Conjugate addition - Dipolar cycloaddition cascade for the synthesis of benzo[a]quinolizine and indolo[a]quinolizine scaffolds: Application to the total synthesis of (±)-yohimbenone

Article abstract of DOI:10.1021/jo9003579

A highly efficient total synthesis of (±)-yohimbenone and a formal synthesis of (±)-emetine is described. The key element of the synthesis consists of a conjugate addition-dipolar cycloaddition of 2,3- bis(phenylsulfonyl)-l,3-butadiene with an appropriate oxime. The resulting cycloadducts are cleaved reductively to provide azapolycyclic scaffolds with strategically placed functionality for further manipulation to the target compounds.

Full text of DOI:10.1021/jo9003579

Conjugate Addition-Dipolar Cycloaddition Cascade for the
Synthesis of Benzo[a]quinolizine and Indolo[a]quinolizine Scaffolds:
Application to the Total Synthesis of (()-Yohimbenone
Chad J. Stearman,† Michael Wilson, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed March 2, 2009
A highly efficient total synthesis of (()-yohimbenone and a formal synthesis of (()-emetine is described.
The key element of the synthesis consists of a conjugate addition-dipolar cycloaddition of 2,3-
bis(phenylsulfonyl)-1,3-butadiene with an appropriate oxime. The resulting cycloadducts are cleaved
reductively to provide azapolycyclic scaffolds with strategically placed functionality for further
manipulation to the target compounds.
Introduction
antiamebic properties,9 as well as activity against breast cancer
tumor cell lines.10 In addition, benzo[a]quinolizines bind to the
benzodiazepine receptor and mimic the physiological effects
typical for benzodiazepine drugs.11 In light of this broad array
of biological activity, many methods for the construction of these
polycyclic heterocycles are known.12 Thus, more than two dozen
syntheses of emetine have been described in the literature which
showcase many elegant and important synthetic transforma-
tions.3 Several of the emetine syntheses proceed by closure of
ring B by a Bischler-Napieralski reaction13 or by related
palladium-catalyzed cyclizations.14 Another method that has
The tricyclic benzo[a]quinolizine ring system (1) is a common
structural motif found in a wide variety of physiologically active
compounds.1-4 The core skeleton is present in berberine (2),5
emetine (3),6 and several other related ipecac alkaloids7 that
exhibit potent clinical activity such as glucosidase inhibition,8
† Current address: Department of Chemistry, Missouri State University,
Springfield, Missouri 65897.
(1) Rozwadowska, M. D. Heterocycles 1994, 39, 903. (b) Chrzanowska, M.;
Rozwadowska, M. D. Chem. ReV. 2004, 104, 3341.
(2) (a) Van der Eycken, E.; Deroover, G.; Toppet, S. M.; Hoornaert, G. J.
Tetrahedron Lett. 1999, 40, 9147. (b) Yamaguchi, R.; Otsuji, A.; Uchimoto, K.
J. Am. Chem. Soc. 1988, 110, 2186.
(9) Bansal, D.; Sehgal, R.; Cawla, Y.; Mahajan, R. C.; Malla, N. Ann. Clin.
Microb. Antimicrob. 2004, 3, 27.
(10) Zhou, Y. D.; Kim, Y. P.; Mohammed, K. A.; Jones, D. K.; Muhammad,
I.; Dunbar, D. C.; Nagle, D. G. J. Nat. Prod. 2005, 68, 947.
(11) (a) Spurr, P. R. Tetrahedron Lett. 1995, 36, 2745. (b) Fischer, U.; Mo¨hler,
H.; Schneider, F.; Widmer, U. HelV. Chim. Acta 1990, 73, 763.
(12) (a) Popp, F. D.; Watts, R. F. Heterocycles 1977, 6, 1189. (b) Rubiralta,
M.; Diez, A.; Balet, A.; Bosch, J. Tetrahedron 1987, 43, 3021. (c) Rubiralta,
M.; Diez, A.; Bosch, J. Heterocycles 1988, 27, 1653. (d) Bosch, J.; Domingo,
A.; Linares, A. J. Org. Chem. 1983, 48, 1075. (e) von Strandtmann, M.; Cohen,
M. P.; Skavel, J., Jr. J. Org. Chem. 1966, 31, 797. (f) Kametani, T.; Terasawa,
H.; Ihara, M. J. Chem. Soc., Perkin Trans. 1 1976, 2547. (g) Beckwith, A. L. J.;
Joseph, S. P.; Mayadunne, R. T. A. J. Org. Chem. 1993, 58, 4198. (h) Ku¨ndig,
E. P.; Xu, L. H.; Romanens, P.; Bernardinelli, G. Synlett 1996, 270.
(13) (a) Itoh, N.; Sugasawa, S. J. Org. Chem. 1959, 24, 2042. (b) Osbond,
J. M. J. Chem. Soc. 1961, 4711. (c) Akaboshi, S.; Kato, T. Chem. Pharm. Bull.
1963, 11, 1446. (d) Teuber, H. J.; Laudien, D. Angew. Chem., Int. Ed. Engl.
1964, 3, 507. (e) Teuber, H. J.; Schroder, K. D. Chem. Ber. 1969, 102, 1779. (f)
Battersby, A. R.; Staunton, J.; Wiltshire, H. R.; Bircher, B. J.; Fuganti, C.
J. Chem. Soc., Perkin Trans. 1 1975, 1162. (h) Shamma, M.; Nugent, J. F.
Tetrahedron 1973, 29, 1265.
(3) (a) Saraf, S.-U. Heterocycles 1981, 16, 803. (b) Popp, F. D.; Watts, R. F.
Heterocycles 1977, 6, 1189.
(4) (a) Bosch, J.; Domingo, A.; Linares, A. J. Org. Chem. 1983, 48, 1075.
(b) Rubiralta, M.; Diez, A.; Balet, A.; Bosch, J. Tetrahedron 1987, 43, 3021.
(c) Rubiralta, M.; Diez, A.; Bosch, J. Heterocycles 1988, 27, 1653.
(5) (a) Jeffs, P. W. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press:
New York, London, 1967; Vol. 9, pp 41-115. (b) Pandey, G. D.; Tiwari, K. P.
Heterocycles 1980, 14, 59. (c) Singh, K. N. Tetrahedron Lett. 1998, 39, 4391.
(d) Memetzidis, G.; Stambach, J. F.; Jung, L.; Schott, C.; Heitz, C.; Stocklet,
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10.1021/jo9003579 CCC: $40.75
Published on Web 04/01/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3491–3499 3491

Stearman et al.
SCHEME 1
FIGURE 1. Some benzo[a]quinolizine alkaloids.
a completely new method which is generally applicable to the
synthesis of both the ipecac and yohimbine alkaloids. The
approach to be described herein is based on our previous success
utilizing the cycloaddition reaction of oximes with 2,3-bis(phe-
nylsulfonyl)-1,3-butadiene (6).23
FIGURE 2. Some typical indolo[a]quinolizine alkaloids.
frequently been used involves the formation of the C1-C11b bond
via a Mannich-type cyclization of a dihydroisoquinolinum ion.15
It has already been noted in several review articles16 that a
structural and biosynthetic parallelism exists between the ipecac
and the rauwolfia class of indole alkaloids.17 Representative
examples of the rauwolfia family include reserpine (4) and
yohimbenone (5). These alkaloids have attracted a great deal
of attention from synthetic chemists as a consequence of their
medicinal properties and intriguing molecular structures.18 The
historic total synthesis of reserpine by Woodward is often cited
as a model of strategy in synthetic organic chemistry.19 The
challenges associated with the construction of the stereochemi-
cally complex indolo[a]quinolizine ring system have stimulated
the development of a number of imaginative synthetic ap-
proaches.20 A major problem in these syntheses is the generation
of the proper stereochemistry at the C3-position. Several studies
have been conducted to understand and control this critical
stereochemical issue.21
Results and Discussion
In previous work, we described the reaction of oximes with
2,3-bis(phenylsulfonyl)-1,3-butadiene (6) followed by a [3 +
2]-cycloaddition of the resulting nitrone as a method for
constructing functionalized piperidone ring systems.23 The first
step in the cascade sequence was shown to involve conjugate
addition to diene 6, and this was followed by proton transfer to
create a transient nitrone 7 that undergoes a subsequent 1,3-
dipolar cycloaddition with the tethered vinyl sulfone (Scheme
1).24 The regiochemistry of the cycloaddition is presumably
controlled by nonbonded interactions in the transition state for
the cycloaddition.
Reductive N-O cleavage of the resulting cycloadduct 8
provides functionalized piperidones of type 9. Our laboratory
has recently begun the exploration of this methodology as an
efficient strategy to access a diverse group of azapolycyclic
natural products.25 As a further demonstration of its potential,
we report herein on a flexible route that was devised to allow
entry to both the isoquinoline and pentacyclic framework of
the rauwolfia alkaloids. The principal advantage of the method
is the presence of the vestigial sulfonyl substituent that allows
further elaboration through site-specific enolate chemistry.
Our retrosynthetic analysis (Scheme 2) reveals a potentially
convenient route to both of these alkaloids based on the above
conjugate addition-dipolar cycloaddition cascade. Our plan
involves formation of a dipolar cycloadduct (i.e., 12) that can
The rauwolfia alkaloid yohimbenone (5) has often served as
a testing ground to evaluate the utility of different synthetic
methodologies.22 In this paper, we report on a formal synthesis
of (()-emetine (3) and a total synthesis of yohimbenone (5) by
(15) (a) Sza´ntay, C.; Rohaly, J. Chem. Ber. 1965, 98, 557. (b) von
Strandtmann, M.; Cohen, M. P.; Shavrel, J., Jr J. Org. Chem. 1966, 31, 797. (c)
Whittaker, N. J. Chem. Soc. 1969, 85. (d) Chapman, D. D. J. Chem. Soc., Chem.
Commun. 1975, 489. (e) Shono, T.; Hamaguchi, H.; Sasaki, M.; Fujita, S.;
Nagami, K. J. Org. Chem. 1983, 48, 1621.
(16) (a) Cordell, G. A. In Introduction to Alkaloids - A Biogenic Approach;
Wiley-Interscience: New York, 1981; pp 574-832. (b) Brown, R. T. In The
Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; John Wiley: New York,
1983; pp 147-199. (c) Martin, S. F. In Strategies and Tactics in Organic
Synthesis; Lindberg, T., Ed.; Academic Press, San Diego, 1989; pp 291-322.
(17) (a) Kisakurek, M. V.; Leeuwenberg, A. J. M.; Hesse, M. In Alkaloids:
Chemical and Biological PerspectiVes; Pelletier, S. W. , Ed.; John Wiley and
Sons: New York, 1983; Vol. 1, Chapter 5.
(18) Woodson, R. E.; Youngken, H. W.; Schittler, E.; Schneider, J. A.
Rauwolfia: Botany, Pharmacognosy, Chemistry and Pharmacology; Little, Brown
and Co.: Boston, 1957.
(19) Woodward, R. B.; Bader, F. B.; Bickel, H.; Frey, A. J.; Kierstead, R. W.
Tetrahedron 1958, 2, 1.
(20) (a) Sza´ntay, C.; Honty, K. In Monoterpenoid Indole Alkaloids; Saxton,
J. E., Ed.; John Wiley & Sons: Chichester, 1994; Chapter 4, pp 161-216. (b)
Hanessian, S.; Pan, J.; Carnell, A.; Bouchard, H.; Lesage, L. J. Org. Chem.
1997, 62, 465.
(21) (a) Sakai, S.; Ogawa, M. Heterocycles 1978, 10, 67. (b) Sakai, S.;
Ogawa, M. Chem. Pharm. Bull. 1978, 26, 678. (c) Honty, K.; Baitz-Gacs, E.;
Blasko, G.; Sza´ntay, C. J. Org. Chem. 1982, 47, 5111. (d) Banerji, A.; Siddhanta,
A. K. J. Ind. Chem. Soc. 1982, 59, 542. (e) Zhang, L. H.; Gupta, A. K.; Cook,
J. M. J. Org. Chem. 1989, 54, 4708.
(23) (a) Padwa, A.; Norman, B. H. Tetrahedron Lett. 1988, 29, 2417. (b)
Norman, B. H.; Gareau, Y.; Padwa, A. J. Org. Chem. 1991, 56, 2154. (c) Padwa,
A.; Watterson, S. H.; Ni, Z. Org. Synth. 1998, 9, 82.
(24) (a) Grigg, R.; Kemp, J.; Thompson, N. Tetrahedron Lett. 1978, 19, 2827.
(b) Grigg, R.; Gunaratne, H. Q.; Kemp, J. J. Chem. Soc., Perkin Trans 1 1984,
41. (c) Grigg, R. Chem. Soc. ReV. 1987, 16, 89. (d) Donegan, G.; Grigg, R.;
Heaney, F.; Surendrakumar, S.; Warnock, W. J. Tetrahedron Lett. 1989, 30,
609. (e) Grigg, R.; Dorrity, M. R. J.; Heaney, F.; Malone, J. F. M.; Rajvirongit,
S.; Sridhararan, V.; Surendrakumar, S. Tetrahedron Lett. 1988, 4323. (f) Grigg,
R.; Markandu, J.; Perrior, T.; Surendrakumar, S.; Warnock, W. J. Tetrahedron
Lett. 1990, 31, 559. (g) Grigg, R.; Malone, J. F.; Dorrity, M. R. J.; Heaney, F.;
Rajviroongit, S.; Sridharan, V.; Surendrakumar, S. Tetrahedron Lett. 1988, 29,
4323. (h) Hassner, A.; Maurya, R. Tetrahedron Lett. 1989, 2289. (i) Hassner,
A.; Murthy, K. S. K. Tetrahedron Lett. 1987, 27, 683. (j) Hassner, A.; Maurya,
R. Tetrahedron Lett. 1989, 30, 5803. (k) Hassner, A.; Murthy, K. S. K.; Padwa,
A.; Chiacchio, U.; Dean, D. C.; Schoffstall, A. Tetrahedron Lett. 1988, 29, 4169.
(25) (a) Flick, A. C.; Caballero, M. J. A.; Padwa, A. Org. Lett. 2008, 10,
1871. (b) Wilson, M. S.; Padwa, A. J. Org. Chem. 2008, 73, 9601.
(22) Baxter, E. W.; Mariano, P. S. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Springer-Verlag: New York, 1992; Vol. 8,
pp 197-319.
3492 J. Org. Chem. Vol. 74, No. 9, 2009

Total Synthesis of (()-Yohimbenone
SCHEME 2
SCHEME 3
SCHEME 4
be obtained from the reaction of diene 6 with the oxime derived
from either benzaldehyde 10 or the indole aldehyde 11. We
envisage that the appropriately positioned ester in the dipolar
cycloadduct would undergo condensation with the resulting
secondary amine after reductive N-O cleavage. This cyclization
would provide either the pyrido[2,1-a]isoquinoline-2,6-dione 13
or the indolo[2,3-a]quinolizine-2,6-dione 14 which, after suitable
modification, would be expected to give the desired natural
products.
Our initial efforts focused on the benzo[a]quinolizine scaffold
as we reasoned that this system might serve as a model for an
eventual approach toward yohimbenone (5). Consequently,
oxime 16 was prepared from commercially available carboxylic
acid 15 by esterification followed by formylation with dichlo-
romethyl methyl ether in the presence of aluminum chloride,26
which afforded aldehyde 10 in 79% yield. Condensation of 10
with hydroxylamine hydrochloride in methanol provided oxime
16 in 97% yield. The addition of 16 to diene 6 afforded
cycloadduct 17 as a single diastereomer in 80% yield. N,O-
Reduction of cycloadduct 17 was readily accomplished using
Ra-Ni under a hydrogen atmosphere in THF which furnished
the cyclized lactam 18 in 81% yield as a 5:1 mixture of
diastereomers. Further reduction of the phenylsulfonyl group
present in 18 could be carried out using radical reduction
conditions (i.e., n-Bu3SnH, AIBN) which produced dihydroiso-
quinolinedione 19 in 70% yield (Scheme 3).27
treated with NaH in DMF followed by the addition of EtI which
afforded a 1:1 mixture of the O- and C-alkylated sulfones 20
and 21 in 86% yield. Radical reduction of 21 furnished 22 as a
7:1 mixture of diastereomers in 75% yield (Scheme 4).
With the key benzoquinolizine intermediate 18 in hand, a
Robinson annulation strategy was next explored as a means of
stitching together the D-ring.28 To this end, the conjugate
addition of 18 to methyl vinyl ketone was carried out using
catalytic triethylamine, which afforded a 1:1 mixture of dia-
stereomers of compound 23 in 84% yield. Treatment of the
crude product with pyrrolidine and acetic acid furnished the
unexpected benzoisoquinolinone 25 in 76% yield. We assume
that the first step of this reaction involves generation of the
expected enamine which then undergoes a subsequent addition
to the neighboring carbonyl group to produce iminium ion 24
as a transient species. Proton loss followed by elimination of
both water and phenylsulfonic acid nicely accounts for the
formation of the observed product (Scheme 5).30
Considering the difficulty we encountered with the pyrroli-
dine-induced Robinson annulation reaction, we modified the
cyclization conditions. Thus, cleavage of the phenylsulfonyl
group in 23 was first carried out using n-Bu3SnH/AIBN which
afforded the desulfonylated product 26 as a 3:1 mixture of
Our initial attempts to introduce an ethyl group into the C3-
position (according to emetine numbering) involved using the
enolate anion derived from 19 with ethyl iodide, and this led to
a mixture of products. Instead, keto sulfone 18 was sequentially
(28) Rosenmund, P.; Brandt, B.; Flecker, P.; Eberhard, H. Liebigs Ann. Chem.
1990, 9, 857.
(29) (a) Battersby, A. R.; Binks, R.; Davidson, D.; Davidson, G. C.; Edwards,
T. P. Chem. Ind. 1957, 982. (b) Brossi, A.; Lindlar, H.; Walter, M.; Schnider,
O. HelV. Chim. Acta 1958, 41, 119. (c) Guiles, J. W.; Meyers, A. I. J. Org.
Chem. 1991, 56, 6873.
(26) Gardiner, J. M.; Bryce, M. R.; Bates, P. A.; Hursthouse, M. B. J. Org.
Chem. 1990, 55, 1261.
(27) Smith, A. B.; Hale, K. J.; McCauley, J. P. Tetrahedron Lett. 1989, 30,
(30) For a related reaction, see: Boger, D.; Mullican, M. D. J. Org. Chem.
1980, 45, 5002.
5579.
J. Org. Chem. Vol. 74, No. 9, 2009 3493

Stearman et al.
SCHEME 5
SCHEME 8
group. Reoxidation of the resulting allylic alcohol mixture with
manganese oxide provided enone 28 (Scheme 7). The formation
of intermediate 28 represents a formal synthesis of (()-emetine
(3) since 28 had been carried on to 3 by Takano and
co-workers.31 Most importantly, the above cascade method
represents a viable approach toward synthesizing compounds
containing an isoquinoline substructure. As further proof of
principle we decided to pursue a synthesis of the structurally
related yohimbenone alkaloid using this methodology.
SCHEME 6
Our synthesis of the yohimbane core starts with a Vilsmeier-
Haack formylation32 of the known indole 29.33 Conversion of
the resulting aldehyde 11 to the corresponding oxime 30 was
uneventfully accomplished with hydroxylamine hydrochloride.
Treatment of 30 with diene 6 under conditions similar to those
used in the emetine synthesis resulted in a smooth conjugate
addition/[3 + 2]-cycloaddition cascade to give cycloadduct 31
in 72% yield (Scheme 8). Reductive N-O cleavage of 31 using
Pd(OH)2 with acetic acid in ethyl acetate under pressurized
hydrogen (45 psi)34 afforded the key ABCD yohimbane ring
structure 32 in 81% yield as a 2:1 mixture of diastereomers.
As was the case in the emetine synthesis, methyl vinyl ketone
was added followed by reductive removal of the phenyl sulfonyl
group to give 33 in 91% yield over the two steps. While
satisfactory results were obtained for the intramolecular aldol
condensation of 33 using NaOMe/MeOH, we found that the
utilization of an enamine rather than an enolate anion was a
more reliable method for forming the final E ring in 34 and the
cyclization reaction occurred in 78% yield. Reduction of 34 with
LAH followed by reoxidation with MnO2 and then removal of
the benzyl protecting group35 provided (()-yohimbenone (5)36
in 72% yield over the three steps (Scheme 9).
SCHEME 7
(31) Takano, S.; Sasaki, M.; Kanno, H.; Shishido, K.; Ogasawara, K. J. Org.
Chem. 1978, 43, 4169.
(32) (a) Qais, N.; Nakao, N.; Hashigaki, K.; Takeuchi, Y.; Yamato, M. Chem.
Pharm. Bull. 1991, 39, 3338. (b) Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.;
Jones, K. Org. Lett. 2000, 2, 2639.
(33) Benson, S. C.; Lee, L.; Yang, L.; Snyder, J. K. Tetrahedron 2000, 56,
1165.
(34) (a) Alibes, R.; Blanco, P.; Casa, E.; Closa, M.; March, P.; Figueredo,
M.; Font, J.; Sanfeliu, E.; Alvarez-Larena, A. J. Org. Chem. 2005, 70, 3157. (b)
Salvati, M.; Cordero, F. M.; Pisaneschi, F.; Bucelli, F.; Brandi, A. Tetrahedron
2005, 61, 8836. (c) Cordero, F. M.; Pisaneschi, F.; Batista, K. M.; Valenza, S.;
Machetti, F.; Brandi, A. J. Org. Chem. 2005, 70, 856.
(35) (a) Murakami, Y.; Watanabe, T.; Kobayashi, A.; Yokoyama, Y. Synthesis
1984, 738. (b) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem. 1996, 61,
1916. (c) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem. 1997, 62, 3597.
(d) Malapel-Andrieu, B.; Merour, J.-Y. Tetrahedron 1998, 54, 11079.
(36) For an earlier synthesis of (()-yohimbenone, see: Benson, W.; Win-
terfeldt, E. Chem. Ber 1979, 112, 1913.
diastereomers in 87% yield. The intramolecular aldol cyclization
of 26 with sodium methoxide in methanol at room temperature
gave 27 in 70% yield. An X-ray crystal structure of 27 confirmed
the stereochemical assignment. As anticipated, compound 27
has the same relative stereochemistry as emetine, with both alkyl
groups of the piperidone ring occupying the thermodynamically
more favorable equatorial position (Scheme 6).29
Reduction of the lactam functionality present in 27 by
employing Lawesson’s reagent for the initial conversion to the
corresponding thioamide followed by Raney nickel reduction
proved to be ineffective. Instead, lithium aluminum hydride was
employed to reduce both the enone carbonyl group and amido
3494 J. Org. Chem. Vol. 74, No. 9, 2009

Total Synthesis of (()-Yohimbenone
SCHEME 9
in CH2Cl2, washed with water and brine, and dried over Na2SO4.
Concentration under reduced pressure left behind a residue which
was purified using flash silica gel chromatography to provide 1.8 g
(97%) of methyl 2-(2-((hydroxyimino)methyl)-4,5-dimethoxyphe-
nyl)acetate (16) as a white solid: mp 120-122 °C; IR (neat) 3442,
1731, 1598, 1516, and 1275 cm-1; 1H NMR (CDCl3, 400 MHz) δ
3.69 (s, 3H), 3.74 (s, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 6.74 (s, 1H),
7.20 (s, 1H), 8.22 (s, 1H), and 8.33 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 38.8, 52.5, 56.1, 109.8, 114.0, 123.5, 126.2, 148.5, 148.9,
150.4, and 172.0; HRMS calcd for [C12H15NO5 + H+] 254.1028,
found 254.1033.
2-(4,5-Bis-benzenesulfonyl-7-oxa-1-azabicyclo[2.2.1]hept-2-yl)-
4,5-dimethoxyphenyl]acetic Acid Methyl Ester (17). A mixture
containing 3.7 g (11 mmol) of 2,3-bis(phenylsulfonyl)-1,3-butadi-
ene23 (6) and 2.6 g (10.1 mmol) of the above oxime 16 in 165 mL
of toluene was heated for 24 h at 125 °C. The solution was
concentrated under reduced pressure, and the resulting residue was
purified using flash silica gel chromatography to provide 4.75 g
(80%) of the titled compound 17 as a white solid: mp 186-187
°C; IR (neat) 2950, 1731, 1516, 1445, and 1327 cm-1; H NMR
1
In conclusion, a synthesis of (()-yohimbenone (5) has been
accomplished. The key element of the synthesis consists of a
conjugate addition-dipolar cycloaddition of 2,3-bis(phenylsul-
fonyl)-1,3-butadiene with the oxime derived from methyl 2-(1-
benzyl-2-formyl-1H-indol-3-yl)acetate. The resulting cycload-
duct was converted into (()-yohimbenone by (1) reductive
cleavage of the bicyclic isoxazolidine adduct, (2) cyclization
of the resulting secondary amine onto the adjacent methyl ester,
(3) conjugate addition with MVK and subsequent sulfone
reduction, and (4) Robinson annulation followed by functional
group manipulation. We have also achieved a formal synthesis
of (()-emetine (3) by intercepting Takano’s intermediate 28
using a similar cascade strategy. The applicability of the new
methodology to other alkaloid targets is currently under study
and will be the subject of future reports.
(CDCl3, 400 MHz) δ 2.08-2.14 (ddd, 1H, J ) 19.2, 8.4, and 3.6
Hz), 3.41 (s, 3H), 3.56 (d, 1H, J ) 16.0 Hz), 3.63 (d, 1H, J ) 16.0
Hz), 3.68-3.71 (m, 1H), 3.74 (s, 3H), 3.77-3.78 (m, 2H), 3.80 (s,
3H), 4.58-4.62 (m, 2H), 6.40 (s, 1H), 6.59 (s, 1H), 7.49-7.53
(m, 2H), 7.63-7.68 (m, 3H), 7.72-7.76 (m, 1H), 7.85-7.87 (m,
2H), and 8.02-8.04 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 38.6,
40.8, 52.6, 55.8, 56.1, 61.4, 67.0, 68.1, 103.1, 109.2, 113.1, 123.3,
129.0, 129.2, 129.8, 130.6, 133.2, 134.9, 135.0, 139.0, 148.3, 148.9,
and 171.9. Anal. Calcd for C28H29NO9S2: C, 57.23; H, 4.97; N,
2.38. Found: C, 56.85; H, 4.83; N, 2.37.
9,10-Dimethoxy-3-(phenylsulfonyl)-3,4-dihydro-1H-pyrido[2,1-
a]isoquinoline-2,6(7H,11bH)-dione (18). A solution containing 2.8 g
(4.8 mmol) of the above cycloadduct 17 and 0.28 g of freshly
washed Raney nickel in 30 mL of THF was heated at reflux under
an atmosphere of hydrogen for 12 h. The resulting solution was
filtered through Celite and concentrated under reduced pressure.
The residue was purified using flash silica gel chromatography to
provide 1.6 g (81%) of the major diastereomer 18 as a white solid:
mp 218-219 °C; IR (neat) 1721, 1654, 1521, 1465, 1450, and 1316
cm-1; 1H NMR (CDCl3, 400 MHz) enol tautomer δ 2.91-2.99 (m,
1H), 3.13-3.25 (m, 2H), 3.59-3.65 (m, 2H), 3.83 (s, 3H), 3.87
(s, 3H), 4.76 (d, 1H, J ) 12.0 Hz), 5.59 (d, 1H, J ) 15.2 Hz), 6.56
(s, 1H), 6.60 (s, 1H), 7.55-7.62 (m, 2H), 7.67-7.72 (m, 1H), and
7.98-8.03 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 34.9, 41.2,
50.7, 56.1, 56.2, 59.3, 71.4, 107.8, 110.2, 122.6, 122.8, 129.3, 129.4,
129.5, 129.6, 134.8, 136.9, 148.5, 149.3, 167.5, and 197.0. Anal.
Calcd for C21H21NO6S: C, 60.71; H, 5.09; N, 3.37. Found: C, 60.32;
H, 5.04; N, 3.33.
Experimental Section
Methyl 2-(2-((Hydroxyimino)methyl)-4,5-dimethoxyphenyl)ac-
etate (16). To a solution containing 10.0 g (51 mmol) of 2-(3,4-
dimethoxyphenyl)acetic acid (15) in 100 mL of methanol at -78
°C was added 7.5 g (61 mmol) of thionyl chloride. The resulting
solution was warmed to 25 °C and was stirred for 12 h before being
concentrated under reduced pressure. The residue was dissolved
in EtOAc and washed with a saturated aqueous NaHCO3 solution
and brine. The organic layer was concentrated under reduced
pressure to provide 10.1 g (94%) of methyl 2-(3,4-dimethoxyphe-
nyl)acetate37 which was used in the next step without further
purification.
To a solution of 2.0 g (9.5 mmol) of the above compound in 50
mL of CH2Cl2 at 0 °C was added 2.5 g (19 mmol) of AlCl3 in
several portions over a 10 min period. To this mixture was added
1.7 g (13 mmol) of dichloromethyl methyl ether at 0 °C. The
resulting solution was stirred for an additional 1 h at 0 °C, warmed
to 25 °C, and stirred for 12 h. The reaction mixture was poured
into ice-water and extracted with CH2Cl2. The combined organic
layer was washed with a 5% aqueous KOH solution, dried over
Na2SO4, and concentrated under reduced pressure yielding 1.8 g
(79%) of methyl 2-(2-formyl-4,5-dimethoxyphenyl)acetate37 (10)
which was used in the next step without further purification.
To a solution containing 1.8 g (7.5 mmol) of the above aldehyde
in 50 mL of methanol was added sequentially 0.6 g (8.2 mmol) of
hydroxylamine hydrochloride and 1.2 g (15 mmol) of sodium
acetate. After being stirred at 25 °C for 12 h, the solution was
concentrated under reduced pressure. The residue was dissolved
9,10-Dimethoxy-3,4-dihydro-1H-pyrido[2,1-a]isoquinoline-2,6-
(7H,11bH)-dione (19). A solution containing 0.11 g (0.28 mmol)
of keto sulfone 18 and 0.05 g (1.1 mmol) of n-Bu3SnH in 8 mL of
toluene was heated at reflux. Two portions of AIBN (0.051 g, 0.31
mmol) were subsequently added over a 20 min period. The reaction
mixture was concentrated under reduced pressure, and the residue
was purified using flash silica gel chromatography to provide 0.053
g (70%) of the titled compound 19 as a pale yellow oil: IR (film)
1
1721, 1644, 1516, 1250, and 1122 cm-1; H NMR (400 MHz,
CDCl3) δ 2.45-2.66 (m, 3H), 2.84 (d, 1H, J ) 14.8 Hz), 2.95-3.03
(ddd, 1H, J ) 12.8, 12.8, and 4.0 Hz), 3.71 (d, 2H, J ) 3.2 Hz),
3.87 (s, 3H), 3.89 (s, 3H), 4.74 (d, 1H, J ) 12.0 Hz), 5.08-5.13
(ddd, 1H, J ) 13.2, 6.8, and 2.0 Hz), 6.57 (s, 1H), and 6.61 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 34.7, 40.8, 41.4, 51.2, 56.1,
56.2, 59.1, 107.7, 110.1, 122.3, 123.7, 148.5, 149.2, 167.4, and
206.1. Anal. Calcd. for C15H17NO4: C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.28; H, 6.31; N, 5.25.
3-Ethyl-9,10-dimethoxy-3,4-dihydro-1H-pyrido[2,1-a]isoquino-
line-2,6-(7H,11bH)-dione (22). To a solution of 0.1 g (0.24 mmol)
of keto sulfone 18 in 1.5 mL of DMF at 0 °C was added 0.01 g
(0.26 mmol) of NaH (60% dispersion in mineral oil). After the
(37) Gardiner, J. M.; Bryce, M. R.; Bates, P. A.; Hursthouse, M., B. J. Org.
Chem. 1990, 55, 1261.
J. Org. Chem. Vol. 74, No. 9, 2009 3495

Stearman et al.
solution was stirred for 5 min, 0.06 g (0.36 mmol) of iodoethane
was added via syringe, and the resulting solution was stirred at 25
°C for 1 h. The reaction mixture was quenched with water and
extracted with EtOAc. The combined organic layer was dried over
Na2SO4, concentrated under reduced pressure, and purified using
flash silica gel chromatography. The first fraction contained 0.048
g of enol ether 20 (45%) as a clear oil: IR (film) 1650, 1516, 1445,
1322, and 1245 cm-1; 1H NMR (600 MHz, CDCl3) δ 1.19 (t, 3H,
J ) 7.2 Hz), 2.31-2.37 (m, 1H), 2.77 (d, 1H, 16.2 Hz), 3.56 (d,
1H, J ) 16.2 Hz), 3.60 (d, 1H, J ) 16.2 Hz), 3.74-3.79 (m, 1H),
3.86 (s, 3H), 3.87 (s, 1H), 3.86-3.89 (m, 1H), 3.95-4.00 (m, 1H),
4.65 (dd, 1H, J ) 11.4 and 3.6 Hz), 5.62 (d, 1H, J ) 11.6 Hz),
6.59 (s, 1H), 6.62 (s, 1H), 7.49-7.52 (m, 2H), 7.57-7.60 (m, 1H),
8.00 (s, 1H), and 8.01 (s, 1H); 13C NMR (150 MHz, CDCl3) δ
10.6, 30.7, 31.7, 36.3, 51.9, 52.0, 52.1, 60.2, 104.0, 106.1, 118.4,
119.1, 123.8, 124.4, 128.8, 138.3, 144.2, 145.1, 153.5, and 162.4.
The second fraction contained 0.045 g (41%) of 3-ethyl-9,10-
dimethoxy-3-(phenylsulfonyl)-3,4-dihydro-1H-pyrido[2,1-a]iso-
quinoline-2,6(7H,11bH)-dione (21) as a white solid: mp 219-220
100 MHz) diastereomer A: δ 26.6, 30.1, 35.6, 37.6, 43.9, 47.5,
56.2, 56.3, 56.7, 75.1, 107.5, 110.4, 122.6, 124.0, 129.2, 131.1,
135.0, 135.5, 148.5, 149.3, 167.9, 201.0, and 207.0; diastereomer
B: δ 24.8, 30.2, 35.4, 37.7, 44.2, 50.2, 56.2, 56.3, 58.7, 73.9, 107.7,
110.4, 123.0, 123.1, 129.4, 131.0, 134.7, 135.0, 148.6, 149.4, 167.7,
199.8, and 206.5. Anal. Calcd for C25H27NO7S: C, 61.84; H, 5.60;
N, 2.88. Found: C, 61.39; H, 5.77; N, 2.61.
2,3-Dimethoxy-11-pyrrolidin-1-yl-5,8,13,13a-tetrahydroisoqui-
no[3,2-a]-isoquinolin-6-one (25). To a solution containing 0.1 g (0.21
mmol) of the above keto sulfone 23 in 1 mL of CH2Cl2 was added
0.01 g (0.18 mmol) of acetic acid and 0.01 g (18 mmol) of
pyrrolidine. After being stirred for 12 h, the solution was concen-
trated under reduced pressure. The crude residue was dissolved in
3 mL of toluene, and 0.02 g (0.1 mmol) of p-toluenesulfonic acid
was added. The resulting solution was heated at reflux for 1 h.
Concentration under reduced pressure left a residue which was
purified by silica gel chromatography to furnish 0.076 g (76%) of
the titled compound 25 as a tan solid: mp 250-251 °C; IR (film)
1
1639, 1521, 1450, 1368, and 1250 cm-1; H NMR (400 MHz,
1
°C; IR (film) 1721, 1655, 1516, 1450, and 1306 cm-1; H NMR
CDCl3) δ 2.01 (brs, 5H), 2.92-2.99 (m, 1H), 3.13 (dd, 1H, J )
15.6 and 3.2 Hz), 3.27 (brs, 4H), 3.65 (d, 1H, J ) 6.4 Hz), 3.90 (s,
3H), 3.91 (s, 3H), 4.22 (d, 1H, J ) 16.0 Hz), 4.72 (d, 1H, J ) 10.8
Hz), 5.58 (d, 1H, 16.0 Hz), 6.32 (s, 1H), 6.50 (d, 1H, J ) 8.4 Hz),
6.63 (s, 1H), 6.73 (s, 1H), and 7.05 (d, 1H, J ) 8.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 25.6, 35.5, 39.3, 44.4, 48.0, 56.2, 56.3, 57.9,
108.4, 110.2, 111.3, 122.9, 125.8, 127.4, 129.8, 130.4, 134.2, 146.9,
148.3, 148.9, and 167.1. Anal. Calcd for C23H26N2O3: C, 72.98; H,
6.93; N, 7.41. Found: 72.87; H, 7.15; N, 7.46.
(400 MHz, CDCl3) δ 0.83 (t, 3H), 1.78-1.87 (m, 1H), 1.95-2.04
(m, 1H), 2.65 (dd, 1H, J ) 16.8 and 10.4 Hz), 3.72 (dd, 1H, J )
16.8 and 4.8 Hz), 3.63 (s, 2H), 3.88 (s, 6H), 4.19 (d, 1H, J ) 14.4
Hz), 4.99 (d, 1H, J ) 14.4 Hz), 5.13 (dd, 1H, J ) 10.4 and 4.8
Hz), 6.62 (s, 1H), 6.63 (s, 1H), 7.58-7.62 (m, 2H), 7.71-7.75 (m,
1H), and 7.87-7.90 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 8.4,
27.4, 36.3, 43.1, 47.3, 55.0, 56.3, 56.4, 76.0, 107.4, 110.5, 123.1,
124.6, 129.1, 131.1, 134.8, 135.5, 148.5, 149.3, 167.8, and 201.3.
Anal. Calcd for C23H25NO6S: C, 62.29; H, 5.68; N, 3.16. Found:
62.04; H, 5.41; N, 3.08.
9,10-Dimethoxy-3-(3-oxobutyl)-3,4-dihydro-1H-pyrido[2,1-a]iso-
quinoline-2,6-(7H,11bH)-dione (26). A solution containing 0.15 g
(0.3 mmol) of keto sulfone 23 and 0.35 g (1.2 mmol) of n-Bu3SnH
in 9 mL of toluene was heated at reflux. Two portions of AIBN
(0.054 g, 0.33 mmol) were subsequently added over the course of
20 min. The reaction mixture was concentrated under reduced
pressure and the residue was purified using flash silica gel
chromatography to provide 0.09 g (87%) of the major diastereomer
26 as a white solid: mp 144-145 °C; IR (neat) 1716, 1644, 1516,
A solution containing 0.05 g (0.12 mmol) of keto sulfone 21
and 0.02 g (0.14 mmol) of n-Bu3SnH in 9 mL of toluene was heated
at reflux. Two portions of AIBN (0.021 g, 0.13 mmol) were
subsequently added over a 20 min period. The reaction mixture
was concentrated under reduced pressure, and the residue was
purified using flash silica gel chromatography to provide 0.03 g
(75%) of the titled compound 22 as a pale yellow oil: IR (film)
1
1445, and 1245 cm-1; H NMR (CDCl3, 400 MHz) δ 1.56-1.62
1
1716, 1644, 1516, 1454, and 1250 cm-1; H NMR (400 MHz,
(m, 1H), 2.05-2.12 (m, 1H), 2.17 (s, 3H), 2.48-2.54 (m, 3H),
2.55-2.62 (m, 1H), 2.65-2.71 (m, 1H), 2.82 (dd, 1H, J ) 9.2 and
2.0 Hz), 3.70 (d, 2H, J ) 4.0 Hz), 3.86 (s, 3H), 3.88 (s, 3H), 4.70
(d, 1H, J ) 8.2 Hz), 5.14 (dd, 1H, J ) 8.2 and 4.0 Hz), 6.56 (s,
1H), and 6.59 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.4, 30.1,
34.6, 41.0, 46.8, 49.1, 51.6, 56.2, 60.1, 107.8, 110.1, 122.3, 123.5,
148.5, 149.3, 167.2, 207.1, and 208.0. Anal. Calcd for C19H23NO5:
C, 66.07; H, 6.71; N, 4.06. Found: C, 65.87; H, 6.62; N, 4.01.
2,3-Dimethoxy-8,8a,9,10,13,13a-hexahydro-5H-isoquino[3,2-a]
isoquinoline-6,11-dione (27). To a solution containing 0.06 g (0.174
mmol) of the above compound 26 in 5 mL of THF was added 4.4
mL of a 0.08 M solution of sodium methoxide in methanol. The
resulting mixture was stirred at 40 °C for 12 h, concentrated under
reduced pressure, and purified using flash silica gel chromatography
to provide 0.04 g (70%) of the titled compound 27 as a yellow
CDCl3) δ 0.89 (t, 3H, J ) 7.6 Hz), 1.92-2.02 (m, 1H), 2.10-2.21
(m, 1H), 2.49-2.54 (m, 2H), 2.87-2.97 (m, 2H), 3.60-3.63 (m,
1H), 3.87-3.94 (m, 7H), 4.69 (d, 1H, J ) 10.0 Hz), 5.18-5.24
(m, 1H), 6.55 (s, 1H), and 6.61 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 11.0, 29.8, 41.4, 41.5, 45.3, 52.0, 56.3, 58.9, 107.5, 110.2,
123.9, 126.6, 148.5, 149.3,169.9, and 206.1; HRMS calcd for
[C17H21NO4 + H+] 304.1549, found 304.1545.
3-Benzenesulfonyl-9,10-dimethoxy-3-(3-oxobutyl)-3,4,7,11b-tet-
rahydro-1H-pyrido[2,1-a]isoquinoline-2,6-dione (23). To a suspen-
sion of 0.5 g (1.2 mmol) of keto sulfone 18 in 10 mL of a 9:1
mixture of THF/MeOH was added 0.6 g (8.5 mmol) of methyl vinyl
ketone. After the mixture was stirred for 2 h, 0.01 g (0.12 mmol)
of triethylamine was added as a 0.8 M solution in THF. The reaction
mixture was stirred at 25 °C for an additional 18 h, poured into
water, and extracted with CH2Cl2. The combined organic layer was
dried over Na2SO4, concentrated under reduced pressure, and
purified using flash silica gel chromatography to provide 0.49 g
(84%) of the titled compound as a 1:1 mixture of diastereomers:
solid: mp 237-238 °C; IR (neat) 1650, 1521, 1465, and 1250 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.63-1.74 (m, 1H), 2.18-2.25 (m,
1H), 2.34-2.47 (m, 3H), 2.51-2.57 (m, 1H), 2.61-2.69 (m, 1H),
2.82 (dd, 1H, J ) 14.8 and 2.8 Hz), 3.67 (s, 2H), 3.89 (s, 3H),
3.91 (s, 3H), 4.55 (d, 1H, J ) 10.8 Hz), 5.05 (dd, 1H, J ) 13.2
and 6.0 Hz), 6.01 (s, 1H), 6.6 (s, 1H), and 6.63 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 25.9, 34.7, 36.5, 36.7, 44.6, 48.1, 56.2, 56.4,
60.1, 108.2, 110.2, 122.5, 124.2, 126.9, 148.5, 160.4, 167.1, and
199.1. Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28.
Found: C, 69.79; H, 6.65; N, 4.03.
mp 190-191 °C; IR (neat) 1716, 1650, 1511, 1445, and 1306 cm-1
;
1H NMR (CDCl3, 400 MHz) diastereomer A: δ 2.05 (s, 1H),
2.07-2.24 (m, 2H), 2.50-2.53 (m, 3H), 2.68-2.77 (m, 2H), 2.97
(dd, 1H, J ) 17.2 and 5.2 Hz), 3.61 (d, 1H, J ) 20.4 Hz), 3.70 (d,
1H, J ) 20.4 Hz), 3.87 (s, 3H), 3.88 (s, 3H), 3.98 (d, 1H, J ) 14.8
Hz), 5.01-5.05 (m, 2H), 6.59 (s, 1H), 6.62 (s, 1H), 7.59-7.63 (m,
2H), 7.71-7.75 (m, 1H), and 7.89-7.91 (m, 2H); diastereomer B:
δ 1.76-1.84 (m, 1H), 2.14 (s, 3H), 2.26-2.34 (m, 1H), 2.50-2.60
(m, 2H), 2.98 (dd, 1H, J ) 15.2 and 2.8 Hz), 3.16 (d, 1H, J ) 14.8
Hz), 3.35 (dd, 1H, J ) 15.2 and 12.4 Hz), 3.66 (d, 1H, J ) 20.0
Hz), 3.87-3.90 (m, 7H), 4.79 (d, 1H, J ) 12.4 Hz), 5.66 (d, 1H,
J ) 15.6 Hz), 6.57 (s, 1H), 6.64 (s, 1H), 7.58-7.62 (m, 2H),
7.70-7.73 (m, 1H), and 7.94-7.96 (m, 2H); 13C NMR (CDCl3,
2,3-Dimethoxy-5,6,8,8a,9,10,13,13a-octahydroisoquino[3,2-a]-
isoquinolin-11-one (28). To a solution of 0.1 g (0.29 mmol) of
lactam 27 in 12 mL of a 1:1 mixture of Et2O/THF at 0 °C was
added 0.1 g (2.6 mmol) of LiAlH4. The resulting suspension was
stirred for 30 min at 0 °C and then heated at 55 °C for 1.5 h. The
reaction mixture was cooled to 0 °C and quenched with 0.12 mL
3496 J. Org. Chem. Vol. 74, No. 9, 2009

Total Synthesis of (()-Yohimbenone
of water, followed by 0.12 mL of a 15% aqueous NaOH solution
and finally an additional 0.36 mL of water. The resulting suspension
was stirred vigorously for 1 h and then anhydrous MgSO4 was
added, and this was followed by an additional 30 min of stirring.
The inorganic salts were removed by filtration, and the filtrate was
concentrated under reduced pressure to give 0.1 g of 2,3-dimethoxy-
5,8,8a,9,-10,11,13,13a-octahydro-6H-isoquino[3,2-a]isoquinolin-11-
ol as a mixture of diastereomers. The crude residue was used in
the next step without further purification.
CH2Cl2, washed with water and brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
using flash silica gel chromatography to yield 4.5 g (81%) of the
titled compound 30 as a white solid: mp 121-122 °C; IR (neat)
1
3355, 1738, 1662, 1453, 1349, and 1256 cm-1; H NMR (CDCl3,
300 MHz) δ 3.69 (s, 3H), 3.94 (s, 2H), 5.68 (s, 2H), 7.03 (d, 1H,
J ) 8.3 Hz), 7.12-7.18 (m, 1H), 7.20-7.30 (m, 6H), 7.66 (d, 1H,
J ) 8.3 Hz) and 8.39 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 30.4,
48.2, 52.2, 110.1, 112.1, 119.6, 120.4, 124.3, 126.1, 127.2, 127.4,
128.2, 128.6, 137.8, 138.3, 142.4 and 171.7; HRMS calcd for
[C19H18N2O3 + H+] 323.1396, found 323.1394.
To a solution of 0.1 g (0.29 mmol) of the above alcoholic mixture
in 30 mL of a 1:1 CH2Cl2/THF mixture was added 0.4 g (4.6 mmol)
of activated manganese dioxide. The resulting suspension was
vigorously stirred for 72 h and then filtered through a Celite plug.
The filtrate was concentrated under reduced pressure and purified
using flash silica gel chromatography to give 0.07 g (75%) of the
titled compound 2831 as a yellow solid: mp 182-185 °C; IR (neat)
1-Benzyl-2-(4,5-bis-benzenesulfonyl-7-oxa-1-azabicyclo[2.2.1]-
hept-2-yl)-1H-indol-3-yl]acetic Acid Methyl Ester (31). A 500
mL flask was charged with 5.5 g (17 mmol) of oxime 30, 6.2 g
(19 mmol) of 2,3-bis(phenylsulfonyl)-1,3-butadiene, and 200 mL
of dry toluene. The mixture was heated at reflux for 41 h. After
cooling, a small amount of silica gel was added, and the slurry
was concentrated under reduced pressure. The resulting residue was
subjected to flash silica gel chromatography to furnish 7.9 g (72%)
of the titled compound 31 as a white solid: mp 142-143 °C; IR
(neat) 1735, 1637, 1613, 1447, and 1324 cm-1; 1H NMR (CDCl3,
300 MHz) δ 2.35-2.40 (m, 1H), 3.38-3.44 (m, 2H), 3.47-3.62
(m, 3H), 3.65 (s, 3H), 4.48-4.54 (m, 1H), 4.83 (t, 1H, J ) 7.6
Hz), 5.15 (d, 1H, J ) 17.1 Hz), 5.30 (d, 1H, J ) 17.1 Hz), 6.98 (d,
2H, J ) 7.6 Hz), 7.09 (t, 1H, J ) 7.6 Hz), 7.16 (t, 1H, J ) 7.6
Hz), 7.18 (d, 1H, J ) 7.6 Hz), 7.24-7.32 (m, 3H), 7.49 (dd, 1H,
J ) 17.1 and 7.6 Hz), 7.51 (d, 2H, J ) 7.6 Hz), 7.65 (t, 2H, J )
7.6 Hz), 7.70 (t, 1H, J ) 7.6 Hz), 7.75 (t, 1H, J ) 7.6 Hz), 7.78
(d, 2H, J ) 7.6 Hz), and 7.95 (d, 2H, J ) 7.6 Hz); 13C NMR
(CDCl3, 100 MHz) δ 29.5, 39.5, 47.1, 51.9, 61.7, 65.0, 67.0, 103.1,
106.6, 109.6, 118.7, 119.9, 122.6, 126.3, 127.5, 127.9, 128.7, 129.1,
129.6, 130.2, 134.4, 134.7, 135.0, 136.7, 137.5, 138.5, and 172.4.
Anal. Calcd for C35H32N2O7S2: C, 64.01; H, 4.91; N, 4.27. Found:
C, 63.86; H, 5.13; N, 4.18.
(12b)-12-Benzyl-1,3,4,12b-tetrahydro-3-(phenylsulfonyl)indolo-
[2,3-a]quinolizine-2,6-(7H,12H)-dione (32). A 30 mL sealed tube
was charged with 0.34 g (0.52 mmol) of cycloadduct 31, 0.15 g
(0.16 mmol) of 20% Pd(OH)2, 50 µL (0.78 mmol) of AcOH, and
3 mL of EtOAc. The resulting suspension was flushed with an
atmosphere of hydrogen, pressurized with hydrogen (45 psi) and
heated at 60 °C for 38 h. The solution was filtered through a plug
of Celite and concentrated under reduced pressure. The residue was
taken up in CH2Cl2 and washed with a saturated aqueous NaHCO3
solution. The resulting biphasic solution was stirred vigorously and
the aqueous phase was separated and extracted with CH2Cl2 and
EtOAc. The combined organic layer was dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was purified
using flash silica gel chromatography to give 0.2 g (81%) of the
titled compound 32 as a 2:1-mixture of diastereomers. The major
diastereomer exhibited the following properties: mp 121-122 °C;
IR (neat) 1698, 1658, 1449, 1322, and 1148 cm-1; 1H NMR (CDCl3,
300 MHz) δ 2.85 (d, 1H, J ) 14.3 Hz), 3.14 (dd, 1H, J ) 15.2
and 4.8 Hz), 3.17-3.22 (m, 1H), 3.81 (d, 1H, J ) 4.8 Hz), 3.89
(d, 1H, J ) 20.9 Hz), 3.99 (d, 1H, J ) 20.9 Hz), 4.82 (d, 1H, J )
11.4 Hz), 5.22 (d, 1H, J ) 17.2 Hz), 5.34 (d, 1H, J ) 17.2 Hz),
5.68 (d, 1H, J ) 15.2 Hz), 6.88 (d, 2H, J ) 7.6 Hz), 7.15-7.31
(m, 6H), 7.56 (d, 1H, J ) 7.6 Hz), 7.60 (t, 2H, J ) 7.6 Hz), 7.70
(t, 1H, J ) 7.6 Hz), and 8.03 (d, 2H, J ) 7.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 29.3, 41.7, 47.1, 49.3, 54.7, 71.5, 106.2, 110.0, 118.8,
120.3, 123.2, 125.4, 125.6, 125.7, 127.9, 129.1, 129.2, 129.5, 134.7,
136.4, 136.7, 137.9, 167.8, and 196.1. Anal. Calcd for C28H24N2O4S:
C, 69.40; H, 4.99; N, 5.78. Found: C, 69.58; H, 5.07; N, 5.68.
(12b)-12-Benzyl-1,3,4,12b-tetrahydro-3-(3-oxobutyl)indolo[2,3-
a]quinolizine-2,6-(7H,12H)-dione (33). To a solution of 0.63 g (1.3
mmol) of keto sulfone 32 in 15 mL of a 9:1 THF/MeOH mixture
was added 0.75 mL (9.0 mmol) of methyl vinyl ketone. After the
mixture was stirred for 3 h, 0.35 mL of a 0.8 M solution of Et3N
in THF was added. The reaction mixture was stirred at 25 °C for
21 h and was concentrated under reduced pressure. The residue
1
1667, 1513, 1464, 1369, 1249, and 1146 cm-1; H NMR (C6D6,
600 MHz) δ 1.13-1.22 (m, 1H), 1.25-1.44 (m, 4H), 1.76 (t, 1H,
J ) 11.4 Hz), 1.96 (dt, 1H, J ) 15.2 and 4.8 Hz), 2.23-2.35 (m,
4H), 2.44 (d, 1H, J ) 16.2 Hz), 2.62 (d, 1H, J ) 9.5 Hz), 2.63 (d,
1H, J ) 11.4 Hz), 2.67-2.72 (m, 1H), 2.67-2.72 (m, 1H),
3.02-3.10 (m, 2H), 3.43 (s, 3H), 3.50 (s, 3H), 5.97 (s, 1H), 6.45
(s, 1H), and 6.56 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 25.9,
29.1, 36.6, 40.3, 51.3, 55.8, 56.1, 61.9, 62.3, 108.0, 111.4, 125.4,
126.5, 128.7, 147.4, 147.7, 163.4, and 199.5.
Methyl 2-(1-Benzyl-1H-indol-3-yl)acetate (29). To a solution of
9.0 g (34 mmol) of 2-(1-benzyl-1H-indol-3-yl)acetic acid38 in 60
mL of dry MeOH at -78 °C was added 3.0 mL (40.7 mmol) of
thionyl chloride. The suspension was slowly allowed to warm to
25 °C and was stirred for 17 h. The deep red solution was
concentrated under reduced pressure and the residue was taken up
in 100 mL of EtOAc. The solution was washed with a saturated
aqueous NaHCO3 solution and brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The resulting residue was
purified using flash silica gel chromatography to furnish 8.3 g (88%)
of the titled compound 2933 as a pale yellow oil: IR (neat) 1737,
1614, 1496, 1164, and 1013 cm-1; 1H NMR (CDCl3, 600 MHz) δ
3.71 (s, 3H), 3.80 (s, 2H), 5.25 (s, 2H), 7.12 (d, 3H, J ) 7.6 Hz),
7.16 (t, 1H. J ) 7.6 Hz), 7.21 (t, 1H, J ) 7.6 Hz), 7.24-7.32 (m,
4H), and 7.66 (d, 1H, J ) 7.6 Hz); 13C NMR (CDCl3, 150 MHz)
δ 31.0, 49.8, 51.8, 107.4, 109.7, 119.0, 119.3, 121.9, 126.7, 127.0,
127.5, 127.8, 128.6, 136.4, 137.3, and 172.3.
Methyl 2-(1-Benzyl-2-formyl-1H-indol-3-yl)acetate (11). A 100
mL flask was charged with 8 mL of dry DMF and 5.2 mL of POCl3.
The resulting solution was stirred at 0 °C for 1 h, and then a solution
of 5.0 g of the above indole 29 in 32 mL of DMF was added
dropwise. The orange solution was heated to 50 °C for 65 h, cooled
to 25 °C, and slowly added to 800 mL of a prechilled 10% aqueous
NaHCO3 solution. The basic solution was stirred vigorously for
90 min and was then extracted with Et2O. The combined organic
layer was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified using
flash silica gel chromatography to furnish 0.19 g (5%) of recovered
indole 29 and 2.4 g (56%) of the titled compound 11: IR (neat)
1
1738, 1664, 1464, 1435, 1351, and 1167 cm-1; H NMR (CDCl3,
600 MHz) δ 3.72 (s, 3H), 4.16 (s, 2H), 5.82 (s, 2H), 7.10 (d, 2H,
J ) 7.1 Hz), 7.20-7.28 (m, 4H), 7.36-7.42 (m, 2H), 7.80 (d, 1H,
J ) 8.1 Hz), and 10.20 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ
29.6, 47.7, 52.3, 110.9, 121.1, 121.2, 121.7, 126.4, 127.2, 127.5,
128.5, 131.0, 137.6, 139.2, 170.8, and 181.3.
[1-Benzyl-2-(hydroxyiminomethyl)-1H-indol-3-yl]acetic Acid
Methyl Ester (30). To a solution of 5.3 g (17.2 mmol) of the above
aldehyde in 130 mL of MeOH was added 1.6 g (22.4 mmol) of
hydroxylamine hydrochloride and 3.6 g (43 mmol) of sodium
acetate. The resulting solution was stirred for 23 h and then
concentrated under reduced pressure. The residue was taken up in
(38) (a) Julia, M.; Tchernoff, G. Bull. Soc. Chim. Fr. 1960, 741. (b) Capman,
R. F.; Phillips, N. I. J.; Ward, R. S. Tetrahedron 1985, 41, 5229.
J. Org. Chem. Vol. 74, No. 9, 2009 3497

Stearman et al.
was purified using flash silica gel chromatography to furnish 0.7 g
(97%) of the titled compound as a mixture of diastereomers. The
diastereomeric mixture was separated by flash silica gel chroma-
tography. Diasteromer A exhibited the following properties: mp
105-106 °C; IR (neat) 1715, 1658, 1600, 1447, 1308, and 1147
cm-1; 1H NMR (CDCl3, 600 MHz) δ 2.07 (s, 3H), 2.11-2.25 (m,
4H), 2.50-2.56 (m, 1H), 2.60 (dd, 1H, J ) 18.1 and 11.4 Hz),
2.71-2.78 (m, 1H), 2.88 (dd, 1H, J ) 17.1 and 4.8 Hz), 2.94 (t,
1H, J ) 7.6 Hz), 3.38 (t, 1H, J ) 7.6 Hz), 3.87 (d, 1H, J ) 15.2
Hz), 3.77-3.90 (m, 2H), 5.18 (d, 1H, J ) 14.3 Hz), 5.19-5.23
(m, 1H), 5.26 (d, 1H, J ) 17.1 Hz), 5.32 (d, 1H, J ) 17.1 Hz),
6.98 (d, 2H, J ) 7.6 Hz), 7.16-7.20 (m, 1H), 7.22-7.33 (m, 5H),
7.53 (d, 1H, J ) 7.6 Hz), 7.58 (d, 2H, J ) 7.6 Hz), 7.71 (t, 1H, J
) 7.6 Hz), and 7.85 (d, 2H, J ) 7.6 Hz); 13C NMR (CDCl3, 150
MHz) δ 26.7, 29.3, 29.9, 37.4, 44.6, 47.4, 47.8, 52.7, 75.1, 105.2,
110.1, 118.7, 120.3, 123.1, 125.4, 125.9, 128.0, 129.0, 129.1, 129.2,
129.4, 130.9, 133.9, 134.8, 135.0, 136.5, 137.9, 167.5, 199.6, and
206.6.
J ) 17.2 Hz), 5.36 (d, 1H, J ) 17.2 Hz), 5.72 (s, 1H), 6.98 (d, 2H,
J ) 6.7 Hz), 7.19 (t, 1H, J ) 7.6 Hz), 7.24-7.33 (m, 5H), and
7.56 (d, 1H, J ) 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 25.5,
29.2, 36.3, 36.4, 43.2, 47.1, 48.5, 55.1, 105.5, 109.8, 118.6, 120.2,
122.9, 125.3, 125.8, 126.7, 127.9, 129.1, 129.8, 136.9, 138.0, 159.1,
167.3, and 198.8; HRMS calcd for [C26H24N2O2 + H+] 397.1911,
found: 397.1905.
(()-Yohimbenone (5). To a solution of 0.27 g (0.68 mmol) of
lactam 34 in 12 mL of Et2O at 0 °C was added 0.21 g (5.4 mmol)
of LiAlH4. The resulting suspension was stirred for 1 h at 0 °C,
slowly warmed to 25 °C, and stirred for 24 h. The reaction mixture
was cooled to 0 °C and quenched with 0.27 mL of water, followed
by 0.27 mL of a 15% aqueous NaOH solution and finally an
additional 0.82 mL of water. The resulting suspension was stirred
vigorously for 1 h, anhydrous MgSO4 was added, and the mixture
was stirred for an additional 30 min. The inorganic salts were
removed by filtration, the filtrate was concentrated, and the resulting
residue was purified using flash silica gel chromatography to give
0.23 g (88%) of 13-benzyl-2,3,4,4a,5,7,8,13,13b,14-decahydroin-
dolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol as a yellow solid: mp
Diastereomer B exhibited the following properties: mp 102-103
1
°C; IR (neat) 1712, 1649, 1451, 1321, 1266, and 1240 cm-1; H
183-184 °C; IR (neat) 3364, 1465, 1350, 1217, and 1182 cm-1
;
NMR (CDCl3, 300 MHz) δ 1.73-1.79 (m, 1H), 2.11 (s, 3H),
2.21-2.27 (m, 1H), 2.44-2.57 (m, 2H), 2.89 (dd, 1H, J ) 15.2
and 1.9 Hz), 3.04 (d, 1H, J ) 15.2 Hz), 3.34 (dd, 1H, J ) 15.2
and 12.4 Hz), 3.92 (d, 1H, J ) 20.9 Hz), 3.99 (d, 1H, J ) 20.9
Hz), 4.88 (d, 1H, J ) 12.4 Hz), 5.25 (d, 1H, J ) 17.1 Hz), 5.38 (d,
1H, J ) 17.1 Hz), 5.82 (d, 1H, J ) 15.2 Hz), 6.94 (d, 2H, J ) 6.7
Hz), 7.17-7.33 (m, 6H), 7.59 (t, 3H, J ) 8.6 Hz), 7.70 (t, 1H, J
) 7.6 Hz), and 7.93 (d, 2H, J ) 7.6 Hz); 13C NMR (CDCl3, 150
MHz) δ 24.6, 29.4, 29.7, 30.1, 37.4, 44.7, 47.2, 49.0, 54.2, 73.8,
106.2, 110.1, 118.8, 120.3, 123.1, 125.5, 125.8, 127.9, 128.1, 129.1,
129.2, 130.7, 134.4, 134.8, 136.5, 137.9, 167.7, 198.8, and 206.2.
To a solution of 0.25 g (0.45 mmol) of the above diasteromeric
mixture in 15 mL of toluene was added 0.5 mL (1.8 mmol) of
n-Bu3SnH. The reaction mixture was heated at reflux and then 0.1 g
(0.61 mmol) of AIBN was added. After heating at reflux for 5 min,
an additional 0.1 g (0.61 mmol) of AIBN was added, followed by
an additional 0.1 g (0.61 mmol) after an additional 20 min. The
resulting solution was further heated at reflux for 1 h, cooled to 25
°C and concentrated under reduced pressure. The residue was
purified using flash silica gel chromatography to furnish 0.18 g
(94%) of the titled compound 33 as a 3:2-mixture of diasteromers:
mp 190-195 °C; IR (neat) 1729, 1648, 1463, 1452, 1236, and 1143
1H NMR (CDCl3, 600 MHz) δ 1.77-1.84 (m, 1H), 2.03-2.10 (m,
1H), 2.26-2.35 (m, 2H), 2.40-2.48 (m, 2H), 2.76-2.83 (m, 1H),
2.87 (dt, 1H, J ) 15.2 and 5.7 Hz), 2.96 (dt, 1H, J ) 15.2 and 5.7
Hz), 3.12 (dd, 1H, J ) 18.1 and 11.4 Hz), 3.24-3.29 (m, 1H),
3.65 (dd, 1H, J ) 10.5 and 2.9 Hz), 4.22 (t, 1H, J ) 6.7 Hz), 5.29
(s, 2H), 5.34 (s, 1H), 7.00 (d, 2H, J ) 7.6 Hz), 7.09-7.16 (m,
3H), 7.21-7.31 (m, 3H), and 7.52-7.56 (m, 1H); 13C NMR (CDCl3,
150 MHz) δ 22.3, 24.6, 31.6, 33.7, 37.4, 47.4, 48.1, 58.1, 62.3,
67.4, 108.6, 109.6, 118.2, 119.3, 121.5, 125.3, 125.8, 127.0, 127.3,
128.8, 136.5, 137.6, 137.7, and 140.2.
To a solution of 0.08 g (0.21 mmol) of the above alcohol in 20
mL of a 1:1 CH2Cl2/THF mixture was added 0.2 g (2.1 mmol) of
activated manganese dioxide. The resulting suspension was vigor-
ously stirred for 65 h and then filtered through a Celite plug. The
filtrate was concentrated under reduced pressure and purified using
flash silica gel chromatography to yield 0.071 g (89%) of 13-benzyl-
3,4,4a,5,8,13,13b,14octahydro-7H-indolo[2′,3′:3,4]pyrido[1,2-b]iso-
quinolin-2-one as a yellow solid: mp 149-150 °C; IR (neat) 1665,
1
1464, 1453, 1264, 1181, and 1028 cm-1; H NMR (CDCl3, 600
MHz) δ 1.53-1.61 (m, 1H), 2.01-2.06 (m, 2H), 2.29-2.36 (m,
1H), 2.42-2.48 (m, 2H), 2.60 (t, 1H, J ) 12.5 Hz), 2.70-2.77
(m, 1H), 2.84-2.89 (m, 1H), 2.91 (dt, 1H, J ) 15.0 and 5.0 Hz),
2.98 (dt, 1H, J ) 15.0 and 5.0 Hz), 3.24-3.31 (m, 2H), 3.77 (dd,
1H, J ) 10.0 and 4.5 Hz), 5.27 (d, 1H, J ) 17.5 Hz), 5.31 (d, 1H,
J ) 17.5 Hz), 5.70 (s, 1H), 6.99 (d, 2H, J ) 7.5 Hz), 7.11-7.20
(m, 3H), 7.22-7.30 (m, 3H), and 7.55 (d, 1H, J ) 7.0 Hz); 13C
NMR (CDCl3, 150 MHz) δ 22.3, 25.7, 34.4, 36.5, 37.8, 47.4, 48.0,
56.9, 61.4, 108.9, 109.6, 118.3, 119.5, 121.9, 125.3, 125.8, 126.8,
127.5, 128.9, 135.6, 137.5, 137.8, 163.0, and 199.3; HRMS calcd
for [C26H26N2O + H+] 383.2123, found 383.2119.
To a solution of 0.05 g (0.12 mmol) of the above compound in
10 mL of anhydrous toluene at 0 °C was added 0.6 g (0.47 mmol)
of anhydrous AlCl3. The resulting slurry was sonicated for 5 h,
and then the solvent was removed under reduced pressure. The
residue was diluted with EtOAc and washed with a 5% aqueous
NaOH solution. The aqueous layer was separated and extracted
with EtOAc. The combined extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified using flash silica gel chromatography to give 0.03 g (92%)
of (()-yohimbenone (5) as a yellow solid: mp 242-244 °C (lit.39
mp 244-245 °C); IR (neat) 3264, 1650, 1449, 1327, 1259, and
1164 cm-1; 1H NMR (DMSO-d6, 600 MHz) δ 1.51-1.65 (m, 1H),
1.97-2.10 (m, 1H), 2.18 (t, 1H, J ) 11.4 Hz), 2.26-2.43 (m, 3H),
2.62-2.69 (m, 1H), 2.70-2.89 (m, 2H), 3.04-3.15 (m, 3H), 3.19
(dd, 1H, J ) 11.4 and 6.4 Hz), 3.35 (s, 1H), 5.83 (s, 1H), 6.95 (t,
1H, J ) 7.3 Hz), 7.03 (t, 1H, J ) 7.3 Hz), 7.29 (d, 1H, J ) 8.3
cm-1 1H NMR (CDCl3, 600 MHz) δ 1.52-1.64 (m, 1H),
;
1.81-1.89 (m, minor), 1.89-1.97 (m, minor), 2.10-2.08 (m, 1H),
2.12 (s, minor), 2.16 (s, 3H), 2.44-2.58 (m, 4H), 2.63-2.72 (m,
1H), 2.74 (dd, 1H, J ) 13.3 and 2.9 Hz), 3.01 (dd, minor, J )
14.3 and 3.8 Hz), 3.80-3.94 (m, 2H), 4.81 (dd, 1H, J ) 12.4 and
2.9 Hz), 4.85 (dd, minor, J ) 11.4 and 2.9 Hz), 4.96 (dd, minor,
J ) 14.3 and 2.9 Hz), 5.15 (d, 1H, J ) 6.7 Hz), 5.24 (d, 1H, J )
18.1 Hz), 5.36 (d, 1H, J ) 18.1 Hz), 6.91 (d, 2H, J ) 7.6 Hz),
7.17-7.30 (m, 6H), and 7.55 (d, 1H, J ) 7.6 Hz); 13C NMR
(CDCl3, 150 MHz) δ 20.2, 29.3, 30.0, 40.8, 47.1, 47.4, 49.3, 50.2,
55.3, 105.6, 110.1, 118.7, 120.3, 123.1, 125.4, 125.7, 127.9, 129.0,
129.1, 136.5, 137.8, 167.6, 206.1, and 207.8; HRMS calcd for
[C26H26N2O3 + H+] 415.2016, found 415.2010.
13-Benzyl-3,4,4a,5,8,13,13b,14-octahydroindolo[2′,3′:3,4]pyrido-
[1,2-b]isoquinoline-2,7-dione (34). To a solution of 0.05 g (0.12
mmol) of the above compound in 52 mL of CH2Cl2 was added
0.009 mL (0.10 mmol) of pyrrolidine and 0.006 mL (0.10 mmol)
of AcOH. The resulting solution was stirred for 68 h and was then
concentrated under reduced pressure. The residue was purified using
flash silica gel chromatography to furnish 0.04 g (78%) of the titled
compound 34 as a yellow solid: mp 195-196 °C; IR (neat) 1713,
1
1668, 1464, 1454, 1246, and 1191 cm-1; H NMR (CDCl3, 400
MHz) δ 2.16-2.22 (m, 1H), 2.27-2.38 (m, 3H), 2.42 (t, 1H, J )
12.4 Hz), 2.50 (dt, 1H, J ) 17.2 and 3.8 Hz), 2.55 (dd, 1H, J )
14.3 and 1.9 Hz), 2.60-2.68 (m, 1H), 3.79 (dd, 1H, J ) 21.0 and
1.9 Hz), 3.88 (dd, 1H, J ) 21.0 and 1.9 Hz), 4.63 (dd, 1H, J )
12.4 and 2.9 Hz), 5.06 (dd, 1H, J ) 13.3 and 5.7 Hz), 5.31 (d, 1H,
(39) Sza´ntay, C.; Honty, K.; Toke, L.; Szabo, L. Chem. Ber. 1976, 109, 1737.
3498 J. Org. Chem. Vol. 74, No. 9, 2009

Total Synthesis of (()-Yohimbenone
Hz), 7.38 (d, 1H, J ) 7.3 Hz), and 10.86 (s, 1H); 13C NMR (DMSO-
d6, 150 MHz) δ 21.5, 25.6, 36.3, 36.6, 38.2, 51.7, 58.9, 60.9, 106.7,
111.1, 117.7, 118.5, 120.7, 124.6, 126.5, 134.7, 136.1, 163.6, and
198.6.
Supporting Information Available: 1H and 13C NMR data
of various key compounds lacking CHN analyses together with
an ORTEP drawing for compound 27 as well as the corre-
sponding CIF file. Atomic coordinates for compound 27 will
be deposited with the Cambridge Crystallographic Data Centre.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The financial support provided by the
National Science Foundation (CHE-0742663) is greatly ap-
preciated. We thank our colleague, Dr. Kenneth Hardcastle, for
his assistance with the X-ray crystallographic studies.
JO9003579
J. Org. Chem. Vol. 74, No. 9, 2009 3499