Establishment of substituent effects in the DNA binding subunit of CBI analogues of the duocarmycins and CC-1065

Bioorganic & Medicinal Chemistry 11 (2003) 3815–3838

Establishment of Substituent Eﬀects in the DNA Binding Subunit

of CBI Analogues of the Duocarmycins and CC-1065

Jay P. Parrish, David B. Kastrinsky, Frederic Stauﬀer, Michael P. Hedrick,

Inkyu Hwang and Dale L. Boger*

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,

10550 North Torrey Pines Road, La Jolla, CA 92037, USA

Received 5 February 2003; accepted 26 March 2003

Abstract—An extensive series of CBI analogues of the duocarmycins and CC-1065 exploring substituent eﬀects within the ﬁrst

indole DNA binding subunit is detailed. In general, substitution at the indole C5 position led to cytotoxic potency enhancements

that can be ꢀ1000-fold providing simpliﬁed analogues containing a single DNA binding subunit that are more potent (IC₅₀=2–3 pM)

than CBI-TMI, duocarmycin SA, or CC-1065.

Introduction

and the alkylation subunit^21ꢁ24have been shown to

have a pronounced eﬀect on the rate and eﬃciency of

DNA alkylation and the resulting biological potency of

the compounds. These eﬀects proved to be independent

of the electronic properties of the substituent and their

inherent eﬀects on reactivity, but could be attributed to

their simple presence and the fact that they extend the

rigid length of the agent. In doing so, they increase the

extent of the DNA binding-induced conformational

CC-1065 (1),¹duocarmycin A (2)²and duocarmycin SA

(3)³constitute the parent members of a class of potent

antitumor antibiotics⁴that derive their properties

through a sequence-selective alkylation of duplex DNA,

Figure 1.^5ꢁ10Recent studies have established that the

catalysis of the DNA alkylation reaction is derived from

a DNA binding-induced conformational change in the

agents which activate them for nucleophilic attack.^11ꢁ16

This conformational change twists the amide linking the

alkylation subunit and attached DNA binding domain

which disrupts the cross-conjugated vinylogous amide

stabilization of the alkylation subunit activating the

cyclopropane for nucleophilic attack. This ground-state

destabilization of the cyclopropane upon DNA binding

is consistent with the proposal that the DNA alkylation

sequence selectivity originates in the noncovalent bind-

ing selectivity of the agents.⁵

Recent studies have indicated that the role of attached

DNA binding domain goes beyond that of simply pro-

viding DNA binding aﬃnity and selectivity, but that it

contributes to and is largely responsible for the DNA

alkylation catalysis.^11ꢁ19Minor groove bound sub-

stituents on both the ﬁrst DNA binding subunit^14ꢁ20

*Corresponding author. Tel.: +1-858-784-7522; fax: +1-858-784-

7550; e-mail: boger@scripps.edu

Figure 1.

doi:10.1016/S0968-0896(03)00194-9

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J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

change, increase the degree of vinylogous amide dis-

ruption, and increase the rate of DNA alkylation.

parent ring system that has been extensively employed,

extended, or modiﬁed in both our work and that of

many others.^{17ꢁ24,30ꢁ60}

For example, the contribution of each of the three

methoxy groups of 5,6,7-trimethoxyindole (TMI) was

established using the DNA alkylation subunits DSA¹⁵

and CPI.²³These studies demonstrated the predominant

importance of the C5 methoxy substituent, which alone

provided a fully active agent, with little or no contri-

bution derived from the C6 and C7 methoxy groups.

Moreover, the cytotoxic potency of these agents nicely

correlated with their DNA alkylation rate and eﬃ-

ciency. The conclusion being that the agents bearing a

C5 methoxy substituent were more eﬀective and that

this was due tothe extended rigid length provided by

the minor groove bound substituent. Subsequently, this

was found to be consistent with the high resolution

NMR structures of (+)-duocarmycin SA²⁵and its

derivative DSI (DSA-indole),²⁶lacking the three meth-

oxy groups, bound to DNA which conﬁrmed that the

presence of C5 methoxy group increased the twist in the

DNA bound agent.²⁷Moreover, the C5 methoxy group

of 3 is found deeply embedded in the minor groove with

methyl group extending into, not away from, the minor

groove ﬂoor, potentially beneﬁting from hydrophobic

contacts (Fig. 2).

Synthesis

The compounds were prepared as shown in Scheme 1.

The non-commercially available indole-2-carboxylic

acids were obtained from the corresponding azido cin-

namates derived from condensation of substituted

benzaldehydes with methyl a-azidoacetate. The azido-

cinnamates were subjected tothe Hemetsberger reac-

tion⁶¹followed by saponiﬁcation of the esters to provide

the substituted indole-2-carboxylic acids. Acid-cata-

lyzed deprotection of seco-N-BOC-CBI (natural or

unnatural enantiomer) followed by coupling of the

resulting hydrochloride salt with the indole-2-carboxylic

acids (3 equiv EDCI, DMF, 25 ^ꢂC, 14 h) in the absence

of added base provided the seco agents.³¹Spirocycliza-

tion was eﬀected by treatment with DBU⁴²or NaH³¹

providing 6B–78B. In the case of 77–78, both enantio-

mers of the compounds were examined, whereas in the

case of 6–76 only the more potent natural enantiomers

were examined.

Despite these studies and reports of limited series of

agents,^28ꢁ30no systematic examination of the DNA

binding subunit C5 substituent has been disclosed. Fol-

lowing observations made in our recent preliminary

study,¹⁹and utilizing the CBI alkylation subunit (1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one),^30ꢁ32herein

we describe an extensive library of nearly 80 derivatives

designed toestablish the impact of substituents placed

on the ﬁrst DNA binding subunit. The CBI subunit was

chosen for the present study because it represents the

synthetically most accessible simpliﬁed alkylation sub-

unit in the series,³⁵exhibits a potency and eﬃcacy that

surpasses that found in 1 and 2 while approaching that

of 3,³¹exhibits stability and reaction regioselectivity

characteristics that are near optimal,³²and constitutes a

Results and Discussion

The comparison compounds for examining the eﬀects of

the indole substituents of the CBI analogues of duo-

carmycin SA (3) are CBI-TMI (4)³⁷and CBI-indole (5,

Table 1). The former contains the 5,6,7-trimethoxy

substituents of duocarmycin SA (3) while the latter

incorporates the parent unsubstituted indole. (+)-CBI-

TMI (4) was found to be nearly 100-fold more potent

than (+)-CBI-indole (5) with the 5,6,7-trimethoxy-

indole substitution increasing the L1210 cytotoxic

potency 90 times. This eﬀect of the 5,6,7-trimethoxy

substitution is analogous, but more pronounced, than

the 6–10-fold eﬀect observed with duocarmycin SA¹⁵

and CPI-TMI.²³

The comparisons in Table 2 detail the systematic

approach taken to establish the eﬀects of the individual

methoxy groups found on the indole. Although the

CBI-based agents proved to be more sensitive to

the removal of the TMI subunit methoxy groups than

Figure 2. Front and groove view of the ¹H NMR derived solution

structure of (+)-duocarmycin SA bound to a high aﬃnity alkylation

site within d(GACTAATTGAC)-d(GTCAATTAGTC) highlighting

the minor groove embedded indole C5 methoxy group (ref. 25).

Scheme 1.

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3817

Table 1. Cytotoxic activity, L1210 (IC₅₀, pM)

of the eﬀects was the relatively potent behavior of 6.

Although it was 16–17-fold less active than CBI-TMI, it

was 4-fold more active than CBI-indole despite the

methoxy substitution at C4. A similar eﬀect is seen with

the dimethoxy derivatives 11 (C5,6 OMe), 12 (C6,7

OMe), and 13 (C5,7 OMe) where the potency of 11

(C5,6 OMe) and 13 (C5,7 OMe) were not distinguish-

able from that of 7 (C5 OMe) being only 1.0–1.3-fold

from that of CBI-TMI, whereas 12 (C6,7 OMe) exhib-

ited a more signiﬁcant 6.6-fold reduction being essen-

tially equivalent to the C6 or C7 monomethoxy

derivatives 8 and 9. Clearly, the C5 position is the most

important site potentiating the cytotoxic activity (C5

OMe>C6 OMeꢀC7 OMe>C4 OMe>H), and addi-

tional methoxy substitutions act in a more modest, but

predictably additive manner. Interestingly, the C4,5

dimethoxy derivative 10 was much less active.

Compd

IC₅₀, pM

(+)-duocarmycin SA

(+)-CC-1065

(+)-duocarmycin A

(+)-CBI-TMI

(+)-CBI-indole

3

1

2

4

5

6–10

20

200

30

2700

Table 2. Ether and thioether substituted indole derivatives

The eﬀect of additional ether and thioether substituted

indoles is also summarized in Table 2. Alterations in the

C5 methoxy group providing longer, ﬂexible, and more

hydrophobic alkyl ethers (15–18) had little eﬀect on the

cytotoxic potency although a signiﬁcant and optimal

additional 5-fold increase was observed with the C5

ethoxy derivative (15, IC₅₀=10 pM), and a 4-fold

reduction in potency was observed with the corres-

ponding C5 free phenol 14 versus C5 methyl ether.

Notably, the triﬂuoromethyl ether series with substitu-

tions at the C5 and C7 positions revealed a possible

deleterious eﬀect derived from ﬂuorine substitution on

the substituents that lie embedded in the minor groove.

A substantial decrease of 2-fold in cytotoxic activity was

seen with the C5 OCF₃group relative to 7 (C5 OMe),

whereas the C7 OCF₃substitution proved essentially

equivalent with 9 (C7 OMe). A thioether series provided

similar observations. The derivative bearing a C5 thio-

methyl group had the same cytotoxic activity as the

corresponding C5 OCH₃derivative (IC₅₀=50 pM).

Likewise, the C7 thiomethyl group was an order of

magnitude less potent and comparable in activity to 9

(C7 OMe). Interestingly, the C5 thioethyl derivative did

not exhibt the increased potency found with 15.

R

Compd

Yield A, B (%)

IC₅₀, pM^a

4-OMe

5-OMe

6-OMe

7-OMe

4,5-OMe

5,6-OMe

6,7-OMe

5,7-OMe

5-OH

6A,B

7A,B

8A,B

47, 92

75, 73

53, 98

52, 94

48, 35

61, 82

43, 65

55, 98

43^b

54, 94

63, 70

46, 88

31, 91

53^b

500

50

300

>1000

30

200

40

200

10

40

50

100

400

50

600

70

9A,B

10A,B

11A,B

12A,B

13A,B

14A

15A,B

16A,B

17A,B

18A,B

19A

5-OEt

5-OPr

5-OBu

5-OBn

5-OCF₃

7-OCF₃

5-SMe

7-SMe

5-SEt

20A

65^b

39, 56

55, 74

62, 82

21A,B

22A,B

23A,B

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

^bPrepared and examined as the A seco derivative only.

As a consequence of these observations, a wide range of

C5 indole substituents were examined. Many of these

are summarized in Table 3 and those that provided the

most potent derivatives or that were examined as a

comparison series are summarized in subsequent tables.

Although no single generalization is easily discerned

from the comparisons summarized in Table 3, some

important trends emerge that are discussed in more

detail with the subsequent series. Addition of a single

heavy atom substituent typically resulted in a modest

1.3–40ꢃ increase in potency which diminishes as the size

of the substituent increased (potency: OH=

NH₂>Cl>Br>Me), unsaturated C5 substituents

proved more potent than the corresponding saturated

counterparts (potency: CꢄCH=CH=CH₂>Et) con-

sistent with restrictions on the optimal size of the C5

substiuent, extension of the rigid length of the unsatu-

rated C5 substiuents smoothly follows the trend

0<1<2>3 heavy atoms, and branching at the site of

C5 attachment with a small hydrophobic group may

the DSA- or CPI-based agents, analogous trends were

observed. When the cytotoxic potency of CBI-TMI (4,

IC₅₀=30 pM)^9,37was compared with the methoxy series

6 (C4 OMe), 7 (C5 OMe), 8 (C6 OMe), 9 (C7 OMe),

decreases of 17ꢃ, 1.6ꢃ, 10ꢃ, and 10ꢃ, respectively,

were observed. Thus, maintenance of the C5 methoxy

group with removal of the C6 and C7 methoxy groups

with analogue 7 maintained the cytotoxic potency,

whereas its removal in 8 and 9 led toa ꢀ10ꢃ reduction

in activity. Similar, but less pronounced, reductions in

potency with the removal of the TMI methoxy sub-

stituents were observed with duocarmycin SA (6.5–10ꢃ)

and CPI (7ꢃ). In the case of duocarmycin SA, the C7

methoxy substituent did not provide a contribution to

cytotoxic potency and that of the C6 methoxy group

was modest, whereas with CBI (7 vs 8 and 9) both the

C7 and C6 methoxy group were found to improve

potency signiﬁcantly, but not nearly of the magnitude

observed with the C5 methoxy group. Most surprising

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J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

Table 3. Substituted indole derivatives

and substitution found in the potent derivatives con-

taining more than one DNA binding subunit (e.g., CBI

indole₂and 1), but Lown has reported signiﬁcant eﬀects

of such amides within a select set of (+)-CPI-N-

methylpyrrole agents constituting hybrid stuructures of

CPI linked with the DNA binding subunits of dis-

tamycin.⁶²Notably the amide derivatives 44–47 proved

to be potent cytotoxic agents (IC₅₀=30 pM) being

slightly more potent than 7 (C5 OMe, IC₅₀=50 pM)

and equivalent with (+)-CBI-TMI (IC₅₀=30 pM) even

though they contain a single C5 substituent. This

activity was invariant within the range of the amides

examined (44=45=46), and was unaﬀected by

N-methylation (44=47) indicating H-bonding plays no

role in their activity. Notably, this series did not exhibit

the trends detailed by Lown for the CPI-pyrrole con-

jugates (NHCOPr>NHCOEt>NHCOMe). Most likely,

this may be attributed to the intrinsically poorer prop-

erties of the CPI–pyrrole conjugates^18,62reported by

Lown and the greater inﬂuence such amide substituents

may have.

R

Compd

Yield A, B (%)

IC₅₀, pM^a

5-H

5A,B

7A,B

57, 93

75, 73

53, 87

44, 61

53, 85

44, 87

56, 38

74, 77

60, 84

70, 21

35, 62

54, 65

41, 88

51, 66

64^b

2700

50

2000

400

2000

500

400

300

30

300

200

500

150

3500

300

5-OMe

5-Me

5-Et

5-CH₂OCH₃

7-CH₂OCH₃

5-Br

5-Cl

5-N₃

5-CN

7-CN

5-Vinyl

7-Vinyl

5-Isopropenyl

7-Isopropenyl

5-CꢄCH

5-CꢄCMe

4-Ph

24A,B

25A,B

26A,B

27A,B

28A,B

29A,B

30A,B

31A,B

32A,B

33A,B

34A,B

35A,B

36A

37A,B

38A,B

39A

33, 87

33, 79

40^b

Interestingly, and analogous to observations made

within the C5 alkoxy series (7, 14, and 15), the C5

aminoderivative 40 was 5-fold more potent than CBI-

indole and the corresponding C5 dimethylamino or

diethylaminoderivatives 41 and 42 were 12–15ꢃ more

potent than 40. The latter twoderivatives ( 41 and 42)

were equipotent with 7, the C5 methoxy derivative.

1000

400,000

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

^bPrepared and examined as the A seco derivative only.

increase potency (MeC=CH₂>HC=CH₂). In each case,

a C5 substituent was more potent than the corres-

ponding C7 substituent, and the impact of the C5 sub-

stituent on potency appears to be related simply to its

presence and shape characteristics while being relatively

independent of its electronic properties (e.g.,

OMe=CN). Most noteworthy in this series is the

potency of the simple nitrile 31 (IC₅₀=30 pM) which is

equivalent with CBI-TMI and slightly more potent than

7 (C5 OMe, IC₅₀=50 pM).

An interesting and perhaps unprecedented series that

was examined exploring the 5, 6, and 7-nitroindoles is

summarized in Table 5. Consistent with the trends

exhibited with the methoxy substitution pattern

(C5>C6>C7; Table 2),^15,23the smooth trend of

49>50>51 was observed. The distinction being that

each was more potent than the corresponding methoxy

derivative with 49 (C5 NO₂, IC₅₀=20 pM) not only

surpassing the potency of 7 (C5 OMe, IC₅₀=50 pM)

but also surpassing the potency of even (+)-CBI-TMI

(4, IC₅₀=30 pM). Nonetheless, the relatively small dis-

tinction between the strongly electron-withdrawing NO₂

versus electron-donating OMe substituent (C5=2.5ꢃ,

C6=5ꢃ, C7=1.5ꢃ) suggest electronic eﬀects⁶³modu-

lated through the indole ring may attenuate activity but

only to minor extent.

An important series examined early in the studies was

the amine and amide derivatives of 5-aminoindole, Table

4. Not only does this represent the linking functionality

Table 4. Amide substituted indole derivatives

Table 5. Nitrosubstituted indole derivatives

R

Compd

Yield A, B (%)

IC₅₀, pM^a

5-NH₂

5-NMe₂

5-NEt₂

5-NHBoc

5-NHCOMe

5-NHCOEt

5-NHCOPr

5-N(Me)COMe

5-N(Et)COMe

40A,B

41A

42A

87, 85

23^b

600

40

50

80

30

80

20^b

43A

55^b

R

Compd

Yield A, B (%)

IC₅₀, pM^a

44A,B

45A,B

46A,B

47A,B

48A

27, 76

30, 68

44, 99

48, 95

39^b

5-NO₂

6-NO₂

7-NO₂

49A

50A

51A

49^b

82^b

29^b

20

60

200

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

^bPrepared and examined as the A seco derivative only.

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

^bPrepared and examined as the A seco derivative only.

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3819

One of the most interesting series that was explored in

detail and that provided exceptionally potent derivatives

was the C5 indole derivatives bearing a carbonyl group

directly attached tothe indloe ( Table 6). Most sig-

niﬁcant of the observations was the behavior of the C5

acyl derivatives 54 and 56. A 1000-fold increase in

potency over (+)-CBI-indole (5) was observed with 54

and 56 representing an additional ꢀ10-fold increase in

potency beyond most C5 substituted derivatives descri-

bed above. Analogues 54 and 56 are exceptionally

potent cytotoxic compounds (IC₅₀=2–3 pM) exceeding

the activity of CBI-TMI (4, 30 pM), CC-1065 (1, 20

pM), and duocarmycin SA (3, 6–10 pM). Interestingly,

the analogue 57 containing a propyl chain reverted to

the potency characteristic of the C5 substituted analo-

gues (IC₅₀=20 pM), and did not show the further

enhancement observed with 54 and 56. As discussed

later, this may reﬂect the adoption of a DNA bound

conformation for 54 and 56 analogous to the angular

fusion of a 5-membered ring (see Fig. 3) with the methyl

or ethyl group of 54 and 56 deeply embedded in the

minor groove. This bound conformation would not be

accessible to 57 because of the extended chain length

and its behavior reverts back to that of an extended,

ﬂexible C5 substituent. The analogous, but less pro-

nounced, enhancement observed with 58 and 60 may

reﬂect a similar behavior. Notably, the methyl group of

the C5 methoxy substituent of duocarmycin SA has

been shown to extend into and be deeply embedded in

the minor groove^25ꢁ27consistent with such a bound

conformation (Fig. 2).

Figure 3.

potency reﬂecting the less hydrophobic character of the

interacting group. Finally, the corresponding carbox-

amide C5 derivatives 61–63, especially 61 and 62, were

potent derivatives and it is tempting to suggest the

enhanced potency of 62 beneﬁts from a similar minor

groove interaction. Notably, 62 was only 5-fold less

potent than 54 and 3-fold more potent than (+)-CBI-

TMI also placing it among the more potent derivatives

examined.

In an interesting extension of these observations, the

sulfone derivatives 64 and 65 were examined, Table 7.

Like 54, the C5 methanesulfonyl derivative 64 proved

exceptionally potent (IC₅₀=3 pM) being 15–20 fold

more active than the corresponding thiomethyl deriva-

tive 21 (IC₅₀=50 pM) or methoxy derivative 7

(IC₅₀=50 pM) and exceeding the activity of even 1–5.

Unlike 56, the corresponding ethanesulfonyl derivative,

while being a potent cytotoxic agent (IC₅₀=40 pM), did

not exhibit this exceptional activity, and was only

slightly more active than the corresponding thioethyl

derivative 23 (IC₅₀=100 pM). This may reﬂect the lar-

ger size of S with 64, no t65, exhibiting shape charac-

teristics closer to the potent ethyl ketone 54, and

uniquely beneﬁting from the embedded minor groove

interactions within the sulfone series.

Consistent with this special role for the methyl and ethyl

groups of 54, 56, 58, and 60, the C5 formyl analogue 52,

which would not beneﬁt from such an interaction,

proved to be 50-fold less potent. Although the corres-

ponding ester derivatives 58 and 60 were signiﬁcantly

less potent with 58>60, the former, but not the latter,

may beneﬁt from an analogous minor groove embedded

methoxy versus precluded ethoxy group with the weaker

As a consequence of these observations, we became

interested in re-examining tricyclic DNA binding sub-

units that bear structural characteristics of the potent

indole derivatives disclosed herein. In prior studies, we

had already disclosed (+)-CBI-CDPI₁(68) embodying

the structural characteristics of the DNA binding sub-

unit of CC-1065 and had shown that it was an excep-

tionally potent, simpliﬁed derivative (IC₅₀=5 pM).²¹It

contains a fused ﬁve-membered ring that may be regar-

ded as a conformationally restricted and more rigid

analogue of 44–48. The results of our examination of

Table 6. Carbonyl substituted indole derivatives

R

Compd

Yield A, B (%)

IC₅₀, pM^a

Table 7. Sulfone substituted indole derivatives

5-CHO

7-CHO

5-COMe

7-COMe

5-COEt

52A

53A,B

54A,B

55A,B

56A,B

57A,B

58A

59A

60A

61A

62A

39^b

20, 48

66, 77

57, 77

63, 46

64, 31

50^b

100

500

2

300

3

20

50

300

200

20

5-COPr

5-COOMe

7-COOMe

5-COOEt

5-CONH₂

5-CONHMe

5-CONMe₂

53^b

50^b

R

Compd

Yield A, B (%)

IC₅₀, pM^a

47^b

30^b

10

40

5-SO₂Me

5-SO₂Et

64A

65A

38^b

71^b

3

40

63A

45^b

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

^bPrepared and examined as the A seco derivative only.

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

^bPrepared and examined as the A seco derivative only.

3820

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

such alternative tricyclic systems that represent rigid or

conformationally restricted analogues of the potent

derivatives are summarized in Table 8. The cyclic struc-

tures representing substitutions at the 4,5 positions were

expected tobe superior tothe 5,6 analogues due totheir

ability to adopt a conformation embodying the embed-

ded minor groove substituent. Where examined, the

4,5-isomer was more potent than the corresponding

5,6-isomer (72 vs 73 and 74 vs 75), and introduction of

unsaturation resulted in rather dramatic losses in activ-

ity (>10-fold, 66 vs 69 and 70 vs 71). Most importantly,

the 4,5 constrained analogues (but not the 5,6 con-

strained analogues) typically matched or exceeded the

potency of the corresponding unconstrained analogue.

For example, 72, but not 73, matched the potency of the

C5 substituted methyl and ethyl ketones 54 and 56.

Similarly, 70 was slightly more potent than 7 (C5 OMe)

and only slightly less potent than 15 (C5 OEt). Both

CDPI and 67 were more potent than their correspond-

ing C5 amine or amide derivatives (40–48, IC₅₀=30–80

pM), and the fused cyclopentyl derivative 76 was more

active than the corresponding C5 alkyl derivatives 24

and 25 (IC₅₀=2000 pM). Analogously, 74 was much

more active than the corresponding unconstrained 4,5

dimethoxy derivative 10 whereas the 5,6 isomer 75 was

substantially less potent than the corresponding uncon-

strained C5,6 dimethoxy derivative 11. Moreover, there

was a pronounced diﬀerence in the relative potency of

the constrained 4,5-derivatives that follows the trends

observed with the analogous C5 substituent (–COR>

–NCOR> –OR, –NR₂>–R where R=alkyl). Impor-

tantly, this series provided some of the most potent

derivatives of CBI being 6–8-fold more potent than

CBI-TMI (IC₅₀=30 pM) and ꢀ10-fold more potent

than 5 (IC₅₀=50 pM) and surpassing the activity of CC-

1065 (IC₅₀=20 pM) and duocarmycin SA (IC₅₀=6–10

pM).

As shown in Table 9, extending the rigid length of the

DNA binding indole by adding a linear or angular fused

benzene ring did not substantially alter the cytotoxic

potency. The linear extension with (+)-78 resulted in a

modest 5-fold increase in potency whereas the angular

extension with (+)-77 resulted in a modest 2-fold

reduction when compared to (+)-CBI-indole (R=H)

and a more signiﬁcant 6–8-fold reduction relative to the

fused pyrrole 69 or the fused furan 71. Consistent with

expectations and past observations, the corresponding

unnatural enantiomers (ꢁ)-77 and (ꢁ)-78 were found to

be approximately 100–1000ꢃ less potent. The behavior

of the angular derivatives (+)-77 and (ꢁ)-77 is espe-

cially striking in comparison with CBI-CDPI (68) and

the related analogues in Table 8 which bear an angular

fused saturated 5-membered ring. Presumably the

increased sized and planar nature of the angularly fused

benzene ring found in (+)-77 and (ꢁ)-77 hinders rather

than facilitates minor groove binding and penetration

required to observe DNA alkylation.

Table 8. Tricyclic indole derivatives

DNA alkylation selectivity, eﬃciency, and rate

Although a number of features of 6–78 can contribute

to distinctions observed in a cellular functional assay for

cytotoxic activity, the most prominent feature that we

probed was the impact that the indole substituent had

on the DNA alkylation properties. Thus, the DNA

alkylation selectivity, eﬃciency, and rate of the simplest

and most potent derivatives 54 and 64 were compared

toduocarmycin SA ( 3), (+)-CBI-TMI (4), (+)-CBI-

indole (5), and 7 in w794 DNA enlisting protocols pre-

viously introduced in our studies.⁶⁴First, noalterations

in the inherent DNA alkylation selectivity were

observed with the new derivatives 54 and 64 consistent

Table 9.

R

Compd

Yield A, B (%) IC₅₀, pM^a

4,5-CH₂CH₂NH

4,5-CH₂CH₂NCOOtBu

4,5-CH₂CH₂NCONH₂68A,B (CDPI₁)

4,5-CHCHNH–

4,5-CH₂CH₂O–

4,5-CHCHO–

4,5-CH₂CH₂CO–

5,6-COCH₂CH₂–

4,5-OCH₂O–

66A

67A

100^b

77^b

86, 74

14^b

53, 69

45, 55

62^b

46^b

57^b

50^c

6

5²¹

800

40

69A

70A,B

71A,B

72A

73A

74A

600

4

50

90

R

Compd

Yield (%)

IC₅₀, pM^a

(+)-CBI-benz[e]indole

(ꢁ)-CBI-benz[e]indole

(+)-CBI-benz[f]indole

(ꢁ)-CBI-benz[f]indole

(+)-77A,B

(ꢁ)-77A,B

(+)-78A,B

(ꢁ)-78A,B

31

45

20

41

5000

3ꢃ10⁵

500

5,6-OCH₂O–

4,5-(CH₂)₃–

75A,B

76A,B

42, 77

62, 92

600

500

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

^bPrepared and examined as the A seco derivative only.

^cUnstable, rapidly oxidizes to 69A.

4ꢃ10⁵

^aL1210 cytotoxic activity, average of 2–7 determinations run in triplicate.

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3821

eﬀect is largely insensitive to the electronic character of

the C5 substituent but is sensitive tothe size, rigid

length, and shape (sp, sp², sp³hybridization) of this

substituent consistent with expectation that the impact

is due simply toits presence. With these substitutions,

simpliﬁed CBI analogues were identiﬁed which surpass

the potency of duocarmycin SA, CC-1065, and CBI-

TMI. The comparison of these derivatives with a select

set of conformationally constrained tricyclic indole

derivatives suggest they additionally beneﬁt from

hydrophobic contacts in a pocket deeply imbedded in

the minor groove. Thus, an indole C5 substituent may

not only extend the rigid length of the compound

enhancing the DNA binding induced disruption of the

alkylation subunit vinylogous amide thereby accelerat-

ing the rate of DNA alkylation, but appropriate sub-

stituents may also beneﬁt from stabilizing contacts

within a minor groove hydrophobic pocket.

Experimental

General procedure for the synthesis of the seco agents:

A solution of the natural enantiomer of seco-N-Boc-

CBI (2.5 mg, 7.5 mmol) in 1 mL of 4 M HCl (EtOAc)

was stirred for 1 h at 25 ^ꢂC. The solvent was then

removed under a stream of N₂. The residue was dried

under high vacuum for 3 h and the indole-2-carboxylic

acid⁶⁶(8.3 mmol) was added. A solution of EDCI (22.5

mmol) in 200 mL DMF was added and the reaction

mixture was stirred for 14 h at 25 ^ꢂC. The reaction mix-

ture was then diluted with CH₂Cl₂(1 mL) and the sol-

vent was removed under a stream of N₂. The product

was puriﬁed by preparative TLC (10ꢃ20 cm, CH₂Cl₂/

acetone 1:1 or THF/hexane 1:1 to 3:1).

Figure 4. w794 DNA alkylation (24 h, 23 ^ꢂC).⁶⁵

Table 10. DNA alkylation properties^a

Compd

Rel. Eﬃciency

Rel. Rate

3 (DSA)

2.0

1.0

0.1

0.95

4.0

7.0

(1.1–1.2)^b

1.0

0.1

4 (CBI–TMI)

5 (CBI–Indole)

7 (C5 OMe)

54 (C5 COMe)

64 (C5 SO₂CH₃)

1.0

2.0

2.5

^aw794 DNA,⁶⁴following a procedure detailed in ref. 37.

^bTaken from ref. 37.

3-(4-Methoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (6A). (1.44 mg,

1

47%) as an oﬀ-white solid: [a]²_D³+33 (c 0.2, THF); H

NMR (acetone-d₆, 500 MHz) d 10.84 (1H, br s), 9.23

(1H, s), 8.25 (1H, d, J=8.6 Hz), 8.10 (1H, br s), 7.90

(1H, d, J=8.6 Hz), 7.55 (1H, ddd, J=8.4, 6.9, 1.4

Hz), 7.39 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 7.17–7.24

(3H, m), 6.59 (1H, dd, J=7.5, 1.1 Hz), 4.87 (1H, dd,

J=10.5, 8.8 Hz), 4.80 (1H, dd, J=10.7, 2.6 Hz),

4.30–4.34 (1H, m), 4.11 (1H, dd, J=11.1, 3.0 Hz),

3.97 (3H, s), 3.86 (1H, dd, J=11.1, 8.1 Hz); MAL-

DIFT-HRMS m/z 407.1162 (M+H⁺, C₂₃H₂₀ClN₂O₃

requires 407.1157).

with past observations now entailing a wide range of

CBI-based analogues (e.g., CBI-TMI vs duocarmycin

SA).^8,37More importantly, the CBI analogues displayed

signiﬁcant distinctions in both their eﬃciencies in DNA

alkylation (Fig. 4 and Table 10) and their rates of DNA

alkylation (Table 10) that proved to correlate with the

relative and absolute trends observed in their cytotoxic

potency. Thus, in the case of the simpliﬁed and excep-

tionally potent derivatives 54 and 64, their enhanced

cytotoxic potency correlates with an enhanced rate and

eﬃciency of DNA alkylation.

3-(5-Methoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (7A). (2.30 mg,

75%) as a white solid: [a]²_D³+14 (c 0.13, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.71 (1H, br s), 9.23

(1H, s), 8.25 (1H, d, J=8.6 Hz), 8.08 (1H, br s), 7.89

(1H, d, J=8.5 Hz), 7.55 (1H, ddd, J=8.1, 6.8, 1.3 Hz),

7.49 (1H, d, J=9.0 Hz), 7.39 (1H, ddd, J=8.1, 6.8, 1.3

Hz), 7.19–7.20 (1H, m), 7.16 (1H, dd, J=2.1, 0.9 Hz),

6.96 (1H, dd, J=9.0, 2.6 Hz), 4.83 (1H, dd, J=10.9, 8.3

Hz), 4.79 (1H, dd, J=10.9, 2.4 Hz), 4.34–4.38 (1H, m),

4.08 (1H, dd, J=11.1, 3.0 Hz), 3.84 (3H, s), 3.81 (1H,

dd, J=11.1, 8.6 Hz); MALDIFT-HRMS m/z 406.1070

(M⁺, C₂₃H₁₉ClN₂O₃requires 406.1084).

Conclusion

C5 substituents on the ﬁrst indole DNA binding subunit

have a pronounced eﬀect on the activity of CBI ana-

logues of the duocarmycins and CC-1065. This eﬀect,

which provides as large as a 1000-fold increase in cyto-

toxic potency with 54 and 64 that correlate well with

accompanying increases in the rate and eﬃciency of

DNA alkylation, is more pronounced with the CBI

versus DSA or CPI based analogues. Moreover, this

3822

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3-(6-Methoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (8A). (1.63 mg,

53%) as a pale yellow solid: [a]²_D³ꢁ45 (c 0.07, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.67 (1H, br s), 9.25

(1H, s), 8.25 (1H, d, J=8.5 Hz), 8.10 (1H, br s), 7.89

(1H, d, J=8.5 Hz), 7.61 (1H, d, J=8.6 Hz), 7.55 (1H,

ddd, J=8.1, 6.8, 1.3 Hz), 7.39 (1H, ddd, J=8.2, 6.9, 1.2

Hz), 7.20 (1H, m), 7.08 (1H, d, J=2.1 Hz), 6.79 (1H,

dd, J=8.8, 2.3 Hz), 4.82 (1H, dd, J=10.5, 8.8 Hz), 4.77

(1H, dd, J=10.7, 2.6 Hz), 4.27–4.31 (1H, m), 4.08 (1H,

dd, J=11.1, 3.4 Hz), 3.84 (3H, s), 3.82 (1H, dd, J=11.5,

8.6 Hz); MALDIFT-HRMS m/z 406.1093 (M⁺,

C₂₃H₁₉ClN₂O₃requires 406.1079).

J=10.6, 9.0 Hz), 4.74 (1H, dd, J=10.9, 2.4 Hz), 4.25–

4.30 (1H, m), 4.07 (1H, dd, J=11.1, 2.6 Hz), 3.97 (3H,

s), 3.93 (3H, s), 3.81 (1H, dd, J=11.1, 8.6 Hz); MAL-

DIFT-HRMS m/z 437.1271 (M+H⁺, C₂₄H₂₂ClN₂O₄

requires 437.1263).

3-(5,7-Dimethoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (13A). (1.81 mg,

1

55%) as an oﬀ-white solid: [a]²_D³+11 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 10.20 (1H, br s), 9.29

(1H, s), 8.25 (1H, d, J=8.6 Hz), 8.04 (1H, br s), 7.88

(1H, d, J=8.6 Hz), 7.55 (1H, ddd, J=8.4, 6.9, 1.4 Hz),

7.39 (1H, ddd, J=8.3, 6.8, 1.3 Hz), 7.12 (1H, d, J=2.1

Hz), 6.76 (1H, d, J=1.7 Hz), 6.47 (1H, d, J=1.7 Hz),

4.80 (1H, dd, J=10.7, 8.6 Hz), 4.74 (1H, dd, J=10.9,

2.4 Hz), 4.25–4.29 (1H, m), 4.07 (1H, dd, J=11.1, 3.0

Hz), 3.96 (3H, s), 3.92 (3H, s), 3.80 (1H, dd, J=11.5, 9.0

Hz); MALDIFT-HRMS m/z 437.1259 (M+H⁺,

C₂₄H₂₂ClN₂O₄requires 437.1263).

3-(7-Methoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (9A). (1.59 mg,

1

52%) as a pale yellow solid: [a]²_D³+1 (c 0.2, THF); H

NMR (acetone-d₆, 500 MHz) d 11.27 (1H, br s), 9.25

(1H, s), 8.26 (1H, d, J=8.6 Hz), 8.06 (1H, br s), 7.89

(1H, d, J=8.6 Hz), 7.55 (1H, ddd, J=8.1, 6.8, 1.3 Hz),

7.40 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 7.31 (1H, d, J=8.1

Hz), 7.22 (1H, d, J=2.6 Hz), 7.06 (1H, t, J=7.9 Hz),

6.82 (1H, d, J=7.7 Hz), 4.82 (1H, dd, J=10.7, 8.5 Hz),

4.76 (1H, dd, J=10.7, 2.1 Hz), 4.26–4.31 (1H, m), 4.08

(1H, dd, J=11.1, 3.0 Hz), 3.99 (3H, s), 3.82 (1H, dd,

J=11.5, 8.5 Hz); MALDIFT-HRMS m/z 407.1170

(M+H⁺, C₂₃H₁₉ClN₂O₂requires 407.1157).

3-(5-Hydroxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (14A). (1.27 mg,

1

43%) as an oﬀ-white solid: [a]²_D³+11 (c 0.06, THF); H

NMR (acetone-d₆, 500 MHz) d 10.63 (1H, br s), 9.26

(1H, s), 8.25 (1H, d, J=8.1 Hz), 8.07 (1H, br s), 7.92

(1H, s), 7.89 (1H, d, J=8.6 Hz), 7.55 (1H, ddd, J=8.4,

6.9, 1.4 Hz), 7.43 (1H, d, J=8.6 Hz), 7.39 (1H, ddd,

J=8.2, 6.9, 1.2 Hz), 7.10 (1H, d, J=2.6 Hz), 7.08 (1H,

m), 6.91 (1H, dd, J=9.0, 2.1 Hz), 4.82 (1H, dd, J=11.1,

8.6 Hz), 4.77 (1H, dd, J=10.7, 2.6 Hz), 4.26–4.30 (1H,

m), 4.07 (1H, d, J=10.7, 2.6 Hz), 3.82 (1H, dd, J=11.3,

8.8 Hz); MALDIFT-HRMS m/z 393.0997 (M+H⁺,

C₂₂H₁₈ClN₂O₃requires 393.1000).

3-(4,5-Dimethoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (10A). (1.9 mg,

1

48%) as a white solid: [a]²_D³+43 (c 0.03, acetone); H

NMR (CDCl₃, 600 MHz) d 10.76 (1H, br s), 9.26 (1H,

s), 8.24 (1H, d, J=8.3 Hz), 8.08 (1H, s), 7.90 (1H, d,

J=8.2 Hz), 7.55 (1H, t, J=7.0 Hz), 7.40 (1H, t, J=7.5

Hz), 7.25 (1H, d, J=8.8 Hz), 7.22 (1H, s), 7.11 (1H, d,

J=8.8 Hz), 4.86 (1H, t, J=9.8 Hz), 4.79 (1H, d,

J=10.5 Hz), 4.30 (1H, m), 4.07 (1H, dd, J=8.3, 3.1

Hz), 4.03 (3H, s), 3.87 (3H, s), 3.84 (1H, m); IR (ﬁlm)

n_max3749, 1684 1558, 1506 cm^ꢁ1, MALDIFT-HRMS

m/z 437.1276 (M+H⁺, C₂₄H₂₁ClN₂O₄requires

437.1263).

3-(5-Ethoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (15A). (1.71 mg,

54%) as a white solid: [a]²_D³+19 (c 0.1, THF); ¹H NMR

(acetone-d₆, 500 MHz) d 10.70 (1H, br s), 9.22 (1H, s),

8.25 (1H, d, J=8.5 Hz), 8.08 (1H, br s), 7.89 (1H, d,

J=8.1 Hz), 7.55 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 7.49

(1H, d, J=9.0 Hz), 7.39 (1H, ddd, J=8.3, 7.1, 1.1 Hz),

7.18 (1H, d, J=2.6 Hz), 7.15 (1H, dd, J=2.1, 0.9 Hz),

6.95 (1H, dd, J=9.0, 2.6 Hz), 4.83 (1H, dd, J=10.7, 8.6

Hz), 4.78 (1H, dd, J=10.7, 2.6 Hz), 4.26–4.31 (1H, m),

4.08 (2H, q, J=7.0 Hz), 4.07–4.08 (1H, m), 3.81 (1H,

dd, J=11.1, 8.5 Hz), 1.40 (3H, t, J=7.1 Hz); MAL-

DIFT-HRMS m/z 421.1295 (M+H⁺, C₂₄H₂₂ClN₂O₃

requires 421.1313).

3-(5,6-Dimethoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (11A). (2.01 mg,

1

61%) as a pale yellow solid: [a]²_D³+11 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 10.60 (1H, br s), 9.25

(1H, s), 8.25 (1H, d, J=8.5 Hz), 8.11 (1H, br s), 7.88

(1H, d, J=8.1 Hz), 7.54 (1H, ddd, J=8.4, 6.9, 1.4 Hz),

7.38 (1H, ddd, J=8.1, 6.8, 1.1 Hz), 7.18 (1H, s), 7.14

(1H, dd, J=2.1, 0.9 Hz), 7.10 (1H, s), 4.81 (1H, dd,

J=10.7, 8.5 Hz), 4.76 (1H, dd, J=10.7, 2.6 Hz), 4.26–

4.30 (1H, m), 4.07 (1H, dd, J=11.1, 3.0 Hz), 3.84 (6H,

s), 3.80 (1H, dd, J=11.1, 9.0 Hz); MALDIFT-HRMS

m/z 436.1179 (M⁺, C₂₄H₂₁ClN₂O₄requires 436.1184).

3-(5-Propyloxyindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (16A). (2.06 mg,

63%) as a beige solid: [a]²_D³+10 (c 0.2, THF); ¹H NMR

(acetone-d₆, 500 MHz) d 10.70 (1H, br s), 9.22 (1H, s),

8.25 (1H, d, J=8.1 Hz), 8.08 (1H, br s), 7.89 (1H, d,

J=8.6 Hz), 7.55 (1H, ddd, J=8.3, 6.8, 1.3 Hz), 7.49

(1H, d, J=9.0 Hz), 7.39 (1H, ddd, J=8.3, 6.8, 1.3 Hz),

7.19 (1H, d, J=2.6 Hz), 7.15 (1H, m), 6.97 (1H, dd,

J=8.8, 2.4 Hz), 4.83 (1H, dd, J=10.7, 8.6 Hz), 4.78

(1H, dd, J=11.1, 2.7 Hz), 4.26–4.31 (1H, m), 4.08 (1H,

dd, J=10.7, 3.0 Hz), 3.99 (2H, t, J=6.4 Hz), 3.81 (1H,

dd, J=11.1, 8.6 Hz), 1.78–1.85 (2H, m), 1.06 (3H, t,

J=7.5 Hz); MALDIFT-HRMS m/z 434.1404 (M⁺,

C₂₅H₂₃ClN₂O₃requires 434.1397).

3-(6,7-Dimethoxyindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (12A). (1.41 mg,

1

43%) as a pale yellow solid: [a]²_D³+9 (c 0.07, THF); H

NMR (acetone-d₆, 500 MHz) d 10.27 (1H, br s), 9.29

(1H, s), 8.25 (1H, d, J=8.6 Hz), 8.06 (1H, br s), 7.89

(1H, d, J=8.6 Hz), 7.55 (1H, m), 7.41 (1H, d, J=8.1

Hz), 7.39 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 7.20 (1H, d,

J=2.6 Hz), 6.99 (1H, d, J=8.6 Hz), 4.81 (1H, dd,

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3823

3-(5-Butyloxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (17A). (1.53 mg,

46%) as a beige solid: [a]²_D³+20 (c 0.1, THF); ¹H NMR

(acetone-d₆, 500 MHz) d 10.70 (1H, br s), 9.23 (1H, s),

8.25 (1H, d, J=8.5 Hz), 8.08 (1H, br s), 7.89 (1H, d,

J=8.1 Hz), 7.55 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.49

(1H, d, J=9.0 Hz), 7.39 (1H, ddd, J=8.2, 6.9, 1.2 Hz),

7.19 (1H, d, J=2.1 Hz), 7.15 (1H, dd, J=2.1, 0.9 Hz),

6.96 (1H, dd, J=8.8, 2.4 Hz), 4.83 (1H, dd, J=10.7, 8.1

Hz), 4.78 (1H, dd, J=11.1, 2.6 Hz), 4.26–4.31 (1H, m),

4.07 (1H, dd, J=11.1, 3.4 Hz), 4.03 (2H, t, J=6.3 Hz),

3.81 (1H, dd, J=11.1, 9.0 Hz), 1.76–1.81 (2H, m), 1.50–

1.57 (2H, m), 0.99 (3H, t, J=7.5 Hz); MALDIFT-

HRMS m/z 449.1611 (M+H⁺, C₂₆H₂₆ClN₂O₃requires

449.1626).

(1H, d, J=8.1 Hz), 7.71 (1H, m), 7.56 (1H, d, J=9.0

Hz), 7.56 (1H, ddd, J=8.1, 6.8, 1.3 Hz), 7.40 (1H, ddd,

J=8.3, 6.9, 1.3 Hz), 7.30 (1H, dd, J=8.6, 1.7 Hz), 7.21

(1H, d, J=2.1 Hz), 4.85 (1H, dd, J=10.7, 8.6 Hz), 4.79

(1H, dd, J=10.9, 2.4 Hz), 4.27–4.32 (1H, m), 4.08 (1H,

dd, J=11.1, 3.0 Hz), 3.83 (1H, dd, J=11.1, 8.6 Hz),

2.52 (3H, s); MALDIFT-HRMS m/z 422.0845 (M⁺,

C₂₃H₁₉ClN₂O₂S requires 422.0850).

3-(7-Thiomethylindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (22A). (1.74 mg,

1

55%) as a yellow solid: [a]²_D³ꢁ19 (c 0.08, THF); H

NMR (acetone-d₆, 500 MHz) d 10.11 (1H, br s), 9.34

(1H, s), 8.26 (1H, d, J=8.1 Hz), 8.06 (1H, br s), 7.90

(1H, d, J=8.1 Hz), 7.66 (1H, d, J=7.7 Hz), 7.56 (1H,

ddd, J=8.1, 6.8, 1.3 Hz), 7.41 (1H, ddd, J=8.2, 6.9, 1.2

Hz), 7.36 (1H, dd, J=7.5, 1.1 Hz), 7.31 (1H, d, J=2.1

Hz), 7.16 (1H, t, J=7.7 Hz), 4.84 (1H, t, J=9.6 Hz),

4.76 (1H, dd, J=10.7, 2.1 Hz), 4.27–4.31 (1H, m), 4.07

(1H, dd, J=11.1, 3.0 Hz), 3.83 (1H, dd, J=11.1, 8.5

Hz), 2.58 (3H, s); MALDIFT-HRMS m/z 422.0855

(M⁺, C₂₃H₁₉ClN₂O₂S requires 422.0850).

3-(5-Benzyloxyindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (18A). (1.12 mg,

31%) as a white solid: [a]²_D³+36 (c 0.06, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.74 (1H, br s), 9.23

(1H, s), 8.25 (1H, d, J=8.1 Hz), 8.08 (1H, br s), 7.89

(1H, d, J=8.6 Hz), 7.55 (1H, ddd, J=8.1, 6.8, 1.3 Hz),

7.51–7.54 (3H, m), 7.38–7.42 (3H, m), 7.31–7.35 (1H,

m), 7.29 (1H, d, J=2.6 Hz), 7.16 (1H, dd, J=2.1, 0.9

Hz), 7.06 (1H, dd, J=8.8, 2.2 Hz), 5.17 (2H, s), 4.82

(1H, dd, J=10.7, 8.6 Hz), 4.78 (1H, dd, J=10.7, 2.6

Hz), 4.26–4.31 (1H, m), 4.07 (1H, dd, J=11.1, 3.4 Hz),

3.81 (1H, dd, J=11.1, 8.6 Hz); MALDIFT-HRMS m/z

483.1466 (M+H⁺, C₂₉H₂₄ClN₂O₃requires 483.1470).

3-(5-Thioethylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (23A). (2.02 mg,

1

62%) as a pale yellow solid: [a]²_D³+8 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 10.95 (1H, br s), 9.27

(1H, s), 8.25 (1H, d, J=7.7 Hz), 8.09 (1H, br s), 7.90

(1H, dd, J=7.3, 0.9 Hz), 7.82 (1H, m), 7.57 (1H, dt,

J=8.5, 0.9 Hz), 7.55 (1H, ddd, J=8.4, 7.0, 1.3 Hz), 7.40

(1H, ddd, J=8.3, 6.8, 1.3 Hz), 7.36 (1H, dd, J=8.6, 1.7

Hz), 7.23 (1H, dd, J=2.1, 0.9 Hz), 4.85 (1H, dd,

J=10.5, 8.8 Hz), 4.79 (1H, dd, J=10.7, 2.1 Hz), 4.28–

4.32 (1H, m), 4.08 (1H, dd, J=11.1, 3.4 Hz), 3.83 (1H,

dd, J=11.1, 8.6 Hz), 2.93 (2H, q, J=7.3 Hz), 1.25 (3H,

t, J=7.3 Hz); MALDIFT-HRMS m/z 437.1086

(M+H⁺, C₂₄H₂₂ClN₂O₂S requires 437.1085).

3-(5-Triﬂuoromethoxyindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (19A).

(1.83 mg, 53%) as a beige solid: [a]²_D³+9 (c 0.1, THF);

¹H NMR (acetone-d₆, 500 MHz) d 11.13 (1H, br s), 9.29

(1H, s), 8.26 (1H, d, J=8.1 Hz), 8.08 (1H, br s), 7.90

(1H, d, J=8.1 Hz), 7.72 (1H, m), 7.69 (1H, d, J=9.0

Hz), 7.56 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.41 (1H, ddd,

J=8.4, 6.9, 1.4 Hz), 7.35 (1H, d, J=1.3 Hz), 7.26 (1H,

m), 4.86 (1H, dd, J=10.7, 9.0 Hz), 4.80 (1H, dd,

J=10.7, 2.1 Hz), 4.29–4.33 (1H, m), 4.08 (1H, dd,

J=11.1, 3.0 Hz), 3.84 (1H, dd, J=11.1, 8.6 Hz); ¹⁹F

NMR (acetone-d₆, 376 MHz) d ꢁ57.5; ESI (negative) m/

z 459 (MꢁH^ꢁ, C₂₃H₁₅ClF₃N₂O₃).

3-(Indole-2-carbonyl)-1-(S)-(chloromethyl)-5-hydroxy-

1,2-dihydro-3H-benz[e]indole (5A, CBI-indole). (1.53

1

mg, 57%) as a white solid: [a]²_D³+10 (c 0.08, THF); H

NMR (acetone-d₆, 500 MHz) d 10.83 (1H, br s), 9.24

(1H, s), 8.25 (1H, d, J=8.3 Hz), 8.09 (1H, br s), 7.89

(1H, d, J=8.3 Hz), 7.74 (1H, d, J=8.3 Hz), 7.60 (1H,

dd, J=8.2, 0.9 Hz), 7.55 (1H, ddd, J=8.3, 6.9, 1.4 Hz),

7.40 (1H, ddd, J=8.3, 6.9, 1.4 Hz), 7.29 (1H, ddd,

J=8.3, 6.9, 1.4 Hz), 7.26 (1H, dd, J=2.3, 0.9 Hz), 7.12

(1H, ddd, J=7.8, 6.9, 0.9 Hz), 4.86 (1H, dd, J=10.8, 8.5

Hz), 4.80 (1H, dd, J=10.7, 2.5 Hz), 4.27–4.32 (1H, m),

4.08 (1H, dd, J=11.0, 3.2 Hz), 3.83 (1H, dd, J=11.2,

8.5 Hz); MALDIFT-HRMS m/z 376.0987 (M⁺,

C₂₂H₁₇ClN₂O₂requires 376.0978).

3-(7-Triﬂuoromethoxyindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (20A).

(2.26 mg, 65%) as a pale yellow solid: [a]²_D³ꢁ7 (c 0.1,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.26 (1H, br

s), 9.32 (1H, s), 8.26 (1H, d, J=7.7 Hz), 8.04 (1H, br s),

7.90 (1H, m), 7.77 (1H, dd, J=8.1, 0.9 Hz), 7.56 (1H,

ddd, J=8.1, 6.8, 1.3 Hz), 7.41 (1H, ddd, J=8.2, 6.9, 1.2

Hz), 7.37 (1H, s), 7.30 (1H, m), 7.20 (1H, t, J=7.9), 4.85

(1H, t, J=9.8 Hz), 4.76 (1H, dd, J=10.9, 1.9 Hz), 4.26–

4.31 (1H, m), 4.07 (1H, dd, J=10.9, 3.2 Hz), 3.83 (1H,

dd, J=11.1, 8.5 Hz); ¹⁹F NMR (acetone-d₆, 376 MHz) d

ꢁ57.4; MALDIFT-HRMS m/z 460.0799 (M⁺,

C₂₃H₁₆ClF₃N₂O₃requires 460.0796).

3-(5-Methylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (24A). (1.55 mg,

1

53%) as a white solid: [a]²_D³+6 (c 0.1, THF); H NMR

(acetone-d₆, 500 MHz) d 10.71 (1H, br s), 9.23 (1H, s),

8.25 (1H, d, J=8.6 Hz), 8.08 (1H, br s), 7.89 (1H, d,

J=8.6 Hz), 7.55 (1H, ddd, J=8.1, 6.8, 1.3 Hz), 7.51

(1H, s), 7.48 (1H, d, J=6.5 Hz), 7.39 (1H, ddd, J=8.2,

6.9, 1.2 Hz), 7.16 (1H, dd, J=2.1, 0.9 Hz), 7.13 (1H, dd,

J=8.1, 1.7 Hz), 4.83 (1H, dd, J=10.7, 8.6 Hz), 4.78

(1H, dd, J=10.7, 2.6 Hz), 4.26–4.30 (1H, m), 4.07 (1H,

3-(5-Thiomethylindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (21A). (1.23 mg,

1

39%) as a yellow solid: [a]²_D³+28 (c 0.05, THF); H

NMR (acetone-d₆, 500 MHz) d 10.92 (1H, br s), 9.28

(1H, s), 8.25 (1H, d, J=7.7 Hz), 8.08 (1H, br s), 7.90

3824

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

dd, J=10.9, 3.2 Hz), 3.82 (1H, dd, J=11.3, 8.8 Hz),

2.42 (3H, s); MALDIFT-HRMS m/z 390.1149 (M⁺,

C₂₃H₁₉ClN₂O₂requires 390.1135).

NMR (acetone-d₆, 500 MHz) d 11.04 (1H, br s), 9.26

(1H, s), 8.26 (1H, d, J=8.5 Hz), 8.07 (1H, br s), 7.89

(1H, d, J=8.6 Hz), 7.76–7.77 (1H, m), 7.61 (1H, d,

J=9.0 Hz), 7.56 (1H, ddd, J=8.6, 6.8, 1.3 Hz), 7.40

(1H, ddd, J=8.1, 6.8, 1.3 Hz), 7.28 (1H, dd, J=8.6, 2.1

Hz), 7.25 (1H, dd, J=2.1, 0.9 Hz), 4.84 (1H, dd,

J=10.5, 8.8 Hz), 4.78 (1H, dd, J=10.7, 2.1 Hz), 4.28–

4.32 (1H, m), 4.08 (1H, dd, J=11.5, 3.0 Hz), 3.83 (1H,

dd, J=11.1, 8.6 Hz); MALDIFT-HRMS m/z 410.0594

(M⁺, C₂₂H₁₆Cl₂N₂O₂requires 410.0583).

3-(5-Ethylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (25A). (1.35 mg,

44%) as a beige solid: [a]²_D³+20 (c 0.07, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.74 (1H, br s), 9.26

(1H, s), 8.25 (1H, d, J=8.1 Hz), 8.08 (1H, br s), 7.89

(1H, d, J=8.5 Hz), 7.55 (1H, ddd, J=8.1, 6.8, 1.3 Hz),

7.54 (1H, m), 7.51 (1H, d, J=8.1 Hz), 7.39 (1H, ddd,

J=8.2, 6.9, 1.2 Hz), 7.17–7.19 (2H, m), 4.84 (1H, dd,

J=10.7, 9.0 Hz), 4.79 (1H, dd, J=10.7, 2.1 Hz), 4.27–

4.31 (1H, m), 4.08 (1H, dd, J=11.3, 3.2 Hz), 3.82 (1H,

dd, J=11.1, 8.6 Hz), 2.74 (2H, q, J=7.7 Hz), 1.27 (3H,

t, J=7.5 Hz); MALDIFT-HRMS m/z 405.1359

(M+H⁺, C₂₄H₂₂ClN₂O₂requires 405.1364).

3-(5-Azidoindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (30A). (1.88 mg,

60%) as a beige solid: [a]²_D³+30 (c 0.07, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.98 (1H, br s), 9.26

(1H, s), 8.26 (1H, d, J=8.1 Hz), 8.08 (1H, br s), 7.89

(1H, m), 7. 65 (1H, d, J=9.0 Hz), 7.56 (1H, ddd, J=8.1,

6.8, 1.3 Hz), 7.47 (1H, d, J=2.1 Hz), 7.40 (1H, ddd,

J=8.1, 6.8, 1.3 Hz), 7.25–7.26 (1H, m), 7.04 (1H, dd,

J=9.0, 2.1 Hz), 4.85 (1H, dd, J=10.7, 8.6 Hz), 4.79

(1H, dd, J=10.7, 2.1 Hz), 4.28–4.23 (1H, m), 4.08 (1H,

dd, J=11.3, 3.2 Hz), 3.83 (1H, dd, J=11.1, 8.6 Hz); MS

(ESI negative) m/z 416 (MꢁH^ꢁ).

3-(5-Methoxymethylindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (26A).

(1.66 mg, 53%) as a beige solid: [a]²_D³+3 (c 0.08,

1

THF); H NMR (acetone-d₆, 500 MHz) d 10.87 (1H, br

s), 9.26 (1H, s), 8.25 (1H, d, J=8.5 Hz), 8.08 (1H, br s),

7.89 (1H, d, J=8.1 Hz), 7.69 (1H, s), 7.57 (1H, d, J=7.7

Hz), 7.55 (1H, ddd, J=8.3, 6.8, 1.4 Hz), 7.40 (1H, ddd,

J=8.1, 7.1, 1.1 Hz), 7.30 (1H, dd, J=8.3, 1.5 Hz), 7.25

(1H, m), 4.85 (1H, dd, J=10.7, 9.0 Hz), 4.80 (1H, dd,

J=10.7, 2.1 Hz), 4.52 (2H, s), 4.27–4.32 (1H, m), 4.08

(1H, dd, J=11.3, 3.2 Hz), 3.83 (1H, dd, J=11.1, 8.6

Hz), 3.33 (3H, s); MALDIFT-HRMS m/z 421.1332

(M+H⁺, C₂₄H₂₂ClN₂O₃requires 421.1313).

3-(5-Cyanoindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (31A). (2.12 mg,

70%) as a beige solid: [a]²_D³+38 (c 0.08, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 11.38 (1H, br s), 9.27

(1H, s), 8.24–8.27 (2H, m), 8.08 (1H, br s), 7.91 (1H, d,

J=8.1 Hz), 7.77 (1H, d, J=8.6 Hz), 7.58 (1H, dd,

J=8.6, 1.7 Hz), 7.57 (1H, ddd, J=8.6, 6.8, 1.3 Hz),

7.39–7.43 (2H, m), 4.88 (1H, m), 4.80 (1H, dd, J=10.7,

2.1 Hz), 4.30–4.35 (1H, m), 4.08 (1H, dd, J=11.3, 3.2

Hz), 3.85 (1H, dd, J=11.1, 8.6 Hz); MALDIFT-

HRMS m/z 401.0927 (M⁺, C₂₃H₁₆ClN₃O₂requires

401.0931).

3-(7-Methoxymethylindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (27A).

(1.40 mg, 44%) as a pale yellow solid: [a]²_D³ꢁ9 (c 0.07,

1

THF); H NMR (acetone-d₆, 500 MHz) d 10.21 (1H, br

s), 9.30 (1H, s), 8.26 (1H, d, J=8.1 Hz), 8.09 (1H, br s),

7.90 (1H, d, J=8.1 Hz), 7.70 (1H, d, J=8.1 Hz), 7.56

(1H, ddd, J=8.5, 7.0, 1.4 Hz), 7.40 (1H, ddd, J=8.2,

6.9, 1.2 Hz), 7.28 (1H, d, J=2.6 Hz), 7.24 (1H, dd,

J=6.8, 0.8 Hz), 7.11 (1H, dd, J=8.1, 7.3 Hz), 4.88 (2H,

m), 4.85 (1H, dd, J=10.5, 9.2 Hz), 4.79 (1H, dd,

J=10.9, 2.4 Hz), 4.28–4.32 (1H, m), 4.08 (1H, dd,

J=11.1, 3.0 Hz), 3.83 (1H, dd, J=11.1, 8.6 Hz), 3.43

(3H, s); MALDIFT-HRMS m/z 420.1255 (M⁺,

C₂₄H₂₁ClN₂O₃requires 420.1235).

3-(7-Cyanoindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (32A). (1.04 mg,

1

35%) as a yellow solid: [a]²_D³ꢁ12 (c 0.05, THF); H

NMR (acetone-d₆, 500 MHz) d 11.36 (1H, br s), 9.28

(1H, s), 8.26 (1H, d, J=8.1 Hz), 8.12 (1H, dd, J=7.4,

1.1 Hz), 8.04 (1H, br s), 7.90 (1H, d, J=8.6 Hz), 7.76

(1H, dd, J=7.5, 1.1 Hz), 7.56 (1H, ddd, J=8.3, 7.1, 1.3

Hz), 7.42–7.43 (1H, m), 7.41 (1H, ddd, J=8.2, 6.9, 1.2

Hz), 7.32 (1H, t, J=7.7 Hz), 4.85 (1H, t, J=9.6 Hz),

4.76 (1H, dd, J=10.7, 2.1 Hz), 4.27–4.32 (1H, m), 4.07

(1H, dd, J=11.3, 3.2 Hz), 3.83 (1H, dd, J=11.1, 8.6

Hz); MALDIFT-HRMS m/z 402.1017 (M+H⁺,

C₂₃H₁₇ClN₃O₂requires 402.1004).

3-(5-Bromoindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (28A). (1.90 mg,

56%) as a beige solid: [a]²_D³+39 (c 0.06, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 11.05 (1H, br s), 9.25

(1H, s), 8.26 (1H, d, J=8.6 Hz), 8.06 (1H, br s), 7.93

(1H, m), 7.90 (1H, d, J=8.1 Hz), 7.57 (1H, d, J=8.6

Hz), 7.54–7.58 (1H, m), 7.41 (1H, ddd, J=8.6, 6.8, 1.1

Hz), 7.40 (1H, dd, J=8.8, 1.9 Hz), 7.25 (1H, dd, J=2.2,

0.9 Hz), 4.84 (1H, t, J=10.8 Hz), 4.78 (1H, dd, J=10.7,

2.1 Hz), 4.28–4.32 (1H, m), 4.08 (1H, dd, J=11.3, 3.2 Hz),

3.83 (1H, dd, J=11.1, 8.5 Hz); MALDIFT-HRMS m/z

454.0085 (M⁺, C₂₂H₁₆BrClN₂O₂requires 454.0084).

3-(5-Vinylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (33A). (1.62 mg,

54%) as a pale yellow solid: [a]²_D³+33 (c 0.08, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.91 (1H, br s), 9.27

(1H, s), 8.25 (1H, d, J=8.5 Hz), 8.08 (1H, br s), 7.90

(1H, d, J=8.6 Hz), 7.76 (1H, m), 7.57 (1H, d, J=8.6

Hz), 7.56 (1H, dd, J=8.1, 1.3 Hz), 7.52 (1H, td, J=8.3,

1.3 Hz), 7.40 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 7.25 (1H,

dd, J=2.1, 0.9 Hz), 6.86 (1H, dd, J=17.5, 10.7 Hz),

5.75 (1H, dd, J=17.5, 0.9 Hz), 5.14 (1H, dd, J=10.9,

1.1 Hz), 4.85 (1H, dd, J=10.9, 8.8 Hz), 4.79 (1H, dd,

J=10.9, 2.4), 4.28–4.32 (1H, m), 4.08 (1H, dd, J=11.1,

3-(5-Chloroindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (29A). (2.28 mg,

74%) as a beige solid: [a]²_D³+22 (c 0.13, THF); ¹H

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3825

3.0 Hz), 3.83 (1H, dd, J=11.1, 8.6 Hz); MALDIFT-

HRMS m/z 403.1220 (M+H⁺, C₂₄H₂₀ClN₂O₂requires

403.1208).

3-[5-(1-Propynyl)indole-2-carbonyl]-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (38A). (1.02 mg,

33%) as a beige solid: [a]²_D³+39 (c 0.07, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.96 (1H, br s), 9.24

(1H, s), 8.25 (1H, d, J=8.4 Hz), 8.07 (1H, br s), 7.89

(1H, d, J=8.4 Hz), 7.79 (1H, s), 7.54–7.57 (2H, m), 7.40

(1H, ddd, J=8.4, 6.4, 1.1 Hz), 7.29 (1H, dd, J=8.6, 1.7

Hz), 7.24 (1H, m), 4.85 (1H, dd, J=9.6, 8.8 Hz), 4.78

(1H, dd, J=9.6, 2.2 Hz), 4.28–4.32 (1H, m), 4.08 (1H,

dd, J=11.4, 3.3 Hz), 3.83 (1H, dd, J=11.4, 8.4 Hz),

2.03 (3H, s); MALDIFT-HRMS m/z 415.1203

(M+H⁺, C₂₅H₂₀ClN₂O₂requires 415.1208).

3-(7 - Vinylindole - 2 - carbonyl) -1 -(S)-(chloromethyl) - 5-

hydroxy-1,2-dihydro-3H-benz[e]indole (34A). (1.24 mg,

41%) as a pale yellow solid: [a]²_D³ꢁ12 (c 0.07, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.56 (1H, br s), 9.31

(1H, s), 8.26 (1H, d, J=8.1 Hz), 8.07 (1H, br s), 7.90

(1H, d, J=8.1 Hz), 7.69 (1H, d, J=7.7 Hz), 7.56 (1H,

ddd, J=8.4, 6.9, 1.4 Hz), 7.54 (1H, d, J=7.3 Hz), 7.49

(1H, dd, J=17.5, 11.1 Hz), 7.40 (1H, ddd, J=8.2, 6.9,

1.2 Hz), 7.28 (1H, d, J=2.1 Hz), 7.16 (1H, t, J=7.7

Hz), 5.96 (1H, dd, J=17.5, 0.9 Hz), 5.41 (1H, dd,

J=11.1, 1.3 Hz), 4.85 (1H, dd, J=10.9, 8.8 Hz), 4.77

(1H, dd, J=10.7, 2.1 Hz), 4.27–4.31 (1H, m), 4.07 (1H,

dd, J=11.3, 3.2 Hz), 3.82 (1H, dd, J=11.1, 8.1 Hz); ESI

(positive) m/z 425 (M+Na⁺, C₂₄H₁₉ClN₂NaO₂), 403

(M+H⁺, C₂₄H₂₀ClN₂O₂); ESI (negative) m/z 401

(MꢁH^ꢁ, C₂₄H₁₈ClN₂O₂).

3-(4-Phenylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (39A). (1.42 mg,

1

42%) as an oﬀ-white solid: [a]²_D³+93 (c 0.07, THF); H

NMR (acetone-d₆, 500 MHz) d 11.05 (1H, br s), 9.28

(1H, s), 8.25 (1H, d, J=8.1 Hz), 8.07 (1H, br s), 7.88

(1H, d, J=8.6 Hz), 7.75–7.77 (2H, m), 7.62 (1H, m),

7.52–7.56 (3H, m), 7.38–7.56 (3H, m), 7.35 (1H, m), 7.22

(1H, dd, J=7.3, 0.9 Hz), 4.82 (1H, t, J=9.6 Hz), 4.75

(1H, dd, J=10.9, 2.4 Hz), 4.24–4.28 (1H, m), 4.05 (1H,

dd, J=11.1, 3.4 Hz), 3.82 (1H, dd, J=11.1, 8.6 Hz);

MALDIFT-HRMS m/z 452.1288 (M⁺, C₂₈H₂₁ClN₂O₂

requires 452.1286).

3-(5-Isopropenylindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (35A). (1.58 mg,

1

51%) as a yellow solid: [a]²_D³+60 (c 0.07, THF); H

NMR (acetone-d₆, 500 MHz) d 10.88 (1H, br s), 9.27

(1H, s), 8.25 (1H, m), 8.09 (1H, br s), 7.90 (1H, d, J=8.1

Hz), 7.84 (1H, m), 7.53–7.57 (3H, m), 7.40 (1H, ddd,

J=8.2, 6.9, 1.2 Hz), 7.27 (1H, d, J=2.1 Hz), 5.41 (1H,

m), 5.05–5.06 (1H, m), 4.85 (1H, dd, J=10.7, 8.6 Hz),

4.80 (1H, dd, J=10.9, 2.4 Hz), 4.28–4.32 (1H, m), 4.08

(1H, dd, J=11.3, 3.2 Hz), 3.83 (1H, dd, J=11.1, 8.6

Hz), 2.23 (3H, t, J=1.1 Hz); ESI (positive) m/z 417

(M+H⁺, C₂₅H₂₂ClN₂O₂); ESI (negative) m/z 415

(MꢁH^ꢁ, C₂₅H₂₀ClN₂O₂).

3-(5-Aminoindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (40A). Prepared

by treatment of 43A (1.0 mg, 1.9 mmol) with 4 N HCl/

EtOAc (500 mL) for 1 h at 23 ^ꢂC, followed by solvent

removal to aﬀord 40A (750 mg, 87%) as a pale yellow

1

solid: H NMR (acetone-d₆, 500 MHz) d 10.48 (1H, br

s), 9.70–9.90 (3H, br s), 8.13 (1H, d, J=8.1 Hz), 7.98

(1H, br s), 7.87 (1H, d, J=8.6 Hz), 7.68 (1H, app s),

7.59 (1H, d, J=9.0 Hz), 7.54 (1H, tm, J=7.4 Hz), 7.38

(1H, tm, J=7.8 Hz), 7.30 (1H, app s), 7.21 (1H, dd,

J=8.8, 1.5 Hz), 4.81 (1H, dd, J=10.5, 9.2 Hz), 4.55

(1H, dd, J=10.9, 1.9 Hz), 4.23–4.27 (1H, m), 4.02 (1H,

dd, J=11.1, 3.0 Hz), 3.88 (1H, dd, J=11.1, 7.3 Hz); ESI

(positive) m/z 392 (M+H⁺, C₂₂H₁₉ClN₃O₂); ESI

(negative) m/z 390 (MꢁH^ꢁ, C₂₂H₁₇ClN₃O₂).

3-(7-Isopropenylindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (36A). (1.99 mg,

64%) as a white solid: [a]²_D³ꢁ10 (c 0.1, THF); ¹H NMR

(acetone-d₆, 500 MHz) d 9.89 (1H br s), 9.33 (1H, br s),

8.26 (1H, d, J=8.1 Hz), 8.08 (1H, br s), 7.90 (1H, d,

J=8.6 Hz), 7.68 (1H, d, J=8.1 Hz), 7.56 (1H, ddd,

J=8.4, 6.9, 1.4 Hz), 7.41 (1H, ddd, J=8.2, 6.9, 1.2 Hz),

7.30 (1H, d, J=2.1 Hz), 7.29 (1H, dd, J=7.3, 1.3 Hz),

7.16 (1H, t, J=7.5 Hz), 5.44–5.45 (2H, m), 4.85 (1H, dd,

J=10.9, 8.8 Hz), 4.78 (1H, dd, J=10.7, 2.1 Hz), 4.28–

4.33 (1H, m), 4.08 (1H, dd, J=11.1, 3.0 Hz), 3.83 (1H,

dd, J=11.1, 8.5 Hz), 2.28 (3H, t, J=1.1 Hz); ESI

(positive) m/z 439 (M+Na⁺, C₂₅H₂₁ClN₂NaO₂), 417

(M+H⁺, C₂₅H₂₂ClN₂O₂); ESI (negative) m/z 415

(MꢁH^ꢁ, C₂₅H₂₀ClN₂O₂).

3-(5-Dimethylaminoindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (41A).

(2.40 mg, 23%) as a yellow solid: [a]²_D³+15 (c 0.026,

CH₂Cl₂); ¹H NMR (CDCl₃, 600 MHz) d 9.26 (1H, br s),

8.28 (1H, d, J=8.3 Hz), 8.17 (1H, br s), 7.74 (1H, d,

J=8.3 Hz), 7.58 (1H, t, J=7.1 Hz), 7.45 (2H, t, J=7.1

Hz), 7.09 (1H, br s), 4.84 (1H, d, J=10.0 Hz), 4.71 (1H,

t, J=9.0 Hz), 4.17 (1H, m), 4.00 (1H, dd, J=11.4, 0.9

Hz), 3.55 (5H, m), 3.48 (1H, t, J=11.0 Hz), 3.02 (4H,

m), 2.97 (1H, s), 2.90 (1H, s); IR (ﬁlm) n_max3323, 2964,

2944, 1626, 1585, 1513, 1405, 1103 cm^ꢁ1; MALDIFT-

HRMS m/z 420.1471 (M+H⁺, C₂₄H₂₃ClN₃O₂requires

420.1473).

3-(5-Ethynylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (37A). (1.00 mg,

33%) as a beige solid: [a]²_D³+37 (c 0.1, THF); ¹H NMR

(acetone-d₆, 500 MHz) d 11.05 (1H, br s), 9.26 (1H, s),

8.26 (1H, d, J=8.6 Hz), 8.08 (1H, br s), 7.93 (1H, s),

7.90 (1H, d, J=8.1 Hz), 7.60 (1H, m), 7.56 (1H, ddd,

J=8.6, 6.8, 1.3 Hz), 7.38–7.42 (1H, m), 7.39 (1H, dd,

J=8.3, 1.5 Hz), 7.28–7.29 (1H, m), 4.85 (1H, t, J=9.6

Hz), 4.79 (1H, dd, J=10.7, 2.1 Hz), 4.28–4.33 (1H, m),

4.08 (1H, dd, J=11.1, 3.0 Hz), 3.84 (1H, dd, J=11.1,

8.5 Hz), 3.50 (1H, s); MALDIFT-HRMS m/z 401.1051

(M+H⁺, C₂₄H₁₈ClN₂O₂requires 401.1051).

3 - (5- Diethylaminoindole - 2 - carbonyl) - 1 - ( S) - (chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (42A).

(2.80 mg, 20%) as a yellow solid: [a]²_D³+33 (c 0.015,

CH₂Cl₂); ¹H NMR (CDCl₃, 500 MHz) d 9.30 (1H, br s),

8.94 (1H, br s), 8.36 (1H, s), 8.32 (1H, d, J=8.4 Hz),

7.72 (1H, d, J=8.4 Hz), 7.56 (1H, t, J=7.0 Hz), 7.44

(2H, m), 7.05 (2H, m), 4.84 (1H, d, J=10.7 Hz), 4.69

3826

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

(1H, app t, J=10.7 Hz), 4.14 (1H, m), 3.99 (1H, dd,

J=11.4, 2.9 Hz), 3.46 (1H, t, J=11.0 Hz), 3.37 (4H, m),

1.18 (6H, t, J=6.6 Hz); IR (ﬁlm) n_max3247, 2967, 2917,

1610, 1581, 1417, 1391, 1254, 1148 cm^ꢁ1; MALDIFT-

HRMS m/z 420.1471 (M+H⁺, C₂₄H₂₃ClN₃O₂requires

420.1473).

(2H, sextet, J=7.5 Hz), 0.98 (3H, t, J=7.5 Hz); MAL-

DIFT-HRMS m/z 462.1565 (M⁺, C₂₆H₂₄ClN₃O₃

requires 462.1579).

3-[5-(N-Acetyl-N-methyl)aminoindole-2-carbonyl]-1-(S)-

(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole

(47A). (1.60 mg, 48%) as a pale yellow solid: [a]²_D³+19

1

3-(5-t-Butyloxycarbonylaminoindole-2-carbonyl)-1-(S)-

(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole

(43A). (2.02 mg, 55%) as a pale yellow solid: [a]²_D³+40

(c 0.2, THF); H NMR (acetone-d₆, 500 MHz) d 11.04

(1H, br s), 9.26 (1H, s), 8.26 (1H, d, J=8.6 Hz), 8.11

(1H, br s), 7.90 (1H, d, J=8.1 Hz), 7.66–7.68 (2H, m),

7.56 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.41 (1H, ddd,

J=8.1, 6.9, 1.2 Hz), 7.31 (1H, s), 7.22 (1H, dd, J=8.6,

1.7 Hz), 4.87 (1H, dd, J=10.7, 8.6), 4.81 (1H, dd,

J=10.9, 2.4 Hz), 4.29–4.33 (1H, m), 4.09 (1H, dd,

J=11.1, 3.0 Hz), 3.84 (1H, dd, J=11.3, 8.3 Hz), 3.24

(3H, s), 1.78 (3H, s); MALDIFT-HRMS m/z 448.1420

(M+H⁺, C₂₅H₂₃ClN₃O₃requires 448.1420).

1

(c 0.02, THF); H NMR (acetone-d₆, 500 MHz) d 10.76

(1H, br s), 9.26 (1H, s), 8.29 (1H, br s), 8.25 (1H, d,

J=8.5 Hz), 8.08 (1H, br s), 8.00 (1H, br s), 7.89 (1H, d,

J=8.6 Hz), 7.55 (1H, ddd, J=8.6, 6.9, 1.4 Hz), 7.50

(1H, d, J=9.0 Hz), 7.42 (1H, dd, J=8.6, 1.7 Hz), 7.39

(1H, ddd, J=8.1, 6.8, 1.3 Hz), 7.20 (1H, dd, J=2.1, 0.9

Hz), 7.21 (1H, dd, J=8.8, 1.5 Hz), 4.85 (1H, dd,

J=10.7, 8.6 Hz), 4.80 (1H, dd, J=10.7, 2.6 Hz), 4.27–

4.31 (1H, m), 4.07 (1H, dd, J=11.1, 3.4 Hz), 3.83 (1H,

dd, J=11.1, 8.5 Hz), 1.50 (9H, s); MALDIFT-HRMS

m/z 514.1501 (M+Na⁺, C₂₇H₂₆ClN₃NaO₄requires

514.1504).

3-[5-(N-Acetyl-N-ethyl)aminoindole-2-carbonyl]-1-(S)-

(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole

(48A). (0.60 mg, 39%) as a pale yellow solid: [a]²_D³+35

(c 0.08, acetone); ¹H NMR (acetone-d₆, 600 MHz) d

9.27 (1H, s), 8.26 (1H, d, J=8.3 Hz), 8.10 (1H, br s),

8.06 (1H, s), 7.90 (1H, d, J=8.3 Hz), 7.68–7.74 (2H, m),

7.56 (1H, t, J=7.9 Hz), 7.41 (1H, t, J=8.3 Hz), 7.39

(1H, s), 5.17 (1H, m), 4.88 (1H, t, J=10.1 Hz), 4.82 (1H,

d, J=10.5 Hz), 4.32 (1H, m), 4.18 (1H, q, J=7.0 Hz),

4.09 (1H, dd, J=7.9, 3.5 Hz), 3.84 (1H, dd, J=8.8, 2.6

Hz), 2.52 (3H, s), 1.15 (3H, t, J=7.0 Hz); IR (ﬁlm) n_max

3276, 2933, 1664, 1610, 1583 cm^ꢁ1; MALDIFT-HRMS

m/z 462.1597 (M+H⁺, C₂₆H₂₄ClN₃O₃requires

462.1579).

3 - (5- Acetylaminoindole - 2 - carbonyl) - 1 - ( S) - (chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (44A).

(0.89 mg, 27%) as a white solid: [a]²_D³+21 (c 0.033,

1

THF); H NMR (acetone-d₆, 500 MHz) d 10.75 (1H, br

s), 9.23 (1H, s), 9.06 (1H, br s), 8.25 (1H, d, J=8.6 Hz),

8.19 (1H, s), 8.07 (1H, br s), 7.89 (1H, d, J=8.1 Hz),

7.55 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.50 (1H, d, J=8.5

Hz), 7.38–7.42 (2H, m), 7.21 (1H, s), 4.85 (1H, dd,

J=10.9, 8.8 Hz), 4.79 (1H, dd, J=10.7, 2.1 Hz), 4.27–4.32

(1H, m), 4.07 (1H, dd, J=11.1, 3.0 Hz), 3.83 (1H, dd,

J=11.3, 8.3 Hz), 2.09 (3H, s); MALDIFT-HRMS m/z

434.1269 (M+H⁺, C₂₄H₂₁ClN₃O₃requires 434.1266).

3-(5-Nitroindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (49A). (1.55 mg,

1

49%) as a yellow solid: [a]²_D³+45 (c 0.07, THF); H

3-(5-Propionylaminoindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (45A).

(1.00 mg, 30%) as a pale yellow solid: [a]²_D³+24 (c

NMR (acetone-d₆, 500 MHz) d 11.48 (1H, br s), 9.26

(1H, s), 8.78 (1H, d, J=2.1 Hz), 8.27 (1H, d, J=8.6

Hz), 8.19 (1H, dd, J=9.2, 2.4 Hz), 8.08 (1H, br s), 7.91

(1H, m), 7.77 (1H, d, J=9.4 Hz), 7.55–7.58 (2H, m),

7.42 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 4.88 (1H, dd,

J=10.5, 8.8 Hz), 4.82 (1H, dd, J=10.7, 2.1 Hz), 4.31–

4.36 (1H, m), 4.09 (1H, dd, J=11.8, 3.2 Hz), 3.85 (1H,

dd, J=11.3, 8.3 Hz); MALDIFT-HRMS m/z 421.0824

(M⁺, C₂₂H₁₆ClN₃O₄requires 421.0824).

1

0.05, THF); H NMR (acetone-d₆, 500 MHz) d 10.76

(1H, br s), 9.24 (1H, s), 8.98 (1H, br s), 8.25 (1H, d,

J=8.6 Hz), 8.21 (1H, m), 8.07 (1H, br s), 7.89 (1H, d,

J=8.6 Hz), 7.55 (1H, ddd, J=8.1, 6.8, 1.3 Hz), 7.50

(1H, d, J=9.0 Hz), 7.43 (1H, dd, J=8.8, 1.9 Hz), 7.39

(1H, ddd, J=8.3, 7.1, 1.1 Hz), 7.20–7.21 (1H, m), 4.85

(1H, dd, J=10.7, 8.6 Hz), 4.79 (1H, dd, J=10.9, 2.4

Hz), 4.27–4.32 (1H, m), 4.07 (1H, dd, J=11.3, 3.2 Hz),

3.83 (1H, dd, J=11.3, 8.3 Hz), 3.39 (2H, q, J=7.6 Hz),

1.17 (3H, t, J=7.7 Hz); MALDIFT-HRMS m/z

447.1350 (M⁺, C₂₅H₂₂ClN₃O₃requires 447.1350).

3-(6-Nitroindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (50A). (2.60 mg,

1

82%) as a yellow solid: [a]²_D³ꢁ26 (c 0.125, THF); H

NMR (acetone-d₆, 500 MHz) d 11.53 (1H, s), 9.30 (1H,

s), 8.57 (1H, dd, J=2.1, 0.9 Hz), 8.27 (1H, d, J=8.6

Hz), 8.08 (1H, br s), 8.02 (1H, dd, J=9.0, 2.1 Hz), 7.96

(1H, d, J=8.6 Hz), 7.91 (1H, m), 7.57 (1H, ddd, J=8.4,

6.9, 1.2 Hz), 7.44–7.45 (1H, m), 7.42 (1H, ddd, J=8.2,

6.9, 1.2 Hz), 4.89 (1H, t, J=9.6 Hz), 4.81 (1H, dd,

J=10.7, 2.1 Hz), 4.30–4.35 (1H, m), 4.08 (1H, dd,

J=11.5, 2.8 Hz), 3.85 (1H, dd, J=11.1, 8.5 Hz); ESI

(positive) m/z 422 (M+H⁺, C₂₂H₁₇ClN₃O₄); ESI

(negative) m/z 420 (MꢁH^ꢁ, C₂₂H₁₅ClN₃O₄).

3 - (5- Butyrylaminoindole - 2 - carbonyl) - 1 - ( S) - (chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (46A).

(1.51 mg, 44%) as a white solid: [a]²_D³+43 (c 0.08,

1

THF); H NMR (acetone-d₆, 500 MHz) d 10.76 (1H, br

s), 9.24 (1H, s), 9.00 (1H, br sCO), 8.25 (1H, d, J=9.0

Hz), 8.22 (1H, s), 8.07 (1H, br s), 7.89 (1H, d, J=8.1

Hz), 7.55 (1H, ddd, J=8.1, 6.8, 1.3 Hz), 7.50 (1H, d,

J=9.0 Hz), 7.43 (1H, dd, J=8.8, 1.9 Hz), 7.39 (1H,

ddd, J=8.3, 6.8, 1.3 Hz), 7.20–7.21 (1H, m), 4.84 (1H,

dd, J=10.9, 8.8 Hz), 4.79 (1H, dd, J=10.9, 2.4 Hz),

4.27–4.31 (1H, m), 4.07 (1H, dd, J=11.3, 3.2 Hz), 3.83

(1H, dd, J=11.1, 8.5 Hz), 2.35 (2H, t, J=7.3 Hz), 1.72

3-(7-Nitroindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (51A). (0.92 mg,

1

29%) as a yellow solid: [a]²_D³+9 (c 0.003, THF); H

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3827

NMR (acetone-d₆, 500 MHz) d 10.82 (1H, br s), 9.38

(1H, s), 8.27–8.34 (3H, m), 8.12 (1H, br s), 7.91 (1H, d,

J=8.3 Hz), 7.57 (1H, ddd, J=8.3, 7.1, 1.2 Hz), 7.55

(1H, m), 7.43 (1H, ddd, J=8.2, 7.0, 1.1 Hz), 7.42 (1H, t,

J=8.1 Hz), 4.89 (1H, t, J=10.0 Hz), 4.79 (1H, dd,

J=10.5, 2.2 Hz), 4.31–4.36 (1H, m), 4.09 (1H, dd,

J=10.5, 3.5 Hz), 3.86 (1H, dd, J=11.2, 8.3 Hz); ESI

(positive) m/z 422 (M+H⁺, C₂₂H₁₇ClN₃O₄); ESI

(negative) m/z 420 (MꢁH^ꢁ, C₂₂H₁₅ClN₃O₄).

3-(5-Propionylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (56A). (2.05 mg,

1

63%) as a pale yellow solid: [a]²_D³+33 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 11.18 (1H, br s), 9.27

(1H, s), 8.50 (1H, m), 8.26 (1H, d, J=8.6 Hz), 8.09 (1H,

br s), 7.96 (1H, dd, J=8.6, 1.7 Hz), 7.90 (1H, d, J=8.6

Hz), 7.66 (1H, m), 7.56 (1H, ddd, J=8.4, 7.1, 1.1 Hz),

7.39–7.43 (2H, m), 4.88 (1H, dd, J=10.7, 9.0 Hz), 4.81

(1H, dd, J=10.7, 2.1 Hz), 4.29–4.34 (1H, m), 4.09 (1H,

dd, J=11.1, 3.0 Hz), 3.84 (1H, dd, J=11.1, 8.6 Hz),

3.13 (2H, q, J=7.3 Hz), 1.20 (3H, t, J=7.3 Hz); MAL-

DIFT-HRMS m/z 432.1232 (M⁺, C₂₅H₂₁ClN₂O₃

requires 432.1235).

3-(5-Formylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (52A). (1.18 mg,

39%) as a beige solid: [a]²_D³+9 (c 0.03, THF); ¹H NMR

(acetone-d₆, 500 MHz) d 11.34 (1H, br s), 10.07 (1H, s),

9.30 (1H, s), 8.39 (1H, m), 8.26 (1H, d, J=7.7 Hz), 8.09

(1H, br s), 7.91 (1H, d, J=8.1 Hz), 7.86 (1H, dd, J=8.6,

1.7 Hz), 7.75 (1H, d, J=8.6 Hz), 7.57 (1H, ddd, J=8.1,

6.8, 1.3 Hz), 7.50 (1H, m), 7.41 (1H, ddd, J=8.2, 6.9, 1.2

Hz), 4.90 (1H, dd, J=10.7, 9.0 Hz), 4.82 (1H, dd, J=10.7,

2.1 Hz), 4.30–4.35 (1H, m), 4.09 (1H, dd, J=11.5, 3.4 Hz),

3.85 (1H, dd, J=11.1, 8.6 Hz); MALDIFT-HRMS m/z

405.1012 (M+H⁺, C₂₃H₁₈ClN₂O₃requires 405.1000).

3-(5-Butyrylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (57A). (2.15 mg,

1

64%) as a pale yellow solid: [a]²_D³+35 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 11.17 (1H, br s), 9.27

(1H, s), 8.52 (1H, m), 8.26 (1H, d, J=8.1 Hz), 8.09 (1H,

br s), 7.97 (1H, dd, J=8.8, 1.5 Hz), 7.90 (1H, m), 7.66

(1H, d, J=9.0 Hz), 7.56 (1H, ddd, J=8.1, 6.8, 1.3 Hz),

7.42–7.43 (1H, m), 7.41 (1H, ddd, J=8.6, 6.8, 1.3 Hz),

4.88 (1H, dd, J=10.7, 9.0 Hz), 4.81 (1H, dd, J=10.7,

2.6 Hz), 4.29–4.34 (1H, m), 4.09 (1H, dd, J=11.1, 3.0

Hz), 3.87 (1H, dd, J=11.1, 8.6 Hz); 3.07 (2H, t, J=7.3

Hz), 1.77 (2H, sextet, J=7.3 Hz), 1.02 (3H, t, J=7.5

3-(7-Formylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (53A). (1.46 mg,

20%) as a yellow solid: [a]²_D³ꢁ33 (c 0.54, 2:1 CH₂CH₂/

1

CDCl₃); H NMR (CDCl₃, 500 MHz) 11.46 (1H, br s),

Hz);

C₂₆H₂₃ClN₂O₃requires 446.1392).

MALDIFT-HRMS

m/z

446.1388

(M⁺,

10.21 (1H, s), 8.33 (1H, d, J=8.4 Hz), 8.15 (1H, br s),

8.06 (1H, d, J=7.7 Hz), 7.84 (1H, dd, J=7.4, 1.1 Hz),

7.74 (1H, d, J=8.1 Hz), 7.58 (1H, t, J=7.1 Hz), 7.47

(1H, t, J=8.5 Hz), 7.38 (1H, t, J=7.7 Hz), 7.21 (1H, d,

J=2.6 Hz), 4.84 (1H, dd, J=10.7, 1.9 Hz), 4.73 (1H, t,

J=9.2 Hz), 4.17 (1H, m), 4.01 (1H, dd, J=11.4, 2.6

Hz), 3.49 (1H, t, J=11.0 Hz); MALDIFT-HRMS m/z

405.1013 (M+H⁺, C₂₃H₁₈ClN₂O₃requires 405.1000).

3-(5-Methoxycarbonylindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (58A).

(1.64 mg, 50%) as a beige solid: [a]²_D³+25 (c 0.08,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.21 (1H, br

s), 9.29 (1H, s), 8.51 (1H, m), 8.26 (1H, d, J=8.6 Hz),

8.08 (1H, br s), 7.96 (1H, dd, J=8.8, 1.5 Hz), 7.91 (1H,

d, J=8.1 Hz), 7.67 (1H, d, J=9.0 Hz), 7.56 (1H, ddd,

J=8.1, 6.8, 1.3 Hz), 7.43–7.44 (1H, m), 7.41 (1H, ddd,

J=8.4, 7.0, 1.4 Hz), 4.88 (1H, t, J=9.3 Hz), 4.81 (1H,

dd, J=10.7, 2.1 Hz), 4.31–4.35 (1H, m), 4.08 (1H, dd,

J=11.1, 3.0 Hz), 3.90 (3H, s), 3.85 (1H, dd, J=11.1, 8.6

Hz); MALDIFT-HRMS m/z 435.1096 (M+H⁺,

C₂₄H₂₀ClN₂O₄requires 435.1106).

3-(5-Acetylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (54A). (2.06 mg,

1

66%) as a pale yellow solid: [a]²_D³+33 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 11.17 (1H, br s), 9.26

(1H, s), 8.51 (1H, s), 8.26 (1H, d, J=8.6 Hz), 8.09 (1H,

br s), 7.98 (1H, dd, J=8.6, 1.5 Hz), 7.90 (1H, d, J=8.1

Hz), 7.66 (1H, d, J=8.6 Hz), 7.56 (1H, ddd, J=8.1, 6.8,

1.3 Hz), 7.43 (1H, m), 7.41 (1H, ddd, J=8.1, 6.8, 1.3

Hz), 4.88 (1H, t, J=9.6 Hz), 4.81 (1H, dd, J=10.7, 2.1

Hz), 4.29–4.34 (1H, m), 4.09 (1H, dd, J=11.1, 3.0 Hz),

3.84 (1H, dd, J=11.1, 8.6 Hz); 2.64 (3H, s); MAL-

DIFT-HRMS m/z 418.1089 (M⁺, C₂₄H₁₉ClN₂O₃

requires 418.1084).

3-(7-Methoxycarbonylindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (59A).

(1.72 mg, 53%) as a yellow solid: [a]²_D³ꢁ6 (c 0.1, THF);

¹H NMR (acetone-d₆, 500 MHz) d 10.61 (1H, br s), 9.35

(1H, s), 8.27 (1H, d, J=8.5 Hz), 8.13 (1H, br s), 8.08

(1H, d, J=7.7 Hz), 8.02 (1H, dd, J=7.5, 1.1 Hz), 7.91

(1H, d, J=8.6 Hz), 7.56 (1H, ddd, J=8.3, 6.8, 1.3 Hz),

7.42 (1H, ddd, J=8.3, 6.8, 1.3 Hz), 7.41 (1H, d, J=2.1

Hz), 7.29 (1H, t, J=7.7 Hz), 4.88 (1H, dd, J=10.5, 8.8

Hz), 4.81 (1H, dd, J=10.7, 2.1 Hz), 4.30–4.35 (1H, m),

4.09 (1H, dd, J=11.1, 3.0 Hz), 4.03 (3H, s), 3.86 (1H,

dd, J=11.1, 8.5 Hz); MALDIFT-HRMS m/z 435.1118

(M+H⁺, C₂₄H₂₀ClN₂O₄requires 435.1106).

3-(7-Acetylindole-2-carbonyl)-1-(S)-(chloromethyl)-5-

hydroxy-1,2-dihydro-3H-benz[e]indole (55A). (1.79 mg,

1

57%) as a pale yellow solid: [a]²_D³ꢁ1 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 11.08 (1H, br s), 9.33

(1H, s), 8.27 (1H, d, J=8.1 Hz), 8.14 (1H, br s), 8.08–

8.10 (2H, m), 7.90 (1H, d, J=8.6 Hz), 7.56 (1H, ddd,

J=8.1, 6.8, 1.3 Hz), 7.41 (1H, ddd, J=8.3, 6.8, 1.3 Hz),

7.39 (1H, d, J=2.6 Hz), 7.31 (1H, t, J=7.7 Hz), 4.88

(1H, dd, J=10.5, 8.8 Hz), 4.81 (1H, dd, J=10.7, 2.6

Hz), 4.20–4.34 (1H, m), 4.09 (1H, dd, J=11.3, 2.8 Hz),

3.85 (1H, dd, J=11.1, 8.5 Hz); 2.74 (3H, s); MAL-

DIFT-HRMS m/z 419.1157 (M+H⁺, C₂₄H₂₀ClN₂O₃

requires 419.1157).

3-(5-Ethoxycarbonylindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (60A).

(1.64 mg, 50%) as a pale yellow solid: [a]²_D³+31 (c 0.1,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.20 (1H, br

s), 9.29 (1H, s), 8.51 (1H, m), 8.26 (1H, d, J=8.1 Hz),

8.09 (1H, br s), 7.97 (1H, dd, J=8.6, 1.7 Hz), 7.91 (1H,

3828

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

d, J=8.6 Hz), 7.67 (1H, d, J=8.6 Hz), 7.56 (1H, ddd,

J=8.1, 6.8, 1.3 Hz), 7.44 (1H, s), 7.41 (1H, ddd, J=8.2,

6.9, 1.2 Hz), 4.88 (1H, t, J=9.6 Hz), 4.81 (1H, dd,

J=10.7, 2.1 Hz), 4.37 (2H, q, J=7.1 Hz), 4.30–4.34

(1H, m), 4.08 (1H, dd, J=11.1, 3.0 Hz), 3.84 (1H, dd,

J=11.1, 8.6 Hz), 1.39 (3H, t, J=7.1 Hz); MALDIFT-

HRMS m/z 449.1246 (M+H⁺, C₂₅H₂₂ClN₂O₄requires

449.1263).

(3H, s); ESI (positive) m/z 455 (M+H⁺,

C₂₃H₂₀ClN₂O₄S); ESI (negative) m/z 453 (MꢁH^ꢁ,

C₂₃H₁₈ClN₂O₄S).

3 - (5- Ethylsulfonylindole - 2 - carbonyl) - 1 - ( S) - (chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (65A).

(2.51 mg, 71%) as a pale yellow solid: [a]²_D³+30 (c

1

0.13, THF); H NMR (acetone-d₆, 500 MHz) d 11.40

(1H, br s), 9.31 (1H, s), 8.37 (1H, s), 8.26 (1H, d, J=8.1

Hz), 8.09 (1H, br s), 7.91 (1H, d, J=8.1 Hz), 7.81 (1H,

m), 7.78 (1H, dd, J=8.6, 1.7 Hz), 7.57 (1H, ddd, J=8.3,

7.1, 1.3 Hz), 7.51 (1H, s), 7.41 (1H, ddd, J=8.2, 6.9, 1.2

Hz), 4.89 (1H, t, J=9.6 Hz), 4.81 (1H, dd, J=10.7, 1.7

Hz), 4.30–4.35 (1H, m), 4.08 (1H, dd, J=11.3, 3.2 Hz),

3.85 (1H, dd, J=11.1, 8.5 Hz), 3.21 (2H, q, J=7.3 Hz),

1.21 (3H, t, J=7.5 Hz); MALDIFT-HRMS m/z

469.0966 (M+H⁺, C₂₄H₂₂ClN₂O₄S requires 469.0983).

3-(5-Carbamoylindole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (61A). (1.49 mg,

47%) as a beige solid: [a]²_D³+18 (c 0.08, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 11.10 (1H, br s), 9.30

(1H, s), 8.39 (1H, m), 8.26 (1H, d, J=8.6 Hz), 8.08 (1H,

br s), 7.96 (1H, br s), 7.91 (1H, dd, J=8.5, 1.7 Hz), 7.90

(1H, d, J=7.7 Hz), 7.63 (1H, dt, J=8.6, 0.9 Hz), 7.56

(1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.40 (1H, ddd, J=8.2,

6.9, 1.2 Hz), 7.36 (1H, d, J=1.7 Hz), 6.47 (1H, br s),

4.87 (1H, t, J=9.6 Hz), 4.80 (1H, dd, J=10.7, 2.1

Hz), 4.28–4.33 (1H, m), 4.08 (1H, dd, J=11.1, 3.4

Hz), 3.84 (1H, dd, J=11.1, 8.6 Hz); MALDIFT-

HRMS m/z 419.1029 (M⁺, C₂₃H₁₈ClN₃O₃requires

419.1031).

3-(1,2-Dihydro-3H-pyrrolo[3,2-e]indole-7-carbonyl)-1-

(S)-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole

(66A). Prepared from 67A (6.3 mg, 12.1 mmol) by treat-

ment with 4 N HCl/EtOAc (0.25 mL), followed by

exposure to Et₃N (13.0 mL) in THF (1 mL) for 1 h

which aﬀorded 66A (5.0 mg, 100%) as a brown solid:

[a]²_D³+34 (c 0.01, CH₂Cl₂); ¹H NMR (CD₃CN,

600 MHz) d 9.84 (1H, br s), 8.16 (1H, d, J=8.3 Hz),

8.05 (1H, m), 7.83 (1H, s), 7.81 (1H, d, J=8.3 Hz), 7.70

(1H, m), 7.54 (1H, t, J=8.3 Hz), 7.39 (1H, t, J=7.9

Hz), 7.22 (1H, d, J=9.2 Hz), 6.95 (1H, s), 6.79 (1H, d,

J=8.3 Hz), 4.71 (2H, m), 4.23 (2H, m), 3.99 (1H, dd,

J=11.4, 3.0 Hz ), 3.76 (1H, m), 3.58 (1H, m), 3.18 (1H,

m); IR (ﬁlm) n_max3292, 2964, 2923, 2851, 1605, 1585,

1400 1256, 1092, 1021, 800 cm^ꢁ1; MALDIFT-HRMS

m/z 417.1244 (M⁺, C₂₄H₂₀ClN₃O₂requires 417.1244).

3-(5-Methylcarbamoylindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (62A).

(0.97 mg, 30%) as a pale yellow solid: [a]²_D³+34 (c

1

0.05, THF); H NMR (acetone-d₆, 500 MHz) d 11.07

(1H, br s), 9.29 (1H, s), 8.32 (1H, m), 8.25 (1H, d, J=8.1

Hz), 8.08 (1H, br s), 7.90 (1H, d, J=8.6 Hz), 7.85 (1H,

dd, J=8.6, 1.7 Hz), 7.63 (1H, br s), 7.62 (1H, d, J=8.6

Hz), 7.56 (1H, ddd, J=8.1, 6.8, 1.3 Hz), 7.41 (1H, ddd,

J=8.6, 7.0, 1.1 Hz), 7.35 (1H, s), 4.86 (1H, t, J=9.6 Hz),

4.80 (1H, dd, J=11.1, 2.1 Hz), 4.28–4.32 (1H, m), 4.08

(1H, dd, J=11.3, 3.2 Hz), 3.83 (1H, dd, J=11.1, 8.6 Hz),

2.93 (3H, d, J=4.7 Hz); MALDIFT-HRMS m/z

434.1276 (M+H⁺, C₂₄H₂₁ClN₃O₃requires 434.1266).

3-(N-t-Butyloxycarbonyl-1,2-dihydro-3H-pyrrolo[3,2-e]-

indole-7-carbonyl)-1-(S)-(chloromethyl)-5-hydroxy-1,2-di-

hydro-3H-benz[e]indole (67A). (6.3 mg, 67%) as a yellow

solid: [a]²_D³ꢁ23 (c 0.04, CH₂Cl₂); ¹H NMR (CDCl₃,

500 MHz) d 9.71 (1H, br s), 9.41 (1H, br s), 8.33 (1H, s),

8.27 (1H, d, J=7.0 Hz), 8.10 (1H, br s), 7.52 (1H, m),

7.43 (1H, t, J=6.6 Hz), 7.25 (1H, br s), 6.81 (1H, s),

4.66 (1H, d, J=7.3 Hz), 4.57 (1H, t, J=7.7 Hz), 4.12

(2H, br m), 3.92 (1H, m), 3.87 (1H, d, J=9.9 Hz), 3.36

(1H, t, J=8.8 Hz), 3.25 (1H, m), 3.15 (1H, m), 1.63 (9H,

m); IR (ﬁlm) n_max3426, 3272, 2964, 2913, 1692, 1605,

1580, 1502, 1410, 1339, 1251, 1139, 800 cm^ꢁ1; ESI

(positive) m/z 518 (M+H⁺, C₂₉H₂₉ClN₃O₄); ESI

(negative) m/z 516 (MꢁH^ꢁ, C₂₉H₂₇ClN₃O₄).

3-(5-Dimethylcarbamoylindole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (63A).

(1.5 mg, 45%) as a pale yellow solid: [a]²_D³+25 (c 0.08,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.05 (1H, br

s), 9.30 (1H, s), 8.25 (1H, d, J=8.1 Hz), 8.09 (1H, br s),

7.90 (1H, m), 7.85–7.86 (1H, m), 7.62 (1H, d, J=8.1

Hz), 7.56 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.40 (1H, ddd,

J=8.6, 6.8, 1.3 Hz), 7.39 (1H, dd, J=8.6, 1.7 Hz), 7.33

(1H, m), 4.86 (1H, t, J=9.6 Hz), 4.80 (1H, dd, J=10.7,

2.1 Hz), 4.28–4.32 (1H, m), 4.08 (1H, dd, J=11.1, 3.2

Hz), 3.84 (1H, dd, J=11.1, 8.6 Hz), 2.83 (3H, s), 2.80

(3H, s); MALDIFT-HRMS m/z 448.1422 (M+H⁺,

C₂₅H₂₃ClN₃O₃requires 448.1422).

3-(Pyrrolo[3,2-e]indole-7-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (69A). (0.43 mg,

14%) as a pale yellow solid: [a]²_D³+184 (c 0.01, THF);

¹H NMR (acetone-d₆, 500 MHz) d 10.79 (1H, br s),

10.37 (1H, br s), 9.22 (1H, s), 8.25 (1H, d, J=8.5 Hz),

8.10 (1H, br s), 7.89 (1H, m), 7.55 (1H, ddd, J=8.4, 6.9,

1.4 Hz), 7.49 (1H, m), 7.44 (1H, m), 7.38 (1H, ddd,

J=8.3, 7.0, 1.3 Hz), 7.37 (1H, d, J=9.0 Hz ), 7.33 (1H,

t, J=2.8 Hz), 6.78–6.79 (1H, m ), 4.90 (1H, dd, J=10.9,

8.3 Hz), 4.86 (1H, dd, J=10.9, 2.8 Hz), 4.28–4.33 (1H,

m), 4.09 (1H, dd, J=11.1, 3.0 Hz), 3.83 (1H, dd,

J=11.1, 8.6 Hz); MALDIFT-HRMS m/z 416.1156

(M+H⁺, C₂₄H₁₉ClN₃O₂requires 416.1160).

3-(5-Methylsulfonylindole -2-carbonyl) -1-( S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (64A).

(1.29 mg, 38%) as a yellow solid: [a]²_D³+26 (c 0.05,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.37 (1H, br

s), 9.28 (1H, s), 8.40–8.41 (1H, m), 8.26 (1H, d, J=7.7

Hz), 8.08 (1H, br s), 7.91 (1H, d, J=8.1 Hz), 7.83 (1H,

dd, J=8.8, 1.5 Hz), 7.80 (1H, m), 7.57 (1H, ddd, J=8.1,

6.8, 1.3 Hz), 7.51 (1H, d, J=1.3 Hz), 7.42 (1H, ddd,

J=8.3, 6.8, 1.3 Hz), 4.89 (1H, t, J=9.6 Hz), 4.81 (1H,

dd, J=11.1, 2.1 Hz), 4.30–4.35 (1H, m), 4.08 (1H, dd,

J=11.1, 3.0 Hz), 3.84 (1H, dd, J=11.5, 8.6 Hz), 3.13

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3829

3-(1,2-Dihydropyrrolo[3,2-e]benzofuran-7-carbonyl)-1-

(S)-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole

(70A). (0.8 mg, 53%) as a white solid: [a]²_D³+25 (c 0.2,

acetone); ¹H NMR (CDCl₃, 600 MHz) d 9.40 (1H, br s),

8.30 (1H, d, J=8.3 Hz), 8.27 (1H, s), 7.73 (1H, d, J=8.3

Hz), 7.58 (1H, t, J=7.9 Hz), 7.46 (1H, t, J=7.9 Hz),

7.31 (1H, d, J=8.3 Hz), 6.99 (1H, d, J=8.3 Hz), 6.95

(1H, s), 4.85 (1H, d, J=10.5 Hz), 4.72 (2H, t, J=10.1

Hz), 4.16 (1H, t, J=9.7 Hz), 4.00 (1H, dd, J=8.8, 2.6

Hz), 3.75 (1H, m), 3.41–3.52 (3H, m); IR (ﬁlm) n_max

3-([1,3]Dioxolo[f]indole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (75A). (1.28 mg,

1

42%) as an oﬀ-white solid: [a]²_D³+1 (c 0.08, THF); H

NMR (acetone-d₆, 500 MHz) d 10.75 (1H, br s), 9.24

(1H, s), 8.24 (1H, d, J=8.1 Hz), 8.09 (1H, br s), 7.88

(1H, d, J=8.1 Hz), 7.54 (1H, ddd, J=8.4, 6.8, 1.3 Hz),

7.38 (1H, ddd, J=8.3, 7.1, 1.1 Hz), 7.14 (1H, m), 7.09

(1H, s), 7.03 (1H, s), 5.99 (2H, s), 4.80 (1H, dd, J=10.5,

8.8 Hz), 4.75 (1H, dd, J=10.7, 2.1 Hz), 4.26-4.30 (1H,

m), 4.07 (1H, dd, J=11.1, 3.4 Hz), 3.81 (1H, dd,

J=11.1, 8.5 Hz); MALDIFT-HRMS m/z 420.0888

(M⁺, C₂₃H₁₇ClN₂O₄requires 420.0871).

3406, 1428, 1048 cm^ꢁ1

; MALDIFT-HRMS m/z

418.1094 (M⁺, C₁₁H₉NO₅requires 418.1079).

3-(Pyrrolo[3,2-e]benzofuran-7-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (71A).

(1.7 mg, 45%) as a white solid: [a]²_D³+42 (c 0.2, ace-

76A: (3.8 mg, 62%) as a yellow solid: [a]²_D³ꢁ39 (c 0.02,

1

CH₂Cl₂); H NMR (acetone-d₆, 500 MHz) d 10.66 (1H,

br s), 10.58 (1H, br s), 9.26 (1H, d, J=13.6 Hz), 8.24

(1H, d, J=8.1 Hz), 8.09 (1H, br s), 7.88 (1H, d, J=8.4

Hz), 7.54 (2H, m), 7.38 (2H, m), 7.25 (1H, m), 7.15 (1H,

m), 7.05 (1H, d, J=8.1 Hz), 4.80 (2H, m), 4.27 (1H, m),

4.07 (1H, m), 3.80 (1H, m), 3.18 (1H, t, J=7.3 Hz), 3.02

(1H, t, J=7.3 Hz), 2.97 (1H, pent, J=7.4 Hz), 2.19 (1H,

t, J=7.3 Hz), 2.09 (1H, t, J=7.3 Hz); MALDIFT-

HRMS m/z 417.1371 (M+H⁺, C₂₅H₂₁ClN₂O₂requires

417.1364).

1

tone); H NMR (CDCl₃, 600 MHz) d 9.27 (1H, s), 8.25

(1H, d, J=7.9 Hz), 8.10 (1H, s), 7.90 (2H, m), 7.56 (5H,

m), 7.40 (1H, t, J=7.5 Hz), 7.23 (1H, d, J=0.9 Hz),

4.86 (2H, m), 4.31 (1H, m), 4.07 (1H, dd, J=8.4, 3.0

Hz), 3.84 (1H, dd, J=8.7, 2.6 Hz); IR (ﬁlm) n_max3735,

3675, 1684, 1647, 1558, 1507, 1457 cm^ꢁ1; MALDIFT-

HRMS m/z 416.0945 (M⁺, C₂₄H₁₇ClN₂O₃requires

416.0928).

3-(6-Oxo-cyclopenten[e]indole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (72A).

(2.0 mg, 62%) as a pale yellow solid: [a]²_D³+75 (c 0.1,

3-[Benz[e]indole-2-carbonyl]-1-(chloromethyl)-5-hydroxy-

1,2-dihydro-3H-benz[e]indole (77A). (1.60–2.30 mg, 37–

54%) as a beige solid: (natural enantiomer [a]²_D³+100 (c

0.08, THF); unnatural enantiomer [a]²_D³ꢁ108 (c 0.1,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.43 (1H, br

1

s), 9.30 (1H, s), 8.26 (1H, d, J=8.1 Hz), 8.10 (1H, br s),

7.91 (1H, d, J=8.6 Hz), 7.63 (1H, d, J=8.6 Hz ), 7.56

(1H, ddd, J=8.4, 7.0, 1.4 Hz), 7.56 (1H, d, J=9.0 Hz),

7.55 (1H, m), 7.41 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 4.92

(1H, t, J=9.6 Hz), 4.84 (1H, dd, J=10.7, 2.1 Hz), 4.30–

4.35 (1H, m), 4.08 (1H, dd, J=11.3, 3.2 Hz), 3.86 (1H,

dd, J=11.3, 8.3 Hz), 3.33–3.34 (2H, m), 2.70 (2H, t,

J=6.0 Hz); MALDIFT-HRMS m/z 431.1157 (M+H⁺,

C₂₅H₂₀ClN₂O₃requires 431.1157).

THF); H NMR (acetone-d₆, 500 MHz) d 11.27 (1H, br

s), 9.23 (1H, s), 8.42 (1H, d, J=8.7 Hz), 8.26 (1H, d,

J=8.3 Hz), 8.12 (1H, br s), 7.95 (1H, m), 7.94 (1H, d,

J=2.0 Hz), 7.91 (1H, m), 7.74–7.77 (2H, m), 7.59 (1H,

ddd, J=8.3, 7.2, 1.2 Hz), 7.56 (1H, ddd, J=8.5, 7.0, 1.6

Hz), 7.46 (1H, ddd, J=8.1, 7.0, 1.2 Hz), 7.40 (1H, ddd,

J=8.5, 6.8, 1.0 Hz), 4.98 (1H, dd, J=10.7, 8.7 Hz), 4.91

(1H, dd, J=10.7, 2.4 Hz), 4.31–4.36 (1H, m), 4.09 (1H,

dd, J=11.3, 3.4 Hz), 3.86 (1H, dd, J=11.1, 8.3 Hz);

MALDI-HRMS m/z 426.1143 (M⁺, C₂₆H₁₉ClN₂O₂

requires 426.1135).

3-(6-Oxo-cyclopenten[f]indole-2-carbonyl)-1-(S)-(chloro-

methyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (73A).

(1.5 mg, 46%) as a pale yellow solid: [a]²_D³+46 (c 0.08,

3-[Benz[f]indole-2-carbonyl]-1-(chloromethyl)-5-hydroxy-

1,2-dihydro-3H-benz[e]indole (78A). (1.00–3.02 mg, 23–

71%) as a yellow solid: (natural enantiomer) [a]²_D³+32

(c 0.05, THF); (unnatural enantiomer) [a]²_D³ꢁ40 (c 0.1,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.27 (1H, br

s), 9.32 (1H, s), 8.21 (1H, d, J=8.3 Hz), 8.08 (1H, s),

8.02 (1H, br s), 7.80 (1H, d, J=8.2 Hz), 7.47–7.50 (2H,

m), 7.30–7.33 (2H, m), 4.76–4.81 (2H, m), 4.17–4.22

(1H, m), 4.01 (1H, dd, J=11.2, 3.4 Hz), 3.61–3.63 (1H,

m), 3.22 (2H, t, J=6.4 Hz), 2.62–2.64 (2H, m); MAL-

DIFT-HRMS m/z 430.1063 (M⁺, C₂₅H₁₉ClN₂O₃

requires 430.1079).

1

THF); H NMR (acetone-d₆, 500 MHz) d 10.80 (1H, br

s), 9.32 (1H, s), 8.35 (1H, s), 8.27 (1H, d, J=8.4 Hz),

8.09 (1H, br s), 8.06 (1H, s), 7.98 (1H, m), 7.95 (1H, m),

7.92 (1H, d, J=8.4 Hz), 7.57 (1H, ddd, J=8.3, 6.9, 1.4

Hz), 7.43–7.44 (1H, m), 7.42 (1H, ddd, J=8.3, 7.0, 1.2

Hz), 7.38 (1H, ddd, J=8.3, 6.3, 1.5 Hz), 7.32 (1H, ddd,

J=8.2, 6.7, 1.4 Hz), 4.92 (1H, t, J=10.2 Hz), 4.86 (1H,

dd, J=10.6, 2.2 Hz), 4.30–4.35 (1H, m), 4.09 (1H, dd,

J=10.8, 3.1 Hz), 3.86 (1H, dd, J=11.4, 8.4 Hz); MAL-

DIFT-HRMS m/z 426.1149 (M⁺, C₂₆H₁₉ClN₂O₂

requires 426.1135).

3-([1,3]Dioxolo[e]indole-2-carbonyl)-1-(S)-(chloromethyl)-

5-hydroxy-1,2-dihydro-3H-benz[e]indole (74A). (1.0 mg,

57%) as a yellow solid: [a]²_D³+30 (c 0.0065, CH₂Cl₂);

¹H NMR (CDCl₃, 500 MHz) d 10.94 (1H, br s), 9.34

(1H, s), 8.33 (1H, d, J=8.1 Hz), 8.15 (1H, br s), 7.98

(1H, d, J=8.4 Hz), 7.63 (1H, t, J=7.0 Hz), 7.47 (2H, t,

J=7.0 Hz), 7.18 (2H, t, J=8.5 Hz), 7.05 (1H, d, J=8.5

Hz), 6.15 (1H, s), 4.94 (1H, m), 4.86 (1H, m), 4.38 (1H,

m), 4.16 (1H, m), 3.92 (1H, t, J=8.3 Hz); IR (ﬁlm) n_max

Data for spirocyclized compounds

N²-[(4-Methoxyindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (6B). A solu-

tion of 6A (0.98 mg, 2.4 mmol) and DBU (0.73 mg, 4.8

3415, 2943, 2862, 1605, 1580, 1241, 1041 cm^ꢁ1

;

MALDI-FTMS m/z 420.0869 (M⁺, C₂₃H₁₇ClN₂O₄

requires 420.0871).

mmol) in 480 mL o f CHCN/THF was stirred for 1 h at

3

3830

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

0 ^ꢂC. The reaction mixture was allowed to reach 25 ^ꢂC

over 2 h, and then puriﬁed by preparative TLC (10ꢃ20

cm, CH₂Cl₂/acetone 1:1) to aﬀord 6B (0.82 mg, 92%) as

(1H, dd, J=7.7, 0.9 Hz), 7.58 (1H, ddd, J=8.1, 7.1, 1.3

Hz), 7.43 (1H, td, J=7.6, 1.0 Hz), 7.28 (1H, d, J=8.3

Hz), 7.22 (1H, d, J=2.1 Hz), 7.20 (1H, m), 7.05 (1H, t,

J=7.9 Hz), 7.00 (1H, s), 4.66 (1H, dd, J=10.0, 4.9 Hz),

4.56 (1H, d, J=10.3 Hz), 3.97 (3H, s), 3.20 (1H, dt,

J=7.7, 4.9 Hz), 1.79 (1H, dd, J=7.7, 4.2 Hz), 1.73 (1H,

t, J=4.7 Hz); IR (ﬁlm) n_max2960, 2868, 1651, 1626,

1600, 1529, 1489, 1393, 1371, 1342, 1312, 1263, 1126,

732 cm^ꢁ1; MALDIFT-HRMS m/z 371.1395 (M+H⁺,

C₂₃H₁₉N₂O₃requires 371.1390).

1

a white solid: [a]²_D³+90 (c 0.04, THF); H NMR (ace-

tone-d₆, 500 MHz) d 10.96 (1H, br s), 8.11 (1H, dd,

J=8.1, 1.3 Hz), 7.58 (1H, ddd, J=8.0, 7.2, 1.2 Hz), 7.43

(1H, td, J=7.6, 1.1 Hz), 7.22-7.25 (2H, m), 7.21 (1H, d,

J=6.8 Hz), 7.17 (1H, m), 7.13 (1H, s), 6.58 (1H, d,

J=7.3 Hz), 4.72 (1H, dd, J=10.0, 4.9 Hz), 4.62 (1H, d,

J=9.8 Hz), 3.96 (3H, s), 3.23 (1H, dt, J=7.7, 4.9 Hz),

1.79 (1H, dd, J=7.9, 4.5 Hz), 1.71 (1H, t, J=4.7 Hz);

IR (ﬁlm) n_max3183, 2915, 2848, 1634, 1592, 1578, 1357,

1366, 1247, 1100, 775 cm^ꢁ1; MALDIFT-HRMS m/z

371.1398 (M+H⁺, C₂₃H₁₉N₂O₃requires 371.1390).

N²- [(4,5- Dimethoxyindole - 2 - yl)carbonyl] - (8b R,9aS)-

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (10B).

A solution of 10A (1.3 mg, 2.9 mmol) and DBU (2.7 mg,

17.8 mmol) in 500 mL o f CHCN–THF was stirred for 1

3

N²-[(5-Methoxyindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (7B). A solu-

tion of 7A (2.28 mg, 5.6 mmol) and DBU (1.7 mg, 11.2

h at 0 ^ꢂC. The reaction mixture was allowed to reach

25 ^ꢂC over 1 h, and then puriﬁed by preparative TLC

(10ꢃ20 cm, EtOAc/hexane 1:1) toaﬀord 10B (0.42 mg,

mmol) in 700 mL o f CHCN was stirred for 1 h at 0 ^ꢂC

35%) as a beige solid: [a]²_D³+225 (c 0.06, acetone); H

1

3

and 3 h at 25 ^ꢂC. The reaction mixture was puriﬁed by

preparative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 7B (1.52 mg, 73%) as white solid: [a]²_D³+122 (c

NMR (acetone-d₆, 500 MHz) d 10.8 (1H, br s), 8.10

(1H, d, J=6.6 Hz), 7.59 (1H, t, J=6.2 Hz ), 7.43 (1H, t,

J=7.0 Hz), 7.12–7.25 (5H, m), 4.72 (1H, m), 4.63 (1H,

d, J=9.9 Hz), 4.01 (3H, s), 3.87 (3H, s), 3.23 (1H, m),

1.70–1.80 (2H, m); IR (ﬁlm) n_max2321, 1656, 1600,

1380, 1267; MALDIFT-HRMS m/z 401.1499 (M+H⁺,

C₂₄H₂₀N₂O₄requires 401.1496).

1

0.08, THF); H NMR (acetone-d₆, 500 MHz) d 10.82

(1H, br s), 8.11 (1H, dd, J=7.9, 1.1 Hz), 7.58 (1H, td,

J=7.6, 1.3 Hz), 7.49 (1H, d, J=9.0 Hz), 7.43 (1H, td,

J=7.5, 1.3 Hz), 7.20 (1H, d, J=8.1 Hz), 7.17–7.18 (1H,

m), 7.15 (1H, d, J=2.6 Hz), 7.09 (1H, s), 6.98 (1H, dd,

J=9.0, 2.1 Hz), 4.68 (1H, dd, J=10.0, 4.9 Hz), 4.59

(1H, d, J=9.8 Hz), 3.82 (3H, s), 3.21 (1H, dt, J=7.8,

4.8 Hz), 1.78 (1H, dd, J=7.7, 4.7 Hz), 1.71 (1H, t,

J=4.7 Hz); IR (ﬁlm) n_max2915, 1647, 1624, 1595, 1517,

1403, 1387, 1266, 1235 cm^ꢁ1; MALDIFT-HRMS m/z

371.1405 (M+H⁺, C₂₃H₁₉N₂O₃requires 371.1390).

N²- [(5,6 - Dimethoxyindole - 2 - yl)carbonyl] - (8bR,9aS) -

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (11B).

A solution of 11A (1.72 mg, 3.9 mmol) in 390 mL

CH₃CN was treated with DBU (1.2 mg, 7.9 mmol) and

stirred for 1 h at 0 ^ꢂC. The reaction mixture was allowed

ꢂ

toreach 25 C over 1 h, and then puriﬁed by preparative

TLC (10ꢃ20 cm, THF/hexane 2:1) toaﬀord 11B (1.29

N²-[(6-Methoxyindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (8B). A solu-

mg, 82%) as a pale yellow solid: [a]²_D³+165 (c 0.07,

1

THF); H NMR (acetone-d₆, 500 MHz) d 10.69 (1H, br

tion of 8A (1.40 mg, 3.4 mmol) in 680 mL o f CHCN/

s), 8.10 (1H, dd, J=7.9, 1.5 Hz), 7.58 (1H, ddd, J=8.0,

7.2, 1.2 Hz), 7.43 (1H, m), 7.19 (1H, m), 7.15 (1H, m),

7.13 (1H, s), 7.12 (1H, s), 7.09 (1H, s), 4.66 (1H, dd,

J=10.3, 5.1 Hz), 4.56 (1H, d, J=9.8 Hz), 3.86 (3H, s),

3.83 (3H, s), 3.21 (1H, dt, J=7.8, 4.9 Hz), 1.77 (1H, dd,

J=7.7, 4.3 Hz), 1.68 (1H, t, J=4.5 Hz); IR (ﬁlm) n_max

3325, 2916, 1634, 1600, 1515, 1498, 1386, 1280, 1262,

1130 cm^ꢁ1; MS (ESI positive) m/z 399 (M+H⁺).

3

THF was treated with DBU (1.05 mg, 6.9 mmol) and

then stirred for 1 h at 0 ^ꢂC. The reaction mixture was

allowed to reach 25 ^ꢂC over 1 h, and then puriﬁed by

preparative TLC (10ꢃ20 cm, THF/hexane 3:2) toaﬀord

8B (1.25 mg, 98%) as an oﬀ-white solid: [a]²_D³+147 (c

1

0.07, THF); H NMR (acetone-d₆, 500 MHz) d 10.76

(1H, br s), 8.10 (1H, dd, J=7.9, 1.1 Hz), 7.56–7.59 (2H,

m), 7.43 (1H, m), 7.22 (1H, dd, J=2.1, 0.9 Hz), 7.20

(1H, d, J=7.3 Hz), 7.13 (1H, s), 7.07 (1H, d, J=2.1

Hz), 6.79 (1H, dd, J=8.6, 2.1 Hz), 4.68 (1H, dd,

J=10.0, 4.9 Hz), 4.59 (1H, d, J=9.8 Hz), 3.84 (3H, s),

3.21 (1H, dt, J=8.0, 4.9 Hz), 1.77 (1H, dd, J=7.7, 4.3

Hz), 1.69 (1H, t, J=4.5 Hz); IR (ﬁlm) n_max3321, 2900,

1644, 1624, 1599, 1505, 1275 cm^ꢁ1; MALDIFT-HRMS

m/z 371.1392 (M+H⁺, C₂₃H₁₉N₂O₃requires

371.1390).

N²- [(6,7 - Dimethoxyindole - 2 - yl)carbonyl] - (8bR,9aS) -

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (12B).

A solution of 12A (1.15 mg, 2.6 mmol) in 260 mL

CH₃CN was treated with DBU (0.80 mg, 5.3 mmol) and

then stirred for 2 h at 0 ^ꢂC. The reaction mixture was

then puriﬁed by preparative TLC (10ꢃ20 cm, THF/

hexane 1:1) toaﬀord 12B (0.68 mg, 65%) as a white

1

solid: [a]²_D³+168 (c 0.025, THF); H NMR (acetone-d₆,

500 MHz) d 10.47 (1H, br s), 8.10 (1H, dd, J=8.3, 1.1

Hz), 7.58 (1H, td, J=7.5, 1.3 Hz), 7.43 (1H, m), 7.39

(1H, d, J=8.5 Hz), 7.22 (1H, d, J=2.6 Hz), 7.20 (1H, d,

J=7.3 Hz), 7.03 (1H, s), 6.99 (1H, d, J=9.0 Hz), 4.66

(1H, dd, J=10.0, 4.9 Hz), 4.55 (1H, d, J=10.3 Hz), 3.94

(3H, s), 3.93 (3H, s), 3.20 (1H, dt, J=7.7, 4.9 Hz), 1.78

(1H, dd, J=7.9, 4.1 Hz), 1.71 (1H, t, J=4.7 Hz); IR

(ﬁlm) n_max3271, 2917, 2848, 1627, 1598, 1379, 1269,

1252 cm^ꢁ1; MALDIFT-HRMS m/z 401.1509 (M+H⁺,

C₂₄H₂₁N₂O₄requires 401.1496).

N²-[(7-Methoxyindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (9B). A solu-

tion of 9A (1.30 mg, 3.2 mmol) and DBU (0.97 mg, 6.4

mmol) in 320 mL o f CHCN and 320 mL of THF were

3

stirred for 1.5 h at 0 ^ꢂC and 1 h from 0 to 25 ^ꢂC. The

reaction mixture was then puriﬁed by preparative TLC

(10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 9B (1.11 mg,

94%) as a pale yellow solid: [a]²_D³+170 (c 0.05, THF);

¹H NMR (acetone-d₆, 500 MHz) d 10.47 (1H, br s), 8.10

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3831

N²- [(5,7 - Dimethoxyindole - 2 - yl)carbonyl] - (8bR,9aS) -

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (13B).

A solution of 13A (1.0 mg, 2.3 mmol) in 230 mL CH₃CN

was treated with DBU (0.70 mg, 4.6 mmol) and stirred

for 1.5 h at 0 ^ꢂC. The reaction mixture was allowed to

reach 25 ^ꢂC over 2 h, and then puriﬁed by preparative

TLC (10ꢃ20 cm, THF/hexane 1:1) toaﬀord 13B (0.90

mg, 98%) as a pale yellow solid: [a]²_D³ꢁ58 (c 0.14,

mmol) in 330 mL o f CHCN and 100 mL of THF was

3

stirred for 1.5 h at 0 ^ꢂC. The reaction mixture was then

puriﬁed by preparative TLC (10ꢃ20 cm, CH₂Cl₂/ace-

tone 1:1) to aﬀord 17B (1.02 mg, 88%) as a beige solid:

[a]²_D³+124 (c 0.05, THF); ¹H NMR (acetone-d₆,

500 MHz) d 10.82 (1H, br s), 8.11 (1H, dd, J=7.7, 1.1

Hz), 7.58 1H, (ddd, J=8.3, 6.9, 1.0 Hz), 7.48 (1H, m),

7.43 (1H, td, J=7.5, 1.1 Hz), 7.20 (1H, dd, J=7.3, 0.7

Hz), 7.16 (1H, dd, J=2.2, 0.7 Hz), 7.15 (1H, d, J=2.6

Hz), 7.09 (1H, s), 6.98 (1H, dd, J=9.0, 2.4 Hz), 4.68

(1H, dd, J=10.1, 5.0 Hz), 4.59 (1H, d, J=9.9 Hz), 4.01

(2H, t, J=6.4 Hz), 3.21 (1H, dt, J=7.8, 4.9 Hz), 1.75–

1.80 (3H, m), 1.71 (1H, t, J=4.6 Hz), 1.49–1.56 (2H, m),

0.98 (3H, t, J=7.3 Hz); IR (ﬁlm) n_max2975, 1651, 1622,

1597, 1515, 1386, 1266, 1236, 1183 cm^ꢁ1; MALDIFT-

HRMS m/z 413.1855 (M+H⁺, C₂₆H₂₄N₂O₃requires

413.1860).

1

CHCl₃); H NMR (acetone-d₆, 500 MHz) d 10.41 (1H,

br s), 8.10 (1H, dd, J=7.9, 1.5 Hz), 7.58 (1H, ddd,

J=8.1, 7.1, 1.3 Hz), 7.43 (1H, td, J=7.6, 1.1 Hz), 7.19

(1H, m), 7.12 (1H, d, J=2.6 Hz), 6.97 (1H, s), 6.71 (1H,

d, J=2.1 Hz), 6.47 (1H, d, J=2.1 Hz), 4.63 (1H, dd,

J=10.0, 4.9 Hz), 4.52 (1H, d, J=10.3 Hz), 3.95 (3H, s),

3.81 (3H, s), 3.19 (1H, dt, J=7.7, 4.9 Hz), 1.79 (1H, dd,

J=7.7, 4.3 Hz), 1.73 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max

3292, 2916, 1652, 1645, 1627, 1598, 1532, 1394, 1312,

1267, 1250 cm^ꢁ1; MALDIFT-HRMS m/z 423.1317

(M+Na⁺, C₂₄H₂₀N₂NaO₄requires 423.1315).

N²-[(5-Benzyloxyindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (18B). A solu-

tion of 18A (0.88 mg, 1.8 mmol) and DBU (0.55 mg, 3.6

N²-[(5-Ethoxyindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (15B). A solu-

tion of 15A (1.56 mg, 3.7 mmol) and DBU (1.13 mg, 7.4

mmol) in 180 mL o f CHCN and 180 mL of THF was

3

stirred for 2.5 h at 0 ^ꢂC. The reaction mixture was then

puriﬁed by preparative TLC (10ꢃ20 cm, CH₂Cl₂/ace-

tone 1:1) to aﬀord 18B (0.74 mg, 91%) as a pale yellow

mmol) in 370 mL o f CHCN and 370 mL of THF was

3

stirred for 1 h at 0 ^ꢂC. The reaction mixture was then

puriﬁed by preparative TLC (10ꢃ20 cm, CH₂Cl₂/ace-

tone 1:1) to aﬀord 15B (1.35 mg, 94%) as a pale yellow

1

solid: [a]²_D³+92 (c 0.1, THF); H NMR (acetone-d₆,

500 MHz) d 10.83 (1H, br s), 8.11 (1H, dd, J=7.7, 0.9

Hz), 7.58 (1H, td, J=7.6, 1.4 Hz), 7.50–7.52 (3H, m),

7.38–7.45 (3H, m), 7.31–7.34 (1H, m), 7.25 (1H, d,

J=2.1 Hz), 7.20 (1H, d, J=7.7 Hz), 7.17 (1H, dd,

J=2.1, 0.9 Hz), 7.09 (1H, s), 7.08 (1H, dd, J=9.0, 2.3

Hz), 5.15 (2H, s), 4.68 (1H, dd, J=9.8, 4.9 Hz), 4.59

(1H, d, J=10.3 Hz), 3.21 (1H, dt, J=7.7, 4.9 Hz), 1.78

(1H, dd, J=7.7, 4.7 Hz), 1.70 (1H, t, J=4.5 Hz); IR

(ﬁlm) n_max2923, 1651, 1623, 1597, 1515, 1388, 1265,

1236, 1171 cm^ꢁ1; MALDIFT-HRMS m/z 447.1693

(M+H⁺, C₂₉H₂₂N₂O₃requires 447.1703).

1

solid: [a]²_D³+144 (c 0.1, THF); H NMR (acetone-d₆,

500 MHz) d 10.81 (1H, br s), 8.11 (1H, dd, J=7.7, 1.3

Hz), 7.58 (1H, td, J=7.5, 1.1 Hz), 7.48 (1H, d, J=8.6

Hz), 7.43 (1H, td, J=7.5, 1.4 Hz), 7.20 (1H, m), 7.16

(1H, dd, J=2.6, 0.9 Hz), 7.14 (1H, d, J=2.6 Hz), 7.09

(1H, s), 6.98 (1H, dd, J=9.0, 2.6 Hz), 4.68 (1H, dd,

J=10.3, 5.1 Hz), 4.59 (1H, d, J=9.8 Hz), 4.06 (2H, q,

J=7.0 Hz), 3.21 (1H, dt, J=7.7, 4.9 Hz), 1.78 (1H, dd,

J=7.7, 4.3 Hz), 1.71 (1H, t, J=4.7 Hz), 1.39 (3H, t,

J=7.1 Hz); IR (ﬁlm) n_max2975, 1651, 1622, 1597, 1515,

1386, 1266, 1236, 1184, 1118 cm^ꢁ1; MALDIFT-HRMS

m/z 384.1483 (M⁺, C₂₄H₂₁N₂O₃requires 384.1474).

N²-[(5-Thiomethylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (21B). A solu-

tion of 21A (1.0 mg, 2.4 mmol) and DBU (0.72 mg, 4.7

N²- [(5- Propyloxyindole - 2 - yl)carbonyl] - (8b R,9aS) -

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (16B).

A solution of 16A (1.80 mg, 4.1 mmol) and DBU (1.26

mmol) in 240 mL o f CHCN was stirred for 1 h at 0 ^ꢂC.

3

The reaction mixture was allowed to reach 25 ^ꢂC o ver 2

h, and then puriﬁed by preparative TLC (10ꢃ20 cm,

THF/hexane 2:1) toaﬀord 21B (0.51 mg, 56%) as a

mg, 8.2 mmol) in 410 mL o f CHCN and 205 mL of THF

3

was stirred for 1.5 h at 0 ^ꢂC. The reaction mixture was

then puriﬁed by preparative TLC (10ꢃ20 cm, CH₂Cl₂/

acetone 1:1) to aﬀord 16B (1.15 mg, 70%) as a pale

1

beige solid: [a]²_D³+136 (c 0.025, THF); H NMR (ace-

tone-d₆, 500 MHz) d 11.00 (1H, br s), 8.10 (1H, m), 7.67

(1H, d, J=1.7 Hz), 7.58 (1H, td, J=7.5, 1.1 Hz), 7.55

(1H, d, J=8.6 Hz), 7.43 (1H, td, J=7.6, 1.1 Hz), 7.32

(1H, dd, J=8.8, 1.9 Hz), 7.22 (1H, d, J=1.7 Hz), 7.21

(1H, d, J=8.6 Hz), 7.10 (1H, s), 4.71 (1H, dd, J=9.8,

5.1 Hz), 4.61 (1H, d, J=10.3 Hz), 3.23 (1H, dt, J=7.8,

4.9 Hz), 2.51 (3H, s), 1.77–1.80 (1H, m), 1.72 (1H, t,

J=4.7 Hz); IR (ﬁlm) n_max3224, 2916, 1651, 1622, 1598,

1403, 1386, 1281, 1265 cm^ꢁ1; MALDIFT-HRMS m/z

387.1164 (M+H⁺, C₂₃H₁₉N₂O₂S requires 387.1162).

1

yellow solid: [a]²_D³+139 (c 0.06, THF); H NMR (ace-

tone-d₆, 500 MHz) d 10.80 (1H, br s), 8.11 (1H, dd,

J=7.7, 1.3 Hz), 7.58 (1H, ddd, J=8.0, 7.2, 1.2 Hz), 7.49

(1H, d, J=9.0 Hz), 7.43 (1H, m), 7.20 (1H, d, J=7.7

Hz), 7.16 (1H, dd, J=2.1, 0.9 Hz), 7.15 (1H, d, J=2.6

Hz), 7.09 (1H, s), 6.99 (1H, dd, J=9.0, 2.6 Hz), 4.68

(1H, dd, J=10.0, 4.9 Hz), 4.59 (1H, d, J=9.8 Hz), 3.97

(2H, t, J=6.4 Hz), 3.21 (1H, dt, J=7.7, 4.9 Hz), 1.77–

1.84 (3H, m), 1.71 (1H, t, J=4.7 Hz), 1.05 (3H, t, J=7.5

Hz); IR (ﬁlm) n_max2963, 1651, 1622, 1597, 1515, 1386,

1266, 1236, 1184 cm^ꢁ1

;

MALDIFT-HRMS m/z

N²-[(7-Thiomethylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (22B). A solu-

tion of 22A (1.5 mg, 3.6 mmol) and DBU (1.08 mg, 7.1

384.1483 (M⁺, C₂₅H₂₁N₂O₃requires 384.1474).

N²-[(5-Butyloxyindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (17B). A solu-

tion of 17A (1.26 mg, 2.8 mmol) and DBU (0.86 mg, 5.6

mmol) in 360 mL o f CHCN was stirred for 1 h at 0 ^ꢂC.

3

The reaction mixture was allowed to reach 25 ^ꢂC o ver 1

h, and then puriﬁed by preparative TLC (10ꢃ20 cm,

3832

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

THF/hexane 1:1) toaﬀord 22B (1.01 mg, 74%) as a

1

1.7 Hz), 7.49 (1H, m), 7.48 (1H, d, J=6.4 Hz), 7.43 (1H,

td, J=7.6, 1.1 Hz), 7.20 (1H, d, J=8.6 Hz), 7.17–7.18

(1H, m), 7.15 (1H, dd, J=8.3, 1.5 Hz), 7.10 (1H, s), 4.69

(1H, dd, J=10.3, 5.1 Hz), 4.60 (1H, d, J=10.3 Hz), 3.21

(1H, dt, J=7.7, 4.9 Hz), 2.41 (3H, s), 1.78 (1H, dd,

J=7.7, 4.4 Hz), 1.71 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max

2921, 1641, 1619, 1594, 1557, 1405, 1388 cm^ꢁ1; MAL-

DIFT-HRMS m/z 355.1441 (M+H⁺, C₂₃H₁₉N₂O₂

requires 355.1441).

beige solid: [a]²_D³+184 (c 0.05, THF); H NMR (ace-

tone-d₆, 500 MHz) d 10.27 (1H, br s), 8.10 (1H, dd,

J=7.7, 1.3 Hz), 7.63 (1H, d, J=8.1 Hz), 7.58 (1H, td,

J=7.6, 1.7 Hz), 7.43 (1H, td, J=7.5, 1.3 Hz), 7.37 (1H,

dd, J=7.3, 0.8 Hz), 7.31 (1H, d, J=2.1 Hz), 7.20 (1H,

d, J=8.6 Hz), 7.16 (1H, t, J=7.7 Hz), 7.03 (1H, s), 4.68

(1H, dd, J=10.0, 4.9 Hz), 4.58 (1H, d, J=9.8 Hz), 3.21

(1H, dt, J=7.8, 4.8 Hz), 2.57 (3H, s), 1.80 (1H, dd,

J=7.7, 4.3 Hz), 1.74 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max

2916, 2848, 1626, 1592, 1568, 1386, 770, 733 cm^ꢁ1

MALDIFT-HRMS m/z 387.1176

(M+H⁺,

C₂₃H₁₉N₂O₂S requires 387.1162).

;

N²-[(5-Ethylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-tetra-

hydrocyclopropa[c]benz[e]indol-4-one (25B). A solution

of 25A (1.1 mg, 2.7 mmol) and DBU (1.18 mg, 7.8 mmol)

in 270 mL o f CHCN was stirred for 1 h at 0 ^ꢂC and 1 h

3

N²-[(5-Thioethylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (23B). A solu-

tion of 23A (1.7 mg, 3.9 mmol) and DBU (1.18 mg, 7.8

at 25 ^ꢂC. The reaction mixture was puriﬁed by pre-

parative TLC (10ꢃ20 cm, THF/hexane 1:1) toaﬀord

25B (0.61 mg, 61%) as a white solid: [a]²_D³+188 (c

mmol) in 390 mL o f CHCN was stirred for 1.5 h at 0 ^ꢂC.

0.025, THF); H NMR (acetone-d₆, 500 MHz) d 10.85

1

3

The reaction mixture was allowed to reach 25 ^ꢂC over

1.5 h, and then puriﬁed by preparative TLC (10ꢃ20 cm,

THF/hexane 1:1) toaﬀord 23B (1.28 mg, 82%) as a pale

(1 h, br s), 8.10 (1H, dd, J=7.7, 0.9 Hz), 7.58 (1H, t,

J=7.6, 1.7 Hz), 7.51 (1H, s), 7.50 (1H, d, J=9.0 Hz),

7.43 (1H, td, J=7.6, 1.1 Hz), 7.19–7.21 (3H, m), 7.10

(1H, s), 4.70 (1H, dd, J=10.3, 5.1 Hz), 4.61 (1H, d,

J=9.8 Hz), 3.22 (1H, dt, J=7.7, 4.9 Hz), 2.72 (2H, q,

J=7.6 Hz), 1.78 (1H, dd, J=7.5, 4.5 Hz), 1.71 (1H, t,

J=4.7 Hz), 1.26 (3H, t, J=7.5 Hz); IR (ﬁlm) n_max3241,

2944, 2913, 2862, 1641, 1615, 1595, 1518, 1385, 1267

1

yellow solid: [a]²_D³+135 (c 0.07, THF); H NMR (ace-

tone-d₆, 500 MHz) d 11.04 (1H, br s), 8.11 (1H, dd,

J=7.9, 1.1 Hz), 7.78 (1H, d, J=1.7 Hz), 7.58 (1H, td,

J=7.5, 1.1 Hz), 7.57 (1H, d, J=8.6 Hz), 7.43 (1H, m),

7.38 (1H, dd, J=8.6, 1.7 Hz), 7.24 (1H, dd, J=2.1, 0.9

Hz), 7.21 (1H, d, J=7.3 Hz), 7.11 (1H, s), 4.70 (1H, dd,

J=10.0, 4.9 Hz), 4.62 (1H, d, J=9.8 Hz), 3.23 (1H, dt,

J=8.0, 4.9 Hz), 2.93 (2H, q, J=7.3 Hz), 1.79 (1H, dd,

J=8.1, 4.3 Hz), 1.72 (1H, t, J=4.7 Hz), 1.24 (3H, t,

J=7.3 Hz); IR (ﬁlm) n_max3231, 2964, 2916, 1646, 1621,

;

cm^ꢁ1MALDIFT-HRMS m/z 369.1585 (M+H⁺,

C₂₄H₂₀N₂O₂requires 369.1597).

N²-[(5-Methoxymethylindole-2-yl)carbonyl]-(8bR,9aS)-

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (26B).

A solution of 26A (1.4 mg, 3.3 mmol) and DBU (1.01

1595, 1380, 1262 cm^ꢁ1

;

MALDIFT-HRMS m/z

423.1131

423.1138).

(M+Na⁺,

C₂₄H₂₀N₂NaO₂S requires

mg, 6.6 mmol) in 330 mL o f CHCN was stirred for 1 h

3

at 0 ^ꢂC. The reaction mixture was then puriﬁed by pre-

parative TLC (10ꢃ20 cm, THF/hexane 3:2) toaﬀord

26B (1.09 mg, 85%) as a beige solid: [a]²_D³+128 (c 0.05,

N²-[(Indole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-tetrahydro-

cyclopropa[c]benz[e]indol-4-one (5B, CBI-indole).

1

A

THF); H NMR (acetone-d₆, 500 MHz) d 10.97 (1H, br

solution of 5A (1.50 mg, 4 mmol) and DBU (1.2 mg, 8

s), 8.11 (1H, dd, J=7.7, 0.9 Hz), 7.67 (1H, m), 7.58 (1H,

ddd, J=8.0, 7.0, 1.3 Hz), 7.57 (1H, d, J=8.1 Hz), 7.43

(1H, td, J=7.5, 1.4 Hz), 7.31 (1H, dd, J=8.6, 1.7 Hz),

7.27 (1H, dd, J=2.1, 0.9 Hz), 7.20 (1H, d, J=7.3 Hz),

7.12 (1H, s), 4.71 (1H, dd, J=10.0, 4.9 Hz), 4.62 (1H, d,

J=10.3 Hz), 4.51 (2H, s), 3.32 (3H, s), 3.23 (1H, dt,

J=7.8, 5.0 Hz), 1.79 (1H, dd, J=7.9, 4.5 Hz), 1.72 (1H,

t, J=4.7 Hz); IR (ﬁlm) n_max3217, 2918, 1651, 1622,

1598, 1403, 1392, 1289, 760 cm^ꢁ1; MALDIFT-HRMS

m/z 385.1558 (M+H⁺, C₂₄H₂₁N₂O₃requires 385.1547).

mmol) in 400 mL o f CHCN was stirred for 1 h at 0 ^ꢂC

3

and the reaction mixture was puriﬁed by preparative

TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 5B (1.25

mg, 93%) as a white solid: [a]²_D³+159 (c 0.07, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.95 (1H, br s, 1H),

8.12 (1H, dd, J=7.5, 1.1 Hz), 7.72 (1H, dd, J=8.1, 0.9

Hz), 7.57–7.61 (2H, m), 7.44 (1H, td, J=7.6, 1.1 Hz),

7.32 (1H, ddd, J=8.2, 6.9, 1.2 Hz), 7.29 (1H, dd, J=2.1,

0.9 Hz), 7.21 (1H, d, J=7.3 Hz), 7.13 (1H, ddd, J=8.0,

6.9, 1.0 Hz), 4.72 (1H, dd, J=9.8, 5.1 Hz), 4.63 (1H, d,

J=9.8 Hz), 3.23 (1H, dt, J=7.8, 4.8 Hz), 1.80 (1H, dd,

J=7.3, 4.7 Hz), 1.73 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max

2924, 1651, 1622, 1597, 1403, 1389, 1343, 1309, 1270,

1252, 744 cm^ꢁ1; MALDIFT-HRMS m/z 341.1276

(M+H⁺, C₂₂H₁₇N₂O₂requires 341.1284).

N²-[(7-Methoxymethylindole-2-yl)carbonyl]-(8bR,9aS)-

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (27B).

A solution of 27A (1.15 mg, 2.7 mmol) and DBU (0.83

mg, 5.5 mmol) in 270 mL o f CHCN was stirred for 1 h

3

at 0 ^ꢂC, and then puriﬁed by preparative TLC (10ꢃ20

cm, THF/hexane 3:2) toaﬀord 27B (0.91 mg, 87%) as a

N²-[(5-Methylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (24B). A solu-

tion of 24A (1.52 mg, 3.9 mmol) and DBU (1.18 mg, 7.8

white solid: [a]²_D³+125 (c 0.04, THF); H NMR (ace-

1

tone-d₆, 500 MHz) d 10.31 (1H, br s), 8.11 (1H, dd,

J=7.9, 1.5 Hz), 7.67 (1H, d, J=7.7 Hz), 7.58 (1H, td,

J=7.6, 1.7 Hz), 7.43 (1H, td, J=7.6, 1.1 Hz), 7.30 (1H,

d, J=2.1 Hz), 7.26 (1H, m), 7.21 (1H, d, J=7.3 Hz),

7.11 (1H, dd, J=8.1, 6.8 Hz), 7.11 (1H, s), 4.86 (2H, s),

4.71 (1H, dd, J=10.0, 4.9 Hz), 4.61 (1H, d, J=10.3 Hz),

3.41 (3H, s), 3.22 (1H, dt, J=7.7, 4.9 Hz), 1.79 (1H, dd,

J=8.1, 4.3 Hz), 1.72 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max

mmol) in 390 mL o f CHCN was stirred for 1.5 h at 0 ^ꢂC

3

and the reaction mixture was puriﬁed by preparative

TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 24B

(1.20 mg, 87%) as a white solid: [a]²_D³+149 (c 0.07,

1

THF); H NMR (acetone-d₆, 500 MHz) d 10.81 (1H, br

s), 8.11 (1H, dd, J=7.5, 1.1 Hz), 7.58 (1H, td, J=7.6,

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3833

3450, 3269, 2825, 1651, 1626, 1599, 1386, 1265, 749

cm^ꢁ1MALDIFT-HRMS m/z 385.1547 (M+H⁺,

C₂₄H₂₁N₂O₂requires 385.1547).

treated with NaH (0.25 mg, 10.5 mmol) and was stirred

for 1.5 h at 0 ^ꢂC. The reaction mixture was then puriﬁed

by preparative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 31B (0.41 mg, 21%) as a beige solid: [a]²_D³+80 (c

;

N²-[(5-Bromoindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (28B). A solu-

tion of 28A (1.72 mg, 3.8 mmol) in 860 mL of THF was

treated with NaH (0.18 mg, 7.6 mmol) and was stirred

for 2 h at 0 ^ꢂC, then warmed to25 ^ꢂC over 1 h and stir-

red for 3 h. The reaction mixture was puriﬁed by pre-

parative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord

28B (0.60 mg, 38%) as a beige solid: [a]²_D³+66 (c 0.03,

0.025, THF); H NMR (acetone-d₆, 500 MHz) d 11.45

1

(1H, br s), 8.22–8.23 (1H, m), 8.11 (1H, dd, J=8.3, 1.1

Hz), 7.77 (1H, dt, J=8.5, 0.9 Hz), 7.60 (1H, dd, J=8.6,

1.3 Hz), 7.57–7.61 (1H, m), 7.42–7.46 (2H, m), 7.21 (1H,

d, J=7.3 Hz), 7.11 (1H, s), 4.74 (1H, dd, J=10.0, 4.9

Hz), 4.65 (1H, d, J=10.3 Hz), 3.24 (1H, dt, J=7.8, 4.9

Hz), 1.80 (1H, dd, J=7.7, 4.7 Hz), 1.75 (1H, t, J=4.7

Hz); IR (ﬁlm) n_max2916, 2219, 1656, 1651, 1644, 1625,

1621, 1598, 1563, 1519, 1407, 1389, 1341, 1292, 1275,

1237 cm^ꢁ1; MALDIFT-HRMS m/z 366.1235 (M+H⁺,

C₂₃H₁₆N₃O₂requires 366.1237).

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.13 (1H, br

s), 8.11 (1H, dd, J=7.9, 1.1 Hz), 7.90 (1H, d, J=1.3 Hz),

7.59 (1H, ddd, J=8.1, 6.8, 1.1 Hz), 7.56 (1H, m), 7.41–

7.45 (1H, m), 7.42 (1H, dd, J=9.0, 2.1 Hz), 7.26–7.27 (1H,

m), 7.20 (1H, d, J=7.7 Hz), 7.10 (1H, s), 4.70 (1H, dd,

J=10.0, 4.9 Hz), 4.62 (1H, d, J=9.8 Hz), 3.23 (1H, dt,

J=7.7, 4.7 Hz), 1.79 (1H, dd, J=7.9, 4.5 Hz), 1.73 (1H, t,

J=4.7 Hz); IR (ﬁlm) n_max2925, 1651, 1645, 1633, 1593,

1563, 1557, 1505, 1393 cm^ꢁ1; MALDIFT-HRMS m/z

419.0408 (M+H⁺, C₂₂H₁₆BrN₂O₂requires 419.0390).

N²-[(7-Cyanoindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (32B). A solu-

tion of 32A (0.69 mg, 1.7 mmol) in 170 mL of DMF was

treated with NaH (0.08 mg, 3.4 mmol) and was stirred

for 1.5 h at 0 ^ꢂC. The reaction mixture was puriﬁed by

preparative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 32B (0.39 mg, 62%) as a pale yellow solid: [a]_D²³

+124 (c 0.05, THF); ¹H NMR (acetone-d₆, 500 MHz) d

11.55 (1H, br s), 8.11 (1H, dd, J=7.3, 0.9 Hz), 8.09 (1H,

dd, J=8.1, 1.3 Hz), 7.78 (1H, dd, J=7.5, 1.1 Hz), 7.59

(1H, ddd, J=7.9, 7.1, 1.3 Hz), 7.44 (1H, td, J=7.5, 1.3

Hz), 7.43 (1H, s), 7.31 (1H, dd, J=8.1, 7.3 Hz), 7.21

(1H, dd, J=7.3, 1.3 Hz), 7.00 (1H, s), 4.70 (1H, dd,

J=10.3, 5.1 Hz), 4.59 (1H, d, J=10.3 Hz), 3.22 (1H, dt,

J=7.7, 5.0 Hz), 1.81 (1H, dd, J=7.7, 4.7 Hz), 1.76 (1H,

t, J=4.7 Hz); IR (ﬁlm) n_max2923, 2222, 1719, 1657,

1626, 1599, 1404, 1389, 1301, 1270, 1252 cm^ꢁ1; MAL-

DIFT-HRMS m/z 365.1169 (M⁺, C₂₃H₁₅N₃O₂requires

365.1164).

N²-[(5-Chloroindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (29B). A solu-

tion of 29A (1.53 mg, 3.8 mmol) in 380 mL of DMF was

treated with NaH (0.18 mg, 7.6 mmol) and was stirred

for 1.5 h at 0 ^ꢂC. The reaction mixture was then puriﬁed

by preparative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 29B (1.08 mg, 77%) as a beige solid: [a]²_D³+108

1

(c 0.05, THF); H NMR (acetone-d₆, 500 MHz) d 11.12

(1H, br s), 8.11 (1H, dd, J=7.9, 1.5 Hz), 7.74 (1H, d,

J=2.3 Hz), 7.61 (1H, m), 7.58 (1H, td, J=7.5, 1.1 Hz),

7.43 (1H, td, J=7.7, 1.5 Hz), 7.30 (1H, dd, J=8.5, 2.1

Hz), 7.26 (1H, dd, J=2.1, 0.9 Hz), 7.20 (1H, d, J=7.3

Hz), 7.10 (1H, s), 4.70 (1H, dd, J=10.3, 5.1 Hz), 4.62

(1H, d, J=9.8 Hz), 3.23 (1H, dt, J=7.8, 4.9 Hz), 1.79

(1H, dd, J=7.7, 4.7 Hz), 1.73 (1H, t, J=4.5 Hz); IR

(ﬁlm) n_max2917, 1644, 1619, 1592, 1508, 1402, 1393,

1267 cm^ꢁ1; MALDIFT-HRMS m/z 375.0901 (M+H⁺,

C₂₂H₁₆ClN₂O₂requires 375.0895).

N²-[(5-Vinylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-tetra-

hydrocyclopropa[c]benz[e]indol-4-one (33B). A solution

of 33A (1.35 mg, 3.4 mmol) and DBU (1.02 mg, 6.7

mmol) in 600 mL o f CHCN/THF was stirred for 1 h at

3

0 ^ꢂC and 1 h at 25 ^ꢂC. The reaction mixture was then

puriﬁed by preparative TLC (10ꢃ20 cm, THF/hexane

1:1) toaﬀord 33B (0.80 mg, 65%) as a beige solid: [a]_D²³

+159 (c 0.03, THF); ¹H NMR (acetone-d₆, 500 MHz) d

11.10 (1H, br s), 8.11 (1H, dd, J=7.7, 0.9 Hz), 7.73 (1H,

s), 7.58 (1H, td, J=7.6, 1.7 Hz), 7.57 (1H, d, J=8.6 Hz),

7.54 (1H, dd, J=8.8, 1.5 Hz), 7.43 (1H, td, J=7.6, 1.1

Hz), 7.27 (1H, dd, J=2.1, 0.9 Hz), 7.21 (1H, d, J=7.3

Hz), 7.12 (1H, s), 6.85 (1H, dd, J=17.7, 10.9 Hz), 5.75

(1H, dd, J=17.7, 1.1 Hz), 5.15 (1H, dd, J=10.9, 1.1

Hz), 4.71 (1H, dd, J=9.8, 5.1 Hz), 4.62 (1H, d, J=10.3

Hz), 3.23 (1H, dt, J=7.7, 4.9 Hz), 1.79 (1H, dd, J=7.9,

4.5 Hz), 1.72 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max3208,

N²-[(5-Azidoindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-tetra-

hydrocyclopropa[c]benz[e]indol-4-one (30B). A solution

of 30A (1.07 mg, 2.6 mmol) and DBU (0.78 mg, 5.1

mmol) in 260 mL o f CHCN was stirred for 1 h at 0 ^ꢂC.

3

The reaction mixture was then puriﬁed by preparative

TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 30B

(0.82 mg, 84%) as a beige solid: [a]²_D³+100 (c 0.05,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.07 (1H, br

s), 8.11 (1H, m), 7.64 (1H, d, J=7.6 Hz), 7.64 (1H, ddd,

J=7.9, 7.3, 1.3 Hz), 7.42–7.45 (2H, m), 7.26 (1H, dd,

J=2.1, 0.9 Hz), 7.20 (1H, d, J=7.3 Hz), 7.10 (1H, s),

7.06 (1H, dd, J=8.6, 2.1 Hz), 4.70 (1H, dd, J=10.0, 4.9

Hz), 4.61 (1H, d, J=9.8 Hz), 3.22 (1H, dt, J=7.7, 4.9 Hz),

1.79 (1H, dd, J=7.9, 4.5 Hz), 1.73 (1H, t, J=4.7 Hz); IR

(ﬁlm) n_max2917, 2104, 1636, 1621, 1593, 1511, 1403, 1386,

1277, 1228, 1129 cm^ꢁ1; MS (ESI positive) m/z 382

(M+H⁺); MS (ESI negative) m/z 380 (MꢁH^ꢁ).

2917, 1651, 1622, 1597, 1520, 1403, 1386, 1271 cm^ꢁ1

MALDIFT-HRMS m/z 367.1442

(M+H⁺,

C₂₄H₁₉N₂O₂requires 367.1441).

;

N²-[(7-Vinylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-tetra-

hydrocyclopropa[c]benz[e]indol-4-one (34B). A solution

of 34A (0.95 mg, 2.4 mmol) and DBU (0.72 mg, 4.7

N²-[(5-Cyanoindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (31B). A solu-

tion of 31A (2.10 mg, 5.2 mmol) in 520 mL of DMF was

mmol) in 400 mL o f CHCN/THF was stirred for 1 h at

3

0 ^ꢂC and 1 h at 25 ^ꢂC. The reaction mixture was puriﬁed

by preparative TLC (10ꢃ20 cm, THF/hexane 1:1) to

3834

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

aﬀord 34B (0.76 mg, 88%) as a beige solid: [a]²_D³+198

(c 0.03, THF); H NMR (acetone-d₆, 500 MHz) d 10.69

J=2.1, 0.9 Hz), 7.20 (1H, d, J=7.5 Hz), 7.11 (1H, s),

4.70 (1H, dd, J=10.0, 4.9 Hz), 4.62 (1H, d, J=9.8 Hz),

3.22 (1H, dt, J=8.0, 4.9 Hz), 2.03 (3H, s), 1.79 (1H, dd,

J=7.5, 4.1 Hz), 1.72 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max

2971, 1651, 1622, 1598, 1519, 1404, 1386, 1269, 1249

1

(1H, br s), 8.11 (1H, dd, J=7.9, 1.5 Hz), 7.67 (1H, d,

J=8.1 Hz), 7.56–7.60 (2H, m), 7.48 (1H, dd, J=17.5,

11.1 Hz), 7.43 (1H, td, J=7.5, 1.3 Hz), 7.30 (1H, d,

J=2.1 Hz), 7.21 (1H, d, J=7.3 Hz), 7.15 (1H, t, J=7.7

Hz), 7.08 (1H, s), 5.95 (1H, dd, J=17.5, 1.3 Hz), 5.40

(1H, dd, J=11.1, 1.3 Hz), 4.70 (1H, dd, J=10.0, 4.9

Hz), 4.60 (1H, d, J=9.8 Hz), 3.22 (1H, dt, J=7.7, 4.9

Hz), 1.79 (1H, dd, J=7.7, 4.3 Hz), 1.72 (1H, t, J=4.7

Hz); IR (ﬁlm) n_max3230, 1652, 1622, 1598, 1401, 1386,

1300, 1263, 1250, 744 cm^ꢁ1; MALDIFT-HRMS m/z

367.1440 (M+H⁺, C₂₄H₁₉N₂O₂requires 367.1441).

cm^ꢁ1

;

C₂₅H₁₈N₂O₂requires 378.1368).

MALDIFT-HRMS m/z 378.1362 (M⁺,

N²-[(5-Aminoindole-2-yl)-carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (40B). A sam-

ple of 43A (0.75 mg, 1.5 mmol) was treated with 4 M

HCl in EtOAc for 1 h at 25 ^ꢂC and then the solvent was

evaporated. Crude 40A was dissolved in 300 mL o f

CH₃CN/THF and treated with DBU (0.69 mg, 2 mmol)

for 1 h at 0 ^ꢂC and then allowed to reach 25 ^ꢂC over 30

min. The reaction mixture was puriﬁed by preparative

TLC (10ꢃ20 cm, THF) toaﬀord 40B (0.46 mg, 85%) as

a yellow solid: [a]²_D³+92 (c 0.025, THF); ¹H NMR

(acetone-d₆, 500 MHz) d 10.77 (1H, br s), 8.10 (1H, dd,

J=7.8, 0.9 Hz), 7.48 (1H, td, J=7.6, 1.2 Hz), 7.43 (1H,

m), 7.18 (1H, d, J=8.7 Hz), 7.12 (1H, s), 7.06 (1H, d,

J=7.8 Hz), 6.87 (1H, d, J=1.8 Hz), 6.75 (1H, d, J=2.3

Hz), 6.71 (1H, dd, J=8.7, 2.3 Hz), 4.53 (1H, dd,

J=10.1, 4.6 Hz), 4.49 (1H, d, J=9.6 Hz), 3.03 (1H, dt,

J=7.6, 4.6 Hz), 1.66 (1H, dd, J=7.8, 4.1 Hz), 1.56 (1H,

t, J=4.6 Hz); IR (ﬁlm) n_max3325, 2927, 1652, 1622,

1598, 1520, 1386, 1267, 1246 cm^ꢁ1; MALDIFT-HRMS

m/z 356.1398 (M+H⁺, C₂₂H₁₈N₃O₂requires 356.1393).

N²-[(5-Isopropenylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (35B). A solu-

tion of 35A (1.3 mg, 3.1 mmol) and DBU (0.95 mg, 6.2

mmol) in 310 mL o f CHCN was stirred for 1 h at 0 ^ꢂC

3

and warmed over 1.5 h to 25 ^ꢂC. The reaction mixture

was puriﬁed by preparative TLC (10ꢃ20 cm, THF/hex-

ane 1:1) toaﬀord 35B (0.79 mg, 66%) as an oﬀ-white

1

solid: [a]²_D³+116 (c 0.05, THF); H NMR (acetone-d₆,

500 MHz) d 10.97 (1H, br s), 8.11 (1H, dd, J=7.7, 0.9

Hz), 7.81 (1H, s), 7.57–7.60 (2H, m), 7.55 (1H, d, J=9.0

Hz), 7.43 (1H, J=7.6 Hz), 7.28 (1H, d, J=1.7 Hz), 7.21

(1H, d, J=7.3 Hz), 7.11 (1H, s), 5.40 (1H, m), 5.05–5.06

(1H, m), 4.71 (1H, dd, J=10.0, 4.9 Hz), 4.62 (1H, d,

J=9.8 Hz), 3.23 (1H, dt, J=7.8, 4.9 Hz), 1.79 (1H, dd,

J=7.7, 4.3 Hz), 1.72 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max

3219, 2916, 1652, 1622, 1598, 1404, 1386, 1275 cm^ꢁ1

;

N²- [(5- Acetylaminoindole - 2 - yl)carbonyl] - (8b R,9aS) -

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (44B).

A solution of 44A (1.37 mg, 3.2 mmol) and DBU (0.96

MALDIFT-HRMS m/z

C₂₅H₂₁N₂O₂requires 381.1597).

381.1591

(M+H⁺,

mg, 6.3 mmol) in 320 mL o f CHCN and 320 mL of THF

3

N²-[(5-Ethynylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (37B). A solu-

tion of 37A (1.52 mg, 3.9 mmol) and DBU (1.18 mg, 7.8

was stirred for 1 h at 0 ^ꢂC and 2 h from 0 to 25 ^ꢂC. The

reaction mixture was then puriﬁed by preparative TLC

(10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 44B (0.95 mg,

mmol) in 390 mL o f CHCN was stirred for 1.5 h at 0 ^ꢂC.

76%) as a pale yellow solid: [a]²_D³+90 (c 0.1, THF); H

1

3

The reaction mixture was then puriﬁed by preparative

TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 37B

(1.20 mg, 87%) as a white solid: [a]²_D³+149 (c 0.07,

NMR (acetone-d₆, 500 MHz) d 10.85 (1H, br s), 9.07

(1H, br s), 8.21 (1H, d, J=1.8 Hz), 8.11 (1H, m), 7.58

(1H, ddd, J=8.3, 6.9, 1.0 Hz), 7.49 (1H, d, J=8.8 Hz),

7.43 (1H, ddd, J=8.1, 7.2, 1.1 Hz), 7.40 (1H, dd, J=8.8,

2.2 Hz), 7.21–7.22 (1H, m), 7.20 (1H, d, J=7.7 Hz), 7.12

(1H, s), 4.70 (1H, dd, J=10.1, 5.0 Hz), 4.62 (1H, d,

J=9.9 Hz), 3.22 (1H, dt, J=7.7, 4.8 Hz), 2.08 (3H, s),

1.78 (1H, dd, J=7.7, 4.4 Hz), 1.71 (1H, t, J=4.6 Hz);

IR (ﬁlm) n_max2971, 2930, 2872, 1658, 1652, 1644, 1634,

1622, 1596, 1563, 1558, 1519, 1487, 1463, 1404, 1386,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.14 (1H, br

s), 8.11 (1H, dd, J=7.7, 1.1 Hz), 7.90 (1H, s), 7.57–7.60

(1H, m), 7.59 (1H, d, J=8.6 Hz), 7.40–7.45 (1H, m),

7.41 (1H, dd, J=8.8, 1.5 Hz), 7.29–7.30 (1H, m), 7.21

(1H, d, J=7.3 Hz), 7.12 (1H, s), 4.71 (1H, dd, J=10.0,

4.9 Hz), 4.63 (1H, d, J=9.8 Hz), 3.51 (1H, s), 3.23 (1H,

dt, J=7.7, 4.9 Hz), 1.78 (1H, dd, J=7.7, 4.7 Hz), 1.73

(1H, t, J=4.7 Hz); IR (ﬁlm) n_max2923, 1642, 1619,

1596, 1561, 1515, 1406, 1386, 1270 cm^ꢁ1; MALDIFT-

HRMS m/z 365.1278 (M+H⁺, C₂₄H₁₇N₂O₂requires

365.1284).

1316, 1292, 1264, 1251, 1237, 1207, 1127, 1066 cm^ꢁ1

MALDIFT-HRMS m/z 398.1512

(M+H⁺,

C₂₄H₂₀N₃O₃requires 398.1499).

;

N²-[(5-Propionylaminoindole-2-yl)carbonyl]-(8bR,9aS)-

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (45B).

A solution of 45A (0.89 mg, 2 mmol) and DBU (0.60 mg,

N²-{5- [1 - (Propynyl)indole -2- yl]carbonyl} -(8b R,9aS) -

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (38B).

A solution of 38A (1.00 mg, 2.4 mmol) and DBU (0.73

4 mmol) in 200 mL o f CHCN and 200 mL of THF was

3

mg, 4.8 mmol) in 240 mL o f CHCN was stirred for 1 h

stirred for 1 h at 0 ^ꢂC and 2 h from 0 to 25 ^ꢂC. The

reaction mixture was puriﬁed by preparative TLC

(10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 45B (0.56 mg,

68%) as a pale yellow solid: [a]²_D³+56 (c 0.05, THF); ¹H

NMR (acetone-d₆, 500 MHz) d 10.87 (1H, br s), 9.01

(1H, br s), 8.24 (1H, br s), 8.11 (1H, dd, J=7.9, 1.5 Hz),

7.58 (1H, td, J=7.6, 1.6 Hz), 7.50 (1H, d, J=8.6 Hz),

7.43 (1H, td, J=7.6, 1.0 Hz), 7.42 (1H, dd, J=9.0, 2.1

3

at 0 ^ꢂC. The reaction mixture was then puriﬁed by pre-

parative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord

38B (0.72 mg, 79%) as a beige solid: [a]²_D³+106 (c 0.07,

1

THF); H NMR (acetone-d₆, 500 MHz) d 11.05 (1H, br

s), 8.10 (1H, dd, J=7.9, 1.1 Hz), 7.76 (1H, s), 7.58 (1H,

td, J=7.5, 1.3 Hz), 7.54 (1H, m), 7.43 (1H, td, J=7.5,

1.3 Hz), 7.31 (1H, dd, J=8.5, 1.3 Hz), 7.25 (1H, dd,

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3835

Hz), 7.22–7.23 (1H, m), 7.21 (1H, d, J=7.7 Hz), 7.13

(1H, s), 4.71 (1H, dd, J=10.0, 4.9 Hz), 4.63 (1H, d,

J=10.3 Hz), 3.23 (1H, dt, J=7.6, 4.9 Hz), 2.38 (2H, q,

J=7.6 Hz), 1.78 (1H, dd, J=7.7, 4.3 Hz), 1.71 (1H, t,

J=4.7 Hz), 1.17 (3H, t, J=7.7 Hz); IR (ﬁlm) n_max2921,

1650, 1621, 1590, 1552, 1515, 1386, 1265, 1250, 1236

Hz), 2.90 (1H, m), 2.23 (1H, t, J=7.5 Hz), 1.80 (1H, dd,

J=7.4, 4.9 Hz), 1.66 (1H, t, J=4.8 Hz); MALDIFT-

HRMS m/z 369.1242 (M+H⁺, C₂₃H₁₆N₂O₃requires

369.1234).

N²-[(5-Acetylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (54B). A solu-

tion of 54A (1.6 mg, 3.8 mmol) in 380 mL of DMF was

treated with NaH (0.18 mg, 7.6 mmol) and was stirred

for 1.5 h at 0 ^ꢂC. The reaction mixture was then puriﬁed

by preparative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 54B (1.08 mg, 77%) as a pale yellow solid: [a]_D²³

;

cm^ꢁ1MALDIFT-HRMS m/z 412.1658 (M+H⁺,

C₂₅H₂₂N₃O₃requires 412.1656).

N²- [(5- Butyrylaminoindole - 2 - yl)carbonyl] - (8b R,9aS) -

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (46B).

A solution of 46A (1.22 mg, 2.6 mmol) and DBU (0.80

1

mg, 5.3 mmol) in 260 mL o f CHCN and 260 mL of THF

+48 (c 0.05, THF); H NMR (acetone-d₆, 500 MHz) d

3

was stirred for 1.5 h at 0 ^ꢂC and 2 h from 0 to 25 ^ꢂC. The

reaction mixture was then puriﬁed by preparative TLC

(10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 46B (1.10 mg,

11.26 (1H, br s), 8.47 (1H, m), 8.11 (1H, dd, J=7.9, 1.1

Hz), 7.97 (1H, dd, J=8.5, 2.1 Hz), 7.66 (1H, m), 7.59

(1H, td, J=7.5, 1.1 Hz), 7.45 (1H, dd, J=2.1, 0.9 Hz),

7.44 (1H, td, J=7.6, 1.1 Hz), 7.21 (1H, d, J=7.3 Hz),

7.11 (1H, s), 4.74 (1H, dd, J=10.0, 4.9 Hz), 4.65 (1H, d,

J=10.3 Hz), 3.24 (1H, dt, J=7.7, 4.9 Hz), 2.63 (3H, s),

1.80 (1H, dd, J=7.7, 4.3 Hz), 1.74 (1H, t, J=4.7 Hz);

IR (ﬁlm) n_max2959, 1661, 1651, 1600, 1386, 1359, 1272,

1195, 1127 cm^ꢁ1; MALDIFT-HRMS m/z 383.1391

(M+H⁺, C₂₄H₁₉N₂O₃requires 383.1390).

1

99%) as a pale yellow solid: [a]²_D³+92 (c 0.1, THF); H

NMR (acetone-d₆, 500 MHz) d 10.85 (1H, br s), 9.01

(1H, br s), 8.23 (1H, d, J=1.7 Hz), 8.11 (1H, dd, J=7.9,

1.1 Hz), 7.58 (1H, td, J=7.5, 1.1 Hz), 7.50 (1H, d,

J=9.0 Hz), 7.41–7.45 (1H, m), 7.42 (1H, dd, J=9.0, 2.1

Hz), 7.22 (1H, m), 7.20 (1H, d, J=7.3 Hz), 7.12 (1H, s),

4.71 (1H, dd, J=10.0, 4.9 Hz), 4.62 (1H, d, J=10.3 Hz),

3.22 (1H, dt, J=7.8, 4.8 Hz), 2.34 (2H, t, J=7.3 Hz),

1.78 (1H, dd, J=7.9, 4.5 Hz), 1.72 (2H, sextet, J=7.4

Hz), 1.71 (1H, t, J=4.7 Hz), 0.97 (3H, t, J=7.5 Hz); IR

(ﬁlm) n_max3292, 2964, 2931, 2873, 1682, 1673, 1667,

1661, 1651, 1644, 1633, 1626, 1622, 1615, 1598, 1563,

1556, 1553, 1548, 1538, 1520, 1515, 1463, 1403, 1386,

1291, 1266, 1252, 1237, 1128 cm^ꢁ1; MALDIFT-HRMS

m/z 426.1819 (M+H⁺, C₂₆H₂₃N₃O₃requires 426.1812).

N²-[(7-Acetylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (55B). A solu-

tion of 55A (1.55 mg, 3.7 mmol) in 370 mL of DMF was

treated with NaH (0.18 mg, 7.4 mmol) and was stirred

for 1 h at 0 ^ꢂC. The reaction mixture was puriﬁed by

preparative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 55B (1.08 mg, 77%) as a white solid: [a]²_D³+196

1

(c 0.1, THF); H NMR (acetone-d₆, 500 MHz) d 11.03

N²-{[5-(N-Acetyl-N-methyl)aminoindole-2-yl]carbonyl}-

(8bR,9aS)-1,2,9,9a-tetrahydrocyclo propa[c]benz[e]indol-

4-one (47B). A solution of 47A (1.20 mg, 2.7 mmol) and

(1H, br s), 8.10–8.12 (2H, m), 8.07 (1H, d, J=8.1 Hz),

7.59 (1H, td, J=7.6, 1.3 Hz), 7.44 (1H, td, J=7.6, 1.1

Hz), 7.39 (1H, d, J=2.6 Hz), 7.32 (1H, t, J=7.7 Hz),

7.21 (1H, d, J=8.6 Hz), 7.15 (1H, s), 4.73 (1H, dd,

J=9.8, 5.1 Hz), 4.64 (1H, d, J=9.8 Hz), 3.24 (1H, dt,

J=8.0, 4.9 Hz), 2.79 (3H, s), 1.80 (1H, dd, J=7.7, 4.3

Hz), 1.76 (1H, t, J=4.7 Hz); IR (ﬁlm) n_max3434, 2918,

2846, 1661, 1651, 1621, 1594, 1557, 1515, 1386, 1307,

1263, 1123 cm^ꢁ1; MALDIFT-HRMS m/z 383.1392

(M+H⁺, C₂₄H₁₉N₂O₃requires 383.1390).

DBU (0.82 mg, 5.4 mmol) in 270 mL o f CHCN and 270

3

mL of THF was stirred for 2 h at 0 ^ꢂC and 1 h from 0 to

25 ^ꢂC. The reaction mixture was then puriﬁed by pre-

parative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord

47B (1.05 mg, 95%) as a pale yellow solid: [a]²_D³+80 (c

0.1, THF); ¹H NMR (acetone-d₆, 500 MHz) d 11.14

(1H, br s), 8.11 (1H, dd, J=7.7, 1.3 Hz), 7.66–7.68 (2H,

m), 7.59 (1H, td, J=7.5, 1.3 Hz), 7.44 (1H, m), 7.32

(1H, m), 7.21 (1H, d, J=7.7 Hz), 7.12 (1H, s), 4.72 (1H,

dd, J=10.1, 4.9 Hz), 4.64 (1H, d, J=9.8 Hz), 3.24 (1H,

dt, J=7.9, 4.8 Hz), 3.22 (3H, s), 1.80 (1H, dd, J=7.3,

4.3 Hz), 1.76 (3H, s), 1.73 (1H, t, J=4.7 Hz); IR (ﬁlm)

n_max2924, 1621, 1598, 1518, 1383, 1273, 1121, 1021,

897, 8.13, 782, 764, 742 cm^ꢁ1; MALDIFT-HRMS m/z

412.1664 (M+H⁺, C₂₅H₂₂N₃O₃requires 412.1656).

N²-[(5-Propionylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (56B). A solu-

tion of 56A (1.95 mg, 4.5 mmol) in 450 mL of DMF was

treated with NaH (0.22 mg, 9.0 mmol) and was stirred

for 1.5 h at 0 ^ꢂC. The reaction mixture was puriﬁed by

preparative TLC (10 20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 56B (0.86 mg, 46%) as a pale yellow solid: [a]_D²³

1

+120 (c 0.1, THF); H NMR (acetone-d₆, 500 MHz) d

N²-[(7-Formylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (53B). A solu-

tion of 53A (940 mg, 2.3 mmol) and DBU (1.9 mL, 12.3

11.27 (1H, br s), 8.48 (1H, d, J=0.9 Hz), 8.11 (1H, dd,

J=8.3, 1.1 Hz), 7.99 (1H, dd, J=8.5, 1.7 Hz), 7.66 (1H,

m), 7.59 (1H, td, J=7.6, 1.4 Hz), 7.44 (1H, dd, J=2.4,

1.1 Hz), 7.44 (1H, td, J=7.6, 1.1 Hz), 7.21 (1H, d,

J=8.6 Hz), 7.12 (1H, s), 4.74 (1H, dd, J=10.0, 4.9 Hz),

4.65 (1H, d, J=10.3 Hz), 3.24 (1H, dt, J=7.8, 4.9 Hz),

3.11 (2H, q, J=7.3 Hz), 1.80 (1H, dd, J=7.7, 4.3 Hz),

1.74 (1H, t, J=4.7 Hz), 1.18 (3H, t, J=7.3 Hz); IR

(ﬁlm) n_max2974, 2934, 2868, 1655, 1621, 1599, 1563,

1404, 1388, 1348, 1321, 1290, 1272, 1250, 1180, 1125

mmol) in 50 mL o f CHCN was stirred for 2 h at 23 ^ꢂC

3

and then puriﬁed by preparative TLC (10ꢃ20 cm,

EtOAc) toaﬀord 53B (0.41 mg, 48%) as a yellow solid:

[a]²_D³+226 (c 0.0023, CHCl₃); ¹H NMR (CDCl₃,

600 MHz) d 10.77 (1H, br s), 10.16 (1H, s), 8.25 (1H, d,

J=7.9 Hz), 7.99 (1H, d, J=7.9 Hz), 7.84 (1H, d, J=7.0

Hz), 7.55 (1H, t, J=7.4 Hz), 7.44 (1H, t, J=8.4 Hz),

7.35 (1H, t, J=7.9 Hz), 7.18 (1H, m), 7.04 (1H, s), 6.95

(1H, d, J=7.4 Hz), 4.50 (2H, m), 4.42 (1H, d, J=10.0

;

cm^ꢁ1MALDIFT-HRMS m/z 397.1546 (M+H⁺,

C₂₅H₂₁N₂O₃requires 397.1547).

3836

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

N²-[(5-Butyrylindole-2-yl)carbonyl]-(8bR,9aS)-1,2,9,9a-

tetrahydrocyclopropa[c]benz[e]indol-4-one (57B). A solu-

tion of 57A (1.92 mg, 4.3 mmol) in 430 mL of DMF was

treated with NaH (0.21 mg, 8.6 mmol) and was stirred

for 1.5 h at 0 ^ꢂC. The reaction mixture was then puriﬁed

by preparative TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to

aﬀord 57B (0.55 mg, 31%) as a pale yellow solid: [a]_D²³

7.16 (1H, dd, J=2.1, 0.9 Hz), 7.12 (1H, s), 7.05 (1H, s),

7.01 (1H, s), 6.00–6.01 (2H, m), 4.66 (1H, dd, J=10.0,

4.9 Hz), 4.56 (1H, d, J=10.3 Hz), 3.21 (1H, dt, J=7.7,

4.9 Hz), 1.77 (1H, dd, J=7.7, 4.3 Hz), 1.68 (1H, t,

J=4.7 Hz); IR (ﬁlm) n_max3321, 2917, 1634, 1594, 1426,

1284, 1262 cm^ꢁ1; MALDIFT-HRMS m/z 385.1196

(M+H⁺, C₂₃H₁₇N₂O₄requires 385.1183).

1

+96 (c 0.1, THF); H NMR (acetone-d₆, 500 MHz) d

11.27 (1H, br s), 8.48–8.49 (1H, m), 8.11 (1H, dd,

J=7.9, 1.5 Hz), 7.99 (1H, dd, J=8.6, 1.7 Hz), 7.66 (1H,

m), 7.59 (1H, ddd, J=8.1, 7.1, 1.3 Hz), 7.45 (1H, dd,

J=2.1, 0.9 Hz), 7.44 (1H, td, J=7.6, 1.1 Hz), 7.21 (1H,

d, J=8.5 Hz), 7.12 (1H, s), 4.74 (1H, dd, J=10.0, 4.9

Hz), 4.65 (1H, d, J=10.3 Hz), 3.25 (1H, dt, J=7.7, 4.9

Hz), 3.06 (2H, t, J=7.3 Hz), 1.80 (1H, dd, J=7.7, 4.3

Hz), 1.76 (2H, sextet, J=7.3 Hz), 1.74 (1H, t, J=4.7

Hz), 1.00 (3H, t, J=7.5 Hz); IR (ﬁlm) n_max2959, 2927,

1655, 1619, 1599, 1405, 1388, 1363, 1341, 1291, 1273,

1128 cm^ꢁ1; MALDIFT-HRMS m/z 411.1708 (M+H⁺,

C₂₆H₂₂N₂O₃requires 411.1703).

76B: A solution of 76A (700 mg, 1.7 mmol) and DBU (1.4

mg, 8.9 mmol) in 60 mL o f CHCN was stirred for 2 h at

3

23^ꢂC and then puriﬁed by preparative TLC (10ꢃ20 cm,

THF/hexane 1:1) toaﬀord 76B (590 mg, 92%) as a yellow

solid: [a]²_D³+26 (c 0.004, CH₂Cl₂); ¹H NMR (aceto ne-d₆,

600 MHz) d 11.21 (1H, br s), 8.10 (1H, d, J=7.9 Hz), 7.58

(1H, t, J=7.4 Hz), 7.49 (1H, t, J=8.3 Hz), 7.42 (1H, m),

7.25 (1H, s), 7.20 (1H, d, J=7.9 Hz), 7.11 (1H, d, J=7.0

Hz), 7.09 (1H, s), 7.05 (1H, d, J=7.9 Hz), 4.68 (2H, m),

4.58 (1H, d, J=10.0 Hz), 3.21 (1H, m), 3.16 (1H, t,

J=7.4 Hz), 3.01 (1H, t, J=7.4 Hz), 2.97 (1H, m), 2.94

(1H, t, J=7.4 Hz), 2.20 (1H, t, J=7.3 Hz), 1.77 (1H,

m), 1.70 (1H, dd, J=10.5, 5.3 Hz; MALDIFT-HRMS

m/z 381.1599 (M+H⁺, C₂₅H₂₀N₂O₂requires 381.1597).

N²-[(1,2-Dihydropyrrolo[3,2-e]benzofuran-7-yl)carbonyl]-

(8bR,9aS) - 1,2,9,9a -tetrahydrocyclopropa[c]benz[e]indol-

4-one (70B). A solution of 70A (0.8 mg, 1.9 mmol) and

N²- [(Benz[e]indole - 2 - yl)carbonyl] - 1,2,9,9a - tetrahydro-

cyclopropa[c]benz[e]indol-4-one (77B). A solution of

77A (2.05 mg, 4.8 mmol) and NaH (0.23 mg, 9.6 mmol) in

480 mL of THF was stirred for 1 h at 0 ^ꢂC and the reac-

tion mixture was separated by preparative TLC (10ꢃ20

cm, THF) and (10ꢃ20 cm, CH₂Cl₂/acetone 3:1) to aﬀord

77B (1.50 mg, 80%) as a beige solid: (natural enantio-

mer) [a]²_D³+114 (c 0.07, THF); (unnatural enantiomer)

[a]²_D³ꢁ111 (c 0.06, THF); ¹H NMR (acetone-d₆,

500 MHz) d 11.37 (1H, br s), 8.41 (1H, d, J=8.1 Hz),

8.12 (1H, dd, J=7.7, 0.9 Hz), 7.95–8.01 (2H, m), 7.77

(1H, d, J=9.0 Hz), 7.75 (1H, d, J=9.0 Hz), 7.57–7.61

(2H, m), 7.46 (1H, ddd, J=8.0, 6.9, 1.2 Hz), 7.42–7.45

(1H, m), 7.22 (1H, d, J=7.3 Hz), 7.19 (1H, s), 4.82 (1H,

dd, J=10.0, 4.9 Hz), 4.75 (1H, d, J=10.3 Hz), 3.26 (1H,

dt, J=7.7, 4.9 Hz), 1.80 (1H, dd, J=7.7, 4.7 Hz), 1.74

(1H, t, J=4.7 Hz); IR (ﬁlm) n_max2922, 1647, 1623, 1595,

1381, 1289, 1264 cm^ꢁ1; MALDIFT-HRMS m/z 391.1454

(M+H⁺, C₂₆H₁₉N₂O₂requires 391.1441).

DBU (1.7 mg, 11.5 mmol) in 500 mL o f CHCN–THF

3

was stirred for 1 h at 0 ^ꢂC. The reaction mixture was

allowed to reach 25 ^ꢂC over 1 h, and then puriﬁed by

preparative TLC (10ꢃ20 cm, EtOAc/hexane 1:1) to

aﬀord 70B (0.5 mg, 69%) as a beige solid: [a]²_D³+90 (c

1

0.07, acetone); H NMR (acetone-d₆, 600 MHz) d 8.10

(1H, d, J=7.9 Hz), 7.58 (1H, t, J=7.5 Hz), 7.43 (1H, t,

J=7.9 Hz), 7.36 (1H, d, J=8.8 Hz), 7.20 (1H, d, J=7.5

Hz), 7.11 (2H, m), 6.85 (1H, d, J=9.2 Hz), 4.70 (1H,

m), 4.61 (3H, m), 3.39 (1H, t, J=8.8 Hz), 3.21 (1H, m),

1.78 (1H, m), 1.71 (1H, m); MALDIFT-HRMS m/z

383.1417 (M+H⁺, C₂₄H₁₈N₂O₃requires 383.1396).

N²-[(Pyrrolo[3,2-e]benzofuran-7-yl)carbonyl]-(8bR,9aS)-

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (71B).

A solution of 71A (0.6 mg, 1.4 mmol) and DBU (1.3 mg,

8.6 mmol) in 500 mL o f CHCN-THF was stirred for 1 h

3

at 0 ^ꢂC. The reaction mixture was allowed to reach 25 ^ꢂC

over 1 h, and then puriﬁed by preparative TLC (10ꢃ20

cm, EtOAc/hexane 1:1) toaﬀord 71B (0.30 mg, 55%) as

N²-[(Benz[f]indole-2-yl)carbonyl]-1,2,9,9a-tetrahydrocyclo-

propa[c]benz[e]indol-4-one (78B). A solution of 78A (1.00

mg, 2.3 mmol) and DBU (0.71 mg, 4.7 mmol) in 240 mL

1

a beige solid: [a]²_D³+185 (c 0.04, acetone); H NMR

(acetone-d₆, 400 MHz) d 8.11 (1H, dd, J=6.8, 1.0 Hz),

7.90 (1H, d, J=2.1 Hz), 7.55–7.61 (4H, m), 7.44 (1H, t,

J=8.1 Hz), 7.21 (2H, m), 7.15 (1H, s), 4.66–4.77 (2H,

m), 3.25 (1H, m), 1.72-1.81 (2H, m); IR (ﬁlm) n_max2914,

1647, 1595, 1277, 739; MALDIFT-HRMS m/z 381.1231

(M+H⁺, C₂₄H₁₆N₂O₃requires 381.1234).

o f CHCN was stirred for 1 h at 0 ^ꢂC and the reaction

3

mixture was separated by twoconsecutive preparative

TLC (10ꢃ20 cm, CH₂Cl₂/acetone 1:1) to aﬀord 78B

(0.53 mg, 58%) as a yellow solid: (natural enantiomer)

[a]²_D³+126 (c 0.03, THF); (unnatural enantiomer) [a]²_D³

ꢁ136 (c 0.025, THF); ¹H NMR (acetone-d₆, 500 MHz) d

10.83 (1H, br s), 8.33 (1H, s), 8.12 (1H, dd, J=7.5, 1.3

Hz), 8.05 (1H, s), 7.97 (1H, d, J=7.7 Hz), 7.94 (1H, d,

J=8.8 Hz), 7.59 (1H, td, J=7.5, 1.5 Hz), 7.42–7.46 (1H,

m), 7.44 (1H, s), 7.38 (1H, ddd, J=8.4, 6.6, 1.1 Hz),

7.31 (1H, ddd, J=8.3, 6.8, 1.3 Hz), 7.22 (1H, d, J=7.3

Hz), 7.13 (1H, s), 4.77 (1H, dd, J=10.0, 5.0 Hz), 4.69

(1H, d, J=9.9 Hz), 3.25 (1H, dt, J=7.7, 5.0 Hz), 1.81

(1H, dd, J=7.7, 4.4 Hz), 1.77 (1H, t, J=4.6 Hz); IR

(ﬁlm) n_max2919, 1645, 1622, 1597, 1406, 1372, 1303,

1270, 1243 cm^ꢁ1; MALDIFT-HRMS m/z 391.1430

(M+H⁺, C₂₆H₁₉N₂O₂requires 391.1441).

N²- [([1,3]Dioxolo[f]indole - 2 - yl)carbonyl] - (8bR,9aS)-

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (75B).

A solution of 75A (1.25 mg, 3.1 mmol) in 310 mL o f

CH₃CN was treated with DBU (0.93 mg, 6.1 mmol) and

then stirred for 1 h at 0 ^ꢂC. The reaction mixture was

allowed to reach 25 ^ꢂC over 1 h, and then puriﬁed by

preparative TLC (10ꢃ20 cm, THF/hexane 2:1) toaﬀord

75B (0.90 mg, 77%) as a pale yellow solid: [a]²_D³+153 (c

1

0.04, THF); H NMR (acetone-d₆, 500 MHz) d 10.81

(1H, br s), 8.10 (1H, dd, J=7.7, 0.9 Hz), 7.57 (1H, m),

7.42 (1H, td, J=7.6, 1.1 Hz), 7.19 (1H, d, J=7.3 Hz),

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

3837

Acknowledgements

18. Boger, D. L.; Schmitt, H.; Fink, B. E.; Hedrick, M. P.

J. Org. Chem. 2001, 66, 6654.

19. Boger, D. L.; Stauﬀer, F.; Hedrick, M. P. Bioorg. Med.

Chem. Lett. 2001, 11, 2021.

20. Boger, D. L.; Bollinger, B.; Johnson, D. S. Bioorg. Med.

Chem. Lett. 1996, 6, 2207.

21. Boger, D. L.; Han, N.; Tarby, C. M.; Boyce, C. W.; Cai,

H.; Jin, Q.; Kitos, P. A. J. Org. Chem. 1996, 61, 4894.

22. Boger, D. L.; McKie, J. A.; Cai, H.; Cacciari, B.; Baraldi,

P. G. J. Org. Chem. 1996, 61, 1710.

23. Boger, D. L.; Santillan, A.; Searcey, M.; Brunette, S. R.;

Wolkenberg, S. E.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000,

65, 4101.

We thank Scott E. Wolkenberg and Bryan Yeung for

providing several starting materials. We gratefully

acknowledge the ﬁnancial support of the National

Institutes of Health (CA41986), Corixa Pharmaceu-

ticals, The Skaggs Institute of Chemical Biology, and

the award of

a

postdoctoral fellowship (F.S.,

2000–2001) by the Swiss National Science Foundation.

D.K. is a Skaggs Fellow.

References and Notes

24. Boger, D. L.; Hughes, T. V.; Hedrick, M. P. J. Org. Chem.

2001, 66, 2207.

1. Chidester, C. G.; Krueger, W. C.; Mizsak, S. A.; Duchamp,

D. J.; Martin, D. G. J. Am. Chem. Soc. 1981, 103, 7629.

2. Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto,

M.; Asano, K.; Kawamoto, I.; Tomita, F.; Nakano, H.

J. Antibiot. 1988, 41, 1915.

3. Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.;

Kawamoto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H.

J. Antibiot. 1990, 43, 1037.

4. Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.;

Ogawa, T.; Takahashi, K.; Sano, H.; Saitoh, Y. Chem. Pharm.

Bull. 1995, 43, 378.

5. Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl.

1996, 35, 1438. For earlier reviews, see: Boger, D. L. Acc.

Chem. Res. 1995, 28, 20. Boger, D. L.; Johnson, D. S. Proc.

Natl. Acad. Sci. U.S.A. 1995, 92, 3642. Boger, D. L. Chem-

tracts: Org. Chem. 1991, 4, 329. Synthesis: Boger, D. L.;

Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. Chem. Rev.

1997, 97, 787.

25. Eis, P. S.; Smith, J. A.; Rydzewski, J. M.; Case, D. A.;

Boger, D. L.; Chazin, W. J. J. Mol. Biol. 1997, 272, 237.

26. Schnell, J. R.; Ketchem, R. R.; Boger, D. L.; Chazin, W. J.

J. Am. Chem. Soc. 1999, 121, 5645.

27. Smith, J. A.; Bifulco, G.; Case, D. A.; Boger, D. L.;

Gomez-Paloma, L.; Chazin, W. J. J. Mol. Biol. 2000, 300,

1195.

28. Warpehoski, M. A.; Gebhard, I.; Kelly, R. C.; Krueger,

W. C.; Li, L. H.; McGovren, J. P.; Prairie, M. D.; Wicnienski,

N.; Wierenga, W. J. Med. Chem. 1988, 31, 590.

29. Atwell, G. J.; Milbank, J. J. B.; Wilson, W. R.; Hogg, A.;

Denny, W. A. J. Med. Chem. 1999, 42, 3400.

30. Boger, D. L.; Yun, W.; Cai, H.; Han, N. Bioorg. Med.

Chem. 1995, 3, 761.

31. Boger, D. L.; Ishizaki, T.; Wysocki, R. J.; Munk, S. A.;

Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111,

6461. Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntorwat, O.

J. Org. Chem. 1990, 55, 5823. Boger, D. L.; Ishizaki, T. Tet-

rahedron Lett. 1990, 31, 793. Boger, D. L.; Ishizaki, T.; Sakya,

S. A.; Munk, S. A.; Kitos, P. A.; Jin, Q.; Besterman, J. M.

Bioorg. Med. Chem. Lett. 1991, 1, 115.

6. Boger, D. L.; Johnson, D. S.; Yun, W.; Tarby, C. M.

Bioorg. Med. Chem. 1994, 2, 115. Boger, D. L.; Coleman,

R. S.; Invergo, B. J.; Sakya, S. M.; Ishizaki, T.; Munk, S. A.;

Zarrinmayeh, H.; Kitos, P. A.; Thompson, S. C. J. Am. Chem.

Soc. 1990, 112, 4623.

32. Boger, D. L.; Munk, S. A.; Ishizaki, T. J. Am. Chem. Soc.

1991, 113, 2779.

7. Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A.;

Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1990, 112,

8961. Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H. J. Am.

Chem. Soc. 1991, 113, 6645.

8. Boger, D. L.; Johnson, D. S.; Yun, W. J. Am. Chem. Soc.

1994, 116, 1635.

33. Drost, K. J.; Cava, M. P. J. Org. Chem. 1991, 56, 2240.

34. Boger, D. L.; Munk, S. A. J. Am. Chem. Soc. 1992, 114,

5487.

35. Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem.

1992, 57, 2873. Boger, D. L.; McKie, J. A. J. Org. Chem. 1995,

60, 1271. Boger, D. L.; McKie, J. A.; Boyce, C. W. Synlett

1997, 515. Boger, D. L.; Boyce, C. W.; Garbaccio, R. M. Tet-

rahedron Lett. 1998, 39, 2227.

9. Warpehoski, M. A.; Hurley, L. H. Chem. Res. Toxicol.

1988, 1, 315.

10. Sugiyama, H.; Hosoda, M.; Saito, I.; Asai, A.; Saito, H.

Tetrahedron Lett. 1990, 31, 7197.

11. Boger, D. L.; Garbaccio, R. M. Bioorg. Med. Chem. 1999,

5, 263.

12. Boger, D. L.; Garbaccio, R. M. Acc. Chem. Res. 1999, 32,

1043.

36. Aristoﬀ, P. A.; Johnson, P. D. J. Org. Chem. 1992, 57,

6234. Aristoﬀ, P. A.; Johnson, P. D.; Sun, D.; Hurley, L. H.

J. Med. Chem. 1993, 36, 1956.

37. Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1994, 116, 7996.

38. Boger, D. L.; Yun, W.; Han, N. Bioorg. Med. Chem. 1995,

3, 1429.

13. Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102,

2477.

14. Boger, D. L.; Bollinger, B.; Hertzog, D. L.; Johnson, D. S.;

Cai, H.; Mesini, P.; Garbaccio, R. M.; Jin, Q.; Kitos, P. A.

J. Am. Chem. Soc. 1997, 119, 4987.

15. Boger, D. L.; Hertzog, D. L.; Bollinger, B.; Johnson, D. S.;

Cai, H.; Goldberg, J.; Turnbull, P. J. Am. Chem. Soc. 1997,

119, 4977.

16. Ambroise, Y.; Boger, D. L. Bioorg. Med. Chem. Lett.

2002, 12, 303.

17. For an alternative source of catalysis, see: Ellis, D. A.;

Wolkenberg, S. E.; Boger, D. L. J. Am. Chem. Soc. 2001, 123,

9299. Boger, D. L.; Wolkenberg, S. E.; Boyce, C. W. J. Am.

Chem. Soc. 2000, 122, 6325. Boger, D. L.; Boyce, C. W. J. Org.

Chem. 2000, 65, 4088. For an alternative source of activation,

see: Boger, D. L.; Garbaccio, R. M. J. Org. Chem. 1999, 64,

8350.

39. Boger, D. L.; Yun, W.; Han, N.; Johnson, D. S. Bioorg.

Med. Chem. 1995, 3, 611. Boger, D. L.; Yun, W.; Cai, H.;

Han, N. Bioorg. Med. Chem. 1995, 3, 761. Boger, D. L.; Han,

N. Bioorg. Med. Chem. 1997, 5, 233.

40. C3-substituted CBI analogues: Boger, D. L.; Brunette,

S. R.; Garbaccio, R. M. J. Org. Chem. 2001, 66, 5163. Iso-

CBI: Boger, D. L.; Garbaccio, R. M.; Jin, Q. J. Org. Chem.

1997, 62, 8875. C₂BI: Boger, D. L.; Palanki, M. S. S. J. Am.

Chem. Soc. 1992, 114, 9318. Boger, D. L.; Johnson, D. L.;

Palanki, M. S. S.; Kitos, P. A.; Chang, J.; Dowell, P. Bioorg.

Med. Chem. 1993, 1, 27. CBQ: Boger, D. L.; Mesini, P. J. Am.

Chem. Soc. 1995, 117, 11647. Boger, D. L.; Mesini, P. J. Am.

Chem. Soc. 1994, 116, 11335. CNA: Boger, D. L.; Turnbull, P.

J. Org. Chem. 1997, 62, 5849. CBI: Boger, D. L.; Turnbull, P.

J. Org. Chem. 1998, 63, 8004.

41. Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Searcey,

M.; Jin, Q. Synthesis 1999, 1505.

3838

J. P. Parrish et al. / Bioorg. Med. Chem. 11 (2003) 3815–3838

42. Boger, D. L.; Santillan, A.; Searcey, M.; Jin, Q. J. Am.

Chem. Soc. 1998, 120, 11554. Boger, D. L.; Santillan, A.;

Searcey, M.; Jin, Q. J. Org. Chem. 1999, 64, 5241.

43. Boger, D. L.; Garbaccio, R. M. J. Org. Chem. 1999, 64,

5666. Boger, D. L.; Boyce, C. W.; Johnson, D. S. Bioorg. Med.

Chem. Lett. 1997, 7, 233.

57. Atwell, G. J.; Tercel, M.; Boyd, M.; Wilson, W. R.;

Denny, W. A. J. Org. Chem. 1998, 63, 9414.

58. Atwell, G. J.; Wilson, W. R.; Denny, W. A. Bioorg. Med.

Chem. Lett. 1997, 7, 1493.

59. Chari, R. V. J.; Jackel, K. A.; Bourret, L. A.; Derr, S. M.;

Tadayoni, B. M.; Mattocks, K. M.; Shah, S. A.; Liu, C.;

44. Chang, A. Y.; Dervan, P. B. J. Am. Chem. Soc. 2000, 122,

4856.

45. Kumar, R.; Lown, J. W. Org. Lett. 2002, 4, 1851.

46. Reddy, B. S. P.; Sharma, S. K.; Lown, J. W. Curr. Med.

Chem. 2001, 8, 475.

Blattler, W. A.; Goldmacher, V. S. Cancer Res. 1995, 55, 4079.

60. Wang, Y.; Wright, S. C.; Larrick, J. L. U.S. Patent 1998,

5843937.

61. Hemetsberger, H.; Knittel, D.; Weidmann, H. Montash.

Chem. 1969, 100, 1599.

¨

47. Denny, W. A. Curr. Med. Chem. 2001, 8, 533.

48. Jia, G. F.; Lown, J. W. Bioorg. Med. Chem. 2000, 8, 1607.

49. Jia, G. F.; Iida, H.; Lown, J. W. Synlett 2000, 603.

50. Wang, Y. Q.; Yuan, H. L.; Ye, W. Q.; Wright, S. C.;

Wang, H.; Larrick, J. W. J. Med. Chem. 2000, 43, 1541.

51. Jia, G. F.; Iida, H.; Lown, J. W. Heterocyclic Commun.

1999, 5, 497.

52. Hay, M. P.; Sykes, B. M.; Denny, W. A.; Wilson, W. R.

Brit. J. Cancer. 1999, Suppl 2, P65.

53. Hay, M. P.; Sykes, B. M.; Denny, W. A.; Wilson, W. R.

Bioorg. Med. Chem. Lett. 1999, 9, 2237.

54. Gieseg, M. A.; Matejovic, J.; Denny, W. A. Anti-Cancer

Drug Des. 1999, 14, 77.

55. Jia, G. F.; Iida, H.; Lown, J. W. Heterocyclic Commun.

1998, 4, 557.

56. Jia, G. F.; Iida, H.; Lown, J. W. Chem. Commun. 1999, 119.

62. Wang, Y.; Gupta, R.; Huang, L.; Luo, W.; Lown, J. W.

Anti-Cancer Drug Des. 1996, 11, 15.

63. Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1994, 116,

5523.

64. Boger, D. L.; Munk, S. A.; Zarrinmayeh, H.; Ishizaki, T.;

Haught, J.; Bina, M. Tetrahedron 1991, 47, 2661.

65. The extent of DNA alkylation is measured by the dis-

appearance of full length DNA (top band) and not by relative

intensities of the alkylation cleavage band (bottom band). A

second short alkylation cleavage band immediately adjacent to

the 5⁰end label is observed (only at the higher compound

concentrations) which results from a second, subsequent

alkylation reaction. For details, see reference 37.

66. Details of the preparation and characterization of all non-

commercially available and new indole-2-carboxylic acids are

available and can be provided upon request.

Article Doi

Establishment of substituent effects in the DNA binding subunit of CBI analogues of the duocarmycins and CC-1065

DOI: 10.1016/S0968-0896(03)00194-9

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Full text of DOI:10.1016/S0968-0896(03)00194-9

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