Syntheses of strychnine, norfluorocurarine, dehydrodesacetylretuline, and valparicine enabled by intramolecular cycloadditions of Zincke aldehydes

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Syntheses of Strychnine, Norfluorocurarine,

Dehydrodesacetylretuline, and Valparicine Enabled by

Intramolecular Cycloadditions of Zincke Aldehydes

David B. C. Martin, Lucas Q. Nguyen, and Christopher D. Vanderwal*

1102 Natural Sciences II, Department of Chemistry, University of California, Irvine, California, 92697-2025

S

* Supporting Information

ABSTRACT: A full account of the development of the base-

mediated intramolecular Diels−Alder cycloadditions of trypt-

amine-derived Zincke aldehydes is described. This important

complexity-generating transformation provides the tetracyclic

core of many indole monoterpene alkaloids in only three steps

from commercially available starting materials and played a key

role in short syntheses of norfluorocurarine (five steps),

dehydrodesacetylretuline (six steps), valparicine (seven steps), and strychnine (six steps). Reasonable mechanistic possibilities for

this reaction, a surprisingly facile dimerization of the products, and an unexpected cycloreversion to regenerate Zincke aldehydes

under specific conditions are also discussed.

in the toolbox of the classical organic chemist (e.g., Hofmann

elimination, Emde degradation, von Braun reaction, Polonovski

reaction).³⁻⁵The similarities (and differences) among

members of the Strychnos and related alkaloid classes

INTRODUCTION

■

The current state-of-the-art of organic chemistry owes much to

the study of alkaloids, and the Strychnos family is certainly

exemplary. The Strychnos alkaloids (Figure 1) were the subject

́

(Aspidosperma, Iboga, Corynanthe) would lead to biogenetic

hypotheses that could be experimentally probed in vivo or in

the chemistry laboratory.⁶Since the 1940s, the intricate

architectures of these alkaloids have challenged chemists to

develop new methods and tactics to achieve ever more efficient,

stereocontrolled syntheses.^7,8To this day, they remain a testing

ground for strategies in alkaloid synthesis.

The most famous and recognizable member of this family,

strychnine (1, Figure 2), is believed to be the first indole alkaloid

ever isolated in pure form, as reported by Pelletier and Caventou

in 1818.¹As suggested above, its elemental composition would be

determined by Regnault a mere 20 years later,²but the correct

structure would not be proposed until 1946 and confirmed in

1948, after a “decades-long chemical degradative assault”.^3,4

Various acid-, base-, and oxidation-induced fragmentations and

rearrangements of the strychnine skeleton were the hallmarks

of this period. The field of alkaloid synthesis took a giant leap

forward with Woodward’s landmark synthesis that was com-

pleted in 1954.^7aThis group took advantage of many lessons

learned from degradation studies in the planning and execution

of this synthesis. Woodward was equally inspired by his early

thoughts on the biogenesis of the Strychnos alkaloids, incor-

porating elements of his proposal into the synthesis.⁹Beginning

in the 1990s, a renaissance of interest in strychnine led to the

completion of a further 17 syntheses.⁷Without exception, these

syntheses have been creative and instructive, often relying on

new technologies that have arisen since the time of Woodward’s

Figure 1. Representative Strychnos alkaloids.

of intense investigation at all stages in the development of

organic chemistry, from the early 1800s to modern day. The

ready availability of certain Strychnos alkaloids in pure form

(e.g., strychnine) allowed their elemental composition to be

determined by the 1830s.^1,2The determination of their

structure took a century of extensive degradation studies and

led to the widespread use and popularization of many reactions

Received: September 29, 2011

Published: December 14, 2011

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INTRAMOLECULAR ZINCKE ALDEHYDE

CYCLOADDITIONS

■

There are two major challenges in the proposed intramolecular

Diels−Alder reaction: first, indoles are stable aromatic

compounds whose C2−C3 π-systems are notoriously poor

dienophilic partners for [4 + 2] cycloadditions. Reported

intermolecular examples generally require triplet photosensiti-

zation,¹⁶stoichiometric generation of an indole radical cation,¹⁷

deprotonation to give the indole anion,¹⁸or feature highly

reactive dienes such as masked o-benzoquinones.¹⁹At least in

some cases, these reactions proceed in a stepwise fashion (with

radical and/or charged intermediates) rather than via concerted

pathways. Intramolecular formal cycloadditions of indoles are

also known, including an interesting Lewis acid-catalyzed

reaction reported by Rosenmund and co-workers that bears a

close resemblance to our desired reaction (eq 1) but makes use

Figure 2. Biogenetic numbering system shown here is used

throughout the text (C22 has been biochemically excised).¹⁰

achievement. In this context, strychnine continues to serve as a

benchmark target against which organic chemists may measure the

state-of-the-art of natural product synthesis strategy.

BACKGROUND: ZINCKE ALDEHYDES AS

VERSATILE BUILDING BLOCKS

■

A major focus of our research group is the use of Zincke

aldehydes (5-amino-2,4-pentadienals) as versatile intermediates

for organic synthesis.¹¹Zincke aldehydes are the products of

the century-old Zincke procedure for ring-opening of

pyridinium salts with secondary amines (Figure 3).¹²Building

of particularly harsh conditions.²⁰In previous approaches to

strychnine, the Bodwell and Padwa groups have demonstrated

Diels−Alder reactions of N-alkyl and N-acyl indoles with a

tethered pyridazine and amidofuran, respectively (Scheme 2,

disconnection a).^7k,nBoth of these reactions occur only at

elevated temperature (150−215 °C) and are likely driven

forward by a subsequent irreversible fragmentation of the

bicyclic [4 + 2] product.²¹Although not directly related to the

cycloaddition that we were planning, two other cycloaddition

approaches to strychnine should also be highlighted. Rawal

reported the first intramolecular Diels−Alder reaction that

constructed both the indoline B-ring and the E-ring (Scheme 2,

disconnection b), allowing for the controlled formation of three

contiguous stereocenters.^7eFinally, the recent synthesis reported

by MacMillan and co-workers established the viability of

incorporating a 2-vinylindole as the 4π component in an elegant

application of their enantioselective iminium catalysis (Scheme 2,

disconnection c).^7rNotably, three of the four Diels−Alder

disconnections that allow direct construction of the C7 quaternary

center have been successfully employed in the synthesis of

strychnine.

The second challenge to our proposed reaction is that Zincke

aldehydes are known to be poorly reactive dienes in

cycloadditions.²²To the best of our knowledge, there are no

reported examples of successful Diels−Alder reactions with

Zincke aldehydes serving as the 4π component, almost certainly

owing to their high donor−acceptor stabilization.²³

Clearly, the problems associated with both components of

our prospective cycloaddition substrates caused some initial

trepidation. Nonetheless, given the intramolecular setting, the

ease of substrate synthesis, and the ready (albeit unattractive)

possibility of electronic perturbation of the indole fragment, we

Figure 3. Zincke aldehydes: versatile intermediates readily available

from pyridines.

upon a considerable body of literature related to Zincke

aldehydes,¹³we have focused our attention on their application

toward complex molecule synthesis via reactions that lead to a

rapid buildup of molecular complexity.

Early on in our studies, we wondered whether the diene of

the Zincke aldehyde could be leveraged in an intramolecular

Diels−Alder reaction to give complex, polycyclic products

suitable for alkaloid synthesis. In particular, we were inspired by

the idea that a tryptamine-derived Zincke aldehyde might

undergo an intramolecular Diels−Alder cycloaddition to

furnish the tetracyclic fragment shown in Scheme 1. This

motif constitutes the ABCE ring system of the curan skeleton

́

(13) common to most Corynanthe-Strychnos alkaloids and is

also found in many members of the Aspidosperma and Iboga

families of alkaloids. Isomerization of the initial cycloaddition

product would generate the conjugated enal, which would

enable a well-precedented closure of the D ring to give the fully

elaborated Strychnos skeleton in only a handful of steps.^7e,14By

judicious choice of the N4-substituent and manipulation of the

aldehyde group, we envisioned the synthesis of many alkaloids

of this class by a unified strategy.^7q,15

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Scheme 1. Common Tetracyclic Core Structure of Many Indole Monoterpene Alkaloids in Addition to Strychnine Might Be

Accessed by an Intramolecular Diels−Alder Cycloaddition of a Tryptamine-Derived Zincke Aldehyde

Scheme 2. Diels−Alder Disconnections Used in Syntheses of

Strychnine

Figure 4. Relative ground-state energies of Zincke aldehyde precursor

and potential cycloaddition products. (Values obtained using

Turbomole v6.3, pbe0 functional, def2-TZVP basis set, and 12a was

not restricted to the conformation shown.)

RESULTS AND DISCUSSION

■

Reaction Discovery. Our initial investigations began with

the synthesis of substrate 12b, which is readily available in two

steps from tryptamine on multigram scale in 83% overall yield.

We began with attempts to perform thermal Diels−Alder

reactions in a variety of solvents. At lower temperatures, we

observed no reaction; however, above approximately 150 °C in

aromatic solvents, we observed the formation of a new, isomeric

1

product. By H NMR, the indole resonances were left intact

while the resonances corresponding to the Zincke aldehyde

were replaced with a new set of signals in the alkene region of

the spectrum. The product was Z-α,β,γ,δ-unsaturated amide 21

(Scheme 3). This completely unexpected reaction is quite

general, and has been observed in attempts to initiate thermal

remained optimistic. In addition, we established that the overall

transformation should be thermodynamically favored by

Diels−Alder reactions with other Zincke aldehydes. While

clearly of no use for the synthesis of Strychnos alkaloids, this

comparison of the calculated ground-state energies of the

starting materials and products, despite loss of aromaticity of

the five-membered indole ring and loss of the extensive

conjugation in the Zincke aldehyde (Figure 4).²⁴Satisfied that

this plan was feasible, and particularly inspired by the potential

utility of the prospective cycloaddition, we set out to reduce

this idea to practice.

interesting reaction has been further explored in our group in

terms of scope and mechanism and is being exploited for the

synthesis of other natural products.^11b,d,f

Our investigations continued with a screen of additives. A

variety of Lewis acids and protic acids did not promote the

desired cycloaddition and, in many cases, resulted in indole

degradation or apparent Pictet−Spengler-like reactivity. Nuhant

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Scheme 3. Unexpected Formation of Z-α,β,γ,δ-Unsaturated

Amide 21 under Thermal Conditions

Scheme 5. Selected Results from the Optimization of the

Base-Mediated Cycloaddition Reaction

a

DNP = 2,4-dinitrophenyl, o-DCB = o-dichlorobenzene.

and co-workers have since reported a method for performing

Pictet−Spengler-type reactions of similar Zincke aldehydes

using TFAA, in a reaction that provides complementary access

to tetrahydro-β-carbolines and appears to be applicable to

several Corynanthe

́

natural products.²⁵We also briefly examined

the use of aminium radical catalysis through the use of the

commercially available salt N(4-BrC₆H₄)₃SbF₆.^17,26We antici-

pated that an indole radical cation would engage the Zincke

aldehyde; however, productive reactivity was never observed.

The final strategy that we explored was a base-induced

cycloaddition. We were inspired by the bicyclization of Marko

(22 → 23, Scheme 4) that proceeded in low yield by a single

a

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, NR = no reaction, μW =

microwave irradiation.

́

basic conditions had caused conjugation of the alkene with

the aldehyde. The relative configuration of the product was

assigned by nOe correlations and was found to match that

of the ABCE ring systems of most indole monoterpene

alkaloids. Further optimization was plagued by issues of repro-

ducibility, which were eventually traced back to the purity of

the substrates. While in most cases the Zincke aldehyde could

be obtained in apparently pure form (>95% by ¹H NMR) after

a single chromatographic separation, further purification by

chromatography always led to the separation of various highly

colored byproducts, eventually providing the Zincke aldehyde

as a yellow solid. No byproducts could be isolated in sufficient

quantity or purity to determine their structure. Based on the

steady march of numerous highly colored bands from the

chromatography column, there are apparently many different

highly conjugated molecules formed in trace quantities during

the Zincke pyridinium ring-opening reaction.²⁹Eventually, an

empirical solution to the reproducibility problem was found:

after chromatographic purification (generally 1−2 iterations),

the Zincke aldehyde was treated with activated charcoal in

CH₂Cl₂for 1 h at rt, filtered through Celite, and concentrated.

The resulting yellow solid (or foam) showed much improved

reliability in our bicyclization reaction, and this protocol is now

used whenever highly pure Zincke aldehyde material is needed.

Reaction optimization led to a simple and reliable protocol:

treatment of Zincke aldehyde 12b in THF (0.06 M) with KO-t-

Bu (1 M solution in THF) at 80 °C in a sealed tube routinely

afforded tetracycle 7b in 85% yield.

Scheme 4. Related Anionic Bicyclization Reported by Marko

́

and Co-workers

base-mediated operation or in higher yield via silica-

induced spirocyclization followed by base-mediated Mannich

ring closure.^27,28In our particular case, we anticipated that

deprotonation of the indole should drive the direct formation of

the desired product, because equilibration of the enolate would not

́

be required as it was in Marko’s chemistry. We explored a

variety of organic and inorganic bases, and obtained promising

results with those featuring potassium counterions (Scheme 5).

Exposure of Zincke aldehyde 12b to a stoichiometric amount of

KO-t-Bu in THF at 50 °C for 4 h led to 40% conversion to a

new product isomeric with the starting material. We identified

the product as tetracyclic aldehyde 7b; not surprisingly, the

Mechanistic Discussion. A detailed mechanistic study has

not been undertaken at this time because of the particular

sensitivity of the reaction toward even modest changes in

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Scheme 6. Two Reasonable Mechanistic Possibilities for the Base-Mediated Cycloaddition Reaction and an Experiment

Suggesting the Importance of the Stabilized Dienolate Product

reaction conditions, including solvent, base stoichiometry,

temperature, and concentration. Nonetheless, we put forth

two plausible mechanistic scenarios (Scheme 6): (1) a con-

certed Diels−Alder reaction between a deprotonated indole

and the Zincke aldehyde diene or (2) a stepwise metalloen-

amine Michael addition to the Zincke aldehyde to form a

dienolate, followed by subsequent Mannich cyclization onto the

transient indolenine. In order to achieve proper orbital align-

ment for a concerted Diels−Alder reaction, molecular models

suggest that conjugation must be broken between the N_b-lone

pair and the dienal of the Zincke aldehyde (see s-cis-12), which

could further favor the inverse electron demand Diels−Alder

reaction (in this case, the nitrogen atom would serve only as an

inductively electron-withdrawing group). From this reactive

conformation, only the desired stereochemical outcome, as

shown in 25, is reasonable. It is possible that the thermal

requirements of the reaction reflect the need to break con-

jugation in the donor−acceptor system, which then enables

inverse-electron-demand cycloaddition. In the stepwise mech-

anism, the Zincke aldehyde must still adopt the s-cis

conformation in order to generate the requisite dienolate

geometry (see Z-27); the s-trans conformation would lead to an

intermediate dienolate with an E-configured double bond that

would be unable to undergo the terminal Mannich cyclization.

Similarly, the improper relative configuration of the two new

stereogenic centers in intermediate Z-27 would preclude

Mannich cyclization. If the stepwise mechanism were operative,

then an improperly configured dienolate would presumably

revert back to starting material, eventually funneling to the

observed product, because no partially cyclized intermediates

have been observed to date. In either case, the unconjugated

enal 25 would presumably be formed first, with subsequent

isomerization to the more stable dienolate 26. Importantly,

dienolate 26 is apparently stable under the reaction conditions,

and self-destruction by elimination of either of the two amino

groups is not significant.^20,30A considerable component of the

thermodynamic driving force for the overall cycloaddition

reaction, regardless of mechanism, might be the formation of

the stable dienolate. The intramolecular Diels−Alder reactions

reported by Bodwell and Padwa also result in loss of

aromaticity of the indole ring (as well as a pyridazine or

furan, respectively) and may be driven forward by a subsequent

entropically favored fragmentation.^7k,nA single experiment to

probe the importance of this equilibration was performed:

when the Zincke aldehyde derived from 3-picoline (28) was

exposed to the cycloaddition reaction conditions, no reaction to

form 29 was observed, even under forcing conditions. This

singular data point provides circumstantial evidence for the

importance of the formation of the stable dienolate.

Substrate Scope. Most of the substrates that we have

successfully employed in our bicyclization reaction are shown in

Table 1 (for some substrates that did not perform well in this

reaction, see below). Larger N-substituents such as benzyl,

p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), and

2-silylbutenyl groups were associated with efficient reactions

1

(see 12b,c,d,j: 80−85% yield). In these cases, the H NMR of

the crude reaction mixture typically showed only the desired

product, and in cases with only moderate isolated yields, the

fate of the mass balance is unclear. Yields are typically lower

with smaller N-substituents such as methyl and primary

aliphatic groups. Consistent with this trend, the yield increases

upon transitioning from allylamine-derived Zincke aldehyde to

the larger methallyl and 2-(trimethylsilyl)butenyl substrates

(48%, 56%, and 84%, respectively). Groups much larger than

benzyl (e.g., benzhydryl) could not be investigated because of

the failure of the pyridinium ring-opening reaction. Propargylic

systems were poor substrates, likely owing to base-induced

isomerization to the corresponding allenamines, which could

react further and lead to decomposition. The siloxacycle 12k

was investigated in an early route to strychnine. Using KO-t-Bu

as the base, we observed exclusively protodesilylation of the

starting material. In an effort to circumvent this problem, we

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e

Significant efforts were made to exclude moisture in these

reactions with only minor improvements; therefore, it appears

as though some other process is causing decomposition via loss

of the Zincke aldehyde. We have found empirically that this

undesired product can be minimized by running the reaction at

higher dilution. For example, as the reaction concentration is

reduced from 0.06 to 0.04 M to 0.02 M, the N-allyl product 7g

is obtained in 48%, 54%, and 64% yield, respectively. These

results suggest that some intermolecular process is at play, but

its exact nature is still unknown.

Table 1. Substrate Scope of Base-Mediated Cycloaddition

Synthesis of Norfluorocurarine: Previous Syntheses

and Retrosynthesis. With the success of our new stereo-

selective bicyclization reaction, we turned our attention to the

synthesis of the Strychnos alkaloid norfluorocurarine. This

relatively simple Strychnos alkaloid was first reported in 1961 by

Stauffacher and was subsequently isolated as a racemate.³³

Norfluorocurarine has been previously synthesized by the

groups of Harley-Mason, Bonjoch, and Rawal.³⁴The Rawal

synthesis relied on the formylation of dehydrotubifoline (32,

Scheme 7), which they had synthesized using an intramolecular

Scheme 7. Successful Approach to Norfluorocurarine via

Dehydrotubifoline As Reported by Rawal and Co-workers

a

b

c

d

e

Isolated yield. 0.04 M. 0.02 M. KHMDS used as base. Reaction

conditions: 1.05 equiv KOt-Bu, 0.06 M in THF (unless otherwise

noted), 80 °C in a sealed tube for 2−4 h. PMB = p-methoxybenzyl;

DMB = 2,4-dimethoxybenzyl.

used KHMDS, which afforded the cyclized product in only 9%

yield. The use of KHMDS with PMB-bearing substrate 12c also

gave a low yield (31% + 15% recovered SM). As a result,

whenever the substrate was stable to an alkoxide base, KO-t-Bu

was used, and KHMDS was used as a backup when problems

arose.

The reaction is also applicable to homotryptamine-derived

substrates, giving products with a 6-membered piperidine C-

ring, although the reaction efficiency suffers substantially (30 →

31, eq 2). There are only two reports of these C-ring

Heck reaction of 33.^14b,35This Heck reaction was the first

reported example of this strategy for the synthesis of a Strychnos

alkaloid, and this versatile method has subsequently been used for

similar ring closures in the synthesis of strychnine, akuammicine

and many other (indole) alkaloids.^{7e,i−k,o,p,r,30,36−38}In addition

to constructing the bridged D-ring via C15−C20 bond forma-

tion, this stereospecific reaction necessarily provides complete

control of alkene geometry.

We envisioned that an intramolecular Heck reaction of a

vinyl halide (either 35 or 36, eq 3), inspired by the work of

homologated structures in the literature.³¹The straightforward

access to these compounds using our Zincke aldehyde

methodology could prove useful for the production of fully

elaborated C-ring homologues of Strychnos and related

alkaloids.

In cases with smaller N-substituents, a large percentage of the

material is recovered as the secondary amine resulting from

cleavage of the Zincke aldehyde. It is known that heating

Zincke aldehydes with aqueous base results in hydrolysis.³²

Rawal, would serve as the final key step to close the D ring

and directly generate the natural product. As outlined above,

this strategy was expected to efficiently close the D-ring

with complete control of alkene geometry. In addition, this

Heck strategy would generate the vinylogous amide of

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norfluorocurarine directly by transposition of the double bond,

taking full advantage of the functionality in our bicyclization

products.

Zincke aldehyde 12j was similarly prepared in a four-step

sequence from commercially available 1-(trimethylsilyl)-

propyne (Scheme 9).¹⁵Following a known procedure,

hydroalumination of 40 with DIBAL-H, treatment of the

resulting vinylalane with methyllithium, and reaction

of the aluminate with paraformaldehyde afforded allylic alcohol

41.⁴⁰This compound was converted to the corresponding

allylic bromide (via the mesylate) and used to alkylate

tryptamine. Zincke aldehyde 12j was produced from secondary

amine 42 under standard conditions. To our delight, the rather

harsh reaction conditions for anionic bicyclization produced

tetracycle 7j in 84% yield, once again as a single diastereomer.

At this stage, an iododesilylation reaction was required to

provide Heck substrate 36;⁴¹however, a variety of attempts

using standard reaction conditions led to complex reaction

mixtures in which only small quantities of desired vinyl iodide

could be observed. This reaction was primarily complicated by

preferential iodination of the electron-rich aromatic ring. We

were hopeful that an azaphilic Lewis acid could be found that

would sufficiently deactivate the indoline ring, possibly with

chelation to the adjacent aldehyde group, but efforts along

these lines were unfruitful. After dozens of attempts to optimize

this reaction, including variation of solvent, source of I⁺,

additives, and temperature, we could obtain 36 in at most

19% yield after painstaking chromatographic separation

(Scheme 10). To obviate these issues of chemoselectivity, a

three-step protocol involving temporary N-trifluoroacetylation

of the indoline was adopted. The trifluoroacetyl group was

introduced and removed with high efficiency, and proved effective

at deactivating the indoline ring, enabling formation of the

desired iodide 36 in a more reasonable 63% overall yield. In

both iododesilylation reactions, the use of HFIP (1,1,1,3,3,3-

hexafluoroisopropyl alcohol) as cosolvent provided optimal

reactivity and avoided issues of stereochemical infidelity.⁴²

Finally, we were able to explore the key Heck cyclization of

iodide 36. Using conditions reported by Rawal (Jeffery’s

conditions)⁴³for his synthesis of dehydrotubifoline,^14bonly

minute quantities of norfluorocurarine were produced.

Recognizing that the electronic nature of our alkene was

different from that in Rawal’s substrate, we explored a variety of

different conditions, and found the more classical conditions

shown to be optimal. Heck cyclization provided up to a 70%

yield of ( )-norfluorocurarine (3), whose spectral data were in

agreement with those previously reported.^33cThis successful

route proceeds via longest linear sequences of five steps from

First-Generation Synthesis of Norfluorocurarine. The

synthesis of our desired Heck reaction substrate 35 was initially

pursued by deprotection of the benzyl-type cycloadducts 7b−d

(Table 1) that could be prepared efficiently in three steps on

large scale. All attempts at deprotection were unsuccessful (for

a detailed discussion, see below). We therefore sought to

prepare vinyl bromide 35 directly from the corresponding

Zincke aldehyde 39 (Scheme 8). This substrate was prepared

Scheme 8. Synthesis of Vinyl Bromide Substrate 39 and

Failed Anionic Bicyclization

by alkylation of tryptamine with known dibromide 37^14b,39

(readily prepared from crotonaldehyde in three steps), followed

by formation of the Zincke aldehyde. Unfortunately, under the

standard reaction conditions for anionic bicyclization, we were

unable to isolate any of desired tetracyclic product 35. The

single identifiable product isolated was the corresponding

alkyne 12l, presumably formed via base-mediated dehydroha-

logenation.^37aOther products might derive from dehydroha-

logenation to afford an unstable allenamine, which could

decompose further. As a result, we were forced to find a suitable

vinyl halide surrogate, which came in the form of a vinylsilane.

Scheme 9. Synthesis and Cycloaddition of Vinylsilane Substrate

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Scheme 10. First-Generation Synthesis of

Norfluorocurarine

Scheme 11. Strategy To Access Valparicine from Synthetic

Norfluorocurarine

a

of an alkaloid with the Strychnos skeleton already in place.

Certainly, there are many degenerate potential pathways for

interconversion among indole monoterpene alkaloids, and some

Strychnos-type alkaloids have been isolated from species of the

genus Kopsia.⁴⁶Regardless of the true biogenesis of valparicine,

we wished to use our synthetic sample of the Strychnos alkaloid

norfluorocurarine as a key precursor to this bioactive alkaloid.⁴⁷

Initially, we aimed to convert norfluorocurarine to valparicine

by carbonyl reduction to give vinylogous hemiaminal 45,

followed by dehydration (Scheme 11). This reduction proved

difficult, and only starting material or over-reduced products

could be recovered. This outcome almost certainly arises from

the vinylogous amide character of this system; indeed, redox

chemistry in related systems has been reported to be

troublesome.⁴⁸

a

NIS = N-iodosuccinimide, HFIP = 1,1,1,3,3,3-hexafluoroisopropyl

We wondered if a simple change in the order of operations

could be used to circumvent these problems. The aldehyde

group of norfluorocurarine precursor 36 might be reduced to

give allylic alcohol 46 (Scheme 12). A Heck reaction of this

alcohol, TFAA = trifluoroacetic anhydride, PMP = 1,2,2,6,6-

pentamethylpiperidine.

tryptamine or seven steps from 1-(trimethysilyl)propyne using

the poorly efficient direct iodination protocol, and seven or

nine steps, respectively, using the optimal three-step iodina-

tion sequence. Our synthesis demonstrates that the cyclo-

addition of tryptamine-derived Zincke aldehydes not only serves

to efficiently construct the tetracyclic core of many Strychnos

alkaloids, but also directly introduces the α,β-unsaturated

aldehyde at the proper position for subsequent D-ring formation

and at the proper oxidation state to enable a particularly concise

synthesis.

Scheme 12. Possible Outcomes for Heck Reaction of Allylic

Alcohol 46

First-Generation Synthesis of Valparicine. Given the

brevity of our approach to norfluorocurarine, we also aimed to

synthesize the structurally similar alkaloid valparicine (9, Schemes

1 and 11), which was recently isolated from Kopsia arborea by

Kam and co-workers.⁴⁴This alkaloid exhibits pronounced

cytotoxicity toward drug-sensitive and drug-resistant KB cells as

well as Jurkat cells. The promising antitumor activity likely arises

from the presence of the α,β-unsaturated imine motif, which

might serve as a Michael acceptor toward nucleophilic motifs

within its biological target.⁴⁵Valparicine features the curan

skeleton, but the isolation group has suggested that it might

biogenetically derive from pericine via its N-oxide, both of

which were also isolated from K. arborea. This hypothesis

was strengthened by this group’s conversion of pericine N-oxide

to valparicine via a Potier−Polonovsky reaction.^44aWhile that

proposal seems very likely to be correct, in the absence of further

supporting evidence, it cannot be ruled out that valparicine might

originate by simpler biochemical functional group manipulations

substrate could have two possible outcomes: β-hydride

elimination could take place toward N1 (as was the case for

norfluorocurarine) to give the desired vinylogous hemiaminal

45. Alternatively, β-hydride elimination could occur in the

direction of the hydroxyl group to give, after tautomerization,

aldehyde 48 (18-deshydroxy-Wieland−Gumlich aldehyde

itself a natural product).⁴⁹The latter outcome would be

welcome because incorporation of a C18 hydroxyl group in the

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Scheme 13. Literature Examples of Relevant β-Hydride Elimination Behavior

Heck substrate would allow for the synthesis of the Wieland−

Gumlich aldehyde, a known precursor to strychnine. At the

time, we were aware of some similar systems that had been

reported to give variable selectivity, and could in at least

one case be tuned by reaction conditions (see 49 → 51/52,

Scheme 13).^14,50Both the Rawal and very recent MacMillan

strychnine syntheses take advantage of D-ring Heck cyclizations

in which β-hydride elimination proceeds away from nitrogen

(53 → 54 and 56 → 57).^7e,r

and He via a different route and converted to dehydrodesa-

cetylretuline, also using a Heck reaction.^34cAlthough the

efficiency is not high, the selectivity in this Heck reaction is

notable, and the factors that determine the direction of β-hydride

elimination in this and closely related systems are unclear,

although a combination of steric effects and stereoelectronic

factors (i.e., alignment of C−H and C−Pd bonds, n_N→σ*_C−H

interactions) is likely at play. In any case, treatment of imine

59 with trifluoroacetic acid induced dehydration to yield

valparicine (9). The spectral data of synthetic valparicine were

identical with those reported by Kam and co-workers.⁴⁴

To test our hypothesis, the aldehyde group of 36 was

reduced to give allylic alcohol 46 (Scheme 14). Under a variety

Improved Strategy for Norfluorocurarine and Valpar-

icine. Based on our experience with the synthesis of

norfluorocurarine and valparicine, as well as some of our initial

forays toward the synthesis of strychnine, we identified some

limitations of our bicyclization reaction. A sampling of Zincke

aldehydes that were incompatible with the reaction conditions

is shown in Figure 5. Problematic functional groups include

Scheme 14. Synthesis of Valparicine via

Dehydrodesacetylretuline

Figure 5. Substrates that were unsuccessful in the bicyclization

reaction.

of Heck conditions, no aldehyde products were observed. The

major product isolated was identified as imine 59, a tautomer of

our expected enamine product 45, which is in fact the known

Strychnos alkaloid dehydrodesacetylretuline.⁵¹We later learned

that allylic alcohol 46 had been previously synthesized by Rawal

vinyl halides, free alcohols, alkynes, and some silicon groups.

Given the desire to evaluate a variety of such substrates in D-

ring-closure experiments, we aimed to find a more general

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strategy to access N4-functionalized tetracycles. More specifi-

cally, we wished to identify a protecting group that could be

incorporated into the Zincke aldehyde (see 60, Scheme 15),

Scheme 16. Dimerization of Tetracyclic Substrates and

Analogous Dimerization of Strychnos Alkaloids

a

Scheme 15. Second-Generation Approach Incorporating a

Protecting Group Would Enable Access to Tetracyclic

Alkaloid Cores with Useful Functionality for Subsequent D

Ring Closure

a

DMB = 2,4-dimethoxybenzyl.

carried through the bicyclization reaction, and removed to

reveal tetracycle 62 bearing a secondary amine. This strategy

would enable the incorporation of a variety of side chains by

alkylation chemistry after the cycloaddition reaction with its

attendant harshly basic conditions. Tetracycle 62 could not be

synthesized directly by cycloaddition, owing to the limited

stability of Zincke aldehydes derived from primary amines

substrate 60 (PG = H) would be expected to readily convert to

the corresponding pyridinium salts under the cycloaddition

conditions. In addition, strongly electron-withdrawing groups

(Boc, Ts, Ac, etc.) are precluded because formation of Zincke

aldehydes is only efficient for relatively electron-rich secondary

amines. We therefore began by experimenting with compounds

that we already had on hand.

Our initial efforts to access the desired N-unsubstituted

tetracycle from a variety of N-substituted precursors were not

successful. Instead, we quickly came to appreciate the sensitive

nature of the intermediates we were working with. Removal of

benzyl-type protecting groups under reductive conditions was

precluded by the reactive α,β-unsaturated aldehyde. Oxidative

removal of PMB and the more electron rich DMB groups was

similarly unsuccessful owing to complications from the

electron-rich aromatic ring. Another method for the removal

of the DMB group from amines is by protonolysis with a strong

acid such as TFA in the presence of a sacrificial nucleophile

such as anisole.⁵²Under these conditions, we observed clean

dimerization of our starting material 7d to give 64 containing a

central 8-membered diazocine ring (Scheme 16). This product

arises from the mutual condensation of the indoline and

aldehyde groups of two molecules to afford the dimer as a

single diastereomer.²⁴Our identification of the product was

guided by the knowledge that dimers such as toxiferine I (66)

are themselves natural products, and similar biomimetic

dimerization of Strychnos alkaloids has been reported to occur

under acidic conditions (AcOH, NaOAc, 70 °C). Natural and

semisynthetic analogues of toxiferine I have been explored due

to their allosteric modulation of the muscarinic acetylcholine

receptor.⁵³At this juncture, the structure of 64 has been

tentatively assigned presuming that there is a strong bias for

homodimerization, and calculations indicate a significant

thermodynamic preference for this outcome.^24,54Other

conditions that resulted in this type of dimerization process

in our studies include: AcOH (solvent), 80 °C; BF₃·OEt₂, TiCl₄

or Sc(OTf)₃in CH₂Cl₂, rt; Meldrum’s acid in CDCl₃, CH₃CN

or MeOH, rt.

Another strategy that held some promise was the acylative

dealkylation using reagents such as TFAA⁵⁵or α-chloroethyl

chloroformate (ACE-Cl).⁵⁶Acylation of the indoline took place

quite readily with several cycloadduct substrates (see 7a,b,c,d →

67, Scheme 17), but under the typical conditions required to

induce acylation of the tertiary amine (and subsequent

dealkylation), we observed no further reaction in any case.

After we had abandoned this approach, Andrade and co-workers

reported their synthesis of strychnine which relied on exactly this

reaction, but with the corresponding methyl ester 69 (rather

than our aldehyde).^7oThey found it necessary to heat the amine

in neat ACE-Cl at 135 °C for 48 h to achieve debenzylation.

Subsequent methanolysis at reflux gave the tetracyclic ester 71

bearing the liberated secondary amine in good overall yield.

Given the sensitivity of our α,β-unsaturated aldehyde under a

variety of conditions, as well as the propensity of our target 62 to

decompose above 0 °C (see below), we chose not to revisit this

strategy, especially given the success of the methods that we

investigated next.

Given the failure of the methods described above, we tried

some more exotic solutions to our problem that deserve brief

comment. Two other protecting groups that we explored were

Si- and Se-substituted ethyl groups. It was our hope that the 2-

(trimethylsilyl)ethyl group could be cleaved with fluoride to

reveal the desired NH product with release of ethylene. For the

selenoethyl group, our hope was that the chalcogen atom could

be oxidized to the selenoxide, setting up for a syn elimination

that would provide an enamine that could be subsequently

hydrolyzed.⁵⁷The required substrates could be accessed from

TMSCH₂CH₂Br and PhSeCH₂CHO in three steps each.²⁴Not

surprisingly, when TMS-ethylamine-derived substrate 7e was

treated with different fluoride sources under a variety of

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Scheme 17. Acylative Dealkylation Is Unsuccessful for Our

Aldehyde-Bearing Substrates but Was Successfully Employed

by Andrade and Co-workers on the Corresponding Ester 69

Scheme 18. Early Efforts in Protecting Group Strategy

Proved that Deprotected Tetracycle Was Isolable

The bicyclization of 12g (Scheme 19) was sensitive to concen-

tration, giving the highest yield (64%) at 0.02 M (see above).

Although we observed small amounts of KO-t-Bu-mediated

deallylation in the course of cycloadditions run above 80 °C, it

was more effective to prevent this reaction and maximize the

yield of the product 7g. We were delighted to observe that Pd-

catalyzed deallylation of 7g was effective under very mild con-

ditions (0 °C, <1 h) using N,N′-dimethylbarbituric acid (75) as

the allyl scavenger;⁵⁸however, this deallylation was accom-

panied by a Knoevenagel condensation followed by Michael

addition of a second equivalent of the nucleophile, delivering

76. This undesired process could be easily prevented by

incorporation of an alkyl group on the barbituric acid derivative

to prevent the dehydration step of the Knoevenagel reaction,

and Bn derivative 77 or commercially available 5-methyl

Meldrum’s acid was used for all our subsequent investigations.

Now, for the first time, we were able to isolate tetracycle 62 in

appreciable yield.⁶⁰As alluded to above, the resultant product

was poorly stable. As a consequence, isolated yields of 62 were

not as high as expected, and storage led to degradation;

however, in situ realkylation of the liberated secondary amine

provided an attractive solution to this problem, giving access to

many new substrates of type 63 in good yields (see below for

examples).

conditions, only slight decomposition of the silane was

observed, and the majority of the starting material was left

unchanged. Attempted alkylation (using electrophiles that

would introduce useful side chains onto the nitrogen atom)

to form the quaternary ammonium salt prior to dealkylation, a

strategy that held more promise, also proved unworkable in the

presence of the free indoline. Conversely, when the selenide 7f

was treated with 1 equiv of mCPBA at −78 °C, clean conver-

sion to the selenoxide was observed. This intermediate was

stable and could be observed after aqueous workup. When

heated to 60 °C to initiate syn elimination, followed by aqueous

workup and column chromatography, we were delighted to

observe the first sample of tetracycle 62 (Scheme 18). It was a

relief to observe that this compound was reasonably stable to

isolation, given the presence of two nucleophilic amines and

two electrophilic carbon atoms. The lengthy synthesis of the

selenide substrate and associated low yields forced us to find a

more readily available substrate that could be deprotected

under mild conditions.

The final protecting group that we would explore was the

allyl group. The allyl group has seen some use as a protecting

group for nitrogen, although Alloc carbamates are much more

prevalent. Deprotection of allylic amines has been accomplished

by KO-t-Bu- or Rh/Ir-mediated isomerization to the enamine

followed by hydrolysis, as well as by Pd-catalyzed deallyla-

tion.^52,58Our synthesis began with N_b-allyltryptamine, a known

compound that is most efficiently prepared by reaction of

tryptophyl bromide with allylamine, which was converted to the

corresponding Zincke aldehyde 12g in 81% overall yield.^24,59

Having developed a short, efficient, and more convergent

approach to substrates that were previously unavailable directly

from the bicyclization reaction, we briefly revisited our

syntheses of norfluorocurarine and valparicine. As discussed

above, the required vinyl halide could not be carried through

the bicyclization reaction owing to competitive dehydrohaloge-

nation. Deallylation of 7g in CDCl₃in the presence of methyl

Meldrum’s acid (78) followed by addition of allylic bromide

79,³⁹Hunig's base and CH CN provided key Heck precursor

̈

3

36 in 68% yield (Scheme 20). It is noteworthy that Pd⁰reacts

with the protonated allylic amine efficiently at 0 °C but that

oxidative addition of residual catalyst to the allylic bromide or

the vinyl iodide is not a competing process at that temperature.

This improved approach accesses intermediate 36 in only four

steps from commercially available tryptophyl bromide and,

most importantly, avoids the problematic iododesilylation step,

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Scheme 19. Smooth Removal of the Allyl Protecting Group Allows in Situ Refunctionalization To Access Products Not

Available by Direct Cycloaddition

Scheme 20. Improved Syntheses of Norfluorocurarine, Dehydrodesacetylretuline and Valparicine

thereby obviating the need for indoline protection. Using the

Heck cyclization that we had previously optimized, the

synthesis of norfluorocurarine can now be carried out in only

five linear steps (25% overall yield), and valparicine can now be

synthesized in seven linear steps (6% overall yield), providing a

practical route for further biological investigations of this

interesting molecule.

vinylsilane substrate 7j to form 18-deshydroxy Wieland−

Gumlich aldehyde (eq 4). As before, this reaction would

serve as a model for an analogous approach to the Wieland−

Gumlich aldehyde itself.

First Attempted Synthesis of Strychnine: An Un-

expected Cycloreversion. Having established an efficient

route to the alkaloids norfluorocurarine and valparicine, we

were excited to develop a concise synthesis of the flagship

member of the Strychnos family. Taking inspiration from many

previous syntheses, our penultimate target en route to

strychnine would be the Wieland−Gumlich aldehyde, and the

missing piece was a method to close the D-ring. Although a

Heck reaction had been successful in our synthesis of

norfluorocurarine, this reaction type precludes access to the

pentacyclic core without introduction of an undesired C2−C16

double bond (see above). Conjugate addition procedures

were therefore evaluated to access products of the desired

oxidation state. Given the established utility of vinylsilanes as

nucleophiles for cyclization reactions,⁶¹we were compelled to

investigate the cyclization of our previously synthesized

We began by simply heating vinylsilane 7j, with or without

microwave irradiation. In most cases no reaction was observed,

although at 220 °C in o-DCB we observed slow decomposition

of the starting material. We next treated this substrate with

Lewis acids to activate the α,β-unsaturated aldehyde toward

nucleophilic attack. A variety of Lewis acids (TiCl₄, Sc(OTf)₃,

etc.) were ineffective in generating any cyclization products,

although in some cases dimerization occurred to give diazocine

products (similar to protic acids; see above). We also con-

sidered the use of a secondary amine to generate a more

electrophilic α,β-unsaturated iminium species; examples of

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iminium-initiated vinylsilane-terminated cyclization reactions

are well-known from Overman and co-workers. An example is

shown in Scheme 21.⁶¹

likely favored by restoration of aromaticity of the indole and the

generation of the stable, highly conjugated iminium ion. This

dichotomy is remarkable and is the subject of ongoing studies.

A Successful Conjugate Addition Strategy Enables a

Six Step Linear Synthesis of Strychnine. Given the failure

of efforts to directly initiate a conjugate addition reaction using

the C19−C20 π-bond of vinylsilane 7j, we returned to the

arena of transition metal catalysis. A conjugate addition reaction

of a suitable vinylmetal species was the most attractive option

to directly deliver the Wieland−Gumlich aldehyde without the

need for subsequent redox manipulations. Most often,

vinylmetal species are generated by lithium−halogen exchange

of the vinyl halide precursors, and the resulting nucleophiles

can engage in conjugate addition processes with catalytic or

stoichiometric quantities of copper salts.^63,64Given the pre-

sence of the indoline NH and sensitive aldehyde, an approach

involving reactive organolithium species seemed unlikely to be

successful, and a few experiments rapidly confirmed that

suspicion. We therefore sought a precursor that could

potentially be directly transmetalated to a transition metal

such as copper. While a vinyltin or vinylboron species might be

ideal for this purpose, potential routes for the stereoselective

synthesis of compounds 88 or 89 (to be incorporated by

alkylation of tetracycle 62) appeared lengthy, especially given

our desire to access this building block in a minimum number

of steps to maximize convergency and minimize step count. In

addition, β-bromostannanes related to 88 were known to be

unstable with respect to allene formation and loss of R₃SnBr.⁶⁵

Based on our previous experience, we expected that the

corresponding vinylsilane (90) would be quite stable. Although

aryl- and vinyltrialkylsilanes generally transmetallate quite

slowly, we recognized that the cis-disposed alcohol might

participate in activation of the silicon toward transmetalation to

copper, as shown by Takeda and co-workers and more recently

by Smith and co-workers (Scheme 23).^66,67

Scheme 21. Vinylsilane-Terminated Iminium Cyclization in

a

the Overman Synthesis of Pumiliotoxin 251D

a

CSA = camphorsulfonic acid.

In our case, the unsaturated iminium ion would be activated

for intramolecular attack at C15, analogous to the iminium

activation popularized by MacMillan and others.⁶²Using

stoichiometric pyrrolidine as a secondary amine with acid

catalysis (TFA or HF), we could observe the apparent

formation of an iminium intermediate 83 (Scheme 22) by

mass spectrometry. Even after substantial heating, no cycliza-

tion was observed, but a new product with the same mass as the

iminium species was observed. After aqueous workup, we

isolated a familiar product: Zincke aldehyde 12j. Similar results

were obtained using different secondary amines (Et₂NH,

morpholine) in different solvents (CD₃CN, CDCl₃, i-PrOH,

HFIP) and using the C18-hydroxylated silane 87 (see below for

its preparation). Seemingly, iminium species 83 undergoes

cycloreversion (stepwise or concerted) to give the fully

conjugated iminium species 85, rather than piperidine 84 that

should lead to deshydroxy Wieland−Gumlich aldehyde.

Contrasting with the successful cycloaddition, in which the

formation of the tetracyclic productas its corresponding

enolateis clearly favored, this unexpected cycloreversion is

Previous routes to electrophiles of the types shown in Figure 6

were lengthy; for example, vinyl iodide 91 used by Rawal and

others was made in six steps from propargyl alcohol, including

three protecting group manipulations. Ultimately, these

operations never served to lengthen the linear reaction

sequence because the synthesis of the core always required

more steps. We felt compelled to advance a new and more

Scheme 22. Attempted Use of Iminium Catalysis To Effect Vinylsilane Cyclization Results in an Unexpected Retro-

Cycloaddition Reaction To Afford Zincke Aldehyde Products

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Scheme 23. Recent Examples of Copper-Mediated Brook

Rearrangements with Functionalization of the Resultant

Vinylcopper

Scheme 24. Stereoselective Synthesis of Trisubstituted

Alkene 102 and Alkylation of the Tetracyclic Core To

Generate 87

Application of conditions reported by Takeda and co-workers

(CuO-t-Bu, THF, or DMF)⁶⁶resulted in recovery of starting

materials at lower temperatures, and decomposition at elevated

temperature. Similarly, conditions inspired by Smith and co-

workers (n-BuLi or NaHMDS, then CuI, THF/HMPA or THF/

DMPU)⁶⁷were not successful in promoting the desired process

in the desired system or model system 103 (Scheme 25), which

Scheme 25. Model System Confirmed That Allylic Amine Is

a

Tolerated in a Brook Rearrangement

Figure 6. Potential reagents for introduction of useful vinylmetalloids

and known vinyl iodide 91.

direct solution. We began with a ruthenium-catalyzed trans-

hydrosilylation of 1,4-butynediol using conditions reported by

Trost and Ball,⁶⁸which provided silane 100 with complete

control of alkene geometry in high yield (Scheme 24). This

reaction is scalable, proceeds with as little as 0.5 mol % catalyst,

and converts inexpensive 1,4-butynediol into the required Z-

vinylsilane, while at the same time differentiating the two

hydroxyl groups. With one of the hydroxyl groups internally

protected as a silyl ether, the other could be converted to the

bromide (101) under standard conditions. Subsequent treatment

with methylmagnesium bromide chemoselectively opened the

siloxacycle and provided the desired vinylsilane 102 in 46% yield

over three steps. This efficient sequence quickly provides access

to significant quantities of this polyfunctional, stereodefined

trisubstituted alkene. Importantly, the free alcohol in 102 did not

readily suffer alkylation, even when it was stored neat at −20 °C.

When allylic bromide 102 was added to the reaction mixture

after complete deallylation of 7g using methyl Meldrum’s acid,

refunctionalized core 87 was isolated in 69% yield. The alkylation

was chemoselective for N_b-alkylation, and the ability to work with

the free hydroxyl group eliminated the need for protecting group

manipulations.

a

NaHMDS = sodium hexamethyldisilazide, NMP = N-methylpyrro-

lidinone, DMPU = 1,3-dimethylpyrimidin-2-one.

also incorporates the potentially problematic allylic tertiary amine.

Smith reported that the addition of a polar cosolvent was

necessary to trigger the Brook rearrangement of the alkoxide.⁶⁷

Indeed it was not until DMPU was used as the sole solvent that

the Brook rearrangement/protonolysis product was observed in

the model system, cleanly generating 104.

When these optimal conditions were applied to the real

system (87), Brook rearrangement could be triggered in the

presence of excess base, but cyclization did not occur; only

protodesilylation to form 105 (Scheme 26) was observed.

When the reaction mixture was heated to 40 °C, partial

cyclization was observed, and small quantities (<5% recovery)

of the Wieland−Gumlich aldehyde (8) were painstakingly

isolated. As we had envisioned, the free alcohol present in 87

enabled a Brook rearrangement of the corresponding alkoxide

With access to vinylsilane 87, we began investigation of the

final C−C bond formation, which we hoped would take the

form of a sequential Brook rearrangement⁶⁹/conjugate addi-

tion process, related to the reactions shown in Scheme 23.

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a

Scheme 26. Completion of the Synthesis of Strychnine Using a Brook Rearrangement/Conjugate Addition Cascade

a

NaHMDS = sodium hexamethyldisilazide, NMP = N-methylpyrrolidinone.

with presumed transmetalation to copper (see 106), followed

by intramolecular conjugate addition to afford the Wieland−

Gumlich aldehyde, albeit in low yield. All optimization to

date led to the identification of NMP as the better solvent,

NaHMDS and KHMDS as preferred bases (Li prevents Brook

rearrangement), and 65 °C as the temperature of choice for

cyclization, yielding the Wieland−Gumlich aldehyde in up to

10% yield. Higher temperatures did not improve the cyclization

yield. While the efficiency of this final bond construction is

certainly lower than desired, there are several other reports that

highlight the difficulty in forging the C15−C20 bond in related

contexts.^7i,37c,65With the known conversion of the Wieland−

Gumlich aldehyde to strychnine, the adoption of this Brook

rearrangement-based strategy enabled the completion of the

synthesis in only six linear steps from commercially available

starting materials because of the rapid, convergent assembly of

vinylsilane 87.

Scheme 27. Attempted Use of an Indoline Protecting Group

to Avoid Protonation

a

In our investigations, we explored a variety of potential

ligands (phosphines, phosphites, phosphine oxides, pyridine,

bipy), precatalysts (CuI, CuCN, CuTC, Cu-NHC com-

plexes),^70,71and additives (NaOAc, Sc(OTf)₃, BF₃·OEt₂), but

were unable to increase the yield above about 10%. In most

reactions, the mass balance consists largely of the formal

protodesilylation product 105 that likely arises via Brook

rearrangement/hydrolysis of the resulting vinylmetal. Given the

presence of acidic protons in the substrate and product, this

premature quenching of the key reactive organometallic reagent

is not readily avoided and results in an inefficient and irre-

producible reaction. In addition, the excess base used may

result in partial deprotonation of the α,β-unsaturated aldehyde,

with the resulting dienolate no longer electrophilic at C15. We

believe that these two issues conspire to render the efficiency of

conversion of 87 to the Wieland−Gumlich aldehyde inherently

limited. In an effort to minimize self-quenching, carbamate-

protected 107 (Scheme 27) was synthesized and subjected to

the Brook rearrangement/conjugate addition conditions. In this

case, no cyclized product was observed and only protodesily-

lated material (108) was isolated. We surmise that the presence

of the carbamate group forces the aldehyde out of conjuga-

tion with the alkene, preventing conjugate addition of the

vinylcopper nucleophile. Once again, deprotonation of the α,β-

a

NaHMDS = sodium hexamethyldisilazide, NMP = N-methylpyrro-

lidinone.

unsaturated aldehyde may also prevent cyclization or

prematurely quench the key reactive intermediate.

Efforts To Develop an Improved D-Ring Closure. Given

the relative inefficiency of the Brook rearrangement/

conjugate addition reaction in accessing the Wieland−Gumlich

aldehyde, we examined slightly altered approaches to improve

the key D-ring formation. We believe that the low yields in this

final reaction primarily arise from premature protonation of the

presumed vinylcopper intermediate, as discussed above. Given

the ease with which the required vinylsilane was constructed,

and the promising reactivity we observed, we wondered if a

change in the order of the last two steps of our synthesis could

circumvent these problems. Inspired by the mechanistic

rationale for the well-established conversion of the Wieland−

Gumlich aldehyde to strychnine,^3c,24we considered the product

of a similar reaction of α,β-unsaturated aldehyde 87 with

dimethyl malonate as a potential starting point for further

investigations. The α,β,γ,δ-unsaturated malonamate derivative

110 (Scheme 28) would have the following advantages in the

requisite Brook rearrangement/conjugate addition cascade:

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Unfortunately, we have thus far been unable to prevent this

unwanted process.

Scheme 28. Formation of Unsaturated Malonamate 110 and

Attempts at Brook Rearrangement/Conjugate Addition

Resulting in Pyridone Products

a

The problems associated with premature protonation of the

basic vinylcopper intermediate led us to also explore rhodium-

(I) as an alternative, because of its established ability to mediate

conjugate addition, its tolerance of water, and the potential to

render the reaction catalytic in transition metal. While there

are reports of transmetalation of tetraorganosilanes to Cu(I)

and to Pd(II) by assistance of a proximal alkoxide, trans-

metalation of these species to Rh(I) was not found in the

literature.⁷⁴We determined the feasibility of the desired process

using our model system 103. Treatment of this vinylsilane with

5 mol % of dimeric Rh(I) catalyst in THF/aq KOH in the

presence of tert-butyl acrylate led to the desired Brook

rearrangement/conjugate addition product in 55% unoptimized

yield (Scheme 29). This result confirmed that the desired

Scheme 29. New Transmetalation Reaction to Rh(I) and Its

Attempted Use To Access the Wieland−Gumlich Aldehyde

a

EDDA = ethylenediamine-N,N′-diacetic acid, NaHMDS = sodium

hexamethyldisilazide, NMP = N-methylpyrrolidinone.

(1) it no longer has an acidic indoline NH group; (2) it no longer

has a reactive aldehyde group; and (3) the olefinic C15 position is

now activated by two electron-withdrawing groups (although

further removed), which could potentially enhance its electro-

philic character. Furthermore, a demethoxycarboxylation reaction

of the product should deliver strychnine (or isostrychnine) in a

single step.

Unsaturated malonamate derivative 110 was accessed by

Knoevenagel condensation of tetracycle 87 under conditions

that minimize acid-catalyzed dimerization of the enal as well as

amine-catalyzed ring-opening (see above).⁷²This condensa-

tion/cyclization was accompanied by trans-esterification of

dimethyl malonate with the primary alcohol, requiring

subsequent methanolysis of the undesired ester in 109.

Although the recent procedure of Andrade and co-workers⁷³

would likely render this transformation more efficient, we

obtained enough material to explore the desired cyclization

reaction using our previously developed conditions. The major

products under the basic conditions used for the Brook

rearrangement/conjugate addition cascade were identified as

pyridones 111 and 112. These products likely derive from

undesired deprotonation at C14 to form stabilized trienolate

113, facilitated by the second electron-withdrawing group. This

product apparently suffers oxidation by molecular oxygen or

copper(I) to give the observed pyridone. Similar pyridone

intermediates had previously been reported by Woodward and

Vollhardt in their respective syntheses of strychnine.^7a,i,65

transmetalation reaction does occur and that the overall process

proceeds well with catalytic quantities of rhodium. We were

eager to apply these conditions to the key C15−C20 bond

formation. Using free indoline 87 resulted in decomposition in

the presence of the rhodium catalyst, while using Boc-protected

indoline 117 resulted only in recovery of starting material; no

Brook rearrangement was observed in this more complex

system. We also subjected malonamate 110 to the rhodium

catalyst, and the basic conditions once again led to facile

oxidation to the pyridone 111 without Brook rearrangement.

The lack of reactivity in these complex systems is not fully

understood at this point, and an extensive evaluation of

different catalysts and conditions has not been undertaken.

Nonetheless, given the promising reactivity observed in the

model system (103 → 116), this type of Brook rearrangement/

32

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chromatography was performed on silica gel (230−400 mesh).

transmetalation/C−C bond-forming reaction is worthy of

1

Melting points uncorrected. H and ¹³C NMR spectra were obtained

further study.

at 500 or 600 MHz at 298 K, unless otherwise indicated. Abbreviations

for multiplicity are as follows: app indicates apparent, br indicates

broad, d indicates doublet, t indicates triplet, q indicates quartet, m

indicates multiplet. Chemical shifts are reported in ppm referenced to

the internal solvent residual of CDCl₃or DMSO-d₆at 7.27 ppm and

CONCLUSION

■

We have developed a base-mediated anionic bicyclization

reaction of tryptamine-derived Zincke aldehydes to form the

ABCE tetracyclic core of a variety of monoterpene indole

alkaloids in just three steps from tryptamine or tryptophyl

bromide. The use of the N-allyl protected tetracycle as a readily

accessible and versatile intermediate enables facile access to

more complex N-functionalized tetracycles that were previously

unavailable due to the harsh conditions required for the

bicyclization reaction. The convergent approach that resulted

enabled concise syntheses of the indole alkaloids norfluorocur-

arine, dehydrodesacetylretuline, valparicine, the Wieland−

Gumlich aldehyde and strychnine, clearly documenting the

utility of Zincke aldehydes for complex molecule synthesis. This

strategy also enables four-step access to complex tetracyclic

intermediates that may prove broadly useful for the synthesis of

many other monoterpene indole alkaloids. Our synthesis of

strychnine is particularly notable; in the course of only four

steps, four new carbon−carbon bonds and one carbon−oxygen

bond are forged to the five carbons of the Zincke aldehyde,

exploiting much of the latent functionality present in this type

of donor−acceptor diene. In the context of this strychnine

synthesis, we also identified a sequence featuring Ru-catalyzed

trans-hydrosilylation and Cu-mediated Brook rearrangement/

transmetalation/conjugate addition that might prove generally

applicable to the synthesis of other stereodefined, trisubstituted

allylic alcohols.

1

2.50 ppm for H NMR and 77.1 ppm and 39.5 ppm for ¹³C NMR,

respectively. IR spectra were obtained on an FT-IR spectrophotometer

using NaCl plates. High-resolution mass spectrometry data were

obtained by LC-ESI or GC-CI.

Notes. (1) Chromatographic purification of Zincke aldehydes

usually yields a brown semisolid that appears pure by ¹H and

¹³C NMR analysis. Further purification by treatment with activated

charcoal in CH₂Cl₂yields a yellow solid. This additional purification

was critical for the success of the cycloaddition reaction. (2) Com-

pound numbering protocols, as referred to in the NMR data provided

below, can be found in the Supporting Information.

Compounds Not Referred to in Text. There are numerous new

compounds made as intermediates in the course of the work described

in this paper that are not explicitly mentioned in the text above.

Experimental details and characterization data for these compounds

can be found below. The chemical structures of these compounds

(labeled S1 through S31) can be found in the Supporting Information.

Compounds Previously Described by Our Research Group.

A graphical listing of compounds mentioned in this paper that were

previously described in refs 7q and 15 can be found in the Supporting

Information.

General Procedure a for Zincke Aldehyde Formation. To a

solution of secondary amine (2.1 equiv) in EtOH (0.4−0.8 M in

amine) was added 1-(2,4-dinitrophenyl)pyridinium chloride (20)^12a

(1.0 equiv). After being stirred for 30 min at rt, the red mixture was

heated to 80 °C for 1−4 h and then cooled to rt. The reaction mixture

was quenched with 2 M NaOH (2−4 equiv NaOH), stirred at rt for

30 min, and then diluted with EtOAc and H₂O. The aqueous layer was

separated and extracted with EtOAc. The combined organic extracts

were washed successively with 2 M NaOH and brine and then dried

over Na₂SO₄. The solvent was evaporated in vacuo, and the crude

material was purified by column chromatography to yield the desired

product as a red-brown solid or oil and recovered amine. Further

purification by column chromatography and treatment with activated

charcoal (∼1 mass equivalent) in CH₂Cl₂for 1 h, followed by filtration

and solvent removal gave a yellow solid or foam.

New aspects of our work described for the first time include:

(1) examination of the substrate scope of the key cycloaddition

reaction; (2) preliminary mechanistic discussion; (3) a second-

generation five-step synthesis of norfluorocurarine; (4) short

syntheses of dehydrodesacetylretuline and the antitumor

alkaloid valparicine; (5) a surprisingly facile dimerization of

our tetracyclic enal intermediates; (6) a fascinating retro-

cycloaddition that converts tetracyclic intermediates back to

Zincke aldehydes; and (7) some new reactivity at the nexus of

Brook rearrangements and Rh(I) catalysis.

The successes and unexpected detours in our efforts to

define short syntheses of several Strychnos alkaloids, including

the benchmark target strychnine, highlight the fascinating yet

largely unexploited reactivity of Zincke aldehydes and their

potential to serve as building blocks for the synthesis of com-

plex natural products.

(1E,3E)-5-Oxopenta-1,3-dienyl pivalate (S8).⁷⁶To a suspen-

sion of potassium glutaconaldehyde⁷⁷(10.2 g, 75.0 mmol, 1.0 equiv)

in CH₂Cl₂(250 mL, 0.30 M) at 0 °C was added triethylamine

(10.4 mL, 75.0 mmol, 1.0 equiv) followed by trimethylacetyl chloride

(10.2 mL, 82.5 mmol, 1.1 equiv). The reaction solution was stirred at

0 °C for 3 h and then washed with saturated aqueous NaHCO₃and

brine. The organic layer was dried (MgSO₄) and concentrated in

vacuo to afford 13.2 g of a yellow oil. The oil was purified by flash

chromatography (15:85 EtOAc/hexanes) to afford the desired product

(12.4 g, 91%) as a crystalline yellow solid: mp = 59−61 °C; R_f=

1

EXPERIMENTAL SECTION

0.3 (1:3 Et₂O/hexanes); H NMR (500 MHz, CDCl₃) δ 9.56 (d, J =

■

8.0 Hz, 1H, CHO), 7.82, (d, J = 12.1 Hz, 1H, δ-CH), 7.13 (dd, J =

15.2, 11.7 Hz, 1H, β-CH), 6.30 (dd, J = 12.1, 11.7 Hz, 1H, γ-CH), 6.20

(dd, J = 15.2, 8.0 Hz, 1H, α-CH), 1.29 (s, 9H, t-Bu); ¹³C NMR (125

MHz, CDCl₃) δ 193.2, 174.7, 148.3, 146.0, 131.7, 113.2, 38.9, 26.8; IR

(thin film) ν 3074, 2977, 1754, 1687, 1645, 1128 cm⁻¹; HRMS (GC-

CI) m/z calcd for C₁₀H₁₅O₃(M + H)⁺183.1021, found 183.1013.

General Procedure B for Zincke Aldehyde Formation. To a

solution of secondary amine (1.0 equiv) in MeOH or i-PrOH (0.10 M)

was added NEt₃(5.0 equiv). The reaction mixture was cooled to

0 °C, pivalate S8 (1.5 equiv) was added, and stirring was continued for

1−3 h at 0 °C. The reaction mixture was quenched with 1 M NaOH

(∼10 equiv), allowed to warm to rt, and diluted with EtOAc and H₂O.

The aqueous layer was separated and extracted with EtOAc. The

combined organic extracts were washed successively with 2 M NaOH

and brine and then dried over Na₂SO₄. The solvent was evaporated in

vacuo, and the crude material was purified by column chromatography

General Methods. All reactions were carried out under an inert

atmosphere of nitrogen or argon in oven-dried or flame-dried

glassware with magnetic stirring, unless otherwise noted. Solvents

were dried by passage through columns of activated alumina. THF (for

anionic bicyclization reactions) and acetone (for hydrosilylation reac-

tions) were degassed by three cycles of freeze/pump/thaw. Pyridine,

diisopropylethylamine, triethylamine, and N-methyl-2-pyrrolidinone

(NMP) were distilled from calcium hydride prior to use. 5-Methyl

Meldrum’s acid (78) was recrystallized from acetone/H₂O.⁷⁵[Cp*Ru-

(CH₃CN)₃]PF₆was purchased from a commercial supplier and stored

in a glovebox at −20 °C. All other reagents were prepared by known

literature procedures or used as obtained from commercial sources,

unless otherwise indicated. Reactions were monitored by thin-layer

chromatography (TLC) carried out on 0.25 mm coated commercial

silica gel plates (F254 precoated glass plates) using UV light as

visualizing agent and KMnO₄and heat as a developing agent. Flash

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The Journal of Organic Chemistry

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to yield the desired product as a red−orange solid or oil. Subsequent

treatment with charcoal is required. This procedure allows for 100%

theoretical yield with respect to the amine partner (rather than ∼50%

for the traditional Zincke reaction) and is substantially higher yielding

for certain substrates.

General Procedure C for the Anionic Cycloaddition Reaction

of Zincke Aldehydes. To a solution of Zincke aldehyde (1.0 equiv)

in THF (0.06 M unless otherwise specified) in a sealed tube

temporarily capped with a septum was added KO-t-Bu (1.0 M in THF,

1.05 equiv), yielding an orange to light brown, slightly cloudy solution.

The tube was tightly sealed, heated to 80 °C for 1−4 h, and then

cooled to rt. A saturated aqueous solution of NaHCO₃was added,

followed by EtOAc and H₂O. The aqueous layer was extracted with

EtOAc, and the combined organics were washed with brine and then

dried over Na₂SO₄. The solvent was evaporated in vacuo, and the

crude material was purified by column chromatography to yield the

desired tetracyclic product.

Zincke Aldehyde 12a. Prepared according to general procedure

B using N_b-methyltryptamine (S9)⁸⁰(251 mg, 1.44 mmol) in i-PrOH

(14 mL) at 0 °C for 2.5 h. The crude material was purified by

column chromatography (SiO₂, 0:0:100 → 0.4:3.6:96 NH₄OH/

MeOH/CH₂Cl₂) to yield the desired product (227 mg, 62%) as a

red-orange foam. Further purification by treatment with activated

charcoal (∼0.2 g) in CH₂Cl₂for 1 h, followed by filtration and solvent

removal, gave a yellow foam: R_f= 0.4 (0.7:6.3:93 NH₄OH/MeOH/

1

CH₂Cl₂); H NMR (500 MHz, CDCl₃) δ 9.26 (d, J = 8.3 Hz, 1H,

CHO), 8.56 (br s, 1H, N_a-H), 7.57 (d, J = 7.8 Hz, 1H, indole C4-H),

7.40 (d, J = 8.1 Hz, 1H, indole C7-H), 7.23 (dd, J = 8.1, 7.3 Hz, 1H,

indole C6-H), 7.16 (dd, J = 7.8, 7.3 Hz, 1H, indole C5-H), 7.00 (dd,

J = 14.3, 12.1 Hz, 1H, ZA [Zincke aldehyde] β-CH), 6.98 (s, 1H,

indole C2-H), 6.67 (d, J = 12.5 Hz, 1H, ZA δ-CH), 5.84 (dd, J = 14.3,

8.3 Hz, 1H, ZA α-CH), 5.26 (dd, J = 12.5, 12.1 Hz, 1H, ZA γ-CH),

3.52 (t, J = 7.0 Hz, 2H, CH₂-N_b), 3.04 (t, J = 7.0 Hz, 2H, Ar−CH₂);

2.89 (s, 3H, N_b-CH₃); ¹³C NMR (125 MHz, DMSO, 373 K) δ 189.6,

155.6, 152.3, 136.0, 126.7, 122.5, 120.4, 117.82 (2C), 117.5, 110.8,

110.5, 96.0, 54.9, 36.5, 23.0; IR (thin film) ν 3038, 2918, 1556, 1150,

743 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₆H₁₉N₂O (M + H)⁺

255.1497, found 255.1490.

Tetracycle 7a. Prepared according to general procedure C using

Zincke aldehyde 12a (34.4 mg, 0.135 mmol) in THF (2.25 mL,

0.06 M) at 80 °C for 1 h. The crude material was purified by column

chromatography (SiO₂, 2:98 → 5:95 MeOH/CH₂Cl₂) to yield the

desired product (14.0 mg, 41%) as a tan solid. A reaction performed

on 86.6 mg of 12a at 0.04 M gave 40.1 mg (46%): mp =78−80 °C;

R_f= 0.3 (8:92 MeOH/CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 9.48

(s, 1H, C17-H), 7.01−7.07 (m, 2H, C9-H + C11-H), 6.84 (dd, J = 5.8,

2.3 Hz, 1H, C15-H), 6.72 (t, J = 7.2 Hz, 1H, C10-H), 6.56 (d, J = 7.8

Hz, 1H, C12-H), 4.49 (br s, 1H, NH), 4.34 (s, 1H, C2-H), 3.26−3.33

(m, 1H, C5-H), 2.86 (app d, J = 4.0 Hz, 1H, C3-H), 2.63 (dd, J = 19.9,

5.5 Hz, 1H, C14-H), 2.54 (td, J = 10.0, 5.9 Hz, 1H, C5-H), 2.39−2.46

(m, 1H, C14-H), 2.40 (s, 3H, NCH₃), 2.25 (ddd, J = 13.2, 8.3, 6.0 Hz,

1H, C6-H), 1.97 (ddd, J = 13.2, 10.2, 5.5 Hz, 1H, C6-H); ¹³C NMR

(125 MHz, CDCl₃) δ 194.8, 150.5, 150.4, 140.8, 131.9, 128.3, 122.6,

118.7, 109.3, 67.0, 60.1, 54.5, 53.7, 41.0, 38.4, 25.8; IR (thin film)

ν 3397, 2947, 1679, 1485, 1177, 743 cm⁻¹; HRMS (LC-ESI) m/z

calcd for C₁₆H₁₉N₂O (M + H)⁺255.1497, found 255.1494.

General Deallylation/Alkylation Procedure of Tetracycle

7g. To a solution of 7g (1 equiv) and 5-methyl Meldrum’s acid

(78) (2.2 equiv) in CDCl₃(0.2 M) at 0 °C was added Pd(PPh₃)₄

(5 mol %). The reaction mixture was stirred at 0 °C for 1 h, at which

1

point H NMR analysis of an aliquot generally indicated complete

deallylation. To the reaction mixture were added diisopropylethyl-

amine (3.5 equiv) and allylic/propargylic bromide (2.2 equiv, neat or

as a solution in CH₃CN) rinsing with CH₃CN (equal volume as

CDCl₃, [final] = 0.1 M). The resulting solution was stirred at 0 °C for

2.5 h, diluted with EtOAc and saturated aqueous NaHCO₃, and

warmed to rt. The mixture was diluted with EtOAc and H₂O. The

layers were separated, and the aqueous layer was extracted with

EtOAc. The combined organic extracts were washed with aqueous

NaHCO₃and brine and then dried over Na₂SO₄. The solvent was

evaporated in vacuo, and the crude material was purified by column

chromatography (SiO₂, 1:4 → 1:3 EtOAc/CH₂Cl₂) to yield the

desired product. The phenallyl group could also be deprotected under

these conditions and gave similar product yields.⁷⁸In previous

experiments, barbituric acid derivative 77 was used in place of

5-methyl Meldrum’s acid with similar results.

α-Methyl Zincke Aldehyde 28. To a solution of N_b-PMB-

tryptamine (S7)¹⁵(2.45 g, 8.74 mmol, 2.1 equiv) in EtOH (22 mL,

0.4 M in amine) was added 1-(2,4-dinitrophenyl)-3-methylpyridinium

chloride⁷⁹(1.23 g, 4.16 mmol, 1.0 equiv). After being stirred for

30 min at rt, the red mixture was heated to 80 °C for 2 h and then cooled

to rt. The reaction mixture was quenched with 2 M NaOH (25 mL,

50 mmol, 12 equiv), stirred at rt for 45 min, and then diluted with

EtOAc (100 mL) and 2 M NaOH (50 mL). The aqueous layer was

separated and extracted with EtOAc (20 mL). The combined organic

extracts were washed successively with 2 M NaOH (20 mL) and brine

(20 mL) and then dried over Na₂SO₄. The solvent was evaporated in

vacuo, and the crude material (∼8.5:1 mixture of α-Me:γ-Me) was

purified by column chromatography (SiO₂, 0:100 → 1:4 EtOAc/

CH₂Cl₂) to yield the desired product as a red−brown oil (1.1 g, 71%).

Further elution (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂) gave recovered

amine (0.94 g, 73% recovery of excess). Further purification by

column chromatography (SiO₂, 4:5:1 → 5:4:1 EtOAc/hexaxes/

CH₂Cl₂) and treatment with activated charcoal (∼1 mass equiv) in

CH₂Cl₂for 1 h, followed by filtration and solvent removal, gave an

Tryptamine S10. A solution of BrCH₂CH₂SiMe₃(72)⁸¹(1.70 g,

9.38 mmol, 1.0 equiv), tryptamine (3.76 g, 23.5 mmol, 2.5 equiv), and

NEt₃(1.57 mL, 11.3 mmol, 1.2 equiv) in CH₃CN (67 mL, 0.14 M)

was heated to 60 °C for 16 h and then cooled to rt. The reaction

mixture was quenched with saturated aqueous NaHCO₃(50 mL),

followed by EtOAc (100 mL) and H₂O (50 mL). The organic layer

was washed with brine (40 mL) and dried over Na₂SO₄. The solvent

was evaporated in vacuo, and the crude material was purified by

column chromatography (SiO₂, 0.2:1.8:98 → 0.7:6.3:93 NH₄OH/

MeOH/CH₂Cl₂) to yield the desired product (622 mg, 25%) as a light

1

brown solid: R_f= 0.2 (1:9:90 NH₄OH/MeOH/CH₂Cl₂); H NMR

(500 MHz, CDCl₃) δ 8.15 (br s, 1H, N_a-H), 7.65 (d, J = 7.9 Hz, 1H,

indole C4-H), 7.38 (d, J = 8.1 Hz, 1H, indole C7-H), 7.21 (dd, J = 8.1,

7.3 Hz, 1H, indole C6-H), 7.13 (dd, J = 7.9, 7.3 Hz, 1H, indole C5-H),

7.05 (s, 1H, indole C2-H), 2.99−3.03 (m, 2H, ArCH₂), 2.95−2.99 (m,

2H, CH₂N_b), 2.64−2.70 (m, 2H, N_bCH₂), 1.66 (br s, 1H, N_b-H),

0.74−0.79 (m, 2H, CH₂Si), −0.02 (s, 9H, SiCH₃); ¹³C NMR (125

MHz, CDCl₃) δ 136.4, 127.4, 121.94, 121.91, 119.2, 118.9, 114.0,

111.1, 49.6, 45.6, 25.7, 18.1, −1.6; IR (thin film) ν 3415, 2951, 1456,

1248, 861, 836, 739 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₅H₂₅N₂Si

(M + H)⁺261.1787, found 261.1780.

Zincke Aldehyde 12e. Prepared according to general procedure

A using tryptamine S10 (546 mg, 2.10 mmol) in EtOH (5.3 mL) at

80 °C for 2 h. The crude material was purified by column

chromatography (SiO₂, 0:0:100 → 0.3:2.7:97 NH₄OH/MeOH/

CH₂Cl₂) to yield the desired product (247 mg, 72%) as a brown

foam along with recovered amine (285 mg, 99% recovery of excess).

Further purification by column chromatography (SiO₂, 4:5:1 → 5:4:1

EtOAc:hexanes:CH₂Cl₂) and treatment with activated charcoal (∼0.2 g)

in CH₂Cl₂for 1 h, followed by filtration and solvent removal gave a

yellow foam (229 mg). General procedure B using 56.3 mg amine gave

1

orange foam: R_f= 0.4 (1:4 EtOAc/CH₂Cl₂); H NMR (500 MHz,

CDCl₃) δ 9.19 (s, 1H, CHO), 8.22 (br s, 1H, N_a-H), 7.52 (d, J = 7.7

Hz, 1H, indole C4-H), 7.40 (d, J = 7.9 Hz, 1H, indole C7-H), 7.23 (t,

J = 7.7 Hz, 1H, indole C6-H), 7.14 (dd, J = 7.9, 7.7 Hz, 1H, indole C5-

H), 7.10 (d, J = 8.3 Hz, 2H, PMB), 7.00 (s, 1H, indole C2-H), 6.82−

6.91 (m, 4H, PMB + ZA β+δ-CH), 5.46 (app t, J = 12.1 Hz, 1H, ZA

γ-CH), 4.27 (br s, 2H, N_b-CH₂), 3.82 (s, 3H, OCH₃), 3.51 (t, J = 7.2

Hz, 2H, CH₂-N_b), 3.03(t, J = 7.2 Hz, 2H, Ar-CH₂), 1.75 (s, 3H, ZA α-

CH₃); ¹³C NMR (125 MHz, DMSO, 373 K) δ 190.1, 158.5, 152.7,

150.6, 136.0, 128.5, 128.4, 126.7, 123.8, 122.4, 120.4, 117.8, 117.4,

113.7, 110.9, 110.6, 94.4, 54.7, 54.3, 51.1, 22.6, 8.2; IR (thin film)

ν 3051, 2922, 1557, 1204, 1010, 741 cm⁻¹; HRMS (LC-ESI) m/z

calcd for C₂₄H₂₇N₂O₂(M + H)⁺375.2072, found 375.2078

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48 mg of product (65%), but purification was more tedious: R_f= 0.5

(1:9:90 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃)

δ 9.27 (d, J = 8.3 Hz, 1H, CHO), 8.18 (br s, 1H, N_a-H), 7.58 (d, J =

8.0 Hz, 1H, indole C4-H), 7.41 (d, J = 8.1 Hz, 1H, indole C7-H), 7.24

(dd, J = 8.1, 7.0 Hz, 1H, indole C6-H), 7.17 (dd, J = 8.0, 7.0 Hz, 1H,

indole C5-H), 7.02−7.10 (m, 1H, ZA β-CH), 7.02 (s, 1H, indole C2-

H), 6.71 (br s, 1H, ZA δ-CH), 5.83 (dd, J = 14.2, 8.3 Hz, 1H, ZA

α-CH), 5.26−5.37 (m, 1H, ZA γ-CH), 3.51 (t, J = 7.2 Hz, 2H, CH₂-

N_b), 3.13−3.19 (m, 2H, N_b-CH₂), 3.05 (t, J = 7.2 Hz, 2H, Ar−CH₂),

0.84−0.90 (m, 2H, CH₂Si), 0.01 (s, 9H, SiCH₃); ¹³C NMR (125

MHz, DMSO, 373 K) δ 189.4, 155.9, 151.1, 136.0, 126.7, 122.4, 120.4,

117.8, 117.43, 117.42, 110.8, 110.7, 95.9, 50.9, 47.1, 23.0, 15.0, −2.4;

IR (thin film) ν 2951, 1568, 1557, 1149, 838, 740 cm⁻¹; HRMS (LC-

ESI) m/z calcd for C₂₀H₂₉N₂OSi (M + H)⁺341.2049, found 341.2040.

Tetracycle 7e. Prepared according to general procedure C using

Zincke aldehyde 12e (204 mg, 0.600 mmol) in THF (12 mL, 0.05 M)

at 80 °C for 2.5 h. The crude material was purified by column

chromatography (SiO₂, 0.1:0.9:99 → 0.7:6.3:93 NH₄OH/MeOH/

CH₂Cl₂) to yield the desired product (92 mg, 45%) as a tan solid:

mp =128−130 °C dec; R_f= 0.3 (0.3:2.7:97 NH₄OH/MeOH/CH₂Cl₂);

¹H NMR (500 MHz, CDCl₃) δ 9.47 (s, 1H, C17-H), 7.00−7.07 (m,

2H, C9-H + C11-H), 6.81 (dd, J = 5.4, 2.5 Hz, 1H, C15-H), 6.71 (t, J = 7.3

Hz, 1H, C10-H), 6.56 (d, J = 7.7 Hz, 1H, C12-H), 4.52 (br s, 1H,

NH), 4.29 (s, 1H, C2-H), 3.18−3.24 (m, 1H, C5-H), 3.05 (app d, J =

3.4 Hz, 1H, C3-H), 2.83−2.90 (m, 1H, C21-H), 2.50−2.62 (m, 2H,

C5-H + C14-H), 2.35−2.43 (m, 2H, C14-H + C21-H), 2.23 (ddd, J =

13.0, 8.3, 4.9 Hz, 1H, C6-H), 1.89 (ddd, J = 13.0, 10.1, 6.3 Hz, 1H, C6-

H), 0.72−0.84 (m, 2H, C20-H₂), 0.01 (s, 9H, SiCH₃); ¹³C NMR (125

MHz, CDCl₃) δ 194.9, 150.8, 150.5, 140.7, 131.9, 128.2, 122.7, 118.6,

109.3, 63.6, 59.9, 53.5, 50.4, 49.3, 37.8, 26.1, 14.7, −1.4; IR (thin film)

ν 2885, 1667, 1645, 1486, 838, 738 cm⁻¹; HRMS (LC-ESI) m/z calcd

for C₂₀H₂₉N₂OSi (M + H)⁺341.2049, found 341.2051.

Tryptamine S11. This reaction is a modification of the procedure

of Pannecoucke et al.⁸²A solution of α-(phenylseleno)acetaldehyde

(73)⁸³(382 mg, 1.92 mmol, 1.0 equiv) and tryptamine (338 mg,

2.11 mmol, 1.1 equiv) in MeOH (19 mL, 0.1 M) was stirred at rt for

17 h. The reaction mixture was cooled to −78 °C, and to this slushy

orange reaction mixture was added solid NaBH₃CN (60.3 mg, 0.96

mmol, 0.50 equiv), followed by AcOH (110 μL, 1.92 mmol, 1.0 equiv)

dropwise. After 1 h of stirring at −78 °C, the heterogeneous reaction

mixture was warmed to −30 °C. After 30 min of stirring at −30 °C,

the homogeneous reaction mixture was quenched with H₂O (10 mL)

and EtOAc (20 mL), warmed to rt, and further diluted with H₂O

(50 mL) and EtOAc (30 mL). The organic layer was washed with 1 M

NaOH (10 mL) and brine (40 mL) and dried over Na₂SO₄. The

solvent was evaporated in vacuo, and the crude material was purified

by column chromatography (SiO₂, 0.2:1.8:98 → 0.4:3.6:96 NH₄OH/

MeOH/CH₂Cl₂) to yield the desired product (132 mg, 20%) as a light

brown solid: R_f= 0.3 (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR

(500 MHz, CDCl₃) δ 8.11 (br s, 1H, N_a-H), 7.62 (d, J = 8.0 Hz, 1H,

indole C4-H), 7.36−7.42 (m, 3H, SePh + indole C7-H), 7.17−7.25

(m, 4H, SePh + indole C6-H), 7.14 (dd, J = 7.7, 7.3 Hz, 1H, indole

C5-H), 7.03 (s, 1H, indole C2-H), 3.03 (t, J = 6.7 Hz, 2H, ArCH₂),

2.93−3.00 (m, 4H, CH₂CH₂Se), 2.89 (t, J = 6.7 Hz, 2H, CH₂N_b), 1.76

(br s, 1H, N_b-H); ¹³C NMR (125 MHz, CDCl₃) δ 136.5, 133.1, 129.4,

129.1, 127.4, 127.1, 122.12, 122.09, 119.4, 118.9, 113.9, 111.2, 49.4,

48.9, 28.4, 25.8; IR (thin film) ν 3413, 3054, 2924, 1456, 1437, 738

cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₈H₂₁N₂Se (M + H)⁺

345.0871, found 345.0874.

abandoning this route: R_f= 0.5 (0.5:4.5:95 NH₄OH/MeOH/

CH₂Cl₂); H NMR (500 MHz, CDCl₃) δ 9.27 (d, J = 8.3 Hz, 1H,

1

CHO), 8.20 (br s, 1H, N_a-H), 7.48−7.53 (m, 3H, SePh + indole C4-

H), 7.40 (d, J = 8.1 Hz, 1H, indole C7-H), 7.28−7.35 (m, 3H, SePh),

7.24 (dd, J = 8.1, 7.3 Hz, 1H, indole C6-H), 7.15 (dd, J = 8.0, 7.3 Hz,

1H, indole C5-H), 6.93−7.02 (m, 2H, ZA β-CH + indole C2-H), 6.59

(d, J = 12.8 Hz, 1H, ZA δ-CH), 5.76 (dd, J = 13.9, 8.3 Hz, 1H, ZA α-

CH), 5.11 (br s, 1H, ZA γ-CH), 3.46 (t, J = 7.2 Hz, 2H, CH₂-N_b), 3.36

(t, J = 7.6 Hz, 2H, N_b-CH₂), 2.99 (t, J = 7.2 Hz, 2H, Ar−CH₂), 2.93 (t,

J = 7.6 Hz, 2H, CH₂Se); IR (thin film) ν 3054, 2925, 1566, 1146, 739

cm⁻¹; HRMS (LC-ESI) m/z calcd for C₂₃H₂₅N₂OSe (M + H)⁺

425.1133, found 425.1137.

Tetracycle 7f. Prepared according to general procedure C using

Zincke aldehyde 12f (6.9 mg, 16 μmol) in THF (0.8 mL, 0.02 M) at

80 °C for 2 h. The crude material was purified by column

chromatography (SiO₂, 4:5:1 → 5:4:1 EtOAc/hexanes/CH₂Cl₂) to

yield the desired product (3.0 mg, 43%) as a yellow foam. This

compound lies on a failed route to strychnine, and it was not possible

to obtain complete characterization data for this compound prior

to abandoning this route: R_f= 0.7 (6:3:1 EtOAc/hexanes/CH₂Cl₂₎;

¹H NMR (500 MHz, CDCl₃) δ 9.48 (s, 1H, C17-H), 7.46−7.50 (m,

2H, Ph), 7.21−7.28 (m, 3H, Ph), 7.00−7.05 (m, 2H, C9-H + C11-H),

6.78 (dd, J = 5.1, 2.6 Hz, 1H, C15-H), 6.70 (t, J = 7.4 Hz, 1H, C10-H),

6.56 (d, J = 7.3 Hz, 1H, C12-H), 4.51 (br s, 1H, NH), 4.27 (s, 1H, C2-

H), 3.21−3.28 (m, 1H, C5-H), 2.97−3.13 (m, 4H, C3-H + C20-H₂+

C21-H), 2.72−2.78 (m, 1H, C21-H), 2.61 (td, J = 10.1, 4.5 Hz, 1H,

C5-H), 2.47−2.54 (m, 1H, C14-H), 2.33−2.40 (m, 1H, C14-H), 2.22

(ddd, J = 12.8, 8.3, 4.5 Hz, 1H, C6-H), 1.93 (ddd, J = 12.8, 10.4, 6.6

Hz, 1H, C6-H); LRMS (LC-ESI) m/z calcd for C₂₃H₂₅N₂OSe (M + H)⁺

425.1/423.1, found 425.1/423.1.

Tryptamine S12. To a solution of technical grade (90%) 3-

chloro-2-methylpropene (1.00 mL, ∼9.14 mmol, 1.0 equiv) and

tryptamine (4.40 g, 27.4 mmol, 3.0 equiv) in CH₃CN (138 mL, 0.2 M

in amine) were added K₂CO₃(1.25 g, 9.14 mmol, 1.0 equiv) and NaBr

(188 mg, 1.83 mmol, 0.20 equiv). The reaction mixture was stirred at

rt for 13 h and then diluted with EtOAc (100 mL), saturated aqueous

NaHCO₃(50 mL), and H₂O (100 mL). The organic layer was washed

with H₂O (50 mL) and brine (50 mL) and then dried over Na₂SO₄.

The solvent was evaporated in vacuo, and the crude material was

purified by column chromatography (SiO₂, 0.4:3.6:96 → 0.6:5.4:94

NH₄OH/MeOH/CH₂Cl₂) to yield the desired product (969 mg,

1

49%) as a brown oil: R_f= 0.4 (1:9:90 NH₄OH/MeOH/CH₂Cl₂); H

NMR (500 MHz, CDCl₃) δ 8.10 (br s, 1H, N_a-H), 7.65 (d, J = 7.9 Hz,

1H, indole C4-H), 7.37 (d, J = 8.1 Hz, 1H, indole C7-H), 7.21 (dd, J =

8.1, 7.5 Hz, 1H, indole C6-H), 7.13 (dd, J = 7.9, 7.5 Hz, 1H, indole

C5-H), 7.06 (d, J = 2.0 Hz, 1H, indole C2-H), 4.85 (s, 1H, C=CH),

4.82 (s, 1H, C=CH), 3.21 (s, 2H, N_bCH₂), 3.00−3.04 (m, 2H,

ArCH₂), 2.94−2.98 (m, 2H, CH₂N_b), 1.74 (br s, 1H, N_b-H), 1.71

(s, 3H, vinyl-CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 143.8, 136.4, 127.5,

122.1, 122.0, 119.3, 119.0, 114.1, 111.2, 110.8, 55.5, 49.3, 25.7, 20.9; IR

(thin film) ν 3414, 2917, 1456, 1106, 893, 740 cm⁻¹; HRMS (LC-ESI)

m/z calcd for C₁₄H₁₉N₂(M + H)⁺215.1548, found 215.1552.

Zincke Aldehyde 12h. Prepared according to general procedure

A using amine S12 (665 mg, 3.10 mmol) in EtOH (5 mL) at 80 °C for

1 h 20 min. The crude material was purified by column chromato-

graphy (SiO₂, 0:0:100 → 0.8:7.2:92 NH₄OH/MeOH/CH₂Cl₂) to

yield the desired product (347 mg, 80%) as a brown foam along with

recovered amine (244 mg, 70% recovery of excess). Further

purification by column chromatography (SiO₂, 4:5:1 → 5:4:1 EtOAc/

hexanes/CH₂Cl₂) and treatment with activated charcoal (∼0.3 g) in

CH₂Cl₂for 1 h, followed by filtration and solvent removal, gave a

yellow foam: R_f= 0.5 (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂); ¹H

NMR (500 MHz, CDCl₃) δ 9.30 (d, J = 8.3 Hz, 1H, CHO), 8.12 (br s,

1H, N_a-H), 7.58 (d, J = 7.7 Hz, 1H, indole C4-H), 7.41 (d, J = 7.9 Hz,

1H, indole C7-H), 7.24 (dd, J = 7.9, 7.3 Hz, 1H, indole C6-H), 7.16

(dd, J = 7.7, 7.3 Hz, 1H, indole C5-H), 7.03−7.11 (m, 1H, ZA β-CH),

7.03 (s, 1H, indole C2-H), 6.76 (d, J = 12.4 Hz, 1H, ZA δ-CH), 5.84

(dd, J = 13.8, 8.3 Hz, 1H, ZA α-CH), 5.34−5.44 (m, 1H, ZA γ-CH),

4.95 (s, 1H, CCH), 4.81 (s, 1H, CCH), 3.64 (s, 2H, N_b-CH₂),

3.47−3.53 (m, 2H, CH₂-N_b), 3.03−3.08 (m, 2H, Ar−CH₂), 1.69

Zincke Aldehyde 12f. Prepared according to general procedure B

using amine S11 (116 mg, 0.338 mmol) in i-PrOH (3 mL) and

MeOH (3 mL for solubility, 0.056 M total) at 0 °C for 40 min and

then rt for 20 min. The crude material was purified by column

chromatography (SiO₂, 0.1:1:99 → 0.5:4.5:95 NH₄OH/MeOH/

CH₂Cl₂) to yield the desired product (84 mg, 59%) as a red-orange

foam along with recovered amine (29 mg, 25% recovery). Further

purification by treatment with activated charcoal (∼60 mg) in CH₂Cl₂

for 1 h, followed by filtration and solvent removal, gave a yellow

foam. This compound lies on a failed route to strychnine, and full

characterization data for this compound was not obtained prior to

35

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Featured Article

(s, 3H, vinyl-CH₃); ¹³C NMR (125 MHz, DMSO, 373 K) δ 189.7,

155.7, 151.8, 139.9, 136.0, 126.7, 122.4, 120.4, 118.2, 117.8, 117.5,

112.0, 110.9, 110.6, 96.6, 56.9, 51.4, 22.7, 18.9; IR (thin film) ν 2967,

1557, 1152, 1016, 742 cm⁻¹; HRMS (LC-ESI) m/z calcd for

C₁₉H₂₂N₂ONa (M + Na)⁺317.1630, found 317.1627.

excess). Further purification of 12i by treatment with activated

charcoal (∼0.6 g) in CH₂Cl₂for 1 h, followed by filtration and solvent

removal, gave a yellow foam that turns brown upon storage at rt: R_f=

0.35 (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500 MHz,

CDCl₃) δ 9.30 (d, J = 8.3 Hz, 1H, CHO), 8.11 (br s, 1H, N_a-H), 7.57

(d, J = 7.8 Hz, 1H, indole C4-H), 7.41 (d, J = 8.2 Hz, 1H, indole C7-

H), 7.27−7.38 (m, 5H, Ph), 7.24 (dd, J = 8.3, 7.3 Hz, 1H, indole C6-

H), 7.16 (dd, J = 7.8, 7.3 Hz, 1H, indole C5-H), 7.05 (t, J = 14.4, 12.0

Hz, 1H, ZA β-CH), 7.00 (s, 1H, indole C2-H), 6.78 (d, J = 12.5 Hz,

1H, ZA δ-CH), 5.83 (dd, J = 14.4, 8.3 Hz, 1H, ZA α-CH), 5.49 (s, 1H,

vinyl-CH), 5.39 (dd, J = 12.5, 12.0 Hz, 1H, ZA γ-CH), 5.10 (s, 1H,

vinyl-CH), 4.11 (s, 2H, N_b-CH₂), 3.52 (t, J = 7.2 Hz, 2H, CH₂-N_b),

3.05 (t, J = 7.2 Hz, 2H, Ar-CH₂); ¹³C NMR (125 MHz, DMSO, 373

K) δ 189.8, 155.6, 151.7, 142.5, 138.2, 136.0, 127.8, 127.3, 126.7,

125.6, 122.4, 120.4, 118.4, 117.8, 117.5, 114.0, 110.9, 110.6, 96.8, 54.8,

51.2, 22.6; IR (thin film) ν 2923, 1574, 1557, 1150, 742 cm⁻¹; HRMS

(LC-ESI) m/z calcd for C₂₄H₂₅N₂O (M + H)⁺357.1967, found

357.1966.

Tetracycle 7i. Prepared according to general procedure C using

Zincke aldehyde 12i (126 mg, 0.353 mmol) in THF (5.9 mL, 0.06 M)

at 80 °C for 3 h. The crude material was purified by column

chromatography (SiO₂, 0:0:100 → 0.1:0.9:99 NH₄OH/MeOH/

CH₂Cl₂) to yield the desired product (64 mg, 51%) as a yellow

foam. A reaction performed on 260 mg of 12i at 0.04 M gave 170 mg

(65%): R_f= 0.6 (0.3:2.7:97 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500

MHz, CDCl₃) δ 9.44 (s, 1H, C17-H), 7.45 (d, J = 7.3 Hz, 2H, Ph),

7.24−7.31 (m, 3H, Ph), 6.98−7.04 (m, 2H, C9-H + C11-H), 6.74 (dd,

J = 4.8, 3.1 Hz, 1H, C15-H), 6.68 (t, J = 7.3 Hz, 1H, C10-H), 6.54 (d,

J = 7.7 Hz, 1H, C12-H), 5.42 (s, 1H, C19-H), 5.26 (s, 1H, C19-H),

4.47 (br s, 1H, NH), 4.24 (s, 1H, C2-H), 3.83 (d, J = 13.6 Hz, 1H,

C21-H), 3.36 (d, J = 13.6 Hz, 1H, C21-H), 3.16 (app t, J = 3.2 Hz, 1H,

C3-H), 3.08−3.14 (m, 1H, C5-H), 2.59−2.69 (s, 2H, C5-H + C14-H),

2.42 (app d, J = 19.8 Hz, 1H, C14-H), 2.15 (ddd, J = 13.0, 8.7, 4.7 Hz,

1H, C6-H), 1.93 (ddd, J = 13.0, 10.2, 6.5 Hz, 1H, C6-H); ¹³C NMR

(125 MHz, CDCl₃) δ 194.7, 150.31, 150.28, 145.5, 140.9, 140.1, 132.0,

128.2, 128.1, 127.6, 126.4, 123.0, 118.6, 114.4, 109.2, 63.8, 59.6, 58.2,

53.5, 50.6, 37.4, 25.8; IR (thin film) ν 2923, 2811, 1682, 1485, 1182,

908, 744 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₂₄H₂₅N₂O (M + H)⁺

357.1967, found 357.1974.

Tetracycle 7h. Prepared according to general procedure C using

Zincke aldehyde 12h (123 mg, 0.418 mmol) in THF (7.0 mL, 0.06 M)

at 80 °C for 2.5 h. The crude material was purified by column

chromatography (SiO₂, 0:0:100 → 0.2:1.8:98 NH₄OH/MeOH/

CH₂Cl₂) to yield the desired product (69 mg, 56%) as a yellow oil:

1

R_f= 0.6 (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂); H NMR (500 MHz,

CDCl₃) δ 9.49 (s, 1H, C17-H), 7.09 (d, J = 7.5 Hz, 1H, C9-H), 7.03

(dd, J = 7.8, 7.6 Hz, 1H, C11-H), 6.81 (dd, J = 5.1, 3.2 Hz, 1H, C15-

H), 6.72 (dd, J = 7.6, 7.5 Hz, 1H, C10-H), 6.57 (d, J = 7.8 Hz, 1H,

C12-H), 4.89 (s, 1H, C19-H), 4.79 (s, 1H, C19-H), 4.52 (br s, 1H,

NH), 4.32 (s, 1H, C2-H), 3.30 (d, J = 13.2 Hz, 1H, C21-H), 3.07−

3.13 (m, 2H, C3-H + C5-H), 2.90 (d, J = 13.2 Hz, 1H, C21-H), 2.53−

2.62 (m, 2H, C5-H + C14-H), 2.36−2.44 (m, 1H, C14-H), 2.18 (ddd,

J = 12.6, 8.7, 4.9 Hz, 1H, C6-H), 1.95 (ddd, J = 12.6, 10.3, 6.6 Hz, 1H,

C6-H), 1.69 (s, C18-H₃); ¹³C NMR (125 MHz, CDCl₃) δ 194.9,

150.6, 150.3, 144.0, 140.9, 132.3, 128.2, 123.0, 118.6, 111.8, 109.2,

63.9, 60.6, 59.7, 53.5, 51.1, 37.5, 26.0, 20.7; IR (thin film) ν 3390,

2917, 2810, 1682, 1485, 743 cm⁻¹; HRMS (LC-ESI) m/z calcd for

C₁₉H₂₃N₂O (M + H)⁺295.1810, found 295.1810.

α-Bromomethylstyrene (S13). According to the procedure of

Suginome,^84aa mixture of α-methylstyrene (1.90 mL, 14.7 mmol,

1.0 equiv) and N-bromosuccinimide (3.00 g, 16.9 mmol, 1.15 equiv) in

CHCl₃(3.0 mL, 5.0 M) was heated to 80 °C for 16 h, cooled to 0 °C,

filtered to remove precipitated succinimide, and concentrated in vacuo.

To remove the remaining succinimide, the crude mixture was taken up

in Et₂O (100 mL), washed with H₂O (2 × 25 mL) and brine (25 mL),

and dried over MgSO₄. The solvent was evaporated in vacuo, and the

crude material (3.08 g, mixture of desired allylic bromide and

corresponding vinyl bromide ∼4:1) was used without further

purification. The spectral data for the major (desired) product S13

were consistent with literature values:^84b¹H NMR (600 MHz, CDCl₃)

δ 7.50 (d, J = 7.5 Hz, 2H, Ar-H), 7.39 (t, J = 7.5 Hz, 2H, Ar-H), 7.33−

7.36 (m, 1H, Ar-H), 5.57 (s, 1H, vinyl-H), 5.50 (s, 1H, vinyl-H), 4.40

(2, 2H, CH₂Br).

Tryptamine S14. A solution of crude bromide S13 (2.95 g,

mixture of isomers, <11.4 mmol allylic bromide) and tryptamine (6.76 g,

42.2 mmol, 3−3.5 equiv) in CH₃CN (70 mL, 0.6 M in tryptamine)

was stirred at rt for 16 h. The reaction mixture was diluted with H₂O

(50 mL), EtOAc (120 mL), saturated aqueous NaHCO₃(50 mL), and

hexanes (80 mL). The organic layer was washed with brine (50 mL)

and dried over Na₂SO₄. The solvent was evaporated in vacuo and the

crude material was purified by column chromatography (SiO₂,

0.2:1.8:98 → 0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂) to yield the

desired product (0.41 g) as a brown solid and mixed material

(1.6 g). The mixed material was further purified by column chromato-

graphy (SiO₂, 0.1:0.9:99 → 0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂) to

yield additional desired product (1.38 g, ∼60% total yield over two

steps): mp =82−83 °C; R_f= 0.25 (0.5:4.5:95 NH₄OH/MeOH/

CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 7.97 (br s, 1H, N_a-H), 7.20

(d, J = 7.9 Hz, 1H, indole C4-H), 7.34−7.39 (m, 3H, Ph + indole C7-

H), 7.24−7.32 (m, 3H, Ph), 7.21 (dd, J = 8.0, 7.2 Hz, 1H, indole C6-

H), 7.12 (dd, J = 7.9, 7.2 Hz, 1H, indole C5-H), 6.95 (d, J = 2.1 Hz,

1H, indole C2-H), 5.37 (app s, 1H, vinyl-CH), 5.22 (d, J = 1.1 Hz, 1H,

vinyl-CH), 3.70 (s, 2H, N_bCH₂), 2.96−3.03 (m, 4H, CH₂CH₂), 1.52

(br s, 1H, N_b-H); ¹³C NMR (125 MHz, CDCl₃) δ 146.5, 140.0, 136.4,

128.5, 127.6, 127.5, 126.2, 122.1, 121.8, 119.3, 119.0, 114.1, 113.2,

111.2, 53.4, 49.2, 25.8; IR (thin film) ν 3417, 3054, 2920, 1456, 1101,

741 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₉H₂₁N₂(M + H)⁺

277.1705, found 277.1707.

4-Tosyloxy-2-butyn-1-ol (S15). This reaction is a modification

of the procedure of Tanabe.^85aTo a solution of 1,4-butynediol (7.75 g,

90.0 mmol, 5 equiv), NEt₃(4.00 mL, 28.8 mmol, 1.6 equiv) and

Me₃N·HCl (172 mg, 1.8 mmol, 0.10 equiv) in CH₃CN (60 mL) at

−6 °C was added TsCl (3.43 g, 18.0 mmol, 1.0 equiv) in one portion.

The reaction mixture was stirred at −6 °C for 40 min, warmed to rt,

and quenched with H₂O (150 mL) and EtOAc (150 mL). The

aqueous layer was extracted with EtOAc (100 mL). The combined

organics were washed with half-saturated aqueous NH₄Cl (80 mL)

and brine (100 mL) and dried over Na₂SO₄. The solvent was

evaporated in vacuo, and the crude material (∼10:1 mono-OTs/bis-

OTs) was purified by column chromatography (SiO₂, 3:7 → 1:1

EtOAc/hexanes) to yield the desired product (2.74 g, 63%) as a

light yellow oil. This compound has been previously synthesized (no

procedure given):^85b¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, J = 8.3

Hz, 2H, ArH), 7.37 (d, J = 8.3 Hz, 2H, ArH), 4.75 (t, J = 1.6 Hz, 2H,

TsOCH₂), 4.18 (dt, J = 6.2, 1.6 Hz, 2H, CH₂OH), 2.47 (s, 3H,

ArCH₃), 1.39 (t, J = 6.2 Hz, 1H).

Tryptamine S16. To a solution of tosylate S15 (2.16 g, 8.99 mmol,

1.0 equiv) in THF (20 mL, 0.45 M) was added LiBr (1.17 g,

13.5 mmol, 1.5 equiv). The reaction mixture warmed (minor

exotherm) and was stirred at rt for 45 min. To the resulting mixture

were added tryptamine (4.3 g, 27 mmol, 3.0 equiv) and THF (40 mL,

final concentration = 0.15 M), and stirring was continued at rt for

15 h. The reaction mixture was quenched with saturated aqueous

NaHCO₃(100 mL), followed by EtOAc (150 mL) and H₂O (50 mL).

The aqueous layer was extracted with EtOAc (100 mL). The

combined organics were washed with saturated aqueous NaHCO₃

(65 mL) and brine (40 mL) and dried over Na₂SO₄. The solvent was

evaporated in vacuo, and the crude material was purified by column

chromatography (SiO₂, 0.5:4.5:95 → 1:9:90 NH₄OH/MeOH/

Zincke Aldehyde 12i. Prepared according to general procedure A

using amine S14 (1.37 g, 4.96 mmol) in EtOH (16.5 mL) at 80 °C for

2.5 h. The crude material was purified by column chromatography

(SiO₂, 0:1 → 1:3 EtOAc/CH₂Cl₂) to yield the desired product (643

mg, 76%) as a brown foam. Further elution (→ 0.3:2.7:97 NH₄OH/

MeOH/CH₂Cl₂) gave recovered amine (660 mg, 92% recovery of

36

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CH₂Cl₂) to yield the desired product (1.37 g, 67%) as a light yellow

oil: R_f= 0.25 (1:9:90 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500

MHz, CDCl₃) δ 8.44 (br s, 1H, N_a-H), 7.62 (d, J = 7.8 Hz, 1H, indole

C4-H), 7.34 (d, J = 8.1 Hz, 1H, indole C7-H), 7.20 (dd, J = 8.1, 7.2

Hz, 1H, indole C6-H), 7.12 (dd, J = 7.8, 7.2 Hz, 1H, indole C5-H),

6.99 (d, J = 2.1 Hz, 1H, indole C2-H), 4.20 (t, J = 1.7 Hz, 2H,

CH₂OH), 3.39 (t, J = 1.7 Hz, 2H, N_bCH₂), 2.94−3.02 (m, 4H,

CH₂CH₂), 2.64 (br s, 2H, N_b-H + OH); ¹³C NMR (125 MHz,

CDCl₃) δ 136.7, 127.5, 122.6, 122.2, 119.4, 119.0, 113.3, 111.6, 83.1,

82.7, 50.8, 48.7, 38.5, 25.5; IR (thin film) ν 3288, 2918, 1456, 1338,

1011, 744 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₄H₁₇N₂O (M +

H)⁺229.1341, found 229.1334.

Zincke Aaldehyde S17. Prepared according to general procedure

B using S16 (535 mg, 2.34 mmol) in MeOH (16 mL, 0.15 M) at 0 °C

for 2.5 h. The crude material was purified by column chromatography

(SiO₂, 0:0:100 → 0.4:3.6:96 NH₄OH/MeOH/CH₂Cl₂) to yield the

desired product (341 mg, 47%) as an orange foam along with

recovered amine (111 mg, 21% recovery). A similar experiment on 253 mg

of amine using 1 M aqueous NaOH (1.66 mL, 1.5 equiv) as base in

MeOH gave 218 mg of product (64%), but purification was more

tedious. This compound lies on a failed route to strychnine, and full

characterization data for this compound was not obtained prior to

abandoning this route. Downstream compound 7k is fully

characterized: R_f= 0.4 (0.8:7.2:92 NH₄OH/MeOH/CH₂Cl₂); ¹H

NMR (500 MHz, CDCl₃) δ 9.29 (d, J = 8.3 Hz, 1H, CHO), 8.16 (br s,

1H, N_a-H), 7.60 (d, J = 7.8 Hz, 1H, indole C4-H), 7.41 (d, J = 8.1 Hz,

1H, indole C7-H), 7.24 (dd, J = 8.1, 7.2 Hz, 1H, indole C6-H), 7.17

(dd, J = 7.8, 7.2 Hz, 1H, indole C5-H), 7.04 (d, J = 2.1 Hz, 1H, indole

C2-H), 7.01 (dd, J = 14.3, 11.7 Hz, 1H, ZA β-CH), 6.66 (d, J = 12.8

Hz, 1H, ZA δ-CH), 5.87 (dd, J = 14.3, 8.3 Hz, 1H, ZA α-CH), 5.40

(dd, J = 12.8, 11.7 Hz, 1H, ZA γ-CH), 4.28 (s, 2H, CH₂OH), 3.93 (s,

2H, N_b-CH₂), 3.60 (t, J = 7.1 Hz, 2H, CH₂-N_b), 3.10 (t, J = 7.1 Hz,

2H, Ar−CH₂), 1.86 (br s, 1H, OH); HRMS (LC-ESI) m/z calcd for

C₁₉H₂₀N₂O₂Na (M + Na)⁺331.1422, found 331.1422.

Zincke Aldehyde 12k. This reaction is a modification of the

procedure of Trost.⁶⁸To a solution of S17 (204 mg, 0.662 mmol,

1.0 equiv) and Me₂Si(OEt)H (109 μL, 0.794 mmol, 1.2 equiv) in

CH₂Cl₂/acetone (2.5 mL + 0.5 mL, 0.2 M) at −10 °C was added

[Cp*Ru(CH₃CN)₃]PF₆(16.7 mg, 33 μmol, 0.05 equiv). The resulting

solution was stirred at −10 °C for 1 h and warmed to rt, and an

additional portion of [Cp*Ru(CH₃CN)₃]PF₆(16.7 mg, 33 μmol,

0.05 equiv) was added. The resulting solution was stirred at rt for 1.5

h, then concentrated in vacuo. The crude material was purified by

column chromatography (SiO₂, 0.2:1.8:98 → 0.5:4.5:95 NH₄OH/

MeOH/CH₂Cl₂) to yield the desired product (79 mg pure +37 mg

mixed with starting material, ∼48%) as a light brown foam. Treatment

with activated charcoal (∼0.1 g) in CH₂Cl₂for 1 h, followed by

filtration and solvent removal gave a yellow foam. This compound lies

on a failed route to strychnine, and full characterization data for this

compound was not obtained prior to abandoning this route.

Downstream compound 7k is fully characterized: R_f= 0.5

(0.8:7.2:92 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500 MHz,

CDCl₃) δ 9.30 (d, J = 8.3 Hz, 1H, CHO), 8.08 (br s, 1H, N_a-H),

7.56 (d, J = 7.8 Hz, 1H, indole C4-H), 7.41 (d, J = 8.1 Hz, 1H, indole

C7-H), 7.25 (dd, J = 8.1, 7.3 Hz, 1H, indole C6-H), 7.17 (dd, J = 7.8,

7.3 Hz, 1H, indole C5-H), 7.02−7.09 (m, 1H, ZA β-CH), 7.02 (s, 1H,

indole C2-H), 6.73 (d, J = 12.7 Hz, 1H, ZA δ-CH), 6.51 (s, 1H, vinyl-

CH), 5.84 (dd, J = 14.3, 8.3 Hz, 1H, ZA α-CH), 5.30−5.39 (m, 1H,

ZA γ-CH), 4.57 (s, 2H, CH₂O), 3.93 (s, 2H, N_b-CH₂), 3.49 (t, J = 7.3

Hz, 2H, CH₂-N_b), 3.06 (t, J = 7.3 Hz, 2H, Ar−CH₂), 0.23 (s, 6H,

SiCH₃); HRMS (LC-ESI) m/z calcd for C₂₁H₂₇N₂O₂Si (M + H)⁺

367.1842, found 367.1847.

NaHCO₃(2 mL) was added, followed by EtOAc (5 mL) and H₂O

(2 mL). The aqueous layer was extracted with EtOAc (5 mL), and the

combined organics were washed with brine (2 mL), then dried over

Na₂SO₄. The solvent was evaporated in vacuo, and the crude material

was purified by column chromatography (SiO₂, 0:0:100 → 0.5:4.5:95

NH₄OH/MeOH/CH₂Cl₂) to yield the desired tetracyclic product

(2.4 mg contaminated with 20% unidentified impurities, <10% yield)

as a yellow film, along with protodesilylated material and decomposition

products. The identity of the product was confirmed by synthesis via a

different route (see below): R_f= 0.4 (0.5:4.5:95 NH₄OH/MeOH/

CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 9.48 (s, 1H, C17-H), 7.01−

7.06 (m, 2H, C9-H + C11-H), 6.78−6.81 (m, 1H, C15-H), 6.71 (t, J =

7.6 Hz, 1H, C10-H), 6.59 (br s, 1H, C19-H), 6.56 (d, J = 7.6 Hz, 1H,

C12-H), 4.59 (d, J = 15.7 Hz, 1H, C18-H), 4.52 (d, J = 15.7 Hz, 1H,

C18-H), 4.50 (br s, 1H, NH), 4.27 (s, 1H, C2-H), 3.64 (dq, J = 13.7,

2.1 Hz, 1H, C21-H), 3.09−3.19 (m, 3H, C3-H + C5-H + C21-H), 2.59

(dd, J = 19.4, 4.8 Hz, 1H, C14-H), 2.49 (ddd, J = 10.3, 10.1, 4.8 Hz,

1H, C5-H), 2.39−2.47 (m, 1H, C14-H), 2.20 (ddd, J = 12.7, 8.5, 4.8

Hz, 1H, C6-H), 1.93 (ddd, J = 12.7, 10.4, 6.5 Hz, 1H, C6-H), 0.18

(s, 3H, SiCH₃), 0.15 (s, 3H, SiCH₃); ¹³C NMR (125 MHz, CDCl₃)

δ 194.7, 150.4, 150.2, 142.1, 141.1, 141.0, 131.5, 128.3, 122.8, 118.6,

109.3, 71.8, 63.7, 59.8, 54.7, 53.5, 51.8, 37.6, 26.2, 0.7, −0.2; IR (thin

film) ν 2922, 2849, 1682, 1485, 1070, 828, 744 cm⁻¹; HRMS (LC-

ESI) m/z calcd for C₂₁H₂₆N₂O₂SiNa (M + Na)⁺389.1661, found

389.1657.

1-Bromo-2-butyn-4-ol (S18). To a solution of monotosylate S15

(1.00 g, 4.16 mmol, 1 equiv) in acetone (6.6 mL, 0.6 M) was added

LiBr (0.72 g, 8.3 mmol, 2.0 equiv) which caused the mixture to warm

(minor exotherm). The mixture was stirred at rt for 1 h and then

diluted with Et₂O (30 mL) and H₂O (15 mL). The organic layer was

washed with brine (5 mL) and dried over MgSO₄. The solvent was

evaporated in vacuo, and the crude material (577 mg, ∼90%) was used

1

without further purification: H NMR (500 MHz, CDCl₃) δ 4.34 (dt,

J = 6.2, 2.0 Hz, 2H, CH₂O), 3.96 (t, J = 2.0 Hz, 2H, BrCH₂), 1.68 (t,

J = 6.2 Hz, 1H, OH); ¹³C NMR (125 MHz, CDCl₃) δ 84.9, 80.9,

51.2, 14.2.

Tetracycle S19. To a solution of 7g (42.8 mg, 0.153 mmol,

1 equiv) and barbituric acid 77 (82.7 mg, 0.336 mmol, 2.2 equiv) in

CDCl₃(0.76 mL, 0.2 M) at 0 °C was added Pd(PPh₃)₄(8.8 mg,

7.7 μmol, 5 mol %). The reaction mixture was stirred at 0 °C for 1 h. To

the reaction mixture were added diisopropylethylamine (93 μL,

0.536 mmol, 3.5 equiv) and propargylic bromide S18 (57 mg, 0.38 mmol,

2.5 equiv) via syringe. The resulting solution was stirred at 0 °C for

4 h, then placed in a fridge (∼4 °C) for 15 h, removed, and stirred

with warming to rt. The reaction mixture was diluted with EtOAc

(10 mL), saturated aqueous NaHCO₃(4 mL), and H₂O (2 mL). The

layers were separated, and the aqueous layer was extracted with EtOAc

(5 mL). The combined organic extracts were washed with aqueous

NaHCO₃(3 mL) and brine (3 mL) and then dried over Na₂SO₄. The

solvent was evaporated in vacuo, and the crude material was purified

by column chromatography (SiO₂, 0.1:0.9:99 → 0:20:80 → 0.4:3.6:96

NH₄OH/MeOH/CH₂Cl₂) to yield the desired product (32.7 mg,

69%) as a yellow foam: R_f= 0.4 (1:9:90 NH₄OH/MeOH/CH₂Cl₂);

¹H NMR (500 MHz, CDCl₃) δ 9.46 (s, 1H, C17-H), 7.08 (d, 1H, J =

7.3 Hz C9-H), 7.04 (dd, J = 7.8, 7.3 Hz, C11-H), 6.78−6.82 (m, 1H,

C15-H), 6.72 (t, J = 7.3 Hz, 1H, C10-H), 6.56 (d, J = 7.8 Hz, 1H, C12-

H), 4.51 (br s, 1H, NH), 4.36 (s, 2H, C18-H₂), 4.31 (s, 1H, C2-H),

3.61 (app d, J = 17.6 Hz, 1H, C21-H), 3.53 (app d, J = 17.6 Hz, 1H,

C21-H), 3.37 (app d, J = 4.2 Hz, 1H, C3-H), 3.14−3.20 (m, 1H, C5-

H), 2.96 (td, J = 10.1, 4.8 Hz, 1H, C5-H), 2.56 (dd, J = 19.7, 5.6 Hz,

1H, C14-H), 2.38−2.45 (m, 1H, C14-H), 2.27 (ddd, J = 12.9, 8.3, 4.9

Hz, 1H, C6-H), 1.94 (ddd, J = 12.8, 10.3, 6.7 Hz, 1H, C6-H), 1.88 (br s,

1H, OH); ¹³C NMR (125 MHz, CDCl₃) δ 194.9, 150.5, 150.1, 140.8,

131.2, 128.4, 122.7, 118.7, 109.4, 83.7, 80.3, 61.3, 59.7, 53.5, 51.2, 49.9,

40.8, 38.2, 25.6; IR (thin film) ν 3394, 2923, 2245, 1674, 1485, 1101,

1018 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₉H₂₁N₂O₂(M + H)⁺

309.1603, found 309.1610.

Tetracycle 7k. General procedure C yielded only protodesilyla-

tion and decomposition. Modified procedure: To a solution of Zincke

aldehyde 12k (19.8 mg, 54.0 μmol) in THF (0.7 mL) was added

a freshly prepared solution of KHMDS (142 μL, 0.4 M in THF,

56.8 μmol, 1.05 equiv), yielding an orange, slightly cloudy solution.

This solution was transferred to a Schlenk tube, rinsing with THF (0.3 mL,

final concentration 0.045 M). The tube was tightly sealed and heated

to 80 °C for 2 h, then cooled to rt. A saturated aqueous solution of

Tetracycle 7k (Alternative Synthesis). This reaction is a

modification of the procedure of Trost.⁶⁸To a solution of propargyl

alcohol S19 (42.0 mg, 0.136 mmol, 1.0 equiv) and Me₂Si(OEt)H

37

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(22.5 μL, 0.163 mmol, 1.2 equiv) in acetone (0.7 mL, 0.2 M) at 0 °C

was added [Cp*Ru(CH₃CN)₃]PF₆(4.3 mg, 7.0 μmol, 0.05 equiv).

The resulting solution was stirred at 0 °C for 5 min, warmed to rt and

stirred at rt for 70 min, then concentrated in vacuo. The crude material

was purified by column chromatography (SiO₂, 0.1:0.9:99 →

0.3:2.7:97 NH₄OH/MeOH/CH₂Cl₂) to yield the desired product

(16.8 mg, 34%) as a yellow foam. (Spectral data tabulated above for

alternate synthesis.)

product (1.19 g, quant) was isolated as a cream solid and used without

further purification. The spectral data were consistent with literature

values.⁸⁷

N-Benzyl-3-(3-indolyl)propylamine (S22). This reaction is a

modification of the procedure of Mewshaw et al.⁸⁸To a solution of

amide S21 (1.19 g, ≤ 4.23 mmol, 1.0 equiv) in THF (8.5 mL, 0.50 M)

cooled in an ice−water bath (0 °C) was added LiAlH₄(482 mg,

12.7 mmol, 3.0 equiv) in three portions over 5 min, and then the mixture

was allowed to warm to rt and stirred for 15 min. The reaction mixture

was then heated to reflux (70 °C oil bath) for 2 h and then cooled

to rt. To the vigorously stirring reaction mixture were added H₂O

(1.3 mL), 0.4 M NaOH (1.3 mL), H₂O (3 × 1.3 mL), and a small scoop

of MgSO₄(∼100 mg). After being stirred at rt for 10 min, the mixture

was filtered, and the white filter cake was washed with EtOAc. The filtrate

was concentrated in vacuo, and the residue was dissolved in EtOAc (50

mL), dried over anhydrous Na₂SO₄, filtered, and concen-

trated in vacuo. The crude material (∼1.2 g) was purified by column

chromatography (SiO₂, 0:5:95, then 0.5:4.5:95 − 0.7:6.3:93 NH₄OH/

MeOH/CH₂Cl₂) to yield the desired product as a viscous, light brown oil

(840 mg, 75% over two steps). The spectral data were consistent with

literature values.⁸⁹

Tryptamine S20. A solution of 1-bromo-2-butyne (0.30 mL,

3.30 mmol, 1.0 equiv), tryptamine (1.6 g, 9.97 mmol, 3.0 equiv), and NEt₃

(0.69 mL, 5.0 mmol, 1.5 equiv) in THF (33 mL, 0.1 M) was stirred at

rt for 19 h. The reaction mixture was quenched with saturated aqueous

NaHCO₃(20 mL), followed by EtOAc (100 mL) and H₂O (50 mL).

The organic layer was washed with H₂O (40 mL) and brine (40 mL)

and then dried over Na₂SO₄. The solvent was evaporated in vacuo,

and the crude material was purified by column chromatography

(SiO₂, 0.3:2.7:97 → 0.6:5.6:94 NH₄OH/MeOH/CH₂Cl₂) to yield the

desired product (404 mg, 57%) as a tan solid: mp = 97−99 °C;

R_f= 0.3 (1:9:90 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500 MHz,

CDCl₃) δ 8.08 (br s, 1H, N_a-H), 7.66 (d, J = 7.8 Hz, 1H, indole C4-

H), 7.38 (d, J = 8.1 Hz, 1H, indole C7-H), 7.21 (dd, J = 8.1, 7.3 Hz,

1H, indole C6-H), 7.13 (dd, J = 7.8, 7.3 Hz, 1H, indole C5-H), 7.07

(d, J = 1.9 Hz, 1H, indole C2-H), 3.40 (q, J = 2.3 Hz, 2H, N_bCH₂),

2.98−3.06 (m, 4H, CH₂CH₂), 1.80 (t, J = 2.3 Hz, 3H, alkyne-CH₃),

1.46 (br s, 1H, N_b-H); ¹³C NMR (125 MHz, CDCl₃) δ 136.5, 127.5,

122.1, 122.0, 119.3, 119.0, 114.0, 111.2, 79.0, 77.3, 48.9, 38.6, 25.7, 3.6;

IR (thin film) ν 3410, 2918, 2238, 1456, 1339, 742 cm⁻¹; HRMS (LC-

ESI) m/z calcd for C₁₄H₁₇N₂(M + H)⁺213.1392, found 213.1391.

Zincke Aldehyde 12l. Prepared according to general procedure B

using amine S20 (182 mg, 0.857 mmol) in MeOH (5 mL, 0.15 M) at

0 °C for 1.5 h. The crude material was purified by column

chromatography (SiO₂, 0.1:0.9:99 → 0.2:1.8:98 NH₄OH/MeOH/

CH₂Cl₂) to yield the desired product (180 mg, 72%) as a red foam.

Further purification by column chromatography (SiO₂, 0:0:100 →

0.2:1.8:98 NH₄OH/MeOH/CH₂Cl₂) and treatment with activated

charcoal (∼150 mg) in CH₂Cl₂for 1 h, followed by filtration and

solvent removal gave a yellow foam: R_f= 0.5 (0.5:4.5:95 NH₄OH/

MeOH/CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 9.29 (d, J = 8.4 Hz,

1H, CHO), 8.46 (br s, 1H, N_a-H), 7.60 (d, J = 7.8 Hz, 1H, indole C4-

H), 7.40 (d, J = 8.1 Hz, 1H, indole C7-H), 7.23 (dd, J = 8.1, 7.2 Hz,

1H, indole C6-H), 7.16 (dd, J = 7.8, 7.2 Hz, 1H, indole C5-H), 7.00−

7.07 (m, 2H, ZA β-CH + indole C2-H), 6.70 (d, J = 12.4 Hz, 1H, ZA

δ-CH), 5.87 (dd, J = 14.3, 8.4 Hz, 1H, ZA α-CH), 5.41 (dd, J = 12.4,

12.1 Hz, 1H, ZA γ-CH), 3.87 (s, 2H, N_b-CH₂), 3.58 (t, J = 7.1 Hz, 2H,

CH₂-N_b), 3.09 (t, J = 7.1 Hz, 2H, Ar−CH₂), 1.85 (s, 3H, alkyne-CH₃);

¹³C NMR (125 MHz, DMSO, 373 K) δ 190.0, 155.4, 150.6, 136.0,

126.7, 122.5, 120.4, 119.0, 117.8, 117.5, 110.9, 110.5, 97.2, 80.6, 73.4,

51.8, 40.2, 22.9, 2.3; IR (thin film) ν 2920, 2850, 2239, 1574, 1567,

1145 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₉H₂₀N₂ONa (M + Na)⁺

315.1473, found 315.1469.

Tetracycle 7l. Prepared according to general procedure C using

Zincke aldehyde 12l (21.9 mg, 74.9 μmol) in THF (1.1 mL, 0.07 M)

at 80 °C for 2 h. Analysis of the crude material indicated substantial

decomposition, and only traces of the desired product (<2 mg, <10%)

could be isolated as a mixture with other decomposition products. It

was not possible to obtain reliable characterization data for this

compound.

N-Benzyl-3-(3-indolyl)propionamide (S21). This reaction is a

modification of the procedure of Pedras et al.⁸⁶To a solution of

indole-3-propionic acid (800 mg, 4.23 mmol, 1.0 equiv) and

triethylamine (1.76 mL, 12.7 mmol, 3.0 equiv) in THF (21 mL,

0.20 M) cooled in an ice−water bath (0 °C) was added methyl

chloroformate (344 μL, 4.44 mmol, 1.05 equiv) dropwise over 5 min.

After the mixture was stirred at 0 °C for 40 min, benzylamine (925 μL,

8.46 mmol, 2 equiv) was added, and the mixture was allowed to

warm to rt and stirred for 1.5 h. The reaction was diluted with EtOAc

(50 mL) and washed with 1 M HCl (30 mL). The aqueous layer was

extracted with EtOAc (20 mL). The combined organic extracts were

washed with 1 M HCl (15 mL) and brine (25 mL), dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo. The desired

Zincke Aldehyde 30. Prepared according to general procedure A

using homotryptamine S22 (688 mg, 2.60 mmol) in EtOH (5.2 mL,

0.5 M in amine) at 80 °C for 2 h. The crude material was purified by

column chromatography (SiO₂, 0:0:100 → 0.6:5.4:94 NH₄OH/

MeOH/CH₂Cl₂) to yield the desired product (360 mg, 95% pure

1

by H NMR, ∼81%) and recovered amine (285 mg, 82% recovery).

Further purification by column chromatography (SiO₂, 4:5:1 EtOAc/

hexanes/CH₂Cl₂) followed by charcoal treatment gave the desired

product (293 mg, 69%) as a yellow foam: R_f= 0.3 (0.5:4.5:95

1

NH₄OH/MeOH/CH₂Cl₂); H NMR (600 MHz, CDCl₃) δ 9.29 (d,

J = 8.4 Hz, 1H, CHO), 8.03 (br s, 1H, N_a-H), 7.54 (d, J = 7.9 Hz, 1H,

indole C4-H), 7.39 (d, J = 8.2 Hz, 1H, indole C7-H), 7.29−7.37 (m,

3H, Ph-H), 7.23 (dd, J = 7.9, 7.2 Hz, 1H, indole C6-H), 7.11−7.17 (m,

3H, Ph-H + indole C5-H), 7.07 (dd, J = 14.4, 11.6 Hz, 1H, ZA β-CH),

6.95 (d, J = 2.2 Hz, 1H, indole C2-H), 6.88 (d, J = 12.6 Hz, 1H, ZA

δ-CH), 5.75 (dd, J = 14.4, 8.4 Hz, 1H, ZA α-CH), 5.29 (dd, J = 12.6,

11.6 Hz, 1H, ZA γ-CH), 4.37 (s, 2H, CH₂Ph), 3.24 (t, J = 7.3 Hz, 2H,

CH₂N), 2.78 (t, J = 7.3 Hz, 2H, ArCH₂), 2.01 (quintet, J = 7.3 Hz, 2H,

ArCH₂CH₂); ¹³C NMR (125 MHz, DMSO, 373 K) δ 189.8, 155.8,

152.0, 136.5, 136.1, 128.0, 126.9, 126.8, 126.7, 121.7, 120.3, 118.4,

117.63, 117.62, 113.2, 110.8, 96.7, 54.8, 50.5, 27.2, 21.5; IR (thin film)

ν 2924, 1574, 1557, 1392, 1149, 742 cm⁻¹; HRMS (LC-ESI) m/z

calcd for C₂₃H₂₄N₂ONa (M + Na)⁺367.1786, found 367.1777.

Tetracycle 31. Prepared according to general procedure C using

Zincke aldehyde 30 (45.0 mg, 0.131 mmol) in THF (2.2 mL, 0.06 M)

at 80 °C for 2 h. Analysis of the crude material by ¹H NMR indicated a

mixture of tetracycle 31 (∼25%), Zincke aldehyde 30 (∼25%), amine

S22 (∼40%), and unknown byproducts (∼10%). The crude material

was purified by column chromatography (SiO₂, 4:96 EtOAc/CH₂Cl₂)

to yield the desired product (8.9 mg, 20%) as a light brown solid: R_f=

0.3 (5:95 EtOAc:CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃, 323 K)

δ 9.46 (s, 1H, C17-H), 7.31 (d, J = 7.6 Hz, 1H, C9-H), 7.18−7.28 (m,

5H, PhH), 7.03 (t, J = 7.6 Hz, 1H, C11-H), 6.74 (t, J = 7.6 Hz, 1H,

C10-H), 6.64 (t, J = 4.1 Hz, 1H, C15-H), 6.58 (d, J = 7.6 Hz, 1H, C12-

H), 4.42 (br s, 1H, NH), 4.41 (s, 1H, C2-H), 3.81 (d, J = 14.0 Hz, 1H,

C21-H), 3.44 (d, J = 14.0 Hz, 1H, C21-H), 3.06 (t, J = 4.8 Hz, 1H, C3-

H), 2.80−2.86 (m, 1H, C5-H), 2.77 (dt, J = 19.4, 4.8 Hz, 1H, C14-H),

2.43−2.52 (m, 2H, C5-H + C14-H), 1.83−1.98 (m, 2H, C6-H + C6′-

H), 1.75−1.83 (m, 1H, C6-H), 1.52 (ddd, J = 12.8, 9.3, 4.9 Hz, 1H,

C6′-H); ¹³C NMR (125 MHz, CDCl₃, 323 K) δ 194.7, 149.7, 149.6,

141.6, 139.7, 134.7, 128.5, 128.2, 128.0, 126.9, 124.3, 118.5, 110.0,

60.5, 59.4, 59.3, 51.0, 48.0, 33.2, 24.5, 22.6; IR (thin film) ν 3030,

2925, 2802, 1678, 1482, 738 cm⁻¹; HRMS (LC-ESI) m/z calcd for

C₂₃H₂₅N₂O (M + H)⁺345.1967, found 345.1966. Selected NOE

correlations for 31 can be found in the Supporting Information.

(Z)-α-Bromocrotonaldehyde (S23). This reaction is a modifica-

tion of the procedure of Dai et al.⁹⁰To a solution of trans-

crotonaldehyde (5.92 mL, 71.4 mmol, 1.0 equiv) in dry CH₂Cl₂

(100 mL, 0.71 M) cooled in an ice−water bath (0 °C) was added

38

dx.doi.org/10.1021/jo2020246 | J. Org. Chem. 2012, 77, 17−46

The Journal of Organic Chemistry

Featured Article

bromine (3.7 mL, 71.8 mmol, 1.01 equiv) in CH₂Cl₂(4 mL) dropwise

over 10 min, followed by stirring at 0 °C for 1 h. Triethylamine

(12 mL, 86.1 mmol, 1.21 equiv) was added, and the mixture was

allowed to stir at rt for 1.5 h. The reaction was quenched with

saturated aqueous Na₂S₂O₃(20 mL), and the organic layer was washed

with 1 M HCl (10 mL), brine (10 mL), dried over anhydrous MgSO₄,

filtered, and concentrated in vacuo. The desired product (9.44 g, 89%,

>95:5 Z:E) was isolated as a pale yellow liquid and used without

further purification. The spectral data of the crude product were

consistent with literature values.⁹⁰

CH₂Cl₂) to yield the desired product mixed with recovered amine

(4.64 g) as a viscous brown oil. Further purification by column

chromatography (SiO₂, 0:0:100 → 0.5:3:96.5 AcOH/MeOH/CH₂Cl₂)

gave desired product (1.79 g, 55%) as a brown foam. Further

purification by treatment with activated charcoal (∼2 g) in CH₂Cl₂for

1 h, followed by filtration and solvent removal gave a yellow foam: R_f=

0.4 (0.4:3.6:96 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500 MHz,

CDCl₃) δ 9.31 (d, J = 8.4 Hz, 1H, CHO), 8.12 (br s, 1H, N_a-H), 7.56

(d, J = 7.8 Hz, 1H, indole C4-H), 7.41 (d, J = 8.0 Hz, 1H, indole C7-

H), 7.24 (dd, J = 8.0, 7.5 Hz, 1H, indole C6-H), 7.16 (dd, J = 7.8,

7.5 Hz, 1H, indole C5-H), 7.10 (br dd, J = 14.3, 12.0 Hz, 1H, ZA

β-CH), 7.03 (d, J = 2.0 Hz, 1H, indole C2-H), 6.76 (d, J = 12.6 Hz,

1H, ZA δ-CH), 5.88 (dd, J = 14.3, 8.4 Hz, 1H, ZA α-CH), 5.79 (q, J =

6.6 Hz, 1H, CCH), 5.43 (dd, J = 12.6, 12.0 Hz, 1H, ZA γ-CH), 3.86

(s, 2H, N_b-CH₂), 3.52 (t, J = 7.2 Hz, 2H, CH₂-N_b), 3.06 (t, J = 7.2 Hz,

2H, Ar−CH₂), 1.77 (d, J = 6.6 Hz, 3H, CH₃); ¹³C NMR (125 MHz,

DMSO, 373 K) δ 190.0, 155.5, 151.3, 136.0, 126.8, 126.7, 123.0, 122.5,

120.5, 119.1, 117.9, 117.5, 110.9, 110.6, 97.1, 59.6, 50.4, 22.5, 15.7; IR

(thin film) ν 2914, 1581, 1557, 1138, 1016, 742 cm⁻¹; HRMS

(LC-ESI) m/z calcd for C₁₉H₂₂N₂OBr (M + H)⁺373.0916, found

373.0911.

(Z)-2-Bromo-2-buten-1-ol (S24). This reaction has been pre-

viously performed by Loh et al. (no experimental procedures given).⁹¹

To a solution of (Z)-α-bromocrotonaldehyde (S23) (9.44 g, 63.4 mmol,

1.0 equiv) in THF/H₂O (9:1, 160 mL, 0.4 M) cooled in an

ice−water bath (0 °C) was added sodium borohydride (1.48 g total,

38.0 mmol, 0.6 equiv) in three portions over 5 min, followed by

stirring at 0 °C for 30 min. The reaction was quenched with 1 M HCl

(10 mL) and warmed to rt. The reaction mixture was diluted with

EtOAc/hexanes (1:4, 175 mL) and H₂O (200 mL). The aqueous layer

was separated and extracted with EtOAc/hexanes (1:4, 175 mL). The

organic layer was separated and washed with brine (50 mL), dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo. The crude

material (8.23 g, 86%) was purified by Kugelrohr distillation (90 °C

oven temp, 15 mmHg) to give the desired product (7.48 g, 78%) as a

(Z)-2-Iodo-2-buten-1-ol (S25). This reaction is a modification of

the procedure of Krafft.⁹²To a solution of trans-crotonaldehyde (5.0 mL,

60 mmol, 1 equiv) in 1:1 THF/H₂O (300 mL) was added K₂CO₃

(10 g, 72 mmol, 1.2 equiv), followed by I₂(23 g, 90 mmol, 1.5 equiv)

and DMAP (1.47 g, 12.1 mmol, 0.2 equiv). After the mixture was stirred

at rt for 2 h, NaBH₄(2.5 g, 66 mmol, 1.1 equiv) was slowly added, and

the mixture lightened in color from purple to red. After the mixture was

stirred at rt for 45 min, saturated aqueous Na₂S₂O₃

(75 mL) was added. The mixture was extracted with ether (2 ×

100 mL). The combined organic extracts were washed with brine

(75 mL) and dried over MgSO₄. The solvent was evaporated in vacuo to

yield the desired product (9.8 g, 82%) as an orange oil that was used

1

pale yellow oil: H NMR (500 MHz, CDCl₃) δ 6.08 (q, J = 6.6 Hz,

1H, vinyl-H), 4.26 (s, 2H, OCH₂), 2.24 (br s, 1H, OH), 1.80 (d, J =

6.6 Hz, 3H, CH₃).

(Z)-1,2-Dibromo-2-butene (37).³⁹To a solution of allylic

alcohol S24 (4.26 g, 28.2 mmol) and NEt₃(4.90 mL, 35.3 mmol,

1.25 equiv) in THF (56 mL, 0.5 M) at −30 °C was added

methanesulfonyl chloride (2.62 mL, 33.9 mmol, 1.2 equiv). The

solution was stirred at −30 °C for 1 h, LiBr (6.10 g, 70.5 mmol,

2.5 equiv) was added, and the reaction mixture was warmed to rt and

stirred for 4 h. The reaction was diluted with hexanes (100 mL) and

quenched with H₂O (100 mL). The layers were separated, and the

aqueous layer was extracted with hexanes (100 mL). The combined

organic extracts were washed with H₂O (50 mL) and brine (50 mL)

and dried over MgSO₄. The solvent was removed in vacuo to give the

desired product as a yellow oil (6.33 g, ∼90% pure by ¹H NMR) that

1

without further purification: H NMR (500 MHz, CDCl₃) δ 5.98 (q,

J = 6.4 Hz, 1H, vinyl-H), 4.25 (d, J = 6.5 Hz, 2H, OCH₂), 2.03 (t, J = 6.5

Hz, 1H, OH), 1.79 (d, J = 6.6 Hz, 3H, CH₃).

(Z)-1-Bromo-2-iodo-2-butene (79).^14bTo a solution of the

crude allylic alcohol S25 (9.8 g, ∼49 mmol, 1 equiv) and NEt₃

(9.6 mL, 69 mmol, 1.4 equiv) in THF (125 mL) at −30 °C was added

methanesulfonyl chloride (4.6 mL, 59 mmol, 1.2 equiv). The solution

was stirred at −30 °C for 1 h, LiBr (11.0 g, 124 mmol, 2.5 equiv) was

added, and the reaction mixture was warmed to rt and stirred for 2 h.

Saturated NH₄Cl (75 mL) was added, followed by H₂O (25 mL). The

mixture was extracted with EtOAc (2 × 100 mL), and the combined

organic extracts were washed with Na₂S₂O₃(75 mL) and brine

(75 mL) and dried over MgSO₄. The solvent was removed in vacuo to

give the desired product as a light brown oil (10 g, 80%, ∼90% pure by

1

was used without further purification: H NMR (500 MHz, CDCl₃)

δ 6.20 (q, J = 6.6 Hz, 1H, vinyl-H), 4.26 (s, J = 6.5 Hz, 2H, BrCH₂),

1.79 (d, J = 6.6 Hz, 3H, CH₃).

Tryptamine 38. To a solution of tryptamine (10.8 g, 67.2 mmol,

3.3 equiv) in CH₃CN (350 mL, 0.19 M in amine) was added crude 37

(4.79 g, ∼90% pure, ∼20.2 mmol). After being stirred for 14 h at rt,

the reaction mixture was concentrated in vacuo, and the crude residue

was diluted with EtOAc (200 mL), saturated aqueous NaHCO₃

(150 mL), and H₂O (150 mL). The layers were separated, and the

aqueous layer was extracted with EtOAc (100 mL). The combined

organic extracts were washed with 1 M NaOH (50 mL) and brine

(120 mL) and dried over Na₂SO₄. The solvent was evaporated in

vacuo, and the crude material (10.7 g) was purified by column

chromatography (SiO₂, 0:0.8:100−0.6:5.4:94 NH₄OH/MeOH/

CH₂Cl₂) to yield the desired product as a viscous, brown oil (4.96 g,

84% over two steps): R_f= 0.2 (0.4:3.6:96 NH₄OH/MeOH/CH₂Cl₂);

¹H NMR (500 MHz, CDCl₃) δ 8.02 (br s, 1H, N_a-H), 7.63 (d, J = 7.9

Hz, 1H, indole C4-H), 7.37 (d, J = 8.0 Hz, 1H, indole C7-H), 7.21

(dd, J = 8.0, 7.4 Hz, 1H, indole C6-H), 7.13 (dd, J = 7.9, 7.4 Hz, 1H,

indole C5-H), 7.07 (d, J = 1.7 Hz, 1H, indole C2-H), 5.88 (q, J =

6.6 Hz, 1H, CCH), 3.51 (s, 2H, N_bCH₂), 2.99 (t, J = 7.2 Hz, 2H,

CH₂-N_b), 2.89 (t, J = 7.2 Hz, 2H, Ar−CH₂), 1.74 (d, J = 6.6 Hz, 3H,

CH₃), 1.61 (br s, 1H, N_b-H); ¹³C NMR (125 MHz, CDCl₃) δ 136.4,

128.4, 127.5, 125.1, 122.1, 121.9, 119.3, 119.0, 114.1, 111.2, 57.9, 48.0,

25.9, 16.6; IR (thin film) ν 3413, 2918, 2851, 1456, 1108, 741 cm⁻¹;

HRMS (LC-ESI) m/z calcd for C₁₄H₁₈N₂Br (M + H)⁺293.0653,

found 293.0656.

1

¹H NMR) that was used without further purification: H NMR (500

MHz, CDCl₃) δ 6.05 (q, J = 6.5 Hz, 1H, vinyl-H), 4.36 (s, 2H,

BrCH₂), 1.81 (d, J = 6.5, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃)

δ 136.1, 103.5, 43.5, 22.3; IR (thin film) ν 2922, 2368, 1208 cm⁻¹.

Tetracycle 36. To a solution of 7g (268.5 mg, 0.958 mmol, 1

equiv) and 5-methyl Meldrum’s acid (333.4 mg, 2.11 mmol, 2.2 equiv)

in CDCl₃(4.8 mL, 0.2 M) at 0 °C was added Pd(PPh₃)₄(56.0 mg,

47.9 μmol, 5 mol %). The reaction mixture was stirred at 0 °C for 1 h,

1

at which point H NMR analysis of an aliquot indicated complete

deallylation. To the reaction mixture were added diisopropylethyl-

amine (550 μL, 3.352 mmol, 3.5 equiv) and allylic bromide 79

(570 mg, 2.107 mmol, 2.2 equiv), rinsing with CH₃CN (total volume =

4.8 mL CH₃CN). The resulting solution was stirred at 0 °C for 2.5 h,

diluted with EtOAc (10 mL) and saturated aqueous NaHCO₃(10 mL),

and warmed to rt. The mixture was diluted with EtOAc (10 mL) and

H₂O (5 mL). The layers were separated, and the aqueous layer was

extracted with EtOAc (10 mL). The combined organic extracts were

washed with aqueous NaHCO₃(10 mL) and brine (10 mL) and then

dried over Na₂SO₄. The solvent was evaporated in vacuo, and the crude

material was purified by column chromatography (SiO₂, 0.4:3.6:96 →

0.8:7.2:92 NH₄OH/MeOH/CH₂Cl₂) to yield the desired product

(275.8 mg, 68%) as a yellow foam. Spectral data were identical with our

previously reported data.^15,73

Zincke Aldehyde 39. Prepared according to general procedure A

using 38 (5.40 g, 18.42 mmol) in EtOH (61 mL, 0.3 M in amine) at

80 °C for 3 h 20 min. The crude material was purified by column

chromatography (SiO₂, 0:0:100 → 0.4:3.6:96 NH₄OH/MeOH/

39

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The Journal of Organic Chemistry

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Allylic Alcohol 46. To a solution of enal 36 (19 mg, 45.2 μmol,

1.0 equiv) in THF/H₂O (9:1, 0.5 mL + 60 μL, 0.01 M) at 0 °C was

added NaBH₄(1.6 mg, 27.1 μmol, 0.06 equiv). The reaction mixture

was stirred at 0 °C for 1 h, quenched with 0.1 M HCl (5 drops),

diluted with EtOAc (8 mL) and H₂O (2 mL), and warmed to rt. The

layers were separated, and the organic layer was extracted with EtOAc

(4 mL). The combined organics were washed with brine (2 mL), and

dried over Na₂SO₄. The solvent was evaporated in vacuo and the crude

material was purified by column chromatography (SiO₂, 0.2:1.8:98 →

0.4:3.6:96 NH₄OH/MeOH/CH₂Cl₂) to yield the desired product

(16.9 mg, 88%) as a light yellow foam. A reaction performed on 220.1 mg

of 36 gave 183.3 mg (83%): R_f= 0.4 (0.5:4.5:95 NH₄OH/MeOH/

(d, J = 7.5 Hz, 1H, C9-H), 7.35 (t, J = 7.7 Hz, 1H, C11-H), 7.23 (t, J =

7.5 Hz, 1H, C10-H), 6.02 (s, 1H, C17-H), 5.51 (q, J = 6.8 Hz,

1H, C19-H), 5.39 (s, 1H, C17-H), 4.08 (s, 1H, C3-H), 3.85 (s, 1H,

C15-H), 3.75 (d, J = 15.0 Hz, 1H, C21-H), 3.31−3.38 (m, 1H, C5-H),

3.28 (d, J = 15.0 Hz, 1H, C21-H), 3.20−3.25 (m, 1H, C5-H), 2.43

(ddd, J = 13.0, 9.3, 6.5 Hz, 1H, C6-H), 2.01 (dt, J = 14.1, 3.2 Hz, 1H,

C14-H), 1.96 (ddd, J = 13.0, 5.9, 4.0 Hz, 1H, C6-H), 1.78 (d, J = 6.8

Hz, 3H, C18-H₃), 1.38 (dt, J = 14.1, 2.5 Hz, 1H, C14-H); ¹³C NMR

(125 MHz, CDCl₃) δ 186.6, 154.5, 144.8, 144.6, 139.3, 128.1, 126.0,

121.2, 120.9, 120.1, 116.6, 65.2(2), 56.6, 54.6, 37.4, 36.9, 27.1, 13.9;

HRMS (LC-ESI) m/z calcd for C₁₉H₂₁N₂(M + H)⁺277.1705, found

277.1703.

1

CH₂Cl₂); H NMR (500 MHz, CDCl₃) δ 7.16 (d, J = 7.6 Hz, 1H, C9-

Tetracycle 87. The synthetic procedure for the synthesis of

tetracycle 87 is found in ref 7q. Incorrect spectral data was provided in

the Supporting Information for ref 7q. Corrected spectral data is

provided: mp = 115−117 °C; R_f= 0.3 (1:3 EtOAc/CH₂Cl₂); ¹H NMR

(500 MHz, CDCl₃) δ 9.48 (s, 1H, C17-H), 7.06 (d, J = 7.5 Hz, 1H,

C9-H), 7.03 (t, J = 7.5 Hz, 1H, C11-H), 6.81 (dd, J = 5.2, 2.9 Hz, 1H,

C15-H), 6.71 (t, J = 7.5 Hz, 1H, C10-H), 6.56 (d, J = 7.5 Hz, 1H, C12-

H), 6.31 (t, J = 6.6 Hz, 1H, C19-H), 4.50 (br s, 1H, NH), 4.26 (s, 1H,

C2), 4.19−4.27 (m, 2H, C18-H), 3.66 (d, J = 11.7 Hz, 1H, C21-H),

2.96−3.02 (m, 2H, C3-H and C5-H), 2.76 (d, J = 11.7 Hz, 1H, C21-

H), 2.60 (app dd, J = 19.9, 3.8 Hz, 1H, C14-H), 2.50 (td, J = 10.2, 5.1

Hz, 1H, C5-H), 2.42 (app d, J = 19.9, 1H, C14-H), 2.16 (ddd, J = 12.8,

8.8, 5.1 Hz, 1H, C6-H), 1.88 (ddd, J = 12.8, 10.3, 6.1 Hz, 1H, C6-H),

1.40 (br s, OH), 0.10 (s, 9H, SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ

194.8 (C17), 150.8 (C15), 150.1 (C13), 142.5 (C19), 141.4 (C20),

140.6 (C16), 132.0 (C8), 128.1 (C11), 122.8 (C9), 118.5 (C10),

109.2 (C12), 63.8 (C3), 62.9 (C), 61.8 (C), 59.7 (C2), 53.3 (C7),

50.8 (C5), 36.9 (C6), 25.6 (C14), 0.1 (CH₃Si); IR (thin film) ν 3380,

2952, 2807, 1679, 1485, 1246, 840, 743 cm⁻¹; HRMS (LC-ESI) m/z

calcd for C₂₂H₃₁N₂O₂Si (M + H)⁺383.2155, found 383.2158.

Nonacyclic Dimer 64. To a solution of enal 7d (27.2 mg,

69.7 μmol, 1.0 equiv) in CH₂Cl₂(0.60 mL, 0.1 M) at 0 °C was added

TFA (10.3 μL, 139 μmol, 2.0 equiv). The reaction mixture was slowly

warmed to rt and then stirred at rt for 14 h. The reaction mixture was

quenched with saturated aqueous NaHCO₃(2 mL) and diluted with

EtOAc (8 mL). The layers were separated, and the aquous layer was

extracted with EtOAc (4 mL). The combined organics were washed

with H₂O (2 mL) and brine (2 mL) and dried over Na₂SO₄. The

solvent was evaporated in vacuo, and the crude material was purified

by column chromatography (SiO₂, 0.2:1.8:98 → 0.5:4.5:95 NH₄OH/

MeOH/CH₂Cl₂) to yield the desired product (20.7 mg, 80%) as a

yellow oil. No DMB-deprotection was observed under a variety of

H), 7.05 (dd, J = 7.6, 7.4 Hz, 1H, C11-H), 6.76 (dd, J = 7.6, 7.4 Hz,

1H, C10-H), 6.64 (d, J = 7.6 Hz, 1H, C12-H), 5.87 (q, J = 6.3 Hz, 1H,

C19-H), 5.76 (t, J = 4.2 Hz, 1H, C15-H), 4.60 (br s, 1H, NH), 4.18−

4.25 (m, 2H, C17-H₂), 4.10 (s, 1H, C2-H), 3.58 (d, J = 14.2 Hz, 1H,

C21-H), 3.29 (d, J = 14.2 Hz, 1H, C21-H), 3.02−3.10 (m, 2H, C3-H +

C5-H), 2.69 (ddd, J = 9.4, 9.3, 6.0 Hz, 1H, C5-H), 2.14−2.20 (m, 2H,

C14-H₂), 1.98−2.14 (m, 2H, C6-H₂), 1.79 (d, J = 6.3 Hz, 3H, C18-H₃);

¹³C NMR (125 MHz, CDCl₃) δ 150.2, 136.7, 134.8, 130.9, 127.9,

124.8, 123.6, 119.2, 110.0, 109.7, 67.5, 65.2, 64.3, 64.2, 54.4, 50.7, 38.4,

24.4, 21.7; IR (thin film) ν 3351, 2919, 2803, 1606, 1484, 990, 742

cm⁻¹; HRMS (LC-ESI) m/z calcd for C₁₉H₂₄N₂OI (M + H)⁺423.0934,

found 423.0942.

Dehydrodesacetylretuline (59). A solution of Pd(OAc)₂(4.0 mg,

18 μmol, 0.20 equiv), PPh₃(9.4 mg, 35 μmol, 0.40 equiv), and

NEt₃(37.0 μL, 264 μmol, 3.0 equiv) in C₆H₆(6.0 mL, 0.015 M in

iodide) was premixed in a sealed tube temporarily capped with a

septum at rt for 1 h. To this catalyst solution was added iodide 46

(37.2 mg, 88.1 μmol, 1.0 equiv). The tube was tightly sealed, heated to

85 °C for 8 h, and then cooled to rt. The reaction mixture was diluted

with EtOAc, filtered through Celite, and concentrated in vacuo, and

the crude material was purified by preparative TLC (SiO₂, 5:5:90

NEt₃/MeOH/Et₂O) to yield the desired product (11.5 mg, 90%

purity, ∼40%) along with recovered starting material (6.3 mg, 15%

recovery). Spectral data were consistent with literature values: R_f= 0.5

(1:9:90 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ

7.55 (d, J = 7.6 Hz, 1H, C12-H), 7.38 (d, J = 7.3 Hz, 1H, C9-H), 7.34

(dd, J = 7.6, 7.3 Hz, 1H, C11-H), 7.23 (t, J = 7.3 Hz, 1H, C10-H), 5.44

(d, J = 6.6 Hz, 1H, C19-H), 4.57 (br s, 1H, O-H), 4.12 (dd, J = 8.6, 3.6

Hz, 1H, C17-H), 4.04 (d, J = 8.6 Hz, 1H, C17-H), 4.00 (s, 1H, C3-H),

3.80 (d, J = 15.4 Hz, 1H, C21-H), 3.38−3.46 (m, 1H, C14-H), 3.27−

3.34 (m, 1H, C14-H), 3.21 (d, J = 15.5 Hz, 1H, C21-H), 3.01−3.06

(m, 1H, C14-H), 2.82 (s, 1H, C15-H), 2.34 (d, J = 7.6 Hz, 1H, C5-H),

2.02−2.09 (m, 1H, C5-H), 1.87 (d, J = 14.2 Hz, 1H, C6-H), 1.71 (d, J =

6.6 Hz, 3H, C18-H₃), 1.08 (d, J = 14.2 Hz, 1H, C6-H); ¹³C NMR (125

MHz, CDCl₃) δ 192.2, 153.6, 144.0, 140.9, 128.0, 125.9, 121.4,

120.2, 119.8, 67.4, 66.0, 64.5, 56.8, 54.5, 46.7, 35.7, 34.3, 26.1, 13.3;

HRMS (LC-ESI) m/z calcd for C₁₉H₂₃N₂O (M + H)⁺295.1810,

found 295.1808.

Valparicine (9). To a solution of dehydrodesacetylretuline (59)

(7.3 mg, 25 μmol, 1.0 equiv) in CH₂Cl₂(1.65 mL, 0.015 M) at

−10 °C was added TFA (99.2 μL, 0.25 M in CH₂Cl₂, 25 μmol, 1.0 equiv).

The reaction mixture was stirred at −10 °C for 2 h, warmed to rt for

0.5 h, quenched with NEt₃(10 μL), and diluted with EtOAc (8 mL),

1 M NaOH (2 mL) and H₂O (2 mL). The layers were separated, and

the organic layer was extracted with EtOAc (4 mL). The combined

organics were washed with brine (2 mL) and dried over Na₂SO₄. The

solvent was evaporated in vacuo, and the crude material was purified

by preparative TLC (SiO₂, 1:9:90 NH₄OH/MeOH/CH₂Cl₂) to yield

the desired product (6.6 mg, ∼65% purity, ∼60%) mixed with OPPh₃

and unidentified byproducts. Half of the material was further purified

by Agilent 1100 reversed-phase HPLC (Phenomenex Gemini-NX

5 μm C18, 250 × 21.20 mm, 13 mL/min, UV detection at 254 nm,

29.7:0.3:70 H₂O/NH₄OH/MeOH). The volatiles were evaporated in

vacuo, and the water was removed by lyophilization to yield pure

valparicine (1 mg, ∼95% purity, ∼30%). Spectral data were consistent

with literature values: R_f= 0.5 (1:9:90 NH₄OH/MeOH/CH₂Cl₂);

¹H NMR (500 MHz, CDCl₃) δ 7.62 (d, J = 7.7 Hz, 1H, C12-H), 7.38

1

similar conditions: R_f= 0.5 (1:9:90 NH₄OH/MeOH/CH₂Cl₂); H

NMR (500 MHz, CDCl₃) δ 7.27 (d, J = 8.9 Hz, 1H, Ar-H), 7.12 (dd,

J = 7.8, 7.6 Hz, 1H, C11-H), 7.07 (d, J = 7.6 Hz, 1H, C9-H), 6.83 (t,

J = 7.6 Hz, 1H, C10-H), 6.62 (d, J = 7.8 Hz, 1H, C12-H), 6.53 (s, 1H,

C17-H), 6.48−6.53 (m, 2H, Ar-H), 6.36 (d, J = 9.9 Hz, 1H, C15-H),

5.64 (dd, J = 9.9, 5.0 Hz, 1H, C14-H), 5.19 (s, 1H, C2-H), 3.97 (d, J =

13.7, 1H, C21-H), 3.83 (s, 6H, OCH₃), 3.77 (d, J = 13.7, 1H, C21-H),

3.34 (d, J = 5.0, 1H, C3-H), 3.09 (ddd, J = 13.5, 9.0, 4.5 Hz, 1H, C5-

H), 2.61−2.68 (m, 1H, C5-H), 2.10−2.17 (m, 1H, C6-H), 1.88 (ddd,

J = 13.5, 9.4, 4.5 Hz, 1H, C6-H); ¹³C NMR (125 MHz, CDCl₃) δ

159.8, 158.7, 145.5, 137.1, 131.74, 131.71, 131.5, 128.1, 122.3, 120.7,

118.6, 116.4, 113.0, 108.9, 103.8, 98.4, 66.5, 62.8, 55.34, 55.31, 53.3,

50.2, 49.6, 40.2; IR (thin film) ν 2931, 2833, 1629, 1591, 1485, 1208,

1035 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₄₈H₄₉N₄O₄(M + H)⁺

745.3754, found 745.3761.

Nonacyclic Dimer S26. A solution of enal 87 (11.1 mg, 29.0 μmol,

1 equiv), dimethyl malonate (6.7 μL, 58 μmol, 2.0 equiv), and

pyrrolidine (0.5 μL, 6 μmol, 0.2 equiv) in AcOH (0.29 mL, 0.1 M) was

heated to 80 °C for 70 min. The reaction mixture was cooled to rt and

diluted with EtOAc (8 mL), saturated aqueous NaHCO₃(2 mL), and

H₂O (2 mL). The aqueous layer was extrated with EtOAc (5 mL).

The combined organics were washed with brine (2 mL) and then

1

dried over Na₂SO₄. The solvent was evaporated in vacuo, and H

NMR analysis of the crude material showed mostly undesired

dimerization product. A similar experiment without pyrrolidine gave

a similar result. The two crude reaction mixtures were combined and

40

dx.doi.org/10.1021/jo2020246 | J. Org. Chem. 2012, 77, 17−46

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purified by column chromatography (SiO₂, 0.1:0.9:99 → 0.2:1.8:98

NH₄OH/MeOH/CH₂Cl₂) to yield the title product (9.6 mg, 45%) as

a tan solid. This product was also made in 72% yield by treatment

of enal 87 with 2 equiv of TFA in THF (see procedure for 64): mp

>230 °C dec; R_f= 0.3 (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR

(500 MHz, CDCl₃) δ 7.12 (dd, J = 7.8, 7.6 Hz, 1H, C11-H), 7.07 (d,

J = 7.3 Hz, 1H, C9-H), 6.84 (dd, J = 7.6, 7.3 Hz, 1H, C10-H), 6.65 (d,

J = 7.8 Hz, 1H, C12-H), 6.54 (s, 1H, C17-H), 6.32 (d, J = 9.8 Hz, 1H,

C15-H), 6.29 (t, J = 6.4 Hz, 1H, C19-H), 5.43 (dd, J = 9.8, 5.4 Hz, 1H,

C14-H), 5.22 (s, 1H, C2-H), 4.20−4.29 (m, 2H, C18-H₂), 3.76 (d, J =

11.5, 1H, C21-H), 3.18 (d, J = 5.3, 1H, C3-H), 2.93−3.20 (m, 1H, C5-

H), 2.79 (d, J = 11.5, 1H, C21-H), 2.34−2.42 (m, 1H, C5-H), 1.97−

2.05 (m, 1H, C6-H), 1.83−1.91 (m, 1H, C6-H), 1.62 (br s, 1H, OH),

0.14 (s, 9H, SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 145.8, 142.2,

142.1, 135.6, 133.7, 131.4, 128.3, 122.4, 121.0, 115.1, 112.8, 109.0,

66.4, 63.1, 62.9, 62.0, 53.9, 50.5, 39.4, −0.5; IR (thin film) ν 2951,

2775, 1627, 1484, 838 cm⁻¹; HRMS (LC-ESI) m/z calcd for

C₄₄H₅₇N₄O₂Si₂(M + H)⁺729.4020, found 729.4002.

Zincke Aldehyde S27 (by Cycloreversion of 87). A solution

of vinylsilane 87 (4.6 mg, 12 μmol, 1 equiv) and pyrrolidine (3.9 μL,

48 μmol, 4 equiv) in HFIP (1 mL, 0.01 M) was heated in a microwave

reactor at 120 °C for 4 h. The solvent was removed in vacuo, and the

residue was diluted with EtOAc (1 mL) and 2 M NaOH (1 mL) and

stirred vigorously for 3 h to ensure complete hydrolysis of iminium

ions. The mixture was diluted with EtOAc (5 mL). The layers were

separated, and the organic layer was washed with brine (2 mL) and

then dried over Na₂SO₄. The solvent was removed in vacuo, and the

crude material was purified by column chromatography (SiO₂,

0.2:1.8:98 → 0.8:7.2:92 NH₄OH/MeOH/CH₂Cl₂) to yield Zincke

aldehyde S27 (2.0 mg, 43%) along with some of the corresponding

secondary amine S28 and Zincke aldehyde 86. It was not possible to

obtain complete characterization data for this compound, and the

structures of S27 and S28 were assigned by analogy to Zincke

aldehyde 12j and amine 42 lacking only the C18 hydroxyl group: R_f=

0.25 (1:9:90 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR (500 MHz,

CDCl₃) δ 9.29 (d, J = 8.4 Hz, 1H, CHO), 8.13 (br s, 1H, N_a-H),

7.56 (d, J = 7.9 Hz, 1H, indole C4-H), 7.41 (d, J = 8.0 Hz, 1H, indole

C7-H), 7.24 (dd, J = 8.0, 7.4 Hz, 1H, indole C6-H), 7.16 (t, J = 7.9, 7.4

Hz, 1H, indole C5-H), 7.07 (app t, J = 12.7 Hz, 1H, ZA β-CH), 7.03

(d, J = 1.8 Hz, 1H, indole C2-H), 6.75 (d, J = 12.0 Hz, 1H, ZA δ-CH),

5.93 (t, J = 6.6 Hz, 1H, vinyl-H), 5.84 (dd, J = 14.2, 8.4 Hz, 1H, ZA

α-CH), 5.27−5.42 (br s, 1H, ZA γ-CH), 4.22 (d, J = 6.6 Hz, 2H, CH₂O),

3.69 (s, 2H, N_b-CH₂), 3.49 (t, J = 6.9 Hz, 2H, CH₂-N_b), 3.04 (t, J = 6.9

Hz, 2H, Ar−CH₂), 1.40 (br s, 1H, OH), 0.11 (s, 9H, SiCH₃); LRMS

(LC-ESI) m/z calcd for C₂₂H₃₁N₂O₂Si (M + H)⁺383.2, found 383.2;

calcd for C₂₂H₃₀N₂O₂SiNa (M + Na)⁺405.2, found 405.2.

aqueous NaHCO₃(10 drops), and then diluted with EtOAc (8 mL)

and H₂O (5 mL). The layers were separated and the aqueous layer was

extracted with EtOAc (5 mL). The combined organic extracts were

washed with brine (2 mL) and then dried over Na₂SO₄. The solvent

was evaporated in vacuo, and the crude material was purified by

column chromatography (SiO₂, 1:9 → 1:4 EtOAc/CH₂Cl₂) to yield

the desired product (14.7 mg, 73%) as a yellow oil. This compound

lies on a failed route to strychnine, and IR data for this compound was

not obtained prior to abandoning this route: R_f= 0.6 (1:3 EtOAc/

CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 9.64 (s, 1H, C17-H), 7.69−

7.77 (m, 1H, C12-H), 7.21 (t, J = 7.6 Hz, 1H, C11-H), 7.19 (d, J = 7.6

Hz, 1H, C9-H), 7.06 (t, J = 7.6 Hz, 1H, C10-H), 7.00 (dd, J = 7.5, 3.2

Hz, 1H, C15-H), 6.29 (t, J = 6.6 Hz, 1H, C19-H), 4.97 (s, 1H, C2-H),

4.17−4.29 (m, 4H, C18-H₂+ C23-H₂), 3.61 (d, J = 11.7 Hz, 1H, C21-

H), 2.98−3.03 (m, 1H, C5-H), 2.62 (ddd, J = 17.0, 7.5, 1.5 Hz, 1H,

C14-H), 2.56−2.59 (m, 1H, C3-H), 2.52 (d, J = 11.7 Hz, 1H, C21-H),

2.32 (dt, J = 17.0, 3.6 Hz, 1H, C14-H), 2.13−2.27 (m, 2H, C5-H +

C6-H), 1.73−1.82 (m, 1H, C6-H), 1.24−1.31 (m, 3H, C24-H₃), 0.12

(s, 9H, SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 191.6, 153.7, 149.9,

143.1, 142.2, 141.1, 139.7, 136.8, 128.1, 123.7, 123.1, 115.4, 73.5, 63.3,

62.0, 61.8, 60.5, 54.1, 53.6, 37.6, 25.4, 14.5, 0.3; LRMS (LC-ESI) m/z

calcd for C₂₅H₃₅N₂O₄Si (M + H)⁺455.2, found 455.2; calcd for

C₂₅H₃₄N₂O₄SiNa (M + Na)⁺477.2, found 477.2.

Carbamate S29. A solution of 7g (64.5 mg, 0.230 mmol, 1 equiv)

and Boc₂O (132 uL, 0.580 mmol, 2.5 equiv) in (CH₂Cl)₂(0.77 mL,

0.3 M) was heated to 80 °C in a sealed tube for 22 h. The reaction

mixture was cooled to rt and concentrated in vacuo, and the crude

material was purified by column chromatography (SiO₂, 1:9 → 1:3

EtOAc/CH₂Cl₂) to yield the desired product (72.1 mg, 82%) as a tan

solid: R_f= 0.25 (1:3 EtOAc/CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ

9.66 (s, 1H, C17-H), 7.66−7.71 (m, 1H, C12-H), 7.19 (t, J = 7.7 Hz,

1H, C11-H), 7.16 (d, J = 7.3 Hz, 1H, C9-H), 7.03 (dd, J = 7.7, 7.3 Hz,

1H, C10-H), 6.98 (dd, J = 7.2, 3.3 Hz 1H, C15-H), 5.91 (dddd, J =

17.1, 10.2, 7.5, 5.5 Hz, 1H, C20-H), 5.20 (d, J = 17.1 Hz, 1H, Z-C19-

H), 5.13 (d, J = 10.2 Hz, 1H, E-C19-H), 4.98 (s, 1H, C2-H), 3.38 (dd,

J = 13.7, 5.5 Hz, 1H, C21-H), 3.11−3.17 (m, 1H, C5-H), 2.87 (dd, J =

13.7, 7.5 Hz, 1H, C21-H), 2.76 (app d, J = 2.0 Hz, 1H, C3-H), 2.61

(ddd, J = 17.2, 7.2, 2.0 Hz, 1H, C14-H), 2.49 (app q, J = 9.0 Hz, 1H,

C5-H), 2.32 (dt, J = 17.2, 3.6 Hz, 1H, C14-H), 2.17 (ddd, J = 13.2, 7.7,

2.6 Hz, 1H, C6-H), 1.87 (ddd, J = 13.2, 8.3, 9.2 Hz, 1H, C6-H), 1.51

(s, 9H, t-Bu); ¹³C NMR (125 MHz, CDCl₃) δ 191.9, 152.9, 148.3,

142.6, 139.8, 136.7, 135.1, 128.0, 123.4, 122.8, 117.4, 115.8, 82.0, 71.5,

60.7, 56.7, 54.0, 53.2, 37.6, 28.6, 25.8; IR (thin film) ν 2875, 2929,

1698, 1480, 1369, 1167, 752 cm⁻¹; HRMS (LC-ESI) m/z calcd for

C₂₃H₂₉N₂O₃(M + H)⁺381.2178, found 381.2171.

Vinylsilane 117. To a solution of S29 (71.6 mg, 0.188 mmol,

1 equiv) and 5-methyl Meldrum’s acid (65.5 mg, 0.414 mmol, 2.2

equiv) in CDCl₃(0.94 mL, 0.2 M) at 0 °C was added Pd(PPh₃)₄(10.9

mg, 9.0 μmol, 5 mol %). The reaction mixture was stirred at 0 °C for 1

h, at which point ¹H NMR analysis of an aliquot indicated incomplete

deallylation. An additional portion of Pd(PPh₃)₄(10.9 mg, 9.0 μmol, 5

mol %) was added, and the reaction mixture was stirred at 0 °C for 2 h.

To the reaction mixture were added diisopropylethylamine (115 μL,

0.658 mmol, 3.5 equiv) and allylic bromide 102 (111 mg, 0.498 mmol,

2.65 equiv) as a solution in CDCl₃, rinsing with CDCl₃(1.0 mL total).

The resulting solution was placed in a refrigerator (∼4 °C) for 12 h,

removed, stirred at 0 °C for 4 h, and then stirred to rt for an additional

3 h. The reaction mixture was diluted with EtOAc (10 mL), saturated

aqueous NaHCO₃(5 mL), and H₂O (5 mL). The layers were

separated, and the aqueous layer was extracted with EtOAc (5 mL).

The combined organic extracts were washed with aqueous NaHCO₃

(3 mL) and brine (3 mL) and then dried over Na₂SO₄. The solvent

was evaporated in vacuo, and the crude material was purified by

column chromatography (SiO₂, 0:1:10 → 0:20:80 → 1:20:79 NEt₃/

EtOAc/CH₂Cl₂) to yield the desired product (69.0 mg, 76%) as a

Allylic Alcohol 105. In the Brook rearrangement reactions, the

major product in most cases was protodemetalated product 105,

isolated as a light yellow oil. See ref for the experimental procedure for

its formation: R_f= 0.3 (0.7:6.3:93 NH₄OH/MeOH/CH₂Cl₂); ¹H

NMR (500 MHz, CDCl₃) δ 9.48 (s, 1H, C17-H), 7.06 (d, J = 7.7 Hz,

1H, C9-H), 7.03 (t, J = 7.7 Hz, 1H, C11-H), 6.82 (dd, J = 5.3, 2.8 Hz,

1H, C15-H), 6.72 (t, J = 7.7 Hz, 1H, C10-H), 6.56 (d, J = 7.7 Hz, 1H,

C12-H), 5.76−5.88 (m, 2H, C19-H + C20-H), 4.51 (br s, 1H, NH),

4.32 (s, 1H, C2-H), 4.17 (app d, J = 4.7 Hz, 2H, C18-H₂), 3.47 (dd,

J = 13.8, 5.0 Hz, 1H, C21-H), 3.15−3.21 (m, 1H, C14−H), 3.10−3.13

(m, 1H, C3-H), 3.02 (dd, J = 13.8, 6.7 Hz, 1H, C21-H), 2.66 (td, J =

19.9, 5.0 Hz, 1H, C14-H), 2.60 (app dd, J = 20.0, 5.1 Hz, 1H, C5-H),

2.37−2.44 (m, 1H, C5-H), 2.21 (ddd, J = 13.1, 8.3, 5.0 Hz, 1H, C6-H),

1.94 (ddd, J = 13.1, 10.0, 5.0 Hz, 1H, C6-H); ¹³C NMR (125 MHz,

CDCl₃) δ 194.9 (C17), 150.44 (C15), 150.37 (C13), 140.8 (C16),

131.94 (C8), 131.87 (C19 or C20), 128.8 (C19 or C20), 128.3 (C11),

122.8 (C9), 118.6 (C10), 109.3 (C12), 63.9 (C3), 63.3 (C18), 59.7

(C2), 55.3 (C21), 53.4 (C7), 51.1 (C5), 37.9 (C6), 26.0 (C14); IR

(thin film) ν 3254, 2918, 1668, 1391, 747 cm⁻¹; HRMS (LC-ESI) m/z

calcd for C₁₉H₂₃N₂O₂(M + H)⁺311.1760, found 311.1761.

1

yellow oil:; R_f= 0.25 (15:85 EtOAc/CH₂Cl₂); H NMR (500 MHz,

Vinylsilane 107. To a solution of vinylsilane 87 (17.0 mg,

44.4 μmol, 1 equiv) in CH₂Cl₂(0.4 mL, 0.1 M) was added ethyl

chloroformate (89 uL, 0.5 M in CH₂Cl₂, 44.4 μmol, 1.0 equiv). The

resulting mixture was stirred at rt for 16 h, quenched with saturated

CDCl₃) δ 9.64 (s, 1H, C17-H), 7.62−7.71 (m, 1H, C12-H), 7.19 (t,

J = 7.5 Hz, 1H, C11-H), 7.15 (d, J = 7.5 Hz, 1H, C9-H), 7.03 (t, J =

7.5 Hz, 1H, C10-H), 6.94−6.98 (m, 1H, C15-H), 6.29 (t, J = 6.5 Hz,

1H, E-C19-H), 4.95 (s, 1H, C2-H), 4.19−4.28 (m, 2H, C18-H₂), 3.63

41

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(d, J = 11.7 Hz, 1H, C21-H), 3.00 (t, J = 8.4 Hz, 1H, C5-H), 2.57−2.64

(m, 2H, C3-H + C14-H), 2.54 (d, J = 11.7 Hz, 1H, C21-H), 2.20−2.37

(m, 1H, C14-H), 2.24 (app q, J = 9.0 Hz, 1H, C5-H), 2.09−2.17 (m, 1H,

C6-H), 1.76−1.85 (m, 1H, C6-H), 1.51 (s, 9H, t-Bu), 0.12 (s, 9H,

SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 191.9, 152.9, 148.6, 143.1,

142.5, 141.2, 139.7, 136.7, 128.0, 123.4, 122.9, 115.7, 82.0, 72.2, 63.4,

61.8, 60.7, 53.9, 53.3, 37.3, 28.6, 25.5, 0.3; IR (thin film) ν 2956, 2803,

1694, 1372, 1249, 1167, 839 cm⁻¹; HRMS (LC-ESI) m/z calcd for

C₂₇H₃₉N₂O₄Si (M + H)⁺483.2679, found 483.2681.

and warmed to rt for 5 min, the septum was replaced with an

unpierced septum cap, and the reaction mixture was heated to 65 °C

for 1 h 40 min. The reaction mixture was cooled, quenched with H₂O,

then diluted with EtOAc (8 mL) and 3% aqueous NH₄OH (4 mL).

The layers were separated and the aqueous layer was extracted with

EtOAc (5 mL). The combined organic extracts were washed aqueous

NH₄OH (2 mL), H₂O (2 × 2 mL), and brine (2 mL) and then dried

over Na₂SO₄. The solvent was evaporated in vacuo and the crude

material was purified by column chromatography (SiO₂, 0.1:0.9:99 →

0.3:2.3:97 NH₄OH/MeOH/CH₂Cl₂) to yield the pyridone 111 (1.6

mg, ∼15%) as a highly fluorescent film along with some recovered

starting material. According to the precedent of Takeda et al.,⁶⁶

reaction using CuO-t-Bu in DMF at 60 °C for 4 h yielded ∼20% of

pyridone 111 along with a small amount of pyridone 112 (assigned by

Ester 109. To a solution of enal 87 (42.0 mg, 0.110 mmol,

1 equiv) and dimethyl malonate (101 μL, 0.88 mmol, 8 equiv) in

toluene (2 mL, 0.05 M) was added ethylenediaminediacetic acid

(10 mg, 0.055 mmol, 0.5 equiv). The resulting mixture was heated to

100 °C for 38 h and then cooled to rt. The reaction mixture was diluted

with EtOAc (8 mL), saturated aqueous NaHCO₃(2 mL), and H₂O

(2 mL). The layers were separated, and the aqueous layer was extracted

with EtOAc (5 mL). The combined organic extracts were washed with

brine (2 mL) and then dried over Na₂SO₄. The solvent was evaporated

in vacuo, and the crude material was purified by column chromato-

graphy (SiO₂, 1:9 → 2:8 EtOAc/CH₂Cl₂) to yield the desired product

(26 mg, 42%) as a yellow oil: R_f= 0.6 (1:3 EtOAc/CH₂Cl₂); ¹H NMR

(500 MHz, CDCl₃) δ 8.20 (d, J = 8.2 Hz, 1H, C12-H), 7.71 (s, 1H,

C17-H), 7.53 (d, J = 7.5 Hz, 1H, C9-H), 7.25 (dd, J = 8.2, 7.7 Hz, 1H,

C11-H), 7.03 (dd, J = 7.7, 7.5 Hz, 1H, C10-H), 6.40 (app d, J = 7.2

Hz, 1H, C15-H), 6.22 (t, J = 6.9 Hz, 1H, C19-H), 4.68−4.78 (m, 2H,

C18-H₂), 4.61 (s, 1H, C2-H), 3.91 (s, 3H, C25-H₃), 3.74 (s, 3H, C29-

H₃), 3.45 (d, J = 12.2 Hz, 1H, C21-H), 3.40 (s, 2H, C27-H₂), 3.25−

3.29 (m, 1H, C5-H), 3.22 (d, J = 12.2 Hz, 1H, C21-H), 2.85 (dd, J =

9.5, 5.1 Hz, 1H, C3-H), 2.64 (app td, J = 10.6, 4.2 Hz, 1H, C5-H), 2.54

(ddd, J = 18.0, 6.5, 5.1 Hz, 1H, C14-H), 2.20−2.31 (m, 2H, C6-H +

C14-H), 2.06−2.13 (m, 1H, C6-H), 0.16 (s, 9H, SiCH₃); ¹³C NMR

(125 MHz, CDCl₃) δ 166.9, 166.3, 165.1, 158.3, 144.1, 144.0, 140.4,

138.9, 136.7, 134.6, 130.5, 128.5, 126.9, 125.4, 124.1, 115.5, 64.4, 63.1,

60.6, 59.0, 52.60, 52.58, 51.8, 48.1, 41.4, 37.1, 23.4, −0.1; IR (thin

film) ν 2950, 1738, 1645, 1479, 838 cm⁻¹; HRMS (LC-ESI) m/z calcd

for C₃₀H₃₆N₂O₇SiNa (M + Na)⁺587.2189, found 587.2197.

Malonamate 110. To a solution of ester 109 (21.1 mg, 37.4

μmol, 1 equiv) in MeOH (1.9 mL, 0.02 M) at 0 °C was added K₂CO₃

(1.9 mg, 18.7 μmol, 0.5 equiv). The resulting mixture was stirred at

0 °C for 1 h 45 min and then diluted with EtOAc (8 mL) and H₂O

(5 mL). The layers were separated, and the aqueous layer was extracted

with EtOAc (5 mL). The combined organic extracts were washed with

brine (2 mL) and then dried over Na₂SO₄. The solvent was evaporated

in vacuo, and the crude material was purified by column chromato-

graphy (SiO₂, 1:20:79 → 1:30:69 NEt₃/EtOAc/CH₂Cl₂) to yield the

desired product (110) (11.3 mg, ∼90% purity, ∼58%) as a yellow oil,

contaminated with a byproduct that we believe has structure S30.²⁴

Further purification by preparative TLC (SiO₂, 1:3 EtOAc/CH₂Cl₂)

gave the desired product 110 (9.2 mg, 53%) as a yellow foam: R_f= 0.4

(1:3 EtOAc/CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J = 8.1

Hz, 1H, C12-H), 7.70 (s, 1H, C17-H), 7.54 (d, J = 7.7 Hz, 1H, C9-H),

7.25 (dd, J = 8.1, 7.7 Hz, 1H, C11-H), 7.03 (t, J = 7.7 Hz, 1H, C10-H),

6.39 (app d, J = 7.3 Hz, 1H, C15-H), 6.29 (t, J = 6.8 Hz, 1H, C19-H),

4.60 (s, 1H, C2-H), 4.20−4.28 (m, 2H, C18-H₂), 3.90 (s, 3H, OCH₃),

3.44 (d, J = 12.1 Hz, 1H, C21-H), 3.23−3.30 (m, 1H, C5-H), 3.21 (d,

J = 12.1 Hz, 1H, C21-H), 2.86 (dd, J = 9.5, 4.9 Hz, 1H, C3-H), 2.65

(app td, J = 10.6, 4.2 Hz, 1H, C5-H), 2.50−2.60 (m, 1H, C14-H),

2.20−2.30 (m, 2H, C6-H + C14-H), 2.05−2.14 (m, 1H, C6-H), 1.63

(br s, 1H, OH), 0.14 (s, 9H, SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ

165.1, 158.3, 144.0, 142.7, 140.8, 140.3, 139.0, 134.7, 130.4, 128.5,

126.9, 125.4, 124.1, 115.5, 63.1, 62.0, 60.5, 59.1, 52.6, 51.8, 48.1, 37.1,

23.4, 0.1; IR (thin film) ν 2959, 2927, 1738, 1651, 1249, 839, 732

cm⁻¹; HRMS (LC-ESI) m/z calcd for C₂₆H₃₂N₂O₄SiNa (M + Na)⁺

487.2029, found 487.2028.

1

analogy to 111 by evaluation of H NMR data, full spectral data not

obtained).

111: R_f= 0.3 (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂); ¹H NMR

(500 MHz, CDCl₃) δ 8.71 (d, J = 8.1 Hz, 1H, C12-H), 8.13 (s, 1H,

C17-H), 7.70 (d, J = 7.7 Hz, 1H, C9-H), 7.44 (dd, J = 8.1, 7.7 Hz, 1H,

C11-H), 7.03 (t, J = 7.7 Hz, 1H, C10-H), 6.46 (dd, J = 10.0, 1.3 Hz,

1H, C14-H or C15-H), 6.38 (t, J = 6.7 Hz, 1H, C19-H), 5.99 (dd, J =

10.0, 1.3 Hz, 1H, C14-H or C15-H), 4.26−4.30 (m, 2H, C18-H₂), 4.24

(s, 1H, C3-H), 3.96 (s, 3H, OCH₃), 3.72 (d, J = 12.1 Hz, 1H, C21-H),

3.45 (d, J = 12.1 Hz, 1H, C21-H), 3.27−3.32 (m, 1H, C5-H), 2.53−

2.62 (m, 2H, C5-H + C6-H), 1.92−1.98 (m, 1H, C6-H), 0.28 (s, 9H,

SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 166.2, 158.2, 158.0, 143.1,

141.9, 140.9, 140.7, 139.3, 128.7, 127.1, 124.1, 123.8, 122.5, 119.1,

118.5, 108.0, 66.7, 62.0, 59.7, 52.8, 52.5, 50.2, 39.7, 0.3; IR (thin film)

ν 2923, 1732, 1667, 1632, 1544, 1200, 838 cm⁻¹; HRMS (LC-ESI)

m/z calcd for C₂₆H₃₀N₂O₄SiNa (M + Na)⁺485.1873, found 485.1863.

Vinylsilane 103. To a solution of bromide 102 (360 mg, 1.61

mmol, 1.0 equiv) in CH₂Cl₂(8.1 mL, 0.2 M) at 0 °C were added

Bn₂NH (0.62 mL, 3.22 mmol, 2.0 equiv) and i-Pr₂NEt (0.56 mL, 3.22

mmol, 2.0 equiv). The reaction mixture was slowly warmed to rt

and stirred at rt for 13 h. The reaction mixture was diluted with EtOAc

(30 mL), saturated aqueous NaHCO₃(50 mL), and H₂O (10 mL).

The aqueous layer was extrated with EtOAc (10 mL). The combined

organics were washed with brine (40 mL) and then dried over

Na₂SO₄. The solvent was evaporated in vacuo and the crude material

was purified by column chromatography (SiO₂, 1:20 → 1:10

EtOAc:hexanes) to yield the desired product (403 mg, 74%) as a

1

colorless oil: R_f= 0.5 (1:3 EtOAc/hexanes); H NMR (500 MHz,

CDCl₃) δ 7.30−7.40 (m, 8H, Ph), 7.23−7.27 (m, 2H, Ph), 6.43 (t, J =

6.8 Hz, 1H, vinyl-CH), 4.25 (d, J = 6.8 Hz, 1H, CH2O), 3.49 (s, 4H,

PhCH₂), 3.11 (s, 2H, NCH₂), 1.24 (br s, 1H, OH), 0.11 (s, 9H,

SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 143.6, 141.4, 139.2, 129.3,

128.2, 126.9, 62.5, 62.1, 57.9, 0.2; IR (thin film) ν 3343, 2951, 2792,

1454, 1248, 839 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₂₁H₃₀NOSi

(M + H)⁺340.2097, found 340.2097.

Ester 116. A solution of vinylsilane 103 (20.8 mg, 61.3 μmol,

1.0 equiv), tert-butyl acrylate (27.0 μL, 184 μmol, 3.0 equiv), [MeORh-

(cod)]₂(1.5 mg, 3.1 μmol, 0.05 equiv), and 1 M aqueous KOH

(61 μL, 61 μmol, 1 equiv) in THF (0.55 mL, 0.1 M) was heated to

70 °C for 16 h. The yellow solution was cooled to rt and concentrated

in vacuo. The crude material was purified by column chromatography

(SiO₂, 1:9 → 1:4 EtOAc/hexanes) to yield the desired product

1

(12.7 mg, 53%) as a colorless oil: R_f= 0.4 (1:3 EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 7.30−7.38 (m, 8H, ArH), 7.24 (t, J = 7.2

Hz, 2H, ArH), 5.77 (t, J = 7.2 Hz, 1H, vinyl-H), 4.16 (d, J = 7.2 Hz,

2H, CH₂OH), 3.48 (s, 4H, PhCH₂), 2.94 (s, 2H, NCH₂), 2.47 (t, J =

7.3 Hz, CH₂CH₂CO₂R), 2.11 (t, J = 7.3 Hz, CH₂CH₂CO₂R), 2.10 (br s,

1H, OH), 1.38 (s, 9H, t-Bu); ¹³C NMR (125 MHz, CDCl₃) δ 173.2,

139.7, 139.6, 128.9, 128.31, 128.29, 127.0, 80.5, 59.3, 58.5, 58.2, 33.0,

28.1, 23.6; IR (thin film) ν 2973, 2795, 1729, 1149, 748 cm⁻¹; HRMS

(LC-ESI) m/z calcd for C₂₅H₃₄NO₃(M + H)⁺396.2539, found

396.2537.

Dihydrofuran S31. If insufficient H₂O is added in the conversion

of 103 to 116, as described above, protonation of the intermediate Rh-

enolate is inefficient and the major product is S31 (54%), which

presumably arises from β-hydride elimination and cyclization of the

Pyridones 111 and 112. To a solution of malonamate 110

(10.6 mg, 22.8 μmol, 1.0 equiv) in NMP (380 μL, 0.06 M) in a 4 mL vial

at 0 °C was added NaHMDS (32 μL, 1 M in THF, 32 μmol, 1.4 equiv).

The reaction mixture was stirred at 0 °C for 15 min, and then

CuBr·SMe₂(328 μL, 0.125 M in NMP, 41.0 μmol, 1.8 equiv) was

added. The resulting brown solution was stirred at 0 °C for 10 min

42

dx.doi.org/10.1021/jo2020246 | J. Org. Chem. 2012, 77, 17−46

The Journal of Organic Chemistry

Featured Article

hydroxyl group of this Heck-type product. For similar observations in

a related Rh-catalyzed conjugate addition/Heck reaction, see ref 93:

R_f= 0.4 (1:3 EtOAc:hexanes); H NMR (500 MHz, CDCl₃) δ 7.30−

2.15−2.30 (m, 3H, C6-H + C14-H + C16-H), 1.57−1.68 (m, 2H, C6-H +

C14-H); ¹³C NMR (125 MHz, CDCl₃, assignments tentative, signals

for C8 or C20 not unambiguously identified) δ 204.6 (C17), 203.0

(C19), 149.7(C13), 128.5 (C11), 122.2 (C9), 118.8 (C10), 109.6 (12),

78.5 (C18), 60.4 (C2), 59.6 (C16), 58.6 (C3), 53.7 (C7), 52.0 (C5),

50.2 (C21), 38.1 (C14), 27.6 (C15), 24.7 (C6); IR (thin film) ν 2950,

2847, 1951, 1714, 1485, 1464, 851 cm⁻¹; HRMS (LC-ESI) m/z calcd

for C₂₀H₂₅N₂O₂(M + MeOH + H)⁺325.1916, found 325.1914.

1

7.38 (m, 8H, ArH), 7.25 (t, J = 7.2 Hz, 2H, ArH), 5.80 (br s, 1H,

C6-H), 5.21−5.26 (m, 1H, C3-H), 4.57−4.66 (m, 2H, C5-H₂), 3.78

(d, J = 13.5 Hz, 2H, C9-H₂), 3.27 (d, J = 13.5 Hz, 2H, C9-H₂), 3.13 (d,

J = 14.4 Hz, 1H, C8-H), 3.02 (d, J = 14.4 Hz, 1H, C8-H), 2.37 (dd, J =

14.9, 2.9 Hz, 1H, C2-H), 2.10 (dd, J = 14.9, 8.2 Hz, 1H, C2-H), 1.47

(s, 9H, t-Bu); ¹³C NMR (125 MHz, CDCl₃) δ 170.6, 140.0, 139.2,

128.9, 128.3, 127.1, 124.1, 83.1, 80.4, 74.5, 58.3, 50.7, 40.4, 28.2; IR

(thin film) ν 2977, 2798, 1731, 1367, 1150, 749, 699 cm⁻¹; HRMS

(LC-ESI) m/z calcd for C₂₅H₃₂NO₃(M + H)⁺394.2382, found

394.2381.

ASSOCIATED CONTENT

* Supporting Information

■

S

Procedures for the synthesis of all new compounds, character-

ization data, and copies of NMR spectra. This material is

available free of charge via the Internet at http://pubs.acs.org.

In Scheme S2 found only in the Supporting Information, we

describe a different, partially successful approach to D-ring formation.

The relevant experimental details follow:

AUTHOR INFORMATION

Corresponding Author

*cdv@uci.edu

Propargylsilane S3. To a solution of 7g (235 mg, 0.838 mmol)

and barbituric acid 77 (454 mg, 1.84 mmol, 2.2 equiv) in CDCl₃

(4.2 mL, 0.2 M) at 0 °C was added Pd(PPh₃)₄(48.4 mg, 42.0 μmol,

5 mol %). The reaction mixture was stirred at 0 °C for 1 h, at which

■

1

point H NMR analysis of an aliquot indicated complete deallylation.

ACKNOWLEDGMENTS

■

To the reaction mixture were added diisopropylethylamine (438 μL,

2.51 mmol, 3.0 equiv) and propargylic bromide S2⁹⁴(378 mg,

1.84 mmol, 2.2 equiv). The resulting solution was stirred at 0 °C for

4.5 h, diluted with EtOAc (10 mL) and saturated aqueous NaHCO₃

(4 mL), and warmed to rt. The mixture was diluted with EtOAc

(10 mL) and H₂O (4 mL). The layers were separated, and the aqueous

layer was extracted with EtOAc (10 mL). The combined organic

extracts were washed with brine (10 mL) and then dried over Na₂SO₄.

The solvent was evaporated in vacuo, and the crude material was

purified by column chromatography (SiO₂, 0:0:100 → 0.2:1.8:98

NH₄OH/MeOH/CH₂Cl₂) to yield the desired product (138 mg,

45%) as a yellow foam: R_f= 0.3 (SiO2, 0.5:4.5:95 NH₄OH/MeOH/

CH₂Cl₂), 0.6 (Al₂O₃, 1:3 EtOAc/CH₂Cl₂); ¹H NMR (500 MHz,

CDCl₃) δ 9.45 (s, 1H, C17-H), 7.01−7.07 (m, 2H, C9-H + C11-H),

6.77−6.81 (m, 1H, C15-H), 6.71 (t, J = 7.6 Hz, 1H, C10-H), 6.56 (d,

J = 7.6 Hz, 1H, C12-H), 4.54 (br s, 1H, NH), 4.30 (s, 1H, C2-H), 3.53

(app q, J = 2.1 Hz, 2H, C21-H₂), 3.46 (app d, J = 4.0 Hz, 1H, C3-H),

3.10−3.17 (m, 1H, C5-H), 3.02 (td, J = 10.2, 4.5 Hz, 1H, C5-H), 2.56

(dd, J = 19.8, 5.5 Hz, 1H, C14-H), 2.35−2.42 (m, 1H, C14-H), 2.31

(ddd, J = 12.8, 8.2, 4.4 Hz, 1H, C6-H), 1.90 (ddd, J = 12.8, 10.5, 6.9

Hz, 1H, C6-H), 1.56 (app t, J = 2.1 Hz, 2H, C18-H₂), 0.17 (s, 9H,

SiCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 195.0, 150.5, 150.2, 140.7,

131.2, 128.4, 122.6, 118.5, 109.3, 83.5, 72.4, 60.4, 59.9, 53.4, 49.3, 40.7,

38.1, 25.5, 7.2, −1.8; IR (thin film) ν 3368, 2951, 2226, 2186, 1666,

844, 742 cm⁻¹; HRMS (LC-ESI) m/z calcd for C₂₂H₂₉N₂OSi (M +

H)⁺365.2049, found 365.2050.

Allene S4. To a solution of silane S3 (10.0 mg, 27.4 μmol,

1.0 equiv) in CH₂Cl₂(1.1 mL, 0.025 M) at 0 °C was added BF₃·OEt₂

(20.3 μL, 164 μmol, 6.0 equiv). The resulting solution was slowly

warmed to rt and stirred at rt for 18 h. The reaction mixture was

diluted with EtOAc (5 mL) and half-saturated Na₂CO₃(2 mL). The

layers were separated, and the aqueous layer was extracted with EtOAc

(5 mL). The combined organic extracts were washed with brine

(2 mL) and then dried over Na₂SO₄. The solvent was evaporated in

vacuo and analysis of the crude material indicated ∼1:1 mixture of

starting material and allene product with small impurities. The crude

material was purified by column chromatography (neutral Al₂O₃,

Brockman activity I, 1:3 EtOAc/CH₂Cl₂) to yield the desired product

mixed with starting material (2.3 mg, ∼ 90% purity, ∼25%) as a yellow

film. Because of the inefficiency of this sequence, a complete

characterization data set could not be compiled, and this avenue of

exploration was not pursued: R_f= 0.15 (Al₂O₃, 1:3 EtOAc/CH₂Cl₂);

¹H NMR (500 MHz, CDCl₃, assignments tentative) δ 9.99 (s, 1H,

C17-H), 7.06 (dd, J = 7.8, 7.3 Hz, 1H, C11-H), 7.01 (d, J = 7.2 Hz,

1H, C9-H), 6.73 (dd, J = 7.3, 7.2 Hz, 1H, C10-H), 6.56 (d, J = 7.8 Hz,

1H, C12-H), 4.77 (dt, J = 10.7, 4.0 Hz, 2H, C18-H), 4.68 (dt, J = 10.7,

4.0 Hz, 2H, C18-H), 4.24 (s, 1H, N-H), 3.85−3.89 (m, 2H, C2-H + C3-

H), 3.82 (dt, J = 15.0, 4.0 Hz, 1H, C21-H), 3.34 (br s, 1H, C15-H), 3.19

(dd, J = 8.4, 9.6 Hz, 1H, C5-H), 2.84−2.94 (m, 2H, C5-H + C21-H),

We thank the NSF (CAREER Award CHE-0847061) for

support of our work. D.B.C.M. is the recipient of graduate

fellowships from Eli Lilly, the NSERC of Canada, and Bristol−

Myers Squibb. L.Q.N. is the recipient of a UC Irvine UROP

fellowship and an Allergan Summer Undergraduate Research

Fellowship. C.D.V. is grateful for support through an Amgen

Young Investigator Award, an AstraZeneca Award for

Excellence in Chemistry, and an Eli Lilly Grantee Award.

C.D.V. is a fellow of the A. P. Sloan Foundation and is a

University of California, Irvine, Chancellor’s Faculty Fellow.

We thank Prof. Zach Ball and Jessica Herron (Rice University)

for the kind gift of several Cu−NHC complexes. We thank

Steve Canham and Jeff Cannon (UC Irvine) for HPLC and

computational assistance. Computational studies were per-

formed on hardware purchased with funding from NSF CRIF

(CHE-0840513).

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Syntheses of strychnine, norfluorocurarine, dehydrodesacetylretuline, and valparicine enabled by intramolecular cycloadditions of Zincke aldehydes

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