Stereoselective synthesis of (+)-euphococcinine and (-)-adaline

Article abstract of DOI:10.1021/jo9001992

(Chemical Equation Presented) We describe the syntheses of (+)-euphococcinine and (-)-adaline, two naturally occurring alkaloids containing a quaternary carbon bearing a nitrogen atom. Key features of the syntheses are a 3,3-sigmatropic rearrangement to give an all-carbon quaternary center, a ring-closing alkene metathesis to give an 8-membered ring, and the use of a single enantiomer of p-menthane-3-carboxaldehyde to make two natural alkaloids of opposite configuration.

Full text of DOI:10.1021/jo9001992

Stereoselective Synthesis of (+)-Euphococcinine and (-)-Adaline
Me´lissa Arbour,† Ste´phanie Roy,† Ce´drickx Godbout,‡ and Claude Spino*
UniVersite´ de Sherbrooke, De´partement de Chimie, 2500 BouleVard UniVersite´, Sherbrooke,
Que´bec, Canada J1K 2R1
claude.spino@usherbrooke.ca
ReceiVed January 29, 2009
We describe the syntheses of (+)-euphococcinine and (-)-adaline, two naturally occurring alkaloids
containing a quaternary carbon bearing a nitrogen atom. Key features of the syntheses are a 3,3-sigmatropic
rearrangement to give an all-carbon quaternary center, a ring-closing alkene metathesis to give an
8-membered ring, and the use of a single enantiomer of p-menthane-3-carboxaldehyde to make two natural
alkaloids of opposite configuration.
Introduction
One of the main challenges in their synthesis is the formation
of the quaternary center bearing nitrogen with control over the
absolute stereochemistry. There are a number of methods to
achieve this, including sigmatropic rearrangements,9 addition
of organometallic reagents on imine,10 and Curtius rearrange-
ment11 from chiral carboxylic acids, among others.12 In that
regard, allylic alcohol 7, derived from the stereoselective
addition of a vinylmetal 6 to p-menthane-3-carboxaldehyde 5,
has proven a useful chiral scaffold on which to perform
rearrangements and displacement reactions to introduce a new
C-C,11b C-N,13,11a,b or C-S14 bond in the product 8 (Scheme
Many natural alkaloids contain quaternary centers bearing a
nitrogen atom, and in particular, the defensive secretion of
Coccinellid contain such alkaloids as exochomine (1),1 eupho-
coccinine (2),2 adaline (3),3 and adalinine (4)4 (Figure 1).
Euphococcinine (2) and adaline (3) are members of the
9-azabicyclo[3.3.1]nonane family and are both potent feeding
deterrents to spiders and ants, part of the chemical defensive
arsenal of Coccinellid beetles.5 According to biosynthetic
studies,6 they are polyacetate in origin. Syntheses of these two
alkaloids as both a racemic7 or a nonracemic mixture8 have been
reported.
(6) Laurent, P.; Lebrun, B.; Braekman, J.-C.; Daloze, D.; Pasteels, J. M.
Tetrahedron 2001, 57, 3403–3412.
(7) (a) (()-Adaline and (()-euphococcinine: Davison, E. C.; Holmes, A. B.;
Forbes, I. T. Tetrahedron Lett. 1995, 36, 9047–9050. (b) Go¨ssinger, E.; Witkop,
B. Monatsh. Chem. 1980, 111, 803–811. (c) Gnecco Medina, D. H.; Grierson,
D. S.; Husson, H.-P. Tetrahedron Lett. 1983, 24, 2099–2102.
(8) (a) (-)- and (+)-adaline: Itoh, T.; Yamazaki, N.; Kibayashi, C. Org.
Lett. 2002, 4, 2469–2472. (b) Yue, C.; Royer, J.; Husson, H.-P. J. Org. Chem.
1992, 57, 4211–4214. (c) Hill, R. K.; Renbaum, L. A. Tetrahedron 1982, 38,
1959–1963. (d) Coombs, T. C.; Zhang, Y.; Garnier-Amblard, E. C.; Liebeskind,
L. S. J. Am. Chem. Soc. 2009, 131, 876–877(+)- and (-)-euphococcinine: (e)
Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 4339–4342. (f)
Murahashi, S.-I.; Sun, J.; Kurosawa, H.; Imada, Y. Heterocycles 2000, 52, 557–
561.
† Present address: Merck-Frosst Center for Therapeutic Research.
‡ Present address: Boehringer-Ingelheim (Canada), Ltd.
(1) Shi, X.; Attygalle, A. B.; Meinwald, J. Tetrahedron 1995, 51, 8711–
8718.
(2) Hart, N. K.; Johns, S. R.; Lamberton, J. A. Aust. J. Chem. 1967, 20,
561–563.
(3) Tursch, B.; Braekman, J. C.; Daloze, D.; Hootele, C.; Losman, D.;
Karlson, R.; Pasteels, J. M. Tetrahedron Lett. 1973, 3, 201–202.
(4) (a) Lognay, G.; Hemptinne, J. L.; Chan, F. Y.; Gaspar, C. H.; Marlier,
M.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. J. Nat. Prod 1996, 59, 510–
511. For a synthesis of adalinine, see: (b) Honda, T.; Kimura, M. Org. Lett.
2000, 2, 3925–3927.
(5) King, A. G.; Meinwald, J. Chem. ReV. 1996, 96, 1105–1122.
3806 J. Org. Chem. 2009, 74, 3806–3814
10.1021/jo9001992 CCC: $40.75 2009 American Chemical Society
Published on Web 04/16/2009

Synthesis of (+)-Euphococcinine and (-)-Adaline
FIGURE 1. Three defensive alkaloids contained in the blood of Coccinellid species.
SCHEME 1. p-Menthyl-3-carboxaldehyde 5 as a Chiral Scaffold for the Synthesis of Quaternary Carbons
SCHEME 2. Retrosynthesis of (-)-Euphococcinine (ent-2) and (-)-Adaline (3) Partly Inspired by Their Biosyntheses
SCHEME 3. Synthesis of the Protected Chiral Amine 14 via 3,3-Sigmatropic Rearrangement of Cyanate to Isocyanate
1). It has proven particularly useful for the formation of all-
carbon quaternary centers (8, Y ) C).11b,15
followed by its dehydration and the resulting cyanate rearranged
instantly at ambient temperature through a 3,3-sigmatropic
rearrangement into isocyanate 10. We had trouble establishing
the % de of this particular isocyanate (see the Supporting
Information), but since this initial route proved unfruitful (vide
infra) it was not pursued further. However, all quaternary
We therefore set out to construct the nitrogen-bearing
quaternary carbons of euphococcinine and adaline considering
that with two properly functionalized carbon chains as in 9, a
Mannich cyclization would conclude their respective syntheses
(Scheme 2). The Mannich cyclization should be viable according
to previous work7c,8c,f and from biosynthetic considerations.6
Our initial synthetic design called for the formation of the
nitrogen-bearing quaternary carbon by a cyanate to isocyanate
rearrangement.13a
(9) Cyanates to isocyanates: (a) Ichikawa, Y. Synlett 2007, 292, 7–2936, and
references cited therein. Sulfimide to thiolamine: (b) Armstrong, A.; Challinor,
L.; Cooke, R. S.; Moir, J. H.; Treweeke, N. R. J. Org. Chem. 2006, 71, 4028–
4030, and references cited therein. Imidate to carbamate. (c) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218–224.
(10) For selected examples, see: (a) Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003–8030. (b) Gro¨ger, H. Chem. ReV. 2003, 103, 2795–
2828. (c) Cativiela, C.; D`ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645–732. (d) Cativiela, C.; D`ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517–3599. (e) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069–
1094. (f) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–8904.
(g) Bloch, R. Chem. ReV. 1998, 98, 1407–1438.
(11) For selected examples, see: (a) Spino, C.; Godbout, C. J. Am. Chem.
Soc. 2003, 125, 12106–12107. (b) Spino, C.; Godbout, C.; Beaulieu, C.; Harter,
M.; Mwene-Mbeja, T. M.; Boisvert, L. J. Am. Chem. Soc. 2004, 126, 13312–
13319. (c) Back, T. G.; Wulff, J. E. Angew. Chem., Int. Ed. 2004, 43, 6493–
6496. (d) Yamada, F.; Kozikowski, A. P.; Reddy, E. R.; Pang, Y.-P.; Miller,
J. H.; McKinney, M. J. Am. Chem. Soc. 1991, 113, 4695–4696. (e) Ihara, M.;
Takahashi, M.; Niitsuma, H.; Taniguchi, N.; Yasui, K.; Fukumoto, K. J. Org.
Chem. 1989, 54, 5413–5415.
Results and Discussion
Vinyl iodide 12 was constructed using Sato’s allyltitanation16
from 5-hexyn-1-ol (see the Supporting Information for its
synthesis) and was transformed into the corresponding vinyl-
lithium, which was added to p-menthane-3-carboxaldehyde 5
to afford a 20:1 ratio of allylic alcohols 11a and 11b, which
were easily separated (Scheme 3). The terminal alkene in 11a
was oxidized using the Wacker protocol to give methyl ketone
13. Activation of the allylic alcohol into a carbamate was
J. Org. Chem. Vol. 74, No. 10, 2009 3807

Arbour et al.
SCHEME 4. Attempted Mannich Cyclization of Compounds
15-17
conditions) derived from any one of the former is not.
Considering that alkylation of the nitrogen in compound 10 and
dealkylation would add at least two more steps to our sequence,
we were not willing to pursue this avenue.
Instead, we investigated a synthetic approach toward
Coccinellid defensive alkaloids that used a Curtius rearrange-
ment to introduce the nitrogen atom. To that effect, an all-carbon
quaternary stereocenter bearing a carboxylic acid, as in 32,
needed to be built (Scheme 6). This could be easily achieved
using chiral auxiliary 5 and cleaving it under oxidative condi-
tions. The ketone and protected aldehyde in 31 would react form
the 8-membered ring, while the carboxylic acid would be
transformed into an amine that would cyclize to give 2.
The sequence began with a lithium-halogen exchange of
vinyl iodide 27, also prepared by Sato’s allyltitanation chemistry
(see the Supporting Information). The resulting vinyllithium was
added to p-menthane-3-carboxaldehyde 5 to give the corre-
sponding alcohol 28 as the major product (Scheme 6). The
allylic alcohol in 28 was activated as its phenylcarbamate (29)
for the syn-selective SN2′ addition of dialkylcuprate reagents.
The addition of a lithium dimethylcuprate gave 30a successfully,
but unfortunately, the addition of a lithium di(n-pentyl)cuprate
did not proceed at all to give 30b, regardless of the nature of
the leaving group or of the cuprate reagent. In our experience,
SN2′ displacements by cuprate reagents are quite sensitive to
steric effects, and bulky cuprates often lead to no reaction or
decomposition products. To compound the problem, the sub-
sequent steps in the synthesis of euphococcinine was a Wacker
oxidation of the alkene to give the methylketone 31, and it
proved problematic. This oxidation would likely not fare better
with the more hindered quaternary carbon of 30b had we been
able to generate it. A slight change in the strategy was therefore
called for.
In this altered strategy, the carboxylic acid 32 would be a
precursor to the alkaloids via a Curtius rearrangement. However,
we would make two modifications: first, find a more general
reaction to generate the quaternary carbon (see 34a f 33,
Scheme 7) to avoid the problematic SN2′ displacement by a
cuprate reagent; second, the 8-membered ring in 32 would be
formed using a ring-closing metathesis (RCM) from enone 33,
thus circumventing the need for an allyltitanation/Wacker
oxidation sequence.18
Initially, we were intrigued by the possibility that the bulky
p-menthyl fragment of our chiral auxiliary could be made to
direct a nucleophilic addition of malonates on a π-allylpalladium
complex prepared from alcohols like 34a. There are numerous
examples of the stereoselective formation of tertiary centers
using π-allylpalladium complexes.19 Examples of the formation
of quaternary centers using this methodology are far less
numerous.20,21 Some chiral ligands22 or directing groups23 were
developed to favor the addition of the nucleophile on the more
isocyanates previously prepared in this way were isolated in
>99% de.13a Isocyanate 10 was transformed into the Fmoc
carbamate 14 using Ti(O-t-Bu)4 as catalyst. This catalyst is
especially useful with hindered isocyanates such as 10.17 Several
other Lewis or Brønsted acids were tried but failed to give a
good yield of addition of fluorenylmethanol onto this congested
quaternary isocyanate.
Then, the primary alcohol in 14 was deprotected and oxidized
to the aldehyde (Scheme 4). A mixture of aldehyde 15 and
enamine 16, resulting from the cyclization of the carbamate on
the aldehyde, was obtained. The ratio varied depending of the
conditions used. Pure aldehyde 15, pure enamine 16, or a
mixture of both, was then submitted to several different acidic
or basic conditions to deprotect the amine and achieve the
desired Mannich cyclizations to 18. However, most experiments
led to decomposition products. Treating aldehyde 15 with
piperidine in DMF gave a 72% yield of imine alcohol 17. This
product was formed by aldol addition of the enamine formed
after deprotection of the nitrogen onto the ketone. The same
reaction did not proceed from 16. The formation of 17 from 15
was perhaps to be expected when basic conditions are used
because enolization of the ketone is not favored. All of our
efforts to convert 17 back to the desired Mannich product 18
were in vain. Scheme 5 shows three similar Mannich reactions
taken from the literature. The difference in behavior between
starting materials 15-17 and 19, 21, or 23 may reside in that
the intermediate iminium (25 or 26) derived from any one of
the latter is alkylated, whereas the iminium (25, R ) H in acidic
(12) (a) Shaw, S. A.; Alema´n, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125,
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H.; Iwata, M. Chem. Lett. 2003, 32, 4–5. (f) Tanaka, M.; Oba, M.; Tamai, K.;
Suemune, H. J. Org. Chem. 2001, 66, 2667–2673. (g) Cativiela, C.; D.-de-
Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517–3599. (h) Cativiela, C.;
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(18) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
Germany, 2003; Vols. 1-3.
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PerspectiVes for the 21st Century, 2nd ed.; John Wiley & Sons: West Sussex,
England, 2004. (b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921–
2944. (c) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395–422. (d)
Tsuji, J. Tetrahedron 1986, 42, 4361–4401. For a similar example, see: (e)
Maezaki, N.; Hirose, Y.; Tanaka, T. Org. Lett. 2004, 6, 2177–2180.
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Challenges and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.;
Wiley-VCH: Weinheim, Germarny, 2005; pp 243-264.
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Tremblay, M.-C.; Godbout, C. Org. Lett. 2004, 6, 2801–2804.
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3808 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of (+)-Euphococcinine and (-)-Adaline
SCHEME 5. Three Different but Similar Mannich Cyclizations Taken from the Literature
SCHEME 6. Formation of a Quaternary Center via a Syn-Directed SN2′ Cuprate Addition
SCHEME 7. Altered Strategy to the Coccinelid Alkaloids
SCHEME 8. Results of the Palladium-Catalyzed Allylic Alkylation of 35 and 37
hindered end of the π-allyl complex, and we felt our chiral
auxiliary should be sufficiently bulky to favor one regioisomer.
This turned out to be true, and after several leaving groups
and reaction conditions were screened, the trifluoroacetate 35
was transformed into a single regioisomer 36 in 82% yield
(>96% de, as determined by 1H NMR) as shown in Scheme 8.
However, the formation of a quaternary stereocenter was what
really interested us, and initial attempts using acetate as the
leaving group left the starting material 37b unreacted. Unfor-
tunately, all other leaving groups and/or reaction conditions that
were attempted led to decomposition or elimination products
38 and 39. This was also true of the Pd-catalyzed decarboxy-
lative allylic alkylation.24
The Claisen rearrangement was an attractive alternative to
form a quaternary carbon center, but there are scant examples
of this reported in the literature and they mostly involve rigid
J. Org. Chem. Vol. 74, No. 10, 2009 3809

Arbour et al.
SCHEME 9. Formation of a Quaternary Center via a 3,3-Sigmatropic Rearrangement
SCHEME 10. Synthesis and RCM of Enone 33
cyclic molecules.25 Regardless of the variant used (Claisen-
Ireland, Carroll, Johnson-Claisen, etc.), the chirality transfer
in these rearrangements is usually high.26 The acetate 37b and
ketoester derivatives 37f and 37g were submitted to basic
conditions, in the presence or absence of a silylating agent
(Claisen-Ireland or Carroll variants), but only starting material
and/or the corresponding dienes 38 and 39 were obtained in
either case. However, the use of the Johnson orthoester Claisen
modification on alcohol 37a led to a 62% yield of the desired
ester 41a (Scheme 9). Meanwhile, heating 37a with a Hg(II)
catalyst27 in a sealed tube afforded a 72% yield of the aldehyde
41b as well as a small amount (10%) of vinyl ether 40b. The
use of palladium salts28 to effect the sequence gave only 36%
yield of the same aldehyde. The diastereomeric excess of 41b
was determined to be >96% by H NMR spectral comparison
with an authentic sample of its diastereomer. We were now
ready to apply this methodology toward the total synthesis of
both Coccinelid alkaloids.
1
The terminal alkyne 42 was prepared according to a
reported procedure29 from 5-bromopentene (Scheme 10).
Then, a Zr-catalyzed carboalumination gave the correspond-
ing vinylalane that was directly added on p-menthane-3-
carboxaldehyde 5 to give allylic alcohols 34a and 34b in a
9:1 ratio. After chromatographic separation, alcohol 34a was
isolated in 67% yield (>99% de, determined by GC). Then,
the Claisen rearrangement on 34a gave 79% of the desired
1
aldehyde 43 (>96% de, determined by H NMR). Vinylmag-
nesium bromide was added to aldehyde 43 to give a mixture
of two diastereoisomeric allylic alcohols 44, which were then
oxidized to the enone 33.
We figured that three products could potentially be formed
during the RCM of enone 33: the desired 8-membered ring 45
(Scheme 10), as well as the 5-membered ring 46 or the
6-membered ring 47 (Figure 2). Initiation at the enone alkene
is unlikely,30 and according to previous work in our laboratory,
6-membered rings are not formed when an all-carbon quaternary
(22) (a) Pre´toˆt, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323–325. (b)
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3810 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of (+)-Euphococcinine and (-)-Adaline
FIGURE 2. Three possible products from the RCM of 33.
SCHEME 11. Formation of Isocyanate 50 and (+)-Euphococcinine 2
center is present at this position.31 Hence, the eight-membered
ring 45 should be the major product even though it is not
entropically favored.32 Grubbs’ first generation catalyst gave
only recovered starting material. With the Grubbs’ catalyst of
second generation, in refluxing dichloromethane, cyclic enone
45 was obtained in 74% yield (Scheme 10). Despite conducting
the reaction under high dilution (5 mM) and/or with slow
addition of the substrate, what we believe is the 16-membered
ring 48 was always isolated in 3-5% yield (Figure 2). When
conducted in refluxing 1,2-dichloroethane, up to 5% of the
5-membered ring 46 has been isolated but no trace was detected
in dichloromethane.
Selective ozonolysis of the chiral auxiliary in 45 with ozone
in the presence of the enone proved impossible.33 The enone is
more electron-poor than the internal alkene but is also a lot
less sterically hindered. There are reported examples in the
literature where it is possible to selectively cleave an isolated
alkene in the presence of an enone when pyridine is used as a
cosolvent34 or when indicators35 are used. Both methods were
tried, but without doubt the most reactive alkene toward
ozone was the enone. Other methods of oxidative cleavage
using large metal oxides would likely lead to the same result.
We therefore decided to temporarily mask the enone by
adding phenylselenol to it and obtained selenide 49 in quantita-
tive yield (Scheme 11). When 49 was submitted to ozonolysis,
the selenide was oxidized to the selenoxide but did not undergo
elimination before the internal alkene was cleaved. However,
after reductive workup of the ozonide and increasing the
temperature, the selenoxide underwent a smooth elimination and
carboxylic acid 32 in 90% was obtained.
The Curtius rearrangement occurred with complete retention
of stereochemistry at the migrating center, as expected.11b,36
Using diphenylphosphoryl azide (DPPA)37 as source of azide,
isocyanate 50 was obtained in 50-65% (Scheme 11). However,
this reaction must be monitored closely because long reaction
times lead to the known elimination product 51 (Figure 3).
Higher temperatures (refluxing xylene for example) afford more
of the byproduct 51.
FIGURE 3. Byproduct formed during the Curtius rearrangement.
The standard conditions to hydrolyze isocyanates are usually
quite acidic and seemed incompatible with a sensitive ꢀ-iso-
cyano ketone 51.38 There exist reductive39 conditions, but they
seemed unsuitable for a substrate containing an enone. There-
fore, we first elected a round-about way and protected the
(31) (a) Boisvert, L.; Beaumier, F.; Spino, C. Can. J. Chem. 2006, 84, 1290–
1293. (b) Spino, C.; Boisvert, L.; Douville, J.; Roy, S.; Lauzon, S.; Minville, J.;
Gagnon, D.; Beaumier, F.; Chabot, C. J. Organomet. Chem. 2006, 691, 5336–
5355.
(32) For examples of eight-membered carbocycles formation, see: (a) Marco-
Contelles, J.; de Opazo, E. J. Org. Chem. 2002, 67, 3705–3717. (b) Takao, K.-
I.; Watanabe, G.; Yasui, H.; Tadano, K.-I. Org. Lett. 2002, 4, 2941–2943. (c)
Boyer, F.-D.; Hanna, I.; Nolan, S. P. J. Org. Chem. 2001, 66, 4094–4096. (d)
Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.; Me´ndez-
Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259–1261. (e) Rodr`ıguez, J. R.; Castedo,
L.; Mascare˜; nas, J. L. Org. Lett. 2000, 2, 3209–3212. (f) Miller, S. J.; Kim,
S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108–2109.
(33) Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem. ReV. 2006, 106,
2990–3001.
(36) Ku¨rti, L.; Czako`, B. In Strategic applications of named reactions in
organic synthesis; Elsevier Academic Press: Burlington, MA, 2005; pp 116-
117.
(37) Shioiri, T.; Ninomiya, K.; Yamada, S.-I. J. Am. Chem. Soc. 1972, 94,
6203–6205.
(38) (a) Engel, P. S.; Allgren, R. L.; Chae, W.-K.; Leckonby, R. A.; Marron,
N. A. J. Org. Chem. 1979, 44, 4233–4239. (b) Oba, M.; Tanaka, M.; Takano,
Y.; Suemune, H. Tetrahedron 2005, 61, 593–598. (c) Braslau, R.; Kuhn, H.;
Burrill, L. C., II; Lanham, K.; Stenland, C. J. Tetrahedron Lett. 1996, 37, 7933–
7936.
(34) Shepherd, D. A.; Donia, R. A.; Allan Campbell, J.; Johnson, B. A.;
Holysz, R. P.; Slomp, G., Jr.; Stafford, J. E.; Pederson, R. L.; Ott, A. C. J. Am.
Chem. Soc. 1955, 77, 1212–1215.
(35) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 10, 807–
809.
(39) Malanga, C.; Urso, A.; Lardicci, L. Tetrahedron Lett. 1995, 36, 8859–
8860.
J. Org. Chem. Vol. 74, No. 10, 2009 3811

Arbour et al.
SCHEME 12. Protection of Isocyanate 50 into a Carbamate
and Subsequent Deprotection
chloride has never been used to hydrolyze isocyanate and
despite its low solubility in water and THF, it gave quite
acceptable yields of (+)-euphococcinine 2, after treatment
with base (Scheme 11). Spectral data were identical to the
one reported for the natural (+)-euphococcinine.2,7a,8b-f
A similar sequence of reactions was used for the synthesis
of natural (-)-adaline. Note that the absolute configuration of
natural adaline is opposite that of natural euphococcinine, yet
we need not change chiral auxiliary for its synthesis. Vinyl
iodide 54 was obtained via a carbocupration of 1-heptyne
(Scheme 13).42 The vinyl iodide was always slightly contami-
nated with the dimer resulting from a homocoupling but the
latter did not interfere with the subsequent reaction and was
removed thereafter. After a lithium-halogen exchange, the
corresponding vinyllithium was added to the p-menthane-3-
carboxaldehyde 5 to give the allylic alcohol 55a in 50% pure
isocyanate into a Troc or Fmoc carbamate, which we planned
on removing under milder conditions to access the free amine
and allow the intramolecular cyclizations to 2. These protections
were effected in modest yield using our catalyst Ti(O-t-Bu)4
(Scheme 12).17 Under typical reductive deprotection conditions
to remove the Troc protecting group (zinc dust), a mixture of
unidentified compounds was obtained, though partial reduction
of the enone was obvious. Removal of the Fmoc proctecting
group under basic conditions, using piperidine or TBAF, did
not fare better and gave a mixture of unknown products.
Possibly, addition of piperidine in a Michael fashion to the enone
caused problems. When the reaction was conducted in deuterated
solvents with the more hindered base DMAP, it was possible
to detect by 1H NMR the formation of euphococcinine and the
latter was isolated in 20% yield.
1
yield (ratio 55a:55b 5:1) (>96% de, determined by H NMR).
We feared that the more sterically demanding quaternary carbon
might lower the yields of the subsequent steps, but that turned
out to be incorrect and (-)-adaline was obtained after the same
sequence of reaction as described for the synthesis of (+)-
euphococcine with similar yields (Scheme 13). The final
hydrolysis of the isocyanate to give (-)-adaline 3 proceeded in
69% yield. Spectral data (1H and 13C NMR, IR, MS, and optical
rotation) were identical to those reported for the natural
(-)-adaline.3,7a,8a,b,f
In summary, p-menthane-3-carboxaldehyde 5 was used for
the formation of quaternary centers using a 3,3-sigmatropic
rearrangement. The total syntheses of two alkaloids containing
a quaternary amine carbon, namely (+)-euphococcinine 2 and
(-)-adaline 3, were achieved in only 10 steps each, with overall
yields of 7.6% and 6.3% and average yields per step of 77%
and 76%, respectively. Both syntheses began with simple
starting materials. The same chiral auxiliary was effectively used
to make those two antipodal alkaloids.
In light of those failures, we decided to investigate the
direct hydrolysis of the isocyanate, despite our earlier
concerns. When the isocyanate was placed in aqueous HCl,
a frequently used acid to accelerate the hydrolysis of
isocyanates,40 followed by a basic treatment, (+)-euphoc-
occinine 2 was isolated in 35-40%. We were pleased by
this result but looked to improving the yield of reaction. Ti(O-
t-Bu)4 and CuCl41 are two Lewis acids used to facilitate
17
the addition of alcohol on isocyanates, but the former cannot
be used with water because of its rapid reaction to form
titanium oxide.17 To the best of our knowledge, copper
SCHEME 13. Ten-Step Total Synthesis of (-)-Adaline from 1-Heptyne
3812 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of (+)-Euphococcinine and (-)-Adaline
aldehyde 43 as a colorless oil (550 mg, 72%, >96% de as
Experimental Section
1
1
determined by H NMR): H NMR (300 MHz, CDCl3) δ (ppm)
9.69 (t, 1H, J ) 3.3 Hz), 5.76 (ddt, 1H, J ) 17.1, 9.4, 6.6 Hz),
5.38 (d, 1H, J ) 15.7 Hz), 5.13 (dd, 1H, J ) 15.7, 9.4 Hz), 4.98
(dd, 1H, J ) 17.1, 1.7 Hz), 4.93 (d, 1H, J ) 9.4 Hz), 2.34 (dd, 1H,
J ) 14.7, 2.8 Hz), 2.23 (dd, 1H, J ) 14.7, 3.6 Hz), 2.00 (q, 2H, J
) 6.6 Hz), 1.94-1.73 (m, 3H), 1.69-1.49 (m, 2H), 1.40-1.27
(m, 5H), 1.10 (s, 3H), 1.01-0.77 (m, 4H), 0.86 (d, 3H, J ) 7.2
Hz), 0.85 (d, 3H, J ) 6.6 Hz), 0.68 (d, 3H, J ) 6.6 Hz); 13C NMR
(75.5 MHz, CDCl3) δ (ppm) 204.0 (d), 138.6 (d), 135.6 (d), 134.1
(d), 114.5 (t), 54.0 (t), 47.1 (d), 45.2 (d), 43.6 (t), 41.7 (t), 38.1 (s),
35.1 (t), 34.0 (t), 32.4 (d), 28.2 (d), 23.9 (t), 23.8 (q), 23.2 (t), 22.6
(q), 21.4 (q), 15.1 (q); IR (film) ν (cm-1) 3081, 2940, 2852, 2737,
1726, 1642, 1456, 1381, 1364; LRMS (m/z, relative intensity) 304
(M+, 5), 260 ([M-C2H4O]+, 30), 235 (25), 217 (100); HRMS calcd
for C21H36O 304.2766, found 304.2775; [R]20D ) -21.6 (c ) 1.00,
CHCl3).
Allylic Alcohols 34a and 34b. Argon was bubbled through a
solution Cp2ZrCl2 (1.53 g, 5.23 mmol) in CH2Cl2 (75 mL) at rt
for 5 min. Then, AlMe3 (11.1 mL, 116 mmol) was added, and
the resulting mixture was stirred for 30 min. The solution was
cooled to 0 °C, hept-1-en-6-yne 4229 (3.62 g, 38.5 mmol) was
added dropwise, and the reaction mixture was stirred for 22 h
at rt. A solution of (-)-p-menthane-3-carboxaldehyde 5 (3.06
g, 18.2 mmol, freshly distilled under reduced pressure) in THF
(70 mL) was slowly transferred via canula at -78 °C over a
period of 10 min. The reaction mixture was stirred for 17 h and
allowed to warm to rt. It was then cooled to 0 °C, a saturated
aqueous solution of K2CO3 was slowly added, and the mixture
was allowed to stir until no more gas evolution was observed
and a white precipitate formed. Then, a 1 N HCl aqueous solution
was added to dissolve completely the precipitate. The phases
were separated, and the aqueous phase was quickly extracted
with three portions of Et2O to avoid rearrangement of the alcohol.
The organic layers were combined, washed with brine, dried
over anhydrous MgSO4, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
on silica gel eluting with a mixture of Et2O and hexanes (5:95
to 10:90) to yield alcohol 34a as a colorless oil (3.48 g, 68%,
>99% de as determined by GC analysis) as the major diastere-
omer and 500 mg of alcohol 34b (9%) as the minor diastereomer.
Cyclooctenone 45. To a solution of Grubbs’ second-generation
catalyst (9 mg, 0.01 mmol) in CH2Cl2 (70 mL) was added a solution
of the enone 33 (117 mg, 0.350 mmol) in CH2Cl2 (70 mL). The
resulting mixture was refluxed for 1 h. It was then opened to the
air and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel eluting with a
mixture of Et2O and hexanes (10:90 to 15:85) to yield enone 45 as
a colorless oil (78 mg, 74%): 1H NMR (300 MHz, CDCl3) δ (ppm)
6.45 (dt, 1H, J ) 12.1, 8.5 Hz), 6.21 (d, 1H, J ) 12.1 Hz), 5.38 (d,
1H, J ) 15.8 Hz), 5.15 (dd, 1H, J ) 15.8, 9.1 Hz), 3.04 (br d, 1H,
J ) 12.1 Hz), 2.72-2.66 (m, 1H), 2.51-2.41 (m, 1H), 2.43 (br d,
1H, J ) 12.1 Hz), 1.93-1.69 (m, 4H), 1.62-1.31 (m, 6H), 1.04
(s, 3H), 1.02-0.79 (m, 4H), 0.87 (d, 3H, J ) 6.6 Hz), 0.86 (d, 3H,
J ) 6.6 Hz), 0.69 (d, 3H, J ) 6.6 Hz); 13C NMR (75.5 MHz,
CDCl3) δ (ppm) 201.4 (s), 142.5 (d), 136.8 (d), 136.6 (d), 132.3
(d), 52.3 (t), 47.3 (d), 44.9 (d), 43.7 (t), 36.9 (s), 35.2 (t), 34.2 (t),
32.5 (d), 28.8 (d), 28.1 (q), 25.9 (t), 24.2 (t), 22.6 (q), 21.4 (q),
20.6 (t), 15.3 (q); IR (film) ν (cm-1) 3014, 2962, 2927, 2868, 1651,
1456, 1213, 807, 772; LRMS (m/z, relative intensity) 302 (M+,
20), 287 ([M - CH3]+, 5), 259 (25), 137 (55), 95 (75), 81 (100);
1
Major isomer 34a: H NMR (300 MHz, CDCl3) δ (ppm) 5.80
(ddt, 1H, J ) 17.3, 10.2, 6.6 Hz), 5.33 (d, 1H, J ) 8.0 Hz),
4.99 (dd, 1H, J ) 17.3, 1.7 Hz), 4.94 (d, 1H, J ) 10.2 Hz),
4.66 (d, 1H, J ) 8.0 Hz), 2.23-2.13 (m, 1H), 2.06-1.98 (m,
4H), 1.75-1.66 (m, 3H), 1.63 (s, 3H), 1.51 (quint, 2H, J ) 7.4
Hz), 1.39-1.23 (m, 3H), 1.03-0.80 (m, 4H), 0.93 (d, 3H, J )
7.2 Hz), 0.88 (d, 3H, J ) 6.6 Hz), 0.77 (d, 3H, J ) 6.6 Hz); 13
C
NMR (75.5 MHz, CDCl3) δ (ppm) 138.7 (d), 136.5 (s), 127.1
(d), 114.5 (t), 67.6 (d), 44.8 (d), 43.1 (d), 39.1 (t), 35.1 (t), 34.0
(t), 33.3 (t), 32.7 (d), 26.9 (t), 26.3 (d), 24.2 (t), 22.8 (q), 21.6
(q), 16.4 (q), 15.5 (q); IR (film) ν (cm-1) 3643-3236, 3081,
2953, 2871, 1724, 1711, 1642, 1441, 610; LRMS (m/z, relative
intensity) 278 (M+, 5), 235 (5), 209 (5), 139 (100); HRMS calcd
HRMS calcd for C21H34O 302.2610, found 302.2615; [R]20
-104.1 (c ) 1.62, CHCl3).
)
D
for C19H34O 278.2610, found 278.2618; [R]20 ) -39.5 (c )
D
Isocyanate 50. To a solution of carboxylic acid 32 (34.5 mg,
0.19 mmol) and triethylamine (32 µL, 0.23 mmol) in toluene
(1.3 mL) was added diphenylphosphoryl azide (47 µL, 0.22
mmol), and the resulting mixture was refluxed for 90 min. A
saturated aqueous solution of NH4Cl was added, the phases were
separated, and the aqueous phase was extracted with three
portions of Et2O. The organic layers were combined, washed
with brine, dried over anhydrous MgSO4, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel eluting with a mixture of Et2O
and hexanes (20:80) to yield isocyanate 50 as a colorless oil
1
0.73, CHCl3). Minor alcohol 34b: H NMR (300 MHz, CDCl3)
δ (ppm) 5.76 (ddt, 1H, J ) 16.9, 10.4, 6.6 Hz), 5.28 (d, 1H, J
) 9.9 Hz), 4.96 (dd, 1H, J ) 16.9, 1.7 Hz), 4.91 (d, 1H, J )
10.4 Hz), 4.54 (dd, 1H, J ) 9.9, 4.1 Hz), 2.02-1.89 (m, 5H),
1.85-1.74 (m, 1H), 1.69-1.41 (m, 5H), 1.66 (s, 3H), 1.35-1.22
(m, 1H), 0.99-0.66 (m, 5H), 0.86 (d, 3H, J ) 6.1 Hz), 0.79 (d,
3H, J ) 6.6 Hz), 0.75 (d, 3H, J ) 6.6 Hz); 13C NMR (75.5
MHz, CDCl3) δ (ppm) 140.0 (s), 138.5 (d), 123.6 (d), 114.5 (t),
67.6 (d), 44.5 (d), 44.1 (d), 39.3 (t), 35.2 (t), 34.0 (t), 33.1 (t),
32.6 (d), 26.9 (t), 26.3 (d), 24.1 (t), 22.8 (q), 21.5 (q), 16.3 (q),
15.2 (q); IR (film) ν (cm-1) 3567-3276, 2966, 2843, 1708, 1447;
LRMS (m/z, relative intensity) 278 (M+, 5), 235 (5), 209 (5),
184 (10), 139 (90), 83 (100); HRMS calcd for C19H34O 278.2610,
1
(22 mg, 65%): H NMR (300 MHz, CDCl3) δ (ppm) 6.53 (dt,
1H, J ) 12.1, 8.8 Hz), 6.24 (d, 1H, J ) 12.1 Hz), 3.18 (d, 1H,
J ) 12.4 Hz), 2.85 (d, 1H, J ) 12.4 Hz), 2.82-2.75 (m, 1H),
2.63-2.53 (m, 1H), 1.94-1.57 (m, 4H), 1.43 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) δ (ppm) 197.7 (s), 143.0 (d), 136.1 (d), 123.0
(s), 57.7 (s), 55.1 (t), 36.1 (t), 31.1 (q), 25.4 (t), 20.1 (t); IR
(film) ν (cm-1) 3026, 2980, 2953, 2868, 2269, 1659, 1651, 1487,
1452, 1306, 1240, 1220, 1134; LRMS (m/z, relative intensity)
179 (M+, 15), 164 (5), 151 ([M - CO]+, 10), 136 (35), 108
(50), 96 (100); HRMS calculated for C10H13NO2 179.0946, found
found 278.2615; [R]20 ) -18.9 (c ) 0.55, CHCl3).
D
Aldehyde 43. In a sealed tube, a solution of alcohol 34a (700
mg, 2.51 mmol), butyl vinyl ether (1.63 mL, 12.6 mmol), and
mercury(II) acetate (115 mg, 0.360 mmol) was heated at 130-135
°C for 20 h. After being cooled to rt, the reaction mixture was
diluted with brine and extracted with three portions of Et2O. The
organic layers were combined, washed with brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel
eluting with a mixture of Et2O and hexanes (3:97 to 10:90) to yield
179.0950; [R]20 ) -62.9 (c ) 0.52, CHCl3).
D
(+)-Euphococcinine 2. To a solution of the isocyanate 50 (14.6
mg, 0.0814 mmol) in a mixture of H2O (0.6 mL) and THF (1.0
mL) was added CuCl (18 mg, 0.18 mmol). The green suspension
was stirred vigorously at rt for 29 h. CuCl (26 mg, 0.26 mmol)
was added, and the resulting mixture was heated to 40 °C for 2.5 h.
A saturated aqueous solution of K2CO3 was added, and the mixture
was stirred vigorously at rt for 15 h and then extracted with three
portions of CH2Cl2. The organic layers were combined, washed
(40) Benalil, A.; Roby, P.; Vaultier, M. Synthesis 1991, 787–788.
(41) Duggan, M. E.; Imagire, J. S. Synthesis 1989, 131–132.
(42) (a) Lipshutz, B. H. Organocopper Chemistry. In Organometallics in
Synthesis A Manual, 2nd ed; Schlosser, M., Ed.; Wiley: West Sussex, England,
2002. (b) Negishi, E.-I.; Ma, S.; Amanfu, J.; Cope´ret, C.; Miller, J. A.; Tour,
J. M. J. Am. Chem. Soc. 1996, 118, 5919–5931. (c) Sato, F.; Jinbo, T.; Sato, M.
Synthesis 1981, 871–872.
J. Org. Chem. Vol. 74, No. 10, 2009 3813

Arbour et al.
with brine, dried over anhydrous MgSO4, and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography on silica gel eluting with a mixture of MeOH and
CH2Cl2 (saturated with NH3) (2:98 to 5:95) to yield (+)-euphoc-
occinine 2 as a white solid (7.9 mg, 63%). All spectroscopic data
correspond to those reported in the literature:2,8c,e mp 34-36 °C;
1H NMR (300 MHz, CDCl3) δ (ppm) 3.72-3.66 (m, 1H), 2.57
(dd, 1H, J ) 16.3, 6.9 Hz), 2.44-2.35 (m, 2H), 2.21 (d, 1H, J )
16.3 Hz), 1.93 (br s, 1H), 1.73-1.44 (m, 6H), 1.19 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) δ (ppm) 211.2 (s), 53.5 (t), 52.3 (s),
49.8 (d), 46.3 (t), 38.6 (t), 31.6 (q), 31.2 (t), 18.1 (t); IR (film) ν
(cm-1) 3337-3156, 2931, 2874, 1704; LRMS (m/z, relative
intensity) 153 (M+, 40), 124 (10), 110 (100), 96 (70); HRMS calcd
for C9H15NO 153.1154, found 153.1161; [R]20D ) +5.4 (c ) 0.65,
MeOH).
Acknowledgment. We thank the Natural Sciences and
Engineering Council of Canada, Merck-Frosst Canada Ltd.,
and the Universite´ de Sherbrooke for their financial sup-
port.
Supporting Information Available: Experimental proce-
dures for all new compounds not included in the Experimental
Section of this article, 1H NMR spectra for all new compounds,
and GC traces for compounds 10, 11a, 11b, 12, 34a, 34b, 55a,
and 55b. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO9001992
3814 J. Org. Chem. Vol. 74, No. 10, 2009