Construction of the 5,10b-phenanthridine skeleton using [3+2]-cycloaddition of a non-stabilized azomethine ylide: Total synthesis of (±)-maritidine and (±)-crinine alkaloids

Article abstract of DOI:10.1002/ejoc.201001263

Vicinal quaternary and tertiary stereocenters of the 5,10b-phenanthridine skeleton 1 are constructed simultaneously in one step by the [3+2]-cycloaddition of non-stabilized azomethine ylide 9, generated by sequential double desilylation of 10 utilizing silver(I) fluoride as a one-electron oxidant. The regio- as well as stereochemical origin of this cycloaddition reaction is explained through a favorable transition state 9″. The strategy is successfully applied for the total synthesis of the biologically active alkaloids (±)-maritidine (1a), (±)-crinine (1b), and their analogues (1d, 1e, and 1f). The synthesis features construction of the BD ring with concomitant installation of a quarternary and tertiary carbon in a single operation by employing intramolecular 1,3-dipolar cycloaddition of a non-stabilizedazomethine ylide. Oxo-maritidine and oxo-crinine were found to be advanced and efficient intermediates for the synthesis of natural products of this class.

Full text of DOI:10.1002/ejoc.201001263

FULL PAPER
DOI: 10.1002/ejoc.201001263
Construction of the 5,10b-Phenanthridine Skeleton Using [3+2]-Cycloaddition
of a Non-Stabilized Azomethine Ylide: Total Synthesis of (؎)-Maritidine and
(؎)-Crinine Alkaloids
Ganesh Pandey,*[a] Nishant R. Gupta,[a] and Smita R. Gadre[a]
Keywords: Natural products / Alkaloids / Cycloaddition / Azomethine ylides / Ylides
Vicinal quaternary and tertiary stereocenters of the 5,10b-
phenanthridine skeleton 1 are constructed simultaneously in
one step by the [3+2]-cycloaddition of non-stabilized azome-
thine ylide 9, generated by sequential double desilylation of
10 utilizing silver(I) fluoride as a one-electron oxidant. The
regio- as well as stereochemical origin of this cycloaddition
reaction is explained through a favorable transition state 9ЈЈ.
The strategy is successfully applied for the total synthesis of
the biologically active alkaloids (Ϯ)-maritidine (1a), (Ϯ)-crin-
ine (1b), and their analogues (1d, 1e, and 1f).
Introduction
its structural analogues, isolated from Pancratium mari-
Alkaloids 1–4, isolated from plants of the Amaryllida- timum, Pancratium tortuosum, and Zephyranthes gen-
ceae[1–4] family have long been a source of structurally intri- era,[7–11] is the first alkaloid with the 5,10b-ethanophen-
guing target molecules that continue to challenge the capa- anthridine nucleus containing dimethoxy rather than
bilities of contemporary organic synthesis. The family has methylenedioxy substituents at the C-8 and C-9 positions
produced over 500 structurally diverse alkaloids with a wide of the crinine skeleton (Figure 1). These alkaloids possess
range of interesting physiological effects, including antitu- fused tetracyclic skeletons displaying adjacent quaternary
mor, antiviral, acetylcholinesterase inhibitory, immunosti- and tertiary carbon stereocenters with fused pyrrolidine
mulatory and antimalarial activities.[5,6] Maritidine (1a) and ring systems for which stereochemical incorporation is the
Figure 1. Representative members of Amaryllidaceae alkaloids.
critical element in their synthesis. Alkaloid 1a is of particu-
[a] Division of Organic Chemistry, National Chemical Laboratory,
lar interest due to its cytotoxic properties[12–15] and limited
Dr. Homi Bhabha Road, Pune 411008, India
supplies from natural sources.[16–23]
Fax: +91-20-2590-2628
E-mail: gp.pandey@ncl.res.in
A number of synthetic efforts have been employed to
solve the challenging problem of incorporating these steri-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001263.
740
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Synthesis of (Ϯ)-Maritidine and (Ϯ)-Crinine Alkaloids
cally congested stereocenters into the 5,10b-ethanophen-
Our continuing interest in exploring the application of
anthridine structural framework. In this context, intramo- non-stabilized azomethine ylides, generated by the sequen-
lecular oxidative para–para phenolic coupling[24–28] and Pic- tial double desilylation of α,αЈ-bis(trimethylsilylmethyl)alk-
tet–Spengler cyclization[19–38] of 3-aryl hydroindole deriva- ylamines[41–42] in the total synthesis of alkaloids[43–45] with
tives have emerged as the two main strategies. In the former complex architecture, and the need to develop a concise and
approach, spiro-fused dienone precursor 7 is obtained by versatile strategy to synthesize these types of alkaloids, led
the para–para coupling of substituted norbelladine deriva- us to envisage the synthesis of 1a through an intramolecular
tives employing various oxidizing agents,[24,25,27] photo- 1,3-dipolar cycloaddition of a non-stabilized azomethine
chemical cyclization,[26] intramolecular Heck reaction,[39] ylide (AMY). This strategy emerged from our success in
and cyclization of an intermediate iron carbonyl com- the construction of examples of the fused polycyclic 5,11-
plex.[27,28] Substituted 3a-arylhydroindoles 6, which are methanomorphanthridine class of alkaloids through the use
used for the Pictet–Spengler reaction, are synthesized of non-stabilized azomethine cycloaddition reactions.[45] We
through key reactions such as regioselective reduction of 1- report herein full details[46] of the intramolecular [3+2]-cy-
methyl-3,3-disubstituted pyrrolidine-2,5-dione,[30] intramo- cloaddition of a non-stabilized azomethine ylide as a route
lecular ene cyclization[31] of an appropriately constructed for the stereoselective synthesis of (Ϯ)-maritidine (1a) and
acylnitroso olefin, or condensation of 3-arylated Δ1-pyrrol- (Ϯ)-crinine (1b).
inium salts with tert-butyl 3-oxopent-4-enoate.[32] A few
other approaches reported for the synthesis of 1 have in-
volved intramolecular cycloamination reactions from an ap-
Results and Discussion
propriate spiro precursor for the carbon–nitrogen bond for-
mation in the construction of the substituted angular phen-
anthridine skeleton (Figure 2).[40]
Retrosynthetic Plan
While designing a route to 5,10b-ethanophenanthridine
alkaloids such as maritidine and crinine via oxomaritidine
1e and oxocrinine 1f, respectively, we speculated on the for-
mation of the C1–C2 double bond by cycloaldolization/con-
densation of the corresponding δ-keto aldehyde from 8,
which possesses vicinal quaternary and tertiary stereocen-
ters at the ring fusion center (Figure 3). A detailed evalu-
ation of the structural framework of 8 revealed the presence
of a fused pyrrolidine ring (BD rings) with adjacent vicinal
quaternary and tertiary stereocenters.
Figure 2. Summary of the strategies reported for the synthesis of
1.
From the above introductory remarks, it is apparent that
these approaches employ sequential generation of vicinal
quaternary and tertiary stereocenters along with the use of
cyclic precursors for C-ring formation. Moreover, the Pic-
tet–Spengler cyclization route has produced only the dihy-
dromaritidine, whose oxidative transformation into maritid-
Figure 3. Retrosynthetic analysis for maritidine and crinine types
of Amaryllidaceae alkaloids.
Therefore, we envisioned that an intramolecular [3+2]-
ine has so far been unsuccessful. Therefore, we surmised cycloaddition reaction of non-stabilized azomethine ylide 9
that a strategy that could deliver all the stereocenters in with a tethered geminally disubstituted dipolarophile would
one step would significantly advance the syntheses of these result in the construction of both C4a–C10b and C11–C12
classes of alkaloids.
bonds in one step with the required stereochemistry of 8.
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G. Pandey et al.
FULL PAPER
The corresponding azomethine ylide intermediate could be
easily generated in situ from the corresponding α,αЈ-bis(tri-
methylsilylmethyl)alkylamine 10 using silver(I) fluoride as
a one-electron oxidant, using a protocol developed in our
group.[41–42]
Regio- as well as stereochemical issues, the two impor-
tant aspects of this cycloaddition strategy, were evaluated
at the planning stage of the synthesis itself. The origin of
the 5,10b-ethanophenanthridine regiochemistry during cy-
cloaddition, in contrast to that of the 5,11-methanophen-
anthridine skeleton,[45] was considered to arise from the
change in the LUMO energy of the dipolarophile due to its
conjugation with the aromatic ring and the ester moiety
present on the same carbon. The cycloaddition reaction of
10 was envisaged to generate the vicinal quaternary and ter-
tiary carbon stereocenters in one step, with the orientation
of substituents in the dipole directing the stereochemical
outcome at the C-4a position. For example, it was hypothe-
sized that the alkyl ketal moiety of the dipole in AMY 9Ј
may experience severe stereoelectronic congestion with the
tethered aromatic ring flanked between the dipole and the
dipolarophile as shown in TS-I (Figure 4), resulting in the
epimeric C-4a stereochemistry of cycloadduct 8. On the
other hand TS-II, in which the alkyl ketal side chain of
Figure 4. Proposed transition state model for the [3+2]-cycload-
dition step.
The requisite key precursor 10 for the transformation
AMY 9ЈЈ and the aromatic ring are distant from each other, was envisaged to be obtained from modified Stille cou-
may generate the desired C-4a stereochemistry in 8. Thus, pling[47] of the corresponding aryl iodide 11 and a suitable
we anticipated that suitable substrate controlled stereoelec- vinylstannane 12.[48] The aryl iodide 11 could, in turn, be
tronic factors operating during cycloaddition of 9ЈЈ would synthesized by alkylation of the bis-silylated (alkylamino)-
reinforce the stereochemical outcome of the formation of alkyl-substituted ketal 13 with the diiodo component 14.
the tricyclic skeleton and lead to a suitable stereochemical These components may be obtained from commercially
disposition of substituents required for assembling the C- available aryl methyl alcohol and methyl vinyl ketone
ring of the target alkaloid.
(MVK).
Scheme 1. Synthesis of the precursor for cycloaddition.
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Eur. J. Org. Chem. 2011, 740–750

Synthesis of (Ϯ)-Maritidine and (Ϯ)-Crinine Alkaloids
Synthesis of (؎)-Maritidine (1a): With the above design
in mind, we began by synthesizing the key precursor 10a
(73% yield) by a modified Stille coupling between appropri-
ately substituted aryl iodide 11a and vinyl stannane 12 by
following Corey’s protocol.[47] The Stille precursor was ob-
tained in 70% yield by N-alkylation of 13 with the corre-
sponding di-iodo component 14a, in the presence of anhy-
drous K2CO3 in CH3CN. Secondary amine 13 was synthe-
sized from 15 as shown in Scheme 1. Compound 15 was
readily obtained from 16 by following a sequence of reac-
tions similar to those previously reported.[45] Compound 16
was obtained in 70% yield by an aza-Michael reaction be-
tween BocNH2 and methyl vinyl ketone, followed by
NaBH4-mediated reduction. Compound 15, on oxidation
with 2-iodoxybenzoic acid (IBX) followed by ketalization,
gave ketal 20 in 85% yield. N-Boc deprotection of 20, fol-
lowed by N-alkylation with iodomethyltrimethylsilane, gave
bis-silylated compound 13 in 70% yield.
Scheme 2. Synthesis of tricyclic core of maritidine.
followed by deprotection of the ketal group to give the
With key precursor 10a in hand, we performed the cru- stable hemiketal 21 as shown in Scheme 3.
cial cycloaddition reaction by dropwise addition of its solu-
Thus, we were compelled to adopt a two-step protocol
tion (2.87 mmol) dissolved in dichloromethane (15 mL) to to obtain 23. Lithium aluminum hydride (LAH) mediated
a stirring mixture of flame-dried silver(I) fluoride in anhy- reduction of the ester moiety of 8a, followed by Swern oxi-
drous dichloromethane. To our delight, the reaction gave dation, produced the aldehyde-ketal 23a in 81% yield. In
the desired cycloadduct 8a in 56% isolated yield along with an attempt to perform one-pot ketal deprotection and aldol
some other minor unidentifiable impurities. The yield of 8a condensation, 23a was initially stirred overnight with 80%
was optimized up to 68% by manipulating the rate of the acetic acid. However, these conditions produced only the
addition of 10a to the stirring suspension of properly dried ketal deprotected compound in poor yield along with traces
silver(I) fluoride. The cycloadduct was fully characterized of 1e. Therefore, 23a was subjected to trans-ketalization
by 1H and 13C NMR experiments. The stereochemical using p-toluenesulfonic acid (p-TsA) and acetone to obtain
assignment was established based on extensive COSY, the corresponding δ-keto aldehyde, which was immediately
NOESY and HETCOR NMR spectroscopic studies treated with NaOH/EtOH to obtain 1e in 65% yield. The
(Scheme 2).[49]
After the successful synthesis and complete characteriza- agreement with the reported data.[39]
spectroscopic data of 1e was also found to be in excellent
tion of the fused tricyclic intermediate 8a with the ABD
Although the synthesis of 1e concludes the formal total
ring, the next task towards completing the synthesis of the synthesis of 1c and 1a, we proceeded further to complete
natural product was to construct ring C. In order to pro- the total synthesis of 1a by subjecting 1e to Luche re-
ceed further, cycloadduct 8a was subjected to diisobutylalu- duction,[50] which produced 1c. Mesylation, followed by
minum hydride (DIBAL-H) mediated reduction. However, substitution using CsOAc and saponification of the result-
this reaction led to the reduction of ester functionality ant acetate, gave 1a in 45% yield (Scheme 4). The spectro-
along with ketal deprotection, presumably through coordi- scopic data of 1a were found to be in excellent agreement
nation of the alkoxy aluminum with the ketal oxygen atom with those of the reported compound.[39a]
Scheme 3. DIBAL-H reduction of 8a.
Eur. J. Org. Chem. 2011, 740–750
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G. Pandey et al.
FULL PAPER
Conclusions
We have successfully developed a conceptually new and
versatile protocol for the construction of 5,10b-eth-
anophenanthridine alkaloids. The significance of the ap-
proach has been demonstrated by synthesizing (Ϯ)-maritid-
ine, (Ϯ)-crinine, and some of their analogues (1d, 1e, and
1f).
Scheme 4. Synthesis of maritidine.
Experimental Section
General: All reactions requiring anhydrous conditions were per-
formed under a positive pressure of argon using oven-dried glass-
ware (110 °C), which were cooled under argon. Solvents for anhy-
drous reactions were dried according to Perrin and Armarego.[54]
Benzene, CH2Cl2, and triethylamine were both distilled from CaH2
and stored over molecular sieves and KOH, respectively. THF and
diethyl ether were distilled from sodium benzophenone ketyl. Sol-
vents used for chromatography were distilled at their respective
boiling points using known procedures. Petroleum ether (PE) used
in the experiments was of 60–80 °C boiling range.
Synthesis of (؎)-Crinine (1b): After accomplishing the to-
tal synthesis of 1a, we turned our attention towards the
total synthesis of (Ϯ)-crinine (1b). The crinine alkaloids
elicit continued interest in the synthetic community due in
part to their intriguing physiological activities,[51,52] as ex-
emplified by a recent study that unveiled the highly selective
apoptosis induction properties against tumor cells at micro-
molar concentrations. Crinine alkaloids have also been
shown to possess immuno-stimulant, antitumor, and antivi-
ral activities.[53]
All commercial reagents were obtained from Sigma–Aldrich or
Lancaster Chemical Co. (UK). s-Butyllithium was titrated using
diphenylacetic acid as an indicator. Trimethylsilyl chloride
(TMSCl) and methanesulfonyl chloride (MsCl) were distilled be-
fore use. Progress of the reactions was monitored by TLC, which
was performed on plates pre-coated with silica gel 60 (Merck, 230–
400 mesh). Compounds were visualized by heating after dipping in
alkaline solution of either KMnO4 or (NH4)6Mo7O24 (6.25 g) in
aqueous H2SO4 (250 mL). Column chromatography was performed
The synthesis of 1b was accomplished through the cyclo-
addition of 10b by following identical synthetic steps to
those described above for 1a (Scheme 5).
The stereochemistry of the cycloadduct was confirmed
by submitting 22b to detailed COSY, NOESY, and
HETCOR NMR spectroscopic studies. The spectroscopic
data of 1b was found to be in good agreement with those
of the reported compound.[39b]
Scheme 5. Synthesis of crinine.
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Eur. J. Org. Chem. 2011, 740–750

Synthesis of (Ϯ)-Maritidine and (Ϯ)-Crinine Alkaloids
with silica gel 60–120/100–200/230–400 mesh. Standard syringe and
cannula techniques were used to transfer air- and moisture-sensitive
reagents.
H; CH2), 1.21 (d, J = 6.32 Hz, 1 H; CH2), 1.12 (d, J = 6.07 Hz, 3
H; CH3), 0.05 [s, 9 H; (CH3)3] ppm. 13C NMR (CDCl3, 50 MHz):
δ = 154.6, 83.7, 79.4, 65.8, 40.3, 34.5, 28.2, 21.9, 16.1, 0.4 ppm.
MS: m/z = 310 [M + Na]+. C14H29NO3Si (287.47): calcd. C 58.49,
H 10.17, N 4.87; found C 58.30, H 10.01, N 4.65.
IR spectra were recorded with a Perkin–Elmer infrared spectrome-
ter model 599-B and model 1620 FTIR. 1H NMR spectra were
recorded with Bruker ACF 200, Bruker AV 400, or Bruker DRX
500 instruments using deuterated solvent. Chemical shifts are re-
ported in ppm. Proton coupling constants (J) are reported as abso-
lute values in Hz; multiplicity is reported as follows: broad (br.),
singlet (s), doublet (d), triplet (t), doublet of triplet (dt), doublet of
doublet of doublet (ddd), multiplet (m). 13C NMR spectra were
recorded with Bruker ACF 200, AV 400, or Bruker DRX 500 in-
struments operating at 50 MHz, 100 MHz, and 125 MHz, respec-
tively. 13C NMR chemical shifts are reported in ppm relative to the
central line of CDCl3 (δ = 77.0 ppm). Mass spectra were recorded
with a PE SCIEX API QSTAR pulsar (LC-MS) and high resolu-
tion mass spectra (HRMS) were recorded with an MSI (U.K.) Au-
toconcept instrument operating in the electron impact mode of ion-
ization (70 eV) at the National Chemical Laboratory, Pune, India.
N-(2-Iodo-4,5-dimethoxybenzyl)-2-(2-methyl-1,3-dioxolan-2-yl)-1-
(trimethylsilyl)-N-[(trimethylsilyl)methyl]ethanamine (11a): To a
stirring solution of 14a (7 g, 17.39 mmol) in anhydrous CH3CN
(51 mL), K2CO3 (12 g, 86.95 mmol) and bis-silylated (alkylamino)-
alkyl-substituted ketal 13 (5 g, 17.39 mmol) were added at r.t. The
resulting suspension was heated to reflux for 8 h. On completion
of the reaction, the mixture was cooled, filtered, and the solvent
was evaporated under vacuum. The resultant pasty mass was taken
in EtOAc and washed with H2O (2ϫ50 mL), brine (2ϫ40 mL),
dried with Na2SO4, and concentrated under vacuum to obtain a
red-brown mass, which was purified by column chromatography
(PE/ethyl acetate, 95:5) to obtain 11a as a pale-yellow oil (6.88 g,
70%). R = 0.4 (PE/EtOAc, 90:10). IR (neat): ν
= 2953, 2843,
˜
f
max
1682, 1595, 1501, 1464, 1437, 1376, 1250, 1207, 1152, 1048,
838 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.24 (s, 1 H; CH), 7.18
(s, 1 H; CH), 3.86 [s, 6 H; (CH3)2], 3.87–3.74 [m, 4 H; (CH2)2], 3.62
(d, J = 15.31 Hz, 1 H; CH2), 3.40 (d, J = 15.31 Hz, 1 H; CH2),
2.36 (dd, J = 4.02, 7.28 Hz, 1 H; CH), 2.24 (d, J = 14.56 Hz, 1 H;
CH2), 2.15 (four-lines pattern, J = 4.27, 14.81, 4.01, 14.55 Hz, 1 H;
CH2), 1.92 (d, J = 14.55 Hz, 1 H; CH2), 1.82 (four-lines pattern, J
= 7.53, 14.81, 7.28, 14.56 Hz, 1 H; CH2), 1.30 (s, 3 H; CH3), 0.12
[s, 9 H; (CH3)3], 0.02 [s, 9 H; (CH3)3] ppm. 13C NMR (CDCl3,
100 MHz): δ = 149.2, 148, 134.8, 121.1, 112.7, 109.9, 87, 64.3, 64.2,
63.7, 56, 55.8, 49.6, 44.4, 34, 24.3, –0.2, –0.9 ppm. MS: m/z =
566.55[M + H]+. C22H40INO4Si2 (565.63): calcd. C 46.72, H 7.13,
N 2.48; found C 46.61, H 7.01, N 2.40.
tert-Butyl 2,6-Dimethyl-1,3-oxazinane-3-carboxylate (18): To a stir-
ring solution of the N-Boc derivative of the aminobutanol 16 (14 g,
73.99 mmol) in benzene (220 mL) and pyridinium p-toluenesulfo-
nate (PPTS; 0.93 g, 3.7 mmol) in a 500 mL round-bottomed flask,
acetaldehyde diethyl acetal (11.6 mL, 81.38 mmol) was added at r.t.
slowly. The reaction mixture was subjected to azeotropic distil-
lation for a period of 16–18 h using a long distillation head. The
vapor temperature was maintained between 67–71 °C. After com-
pletion of the reaction, the brown reaction mixture was allowed to
cool and washed with saturated NaHCO3 (100 mL), water
(2ϫ100 mL), brine (2ϫ50 mL), dried with Na2SO4, and concen-
trated under reduced pressure. The residue was purified by vacuum
distillation (b.p. 75–78 °C/1 Torr) to obtain 18 (13.86 g, 87%) as a
Methyl 2-[4,5-Dimethoxy-2-({[2-(2-methyl-1,3-dioxolan-2-yl)-1-(tri-
methylsilyl)ethyl][(trimethylsilyl)methyl]amino}methyl)phenyl]-
acrylate (10a): A 100 mL two-necked round-bottomed flask was
charged with LiCl (0.9 g, 21.22 mmol) and flame-dried under high
vacuum. Upon cooling, [Pd(PPh3)4] (0.061 g, 0.53 mmol) and CuCl
(1.75 g, 17.68 mmol) were added, and the mixture was degassed (3–
4 times) under high vacuum with an argon purge. Anhydrous
DMSO (25 mL) was introduced with concomitant stirring, fol-
lowed by the sequential addition of 11a (2 g, 3.53 mmol) and vinyl
stannane compound 12 (1.59 g, 4.24 mmol), both diluted with
DMSO (1 mL). The resulting mixture was rigorously degassed (4
times) by the freeze-thaw cycles (–78 to 25 °C, Ar). The reaction
mixture was stirred at r.t. for 1 h followed by heating at 60 °C for
2 h. Following completion of the coupling as monitored by TLC,
the reaction mixture was cooled, diluted with Et2O (70 mL), and
washed with a mixture of brine (2ϫ40 mL) and 5% aqueous
NH4OH (100 mL). The aqueous layer was further extracted with
ethyl acetate (2ϫ100 mL), and the combined organic layers were
washed with water (2ϫ100 mL), brine (2ϫ50 mL), dried with
Na2SO4 and concentrated under reduced pressure. The reddish-
brown residue was purified by column chromatography (PE/ethyl
acetate, 90:10) to yield 10a (1.35 g, 73%) as a yellow viscous liquid.
colorless oil. R = 0.3 (PE/EtOAc, 85:15). IR (neat): ν
= 2977,
˜
f
max
1
2934, 1698, 1410, 1366, 1337, 1161, 1092, 945, 861 cm–1. H NMR
(CDCl3, 200 MHz): δ = 5.74 (br. q, J = 6.35, 10.56 Hz, 1 H; CH),
3.92 (m, 2 H; H of CH and H of CH2), 3.06 (m, 1 H; CH2), 1.45
(m, 2 H; CH2), 1.40 [s, 9 H; (CH3)3], 1.38 (d, J = 6.32 Hz, 3 H;
CH3), 1.11 (d, J = 6.06 Hz, 3 H; CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 153.4, 79.8, 78.3, 64, 36.2, 32.7, 28.3, 21.7,
15.6 ppm. MS: m/z = 238.27 [M + Na]+. C11H21NO3 (215.29):
calcd. C 61.37, H 9.83, N 6.51; found C 61.19, H 9.65, N 6.32.
tert-Butyl 2,6-Dimethyl-4-(trimethylsilyl)-1,3-oxazinane-3-carboxyl-
ate (19): A solution of 18 (10 g, 46.46 mmol) in anhydrous THF
(92 mL) was charged into a 250 mL two-necked round-bottomed
flask equipped with magnetic stirring bar and an argon gas bal-
loon, and was cooled to –78 °C. TMEDA (9 mL, 92.91 mmol) fol-
lowed by sBuLi (1.5 m in cyclohexane, 62 mL, 92.91 mmol) were
introduced to the stirring mixture dropwise over a period of 30 min.
The mixture was further stirred for 4 h at –78 °C. TMSCl (13.6 mL,
106.84 mmol) was added dropwise to the reaction mixture at
–78 °C, which was then warmed to r.t. slowly and further stirred
for 2 h. The reaction was quenched by addition of saturated aque-
ous NH4Cl (40 mL). The mixture was extracted with ethyl acetate
(3ϫ120 mL) and the combined organic layer was washed with
brine (2ϫ75 mL), dried with Na2SO4 and concentrated under vac-
uum. The yellowish mixture was purified by column chromatog-
raphy (ethyl acetate/PE, 3:97) to obtain 19 (11.35 g, 85%) as a col-
R = 0.3 (PE/EtOAc, 80:20). IR (CHCl ): νmax = 3018, 2956, 2873,
˜
f
3
2852, 1720, 1600, 1509, 1465, 1440, 1376, 1249, 1216, 1136, 1048,
838, 756 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.31 (s, 1 H; CH),
6.60 (s, 1 H; CH), 6.47 (br. d, J = 1.26 Hz, 1 H; CH), 5.64 (br. d,
J = 1.25 Hz, 1 H; CH), 3.88 (s, 3 H; CH3), 3.87–3.80 [m, 4 H;
(CH2)2], 3.84 (s, 3 H; CH3), 3.72 (s, 3 H; CH3), 3.37 (q, J = 14.56,
16.81, Hz, 2 H; CH2), 2.37 (dd, J = 4.27, 7.53 Hz, 1 H; CH), 2.11
(d, J = 14.56 Hz, 1 H; CH2), 2.01 (dd, J = 4.26, 14.56 Hz, 1 H;
orless oil. R = 0.3 (PE/EtOAc, 95:5). IR (neat): νmax = 2977, 2934,
˜
f
1698, 1416, 1365, 1318, 1289, 1248, 1168, 1096, 843 cm–1. 1H NMR
(CDCl3, 200 MHz): δ = 5.78 (q, J = 6.44 Hz, 1 H; CH), 3.97 (m,
1 H, CH), 2.69 (dd, J = 2.91 Hz, 1 H, 12.38; CH), 1.47 (d, J = CH2), 1.86 (d, J = 14.56 Hz, 1 H; CH2), 1.71 (dd, J = 7.53,
6.57 Hz, 3 H; CH3), 1.42 [s, 9 H; (CH3)3], 1.35 (d, J = 5.69 Hz, 1 14.56 Hz, 1 H; CH2), 1.24 (s, 3 H; CH3), 0.06 [s, 9 H; (CH3)3], 0.01
Eur. J. Org. Chem. 2011, 740–750
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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745

G. Pandey et al.
[s, 9 H; (CH3)3] ppm. 13C NMR (CDCl3, 50 MHz): δ = 167.1, added to the reaction flask and the solution was cooled to –78 °C.
FULL PAPER
148.7, 146.7, 140.8, 129, 128.6, 128.3, 112.5, 111.3, 109.9, 64.2, 64,
56.1, 55.8, 55.7, 52.1, 49.4, 44, 33.7, 24.1, –0.3, –0.9 ppm. MS: m/z
= 524.3 [M + H]+. C26H45NO6Si2 (523.81): calcd. C 59.62, H 8.66,
N 2.67; found C 59.48, H 8.50, N 2.50.
To the solution of cycloadduct in anhydrous CH2Cl2 was added
DIBAL-H (1.2 m in toluene, 0.278 mmol) at –78 °C and the mix-
ture was stirred at the same temperature for 30 min. The reaction
was quenched by addition of a few drops of a saturated aq. sodium
potassium tartrate solution. Solid sodium sulfate was added to the
reaction flask and the mixture was further stirred at r.t. for 1 h
and then filtered through a sintered funnel. Concentration of the
reaction mixture followed by column chromatography (EtOAc/hex-
ane, 70%) afforded 21 as a gummy liquid in 70% yield. Rf = 0.2
Synthesis of 8a from 10a: A solution of 10a (1.5 g, 2.87 mmol) in
anhydrous CH2Cl2 (15 mL) was introduced dropwise over a period
of 1 h into an argon-flushed 500 mL two-neck flask containing
flame-dried AgF (1.82 g, 14.33 mmol) in anhydrous CH2Cl2
(200 mLCH2Cl2). The color of the reaction mixture gradually
turned to dark-brown with concomitant deposition of silver on the
inner surface of the flask in the form of a mirror. The progress of
reaction was monitored periodically by TLC. After completion, the
reaction mixture was filtered through a small plug of basic alumina
(eluent MeOH) and the solvent was evaporated to obtain a crude
brown residue, which was purified by silica gel chromatography
(PE/acetone, 75:25) to obtain 8a (0.73 g, 68%) as yellow gummy
1
(hexane/EtOAc, 10:90). H NMR (CDCl3, 400 MHz): δ = 6.51 (s,
1 H; CH), 6.42 (s, 1 H; CH), 4.40 (d, J = 16.82 Hz, 1 H; CH2),
4.28 (d, J = 11.04 Hz, 1 H; CH2), 4.21 (d, J = 11.04 Hz, 1 H; CH2),
3.88 (d, J = 16.82 Hz, 1 H; CH2), 3.83 (s, 3 H; CH3), 3.81 (s, 3 H;
CH3), 3.38–3.33 (m, 2 H; H of CH and H of CH2), 2.87–2.80 (m,
1 H; CH2), 2.42–2.35 (m, 2 H; CH2), 1.94–1.86 (m, 2 H; CH2), 1.48
(s, 3 H; CH3) ppm. MS: m/z = 306.36 [M + H]+.
Oxidation of 22a to 23a: To a mixture of DMSO (0.15 mL,
2.15 mmol) in CH2Cl2 (3 mL), oxalyl chloride (0.19 mL,
2.15 mmol) was added dropwise at –78 °C, and the resulting mix-
ture was stirred for 15 min. A solution of alcohol 20a (0.5 g,
1.43 mmol) in CH2Cl2 (1 mL) was added dropwise to the reaction
flask at –78 °C. The mixture was stirred for 1 h, then triethylamine
(1 mL, 7.15 mmol) was added dropwise and the resultant mixture
was gradually warmed to r.t.. over 1 h by removing the cooling
bath and stirred for a further 1 h. The reaction mixture was
quenched with water (5 mL) and extracted with CH2Cl2
(2ϫ25 mL). The combined organic layer was washed with brine,
dried with Na2SO4, filtered and concentrated under vacuum. Puri-
fication of the residue by silica gel column chromatography
(CH2Cl2/MeOH, 92:8) afforded aldehyde 23a (0.447 g, 90%) as a
liquid. R = 0.4 (PE/Acetone, 60:40). IR (CHCl ): ν = 3018,
˜
max
f
3
2956, 1730, 1611, 1518, 1466, 1260, 1215, 1130, 854, 754 cm–1. H
NMR (CDCl3, 400 MHz): δ = 6.49 (s, 1 H; CH), 6.27 (s, 1 H; CH),
4.39 (d, J = 16.81 Hz, 1 H; CH2), 3.94 [m, 4 H; (CH2)2], 3.80 (br.
s, 4 H; CH3, CH2), 3.77 [s, 6 H; (CH3)2], 3.56 (br. d, J = Hz, 1 H
7.78; CH), 3.36 (m, 1 H; CH2), 2.76 (m, 1 H; CH2), 2.48 (m, 1 H;
CH2), 2.12 (m, 1 H; CH2), 1.67 (dd, J = 9.54, 14.56 Hz, 1 H; CH2),
1.56 (dd, J = 2.51, 14.56 Hz, 1 H; CH2), 1.42 (s, 3 H; CH3) ppm.
13C NMR (CDCl3, 100 MHz): δ = 174.3, 148.3, 147.4, 134.2, 123.5,
109.5, 109.1, 108.1, 66.3, 64.6, 64.2, 61.4, 57.3, 55.9, 55.8, 51.8,
50.8, 38.3, 37.9, 23.8 ppm. MS: m/z = 378.27[M + H]+. C20H27NO6
(377.43): calcd. C 63.64, H 7.21, N 3.71; found C 63.50, H 7.15, N
3.65.
1
Reduction of 8a to 22a: To a suspension of LAH (0.12 g,
3.18 mmol) and anhydrous THF (8 mL) in a 25 mL two-necked
round-bottomed flask equipped with magnetic stirring bar and an
argon balloon system at 0 °C, was added dropwise by using a can-
nula, a solution of 8a (0.6 g, 1.59 mmol) dissolved in anhydrous
THF (1 mL) over a period of 2 min. The reaction mixture was
warmed to r.t. and stirred for 24 h. After completion of reaction,
the suspension was cooled to 0 °C and quenched by dropwise ad-
dition of 1 n NaOH. The mixture was then stirred at r.t. for 2 h.
The whole mass was taken up into CH2Cl2 (25 mL) and washed
with water. The aqueous layer was then partitioned with CH2Cl2
(2ϫ10 mL), and the combined organic layer was shaken with brine
and dried with Na2SO4. The solvent was removed in vacuo to ob-
tain a gummy mass, which, on column chromatography (CH2Cl2/
MeOH, 85:15), afforded 22a as a yellow gummy liquid (0.528 g,
gummy liquid. R = 0.3 (CH Cl /MeOH, 85:15). IR (CHCl ): ν
˜
max
f
2
2
3
= 3018, 2930, 2854, 1713, 1609, 1516, 1464, 1362, 1260, 1217, 1119,
1
1032, 856, 756 cm–1. H NMR (CDCl3, 400 MHz): δ = 9.93 (s, 1
H; CH), 6.60 (s, 1 H; CH), 6.27 (s, 1 H; CH), 4.48 (d, J = 16.81 Hz,
1 H; CH2), 3.90 [m, 4 H; (CH2)2], 3.83 (br. s, 4 H; CH3 and CH),
3.80 (s, 3 H, CH3), 3.60 (t, J = 4.95 Hz, 1 H; CH), 3.35 (dt, J =
3.26, 10.42, 13.30 Hz, 1 H; CH2), 2.81 (five-lines pattern, J = 8.03,
8.28, 5.27, 6.52, Hz, 1 H; CH2), 2.53 (ddd, J = 6.53, 10.79,
17.07 Hz, 1 H; CH2), 1.88 (m, 1 H; CH2), 1.67 (dd, J = 6.53,
14.56 Hz, 1 H; CH2), 1.61 (dd, J = 3.51, 14.55 Hz, 1 H; CH2), 1.37
(s, 3 H; CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 202.2, 148.6,
147.6, 132.2, 124, 109.7, 109.4, 108.2, 64.7, 64.5, 64.4, 61.5, 61.4,
56, 55.9, 51.3, 39.4, 34.76, 24 ppm. MS: m/z = 348.4 [M + H]+.
C19H25NO5 (347.41): calcd. C 65.69, H 7.25, N 4.03; found C
65.50, H 7.10, N 3.91.
90%). R = 0.3 (CH Cl /MeOH, 80:20). IR (CHCl ): ν = 3449,
˜
max
f
2
2
3
Oxomaritidine (1e) from 23a: To a solution of 23a (0.020 g,
0.06 mmol) in acetone (0.18 mL), pTSA (0.011 g, 0.06 mmol) was
added at r.t., and the reaction mixture was stirred for 3 h. Progress
of the reaction was monitored by TLC. On completion of the reac-
tion, the solvent was evaporated under vacuum and the residue was
dissolved in CH2Cl2 (25 mL) and washed with saturated NaHCO3
(2ϫ10 mL), brine (2ϫ5 mL), dried with Na2SO4 and concentrated
under vacuum to obtain a crude mass, which was used in the next
step without any purification. To a stirred solution of the crude
reaction mixture of δ-keto aldehyde (0.014 g, 0.05 mmol) in EtOH
(2 mL) at r.t. was added solid NaOH (0.011 g, 0.28 mmol) and the
resulting mixture was stirred for 20 h. The reaction mixture was
concentrated and the residue was dissolved in CH2Cl2 (20 mL),
washed with water (5 mL), brine (2ϫ5 mL), dried with anhydrous
Na2SO4, filtered and concentrated. Purification of the residue by
flash column chromatography (CH2Cl2/MeOH, 95:5) afforded 1e
as a white powder (0.011 g, 65% over two steps). Rf = 0.4 (CH2Cl2/
3018, 2959, 2937, 2854, 2343, 2359, 1610, 1516, 1466, 1260, 1215,
1
1045, 854, 754 cm–1. H NMR (CDCl3, 500 MHz): δ = 6.92 (s, 1
H; CH), 6.54 (s, 1 H; CH), 4.64 (d, J = 16.23 Hz, 1 H; CH2), 4.36
(d, J = 13.20 Hz, 1 H; CH2), 4.11 (d, J = 16.50 Hz, 1 H; CH2),
4.04–3.99 [m, 4 H; (CH2)2], 3.90 (d, J = 13.20 Hz, 1 H; CH2), 3.89
(s, 3 H; CH3), 3.82 (s, 3 H; CH3), 3.67 (br. t, J = 4.95, 15.13,
10.18 Hz, 1 H; CH), 3.61 (t, J = 4.24 Hz, 1 H; CH2), 3.06 (five-
lines pattern, J = 7.98, 14. 85 Hz, 1 H; CH2), 2.18 (m, 2 H; CH2),
1.91 (m, 1 H; CH2), 1.85 (m, 1 H; CH2), 1.43 (s, 3 H; CH3) ppm.
13C NMR (CDCl3, 100 MHz): δ = 148.4, 147.4, 133.8, 121.7, 109.5,
109.4, 107.4, 64.8, 64.5, 64.4, 60.7, 60.3, 56.1, 56, 51.6, 51.2, 37,
36.6, 24 ppm. MS: m/z = 350.3[M + H]+. C19H27NO5 (349.42):
calcd. C 65.31, H 7.79, N 4.01; found C 65.20, H 7.60, N 3.90.
DIBAL-H Mediated Reduction of 8a to 21: The cycloadduct 8a
(0.050 g, 0.132 mmol) was taken in a 10 mL two-necked round-bot-
tomed flask charged with argon. Anhydrous CH2Cl2 (0.4 mL) was
746
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 740–750

Synthesis of (Ϯ)-Maritidine and (Ϯ)-Crinine Alkaloids
MeOH, 90:10). IR (CHCl ): ν = 2961, 2925, 1682, 1609, 1515, The resultant pasty mass was taken in EtOAc (150 mL) and washed
˜
3
max
1261, 1220, 1134, 1038 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
7.70 (d, J = 10.17 Hz, 1 H; CH), 6.90 (s, 1 H; CH), 6.55 (s, 1 H;
CH), 6.12 (d, J = 10.18 Hz, 1 H; CH), 4.43 (d, J = 16.78 Hz, 1 H;
CH2), 3.90 (s, 3 H; CH3), 3.86 (d, J = 16.90 Hz, 1 H; CH2), 3.83
(s, 3 H; CH3), 3.67 (dd, J = 5.77, 12.93 Hz, 1 H; CH), 3.58 (ddd,
J = 3.85, 10.73, 13.76 Hz, 1 H; CH2), 3.03 (ddd, J = 6.5, 9.0,
13.14 Hz, 1 H; CH2), 2.71 (dd, J = 5.50, 16.78 Hz, 1 H; CH2), 2.49
(dd, J = 13.21, 16.78 Hz, 1 H; CH2), 2.40 (ddd, J = 3.85, 9.08,
12.65 Hz, 1 H; CH2), 2.17 (ddd, J = 6.43, 10.58, 12.24 Hz, 1 H;
CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 197.4, 148.8, 148.2,
with H2O (2ϫ50 mL), brine (2ϫ40 mL), dried with Na2SO4, and
concentrated under vacuum to obtain a red-brown mass, which was
purified by column chromatography (PE/ethyl acetate, 97:3) to ob-
tain 11b as a pale-yellow oil (6.44 g, 65%). Rf = 0.5 (PE/EtOAc,
90:10). IR (CHCl ): ν
= 3015, 2953, 1683, 1503, 1474, 1247,
˜
3
max
1040, 935, 837, 757, 667 cm–1. 1H NMR (CDCl3, 200 MHz): δ =
7.25 [s, 2 H; (CH)2], 6.01 (ABq, J = 1.39, 5.06 Hz, 2 H; CH2), 3.96–
3.88 [m, 3 H; (CH2)2], 3.83 [dd, J = 3.66, 9.34 Hz, 1 H; (CH2)2],
3.59 (d, J = 15.66 Hz, 1 H; CH2), 3.42 (d, J = 15.66 Hz, 1 H; CH2),
2.41 (dd, J = 3.80, 7.20 Hz, 1 H; CH), 2.24 (d, J = 14.66 Hz, 1 H;
147.9, 134.2, 129, 124.1, 110.1, 105.4, 68.7, 61.1, 56.2, 55.9, 53.8, CH2), 2.23 (dd, J = 3.90, 14.78 Hz, 1 H; CH2), 1.96 (d, J =
44.5, 44.3, 39.6 ppm. MS: m/z = 286.5 [M + H]+, 308.6 [M +
14.65 Hz, 1 H; CH2), 1.89 (dd, J = 7.20, 14.78 Hz, 1 H; CH2), 1.36
(s, 3 H; CH3), 0.16 [s, 9 H; (CH3)3], 0.09 [s, 9 H; (CH3)3] ppm. 13C
NMR (CDCl3, 50 MHz): δ = 148.3, 146.8, 135.9, 118, 110.1, 109.8,
101.3, 86.5, 64.3, 64.2, 64.1, 49.4, 44.3, 33.9, 24.3, –0.41, –0.95 ppm.
MS: m/z = 550.23 [M + H]+.
Na]+, 324.6 [M + K]+.
Maritidine (1a) from Oxomaritidine (1e):[39a] To a solution of 1e
(0.066 g; 0.02 mmol) in anhydrous MeOH (0.7 mL) was added
NaBH4 (0.016 g, 0.05 mmol) and CeCl3·7H2O (0.172 g, 0.05 mmol)
at r.t. After stirring for 45 min at the same temperature, the reaction
mixture was filtered through Celite (elution with MeOH) and the
solvents evaporated. The residue was extracted with CHCl3
(2ϫ5 mL) and the combined organic layers were washed with
aqueous saturated NaHCO3, dried with Na2SO4, evaporated and
used directly for the further synthesis of maritidine. To a solution
of the crude reaction mixture of epi-maritidine 1c (0.066 g,
0.02 mmol) in anhydrous CH2Cl2 (0.5 mL), was added MsCl
(12 μL, 0.11 mmol) and Et3N (15 μL, 0.11 mmol) at r.t. After stir-
ring the reaction mixture for 1 h at r.t., the solvent was removed
under reduced pressure and the residue was dissolved in DMF
(0.5 mL) and transferred by using a syringe to a flask containing
CsOAc (0.063 g, 0.33 mmol). The resulting greenish suspension was
stirred at r.t. for 40 h then filtered (elution with EtOAc). The com-
bined filtrates were dissolved in 1 n HCl and the aqueous solution
was washed with Et2O (2ϫ5 mL). The aqueous phase was basified
with saturated K2CO3 to pH 12 and then extracted with CH2Cl2
(2ϫ10 mL). The combined organic layers were washed with water
(2ϫ5 mL), brine (5 mL), and dried using Na2SO4. Filtration, fol-
lowed by solvent evaporation under reduced pressure gave the
crude allylic acetate, which was immediately dissolved in anhydrous
MeOH (0.5 mL) containing powdered K2CO3 (0.026 g,
0.19 mmol). After stirring the reaction mixture for 2 h at r.t., the
solvent was removed in vacuo. The residue was dissolved in CH2Cl2
(20 mL) and washed with saturated NaHCO3 (5 mL). The com-
bined organic layers were washed with water, brine, dried with an-
hydrous Na2SO4 and concentrated. Preparative thin layer
chromatography of the reaction mixture (CH2Cl2/MeOH/Et3N,
9:1:1) yielded 1a (0.03 g, 45% over 4 steps) as a white powder. Rf
Methyl 2-[6-({[2-(2-Methyl-1,3-dioxolan-2-yl)-1-(trimethylsilyl)-
ethyl]-[(trimethylsilyl)methyl]amino}methyl)benzo[d][1,3]dioxol-5-
yl]acrylate (10b): A 100 mL two-necked round-bottomed flask was
charged with LiCl (0.93 g, 21.85 mmol) and flame-dried under high
vacuum. Upon cooling, [Pd(PPh3)4] (0.42 g, 0.36 mmol) and CuCl
(1.80 g, 18.21 mmol) were added and the mixture was degassed (3–
4 times) under high vacuum with an argon purge. Anhydrous
DMSO (26 mL) was introduced with concomitant stirring, fol-
lowed by sequential addition of 11b (2 g, 3.64 mmol) and vinyl
stannane compound 12 (1.639 g, 4.37 mmol), both diluted with
DMSO (1 mL). The resulting mixture was rigorously degassed (4
times) by freeze–thaw cycles (–78 to 25 °C, Ar). The reaction mix-
ture was stirred at r.t. for 1 h then heated at 60 °C for 2 h. Follow-
ing completion of the coupling (reaction monitored by TLC), the
reaction mixture was cooled, diluted with Et2O (70 mL), and
washed with a mixture of brine (2 ϫ 40 mL) and 5 % aqueous
NH4OH (100 mL). The aqueous layer was further extracted with
ethyl acetate (2ϫ100 mL), and the combined organic layers were
washed with water (2 ϫ 100 mL), brine (2 ϫ50 mL), dried with
Na2SO4, and concentrated under reduced pressure. The reddish-
brown residue was purified by column chromatography (PE/ethyl
acetate, 90:10) to yield 10b (1.44 g, 73%) as a yellow viscous liquid.
R = 0.3 (PE/EtOAc, 80:20). IR (CHCl ): νmax = 2951, 1723, 1679,
˜
f
3
1622, 1503, 1480, 1375, 1247, 1105, 1041, 938, 837, 752, 667 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 7.25 (s, 1 H; CH), 6.59 (s, 1 H;
CH), 6.47 (d, J = 1.50 Hz, 1 H; CH), 5.96 (ABq, J = 10.54 Hz, 2
H; CH2), 5.64 (d, J = 1.75 Hz, 1 H; CH), 3.92–3.84 [m, 4 H;
(CH2)2], 3.73 (s, 3 H; CH3), 3.34 (d, J = 14.80 Hz, 1 H; CH2), 3.30
(d, J = 14.80 Hz, 1 H; CH2), 2.37 (dd, J = 4.02, 7.53 Hz, 1 H; CH),
2.11 (d, J = 14.81 Hz, 1 H; CH2), 2.03 (dd, J = 4.02, 14.56 Hz, 1
H; CH2), 1.84 (d, J = 14.56 Hz, 1 H; CH2), 1.72 (dd, J = 7.52,
14.56 Hz, 1 H; CH2), 1.26 (s, 3 H; CH3), 0.08 [s, 9 H; (CH3)3], 0.03
[s, 9 H; (CH3)3] ppm. 13C NMR (CDCl3, 100 MHz): δ = 167, 147.6,
145.4, 140.9, 133, 129.2, 128.7, 110, 109.6, 108.6, 100.9, 64.2, 64,
56.2, 52.2, 49.1, 43.8, 33.7, 24.1, –0.3, –0.9 ppm. HRMS (EI): calcd.
for C25H41NO6Si2: 507.2472; found 507.2466.
= 0.4 (CH Cl /MeOH/Et N, 90:10:10). IR (CHCl ): ν = 3406,
˜
max
2
2
3
3
3019, 2956, 2925, 2853, 1610, 1514, 1464, 1311, 1262, 1133, 1092,
1039 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 6.85 (s, 1 H; CH),
6.65 (d, J = 9.9 Hz, 1 H; CH), 6.52 (s, 1 H; CH), 5.99 (dd, J = 9.8,
5 Hz, 1 H; CH), 4.46 (d, J = 16.3 Hz, 1 H; CH2), 4.36 (m, 1 H;
CH), 3.88 (s, 3 H; CH3), 3.83 (d, J = 16.5 Hz, 1 H; CH2), 3.82 (s,
3 H; CH3), 3.5–3.40 (m, 2 H; H of CH and H of CH2), 2.93 (m, 1
H; CH2), 2.21 (m, 1 H; CH2), 2.06 (m, 1 H; CH2), 1.96 (m, 1 H;
CH2), 1.77 (m, 1 H) ppm. MS: m/z = 288 [M + H]+.
Synthesis of 8b from 10b: A solution of 10b (1.5 g, 2.957 mmol) in
N-{(6-Iodobenzo[d][1,3]dioxol-5-yl)methyl}-2-(2-methyl-1,3-di-
anhydrous CH2Cl2 (20 mL) was introduced dropwise over a period
oxolan-2-yl)-1-(trimethylsilyl)-N-[(trimethylsilyl)methyl]ethanamine of 1 h into an argon-flushed 500 mL two-necked flask containing
(11b): To a stirring solution of 14b (7 g, 18.048 mmol) in anhydrous
CH3CN (54 mL), K2CO3 (12.47 g, 90.24 mmol) and the bis-
silylated (alkylamino)alkyl-substituted ketal 13 (5.189 g,
18.048 mmol) were added at r.t. The resultant suspension was
heated to reflux for 8 h. On completion of the reaction, the mixture
was cooled, filtered, and the solvent was evaporated under vacuum.
flame-dried AgF (1.876 g, 14.78 mmol) in anhydrous CH2Cl2
(200 mL). The color of the reaction mixture gradually turned to
dark-brown with concomitant deposition of silver on the inner sur-
face of the flask in the form of a mirror. The progress of the reac-
tion was monitored periodically by TLC. After completion, the re-
action mixture was filtered through a small plug of basic alumina
Eur. J. Org. Chem. 2011, 740–750
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
747

G. Pandey et al.
FULL PAPER
(eluent MeOH) and the solvent was evaporated to obtain a crude
brown residue, which was purified by silica gel chromatography
(s, 1 H; CH), 5.91 (s, 2 H; CH2), 4.46 (d, J = 17.06 Hz, 1 H; CH2),
3.95–3.87 [m, 4 H; (CH2)2], 3.83 (d, J = 16.81 Hz, 1 H; CH2), 3.59
(PE/ethyl acetate, 45:55) to obtain 8b (0.587 g, 56 %) as yellow (br. t, J = 5.27 Hz, 1 H; CH), 3.38 (ddd, J = 3.52, 10.80, 13.56 Hz,
gummy liquid. R = 0.3 (PE/EtOAc, 10:90). IR (CHCl ): ν =
˜
max
2956, 1730, 1671, 1504, 1483, 1437, 1246, 1119, 1039, 935, 753,
1 H; CH2), 2.83 (five-lines pattern, J = 8.04, 14.81 Hz, 1 H; CH2),
2.54 (ddd, J = 6.52, 10.54, 12.29 Hz, 1 H; CH2), 1.87 (seven-lines
f
3
722 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 6.46 (s, 1 H; CH), 6.29 pattern, J = 3.27, 8.79, 12.30 Hz, 1 H; CH2), 1.74 (dd, J = 6.53,
(s, 1 H; CH), 5.87 (ABq, J = 6.12 Hz, 2 H; CH2), 4.36 (d, J = 14.81 Hz, 1 H; CH2), 1.62 (dd, J = 4.02, 14.81 Hz, 1 H; CH2), 1.37
16.87 Hz, 1 H; CH2), 3.97–3.91 [m, 4 H; (CH2)2], 3.89–3.85 (m, 1 (s, 3 H; CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 201.4, 147.1,
H; CH2), 3.77 (s, 3 H; CH3), 3.54 (br. d, J = 8.80 Hz, 1 H; CH),
146.4, 133, 125, 109.2, 107.1, 105.4, 101, 64.59, 64.56, 64.4, 61.7,
3.35 (m, 1 H; CH2), 2.76 (m, 1 H; CH2), 2.48 (m, 1 H; CH2), 2.11 61.5, 51.3, 39.1, 34.7, 24 ppm. HRMS (EI): calcd. for C18H21NO5:
(m, 1 H; CH2), 1.66 (dd, J = 9.78, 14.43 Hz, 1 H; CH2), 1.55 (dd, 331.1420; found 331.1403.
J = 2.20, 14.42 Hz, 1 H; CH2), 1.42 (s, 3 H; CH3) ppm. 13C NMR
Synthesis of Oxo-crinine (1f) from 23b: To a solution of 19b
(CDCl3, 125 MHz): δ = 174.1, 146.7, 146.1, 135.2, 124.8, 109.5,
(0.020 g, 0.06 mmol) in acetone (0.18 mL), pTSA (0.023 g,
106.3, 105.1, 100.9, 66.2, 64.6, 64.3, 61.6, 57.8, 52.0, 50.8, 38.2,
0.12 mmol) was added at r.t., and the reaction mixture was stirred
38.0, 23.8 ppm. HRMS (EI): calcd. for C19H23NO6: 361.1525;
for 3 h. Progress of the reaction was monitored by TLC. On com-
pletion of reaction, the solvent was evaporated under vacuum and
found 361.1552.
Reduction of 8b to 22b: To a suspension of LAH (0.126 g,
3.322 mmol) and anhydrous THF (9 mL) in a 25 mL two-necked
round-bottomed flask equipped with magnetic stirring bar and an
argon balloon system at 0 °C, was added dropwise by using a can-
nula, a solution of 8b (0.6 g, 1.661 mmol) dissolved in anhydrous
THF (1 mL) over a period of 2 min. The reaction mixture was
warmed to r.t. and stirred for 24 h. After completion of the reac-
tion, the suspension was cooled to 0 °C and quenched by dropwise
addition of 1 n NaOH, then stirred at r.t. for 2 h. The whole mass
was dissolved in CH2Cl2 (25 mL) and washed with water. The
aqueous layer was then partitioned with CH2Cl2 (2ϫ25 mL), and
the combined organic layer was shaken with brine and dried with
Na2SO4. The solvent was removed in vacuo to obtain a gummy
mass, which was purified by column chromatography (CH2Cl2/
MeOH, 85:15) to afford 22b as a yellow gummy liquid (0.5 g, 90%).
the residue was dissolved in CH2Cl2 (25 mL) and washed with satu-
rated NaHCO3 (2ϫ10 mL), brine (2ϫ5 mL), dried with Na2SO4,
and concentrated under vacuum to obtain a crude mass, which was
used in the next step without any purification. To a stirred solution
of the crude reaction mixture of δ keto aldehyde (0.014 g,
0.05 mmol) in EtOH (2.1 mL) at r.t. was added solid NaOH
(0.012 g, 0.292 mmol) and the resulting mixture was stirred for
20 h. The reaction mixture was concentrated and the residue was
dissolved in CH2Cl2 (20 mL), washed with water (5 mL), brine
(2ϫ5 mL), dried with anhydrous Na2SO4, filtered, and concen-
trated. Purification of the residue by flash column chromatography
(CH2Cl2/MeOH, 95:5) afforded 1f as a white powder (0.011 g, 65%
over two steps). R = 0.5 (CH Cl /MeOH, 85:15). IR (CHCl ): ν
˜
max
f
2
2
3
= 3014, 2926, 1708, 1681, 1504, 1483, 1398, 1315, 1247, 1159, 1109,
1039, 1001, 935, 854, 754, 667 cm–1. 1H NMR (CDCl3, 500 MHz):
δ = 7.61 (d, J = 10.37 Hz, 1 H; CH), 6.90 (s, 1 H; CH), 6.51 (s, 1
H; CH), 6.09 (d, J = 10.4 Hz, 1 H; CH), 5.92 (ABq, 2 H; CH2),
R = 0.3 (CH Cl /MeOH, 80:20). IR (CHCl ): ν = 3455 (br),
˜
max
f
2
2
3
3016, 2957, 1622, 1505, 1480, 1378, 1238, 1143, 1041, 939, 857,
667 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 6.90 (s, 1 H; CH), 6.45 4.41 (d, J = 16.79 Hz, 1 H; CH2), 3.81 (d, J = 16.79 Hz, 1 H; CH2),
(s, 1 H; CH), 5.88 (ABq, J = 0.91, 15.56 Hz, 2 H; CH2), 4.43 (d, J 3.64 (dd, J = 5.8, 13.12 Hz, 1 H; CH), 3.54 (ddd, J = 3.97, 10.38,
= 16.78 Hz, 1 H; CH2), 4.30 (d, J = 13.13 Hz, 1 H; CH2), 3.97 [s,
13.74 Hz, 1 H; CH2), 3.00 (ddd, J = 6.10, 8.85, 14.65 Hz, 1 H;
4 H; (CH2)2], 3.86 (d, J = 13.13 Hz, 1 H; CH2), 3.81 (d, J = CH2), 2.70 (dd, J = 5.80, 16.79 Hz, 1 H; CH2), 2.47 (dd, J = 13.13,
16.78 Hz, 1 H; CH2), 3.34 (t, J = 4.27 Hz, 1 H; CH), 3.28 (br. d, J 16.79 Hz, 1 H; CH2), 2.37 (ddd, J = 3.97, 8.8, 12.82 Hz, 1 H; CH2),
= 3.97, 10.98, 16.48 Hz, 1 H; CH2), 2.88 (br. d, J = 6.72, 8.55,
14.35 Hz, 1 H; CH2), 2.07 (dd, J = 4.89, 14.96 Hz, 1 H; CH2), 1.86
(dd, J = 3.97, 14.96 Hz, 1 H; CH2), 1.79 (ddd, J = 3.97, 8.85,
12.51 Hz, 1 H; CH2), 1.67 (ddd, J = 6.24, 10.65, 12.32 Hz, 1 H;
CH2), 1.39 (s, 3 H, CH3) ppm. 13C NMR (CDCl3, 125 MHz): δ =
146.5, 146.1, 136.5, 126.1, 109.9, 106.4, 104.1, 100.7, 64.4, 64.3,
63.5, 61.46, 61.44, 51.4, 50.7, 38.4, 37.9, 23.4 ppm. HRMS (EI):
calcd. for C18H23NO5: 333.1576; found 333.1556.
2.17 (ddd, J = 6.10, 10.38, 12.20 Hz, 1 H; CH2) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 198, 149.4, 146.5, 146.3, 135.9, 128.8,
126.2, 107.2, 102.5, 101, 68.8, 61.7, 54, 44.76, 44.7, 40 ppm. HRMS
(EI): calcd. for C16H15NO3: 269.1052; found 269.1073.
Synthesis of epi-Crinine (1d) from 1f: To a solution of 1f (0.010 g,
0.037 mmol) in anhydrous MeOH (1 mL) was added NaBH4
(0.026 g, 0.074 mmol) and CeCl3·7H2O (0.028 g, 0.074 mmol) at r.t.
After stirring for 45 min at same temperature, the reaction mixture
was filtered through Celite (elution with MeOH) and the solvents
evaporated. The residue was extracted with CHCl3 (2ϫ25 mL) and
the combined organic layers were washed with aqueous saturated
NaHCO3, dried with Na2SO4 and the solvents evaporated in vacuo
to obtain a gummy mass, which was purified by column
chromatography (CH2Cl2/MeOH, 85:15) to afford 1d as a yellow
gummy liquid (9 mg, 90%). Rf = 0.3 (CH2Cl2/MeOH, 80:20). IR
Swern Oxidation of 22b to 23b: To a mixture of DMSO (0.21 mL,
3 mmol) in CH2Cl2 (3 mL), oxalyl chloride (0.25 mL, 3 mmol) was
added dropwise at –78 °C, and the resulting mixture was stirred
for 15 min. A solution of alcohol 22b (0.5 g, 1.5 mmol) in CH2Cl2
(1.5 mL) was added dropwise to the reaction flask at –78 °C. The
mixture was stirred for 1 h, triethylamine (1.04 mL, 7.5 mmol) was
added dropwise, and the resultant mixture was gradually warmed
to r.t. over 1 h by removing the cooling bath and the mixture was
stirred for another 1 h. The reaction mixture was quenched with
water (5 mL) and extracted with CH2Cl2 (2ϫ25 mL), and the com-
bined organic layer was washed with brine, dried with Na2SO4,
filtered, and concentrated under vacuum. Purification of the resi-
due by silica gel column chromatography (CH2Cl2/MeOH, 94:6)
afforded the aldehyde 23b (0.447 g, 90%) as a gummy liquid. Rf =
(CHCl ): ν
= 3142 (br), 3018, 2926, 1506, 1483, 1365, 1317,
˜
3
max
1232, 1091, 1039, 1001, 935, 862, 754, 667 cm–1. 1H NMR (CDCl3,
500 MHz): δ = 6.80 (s, 1 H; CH), 6.48 (s, 1 H; CH), 6.39 (dd, J =
2.13, 10.37 Hz, 1 H; CH), 5.89 (ABq, 2 H; CH2), 5.79 (d, J =
10.37 Hz, 1 H; CH), 4.45 (d, J = 16.48 Hz, 1 H; CH2), 4.4 (m, 1
H; CH), 3.83 (d, J = 16.78 Hz, 1 H; CH2), 3.50 (ddd, J = 4.23,
10.30, 13.62 Hz, 1 H: CH2), 3.29 (dd, J = 3.66, 13.42 Hz, 1 H;
0.4 (CH Cl /MeOH, 90:10). IR (CHCl ): ν = 2927, 1713, 1672, CH2), 2.95 (ddd, J = 6.10, 9.15, 15.45 Hz, 1 H; CH2), 2.25–2.08
˜
max
2
2
3
1504, 1484, 1379, 1239, 1091, 1039, 936, 857, 755 cm–1. H NMR
(m, 3 H; CH2 and H of CH), 1.64 (four-lines pattern, J = 11.90 Hz,
1
(CDCl3, 400 MHz): δ = 9.86 (s, 1 H; CH), 6.56 (s, 1 H; CH), 6.30
1 H; CH2) ppm. 13C NMR (CDCl3, 125 MHz): δ = 146.3, 145.9,
748
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 740–750

Synthesis of (Ϯ)-Maritidine and (Ϯ)-Crinine Alkaloids
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as a white powder. Rf = 0.4 (CH2Cl2/MeOH/Et3N, 90:10:10). IR
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(CHCl ): ν
= 3325 (br), 2926, 1504, 1484, 1317, 1234, 1039,
˜
3
max
757 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 6.78 (s, 1 H; CH), 6.55
(d, J = 10.07 Hz, 1 H; CH), 6.47 (s, 1 H; CH), 5.98 (dd, J = 4.88,
10.07 Hz, 1 H; CH), 5.89 (ABq, 2 H; CH2), 4.49 (d, J = 16.48 Hz,
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H; CH2), 1.97–1.94 (m, 2 H; H of CH2 and H of CH2), 1.75 (ddd,
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63.7, 63, 61.8, 53.1, 44.48, 44.42, 32.1 ppm. MS: m/z = 272.2 [M +
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Supporting Information (see also the footnote on the first page of
this article): Copies of the 1H and 13C NMR spectra for com-
pounds 11a, 10a, 8a, 22a, 21, 23a, 1e, 1a, 11b, 10b, 8b, 22b, 23b, 1f,
1d, 1b and a Table for comparison of NMR spectroscopic data for
compounds 1a and 1b with the literature.
Acknowledgments
The authors are thankful to the Department of Science and Tech-
nology (DST), New-Delhi for funding this research program.
N. R. G. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a Research Fellowship.
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Published Online: December 13, 2010
750
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 740–750