Enantioselective total synthesis of (-)-strychnine: Development of a highly practical catalytic asymmetric carbon-carbon bond formation and domino cyclization

Tetrahedron 60 (2004) 9569–9588

Enantioselective total synthesis of (K)-strychnine: development of

a highly practical catalytic asymmetric carbon–carbon bond

formation and domino cyclization

*

Takashi Ohshima, Youjun Xu, Ryo Takita and Masakatsu Shibasaki

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Received 15 May 2004; revised 4 June 2004; accepted 7 June 2004

Available online 24 August 2004

Dedicated to Professor Alois Fu¨rstner in recognition of his receipt of the Tetrahedron Chair in Organic Synthesis 2004

Abstract—An enantioselective total synthesis of (K)-strychnine was accomplished through the use of the highly practical catalytic

asymmetric Michael reaction (0.1 mol% of (R)-ALB, greater than kilogram scale, without chromatography, 91% yield and O99% ee), and a

domino cyclization that simultaneously constructed the B- and D- rings of strychnine (O77% yield). Newly-developed reaction conditions

for thionium ion cyclization, NaBH₃CN reduction of the imine moiety in the presence of a Lewis acid to prevent the ring-opening reaction,

and chemoselective reduction of the thioether (desulfurization) in the presence of exocyclic oleﬁn were pivotal to complete the synthesis. The

described chemistry paves the way for the synthesis of more advanced Strychnos alkaloids.

1. Introduction

the high potency of the catalytic asymmetric carbon–carbon

bond formation. Other key reactions to realize enantio-

selective synthesis of strychnine were a novel domino

cyclization promoted by Zn for simultaneous construction

of the B- and D-rings of strychnine, a modiﬁed intra-

molecular alkylation by dimethyl(methylthio)sulfonium

tetraﬂuoroborate (DMTSF) (C-ring formation), a selective

imine reduction by NaBH₃CN with a Lewis acid, and a

chemoselective reduction of thioether in the presence of

exo-oleﬁn.

The use of catalytic asymmetric reactions for the synthesis

of highly enantiomerically enriched chiral compounds is of

growing importance in organic chemistry and in industrial

production in terms of atom economy.¹A number of highly

efﬁcient asymmetric catalyses, such as Rh(I)-catalyzed

hydrogenation of oleﬁns,²Ru(II)-catalyzed hydrogenation

of ketones,³Ti(IV)-catalyzed epoxidation of allylic alco-

hols,⁴Cu-catalyzed cyclopropanation of oleﬁns,⁵and Rh(I)-

catalyzed isomerization of allylic amines,⁶etc. have been

successfully utilized for the syntheses of various complex

natural products and industrial applications. Most catalytic

asymmetric carbon–carbon bond formations, however, are

difﬁcult to produce on a large scale in terms of catalyst

efﬁciency, enantioselectivity, or chemical yield, resulting in

only a few synthetic applications. To address this issue,

intensive efforts have been focused on developing a

practical asymmetric carbon–carbon bond formation^1,7

and only a few manufacturing scale syntheses have been

achieved.⁵Herein, we present the development of a highly

practical catalytic asymmetric Michael reaction⁸and a full

account of its synthetic application to the enantioselective

total synthesis of (K)-strychnine (Fig. 1),^9,10demonstrating

2. Results and discussion

2.1. Retrosynthetic analysis of (K)-strychnine

(K)-Strychnine (1) is the ﬂagship compound of the family

of Strychnos alkaloids and, considering its molecular

Keywords: Enantioselective total synthesis; (K)-Strychnine; Catalytic

asymmetric Michael reaction; Domino cyclization.

* Corresponding author. Tel.: C81-3-5684-0651; fax: C81-3-5684-5206;

e-mail: mshibasa@mol.f.u-tokyo.ac.jp

Figure 1. 2D (left) and 3D (right) structure of (K)-strychnine (1).

doi:10.1016/j.tet.2004.06.141

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T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

weight, is one of the most complex natural products.¹¹Only

24 skeletal atoms are assembled in 7 rings and its structure

contains 6 contiguous asymmetric carbon atoms, 5 of which

are included within 1 saturated 6-membered ring (E-ring).

Strychnine was ﬁrst isolated in 1818 from the Southeast

Asian Strychnos nux-vomica and Strychnos ignatti.¹²

Extensive degradative and structural studies culminated in

the elucidation of strychnine’s structure in 1946.¹³The

relative^14a–dand absolute^14e,fconﬁgurations were later

conﬁrmed by X-ray crystal analyses. Strychnine toxicity

results from a block of postsynaptic inhibition in the spinal

cord and lower brain stem, where it acts as a competitive

ligand at the neuronal glycine receptor.¹⁵This property has

made strychnine very useful as a tool in experimental

pharmacology.

The structural complexity of strychnine coupled with its

biological activity has served as the impetus for numerous

synthetic investigations. The ﬁrst total synthesis, one of the

most signiﬁcant achievements in the history of organic

synthesis, was reported by Woodward in 1954.^16aNearly 40

years after Woodward’s pioneering work, a number of

groups reported the total synthesis,¹⁶and four of which

culminated in an enantioselective synthesis of the natural

enantiomer.^16c,e,g,jAs summarized in Bonjoch’s excellent

review,^11athe major stumbling blocks in the synthesis are

the generation of the spirocenter at C7 and the assembly of

the bridged framework (CDE core ring). In previous

strategies, the C6–C7 bond was generated in the early

stage of synthesis, probably due to difﬁculties generating the

C7 quaternary center; thus, in many cases, the CDE ring

system was assembled in the direction of the C-ring to

D-ring. Although an intramolecular alkylation strategy was

applied for the construction of the C-ring in the synthesis of

structurally simpler indole alkaloids,^17,18this strategy has

not been utilized for the synthesis of strychnine. The reason

for this might be that intramolecular alkylation of

dithioacetal is the only method that affords a cyclic product,

thus desulfurization in the presence of exocyclic oleﬁn is

inevitable. We previously developed a catalytic asymmetric

Michael reaction of malonates to cyclic enones.¹⁹To

effectively utilize the Michael product 5 in our synthesis,

we planned to assemble the CDE ring system from the

D-ring to the C-ring and constructed the C7 spirocenter in

the last stage by intramolecular alkylation. Our ﬁnal

retrosynthetic analysis after several unsatisfactory attempts

(vide infra) is shown in Scheme 1.

Scheme 1. Retrosynthetic analysis of (K)-strychnine (1).

MS4A, accelerating the reaction with a slight improvement

in both chemical yield and enantioselectivity (entry 2).^18a

Although there are several efﬁcient asymmetric catalysts for

the asymmetric Michael reaction,^19–21including the LaNa_3-

tris(binaphthoxide) complex,^19bGaNabis(binaphthoxide)

complex,^19dand La–O-linked-BINOL complex,^19e–gALB

is the most effective catalyst for the present Michael

reaction in terms of catalyst efﬁciency.²²In addition, all

materials in the reaction, including each enantiomer of

BINOL, are inexpensive and commercially available. Even

using the improved procedure, however, 1 mol% of the

catalyst was required to obtain the product in excellent yield

and high enantiomeric excess (entry 2), and 0.3 mol% of the

catalyst required 120 h at room temperature to complete the

reaction (entry 3).^18aTo apply this chemistry to a complex

natural product synthesis as well as a manufacturing scale

synthesis, we attempted to further improve not only catalyst

efﬁciency, such as reducing catalyst loading and reaction

time, but also the work-up procedure, such as eliminating

the need for chromatographic separation. We ﬁrst focused

on acceleration of the reaction at ambient temperature. We

examined the additive effects, solvent effects, and ligand

tuning, and eventually discovered that under highly

concentrated conditions even 0.25 mol% of the catalyst

induced the reaction to proceed very quickly (15 h) without

lowering the chemical yield (95% combined yield for two

successive recrystallizations, vide infra) or high enantio-

meric excess (O99% ee) (entry 4). The catalyst loading was

further reduced. The use of only 0.05 mol% of the catalyst

forced the reaction to completion with a similar chemical

yield (94%) and enantioselectivity (98% ee), although it

required 48 h to complete (entry 8). In addition, a relatively

large-scale reaction (0.5 mol scale) proceeded smoothly

without any difﬁculty (entry 9).⁸

2.2. Catalytic asymmetric Michael reaction

The catalytic asymmetric Michael reaction is an efﬁcient

method for enantioselective carbon–carbon bond for-

mations because of the usefulness of the corresponding

enantiomerically-enriched Michael adducts as an attractive

chiral source.^18–21Therefore, the development of a highly

practical method to synthesize Michael adducts is very

desirable. In 1996, we reported that the multifunctional

asymmetric catalyst, AlLibis(binaphthoxide) complex

(ALB), which was prepared from LiAlH₄and BINOL in a

ratio of 1:2, was highly effective for the catalytic

asymmetric Michael reaction of cyclic enones with

malonates (Table 1, entry 1).^19cLater, this catalyst system

was improved by using additional base (KO-t-Bu) and

We also examined the work-up procedure of the reaction. In

our previous procedure, chromatographic separation was

necessary to obtain a high yield (total 96% yield) after two

successive crystallizations from toluene/hexane (82%

combined yield).^18aMoreover, recovery of BINOL from

the crude mixture using chromatographic separation is not

very easy on a large-scale because of the small difference in

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

Table 1. Catalytic asymmetric Michael reaction promoted by ALB

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Entry

Scale (mol)

ALB (mol%)

Total amount of

THF (mL/mol)

Time (h)

ee (%)^a

Yield (%)^b

ee (%)^c

1^d

2

3

4

5

6

7

8

9

0.001

0.5

10.0

1.0

0.3

0.25

0.20

0.10

0.05

0.10

1690

895

752

51

41

21

10

21

72

120

15

24

10

24

48

24

93

99

O99

98

90

96

94

—

O99

0.002

0.005

0.5

95^e

74^e

92^e

94^e

92^e

98

a

Enantiomeric excess of the crude product determined by HPLC analysis.

Isolated yield.

Enantiomeric excess of the crystal determined by HPLC analysis.

Reaction was performed without the addition of KO-t-Bu or MS4A.

Combined yield of 5 after two successive crystallizations.

b

c

d

e

Figure 2. The improved work-up procedure of the catalytic asymmetric Michael reaction promoted by ALB.

polarity between BINOL and the product 5. The new

improved procedure (Fig. 2) was streamlined by eliminating

the need for chromatographic separation to obtain the

product 5 in reasonable yield (O90%) in an optically and

chemically pure manner. After an ordinary quenching

procedure, the organic layer was half concentrated and

treated with hexane with maintenance of the solvent ratio

(EtOAc–hexane, 1:4) to afford a pure Michael adduct 5 as a

white crystal in more than 90% yield. After concentration of

the mother liquor followed by one successive recrystalliza-

tion from EtOAc–hexane (1:4), the combined yield was up

to 95% (Table 1, entries 4 and 5, 1st: 93%, 2nd: 2%). In

addition, BINOL was recovered from the mother liquor in

approximately 80% yield by subsequent fractional extrac-

tion (See Section 4).

Having achieved a highly practical catalytic asymmetric

synthesis of the Michael adduct 5, we next performed pre-

manufacturing scale (greater than kilogram scale) synthesis

(Scheme 2). From an industrial point of view, we used

Scheme 2. Catalytic asymmetric Michael reaction promoted by ALB on a greater than kilogram scale.

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T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

0.1 mol% of the catalyst to complete the reaction in 24 h at

ambient temperature. 2-Cyclohexen-1-one (6) (581 mL, 6.0

mol) was added to a suspension of dried MS4A (150 g),

dimethyl malonate (7) (686 mL, 6.0 mol), 0.1 mol% of

(R)-ALB in THF (containing only 3.4 g of BINOL), and

0.09 mol% of KO-t-Bu in THF at 4 8C (ice-water bath).

Because there was a signiﬁcant increase in the reaction

temperature (O30 8C) without cooling, the reaction tem-

perature was maintained at ca. 4 8C using an ice-water

bath for 2 h. After additional stirring at ambient temperature

(20–25 8C) for 22 h, 1.24 kg of the desired product 5 was

obtained as a white crystal in 91% combined yield following

three successive crystallizations (1st: 76%, 2nd, 11%, 3rd:

4%). HPLC analysis revealed that the enantiomeric excess

of the crude product and the crystal was 98% and greater

than 99%, respectively. The purity of the crystal was

estimated to be greater than 99% on the basis of elemental

Z-product. These ﬁndings suggested the possibility of

selective synthesis of the anti-aldol product and subsequent

syn-elimination to obtain the E-product.

Because of the difﬁcult selective preparation of the anti-

aldol product 9 by an aldol reaction of 8, we synthesized

the anti-aldol product using anti-selective reduction of

the b-keto ester 12, which was prepared by alkylation of 8

using a Weinreb amide 11 in 72% yield (conversion 82%)

(Table 2). Examination of several reduction conditions

indicated that anti-selective reduction of b-keto ester 12 by

NaBH₃CN with TiCl₄at K78 8C and subsequent syn-

elimination by DCC-CuCl under neutral conditions, as

reported by Overman,^16cgave the best result (61% for 2

steps, E/ZZ5.7:1). In this case, yield and selectivity of the

reduction were highly dependent on the reaction tempera-

ture. An internal temperature of K55 8C was best in terms

of both yield and selectivity, which reached 72% (conver-

sion 79%) and 15.7:1, respectively (entry 4). The anti-

selective reduction should proceed through an unusual

7-membered chelate conformation, proposed by

Overman.^16c

1

analysis and H and ¹³C NMR spectra. To the best of our

knowledge, the described method is one of the most

practical and efﬁcient catalytic asymmetric carbon–carbon

bond forming reactions with great enantioselectivity.²³This

greater than kilogram scale reaction can be performed with a

conventional 2 L ﬂask because of the very high concen-

tration of the reaction.⁸

2.4. Transformation to the key intermediate for

construction of the BCDE-ring system of strychnine

2.3. Stereoselective elaboration of the hydroxyethylidene

substituent

DIBAL reduction of 10a (inseparable mixture of E- and

Z-isomers, E/ZZ15.7:1) followed by silylation of the

primary alcohol with TIPSOTf and conversion of the acetal

to ketone afforded, after silica gel chromatography, pure

(E)-14 (Scheme 4). Regioselective enol silyl ether formation

was facilitated by the action of a sterically bulky base:

lithium 2,2,6,6-tetramethylpiperidide to form the corre-

sponding enol silyl ether regioselectively (15:16ZO6:1). A

subsequent Saegusa–Ito reaction²⁵under conventional

stoichiometric conditions (1.2 equiv of Pd(OAc)₂) provided

the enone in 79% yield as an inseparable mixture of

regioisomers (17:18ZO6:1).

With large quantities of pure (C)-5 in hand, we focused on

the transformation of 5 to the key intermediate 4 for the

synthesis of strychnine (Scheme 1). Our ﬁrst step was

the introduction of the hydroxyethylidene substituent in an

E-selective manner. We initially investigated the synthesis

of 10 through a syn-selective aldol reaction and subsequent

anti-elimination of the corresponding mesylate under basic

conditions as in our previous synthesis of (K)-tubifolidine

and (K)-19,20-dihydroakuammicine (Scheme 3).^18,24Syn-

selectivity of the aldol reaction, however, was moderate (up

to 4:1), and there was a decrease in stereoselectivity due to

the rapid epimerization at the a-position of the ester during

the elimination under basic conditions. Epimerization did

not proceed during syn-elimination under neutral conditions

(DCC, CuCl), although the major product was the undesired

Large-scale synthesis, however, required a catalytic process

for this reaction.²⁶Tsuji et al. established a catalytic

Saegusa–Ito reaction using allyl carbonate as an oxidant, in

which a catalytic amount of Pd(OAc)₂, with or without a

Scheme 3. Initial attempts to elaborate the hydroxyethylidene substituent in an E-selective manner.

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

Table 2. Temperature effects on anti-selective reduction of 12

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Entry

Temperature (8C)^a

Yield (%)^b

Yield (%)^c

E/Z^d

1

2

3

4

5

6

K78

K65

K60

K55

K50

K45

61

73

71

72

58

67

91

79

81

79

62

—

5.7:1

9.1:1

11.5:1

15.7:1

11.3:1

10.2:1

a

Internal temperature of the reaction.

b

c

d

Isolated yield of 10a a mixture of E and Z-isomers.

Conversion yield of 10a based on the recovery of 12.

E/Z ratio of 10a determined by ¹H NMR analysis.

phosphine ligand, usually gave successful results.²⁷

Unfortunately, in our system, both conditions gave

unsatisfactory results (Table 3, entry 1 and 3). Finally,

this stoichiometric process evolved into a catalytic process

by using Pd₂(dba)₃$CHCl₃instead of Pd(II) in the absence

of a phosphine ligand in superb yield (90% for 2 steps,

conversion 99%) without any loss of selectivity. Under

these conditions, DBA might act as a weak ligand to prevent

decomposition of the Pd(0) species.

5).^28,29To introduce the A-ring moiety, we selected a Stille

coupling reaction based on its mild reaction conditions as

compared with other Pd-catalyzed coupling reactions.³⁰

Although extremely poor results (!5%) were obtained

using several combinations of Pd sources and ligands, a

catalytic amount of CuI dramatically accelerated the

reaction to afford 21 in quantitative yield. Finally, removal

of the TIPS group using a very mild desilylation reagent,

3HF$Et₃N,³¹provided 22 in excellent yield (quant).³²

Using an inseparable mixture of 17 and 18, a-iodination of

enone 17 was successfully promoted by DMAP (89%)

instead of commonly used pyridine (half conversion), and

undesired isomer 18 remained unchanged, making it

possible to easily separate the regioisomers because of the

large difference in polarity between 19 and 18 (Scheme

2.5. Examination of D-ring formation (1): simple

1,4-addition of amine to enone

We then focused on construction of the BCDE-ring system.

Initially, we examined a 1,4-addition of the secondary

amine to the enone after introduction of the amine moiety at

Scheme 4. Regioselective enone formation using a stoichiometric amount of Pd.

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T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

Table 3. Regioselective enone formation using a catalytic amount of Pd with diallyl carbonate

Entry

Pd catalyst

Ligand^a

Yield (%)^b

17:18^c

1

Pd(OAc)₂

Pd₂(dba)₃$CHCl₃

DPPE

—

Trace

46

19

—

2^d

3

2.9:1

O6:1

4

—

90

a

10 mol% of ligand was used.

b

c

d

Isolated yield as an inseparable mixture of 17 and 18.

Ratio of 17 and 18 determined by ¹H NMR analysis.

Reaction was performed under reﬂux conditions.

C21 of 22 for D-ring formation (Scheme 6). This approach,

however, was very difﬁcult to utilize for the present

synthesis. Amination via an allylic mesylate intermediate³³

provided an equilibrium mixture of the open form 23 and

the cyclic form 24, which was too unstable to isolate and be

used for the next C-ring formation (24/25) because of the

rapid retro reaction (24/23). To prevent the retro reaction,

we examined a domino cyclization³⁴(D- and C-ring

formation) by introducing the leaving group on the amine

side-chain (e.g. XZCH₂Br or CO₂Me) and another

sequential cyclization (e.g. XZCH(OMe)₂or CH(SEt)₂),

however, all attempts were unsatisfactory (very low yield

and low reproducibility). In contrast, in the case of an

aniline analogue 26, which was prepared from 19 using

[2-(benzyloxycarbonylamino)phenyl]trimethylstannane for

the Stille coupling reaction instead of 20, even the hydroxyl

group cyclized easily to afford stable cyclic ether 27.³⁵

Although the reason for the dramatic difference in stability

Scheme 5. a-Iodination and Stille coupling reaction.

Scheme 6. Examination of D-ring formation by 1,4-addition of amine to enone.

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

9575

Scheme 7. Examination of D-ring formation by oxidative cyclization after indole formation.

between 24 and 27 is not clear, the instability of 27 is

probably caused by the nitro group on the A-ring.³⁶

2.7. Examination of D-ring formation (3): domino

cyclization constructing B- and D-rings

The above-mentioned unsuccessful trials prompted us to

consider the feasibility of domino cyclization using 38

(Scheme 9).³⁷After introduction of the amine moiety via

allylic triﬂate 37, the crude 38, which existed as an

equilibrium mixture of the open and cyclic forms as

shown in Scheme 6, was simply treated with Zn in MeOH

and aq NH₄Cl to provide the desired tetracyclic compound

39 in 80% yield. This domino cyclization might proceed by

the following sequence: (1) reduction of the nitro group to

amine by Zn (38/40), (2) indole formation (40/41),

and (3) 1,4-addition of the secondary amine (41/39)

(see Scheme 8) or (1) reduction of the nitro group to amine

by Zn (38/40), (2) 1,4-addition of the secondary amine

(40/42), and (3) irreversible indole formation of the

aniline moiety with the resulting ketone (42/39) (see

Scheme 6). Remarkably, the present process made it

possible to skip more than 8 steps in the synthesis as

compared with the step-wise route shown in Scheme 7.

2.6. Examination of D-ring formation (2): oxidative

cyclization after indole formation

We assembled the ABDE-ring system using a conventional

stepwise process, including a one-pot oxidative cyclization

(32/33) that we previously developed (Scheme 7).¹⁸This

process required 11 steps, however, even using a model

compound, which did not have one carbon unit at C16.

In addition, we were unable to synthesize a dithioacetal

derivative instead of dimethoxyacetal using this strategy

(vide infra).

When enone 34 was used for the indole formation instead of

ketone 28, cyclized product 35 easily underwent aromatiza-

tion to afford 36 (Scheme 8). This result suggested that if an

appropriate nucleophile existed in the reaction, it might

proceed to a 1,4-addition to the unstable, very reactive

iminium cation intermediate 35.

Scheme 8. Indole formation using enone 34.

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T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

Scheme 9. Construction of B- and D-rings by domino cyclization promoted by Zn.

2.8. Introduction of the C1 unit at the C16 position and

further transformation

aromatization of the corresponding cyclic b-keto ester and

elimination of the corresponding b-hydroxyketone to the

enone occurred. Instead, the mild aldol reaction of enol silyl

ether in aqueous formaldehyde developed by Kobayashi et

al.³⁸was effective for the formation of 43 (C16a/C16bZ

3.5:1) (Scheme 10).³⁹Both diastereomers were expected to

be applicable to the synthesis because the C16 stereocenter

Because of difﬁculty introducing one carbon unit at C16

after the indole formation, we next attempted methoxy-

carbonylation and hydroxymethylation prior to the above-

mentioned domino cyclization. In most cases, however,

Scheme 10. Hydroxymethylation at C16 and transformation to the key intermediate 4.

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

9577

can be epimerized in the last stage,¹⁶whereas using 43b

desired product 45b was not obtained and unexpected

aromatization proceeded in the next iodination step with

C16 epimers 43a and 45a. Thus, 43b was converted to

the thermodynamically more stable 43a by treatment with

DBU prior to the iodination (57% from the mixture of

regioisomers 17 and 18, conversion 80%). Subsequent

a-iodination of 43a with DMAP (89%) and the Stille

coupling reaction in the presence of CuI (quant.) effectively

produced 46. Finally, protection of the primary alcohol with

SEMCl and removal of the TIPS group provided the key

intermediate 4 in excellent yield (quant. for 2 steps).

results.^16–18Reductions of imine in similar indole alkaloids

under neutral conditions, or in the presence of weak acids,

often result in the cleavage of the C3–C7 bond. For

example, under neutral conditions (NaBH₄in MeOH) the

ring-opening reaction proceeded through 48, and was

superior to the imine reduction, resulting in 49 (60%)

without formation of 2 (Scheme 12). Other neutral reduction

conditions, such as LiAlH₄, DIBAL, and H₂/cat.

[Rh(nbd)(dppe)]^CBF₄^K, were also unsuccessful. Acidic

conditions, such as NaBH₃CN in AcOH^16eand Zn in 10%

H₂SO₄in MeOH reﬂux,^16b,cconsistently solved this

problem to give the desired related indole product. The

reported conditions improved selectivity to afford the

desired indole 2. Under acidic conditions, however,

signiﬁcant decomposition of 47 proceeded through elimi-

nation of the ‘SEMO’ moiety (47/51). For example,

treatment of 47 with AcOH at 4 8C for 30 min without

reductant provided 51 in ca. 80% yield. Yield and/or

reproducibility were not acceptable even after optimization,

probably due to the instability of 47 against Brønsted acid.

2.9. C-ring formation

Domino cyclization using 4 after introduction of the amine

moiety via allylic triﬂate also proceeded very efﬁciently to

afford tetracyclic indole compound 3 in 77% yield (Scheme

11). Our next goal was to construct the C-ring by connecting

the C6–C7 bond. We initially attempted to employ C-ring

formation using b-haloamine, b-sulfonyloxyamine,

b,b-dialkoxyamine, a-aminoaldehyde, and a-aminoester

derivatives instead of b,b-bis(ethylthio)amine to avoid

problematic desulfurization in the later stage. All trials

failed (very low yield), however, probably due to the

difﬁculty of selective activation of an electrophile in the

presence of an indole moiety.⁴⁰We then examined

the intramolecular electrophilic attack of a thionium ion to

generate a C7 spirocenter. C-ring formation using a variety

of silver salts,^17chypervalent iodine, and DMTSF,^17a,b,18,41

however, provided unsatisfactory results: no reaction,

decomposition, low yield (!20%), respectively. With

DMTSF, aldehyde was generated, an unknown dimmer

was formed, and over reaction of the desired product 47

occured. To prevent such side reactions and optimize this

reaction, we examined the additive, reaction temperature,

concentration, etc., and succeeded in improving the yield

(up to 86%) under the following conditions: DMTSF

(5 equiv), activated MS4A, CH₂Cl₂(0.005 M), room

temperature, and direct puriﬁcation by silica gel chroma-

tography without an aqueous work-up and concentration

before puriﬁcation.⁴²

After testing numerous neutral or acidic conditions, we

discovered a workable new method. To prevent an

undesired ring-opening reaction (47/49) and elimination

(47/51), we examined the addition of a Lewis acid to the

reaction at low temperature. At this point, we expected that

the Lewis acid would coordinate to not only the imine but

also to the tertiary amine more strongly; thus, the former

coordination would accelerate imine reduction (even under

very low temperature) and the latter coordination would

effectively prevent ring-opening reaction. Indeed, treatment

with 5 equiv of TiCl₄at K78 8C before the addition of

NaCH₃CN effectively prevented the ring-opening reaction

and, as a result, 2 was obtained in 68% yield with ca. 6% of

49 with high reproducibility (Scheme 13).⁴³

2.11. Chemoselective reduction of thioether

(desulfurization) in the presence of exo-oleﬁn

The stage was now set for the completion of the synthesis.

The last major hurdle involved chemoselective reduction of

thioether (desulfurization)⁴⁴in the presence of exo-oleﬁn. A

Raney Ni (W-2) reduction was the ﬁrst choice for this

purpose. Even deactivated Raney Ni in acetone, however,

promoted considerable migration of exo-oleﬁn to endo-

oleﬁn to afford 54 (Scheme 14).^45,46To prevent undesired

oleﬁn migration, new deactivation methods were further

2.10. Reduction of imine to amine

Reduction of the imine 47 to amine 2, in turn, was more

problematic than we expected based on previous successful

Scheme 11. Domino cyclization of 4 and C-ring formation using DMTSF under optimized conditions (construction of BCDE-ring system).

9578

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

Scheme 12. Reduction of imine moiety on 47 under neutral and acidic conditions.

examined. The addition of a newly designed allyl amine

mimic, N-allylpiperidine (57), effectively improved the

selectivity. For example, a relatively reactive C–S bond

(allylic thio ether) in 49 was efﬁciently cleaved in 82% yield

with high selectivity (O20:1), while, without the additive,

the migration was the major process. This additive also

slightly improved the desulfurization of 2 and 58 (!1:10 to

1:5). Fortunately, the selectivity was further improved to ca.

1:1 by changing the protecting group of the allylic alcohol

from PMB to TIPS, which can shield the exo-oleﬁn moiety.

Raney Ni, however, has several drawbacks, such as its

pyrophoric nature, loss of activity on storage, and difﬁculty

in determining the amount of Ni used. In light of the low

selectivity and low reproducibility, we examined alternative

desulfurization methods. Toward this end, Bu₃SnH-AIBN,

lithium naphthalide, NiCRA, and a combination of a

transition metal with aluminum hydride or borohydride

species were tested.⁴⁴Ni Boride⁴⁷emerged as a promising

candidate. The conventional protocol caused another side

reaction: over reduction instead of migration.⁴⁸By changing

the solvent (EtOH–MeOHZ4:1) and addition order (simul-

taneous addition of EtOH and MeOH to a mixture of NaBH₄

and NiCl₂), however, the desired product 62 was obtained in

91% yield based on consumed starting material with high

selectivity (O10:1). A pre-mixed 4:1 mixture of EtOH and

MeOH caused more over-reduction (62:64Z3.6:1). After

repeating this process twice (total three times), the isolated

yield reached 61% as an inseparable mixture of 62 and its

19,20-dihydro derivative 64 (O10:1).

2.12. Completion of the total synthesis of (K)-strychnine

Consecutive SO₃$Py oxidation of the primary alcohol and

removal of the TIPS group afforded (C)-diaboline (65)^49,50

([a]_DC39.5, lit. [a]_DC27.8) through epimerization of the

C16 stereocenter (Scheme 15). Finally, removal of the

acetyl group provided the crude Wieland–Gumlich alde-

hyde (66), which was converted to (K)-strychnine (1)^16,50

([a]_DK136, lit. [a]_DK139) by the established method.¹⁶

3. Conclusion

An enantioselective total synthesis of (K)-strychnine was

achieved through the use of the highly practical catalytic

asymmetric Michael reaction as well as a domino

Scheme 13. Reduction of the imine moiety on 47 in the presence of Lewis acid.

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

9579

Scheme 14. Chemoselective reduction of thioether (desulfurization) in the presence of exo-oleﬁn.

cyclization that simultaneously construct the B- and D-rings.

Moreover, newly-developed reaction conditions for the

4. Experimental

thionium ion cyclization, reduction of the imine moiety, and

desulfurization were pivotal to complete the synthesis. The

described chemistry paves the way for the synthesis of more

advanced Strychnos alkaloids, especially those with further

functionalities on the A- and C-rings, for chemical biology

studies.

4.1. General

All reactions were carried out under an argon atmosphere

with dry solvents, unless otherwise stated. Reagents were

puriﬁed by the usual methods. Reactions were monitored by

thin-layer chromatography carried out on 0.25 mm Merck

silica gel plates (60F-254). Column chromatography was

performed with silica gel Merck 60 (230–400 mesh ASTM)

or activated alumina (Wako, 300 mesh). Infrared (IR)

spectra were recorded on a JASCO FT/IR 410 Fourier

transform infrared spectrophotometer. NMR spectra were

recorded on a JEOL JNM-LA500 spectrometer, operating at

500 MHz for H NMR and 125.65 MHz for ¹³C NMR and

1

calibrated using residual undeuterated solvent as an internal

reference. Optical rotations were measured on a JASCO

P-1010 polarimeter. ESI mass spectra were measured on a

Finnigan LCQ ion trap mass spectrometer (Finnigan MAT,

San Jose, CA, USA) coupled with an electrospray ionization

source (for MS-MS) or a Waters micromass ZQ with Waters

2695 Separation Module (for LC-MS). Experiments were

performed in positive ion mode. HR-MS spectra were

measured on a quadruple time-of-ﬂight (Q-TOF) mass

spectrometer (ABI, USA) equipped with a TurboIonSpray

interface operated in positive ion mode. Calibration

Scheme 15. Completion of the total synthesis of (K)-strychnine (1) via

(C)-diaboline (65) and (K)-Wieland–Gumlich aldehyde (66).

9580

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

calculations were automatically performed by the instru-

found: C, 57.90; H, 7.12; [a]²_D⁸C3.75 (c 2.28, CHCl₃)

(O99% ee); mp 54.5–55.5 8C.

1

mental software (Bruker Xacq). All H and ¹³C NMR data

for the new compounds were assigned by DEPT, COSY and

HMQC experiments. ¹H, ¹³C and DEPT NMR spectra were

attached to the Supporting Information of Ref. 9. The

numbering system based on the biogenetic interrelationship

4.1.2. Synthesis of methyl (R)-1,4-dioxaspiro[4.5]decane-

7-acetate (8). TsOH$H₂O (5.70 g, 30 mmol, 30 mol%) was

added to a solution of 5 (228 g, 1.00 mol) in 2,2-ethylene-

dioxybutane (267 g, 2.3 mol, 2.3 equiv) at rt. After stirring

for 16 h at the same temperature, the reaction mixture was

quenched by the addition of saturated NaHCO₃aqueous

solution and extracted with CH₂Cl₂(three times). The

combined organic layers were washed with brine, dried over

Na₂SO₄, and concentrated to afford crude acetal, which was

used for the next step without further puriﬁcation. The

residue was dissolved in DMSO (500 mL, 2.0 M) and water

(19.8 mL, 1.10 mol, 1.1 equiv.), and then LiCl (89 g,

2.1 mol, 2.1 equiv) was added. The reaction mixture was

stirred for 17 h at 140 8C, cooled to rt, quenched by the

addition of water, and extracted with EtOAc (twice). The

combined organic layers were washed with 1 N HCl

aqueous solution, saturated NaHCO₃aqueous solution and

brine, dried over Na₂SO₄, and concentrated. The residue

was puriﬁed by ﬂash column chromatography (silica gel,

10% EtOAc in hexane) to afford 8 (208 g, two steps 97%) as

a colorless oil: R_fZ0.54 (silica gel, EtOAc–hexane, 1:1);

[a]²_D⁴C3.34 (c 1.1, CHCl₃); FT-IR (neat) n_max2939, 1738,

1

of indole alkaloids is used for assignment of H and ¹³C

NMR.¹⁰

4.1.1. Catalytic asymmetric Michael reaction on a

greater than kilogram scale: synthesis of (R)-3-[bis(meth-

oxycarbonyl)methyl]cyclohexanone (5). A dried 2 L

round-bottomed ﬂask containing dried powdered MS4A

(150 g) was purged with argon and cooled to 4 8C in an ice-

water bath. Dimethyl malonate (7) (686 mL, 6.0 mol),

0.1 M THF solution of (R)-ALB^8,18,19c(60 mL, 0.1 mol%),

and 0.086 M THF solution of KO-t-Bu (63 mL, 0.09 mol%)

were successively added to the ﬂask. Finally, 2-cyclo-

hexenone (6) (581 mL, 6.0 mol) was slowly added to the

mixture within 30 min. After stirring for 90 min, the ice-

water bath was removed and the reaction mixture was

allowed to warm to room temperature and stirred for 22 h.

At this point, the desired Michael adduct 5 precipitated out

as a white solid. The precipitate was dissolved with EtOAc

(1 L) and the resulting suspension was ﬁltered through a

Celite pad eluting with EtOAc (3!200 mL) to remove

MS4A. The combined organic layers were washed with 1 N

HCl (2!200 mL), saturated aqueous NaHCO₃solution

(200 mL), and brine (2!200 mL). The organic extract was

dried over Na₂SO₄and concentrated to ca. 2 L, containing

ca. 700 mL of EtOAc, under reduced pressure. The

enantiomeric excess of the crude product was determined

to be 98% ee after puriﬁcation of an analytical amount (ca.

20 mg) of the crude product by silica gel column

chromatography (acetone–hexane, 1:9). Hexane (3 L) was

added to the residue with vigorous stirring to afford 5 (1st:

1036 g) as a white crystal. The mother liquor was

concentrated and crystallized from EtOAc–hexane (1:4) to

afford 5 (2nd: 154 g). After one additional crystallization

(3rd: 53 g), the combined yield reached 91%. The

enantiomeric excess of each crystal was determined to be

greater than 99% ee [DAICEL CHIRALPAK AS, hexane/

2-propanol (87.5:12.5, v/v), ﬂow rate: 0.5 mL/min, retention

time: 47 min (R)-isomer and 67 min (S)-isomer, detected at

210 nm]. In addition, (R)-BINOL was recovered from the

mother liquor as follows. After separation of the product 5

by three successive crystallizations, the mother liquor was

concentrated under reduced pressure, and the residue was

dissolved with toluene (200 mL) and extracted with 1 N

NaOH (2!150 mL). The combined aqueous layers were

acidiﬁed to pH 3 with 1 N HCl and extracted with EtOAc

(2!200 mL). The combined organic layers were washed

with saturated aqueous NaHCO₃solution and brine, dried

over Na₂SO₄, and concentrated under reduced pressure to

afford BINOL (2.73 g, ca.79%) as a pale yellow solid. The

enantiomeric excess of the recovered BINOL was deter-

mined to be greater than 99% ee [DAICEL CHIRALPAK

AD, hexane/2-propanol (90:10, v/v), ﬂow rate: 0.75 mL/

min, retention time: 24 min (R)-isomer and 28 min

(S)-isomer, detected at 254 nm]. The spectral data and

analytical data of 5 were in agreement with those previously

reported.^19cAnal. calcd for C₁₁H₁₆O₅: C, 57.88; H, 7.07;

1

1436, 1355, 1286, 1172, 1095 cm^K1; H NMR (500 MHz,

CDCl₃) d 3.94 (s, 4H; OCH₂CH₂O), 3.66 (s, 3H; CO₂CH₃),

2.23 (d, JZ7.5 Hz, 2H; H-20), 2.14–2.05 (m, 1H; H-15),

1.78 (br-d, JZ12.5 Hz, 1H; H-16a), 1.75–1.68 (m, 3H;

H-3b, H-7a, H-14a), 1.59–1.50 (m, 1H; H-3a), 1.42 (td, JZ

13.5, 3.5 Hz, 1H; H-7b), 1.23 (t, JZ12.5 Hz, 1H; H-16b)

0.98–0.90 (m, 1H; H-14b); ¹³C NMR (125 MHz, CDCl₃)

d 172.9 (C-21), 108.8 (C-2), 64.2 (OCH₂CH₂O), 64.1

(OCH₂CH₂O), 51.4 (CO₂CH₃), 41.13 (C-20), 41.06 (C-16),

34.6 (C-7), 32.6 (C-15), 31.4 (C-14), 22.8 (C-3); MS (ESI

(C)) m/z 215 (MCH^C). Anal. calcd for C₁₁H₁₈O₄: C 61.66,

H 8.47; found C 64.41, H 8.40.

4.1.3. Synthesis of methyl (7R)-a-[[(4-methoxyphenyl)-

methoxy]acetyl]-1,4-dioxaspiro[4.5]decane-7-acetate

(12). A 1.57 N hexane solution of BuLi (64.8 mL,

102 mmol, 1.2 equiv) was added to a solution of diiso-

propylamine (14.4 mL, 110 mmol, 1.3 equiv) in THF

(112 mL) at K78 8C. After stirring for 1 h at the same

temperature, a solution of 8 (18.16 g, 84.8 mmol), which

was azeotroped with toluene prior to being used, in THF

(50 mL) was added dropwise to the mixture via cannula.

After stirring for 1 h at the same temperature, a solution of

N-methoxy-2-(4-methoxybenzyloxy)-N-methylacetamide

(11)⁵¹(24.3 g, 102 mmol, 1.2 equiv), which was azeotroped

with toluene prior to being used, in THF (50 mL) was added

dropwise to the mixture via cannula. After stirring for

additional 18 h at the same temperature, the reaction

mixture was quenched by the addition of saturated NH₄Cl

aqueous solution and extracted with EtOAc (twice). The

combined organic layers were washed with brine, dried over

Na₂SO₄, and concentrated. The residue was puriﬁed by ﬂash

column chromatography (silica gel, 10 to 50% EtOAc in

hexane) to afford ca. 1:1 diastereomixture of b-keto esters

12 (18.4 g, 72%, conv. 82%) as a colorless oil with recovery

of 8 (1.65 g, 12%) and 11 (5.76 g): R_fZ0.46 (silica gel,

EtOAc–hexane, 1:1); [a]²_D⁴K9.6 (c 1.5, CHCl₃); FT-IR

(neat) n_max2947, 2880, 1723, 1612, 1514, 1435, 1249, 1172,

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

9581

1

1092, 1032 cm^K1; H NMR (500 MHz, CDCl₃) d 7.26 (d,

(C-16), 36.1 (C-15), 34.4 (C-7), 29.0 (C-14), 23.4 (C-3);

MS (ESI (C)) m/z 394 (MCNH^C₄), 377 (MCH^C). Anal.

calcd for C₂₁H₂₈O₆: C 67.00, H 7.50; found C 66.73, H 7.37.

JZ8.5 Hz, 2H; Ar), 6.88 (d, JZ8.5 Hz, 2H; Ar), 4.50 (s,

2H; ArCH₂O), 4.10 and 4.09 (s, 2H; H-18), 4.00–3.85 (m,

4H; OCH₂CH₂O), 3.81 (s, 3H; ArOCH₃), 3.66 (s, 3H;

CO₂CH₃), 3.54 and 3.53 (d, JZ8.5, 8.0 Hz, respectively,

1H; H-20), 2.50–2.43 (m, 1H; H-15), 1.77–1.53 (m, 5H;

H-3a, H-3b, H-7a, H-14a, H-16a), 1.47–1.40 (m, 1H;

H-7b), 1.32–1.23 (m, 1H; H-16b), 1.05–0.93 (m, 1H;

H-14b); ¹³C NMR (125 MHz, CDCl₃) d 202.7 and 202.5

(C-19), 168.7 and 168.6 (C-21), 159.4 (Ar), 129.5 (Ar, 2 C),

128.9 (Ar), 113.8 (Ar, 2 C), 108.5 and 108.4 (C-2), 74.41

and 74.39 (C-18), 72.91 and 72.89 (ArCH₂O), 64.16

(OCH₂CH₂O), 64.14 (OCH₂CH₂O), 60.6 and 59.9 (C-20),

55.2 (ArOCH₃), 52.09 and 52.08 (CO₂CH₃), 38.8 and 38.4

(C-16), 34.8 and 34.6 (C-15), 34.60 and 34.57 (C-7), 29.4

and 28.8 (C-14), 22.7 and 22.4 (C-3); MS (ESI (C)) m/z 807

(2MCNa^C), 415 (MCNa^C), 410 (MCNH^C₄). Anal. calcd

for C₂₁H₂₈O₇: C 64.27, H 7.19; found C 63.98, H 7.39.

4.1.5. Synthesis of [[(2E)-2-(7R)-1,4-dioxaspiro[4.5]dec-

7-yl-4-[(4-methoxyphenyl)methoxy]-2-butenyl]oxy]tris-

(1-methylethyl)silane (13). A 1.0 M hexane solution of

DIBAL (24.0 mL, 24 mmol, 3.0 equiv) was added to a

solution of 10a (3.01 g, 7.98 mmol, E/Z mixture O15:1) in

CH₂Cl₂(56 mL, 0.14 M) at K78 8C. After stirring for 1 h at

the same temperature, the reaction mixture was quenched by

the addition of saturated NH₄Cl aqueous solution, followed

by 1 N HCl aqueous solution, extracted with CH₂Cl₂, dried

over Na₂SO₄, and concentrated to afford allyl alcohol,

which was used for the next step without further puriﬁ-

cation. The residue was dissolved with CH₂Cl₂(27 mL,

0.3 M), and then triethylamine (2.08 mL, 12.0 mmol,

1.5 equiv) and TIPSOTf (2.36 mL, 8.78 mmol, 1.1 equiv)

were added at K78 8C. After stirring for 10 min at the same

temperature, the reaction mixture was quenched by the

addition of saturated NH₄Cl aqueous solution, extracted

with CH₂Cl₂, dried over Na₂SO₄, and concentrated. The

residue was puriﬁed by ﬂash column chromatography (silica

gel, 10% EtOAc in hexane) to afford TIPS ether 13 (3.93 g,

two steps 98%, E/Z mixture O15:1) as a colorless oil: R_fZ

0.54 (silica gel, EtOAc–hexane, 1:3); [a]²_D²C14.3 (c 0.8,

CHCl₃); FT-IR (neat) n_max2942, 2865, 1613, 1513, 1463,

1245, 1085 cm^K1; For (E)-isomer: ¹H NMR (500 MHz,

CDCl₃) d 7.27 (d, JZ8.5 Hz, 2H; Ar), 6.87 (d, JZ8.5 Hz,

2H; Ar), 5.74–5.67 (m, 1H; H-19), 4.44 (s, 2H; ArCH₂O),

4.22–4.11 (m, 4H; H-18; H-21), 3.93–3.87 (m, 4H, OCH_2-

CH₂O), 3.80 (s, 3H; ArOCH₃), 2.76–2.68 (m, 1H; H-15),

1.77–1.70 (m, 2H; H-3b, H-7a), 1.65–1.60 (m, 2H; H-16),

1.58–1.32 (m, 4H; H-3a, H-7b, H-14a, H-14b), 1.20–1.02

(m, 21H; TIPS); ¹³C NMR (125 MHz, CDCl₃) d 159.1 (Ar),

144.5 (C-20), 130.7 (Ar), 129.3 (Ar, 2 C), 120.9 (C-19), 113.7

(Ar, 2 C), 109.0 (C-2), 71.6 (ArCH₂O), 65.6 (C-18), 64.3

(OCH₂CH₂O), 64.1 (OCH₂CH₂O), 64.0 (C-21), 55.3

(ArOCH₃), 39.4 (C-16), 36.2 (C-15), 34.7 (C-7), 30.0 (C-

14), 23.5 (C-3), 18.1 (SiCH(CH₃)₂, 6 C), 12.0 (SiCH(CH₃)₂,

3 C); MS (ESI (C)) m/z 522 (MCNH^C₄). Anal. calcd for

C₂₉H₄₈O₅Si: C 69.00, H 9.58; found C 68.86, H 9.56.

4.1.4. Synthesisofmethyl(aE,7R)-a-[2-[(4-methoxyphenyl)-

methoxy]ethylidene]-1,4-dioxaspiro[4.5]decane-7-acetate

(10a) by anti-selective reduction and following syn-

elimination. A 2.5 M CH₂Cl₂solution of TiCl₄(35.6 mL,

89.0 mmol, 2.0 equiv) was added to a white suspension of

NaBH₃CN (10.2 g, 162 mmol, 3.64 mol equiv) in THF

(200 mL) at K78 8C. A solution of 12 (17.45 g, 44.5 mmol)

in THF (76 mL) was added dropwise over 30 min to the

resulting yellow suspension via cannula, then the reaction

mixture was maintained at K55 8C (internal temperature)

for 10 h, quenched by the addition of saturated NH₄Cl

aqueous solution, diluted with EtOAc, washed with 1 N HCl

aqueous solution. The organic layer was washed with water

and brine, dried over Na₂SO₄, and concentrated. The residue

was puriﬁed by ﬂash column chromatography (silica gel, 40

to 60% EtOAc in hexane) to afford diastereomixture of the

corresponding b-hydroxy esters (ca. 16.77 g, ca. 96%) as a

colorless oil. A solution of the residue in benzene (20 mL)

was added to a white suspension of CuCl (5.47 g,

55.3 mmol, 1.3 equiv) and DCC (10.5 g, 51.0 mmol,

1.2 equiv) in benzene (85 mL) via cannula, then the

reaction mixture was reﬂuxed for 5 h, ﬁltered through

Celite pad eluting with toluene, washed with brine, dried

over Na₂SO₄, and concentrated. The residue was puriﬁed by

ﬂash column chromatography (silica gel, 20 to 60% EtOAc

in hexane) to afford inseparable E/Z mixture (O15:1) of

a,b-unsaturated esters 10a (11.73 g, two steps 70%) as a

colorless oil: R_fZ0.35 (silica gel, EtOAc–hexane, 1:3);

[a]²_D³C21.8 (c 0.8, CHCl₃); FT-IR (neat) n_max2934, 2871,

1714, 1613, 1514, 1435, 1247, 1091 cm^K1; For (E)-isomer:

¹H NMR (500 MHz, CDCl₃) d 7.27 (d, JZ8.5 Hz, 2H; Ar),

6.88 (d, JZ8.5 Hz, 2H; Ar), 6.71 (t, JZ5.5 Hz, 1H; H-19),

4.47 (s, 2H; ArCH₂O), 4.24 (dd, JZ14.0, 5.5 Hz, 1H;

H-18), 4.21 (dd, JZ14.0, 5.5 Hz, 1H; H-18), 3.95–3.87 (m,

4H, OCH₂CH₂O), 3.80 (s, 3H; ArOCH₃), 3.70 (s, 3H;

CO₂CH₃), 2.69 (tt, JZ12.5, 3.5 Hz, 1H; H-15), 2.05 (t, JZ

12.5 Hz, 1H; H-16b), 1.78–1.70 (m, 3H; H-3b, H-7a, H-

14a), 1.56 (br-d, JZ12.5 Hz, 1H; H-16a), 1.57–1.46 (m,

3H; H-3a, H-7b, H-14b), For (Z)-isomer: d 6.00 (td, JZ5.5,

1.5 Hz, 1H; H-19); ¹³C NMR (125 MHz, CDCl₃) d 167.4

(C-21), 159.3 (Ar), 138.5 (C-19), 136.6 (C-20), 129.8

(Ar), 129.4 (Ar, 2 C), 113.8 (Ar, 2 C), 108.9 (C-2),

72.4 (ArCH₂O), 66.0 (C-18), 64.2 (OCH₂CH₂O), 64.1

(OCH₂CH₂O), 55.3 (ArOCH₃), 51.5 (CO₂CH₃), 38.6

4.1.6. Synthesis of (3R)-3-[(1E)-3-[(4-methoxyphenyl)-

methoxy]-1-[[[tris(1-methylethyl)silyl]oxy]methyl]-1-

propenyl]cyclohexanone (14). The TIPS ether 13 (7.23 g,

14.3 mmol, E/Z mixture O15:1) was treated with 0.01 M

acetone solution of dl-CSA (71 mL, 0.71 mmol, 5 mol%) at

rt. After stirring for 2 d at the same temperature, the reaction

mixture was quenched by the addition of saturated NaHCO₃

aqueous solution, and extracted with CH₂Cl₂. The organic

layer was washed with brine, dried over Na₂SO₄, and

concentrated. The residue was puriﬁed by ﬂash column

chromatography (silica gel, 5 to 10% EtOAc in hexane) to

afford pure (E)-14 (4.08 g, 62%, conv. 90%) as a colorless

oil with (Z)-14 (ca. 260 mg, 4%) and the recovery of 13

(2.27 g, 31%): R_fZ0.49 (silica gel, EtOAc–hexane, 1:3);

[a]²_D²C15.4 (c 1.6, CHCl₃); FT-IR (neat) n_max2948, 2865,

1715, 1613, 1514, 1464, 1249, 1056 cm^K^{1 1}H NMR

;

(500 MHz, CDCl₃) d 7.24 (d, JZ8.5 Hz, 2H; Ar), 6.87 (d,

JZ8.5 Hz, 2H; Ar), 5.70 (t, JZ6.5 Hz, 1H; H-19), 4.43 (s,

2H; ArCH₂O), 4.27 (d, JZ12.5 Hz, 1H; H-21), 4.22 (d, JZ

12.5 Hz, 1H; H-21), 4.06 (dd, JZ12.0, 6.5 Hz, 1H; H-18),

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T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

4.01 (dd, JZ12.0, 6.5 Hz, 1H; H-18), 3.80 (s, 3H;

ArOCH₃), 2.77 (tt, JZ12.5, 3.5 Hz, 1H; H-15), 2.60 (t,

JZ12.5 Hz, 1H; H-16b), 2.37 (br-d, JZ14.5 Hz, 1H;

H-7a), 2.33 (br-d, JZ12.5 Hz, 1H; H-16a), 2.30–2.21 (m,

1H; H-7b), 2.10–2.06 (m, 1H; H-3b), 1.85 (qd, JZ12.5,

3.5 Hz, 1H; H-14b), 1.75 (br-d, JZ12.5 Hz, 1H; H-14a),

1.63–1.56 (m, 1H; H-3a), 1.27–0.96 (m, 21H; TIPS); ¹³C

NMR (125 MHz, CDCl₃) d 211.0 (C-2), 159.2 (Ar), 143.0

(C-20), 130.2 (Ar), 129.4 (Ar, 2 C), 123.1 (C-19), 113.8 (Ar,

2 C), 71.9 (ArCH₂O), 65.08 (C-18), 65.05 (C-21), 55.3

(ArOCH₃), 46.5 (C-16), 41.2 (C-7), 39.5 (C-15), 29.7 (C-14),

25.8 (C-3), 18.1 (SiCH(CH₃)₂, 6 C), 11.9 (SiCH(CH₃)₂, 3 C);

MS (ESI (C)) m/z 478 (MCNH^C₄). Anal. calcd for

C₂₇H₄₄O₄Si: C 70.39, H 9.63; found C 70.14, H 9.50.

4.1.8. Synthesis of (5R,6R)-6-(hydroxymethyl)-5-[(1E)-3-

[(4-methoxyphenyl)methoxy]-1-[[[tris(1-methylethyl)-

silyl]oxy]methyl]-1-propenyl]-2-cyclohexen-1-one (43a).

A 1.51 N hexane solution of BuLi (2.76 mL, 4.16 mmol,

1.2 equiv) was added to a solution of diisopropylamine

(0.73 mL, 5.21 mmol, 1.5 equiv) in THF (50 mL) at

K78 8C. After stirring for 1 h at the same temperature,

TMSCl (0.53 mL, 4.16 mmol, 1.2 equiv) was added to

the reaction mixture, followed by the addition of a solution

of 17 and 18 (1.59 g, 3.47 mmol, mixture of regioisomers

O6:1) in THF (20 mL) via cannula. After stirring for 2 h at

the same temperature, the reaction mixture was quenched

by the addition of saturated NaHCO₃aqueous solution,

extracted with CH₂Cl₂, dried over Na₂SO₄, and concen-

trated to afford crude enol silyl ether, which was used for the

next step without further puriﬁcation. The residue was

dissolved with THF (28.0 mL, 0.125 M), then 37% aqueous

solution of formaldehyde (7.0 mL, 0.50 M) and Yb(OTf)₃

(430 mg, 0.69 mmol, 20 mol%) were added at rt. After

stirring for 3 d at the same temperature, the reaction mixture

was quenched by the addition of saturated NaHCO₃aqueous

solution, extracted with CH₂Cl₂, dried over Na₂SO₄, and

concentrated. The residue was roughly puriﬁed by ﬂash

column chromatography (silica gel, 20 to 50% EtOAc in

hexane) to afford regio- and diastereomixture of aldol

products (43a, 43b, and 44) (ca 1.3 g) as a colorless oil with

the recovery of starting material (17:18ZO6:1) (0.47 g,

29%). A mixture of the aldol products was dissolved with

CH₂Cl₂(10 mL) and treated with DBU at rt. After stirring

for 1 h at the same temperature, the reaction mixture was

quenched by the addition of saturated NH₄Cl aqueous

solution, extracted with Et₂O, dried over Na₂SO₄, and

concentrated. The residue was puriﬁed by ﬂash column

chromatography (silica gel, 30 to 50% EtOAc in hexane) to

afford (6R)-aldol product 43a (0.963 g, 57%, conv. 80%) as

a colorless oil, which became a white solid after storage in

refrigerator: R_fZ0.20 (silica gel, EtOAc–hexane, 1:3); mp

35–36 8C; [a]²_D⁴C19.0 (c 1.0, CHCl₃); FT-IR (neat) n_max

3459, 2941, 2865, 1672, 1613, 1514, 1464, 1389, 1249,

4.1.7. Synthesis of (5R)-5-[(1E)-3-[(4-methoxyphenyl)-

methoxy]-1-[[[tris(1-methylethyl)silyl]oxy]methyl]-1-

propenyl]-2-cyclohexen-1-one (17) by catalytic Saegusa–

Ito reaction. A 1.48 N hexane solution of BuLi (0.79 mL,

1.22 mmol, 1.4 equiv) was added to a solution of 2,2,6,6-

tetramethylpiperidine (0.22 mL, 1.31 mmol, 1.5 equiv) in

THF (6.0 mL) at 4 8C (ice-water bath). After stirring for 1 h

at the same temperature, the reaction mixture was cooled to

K78 8C. TMSCl (0.17 mL, 1.22 mmol, 1.4 equiv) was then

added, followed by addition of a solution of 14 (402 mg,

0.873 mmol) in THF (6.0 mL) via cannula. After stirring for

2 h at the same temperature, the reaction mixture was

quenched by the addition of saturated NaHCO₃aqueous

solution, extracted with Et₂O, dried over Na₂SO₄, and

concentrated to afford crude enol silyl ether, which was used

for the next step without further puriﬁcation. The residue

was dissolved with CH₃CN (4.7 mL, 0.125 M), then diallyl

carbonate (0.17 mL, 1.2 mmol, 1.4 equiv) and Pd₂(dba)₃$

CHCl₃(61 mg, 59 mmol, 7 mol%) were added at rt. After

stirring for 12 h at the same temperature, the reaction

mixture was quenched by the addition of saturated NaHCO₃

aqueous solution, extracted with CH₂Cl₂, dried over

Na₂SO₄, and concentrated. The residue was puriﬁed by

ﬂash column chromatography (silica gel, 15 to 20% EtOAc

in hexane) to afford an inseparable mixture of regioisomers

(O6:1) 17 and 18 (361.3 mg, two steps 90%) as a colorless

oil with the recovery of 14 (35 mg, 9%): R_fZ0.43 (silica

gel, EtOAc–hexane, 1:3); [a]²_D⁴C37.6 (c 2.8, CHCl₃);

FT-IR (neat) n_max2946, 2865, 1682, 1613, 1513, 1464,

1

1106 cm^K1; H NMR (500 MHz, CDCl₃) d 7.23 (d, JZ

8.5 Hz, 2H; Ar), 6.98 (ddd, JZ10.1, 5.0, 2.0 Hz, 1H; H-3),

6.85 (d, JZ8.5 Hz, 2H; Ar), 6.05 (dd, JZ10.0, 2.0 Hz, 1H;

H-7), 5.92 (t, JZ7.0 Hz, 1H; H-19), 4.44 (d, JZ11.5 Hz,

1H; ArCHHO), 4.42 (d, JZ11.5 Hz, 1H; ArCHHO), 4.29 (s,

2H; H-21), 4.08 (dd, JZ12.0, 7.0 Hz, 1H; H-18), 4.01 (dd,

JZ12.0, 7.0 Hz, 1H; H-18), 3.95 (br-d, JZ11.5 Hz, 1H,

H-17), 3.80 (s, 3H; ArOCH₃), 3.19–3.12 (m, 1H; H-15),

2.68 (dd, JZ15.5, 14.5 Hz, 1H; H-16b), 2.68–2.61 (m, 1H;

H-14b), 2.40 (dd, JZ15.5, 3.5 Hz, 1H; H-16a), 2.27 (dt, JZ

14.0, 5.5 Hz, 1H; H-14a), 1.15–1.03 (m, 21H; TIPS); ¹³C

NMR (125 MHz, CDCl₃) d 201.4 (C-2), 159.3 (Ar), 150.0

(C-3), 141.3 (C-20), 129.8 (Ar), 129.5 (C-7 and Ar, 3 C),

125.7 (C-19), 113.8 (Ar, 2 C), 72.2 (ArCH₂O), 64.9 (C-18),

64.7 (C-21), 59.8 (C-17), 55.2 (ArOCH₃), 50.9 (C-16), 36.7

(C-15), 30.7 (C-14), 18.0 (SiCH(CH₃)₂, 6 C), 11.9

(SiCH(CH₃)₂, 3 C); MS (ESI (C)) m/z 999 (2MCNa^C),

489 (MCH^C). Anal. calcd for C₂₈H₄₄O₅Si: C 68.81, H

9.07; found C 68.55, H 9.07.

1

1386, 1248, 1106 cm^K1; For the major regioisomer 17: H

NMR (500 MHz, CDCl₃) d 7.24 (d, JZ9.0 Hz, 2H; Ar),

7.00–6.96 (m, 1H; H-3), 6.87 (d, JZ9.0 Hz, 2H; Ar), 6.03

(dd, JZ10.0, 3.6 Hz, 1H; H-7), 5.76 (t, JZ6.5 Hz, 1H;

H-19), 4.44 (d, JZ11.5 Hz, 1H; ArCHHO), 4.42 (d, JZ

11.5 Hz, 1H; ArCHHO), 4.28 (d, JZ13.5 Hz, 1H; H-21),

4.24 (d, JZ13.5 Hz, 1H; H-21), 4.06 (dd, JZ15.0, 6.5 Hz,

1H; H-18), 4.02 (dd, JZ15.0, 6.5 Hz, 1H; H-18), 3.80 (s,

3H; ArOCH₃), 3.19–3.12 (m, 1H; H-15), 2.68 (dd, JZ15.5,

14.5 Hz, 1H; H-16b), 2.68–2.61 (m, 1H; H-14b), 2.40 (dd,

JZ15.5, 3.5 Hz, 1H; H-16a), 2.27 (dt, JZ14.0, 5.5 Hz, 1H;

H-14a), 1.15–1.03 (m, 21H; TIPS); ¹³C NMR (125 MHz,

CDCl₃) d 199.5 (C-2), 159.2 (Ar), 150.2 (C-3), 142.3

(C-20), 130.1 (Ar), 129.4 (C-7 and Ar, 3 C), 124.2 (C-19),

113.8 (Ar, 2 C), 72.0 (ArCH₂O), 65.3 (C-21), 65.0 (C-18),

55.3 (ArOCH₃), 42.5 (C-16), 35.7 (C-15), 31.0 (C-14), 18.0

(SiCH(CH₃)₂, 6 C), 11.9 (SiCH(CH₃)₂, 3 C); MS (ESI (C))

m/z 476 (MCNH^C₄), 459 (MCH^C). Anal. calcd for

C₂₇H₄₂O₄Si: C 70.70, H 9.23; found C 70.57, H 9.25.

4.1.9. Synthesis of (5R,6R)-6-(hydroxymethyl)-2-iodo-5-

[(1E)-3-[(4-methoxyphenyl)methoxy]-1-[[[tris(1-methyl-

ethyl)silyl]oxy]methyl]-1-propenyl]-2-cyclohexen-1-one

(45a). A 0.05 M CH₂Cl₂solution of I₂(214 mL, 10.7 mmol,

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

9583

1.2 equiv) was added dropwise over 20 min to a solution of

43a (4.35 g, 8.90 mmol) and DMAP (2.17 g, 17.8 mmol,

2.0 equiv) in CH₂Cl₂(50 mL) at rt. After stirring for 5 h at

the same temperature, the reaction mixture was quenched by

the addition of water and extracted with CH₂Cl₂. The

organic layer was washed with 1 N HCl aqueous solution,

water, 10% Na₂S₂O₃aqueous solution, water and brine,

extracted with CH₂Cl₂, dried over Na₂SO₄, and concen-

trated. The residue was puriﬁed by ﬂash column chroma-

tography (silica gel, 10 to 20% EtOAc in hexane) to afford

iodide 45a (4.86 g, 89%) as a pale yellow oil: R_fZ0.37

(silica gel, EtOAc–hexane, 1:3); [a]²_D³C4.53 (c 1.1,

CHCl₃); FT-IR (neat) n_max3434, 2942, 2867, 1682, 1612,

(m, 2H; H-16, OH), 2.50 (ddd, JZ18.5, 6.5, 4.5 Hz, 1H;

H-14a), 1.19–1.03 (m, 21H; TIPS); ¹³C NMR (125 MHz,

CDCl₃) d 198.6 (C-2), 159.2 (Ar), 148.4 (C-13), 146.1

(C-3), 140.8 (C-20), 139.0 (C-7), 133.4 (C-10), 131.8 (C-9),

131.7 (C-8), 130.0 (Ar), 129.5 (Ar, 2 C), 128.9 (C-11), 126.0

(C-19), 124.3 (C-12), 113.8 (Ar, 2 C), 72.2 (ArCH₂O), 65.1

(C-21), 64.8 (C-18), 59.8 (C-17), 55.2 (ArOCH₃), 51.2

(C-16), 36.5 (C-15), 30.9 (C-14), 18.0 (SiCH(CH₃)₂, 6 C),

11.9 (SiCH(CH₃)₂, 3 C); MS (ESI (C)) m/z 1241 (2MC

Na^C), 627 (MCNH^C₄), 610 (MCH^C). Anal. calcd for

C₃₄H₄₇NO₇Si: C 66.96, H 7.77, N 2.30; found C 66.73, H

7.97, N 2.07.

1

1514, 1463, 1248, 1173, 1080 cm^K1; H NMR (500 MHz,

4.1.11. Synthesis of (5R,6R)-5-[(1E)-3-[(4-methoxyphe-

nyl)methoxy]-1-[[[tris(1-methylethyl)silyl]oxy]methyl]-

1-propenyl]-2-(2-nitrophenyl)-6-[[[2-(trimethylsilyl)-

ethoxy]methoxy]methyl]-2-cyclohexen-1-one. SEMCl

(0.054 mL, 0.308 mmol, 1.5 equiv) was added to a solution

of 46 (125 mg, 0.205 mmol) and N,N-diisopropylethyl-

amine (0.11 mL, 0.615 mmol, 3.0 equiv) in CH₂Cl₂

(2.0 mL, 0.1 M) at 4 8C (ice-water bath). After stirring for

24 h at rt, the reaction mixture was quenched by the addition

of saturated NH₄Cl aqueous solution, extracted with

CH₂Cl₂, dried over Na₂SO₄, and concentrated. The residue

was puriﬁed by ﬂash column chromatography (silica gel,

20% EtOAc in hexane) to afford SEM ether (152 mg, quant)

as a pale yellow oil: R_fZ0.58 (silica gel, EtOAc–hexane,

1:3); [a]²_D⁴C119.6 (c 0.9, CHCl₃); FT-IR (neat) n_max2944,

2857, 1681, 1612, 1529, 1356, 1248, 1105 cm^K1; ¹H NMR

(500 MHz, CDCl₃) d 8.02 (d, JZ8.0 Hz, 1H; H-12), 7.59

(td, JZ8.0, 1.5 Hz, 1H; H-10), 7.48 (td, JZ8.0, 1.5 Hz, 1H;

H-11), 7.28–7.25 (m, 3H; H-9, Ar (2H)), 6.98 (dd, JZ6.0,

2.0 Hz, 1H; H-3), 6.87 (d, JZ8.5 Hz, 2H; Ar), 5.92 (t, JZ

7.0 Hz, 1H; H-19), 4.57 (d, JZ6.5 Hz, 1H; OCHHO), 4.51

(d, JZ6.5 Hz, 1H; OCHHO), 4.48 (s, 2H; ArCH₂O), 4.35 (s,

2H; H-21), 4.24 (dd, JZ11.5, 7.0 Hz, 1H; H-18), 4.14–4.07

(m, 2H; H-17, H-18), 3.79 (s, 3H; ArOCH₃), 3.56–3.44 (m,

4H; H-15, H-17, OCH₂CH₂Si (2H)), 2.95 (dd, JZ18.5,

11.5 Hz, 1H; H-14b), 2.85 (br-d, JZ8.0 Hz, 1H; H-16), 2.51

(dt, JZ18.5, 5.5 Hz, 1H; H-14a), 1.17–1.03 (m, 21H;

TIPS), 0.88 (t, JZ8.5 Hz, 2H; OCH₂CH₂Si), K0.04 (s, 9H;

Si(CH₃)₃); ¹³C NMR (125 MHz, CDCl₃) d 195.1 (C-2),

159.1 (Ar), 148.6 (C-13), 145.4 (C-3), 140.2 (C-20), 139.1

(C-7), 133.1 (C-10), 132.1 (C-8), 131.8 (C-9), 130.3 (Ar),

129.3 (Ar, 2 C), 128.7 (C-11), 126.0 (C-19), 124.2 (C-12),

113.7 (Ar, 2 C), 95.3 (OCH₂O), 72.0 (ArCH₂O), 65.7

(C-18), 64.9 (OCH₂CH₂Si), 64.8 (C-21), 63.6 (C-17), 55.2

(ArOCH₃), 49.8 (C-16), 36.5 (C-15), 30.9 (C-14), 18.1

(SiCH(CH₃)₂, 6 C), 18.0 (OCH₂CH₂Si), 11.9 (SiCH(CH₃)₂,

3 C), K1.5 (Si(CH₃)₃, 3 C); MS (ESI (C)) m/z 757 (MC

NH^C₄). Anal. calcd for C₄₀H₆₁NO₈Si₂: C 64.92, H 8.31, N

1.89; found C 64.70, H 8.24, N 1.78.

CDCl₃) d 7.73 (dd, JZ6.5, 2.0 Hz, 1H; H-3), 7.22 (d, JZ

8.5 Hz, 2H; Ar), 6.86 (d, JZ8.5 Hz, 2H; Ar), 5.92 (t, JZ

7.0 Hz, 1H; H-19), 4.43 (d, JZ11.5 Hz, 1H; ArCHHO),

4.41 (d, JZ11.5 Hz, 1H; ArCHHO), 4.27 (s, 2H; H-21),

4.06 (dd, JZ12.0, 7.0 Hz, 1H; H-18), 4.04–4.00 (m, 1H;

H-17), 3.98 (dd, JZ12.0, 7.0 Hz, 1H; H-18), 3.80 (s, 3H;

ArOCH₃), 3.60 (ddd, JZ11.5, 5.5, 4.5 Hz, 1H, H-17), 3.33

(ddd, JZ13.5, 11.5, 4.5 Hz, 1H; H-15), 2.99 (dd, JZ8.0,

5.5 Hz, 1H; OH), 2.89 (ddd, JZ18.5, 11.5, 2.0 Hz, 1H;

H-14b), 2.81 (ddd, JZ13.5, 4.5, 2.5 Hz, 1H; H-16), 2.32

(ddd, JZ18.5, 6.5, 4.5 Hz, 1H; H-14a), 1.14–1.00 (m, 21H;

TIPS); ¹³C NMR (125 MHz, CDCl₃) d 194.1 (C-2), 159.3

(Ar), 158.6 (C-3), 140.6 (C-20), 129.6 (Ar), 129.5 (Ar, 2 C),

126.5 (C-19), 113.8 (Ar, 2 C), 103.1 (C-7), 72.3 (ArCH₂O),

65.0 (C-21), 64.7 (C-18), 60.0 (C-17), 55.2 (ArOCH₃), 51.3

(C-16), 36.7 (C-15), 34.6 (C-14), 18.0 (SiCH(CH₃)₂, 6 C),

11.8 (SiCH(CH₃)₂, 3 C); MS (ESI (C)) m/z 1251 (2MC

Na^C), 632 (MCNH^C₄), 615 (MCH^C). Anal. calcd for

C₂₈H₄₃IO₅Si: C 54.72, H 7.05; found C 54.61, H 6.92.

4.1.10. Synthesis of (5R,6R)-6-(hydroxymethyl)-5-[(1E)-

3-[(4-methoxyphenyl)methoxy]-1-[[[tris(1-methylethyl)-

silyl]oxy]methyl]-1-propenyl]-2-(2-nitrophenyl)-2-cyclo-

hexen-1-one (46) by Stille coupling reaction.

Pd₂(dba)₃$CHCl₃(13 mg, 12.2 mmol, 5.0 mol%, 10 mol%

on Pd), Ph₃As (15 mg, 48.8 mmol, 20 mol%), and CuI

(4.6 mg, 24.4 mmol, 10 mol%) were added to a solution of

45a (150 mg, 0.244 mmol) and trimethyl(2-nitrophenyl)-

stannane⁵²(105 mg, 0.366 mmol, 1.5 equiv) in DMF

(4.9 mL, 0.05 M) at rt. After being degassed by a freeze-

pump-thaw cycle, the reaction mixture was stirred for 48 h

at rt, quenched by the addition of saturated NH₄Cl aqueous

solution, extracted with Et₂O (three times). The combined

organic layers were dried over Na₂SO₄and concentrated.

The residue was puriﬁed by ﬂash column chromatography

(silica gel, 5 to 30% EtOAc in hexane) to afford 46 (151 mg,

quant) as a pale yellow oil: R_fZ0.19 (silica gel, EtOAc–

hexane, 1:3); [a]_D²²C86.8 (c 1.5, CHCl₃); FT-IR (neat) n_max

3445, 2940, 2862, 1681, 1612, 1530, 1463, 1354, 1247,

1

1101 cm^K1; H NMR (500 MHz, CDCl₃) d 8.03 (dd, JZ

4.1.12. Synthesis of (5R,6R)-5-[(1E)-1-(hydroxymethyl)-

3-[(4-methoxyphenyl)methoxy]-1-propenyl]-2-(2-nitro-

phenyl)-6-[[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-

2-cyclohexen-1-one (4). 3HF$Et₃N (0.56 mL, 3.46 mmol,

10 equiv) was added to a solution of the SEM ether

(256 mg, 0.346 mmol) in THF (3.5 mL, 0.1 M) at rt. After

stirring for 50 h at rt (more than 25 8C), the reaction mixture

was cooled with ice-water bath, quenched carefully by the

addition of saturated NaHCO₃aqueous solution, extracted

with CH₂Cl₂, dried over Na₂SO₄, and concentrated. The

8.0, 1.0 Hz, 1H; H-12), 7.60 (td, JZ8.0, 1.0 Hz, 1H; H-10),

7.48 (td, JZ8.0, 1.0 Hz, 1H; H-11), 7.26–7.24 (m, 3H; H-9,

Ar (2H)), 6.99 (dd, JZ6.5, 2.0 Hz, 1H; H-3), 6.85 (d, JZ

9.0 Hz, 2H; Ar), 5.95 (t, JZ7.0 Hz, 1H; H-19), 4.46 (d, JZ

11.5 Hz, 1H; ArCHHO), 4.43 (d, JZ11.5 Hz, 1H;

ArCHHO), 4.34 (s, 2H; H-21), 4.14–4.07 (m, 2H; H-18),

4.00–3.96 (m, 1H; H-17), 3.96 (s, 3H; ArOCH₃), 3.70–3.60

(m, 1H; H-17), 3.40 (ddd, JZ13.5, 11.5, 4.5 Hz, 1H; H-15),

2.97 (ddd, JZ18.5, 11.5, 2.0 Hz, 1H; H-14b), 2.87–2.82

9584

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

residue was puriﬁed by ﬂash column chromatography (silica

gel, 50 to 60% EtOAc in hexane) to afford 4 (202 mg,

quant.) as a colorless oil, which became a white solid after

storage in refrigerator: R_fZ0.33 (silica gel, EtOAc–hexane,

1:1); mp 64–65 8C; [a]_D²⁴C126.1 (c 1.5, CHCl₃); FT-IR

(neat) n_max3439, 2951, 2876, 1678, 1527, 1355, 1249,

JZ8.0 Hz, 1H; H-12), 7.33 (d, JZ8.0 Hz, 1H; H-9), 7.29

(d, JZ8.5 Hz, 2H; Ar), 7.11 (t, JZ8.0 Hz, 1H; H-10), 7.06

(t, JZ8.0 Hz, 1H; H-11), 6.89 (d, JZ8.5 Hz, 2H; Ar), 5.45

(t, JZ7.0 Hz, 1H; H-19), 4.68 (s, 2H; OCH₂O), 4.46 (s, 2H;

ArCH₂O), 4.21 (br-s, 1H; H-3), 4.10 (d, JZ7.0 Hz, 2H;

H-18), 4.04 (dd, JZ7.5, 6.5 Hz, 1H; H-6), 3.80 (s, 3H;

ArOCH₃), 3.68–3.53 (m, 4H; H-17, OCH₂CH₂Si), 3.10 (dd,

JZ13.5, 7.5 Hz, 1H; H-5), 3.03–2.94 (m, 3H; H-15, H-16,

H-21), 2.84 (d, JZ12.5 Hz, 1H; H-21), 2.79–2.59 (m, 4H;

SCH₂CH₃), 2.51 (dd, JZ13.5, 6.5 Hz, 1H; H-5), 2.04 (br-d,

JZ12.5 Hz, 1H; H-14), 1.92 (br-d, JZ12.5 Hz, 1H; H-14),

1.29 (t, JZ7.0 Hz, 3H; SCH₂CH₃), 1.24 (t, JZ7.0 Hz, 3H;

SCH₂CH₃), 0.89 (t, JZ8.0 Hz, 2H; OCH₂CH₂Si), K0.04 (s,

9H; Si(CH₃)₃); ¹³C NMR (125 MHz, CD₂Cl₂) d 159.6 (Ar),

143.4 (C-20), 137.9 (C-2), 136.2 (C-13), 131.0 (Ar), 129.6

(Ar, 2 C), 127.8 (C-8), 121.5 (C-10), 120.2 (C-19), 119.7

(C-11), 118.9 (C-12), 113.9 (Ar, 2 C), 111.0 (C-9), 107.8

(C-7), 95.4 (OCH₂O), 72.2 (ArCH₂O), 71.0 (C-17), 65.8

(C-18), 65.5 (OCH₂CH₂Si), 62.4 (C-5), 55.5 (ArOCH₃),

53.9 (C-21), 51.5 (C-3), 50.1 (C-6), 40.0 (C-16), 32.2

(C-15), 30.7 (C-14), 24.7 (SCH₂CH₃), 24.6 (SCH₂CH₃),

18.3 (OCH₂CH₂Si), 14.8 (SCH₂CH₃, 2 C), K1.5 (Si(CH₃)₃,

3 C); MS (ESI (C)) m/z 683 (MCH^C); HRMS (TOF (C))

calcd for C₃₇H₅₅N₂O₄S₂Si (MCH^C): 683.3367; found

683.3362.

1

1065 cm^K1; H NMR (500 MHz, CDCl₃) d 8.04 (d, JZ

8.0 Hz, 1H; H-12), 7.61 (dd, JZ8.0, 1.5 Hz, 1H; H-10), 7.49

(dd, JZ8.0, 1.5 Hz, 1H; H-11), 7.27–7.25 (m, 3H; H-9, Ar

(2H)), 6.99 (dd, JZ6.5, 2.0 Hz, 1H; H-3), 6.87 (d, JZ

8.5 Hz, 2H; Ar), 5.87 (dd, JZ6.5, 6.0 Hz, 1H; H-19), 4.58

(d, JZ7.0 Hz, 1H; OCHHO), 4.55 (d, JZ7.0 Hz, 1H;

OCHHO), 4.46 (s, 2H; ArCH₂O), 4.30 (dd, JZ13.5, 6.5 Hz,

1H; H-21), 4.20 (dd, JZ13.5, 4.5 Hz, 1H; H-21), 4.18 (dd,

JZ12.5, 6.5 Hz, 1H; H-18), 4.08 (dd, JZ12.5, 6.0 Hz, 1H;

H-18), 3.86 (dd, JZ10.0, 4.5 Hz, 1H; H-17), 3.78 (s, 3H;

ArOCH₃), 3.78 (dd, JZ10.0, 2.5 Hz, 1H; H-17), 3.58–3.47

(m, 2H; OCH₂CH₂Si), 3.40 (td, JZ11.5, 4.5 Hz, 1H; H-15),

2.99–2.92 (m, 2H; H-14b, H-16), 2.52 (ddd, JZ19.0, 6.5,

4.5 Hz, 1H; H-14a), 2.37 (dd, JZ6.5, 4.5 Hz, 1H; OH), 0.89

(t, JZ8.5 Hz, 2H; OCH₂CH₂Si), K0.01 (s, 9H; Si(CH₃)₃);

¹³C NMR (125 MHz, CDCl₃) d 195.0 (C-2), 159.2 (Ar),

148.5 (C-13), 145.3 (C-3), 141.2 (C-20), 138.9 (C-7), 133.3

(C-10), 131.9 (C-8), 131.8 (C-9), 130.0 (Ar), 129.4 (Ar, 2

C), 128.8 (C-11), 127.3 (C-19), 124.2 (C-12), 113.8 (Ar, 2

C), 95.2 (OCH₂O), 72.3 (ArCH₂O), 65.5 (C-18), 65.2

(OCH₂CH₂Si), 65.0 (C-21), 64.3 (C-17), 55.2 (ArOCH₃),

50.4 (C-16), 37.9 (C-15), 30.9 (C-14), 17.9 (OCH₂CH₂Si),

K1.5 (Si(CH₃)₃, 3 C); MS (ESI (C)) m/z 1189 (2MCNa^C),

601 (MCNH^C₄). Anal. calcd for C₃₁H₄₁NO₈Si: C 63.78, H

7.08, N 2.40; found C 63.58, H 7.30, N 2.38.

4.1.14. Synthesis of (6R,16a,19E)-1,2,19,20-tetra-

dehydro-6-(ethylthio)-18-[(4-methoxyphenyl)methoxy]-

17-[[2-(trimethylsilyl)ethoxy]methoxy]curan (47) by

intramolecular alkylation of dithioacetal. A suspension

of DMTSF (158 mg, 0.81 mmol, 5.0 equiv) and MS4A

(1.61 g), which was dried by heat-gun prior to being used, in

CH₂Cl₂(16 mL) was stirred for 1 h at rt. A solution of 3

(110 mg, 0.161 mmol), which was azeotroped with toluene

prior to being used, in CH₂Cl₂(16 mL) was added dropwise

to the mixture via cannula. After stirring for 2 h at the same

temperature, the reaction mixture was directly puriﬁed by

ﬂash column chromatography (silica gel deactivated with

Et₃N, 60 to 100% EtOAc in hexane) to afford 47 (86.6 mg,

86%) as a colorless oil: R_fZ0.17 (silica gel, EtOAc–hexane,

1:1); [a]²_D⁶K29.3 (c 0.9, CHCl₃); FT-IR (neat) n_max2923,

4.1.13. Synthesis of (1S,4E,5R,6S)-2-[2,2-bis(ethylthio)-

ethyl]-2,3,4,5,6,7-hexahydro-4-[2-[(4-methoxyphenyl)-

methoxy]ethylidene]-6-[[[2-(trimethylsilyl)ethoxy]-

methoxy]methyl]-1,5-methano-1H-azocino[4,3-b]indole

(3) by domino cyclization. A 0.2 M CH₂Cl₂solution of

Tf₂O (0.80 mL, 0.16 mmol, 1.2 equiv) was added dropwise

to a solution of 4 (77.9 mg, 0.133 mmol) and N,N-

diisopropylethylamine (69 mL, 0.40 mmol, 3.0 equiv) in

CH₂Cl₂(0.67 mL, 0.2 M) at K78 8C. After stirring for

30 min at the same temperature, a 0.2 M CH₂Cl₂solution of

2,2-bis(ethylthio)ethylamine⁵³(1.0 mL, 0.20 mmol,

1.5 equiv) was added to the reaction mixture. After stirring

for additional 60 min at the same temperature, the reaction

was quenched by the addition of saturated NaHCO₃aqueous

solution, warmed to rt, extracted with CH₂Cl₂, dried over

Na₂SO₄, and concentrated to afford crude allyl amine,

which was used for the next step without further

puriﬁcation. The residue was dissolved with MeOH

(13 mL, 0.01 M) and saturated NH₄Cl aqueous solution

(1.3 mL, 1.0 M), and then Zn dust (Aldrich, 869 mg,

13.3 mmol, 100 equiv) was added at rt. After vigorous

stirring for 2 h at the same temperature, the reaction mixture

was quenched by the addition of saturated NaHCO₃aqueous

solution, ﬁltered through Celite pad eluting with EtOAc,

washed with brine, dried over Na₂SO₄, and concentrated.

The residue was puriﬁed by ﬂash column chromatography

(alumina, 20% EtOAc in hexane) to afford 3 (70.0 mg, 2

steps 77%) as a colorless oil: R_fZ0.57 (silica gel, EtOAc–

hexane, 1:1); [a]_D²⁴C94.5 (c 0.9, CHCl₃); FT-IR (neat) n_max

1

1612, 1566, 1513, 1455, 1248, 1059, 836 cm^K1; H NMR

(500 MHz, CD₂Cl₂) d 7.48 (d, JZ7.5 Hz, 1H; H-9), 7.37 (d,

JZ7.5 Hz, 1H; H-12), 7.31 (t, JZ7.5 Hz, 1H; H-10), 7.24

(d, JZ8.5 Hz, 2H; Ar), 7.15 (t, JZ7.5 Hz, 1H; H-11), 6.86

(d, JZ8.5 Hz, 2H; Ar), 5.61 (t, JZ7.5 Hz, 1H; H-19), 4.74

(d, JZ6.5 Hz, 1H; OCHHO), 4.70 (d, JZ6.5 Hz, 1H;

OCHHO), 4.45 (d, JZ11.5 Hz, 1H; ArCHHO), 4.44 (d, JZ

11.5 Hz, 1H; ArCHHO), 4.33 (dd, JZ11.5, 7.5 Hz, 1H;

H-18), 4.32 (dd, JZ9.5, 4.5 Hz, 1H; H-17), 4.16 (dd, JZ

11.5, 7.5 Hz, 1H; H-18), 4.05 (br-s, 1H; H-3), 3.94 (d, JZ

15.5 Hz, 1H; H-21), 3.88 (dd, JZ12.0, 6.0 Hz, 1H; H-6),

3.78 (s, 3H; ArOCH₃), 3.74 (t, JZ9.5 Hz, 1H; H-17), 3.65

(dd, JZ9.0, 7.5 Hz, 2H; OCH₂CH₂Si), 3.48 (dd, JZ12.5,

6.0 Hz, 1H; H-5a), 3.39 (dd, JZ6.5, 4.5 Hz, 1H; H-16),

3.38 (t, JZ12.5 Hz, 1H; H-5b), 3.25 (br-s, 1H; H-15), 3.19

(d, JZ15.5 Hz, 1H; H-21), 2.25–2.17 (m, 2H; SCH₂CH₃),

1.97 (br-d, JZ15.0 Hz, 1H; H-14), 1.20 (br-d, JZ15.0 Hz,

1H; H-14), 1.00–0.94 (m, 5H; SCH₂CH₃, OCH₂CH₂Si),

0.02 (s, 9H; Si(CH₃)₃); ¹³C NMR (125 MHz, CD₂Cl₂) d

188.0 (C-2), 159.6 (Ar), 155.7 (C-13), 145.6 (C-8), 142.0

(C-20), 131.1 (Ar), 129.6 (Ar, 2 C), 128.5 (C-10), 124.9

(C-11), 123.9 (C-12), 122.8 (C-19), 120.4 (C-9), 114.0 (Ar,

1

3397, 2925, 1612, 1513, 1458, 1248, 1036, 835 cm^K1; H

NMR (500 MHz, CD₂Cl₂) d 8.55 (br-s, 1H, NH), 7.57 (d,

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

9585

2 C), 95.5 (OCH₂O), 72.5 (ArCH₂O), 68.6 (C-7), 68.5 (C-3),

68.4 (C-17), 66.6 (C-5), 65.61 (C-18), 65.57 (OCH₂CH₂Si),

57.0 (C-21), 55.6 (ArOCH₃), 49.9 (C-6), 46.6 (C-16), 34.5

(C-15), 26.7 (SCH₂CH₃), 25.6 (C-14), 18.4 (OCH₂CH₂Si),

15.3 (SCH₂CH₃), K1.4 (Si(CH₃)₃, 3 C); MS (ESI (C)) m/z

621 (MCH^C); HRMS (TOF (C)) calcd for C₃₅H₄₉

N₂O₄SSi (MCH^C): 621.3177; found 621.3172.

puriﬁcation. The residue was dissolved with pyridine

(0.35 mL, 4.33 mmol, 100 equiv), and then Ac₂O

(0.20 mL, 2.17 mmol, 50 equiv) was added at rt. After

stirring for 36 h at the same temperature, the reaction

mixture was quenched by the addition of saturated NaHCO₃

aqueous solution, and extracted with CH₂Cl₂(three times).

The combined organic layers were dried over Na₂SO₄and

concentrated to give crude triacetate, which was used for the

next step without further puriﬁcation. The residue was

dissolved with MeOH (0.86 mL, 0.05 M), and then 1.0 M

NaOMe in MeOH (0.35 mL, 0.346 mmol, 8 equiv) was

added at rt. After stirring for 30 min at the same

temperature, the reaction mixture was quenched by the

addition of saturated NaHCO₃aqueous solution, saturated

with NaCl, and extracted with CH₂Cl₂(three times). The

combined organic layers were dried over Na₂SO₄, concen-

trated, and ﬁltrated through short pad alumina column (10%

MeOH in EtOAc) to remove water and less polar side

products, such as p-methoxybenzyl methyl ether. After

concentration, the residue was pumped-up for several hours

to remove residual MeOH to afford N-acetyl diol as a white

solid, which was dissolved with DMF (0.86 mL, 0.05 M),

then imidazole (58.8 mg, 0.864 mmol, 20 equiv) and 1.0 M

CH₂Cl₂solution of TIPSCl (0.108 mL, 0.108 mmol,

2.5 equiv) was added at 4 8C (ice-water bath). After stirring

for 1 h at the same temperature, additional 1.0 M CH₂Cl₂

solution of TIPSCl (0.108 mL, 0.108 mmol, 2.5 equiv) was

added dropwise at the same temperature. After stirring for

additional 1 h at the same temperature, the reaction was

quenched by the addition of saturated NaHCO₃aqueous

solution, extracted with CH₂Cl₂, dried over Na₂SO₄, and

concentrated. The residue was puriﬁed by ﬂash column

chromatography (alumina, 5 to 20% EtOAc in hexane) to

afford 61 (12.6 mg, 4 steps 51%) as a white solid with

diTIPS compound (4.8 mg, 4 steps 20%) as a colorless oil.

This by-product was converted to the N-acetyl diol in ca.

80% yield by treatment of 3HF$Et₃N in THF: R_fZ0.49

(silica gel, EtOAc); mp 90–94 8C; [a]²_D⁵C13.5 (c 0.6,

CHCl₃); FT-IR (KBr) n_max3398, 2925, 2865, 1655, 1459,

4.1.15. Synthesis of (6R,16a,19E)-19,20-didehydro-6-

(ethylthio)-18-[(4-methoxyphenyl)methoxy]-17-[[2-(tri-

methylsilyl)ethoxy]methoxy]curan (2) by NaBH₃CN

reduction in the presence of TiCl₄. A 1.0 M CH₂Cl₂

solution of TiCl₄(0.19 mL, 0.19 mmol, 5.0 equiv) was

added to a solution of 47 (23.3 mg, 37.5 mmol) in THF

(1.9 mL, 0.02 M) at K78 8C. After stirring for 5 min at the

same temperature, NaBH₃CN (9.4 mg, 0.15 mmol, 4.0 mol

equiv) was added to the reaction mixture. After stirring for

additional 60 min at the same temperature, the reaction was

quenched by the addition of saturated NaHCO₃aqueous

solution, warmed to rt, followed by 25% ammonia aqueous

solution, and extracted with CH₂Cl₂(three times). The

combined organic layers were dried over Na₂SO₄and

concentrated. The residue was puriﬁed by ﬂash column

chromatography (silica gel deactivated with Et₃N, 50 to

70% EtOAc in hexane) to afford 2 (16.0 mg, 68%) as a

colorless oil: R_fZ0.12 (silica gel, EtOAc–hexane, 1:1);

[a]²_D⁵K30.6 (c 0.5, CHCl₃); FT-IR (neat) n_max3372, 2925,

1608, 1514, 1465, 1248, 1102, 1059 cm^K^{1 1}H NMR

;

(500 MHz, CD₂Cl₂) d 7.25 (d, JZ8.5 Hz, 2H; Ar), 7.19

(d, JZ7.5 Hz, 1H; H-9), 7.04 (t, JZ7.5 Hz, 1H; H-11), 6.87

(d, JZ8.5 Hz, 2H; Ar), 6.70 (t, JZ7.5 Hz, 1H; H-10), 6.58

(d, JZ7.5 Hz, 1H; H-12), 5.48 (t, JZ6.0 Hz, 1H; H-19),

4.60 (d, JZ7.0 Hz, 1H; OCHHO), 4.55 (d, JZ7.0 Hz, 1H;

OCHHO), 4.42 (d, JZ11.5 Hz, 1H; ArCHHO), 4.39 (d, JZ

11.5 Hz, 1H; ArCHHO), 4.07–4.00 (m, 2H; H-18), 3.86 (d,

JZ6.0 Hz, 1H; H-3), 3.79 (s, 3H; ArOCH₃), 3.62 (d, JZ

14.5 Hz, 1H; H-21), 3.67–3.57 (m, 2H; OCH₂CH₂Si), 3.53

(t, JZ9.5 Hz, 1H; H-17), 3.46–3.42 (m, 2H; H-2, H-17),

3.38–3.30 (m, 2H; H-6, H-5b), 3.28 (d, JZ14.5 Hz, 1H;

H-21), 3.12 (dd, JZ11.5, 7.5 Hz, 1H; H-5a), 2.56 (br-s, 1H;

H-15), 2.34–2.26 (m, 1H; SCHHCH₃), 2.21–2.15 (m, 2H;

H-16, SCHHCH₃), 1.88 (br-d, JZ14.0 Hz, 1H; H-14), 1.72

(br-d, JZ14.0 Hz, 1H; H-14), 1.09 (t, JZ7.5 Hz, 3H;

SCH₂CH₃), 0.93 (t, JZ8.0 Hz, 2H; OCH₂CH₂Si), 0.02 (s,

9H; Si(CH₃)₃); ¹³C NMR (125 MHz, CD₂Cl₂) d 159.7 (Ar),

151.3 (C-13), 142.6 (C-20), 131.1 (Ar), 129.9 (C-8), 129.7

(Ar, 2 C), 128.6 (C-11), 125.8 (C-9), 121.5 (C-19), 118.4

(C-10), 114.1 (Ar, 2 C), 109.5 (C-12), 95.5 (OCH₂O), 72.3

(ArCH₂O), 69.9 (C-17), 65.9 (OCH₂CH₂Si), 65.7 (C-18),

63.7 (C-3), 63.2 (C-2), 62.2 (C-5), 58.5 (C-7), 55.6

(ArOCH₃), 54.1 (C-21), 52.4 (C-6), 40.3 (C-16), 30.4

(C-15), 27.0 (SCH₂CH₃), 23.4 (C-14), 18.5 (OCH₂CH₂Si),

14.9 (SCH₂CH₃), K1.3 (Si(CH₃)₃, 3 C); MS (ESI (C)) m/z

623 (MCH^C); HRMS (TOF (C)) calcd for C₃₅H₅₁N₂O_4-

SSi (MCH^C): 623.3333; found 623.3308.

1

1399, 1052 cm^K1; For the major isomer of rotamers: H

NMR (500 MHz, CD₂Cl₂) d 8.01 (d, JZ8.0 Hz, 1H; H-12),

7.32 (d, JZ8.0 Hz, 1H; H-9), 7.26 (d, JZ8.0 Hz, 1H;

H-11), 7.08 (d, JZ8.0 Hz, 1H; H-10), 5.54 (t, JZ6.0 Hz,

1H; H-19), 4.39–4.33 (m, 2H; H-18), 4.13 (d, JZ7.5 Hz,

2H; H-17), 4.03 (br-s, 1H; H-3), 3.79 (d, JZ16.0 Hz, 1H;

H-21), 3.36 (dd, JZ11.5, 6.5 Hz, 1H; H-5), 3.31 (dd, JZ

11.0, 5.0 Hz, 1H; H-17), 3.23 (d, JZ11.5 Hz, 1H; H-5),

3.17–3.12 (m, 2H; H-6, OH), 3.07–3.04 (m, 1H; H-15), 3.01

(d, JZ11.0 Hz, 1H; H-17), 2.89 (d, JZ16.0 Hz, 1H; H-21),

2.51 (br-s, 1H, H-16), 2.26 (s, 3H; C(O)CH₃), 1.94 (br-d,

JZ14.0 Hz, 1H; H-14), 1.86–1.81 (m, 1H; SCHHCH₃),

1.64–1.58 (m, 1H; SCHHCH₃), 1.57 (br-d, JZ14.0 Hz, 1H;

H-14), 1.15–0.96 (m, 21H; TIPS), 0.88 (t, JZ7.5 Hz, 3H;

SCH₂CH₃); ¹³C NMR (125 MHz, CD₂Cl₂) d 168.7

(C(O)CH₃), 143.9 (C-20), 138.2 (C-13), 132.1 (C-8),

129.0 (C-11), 127.8 (C-19), 124.9 (C-9), 123.9 (C-10),

116.8 (C-12), 66.8 (C-2), 61.1 (C-17), 60.8 (C-18), 59.6

(C-5), 56.8 (C-7), 54.9 (C-21), 53.7 (C-6), 45.8 (C-16), 30.0

(C-15), 26.9 (SCH₂CH₃), 23.6 (C(O)CH₃), 18.9 (C-14), 18.2

(SiCH(CH₃)₂, 6 C), 14.3 (SCH₂CH₃), 12.4 (SiCH(CH₃)₂, 3

C); MS (ESI (C)) m/z 571 (MCH^C); HRMS (TOF (C))

calcd for C₃₂H₅₁N₂O₃SSi (MCH^C): 571.3390; found

571.3390.

4.1.16. Synthesis of (6R,16a,19E)-1-acetyl-19,20-di-

dehydro-6-(ethylthio)-18-[[tris(1-methylethyl)silyl]oxy]-

curan-17-ol (61). The indoline 2 (27.0 mg, 43.3 mmol) was

treated with 1.0 N HCl in MeOH (0.87 mL, 0.87 mmol,

20 equiv) for 3 h at 55 8C. After cooling to rt, the reaction

was concentrated under reduced pressure to give crude diol,

which was used for the next step without further

9586

T. Ohshima et al. / Tetrahedron 60 (2004) 9569–9588

4.1.17. Synthesis of (K)-diabolene (65) through desul-

furization. EtOH (2.88 mL) and MeOH (0.72 mL) were

simultaneously added to a mixture of NaBH₄(136 mg,

3.60 mmol, 200 equiv) and NiCl₂(233 mg, 1.80 mmol,

100 equiv) at rt with vigorous generation of H₂. After

stirring for 10 min, a solution of 61 (10.3 mg, 18.0 mmol) in

EtOH (0.2 mL) was added. After stirring additional 30 min,

the reaction mixture was ﬁltered through short pad alumina

column eluting with 20% MeOH in EtOAc and concen-

trated. The selectivity of this reaction was 32:65:2:!1 for

62:61:64:63, which was estimated based on the results of

LC-MS (ESI) analysis of the crude mixture. The residue was

puriﬁed by ﬂash column chromatography (alumina, 20 to

100% EtOAc in hexane followed by 10% MeOH in EtOAc)

to afford inseparable mixture of 62 and its 19,20-dihydro

derivative 64 (3.2 mg, 33%, O10:1 selectivity) with the

recovery of 61 (6.7 mg, 65%). Both over reduction and

migration of 61 were not observed. After repeating this

process twice (total three times), yield of 62 was reached to

61% (5.6 mg, O10:1 selectivity) with 61 (2.7 mg, 26%).

The mixture of 62 (5.6 mg, 11.0 mmol) was dissolved in

DMSO (0.11 mL, 0.1 M), and then triethylamine (45 mL,

0.33 mmol, 30 equiv) and SO₃$Py (18 mg, 0.11 mm***pl,

10 equiv) were added at rt. After stirring for 1 h, the

reaction mixture was quenched by the addition of saturated

NaHCO₃aqueous solution and extracted with Et₂O (three

times). The combined organic layers were washed with

water and brine, dried over Na₂SO₄, and concentrated to

give crude aldehyde, which was used for the next step

without further puriﬁcation. 3HF$Et₃N (36 mL, 0.22 mmol,

20 equiv) was added to a solution of the crude aldehyde in

THF (0.22 mL, 0.05 M) at rt. After stirring for 12 h at the

same temperature (more than 25 8C), the reaction mixture

was cooled with ice-water bath, quenched carefully by the

addition of saturated NaHCO₃aqueous solution, extracted

with CH₂Cl₂, dried over Na₂SO₄, and concentrated. The

residue was puriﬁed by ﬂash column chromatography

(alumina, 10% MeOH in EtOAc) to afford diaboline (65)

(3.2 mg, 2 steps 83%) as a white solid: R_fZ0.09 (silica gel,

2% Et₃N and 30% MeOH in EtOAc); mp 182–185 8C: lit.

185–187 8C (crystals from EtOAc); [a]²_D⁵C74 (c 1.3,

MeOH); [a]²_D⁵C39 (c 0.5, CHCl₃): lit. [a]²_D⁰C36 (c 0.8,

CHCl₃); FT-IR (KBr) n_max3375, 2925, 1655, 1479, 1395,

4.1.18. Completion of total synthesis of (K)-strychnine

(1). Diaboline (65) (13.0 mg, 36.9 mmol) was treated with

1.0 M MeOH solution of NaOMe (0.5 mL, 14 equiv) at

40 8C for 2 d. The reaction was quenched by the addition of

saturated NH₄Cl aqueous solution followed by saturated

NaHCO₃aqueous solution, and extracted with CH₂Cl₂

(three times). The combined organic layers were dried over

Na₂SO₄and concentrated to give crude Wieland–Gumlich

aldehyde (66). The crude Wieland–Gumlich aldehyde was

converted to (K)-strychnine (1) (5.2 mg, 2 steps 42%) by

treatment of HOAc (0.5 mL), NaOAc (67 mg, 0.80 mmol,

22 equiv), malonic acid (67 mg, 0.63 mmol, 17 equiv), and

Ac₂O (13 mL, 0.13 mmol, 3.5 equiv) under reﬂux con-

dition.^16c: R_fZ0.17 (silica gel, 2% Et₃N and 50% MeOH in

EtOAc); [a]²_D⁵K136 (c 0.26, CHCl₃): lit. [a]²_D⁵K139 (c 2.0

CHCl₃); ¹H NMR (500 MHz, CDCl₃) and ¹³C NMR

(125 MHz, CDCl₃) were indistinguishable from those of

natural strychnine.

Acknowledgements

This work was supported by the RFTF and Encouragement

of Young Scientists (A) of Japan Society for the Promotion

of Science, a Grant-in-Aid for Scientiﬁc Research on

Priority Areas (A) ‘Exploitation of Multi-Element Cyclic

Molecules’ from the Ministry of Education, Culture, Sports,

Science, and Technology, Japan, Grant-in-Aid from the

Tokyo Biochemical Research Foundation, and fellowship

from Heiwa Nakajima Foundation (to Y.X.). We thank

Dr. S. Shimizu for his contribution in our initial investi-

gation and Dr. D. Zhong (Syehyang Pharmaceutical

University) for help with structural determination using

ESI (MS–MS) and TOF mass analyses.

References and notes

1. For general reviews, see: (a) Ojima, I. Catalytic Asymmetric

Synthesis, 2nd ed.; Wiley: New York, 2000. (b) Compre-

hensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,

Yamamoto, H., Eds.; Springer: New York, 1999. (c) Noyori,

R. Asymmetric Catalysis in Organic Synthesis; Wiley: New

York, 1994.

1

1125, 1075 cm^K1; For major isomer: H NMR (500 MHz,

CD₂Cl₂) d 7.87 (d, JZ8.0 Hz, 1H; H-12), 7.25–7.20 (m, 1H;

H-11), 7.16–7.08 (m, 2H; H-9, H-10), 5.84 (br-s, 1H; H-19),

5.32–5.23 (m, 1H; H-17), 4.83 (dd, JZ13.5, 4.0 Hz, 1H;

H-18), 4.20 (d, JZ11.5 Hz, 1H; H-2), 3.93–3.85 (m, 1H;

H-3), 3.71–3.64 (m, 2H; H-18, H-21), 3.39 (br-s, 1H; H-15),

3.29–3.25 (m, 1H; H-5), 2.88–2.83 (m, 1H; H-5), 2.68 (d,

JZ15.5 Hz, 1H; H-21), 2.00 (s, 3H; C(O)CH₃), 2.22 (br-d,

JZ14.0 Hz, 1H; H-14), 1.92 (dd, JZ12.5, 6.0 Hz, 1H; H-6),

1.67–1.61 (m, 1H; H-6), 1.51 (d, JZ11.5 Hz, 1H; H-16),

1.38 (br-d, JZ14.0 Hz, 1H; H-14); ¹³C NMR (125 MHz,

CD₂Cl₂) d 170.2 (C(O)CH₃), 143.9 (C-13), 142.8 (C-20),

135.4 (C-8), 127.9 (C-11), 126.2 (C-19), 125.0 (C-10),

122.1 (C-9), 119.9 (C-12), 94.1 (C-17), 65.3 (C-2), 59.3

(C-3), 55.7 (C-18), 53.7 (C-21), 52.9 (C-7), 51.9 (C-5), 47.5

(C-16), 39.1 (C-6), 29.1 (C-15), 25.9 (C-14), 23.4

(C(O)CH₃); MS (ESI (C)) m/z 353 (MCH^C); HRMS

(TOF (C)) calcd for C₂₁H₂₅N₂O₃(MCH^C): 353.1860;

found 353.1855.

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Article Doi

Enantioselective total synthesis of (-)-strychnine: Development of a highly practical catalytic asymmetric carbon-carbon bond formation and domino cyclization

DOI: 10.1016/j.tet.2004.06.141

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