Applications of vinylogous mannich reactions. Concise enantiospecific total syntheses of (+)-croomine

Article abstract of DOI:10.1021/ja990077r

Because the vinylogous Mannich reaction of substituted furans with iminium ions is a useful construction in alkaloid synthesis, it is important to know what effects substituents on the two reacting partners have upon the stereoselectivity of the reaction. Toward this end, the additions of the methylated furans 9a-h to the iminium ion generated in situ from the ethoxy carbamate 10 were examined. Generally, mixtures (3-24:1) of the threo and erythro adducts 11a-h and 12a-h were obtained in 50-96% combined yields, with the threo isomers being the major products. Two extraordinarily concise asymmetric syntheses of (+)-croomine (1) have been completed using a novel strategy, highlighted by two vinylogous Mannich reactions as key constructions. The first such reaction involved the addition of 5-(4-bromobut-1-yl)-3-methyl-2-(triisopropylsilyloxy)furan to the N-acyliminium salt derived from the L-pyroglutamic acid derivative 17 to give the adduct [5(S),2′(S),5′(S)]-5-(4″-bromobut-1″yl)-5-[N-(tert- butoxycarbonyl)-2′-(methoxycarbonyl)-pyrrolidin-5′-yl]-3-methyl- 2(5H)-furanone (18) as the major product. Refunctionalization of 18 led to the tricyclic intermediate [3′S-[3′α,9′α(5*),9′aα]]- decahydro-4-methyl-5-oxospiro[furan-2(3H),9′-[9H]pyrrolo[1,2-a]azepin]- 3′-carboxylic acid, hydrobromide salt, which was, in turn, converted to an iminium salt that underwent a second vinylogous Mannich reaction to give [3′S-[3′α(R*),9′α(S*), 9′aα]]-3′-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)decahydro-4- methylspiro[furan-2(5H),9′-[9H]pyrrolo[1,2-a]azepin-5-one (24) as the major adduct. Stereoselective reduction of the unsaturated lactone 24 gave 1, completing a synthesis that required a total of only 11 chemical steps from commercially available starting materials. In a second approach, the initial Mannich adduct [5(S),2′(S),5′(S)]-5-(4″-bromobut-1″-yl)-5-[2′- (methoxycarbonyl)pyrrolidin-5′-yl]-3-methyl-2(5H)-furanone was transformed into the unsaturated tricyclic intermediate [3′S-[3′α(R*),9′α(S*), 9′aα]]-3′-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)-1′, 2′,3′,5′,6′,7′,8′-octahydro-4- methylspiro[furan-2(5H),9′-[9H]-pyrrolo[1,2-a]azepin]-5-one, which underwent hydrogenation to give 1 as the only isolable product, thereby completing a synthesis that required only 10 steps.

Full text of DOI:10.1021/ja990077r

6990
J. Am. Chem. Soc. 1999, 121, 6990-6997
Applications of Vinylogous Mannich Reactions. Concise
Enantiospecific Total Syntheses of (+)-Croomine
Stephen F. Martin,* Kenneth J. Barr, Dudley W. Smith, and Scott K. Bur
Contribution from the Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
ReceiVed January 8, 1999
Abstract: Because the vinylogous Mannich reaction of substituted furans with iminium ions is a useful
construction in alkaloid synthesis, it is important to know what effects substituents on the two reacting partners
have upon the stereoselectivity of the reaction. Toward this end, the additions of the methylated furans 9a-h
to the iminium ion generated in situ from the ethoxy carbamate 10 were examined. Generally, mixtures (3-
24:1) of the threo and erythro adducts 11a-h and 12a-h were obtained in 50-96% combined yields, with
the threo isomers being the major products. Two extraordinarily concise asymmetric syntheses of (+)-croomine
(1) have been completed using a novel strategy, highlighted by two vinylogous Mannich reactions as key
constructions. The first such reaction involved the addition of 5-(4-bromobut-1-yl)-3-methyl-2-(triisopropyl-
silyloxy)furan to the N-acyliminium salt derived from the L-pyroglutamic acid derivative 17 to give the adduct
[5(S),2′(S),5′(S)]-5-(4′′-bromobut-1′′yl)-5-[N-(tert-butoxycarbonyl)-2′-(methoxycarbonyl)-pyrrolidin-
5′-yl]-3-methyl-2(5H)-furanone (18) as the major product. Refunctionalization of 18 led to the tricyclic
intermediate [3′S-[3′R,9′R(S*),9′aR]]-decahydro-4-methyl-5-oxospiro[furan-2(3H),9′-[9H]pyrrolo[1,2-a]azepin]-
3′-carboxylic acid, hydrobromide salt, which was, in turn, converted to an iminium salt that underwent a
second vinylogous Mannich reaction to give [3′S-[3′R(R*),9′R(S*),9′aR]]-3′-(2,5-dihydro-4-methyl-5-oxo-2-
furanyl)decahydro-4-methylspiro[furan-2(5H),9′-[9H]pyrrolo[1,2-a]azepin-5-one (24) as the major adduct.
Stereoselective reduction of the unsaturated lactone 24 gave 1, completing a synthesis that required a total of
only 11 chemical steps from commercially available starting materials. In a second approach, the initial Mannich
adduct [5(S),2′(S),5′(S)]-5-(4′′-bromobut-1′′-yl)-5-[2′-(methoxycarbonyl)pyrrolidin-5′-yl]-3-methyl-2(5H)-
furanone was transformed into the unsaturated tricyclic intermediate [3′S-[3′R(R*),9′R(S*),9′aR]]-
3′-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)-1′,2′,3′,5′,6′,7′,8′-octahydro-4-methylspiro[furan-2(5H),9′-[9H]-
pyrrolo[1,2-a]azepin]-5-one, which underwent hydrogenation to give 1 as the only isolable product, thereby
completing a synthesis that required only 10 steps.
Extracts from plants used for medicinal purposes have long
to a 1-azabicyclo[5.3.0]decane nucleus. This unusual molecular
architecture has served as a stimulus for the development of
new chemistry and strategies for the construction of the skeleton,
and the successful total syntheses of a number of the natural
alkaloids as well as simpler model structures have been
recorded.3,4
Our interest in alkaloids of the Stemona family arose from
more general investigations of the vinylogous Mannich reaction
as a key construction for the synthesis of alkaloid natural
products.5-7 In the context of rapidly assembling the molecular
framework of croomine (1), we envisioned that two substituted
silyloxyfuran subunits, which would be the progenitors of the
been the source of natural products with interesting biological
properties. Indeed, plants belonging to the Stemonaceae family
(Stemona and Croomia species) were used historically in
Chinese and Japanese medicine to treat respiratory disorders,
including pertussis, pulmonary tuberculosis, and bronchitis, and
several alkaloids exhibit insecticidal and neuromuscular activ-
ity.1,2 The extracts of these plants were found to be rich in
alkaloids having novel structures, as is illustrated by the
representative members of this class croomine (1), stemonine
(2), and tuberostemonine (3). Each of these alkaloids incorpo-
rates a butyrolactone ring that is either appended or annelated
(1) Goetz, M.; Edwards, O. E. In The Alkaloids; Manske, R. H. F., Ed.;
Academic Press: New York, 1976; Vol. IX, p 545 and references therein.
(2) For leading references to structural and biological investigations of
the Stemona alkaloids, see: (a) Koyanma, H.; Oda, K. J. Chem. Soc. (B)
1970, 268. (b) Lizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Uyeo, S. J. Chem.
Soc., Chem. Commun. 1973, 125. (c) Nakanishi, K.; Goto, T.; Ito, S.; Natori,
S.; Nozoe, S. In Natural Products Chemistry; Academic Press: New York,
1975; Vol. 2, p 292 ff. (d) Sakata, K.; Aoki, K.; Chang, C.-F.; Sakaurai,
A.; Tamura, S.; Mukakoshi, S. Agric. Biol. Chem. 1978, 42, 457. (e) Noro,
T.; Fukushima, S.; Ueno, A.; Litaka, Y.; Saiki, Y. Chem. Pharm. Bull. 1979,
27, 1495. (f) Xu, R.-S.; Lu, Y.-J.; Chu, J.-H.; Iwashita, T.; Naoki, H.; Naya,
Y.; Nakanishi, K. Tetrahedron 1982, 38, 2667. (g) Tereda, M.; Sano, M.;
Ishii, A. I.; Kino, H.; Fukushima, S.; Noro, T. J. Pharm. Soc. Jpn. 1982,
79, 93. (h) Cheng, D.; Guo, J.; Chu, T. T.; Ro¨der, E. J. Nat. Prod. 1988,
51, 202. (i) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571. (j)
Ye, Y.; Qin, G.; Xu, R. Phytochemistry 1994, 37, 1201, 1205.
(3) (a) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem.
Soc. 1989, 111, 1923. (b) Chen, C.-y.; Hart, D. J. J. Org. Chem. 1990, 55,
6236. (c) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33, 5477. (d) Morimoto,
Y.; Nishida, K.; Hayashi, Y. Tetrahedron Lett. 1993, 34, 5773. (e) Chen,
C.-y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840. (f) Williams, D. R.; Reddy,
J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417. (g) Wipf, P.; Kim,
Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106. (h) Morimoto,
Y.; Iwahashi, M. Synlett 1995, 1221. (i) Goldstein, D. M.; Wipf, P.
Tetrahedron Lett. 1996, 37, 739. (j) Kohno, Y.; Narasaka, K. Bull. Chem.
Soc. Jpn. 1996, 69, 2063. (k) Kinoshita, A.; Mori, M. J. Org. Chem. 1996,
61, 8356; Heterocycles 1997, 46, 287. (l) Jacobi, P. A.; Lee, K. J. Am.
Chem. Soc. 1997, 119, 3409. (m) Rigby, J. H.; Laurent, S.; Cavezza, A.;
Heeg, M. J. J. Org. Chem. 1998, 63, 5587.
(4) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
(5) (a) Martin, S. F.; Corbett, J. W. Synthesis 1992, 55. (b) Martin, S.
F.; Bur, S. K. Tetrahedron Lett. 1997, 38, 7641.
10.1021/ja990077r CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/14/1999

Applications of Vinylogous Mannich Reactions
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 6991
Scheme 1
Scheme 2
A and D butyrolactone rings in 1, might be appended to the
pyrrolidine core C via vinylogous Mannich reactions to form
bonds a and c. At some stage in the synthesis, the seven-
membered B ring would be constructed via an intramolecular
N-alkylation to make bond b.
The key to the successful implementation of this novel plan
lay in the feasibility and the stereoselectivity of the vinylogous
Mannich reactions of silyloxyfurans with cyclic iminium salts.8
As a preliminary step toward examining these two issues, we
found that 2-trimethylsilyloxyfuran (5) added to the iminium
ion 4 to give a mixture (5:1) of the threo and erythro adducts
6 and 7, respectively, in which the threo isomer dominated
(Scheme 1).5a Significantly, the relative stereochemistry at the
newly created stereogenic centers in the major adduct 6
corresponds to the pairwise relationships at C(9)-C(9a) and
C(3)-C(14) of (+)-croomine (1). Thus, the critical reactivity
and stereochemical elements in our strategy for the synthesis
of 1 had been validated, and it then remained to reduce these
discoveries to practice. In tandem with our efforts directed
toward the synthesis of the Stemona and other alkaloids, we
were interested in developing a better understanding of the
factors that controlled the stereochemical course in the vinyl-
ogous Mannich reactions of substituted silyloxyfurans with
cyclic iminium salts.5c We now report the details of these
stereochemical studies, together with an account of the suc-
cessful implementation of two sequential vinylogous Mannich
reactions in completing convergent and extraordinarily concise,
enantioselective syntheses of (+)-croomine (1).
Stereochemical Studies of Vinylogous Mannich Reactions.
In early studies of the vinylogous Mannich reactions of
silyloxyfurans with cyclic iminium, we found that there was a
preference for formation of the threo adduct.5a However, we
were interested in determining the basis for this preference and
what effect the position and the number of substitutents on the
furan ring had on the stereochemical course of the process. To
address this issue, we prepared the series of methyl-substituted
triisopropylsilyloxyfurans 9a-h. The starting butenolides 8a,b
are commercially available, and 8c,d were prepared by modi-
fication of known procedures.9 Reaction of 8a-d with TIPS-
OTf in the presence of Et3N then furnished the corresponding
silyloxyfurans 9a-d.10,11 Metalation of 9a-d followed by
methylation then gave 9e-h (Scheme 2).
The reactions of the furans 9a-h with the iminium ion that
was generated in situ upon treatment of the ethoxy carbamate
1012 with BF3‚OEt2 were then examined using a standard set
of conditions similar to those reported previously.5a Mixtures
of the threo and erythro adducts 11a-h and 12a-h, respec-
tively, were obtained, and the results of these experiments are
summarized in Table 1. The diastereomeric ratios were obtained
by integrating several diagnostic signals in the 1H NMR
spectrum of crude reaction mixtures. Typically, the protons
having distinct chemical shifts were the R- and â-butenolide
protons and the protons R to nitrogen at C(2′). Because this
analysis was complicated by the presence of rotamers when the
spectra were acquired at room temperature, it was necessary to
obtain the spectra at 100 °C. At this elevated temperature, the
diagnostic signals assigned to rotational isomers coalesced, and
integrals arising from each diastereomer could be reproducibly
measured.
(6) (a) Martin, S. F.; Liras, S. J. Am. Chem. Soc. 1993, 115, 10450. (b)
Martin, S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236.
(c) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem. Soc.
1996, 118, 9804. (d) Martin, S. F.; Bur, S. K. Tetrahedron, in press.
(7) For a recent review of the Mannich reaction, see: Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 1045.
(8) For a review of the reactions of trialkylsilyloxy furans with
electrophiles, see: (a) Casiraghi, G.; Rassu, G. Synthesis 1995, 607. For
related reactions, see: (b) Harding, K. E.; Coleman, M. T.; Liu, L. T.
Tetrahedron Lett. 1991, 31, 3795. (c) Morimoto, Y.; Nishida, K.; Hayashi,
Y. Tetrahedron Lett. 1993, 34, 5773. (d) Pelter, A.; Ward, R. S.; Sirit, A.
Tetrahedron: Asymmetry 1994, 5, 1745. (e) Hanessian, S.; Raghavan, S.
Biorg. Med. Chem. Lett. 1994, 4, 1697. (f) Pichon, M.; Figade´re, B.; Cave´,
A. Tetrahedron Lett. 1996, 37, 7963.
(10) The structure assigned to each compound is in full accord with its
spectral (1H and 13C NMR, IR, mass) characteristics; the molecular
composition of new compounds was established by high-resolution mass
measurements of purified materials. All yields are based on isolated, purified
material judged >95% pure by1H NMR spectroscopy; the structures of
compounds 11b-g, 14c, 18, 19, 24, and 26 were determined by X-ray
crystallography.
(11) (a) Brimble, M. A.; Brimble, M. T.; Gibson, J. J. J. Chem. Soc.,
Perkin Trans. 1 1989, 179. (b) Jefford, C. W.; Sledeski, A. W.; Rossier,
J.-C.; Boukouvalas, J. Tetrahedron Lett. 1990, 31, 5741. (c) Boukouvalas,
J.; Lachance, N. Synlett 1998, 31.
(9) (a) Stewart, J. M.; Woolley, D. W. J. Am. Chem. Soc. 1959, 81, 4951.
(b) Epstein, W. W.; Sonntag, A. C. J. Org. Chem. 1967, 32, 3390.
(12) Nagasaka, T.; Tamano, H.; Hamaguchi, F. Heterocycles 1986, 24,
1231.

6992 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Martin et al.
Table 1. Stereoselectivity of Vinylogous Mannich Reaction of
Furans 9a-h
entry
furan 9
yield (%)a
11:12b
1
2
3
4
5
6
7
8
a
b
c
d
e
f
70
87
88
80
70
96
88
83
15:1
8:1
9:1
5:1
3.5:1
3:1
g
h
5:1
3.5:1
a Yields are of purified material and are unoptimized. b Ratios of
11a-h:12a-h were determined by 1H NMR analysis of the crude
reaction mixtures.
As is evident from examination of Table 1, the introduction
of methyl groups at any position on the furan ring resulted in
somewhat lower diastereoselectivity, although the yields re-
mained high (70-96%). Substitution at C(5) of the furan ring
(entries 5-8) had the greatest effect upon lowering the
stereoselectivity of the addition. Moreover, the presence of a
methyl group at C(5) on the furan significantly decreased the
rate of the reaction.
The major threo diastereomers 11b-g were isolated as
crystalline solids whose structures were determined by single-
crystal X-ray analysis, whereas the structure of 11a had been
previously determined by X-ray analysis of a crystalline
derivative.5a The structures of 11h and 12h were assigned by
1
comparisons of their 13C and H NMR spectra with those of
other adducts, as some apparent trends were observed. For
example, the 13C chemical shifts of the C(5) carbon of 11a-d
were deshielded relative to those of the C(5) carbon in 12a-d.
However, in compounds having a C(5) methyl substituent, the
trend was reversed as the chemical shifts of the C(5) carbon in
11g,h were shielded relative to those of 12g,h; the signals for
the C(5) carbon in 11e,f and 12e,f overlapped. Some relation-
Figure 1. Limiting transition states for the addition of silyloxyfurans
to cyclic iminium ions.
Scheme 3
1
ships in the observed chemical shifts in the H NMR spectra
for the protons at C(2′) and C(5) were also predictive. For
example, the C(2′) proton in 11a-d was deshielded relative to
the C(2′) proton in 12a-d, whereas the C(2′) proton in
compounds 11e-h, having a methyl group at C(5), was shielded
relative to that in 12e-h.
The structure of the cyclic iminium ion also appears to have
an effect on the stereochemical course of the vinylogous
Mannich reaction. For example, we found that the iminium ion
generated from the ethoxy pyrrolidinone 13 underwent additions
with the methyl silyloxyfurans 9a-c,e, albeit with low diaste-
reoselectivity (1.1-2.8:1). The reactions of 13 required higher
temperatures and longer reaction times than the related additions
involving 10. Although it was not possible to make unequivocal
structure assignments to the products on the basis of their NMR
spectra, we did obtain an X-ray crystal structure of 14c, which
was the major product from the reaction of 13 with 9c. We
presume that the major products of the other reactions are also
the threo adducts 14a,b,e. Because these processes were not
very stereoselective, they were not examined in greater detail
(Scheme 3).
At the outset of these studies, we had hoped to identify some
of the stereochemical control elements and to gain insights
regarding geometric features of the transition states for viny-
logous Mannich reactions. Examination of the data in Table 1
clearly reveals that the presence of alkyl substituents on the
furan ring does affect the stereochemical course of the reaction.
However, because of the relatively small energetic differences
between the competing transition states, it is not possible to
conclude with certainty whether these additions proceed via
limiting Diels-Alder, A and C, or open geometries, B and D
(Figure 1). It is nonetheless possible to identify some apparent
stereochemical features associated with these processes that will
require further testing. For example, the loss of diastereoselec-
tivity observed in the vinylogous Mannich reaction of 9b, which
has a methyl group as the R1 substituent at C(3), seems to be
more consistent with a Diels-Alder transition state than an open
one. Namely, a group R1 * H clearly incurs steric interactions
with the iminium ion in transition states A and C, whereas there
are no such interactions apparent in B and D. Thus, if an open
transition state were operative, one would not expect to observe
any difference in the stereochemical outcome of the addition
depending upon the nature of R1. Modeling suggests that R2 *
H would sterically encounter the proton at C(3′) of the iminium
ion in transition states B and C, whereas this interaction is absent
in A and D. That the threo adduct is the major product whenever
R2 ) Me (entries 3, 7, and 8; Table 1) suggests that the Diels-
Alder transition state A is preferred.
First-Generation Synthesis of (+)-Croomine (1). The
application of vinylogous Mannich reactions to the enantio-
selective synthesis of (+)-croomine required the trialkylsilyloxy
furan 9b as the common precursor of both the A and D rings.

Applications of Vinylogous Mannich Reactions
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 6993
Scheme 4
Figure 2. ORTEP plot of compound 18.
eventually afforded the threo adduct 19, albeit in less than 1%
yield. The structural assignment of 19, which was produced by
the nucleophilic addition of the furan 16 to the more hindered
face of the intermediate acyl iminium ion, was confirmed by
X-ray crystallography. Although neither of the two possible
erythro isomers was isolated, it is not possible to exclude their
formation. The failure to identify erythro adducts in the mixture
is all the more puzzling because we have recently found that
both threo and erythro adducts were formed in a related
vinylogous Mannich reaction.6d
Attempted reduction of the carbon-carbon double bond in
18 by catalytic hydrogenation using Pd/C, Pd(OH2)/C, Ru/C,
and Rh/C under 1 atm of H2 was unsuccessful, and some
hydrogenolysis of the alkyl bromide group was observed when
using various palladium catalysts. The reluctance of 18 to
undergo hydrogenation may be rationalized upon examination
of the X-ray structure (Figure 2), which suggests that both faces
of the butenolide double bond are highly sterically encumbered.
On the other hand, reduction of the amine 20, which was
prepared by the acid-catalyzed removal of the tert-butyloxy-
carbonyl protecting group from 18, proceeded stereoselectively
to give the saturated amine 21 as the only detectable stereo-
isomer in >96% overall yield. The stereochemical course of
this reduction is consistent with steric approach control, but it
is also possible that the hydrogenation is directed by the basic
nitrogen of the pyrrolidine ring.16
At this juncture, the seven-membered B ring of croomine was
formed by heating 21 in refluxing dimethylformamide (DMF)
in the presence of N-methylmorpholine (NMM) to give 22 (80%
yield) (Scheme 5). When stronger bases, such as Hu¨nig’s base
or triethylamine, were used to effect this cyclization, significant
epimerization at C(11) occurred to give 25. In a separate study,
a mixture (2:1) of 22 and 25 was equilibrated with methanolic
NaOMe to return a new mixture (1:2) of diastereoisomers in
which 23 was the major product; no epimerization of the center
R to the methyl ester at C(3) was observed. Thus, the unnatural
configuration at C(11) in these tricyclic intermediates is
thermodynamically preferred.
The stage for the first of these was set by preparing the furan
16 in 83% yield by alkylation of the lithio derivative of 9b with
1,4-dibromobutane (Scheme 4).13 It was also necessary to select
a suitable iminium ion precursor, and the known methoxy-
pyrrolidine 1714 appeared to be ideally suited to the task.
Namely, we envisioned that the carboxyl function at C(3) in
the iminium ion produced by loss of the methoxy group from
17 would direct the furan nucleophile to the opposite face,
thereby setting the absolute stereochemistry at C(9a) of croom-
ine.15 The carboxyl function would later serve as a functional
handle to direct the formation of the iminium ion in the second
vinylogous Mannich reaction (vide infra). In the event, when
16 was allowed to react with the chiral acyl iminium ion
generated in situ by the triisopropylsilyl triflate-catalyzed
ionization of 17, a mixture was obtained from which the threo
adduct 18 crystallized in 32% yield; the structure of 18 was
unequivocally established by X-ray crystallography. Despite
considerable experimentation with different Lewis acid promot-
ers and solvents, we were unable to improve the efficiency of
this key addition. Nevertheless, it is noteworthy that the requisite
absolute stereochemical relationships at C(9) and C(9a) of
croomine were secured in a single step via a vinylogous
Mannich reaction proceeding via a threo manifold in which the
furan approached the iminium ion from the face opposite the
carboxyl function at C(3).
The 1H and 13C NMR spectra of the crude mixture from the
reaction of 16 with 17 were complex, but only one diagnostic
singlet, corresponding to the â-proton on the butenolide moiety,
1
was readily visible in the H NMR spectrum (δ 7.17 ppm),
suggesting the primary formation of only one adduct. Repeated
separation of the mixture by column and HPLC chromatography
(13) Cf.: Perron, F.; Albizati, K. F. J. Org. Chem. 1989, 54, 2044.
(14) Shono, T.; Matsumura, Y.; Tsubatya, K.; Sugihara, Y.; Shin-ichiro,
Y.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697. See also
ref 8e.
The plan to complete the total synthesis of (+)-croomine
required that the carboxyl group at C(3) of 22 would serve as
a precursor of a regioselectively generated iminium ion that
(15) Numbering of all intermediates corresponds to the numbering
scheme shown for croomine (1).
(16) Brown, J. Angew. Chem., Int. Ed. Engl. 1987, 26, 190.

6994 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Martin et al.
Scheme 5
Scheme 6
level of selectivity, as both faces appeared approximately equally
accessible. Indeed, we found that catalytic hydrogenation of 27
(H2/10% Pd-C, EtOH, HCl) gave an inseparable mixture
(2:1) of 22 and its C(11) epimer 25. The aforementioned
equilibration studies with 22 and 25 also offered no encourage-
ment that the configuration at C(11) corresponding to that found
in croomine was more stable. However, we judged these
negative omens as insufficient to deter our interest and
enthusiasm in the potential reward of an even shorter synthesis
of croomine.
would undergo a vinylogous Mannich reaction to form the
C(3)-C(14) bond and introduce the pendant butyrolactone D
ring. As precedent for this critical transformation, Rapoport
reported that acid chlorides derived from tertiary R-amino acids
are thermally unstable and decarbonylate to give iminium salts
that may be trapped with nucleophiles;17 similar reactions have
been reported by others.18 Although the base-induced hydrolysis
of the methyl ester in 22 afforded mixtures of products,
hydrolysis in refluxing aqueous 3 M HBr cleanly furnished the
carboxylic acid 23 in 93% yield. Treatment of 23 with POCl3
in DMF at room temperature and subsequent reaction of the
intermediate iminium salt in situ with the furan 9b gave a
separable mixture (ca. 2:1) of the requisite threo adduct 24,
together with the erythro product 26 in 47% combined yield.19
Both 24 and 26 were characterized by X-ray crystallography.
The synthesis was then completed by the stereoselective
hydrogenation from the less hindered face of the hydrochloride
salt of 24 to deliver (+)-croomine (1) (85% yield). The spectral
characteristics (1H and 13C NMR) of the synthetic 1 thus
obtained were identical to those reported.2e,3a
The feasibility of applying this modified plan was evaluated
in unoptimized series of reactions in which 20 was first cyclized
in the presence of N-methylmorpholine (NMM) to give the
unsaturated tricycle 27 (Scheme 6). Acid-catalyzed hydrolysis
of the methyl ester as before, followed by reaction of the
intermediate iminium ion with the furan 9b, then furnished the
expected mixture (ca. 2:1) of 28 and 29. To our considerable
delight and surprise, catalytic hydrogenation of 28 delivered
croomine (1) as the only isolable product in 81% yield; synthetic
1
samples of croomine (1) from both routes gave identical H
and 13C NMR spectra.
Second-Generation Synthesis of (+)-Croomine (1). Despite
the remarkable brevity of this asymmetric synthesis of croomine
(1), we were intrigued by the possibility of devising an even
shorter route. It thus occurred to us that postponing the
hydrogenation of the C(10)-C(11) carbon-carbon double bond
until the last step in the synthesis would trim one step from the
sequence. This maneuver was not without risk, however, as a
preliminary examination of molecular models of 28, the
penultimate intermediate in the new route, suggested that
reduction of the C(10)-C(11) carbon-carbon double bond
would not be expected to occur from either face with a high
To explore the possible basis for this remarkable result, we
undertook a series of computational studies to verify whether
our original molecular models were misleading. Perhaps we had
missed a low-energy conformation in which there was a clear
steric bias about the C(10)-C(11) double bond that would favor
the observed stereochemical mode of addition of hydrogen. A
search of conformational space for 26 was therefore performed
by both Monte Carlo methods and stochastic dynamics using
MM220 and Tripos21 force fields. Under the acidic conditions
of the reduction, the central nitrogen atom is protonated, and
the calculations suggested that protonation syn to the bridgehead
methine at C(9a) to give a cis-fused [5.3.0] bicyclic array was
several kilocalories per mole lower in energy than the corre-
sponding anti configuration. A low-energy conformation of
(17) (a) Dean, R. T.; Padgett, H. C.; Rapoport, H. J. Am. Chem. Soc.
1976, 98, 7448. (b) Bates, H. A.; Rapoport, H. J. Am. Chem. Soc. 1979,
101, 1259. (c) Johansen, J. E.; Christie, B. D.; Rapoport, H. J. Org. Chem.
1981, 46, 4914.
(18) For example, see: (a) Wasserman, H.; Tremper, A. W. Tetrahedron
Lett. 1977, 1449. (b) van Tamelen, E. E.; Haarstead, V. B.; Orvis, R. L.
Tetrahedron 1967, 24, 687. (c) van Tamelen, E. E.; Oliver, L. K. J. Am.
Chem. Soc. 1970, 92, 2136; Bioorg. Chem. 1976, 5, 309.
(19) Approximately 5% of another stereoisomer that was not identified
was also isolated.
(20) As implemented by MacroModel v6.0, available from Columbia
University. See: Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp,
R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. J.
Comput. Chem. 1990, 11, 440.
(21) As implemented by CONFORT v2 from Dr. Robert Pearlman at
the University of Texas at Austin.

Applications of Vinylogous Mannich Reactions
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 6995
gold oil with a suspended precipitate. A small volume of pentane was
added, the mixture was filtered through a plug of Celite, and the filtrate
was concentrated under reduced pressure to give 19.4 g (83%) of 16
as a gold oil that was pure by NMR and was used directly in the next
step: 1H NMR (250 MHz) δ 1.09 (d, J ) 6.5 Hz, 18 H), 1.22 (sept, J
) 6.5 Hz, 3 H), 1.66-1.73 (m, 2 H), 1.79 (s, 3 H), 1.82-1.90 (m, 2
H), 2.48 (t, J ) 7.1 Hz, 2 H), 3.40 (t, J ) 6.7 Hz, 2 H), 5.69 (s, 1 H);
13C NMR (62.5 MHz) δ 8.5, 12.3, 17.6, 26.8, 27.0, 31.9, 33.5, 91.4,
108.9, 142.8, 151.3; IR (film) 1265, 1406, 1463, 1590, 1661 cm-1
;
HRMS (CI) m/z 388.1430 (C18H33BrO2Si requires 388.1433).
[5(S),2′(S),5′(S)]-5-(4′′-Bromobut-1′′yl)-5-[N-(tert-butoxycarbonyl)-
2′-(methoxycarbonyl)pyrrolidin-5′-yl]-3-methyl-2(5H)-furanone (18).
TIPSOTf (0.61 g, 2.00 mmol) was slowly added to a solution of 17
(10.4 g, 40.0 mmol) and 16 (15.9 g, 40.0 mmol) in dry CH2Cl2 (120
mL) at 0 °C. After 16 h, saturated, aqueous NaHCO3 (40 mL) was
added, and the layers were separated. The aqueous phase was extracted
with CH2Cl2 (2 × 60 mL), and the combined organic portions were
dried (MgSO4) and concentrated under reduced pressure. Recrystal-
ization of the residual oil from pentane/ether (1:1) afforded 5.89 g (32%)
of 18 as colorless crystals. Alternatively, purification of the residue by
flash column chromatography, eluting with hexane/EtOAc (gradient
elution with 80:20 and 70:30), provided 5.16 g (28%) of 18 as a white
powder and a mixture that was further purified by HPLC, eluting with
hexane/EtOAc (70:30), to provide 99 mg (0.5%) of 19 as colorless
crystals.
Figure 3. Low-energy conformer of 28.
protonated 28 was thus identified in which the face of each
double bond that is syn to the hydrogen at C(9a) and anti to the
hydrogen at C(14) can be simultaneously presented to the
surface of the catalyst (Figure 3). If one then presumes that the
substrate is not released from the surface of the catalyst prior
to the second reduction, the stereoselective reduction of both
olefinic functions can produce the observed product.
These asymmetric syntheses of the complex alkaloid (+)-
croomine (1) are remarkably concise and highlight the power
of vinylogous Mannich reactions in alkaloid synthesis. The first
requires only 9 steps in the longest linear sequence, with a total
of 11 steps from commercially available starting materials,
whereas the second contains 8 steps in the longest linear
sequence and a total of 10 steps. All of the chirality in the target
was derived from L-pyroglutamic acid. Although the two key
vinylogous Mannich constructions proceeded with modest
efficiencies, this useful methodology allows for the rapid
assembly of the skeletal framework of alkaloids of the Stemo-
naceae family. Other novel applications of vinylogous Mannich
reactions will be reported in due course.
1
For 18: mp 152.5-155.5 °C; [R]D -90.8° (c ) 0.97, CHCl3); H
NMR (500 MHz) δ 1.23-1.42 (comp, 11 H), 1.73-1.89 (comp, 8 H),
2.05-2.19 (m, 2 H), 2.48-2.59 (m, 1 H), 3.36 (t, J ) 6.6 Hz, 2 H),
3.69 (s, 3 H), 4.18 (d, J ) 9.3 Hz, 1 H), 4.24 (d, J ) 7.8 Hz, 1 H),
7.17 (s, 1 H); 13C NMR (125 MHz) δ 10.2, 22.1, 25.0, 27.9, 29.3,
32.6, 32.8, 33.6, 51.9, 60.3, 61.7, 80.4, 91.3, 127.5, 151.2, 154.3, 173.7,
174.0; IR (film) 1697, 1740, 1750 cm-1; HRMS (CI) m/z 460.1308
(C20H30BrNO6 requires 460.1335).
1
For 19: mp 108.0-108.5 °C; [R]D +84.6° (c ) 1.35, CHCl3); H
NMR (500 MHz) δ 1.25-1.43 (comp, 11 H), 1.75-1.92 (comp, 8 H),
1.97-2.05 (m, 1 H), 2.13-2.17 (comp, 2 H), 3.36 (t, J ) 6.6 Hz, 2 H)
3.68 (s, 3 H), 4.10-4.18 (m, 2 H), 7.20 (s, 1 H); 13C NMR (125 MHz)
δ 9.6 21.3, 25.8, 27.3, 28.7, 32.0, 32.2, 33.7, 51.4, 60.2, 61.5, 80.0,
90.3, 128.3, 149.2, 153.8, 171.8, 173.4); IR (film) 2979, 1757, 1698,
1381, 1155 cm-1; HRMS (CI) m/z 460.1319 (C20H30BrNO6 requires
460.1335).
Experimental Section
General Procedures. Boron trifluoride etherate (BF3‚OEt2), dichlo-
romethane (CH2Cl2), dimethylformamide (DMF), N-methylmorpholine
(NMM), tetramethylethylenediamine (TMEDA), and triethylamine
(Et3N) were distilled from CaH2 prior to use. Thionyl chloride was
distilled from quinoline immediately prior to use. Tetrahydrofuran
(THF) was distilled from sodium benzoquinone ketyl prior to use. All
other solvents and reagents were available from commercial sources
and were used without further purification. All reactions involving
organometallic reagents or other moisture-sensitive reactants were
executed under an atmosphere of dry nitrogen or argon using oven-
dried glassware. Flash chromatography was performed using silica gel
60 (230-400 mesh ASTM) with the indicated solvent. Melting points
[5(S),2′(S),5′(S)]-5-(4′′-Bromobut-1′′-yl)-5-[2′-(methoxycarbonyl)-
pyrrolidin-5′-yl]-3-methyl-2(5H)-furanone (20). Neat CF3CO2H (11.4
g, 100 mmol) was slowly added with stirring to a solution of 18 (4.60
g, 10.00 mmol) in CH2Cl2 (30 mL) at room temperature. After 5 h, the
mixture was concentrated under reduced pressure, and the residue was
dissolved in CH2Cl2 (30 mL). The solution was carefully washed with
saturated NaHCO3 (30 mL), and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (5 × 10 mL), and the combined organic
fractions were dried (MgSO4) and concentrated under reduced pressure
to provide 3.60 g (100%) of crude 20 as a clear, colorless oil that was
pure by NMR and was used directly in the next step: [R]D -28.5° (c
1
are uncorrected. HPLC was performed on a Waters 2000 system. H
and 13C NMR spectra of compounds were recorded at the indicated
field strength as solutions in deuteriochloroform (CDCl3) unless
otherwise indicated. Chemical shifts are expressed in parts per million
(ppm, δ) downfield from tetramethylsilane (TMS) (δ ) 0.00 ppm) and
referenced to the solvent. Splitting patterns are recorded as singlet (s),
doublet (d), triplet (t), quartet (q), pentuplet (p), septet (sept), multiplet
1
) 1.07, CHCl3); H NMR (500 MHz) δ 1.24-1.44 (m, 2 H), 1.52-
1.59 (m, 1 H), 1.77-1.92 (comp, 6 H), 1.94 (s, 3 H), 2.03-2.10 (m,
1 H), 2.46 (br s, 1 H), 3.37 (t, J ) 6.6 Hz, 2 H), 3.63 (app t, J ) 7.1
Hz, 1 H), 3.72 (s, 3 H), 3.76 (dd, J ) 5.2, 8.4 Hz, 1 H), 6.94 (s, 1
H);13C NMR (125 MHz) δ 10.6, 21.8, 25.7, 29.9, 32.6, 33.0, 33.5,
52.1, 60.0, 62.3, 90.2, 131.3, 149.5, 173.7, 175.5; IR (film) 2951, 1748,
1434, 1216 cm-1; HRMS (CI) m/z 360.0806 (C15H23BrNO4 requires
360.0810).
1
(m), complex multiplet composed of chemically nonequivalent H’s
(comp), broad (br), and apparent (app). IR spectra were recorded either
as films on sodium chloride plates or as solutions in CHCl3 as indicated
and reported in wavenumbers (cm-1). Optical rotations were recorded
in CHCl3 that was stabilized with 1% ethanol unless otherwise indicated.
5-(4-Bromobut-1-yl)-3-methyl-2-(triisopropylsilyloxy)furan (16).
sec-Butyllithium (98.2 mL of a 1.10 M solution in cyclohexane, 108
mmol) was slowly added to a solution of 9b (15.3 g, 60.0 mmol) and
TMEDA (12.6 g, 108 mmol) in THF (300 mL) at 0 °C. After 2 h,
1,4-dibromobutane (51.8 g, 240 mmol) was added and the mixture
stirred for 14 h at 0 °C. A mixture (2:1) of H2O and saturated, aqueous
NaHCO3 was added, and the resulting mixture was extracted with Et2O
(3 × 200 mL). The organic layer was dried (MgSO4) and then
concentrated under reduced pressure (80 °C, 0.1 mmHg) to provide a
5-(S)-(Methoxycarbonyl)-2-(S)-[r-(R)-methyl-γ-(bromobutyl)-(S)-
lacton-γ-yl]pyrrolidine (21). A mixture of 20 (1.08 g, 3.00 mmol)
and 5% Rh/C (0.185 g, 0.09 mmol) in EtOAc/EtOH (2:1, 30 mL) was
stirred under H2 (1 atm) for 4 h. The mixture was then filtered through
Celite, and the pad was rinsed with EtOAc/EtOH (2:1, 10-15 mL).
The filtrate was concentrated under reduced pressure to provide a pale
amber oil that was purified by flash chromatography eluting with
pentane/Et2O (2:3) to provide 1.06 g (98%) of 21 as a clear, colorless
1
oil: [R]D -20.4° (c ) 1.10, CHCl3); H NMR (500 MHz) δ 1.23 (d,
J ) 7.8 Hz, 3 H), 1.45-1.52 (m, 2 H), 1.58-1.77 (comp, 4 H), 1.78-
1.95 (comp, 4 H), 2.20 (dt, J ) 5.0, 17.3 Hz, 1 H), 2.30 (br s, 1 H),

6996 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Martin et al.
2.40 (dd, J ) 10.3, 13.1 Hz, 1 H), 3.07-3.17 (m, 1 H), 3.42 (t, J )
6.6 Hz, 2 H), 3.48 (app t, J ) 7.5 Hz, 1 H), 3.70 (app t, J ) 7.0 Hz,
1 H), 3.72 (s, 3 H); 13C NMR (125 MHz) δ 17.1, 21.7, 26.2, 31.3,
32.6, 33.2, 35.8, 36.5, 38.2, 52.1, 60.1, 64.3, 87.2, 175.8, 180.4; IR
(film) 3626, 3507, 3342, 2850, 1740, 1732, 1453 cm-1; HRMS (CI)
m/z 362.0965 (C15H25BrNO4 requires 360.0810).
1.51-1.58 (m, 1 H), 1.55-1.62 (m, 1 H), 1.62-1.67 (m, 1 H), 1.67-
1.80 (comp, 3 H), 1.82-1.87 (m, 1 H), 1.88-1.94 (m, 1 H), 1.94 (s,
3 H), 1.96-2.03 (m, 1 H), 2.50 (dd, J ) 10.8, 13.7 Hz, 1 H), 2.66-
2.74 (m, 1 H), 2.93-2.98 (m, 1 H), 3.07-3.13 (m, 1 H), 3.45-3.50
(comp, 2 H), 5.15-5.18 (m, 1 H), 6.97-6.99 (m, 1 H); 13C NMR (125
MHz) δ 10.8, 18.0, 21.5, 24.6, 27.6, 27.9, 36.0, 36.9, 41.6, 48.1, 65.2,
68.0, 81.2, 88.8, 130.8, 147.1, 174.1, 179.3; IR (KBr) 1754, 1454 cm-1
;
[3′S-[3′r,9′r(S*),9′ar]]-Decahydro-4-methyl-5-oxospiro[furan-
2(3H),9′-[9H]pyrrolo[1,2-a]azepin]-3′-carboxylic Acid, Methyl Ester
(22). A solution of 21 (0.388 g, 1.00 mmol) and NMM (0.607 g, 6.00
mmol) in DMF (10 mL) was heated to reflux. After 30 min, the reaction
mixture was cooled to room temperature and concentrated under
reduced pressure. A mixture (3:1) of saturated, aqueous NaHCO3 and
brine (10 mL) was added, and the resulting mixture was extracted with
CH2Cl2 (3 × 10 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. The residue was
purified by flash chromatography, eluting with pentane/Et2O (1:1) to
afford 0.281 g (80%) of 22 as a clear, colorless oil: [R]D -44.0° (c )
0.99, CHCl3); 1H NMR (500 MHz) δ 1.32 (d, J ) 7.3 Hz, 3 H), 1.47-
1.58 (m, 3 H), 1.58-1.67 (m, 1 H), 1.67-1.78 (m, 2 H), 1.78-1.86
(m, 2 H), 1.88-1.94 (m, 1 H), 2.01-2.08 (m, 1 H), 2.22-2.30 (m, 1
H), 2.61 (dd, J ) 11.0, 13.8 Hz, 1 H), 2.68-2.87 (m, 1 H), 2.82-2.87
(comp, 2 H), 3.53 (dd, J ) 3.2, 9.4 Hz, 1 H), 3.69 (s, 3 H), 3.86 (dd,
J ) 1.3, 7.6 Hz, 1 H); 13C NMR (125 MHz) δ 18.3, 20.6, 26.7, 28.3,
28.8, 35.7, 36.2, 43.4, 49.4, 51.2, 67.0, 67.5, 88.8, 174.6, 179.5; IR
(film) 1731, 1766 cm-1; HRMS (CI) m/z 282.1702 (C15H23NO4 requires
282.1705).
HRMS (CI) m/z 320.1859 (C18H26NO4 requires 320.1862).
[3′S-[3′r,9′r(S*),9′ar]]-1′,2′,3′,5′,6′,7′,8′-Octahydro-4-methyl-5-
oxospiro[furan-2(5H),9′-[9H]pyrrolo[1,2-a]azepin]-3′-carboxylic Acid,
Methyl Ester (27). A solution of 20 (1.09 g, 3.00 mmol) and NMM
(1.82 g, 18.00 mmol) in DMF (30 mL) was heated at reflux for 30
min, whereupon the mixture was cooled to room temperature and then
concentrated under reduced pressure. A mixture (3:1) of saturated,
aqueous NaHCO3 and brine (30 mL) was added to the residue, and the
resulting mixture was extracted with CH2Cl2 (3 × 30 mL). The
combined organic extracts were dried (MgSO4) and concentrated under
reduced pressure, and the residue was purified by flash chromatography,
eluting with hexane/EtOAc (7:3), to afford 0.43 g (51%) of 27 as a
clear, colorless oil that solidified upon standing: mp 121-122 °C; [R]D
1
+3.85° (c ) 1.04, CHCl3); H NMR (500 MHz) δ 1.23-1.28 (m, 1
H), 1.58-1.74 (comp, 4 H), 1.75-1.88 (comp, 4 H), 1.93 (s, 3 H),
2.12-2.20 (m, 1 H), 2.83-2.88 (m, 1 H), 2.88-2.94 (m, 1 H), 3.64
(dd, J ) 1.6, 9.5 Hz, 1 H), 3.68 (s, 3 H), 3.78-3.81 (m, 1 H), 7.21 (d,
J ) 1.4 Hz, 1 H); 13C NMR (125 MHz) δ 10.7, 21.6, 23.6, 29.0, 29.5,
39.6, 49.7, 51.2, 65.3, 67.5, 90.7, 130.4, 150.9, 173.5, 174.2; IR (KBr)
2932, 1740, 1448, 1160, 754 cm-1; HRMS (CI) m/z 280.1538 (C15H21-
NO4 requires 280.1549).
[3′S-[3′r,9′r(S*),9′ar]]-Decahydro-4-methyl-5-oxospiro[furan-
2(3H),9′-[9H]pyrrolo[1,2-a]azepin]-3′-carboxylic Acid, Hydrobro-
mide Salt (23). A solution of 22 (0.281 g, 1.00 mmol) in 3 M aqueous
HBr (3 mL) was heated to 80 °C for 4 h, and then the solution was
concentrated under reduced pressure. The residue was recrystallized
from hot acetonitrile to give 0.324 g (93%) of 23 as colorless crystals:
[3′S-[3′r,9′r(S*),9′ar]]-1′,2′,3′,5′,6′,7′,8′-Octahydro-4-methyl-5-
oxospiro[furan-2(5H),9′-[9H]pyrrolo[1,2-a]azepin]-3′-carboxylic Acid,
Hydrobromide Salt. A solution of 27 (0.279 g, 1.00 mmol) in 3 M
aqueous HBr (3 mL) was heated at 85 °C for 4 h, whereupon the water
was removed under reduced pressure. Recrystallization of the residue
from hot MeCN provided 0.329 g (95%) of the hydrobromide salt of
the amino acid as colorless crystals: mp 203 °C dec; [R]D +144.2° (c
) 0.89, H2O); 1H NMR (500 MHz, D2O/DDS) δ 1.72-1.92 (comp, 6
H), 1.92-2.13 (comp, 4 H), 2.55-2.68 (m, 1 H), 3.53-3.67 (m, 1 H),
3.75-3.88 (m, 1 H), 4.06 (dd, J ) 6.9, 11.2 Hz, 1 H), 4.63 (dd, J )
6.8, 11.0 Hz, 1 H), 7.50 (s, 1 H); 13C NMR (125 MHz, D2O/DDS) δ
12.2, 25.2, 26.0, 30.5, 30.6, 35.1, 56.4, 70.1, 74.2, 90.7, 132.7, 154.5,
1
mp 238.0-239.0 °C; [R]D -24.0° (c ) 0.82, H2O); H NMR (500
MHz, D2O/DDS) δ 1.28 (d, J ) 9.3 Hz, 3 H), 1.72-1.87 (m, 2 H),
1.87-2.04 (comp, 3 H), 2.04-2.16 (comp, 2 H), 2.16-2.32 (comp, 2
H), 2.36-2.43 (m, 1 H), 2.58-2.66 (m, 2 H), 3.04 (dd, J ) 9.5, 16.8
Hz, 1 H), 3.46 (dd, J ) 6.6, 13.8 Hz, 1 H), 3.71 (dd, J ) 9.6, 14.4 Hz,
1 H), 4.22 (dd, J ) 6.0, 12.4 Hz, 1 H), 4.59 (dd, J ) 7.0, 11.4 Hz, 1
H); 13C NMR (125 MHz, D2O/DDS) δ 18.1, 24.8, 25.2, 30.4, 30.8,
37.2, 39.0, 43.9, 57.2, 71.2, 75.2, 89.3, 173.0, 184.9; IR (KBr) 1778,
1738, 1187 cm-1; HRMS (CI) m/z 346.06542 (C14H21NO4Br requires
346.0654).
172.5, 177.7; IR (KBr) 2923, 1765, 1727, 1460, 1358, 1218, 1195 cm-1
HRMS (CI) m/z 344.0488 (C14H19NO4Br requires 344.0497).
;
[3′S-[3′r(R*),9′r(S*),9′ar]]-3′-(2,5-Dihydro-4-methyl-5-oxo-2-
furanyl)decahydro-4-methylspiro[furan-2(5H),9′-[9H]pyrrolo[1,2-
a]azepin-5-one (24) and [3′S-[3′r(S*),9′r(S*),9′ar]]-3′-(2,5-Dihydro-
4-methyl-5-oxo-2-furanyl)decahydro-4-methylspiro[furan-2(5H),9′-
[9H]pyrrolo[1,2-a]azepin-5-one (26). POCl3 (94 mg, 0.60 mmol) was
slowly added to a solution of 23 (0.174 g, 0.50 mmol) in anhydrous
DMF (5 mL) at room temperature, upon which gas evolution was
observed. After 15 min, the mixture was concentrated under reduced
pressure to provide a dark residue that was dissolved in DMF (5 mL).
Furan 9b (0.509 g, 2.00 mmol) was added, and the resulting mixture
was stirred for 6 h at room temperature. Saturated, aqueous NaHCO3
(10 mL) was carefully added, and the mixture was extracted with Et2O/
MeCN (1:1, 4 × 10 mL). The combined organic extracts were dried
(MgSO4) and then concentrated under reduced pressure. The residual
mixture was initially separated by flash column chromatography, eluting
with hexane/EtOAc (2:3), and then by HPLC, eluting with hexane/
EtOAc (7:3), to give 49 mg (31%) of 24 and 25 mg (16%) of 26 as
clear oils.
[3′S-[3′r(R*),9′r(S*),9′ar]]-3′-(2,5-Dihydro-4-methyl-5-oxo-2-
furanyl)-1′,2′,3′,5′,6′,7′,8′-octahydro-4-methylspiro[furan-2(5H),9′-
[9H]pyrrolo[1,2-a]azepin]-5-one (28) and [3′S-[3′r(S*),9′r(S*),9′ar]]-
3′-(2,5-Dihydro-4-methyl-5-oxo-2-furanyl)-1′,2′,3′,5′,6′,7′,8′-octahydro-
4-methylspiro[furan-2(5H),9′-[9H]pyrrolo[1,2-a]azepin]-5-one (29).
Phosphorus oxychloride (69 mg, 0.20 mmol) was slowly added to a
solution of the amino acid hydrobromide salt from the preceding
experiment (37 mg, 0.24 mmol) in DMF (2 mL); gas evolution was
observed. After 15 min, the mixture was concentrated under reduced
pressure to provide a dark residue that was redissolved in DMF (5 mL),
and furan 9b (0.203 g, 0.80 mmol) was added. After the mixture was
stirred for 6 h at room temperature, saturated, aqueous NaHCO3 (2
mL) was carefully added. The mixture was extracted with Et2O/MeCN
(1:1, 4 × 2 mL), and the combined organic extracts were dried (MgSO4)
and concentrated under reduced pressure. The residue was partially
purified by flash column chromatography, eluting with hexane/EtOAc
(2:3), to give a mixture of 28 and 29 that was separated by HPLC,
eluting with hexane/EtOAc (7:3), to give 21 mg (27%) of 28 and 9 mg
(12%) of 29 as clear oils.
1
For 24: mp 142.1-142.3 °C; [R]D 58.8° (c ) 0.94, CHCl3); H
1
NMR (500 MHz) δ 1.31 (d, J ) 77.4 Hz, 3 H), 1.43-1.68 (comp, 5
H), 1.64 (dd, J ) 7.8, 13.6 Hz, 1 H), 1.68-1.97 (comp, 5 H), 1.93 (s,
3 H), 2.41 (dd, J ) 10.6, 13.6 Hz, 1 H), 2.67-2.75 (m, 1 H), 3.04-
3.10 (m, 1 H), 3.15-3.22 (m, 1 H), 3.47-3.52 (comp, 2 H), 4.98-
5.02 (m, 1 H), 7.00 (m, 1 H); 13C NMR (125 MHz) δ 10.7, 17.9, 22.1,
25.8, 27.2, 27.8, 35.8, 27.3, 40.9, 48.3, 65.2, 68.5, 82.5, 89.2, 131.2,
146.4, 173.9, 179.2; IR (KBr) 1757, 1658, 1454, 1190 cm-1; HRMS
(CI) m/z 320.1871 (C18H26NO4 requires 320.1862).
For 28: [R]D +43.9° (c ) 0.23, CHCl3); H NMR (500 MHz) δ
1.31-1.37 (m, 1 H), 1.37-1.43 (m, 1 H), 1.52-1.63 (comp, 3 H),
1.63-1.74 (comp, 2 H), 1.74-1.84 (m, 1 H), 1.84-1.90 (comp, 2 H),
1.92 (s, 3 H), 1.93 (s, 3 H), 3.12-3.20 (m, 1 H), 3.21-3.28 (m, 1 H),
3.34-3.38 (m, 1 H), 3.56 (dd, J ) 3.5, 8.2 Hz, 1 H), 4.98-5.02 (m,
1 H), 6.97 (s, 1 H), 7.06 (s, 1 H); 13C NMR (125 MHz) δ 10.8, 22.8,
25.8, 26.4 27.8, 38.6, 48.9, 65.1, 66.8, 81.9, 90.9, 130.6, 131.2, 146.3,
150.4, 173.1, 173.8; IR (film) 2928, 1745, 1659, 1447 cm-1; HRMS
(CI) m/z 317.1633 (C18H23NO4 requires 317.1627).
1
For 26: mp 150.5-151.5 °C; [R]D +94.1° (c ) 4.23, CHCl3); H
1
NMR (500 MHz) δ 1.28 (d, J ) 7.4 Hz, 3 H), 1.40-1.50 (comp, 2 H),
For 29: [R]D -163.8° (c ) 0.37, CHCl3); H NMR (500 MHz) δ

Applications of Vinylogous Mannich Reactions
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 6997
1.17-1.32 (comp, 2 H), 1.32-1.52 (comp, 2 H), 1.52-1.99 (comp,
12 H), 2.95-3.05 (m, 1 H), 3.12-3.27 (m, 1 H), 3.38-3.44 (m, 1 H),
3.62 (dd, J ) 2.6, 8.7 Hz, 1 H), 5.24 (m, 1 H), 6.94 (s, 1 H), 7.14 (s,
1 H); 13C NMR (125 MHz) δ 10.8, 22.1, 24.8, 26.5, 28.8, 39.2, 48.2,
64.9, 66.1, 80.9, 90.7, 130.4, 130.9, 147.0, 150.8, 173.3, 174.0; IR (film)
2927, 1747, 1656, 1447 cm-1; HRMS (CI) m/z 317.1623 (C18H23NO4
requires 317.1627).
(1 atm) for 8 h, whereupon saturated, aqueous NaHCO3 (6 mL) was
added. The mixture was extracted with CH2Cl2 (6 × 1 mL), and the
combined organic extracts were dried (MgSO4) and concentrated under
reduced pressure to provide 13 mg (81%) of pure croomine as a clear,
colorless oil.
Acknowledgment. We thank the National Institutes of
Health and the Robert A. Welch Foundation for supporting this
research. We are grateful to Professor David R. Williams
(Indiana University) for providing 1H and 13C NMR spectra of
croomine for comparison. We also thank Dr. Vincent M. Lynch
(The University of Texas) for performing the X-ray crystal-
lographic analyses of compounds 11b-g, 14c, 18, 19, 24, and
26, and Dr. Robert Pearlman (The University of Texas) for help
with the molecular modeling.
Croomine (1). Method A. A solution of 24 (32 mg, 0.10 mmol)
and 10% Pd/C (27 mg) in 10% concentrated HCl/EtOH (2 mL) was
stirred under H2 (1 atm) for 8 h, and the mixture was filtered through
a Celite pad that was washed with MeOH (1 mL). Saturated, aqueous
NaHCO3 (12 mL) was added to the filtrate, and the mixture was
extracted with CH2Cl2 (6 × 2 mL). The combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure to provide
27 mg (85%) of croomine as a clear, colorless oil: [R]D +15.6° (c )
0.34, CHCl3), lit.1d [R]D +9.8° (c ) 0.11, CHCl3); 1H NMR (500 MHz)
δ 1.26 (d, J ) 7.0 Hz, 3 H), 1.31 (d, J ) 7.4 Hz, 3 H), 1.45-1.60
(comp, 3 H), 1.65 (dd, J ) 7.6, 13.7 Hz, 1 H), 1.65-1.82 (m, 4 H),
1.82-1.93 (m, 3 H), 1.93-2.02 (m, 1 H), 2.34-2.39 (m, 1 H), 2.54
(dd, J ) 10.7, 13.7 Hz), 2.56-2.65 (m, 1 H), 2.68-2.74 (m, 1 H),
3.08-3.17 (comp, 2 H), 3.36 (dd, J ) 6.6, 13.8 Hz, 1 H), 3.49 (app t,
J ) 7.2 Hz, 1 H), 4.29-4.34 (m, 1 H); 13C NMR (125 MHz) δ 14.9
18.0, 22.0, 26.3, 27.1, 27.7, 34.8, 35.0, 36.0, 37.1, 41.1, 48.5, 66.9,
Supporting Information Available: Experimental proce-
dures and spectral data for compounds 9a-h and 11a-h, partial
spectral data for 14a-c,e and 15a-c,e, and X-ray crystal-
lographic data for compounds 11b-g and 14c (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
68.8, 80.6, 89.5, 179.4 (2 C’s); IR (film) 2934, 1762, 1454, 1191 cm-1
;
HRMS (CI) m/z 322.2012 (C18H28NO4 requires 322.2018).
Method B. A solution of 28 (16 mg, 0.050 mmol) and 10% Pd/C
(13 mg) in 10% concentrated HCl/EtOH (2 mL) was stirred under H2
JA990077R