Revisiting a classic approach to the Aspidosperma alkaloids: An intramolecular Schmidt reaction mediated synthesis of (+)-aspidospermidine

Article abstract of DOI:10.1021/jo051212n

A total synthesis of (+)-aspidospermidine (1) is described. The key reactions used in the synthesis of this pentacyclic Aspidosperma alkaloid were a deracemizing imine alkylation/Robinson annulation sequence, a selective "redox ketalization", and an intramolecular Schmidt reaction. A Fischer indolization step carried out on a tricyclic ketone mirrored the sequence reported by Stork and Dolfini in their classic aspidospermine synthesis.

Full text of DOI:10.1021/jo051212n

Revisiting a Classic Approach to the Aspidosperma Alkaloids:
An Intramolecular Schmidt Reaction Mediated Synthesis of
(+)-Aspidospermidine
Rajesh Iyengar, Klaas Schildknegt, Martha Morton, and Jeffrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Room 4070, Malott Hall,
University of Kansas, Lawrence, Kansas 66045-7582
jaube@ku.edu
Received June 14, 2005
A total synthesis of (+)-aspidospermidine (1) is described. The key reactions used in the synthesis
of this pentacyclic Aspidosperma alkaloid were a deracemizing imine alkylation/Robinson annulation
sequence, a selective “redox ketalization”, and an intramolecular Schmidt reaction. A Fischer
indolization step carried out on a tricyclic ketone mirrored the sequence reported by Stork and
Dolfini in their classic aspidospermine synthesis.
Introduction
The Aspidosperma alkaloids have inspired considerable
interest since the early days of complex organic synthetic
chemistry research.1 Over the years, a number of race-
mic2,3 syntheses as well as enantioselective4 approaches
to (+)-aspidospermidine and (-)-aspidospermine, the
prototypical members of the group, have been reported.
The first successful foray into this class was the total
synthesis of (()-aspidospermine 2 by Stork and Dolfini.2
One highlight of this synthesis was the use of a Fischer
indole condensation to generate the core structure of the
natural product (Scheme 1). This reaction proceeded
through iminium ion 4, so the configurations of C-7 and
C-21 were controlled relative to the quaternary center
C-22. The final stereocenter (C-3) was set through a
stereoselective reduction of imine 5. Thus, a stereoselec-
tive route to aspidospermine or aspidospermidine could
arise, in principle, from any diastereomer of the Stork
ketone 3. Accordingly, an asymmetric synthesis of 3
presents a worthwhile challenge.5 Herein we disclose a
total synthesis of (+)-aspidospermidine (1) that uses the
Stork approach in the context of modern enantioselective
* To whom correspondence should be addressed. Tel: 785.864.4496.
Fax: 785.864.5326.
(1) Saxton, J. E. In The Alkaloids: Chemistry and Biology; Cordell,
G. A., Ed.; Academic Press: San Diego, CA, 1998; Vol. 51, pp 1-197.
(2) Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872-2973.
(3) (a) Ban, Y.; Sato, Y.; Inoue, I.; Nagai, M.; Oishi, T.; Terashima,
M.; Yonemitsu, O.; Kanaoka, Y. Tetrahedron Lett. 1965, 2261-2268.
(b) Barton, J. E. D.; Harley-Mason, J. Chem. Commun. 1965, 298-
299. (c) Kutney, J. P.; Abdurahman, N.; Le Quesne, P.; Piers, E.;
Vlattas, I. J. Am. Chem. Soc. 1966, 88, 3656-3657. (d) Harley-Mason,
J.; Kaplan, M. Chem. Commun. 1967, 915-916. (e) Inoue, I.; Ban, Y.
J. Chem. Soc. 1970, 602-610. (f) Kutney, J. P.; Abdurahman, N.;
Gletsos, C.; Le Quesne, P.; Piers, E.; Vlattas, I. J. Am. Chem. Soc. 1970,
92, 1727-1735. (g) Klioze, S. S.; Darmory, F. P. J. Org. Chem. 1975,
40, 1588-1592. (h) Dufour, M.; Gramain, J. C.; Husson, H. P.;
Sinibaldi, M. E.; Troin, Y. J. Org. Chem. 1990, 55, 5483-5490. (i)
Benchekroun-Mounir, N.; Dugat, D.; Gramain, J. C.; Husson, H. P. J.
Org. Chem. 1993, 58, 6457-6465. (j) Wenkert, E.; Liu, S. J. Org. Chem.
1994, 59, 7677-7682. (k) Callaghan, O.; Lampard, C.; Kennedy, A.
R.; Murphy, J. A. J. Chem. Soc., Perkin Trans. 1 1999, 995-1002. (l)
Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. Tetrahedron
Lett. 1999, 40, 161-164. (m) Patro, B.; Murphy, J. A. Org. Lett. 2000,
2, 3599-3601. (n) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000,
65, 2642-2645. (o) Banwell, M. G.; Smith, J. A. J. Chem. Soc., Perkin
Trans. 1 2002, 2613-2618. (p) Banwell, M. G.; Lupton, D. W. Org.
Biomol. Chem. 2005, 3, 213-215.
(4) (a) Node, M.; Nagasawa, H.; Fuji, K. J. Org. Chem. 1990, 55,
517-521. (b) d'Angelo, J.; Revial, G.; Costa, P. R. R.; Castro, R. N.;
Antunes, O. A. C. Tetrahedron: Asymmetry 1991, 2, 199-202. (c)
Desmae¨le, D.; d'Angelo, J. J. Org. Chem. 1994, 59, 2292-2303. (d)
Schultz, A. G.; Pettus, L. J. Org. Chem. 1997, 62, 6855-6861. (e)
Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc.
2002, 124, 4628-4641. (f) Marino, J. P.; Rubio, M. B.; Cao, G.; de Dios,
A. J. Am. Chem. Soc. 2002, 124, 13398-13399. (g) Tanino, H.;
Fukuishi, K.; Ushiyama, M.; Okada, K. Tetrahedron Lett. 2002, 43,
2385-2388. (h) Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K.
Tetrahedron 2004, 60, 3273-3282.
10.1021/jo051212n CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/30/2005
J. Org. Chem. 2005, 70, 10645-10652
10645

Iyengar et al.
SCHEME 1
SCHEME 3a
SCHEME 2
a Reagents and conditions: (a) (S)-R-methylbenzylamine; (b) 11,
hydroquinone, 60 °C; (c) 10% aq AcOH; (d) NaOMe, MeOH, reflux;
(e) isopropenyl acetate; (f) Oxone, acetone; (g) PCC, CH2Cl2.
major themes: (1) the development of a synthesis of dione
7, (2) investigation of the key intramolecular Schmidt
reaction, and (3) the conversion of enantiomerically pure
Stork intermediate 6 into (+)-aspidospermidine.8 Finally,
a ketal-mediated rearrangement reaction, discovered
during the course of this work, was the first time a
bridged ring system was observed to result from an
intramolecular Schmidt reaction.
Results and Discussion
Synthesis of Key Bicyclic Diketo Azide. Early
Results. Our first route to the bicyclic ring system
revolved around the intermediacy of enone 9 (Scheme 3).
The plan was to synthesize compound 13 from 2-ethyl-
1,3-pentanedione using the well-documented Hajos-
Parrish reaction,9 followed by reduction of the saturated
ketone carbonyl group. Once in hand, we planned to
remove the extraneous alcohol in 13 using a deoxygen-
ation or elimination reaction.10 Although 13 was readily
synthesized as planned, all attempts at converting 13 to
9 or 14 were unsuccessful. In contrast, the application
of the d’Angelo annulation protocol to racemic 2-ethyl-
cyclohexanone was successful and provided enone 9 in
modest yield. The enone function provided a convenient
handle for installing a carbonyl in the γ position. Thus,
enone 9 was allowed to reflux briefly with isopropenyl
acetate and p-TsOH to effect its quantitative transforma-
tion to the corresponding dienol acetate depicted. Oxida-
tion of this material with Oxone followed by PCC afforded
enedione 15 in excellent overall yields for the three-step
protocol.
synthesis and also provided an opportunity to carefully
examine the late-stage Fischer indole step.
Our plan for the construction of enantiomerically pure
6 involved an intramolecular Schmidt reaction6 of 7
(Scheme 2), which could be derived from bicyclic enone
8. To be successful, this step would require the selective
Schmidt reaction of the azide with the cyclopentanone
embedded in 7 (path a) to the exclusion of the six-
membered cyclic ketone (path b). Although such selectiv-
ity had not been demonstrated prior to this work, model
studies showed that compounds with four carbons sepa-
rating the two reactive moieties underwent ring expan-
sion chemistry much more easily than those with only
three, which would support the selective formation of the
desired product.6 We envisioned an asymmetric synthesis
of a precursor enone 8 or 9 from 2-ethylcyclopentanone
12 using the asymmetric variant of the Robinson annu-
lation invented by d’Angelo’s group,7 thus establishing
the critical quaternary stereocenter in the desired con-
figuration.
The direct installation of an alkyl side chain by vinyl
cuprate 1,4-addition to enedione 15 was unsuccessful,
affording only reduction products. A variety of other
reactions, including allylsilane additions to 15 or various
reduction products of same, were unsuccessful, nonselec-
Herein, we describe the successful implementation of
this strategy. The discussion is arranged along three
(5) (a) Meyers, A. I.; Berney, D. J. Org. Chem. 1989, 54, 4673-4676.
(b) Fukuda, Y.-I.; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, 749-
751. (c) Gnecco, D.; Vazquez, E.; Galindo, A.; Teran, J. L.; Orea, L.;
Bernes, S.; Enriquez, R. G. ARKIVOC (Gainesville, FL, U.S.) 2003,
part xi, 185-192.
(6) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc. 1995,
117, 10449-10459.
(7) d'Angelo, J.; Desmae¨le, D.; Dumas, F.; Guingant, A. Tetrahe-
dron: Asymmetry 1992, 3, 459-505.
(8) Iyengar, R.; Schildknegt, K.; Aube´, J. Org. Lett. 2000, 2, 1625-
1627.
(9) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-
1621. (b) List, B. Tetrahedron 2002, 58, 5573-5590.
(10) Abel, U.; Koch, C.; Speitling, M.; Hansske Friedrich, G. Curr.
Opin. Chem. Biol. 2002, 6, 453-458.
10646 J. Org. Chem., Vol. 70, No. 26, 2005

Synthesis of (+)-Aspidospermidine
SCHEME 4a
SCHEME 5
a Reagents and conditions: (a) NaH, BnBr, DMF; (b) PCC,
CH2Cl2; (c) CH2dCH2MgBr, THF; (d) CrO3, H2SO4, acetone; (e)
(S)-R-methylbenzylamine; (f) 10, hydroquinone, fused ZnCl2, Et2O,
reflux; (g) 10% aq AcOH; (h) NaOMe, MeOH, reflux.
SCHEME 6
tive, or inefficient. Accordingly, we redirected our efforts
to obtain enone 8, already bearing the necessary side
chain, in a more convergent fashion (Scheme 4). To this
end, the R,â-unsaturated ketone 10 was synthesized from
1,4-butanediol. Turning again to the d’Angelo deracem-
ization protocol, cyclopentanone 12 was condensed with
(S)-R-methylbenzylamine, and the resulting enamine was
condensed with vinyl ketone 10. Alkene polymerization
was moderated by the addition of a small amount of 1,4-
hydroquinone. The multiday reaction was followed by
acidic hydrolysis (10% aqueous CH3COOH) and intramo-
lecular aldol reaction under basic conditions (NaOMe,
MeOH) to afford the bicyclic enone 8 in 49% overall yield
and 66% ee (HPLC, Chiralcel AS, 20% 2-propanol/
hexanes, 254 nm). The relatively low enantioselectivity
was not surprising because the literature indicates that
additional steric bulk in the enamine intermediate may
result in poor face selectivity.7 Ultimately, the selectivity
was improved by applying Lewis acid activation11 (fused
ZnCl2, refluxing ether, 3 d), followed by the usual
cyclization methods, to generate 84-86% ee material in
similar yield as before. This material was brought to
enantiomeric purity at a later step.
With an appropriately substituted [4.3.0]bicyclonon-
enone in hand, it remained to install the azide nucleo-
phile and an additional ketone function to arrive at the
required Schmidt reaction substrate. It soon became
apparent that precise choice and ordering of the steps
was crucial. Initially, we envisioned utilizing a Mitsunobu
reaction to transform the primary alcohol derived from
8 into the requisite azide. However, catalytic debenzyl-
ation of 8 performed under a variety of conditions also
led to unwanted reduction of the enone function. Selective
deprotection of the side chain could be achieved by brief
exposure of the substrate to either boron tribromide or
boron trichloride to directly yield the corresponding alkyl
bromide 16a or chloride 16b, respectively (Scheme 5).12
The unexpected halogenation of the terminal alcohol was
considered a bonus as alkyl halides easily succumb to
nucleophilic azide displacement. The chloride (prepared
in higher yield and more stable than 16a) was therefore
transformed to the corresponding enedione 17 as in
Scheme 5.
The chemoselective reduction of the double bond in
enedione 17 was accomplished by treatment with con-
centrated HCl and sodium iodide to afford the bicyclic
scaffold 18 as a 1:1 diastereomeric mixture (Scheme 6).13
This reduction presumably involves initial 1,4-attack of
iodide followed by a second displacement on the R-io-
doketone to produce the reduced 1,4-dione. The stage was
now set for azide displacement of the chloride; however,
the reaction afforded mixtures of the expected product 7
and an undesired cyclopropane 19. The ease of the
intramolecular displacement process was confirmed by
exposing 18 to base, which cleanly afforded 19 as the only
product. This compound proved resistant to all nucleo-
philic ring opening attempts. In an effort to circumvent
this problem, enone 16b was subjected to base, cleanly
affording cyclopropane 20 containing a nonconjugated
double bond. In contrast to 19, cyclopropane 20 proved
amenable to ring opening, presumably because of the
(11) Williams, D.; Cortez, G. S. Tetrahedron Lett. 1998, 39, 2675-
2678.
(12) (a) Amrollah-Madjdabadi, A.; Pham, T. N.; Ashby, E. C.
Synthesis 1989, 614-616. (b) Pelletier, J. D.; Poirier, D. Tetrahedron
Lett. 1994, 35, 1051-1054.
(13) (a) Utaka, M.; Fujii, Y.; Takeda, A. Chem. Lett. 1986, 1103-
1104. (b) Vankar, Y. D.; Kumaravel, G.; Mukherjee, N.; Rao, C. T.
Synth. Commun. 1987, 17, 181-187. (c) Gondos, G.; Orr, J. C. Liebigs
Ann. Chem. 1990, 213-215.
J. Org. Chem, Vol. 70, No. 26, 2005 10647

Iyengar et al.
SCHEME 7a
SCHEME 8
a Reagents and conditions: (a) isopropenyl acetate; (b) Oxone,
acetone; (c) bis(trimethylsilyl)neopentyl glycol, TMSOTf, CH2Cl2,
0 °C f rt; (d) H2, 10% Pd/C; (e) HN3, PPh3, DEAD, PhH, 0 °C f
rt.
dicated that the major component of this ca. 12:1 mixture
had the stereostructure shown in Scheme 7. For details
regarding this and other important structural assign-
ments in this work, see Supporting Information.
Study of the Intramolecular Schmidt Reaction.
The scaffold was now appropriately functionalized for
intramolecular Schmidt reaction with the unprotected
carbonyl. Our initial attempts using TFA on 28 provided
deketalized compound 6 as the single diastereomer
shown, in 21% yield (Scheme 8; see Supporting Informa-
tion for this structural elucidation). This isomer thus
derives from the minor diastereomer of 28, which is
present in only a few percent in the starting material.
The poor yield in the Schmidt reaction is likely due to
competitive pathways occurring in lieu of cyclization. It
is possible that the azide in the major isomer â-28 cannot
reach the necessary carbonyl group and therefore azide
decomposition occurs faster than deketalization or epimer-
ization (note that cyclization of this isomer would afford
a product containing a strained trans-[4.3.0]bicyclo ring
system). Using TFA, only the isomer with the side chain
in the axial position (R-28) underwent cyclization to form
the all-cis version of 6 (Scheme 8). The fact that the
overall yield exceeds the amount of minor azido ketal
R-28 present in the reaction mixture probably means that
some deketalization can occur prior to Schmidt reaction
but that this process is poorly competitive with azide
decomposition. Deketalization may proceed prior to
Schmidt reaction in R-28 as well, as shown in Scheme 8,
but we have no evidence either in support of or against
this.)
In contrast, treating the 12:1 mixture of 28 with TiCl4
afforded 29 isolated in moderate yields (Scheme 9). This
product apparently arose from Lewis acid activation of
the ketal to afford oxenium ion, followed by attack of the
azide and C f N migration. Under these conditions, none
of the desired compound 6 was isolated.
This result was surprising in several ways. Although
reactions of azides with ketals or enol ethers had been
previously demonstrated,15 we had expected that the
ketal would in this case fulfill its designated role as a
protecting group. The preferential reaction of the ketal
over the carbonyl could be due to stereochemistry. Thus,
carbonyl activation might occur but azide may not attack
due to the trans relationship of the side chain to the
ketone. Alternatively, TiCl4 activation of the ketal could
greater stability of the enolate anion formed upon nu-
cleophilic attack.14 The enone in 21 could be functional-
ized by γ-oxidation, but this route was abandoned
because of the difficulty of selective double bond reduction
in azide 22.
Since enolization/intramolecular trapping was the
major hurdle in the functionalization of 18, we decided
to reduce both carbonyls to alcohols, followed by an
azidation/oxidation sequence. Thus, dione 18 was reduced
with NaBH4 to diol 23, which was isolated as an
inseparable mixture of products. This mixture was im-
mediately subjected to azidation and oxidation to afford
7. Unfortunately, the interference of another intramo-
lecular process (displacement of the chloride by the
proximal alcohol) gave the cyclic ether 24 as an unwanted
byproduct (a 4:1 mixture of 7 and 24 was obtained).
Compound 7 as obtained in these reactions was valuable
as it allowed us to rehearse the critical Schmidt reaction
and complete a first-generation synthesis of aspidosper-
midine (all such experiments are collected in the follow-
ing section). However, all of the above routes were
ultimately rejected for use in the final synthesis because
of their inability to cleanly deliver the key intermediate
7.
Effective Synthesis of Key Bicyclic Diketo Azide
7. Rethinking our plan, we decided to protect the bicyclic
scaffold prior to side chain manipulation. Thus, γ-oxida-
tion of 8 afforded alcohol 25, which was treated with bis-
(TMS)neopentyl glycol and a catalytic amount of TMSOTf
to afford ketal 26 directly (Scheme 7). This “redox
ketalization” involves regioselective ketal and concomi-
tant deconjugation, leading to an enol that undergoes
tautomerization to ketone 26. This step also rendered the
carbon bearing the side chain nonepimerizable. 1H NMR
analysis of 26 revealed a 12:1 mixture of diastereomers
that contained other inseparable impurities. This mater-
ial proved to be unstable and so was rapidly subjected to
reductive debenzylation followed by a Mitsunobu reaction
to afford azide 28. Detailed examination of the NMR
spectra, including NOESY and COSY experiments, in-
(14) The ring opening of activated cyclopropanes is well established
to proceed better when two activating groups are present. Danishefsky,
S. Acc. Chem. Res. 1979, 12, 66-72.
(15) Mossman, C. J.; Aube´, J. Tetrahedron 1995, 52, 3403-3408.
10648 J. Org. Chem., Vol. 70, No. 26, 2005

Synthesis of (+)-Aspidospermidine
SCHEME 9
SCHEME 10
SCHEME 11a
preferentially effect ketal opening over coordination to
the CdO group. Unfortunately, the less stable γ-epimer
was not easily prepared to address this question directly.
However, we could confirm that â-28 led to 29 by X-ray
confirmation of the latter structure (Supporting Informa-
tion).
a Reagents and conditions: (a) bis(trimethylsilyl)neopentyl
glycol, TMSOTf, CH2Cl2, 0 °C f rt; (b) LAH, THF, reflux; (c) LiBF4,
aq CH3CN, reflux; (d) PhNHNH2; (e) AcOH, reflux.
tallized from EtOAc/hexanes to enantiomeric purity (50%
overall yield after recrystallization, g99% ee, Chiralcel
OD, 10% EtOH/hexanes).
Also noteworthy was the isolation of the bridged
orthoaminal 29 in this reaction. Prior to this experiment,
no bridged product had been isolated in an azido-Schmidt
reaction carried out in our laboratory. In the present case,
it is likely that ring system 30 containing a four-
membered ring did not form due to strain. It is also
possible that the azido-Schmidt reaction of the ketal
better accommodates bridged product formation than the
ketone version; in the latter case, the fused amide product
enjoys resonance stabilization, whereas the bridged (or
“twisted”)16 amide cannot. After this study, we discovered
some specialized examples of bridged amides from azido
ketones resulting from intramolecular Schmidt reactions
of azides and ketones.17 The factors that influence bridged
versus fused product formation in intramolecular Schmidt
reactions is the subject of current research in this
laboratory.
In light of this result, we returned to our original plan
of selectively carrying out the ring expansion on diketone
7, postulating that epimerization would precede Schmidt
reaction in this substrate. Gratifyingly, deketalization
was easily effected under mild conditions to afford the
diketo azide 7, predominantly as the desired isomer (1:
10 â/R, Scheme 10; see Supporting Information for
structural assignment of 7).
Conversion of the Stork Ketone to Aspidosper-
midine. All that remained was the completion of the
synthesis using the Fischer indole protocol. Most litera-
ture examples of this particular reaction have been
reported to proceed in poor yield (or no yield was reported
at all), a fact that lessens the impact of formal syntheses
invoking the Stork2 or related intermediates as well.5 We
therefore wished to directly address this issue.
As reported for related lactams,5b,c 6 did not prove
amenable to a direct Fischer indole synthesis and so was
reduced in a three-step process to the corresponding keto
amine 3 by selective protection of the ketone carbonyl
followed by a reduction/deprotection sequence (Scheme
11). Treatment of 3 with phenylhydrazine, acid, and
finally LAH afforded (+)-aspidospermidine (1, 51% over-
all yield from 3) accompanied by 13% of a side product
31. This side product presumably arose via the Fischer
indolization of the less-substituted enamine isomer. A
similar product was mentioned in a paper addressing the
synthesis of an oxygenated analogue of aspidospermine
without ratios or yields.18
The structural analysis of this latter compound was
nontrivial, and extensive NMR experiments were needed
to deduce the structure (Supporting Information). Inter-
estingly, it was necessary to rigorously rid (+)-aspi-
dospermidine of 31 for analysis as even minor quantities
of this “impurity” threw off the optical rotation of 1
substantially on account of large levorotatory rotation of
(-)-31 ([R]D ) -100 (c 0.4, EtOH)) relative to that of (+)-
1. Spectral data (1H and 13C NMR, IR, MS), mp (118-
119 °C), and specific rotation ([R]D ) 20.6 (c 0.64, EtOH))
In contrast to the above examples, treatment of 7 with
TiCl4 gave tricyclic lactam 6 as a single diastereomer in
82% yield and 84% ee. The exclusive formation of this
product confirmed our original hypothesis that a regio-
selective Schmidt reaction was possible in this system.
The enantiomerically enriched lactam was then recrys-
(16) Greenberg, A. In Structure and Reactivity; Liebman, J. F.,
Greenberg, A., Eds.; VCH: New York, 1988; pp 139-178.
(17) (a) Golden, J. E.; Aube´, J. Angew. Chem., Int. Ed. 2002, 41,
4316-4318. (b) Lei, Y.; Wrobleski, A. D.; Golden, J. E.; Powell, D. R.;
Aube´, J. J. Am. Chem. Soc. 2005, 127, 4552-4553.
(18) Inoue, I.; Ban, Y. J. Chem. Soc. C 1970, 602-610.
J. Org. Chem, Vol. 70, No. 26, 2005 10649

Iyengar et al.
vacuo to afford a brown oil. Baseline impurities were removed
by silica gel chromatography, eluting with 10% EtOAc in
hexanes, and the crude product was distilled (200-220 °C, 1
Torr) to yield 7.00 g (49%) of the title compound 8 (Rf ) 0.20,
20% Et2O in hexanes) as a light yellow oil. [R]D ) -33.3 (c
3.63, CH2Cl2); IR (film) 1645 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.65 (t, J ) 7.5 Hz, 3H), 1.27 (m, 1H), 1.44 (q, J ) 7.5 Hz,
2H), 1.63 (td, J ) 13.8, 5.4 Hz, 1H), 1.81 (m, 2H), 2.00 (dt, J
) 12.6, 4.2 Hz, 1H), 2.18 (ddd, J ) 13.3, 5.3, 1.9 Hz, 1H), 2.33
(ddd, J ) 18.2, 5.4, 1.9 Hz, 1H), 2.45 (dd, J ) 14.2, 5.3 Hz,
1H), 2.55 (m, 2H), 2.64 (t, J ) 7.7 Hz, 2H), 3.49 (m, 2H), 4.50
(s, 2H), 7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 9.6, 22.0,
26.0, 27.5, 30.4, 31.3, 33.9, 36.8, 46.7, 69.5, 73.1, 127.78, 127.83,
128.3, 128.7, 139.2, 175.5, 198.9; CIMS m/z (relative intensity)
299 (MH+, 90), 207 (25), 191 (65), 91 (40). Anal. Calcd for
C20H26O2: C, 80.50; H, 8.78. Found: C, 80.22; H, 9.00.
SCHEME 12
4-(2’-Benzyloxyethyl)-7a-ethyl-3-hydroxy-1,2,3,6,7,7a-
hexahydroinden-5-one (25). A solution of enone 8 (2.0 g,
6.7 mmol) and p-TsOH (0.25 g) in isopropenyl acetate (10 mL)
was heated at reflux for 5 h. The reaction mixture was then
cooled to room temperature and diluted with Et2O. The organic
layer was washed with saturated NaHCO3 and brine and dried
over MgSO4. The resulting solution was concentrated in vacuo
to a light yellow oil. The residue was immediately dissolved
in a mixture of acetone (40 mL), saturated aqueous NaHCO3
(20 mL), and H2O (20 mL) and treated with 6 g of Oxone. After
3 h, the reaction mixture was poured into H2O and extracted
with EtOAc. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The
resulting residue was purified by silica gel chromatography-
(25% EtOAc/hexanes) to yield 1.85 g (88%) of 25 (Rf ) 0.35,
30% EtOAc in hexanes) as a clear oil. [R]D ) -7.5 (c 3.25,
of purified 1 were fully consistent with reported values
(mp 119.5-121 °C, [R]D ) 21 (EtOH)).19
Summary
In summary, a total synthesis of (+)-aspidospermidine
was completed, with the ultimately crafted version sum-
marized in Scheme 12. The most linear route comprised
22 steps and took place in 1.1% overall yield from
butylene glycol. The most noteworthy elements of this
synthesis include (1) a highly selective intramolecular
Schmidt reaction on a nonsymmetrical diketone, (2) the
establishment of the quaternary stereogenic center via
a d’Angelo deracemization process (from which all of the
rest of the target’s stereocenters derive), (3) the conver-
sion of an γ-hydroxy-R,â-unsaturated ketone to a 1,4-
diketone via an internal redox process, and (4) the first
observation of a bridged orthoaminal from an intramo-
lecular azide insertion process on a ketal.
EtOH); IR (CH2Cl2) 3401, 1657 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 0.89 (t, J ) 7.4 Hz, 3H), 1.25-1.40 (m, 2H), 1.67-
1.72 (m, 2H), 1.80-1.88 (m, 2H), 1.90-2.00 (m, 1H), 2.15-
2.20 (m, 1H), 2.30-2.35 (m, 1H), 2.39-2.47 (m, 2H), 2.78 (dt,
J ) 2.2, 14.0 Hz, 1H), 3.35 (ddd, J ) 2.2, 9.0, 11.5 Hz, 1H),
3.58 (dt, J ) 4.0, 9.0 Hz, 1H), 4.47 (d, J ) 5.6 Hz, 1H), 4.51 (s,
1H), 4.78 (d, J ) 5.6 Hz, 1H), 7.22-7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 9.4, 27.3, 27.7, 30.6, 32.3, 33.2, 33.5, 46.0,
67.0, 70.9, 73.0, 127.8, 127.85, 128.3, 129.7, 137.0, 175.6, 199.3;
CIMS m/z (relative intensity) 315 (MH+, 100), 297 (45), 207
(52), 91 (49); HRMS calcd for C20H26O3 314.1882, found
314.1902.
Experimental Section
4-(2’-Benzyloxyethyl)-7a-ethyl-1,2,3,6,7,7a-hexahydroin-
den-5-one (8). A solution of 2-ethylcyclopentanone20 (5.36 g,
47.9 mmol), (S)-R-methylbenzylamine (6.38 g, 52.6 mmol) and
p-TsOH (0.45 g, 2.4 mmol) in benzene (25 mL) was thoroughly
degassed and was allowed to reflux for 17 h using a Dean-
Stark trap. After the theoretical amount of H2O had been
removed, the remaining benzene was distilled off at atmo-
spheric pressure, and the crude imine residue was cooled to
room temperature and suspended in Et2O (10 mL).
Fused ZnCl2 (3.26 g, 24 mmol) was suspended in Et2O (15
mL) and was added to the imine, followed by 6-benzyloxy-1-
hexen-3-one (11.7 g, 57.4 mmol) and hydroquinone (ca. 100
mg). The resulting solution was heated at reflux for 72 h, then
cooled to room temperature and stirred for an additional 8 h.
Aqueous acetic acid (25%, 60 mL) was added and the resulting
biphasic solution was stirred vigorously for 3 h. The mixture
was poured over 1 M HCl and extracted with Et2O. The
combined organic layers were successively washed with satu-
rated aqueous NaHCO3 and brine, dried over MgSO4, and
concentrated. The residue was added to a solution of sodium
methoxide (119.7 mmol) in methanol (70 mL) and allowed to
reflux for 24 h. The reaction mixture was then cooled to room
temperature, quenched with a few drops of acetic acid, and
concentrated to yield a brown oil that was dissolved in Et2O,
washed with brine, dried over MgSO4, and concentrated in
7-(2’-Benzyloxyethyl)-3a-ethyl-6-(5’,5’-dimethyl[1,3]di-
oxan-2’-yl)octahydroinden-1-one (26). TMSOTf (0.848 g,
3.82 mmol) was added dropwise to a 0 °C solution of allylic
alcohol 25 (4.00 g, 12.7 mmol) and bis(trimethylsilyl)neopentyl
glycol (4.74 g, 19.1 mmol) in CH2Cl2 (30 mL). This mixture
was stirred for 10 h while it was allowed to warm to room
temperature. The reaction was then quenched with saturated
aqueous NaHCO3 (20 mL), extracted with CH2Cl2, dried over
MgSO4, and concentrated in vacuo. The resulting residue was
purified by silica gel chromatography (10% EtOAc/hexanes)
to yield 3.50 g (69%) of 26 (Rf ) 0.7, 25% EtOAc in hexanes)
as a yellow oil. [R]D ) +30.6 (c 3.6, CH2Cl2); IR (CH2Cl2) 1734
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.77 (s, 3H), 0.86 (t, J )
7.4 Hz, 3H), 1.05 (s, 3H), 1.43-1.95 (m, 11H), 2.12-2.20 (m,
1H), 2.29-2.36 (m, 1H), 2.99 (d, J ) 9.4 Hz, 1H), 3.16 (dd, J
) 2.0, 11.7 Hz, 1H), 3.26 (dd, J ) 2.0, 11.7 Hz, 1H), 3.49-3.61
(m, 4H), 4.50 (d, J ) 3.0 Hz, 2H), 7.24-7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 8.17, 22.3, 23.0, 26.7, 28.0, 28.3, 29.5, 30.6,
31.3, 32.0, 34.6, 40.9, 53.2, 69.1, 69.5, 69.6, 70.5, 72.8, 96.5,
127.4, 127.5, 128.1, 128.2, 138.5, 219.0; FAB m/z (relative
intensity) 401 (MH+, 35), 307 (32), 207 (49), 154 (100); 136
(100); HRMS calcd for C25H36O4 400.2599, found 400.2614.
7-(2’-Hydroxyethyl)-3a-ethyl-6-(5,5-dimethyl-[1,3]dioxan-
2-yl)-octahydro-inden-1-one (27). Benzyl ether 26 (3.10 g,
7.75 mmol) and 10% Pd/C (0.465 g, 15% w/w) were stirred in
MeOH (75 mL) under a hydrogen atmosphere (balloon). After
12 h, the reaction mixture was filtered through a pad of Celite
and concentrated in vacuo, and the crude product residue was
(19) Camerman, A.; Camerman, N.; Kutney, J. P.; Piers, E.; Trotter,
J. Tetrahedron Lett. 1965, 637-642.
(20) Bernady, K. F.; Poletto, J. F.; Nocera, J.; Mirando, P.; Schaub,
R. E.; Weiss, M. J. J. Org. Chem. 1980, 45, 4702-4715.
10650 J. Org. Chem., Vol. 70, No. 26, 2005

Synthesis of (+)-Aspidospermidine
purified by chromatography (30% EtOAc/hexanes) to yield 2.05
g (85%) of 27 (Rf ) 0.24) as a clear oil. [R]D ) +28.1 (c 1.4,
CH2Cl2); IR (film) 3429, 1733 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.87 (t, J ) 7.4 Hz, 3H), 0.94 (s, 3H), 0.97 (s, 3H), 1.40-1.49
(m, 3H), 1.55-1.70 (m, 5H), 1.75-1.85 (m, 1H), 1.89 (d, J )
6.2 Hz, 1H), 1.95-2.05 (m, 1H), 2.06-2.15 (m, 1H), 2.17-2.25
(m, 1H), 2.33-2.45 (m, 1H), 2.54 (m, 1H), 3.35-3.41 (m, 2H),
3.48-3.65 (m, 3H), 3.65-3.75 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 8.1, 22.7, 25.7, 27.1, 28.8, 29.7, 30.2, 32.3, 34.6, 35.8,
41.0, 57.3, 62.0, 69.6, 69.7, 98.5, 219.9; CIMS m/z (relative
intensity) 310 (M+, 3), 293 (9), 207 (100), 141 (65); 55 (16);
HRMS calcd for C18H30O4 310.2144, found 310.2131.
7-(2’-Azidoethyl)-3a-ethyl-6-(5’,5’-dimethyl[1,3]dioxan-
2’-yl)-octahydroinden-1-one (28). DEAD (2.58 g, 14.8 mmol)
was added to a 0 °C solution of 27 (2.30 g, 7.42 mmol), PPh3
(3.9 g, 14.8 mmol) and HN3 (8.9 mL of a 2.5 M solution in
benzene, 22.3 mmol) in benzene (40 mL) and stirred for 11 h
while it was allowed to warm to room temperature. The
reaction was quenched with H2O (100 mL) and extracted with
Et2O. The organic extracts were washed with saturated
aqueous NaHCO3, water, and brine (20 mL each), dried over
MgSO4, and concentrated in vacuo, and the resulting residue
was purified by chromatography (5% EtOAc/hexanes), to yield
1.81 g (73%) of 28 (Rf ) 0.73, 30% EtOAc in hexanes) as a
light yellow oil. [R]D ) +37.9 (c 5.54, CH2Cl2); IR (CH2Cl2) 2957,
2100, 1733 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 7.4
Hz, 3H), 0.91 (s, 3H), 0.97 (s, 3H), 1.39-1.50 (m, 3H), 1.58-
1.70 (m, 4H), 1.77-1.82 (m, 2H), 1.96-2.02 (m, 2H), 2.18-
2.25 (m, 1H), 2.32-2.42 (m, 1H), 2.53-2.57 (m, 1H), 3.28-
3.55 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 8.1, 22.6, 22.7,
26.5, 26.8, 27.0 (2 peaks), 29.4, 29.6, 32.2, 34.2, 34.6, 50.8, 56.7,
69.6, 69.7, 98.5, 218.9; CIMS m/z (relative intensity) 336 (MH+,
4), 293 (9), 308 (39), 279 (14), 222 (41); 141 (100); HRMS calcd
for C18H29N3O3 335.2209, found 335.2202.
6-Ethyl-12-(5’,5’-dimethyl[1,3]dioxan-2’-yl)-9-azatricy-
clo[7.2.1.0]dodecan-3-one (29). TiCl4 (0.07 g, 0.36 mmol) was
added dropwise to a solution of 28 (0.040 g, 0.12 mmol) in CH2-
Cl2 (5 mL) maintained at 0 °C and stirred for 3 h while it
warmed to room temperature. The reaction was quenched with
saturated aqueous NaHCO3 and i-PrOH (5 mL), poured into
brine, and filtered through a pad of wet Celite. It was then
extracted with CH2Cl2, the organic extracts were washed with
saturated aqueous NaHCO3, water and brine (10 mL each),
dried over MgSO4, and concentrated in vacuo, and the result-
ing residue was purified by chromatography, eluting with
EtOAc and then 10% MeOH in EtOAc, to yield 0.020 g (52%)
of 29 (Rf ) 0.75, 10% MeOH in EtOAc) as a light yellow solid:
mp ) 74-76 °C; IR (CCl4) 2948, 1737 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.71 (s, 3H), 0.87 (t, J ) 7.4 Hz, 3H), 1.10 (s, 3H),
1.25 (m, 1H), 1.36-1.43 (m, 3H), 1.52-1.60 (m, 1H), 1.79 (d,
J ) 3.6 Hz, 1H), 2.00-2.04 (m, 1H), 2.14-2.20 (m, 2H), 2.23-
2.27 (m, 2H), 2.69 (m, 1H), 2.76 (m, 1H), 2.95-3.04 (m, 3H),
3.12 (dd, J ) 10.6, 2.4 Hz, 1H), 3.22 (dd, J ) 10.3, 2.4 Hz,
1H), 3.61 (d, J ) 10.3 Hz, 1H), 3.81 (d, J ) 10.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 8.6, 21.7, 22.8, 28.8, 29.3, 29.35,
33.0, 36.6, 38.8, 44.3, 44.8, 47.0, 49.0, 56.0, 68.0, 72.0, 112.0,
213.0; CIMS m/z (relative intensity) 308 (MH+, 100), 307 (M+,
14), 222 (51), 121 (45), 84 (20), 79 (15), 55 (31); HRMS calcd
for C18H30NO3 308.2226, found 308.2202.
7-(2’-Azidoethyl)-3a-ethylhexahydroindene-1,6-dione
(7). LiBF4 (0.36 g, 3.88 mmol) was added to 28 (0.26 g, 0.77
mmol) in 20% H2O in CH3CN (20 mL total volume) and heated
at 70 °C for 18 h. The reaction was then diluted with H2O,
extracted with Et2O, dried (MgSO4), concentrated in vacuo,
and chromatographed to afford 0.17 g (89%) of 7 (Rf ) 0.44,
30% EtOAc in hexanes) as a colorless oil. IR (CH2Cl2) 3053,
1737, 1712 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J ) 7.4
Hz, 3H), 1.40 (sextet, J ) 7.0 Hz, 1H), 1.54-1.60 (m, 2H),
1.81-2.10 (m, 8H), 2.36-2.45 (m, 4H), 2.58-2.62 (m, 1H),
3.26-3.31 (m, 1H), 3.39-3.44 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 8.0, 28.5, 29.3, 29.7, 31.1, 34.8, 35.8, 41.8, 43.6, 49.4,
60.1, 211.1, 217.9; CIMS m/z (relative intensity) 250 (MH+,
2), 222 (44), 192 (12), 165 (17), 43 (100); HRMS calcd for
C13H20N3O2 250.1555, found 250.1547.
(6aS)-Ethyloctahydropyrrolo[3,2,1-ij]quinoline-4,9-di-
one (6). TiCl4 (0.049 g, 0.256 mmol) was added dropwise to a
0 °C solution of diketo azide 7 (0.058 g, 0.233 mmol) in CH2-
Cl2 (3 mL) and stirred for 2 h, then allowed to warm to room
temperature and stirred for an additional 15 min. The reaction
was quenched with solid NaHCO3/i-PrOH, poured into brine,
and filtered through a pad of wet Celite. The filtrate was
extracted with CH2Cl2, and the organic extracts washed with
saturated aqueous NaHCO3, dried (MgSO4), and concentrated
in vacuo. The brown residue was purified by chromatography,
eluting with EtOAc followed by 10% MeOH in EtOAc, to afford
0.042 g (82%) of 6 (Rf ) 0.24, EtOAc) as a light yellow
crystalline solid. Mp ) 139-140 °C; [R]D ) -89.1 (c 1.575, CH2-
1
Cl2); IR (film) 1705, 1630 cm-1; H NMR (500 MHz, CDCl3) δ
1.00 (t, J ) 7.5 Hz, 3H), 1.50 (m, 1H), 1.57-1.73 (m, 3H), 1.83
(m, 2H), 2.00 (m, 1H), 2.25-2.50 (m, 4H), 2.63 (m, 1H), 2.86
(t, J ) 5.9 Hz, 1H), 3.42 (dd, J ) 10.0, 4.7 Hz, 2H), 3.63 (d, J
) 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 7.4, 22.1, 25.2,
27.9, 29.2, 29.7, 34.1, 36.3, 43.8, 49.4, 68.5, 168.2, 208.6; EIMS
m/z (relative intensity) 222 (MH+, 80), 49 (30); HRMS calcd
for C13H20NO2 222.1504, found 222.1494.
6a-Ethyldecahydropyrrolo[3,2,1-ij]quinolin-9-one (3).
TMSOTf (0.06 g, 0.27 mmol) was added to a mixture of 6 (0.06
g, 0.27 mmol) and bis(trimethylsilyl)neopentyl glycol (0.402
g, 1.62 mmol) in CH2Cl2 (5 mL) maintained at 0 °C. The
reaction was stirred for 6 h and warmed to room temperature.
It was quenched with saturated aqueous NaHCO3, extracted
with CH2Cl2, dried (MgSO4), and concentrated to a brown oil.
Rf ) 0.5 (10% MeOH in EtOAc); IR (CCl4) 2951, 1638 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.69 (s, 3H), 0.87 (t, J ) 7.4 Hz,
3H), 1.17 (s, 3H), 1.20-1.25 (m, 3H), 1.50-1.56 (m, 2H), 1.72-
1.79 (m, 3H), 2.23 (dd, J ) 7.0, 5.4 Hz, 1H), 2.29-2.33 (m,
2H), 2.37-2.42 (m, 1H), 2.57 (dt, J ) 10.5, 3.6 Hz, 1H), 3.22-
3.31 (m, 4H), 3.48 (d, J ) 11.4 Hz, 1H), 3.72 (d, J ) 11.4 Hz,
1H), 3.80 (q, J ) 11.2 Hz, 3H).
The crude ketal was added to LiAlH4 (0.05 g, 1.35 mmol) in
THF (5 mL) and heated at reflux for 10 h. The reaction was
quenched with water, filtered through wet Celite, and ex-
tracted with Et2O. The organic extracts were dried (MgSO4)
and concentrated to a brown oil. This oil was charged with
LiBF4 (0.126 g, 1.35 mmol) and dissolved in 10% H2O/CH3CN
and heated at 80 °C for 8 h. The reaction was then diluted
with water, extracted with Et2O, dried (MgSO4), concentrated,
and chromatographed to give 0.037 g (66% overall) of 3 as a
colorless oil. Rf ) 0.51 (10% MeOH in EtOAc); IR (film) 1700
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.95 (t, J ) 7.5 Hz, 3H),
1.12 (td, J ) 13.4, 4.6 Hz, 1H), 1.34 (m, 1H), 1.51 (m, 2H),
1.59-1.87 (m, 4H), 1.93 (m, 3H), 2.22-2.47 (m, 4H), 2.68 (m,
1H), 3.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 7.6, 21.69,
21.72, 26.5, 30.5, 33.3, 35.1, 37.2, 48.6, 53.3, 53.6, 74.0, 211.9;
CIMS m/z (relative intensity) 208 (MH+, 100), 178 (30), 82 (50).
(+)-Aspidospermidine 1 and Byproduct 31. Amino
ketone 3 (0.036 g, 0.174 mmol) and phenylhydrazine (0.02 g,
0.208 mmol) in 5 mL of PhH were allowed to reflux for 3.5 h.
The reaction was then cooled to room temperature and
concentrated in vacuo. The crude phenylhydrazone was al-
lowed to reflux in 5 mL of AcOH for 4 h and then concentrated
in vacuo to afford the crude indoline as a dark brown oil. This
material was dissolved in THF (5 mL), treated with LiAlH4
(0.066 g, 1.74 mmol), and allowed to reflux for 12 h. After
cooling to 0 °C and quenching with H2O/NaOH, the mixture
was filtered through a plug of Celite and concentrated in vacuo.
The resulting residue was purified by chromatography (EtOAc)
to yield 0.025 g (51%) aspidospermidine (1) as a pale yellow
oil that crystallized upon standing and 31 (0.0065 g, 13%) as
a colorless oil. Data for (+)-aspidospermidine (1): Rf ) 0.29
(10% MeOH/EtOAc); mp ) 117-119 °C (acetone) (lit.19 119-
121 °C) [R]D ) +20.6 (c 0.65, EtOH) (lit.2 +21 (c 7.4, EtOH));
1
IR (film) 3320, 1600 cm-1; H NMR (400 MHz, CDCl3) δ 0.66
(t, J ) 7.5 Hz, 3H), 0.88 (m, 1H), 1.07 (m, 1H), 1.13 (td, J )
J. Org. Chem, Vol. 70, No. 26, 2005 10651

Iyengar et al.
13.5, 4.6 Hz, 1H), 1.36-1.57 (m, 4H), 1.66 (m, 2H), 1.76 (qt, J
) 12.8, 3.9 Hz, 1H), 1.97 (m, 2H), 2.24 (s, 1H), 2.22-2.37 (m,
2H), 3.08 (m, 1H), 3.14 (m, 1H), 3.53 (dd, J ) 11.0, 6.2 Hz,
1H), 6.66 (d, J ) 7.8 Hz, 1H), 6.75 (t, J ) 7.3 Hz, 1H), 7.04
(td, J ) 7.6, 0.9 Hz, 1H), 7.10 (d, J ) 7.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 7.2, 22.2, 23.4, 28.5, 30.4, 34.9, 36.0, 39.2,
53.5, 53.8, 54.3, 66.1, 71.7, 110.7, 119.4, 123.3, 127.5, 136.1,
149.8; CIMS m/z (relative intensity) 283 (MH+, 60), 254 (25),
210 (25), 124 (100).
Data for 5a-Ethyl-1,3,4,5,5a,6,11,11d-octahydro-2H,-
11cH-2a,11-diazo-indeno[1,7-ab]fluorene (31): Rf ) 0.1
(10% MeOH/EtOAc); [R]D ) -100 (c 0.4, EtOH); IR (CH2Cl2)
3459, 2934 cm-1; 1H NMR (400 MHz, MeOH-d4) δ 0.86 (t, J )
7.5 Hz, 3H), 1.23-1.38 (m, 3H), 1.45-1.55 (sextet, J ) 7.5 Hz,
1H), 1.68-1.77 (m, 2H), 1.89-2.05 (m, 3H), 2.16 (m, 1H), 2.24
(m, 1H), 2.36 (q, J ) 12.0 Hz, 1H), 2.51 (d, J ) 15.0 Hz, 1H),
2.79 (d, J ) 15.0 Hz, 1H), 3.12 (br t, J ) 9.0 Hz, 1H), 3.52 (m,
1H), 6.94 (td, J ) 7.0, 1.0 Hz, 1H), 7.04 (td, J ) 7.0, 1.0 Hz,
1H), 7.24 (d, J ) 7.8 Hz, 1H), 7.37 (d, J ) 7.8 Hz, 1H); 13C
NMR (100 MHz, MeOH-d4-CDCl3) δ 5.6, 20.5, 22.1, 26.7, 29.2,
31.5, 32.7, 35.2, 52.2, 53.7, 71.5, 103.7, 104.3, 109.3, 116.2,
117.1, 119.3, 126.9, 136.4; EIMS m/z (relative intensity) 281
(MH+, 100), 124 (70), 58 (14); HRMS calcd for C19H25N2
281.2018, found 281.2025.
Acknowledgment. We thank the National Insti-
tutes of Health (GM-49093) for the support of this work,
David Vander Velde for NMR spectroscopy consultation,
Doug Powell for X-ray crystallography, and Timothy
Ribelin for help with compound characterization.
Supporting Information Available: Details of stereo-
chemical assignments, additional experimental details, copies
of 1H and 13C NMR spectra, and X-ray crystallographic details
for compound 29 (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JO051212N
10652 J. Org. Chem., Vol. 70, No. 26, 2005