1

PERKIN
A formal synthesis of reserpine: hydrindane approach to the
Woodwards ring-E precursor

Goverdhan Mehta * and D. Srinivasa Reddy

School of Chemistry, University of Hyderabad, Hyderabad 500 046, India

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India

Received (in Cambridge, UK) 17th January 2000, Accepted 2nd March 2000
Published on the Web 11th April 2000

A new synthetic approach to a functionally and stereochemically embellished cyclohexanoid, corresponding to the
Woodwards ring-E intermediate 24 of the complex indole alkaloid reserpine 1 is delineated. Our scheme emanates
from a readily available endo-tricyclo[5.2.1.02,6]decane system from which cis-hydrindane and cyclohexanoid moieties
are sequentially extracted. The strategy outlined here exploits the propensity of the endo-tricyclo[5.2.1.02,6]decane
and cis-hydrindane systems to react from the convex face to generate the requisite stereochemical pattern. Since
24 has been previously elaborated to the natural product, the present eort constitutes a formal synthesis of
rac-reserpine.

The pentacyclic indole alkaloid reserpine 1, rst isolated from chemistry. Intramolecular [2 2] photocycloaddition in a
the Indian snake root, Rauwola serpentina Benth, occupies a cyclohexene derivative and cyclobutane fragmentation was the
historically important position among natural products for a stratagem employed by Pearlman 3b in accessing ring E of 1.
variety of reasons.1,2 Besides having a complex structure, 1 2 was Stork et al.3e and Liao et al.3g employed the bicyclo[2.2.2]octane
among the very rst few natural products to have been used scaold to deliver the desired stereochemistry of ring E. Fraser-
clinically. For quite some time, reserpine 1 was commonly Reid 3f and Hanessian 3h employed glucose and quinic acid,
employed for the treatment of hypertension and mental dis- respectively, as chirons in their approach to reserpine 1.
orders. The pentacyclic framework of reserpine 1 with six stereo- On the other hand, Wender et al.3c and Martin et al.3d in their
genic centres and ample functionalisation was considered as a successful synthesis of reserpine have focused on assembling a
major synthetic challenge in the 1950s and 1960s. Its rst syn- cis-hydroisoquinoline moiety 3, incorporating the DE-rings of
thesis by Woodward,3a nearly forty years ago, was a landmark the natural product, employing DielsAlder/Cope rearrange-
and ranks among the classics of modern organic synthesis. ment and intramolecular DielsAlder reaction as the key steps,
Over the years, reserpine has continued to sustain the interest respectively. In both, the E-ring as well as DE-ring approaches,
and attention of synthetic chemists 3,4 and as many as eight total appropriately constructed precursors 2 and 3 are condensed
syntheses have been recorded to date.3ah The approaches with indole derived AB-ring partners 4 and 5, respectively, to
adopted towards the successful syntheses of 1 fall into two generate the pentacyclic framework of reserpine 1, Scheme 1.
broad categories. In the rst group are the approaches that Several innovative and interesting solutions to ring-E con-
focus on the construction of ring E of reserpine wherein ve of struction have been presented en route to the synthesis of 1. We
the six stereogenic centres and much of the functionality reside. have conceptualised a new approach to Woodwards ring-E
The original Woodward approach 3a and those of Pearlman,3b precursor of reserpine 1 from readily accessible endo-tricyclo-
Stork,3e Fraser-Reid,3f Liao 3g and Hanessian 3h have targeted an [5.2.1.02,6]decane derivative 6.5 The key feature of this strategy
appropriately functionalised ring-E precursor 2 in which the is the retrieval of the six-membered ring (see bold portion in 6)
requisite stereochemistry is built in. Woodward 3a employed the embedded within the tricyclic frame of 6. Another distinctive
DielsAlder adduct of vinylacrylic acid and benzoquinone as aspect of this approach is that all the ten carbon atoms of
the starting material in which a series of clever functional group Woodwards ring-E intermediate (see 8) are present in the tri-
manipulations were orchestrated to attain the ring-E stereo- cyclic framework 6, which in turn is assembled from two C5

Scheme 1

DOI: 10.1039/b000430h J. Chem. Soc., Perkin Trans. 1, 2000, 13991404 1399

This journal is The Royal Society of Chemistry 2000
cyclopentadiene units (vide infra). Thus, no carbon needs to be
added or removed from the tricyclic precursor 6, only skeletal
restructuring and functional group changes are required. In
practical terms, elaboration of 6 to 8 requires opening-up of the
bridge (67), functional group adjustment as called for and
nally oxidative cleavage of the double bond in 7 to deliver the
ring-E intermediate 8. A particularly attractive feature of our
simple approach is that both endo-tricyclic system 6 and the cis-
hydrindane 7 are amenable to stereochemical control through
Fig. 1
their skeletal topology, with reagent addition expected to occur
only from the exo/convex face of the molecule. We report here
the successful execution of the approach towards Woodwards
ring-E intermediate 9 as shown in Scheme 2, which in a formal
sense constitutes a new synthesis of rac-reserpine 1.

Scheme 2

Our approach emanated from two abundantly available C5

building blocks, cyclopentadiene and 5,5-dimethoxytetra-
chlorocyclopentadiene 10, which readily enter into DielsAlder
reaction to furnish the known tricyclic endo-adduct 11.6 The
rst priority was to protect the distal disubstituted cyclopen-
tene double bond in a manner that at an appropriate stage it
could be oxidatively cleaved to generate the cis disposed sub- Scheme 3 Reagents and conditions: (a) OsO4, Me2COH2Ot-BuOH
stituents at C15 and C16 (reserpine numbering) on the E-ring (5 : 3 : 1), 24 h, 90%; (b) NaNH3, THF, EtOH, 15 min, 50%; (c)
of 1. Regioselective, catalytic cis-dihydroxylation of 11 led to Me2COAmberlyst-15, 6 h, 83%; (d) MCPBA, DCM, 30 min; KOH,
the tricyclic exo,exo-diol 12 which was directly subjected MeOH, 20 min, 63%.
to exhaustive reductive dehalogenation in metalammonia
solution to furnish 13. Exposure of 13 to acetone in the presence centre (C20 of reserpine), taking advantage of the topology of
of Amberlyst-15 resulted in the two desired protection the cis-hydrindane framework.
deprotection events taking place in a single-pot reaction. While The free hydroxy group in the required regioisomer 15 was
the cis-diol moiety was protected as the acetonide derivative, methylated employing methyl iodide and solid KOH under
the dimethyl acetal was deprotected to give keto-acetonide solvent free conditions 7 to furnish the methoxy ester 17. It was
14, Scheme 3. The stage was now set for the removal of now proposed to functionalise the allylic position in the ester 17
the carbonyl bearing bridge in 14 to unravel the hydrindane to generate the C18 centre of reserpine 1 present in ring E.
framework. This was accomplished via BaeyerVilliger (BV) Several reagents like Cr(CO)6t-BuOOH,8a CrO3dimethyl-
oxidation. Reaction of 14 with m-chloroperbenzoic acid and pyrazole,8b CrO3AcOH,8c SeO2 (cat)t-BuOOH 8d etc. were
methanolysis of the resulting lactones led to the formation of tried to oxidise 17 to the ,-unsaturated enone 18 but none of
regioisomeric hydroxy esters 15 and 16 in a 55 : 45 ratio, Scheme them proved to be entirely satisfactory. Best results were
3. Apparently, the distal acetonide group in 14 has very little obtained with PDC on Celite in the presence of tert-butyl
eect on the regiochemistry of BV oxidation and nearly equal hydroperoxide and 18 was obtained in ~30% yield,8e Scheme 4.
amounts of 15 and 16 are obtained. The two esters 15 and 16 Luche reduction 9 of the enone carbonyl in 18 proceeded stereo-
are readily separable and could be distinguished through an selectively in an expected fashion to furnish 19. The hydride
incisive analysis of their 1H1H COSY spectra derived con- addition to the carbonyl group in 18 was from the convex face
nectivities as depicted in Fig. 1. Although the lack of BV of the cis-hydrindane moiety and the correct stereochemistry
oxidation regioselectivity in 14 was a somewhat unsatisfactory corresponding to the C18 centre of reserpine was established.
outcome, the redeeming feature was the desired migration of The next key step was to set the stereochemistry of the meth-
the olenic bond into conjugation with the ester moieties in 15 oxycarbonyl bearing centre and towards that end the double
and 16 during methanolysis. This was considered necessary to bond in 19 was subjected to catalytic hydrogenation. The reduc-
recreate the correct stereochemistry at the ester bearing carbon tion was fairly stereoselective and an 85 : 15 mixture of epi-

1400 J. Chem. Soc., Perkin Trans. 1, 2000, 13991404

Scheme 4 Reagents and conditions: (a) KOH, MeI, 20 h, 90%; (b) PDC, t-BuOOH, Celite, benzene, 1 h, 30%; (c) NaBH4, CeCl37H2O, MeOH,
20 C, 15 min, 62%; (d) H2, PtO2, EtOH, 1 h; (e) DIBAL-H, DCM, 78 C, 30 min; (f ) MePPh3I, n-BuLi, 15 min, 48% (for 3 steps); (g) Ac2O,
pyridine, DMAP, 2 h, 86%; (h) 30% TFA, 1 h; NaIO4, 10% aq. THF, 15 min; Jones oxidation, Me2CO; CH2N2, ether, 21% (for 4 steps).

mers 20 was obtained. The major epimer formed during the Experimental
reduction of 19 was the -isomer with endo-methoxycarbonyl
group corresponding to the required C20-stereochemistry in 1. General
The separation of epimers 20 proved dicult at this stage and Melting points were recorded on a Bchi SMP-20 apparatus
therefore we proceeded further as such towards the Wood- and are uncorrected. Infrared spectra were recorded on Perkin-
wards intermediate. DIBAL-H reduction of 20 to the Elmer model 1310 or JASCO FT-IR. Solid samples were
aldehyde 21 and Wittig olenation furnished 22. The Wittig recorded as KBr pellets and liquids as thin lms. 1H NMR
olenation was necessitated by our intent to protect the alde- spectra were recorded at 200 MHz or 300 MHz and 13C NMR
hyde functionality in 21 during subsequent steps. It was spectra were recorded at 50 MHz or 75 MHz on Bruker AC 200
reasoned that the aldehyde functionality, which is present in the or JNM -300 spectrometers respectively. 1H and 13C NMR
target structure could be readily regenerated at an appropriate samples were made in CDCl3 solvent and chemical shifts are
stage from the olen. As 22 turned out to be a nice solid, crys- reported on the scale using tetramethylsilane (Me4Si) as the
tallization led to ready purication and it was obtained as a internal standard. J values are given in Hz. The standard
single stereoisomer and fully characterized. The secondary abbreviations br, s, d, t, q and m refer to broad, singlet, doublet,
hydroxy group in 22 was now acetylated to 23. The nal man- triplet, quartet and multiplet, respectively. Mass spectra
oeuvre now was the unraveling of the cis disposed methoxy- measurements were carried out on a JEOL JMS DX-303
carbonyl and acetic acid side arms on the E-ring, corresponding spectrometer. Elemental analyses were carried out using a
to C16 and C15 of reserpine, respectively, from the ve mem- Perkin-Elmer 240C elemental analyzer or Carlo Erba 1106-
bered ring of the cis-hydrindane 23. A four step sequence con- CHN analyzer. Analytical thin-layer chromatography (TLC)
sisting of acetonide deprotection, periodate cleavage of the was performed on (10 5 cm) glass plates coated with
resultant diol to dialdehyde, Jones oxidation to the dicarboxylic Acmes silica gel G (containing 13% calcium sulfate as binder).
acid and diazomethane esterication led to the diester 24 in Column chromatography was performed using Acmes silica gel
modest yield, Scheme 4. The diester 24 has been recently (100200 mesh) and ethyl acetatehexane was used as eluent.
reported by Fraser-Reid et al.3f and our synthetic sample was Moisture sensitive reactions were performed using standard
found to be identical with their sample in all respects. On syringe-septum techniques under a nitrogen atmosphere. All
ozonolysis, the olenic moiety in 24 is readily transformed to solvents were distilled over appropriate drying agents, prior to
the aldehyde functionality and the resulting product is the use. Yields reported are isolated yields of materials judged
Woodwards reserpine precursor 9,3f which has been earlier homogeneous by TLC and NMR.
elaborated to the natural product.3a
In short, we have outlined a new approach to a densely func-
1,7,8,9-Tetrachloro-10,10-dimethoxytricyclo[5.2.1.02,6]dec-8-
tionalised cyclohexanoid, identical with Woodwards ring-E
ene-3,4-diol 12
intermediate from readily available cyclopentadiene based
building-blocks. Our approach, notable for its conceptual Osmium tetroxide (115 mg, 0.45 mmol, 0.5 mol%) was added to
simplicity, relies on the topology of the endo-tricyclo- a stirred solution of adduct 11 (30 g, 90 mmol), prepared from
[5.2.1.02,6]decane and cis-hydrindane ring systems to achieve the tetrachlorodimethoxycyclopentadiene 10 and cyclopentadiene
desired stereoselectivity. by following the literature procedure,5 NMO (16 g, 136

J. Chem. Soc., Perkin Trans. 1, 2000, 13991404 1401

mmol) in acetone (100 ml), water (100 ml) and t-BuOH (20 ml) The crude mixture of the lactones (~4.8 g) obtained after the
at room temperature (25 C) with stirring. The reaction was removal of solvent was dissolved in dry methanol (15 ml) and a
slightly exothermic initially and was maintained at room tem- small pellet of KOH was added. The contents were then stirred
perature with a water bath. After stirring for 24 h, the osmate for 20 min at room temperature. After the removal of the
ester was hydrolyzed with a saturated solution of NaHSO3 and methanol under vacuum, the residue was diluted with water
extracted with EtOAc several times. The combined organic and extracted with diethyl ether. The ethereal layer was washed
layer was washed with water, brine and dried. The residue with water and dried. The crude residue obtained after the
obtained after the removal of the solvent was passed through a removal of the solvent was loaded on the silica gel column and
small silica gel column to furnish diol 12 (~29 g) in 88% yield as eluted with 20% ethyl acetatehexane to furnish the hydroxy
a white solid and was recrystallized from DCMhexane. Mp: esters 15 (1.85 g) and 16 (1.62 g) in 63% overall yield in 55 : 45
111 C; IR (KBr): max 3362, 1604, 1450, 1192 cm1; 1H NMR ratio.
(200 MHz, CDCl3): 4.003.80 (m, 2H), 3.59 (s, 3H), 3.54 (s, 15: IR: max 3445, 1714, 1647, 1379, 1209, 750 cm1; 1H NMR
3H), 3.423.31 (m, 1H), 3.06 (dd, 1H, J = 9.5, 4.3), 2.4 (br s, (200 MHz, CDCl3): 6.84 (m, 1H), 4.85 (d, 1H, J = 5.6), 4.70
2H), 1.89 (dd, 1H, J = 12.8, 8.8, 5), 1.681.50 (m, 1H); 13C (t, 1H, J = 5.2), 3.74 (s, 3H), 3.603.20 (m, 2H), 2.64 (dt, 1H,
NMR (50 MHz, CDCl3): 130.1, 129.4, 114.8, 76.4, 74.8, 72.9, J = 18.4, 5.8), 2.42 (dd, 1H, J = 14, 6.6), 2.16 (m, 1H), 2.02 (dd,
58.9 (2C), 52.5, 51.6, 51.4, 30.6; m/z (EI): 328 (M Cl); 1H, J = 11.4, 6.6), 1.48 (s, 3H), 1.32 (m, 1H), 1.31 (s, 3H);
Found: C, 39.55; H, 3.81. C12H14O4Cl4 requires: C, 39.59; H, 13
C NMR (50 MHz, CDCl3): 166.9, 136.4, 132.5, 109.4, 89.9,
3.88%. 79.9, 64.4, 52.1, 51.6, 39.3, 37.2, 35.4, 26.3, 23.9; Found: C,
62.63; H, 7.53. C14H20O5 requires C, 62.67; H, 7.51%.
10,10-Dimethoxytricyclo[5.2.1.02,6]dec-8-ene-3,4-diol 13 16: IR: max 3439, 1714, 1647, 1259, 1209, 748 cm1; 1H NMR
(200 MHz, CDCl3): 6.87 (m, 1H), 4.87 (m, 2H), 4.05 (m, 1H),
In a 1 l three necked round bottomed ask tted with a con- 3.78 (s, 3H), 3.05 (m, 1H), 2.80 (m, 1H), 2.39 (m, 2H), 1.92 (dd,
denser, KOH guard tube and a septum, 600 ml of distilled 1H, J = 13.6, 5.8), 1.49 (s, 3H), 1.35 (m, 1H), 1.30 (s, 3H);
liquid ammonia was taken and a solution of diol 12 (18.2 g, 50 13
C NMR (50 MHz, CDCl3): 167.1, 136.4, 129.3, 109.8, 84.7,
mmol) in 80 ml dry THF and 8 ml of dry ethanol were added. 79.0, 65.3, 51.7, 42.6, 41.0, 34.5, 30.3, 26.4, 24.1; m/z (EI): 253
Small pieces of freshly cut sodium were slowly added to the (M 15).
reaction mixture with stirring till the blue color persisted. The
reaction mixture was stirred for another 15 minutes and ~5 g of
Methyl 4-methoxy-2,2-dimethyl-3b,4,5,7a,8,8a-hexahydro-3aH-
solid NH4Cl were added. Ammonia was allowed to evaporate
indeno[1,2-d][1,3]dioxole-7-carboxylate 17
and the residue was diluted with water. Extraction with ethyl
acetate, washing with brine and removal of solvent aorded a A mixture of 15 (1.5 g, 5.6 mmol), methyl iodide (2.6 ml, 40
viscous liquid which was distilled at 165 C/1 Torr to furnish mmol) and KOH (~360 mg, 6 mmol) was stirred at rt for 20 h
pure diol 13 (6.9 g) in 45% yield. IR (neat): max 3406, 3061, and then loaded on a pad of silica gel and eluted with 10%
1440, 1273 cm1; 1H NMR (200 MHz, CDCl3): 6.196.17 (m, EtOAchexane to aord 17 (1.41 g) in 90% yield. IR: max 1712,
2H), 4.00 (m, 1H), 3.52 (t, 1H, J = 5), 3.28 (s, 3H), 3.12 (s, 3H), 1649, 1437, 1379, 1248, 750 cm1; 1H NMR (200 MHz, CDCl3):
3.052.60 (series of m, 4H), 1.821.70 (m, 1H), 1.221.10 (m, 6.90 (m, 1H), 4.804.60 (m, 2H), 4.05 (m, 1H), 3.75 (s, 3H),
1H); 13C NMR (50 MHz, CDCl3): 134.2, 133.6, 122.3, 77.4, 3.38 (s, 3H), 3.102.90 (m, 1H), 2.75 (dt, 1H, J = 18.4, 5.8), 2.47
75.9, 51.8, 49.9 (2C), 48.3, 46.8, 42.0, 33.7; m/z (EI): 226 (M); (dd, 1H, J = 17.5, 6), 2.102.00 (m, 2H), 1.48 (s, 3H), 1.36 (m,
Found: C, 63.75; H, 8.05. C12H18O5 requires: C, 63.60; H, 1H), 1.32 (s, 3H); 13C NMR (50 MHz, CDCl3): 167.0, 136.2,
8.02%. 132.5, 109.3, 82.2, 79.9, 72.7, 56.2, 51.6, 49.8, 39.4, 36.9, 30.6,
26.3, 24.0; m/z (EI): 282 (M); Found: C, 63.85; H, 7.87.
5,5-Dimethyl-4,6-dioxatetracyclo[8.2.1.02,9,03,7]tridec-11-en-13- C15H22O5 requires: C, 63.81; H, 7.85%.
one 14
Methyl 4-methoxy-2,2-dimethyl-5-oxo-3b,4,5,7a,8,8a-hexa-
To a solution of diol 13 (8 g, 35.4 mmol) in acetone (25 ml),
hydro-3aH-indeno[1,2-d][1,3]dioxole-7-carboxylate 18
Amberlyst-15 catalyst was added and the resulting hetero-
geneous mixture was stirred at rt for 6 h. Filtration of the resin To an ice-cooled solution of 17 (1.2 g, 4.25 mmol) in benzene
and concentration furnished the keto-acetonide 14 (6.1 g) in (15 ml) was added Celite (200 mg), PDC (3.16 g, 8.5 mmol) and
83% yield as a colorless solid. Mp: 74 C; IR (KBr): max 1778, 0.4 ml of 80% tert-butyl hydroperoxide. The reaction mixture
1373, 1062, 719 cm1; 1H NMR (200 MHz, CDCl3): 6.546.51 was stirred at rt for 1 h and then ltered through a small Celite
(m, 2H), 4.39 (m, 1H), 4.17 (m, 1H), 3.302.70 (series of m, pad. The crude product obtained after evaporation of the
4H), 2.202.00 (m, 1H), 1.601.55 (m, 1H), 1.47 (s, 3H), 1.26 (s, solvent was loaded on a silica gel column and eluted with 10%
3H); 13C NMR (50 MHz, CDCl3): 202.2, 133.0, 132.0, 110.8, EtOAchexane to furnish enone 18 (230 mg) and unreacted
84.3, 83.4, 52.0, 50.2, 48.5, 42.2, 35.0, 27.9, 25.4; m/z (EI): starting material (450 mg) in 30% yield (on the basis of recovery
207 (M 1); Found: C, 70.62; H, 7.34. C13H16O3 requires: of starting material). IR: max 1724, 1701, 1439, 1253, 1209, 756
C, 70.89; H, 7.32%. cm1; 1H NMR (200 MHz, CDCl3): 6.71 (s, 1H), 4.86 (t, 1H,
J = 5.4), 4.69 (d, 1H, J = 5.6), 3.85 (s, 3H), 3.61 (s, 3H), 3.59
Methyl 4-hydroxy-2,2-dimethyl-3b,4,5,7a,8,8a-hexahydro- 3.50 (m, 2H), 2.702.48 (m, 2H), 1.851.75 (m, 1H), 1.49 (s,
3aH-indeno[1,2-d][1,3]dioxole-7-carboxylate 15 and methyl 3H), 1.33 (s, 3H); 13C NMR (50 MHz, CDCl3): 198.5, 165.9,
7-hydroxy-2,2-dimethyl-3b,6,7,7a,8,8a-hexahydro-3aH-indeno- 148.2, 131.7, 109.7, 82.2, 80.5, 78.6, 59.5, 52.7, 51.4, 37.7, 37.3,
[1,2-d][1,3]dioxole-4-carboxylate 16 26.2, 23.8; m/z (EI): 296 (M 1); Found: C, 60.62; H, 6.83.
C15H22 O5 requires: C, 60.80; H, 6.80%.
To an ice-cooled solution of the tricyclic ketone 14 (4.4 g, 20
mmol) and anhydrous Na2CO3 (2.2 g, 20.6 mmol in dry
Methyl 5-hydroxy-4-methoxy-2,2-dimethyl-3b,4,5,7a,8,8a-hexa-
dichloromethane (50 ml) m-chloroperbenzoic acid (5.4 g, 70%,
hydro-3aH-indeno[1,2-d][1,3]dioxole-7-carboxylate 19
22 mmol) was added and the reaction mixture was stirred for
30 min. The reaction was quenched with saturated aq. NaHCO3 To a solution of enone 18 (220 mg, 0.74 mmol) and
and the contents were stirred for another 15 min. The organic CeCl37H2O (335 mg, 0.9 mmol) in dry methanol (5 ml) was
layer was separated and the aqueous layer was further extracted added NaBH4 (35 mg, 0.9 mmol) at 20 C and the mixture
with dichloromethane. The combined organic extracts were was stirred for 15 min at the same temperature. Methanol was
again washed with saturated aq. NaHCO3, followed by brine. removed under reduced pressure and the residue obtained was

1402 J. Chem. Soc., Perkin Trans. 1, 2000, 13991404

dissolved in water and extracted with ethyl acetate. The organic water, brine, and dried over Na2SO4. Evaporation of the solvent
extract was washed, dried and evaporated to furnish allylic and purication through a silica gel column (elution with 10%
alcohol 19 (138 mg) in 62% yield. IR: max 3460, 1715, 1440, EtOAchexane) furnished 23 (40 mg) in 86% yield. IR(neat):
1335, 755 cm1; 1H NMR (300 MHz, CDCl3): 6.71 (s, 1H), max 1725, 1370, 1240, 1020 cm1; 1H NMR (500 MHz, CDCl3):
4.764.68 (m, 2H), 4.41 (d, 1H, J = 8.1), 3.67 (s, 3H), 3.59 (s, 5.71 (ddd, 1H, J = 17, 10, 6.5), 4.98 (d, 1H, J = 4.2), 4.96 (s,
3H), 3.29 (dt, 1H, J = 12.6, 6.6), 2.99 (dd, 1H, J = 12.3, 7.8), 1H), 4.834.78 (m, 1H), 4.69 (t, 1H, J = 5.5), 4.55 (d, 1H,
2.47 (dd, 1H, J = 12.3, 6.3), 2.30 (dd, 1H, J = 12.3, 6.9), 2.26 J = 5.6), 3.47 (s, 3H), 2.85 (t, 1H, J = 10.5), 2.612.50 (m, 2H),
(br s, 1H), 1.551.44 (m, 1H), 1.47 (s, 3H), 1.32 (s, 3H); 13C 2.07 (s, 3H), 2.06 (dd, 1H, J = 10.8, 3.7), 1.92 (td, 1H, J = 8.6,
NMR (75 MHz, CDCl3): 166.4, 139.4, 132.5, 109.3, 81.5, 80.5, 4), 1.70 (dd, 1H, J = 14.1, 6.4), 1.52 (dt, 1H, J = 13.5, 5.5), 1.44
80.3, 72.4, 58.9, 51.9, 49.0, 39.0, 37.5, 26.3, 23.9; Found: C, (s, 3H), 1.40 (q, 1H, J = 12.1), 1.30 (s, 3H); 13C NMR (125
60.62; H, 6.83. C15H22O6 requires: C, 60.82; H, 6.80%. MHz, CDCl3): 170.1, 139.9, 113.9, 108.9, 82.6, 79.1, 78.4,
76.3, 59.5, 50.5, 39.2, 37.7, 31.4, 30.0, 25.9, 23.6, 21.3; Found:
4-Methoxy-2,2-dimethyl-7-vinylperhydroindeno[1,2-d][1,3]- C, 65.84; H, 8.48. C17H26O5 requires: C, 65.78; H, 8.44%.
dioxol-5-ol 22
Methyl 2-(3-methoxy-4-acetoxy-2-methoxycarbonyl-6-vinyl-
To a solution of unsaturated alcohol 19 (130 mg, 0.44 mmol) in
cyclohexyl)acetate 24
absolute ethanol (5 ml) was added PtO2 (2 mg) catalyst and the
mixture was stirred under a hydrogen atmosphere for 1 h at rt. Acetonide 23 (36 mg, 0.116 mmol) was dissolved in 2 ml of
The reaction mixture was ltered through a silica gel pad and 30% aqueous triuoroacetic acid and stirred at rt for 1 h. The
the ltrate was concentrated to aord a mixture of saturated volatile material was removed under vacuum and the residue in
alcohols 20 (112 mg, 84%) in an 85 : 15 ratio (from 1H NMR) 3 ml of 10% aqueous THF was treated with NaIO4 (30 mg, 0.14
and was subjected to the next step as such. IR: max 3450, 1725, mmol) at ice temperature. The solution was stirred for 15 min,
1340, 750 cm1; 1H NMR (300 MHz, CDCl3): 4.754.69 (m, diluted with water and extracted with diethyl ether. The organic
1H), 4.60 (d, 1H, J = 6), 3.69 (s, 3H), 3.56 (s, 3H), 3.643.54 (m, layer was washed, dried and concentrated. The crude dialde-
2H), 2.822.65 (m, 2H), 2.242.00 (m, 2H), 1.821.60 (m, 3H), hyde obtained was dissolved in acetone (2 ml) and treated with
1.46 (s, 3H), 1.31 (s, 3H). 45 drops of 0.7 M Jones reagent. The mixture was stirred for
To a solution of 20 (112 mg, 0.37 mmol) in dry DCM (5 ml) 15 min, diluted with water and extracted with diethylether. The
at 78 C, 1 M DIBAL-H (0.4 ml) was added under N2 and the organic layer was washed, dried and concentrated to aord the
mixture was stirred at 78 C for 30 min. The reaction was crude diacid. The diacid in dry ether (2 ml) was treated with
quenched with saturated NH4Cl solution and diluted with excess of diazomethane in ether and left for 10 min at ice tem-
DCM. The organic layer was separated and the aqueous layer perature. The excess diazomethane was quenched with AcOH
was extracted with DCM. The combined organic extract was and the volatile materials were removed under reduced pressure.
washed with water, brine, dried over Na2SO4 and then concen- The residue was puried by silica gel column chromatography
trated to aord the aldehyde 21 (~90 mg). The crude aldehyde (elution with 10% EtOAchexane) to furnish the diester 24
obtained was subjected to the next step as such. IR: max 3460, (8 mg) in 21% overall yield, from 23. IR (neat): max 2960, 1730,
2710, 1720, 1370, 1200, 1045 cm1; 1H NMR (300 MHz, 1440, 1370, 1240, 1090 cm1; 1H NMR (300 MHz, CDCl3):
CDCl3): 9.67 (s, 1H), 4.74 (t, 1H, J = 5.7), 4.61 (d, 1H, 5.73 (ddd, 1H, J = 17.1, 10.5, 4.8), 5.03 (m, 2H), 4.78 (ddd,
J = 5.7), 3.653.54 (m, 1H), 3.57 (s, 3H), 3.022.94 (m, 1H), 1H, J = 14.4, 11.7, 5.1), 3.67 (s, 3H), 3.65 (m, 1H), 3.62 (s, 3H),
2.772.62 (m, 2H), 2.201.48 (series of m, 5H), 1.47 (s, 3H), 3.45 (s, 3H), 2.81 (m, 1H), 2.67 (dd, 1H, J = 11.4, 4.2), 2.45 (m,
1.32 (s, 3H). 2H), 2.10 (s, 3H), 2.07 (m, 1H), 1.25 (m, 2H); 13C NMR (75
To a suspension of methyltriphenylphosphonium iodide (270 MHz, CDCl3): 173.0, 172.7, 170.3, 138.3, 115.9, 78.3, 76.6,
mg, 0.66 mmol) in dry THF (3 ml) was added 1.6 M n-BuLi (0.4 60.9, 52.0, 51.7, 51.3, 41.1, 36.1, 29.2, 29.1, 21.3. The spectral
ml) under nitrogen atmosphere. and the mixture was stirred for data for 24 were found to be identical through direct com-
5 min at rt. To the canary yellow ylide that formed was added 21 parison with the same compound reported by Fraser-Reid
(90 mg, 0.33 mmol) in THF (2 ml) and the reaction mixture et al.3f
stirred further for 15 min and quenched with water. The organic
layer was separated and the aqueous layer was extracted with
Acknowledgements
ether. The combined organic layer was washed with water,
brine, dried over Na2SO4 and concentrated. The residue was We thank Professor B. Fraser-Reid for providing the spectral
puried by silica gel column chromatography (elution with 20% data on 24 for comparison purposes. D. S. R. thanks UGC,
EtOAchexane) and crystallization yielded the pure major iso- New Delhi, for a research fellowship. This research was sup-
mer 22 (48 mg) as a white crystalline solid in 48% overall yield. ported by the Jawaharlal Nehru Center for Advanced Scientic
Mp: 88 C; IR (KBr): max 3450, 1640, 1370, 1265, 1205, 900 Research, Bangalore.
cm1; 1H NMR (300 MHz, CDCl3): 5.76 (ddd, 1H, J = 16.8,
10.8, 6.3), 5.034.96 (m, 2H), 4.70 (t, 1H, J = 5.4), 4.61 (d, 1H, References
J = 6), 3.683.62 (m, 1H), 3.55 (s, 3H), 2.72 (t, 1H, J = 11.1),
2.592.52 (m, 2H), 2.07 (dd, 1H, J = 10.8, 5.4), 1.87 (td, 1H, 1 Isolation, see: (a) J. M. Muller, E. Schlittler and H. J. Bein,
J = 12.9, 3), 1.69 (dd, 1H, J = 14.1, 5.1), 1.651.56 (m, 2H), 1.45 Experientia, 1952, 8, 338; (b) A. Chatterjee, Fortschr. Chem. Org.
Naturst., 1953, 10, 390; (c) A. Chatterjee, S. C. Pakrashi and
(s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz, CDCl3): 140.4, G. Werner, Fortschr. Chem. Org. Naturst., 1956, 13, 346.
113.6, 108.8, 82.3, 81.7, 79.2, 73.2, 58.7, 49.7, 39.7, 38.0, 32.3, 2 For structure and stereochemistry determination, see: (a) L.
31.5, 25.9, 23.6; Found: C, 66.83; H, 9.04. C15H24O4 requires: Dorfman, A. Furlenmeier, C. F. Huebner, R. Lucas, H. B. Mac-
C, 67.14; H, 9.01%. Phillamy, J. M. Mueller, E. Schlittler, R. Schwyzer and A. F.
St. Andre, Helv. Chim. Acta, 1954, 37, 59; (b) E. E. van Tamelen and
4-Methoxy-2,2-dimethyl-7-vinylperhydroindeno[1,2-d][1,3]- P. D. Hance, J. Am. Chem. Soc., 1955, 77, 4692; (c) E. Wenkert and
L. H. Liu, Experientia, 1955, 11, 302; (d ) P. A. Diassi, F. Weisenborn,
dioxol-5-yl acetate 23 C. M. Dylion and O. Wintersteiner, J. Am. Chem. Soc., 1955, 77,
To a solution of alcohol 22 (40 mg, 0.15 mmol) in dry pyridine 4687.
(2 ml), cooled in an ice-bath, were added a catalytic amount of 3 For the total synthesis of reserpine accomplished so far, see: (a) R. B.
Woodward, F. E. Bader, H. Bickel, A. J. Frey and R. W. Kierstead,
DMAP and 0.5 ml of Ac2O and the mixture was stirred at rt for J. Am. Chem. Soc., 1956, 78, 2023; R. B. Woodward, F. E. Bader,
2 h. The reaction was quenched with crushed ice and extracted H. Bickel, A. J. Frey and R. W. Kierstead, J. Am. Chem. Soc., 1956,
with diethyl ether. The organic layer was washed with dil. HCl, 78, 2657; R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey and

J. Chem. Soc., Perkin Trans. 1, 2000, 13991404 1403

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1404 J. Chem. Soc., Perkin Trans. 1, 2000, 13991404