxazole 17. By far the
most convenient of these employed the methoxylactam 24,
which was derived from 22 by selective reduction with NaBH4
(22f23),7 followed by workup with MeOH/H+ (72% overall
yield).8 Finally, BF3‚Et2O catalyzed condensation of 24 with
(1-propynyl)tributylstannane gave a 92% yield of the target
oxazole 17.9 In similar fashion, we prepared the “activated”
alkyne oxazole 25 (R ) CO2Me) by in situ activation of 23
with oxaloyl chloride, followed by trapping of the presumed
acyliminium intermediate with lithio methyl propiolate. Alkyne
25 proved to be a useful model system for exploring subsequent
Diels-Alder cyclizations.
In preliminary studies the activated alkyne oxazole 25 readily
underwent the desired IMDA reaction. Thus, brief heating of
25 in toluene afforded an 89% yield of the furan ester 26, which
was isolated as a stable solid (Scheme 3). We also briefly
Scheme 3
pathway (i.e. initial protonation at the R-face). However, we
were confident that the desired 8R-stereochemistry would be
favored under equilibrating conditions (cf. Figure 4). An
attractive feature of this approach was the simplicity of the
alkyne oxazole 17, which we planned to synthesize by coupling
of the 2-(3-chloropropyl) oxazole 14 with a suitable amine
nucleophile. Potential coupling partners included succinimide
(15) and the alkyne lactam 16, the latter of which might
eventually be prepared in homochiral form (vide infra).
The required 2-(3-chloropropyl) oxazole 14 was efficiently
prepared by acylation of methyl alaninate with γ-chlorobutryl
chloride (20), followed by cyclodehydration with P2O5 (20 g
scale, 80%) (Scheme 2).5a It was not necessary to isolate the
Scheme 2
explored the possibility that 26 might be further elaborated to
the desired butenolide 12b by either of two reaction pathways.
The first of these involved chemoselective reduction of 26 to
the corresponding methylfuran 19, followed by acid-catalyzed
hydrolysis. However, 26 proved to be remarkably stable to most
reducing agents, and under forcing conditions suffered mainly
decomposition. Similarly, an alternative route involving initial
hydrolysis of 26 to the butenolide 27 also failed, due to the
inertness of the furan ester 26 to even concentrated acid
conditions. The stability of alkoxyfurans bearing strong electron
withdrawing substituents has been noted previously.5
Not surprisingly, the “nonactivated” alkyne oxazole 17 was
much less reactive toward the desired (Diels-Alder)-(retro-
Diels-Alder) reaction sequence (Scheme 4). At temperatures
(7) Hart, D. J.; Sun, L.-Q.; Kozikowski, A. P. Tetrahedron Lett. 1995,
36, 7787.
(8) Choi, J.-K.; Ha, D.-C.; Hart, D. J.; Lee, C.-S.; Ramesh, S.; Wu, S. J.
Org. Chem. 1989, 54, 279.
(9) See, for example: (a) Koot, W.-J.; van Ginkel, R.; Kranenburg, M.;
Hiemstra, H.; Louwrier, S.; Moolenaar, M. J.; Speckamp, W. N. Tetrahedron
Lett. 1991, 32, 401. (b) Thaning, M.; Wistrand, L.-G. J. Org. Chem. 1990,
55, 1406. (c) Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico, C.; Villa,
R. Tetrahedron Lett. 1990, 31, 4949. (d) Keinan, E.; Peretz, M. J. Org.
Chem. 1983, 48, 5302.

4298 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Jacobi and Lee
up to 135 °C (ethylbenzene, reflux), 17 suffered mainly slow
decomposition to intractable tars, with at best only trace amounts
of 19 detectable by GC. Various efforts at catalyzing this
reaction with Lewis acids also failed.10 However, at higher
temperatures we obtained mixtures of the anticipated methoxy-
furan 19 as well as the butenolide 12b, our projected precursor
to stemoamide (1). In refluxing diethylbenzene (182 °C), this
reaction afforded 50-55% of 12b on gram scales and larger,
together with only trace amounts of byproducts (see below).
Although 19 was the major product by GC-MS analysis, it
suffered rapid hydrolysis to 12b upon attempted isolation. The
difference in stability between methoxyfuran 19, containing no
electron withdrawing group, and methoxyfuran 26 is notewor-
thy.5
Figure 5. Byproducts from thermolysis of 17.
Scheme 4
pathways. Following path a, single electron reduction of 32
would afford the methoxyfuran 19, a step that might propagate
a chain process initiated by electron donation from oxazole 17.
Under ordinary circumstances this pathway is apparently highly
favored, since 19 is by far the major product (see below,
however). Following path c, both 30 and 31 could be derived
by methyl radical abstraction (C8 and C10), followed by single
electron reduction (a concerted 1,5-methyl shift to afford 30
directly is geometrically impossible; an ionic mechanism,
involving Me+, is equally unlikely). Finally, following path b,
oxidation products 28 and 29 could arise by initial deprotonation
at C9R, followed by oxidation of the labile radical 33 and
subsequent hydrolysis.12b
Scheme 5
In agreement with the calculations summarized in Figure 4,
we could detect none of the epimeric cis-substituted butenolide
12a upon hydrolysis of 19. If formed at all, 12a underwent
spontaneous isomerization to 12b. However, we did isolate and
characterize a number of byproducts from the thermolysis of
17 (Figure 5). The most interesting of these were the diene 28
and the ring-opened ester 29, both clearly derived by oxidation,
and the unsaturated lactones 30 and 31. These last two
compounds are formally derived by methyl migration from
-OMe to C8 and C10, respectively (stemoamide numbering).
In addition to exhibiting the expected analytical and spectral
properties, the identities of 28 and 29 were confirmed by
chemical correlation.11a The structure of 30 was proven by X-ray
analysis.11b Although each of these compounds was isolated in
only 2-3% yield, their presence raised several mechanistic
questions. In particular, the formation of 30 and 31 implicated
a stepwise process for at least part of the cyclization sequence
(control experiments demonstrated that neither of these com-
pounds was formed upon thermolysis of 19).
Taken together, these observations are consistent with an
electron-transfer mechanism, in which oxazole 17 is in thermal
equilibrium with the corresponding radical cation 17•+ (Scheme
5). Electrochemical studies indicate that this process should be
feasible in the presence of mild oxidants (E1/2Ox for 17 ) 0.84
V at 25 °).12a,b Radical cation 17•+, which is activated toward
cyclization,13a could then undergo an inverse electron demand
Diels-Alder reaction,13b affording the furan radical cation 32.
This last material can now partition between several reaction
In principle, path b is subject to experimental verification,
since the rate of formation of 28 and 29 should correlate roughly
with the rate of proton abstraction from 32. This turned out to
be the case. Thus, under the usual conditions (base-free), the
ratio of 19 to 29 after 48 h at 182 °C was >14:1 (GC-MS
analysis with fluorene as internal standard). With added diiso-
propylethylamine this ratio decreased to 8:1 under identical
conditions of time and temperature, and with suspended Na2-
CO3, 19 and 29 were formed in essentially equal amounts (1.3:
(10) Including, for example, BF3‚Et2O, Et2AlCl, TiCl4, SnCl4, AlCl3,
SiO2, p-TsOH, Bu3SnOMe, and others.
(11) (a) Upon treatment with BF3‚Et2O, methyl ester 29 was cleanly
converted to butenolide 28. (b) We are grateful to Dr. Victor G. Young, of
The University of Minnesota, for carrying out the X-ray analysis of 30.

Total Syntheses of Stemoamide
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4299
1). Finally, utilizing base-washed glassware (saturated NaOH
in EtOH), 29 became the major product (19:29 ) 0.6:1.0), both
by GC analysis and by isolation. Significant amounts of oxidized
butenolide 28 were also formed. At present it is impossible to
say whether the electron transfer mechanism represents the
predominant reaction pathway, or simply operates in competition
with the thermal Diels-Alder process. However, it is interesting
to note that on large scales the cyclization of oxazole 17 to
methoxyfuran 19 is facilitated by electron acceptors such as
benzoquinone (cf. Experimental Section).14
epimerization at C10.15c (()-Stemoamide (1) thus prepared, in
two steps from acetylenic oxazole 17 and 7 steps overall from
20 (Figure 6), had identical 500 MHz NMR, IR, and mass
spectra as an authentic sample.4f,16
The identity of butenolide 12b was established by its highly
characteristic NMR and IR spectra, and confirmed by its
subsequent conversion to (()-stemoamide (1). The remaining
steps necessary to synthesize (()-1 involved (1) stereoselective
cis-reduction of 12b from the â-face (12bf13) and (2)
epimerization at C10 (13f1, Scheme 6). Several reagents and
Figure 6. Summary of synthesis of (()-1.
Synthesis of (-)-Stemoamide (1). To extend these studies
to the synthesis of (-)-stemoamide (1), it was necessary to
prepare the enantiomerically pure alkyne oxazole S-17. Two
routes were explored for making this compound, both of which
took advantage of the ready availability of L-pyroglutamic acid
(S-35) (Scheme 7). One approach involved initial conversion
of S-35 to the alkyne lactam S-16, followed by alkylation with
the 2-(3-chloropropyl) oxazole 14 (path a). Alternatively, the
order of alkylation could be reversed, entailing preliminary
construction of the oxazole lactam S-36, followed by elaboration
of the propyne side chain (path b).
Scheme 6
Scheme 7
catalyst systems were explored to effect this transformation.
Butenolide 12b was completely unreactive to standard hydro-
genation conditions (PtO2, Pd, or Ni/H2), and was recovered
unchanged upon treatment with various hydride reducing
reagents. However, we obtained excellent results with the nickel
boride catalyst derived from NiCl2 and NaBH4,15a which we
have previously employed in the synthesis of methyllactones.5,15b
When this reaction was carried out at -30 °C in MeOH we
obtained a 73% yield of (()-stemoamide (1) as a colorless
crystalline solid, mp 184-85 °C [lit. mp for (-)-1 190-91 °C4f
and 187-88 °C4h]. As in the case with 12 above (Scheme 4),
we could detect none of the C10 epimer 13, which underwent
quantitative isomerization to (()-1. The only other compound
isolated from this reaction was a small amount of the cis-lactone
34 (15%), derived by R-face reduction of 12b followed by
The viability of path a was first tested with the racemic alkyne
lactam 16, which was prepared in 77% yield by condensation
of 1-lithiopropyne with the known thiophenyl derivative 3717
(ZnCl2 catalysis;18 Scheme 8). Encouragingly, 16 afforded good-
to-excellent yields of the displacement products 38 upon
alkylation with a variety of electrophiles (E ) Me, Bn, 14).
We then investigated the preparation of enantiomerically pure
S-16. Excellent precedent for this synthesis existed in the work
of Stevenson et al.,19 who prepared the terminal alkyne
derivative S-40 by condensation of aldehyde S-39 with dieth-
ylmethyldiazophosphonate (Gilbert’s procedure).20 Subsequent
cleavage of the 2,4-dimethoxybenzyl protecting group in S-40,
(12) (a) One possible source of oxidant is trace amounts of air in the
reaction mixture. Under 1 atm of air 17 undergoes rapid decomposition in
refluxing diethylbenzene (182 °C). (b) Oxidation potentials were measured
on 7 mM solutions of 17 in MeCN containing 0.1 M Bu4NPF6 as electrolyte,
employing a Pt working electrode and a Ag/AgNO3 reference electrode.
We gratefully acknowledge Mr. John Porter and Professor Albert Fry, of
Wesleyan University, for assistance in carrying out these experiments.
Helpful discussions with Professor Kevin Moeller, of Washington Univer-
sity, St. Louis, are also acknowledged.
(16) We are grateful to Professor David R. Williams, of Indiana
University, for providing us with NMR, IR, and mass spectra of authentic
(-)-1.
(17) (a) Iwasaki, T.; Horikawa, H.; Matsumoto, K.; Miyoshi, M. J. Org.
Chem. 1979, 44, 1552. (b) Nagasaka, T.; Abe, M.; Ozawa, N.; Kosugi, Y.;
Hamaguchi, F. Heterocycles 1983, 20 (6), 985.
(18) (a) Mori, S.; Iwakura, H.; Takeshi, S. Tetrahedron Lett. 1988, 5391.
(b) Olsen, R. K.; Kolar, A. J. Tetrahedron Lett. 1975, 3579. (c) Scott, W.
A.; Edwards, O. E.; Grieco, C.; Rank, W.; Sano, T. Can. J. Chem. 1975,
53, 463.
(19) McAlonan, H.; Stevenson, P. J. Tetrahedron: Asymmetry 1995, 6,
239.
(13) (a) Yueh, W.; Bauld, N. L. J. Chem. Soc., Perkin Trans. 2 1995,
871 and references therein. (b) Boger, D. L.; Robarge, K. D. J. Org. Chem.
1988, 53, 5793 and references therein.
(14) It is possible that the low oxidation potential of oxazoles plays a
role in their exceptional reactivity as dienes in Diels-Alder reactions.5a
(15) (a) Kido, F.; Tsutsumi, K.; Maruta, R.; Yoshikoshi, A. J. Am. Chem.
Soc. 1979, 101, 6420 and references therein. (b) Jacobi, P. A.; Frechette,
R.; Arrick, B.; Walker, D.; Craig, T. J. Am. Chem. Soc. 1984, 106, 5585.
(c) During the course of this work, Kinoshita and Mori reported an
independent synthesis of (-)-1 employing butenolide (-)-12b (ref 4h).
These authors reported a single product from the reduction of (-)-12b to
give (-)-1. In our hands this reduction consistently produced an ∼5:1
mixture of 1 and 34.
(20) (a) Gilbert, J. C.; Weerasooniga, U. J. Org. Chem. 1979, 44, 4997.
See also: (b) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971,
36, 1379.

4300 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Jacobi and Lee
Scheme 8
the aldehyde S-47,19 which although unstable, was of sufficient
purity for subsequent steps. One method for converting aldehyde
S-47 to the propyne lactam S-17 made use of the Corey-Fuchs
procedure,23 which offered the possibility of effecting the desired
transformation without isolation of an intermediate terminal
alkyne. Following this protocol, aldehyde S-47 was first
converted to the dibromoalkene S-48 by reaction with the ylide
derived in situ from PPh3 and CBr4. Although this step was
clean, the overall yield of S-48 from the alcohol S-36 was
disappointingly low (38%). In part this was due to the high H2O
solubility of aldehyde S-47, which made its isolation from
aqueous reaction mixtures tedious. Also, we had difficulty
separating the dibromoalkene S-48 from the large amounts of
triphenylphosphine oxide (OdPPh3) produced during the cou-
pling process. Eventually we found that this last difficulty was
eliminated through the use of hexamethylphosphorus triamide
(HMPT) in place of PPh3,24 a modification that produced H2O-
soluble hexamethylphosphoramide (HMPA) as the byproduct.
Scheme 10
although problematic, was ultimately accomplished in 54% yield
using DDQ in refluxing CHCl3 (S-40 f S-41).19 Following the
literature procedure we prepared gram quantities of S-40,19
which was readily converted to the propyne lactam S-42 by
methylation with MeI/LDA. In contrast to the case with S-40,
however, we were unable to cleave the DMB protecting group
in S-42 without concomitant decomposition.21a Therefore, this
route to S-17 was not pursued further.
Increasing attention was now devoted to path b (cf. Scheme
7), for which a logical starting point was the known hydroxy-
methyl lactam S-45 (Scheme 9).22 This material was prepared
in three steps beginning with L-pyroglutamic acid (S-35), by a
route involving esterification (SOCl2/MeOH, 90%), followed
by ester reduction (NaBH4/MeOH, 92%), and protection of the
resulting primary alcohol with ethyl vinyl ether (H+, 93%).22
The desired oxazole alcohol S-36 was then obtained in enan-
tiomerically pure form by alkylation of S-45 with the 2-(3-
chloropropyl) oxazole 14 (NaH/DMF, 67%), followed by
deprotection using TsOH in MeOH (83%). This synthesis was
readily amenable to preparing S-36 on multigram scales with
no racemization.
Scheme 9
Our next experiments dealt with converting the dibromoalkene
S-48 to the propyne derivative S-17. This transformation was
first effected by reacting the dibromoalkene S-48 with 2 equiv
of n-BuLi, followed by quenching with excess MeI (Scheme
10). Under these conditions the initially formed 1-lithioalkyne
(21) (a) Reagents explored included DDQ,19 TFA,21b CAN,21c CrO3/
HOAc/H2O,21d and t-BuOOH/Ru,21e among others. (b) Schlessinger, R. H.;
Bebernitz, G. R.; Lin, P.; Poss, A. Y. J. Am. Chem. Soc. 1985, 107, 1777.
(c) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984,
2371. (d) Angyal, S. J.; James, K. Carbohydr. Res. 1970, 12, 147. (e)
Murahashi, S.; Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi, H.;
Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820.
(22) (a) Saijo, S.; Wada, M.; Himizu, J.; Ishida, A. Chem. Pharm. Bull.
1980, 28, 1449. (b) Otsuka, M.; Masuda, T.; Haupt, A.; Ohno, M.; Shirak,
T.; Sugiura, Y.; Maeda, K. J. Am. Chem. Soc. 1990, 112, 838.
The remaining steps necessary to convert S-36 to the required
propyne derivative S-17 were thought to be straightforward
(Scheme 10). Overall, this transformation closely modeled our
earlier synthesis of the alkyne lactam S-42 (cf. Scheme 8). Thus,
Swern oxidation of alcohol S-36 proceeded normally to afford
(23) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(24) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L.,
Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947.

Total Syntheses of Stemoamide
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4301
was directly alkylated to give S-17 in a single step. However,
this approach was only partly successful, affording a 23% yield
of the anticipated product S-17, along with 15% of the bis-
methylation product S-50. The structure of S-50 was assigned
on the basis of analytical and NMR spectral data, as well as
literature precedent.25 Particularly diagnostic was the presence
of an sp3 methyl doublet at δ 1.18 ppm, which collapsed to a
singlet upon irradiation of the C4 methine proton (stemoamide
numbering). In an effort to avoid bis-methylation, we also
investigated the conventional two-step conversion involving
isolation of the terminal alkyne S-49. On small scales this
compound was obtained in 62% yield by quenching the Corey-
Fuchs intermediate with MeOH instead of MeI (S-48 f S-49,
Scheme 10).23 However, for preparative purposes, S-49 was
more conveniently derived employing the Gilbert procedure
([MeO]2P(O)CHN2; cf. also Scheme 8),20 which gave a 65%
overall yield of the alkyne S-49 from alcohol S-36. In addition
to affording better yields, this methodology is less prone to
causing epimerization at sensitive stereocenters.19,26 With ample
quantities of S-49 now available, we were able to increase the
yield in the alkylation step leading to S-17 to 32%. However,
despite numerous modifications in both reagents and conditions,
bis-methylation to form S-50 was always a competing reaction.
Finally, the transformation of S-17 to enantiomerically pure
(-)-stemoamide (1) followed in exactly analogous fashion to
our earlier synthesis of (()-1. This involved thermolysis of S-17
to afford the enantiomerically pure butenolide (-)-12b (52%),15c
followed by reduction with the NaBH4/NiCl2 reagent pre-
viously employed in the synthesis of (()-1 (Schemes 4 and 6).
(-)-Stemoamide (1) thus obtained, in 73% yield, had iden-
tical physical and spectral properties as an authentic sample of
(-)-1,16 and closely matching optical rotation (cf. Experimental
Section). For clarity, the complete reaction sequence leading
from L-pyroglutamic acid (S-35) to (-)-stemoamide (1) is
summarized in Figure 7.
synthesis (in the final product, only C10 is subject to equilibra-
tion). These same principles were readily extended to the
synthesis of (-)-1, which although slightly longer (9 steps; ∼4%
overall yield), also produced (-)-1 as a single stereoisomer.27a
Experimental Section27b
Melting points were determined in open capillaries and are uncor-
1
rected. H NMR spectra were recorded at 300, 400, or 500 MHz and
are expressed as ppm downfield from tetramethylsilane. All reactions
were carried out in oven-dried glassware under an inert atmosphere of
nitrogen or argon.
Methyl 3-{1-[3-(5-Methoxy-4-methyl-1,3-oxazol-2-yl)propyl]-5-
oxotetrahydro-1H-2-pyrrolyl}-2-propynoate (25). A solution of 250
mg (0.98 mmol) of 23 in 10 mL of CH2Cl2 was cooled to -78 °C, and
was treated dropwise with 250 mg (1.97 mmol, 2 equiv) of oxalyl
chloride. The resulting mixture was stirred for 30 min at -78 °C to
afford a crude chlorolactam. At the end of this period the solvent was
evaporated under reduced pressure (cold water bath), and the residue
was dissolved in 4 mL of CH2Cl2. In a separate flask, 1-lithio methyl
propriolate was generated by dropwise addition of 0.59 mL (1.47 mmol)
of 2.5 M n-BuLi/hexane to a solution of 124 mg (1.47 mol) of methyl
propiolate in 10 mL of CH2Cl2 maintained at -90 °C. The resulting
solution was then treated dropwise, at -90 °C, with the crude
chlorolactam solution described above, and the reaction was stirred
for an additional 1 h at -90 °C. The reaction was then quenched with
saturated NH4Cl and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, concentrated under reduced pressure, and chro-
matographed to give 71 mg (23%) of 25 as a yellow oil: Rf 0.43 (5%
MeOH/CH2Cl2); IR (neat) 2237, 1717, 1697, 1257 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.89-2.09 (m, 2 H), 1.98 (s, 3 H), 2.10-2.25 (m, 1
H), 2.27-2.55 (m, 3 H), 2.61 (app t, J ) 6.7 Hz, 2 H), 3.10-3.20 (m,
1 H), 3.66-3.78 (m, 1 H), 3.76 (s, 3 H), 3.85 (s, 3 H), 4.47-4.51 (m,
1 H); LRMS m/e 279 (M+ - 41), 264, 248, 232, 218, 204, 176, 160,
148, 132, 120.
Methyl
2-Methoxy-8-oxo-5,6,8,9,10,10a-hexahydro-4H-furo-
[3,2-c]pyrrolo[1,2-a]azepine-1-carboxylate (26). A mixture of 69 mg
(0.22 mmol) of alkyne 25 and a catalytic amount of tert-butylcatechol
in 11 mL of dry toluene was heated at reflux for 2 h under an Ar
atmosphere, and was then concentrated to dryness under reduced
pressure. The residue was chromatographed (silica gel, 1% MeOH/
CH2Cl2) to afford 54 mg (89%) of 26 as a colorless solid: Rf 0.41 (5%
MeOH/CH2Cl2); IR (neat) 1691, 1602, 1372, 1094 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.80-1.94 (m, 2 H), 2.06-2.20 (m, 1 H), 2.43 (app
t, J ) 8.0 Hz, 2 H), 2.54-2.67 (m, 2 H), 2.70-2.81 (m, 1 H), 2.88
(ddd, J ) 7.0, 8.9, 15.8 Hz, 1 H), 3.80 (s, 3 H), 4.07 (s, 3 H), 4.17
(ddd, J ) 3.6, 7.5, 14.0 Hz, 1 H), 4.87 (app t, J ) 7.5 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 23.6, 25.1, 27.7, 30.7, 40.1, 51.7, 58.4, 58.6,
90.8, 121.3, 122.4, 140.9, 164.0, 175.8; HRMS (EI) calcd for C14H17-
NO5 279.1107, found 279.1107.
Figure 7. Summary of synthesis of (-)-1.
Summary
In this paper we describe a highly efficient synthesis of
(()-stemoamide (1), which was prepared in 7 steps, and ∼20%
overall yield, from simple and inexpensive starting materials.
All of the reactions utilized are readily amenable to scale-up,
and the final product (()-1 was routinely produced in 0.4-1.0
g quantities. The key ring forming process involved an alkyne-
oxazole (Diels-Alder)-(retro-Diels-Alder) reaction, which
established the tricyclic skeleton of (()-1 in a single step. Of
the four stereocenters in (()-1, only C9 was introduced by
asymmetric induction (kinetic control). The remaining three
centers (C8, C9a, C10) were set on the basis of molecular
mechanics calculations, which indicated that the “natural”
configuration of (()-1 was the most stable. Our strategy then
built upon thermodynamic control, in which each of these
centers would be epimerizable at an appropriate stage of the
5-(1-Propynyl)-2-pyrrolidinone (16). A solution of 25.2 mL (63.1
mmol) of 2.5 M n-BuLi/hexane and 20 mg of triphenylmethane in 75
mL of dry THF was cooled to -78 °C, and was treated with propyne
gas until the pink color was discharged. After the mixture was stirred
for an additional 20 min, the reaction was treated dropwise with 83
mL (63.1 mmol, 1.0 equiv) of 0.5 M ZnCl2/THF,18 and the cooling
bath was replaced with an ice-water bath. The mixture was then stirred
for 30 min at 0 °C and the solvent was removed carefully under reduced
pressure. The resulting gummy residue was diluted with 80 mL of dry
benzene and treated dropwise, with vigorous stirring, with a solution
of 1.19 g (6.20 mmol) of phenylthiolactam 3717 in 20 mL of dry
benzene. The reaction was then heated for 90 min at 60 °C, cooled,
and quenched with saturated NH4Cl, and the layers were separated.
The aqueous layer was extracted with EtOAc, and the combined extracts
were dried over anhydrous MgSO4 and concentrated under reduced
pressure, and the crude product was purified by flash chromatography
(eluent 33% hexane/EtOAc) to give 584 mg (77%) of 16 as a colorless
(25) Katritzky, A. R.; Boulton, A. J., Eds. AdVances in Heterocyclic
Chemistry; Academic Press: New York, 1974; Vol. 17.
(26) Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling,
D. E.; Schreiber, S. J. Am. Chem. Soc. 1990, 112, 5583.
(27) (a) Financial support of this work by NSF Grant No. CHE-9424476
is gratefully acknowledged. (b) Additional spectral and analytical data are
available in the Supporting Information section of ref 4i.

4302 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Jacobi and Lee
solid: Rf 0.28 (33% hexane/EtOAc); IR (neat) 3212, 2240, 1693, 1334,
yl)propyl]tetrahydro-1H-2-pyrrolone (S-36). A solution of 2.78 g
(8.17 mmol) of S-46 and a catalytic amount of p-TsOH in 15 mL of
MeOH was stirred for 9 h at room temperature. The reaction was then
concentrated under reduced pressure, and the crude product was purified
by flash chromatography (eluent 5% MeOH/CH2Cl2) to give 1.83 g
(83%) of S-36 as a colorless oil: [R]D25 +20.7° (c 1.78, EtOH); Rf 0.27
(5% MeOH/CHCl3); IR (neat) 3351, 1675, 1459, 1235 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.81-2.49 (m, 6 H), 2.00 (s, 3 H), 2.63-2.78
1
1259, 753 cm-1; H NMR (300 MHz, CDCl3) δ 1.80 (s, 3 H), 2.09-
2.50 (m, 4 H), 4.31-4.38 (m, 1 H), 5.79 (br s, 1 H); LRMS m/e 123
(M+), 108, 94, 79, 77, 68.
(5S)-1-(2,4-Dimethoxybenzyl)-5-(1-propynyl)tetrahydro-1H-2-
pyrrolone (S-42). A total of 7.1 mL (11 mmol) of 1.54 M n-BuLi/
hexane was added dropwise at -78 °C to a stirring solution of 1.7 mL
(12 mmol) of i-Pr2NH in 40 mL of freshly distilled THF. After addition
was complete, the mixture was warmed to 0 °C and stirred for an
additional 10 min to complete the formation of LDA. A solution
consisting of 2.6 g (10 mmol) of alkyne S-4019 and 2.1 mL (12 mmol)
of HMPA in 20 mL of THF was added dropwise to the stirring LDA
solution, and the resulting mixture was stirred for 10 min at -78 °C
and then 30 min at 0 °C. A total of 3.1 mL (50 mmol) of CH3I was
then added in one portion. After the mixture was stirred an additional
1 h at 0 °C, the reaction was quenched with saturated NH4Cl and diluted
with 0.5 N HCl, and the aqueous layer was extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, concentrated under reduced pressure, and purified
by flash chromatography (eluent 10% hexane/Et2O) to give 1.6 g (59%)
(m, 2 H), 3.31-3.51 (m, 2 H), 3.64-3.85 (m, 3 H), 3.88 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 11.2, 22.8, 25.9, 27.2, 32.0, 42.1. 61.9, 62.7,
64.7, 112.4, 156.2, 177.7; HRMS (EI) calcd for C13H20N2O4 268.1423,
found 0.268.1424.
(2S)-1-[3-(5-Methoxy-4-methyl-1,3-oxazol-2-yl)propyl]-5-oxotet-
rahydro-1H-2-pyrrolecarbaldehyde (S-47). A solution of 988 mg
(0.68 mL, 7.78 mmol) of (COCl)2 in 15 mL of dry CH2Cl2 was cooled
to -78 °C with stirring, and was treated dropwise with 608 mg (0.55
mL, 7.78 mmol, 1.0 equiv) of dry DMSO. After addition was complete
stirring was continued at -78 °C for an additional 15 min, and the
reaction was then treated dropwise over 10 min with a solution of 1.74
g (6.49 mmol) of alcohol S-36 in 5 mL of dry CH2Cl2. After the mixture
was stirred an additional 1 h at -78 °C, the reaction was treated slowly
with 4.52 mL (32.4 mL) of freshly distilled NEt3, and the resulting
creamy suspension was allowed to warm to room temperature. The
reaction was then diluted with 5 mL of H2O and 10 mL of 0.1 N HCl
(vigorous stirring), the layers were separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure to give 1.03 g of aldehyde S-47 as an unstable yellow
oil, which was utilized immediately for the next step: Rf 0.31 (5%
25
of S-42 as a pale yellow oil: [R]D -30.5 (c 2.08, MeOH); Rf 0.31
(Et2O); IR (neat) 2939, 2836, 1689, 1612, 1508, 1411, 1208, 1034 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.84 (d, J ) 2.1 Hz, 3 H), 1.96-2.07
(m, 1 H), 2.14-2.26 (m, 1 H), 2.29-2.40 (m, 1 H), 2.48-2.59 (m, 1
H), 3.80 (s, 3 H), 3.81 (s, 3 H), 4.10-4.15 (m, 1 H), 4.14 (d, J ) 15
Hz, 1 H), 4.85 (d, J ) 15 Hz, 1 H), 6.42-6.46 (m, 1 H), 6.45 (s, 1 H),
7.16 (d, J ) 8.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 4.07, 27.0,
30.7, 39.7, 49.7, 55.9, 56.0, 77.9, 81.3, 99.0, 104.6, 117.7, 131.3, 159.3,
161.0, 174.6; HRMS (EI) calcd for C16H19NO3 273.1365, found
273.1366.
1
MeOH/CHCl3); H NMR (300 MHz, CDCl3) δ 1.86-2.44 (m, 4 H),
1.98 (s, 3 H), 2.62 (t, J ) 7 Hz, 2 H), 3.05-3.16 (m, 2 H), 3.70-3.81
(5S)-5-[(1-Ethoxyethyl)methyl]tetrahydro-1H-2-pyrrolone (S-
45).22 A solution consisting of 4.95 g (43 mmol) of hydroxymethyl
lactam S-44,22 4.65 g (6.2 mL, 65 mmol, 1.5 equiv) of ethyl vinyl ether,
and 141 mg (0.86 mmol) of trichloroacetic acid in 30 mL of dry
chloroform was stirred for 4 h at room temperature. The reaction
mixture was then washed with saturated NaHCO3 and brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (silica gel, 5% MeOH/
CH2Cl2) to give 7.45 g (93%) of S-4522 as a colorless oil: [R]D26 +24.1°
(m, 2 H), 3.38 (s, 3 H), 4.18-4.23 (m, 1 H), 9.61 (s, 1 H).
(5S)-5-(2,2-Dibromovinyl)-1-[3-(5-methoxy-4-methyl-1,3-oxazol-
2-yl)propyl]tetrahydro-1H-2-pyrrolone (S-48). Method A: A mixture
consisting of 288 mg (4.41 mmol) of zinc dust, 1.16 g (4.41 mmol) of
Ph3P, and 1.46 g (4.41 mmol) of CBr4 in 15 mL of dry CH2Cl2 was
stirred for 16 h at room temperature. A solution of 587 mg (2.20 mmol)
of crude aldehyde S-47 in 5 mL of CH2Cl2 was added to the mixture,
and the reaction was stirred for an additional 18 h at room temperature.
The resulting mixture was then filtered through a short plug of SiO2
and concentrated under reduced pressure (two repetitions), and the
residue was purified by flash chromatography (eluent 1% i-PrOH/
CHCl3) to give 580 mg (38% from alcohol S-36) of S-48 as a colorless
oil.
24
(c 1.99, EtOH) {lit. [R]D +20.8° (c 2.0, EtOH)22a}; Rf 0.41 (5%
MeOH/CH2Cl2); IR (neat) 3228, 1698, 1134, 1051 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.20 (t, J ) 7 Hz, 3 H), 1.30 (d, J ) 5.4 Hz, 3 H),
1.68-1.81 (m, 1 H), 2.16-2.29 (m, 1 H), 2.35 (app t. J ) 7 Hz, 2 H),
3.23-3.68 (m, 4 H), 3.81-3.88 (m, 1 H), 4.68-4.74 (m, 1 H), 5.98
(br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 15.8, 20.2, 23.8, 30.3, 54.5,
61.7, 69.2, 100.3, 178.5; HRMS (CI) calcd for C9H18NO3 (M + H)
188.1287, found 188.1285.
Method B: A total of 2.2 mL (12 mmol) of hexamethylphospho-
triamide (HMPT) was added dropwise, and with vigorous stirring, to
a solution of 2.0 g (6.05 mmol) of CBr4 in 50 mL of THF maintained
at -30 °C. After being stirred an additional 10 min, the resulting
mixture was treated dropwise with a solution of 322 mg (1.2 mmol) of
aldehyde S-47 in 6 mL of THF, and the reaction was allowed to warm
to 0 °C over a period of 1 h with stirring. The reaction was then
quenched with saturated NaHCO3 and the layers were separated. The
aqueous layer was extracted with CH2Cl2, and the combined organic
extracts were washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (eluent 1% i-PrOH/CHCl3) to give 214 mg (24% from
(5S)-5-[(1-Ethoxyethyl)methyl]-1-[3-(5-methoxy-4-methyl-1,3-ox-
azol-2-yl)propyl]tetrahydro-1H-2-pyrrolone (S-46). A solution of
2.02 g (10.8 mmol) of S-45 in 5 mL of DMF was added dropwise to
a stirring suspension of 561 mg (14.0 mmol, 1.3 equiv) of 60% NaH/
mineral oil in 23 mL of DMF maintained at 0 °C. The reaction mixture
was stirred for an additional 1 h at 0 °C, and was then treated dropwise
with a solution of 2.25 g (11.9 mmol, 1.1 equiv) of the 2-(3-
chloropropyl) oxazole 14 in 2 mL of DMF. The resulting yellow mixture
was then stirred at 70 °C for 24 h. At the end of this period the reaction
was concentrated under reduced pressure, and the residue was
partitioned between CH2Cl2 and H2O. The aqueous layer was extracted
with CH2Cl2, and the combined organic extracts were washed with
brine, dried over anhydrous MgSO4, and concentrated under reduced
pressure. The crude product was purified by flash chromatography (33%
26
alcohol S-36) of dibromide S-48 as a colorless oil: [R]D +39.7° (c
1.85, EtOH); Rf 0.46 (5% i-PrOH/CHCl3); IR (neat) 1691, 1414, 1329,
1277 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.73-1.84 (m, 1 H), 1.86-
2.06 (m, 2 H), 1.99 (s, 3 H), 2.21-2.46 (m, 3 H), 2.62 (t, J ) 7.6 Hz,
2 H), 2.96 (ddd, J ) 5.4, 8, 14 Hz, 1 H), 3.63 (dt, J ) 8, 14.3 Hz, 1
H), 3.87 (s, 3 H), 4.35-4.42 (m, 1 H), 6.32 (d, J ) 8.9 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 10.4, 24.5, 25.1, 26.4, 30.2, 40.9, 60.5, 61.6,
93.4, 111.6, 138.1, 154.5, 155.1, 174.9; HRMS (EI) calcd for C14H18-
Br2N2O3 419.9684, found 419.9684.
25
hexane/EtOAc) to give 2.46 g (67%) of S-46 as a pale yellow oil: [R]D
+15.0 (c 2.04, EtOH); Rf 0.43 (5% MeOH/CH2Cl2); IR (neat) 2977,
2935, 1682, 1235, 1134, 1101 cm-1; H NMR (300 MHz, CDCl3) δ
1
1.15 (t, J ) 7 Hz, 3 H), 1.25 (d, J ) 5.5 Hz, 3 H), 1.78-2.45 (m, 6
H), 1.96 (s, 3 H), 2.58 (t, J ) 7.6 Hz, 2 H), 3.02-3.11 (m, 1 H),
3.35-3.75 (m, 6 H), 3.84 (s, 3 H), 4.63-4.72 (m, 1 H); 13C NMR (75
MHz, CDCl3) δ 11.5, 16.8, 21.1, 23.5, 26.1, 27.5, 31.7, 41.7, 58.8,
62.5, 67.0, 67.3, 101.2, 112.7, 155.9, 177.0; HRMS (EI) calcd for
C17H28N2O5 340.1998, found 340.1996.
(5S)-5-Ethynyl-1-[3-(5-methoxy-4-methyl-1,3-oxazol-2-yl)propyl]-
tetrahydro-1H-2-pyrrolone (S-49). A suspension of 521 mg (4.64
mmol) of potassium tert-butoxide in 9 mL of THF was cooled to -78
°C, and was treated dropwise, over a period of 10 min, with a solution
of 697 mg (4.64 mmol) of dimethyl (diazomethyl)phophonate in 12
mL of dry THF. After the mixture was stirred an additional 10 min at
(5S)-5-(Hydroxymethyl)-1-[3-(5-methoxy-4-methyl-1,3-oxazol-2-

Total Syntheses of Stemoamide
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4303
-78 °C, the reaction was treated dropwise with a solution of 1.03 g
(3.87 mmol) of aldehyde S-47 in 11 mL of THF. Stirring was continued
for 7 h at -78 °C, and the reaction mixture was then quenched with
ice water. The layers were separated and the aqueous layer was extracted
with CH2Cl2. The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash chromatography (eluent 1% i-PrOH/
CHCl3) to give 658 mg (65% from alcohol S-36) of S-49 as a colorless
S-50: Rf 0.40 (5% i-PrOH/CHCl3); IR (neat) 2361, 2342, 1694, 1419,
1234 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.18 (d, J ) 7.1 Hz, 3 H),
1.81 (s, 3 H), 1.78-2.08 (m, 3 H), 2.01 (s, 3 H), 2.23-2.39 (m, 1 H),
2.55-2.69 (m, 1 H), 2.63 (app t, J ) 7 Hz, 2 H), 3.12-3.23 (m, 1 H),
3.64-3.75 (m, 1 H), 3.89 (s, 3 H), 4.23-4.31 (m, 1 H); 13C NMR (75
MHz, CDCl3) δ 3.97, 10.4, 16.3, 25.1, 26.5, 36.0, 41.0, 48.0, 53.9,
61.6, 73.5, 81.3, 111.7, 155.0, 177.7, 186.9; HRMS (EI) calcd for
C16H22N2O3 290.1630, found 290.1629.
25
oil: [R]D -10.5° (c 1.6, EtOH), -14.4° (c 1.38, MeOH); Rf 0.39
(3aR,10aS)-1-Methyl-3a,4,5,6,8,9,10,10a-octahydro-2H-furo-
[3,2-c]pyrrolo[1,2-a]azepine-2,8-dione [(-)-12b]. This material was
prepared in 52% yield from 65 mg of S-17, following an identical
procedure to that descrtibed above for (()-12b.
(5% i-PrOH/CHCl3); IR (neat) 3224, 2945, 2110, 1682, 1576, 1416,
1
1235 cm-1; H NMR (300 MHz, CDCl3) δ 1.92-2.19 (m, 4 H), 2.01
(s, 3 H), 2.27-2.55 (m, 2 H), 2.40 (d, J ) 2.3 Hz, 1 H), 2.64 (app t,
J ) 7 Hz, 2 H), 3.21 (ddd, J ) 5.5, 7.7, 14 Hz, 1 H), 3.72 (dt, J ) 7.8,
14 Hz, 1 H), 3.89 (s, 3 H), 4.35-4.39 (m, 1 H); 13C NMR (75 MHz,
CDCl3) δ 10.4, 24.9, 26.4, 26.6, 30.2, 40.8, 49.4, 61.5, 74.1, 81.8, 111.6,
154.6, 155.1, 174.7; HRMS (EI) calcd for C14H18N2O3 262.1317, found
262.1316.
(-)-12b: colorless solid, mp 166-67 °C (lit.4h mp 127-29 °C);
[R]D -261.05° (c 1.33, MeOH) {lit.4h [R]D -246.3° (c 0.63,
MeOH)}; Rf 0.34 (5% CH3OH/CHCl3); identical IR and NMR data as
(()-12b described above; HRMS (EI) calcd for C12H15NO3 221.1052,
found 221.1052 Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N,
6.33. Found: C, 65.04; H, 6.81; N 6.28.
24
27
(5S)-1-[3-(5-Methoxy-4-methyl-1,3-oxazol-2-yl)propyl]-5-(1-pro-
pynyl)tetrahydro-1H-2-pyrrolone (S-17). A solution of 196 mg (0.75
mmol) of alkyne S-49 in 10 mL of dry THF was cooled to -78 °C
with stirring, and was treated dropwise with a solution of 0.75 mL
(1.50 mmol, 2 equiv) of 2 M LDA in heptane/THF/ethylbenzene. The
resulting mixture was stirred for an additional 2.5 h at -78 °C, and
was then treated with 530 mg (0.23 mL, 3.74 mmol) of MeI and 267
mg (0.26 mL, 1.50 mmol, 2 equiv) of hexamethylphosphoramide. After
being stirred an additional 3.5 h at -78 °C, the reaction mixture was
quenched with ice water and the layers were separated. The aqueous
layer was extracted with CH2Cl2, and the combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash chromatog-
raphy (eluent 1% i-PrOH/CHCl3) to yield 66 mg (32%) of S-17 and
72 mg (33%) of the bis-methylation product (S-50) as pale yellow oils.
(-)-Stemoamide [(-)-1]: This material was prepared in 73% yield
from 24 mg of (-)-12b, following an identical procedure to that
descrtibed above for (()-1.
(-)-1: colorless solid, mp 186-187 °C (lit. mp 187-88 °C4h and
190-91 °C4f); [R]D25 -183.5° (c 1.36, MeOH) {lit. [R]D30 -219.3° (c
26
0.50, MeOH);4h [R]D -141° (c 0.19, MeOH)4f and -181° (c 0.89,
MeOH);4f Rf 0.38 (5% i-PrOH/CHCl3); identical IR and NMR data as
(()-1 described above. HRMS (EI) calcd for C12H17NO3 223.1208,
found 223.1209; Anal. Calcd for C, 64.54; H, 7.68; N, 6.28. Found:
C, 64.63; H, 7.72; N, 6.30.
Supporting Information Available: Copies of 1H- and 13C-
NMR spectra for compounds 16, 25, 26, S-36, 37, S-40, S-41,
(S-44)-(S-46), and (S-48)-(S-50) (PDF).27b This material is
available free of charge via the Internet at http://pubs.acs.org.
25
S-17: [R]D -21.5 (c 1.18, MeOH); Rf 0.36 (5% i-PrOH/CHCl3);
identical IR and NMR data as (()-17 described above; HRMS (EI)
calcd for C15H20N2O3 276.1474, found 276.1473.
JA994214W