Asymmetric total synthesis of (+)-cannabisativine

Article abstract of DOI:10.1021/jo049724+

The asymmetric total synthesis of natural (+)-cannabisativine 1 was completed in 19 steps and 7% overall yield. The key synthetic intermediate 29 was prepared with a high degree of stereocontrol in 12 steps starting from chiral 1-acylpyridinium salt 10. Addition of zinc enolate 11 to pyridinium salt 10 furnished dihydropyridone 12 containing two contiguous stereocenters of the correct absolute configuration. Luche reduction of ketone 16 afforded diol 17 in high yield (96%) and excellent diastereoselectivity. The Mukaiyama-Michael reaction of pyridones 27a/b with O-silyl ketene acetal 32 gave phenyl selenyl ketones 33a/b with complete stereoselectivity. Elimination of cis-β-hydroxyselenides 34 and 35 effected the regiocontrolled preparation of tetrahydropyridine derivative 29. Several approaches to the macrocyclic ring closure of the 13-membered ring were investigated, ultimately leading to the completion of an asymmetric synthesis of the target compound with a high degree of stereocontrol.

Full text of DOI:10.1021/jo049724+

Asym m etr ic Tota l Syn th esis of (+)-Ca n n a bisa tivin e
J effrey T. Kuethe and Daniel L. Comins*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received February 16, 2004
The asymmetric total synthesis of natural (+)-cannabisativine 1 was completed in 19 steps and
7% overall yield. The key synthetic intermediate 29 was prepared with a high degree of stereocontrol
in 12 steps starting from chiral 1-acylpyridinium salt 10. Addition of zinc enolate 11 to pyridinium
salt 10 furnished dihydropyridone 12 containing two contiguous stereocenters of the correct absolute
configuration. Luche reduction of ketone 16 afforded diol 17 in high yield (96%) and excellent
diastereoselectivity. The Mukaiyama-Michael reaction of pyridones 27a /b with O-silyl ketene acetal
32 gave phenyl selenyl ketones 33a /b with complete stereoselectivity. Elimination of cis-â-
hydroxyselenides 34 and 35 effected the regiocontrolled preparation of tetrahydropyridine derivative
29. Several approaches to the macrocyclic ring closure of the 13-membered ring were investigated,
ultimately leading to the completion of an asymmetric synthesis of the target compound with a
high degree of stereocontrol.
Macrocyclic polyamine alkaloids containing the bioge-
netic base spermidine have been isolated from a variety
of plant sources.1 Many of these natural products contain
a 13-membered lactam ring system that is annulated to
a disubstituted tetrahydropyridine ring (i.e., cannabisa-
tivine (1), anhydrocannabisativine (2), and palustrine
(3)). However, lactam alkaloids possessing a 17-, 18-, and
22-membered spermidine skeleton with a monosubsti-
tuted piperidine ring such as oncinotine (5) and isoonci-
notine (6) have also been isolated (Figure 1).2,3 These
piperidine-based alkaloids have received considerable
attention in recent years due to their unique architecture
which presents significant synthetic challenges.4-7 Per-
haps the most unusual and challenging alkaloid of this
class is (+)-cannabisativine which was isolated from the
roots and leaves of the common marijuana plant, Can-
nibis sativa L.8 Cannabisativine was the first reported
nonquaternary alkaloid possessing the pyrido[1,2-d]-
[1,5,9]-triazacyclotridecine nucleus isolated from Can-
nabis sativa L. The relative structure of cannabisativine
was determined by single-crystal X-ray analysis,8 and the
absolute stereochemistry was established through syn-
thesis of the unnatural (-)-enantiomer.4c Recently, we
reported the first asymmetric synthesis of natural (+)-
cannabisativine based on the addition of a metallo
enolate to a chiral 1-acylpyridinium salt.9 Herein, we
provide a complete account of our work in this area.
Resu lts a n d Discu ssion
(1) For reviews of macrocyclic spermidine alkaloids, see: (a) Mat-
suyama, H. Yuki Gosei Kagaku Kyokaishi 1981, 39, 1152. (b) Wasser-
man, H. H.; Wu, J . S. Heterocycles 1982, 17, 581. (c) Guggisberg, A.;
Hesse, M. In The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando,
1983; Vol. 22, Chapter 3, p 85.
(2) For the isolation of (-)-oncinotine and (-)-isooncinotine and
related alkaloids, see: (a) Badawi, M. M.; Guggisberg, A.; van den
Broek, P.; Hesse, M.; Schmid, H. Helv. Chim. Acta 1968, 51, 1813. (b)
Guggisberg, A.; Badawi, M. M.; Hesse, M.; Schmid, H. Helv. Chim.
Acta 1974, 57, 414.
(3) For the synthesis of (-)-oncinotine and (-)-isooncinotine and
related alkaloids, see: (a) Ina, H.; Ito, M.; Kibayashi, C. J . Org. Chem.
1996, 61, 1023. (b) Ina, H.; Ito, M.; Kibayashi, C. J . Chem. Soc., Chem.
Commun. 1995, 1015. (c) Bienz, S.; Guggisberg, A.; Walchli, R.; Hesse,
M. Helv. Chim. Acta 1988, 71, 1708. (d) Schneider, F.; Bernauer, K.;
Guggisberg, A.; van den Broek, P.; Hesse, M.; Schmid, H. Helv. Chim.
Acta 1974, 57, 434. (e) Guggisberg, A.; van den Broek, A.; Hesse, M.;
Schmid, H.; Schneider, F.; Bernauer, K. Helv. Chim. Acta 1976, 59,
3013.
(4) For racemic syntheses of cannabisativine, see: (a) Ogawa, M.;
Kuriya, N.; Natsume, M. Tetrahedron Lett. 1984, 25, 969. (b) Wasser-
man, H. H.; Leadbetter, M. R. Tetrahedron Lett. 1985, 26, 2241. For
an enantioselective synthesis of the unnatural (-)-enantiomer of
cannabisativine, see: (c) Hamada, T.; Zenkoh, T.; Sato, H.; Yonemitsu,
O. Tetrahedron Lett. 1991, 32, 1649.
Our retrosynthetic approach to (+)-cannabisativine is
outlined in Scheme 1, where the natural product was
envisioned as arising from key intermediate 7. The acetic
acid moiety and the double bond of 7 would then come
from a highly diastereoselective 1,4-addition to the enone
functionality of 8 followed by a regioselective ketone to
alkene conversion. Finally, dihydropyridone 8 would be
prepared by elaboration of dioxolanone 9, which in turn
would come from the addition of zinc enolate 11 to chiral
1-acylpyridinium salt 10 (TCC ) trans-2-(R-cumyl)-
cyclohexyl).
The synthesis of (+)-cannabisativine began with the
addition of the zinc enolate 11, prepared by deprotonation
of 2,2-diethyl-1,3-dioxolan-4-one10 with LDA followed by
transmetalation with ZnCl2, to chiral 1-acylpyridinium
(7) For the synthesis of dihydropalustrine, see: (a) Natsume, M.;
Ogawa, M.; Yoda, I.; Shiro, M. Chem. Pharm. Bull. 1984, 32, 812. (b)
Wasserman, H. H.; Leadbetter, M. R.; Kopka, I. E. Tetrahedron Lett.
1984, 25, 2391.
(8) (a) Lotter, H. L.; Abraham, D. J .; Turner, C. E.; Knapp, J . E.;
Schiff, P. L.; Slatkin, D. J . Tetrahedron Lett. 1975, 7, 2815. (b) Turner,
C. E.; Hsu, M.-F. H.; Knapp, J . E.; Schiff, P. L.; Slatkin, D. L. J . Pharm.
Sci. 1976, 65, 1084.
(5) For the synthesis of anhydrocannabisativine, see: (a) Bailey, T.
R.; Garigipati, R. S.; Morton, J . A.; Weinreb, S. M. J . Am. Chem. Soc.
1984, 106, 3240. (b) Wasserman, H. H.; Pearce, B. C. Tetrahedron Lett.
1985, 26, 2237.
(6) For the synthesis of palustrine, see: Natsume, M.; Ogawa, M.
Chem. Pharm. Bull. 1984, 32, 3789.
(9) Kuethe, J . T.; Comins, D. L. Org. Lett. 2000, 2, 855.
10.1021/jo049724+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/29/2004
J . Org. Chem. 2004, 69, 5219-5231
5219

Kuethe and Comins
F IGURE 1.
SCHEME 1. Retr osyn th etic Ap p r oa ch to
SCHEME 3
(+)-Ca n n a bisa tivin e
SCHEME 2
were pleased that the addition of 11 to 10 provided
dihydropyridone 12 as the major diastereomer (>95 de)
in 85% isolated yield. The stereochemistry was deter-
1
mined to be anti by H NMR and single-crystal X-ray
analysis. The facial selectivity can be explained by assum-
ing an acyclic transition state (13) with a synclinal orien-
tation. This transition-state conformation may be favored
due to reduced nonbonded interactions with the pyri-
dinium ring and electrostatic attraction of the positively
charged nitrogen and the negative enolate oxygen.13
Reaction of 12 with N,O-dimethylhydroxylamine hy-
14
drochloride in the presence of AlMe3 provided the
salt 10 (Scheme 2).9,11-12 The stereochemistry of an
enolate (E/Z) can often determine the relative configu-
ration (syn/anti) of two new chiral centers in a product
derived from the addition of a prochiral enolate to an
electrophile having diastereotopic faces. Accordingly, we
Weinreb’s amide 14 in near quantitative yield (Scheme
3).12 Reaction of 14 with pentylmagnesium bromide at
low temperature (-78 °C) or at rt did not give the
expected ketone. Instead, the only identifiable reaction
product was pyridone 15 resulting from a retro-Michael
elimination of the chiral side chain. Attempts to install
the alkyl side chain by the direct addition of pentylmag-
nesium bromide to dioxolanone 12 also afforded 15 as
(10) Fairbanks, A. J .; Sinay, P. Tetrahedron Lett. 1995, 36, 893.
(11) Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem. Soc.
1994, 116, 4719.
(12) For an account on the diastereoselective addition of prochiral
metallo enolates to chiral 1-acylpyridinium salts, see: Comins, D. L.;
Kuethe, J . T.; Hong, H.; Lakner, F. J .; Concolino, T. E.; Rheingold, A.
L. J . Am. Chem. Soc. 1999, 121, 2651.
(13) An acyclic TS is proposed on the basis of an apparent low-energy
conformation that does not favor a chelate; however, some sort of
chelation control cannot be ruled out.
5220 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Total Synthesis of (+)-Cannabisativine
SCHEME 4
the only identifiable reaction product in low isolated
yield. With these results in hand, our attention turned
to the addition of the less basic pentynyl anion to amide
14. Addition of pentynylmagnesium bromide to 14 pro-
vided the desired ketone 16 in 80% yield. Better results
were obtained with the corresponding pentynyllithium.
Addition of pentynyllithium (5 equiv) to 14 at -78 °C
followed by warming to -25 °C gave 16 in 96% isolated
yield. Reduction of 16 under standard Luche conditions
(NaBH4, CeCl3‚7H2O) provided diol 17 as a single dias-
tereomer in 96% yield, where the diastereoselectivity was
determined to be greater than 95% by HPLC analysis.
Our rationalization of this observed diastereoselectivity
can best be explained by Cram’s rule,15 where hydride is
delivered from the least sterically demanding side of
intermediate 18, although a chelation-controlled inter-
mediate 19 cannot be ruled out and would also be
attacked by hydride from the same side.
To elaborate the dihydropyridone functionality, protec-
tion of diol 17 was required. Initial attempts (base/BnBr,
Ag2O/BnBr, BnOCNHCCl3/cat. acid) to protect 17 as its
bis-benzyl ether proved difficult and led to multiple
reaction products. Interestingly, reaction of 17 first with
NaH followed by the addition of BnBr did not give the
expected bis-benzyl ether, but gave carbamate 20 in 58%
yield (Scheme 4). Optimization of the reaction conditions
led to the isolation of 20 in 88% yield when 17 was
treated with sodium hydride in THF. In addition, the
released chiral auxiliary, (+)-TCC,16 was recovered in
94% yield. There was no evidence that the six-membered
carbamate 21 was formed under these reaction condi-
tions.17 The remaining secondary hydroxyl group of 20
was protected as its benzyl ether using benzyl trichloro-
acetimidate/cat. TfOH18 and gave 22 in 86% yield. The
previous steps were accomplished in high overall yield
due to the C-5 TIPS group which protected the dihydro-
pyridone against nucleophilic attack. With the TIPS
group still protecting the enone system, clean reduction
of the alkyne bond was achieved via catalytic hydrogena-
tion over Pt/C which gave 23 in 97% yield.
Removal of the TIPS protecting group of dihydropyri-
done 23 was first accomplished by protodesilylation using
refluxing formic acid19 for 30 min and gave bicyclic
carbamate 24 in 60% yield. The major byproduct of this
reaction was identified as formate ester 25 (36%). Evi-
dently the harsh reaction conditions resulted in cleavage
of the benzyl ether with concomitant reaction with formic
acid to give 25. Attempts to conduct the deprotection at
a lower temperature (50 °C) did not improve the ratio of
24:25, and, when conducted at rt, no reaction was
observed. After considerable experimentation, it was
discovered that the yield of 24 was improved to 77% by
reaction with refluxing 1:1 TFA/CHCl3. Under these
conditions, cleavage of the benzyl ether was minimized
but not totally eliminated, as alcohol 26 was also formed
in 10% yield. The separation of 24 from formate ester 25
or alcohol 26 could easily be effected by chromatography.
It was envisioned that the double bond of the target
molecule could be installed regioselectively through the
use of selenium chemistry (Scheme 5). It was anticipated
that reaction of dihydropyridone 24 with phenylselenyl
chloride would give phenylselenide 27. Subsequent 1,4-
(14) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685
and references therein.
(15) For a discussion of such rules, see: Eliel, E. L. The Stereo-
chemistry of Carbon Compounds; McGraw-Hill: New York, 1962; pp
68-74. For reviews of the stereochemistry of addition to carbonyl
compounds, see: (a) Bartlett, P. A. Tetrahedron 1980, 36, 2. (b) Ashby,
E. C.; Laemmle, J . T. Chem. Rev. 1975, 75, 521.
(16) (a) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656.
(b) (+)- and (-)-TCC alcohols are available from Aldrich Chemical Co.
(17) For a complete analysis of structures of type 21, see: Comins,
D. L.; Hong, H. J . Org. Chem. 1993, 58, 5035.
(18) Iversen, T.; Bundle, D. R. J . Chem. Soc., Chem. Commun. 1981,
1240.
(19) Comins, D. L.; Huang, S.; McArdle, C. L.; Ingalls, C. L. Org.
Lett. 2001, 3, 469.
J . Org. Chem, Vol. 69, No. 16, 2004 5221

Kuethe and Comins
SCHEME 5
diastereomers in quantitative yield. The stereochemical
outcome of this reaction is in full agreement with similar
studies from these laboratories where 1,4-addition to a
1-acyl-2,3-dihydropyridone enone moiety occurs via ste-
reoelectronically controlled axial attack of the nucleo-
phile.23 Because the C-2 side chain of the piperidine ring
occupies an equatorial position, axial attack leads to 33
where the C-2 substituent and the C-6 acetic acid unit
are in a trans-relationship. Luche reduction of ketones
33a /b gave an 85% combined yield of two alcohols 34 and
35 which could easily be separated from one another by
chromatography. Interestingly, the reduction of the di-
astereomeric ketones 33a /b gave exclusively cis-â-hy-
droxyselenides 34 and 35 as the sole reaction products.
Evidently, the R-phenylselenyl functionality is suffi-
ciently large to cause hydride delivery from the least
sterically demanding side of the ketone carbonyl. In the
case of 33a , the equatorial phenylselenyl group caused
the hydride to be delivered from the â-face to give 34. In
the case of 33b, the axial phenylselenyl group directed
hydride to be delivered from R-face leading to 35. The
stereochemistry of each individual isomer was assigned
by NMR experiments which clearly showed a cis-orienta-
tion of the hydroxyl and phenylselenyl groups.
conjugate addition of an acetic acid unit to the enone
moiety followed by reduction of the resulting ketone
would provide â-hydroxyselenide 28. Olefin formation by
elimination of the â-hydroxyselenide moiety would give
key intermediate 29 possessing the double bond and all
of the required stereochemical features of cannabisati-
vine.
To this end, phenylselenyl chloride was added to 24 in
EtOAc at rt, but the expected selenide 27a /b was not
obtained (Scheme 6).20 Instead, phenylselenide 30 was
isolated in 90% yield. To avoid this undesired reaction
pathway, deprotonation of 24 with LiHMDS followed by
quenching with phenylselenyl chloride afforded an in-
separable mixture (3.5:1) of diastereomeric selenides 27a
and 27b in 73% combined yield. We assume that the
major diastereomer 27a arises from selenation occurring
through a boat-type transition state 31a . Because the
â-face is blocked by the benzyl ether and a pentyl group,
attack of the phenylselenyl group occurs from the R-face,
giving predominantly the equatorial phenylselenyl group
in the isolated product. However, some selenation occurs
through chair transition state 31b leading to the minor
isomer 27a with the phenylselenyl group occupying an
axial orientation. The structures of isomers 27a /b were
rigorously determined by NMR analysis.
While trans-â-hydroxyselenides are known to eliminate
to olefins under a variety of reaction conditions (TsOH,
HClO4, MsCl/TEA, TFAA/TEA), cis-â-hydroxyselenides
fail to undergo this type of elimination.24 Attempted
elimination of 34 or 35 under conditions known to affect
this type of reaction led to recovered starting materials
in all cases, thus providing further support for our
stereochemical assignment. Earlier model studies20 in-
dicated that the desired elimination could be obtained
by taking advantage of the fact that both phenylselenyl
groups and thiocarbamates are effective radical precur-
sors. Reaction of 34 with 1,1′-thiocarbonyldiimidazole in
refluxing toluene containing a catalytic amount of DMAP
provided thiocarbamate 36 in 91% yield (Scheme 8). On
treatment with Bu3SnH/AIBN in refluxing toluene (10
min), 36 was converted to 29 in 91% yield. It was more
convenient to directly add Bu3SnH/AIBN to the crude
reaction mixture containing 36 to afford tetrahydropy-
ridine 29 in high overall yield. In similar fashion, reaction
of â-hydroxyselenide 35 under identical reaction condi-
tions afforded thiocarbamate 37 in 95% yield. Reduction
of 37 with Bu3SnH/AIBN also gave 29 in high yield. A
At this stage, a latent acetic acid unit needed to be
introduced stereoselectively at the C-6 position of 27
(Scheme 7). Treatment of the diastereomeric mixture of
27a and 27b with BF3 etherate in the presence of O-silyl
ketene acetal 3221 under standard Mukaiyama-Michael
reaction conditions,20,22 followed by acidic workup, af-
forded ketones 33a /b as an inseparable mixture of
SCHEME 6
5222 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Total Synthesis of (+)-Cannabisativine
SCHEME 7
SCHEME 8
one-pot procedure was developed whereby the crude
mixture containing 34/35 was subjected to thiocar-
bamate formation and in situ reduction to give 29 in an
85% overall yield.
At this point, there were two possible synthetic ap-
proaches considered for macrocyclization and completion
of the synthesis (Scheme 9). The first approach (route
A) would rely on the preparation of an intermediate of
type 38 where macrocyclization might occur between the
secondary amine and a suitable leaving group to provide
macrocycle 40. The second approach (route B) would be
to follow a more classical macrocyclization procedure
between tosylated amine of 39 and the tethered mesylate.
Because route A appeared to be more novel and direct,
this approach was pursued first.
Exploration of route A began with the synthesis of the
requisite side chain (Scheme 10). Treatment of 4125 with
methyl acrylate in MeCN in the presence of anhydrous
K2CO3 gave Michael addition product 42 in quantitative
yield. Reduction of 42 with LAH afforded amino alcohol
43 in 70% yield. Reductive amination of 43 with benzal-
(20) Comins, D. L.; Kuethe, J . T. Org. Lett. 1999, 1, 1031.
(21) The 1-methoxy-1-trimethylsiloxyethene (32) was prepared by
a literature procedure: Collins, D. J .; Cullen, J . D. Aust. J . Chem. 1988,
41, 735.
(22) Saigo, K.; Osaki, M.; Mukaiyama, T. Chem. Lett. 1976, 163.
(23) For leading references, see: Comins, D. L.; J oseph, S. P. In
Advances in Nitrogen Heterocycles; Moody, C. J ., Ed.; J AI Press, Inc.:
Greenwich, CT, 1996; Vol. 2, pp 251-294 and references therein.
(24) (a) Reich, H. J .; Chow, F. J . Chem. Soc., Chem. Commun. 1975,
790. (b) Re´mion, J .; Dumont, W.; Krief, A. Tetrahedron Lett. 1976, 17,
1385.
(25) Hoffmann-LaRoche; Neth. Appl. 6,603,655, 1966; Chem. Abstr.
1966, 66, 37642.
J . Org. Chem, Vol. 69, No. 16, 2004 5223

Kuethe and Comins
SCHEME 9
SCHEME 10
dehyde yielded N-benzylamino alcohol 44 in 41% yield.
Hydrolysis of ester 29 gave acid 45 which was converted
to its acid chloride 46 with oxalyl chloride. Reaction of
46 with either 43 or 44 using Schotten-Baumann
conditions (NaOH, CH2Cl2, rt) gave amides 47 (96%) and
48 (81%). Attempted opening of the oxazolidinone ring
of 47 with 50% KOH/MeOH at reflux only afforded trace
amounts of the desired aminodiol 49. The major byprod-
ucts of the reaction were identified as amino acid 5026
and recovered amine 43 where hydrolysis of the amide
was competitive with hydrolysis of the carbamate. On the
other hand, reaction of tertiary amide 48 with 50% KOH/
MeOH at reflux gave the desired aminodiol 51 in 79%
yield. Unfortunately, despite a considerable amount of
effort to form either the primary triflate, mesylate, or
tosylate and have it undergo macrocyclization under
dilute reaction conditions in the presence of various
bases, only complex mixtures of products resulted.27
The reductive cyclization of 54 was also investigated
(Scheme 11). Reaction of 41 with iodide 5228 in the
presence of K2CO3 in MeCN followed by reduction with
LAH and then reductive amination with benzaldehyde
(26) Amino acid 50 could not be isolated cleanly due to its high
solubility in water and low solubility in most organic solvents.
(27) For a similar approach to macrocyclization, see: Winkler, J .
D.; Axten, J . M. J . Am. Chem. Soc. 1998, 120, 6425.
5224 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Total Synthesis of (+)-Cannabisativine
SCHEME 11
SCHEME 12
gave amino dimethyl acetal 53 in 40% overall yield.
Reaction of 53 with acid chloride 46 and subsequent
hydrolysis afforded amino alcohol 54 in 46% unoptimized
yield. Hydrolysis of dimethyl acetal 54 with aqueous acid,
buffering the reaction mixture to pH 5.5 with citrate:
phosphate buffer, and subsequent treatment with NaBH3-
CN3a gave only trace amounts of macrocyclization product
55. The major product was identified as aminodiol 51 in
all attempts. Although considerable experimentation
with regard to both reaction times and temperature was
investigated, the yield of 55 never rose above 3% and this
approach was abandoned.
Having been unsuccessful in obtaining an acceptable
macrocyclic ring closure through route A, we elected to
pursue route B in an effort to complete the synthesis
(Scheme 12). Reaction of acid chloride 46 with N-benzyl
protected amino alcohol 5629 gave the expected amide 57
in 82% overall yield from ester 29. Hydrolysis of the
oxazolidinone ring of 57 afforded aminodiol 58 in 88%
yield. Treatment of 58 with triflate 59 in the presence of
Hunig’s base yielded the tertiary amine 60 in 84% yield.30
After conversion of the primary alcohol of 60 to the
corresponding mesylate with methanesulfonyl chloride
in the presence of triethylamine (95%), cyclization was
carried out in acetonitrile/K2CO3 to provide lactam 55 in
70% yield. Global deprotection using sodium in liquid
ammonia gave a 76% yield of (+)-cannabisativine (1),
which exhibited spectral data in agreement with reported
data for authentic material.8 The melting point (165-
166 °C) and optical rotation, [R]23D +51.8 (c 0.425, CHCl3),
were also in agreement with the literature values [mp
167-168 °C; [R]D +55.1 (c 0.53, CHCl3)].8
In conclusion, the first asymmetric synthesis of (+)-
cannabisativine (1) was accomplished in 19 synthetic
steps with a high degree of stereocontrol. Key to the
success of this synthesis was the metallo enolate addition
to chiral 1-acylpyridinium salt 10, which allowed for the
(28) Clive, D. L.; Chua Paul, C.; Wang, Z. J . Org. Chem. 1997, 62,
7028.
(29) Lesher, G. Y.; Surrey, A. R. J . Am. Chem. Soc. 1955, 77, 636.
(30) Bailey, T. R.; Garigipati, R. S.; Morton, J . A.; Weinreb, S. M. J .
Am. Chem. Soc. 1984, 106, 3240.
J . Org. Chem, Vol. 69, No. 16, 2004 5225

Kuethe and Comins
isop r op ylsilyl)-2,3-d ih yd r o-4-p yr id on e (16). To a solution
of 440 mg (0.716 mmol) of 14 in 30 mL of THF at -78 °C was
added dropwise 7.20 mL (3.58 mmol) of a 0.5 M solution of
1-pentynyllithium. The reaction was allowed to slowly warm
to -25 °C and quenched with saturated aqueous NH4Cl. The
mixture was extracted with ethyl acetate (3 × 15 mL). The
organic extracts were dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by radial
PLC (silica gel, 20% EtOAc/hexanes) to give 427 mg (96%) of
preparation of dihydropyridone building block 12 con-
taining the two required contiguous stereocenters of the
correct absolute stereochemistry. Conversion of dihydro-
pyridone 17 to bicyclic carbamate 24 set the stage for a
highly diastereoselective addition of an acetic acid unit
with complete control of stereochemistry. Elimination of
cis-â-hydroxyselenides 34 and 35 allowed for the regio-
controlled preparation of tetrahydropyridine 29, a key
intermediate which was efficiently converted to the
natural product in seven steps. The strategy described
herein should be useful for the enantioselective prepara-
tion of other complex piperidine-containing alkaloids.
Efforts in this direction are ongoing in our laboratories.
16 as a colorless oil: [R]23 -36.6 (c 0.99, CHCl3); IR (neat)
D
3469, 2935, 2849, 2208, 1719, 1666, 1580, 1463, 1383, 1324,
1255 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.02-1.38 (m, 33H),
1.68 (m, 5H), 2.09 (m, 4H), 2.41 (m, 3H), 3.03 (m, 1H), 3.13
(m, 1H), 4.12 (m, 1H), 4.91 (m, 1H), 7.13 (m, 1H), 7.28 (m,
4H), 7.76 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 11.4, 13.8, 19.0,
21.3, 21.6, 24.9, 26.0, 27.0, 31.3, 33.4, 37.4, 39.7, 51.3, 54.5,
78.7, 81.6, 101.2, 111.3, 125.3, 125.6, 128.3, 147.9, 151.8, 152.3,
186.3, 195.6; HRMS calcd for C37H55NO5Si, 622.3928 [M + H]+;
found, 622.3927 [M + H]+.
Exp er im en ta l Section
(2S)-2-((5S)-2,2-Dieth yl-1,3-d ioxola n -4-on e)-1-[((1S,2R)-
2-(1-m eth yl-1-p h en yleth yl) cycloh exyloxy)ca r bon yl]-5-
(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-p yr id on e (12). To a so-
lution of LDA, prepared at -23 °C from diisopropylamine (1.85
mL, 13.18 mmol) and n-butyllithium (6.13 mL, 13.18 mmol,
2.15 M in hexane) in 25 mL of THF, was added dropwise 1.90
g (13.18 mmol) of 2,2-diethyl-1,3-dioxolan-4-one10 in 2 mL of
THF at -78 °C. After 10 min, 13.18 mL of a 1 M solution of
anhydrous zinc chloride in ether was added, and stirring was
continued for 20 min. The resulting zinc enolate was cannu-
lated into a solution of pyridinium salt 10 at -78 °C, which
was formed from 1.0 g (3.77 mmol) of 4-methoxy-3-(triisopro-
pylsilyl)pyridine and 3.77 mL of a 1 M solution of (1S,2R)-2-
(R-cumyl)cyclohexyl chloroformate in toluene at -23 °C for 40
min. After the mixture was stirred for 3 h, 25 mL of aqueous
10% HCl was added. The mixture was allowed to warm to rt
and was extracted with ethyl acetate (3 × 20 mL). The organic
extracts were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by radial PLC
(silica gel, 10% EtOAc/hexanes) to give 2.05 g (85%) of 12 as
(2R)-2-((1R,2S)-Dih yd r oxy-h ep t-3-yn e)-1-[((1S,2R)-2-(1-
m et h yl-1-p h en ylet h yl) cycloh exyloxy)ca r bon yl]-5-(t r i-
isop r op ylsilyl)-2,3-d ih yd r o-4-p yr id on e (17). To a solution
of 100 mg (0.161 mmol) of 16 in 7 mL of methanol was added
66 mg (0.177 mmol) of cerium(III) chloride heptahydrate in
one portion. After being stirred for 10 min, the mixture was
cooled to -50 °C, and 9 mg (0.241 mmol) of sodium borohydride
was added. The reaction mixture was stirred for an additional
10 min, quenched with 10 mL of water, and extracted with
CH2Cl2 (3 × 10 mL). The combined extracts were dried over
MgSO4 and concentrated under reduced pressure. The residue
was purified by radial PLC (silica gel, 30% EtOAc/hexanes)
to give 96 mg (96%) of 17 as a colorless oil: [R]23 +49.5 (c
D
0.28, CHCl3); IR (neat) 3422, 2931, 2868, 2241, 1718, 1650,
1577, 1462, 1389, 1326, 1248, 1013 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.97-1.40 (m, 33H), 1.49-1.89 (m, 7H), 1.92-2.52 (m,
7H), 2.87 (m, 1H), 3.49 (m, 1H), 4.14 (m, 1H), 4.89 (m, 1H),
7.15 (m, 1H), 7.30 (m, 4H), 7.74 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 11.4, 13.8, 19.1, 21.1, 22.2, 24.9, 26.0, 27.2, 29.9, 31.0,
33.7, 37.1, 39.7, 51.2, 52.8, 64.8, 75.1, 89.5, 111.3, 125.5, 128.4,
148.2, 152.2, 153.3, 196.8; HRMS calcd for C37H57NO5Si,
624.4084 [M + H]+; found, 624.4077 [M + H]+.
a white solid: mp 141-142 °C (hexane); [R]23 +17.2 (c 0.5,
D
CHCl3); IR (thin film) 2948, 1796, 1718, 1662, 1588, 1236 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.80-1.39 (m, 38H), 1.59-2.08
(m, 8H), 2.24 (m, 1H), 2.47 (dd, 1H, J ) 16.4 and 7.2 Hz), 3.35
(m, 1H), 4.15 (m, 1H), 4.95 (m, 1H), 7.12 (m, 1H), 7.30 (m,
4H), 7.76 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 7.7, 11.4, 19.0,
21.6, 24.9, 25.9, 26.9, 29.6, 30.0, 31.3, 33.6, 37.2, 39.6, 51.3,
52.7, 75.1, 78.5, 110.8, 115.6, 125.3, 128.1, 128.3, 147.8, 151.7,
152.4, 169.9, 194.9. Anal. Calcd for C37H57NO6Si: C, 69.44;
H, 8.98; N, 2.19. Found: C, 69.37; H, 8.92; N, 2.20.
(1R,1′S,9R)-1-(1′-Hyd r oxyh ex-2-yn yl)-1,2,8,8a -tetr a h y-
d r o-6-tr iisop r op ylsilyl-2-oxa in d olizin e-3,7-d ion e (20). To
a solution of 91 mg (0.146 mmol) of 17 in 15 mL of THF was
added 12 mg (0.306 mmol) of 60% NaH in mineral oil. After 3
h, the reaction was quenched with saturated aqueous NH4Cl
and extracted with CH2Cl2. The organic extracts were dried
over MgSO4 and concentrated under reduced pressure. The
residue was purified by radial PLC (silica gel, 20% EtOAc/
hexanes) to give 52 mg (88%) of 20 as a clear oil: [R]23D -284.6
(c 0.45, CHCl3); IR (neat) 3414, 2938, 2865, 1778, 1659, 1568,
2-(2S -H yd r oxy-N -m e t h oxy-N -m e t h yla ce t a m id e )-1-
[((1S,2R)-2-(1-m eth yl-1-p h en yleth yl) cycloh exyloxy)ca r -
bon yl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-p yr id on e (14).
To a suspension of 2.29 g (23.44 mmol) of N,O-dimethylhy-
droxylamine hydrochloride in 75 mL of CH2Cl2 at 0 °C was
added 7.81 mL (2.0 M in toluene, 15.6 mmol) of trimethyla-
luminum. The mixture was warmed to rt and stirred for 45
min. A solution of 1.00 g (1.56 mmol) of 12 in 3 mL of CH2Cl2
was added dropwise, and the mixture was stirred at rt for 1.5
h. The reaction was carefully quenched with 3 mL of 10% HCl
and extracted with CH2Cl2. The combined organic extracts
were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by radial PLC (silica gel,
35% EtOAc/hexanes) to afford 931 mg (97%) of 14 as a colorless
1
1399, 1266 cm-1; H NMR (CDCl3, 300 MHz) δ 0.98 (t, 3H, J
) 7.3 Hz), 1.06 (m, 18H), 1.33 (m, 3H), 1.52 (m, 2H), 2.19 (t,
2H, J ) 7.1 Hz), 2.53 (d, 1H, J ) 6.8 Hz), 2.71 (dd, 1H, J )
15.4 and 4.0 Hz), 3.29 (t, 1H, J ) 15.4 Hz), 4.63 (m, 2H), 4.77
(d, 1H, J ) 8.3 Hz), 7.57 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
11.2, 13.8, 18.9, 20.9, 22.0, 37.2, 53.6, 62.7, 75.4, 78.2, 91.1,
112.9, 143.7, 152.1, 195.7; HRMS calcd for C22H35NO4Si,
406.2414 [M + H]+; found, 406.2421 [M + H]+.
(1R,1′S,9R)-1-((1′-P h en ylm eth oxy)h ex-2-yn ly)-1,2,8,8a -
t e t r a h yd r o-6-t r iisop r op ylsilyl-2-oxa in d olizin e -3,7-d i-
on e (22). To a solution of 955 mg (2.35 mmol) of 20 in 50 mL
of anhydrous ether was added 773 mg (3.10 mmol) of benzyl
2,2,2-trichloroacetimidate followed by 3 drops of triflic acid.
The mixture was stirred at rt for 5 h and then quenched with
10 mL of 5% HCl. The layers were separated, and the aqueous
layer was extracted with ether. The combined organic extracts
were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by radial PLC (silica gel,
15% EtOAc/hexanes) to give 1.00 g (86%) of 22 as a colorless
solid: mp 174-175 °C (EtOAc/hexanes); [R]23 +18.4 (c 0.44,
D
CHCl3); IR (thin film) 3439, 2936, 2859, 1714, 1661, 1578,
1
1385, 1327, 1254 cm-1; H NMR (CDCl3, 300 MHz) δ 1.02-
1.38 (m, 33H), 1.67-2.20 (m, 6H), 3.05 (br s, 1H), 3.24 (s, 3H),
3.68 (s, 3H), 4.33-4.62 (br m, 1H), 4.88 (m, 1H), 7.13 (m, 1H),
7.28 (m, 4H), 7.76 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 11.5,
19.2, 22.5, 24.9, 26.0, 27.3, 30.8, 33.9, 36.7, 40.0, 51.3, 54.0,
55.1, 61.7, 69.7, 78.4, 110.6, 125.1, 125.2, 125.6, 128.1, 148.1,
148.6, 152.1, 195.9. Anal. Calcd for C34H54N2O6Si: C, 66.41;
H, 8.85; N, 4.56. Found: C, 66.30; H, 8.85; N, 4.58.
(2R)-2-((1R)-Hyd r oxy-1-h ep t-3-yn -2-on e)-1-[((1S,2R)-2-
(1-m eth yl-1-p h en yleth yl) cycloh exyoxy)ca r bon yl]-5-(tr i-
oil: [R]23 -118.1 (c 0.21, CHCl3); IR (neat) 2941, 2864, 2241,
D
1782, 1659, 1397, 1265, 1210, 1064 cm-1; 1H NMR (CDCl3, 300
5226 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Total Synthesis of (+)-Cannabisativine
MHz) δ 1.01 (m, 21H), 1.29 (m, 3H), 1.56 (m, 2H), 2.22 (t, 2H,
J ) 7.0 Hz), 2.72 (dd, 1H, J ) 15.4 and 4.2 Hz), 3.32 (t, 1H, J
) 15.4 Hz), 4.55 (m, 3H), 4.74 (dd, 1H, J ) 8.0 and 2.4 Hz),
4.83 (d, 1H, J ) 11.6 Hz), 7.28 (m, 5H), 7.53 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 11.2, 13.8, 18.9, 20.9, 27.0, 38.0, 53.8, 69.0,
71.3, 73.4, 77.4, 91.9, 112.1, 127.8, 128.0, 128.7, 137.0, 143.7,
152.1, 196.1; HRMS calcd for C29H41NO4Si, 496.2883 [M + H]+;
found, 496.2860 [M + H]+.
as a colorless oil: [R]24 -206.2 (c 0.095, CHCl3); IR (neat)
D
2931, 1783, 1666, 1601, 1437, 1325, 1249, 1090 cm-1; 1H NMR
(CDCl3, 300 MHz) δ (major isomer) 0.86 (t, 3H, J ) 6.9 Hz),
1.17-1.61 (m, 7H), 1.77 (m, 1H), 3.89 (m, 1H), 4.08 (d, 1H, J
) 15.0 Hz), 4.43 (dd, 1H, J ) 15.0 and 7.3 Hz), 4.55 (d, 1H, J
) 11.4 Hz), 4.60 (d, 1H, J ) 11.4 Hz), 4.91 (dd, 1H, J ) 7.3
and 2.1 Hz), 5.47 (d, 1H, J ) 7.9 Hz), 7.33 (m, 8H), 7.48 (d,
1H, J ) 7.9 Hz), 7.56 (d, 2H, J ) 7.5 Hz); 13C NMR (CDCl3, 75
MHz) δ 14.1, 22.7, 25.3, 30.6, 31.8, 44.3, 58.0, 72.7, 78.2, 79.0,
107.2, 125.6, 128.2, 128.7, 129.5, 129.6, 135.8, 136.4, 137.5,
138.3, 152.2, 188.5; HRMS calcd for C26H29NO4Se, 500.1342
[M + H]+; found, 500.1341 [M + H]+.
(1R,1′S,9R)-1-((1′-P h en ylm eth oxy)h exa n e)-1,2,8,8a -tet-
r ah ydr o-6-tr iisopr opylsilyl-2-oxain dolizin e-3,7-dion e (23).
To a solution of 360 mg (0.726 mmol) of 22 in 10 mL of ethyl
acetate was added 160 mg (2.17 mmol) of lithium carbonate
followed by 10 mg of 5% Pt/C. The mixture was stirred under
a balloon pressure of hydrogen for 12 h. The reaction mixture
was filtered over Celite and concentrated under reduced
pressure. The crude residue was purified by radial PLC (silica
gel, 20% EtOAc/hexanes) to give 352 mg (97%) of 23 as a
(1R*,1′S*,9R*)-1-(1′-P h en ylm eth oxy)h ep ta n e)-1,2,8,8a -
tetr ah ydr o-6-ph en ylselan yl-2-oxain dolizin e-3,7-dion e (30).
To a solution of 25 mg (0.073 mmol) of 24 in 7 mL of EtOAc
was added 17 mg (0.087 mmol) of phenylselenyl chloride. The
resulting mixture was stirred for 3 h at rt and concentrated
under reduced pressure. The residue was purified by radial
PLC (silica gel, 30% EtOAc/hexanes) to give 33 mg (90%) of
30 as a colorless oil: IR (neat) 2931, 2860, 1778, 1672, 1572,
colorless oil: [R]23 -160.0 (c 0.15, CHCl3); IR (neat) 2942,
D
2860, 1772, 1659, 1570, 1464, 1397, 1266 cm-1
;
1H NMR
(CDCl3, 300 MHz) δ 0.92 (t, 3H, J ) 6.6 Hz), 1.04 (m, 18H),
1.34 (m, 9H), 1.74 (m, 2H), 2.65 (dd, 1H, J ) 15.0 and 4.2 Hz),
2.97 (t, 1H, J ) 15.0 Hz), 4.49 (d, 1H, J ) 10.5 Hz), 4.60 (m,
4H), 7.31 (m, 5H), 7.55 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
11.3, 14.4, 19.1, 22.9, 24.5, 29.9, 32.2, 38.4, 54.5, 72.6, 78.0,
112.8, 128.4, 128.9, 137.6, 144.2, 152.3, 196.3; HRMS calcd
for C29H45NO4Si, 500.3196 [M + H]+; found, 500.3173 [M +
H]+.
1
1401, 1249 cm-1; H NMR (CDCl3, 300 MHz) δ 0.89 (m, 3H),
1.37 (m, 6H), 1.69 (m, 2H), 2.87 (d, 1H, J ) 16.0 Hz), 3.08 (t,
1H, J ) 15.1 Hz), 3.82 (m, 1H), 4.44 (m, 1H), 4.61 (m, 3H),
7.29 (m, 8H), 7.44 (m, 2H), 7.75 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 14.2, 22.7, 24.4, 29.8, 32.0, 37.7, 54.6, 72.5, 77.1, 111.4,
128.1, 128.3, 128.8, 129.7, 133.4, 137.2, 141.4, 151.4, 152.0,
169.3, 188.8.
(1R,1′S,9R)-1-((1′-P h en ylm eth oxy)h exa n e)-1,2,8,8a -tet-
r a h yd r o-2-oxa in d olizin e-3,7-d ion e (24). To 284 mg (0.57
mmol) of 23 was added 15 mL of a 1:1 mixture of TFA/CHCl3.
The mixture was heated to reflux for 12 h, cooled to rt, and
concentrated under reduced pressure. The residue was purified
by radial PLC (silica gel, 40% EtOAc/hexanes). The first
product (150 mg, 77%) to elute was identified as 24 and
(1R,1′S,5R,8S,9S)-1-((1′-P h en ylm eth oxy)h exa n e)-8-p h e-
n ylselen yl-1,2,5,6,6a ,8-h exa h yd r o-2-oxa in d olizin e-3,5-d i-
on e Acetic Acid Meth yl Ester (33a /b). To a solution of 70
mg (0.140 mmol) of 27a /b and 103 mg (0.704 mmol) of
1-methoxy-1-trimethylsiloxyethene (32)21 in 15 mL of CH2Cl2
at -78 °C was added dropwise 22 mg (0.154 mmol) of boron
trifluoride etherate. The reaction mixture was allowed to stir
at -78 °C for 30 min and then quenched with saturated
aqueous NaHCO3. The organic layer was separated and
concentrated under reduced pressure. The crude residue was
redissolved in 7 mL of THF, and 1 mL of H2O followed by 2
drops of 5% HCl was added. After 1 h, the reaction mixture
was diluted with water and extracted with ethyl acetate. The
combined organic extracts were dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified
by radial PLC (silica gel, 20% EtOAc/hexanes) to give 79 mg
(100%) of 33a /b as an inseparable mixture of diastereomers
isolated as a colorless solid: mp 68-69 °C (EtOAc); [R]22
D
-265.9 (c 0.085, CHCl3); IR (thin film) 2933, 2858, 1773, 1666,
1596, 1438, 1359, 1262, 1097 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.91 (t, 3H, J ) 6.4 Hz), 1.35 (m, 6H), 1.73 (m, 2H), 2.69 (dd,
1H, J ) 15.9 and 4.2 Hz), 2.97 (t, 1H, J ) 15.9 Hz), 3.83 (q,
1H, J ) 5.2 Hz), 4.47 (d, 1H, J ) 11.0 Hz), 4.64 (m, 3H), 5.47
(d, 1H, J ) 7.9 Hz), 7.34 (m, 5H), 7.60 (d, 1H, J ) 7.9 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 14.2, 22.7, 24.3, 29.7, 32.1, 37.7, 54.7,
72.3, 77.0, 108.7, 128.1, 128.3, 128.8, 137.4, 138.8, 152.1, 192.3.
Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found:
C, 69.67; H, 7.44; N, 3.97.
and a clear oil: [R]23 +66.7 (c 0.075, CHCl3); IR (neat) 2935,
D
1761, 1732, 1402, 1213, 1074, 1019 cm-1; 1H NMR (CDCl3, 300
MHz) δ (major isomer) 0.89 (t, 3H, J ) 6.5 Hz), 1.29 (m, 3H),
1.44 (m, 3H), 1.87 (m, 2H), 2.44 (m, 2H), 2.56 (m, 2H), 3.65 (s,
3H), 3.96 (m, 1H), 4.10 (d, 1H, J ) 9.6 Hz), 4.35 (m, 1H), 4.60
(m, 4H), 7.29 (m, 8H), 7.53 (d, 2H, J ) 7.5 Hz); 13C NMR
(CDCl3, 75 MHz) δ 14.2, 22.8, 24.2, 30.1, 32.0, 37.9, 41.3, 45.3,
47.8, 52.1, 58.1, 71.8, 77.4, 128.0, 128.2, 128.6, 129.6, 129.8,
The second product (18.7 mg, 13%) to elute, (1R,1′S,9R)-1-
((1′-hydroxy)hexane)-1,2,8,8a-tetrahydro-2-oxaindolizine-3,7-
dione (26), was isolated as a white solid: mp 112-113 °C
(EtOAc/hexanes); [R]22 -392.5 (c 0.24, CHCl3); IR (thin film)
D
3447, 2931, 2860, 1777, 1665, 1598, 1445, 1363, 1330, 1264,
1
1182, 1102, 989 cm-1; H NMR (CDCl3, 300 MHz) δ 0.91 (m,
3H), 1.31 (m, 5H), 1.54 (m, 2H), 1.73 (m, 2H), 2.79 (dd, 1H, J
) 16.0 and 4.1 Hz), 2.99 (t, 1H, J ) 16.0 Hz), 3.93 (m, 1H),
4.51 (m, 1H), 4.62 (m, 1H), 5.49 (d, 1H, J ) 7.8 Hz), 7.59 (d,
1H, J ) 7.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7, 24.7,
31.8, 33.6, 37.6, 54.8, 69.8, 78.6, 108.8, 139.1, 152.1, 193.1.
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found:
C, 61.71; H, 7.59; N, 5.43.
135.1, 136.7, 137.9, 156.0, 170.4, 202.4; HRMS calcd for C29H35
-
NO6Se: 574.1710 [M + H]+; found, 574.1721 [M + H]+.
Lu ch e Red u ction of 33a /b. To a solution of 20 mg (0.0349
mmol) of 33a /b in 8 mL of MeOH was added 14 mg (0.0376
mmol) of cerium(III) trichloride heptahydrate. After 5 min, 2
mg (0.0529 mmol) of NaBH4 was added in one portion, and
stirring was continued for 15 min. The reaction mixture was
diluted with 10 mL of water and then extracted with CH2Cl2.
The combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by radial PLC (silica gel, 30% EtOAc/hexanes). The
first product to elute (13 mg, 65%) was identified as
(1R,1′S,5R,7R,8S,9S)-7-hydroxy-1-((1′-phenylmethoxy)hexane)-
8-phenylselenyl-1,2,5,6,6a,7,8-hexahydro-2-oxaindolizine-3,5-
(1R,1′S,8S,9R)-1-((1′-P h en ylm eth oxy)h exa n e)-1,2,8-tet-
r a h yd r o-8-p h en ylselen yl-2-oxa in d olizin e-3,7-d ion e (27a /
b). To a solution of 183 mg (0.533 mmol) of 24 in 20 mL of
THF at -78 °C was added 0.64 mL of a 1.0 M solution of
lithium hexamethyldisilazide in THF. The reaction mixture
was stirred for 15 min at -78 °C and then allowed to warm to
-40 °C for 30 min. The mixture was cooled to -78 °C, and
122 mg (0.637 mmol) of phenylselenyl chloride in 1 mL of THF
was added dropwise. After 1 h, the reaction was quenched with
saturated aqueous NaHCO3 and then extracted with ethyl
acetate. The organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by radial PLC (silica gel, 30% EtOAc/hexanes) to give 195 mg
(73%) as an inseparable 3:1 mixture of diastereomers (27a /b)
dione acetic acid methyl ester (34) as a colorless oil: [R]22
D
-56.5 (c 0.115, CHCl3); IR (neat) 3434, 2936, 2858, 1751, 1736,
1405, 1331, 1253, 1051 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
0.83 (t, 3H, J ) 7.0 Hz), 1.21 (m 5H), 1.51 (m, 2H), 1.72 (m,
1H), 1.83 (m, 1H), 2.22 (dd, 1H, J ) 14.6 and 2.4 Hz), 2.89 (m,
3H), 3.18 (d, 1H, J ) 12.0 Hz), 3.67 (s, 3H), 3.90 (m, 1H), 4.09
J . Org. Chem, Vol. 69, No. 16, 2004 5227

Kuethe and Comins
(m, 1H), 4.17 (dd, 1H, J ) 12.0 and 8.0 Hz), 4.35 (m, 1H), 4.55
(d, 1H, J ) 11.5 Hz), 4.67 (d, 1H, J ) 11.5 Hz), 4.79 (dd, 1H,
mg (0.231 mmol) of 36 and 2 mg of AIBN in 10 mL of toluene
was added dropwise 74 mg (0.254 mmol) of tributyltin hydride.
After 5 min, the reaction mixture was cooled and concentrated
under reduced pressure. The crude residue was purified by
radial PLC (silica gel, 25% EtOAc/hexanes) to give 85 mg (91%)
J ) 8.0 and 3.5 Hz), 7.33 (m, 8H), 7.45 (d, 2H, J ) 7.4 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 14.2, 22.9, 24.6, 29.6, 32.0, 32.2, 37.3,
45.2, 47.5, 51.8, 52.0, 65.9, 70.8, 125.9, 128.0, 128.2, 128.6,
129.2, 130.0, 135.1, 138.3, 156.5, 171.8; HRMS calcd for C29H37
-
of 29 as a colorless oil: [R]23 +27.3 (c 1.40, CHCl3); IR (neat)
D
NO6Se, 576.1867 [M + H]+; found, 576.1876 [M + H]+.
2931, 2860, 1760, 1736, 1413, 1372, 1219, 1072 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.89 (t, 3H, J ) 6.3 Hz), 1.32 (m, 3H),
1.45 (m, 2H), 1.78 (m, 2H), 1.93 (dd, 1H, J ) 18.3 and 3.6 Hz),
2.59 (m, 4H), 3.64 (m, 1H), 3.70 (s, 3H), 4.38 (d, 1H, J ) 11.0
Hz), 4.46 (m, 1H), 4.54 (m, 2H), 4.63 (d, 1H, J ) 11.0 Hz),
5.74 (m, 1H), 5.84 (m, 1H), 7.33 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 14.2, 22.8, 23.0, 27.3, 29.1, 32.3, 37.1, 45.8, 52.2, 52.9,
70.6, 76.6, 123.2, 126.8, 127.9, 128.1, 128.7, 138.0, 157.2, 171.1;
The second product to elute (4 mg, 20%) was (1R,1′S,5R,7S,-
8R,9S)-7-hydroxy-1-((1′-phenylmethoxy)hexane)-8-phenylsele-
nyl-1,2,5,6,6a,7,8-hexahydro-2-oxaindolizine-3,5-dione acetic
acid methyl ester (35) as a colorless oil: [R]23 -31.5 (c 0.13,
D
CHCl3); IR (neat) 3430, 2938, 2860, 1755, 1732, 1400, 1338,
1
1254 cm-1; H NMR (CDCl3, 300 MHz) δ 0.92 (t, 3H, J ) 6.9
Hz), 1.32 (m, 6H), 1.77 (m, 3H), 1.91 (dd, 1H, J ) 14.0 and 4.3
Hz), 2.62 (d, 2H, J ) 8.1 Hz), 2.67 (s, 1H), 3.05 (d, 1H, J )
10.8 Hz), 3.64 (m, 1H), 3.73 (s, 3H), 3.91 (m, 1H), 4.08 (d, 1H,
J ) 10.8 Hz), 4.12 (m, 1H), 4.29 (dt, 1H, J ) 10.2 and 3.6 Hz),
4.50 (dd, 1H, J ) 10.2 and 7.2 Hz), 4.61 (m, 1H), 7.01 (m, 2H),
7.33 (m, 6H), 7.64 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.2,
22.6, 22.7, 29.8, 32.3, 35.3, 38.1, 45.9, 52.2, 56.8, 57.5, 66.3,
69.7, 75.1, 76.4, 127.3, 127.8, 128.1, 128.5, 129.9, 138.1, 155.9,
170.4; HRMS calcd for C29H37NO6Se, 567.1867 [M + H]+;
found, 567.1873 [M + H]+.
HRMS calcd for
C
23H31NO5, 402.2280 [M + H]+; found,
402.2286 [M + H]+.
F r om 37: To a refluxing mixture of 16 mg (0.0234 mmol)
of 37 and 1 mg of AIBN in 5 mL of toluene was added dropwise
7.5 mg (0.0257 mmol) of tributyltin hydride. After 5 min, the
reaction mixture was cooled and concentrated under reduced
pressure. The crude residue was purified by radial PLC (silica
gel, 25% EtOAc/hexanes) to give 8.56 mg (95%) of 29.
On e-P ot Syn th esis of 29 fr om a Dia ster eom er ic Mix-
tu r e of 34 a n d 35. To a solution of 89 mg (0.155 mmol) of
33a /b in 8 mL of MeOH was added 64 mg (0.172 mmol) of
cerium(III) trichloride heptahydrate. After 5 min, 7.1 mg (0.188
mmol) of NaBH4 was added in one portion, and stirring was
continued for 15 min. The reaction mixture was diluted with
water, extracted with CH2Cl2, and dried over MgSO4. The
solvent was removed under reduced pressure, and the residue
was filtered over a small plug of silica gel to give 76 mg (85%)
of a mixture of 34 and 35 which was used without further
purification.
To a solution of 76 mg (0.132 mmol) of 34 and 35 and 60
mg (0.337 mmol) of 1,1′-thiocarbonyldiimidazole in 5 mL of
toluene was added 3 mg of DMAP, and the mixture was heated
to reflux for 3 h. To the reaction mixture was added 3 mg of
AIBN followed by 46 mg (0.158 mmol) of tributyltin hydride.
The mixture was refluxed for an additional 15 min, cooled to
rt, and concentrated under reduced pressure. The residue was
purified by radial PLC (silica gel, EtOAc/hexanes) to give 45
mg (85%) of 29.
(1R,1′S,5R,7R,8S,9S)-7-(Im id a zole-1-ca r both ioyloxy)-1-
((1′-ph en ylm eth oxy)h exan e)-8-ph en ylselen yl-1,2,5,6,6a,7,8-
h exa h yd r o-2-oxa in d olizin e-3,5-d ion e Acetic Acid Meth yl
Ester (36). To a solution of 10 mg (0.0174 mmol) of 34 and 9
mg (0.0505 mmol) of 1,1′-thiocarbonyldiimidazole in 10 mL of
toluene was added 1 mg of DMAP, and the mixture was heated
to reflux for 3 h. The reaction was cooled to rt and concentrated
under reduced pressure. The crude reaction mixture was
purified by radial PLC (silica gel, 40% EtOAc/hexanes) to give
10.8 mg (91%) of 36 as a colorless solid: mp 138-139 °C
(EtOAc/hexanes); [R]23 -73.9 (c 0.13, CHCl3); IR (thin film)
D
2946, 2858, 1758, 1385, 1322, 1282, 1224, 1104, 1027 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.85 (t, 3H, J ) 7.0 Hz), 1.25
(m, 5H), 1.55 (m, 2H), 1.89 (m, 2H), 2.45 (dd, 1H, J ) 14.5
and 9.4 Hz), 2.54 (m, 1H), 2.69 (dd, 1H, J ) 14.2 and 6.9 Hz),
3.46 (dd, 1H, J ) 11.7 and 3.0 Hz), 3.53 (s, 3H), 4.08 (m, 1H),
4.27 (dd, 1H, J ) 11.7 and 8.0 Hz), 4.45 (m, 1H), 4.57 (d, 1H,
J ) 11.5 Hz), 4.69 (d, 1H, J ) 11.5 Hz), 4.88 (dd, 1H, J ) 7.6
and 3.5 Hz), 5.72 (m, 1H), 7.10 (s, 1H), 7.33 (m, 10H), 7.59 (s,
1H), 8.29 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 22.8, 24.7,
29.9, 30.1, 31.9, 36.6, 41.7, 44.9, 52.2, 53.8, 71.3, 77.1, 78.2,
118.0, 126.0, 128.1, 128.3, 128.7, 129.4, 129.9, 131.5, 135.6,
137.1, 138.1, 156.2, 170.4, 182.5. Anal. Calcd for C33H39N3O6-
SSe: C, 57.89; H, 5.74; N, 6.14. Found: C, 57.83; H, 5.88; N,
6.06.
3-[(3-Cya n op r op yl)-p-tolu en esu lfon yla m in o]p r op ion -
ic Acid Meth yl Ester (42). To 715 mg (3.00 mmol) of 4125 in
20 mL of acetonitrile was added 2.74 g (19.80 mmol) of
anhydrous K2CO3 followed by 1.35 mL (15.0 mmol) of methyl
acrylate. After being stirred for 4 h at rt, the reaction mixture
was filtered and concentrated under reduced pressure. The
crude residue was purified by radial PLC (silica gel, EtOAc/
hexanes) to give 973 mg (100%) of 42 as a colorless oil: IR
(1R,1′S,5R,7S,8R,9S)-7-(Im id a zole-1-ca r both ioyloxy)-1-
((1′-ph en ylm eth oxy)h exan e)-8-ph en ylselen yl-1,2,5,6,6a,7,8-
h exa h yd r o-2-oxa in d olizin e-3,5-d ion e Acetic Acid Meth yl
Ester (37). To a solution of 15 mg (0.0261 mmol) of 35 and 14
mg (0.0786 mmol) of 1,1′-thiocarbonyldiimidazole in 5 mL of
toluene was added 1 mg of DMAP, and the mixture was heated
to reflux for 3 h. The reaction was cooled to rt and concentrated
under reduced pressure. The crude product was purified by
radial PLC (silica gel, 40% EtOAc/hexanes) to give 17 mg (95%)
of 37 as a colorless oil: [R]23D +112.4 (c 0.105, CHCl3); IR (neat)
2934, 2861, 1763, 1736, 1388, 1325, 1283, 1229, 1096, 996
(neat) 2954, 2249, 1736, 1595, 1437, 1339, 1200, 1159 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.95 (m, 2H), 2.44 (m, 5H), 2.64
(t, 2H, J ) 7.1 Hz), 3.20 (t, 2H, J ) 6.8 Hz), 3.40 (t, 2H, J )
7.1 Hz), 3.68 (s, 3H), 7.33 (d, 2H, J ) 8.0 Hz), 7.69 (d, 2H, J
) 8.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.6, 21.5, 25.0, 34.3,
45.1, 48.2, 51.9, 119.1, 127.3, 130.0, 135.6, 144.0, 171.6; HRMS
calcd for C15H20N2O4S, 325.1222 [M + H]+; found, 325.1232
[M + H]+.
N-(4-Am in obu t yl)-N-(3-h yd r oxyp r op yl)-4-m et h ylb en -
zen esu lfon a m id e (43). To a solution of 1.00 g (3.08 mmol)
of 42 in 35 mL of THF at 0 °C was added dropwise 6.20 mL
(6.16 mmol) of a 1.0 M solution of LAH in THF. The resulting
mixture was allowed to warm to rt and stirred for 5 h. The
solution was cooled to 0 °C, carefully quenched with water,
and extracted with ethyl acetate. The combined organic
extracts were dried over MgSO4, and the solvent was removed
under reduced pressure. The residue was purified by radial
PLC (silica gel, EtOAc/hexanes) to give 645 mg (70%) of 43 as
a colorless oil: IR (neat) 3367, 2939, 2870, 1597, 1460, 1331,
1155 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.54 (m, 5H), 1.75 (t,
2H, J ) 5.9 Hz), 2.40 (s, 3H), 2.71 (t, 2H, J ) 6.2 Hz), 3.00 (br
m, 2H), 3.10 (t, 2H, J ) 7.0 Hz), 3.19 (t, 2H, J ) 6.5 Hz), 3.67
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.90 (t, 3H, J ) 7.5 Hz),
1.36 (m, 6H), 1.81 (m, 2H), 2.04 (dd, 1H, J ) 13.2 and 3.6 Hz),
2.68 (m, 3H), 3.72 (s, 3H), 3.74 (d, 1H, J ) 11.1 Hz), 4.22 (m,
2H), 4.40 (d, 1H, J ) 11.1 Hz), 4.57 (m, 2H), 4.77 (m, 1H),
5.74 (m, 1H), 6.91 (s, 1H), 7.11 (m, 2H), 7.20 (m, 2H), 7.33 (m,
7H), 8.00 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 22.6, 22.8,
29.7, 29.8, 32.3, 38.3, 45.8, 47.0, 52.4, 56.3, 70.0, 74.7, 76.4,
78.6, 117.9, 127.6, 127.9, 128.1, 128.8, 129.0, 129.8, 131.1,
132.6, 137.0, 138.0, 155.7, 170.2, 182.6; HRMS calcd for
C
33H39N3O6SSe, 686.1805 [M + H]+; found, 686.1793 [M + H]+.
(1R,1′S,5R,9R)-3-Oxo-1-((1′-p h en ylm et h oxy)h exa n e)-
1,5,6,8a-tetr ah ydr o-oxazolo[3,4-a ]pyr idin -5-yl Acetic Acid
Meth yl Ester (29). F r om 36: To a refluxing mixture of 158
5228 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Total Synthesis of (+)-Cannabisativine
(t, 2H, J ) 5.3 Hz), 7.28 (d, 2H, J ) 8.1 Hz), 7.66 (d, 2H, J )
7.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.6, 26.3, 29.9, 31.9,
41.4, 45.6, 49.3, 58.9, 127.3, 128.9, 136.4, 143.4; HRMS calcd
for C14H24N2O3S, 301.1586 [M + H]+; found, 301.1591 [M +
H]+.
(1R*,1′S*,5R*,9R*)-N-Ben zyl-N-{4-[((3-h yd r oxyp r op yl)-
(tolu en e-4-su lfon yl)a m in o]-2-[3-oxo-1-(1′-p h en ylm eth ox-
yh exyl)-1,5,6,8a -tetr a h yd r o-oxa zolo[3,4-a ]p yr id in -5-yl]-
a ceta m id e (48). To a stirred solution of 19 mg (0.049 mmol)
of carboxylic acid 45 in 5 mL of CH2Cl2 was added 7 mg (0.057
mmol) of oxalyl chloride followed by 1 drop of DMF. The
resulting mixture was stirred for 1 h and concentrated under
reduced pressure. The crude acid chloride (46) was redissolved
in 1 mL of CH2Cl2 and added dropwise to a mixture of 57 mg
(0.146 mmol) of 44 in a mixture of 3 mL of CH2Cl2 and 0.5 mL
of 10% NaOH. The reaction mixture was allowed to stir for
1.5 h, diluted with CH2Cl2, and the organic layer was sepa-
rated. The aqueous layer was extracted with CH2Cl2, and the
combined extracts were dried over MgSO4. The solvent was
removed under reduced pressure, and the residue was purified
by radial PLC (silica gel, EtOAc) to give 30 mg (81%) of 48 as
a colorless oil: IR (neat) 3455, 2931, 2867, 1750, 1637, 1450,
1413, 1333, 1221, 1157, 1087 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.89 (t, 3H, J ) 6.3 Hz), 1.26-1.77 (m, 14H), 2.13 (m, 1H),
2.41 (s, 3H), 2.64 (m, 4H), 3.18 (m, 6H), 3.42 (m, 1H), 3.63 (m,
3H), 4.37 (t, 1H, J ) 11.2 Hz), 4.56 (m, 5H), 5.68 (m, 1H), 5.80
(m, 1H), 7.26 (m, 12H), 7.65 (m, 2H); 13C NMR (CDCl3, 75
MHz) δ 14.2, 21.7, 22.8, 23.0, 24.8, 25.6, 26.4, 27.5 and 27.7
(due to rotamers), 29.1, 32.0 and 32.3 (due to rotamers), 35.9
and 36.1 (due to rotamers), 45.6 and 46.0 (due to rotamers),
45.8, 47.0, 48.4, 49.0 and 49.3 (due to rotamers), 51.3, 52.9
and 53.0 (due to rotamers), 59.2, 70.6, 76.6, 122.9 and 123.1
(due to rotamers), 126.4, 126.6, 126.8, 127.3, 127.6, 127.9,
128.1, 128.7, 128.8, 129.2, 129.9, 136.5 and 136.7 (due to
rotamers), 137.7 and 138.1 (due to rotamers), 143.4 and 143.7
(due to rotamers), 157.0, 169.9 and 170.4 (due to rotamers).
HRMS calcd for C43H57N3O7S, 760.3995 [M + H]+; found,
760.4002 [M + H]+.
N-(4-Ben zyla m in obu tyl)-N-(3-h yd r oxyp r op yl)-4-m eth -
ylben zen esu lfon a m id e (44). To a solution of 380 mg (1.26
mmol) of 43 in 20 mL of CHCl3 was added 1.00 g of MgSO4
followed by 134 mg (1.26 mmol) of benzaldehyde. The resulting
mixture was heated at reflux for 18 h, cooled to rt, and
concentrated under reduced pressure. The crude imine was
dissolved in 15 mL of methanol, cooled to 0 °C, and 62 mg
(1.64 mmol) of sodium borohydride was added. The mixture
was stirred an additional 1 h at rt, quenched with water, and
extracted with CH2Cl2. The solvent was removed under
reduced pressure, and the product was purified by radial PLC
(silica gel, EtOAc/hexanes) to give 200 mg (41%) of 44 as a
colorless oil: IR (neat) 3366, 2940, 2869, 1595, 1460, 1330
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.52 (m, 3H), 1.74 (m, 2H),
2.39 (s, 3H), 2.59 (t, 2H, J ) 6.1 Hz), 2.75 (m, 2H), 3.09 (m,
2H), 3.20 (m, 2H), 3.67 (m, 3H), 3.75 (s, 2H), 7.28 (m, 7H),
7.65 (d, 2H, J ) 6.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.6,
26.7, 27.2, 31.8, 45.4, 48.7, 49.1, 54.0, 58.9, 127.1, 127.2, 128.3,
128.6, 129.8, 136.6, 140.1, 143.1; HRMS calcd for C21H30N2O3S,
391.2065 [M + H]+; found, 391.2055 [M + H]+.
(1R,1′S,5R,9R)-3-Oxo-1-((1′-p h en ylm et h oxy)h exa n e)-
1,5,6,8a-tetr ah ydr o-oxazolo[4,3-a ]pyr idin -5-yl Acetic Acid
(45). To a stirred solution of 40 mg (0.10 mmol) of 29 in 3 mL
of MeOH was added 39 mg (0.70 mmol) of KOH in 1 mL of
H2O. The resulting mixture was stirred for 2 h at rt and then
concentrated to a small volume. The crude material was
redissolved in 10 mL of H2O and then washed with ether. The
aqueous layer was acidified with 10% HCl and extracted with
ethyl acetate. The organic extracts were dried over MgSO4 and
concentrated under reduced pressure to afford 39 mg (100%)
(1′R*,2R*,2′S*,6R*)-N-Ben zyl-2-[6-(2′-p h en ylm et h oxy-
1′-h yd r oxyh ep t yl)-1,2,3,6-t et r a h yd r op yr id in -2-yl]-N-[4-
[(3-h yd r oxyp r op yl)-(tolu en e-4-su lfon yl)a m in o]bu tyl]a c-
eta m id e (51). To a solution of 20 mg (0.0263 mmol) of 48 in
1.5 mL of MeOH was added 1.5 mL of 50% KOH in water.
The resulting solution was heated at reflux for 18 h and
concentrated to dryness under reduced pressure. The crude
residue was extracted with CH2Cl2, and the organic extracts
were filtered over anhydrous K2CO3. The solvent was removed
under reduced pressure, and the product was purified by radial
PLC (silica gel, 7% MeOH/CHCl3) to give 15 mg (79%) of 51
as a colorless oil: IR (neat) 3401, 2931, 2856, 1627, 1450, 1333,
of 45 as a colorless oil: [R]23 +23.5 (c 1.95, CHCl3); IR (neat)
D
2930, 1749, 1414, 1224, 1066 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.89 (t, 3H, J ) 6.4 Hz), 1.31 (m, 4H), 1.44 (m, 3H), 1.75 (m,
2H), 1.95 (dd, 1H, J ) 18.2 and 3.6 Hz), 2.61 (m, 3H), 3.63 (m,
1H), 4.37 (d, 1H, J ) 11.1 Hz), 4.46 (m, 1H), 4.56 (m, 1H),
4.62 (d, 1H, J ) 11.1 Hz), 5.74 (m, 1H), 5.85 (m, 1H), 7.33 (m,
5H), 9.11 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 22.8,
23.0, 27.3, 29.1, 32.3, 36.9, 45.7, 52.8, 70.6, 76.6, 123.1, 126.7,
127.9, 128.0, 128.7, 137.9, 157.3, 175.6; HRMS calcd for C22H29
-
NO5, 388.2124 [M + H]+; found, 388.2130 [M + H]+.
1
1151 cm-1; H NMR (CDCl3, 300 MHz) δ 0.88 (m, 3H), 1.26-
2-[1-(1-Bezyloxyh exyl)-3-oxo-1,5,6,8a -t et r a h yd r o-ox-
a zolo[3,4-a ]p yr id in e-5-yl]-N-{4-[(3-h yd r oxyp r op yl)-(tolu -
en e-4-su lfon yl)-a m in o]-bu tyl}a ceta m id e (47). To a stirred
solution of 19 mg (0.049 mmol) of carboxylic acid 45 in 5 mL
of CH2Cl2 was added 7 mg (0.0568 mmol) of oxalyl chloride
followed by 1 drop of DMF. The resulting mixture was stirred
for 1 h and concentrated under reduced pressure. The crude
acid chloride (46) was redissolved in 1 mL of CH2Cl2 and added
dropwise to a mixture of 44 mg (0.146 mmol) of 43 in a mixture
of 3 mL of CH2Cl2 and 0.5 mL of 10% NaOH. The reaction
mixture was allowed to stir for 1.5 h, diluted with CH2Cl2, and
the organic layer was separated. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
dried over MgSO4. The solvent was removed under reduced
pressure, and the residue was purified by radial PLC (silica
gel, EtOAc) to give 32 mg (96%) of 47 as a colorless oil: IR
(thin film) 3332, 2934, 2863, 1743, 1646, 1549, 1417, 1330,
1.73 (m, 16H), 2.26 (m, 2H), 2.42 (s, 3H), 2.53 (m, 1H), 2.81-
3.40 (m, 8H), 3.67 (m, 6H), 4.56 (m, 4H), 5.82 (m, 2H), 7.28
(m, 12H), 7.66 (d, 2H, J ) 7.6 Hz); 13C NMR (CDCl3, 75 MHz)
δ 14.1 and 14.3 (due to rotamers), 21.7, 22.9, 24.6, 24.7 and
24.8 (due to rotamers), 25.6, 26.4 and 26.5 (due to rotamers),
29.2 and 29.4 (due to rotamers), 30.4 and 30.5 (due to
rotamers), 32.2 and 32.3 (due to rotamers), 37.0, 45.4, 45.8
and 46.0 (due to rotamers), 46.7, 48.4, 49.3, 51.0, 52.3 and 52.5
(due to rotamers), 71.8, 74.6 and 74.7 (due to rotamers), 79.6
and 79.7 (due to rotamers), 125.6 and 125.8 (due to rotamers),
126.4, 126.7, 127.3, 127.6, 127.8, 127.9, 128.1, 128.6, 128.9,
129.2, 129.9, 130.0, 136.6, 138.8, 143.5 and 143.7 (due to
rotamers), 172.5. HRMS calcd for C42H59N3O6S, 734.4203 [M
+ H]+; found, 734.4243 [M + H]+.
N-(4-Ben zyla m in ob u t yl)-N-(3,3-d im et h oxyp r op yl)-4-
m eth ylben zen esu lfon a m id e (53). To a solution of 100 mg
(0.420 mmol) of 4125 in 6 mL of acetonitrile was added 290
mg (2.10 mmol) of K2CO3 followed by 193 mg (0.840 mmol) of
iodide 52.28 The mixture was heated to reflux for 16 h, filtered,
and concentrated under reduced pressure. The residue was
purified by radial PLC (silica gel, EtOAc/hexanes) to give 135
mg (94%) of N-(3-cyanopropyl)-N-(3,3-dimethoxypropyl)-4-
methyl-benzenesulfonamide as a colorless oil: IR (neat) 2942,
1
1228, 1157, 1091 cm-1; H NMR (CDCl3, 300 MHz) δ 0.84 (t,
3H, J ) 6.5 Hz), 1.30 (m, 5H), 1.44 (m, 2H), 1.56 (m, 4H), 1.78
(m, 3H), 2.00 (dd, 1H, J ) 17.6 and 4.3 Hz), 2.43 (s, 3H), 2.54
(m, 3H), 3.10 (m, 2H), 3.21 (m, 4H), 3.59 (m, 1H), 3.72 (t, 2H,
J ) 5.3 Hz), 4.39 (m, 2H), 4.58 (m, 3H), 5.78 (m, 1H), 5.86 (m,
1H), 6.31 (m, 1H), 7.33 (m, 7H), 7.68 (d, 2H, J ) 8.0 Hz); 13C
NMR (CDCl3, 75 MHz) δ 14.2, 21.7, 22.8, 23.1, 26.4, 26.6, 27.6,
29.0, 32.0, 32.3, 39.1, 39.3, 45.8, 46.0, 49.3, 52.6, 59.2, 70.7,
76.6, 77.0, 122.7, 126.4, 127.4, 127.9, 128.1, 128.7, 130.0, 136.3,
137.9, 143.6, 157.4, 169.9.
2249, 1596, 1459, 1338, 1156, 1121, 1060 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.85 (m, 2H), 1.94 (m, 2H), 2.44 (m, 5H),
3.18 (m, 4H), 3.31 (s, 6H), 4.38 (t, 1H, J ) 5.4 Hz), 7.32 (d,
J . Org. Chem, Vol. 69, No. 16, 2004 5229

Kuethe and Comins
2H, J ) 8.1 Hz), 7.68 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3, 75
MHz) δ 14.7, 21.6, 25.3, 32.4, 45.3, 47.9, 53.5, 102.5, 119.2,
127.3, 129.9, 136.0, 143.8.
128.0, 128.1, 128.7, 128.8, 129.2, 129.6, 130.0, 136.8 and 137.0
(due to rotamers), 137.7 and 138.1 (due to rotamers), 170.2.
To a solution of 11 mg (0.0137 mmol) of the above carbamate
in 1.5 mL of MeOH was added 1.5 mL of 50% KOH in water.
The resulting solution was heated at reflux for 18 h and
concentrated to dryness under reduced pressure. The crude
residue was extracted with CH2Cl2, and the organic extracts
were dried over anhydrous K2CO3. The solvent was removed
under reduced pressure, and the product was purified by radial
PLC (silica gel, 7% MeOH/CHCl3) to give 8.5 mg (80%) of 54
as a colorless oil: IR (neat) 3412, 2931, 1631, 1454, 1337, 1155,
To a solution of 135 mg (0.397 mmol) of the above cyano
compound in 10 mL of THF at 0 °C was added dropwise 0.40
mL (0.400 mmol) of a 1.0 M solution of LAH in THF. The
resulting mixture was allowed to warm to rt and stirred for 5
h. The solution was cooled to 0 °C, carefully quenched with
water, and extracted with ethyl acetate. The combined organic
extracts were dried over MgSO4, and the solvent was removed
under reduced pressure. The residue was purified by radial
PLC (silica gel, EtOAc/hexanes) to give 117 mg (85%) of N-(4-
aminobutyl)-N-(3,3-dimethoxypropyl)-4-methyl-benzenesulfona-
mide as a colorless oil: IR (neat) 3374, 2936, 1597, 1458, 1335,
1157, 1123, 1061 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.43 (m,
2H), 1.57 (m, 3H), 1.86 (m, 3H), 2.41 (s, 3H), 2.67 (t, 2H, J )
7.0 Hz), 3.14 (m, 4H), 3.31 (s, 6H), 4.38 (m, 1H), 7.27 (d, 2H,
J ) 7.9 Hz), 7.67 (d, 2H, J ) 7.9 Hz); 13C NMR (CDCl3, 75
MHz) δ 21.6, 26.3, 30.9, 32.5, 41.9, 44.4, 48.8, 53.4, 102.7,
127.3, 129.8, 136.9, 143.3; HRMS calcd for C16H28N2O4S,
345.1848 [M + H]+; found, 345.1848 [M + H]+.
1
1119, 1089 cm-1; H NMR (CDCl3, 300 MHz) δ 0.88 (m, 3H),
1.30-1.89 (m, 18H), 2.24-2.63 (m, 6H), 3.10 (m, 6H), 3.30 (s,
6H), 3.39-3.80 (m, 4H), 4.35 (m, 1H), 4.50 (m, 1H), 4.57 (m,
2H), 5.80 (m, 1H), 5.88 (m, 1H), 7.13 (m, 1H), 7.30 (m, 11H),
7.65 (d, 2H, J ) 7.9 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.3,
21.7, 22.9, 24.7 and 24.8 (due to rotamers), 25.6, 26.3 and 26.5
(due to rotamers), 29.3 and 29.4 (due to rotamers), 29.8 and
30.2 (due to rotamers), 32.4 and 32.6 (due to rotamers), 36.5,
44.7, 45.8, 36.9 and 47.1 (due to rotamers), 48.6 and 48.8 (due
to rotamers), 51.1, 52.3 and 52.5 (due to rotamers), 53.5 and
53.6 (due to rotamers), 71.8, 74.3 and 74.4 (due to rotamers),
79.1, 102.5, 125.5, 126.4, 126.7, 127.4, 127.6, 127.8, 128.6,
128.9, 129.2, 130.0, 136.7 and 136.8 (due to rotamers), 137.8
and 138.8 (due to rotamers), 143.4, 171.8 and 172.3 (due to
rotamers). HRMS calcd for C44H63N3O7S, 778.4465 [M + H]+;
found, 778.4508 [M + H]+.
To a solution of 220 mg (0.64 mmol) of the above amine in
20 mL of CHCl3 was added 1.00 g of MgSO4 followed by 68
mg (0.64 mmol) of benzaldehyde. The resulting mixture was
heated at reflux for 18 h, cooled to rt, and concentrated under
reduced pressure. The crude imine was dissolved in 15 mL of
methanol, cooled to 0 °C, and 29 mg (0.767 mmol) of sodium
borohydride was added. The mixture was stirred an additional
1 h at rt, quenched with water, and extracted with CH2Cl2.
The combined organic extracts were dried (K2CO3), and the
solvent was removed under reduced pressure. The crude
product was purified by radial PLC (silica gel EtOAc/hexanes)
to give 139 mg (50%) of 53 as a colorless oil: IR (neat) 3204,
(1R,1′S,5R,9R)-N-Ben zyl-2-[3-oxo-1-((1-ph en ylm eth oxy)-
h exa n e)-1,5,6,8a -tetr a h yd r o-oxa zolo[3,4-a ]p yr id in -5-yl]-
N-(4-h yd r oxybu tyl)a ceta m id e (57). To a stirred solution of
20 mg (0.0516 mmol) of carboxylic acid 45 in 5 mL of CH2Cl2
was added 7 mg (0.0568 mmol) of oxalyl chloride followed by
1 drop of DMF. The resulting mixture was stirred for 1 h and
then concentrated under reduced pressure. The crude acid
chloride was redissolved in 1 mL of CH2Cl2 and added dropwise
to a mixture of 54 mg (0.300 mmol) of 4-benzylamino-butan-
1-ol (56) in 3 mL of CH2Cl2 and 0.5 mL of 10% NaOH. The
reaction mixture was allowed to stir for 1.5 h and then diluted
with CH2Cl2. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by radial
PLC (silica gel, EtOAc) to give 25.5 mg (82%) of 57 as a
colorless oil: [R]23D +26.8 (c 1.70, CHCl3); IR (neat) 3448, 2930,
2867, 1749, 1637, 1452, 1417, 1376, 1223, 1070 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.88 (m, 3H), 1.29-1.75 (m, 15H), 2.05
(m, 1H), 2.61 (m, 3H), 3.25 (m, 1H), 3.62 (m, 3H), 4.38 (m,
2H), 4.57 (m, 4H), 5.78 (m, 2H), 7.30 (m, 10H); 13C NMR
(CDCl3, 75 MHz) δ 14.2, 22.8 and 23.0 (due to rotamers), 24.1,
25.3, 27.4 and 27.6 (due to rotamers), 29.0, 29.7 and 29.8 (due
to rotamers), 32.3, 36.0 and 36.2 (due to rotamers), 45.8 and
46.0 (due to rotamers), 47.3, 48.4, 51.4, 53.0 and 53.1 (due to
rotamers), 62.2 and 62.6 (due to rotamers), 70.6, 76.6, 123.0,
126.4, 126.6, 127.0, 127.6, 127.9, 128.0, 128.1, 128.8, 129.2,
136.7, 137.7 and 138.0 (due to rotamers), 157.0, 169.9 and
170.4 (due to rotamers); HRMS calcd for C33H44N2O5, 549.3328
[M + H]+; found, 549.3345 [M + H]+.
2940, 1595, 1460, 1332 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1.45-1.71 (m, 4H), 1.85 (m, 3H), 2.43 (s, 3H), 2.62 (t, 2H, J )
7.0 Hz), 3.17 (m, 4H), 3.30 (s, 6H), 3.77 (s, 2H), 4.38 (t, 1H, J
) 5.0 Hz), 7.31 (m, 7H), 7.67 (d, 2H, J ) 7.9 Hz); 13C NMR
(CDCl3, 75 MHz) δ 21.6, 26.6, 27.3, 32.5, 44.3, 48.8, 48.9, 53.4,
54.1, 102.7, 127.1, 127.3, 128.2, 128.5, 129.8, 136.9, 140.5,
143.2.
(1′R*,2R*,2′S*,6R*)-N-Ben zyl-2-[6-(2′-p h en ylm et h oxy-
1′-h yd r oxyh e p t yl)-1,2,3,6-t e t r a h yd r op yr id in -2-yl]-N -
[4[((3,3-d im et h oxyp r op yl)-(t olu en e-4-su lfon yl)-a m in o]-
bu tyl]a ceta m id e (54). To a stirred solution of 20 mg (0.052
mmol) of carboxylic acid 45 in 5 mL of CH2Cl2 was added 7
mg (0.057 mmol) of oxalyl chloride followed by 1 drop of DMF.
The resulting mixture was stirred for 1 h and concentrated
under reduced pressure. The crude acid chloride was redis-
solved in 1 mL of CH2Cl2 and added dropwise to a mixture of
67 mg (0.154 mmol) of 53 in 3 mL of CH2Cl2 and 0.5 mL of
10% NaOH. The reaction mixture was stirred for 1.5 h, diluted
with CH2Cl2, and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2, and the combined
organic extracts were dried over MgSO4. The solvent was
removed under reduced pressure, and the residue was purified
by radial PLC (silica gel, EtOAc) to give 24 mg (57%) of (1R*,
1′S*,5R*,9R*)-N-benzyl-N-[4-[(3,3-dimethoxypropyl)-(toluene-
4-sulfonyl)amino]butyl]-2-[3-oxo-1-(1′-phenylmethoxyhexyl)-
1,5,6,8a-tetrahydro-oxazolo[3,4-a]pyridin-5-yl]acetamide as a
colorless oil: IR (neat) 2930, 1637, 1455, 1336, 1152, 1120
(1′R,2R,2′S,6R)-N-Ben zyl-2-[6-(2′-p h en ylm eth oxy-1′-h y-
d r oxyh ep t yl)-1,2,3,6-t et r a h yd r o-p yr id in -2-yl]-N-(4-h y-
d r oxybu tyl)a ceta m id e (58). To a solution of 25 mg (0.0456
mmol) of 57 in 1.5 mL of MeOH was added 1.5 mL of 50%
aqueous KOH. The resulting solution was heated at reflux for
18 h and then concentrated to dryness under reduced pressure.
The crude residue was extracted with CH2Cl2 and filtered over
anhydrous K2CO3. The solvent was removed under reduced
pressure, and the product was purified by radial PLC (silica
gel, 7% MeOH/CHCl3) to give 21 mg (88%) of 58 as a colorless
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.89 (t, 3H, J ) 6.4 Hz),
1.26-1.84 (m, 16H), 1.97-2.19 (m, 1H), 2.41 (s, 3H), 2.61 (m,
1H), 3.10 (m, 6H), 3.25 (m, 1H), 3.30 (s, 6H), 3.40 (m, 1H),
3.60 (m, 1H), 4.32-4.58 (m, 6H), 5.68 (m, 1H), 5.82 (m, 1H),
7.51 (m, 12H), 7.67 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.2,
21.7, 22.8 and 23.0 (due to rotamers), 24.7, 25.4, 26.4, 27.5,
29.1, 32.3 and 32.5 (due to rotamers), 35.8 and 35.9 (due to
rotamers), 41.6, 44.6 and 44.7 (due to rotamers), 45.8 and 45.9
(due to rotamers), 46.9, 48.4 and 48.7 (due to rotamers), 51.3,
53.0, 53.4 and 53.6 (due to rotamers), 70.6, 76.5 and 76.6 (due
to rotamers), 78.0, 102.7, 123.0 and 123.2 (due to rotamers),
123.8, 126.4 and 126.9 (due to rotamers), 127.3, 127.5, 127.8,
oil: [R]23 +36.8 (c 1.15, CHCl3); IR (neat) 3401, 2920, 2856,
D
1627, 1450, 1359, 733, 698 cm-1; H NMR (CDCl3, 300 MHz)
1
δ 0.88 (m, 3H), 1.26-1.72 (m, 13H), 1.92-2.80 (m, 4H), 3.21
(t, 1H, J ) 7.7 Hz), 3.42 (m, 1H), 3.61 (m, 3H), 3.84 (m, 5H),
4.56 (m, 4H), 5.78 (m, 2H), 7.25 (m, 10H); 13C NMR (CDCl3,
5230 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Total Synthesis of (+)-Cannabisativine
75 MHz) δ 14.3, 22.9, 24.3 and 24.7 (due to rotamers), 25.2,
29.4, 29.9 and 30.5 (due to rotamers), 32.4, 36.6 and 36.8 (due
to rotamers), 46.0, 46.9 and 47.1 (due to rotamers), 48.5, 51.2,
52.1 and 52.3 (due to rotamers), 62.2 and 62.5 (due to
rotamers), 71.7 and 71.9 (due to rotamers), 74.5, 79.7, 125.9,
126.4, 126.7, 127.9, 128.1, 128.6, 128.8, 129.2, 136.8 and 137.9
(due to rotamers), 138.3, 171.8 and 172.4 (due to rotamers);
HRMS calcd for C32H46N2O4, 523.3536 [M + H]+; found,
523.3560 [M + H]+.
(1′R,4R,2′S,15a R)-13-Ben zyl-4-(2′-p h en ylm eth oxy-1′-h y-
d r oxyh ep t yl)-8-(t olu en e-4-su lfon yl)-1,4,6,7,8,9,10,11,12,-
13,15,15a-dodecah ydr o-5H-4a,8,13-tr iazaben zocyclotr ide-
cen -14-on e (55). To a solution of 39 mg (0.048 mmol) of the
above mesylate in 150 mL of anhydrous acetonitrile was added
2.0 g (14.5 mmol) of anhydrous potassium carbonate. The
mixture was refluxed for 24 h, cooled to rt, and filtered through
a pad of Celite. The solvent was removed under reduced
pressure, and the crude residue was purified by radial PLC
(silica gel, 7% MeOH/CHCl3) to give 24 mg (70%) of 55 as a
(1′R,2R,2′S,6R)-N-Ben zyl-2-[6-(2′-p h en ylm eth oxy-1′-h y-
d r oxyh e p t yl)-1-[3-(t olu e n e -4-su lfon yla m in o)p r op yl]-
1,2,3,6-tetr a h yd r o-p yr id in -2-yl]-N-(4-h yd r oxybu tyl)a ce-
ta m id e (60). To a stirred solution of 45 mg (0.0861 mmol) of
58 in 7 mL of CH2Cl2 was added 45 mg (0.344 mmol) of N,N-
diisopropylethylamine followed by 53 mg (0.146 mmol) of
trifluoromethanesulfonic acid 3-(toluene-4-sulfonylamino)pro-
pyl ester (59).30 After 3 h, the reaction was quenched with 1
mL of saturated NaHCO3 and then extracted with CH2Cl2. The
combined organic extracts were dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified
by radial PLC (silica gel, 7% MeOH/CHCl3) to give 53 mg (84%)
of 60 as a clear oil: [R]23D +41.5 (c 0.40, CHCl3); IR (neat) 3436,
3271, 2931, 2860, 1619, 1454, 1325, 1155, 1090 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.89 (m, 3H), 1.30-2.08 (m, 17H), 2.43
(m, 8H), 2.95 (m, 2H), 3.00-3.65 (m, 6H), 3.79 (m, 2H), 4.54
(m, 4H), 5.61 (m, 1H), 5.91 (m, 1H), 6.05 (m, 1H), 7.29 (m,
12H), 7.34 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.3, 21.7,
22.9, 24.2 and 24.5 (due to rotamers), 25.3, 27.2 and 27.4 (due
to rotamers), 29.6 and 30.2 (due to rotamers), 29.8, 32.4, 32.2
and 33.3 (due to rotamers), 41.3 and 41.5 (due to rotamers),
45.0 and 45.1 (due to rotamers), 46.4, 47.4, 48.7, 51.4, 58.8
and 58.9 (due to rotamers), 62.2 and 62.4 (due to rotamers),
71.5, 73.0 and 73.6 (due to rotamers), 79.8 and 80.1 (due to
rotamers), 124.8 and 124.9 (due to rotamers), 126.4, 127.3,
127.5, 127.8, 127.9, 128.1, 128.6, 129.2, 129.8, 136.9 and 137.2
(due to rotamers), 137.4 and 137.9 (due to rotamers), 138.7,
143.2 and 143.3 (due to rotamers), 171.9 and 172.8 (due to
rotamers); HRMS calcd for C42H59N3O6S, 734.4203 [M + H]+;
found, 734.4237 [M + H]+.
colorless oil: [R]23 +24.9 (c 0.225, CHCl3); IR (neat) 3394,
D
2922, 2860, 1635, 1451, 1338, 1158, 1092 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.87 (m, 3H), 1.27 (m, 6H), 1.60 (m, 7H),
1.70-2.17 (m, 5H), 2.43 (s, 3H), 2.55 (m, 1H), 2.74 (m, 1H),
2.85-3.18 (m, 4H), 3.53 (m, 3H), 3.76 (m, 1H), 4.00 (m, 3H),
4.60 (m, 3H), 5.25 (d, 1H, J ) 14.7 Hz), 5.77 (m, 1H), 5.96 (m,
1H), 7.29 (m, 12H), 7.66 (m, 2H); 13C NMR (CDCl3, 75 MHz)
δ 14.3 and 14.4 (due to rotamers), 21.7, 22.9, 23.9 and 24.4
(due to rotamers), 24.9 and 25.2 (due to rotamers), 25.8, 26.6,
28.3 and 28.9 (due to rotamers), 29.6 and 29.9 (due to
rotamers), 31.7 and 32.3 (due to rotamers), 34.6 and 35.4 (due
to rotamers), 43.0 and 43.4 (due to rotamers), 46.9 and 47.0
(due to rotamers), 49.4, 50.8 and 51.0 (due to rotamers), 51.6
and 52.2 (due to rotamers), 60.1, 71.3 and 71.5 (due to
rotamers), 74.4, 79.9, 126.3 and 126.5 (due to rotamers), 127.3
and 127.5 (due to rotamers), 127.7 and 127.8 (due to rotamers),
127.9 and 128.0 (due to rotamers), 128.2, 128.4, 128.7, 129.1,
129.9, 135.3, 138.0, 139.3, 143.6, 172.5; HRMS calcd for
C
42H57N3O5S, 716.4097 [M + H]+; found, 716.4111 [M + H]+.
P r ep a r a tion of (+)-Ca n n a bisa tivin e (1). To a solution
of 12 mL of liquid NH3 at -78 °C was added 77 mg (0.108
mmol) of 55 in 3 mL of THF. Small pieces of sodium were
added until a blue color persisted. The reaction mixture was
refluxed for 20 min, and then the ammonia was allowed to
evaporate. To the residue was carefully added 5 mL of water.
The mixture was extracted with ethyl acetate (3 × 15 mL).
The combined organic extracts were dried over K2CO3 and
concentrated under reduced pressure. The crude residue was
purified by flash silica gel chromatography (CHCl3/MeOH/NH4-
OH, 90:9:1) to give 31 mg (76%) of 1 as a colorless solid: mp
(1′R,2R,2′S,6R)-Meth a n esu lfon ic Acid 4-[Ben zyl-({6-(2′-
p h en ylm eth oxy-1′-h yd r oxy-h ep tyl)-1-[3-(tolu en e-4-su lfo-
n ylam in o)pr opyl]-1,2,3,6-tetr ah ydr o-pyr idin -2-yl}am in o]-
bu tyl Ester (61). To a solution of 41 mg (0.56 mmol) of 60 in
7 mL of CH2Cl2 at -20 °C was added 12.4 mg (0.123 mmol) of
triethylamine followed by 9 µL (0.112 mmol) of methanesulfo-
nyl chloride. The reaction was stirred for 30 min at -20 °C,
quenched with 1 mL of saturated aqueous NaHCO3, and
extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure.
The crude residue was purified by radial PLC (silica gel, 7%
MeOH/CHCl3) to afford 43 mg (95%) of the mesylate 61 as a
colorless oil: [R]23D +59.0 (c 0.20, CHCl3); IR (neat) 3283, 2928,
165-166 °C (lit.5 167-168 °C); [R]23 +51.76 (c 0.425, CHCl3)
D
[lit.5 +55.1 (c 0.53, CHCl3)]; IR (neat) 3300, 2995, 1635, 1540,
1
1260 cm-1; H NMR (CDCl3, 300 MHz) δ 0.88 (m, 3H), 1.30
(m, 9H), 1.60 (m, 5H), 1.94 (m, 5H), 2.11 (d, 1H, J ) 13.8 Hz),
2.47 (m, 3H), 2.65-2.95 (m, 5H), 3.05 (m, 1H), 3.25 (m, br s,
1H), 3.55 (m, 3H), 5.90 (m, 1H), 9.50 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.4, 23.0, 25.4, 26.4, 27.6, 28.1, 29.9, 32.4,
32.9, 40.0, 40.1, 42.1, 47.7, 50.8, 52.5, 61.5, 75.0, 75.8, 125.7,
127.4, 171.3.
1
2869, 1625, 1453, 1352, 1329, 1160, 1093, 937, 815 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.89 (m, 3H), 1.30 (m, 4H), 1.48 (m,
2H), 1.70 (m, 8H), 2.01 (m, 3H), 2.43 (m, 7H), 3.05 (m, 5H),
3.27 (m, 2H), 3.48 (m, 3H), 3.81 (m, 2H), 4.23 (m, 2H), 4.57
(m, 4H), 5.76 (m, 2H), 7.28 (m, 12H), 7.75 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 14.3, 21.5, 22.7, 23.6 and 24.3 (due to
rotamers), 24.6 and 24.8 (due to rotamers), 26.5 and 26.6 (due
to rotamers), 27.2 and 27.5 (due to rotamers), 28.3, 29.8 and
30.1 (due to rotamers), 32.0 and 32.3 (due to rotamers), 37.3,
41.4 and 41.6 (due to rotamers), 44.5 and 45.2 (due to
rotamers), 45.8 and 46.6 (due to rotamers), 48.6, 50.5, 50.9
and 51.2 (due to rotamers), 56.6 and 58.7 (due to rotamers),
69.4 and 69.8 (due to rotamers), 71.3 and 71.4 (due to
rotamers), 72.7 and 73.5 (due to rotamers), 79.5 and 79.9 (due
to rotamers), 125.0, 126.4, 127.3, 127.6, 127.8, 127.9, 128.2,
128.5, 128.8, 129.2, 129.8, 136.8 and 137.1 (due to rotamers),
137.4 and 137.9 (due to rotamers), 138.7 and 138.8 (due to
rotamers), 143.2, 171.9 and 172.8 (due to rotamers); HRMS
calcd for C43H61N3O8S2, 812.3978 [M + H]+; found, 812.3981
[M + H]+.
Ack n ow led gm en t. We express appreciation to the
National Institutes of Health (Grant GM 34442) for
financial support of this research. We are grateful to
1
Dr. H. Wasserman for 500 MHz H NMR spectral data
of cannabisativine. NMR and mass spectra were ob-
tained at NCSU instrumentation laboratories, which
were established by grants from the North Carolina
Biotechnology Center and the National Science Founda-
tion (Grants CHE-9509532 and CHE-0078253).
Su p p or tin g In for m a tion Ava ila ble: Comparison tables
1
of NMR data for synthetic 1, and H and 13C NMR spectra of
16, 17, 20, 22, 23, 27, 29, 33-35, 37, 42-45, 47, 48, 51, 54,
55, 57, 58, 60, 61, and 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O049724+
J . Org. Chem, Vol. 69, No. 16, 2004 5231