Asymmetric construction of a quaternary carbon center by tandem [4 + 2]/[3 + 2] cycloaddition of a nitroalkene. The total synthesis of (-)-mesembrine

Article abstract of DOI:10.1021/jo970079z

An efficient, total synthesis of the Sceletium alkaloid (-)-mesembrine is accomplished in seven steps and 19% yield from a functionalized nitroalkene (itself prepared in six steps and 34% yield from ethyl 3-bromopropionate). The construction of the octahydroindole framework of mesembrine features a tandem inter [4 + 2]/intra [3 + 2] cycloaddition of a 2,2-disubstituted 1-nitroalkene and a chiral vinyl ether derived from (1R,2S)-2-(1-methyl-1-phenylethyl)cyclohexanol as the central strategic element. The two stereogenic centers of the natural product, which include a benzylic, quaternary center, were established in 26/1 selectivity in the tandem process.

Full text of DOI:10.1021/jo970079z

J . Org. Chem. 1997, 62, 1675-1686
1675
Asym m etr ic Con str u ction of a Qu a ter n a r y Ca r bon Cen ter by
Ta n d em [4 + 2]/[3 + 2] Cycloa d d ition of a Nitr oa lk en e. Th e Tota l
Syn th esis of (-)-Mesem br in e
Scott E. Denmark* and Lawrence R. Marcin
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
Received J anuary 15, 1997X
An efficient, total synthesis of the Sceletium alkaloid (-)-mesembrine is accomplished in seven
steps and 19% yield from a functionalized nitroalkene (itself prepared in six steps and 34% yield
from ethyl 3-bromopropionate). The construction of the octahydroindole framework of mesembrine
features a tandem inter [4 + 2]/intra [3 + 2] cycloaddition of a 2,2-disubstituted 1-nitroalkene and
a chiral vinyl ether derived from (1R,2S)-2-(1-methyl-1-phenylethyl)cyclohexanol as the central
strategic element. The two stereogenic centers of the natural product, which include a benzylic,
quaternary center, were established in 26/1 selectivity in the tandem process.
In tr od u ction
The tandem [4 + 2]/[3 + 2] cycloaddition of nitroal-
kenes is emerging as an excellent method for the rapid
construction of useful polycyclic, nitrogen-containing ring
systems.1 A number of inter- and intramolecular vari-
ants of the tandem sequence have been explored which
provide access to structural frameworks contained within
pyrrolidine,2 pyrrolizidine,3 Amaryllidaceae,4 and Scele-
tium5 alkaloids. Recent reports from these laboratories
have described efficient total syntheses of several pyr-
rolizidine alkaloids including (-)-hastanecine,6 (-)-ros-
marinecine,7 (-)-crotanecine,8 and (-)-platynecine.9 These
syntheses have served to establish the viability of the
tandem cycloaddition approach to pyrrolizidines by in-
corporating the requisite functional groups, and by
demonstrating the ability to set all of the critical stereo-
genic centers.
One of the many structural and stereochemical chal-
F igu r e 1. Several cis-3a-aryloctahydroindole-based natural
lenges which can be addressed by the tandem cycload-
dition is the ability to incorporate quaternary stereogenic
centers at a carbon â to the nitrogen atom. This is a
feature common to many octahydroindole-based alka-
loids. Indeed, a large number of structurally complex and
biologically interesting alkaloids possess this core nucleus,
such as the Amaryllidaceae alkaloids crinine, pretazzet-
tine, and amabiline as well as the Sceletium alkaloid A-4,
Figure 1.
products.
Sch em e 1
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
(2) (a) Attygalle, A. B.; Morgan, D. E. Chem. Soc. Rev. 1984, 13,
245. (b) Massiot, G.; Delaude, C. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1986; Vol. 27, Chapter 3. (c) Numata, A.;
Ibuka, T. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York,
1987; Vol. 31, Chapter 6.
(3) (a) Leonard, N. J . In The Alkaloids; Manske, R. H. F., Ed.;
Academic: New York, 1960; Vol. 6, Chapter 3. (b) Naturally Occurring
Pyrrolizidine Alkaloids; Rizk, A.-F. M., Ed.; CRC: Boston, 1991. (c)
Robins, D. J . Nat. Prod. Rep. 1992, 9, 313 and references to earlier
installments.
(4) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic: New
York, 1987; Vol. 30, Chapter 3.
As a vehicle to showcase the tandem method and also
guide the development of variants, we selected the
Sceletium alkaloid mesembrine (1) as a target for total
synthesis, Scheme 1. We had envisioned that the cis-
octahydroindole skeleton of mesembrine could be ef-
fectively constructed through a tandem inter [4 + 2]/intra
[3 + 2] cycloaddition of an appropriately functionalized
nitroalkene followed by a reduction of the resulting
nitroso acetal and cleavage of the C(7) hydroxymethyl
(5) (a) J effs, P. W. In The Alkaloids, Rodrigo, R. G. A., Ed.;
Academic: New York, 1981; Vol. 19, Chapter 1. (b) Lewis, J . R. Nat.
Prod. Rep. 1995, 12, 339 and references to earlier installments.
(6) Denmark, S. E.; Thorarensen, A. J . Org. Chem. 1994, 59, 5672.
(7) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J . Am. Chem.
1996, 118, 8266.
(8) Denmark, S. E.; Thorarensen, A. J . Am. Chem. Soc. 1997, 119,
125.
(9) Denmark, S. E.; Parker, D. L. J r.; Dixon, J . A. J . Org. Chem.
1997, 62, 435.
S0022-3263(97)00079-0 CCC: $14.00 © 1997 American Chemical Society

1676 J . Org. Chem., Vol. 62, No. 6, 1997
Denmark and Marcin
Sch em e 2
residue. Previously, we had documented the construction
of six-membered carbocycles by the use of a three-atom
tether between the nitronate and the dipolarophile.10
However, the synthesis of mesembrine would require the
incorporation of a ketone or carbonyl equivalent in the
tether. Additionally, the use of a nonracemic, chiral vinyl
ether in the [4 + 2] cycloaddition allows for an asym-
metric synthesis of natural mesembrine to be realized.
In the following report we detail our efforts to develop
an asymmetric [4 + 2] cycloaddition of a 2,2-disubstituted
1-nitroalkene with various chiral vinyl ethers. This
method has been effectively coupled to an intramolecular
[3 + 2] cycloaddition to serve as the key step in a total
synthesis of natural (-)-mesembrine.
S. strictum, and S. tortuosum.5a Structural investigations
began in 1957, when it was revealed that mesembrine
contains a ketone, a tertiary amine, and two methoxy
substituents.16 In 1960 the complete structure was
elucidated by Popelak and co-workers through a combi-
nation of degradation and synthetic methods.17
The absolute configuration of natural (-)-mesembrine
remained unassigned until 1969, when J effs and co-
workers proposed a (3aS,7aS) configuration through the
comparison of circular dichroism spectra of mesembrine
to closely related natural products.18 In 1971, the first
asymmetric synthesis of enantiomerically enriched mesem-
brine was accomplished.19a Unfortunately, the authors
prepared (+)-(3aR,7aR) mesembrine which proved to be
the unnatural antipode. Thus, J effs’s original proposal
of a (3aS,7aS) configuration was indeed correct.
Tota l Syn th eses of Mesem br in e. Although pure
mesembrine was found to be void of interesting biological
activity, it has received an enormous amount of attention
from synthetic chemists for the past three decades.
Primarily, it has provided a touchstone for the develop-
ment of new synthetic methods and the application of
existing technology. In all, 12 total syntheses of racemic
mesembrine have been reported,20 as well as three formal
syntheses.21 The first total synthesis was reported in
1965 and involved a synthetic sequence of 20 steps which
afforded the racemic natural product in ∼3% overall
yield.20a Remarkably, racemic mesembrine can now be
prepared in a minimum of three steps20c,n and as high as
40% overall yield from commercially available materials.20j
Ba ck gr ou n d
3,3-Disu bstitu ted P yr r olid in es. The creation of
quaternary stereogenic centers in enantiomerically en-
riched form remains a serious challenge in organic
synthesis, and methods to effectively accomplish this
endeavor are still needed.11 Accordingly, we envisioned
the possibility of using 2,2-disubstituted 1-nitroalkenes
as heterodiene components in asymmetric [4 + 2] cy-
cloadditions with chiral vinyl ethers.12 The resulting
nitronates, containing a newly created quaternary car-
bon, would be useful intermediates for the synthesis of
interesting heterocyclic compounds which incorporate
this feature.
Toward this goal, we have previously developed a
general method for the expedient synthesis of 2,2-
disubstituted 1-nitroalkenes from readily available ma-
terials.13 These hindered nitroalkenes were found to
undergo Lewis acid-promoted [4 + 2] cycloadditions with
n-butyl vinyl ether to afford the corresponding cyclic
nitronates as anomeric mixtures in good yield.14 Another
report from these laboratories has described the use of
2,2-disubstituted 1-nitroalkenes as heterodiene compo-
nents in the synthesis of 3-hydroxy 4,4-disubstituted
pyrrolidines.15 Significantly, this report contains an
example of an effective asymmetric [4 + 2] cycloaddition
of a 2,2-disubstituted 1-nitroalkene and a chiral, nonra-
cemic 2-(acyloxy)vinyl ether, Scheme 2. The resulting
nitronate was then reduced to afford the corresponding
pyrrolidine in enantiomerically enriched form (96% ee).
Thus, among the many challenges that we needed to
address for the synthesis of (-)-mesembrine, one of the
most critical was to demonstrate that the cycloaddition
could tolerate functionalized precursors and deliver cy-
cloadducts in high yield and selectivity.
(16) Bodendorf, K.; Kreiger, W. Arch. Pharm. Ber. Dtsch. Pharm.
Ges. 1957, 290, 441.
(17) (a) Popelak, A.; Haack, E.; Lettenbaur, G.; Springer, H. Natur-
wissenschaften 1960, 47, 156. (b) Popelak, A.; Haack, E.; Lettenbaur,
G.; Springer, H. Naturwissenschaften 1960, 47, 231.
(18) J effs, P. W.; Hawks, R. L.; Farrier, D. S. J . Am. Chem. Soc.
1969, 91, 3831.
Histor y, Isola tion , a n d Str u ctu r e Deter m in a tion
of Mesem br in e. The alkaloid mesembrine is an octahy-
droindole-based natural product that can be isolated in
amounts of up to 1% (of the dried weight) from certain
plants of the Sceletium genus, namely S. namaquense,
(19) For total syntheses of (+)-mesembrine see: (a) Yamada, S.;
Otani, G. Tetrahedron Lett. 1971, 12, 1133. (b) Kosugi, H.; Miura, Y.;
Kanna, H.; Uda, H. Tetrahedron Asymmetry 1993, 4, 1409. (c) Meyers,
A. I.; Hanreich, R.; Wanner, K. T. J . Am. Chem. Soc. 1985, 107, 7776.
(20) (a) Shamma, M.; Rodriquez, H. R. Tetrahedron Lett. 1965, 6,
4847. (b) Shamma, M.; Rodriquez, H. R. Tetrahedron 1968, 24, 6583.
(c) Curpney, T. J .; Kim, H. L. Tetrahedron Lett. 1968, 9, 1441. (d)
Stevens, R. V.; Wentland, M. P. J . Am. Chem. Soc. 1968, 90, 5580. (e)
Keely, S. L., J r.; Tahk, F. C. J . Am. Chem. Soc. 1968, 90, 5584. (f)
Oh-ishi, T.; Kugita, H. Tetrahedron Lett. 1968, 9, 5445. (g) Oh-ishi,
T.; Kugita, H. Chem. Pharm. Bull. 1970, 18, 291. (h) Oh-ishi, T.;
Kugita, H. Chem. Pharm. Bull. 1970, 18, 299. (i) Wijnberg, J . B. P. A.;
Speckamp, W. N. Tetrahedron 1978, 34, 2579. (j) Martin, S. F.;
Puckette, T. A.; Colapret, J . A. J . Org. Chem. 1979, 44, 3391. (k)
Sanchez, I. H.; Tallabs, F. R. Chem. Lett. 1981, 891. (l) Takano, S.;
Imamura, Y.; Ogasawara, K. Chem. Lett. 1981, 1385. (m) Keck, G. E.;
Webb, R. R., II. J . Org. Chem. 1982, 47, 1302. (n) Kochhar, K. S.;
Pinnick, H. W. Tetrahedron Lett. 1983, 24, 4785. (o) Winkler, J . D.;
Muller, C. L.; Scott, R. D. J . Am. Chem. Soc. 1988, 110, 4831.
(21) (a) J effs, P. W.; Redfearn, R.; Wolfrom, J . J . Org. Chem. 1983,
48, 3861. (b) Gramain, J .-C.; Remuson, R. Tetrahedron Lett. 1985, 26,
4083. (c) Hackett, S.; Livinghouse, T. J . Org. Chem. 1986, 51, 1629.
(10) Denmark, S. E.; Senanayake, C. B. W. Tetrahedron 1996, 52,
11579.
(11) (a) Martin, S. F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem.
Rev. 1993, 93, 2037. (c) Barta, N. S.; Brode, A.; Stille, J . R. J . Am.
Chem. Soc. 1994, 116, 6201.
(12) The use of chiral vinyl ethers in the cycloaddition of (E)-2-
substituted and (E)-1,2-disubstituted 1-nitroalkenes is extrememly
effective in providing enantiomerically enriched cycloadducts in good
yield and with high diastereocontrol. For examples see footnotes 1 and
28 as well as: Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1995, 60,
3221.
(13) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3850.
(14) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3857.
(15) Denmark, S. E.; Schnute, M. E. J . Org. Chem. 1994, 59, 4576.

Total Synthesis of (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 6, 1997 1677
Ta ble 1. Asym m etr ic [4 + 2] Cycloa d d ition s of a Mod el
Seven total syntheses of enantiomerically enriched
mesembrine have been accomplished.19,22 These seven
are supplemented with four formal syntheses in nonra-
cemic form.23 The most efficient asymmetric synthesis
of mesembrine can be credited to Meyers and co-
workers.19c These authors were able to prepare un-
natural (+)-mesembrine (>99% ee) in nine steps and in
23% overall yield from (3,4-dimethoxyphenyl)acetic acid.
Nitr oa lk en e
Resu lts
Asym m etr ic [4 + 2] Cycloa d d ition of a Nitr oa lk -
en e Mod el System . The veratryl-derived nitroalkene
2 was selected as a model diene to address the feasibility
of creating a quaternary stereogenic center in an asym-
metric [4 + 2] cycloaddition, Table 1.24 This nitroalkene
was chosen because it closely resembles the substitution
pattern and electronic nature of the specific nitroalkene
that would be suitable for the synthesis of mesembrine.
Cycloaddition results of the model nitroalkene with
the chiral vinyl ethers derived from (R)-2,2-diphenyl-
cyclopentanol (DPC),25 (1R,2S)-2-phenylcyclohexanol
(PCH),26 and (1R,2S)-2-(1-methyl-1-phenylethyl)cyclo-
hexanol (TCC)27 are summarized in Table 1. All of these
chiral vinyl ethers have been found to be highly effective
in asymmetric [4 + 2] cycloadditions involving (E)-2-
substituted 1-nitroalkenes.28 A survey of Lewis acids
revealed that only methylaluminum bis(2,6-di-tert-butyl-
4-methylphenoxide) (MAD)29 and methylaluminum bis-
(4-bromo-2,6-diphenylphenoxide) (MABr) were useful in
promoting cycloadditions of the model substrate.30 Cy-
cloadditions of either the pure (Z)- or (E)-nitroalkenes
with the chiral vinyl ether derived from DPC in the
presence of 3 equiv of MAD unselectively afforded ternary
mixtures of diastereomeric nitronates 3 in similar ratios,
Table 1, entries 1 and 2. The use of MABr as the Lewis
acid promoter provided no improvement in the diaste-
reoselectivity of the reaction, entry 3. Cycloaddition of
(Z)-2 with the chiral vinyl ether derived from PCH
afforded an equal mixture of two nitronate diastereomers
in 86% yield, entry 4. When using the TCC-derived
chiral vinyl ether, the (E)-nitroalkene, and MABr as the
alkene
geometry
Lewis
acid a
yield,
%
diastereomeric
ratiob
entry
G*
1
2
3
4
5
6
7
Z
E
Z
Z
E
Z
Z
MAD
MAD
MABr
MAD
MABr
MADc
MADc
DPC
DPC
DPC
PCH
TCC
DPC
TCC
73
48
nd
86
76
78
79
1.5/1.0/1.9
1.9/1.0/1.4
1.7/1.7/1.0
1/1
3.8/1.0
2.7/2.1/1.0
4/1
a
The Lewis acid was introduced to a solution of nitroalkene
and vinyl ether at 0 °C. b Determined by 1H NMR integration.c The
Lewis acid was added to a solution of the nitroalkene at 0 °C and
allowed to stir for 15-60 min before introduction of the chiral vinyl
ether.
Sch em e 3
Lewis acid promoter, a 3.8/1.0 diastereomeric mixture of
two nitronates was obtained, entry 5.
To obtain more stereochemical information about the
asymmetric cycloaddition, a control experiment was
performed in which a sample of pure (Z)-2 was subjected
to the reaction conditions and then reisolated, Scheme
3. Analysis of the recovered nitroalkene revealed that
isomerization to an 11/1 (E/Z) mixture of isomers had
occurred.31 This interesting result prompted more cy-
cloaddition experiments in which the nitroalkene was
preequilibrated with the Lewis acid for 15-60 min prior
to introduction of the chiral vinyl ether. Interestingly,
when this modified protocol was employed, no significant
change in diastereoselectivity was observed, Table 1,
entries 6 and 7.
The stereostructures of the various diastereomers
generated in the asymmetric cycloadditions could not be
unambiguously assigned through routine spectroscopic
methods. Thus, chemical transformation of the diaste-
reomerically enriched nitronates 3 into an enantiomeri-
cally enriched 3,3-disubstituted pyrrolidine 4 was per-
formed, Table 2. Reduction was accomplished with
hydrogen and a catalytic amount of platinum oxide in
the presence of 1 equiv of acetic acid according to the
developed method.14 Reaction of the crude hydrogenoly-
(22) For total syntheses of natural (-)-mesembrine see: (a) Strauss,
H. F.; Weichers, A. Tetrahedron Lett. 1979, 20, 4495. (b) Takano, S.;
Imamura, Y.; Ogasawara, K. Tetrahedron Lett. 1981, 22, 4479. (c)
Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett. 1990, 1239. (d)
Yoshimitsu, T.; Ogasawara, K. Heterocycles 1996, 42, 135.
(23) (a) Bauermeister, S.; Gouws, I. D.; Strauss, H. F.; Venter, E.
M. M. J . Chem. Soc., Perkin Trans. 1 1991, 561. (b) Yokomatsu, T.;
Iwasawa, H.; Shibuya, S. Tetrahedron Lett. 1992, 33, 6999. (c) Nemoto,
H.; Tanabe, T.; Fukumoto, K. Tetrahedron Lett. 1994, 35, 6499. (d)
Nemoto, H.; Tanabe, T.; Fukumoto, K. J . Org. Chem. 1995, 60, 6785.
(24) For the preparation of nitroalkene 2 see reference 13.
(25) Denmark, S. E.; Marcin, L. R.; Schnute, M. E.; Thorarensen,
A. Org. Synth. 1996, 74, 33.
(26) Schwartz, A.; Madan, P.; Whitesell, J . K.; Lawrence, R. M. Org.
Synth. 1990, 69, 1.
(27) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656.
(28) (a) Denmark, S. E.; Senanayake, C. B. W.; Ho, G.-D. Tetrahe-
dron 1990, 46, 4857. (b) Denmark, S. E.; Schnute, M. E. J . Org. Chem.
1991, 56, 6738. (c) Denmark, S. E.; Senanayake, C. B. W. J . Org. Chem.
1993, 58, 1853. (d) Denmark, S. E.; Schnute, M. E.; Senanayake, C.
B. W. J . Org. Chem. 1993, 58, 1859. (e) Denmark, S. E.; Schnute, M.
E.; Marcin, L. R.; Thorarensen, A. J . Org. Chem. 1995, 60, 3205. (f)
Denmark, S. E.; Stolle, A.; Dixon, J . A.; Guagnano, V. J . Am. Chem.
Soc. 1995, 117, 2100.
(29) (a) Maruoka, K.; Yamamoto, H. Tetrahedron 1988, 44, 5001.
(b) Maruoka, K.; Itoh, T.; Yamamoto, H. J . Am. Chem. Soc. 1985, 107,
4573. (c) Maruoka, K.; Oishi, M.; Shiohara, K.; Yamamoto, H Tetra-
hedron 1994, 50, 8983.
(31) Isomerization can also be achieved using DMAP in methylene
chloride. Starting from either the pure (Z)- or (E)-nitroalkene, a
mixture of nitroalkenes isomers was recovered in approximately a 5/1
(E/Z) ratio in 53% yield. The rest of the material consisted of a mixture
of nitroalkenes in which the olefin had isomerized away from the nitro
substituent.
(30) Other Lewis acids, including Ti(Oi-Pr)2Cl2, SnCl4, BF3‚OEt2,
EtAlCl2, methylaluminum(bis-2,6-diisopropylphenoxide) (MAIPh), and
methyl aluminum bis(2,6-diphenylphenoxide) (MAPh) were found to
be ineffective in promoting the desired cycloaddition.

1678 J . Org. Chem., Vol. 62, No. 6, 1997
Denmark and Marcin
Ta ble 2. Red u ction of Dia ster eom er ic Nitr on a te
Mixtu r es
Sch em e 5
diastereomeric
G*
ratio of 3
yield of 4, %
ee of 4, % a
(R)-DPC
(1R,2S)-TCC
2.7/2.1/1.0
4/1
80
83
6
56
a
Determined by chiral HPLC analysis (Diacel Chiralpak AD
column).
Sch em e 4
Sch em e 6
sis products with p-toluenesulfonyl chloride and trieth-
ylamine afforded the corresponding N-protected pyrro-
lidine 4. In the reduction of a 2.7/2.1/1.0 diastereomeric
mixture of DPC-derived nitronates, the protected pyrro-
lidine 4 was isolated in 80% yield and was found to be of
6% enantiomeric excess (ee) by chiral HPLC analysis.
Reduction of a 4/1 mixture of TCC-derived nitronates
afforded the same pyrrolidine in 83% yield and 56% ee.
Although the results from the model system were less
than encouraging, we did learn that a TCC-based aux-
iliary in connection with MAD as the Lewis acid gave
the highest yield and best selectivity in asymmetric [4 +
2] cycloadditions. We next moved forward to investigate
cycloadditions of the actual nitroalkene that could be
used for the total synthesis of mesembrine.
Syn th esis of th e Ta n d em Cycloa d d ition P r ecu r -
sor . A conjugated nitroalkene that would be suitable for
the synthesis of mesembrine must possess a ketone or
latent ketone functionality on the third carbon atom of
the dipolarophile tether, Scheme 4. After suspecting that
an unprotected enone might compromise the nitroalkene
hetero-Diels-Alder reaction, we chose to pursue the
preparation of a ketal-protected substrate. This was
envisioned to be available from an (E)-2-substituted
1-nitroalkene and a functionalized alkyl cuprate.
73% combined yield. The mixture was separated by
column chromatography on basic alumina (activity II),
and the dibromide 8 was resubjected to the reaction
conditions. After being heated to reflux for an additional
2.5 days, a 1.0/3.7 (8/9) mixture of products was afforded
in 72% yield. From this mixture, the pure vinyl dioxane
9 was isolated in 58% yield after column chromatography.
Thus, the desired vinyl ketal 9 could be obtained in 64%
overall yield from 1,5-dibromopentan-3-one (7) through
ketalization and one recycling step.
Reaction of the bromo ketal 9 with sodium iodide in
refluxing acetone afforded the corresponding iodide 10
in 89% yield, Scheme 6. Treating the iodide with
activated zinc, followed by transmetalation with copper
cyanide in the presence of lithium chloride provided the
intermediate organocopper species. This reagent added
in a 1,4-conjugate fashion to (E)-2-(3,4-dimethoxyphenyl)-
1-nitroethene (11)33 to afford, after trapping with phen-
ylselenenyl bromide, the corresponding nitro selenide 12.
Oxidation and elimination of the selenide was accom-
plished with aqueous hydrogen peroxide in THF at room
temperature. The desired nitroalkene 13 was obtained
in 72% overall yield (from 10) as a 1.0/1.5 (E/Z) mixture
of geometric isomers.
According to the literature procedure,32 ethylmagne-
sium bromide was added to a solution of ethyl 3-bro-
mopropionate (5) in the presence of a catalytic amount
of Ti(Oi-Pr)4 to afford the cyclopropanol 6, Scheme 5.
Treatment of the cyclopropanol with N-bromosuccinimide
(NBS) provided 1,5-dibromopentan-3-one (7) in 82%
overall yield. Ketalization of the dibromo ketone with
2,2-dimethyl-1,3-propanediol provided a mixture of the
dibromide 8 and the vinyl dioxane 9. The ratio of the
products was observed to be dependent on the duration
of heating. A larger amount of the desired vinyl deriva-
tive was produced when the reaction was maintained at
reflux for longer periods of time. Thus, after heating for
2.5 days, a 1.0/2.3 mixture (8/9) could be obtained in a
Syn th esis of Mesem br in e. Since we were concerned
that the poor ratio of E/Z-isomers in 13 would presage a
low diastereoselectivity in the [4 + 2] cycloaddition, a
number of Lewis acid-assisted E/Z-isomerization experi-
ments were conducted. As shown in Table 3, no change
(32) Sviridov, S. V.; Vasilevskii, D. A.; Kulinkovich, O. G. Zh. Org.
Khim. 1991, 27, 1431.
(33) Sheth, J . P.; Bhattacharyya, S. C. Indian J . Chem. 1977, 15B,
595.

Total Synthesis of (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 6, 1997 1679
Ta ble 3. Lew is Acid -Assisted Isom er iza tion of
Nitr oa lk en e 13
Ta ble 4. Op tim iza tion of th e Asym m etr ic [4 + 2]
Cycloa d d ition
in-situ
E/Z ratioa
of 13
isomerization,
yield of diastereomeric
entry
time (procedure)b
17, %
ratioa of 17
Lewis acid,
equiv
time,
min
recovery
of 14, %
ratio,
1
2
3
4
5
∼1/1
∼1/1
∼1/1
26/1
∼1/1
no (A)
91
76
78
83
84
7/1
13/1
15/1
18/1
26/1
entry
E/Za
yes, 2 h (B)
yes, 30 min (C)
no (D)
1
2
3
4
0.10
0.75
1.00
1.00
240
60
15
94
90
93
94
1/1.3
6.3/1.0
12/1.0
23/1.0
yes, 5 m in (E)
a
Determined by 1H NMR integrations (400 MHz). b Procedures:
(A) Slow addition of MAD (2 equiv) over 1 h to vinyl ether and
nitroalkene. (B) Addition of MAD (1 equiv) to nitroalkene, stir 2
h, and then add vinyl ether and more MAD (1 equiv). (C) Addition
of MAD (2 equiv), stir 30 min, and then add vinyl ether. (D) Slow
addition of MAD (2 equiv) over 2 h to vinyl ether and nitroalkene.
(E) Addition of MAD (1 equiv) to nitroalkene, stir 5 min, introduce
vinyl ether, stir 1 h, and then slowly added more MAD (1 equiv)
over 1 h.
120
Determined by 1H NMR integration (400 MHz) of the vinylic
proton R to the nitro group.
a
Sch em e 7
variables in all the experiments were held constant.
First, 2 equiv of Lewis acid was deemed necessary for
the reaction to reach completion. Second, the reactions
proceeded at a reasonable rate (2 h) and afforded the best
selectivity when conducted at -10 °C. Lastly, the use of
3 equiv of the chiral vinyl ether was required to achieve
respectable yields. With these criteria fixed, manipula-
tion of other experimental details were explored, Table
4. Simply adding the Lewis acid slowly over 1 h to a
solution of the nitroalkene 13 and vinyl ether 16 provided
a 7/1 mixture of diastereomeric nitronates 17 in 91%
yield, entry 1. This selectivity is significantly better than
that of the model nitroalkene (∼4/1). Preequilibrating
the nitroalkene with 1 equiv of MAD for 2 h and then
adding the vinyl ether along with another 1 equiv of MAD
afforded a 13/1 mixture of diastereomers in 76% yield,
entry 2. The use of 2 equiv of the Lewis acid in a brief
isomerization (30 min) provided the nitronate in 78%
yield as a 15/1 mixture of diastereomers, entry 3.
Interestingly, if nearly pure (E)-13 was used with no in-
situ isomerization, the [4 + 2]-cycloadduct could be
obtained in good yield (83%) and high selectivity (18/1),
entry 4. After extensive optimization, a satisfactory
protocol that provided the highest yield and best diaste-
reoselectivity was developed, entry 5. Thus, the (E/Z)-
nitroalkene mixture was treated with 1 equiv of MAD
and was allowed to stir for 5 min, and then the chiral
vinyl ether was introduced. After 1 h, an additional 1
equiv of MAD was slowly added to drive the reaction to
completion. This protocol reproducibly provided the
desired [4 + 2]-cycloadduct in 82-86% yield and 25-29/1
diastereoselectivity.
in the E/Z ratio was observed when a 1/1 mixture of
nitroalkene isomers was stirred in toluene for 4 h in the
presence of 10 mol % of MAD, entry 1. However,
enrichment to a 6.3/1.0 (E/Z) ratio was observed after 1
h when 75 mol % of the Lewis acid was used, entry 2.
Interestingly, when using 1 equiv of MAD, rapid equili-
bration to a 12/1.0 (E/Z) ratio occurred in 15 min, entry
3. Under these same conditions for 2 h, a 23/1 (E/Z)
mixture of nitroalkene isomers was obtained. It should
be noted that, in all of the isomerization experiments,
except entry 1, the reisolated nitroalkene was contami-
nated with a small amount (<5%) of a common byprod-
uct. 1H NMR analysis suggested structure 14 in which
the olefin has shifted out of conjugation with the nitro
substituent.
Cycloadditions of the functionalized nitroalkene with
the chiral vinyl ether derived from TCC were investi-
gated. The choice of auxiliary was based on the observa-
tion that the TCC vinyl ether provided the highest levels
of diastereoselectivity (∼4/1) in [4 + 2] cycloadditions
with the model nitroalkene. The chiral vinyl ether (-)-
16 was readily prepared in 73% yield from the corre-
sponding alcohol (-)-15 through a mercury-catalyzed
transetherification in refluxing n-butyl vinyl ether, Scheme
7.34
Since the functionalized nitroalkene 13 undergoes
rapid equilibration to the E-isomer in the presence of
MAD, efforts were focused on developing an in-situ
isomerization/[4 + 2] cycloaddition protocol. While sev-
eral procedural variations were explored to optimize the
yield and diastereoselectivity of this reaction, three
The configurational assignments for the [4 + 2]-cy-
cloadduct 17 could not be secured through routine
methods, but are based on the results from analogous
tandem cycloadditions from these laboratories.7b,34 Ul-
timately, the absolute configuration of the quaternary
center was unambiguously proven by conversion of the
nitronate into natural (-)-mesembrine.
(34) (a) Denmark, S. E.; Thorarensen, A. J . Org. Chem. 1996, 61,
6727. (b) The TCC vinyl ether 16 has been found to undergo highly
selective exo-mode [4 + 2] cycloadditions when using the aluminum-
based Lewis acid MAPh.

1680 J . Org. Chem., Vol. 62, No. 6, 1997
Denmark and Marcin
Sch em e 8
Sch em e 10
N-methylated amino alcohol 22 in 81% yield, Scheme 10.
The intermediate could be isolated and purified using
silica gel column chromatography and was assigned to
be the corresponding tricyclic aminal 21.
Sch em e 9
The removal of the unnecessary hydroxymethyl group
in 22 by oxidation to the corresponding amino acid 23
proved impossible. Unsuccessful methods included J ones
reagent (CrO3/H2SO4/acetone),36a chromic acid (CrO3/H2-
SO4/HOAc),36b pyridinium dichromate (PDC) in dimeth-
ylformamide (DMF),36c ruthenium trichloride with so-
dium periodate,36d purple benzene (KMnO4/n-Bu4NBr/
C6H6),36e and platinum oxide with oxygen.36f In most
cases an impure mixture of starting material and inter-
mediate aldehyde was reisolated, but this typically
Tandem, intramolecular [3 + 2]-dipolar cycloaddition
of the nitronate 17 proceeded smoothly in refluxing
benzene to afford the crystalline tricyclic nitroso acetal
18, as a 30/1 mixture of diastereomers, in 79% overall
yield (from 13), Scheme 8. Recrystallization provided an
analytically pure sample of 18 as a single diastereomer
in 66% yield. The trans assignment for the B-C ring
accounted for less than 50% of the mass balance.
A
reversed approach, involving initial deprotection of the
ketal followed by oxidation of the alcohol also failed.
Reaction of the N-methylamino alcohol 22 with 50% TFA,
at room temperature for 8 h, provided the undesired
enone 24 in modest yield (55%).
We next assayed the possibility of removing the
vestigial carbon at the aldehyde oxidation state by
deformylation reactions. Thus, oxidation of the N-
methylamino alcohol 22 with pyridinium chlorochromate
(PCC)37 in methylene chloride provided a compound in
70-75% yield that was tentatively assigned to be the
corresponding aldehyde. Isolation of the pure product,
free from all chromium species, proved to be very difficult.
Many alternative methods to accomplish the same oxida-
tion were examined without success, resulting in the
isolation of varying mixtures of starting material and
product aldehyde in poor yields.38
1
fusion was based on a large H NMR coupling constant
(J a-b ) 12.0 Hz) between the ring protons Ha and Hb.
The cis assignment for the A-B ring fusion is based on
geometrical constraints that only permit the intramo-
lecularly tethered dipolarophile to approach the same
face of the nitronate dipole to which the tether is
connected. Additionally, these stereochemical assign-
ment are in agreement with previous tandem cycloaddi-
tion results from these laboratories involving three-
methylene tethered unactivated dipolarophiles.10
Reduction of the nitroso acetal 18 to the corresponding
amine 19 was accomplished in 74% yield using W2
Raney-nickel catalyst under 300 psi of hydrogen, Scheme
9. The chiral auxiliary (-)-15 was recovered in 91%
yield. A small portion of the amino alcohol 19 was
transformed into its N-p-toluenesulfonamide 20 in 88%
yield. Chiral HPLC analysis of the sulfonamide showed
the product to be enantiomerically enriched to the extent
of >99% ee.35
(35) A racemic sample of the N-protected amine (()-20 that was
needed to establish chiral HPLC conditions was prepared from racemic
vinyl ether (()-16 using a parallel sequence of reactions.
(36) (a) Bowers, A.; Halsall, T. G.; J ones, E. R. H.; Lemin, A. J . J .
Chem. Soc. 1953, 2548. (b) Newman, M. S.; Arkell, A.; Fukunaga, T.
J . Am. Chem Soc. 1960, 82, 2498. (c) Corey, E. J .; Schmidt, G.
Tetrahedron Lett. 1979, 399. (d) Carlsen, P. H. J .; Katsuki, T.; Martin,
V. S.; Sharpless, K. B. J . Org. Chem. 1981, 46, 3936. (e) Herriot, A.
W.; Picker, D. Tetrahderon Lett. 1974, 1511. (f) Marino, J . P.; Pradilla,
R. F.; Laborde, E. J . Org. Chem. 1987, 52, 4898.
Reaction of the amino alcohol 19 with formaldehyde
produced an intermediate that was subsequently reduced
with hydrogen (1 atm) over Raney-nickel to afford the
(37) Herscovici, J .; Egron, M.-J .; Antonakis, K. J . Chem. Soc., Perkin
Trans. 1 1982, 1967.

Total Synthesis of (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 6, 1997 1681
Sch em e 11
Sch em e 12
Ultimately, it was found that an aldehyde, identical
to that from the PCC oxidation, could be obtained in 80%
yield by employing the oxidation method developed by
Mukaiyama (1,1′-(azodicarbonyl)dipiperidine (ADD) and
tert-butoxymagnesium bromide),39 Scheme 11. Subse-
quently it was discovered that the initial structural
assignment was incorrect. Collective spectroscopic data
are more consistent with an isomeric enal structure 25,
in which the dioxane ring had opened.
Discu ssion
Nitr oa lk en e P r ep a r a tion . The ketalization of 1,5-
dibromopentan-3-one (7) with 2,2-dimethylpropanediol
provided an interesting result that is worthy of discus-
sion. The reaction was expected to afford the corre-
sponding dibromoketal 8; however, a mixture of the
dibromoketal and the vinyl dioxane 9 was obtained. This
result was propitious, since it ultimately eliminated a
step in the synthesis of the desired nitroalkene. Forma-
tion of the vinyl derivative 9 may result from an irrevers-
ible elimination of the dibromide 8. A plausible mech-
anism to explain this conversion is presented in Scheme
12.
This proposal is supported by the following observa-
tions: (1) the vinyl compound 9 could be obtained by
resubjecting the purified dibromide 8 to the reaction
conditions, (2) the evolution of acidic vapors from the
reaction was detected using litmus paper, and (3) at-
tempted ketalization of 5-bromo-1-penten-3-one under
the same reaction conditions did not provide any of the
vinyl dioxane 9. Regardless, it is curious as to why the
elimination does not proceed further and eliminate both
bromides to afford the corresponding divinyl ketal.
Nitr oa lk en e Isom er iza tion . The ability to equili-
brate the E/Z-mixture of nitroalkene isomers 13 to
predominantly the E-isomer was critical to the success
of the asymmetric [4 + 2] cycloaddition. Furthermore,
the development of an effective in-situ isomerization was
highly advantageous. In fact, the Lewis acid-promoted
isomerization of a 2,2-disubstituted 1-nitroalkene has
precedent. In related investigations, the isomerization
of pure (Z)-2-(3,4-dimethoxyphenyl)-1-nitrobutene (2) to
a 17/1 (E/Z) isomeric mixture using SnCl4 for 30 min at
-78 °C was documented.15 This result was rationalized
by invoking a reversible conjugate addition of chloride
ion to the nitroalkene-Lewis acid complex. In the
current work, MAD was used to promote the isomeriza-
tion of both the model nitroalkene 2 as well as the
functionalized nitroalkene 13. When using MAD as the
Lewis acid, it is again possible to postulate that the
isomerization could be occurring through a reversible 1,4-
Despite the unanticipated result, the enal 25 proved
to be a suitable intermediate for conversion into mesem-
brine. Reaction of the enal with 60% trifluoroacetic acid,
for 28 h at room temperature, provided a compound that
was presumed to be the enolic â-keto aldehyde 26.40
Following a traditional procedure,41 the alkoxymethylene
group in the unpurified enol intermediate 26 was cleaved
under basic conditions to afford, after chromatography,
94 mg (60%, two steps) of a pure product that was
determined to be identical with a sample of natural
mesembrine.42 An analytically pure sample of the syn-
thetic material was obtained after bulb-to-bulb distilla-
tion under reduced pressure (0.01 Torr/160 °C). The
optical rotation of the synthetic product, [R]D ) -63.3°
(MeOH, c ) 1.13), was in close agreement with values
reported in the literature for natural mesembrine, [R]D
) -55.4°, -59° (MeOH).17,43 Spectral data, including 1H
NMR, 13C NMR, and IR, were collected for both the
natural and synthetic samples and found to be in full
agreement.44
(38) Other methods that were explored included (a) tetrapropylam-
monium perruthenate (TPAP): Griffith, W. P. Aldrichim. Acta 1990,
23, 13. (b) Swern oxidation (oxalyl chloride, DMSO, triethylamine):
Mancuso, A. J .; Brownfain, D. S.; Swern, D. J . Org. Chem. 1979, 44,
4148. (c) Phenyl dichlorophosphate with DMSO and triethylamine:
Liu, H.-J .; Nyangulu, J . M. Tetrahedron Lett. 1988, 29, 3167. (d) PDC
in dichloromethane.38c (e) Dess-Martin periodinane: Dess, D. B.;
Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(39) Narasaka, K.; Morikawa, A.; Saigo, K.; Mukaiyama, T. Bull.
Chem. Soc. J pn. 1977, 50, 2773.
(40) This reaction was optimized using NMR scale experiments (CF3-
CO2D/D2O) that followed the conversion of the starting aldehyde into
a single product.
(41) The alkoxymethylene group has been commonly used as a
blocking group for alkylations of unsymmetrical ketones. J ohnson, W.
S.; Posvic, H. J . Am. Chem. Soc. 1947, 69, 1361.
(42) A sample of the hydrochloride salt of natural mesembrine (∼7
mg) was kindly provided by Professor Steven A. Martin (University of
Texas). Conversion of the hydrochloride salt back to the free amine
was accomplished by passing a chloroform solution of the sample
through a short plug of basic alumina (activity I).
(43) Nieuwenhuis, J . J . M. Sc. Thesis, University of Pretoria, 1971.
(44) A comparison of the 1H and 13C NMR spectra of natural and
synthetic mesembrine is included in the Supporting Information.

1682 J . Org. Chem., Vol. 62, No. 6, 1997
Denmark and Marcin
Sch em e 13
conjugate addition, since in the presence of trace amounts
of oxygen, BHT forms radicals that have been shown to
add conjugatively nitroalkenes.45
P er iselectivity. While an intramolecular [4 + 2]
cycloaddition of nitroalkene 13 to afford the bicyclic
nitronate 27 might be expected to compete with an
intermolecular reaction involving a bulky chiral vinyl
ether, none of the cycloadduct 27 was ever detected,
Scheme 13. This was still the observation when the
nitroalkene was stirred with the Lewis acid, MAD, in the
absence of the vinyl ether for extended periods of time
(∼2 h). Apparently, the tethered olefin is not sufficiently
activated (electron-rich) to participate in an inverse
electron demand [4 + 2] cycloaddition under the reaction
conditions (MAD, toluene, -10 °C). These results are
consistent with previous investigations involving tandem
cycloadditions of nitroalkenes bearing three-methylene
tethered, unactivated olefins.10 In those experiments
exclusive intermolecular [4 + 2] cycloaddition with n-
butyl vinyl ether was observed when Ti(Oi-Pr)2Cl2 was
used as the Lewis acid promoter.
F igu r e 2. Minimized conformations of vinyl ether 16.
Or igin of Dia ster eoselectivity in th e Cycloa d d i-
tion . The stereochemical course of an asymmetric ni-
troalkene [4 + 2] cycloaddition is governed by two
principle criteria: (1) the orientation of the vinyl ether
in its approach to the nitroalkene (exo or endo) and (2)
the stereodifferentiation for one π-face of the nitroalkene
by the chiral vinyl ether.28e We have previously shown
that the vinyl ether derived from TCC has a strong
preference to undergo exo-mode [4 + 2] cycloadditions
with E-2-substituted nitroalkenes when using MAPh as
the Lewis acid promoter.7b,34 This phenomenon has been
attributed to a minimization of steric interactions be-
tween the bulky aluminum-based Lewis acid and the
significantly large chiral auxiliary on the vinyl ether.
Facial selectivity in the [4 + 2] cycloaddition is dictated
by the shape of the chiral auxiliary as well as the reactive
conformation of its vinyl ether, s-cis or s-trans. Molecular
mechanics (MM2) calculations on vinyl ether 16 revealed
two significantly different ground state conformations,
nearly equal in energy, Figure 2.46,47 In the slightly lower
energy conformation (a ), the vinyl ether exists in a
pseudo s-trans geometry, Φ ) 141.09° (the CdCsOsC
dihedral angle is defined as Φ), with the phenyl sub-
stituent providing moderate re-face shielding of the vinyl
group.48 In the slightly higher energy conformation (b),
the vinyl ether is maintained in a near perfect s-cis
geometry (Φ ) -3.48°); however, no significant π-facial
shielding is apparent. Given the high diastereoselectivity
F igu r e 3. Proposed model of the asymmetric [4 + 2] cycload-
dition.
that is observed in the asymmetric [4 + 2] cycloaddition,
it is highly unlikely that the s-cis conformation (b) can
be considered as a reactive species. Moreover, the re-
face shielding in the s-trans conformation (a ) is consistent
with the observed stereochemical course of the reaction.
A model to rationalize the asymmetric cycloaddition
is shown in Figure 3. In this model, it is proposed that
the nitroalkene reacts through the more abundant E-
isomer in an exo-mode [4 + 2] cycloaddition. Since
complete isomerization of the starting nitroalkene to the
E-isomer does not occur, it suspected that the Z-isomer
is considerably less reactive. The chiral vinyl ether is
depicted in a low energy pseudo s-trans conformation and
approaches the si-face of the nitroalkene.49
In tr a m olecu la r [3 + 2] Cycloa d d ition . Intramo-
lecular [3 + 2] cycloadditions of cyclic nitronates bearing
unactivated three-methylene tethered dipolarophiles have
been studied in detail.10 Nitronate 17, lacking a C(3)
substituent, undergoes a rather facile intramolecular [3
(45) Middleton, D. S. Unpublished results, University of Illinois,
Urbana.
(46) The program Macromodel version 3.5a, Columbia University,
was employed for these caculations.
(47) The third lowest energy conformation (s-trans, Erel ) 0.55 kcal/
mol) exhibited very little π-facial shielding.
(48) The si- and re-faces of the enol ether are defined with respect
to the C(1) alkoxy-bearing carbon atom.
(49) The re- and si-faces of the nitroalkene are defined at the
â-carbon atom of the nitroalkene.

Total Synthesis of (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 6, 1997 1683
dried (Na2SO4/MgSO4, 1/1), filtered, and concentrated. The
crude concentrate was purified by column chromatography on
basic alumina (activity II) (hexane/TBME, 30/1) to provide 1.05
1
g of 8 and 2.59 g of a 7/1 mixture (by H NMR integration) of
9 and 8. The 7/1 mixture was separated by column chroma-
tography on basic alumina (activity II) (hexane/TBME, 30/1)
to provide, after bulb-to-bulb distillation, 2.14 g (50%) of 9 as
a clear colorless oil and 0.350 g of 8. An analytical sample of
9 was obtained after further purification using silica gel
column chromatography (hexane/CH2Cl2, 10/1) and bulb-to-
bulb distillation. The two samples of 8 were combined and
further purified by chromatography on basic alumina (activity
II) (hexane/TBME, 30/1) to afford 1.25 g (22%) of 8 as a white
solid. A portion of 8 was recrystallized (hexane) to provide
an analytically pure sample as white needles. Data for 8: mp
49-50 °C (hexane); 1H NMR (400 MHz) 3.48 (s, 4 H), 3.44
(AA′XX′, J AA′ ) -10, J XX′ ) -7, J AX ) 13, J AX′ ) 6, 4 H), 2.29
(AA′XX′, J AA′ ) -10, J XX′ ) -7, J AX ) 13, J AX′ ) 6, 4 H), 0.94
(s, 6 H); 13C NMR (100.6 MHz) 99.01, 70.20, 38.19, 29.51, 26.58,
22.56; IR (CCl4) 1365 (m), 1223 (m), 1112 (s), 1102 (s), 1038
(m); MS (CI, CH4) 329 (M+ + 1, 4); TLC Rf 0.31 (hexane/EtOAc,
20/1). Anal. Calcd for C10H18Br2O2 (327.97): C, 36.39; H, 5.50;
Br, 48.42. Found: C, 36.37; H, 5.38; Br, 48.45. Data for 9:
bp 95 °C (0.3 Torr) (air bath temperature); 1H NMR (400 MHz)
5.67 (dd, J ) 17.8, 11.0, 1 H), 5.43 (dd, J ) 11.0, 1.5, 1 H),
5.39 (dd, J ) 17.6, 1.6, 1 H), 3.59 (d, J ) 11.2, 2 H), 3.53
(AA′XX′, J AA′ ) -10, J XX′ ) -7, J AX ) 13, J AX′ ) 6, 2 H), 3.31
F igu r e 4. Proposed model of the intramolecular [3 + 2]
cycloaddition of 17.
+ 2] cycloaddition as expected. The stereochemical
outcome of this cycloaddition is consistent with an
exclusive preference for an exo-fold of the side chain as
illustrated in Figure 4. The nitronate is depicted in a
half chair conformation and the chiral auxiliary is axially
oriented in order to maintain favorable anomeric stabi-
lization.
Su m m a r y of Syn th esis. The total synthesis of enan-
tiomerically pure (-)-mesembrine (94 mg) was accom-
plished in seven steps and 19% yield from the 2,2-
disubstituted 1-nitroalkene 13, which was prepared in
six steps and 34% yield from commercially available ethyl
3-bromopropionate (5). The benzylic stereogenic center
(C(3a)) in the natural product was established in 26/1
selectivity through an auxiliary-controlled asymmetric [4
+ 2] cycloaddition. Exclusive selectivity in the formation
of C(7a) was achieved through an intramolecular [3 + 2]
cycloaddition.
(dt, J d ) 11.2, J t ) 1.4, 2 H), 2.20 (AA′XX′, J AA′ ) -10, J XX′
)
-7, J AX ) 13, J AX′ ) 6, 2 H), 1.14 (s, 3 H), 0.68 (s, 3 H); 13C
NMR (100.6 MHz) 136.83, 119.88, 99.73, 71.33, 45.23, 30.06,
29.51, 26.95, 22.83, 21.94; IR (CCl4) 2956 (s), 2872 (s), 1172
(s); MS (CI, CH4) 249 (M+ + 1, 31); TLC Rf 0.37 (hexane/EtOAc,
20/1). Anal. Calcd for C10H17BrO2 (248.04): C, 48.21; H, 6.88;
Br, 32.07. Found: C, 48.47; H, 6.99; Br, 31.75.
Con ver sion of 8 in to 9. To a round bottom flask, fitted
with a Dean-Stark trap and a reflux condenser, were added
the dibromide 8 (1.5 g, 4.5 mmol), TsOH‚H2O (43 mg, 0.23
mmol, 5 mol %), and benzene (180 mL). The resulting mixture
was heated to reflux for 2.5 days. During this time, the Dean-
Stark trap (5 mL) was drained approximately every 4-6 h,
and fresh benzene was added to maintain the reaction at a
constant volume. After cooling to room temperature, the
mixture was poured into a saturated, aqueous NaHCO3
solution (50 mL) and extracted with TBME (3 × 50 mL). The
combined organic layers were washed with brine (50 mL),
dried (Na2SO4/MgSO4, 1/1), filtered, and concentrated. The
crude concentrate was purified by column chromatography on
basic alumina (activity II) (hexane/TBME, 30/1) to afford 0.922
Con clu sion
The asymmetric, total synthesis of the Sceletium
alkaloid (-)-mesembrine was accomplished using an
asymmetric, tandem inter [4 + 2]/intra [3 + 2] cycload-
dition sequence as the key strategic transformation.
Moreover, this work demonstrates the effective use of a
2,2-disubstituted 1-nitroalkene in an asymmetric [4 + 2]
cycloaddition with a chiral vinyl ether to establish the
quaternary stereogenic center with high diastereocontrol.
This advance should provide the groundwork for future
applications of tandem cycloadditions to the total syn-
thesis of more complex alkaloids containing similar cis-
3a-aryloctahydroindole skeleta.
1
g (77%) of a 3.7/1.0 mixture (by H NMR integration) of 9 and
8. The mixture was separated by column chromatography on
a basic alumina (activity II) (pentane/TBME, 1/0, 30/1, 10/1)
to provide 0.206 g (14%) of 8 as a white solid and 0.644 g (58%)
of pure 9 as a clear, colorless oil.
5,5-Dim eth yl-2-eth en yl-2-(2-iodoeth yl)-1,3-dioxan e (10).
A solution of 9 (6.50 g, 26.1 mmol) dissolved in dry acetone
(20 mL) was added to a round bottom flask charged with a
mixture of sodium iodide (39.1 g, 0.261 mol, 10 equiv) and
acetone (241 mL). The flask and reflux condenser were
enclosed in aluminum foil (to eliminate exposure to light), and
the mixture was heated to reflux for 26 h. After cooling to
room temperature, the reaction mixture was poured into a
saturated, aqueous NaHCO3 solution (20 mL) and water (230
mL) and extracted with TBME (3 × 100 mL). The combined
organic layers were washed with brine (20 mL), dried (MgSO4),
filtered, and concentrated. The crude concentrate was purified
by column chromatography on basic alumina (activity II)
(pentane/TBME, 1/0, 30/1) to provide 6.80 g (89%) of 10 as a
clear, colorless oil: bp 95 °C (0.3 Torr) (air bath temperature);
1H NMR (400 MHz) 5.64 (dd, J ) 17.6, 11.0, 1 H), 5.43 (dd, J
) 11.0, 1.4, 1 H), 5.37 (dd, J ) 17.7, 1.4, 1 H), 3.58 (d, J )
11.0, 2 H), 3.30 (dt, J d ) 11.2, J t ) 1.3, 2 H), 3.27 (AA′XX′,
J AA′ ) -10, J XX′ ) -7, J AX ) 13, J AX′ ) 6, 2 H), 2.22 (AA′XX′,
J AA′ ) -10, J XX′ ) -7, J AX ) 13, J AX′ ) 6, 2 H), 1.14 (s, 3 H),
0.67 (s, 3 H); 13C NMR (100.6 MHz) 136.75, 119.88, 100.28,
71.32, 46.73, 30.06, 22.81, 21.93, 21.83; IR (neat) 2955 (s), 1471
Exp er im en ta l Section
Gen er a l. See Supporting Information for details.
Ma ter ia ls. 2-(3,4-Dimethoxyphenyl)-1-nitrobutene (2),13
1,5-dibromopetan-3-one (7),32 (E)-1-(3′,4′-dimethoxyphenyl)-2-
nitroethene (11),33 and (1R,2S)-(1-methyl-1-phenethyl)cyclo-
hexanol (15)27 were prepared by the literature methods.
2,2-Bis(2-br om oeth yl)-5,5-d im eth yl-1,3-d ioxa n e (8) a n d
2-(2-Br om oeth yl)-5,5-d im eth yl-2-eth en yl-1,3-d ioxa n e (9).
To a round bottom flask, fitted with a Dean-Stark trap and
a reflux condenser, were added 1,5-dibromo-3-pentanone (7)
(4.16 g, 17.1 mmol), 2,2-dimethyl-1,3-propanediol (1.95 g, 18.8
mmol, 1.1 equiv), TsOH‚H2O (81 mg, 0.43 mmol, 2.5 mol %),
and benzene (170 mL). The resulting mixture was heated to
reflux under nitrogen for 2.5 days (the evolution of acidic vapor
was detected using litmus paper). During this time, the
Dean-Stark trap (5 mL) was drained approximately every 4-6
h, and fresh benzene was added to maintain the reaction at a
constant volume. After cooling to room temperature, the
mixture was poured into a saturated, aqueous NaHCO3
solution (100 mL) and extracted with TBME (3 × 50 mL). The
combined organic layers were washed with brine (50 mL),

1684 J . Org. Chem., Vol. 62, No. 6, 1997
Denmark and Marcin
(m), 1170 (s), 1076 (s); MS (CI, CH4) 297 (M+ + 1, 36); TLC:
Rf 0.34 (hexane/EtOAc, 20/1).
second portion of K2CO3 solution (100 mL), and the aqueous
layers were back-extracted with TBME (2 × 100 mL). The
combined organic layers were washed with brine (50 mL),
dried (Na2SO4), filtered, and concentrated. The crude concen-
trate was purified by column chromatography using basic
alumina (activity II) (pentane/TBME, 1/0, 1/1) to provide (-)-
16 as a clear oil and a sample of recovered (-)-15. The vinyl
ether (-)-16 was further purified by column chromatography
using basic alumina (activity II) to afford after bulb-to-bulb
distillation 4.51 g (73%) of analytically pure (-)-16. The
recovered alcohol was repurified by silica gel column chroma-
tography (hexane/EtOAc, 10/1) to provide 0.940 g (17% recov-
ery) of (-)-15 as a clear viscous oil. Data for (-)-16: bp 150
°C (0.2 Torr) (air bath temperature); 1H NMR (400 MHz) 7.25
(m, 4 H), 7.11 (m, 1 H), 6.12 (dd, J ) 14.2, 6.6, 1 H), 4.12 (dd,
2-[4-[2-(3,4-Dim et h oxyp h en yl)-1-n it r o-1-b u t en yl]]-2-
et h en yl-5,5-d im et h yl-1,3-d ioxa n e (13). A suspension of
zinc dust (1.42 g, 21.3 mmol, 1.7 equiv) in THF (3.2 mL) was
sonicated for 30 min at room temperature in an ultrasonic
cleaning bath. The ultrasonic bath was removed and replaced
with a magnetic stirring apparatus. Dibromoethane (70.0 µL,
0.813 mmol, 6 mol %) was added and the stirred suspension
heated at 63-65 °C (internal temperature) for 2 min. After
cooling to room temperature, chlorotrimethylsilane (83.0 µL,
0.652 mmol, 5 mol %) was added, and the mixture was stirred
for 10 min before introducing a solution of the iodide 10 (6.00
g, 20.3 mmol, 1.6 equiv) in THF (13 mL). The resulting
suspension was stirred for 12 h at 35-37 °C (some unreacted
zinc remained) and was subsequently cooled to -10 °C, and a
solution of copper(I) cyanide (1.60 g, 17.9 mmol, 1.4 equiv) and
lithium chloride (1.52 g, 35.8 mmol, 2.8 equiv) in THF (18 mL)
was added. The resulting brown mixture was stirred for 10
min at 0 °C and cooled to -30 °C. A solution of nitroalkene
11 (2.67 g, 12.8 mmol, 1 equiv) in THF (48 mL) was added to
the prepared organometallic reagent at -30 °C. The mixture
was allowed to warm to 0 °C, stirred for 3 h, and then
quenched with a solution of PhSeBr (4.29 g, 17.9 mmol, 1.4
equiv) in THF (13 mL). After an additional 1 h at 0 °C, the
reaction mixture was poured into water (150 mL) and ex-
tracted with TBME (4 × 150 mL). The combined organic
layers were washed with brine (50 mL), dried (MgSO4),
filtered, and concentrated. The concentrate was purified by
silica gel column chromatography (hexane/EtOAc, 3/1) to afford
5.79 g of the intermediate selenide 12 as a viscous yellow oil.
The selenide 12 was dissolved in THF (110 mL) and treated
J ) 14.2, 1.5, 1 H), 3.90 (dd, J ) 6.6, 1.5, 1 H), 3.50 (td, J t
)
10.3, J d ) 6.1, 1 H), 2.00 (m, 1 H), 1.82 (ddd, J ) 12.2, 10.1,
3.7, 1 H), 1.64 (m, 1 H), 1.50 (m, 1 H), 1.38 (m, 1 H), 1.36 (s,
3 H), 1.28 (s, 3 H), 1.23 (m, 1 H), 1.12-1.01 (m, 2 H), 0.83 (qd,
J q ) 12.9, J d ) 3.4, 1 H); 13C NMR (100.6 MHz) 150.54, 150.16,
127.70, 125.89, 125.03, 87.66, 81.10, 51.94, 40.52, 32.90, 29.02,
27.43, 25.93, 24.95, 24.68; IR (neat) 2996 (s), 2963 (s), 2931
(s), 2877 (s), 1630 (s), 1191 (s), 1088 (s); MS (EI, 70 eV) 377
(M+, 13); TLC Rf 0.16 (hexane); Optical rotation [R]23D ) -25.1°
(c ) 3.41, CHCl3). Anal. Calcd for C17H24O (244.38): C, 83.55;
H, 9.90. Found: C, 83.60; H, 9.79.
(4S,6S)-4-[5-[3,3-(2,2-Dim eth ylp r op ylen ed ioxy)-1-p en -
ten yl]]-4-(3,4-d im eth oxyp h en yl)-6-[[(1R,2S)-2-(1-m eth yl-
1-p h en ylet h yl)cycloh exyl]oxy]-5,6-d ih yd r o-4H -[1,2]ox-
a zin e N-Oxid e (17). Trimethylaluminum (2.0 M in toluene,
2.12 mL, 4.24 mmol, 2 equiv) was added dropwise to a solution
of 2,6-di-tert-butyl-4-methylphenol (1.91 g, 8.69 mmol, 4 equiv)
in CH2Cl2 (12.0 mL) at room temperature. Gas evolution (CH4)
was observed as the solution was stirred at room temperature
for 30 min. Half of the resulting solution of MAD (8.0 mL)
was added over 2 min to a solution the nitroalkene 13 dissolved
in toluene (3 mL) which was maintained between -15 and -10
°C (internal temperature). The resulting dark red mixture was
stirred at -15 °C for 7 min, and then a solution of the chiral
vinyl ether (-)-16 dissolved in toluene (5 mL) was added.
After stirring for 1 h at -15 °C, the remainder of the MAD
solution (8 mL) was added over 1 h. After complete addition,
the reaction mixture was left to stir an additional 90 min at
-15 °C. The cold reaction contents were added to CH2Cl2 (250
mL) and washed with water (3 × 250 mL). The aqueous layers
were back-extracted with CH2Cl2 (3 × 150 mL), and the
combined organic layers were washed with brine (50 mL),
dried (Na2SO4), filtered, and concentrated (never warming
above 27 °C). The crude material was purified by silica gel
column chromatography (pentane/TBME, 2/1 (500 mL); 1/1
(500 mL); 2/3 (1000 mL)) to afford 1.14 g (∼86%) of 17 as a
with
a 30% aqueous solution of H2O2 (22 mL) at room
temperature. After 2.5 h, the yellow reaction mixture was
poured into a saturated, aqueous NaHCO3 solution (10 mL)
and water (90 mL) and extracted with CH2Cl2 (3 × 100 mL).
The combined organic extracts were washed with water (50
mL) and brine (50 mL), dried (MgSO4), filtered, and concen-
trated. The crude concentrate was purified by silica gel
column chromatography (hexanes/EtOAc, 4/1) to afford 3.49
g (72%) of 13 as a bright yellow oil. The product was
determined to be a 1.0/1.5 (E/Z) mixture of isomers by 1H NMR
integration. A small portion of 13 was further purified by
chromatography (CH2Cl2/TBME, 9/1) to provide an analytically
pure sample that was a 1.9/1.0 (E/Z) mixture of isomers. Data
for (E/Z)-13: 1H NMR (400 MHz) Z-isomer: 7.03 (t, J ) 1.2,
1 H), 6.86 (d, J ) 8.3, 1 H), 6.76 (dd, J ) 8.3, 2.0, 1 H), 6.68
(d, J ) 2.0, 1 H), 5.62 (dd, J ) 17.8, 11.0, 1 H), 5.41 (dd, J )
11.0, 1.5, 1 H), 5.33 (dd, J ) 17.6, 1.5, 1 H), 3.89 (s, 3 H), 3.85
(s, 3 H), 3.59 (d, J ) 10.7, 2 H), 3.30 (d, J ) 11.2, 2 H), 2.66
(m, 2 H), 1.66 (m, 2 H), 1.15 (s, 3 H), 0.66 (s, 3 H); E-isomer:
7.31 (s, 1 H), 7.13 (dd, J ) 8.5, 2.4, 1 H), 7.07 (d, J ) 2.2, 1 H),
6.89 (d, J ) 8.5, 1 H), 5.71 (dd, J ) 17.6, 11.0, 1 H), 5.44 (dd,
J ) 11.0, 1.5, 1 H), 5.39 (dd, J ) 17.6, 1.6, 1 H), 3.92 (s, 3 H),
3.91 (s, 3 H), 3.62 (d, J ) 10.7, 2 H), 3.34 (d, J ) 11.2, 2 H),
3.26 (m, 2 H), 1.86 (m, 2 H), 1.16 (s, 3 H), 0.70 (s, 3 H); 13C
NMR (100.6 MHz) Z-isomer: 152.12, 149.33, 148.64, 136.97,
133.96, 128.08, 119.73, 119.47, 110.82, 110.13, 99.28, 71.31,
55.83, 55.71, 39.13, 30.94, 30.01, 22.81, 21.84; E-isomer:
153.66, 150.94, 149.04, 137.00, 134.81, 129.01, 120.21, 119.53,
111.03, 109.94, 99.58, 71.34, 55.88, 55.83, 39.34, 30.08, 24.64,
22.85, 21.93; IR (CCl4) 2957 (s), 1523 (s), 1519 (s), 1515 (s),
1464 (s), 1334 (s), 1268 (s), 1176 (s), 1089 (s), 1030 (s); MS
(EI, 70 eV) 377 (M+, 13); TLC Rf 0.26 (hexane/EtOAc, 3/1).
Anal. Calcd for C20H27NO6 (377.44): C, 63.65; H, 7.21; N, 3.71.
Found: C, 63.62; H, 6.98; N, 3.68.
1
white crusty foam. The product was determined by H NMR
integration to be a 26/1 mixture of nitronate diastereomers
17 contaminated with ∼5% of the tandem cycloadduct 18. Data
for 17: 1H NMR (400 MHz) 7.26-7.09 (m, 5 H), 6.80 (d, J )
8.3, 1 H), 6.67 (dd, J ) 8.3, 2.2, 1 H), 6.64 (d, J ) 2.2, 1 H),
6.46 (s, 1 H), 5.58 (dd, J ) 17.7, 11.0, 1 H), 5.39 (dd, J ) 11.0,
1.7, 1 H), 5.30 (dd, J ) 17.7, 1.7, 1 H), 4.89 (dd, J ) 5.3, 3.8,
1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.57 (m, 2 H), 3.42 (td, J t
)
10.0, J d ) 4.3, 1 H), 3.27 (m, 2 H), 3.15 (ddd, J ) 13.9, 12.2,
4.5, 1 H), 2.29 (m, 1 H), 1.98-1.87 (m, 2 H), 1.83 (dd, J ) 13.9,
3.7, 1 H), 1.64 (m, 3 H), 1.44-1.26 (m, 8 H), 1.19-0.99 (m, 8
H), 0.68 (s, 3 H); 13C NMR (100.6 MHz) 151.33, 149.07, 147.85,
137.32, 135.97, 127.91, 125.40, 124.90, 119.31, 118.58, 117.82,
111.01, 109.10, 103.60, 99.67, 82.81, 71.33, 71.31, 55.93, 55.84,
51.95, 41.85, 40.00, 38.78, 36.03, 34.97, 33.31, 30.12, 28.76,
27.02, 26.10, 25.69, 24.55, 23.02, 21.94; IR (CCl4) 2957 (s), 2935
(s), 1257 (s), 1241 (s), 1085 (s), 1032 (s); TLC Rf 0.19 (TBME/
pentane, 3/2).
(-)-(1R,2S)-[[2-(1-Meth yl-1-ph en yleth yl)cycloh exyl]oxy]-
eth en e ((-)-16). A mixture of mercuric acetate (4.82 g, 15.1
mmol, 0.6 equiv), chiral alcohol (-)-15 (5.51 g, 25.2 mmol), and
n-butyl vinyl ether (350 mL) were heated to reflux for 24 h.
The mixture was subsequently cooled to room temperature,
and a second portion of mercuric acetate (4.82 g, 15.1 mmol,
0.6 equiv) was added. After heating to reflux for an additional
24 h, the reaction was cooled to room temperature and poured
into a mixture of aqueous K2CO3 solution (100 mL) and TBME
(100 mL). The separated organic layer was washed with a
(+)-(5S,6aS,9aR,9bS)-9,9-(2,2-Dim eth ylpr opylen edioxy)-
6a -(3,4-d im e t h o x y p h e n y l)-5-[[(1R ,2S )-2-(1-m e t h y l-1-
p h en yleth yl)cycloh exyl]oxy]h exa h yd r o-1H-isooxa zolo-
[2,3,3-h ] [2,1]ben zoxazin e (18). The 26/1 mixture of nitronate
diastereomers 17 was dissolved in benzene (50 mL) and heated
at reflux for 1 h. After cooling to room temperature, the
reaction mixture was concentrated to afford a slightly yellow,

Total Synthesis of (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 6, 1997 1685
viscous oil. The crude material was purified by silica gel
column chromatography (hexane/EtOAc, 4/1) to afford 1.04 g
(79%, based on nitroalkene) of 18 as a white crusty foam. The
extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were washed with brine (5 mL), dried (Na2SO4), filtered,
and concentrated. The crude concentrate was purified by silica
gel column chromatography (hexane/EtOAc, 1/1, 2/3) to afford
0.025 mg (89%) of 20 as white solid that was determined to
be >99% ee by chiral HPLC analysis. An analytical sample
of 20 was obtained after recrytallization (EtOAc/hexane): mp
193-194 °C (EtOAc/hexane); 1H NMR (400 MHz) 7.16 (d, J )
8.3, 2 H), 6.87 (d, J ) 8.0, 2 H), 6.64 (dd, J ) 8.3, 2.2, 1 H),
6.50 (d, J ) 8.5, 1 H), 6.43 (d, J ) 2.2, 1 H), 4.35-4.21 (m, 3
H), 3.83 (s, 3 H), 3.79 (d, J ) 11.2, 1 H), 3.71 (s, 3 H), 3.65 (dd,
J ) 8.8, 4.1, 1 H), 3.60 (d, J ) 11.0, 1 H), 3.56-3.43 (m, 3 H),
3.24 (td, J t ) 10.3, J d ) 7.8, 1 H), 2.62 (ddd, J ) 14.4, 4.4, 2.7,
1 H), 2.44 (dt, J d ) 14.2, J t ) 9.8, 1 H), 2.31 (s, 3 H), 2.26 (td,
J t ) 13.9, J d ) 7.6, 1 H), 1.86 (ddd, J ) 9.3, 6.8, 2.4, 1 H), 1.76
(td, J t ) 14.2, J d ) 4.4, 1 H), 1.64 (m, 1 H), 1.36 (td, J t ) 14.2,
J d ) 4.4, 1 H), 1.32 (s, 3 H), 0.77 (s, 3 H); 13C NMR (100.6
MHz) 148.54, 147.72, 142.31, 138.04, 134.63, 128.65, 127.07,
118.06, 110.43, 108.94, 100.67, 70.17, 69.66, 67.18, 59.28,
55.56, 55.35, 51.42, 48.93, 44.67, 33.93, 30.19, 30.03, 23.16,
23.13, 22.16, 21.32; IR (CHCl3) 3528 (br, w), 2961 (s), 1520
(s), 1338 (s), 1266 (s), 1251 (s), 1163 (s), 1151 (s), 1107 (s), 1089
(s), 1028 (s); MS (FAB) 546 (M+ + 1, 27); TLC Rf 0.17 (EtOAc/
1
product was determined by H NMR integration to be a 30/1
mixture of nitroso acetal diastereomers. The entire sample
was recrystallized (EtOH/MeOH, 1/1) to provide 0.833 g of a
single nitroso acetal diastereomer 18 as white prisms. The
mother liquor was concentrated and repurified by silica gel
chromatography (hexane/EtOAc, 4/1) to provide 78 mg of 18
as a white, solid foam. The material was recrystallized (EtOH/
MeOH, 1/1) to afford an additional 37 mg of 18, for a total
combined mass of 0.870 g (66% over two steps) of 18 as a single
1
diastereomer: mp 133-135 °C (EtOH/MeOH); H NMR (400
MHz) 7.17-7.03 (m, 7 H), 6.88 (d, J ) 8.5, 1 H), 4.42 (m, 2 H),
4.19 (dd, J ) 10.3, 6.3, 1 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.71
(d, J ) 11.5, 1 H), 3.68 (d, J ) 12.0, 1 H), 3.50 (d, J ) 11.5, 1
H), 3.34-3.21 (m, 4 H), 2.65 (m, 1 H), 2.29 (m, 1 H), 2.01 (m,
1 H), 1.92 (dd, J ) 13.1, 9.9, 1 H), 1.78 (m, 1 H), 1.61-1.45
(m, 4 H), 1.36-1.25 (m, 6 H), 1.12 (s, 6 H), 1.02, (m, 2 H), 0.77
(m, 1 H), 0.71 (s, 3 H); 13C NMR (100.6 MHz) 151.08, 148.50,
147.41, 139.51, 127.70, 125.53, 124.84, 118.94, 110.77, 110.13,
99.84, 98.32, 83.71, 70.70, 70.20, 69.87, 56.00, 55.86, 51.95,
45.14, 40.35, 39.91, 36.04, 35.64, 35.38, 30.01, 28.78, 27.57,
25.90, 25.87, 25.08, 24.86, 22.88, 21.98; IR (CHCl3) 2961 (s),
2936 (s),1520 (s), 1252 (s), 1161 (s), 1148 (s), 1126 (s), 1095
(s), 1027 (s); MS (FAB) 622 (M+ + 1, 53); TLC Rf 0.35 (hexane/
Hex, 3/2); Optical rotation [R]23 ) 42.2° (c ) 0.55, CHCl3);
D
chiral HPLC (column: DIACEL Chiralpak AD (EtOH/hexane,
65/35), 1.0 mL/min) tR (3aS,7R,7aS)-20 5.24 min (99.6%); tR
(3aR,7S,7aR)-20 13.3 min (0.4%), >99% ee. Anal. Calcd for
C29H39NSO7 (545.70): C, 63.83; H, 7.20; N, 2.57. Found: C,
63.86; H, 7.27; N, 2.48.
EtOAc, 2/1); Optical rotation [R]23 ) 12.3° (c ) 1.09, CHCl3).
D
Anal. Calcd for C37H51NO7 (621.81): C, 71.47; H, 8.27; N, 2.25.
Found: C, 71.36; H, 8.37; N, 2.31.
(+)-[(3a S,7R,7a S)-3a -(3,4-Dim et h oxyp h en yl)-6,6-(2,2-
d im e t h ylp r op yle n e d ioxy)oct a h yd r oin d ol-7-yl]m e t h -
a n ol (19). Two small spatulas of W-2 Raney nickel catalyst,
which had been prewashed with methanol (5 × 10 mL), were
added to a solution of nitroso acetal 18 (0.500 g, 0.804 mmol)
dissolved in warm methanol (∼150 mL). The flask was placed
in a steel autoclave which was then purged and filled with
hydrogen to a pressure of 300 psi. After stirring (magnetically)
for 48 h at rt, the vessel was slowly depressurized and
subsequently flushed with nitrogen. The resulting superna-
tant was passed through a short (4 cm) plug of Celite, using
nitrogen as the pressure source. The residual nickel in the
reaction vessel was thoroughly washed with fresh methanol
(4 × 20 mL) under an atmosphere of nitrogen. The clear
filtrate was concentrated and the resulting oil purified by silica
gel column chromatography (chloroform/methanol, 95/5, 85/
15) to provide 0.268 g (85%) of slightly impure amino alcohol
19 and 180 mg of recovered chiral alcohol (-)-15. The amino
alcohol was further purified using silica gel column chroma-
tography (chloroform/methanol, 80/10) to afford 0.233 g (74%)
of pure 19 as a white foam. The recovered chiral alcohol was
also repurified using silica gel column chromatography (hex-
ane/EtOAc, 12/1) to afford 0.160 g (91%) of pure (-)-15 as a
clear oil. Data for 19: 1H NMR (400 MHz) 6.88 (m, 2 H), 6.77
(m, 1 H), 4.24 (dd, J ) 10.4, 3.6, 1 H), 3.88 (dd, J ) 10.3, 8.5,
1 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 3.72 (d, J ) 11.5, 1 H), 3.57
(d, J ) 10.7, 1 H), 3.55 (d, J ) 11.2, 1 H), 3.32 (dd, J ) 11.2,
2.4, 1 H), 3.31 (dd, J ) 11.2, 2.4, 1 H), 3.05 (ddd, J ) 12.5, 9.5,
3.4, 1 H), 2.89 (dt, J d ) 12.0, J t ) 8.5, 1 H), 2.58 (dt, J d ) 14.6,
J t ) 3.9, 1 H), 2.25-2.12 (m, 2 H), 1.89-1.76 (m, 3 H), 1.38
(ddd, J ) 14.2, 12.2, 5.7, 1 H), 1.13 (s, 3 H), 0.69 (s, 3 H); 13C
NMR (100.6 MHz) 148.74, 147.37, 139.70, 117.80, 110.66,
109.74, 98.93, 69.82, 69.51, 67.69, 62.74, 55.82, 55.70, 50.37,
46.29, 42.60, 31.84, 31.78, 29.74, 22.95, 22.88, 22.01; IR
(CHCl3) 3200 (br, w), 2960 (s), 1519 (s), 1465 (s), 1262 (s), 1249
(+)-(3a R,6a S,6b S)-6a -(3,4-Dim et h oxyp h en yl)-4,4-(2,2-
d im e t h ylp r op yle n e d ioxy)p e r h yd r op yr r olo[3,2,1-i,j]-
ben zoxa zin e (21). An aqueous solution of formaldehyde
(35.7%, 77.0 µL, 0.965 mmol, 2.5 equiv) was added to a solution
of amino alcohol 19 (0.151 g, 0.386 mmol) dissolved in
methanol (10 mL) at room temperature. After stirring for 1
h, the mixture was concentrated to afford an opaque residue.
The residue was dissolved in CH2Cl2 and purified by silica gel
column chromatography (hexane/EtOAc, 1/1) to afford 109 mg
(70%) of 21 as a white foam: 1H NMR (400 MHz) 6.98 (m, 2
H), 6.80 (d, J ) 8.5, 1 H), 4.52, 4.45 (ABq, J ) 10.7, 2 H), 4.37
(dd, J ) 10.5, 3.2, 1 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 3.71 (d, J
) 11.0, 1 H), 3.68 (t, J ) 10.6, 1 H), 3.60 (d, J ) 11.0, 1 H),
3.52 (d, J ) 11.2, 1 H), 3.36-3.27 (m, 3 H), 2.98 (dt, J d ) 9.0,
J t ) 5.9, 1 H), 2.36-2.20 (m, 3 H), 2.14 (td, J t ) 10.0, J d
)
3.4, 1 H), 1.90-1.75 (m, 2 H), 1.59 (ddd, J ) 14.2, 11.0, 4.9, 1
H), 1.12 (s, 3 H), 0.70 (s, 3 H); 13C NMR (100.6 MHz) 148.57,
147.01, 141.47, 117.66, 110.63, 109.98, 97.85, 80.28, 69.92,
65.98, 64.95, 55.78, 55.69, 48.19, 45.09, 40.11, 34.35, 32.73,
29.92, 25.01, 22.69, 21.94; IR (CCl4) 2955 (s), 1519 (s), 1263
(s), 1250 (s), 1182 (s), 1152 (s), 1142 (s), 1094 (s), 1033 (s), 1016
(s); MS (FAB) 404 (M+ + 1, 100); TLC Rf 0.28 (hexane/EtOAc,
1/1); Optical rotation [R]23 ) 4.71° (c ) 0.595, CHCl3).
D
(+)-(3a S,7R,7a S)-[3a -(3,4-Dim et h oxyp h en yl)-6,6-(2,2-
d im eth ylp r op ylen ed ioxy)-1-m eth ylocta h yd r oin d ol-7-yl]-
m eth a n ol (22). An aqueous solution of formaldehyde (35.7%,
254 µL, 3.18 mmol, 2.5 equiv) was added to a solution of amino
alcohol 19 (0.498 g, 1.27 mmol) dissolved in methanol (25 mL)
at room temperature. After stirring for 10 min, the mixture
was transferred to a flask charged with one spatula of W-2
Raney nickel catalyst, which had been prewashed with metha-
nol (5 × 6 mL). The flask was stirred under one atmosphere
of hydrogen for 48 h. The nickel catalyst was removed by
filtration through a small plug of Celite (4 cm). The reaction
vessel and Celite were washed with fresh methanol (4 × 15
mL). The clear filtrate was concentrated and the residue
purified by silica gel column chromatography (chloroform/
methanol, 99/1, 85/15) to afford 0.75 mg (15%) of intermediate
aminal 21 and 0.376 g (73%) of pure N-methylamino alcohol
22 as a white foam. An analytical sample of 22 was obtained
after heating the entire sample at 100 °C under vacuum (0.2
Torr) for 24 h. The recovered aminal 21 (75 mg) was
resubjected to the reaction conditions for 48 h to provide, after
purification, an additional 40 mg (8%) of 22 as a white foam,
for a total combined mass of 0.416 g (81%) of 22: 1H NMR
(400 MHz) 6.99 (dd, J ) 8.2, 2.3, 1 H), 6.97 (d, J ) 2.2, 1 H),
(s), 1159 (s), 1146 (s), 1105 (s), 1027 (s); MS (FAB) 392 (M+
+
D
1, 100); TLC Rf 0.21 (CHCl3/EtOH, 8/1); Optical rotation [R]23
) 16.0° (c ) 0.50, CHCl3).
(+)-[(3a S,7R,7a S)-3a -(3,4-Dim et h oxyp h en yl)-6,6-(2,2-
d im eth ylp r op ylen ed ioxy)-1-[(4-m eth ylp h en yl)su lfon yl]-
octa h yd r oin d ol-7-yl]m eth a n ol (20). A small portion of the
free amino alcohol 19 (20 mg, 0.051 mmol) was dissolved in
CH2Cl2 (2 mL) and cooled to 0 °C, and triethylamine (17.8 µL,
0.128 mmol, 2.5 equiv) was added, followed by TsCl (19.4 mg,
0.102 mmol, 2.0 equiv). The mixture was allowed to stir for 1
h at 0 °C and then was poured into water (25 mL) and

1686 J . Org. Chem., Vol. 62, No. 6, 1997
Denmark and Marcin
6.81 (d, J ) 8.3, 1 H), 4.22 (dd, J ) 10.5, 3.9, 1 H), 4.01 (dd, J
) 10.5, 6.3, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.73 (d, J ) 11.2,
1 H), 3.54 (d, J ) 11.2, 1 H), 3.48 (d, J ) 10.7, 1 H), 3.36 (dd,
J ) 11.5, 2.7, 1 H), 3.33 (dd, J ) 11.6, 2.7, 1 H), 3.18 (ddd, J
) 9.8, 7.6, 2.2, 1 H), 2.41 (td, J t ) 10.0, J d ) 6.6, 1 H), 2.35-
2.23 (m, 3 H), 2.20 (s, 3 H), 1.86-1.68 (m, 4 H), 1.5 (ddd, J )
14.2, 11.7, 4.4, 1 H), 1.20 (s, 3 H), 0.72 (s, 3 H); 13C NMR (100.6
MHz) 148.54, 147.18, 140.63, 118.39, 110.52, 110.25, 99.98,
72.18, 69.84, 69.68, 61.85, 55.90, 55.70, 52.78, 50.16, 49.27,
45.42, 34.32, 34.28, 29.88, 23.59, 22.99, 22.09; IR (CHCl3) 3515
(br, w), 2960 (s), 1519 (s), 1249 (s), 1027 (s). MS (FAB) 406
(M+ + 1, 100); TLC Rf 0.29 (CHCl3/EtOH, 85/15); Optical
(-)-(3a S,7a S)-3a -(3,4-Dim et h oxyp h en yl)oct a h yd r o-1-
m eth yl-6H-in d ol-6-on e (1). (-)-Mesem br in e. Amino al-
dehyde 25 (220 mg, 0.545 mmol) was dissolved in an aqueous
solution of trifluoroacetic acid (65%, 10 mL) and allowed to
stir at room temperature for 28 h. The reaction mixture was
cooled to 0 °C and made basic by the addition of an aqueous
solution of NaOH (30%, 22.4 mL). The resulting mixture was
heated to reflux for 2.5 h. After cooling to room temperature,
the reaction mixture was poured into water (100 mL) and
extracted with CH2Cl2 (5 × 75 mL). The combined organic
layers were washed with brine (10 mL), dried (Na2SO4),
filtered, and concentrated to afford a brown oil. The crude
concentrate was purified twice by silica gel column chroma-
tography (chloroform/acetone, 8/1) to provide a clear colorless
oil. The oil was passed through a small plug of basic alumina
(activity I) (chloroform/acetone, 8/1) to afford 94 mg (60%) of
pure 1. An analytical sample of 1 was obtained after bulb-
to-bulb distillation and found to be identical with a sample of
natural (-)-mesembrine.42,44 Data for synthetic 1: bp 160 °C
rotation [R]23 ) 19.2° (c ) 0.50, CHCl3). Anal. Calcd for
D
C
23H35NO5 (405.54): C, 68.12; H, 8.70; N, 3.45. Found: C,
68.30; H, 8.78; N, 3.45.
(+)-(3a S,7a S)-3a -(3,4-Dim et h oxyp h en yl)-1-m et h yl-6-
[(2,2-d im eth yl-3-h yd r oxyp r op yl)oxy]-7-for m yl-2,3,3a ,4,5,-
7a -h exa h yd r o-6H-in d ole (25). tert-Butyl alcohol (0.176 mL,
1.85 mmol, 3 equiv) was added to a stirred mixture of
ethylmagnesium bromide (3.0 M/Et2O, 0.616 mL, 1.85 mmol,
3.0 equiv) and THF (5 mL) at room temperature. After 10
min, a solution of amino alcohol 22 (250 mg, 0.616 mmol)
dissolved in THF (7 mL) was introduced, and the resulting
mixture was stirred for an additional 10 min. A solution of
1,1′-(azodicarbonyl)dipiperidine (0.651g, 1.85 mmol, 3 equiv)
dissolved in THF (7 mL) was added, and the dark red reaction
mixture was stirred at room temperature for 2.5 h. The
mixture was poured into CH2Cl2 (75 mL) and washed with
water (2 × 50 mL). The aqueous layers were back-extracted
with CH2Cl2 (3 × 75 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), filtered, and
concentrated. The concentrate was purified twice by silica gel
column chromatography (chloroform/methanol, 99/5, 85/15) to
afford 200 mg (80%) of 25 as a slightly brown foam. A small
portion of 25 was further purified by recrystallization (EtOAc/
hexane) to provide a tan powder-like solid: mp 173-175 °C
(EtOAc/hexane); 1H NMR (400 MHz) 10.31 (s, 1 H), 6.77 (d, J
) 8.0, 1 H), 6.57 (d, J ) 1.9, 1 H), 6.55 (dd, J ) 8.3, 2.4, 1 H),
1
(0.01 Torr) (air bath temperature); H NMR (500 MHz) 6.92
(dd, J ) 8.4, 2.3, 1 H), 6.89 (d, J ) 2.2, 1 H), 6.83 (d, J ) 8.3,
1 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.13 (ddd, J ) 9.6, 7.9, 2.8, 1
H), 2.94 (t, J ) 3.5, 1 H), 2.59 (m, 2 H), 2.42, (m, 1 H), 2.32
(m, 1 H), 2.31 (s, 3 H), 2.25-2.05 (m, 5 H); 13C NMR (100.6
MHz) 211.45, 148.93, 147.42, 140.15, 117.85, 110.89, 109.86,
70.34, 55.95, 55.35, 54.82, 47.46, 40.53, 40.05, 38.79, 36.20,
35.24; IR (CCl4) 2952 (s), 2935 (s), 1723 (s), 1520 (s), 1464 (s),
1454 (s), 1256 (s), 1233 (s), 1149 (s), 1032 (s); MS (FAB) 290
(M+ + 1, 100); TLC Rf 0.16 (CHCl3/acetone, 6/1); Optical
rotation [R]24 ) -63.3° (c ) 1.13, MeOH). Anal. Calcd for
D
C17H23NO3 (289.38): C, 70.56; H, 8.01; N, 4.84. Found: C,
70.49; H, 8.13; N, 4.84.
Ack n ow led gm en t. We are grateful to the National
Insitutes of Health (PHS GM-30938) for generous
financial support. L.R.M. also thanks the University
of Illinois and the Department of Education for Gradu-
ate Fellowships. Additionally, we thank Prof. Peter A.
1
Petillo for his help assigning H and 13C NMR spectra
4.59 (s, 1 H), 4.35 (d, J ) 10.0, 1 H), 4.00 (dt, J d ) 11.7, J t
)
as well as Prof. Stephen F. Martin (Univ. of Texass
Austin) for kindly providing a sample of natural (-)-
mesembrine hydrochloride.
8.5, 1 H), 3.84 (s, 3 H), 3.81 (s, 3 H), 3.72 (br s, 1 H), 3.56 (dd,
J ) 10.5, 4.6, 1 H), 3.55 (d, J ) 10.0, 1 H), 3.23 (dd, J ) 10.5,
2.4, 1 H), 3.11 (dd, J ) 18.8, 4.8, 1 H), 2.95 (td, J t ) 11.2, J d
) 4.2, 1 H), 2.84 (m, 4 H), 2.41-2.22 (m, 2 H), 2.10 (dd, J )
14.5, 6.5, 1 H), 1.92 (ddd, J ) 18.3, 11.0, 6.6, 1 H), 0.97 (s, 3
H), 0.93 (s, 3 H); 13C NMR (100.6 MHz) 188.67, 177.82, 148.67,
147.52, 135.84, 117.72, 111.57, 110.83, 109.01, 73.13, 67.16,
63.57, 55.75, 55.73, 53.13, 45.72, 41.40, 38.10, 37.05, 31.78,
24.62, 21.60, 21.31; IR (CHCl3) 2962 (s), 1648 (s), 1601 (s), 1519
(s), 1250 (s), 1236 (s), 1185 (s), 1146 (s), 1028 (s); MS (FAB)
404 (M+ + 1, 100); TLC Rf 0.16 (CHCl3/MeOH, 85/15); Optical
rotation [R]23D ) 208.2° (c ) 0.83, CHCl3); HRMS (FAB) Calcd
for C23H34NO5, 404.2437. Found, 404.2439.
Su p p or tin g In for m a tion Ava ila ble: Complete 1H and
13C NMR assignments, IR and MS data for all characterized
compounds, along with 1H and 13C NMR spectra of natural
and synthetic (-)-mesembrine (19 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O970079Z