Diverse alkaloid-like structures from a common building block

Tetrahedron 69 (2013) 242e256

Contents lists available at SciVerse ScienceDirect

Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

Diverse alkaloid-like structures from a common building block

*

Dane A. Goff

Rigel Pharmaceuticals, 1180 Veterans Blvd., S. San Francisco, CA 94080, USA

a r t i c l e i n f o

a b s t r a c t

Article history:

A wealth of unique enantiopure polycyclic alkaloid-like scaffolds can be prepared on a multigram scale in

only a few steps from a common, commercially available intermediate. The attached nitromethyl group

can then be used to construct highly diverse functionalized libraries suitable for screening against bi-

ological targets of interest.

Received 4 September 2012

Received in revised form 10 October 2012

Accepted 11 October 2012

Available online 18 October 2012

Keywords:

Diversity oriented synthesis

Alkaloid-like molecule

Nitromethyl group

1. Introduction

The diversity-oriented synthesis of natural product-like mole-

cules for drug discovery is a topic of much current interest.¹Espe-

cially sought after are non-planar ring systems, which can be

readily constructed on scale and display varied substituents in di-

verse orientations in three-dimensional space. Recent analysis has

shown that increasing the fraction of sp³hybridized carbons and

chiral centers in a molecule leads to improved drug-like properties

(aqueous solubility and oral bioavailability) and, potentially, better

target selectivity.²It is also highly desirable to build in the capacity

for advanced optimization by what has been termed a post-

screening maturation process.^1d,eIt is challenging to achieve both

these goals with a single synthetic platform.

Fig. 1. Natural product-like scaffolds of increasing complexity from a common building

block.

molecular weight and novelty of these scaffolds were also seen as

Deprez-Poulain et al. have used commercially available chiral

keto-carboxylic acid 1 to construct Meyers’ bicyclic lactams³

(Fig. 1). We felt that the deﬁned stereochemistry and rich orthog-

onal functionality of 1 could be exploited to make new series of

more complex polycyclic alkaloid-like molecules with different ring

sizes and topologies using methodologies developed for acyl imi-

nium cyclizations.⁴The versatile nitromethyl group could then be

converted to an amine, alcohol, aldehyde or carboxylic acid func-

tional group or heterocycle as part of the post-screening matura-

tion process.⁵Our goal was to construct small libraries from these

derivatives, which could be used for high-throughput screening. In

particular, we hoped that these libraries would show activity

against G-protein-coupled receptors, as is well documented for

indole and tetrahydroisoquinoline alkaloids.⁶The relatively low

a beneﬁt for new lead discovery.

2. Results and discussion

2.1. Preparation of core structures

The polycyclic alkaloid-like molecules discussed in this paper are

shown in Fig. 2. Each of these complex scaffolds was obtained in just

two steps by coupling the appropriate amine to building block 1,

followed by acid catalyzed cyclization. Structural diversity was in-

troduced in various ways. Thus the C ring could be six- or seven-

membered depending on the length of the amine bearing side chain.

Unfortunately, as precedented in the literature, we failed to synthe-

size molecules containing a ﬁve-membered C ring using acyl iminium

chemistry.⁴The aromatic ring system could be either an electron rich

benzene or an indole. Further studies to be reported later have shown

that pyrroles, furans, thiophenes, benzothiophenes, and benzofurans

* Tel.: þ1 650 624 1125; fax: þ1 650 624 1101; e-mail address: dagoff@rigel.com.

http://dx.doi.org/10.1016/j.tet.2012.10.038

D.A. Goff / Tetrahedron 69 (2013) 242e256

243

Fig. 2. Polycyclic alkaloid-like molecules from 1.

all successfully participate in these cyclizations. Incorporation of an

alkoxycarbonyl group into the C ring gave an additional point of di-

versiﬁcation. All these molecules are azaspirocycles containing

a quaternary carbon. This motif is found in naturally occurring alka-

loids from many different families, although systems containing two

fused ﬁve-memberedrings are muchlesscommonthan systems with

ﬁve-membered rings fused to six- or seven-membered rings (Fig. 3).⁷

Interestingly, Heathcock et al. used classical acyl iminium chemistry

starting from 2-oxocyclopentane acetic acid to craft methyl homo-

daphniphyllate, which also contains a 6.5.5. azaspirocycle at its core.⁸

The synthesis of the 6.6.5.5 A-norerythrinan-like series is shownin

more detail in Fig. 4. Until recently the only reported examples of this

ring system contained an additional carbonyl group at C-4.^9,10The

homologous 6.6.5.6 erythrinan ring system characteristic of alkaloids

such as (þ)-erysotramidine 3, however, is very well known and its

representatives show sedative, hypotensive, muscle-relaxant, anti-

convulsant, and CNS-depressant activities.^4b,d,11The synthesis of the

erythrinan ring system from 2-oxocyclohexane acetic acid has been

reported.^4h

Thuscouplingof 3,4-dimethoxyphenethyl aminetobuildingblock

1 gave hemiketal 2, which was initially isolated by column

Fig. 3. Some naturally occurring azaspirocycles.

Fig. 4. Preparation of the A-norerythrinan ring system.

244

D.A. Goff / Tetrahedron 69 (2013) 242e256

chromatography, then cyclized with p-toluenesulfonic acid in

reﬂuxingtoluene. Itwaslaterdeterminedthatthisintermediatecould

be cyclized directly without puriﬁcation. Alternatively, the cyclization

could be performed with 5% TFA in dichloromethane at rt. LCMS

analysis of the crude product showed a single peak with the expected

molecular weight and a single diastereomer, compound 4a, was iso-

lated by column chromatography.¹²The newly formed ﬁve-

membered ring lactam was shown to be cis-fused by X-ray crystal-

lographic analyses of compound 4a (CCDC 896743) as well as its de-

rivative compound 4c (see inset to Fig. 2) The mono-methoxy

analogue5awassimilarlypreparedfrom3-methoxyphenethylamine.

2.2. Transformation of the nitromethyl group

Having demonstrated the versatility of building block 1 in pre-

paring non-racemic tetracyclic alkaloid-like structures with dif-

ferent ring sizes and substitution patterns, we then explored the

transformations of the nitromethyl group. As described above, this

chemical handle serves as a highly versatile point of diversiﬁcation.

This versatility is illustrated for parent compound 4a in Fig. 5. Thus

the nitromethyl group of compound 4a was readily reduced to

amine 4b by catalytic transfer hydrogenation.³The nitromethyl

group of compound 4a could also be readily oxidized to carboxylic

acid 4c using sodium nitrite in a mixture of DMF and acetic acid.¹⁴

Acid 4c could be reduced to alcohol 4d and then re-oxidized to

aldehyde 4e with DesseMartin periodinane.¹⁵Finally, acid 4c was

subjected to a recently described variant of the Curtius rearrange-

ment to yield Boc protected amine 4f (not shown), followed by

conversion to free amine 4g.¹⁶Small screening libraries of amides

have been prepared by acylation of compounds 4b and 4g.

The newly generated aldehyde and carboxylic acid groups are

particularly interesting from the standpoint of further di-

versiﬁcation. Thus a focused screening library of amides was gen-

erated by coupling amines to compound 4c (Fig. 5). Carboxylic acids

can also be readily converted to heterocycles, which in some cases

act as bio-isosteres. Thus carboxylic acid 4c was converted to oxa-

diazole 4h by condensation with benzoic hydrazide.¹⁷Aldehyde 4e

can potentially be transformed in many ways, the most obvious is

reductive amination (Fig. 5). The nitromethyl group also serves as

Diversity could be introduced into the C ring by using L-3,4-

dimethoxyphenylalanine methyl ester to give compound 6a. The

C-7 ester group provides an opportunity for post-synthetic modi-

ﬁcation. Ring C could also be expanded to a seven-membered ring

by combining building block 1 and 3-(3,4-dimethoxyphenyl)propyl

amine to give compound 7a, which contains an uncommon 6.7.5.5

tetracyclic ring system. We found only a single example of the

parent A-norschelhammerane ring system in the literature.¹⁰The

homologous 6.7.5.6 homoerythrinan ring system is found in alka-

loids such as schelhammeridine (Fig. 3) although little has been

reported regarding biological activity.¹³The mono-methoxy ana-

logue 8a was similarly prepared. The crystal structure of this

compound is also shown in Fig. 2. It should be emphasized at this

point that all of the parent nitromethyl compounds shown in Fig. 2

were readily obtained on a multigram scale making further trans-

formations practical.

MeO

N

MeO

O

MeO

N

O

N

4h

N

Ph

CH₂OH

c,h

N

f

c,e

N

4d

O

Ph

MeO

4i

O

c,g

NO₂

a

c,h,i

c

4a

MeO

N

O

NH₂

CO₂H

CHO

NH₂

4b

4c

4e

4g

b

d

j

b

MeO

N

O

NHCOR

amine library

CONR₁R₂

amine library

NR₁R₂

amine library

NHCOR

amine library

Fig. 5. Transformations of the nitromethyl group. (a) Ammonium formate, Pd/C, MeOH; (b) RCO₂H, HATU, DIEA, CH₂Cl₂; (c) NaNO₂, DMF, HOAc; (d) R₁R₂NH, HATU, DIEA, CH₂Cl₂; (e)

PhCONHNH₂, PSePh₃P, CH₃CN, Cl₃CCN, mwave; (f) Boc₂O, DMAP, PhCCH; (g) Boc₂O, NaN₃, Bu₄NBr, Zn(OTf)₂, THF then TFA; (h) BH₃/THF; (i) DesseMartin periodinane, CH₂Cl₂; (j) R₁R₂NH,

Na(OAc)₃BH.

D.A. Goff / Tetrahedron 69 (2013) 242e256

245

a nitrile oxide precursor, which can then undergo [3þ2] cycload-

dition reactions.¹⁸Thus the nitromethyl group of compound 4a was

converted in situ to a nitrile oxide and condensed with phenyl

acetylene to give isoxazole 4i.

The two basic transformations of the nitromethyl group, oxidation

and reduction, have been successfully applied to most of the parent

azaspirocycles shownin Fig. 2. Forexample, parent compound 6awas

converted to compound 6c; containing two differentiated carboxylic

acids, which could, in principle, be selectively modiﬁed.

and 15 (Fig. 7). These pentacyclic natural product-like ring systems

are not well known.¹⁹Coupling of tryptamine to building block 1

gave cyclic hemiketal 11, which was puriﬁed by radial chromatog-

raphy and characterized by ¹H NMR. We found, however, that

compound 12a could be prepared in good yield by treating the crude

isolated EDC reaction product, either with p-toluenesulfonic acid

(73%) or with TFA (86%).

The nitromethyl group of compound 12a was readily reduced

to amine 12b, which again provided a good handle for de-

rivatization. However, oxidation of compound 12a, containing an

unprotected indole NH, with nitrous acid failed to give sufﬁciently

pure carboxylic acid 12c. Therefore the sequence was repeated

with N-1 tosyl tryptamine to give compound 13a. Oxidation now

proceeded smoothly to give N-tosyl protected acid 13b. Several

literature methods were evaluated to remove the tosyl group; the

best turned out to be heating with excess Cs₂CO₃in THF/methanol

at 90 ^ꢀC in a sealed tube to give deprotected acid 12c in modest

yield.²⁰Coupling of scaffold 12c to diverse amines should give an

2.3. Introduction of a phenol

Introduction of a free phenolic group to the D ring was also

investigated. Not only would the phenol be expected to contribute

to biological activity, but could also potentially be used for post-

screening structural optimization. Preparation of 10-benzyloxy

compound

9 proceeded uneventfully on a multigram scale

(Fig. 6). Catalytic hydrogenation of methyl ester 9b gave the free

phenol 9c cleanly. The X-ray crystallographic structure of

compound 9c is shown in Fig. 6. Reaction of compound 9c with

triﬂic anhydride gave triﬂate 9d, which should be an interesting

building block for palladium catalyzed cross-coupling chemistry.

More vigorous cyclization conditions, reﬂuxing with 10% TFA,

were required to obtain the 11-benzyloxy isomer, compound 10,

presumably due to the fact that the electron donating benzyloxy

substituent is meta to the carbon undergoing cyclization. In this

case the cyclic hemiketal (Intermediate A) was isolated and char-

acterized by NMR. Oxidation gave carboxylic acid 10a.

interesting screening collection. Use of L-tryptophan methyl ester

gave facile access to ester substituted analogues 14a,b.

Previously undescribed pentacycle 15a, containing a seven-

membered ring C, could likewise be prepared from 3-(3-

aminopropyl)indole in 47% un-optimized yield (Fig. 7). Conver-

sion of the nitromethyl to an aminomethyl group proceeded

smoothly to give scaffold 15b.

2.5. Focused library synthesis and screening

A variety of small focused libraries have been made from the

azaspiro building blocks shown in Fig. 2. Fig. 8 illustrates a collec-

tion of amides that was made from scaffold 8c. Primary and sec-

2.4. Pentacyclic indoles

The fascinating structural diversity and medicinal importance of

ondary amines as well as

a-amino acid esters were smoothly

the indole alkaloids further inspired us to prepare scaffolds 12, 14,

coupled using the combination of HOAt and EDC to give amides

Fig. 6. Preparation of tetracyclic phenols.

246

D.A. Goff / Tetrahedron 69 (2013) 242e256

Fig. 7. Preparation of indole-alkaloid-like scaffolds.

log P values for this small subset of compounds range from 1.61

(16d) to 3.13 (16f), which is within the value of 2e3 often suggested

as optimal for an oral drug.²³

3. Conclusion

In summary, commercially available enantiopure building block

1 has been used to construct a diverse range of tetra and pentacylic

natural product-like scaffolds containing four or ﬁve stereogenic

centers in good overall yield on a multigram scale. The scaffolds can

be designed to contain multiple functional groups. The nitromethyl

handle is especially versatile and several of its transformations have

been demonstrated. These derivatives can then serve as branch

points for post-synthetic optimization of initial leads generated

from screening. As previously mentioned, we have incorporated

other heterocyles such as pyrrole, furan, and thiophene into these

scaffolds and will report these in the future.

Fig. 8. Scaffold modiﬁcation with diverse amines.

4. Experimental

4.1. General

16aeg in 53e72% yield as white solids after RP-HPLC puriﬁcation.

These molecules, along with the building blocks described in this

paper, have all been submitted to high-throughput screening

against a variety of targets. Interestingly, several of the molecules

described here have shown promising activity against TGR5, a G-

protein-coupled receptor of current interest in the treatment of

type 2 diabetes and metabolic syndrome.²¹These results, while

preliminary, suggest that focused library synthesis based on natural

product-like building blocks is a practical strategy for new lead

drug discovery. In addition, the scaffolds presented in this paper

appear to have good drug-like properties. The mean fraction of sp³

hybridized carbons (Fsp³) in the core scaffolds (excluding the amide

derivatives 16aeg) is 0.55, similar to that of approved drugs.²The

mean Fsp³of compounds 16aeg is 0.60. It may also be noted that

the molecular weights of all but one of the compounds in the fo-

cused amide library (16aeg) are less than 500, and all the other

Lipinski rule-of-ﬁve parameters are satisﬁed.²²The calculated

NMR was performed on a Varian Mercury 300 MHz NMR.

Chemical shifts were referenced to solvents. Assignments were

based on chemical shifts and COSY experiments or DEPT experi-

ments for ¹³C and in some cases are tentative. Flash chromatogra-

phy used J.T. Baker Silica Gel, 60e200 mesh. Radial chromatography

was performed on a chromatotron (Harrison Research, Model

7924T). HPLC used a Waters 2695 Separation module equipped

with a Micromass ZQ mass spectrometer operating in the electro-

spray mode. High resolution mass spectra were obtained on a Wa-

ters Acquity system using method A. HPLC methods: (A) Column:

Kinetex C-18, 2.6

95% H₂O containing 0.05% HCO₂H/5% CH₃CN to 100% CH₃CN in

3 min. (B) Phenomenex C-18 column, 3ꢁ100 mm, 5 m. Flow rate

1.5 mL/min. Gradient containing 95% H₂O with 0.05% HCO₂H/5%

m

m, 2.1ꢁ50 mm, ﬂow rate 0.73 mL/min, gradient

m

D.A. Goff / Tetrahedron 69 (2013) 242e256

247

3. Reduction of the nitromethyl group to the amine

CH₃CN to 100% CH₃CN in 10 min. Purity was assessed by UV ab-

sorption at 254 nm or qualitatively by evaporative light scattering

(ELSD). Preparative HPLC was performed on a Waters C-18 mass

directed puriﬁcation system. Microwave experiments were per-

formed with a CEM Explorer microwave in closed vials with

a constant temperature as indicated and a maximum power of

300 W. Optical rotations were performed on a Rudolph Autopol IV

polarimeter. Chemical names and atom numbering for compounds

4c, 6c, 7a, 12c, and 15a were provided by the Chemical Abstracts

Service and the other compounds were named by analogy. The

numbering for NMR assignments is shown in Scheme 1.

The nitromethyl compound (1 equiv) was dissolved in methanol

(20 mL/mmol) and treated with ammonium formate (0.8 equiv)

and 10% Pd/C (wet, Degussa type E101 NE/W, Aldrich Cat. #330108,

0.65 g/mmol of nitromethyl compound). The mixture was heated at

80 ^ꢀC until HPLC analysis showed complete consumption of starting

material (approx. 5 h). The mixture was ﬁltered hot over Celite and

the cake was washed with hot MeOH. The ﬁltrate was concentrated

under reduced pressure. The residue was dissolved in a mixture of

EtOAc and MeOH and washed with several small portions of satd aq

NaCl solution. The organic layer was dried over anhydrous sodium

sulfate and concentrated under reduced pressure to give the ami-

nomethyl compound.

4. Oxidation of the nitromethyl group to the carboxylic acid

The nitromethyl compound (1 equiv) was dissolved in DMF

(4e5 mL/mmol) and treated with NaNO₂(7 equiv) and HOAc

(20 equiv). The reaction mixture was heated at 50 ^ꢀC for 7 h, then

poured onto ice and carefully neutralized with solid NaHCO₃. The

mixture was extracted with Et₂O (discarded) and then acidiﬁed

with concd HCl. The aqueous layer was extracted twice with EtOAc.

The combined organic layers were dried over anhydrous sodium

sulfate and concentrated under reduced pressure. The residue was

re-dissolved in EtOAc and extracted 10 times with satd aq NaCl

solution (necessary to completely remove residual HOAc). The or-

ganic layer was dried over anhydrous sodium sulfate and concen-

trated under reduced pressure to give the crude carboxylic acid.

5. Deprotection of the Boc group

The Boc protected amine was dissolved in p-dioxane (1e1.5 mL/

g) and treated with 4 M HCl in dioxane (5 mL/gm) at rt for 3.5 h. Dry

Et₂O was added and the reaction mixture was ﬁltered. The solid

was washed with Et₂O and dried under vacuum to give the amine

hydrochloride.

4.2.1. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-nitromethyl,1,2,3,

3a,4,5,7,8-octahydro-10,11-dimethoxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-4a. [1S-(1

b

,2

a

,3

b

)]-(þ)-3-Methyl-2-(nitromethyl)-

5-oxocyclopentane acetic acid (Aldrich, Cat. #647497) (1) (13.0 g,

60.4 mmol) and 3,4-dimethoxyphenethylamine (12.2 g, 67.3 mmol)

were coupled using general procedure 1. The crude product was

cyclized according to general procedure 2 (5 h). Puriﬁcation by ﬂash

column chromatography on silica gel, eluting with 2% MeOH in

CH₂Cl₂gave 4a, 12.2 g (56%). HPLC (method A) t_R¼1.63 min, (method

Scheme 1. Numbering for NMR assignments.

4.2. General procedures

1. Amide bond formation

B) t_R¼5.92 min (93%); [

a

]

²²þ140 (c 1.05, CHCl₃); ¹H NMR (300 MHz,

D

CDCl₃):

d

6.55 (s, 1H), 6.52 (s, 1H), 4.60e4.68 (m, 2H, CH₂NO₂),

The carboxylic acid (1.0 equiv) and the amine (1.0e1.1 equiv)

were dissolved in CH₂Cl₂(3e4 mL/mmol) and treated with N-(3-

dimethylaminopropyl)-N⁰-ethylcarbodiimide hydrochloride (EDC)

(1.1 equiv), 1-hydroxybenzotriazole hydrate (HOBt) (1.1 equiv), and

Et₃N (2.4 equiv or 3.4 equiv for amine hydrochlorides) and stirred at

rt overnight. If the reaction was heterogeneous, DMF was added

until homogeneity was obtained. The reaction mixture was washed

with water, 10% aq HCl solution, and satd aq NaHCO₃solution then

dried over anhydrous sodium sulfate and concentrated under re-

duced pressure.

4.20e4.27 (m, 1H, H-7b), 3.86 (s, 3H, OMe), 3.82 (s, 3H, OMe),

3.07e3.13 (m, 1H, H-7a or H-8b), 2.95e3.02 (m, 1H, H-8b or H-7a),

2.87e2.91 (m, 1H, H-3a), 2.55e2.65 (m, 2H, H-8a and H-4b),

2.28e2.35 (m, 3H, H-4a, H-1b, and H-2), 2.01e2.07 (m, 1H, H-3),

1.74e1.81 (m, 1H, H-1a), 1.10 (d, J¼5.9 Hz, 3H, 2-CH₃); ¹³C NMR

(75 MHz, CDCl₃): d 171.9 (CO), 148.1 (C), 148.0 (C), 133.6 (C), 125.1 (C),

111.7 (CH), 107.0 (CH), 76.5 (CH₂NO₂), 70.3 (C-12b), 56.2 (OMe), 55.9

(OMe), 52.9 (CH), 51.5 (CH₂), 47.2 (CH), 37.7 (CH), 36.2 (CH₂), 35.9

(CH₂), 27.0 (CH₂), 17.5 (2-CH₃); MS (ES): C₁₉H₂₄N₂O₅calcd: 361.1764

[MþH]^þ; found: 361.1773 [MþH]^þ.

2. Cyclization with TFA

4.2.2. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-aminomethyl,1,2,3,

3a,4,5,7,8-octahydro-10,11-dimethoxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-4b. Compound 4a (5.18 g, 14.4 mmol) was reduced

to the amine according to general procedure 3. The residue was

dissolved in anhydrous MeOH and cooled on an ice bath. HCl (g) was

bubbled in, followed by addition of dry Et₂O. Filtration and drying

The crude amide was stirred with 5% TFA in CH₂Cl₂(2 mL/mmol)

at rt for the time indicated. The reaction mixture was concentrated

under reduced pressure. The residue was dissolved in CH₂Cl₂,

washed with water and satd aq NaHCO₃solution, dried with an-

hydrous sodium sulfate, and concentrated under reduced pressure.

248

D.A. Goff / Tetrahedron 69 (2013) 242e256

under vacuum gave 4b (HCl salt) as a white solid, 2.77 g (58%). HPLC

(method B) t_R¼2.13 min (95%). For analytical purposes the hydro-

chloride salt (2.60 g) was converted to the free base by partitioning

between CH₂Cl₂and satd aq K₂CO₃solution. Y¼2.20 g. HPLC (method

B) t_R¼2.13 min (100%), (method A) t_R¼1.00 min; ¹H NMR (300 MHz,

a white foam, 0.19 g (44%). HPLC (method B) t_R¼4.41 min (97%); ¹H

NMR (300 MHz, CDCl₃): d 9.85 (s, 1H, CHO), 6.66 (s, 1H), 6.49 (s, 1H),

4.15e4.22 (m, 1H, H-7b), 3.82 (s, 3H, OMe), 3.80 (s, 3H, OMe),

3.10e3.20 (m, 1H), 3.04e3.08 (m, 1H), 2.88e2.98 (m, 1H), 2.49e2.66

(m, 4H), 2.22e2.28 (dd, J¼17.7, 2.1 Hz, 1H), 2.13e2.20 (dd, J¼13.4,

7.2 Hz,1H),1.78e1.87 (dd, J¼13.4, 9.2 Hz, 1H), 1.14 (d, J¼6.0 Hz, 3H, 2-

CDCl₃): d 6.67 (s,1H), 6.45 (s,1H), 4.09e4.17 (m, 1H, H-7b), 3.76 (s, 3H,

OMe), 3.73 (s, 3H, OMe), 2.93e3.07 (m, 1H), 2.79e2.95 (m, 3H),

2.66e2.70 (m, 1H), 2.54e2.66 (m, 2H), 2.16e2.28 (m, 2H), 2.00e2.06

(m, 1H), 1.57e1.66 (m, 1H), 1.35e1.40 (m, 1H), 0.94 (d, J¼6.1Hz, 3H, 2-

CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 202.0, (CHO), 172.5 (CO), 148.3,

148.2, 133.4, 125.6, 111.8, 107.7, 72.3, 67.2, 56.4, 56.1, 50.6, 44.3, 37.5,

37.1, 36.3, 27.2, 19.4; MS (ES): C₁₉H₂₃NO₄calcd: 330.1705 [MþH]^þ;

found: 330.1704 [MþH]^þ.

CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 172.6 (CO), 147.7 (2C), 135.0 (C),

125.0 (C), 111.5 (CH), 107.6 (CH), 70.7 (C-12b), 57.4 (CH), 56.1 (OMe),

55.8 (OMe), 52.0 (CH₂), 47.3 (CH), 42.6 (CH₂), 37.5 (CH₂), 36.9 (CH),

35.8 (CH₂), 27.1 (CH₂), 18.1 (2-CH₃); MS (ES): C₁₉H₂₆N₂O₃. calcd:

331.2022 [MþH]^þ; found: 331.2016 [MþH]^þ.

4.2.6. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-(N-tert-butox-

ycarbonyl)amino-1,2,3,3a,4,5,7,8-octahydro-10,11-dimethoxy-2-

methyl-5-oxo-(2S,3R,3aS,12bR)-4f. Compound

4c

(3.05

g,

8.84 mmol) was dissolved in dry THF (100 mL) and treated with

Bu₄NBr (0.60 g, 1.86 mmol), NaN₃(2.20 g, 33.8 mmol), di-tert-

butyldicarbonate (2.50 g, 11.4 mmol), and Zn(OTf)₂(0.11 g,

0.30 mmol) and then heated at 45 ^ꢀC for 23 h. The reaction mixture

was cooled to rt and a solution of NaNO₂(8.00 g,119 mmol) in water

(75 mL) was added. After stirring for 1 h the reaction mixture was

extracted twice with EtOAc. The organic layers were washed twice

with satd aq NH₄Cl solution, once with satd aq NaHCO₃solution

then dried over anhydrous sodium sulfate and concentrated under

reduced pressure. The crude product was passed over a pad of silica

gel, eluting with 5% MeOH in CH₂Cl₂to give 4f, 2.50 g (68%), suf-

ﬁciently pure for deprotection. An analytical sample was prepared

by HPLC; t_R¼1.81 min (method A); ¹H NMR (300 MHz, CDCl₃,

4.2.3. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-carboxylic acid,1,2,3,

3a,4,5,7,8-octahydro-10,11-dimethoxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-4c. Compound 4a (12.0 g, 33.3 mmol) was oxidized

according to general procedure 4 to give carboxylic acid 4c as an or-

ange solid, 5.57 g (48%) sufﬁciently pure for further use. HPLC

(method B) t_R¼4.12 min (90%). An analytical sample was prepared by

HPLC; t_R¼1.55 (method A); ¹H NMR (300 MHz, CDCl₃):

d 6.87 (s, 1H),

6.55 (s, 1H), 4.21e4.28 (m, 1H, H-7b), 3.87 (s, 3H, OMe), 3.83 (s, 3H,

OMe), 3.12e3.24 (m, 2H, H-7a and H-3a), 2.93e3.05 (m, 1H, H-8b),

2.58e2.70 (m, 3H, H-8a, H-4b, and H-2), 2.39e2.51 (m, 2H, H-3 and H-

4a), 2.27e2.34 (dd, J¼13.0, 7.0 Hz,1H, H-1b), 1.80 (t, J¼11.4 Hz,1H, H-

1a), 1.16 (d, J¼6.4 Hz, 2-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 177.4 (CO),

172.6 (CO), 148.5 (C), 148.4 (C), 133.8 (C), 125.3 (C), 112.3 (CH), 108.3

(CH), 71.8 (C-12b), 59.4 (CH), 56.3 (OMe), 56.0 (OMe), 51.3 (CH₂), 48.1

(CH), 39.2 (CH), 37.1 (CH₂), 36.2 (CH₂), 27.0 (CH₂), 18.4 (2-CH₃); MS

(ES): C₁₉H₂₃NO₅calcd: 346.1654 [MþH]^þ; found: 346.1662 [MþH]^þ.

60 ^ꢀC):

d 6.83 (s,1H), 6.51 (s,1H), 4.81 (m,1H, NH), 4.17e4.24 (m,1H,

H-7b), 3.27e3.37 (m, 1H, H-3), 3.06e3.15 (m, 1H, H-7a), 2.88e3.04

(m, 1H, H-8b), 2.79 (br m, 1H, H-4b), 2.52e2.58 (m, 3H, H-3a, H-4a

and H-8a), 2.29 (br m, 1H, H-2), 2.15e2.20 (m, 1H, H-1b), 1.65e1.75

(m, 1H, H-1a), 1.44 (s, 9H, t-Bu), 1.05 (d, J¼6.4 Hz, 2-CH₃); ¹³C NMR

4.2.4. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-hydroxymethyl,1,2,-

3,3a,4,5,7,8-octahydro-10,11-dimethoxy-2-methyl-5-oxo-(2S,3R,3aS,-

12bR)-4d. Compound 4c (3.00 g, 8.69 mmol) was dissolved in dry

THF (60 mL) and treated with 9.0 mL of 1 M borane/THF at rt for 1.5 h.

The reaction mixture was treated with 10% aq HCl solution and then

extracted three times with a mixture of EtOAc and MeOH. The or-

ganic layer was dried over anhydrous sodium sulfate and concen-

trated under reduced pressure. The crude product was puriﬁed by

ﬂash chromatography on silica gel, eluting with 5% MeOH in CH₂Cl₂

to give 4d, 2.26 g (79%) as a white foam. HPLC (method B) t_R¼4.11 min

(95%). An analytical sample was prepared by HPLC; t_R¼1.31 min

(75 MHz, CDCl₃): d 172.7 (CO),155.5 (CO),148.0 (2C), 134.3 (C), 125.1

(C), 111.6 (CH), 107.7 (CH), 79.4 (C(CH₃)₃), 69.0 (C-12b), 65.6 (CH),

56.2 (OMe), 55.8 (OMe), 49.3 (2C; 1CH, 1CH₂), 39.5 (CH), 35.7 (CH₂),

28.3 (4C overlap, C(CH₃)₃and 1 CH₂), 27.0 (CH₂), 17.1 (2-CH₃); MS

(ES): C₂₃H₃₂N₂O₅calcd: 417.2390 [MþH]^þ; found: 417.2373

[MþH]^þ.

4.2.7. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-amino-1,2,3,3a,4,5,-

7,8-octahydro-10,11-dimethoxy-2-methyl-5-oxo-(2S,3R,3aS,12bR)-

4g. Compound 4f (2.50 g, 6.0 mmol) was deprotected using general

procedure 5 to give the HCl salt of 4g as an off-white solid, 2.00 g

(94%). HPLC (method A) t_R¼0.93 min. For NMR analysis the free base

(method A); [

a

]

²²þ132.6 (c 0.91 CHCl₃); ¹H NMR (300 MHz, DMSO-

D

d₆):

d

6.79 (s, 1H), 6.61 (s, 1H), 3.74e3.98 (m, 1H, H-7b), 3.70 (s, 3H,

was made by partitioning the HCl salt between CH₂Cl₂and satd aq

24

OMe), 3.68 (s, 3H, OMe), 3.55e3.62 (m, 2H, CH₂OH), 3.00e3.15 (m,

1H, H-7a), 2.70e2.77 (m, 2H, H-8b and H-3a), 2.51e2.60 (m, 1H, H-

8a), 2.33e2.43 (m, 1H, H-4b), 2.12e2.25 (m, 2H, H-4a and H-2),

2.02e2.16 (m, 1H, H-1b), 1.59e1.66 (t, J¼12.1 Hz, 1H, H-1a), 1.35e1.42

(m, 1H, H-3), 0.95 (d, J¼6.3 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz, DMSO-

K₂CO₃solution. HPLC (method B) t_R¼1.78 min; [

a

]

þ182.5 (c 0.80,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d

6.74 (s, 1H), 6.50 (s, 1H),

4.06e4.23 (m, H-7a), 3.85 (s, 3H, OMe), 3.80 (s, 3H, OMe), 3.03e3.09

(m, 1H), 2.98e3.00 (m, 1H), 2.61e2.65 (m, 1H), 2.47e2.58 (m, 3H),

2.34e2.44 (m, 1H), 2.13e2.22 (m, H-1b), 1.96 (m, 1H, H-2), 1.88 (br s,

d₆):

d

172.5 (CO),148.1 (2C),135.7 (C),125.4 (C),112.7 (CH),108.7 (CH),

2H, NH₂), 1.66e1.74 (m, 1H, H-1a), 1.04 (d, J¼6.1 Hz, 3H, 2-CH₃); ¹³

C

70.6 (C-12b), 60.8 (CH₂), 57.7 (CH), 56.3 (OMe), 56.1 (OMe), 52.5

(CH₂), 46.6 (CH), 39.4 (CH₂), 37.5 (CH₂), 36.0 (CH), 27.2 (CH₂), 18.8 (2-

CH₃); MS (ES): C₁₉H₂₅NO₄calcd: 332.1862 [MþH]^þ; found: 332.1877

[MþH]^þ]^þ.

NMR (75 MHz, CDCl₃): d 173.0 (CO), 147.4 (2C overlap), 134.2, 125.2,

111.6, 107.5, 69.6, 66.2, 56.2 (OMe), 55.9 (OMe), 52.5, 49.8, 43.1, 35.7

(2C overlap), 27.1, 17.0 (2-CH₃); ¹³C NMR (75 MHz, DMSO-d₆):

d

172.0

(CO), 148.2 (C), 148.1 (C) (these two aromatic carbons overlap at

147.4 ppm in CDCl₃), 133.8 (C), 125.0 (C), 112.5 (CH), 108.6 (CH), 69.5

(C-12b), 63.8 (CH), 56.8 (OMe), 55.9 (OMe), 49.6 (CH₂), 47.6 (CH), 8.0

(CH), 35.6 (CH₂), 35.2 (CH₂) (these two CH₂s overlap at 35.7 ppm in

CDCl₃), 26.7 (CH₂), 16.9 (2-CH₃); MS (ES): C₁₈H₂₄N₂O₃calcd: 317.1865

[MþH]^þ; found: 317.1858 [MþH]^þ.

4.2.5. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-formyl-1,2,3,3a,4,-

5,7,8-octahydro-10,11-dimethoxy-2-methyl-5-oxo-(2S,3R,3aS,12bR)-

4e. Compound 4d (0.43 g, 1.3 mmol) was dissolved in dry CH₂Cl₂

(15 mL) and treated with NaHCO₃(0.13 g, 1.2 equiv) and

DesseMartin periodinane (0.66 g, 1.2 equiv). After 3 h the reaction

was quenched with 1 M aq sodium thiosulfate and satd aq NaHCO₃

solutions, then extracted twice with Et₂O. The organic layer was

dried over anhydrous sodium sulfate and concentrated under re-

duced pressure. The crude product was puriﬁed by radial chroma-

tography on silica gel, eluting with 2% MeOH in CH₂Cl₂to give 4e as

4.2.8. Compound 4h. Compound 4c (100 mg, 0.29 mmol) was

treated with benzoic hydrazide (1.1 equiv, 44 mg), polymer sup-

ported triphenylphosphine (570 mg, 3 equiv, Polymer Systems

1.52 mmol/g), and dry CH₃CN (3 mL). Then Cl₃CCN (60

mL, 2 equiv)

was added followed by irradiation in the microwave at 150 ^ꢀC for

D.A. Goff / Tetrahedron 69 (2013) 242e256

249

20 min. The reaction mixture was ﬁltered and the resin was washed

with MeOH. The ﬁltrate was concentrated under reduced pressure

and the residue was puriﬁed byHPLC to give 4h as an oil,12 mg. HPLC

(method A) t_R¼1.75 min, (method B) t_R¼5.57 min; ¹H NMR

obtained, so the solvent was removed under reduced pressure. Trit-

urationwith Et₂O gave thewhite solid HCl saltof 5b. HPLC(methodA)

t_R¼1.08 min. For NMR analysis the free basewas made by partitioning

the HCl salt between CH₂Cl₂and satd aq K₂CO₃solution to give 5b as

yellow oil, 1.82 g (39%). HPLC (method B) t_R¼1.78 min; ¹H NMR

(300 MHz, CDCl₃):

d 8.03e8.08 (m, 2H, Ph), 7.45e7.57 (m, 3H, Ph),

6.86 (s,1H), 6.56 (s,1H), 4.25e4.33 (m,1H), 3.90 (s, 3H, OMe), 3.86 (s,

3H, OMe), 3.32e3.40 (m, 1H), 3.15e3.24 (m, 1H), 2.96e3.09 (m, 2H),

2.75e2.86 (m, 1H, H-2), 2.46e2.72 (m, 3H), 2.39e2.46 (dd, J¼13.2,

7.0 Hz,1H, H-1b),1.90e1.99 (t, J¼11.4 Hz,1H, H-1a),1.22 (d, J¼6.5 Hz,

(300 MHz, CDCl₃):

d

6.90 (d, J¼8.8 Hz, 1H, H-12), 6.51 (dd, J¼8.8,

2.4 Hz,1H, H-11), 6.32 (d, J¼2.4 Hz,1H, H-9), 3.89e3.96 (m,1H, H-7b),

3.48 (s, 3H, OMe), 2.84e2.94 (m, 1H), 2.60e2.78 (m, 3H), 2.22e2.51

(m, 3H), 2.06e2.12 (m,1H),1.81e1.94 (m, 2H),1.35e1.48 (m, 3H),1.18

(m, 1H), 0.77 (d, J¼5.8 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz, CDCl₃):

3H, 2-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 172.2 (CO), 167.2, 165.2,

148.2,148.1,133.1,131.9,129.2,128.8,125.3,123.7,111.8,107.2, 71.3 (C-

12b), 56.2, 55.9, 51.4, 51.3, 49.3, 40.3, 36.7, 36.1, 27.0,18.3 (2-CH₃); MS

(ES): C₂₆H₂₇N₃O₄calcd: 446.2080 [MþH]^þ; found: 446.2063

[MþH]^þ.

d 172.5 (CO),157.9 (C),135.2 (C),134.1 (C),125.1 (CH),113.4 (CH),112.7

(CH), 70.4 (C-12b), 57.0 (CH), 54.9 (OMe), 52.0 (CH₂), 47.3 (CH), 42.6

(CH₂), 37.2 (CH₂), 36.7 (CH), 35.5 (CH₂), 27.7 (CH₂), 17.9 (2-CH₃); MS

(ES): C₁₈H₂₄N₂O₂calcd: 301.1916 [MþH]^þ; found: 301.1911 [MþH]^þ.

4.2.9. Compound 4i. To a solution of phenyl acetylene (305

m

L,

4.2.12. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-carboxylic acid-

1,2,3,3a,4,5,7,8-octahydro-10-methoxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-5c. Compound 5a (11.7 g, 35.4 mmol) was oxi-

dized according to general procedure 4 to give carboxylic acid 5c as

an orange solid, 9.47 g (86%). An analytical sample was prepared by

HPLC; t_R¼1.46 min (method A), t_R¼4.53 min (method B); ¹H NMR

5 equiv), DMAP (15 mg), di-tert-butyldicarbonate (220 mg, 1 mmol,

1.8 equiv) in dry CH₃CN (5 mL) was added 4a (200 mg, 0.56 mmol).

The reaction mixture stirred at rt overnight whereupon it was

concentrated under reduced pressure. The residue was dissolved in

CH₂Cl₂, washed with satd aq NaCl solution, dried over anhydrous

sodium sulfate, and concentrated under vacuum. The crude product

was puriﬁed by radial chromatography on silica gel, eluting with

1e2% MeOH in CH₂Cl₂to give 4i as a white foam, 74 mg (30%). HPLC

(method A) t_R¼2.03 min, (method B) t_R¼6.47 min (100%); ¹H NMR

(300 MHz, DMSO-d₆):

d

7.20 (d, J¼8.8 Hz, H-12), 6.82 (dd, J¼8.8,

2.6 Hz, 1H, H-11), 6.65 (d, J¼2.6 Hz, 1H, H-9), 3.89e3.97 (m, 1H, H-

7b), 3.71 (s, 3H, OMe), 3.10e3.16 (m, 1H, H-7a), 2.96e3.04 (m, 1H,

H-3a), 2.76e2.82 (m, 1H, H-8b), 2.62e2.72 (m, 1H, H-8a), 2.40e2.50

(m, 2H, H-2 and H-4b), 2.20e2.32 (m, 2H, H-3 and H-4a), 2.04e2.11

(dd, J¼13.2, 7.0 Hz, 1H, H-1b), 1.79 (t, J¼12.2 Hz, 1H, H-1a), 1.03 (d,

(300 MHz, CDCl₃):

d 7.75e7.81 (m, 2H, Ph), 7.44e7.51 (m, 3H, Ph),

6.84 (s, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 4.25e4.31 (m, 1H, H-7b), 3.91

(s, 3H, OMe), 3.85 (s, 3H, OMe), 3.08e3.18 (m, 2H, H-7a and H-8b),

2.98e3.05 (m, 1H, H-3a), 2.77e2.81 (m, 1H, H-3), 2.56e2.68 (m, 3H,

H-8a, H-2 and H-4b), 2.35e2.42 (m, 2H, H-4a and H-1b), 1.85e1.93

(t, J¼12.8 Hz, 1H, H-1a), 1.12 (d, J¼6.1 Hz, 3H, 2-CH₃). Assignments

are tentative, based on the COSY spectrum; ¹³C NMR (75 MHz,

J¼6.2 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz, DMSO-d₆):

d 175.1 (CO),

172.0 (CO), 158.6 (C), 135.3 (C), 135.2 (C), 125.7 (CH), 114.4 (CH),

113.6 (CH), 71.2 (C-12b), 59.7 (CH), 55.8 (OMe), 51.6 (CH₂), 48.2

(CH), 38.9 (CH), 37.1 (CH₂), 36.1 (CH₂), 27.8 (CH₂), 18.8 (2-CH₃); MS

(ES): C₁₈H₂₁NO₄calcd: 316.1549 [MþH]^þ; found: 316.1532 [MþH]^þ.

CDCl₃):

d 172.6 (CO), 170.3, 164.6, 148.1, 133.8, 130.3, 129.0, 127.3,

125.8, 125.4, 111.7, 107.6, 105.0, 98.5, 71.0 (C-12b), 56.3, 55.9, 52.6,

51.6, 50.2, 41.0, 36.5, 36.0, 27.1, 18.0 (2-CH₃); MS (ES): C₂₇H₂₈N₂O₄

calcd: 445.2127 [MþH]^þ; found: 445.2122 [MþH]^þ.

4.2.13. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-(N-tert-butox-

ycarbonyl)amino-1,2,3,3a,4,5,7,8-octahydro-10-methoxy-2-methyl-

5-oxo-(2S,3R,3aS,12bR)-5f. Compound 5c (3.00 g, 9.50 mmol) was

dissolved in dry THF (100 mL) and treated with Bu₄NBr (0.58 g,

1.80 mmol), NaN₃(2.20 g, 33.8 mmol), di-tert-butyldicarbonate

(2.50 g,11.4 mmol), and Zn(OTf)₂(0.11 g, 0.30 mmol) and then heated

at 45 ^ꢀC for 18 h. The reaction mixture was cooled to rt and a solution

of NaNO₂(8.00g,119mmol)inwater(75mL)wasadded.Afterstirring

for 1 h the reaction mixture was diluted with EtOAc. After stirring for

another 20min, the reaction mixture was extracted twicewith EtOAc.

The organic layers were washed twice with satd aq NH₄Cl solution,

twice with satd aq NaHCO₃solution then dried over anhydrous so-

dium sulfate and concentrated under reduced pressure. The crude

product was passed over a pad of silica gel, eluting with 80:20 hex-

anes/EtOAc, then with 2% MeOH in CH₂Cl₂to give 5f, 2.82 g (77%),

sufﬁciently pure for deprotection. An analytical sample was prepared

by HPLC; t_R¼1.94 min (method A), t_R¼5.99 min (method B); ¹H NMR

(300 MHz, CDCl₃, 60 ^ꢀC): dd7.14 (d, J¼8.5 Hz, 1H, H-12), 6.74 (d,

J¼8.5 Hz, 1H, H-11), 6.57 (s, 1H, H-9), 4.87 (d, J¼7.9 Hz, 1H, NH),

4.13e4.21 (m, 1H, H-7b), 3.74 (s, 3H, OMe), 3.39e3.42 (m, 1H, H-3),

3.08e3.14 (m, 1H, H-7a), 2.95e3.02 (m, 1H, H-8b), 2.45e2.69 (m, 4H,

H-8a, H-4b, H-4a, H-3a), 2.10e2.16 (m, 2H, H-2 and H-1b), 1.66e1.74

(m,1H, H-1a),1.45 (s, 9H, t-Bu),1.04 (d, J¼5.9 Hz, 3H, 2-CH₃); ¹³C NMR

4.2.10. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-nitromethyl-

1,2,3,3a,4,5,7,8-octahydro-10-methoxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-5a. Compound

1 (30.6 g, 0.132 mol) and 3-

methoxyphenethylamine (24.0 g, 0.158 mol) were coupled using

general procedure 1, then cyclized according to general procedure 2

(6.5 h). The crude product was puriﬁed by ﬂash column chromatog-

raphyonsilicagel,elutingwith1e2% MeOH in CH₂Cl₂to yield 5a,17.2g

(39%) as white foam. Additional impure material was also obtained. A

smaller scale run on 5.0 g of 1 gave 5a in 46% yield. HPLC (method B)

t_R¼5.45 min (91%). An analytical sample was prepared by HPLC;

24

t_R¼1.77 min (method A); [

a

]

þ128.7 (c 0.55, CHCl₃); ¹H NMR

D

(300 MHz, CDCl₃/CD₃OD):

d

7.05 (d, J¼8.5 Hz, 1H, H-12), 6.75 (dd,

J¼8.5, 2.0 Hz, 1H, H-11), 6.60 (d, J¼2.0 Hz, 1H, H-9), 4.62e4.72 (m, 2H,

CH₂NO₂), 4.06e4.13 (m,1H, H-7b), 3.72 (s, 3H, OMe), 3.16e3.25(m,1H,

H-7a), 2.90e3.01 (m, 1H, H-8b), 2.79e2.85 (m, 1H, H-3a), 2.67e2.73

(m, 1H, H-8a), 2.50e2.60 (m, 1H, H-4b), 2.24e2.30 (m, 1H, H-4a),

2.10e2.22 (m, 3H, H-2, H-3 and H-1b),1.74e1.81 (m,1H, H-1a),1.06 (d,

J¼4.7 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz, CDCl₃/CD₃OD):

d 173.2 (CO),

158.7 (C), 134.4 (C), 134.2 (C), 125.1 (CH), 114.0 (CH), 113.3 (CH), 77.4

(CH₂NO₂), 71.3 (C-12b), 55.2 (OMe), 52.8 (CH), 51.6 (CH₂), 48.0 (CH),

38.0 (CH), 36.6 (CH₂), 36.2 (CH₂), 27.8 (CH₂), 17.1 (2-CH₃); MS (ES):

C₁₈H₂₂N₂O₄calcd: 331.1658 [MþH]^þ; found: 331.1656 [MþH]^þ.

(75 MHz, CDCl₃):d 172.8 (CO),158.2 (C),155.8 (CO),134.7(C),134.4(C),

125.1 (CH), 113.6 (CH), 113.1 (CH), 79.4 (C), 68.7 (C), 64.8 (CH), 55.2

(OMe), 50.0 (CH), 49.4 (CH₂), 40.1 (CH), 35.6 (CH₂), 28.4 (C(CH₃)₃),

27.81 (2CH₂overlap), 16.9 (2-CH₃); MS (ES): C₂₂H₃₀N₂O₄calcd:

387.2284 [MþH]^þ; found: 387.2284 [MþH]^þ.

4.2.11. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-aminomethyl-

1,2,3,3a,4,5,7,8-octahydro-10-methoxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-5b. Compound 5a (5.17 g, 15.7 mmol) was reduced

to the amine following general procedure 3. The crude product was

dissolved in anhydrous MeOH and cooled on an ice bath. HCl (g) was

bubbled in, followed by addition of dry Et₂O. A gummy residue was

4.2.14. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-amino-1,2,3,3a,4,

5,7,8-octahydro-10-methoxy-2-methyl-5-oxo-(2S,3R,3aS,12bR)-5g.

Compound 5f (2.40 g, 6.2 mmol) was deprotected using general

procedure 5 to give the HCl salt of 5g as a white solid, 1.92 g (96%).

250

D.A. Goff / Tetrahedron 69 (2013) 242e256

HPLC (method A) t_R¼1.09 min, (method B) t_R¼2.04 min. For NMR

(2S,3R,3aS,7S,12bR)-7-methyl ester-6c. Compound 6a (3.15 g,

7.54 mmol) was oxidized according to general procedure 4 to give

carboxylic acid 6c as a pale orange solid, 2.34 g (72%). An analytical

sample was prepared by HPLC; t_R¼1.42 min (method A), t_R¼4.41 min

analysis the free base was prepared by partitioning the HCl salt of 5g

24

between CH₂Cl₂and satd aq K₂CO₃solution. [

a

]

þ108.2 (c 1.45,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d

7.15 (d, J¼8.8 Hz, 1H, H-12), 6.73

(d, J¼8.3 Hz, 1H, H-11), 6.54 (s, 1H, H-9), 4.12e4.18 (m, 1H, H-7b), 3.72

(s, 3H, OMe), 2.90e3.10 (m, 2H), 2.33e2.62 (m, 5H), 2.09e2.16 (m,

1H), 1.92 (m, 1H), 1.62e1.70 (m, 1H, H-1a), 1.47 (br s, 2H, NH₂), 1.01 (d,

(method B); ¹H NMR (300 MHz, CDCl₃):

d 7.14 (s, 1H), 6.74 (s, 1H),

4.40e4.47 (dd, J¼11.6, 6.9 Hz, 1H, H-7), 3.89 (s, 3H), 3.86 (s, 3H), 3.81

(s, 3H), 3.46e3.51 (m,1H, H-3a), 3.18e3.26 (dd, J¼15.4, 6.9 Hz, 1H, H-

8b), 2.91e3.00 (dd, J¼15.1, 11.8 Hz, 1H, H-8a), 2.76e2.82 (dd, J¼17.6,

10.8 Hz, 1H, H-4b), 2.50e2.60 (dd, J¼17.9, 6.2 Hz, 1H, H-4a),

2.35e2.48 (m, 2H, H-2 and H-3), 2.20 (t, J¼12.1 Hz, 1H, H-1b),

1.97e2.03 (m, 1H, H-1a), 1.16 (d, J¼6.1 Hz, 3H, 2-CH₃); ¹³C NMR

J¼6.1 Hz, 2-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 172.8 (CO), 158.0 (C),

134.8 (C), 134.2 (C), 125.2 (CH), 113.5 (CH), 113.0 (CH), 69.0 (C-12b),

66.5 (CH), 55.1 (OMe), 52.5 (CH), 50.0 (CH₂), 42.9 (CH), 35.7 (CH₂),

35.4 (CH₂), 27.7 (CH₂), 16.8 (2-CH₃); MS (ES): C₁₇H₂₂N₂O₂calcd:

287.1760 [MþH]^þ; found: 287.1767 [MþH]^þ.

(75 MHz, CDCl₃):

d 179.1 (CO), 173.0 (CO), 171.9 (CO), 148.1 (C), 147.9

(C), 135.1 (C), 123.9 (C), 111.6 (CH), 107.5 (CH), 71.6 (C-12b), 59.2 (CH),

56.2 (OMe), 56.1 (OMe), 52.6 (CO₂Me), 52.0 (CH), 50.0 (CH₂), 45.3

(CH), 39.3 (CH), 37.8 (CH₂), 30.0 (CH₂), 17.9 (2-CH₃); MS (ES):

C₂₁H₂₅NO₇calcd: 404.1709 [MþH]^þ; found: 404.1720 [MþH]^þ.

4.2.15. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-nitromethyl-7-

carboxylic acid 1,2,3,3a,4,5,7,8-octahydro-10,11-dimethoxy-2-methyl-

5-oxo-(2S,3R,3aS,7S,12bR)-methyl ester-6a. Compound 1 (5.20 g,

22.6 mmol) and

L-3,4-dimethoxyphenylalanine methyl ester

(5.40 g, 22.6 mmol) were coupled using general procedure 1, fol-

lowed by cyclization according to general procedure 2 (6 h). The

crude product was puriﬁed by ﬂash column chromatography on

silica gel, eluting with 1e2% MeOH in CH₂Cl₂to yield 6a, 6.41 g

4.2.18. 4H-Cyclopenta[2,3]pyrrolo[2,1-a][2]benzazepine-2(1H)-

one,5,6,11,12,13,13a-hexahydro-8,9-dimethoxy-12-methyl-13-(nitro-

methyl)-(10bR,12S,13R,13aS)-7a. 3,4-Dimethoxycinnamonitrile

(5.00 g) was dissolved in a mixture of EtOH (100 mL) and concd

HCl (10 mL) and hydrogenated with 10% Pd/C (wet, Degussa

Type E101, Aldrich) at 65 psi on a Parr shaker for 70 h. The

reaction mixture was ﬁltered over Celite and the ﬁltrate was

concentrated to remove most of the EtOH. The residue was

extracted twice with Et₂O (discarded) and then cooled with ice

and made strongly basic with 10 M aq NaOH solution. The basic

aqueous layer was extracted with Et₂O and the organic layer

was dried over anhydrous sodium sulfate and concentrated

under reduced pressure to give 3-(3,4-dimethoxyphenyl)pro-

pylamine (5.07 g) as a pale yellow oil. ¹H NMR (300 MHz,

(68%) as pale yellow foam. An analytical sample was prepared by

24

HPLC; t_R¼1.72 min (method A), t_R¼5.36 min (method B); [

a]

D

þ12.7 (c 0.805, CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d 6.74 (s, 1H),

6.64 (s, 1H), 4.62e4.72 (m, 2H, CH₂NO₂), 4.41e4.48 (dd, J¼11.3,

7.1 Hz, 1H, H-7), 3.88 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.18e3.25 (m,

2H, H-3a and H-8b), 2.90e3.00 (dd, J¼18.1, 10.6 Hz, 1H, H-8a),

2.68e2.78 (dd, J¼18.1, 10.6 Hz, 1H, H-4b), 2.39e2.47 (dd, J¼18.1,

4.2 Hz, 1H, H-4a), 2.12e2.23 (m, 2H, H-1b and H-3), 1.94e1.99 (m,

2H, H-1a and H-2), 1.07 (d, J¼6.0 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz,

CDCl₃, 60 ^ꢀC):

d 173.2 (CO), 171.9 (CO), 149.0 (C), 148.5 (C), 135.3 (C),

124.7 (C), 113.0 (CH), 107.6 (CH), 76.8 (CH₂NO₂), 70.93 (C-12b), 56.8

(OMe), 56.5 (OMe), 53.5 (CH), 52.6 (CO₂Me), 52.1 (CH), 50.1 (CH₂),

44.4 (CH), 37.0 (CH₂), 36.9 (CH), 30.1 (CH₂), 16.9 (2-CH₃); MS (ES):

C₂₁H₂₆N₂O₇calcd: 419.1818 [MþH]^þ; found: 419.1807 [MþH]^þ.

CDCl₃): d 6.68e6.78 (m, 3H), 3.83 (s, 3H, OMe), 3.82 (s, 3H,

OMe), 2.70 (t, J¼7.0 Hz, 2H), 2.58 (t, J¼7.2 Hz, 2H), 1.70e1.75

(m, 2H), 1.17 (br s, 2H, NH₂).

Compound 1 (6.35 g, 29.5 mmol) and 3-(3,4-dimethoxyphenyl)

propylamine (5.37 g, 27.5 mmol) were coupled using general pro-

cedure 1. The crude product was cyclized according to general

procedure 2 (7 h). Puriﬁcation by ﬂash column chromatography on

silica gel, eluting with 1% MeOH in CH₂Cl₂gave 7a, 6.13 g (60%) as

4.2.16. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-aminomethyl-7-

carboxylic acid 1,2,3,3a,4,5,7,8-octahydro-10,11-dimethoxy-2-methyl-

5-oxo-(2S,3R,3aS,7S,12bR)-methyl ester-6b. Compound 6a (3.00 g,

7.2 mmol) was reduced to the amine following general procedure 3.

The crude product was dissolved in anhydrous MeOH and cooled

on an ice bath. HCl (g) was bubbled in, followed by addition of dry

Et₂O. A solid did not form, so the mixture was concentrated under

reduced pressure to give a pinkish foam of the HCl salt of 6b, 2.20 g

(79%). HPLC (method A) t_R¼1.09 min, (method B) t_R¼2.49 min

(85%). The compound was further puriﬁed by making the free base

by partitioning between CH₂Cl₂and satd aq K₂CO₃solution, fol-

lowed by ﬂash chromatography on silica gel, eluting with 5e10%

MeOH in CH₂Cl₂and then with 10% 2 M NH₃in MeOH/90% CH₂Cl₂.

a pale orange foam. An analytical sample was prepared by HPLC;

24

t_R¼1.63 min (method A), t_R¼5.20 min (83%) (method B); [

a]

D

þ133.6 (c 0.855, CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d 6.67 (s, 1H),

6.50 (s, 1H), 4.57e4.59 (m, 2H, CH₂NO₂), 4.18e4.26 (m, 1H, H-4b),

3.84 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.04e3.08 (m, 1H, H-4b),

2.85e2.91 (m, 1H), 2.70e2.75 (m, 1H), 2.52e2.61 (m, 2H),

2.29e2.38 (m, 2H), 2.07e2.22 (m, 2H), 1.90e1.98 (m, 2H), 1.77 (m,

1H), 1.13 (d, J¼5.0 Hz, 3H, 12-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d

172.9 (CO), 147.4 (C), 147.3 (C), 135.8 (C), 132.6 (C), 114.0 (CH), 110.1

(CH), 76.2 (CH₂NO₂), 75.5 (C-10b), 56.3 (OMe), 55.8 (OMe), 51.6

(CH), 50.8 (CH), 47.9 (CH₂), 38.6 (CH), 38.0 (CH₂), 33.9 (CH₂), 32.2

(CH₂), 26.5 (CH₂), 18.1 (12-CH₃); MS (ES): C₂₀H₂₆N₂O₅calcd:

375.1920 [MþH]^þ; found: 375.1927 [MþH]^þ.

¹H NMR (300 MHz, CDCl₃, 60 ^ꢀC):

d 6.94 (s, 1H), 6.71 (s, 1H),

4.41e4.47 (m, 1H, H-7), 3.83 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H),

3.50e3.70 (br s, 2H, NH₂), 3.07e3.19 (m, 3H, H-3a, H-8b, and

CH_aH_bNH₂), 2.91e3.01 (m, 2H, H-8a and CH_aH_bNH₂), 2.67e2.77 (dd,

J¼18.1, 10.7 Hz, 1H, H-4b), 2.46e2.54 (dd, J¼18.1, 4.7 Hz, 1H, H-4a),

2.09e2.18 (m, 1H, H-1b), 1.80e1.91 (m, 2H, H-1a and H-2),

1.63e1.70 (m, 1H, H-3), 1.00 (d, J¼5.9 Hz, 3H, 2-CH₃); ¹³C NMR

4.2.19. 4H-Cyclopenta[2,3]pyrrolo[2,1-a][2]benzazepine-2(1H)-

one,5,6,11,12,13,13a-hexahydro-8,9-dimethoxy-12-methyl-13-(ami-

nomethyl)-(10bR,12S,13R,13aS)-7b. Compound 7a (1.90 g, 5.10 mmol)

was reduced to the amine following general procedure 3. The crude

product was puriﬁed by ﬂash chromatography on silica gel, eluting

with 5e10% MeOH in CH₂Cl₂to give 7b as a yellow oil, 0.57g (33%).

HPLC (method A) t_R¼0.92 min, (method B) t_R¼2.37 min; ¹H NMR

(75 MHz, CDCl₃, 25 ^ꢀC):

d 173.7 (CO), 172.0 (CO), 147.9 (C), 147.7 (C),

136.0 (C), 124.2 (C), 111.7 (CH), 107.4 (CH), 71.0 (C-12b), 56.4 (2C

overlap, OMe and CHe at 60 ^ꢀC these resonances are separated:

56.6 and 56.5 ppm), 56.1 (OMe), 52.5 (CO₂Me), 52.0 (CH), 50.4

(CH₂), 44.4 (CH), 42.5 (CH₂), 37.9 (CH₂), 36.4 (CH), 30.0 (CH₂), 17.3

(2-CH₃); MS (ES): C₂₁H₂₈N₂O₅calcd: 389.2076 [MþH]^þ; found:

389.2060 [MþH]^þ.

(300 MHz, CDCl₃, 60 ^ꢀC):

d 6.76 (s, 1H), 6.44 (s,1H), 4.10e4.21 (m, 1H,

H-4b), 3.77 (s, 3H, OMe), 3.74 (s, 3H, OMe), 2.95e3.04 (m, 1H, H-4a),

2.78e2.87 (m, 2H), 2.65e2.73 (m, 2H), 2.41e2.55 (m, 2H), 2.10e2.23

(m, 3H), 1.96e2.03 (m, 1H), 1.80e1.90 (m, 1H), 1.66e1.73 (m, 1H), 1.38

4.2.17. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3,7-dicarboxylic acid

1,2,3,3a,4,5,7,8-octahydro-10,11-dimethoxy-2-methyl-5-oxo-

(br s, 2H, NH₂), 1.25e1.35 (m, 1H), 1.00 (d, J¼6.3 Hz, 3H, 12-CH₃); ¹³

C

NMR (75 MHz, CDCl₃, 60 ^ꢀC):

d 173.8 (CO),147.7 (C),147.6 (C),137.5 (C),

D.A. Goff / Tetrahedron 69 (2013) 242e256

251

133.0 (C), 114.9 (CH), 111.8 (CH), 76.3 (C-10b), 56.7 (OMe), 56.1 (OMe),

55.2 (CH), 51.8 (CH₂), 48.6 (CH), 42.5 (CH₂), 38.3 (CH₂), 38.0 (CH), 35.2

(CH₂), 32.7 (CH₂), 26.8 (CH₂), 18.9 (12-CH₃); MS (ES): C₂₀H₂₈N₂O₃

calcd: 345.2178 [MþH]^þ; found: 345.2182 [MþH]^þ.

76.8 (CH₂NO₂), 75.9 (C-10b), 55.0 (OMe), 51.2 (CH), 50.3 (CH), 47.3

(CH₂), 38.7 and 38.6 (CH and CH₂), 33.7 (CH₂), 33.1 (CH₂), 26.2

(CH₂), 17.5 (12-CH₃); MS (ES): C₁₉H₂₄N₂O₄calcd: 345.1814 [MþH]^þ;

found: 345.1821 [MþH]^þ.

4.2.20. 4H-Cyclopenta[2,3]pyrrolo[2,1-a][2]benzazepine-2(1H)-

one,5,6,11,12,13,13a-hexahydro-8,9-dimethoxy-12-methyl-13-

carboxylic acid-(10bR,12S,13R,13aS)-7c. Compound 7a (3.81 g,

10.2 mmol) was oxidized using general procedure 4 to give car-

boxylic acid 7c as a pale yellow foam, 2.39 g (65%). HPLC (method A)

t_R¼1.68 min, (method B) t_R¼4.29 min (90%); ¹H NMR (300 MHz,

4.2.22. 4H-Cyclopenta[2,3]pyrrolo[2,1-a][2]benzazepine-2(1H)-

one,5,6,11,12,13,13a-hexahydro-8-methoxy-12-methyl-13-

aminomethyl-(10bR,12S,13R,13aS)-8b. Compound 8a (5.10 g,

14.8 mmol) was reduced according to general procedure 3 to give

amine 8b, 3.22 g (69%) as a pale yellow solid. HPLC (method A)

t_R¼1.15 min, (method B) t_R¼2.64 min (84%); ¹H NMR (300 MHz,

CDCl₃):

d

11.08 (br s, CO₂H), 6.81 (s, 1H), 6.48 (s, 1H), 4.18e4.26 (m,

CDCl₃):

d

7.17 (d, J¼8.8 Hz, 1H, H-10), 6.67 (dd, J¼8.5, 2.5 Hz, 1H, H-

1H), 3.83 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.11e3.21 (m, 1H),

3.03e3.10 (m,1H), 2.54e2.76 (m, 4H), 2.33e2.46 (m,1H), 2.28e2.33

(m, 2H), 1.92e2.10 (m, 2H), 1.70e1.78 (m, 1H), 1.12 (d, J¼6.4 Hz, 3H,

9), 6.51 (d, J¼2.6 Hz, 1H, H-7), 4.16e4.22 (m, 1H), 3.70 (s, 3H, OMe),

3.01e3.06 (m, 1H), 2.84e2.87 (m, 2H), 2.60e2.77 (m, 3H),

2.42e2.51 (m, 1H), 2.12e2.27 (m, 3H), 1.90e1.99 (m, 2H), 1.74 (m,

1H), 1.61 (br s, 2H, NH₂), 1.32 (m, 1H), 1.01 (d, J¼5.9 Hz, 3H, 12-CH₃);

12-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 177.2 (CO), 174.2 (CO), 147.2

(2C), 135.4 (C), 132.4 (C), 113.9 (CH), 110.2 (CH), 76.7 (C-10b), 57.5

(CH), 56.2 (OMe), 55.8 (OMe), 52.4 (CH), 47.6 (CH₂), 39.7 (CH), 38.5

(CH₂), 34.4 (CH₂), 32.3 (CH₂), 26.4 (CH₂), 18.7 (12-CH₃); MS (ES):

C₂₀H₂₅NO₅calcd: 360.1811 [MþH]^þ; found: 360.1815 [MþH]^þ.

¹³C NMR (75 MHz, CDCl₃):

d 174.1 (CO),158.3 (C), 142.1 (C), 137.7 (C),

128.2 (CH), 116.7 (CH), 112.2 (CH), 76.2 (C-10b), 55.7 (OMe), 55.0

(CH), 51.5 (CH), 48.5 (CH₂), 42.7 (CH₂), 38.9 (CH₂), 38.0 (CH), 35.4

(CH₂), 34.0 (CH₂), 27.1 (CH₂), 19.3 (12-CH₃); MS (ES): C₁₉H₂₆N₂O₂

calcd: 315.2072 [MþH]^þ; found: 315.2079 [MþH]^þ.

4.2.21. 4H-Cyclopenta[2,3]pyrrolo[2,1-a][2]benzazepine-2(1H)-

one,5,6,11,12,13,13a-hexahydro-8-methoxy-12-methyl-13-(nitro-

methyl)-(10bR,12S,13R,13aS)-8a. 3-Methoxybenzaldehyde (20.8 g,

0.153 mol) was treated with toluene (dry, 140 mL), pyridine (dry,

60 mL), ammonium acetate (0.59 g), and cyanoacetic acid (11.9 g,

0.140 mol) and then heated under reﬂux with a DeaneStark trap for

71 h according to the procedure of Montgomery et.al.²⁴The re-

action mixture was concentrated under reduced pressure. The

residue was dissolved in CH₂Cl₂and washed with 10% aq HCl so-

lution, dried over anhydrous sodium sulfate, and concentrated

under reduced pressure. The crude product was puriﬁed by ﬂash

chromatography on silica gel, eluting with 2e5% EtOAc in hexanes

to give 3-methoxycinnamonitrile, 14.65 g (60%). This material was

dissolved in EtOH (75 mL) and concd HCl (15 mL) and hydrogenated

with 10% Pd/C (2.00 g) at 70 psi on a Parr shaker for 67 h. The re-

action mixture was ﬁltered over Celite. The ﬁltrate was extracted

with EtOAc, and the EtOAc layer was concentrated under vacuum to

give the hydrochloride salt of 3-(3-methoxyphenyl)propylamine as

a waxy white solid, 17.3 g (93%). HPLC (method B) t_R¼1.28 min

4.2.23. 4H-Cyclopenta[2,3]pyrrolo[2,1-a][2]benzazepine-2(1H)-

one,5,6,11,12,13,13a-hexahydro-8-methoxy-12-methyl-13-carboxylic

acid-(10bR,12S,13R,13aS)-8c. Compound 8a (4.82 g, 14.0 mmol) was

oxidized according to general method 4. The crude carboxylic acid

was puriﬁed by ﬂash chromatography on silica gel eluting with 5%

EtOAc in hexanes to give 8c as a pale yellow foam, 2.60 g (56%).

HPLC (method A) t_R¼1.57 min, (method B) t_R¼4.77 min (90%); ¹H

NMR (300 MHz, DMSO-d₆, 60 ^ꢀC):

d 12.2 (br s, 1H, CO₂H), 7.27 (d,

J¼8.4 Hz, 1H, H-10), 6.77 (dd, J¼8.6, 2.7 Hz, 1H, H-9), 6.22 (d,

J¼2.5 Hz, 1H, H-7), 4.02e4.10 (m, 1H), 3.70 (s, 3H, OMe), 3.02e3.10

(m, 2H), 2.63e2.69 (m, 2H), 2.47e2.57 (m, 1H), 2.34e2.43 (m, 1H),

2.10e2.20 (m, 4H), 1.79e1.84 (m, 1H), 1.68e1.73 (m, 1H), 1.04 (d,

J¼6.6 Hz, 3H, 12-CH₃); ¹³C NMR (300 MHz, DMSO-d₆, 60 ^ꢀC):

d 175.3

(CO), 172.3 (CO), 158.3 (C), 142.2 (C), 137.1 (C), 127.9 (CH), 116.9 (CH),

112.4 (CH), 75.9 (C-10b), 57.9 (CH), 55.7 (OMe), 51.7 (CH), 47.3 (CH₂),

39.2 (CH), 38.6 (CH₂), 34.6 (CH₂), 33.5 (CH₂), 27.0 (CH₂), 19.0 (12-

CH₃); MS (ES): C₁₉H₂₃NO₄calcd: 330.1705 [MþH]^þ; found:

330.1700 [MþH]^þ.

[MþH]^þ¼166.30; ¹H NMR (300 MHz, CDCl₃/CD₃OD):

d 7.14e7.19

(m, 1H), 6.70e6.77 (m, 3H), 4.51e4.58 (m, 2H), 3.75 (s, 3H, OMe),

2.85e2.91 (m, 2H), 2.63e2.68 (m, 2H), 1.95e2.01 (m, 2H).

4.2.24. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-nitromethyl,1,2,3,-

3a,4,5,7,8-octahydro-10-benzyloxy-2-methyl-5-oxo-(2S,3R,3aS,12bR)-

9. A solution of 2-(3-hydroxyphenyl)ethylamine (5.15 g, 29.7 mmol)

in THF (65 mL) was treated with Et₃N (9.30 mL, 2.2 equiv) and cooled

on an ice-water bath. Di-tert-butyldicarbonate (6.80 g, 31.1 mmol)

was added and the cooling bath was removed. After approx. 0.5 h

THF (35 mL) and Et₃N (5.0 mL) were added to improve solubility.

After stirring overnight, the reaction mixture was diluted with

EtOAc, washed with water and satd aq NaCl solution, dried over

anhydrous sodium sulfate, and concentrated under reduced pres-

sure. The residue was dissolved in acetone (100 mL) and treated with

benzyl bromide (3.90 mL, 33 mmol) and K₂CO₃(4.50 g, 33 mmol).

The reaction mixture was heated at 50 ^ꢀC for 19 h. The solvent was

removed under reduced pressure. The residue was partitioned be-

tween CH₂Cl₂and 2 M aq NaOH. The organic layer was washed with

satd aq NaCl solution, dried over anhydrous sodium sulfate, and

concentrated under reduced pressure. The crude product, containing

a small amount of residual benzyl bromide, was deprotected using

general procedure 5 to give 2-(3-benzyloxyphenyl)ethylamine hy-

drochloride as a white solid, 5.49 g. HPLC (method A) t_R¼2.85 min

Compound 1 (14.8 g, 68.8 mmol) and 3-(3-methoxyphenyl)

propylamine hydrochloride (17.3 g, 85.6 mmol) were coupled using

general procedure 1. The crude product was stirred with 5% TFA in

CH₂Cl₂(200 mL) at rt for 3 h. Since the reaction had only gone 35%

to completion (HPLC), an additional 10 mL of TFA was added, fol-

lowed by heating at reﬂux for 3 h. The reaction mixture was con-

centrated under reduced pressure. The residue was dissolved in

CH₂Cl₂, washed once with water and twice with sat aq NaHCO₃

solution, dried with anhydrous sodium sulfate, and concentrated

under reduced pressure. The crude product was puriﬁed by ﬂash

column chromatography on silica gel, eluting with 1e5% MeOH in

CH₂Cl₂to yield 8a, 11.06 g (46%) as a tan foam. HPLC (method B)

t_R¼5.75 min (84%). An analytical sample was prepared by HPLC;

t_R¼1.89 min (method A); ¹H NMR (300 MHz, CDCl₃/CD₃OD):

d 6.92

(d, J¼8.8 Hz, 1H, H-10), 6.50 (dd, J¼8.8, 2.8 Hz, 1H, H-9), 6.34 (d,

J¼2.5 Hz, 1H, H-7), 4.34e4.41 (m, 2H, CH₂NO₂), 3.90e4.00 (m, 1H,

H-4b), 3.51 (s, 3H, OMe), 2.87e2.94 (m,1H, H-4a), 2.61e2.65 (m,1H,

H-6b), 2.33e2.48 (m, 2H, H-1a and H-1b), 2.24e2.33 (dd. J¼17.5,

7.9 Hz, 1H, H-6a), 1.90e2.09 (m, 3H, H-12, H-11b and H-5b),

1.72e1.85 (m, 3H, H-5a, H-11a and H-13), 1.53e1.60 (m, 1H, H-13a),

0.86 (d, J¼5.8 Hz, 3H, 12-CH₃). The assignments are tentative, based

(94%); ¹H NMR (300 MHz, DMSO-d₆):

d

8.04 (br s, 3H, NH^þ₃),

7.34e7.42 (m, 4H), 7.22 (t, J¼7.7 Hz, 1H), 6.80e6.91 (m, 3H), 5.07 (s,

2H, PhCH₂O), 3.00 (m, 2H), 2.81e2.85 (m, 2H).

on the COSY spectrum; ¹³C NMR (75 MHz, CDCl₃/CD₃OD):

d

173.7

Compound 1 (4.49 g, 20.9 mmol) and 2-(3-benzyloxyphenyl)

ethylamine hydrochloride (5.49 g, 20.9 mmol) were coupled using

(CO), 158.1 (C), 141.4 (C), 135.6 (C), 127.2 (CH), 116.4 (CH), 111.8 (CH),

252

D.A. Goff / Tetrahedron 69 (2013) 242e256

general method 1. The crude product was cyclized using general

procedure 2 (4 h). Puriﬁcation by ﬂash column chromatography on

silica gel, eluting with 1% MeOH in CH₂Cl₂gave 9, 4.69 g (55%) as

a foam. HPLC (method B)t_R¼6.86min(88%). Ananalyticalsamplewas

prepared by HPLC; t_R¼2.71 min; ¹H NMR (300 MHz, CDCl₃):

(1.5 g) at 34 psi of H₂in a Parr shaker for 7 h. The reaction mixture

was ﬁltered over Celite and the ﬁltrate was concentrated under

reduced pressure to give 9c as a tan solid, 2.06 g (87%). An analytical

sample was puriﬁed by ﬂash chromatography on silica gel, eluting

with 2% MeOH in CH₂Cl₂. HPLC (method A) t_R¼1.63 min, (method B)

d

7.25e7.39 (m, 5H, Ph), 7.01 (d, J¼8.8 Hz, 1H, H-12), 6.83 (dd, J¼8.6,

t_R¼4.22 min (96%); [

CDCl₃):

a]

²⁴þ124.4 (c 0.73, CHCl₃); ¹H NMR (300 MHz,

D

2.5 Hz, 1H, H-11), 6.68 (d, J¼2.8 Hz, 1H, H-9), 5.01 (s, 2H, PhCH₂O),

4.50e4.69 (m, 2H, CH₂NO₂), 4.16e4.24 (m, 1H, H-7b), 3.10e3.20 (m,

1H, H-7aorH-8b), 2.95e3.06 (m,1H, H-8bor H-7a), 2.76e2.80(m,1H,

H-3a), 2.63e2.69 (m, 1H, H-8a), 2.52e2.62 (m, 1H, H-4b), 2.23e2.29

(m, 2H, H-4a and H-1b), 2.08e2.22 (m, 2H, H-2 and H-3), 1.73e1.82

(m,1H, H-1a),1.08 (d, J¼5.5 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d

9.74 (br s, 1H, OH), 7.13 (d, J¼8.8 Hz, 1H, H-12), 6.74 (dd,

J¼8.5, 2.6 Hz, 1H, H-11), 6.56 (d, J¼2.3 Hz, 1H, H-9), 4.12e4.20 (m,

1H, H-7b), 3.76 (s, 3H, CO₂Me), 3.08e3.18 (m, 2H, H-7a and H-3a),

2.89e3.00 (m, 1H, H-8b), 2.50e2.68 (m, 3H, H-4b, H-8a and H-2),

2.29e2.45 (m, 2H, H-4a and H-3), 2.19e2.26 (m, 1H, H-1b),

1.69e1.78 (t, J¼12.5 Hz, 1H, H-1a), 1.06 (d, J¼6.4 Hz, 3H, 2-CH₃); ¹³

C

d

172.4 (CO), 157.8 (C), 137.0 (C), 134.8 (C), 134.7 (C), 128.9 (CH), 128.2

NMR (75 MHz, CDCl₃): d 174.7 (CO), 173.0 (CO), 155.7 (C), 134.2 (C),

(CH),127.7 (CH),125.1 (CH),115.2 (CH),114.1 (CH), 77.5 (CH₂NO₂), 70.6

(C-12b),70.2(PhCH₂O), 52.9(CH), 51.8(CH₂), 48.1(CH),38.2(CH), 36.5

(CH₂), 36.1 (CH₂), 28.0 (CH₂),17.7 (2-CH₃); MS (ES): C₂₄H₂₆N₂O₄calcd:

407.1971 [MþH]^þ; found: 407.1978 [MþH]^þ.

133.0 (C), 125.3 (CH), 115.4 (CH), 114.5 (CH), 71.7 (C-12b), 59.3 (CH),

52.1 (CO₂Me), 51.5 (CH₂), 48.0 (CH), 39.0 (CH), 36.8 (CH₂), 36.2

(CH₂), 27.6 (CH₂), 18.1 (2-CH₃); MS (ES): C₁₈H₂₁NO₄calcd: 316.1549

[MþH]^þ; found: 316.1554 [MþH]^þ.

4.2.25. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-carboxylic

acid,1,2,3,3a,4,5,7,8-octahydro-10-benzyloxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-9a. Compound 9 (4.60 g, 11.3 mmol) was oxidized

according to general procedure 4. The crude acid was puriﬁed by

ﬂash chromatography on silica gel eluting with 5% MeOH in CH₂Cl₂

to give 9a as a foam, 2.13 g (48%). HPLC (method B) t_R¼6.02 min

(75% by UV, >90% ELSD). An analytical sample was prepared by

4.2.28. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-carboxylic

acid,1,2,3,3a,4,5,7,8-octahydro-10-(triﬂuoromethanesulfonyl)oxy-2-

methyl-5-oxo-(2S,3R,3aS,12bR)-methyl ester 9d. Compound 9c

(1.14 g, 3.62 mmol) was dissolved in dry CH₂Cl₂(20 mL), treated

with Et₃N (1.20 mL, 8.60 mmol), and cooled on an ice-water bath. A

solution of triﬂuoromethanesulfonic anhydride (0.73 mL,

4.30 mmol) in CH₂Cl₂(5 mL) was added dropwise. After 1.5 h the

reaction mixture was washed with satd aq NaHCO₃and satd aq

NaCl solutions, dried over anhydrous sodium sulfate, and concen-

trated under reduced pressure. The residue was puriﬁed by ﬂash

column chromatography on silica gel, eluting with 1:1 hexanes/

EtOAc to give 9d as a brown oil, 0.83 g (51%). HPLC (method A)

t_R¼2.03 min, (method B) t_R¼6.43 min; ¹H NMR (300 MHz, CDCl₃):

HPLC; t_R¼2.32 min (method A); [

a

]

²⁴þ88.5 (c 0.61, CHCl₃); ¹H NMR

D

(300 MHz, CDCl₃):

d

8.50 (br s, 1H, CO₂H), 7.33e7.40 (m, 5H, Ph),

7.25 (d, J¼8.5 Hz, 1H, H-12), 6.85 (dd, J¼8.5, 2.2 Hz, 1H, H-11), 6.68

(d, J¼2.2 Hz, 1H, H-9), 5.02 (s, 2H, PhCH₂O), 4.19e4.26 (m, 1H, H-

7b), 3.14e3.20 (m, 2H, H-3a and H-7a), 2.99e3.08 (m, 1H, H-8b),

2.47e2.68 (m, 4H, H-8a, H-4b, H-4a, H-2), 2.34e2.42 (t, J¼10.2 Hz,

1H, H-3), 2.22e2.29 (dd, J¼12.8, 7.0 Hz, 1H, H-1b), 1.72e1.81 (t,

J¼12.5, 1H, H-1a), 1.13 (d, J¼6.3 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz,

d

7.39 (d, J¼8.5 Hz, 1H, H-12), 7.09 (dd, J¼8.5, 2.5 Hz, 1H, H-11), 6.96

(d, J¼2.5 Hz, 1H, H-9), 4.17e4.24 (m, 1H, H-7b), 3.74 (s, 3H, CO₂Me),

3.05e3.18 (m, 2H), 2.96e3.02 (m,1H), 2.70e2.76 (m, 1H), 2.50e2.61

(m, 2H), 2.33e2.41 (m, 2H), 2.20e2.33 (m, 1H), 1.71e1.80 (t,

J¼12.5 Hz, 1H, H-1a), 1.07 (d, J¼6.3 Hz, 3H, 2-CH₃); ¹³C NMR

CDCl₃):

d 178.3 (CO), 173.2 (CO), 157.9 (C), 137.0 (C), 134.6 (C), 134.5

(C), 128.8 (CH), 128.3 (CH), 127.7 (CH), 125.6 (CH), 115.1 (CH), 114.1

(CH), 71.8 (C-12b), 70.3 (PhCH₂O), 59.7 (CH), 51.9 (CH₂), 48.3 (CH),

39.2 (CH), 37.1 (CH₂), 36.3 (CH₂), 28.1 (CH₂), 18.4 (2-CH₃); MS (ES):

C₂₄H₂₅NO₄calcd:392.1862 [MþH]^þ; found: 392.1872 [MþH]^þ.

(75 MHz, CDCl₃):

d 174.4 (CO), 172.2 (CO), 148.2, 142.5, 136.2, 126.5,

121.9, 120.0, 117.8 (q, CF₃, J_C,F¼320 Hz), 71.4, 59.6, 52.4, 51.6, 48.6,

39.6, 37.0, 35.7, 27.9, 18.5 (2-CH₃); MS (ES): C₁₉H₂₀F₃NO₆S calcd:

448.1042 [MþH]^þ; found: 448.1023 [MþH]^þ.

4.2.26. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-carboxylic

acid,1,2,3,3a,4,5,7,8-octahydro-10-benzyloxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-methyl ester 9b. Compound 9a (1.46 g, 3.72 mmol)

was dissolved in a 1:1 mixture of MeOH and CH₂Cl₂(20 mL) and

treated with excess 2 M TMS diazomethane in Et₂O. After 0.5 h the

solvent was removed under reduced pressure and the residue was

puriﬁed by ﬂash column chromatography on silica gel, eluting with

1e2% MeOH in CH₂Cl₂to give 9b as a yellow oil, 1.29 g (85%). HPLC

(method A) t_R¼2.25 min, (method B) t_R¼6.86 min (100%); ¹H NMR

4.2.29. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-nitromethyl,1,2,3,-

3a,4,5,7,8-octahydro-11-benzyloxy-2-methyl-5-oxo-(2S,3R,3aS,12bR)-

10. A solution of tyramine (10.1 g, 73.6 mmol) in THF (100 mL) was

treated with Et₃N (8.30 mL, 59.5 mmol) and cooled on an ice-water

bath. Di-tert-butyldicarbonate (14.5 g, 66.4 mmol) was added and

the cooling bath was removed. After stirring overnight, the reaction

mixture was diluted with EtOAc, washed with water and satd aq NaCl

solution, dried over anhydrous sodium sulfate, and concentrated un-

der reduced pressure. The residue was dissolved in acetone (100 mL)

and treated with benzyl bromide (8.00 mL, 67.2 mmol) and K₂CO₃

(9.10 g, 65.6 mmol). The reaction mixture was heated at 50 ^ꢀC for 7.5 h.

The solvent was removed under reduced pressure. The residue was

partitioned between CH₂Cl₂and 2 M aq NaOH. The organic layer was

washed with satd aq NaCl solution, dried over anhydrous sodium

sulfate, and concentrated under reduced pressure to give N-(tert-

butoxycarbonyl)-2-[4-(benzyloxy)phenyl]ethylamineasawhitesolid,

17.5 g (73%). HPLC (method B) t_R¼7.71 min (>95% purity by ELSD)

[M]^ꢂ¼326.19 (C₂₀H₂₅NO₃¼327); ¹H NMR (300 MHz, CDCl₃):

(300 MHz, CDCl₃):

d

7.29e7.42 (m, 5H, Ph), 7.23 (d, J¼8.8 Hz, 1H, H-

12), 6.85 (dd, J¼8.5, 2.6 Hz, 1H, H-11), 6.68 (d, J¼2.6 Hz, 1H, H-9),

5.03 (s, 2H, PhCH₂O), 4.16e4.24 (m, 1H, H-7b), 3.77 (s, 3H, CO₂Me),

3.10e3.17 (m, 2H, H-7b and H-3a), 2.95e3.06 (m, 1H, H-8b),

2.65e2.69 (m, 1H, H-8a), 2.51e2.63 (m, 2H, H-4b and H-2),

2.36e2.42 (m, 2H, H-4a and H-3), 2.20e2.27 (dd, J¼13.1, 7.2 Hz, 1H,

H-1b), 1.72e1.80 (t, J¼12.2 Hz, 1H, H-1a), 1.08 (d, J¼6.5 Hz, 3H, 2-

CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 174.4 (CO), 172.2 (CO), 157.5

(C), 136.9 (C), 134.4 (2 C), 128.5 (CH), 127.9 (CH), 127.3 (CH), 125.3

(CH), 114.8 (CH), 113.8 (CH), 71.1 (C-12b), 69.8 (PhCH₂O), 59.2 (CH),

51.9 (CO₂Me), 51.5 (CH₂), 48.1 (CH), 39.0 (CH), 36.7 (CH₂), 35.8 (CH₂),

27.7 (CH₂), 18.2 (2-CH₃); MS (ES): C₂₅H₂₇NO₄calcd: 406.2018

[MþH]^þ; found: 406.2006 [MþH]^þ.

d

7.26e7.44 (m, 4H), 7.10 (d, J¼8.5 Hz, 2H), 6.91 (d, J¼8.5 Hz, 2H), 5.05

(s, 2H, PhCH₂O), 3.33 (m, 2H), 2.70e2.75 (m, 2H), 1.43 (s, 9H, Boc).

The crude product above, 15.4 g, containing a small amount of

residual benzyl bromide, was deprotected according to general pro-

cedure 5 to give 2-[4-(benzyloxy)phenyl]ethylamine hydrochloride

as a white solid, 11.7 g. HPLC (method B) t_R¼2.72 min (96%); ¹H NMR

4.2.27. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-carboxylic

acid,1,2,3,3a,4,5,7,8-octahydro-10-hydroxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-methyl ester 9c. Compound 9b (3.05 g, 7.53 mmol)

was dissolved in EtOH (60 mL) and hydrogenated with 10% Pd/C

(300MHz,DMSO-d₆):d

8.06(brs,3H, NH^þ₃), 7.28e7.40(m, 4H), 7.15(d,

D.A. Goff / Tetrahedron 69 (2013) 242e256

253

J¼8.5 Hz, 2H), 6.94 (d, J¼8.5 Hz, 2H), 5.06 (s, 2H, PhCH₂O), 2.93 (m,

2H), 2.77e2.83 (m, 2H).

MeOH in CH₂Cl₂to give 10a as a foam, 3.21 g (65%). HPLC (method

A) t_R¼1.92 min, (method B) t_R¼5.79 min (100% purity by ELSD);

The free base was made by partitioning the solid between Et₂O

and 2 M aq NaOH solution. The organic layer was washed with satd

aq NaCl solution, dried over anhydrous sodium sulfate, and con-

centrated under reduced pressure to give 2-[4-(benzyloxy)phenyl]

ethylamine as a white solid, 8.92 g.

[a

]

²²þ134.7 (c 0.95, CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d 7.26e7.43

D

(m, 5H, Ph), 6.98 (d, J¼8.5 Hz, 1H, H-9), 6.92 (d, 1H, J¼2.3 Hz, 1H, H-

12), 6.80 (dd, J¼8.5, 2.6 Hz, 1H, H-10), 5.04 (s, 2H, PhCH₂O),

4.17e4.24 (m, 1H, H-7b), 3.10e3.21 (m, 2H), 2.94e3.02 (m, 1H),

2.44e2.68 (m, 4H), 2.31e2.39 (t, J¼10.2 Hz, 1H), 2.19e2.26 (dd,

J¼13.0, 6.9 Hz, 1H), 1.69e1.78 (t, J¼12.4 Hz, 1H, H-1a), 1.10 (d,

4.2.30. Intermediate A. Compound 1 (9.07 g, 39.3 mmol) and 2-[(4-

benzyloxyphenyl)]ethylamine (8.92 g, 39.3 mmol) were coupled

using general procedure 1. The crude product was puriﬁed by ﬂash

chromatography on silica gel to give intermediate A, 8.44 g (51%) as

J¼6.5 Hz, 3H, 2-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 177.1 (CO), 172.7

(CO), 157.5, 142.9, 136.8, 130.1, 128.6, 128.0, 127.6, 125.1, 113.7, 110.7,

71.8, 70.1, 59.4, 51.6, 48.0, 39.0, 36.8, 36.3, 26.7, 18.1 (2-CH₃); MS

(ES): C₂₄H₂₅NO₄calcd: 392.1862 [MþH]^þ; found: 392.1860

[MþH]^þ.

a

pale yellow solid. HPLC (method B) t_R¼6.47 min (90%)

[MꢂOH]^þ¼407.28, [M]^ꢂ¼423.21 (C₂₄H₂₈N₂O₅¼424); ¹H NMR

(300 MHz, DMSO-d₆):

d

7.29e7.40 (m, 5H), 7.11 (d, J¼8.5 Hz, 2H),

4.2.32. Intermediate 11. Compound 1 (6.57 g, 28.1 mmol) and

tryptamine (5.40 g, 33.7 mmol) were coupled using general pro-

cedure 1 to give crude 11 as a solid. HPLC (method B) peak 1

6.92 (d, J¼8.5 Hz, 2H), 5.93 (s, 1H, 7-OH, exchanges with D₂O), 5.04

(s, 2H, PhCH₂O), 4.69e4.73 (m, 1H, CH_bH_aNO₂), 4.52e4.59 (m, 1H,

CH_bH_aNO₂), 3.20e3.33 (m, 2H), 2.73e2.88 (m, 2H), 2.44e2.54 (dd,

J¼17.2, 9.8 Hz, 1H), 2.13e2.21 (m, 1H), 1.98e2.08 (m, 2H), 1.75e1.93

(m, 2H), 1.81 (t, J¼12.0 Hz, 1H), 0.85 (d, J¼6.0 Hz, 3H, 2-CH₃); ¹³C

t_R¼5.11 min (84%) [MꢂOH]^þ¼340.2, [M]^ꢂ¼356.13; peak

2

t_R¼5.31 min (16%) [MþH]^þ¼358.19, [M]^ꢂ¼356.13 (C₁₉H₂₃N₃O₄

FW¼357). A portion of crude 11 was puriﬁed by radial chromatog-

raphy on silica gel, eluting with 2% MeOH in CH₂Cl₂. Two bands were

collected but only the more polar band gave sufﬁcient material for

analysis. HPLC (method B) t_R¼5.06 min [MꢂOH]^þ¼340.24,

[M]^ꢂ¼356.13 (84%). From the predominant loss of H₂O in the posi-

tive ion ESMS and the NMR spectra, it was concluded that the major

species present in crude 11 was the hemiketal as shown. ¹H NMR

NMR (75 MHz, DMSO-d₆): d 172.5 (CO), 157.3 (C), 137.7 (C), 132.1 (C),

130.1 (CH), 128.8 (CH), 128.2 (CH), 128.0 (CH), 115.2 (CH), 98.2 (C,

assigned to C-7), 78.2 (CH₂NO₂), 69.6 (PhCH₂O), 52.1 (CH), 49.5

(CH), 47.1 (CH₂), 41.9 (CH₂), 36.5 (CH), 35.5 (CH₂), 33.9 (CH₂),17.2 (2-

CH₃). No peaks at >172 ppm corresponding to a ketone carbonyl

were observed. When this reaction was repeated, the chromato-

graphed intermediate A contained approx. 15% of what appeared to

be an epimer at C-7 (as judged by the ratio of two broadened sin-

glets at 5.63 ppm (15%) and 5.53 ppm (85%) assigned to the 7-OH-

both peaks exchanged with D₂O). The 2-CH₃also appeared as a pair

of doublets at 0.61 ppm (72%) and 0.58 ppm (28%).

Intermediate A (1.00 g, 2.4 mmol) was stirred with 5% TFA in

CH₂Cl₂(25 mL) at rt for 4 h. By LCMS analysis, only unreacted A was

present (t_R¼6.49 min). TFA (1.25 mL) was added and the reaction

mixture was heated to reﬂux for 5.5 h. LCMS analysis indicated 90%

conversion to 10 (t_R¼6.85 min). After reﬂuxing overnight, the re-

action mixture was diluted with CH₂Cl₂, washed with water and sat

aq NaHCO₃solution, dried with anhydrous sodium sulfate, and

concentrated under reduced pressure. The crude product was pu-

riﬁed by ﬂash column chromatography on silica gel, eluting with 2%

MeOH in CH₂Cl₂to yield 10, 0.82 g (86%) as a yellow oil. HPLC

(method B) t_R¼6.85 min (95%). An analytical sample was prepared

by HPLC; t_R¼2.25 min (method A); ¹H NMR (300 MHz, CDCl₃/

(300 MHz, DMSO-d₆):

d

10.80 (s, 1H, NH), 7.55 (d, J¼7.7 Hz, 1H), 7.31

(d, J¼8.0 Hz, 1H), 7.15 (d, J¼2.2 Hz, 1H, indole-2H), 7.05 (t, J¼7.6 Hz,

1H), 6.97 (t, J¼7.6 Hz, 1H), 5.94 (s, 1H), 4.51e4.75 (m, 2H, CH₂NO₂),

3.30e3.86 (m, 2H), 2.91e3.00 (m, 2H), 2.48e2.56 (m,1H), 2.15e2.19

(m, 1H), 2.03e2.10 (m, 1H), 1.92e2.00 (m, 1H), 1.85e1.91 (m, 1H),

1.70e1.84 (m,1H),1.27 (t, J¼12.1 Hz,1H), 0.83 (d, J¼6.0 Hz, 3H, CH₃);

¹³C NMR (75 MHz, DMSO-d₆):

d 172.7 (CO),136.9 (C),127.9 (C),123.3

(CH),121.7 (CH), 119.0 (CH), 112.6 (CH), 112.1 (C), 98.5 (C, assigned to

C-7), 78.6 (CH₂NO₂), 52.4 (CH), 49.9 (CH), 47.4 (CH₂), 36.8 (CH), 35.8

(CH₂), 25.2 (CH₂), 17.4 (2-CH₃). No resonances greater than 172 ppm

corresponding to a ketone carbonyl were observed.

4.2.33. 4H-Cyclopent[1,8a]indolizino[8,7-b] indole-13-nitromethyl,1,2,-

5,10,11,12,13,13a-octahydro-12-methyl-2-oxo-(10bR,12S,13R,13aS)-

12a. Crude 11 (14 mmol) was cyclized using general method 2

(3.5 h). Puriﬁcation by ﬂash column chromatography on silica gel,

eluting with 2% MeOH in CH₂Cl₂gave 12a, 4.10 g (86%) as a beige

foam. HPLC (method B) t_R¼5.92 min (91%) [MþH]^þ¼340.26. An an-

alytical sample was obtained by re-puriﬁcation of this material on

silica gel, eluting 1e2% MeOH in CH₂Cl₂. HPLC (method A)

CD₃OD):

d

7.24e7.36 (m, 5H, Ph), 6.95 (d, J¼8.5 Hz, 1H, H-9), 6.79

(dd, J¼8.1, 2.5 Hz, 1H, H-10), 6.61 (d, J¼2.4 Hz, 1H, H-12), 5.02 (s, 2H,

PhCH₂O), 4.45e4.65 (m, 2H, CH₂NO₂), 4.06e4.13 (m, 1H, H-7b),

3.08e3.18 (m, 1H, H-7a), 2.78e2.95 (m, 1H, H-8b), 2.72e2.77 (m,

1H, H-3a), 2.58e2.66 (m, 1H, H-8a), 2.49e2.55 (m, 1H, H-4b),

2.19e2.27 (m, 2H, H-4a and H-1b), 1.95e2.08 (m, 2H, H-2 and H-3),

t_R¼1.91 min; ¹H NMR (300 MHz, CDCl₃):

d 7.95 (br s, 1H, NH), 7.45 (d,

J¼7.6 Hz, 1H), 7.33 (d, J¼7.9 Hz, 1H), 7.18 (t, J¼7.5 Hz, 1H), 7.11 (t,

J¼7.5 Hz, 1H), 4.58e4.71 (m, 2H, CH₂NO₂), 4.46e4.51 (m, 1H, H-4b),

3.08e3.14 (m, 1H, H-5b), 2.93e3.00 (m, 1H, H-4a), 2.83e2.91 (m, 1H,

H-13a), 2.64e2.74 (m, 2H, H-1b and H-5a), 2.46e2.53 (dd, J¼13.1,

6.9 Hz,1H, H-11b), 2.32e2.39 (dd, J¼17.7, 2.5 Hz,1H, H-1a), 2.22e2.30

(m, 1H, H-12), 2.08e2.20 (m, 1H, H-13), 1.85e1.94 (m, 1H, H-11a), 1.13

1.66e1.75 (t, J¼12.0 Hz, 1H, H-1a), 1.01 (d, J¼5.5 Hz, 3H, 2-CH₃); ¹³

C

NMR (75 MHz, CDCl₃):

d 172.0 (CO), 157.4 (C), 142.9 (C), 136.8 (C),

130.4 (CH), 128.7 (CH), 128.1(CH), 127.5 (CH), 125.3 (C), 113.5 (CH),

110.7 (CH), 76.6 (CH₂NO₂), 70.7 (C-12b), 70.3 (PhCH₂O), 52.8 (CH),

51.6 (CH₂), 47.9 (CH), 38.1(CH), 36.3 (CH₂), 36.1 (CH₂), 26.6 (CH₂),

17.4 (2-CH₃); MS (ES): C₂₄H₂₆N₂O₄calcd: 407.1971 [MþH]^þ; found:

407.1955 [MþH]^þ.

(d, J¼6.5 Hz, 3H, 12-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 173.1 (CO),

136.4 (two non-protonated carbons overlap), 126.7 (C), 122.3 (CH),

119.9 (CH), 118.3 (CH), 111.2 (CH), 107.6 (C), 76.8 (CH₂NO₂), 69.1 (C-

10b), 52.8 (CH), 49.0 (CH₂), 45.3 (CH), 37.7 (CH), 36.8 (2 CH₂overlap),

When a new batch of intermediate A (7.24 g) was heated at reﬂux

for 10.5 h in a mixture of CH₂Cl₂(70 mL) and TFA (7 mL), followed

by workup and silica gel chromatography, 10 was obtained as a pale

yellow foam, 5.12 g (74%).

20.5 (CH₂), 17.5 (12-CH₃); ¹³C NMR (75 MHz, DMSO-d₆):

d 172.7 (CO),

138.1 (C), 136.6 (C), 126.8 (C), 121.7 (CH), 119.2 (CH), 118.3 (CH), 111.7

(CH), 106.2 (C), 78.5 (CH₂NO₂), 69.0 (C-10b), 52.6 (CH), 49.0 (CH₂),

45.8 (CH), 37.4 (CH), 36.6 (CH₂), 36.3 (CH₂), 20.5 (CH₂), 17.7 (12-CH₃).

The two overlapping sets of resonances in the CDCl₃spectrum at

136.4 and 36.8 ppm are resolved in the DMSO-d₆spectrum; MS (ES):

C₁₉H₂₁N₃O₃calcd: 340.1661 [MþH]^þ; found: 340.1651 [MþH]^þ.

Alternatively, crude 11 (14 mmol) was cyclized by reﬂuxing in

toluene (150 mL) containing p-toluenesulfonic acid monohydrate

4.2.31. Cyclopenta[2,3]pyrrolo[2,1-a]isoquinoline-3-carboxylic

acid,1,2,3,3a,4,5,7,8-octahydro-11-benzyloxy-2-methyl-5-oxo-

(2S,3R,3aS,12bR)-10a. Compound 10 (5.12 g, 12.6 mmol) was oxi-

dized according to general procedure 4. The crude product was

puriﬁed by ﬂash chromatography on silica gel eluting with 3%

254

D.A. Goff / Tetrahedron 69 (2013) 242e256

(500 mg) with a DeaneStark trap. After 3.5 h the reaction mixture

was concentrated under reduced pressure. The residue was dis-

solved in CH₂Cl₂, washed once with water and sat aq NaHCO₃so-

lution, dried with anhydrous sodium sulfate and concentrated

under reduced pressure. The crude product was puriﬁed by ﬂash

column chromatography on silica gel, eluting with 2% MeOH in

CH₂Cl₂to yield 12a, 3.48 g (73%) as a beige foam. HPLC (method B)

t_R¼5.92 min (93%) [MþH]^þ¼340.26.

(CH), 115.5 (CH), 78.8 (CH₂NO₂), 73.9 (C-10b), 52.8 (CH), 47.2 (CH₂),

47.0 (CH), 37.5 (CH), 35.8 (CH₂), 35.0 (CH₂), 21.8 (Ts-CH₃), 21.1 (CH₂),

20.4 (12-CH₃); MS (ES): C₂₆H₂₇N₃O₅S calcd: 494.1750 [MþH]^þ;

found: 494.1697 [MþH]^þ.

4.2.37. Compound 13b. Compound 13a (2.89 g, 5.86 mmol) was

oxidized using general procedure 4 to give carboxylic acid 13b as an

orange foam, 2.57 g (89%). HPLC (method B) t_R¼6.34 min (95%). An

analytical sample was prepared by HPLC; t_R¼2.07 min (method A);

4.2.34. 4H-Cyclopent[1,8a]indolizino[8,7-b]indole-13-aminomethyl,1,-

2,5,10,11,12,13,13a-octahydro-12-methyl-2-oxo-(10bR,12S,13R,13aS)-

12b. Compound 12a (2.50 g, 7.37 mmol) was reduced using general

procedure 3 to give amine 12b, 2.09 g (93%) as a white foam. HPLC

¹H NMR (300 MHz, CDCl₃):

d

8.06 (d, J¼7.6 Hz,1H), 7.44 (d, J¼8.2 Hz,

2H), 7.32e7.36 (m, 1H), 7.26e7.32 (m, 2H), 7.17 (d, J¼8.2 Hz, 2H),

4.29e4.33 (m, 1H, H-4b), 3.88e3.95 (m, 1H, H-13a), 3.00e3.14 (m,

3H, H-12, H-4a, H-5b), 2.73e2.82 (m, 1H, H-11b), 2.60e2.65 (m, 1H,

H-5a), 2.48e2.52 (m,1H, H-1b), 2.35e2.45 (m,1H, H-13), 2.32 (s, 3H,

Ts-CH₃), 2.10e2.19 (dd, J¼17.6, 7.6 Hz, 1H, H-1a), 1.80e1.87 (dd,

J¼14.0, 8.8 Hz, 1H, H-11a), 1.17 (d, J¼6.4 Hz, 3H, 12-CH₃); ¹³C NMR

(method A) t_R¼1.26 min, (method B) t_R¼2.83 min (93%); [

a

]

²⁴þ124.9

D

(c 1.02, CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d

10.10 (s, 1H, indo-

leeNH), 7.44 (d, J¼8.2 Hz, 1H), 7.28 (d, J¼8.2 Hz, 1H), 7.04e7.26 (m,

2H), 4.45e4.52 (m, 1H), 3.08e3.16 (m, 1H), 3.01 (m, 2H), 2.85e2.97

(m, 1H), 2.70e2.85 (m, 3H), 2.38e2.69 (m, 3H), 1.99 (br s, 2H),

1.72e1.82 (m, 1H), 1.60e1.62 (m, 1H), 1.10 (d, J¼6.1 Hz, 3H, 12-CH₃);

(75 MHz, CDCl₃):

d 178.8 (CO), 175.4 (CO), 144.9 (C), 137.5 (C), 136.7

(C), 136.3 (C), 130.0 (CH), 128.8 (CH), 125.7 (CH and C: in DMSO-d₆

these two carbons are observed at 126.37 and 126.22 ppm), 123.9

(CH), 120.7 (C), 118.7 (CH), 115.3 (CH), 73.5 (C-10b), 58.2 (CH), 47.0

(CH₂), 46.2 (CH), 36.9 (CH), 35.5 (CH₂), 34.7 (CH₂), 21.5 (Ts-CH₃), 21.0

(CH₂), 20.2 (12-CH₃); MS (ES): C₂₇H₂₆N₂O₅S calcd: 479.1641

[MþH]^þ; found: 479.1666 [MþH]^þ.

¹³C NMR (75 MHz, CDCl₃):

d 172.4 (CO), 138.7 (C), 136.3 (C), 126.6 (C),

121.6 (C), 119.4 (CH), 118.2 (CH), 111.2 (CH), 105.9 (CH), 69.5 (C-10b),

55.9 (CH), 48.9 (CH₂), 44.6 (CH), 40.8 (CH₂), 39.2 (CH₂), 36.4 (CH₂),

35.7 (CH), 20.8 (CH₂),18.5 (CH₃); MS (ES): C₁₉H₂₃N₃O calcd: 310.1919

[MþH]^þ; found: 310.1916 [MþH]^þ.

4.2.38. 4H-Cyclopent[1,8a]indolizino[8,7-b]indole-4-carboxylic

acid,1,2,5,10,11,12,13,13a-octahydro-12-methyl-13-nitromethyl-2-

oxo-methyl ester (10bR,12S,13R,13aS)-14a. Compound 1 (4.30 g,

4.2.35. 4H-Cyclopent[1,8a]indolizino[8,7-b]indole-13-carboxylic

acid,1,2,5,10,11,12,13,13a-octahydro-12-methyl-2-oxo-

(10bR,12S,13R,13aS)-12c. Compound 13b (1.00 g, 2.09 mmol) in

a mixture of THF/MeOH (1:3, 32 mL) with Cs₂CO₃(4.07 g, 6 equiv)

was heated at 90 ^ꢀC in a sealed tube for 21 h. The reaction mixture

was cooled to rt and then poured into ice-water. The mixture was

extracted with Et₂O and then acidiﬁed with concd HCl. The aqueous

layer was extracted twice with a mixture of EtOAc and MeOH, dried

over anhydrous sodium sulfate, and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash chromatography on

silica gel, eluting with 5% MeOH in CH₂Cl₂to give 12c as a tan foam,

0.24 g (36%). HPLC (method A) t_R¼1.65 min, (method B) t_R¼5.13 min

20.0 mmol) and L-tryptophan methyl ester hydrochloride (5.10 g,

20.0 mmol) were coupled using general procedure 1. The crude

product was treated cyclized using general procedure 2 (5 h). Pu-

riﬁcation by ﬂash chromatography on silica gel, eluting with 0.5%

MeOH in CH₂Cl₂gave 14a as a white foam, 2.85 g (36%, 98% HPLC

purity). Another 400 mg of slightly impure material (92% HPLC

purity) was also obtained. HPLC (method A) t_R¼1.83 min, (method

24

B) t_R¼5.82 min (98%); [

a]

þ99.5 (c 0.75, CHCl₃); ¹H NMR

D

(300 MHz, CDCl₃):

d

9.02 (s, 1H, NH), 7.48 (d, J¼7.6 Hz, 1H), 7.31 (m,

1H), 7.10e7.14 (m, 2H), 5.49 (d, J¼7.9 Hz,1H, H-4), 4.58e4.61 (m, 2H,

CH₂NO₂), 3.71 (s, 3H, CO₂Me), 3.44 (d, J¼16.1 Hz, H-5b), 3.13e3.16

(dd, J¼15.9, 7.8 Hz, H-5a), 2.75e2.90 (m, 2H, H-13a and H-1b),

2.45e2.53 (dd, J¼17.0, 3.8 Hz, H-1a), 2.05e2.30 (m, 4H, H-11a, H-

11b, H-12, H-13), 1.12 (d, J¼5.3 Hz, 3H, 12-CH₃); ¹H NMR (300 MHz,

(96%); ¹H NMR (300 MHz, CDCl₃, 60 ^ꢀC):

d 8.80 (s, 1H, NH), 7.42 (d,

J¼7.9 Hz, 1H), 7.27 (d, J¼7.9 Hz, 1H), 7.08e7.15 (m, 2H), 4.49e4.56

(m, 1H, H-4b), 3.13e3.19 (m, 2H, H-5b and H-13a), 2.89e2.95 (m,

1H, H-4a), 2.80e2.88 (m, 1H, H-1b), 2.68e2.80 (m, 2H, H-5a and H-

12), 2.62e2.68 (m, 1H, H-1a), 2.45e2.60 (m, 2H, H-13 and H-11b),

1.90e1.98 (dd, J¼13.5, 8.0 Hz, 1H, H-11a), 1.24 (d, J¼6.5 Hz, 3H, 12-

DMSO-d₆, 60 ^ꢀC):

d

10.57 (s, 1H, NH), 7.40 (d, J¼7.9 Hz, 1H), 7.34 (d,

J¼7.9 Hz, 1H), 7.05e7.12 (m, 1H), 6.95e7.02 (m, 1H), 5.28 (dd, J¼7.8,

1.4 Hz, 1H, H-4), 4.82e4.89 (m, 2H, CH₂NO₂), 3.63 (s, 3H, CO₂Me),

3.17e3.23 (dd, J¼16.1, 1.5 Hz, 1H, H-5b), 2.82e2.90 (dd, J¼16.1,

7.5 Hz, 1H, H-5a), 2.65e2.75 (m, 1H, H-13a), 2.55e2.64 (m, 1H, H-

1b), 2.33e2.43 (dd, J¼17.5, 4.6 Hz, 1H, H-1a), 2.23e2.33 (m, 2H, H-

12 and H-13),1.98e2.02 (dd, J¼12.6, 5.5 Hz,1H, H-11b),1.88e1.93 (t,

J¼12.4,1H, H-11a),1.02 (d, J¼5.9 Hz, 3H,12-CH₃); ¹³C NMR (75 MHz,

CH₃); ¹³C NMR (75 MHz, CDCl₃/CD₃OD):

d 177.2 (CO), 174.5 (CO),

136.8 (C), 136.4 (C), 126.6 (C), 121.9 (CH), 119.4 (CH), 118.0 (CH), 111.4

(CH), 100.7 (C), 71.1 (C-10b), 59.1 (CH), 48.0 (CH₂), 45.8 (CH), 38.9

(CH), 37.1 ( 2CH₂), 20.5 (CH₂), 18.2 (12-CH₃); MS (ES): C₁₉H₂₀N₂O₃

calcd: 325.1552 [MþH]^þ; found: 325.1541 [MþH]^þ.

4.2.36. Compound 13a. Compound 1 (9.25 g, 43.0 mmol) and N-1-

tosyl tryptamine²⁵(10.7 g, 43.0 mmol) were coupled using general

procedure 1, then cyclized according to general procedure 2 (5 h).

Puriﬁcation by ﬂash chromatography on silica gel, eluting with 1%

MeOH in CH₂Cl₂gave 13a asa light yellow foam,10.8 g(51%, 88%pure

by HPLC). An analytical sample was prepared by radial chromatog-

raphy on silica gel, eluting with 2% MeOH in CH₂Cl₂. HPLC (method

A) t_R¼2.26 min, (method B) t_R¼7.24 min (97%); ¹H NMR (300 MHz,

CDCl₃): d 173.9 (CO), 171.2 (CO), 136.4 (C), 135.9 (C), 126.4 (C), 122.6

(CH), 120.1 (CH), 118.5 (CH), 111.2 (CH), 105.3 (C), 76.8 (CH₂NO₂),

68.6 (C-10b), 53.3 (CH), 52.4 (CO₂Me), 50.0 (CH), 49.0 (CH₂), 46.2

(CH), 38.1 (CH), 37.6 (CH₂), 21.6 (CH₂), 17.4 (12-CH₃); MS (ES):

C₂₁H₂₃N₃O₅calcd:398.1716 [MþH]^þ; found: 398.1694 [MþH]^þ.

4.2.39. 4H-Cyclopent[1,8a]indolizino[8,7-b]indole-4-carboxylic

acid,1,2,5,10,11,12,13,13a-octahydro-12-methyl-13-aminomethyl-2-

oxo-methyl ester (10bR,12S,13R,13aS)-14b. Compound 14a (3.08 g,

7.75 mmol) was reduced using general procedure3. The crude amine

was puriﬁed by ﬂash chromatography on silica gel, eluting with

CDCl₃):

d

8.00 (d, J¼8.0 Hz,1H), 7.34e7.37 (m, 3H), 7.25e7.29 (m, 2H),

7.19 (d, J¼8.5 Hz, 2H), 4.52e4.58 (m, 2H, CH₂NO₂), 4.30e4.35 (m,1H,

H-4b), 3.50e3.52 (m,1H, H-13a), 3.09e3.14 (m,1H, H-4a), 3.00e3.09

(m, 1H, H-5b), 2.75e2.83 (dd, J¼14.0, 9.9 Hz, H-11b), 2.60e2.65 (m,

1H, H-5a), 2.50e2.60 (m, 1H, H-12), 2.34 (s, 3H, TseCH₃), 2.28e2.30

(m,1H, H-13), 2.12e2.16 (m, 2H, H1a and H1b),1.84e1.92 (dd, J¼14.0,

7.7 Hz, H-11a), 1.09 (d, J¼6.6 Hz, 3H, 12-CH₃); ¹³C NMR (75 MHz,

5e10% MeOH in CH₂Cl₂to give 14b as a white foam, 1.85 g (65%).

24

HPLC (method A) t_R¼1.12 min, (method B) t_R¼5.13 min (97%); [

a]

D

þ57.6 (c 0.74, CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d 11.19 (s, 1H, NH),

7.49 (m, 1H), 7.28 (m 1H), 7.08e7.13 (m, 2H), 5.36 (dd, J¼8.4, 1.9 Hz,

1H, H-4), 3.72 (s, 3H, CO₂Me), 3.44e3.51 (dd, J¼16.0, 1.8 Hz, H-5b),

3.06e3.14 (dd, J¼16.0, 8.4 Hz, 1H, H-5a), 3.00 (br s, 2H, CH₂NH₂),

CDCl₃):

d 174.9 (CO), 145.3 (C), 137.7 (C), 136.8 (C), 136.6 (C), 130.3

(CH), 129.0 (C), 126.0 (C), 125.8 (CH), 124.3 (CH), 121.1 (CH), 119.0

D.A. Goff / Tetrahedron 69 (2013) 242e256

255

2.80e2.89 (dd, J¼16.5, 10.6 Hz, H-1b), 2.63e2.69 (m, 1H, H-13a),

2.45e2.58 (m, 2H, H-1a, H-12), 2.17e2.23 (dd, J¼12.5, 6.2 Hz, H-11b),

1.95e2.04 (t, J¼12.6, 1H, H-11a), 1.74 (br s, 2H, NH₂, exchanges with

D₂O), 1.61 (m, 1H, H-13), 1.09 (d, J¼6.4 Hz, 3H, 12-CH₃); ¹³C NMR

4.3.1. Compound 16a. White solid, 39.9 mg, 75%. HPLC (method A)

t_R¼1.52 min; ¹H NMR (300 MHz, CDCl₃):

7.36 (d, J¼8.5 Hz,1H, H-10),

d

6.80 (br s,1H, NH), 6.72 (dd, J¼8.5, 2.3 Hz, 1H, H-9), 6.56 (d, J¼2.2 Hz,

1H, H-7), 4.22e4.27 (m, 1H, H-4b), 3.76 (s, 3H, OMe), 3.27e3.31 (m,

1H), 3.10e3.14 (m,1H), 2.82 (d, J¼4.7 Hz, NHCH₃), 2.70e2.80 (m, 3H),

2.45 (dd, J¼17.0, 7.7 Hz, 1H), 2.12e2.29 (m, 2H), 1.92e2.02 (m, 3H),

1.75e1.85 (m, 1H), 1.04 (d, J¼6.0 Hz, 3H, 12-CH₃); ¹³C NMR (75 MHz,

(75 MHz, CDCl₃):

d 173.0 (CO), 171.7 (CO), 138.5 (C), 136.4 (C), 126.4

(C), 121.6 (CH), 119.4 (CH), 118.4 (CH), 111.3 (CH), 103.4 (C), 68.6 (C-

10b), 55.5 (CH), 52.4 (CO₂Me), 49.0 (CH), 48.6 (CH₂), 46.0 (CH), 40.4

(CH₂), 40.0 (CH₂), 35.4 (CH), 21.6 (CH₂), 18.6 (12-CH₃); MS (ES):

C₂₁H₂₅N₃O₃calcd: 368.1974 [MþH]^þ; found: 368.1958 [MþH]^þ.

CDCl₃):

d 173.5 (2 CO), 158.2, 141.7, 136.3, 128.0, 116.6, 111.7, 76.3 (C-

10b), 60.0, 55.4, 51.9, 47.4, 39.6, 38.9, 34.4, 33.7, 26.6,18.5 (12-CH₃); MS

(ES): C₂₀H₂₆N₂O₃calcd:343.2022[MþH]^þ; found: 343.2032 [MþH]^þ.

4.2.40. Cyclopenta[2⁰,3⁰]pyrrolo[1⁰,2⁰:1,2]azepino[3,4-b]indole-14-

nitromethyl,1,2,5,10,11,12,13,13a-octahydro-13-methyl-2-oxo-,

(10bR,12S,13R,13aS)-15a. Compound 1 (4.00 g, 18.5 mmol) and 3-

(3-aminopropyl)indole (3.22 g, 18.5 mmol)²⁶were coupled

according to general procedure 1. The crude product was cyclized

according to general procedure 2 (4 h). Puriﬁcation by ﬂash chro-

matography on silica gel, eluting with 2e5% MeOH in CH₂Cl₂gave

15a as a white foam, 3.06 g (47%). An analytical sample was pre-

pared by HPLC; t_R¼1.99 min (method A), t_R¼6.06 min (method B);

4.3.2. Compound 16b. White solid, 44.6 mg, 74%. HPLC (method A)

t_R¼2.00 min; ¹H NMR (300 MHz, CDCl₃):

7.43 (d, J¼8.5 Hz, 1H, H-

d

10), 6.71 (dd, J¼8.7, 2.6 Hz, 1H, H-9), 6.56 (d, J¼2.6 Hz, 1H, H-7),

4.22e4.40 (m, 1H, H-4b), 3.76 (s, 3H, OMe), 3.35e3.52 (m, 5H, 2

NCH₂CH₃and 1H), 3.05e3.15 (m, 1H), 2.70e2.80 (m, 3H), 2.45e2.57

(m, 2H), 2.24e2.31 (dd, J¼13.5, 7.7 Hz, 1H), 1.96e2.13 (m, 3H),

1.75e1.85 (m, 1H), 1.15e1.21 (m, 6H, 2 NCH₂CH₃), 1.03 (d, J¼6.6 Hz,

3H, 12-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 173.4 (CO), 172.6 (CO),

¹H NMR (300 MHz, CDCl₃):

d

8.05 (s, 1H, NH), 7.45e7.48 (m, 1H),

158.1, 141.7, 136.5, 128.2, 116.4, 111.7, 76.2 (C-10b), 55.4, 53.7, 52.9,

47.6, 42.2, 41.1, 38.9, 34.4, 33.7, 26.7, 18.5, 15.6, 13.4; MS (ES):

C₂₃H₃₂N₂O₃calcd: 385.2491 [MþH]^þ; found: 385.2493 [MþH]^þ.

7.25e7.28 (m, 1H), 7.09e7.14 (m, 2H), 4.58e4.62 (m, 2H, CH₂NO₂),

4.34e4.40 (m,1H, H-4b), 3.13e3.18 (m,1H, H-4a), 2.98e3.05 (m,1H,

H-14a), 2.80e2.88 (m, 2H, H-6a and H-6b), 2.60e2.70 (dd, J¼17.6,

8.8 Hz, 1H, H-1b), 2.38e2.46 (dd, 1H, J¼17.6, 7.6 Hz, H-12b),

2.25e2.29 (m, 2H, H-13, H-1a), 2.08e2.11 (m, 1H, H-5b), 1.91e2.08

(m, 3H, H-5a, H-12a, and H-14), 1.11 (d, J¼6.0 Hz, 3H, 13-CH₃). As-

signments are tentative, based on the COSY spectrum; ¹³C NMR

4.3.3. Compound 16c. White solid, 42.7 mg, 74%. HPLC (method A)

t_R¼1.72 min; ¹H NMR (300 MHz, CDCl₃):

d

7.36 (d, J¼8.8 Hz, 1H, H-

10), 6.92 (d, J¼3.0 Hz, 1H, NH), 6.72 (dd, J¼8.5, 2.7 Hz, 1H, H-9), 6.56

(d, J¼2.7 Hz, 1H, H-7), 4.18e4.25 (m, 1H, H-4b), 3.76 (s, 3H, OMe),

3.27e3.33 (m, 1H), 3.05e3.10 (m, 1H), 2.72e2.82 (m, 4H), 2.41e2.50

(dd, J¼17.0, 7.7 Hz, 1H), 2.21e2.29 (dd, J¼13.6, 8.1 Hz, 1H), 2.13 (d,

J¼17.0 Hz, 1H), 1.88e1.98 (m, 3H), 1.75e1.85 (m, 1H), 1.03 (d,

J¼6.6 Hz, 3H, 12-CH₃), 0.74e0.78 (m, 2H, CH₂ecyclopropyl),

0.47e0.50 (m, 2H, CH₂ecyclopropyl); ¹³C NMR (75 MHz, CDCl₃):

(75 MHz, CDCl₃):

d 173.1 (CO), 137.9 (C), 135.7 (C), 128.4 (C), 122.4

(CH),119.8 (CH),118.5 (CH),113.3 (C),111.0 (CH), 76.7 (CH₂NO₂), 72.5

(C-11b), 51.4 (CH), 47.5 (CH), 47.0 (CH₂), 40.5 (CH₂), 37.9 (CH), 35.0

(CH₂), 27.6 (CH₂), 22.0 (CH₂), 17.9 (13-CH₃); MS (ES): C₂₀H₂₃N₃O₄

calcd: 354.1818 [MþH]^þ; found: 354.1810 [MþH]^þ.

d

173.9 (CO),173.0 (CO),157.8,141.3,135.9, 127.7, 116.3,111.5, 76.1 (C-

4.2.41. Cyclopenta[2⁰,3⁰]pyrrolo[1⁰,2⁰: 1,2]azepino[3,4-b]indole-14-

aminomethyl,1,2,5,10,11,12,13,13a-octahydro-13-methyl-2-oxo-,

(10bR,12S,13R,13aS) 15b. Compound 15a (2.04 g, 5.78 mmol) was

reduced using general method 3. The crude amine was puriﬁed by

ﬂash chromatography on silica gel, eluting with 5% MeOH in

CH₂Cl₂, then 10% 2 M NH₃in MeOH/90% CH₂Cl₂to give 15b as

10b), 59.4, 55.3, 51.8, 47.3, 42.8, 39.4, 38.7, 34.2, 33.5, 26.5, 22.9, 18.4

(12-CH₃), 6.7 (2-cyclopropyl CH₂); MS (ES): C₂₂H₂₈N₂O₃calcd:

369.2178 [MþH]^þ; found: 369.2187 [MþH]^þ.

4.3.4. Compound 16d. White solid, 44.6 mg, 64%. HPLC (method A)

t_R¼1.72 min; ¹H NMR (300 MHz, CDCl₃):

d 7.37 (s, 1H, NH), 7.33 (d,

a white foam, 0.52 g (28%). HPLC (method A) t_R¼1.55 min, (method

J¼8.5 Hz, 1H, H-10), 6.72 (dd, J¼8.6, 2.5 Hz, 1H, H-9), 6.55 (d,

24

B) t_R¼3.05 min (92%); [

a

]

þ45.6 (c 0.61, CHCl₃); ¹H NMR

J¼2.5 Hz,1H, H-7), 4.65e4.69 (dd, J¼9.0, 2.5 Hz,1H, H-

a), 4.24e4.34

D

(300 MHz, CDCl₃, 60 ^ꢀC):

d

10.44 (br s, 1H, NH), 7.46 (m, 1H),

(m, 2H, H- and H-4b), 3.76 (s, 3H, OMe), 3.26e3.31 (m, 1H),

b

7.25e7.30 (m, 1H), 7.02e7.07 (m, 2H), 4.33e4.42 (m, H-4b), 3.22 (br

s, 2H), 3.02e3.23 (m, 3H), 2.80e3.00 (m, 3H), 2.64e2.73 (m, 1H),

2.20e2.36 (m, 3H), 1.97e2.07 (m, 2H), 1.71e1.78 (m, 1H), 1.39e1.45

(m, 1H), 0.99 (d, J¼6.1 Hz, 3H, 13-CH₃); ¹³C NMR (75 MHz, CDCl₃,

3.10e3.16 (m, 1H), 2.70e2.75 (m, 3H), 2.47e2.50 (dd, J¼17.4, 7.4 Hz,

1H), 2.30e2.41 (m, 1H), 2.10e2.18 (t, J¼10.8 Hz, 1H), 1.99e2.05 (m,

2H), 1.79e1.90 (m, 1H), 1.21 (d, J¼6.3 Hz, 3H, CH(OH)CH₃), 1.11 (d,

J¼6.3 Hz, 12-CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 174.1 (CO), 173.5

60 ^ꢀC):

d

173.1 (CO), 139.8 (C), 135.3 (C), 128.3 (C), 121.4 (CH), 119.0

(CO), 171.6 (CO), 158.2, 141.6, 136.0, 128.0, 116.6, 111.9, 76.8 (C-10b),

68.1, 60.0, 58.1, 55.4, 52.7, 52.3, 47.7, 39.8, 39.0, 34.3, 33.5, 26.5, 20.5,

18.5 (12-CH₃); MS (ES): C₂₄H₃₂N₂O₆calcd: 445.2339 [MþH]^þ;

found: 445.2357 [MþH]^þ.

(CH), 118.1 (CH), 111.4 (CH), 110.8 (C), 73.0 (C-11b), 55.6 (CH), 48.2

(CH₂), 45.6 (CH), 41.5 (CH₂), 40.7 (CH₂), 37.2 (CH₂). 35.4 (CH), 27.8

(CH₂), 22.9 (CH2), 18.1 (13-CH₃); MS (ES): C₂₀H₂₅N₃O calcd:

324.2076 [MþH]^þ; found: 324.2086 [MþH]^þ.

4.3.5. Compound 16e. White solid, 31.3 mg, 55%. HPLC (method A)

4.3. Compounds 16aeg. General procedure

t_R¼1.73 min; ¹H NMR (300 MHz, CDCl₃):

d 8.42 (br t,1H, NH), 7.33 (d,

J¼8.8 Hz,1H, H-10), 6.74 (dd, J¼8.7, 2.7 Hz,1H, H-9), 6.59 (d, J¼2.5 Hz,

Compound 8c (800 mg, 2.43 mmol) was dissolved in a mixture

of CH₂Cl₂(15 mL) and THF (5 mL) and 1.30 mL (0.156 mmol) of this

stock solution was aliquoted to seven glass vials. The appropriate

amine (0.20 mmol) was added to each vial, followed by 1.0 mL of

1H, H-7), 4.22e4.26 (m,1H, H-4b), 4.15e4.20 (m, 2H, a-CH₂), 3.77 (s,

3H, OMe), 3.24e3.28 (m, 1H), 3.15e3.20 (m, 1H), 2.70e2.77 (m, 3H),

2.50e2.54 (dd, J¼17.0, 7.7 Hz,1H), 2.25e2.33 (m, 1H), 2.09e2.20 (m,

1H), 1.97e2.20 (m, 3H), 1.80e1.85 (m, 1H), 1.08 (d, J¼6.3 Hz, 3H, 12-

a

stock solution prepared from 1-hydroxy-7-azabenzotriazole

CH₃); ¹³C NMR (75 MHz, CDCl₃):

d 173.6 (CO),173.5 (CO),158.3,141.6,

(1.22 g, 8.97 mmol), EDC (1.72 g, 8.97 mmol) and Et₃N (3.8 mL,

27.2 mmol) in dry CH₂Cl₂(45 mL). The vials were shaken at rt for

48 h. The mixtures were diluted with CH₂Cl₂and washed either

with satd aq NaCl solution or 10% aq HCl solution as appropriate.

After concentration under reduced pressure, the crude residues

were puriﬁed by C-18 RP-HPLC to give 16aeg in the yields

indicated.

135.7,127.9,116.7,116.5,111.9, 76.7 (C-10b), 59.0, 55.5, 52.2, 47.4, 39.7,

39.0, 34.4, 33.6, 27.6, 26.6,18.4 (12-CH₃); MS (ES): C₂₁H₂₅N₃O₃calcd:

368.1974 [MþH]^þ; found: 368.1997 [MþH]^þ.

4.3.6. Compound 16f. Oil, 54.5 mg, 69%. HPLC (method A)

t_R¼2.40 min; ¹H NMR (300 MHz, CDCl₃):

7.41 (d, J¼8.6 Hz, 1H, H-

d

10), 7.14e7.18 (m, 1H), 6.74 (dd, J¼8.5, 2.8 Hz, 1H, H-9), 6.57 (d,

256

D.A. Goff / Tetrahedron 69 (2013) 242e256

J¼2.8 Hz, H-7), 6.44e6.54 (m, 3H), 4.25e4.30 (m, 1H, H-4b), 3.79 (s,

3H, OMe), 3.76 (s, 3H, OMe), 3.70e4.00 (m, 4H), 3.46e3.52 (t,

J¼8.5 Hz, 1H), 3.11e3.20 (m, 6H), 2.65e2.75 (m, 3H), 2.46e2.57 (dd,

J¼17.0, 8.0 Hz, 1H), 2.27e2.34 (dd, J¼13.6, 7.3 Hz, 1H), 1.98e2.08 (m,

3H), 1.80e1.85 (m, 1H), 1.05 (d, J¼6.0 Hz, 3H, 12-CH₃); ¹³C NMR

References and notes

1. (a) Kumar, K.; Waldmann, H. Angew. Chem., Int. Ed. 2009, 48, 3224; (b) Galloway,

W. R. J. D.; Bender, A.; Welch, M.; Spring, D. R. Chem. Commun. 2009, 2446; (c)

Shaw, J. T. Nat. Prod. Rep. 2009, 26, 11; (d) Burke, M. D.; Schreiber, S. L. Angew.

Chem., Int. Ed. 2004, 43, 46; (e) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int.

Ed. 2008, 47, 48.

2. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.

3. Deprez-Poulain, R.; Willand, N.; Boutillon, C.; Nowogrocki, G.; Azaroual, N.;

Deprez, B. Tetrahedron Lett. 2004, 45, 5287; Jida, M.; Deprez-Poulain, R.;

Malaquin, S.; Roussel, P.; Agbossou-Niedercom, F.; Deprez, B.; Laconde, G. Green

Chem. 2010, 12, 961.

4. For an excellent review of acyl iminium chemistry see: Maryanoff, B. E.; Zhang,

H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431; For

selected recent examples see: (a) Holloway, C. A.; Muratore, M. E.; Storer, R. I.;

Dixon, D. J. Org. Lett. 2010, 12, 4720; (b) Tietze, L. F.; Tolle, N.; Kratzert, D.; Stalke,

D. Org. Lett. 2009, 11, 5230; (c) Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009,

48, 787; (d) Zhang, F.; Simpkins, N. S.; Blake, A. J. Org. Biomol. Chem. 2009, 7,

1963; (e) Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org. Lett. 2008, 10, 1577; (f)

Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129, 12070; (g) Rose,

M. D.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. J. Org. Chem. 2007, 72, 538;

(h) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601; (i) Padwa, A.; Lee, H. I.;

Rashatasakhon, P.; Rose, M. J. Org. Chem. 2004, 69, 8209.

5. Reviews: (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New

York, NY, 2001; (b) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017; (c) Ballini,

R.; Barboni, L.; Fringuelli, F.; Palmieri, A.; Pizzo, F.; Vaccaro, L. Green Chem. 2007,

9, 823.

6. Indole alkaloids and G-protein-coupled receptors: Rodrigues de Sa Alves, F.;

Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem. 2009, 9, 782.

7. For recent diversity-oriented syntheses of aza-spirocycles see: (a) Santra, S.;

Andeana, P. R. Angew. Chem., Int. Ed. 2011, 50, 9418; (b) Gu, P.; Zhao, Y.-M.; Tu, Y.

Q.; Ma, Y.; Zhang, F. Org. Lett. 2006, 8, 5271.

(75 MHz, CDCl₃):

d 173.4 (CO), 172.1 (CO), 160.9, 158.2, 152.2, 141.8,

136.3, 130.2, 128.1, 116.5, 111.8, 109.5, 105.7, 103.4, 76.3 (C-10b), 55.5,

55.4, 53.4, 52.7, 50.4, 49.9, 47.6, 46.1, 42.5, 41.0, 38.9, 34.6, 33.7, 26.7,

18.7 (12-CH₃); MS (ES): C₃₀H₃₇N₃O₄calcd: 504.2862 [MþH]^þ;

found: 504.2820 [MþH]^þ.

4.3.7. Compound 16g. White solid, 42.5 mg, 60%. HPLC (method A)

€

t_R¼2.24 min; ¹H NMR (300 MHz, CDCl₃):

7.34 (d, J¼8.8 Hz, 1H, H-

d

ꢀ

10), 6.71 (dd, J¼8.8, 2.6 Hz,1H, H-9), 6.57 (d, J¼2.9 Hz,1H, H-7), 6.49

(d, J¼8.3 Hz, 1H, NH), 4.63e4.70 (m, 1H, H-

a), 4.23e4.31 (m, 1H, H-

4b), 3.76 (s, 3H), 3.74 (s, 3H), 3.28e3.35 (m, 1H), 3.06e3.15 (m, 1H),

2.67e2.77 (m, 3H), 2.45e2.54 (dd, J¼17.0, 7.7 Hz, 1H), 2.23e2.30

(dd, J¼13.6, 8.1 Hz, 1H), 2.09e2.19 (m, 1H), 1.51e1.70 (m, 3H),

1.95e2.06 (m, 3H), 1.80e1.84 (m, 1H), 1.10 (d, J¼6.6 Hz, 3H, 12-CH₃),

0.93 (d, J¼6.0 Hz, 6H, CH(CH₃)₂); ¹³C NMR (75 MHz, CDCl₃):

d 173.6

(CO), 173.2 (CO), 172.9 (CO), 158.2, 141.8, 136.2, 127.9, 116.6, 111.7,

76.2 (C-10b), 59.8, 55.4, 52.5, 51.9, 51.1, 47.5, 41.5, 39.9, 38.8, 34.3,

33.7, 26.7, 25.2, 23.1, 21.9, 18.4 (12-CH₃); MS (ES): C₂₆H₃₆N₂O₅calcd:

457.2702 [MþH]^þ; found: 457.2693 [MþH]^þ.

8. Heathcock, C. H.; Davidsen, S. K.; Mills, S. G.; Sanner, M. A. J. Org. Chem. 1992, 57,

2531.

9. (a) Tsuda, Y.; Sakai, Y.; Nakai, A.; Kaneko, M.; Ishiguro, Y.; Isobe, K.; Kimiaki, T.;

Taga, J.; Sano, T. Chem. Pharm. Bull. 1990, 38, 1462; (b) Tsuda, Y.; Sakai, Y.;

Kaneko, M.; Ishiguro, Y.; Isobe, K.; Taga, J.; Sano, T. Heterocycles 1981, 15, 431.

10. Reimann, E.; Ettmayr, C. Monatsh. Chem. 2004, 135, 959.

5. Crystal structure data

Crystallographic data (excluding structure factors) for the

structures in this paper have been deposited with the Cambridge

Crystallographic Data Centre as supplementary publications

896741 (4c), 896742 (8a), 896743 (4a), and 896744 (9c). Copies of

the data can be obtained, free of charge, on application to CCDC, 12

Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or

e-mail: deposit@ccdc.cam.ac.UK).

11. Reviews: (a) Reimann, E. Prog. Chem. Org. Nat. Prod. 2007, 88, 1; (b) Bentley, K.

W. Nat. Prod. Rep. 2004, 21, 395.

12. Acyl iminium ion cyclizations conducted under mild conditions typically are

under kinetic control and the initially formed product does not equilibrate

under the reaction conditions. See Ref. 4.

13. Review: Bick, I.; Panichanun, S. In Alkaloids: Chemical and Biological Perspec-

tives; Pelletier, S. W., Ed.; Springer: New York, NY, 1991; Vol. 7, pp 1e41.

14. Mineno, T.; Miller, M. J. J. Org. Chem. 2003, 68, 6591.

15. We did not attempt to generate the aldehyde directly from the nitromethyl

group since our attempts to oxidize other compounds derived from 1 with

KMnO₄or buffered TiCl₃were not very successful

16. Leogane, O.; Lebel, H. Org. Synth. 2009, 86, 113.

17. Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 105.

18. Basel, Y.; Hassner, A. Synthesis 1997, 309.

Acknowledgements

ꢀ

ꢁ

We would like to thank Mark Irving, Duayne Tokushige, and

Vanessa Nguyen for help with HPLC analysis and puriﬁcation, Dr.

Rajinder Singh for his support of this work and Dr. Simon Shaw and

Prof. Martin Burke, Univ. of Illinois Champaign-Urbana for their

useful comments. X-ray crystallography was performed by Dr. Peter

S. White at the University of North CarolinadChapel Hill.

19. In Ref. 4a Dixon et al. report the synthesis of the core ring system of 12 from 2-

oxocyclopentane acetic acid.

20. Bajwa, S.; Chen, G.-P.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron Lett.

ꢂ

2006, 47, 6425.

21. Xu, Y. In Annual Reports in Medicinal Chemistry; Macor, J. E., Ed.; Elsevier: 2011;

Vol. 46, pp 69e87.

22. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.

2001, 46, 3.

23. The Lipinski and log P values were calculated using Accelrys RS³software (www.

accelyrys.com). For a discussion of optimal log P parameters see: Ryckmans, T.;

Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.; Thompson, L. R.; Tran, I.;

Tutt, M. F.; Young, T. Bioorg. Med. Chem. Lett. 2009, 19, 4406.

24. Montgomery, J. A.; Niwas, S.; Rose, J. D.; Secrist, J. A., III; Babu, Y. S.; Bugg, C. E.;

Erion, M. D.; Guida, W. C.; Ealick, S. E. J. Med. Chem. 1993, 36, 55.

25. Loegers, M.; Overman, L. E.; Weimaker, G. S. J. Am. Chem. Soc. 1995, 117, 9139.

26. Kuehne, M. E.; Cowen, S. D.; Xu, F.; Borman, L. S. J. Org. Chem. 2001, 66, 5303.

Supplementary data

¹H and ¹³C NMR spectra. Supplementary data associated with

this article can be found in the online version, at http://dx.doi.org/

10.1016/j.tet.2012.10.038.

Article Doi

Diverse alkaloid-like structures from a common building block

DOI: 10.1016/j.tet.2012.10.038

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2012.10.038

Full text of DOI:10.1016/j.tet.2012.10.038

Products guided by the article

R&D Labs maybe for 1415684-15-9

Relevant to this article

Hot Product