Stereospecific synthesis of 2,2,3-trisubstituted tetrahydroquinolines: Application to the total syntheses of benzastatin E and natural virantmycin

Tetrahedron 61 (2005) 2075–2104

Stereospeciﬁc synthesis of 2,2,3-trisubstituted

tetrahydroquinolines: application to the total syntheses

of benzastatin E and natural virantmycin

*

Mayuko Ori, Narihiro Toda, Kazuko Takami, Keiko Tago and Hiroshi Kogen

Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Received 13 October 2004; revised 20 December 2004; accepted 20 December 2004

Available online 22 January 2005

Abstract—An efﬁcient methodology for the synthesis of 2,2,3-trisubstituted tetrahydroquinolines has been developed, which involves the

triphenylphosphine–CCl₄-mediated stereospeciﬁc rearrangement of a,a-disubstituted indoline-2-methanols 15 to 2,2,3-trisubstituted

tetrahydroquinolines 26. The rearrangement precursors 15 are readily prepared by the diastereoselective Grignard addition to 2-acylindolines

13. The total syntheses of (C)-benzastatin E (1) and natural virantmycin (2a) were accomplished utilizing this methodology. This

rearrangement reaction might afford some chemical precedent for the biogenetic pathway of the benzastatin family.

1. Introduction

general, stereoselective synthesis of 2,2-disubstituted

tetrahydroquinolines.

The stereoselective construction of chiral quaternary carbon

centers is one of the most difﬁcult transformations in

organic synthesis. The difﬁculty is magniﬁed when

quaternary stereogenic centers is involved.¹Substituted

tetrahydroquinolines and tetrahydroisoquinolines are com-

pounds of great interest, because many biologically and

pharmacologically active alkaloids bear this skeleton.²

Chiral quaternary carbons are often essential for these

compounds, and thus, the asymmetric synthesis of these ring

systems has been the subject of intense research³though this

still remains to be a challenging task. Few publications have

described the enantioselective synthesis of isoquinoline

derivatives containing C-1 quaternary stereocenter⁴or C-3

quaternary stereocenter.⁵Among them, Shibasaki et al. has

recently reported an elaborate enantioselective synthesis of

1,1-disubstituted isoquinolines using a Reissert-type reac-

tion.^4aOn the other hand, methods for asymmetric synthesis

of quinoline derivatives with quaternary stereocenter has

been relatively undeveloped. Recently, Mikami et al. has

described an efﬁcient enantioselective synthesis of quino-

lines bearing a C-3 quaternary stereocenter or a spiro ring,

by the catalytic ene-type reaction of 1,7-enynes.⁶To the best

of our knowledge, however, there has been no reports of a

The benzastatin family and virantmycin are a novel class of

indoline and tetrahydroquinoline alkaloids isolated from

Streptomyces nitrosporeous.^7–10Benzastatins show inhibi-

tory activity against glutamate toxicity and lipid peroxi-

dation in rat liver microsomes that can be used to prevent

brain ischemia injury, and consists of indoline alkaloids

such as benzastatin E, and tetrahydroquinoline alkaloids

such as benzastatin C which are structurally related to

virantmycin.^7,8(K)-Virantmycin, a potent inhibitor towards

RNA and DNA viruses, is a unique 2,2-disubstituted

tetrahydroquinoline alkaloid with contiguous quaternary

and tertiary stereocenters.^9,10To date, several research

groups have reported the total syntheses of (G)-virantmy-

cin,^11,12and the total synthesis of unnatural (C)-virantmy-

cin was reported by Shirahama et al. in 1996.¹³The

synthesis of natural occurring form of virantmycin,

however, has not been accomplished.

Several biosynthetic pathways have been suggested for the

benzastatin family based on the cooccurence of indolines

and tetrahydroquinolines. Yoo et al. speculated that the

simple benzastatin A is oxygenated at the double bond to

form an intermediate epoxide, which can then undergo

cyclization to form the indoline or the tetrahydroquinoline

skeleton.⁸On the other hand, Yoo et al. proposed that the

indoline and the tetrahydroquinoline skeletons can inter-

convert through an aziridine intermediate, demonstrated by

the treatment of simple aziridine compound with anhydrous

Keywords: Diastereoselective Grignard addition; Benzastatin E; Rearrange-

ment; Ring expansion reaction; Virantmycin.

* Corresponding author. Tel.: C81 3 3492 3131; fax: C81 3 5436 8561;

e-mail: hkogen@sankyo.co.jp

doi:10.1016/j.tet.2004.12.041

2076

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

hydrogen chloride giving a mixture of indoline and

tetrahydroquinoline.¹⁴This latter proposal indicates the

biogenetic relationship between the indoline and the

tetrahydroquinoline skeletons, and inspired us with

the possibility of constructing the tetrahydroquinoline

skeleton from indoline precursors via the intermediacy of

aziridines, in a manner mimicking the biosynthetic process.

Based on this proposed hypothesis, we designed the

triphenylphosphine–CCl₄-mediated rearrangement from

a,a-disubstituted indoline-2-methanol to 2,2,3-trisubsti-

tuted tetrahydroquinoline via the aziridine, followed by

the ring opening attack of the chloride anion to the sterically

less hindered carbon (Scheme 1). In this paper, we disclose

the details of our development of stereoselective preparation

of a,a-disubstituted indoline-2-methanols, and the stereo-

speciﬁc rearrangement of these precursors to furnish

2,2,3-trisubstituted tetrahydroquinolines, simultaneously

constructing the contiguous quaternary and tertiary stereo-

genic centers. These methodologies were applied to efﬁcient

total syntheses of (C)-benzastatin E and natural virantmy-

cin, which illustrates the utility of this methodology for the

synthesis of various chiral indoline and tetrahydroquinoline

alkaloids.^15,16

Scheme 2. Retrosynthetic analysis of a,a-disubstituted indoline-2-metha-

nols 7.

prepared from the commercially available (S)-(K)-indo-

line-2-carboxylic acid (9) as shown in Scheme 3. Carb-

oxylic acid 9 was treated with sulfuric acid in methanol,

followed by nitrogen protection with di-tert-butyl dicarbo-

nate to provide methyl ester 10 in 92% yield. Bromination

of 10 with NBS (1 equiv) in DMF afforded bromide 11 in

93% yield. The bromide was converted to Weinreb amide¹⁷

12a by treatment with N,O-dimethylhydroxylamine hydro-

chloride and i-propylmagnesium chloride¹⁸in 83% yield.

Coupling of methoxymethyl lithium,¹⁹derived from Sn–Li

exchange of methyl tributylstannylmethyl ether, with 12a

afforded ketone 13a in 61% yield. Simple 2-acylindoline

13b with no substituent on the phenyl ring was obtained by

directly converting 10 to Weinreb amide 12b in 72% yield,

followed by the coupling with methoxymethyl lithium to

give 13b in 56% yield.

Scheme 3. Reagents and conditions: (a) (i) MeOH, H₂SO₄, 80 8C;

(ii) Boc₂O, CH₂Cl₂, rt, 92% (2 steps). (b) NBS, DMF, 0 8C, 93%.

(c) i-PrMgCl, Me(MeONH)$HCl, THF, K20 to K10 8C, 83%.

(d) i-PrMgCl, Me(MeONH)$HCl, THF, K20 to K10 8C, 72%.

(e) MeOCH₂Sn(n-Bu)₃, n-BuLi, THF, K78 8C, 61% (13a), 56% (13b).

Scheme 1. Transformation of indolines to tetrahydroquinolines based on

the proposed biosynthetic hypothesis.

2. Results and discussion

The Grignard addition to 2-acylindoline 13 proceeded with

high diastereoselectivity and afforded the corresponding

indoline-2-methanols in moderate to excellent yields.²⁰

In an initial experiment, reaction of 2-acylindoline 13a

with 3,4-dimethyl-3-pentenylmagnesium bromide²¹in THF

at K78 8C furnished tert-alcohols in a 25:1 ratio of

separable isomers (major-14 and minor-14) (Scheme 4).

The diastereoselectivity was determined by the HPLC

analysis of the crude reaction mixture. The deprotection of

the N-Boc group of major-14 was achieved with HCO₂H/

CH₂Cl₂to give the rearrangement substrate, a,a-disubsti-

tuted indoline-2-methanol 15. In order to determine the

conﬁguration of the newly created stereocenters, the tert-

alcohols 14 were further converted to the corresponding

2.1. Diastereoselective synthesis of a,a-disubstituted

indoline-2-methanols

Our investigation of the stereospeciﬁc rearrangement of

a,a-disubstituted indoline-2-methanols to 2,2,3-trisubsti-

tuted tetrahydroquinolines began with the development of a

general route for the preparation of the rearrangement

precursors. The synthetic scheme is outlined in Scheme 2.

The key step, in terms of constructing the tert-alcohol

moiety, is the diastereoselective Grignard addition to

2-acylindoline 8.

The key intermediate 2-acylindoline 13 can be readily

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2077

Scheme 4. Reagents and conditions: (a) 3,4-dimethyl-3-pentenylmagnesium bromide, THF, K78 8C, 91% (dsZ25:1). (b) HCO₂H, CH₂Cl₂, 40 8C, 52%.

(c) Me₂C(OMe)₂, PPTS, CH₂Cl₂, rt, 91%. (d) (i) HCO₂H, CH₂Cl₂, 40 8C, 76%; (ii) Me₂C(OMe)₂, PPTS, CH₂Cl₂, rt, 72%.

acetonides 16. The absolute conﬁguration of major-14 was

assigned as (9S,10R), and minor-14 as (9S,10S), by the NOE

experiment of the acetonides. The stereochemistry outcome

of the diastereoselective Grignard addition can be rational-

ized by the Felkin–Anh model²²depicted in Figure 1.

Furthermore, we satisfactorily accomplished the total

synthesis of (C)-benzastatin E (1) in three steps from

major-16 as shown in Scheme 5. Benzastatin E (1) is the

most potent inhibitor of glutamate toxicity using neuronal

hybridoma N18-RE-10⁵among the benzastatin family.⁸The

relative stereochemistry of 1 was elucidated by extensive

NMR spectroscopic analysis, but the absolute stereo-

chemistry was undetermined, leaving the question of

which stereoisomer to aim at. Taking into account the

proposed biosynthesis of benzastatins proceeding via the

aziridine intermediate, the absolute conﬁguration of indo-

line skeleton would be anticipated to reﬂect the conﬁgu-

ration of tetrahydroquinolines such as (K)-virantmycin.

Thus, one could speculate the absolute stereochemistry of

benzastatin E to be 9S, and therefore the total synthesis

of benzastatin E was carried out with major-16. Lithiation

of major-16 followed by the carboxylation with CO₂

pro₀vided 17. Amidation of 17 with aqueous ammonia and

1,1 -carbonyldiimidazole (CDI) gave amide 18. Removal of

the acetonide protecting group from 18 with PPTS/MeOH

furnished (C)-benzastatin E (1) [a]²_D⁴ZC21.3 (c 0.10,

MeOH) (lit.⁸[a]_D¹⁸ZC17 (c 0.1, MeOH))] in 64% yield.

Figure 1. Diastereoselective Grignard addition.

To broaden the scope of this reaction, various 2-acylindo-

lines were reacted with a series of Grignard reagents or

alkyllithiums. The results are summarized in Table 1. In

most cases, the reaction proceeded smoothly with high

diastereoselectivities. It is noteworthy that either dia-

stereomer can be easily obtained by exchanging the order

of the metal reagent addition to Weinreb amide 12, as shown

in entries 1 and 2. The enantiomer of 14 can also be prepared

by using (R)-(C)-indoline-2-carboxylic acid²³as the

starting material (entry 3). 2-Acylindolines with methoxy-

methyl group as the acyl group (13a and 13b) reacted with

variety of Grignard reagents and alkyllithiums, including

vinyl Grignards (entries 8 and 9). However, the scope of

the diastereoselective addition is somewhat limited when

2-acylindolines with alkyl groups (13c, 13e–h) were applied

as substrates. Alkyllithiums, such as methyllithium (entries

14 and 16), lithium phenylacetilide (entry 15) or phenyl-

lithium (entry 17) reacts readily to furnish the corresponding

tert-alcohols, whereas the Grignard reagents seemed to be

less reactive. For example, 13h does not react with

methylmagnesium bromide under the standard conditions,

resulting in the recovery of the starting material; the same

applies to 13e with 3-butenylmagnesium bromide, and 13f

with phenethylmagnesium chloride. All the obtained tert-

alcohols 14 were converted to indoline-2-methanols 15 by

the deprotection of the N-Boc group, thus efﬁciently

providing the rearrangement precursors. The chiral HPLC

analysis²⁴of 15a (the Boc-deprotected 14a) shows that

no racemization occurs during these manipulations (from 10

to 15).

1

Spectral data (IR, H NMR and ¹³C NMR) for synthetic

(C)-1 are identical to that reported for the natural product.

Therefore, the absolute stereochemistry of benzastatin E

was conﬁrmed as (9S,10R) as expected.

2.2. Stereospeciﬁc rearrangement from a,a-disubstituted

indoline-2-ethanols to 2,2,3-trisubstituted tetrahydro-

quinolines

Having established the efﬁcient method for the preparation

of a,a-disubstituted indoline-2-methanols, the stereo-

speciﬁc rearrangement to 2,2,3-trisubstituted tetrahydro-

quinolines was investigated. Cossy et al. previously reported

the ring-expansion reaction of N-benzylpyrrolidine-2-

methanols to N-3-chloropiperidines using methanesulfonyl

chloride, though they stated that no rearrangement occurs

with a,a-disubstituted N-benzylpyrrolidine-2-methanols.²⁵

As speculated, this rearrangement did not proceed with our

substrate 15a resulting in crude mixture, probably due to the

steric hindrance (Scheme 6).

Prior to the investigation of the rearrangement reaction

of tertiary alcohols 15, we decided to conduct a pre-

liminary experiment with racemic a-monosubstituted

Table 1. Diastereoselective Grignard addition to 2-acylindolines 13

Entry

1

Substrate 13^a

Product 14^b

Yield^c

Entry

10

Substrate 13^a

Product 14^b

Yield^c

57% (16:1)^d

13b

63 (38:1)

13b

13c

14a

14j

2^e

86% (13:1)

11

67% (9:1)

14b

14c

14d

13a

13b

14k

14l

3

4

62% (17:1)

94% (15:1)

12

13

68% (8:1)

13d

13b

82% (11:1)

14m

5

13b

84% (7:1)

14^e

62%

14e

13e

14n

14o

6

13b

61% (9:1)

15^e

85% (8:1)

14f

13f

7^f

13b

85% (18:1)

16^e

47% (10:1)

68% (38:1)

14g

14h

14i

13g

13h

14p

14q

8

9

13b

97% (12:1)

17^e,g

100% (13:1)

^aReadily prepared from the corresponding Weinreb amide and either Grignard reagent or alkyllithium by the same method for preparation of 13 except for 13d. Substrate 13d was prepared from (R)-(C)-indoline-2-

carboxylic acid.

^bAbsolute conﬁguration of the major isomer was determined by NOE experiments of the corresponding acetonide derivative.

^cIsolated yield of a mixture of diastereomers.

^dDiastereomeric ratios determined by HPLC analysis of crude product mixtures.

^eAlkyl lithium was used.

f

10 equiv of cyclohexylmagnesium bromide was used.

^g6 equiv of phenyllithium was used.

2080

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

the Grignard reaction with 2-acylindolines 13 being highly

diastereoselective, the Grignard reaction of the aldehyde 19

with 3-butenylmagnesium bromide proceeded in low

diastereoselectivity. Lowering the reaction temperature to

K87 8C was ineffective. The relative conﬁguration of the

Grignard adduct 20 was determined by the NOE experiment

of the acetonide 21, which was derived from 20 by

deprotection of the N-Boc group, followed by the reaction

with 1,1-dimethoxycyclohexane. The bromide on the

phenyl ring of 21 was converted to a methyl ester group

through a three step sequence, thus giving rise to the

rearrangement precursor, a-monosubstituted indoline-2-

methanol 22.

Scheme 5. Reagents and conditions: (a) t-BuLi, CO₂, Et₂O, K78 to 0 8C,

53%. (b) (i) CDI, 28%; (ii) aq NH₃, THF, rt, 74%; (c) PPTS, MeOH, rt,

64%.

Reaction of a-monosubstituted indoline-2-methanol 22 with

PPh₃(3 equiv) and CCl₄(10 equiv) in CH₂Cl₂at room

temperature for 3 h delivered a 3:1 mixture of the desired

rearrangement product 23 and Cl-substituted indoline 24

which was relatively unstable (the structure of 24 was

1

characterized by H NMR, ¹³C NMR and EIMS) (Scheme

8).²⁶The 5- and 6-membered ring of the products were

conﬁrmed by the HMBC experiments, and the relative

stereochemistry was determined by the NOE experiment of

the aziridine 25, derived from 23 and 24 by: (1) formation of

the aziridine ring by t-BuOK and (2) esteriﬁcation of the

resulting carboxylic acid. The indoline product 24 could be

formed either by direct chlorination of the OH group of the

substrate 22, or via an aziridine intermediate as depicted in

Scheme 1, in this case the chloride anion attacking the

bridgehead carbon of the aziridine.

Scheme 6. Attempt for the ring expansion using methanesulfonyl chloride.

indoline-2-methanols. Synthesis of a representative sub-

strate 22 is outlined in Scheme 7. Racemic ethyl ester 11

was converted to corresponding aldehyde 19 by reduction of

11 with LAH followed by Swern oxidization. In contrast to

With the above result in mind, the triphenylphosphine–

CCl₄-mediated rearrangement using a,a-disubstituted indo-

line-2-methanols 15a and 15b as substrates were initially

examined. To our delight, treatment of 15a with PPh₃

(3 equiv) and CCl₄(10 equiv) in CH₂Cl₂under reﬂux for

30 min afforded solely the desired rearrangement product

tetrahydroquinoline 26a as a single isomer in 63% yield

(Scheme 9). Treatment of the diastereomer 15b also gave

26b as a sole isomer in 74% yield. Relative conﬁgurations

of 26a and 26b were determined by comparison with the

corresponding authentic racemic samples, reported by

Shirahama et al.¹²Exposure of 26b to (n-Bu)₃SnH and

azobisisobutyronitrile afforded the dechlorinated deriva-

tive 27b, which was identical with the dechlorinated

compound 27a derived from 26a except for the optical

rotation. These results indicate that 26a and 26b have

the opposite substituent orientation at C-2 position.

The absolute conﬁguration of 26a was veriﬁed by the

X-ray analysis as 2R,3R by the X-ray analysis of

Scheme 7. Reagents and conditions: (a) (i) LiAlH₄, THF, K78 to 0 8C;

(ii) SO₃$py, Et₃N, DMSO, CH₂Cl₂, 0 8C, 51% (2 steps). (b) 3-Butenylmag-

nesium bromide, THF, K78 8C, 75% (dsZ3:1). (c) (i) TFA, CH₂Cl₂, 0 8C

to rt, 59%; (ii) 1,1-dimethoxycyclohexane, p-TsOH, CH₂Cl₂, rt, 72%.

(d) (i) t-BuLi, CO₂, Et₂O, K78 to 0 8C; (ii) TMSCH₂N₂, MeOH, 0 8C to rt;

(iii) Amberlyst-15^wion exchange resin, MeOH, rt, 62% (3 steps).

Scheme 8. Reagents and conditions: (a) PPh₃, CCl₄, CH₂Cl₂, rt, 91% (yield of a 3:1 mixture of 23 and 24). (b) (i) t-BuOK, t-BuOH, 60 8C; (ii) TMSCH₂N₂,

AcOH, MeOH, 0 8C to rt, 26% (2 steps). (c) (i) t-BuOK, t-BuOH, 60 8C; (ii) TMSCH₂N₂, AcOH, MeOH, 0 8C to rt, 47% (2 steps).

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2081

group (entry 17), and treatment of 1 resulted in the reduction

of the amide group (entry 18).

Gratifyingly, the total synthesis of natural virantmycin was

achieved utilizing our developed methodology for the

construction of 2,2,3-trisubstituted tetrahydroquinolines

(Scheme 11). Acylindoline 13b was treated with iodine

monochloride to afford 31 in 91% yield. Iodide 31 was

subjected to diastereoselective Grignard addition with

2,3-dimethyl-3-pentenylmagnesium bromide²¹to give tert-

alcohols 32 as a 19:1 mixture of separable isomers, as

determined by HPLC analysis of the product mixture. The

Boc protecting group of the major isomer was removed by

treatment with HCO₂H to afford the rearrangement

precursor 33. The conﬁgurations of the newly created

asymmetric centers in the Grignard adduct were determined

by the NOE experiments of the acetonide derivative of 33.

Unfortunately, the rearrangement reaction was sluggish

when 33 was subjected to the standard condition, giving a

mixture of products including an undesired deiodinated

product and an indole derivative (formed by dehydration

followed by isomerization), along with the decomposition

of the polysubstituted oleﬁn (deduced from the disappear-

ance of the oleﬁnic carbon peak in the ¹³C NMR spectrum).

To overcome these problems we screened a number of

aromatic and aliphatic phosphines, and found that the

observed side reactions, such as reduction and isomerization

to an indole, are suppressed to a certain extent with the

usage of tri-n-butylphosphine as an alternative. As a result,

tetrahydroquinoline 34 was provided as a single isomer in

45% yield by treating 33 with tri-n-butylphosphine and

CCl₄. The tetrahydroquinoline 34 was carbonylated by

reaction with 1 atm of CO in H₂O/DMF in the presence of

catalytic Pd(OAc)₂and K₂CO₃to give (K)-virantmycin

(2a) in 53% yield (80% based on recovered starting

material). Synthetic 2a was identical in all respects to

Scheme 9. Reagents and conditions: (a) PPh₃, CCl₄, CH₂Cl₂, 40 8C, 63%.

(b) (n-Bu)₃SnH, AIBN, benzene, 80 8C, 95%. (c) PPh₃, CCl₄, CH₂Cl₂,

40 8C, 64%; (b) (n-Bu)₃SnH, AIBN, benzene, 80 8C, 75%.

(1S,2R,3R)-(K)-camphorsultam²⁷derivative 30, derived

from 26a in a two-step sequence (Scheme 10).¹⁶Moreover,

no racemization occurred during the rearrangement, con-

ﬁrmed by the chiral HPLC analysis of 26a.²⁸In the light of

these results, the rearrangement is considered to be

stereospeciﬁc.²⁹

1

natural virantmycin^10,13[IR, H NMR, ¹³C NMR spectra,

and [a]²_D⁴ZK16.5 (c 0.11, CHCl₃) (lit.¹³[a]¹_D⁸ZK11.1 (c

0.175, CHCl₃))]. Our synthesis required only nine steps

from the commercially available (S)-(K)-indoline-2-

carboxylic acid (9).

Scheme 10. Reagents and conditions: (a) AlCl₃, Me₂S, CH₂Cl₂, rt, 86%. (b)

(1S,2R,4R)-(K)-29, DCC, DMAP, CH₂Cl₂, reﬂux, 64%.

In summary, we have developed a new method for the

synthesis of chiral 2,2,3-trisubstituted tetrahydroquinolines,

involving the stereoselective preparation of a,a-disubsti-

tuted indoline-2-methanols, and its biomimetically inspired

stereospeciﬁc rearrangement to tetrahydroquinolines in

which contiguous quaternary and tertiary stereogenic

centers are constructed in complete stereocontrol. The

utility of this methodology for accessing various chiral

indoline and tetrahydroquinoline alkaloids was clearly

demonstrated by the total syntheses of benzastatin E

and natural virantmycin.³¹The latter synthesis required

only nine steps from the commercially available

compound, which exhibits a sharp contrast to the previous

syntheses of racemic and unnatural virantmycin. We

believe that this stereospeciﬁc rearrangement reaction

supports the biogenetic theory of benzastatin family

involving the aziridine intermediate, though the alternative

formation of these compounds via the epoxide intermediate

cannot be ruled out without further biosynthetic

experiments.

The utility of this rearrangement was investigated using

various chiral indoline-2-methanol derivatives, as shown in

Table 2. In most cases, the reactions provided single isomers

in moderate to good yield.³⁰The reaction of 15c

(enantiomer of 15a) provided the antipode of 26a (entry

1). Notably, the use of polymer-supported triphenylpho-

sphine was also effective (entry 9). Unfortunately, the

rearrangement was unsuccessful with some substrates. In

the case of 15e, a trace of rearrangement product 26e was

observed, but could not be isolated because of decompo-

sition (entry 3). As shown in entries 17 and 18, the

rearrangement proved to be quite sensitive to the substituent

on the indoline aryl ring. Although the rearrangement

proceeded smoothly with substrates with Br (entries 12 and

13) or ester groups (entries 14–16) substituted on the aryl

ring, no reaction occurred with 15w containing a carboxyl

Table 2. Rearrangement from indolines 15 to tetrahydroquinolines 26

Entry^a

Substrate 15

Product 26^b

Yield^c

63%

Entry^a

10

Substrate 15

Product 26^b

Yield^c

63%

1

15c

15d

26c

26d

15j

15s

26j

26s

2

3

63%

11

12

55%

62%

Trace

15e

26e

15p

26p

4

5

33%

53%

13

14

41%

50%

15f

15r

26f

26r

15k

15t

26k

26t

6

7

38%

65%

15

16

52%

46%

15g

15n

26g

26n

15u

15v

26u

26v

8

9

31%

17^d

No reaction

15h

26h

15w

26j

37%

(44%)^e

18

61%

15i

26i

1

^aAll the reactions conducted were with Ph₃P (3 equiv) and CCl₄(10 equiv), except for entry 9.

^bThe absolute stereochemistry was tentatively assigned by analogy with the reaction mechanism, except for 26c (enantiomer of 26a).

^cYield of isolated product after column chromatography.

^dRacemic 15w was used as a substrate.

^ePolymer-supported triphenylphosphine was used.

Scheme 11. Reagents and conditions: (a) ICl, 2,6-di-t-butyl-4-methylpyridine, CH₂Cl₂, 0 8C to rt, 91%. (b) 3,4-Dimethyl-3-pentenylmagnesium bromide, THF, K78 8C, 73% (dsZ19:1). (c) HCO₂H, CH₂Cl₂, 50 8C,

59%. (d) (n-Bu)₃P, CCl₄, CH₂Cl₂, reﬂux, 45%. (e) CO 1 atm, K₂CO₃, Pd(OAc)₂, H₂O/DMF, rt, 53% (80% based on recovered starting material).

2084

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

3. Experimental

of water (50 ml), the aqueous solution was extracted with

AcOEt (50 ml!2). The combined organic extracts were

washed with water (50 ml), brine (50 ml), dried over

Na₂SO₄, ﬁltered and evaporated. Puriﬁcation by silica gel

column chromatography (hexane–AcOEt 5:1 to 2:1)

provided 11 (16.4 g, 93%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 1.49 (9H, br), 3.09 (1H, d, JZ

16.5 Hz), 3.45–3.51 (1H, m), 3.75 (3H, s), 4.86 (1H, br),

7.22 (1H, s), 7.30 (1H, br d, JZ7.0 Hz), 7.77 (1H, br s); ¹³C

NMR (125 MHz, CDCl₃) d 28.1 (!3), 32.2, 52.3, 60.4,

81.6, 114.7, 115.9, 127.3, 130.1, 130.6, 141.7, 151.3, 171.9;

IR (CHCl₃) cm^K1: 2981, 1745, 1709, 1477, 1377, 1312,

1257, 1159, 1025; HRMS calcd for C₁₅H₁₈NO₄Br (M)^C

355.0419, found 355.0418; [a]²_D⁴ZK31.9 (c 0.83,

CHCl₃).

3.1. General procedure

Unless otherwise noted, all reactions were carried out in

oven-dried glassware under a nitrogen atmosphere. Tetra-

hydrofuran (THF) was distilled from sodium metal/benzo-

phenone ketyl. Dichloromethane (CH₂Cl₂) was distilled

from calcium hydride. All other dry solvents were

purchased from Aldrich in SureSeale containers. All

other commercially obtained reagents were used as

1

received. H NMR and ¹³C NMR spectra were recorded

on a Varian 400 or 500 spectrometer. The following

abbreviations were used to explain the multiplicities: sZ

singlet, dZdoublet, tZtriplet, qZquartet, mZmultiplet,

brZbroadened. In the NMR spectral lists, chemical shifts

which are assigned to the minor conformer are marked with

an asterisk. Infrared spectra were recorded on a JASCO

FT-IR-8900 spectrometer. Mass spectra were obtained on a

JEOL HX-100, a SX-102A or a JMS-AX-505H mass

spectrometer. Optical rotations were measured on a JASCO

P-1030 polarimeter. Analytical TLC was performed on

0.25 mm pre-coated Merck silica gel 60 F₂₅₄plates. Flash

column chromatography was performed on Merck silica gel

60 (230–400 mesh).

3.2.3. tert-Butyl (2S)-5-bromo-2-{[methoxy(methyl)-

amino]carbonyl}indoline-1-carboxylate (12a). To a slurry

of Me(MeO)NH$HCl (2.36 g, 24.3 mmol) and 11 (5.76 g,

16.2 mmol) in THF (20 ml) was added i-PrMgCl in THF

(16.1 ml, 2.0 M) dropwise at K20 8C. The mixture was

stirred for 20 min at K10 8C. To the reaction mixture

were added Me(MeO)NH$HCl (2.36 g, 24.3 mmol) and

i-PrMgCl in THF (16.1 ml, 2.0 M) at K20 8C. After stirring

for 10 min at K10 8C, the reaction was quenched with satd

NH₄Cl aq (80 ml) and extracted with AcOEt (70 ml!2).

The combined organic solution was washed with brine

(80 ml), dried over Na₂SO₄, ﬁltered and evaporated.

Puriﬁcation by silica gel column chromatography (hex-

ane–AcOEt 5:1 to 1:1) gave 12a (5.2 g, 83%) as a colorless

3.2. Preparation of 2-acylindolines 13a, b

3.2.1. 1-tert-Butyl 2-methyl (2S)-indoline-1,2-dicarboxyl-

ate (10). To a solution of carboxylic acid 9 (20.0 g,

123 mmol) in MeOH (200 ml) was added sulfuric acid

(15 ml) dropwise at room temperature. The mixture was

stirred for 6 h at 80 8C. The solvent was removed in vacuo.

The residue was neutralized with 15% NaOH aq, then

extracted with AcOEt (100 ml!2). The combined organic

extracts were washed with 1 N NaOH aq (50 ml!2), brine

(50 ml), dried over Na₂SO₄, ﬁltered and evaporated to give

the corresponding methyl ester (20.3 g, 94%).

1

solid (mp 105–106 8C). H NMR (400 MHz, CDCl₃, two

rotamers) d 1.48 (6H, br s), 1.59 (3H, br s), 2.97 (1H, d, JZ

16.4 Hz), 3.22 (3H, s), 3.47 (1H, dd, JZ11.6, 16.4 Hz), 3.75

(2H, br s), 3.81 (1H, br s), 5.20 (1H, br), 7.18 (1H, s), 7.28

(1H, br s), 7.35 (0.5H, br), 7.80 (0.5H, br d, JZ8.0 Hz); ¹³C

NMR (125 MHz, CDCl₃, two rotamers) d 28.2 (!3), 31.6*,

32.1, 32.6, 58.5*, 58.9, 61.3, 81.3, 82.3*, 114.5, 115.9,

127.2, 127.5, 130.5, 142.5, 151.5, 172.0; IR (KBr) cm^K1

:

3000, 1702, 1679, 1478, 1378, 1320, 1256, 1161, 1029, 824;

HRMS calcd for C₁₆H₂₁N₂O₄BrNa (MCNa)^C407.0582,

found 407.0583. Anal. Calcd for C₁₆H₂₁N₂O₄Br: C, 49.88;

H, 5.49; N, 7.27; Br, 20.74. Found: C, 49.99; H, 5.50; N,

7.28; Br, 20.44; [a]²_D⁴ZK89.4 (c 0.90, CHCl₃).

To a solution of methyl ester (20.3 g, 114 mmol) in CH₂Cl₂

(100 ml) was added Boc₂O (40.3 g, 185 mmol) in CH₂Cl₂

(100 ml) at room temperature. After stirring at room

temperature overnight, the solvent was evaporated. Puriﬁ-

cation by silica gel column chromatography (hexane to

hexane–AcOEt 1:1) gave 10 (31.4 g, 92% from 9) as a

colorless solid (mp 43–45 8C). ¹H NMR (500 MHz, CDCl₃,

two rotamers) 1.50 (9H, br), 3.11 (1H, dd, JZ4.0, 16.0 Hz),

3.50 (1H, dd, JZ14.0, 16.0 Hz), 3.75 (3H, s), 4.87 (1H, br),

6.95 (1H, t, JZ7.0 Hz), 7.11 (1H, d, JZ7.0 Hz), 7.14–7.22

(1H, m), 7.49* (0.3H, br), 7.89 (0.7H, br); ¹³C NMR

(125 MHz, CDCl₃, two rotamers) d 28.2 (!3), 31.9*, 32.7,

52.3, 60.4, 81.3, 82.3*, 114.6, 122.5, 124.3, 124.4, 127.9,

3.2.4. tert-Butyl (2S)-2-{[methoxy(methyl)amino]carbo-

nyl}indoline-1-carboxylate (12b). The procedure for the

synthesis of 12a was followed using 11 (7.03 g,

25.35 mmol), Me(MeO)NH$HCl (4.95 g, 50.7 mmol) and

i-PrMgCl in THF (50.7 ml, 2.0 M) in THF (50 ml) to give

12b (5.59 g, 72%) as a colorless solid (mp 109–111 8C). ¹H

NMR (500 MHz, CDCl₃, two rotamers) d 1.49 (6H, br s),

1.60 (3H, br s), 2.99 (1H, br), 3.22 (3H, s), 3.49 (1H, dd, JZ

11.8, 15.8 Hz), 3.75 (2H, br s), 3.82 (1H, br s), 5 18 (1H, br),

6.91 (1H, t, JZ7.6 Hz), 7.07 (1H, d, JZ7.6 Hz), 7.17 (1H,

br), 7.50* (0.4H, br), 7.92 (0.6H, br), ¹³C NMR (100 MHz,

CDCl₃, two rotamers) d 28.4 (!3), 32.0, 32.7, 58.3*, 58.8,

61.4, 80.9, 81.9*, 114.5, 122.1, 124.0, 124.5, 127.6, 128.0*,

129.0*, 142.1*, 143.0, 151.5, 152.5*, 171.6*, 172.3; IR

(KBr) cm^K1: 2987, 1706, 1675, 1486, 1388, 1174, 757;

HRMS calcd for C₁₆H₂₂N₂O₄BrNa (MCNa)^C329.1477,

found 329.1479. Anal. Calcd for C₁₆H₂₂N₂O₄: C, 62.73; H,

7.24; N, 9.14. Found: C, 62.66; H, 7.28; N, 9.12;

[a]²_D⁴ZK117.0 (c 0.46, CHCl₃).

141.6*, 142.5, 151.6, 152.6*, 172.4; IR (CHCl₃) cm^K1

:

2981, 1741, 1709, 1485, 1390, 1169; HRMS calcd

for C₁₅H₁₉NO₄(M)^C277.1314, found 277.1305. Anal.

Calcd for C₁₅H₁₉NO₄: C, 64.97; H, 6.91; N, 5.05.

Found: C, 64.76; H, 6.70; N, 5.07; [a]²_D⁴ZK70.6 (c

0.84, CHCl₃).

3.2.2. 1-tert-Butyl 2-methyl (2S)-5-bromoindoline-1,2-

dicarboxylate (11). NBS (8.79 g, 49.4 mmol) was added

to a solution of 10 (13.7 g, 49.4 mmol) in DMF (50 ml) at

0 8C. The mixture was stirred for 2 h at 0 8C. After addition

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2085

3.2.5. tert-Butyl (2S)-5-bromo-2-(methoxyacetyl)indo-

line-1-carboxylate (13a). To a solution of MeOCH₂Sn

(n-Bu)₃(1.30 g, 3.90 mmol) in THF (10 ml) was added

n-BuLi in hexane (3.90 ml, 1.6 M) dropwise at K78 8C.

After stirring for 10 min at K78 8C, a solution of Weinreb

amide 12a (500 mg, 1.30 mmol) in THF (5 ml) was added to

the reaction mixture at K78 8C. The mixture was stirred for

15 min at K78 8C and quenched with satd NH₄Cl aq

(20 ml). The product was extracted with AcOEt (30 ml!2)

and the organic solution was washed with brine (30 ml),

dried over Na₂SO₄, ﬁltered and evaporated. Puriﬁcation by

silica gel column chromatography (hexane–AcOEt 10:1 to

3.27 (1H, dd, JZ11.0, 17.5 Hz), 3.35 (3H, s), 3.40 (2H, s),

4.74 (1H, d, JZ9.5 Hz), 7.25–7.33 (3H, m); ¹³C NMR

(125 MHz, CDCl₃) d 18.0, 19.7, 20.4, 27.9, 28.1 (!3), 29.7,

31.2, 59.2, 64.8, 76.2, 76.7, 82.2, 115.3, 117.6, 123.9, 127.0,

127.2, 129.6 (!2), 134.3, 142.0; IR (CHCl₃) cm^K1: 3554,

3373, 2983, 2927, 1672, 1477, 1371, 1255, 1164, 1016, 909;

HRMS calcd for C₂₃H₃₄NO₄BrNa (MCNa)^C490.1569,

found 490.1571; [a]²_D⁴ZK45.4 (c 0.86, CHCl₃).

3.3.2. tert-Butyl (2S)-5-bromo-2-[(1S)-1-hydroxy-1-

methoxymethyl-4,5-dimethylhex-4-enyl]indoline-1-car-

boxylate (minor-14). ¹H NMR (400 MHz, CDCl₃) d 1.55–

1.68 (2H, m), 1.58 (9H, s), 1.63 (6H, s), 1.65 (3H, s), 2.08–

2.19 (2H, m), 2.98 (3H, s), 3.07 (1H, d, JZ9.8 Hz), 3.15

(1H, d, JZ9.8 Hz), 3.19–3.27 (2H, m), 4.65 (1H, dd, JZ

2.4, 10.2 Hz), 7.25 (2H, d, JZ9.8 Hz), 7.31 (1H, br s); ¹³C

NMR (500 MHz, CDCl₃) d 18.3, 19.9, 20.5, 27.5, 28.3 (!

3), 30.3, 33.2, 58.6, 66.0, 75.0, 76.2, 82.9, 115.6, 117.6,

124.0, 127.2, 127.6, 129.6, 135.0, 141.5, 155.2; IR

(KBr) cm^K1: 3447, 2984, 2921, 2908, 2887, 2860, 1665,

1481, 1379, 1369; HRMS calcd for C₂₃H₃₄NO₄BrNa (MC

Na)^C490.1569, found 490.1567. Anal. Calcd for

C₂₃H₃₄BrNO₄: C, 58.97; H, 7.32; N, 2.99; Br, 17.06.

Found: C, 59.26; H, 7.20; N, 2.76; Br, 16.67; [a]²_D⁴ZK77.5

(c 0.98, CHCl₃); mp 103–106 8C.

1

2:1) gave 13a (295 mg, 61%) as a colorless oil. H NMR

(400 MHz, CDCl₃) d 1.49 (9H, br), 2.98 (1H, dd, JZ4.4,

16.8 Hz), 3.44 (3H, s), 3.48 (1H, br), 4.16 (2H, br), 5.07

(1H, br), 7.21 (1H, s), 7.31 (1H, br), 7.79 (1H, br); ¹³C NMR

(125 MHz, CDCl₃, two rotamers) d 28.9 (!3), 31.1*, 32.0,

60.3, 63.9*, 64.7, 75.8, 82.7, 115.7, 116.8, (!2), 128.2,

131.5, 142.7, 151.9, 205.0; IR (CHCl₃) cm^K1: 2981, 1707,

1478, 1372, 1256, 1153, 1106, 1023, 909; HRMS calcd

for C₁₆H₂₀NO₄Br (M)^C369.0576, found 369.0567;

[a]²_D⁴ZK53.9 (c 1.07, CHCl₃).

3.2.6. tert-Butyl (2S)-2-(methoxyacetyl)indoline-1-carb-

oxylate (13b). The procedure for the synthesis of 13a was

followed using 12b (2.12 g, 6.92 mmol), MeOCH₂Sn

(n-Bu)₃(6.96 g, 20.76 mmol), n-BuLi in hexane (13.1 ml,

1.6 M) in THF (50 ml) to give 13b (1.13 g, 56%) as a

colorless solid (mp 58–60 8C). ¹H NMR (500 MHz, CDCl₃,

two rotamers) d 1.50 (9H, br), 3.00 (1H, dd, JZ4.5,

16.5 Hz), 3.43 (3H, s), 3.47 (1H, br), 4.18 (2H, br), 5.03

(1H, br), 6.94 (1H, t, JZ7.5 Hz), 7.10 (1H, d, JZ7.5 Hz),

7.19 (1H, br s), 7.48* (0.4H, br), 7.90 (0.6H, br); ¹³C NMR

(125 MHz, CDCl₃, two rotamers) d 28.2 (!3), 30.9*, 31.7,

59.4, 63.3*, 64.0, 74.8, 75.4*, 81.6, 114.7 (!2), 122.6,

124.5, 127.9, 128.8*, 141.7*, 142.5, 151.4, 152.5*, 204.8;

IR (KBr) cm^K1: 2976, 1732, 1704, 1488, 1395, 1154, 1111,

762; HRMS calcd for C₁₆H₂₁NO₄Na (MCNa)^C314.1368,

found 314.1373. Anal. Calcd for C₁₆H₂₁NO₄: C, 65.96;

H, 7.27; N, 4.81. Found: C, 65.91; H, 7.11; N, 4.84;

[a]²_D⁴ZK92.4 (c 0.65, CHCl₃).

3.3.3. (2R)-2-[(2S)-5-Bromo-2,3-dihydro-1H-indol-2-yl]-

1-methoxy-5,6-dimethylhept-5-en-2-ol (15). To a solution

of major-14 (2.29 g, 4.89 mmol) in CH₂Cl₂(10 ml) was

added formic acid (20 ml) at room temperature. After

stirring for 18 h at room temperature, the reaction mixture

was neutralized with 15% NaOH aq and extracted with

AcOEt (50 ml!2). The combined organic extracts were

washed with brine (50 ml), dried over Na₂SO₄, ﬁltered and

evaporated. Puriﬁcation by silica gel column chromatog-

raphy (hexane–AcOEt 5:1) yielded 15 (938 mg, 52%) as a

colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.44–1.59 (2H,

m), 1.64 (3H, s), 1.64 (3H, s), 1.66 (3H, s), 2.01 (1H, dt, JZ

5.5, 12.0 Hz), 2.15 (1H, dt, JZ5.5, 12.0 Hz), 2.79 (1H, s),

2.90 (1H, dd, JZ9.0, 15.5 Hz), 3.05 (1H, dd, JZ10.5,

15.5 Hz), 3.39 (1H, d, JZ9.5 Hz), 3.40 (3H, s), 3.49 (1H, d,

JZ9.5 Hz), 4.08 (1H, dd, JZ9.0, 10.5 Hz), 4.26 (1H, br s),

6.49 (1H, d, JZ8.5 Hz), 7.09 (1H, d, JZ8.5 Hz), 7.15 (1H,

s); ¹³C NMR (125 MHz, CDCl₃) d 18.2, 19.9, 20.5, 28.1,

30.3, 32.8, 59.4, 65.9, 72.7, 78.1, 110.3, 110.5, 124.2, 127.1,

127.3, 129.7, 131.0, 149.7; IR (CHCl₃) cm^K1: 3405, 2924,

1604, 1481, 1247, 1166, 1111; HRMS calcd for

C₁₈H₂₆NO₂Br (M)^C367.1147, found 367.1150; [a]²_D⁴Z

K33.5 (c 0.75, CHCl₃).

3.3. Investigation of the diastereoselective Grignard

addition

3.3.1. tert-Butyl (2S)-5-bromo-2-[(1R)-1-hydroxy-1-

methoxymethyl-4,5-dimethylhex-4-enyl]indoline-1-car-

boxylate (major-14). To a solution of ketone 13a (282 mg,

0.761 mmol) in THF (10 ml) was added 3,4-dimethyl-3-

pentenylmagnesium bromide in THF (freshly prepared from

the corresponding bromide (714 mg, 0.457 mmol) and Mg

(146 mg, 0.686 mmol)) dropwise at K78 8C. The mixture

was stirred for 15 min at K78 8C. The reaction was

quenched with satd NH₄Cl aq (20 ml) and extracted with

AcOEt (20 ml!2). The combined organic extracts were

washed with brine (20 ml), dried over Na₂SO₄, ﬁltered and

evaporated. The diastereoselectivity (25:1) was determined

by HPLC analysis. Puriﬁcation by silica gel column

chromatography (hexane–AcOEt 5:1) gave major-14

(323 mg, 91%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.30 (1H, dt, JZ5.0, 13.0 Hz), 1.40 (1H, dt, JZ

5.0, 13.0 Hz), 1.47 (3H, s), 1.55 (3H, s), 1.56 (3H, s), 1.56

(9H, s), 1.95–2.06 (2H, m), 3.07 (1H, dd, JZ2.0, 17.5 Hz),

3.3.4.

(1R,9aS)-7-Bromo-1-methoxymethyl-3,3-di-

methyl-1-(3,4-dimethylpent-3-enyl)-9,9a-dihydro-1H-

[1,3]oxazolo[3,4-a]indole (major-16). To a solution of

15 (932 mg, 2.53 mmol) in CH₂Cl₂(20 ml) was added

2,2-dimethoxypropane (3.11 ml, 25.3 mmol) and pyri-

dinium p-toluenesulfonate (100 mg) at room temperature.

The mixture was stirred for 4 h at room temperature. The

solvent was concentrated in vacuo and satd NaHCO₃aq

(20 ml) was added to the residue. The product was extracted

with AcOEt (20 ml!2) and the organic extracts were

washed with brine (20 ml), dried over Na₂SO₄, ﬁltered and

evaporated. Puriﬁcation by silica gel column chroma-

tography (hexane–AcOEt 10:1 to 5:1) gave major-16

2086

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

1

13d (52 mg, 44%) as a colorless oil. H NMR (500 MHz,

(945 mg, 91%) as a colorless oil. ¹H NMR (400 MHz,

CDCl₃) d 1.08 (1H, dt, JZ4.4, 13.2 Hz), 1.50 (3H, s), 1.51

(3H, s), 1.55 (3H, s), 1.57 (3H, s), 1.57–1.62 (1H, m), 1.65

(3H, s), 1.95 (1H, dt, JZ4.4, 13.2 Hz), 2.05 (1H, dt, JZ4.4,

13.2 Hz), 3.03 (1H, dd, JZ9.8, 17.6 Hz), 3.09 (1H, dd, JZ

4.4, 17.6 Hz), 3.28 (1H, d, JZ9.6 Hz), 3.38 (3H, s), 3.52

(1H, d, JZ9.6 Hz), 4.34 (1H, dd, JZ4.4, 9.8 Hz), 6.49 (1H,

d, JZ8.0 Hz), 7.09 (1H, dd, JZ2.4, 8.0 Hz), 7.12 (1H, s);

¹³C NMR (125 MHz, CDCl₃) d 18.2, 19.8, 20.5, 25.8, 28.1,

29.0, 29.2, 31.3, 59.5, 70.3, 76.3, 82.1, 94.8, 110.7, 113.0,

CDCl₃, two rotamers) d 1.50 (9H, br), 3.00 (1H, dd, JZ4.5,

16.5 Hz), 3.43 (3H, s), 3.47 (1H, br), 4.18 (2H, br), 5.03

(1H, br), 6.94 (1H, t, JZ7.5 Hz), 7.10 (1H, d, JZ7.5 Hz),

7.19 (1H, br s), 7.48* (0.4H, br), 7.90 (0.6H, br); ¹³C NMR

(125 MHz, CDCl₃, two rotamers) d 28.2 (!3), 30.9*, 31.7,

59.4, 63.3*, 64.0, 74.8, 75.4*, 81.6, 114.7 (!2), 122.6,

124.5, 127.9, 128.8*, 141.7*, 142.5, 151.4, 152.5*, 204.8;

IR (KBr) cm^K1: 2976, 1732, 1704, 1488, 1395, 1154, 1111,

762; HRMS calcd for C₁₆H₂₁NO₄Na (MCNa)^C314.1368,

found 314.1373; [a]²_D⁴ZC69.3 (c 0.32, CHCl₃).

124.0, 127.3, 127.5, 129.4, 134.4, 147.8; IR (CHCl₃) cm^K1

:

2928, 1596, 1474, 1371, 1259, 1118, 969, 862; HRMS calcd

for C₂₁H₃₀NO₂Br (M)^C407.1460, found 407.1470;

[a]²_D⁴ZC101.5 (c 1.59, CHCl₃).

3.4.1.3. tert-Butyl (2S)-2-acetylindoline-1-carboxylate

(13e). The procedure for the synthesis of 13c was followed

using 12b (1.3 g, 4.24 mmol), MeLi in diethyl ether (5.6 ml,

1.14 M) and THF (10 ml) to give 13e (800 mg, 72%) as a

colorless solid (mp 100–102 8C). ¹H NMR (500 MHz,

CDCl₃, two rotamers) d 1.50 (9H, br), 2.15 (3H, br s), 2.97

(1H, dd, JZ5.0, 16.5 Hz), 3.47 (1H, br), 4.78 (1H, br), 6.95

(1H, t, JZ7.5 Hz), 7.12 (1H, d, JZ7.5 Hz), 7.20 (1H, br s),

7.49* (0.4H, br), 7.90 (0.6H, br); ¹³C NMR (125 MHz,

CDCl₃, two rotamers) d 24.7, 25.6*, 28.2 (!3), 30.9*, 31.6,

66.8, 81.7, 114.8 (!2), 122.7, 124.5, 128.0, 142.5, 151.6,

206.2; IR (KBr) cm^K1: 2984, 1699, 1485, 1395, 1321, 1262,

1157, 752; HRMS calcd for C₁₅H₁₉NO₃(M)^C261.1364,

found 261.1360. Anal. Calcd for C₁₅H₁₉NO₃: C, 68.94;

H, 7.33; N, 5.36. Found: C, 68.90; H, 7.01; N, 5.40;

[a]²_D⁴ZK82.8 (c 0.28, CHCl₃).

3.3.5. (1S,9aS)-7-Bromo-1-methoxymethyl-3,3-dimethyl-

1-(3,4-dimethylpent-3-enyl)-9,9a-dihydro-1H-[1,3]oxa-

zolo[3,4-a]indole (minor-16). ¹H NMR (400 MHz, CDCl₃)

d 1.50 (3H, s), 1.59–1.64 (1H, m), 1.63 (3H, s), 1.64 (3H, s),

1.66 (6H, s), 1.74–1.81 (1H, m), 2.04–2.17 (2H, m), 2.96

(1H, dd, JZ10.3, 17.1 Hz), 3.08 (1H, d, JZ9.8 Hz), 3.12

(1H, d, JZ9.8 Hz), 3.19 (3H, s), 3.39 (1H, dd, JZ2.9,

17.1 Hz), 4.17 (1H, dd, JZ2.9, 10.3 Hz), 6.55 (1H, d, JZ

7.8 Hz), 7.12 (1H, d, JZ7.8 Hz), 7.16 (1H, s); ¹³C NMR

(500 MHz, CDCl₃) d 18.4, 19.9, 20.5, 25.8, 28.2, 28.6, 31.3,

34.9, 59.0, 70.1, 73.7, 82.4, 95.1, 111.1, 113.4, 124.1, 127.4,

127.5, 129.4, 134.4, 148.2; IR (KBr) cm^K1: 3429, 2983,

2928, 2913, 2896, 2863, 1596, 1472, 1337, 1250, 1105.

Anal. Calcd for C₂₁H₃₀BrNO₂$1/6H₂O: C, 61.31; H, 7.43;

N, 3.40; Br, 19.42. Found: C, 61.35; H, 7.29; N, 3.41; Br,

19.42; [a]²_D⁴ZC98.9 (c 0.66, CHCl₃); mp 68–70 8C.

3.4.1.4. tert-Butyl (2S)-5-bromo-2-butyrylindoline-1-

carboxylate (13f). The procedure for the synthesis of 13c

was followed using 12a (1.0 g, 2.60 mmol), n-PrMgCl in

diethyl ether (3.9 ml, 2.0 M) and THF (15 ml) to give 13f

(238 mg, 25%) as a colorless solid (mp 70–71 8C) along

with the recovered 12a (s27%). ¹H NMR (400 MHz, CDCl₃,

two rotamers) d 0.92 (3H, t, JZ7.4 Hz), 1.48 (6H, br s),

1.56–1.66 (5H, m), 2.38–2.46 (2H, br m), 2.92 (1H, dd, JZ

4.9, 17.1 Hz), 3.46 (1H, br), 4.85 (1H, br), 7.22 (1H, br s),

7.32 (1.4H, br), 7.79* (0.6H, br); ¹³C NMR (125 MHz,

CDCl₃, two rotamers) d 14.0, 16.8, 28.4 (!3), 30.7*, 31.6,

39.7, 40.5*, 66.1*, 66.6, 82.1, 115.2, 116.4 (!2), 127.8,

130.4*, 131.1, 142.3, 152.0, 207.5; IR (KBr) cm^K1: 2976,

2962, 2934, 2874, 1712, 1701, 1480, 1374, 1155, 1143;

HRMS calcd for C₁₇H₂₂NO₃BrNa (MCNa)^C390.0681,

found 390.0673. Anal. Calcd for C₁₇H₂₂NO₃Br: C, 55.44;

H, 6.02; N, 3.80; Br, 21.70. Found: C, 55.63; H, 5.65; N,

3.75; Br, 21.67; [a]²_D⁴ZK34.8 (c 0.58, CHCl₃).

3.4. Diastereoselective Grignard addition to

2-acylindolines 13

3.4.1. Preparation of 2-acylindolines 13c–h.

3.4.1.1. tert-Butyl (2S)-2-propionylindoline-1-car-

boxylate (13c). To a solution of 12b (1.22 g, 3.98 mmol)

in THF (5 ml) was added EtMgBr in Et₂O (4.0 ml, 3 M)

dropwise at 0 8C. After stirring at 0 8C for 1.5 h, the reaction

was quenched with satd NH₄Cl aq (10 ml) and extracted

with AcOEt (10 ml!2). The combined organic extracts

were washed with brine (10 ml), dried over Na₂SO₄, ﬁltered

and evaporated. Puriﬁcation by silica gel column chroma-

tography (hexane–AcOEt 10:1 to 5:1) gave 13c (611 mg,

56%) as a colorless solid (mp 74–76 8C). ¹H NMR

(500 MHz, CDCl₃) d 1.07 (3H, t, JZ6.5 Hz), 1.48 (9H,

br), 2.53 (2H, br), 2.94 (1H, dd, JZ5.0, 16.5 Hz), 3.48 (1H,

br), 4.83 (1H, br), 6.95 (1H, t, JZ7.5 Hz), 7.10 (1H, d, JZ

7.5 Hz), 7.20 (1H, br s), 7.91 (1H, br); ¹³C NMR (125 MHz,

CDCl₃) d 7.35, 28.2 (!3), 30.5, 31.9, 66.3, 81.5, 114.7,

122.6, 124.4, 127.9, 142.6, 151.6, 160.9, 208.7; IR

(KBr) cm^K1: 2978, 1720, 1700, 1485, 1397, 1322, 1151,

748; HRMS calcd for C₁₆H₂₁NO₃(M)^C275.1521, found

275.1524. Anal. Calcd for C₁₆H₂₁NO₃: C, 69.79; H, 7.69; N,

5.09. Found: C, 69.57; H, 7.61; N, 5.13; [a]²_D⁴ZK80.2 (c

0.32, CHCl₃).SO

3.4.1.5. tert-Butyl (2S)-5-bromo-2-(5-methylhex-4-

enoyl)indoline-1-carboxylate (13g). The procedure for

the synthesis of 13c was followed using 12a (2.1 g,

5.45 mmol), 4-methyl-3-pentenylmagnesium bromide in

THF (freshly prepared from the corresponding bromide

(5.96 g, 36.6 mmol) and Mg (1.33 g, 54.8 mmol)) and THF

1

(15 ml) to give 13g (991 mg, 45%) as a colorless oil. H

NMR (400 MHz, CDCl₃) d 1.48 (9H, br), 1.65 (3H, s), 1.68

(3H, s), 2.26 (2H, q, JZ7.2 Hz), 2.39–2.56 (2H, m), 2.91

(1H, dd, JZ5.2, 16.8 Hz), 3.43 (1H, br t, JZ14.0 Hz), 4.81

(1H, br), 5.11 (1H, dt, JZ1.2, 7.6 Hz), 7.20 (1H, s), 7.30

(1H, d, JZ7.2 Hz), 7.74 (1H, br); ¹³C NMR (100 MHz,

CDCl₃) d 17.7, 21.9, 25.7, 28.2 (!3), 31.3, 37.7, 66.4, 81.9,

114.9, 116.0, 122.3, 124.6, 127.3, 130.7, 132.9, 141.8,

151.3, 206.7; IR (CHCl₃) cm^K1: 2977, 2930, 1708, 1477,

3.4.1.2. tert-Butyl (2R)-2-(methoxyacetyl)indoline-1-

carboxylate (13d). The procedure for the synthesis of 13a

was followed using enantiomer of 12b (124 mg,

0.405 mmol), MeOCH₂Sn(n-Bu)₃(407 mg, 1.215 mmol),

n-BuLi in hexane (0.8 ml, 1.6 M) and THF (5 ml) to give

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2087

1373, 1257, 1151; HRMS calcd for C₂₀H₂₆NO₃BrNa (MC

Na)^C430.0994, found 430.0969; [a]²_D⁴ZK25.3 (c 0.65,

CHCl₃).

142.0; IR (CHCl₃) cm^K1: 3385, 2981, 1659, 1484, 1387,

1165; HRMS calcd for C₁₈H₂₇NO₄Na (MCNa)^C344.1837,

found 344.1860; [a]²_D⁴ZK78.5 (c 0.43, CHCl₃).

3.4.1.6. tert-Butyl(2S)-5-bromo-2-(3-phenylpropionyl)-

indoline-1-carboxylate (13h). The procedure for the

synthesis of 13c was followed using 12a (212 mg,

0.691 mmol), phenethylmagnesium chloride in THF

(2.1 ml, 1.0 M) and THF (2 ml) to give 13h (200 mg,

3.4.2.3. tert-Butyl (2R)-2-[(1S)-1-hydroxy-1-(methoxy-

methyl)propyl]indoline-1-carboxylate (14c). The general

procedure was followed using 13d (51 mg, 0.175 mmol),

EtMgBr in THF (0.35 ml, 1.0 M) and THF (1 ml) to give

1

14c (35 mg, 62%) as a colorless oil. H NMR (500 MHz,

1

83%) as a colorless oil. H NMR (500 MHz, CDCl₃, two

CDCl₃) d 0.83 (3H, t, JZ7.0 Hz), 1.24–1.31 (1H, m), 1.35–

1.38 (1H, m), 1.57 (9H, s), 3.03 (1H, dd, JZ2.0, 16.5 Hz),

3.28 (1H, dd, JZ10.5, 16.5 Hz), 3.64 (3H, s), 3.39 (1H, d,

JZ10.0 Hz), 3.41 (1H, d, JZ10.0 Hz), 4.80 (1H, d, JZ

9.5 Hz), 6.95 (1H, t, JZ7.5 Hz), 7.11–7.15 (2H, m), 7.45

(1H, br); ¹³C NMR (125 MHz, CDCl₃) d 7.26, 24.9, 28.3 (!

3), 30.1, 59.3, 64.6, 76.0, 77.2, 82.1, 116.3 (!2), 122.8,

124.1, 126.9, 131.9, 142.8; IR (CHCl₃) cm^K1: 3373, 2981,

1667, 1484, 1382, 1331, 1287, 1165, 1115, 1015; HRMS

calcd for C₁₈H₂₇NO₄Na (MCNa)^C344.1838, found

344.1845; [a]²_D⁴ZC52.7 (c 0.32, CHCl₃).

rotamers) d 1.52 (9H, br), 2.76 (1H, dd, JZ5.4, 16.6 Hz),

2.80–2.93 (4H, m), 3.39 (1H, br), 4.85 (1H, br), 6.94 (1H, t,

JZ7.3 Hz), 7.06 (1H, d, JZ7.3 Hz), 7.13–7.26 (6.5H, m),

7.89* (0.5H, br s); ¹³C NMR (125 MHz, CDCl₃, two

rotamers) d 28.2 (!3), 29.2, 31.5, 39.1, 39.9*, 66.5, 81.6,

114.8 (!2), 122.7, 124.5, 126.1, 128.0, 128.4 (!2), 128.5

(!2), 140.9, 142.5, 152.0, 207.0; IR (CHCl₃) cm^K1: 2980,

1725, 1700, 1487, 1394, 1158, 753; HRMS calcd for

C₂₂H₂₅NO₃(M)^C351.1835, found 351.1842; [a]²_D⁴Z

K68.5 (c 1.05, CHCl₃).

3.4.2.4. tert-Butyl (2S)-2-[(1R)-1-hydroxy-2-methoxy-

1-phenethyl]indoline-1-carboxylate (14d). The general

procedure was followed using 13b (353 mg, 1.21 mmol),

PhMgBr in THF (2.4 ml, 1.0 M) and THF (3 ml) to give 14d

(418 mg, 94%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.60 (9H, s), 2.85 (1H, d, JZ16.5 Hz), 2.99

(1H, dd, JZ10.0, 16.5 Hz), 3.28 (3H, s), 3.73 (1H, d, JZ

10.0 Hz), 3.87 (1H, d, JZ10.0 Hz), 4.91 (1H, br), 6.90 (1H,

t, JZ7.5 Hz), 7.03 (1H, d, JZ7.5 Hz), 7.11 (1H, t, JZ

7.5 Hz), 7.24 (1H, t, JZ7.5 Hz), 7.33 (2H, t, JZ7.5 Hz),

7.48 (3H, d, JZ7.5 Hz); ¹³C NMR (125 MHz, CDCl₃) d

28.3 (!3), 30.0, 59.4, 64.8, 77.9, 79.5, 81.4, 115.9 (!2),

122.7, 123.7, 125.6 (!2), 126.6, 127.1, 128.1, 128.2 (!2),

132.4, 142.3; IR (CHCl₃) cm^K1: 3549, 2981, 2932, 1685,

1602, 1484, 1381, 1282, 1258, 1166, 1135; HRMS calcd for

C₂₂H₂₇NO₄Na (MCNa)^C392.1838, found 392.1837;

[a]²_D⁴ZK41.7 (c 0.53, CHCl₃).

3.4.2. Diastereoselective Grignard addition to 2-acylin-

dolines 13.

3.4.2.1. tert-Butyl (2S)-2-[(1R)-1-hydroxy-1-(methoxy-

methyl)propyl]indoline-1-carboxylate (14a). To

a

solution of 13b (1.06 g, 3.64 mmol) in THF (10 ml) was

added EtMgBr in THF (7.3 ml, 1.0 M) dropwise at K78 8C.

The mixture was stirred for 15 min at K78 8C. The reaction

was quenched with satd NH₄Cl aq (10 ml) and extracted

with AcOEt (10 ml!2). The combined organic extracts

were washed with brine (10 ml), dried over Na₂SO₄, ﬁltered

and evaporated. The diastereoselectivity (16:1) was deter-

mined by HPLC analysis. Puriﬁcation by silica gel column

chromatography (hexane–AcOEt 5:1) gave 14a (2.1 mg,

57%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) d 0.83

(3H, t, JZ7.0 Hz), 1.24–1.31 (1H, m), 1.35–1.38 (1H, m),

1.57 (9H, s), 3.03 (1H, dd, JZ2.0, 16.5 Hz), 3.28 (1H, dd,

JZ10.5, 16.5 Hz), 3.64 (3H, s), 3.39 (1H, d, JZ10.0 Hz),

3.41 (1H, d, JZ10.0 Hz), 4.80 (1H, d, JZ9.5 Hz), 6.95 (1H,

t, JZ7.5 Hz), 7.11–7.15 (2H, m), 7.45 (1H, br); ¹³C NMR

(125 MHz, CDCl₃) d 7.26, 24.9, 28.3 (!3), 30.1, 59.3, 64.6,

76.0, 77.2, 82.1, 116.3 (!2), 122.8, 124.1, 126.9, 131.9,

142.8; IR (CHCl₃) cm^K1: 3373, 2981, 1667, 1484, 1382,

1331, 1287, 1165, 1115, 1015; HRMS calcd for

C₁₈H₂₇NO₄Na (MCNa)^C344.1838, found 344.1845;

[a]²_D⁴ZK62.1 (c 0.80, CHCl₃).

3.4.2.5. tert-Butyl (2S)-2-[(1R)-1-(4-dimethylamino-

phenyl)-1-hydroxy-2-methoxyethyl]indoline-1-carboxyl-

ate (14e). The general procedure was followed using 13b

(253 mg, 0.87 mmol), 4-(N,N-dimethyl)aniline magnesium

bromide in THF (3.5 ml, 0.5 M) and THF (2 ml) to give 14e

(300 mg, 84%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.61 (9H, s), 2.89 (1H, d, JZ15.0 Hz), 2.94 (6H,

s), 2.98 (1H, dd, JZ10.0, 15.0 Hz), 3.12 (1H, br s), 3.28

(3H, s), 3.71 (1H, d, JZ9.3 Hz), 3.81 (1H, d, JZ9.3 Hz),

4.85 (1H, br s), 6.72 (2H, d, JZ8.8 Hz), 6.91 (1H, t, JZ

7.3 Hz), 7.05 (1H, d, JZ7.3 Hz), 7.12 (1H, t, JZ7.3 Hz),

7.34 (2H, d, JZ8.8 Hz), 7.49 (1H, br); ¹³C NMR (125 MHz,

CDCl₃) d 28.7 (!3), 30.4, 40.8 (!2), 59.8, 65.2, 78.6, 79.5,

81.5, 112.6 (!2), 116.3 (!2), 123.0, 124.0, 126.6 (!2),

Synthesis of compounds 14b–q were carried out by the

method similar to that used for 14a.

3.4.2.2. tert-Butyl (2S)-2-[(1S)-1-hydroxy-1-(methoxy-

methyl)propyl]indoline-1-carboxylate (14b). The general

procedure was followed using 13c (584 mg, 2.12 mmol),

MeOCH₂Sn(n-Bu)₃(1.42 g, 4.24 mmol), n-BuLi in hexane

(2.4 ml, 1.6 M) and THF (5 ml) to give 14b (586 mg, 86%)

as a colorless oil. ¹H NMR (400 MHz, CDCl₃) d 0.97 (3H, t,

JZ7.8 Hz), 1.58 (9H, s), 1.61–1.70 (2H, m), 2.83 (3H, s),

3.06 (1H, d, JZ9.0 Hz), 3.13 (1H, dd, JZ2.0, 16.0 Hz),

3.16 (1H, d, JZ9.0 Hz), 3.25 (1H, dd, JZ10.4, 16.0 Hz),

4.66 (1H, dd, JZ2.0, 10.4 Hz), 6.96 (1H, t, JZ7.2 Hz),

7.12–7.21 (2H, m), 7.45 (1H, br d, JZ6.4 Hz); ¹³C NMR

(100 MHz, CDCl₃) d 7.05, 27.2, 28.3 (!3), 30.4, 58.5, 65.3,

74.6, 76.2, 82.2, 114.5, 116.1, 122.8, 123.9, 126.4, 132.3,

126.8, 130.2, 133.0, 143.5, 149.9; IR (thin ﬁlm) cm^K1

:

3554, 2977, 1695, 1615, 1522, 1484, 1382, 1369, 1167,

1135, 751; HRMS calcd for C₂₄H₃₃N₂O₄(MCH)^C

413.2440, found 413.2430; [a]²_D⁴ZK52.9 (c 0.29, CHCl₃).

3.4.2.6. tert-Butyl (2S)-2-[(1R)-1-(4-chlorophenyl)-1-

hydroxy-2-methoxyethyl]indoline-1-carboxylate (14f).

The general procedure was followed using 13b (320 mg,

1.10 mmol), 4-chlorophenylmagnesium bromide in diethyl

ether (2.2 ml, 1.0 M) and THF (3 ml) to give 14f (265 mg,

2088

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

61%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.60

(9H, s), 2.83 (1H, d, JZ16.3 Hz), 3.02 (1H, dd, JZ10.0,

16.3 Hz), 3.30 (3H, s), 3.44 (1H, br), 3.70 (1H, d, JZ

9.6 Hz), 3.82 (1H, d, JZ9.6 Hz), 4.87 (1H, br), 6.92 (1H, t,

JZ7.3 Hz), 7.04 (1H, d, JZ7.3 Hz), 7.12 (1H, t, JZ

7.3 Hz), 7.29 (2H, d, JZ8.6 Hz), 7.42 (2H, d, JZ8.6 Hz),

7.45 (1H, br); ¹³C NMR (125 MHz, CDCl₃) d 28.7 (!3),

30.4, 59.8, 65.0, 78.0, 79.6, 81.9, 116.3 (!2), 123.2, 124.1,

127.0, 127.5 (!2), 128.6 (!2), 132.4, 133.4, 141.1, 143.2;

IR (KBr) cm^K1: 3457, 2978, 1689, 1485, 1381, 1369, 1168,

751; HRMS calcd for C₂₂H₂₇ClNO₄(MCH)^C404.1629,

found 404.1622; [a]²_D⁴ZK62.8 (c 0.44, CHCl₃).

(MCNa)^C356.1838, found 356.1838; [a]²_D⁴ZK53.1

(c 0.23, CHCl₃).

3.4.2.10. tert-Butyl (2S)-2-[(1R)-1-hydroxy-1-(meth-

oxymethyl)-3-trimethylsilanylprop-2-ynyl]indoline-1-

carboxylate (14j). The general procedure was followed

using 13a (330 mg, 1.13 mmol), (trimethylsilylmethyl)

magnesium bromide in THF (freshly prepared from

trimethylsilylacetylene (0.96 ml, 6.79 mmol), MeMgBr in

diethyl ether (1.13 ml, 3.40 mmol) and THF (1 ml)) and

THF (5 ml) to give 14j (280 mg, 63%) as a colorless oil. ¹H

NMR (500 MHz, CDCl₃) d K0.13 (9H, s), 1.58 (9H, s),

3.05 (1H, d, JZ16.5 Hz), 3.38 (1H, dd, JZ10.5, 16.5 Hz),

3.47 (3H, s), 3.54 (1H, d, JZ10.5 Hz), 3.66 (1H, d, JZ

10.5 Hz), 4.90 (1H, d, JZ10.5 Hz), 6.95 (1H, t, JZ7.5 Hz),

7.11 (1H, d, JZ7.5 Hz), 7.13 (1H, t, JZ7.5 Hz), 7.42 (1H,

br); ¹³C NMR (125 MHz, CDCl₃) d K0.55 (!3), 28.2

(!3), 31.1, 59.8, 63.5, 75.0, 77.0, 82.5, 89.8, 102.7, 116.2

3.4.2.7. tert-Butyl (2S)-2-[(1R)-1-cyclohexyl-1-

hydroxy-2-methoxyethyl]indoline-1-carboxylate (14g).

The general procedure was followed using 13b (200 mg,

0.69 mmol), cyclohexylmagnesium bromide in THF

(6.7 ml, 1.0 M) and THF (2 ml) to give 14g (154 mg,

85%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.01–

1.17 (4H, m), 1.52–1.57 (2H, m), 1.57 (9H, s), 1.65 (1H, br),

1.76 (3H, br), 1.88 (1H, br), 3.16–3.26 (2H, m), 3.30 (3H, s),

3.47 (1H, d, JZ9.3 Hz), 3.53 (1H, d, JZ9.3 Hz), 4.77 (1H,

br), 6.94 (1H, t, JZ8.0 Hz), 7.12 (2H, t, JZ8.0 Hz), 7.47

(1H, br); ¹³C NMR (125 MHz, CDCl₃) d 26.8, 27.2, 27.4,

27.4, 28.1 (!3), 28.7, 30.7, 44.2, 59.5, 64.0, 74.8, 78.1,

81.6, 116.5 (!2), 123.0, 124.1, 126.9, 133.2, 143.3; IR

(thin ﬁlm) cm^K1: 3551, 3393, 2977, 2928, 2854, 1697, 1485,

1387, 1169, 751; HRMS calcd for C₂₂H₃₄NO₄(MCH)^C

376.2488, found 376.2486; [a]²_D⁴ZK47.9 (c 0.71, CHCl₃).

(!2), 122.8, 124.0, 126.7, 131.6, 142.5; IR (CHCl₃) cm^K1

:

3317, 2981, 1664, 1484, 1383, 1251, 1165, 1135, 861, 845;

HRMS calcd for C₂₁H₃₁NO₄SiNa (MCNa)^C412.1920,

found 412.1941; [a]²_D⁴ZK68.8 (c 0.35, CHCl₃).

3.4.2.11. tert-Butyl (2S)-5-bromo-2-[(1R)-1-hydroxy-

1-(methoxymethyl)-5-methylhex-4-enyl]indoline-1-carb-

oxylate (14k). The general procedure was followed using

13a (1.20 g, 3.24 mmol), 4-methyl-3-pentenylmagnesium

bromide in THF (freshly prepared from the corresponding

bromide (2.5 g, 15.3 mmol) and Mg (550 mg, 23 mmol))

and THF (15 ml) to give 14k (992 mg, 67%) as a colorless

1

oil. H NMR (500 MHz, CDCl₃) d 1.26 (1H, dt, JZ5.0,

3.4.2.8. tert-Butyl (2S)-2-[(1R)-1-hydroxy-1-(methoxy-

methyl)prop-2-enyl]indoline-1-carboxylate (14h). The

general procedure was followed using 13b (200 mg,

0.69 mmol), vinylmagnesium bromide in THF (2.1 ml,

1.0 M) and THF (2 ml) to give 14h (213 mg, 97%) as a

14.0 Hz), 1.34–1.40 (1H, m), 1.53 (3H, s), 1.56 (9H, s), 1.62

(3H, s), 1.91–1.97 (1H, m), 2.01–2.07 (1H, m), 3.04 (1H, d,

JZ16.5 Hz), 3.26 (1H, dd, JZ10.5, 16.5 Hz), 3.33 (3H, s),

3.38 (2H, s), 4.76 (1H, d, JZ10.5 Hz), 4.96 (1H, t, JZ

7.0 Hz), 7.21–7.24 (2H, m), 7.32 (1H, br); ¹³C NMR

(125 MHz, CDCl₃) d 17.4, 21.5, 25.5, 28.1 (!3), 29.7, 32.5,

59.2, 64.8, 76.8, 76.9, 82.3, 115.3, 117.5, 124.3, 127.0,

129.6, 131.3, 134.2, 142.0, 154.4; IR (CHCl₃) cm^K1: 3381,

2981, 2930, 1672, 1477, 1371, 1254, 1164; HRMS calcd for

C₂₂H₃₂NO₄BrNa (MCNa)^C476.1412, found 476.1412;

[a]²_D⁴ZK43.5 (c 0.93, CHCl₃).

1

colorless oil. H NMR (400 MHz, CDCl₃) d 1.58 (9H, s),

3.03 (1H, dd, JZ2.0, 16.8 Hz), 3.27 (1H, dd, JZ10.0,

16.8 Hz), 3.40 (3H, s), 3.43 (1H, d, JZ9.6 Hz), 3.54 (1H, d,

JZ9.6 Hz), 4.74 (1H, d, JZ10.0 Hz), 5.14 (1H, dd, JZ1.2,

11.0 Hz), 5.42 (1H, dd, JZ1.2, 17.2 Hz), 5.66 (1H, dd, JZ

11.0, 17.2 Hz), 6.94 (1H, t, JZ7.2 Hz), 7.10–7.15 (2H, m),

7.44 (1H, br); ¹³C NMR (125 MHz, CDCl₃) d 28.3 (!3),

29.8, 30.0, 59.5, 63.6, 78.7, 82.0, 116.1 (!2), 116.4, 122.8,

123.9, 126.9, 131.7, 136.8, 142.7; IR (CHCl₃) cm^K1: 3357,

2982, 2931, 1686, 1484, 1383, 1287, 1258, 1352, 1166,

1133, 1017, 936; HRMS calcd for C₁₈H₂₅NO₄Na (MC

Na)^C342.1681, found 342.1682; [a]²_D⁴ZK56.6 (c 0.69,

CHCl₃).

3.4.2.12. tert-Butyl (2S)-5-bromo-2-[(1R)-1-hydroxy-

1-(methoxymethyl)-3-phenylpropyl]indoline-1-carboxy-

late (14l). The general procedure was followed using 13a

(1.0 g, 2.70 mmol), phenethylmagnesium chloride in THF

(3.2 ml, 1.0 M) and THF (15 ml) to give 14l (871 mg, 68%)

1

as a colorless oil. H NMR (400 MHz, CDCl₃) d 1.53 (9H,

s), 1.61–1.70 (2H, m), 2.54 (1H, dt, JZ5.2, 11.8 Hz), 2.67

(1H, dt, JZ5.2, 11.8 Hz), 3.04 (1H, d, JZ16.9 Hz), 3.25

(1H, dd, JZ10.3, 16.9 Hz), 3.32 (3H, s), 3.38 (2H, s), 4.77

(1H, d, JZ10.3 Hz), 7.01 (2H, d, JZ6.6 Hz), 7.07–7.27

(6H, m); ¹³C NMR (125 MHz, CDCl₃) d 28.2 (!3),

29.3, 29.8, 34.6, 59.3, 65.0, 76.3, 76.7, 82.6, 115.5, 117.7,

125.6, 127.2, 128.2 (!2), 128.3 (!2), 129.8, 134.1, 141.9,

142.4, 154.6; IR (ﬁlm) cm^K1: 3394, 2978, 2930, 1702,

1668, 1476, 1369, 1329, 1166, 1137, 757; HRMS calcd for

C₂₄H₃₀NO₄BrNa (MCNa)^C498.1256, found 498.1265;

[a]²_D⁴ZK37.8 (c 1.03, CHCl₃).

3.4.2.9. tert-Butyl (2S)-2-[(1R)-1-hydroxy-1-(methoxy-

methyl)-2-methylallyl]indoline-1-carboxylate (14i). The

general procedure was followed using 13b (320 mg,

1.10 mmol), 2-methylallylmagnesium bromide in THF

(6.6 ml, 0.5 M) and THF (5 ml) to give 14i (380 mg,

100%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.61

(9H, s), 1.84 (3H, s), 3.08–3.16 (2H, m), 3.37 (3H, s), 3.52

(1H, d, JZ10.0 Hz), 3.75 (1H, d, JZ10.0 Hz), 4.73 (1H,

br), 5.09 (1H, s), 5.22 (1H, s), 6.96 (1H, t, JZ7.5 Hz), 7.13–

7.17 (2H, m), 7.52 (1H, br); ¹³C NMR (125 MHz, CDCl₃) d

19.6, 28.2 (!3), 29.3, 59.3, 61.5, 75.7, 80.6, 81.2, 113.6,

116.0, 122.7, 123.6, 126.4, 132.6, 142.9, 145.2, 153.7; IR

(CHCl₃) cm^K1: 3559, 2980, 2930, 1685, 1484, 1373, 1285,

1166, 1135, 1014, 911; HRMS calcd for C₁₉H₂₇NO₄Na

3.4.2.13. tert-Butyl (2S)-5-bromo-2-[(1R)-1-hydroxy-

1-(methoxymethyl)-pent-4-enyl]indoline-1-carboxylate

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2089

(14m). The general procedure was followed using 13a

(715 mg, 1.93 mmol), 3-butenylmagnesium chloride in

THF (4.6 ml, 0.5 M) and THF (10 ml) to give 14m

(671 mg, 82%) as a colorless oil. ¹H NMR (400 MHz,

CDCl₃) d 1.28–1.36 (1H, m), 1.38–1.46 (1H, m), 1.57 (9H,

s), 1.95–2.04 (1H, m), 2.13–2.24 (1H, m), 3.04 (1H, d, JZ

16.9 Hz), 3.26 (1H, dd, JZ9.5, 16.9 Hz), 3.35 (3H, s), 3.38

(2H, s), 4.77 (1H, d, JZ10.9 Hz), 4.87 (1H, d, JZ10.9 Hz),

4.92 (1H, d, JZ19.1 Hz), 5.66–5.76 (1H, m), 7.24–7.26

(2H, m), 7.32 (1H, br); ¹³C NMR (125 MHz, CDCl₃) d 27.2,

28.2 (!3), 29.8, 31.6, 59.3, 64.9, 76.0, 76.7, 82.5, 114.2,

115.4, 117.6, 127.1, 129.8, 134.2, 138.8, 142.0, 154.2; IR

(ﬁlm) cm^K1: 3401, 2977, 2928, 1703, 1670, 1477, 1369,

1167, 1015, 815; HRMS calcd for C₂₀H₂₈NO₄BrNa (MC

Na)^C448.1100, found 448.1122; [a]²_D⁴ZK50.8 (c 1.06,

CHCl₃).

CDCl₃) d 17.5, 20.9, 21.5, 25.5, 28.1 (!3), 30.5, 39.2, 66.5,

75.9, 82.7, 115.4, 117.5, 124.2, 127.1, 129.9, 131.5, 133.6,

141.8, 155.0; IR (CHCl₃) cm^K1: 3437, 2979, 1668, 1477,

1372, 1163, 1015; HRMS calcd for C₂₁H₃₀NO₃Br (M)^C

423.1409, found 423.1400; [a]²_D⁴ZK72.1 (c 0.38, CHCl₃).

3.4.2.17. tert-Butyl (2S)-2-[(1R)-1-hydroxy-1,3-di-

phenylpropyl]indoline-1-carboxylate (14q). The general

procedure was followed using 13h (17 mg, 0.048 mmol),

phenyllithium in diethyl ether (0.3 ml, 0.94 M) and THF

(1 ml) to give 14q (14 mg, 68%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 1.55 (9H, s), 2.19 (1H, dt, JZ4.9,

12.7 Hz), 2.32 (1H, br), 2.45 (1H, dt, JZ3.9, 12.7 Hz), 2.65

(1H, br), 2.87 (1H, d, JZ16.1 Hz), 3.11 (1H, br), 4.90

(1H, d, JZ9.3 Hz), 6.86 (1H, t, JZ7.0 Hz), 6.97 (1H, d, JZ

7.0 Hz), 7.03 (1H, br), 7.11–7.26 (9H, m), 7.43 (2H, d, JZ

7.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d 28.5 (!3), 29.9,

30.9, 42.0, 67.9, 80.9, 82.3, 116.5 (!2), 123.3, 124.1,

125.9, 126.3, 127.0, 127.1, 127.6, 128.2, 128.3, 128.6 (!2),

3.4.2.14. tert-Butyl (2S)-2-(1-hydroxy-1-methylethyl)-

indoline-1-carboxylate (14n). The general procedure was

followed using 13e (760 mg, 2.91 mmol), methyllithium in

diethyl ether (7.7 ml, 1.1 M) and THF (10 ml) to give 14n

(500 mg, 62%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.00 (3H, s), 1.22 (3H, s), 1.58 (9H, s), 2.84 (1H,

d, JZ16.5 Hz), 3.32 (1H, dd, JZ10.5, 16.5 Hz), 4.51 (1H,

d, JZ10.5 Hz), 6.95 (1H, t, JZ7.5 Hz), 7.12 (1H, d, JZ

7.5 Hz), 7.15 (1H, t, JZ7.5 Hz), 7.47 (1H, br); ¹³C NMR

(125 MHz, CDCl₃) d 23.3, 26.8, 28.2 (!3), 30.9, 67.5, 74.3,

82.1, 116.2 (!2), 122.9, 124.1, 127.0, 131.4, 142.5; IR

(CHCl₃) cm^K1: 3405, 2981, 1665, 1484, 1384, 1288, 1256,

1165, 1045, 1019; HRMS calcd for C₁₆H₂₃NO₃Na

(MCNa)^C300.1576, found 300.1568; [a]²_D⁴ZK69.7 (c

0.69, CHCl₃).

128.6 (!2), 128.7, 132.2, 142.1, 142.9; IR (KBr) cm^K1

:

2976, 2929, 1702, 1682, 1483, 1369, 1167, 751, 701; HRMS

calcd for C₂₈H₃₂NO₃(MCH)^C430.3282, found 430.2387;

[a]²_D⁴ZK59.6 (c 1.40, CHCl₃).

3.5. Synthesis of (C)-benzastatin E (1)

3.5.1. (1R,9aS)-1-(Methoxymethyl)-3,3-dimethyl-1-(3,4-

dimethylpent-3-enyl)-9,9a-dihydro-1H-[1,3]oxazolo[3,4-

a]indole-7-carboxylic acid (17). To a solution of major-16

(919 mg, 2.25 mmol) in ether (15 ml) was added t-BuLi in

pentane (6.0 ml, 1.5 M) dropwise at K78 8C. After stirring

for 15 min at K78 8C, a portion of CO₂(2.0 g) was added to

the reaction mixture at K78 8C. After warming up to room

temperature, the reaction was quenched with satd NH₄Cl aq

(30 ml) and extracted with AcOEt (30 ml!2). The

combined organic extracts were washed with brine

(30 ml), dried over Na₂SO₄, ﬁltered and evaporated.

Puriﬁcation by silica gel column chromatography (hex-

ane–AcOEt 10:1 to 1:2) provided 17 (446 mg, 53%) as a

colorless solid (mp 210–213 8C). ¹H NMR (400 MHz,

CDCl₃) d 1.08 (1H, dt, JZ4.4, 13.2 Hz), 1.49 (3H, s), 1.54

(6H, s), 1.55 (3H, s), 1.56–1.65 (1H, m), 1.73 (3H, s), 1.95

(1H, dt, JZ4.4, 13.2 Hz), 2.07 (1H, dt, JZ4.4, 13.2 Hz),

3.06–3.10 (2H, m), 3.32 (1H, d, JZ9.6 Hz), 3.40 (3H, s),

3.53 (1H, d, JZ9.6 Hz), 4.45 (1H, dd, JZ6.0, 9.6 Hz), 6.60

(1H, d, JZ8.8 Hz), 7.74 (1H, s), 7.82 (1H, dd, JZ1.6,

8.8 Hz); ¹³C NMR (100 MHz, CDCl₃) d 18.4, 20.6, 26.0,

28.0, 28.5, 28.9, 30.7, 59.6, 70.2, 75.9, 82.1, 93.9, 109.3,

118.7, 124.0, 126.5, 127.0, 130.8, 131.9, 132.5, 152.9,

171.8; IR (KBr) cm^K1: 2913, 1666, 1607, 1450, 1369, 1296,

1272, 1217, 1120, 827, 768; HRMS calcd for C₂₂H₃₁NO₄

(M)^C373.2253, found 373.2265; [a]²_D⁴ZC223.5 (c 0.42,

CHCl₃).

3.4.2.15. tert-Butyl (2S)-5-bromo-2-[(1R)-1-hydroxy-

1-phenylethynylbutyl]indoline-1-carboxylate (14o). The

general procedure was followed using 13f (220 mg,

0.60 mmol), phenylacetyllithium in THF (1.8 ml, 1.0 M)

and THF (5 ml) to give 14o (240 mg, 85%) as a colorless

solid (mp 122–124 8C). ¹H NMR (500 MHz, CDCl₃) d 1.01

(3H, t, JZ7.1 Hz), 1.58 (9H, s), 1.66–1.76 (3H, m), 1.80–

1.86 (1H, m), 3.12 (1H, dd, JZ1.7, 16.8 Hz), 3.42 (1H, dd,

JZ9.9, 16.8 Hz), 4.70 (1H, dd, JZ1.7, 9.9 Hz), 6.88 (2H, d,

JZ7.3 Hz), 7.16–7.34 (6H, m); ¹³C NMR (125 MHz,

CDCl₃) d 14.6, 17.2, 28.5 (!3), 31.7, 42.2, 67.5, 75.7,

83.5, 84.7, 89.0, 115.9, 118.1, 122.6, 124.5, 127.4, 128.3

(!2), 128.4, 130.2, 131.8 (!2), 134.6, 142.2; IR

(KBr) cm^K1: 3489, 2960, 2931, 2872, 1688, 1668, 1479,

1369, 1335, 1165, 757; HRMS calcd for C₂₅H₂₈NO₃BrNa

(MCNa)^C492.1150, found 492.1158. Anal. Calcd for

C₂₅H₂₈NO₃Br: C, 63.83; H, 6.00; N, 2.98; Br, 16.99. Found:

C, 63.98; H, 5.70; N, 2.99; Br, 16.90; [a]²_D⁴ZK48.8 (c 0.94,

CHCl₃).

3.4.2.16. tert-Butyl (2S)-5-bromo-2-[(1S)-1-hydroxy-

1,5-dimethylhex-4-enyl]indoline-1-carboxylate (14p).

The general procedure was followed using 13g (20 mg,

0.049 mmol), methyllithium in diethyl ether (0.13 ml,

1.1 M) and THF (2 ml) to give 14p (10 mg, 47%) as a

3.5.2. (1R,9aS)-1-Methoxymethyl-3,3-dimethyl-1-(3,4-

dimethylpent-3-enyl)-9,9a-dihydro-1H-[1,3]oxazolo[3,4-

a]indole-7-carboxamide (18). To a solution of 17 (103 mg,

0.276 mmol) in THF (5 ml) was added 1,1⁰-carbonyldi-

imidazole (134 mg, 0.827 mmol) at room temperature.

The mixture was stirred for 30 min at room temperature.

1,1⁰-Carbonyldiimidazole (134 mg, 0.827 mmol) was added

and stirred for another 30 min at room temperature. 28%

NH₃aq (5.0 ml) was added to the reaction mixture at room

1

colorless oil. H NMR (400 MHz, CDCl₃) d 0.89 (3H, s),

1.47–1.54 (2H, m), 1.57 (9H, s), 1.63 (3H, s), 1.69 (3H, s),

2.12–2.21 (2H, m), 2.77 (1H, d, JZ16.8 Hz), 3.30 (1H, dd,

JZ10.4, 16.8 Hz), 4.60 (1H, dd, JZ2.4, 10.4 Hz), 5.12 (1H,

t, JZ6.4 Hz), 7.23–7.33 (3H, m); ¹³C NMR (125 MHz,

2090

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

temperature and stirred for 12 h at this temperature. After

addition of water (20 ml), the aqueous solution was

extracted with AcOEt (20 ml!2). The combined organic

extracts were washed with brine (20 ml), dried over

Na₂SO₄, ﬁltered and evaporated. Puriﬁcation by silica gel

column chromatography (hexane–AcOEt 1:1 to AcOEt)

gave 18 (76 mg, 74%) as a colorless oil. ¹H NMR

(400 MHz, CDCl₃) d 1.06 (1H, dt, JZ5.5, 13.2 Hz), 1.48

(3H, s), 1.53 (6H, s), 1.55 (3H, s), 1.55–1.62 (1H, m), 1.71

(3H, s), 1.95 (1H, dt, JZ5.5, 13.2 Hz), 2.06 (1H, dt, JZ5.5,

13.2 Hz), 3.01–3.17 (2H, m), 3.31 (1H, d, JZ9.6 Hz), 3.39

(3H, s), 3.53 (1H, d, JZ9.6 Hz), 4.42 (1H, dd, JZ5.2,

8.8 Hz), 5.90 (2H, br), 6.59 (1H, d, JZ8.8 Hz), 7.49 (1H,

dd, JZ2.4, 8.8 Hz), 7.52 (1H, s); ¹³C NMR (100 MHz,

CDCl₃) d 18.4, 19.9 (!2), 20.6, 26.0, 28.0, 28.8, 28.9, 31.0,

59.6, 70.2, 76.0, 82.1, 94.2, 109.8, 123.0, 123.9, 124.1,

127.1, 132.1, 151.7, 169.4; IR (CHCl₃) cm^K1: 3534, 3417,

2928, 1663, 1609, 1492, 1444, 1370, 1272, 1118, 909;

HRMS calcd for C₂₂H₃₂N₂O₃Na (MCNa)^C395.2311,

found 395.2313; [a]²_D⁴ZC154.2 (c 0.20, CHCl₃).

To a solution of alcohol (5.78 g, 15.5 mmol) in CH₂Cl₂

(150 ml) was added Et₃N (8.7 ml, 62.1 mmol), DMSO

(7.3 ml, 102.5 mmol), and pyridine sulfur trioxide com-

plex(7.41 g, 46.6 mmol) at 0 8C. After stirring at room

temperature for 3 h, H₂O (150 ml) was added, and the

product was extracted with CH₂Cl₂(50 ml!3). The

combined organic extracts were washed with brine

(150 ml), dried over Na₂SO₄, ﬁltered and evaporated.

Puriﬁcation by silica gel column chromatography (hex-

ane–AcOEt 4:1 to 3:2) yielded aldehyde 19 (3.09 g, 61%) as

a colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.52 (9H, br),

3.14 (1H, dd, JZ4.9, 16.6 Hz), 3.38 (1H, br), 4.75 (1H, br),

7.26 (1H, s), 7.32 (1H, s), 7.78 (1H, br s), 9.63 (1H, br s);

¹³C NMR (125 MHz, CDCl₃, two rotamers) d 28.2 (!3),

29.3, 60.0, 82.4, 115.2, 116.2 (!2), 127.6, 130.2*, 130.8,

141.6, 151.4, 198.3; IR (KBr) cm^K1: 3282, 3063, 2929,

1672, 1645, 1223, 751; HRMS calcd for C₁₄H₁₆NO₃BrK

(MCK)^C363.9951, found 363.9952.

3.6.1.2. tert-Butyl (2S*)-5-bromo-2-[(1R*)-1-hydroxy-

pent-4-enyl]indoline-1-carboxylate (20). This diastereo-

selective Grignard addition was carried out by a method

similar to that used for synthesis of 14a with 19 (300 mg,

0.92 mmol), 3-butenylmagnesium bromide in THF (2.2 ml,

0.5 M) and THF (10 ml) to give 20 (264 mg, 75%) as a

colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.43–1.44 (1H,

m), 1.52–1.57 (1H, m), 1.57 (9H, s), 2.10–2.18 (1H, m),

2.27–2.31 (1H, m), 2.99 (1H, br), 3.20–3.25 (1H, m), 3.98

(1H, br), 4.49 (1H, br), 4.98 (1H, d, JZ10.3 Hz), 5.05 (1H,

dd, JZ1.5, 15.6 Hz), 5.78–6.86 (1H, m), 7.24 (1H, s), 7.26

(1H, s), 7.47 (1H, br); ¹³C NMR (125 MHz, CDCl₃) d 28.6

(!4), 30.3, 31.6, 64.5, 73.3, 82.4, 115.4, 115.4, 116.8,

127.7, 130.3 (!2), 133.4, 138.4, 142.1; IR (liquid

ﬁlm) cm^K1: 3464, 2977, 2933, 1702, 1479, 1385, 1370,

1168, 1142; HRMS calcd for C₁₈H₂₄NO₃BrNa (MCNa)^C

404.08373, found 404.08407.

3.5.3. (C)-Benzastatin E (1). To a solution of 18 (70 mg,

0.188 mmol) in MeOH (5 ml) was added pyridinium

p-toluenesulfonate (10 mg) at room temperature. The

mixture was stirred for 3 h at room temperature. The

solvent was concentrated in vacuo. The residue was puriﬁed

by silica gel column chromatography (AcOEt to AcOEt–

MeOH 10:1) to give 1 (40 mg, 64%) as a colorless solid (mp

1

171–174 8C). H NMR (500 MHz, CDCl₃) d 1.48 (1H, dd,

JZ5.5, 14.0 Hz), 1.57 (1H, dd, JZ4.5, 14.0 Hz), 1.64 (6H,

s), 1.66 (3H, s), 2.01 (1H, dd, JZ5.5, 13.0 Hz), 2.15 (1H,

dd, JZ4.5, 13.0 Hz), 2.70 (1H, br s), 2.97 (1H, dd, JZ8.5,

16.0 Hz), 3.07 (1H, dd, JZ11.0, 16.0 Hz), 3.42 (3H, s), 3.42

(1H, d, JZ9.5 Hz), 3.52 (1H, d, JZ9.5 Hz), 4.15 (1H, t, JZ

9.5 Hz), 4.65 (1H, br), 5.60 (2H, br), 6.58 (1H, d, JZ

7.5 Hz), 7.50 (1H, d, JZ7.5 Hz), 7.55 (1H, s); ¹³C NMR

(125 MHz, CDCl₃) d 18.3, 20.0, 20.6, 28.2, 30.0, 32.7, 59.6,

66.2, 73.0, 78.4, 107.8, 123.1, 124.1, 124.5, 127.2, 128.0,

128.6, 154.5, 169.3; IR (KBr) cm^K1: 3416, 3312, 2918,

1645, 1606, 1441, 1380, 1262, 1112, 773; HRMS calcd for

C₁₉H₂₉N₂O₃(MCH)^C333.2178, found 333.2187. Anal.

Calcd for C₁₉H₂₈N₂O₃$0.3H₂O: C, 67.55; H, 8.53; N, 8.29.

Found: C, 67.48; H, 8.59; N, 8.24; [a]²_D⁴Z C21.3 (c 0.10,

MeOH).

3.6.1.3.

(1R*,9aS*)-7-Bromo-1-but-3-enyl-3,3-

dimethyl-9,9a-dihydro-1H-[1,3]oxazolo-[3,4-a]indole-3-

spiro-1⁰-cyclohexane (21). To a solution of 20 (144 mg,

0.38 mmol) in CH₂Cl₂was added TFA (1 ml) at 0 8C. After

stirring at room temperature for 20 min, the reaction

mixture was neutralized with satd NaHCO₃aq and extracted

with AcOEt (5 ml!2). The combined organic extracts were

washed with brine (10 ml), dried over Na₂SO₄, ﬁltered and

evaporated. Puriﬁcation by silica gel column chroma-

tography (hexane–AcOEt 9:1) gave the corresponding

3.6. Stereoselectiverearrangementfroma,a-disubstituted

indoline-2-methanols to 2,2,3-trisubstituted tetrahydro-

quinolines

1

indoline-2-methanol (62 mg, 59%) as a colorless oil. H

NMR (500 MHz, CDCl₃) d 1.43–1.60 (2H, m), 2.08–2.18

(1H, m), 2.21 (1H, s), 2.24–2.31 (1H, m), 2.88 (1H, dd, JZ

9.5, 16.0 Hz), 3.00 (1H, dd, JZ9.9, 16.0 Hz), 3.71–3.73

(1H, m), 3.82 (1H, br), 3.95 (1H, dt, JZ3.7, 9.5 Hz), 4.96

(1H, d, JZ9.6 Hz), 5.03 (1H, dd, JZ1.8, 17.3 Hz), 5.76–

5.86 (1H, m), 6.46 (1H, d, JZ8.1 Hz), 7.06 (1H, br d, JZ

8.1 Hz), 7.13 (1H, s); ¹³C NMR (125 MHz, CDCl₃) d 29.3,

30.2, 31.9, 64.5, 71.3, 110.7 (!2), 115.0, 127.5, 129.7,

131.3, 137.9, 149.4; IR (KBr) cm^K1: 3304, 3327, 2929,

2889, 1483, 1248, 920, 814; HRMS calcd for C₁₃H₁₆NOBr

(M)^C281.0415, found 281.0418.

3.6.1. Investigation of the rearrangement reaction with

a-monosubstituted indoline-2-methanol 22.

3.6.1.1. tert-Butyl 5-bromo-2-formylindoline-1-car-

boxylate (19). To a solution of lithium aluminum hydride

(1.67 g, 44.1 mmol) in THF (40 ml) was added racemic-11

(7.85 g, 22.0 mmol) in THF (20 ml) dropwise at K78 8C.

After stirring for 3 h at K40 8C, the reaction mixture was

quenched with H₂O (1.7 ml), 5 N NaOH aq (1.7 ml), then

H₂O (5.1 ml), and stirred at room temperature for 30 min.

To the mixture was added magnesium sulfate (10 g) and

AcOEt (30 ml), and the mixture was ﬁltered and evaporated.

Puriﬁcation by silica gel column chromatography (hexane–

AcOEt 6:1 to 1:1) gave the corresponding alcohol (6.00 g,

83%).

To a solution of indoline-2-methanol (110 mg, 0.39 mmol)

in CH₂Cl₂was added 1,1-dimethoxycyclohexane (0.6 ml,

3.9 mmol) and p-TsOH (7 mg, 0.04 mmol) at room

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2091

temperature. The mixture was stirred at 30 min at room

temperature. After concentration of the reaction mixture,

puriﬁcation by silica gel column chromatography (hexane–

AcOEt 19:1 to 9:1) afforded 21 (102 mg, 72%) as a colorless

oil. ¹H NMR (400 MHz, CDCl₃) d 1.13–1.21 (1H, m), 1.29–

1.33 (1H, m), 1.42–1.63 (8H, m), 1.78 (1H, dt, JZ4.2,

12.3 Hz), 2.00–2.03 (1H, m), 2.06–2.15 (1H, m), 2.19–2.26

(1H, m), 2.72 (1H, dd, JZ9.5, 16.0 Hz), 3.07 (1H, dd, JZ

7.7, 16.0 Hz), 4.11 (1H, dd, JZ5.9, 14.5 Hz), 4.32 (1H, dd,

JZ8.4, 14.5 Hz), 4.95 (1H, d, JZ10.3 Hz), 5.01 (1H, dd,

JZ1.8, 17.3 Hz), 5.75–5.85 (1H, m), 6.64 (1H, d, JZ

8.5 Hz), 7.09 (1H, d, JZ8.5 Hz), 7.14 (1H, s); ¹³C NMR

(125 MHz, CDCl₃) d 23.4, 23.9, 25.4, 30.2, 30.5, 30.8, 35.4,

37.2, 67.3, 74.4, 96.2, 113.6, 115.0, 117.9, 127.3, 129.3,

136.4, 138.0, 148.5; IR (liquid ﬁlm) cm^K1: 2936, 2857,

1473; HRMS calcd for C₁₉H₂₄NOBr (M)^C361.1041, found

361.1032.

puriﬁcation by Lobar column chromatography (hexane–

AcOEt 19:1). H NMR (400 MHz, CD₃OD) d 1.53–1.61

1

(1H, m), 1.63–1.72 (1H, m), 2.10–2.19 (1H, m), 2.21–2.28

(1H, m), 2.93 (1H, dd, JZ5.9, 16.9 Hz), 3.22 (1H, dd, JZ

4.4, 16.9 Hz), 3.37–3.41 (1H, m), 3.76 (3H, s), 4.25 (1H, dd,

JZ5.5, 9.9 Hz), 4.95 (1H, d, JZ10.3 Hz), 5.05 (1H, dd, JZ

1.5, 16.8 Hz), 5.76–5.86 (1H, m), 6.51 (1H, d, JZ8.8 Hz),

7.54–7.58 (2H, m); ¹³C NMR (125 MHz, CD₃OD) d 30.3,

35.3, 35.3, 51.9, 56.5, 58.0, 113.6, 115.6, 116.9, 117.8,

130.6, 132.5, 139.1, 149.3, 169.3; IR (KBr) cm^K1: 3367,

1696, 1684, 1609, 1293, 1282, 1238. Anal. Calcd for

C₁₅H₁₈NO₂Cl: C, 64.40; H, 6.49; N, 5.01; Cl, 12.67. Found:

C, 64.10; H, 6.29; N, 4.97; Cl, 12.59.

3.6.1.6. Methyl (2S*)-2-[(1R*)-1-chloropent-4-enyl]-

indoline-5-carboxylate (24). ¹H NMR (400 MHz, CD₃OD)

d 1.63–1.73 (1H, m), 1.90–1.98 (1H, m), 2.13–2.22 (1H, m),

2.29–2.38 (1H, m), 2.95 (1H, dd, JZ7.3, 16.3 Hz), 3.19

(1H, dd, JZ9.9, 16.3 Hz), 3.76 (3H, s), 3.87–3.91 (1H, m),

4.06–4.12 (1H, m), 4.96 (1H, d, JZ10.2 Hz), 5.03 (1H, d,

JZ15.4 Hz), 5.74–5.84 (1H, m), 6.44 (1H, d, JZ8.1 Hz),

7.59 (1H, d, JZ1.5 Hz), 7.62 (1H, d, JZ8.1 Hz); ¹³C NMR

(125 MHz, CD₃OD) d 31.6, 33.9, 34.5, 52.0, 65.4, 67.4,

107.7, 116.0, 119.6, 126.8, 128.8, 132.0, 138.5, 157.4,

169.4; EI-MS m/z 279 (M)^C, 248, 224, 202, 188, 176, 144,

132, 117, 90, 77, 59, 41.

3.6.1.4. Methyl (2S*)-2-[(1R*)-1-hydroxypent-4-enyl]-

indoline-5-carboxylate (22). A method for the preparation

of 17 was followed using 21 (115 mg, 0.32 mmol), t-BuLi

in pentane (0.58 ml, 1.5 M) and THF (3 ml) to give the

corresponding carboxylic acid (96 mg, crude yield 90%).

The obtained carboxylic acid was used without further

puriﬁcation.

To a solution of crude carboxylic acid in MeOH (6 ml) was

added TMSCH₂N₂in hexane (2.5 ml, 2 M) at 0 8C. After

stirring at room temperature overnight, the solvent was

evaporated. The residue was puriﬁed by silica gel column

chromatography (hexane–AcOEt 10:1) to give the corre-

sponding methyl ester (92 mg, crude yield 92%). The

obtained methyl ester was used without further puriﬁcation.

3.6.1.7. Methyl (1S*,7aS*)-1-but-3-enyl-7,7a-dihydro-

1H-azireno[1,2-a]indole-5-carboxylate (25). To a solution

of 23 (10 mg, 0.036 mmol) in t-BuOH (0.3 ml) was added

t-BuOK in t-BuOH (0.05 ml, 1 M) at room temperature.

After stirring at 60 8C for 3 h, the solvent was evaporated.

To this residue was added MeOH (0.3 ml), followed by the

addition of acetic acid in MeOH (0.36 ml, 0.1 N), then

TMSCH₂N₂in hexane (0.2 ml, 2 M) at 0 8C. The mixture

was stirred at room temperature for 40 min. After addition

of water (5 ml), the aqueous solution was extracted with

AcOEt (5 ml!2). The combined organic extracts were

washed with brine (10 ml), dried over Na₂SO₄, ﬁltered and

evaporated. Puriﬁcation by silica gel column chroma-

tography (hexane–AcOEt 4:1) afforded 25 (1.6 mg, 26%

from 23) as a colorless oil.

To a solution of methyl ester in MeOH (1 ml) was added

Amberlyst-15^wion exchange resin (10 mg) at room

temperature. After stirring at room temperature for 4 h,

the mixture was ﬁltered and evaporated. Puriﬁcation by

silica gel column chromatography (hexane–AcOEt 7:3)

1

gave 22 (51 mg, 62% from 21) as a colorless oil. H NMR

(500 MHz, CDCl₃) d 1.51–1.66 (2H, m), 2.13 (1H, s), 2.15–

2.23 (1H, m), 2.29–2.36 (1H, m), 3.01 (1H, dd, JZ10.3,

16.1 Hz), 3.07 (1H, dd, JZ9.8, 16.1 Hz), 3.78–3.80 (1H,

m), 3.86 (3H, s), 4.07 (1H, dt, JZ2.9, 9.3 Hz), 4.22 (1H, br

s), 5.02 (1H, d, JZ10.7 Hz), 5.09 (1H, d, JZ16.6 Hz),

5.82–5.90 (1H, m), 6.59 (1H, d, JZ8.8 Hz), 7.75 (1H, s),

7.78 (1H, d, JZ8.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d

28.9, 30.1, 31.7, 51.6, 64.4, 71.8, 107.8, 115.2, 120.4, 126.7,

128.5, 130.6, 138.1, 155.0, 167.3; IR (KBr) cm^K1: 3404,

2932, 1676, 1616, 1307, 1276, 1121, 1090, 767; HRMS

calcd for C₁₅H₁₉NO₃(M)^C261.1365, found 261.1367.

Compound 25 was obtained from 24 (3.5 mg, 0.0125 mmol)

by the similar procedure (1.4 mg, 47% from 24). H NMR

1

(500 MHz, CDCl₃) d 1.53–1.56 (1H, m), 1.66–1.71 (2H, m),

2.23–2.33 (2H, m), 2.89 (1H, td, JZ3.2, 6.7 Hz), 3.29 (1H,

dd, JZ6.7, 16.9 Hz), 3.34 (1H, d, JZ16.9 Hz), 3.89 (3H, s),

4.99 (1H, d, JZ9.8 Hz), 5.06 (1H, d, JZ18.6 Hz), 5.81–

5.89 (1H, m), 7.28 (1H, s), 7.85–7.87 (2H, m); ¹³C NMR

(125 MHz, CDCl₃) d 31.4, 32.0, 32.8, 47.0, 52.2, 52.5,

115.5, 119.3, 126.8, 127.4, 129.8, 137.2, 137.9, 146.7,

162.6; IR (liquid ﬁlm) cm^K1: 3386, 2922, 1718, 1611, 1438,

1275; HRMS calcd for C₁₅H₁₇NO₂(M)^C243.1260, found

243.1267.

3.6.1.5. Methyl (2S*,3R*)-2-but-3-enyl-3-chloro-

1,2,3,4-tetrahydroquinoline-6-carboxylate (23). To a

solution of 22 (10 mg, 0.038 mmol) in CH₂Cl₂was added

CCl₄(0.04 ml, 0.42 mmol) and triphenylphosphine (30 mg,

0.11 mmol) at room temperature. The mixture was stirred at

room temperature for 3 h, and concentrated. The ratio of 23

and 24 (23:24Z3:1) was determined by the ¹H NMR

analysis of the crude residue. Puriﬁcation by silica gel

column chromatography (hexane–AcOEt 19:1 to 4:1) gave

a mixture of 23 and 24 (23/24Z3:1, total 9.7 mg, total yield

91%). Analytical sample was obtained by further

3.6.2. Investigation of the rearrangement reaction of

indoline-2-methanols 15a, b to tetrahydroquinolines

26a, b.

3.6.2.1. (2R,3R)-3-Chloro-2-ethyl-2-(methoxymethyl)-

1,2,3,4-tetrahydroquinoline (26a). Triphenylphosphine

(135 mg, 0.420 mmol) was added to a solution of 15a

(31 mg, 0.14 mmol) and CCl₄(135 ml, 1.40 mmol) in

2092

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

CH₂Cl₂(3 ml) at 40 8C. The mixture was stirred under

reﬂux conditions for 30 min, and then concentrated.

Puriﬁcation by silica gel column chromatography (hex-

ane–AcOEt 10:1 to 2:1) gave tetrahydroquinoline 26a

(21 mg, 63%) as a colorless oil. ¹H NMR (400 MHz,

CDCl₃) d 0.92 (3H, t, JZ7.3 Hz), 1.66 (1H, dq, JZ7.3,

14.8 Hz), 1.76 (1H, dq, JZ7.3, 14.8 Hz), 3.05 (1H, dd, JZ

6.6, 16.8 Hz), 3.30 (1H, dd, JZ5.2, 16.8 Hz), 3.35 (3H, s),

3.48 (1H, d, JZ9.2 Hz), 3.53 (1H, d, JZ9.2 Hz), 3.99 (1H,

br s), 4.33 (1H, dd, JZ5.2, 6.6 Hz), 6.53 (1H, d, JZ8.1 Hz),

6.63 (1H, t, JZ8.1 Hz), 6.96 (1H, d, JZ8.1 Hz), 7.01 (1H, t,

JZ8.1 Hz); ¹³C NMR (100 MHz, CDCl₃) d 7.1, 27.2, 33.9,

57.0, 57.6, 59.4, 73.5, 114.7, 117.2, 117.6, 127.4, 129.4,

142.3; IR (CHCl₃) cm^K1: 3422, 2972, 2935, 2896, 1607,

1588, 1482, 1312, 1260, 1112, 980, 960, 834; HRMS calcd

for C₁₃H₁₈NOCl (M)^C239.1077, found 239.1075;

[a]²_D⁴ZC7.2 (c 0.45, CHCl₃).

9.0 Hz), 6.58 (1H, dt, JZ2.0, 9.0 Hz), 6.95 (1H, d, JZ

9.0 Hz), 6.97 (1H, t, JZ9.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 7.97. 23.4, 27.0, 29.1, 53.9, 59.3, 59.4, 114.2,

116.4, 120.3, 126.6, 128.9, 143.5; IR (CHCl₃) cm^K1: 3421,

2968, 2930, 1605, 1482, 1313, 1110; HRMS calcd for

C₁₃H₁₉NO (M)^C205.1467, found 205.1461; [a]²_D⁴ZK27.6

(c 0.31, CHCl₃).

3.6.2.5. (2R,3R)-3-Chloro-2-ethyl-2-(hydroxymethyl)-

1,2,3,4-tetrahydroquinoline (28). To a solution of 26a

(131mg, 0.55 mmol) in CH₂Cl₂(5 ml) was added AlCl₃

(364 mg, 2.73 mmol) and Me₂S (401 ml, 5.46 mmol) at

room temperature. After stirring at room temperature for

31 h, satd NaHCO₃aq (10 ml) was added and extracted with

AcOEt (10 ml!2). The combined organic extracts were

washed with brine (20 ml), dried over Na₂SO₄, ﬁltered and

evaporated. Puriﬁcation by silica gel chromatography

(hexane–AcOEt 5:1 to 2:1) gave 28 (106 mg, 86%) as a

colorless solid (mp 118–120 8C). ¹H NMR (400 MHz,

CDCl₃) d 0.97 (3H, t, JZ7.6 Hz), 1.72 (2H, q, JZ7.6 Hz),

3.13 (1H, dd, JZ8.0, 16.4 Hz), 3.28 (1H, dd, JZ6.0,

16.4 Hz), 3.75 (2H, br d, JZ3.6 Hz), 3.89 (1H, br s), 4.34

(1H, dd, JZ6.0, 8.0 Hz), 6.57 (1H, d, JZ8.0 Hz), 6.67 (1H,

t, JZ8.0 Hz), 6.96 (1H, d, JZ8.0 Hz), 7.03 (1H, t, JZ

8.0 Hz); ¹³C NMR (100 MHz, CDCl₃) d 7.0, 27.5, 34.0,

57.5, 58.0, 64.0, 114.5, 118.0 (!2), 127.5, 129.2, 142.0; IR

(KBr) cm^K1: 3393, 2267, 1493, 1315, 1046, 752; HRMS

calcdforC₁₂H₁₆NOCl(M)^C225.0920, found225.0922. Anal.

Calcd for C₁₂H₁₆NOCl: C, 63.85; H, 7.15; N, 6.21. Found: C,

63.82; H, 7.06; N, 6.24; [a]²_D⁴ZC8.3 (c 0.18, CHCl₃).

3.6.2.2. (2S,3R)-3-Chloro-2-ethyl-2-(methoxymethyl)-

1,2,3,4-tetrahydroquinoline (26b). The method for the

synthesis of 26a was followed with 15b (100 mg,

0.45 mmol), PPh₃(355 mg, 1.35 mmol) and CCl₄(434 ml,

4.50 mmol) and CH₂Cl₂(5 ml) to give 26b (80 mg, 74%) as

1

a colorless oil. H NMR (500 MHz, CDCl₃) d 0.94 (3H, t,

JZ7.6 Hz), 1.72 (1H, dq, JZ7.6, 14.5 Hz), 1.82 (1H, dq,

JZ7.6, 14.5 Hz), 3.09 (1H, dd, JZ6.8, 16.5 Hz), 3.24 (1H,

dd, JZ4.8, 16.5 Hz), 3.35 (3H, s), 3.40 (1H, d, JZ9.5 Hz),

3.42 (1H, d, JZ9.5 Hz), 3.99 (1H, br s), 4.44 (1H, dd, JZ4.8,

6.8 Hz), 6.57 (1H, d, JZ8.0 Hz), 6.67 (1H, t, JZ8.0 Hz), 6.97

(1H, d, JZ8.0 Hz), 7.01 (1H, t, JZ8.0 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 7.5, 25.4, 34.0, 57.5, 57.9, 59.3, 75.1,

115.0, 117.7, 117.8, 127.3, 129.3, 142.1; IR (CHCl₃) cm^K1

:

(1S,2R,3R)-(K)-30. To

a solution of 28 (5 mg,

3424, 2972, 2935, 2883, 1607, 1588, 1498. 1481, 1307, 1156,

1111, 962; HRMS calcd for C₁₃H₁₈NOCl (M)^C239.1077,

found 239.1081; [a]²_D⁴ZK30.2 (c 0.67, CHCl₃).

0.0222 mmol) and 29 (14.4 mg, 0.0333 mmol) in CH₂Cl₂

(5 ml) was added DCC (6.9 mg, 0.0333 mmol) and DMAP

(3 mg) at 50 8C. The mixture was stirred at 50 8C for 1 h,

and then concentrated. Puriﬁcation by silica gel column

chromatography (hexane–AcOEt 5:1 to 2:1) gave 30 as a

colorless solid (9 mg, 64%). Recrystallization from ethanol

gave an analytical sample (mp 212–215 8C). ¹H NMR

(500 MHz, CDCl₃) d 0.98 (3H, s), 0.99 (3H, t, JZ6.5 Hz),

1.20 (3H, s), 1.35–1.44 (2H, m), 1.55–1.69 (1H, m), 1.82–

1.90 (1H, m), 1.92 (3H, br s), 2.12–2.20 (1H, m), 2.40–2.48

(1H, m), 3.17 (1H, dd, JZ9.5, 17.0 Hz), 3.31 (1H, dd, JZ

5.5, 17.0 Hz), 3.39 (1H, d, JZ14.0 Hz), 3.45 (1H, d, JZ

14.0 Hz), 4.04 (2H, br t, JZ7.0 Hz), 4.36 (1H, dd, JZ5.5,

9.5 Hz), 4.44 (1H, d, JZ11.5 Hz), 4.51 (1H, d, JZ11.5 Hz),

6.56 (1H, d, JZ8.0 Hz), 6.67 (1H, t, JZ8.0 Hz), 6.98 (1H,

d, JZ8.0 Hz), 6.99 (1H, t, JZ8.0 Hz), 7.26 (1H, s), 7.50

(1H, s), 7.73 (1H, s); ¹³C NMR (125 MHz, CDCl₃) d 6.73,

19.9, 20.7, 26.4, 27.8, 33.1, 34.3, 37.7, 44.7, 47.7, 48.5,

53.1, 56.8, 57.3, 65.7, 67.1, 114.5, 117.5, 118.0, 127.6,

128.2, 129.0, 131.1, 131.5, 134.4, 135.0, 136.8, 142.4,

163.5, 165.2; IR (KBr) cm^K1: 3398, 2959, 1730, 1670,

1489, 1299, 1140, 1098, 750, 540; HRMS calcd for

C₃₀H₃₃N₂O₅Cl₃SNa (MCNa)^C661.1073, found

661.1071. Anal. Calcd for C₃₀H₃₃N₂O₅Cl₃S$0.5H₂O: C,

55.52; H, 5.28; N, 4.32. Found: C, 55.69; H, 5.02; N, 4.24;

[a]²_D⁴ZK40.9 (c 0.29, CHCl₃).

3.6.2.3. (2S)-2-Ethyl-2-(methoxymethyl)-1,2,3,4-tetra-

hydroquinoline (27a). To a solution of 26a (21 mg,

0.088 mmol) in benzene (5 ml) was added (n-Bu)₃SnH

(0.047 ml, 0.175 mmol) and AIBN (catalytic) at room

temperature. The mixture was stirred at 80 8C for 3 h.

After concentration, satd KF aq was added, and the mixture

was ﬁltered. The product was extracted with AcOEt (5 ml!

2), and the combined organic extracts were washed with

brine (10 ml), dried over Na₂SO₄, ﬁltered and evaporated.

Puriﬁcation by silica gel chromatography (hexane–AcOEt

5:1) afforded 27a (17 mg, 95%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 0.88 (3H, t, JZ9.0 Hz), 1.57–1.72

(4H, m), 2.70 (2H, t, JZ8.0 Hz), 3.17 (1H, d, JZ11.0 Hz),

3.35 (3H, s), 3.36 (1H, d, JZ11.0 Hz), 3.99 (1H, br s), 6.49

(1H, dd, JZ2.0, 9.0 Hz), 6.58 (1H, dt, JZ2.0, 9.0 Hz), 6.95

(1H, d, JZ9.0 Hz), 6.97 (1H, t, JZ9.0 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 7.97. 23.4, 27.0, 29.1, 53.9, 59.3, 59.4,

114.2, 116.4, 120.3, 126.6, 128.9, 143.5; IR (CHCl₃) cm^K1

:

3421, 2968, 2930, 1605, 1482, 1313, 1110; HRMS calcd for

C₁₃H₁₉NO (M)^C205.1467, found 205.1461; [a]²_D⁴ZC25.3

(c 0.31, CHCl₃).

3.6.2.4. (2R)-2-Ethyl-2-(methoxymethyl)-1,2,3,4-

tetrahydroquinoline (27b). H NMR (500 MHz, CDCl₃)

d 0.88 (3H, t, JZ9.0 Hz), 1.57–1.72 (4H, m), 2.70 (2H, t,

JZ8.0 Hz), 3.17 (1H, d, JZ11.0 Hz), 3.35 (3H, s), 3.36

(1H, d, JZ11.0 Hz), 3.99 (1H, br s), 6.49 (1H, dd, JZ2.0,

1

3.6.3. Preparation of indoline-2-methanols 15 and the

determination of the stereochemistry.

3.6.3.1. (2R)-2-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxybutan-2-ol (15a). To a solution of 14a (650 mg,

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2093

2.02 mmol) in CH₂Cl₂(3 ml) was added TFA (3 ml) at 0 8C.

After stirring at room temperature for 3 h, the reaction

mixture was neutralized with satd NaHCO₃aq and extracted

with AcOEt (10 ml!2). The combined organic extracts

were washed with brine (20 ml), dried over Na₂SO₄, ﬁltered

and evaporated. Puriﬁcation by silica gel chromatography

(hexane–AcOEt 2:1) afforded 15a (440 mg, 99%) as a

colorless oil. ¹H NMR (500 MHz, CDCl₃) d 0.97 (3H, t, JZ

7.7 Hz), 1.50–1.56 (1H, m), 1.62–1.69 (1H, m), 2.90 (1H, s),

2.92 (1H, dd, JZ8.9, 17.5 Hz), 3.05 (1H, dd, JZ10.9,

17.5 Hz), 3.38 (1H, d, JZ9.8 Hz), 3.41 (3H, s), 3.49 (1H, d,

JZ9.8 Hz), 4.08 (1H, dd, JZ8.9, 10.9 Hz), 4.24 (1H, br s),

6.65 (1H, d, JZ7.5 Hz), 6.72 (1H, t, JZ7.5 Hz), 7.02 (1H, t,

JZ7.5 Hz), 7.08 (1H, d, JZ7.5 Hz); ¹³C NMR (100 MHz,

CDCl₃) d 7.94, 27.4, 30.5, 59.5, 65.6, 72.9, 78.1, 109.4,

118.8, 124.4, 127.1, 128.6, 150.5; IR (CHCl₃) cm^K1: 3485,

3405, 2975, 2932, 2893, 1609, 1486, 1467, 1247, 1110;

HRMS calcd for C₁₃H₂₀NO₂(MCH)^C222.1494, found

222.1490; [a]²_D⁴ZK44.2 (c 0.62, CHCl₃).

(264 mg, 89%) as a colorless oil. ¹H NMR (400 MHz,

CDCl₃) d 2.49 (1H, dd, JZ8.8, 15.8 Hz), 2.68 (1H, dd, JZ

11.1, 15.8 Hz), 3.43 (3H, s), 3.49 (1H, d, JZ9.9 Hz), 3.75

(1H, d, JZ9.9 Hz), 3.77 (1H, s), 4.53 (1H, dd, JZ8.8,

11.1 Hz), 4.51 (1H, br s), 6.66 (1H, d, JZ7.3 Hz), 6.68 (1H,

d, JZ7.3 Hz), 6.92 (1H, d, JZ7.3 Hz), 7.00 (1H, t, JZ

7.3 Hz), 7.29–7.31 (1H, m), 7.35–7.39 (2H, m), 7.50 (1H, s),

7.51–7.52 (1H, m); ¹³C NMR (100 MHz, CDCl₃) d 32.2,

59.7, 67.0, 74.6, 82.2, 109.3, 119.0, 124.3, 125.1 (!2),

127.0, 127.0, 128.0 (!2), 128.2, 141.7, 150.4; IR (CHCl₃)

cm^K1: 3405, 2930, 2894, 1732, 1610, 1486, 1089; HRMS

calcd for C₁₇H₂₀NO₂(MCH)^C270.1494, found 270.1491;

[a]²_D⁴ZK97.0 (c 0.41, CHCl₃).

3.6.3.5. (1R)-1-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-[4-

(dimethylamino)phenyl]-2-methoxy-ethanol (15e). The

general method was followed using 14e (126 mg,

0.31 mmol) to give 15e (86 mg, 90%) as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d 2.55 (1H, dd, JZ8.9,

16.1 Hz), 2.71 (1H, dd, JZ13.9, 16.1 Hz), 2.96 (6H, s), 3.42

(3H, s), 3.47 (1H, d, JZ9.8 Hz), 3.68 (1H, s), 3.72 (1H, d,

JZ9.8 Hz), 4.50 (1H, dd, JZ8.9, 13.9 Hz), 4.52 (1H, br),

6.65 (2H, t, JZ6.8 Hz), 6.73 (2H, d, JZ8.8 Hz), 6.92 (1H,

d, JZ6.8 Hz), 6.99 (1H, t, JZ6.8 Hz), 7.35 (2H, d, JZ

8.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d 32.5, 40.8 (!2),

59.8, 67.6, 74.6, 82.8, 109.6, 112.4 (!2), 119.1, 124.6,

126.3 (!2), 127.4, 128.7, 129.9, 149.9, 151.0; IR (liquid

ﬁlm) cm^K1: 3403, 2888, 1614, 1523, 1486, 1083, 750;

HRMS calcd for C₁₉H₂₅N₂O₂(MCH)^C313.1916, found

313.1909; [a]²_D⁴ZK97.4 (c 0.45, CHCl₃).

Compounds 15b–j, 15n, 15q were prepared by the method

similar to that used for the preparation of 15a.

Compounds 15k and 15p were prepared by the method

similar to that used for the preparation of 15.

3.6.3.2. (2S)-2-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxybutan-2-ol (15b). The general method was fol-

lowed using 14b (580 mg, 1.80 mmol) to give 15b (350 mg,

88%) as a colorless solid (mp 49–51 8C). ¹H NMR

(500 MHz, CDCl₃) d 0.97 (3H, t, JZ7.8 Hz), 1.55–1.70

(2H, m), 2.37 (1H, s), 2.97 (1H, dd, JZ10.1, 16.2 Hz), 3.02

(1H, dd, JZ10.1, 16.2 Hz), 3.30 (1H, d, JZ8.8 Hz), 3.36

(3H, s), 3.49 (1H, d, JZ8.8 Hz), 3.95 (1H, br s), 4.05 (1H, t,

JZ10.1 Hz), 6.64 (1H, d, JZ7.3 Hz), 6.71 (1H, t, JZ

7.3 Hz), 7.01 (1H, t, JZ7.3 Hz), 7.08 (1H, d, JZ7.3 Hz);

¹³C NMR (125 MHz, CDCl₃) d 7.66, 28.6, 30.3, 59.4, 64.3,

74.0, 74.3, 109.6, 119.0, 124.6, 127.2, 129.0, 150.6; IR

(KBr) cm^K1: 3468, 3320, 2919, 2883, 1489, 1463, 1111,

753; HRMS calcd for C₁₃H₂₀NO₂(MCH)^C222.1494,

found 222.1500. Anal. Calcd for C₁₃H₁₉NO₂: C, 70.56;

H, 8.65; N, 6.33. Found: C, 70.51; H, 8.40; N, 6.53;

[a]²_D⁴ZK21.7 (c 0.43, CHCl₃).

3.6.3.6. (1R)-1-(4-Chlorophenyl)-1-[(2S)-2,3-dihydro-

1H-indol-2-yl]-2-methoxyethanol (15f). The general

method was followed using 14f (150 mg, 0.37 mmol) to

give 15f (74 mg, 66%) as an orange oil. ¹H NMR (500 MHz,

CDCl₃) d 2.50 (1H, dd, JZ8.8, 15.9 Hz), 2.66 (1H, dd, JZ

10.7, 15.9 Hz), 3.42 (3H, s), 3.48 (1H, d, JZ9.8 Hz), 3.68

(1H, d, JZ9.8 Hz), 3.72 (1H, s), 4.45 (1H, br s), 4.50 (1H, t,

JZ9.8 Hz), 6.68 (2H, m), 6.94 (1H, d, JZ7.6 Hz), 7.01

(1H, t, JZ7.6 Hz), 7.34 (2H, d, JZ8.6 Hz), 7.46 (2H, d, JZ

8.6 Hz); ¹³C NMR (125 MHz, CDCl₃) d 32.2, 59.9, 66.7,

74.7, 81.9, 109.9, 119.6, 124.7, 127.1 (!2), 127.5, 128.5,

128.6 (!2), 133.3, 140.8, 150.7; IR (thin ﬁlm) cm^K1: 3400,

2892, 1611, 1488, 1092, 753; HRMS calcd for

C₁₇H₁₉NO₂Cl (MCH)^C304.11043, found 304.11038;

[a]²_D⁴ZK92.6 (c 0.25, CHCl₃).

3.6.3.3. (2S)-2-[(2R)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxybutan-2-ol (15c). The general method was fol-

lowed using 14c (210 mg, 0.65 mmol) to give 15c (137 mg,

95%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) d 0.97

(3H, t, JZ7.7 Hz), 1.50–1.56 (1H, m), 1.62–1.69 (1H, m),

2.90 (1H, s), 2.92 (1H, dd, JZ8.9, 17.5 Hz), 3.05 (1H, dd,

JZ10.9, 17.5 Hz), 3.38 (1H, d, JZ9.8 Hz), 3.41 (3H, s),

3.49 (1H, d, JZ9.8 Hz), 4.08 (1H, dd, JZ8.9, 10.9 Hz),

4.24 (1H, br s), 6.65 (1H, d, JZ7.5 Hz), 6.72 (1H, t, JZ

7.5 Hz), 7.02 (1H, t, JZ7.5 Hz), 7.08 (1H, d, JZ7.5 Hz);

¹³C NMR (100 MHz, CDCl₃) d 7.94, 27.4, 30.5, 59.5, 65.6,

72.9, 78.1, 109.4, 118.8, 124.4, 127.1, 128.6, 150.5; IR

(CHCl₃) cm^K1: 3485, 3405, 2975, 2932, 2893, 1609, 1486,

1467, 1247, 1110; HRMS calcd for C₁₃H₂₀NO₂(MCH)^C

222.1494, found 222.1490; [a]²_D⁴ZC34.5 (c 0.64, CHCl₃).

3.6.3.7. (1R)-1-Cyclohexyl-1-[(2S)-2,3-dihydro-1H-

indol-2-yl]-2-methoxyethanol (15g). The general method

was followed using 14g (150 mg, 0.40 mmol) to give 15g

(80 mg, 73%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) d

1.03–1.32 (5H, m), 1.56 (1H, tt, JZ2.9, 12.2 Hz), 1.65 (1H,

d, JZ12.7 Hz), 1.71 (1H, d, JZ12.2 Hz), 1.76–1.82 (2H,

m), 2.07 (1H, d, JZ12.7 Hz), 2.87 (1H, dd, JZ8.4,

15.3 Hz), 3.05 (1H, dd, JZ12.1, 15.3 Hz), 3.28 (1H, br s),

3.39 (3H, s), 3.45 (1H, d, JZ9.3 Hz), 3.56 (1H, d, JZ

9.3 Hz), 4.18 (1H, dd, JZ8.4, 12.1 Hz), 4.41 (1H, br s), 6.65

(1H, d, JZ7.3 Hz), 6.7 (1H, t, JZ7.3 Hz), 7.01 (1H, t, JZ

7.3 Hz), 7.08 (1H, d, JZ7.3 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 27.0, 27.2, 27.3, 27.6, 28.2, 30.5, 45.1, 59.7, 66.4,

73.8, 78.2, 109.7, 119.1, 124.7, 127.4, 128.8, 150.9; IR

(KBr) cm^K1: 3390, 2931, 2853, 1610, 1488, 1098, 760;

3.6.3.4. (1R)-1-[(2S)-2,3-Dihydro-1H-indol-2-yl]-2-

methoxy-1-phenylethanol (15d). The general method was

followed using 14d (410 mg, 1.11 mmol) to give 15d

2094

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

HRMS calcd for C₁₇H₂₅NO₂(M)^C255.1885, found

149.8; IR (CHCl₃) cm^K1: 3512, 3406, 2929, 1481, 1249,

1108; HRMS calcd for C₁₇H₂₄NO₂BrNa (MCNa)^C

376.0889, found 370.0890; [a]²_D⁴ZK31.6 (c 0.24, CHCl₃).

275.1881; [a]²_D⁴ZK36.6 (c 0.58, CHCl₃).

3.6.3.8. (2R)-2-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxybut-3-en-2-ol (15h). The general method was

followed using 14h (213 mg, 0.67 mmol) to give 15h

(107 mg, 73%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 2.89 (1H, dd, JZ9.3, 16.1 Hz), 2.97 (1H, dd, JZ

10.3, 16.1 Hz), 3.22 (1H, br s), 3.42 (1H, d, JZ9.3 Hz), 3.43

(3H, s), 3.49 (1H, d, JZ9.3 Hz), 4.15 (1H, t, JZ9.8 Hz),

4.33 (1H, br s), 5.26 (1H, d, JZ10.2 Hz), 5.52 (1H, d, JZ

16.7 Hz), 5.84 (1H, dd, JZ10.2, 16.7 Hz), 6.65 (1H, d, JZ

7.8 Hz), 6.72 (1H, t, JZ7.8 Hz), 7.03 (1H, t, JZ7.8 Hz),

7.07 (1H, d, JZ7.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d

31.3, 59.5, 64.8, 74.4, 79.7, 109.4, 115.5, 118.9, 124.4,

127.1, 128.5, 137.1, 150.6; IR (CHCl₃) cm^K1: 3406, 2930,

2894, 1609, 1486, 1465, 1094; HRMS calcd for C₁₃H₁₈NO₂

(MCH)^C220.1338, found 220.1331; [a]²_D⁴ZK34.6 (c

0.28, CHCl₃).

3.6.3.12. 2-[(2S)-2,3-Dihydro-1H-indol-2-yl]propan-2-

ol (15n). The general method was followed using 14n

(500 mg, 1.80 mmol) to give 15n (270 mg, 85%) as a

1

colorless oil. H NMR (500 MHz, CDCl₃) d 1.21 (3H, s),

1.28 (3H, s), 3.01 (1H, dd, JZ9.8, 15.7 Hz), 3.05 (1H, dd,

JZ9.8, 15.7 Hz), 3.85 (1H, t, JZ9.8 Hz), 6.67 (1H, d, JZ

7.2 Hz), 6.74 (1H, t, JZ7.2 Hz), 7.04 (1H, t, JZ7.2 Hz),

7.10 (1H, d, JZ7.2 Hz); ¹³C NMR (125 MHz, CDCl₃) d

24.4, 28.2, 30.9, 68.5, 70.7, 109.6, 119.2, 124.6, 127.2,

129.3, 150.7; IR (CHCl₃) cm^K1: 3393, 2978, 1608, 1487,

1467, 1247; HRMS calcd for C₁₁H₁₅NO (M)^C177.1154,

found 177.1157; [a]²_D⁴ZK53.5 (c 0.60, CHCl₃).

3.6.3.13. (2S)-2-[(2S)-5-Bromo-2,3-dihydro-1H-indol-

2-yl]-6-methylhept-5-en-2-ol (15p). The general method

was followed using 14p (210 mg, 0.49 mmol) to give 15p

(98 mg, 61%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.14 (3H, s), 1.44–1.57 (2H, m), 1.64 (3H, s), 1.71

(3H, s), 2.03–2.10 (1H, m), 2.12–2.18 (1H, m), 2.95 (1H, dd,

JZ9.2 Hz, 16.0), 3.02 (1H, dd, JZ10.7, 16.0 Hz), 3.88 (1H,

t, JZ9.8 Hz), 3.98 (1H, br), 5.14 (1H, br t, JZ6.8 Hz), 6.48

(1H, d, JZ7.8 Hz), 7.09 (1H, d, JZ7.8 Hz), 7.15 (1H, s);

¹³C NMR (125 MHz, CDCl₃) d 17.6, 21.1, 22.3, 25.6, 30.7,

40.6, 67.5, 72.7, 110.5, 110.7, 124.1, 127.5, 129.8, 131.5,

131.9, 149.8; IR (CHCl₃) cm^K1: 2978, 2918, 1481; HRMS

calcd for C₁₆H₂₃NOBr (MCH)^C324.0963, found

324.0956; [a]²_D⁴ZK16.0 (c 0.72, CHCl₃).

3.6.3.9. (2R)-2-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxy-3-methylbut-3-en-2-ol (15i). The general method

was followed using 14i (380 mg, 1.14 mmol) to give 15i

(232 mg, 87%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.83 (3H, s), 2.87 (1H, dd, JZ9.3 Hz, 15.9), 2.97

(1H, dd, JZ10.7, 15.9 Hz), 3.44 (1H, d, JZ9.2 Hz), 3.44

(4H, s), 3.62 (1H, d, JZ9.2 Hz), 4.27 (1H, t, JZ9.8 Hz),

4.35 (1H, br s), 5.03 (1H, s), 5.25 (1H, s), 6.67 (1H, d, JZ

7.0 Hz), 6.73 (1H, t, JZ7.0 Hz), 7.02–7.08 (1H, m); ¹³C

NMR (125 MHz, CDCl₃) d 19.6, 31.2, 59.5, 64.7, 75.7,

80.1, 109.3, 112.3, 118.9, 124.3, 127.0, 128.3, 144.3, 150.5;

IR (CHCl₃) cm^K1: 3406, 2926, 2895, 1610, 1486, 1125,

1090; HRMS calcd for C₁₄H₂₀NO₂(MCH)^C234.1494,

found 234.1471; [a]²_D⁴ZK46.5 (c 0.22, CHCl₃).

3.6.3.14. (1R)-1-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1,3-

diphenylpropan-1-ol (15q). The general method was

followed using 14q (90 mg, 0.21 mmol) to give 15q

(69 mg, 100%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 2.09 (1H, dt, JZ4.3, 13.2 Hz), 2.15–2.22 (2H, m),

2.47 (1H, dd, JZ9.0, 16.3 Hz), 2.76 (1H, dt, JZ4.3,

12.7 Hz), 2.83 (1H, dd, JZ10.3, 16.3 Hz), 2.96 (1H, s), 4.03

(1H, br s), 4.29 (1H, t, JZ10.0 Hz), 6.67 (1H, d, JZ7.3 Hz),

6.71 (1H, t, JZ7.3 Hz), 6.93 (1H, d, JZ7.3 Hz), 7.01 (1H, t,

JZ7.6 Hz), 7.10 (2H, d, JZ7.3 Hz), 7.15 (1H, t, JZ

6.8 Hz), 7.24 (2H, t, JZ7.6 Hz), 7.29 (1H, t, JZ6.8 Hz), 7.4

(2H, t, JZ7.6 Hz), 7.51 (2H, d, JZ6.8 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 30.2, 31.7, 44.5, 69.1, 76.1, 110.4,

120.2, 124.9, 125.7 (!2), 125.9, 127.0, 127.4, 128.6 (!2),

128.6 (!2), 128.6 (!2), 129.6, 142.9, 143.0, 150.5; IR

(KBr) cm^K1: 3466, 3362, 3027, 1486, 1245, 770, 700;

HRMS calcd for C₂₃H₂₄NO (MCH)^C330.18579, found

330.18813; [a]²_D⁴ZK80.7 (c 0.42, CHCl₃).

3.6.3.10. (2R)-2-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxy-4-trimethylsilanylbut-3-yn-2-ol (15j). The gen-

eral method was followed using 14j (280 mg, 0.72 mmol) to

give 15j (166 mg, 80%) as a colorless oil. ¹H NMR

(400 MHz, CDCl₃) d 0.13 (9H, s), 3.15 (1H, dd, JZ9.2,

15.8 Hz), 3.21 (1H, dd, JZ8.4, 15.8 Hz), 3.46 (4H, s), 3.58

(2H, s), 4.17 (1H, t, JZ9.2 Hz), 4.34 (1H, br s), 6.63 (1H, d,

JZ7.3 Hz), 6.72 (1H, t, JZ7.3 Hz), 7.01 (1H, t, JZ7.3 Hz),

7.08 (1H, d, JZ7.3 Hz); ¹³C NMR (100 MHz, CDCl₃) d

K0.12 (!3), 32.5, 59.7, 64.6, 71.4, 78.6, 90.5, 103.7,

109.3, 118.9, 124.2, 127.0, 128.3, 150.3; IR (CHCl₃) cm^K1

:

3403, 2962, 2933, 2899, 1609, 1486, 1252, 1123, 1083;

HRMS calcd for C₁₆H₂₄NO₂Si (MCH)^C290.1576, found

290.1585; [a]²_D⁴ZK52.7 (c 0.30, CHCl₃).

3.6.3.11. (2R)-2-[(2S)-5-Bromo-2,3-dihydro-1H-indol-

2-yl]-1-methoxy-6-methylhept-5-en-2-ol (15k). The gen-

eral method was followed using 14k (990 mg, 2.18 mmol)

The conﬁgurations of the newly created asymmetric centers

in 15 were determined by the NOE experiments of the

corresponding acetonides. The acetonides 16a–b, 16d–k,

16p–q were prepared by the method similar to that used for

the preparation of major-16.

1

to give 15k (411 mg, 53%) as a colorless oil. H NMR

(500 MHz, CDCl₃) d 1.43–1.50 (1H, m), 1.54–1.60 (1H, m),

1.63 (3H, s), 1.70 (3H, s), 1.97–2.05 (1H, m), 2.10–2.18

(1H, m), 2.80 (1H, s), 2.90 (1H, dd, JZ8.8, 15.9 Hz), 3.04

(1H, dd, JZ11.2 Hz, 15.9), 3.37 (1H, d, JZ9.8 Hz), 3.40

(3H, s), 3.48 (1H, d, JZ9.8 Hz), 4.07 (1H, t, JZ9.8 Hz),

4.26 (1H, br s), 5.11 (1H, br t, JZ7.3 Hz), 6.49 (1H, d, JZ

8.8 Hz), 7.09 (1H, d, JZ8.8 Hz), 7.15 (1H, s); ¹³C NMR

(125 MHz, CDCl₃) d 17.6, 21.9, 25.7, 30.4, 34.5, 59.4, 66.1,

72.8, 78.2, 110.3, 110.6, 124.1, 127.4, 129.8, 131.1, 131.9,

3.6.3.15. (1R,9aS)-1-Ethyl-1-(methoxymethyl)-3,3-

dimethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole

(16a). The general method was followed using 15a (30 mg,

0.14 mmol) to give 16a (32 mg, 87%) as a colorless oil. ¹H

NMR (500 MHz, CDCl₃) d 0.81 (3H, t, JZ7.3 Hz), 1.14–

1.21 (1H, m), 1.49–1.62 (1H, m), 1.54 (3H, s), 1.67 (3H, s),

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2095

3.03 (1H, dd, JZ9.7, 16.8 Hz), 3.09 (1H, dd, JZ4.2,

16.8 Hz), 3.27 (1H, d, JZ9.3 Hz), 3.39 (3H, s), 3.51 (1H, d,

JZ9.3 Hz), 4.34 (1H, dd, JZ4.2, 9.7 Hz), 6.66 (1H, d, JZ

7.3 Hz), 6.72 (1H, t, JZ7.3 Hz), 7.01 (1H, t, JZ7.3 Hz),

7.04 (1H, d, JZ7.3 Hz); ¹³C NMR (125 MHz, CDCl₃) d

7.10, 23.0, 25.5, 29.3, 31.3, 59.4, 69.6, 75.6, 82.0, 94.8,

(43 mg, 0.14 mmol) to give 16f (28 mg, 57%) as a colorless

oil. ¹H NMR (500 MHz, CDCl₃) d 1.71 (3H, s), 1,72 (3H, s),

2.63 (1H, dd, JZ5.3, 16.2 Hz), 2.86 (1H, dd, JZ9.0,

16.2 Hz), 3.41 (3H, s), 3.75 (1H, d, JZ9.8 Hz), 3.79 (1H, d,

JZ9.8 Hz), 4.55 (1H, dd, JZ5.3, 9.0 Hz), 6.67–6.73 (2H,

m), 6.81 (1H, d, JZ7.7 Hz), 6.69 (1H, t, JZ7.7 Hz), 7.13

(2H, d, JZ8.8 Hz), 7.22 (2H, d, JZ8.8 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 26.1, 31.8, 32.8, 59.9, 70.6, 79.8, 85.3,

97.9, 114.5, 121.4, 124.6, 127.0, 127.8 (!2), 128.1 (!2),

132.3, 132.9, 140.5, 149.0; IR (thin ﬁlm) cm^K1: 2987, 2929,

1478, 1092, 753; HRMS calcd for C₂₀H₂₃NO₂Cl (MCH)^C

344.14173, found 344.14187; [a]²_D⁴ZK61.5 (c 1.34,

CHCl₃).

111.9, 118.7, 124.2, 126.4, 131.8, 148.6; IR (CHCl₃) cm^K1

:

2986, 2932, 2894, 1603, 1478, 1462, 1266, 1113; HRMS

calcd for C₁₆H₂₃NO₂(M)^C261.1729, found 261.1724;

[a]²_D⁴ZC135.6 (c 0.78, CHCl₃).

3.6.3.16. (1S,9aS)-1-Ethyl-1-(methoxymethyl)-3,3-

dimethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole

(16b). The general method was followed using 15b (66 mg,

0.30 mmol) to give 16b (56 mg, 72%) as a colorless oil. ¹H

NMR (500 MHz, CDCl₃) d 0.98 (3H, t, JZ7.3 Hz), 1.51

(3H, s), 1.66 (3H, s), 1.70–1.79 (2H, m), 2.97 (1H, dd, JZ

10.6, 16.8 Hz), 3.07 (1H, d, JZ9.8 Hz), 3.17 (1H, d, JZ

9.8 Hz), 3.18 (3H, s), 3.34 (1H, dd, JZ2.9, 16.8 Hz), 4.17

(1H, dd, JZ2.9, 10.6 Hz), 6.69 (1H, d, JZ7.5 Hz), 6.73

(1H, t, JZ7.5 Hz), 7.02 (1H, t, JZ7.5 Hz), 7.06 (1H, d, JZ

7.5 Hz); ¹³C NMR (125 MHz, CDCl₃) d 8.08, 26.0, 28.4,

28.7, 31.5, 59.0, 69.2, 73.5, 82.6, 95.1, 112.3, 119.1, 124.5,

126.7, 131.8, 148.9; IR (CHCl₃) cm^K1: 2987, 2931, 1603,

1478, 1461, 1264, 1106; HRMS calcd for C₁₆H₂₃NO₂(M)^C

261.1728, found 261.1725; [a]²_D⁴ZC144.3 (c 1.06, CHCl₃).

3.6.3.20. (1R,9aS)-1-Cyclohexyl-1-(methoxymethyl)-

3,3-dimethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole

(16g). The general method was followed using 15g (53 mg,

1

0.19 mmol) to give 16g (45 mg, 74%) as a yellow oil. H

NMR (500 MHz, CDCl₃) d 1.13–1.21 (5H, m), 1.40 (3H, s),

1.55 (3H, s), 1.59–1.73 (5H, m), 1.81 (1H, d, JZ11.7 Hz),

2.95 (1H, dd, JZ9.6, 16.2 Hz), 3.25 (1H, dd, JZ8.1,

16.2 Hz), 3.38 (3H, s), 3.46 (1H, d, JZ9.8 Hz), 3.53 (1H, d,

JZ9.8 Hz), 4.40 (1H, dd, JZ8.1, 9.6 Hz), 6.70 (1H, d, JZ

7.6 Hz), 6.78 (1H, t, JZ7.6 Hz), 7.04 (1H, t, JZ7.6 Hz),

7.10 (1H, d, JZ7.6 Hz); ¹³C NMR (125 MHz, CDCl₃) d

26.8, 26.9, 27.2, 27.2, 28.2, 29.6, 31.5, 31.6, 43.6, 59.6,

70.9, 77.0, 84.2, 95.4, 113.5, 120.4, 124.7, 127.2, 133.9,

148.5; IR (liquid ﬁlm) cm^K1: 2924, 2853, 1481, 1104, 745;

HRMS calcd for C₂₀H₂₉NO₂(M)^C315.2198, found

312.2205; [a]²_D⁴ZC73.6 (c 0.62, CHCl₃).

3.6.3.17. (1R,9aS)-1-(Methoxymethyl)-3,3-dimethyl-

1-phenyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole

(16d). The general method was followed using 15d (33 mg,

0.12 mmol) to give 16d (30 mg, 80%) as a colorless oil. ¹H

NMR (500 MHz, CDCl₃) d 1.70 (3H, s), 1.74 (3H, s), 2.67

(1H, dd, JZ7.1, 16.1 Hz), 2.84 (1H, dd, JZ9.3, 16.1 Hz),

3.43 (3H, s), 3.82 (2H, s), 4.61 (1H, dd, JZ7.1, 9.3 Hz),

6.69 (1H, t, JZ7.3 Hz), 6.73 (1H, d, JZ7.3 Hz), 6.83 (1H,

d, JZ7.3 Hz), 7.00 (1H, t, JZ7.3 Hz), 7.16–7.21 (3H, m),

7.31 (2H, d, JZ7.3 Hz); ¹³C NMR (125 MHz, CDCl₃) d

26.1, 31.7, 32.9, 59.7, 70.5, 79.7, 85.6, 97.5, 114.4, 121.1,

124.2, 126.4 (!2), 126.7, 126.8, 127.4 (!2), 132.6, 141.6,

148.9; IR (CHCl₃) cm^K1: 2930, 2894, 1477, 1258, 1102;

HRMS calcd for C₂₀H₂₄NO₂(MCH)^C310.1807, found

310.1812; [a]²_D⁴ZK39.1 (c 1.15, CHCl₃).

3.6.3.21. (1R,9aS)-1-(Methoxymethyl)-3,3-dimethyl-

1-vinyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole (16h).

The general method was followed using 15h (47 mg,

1

0.21 mmol) to give 16h (56 mg, 100%) as a yellow oil. H

NMR (500 MHz, CDCl₃) d 1.60 (3H, s), 1.79 (3H, s), 3.06–

3.08 (2H, m), 3.43 (3H, s), 3.47 (1H, d, JZ9.3 Hz), 3.51

(1H, d, JZ9.3 Hz), 4.40 (1H, dd, JZ4.9, 6.8 Hz), 4.98 (1H,

d, JZ18.5 Hz), 5.24 (1H, d, JZ13.4 Hz), 5.75 (1H, dd, JZ

13.4, 18.5 Hz), 6.75 (2H, t, JZ7.8 Hz), 7.01 (2H, t, JZ

7.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d 25.7, 30.2, 31.4,

59.7, 68.3, 77.6, 83.1, 96.5, 113.0, 115.7, 119.7, 124.5,

126.6, 131.2, 136.6, 148.5; IR (CHCl₃) cm^K1: 2931, 2894,

1712, 1604, 1478, 1461, 1105; HRMS calcd for C₁₆H₂₁NO₂

(M)^C259.1572, found 259.1575; [a]²_D⁴ZC82.2 (c 0.16,

CHCl₃).

3.6.3.18. (1R,9aS)-1-(Methoxymethyl)-1-[4-(dimethyl-

amino)phenyl]-3,3-dimethyl-9,9a-dihydro-1H-[1,3]oxa-

zolo[3,4-a]indole (16e). The general method was followed

using 15e (50 mg, 0.16 mmol) to give 16e (14 mg, 25%) as a

1

colorless oil. H NMR (500 MHz, CDCl₃) d 1.60 (3H, s),

1.71 (3H, s), 2.70 (1H, dd, JZ6.6, 16.1 Hz), 2.80 (1H, dd,

JZ9.1, 16.1 Hz), 2.89 (6H, s), 3.42 (3H, s), 3.74 (1H, d, JZ

9.8 Hz), 3.77 (1H, d, JZ9.8 Hz), 4.59 (1H, dd, JZ6.6,

9.1 Hz), 6.58 (2H, d, JZ8.8 Hz), 6.69 (1H, t, JZ7.8 Hz),

6.80 (2H, t, JZ7.8 Hz), 6.99 (1H, t, JZ7.8 Hz), 7.15 (2H, d,

JZ8.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d 26.5, 31.9, 33.6,

40.8 (!2), 59.9, 71.0, 80.2, 85.8, 97.4, 112.0 (!2), 114.8,

121.3, 124.6, 126.3, 126.8, 127.3 (!2), 133.5, 149.3, 149.6;

IR (thin ﬁlm) cm^K1: 2984, 2990, 1615, 1522, 1478; HRMS

calcd for C₂₂H₂₉N₂O₂(MCH)^C353.2229, found 353.2239;

[a]²_D⁴ZK58.2 (c 0.47, CHCl₃).

3.6.3.22. (1R,9aS)-1-Isopropenyl-1-(methoxymethyl)-

3,3-dimethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole

(16i). The general method was followed using 15i (36 mg,

1

0.15 mmol) to give 16i (19 mg, 45%) as a colorless oil. H

NMR (400 MHz, CDCl₃) d 1.34 (3H, s), 1.53 (3H, s), 1.54

(3H, s), 2.80 (1H, dd, JZ9.5, 16.1 Hz), 3.04 (1H, dd, JZ

7.7, 16.1 Hz), 3.33 (3H, s), 3.52 (1H, d, JZ9.9 Hz), 3.56

(1H, d, JZ9.9 Hz), 4.21 (1H, dd, JZ7.7, 9.5 Hz), 4.89 (1H,

s), 5.01 (1H, s), 6.70 (1H, d, JZ7.6 Hz), 6.73 (1H, t, JZ

7.6 Hz), 6.93–6.97 (2H, m); ¹³C NMR (125 MHz, CDCl₃) d

20.8, 26.3, 32.0, 32.8, 59.6, 69.9, 78.3, 86.8, 97.4, 113.2,

115.1, 121.4, 124.5, 126.9, 133.7, 144.7, 148.8; IR

(CHCl₃) cm^K1: 2928, 2895, 1477, 1560, 1095; HRMS

calcd for C₁₇H₂₄NO₂(MCH)^C274.1807, found 274.1811;

[a]²_D⁴ZC26.4 (c 0.69, CHCl₃).

3.6.3.19. (1R,9aS)-1-(4-Chlorophenyl)-1-(methoxy-

methyl)-3,3-dimethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-

a]indole (16f). The general method was followed using 15f

2096

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

3.6.3.23. (1R,9aS)-1-(Methoxymethyl)-3,3-dimethyl-

for C₂₆H₂₈NO (MCH)^C370.21709, found 370.21417;

[a]²_D⁴ZK32.0 (c 0.21, CHCl₃).

1-trimethylsilylethynyl-9,9a-dihydro-1H-[1,3]oxazolo-

[3,4-a]indole (16j). The general method was followed using

15j (25 mg, 0.086 mmol) to give 16j (22 mg, 77%) as a

colorless oil. ¹H NMR (400 MHz, CDCl₃) d K0.15 (9H, s),

1.50 (3H, s), 1.73 (3H, s), 3.06 (1H, dd, JZ9.9, 16.5 Hz),

3.26 (1H, dd, JZ2.6, 16.5 Hz), 3.43 (3H, s), 3.51 (2H, s),

4.28 (1H, dd, JZ2.6, 9.9 Hz), 6.62 (1H, d, JZ7.7 Hz), 6.70

(1H, t, JZ7.7 Hz), 6.94–7.00 (2H, m); ¹³C NMR (100 MHz,

CDCl₃) d K0.39 (!3), 25.0, 30.8, 31.6, 60.2, 67.8, 75.4,

79.2, 91.3, 97.6, 103.8, 112.8, 119.4, 124.4, 126.3, 131.8,

148.4; IR (CHCl₃) cm^K1: 2961, 2931, 1479, 1461, 1266,

1251, 1106; HRMS calcd for C₁₉H₂₈NO₂Si (MCH)^C

330.1881, found 330.1887; [a]²_D⁴ZC194.0 (c 0.44, CHCl₃).

3.6.4. Preparation of 15r.

3.6.4.1. (2R)-2-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxy-3-methylbutan-2-ol (15r). A solution of 15i

(50 mg, 0.214 mmol), 20 wt% Pd(OH)₂/C (50 mg) in

methanol (5 ml) was stirred under H₂atmosphere at room

temperature for 2.5 h. Pd(OH)₂was removed by ﬁltration

and the ﬁltrate was evaporated. The resulting residue was

puriﬁed by silica gel column chromatography (hexane–

AcOEt 5:1) to give 15r (32 mg, 63%) as a colorless oil. ¹H

NMR (500 MHz, CDCl₃) d 0.96 (3H, d, JZ6.8 Hz), 1.08

(3H, d, JZ6.8 Hz), 1.90–1.96 (1H, m), 2.90 (1H, dd, JZ

8.0, 15.2 Hz), 3.03–3.09 (1H, m), 3.25 (1H, s), 3.41 (3H, s),

3.44 (1H, d, JZ9.8 Hz), 3.58 (1H, d, JZ9.8 Hz), 4.23 (1H,

dd, JZ8.0, 11.7 Hz), 4.42 (1H, s), 6.66 (1H, d, JZ7.2 Hz),

6.72 (1H, t, JZ7.2 Hz), 7.03 (1H, t, JZ7.2 Hz), 7.10 (1H, d,

JZ7.2 Hz); ¹³C NMR (125 MHz, CDCl₃) d 17.3, 17.3, 30.1,

33.7, 59.5, 66.0, 73.8, 77.2, 109.4, 118.9, 124.4, 127.1,

128.5, 150.7; IR (KBr) cm^K1: 3417, 3385, 2963, 2933,

1611, 1469, 1250, 1107; HRMS calcd for C₁₄H₂₂NO₂(MC

H)^C236.1651, found 236.1638; [a]²_D⁴ZK51.2 (c 0.16,

CHCl₃) (Scheme 12).

3.6.3.24. (1R,9aS)-1-(Methoxymethyl)-3,3-dimethyl-

1-(4-methylpent-3-enyl)-9,9a-dihydro-1H-[1,3]oxazolo-

[3,4-a]indole (16k). The general method was followed

using 15k (436 mg, 1.23 mmol) to give 16k (370 mg, 76%)

as a colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.11 (1H,

dt, JZ6.8, 12.7 Hz), 1.52 (3H, s), 1.54 (3H, s), 1.55–1.60

(1H, m), 1.63 (3H, s), 1.64 (3H, s), 1.91–1.97 (1H, m), 2.01–

2.07 (1H, m), 3.02 (1H, dd, JZ10.3, 17.3 Hz), 3.07 (1H, dd,

JZ4.7, 17.3 Hz), 3.29 (1H, d, JZ8.8 Hz), 3.38 (3H, s), 3.53

(1H, d, JZ8.8 Hz), 4.35 (1H, dd, JZ4.7, 10.3 Hz), 4.99

(1H, br t, JZ6.8 Hz), 6.50 (1H, d, JZ7.8 Hz), 7.11 (1H, d,

JZ7.8 Hz), 7.13 (1H, s); ¹³C NMR (125 MHz, CDCl₃) d

17.5, 21.8, 25.6, 25.7, 29.2, 30.8, 31.4, 59.6, 70.2, 76.2,

82.0, 94.9, 110.8, 113.0, 124.4, 127.5, 129.4, 131.4, 134.4,

147.9; IR (CHCl₃) cm^K1: 2629, 1474, 1259, 1112; HRMS

calcd for C₂₀H₂₈NO₂Br (M)^C393.1303, found 393.1303;

[a]²_D⁴ZC131.0 (c 0.36, CHCl₃).

Scheme 12. Reagents and conditions: (a) H₂, Pd(OH)₂/C, MeOH, rt, 63%.

3.6.5. Preparation of 15s.

3.6.3.25. (1S,9aS)-7-Bromo-1,3,3-trimethyl-1-(4-

methylpent-3-enyl)-9,9a-dihydro-1H-[1,3]oxazolo[3,4-

a]indole (16p). The general method was followed using 15p

(95 mg, 0.293 mmol) to give 16p (86 mg, 80%) as a

3.6.5.1. (2R)-2-[(2S)-2,3-Dihydro-1H-indol-2-yl]-1-

methoxy-but-3-yn-2-ol (15s). To a solution of 15j

(91 mg, 0.314 mmol) in THF (1 ml) was added TBAF in

THF (0.35 ml, 1 M) at room temperature. The mixture was

stirred under the same temperature for 1 h. After addition of

water, the aqueous solution was extracted with AcOEt. The

combined organic extracts were washed with brine, dried

over Na₂SO₄, ﬁltered and evaporated. Puriﬁcation by silica

gel chromatography (hexane–AcOEt 5:1 to 2:1) gave 15s

(59 mg, 86%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 2.45 (1H, s), 3.15 (1H, dd, JZ10.0 Hz, 16.9), 3.21

(1H, dd, JZ10.3, 16.9 Hz), 3.37 (1H, br s), 3.46 (3H, s),

3.55 (1H, d, JZ9.8 Hz), 3.58 (1H, d, JZ9.8 Hz), 4.19 (1H,

t, JZ9.5 Hz), 4.50 (1H, br), 6.65 (1H, d, JZ7.5 Hz), 6.72

(1H, t, JZ7.5 Hz), 7.01 (1H, t, JZ7.5 Hz), 7.07 (1H, d, JZ

7.5 Hz); ¹³C NMR (125 MHz, CDCl₃) d 32.3, 59.7, 64.6,

71.4, 74.1, 78.4, 82.5, 109.6, 119.2, 124.4, 127.3, 128.3,

150.3; IR (CHCl₃) cm^K1: 3556, 3402, 3306, 2933, 2898,

1609, 1486, 1466, 1124, 1085; HRMS calcd for

C₁₃H₁₅NO₂Na (MCNa)^C240.1000, found 240.0986;

[a]²_D⁴ZK65.4 (c 0.15, CHCl₃) (Scheme 13).

1

colorless oil. H NMR (500 MHz, CDCl₃) d 0.99 (3H, s),

1.49 (3H, s), 1.58–1.62 (2H, m), 1.64 (3H, s), 1.65 (3H, s),

1.70 (3H, s), 2.04–2.10 (2H, m), 2.93 (1H, dd, JZ3.4,

17.1 Hz), 3.05 (1H, dd, JZ10.3, 17.1 Hz), 4.15 (1H, dd, JZ

3.4, 10.3 Hz), 5.12 (1H, br t, JZ6.8 Hz), 6.54 (1H, d, JZ

8.2 Hz), 7.12 (1H, d, JZ8.2 Hz), 7.15 (1H, s); ¹³C NMR

(125 MHz, CDCl₃) d 17.7, 21.0, 22.8, 25.6, 25.8, 29.6, 31.6,

41.0, 70.0, 81.8, 94.3, 110.7, 113.1, 124.1, 127.5, 129.5,

131.8, 133.8, 148.2; IR (CHCl₃) cm^K1: 2985, 2931, 1474,

1381, 1370, 1256; HRMS calcd for C₁₉H₂₇NOBr (MCH)^C

364.1276, found 364.1259; [a]²_D⁴ZC97.5 (c 0.47, CHCl₃).

3.6.3.26.

(1R,9aS)-3,3-Dimethyl-1-phenethyl-1-

phenyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole (16q).

The general method was followed using 15q (23 mg,

0.070 mmol) to give 16q (mg, 54%) as a colorless oil. H

1

NMR (500 MHz, CDCl₃) d 1.58 (3H, s), 1.76 (3H, s), 2.28–

2.49 (3H, m), 2.61 (1H, dd, JZ7.4, 16.1 Hz), 2.71 (1H, dd,

JZ8.6, 16.1 Hz), 2.79–2.86 (1H, m), 4.51 (1H, t, JZ

8.0 Hz), 6.73 (1H, t, JZ7.4 Hz), 6.78 (1H, d, JZ7.4 Hz),

6.84 (1H, d, JZ7.4 Hz), 7.02 (1H, d, JZ7.4 Hz), 7.13–7.34

(10H, m); ¹³C NMR (125 MHz, CDCl₃) d 27.0, 30.5, 32.4,

34.0, 45.4, 75.9, 86.3, 97.6, 115.5, 121.9, 124.5, 125.9,

126.4 (!2), 126.8, 127.0, 128.0 (!2), 128.5 (!2), 128.6

(!2), 133.7, 142.9, 143.1, 149.5; IR (thin ﬁlm) cm^K1

3026, 2986, 2934, 1477, 1237, 1207, 747, 701; HRMS calcd

:

Scheme 13. Reagents and conditions: (a) 1 M TBAF, THF, rt, 86%.

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2097

3.6.6. Preparation of 15t.

JZ8.8 Hz), 3.80 (3H, s), 4.14 (1H, t, JZ9.5 Hz), 4.65 (1H,

br s), 6.53 (1H, d, JZ8.1 Hz), 7.17 (3H, m), 7.23–7.27 (2H,

m), 7.67 (1H, s), 7.72 (1H, dd, JZ1.5, 8.1 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 29.6, 29.9, 36.2, 51.5, 59.5, 66.1, 73.0,

78.0, 107.7, 120.0, 125.9, 126.0, 128.0, 128.2 (!2), 128.4

(!2), 130.6, 142.1, 155.1, 167.3; IR (KBr) cm^K1: 3431,

3370, 2949, 2905, 1699, 1611, 1437, 1285, 1269, 1092;

HRMS calcd for C₂₁H₂₆NO₄(MCH)^C356.1862, found

356.1846. Anal. Calcd for C₂₁H₂₅NO₄: C, 70.96; H, 7.09; N,

3.94. Found: C, 70.71; H, 7.04; N, 3.89; [a]²_D⁴ZK6.1 (c

1.05, CHCl₃).

3.6.6.1. (1R,9aS)-1-(Methoxymethyl)-3,3-dimethyl-1-

phenethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole-7-

carboxylic acid methyl ester (16t). The procedure for the

preparation of 15a was followed using 14l (868 mg,

1.82 mmol) to give the corresponding indoline-2-methanol

(660 mg, 96%) (Scheme 14).

3.6.7. Preparation of 15u.

3.6.7.1. (3R)-3-[(2S)-5-Bromo-2,3-dihydro-1H-indol-

2-yl]-1-phenylhexan-3-ol (35). A solution of 14o (66 mg,

0.139 mmol), 10 wt% Pd/C (7 mg) in AcOEt (1 ml) was

stirred under H₂atmosphere at room temperature for 24 h.

Pd/C was removed by ﬁltration and the ﬁltrate was

evaporated. The resulting residue was puriﬁed by silica

gel column chromatography (hexane–AcOEt 19:1) to give

the crude reduced product (24 mg, crude yield 36%). The

obtained product was used without further puriﬁcation

(Scheme 15).

Scheme 14. Reagents and conditions: (a) (i) TFA, CH₂Cl₂, rt, 96%; (ii) 2,2-

dimethoxypropane, p-TsOH, CH₂Cl₂, rt, 78%; (iii) t-BuLi, CO₂, Et₂O,

K78 8C, 82%; (iv) TMSCH₂N₂, MeOH, ice bath, 95%. (b) PPTS, MeOH,

rt, 95%.

The obtained indoline-2-methanol (64 mg, 1.70 mmol) was

converted to the corresponding acetonide (554 mg, 78%)

by the method similar to that used for the synthesis of

major-16.

The conversion of the obtained acetonide (543 mg,

1.3 mmol) to the corresponding carboxylic acid (405 mg,

82%) was carried out by the method similar to that used for

the synthesis of 17.

The method for the synthesis of 22 was followed using the

obtained carboxylic acid (300 mg, 0.79 mmol) to give 16t

(294 mg, 95%) as a colorless solid (mp 124–126 8C). H

1

NMR (500 MHz, CDCl₃) d 1.39 (1H, dt, JZ4.4, 13.0 Hz),

1.57 (3H, s), 1.75 (3H, s), 1.92 (1H, dt, JZ5.4, 12.7 Hz),

2.59 (1H, dt, JZ5.4, 13.0 Hz), 2.68 (1H, dt, JZ4.4,

12.7 Hz), 3.07–3.08 (2H, m), 3.34 (1H, d, JZ9.3 Hz),

3.39 (3H, s), 3.58 (1H, d, JZ9.3 Hz), 3.83 (3H, s), 4.45 (1H,

dd, JZ6.3, 8.3 Hz), 6.58 (1H, d, JZ8.3 Hz), 7.05 (2H, d,

JZ7.3 Hz), 7.12 (1H, t, JZ7.3 Hz), 7.20 (2H, t, JZ7.3 Hz),

7.65 (1H, s), 7.74 (1H, d, JZ8.3 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 26.1, 28.8, 29.7, 31.1, 32.7, 51.8, 59.9, 70.7, 76.4,

82.2, 94.7, 110.0, 120.4, 126.0, 126.4, 128.5 (!2), 128.6

Scheme 15. Reagents and conditions: (a) (i) H₂, Pd/C, AcOEt, rt; (ii) TFA,

CH₂Cl₂, rt, 32% (2 steps). (b) 2,2-Dimethoxypropane, PPTS, CH₂Cl₂, 72%.

(c) (i) t-BuLi, CO₂, Et₂O, K78 8C, 87%; (ii) allylbromide, K₂CO₃, DMF, rt,

89%. (d) PPTS, MeOH–CH₂Cl₂, rt, 92%.

Deprotection of the N-Boc group was carried out by the

method similar to that used for the preparation of 15a to give

35 (11 mg, 32% from 14o) as a colorless solid (mp 128–

(!2), 130.3, 132.1, 142.6, 152.7, 167.5; IR (KBr) cm^K1

:

2938, 1699, 1607, 1273; HRMS calcd for C₂₄H₃₀NO₄(MC

H)^C396.21748, found 396.21800; [a]²_D⁴ZC201.5 (c 1.06,

CHCl₃).

1

129 8C). H NMR (400 MHz, CDCl₃) d 0.92 (3H, t, JZ

7.3 Hz), 1.27–1.50 (3H, m), 1.54–1.65 (2H, m), 1.78 (1H,

dt, JZ4.9, 12.9 Hz), 2.07 (1H, s), 2.51 (1H, dt, JZ4.9,

12.9 Hz), 2.65 (1H, dt, JZ4.9, 12.9 Hz), 2.82 (1H, dd, JZ

9.2, 16.0 Hz), 3.04 (1H, dd, JZ10.2, 16.0 Hz), 3.17 (1H, br

s), 3.94 (1H, t, JZ9.9 Hz), 6.45 (1H, d, JZ8.8 Hz), 7.03

(1H, d, JZ8.8 Hz), 7.08–7.13 (4H, m), 7.18–7.23 (2H, m);

¹³C NMR (125 MHz, CDCl₃) d 14.8, 17.1, 29.7, 30.0, 36.2,

39.9, 66.3, 73.7, 111.0, 111.1, 125.9, 127.6, 128.2 (!2),

3.6.6.2. (2S)-2-[(1R)-1-Hydroxy-1-(methoxymethyl)-

3-phenylpropyl]-2,3-dihydro-1H-indole-5-carboxylic

acid methyl ester (15t). The method for the synthesis of 1

was followed using 16t (257 mg, 0.65 mmol) to give 15t

1

(220 mg, 95%) as a colorless solid (mp 129–130 8C). H

NMR (500 MHz, CDCl₃) d 1.73 (1H, dt, JZ5.1, 13.2 Hz),

1.83 (1H, dt, JZ5.1, 13.2 Hz), 2.60 (1H, dt, JZ5.1,

12.8 Hz), 2.69 (1H, s), 2.77 (1H, dt, JZ5.1, 12.8 Hz),

2.91 (1H, dd, JZ9.2, 15.8 Hz), 3.02 (1H, dd, JZ10.6,

15.8 Hz), 3.39 (3H, s), 3.44 (1H, d, JZ8.8 Hz), 3.51 (1H, d,

128.4 (!2), 129.8, 131.7, 142.2, 149.5; IR (KBr) cm^K1

:

3373, 3300, 2956, 2872, 1482, 1252; HRMS calcd for

C₂₀H₂₅NOBr (MCH)^C374.1119, found 374.1136. Anal.

Calcd for C₂₀H₂₄NOBr: C, 64.17; H, 6.46; N, 3.74; Br,

2098

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

21.35. Found: C, 64.26; H, 6.33; N, 3.72; Br, 21.29;

[a]²_D⁴ZK36.5 (c 1.00, CHCl₃).

JZ15.6 Hz), 5.99–6.07 (1H, m), 6.62 (1H, d, JZ8.3 Hz),

7.19–7.22 (3H, m), 7.29–7.32 (2H, m), 7.77 (1H, s), 7.81

(1H, d, JZ8.3 Hz); ¹³C NMR (125 MHz, CDCl₃) d 14.8,

17.1, 29.6, 29.7, 36.3, 39.8, 65.0, 66.3, 74.1, 108.2, 117.6,

120.6, 125.9, 126.3, 128.2 (!2), 128.5 (!2), 128.8, 130.6,

132.7, 142.1, 155.0, 166.4; IR (KBr) cm^K1: 3452, 3309,

2950, 1682, 1614, 1269; HRMS calcd for C₂₄H₃₀NO₃

(MCH)^C380.2226, found 380.2246. Anal. Calcd for

C₂₄H₂₉NO₃: C, 75.96; H, 7.70; N, 3.69. Found: C, 75.83;

H, 7.41; N, 3.70; [a]²_D⁴ZK14.9 (c 1.15, CHCl₃).

3.6.7.2. (1R,9aR)-7-Bromo-3,3-dimethyl-1-phenethyl-

1-propyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole

(36). The method for the preparation of major-16 was

followed using 35 (4.8 mg, 0.013 mmol) to give 36 (3.8 mg,

72%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) d 0.94

(3H, t, JZ7.3 Hz), 1.25–1.44 (4H, m), 1.49 (3H, s), 1.64

(3H, s), 1.68–1.72 (1H, m), 1.78–1.86 (1H, m), 2.53 (1H, dt,

JZ5.1, 12.9 Hz), 2.68 (1H, dt, JZ4.4, 12.9 Hz), 2.95–2.97

(2H, m), 4.21 (1H, dd, JZ5.9, 8.8 Hz), 6.41 (1H, d, JZ

8.8 Hz), 7.01–7.04 (4H, m), 7.08–7.12 (1H, m), 7.17–7.22

(2H, m); ¹³C NMR (125 MHz, CDCl₃) d 14.7, 17.6, 25.7,

29.3, 29.5, 31.6, 34.0, 39.7, 70.9, 83.3, 94.1, 110.4, 112.4,

125.7, 127.6, 128.3 (!2), 128.4 (!2), 129.6, 133.9, 142.5,

147.7; IR (liquid ﬁlm) cm^K1: 2958, 2933, 1476, 1367, 1262;

HRMS calcd for C₂₃H₂₉NOBr (MCH)^C414.1433, found

414.1454; [a]²_D⁴ZC114.1 (c 0.65, CHCl₃).

3.6.8. Preparation of 15v.

3.6.8.1. (1R,9aS)-1-But-3-enyl-1-(methoxymethyl)-

3,3-dimethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]-

indole-7-carboxylic acid allyl ester (16v). Compound 14m

(459 mg, 1.08 mmol) was converted to the corresponding

indoline-2-methanol (290 mg, 83%) by the method similar

to that used for the preparation of 15a (Scheme 16).

3.6.7.3. (1R,9aR)-3,3-Dimethyl-1-phenethyl-1-propyl-

9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole-7-carboxylic

acid allyl ester (16u). Compound 36 (74 mg, 0.179 mmol)

was converted to the corresponding carboxylic acid (59 mg,

87%) by the method similar to that used for the preparation

of 17.

To the solution of carboxylic acid (59 mg, 0.155 mmol) in

DMF (1.2 ml) was added K₂CO₃(32 mg, 0.23 mmol) and

allyl bromide (0.02 ml, 0.236 mmol) at room temperature.

After stirring at room temperature for 2 h, water (10 ml) was

added. The product was extracted with diethyl ether

(10 ml!2), and the combined organic extracts were washed

with brine (20 ml), dried over Na₂SO₄, ﬁltered and

evaporated. Puriﬁcation by silica gel column chroma-

tography (hexane–AcOEt 9:1) gave 16u (58 mg, 89%) as

Scheme 16. Reagents and conditions: (a) (i) TFA, CH₂Cl₂, rt, 83%; (ii) 2,2-

dimethoxypropane, PPTS, CH₂Cl₂, 72%; (iii) t-BuLi, CO₂, Et₂O, K78 8C,

83%; (iv) AllylBr, K₂CO₃, DMF, rt, 96%. (b) PPTS, MeOH, rt, 80%.

The obtained indoline-2-methanol (280 mg, 0.86 mmol)

was converted to the corresponding acetonide (227 mg,

72%) by the method similar to that used for the synthesis of

major-16.

1

a colorless oil. H NMR (400 MHz, CDCl₃) d 0.95 (3H, t,

JZ7.0 Hz), 1.27–1.49 (4H, m), 1.51 (3H, s), 1.65–1.73 (1H,

m), 1.69 (3H, s), 1.79–1.87 (1H, m), 2.54 (1H, dt, JZ4.7,

12.0 Hz), 2.69 (1H, dt, JZ4.7, 13.2 Hz), 2.93–3.05 (2H, m),

4.29 (1H, dd, JZ5.5, 9.9 Hz), 4.69–4.71 (2H, m), 5.20 (1H,

d, JZ9.5 Hz), 5.33 (1H, d, JZ19.0 Hz), 5.92–6.01 (1H, m),

6.59 (1H, d, JZ8.3 Hz), 7.00 (2H, d, JZ7.3 Hz), 7.08 (1H,

t, JZ7.3 Hz), 7.17 (2H, t, JZ7.3 Hz), 7.61 (1H, d, JZ

1.7 Hz), 7.72 (1H, dd, JZ1.7, 8.3 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 14.7, 17.6, 25.9, 28.6, 29.3, 30.9, 33.7, 39.3, 64.9,

70.9, 83.3, 93.3, 109.0, 117.6, 119.6, 125.7, 126.2, 128.2

(!2), 128.4 (!2), 130.4, 131.5, 132.7, 142.3, 152.3, 166.4;

IR (liquid ﬁlm) cm^K1: 2958, 2934, 2872, 1707, 1610, 1292,

1265, 1217, 1169; HRMS calcd for C₂₇H₃₄NO₃(MCH)^C

420.2539, found 420.2520; [a]²_D⁴ZC209.8 (c 0.57, CHCl₃).

Conversion of the obtained acetonide (206 mg, 0.56 mmol)

to the corresponding carboxylic acid (154 mg, 83%) was

carried out by the method similar to that used for the

synthesis of 17.

Method for the synthesis of 16u was followed using the

obtained carboxylic acid (128 mg, 0.39 mmol) to give 16v

(137 mg, 96%) as a colorless oil. ¹H NMR (400 MHz,

CDCl₃) d 1.12–1.19 (1H, m), 1.53 (3H, s), 1.60–1.65 (1H,

m), 1.68 (3H, s), 1.96–2.06 (1H, m), 2.08–2.17 (1H, m),

3.07–3.08 (2H, m), 3.29 (1H, d, JZ8.8 Hz), 3.38 (3H, s),

3.51 (1H, d, JZ8.8 Hz), 4.42 (1H, dd, JZ6.2, 8.4 Hz), 4.77

(2H, dd, JZ1.5, 5.9 Hz), 4.85 (1H, d, JZ10.3 Hz), 4.91

(1H, dd, JZ1.8, 19.0 Hz), 5.30 (1H, dd, JZ1.5, 10.3 Hz),

5.39 (1H, dd, JZ1.5, 19.0 Hz), 5.63–5.74 (1H, m), 5.98–

6.08 (1H, m), 6.59 (1H, d, JZ7.8 Hz), 7.2 (1H, d, JZ

1.5 Hz), 7.79 (1H, d, JZ7.8 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 25.7, 27.2, 28.5, 29.7, 30.7, 59.5, 64.9, 70.2, 75.9,

81.8, 94.2, 109.7, 114.2, 117.7, 120.0, 126.0, 130.1, 131.9,

132.7, 138.6, 152.6, 166.3; IR (liquid ﬁlm) cm^K1: 2985,

2929, 1709, 1610, 1292, 1265, 1212, 1169, 1122; HRMS

calcd for C₂₂H₂₉NO₄Na (MCNa)^C394.1994, found

394.2021; [a]²_D⁴ZC229.8 (c 0.52, CHCl₃).

3.6.7.4. (2S)-2-[(1R)-1-Hydroxy-1-(2-phenylethyl)bu-

tyl]indoline-5-carboxylic acid allyl ester (15u). Method

for the synthesis of 1 was followed using 16u (56 mg,

0.133 mmol) to give 15u (47 mg, 92%) as a colorless solid

(mp 125–126 8C). ¹H NMR (500 MHz, CDCl₃) d 1.02 (3H,

t, JZ7.3 Hz), 1.38–1.53 (2H, m), 1.55–1.61 (1H, m), 1.65–

1.75 (2H, m), 1.90 (1H, dt, JZ4.9, 13.2 Hz), 1.96 (1H, s),

2.62 (1H, dt, JZ4.9, 13.2 Hz), 2.75 (1H, dt, JZ4.9,

13.0 Hz), 2.98 (1H, dd, JZ9.3, 15.9), 3.14 (1H, dd, JZ

10.7, 15.9 Hz), 4.10 (1H, t, JZ9.8 Hz), 4.24 (1H, br s),

4.77–4.78 (2H, m), 5.26 (1H, d, JZ11.7 Hz), 5.39 (1H, d,

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2099

3.6.8.2. (2S)-2-[(1R)-1-Hydroxy-1-(methoxymethyl)-

pent-4-enyl]indoline-5-carboxylic acid allyl ester (15v).

Method for the synthesis of 1 was followed using 16v

(135 mg, 0.363 mmol) to give 15v (96 mg, 80%) as a

colorless solid (mp 132–134 8C). ¹H NMR (500 MHz,

CDCl₃) d 1.51–1.65 (1H, m), 1.68 (1H, dt, JZ5.5, 13.0 Hz),

2.06–2.13 (1H, m), 2.22–2.28 (1H, m), 2.70 (1H, s), 2.98

(1H, dd, JZ8.8, 15.9 Hz), 3.07 (1H, dd, JZ10.3, 15.9 Hz),

3.42 (1H, d, JZ9.3 Hz), 3.43 (3H, s), 3.51 (1H, d, JZ

9.3 Hz), 4.17 (1H, t, JZ9.8 Hz), 4.71 (1H, br s), 4.78 (2H,

d, JZ5.9 Hz), 4.99 (1H, d, JZ8.8 Hz), 5.07 (1H, d, JZ

18.6 Hz), 5.27 (1H, d, JZ11.7 Hz), 5.40 (1H, d, JZ

15.6 Hz), 5.80–5.88 (1H, m), 6.00–6.08 (1H, m), 6.58 (1H,

d, JZ8.8 Hz), 7.76 (1H, s), 7.81 (1H, d, JZ8.8 Hz); ¹³C

NMR (125 MHz, CDCl₃) d 27.4, 29.8, 33.3, 59.4, 64.8,

66.0, 73.0, 78.0, 107.5, 114.6, 117.5, 119.8, 126.0, 128.0,

130.7, 132.7, 138.4, 155.2, 166.4; IR (KBr) cm^K1: 3434,

3284, 2907, 1681, 1613, 1271, 1234, 1117, HRMS calcd for

C₁₉H₂₅NO₄Na (MCNa)^C354.1691, found 354.1690. Anal.

Calcd for C₁₉H₂₅NO₄: C, 68.86; H, 7.60; N, 4.23. Found: C,

68.60; H, 7.58; N, 4.28; [a]²_D⁴ZC4.6 (c 0.27, CHCl₃).

7-carboxylic acid (16w). Method for the synthesis of 17

was followed using 37 (280 mg, 0.672 mmol) to give 16w

(159 mg, 63%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.43 (1H, dt, JZ3.9, 12.7 Hz), 1.59 (3H, s), 1.78

(3H, s), 1.96 (1H, dt, JZ5.1, 12.7 Hz), 2.62 (1H, dt, JZ5.1,

12.7 Hz), 2.69 (1H, dt, JZ3.9, 12.7 Hz), 3.10–3.11 (2H, m),

3.37 (1H, d, JZ9.3 Hz), 3.41 (3H, s), 3.61 (1H, d, JZ

9.3 Hz), 4.49 (1H, dd, JZ6.2, 8.3 Hz), 6.61 (1H, d, JZ

8.8 Hz), 7.08 (2H, d, JZ7.2 Hz), 7.14 (1H, t, JZ7.2 Hz),

7.23 (2H, t, JZ7.2 Hz), 7.72 (1H, s), 7.83 (1H, d, JZ

8.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d 25.9, 27.0, 28.5,

29.4, 30.7, 32.5, 59.7, 70.5, 76.0, 82.0, 94.3, 109.5, 119.0,

125.8, 126.8, 128.3 (!2), 128.4, 131.1, 132.0, 142.3, 153.0,

172.3; IR (KBr) cm^K1: 2984, 2929, 1672, 1607, 1270;

HRMS calcd for C₂₃H₂₈NO₄(MCH)^C382.2018, found

382.2009.

3.6.9.3.

(2S*)-2-[(1R*)-1-Hydroxy-1-(methoxy-

methyl)-3-phenylpropyl]-2,3-dihydro-1H-indole-5-car-

boxylic acid (15w). Method for the synthesis of 22 was

followed using 16w (44 mg, 0.116 mmol) to give 15w

(20 mg, 51%) as a colorless oil. ¹H NMR (500 MHz,

CD₃OD) d 1.80 (2H, t, JZ8.8 Hz), 2.62–2.68 (1H, m),

2.73–2.79 (1H, m), 3.00 (1H, dd, JZ9.8, 16.4 Hz), 3.11

(1H, dd, JZ9.2, 16.4 Hz), 3.41 (3H, s), 3.47 (1H, d, JZ

9.3 Hz), 3.51 (1H, d, JZ9.3 Hz), 4.16 (1H, t, JZ9.8 Hz),

6.54 (1H, d, JZ8.8 Hz), 7.14 (1H, t, JZ7.2 Hz), 7.20 (2H,

d, JZ7.2 Hz), 7.25 (2H, t, JZ7.2 Hz), 7.64 (1H, s), 7.68

(1H, d, JZ8.8 Hz); ¹³C NMR (125 MHz, CD₃OD) d 30.5,

30.6, 37.5, 59.6, 65.9, 75.3, 76.9, 108.0, 119.8, 126.7, 127.0,

129.3 (!2), 129.4 (!2), 129.6, 132.0, 144.1, 158.0, 170.9;

IR (KBr) cm^K1: 3408, 2926, 1673, 1609, 1285, 1264;

HRMS calcd for C₂₀H₂₄NO₄(MCH)^C342.1705, found

342.1706.

3.6.9. Preparation of 15w.

3.6.9.1. (1R*,9aS*)-7-Bromo-1-(methoxymethyl)-3,3-

dimethyl-1-phenethyl-9,9a-dihydro-1H-[1,3]oxazolo-

[3,4-a]indole (37). Compound 14l (868 mg, 1.82 mmol)

was converted to the corresponding indoline-2-methanol

(660 mg, 96%) by the method similar to that used for the

preparation of 15a (Scheme 17).

Method for the synthesis of major-16 was followed using

the obtained indoline-2-methanol (641 mg, 1.70 mmol)

to give 37 (554 mg, 78%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 1.43 (1H, dt, JZ4.6, 13.0 Hz), 1.55

(3H, s), 1.70 (3H, s), 1.92 (1H, dt, JZ5.2, 13.0 Hz), 2.60

(1H, dt, JZ5.2, 13.0 Hz), 2.69 (1H, dt, JZ4.6, 13.0 Hz),

3.04 (1H, dd, JZ9.3, 17.1 Hz), 3.09 (1H, dd, JZ4.4,

17.1 Hz), 3.33 (1H, d, JZ8.8 Hz), 3.39 (3H, s), 3.59 (1H, d,

JZ8.8 Hz), 4.39 (1H, dd, JZ4.9, 7.8 Hz), 6.51 (1H, d, JZ

8.8 Hz), 7.07–7.11 (4H, m), 7.15 (1H, t, JZ7.3 Hz), 7.22–

7.27 (2H, m); ¹³C NMR (125 MHz, CDCl₃) d 25.8, 29.3,

29.6, 31.4, 32.8, 59.6, 70.5, 76.4, 82.0, 95.2, 111.0, 113.1,

125.7, 127.6, 128.3 (!2), 128.3 (!2), 129.5, 134.3, 142.4,

147.8; IR (CHCl₃) cm^K1: 2931, 1475, 1259, 1109; HRMS

calcd for C₂₂H₂₆NO₄Br (M)^C415.1147, found 415.1128.

3.6.10. Rearrangement from indoline-2-methanols 15 to

tetrahydroquinolines 26. Compounds 26c–d, 26f–k, 26n,

26p, 26r–v, 15x were obtained by the method similar to that

used for the synthesis of 26a.

3.6.10.1.

(2S,3S)-3-Chloro-2-ethyl-2-(methoxy-

methyl)-1,2,3,4-tetrahydroquinoline (26c). The general

method was followed using 15c (6.1 mg, 0.028 mmol) to

give 26c (5.4 mg, 80%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 0.92 (3H, t, JZ7.3 Hz), 1.66 (1H,

dq, JZ7.3, 14.8 Hz), 1.76 (1H, dq, JZ7.3, 14.8 Hz), 3.05

(1H, dd, JZ6.6, 16.8 Hz), 3.30 (1H, dd, JZ5.2, 16.8 Hz),

3.35 (3H, s), 3.48 (1H, d, JZ9.2 Hz), 3.53 (1H, d, JZ

3.6.9.2. (1R*,9aS*)-1-(Methoxymethyl)-3,3-dimethyl-

1-phenethyl-9,9a-dihydro-1H-[1,3]oxazolo[3,4-a]indole-

Scheme 17. Reagents and conditions: (a) (i) TFA, CH₂Cl₂, rt, 96%; (ii) 2,2-dimethoxypropane, PPTS, CH₂Cl₂, 78%. (b) (i) t-BuLi, CO₂, Et₂O, K78 8C, 63%;

(ii) Amberlyst-15^wion exchange resin, MeOH, rt, 51%.

2100

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

9.2 Hz), 3.99 (1H, br s), 4.33 (1H, dd, JZ5.2, 6.6 Hz), 6.53

(1H, d, JZ8.1 Hz), 6.63 (1H, t, JZ8.1 Hz), 6.96 (1H, d, JZ

8.1 Hz), 7.01 (1H, t, JZ8.1 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 7.1, 27.2, 33.9, 57.0, 57.6, 59.4, 73.5, 114.7,

117.2, 117.6, 127.4, 129.4, 142.3; IR (CHCl₃) cm^K1: 3422,

2972, 2935, 2896, 1607, 1588, 1482, 1312, 1260, 1112, 980,

960, 834; HRMS calcd for C₁₃H₁₈NOCl (M)^C239.1077,

found 239.1075; [a]²_D⁴ZK6.9 (c 0.32, CHCl₃).

(1H, dd, JZ5.1, 17.0 Hz), 3.33 (3H, s), 3.51 (1H, d, JZ

9.3 Hz), 3.63 (1H, d, JZ9.3 Hz), 4.06 (1H, br s), 4.50 (1H, t,

JZ5.1 Hz), 6.54 (1H, d, JZ7.3 Hz), 6.65 (1H, dt, JZ1.0,

7.3 Hz), 6.97 (1H, d, JZ7.3 Hz), 7.01 (1H, t, JZ7.3 Hz);

¹³C NMR (125 MHz, CDCl₃) d 26.8, 27.3, 27.4, 27.5, 27.9,

34.6, 44.7, 57.3, 59.2, 59.5, 73.6, 114.7, 117.5, 117.5, 127.7,

129.5, 142.5; IR (KBr) cm^K1: 3402, 3365, 2926, 2852,

1487, 1099, 746; HRMS calcd for C₁₇H₂₄NOCl (M)^C

293.1546, found 293.1568; [a]²_D⁴ZC11.6 (c 0.46, CHCl₃).

3.6.10.2. (2R,3R)-3-Chloro-2-(methoxymethyl)-2-phe-

nyl-1,2,3,4-tetrahydroquinoline (26d). The general

method was followed using 15d (14 mg, 0.052 mmol) to

give 26d (9.5 mg, 63%) as a colorless oil. ¹H NMR

(400 MHz, CDCl₃) d 2.76 (2H, m), 3.29 (3H, s), 3.93 (1H,

d, JZ8.8 Hz), 3.99 (1H, d, JZ8.8 Hz), 4.57 (1H, t, JZ

3.5 Hz), 4.84 (1H, br s), 6.65 (1H, d, JZ8.0 Hz), 6.72 (1H, t,

JZ8.0 Hz), 6.86 (1H, d, JZ8.0 Hz), 7.10 (1H, t, JZ

8.0 Hz), 7.22–7.39 (5H, m); ¹³C NMR (100 MHz, CDCl₃)

d 33.5, 57.7, 59.6, 61.9, 78.7, 113.0, 116.2, 117.2, 125.8

(!2), 127.2, 127.5, 128.6 (!2), 129.6, 141.6, 142.9; IR

(CHCl₃) cm^K1: 3437, 2926, 1606, 1484, 1316, 1271, 1109,

972; HRMS calcd for C₁₇H₁₈NOCl (M)^C287.1073, found

287.1078; [a]²_D⁴ZC142.0 (c 0.20, CHCl₃).

3.6.10.6. (2R,3R)-3-Chloro-2-dimethyl-2-(methoxy-

methyl)-1,2,3,4-tetrahydroquinoline (26n). The general

method was followed using 15n (35 mg, 0.198 mmol) to

give 26n (25 mg, 65%) as a colorless oil. ¹H NMR

(400 MHz, CDCl₃) d 1.25 (3H, s), 1.32 (3H, s), 3.07 (1H,

dd, JZ9.0, 17.5 Hz), 3.23 (1H, dd, JZ6.0, 17.5 Hz), 3.73

(1H, br s), 4.10 (1H, dd, JZ6.0, 9.0 Hz), 6.51 (1H, d, JZ

8.0 Hz), 6.67 (1H, t, JZ8.0 Hz), 6.98 (1H, d, JZ8.0 Hz),

7.02 (1H, t, JZ8.0 Hz); ¹³C NMR (100 MHz, CDCl₃) d

23.0, 28.4, 34.8, 53.2, 62.6, 114.6, 117.7, 118.0, 127.5,

129.2, 142.4; IR (CHCl₃) cm^K1: 3473, 3415, 2972, 2936,

1608, 1588, 1497, 1485, 1462; HRMS calcd for C₁₁H₁₄NCl

(M)^C195.0815, found 195.0820; [a]²_D⁴ZK28.9 (c 0.34,

CHCl₃).

3.6.10.3. (2R,3R)-3-Chloro-2-(4-chlorophenyl)-2-

(methoxymethyl)-1,2,3,4-tetrahydroquinoline (26f).

The general method was followed using 15f (74 mg,

0.244 mmol) to give 26f (26 mg, 33%) as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d 2.75 (1H, dd, JZ3.7,

16.9 Hz), 2.82 (1H, dd, JZ3.7, 16.9 Hz), 3.31 (3H, s), 3.89

(1H, d, JZ8.8 Hz), 3.94 (1H, d, JZ8.8 Hz), 4.53 (1H, t, JZ

3.7 Hz), 4.77 (1H, s), 6.67 (1H, t, JZ7.6 Hz), 6.73 (1H,

d, JZ7.6 Hz), 6.88 (1H, d, JZ7.6 Hz), 7.71 (1H, t, JZ

7.6 Hz), 7.28 (2H, d, JZ8.8 Hz), 7.34 (2H, d, JZ8.8 Hz);

¹³C NMR (125 MHz, CDCl₃) d 33.6, 57.7, 59.9, 62.0, 78.6,

113.7, 116.6, 118.0, 127.9 (!2), 128.1, 129.1 (!2), 130.1,

133.6, 141.7, 142.0; IR (thin ﬁlm) cm^K1: 3428, 3380, 2924,

2896, 1488, 1110, 752; HRMS calcd for C₁₇H₁₇NOCl₂

(M)^C321.0687, found 321.0668; [a]²_D⁴ZC109.2 (c 0.35,

CHCl₃).

3.6.10.7. (2R,3R)-3-Chloro-2-(methoxymethyl)-2-

vinyl-1,2,3,4-tetrahydroquinoline (26h). The general

method was followed using 15h (32 mg, 0.146 mmol) to

give 26h (10.8 mg, 31%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 2.93 (1H, dd, JZ4.0 Hz, 17.5), 3.28

(1H, dd, JZ4.0, 17.5 Hz), 3.41 (3H, s), 3.58 (1H, d, JZ

8.5 Hz), 3.63 (1H, d, JZ8.5 Hz), 4.24 (1H, t, JZ4.0 Hz),

4.32 (1H, br s), 5.26 (1H, d, JZ9.5 Hz), 5.29 (1H, d, JZ

16.5 Hz), 5.89 (1H, dd, JZ9.5, 16.5 Hz), 6.63 (1H, d, JZ

8.0 Hz), 6.66 (1H, t, JZ8.0 Hz), 6.95 (1H, d, JZ8.0 Hz),

7.05 (1H, t, JZ8.0 Hz); ¹³C NMR (125 MHz, CDCl₃) d

10.0, 33.7, 56.3, 59.6, 60.4, 113.7, 116.6, 117.1, 117.6,

127.5, 129.6, 139.0, 141.6; IR (CHCl₃) cm^K1: 3433, 2927,

2897, 1608, 1590, 1482, 1313, 1271, 1115, 933; HRMS

calcd for C₁₃H₁₆NOCl (M)^C237.0920, found 237.0917;

[a]²_D⁴ZC72.4 (c 0.22, CHCl₃).

3.6.10.4. (2R,3R)-3-Chloro-2-isopropyl-2-(methoxy-

methyl)-1,2,3,4-tetrahydroquinoline (26r). The general

method was followed using 15r (35 mg, 0.198 mmol) to

give 26r (25 mg, 65%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 1.04 (6H, t, JZ8.0 Hz), 2.00–2.07

(1H, m), 3.10 (1H, dd, JZ7.0, 17.0 Hz), 3.26 (1H, dd, JZ

5.0, 17.0 Hz), 3.32 (3H, s), 3.53 (1H, d, JZ9.0 Hz), 3.63

(1H, d, JZ9.0 Hz), 4.03 (1H, br s), 4.48 (1H, dd, JZ5.0,

7.0 Hz), 6.55 (1H, d, JZ8.0 Hz), 6.65 (1H, t, JZ8.0 Hz),

6.96 (1H, d, JZ8.0 Hz), 7.01 (1H, t, JZ8.0 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 16.6, 17.7, 33.6, 34.4, 57.2, 58.8, 59.2,

73.3, 114.5, 117.3 (!2), 127.4, 129.1, 142.3; IR (CHCl₃)

cm^K1: 3429, 2966, 2930, 1607, 1482, 1311, 1261, 1116,

980; HRMS calcd for C₁₄H₂₀NOCl (M)^C253.1233, found

253.1232; [a]²_D⁴ZC25.0 (c 0.15, CHCl₃).

3.6.10.8. (2R,3R)-3-Chloro-2-isopropenyl-2-(methoxy-

methyl)-1,2,3,4-tetrahydroquinoline (26i). The general

method was followed using 15i (48 mg, 0.206 mmol) to

give 26i (19 mg, 37%) as a colorless oil. ¹H NMR

(400 MHz, CDCl₃) d 1.81 (3H, s), 2.86 (1H, dd, JZ3.2,

16.8 Hz), 3.22 (1H, dd, JZ3.6, 16.8 Hz), 3.41 (3H, s), 3.68

(1H, d, JZ9.2 Hz), 3.76 (1H, d, JZ9.2 Hz), 4.42 (1H, br t,

JZ2.8 Hz), 4.58 (1H, br s), 5.05 (1H, s), 5.07 (1H, s), 6.59

(1H, d, JZ8.0 Hz), 6.63 (1H, t, JZ8.0 Hz), 6.92 (1H, d, JZ

8.0 Hz), 7.04 (1H, t, JZ8.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 18.7, 33.6, 55.6, 59.5, 62.8, 76.6, 112.9, 115.8,

115.9, 117.1, 127.5, 129.6, 141.8, 144.9; IR (CHCl₃) cm^K1

:

3456, 2926, 1609, 1502, 1483, 1315, 1275, 1112, 971, 914;

HRMS calcd for C₁₄H₁₉NOCl (MCH)^C252.1156, found

252.1160; [a]²_D⁴ZC63.5 (c 0.17, CHCl₃).

3.6.10.5. (2R,3R)-3-Chloro-2-cyclohexyl-2-(methoxy-

methyl)-1,2,3,4-tetrahydroquinoline (26g). The general

method was followed using 15g (80 mg, 0.290 mmol) to

give 26g (32 mg, 38%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 1.16–1.40 (5H, m), 1.59–1.65 (2H,

m), 1.77–1.83 (4H, m), 3.07 (1H, dd, JZ6.4, 17.0 Hz), 3.28

3.6.10.9. (2R,3R)-3-Chloro-2-(methoxymethyl)-2-tri-

methylsilanylethynyl-1,2,3,4-tetrahydroquinoline (26j).

The general method was followed using 15j (30 mg,

0.104 mmol) to give 26j (20 mg, 63%) as a colorless

oil. ¹H NMR (500 MHz, CDCl₃) d 0.11 (9H, s), 3.24 (2H, d,

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2101

JZ8.5 Hz), 3.41 (3H, s), 3.77 (2H, s), 4.35 (1H, br s), 4.36

(1H, t, JZ8.5 Hz), 6.62 (1H, d, JZ8.0 Hz), 6.68 (1H, t, JZ

8.0 Hz), 7.00 (1H, t, JZ8.0 Hz), 7.05 (1H, d, JZ8.0 Hz);

¹³C NMR (125 MHz, CDCl₃) d K0.3 (!3), 33.0, 59.9,

64.8, 68.3, 77.9, 93.6, 108.8, 118.5, 124.1, 127.3, 127.8,

128.1, 150.3; IR (CHCl₃) cm^K1: 3410, 2962, 1610, 1485,

1468, 1403, 1251, 1096, 846; HRMS calcd for C₁₆H₂₂-

NOClSi (M)^C307.1159, found 307.1158; [a]²_D⁴ZC19.0

(c 0.14, CHCl₃).

(1H, m), 1.95–2.01 (1H, m), 2.58 (2H, t, JZ8.4 Hz), 3.01

(1H, dd, JZ6.6, 16.9 Hz), 3.23–3.28 (1H, m), 3.28 (3H, s),

3.46 (1H, d, JZ9.2 Hz), 3.50 (1H, d, JZ9.2 Hz), 3.74

(3H, s), 4.31 (1H, t, JZ5.9 Hz), 4.39 (1H, s), 6.39 (1H, d,

JZ9.5 Hz), 7.05–7.10 (3H, m), 7.15–7.18 (2H, m), 7.60–

7.62 (2H, m); ¹³C NMR (100 MHz, CDCl₃) d 29.3, 33.6,

37.0, 51.5, 56.3, 58.0, 59.4, 73.8, 113.7, 116.0, 118.8, 126.0,

128.2 (!2), 128.5 (!2), 129.6, 131.6, 141.4, 146.3, 167.1;

IR (KBr) cm^K1: 3361, 2948, 1707, 1610, 1436, 1288, 1253,

1128, 1104; HRMS calcd for C₂₁H₂₄NO₃ClK (MCK)^C

412.1082, found 412.1074; [a]²_D⁴ZK29.4 (c 0.10, CHCl₃).

3.6.10.10. (2R,3R)-3-Chloro-2-ethynyl-2-(methoxy-

methyl)-1,2,3,4-tetrahydroquinoline (26s). The general

method was followed using 15s (55 mg, 0.253 mmol) to

give 26s (33 mg, 55%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d 2.70 (1H, s), 3.24 (2H, d, JZ

9.0 Hz), 3.48 (3H, s), 3.76 (1H, d, JZ10.5 Hz), 3.79 (1H,

d, JZ10.5 Hz), 4.30 (1H, br s), 4.40 (1H, t, JZ9.0 Hz), 6.64

(1H, d, JZ8.0 Hz), 6.70 (1H, t, JZ8.0 Hz), 7.02 (1H, t, JZ

8.0 Hz), 7.06 (1H, d, JZ8.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 32.9, 59.8, 65.1, 67.3, 77.6, 109.1, 115.0, 118.9,

124.3, 127.4, 127.8, 129.6, 150.0; IR (CHCl₃) cm^K1: 3408,

3305, 2934, 1610, 1485, 1248, 1117, 1097, 968; HRMS

calcd for C₁₃H₁₄NOCl (M)^C235.0764, found 235.0768;

[a]²_D⁴ZK24.0 (c 0.30, CHCl₃).

3.6.10.14. (2S,3R)-3-Chloro-2-phenethyl-2-propyl-

1,2,3,4-tetrahydroquinoline-6-carboxylic acid allyl ester

(26u). The general method was followed using 15u

(300 mg, 0.791 mmol) to give 26u (164 mg, 52%) as a

colorless oil. ¹H NMR (400 MHz, CDCl₃) d 0.93 (3H, t, JZ

7.3 Hz), 1.25–1.32 (1H, m), 1.37–1.45 (1H, m), 1.55 (1H,

dt, JZ4.4, 12.8 Hz), 1.71 (1H, dt, JZ4.4, 13.0 Hz), 1.78

(1H, dt, JZ4.4, 13.0 Hz), 1.91 (1H, dt, JZ5.9 Hz, 12.8),

2.60 (1H, dt, JZ5.1, 12.6 Hz), 2.69 (1H, dt, JZ5.1,

12.6 Hz), 3.10 (1H, dd, JZ6.6, 17.3 Hz), 3.29 (1H, dd,

JZ5.1, 17.3 Hz), 4.05–4.10 (1H, m), 4.29 (1H, dd, JZ5.1,

6.6 Hz), 4.72–4.73 (2H, m), 5.21 (1H, d, JZ9.5 Hz), 5.34

(1H, d, JZ19.1 Hz), 5.94–6.03 (1H, m), 6.42 (1H, d, JZ

8.1 Hz), 7.09–7.25 (5H, m), 7.69–7.71 (2H, m); ¹³C NMR

(100 MHz, CDCl₃) d 14.4, 16.0, 29.3, 33.5, 36.2, 37.9, 57.6,

58.3, 64.9, 113.5, 116.1, 117.6, 118.5, 126.0, 128.2, 128.5,

129.6 (!2), 131.7 (!2), 132.7, 141.5, 146.6, 166.3; IR

(thin ﬁlm) cm^K1: 3368, 2959, 2935, 2873, 1693, 1610,

1513, 1281, 1250, 1129; HRMS calcd for C₂₄H₂₉NO₂Cl

(MCH)^C398.1887, found 398.1914; [a]²_D⁴ZK2.2 (c 0.31,

CHCl₃).

3.6.10.11. (2R,3R)-6-Bromo-3-chloro-2-methyl-2-(4-

methylpent-3-enyl)-1,2,3,4-tetrahydroquinoline (26p).

The general method was followed using 15p (45 mg,

0.139 mmol) to give 26p (30 mg, 62%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) d 1.25 (3H, s), 1.46–1.55 (1H,

m), 1.57 (3H, s), 1.68 (3H, s), 1.72–1.80 (1H, m), 1.97–2.10

(2H, m), 3.05 (1H, dd, JZ7.4, 16.8 Hz), 3.23 (1H, dd, JZ

5.6, 16.8 Hz), 3.83 (1H, br s), 4.11 (1H, dd, JZ5.6, 7.4 Hz),

5.09 (1H, t, JZ7.2 Hz), 6.38 (1H, d, JZ9.6 Hz), 7.08 (1H,

s), 7.09 (1H, d, JZ9.6 Hz); ¹³C NMR (100 MHz, CDCl₃) d

17.7, 22.0, 24.8, 25.7, 34.0, 34.8, 55.2, 61.2, 109.0, 116.1,

3.6.10.15. (2R,3R)-2-But-3-enyl-3-chloro-2-(methoxy-

methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

allyl ester (26v). The general method was followed using

15v (83 mg, 0.250 mmol) to give 26v (41 mg, 46%) as a

colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.70–1.76 (1H,

m), 1.84–1.90 (1H, m), 2.16 (2H, q, JZ7.8 Hz), 3.11 (1H,

dd, JZ6.3, 17.1 Hz), 3.36 (1H, dd, JZ4.4, 17.1 Hz), 3.39

(3H, s), 3.54 (1H, d, JZ9.3 Hz), 3.58 (1H, d, JZ9.3 Hz),

4.35 (1H, t, JZ5.4 Hz), 4.52 (1H, s), 4.78 (2H, d, JZ

5.8 Hz), 4.99 (1H, d, JZ8.8 Hz), 5.06 (1H, d, JZ14.7 Hz),

5.27 (1H, d, JZ8.8 Hz), 5.39 (1H, d, JZ18.6 Hz), 5.76–

5.85 (1H, m), 6.00–6.08 (1H, m), 6.54 (1H, d, JZ8.8 Hz),

7.74 (1H, s), 7.76 (1H, d, JZ8.8 Hz); ¹³C NMR (100 MHz,

CDCl₃) d 21.5, 33.8, 34.5, 56.4, 58.0, 59.6, 65.0, 73.9,

113.5, 115.0, 116.0, 117.7, 118.7, 129.7, 131.7, 132.7,

137.8, 146.2, 166.2; IR (liquid ﬁlm) cm^K1: 3364, 2928,

1704, 1611, 1515, 1281, 1252, 1128, 1105; HRMS calcd for

C₁₉H₂₅NO₃Cl (MCH)^C350.1522, found 350.1526;

[a]²_D⁴ZC17.1 (c 1.01, CHCl₃).

119.8, 123.6, 130.0, 131.6, 132.0, 141.1; IR (CHCl₃) cm^K1

:

3424, 2971, 2932, 1716, 1599, 1488, 1447, 1380, 1301,

1123; HRMS calcd for C₁₆H₂₁NClBr (M)^C341.0545,

found 341.0544; [a]²_D⁴ZC37.4 (c 0.56, CHCl₃).

3.6.10.12. (2R,3R)-6-Bromo-3-chloro-2-(methoxy-

methyl)-2-(4-methylpent-3-enyl)-1,2,3,4-tetrahydro-

quinoline (26k). The general method was followed using

15k (39 mg, 0.110 mmol) to give 26k (17 mg, 41%) as a

colorless oil. ¹H NMR (500 MHz, CDCl₃) d 1.55–1.63 (1H,

m), 1.59 (3H, s), 1.67 (3H, s), 1.69–1.75 (1H, m), 1.98–2.08

(2H, m), 3.02 (1H, dd, JZ6.0, 17.5 Hz), 3.29 (1H, dd, JZ

4.5, 17.5 Hz), 3.36 (3H, s), 3.47 (1H, d, JZ9.5 Hz), 3.52

(1H, d, JZ9.5 Hz), 4.05 (1H, br s), 4.31 (1H, t, JZ6.0 Hz),

5.07 (1H, br t, JZ7.0 Hz), 6.42 (1H, d, JZ9.0 Hz), 7.08

(1H, s), 7.09 (1H, d, JZ9.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 17.6, 21.6, 25.6, 33.6, 34.5, 56.6, 57.6, 59.3, 73.7,

109.0, 116.2, 119.2, 123.5, 130.2, 131.8, 132.1, 141.2; IR

(CHCl₃) cm^K1: 3426, 2929, 1711, 1599, 1489, 1377, 1301,

1111, 977; HRMS calcd for C₁₇H₂₃NOClBr (M)^C

371.0651, found 371.0655; [a]²_D⁴ZK11.6 (c 0.39, CHCl₃).

3.6.10.16. (2S)-2-[(1S)-1-Hydroxy-1-(methoxymethyl)-

4,5-dimethylhex-4-enyl]indoline-5-carbonitrile (15x).

The general method was followed using 1 (26 mg,

0.0782 mmol) to give 15!(15 mg, 61%) as a colorless

1

3.6.10.13. Methyl (2R,3R)-3-chloro-2-(methoxy-

methyl)-2-(2-phenylethyl)-1,2,3,4-tetrahydroquinoline-

6-carboxylate (26t). The general method was followed

using 15t (102 mg, 0.304 mmol) to give 26t (45 mg, 50%)

as a colorless oil. ¹H NMR (400 MHz, CDCl₃) d 1.82–1.87

oil. H NMR (500 MHz, CDCl₃) d 1.47 (1H, dt, JZ5.0,

12.5 Hz), 1.55 (1H, dt, JZ5.0, 12.5 Hz), 1.63 (6H, s), 1.65

(3H, s), 1.99 (1H, dt, JZ5.0, 12.5 Hz), 2.15 (1H, dt, JZ5.0,

12.5 Hz), 2.61 (1H, s), 2.96 (1H, dd, JZ9.0, 16.5 Hz),

3.06 (1H, dd, JZ11.0, 16.5 Hz), 3.42 (3H, s), 3.43 (1H, d,

2102

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

1

boxylate (minor-32). H NMR (400 MHz, CDCl₃) d 1.57

JZ9.0 Hz), 3.52 (1H, d, JZ9.0 Hz), 4.15 (1H, t, JZ

9.5 Hz), 4.84 (1H, br s), 6.54 (1H, d, JZ8.0 Hz), 7.25 (1H,

s), 7.29 (1H, d, JZ8.0 Hz); ¹³C NMR (125 MHz, CDCl₃) d

18.2, 19.9, 20.5, 28.0, 29.9, 32.6, 59.5, 66.0, 72.9, 78.4,

99.9, 108.0, 120.6, 124.6, 126.9, 127.8, 128.9, 133.0, 154.6;

IR (CHCl₃) cm^K1: 3543, 3423, 2923, 2215, 1614, 1495,

1412, 1264, 1109, 972; HRMS calcd for C₁₉H₂₇N₂O₂(MC

H)^C315.2072, found 315.2065; [a]²_D⁴ZC14.5 (c 0.29,

CHCl₃).

(9H, s), 1.62 (6H, s), 1.65 (3H, s), 1.57–1.65 (2H, m), 2.11

(1H, dt, JZ5.3, 12.5 Hz), 2.18 (1H, dt, JZ5.3, 12.5 Hz),

2.88 (3H, s), 3.07 (1H, d, JZ9.5 Hz), 3.15 (1H, d, JZ

9.5 Hz), 3.16–3.26 (2H, m), 4.64 (1H, dd, JZ2.9, 10.2 Hz),

7.20–7.22 (1H, m), 7.43–7.45 (2H, m); ¹³C NMR

(125 MHz, CDCl₃) d 18.3, 19.9, 20.5, 27.6, 28.2, 28.3,

28.9, 30.2, 33.3, 58.7, 65.9, 75.0, 76.3, 77.4, 82.9, 85.9,

118.2, 124.1, 127.6, 133.1, 135.4, 135.6, 142.3; IR

(CHCl₃) cm^K1: 2983, 2926, 1665, 1476, 1371, 1163;

HRMS calcd for C₂₃H₃₄NO₄INa (MCNa)^C538.1431,

found 538.1437; [a]²_D⁴ZK53.9 (c 0.49, CHCl₃).

3.6.11. Synthesis of (K)-virantmycin.

3.6.11.1. tert-Butyl (2S)-5-iodo-2-(methoxyacetyl)-

indoline-1-carboxylate (31). Iodine monochloride in

CH₂Cl₂(1.4 ml, 1.0 M) was added to a solution of 13b

(100 mg, 0.34 mmol) and 2,6-di-tert-butyl-4-methylpyri-

dine (282 mg, 1.37 mmol) in CH₂Cl₂(2 ml) at 0 8C, and the

mixture was stirred at room temperature for 1 h. The

reaction mixture was diluted with AcOEt (10 ml), poured

into Na₂S₂O₃aq (10 ml) and the organic material was

extracted with AcOEt(10 ml!2). The combined extracts

were washed with 1 N HCl (20 ml), satd NaHCO₃aq

(20 ml) and brine (20 ml), dried over Na₂SO₄and

concentrated. Puriﬁcation by silica gel ﬂash chromato-

graphy (toluene–AcOEt 9:1) furnished 31 (130 mg, 91%) as

a colorless solid (mp 72–74 8C). ¹H NMR (500 MHz,

CD₃OD, two rotamers) d 1.44–1.54 (9H, m), 2.96 (1H, br d,

JZ17.6 Hz), 3.41 (3H, s), 3.41–3.42 (1H, br m), 4.21 (2H,

s), 5.09 (1H, dd, JZ11.7, 4.9 Hz), 7.23* (0.3H, br s), 7.40

(1H, s), 7.44 (1H, d, JZ8.8 Hz), 7.55 (0.7H, br s); ¹³C NMR

(125 MHz, CD₃OD) d 28.5 (!3), 31.8, 59.8, 64.6, 76.1,

82.9, 117.3, 132.5, 134.7, 137.6 (!2), 144.2, 152.8, 206.2;

IR (CHCl₃) cm^K1: 2981, 2935, 1708, 1693, 1476, 1371,

1152; HRMS calcd for C₁₆H₂₀NO₄INa (MCNa)^C

440.0335, found 440.0358; [a]²_D⁴Z K46.0 (c 0.82, CHCl₃).

3.6.11.4. (2R)-2-[(2S)-2,3-Dihydro-5-iodo-1H-indol-2-

yl]-1-methoxy-5,6-dimethylhept-5-en-2-ol (33). Formic

acid (1 ml) was added to a solution of 32 (115 mg,

0.22 mmol) in CH₂Cl₂(1 ml) at room temperature, and

the mixture was stirred under reﬂux conditions for 2 h. The

reaction mixture was poured into water, basiﬁed to pH 8

with NaHCO₃, and the organic material was extracted with

AcOEt (5 ml!2). The combined organic extracts were

washed with brine (10 ml), dried over Na₂SO₄and

concentrated. The crude product was puriﬁed by silica gel

ﬂash chromatography (hexane–AcOEt 3:2) to give 33

1

(55 mg, 59%) as a colorless solid (mp 104–106 8C). H

NMR (400 MHz, CDCl₃) d 1.47 (1H, dt, JZ5.1, 13.9 Hz),

1.55 (1H, dt, JZ5.1, 13.9 Hz), 1.64 (3H, s), 1.66 (6H, s),

2.01 (1H, dt, JZ5.1, 12.5 Hz), 2.15 (1H, dt, JZ5.1,

12.5 Hz), 2.78 (1H, s), 2.89 (1H, dd, JZ8.8, 16.1 Hz),

3.05 (1H, dd, JZ11.0, 16.1 Hz), 3.39 (1H, d, JZ9.5 Hz),

3.40 (3H, s), 3.49 (1H, d, JZ9.5 Hz), 4.07 (1H, t, JZ

9.9 Hz), 4.28 (1H, br s), 6.41 (1H, d, JZ8.1 Hz), 7.27 (1H,

d, JZ8.1 Hz), 7.33 (1H, s); ¹³C NMR (100 MHz, CDCl₃) d

18.5, 20.1, 20.7, 28.3, 30.3, 33.0, 59.5, 66.0, 72.7, 78.3,

79.5, 111.2, 124.3, 127.1, 131.5, 133.0, 135.7, 150.3; IR

(CHCl₃) cm^K1: 3513, 3407, 2925, 1602, 1479, 1417, 1248,

1112; HRMS calcd for C₁₈H₂₇NO₂I (MCH)^C416.1087,

found 416.1073. Anal. Calcd for C₁₈H₂₆NO₂I: C, 52.06; H,

6.31; N, 3.37; I, 30.56. Found: C, 52.08; H, 6.40; N, 3.55; I,

30.69; [a]²_D⁴ZK25.9 (c 0.19, CHCl₃).

3.6.11.2. tert-Butyl (2S)-2-[(1R)-1-hydroxy-1-methoxy-

methyl-4,5-dimethylhex-4-enyl]-5-iodoindoline-1-carb-

oxylate (major-32). The prepared Grignard reagent (0.5 M

THF solution, 7.8 ml) was added dropwise to a solution of

31 (813 mg, 1.95 mmol) in THF (3 ml) at K78 8C in N₂

atmosphere, and the reaction mixture was stirred at this

temperature for 1 h. After the addition of satd NH₄Cl aq, the

reaction mixture was allowed to warm to room temperature.

The organic material was extracted with AcOEt (10 ml!2),

and then the combined extracts were washed with brine

(20 ml), dried over Na₂SO₄and concentrated. Puriﬁcation

by silica gel ﬂash chromatography (hexane–AcOEt 9:1)

furnished the corresponding alcohol 32 (770 mg, 77%) as a

3.6.11.5. (2R,3R)-3-Chloro-2-(3,4-dimethyl-pent-3-

enyl)-6-iodo-2-methoxymethyl-1,2,3,4-tetrahydroquino-

line (34). Tri-n-butylphosphine (140 ml, 0.54 mmol) was

added dropwise to a solution of 33 (15 mg, 0.036 mmol) and

carbon tetrachloride (110 ml, 1.08 mmol) in CH₂Cl₂(2 ml)

at reﬂux (bath temp. 55 8C) in N₂atmosphere. The reaction

mixture was stirred under reﬂux conditions for 1 h, and then

concentrated. The resulting residue was puriﬁed by silica

gel ﬂash chromatography (hexane–AcOEt 19:1) to give 34

(7.1 mg, 45%) as a colorless solid (mp 98–100 8C). ¹H NMR

(500 MHz, CDCl₃) d 1.54 (3H, s), 1.57–1.62 (7H, m), 1.75

(1H, dt, JZ5.2, 13.2 Hz), 2.00 (1H, dt, JZ4.6, 12.2 Hz),

2.08 (1H, dt, JZ4.6, 12.2 Hz), 3.02 (1H, dd, JZ5.9,

17.1 Hz), 3.29 (1H, dd, JZ5.9, 17.1 Hz), 3.36 (3H, s), 3.49

(1H, d, JZ7.8 Hz), 3.53 (1H, d, JZ7.8 Hz), 4.10 (1H, s),

4.31 (1H, t, JZ5.9 Hz), 6.34 (1H, d, JZ7.8 Hz), 7.26 (1H,

s), 7.27 (1H, d, JZ7.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d

18.4, 19.9, 20.6, 27.7, 33.0, 33.5, 56.4, 57.6, 59.4, 73.7,

78.1, 116.8, 119.8, 124.6, 126.7, 136.1, 137.7, 142.0; IR

(CHCl₃) cm^K1: 2926, 1597, 1488, 1299, 1109; HRMS calcd

for C₁₈H₂₅NOClI (M)^C433.0670, found 433.0652;

[a]²_D⁴ZK10.3 (c 0.64, CHCl₃).

1

colorless oil. H NMR (400 MHz, CDCl₃) d 1.31 (1H, dt,

JZ5.2, 12.7 Hz), 1.41 (1H, dt, JZ5.2 Hz, 12.7), 1.52 (3H,

s), 1.55 (3H, s), 1.57 (9H, s), 1.58 (3H, s), 1.99 (1H, dt, JZ

5.2, 12.7 Hz), 2.04 (1H, dt, JZ5.2, 12.7 Hz), 3.08 (1H, dd,

JZ2.0, 16.9 Hz), 3.26 (1H, dd, JZ10.3, 16.9 Hz), 3.35 (3H,

s), 3.40 (2H, s), 4.73 (1H, br d, JZ9.8 Hz), 7.24 (1H, br s),

7.43–7.44 (2H, m); ¹³C NMR (125 MHz, CDCl₃) d 18.2,

19.8, 20.5, 28.1, 28.3 (!3), 29.6, 31.4, 59.3, 64.7, 76.3,

76.9, 82.4, 85.8, 118.3, 124.1, 127.4, 133.0, 134.8, 135.8 (!

2), 142.8; IR (CHCl₃) cm^K1: 2983, 2928, 1687, 1672, 1475,

1370, 1164; HRMS calcd for C₂₃H₃₄NO₄INa (MCNa)^C

538.1431, found 538.1417; [a]²_D⁴ZK36.3 (c 0.46, CHCl₃).

3.6.11.3. tert-Butyl (2S)-2-[(1S)-1-hydroxy-1-methoxy-

methyl-4,5-dimethylhex4-enyl]-5-iodoindoline-1-car-

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

2103

3.6.11.6. (K)-Virantmycin (2a). A mixture of 34

Acknowledgements

(21 mg, 0.048 mmol), Pd(OAc)₂(6.1 mg, 0.027 mmol)

and K₂CO₃(27 mg, 0.194 mmol) in 0.5 ml of H₂O and

0.5 ml of methanol was stirred vigorously at room

temperature in 1 atm CO atmosphere for 18 h. After the

addition of water, the organic material was extracted with

AcOEt (5 ml!2). The combined organic extracts were

washed with brine (10 ml), dried over Na₂SO₄and

concentrated. The crude residue was puriﬁed by silica gel

ﬂash chromatography (hexane–AcOEt 9:1 to 1:1) to give

(K)-virantmycin (2a) as a yellow oil (9.0 mg, 53%) along

¯

We thank Prof. Satoshi Omura (Kitasato Institute) for

providing copies of NMR spectra of natural virantmycin.

References and notes

1. (a) Fuji, K. Chem. Rev. 1993, 93, 2037. (b) Corey, E. J.;

Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.

(c) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,

4591.

1

with the recovered 34 (7.1 mg, 34%). H NMR (500 MHz,

CDCl₃) d 1.61 (6H, s), 1.63 (3H, s), 1.61–1.67 (1H, m), 1.81

(1H, dt, JZ4.9, 13.2 Hz), 2.01 (1H, dt, JZ4.9, 12.2 Hz),

2.09 (1H, dt, JZ4.9, 12.2 Hz), 3.12 (1H, dd, JZ5.9,

17.6 Hz), 3.37 (1H, dd, JZ4.9, 17.6 Hz), 3.39 (3H, s), 3.56

(1H, d, JZ8.8 Hz), 3.58 (1H, d, JZ8.8 Hz), 4.37 (1H, t, JZ

5.4 Hz), 4.65 (1H, br s), 6.54 (1H, d, JZ7.8 Hz), 7.76–7.78

(2H, m); ¹³C NMR (125 MHz, CDCl₃) d 18.4, 19.9, 20.6,

27.8, 33.5, 33.6, 56.2, 58.0, 59.4, 74.0, 113.5, 116.0, 117.6,

2. (a) Michael, J. P. Nat. Prod. Rep. 2000, 17, 603. (b) Scott,

J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.

3. Chrzanoeska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,

3341.

4. (a) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am.

Chem. Soc. 2001, 123, 10784. (b) Meyers, A. I.; Gonzalez,

M. A.; Struzka, V.; Akahane, A.; Guiles, J.; Warmus, J. S.

Tetrahedron Lett. 1991, 32, 5501. (c) Bravo, P.; Crucianelli,

M.; Farina, A.; Valdo Meille, S.; Volonterio, A.; Zanda, M.

Eur. J. Org. Chem. 1998, 435. (d) Okamoto, S.; Teng, X.;

Fujii, S.; Takayama, Y.; Sato, F. J. Am. Chem. Soc. 2001, 123,

3462.

124.8, 126.5, 130.4, 132.4, 147.2, 171.6; IR (CHCl₃) cm^K1

:

2926, 1710, 1675, 1609, 1290, 1132, 1111; HRMS calcd for

C₁₉H₂₇NO₃Cl (MCH)^C352.1679, found 352.1668;

[a]²_D⁴ZK16.5 (c 0.11, CHCl₃).

5. (a) Ooi, T.; Takeuchi, M.; Maruoka, K. Synthesis 2001, 11,

1716. (b) Kawabata, T.; Ozturk, O.; Suzuki, H.; Fuji, K.

Synthesis 2003, 4, 505.

3.6.11.7. Determination of the stereochemistry of

major-32. The conﬁgurations of the newly created asym-

metric centers in major-32 was determined after NOE

experiments of the acetonide 38, which was derived from 33

by acetonization with 2,2-dimethoxypropane. As a result,

major-32 has (2S,8R) conﬁguration (Scheme 18).

6. Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704.

7. (a) Kim, W. G.; Kim, J. P.; Kim, C. J.; Lee, K. H.; Yoo, I. D.

J. Antibiot. 1996, 49, 20. (b) Kim, W. G.; Kim, J. P.; Yoo, I. D.

J. Antibiot. 1996, 49, 26.

8. Kim, W. G.; Kim, J. P.; Koshino, H.; Shin-Ya, K.; Seto, H.;

Yoo, I. D. Tetrahedron 1997, 53, 4309.

¯

9. (a) Omura, S.; Nakagawa, A.; Hashimoto, H.; Oiwa, R.; Iwai,

Y.; Hirano, A.; Shibukawa, N.; Kojima, Y. J. Antibiot. 1980,

33, 1395. (b) Nakagawa, A.; Iwai, Y.; Hashimoto, H.;

Miyazaki, N.; Oiwa, R.; Takahashi, Y.; Hirano, A.;

¯

Shibukawa, N.; Kojima, Y.; Omura, S. J. Antiobiot. 1981,

34, 1408.

¯

10. Omura, S.; Nakagawa, A. Tetrahedron Lett. 1981, 22, 2199.

Scheme 18. Reagents and conditions: (a) 2,2-dimethoxypropane, PPTS,

CH₂Cl₂, rt, 64%.

11. (a) Hill, M. L.; Raphael, R. A. Tetrahedron 1990, 46, 4587.

(b) Steinhagen, H.; Corey, E. J. Org. Lett. 1990, 1, 823.

12. (a) Morimoto, Y.; Matsuda, F.; Shirahama, H. Tetrahedron

Lett. 1990, 31, 6031. (b) Morimoto, Y.; Matsuda, F.;

Shirahama, H. Synlett 1991, 201. (c) Morimoto, Y.; Matsuda,

F.; Shirahama, H. Tetrahedron 1996, 52, 10609.

3.6.11.8. (1R,9aS)-7-Iodo-1-methoxymethyl-3,3-di-

methyl-1-(3,4-dimethylpent-3-enyl)-9,9a-dihydro-1H-

[1,3]oxazolo[3,4-a]indole (38). Method for the synthesis of

major-16 was followed using 33 (17 mg, 0.041 mmol) to

give 38 (12 mg, 64%) as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) d 1.09 (1H, dt, JZ4.2, 13.2 Hz), 1.50 (6H, s), 1.55–

1.60 (7H, m), 1.65 (3H, s), 1.94 (1H, dt, JZ4.9, 12.6 Hz),

2.05 (1H, dt, JZ4.2, 12.6 Hz), 3.01 (1H, dd, JZ10.3,

17.4 Hz), 3.07 (1H, dd, JZ4.4, 17.4 Hz), 3.28 (1H, d, JZ

9.8 Hz), 3.38 (3H, s), 3.52 (1H, d, JZ9.8 Hz), 4.33 (1H, dd,

JZ4.4, 10.3 Hz), 6.41 (1H, d, JZ7.8 Hz), 7.27 (1H, d, JZ

7.8 Hz), 7.30 (1H, s); ¹³C NMR (125 MHz, CDCl₃) d 18.3,

19.9, 20.5, 25.8, 28.1, 29.1, 29.1, 31.3, 59.6, 70.1, 76.3,

80.1, 82.2, 94.8, 113.7, 124.1, 127.4, 133.3, 135.0, 135.4,

148.5; IR (CHCl₃) cm^K1: 2928, 2862, 1474, 1258, 1117;

HRMS calcd for C₂₁H₃₁NO₂I (MCH)^C456.1399, found

456.1407; [a]²_D⁴ZC68.4 (c 1.20, CHCl₃).

13. (a) Morimoto, Y.; Oda, K.; Shirahama, H.; Matsumoto, T.;

¯

Omura, S. Chem. Lett. 1988, 909. (b) Morimoto, Y.;

Shirahama, H. Tetrahedron 1996, 52, 10631.

14. Yoo, S. E.; Kim, J. H.; Yi, K. Y. Bull. Kor. Chem. Soc. 1999,

20, 139.

15. Toda, N.; Ori, M.; Takami, K.; Tago, K.; Kogen, H. Org. Lett.

2003, 5, 269.

16. Ori, M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H. Angew.

Chem., Int. Ed. 2003, 42, 2540.

17. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.

18. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;

Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36,

5461.

19. Kaufman, T. S. Synlett 1997, 1377.

20. Ding et al. reported the diastereoselective addition of lithium

2104

M. Ori et al. / Tetrahedron 61 (2005) 2075–2104

ethyl propiolate to 2-acetylpyrrolidine derivative Ni, Y.; Zhao,

G.; Ding, Y.; et al J. Chem. Soc., Perkin Trans. 1 2000, 3264.

29. There is no direct evidence for the formation of aziridine

intermediate 6. A stepwise sequence may be possible

(1. formation of tertiary chloride; 2. intramolecular cyclization

to an aziridine; 3. ring opening by the attack of chloride anion).

However, the tertiary chloride could not be obtained by

treatment of 15a with various chlorinating agents. Addition-

ally, no aziridine compound was obtained by subjecting 15a to

Mitsunobu conditions. For the ring-opening reaction of an

aziridine, such as 6, with chloride anions to provide

tetrahydroquinoline 4, see Ref. 12.

21. De Silva, A. N.; Francis, C. L.; Ward, D. Aust. J. Chem. 1993,

46, 1657.

22. Anh, N. T. Top. Curr. Chem. 1980, 88, 145.

23. Gross, K. M.; Jun, Y. M.; Beak, P. J. Org. Chem., 1997, 62,

7679.

24. DAICEL CHIRALCEL OD (0.46 cm: 25 cm), n-hexane-i-

PrOH (95:5), 1 ml/min.

25. Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem.

1999, 1693.

30. All other products were highly polar materials which were not

isolated.

26. Reaction of a-unsubstituted indoline-2-methanols gave com-

plex mixtures.

31. Very recently, Back and Wulff reported total syntheses of (C)-

and (K)-virantmycin. Back, T. G.; Wulff, J. E. Angew. Chem.,

Int. Ed. 2004, 43, 6493.

27. Harada, N.; Koumura, N.; Robillard, M. Enantiomer 1997, 2,

303.

28. DAICEL CHIRALCEL OJ (0.46 cm:25 cm), n-hexane-i-

PrOH (95:5), 1 ml/min.

Article Doi

Stereospecific synthesis of 2,2,3-trisubstituted tetrahydroquinolines: Application to the total syntheses of benzastatin E and natural virantmycin

DOI: 10.1016/j.tet.2004.12.041

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2004.12.041

Full text of DOI:10.1016/j.tet.2004.12.041

Products guided by the article

R&D Labs maybe for 849480-05-3

Relevant to this article

Hot Product