Asymmetric synthesis of enantioenriched (+)-elaeokanine A

Article abstract of DOI:10.1021/jo060717q

The key transformation in the total synthesis of (+)-elaeokanine A was accomplished by asymmetric deprotonation of N-Boc pyrrolidine, followed by the reaction of the in situ generated enantioenriched stereogenic cuprate reagent with (E)-4-bromo-l-iodo-l-trimethylsilyl-l-butene with retention of configuration. N-Boc deprotection, followed by a one-pot olefin isomerization and intramolecular amine alkylation afforded a bicyclic vinyl bromide that was converted into (+)-elaeokanine A by sequential halogen metal exchange and reaction of the organolithium reagent with N-butanoylmorpholine.

Full text of DOI:10.1021/jo060717q

Asymmetric Synthesis of Enantioenriched (+)-Elaeokanine A
R. Karl Dieter* and Ningyi Chen
Department of Chemistry, Hunter Laboratory, Clemson UniVersity, Clemson, South Carolina 29634-0973
dieterr@clemson.edu
ReceiVed April 4, 2006
The key transformation in the total synthesis of (+)-elaeokanine A was accomplished by asymmetric
deprotonation of N-Boc pyrrolidine, followed by the reaction of the in situ generated enantioenriched
stereogenic cuprate reagent with (E)-4-bromo-1-iodo-1-trimethylsilyl-1-butene with retention of config-
uration. N-Boc deprotection, followed by a one-pot olefin isomerization and intramolecular amine alkylation
afforded a bicyclic vinyl bromide that was converted into (+)-elaeokanine A by sequential halogen metal
exchange and reaction of the organolithium reagent with N-butanoylmorpholine.
Introduction
The indolizidine alkaloids elaeokanine A (1), B (2), and C
(3; Figure 1) were isolated from Ekaeocarous kaniensis Schltr.,
a large rain-forest tree found in New Guinea, along with the
pyrrolo[2,1-f][1,6]naphthyridin-1(2H)-one tricyclic elaeokani-
dine alkaloids containing two nitrogen atoms.1 Although elaeo-
kanine A has been synthesized in racemic form numerous times,2
only a few syntheses of the naturally occurring (+)-enantiomer
have been reported.3 Racemic synthetic routes to these com-
pounds have largely involved iminium ion pathways,2b,d,e,g-i,k
FIGURE 1. Naturally occurring (+)-elaeokanine A (1), (-)-B (2),
and (-)-C (3).
nitrone 1,3-dipolar additions,2a,j,o or imino Diels-Alder2l,m
reactions, while the asymmetric routes have all employed chiral
auxiliary methodology. Asymmetric routes to (+)-elaeokanine
A have utilized chiral N-acylpyridinium salts (4),3a chiral
sulfoxides (5),3b or a chiral maleimide derived from 10-
mercaptoisoborneol,3c generating the natural product in 3-6%
overall yields (Scheme 1). The chiral sulfoxide mediated route
(i.e., 5) actually provides for a more efficient synthesis of (-)-
elaeokanine (i.e., 12% overall yield), because a NaBH4 reduction
of a bicyclic imine gives a 4:4:1:1 mixture of diastereomers,
where 80% of the material can be converted to (-)-1.3b
(1) Hart, N. K.; Johns, S. R.; Lamberton, J. A. Aust. J. Chem. 1972, 25,
817-835.
(2) (a) Cordero, F. M.; Anichini, B.; Goti, A.; Brandi, A. Tetrahedron
1993, 49, 9867-9876. (b) Taber, D. F.; Hoerrner, R. S.; Hagen, M. D. J.
Org. Chem. 1991, 56, 1287-1289. (c) Comins, D. L.; Myoung, Y. C. J.
Org. Chem. 1990, 55, 292-298. (d) Gribble, G. W.; Switzer, F. L.; Sol, R.
M. J. Org. Chem. 1988, 53, 3164-3170. (e) Flann, C.; Malone, T. C.;
Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6097-6107. (f) Yamazaki,
T.; Takahata, H.; Yamabe, K.; Suzuki, T. Heterocycles 1986, 24, 37-39.
(g) Shone, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.; Makino, A. J. Org.
Chem. 1984, 49, 300-304. (h) Chamberlin, A. R.; Nguyen, H. D.; Chung,
J. Y. L. J. Org. Chem. 1984, 49, 1682-1688. (i) Overman, L. E.; Malone,
T. C.; Meier, G. P. J. Am. Chem. Soc. 1983, 105, 6993-6994. (j) Otomasu,
H.; Takatsu, N.; Honda, T.; Kametani, T. Tetrahedron 1982, 38, 2627-
2633. (k) Wijnberg, B. P.; Speckamp, W. N. Tetrahedron Lett. 1981, 22,
5079-5082. (l) Khatri, N. A.; Schmitthenner, H. F.; Shringarpure, J.;
Weinreb, S. M. J. Am. Chem. Soc. 1981, 103, 6387-6393. (m) Schmit-
thenner, H. F.; Weinreb, S. M. J. Org. Chem. 1980, 45, 3373-3375. (n)
Watanabe, T.; Nakashita, Y.; Katayama, S.; Yamauchi, M. Heterocycles
1980, 14, 1433-1436. (o) Tufariello, J. J.; Ali, S. A. Tetrahedron Lett.
1979, 4445-4448.
Our development of R-(N-carbamoyl)alkylcuprate chemistry4
provides for the rapid construction of N-heterocycles.5 The
method is particularly efficient for the synthesis of pyrrolizidine
and indolizidine alkaloids,6 where utilization of enantioenriched
(4) (a) Dieter, R. K.; Topping, C. M.; Nice, L. E. J. Org. Chem. 2001,
66, 2302-2311. (b) For a review, see: Dieter, R. K. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; Chapter 3, pp 79-144.
(5) (a) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858. (b) Dieter,
R. K.; Lu, K. J. Org. Chem. 2002, 67, 847-855. (c) Dieter, R. K.; Chen,
N.; Yu, H.; Nice, L. E.; Gore, V. K. J. Org. Chem. 2005, 70, 2109-2119.
(3) (a) Comins, D. L.; Hong, H. J. Am. Chem. Soc. 1991, 113, 6672-
6673. (b) Hua, D. H.; Bharathi, S. N.; Robinson, P. D.; Tsujimoto, A. J.
Org. Chem. 1990, 55, 2128-2132. (c) Ari, Y.; Kontani, T.; Koizumi, T. J.
Chem. Soc., Perkin Trans. 1 1994, 15-23.
10.1021/jo060717q CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/23/2006
5674
J. Org. Chem. 2006, 71, 5674-5678

Asymmetric Synthesis of (+)-Elaeokanine A
SCHEME 1
) Me3Si, X ) Br) could be accomplished on a large scale (e.g.,
100 mmol) and with excellent yields.
Vinylation of the bis-pyrrolidinylcuprate 8 (L ) N-Boc-2-
pyrrolidinyl) with (Z)-vinyl iodide 9 proved to be problematic
as a result of the steric hindrance arising in the vinyl silane
moiety, the reactive center being sterically encumbered both
by the trimethylsilyl substituent and by the alkyl substituent
cis to the iodide reactive center. All efforts to effect this
transformation using either dialkylcuprates or alkylcyanocuprates
8 (L ) CN) resulted in only trace amounts of the vinylation
product (i.e., trans-diastereomer of 12). Most of the starting
N-Boc-pyrrolidine and some of the vinyl iodide were recovered.
Although the reaction of cuprate 8 (L ) CN) with 10
(TMEDA, THF, -78 °C) gave low chemical yields, vinylation
of the bis-pyrrolidinylcuprate 8 (L ) N-Boc-2-pyrrolidinyl,
TMEDA, THF) with 10 did afford 12 in 79% yield when the
reaction mixture was allowed to warm slowly from -70 °C to
room temperature. Loss of the starting vinyl iodide suggested
that vinyl iodide decomposition pathways were competitive with
the cuprate vinylation reaction. When the coupling reaction was
carried out at -40 °C for several hours, the vinyl iodide
decomposition pathways were suppressed and good yields of
the coupling product could be obtained. These preliminary
studies were performed in THF, which is not conducive to the
formation of stable enantioenriched 2-lithio-N-Boc-pyrrolidine.14
After optimization of the chemical yields was achieved, the
asymmetric coupling reaction was examined.
Asymmetric deprotonation of N-Boc-pyrrolidine according
to the Beak et al.14 protocol [Et2O, s-BuLi, (-)-sparteine, 1 h],
followed by formation [i.e., CuCN‚2LiCl, THF]15 of the
enantioenriched stereogenic cuprate reagent 8 (L ) N-Boc-2-
pyrrolidinyl) and coupling with vinyl iodide 10 afforded coupled
product 12 in various chemical yields and enantiomeric ratios
(Table 1) depending upon reaction conditions. Utilization of
the optimized procedure developed for the THF reactions in
the Et2O/THF solvent mixture (1:1) gave comparable chemical
yields (Table 1, entry 1) but little to no enantioselectivity.
Holding the reaction temperature at -78 °C for several hours
resulted in lower chemical yields and similarly poor enantiose-
lectivity (entry 2), although slightly better enantioselectivity
could be achieved by holding the reaction mixture at -50 °C
for 8 h (entry 3). Efforts to improve the enantioselectivity by
employing pure Et2O as solvent gave lower chemical yields and
similar enantiomeric ratios (entry 4). In these experiments using
Et2O as solvent, the CuCN was solubilized with n-Bu3P, because
the use of a soluble source of Cu(I) salts is essential for cuprate
formation at -78 °C. Utilization of higher reaction temperatures
or slow cuprate formation results in racemization of the
enantioenriched organolithium reagent.15
SCHEME 2
pyrrolidinylcuprates provides a protocol for asymmetric syn-
thesis. We undertook a synthesis of (+)-elaeokanine A to
explore the potential of enantioenriched stereogenic (i.e., a
stereogenic carbon center bound to the copper atom) organo-
cuprate reagents in target directed synthesis. Specifically, how
would this methodology for the rapid introduction of the
stereogenic center compare (i.e., in number of linear steps and
final enantiopurity) with the chiral auxiliary based methods
previously employed, and what types of problems might arise
in the asymmetric reaction itself.
Results and Discussion
Focusing on R-(N-carbamoyl)alkylcuprate methodology, retro-
synthetic analysis for 1 (Scheme 2) leads to the 2-(1-butenyl)-
pyrrolidine derivative 7 containing a functional group (FG) for
elaboration of the 1-oxobutyl side chain and a nucleofuge X
for construction of the indolizidine skeleton via intramolecular
cyclization. The substituted pyrrolidine 7 is potentially available
from the enantioenriched stereogenic pyrrolidinyl cuprate 8 and
the stereodefined vinyl iodide 9 or 10, which in turn can be
prepared from a bis-functionalized alkyne 11. Elaeokanine A
(1) contains the latent functionality necessary for conversion
into elaeokanine B (2) and C (3), provided stereocontrol can
be achieved. The ultimate length of this highly convergent route
to the elaeokanines will hinge upon potential problems involving
reactivity and stereocontrol.
The requisite vinyl mesylate 9 (FG ) Me3Si, X ) OMs) was
prepared from (Z)-4-iodo-4-trimethylsilyl-3-buten-1-ol7 that was
itself synthesized in three steps from commercially available
3-butyn-1-ol by established procedures.8-10 The straightforward
three-step preparation8,9,11,12 of known (E)-vinyl iodide 1013 (FG
Aware that reductive elimination was suggested to be the slow
step in cuprate mediated conjugate addition reactions,16 we
decided to explore the use of mixed cuprates containing a
(11) Nicolaou, K. C.; Ramphal, J. Y.; Abe, Y. Synthesis 1989, 898-
901.
(6) (a) Watson, R. T.; Gore, V. K.; Chandupatla, K. R.; Dieter, R. K.;
Snyder, J. P. J. Org. Chem. 2004, 69, 6105-6114. (b) Dieter, R. K.; Chen,
N.; Watson, R. T. Tetrahedron 2005, 61, 3221-3230.
(7) Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A.
Tetrahedron 1996, 52, 11601-11624.
(12) Zweifel, G.; Lewis, W. J. Org. Chem. 1978, 43, 2739-2744.
(13) Negishi, E.; Boardman, L. D.; Sawada, H.; Bagheri, V.; Stoll, A.
T.; Tour, J. M.; Rand, C. L. J. Am. Chem. Soc. 1988, 110, 5383-5396.
(14) (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708-
9710. (b) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231-3832.
(15) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu,
K.; Watson, R. T. J. Org. Chem. 2004, 69, 3076-3086.
(16) Frantz, D. E.; Singleton, D. A.; Snyder, J. P. J. Am. Chem. Soc.
1997, 119, 3383-3384.
(8) Overman, L. E.; Brown, M. J.; McCann, S. F. Org. Synth. 1990, 68,
182-187.
(9) Ma, S. M.; Liu, F.; Negishi, E. Tetrahedron Lett. 1997, 38, 3829-
3832.
(10) Le Menez, P.; Brion, J.-D.; Lensen, N.; Chelain, E.; Pancrazi, A.;
Ardisson, J. Synthesis 2003, 2530-2534.
J. Org. Chem, Vol. 71, No. 15, 2006 5675

Dieter and Chen
SCHEME 3a
TABLE 1. Vinylation of N-Boc-pyrrolidinylcuprates with Vinyl
Iodide 10
a Reagents and conditions: (a) (i) MeOH, TMSCl, 12 h. (ii) NaHCO3,
CH2Cl2 extract (95%). (b) (i) Et2O, HBr (1.1 equiv). (ii) NBS, NaBr. (iii)
H2SiF6 (67%). (c) (i) t-BuLi, THF. (ii) N-butanoylmorpholine (53-80%).
reaction conditions
Cu(I)
rxn temp
% yieldd
12
entry equiva solventb
°C (h)c
ere
1
2
3
4
0.5
0.5
0.5
0.5
1.0
1.0
1.0
A
A
A
B
A
A
B
-78 to 25 (12) 71-76
50:50-61:39
50:50-55:45
63:37
67:33
60:40-63:37
75:25
from the (Z)-geometry to the (E)-geometry by irradiation with
a UV sun lamp in the presence of N-bromosuccinimide (NBS)
and pyridine proved unsuccessful, giving only recovered starting
material.18 The ready conversion of a mixture of (E)- and (Z)-
γ-amino-R,â-enones to pyrroles19 suggested the possibility of
facile isomerization of R,â-enones under cyclization conditions.
To this end, attempted acylation of vinyl silane20 12 with
n-butanoyl chloride gave a 20:80 mixture of starting material
and a new product in which the N-Boc protecting group was
replaced with the N-butanoyl group.21 This transformation
suggested that N-Boc deprotection and N-acylation were sig-
nificantly faster than acylation of the vinyl silane moiety.
At this point, we attempted to invert the olefin configuration
and introduce a vinyl bromide functionality for subsequent
synthetic elaboration by a bromination-desilylbromination
sequence. Addition of bromine to 12, followed by treatment of
the reaction mixture with tetrabutylammonium fluoride, afforded
a complex mixture of products,22 as did a reported procedure12
for the isomerization of vinyl silanes. Deprotection of N-Boc-
pyrrolidine 12 with methanolic HCl (TMSCl/MeOH) gave, after
neutralization, pyrrolidine 13 in nearly quantitative yield
(Scheme 3). Conversion of 13 to the hydrobromide salt followed
by addition of NBS and NaBr afforded, after quenching with
fluosilicic acid, vinyl bromide 14 in 67% yield.
-78 (3)
-50 (8)
-78 (3)
47
51
41
5f,g
6f,h
7f,h
-78 to 25 (12) 58
-78 to 25 (12) 67
-78 to 25 (12) 43-45
89:11-95:5
a CuCN‚2LiCl was employed and reactions were run on a 1.0 mmol
scale unless otherwise noted. Cuprate formation was achieved at -78 °C
for 1 h. b A ) THF/Et2O solvent ratio (1:1, v/v, unless otherwise noted),
which arose by the deprotonation of carbamate in Et2O, followed by the
addition of a THF solution of CuCN‚2LiCl. B ) pure Et2O arising by
deprotonation of carbamate in Et2O, followed by the addition of a Et2O
solution of n-Bu3P‚CuCN. c Temperature and time at which the cuprate/
d
electrophile reaction was allowed to proceed. Yields are based on products
purified and isolated by flash column chromatography. Enantioselectivity
e
(e.g., er) was measured by chiral stationary phase HPLC on a Chiralcel
OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel].
f Neophyllithium was employed as a nontransferable ligand in dialkylcuprate
formation. g Neophyllithium (2-phenyl-2-methylpropyllithium) was added
to the solution of lithium (S)-N-Boc-2-pyrrolidinyl(cyano)cuprate. h Neo-
phyllithium was added to the solution of (S)-N-Boc-2-pyrrolidinyllithium,
followed by CuCN‚2LiCl (THF) or n-Bu3P‚CuCN (Et2O).
sterically hindered nontransferable ligand. Utilization of neo-
phyllithium17 (i.e., PhCMe2CH2Li) for generation of a mixed
dialkylcuprate reagent (i.e., 8; L ) neophyl) resulted in
formation of 12 with modest chemical yields and enantioselec-
tivity with the THF/Et2O protocol (Table 1, entry 5) when the
neophyllithium reagent was added to 8 (L ) CN). When CuCN‚
2LiCl was added to a mixture of (S)-N-Boc-2-pyrrolidinyllithium
and neophyllithium, higher enantioselectivities were obtained
(entry 6). When pure Et2O was employed as solvent by
dissolving CuCN in Et2O with the aid of 2.0 equiv of n-Bu3P
and the resulting n-Bu3P‚CuCN was added to a mixture of (S)-
N-Boc-2-pyrrolidinyllithium and neophyllithium, the enantio-
meric ratio of 12 was increased up to 95:5 (entry 7). Although
the chemical yield decreased with this mixed dialkylcuprate,
this reagent efficiently required only one stereogenic pyrrolidinyl
ligand, and the enantioselectivity of the reaction improved to
synthetically useful levels.
Vinyl bromide 14 was a key intermediate in the synthesis by
Overman et al.2e,i of racemic elaeokanine A and involved the
reaction of the vinyllithium reagent generated from 14 with
butanal to give elaeokanine B (1:1 mixture of diastereomers),
followed by oxidation of elaeokanine B to elaeokanine A.
Enantioenriched 14 was readily converted to (+)-elaeokanine
A by halogen-metal exchange and acylation with N-butanoyl-
1
morpholine (Scheme 3). The synthetic material gave H NMR
spectral data in agreement with the published data.1,3a Com-
parison of the optical rotation ([R]22 +38.2 (c 1.5, CH2Cl2))
D
with the reported literature value [synthetic, ([R]23D +47 (c 0.31
in CHCl3),3a ([R]22 +49 (c 0.5 in CHCl3)3b, ; isolated,1 [R]D
D
+13 (c 0.9 in CHCl3)] indicated an enantiomeric ratio of 89:
11, which was identical to the enantiomeric ratio achieved in
the vinylation of (S)-N-Boc-2-pyrrolidinylcuprates under the
optimal conditions (Table 1, entry 7). Although the correlation
of optical purity with enantiomeric ratio can be problematic,23
Successful enantioselective construction of key intermediate
12 set the stage for indolizidine ring formation and introduction
of the 1-oxobutyl side chain. The tactical necessity of employing
vinyl iodide 10 with the incorrect olefin geometry required olefin
isomerization for eventual annulation leading to the indolizidine
ring system. Attempted isomerization of the double bond in 12
(18) Zweifel, G.; On, H. P. Synthesis 1980, 803-805.
(19) Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283-2286.
(20) Capperucci, A.; Degl’Innocenti, A; Dondoli, P.; Nocentini, T.;
Reginato, G.; Ricci, A. Tetrahedron 2001, 6267-6276.
(17) (a) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org. Lett. 2003, 5,
1229-1231. (b) Jones, P.; Reddy, K.; Knochel, P. Tetrahedron 1998, 54,
1471-1490. (c) For preparation of neophyllithium, see: Cano, A.; Cuenca,
T.; Galakhov, M.; Rodriguez, G. M.; Royo, P.; Cardin, C. J.; Convery, M.
A. J. Organomet. Chem. 1995, 493, 17-25.
(21) A (M + 2) parent molecular ion in the GC-MS trace [m/z 345 (5),
347 (5)] and a methyl absorption in the 1H NMR spectrum [δ 2.75 (t, J )
7.2 Hz, 3H)] are consistent with the assigned structure.
(22) Barth, W.; Paquette, L. A. J. Org. Chem. 1985, 50, 2438-2443.
5676 J. Org. Chem., Vol. 71, No. 15, 2006

Asymmetric Synthesis of (+)-Elaeokanine A
The enantiomeric purity of 12 was determined by chiral stationary
phase HPLC on a Chiracel OD column [cellulose tris(3,5-dimeth-
ylphenylcarbamate) on silica gel] to be a 95:5 er [hexane/i-PrOH,
99:1 (v/v), flow rate at 0.5 mL/min, detection at λ ) 210 nm]. The
major enantiomer eluted first with a retention time of 11.7 min,
followed by the minor isomer at 12.6 min.
consistency between the chiral HPLC determination of the
enantiomeric ratio for 12 and the optical purity measured for
synthetic (+)-1 appears to be reliable24 given the unlikely
isomerization of the stereogenic center in the transformations
after its generation.
(R)-2-[(Z)-4-Bromo-1-(trimethylsilyl)-1-butenyl]pyrrolidine (13).
Carbamate 12 (375 mg, 1.0 mmol) was dissolved in methanol (5.0
mL) at 25 °C, and trimethylsilyl chloride (TMSCl, 540 mg, 5.0
mmol) was added dropwise by syringe. The mixture was stirred at
room temperature overnight, then quenched with saturated aqueous
NaHCO3 until pH > 8. The mixture was diluted with methylene
chloride, two layers were separated, and the organic layer was
extracted three times with methylene chloride and dried (MgSO4).
Concentration in vacuo gave 13 as a clear, colorless liquid (0.268
g, 97%): IR (neat) 3427 (br s), 2957 (s), 2769 (w), 1632 (s), 1265
Conclusions
The convergent asymmetric synthesis of (+)-elaeokanine A
in four linear steps from an enantioenriched stereogenic cuprate
regent and (E)-4-bromo-1-iodo-1-trimethylsilyl-1-butene, itself
prepared in three steps, has been achieved in 10-16% overall
yield (using the lowest and highest yields for each transforma-
tion, respectively, obtained over several experiments) with an
optical purity of 81% (90.5:9.5 er). The synthesis demonstrates
the power of enantioenriched stereogenic N-Boc-2-pyrrolidi-
nylcuprates for the rapid asymmetric synthesis of functionalized
indolizidine alkaloids. The key copper-mediated asymmetric
carbon-carbon bond-forming reaction occurs between two
sterically hindered ligands, which proved problematic with
regard to chemical yields and enantioselectivity. The utilization
of a sterically hindered nontransferable ligand to significantly
improve the enantioselectivity of the reaction may provide a
general strategy for controlling enantioselectivity in enantioen-
riched stereogenic organocuprate reactions.
1
(s), 863 (s), 761 (s), 649 (s) cm-1; H NMR (CDCl3) δ 0.22 (s,
9H), 1.70-1.77 (m, 1H), 1.96-2.19 (m, 3H), 2.69-2.81 (m, 2H),
3.37-3.43 (m, 2H), 3.44-3.49 (m, 3H), 4.18 (br s, 1H), 6.35 (t, J
) 9 Hz, 1H); 13C NMR (CDCl3) δ 0.2, 22.8, 31.7, 32.8, 34.9, 45.1,
62.3, 137.5, 140.4; mass spectrum m/z (relative intensity) EI 262
(4), 260 (4), 196 (12), 70 (100).
(R)-8-Bromo-1,2,5,6,8a-hexahydroindolizine (14). To a solution
of 13 (276 mg, 1.0 mmol) in diethyl ether (10 mL) at 0 °C was
added aqueous HBr (0.15 mL, 1.1 mmol). The solution was stirred
for 5 min, followed by the addition of NaBr (123 mg, 1.2 mmol)
and NBS (214 mg, 1.2 mmol) in one portion at 0 °C and then
warmed to room temperature over 30 min. Then, after a few
minutes, H2SiF6 (0.5 mL, 1.1 mmol) was added dropwise. The
reaction mixture was stirred for 12 h at room temperature, diluted
with methylene chloride (10 mL), and washed with saturated
NaHCO3 (5 mL). After gentle shaking, the organic layer was
separated, and the aqueous layer was exacted three times with
methylene chloride (10 mL), dried over MgSO4, and concentrated
in vacuo. Kugelrohr distillation (60 °C, 30 mmHg) of the residue
gave 14 as a clear colorless liquid (136 mg, 67%): IR (neat) 2951
Experimental
(1,1-Dimethylethyl)-(R)-2-[(Z)-4-bromo-1-(trimethylsilyl)-1-
butenyl]-1-pyrrolidinecarboxylate (12). N-Boc-pyrrolidine (0.855
g, 5.0 mmol) was dissolved in freshly distilled diethyl ether (15.0
mL) along with (-)-sparteine (1.345 g, 5.5 mmol). The reaction
mixture was cooled to -78 °C under an argon atmosphere and sec-
BuLi (2.5 mL, 2.2 M, 5.5 mmol) was added dropwise by syringe.
The resultant solution was stirred at -78 °C for 1 h. Then the neo-
phyllithium (5.0 mL, 5.0 mmol) was added at -78 °C, followed by
the slow addition of a solution containing CuCN (450 mg, 5.0
mmol) and n-PBu3 (2.02 g, 10.0 mmol) in diethyl ether (15.0 mL)
via syringe. Stirring was continued at -78 °C for 30 min before
the addition of vinyl iodide 10 (1.83 g, 5.5 mmol). The mixture was
allowed to stir at -78 °C for 1 h. Then the reaction mixture was
warmed to room temperature overnight. It was diluted with Et2O
(30 mL) and quenched with 5% aqueous HCl (15 mL). After shak-
ing vigorously, the layers were separated. The aqueous layer was
extracted with Et2O (20 mL) three times, and the combined organic
layer was dried (MgSO4) and concentrated in vacuo to give an oil
that was purified by column chromatography [silica gel, Rf 0.35,
petroleum ether/EtOAc, 80:20, v/v] as a clear, colorless oil (0.85
g, 45%): IR (neat) 2965 (br s), 2863 (w), 1683 (vs), 1401 (vs), 1265
(s), 1179 (s), 829 (s) cm-1; 1H NMR (CDCl3) δ 0.17 (s, 9H), 1.23-
1.37 (br s, 9H), 1.75-2.02 (m, 4H), 2.69 (t, J ) 7.2 Hz, 2H), 3.32
(t, J ) 7.2 Hz, 2H), 3.34-3.39 (m, 2H), 4.35-4.47 (m, 1H), 5.68
(t, J ) 9 Hz, 1H); 13C NMR (CDCl3) δ 0.2, 21.3, 28.4, 32.1 (31.7,
rotamer), 32.5, 34.6 (34.4, rotamer), 46.6 (46.9, rotamer), 61.0 (61.3,
rotamer), 78.7, 134.0, 143.6, 154.2 (154.0, rotamer); mass spectrum
m/z (relative intensity) EI 377 (1), 375 (1), 306 (73), 304 (73), 114
(100), 70 (85), 57 (65); High-resolution mass spectrum m/z calcd
for C16H30BrNO2Si, 375.1229; found, 375.1235 (M+).
1
(w), 1634 (s), 1453, 1247, 843 cm-1; H NMR (CDCl3) δ 1.74-
1.83 (m, 2H), 2.03-2.13 (m, 3H), 2.34-2.49 (m, 1H), 2.80-2.97
(m, 4H), 3.60-3.65 (m, 1H), 6.05 (t, J ) 2.8, 1H); 13C NMR
(CDCl3) δ 126.9, 126.4, 63.8, 50.7, 44.9, 30.3, 24.9, 22.7; mass
spectrum m/z (relative intensity) EI 203 (29, M+ + 1), 201 (30),
202 (30, M+), 200 (30), 175 (32), 173 (32), 122 (100). [lit.2i 13
C
NMR δ 126.9, 63.7, 50.7, 44.7, 30.3, 24.9, 22.7].
(+)-Elaeokanine A (1). To a dry 25 mL round-bottom flask
equipped with a nitrogen inlet and kept under a static pressure of
nitrogen was added 14 (100 mg, 0.5 mmol) and anhydrous THF (5
mL). The solution was cooled to -78 °C, followed by the slow
addition of t-BuLi via syringe (0.55 mL, 1.8 M, 1.0 mmol) at -78
°C. Stirring was continued for 1 h at -78 °C. Then N-butanoyl-
morpholine was added (94 mg, 0.6 mmol) dropwise, followed by
warming up to room temperature over 2 h. The reaction mixture
was diluted with diethyl ether. Then 10 N HCl (0.20 mL) was added
to give a cloudy suspension; the organic solvent was evaporated to
yield a hydrochloride salt. The salt was treated with 10% K2CO3,
and the mixture was extracted with methylene chloride twice. The
combined CH2Cl2 extract was washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to give 1 (58 mg,
60%; 60-80% in several experiments on racemic material) after
flash column chromatography [Et3N/MeOH/CH2Cl2, 1:1:98] puri-
fication: [R]22D ) +38.2 (c 1.5, CHCl3), [synthetic, [R]23D +47 (c
(23) Gawley, R. E. J. Org. Chem. 2006, 71, 2411-2416.
0.31 in CHCl3),3a [R]22 +49 (c 0.5 in CHCl3)3b; isolated,1 [R]D
D
(24) The specific rotation can vary with concentration, temperature,
solvent, and the presence of soluble impurities in the sample. The optical
and enantiomeric purities may be nonequivalent (Horeau effect), although
this is generally a small effect observed in weakly polar solvents that
disappears in polar solvents. In a recent synthesis of pseudoheliotridane,
the optical rotation of a mixture of diastereomers showed a small nonlinearity
over a 4-fold range of concentrations, and the calculated optical purity
showed an excellent agreement with the enantiomeric ratio measured for a
key intermediate (see ref 6b).
+13 (c 0.9 in CHCl3)]; IR (neat) 3320 (br), 2995, 1668 (s), 1271
1
cm-1; H NMR (CDCl3) δ 0.93 (t, J ) 7.2 Hz, 3H), 1.31-1.42
(m, 1H), 1.61 (q, J ) 7.2 Hz, 2H), 1.71-1.95 (m, 3H), 2.23-2.48
(m, 3H), 2.56 (dt, J ) 8.8, 1.9 Hz, 2H), 2.70-3.00 (m, 3H), 3.56
(t, J ) 1.8 Hz, 1H), 6.89 (t, J ) 1.8 Hz, 1H); mass spectrum m/z
(relative intensity) EI 193 (16, M+), 178 (15), 164 (17), 150 (100),
122 (42); high-resolution mass spectrum m/z calcd for C12H19NO,
J. Org. Chem, Vol. 71, No. 15, 2006 5677

Dieter and Chen
1
193.1467; found, 193.1469 (M+). H NMR data are in agreement
Supporting Information Available: General experimental
with published spectra.3b,c
1
information, materials, H and 13C NMR spectra for 10, 12-14,
1H NMR spectrum for (+)-1, chiral HPLC trace for (R)-12, and
GC-MS trace for (+)-1. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. This work was generously supported by
the National Science Foundation (CHE-0132539). Support of
the NSF Chemical Instrumentation Program for purchase of a
JEOL 500 MHz NMR instrument is gratefully acknowledged
(CHE-9700278).
JO060717Q
5678 J. Org. Chem., Vol. 71, No. 15, 2006