Enantioselective total syntheses of (-)-palau'Amine, (-)-axinellamines, and (-)-massadines

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Enantioselective Total Syntheses of (ꢀ)-Palau’amine,

(ꢀ)-Axinellamines, and (ꢀ)-Massadines

Ian B. Seiple, Shun Su,^†Ian S. Young,^†Akifumi Nakamura, Junichiro Yamaguchi, Lars Jørgensen,

Rodrigo A. Rodriguez, Daniel P. O’Malley, Tanja Gaich, Matthias K€ock, and Phil S. Baran*

Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States

S Supporting Information

b

ABSTRACT: Dimeric pyrroleꢀimidazole alkaloids represent a

rich and topologically unique class of marine natural products.

This full account will follow the progression of eﬀorts that

culminated in the enantioselective total syntheses of the most

structurally ornate members of this family: the axinellamines,

the massadines, and palau’amine. A bio-inspired approach

capitalizing on the pseudo-symmetry of the members of this

class is recounted, delivering a deschloro derivative of the

natural product core. Next, the enantioselective synthesis of

the chlorocyclopentane core featuring a scalable, catalytic,

enantioselective DielsꢀAlder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this

core to each of the aforementioned natural products, and the ensuing methodological developments, are described.

’ INTRODUCTION

palau’amine (12,17-epi-13), with the exception of the relative stereo-

chemistry at C12 and C17.⁵A few years later, massadine (11)

was isolated by Fusetani et al., representing a second tetracyclic

pyrroleꢀimidazole alkaloid with a mode of cyclization diﬀering from

that found in the axinellamines, and with a hydroxyl group instead of a

chloro substituent at C17 (palau’amine numbering).⁶The stylissa-

dines, published in 2006, represent the ﬁrst tetrameric members of

the pyrroleꢀimidazole alkaloids, and are apparent dimers of massa-

dine (11).⁷Insight into their genesis was revealed with the isolation of

massadine chloride (12) in 2007 in collaboration with the K€ock

group.⁸It was found that this natural product converts to massadine

(11) in aqueous media, presumably via the intermediacy of “massa-

dine aziridine”.⁹It is important to note that none of the absolute

conﬁgurations of these natural products are known, but that predic-

tions have been made by Fusetani (for massadine (11))⁶and Lindel,

Kinnel, and K€ock (for palau’amine (13)).¹⁰

The striking discrepancy that existed between the tetracyclic

pyrroleꢀimidazole alkaloids and the originally reported structure of

the hexacyclic palau’amine (12,7-epi-13, Scheme 1) was intriguing.

The axinellamines (9, 10) and the massadines (11, 12) possessed

trans-pyrrole amide side chains, matching the all-trans nature of

sceptrin (4) and ageliferin (5). In contrast, the hexacyclic com-

pounds palau’amine (12,17-epi-13), styloguanidine, and konbu’aci-

din appeared to stand alone in the family of dimers with two inverted

stereocenters at C12 and C17. However, numerous approaches

toward the synthesis of the originally assigned structure of palau’a-

mine (12,17-epi-13) continued to appear in the literature, indicating

that the initial stereochemical assignment was generally accepted.

Within the ﬁeld of natural product synthesis, alkaloids continue

to be studied with great zeal and represent veritable gold mines for

organic chemistry. Indeed, these molecules continually lead to the

discovery of new reactivity, provide fertile testing grounds for new

methodology, and exhibit profound medicinal potential. This full

account traces the progression of studies that successfully led to

enantioselective total syntheses of the most complex members of

the marine-derived pyrroleꢀimidazole alkaloid family.

The isolation of the marine natural product sceptrin (4,Scheme1)

from the sponge Agelas sceptrum in 1981 by Faulkner and Clardy

marked the ﬁrst report of a dimer of the pyrroleꢀimidazole alkaloid

family.¹This symmetric alkaloid contains a cyclobutane core and is

enantioenriched, indicating a probable enzyme-mediated, head-to-

head cyclization of the natural product hymenidin (2) that is also

present in the isolation extract. This report was followed by the

discovery of the bicyclic, nonsymmetrical dimer ageliferin (5) in1986

by Rinehart.²In 1993, this family reached a new pinnacle of archi-

tectural complexity with the isolation by Scheuer and co-workers of

palau’amine, which was assigned the structure 12,17-epi-13 (Scheme1,

palau’amine numbering used for all molecules herein).³This

natural product contains a fully substituted cyclopentane core

woven into a dense hexacyclic architecture containing eight

contiguous stereocenters and nine nitrogen atoms, and is notably

lacking one of the acylpyrrole units. Over the next few years, the

styloguanidines and konbu’acidins, which possessed hexacyclic

architectures similar to palau’amine (12,17-epi-13), were re-

ported, some containing the missing second acylpyrrole unit.⁴

The publication of the axinellamines (9, 10) in 1999 by Quinn

and co-workers marked the ﬁrst report of tetracyclic pyrroleꢀ

imidazole alkaloids that contained a similar cyclopentane cores as

Received: May 23, 2011

Published: August 23, 2011

r

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Scheme 1. Biosynthesis of PyrroleꢀImidazole Alkaloids

We began to question the original stereochemical assignment

of palau’amine (12,17-epi-13) in 2004 during investigations into

the conversion of (ꢀ)-sceptrin (4) to (ꢀ)-ageliferin (5) via a vinyl-

cyclobutane rearrangement.¹¹It was reasoned that a similar con-

version could happen in Nature, as sceptrin (4) is almost always

the most abundant pyrroleꢀimidazole alkaloid found in isolation

extracts which contain the more complex dimers.¹²Thus, it was

speculated that the genesis of the tetracyclic and hexacyclic con-

geners (e.g., 9ꢀ13) would not require the invocation of a sepa-

rate enzymatic pathway, but simply an oxidative ring expansion of

sceptrin (4) via intermediate 7, or an isomerization/oxidative

ring contraction of ageliferin (5) via intermediates 6 and 7, as

shown in Scheme 1. The 2-aminoimidazole in 7 could undergo

further oxidation to produce “pre-axinellamine” (8), which is

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primed to undergo intramolecular cyclization to access each of

the more intricate structures 9ꢀ13. This hypothesis was further

supported by the successful conversion of ageliferin (5) into the

carbogenic core of the axinellamines (9, 10).¹³

Scheme 2. Bio-inspired Retrosynthetic Scheme Based on an

Oxidative Cyclization from the Symmetric seco-Sceptrin-N₃

(16)

In order for hexacyclic pyrroleꢀimidazole alkaloids such as

palau’amine (12,17-epi-13) to ﬁt into this hypothesis, the stere-

ochemistry at C12 would have to be inverted to match that of

sceptrin (4) and ageliferin (5). Additionally, it would not be a

logical leap of faith to assume that the stereochemistry of the

chlorine atom (C17) should also match that of the rest of the

family (e.g., 9ꢀ12). Finally, in 2007, reports from the K€ock,¹⁴

Quinn,^7b,15and Matsunaga¹⁶groups simultaneously appeared in

the literature that oﬃcially reassigned palau’amine (to structure

13) to match the axinellamines (9, 10) and massadines (11, 12),

thus bringing uniformity to the entire family of alkaloids. These

groups used 2-D NMR spectroscopy (and in one case a

quantitative computational approach)¹⁴to support the revised

structure, as a crystal of these alkaloids suitable for X-ray analysis

has never been acquired. An elegant synthesis of an analogue of

the hexacyclic core of cis-palau’amine (12,17-epi-13) by the

Overman laboratory demonstrated that the spectral data were

not in agreement with those reported in the isolation papers,

giving further support to the trans structure.¹⁷

While several members of the pyrroleꢀimidazole alkaloid family

possess notable biological activity,^{2ꢀ6,7b,16,18}the primary inspiration

for chemists to pursue their synthesis lies in their intriguing struc-

tures. Notably, the axinellamines (9, 10), massadines (11, 12), and

palau’amine (13) have densely functionalized cores with eight

contiguous stereocenters, high nitrogen content (ca. 1:2 N:C), and

sensitive functional groups such as hemiaminals and labile halogens.

Several groups have reported eﬀorts toward the synthesis of the

axinellamines (9, 10)^9,13,19and the massadines (11, 12),^9,19c,19d,20

although the majority of synthetic approaches to these molecules have

focused on palau’amine (13),^{9,17,19b,19c,19f,21}and there are numerous

reviews on these approaches.²²Additionally, several Ph.D. theses have

emerged with a wealth of unpublished chemistry.²³Several of these

approaches occurred during the 14-year interim between the original

report and the structural reassignment,^{9,17,19b,19c,21aꢀ21j}while others

have recently targeted the correct structure.^{19f,21kꢀ21u}The ﬁrst suc-

cessful synthesis of one of the complex pyrroleꢀimidazole alkaloids

emerged from our laboratory in 2008, with the completion of

axinellamines A (9) and B (10),²⁴and was followed later that year

with the synthesis of massadine (11) and massadine chloride (12).²⁵

In 2010, palau’amine (13) ﬁnally succumbed to synthesis, conﬁrming

the structural reassignment.²⁶This article will recount the details of

the eﬀorts that culminated in the ﬁnal racemic routes to each of these

molecules. Additionally, a catalytic enantioselective route that deliv-

ered the natural enantiomer of each of the alkaloids 9ꢀ13 is reported,

conﬁrming their absolute stereochemistry to match that of sceptrin

(4) and ageliferin (5).

represents one pathway among a plethora of possibilities, there is

precedent from the Horne group that 2-aminoimidazoles could be

induced to react in such a manner.²⁷Additionally, although the

formation of such a hindered quaternary center could be out-

competed by several less strained cyclization modes, the Harran

group has showed promising results in similar cyclizations.^21g,j,oThe

risky nature of such a step was outweighed by the rapidity with which

a structure such as seco-sceptrin azide could be accessed: imidazole

formation from diketone 17, which could in turn be derived from

ozonolysis of DielsꢀAlder product 18.

In the forward sense, a thermal [4+2] cycloaddition between

dimethyl fumarate and 2,3-dimethylbutadiene followed by functional

group manipulations yielded diazide 18 in 78% yield over four steps

(Scheme 3). Ozonolysis and bromination provided the linear

diketone 17 in 45% overall yield, which was treated with Boc-

guanidine and deprotected with triﬂuoroacetic acid to deliver seco-

sceptrin-N₃(16). With this key precursor in hand, several oxidative

conditions were applied in an attempt to obtain a cyclized product.

These conditions included several electrophilic halogen sources

(NCS, NBS, tBuOCl), hypervalent iodine sources (PhIO, PhI-

(OAc)₂, Koser’s reagent), and other oxidants (m-CPBA, DMDO,

TFDO) in a variety of solvents and at varying pH. Unfortunately, no

evidence of the desired cyclization to 14 or of the existence of the

oxidized intermediate 15 was ever encountered. It appeared that the

main products were oxidized 2-aminoimidazoles that subsequently

captured solvent or residual water (subsequent cyclization of these

intermediates could not be induced). Thermal and acidic conditions

in an attempt to cyclize through a simple isomerization also failed.

Fortunately, aspects of the route to seco-sceptrin-N₃(16) did

deliver some promising results. During the isolation of diketone

17 by column chromatography on silica gel, a signiﬁcant amount

’ RESULTS AND DISCUSSION

Bio-inspired Approach to the Cyclopentane Core. Due to

the dimeric nature of the complex pyrroleꢀimidazole alkaloids

9ꢀ13, it would appear on first inspection that they could arise

from a simple, symmetrical precursor. Initial investigations into

the synthesis of the cyclopentane core of 9ꢀ13 attempted to

capitalize on their pseudo-symmetry by targeting a seco-sceptrin

derivative (16, Scheme 2). It was envisioned that such a

precursor could be oxidatively cyclized to generate a deschloro

version of the core, such as 14. Although such a cyclization

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Scheme 3. Attempt To Secure the Core of the PyrroleꢀImidazole Alkaloids with an Oxidative Cascade from a Linear Precursor

(16)^a

^aReagents and conditions: (a) dimethyl fumarate (1.0 equiv), 2,3-dimethylbutadiene (1.0 equiv), neat, 135 °C, 1.5 h; (b) LiAlH₄(2.0 equiv), THF, 0 °C,

1 h; (c) methanesulfonyl chloride (4.0 equiv), pyridine, 0 f 23 °C, 1 h; (d) sodium azide (6.0 equiv), DMF, 100 °C, 2 h, 78% for four steps; (e) O₃, MeOH,

ꢀ78 °C, 15 min, then DMS (3.0 equiv), 23 °C, 20 h; (f) diisopropylethylamine (6.0 equiv), TMSOTf (4.0 equiv), 0 f 23 °C, then NBS (2.0 equiv), MeCN,

THF, 0 °C, 15 min, 45% for two steps; (g) Boc-guanidine (10 equiv), DMF, 23 °C, 65 h, 14%; (h) TFA:DCM (1:2), 23 °C, 6 h, quant. THF = tetrahydro-

furan, DMF = N,N-dimethylformamide, DMS = dimethylsulﬁde, TMSOTf = trimethylsilyl triﬂuoromethanesulfonate, NBS = N-bromosuccinimide, TFA =

triﬂuoroacetic acid, DCM = dichloromethane.

Scheme 4. Access to a Deschloro Core Structure (22)^a

Abiotic Approach to the Cyclopentane Core. The two main

roadblocks encountered during the bio-inspired approach that

culminated in Scheme 4 were (1) the lack of a chlorine substituent

at C17 on the cyclopentane and (2) the undesired stereochemical

outcome at C16. Additionally, C20 would have to be oxidized to a

hemiaminal, and although ample precedent for amine-to-imine con-

version existed in the literature,²⁸as well as for amides to N-acyli-

mines,²⁹no such chemistry had ever been applied to 4,4-disubstituted

imidazolines. With these considerations in mind, a revised retro-

synthesis was forged (Scheme 5).

The ﬁrst disconnection to dideoxy-pre-axinellamine (23, des-

cribed in our biosynthetic hypothesis)^22bconsists of two separate

(but equally important) steps: oxidation of the 2-aminoimidazole

with intramolecular nucleophilic capture of the resulting

iminium(s), and oxidation of C20. The former closely follows

the biosynthetic hypothesis that was reviewed in 2007.^22bIt was

believed that this oxidation occurs in Nature to make all of these

natural products, and that there would be a thermodynamic bias

for them to undergo similar transformations in the laboratory.

It is worth noting that several other biosynthetic hypotheses

have been published by other groups,^{3a,9,21a,21t,21u,22c,30}and that

our hypothesis builds on pioneering work by Rinehart^2dand

Horne.^27,31The oxidation of C20 is a strategic disconnection: by

saving the oxidation of C20 for the ultimate or penultimate step

of the synthesis, the stability and reactivity problems associated

with a hemiaminal could be avoided during the majority of the

skeleton-building steps. As alluded to earlier, this disconnection

was notably lacking in precedent, and thus its inclusion into the

retrosynthesis was not without a signiﬁcant amount of risk.

Dideoxy-pre-axinellamine (23) could arise from acylation of

bis-azide 24, which could in turn be generated from the spiro-

cyclic amino ketone 25. Taking lessons from the bio-inspired

route (Scheme 2), 25 was envisioned to arise from a guanidine

addition to enone 26 followed by amination. Unlike the des-

chloro route (vide supra), the proximal substitution at C17 has

the potential to direct the aza-Michael addition, possibly avoiding

the exclusive formation of the wrong spiro center. Enone 26

could be traced back to diketone 27 via intramolecular aldol and

^aReagents and conditions: (a) SiO₂, 23 °C, 12 h, 90%; (b) 2,6-lutidine

(4.0 equiv), SOCl₂(2.0 equiv), DCM, 0 °C, 1 h, 30%; (c) Boc-guanidine

(7.0 equiv), THF, 55 °C, 12 h; (d) TFA:DCM (1:1), 23 °C, 1 h, 22% for

two steps.

of a byproduct was being formed, and was later identiﬁed as aldol

product 20 (Scheme 4). It was intriguing to realize that prior to

2-aminoimidazole formation, the desired carbonꢀcarbon bond

was being formed by weak Brønsted-acid-induced cyclization.

After dehydration to form cyclopentene 21, exposure to Boc-

guanidine followed by deprotection provided the cyclized cyclo-

pentane 22, which bore a striking resemblance to the core found

in the natural products 9ꢀ13. The cascade resulting in the

formation of this product most likely involves two S_N2 reactions,

a conjugate addition, and a condensation to form the ﬁnal

2-aminoimidazole. Unfortunately, 2-D NMR data revealed that

the stereochemistry at the spiro junction at C16 was epimeric to

that found in the natural products. Additionally, no functional

handles were available to selectively introduce the chlorine atom

needed at C17. However, these results inspired us to adapt the

approach with a pre-functionalized C17, perhaps permitting

elaboration to a fully functionalized cyclopentane core.

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Scheme 5. Revised Retrosynthetic Analysis of the Axinellamines (9, 10) and Palau’amines (e.g., 13)^a

^aR = H or acyl-2-(4,5-dibromopyrrole).

chlorination. Finally, 27 could arise from the [4+2] cycloaddition

product 28.

allylic alcohol could then be protected as the p-methoxybenzyl

ether and ozonized to deliver diketone 42 (86%, two steps),

which could be brominated and cyclized on warm silica gel to

deliver the fully substituted cyclopentane 43. Unfortunately,

attempts to avoid the protecting group interchange by carrying

the triisopropylsilyl group forward were very low-yielding, pre-

sumably due to the increased steric hindrance of the TIPS group

for the bromination and aldol cyclization steps.

The synthesis of 28 via a [4+2] cycloaddition provided a unique

opportunity to render the entire route asymmetric, as numerous

asymmetric cycloadditions of siloxydienes have been reported

in the literature (albeit rarely with a 1-siloxy substituent).³²A brief

summary of the eﬀorts to achieve an asymmetric [4+2] cycloaddition

(leading to cyclohexenes 32) with TIPS diene 31 can be found in

Table 1. Utilizing Corey’s oxazaborolidine catalyst 33 with triﬂuoro-

methanesulfonimide³³or aluminum tribromide³⁴and various die-

nophiles gave little to no enantiomeric excess. Evans’s ligand 34 with

copper(II) triﬂate³⁵did induce some asymmetry with dienophile 35,

but was not eﬃcient enough (ca. 10% yield) to justify further opti-

mization. The Shibasaki catalyst FujiCAPO (36)³⁶provided the

product in excellent yield (using a TMS version of the diene), but

predominantly gave the exo-stereoisomer (epimeric at C17). Pro-

mising results came when the Ishihara catalyst 37³⁷was employed

with dienophile 35: copper(II) triﬂate gave excellent enantiomeric

excess (96%) in nitromethane, with acceptable yield (61%). When

the Lewis acid was exchanged for copper(II) triﬂuoromethanesulfo-

nimide, the yield was virtually quantitative while enantioselectivities

remained excellent. This procedure proved to be scalable with a

minimal depreciation in yield and enantioselectivity. Additionally, the

product was crystalline and X-ray crystallographic analysis secured

the absolute conﬁguration as that corresponding to the stereochem-

istry of sceptrin (4) and ageliferin (5). It should be noted that

intermediates that were only synthesized in a racemic manner will be

annotated with a ((), while those synthesized using enantioenriched

material will be annotated with the sign of their optical rotation

henceforth in this article.

Although seemingly straightforward, the dehydration and

chlorination of 43 to the desired trihaloenone 26 proved sur-

prisingly laborious (Scheme 7). Treatment of 43 with Brønsted

acids and Lewis acids failed to deliver the dehydrated product 44,

and basic conditions only led to epoxide formation to yield

oxirane 45. Burgess reagent eﬃciently formed sulfamidate 46,

but 46 could not be further elaborated to the desired carbamoyl

enone 47. In an attempt to moderate the reactivity of the R position,

bromoketone 43 was treated with lithium chloride to provide

chloroketone 48, which was equally resistant to dehydration con-

ditions (albeit generating less decomposition products than 43).

Deprotection of the p-methoxybenzyl group with triﬂuoroacetic

acid provided diol 50, which proved resistant to dehydration but

could be reacted with thionyl chloride to yield cyclic sulﬁte 52

(which was resistant to elimination). Upon exposure to sulfuryl

chloride, however, diol 50 underwent a cascade reaction to accom-

plish not only the dehydration but also an in situ chlorination with

inversion, directly providing the desired chlorine at C17 with the

correct stereochemistry. This reaction has been optimized to 60%

yield, and can provide the desired enone 26 on a multi-gram scale.

Trihalo enone 26 bears close resemblance to its deschloro

derivative 21 (Scheme 4), so several conditions were attempted

to eﬀect the direct conversion of 26 into the fully substituted core

54 (Scheme 8). Unfortunately, due to the highly sensitive nature

of enone 26 (which contains ﬁve highly electrophilic sites), no

appreciable amounts of product were ever detected. To temper the

reactivity of enone 26, a Luche reduction was carried out (thus

mitigating the reactivity of three of the electrophilic sites), followed

by displacement of the allylic bromide with bis-Boc-guanidine, to

deliver allylic guanidine 55 in 55% yield over two steps (4.2 g scale).

Upon exposure to several oxidative conditions, 55 swiftly converted

The reduction of cyclohexene 38 (Scheme 6) to intercept the

racemic route proved surprisingly diﬃcult. Several harsh reduc-

tive conditions failed to deliver the desired diol, and instead

reduced the oxazolidinone to deliver products such as 39. To

circumvent this problem, 38 was treated with dodecanethiol to

deliver thioester 40, which could readily be reduced with lithium

aluminum hydride to intercept the racemic route (86% yield, 60 g

scale). Mesylation, displacement with azide, and TIPS deprotec-

tion provided cyclohexenol 41 in 81% yield over three steps. This

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Table 1. Catalytic Asymmetric [4+2] Cycloadditions At-

tempted on TIPS Diene 31

Scheme 6. Elaboration to a Fully Substituted Cyclopentane

Core^a

^aReagents and conditions: (a) dodecanethiol (4.4 equiv), n-butyllithium

(4.0 equiv), THF, ꢀ78 °C f 0 °C, 18 h, 74%; (b) LiAlH₄(3.0 equiv),

Et₂O, 0 °C, 1 h, 86%; (c) methanesulfonyl chloride (4.0 equiv), pyridine,

0 °C f 23 °C, 1 h; (d) sodium azide (6.0 equiv), DMF, 100 °C, 11 h;

(e) TBAF (1.1 equiv), THF, 23 °C, 1 h, 81% for three steps; (f) NaH

(2.0 equiv), PMBCl (1.1 equiv), TBAI (0.1 equiv), DMF, 0 °C f 23 °C,

2 h; (g) O₃, MeOH, ꢀ78 °C, 1 h then DMS (3.0 equiv), 23 °C, 16 h,

86% for two steps; (h) diisopropylethylamine (6.0 equiv), TMSOTf

(4.0 equiv), 0 °C f 23 °C, 1.5 h, then NBS (2.0 equiv), THF, MeCN,

0 °C, 15 min, then SiO₂, 50 °C, 16 h, 66%. TBAF = tetra-n-butylammo-

nium ﬂuoride, PMBCl = p-methoxybenzyl chloride, TBAI = tetra-n-

butylammonium iodide.

^aReactions performed in the Shibasaki laboratory, using the TMS

version of 31. GC yields reported for this experiment. ^bProcedure for

sub-gram scale: dienophile 35 (1.0 equiv), diene 31 (3.0 equiv), ligand

37 (0.10 equiv), Cu(NTf₂)₂(0.11 equiv), MeNO₂, ꢀ20 °C, 96 h, 97%

c

isolated yield, 95% ee. Procedure for multi-gram scale: dienophile 35

(1.0 equiv), diene 31 (2.5 equiv), ligand 37 (0.050 equiv), Cu(NTf₂)₂

(0.055 equiv), MeNO₂, ꢀ20 f 4 °C, 15 h, 84% isolated yield, 89% ee.

Product could be recrystallized (hexane:2-propanol) to >99% ee.

that is more amenable to scale-up is reported herein. Originally, the

mixture of C16 isomers (56/57) was tediously separated by

preparative TLC. It was later found that exposure of 56/57 to

sodium diformylamide followed by deprotection with triﬂuoroacetic

acid allowed for facile isolation of aminoketone 25 along with its

C16 isomer (69% total, 36% 25, 820 mg scale, wrong diastereomer

reacts more eﬃciently). Exposure of 25 to cyanamide in brine

produced 24 in 71% yield. The judicious choice of brine (instead of

water) was critical in this transformation to avoid displacement of the

C17 chlorine with water (vide infra). With access to hundreds of

milligrams of the fully substituted cyclopentane core, the ﬁrst investi-

gations into biomimetic closures to deliver the axinellamines (9, 10),

massadines (11, 12), and palau’amine (13) could ﬁnally be explored.

Explorations on Biomimetic Closures and Formation of a

Universal Retrosynthetic Plan. Upon close inspection of the

natural products 9ꢀ13, it becomes apparent that there are

several potentially unstable functional groups and substructures.

Palau’amine (13) has a strained trans-5,5 system that is only held

together by two aminal moieties. The axinellamines (9, 10) contain

an aminal to anchor the core, while the massadines (11, 12) are held

together by N,O-ketals. Despite all of these seemingly labile

substructures, all of the natural products 9ꢀ13 were reported to

be stable to isolation conditions and extended storage. For this

to the spirocycle 56 via aza-Michael addition to the transient enone.

Over 50 conditions were tried at room temperature and below, but

in every case only the wrong stereoisomer at C16 was produced. In a

ﬁnal series of experiments, high-temperature oxidations that had the

potential to override the kinetic bias toward the wrong spiro isomer

were explored. Indeed, exposure of 55 to o-iodoxybenzoic acid in

reﬂuxing benzene was able to provide the desired diastereomer 57 in

a 1.3:1 ratio to 56 at C16 (70%, 1.8 g scale). Attempts to resubject

56 to the same reaction conditions to eﬀect a retro-aza-Michael/aza-

Michael equilibration were unsuccessful, indicating that the aza-

Michael addition was irreversible under the reaction conditions.

With every desired functional group bearing the correct

stereochemistry in the cyclopentane core of 57, all that was

required to reach the key precursor 24 was the formation of the

2-aminoimidazole from the chloroketone. However, even this

simple transformation was met with roadblocks, as several guanidine

sources in a variety of solvents delivered only the base-induced

cyclization product 58 (this was not a problem on the wrong C16

isomer 56, resulting in several misleading model studies). An interim

solution was devised in our 2008 synthesis by utilizing mono-Boc-

guanidine in THF without additional base.^24aAn improved route

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Scheme 7. Roadblocks En Route to the Trihalogenated Enone 26^a

^aReagents and conditions: (a) LiCl (3.3 equiv), DMF, 23 °C, 1.5 h; (b) TFA:DCM (1:9), anisole (2.0 equiv), 0 °C, 1 h, 72% for two steps; (c) NaOH

(1.1 equiv), THF, H₂O, 0 °C, 45 min, 75%; (d) Burgess reagent (5.0 equiv), benzene, 50 °C, 6 h, 95%; (e) 2,6-lutidine (3.0 equiv), SOCl₂(2.0 equiv),

DCM, 0 °C, 2 h, 78%; (f) SO₂Cl₂(2.0 equiv), 2,6-lutidine (3.0 equiv), DCM, 0 °C, 30 min, 60%.

Scheme 8. Elaboration of Enone 26 to the Fully Substituted Core 24^a

^aReagents and conditions: (a) NaBH₄(1.0 equiv), CeCl₃7H₂O (0.5 equiv), MeOH, 0 °C, 15 min; (b) N,N⁰-bis-Boc-guanidine (1.2 equiv), DBU

3

(1.2 equiv), DMF, ꢀ20 to 0 °C, 4 h, 55% for two steps; (c) IBX (2.0 equiv), benzene, 83 °C, 16 h, 70%, 1.3:1 57:56; (d) N-Boc-guanidine (6.0 equiv), DMF or

MeCN, 23 °C, 24ꢀ48 h, 5ꢀ20%; (e) NaN(CHO)₂(1.5 equiv), TBAI (0.1 equiv), THF, 23 °C, 3 h; (f) TFA:H₂O (1:1), 50 °C, 24 h, 69% for two steps, 36%

25, 33% 16-epi-25; (g) H₂NCN (40 equiv), pH 5, brine, 70 °C, 4 h, 71%. DBU = 1,8-diazabicycloundec-7-ene, IBX = o-iodoxybenzoic acid.

reason, it was believed that any open-chain versions of these natural

products would be thermodynamically inclined to form the corre-

sponding closed structures found in Nature, as reasoned in the

biosynthetic hypotheses (and outlined in Scheme 5). Therefore, the

synthesis of dideoxy-pre-axinellamine (23, Scheme 5) was accom-

plished by the reduction of the azides in 24 with hydrogen over

platinum oxide, followed by acylation with dibromopyrrole 59 to

provide 23 in 26% overall yield along with 17% of the mono-

acylated product. Dideoxy-pre-axinellamine (23) is also available via

a fully protected route, as noted in the original communication.^24a

It was expected that the oxidation of the 2-aminoimidazole in

23 would cause a spontaneous closure to one or all of the

axinellamine (60) or palau’amine (61) congeners via intramole-

cular capture with the spirocenter nitrogen or the pyrroleꢀamide

side chain (massadine-type closure was not possible without C20

oxidation). Indeed, several oxidants such as NBS, NCS, MnO₂,

DMDO, and others were able to selectively oxidize the 2-ami-

noimidazole found in 23, although oxidation of the dibromo-

pyrroles was a very common side reaction (Scheme 9). In several

cases, if a nucleophilic solvent was used, oxidized derivatives such

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Scheme 9. Failed Biomimetic Approaches to the PyrroleꢀImidazole Alkaloids^a

^aReagents and conditions: (a) PtO₂(0.1 equiv), H₂(1 atm), TFA:H₂O (1:9), 23 °C, 2 h; (b) (trichloroacetyl)pyrrole 59 (3.0 equiv), diisopropylethylamine

(3.0 equiv), DMF, 40 °C, 3 h, 26% + 17% monoacylated product; (c) NBS (1.0 equiv), MeOH, ꢀ78 °C, 26 h; (d) neat TFA, 30 °C, 24 h, 34%.

as 62 could even be detected by spectroscopy. However, it was

perplexing to observe that even though intermediates such as 62

were found, the only product that could ever be isolated from the

oxidative attempts was the unsaturated cyclopentene 63. This

product represented a veritable dead end: two stereocenters had

been destroyed, and another reactive oleﬁn was added to the

system. Under no circumstances were any products with desired

modes of cyclization found in even trace amounts, with hundreds

of conditions attempted.

The failures of such a seemingly promising biomimetic ﬁnale

did not come without useful reconnaissance. The use of strong

oxidants resulted in overoxidation of the pyrrole moieties in

addition to the desired 2-aminoimidazole oxidation. Addition-

ally, no oxidation of C20 was ever observed, even when extensive

oxidation of the rest of the molecule was taking place. Finally, closure

to the complete natural product cores would not be an easy feat to

accomplish, and would require careful synthetic planning. Taking

these lessons into account, a detailed non-biomimetic retrosynthetic

analysis was forged. The general rules for the disconnections were as

follows: C20 oxidation and pyrrole installation should be saved until

the latest possible step, intramolecular closure should take place in a

manner that is thermodynamically biased, and the molecules’inherent

reactivity should be harnessed (avoiding the protection of functional

groups). These guidelines led to the complete retrosynthesis shown

in Scheme 10.

The axinellamines (9, 10) presented the most straightforward

targets, as they did not necessitate the installation of the C20 hydroxy

or either of the pyrrole moieties prior to core cyclization. Therefore,

the installation of the pyrroles would be saved for the last step, leading

to axinellamine azide (68). The next disconnection would prove

crucial to the completion of each of the natural products outlined in

this scheme: deletion of the C20 hydroxy group (amounting to a

formal CꢀH oxidation in the forward direction) to give the axinell-

amine core structure 69. It was anticipated that this step would be far

from trivial, as no such oxidations were present in the literature (vide

infra). Compound 69 could be drawn back to 2-aminoimidazole 24,

requiring oxidation and closure with only one proximal nucleophile

present to form the core structure.

Analysis of the massadines (11, 12) bears resemblance to the

axinellamine retrosynthesis, with one key exception: oxidation of

C20 in the massadine retrosynthesis had to precede closure to the

core, since the C20 hydroxyl group formed an integral part of its

architecture. Thus, after removal of the pyrroles to yield massadine

chloride azide 70, scission of the bridging C20 hydroxyl group would

lead back to diol 71. It was anticipated that the closure from 71 to 70

would be selective at the hydroxy group (thus outcompeting

axinellamine closure) under acidic conditions. Diol 71 could arise

from oxidation of the 2-aminoimidazole in 72, which could in turn

be reached via imidazole synthesis from aminoketone 73. Finally, in

a circumstance even more challenging than the axinellamine route,

the C20 hydroxy group would need to be installed on the common

precursor 25, which contains a primary ammonium group.

Palau’amine (13) presented the most challenging structure by

far: installation of the pyrrole unit could not be left until the ﬁnal

stages of the synthesis. Additionally, biomimetic eﬀorts toward

the core (Scheme 9) had shown absolutely no promise for an

oxidative closure of a pyrroleꢀamide side chain onto an oxidized

2-aminoimidazole. Finally, of the two azide moieties present in

the common precursor 25, one of them would need to be selectively

acylated, despite their virtually identical chemical environments.

These considerations led to two retrosynthetic routes to palau’amine

(5) that capitalized on a strategy that would simultaneously allow

the selective acylation of one of the azides and generate a

structure that was thermodynamically biased to close to the

natural product core upon selective acylation of one azide.

In Route 1 (Scheme 10), oxidation of C20 was reserved until

the ﬁnal step in order to minimize side reactions stemming from the

reactive hemiaminal moiety throughout the synthesis, even though

the success of such an oxidation was questionable in the presence of

the pyrrole moiety found in 64. Deoxypalau’amine azide 64 could be

drawn back to its constitutional isomer 65, which contained a nine-

membered macrocyclic lactam that appeared by molecular models

to be poised to undergo transannular cyclization upon isomerization

of the 2-aminoimidazole. This strategic disconnection was designed

speciﬁcally to overcome the barrier that would likely be encoun-

tered in forming the trans-5,5 core by capitalizing on a potential

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Scheme 10. Non-biomimetic Retrosynthesis of the PyrroleꢀImidazole Alkaloids to a Common Precursor (25)

relief of transannular strain present in a nine-membered macrocycle

to the conformationally stable (albeit still strained) bicyclo-

[3.3.0]octane of palau’amine (13). Thus, it was postulated that

a dynamic equilibrium among conformational macrocyclic

isomers of 65 would eventually lead to the thermodynamic

sink of deoxy-palau’amine-azide (64) by a net irreversible

ringꢀchain tautomerization. A conceptually similar approach

to topology control had been demonstrated in our synthesis of

the kapakahines.³⁸It was envisioned that 65 could arise from a

Staudinger ligation from 66 to form the amide bond, a strategy

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that was pioneered by Raines and Bertozzi³⁹and has been

shown to be especially eﬀective at the formation of medium-

sized rings.⁴⁰The ﬁnal retrosynthetic barrier to overcome

would be the attachment of the pyrrole, which could arise by a

formal S_NAr reaction on the bromo-2-aminoimidazole 67.

The potential complications arising from the oxidation of C20

in the last step of Route 1 led to the generation of an alternate

plan. Route 2 contains the same general strategy as the ligation

route with two key exceptions: the C20 oxidation would be

performed at the same stage as the massadine route (25 f 73),

and the elaborate Staudinger ligation would be replaced with a

more traditional macrolactamization in the penultimate step.

Certainly this route would present problems with chemoselectivity

due to the ever-present hemiaminal, but if it could not be

installed at a later stage as in Route 1, then its presence would

be unavoidable.

Total Synthesis of (ꢀ)-Axinellamine A and (ꢀ)-Axinella-

mine B^24b. To attempt a synthesis of the axinellamines (9, 10),

two main hurdles would have to be overcome: first, closure to the

core would have to proceed where it failed on dideoxy-pre-

axinellamine (23); second, a suitable oxidative reaction to install

the C20 hemiaminal would need to be invented. The former

could only be solved by trial-and-error, but the latter could be

studied on a model system. It is worth noting that there are two

inherent challenges to this type of oxidation: chemoselectivity on

a complex system (with several Lewis basic atoms and multiple

oxidizable sites) and redox control (the hemiaminal product has

a higher potential to be oxidized than the starting material). To

selectively study this redox challenge, 1,3-diazaspiro[4.4]nonan-

2-imine (78) was prepared and exposed to several oxidative

conditions (Scheme 11).^23x

Halogenating reagents (NCS, NBS, NaOCl, NaOBr, tBuOCl, I₂)

usually reacted at nitrogen, and some of the resulting N-halo species

were stable enough to be observed by NMR. Attempts to eliminate

these N-halo species to the desired iminium with base proved

unsuccessful, causing decomposition of the substrate. Ruthenium

protocols that have been successful in the oxidation of amines

(RuCl₃/H₂O₂, RuꢀC/tBuOOH, RuCl₂(PPh₃)₃/tBuOOH,) gen-

erally provided complex mixtures, with both 79 and 80 present in

varying ratios. Hypervalent iodine reagents (I₂O₅, PhIOH(OTs),

IBX, PhIO, PhI(OAc)₂, HIO₃) proved generally unreactive, with

the exception of iodosobenzene and iodobenzene diacetate, which

gave trace product in MeOH. Stronger oxidants such as potassium

ferrate gave rapid overoxidation to 80. Potassium persulfate gave 79

as the major product, with some 80 and some leftover starting material.

Silver(II) oxide in the presence of nitric acid gave product, but with

poor reproducibility. The most promising results, however, were

achieved by employing a ligand-decorated silver(II) complex: silver(II)

picolinate. This complex was studied by the Bacon and Lee groups in

the 1950’s to 1970’s, and was found to oxidize amines to imines

(cleaved in situ to aldehydes) without extensive overoxidation.⁴¹It was

non-basic, and the oxidations were performed in water (pyrroleꢀ

imidazole alkaloids are generally stable in aqueous acidic media),

making it ideal for the application to the axinellamines (9, 10).

However, before the conditions could be applied to the

axinellamine system, a synthesis of the desired core structure 69

would need to be carried out, and is illustrated in Scheme 12. The

synthesis commenced with the oxidation of 24 with dimethyldiox-

irane to give a transient diol, which was treated with triﬂuoroacetic

acid to eﬀect closure to the tetracyclic core 69 as a mixture of

diastereomers (both of which would be used to generate the

stereoisomeric pair of the natural products 9 and 10). It was

gratifying that no elimination byproducts (analogous to the 62 f

63 conversion in Scheme 9) were observed during this cyclization.

The core structure 69 was now poised to undergo oxidation at C20,

but it remained to be seen if the insight gained from the model study

in Scheme 11 would be compatible with such a complex system.

Scheme 11. Model System for the Oxidation of Spiro-annu-

lated Imidazolines^a

^aReactions monitored by HPLC-MS and ¹H NMR comparison to

known standards of 79 and 80.

Scheme 12. Enantioselective Total Synthesis of (ꢀ)-Axinellamine A (9) and (ꢀ)-Axinellamine B (10)^a

^aReagents and conditions: (a) DMDO (0.35 mL of 0.09 M solution), H₂O, 0 °C, 15 min; (b) TFA:DCM (2:1), 23 °C, 17 h; (c) silver(II) picolinate

(3.5 equiv), TFA:H₂O (1:9), 23 °C, 30 min, 43% (3:4 68R:68β); (d) 1,3-propanedithiol (15ꢀ20 equiv), Et₃N (11ꢀ14 equiv), MeOH, 23 °C, 2 h;

(e) (trichloroacetyl)pyrrole 59 (3.0 equiv), diisopropylethylamine (3.0 equiv), DMF, 45 °C, 6ꢀ11 h; 9 = 45%, 10 = 24%. DMDO = dimethyldioxirane.

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Indeed, 69 possessed several sites that could be oxidized, as well as a

hemiaminal and an alkyl halide that could complicate selective

oxidation at C20. In the event, 69 was exposed to silver(II)

picolinate (81) in 10% aqueous triﬂuoroacetic acid to deliver 68R

and 68β in 43% yield over three steps. It is worth noting that this

ﬁnal oxidation proceeds at room temperature in an open ﬂask in

under 30 min, and the disappearance of the brick-red silver(II)

picolinate can be observed as the reaction turns to a clear, homo-

geneous solution. Additionally, when the separated diastereomers of

tetracycle 69 are exposed to the same conditions, yields of up to 77%

can be obtained for this single step.

Scheme 13. Attempts To Secure Both the 2-Aminoimidazole

and the C20 Hemiaminal En Route to the Massadines (11, 12)^a

The completion of the enantioselective synthesis of the

axinellamines (9, 10) required the reduction of the azides followed

by acylation with a dibromoacylpyrrole surrogate. The former step

proved surprisingly diﬃcult, presumably due to complications with

the highly polar, sensitive substrate. Phosphine reduction of the

azides resulted in general decomposition, and hydrogenation over

various metals provided inconsistent results (although platinum

oxide allowed for low yields of diamine to be obtained). The best

results were obtained by exposure to propanedithiol and triethyla-

mine, providing the diamine in suﬃcient purity to carry forward.

Selective acylation with (trichloroacetyl)pyrrole 59 provided

enantioenriched axinellamine A (9) and axinellamine B (10) in

45% and 24% yield over two steps, respectively. The optical

rotation and circular dichroism spectra matched both the re-

ported data^5aand data for natural samples provided by the Quinn

laboratory, indicating that the natural enantiomer of these

alkaloids had been synthesized. It should be noted that the

absolute stereochemistry of these enantiomers matches that

found in sceptrin (4) and ageliferin (5), lending further credence

to the biosynthetic hypothesis outlined in Scheme 1.

Total Synthesis of (ꢀ)-Massadine and (ꢀ)-Massadine

Chloride and Their Epi Analogues²⁵. Although the retrosynthe-

sis of the massadines (11, 12) outlined in Scheme 10 bears

resemblance to that of the axinellamines, it represents the product of

several initial explorations that were met with failure. The main goal

of these explorations was to uncover the ideal stage at which to

install the C20 oxidation state on the massadine scaffold, and a brief

summary of these efforts is shown in Scheme 13. Initial explorations

involved C20 oxidation prior to 2-aminoimidazole formation, but it

was quickly discovered that the C20 hemiaminal was incompatible

with basic conditions necessary to install the 2-aminoimidazole.

Therefore, two alternative routes were investigated: Route 1 was an

attempt to install the C20 hydroxyl group and form the tetrahy-

dropyran core prior to 2-aminoimidazole formation. This approach

began with the silver(II) picolinate-mediated oxidation of R-acet-

oxyketone 83 to provide 84 in 54% yield. Treatment of this

intermediate with aqueous trifluoroacetic acid provided the desired

ether formation in 65% yield, providing three out of the four rings in

the massadine core. Unfortunately, all attempts to elaborate tetra-

hydropyran 85 to the necessary 2-aminoimidazole were met with

failure, reminiscent of tricycle 58 (Scheme 8), which could not be

elaborated to the axinellamines (9, 10). Therefore, oxidation of

C20 was attempted with the 2-aminoimidazole already in place, as

shown in Route 2. Disappointingly, overoxidation of the 2-ami-

noimidazole occurred prior to oxidation of C20, proving that the

electron-rich heterocycle was not compatible with the silver(II)

picolinate conditions.

^aReagents and conditions: (a) silver(II) picolinate (2.5 equiv), TFA:

H₂O (1:9), 23 °C, 30 min, 54%. (b) TFA:H₂O (2:1), 50 °C, 20 h, 65%.

version of 25 under the assumption that oxidation of the primary

amine would outcompete oxidation of C20 (as shown in Bacon’s

original report).^41cHowever, it was found that the optimized con-

ditions (which employed excess triﬂuoroacetic acid) were suﬃcient

to completely temper the reactivity of the primary amine, allowing

for the oxidation of C20 to occur in 69% yield, delivering 73 without

any protecting groups. Formation of the 2-aminoimidazole was also

optimized since the original report, utilizing brine as a solvent, which

greatly reduced the amount of ClꢀOH exchange at C17, providing

72 in 65% yield. Oxidation to the transient diol 65 with DMDO

followed by acid-mediated cyclization provided massadine chloride

azide 70 in 71% yield as a 1:3.7 ratio of diastereomers. Interestingly,

attack from the spiroguanidine nitrogens (to form the axinellamine

core) was not observed, presumably because the acidic conditions

hindered their reactivity. Unfortunately, the major diastereomer was

epimeric to the natural products 11, 12, although it is a possibility

that the alkaloids corresponding to this diastereomer exist in Nature

and have yet to be isolated (note the similarity to axinellamines A

and B, 9 and 10).

The completion of the synthesis required reduction of the

azides and acylation in a manner similar to that followed for the

axinellamines (9, 10). However, propanedithiol could not be used

due to the more sensitive nature of the massadine scaﬀold to

nucleophiles and base, and therefore hydrogenation over platinum

oxide was employed. Acylation of 70β provided 6,10-epi-massadine

chloride (88) and 6,10-epi-massadine (89) in a 4:1 ratio in 55% yield

(88 could be converted to 89 with mild heating in aqueous media,

A solution was found with a two-step 2-aminoimidazole synthe-

sis, allowing for all basic conditions to precede C20 oxidation by

beginning with aminoketone 25 (Scheme 14). The originally

reported synthesis of the massadines (11, 12)²⁵utilized a protected

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Scheme 14. Total Synthesis of (ꢀ)-Massadine (11) and (ꢀ)-Massadine Chloride (12)^a

^aReagents and conditions: (a) silver(II) picolinate (2.5 equiv), TFA:H₂O (1:9), 23 °C, 30 min, 69%; (b) H₂NCN (40 equiv), pH 5, brine, 70 °C, 4 h, 65%;

(c) DMDO (1.3 equiv), TFA:H₂O (1:9), 0 °C, 1 h; (d) neat TFA, 23 °C, 3 h, 71% (1:3.7 dr at C6/C10); (e) PtO₂(0.3 equiv), H₂(1 atm), TFA:H₂O (1:19),

1 h, 23 °C; (f) (trichloroacetyl)pyrrole 59 (16 equiv), diisopropylethylamine (16 equiv), DMF, 23 °C, 14 h, 60% from 70R (2:1 12:11), 55% from 70β

(4:1 88:89); (g) H₂O, 60 °C, 4 h, quant.

occurring much slower than that of the natural analogues 11 and

12).²⁵Acylation of 70R with (trichloroacetyl)pyrrole 59 provided

massadine chloride (12) and massadine (11) in 60% yield as a 2:1

ratio (the conversion of 11 to 12 occurs readily in aqueous media with

mild heating).^8,25The optical rotation and circular dichroism spectra

of these natural products matched both the literature reports^6,8and

data for natural samples provided by the K€ock group, thus conﬁrming

their absolute conﬁgurations. This further supported the biosynthetic

hypothesis outlined in Scheme 1, as the absolute stereochemistry of

the massadines (11, 12) matched that of the axinellamines (9, 10),

sceptrin (4), and ageliferin (5). It is interesting to note that the epi

series (88 and 89) has not been discovered in natural extracts (unlike

with the axinellamines, where the epi series was isolated from the same

sponge).^5aIt is possible that 88 and 89 are natural products that have

not yet been identiﬁed from natural sources.

Scheme 15. Initial Investigations into the Generation of an

N-Coupled Pyrrole^a

Total Synthesis of (ꢀ)-Palau’amine. Compared to the

axinellamines (9, 10) and the massadines (11, 12), the planned

retrosyntheses of palau’amine (13) were ridden with questionable

steps. The first of these steps was shared between the two routes in

Scheme 10: the coupling of a pyrrole moiety to the 2-aminoimidazole.

During the synthesis of the axinellamines (9, 10), the 2-aminoimi-

dazole 24 was treated with electrophilic bromine sources in non-

nucleophilic solvents in an attempt to induce intramolecular capture

by the spirocyclic guanidine to yield 70 (Scheme 15A). However, it

was found that bromination of the 2-aminoimidazole was followed by

an isomerization instead of nucleophilic capture, providing products

such as 67 (Scheme 10). The potential of such products to be utilized

as coupling partners for transition-metal-mediated aminations

was evaluated on model C16 epimer 90, and several conditions

were tried to effect palladium-⁴²or copper-catalyzed⁴³amina-

tion of bromo-2-aminoimidazoles. Although these couplings

were met with universal failure, a common byproduct did not

escape notice: imidazolinone 91 was present in several crude

reaction mixtures, presumably arising from capture of the highly

active imidoyl bromide isomer of 90 with residual water at the high

temperatures commonly employed during BuchwaldꢀHartwig

^aReagents and conditions: (a) 90 (1.0 equiv), TFA:H₂O, 60 °C, 24 h, 82%;

(b) 90 (1.0 equiv), neat pyrrole, 60 °C, 2 h, 71%; (c) 90 (1.0 equiv), AcOH

(3.0 equiv), pyrrolidine (3.0 equiv), 40 °C, 3 h, 48%; (d) 90 (1.0 equiv),

AcOH (3.0 equiv), benzylamine (3.0 equiv), 40 °C, 3 h, 72%.

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Scheme 16. Synthesis of Deoxypalau’amine Azide 64^a

^aReagents and conditions: (a) TFAA:TFA (1:1), 1 h, then Br₂(2.0 equiv), 1 h, then TFA:H₂O (1:1), 1 h, 38 °C, 58%; (b) AcOH (3.0 equiv), 97 (3.0 equiv),

THF, 38 °C, 6 h; (c) TFA:DCM (1:30 to 1:1), 23 °C, 12 h, 48%; (d) EDC (1.5 equiv), DMAP (2.0 equiv), thiol 99 (1.2 equiv), MeCN, 23 °C, 2 h, 48%;

(e) DABCO (7.5 equiv), THF, 60 °C, 6 h, 20%; (f) neat TFA, 70 °C, 23 h, 38% (ca. 75% conversion). TFAA = triﬂuoroacetic anhydride, EDC = 3-(ethyl-

iminomethyleneamino)-N,N-dimethylpropan-1-amine, DMAP = 4-(N,N-dimethylamino)pyridine, DABCO = 1,4-diazabicyclo[2.2.2]octane.

and Ullmann aminations. The removal of all base, ligand, and

catalyst from the reaction conditions quickly confirmed this result,

delivering 91 directly with mild heating.

acid was coupled with thiol 99, delivering the thioester 66 (48%

yield), which was poised to undergo ligation upon deprotection of

the phosphine with a nucleophilic amine. Several failed attempts at

the ligation (with various conditions for phosphine deprotection)

ultimately culminated in the treatment of 66 with DABCO in dry

THF⁴⁰to deliver the 20-deoxymacropalau’amine azide 65 in 20%

yield. To our delight, the macrocyclization was selective for

the adjacent azide (albeit low-yielding), and the product was

stable enough for 2-D NMR studies, revealing the intriguing

folded structure shown with ROESY correlations. A correla-

tion between C11 and N14 was very promising: the transan-

nular cyclization would require proximity to exist between the

2-aminoimidazole and the amide nitrogen, and that proximity

already appeared to exist in solution.

Unfortunately, Scheme 16 does not accurately convey the

diﬃculty that was encountered in the several attempted conversions

of macrocycle 65 to deoxypalau’amine azide 64.⁴⁴Indeed, over 50

reaction conditions were tried on very limited amounts of material,

ranging from standard heat and acid to exotic, transition-metal-

catalyzed N-arylation attempts. It was only after considerable

screening that the successful conditions of warm, neat triﬂuoroacetic

acid were discovered to successfully acquire 64 in 38% yield. With

the core of palau’amine (13) in hand, conditions for the oxidation of

C20 were applied to 64 to approach palau’amine azide (100).

Unfortunately, oxidation of the pyrrole completely outcompeted

oxidation at C20 with any oxidant employed, from silver(II)

picolinate to potassium persulfate, and several of the others men-

tioned on the model study in Scheme 11. Consistently, the desired

increase in mass was detected by HPLC-MS, but crude NMR

spectra showed that oxidation had not occurred at the spirocyclic

C20 position, but instead on the pyrrole moiety. This roadblock

could not be overcome, so our sights were turned away from 64

The hydrolysis of an aryl bromide would not prove useful in

the synthesis of the desired N-arylpyrrole, so the reactivity of 90

was further explored using diﬀerent nucleophiles (Scheme 15B).

An attempt to install a pyrrole directly unsurprisingly led to

reactivity at the pyrrole C2, providing 92, which unfortunately

possesses a connectivity that holds no worth in the synthesis of

the natural products. A glimmer of hope was found when

alkylamines such as pyrrolidine and benzylamine were employed,

providing the N-coupled products 93 and 94. The answer was

now clear: an alkylamine pyrrole surrogate could be coupled to

the 2-aminoimidazole followed by conversion to the pyrrole after

attachment. Three such surrogates are shown in Scheme 14C:

the dihydropyrrole ester 95, the dihydrooxazine ester 96, and the

linear primary amine 97.

The optimized synthesis of the correct C16 isomer of the

bromo-2-aminoimidazole was accomplished by treatment of 24

with elemental bromine in a triﬂuoroacetic anhydride/triﬂuor-

oacetic acid solvent mix in 58% yield (Scheme 16). Triﬂuoroacetic

anhydride (TFAA) was essential, mediating an in situ triﬂuoroacety-

lation of the 2-aminoimidazole to cause the desired bromination to

occur. Without TFAA, a major byproduct was dihydroxylation of the

2-aminoimidazole (similar to what is seen upon treatment with

electrophilic halogen sources in the presence of water). The coupling

of the resulting bromide 67 with pyrrole surrogates 95 and 97

proceeded smoothly, whereas dihydrooxazine 96 failed to deliver any

product. Linear amine 97 was favored for the ﬁnal sequence, since

mild treatment with acid could convert it directly to the desired

pyrrole acid 98 in 45% overall yield from 67 (at least ﬁve transforma-

tions occur in one pot to deliver the desired product). This pyrrole

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Scheme 17. Enantioselective Total Synthesis of

(ꢀ)-Palau’amine (13)^a

Figure 1. Structural conformation of 20-deoxymacropalau’amine-N₃

(65) based on the average of 52 structures calculated from 19 inter-

proton distances from a 100 ms ROESY spectrum.

(which bore such close resemblance to palau’amine that their ¹H

NMR spectra were almost identical, except for one key hemiaminal

peak) and toward Route 2 in Scheme 10.

The interesting, folded structure of 20-deoxymacropalau’a-

mine-azide (65) merited more detailed inspection, possibly provid-

ing insight into the oxidized derivative (macropalau’amine, 74,

Scheme 10) that would have to be synthesized for the revised

route. The fc-rDG/DDD method^14,45was applied to 65 with

ﬂoating chirality to the ﬁve stereogenic centers. The basis for the

conformational and conﬁgurational analysis is a ROESY spectrum

from which cross-peaks are translated into interproton distances.

For compound 65, we were able to obtain 19 interproton distances

from a ROESY spectrum with a mixing time of 100 ms (complete

details in the Supporting Information). This resulted in 91 out of 99

structures that have the same relative conﬁguration, which are

divided into two families (family I and family II). Due to small

conformational diﬀerences, family I was further divided into family

Ia (52 structures) and family Ib (24 structures), and family Ia served

as reference for the conformational analysis of 65; an averaged struc-

ture is depicted in Figure 1. Two key interproton distances were of

interest: H5/H12 (3.6 Å) and H11/H14 (2.8 Å). The proximity of

these key protons was indicative of the interesting, folded nature of

65. The most telling inter-atom distance, however, was the H14/C10

distance (3.3 Å, red arrow), which indicated that, even in solution at

room temperature, the two atoms between which the desired tran-

sannular reaction was to occur were already in proximity with each

other. The expectation was that the conformation of macrocycle 65

would exist in the analogous system with the required C20 oxidation

already in place (macropalau’amine (74), Scheme 10).

^aReagents and conditions: (a) TFAA:TFA (1:1), 1 h, then Br₂

(2.0 equiv), 1 h, then TFA:H₂O (1:1), 38 °C, 1 h, 54%; (b) AcOH

(3.0 equiv), 97 (3.0 equiv), THF, 38 °C, 6 h, then TFA:DCM (1:30 to

1:1), 23 °C, 12 h, 44%; (c) Pd(OAc)₂(1.6 equiv), H₂(1 atm), TFA:

H₂O (1:9), 23 °C; (d) EDC (3.0 equiv), DMF, 23 °C, 3 h; (e) neat TFA,

70 °C, 24 h, 17% for three steps.

derivative 76 failed to provide any product. This appeared to be due

to the sensitive nature of the hemiaminal moiety during attempts to

couple the highly nucleophilic ligation precursor 99 to the pyrrole

acid found in 76. However, an even more direct route was followed in

a ﬁnal sequence which was carried out without puriﬁcation of

intermediates. First, hydrogenation of the azide moieties in 76 over

palladium acetate provided diamine 75 in suﬃcient purity to

be carried forward. The choice of palladium acetate was critical:

palladium-on-carbon adsorbed all of the material, while platinum

oxide reduced the pyrrole.

Crude diamine 75 was subjected to several coupling reagents,⁴⁶

including (but not limited to) HATU, HBTU, TCTU, DPPA, T3P,

EDC, DIC, DCC, BOP, BOP-Cl, PyAOP, PyBOP, PyBrOP, and

cyanuric chloride in several combinations of polar solvents (75 was

only soluble in DMF, DMSO, and water in solvent screens).

Interestingly, base seemed to inhibit this reaction (and eventually

cause decomposition). However, EDC provided the desired mass of

macropalau’amine 74 (420) by HPLC-MS (with or without HOBt

additive), and exposure to hot triﬂuoroacetic acid (analogous to

Scheme 16) provided palau’amine (13) in 17% overall yield for the

The “backup” route to palau’amine (13) involved early installation

of the C20 hemiaminal, diverging from the massadine synthesis at

2-aminoimidazole 71 (Scheme 17). Bromination of 72 with ele-

mental bromine in the presence of triﬂuoroacetic anhydride delivered

77 in 54% yield, and attachment of the pyrrole surrogate 97 followed

by pyrrole generation proceeded in 44% yield. All attempts to employ

the Staudinger ligation steps used in Scheme 16 on the C20-oxidized

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ﬁnal three-step sequence. The optical rotation and circular dichroism

spectra correlated well with the published results,¹⁵indicating that the

correct enantiomer of the natural product had been synthesized, and

proving its absolute conﬁguration. The absolute stereochemistry

matched that of the massadines (11, 12), axinellamines (9, 10),

sceptrin (4), and ageliferin (5), thus tying together the entire family

of pyrroleꢀimidazole alkaloids in uniform handedness.

helpful discussion. We thank Prof. A. Rheingold for X-ray crystal-

lographic measurements. We are grateful to the NSF (predoctoral

fellowships to I.B.S. and R.A.R.), the Japan Society for the Promotion

of Science (JSPS, postdoctoral fellowships to J.Y. and A.N.), the

Natural Sciences and Engineering Research Council of Canada

(NSERC, postdoctoral fellowship to I.S.Y.), the U.S. Department

of Defense and the Hertz Foundation (predoctoral fellowships to

D.P.O), and the German Academic Exchange Service (DAAD) for a

postdoctoral fellowship to T.G. Financial support for this work was

provided by the NIH/NIGMS (GM-073949) and Bristol-Myers

Squibb (unrestrictred research grant). M.K. (AWI Bremerha-

ven, Germany) thanks the Deutsche Forschungsgemeinschaft

(DFG) for grants Ko 1314/5-1 and Ko 1314/5-2 (DFG-

Forschergruppe FOR 934).

’ CONCLUSION

This article has traced the evolution of the ﬁrst laboratory

syntheses of (ꢀ)-palau’amine (13), (ꢀ)-axinellamine A (9),

(ꢀ)-axinellamine B (10), (ꢀ)-massadine (11), and (ꢀ)-massa-

dine chloride (12). These pyrroleꢀimidazole alkaloids have

inspired and confounded chemists for almost two decades, and

have provided a driving force for creativity and innovation in our

laboratory and several others. The natural enantiomer of each of

these natural products was synthesized with one unifying route,

which was enabled by the power of a catalytic, enantioselective

DielsꢀAlder reaction. The absolute conﬁgurations of 9ꢀ13 were

found to share common stereochemistry with the structurally

simpler family members (ꢀ)-sceptrin (4) and (ꢀ)-ageliferin (5),

supporting a common biogenesis such as the one proposed in

2004. The syntheses of these marine natural products have led to

the development of a powerful oxidation protocol which utilizes

silver(II) picolinate to selectively oxidize spiroimidazolines in

complex molecular architectures without overoxidation. This

chemistry also led to further exploration of silver chemistry, inspiring

the development practical methods for the direct CꢀH arylation of

heterocycles⁴⁷and quinones as well as a C -H triﬂuoromethylation of

heterocycles.⁴⁹Additionally, nuances of the reactivity of bromo-2-

aminoimidazoles have been reported, including their hydrolysis and

innate coupling to heterocycles and amines. Finally, a macrocycliza-

tion combined with a strategic transannular cyclization enabled the

synthesis of palau’amine (13), and proved the structural revisions

published in 2007. It is worth noting that the success of each of these

syntheses relied heavily on the innate reactivity present in each of the

advanced intermediates, which would never have been unveiled had

they been shielded with excessive protecting groups.⁴⁹Access to each

of these enantioenriched natural products has enabled several

collaborations to investigate their relatively unexplored biological

activity, the results of which will be reported in due course.⁵¹

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Supporting Information. Experimental details, spectra,

b

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’ AUTHOR INFORMATION

Corresponding Author

pbaran@scripps.edu

Author Contributions

^†These authors contributed equally to this paper.

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dx.doi.org/10.1021/ja2047232 |J. Am. Chem. Soc. 2011, 133, 14710–14726

Article Doi

Enantioselective total syntheses of (-)-palau'Amine, (-)-axinellamines, and (-)-massadines

DOI: 10.1021/ja2047232

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