Syntheses of the Stemona alkaloids (±)-stenine, (±)- neostenine, and (±)-13-epineostenine using a stereodivergent Diels-Alder/azido-Schmidt reaction

Article abstract of DOI:10.1021/ja800574m

A tandem Diels-Alder/azido-Schmidt reaction sequence provides rapid access to the core skeleton shared by several Stemona alkaloids including stenine, neostenine, tuberostemonine, and neotuberostemonine. The discovery and evolution of inter- and intramole

Full text of DOI:10.1021/ja800574m

Published on Web 04/09/2008
Syntheses of the Stemona Alkaloids (()-Stenine,
(()-Neostenine, and (()-13-Epineostenine Using a
Stereodivergent Diels–Alder/Azido-Schmidt Reaction
Kevin J. Frankowski, Jennifer E. Golden, Yibin Zeng, Yao Lei, and Jeffrey Aubé*
Department of Medicinal Chemistry and Center for Chemical Methodologies and Library
DeVelopment, UniVersity of Kansas, Malott Hall, Room 4070, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
Received January 29, 2008; E-mail: jaube@ku.edu
Abstract: A tandem Diels–Alder/azido-Schmidt reaction sequence provides rapid access to the core skeleton
shared by several Stemona alkaloids including stenine, neostenine, tuberostemonine, and neotuberostemonine.
The discovery and evolution of inter- and intramolecular variations of this process and their applications to
total syntheses of (()-stenine and (()-neostenine are described. The stereochemical outcome of the reaction
depends on both substrate type and reaction conditions, enabling the preparation of both (()-stenine and
(()-neostenine from the same diene/dienophile combination.
Chinese and Japanese traditional medicines have for centuries
utilized extracts of stemonaceous plants as remedies for the
treatment of respiratory ailments. These extracts and the isolated
Stemona alkaloids have been associated with insecticidal,
anthelmintic, antitussive, and various neurochemical effects,
although mechanisms have rarely been identified.1 Recently,
interest in these alkaloids was further piqued by the demonstra-
tion of effective in vivo activity of two skeletally related
Stemona alkaloids, neostenine 3 and neotuberostemonine 4,
against citric acid induced cough in guinea pig animal models.2
In addition, the Stemona alkaloid tuberostemonine 2 has
demonstrated inhibitory activity on excitatory transmission at
the crayfish neuromuscular junction.3 The Stemona alkaloids
have attracted substantial interest from synthetic chemists partly
because of these links to biological activity and partly from their
challenging structural complexity. Stenine has been the focus
of several successful synthetic efforts4 and has inspired a number
of synthetic approaches.5 In addition, tuberostemonine 2 was
synthesized by Wipf.6 However the stenine isomer, neostenine
3, had not yet been prepared via total synthesis at the outset of
this project7(Figure 1).
A noteworthy challenge in any stenine synthesis is the
construction of the B ring, which is fused to three additional
rings. In addition, each of its carbon atoms is a stereogenic
center. This issue was addressed using an intramolecular
Diels–Alder cyclization in three out of the four first-published
syntheses of this target (Scheme 1; the stenine numbering system
used throughout is that presented in a recent review1f). The first
synthesis of stenine by Hart in 1990 not only set the precedent
for utilizing a Diels–Alder approach to this target but also
established an iodolactonization/Keck allylation sequence as a
solutiontotheproblemofstereoselectiveethylgroupinstallation.4a,b
Morimoto utilized a chiral oxazoline-based intramolecular
Diels–Alder cyclization of 5 to synthesize the naturally occurring
enantiomer of stenine.4c–e Padwa applied an impressive Diels–
Alder/ring opening/1,2-methylthioshift cascade to append the
B and D rings onto an existing seven-membered C ring in a
single operation.4g,h Of all the completed syntheses to date, only
the route used by Wipf does not employ a Diels–Alder approach
for the construction of the cyclohexane ring.4f These workers
utilized the selective reduction of a π-allyl palladium complex
(1) (a) For reviews, see: Götz, M.; Edwards, O. E. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol 9, pp
545–551. (b) Götz, M.; Strunz, G. M. In Alkaloids; Wiesner, K., Ed.;
Butterworth: London, 1973; Vol. 9, pp 143–160. (c) Lin, W.-H.; Ye,
Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571–576. (d) Xu, R.-S. Stud.
Nat. Prod. Chem. 2000, 21, 729–772. (e) Pilli, R. A.; Ferreira de
Oliveira, M. d. C Nat. Prod. Rep. 2000, 17, 117–127. (f) Greger, H.
Planta Med. 2006, 72, 99–113. (g) Xu, Y.-T.; Hon, P.-M.; Jiang, R.-
W.; Cheng, L.; Li, S.-H.; Chan, Y.-P.; Xu, H.-X.; Shaw, P.-C.; But,
P. P.-H. J. Ethnopharmacol. 2006, 108, 46–53.
(2) (a) Chung, H.-S.; Hon, P.-M.; Lin, G.; But, P. P-H.; Dong, H. Planta
Med. 2003, 69, 914–920. (b) Leung, P. H. H.; Zhang, L.; Zuo, Z.;
Lin, G Planta Med. 2006, 72, 211–216.
(5) (a) Morimoto, Y.; Nishida, K.; Hayashi, Y.; Shirahama, H. Tetrahedron
Lett. 1993, 34, 5773–5776. (b) Morimoto, Y.; Iwahashi, M. Synlett
1995, 1221–1222. (c) Goldstein, D. M.; Wipf, P. Tetrahedron Lett.
1996, 37, 739–42. (d) Jung, S. H.; Lee, J. E.; Joo, H. J.; Kim, S. H.;
Koh, H. Y. Bull. Korean Chem. Soc. 2000, 21, 159–160. (e) Booker-
Milburn, K. I.; Hirst, P.; Charmant, J. P. H.; Taylor, L. H. J. Angew.
Chem., Int. Ed. 2003, 42, 1642–1644. (f) Zhu, L.; Lauchli, R.; Loo,
M.; Shea, K. J. Org. Lett. 2007, 9, 2269–2271.
(3) Shinozaki, H.; Ishida, M. Brain Res. 1985, 334, 33–40.
(4) (a) Chen, C.-Y.; Hart, D. J. Org. Chem. 1990, 55, 6236–6240. (b)
Chen, C.-Y.; Hart, D. J. Org. Chem. 1993, 58, 3840–3849. (c)
Morimoto, Y.; Iwahashi, M.; Nishida, K.; Hayashi, Y.; Shirahama,
H. Angew. Chem. 1996, 108, 968–970. (d) Morimoto, Y.; Iwahashi,
M.; Nishida, K.; Hayashi, Y.; Shirahama, H. Angew. Chem., Int. Ed.
Engl. 1996, 35, 904–906. (e) Morimoto, Y.; Iwahashi, M.; Kinoshita,
T.; Nishida, K. Chem.sEur. J. 2001, 7, 4107–4116. (f) Wipf, P.; Kim,
Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106–11112. (g)
Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515–1517. (h) Padwa, A.;
Ginn, J. D. J. Org. Chem. 2005, 70, 5197–5206.
(6) (a) Wipf, P.; Spencer, S. R.; Takahashi, H J. Am. Chem. Soc. 2002,
124, 14848–14849. (b) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc.
2005, 127, 225–235.
(7) Professor Kevin Booker-Milburn and coworkers have recently com-
pleted an independent synthesis of neostenine (personal communica-
tion).
9
6018 J. AM. CHEM. SOC. 2008, 130, 6018–6024
10.1021/ja800574m CCC: $40.75
2008 American Chemical Society

Syntheses of Stemona Alkaloids
A R T I C L E S
Figure 1. Selected Stemona alkaloids.
Scheme 1
Scheme 2
Diels–Alder reaction similar to Hart’s synthesis (and sharing
the same basic disconnection with Morimoto’s route). In this
full account, we describe the pursuit of this strategy, which led
to the discovery that both the Diels–Alder and the Schmidt
reaction steps could be accomplished in a single chemical
operation. This not only streamlined the stenine synthesis but
also led to the development of a general synthetic methodology
based on this tandem reaction.9 Furthermore, we describe how
the reconsideration of possible Diels–Alder routes to cis-1-
decalones permitted a second generation, extremely efficient
approach to stenine and ultimately to the total synthesis of the
antitussive agent neostenine.
Results and Discussion
First Generation Approach: A Formal Synthesis of Stenine. In
its original formulation, the total synthesis of stenine was built
around the idea of carrying out an intramolecular Diels–Alder
reaction on a substrate like 7 (Scheme 2). Although we
considered the possibility that this step could be combined with
its subsequent intramolecular Schmidt reaction, as both reactions
entailed the use of Lewis acid promotion, there was at the time
no experimental evidence that such a step would be possible.
A key element of this plan was that the intramolecular
Diels–Alder reaction would occur via an endo transition state,
an outcome for which precedence existed.10
of the indolone 6, which was readily synthesized from L-tyrosine
and converted into the natural enantiomer of stenine in 22 steps.
Our own interest in Stemona alkaloid synthesis arose from
the recognition that the seven-membered C ring could arise from
an intramolecular Schmidt reaction8 of an azide such as 8
(Scheme 2). This step would also form the D ring of stenine
while opening the door to constructing 8 via an intramolecular
(8) (a) Aubé, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965–
8966. (b) Aubé, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem.
1992, 57, 1635–1637. (c) Milligan, G. L.; Mossman, C. J.; Aubé, J.
J. Am. Chem. Soc. 1995, 117, 10449–10459. (d) Desai, P.; Schildknegt,
K.; Agrios, K. A.; Mossman, C. J.; Milligan, G. L.; Aubé, J. J. Am.
Chem. Soc. 2000, 122, 7226–7232.
(9) Zeng, Y.; Reddy, S.; Hirt, E.; Aubé, J. Org. Lett. 2004, 6, 4993–
4995.
(10) (a) Gras, J.-L.; Bertrand, M. Tetrahedron Lett. 1979, 4549–4552. (b)
Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915–930.
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A R T I C L E S
Frankowski et al.
Scheme 3
Table 1. Selected Optimization Trials for the Tandem Diels-Alder/
Azido-Schmidt Reaction
Lewis acid
equiv
combined
9 yield (%) 18 yield (%) 17 yield (%) yield (%)
entry Lewis acid
1
2
3
4
5
InCl3
AlMe3
1.0 × 2
20
18
22
60
0
60
78
79
1.0
Et2AlCl 0.65 × 2
28
41
43
12
9
12
20
28
24
Et2AlCl 1.0
MeAlCl2 1.0
IR absorption near 2100 cm-1. These data permitted the as-
signment of this material as a bridged lactam product (compound
17, Table 1).14 Upon closer examination, the desired fused amide
9 and a stereoisomer 18 were also found; both of these lactams
were considerably more polar than 17 and required more polar
chromatography conditions for isolation. Following a series of
optimization experiments, we settled on the treatment of 7 with
1 equiv of MeAlCl2 in refluxing dichloromethane, which
afforded the tricyclic lactam 9 in 43% yield and its bridged
and fused isomers 17 and 18 in a combined yield of 36% yield
(Table 1). Assuming that only the major component of the 85:
15 mixture of 11,12-olefin geometry isomers of 7 reacts, this
yield corresponds to an overall conversion of the reactive
trans-trans triene isomer to lactam 9 in 51% yield. Only poor
yields of the desired lactam were obtained using other non-
aluminum-based Lewis acids.
The requisite azido triene 7 was constructed using standard
means. The building blocks 13 and 14 were prepared from 1,3-
propanediol and 1,5-pentanediol, accordingly (Scheme 3). A
modified Julia coupling11 between sulfone 13 and aldehyde 14
afforded 15 as an inseparable 85:15 mixture of isomers at the
new double bond. Although it was not possible to completely
remove the undesired cis isomer at any step prior to the
Diels–Alder, we expected the E, Z diene to be less reactive in
the downstream cycloaddition reaction. Removal of the silyl
protecting group of 15, followed by Swern oxidation, gave an
aldehyde that was treated with the lithium anion of dimethyl
methylphosphonate. This provided a ꢀ-hydroxyphosphonate that
was subsequently oxidized with TPAP/NMO to give the
ꢀ-oxophosphonate 16. This sequence gave better overall yields
than an alternative path that entailed initial conversion to the
corresponding carboxylic ester followed by lithiomethyl dimethyl-
phosphonate addition. The resulting ꢀ-oxophosphonate 16 was
subjected to a Horner-Wadsworth-Emmons reaction12 with
3-azidopropanal13 to afford the triene 7 in 85% yield.
The outcomes of the tandem Diels–Alder/Schmidt reaction
for triene substrate 7 arise as shown in Scheme 4. Both the
desired lactam product 9 and the bridged lactam 17 are obtained
from the same Diels–Alder intermediate formed via an endo
transition state.10 Following azide addition to carbonyl and
assuming antiperiplanar C f N bond migration,15 an intermedi-
ate containing an equatorial N2+ group would afford lactam 9,
whereas an axially oriented leaving group would give the
bridged compound 17. Lactam 18 results from an exo transition
state in the Diels–Alder cyclization, followed by the D-ring-
forming/C-ring-expansion process. Interestingly, no bridged
adduct is formed from the exo Diels–Alder product because
+
the azidohydrin intermediate bearing an axial N2 group is
antiperiplanar to a hydroxyl group instead of a migratable
carbon.
We briefly attempted to improve the overall conversion of
triene to lactam by deliberately carrying out the Diels–Alder
and the Schmidt reactions separately (Scheme 5). The former
step could be nicely optimized, but deprotection of the hydroxy
group with PPTS led to partial epimerization of the cis-decalone
20 to the undesired trans isomer. This was not an issue at all in
the combined reaction, suggesting another advantage in using
the domino procedure. While this work was in progress, Jung
and co-workers reported the successful synthesis of an advanced
intermediate of stenine using a similar Diels–Alder reaction to
Our earliest attempts to carry out a combined Diels–Alder/
Schmidt reaction resulted only in the isolation of a single product
in modest yields (16–38%). Specifically, treatment of 7 with
1.5 equiv of Et2AlCl led to gas evolution upon heating the
reaction to ca. 45 °C. The first product isolated from this reaction
had an absorption in the IR spectrum at 1680 cm-1 and a 13C
NMR signal at 188 ppm, with no trace of the diagnostic azide
(11) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26–28. (b) Kocienski, P. J.; Bell, P. R.; Blakemore, P. R. Synlett
2000, 365–366.
(14) For a review of bridged amides, see: Greenberg, A. In Structure and
ReactiVity; Liebman, J. F., Greenberg, A., Eds.; VCH: New York,
1988; pp 139–178.
(12) Paterson, I.; Yeung, K. S.; Smaill, J. B. Synlett 1993, 774–776.
(13) (a) Boyer, J. H. J. Am. Chem. Soc. 1951, 73, 5248–5252. (b) Ma, Y.
Heteroatom. Chem. 2002, 13, 307–309.
(15) Kishi, Y.; Goodman, R. M. J. Am. Chem. Soc. 1998, 120, 9392–9393.
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Syntheses of Stemona Alkaloids
A R T I C L E S
Scheme 4
Scheme 6
methylation of the lactone proceeded stereoselectively to provide
the Hart intermediate 24 in 67% yield over two steps. Cleanly
carrying out the methylation of the lactone required a little work.
Initial attempts using up to 2 equiv of LDA to deprotonate the
lactone resulted in mainly unreacted starting material. The ability
of LHMDS to deprotonate lactones is documented,17 however
allowing this enolate to react with 10 equiv of MeI for 1.5–2.0
h at -78 °C afforded predominantly the dimethylated derivative.
Finally it was determined that treatment of the lactone 23 with
1.8 equiv of LHMDS at -78 °C, followed by the addition of
10 equiv of MeI at the same temperature for 40 min, afforded
exclusively the monomethylated product 24 in 72% yield for
the alkylation step and completed the formal synthesis of
stenine.18 In Hart’s synthesis of stenine,4a,b 24 was carried on
to the stenine 1 in four steps and 63% yield. Overall, this first
generation formal synthesis, including the final four steps as
reported by Hart,4a,b would require 21 steps from commercially
available material and afford stenine in 7.2% overall yield. This
would constitute the highest overall yield for known syntheses
at the time (range 0.9–3.0%), but the route was longer than the
shortest known route at the time (Padwa’s; 16 steps4g,h).
Second-Generation Synthesis of (()-Stenine. Having com-
pleted this synthetic effort, our attention turned to the further
development of the tandem Diels–Alder/intramolecular Schmidt
reaction. In particular, we learned that the sequence could nicely
accommodate intermolecular Diels–Alder reactions.9 Also, the
2003 report that neostenine exhibited strong antitussive activity
in a guinea pig model2a provided strong motivation to revisit
the problem of Stemona alkaloid synthesis in general, with an
eye toward practical routes that would be amenable to analogue
synthesis. The possibility of using an intermolecular Diels–
Alder/intramolecular Schmidt sequence was especially attractive
because it would require many fewer steps in starting material
preparation than our first-generation route. We accordingly
contemplated a Diels–Alder disconnection between C-9/C-10
and C-9a/C-1, which retrosynthetically leads to cyclohex-2-en-
1-one and silyloxydiene 10 as starting materials (Scheme 2).
This route would additionally allow early incorporation of the
ethyl side chain, obviating the need for a multistep removal of
the terminal ethylene from an allylated precursor (i.e., 24 f 1,
Scheme 6).
Scheme 5
that in Scheme 5, followed by a four-step Beckmann rearrange-
ment/N-alkylation sequence to form the BCD ring skeleton of
stenine.5d
The formal synthesis of stenine was accomplished as shown
in Scheme 6. Removal of the benzyl ether from 9, oxidation of
the resulting hydroxy group, and iodolactonization gave butyro-
lactone 23 in 80% yield from 9. Keck allylation16 followed by
These tenets were rapidly verified, and an interesting stereo-
chemical situation was revealed through the experiments shown
(17) Rathke, M. W. J. Am. Chem. Soc. 1970, 92, 3222–3223.
(16) Yates, J. B.; Keck, G. E J. Am. Chem. Soc. 1982, 104, 5829–5830.
(18) Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316–4318.
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Scheme 7
Scheme 9
Scheme 8
Table 2. Stereochemical Studies of the Diels-Alder/Schmidt
Sequence
entry diene
Lewis acid
product(s)
yield (exo/endo ratio)
1
2
10
10
SnCl4
BF3 ·OEt2 26
12, 26
70% (3:1)
55% (endo only; mixture of ethyl
epimers)
3
30
SnCl4 31, 32
82% (1:3.4)
The completion of the synthesis is shown in Scheme 9. All
of the additional stereocenters were generated by highly selective
substrate-directed reactions: axially directed alkylation and
reduction reactions on purified 12 afforded compounds 27 and
28, respectively. An X-ray crystal structure of lactone 28 verified
the stereostructure shown (see Supporting Information). The
installation of the final methyl group and removal of the lactam
carbonyl were carried out as previously established. Thus,
alkylation of the lactone 28 proceeded smoothly to give the
known oxostenine 29; reduction via the thiolactam as reported
by others afforded stenine 1.4a,b,f–h,6 The spectrum of the natural
product thus prepared fully matched those of the literature
values. Overall, the total synthesis was accomplished in nine
steps from commercially available reagents and 14% overall
yield.21
Stereochemical Divergence of the Diels–Alder/Schmidt Reac-
tion: Syntheses of Neostenine and 13-Epineostenine. The analy-
sis in Scheme 8 indicated that modification of the stereochemical
outcome of the Diels–Alder/Schmidt reaction from exo to endo
selectivity could lead to a viable neostenine intermediate.
Accordingly, we investigated the effect of changing the diene
structure and Lewis acid on the stereochemistry of the key step
(Table 2). As used above, SnCl4 gave the best overall result,
yielding the Diels–Alder/Schmidt product in a 70% yield as a
3:1 mixture of exo and endo isomers. The predominant endo
stereochemistry could be obtained in two ways. First, the use
of a less strongly coordinating Lewis acid such as BF3 ·OEt2
gave exclusively the endo Diels–Alder product in modest yield,
in Scheme 7. Thus, the known19 Horner-Wadsworth-Emmons
reagent 25 was prepared in 99% yield from commercially
available dimethyl methylphosphonate and butyryl chloride.
Olefination of 3-azidopropanal13b (available in a single step from
acrolein and HN3) afforded an enone that was readily converted
to the corresponding trimethylsilyloxy diene 10. Treatment of
cyclohexenone with SnCl4 and diene 10 afforded a ca. 3:1 ratio
of Diels–Alder/Schmidt adducts 12 and 26, with the former
compound, arising from an exo-selective Diels–Alder step,
predominating.
This quick success was gratifying as it permitted the
preparation of a key intermediate containing three rings and
four stereocenters in the targeted compound in only four steps
from very simple starting materials. However, the stereochemical
outcome of this sequence determines which ultimate target can
be obtained using it, as shown in Scheme 8. Thus, the exo
approach observed here maps the four centers obtained in
compound 12 nicely onto stenine, whereas the alternative endo
reaction would find utility in the synthesis of the isomeric
neostenine 3, pending a successful epimerization of the ethyl
group along the way. Predominant exo selectivity in Diels–Alder
reactions of cyclic dienophiles has been previously noted by
Corey and co-workers20 and is here likely due to significant
steric interactions between one of the γ protons of the cyclo-
hexenone with the incoming nucleophilic silyl enol ether.
(19) Khatri, N. A.; Schmitthenner, H. F.; Shringarpure, J.; Weinreb, S. M.
J. Am. Chem. Soc. 1981, 103, 6387–6393.
(20) Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett. 2000, 2, 1927–1929.
(21) Zeng, Y.; Aubé, J. J. Am. Chem. Soc. 2005, 127, 15712–15713.
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A R T I C L E S
Scheme 10
Scheme 11
Scheme 12
albeit as a mixture of isomers at the ethyl group (resulting from
partial epimerization). Alternatively, the silyloxy diene 30,
lacking the ethyl side chain, also afforded predominantly the
endo lactam 32.
It is likely that the removal of the ethyl group from the diene
affords predominantly the endo product due to the easing of
steric interactions between the diene and the cyclohexenone (eq
1). A dependence of stereochemistry on diene substitution was
previously registered by Corey and co-workers, who analyzed
it in the context of changes in diene size and conformation.20
The reason for the switch in stereochemistry due to the use of
BF3 ·OEt2 is less clear, although it could be due to a lengthening
of the bond forming between the ꢀ carbon of the enone and the
silyl enol ether in the transition state leading to 26.
reaction to reflux, or the addition of 1 equiv of TiCl4 to the
reaction mixture after stirring at room temperature all gave lower
isolated yields of 26a,b. MM2 calculations suggested that 26a,
containing a pseudoaxial ethyl group, would be 4.4 kcal/mol
higher in energy relative to the desired, equatorial isomer 26b.
Thus, the keto lactam mixture readily converged onto 26b upon
base treatment.
Ketone 26b was regio- and stereospecifically alkylated with
ethyl bromoacetate to give ketoester 34 (Scheme 11). Initial
attempts to reduce 34 with NaBH4 gave an inseparable mixture
of lactone products in 54% yield (35a and 35b, ratios not
rigorously determined). A screen of reducing reagents revealed
that the combination of CeCl3 and L-Selectride gave a complex
mixture of products that contained a pair of chemical shifts in
the 13C NMR spectrum at 97.7 and 98.4 ppm. Based on these
downfield signals we proposed that the mixture contained the
diastereomeric lactols 36 shown in Scheme 11. This was
confirmed by TPAP oxidation of the mixture, which led
smoothly to a single lactone 35a.
Neostenine was prepared by the methylenation/hydrogenation
sequence shown in Scheme 12. Greene and co-workers have
developed a two-step sequence for the methylenation of esters
and lactones involving initial formation of an R-carboxylic acid
followed by condensation with formaldehyde and subsequent
decarboxylation.22 We found that this sequence gave better
The endo-selective tandem Diels–Alder/Schmidt reaction was
scaled up as shown in Scheme 10. Addition of 1.5 equiv of
silyloxy diene 10 to a mixture of cyclohex-2-en-1-one and 1
equiv BF3 ·OEt2 at -78 °C, followed by the further addition of
1.5 equiv of BF3 ·OEt2 after warming to ca. -30 °C provided
the tricyclic lactams 26a,b as a mixture of ethyl epimers in 43%
yield, the major component being the expected isomer 26a
(Scheme 7, R ethyl isomer). Under these conditions, we also
isolated an azide-containing mixture to which we assigned
structure 33 as the major component, based mainly on the 13C
NMR spectrum of the mixture (diagnostic ketone peaks at 212.1
and 213.0 ppm). Treatment of a CH2Cl2 solution of this mixture
with TiCl4 afforded an additional quantity (12% yield based on
10) of the tricyclic lactams 26a,b. Attempts to improve the one-
pot yield of 26a,b through longer reaction times, heating of the
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A R T I C L E S
Frankowski et al.
1
of 40 and its H and 13C NMR spectra were consistent with a
stereoisomer of the natural product, which we have assigned
as the previously unknown 13-epineostenine.
Scheme 13
Conclusion
The productive relationship between synthetic methodology
development and the total synthesis of natural products has been
much discussed and is well illustrated in the work described in
this paper. The first-generation total synthesis of stenine
demonstrated the first combination of an intramolecular Diels–
Alder reaction and an intramolecular Schmidt reaction. This
discovery spurred on additional development of this useful
synthetic method, described elsewhere,9 which in turn led us
to unusually efficient syntheses of two natural products (stenine
and neostenine) and one novel analogue (13-epineostenine).
Although not discussed here at all, even an unanticipated side
product of the main reaction, bridged bicyclic lactam 17, led to
a separate research project directed toward the understanding
of the unusual chemical properties of this previously unknown
class of “twisted amides”.26
These projects required the optimization of different stereo-
chemical outcomes of the intermolecular Diels–Alder/intramo-
lecular Schmidt domino reaction, a very useful aspect of the
sequence that we are currently using in a broader program to
discover fully synthetic analogues of these alkaloids. In addition,
the brevity of these routes have provided sufficient quantities
of stenine congeners that will be used to investigate the as yet
unknown mode of action of the observed antitussive activity of
some of these alkaloids. This work will be published in due
course.
overall yields to the more common Eschenmosher salt alkylation
method.23 The R-carboxylic acid intermediate was not purified
but used directly in the condensation/decarboxylation sequence
to provide methylene lactone 37 in 49% isolated yield.
Hydrogenation over Adams catalyst in methanol/acetic acid (1:1
mixture) gave a single methylated lactone 38 in 91% yield, while
hydrogenation over palladium on carbon produced a mixture
containing traces of the epimeric methyl isomer (compound 39;
see Scheme 13). Selective thioamide formation was achieved
using a P2S10 method developed by Curphy,24 which gave a
more easily purified reaction mixture than Lawesson’s reagent.
Reduction of the thioamide with Raney nickel proceeded
smoothly to give racemic neostenine 3 in 93% yield. Spectral
comparison of the synthetic material to reported values con-
firmed its identity.25 X-ray crystallography of our synthetic
material unambiguously showed it to be identical to the reported
structure of the natural product. Overall, the total synthesis was
accomplished in 13 steps from commercially available reagents
and 10% overall yield.
Since one goal of our global program is the preparation of
stenine analogues for biological screening, lactone 35a was
converted to the methyl epimer of neostenine via the three-step
sequence shown in Scheme 13. Alkylation with LiHMDS and
methyl iodide provided the single methyl lactone 39 in 89%
yield. As expected, this alkylation provided the C-13 epimer of
neostenine due to approach of the alkylating agent from the
convex face formed by the cis-fused AB ring junction.
Compound 39 was converted to 13-epineostenine 40 analogous
to the method used above24 for the reduction of the lactam
carbonyl to a tertiary amine. The high-resolution mass spectrum
Acknowledgment. We acknowledge Professor Ge Lin for
generously providing detailed NMR spectra of neostenine for
comparison. We thank the National Institute of General Medical
Sciences (GM-49093 and PO50-GM069663) for financial sup-
port, Benjamin Neuenswander for HPLC-MS, David Vander
Velde and Sarah Neuenswander for NMR assistance, and
Douglas Powell and Victor Day for X-ray crystallography.
J.E.G. gratefully acknowledges the Madison A. and Lila Self
Fellowship Program for its support.
(22) Murta, M. M.; de Azevedo, M, B. M.; Greene, A. E. Synth. Commun.
1993, 23, 495–503.
Supporting Information Available: Experimental details and
characterization data for all new compounds, including X-ray
structures (CIF files) of 3 and 28. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) (a) For reviews on the synthesis of R-methylene lactones, see: Grieco,
P. A. Synthesis 1975, 67–82. (b) Hoffman, H. M. R.; Rabe, J. Angew.
Chem., Int. Ed. Engl. 1985, 24, 94–110. (c) Petragnani, N.; Ferraz,
H. M. C.; Silva, G. V. J. Synthesis 1986, 157–183.
(24) Curphey, T. J. J. Org. Chem. 2002, 67, 6461–6473.
(25) The originally reported spectrum of neostenine contains a typographical
error. The 13C NMR chemical shift originally reported by Lin and
coworkers2a at 39.79 ppm actually appears at 37.97 ppm. We thank
Professor Lin for kindly confirming this and for providing the NMR
spectra of naturally occurring neostenine.
JA800574M
(26) Lei, Y.; Wrobleski, A. D.; Golden, J. E.; Powell, D. R.; Aubé, J. J. Am.
Chem. Soc. 2005, 127, 4552–4553.
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