Preparation of perhydroisoquinolines via the intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates: A formal synthesis of (±)-reserpine

Article abstract of DOI:10.1021/jo0341362

The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl- 6-benzyloxy-3Z, 5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS*,7R*,8aS*)-7-benzyloxy-5-((2-trimethylsilyl) ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS*,5S*,6R*,7R*,8aR*)-6-methoxy-5- methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.

Full text of DOI:10.1021/jo0341362

P r ep a r a tion of P er h yd r oisoqu in olin es via th e In tr a m olecu la r
Diels-Ald er Rea ction of N-3,5-Hexa d ien oyl Eth yl Acr ylim id a tes: A
F or m a l Syn th esis of (()-Reser p in e
Steven M. Sparks, Arnold J . Gutierrez, and Kenneth J . Shea*
Department of Chemistry, University of California, Irvine, California 92697-2025
kjshea@uci.edu
Received J anuary 30, 2003
The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an
efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the
stereochemical control offered by this cycloaddition, two approaches to the construction of the DE
rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-
6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to pro-
duce as the major product (4aS*,7R*,8aS*)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-
3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated
to (4aS*,5S*,6R*,7R*,8aR*)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahy-
droisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to
reserpine.
In tr od u ction
line synthesis than the yohimbine alkaloids. Isolated
from species of the Indian shrub Rauwolfia, the yohim-
bine alkaloids were traditionally used as a cure-all for
ailments including cholera and insanity.4 Clinical interest
in these alkaloids stemmed from potent antihypertensive
and sedative effects elicited by extracts from the roots
and bark of Rauwolfia serpentia. The principle compound
of medicinal interest, (-)-reserpine (1, Scheme 1), was
isolated and structurally characterized in 1955.5
Perhydroisoquinoline ring systems are a common
structural feature found in a variety of biologically active
natural products and pharmaceuticals.1 The occurrence
of perhydroisoquinolines in medicinally important com-
pounds has spurred a large research effort directed
toward their preparation. Representative octahydroiso-
quinoline-containing natural products includes morphine
from the opioid family and manzamine A from the
manzamine alkaloid family.2 A number of pharmaceuti-
cals also contain perhydroisoquinoline ring systems
including several HIV-1 protease inhibitors including
Viracept.3
In addition to reserpine’s interesting biological proper-
ties, its complex molecular structure poses a significant
synthetic challenge. The E ring of reserpine contains five
contiguous asymmetric centers embedded in a cis-fused
perhydroisoquinoline ring system. The difficulties associ-
ated with the construction of the stereochemically com-
plex perhydroisoquinoline ring system present in reser-
pine have stimulated the development of a number of
synthetic approaches, which have culminated in both
total and formal syntheses of reserpine.6,7 Indeed, the
broad range of synthetic methodologies applied to the
synthesis of reserpine underscores its utility as a target
for the development of novel synthetic transformations.
(4) Woodson, R. E.; Youngken, H. W.; Schlittler, E.; Schneider, J .
A. Rauwolfia: Botany, Pharmacognosy, Chemistry and Pharmacology;
Little, Brown and Co.: Boston, 1957.
(5) Dorfman, L.; Furlenmeier, A.; Huebner, C. F.; Lucas, R.; Ma-
cHullamy, H. B.; Mueller, J . M.; Schlittler, E.; Schwyzer, R.; St. Andre,
A. F. Helv. Chim. Acta 1954, 37, 59-75.
(6) For reviews of synthetic entries to the yohimbine alkaloids, see:
(a) Aube, J .; Ghosh, S. In Advances in Heterocyclic Natural Product
Synthesis; Pearson, W. H., Ed.; J AI Press: Greenwich, CT, 1996; Vol.
3, pp 99-150. (b) Szantay, C.; Honty, K. In Monoterpenoid Indole
Alkaloids; Saxton, J . E., Ed.; J ohn Wiley & Sons: Chichester, 1994;
Vol. 25, pp 161-216. (d) Baxter, E. W.; Mariano, P. S. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Springer-
Verlag: New York, 1992; Vol. 8, pp 197-319. (d) Szantay, C.; Blasko,
G.; Honty, K.; Dornyei, G. In The Alkaloids; Brossi, A., Ed.; Academic
Press: Orlando, 1986; Vol. 27, pp 131-268.
Perhaps no group of compounds has contributed more
to the development of methodology for perhydroisoquino-
* Corresponding author.
(1) (a) Bentley, K. W. Nat. Prod. Rep. 2001, 18, 148-170. (b) Bentley,
K. W. Nat. Prod. Rep. 1999, 16 367-388.
(2) (a) Lednicer, D.; Mitscher, L. A. The Organic Chemistry of Drug
Synthesis; Wiley: New York, 1997. (b) Magnier, E.; Langlois, Y.
Tetrahedron 1998, 54, 6201-6258.
(3) Kaldor, S. W.; Kalish, V. J .; Davies, J . F.; Shetty, B. V.; Fritz, J .
E.; Appelt, K.; Burgess, J . A.; Campanale, K. M.; Chirgadze, N. Y.;
Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M.
B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su,
K. S.; Tatlock, J . H. J . Med. Chem. 1997, 40, 3979-3985.
10.1021/jo0341362 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/23/2003
5274
J . Org. Chem. 2003, 68, 5274-5285

Formal Synthesis of (()-Reserpine
SCHEME 1
In this manner, reserpine has stood as a milestone by
which to test the utility of synthetic methodology.
Our laboratory has been involved in the utilization of
intramolecular Diels-Alder reactions for the preparation
of perhydroisoquinoline ring systems (eq 1). The intramo-
lecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl
acrylimidates allows for a mild and efficient synthesis
of cis-fused hexahydroisoquinolones.8 The hexahydroiso-
quinolone cycloadducts produced from the reaction are
highly functionalized and hold considerable potential for
stereoselective elaboration. As a demonstration of this
potential, the synthesis of perhydroisoquinoline 3, an
intermediate previously transformed to reserpine, is
described below.
both oxidation states can be accessed via a common
Diels-Alder adduct.8b Preparation of Woodward inter-
mediate 2, which incorporates the DE rings as an
perhydroisoquinol-3-one, would permit regioselective clo-
sure of ring C.7a,b Alternatively the synthesis of perhy-
droisoquinoline 3, a late stage intermediate in Wender’s
synthesis of reserpine, leads to a regioisomeric mixture
upon oxidative cyclization leading to C-ring formation.7d,e
With these considerations in mind, Woodward intermedi-
ate 2 was chosen as our initial goal.
Our retrosynthetic strategy for the assembly of targets
2 and 3, which compromise the fully elaborated DE rings
of reserpine, is outlined in Scheme 1. Perhydroisoquino-
lines 2 or 3 would arise from reduction and functional
group manipulation of hexahydroisoquinolone 4, which
in turn arises from the intramolecular Diels-Alder
cycloaddition of N-3,5-hexadienoyl ethyl acrylimidate 5.
In this approach, all E ring functionality is confined to
the diene fragment 6, which upon cyclization in the tether
endo mode would establish three of the five asymmetric
centers. Diels-Alder precursor 5 would result from the
coupling of hexadienoic acid 6 with 1-aza-2-ethoxy-1,3-
butadiene (7).
Resu lts a n d Discu ssion
At the outset of our studies, two potential targets were
identified which differed in the oxidation state of the C3
(isoquinoline numbering) carbon atom and substitution
on nitrogen (Scheme 1). As the hexahydroisoquinolone
cycloadducts produced from the Diels-Alder reaction of
N-3,5-hexadienoyl ethyl acrylimidates can be processed
to afford either the perhydroisoquinol-3-one by partial
reduction or perhydroisoquinoline by complete reduction,
The efficient preparation of substituted 3,5-hexadienoic
acids of type 6 was central to the success of our outlined
strategy (Scheme 1). As such, several pathways for their
synthesis were devised via the intermediacy of 2,4-
hexadienoic acids. While the deconjugation of 2,4-hexa-
dienoic acid derivatives has been documented,8b,9 few
examples containing substitution at both the 4 and
6-positions have been reported; this highlighted the need
for exploratory studies of this key isomerization with
regard to olefin geometry about the starting 2,4-hexadi-
enoic acid derivatives to deliver the required 3(Z),5(E)
hexadienoic acid derivatives.
(7) For total syntheses of reserpine, see: (a) Woodward, R. B.; Bader,
F. E.; Bickel, H.; Frey, A. J .; Kierstead, R. W. J . Am. Chem. Soc. 1956,
78, 2023-2025. (b) Woodward, R. B.; Bader, F. E.; Bickel, H.; Kierstead,
R. W. Tetrahedron 1958, 2, 1-57. (c) Pearlman, B. A. J . Am. Chem.
Soc. 1979, 101, 6404-6408. (d) Wender, P. A.; Schaus, J . M.; White,
A. W. J . Am. Chem. Soc. 1980, 102, 6157-6159. (e) Wender, P. A.;
Schaus, J . M.; White, A. W. Hetereocycles 1987, 25, 263-270. (f) Martin,
S. F.; Grzejszczak, S.; Ru¨eger, H.; Williamson, S. A. J . Am. Chem. Soc.
1985, 107, 4072. (g) Martin, S. F.; Ru¨eger, H.; Williamson, S. A.;
Grzejszczak, S. J . Am. Chem. Soc. 1987, 109, 6124-6136. (h) Stork,
G. Pure Appl. Chem. 1989, 61, 439-442. (i) Hanessian, S.; Pan, J . W.;
Carnell, A.; Bouchard, H.; Lesage, L. J . Org. Chem. 1997, 62, 465-
473.
F ir st Gen er a tion Ap p r oa ch : P r ep a r a tion of P er -
h yd r osoqu in ol-3-on e 24. Transition-metal-mediated
couplings of a vinylorganometallic with a vinyl halide
(9) (a) Greico, P. A.; Vidari, G.; Ferrin˜o, Haltiwanter, R. C. Tetra-
hedron Lett. 1980, 21, 1619-1622. (b) Martin, S. F.; Tu, C.; Chou, T.
J . Am. Chem. Soc. 1980, 102, 5274-5279. (c) Krebs, E.-P. Helv. Chim.
Acta 1981, 64, 1023. (d) Kende, A. S.; Toder, B. H. J . Org. Chem. 1982,
47, 163-167. (e) Fleming, I.; Iqbal, J .; Krebs, E.-P. Tetrahedron 1983,
39, 841-846.
(8) (a) Shea, K. J .; Svoboda, J . J . Tetrahedron Lett. 1986, 27, 4837-
4840. (b) Gutierrez, A. J .; Shea, K. J .; Svoboda, J . J . J . Org. Chem.
1989, 54, 4335-4344. (c) Sparks, S. M.; Shea, K. J . Tetrahedron Lett.
2000, 41, 6721-6724. (d) Sparks, S. M.; Shea, K. J . Org. Lett. 2001, 3,
2265-2267.
J . Org. Chem, Vol. 68, No. 13, 2003 5275

Sparks et al.
SCHEME 2
were deemed the most expedient route to the required
3,5-hexadienoic acid (via a 2,4-hexadienoic acid deriva-
tive). On the basis of the starting geometry of the
coupling partners, all possible olefin isomers of the
intermediate 2,4-hexadienoic acid derivatives are acces-
sible, thus allowing for a thorough examination of the
key deconjugation step with regard to the configuration
of the 2,4-hexadienoic ester.
The synthesis of our first generation diene of type 6
was initiated via a Stille coupling protocol.10 A survey of
conditions for the Stille coupling of stannane 811 with
methyl 3(E)-bromoacrylate12 revealed the use of Pd2(dba)3
(2 mol %), 2-trifurylphosphine (TFP, 16 mol %), and
stoichiometric copper iodide (1.4 equiv) in N-methylpyr-
rolidinone (NMP) at 65 °C afforded conjugated ester 9
in good yield.13 Other standard conditions employed to
effect Stille couplings either returned starting materials
(Pd(PPh3)4, THF, 70 °C) or provided a mixture of geo-
metric isomers (PdCl2(MeCN)2, DMF), highlighting the
problems associated with the use of R-substituted vinyl-
stannanes in the Stille coupling.14 Benzylation of the
primary hydroxyl utilizing the conditions developed by
Bundle15 afforded protected diene 10 (Scheme 2). At-
tempted deconjugation of diene 10 resulted in a complex
reaction mixture, potentially due to the instability of the
resulting silylenol ether to the reaction conditions. To
circumvent this complication, the silyl protecting group
was converted to the more robust methoxymethyl ether
via silyl deprotection (HF‚pyr, THF) followed by alkyla-
tion (MOMCl, i-Pr2NEt, CH2Cl2).
F IGURE 1.
THF, -78 °C, which gave, following an acidic quench
(10% HCl), a single product in 70% isolated yield. Both
1H NMR and subsequent chemical studies established
that the reaction gave the 3(Z),5(E)-dienoic ester 13
(Figure 1). Exclusive formation of 5(E) stereochemistry
from the 4(Z) precursor was somewhat surprising and
implies that rotamer 12A is the reacting species at -78
°C. Hydrolysis of ester 13 (KOH/aq MeOH) provided acid
14 in quantitative yield.
The Diels-Alder precursor was prepared by coupling
of diene acid 14 with O-ethylvinylimidate (15, eq 2).8b
Several coupling methods were screened including car-
bodiimide mediated coupling (DCC) and activation of acid
14 as the acyl chloride ((COCl)2, cat. DMF, CH2Cl2) but
failed due to product hydrolysis during silica gel chro-
matography and decomposition of the intermediate acyl
chloride, respectively. These failures suggested a method
was required which minimized exposure to silica gel and
provided a reactive intermediate which would not un-
dergo decomposition, as did the acyl chloride. This was
achieved with the coupling acid 14 and imidate 15
mediated by 2-chloro-1-methylpyridinium iodide, the
Mukaiyama reagent.16 When acid 14, imidate 15, and the
Mukaiyama salt were stirred at 0 °C in the presence of
2 equiv of triethylamine, Diels-Alder precursor 16 was
isolated in 83% yield following purification via quick
filtration of the reaction mixture through a short plug of
Kinetic deconjugation of 2,4-hexadienoic ester deriva-
tive 12 was accomplished with lithium diisopropylamide
(LDA, 1.1 equiv)/hexamethylphosphoramide (HMPA)/
(10) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J . The Stille
Reaction; Wiley: New York, 1998. (b) Farina, V.; Krishnamurthy, V.;
Scott, W. J . Farina, V.; Krishnamurthy, V.; Scott, W. J . Org. React.
1997, 50, 1.
(11) Barrett, A. G. M.; Barta, T. E.; Flygare, J . A. J . Org. Chem.
1989, 54, 4246-4249.
(12) Weir, J . R.; Patel, B. A.; Heck, R. F. J . Org. Chem. 1980, 45,
4926-4931.
(13) (a) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J . Org. Chem. 1994, 59, 5905-5911. (b) Farina, V.; Krishnan, B.
J . Am. Chem. Soc. 1991, 113, 9585-9595. (c) Liebeskind, L. S.; Fengl,
R. W. J . Org. Chem. 1990, 55, 5359-5364.
(14) (a) Flohr, A. Tetrahedron Lett. 1998, 39, 5177. (b) Quayle, P.;
Wang, J . Y.; Xu, J .; Urch, C. J . Tetrahedron Lett. 1998, 39, 489. (c)
Farina, V.; Hossain, M. A. Tetrahedron Lett. 1996, 37, 6997.
(15) Iversen, T.; Bundle, D. R. J . Chem. Soc., Chem. Commun. 1981,
1240-1241.
(16) (a) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-
1166. (b) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707-
808.
5276 J . Org. Chem., Vol. 68, No. 13, 2003

Formal Synthesis of (()-Reserpine
silica gel. Low yields (∼5%) of cycloadduct 17 (eq 3) were
also detected in the reaction mixture of the coupling
reaction, suggesting the possibility that an incipient
N-acyl iminium ion may be present and undergoing
cycloaddition at 0 °C. This possibility suggests that the
cycloaddition may be catalyzed by protonic or Lewis acids.
step epoxidation/epoxide fragmentation approach. This
sequence was initiated by m-CPBA epoxidation in EtOH
at 60 °C to provide a 5:1 ratio of separable epoxides in
67% yield (eq 5). Formation of R-epoxide 20 as the major
isomer was confirmed by X-ray crystallography, which
corroborated the stereochemical assignments. A study of
solvents for this reaction revealed a diminished diaster-
eomeric ratio (2:1) when the reaction was run in CH2-
Cl2, potentially indicating the ability of the C7 meth-
oxymethyl group to partially direct the epoxidation to the
â-face of the olefin. Utilization of a solvent capable of
hydrogen bonding (EtOH) diminished this interaction to
afford a higher ratio favoring R-epoxide 20.
With the Diels-Alder precursor in hand, conditions to
effect the key transformation were examined. Several
solvents were screened which indicated chloroform as a
superior solvent for both chemical yield and diastereo-
meric ratio. When a dilute solution (0.05 M) of precursor
16 in CHCl3 was heated to 60 °C in chloroform containing
4 Å molecular sieves, two cycloadducts were isolated in
95% combined yield (eq 3). Gas chromatography indicated
an 8:1 ratio of cycloadducts. An analytical sample of the
major cycloadduct (17) could be obtained in low yield by
silica gel chromatography; however, in practice the
isomeric mixture was taken directly into the reduction
sequence. The major cycloadduct 17 was assigned the cis-
In preparation for the epoxide fragmentation reaction,
conversion of the C5 benzyloxymethyl to a carbomethoxy
group was undertaken (eq 6). Hydrogenolysis (10% Pd-
C, EtOH, 12 h, 87%) of the benzyl protecting group
followed by ruthenium-catalyzed oxidation (RuCl3‚H2O,
NaIO4, CCl4/CH3CN)18 and esterification employing ethe-
real diazomethane afforded ester 22 (61% yield for two
steps).
1
ring fusion on the basis of H NMR (J H4a-H8a ) 5.3 Hz)
corresponding to an endo tether mode of cycloaddition.
This level of diastereoselectivity is consistent with our
earlier examination of substitution on the diene partner.
In this study a 4-methyl-substituted precursor afforded
a 9.5:1 diastereomeric ratio favoring cis-ring fusion,
whereas a 6E-methoxy substituent provided a decreased
5:1 ratio also favoring the cis-ring junction.8b
Attempted elaboration of 17 to intermediate 2 required
N-acylimidate reduction followed by functional group
manipulation of the E-ring. Reduction was accomplished
by a two-step sequence initiated by treatment of the
diastereomeric imidates 17 and 18 with excess NaBH4
in MeOH to furnish the intermediate ethoxy lactams,
which were further reduced by NaCNBH3 in a 9:1
mixture of EtOH/TFA to afford isoquinol-3-one 19 in 45%
yield for the two steps following chromatographic separa-
tion of the trans-fused diastereomer (eq 4). With the
D-ring functionality in hand, efforts were directed toward
installation of the C17 methoxy group.
Reduction of epoxy ester 22 was attempted with
several mild reducing reagents including Al/Hg and Zn/
AcOH in MeOH, which both resulted in recovered start-
ing material. However, when ester 22 was treated with
2.1 equiv of sodium in liquid ammonia at -78 °C, low
yields (10%) of opened epoxides 24 and 25 were isolated
following a methanol quench. Lactam 24 could be exclu-
sively isolated in low yield under identical conditions
substituting solid NH4Cl for MeOH in the quenching
step. In both reactions, 50% of the starting material could
be recovered. Upon increasing the amount of sodium
metal in liquid ammonia at -78 °C to 4.1 equiv followed
by quenching with an excess of NH4Cl, no starting
material was detected and a 50% yield of 24 was isolated
(Scheme 3). The stereochemistry of the newly formed
carbomethoxy was determined by examination of the
coupling constants of H5 at 2.68 ppm. Coupling constants
of 4.6 Hz (J H5-H4a) and 10.7 Hz (J H5-H6) indicate that the
carbomethoxy group is equatorial. This result suggests
a kinetic quench of trianion 23 from the R-face. The
overall transformation of 22 to 24 entails a regioselective
addition of H2 across an epoxy C-O bond with retention
of configuration, which provides the fully stereochemi-
cally elaborated DE rings of reserpine.
Attempted hydroboration of the trisubstituted olefin
of lactam 19 employing 1 equiv of BH3‚THF provided
returned starting material in addition to reduced lactam
byproducts.17 While protection of the amide nitrogen atom
of 19 may have allowed for a successful hydroboration
to occur, the added protection and deprotection steps
detracted from our overall approach. This complication
led to the introduction of the C6 oxygen atom via a two
(18) (a) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K.
B. J . Org. Chem. 1981, 46, 3936. (b) Denis, J .-N.; Greene, A. E.; Serra,
A. A.; Luche, M.-J . J . Org. Chem. 1986, 51, 46.
(17) Gutierrez, A. J . Ph.D. Dissertation, University of California,
Irvine, 1990.
J . Org. Chem, Vol. 68, No. 13, 2003 5277

Sparks et al.
SCHEME 3
27 proceeded in the presence of Pd(PPh3)4 (3 mol %) and
sodium methoxide in refluxing toluene/methanol to afford
2(E),4(E)-hexadienoic ester 29 in 75% yield.
The kinetic deconjugation of dienoic ester 29 was next
examined. Slow addition of diene 29 to a solution of LDA
(1.2 equiv) and N,N-dimethylpropyleneurea (DMPU) in
THF at -78 °C followed by an acidic quench (10% HCl)
led to the formation of two inseparable isomers in a 3.6:
1.0 ratio as determined by integration of the 1H NMR
spectrum (Scheme 5). The 1H NMR spectrum of the
mixture revealed the major isomer to contain the 3(Z),5-
(E) geometry (30, J H5-H6 ) 12.5 Hz). Due to signal overlap
in the 1H NMR spectrum of the minor isomer, the
mixture was saponified which revealed the minor isomer
to contain the 3(Z),5(Z) geometry (33, J H5-H6 ) 7.2 Hz).
Various conditions were screened for the deconjugation
of diene 29 with no improvement in the isomeric ratio.
While the isomeric mixture of acids 32 and 33 could
be carried through to the key Diels-Alder cycloaddition,
a more selective method for preparation of the 3(Z),5-
(E)-hexadienoic acid was sought. Toward this end, a
modified version of the Stille coupling approach we
previously explored (Scheme 2) was undertaken.10 Pal-
ladium-catalyzed hydrostannylation23 of alkynoate 3424
with tributyltin hydride (TBTH) followed by DIBALH
reduction afforded vinylstannane 35 (Scheme 6). Subject-
ing vinylstannane 35 to the Stille conditions that were
previously employed (Scheme 2) at a slightly higher
temperature (65 °C) and for a longer duration (3 h)
delivered conjugated ester 36 in high yield. Protection
of the hydroxyl group of diene 36 as a â-trimethylsi-
lylethoxymethoxy ether (SEM) furnished 2,4-hexadienoic
ester 37 in 92% yield. The preparation of diene 37 from
alkynoate 34 in four steps represents a substantial
improvement over our initial route to 2(E),4(Z)-dienoic
esters (Scheme 2).
With the preparation of 2(E),4(Z)-dienoic ester 37
secured, the key deconjugation was investigated. In the
event, slow addition of ester 37 to a solution of LDA and
DMPU in THF at -78 °C followed by a methanolic
quench afforded a single product in 89% yield (Scheme
7). Both 1H NMR (J H5-H6 ) 12.6 Hz) and subsequent
chemical studies established that the reaction gave
exclusively the 3(Z),5(E) dienoic acid ester (38). Saponi-
fication yielded diene acid 39 in 97% yield. With the
preparation of dienoic acid 39 in six steps and 53% overall
yield from alkynoate 34 accomplished, the crucial in-
tramolecular Diels-Alder cycloaddition was examined.
Syn th esis of P er h yd r oisoqu in olin e 3: A F or m a l
Syn th esis of (()-Reser p in e. The completion of the
synthesis of perhydroisoquinoline 3 entailed two objec-
tives, preparation of the Diels-Alder precursor followed
The remaining transformations to form the Woodward
intermediate 2 from lactam 24 required methylation of
the C6 hydroxyl group and alkylation of the amide
nitrogen atom with a 6-methoxytryptophyl electrophile.
Several attempts at methylating the sterically congested
C6 hydroxyl resulted in partial epimerization of the C5
carbomethoxy group. Indeed, several studies have docu-
mented the difficult nature of this methylation due to
the hindered nature of the hydroxyl group, which is
shielded by equatorial substituents on both sides. Ad-
ditionally, model efforts aimed at the alkylation of
valerolactam with various 3-(2-substituted)indole elec-
trophiles furnished 3-vinylindole as the major product
via an E2 elimination pathway. The elimination pathway,
endemic to substitution reactions of 3-(2-haloethyl)indoles
with metalated amides,19 could be bypassed by employing
an indoline electrophile which could be subsequently
oxidized to the required indole. This approach was
successfully applied in our synthesis of (()-alloyohim-
bane;8c however, the C5 carbomethoxy group present in
lactam 24 precluded its application in this case due to
potential epimerization.
Limited quantities of lactam 24 in addition to the
problems associated with the final transformations re-
sulted in a strategic change in our synthesis plan.
Perhydroisoquinoline 3 was chosen as a second-genera-
tion target, which would allow for the refinement of our
approach. Several goals including a more efficient syn-
thesis of the 3,5-hexadienoic acid of type 6 and one-step
C6 hydroxyl installation with increased diastereoselec-
tivity were set to streamline the synthetic route.
Secon d Gen er a tion Ap p r oa ch : Syn th esis of Su b-
stitu ted 2,4-Hexa d ien oic Ester s. A Suzuki coupling
protocol was explored for our next entry into the required
2,4-hexadienoic ester (Scheme 4).20 Protection of alcohol
2621 as its methoxymethyl ether afforded vinyl iodide 27.
Suzuki coupling of known boronic ester 2822 with iodide
SCHEME 4
5278 J . Org. Chem., Vol. 68, No. 13, 2003

Formal Synthesis of (()-Reserpine
SCHEME 5
SCHEME 8
SCHEME 6
SCHEME 9
SCHEME 7
cycloaddition sets three of the five stereocenters required
for the DE perhydroisoquinoline ring system in reserpine.
In addition, the resulting unsaturation at C5-C6 allows
for the one-step formation of the C5 and C6 stereocenters.
First, however, the N-acylimidate functionality of the
mixture of diastereomeric cycloadducts was reduced with
lithium aluminum hydride and acylated with methyl
chloroformate to afford methyl carbamate 43 in 73%
overall yield for the two steps following chromatographic
separation of the trans-fused diastereomer.
Introduction of the C6 hydroxy group was next exam-
ined. Treatment of olefin 43 with BH3‚THF complex was
followed by oxidation (H2O2, NaOH) to afford a single
alcohol (44) in 73% yield (Scheme 9). The stereochemistry
of the newly formed alcohol was secured by 1H HMR.
Proton coupling constants of 10 Hz indicated a trans
diaxial relationship between the protons at C5 and C7
with the C6 proton (J H5-H6 ) J H6-H7 ) 10.0 Hz). Methyl
ether formation using conditions previously employed for
related systems (n-BuLi, THF, -78 °C; MeOTf) provided
a complex reaction mixture with only a low yield of the
desired product (<10%).8d,25 This problem was overcome
by treatment of alcohol 44 with trimethyloxonium tet-
rafluoroborate (6 equiv), Proton Sponge (7 equiv), and 4
Å molecular sieves in CH2Cl2 to furnish methyl ether 45
in 97% yield.26
by cycloaddition and elaboration of the E-ring. These
goals were accomplished in the following manner.
In analogy with our initial entry, the Diels-Alder
substrate was prepared by the coupling of 1-aza-2-ethoxy-
1,3-butadiene (15)8b with 3,5-hexadienoic acid 39 medi-
ated by 2-chloro-1-methylpyridinium iodide (Scheme 8).16
This method provided N-acylvinylimidate 40 in 85%
isolated yield after filtration of the reaction mixture
through silica gel. Cycloaddition occurred in refluxing
chloroform to provide a 6:1 ratio of cycloadducts in 90%
yield. The major cycloadduct, 41, was assigned the cis-
1
ring fusion on the basis of H NMR (J H4a-H8a ) 5.5 Hz),
corresponding to a tether endo cycloaddition. This key
(19) Bergmeier, S. C.; Seth, P. P. J . Org. Chem. 1999, 64, 3237.
(20) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(b) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-168.
(21) Rawal, V. H.; Isawa, S. J . Org. Chem. 1994, 59, 2685-2686.
(22) Rassetdeloge, C.; Martinezfresneda, P.; Vaultier, M. Bull. Soc.
Chim. Fr. 1992, 129, 285-290.
(23) Zhang, H. X.; Guibe, F.; Balavoine, G. J . Org. Chem. 1990, 55,
1857-1867.
(24) Heathcock, C. H.; Stafford, J . A.; Clark, D. L. J . Org. Chem.
1992, 57, 2575-2585.
(25) Baxter, E. W.; Labaree, D.; Ammon, H. L.; Mariano, P. S. J .
Am. Chem. Soc. 1990, 112, 7682-7692.
(26) Ireland, R. E.; Liu, L.; Roper, T. D.; Gleason, J . L. Tetrahedron
1997, 53, 13257-13284.
J . Org. Chem, Vol. 68, No. 13, 2003 5279

Sparks et al.
Proton NMR spectra were recorded on a Bruker Avance
DRX (500 MHz). The chemical shifts are reported in the δ scale
in ppm with the solvent indicated as the internal reference.
Coupling constants (J ) are reported in Hz, and the splitting
abbreviations used are as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad. Carbon NMR are
obtained using the above instrument operating at 125.8 MHz
(Avance DRX) using the solvent indicated as the internal
reference. Infrared spectra (FTIR) were obtained using an
Analect RFX-40 FTIR spectrometer. High-resolution mass
spectra (HRMS) (EI, 70 eV or CI, isobutane or ammonia) were
obtained on a VG 7070E high-resolution mass spectrometer
or Fisons Autospec mass spectrometer.
SCHEME 10
Meth yl 6-(ter t-bu tyld ip h en ylsiloxy)-4-h yd r oxym eth yl-
2E,4Z-h exa d ien oa te (9). A degassed Solution of 4-tert-
butyldiphenylsiloxy-2(E)-(tributylstannyl)-2-buten-1-ol (8, 0.5
g, 0.8 mmol) and methyl 3(E)-bromoacrylate (0.13 g, 0.8 mmol)
in 1-methyl-2-pyrrolidinone (4 mL) was added via cannula to
a degassed solution of Pd2(dba)3 (15 mg, 0.016 mmol, 2 mol
%), tri-2-furylphosphine (30 mg, 0.13 mmol, 8 mol %), and CuI
(0.22 g, 1.14 mmol) in 1-methyl-2-pyrrolidinone (4 mL). The
solution was heated to 50 °C for 2.5 h, cooled, and then poured
onto 10% aqueous KF (5 mL) and water (5 mL). The solution
was stirred for 20 min and then filtered through Celite. The
mixture was extracted with Et2O (2 × 20 mL), and the organics
were separated, dried (MgSO4), and concentrated. The residue
was chromatographed (10% to 15% EtOAc/hexane) to afford
0.26 g (79%) of diene 9 as a colorless oil: 1H NMR (CDCl3) δ
7.66 (d, J ) 7.5 Hz, 4 H), 7.46-7.38 (m, 6 H), 7.24 (d, J ) 15.9
Hz, 1 H), 6.12 (t, J ) 6.1 Hz, 1 H), 6.06 (d, J ) 15.9 Hz, 1 H),
4.20 (d, J ) 6.1 Hz, 2 H), 4.17 (s, 2 H), 3.76 (s, 3 H), 1.59 (br
s, 1 H), 1.05 (s, 9 H); 13C NMR (CDCl3) δ 167.6, 145.9, 141.0,
136.8, 135.5, 132.9, 129.9, 127.8, 118.0, 60.6, 57.4, 51.6, 26.7,
19.1; IR (NaCl film) 3444, 3062, 2948, 2844, 1713, 1620, 1310,
1108, 1031 cm-1; HRMS (CI) calcd for C24H31O4Si (MH+)
411.1991, obsd 411.1974.
Completion of the synthesis of perhydroisoquinoline 2
required conversion of the C5 hydroxymethyl group to a
methyl ester and conversion of the C7 benzyloxy group
to the 3,4,5-trimethoxybenzoyl (TMB) group. This was
accomplished by removal of the SEM protecting group
with TBAF in DMPU containing 4 Å molecular sieves27
followed by PDC oxidation of the resulting primary
alcohol and esterification (CH2N2, Et2O, 0 °C) to yield
methyl ester 46 (Scheme 10). The final stage of the
synthesis required installation of the 3,4,5-trimethoxy-
benzoyl ester, which was accomplished by hydrogenolysis
(10% Pd-C, H2, MeOH, 100%) of the benzyl protecting
group followed by esterification with 3,4,5-trimethoxy-
benzoyl chloride (TMBCl) to provide the desired target,
decahydroisoquinoline 3. Confirmation of the stereo-
chemistry of synthetic 3 was secured by comparison of
the 1H and 13C NMR spectra of synthetic 3 to that
recorded for natural 3 prepared from (-)-reserpine.7d
In conclusion, we have established that the intramo-
lecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl
acrylimidates provides an efficient method for the prepa-
ration of cis-fused hexahydroisoquinolines. The syntheses
of decahydroisoquinolone 24 and decahydroisoquinoline
3, an intermediate that contains five of the six stereo-
centers of reserpine and constitutes its formal synthesis,
demonstrates the utility of this reaction for the prepara-
tion of stereochemically complex perhydroisoquinoline
containing natural products.
Meth yl 6-(ter t-Bu tyldiph en ylsiloxy)-4-(ben zyloxy)m eth -
yl-2E,4Z-h exa d ien oa te (10). To a solution of diene 9 (0.41
g, 1.0 mmol) in CH2Cl2 (10 mL) was added benzyl 2,2,2-
trichloroacetimidate (0.28 g, 1.1 mmol) followed by triflic acid
(1 drop). The reaction was stirred for 10 h, concentrated, and
redissolved in EtOAc (20 mL). The reaction mixture was then
washed with saturated NaHCO3 (20 mL), dried (MgSO4),
concentrated, and chromatographed (hexane to 15% EtOAc/
hexane) to afford 0.35 g (70%) of diene 10 as a colorless oil:
1H NMR (CDCl3) δ 7.66-7.63 (m, 4 H), 7.47-7.36 (m, 6 H),
7.29-7.25 (m, 4 H), 7.20-7.19 (m, 2 H), 6.24 (t, J ) 6.0 Hz, 1
H), 6.04 (d, J ) 15.9 Hz, 1 H), 4.39 (d, J ) 6.0 Hz, 2 H), 4.33
(s, 2 H), 3.98 (s, 2 H), 3.77 (s, 3 H), 1.06 (s, 9 H); 13C NMR
(CDCl3) δ 167.6, 146.2, 143.4, 137.6, 135.5, 133.3, 133.1, 129.8,
128.4, 127.8, 127.7, 127.7, 118.0, 72.0, 64.0, 60.8, 51.6, 26.7,
19.1; IR (NaCl film) 3064, 2939, 2855, 1718, 1619, 1311, 1107
cm-1; HRMS (CI) calcd for C31H37O4Si (MH+) 501.2461, found
501.2468.
Exp er im en ta l Section
Gen er a l Meth od s. Tetrahydrofuran, diethyl ether, meth-
ylene chloride, and benzene were dried by filtration through
alumina according to the procedure described by Grubbs.28 All
other solvents were distilled from drying agents (CaH2 or Na/
benzophenone) immediately prior to use. Glassware was
cleaned by soaking in an alcoholic KOH solution overnight and
rinsing with water; glassware was oven dried overnight. All
reactions were run under a N2 atmosphere. Volatile solvents
were removed under reduced pressure using a Bu¨chi rotary
evaporator; this procedure is referred to as removing solvents
in vacuo. Thin-layer chromatography was run on precoated
plates of silica gel with a 0.25 mm thickness containing 60F-
254 indicator (Merck). Liquid chromatography was performed
using forced flow (flash chromatography) of the indicated
solvent system on 230-400 mesh silica gel (E. Merck reagent
silica gel 60).
Meth yl 4-Ben zyloxym eth yl-6-h yd r oxy-2E,4Z-h exa d i-
en oa te (11). HF‚pyridine (2 mL) was added to a solution of
diene 10 (0.65 g, 1.30 mmol) in THF (12 mL) in a polyethylene
bottle. The solution was stirred 2 h, and then saturated
NaHCO3 was added slowly until bubbling ceased. The layers
were separated, and the aqueous layer was extracted with
Et2O (20 mL). The combined organic layers were combined and
washed with brine (10 mL), dried (MgSO4), concentrated, and
chromatographed (30% EtOAc/hexane) to afford 0.17 g (50%)
of diene 11 as a colorless oil: 1H NMR (CDCl3) δ 7.37-7.29
(m, 5 H), 7.28 (d, J ) 15.9 Hz, 1 H), 6.23 (t, J ) 6.5 Hz, 1 H),
6.04 (d, J ) 15.9 Hz, 1 H), 4.51 (s, 2 H), 4.30 (d, J ) 6.5 Hz,
2 H), 4.21 (s, 2 H), 3.76 (s, 3 H), 2.80 (br s, 1 H); 13C NMR
(CDCl3) δ 167.5, 146.0, 142.2, 137.4, 134.8, 128.6, 128.0, 127.9,
118.3, 72.6, 64.2, 59.2, 51.6; IR (NaCl film) 3429, 3033, 2949,
2855, 1713, 1619, 1306, 1170, 1071 cm-1; HRMS (CI) calcd for
(27) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149-
7152.
(28) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518-1520.
C
15H19O4 (MH+) 263.1283, obsd 263.1276.
5280 J . Org. Chem., Vol. 68, No. 13, 2003

Formal Synthesis of (()-Reserpine
Meth yl 6-(Meth oxym eth oxy)-4-ben zyloxym eth yl-2E,4Z-
h exa d ien oa te (12). MOMCl (0.08 g, 0.97 mmol) was added
to a solution of alcohol 11 (0.17 g, 0.65 mmol) and i-Pr2NEt
(0.15 g, 0.97 mmol) in CH2Cl2 (6 mL). The solution was stirred
for 12 h and then concentrated and redissolved in EtOAc (10
mL). The reaction mixture was washed with saturated NaH-
CO3 (10 mL), dried (MgSO4), concentrated, and chromato-
graphed (30% EtOAc/hexane) to give 0.15 g (76%) of diene 12
as a colorless oil: 1H NMR (CDCl3) δ 7.37-7.29 (m, 5 H), 7.28
(d, J ) 16.0 Hz, 1 H), 6.18 (t, J ) 6.4 Hz, 1 H), 6.10 (d, J )
15.9 Hz, 1 H), 4.61 (s, 2 H), 4.49 (s, 2 H), 4.25 (d, J ) 6.4 Hz,
2 H), 4.20 (s, 2 H), 3.75 (s, 3 H), 3.35 (s, 3 H); 13C NMR (CDCl3)
δ 167.5, 145.8, 139.7, 137.7, 135.2, 128.5, 127.9, 118.6, 96.0,
72.3, 64.1, 63.6, 55.4, 51.6; IR (NaCl film) 3033, 2949, 2876,
1708, 1624, 1306, 1170, 1107, 1040 cm-1; HRMS (CI) calcd for
1656, 1587 cm-1; HRMS (CI) calcd for C21H28NO5 (MH+)
374.1960, obsd 374.1939.
(4a S*,7R*,8a S*)-5-Ben zyloxym eth yl-1-eth oxy-7-(m eth -
oxym eth oxy)-3,4,4a,7,8,8a-h exah ydr oisoqu in ol-3-on e (17).
A solution of vinylimidate 16 (13.9 g, 37.7 mmol) in CHCl3
(700 mL) containing 4 Å molecular sieves was heated to reflux
for 6 days. The solution was cooled, filtered through Celite,
and concentrated in vacuo to afford 13.2 g (95%) of an 8:1
mixture of diastereomeric cycloadducts 17 and 18 as a yellow
oil. An analytical sample was purified in low yield by chro-
matography on silica gel eluting with hexanes/EtOAc (2:1).
17: 1H NMR (500 MHz, CDCl3) 7.36-7.28 (m, 5 H), 5.83 (br
s, 1 H), 4.73 (d, J ) 6.9 Hz, 1 H), 4.70 (d, J ) 6.9 Hz, 1 H),
4.50 (d, J ) 11.9 Hz, 1 H), 4.47 (d, J ) 11.9 Hz, 1 H), 4.40-
4.38 (m, 2 H), 4.33 (m, 1 H), 4.04 (d, J ) 12.0 Hz,1 H), 3.89 (d,
J ) 12.0 Hz, 1 H), 3.39 (s, 3 H), 2.85-2.74 (m, 2 H), 2.68 (ddd,
J ) 11.5, 6.1, 5.3 Hz, 1 H), 2.35 (dd, J ) 14.1, 11.6 Hz, 1 H),
2.30 (ddd, J ) 12.4, 8.1, 5.9 Hz, 1 H), 1.74 (ddd, J ) 12.6, 9.6,
7.1 Hz, 1 H), 1.37 (t, J ) 7.1 Hz, 3 H); 13C NMR (125.8 MHz,
CDCl3) δ 182.3, 181.8, 138.1, 137.7, 128.2, 127.8, 127.8, 127.7,
95.4, 72.6, 71.7, 71.4, 64.2, 55.5, 35.6, 34.3, 31.5, 28.4, 14.0;
IR (NaCl film) 2962, 2931, 2888, 1706, 1587 cm-1; HRMS (CI)
calcd for C21H28NO5 (MH+) 374.1960, obsd 374.1968.
C
17H23O5 (MH+) 307.1545, obsd 307.1552.
4-(Ben zyloxy)m et h yl-6-(m et h oxym et h oxy)-3(E),5(E)-
h exa d ien oic Acid (14). To a solution of lithium diisopropyl
amide (84.7 mmol) in THF (190 mL) at -78 °C was added
HMPA (12.7 mL, 72.8 mmol), and the solution was stirred for
30 min. Ester 12 (23.3 g, 72.8 mmol) dissolved in THF (80 mL)
was added dropwise over 1.5 h, maintaining the temperature
below -72 °C. The mixture was stirred for 2 h and poured
onto 10% HCl (160 mL). The organic layer was separated and
washed with saturated NaHCO3 (150 mL), H2O (150 mL), and
brine (150 mL). The solvent was dried (MgSO4) and concen-
trated in vacuo. (An analytical sample was purified by chro-
matography on silica gel eluting with hexanes/EtOAc (4:1) to
provide diene 13 as a pale yellow oil: 1H NMR (300 MHz,
CDCl3) δ 7.36-7.29 (m, 5 H), 6.74 (d, J ) 12.0 Hz, 1 H), 5.79
(d, J ) 12.0 Hz, 1 H), 5.67 (t, J ) 6.0 Hz, 1 H), 4.83 (s, 2 H),
4.48 (s, 2 H), 4.16 (s, 2 H), 4.13 (q, J ) 7.0 Hz, 2 H), 3.40 (s, 3
H), 3.15 (d, J ) 6.0 Hz, 2 H), 1.26 (t, J ) 7.0 Hz, 3 H); 13C
NMR (125.8 MHz, CDCl3) δ 171.4, 145.4, 138.0, 134.3, 128.3,
127.9, 127.6, 122.1, 111.4, 95.9, 71.6, 64.6, 60.7, 55.8, 33.6, 14.1;
IR (NaCl film) 2956, 2935, 2898, 1733, 1654 cm-1.) The
resulting yellow oil was dissolved in MeOH (250 mL) and was
added to a stirred solution of KOH (6.5 g, 0.101 mol) in H2O
(250 mL) at 0 °C. The mixture was stirred for 4 h during which
time the solution became homogeneous. The solvent was
reduced to 250 mL in vacuo and washed with Et2O (100 mL).
The aqueous phase was acidified to pH ) 3 with 10% HCl and
extracted with ether (5 × 100 mL). The extracts were dried
(MgSO4) and concentrated to afford 13.7 g (70%) of acid 14 as
a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.36-7.29 (m,
5 H), 6.69 (d, J ) 12.0 Hz, 1 H), 5.76 (d, J ) 12.0 Hz, 1 H),
5.63 (t, J ) 6.0 Hz, 1 H), 4.82 (s, 2 H), 4.50 (s, 2 H), 4.13 (s, 2
H), 3.39 (s, 2 H), 3.18 (d, J ) 6.0 Hz, 2 H); 13C NMR (125.8
MHz, CDCl3) δ 175.7, 145.6, 137.6, 135.1, 128.5, 128.3, 121.3,
111.4, 96.0, 72.0, 64.7, 55.9, 33.6; IR (NaCl film) 3500-3200,
2954, 2900, 1656, cm-1; HRMS (CI) calcd for C16H20O5 (M+)
292.1311, obsd 292.1309.
(4a S*,7R*,8a S*)-5-Ben zyloxym eth yl-1-eth oxy-7-(m eth -
oxym e t h oxy)-1,2,3,4,4a ,7,8,8a -oct a h yd r oisoq u in ol-3-
on e. Sodium borohydride (6.60 g, 174.5 mmol) was added in
two portions to a solution of imidate cycloadducts 17 and 18
(13.2 g, 35.4 mmol) in MeOH (170 mL) at 0 °C. The reaction
was stirred at 0 °C for 1 h and then concentrated to one-half
the original volume and diluted with CH2Cl2 (200 mL). The
organic phase was washed with saturated NaHCO3 (100 mL),
H2O (100 mL), and brine (100 mL) and dried (MgSO4). The
solvent was filtered through Florisil and concentrated in vacuo
to give 9.3 g (70%) of ethoxy lactam as an oil. An analytical
sample was purified with loss of ca. 30% of the material by
chromatography on silica gel eluting with EtOAc: 1H NMR
(500 MHz, CDCl3) 7.38-7.28 (m, 5 H), 6.18 (br s, 1 H), 5.70 (s,
1 H), 4.75 (d, J ) 7.0 Hz, 1 H), 4.74 (d, J ) 5.3 Hz, 1 H), 4.70
(d, J ) 7.0 Hz, 1 H), 4.49 (d, J ) 12.0 Hz, 1 H), 4.46 (d, J )
12.0 Hz, 1 H), 4.29 (br dd, J ) 8.5, 7.6 Hz, 1 H), 4.00 (d, J )
12.1 Hz, 1 H), 3.87 (d, J ) 12.1 Hz, 1 H), 3.63 (m, 1 H), 3.52
(m, 1 H), 3.39 (s, 2 H), 2.63-2.56 (m, 2 H), 2.30-2.19 (m, 3
H), 1.47 (ddd, J ) 16.2, 13.1, 10.2 Hz, 1 H), 1.24 (t, J ) 7.0
Hz, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 171.0, 140.4, 137.9,
128.5, 127.8, 127.7, 127.0, 95.1, 84.5, 72.6, 72.5, 71.8, 64.3, 55.4,
35.2, 30.3, 22.9, 15.3; IR (NaCl film) 3207, 2975, 2931, 1664,
1469 cm-1; HRMS (CI) calcd for C21H29NO5 (M+) 376.2124,
obsd 376.2022; calcd for
330.1705, obsd 330.1699.
C
19H23NO4 (M - CH3CH2OH+)
(4a S*,7R*,8a R*)-5-Ben zyloxym eth yl-7-(m eth oxym eth -
oxy)-1,2,3,4,4a ,7,8,8a -octa h yd r oisoqu in ol-3-on e (19). So-
duim cyanoborohydride (2.76 g, 43.95 mmol) was added in one
portion to a solution of ethoxy lactam (5.50 g, 14.65 mmol) in
EtOH (65 mL) at ambient temperature. The solution was
stirred for 30 min and then cooled to 0 °C. Trifluoroacetic acid
(6.5 mL) was added dropwise over 15 min, and the resulting
solution was stirred for 5 h. The mixture was then concen-
trated in vacuo and redissolved in CHCl3 (200 mL). Saturated
NaHCO3 (50 mL) was added to the stirring mixture over 15
min, the layers were then separated, and the aqueous phase
was extracted with CHCl3 (3 × 50 mL). The combined extracts
were dried (MgSO4), concentrated in vacuo, and purified by
chromatography on silica gel eluting with CH2Cl2/2-propanol
(10:1) to afford 3.16 g (65%) of lactam 19 as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.36-7.26 (m, 5 H), 6.38 (br s, 1 H),
5.71 (s, 1 H), 4.72 (d, J ) 7.0 Hz, 1 H), 4.70 (d, J ) 7.0 Hz, 1
H), 4.51 (d, J ) 12.0 Hz, 1 H), 4.46 (d, J ) 12.0 Hz, 1 H), 4.32
(dd, J ) 8.0, 7.5 Hz, 1 H), 4.02 (d, J ) 12.0 Hz, 1 H), 3.88 (d,
J ) 12.0 Hz, 1 H), 3.55 (dd, J ) 12.5, 5.0 Hz, 1 H), 3.16 (dt, J
) 11.5, 3.5 Hz, 1 H), 2.66 (dd, J ) 20.0, 7.0 Hz, 1 H), 2.64 (m,
1 H), 2.25 (dd, J ) 20.0, 12.0 Hz, 1 H), 2.06 (dd, J ) 13.5, 2.0
Hz, 1 H), 1.96 (dd, J ) 12.0, 4.5 Hz, 1 H), 1.81 (ddd, J ) 13.0,
N-(4-(Ben zyloxy)m et h yl-6-(m et h oxym et h oxy)-3(E),5-
(E)-h exa d ien oyl)-2-eth oxy-1-a za -1,3-bu ta d ien e (16). A so-
lution of acid 14 (13.0 g, 44.7 mmol), imidate 15 (4.43 g, 44.7
mmol), and NEt3 (15.0 mL, 107.6 mmol) in CH2Cl2 (150 mL)
was added dropwise over 30 min to a suspension of 2-chloro-
1-methylpyridinium iodide (13.7 g, 53.7 mmol) in CH2Cl2 (250
mL) at 0 °C. The solution was stirred 4 h at 0 °C and then
concentrated to one-quarter of the original volume and filtered
through a pad of SiO2 eluting with 30% EtOAc/hexane. The
filtrate was concentrated in vacuo to afford 13.9 g (83%) of
imidate 16 as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ
7.35-7.30 (m, 5 H), 6.73 (d, J ) 12.3 Hz, 1 H), 6.15 (dd, J )
16.8, 2.4 Hz, 1 H), 6.06 (dd, J ) 17.1, 9.6 Hz, 1 H), 5.79 (d, J
) 12.6 Hz, 1 H), 5.69 (t, J ) 7.8 Hz, 1 H), 5.66 (dd, J ) 9.6,
2.4 Hz, 1 H), 4.83 (s, 2 H), 4.47 (s, 2 H), 4.15 (q, J ) 7.2 Hz, 2
H), 3.40 (s, 3 H), 3.28 (d, J ) 7.5 Hz, 2 H), 1.33 (t, J ) 7.2 Hz,
3 H); 13C NMR (125.8 MHz, CDCl3) δ 183.1, 156.2, 145.3, 138.0,
134.3, 128.3, 127.9, 127.6, 127.4, 125.5, 122.3, 111.6, 95.9, 71.6,
64.8, 62.7, 55.8, 38.5, 13.8; IR (NaCl film) 2933, 2898, 1702,
J . Org. Chem, Vol. 68, No. 13, 2003 5281

Sparks et al.
9.5, 9.2 Hz, 1 H); 13C NMR (125.8 MHz, CDCl3) δ 171.4, 140.9,
137.9, 128.8, 128.4, 127.7, 126.2, 95.5, 72.9, 72.5, 71.7, 55.4,
46.4, 33.9, 31.8, 30.2, 29.9; IR (NaCl film) 3224, 2935, 2884,
1664, 1494 cm-1; HRMS (CI) calcd for C19H26NO4 (MH+)
332.1855, obsd 332.1869.
of epoxy alcohol (0.10 g, 0.40 mmol) in a mixture of CCl4 (1
mL), CH3CN (1 mL), and H2O (1 mL). RuCl3‚H2O (1.8 mg,
0.009 mmol) was added, and the reaction was vigorously
stirred for 2 h. The mixture was then diluted with CH2Cl2 (20
mL), and H2O (20 mL) was added. The layers were separated,
and the organic layer was filtered through Celite and recom-
bined with the aqueous layer. The solvents were removed in
vacuo, and the resulting solid was dissolved in boiling EtOH
(20 mL). The solution was filtered, and the solvent was
concentrated in vacuo. The residue was dissolved in THF (5
mL) and treated with excess ethereal diazomethane for 1 h.
The solvent was concentrated, and the resulting oil was
purified by chromatography on silica gel eluting with EtOAc/
EtOH (10:1) to afford 66 mg (61%) of ester 22 as a colorless
oil: 1H NMR (500 MHz, CDCl3) δ 6.45 (br s, 1 H), 4.77 (d, J )
6.9 Hz, 1 H), 4.74 (d, J ) 6.9 Hz, 1 H), 4.12 (t, J ) 8.5 Hz, 1
H), 3.79 (s, 3 H), 3.67 (s, 1 H), 3.52 (dd, J ) 12.5, 4.3 Hz, 1 H),
3.43 (s, 3 H), 3.12 (ddd, J ) 12.5, 4.3, 1.8 Hz, 1 H), 2.99 (dd,
J ) 18.2, 6.7 Hz, 1 H), 2.90 (ddd, J ) 11.4, 6.9, 4.6 Hz, 1 H),
2.38 (dd, J ) 18.2, 11.5 Hz, 1 H), 2.08 (m, 1 H), 1.84 (ddd, J )
14.0, 8.2, 3.2 Hz, 1 H), 1.65 (ddd, J ) 13.8, 11.7, 8.9 Hz, 1 H);
13C NMR (125.8 MHz, CDCl3) δ 170.1, 168.7, 95.7, 69.6, 61.0,
59.1, 55.7, 52.8, 46.2, 31.4, 30.6, 27.2, 24.2; IR (NaCl film) 3201,
2954, 2896, 1735, 1664 cm-1; HRMS (CI) calcd for C13H20NO6
(MH+) 286.1289, obsd 286.1292.
(4a S*,5R*,6S*,7R*,8a R*)-5-Ben zyloxym eth yl-7-(m eth -
oxym eth oxy)d eca h yd r oisoqu in ol-3-on e-5,6-oxir a n e (20)
an d (4aS*,5S*,6R*,7R*,8aR*)-5-Ben zyloxym eth yl-7-(m eth -
oxym eth oxy)d eca h yd r oisoqu in ol-3-on e-5,6-oxir a n e (21).
Lactam 19 (1.02 g, 3.08 mmol) was dissolved in EtOH (15 mL),
and 85% m-CPBA (2.5 g, 12.3 mmol) was added in one portion.
The reaction was heated to reflux for 48 h and cooled. The
solvent was concentrated in vacuo. The resulting solid was
redissolved in CH2Cl2 (75 mL) and washed with sodium
bisulfite (40 mL), saturated NaHCO3 (2 × 40 mL), H2O (40
mL), and brine (40 mL). The organic layer was dried (MgSO4)
and concentrated to give 0.71 g (67%) of epoxides 20 and 21
as an oil in a 5:1 ratio as determined by 1H NMR. Purification
by chromatography on silica gel eluting with CH2Cl2/2-pro-
panol (10:1) afforded 0.55 g of major epoxide 20 as a colorless
oil. The oil was triturated with Et2O and recrystallized with
Et2O/CH2Cl2 to furnish X-ray quality crystals. 20: mp 118-
119 °C; 1H NMR (500 MHz, CDCl3) δ 7.38-7.28 (m, 5 H), 6.35
(br s, 1 H), 4.73 (d, J ) 12.0 Hz, 1 H), 4.59 (d, J ) 11.9 Hz, 1
H), 4.50 (d, J ) 11.9 Hz, 1 H), 4.05 (dd, J ) 9.4, 7.8 Hz, 1 H),
3.90 (d, J ) 11.5 Hz, 1 H), 3.48 (dd, J ) 12.4, 4.4 Hz, 1 H),
3.38 (s, 3 H); 3.19 (d, J ) 11.5 Hz, 1 H), 3.09 (ddd, J ) 12.4,
4.2, 1.5 Hz, 1 H), 3.02 (s, 1 H), 2.78 (ddd, J ) 9.0, 7.0, 4.0 Hz,
1 H), 2.62 (dd, J ) 18.0, 6.7 Hz, 1 H), 2.35 (dd, J ) 18.0, 12.1
Hz, 1 H), 2.01 (m, 1 H), 1.77 (ddd, J ) 13.4, 7.5, 2.4 Hz, 1 H),
1.57 (ddd, J ) 14.1, 12.7, 9.5 Hz); 13C NMR (125.8 MHz, CDCl3)
δ 170.1, 137.5, 128.3, 127.7, 127.6, 95.6, 73.4, 70.8, 70.4, 63.4,
57.0, 55.5, 46.4, 31.2, 30.1, 27.9, 24.0; IR (NaCl film) 3299,
3029, 2944, 1666 cm-1; HRMS (CI) calcd for C19H26NO5 (MH+)
348.1811, obsd 348.1793. Anal. Calcd for C19H25NO5: C, 65.69;
H, 7.25; N, 4.03. Found: C, 65.72; H 7.23; N 4.00. 21: 1H NMR
(500 MHz, CDCl3) δ 7.39-7.30 (m, 5 H), 6.28 (br s, 1 H), 4.75
(s, 2 H), 4.56 (d, J ) 11.9 Hz, 1 H), 4.50 (d, J ) 12.2 Hz, 1 H),
4.00 (ddd, J ) 10.5, 5.6, 1.6 Hz, 1 H), 3.53 (d, J ) 10.8 Hz, 1
H), 3.46 (ddd, J ) 12.7, 5.6, 1.5 Hz, 1 H) 3.41 (s, 3 H), 3.38 (d,
J ) 10.8 Hz, 1 H), 3.32 (s, 1 H), 3.03 (dt, J ) 12.7, 3.4 Hz, 1
H), 2.64 (dd, J ) 15.3, 9.6 Hz, 1 H), 2.55 (m, 1 H), 2.51 (dd, J
) 15.6, 5.9 Hz, 1 H), 1.79 (m, 1 H), 1.68 (ddd, J ) 13.9, 10.9,
10.2 Hz, 1 H), 1.55 (ddd, J ) 13.9, 5.6, 2.5 Hz, 1 H); 13C NMR
(125.8 MHz, CDCl3) δ 172.6, 137.5, 128.4, 127.8, 127.7, 95.4,
73.9, 73.5, 72.8, 63.4, 59.8, 55.4, 45.5, 30.3, 29.7, 29.0, 26.7;
IR (NaCl film) 3212, 2938, 2888, 1666,1496 cm-1; LRMS (CI)
m/z (relative intensity) 348 (MH+, 100), 332 (8), 302 (8), 107
(38).
(4aS*,5S*,6R*,7R*,8aR*)-5-Meth oxycar bon yl-6-h ydr oxy-
7-(m eth oxym eth oxy)-d eca h yd r oisoqu in ol-3-on e (24). Ep-
oxide 22 (0.11 g, 0.39 mmol) dissolved in THF (5 mL) was
stirred in a flask equipped with a low-temperature thermom-
eter, N2 inlet, and Dewar condenser. The reaction was cooled
to -78 °C, and dry ice/acetone was placed in the condenser.
Gaseous ammonia (ca. 30 mL) was condensed in the flask at
-78 °C and stirred for 5 min. Sodium metal (37 mg, 1.61 mmol)
was added in one portion, and the reaction was stirred for 1 h
until the faint blue color disappeared. Solid ammonium
chloride (0.5 g, 9.3 mmol) was added in one portion at -78 °C
and stirred for 15 min. The cooling bath and condenser were
removed, and the liquid ammonia was evaporated. THF (30
mL) was added to the residue with stirring to break up the
resulting solid. The solution was filtered, and the solids were
washed with THF (3 × 20 mL). The filtrate and washings were
combined, and the solvent was concentrated in vacuo to afford
92 mg of a slightly colored oil. The oil was purified by
chromatography on silica gel eluting with CH2Cl2/2-propanol
(4:1) to afford 56 mg (50%) of lactam 24 as a white foam: 1H
NMR (500 MHz, CDCl3) δ 5.92 (br s, 1 H), 4.80 (m, 2 H), 4.02
(dd, J ) 10.5, 9.5 Hz, 1 H), 3.77 (s, 3 H), 3.59 (dd, J ) 12.4,
4.7 Hz, 1 H), 3.49 (ddd, J ) 11.4, 9.0, 5.2 Hz, 1 H), 3.46 (s, 3
H), 3.18 (ddd. J ) 12.4, 4.1, 1.3 Hz, 1 H), 2.68 (dd, J ) 10.7,
4.6 Hz, 1 H), 2.62 (m, 1 H), 2.43 (dd, J ) 18.7, 12.2 Hz, 1 H),
2.30 (dd, J ) 18.3, 6.8 Hz, 1 H), 2.08 (m, 1 H), 1.92 (dt, J )
13.3, 3.9 Hz, 1 H), 1.84 (m, 1 H); 13C NMR (125.8 MHz, CDCl3)
δ 171.9, 170.1, 97.0, 82.0, 69.5, 55.8, 52.2, 51.1, 46.2, 33.6, 31.9,
30.0, 29.4; IR (NaCl film) 3349, 2931, 1737, 1658 cm-1; HRMS
(CI) calcd for C13H22NO6 (MH+) 288.1447, obsd 288.1452.
(4a S*,5R*,6S*,7R*,8a R*)-5-H yd r oxym et h yl-7-(m et h -
oxym eth oxy)d eca h yd r oisoqu in ol-3-on e-5,6-oxir a n e. Ep-
oxide 20 (1.39 g, 4.00 mmol) was dissolved in EtOH (25 mL),
and 10% Pd/C (42.5 mg, 0.40 mmol Pd) was carefully added
in one portion. The flask was evacuated, and an atmosphere
of H2 was introduced (1 atm). The reaction was stirred for 12
h and then filtered through Celite. The solvent was concen-
trated in vacuo to afford 0.89 g (87%) of debenzylated epoxide
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 6.18 (br s, 1
H), 4.73 (d, J ) 5.5 Hz, 1 H), 4.70 (d, J ) 5.5 Hz, 1 H), 4.06
(dd, J ) 9.1, 8.7 Hz, 1 H) 3.89 (dd, J ) 12.0, 2.5 Hz, 1 H) 3.55
(dd, J ) 12.0, 4.3 Hz, 1 H) 3.50 (dd, J ) 12.0, 4.3 Hz, 1 H),
3.39 (s, 3 H), 3.21 (br s, 1 H), 3.15 (ddd, J ) 12.6, 4.2, 2.4 Hz,
1 H), 2.65 (ddd, J ) 10.8, 4.7, 4.1 Hz, 1 H) 2.61 (dd, J ) 17.5,
6.8 Hz, 1 H), 2.36 (dd, J ) 17.5, 10.9 Hz, 1 H), 2.12 (m, 1 H),
2.04 (br d, J ) 12.0 Hz, 1 H), 1.81 (m, 1 H), 1.59 (ddd, J )
14.0, 12.5, 9.5 Hz, 1 H); 13C NMR (125.8 MHz, CDCl3) δ 169.9,
95.6, 70.3, 64.4, 62.2, 57.7, 55.6, 46.4, 31.3, 29.9, 27.9, 24.0;
IR (NaCl film) 3309, 2931, 1654 cm-1; HRMS (CI) calcd for
4-Ben zyloxy-3-iod obu t-2(Z)-en -1-ol (26). To a stirring
solution of 4-benzyloxy-2-butyn-1-ol (1.0 g, 5.67 mmol) in Et2O
(20 mL) at 0 °C was added Red-Al (4.4 mL, 3.2 M in toluene)
dropwise. The solution was warmed to room temperature and
stirred for 12 h. The solution was then cooled to 0 °C and
EtOAc (0.5 g, 0.55 mL, 5.67 mmol) was added dropwise and
stirred 10 min. The solution was then cooled to -78 °C and
iodine (2.16 g, 8.51 mmol) was added in one portion. The
solution was stirred at -78 °C for 40 min and then warmed
to room temperature and stirred 2 h. The reaction mixture
was poured onto saturated Na2S2O3 (30 mL) and extracted
with EtOAc (2 × 80 mL). The extracts were washed with brine
(50 mL), dried (MgSO4), concentrated, and chromatographed
(15% EtOAc/Hexane) to afford 2.04 g (66%) of 4-benzyloxy-3-
iodo-2(Z)-buten-1-ol (26) as a colorless oil: 1H NMR (CDCl3) δ
7.37-7.29 (m, 5 H), 6.27 (t, J ) 5.7 Hz, 1 H), 4.53 (s, 2 H),
4.28 (d, J ) 5.7 Hz, 2 H), 4.18 (s, 2 H), 1.61 (s, 1 H); 13C NMR
C
12H20NO5 (MH+) 258.1342, obsd 258.1355.
(4a S*,5R*,6S*,7R*,8a R*)-5-Meth oxyca r bon yl-7-(m eth -
oxym eth oxy)d eca h yd r oisoqu in ol-3-on e-5,6-oxir a n e (22).
Sodium periodate (0.34 g, 1.61 mmol) was added to a solution
5282 J . Org. Chem., Vol. 68, No. 13, 2003

Formal Synthesis of (()-Reserpine
(CDCl3) δ 137.5, 135.9, 128.5, 127.9, 127.9, 104.6, 77.5, 71.8,
66.6; IR (NaCl film) 3396, 3032, 2918, 2861, 1639, 1451, 1354,
1089 cm-1; HRMS (CI) calcd for C11H12IO2 (M - H+) 302.9883,
obsd 302.9881.
1450, 1201, 1086 cm-1; HRMS (CI) calcd for C20H31O3Sn (M -
Bu+) 439.1299, obsd 439.1303.
4-Ben zyloxy-2(E)-tr ibu tylsta n n yl-bu t-2-en -1-ol (35). To
a
solution of methyl (E)-4-benzyloxy-2-tributylstannyl-2-
butenoate (1.0 g, 2.0 mmol) in toluene (10 mL) at -78 °C was
added Dibal-H (2.8 mL of a 1.5 M solution, 4.14 mmol)
dropwise. After 90 min at -78 °C, the reaction was warmed
to room temperature and quenched with saturated sodium
potassium tartrate (20 mL). The aqueous layer was extracted
with EtOAc (2 × 20 mL), and the extracts were dried (MgSO4),
concentrated, and chromatographed (10% EtOAc/Hexane) to
afford 0.8 g (86%) of stannane 35 as a colorless oil: 1H NMR
(CDCl3) 7.37-7.27 (m, 5 H), 5.78 (tt, J ) 5.8, 2.0 Hz, J 119Sn-H
) 33.6 Hz, 1 H), 4.52 (s, 2 H), 4.33 (d, J ) 2.0 Hz, 2 H), 4.06
(d, 5.7 Hz, 2 H), 1.69 (t, J ) 5.0 Hz, 1 H), 1.58-1.43 (m, 6 H),
1.32 (septet, J ) 7.3 Hz, 6 H), 0.99-0.87 (m, 6 H), 0.89 (t, J )
7.3 Hz, 9 H); 13C NMR (CDCl3) δ 150.6, 138.0, 135.2, 128.4,
127.9, 127.7, 72.3, 66.9, 63.7, 29.2, 27.4, 13.7, 10.1; IR (NaCl
film) 3449, 2913, 2849, 1452, 1357, 1068 cm-1; HRMS (FAB)
calcd for C23H40O2SnNa (M + Na+) 491.1948, obsd 491.1941.
Meth yl 6-(Ben zyloxy)-4-h yd r oxym eth y-2E,4E-h exa d i-
en oa te (36). A degassed solution of 4-benzyloxy-2(E)-tribu-
tylstannyl-but-2-en-1-ol (35) (5.62 g, 12.0 mmol) and methyl
(E)-3-bromoacrylate (2.18 g, 13.2 mmol) in NMP (25 mL) was
cannula transferred to a degassed solution of Pd2(dba)3 (0.22
g, 0.24 mmol), tri-2-furyl phosphine (0.44 g, 1.92 mmol), and
CuI (3.20 g, 16.8 mmol) in NMP (95 mL). The solution was
heated to 65 °C for 3.5 h, cooled to room temperature, and
poured onto 10% KF (20 mL) and water (60 mL). The mixture
was extracted with EtOAc (4 × 100 mL), and the extracts were
filtered through Celite, concentrated, and redissolved in EtOAc
(50 mL). The organics were washed with water (30 mL) and
brine (30 mL), dried (MgSO4), concentrated, and chromato-
graphed (20% EtOAc/hexane) to afford 2.98 g (94%) of diene
36 as a gold oil: 1H NMR (CDCl3) δ 7.38-7.29 (m, 5 H), 7.26
(d, J ) 16.0 Hz, 1 H), 6.17 (t, J ) 6.2 Hz, 1 H), 6.12 (d, J )
16.0 Hz, 1 H), 4.55 (s, 2 H), 4.31 (s, 2 H), 4.26 (d, J ) 6.2 Hz,
2 H), 3.76 (s, 3 H), 1.77 (br s, 1 H); 13C NMR (CDCl3) δ 167.5,
145.7, 139.0, 138.1, 137.5, 128.5, 128.0, 127.9, 118.3, 73.0, 66.0,
57.4, 51.7; IR (NaCl film) 3442, 3023, 2952, 2856, 1716, 1620,
1315, 1100, 1016 cm-1; HRMS (CI) calcd for C15H19O4 (MH+)
263.1283, obsd 263.1279.
Meth yl 6-(Ben zyloxy)-4-((2-tr im eth ylsilyl)eth oxym eth -
oxy)m eth yl-2E,4E-h exa d ien oa te (37). To a solution of
alcohol 36 (9.5 g, 36.2 mmol) in CH2Cl2 (65 mL) at 0 °C was
added i-Pr2NEt (23.4 g, 181.0 mmol) followed by SEMCl (9.06
g, 54.33 mmol). The solution was allowed to warm to room
temperature and stirred 12 h. The reaction mixture was
diluted with CH2Cl2 (100 mL), washed with saturated NaHCO3
(50 mL) and brine (50 mL), dried (MgSO4), and concentrated.
The residue was chromatographed (10% EtOAc/hexane) to
afford 13.0 g (92%) of SEM ether 37 as a pale yellow oil: 1H
NMR (CDCl3) δ 7.36-7.29 (m, 5 H), 7.28 (d, J ) 15.8 Hz, 1
H), 6.23 (t, J ) 6.3 Hz, 1 H), 6.10 (d, J ) 15.9 Hz, 1 H), 4.62
(s, 2 H), 4.53 (s, 2 H), 4.29 (d, J ) 6.3 Hz, 2 H), 4.24 (s, 2 H),
3.75 (s, 3 H), 3.60 (t, J ) 8.7 Hz, 2 H), 0.94 (t, J ) 8.7 Hz, 2
H), 0.01 (s, 9 H); 13C NMR (CDCl3) δ 167.5, 145.8, 140.4, 137.7,
134.8, 128.5, 127.8, 127.8, 118.5, 93.8, 72.7, 66.3, 65.5, 61.1,
51.6, 18.1, -1.5; IR (NaCl film) 2952, 1716, 1620, 1171, 1040
cm-1; HRMS (FAB) calcd for C21H32O5SiNa (M + Na+) 415.1917,
obsd 415.1906.
Meth yl 6-(Ben zyloxy)-4-(2-(tr im eth ylsilyl)eth oxym eth -
oxy)m eth yl-3E,5E-h exa d ien oa te (38). To a solution of di-
isopropylamine (0.62 g, 6.11 mmol) in THF (70 mL) at -78 °C
was added n-BuLi (2.54 mL, 6.11 mmol, 2.4 M) dropwise. The
solution was stirred for 30 min, and then DMPU (0.65 g, 5.09
mmol) was added and the mixture allowed to stir an additional
30 min. Ester 37 (2.0 g, 5.09 mmol) dissolved in THF (30 mL)
was then added dropwise at 0.4 mL/min. After addition was
complete, the solution was stirred for 30 min, MeOH (5 mL)
was added, and the mixture wasstirred 3 min. The reaction
mixture was poured onto water (200 mL) and EtOAc (75 mL).
(Z)-1-Ben zyloxy-2-iod o-4-m et h oxym et h oxy-2-b u t en e
(27). To a solution of 4-benzyloxy-3-iodo-2(Z)-buten-1-ol (1.99
g, 6.53 mmol) in CH2Cl2 (60 mL) was added i-Pr2NEt (2.11 g,
2.8 mL, 16.35 mmol) followed by chloromethyl methyl ether
(1.05 g, 1.0 mL, 13.07 mmol). The solution was stirred 12 h,
poured onto saturated NaHCO3 (50 mL), and separated. The
organics were washed with brine (50 mL), dried (MgSO4),
concentrated, and chromatographed (5% EtOAc/hexane) to
afford 1.95 g (86%) of iodide 27 as a colorless oil: 1H NMR
(CDCl3) δ 7.37-7.28 (m, 5 H), 6.26 (tt, J ) 5.4, 1.2 Hz, 1 H),
4.66 (s, 2 H), 4.53 (s, 2 H), 4.22-4.19 (m, 4 H), 3.39 (s, 3 H);
13C NMR (CDCl3) δ 137.6, 133.8, 128.4, 127.9, 127.8, 105.0,
96.2, 77.6, 71.8, 71.1, 55.4; IR (NaCl film) 3030, 2929, 2872,
1650, 1451, 1103, 1041 cm-1; HRMS (CI) calcd for C13H17IO3
(M+) 348.0224, obsd 348.0220.
Meth yl 6-(Meth oxym eth oxy)-4-(ben zyloxy)m eth yl-2E,
4E-h exa d ien oa te (29). To a stirred solution of iodide 27 (0.2
g, 0.57 mmol) and Pd(PPh3)4 (33 mg, 0.02 mmol) in toluene (2
mL) was added boronic ester 28 (0.18 g, 0.86 mmol) dissolved
in toluene (1 mL) followed by 0.5 M NaOMe in MeOH (1.37
mL). The solution was heated to reflux for 13 h, cooled, and
poured onto saturated NH4Cl (10 mL). The mixture was
extracted with EtOAc (2 × 10 mL), and the organics were dried
(MgSO4), concentrated, and chromatographed (10% to 20%
EtOAc/hexane) to afford 0.12 g (69%) of diene 29 as a yellow
1
oil: H NMR (CDCl3) δ 7.58 (d, J ) 16.0 Hz, 1 H), 7.37-7.27
(m, 5 H), 6.13 (t, J ) 6.5 Hz, 1 H), 6.10 (d, J ) 16.1 Hz, 1 H),
4.66 (s, 2 H), 4.52 (s, 2 H), 4.37 (d, J ) 6.5 Hz, 2 H), 4.18 (s, 2
H), 3.76 (s, 3 H), 3.39 (s, 3 H); 13C NMR (CDCl3) δ 167.4, 137.9,
137.8, 135.3, 133.9, 128.4, 127.8, 120.1, 96.1, 72.3, 70.9, 63.0,
55.4, 51.7, the lack of 15 carbon signals indicates two signals
are overlapping; IR (NaCl film) 2952, 2884, 1713, 1616, 1280,
1172, 1041 cm-1; HRMS (CI) calcd for C17H22O5 (M+) 306.1467,
obsd 306.1469.
Meth yl 4-Ben zyloxy-2-bu tyn oa te (34). To a stirred solu-
tion of 3-benzyloxy-1-propyne (12.9 g, 88 mmol) in THF (300
mL) at -78 °C was added n-BuLi (11.0 mL, 97 mmol, 8.8 M)
dropwise. After addition was complete, the reaction was stirred
30 min at -78 °C and then warmed to -20 °C for 20 min. The
solution was cooled back to -78 °C, and methyl chloroformate
(10.8 g, 8.86 mL, 115 mmol) was added in one portion. The
reaction was stirred at -78 °C for 30 min and then warmed
to room temperature. The reaction mixture was then poured
onto saturated NH4Cl (200 mL) and extracted with EtOAc (2
× 200 mL). The extracts were washed with brine (50 mL),
dried (MgSO4), concentrated, and chromatographed (5% EtOAc/
hexane) to afford 15.0 g (83%) of methyl 4-benzyloxy-2-
butynoate (34) as a colorless oil: 1H NMR (CDCl3) δ 7.37-
7.29 (m, 5 H), 4.62 (s, 2 H), 4.29 (s, 2 H), 3.80 (s, 3 H); 13C
NMR (CDCl3) δ 153.5, 136.7, 128.5, 128.1, 83.6, 77.9, 72.0, 56.7,
52.8; the absence of one carbon signal indicates two signals
are overlapping; IR (NaCl film) 3032, 2955, 2861, 2236, 1720,
1433, 1261, 1060 cm-1
.
Meth yl (E)-4-Ben zyloxy-2-tr ibu tylsta n n yl-2-bu ten oa te.
To a solution of alkynoate 34 (2.0 g, 9.8 mmol) and Pd(PPh3)4
(0.22 g, 0.2 mmol) in THF (28 mL) was added Bu3SnH (2.85
g, 2.63 mL, 9.8 mmol) dropwise. The reaction was stirred for
30 min, concentrated, diluted with hexane (20 mL), filtered
through Celite, concentrated, and chromatographed (10%
EtOAc/hexane) to give 3.97 g (82%) of methyl (E)-4-benzyloxy-
2-tributylstannyl-2-butenoate as a colorless oil: 1H NMR
(CDCl3) δ 7.37-7.27 (m, 5 H), 6.31 (t, J ) 4.9 Hz, J (119Sn-H)
) 29.7 Hz, 1 H), 4.53 (s, 2 H), 4.45 (d, J ) 4.9 Hz, 2 H), 3.66
(s, 3 H), 1.53-1.44 (m, 6 H), 1.30 (septet, J ) 7.4 Hz, 6 H),
1.02-0.90 (m, 6 H), 0.88 (t, J ) 7.3 Hz, 9 H); 13C NMR (CDCl3)
δ 170.8, 152.2, 138.1, 136.5, 128.4, 127.9, 127.7, 72.7, 70.4, 51.4,
28.9, 27.2, 13.6, 10.2; IR (NaCl film) 2955, 2853, 1707, 1608,
J . Org. Chem, Vol. 68, No. 13, 2003 5283

Sparks et al.
The organics were separated, washed with aq NaHCO3, H2O,
and brine, dried (MgSO4), and concentrated. The residue was
chromatographed (10% EtOAc/hexane) to afford 1.78 g (89%)
of 3,5-hexadienoic ester 38 as a pale yellow oil: 1H NMR
(CDCl3) δ 7.36-7.29 (m, 5 H), 6.85 (d, J ) 12.9 Hz, 1 H), 5.66
(d, J ) 12.4 Hz, 1 H), 6.65 (t, J ) 7.5 Hz, 1 H), 4.80 (s, 2 H),
4.63 (s, 2 H), 4.20 (s, 2 H), 3.68 (s, 3 H), 3.63 (t, J ) 8.4 Hz, 2
H), 3.25 (d, J ) 7.5 Hz, 2 H), 0.95 (t, J ) 8.5 Hz, 2 H), 0.02 (s,
9 H); 13C NMR (CDCl3) δ 172.0, 147.9, 136.8, 134.3, 128.5,
128.0, 127.5, 121.5, 108.6, 93.4, 71.7, 65.3, 61.8, 51.9, 33.3, 18.2,
2883, 1707, 1586, 1248, 1096 cm-1; HRMS (FAB) calcd for
C
(4a S *,7R *,8a R *)-7-Be n zyloxy-5-(2-(t r im e t h ylsilyl)-
25H38NO5Si (MH+) 460.2519, obsd 460.2530.
et h oxym et h oxy)m et h yl-1,2,3,4,4a ,7,8,8a -oct a h yd r oiso-
qu in olin e-2-ca r boxylic Acid Meth yl Ester (43). To a
suspension of lithium aluminum hydride (0.66 g, 17.5 mmol)
in Et2O (20 mL) at 0 °C was added a solution of cycloadducts
41 and 42 (1.61 g, 3.50 mmol) in Et2O (15 mL) dropwise. The
solution was allowed to warm to room temperature and stirred
for 10 h. The reaction was quenched by sequential addition of
H2O (0.66 mL), 10% NaOH (0.66 mL), and H2O (2.0 mL). The
solution was filtered and concentrated to afford a colorless oil
(1.39 g). The oil was dissolved in CH2Cl2 (20 mL), and the
solution was cooled to 0 °C. Diisopropylethylamine (2.00 g, 15.7
mmol) was added followed by methyl chloroformate (1.00 g,
10.5 mmol). The reaction was stirred for 90 min, poured onto
H2O (50 mL), and extracted with CH2Cl2 (50 mL). The extracts
were dried (MgSO4), concentrated, and chromatographed (25%
EtOAc/CH2Cl2) to afford 1.17 g (73%) of carbamate 43 as a
colorless oil: 1H NMR (DMSO, 363 K) δ 7.35-7.24 (m, 5 H),
5.70 (s, 1 H), 4.59 (s, 2 H), 4.53 (s, 2 H), 4.16 (t, J ) 7.2 Hz, 1
H), 4.01 (d J ) 12.5 Hz, 1 H), 3.95 (dquintets, J ) 13.1, 2.2
Hz, 1 H), 3.91 (d, J ) 12.5 Hz, 1 H), 3.87 (d, J ) 13.5 Hz, 1 H),
3.61-3.57 (m, 2 H), 3.59 (s, 3 H), 3.05 (dd, J ) 13.5, 3.6 Hz, 1
H), 2.76 (td, J ) 12.9, 3.0 Hz, 1 H), 2.23-2.28 (m, 1 H), 1.85-
1.72 (m, 3 H) 1.55 (td, J ) 12.9, 9.4 Hz, 1 H), 1.37 (qd, J )
12.6, 4.4 Hz, 1 H), 0.91-0.87 (m, 2 H), 0.01 (s, 9 H); 13C NMR
(C6D6, 333 K) δ 156.5, 141.1, 140.2, 128.8, 128.1, 127.8, 126.8,
94.9, 75.5, 70.6, 69.7, 65.8, 52.5, 49.8, 44.9, 36.2, 33.9, 29.5,
27.9, 18.8, -0.9; IR (NaCl film) 2953, 2866, 1702, 1241, 1057
cm-1; HRMS (CI) calcd for C25H40NO5Si (MH+) 462.2676, obsd
462.2675.
-1.4; IR (NaCl film) 2952, 1740, 1650, 1620, 1159, 1040 cm-1
;
HRMS (TOFES) calcd for C21H32O5SiNa (M + Na+) 415.1917,
obsd 415.1917.
6-(Ben zyloxy)-4-(2-(t r im et h ylsilyl)et h oxym et h oxy)-
m eth yl-3E,5E-h exa d ien oic Acid (39). A solution of LiOH‚
H2O (0.57 g, 13.6 mmol) in water (11 mL) was added to a
solution of ester 38 (1.78 g, 4.53 mmol) in acetone (18 mL).
The solution was stirred for 90 min and then acidified to a pH
) 2 with 1% HCl. The mixture was extracted with Et2O (2 ×
40 mL), and the extracts were dried (MgSO4) and concentrated.
The residue was chromatographed (5% MeOH/CH2Cl2) to
afford 1.66 g (97%) of acid 29 as a yellow oil: 1H NMR (CDCl3)
δ 7.37-7.28 (m, 5 H), 6.88 (d, J ) 12.7 Hz, 1 H), 5.67 (d, J )
12.5 Hz, 1 H), 5.64 (t, J ) 7.5 Hz, 1 H), 4.81 (s, 2 H), 4.66 (s,
2 H), 4.22 (s, 2 H), 3.66-3.63 (m, 2 H), 3.30 (d, J ) 7.6 Hz, 2
H), 0.98-0.95 (m, 2 H), 0.02 (s, 9 H); 13C NMR (CDCl3) δ 176.1,
147.8, 136.4, 134.4, 128.3, 127.8, 127.3, 120.7, 108.2, 93.1, 71.7,
65.5, 61.7, 33.7, 18.3, -1.1; IR (NaCl film) 3500-2500 (br),
3033, 2952, 1713, 1650, 1034 cm-1; HRMS (TOFES) calcd for
C
20H30O5SiNa (M + Na+) 401.1760, obsd 401.1766.
N-(4-(2-(Tr im eth ylsilyl)eth oxym eth oxy)m eth yl-6-ben -
zyloxy-3E,5E-h exa d ien oyl)-1-a za -2-et h oxy-1,3-b u t a d i-
en e (40). A solution of acid 39 (1.56 g, 4.12 mmol), imidate
15 (0.41 g, 4.12 mmol), and NEt3 (1.00 g, 1.4 mL, 9.86 mmol)
in CH2Cl2 (20 mL) was added dropwise over 90 min to a
suspension of 2-chloro-1-methylpyridinium iodide (1.26 g, 4.94
mmol) in CH2Cl2 (30 mL) at 0 °C. The solution was stirred for
90 min and then concentrated to half of the original volume
and filtered through a pad of SiO2 eluting with 30% EtOAc/
hexane. The filtrate was concentrated in vacuo to afford 1.61
g (85%) of imidate 40 as a pale yellow oil: 1H NMR (CDCl3) δ
7.20-7.17 (m, 2 H), 7.15-7.11 (m, 2 H), 7.09 (d, J ) 12.6 Hz,
1 H), 7.08-7.05 (m, 1 H), 6.24 (dd, J ) 17.1, 10.8 Hz, 1 H),
5.97 (d, J ) 17.1 Hz, 1 H), 5.90 (t, J ) 7.4 Hz, 1 H), 5.78 (d, J
) 12.8 Hz, 1 H), 5.19 (d, J ) 10.8 Hz, 1 H), 4.61 (s, 2 H), 4.96
(s, 2 H), 4.29 (s, 2 H), 3.93 (q, J ) 7.1 Hz, 2 H), 3.64 (t, J ) 8.1
Hz, 2 H), 3.46 (d, J ) 7.4 Hz, 2 H), 0.95 (t, J ) 7.1 Hz, 3 H),
0.95 (t, J ) 8.1 Hz, 2 H), 0.00 (s, 9 H); 13C NMR (CDCl3) δ
182.5 (2), 157.1, 148.7, 137.9, 135.0, 129.0, 128.1, 126.9, 126.6,
123.0, 109.7, 93.6, 71.9, 65.7, 62.9, 62.4, 39.3, 18.7, 14.2, -0.9;
IR (NaCl film) 3032, 2951, 2893, 1693, 1659, 1601, 1156, 1072
cm-1; HRMS (CI) calcd for C25H36NO5Si (M - H+) 458.2363,
obsd 458.2367.
(4a S*,5S*,6R*,7R*,8a R*)-7-Ben zyloxy-6-h yd r oxy-5-(2-
(tr im eth ylsilyl)eth oxym eth oxy)m eth yldecah ydr oisoqu in -
olin e-2-ca r boxylic Acid Meth yl Ester (44). To a solution
of olefin 43 (0.75 g, 1.63 mmol) in THF (27 mL) at 0 °C was
added a solution of BH3‚THF (8.12 mL of a 1 M solution, 8.12
mmol) dropwise. The reaction was allowed to warm to room
temperature and stir for 12 h. The solution was then cooled
to 0 °C, and 10 mL of 3 N NaOH was added followed by 10
mL of 30% H2O2. The solution was stirred for 2 h and then
diluted with H2O (30 mL) and CH2Cl2 (30 mL). The reaction
mixture was then acidified to pH ) 3 with 10% HCl and
extracted with CH2Cl2 (2 × 30 mL). The extracts were dried
(MgSO4), concentrated, and chromatographed (30% EtOAc/
hexanes) to afford 0.57 g (73%) of alcohol 44 as a colorless oil:
1H NMR (DMSO, 363 K) 7.37-7.29 (m, 4 H), 7.25-7.21 (m,
1H), 4.63 (d, J ) 12.2 Hz, 1 H), 4.61 (d, J ) 12.2 Hz, 1 H),
4.59 (s, 2 H), 4.26 (d, J ) 3.7 Hz, 1 H), 4.06 (br d, J ) 13.1 Hz,
1 H), 3.82 (br d, J ) 13.3 Hz, 1 H), 3.79 (dd, J ) 9.9, 4.3 Hz,
1 H), 3.60-3.55 (m, 1 H), 3.57 (s, 3 H), 3.44 (t, J ) 10.0 Hz, 1
H), 3.31-3.24 (m, 2 H), 2.94 (dd, J ) 13.3, 3.2 Hz, 1 H), 2.62
(td, J ) 12.7, 3.5 Hz, 1 H), 2.01-1.96 (m, 1 H), 1.79-1.67 (m,
3 H), 1.49-1.35 (m, 3 H), 0.91-0.86 (m, 2 H), 0.01 (s, 9 H);
13C NMR (C6D6, 333 K) δ 156.5, 139.9, 129.0, 128.1, 96.0, 84.0,
72.0, 71.6, 67.6, 65.8, 52.6, 49.7, 45.8, 45.2, 36.6, 35.6, 29.0,
22.0, 18.8, -0.9, one aromatic signal is coincident with the
(4a S*,7R*,8a S*)-7-Ben zyloxy-1-eth oxy-5-(2-(tr im eth yl-
silyl)eth oxym eth oxy)m eth yl-3,4,4a ,7,8,8a -h exa h yd r oiso-
qu in ol-3-on e (41). A solution of 40 (1.61 g, 3.50 mmol) and 4
Å molecular sieves in CHCl3 (250 mL) was heated to 60 °C for
24 h. The reaction mixture was cooled to room temperature
and filtered through Celite. The filtrate was concentrated and
filtered through a pad of SiO2 eluting with 3% MeOH/CH2Cl2
to afford 1.44 g (90%) of a 6:1 mixture of cycloadducts 41 and
42 as a yellow oil. 41: 1H NMR (CDCl3) δ 7.37-7.28 (m, 5 H),
5.92 (s, 1 H), 4.65 (s, 2 H), 4.63 (d, J ) 10.3 Hz, 1 H), 4.59 (d,
J ) 10.3 Hz, 1 H), 4.45-4.34 (m, 2 H), 4.20 (t, J ) 7.3 Hz, 1
H), 4.07 (d, J ) 12.3 Hz, 1 H), 3.99 (d, J ) 12.3 Hz, 1 H), 3.65-
3.57 (m, 2 H), 2.82-2.76 (m, 2 H), 2.71-2.64 (m, 1 H), 2.37
(dd, J ) 17.0, 14.0 Hz, 1 H), 2.35-2.29 (m, 1 H), 1.77 (td, J )
12.8, 9.5 Hz, 1 H), 1.34 (t, J ) 7.1 Hz, 3 H), 0.97-0.91 (m, 2
H), 0.01 (s, 9 H); 13C NMR (CDCl3) δ 182.1, 181.6, 138.0, 137.7,
128.4, 127.8, 127.6, 127.4, 94.3, 73.0, 70.6, 68.6, 65.4, 64.1, 35.6,
34.3, 31.8, 27.8, 18.1, 14.0, -1.4; IR (NaCl film) 3062, 2951,
solvent peak; IR (NaCl film) 3462, 2949, 2875, 1698, 1057 cm-1
;
HRMS (FAB) calcd for C25H41NO6SiNa (M + Na+) 502.2601,
obsd 502.2604.
(4a S*,5S*,6R*,7R*,8a R*)-7-Ben zyloxy-6-m eth oxy-5-(2-
(tr im eth ylsilyl)eth oxym eth oxy)m eth yldecah ydr oisoqu in -
olin e-2-ca r boxylic Acid Meth yl Ester (45). To a solution
of alcohol 44 (0.45 g, 0.15 mmol) in CH2Cl2 (40 mL) was added
Proton Sponge (1.40 g, 6.57 mmol), 4 Å molecular sieves (0.90
g), and Me3OBF4 (0.83 g, 5.62 mmol). The solution was stirred
vigorously for 3.5 h and then filtered. The solid was washed
with EtOAc, and the organics were washed with water (50 mL)
and 10% CuSO4 (50 mL). The organics were dried (MgSO4),
concentrated, and chromatographed (40% EtOAc/hexane) to
afford 0.45 g (98%) of methyl ether 45 as a colorless oil: 1H
NMR (DMSO, 363 K) 7.36-7.23 (m, 5 H), 4.64-4.54 (m, 4 H),
5284 J . Org. Chem., Vol. 68, No. 13, 2003

Formal Synthesis of (()-Reserpine
4.06 (br d, J ) 13.1 Hz, 1 H), 3.82 (d, J ) 13.2 Hz, 1 H), 3.67
(dd, J ) 9.8 4.0 Hz, 1 H), 3.62-3.57 (m, 2 H), 3.58 (s, 3 H),
3.50 (t, J ) 9.7 Hz, 1 H), 3.46-3.40 (m, 1 H), 3.39 (s, 3 H),
3.02 (dd, J ) 11.1, 8.8 Hz, 1 H), 2.94 (dd, J ) 13.2, 3.4 Hz, 1
H), 2.62 (td, J ) 12.6, 3.5 Hz, 1 H), 2.03-1.96 (m, 1 H), 1.84-
1.76 (m, 2 H), 1.74-1.66 (m, 1 H), 1.55-1.39 (m, 3 H), 0.91-
0.86 (m, 2 H), 0.02 (s, 9 H); 13C NMR (C6D6, 333 K) δ 156.5,
140.3, 128.9, 128.1, 127.8, 96.0, 84.3, 81.8, 72.1, 66.9, 65.7, 60.9,
52.5, 49.6, 46.3, 45.2, 36.7, 35.5, 30.2, 21.9, 18.8, -0.9; IR (NaCl
film) 2949, 2874, 1698, 1453, 1108 cm-1; HRMS (CI) calcd for
2871, 1742, 1705, 1448, 1107 cm-1; HRMS (CI) calcd for C21H29
NO6 (M+) 391.1995, obsd 391.1993.
-
(4a S*,5S*,6R*,7R*,8a R*)-7-Hyd r oxy-6-m eth oxy-5-m eth -
oxyca r b on yld eca h yd r oisoq u in olin e-2-ca r b oxylic Acid
Meth yl Ester . To a solution of ester 46 (37 mg, 0.095 mmol)
in MeOH (2 mL) was added 10% Pd-C (5 mg). The solution
was purged with N2 and then placed under a H2 atmosphere.
The reaction mixture was stirred for 10 h, filtered through
Celite, and concentrated. The residue was chromatographed
(5% MeOH/CH2Cl2) to afford 28 mg (100%) of the secondary
alcohol as a colorless solid: mp 160-162 °C; 1H NMR (DMSO,
363 K) δ 4.46 (d, J ) 5.8 Hz, 1 H), 4.03 (br d, J ) 13.3 Hz, 1
H), 3.81 (d, J ) 13.3 Hz, 1 H), 3.62 (s, 3 H), 3.58 (s, 3 H), 3.42
(s, 3 H), 3.42-3.36 (m, 1 H), 3.25 (dd, J ) 11.1, 8.8 Hz, 1 H),
2.92 (dd, J ) 13.3, 3.3 Hz, 1 H), 2.62 (td, J ) 12.8, 2.8 Hz, 1
H), 2.07-2.01 (m, 1 H), 1.81 (br d, J ) 13.3 Hz, 1 H), 1.57-
1.42 (m, 3 H), 1.18 (br d, J ) 13.4 Hz, 1 H); 13C NMR (C6D6,
333 K) δ 172.5, 156.4, 82.0, 75.8, 61.2, 52.8, 52.5, 51.3, 49.0,
44.8, 38.4, 35.5, 32.6, 23.5; IR (CCl4) 3611, 3468, 2951, 2862,
C
26H44NO6Si (MH+) 494.2937, obsd 494.2933.
(4a S*,5S*,6R*,7R*,8a R*)-7-Ben zyloxy-6-m eth oxy-5-(h y-
d r oxy)m eth yld eca h yd r oisoqu in olin e-2-ca r boxylic Acid
Meth yl Ester . A solution of TBAF (1.01 mL, 1.01 mmol, 1.0
M in THF) was added to ether 45 (0.10 g, 0.20 mmol) in a
pear-shaped flask. The mixture was placed under vacuum to
remove the THF, and then DMPU (1.5 mL) was added under
a N2 atmosphere. Powdered 4 Å molecular sieves (0.15 g) were
added, and the solution was heated to 80 °C for 4 h. The
solution was then cooled to room temperature and diluted with
Et2O (15 mL). The organics were washed with water (5 mL)
and brine (5 mL) and dried (MgSO4). The organics were then
concentrated and chromatographed (EtOAc) to afford 57 mg
(78%) of the primary alcohol as a colorless oil: 1H NMR
(DMSO, 363 K) 7.36-7.23 (m, 5 H), 4.62 (d, J ) 12.0 Hz, 1
H), 4.55 (d, J ) 12.0 Hz, 1 H), 4.06 (br d, J ) 13.1 Hz, 1 H),
3.89 (br s, 1 H), 3.83 (d, J ) 13.2 Hz, 1 H), 3.72-3.67 (m, 1
H), 3.58 (s, 3 H), 3.44-3.38 (m, 2 H), 3.39 (s, 3 H), 2.99 (dd, J
) 11.1, 8.8 Hz, 1 H), 2.96-2.93 (m, 1 H), 2.63 (td, J ) 12.9,
3.2 Hz, 1 H), 2.03 (dq, J ) 12.7, 4.2 Hz, 1 H), 1.82-1.76 (m, 1
H), 1.70-1.61 (m, 2 H), 1.57-1.51 (m, 1 H), 1.43 (q, J ) 12.9
Hz, 1 H), 1.40 (qd, J ) 12.9, 4.8 Hz, 1 H); 13C NMR (C6D6, 333
K) δ 156.5, 140.1, 128.9, 128.1, 127.9, 84.4, 84.2, 72.0, 64.3,
61.0, 52.5, 49.4, 48.0, 45.0, 37.7, 35.5, 30.1, 22.0; IR (NaCl film)
3478, 2929, 2866, 1681, 1454, 1106 cm-1; HRMS (CI) calcd for
1741, 1706, 1448, 1242, 1098 cm-1; HRMS (CI) calcd for C14H23
NO6 (M+) 301.1525, obsd 301.1522.
-
(4aS*,5S*,6R*,7R*,8aR*)-6-Meth oxy-5-m eth oxycar bon yl-
7-(3,4,5-tr im eth oxy)ben zoyldecah ydr oisoqu in olin e-2-car -
boxylic Acid Meth yl Ester (3). To a solution of alcohol (22
mg, 0.073 mmol) in CH2Cl2 (1.5 mL) were added NEt3 (30 mg,
40 µL), DMAP (5 mg), and 3,4,5-trimethoxybenzoyl chloride
(37 mg, 0.14 mmol). The solution was stirred 20 h, diluted with
EtOAc (10 mL), and washed with water (5 mL), saturated
NaHCO3 (5 mL), and brine (5 mL). The organic layer was dried
(MgSO4), concentrated, and chromatographed (70% EtOAc/
hexanes) to afford 25 mg (70%) of ester 3 as a colorless oil: 1H
NMR (C6D6, 333 K) δ 7.53 (s, 2 H), 5.24 (ddd, J ) 11.8, 9.5,
5.1 Hz, 1 H), 4.30-4.00 (br m, 1 H), 3.85 (dd, J ) 11.0, 9.6 Hz,
1 H), 3.85-3.80 (m, 1 H), 3.80 (s, 3 H), 3.60 (s, 3 H), 3.43 (s, 9
H), 3.38 (s, 3 H), 2.62 (dd, J ) 11.1, 4.9 Hz, 1 H), 2.36 (dd, J
) 13.5, 3.3 Hz, 1 H), 2.16 (td, J ) 13.0, 3.0 Hz, 1 H), 1.95 (dt,
J ) 12.8, 4.1 Hz, 1 H), 1.75 (q, J ) 13.0 Hz, 1 H), 1.73-1.68
(m, 1 H), 1.45 (qd, J ) 13.1, 4.7 Hz, 1 H), 1.22-1.16 (m, 1 H),
1.06-1.00 (m, 1 H); 13C NMR (C6D6, 333 K) δ 172.2, 166.0,
156.3, 154.4, 144.6, 126.4, 108.9, 78.8, 78.4, 61.2, 60.9, 56.5,
53.1, 52.5, 51.4, 48.7, 44.6, 37.8, 34.9, 29.7, 23.4; IR (CCl4) 3000,
2953, 2839, 1741, 1708, 1415, 1132 cm-1; HRMS (CI) calcd for
C
20H28NO5 (M - H+) 362.1967, obsd 362.1974.
(4aS*,5S*,6R*,7R*,8aR*)-7-Ben zyloxy-6-m eth oxy-5-m eth -
oxyca r b on yld eca h yd r oisoq u in olin e-2-ca r b oxylic Acid
Meth yl Ester (46). To a solution of the preceding alcohol (46
mg, 0.13 mmol) in DMF (2.0 mL) was added PDC (0.24 g, 0.63
mmol), and the solution was stirred for 20 h. Cold 0.1 N HCl
(3 mL) was then added, and the mixture was extracted with
Et2O (3 × 5 mL). The extracts were dried (MgSO4) and
concentrated. The residue was dissolved in Et2O (2 mL) and
cooled to 0 °C. Diazomethane in Et2O was added to the mixture
until a yellow color persisted. The mixture was then stirred
for 10 min and quenched by addition of acetic acid. The
solution was diluted with Et2O (10 mL), washed with water
(5 mL) and brine (5 mL), dried (MgSO4), and concentrated.
The residue was chromatographed (EtOAc) to afford 39 mg
(80%) of ester 46 as a colorless oil: 1H NMR (DMSO, 363 K)
δ 7.36-7.23 (m, 5 H), 4.64 (d, J ) 12.1 Hz, 1 H), 4.55 (d, J )
12.1 Hz, 1 H), 4.03 (br d, J ) 13.4 Hz, 1 H), 3.83 (d, J ) 13.3
Hz, 1 H), 3.64 (s, 3 H), 3.58 (s, 3 H), 3.46-3.39 (m, 2 H), 3.43
(s, 3 H), 2.93 (dd, J ) 13.3, 3.2 Hz, 1 H), 2.63 (td, J ) 13.0, 3.0
Hz, 1 H), 2.59-2.55 (m, 1 H), 2.10-2.04 (m, 1 H), 1.88-1.78
(m, 2 H), 1.53 (qd, J ) 13.1, 4.6 Hz, 1 H), 1.42 (q, J ) 12.4 Hz,
1 H), 1.19 (br d, J ) 13.4 Hz, 1 H); 13C NMR (C6D6, 333 K) δ
172.4, 156.4, 140.1, 128.9, 128.0, 127.9, 83.5, 80.5, 72.1, 61.4,
53.3, 52.6, 51.3, 49.1, 44.7, 38.1, 35.3, 29.8, 23.4; IR (CCl4) 2951,
C
24H33NO10 (M+) 495.2104, obsd 495.2092.
Ack n ow led gm en t. This work was supported in part
by the National Institutes of Health. We thank Professor
Paul Wender for supplying detailed procedures of the
degradation of (-)-reserpine to compound 3 and Dr.
J ohn Greaves and Dr. J ohn Mudd for mass spectromet-
ric analysis. Graduate fellowship support to S.M.S. from
Pharmacia is gratefully acknowledged. NMR and mass
spectra were obtained at UCI using instrumentation
acquired with the assistance of NSF and NIH Shared
Instrumentation programs.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0341362
J . Org. Chem, Vol. 68, No. 13, 2003 5285