Unified Total Synthesis of Madangamine Alkaloids

Advance Publication Cover Page

Takahiro Suto, Yuta Yanagita, Yoshiyuki Nagashima, Shinsaku Takikawa, Yasuhiro Kurosu, Naoya Matsuo,

Kazuki Miura, Siro Simizu, Takaaki Sato,* and Noritaka Chida*

Advance Publication on the web December 13, 2018

doi:10.1246/bcsj.20180334

Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire

manuscripts and a portion of the graphical abstract can be released on the web as soon as the submission is accepted. Note that the

Chemical Society of Japan bears no responsibility for issues resulting from the use of information taken from unedited, Advance

Publication manuscripts.

Unified Total Synthesis of Madangamine Alkaloids

Takahiro Suto, Yuta Yanagita, Yoshiyuki Nagashima, Shinsaku Takikawa, Yasuhiro Kurosu, Naoya Matsuo, Kazuki

Miura, Siro Simizu, Takaaki Sato* and Noritaka Chida*

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522,

Japan

E-mail: takaakis@applc.keio.ac.jp , chida@applc.keio.ac.jp

Takaaki Sato received his B.Sc. degree in 2001 from Tohoku University, and his Ph.D. degree in 2006 from Tohoku

University under the direction of Professor Masahiro Hirama. He spent two years in Professor Larry E. Overman’s

research group at the University of California, Irvine as a JSPS fellow. He joined the Department of Applied Chemistry,

Keio University as an assistant professor in 2008. He was promoted to Associate Professor of Keio University in 2016.

He was awarded Young Scientist's Research Award in Natural Product Chemistry in 2014, and Incentive Award in

Synthetic Organic Chemistry, Japan in 2016.

Noritaka Chida received his B.Sc. degree in 1979 from Keio University, and Ph.D. degree in 1984 from Tohoku

University under the direction of Professor Akira Yoshikoshi. From 1984 to 1987, he worked for Mercian Co. Ltd., as a

researcher. In 1987, he joined the Department of Applied Chemistry, Keio University as a research assistant, and in

1988-1989, he spent one year as a postdoctoral researcher at the University of Pennsylvania with Professor A. B. Smith,

III. He was promoted to Professor of Keio University in 2003. In 2002, he was awarded the “BCSJ Award” from the

Chemical Society of Japan.

Abstract

The full details of

a unified total synthesis of

madangamine alkaloids are disclosed. Our central strategy is

based on the construction of a common ABCE-tetracyclic

system, followed by the late-stage installation of various

D-rings. The common intermediate is assembled through

N-acyliminium cyclization of a propargylsilane, and formation

of the (Z,Z)-skipped diene. Stereoselective synthesis of the

(Z,Z)-skipped diene is especially challenging, and is

accomplished by the combination of Z-selective hydroboration

of

the

1,1-disubstituted

allene

and

subsequent

Migita-Kosugi-Stille coupling. Macrocyclic alkylation enables

the late-stage variation of the D-rings on the common

tetracyclic intermediate, resulting in the collective total

syntheses of madangamines A-E. The synthetic madangamine

alkaloids exhibited inhibitory activities against a variety of

human cancer cell lines.

Scheme 1. Structures of madangamine alkaloids

1. Introduction

synthetic chemists, culminating in the first total synthesis of

madangamine D (4) by the Amat group in 2014.^3,4They

successfully provided a pure synthetic sample of madangamine

D (4) for biological studies, which revealed cytotoxicity against

human cancer cell lines. Although this landmark achievement

suggested that a variable D-ring structure might be important

for the cytotoxic spectrum of activity, resolving this issue

would require the collective total synthesis of a series of

madangamine alkaloids. Unfortunately, the Amat group

constructed the variable D-ring in the middle stage of the total

synthesis, causing difficulties in synthesizing other members of

the madangamine alkaloids. In this article, we describe the full

details of our unified total synthesis of madangamines A-E

(1-5),⁵whose key steps were the N-acyliminium cyclization of

a propargylsilane, and the subsequent construction of a skipped

diene through stereoselective hydroboration of an allene. These

reactions supplied a common ABCE-tetracyclic intermediate.

The late-stage installation of a variety of D-rings enabled a

In 1994, Andersen and co-workers reported the isolation

of a new class of pentacyclic alkaloid, madangamine A (1),

from the sponge Xestospongia ingens from the reefs of Madang,

Papua New Guinea.^1,2aStructurally, madangamine A (1)

appeared to be derived biogenetically from a partially reduced

bis-3-alkylpyridine precursor proposed by Whitehead and

Baldwin as seen in the manzamine alkaloids, but possessed an

unprecedented 2-azabicyclo[3.3.1]nonane structure. Andersen

then reported isolation of madangamines B-E (2-5), which

shared a common ABCE-tetracyclic ring system with a variety

of D-rings.^2bIn 2007, the Berlinck group isolated

madangamine

F (6) from a different marine sponge

Pachychalina alcaloidifera.^2cMadangamines A (1) and F (6)

exhibited in vitro cyctotoxicity against a variety of human

cancer cell lines.^2a,cHowever, biological activities of the other

members of the madangamine family have not been examined

because of their scarcity. Their unique architecture and the

unexplored biological activities have inspired a number of

collective total synthesis of several madangamine alkaloids,

which were tested for their inhibitory activities against a variety

of human cancer cell lines.

2. Results and Discussion

To achieve the unified total synthesis of madangamine

alkaloids, we planned the late-stage installation of various

D-rings to the common ABCE-tetracyclic intermediate 11

(Scheme 2A). Synthesis of the common intermediate 11 has to

solve two structural challenges; i) a diazatricyclic ABC-ring

core, and ii) a skipped diene containing the Z-trisubstituted

olefin. Historically, the construction of the unprecedented

diazatricyclic system has drawns much more attention from

synthetic chemists than the skipped diene. As a result, a number

of solutions^3,4including our racemic synthesis^5ahave been

reported for the synthesis of the diazatricyclic system. On the

other hand, the stereoselective synthesis of the skipped diene

has been neglected as a synthetic issue.⁶Recent studies

revealed that stereocontrol of the (Z)-trisubstituted olefin was a

daunting task (Scheme 2B). The Kibayashi group documented

the first model study of the skipped diene, in which the

Still-Gennari olefination⁷of 12 formed (Z)-trisubstituted olefin

13, and subsequent Migita-Kosugi-Stille coupling⁸installed the

(Z,Z)-skipped diene.^4dAmat and co-workers reported that their

model

Scheme 3. Initial route to chiral A-ring moiety 27 through

chirality transfer using the Claisen rearrangement.

compound exhibited better results by the Wittig reaction of 14

than the Still-Gennari modification to give (Z,Z)-skipped diene

15.^3cUnfortunately, low (Z)-selectivity was observed when

applying the methodology to the fully functionalized

intermediate 16 in their landmark total synthesis (Z/E =

2.2:1).^3e

To solve these synthetic challenges of the madangamine

alkaloids, we envisioned two consecutive processes involving

N-acyliminium cyclization⁹of enamine 7 and stereoselective

synthesis of skipped diene (Z,Z)-10 from 1,1-disubstituted

allene 8 (Scheme 2A). Protonation of enamine 7 would

generate the transient N-acyliminium ion, which would form

the diazatricyclic ABC-ring core through intramolecular

cyclization. The resulting 1,1-disubstituted allene 8 could be a

precursor of the (Z,Z)-skipped diene. We previously reported a

stereodivergent synthesis of a skipped diene from an allene.^6t

The method consisted of hydroboration of the allene and

subsequent Migita-Kosugi-Stille coupling⁸to give all four

possible stereoisomers of the skipped diene. The key to success

of this method was the stereodivergent hydroboration of the

allene.¹⁰While hydroboration with sterically small 9-BBN gave

a thermodynamic E-allylic alcohol, the reaction with sterically

large (Sia)₂BH provided a kinetic Z-allylic alcohol. Therefore,

in the case of the madangamine alkaloids, hydroboration of

1,1-disubstituted allene 8 with (Sia)₂BH would provide the

Z-allylic alcohol, which could undergo the Migita-Kosugi-Stille

coupling with (Z)-vinyl stannane 9, giving skipped diene

(Z,Z)-10. After the macrolactamization of (Z,Z)-10, the unified

total synthesis of madangamines A-E would be accomplished

from the common tetracyclic intermediate 11.

Scheme 2. (A) Synthetic plan toward the unified total synthesis

of madangamine alkaloids. (B) Precedents for synthesis of the

Z-trisubstituted olefin in the skipped diene of the madangamine

alkaloids.

The first synthetic task toward the unified total synthesis

of the madangamine alkaloids was the enantioselective

synthesis of A-ring 27 including a quaternary carbon center

(Scheme 3). The synthesis commenced with the

Suzuki-Miyaura coupling of known enol tosylate 19, which

was prepared from N-Boc glycine 18 in two steps, to form 20.¹¹

After DIBAL-H reduction of 20 in the presence of BF₃·Et₂O,¹²

the resulting alcohol was protected as an acetate. N-Allylation

of 21 and subsequent methanolysis of the acetate gave allylic

alcohol 22. The quaternary carbon center was constructed by

the Johnson-type Claisen rearrangement of the chiral secondary

alcohol. After IBX oxidation of allylic alcohol 22,¹³the

catalytic enantioselective alkylation of 23 provided allylic

alcohol 24 in 97% ee.¹⁴

A

solution of 24 and

trimethylorthoacetate was heated to 160 °C in the presence of

2-nitrophenol, installing the quaternary carbon center of 25,

which was isolated in 77% yield.¹⁵The resulting methyl ester

25 was converted to carbamate 26 by a three-step procedure

including hydrolysis with TMSOK, condensation with

ammonia and the Hofmann rearrangement.¹⁶Ring closing

metathesis¹⁷of 26 furnished the A-ring moiety 27 in 93% yield

and 92% ee. The enantiomeric excess of 27 was slightly

decreased through the chirality transfer by the Claisen

rearrangement.

An alternative robust route to A-ring moiety 27 was then

examined to improve both the number of steps and the

enantiomeric excess (Scheme 4). The synthesis began with

preparation of protected N-benzyl amine 29. After

N-propargylation of 29, the TMS group was installed at the

terminal alkyne of 30. We expected that this TMS group could

control the regioselectivity in the subsequent nickel-catalyzed

[4+2] cycloaddition¹⁸and the enantioselectivity in the CBS

reduction.¹⁹Indeed, the [4+2] cycloaddition of alkyne 31 with

azetidinone 32 took place smoothly under Louie’s conditions to

afford A-ring moiety 33 with high regioselectivity, along with

minor regioisomer 34. The CBS reduction of the inseparable

mixture of 33 and 34 gave the desired allylic alcohol 35 in 78%

yield with 95% ee, and 36 in 7.2% yield with 95% ee. The

regioisomeric allylic alcohol 36 was separated at this stage. The

TMS group in 35 was then removed by Brook rearrangement,

and the remaining alcohol was converted to picolinate 37.

Anti-S_N2’ reaction of 37 under Kobayashi’s conditions

installed the quaternary carbon center in 97% yield with

complete regioselectivity and stereoselectivity.²⁰The

enantiomeric excess of the product was confirmed after

removal of the benzyl group by Birch reduction, and was found

to be well preserved (27, 99%, 95% ee).

Scheme 4. Improved route to chiral A-ring moiety 27 through

chirality transfer using S_N2’ reaction.

With the chiral A-ring moiety 27 in hand, we turned our

attention to the synthesis of the bicyclic AB-ring by

palladium-catalyzed cycloisomerization (Scheme 5). The

cyclization required methyl alkynoate 39, which was prepared

in a two-step procedure including N-propargylation of 27 and

carbonylation of the terminal alkyne. The palladium-catalyzed

cycloisomerization of 39 under Trost’s conditions²¹smoothly

took place at 60 °C in the presence of Pd₂dba₃·CHCl₃(2

mol %) and HCO₂H in PhMe/MeCN = 49. The reaction

provided the cis-fused bicyclic ring 40²²in 87% yield,

associated with construction of the N-Boc-enamine group as an

iminium ion equivalent. Next, Narisada’s 1,4-reduction of

,-unsaturated ester with NaBH₄and CuCl gave 41 in 94%

yield with 10.8:1 diastereoselectivity.²³The methyl ester of 41

was converted to aldehyde 42 by stepwise reduction via the

Weinreb amide.²⁴Propargylsilane 7 was synthesized from

aldehyde 42 by the Ohira-Bestmann reaction²⁵and alkylation

with (iodomethyl)trimethylsilane.

Scheme 5. Synthesis of bicyclic AB-rings 7.

The stage was now set for the crucial N-acyliminium

cyclization to form the diazatricyclic ABC-ring core (Scheme

6). Addition of TFA to enamine 7 in MeCN/EtOH = 9 at 50 °C

initiated protonation of the enamine to generate N-acyliminium

ion 44a. In the most stable conformation, the propargyl silane

group of 44a adopted the equatorial position and was located

away from the N-acyliminium ion. Therefore, the cyclization

required a conformational flip to place the propargyl silane in

the axial position. Intramolecular allenylation then took place

via the conformation of 44b, providing 1,1-disubstituted allene

8 in 85% yield. The key to success was a combination of the

sterically small propargyl silane and the highly electrophilic

N-acyliminium ion. Addition of ethanol was also important to

form N,O-acetal 45 as a stable transient intermediate under

equilibrium conditions. In addition, ethanol modulated the

acidity of the reaction media. The reaction without ethanol took

place at room temperature, but caused significant cleavage of

the TIPS group (8: 52%; 46: 32%). In contrast, the reaction

with ethanol required a higher temperature at 50 °C, but

formation of primary alcohol 46 was completely suppressed.

(E)-47 or (Z)-47 from the same allene 8 by simply changing

organoborane reagents.

Table 1. Stereoselective hydroboration of 1,1-disubstituted

allene 8.

Entry

R₂BH

Combined Yield

E:Z ^c)

of 47 [%]^c)

1^a)

2^b)

3^b)

4^b)

9-BBN

83

44

78

93

6.1:1

1:1.5

1:4.7

1:20

(Thx)BH₂

Cy₂BH

(Sia)₂BH

a) 8 (1 equiv), R₂BH (5 equiv), THF, rt, 3 h; then 3 M NaOH aq,

30% H₂O₂aq, rt, 1 h. b) 8 (1 equiv), R₂BH (2 equiv), THF, rt,

10 min; then 3 M NaOH aq, 30% H₂O₂aq, rt, 1 h. c) Yields and

ratios of isolated products after purification by column

chromatography are given.

Scheme 6. Synthesis of 1,1-disubstituted allene 8 through

N-acyliminium cyclization.

With 1,1-disubstituted allene 8 in hand, the next challenge

was the stereoselective construction of the (Z,Z)-skipped diene

(Table 1).^6tFirst, Z-selective hydroboration of

8

was

reagents.

with 9-BBN took place in both

investigated

with

various

organoborane

Hydroboration of

8

regioselective and stereoselective fashions to give allylic

alcohol (E)-47 as the major product after oxidative work-up

(Table 1, Entry1, E:Z = 6.1:1). Use of (Thx)BH₂and Cy₂BH

resulted in moderate (Z)-stereoselectivities (Table 1, Entries 2

and 3). Gratifyingly, high (Z)-selectivity was realized with

(Sia)₂BH to afford allylic alcohol (Z)-47 in 89% yield (Table 1,

Entry 4, E:Z = 1:20).

The mechanistic rational for the stereodivergent

hydroboration of 1,1-disubstituted allene 8 is depicted in

Scheme 7.^6tIn contrast to the hydroboration of alkenes and

alkynes, the hydroboration of allenes requires precise control of

three selectivities (regio-, facial-, and kinetic vs.

thermodynamic). In the case of 1,1-disubstituted allene 8,

hydroboration took place regioselectively at the terminal

position of the two olefins. The facial selectivity was controlled

by the large Boc group. The organoborane reagents approached

from the opposite side of the Boc group to avoid steric

repulsion. Therefore, allylic borane (Z)-48 would be formed in

the initial step. The most challenging issue was control of the

1,3-allylic rearrangement. When a small organoborane reagent

such as 9-BBN was used, (Z)-48 quickly underwent two

1,3-allylic rearrangements^10,26via 49 under equilibrium

conditions, giving thermodynamically stable (E)-48 which was

converted to allylic alcohol (E)-47 after oxidative work-up. On

the other hand, use of sterically large (Sia)₂BH prevented the

1,3-allylic rearrangement of (Z)-48, directly giving allylic

alcohol (Z)-47 as the major product. Thus, we demonstrated the

stereodivergent hydroboration to produce either stereoisomer

Scheme 7. Mechanistic rationale for stereodivergent

hydroboration of 1,1-disubstituted allene 8.

We turned our attention to the Migita-Kosugi-Stille

coupling⁸to provide skipped diene (Z,Z)-10 (Scheme 8). The

primary alcohol (Z)-47 was converted to methyl carbonate 50,

which underwent a palladium-catalyzed coupling reaction with

vinyl stannane (Z)-9, giving (Z,Z)-10 in 91% yield. This is the

first successful example of the stereoselective synthesis of the

skipped diene in fully functionalized madangamine

intermediates. Our results indicated that the developed

sequence involving the stereodivergent hydroboration and

subsequent coupling reaction could become a general approach

to give access to skipped dienes comprised of trisubstituted

olefins, which are often seen in a number of biologically active

natural products.

The next challenge was the synthesis of madangamine E

(5) with a saturated thirteen-membered D-ring (Scheme 9B).

Structurally, the saturated D-ring seemed to be simpler than the

unsaturated series, but its construction proved to be more

challenging because it had no functional bias such as a

cis-olefin to facilitate the macrocyclization. Indeed, an initial

attempt using the same macrolactamization procedure as in the

synthesis of madangamine C (3) led to the formation of a

significant amount of the dimer through intermolecular

coupling. The Amat group employed a reaction sequence

including ring-closing metathesis and hydrogenation to

construct a saturated D-ring in their landmark total synthesis of

madangamine

D (4). However, their sequence was not

The common tetracyclic intermediate of the madangamine

alkaloids was then prepared from the skipped diene (Z,Z)-10 in

four steps (Scheme 8). Hydrolysis of the methyl ester and

removal of the Boc group with TMSOTf provided the amino

acid, which underwent macrolactamization with the

Mukaiyama reagent (CMPI, 2-chloro-1-methylpyridinium

iodide)²⁷to construct the eleven-membered E-ring. The TIPS

group of the resulting 52 was selectively removed with CSA in

methanol without affecting the Teoc group, giving

ABCE-tetracyclic common intermediate 11 in quantitative

yield.

applicable in our case because we installed the unsaturated

E-ring prior to the D-ring for the efficient collective synthesis.

Gratifyingly, we found that the following macrocyclic

alkylation suppressed the unfavorable dimerization. Appel

reaction of primary alcohol 11 provided bromide 56, which

underwent a copper-catalyzed alkylation with Grignard 57

reported by Cahiez and co-workers.²⁹The TIPS group was then

cleaved with CSA in methanol. The generated primary alcohol

was then converted to tosylate 58. Cleavage of the Teoc group

in 58 provided the substrate for the macrocyclic alkylation. A

solution of the resulting secondary amine in MeCN was heated

to 80 °C in the presence of K₂CO₃. The macrocyclization took

place smoothly in 61% yield over two steps without

observation of dimerization. Finally, the total synthesis of

madangamine E (5) was accomplished by LiAlH₄- reduction.

Madangamine

D

(4),

possessing

the

saturated

fourteen-membered D-ring, was prepared in an identical

fashion in 34% yield over seven steps from the common

intermediate 11 (Scheme 9C).

In contrast to madangamines D and E, madangamine A (1)

possesses a sensitive skipped (Z,Z,Z)-triene in the D-ring

(Scheme 9D). The synthesis of madangamine A (1) started with

the Wittig reaction of aldehyde 53 and subsequent cleavage of

the TIPS group, affording skipped triene 62 as a single

diastereomer. The skipped triene was a sensitive functional

group, and limited the possible transformations for construction

of the macrocyclic D-ring. For example, we first envisioned

reductive amination or macrolactamization to form the D-ring,

but the oxidation of primary alcohol 62 to form either an

aldehyde or carboxylic acid resulted in significant

decomposition. However, the macrocyclic alkylation that we

developed proved to be highly general even for the D-ring

including the sensitive skipped triene. After tosylation of 62

and removal of the Teoc group, macrocyclic alkylation with

iPr₂NEt took place at 70 °C without causing elimination of the

tosylate or isomerization of the skipped triene to the conjugated

olefin. LiAlH₄-reduction of the macrolactam completed the

total synthesis of madangamine A (1).

Synthesis of madangamine B (2) from the common

intermediate 11 proved to be the most challenging because the

position of the double bond was different from madangamines

A (1) and C (3) (Scheme 9E). In fact, aldehyde 53 was not a

productive intermediate to install the D-ring unit of

madangamine B (2). After extensive study, we found that the

aldehyde 64 was a possible intermediate to introduce the

carbon chain of the D-ring, and could be prepared by a

three-step sequence involving one-carbon dehomologation.

First, -oxybenzoylation of aldehyde 53 under Ishihara’s

conditions provided 63, which underwent reduction of the

aldehyde and subsequent hydrolysis in a one-pot process.³⁰The

resulting diol was converted to aldehyde 64 by oxidative

cleavage with Pb(OAc)₄in 50% yield over three steps.

Scheme 8. Synthesis of common tetracyclic intermediate 11.

As shown in parallel in Scheme 9, common

ABCE-tetracyclic intermediate 11 was converted to each

madangamine alkaloid. We began our collective total synthesis

by targeting madangamine

C (3), which possesses the

thirteen-membered macrocyclic D-ring including the cis-olefin

(Scheme 9A). The carbon framework of the D-ring was

installed by AZADO oxidation of primary alcohol 11,²⁸

followed by the Wittig coupling with 54, giving 55 in 88%

yield. After hydrolysis of the methyl ester and removal of the

Teoc group, the resulting amino acid smoothly underwent

macrolactamization with HOBt and EDCI to give the

pentacyclic product in 71% yield over two steps.^3eReduction of

the bismacrolactam with LiAlH₄furnished madangamine C (3)

in 76% yield. Thus, the total synthesis of madangamine C (3)

was accomplished in 40% overall yield in six steps from the

common intermediate 11.

Scheme 9. Unified total synthesis of madangamine alkaloids

CrCl₂-mediated Takai olefination³¹of aldehyde 64 with

diiodide 65 provided an inseparable mixture of olefins in 79%

yield (E:Z = 4.8:1). After hydrolysis of the cyclic acetal, the

(Z,Z)-skipped diene 68 was formed by the Wittig reaction of 66

with 67 with complete cis-stereoselectivity. The two

stereoisomers derived from the Takai olefination were

separated at this stage. Finally, the macrocyclic alkylation and

LiAlH₄-reduction completed the total synthesis of

madangamine B (2).

contain the fifteen-membered D-rings with trienes. In contrast,

madangamines D (4) and E (5) bearing saturated D-rings were

less potent than other madangamines with unsaturated D-rings.

In addition, madangamine C (3) containing a cis-olefin in the

thirteen-membered D-ring demonstrated a slightly higher

potency than madangamine

E (5) with the saturated

thirteen-membered D-ring. These results suggest an important

role of the olefin groups in the D-rings for the cytotoxicity.

With a series of synthetic madangamines A-E (1-5) in

hand, their growth inhibitory activities were evaluated against

thirteen human cancer cell lines including lung adenocarcinoma

A549, melanoma CHL-1 and SK-MEL-28, colon carcinoma

HCT116, cervix adenocarcinoma HeLa, fibrosarcoma HT1080,

breast carcinoma MCF-7 and MDA-MB-23, pancreatic

carcinoma Panc-1 and PK-1, prostate adenocarcinoma PC-3,

bladder carcinoma T24, and acute monocytic leukemia THP1

(Table 2). All synthetic madangamines showed antiproliferative

effects against these cancer cell lines, but their IC₅₀values were

depended on the structure of the D-ring. The most potent

alkaloids were madangamines A (1) and B (2), both of which

3. Conclusion

We accomplished

synthesis of madangamine alkaloids via

a

unified enantioselective total

common

a

ABCE-tetracyclic intermediate. The synthetic sequence

includes a number of key transformations. First, the chiral

diazatricyclic ABC-ring core was constructed through three

cyclization events involving Ni-catalyzed [4+2] cycloaddition,

palladium-catalyzed cycloisomerization and N-acyliminium

cyclization of the propargylsilane. One of the most challenging

issues in the synthesis was the stereoselecitve construction of

the (Z,Z)-skipped diene, which was accomplished by

Z-selective hydroboration/oxidation of the 1,1-disubstituted

Table 2. Cytotoxicity of synthetic madangamines A-E against various cancer cell lines (IC₅₀values in M)^a)

IC₅₀(M)

Cell Line

Madangamine A (1)

Madangamine B (2) Madangamine C (3) Madangamine D (4) Madangamine E (5)

A549

11.8

7.5

8.8

7.4

5.1

6.2

9.8

7.6

11.8

7.7

8.4

12.1

6.1

10.6

7.5

16.3

14.1

18.9

13.3

6.6

>20

16.3

6.9

>20

17.0

19.8

6.7

CHL-1

SK-MEL-28

HCT116

HeLa

10.0

7.4

4.3

HT1080

MCF-7

MDA-MB-231

Panc-1

PK-1

6.7

8.7

>20

13.0

>20

7.4

14.2

>20

13.5

>20

9.2

11.0

6.1

>20

10.3

18.3

8.3

10.8

6.8

PC-3

9.8

14.9

16.3

3.4

15.3

>20

5.0

T24

10.8

3.3

THP1

a) Antiproliferative effects of tested compounds against human cancer cell lines in a 48 h growth inhibitory assay using the MTT

method.

allene with (Sia)₂BH and subsequent Migita-Kosugi-Stille

coupling. The late-stage variation of the D-rings was realized

from the common tetracyclic intermediate. The macrocyclic

alkylation proved to be a general method for the synthesis of

various types of D-rings. Our developed route enabled the

supply of a series of synthetic madangamines for the first time,

and elucidated the role of the D-rings in their proliferative

effects against a variety of human cancer cell lines.

reported in ppm with reference to solvent signals [¹H NMR:

CDCl₃(7.26), C₆D₆(7.16), (CD₃)₂CO (2.05); ¹³C NMR: CDCl₃

(77.16), C₆D₆(128.06), (CD₃)₂CO (206.26); ¹⁹F NMR: C₆F₆

(‒164.9)]. Signal patterns are indicated as br, broad; s, singlet;

d, doublet; t, triplet; q, quartet; m, multiplet. MPLC was

performed on Yamazen, YFLC AI-580. Infrared spectra were

recorded using a BRUKER ALPHA FT-IR spectrometer. Mass

spectra were measured with Waters, LCT Premier XE

(ESI-TOF). Optical rotations were measured with a JASCO

P-2100 polarimeter. Melting points were measured with a

Yanaco MODEL MP-S3.

4. Experimental

General Details. Reactions were performed in oven-dried

glassware fitted with rubber septa under an argon atmosphere.

Toluene and DMSO were distilled from CaH₂. DMF and

MeOH were distilled from CaSO₄. Pyridine was distilled from

sodium hydroxide. Hexamethylphosphoric triamide was

distilled from CaO. Toluene, DMSO, DMF, MeOH, pyridine,

CH₂Cl₂, MeCN and EtOH were dried over activated 3Å

molecular sieves. THF (dehydrated, stabilizer free) and Et₂O

(dehydrated, stabilizer free) was purchased from KANTO

CHEMICAL CO., INC. Commercial reagents were used

without further purification. Thin-layer chromatography was

performed on Merck 60 F₂₅₄precoated silica gel plates, which

were visualized by exposure to UV (254 nm) or stained by

submersion in p-anisaldehyde solution or ethanolic

phosphomolybdic acid solution followed by heating on a hot

plate. Flash column chromatography was performed on silica

gel (Silica Gel 60 N; 63‒210 or 40‒50 mesh, KANTO

CHEMICAL CO., INC.) and basic alumina (Alumina,

Activated, about 200 mesh, WAKO PURE CHEMICAL

INDUSTRIES, Ltd.). Preparative layer chromatography was

performed on Merck PLC silica gel 60 F₂₅₄. ¹H NMR spectra

were recorded at 500 MHz with JEOL ECA-500 spectrometer

or 400 MHz with JEOL ECS-400 spectrometer. ¹³C NMR

spectra were recorded at 125 MHz with JEOL ECA-500

spectrometers. ¹⁹F NMR spectra were recorded at 470 MHz

with JEOL ECA-500 spectrometers. Chemical shifts are

Unsaturated ester (20): 9-Borabicyclo[3.3.1]nonane (0.5 M

solution in THF, 23 mL, 12 mmol) was added to a solution of

(allyloxy)triisopropylsilane³²(1.62 g, 7.56 mmol) and THF (3.8

mL) at 0 °C. The solution was allowed to warm to room

temperature, maintained for 1 h at room temperature, and

quenched with H₂O (1.6 mL, 91 mmol). This solution was

added to

a mixture of Cs₂CO₃(4.93 g, 15.1 mmol),

PdCl₂(dppf)∙CH₂Cl₂(247 mg, 302 µmol). A solution of tosylate

19 (3.02 g, 7.56 mmol), H₂O (1.9 mL) and THF (19 mL) was

then added to the resulting mixture. The mixture was allowed

to warm to 60 °C, and stirred for 1 h. After cooling to 0 °C, the

mixture was quenched with NaBO₃∙4H₂O (3.49 g, 22.7 mmol)

and H₂O (19 mL) at 0 °C, stirred for 1 h at room temperature,

and extracted with EtOAc (2x 20 mL). The combined organic

extracts were washed with brine (20 mL), dried over Na₂SO₄

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:9 to 1:4) to give unsaturated

ethyl ester 20 (2.77 g, 83%): a colorless oil; IR (film) 3368,

2943, 2867, 1719, 1517, 1463, 1367, 1247, 1178, 1105, 882,

1

681 cm^-1; H NMR (500 MHz, CDCl₃, 60 °C) δ 5.77 (s, 1H),

4.67 (brs, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.83 (d, J = 5.7 Hz,

2H), 3.75 (t, J = 6.3 Hz, 2H), 2.65 (t, J = 7.9 Hz, 2H), 1.75 (tt, J

= 7.9, 6.3 Hz, 2H), 1.46 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H),

1.14‒1.05 (m, 21H); ¹³C NMR (125 MHz, CDCl₃) δ 166.3 (C),

159.8 (C), 155.8 (C), 114.7 (CH), 79.9 (C), 63.4 (CH₂), 59.8

(CH₂), 46.3 (CH₂), 32.1 (CH₂), 28.5 (CH₃), 27.4 (CH₂), 18.1

(CH₃), 14.4 (CH₃), 12.1 (CH); HRMS (ESI), calcd for

C₂₃H₄₅NO₅SiNa⁺(M+Na)⁺466.2965, found 466.2962.

Aldehyde (23): 2-Iodoxybenzoic acid (174 mg, 622 mol)

was added to a solution of allylic alcohol 22 (128 mg, 311

mol) and DMSO (3.1 mL) at room temperature. This solution

was maintained at this temperature for 1 h, quenched with H₂O

(1 mL), and filtrated through a pad of Celite^®. The resulting

mixture was extracted with Et₂O (3x 5 mL). The combined

organic extracts were washed with brine (5 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel colomun chromatography (EtOAc/hexane 1:15 to 1:9) to

give aldehyde 23 (122 mg, 89%): a colorless oil; IR (film) 2943,

2867, 1701, 1679, 1457, 1397, 1366, 1248, 1170, 1109, 882

cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 10.07 (d, J = 7.7 Hz,

1H), 5.85 (ddd, J = 7.7, 1.5, 1.4 Hz, 1H), 5.77 (dddd, J = 16.9,

10.3, 6.1, 5.7 Hz, 1H), 5.15 (dddd, J = 10.3, 1.5, 1.4, 1.2 Hz,

1H), 5.11 (dd, J = 16.9, 1.4 Hz, 1H), 4.04‒3.90 (m, 2H),

3.85‒3.72 (m, 2H), 3.75 (t, J = 6.1 Hz, 2H), 2.66‒2.61 (m, 2H),

1.82‒1.75 (m, 2H), 1.46 (s, 9H), 1.15‒1.04 (m, 21H); ¹³C NMR

(125 MHz, CDCl₃, 60 °C) δ 190.8 (CH), 162.4 (C), 155.5 (C),

133.6 (CH), 126.2 (CH), 117.2 (CH₂), 80.6 (C), 62.5 (CH₂),

51.6 (CH₂), 49.9 (CH₂), 33.0 (CH₂), 28.5 (CH₃), 26.1 (CH₂),

18.2 (CH₃), 12.3 (CH); HRMS (ESI), calcd for C₂₄H₄₆NO₄Si⁺

(M+H)⁺440.3196, found 440.3199.

Allylic acetate (21): Boron trifluoride diethylether complex

(3.0 mL, 25 mmol) was added to a solution of unsaturated ethyl

ester 20 (9.99 g, 22.5 mmol) and CH₂Cl₂(45 mL) at ‒78 °C.

After maintaining for 30 min at ‒78 °C, diisobutylalminium

hydride (1.0 M in hexane, 68 mL, 68 mmol) was added

dropwise to the solution. This solution was quenched with

saturated aqueous (+)-potassium sodium tartrate (50 mL),

allowed to warm to room temperature, stirred for 3 h at room

temperature, and extracted with EtOAc (3x 50 mL). The

combined organic extracts were washed with brine (50 mL),

dried over Na₂SO₄, and concentrated. The residue was purified

by silica gel column chromatography (EtOAc/hexane 1:4) to

give allylic alcohol 69 (8.50 g, 94%): a colorless oil; IR (film)

3350, 2942, 2866, 1696, 1514, 1463, 1271, 1172, 1106, 882,

1

681 cm^-1; H NMR (500 MHz, CDCl₃) δ 5.62 (t, J = 6.9 Hz,

1H), 4.61 (brs, 1H), 4.17 (d, J = 6.9 Hz, 2H), 3.71 (d, J = 5.2

Hz, 2H), 3.68 (t, J = 5.7 Hz, 2H), 2.22 (t, J = 7.5 Hz, 2H), 1.65

(tt, J = 7.5, 5.7 Hz, 2H), 1.44 (s, 9H), 1.14‒1.02 (m, 21H); ¹³C

NMR (125 MHz, CDCl₃) δ 156.0 (C), 140.0 (C), 125.2 (CH),

79.5 (C), 62.4 (CH₂), 58.6 (CH₂), 45.5 (CH₂), 31.5 (CH₂), 28.5

(CH₃), 25.0 (CH₂), 18.1 (CH₃), 12.1 (CH); HRMS (ESI), calcd

for C₂₁H₄₃NO₄SiNa⁺(M+Na)⁺424.2859, found 424.2861.

Acetic anhydride (5.8 mL, 61 mmol) was added to a solution of

allyic alcohol 69 (12.3 g, 30.6 mmol), pyridine (5.0 mL, 61

mmol), N,N-dimethyl-4-aminopyridine (374 mg, 3.06 mmol)

and CH₂Cl₂(102 mL) at 0 °C. This solution was allowed to

warm to room temperature, maintained for 1 h at room

temperature, and concentrated. The residue was purified by

silica gel column chromatography (EtOAc/hexane 1/6) to give

allylic acetate 21 (13.5 g, 99%): a colorless oil; IR (film) 3367,

2943, 2867, 1742, 1719, 1510, 1463, 1367, 1235, 1171, 1106,

Allylic alcohol (24): Isopropyl titanate (160 µL, 831 mol)

was added to

a

mixture of (1R)-trans-N,N’-1,2-

cyclohexanediylbis(1,1,1-trifluoromethanesulfonamide) (10.5

mg, 27.7 µmol) and toluene (1.4 mL) at room temperature. The

resulting mixture was heated to 40 °C, stirred for 20 min at this

temperature, and cooled to ‒78 °C. Diethylzinc (1.1 M, 740 µL,

810 mol) was added to the resulting solution at ‒78 °C and

maintained for 10 min at this temperature. A solution of

aldehyde 23 (122 mg, 277 mol) and toluene (1.4 mL) was

added dropwise to the solution at ‒78 °C and warmed to ‒30 °C.

The solution was maintained for 2 h, and quenched with

saturated aqueous NH₄Cl (5 mL). The resulting mixture was

extracted with EtOAc (3x 5 mL). The combined organic

extracts were washed with brine (5 mL), dried over Na₂SO₄,

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:12 to 1:5) to give allylic

alcohol 24 (132 mg, 100%, 97% ee by HPLC (CHIRALPAK

AD-H, 250×4.6 mm, UV 210 nm, iPrOH/hexane 1:100 (v/v),

1.0 mL/min, 24: T_R= 12.6 min, ent-24: T_R= 10.8 min)): a

colorless oil; [α]²⁵_D‒7.3 (c 1.00, CHCl₃); IR (film) 3448, 2961,

2942, 2867, 1697, 1460, 1411, 1366, 1247, 1170, 1105, 882,

681 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 5.76 (dddd, J =

16.9, 10.3, 5.8, 4.6 Hz, 1H), 5.24 (d, J = 8.9 Hz, 1H), 5.13‒5.06

(m, 2H), 4.36 (ddd, J = 8.9, 6.6, 6.3 Hz, 1H), 3.95‒3.65 (m,

6H), 2.22 (ddd, J = 13.5, 9.2, 6.9 Hz, 1H), 2.11 (ddd, J = 13.5,

9.2, 5.7 Hz, 1H), 1.73‒1.57 (m, 3H), 1.55‒1.43 (m, 1H), 1.46 (s,

9H), 1.15‒1.05 (m, 21H), 0.92 (t, J = 7.5 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃, 60 °C) δ 155.7 (C), 138.0 (C), 134.1 (CH),

130.5 (CH), 116.5 (CH₂), 79.8 (C), 69.4 (CH), 63.1 (CH₂), 51.1

(CH₂), 48.7 (CH₂), 32.1 (CH₂), 30.7 (CH₂), 28.6 (CH₃), 25.3

(CH₂), 18.2 (CH₃), 12.4 (CH), 9.9 (CH₃); HRMS (ESI), calcd

for C₂₆H₅₁NO₄SiK⁺(M+K)⁺508.3224, found 508.3219.

1

882, 681 cm^-1; H NMR (500 MHz, CDCl₃, 60 °C) δ 5.49 (t, J

= 6.9 Hz, 1H), 4.64 (d, J = 6.9 Hz, 2H), 4.53 (brs, 1H), 3.73 (d,

J = 5.7 Hz, 2H), 3.70 (t, J = 6.1 Hz, 2H), 2.21 (t, J = 7.8 Hz,

2H), 2.04 (s, 3H), 1.65 (tt, J = 7.8, 6.1 Hz, 2H), 1.46 (s, 9H),

1.14‒1.05 (m, 21H); ¹³C NMR (125 MHz, CDCl₃) δ 171.0 (C),

155.9 (C), 142.8 (C), 119.6 (CH), 79.5 (C), 62.8 (CH₂), 60.8

(CH₂), 45.6 (CH₂), 32.0 (CH₂), 28.5 (CH₃), 25.6 (CH₂), 21.1

(CH₃), 18.1 (CH₃), 12.1 (CH); HRMS (ESI), calcd for

C₂₃H₄₅NO₅SiNa⁺(M+Na)⁺466.2965, found 466.2965.

Allylic alcohol (22): Sodium hydride (2.3 g, 61 mmol) was

added to a solution of allylic acetate 21 (9.00 g, 20.3 mmol),

allyl bromide (2.1 mL, 24 mmol), tetrabutylammonium iodide

(750 mg, 2.03 mmol) and DMF (100 mL) at 0 °C. After

maintaining for 2 h at this temperature, methanol (51 mL) was

added to the solution. This solution was maintained at 0 °C for

30 min, quenched with saturated aqueous NH₄Cl (80 mL), and

extracted with EtOAc/hexane = 1:3 (3x 80 mL). The combined

organic extracts were washed with brine (50 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel column chromatography (EtOAc/hexane 1:9) to give allylic

alcohol 22 (7.62 g, 85%): a colorless oil; IR (film) 3435, 2943,

Methyl ester (25): A sealed tube was charged with allylic

alcohol 24 (36.6 mg, 77.9 mmol), 2-nitrophenol (10.8 mg, 77.9

mmol), trimethyl orthoacetate (200 µL, 1.60 mmol) and

o-xylene (1.6 mL). The solution was heated to 160 °C, and

maintained for 2 h at this temperature. After cooling to room

temperature, the solvent was removed under reduced pressure.

The residue was purified by silica gel column chromatography

(EtOAc/hexane 1:29 to 1:7) to give methyl ester 24 (31.6 mg,

1

2866, 1698, 1460, 1411, 1247, 1171, 1106, 882, 681 cm^‒1; H

NMR (500 MHz, CDCl₃, 60 °C) δ 5.77 (ddt, J = 16.9, 10.3, 5.8

Hz, 1H), 5.50 (t, J = 6.9 Hz, 1H), 5.12 (dt, J = 10.3, 1.2 Hz,

1H), 5.09 (dt, J = 16.9, 1.2 Hz, 1H), 4.21 (d, J = 6.9 Hz, 2H),

3.81 (brs, 2H), 3.77 (brs, 2H), 3.69 (t, J = 6.0 Hz, 2H), 2.16 (t,

J = 7.2 Hz, 2H), 1.70‒1.62 (m, 2H), 1.46 (s, 9H), 1.15‒1.05 (m,

21H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 155.7 (C), 138.6

(C), 134.0 (CH), 126.3 (CH), 116.5 (CH₂), 79.8 (C), 62.9 (CH₂),

58.9 (CH₂), 51.1 (CH₂), 48.7 (CH₂), 31.9 (CH₂), 28.5 (CH₃),

25.0 (CH₂), 18.1 (CH₃), 12.3 (CH); HRMS (ESI), calcd for

C₂₄H₄₇NO₄SiNa⁺(M+Na)⁺464.3172, found 464.3167.

77%): a colorless oil; [α]²⁸+10.0 (c 1.00, CHCl₃); IR (film)

D

2960, 2944, 2866, 1739, 1699, 1462, 1405, 1366, 1247, 1172,

1103, 882, 681 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 5.74

(ddt, J = 17.2, 10.6, 5.5 Hz, 1H), 5.45‒5.34 (m, 2H), 5.09 (ddt,

J = 10.6, 1.5, 1.4 Hz, 1H), 5.05 (dtd, J = 17.2, 1.8, 1.4 Hz, 1H),

3.90‒3.80 (m, 2H), 3.70‒3.64 (m, 2H), 3.63 (s, 3H), 3.41 (d, J

= 14.6 Hz, 1H), 3.31 (d, J = 14.6 Hz, 1H), 2.46 (d, J = 15.2 Hz,

1H), 2.42 (d, J = 15.2 Hz, 1H), 2.04 (qd, J = 7.5, 5.2 Hz, 2H),

1.66‒1.50 (m, 4H), 1.44 (s, 9H), 1.13‒1.03 (m, 21H), 0.98 (t, J

= 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 172.3 (C),

156.6 (C), 134.6 (CH), 134.5 (CH), 130.7 (CH), 115.8 (CH₂),

79.7 (C), 64.2 (CH₂), 54.2 (CH₂), 51.7 (CH₂), 51.1 (CH₃), 43.5

(C), 39.2 (CH₂), 32.3 (CH₂), 28.6 (CH₃), 27.7 (CH₂), 26.1

(CH₂), 18.2 (CH₃), 13.9 (CH₃), 12.3 (CH); HRMS (ESI), calcd

for C₂₉H₅₆NO₅Si⁺(M+H)⁺526.3928, found 526.3930.

2-trimethylsilyl ethanol (150 µL, 1.10 mmol) and (CH₂Cl)₂(2.1

mL) at room temperature. The solution was heated to 60 °C,

and maintained for 15 h at this temperature. After cooling to

room temperature, the solution was quenched with saturated

aqueous NaHCO₃(3 mL), and extracted with CH₂Cl₂(3x 5

mL). The combined organic extracts were washed with brine (5

mL), dried over Na₂SO₄, and concentrated. The residue was

purified by silica gel chromatography (EtOAc/hexane 1:44 to

1:34) to give 2-(trimethylsilyl)ethyl carbamate 26 (51.3 mg,

78%): a colorless oil; [α]²⁶+29.5 (c 1.00, CHCl₃); IR (film)

D

3367, 2945, 2866, 1723, 1684, 1518, 1463, 1410, 1367, 1250,

1160, 1104, 883, 860, 838, 686 cm^-1; ¹H NMR (500 MHz,

CDCl₃, 60 °C) δ 6.50‒5.90 (m, 1H), 5.71 (dddd, J = 17.2, 10.3,

5.5, 5.2 Hz, 1H), 5.43 (dt, J = 16.3, 6.3 Hz, 1H), 5.27 (dt, J =

16.3, 1.5 Hz, 1H), 5.10 (dddd, J = 10.3, 1.5, 1.4, 1.2 Hz, 1H),

5.03 (dddd, J = 17.2, 1.7, 1.5, 1.5 Hz, 1H), 4.19‒4.08 (m, 2H),

3.92‒3.78 (m, 1H), 3.73 (dd, J = 16.1, 5.5 Hz, 1H), 3.68 (ddd, J

= 9.8, 6.0, 5.7 Hz, 1H), 3.61 (ddd, J = 9.8, 6.6, 6.3 Hz, 1H),

3.35 (d, J = 14.7 Hz, 1H), 3.27 (dd, J = 13.5, 7.8 Hz, 1H),

3.13‒2.90 (m, 1H), 2.99 (d, J = 14.7 Hz, 1H), 2.04 (qdd, J = 7.5,

6.3, 1.5 Hz, 2H), 1.66‒1.54 (m. 1H), 1.52‒1.26 (m, 3H), 1.45 (s,

9H), 1.13‒1.03 (m, 21H), 1.00‒0.95 (m, 3H), 0.98 (t, J = 7.5

Hz, 2H), 0.04 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 157.43

(C), 157.41 (C), 133.9 (CH), 133.3 (CH), 131.6 (CH), 116.0

(CH₂), 80.2 (C), 64.0 (CH₂), 62.5 (CH₂), 52.4 (CH₂), 51.9

(CH₂), 44.6 (C), 42.8 (CH₂), 31.0 (CH₂), 28.4 (CH₃), 27.1

(CH₂), 26.4 (CH₂), 18.2 (CH₃), 17.9 (CH₂), 13.9 (CH₃), 12.1

(CH), ‒1.3 (CH₃); HRMS (ESI), calcd for C₃₃H₆₆N₂O₅Si₂K⁺

(M+K)⁺665.4147, found 665.4157.

2-(Trimethylsilyl)ethyl carbamate (26): Potassium

trimethylsilanolate (161 mg, 1.26 mmol) was added to a

solution of methyl ester 25 (66.0 mg, 126 µmol) and Et₂O (2.5

mL) at room temperature. The solution was maintained for 18 h

at room temperature, and quenched with saturated aqueous

NH₄Cl (5 mL). The resulting mixture was extracted with

EtOAc (3x 5 mL). The combined organic extracts were washed

with brine (5 mL), dried over Na₂SO₄, and concentrated. The

residue was purified by silica gel column chromatography

(EtOAc/hexane 1:9 to 1:5) to give carboxylic acid 70 (58.9 mg,

91%): a colorless oil; [α]²⁸+53.4 (c 1.00, CHCl₃); IR (film)

D

3082, 2961, 2867, 1703, 1463, 1408, 1249, 1162, 1104, 920,

882, 682 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 5.71

(dddd, J = 17.2, 10.3, 5.7, 4.9 Hz, 1H), 5.40 (dt, J = 15.8, 6.3

Hz, 1H), 5.31 (d, J = 15.8 Hz, 1H), 5.12 (dddd, J = 10.3, 1.7,

1.4, 1.2 Hz, 1H), 5.05 (dddd, J = 17.2, 1.7, 1.5, 1.4 Hz, 1H),

3.92 (dd, J = 16.3, 5.7 Hz, 1H), 3.75‒3.58 (m, 3H), 3.55 (d, J =

14.9 Hz, 1H), 3.15‒2.85 (m, 1H), 2.47 (d, J = 13.5 Hz, 1H),

2.43 (d, J = 13.5 Hz, 1H), 2.06 (qdd, J = 7.5, 6.3, 0.9 Hz, 2H),

1.80‒1.65 (m, 1H), 1.55‒1.44 (m, 3H), 1.46 (s, 9H), 1.12‒1.03

(m, 21H), 0.99 (t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃,

60 °C) δ 173.1 (C), 158.3 (C), 134.0 (CH), 133.5 (CH), 131.8

(CH), 116.5 (CH₂), 81.6 (C), 63.8 (CH₂), 54.6 (CH₂), 52.8

(CH₂), 43.4 (C), 40.1 (CH₂), 33.3 (CH₂), 28.4 (CH₃), 27.4

(CH₂), 26.1 (CH₂), 18.2 (CH₃), 13.7 (CH₃), 12.3 (CH); HRMS

(ESI), calcd for C₂₈H₅₄NO₅Si⁺(M+H)⁺512.3771, found

512.3764.

1-Hydroxylbenzotriazole monohydrate (HOBt, 23.3 mg, 173

mol) was added to a mixture of carboxylic acid 70 (58.9 mg,

115 mol), NH₄Cl (35.3 mg, 230 mol), EDCI (33.1 mg, 173

mol), trimethylamine (40 µL, 290 mol), and THF (2.3 mL)

at room temperature. The mixture was stirred for 15 h at room

temperature, and quenched with H₂O (3 mL). The resulting

mixture was extracted with EtOAc (3x 3 mL). The combined

organic extracts were washed with brine (5 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel column chromatography (EtOAc/hexane 1:9 to 1:3) to give

primary amide 71 (53.6 mg, 91%): a colorless oil; [α]²⁶_D+48.5

(c 1.00, CHCl₃); IR (film) 3345, 3191, 2960, 2943, 2866, 1681,

1621, 1464, 1407, 1249, 1162, 1102, 921, 883, 733, 681 cm^-1;

¹H NMR (500 MHz, CDCl₃, 60 °C) δ 8.30‒7.00 (m, 1H), 5.71

(dddd, J = 17.2, 10.3, 5.5, 5.2 Hz, 1H), 5.45‒5.35 (m, 2H),

5.35‒5.20 (m, 1H), 5.09 (ddt, J = 10.3, 1.7, 1.5 Hz, 1H), 5.04

(ddt, J = 16.9, 1.7, 1.5 Hz, 1H), 3.93‒3.86 (m, 1H), 3.78‒3.52

(m, 4H), 3.20‒2.90 (m, 1H), 2.39 (d, J = 13.5 Hz, 1H), 2.28 (d,

J = 13.5 Hz, 1H), 2.06 (qd, J = 7.5, 4.9 Hz, 2H), 1.80‒1.65 (m,

1H), 1.58‒1.40 (m, 3H), 1.44 (s, 9H), 1.12‒1.03 (m, 21H), 0.98

(t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ

173.7 (C), 157.6 (C), 134.9 (CH), 134.1 (CH), 131.3 (CH),

116.1 (CH₂), 80.4 (C), 64.0 (CH₂), 54.3 (CH₂), 52.4 (CH₂),

43.3 (C), 41.1 (CH₂), 33.2 (CH₂), 28.5 (CH₃), 27.6 (CH₂), 26.1

(CH₂), 18.2 (CH₃), 13.8 (CH₃), 12.3 (CH); HRMS (ESI), calcd

for C₂₈H₅₄N₂O₄SiK⁺(M+K)⁺549.3490, found 549.3496.

(Diacetoxyiodo)benzene (50.7 mg, 158 mol) was added to a

solution of primary amide 71 (53.6 mg, 105 mol),

A-ring (27): A solution of 2-(trimethylsilyl)ethyl carbamate

26 (48.9 mg, 78.0 µmol) and CH₂Cl₂(1.6 mL) was heated to

reflux, and maintained for 2 h at this temperature. The Grubbs

2^ndgeneration catalyst (3.3 mg, 3.9 µmol) was then added to

the solution at room temperature, and maintained for 3 h at this

temperature. This solution was quenched with a solution of

potassium 2-isocyanoacetate³³(4.8 mg, 39 µmol) and MeOH

(500 µL) at room temperature, maintained for 1 h, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:9 to 1:5) to give A-ring 27

(41.6 mg, 93%, 92% ee by HPLC (CHIRALPAK AD-H,

250×4.6 mm, UV 210 nm, iPrOH/hexane 1:85 (v/v), 1.0

mL/min, 27: T_R= 7.2 min, ent-27: T_R= 8.5 min)): a colorless

oil; [α]²⁵‒9.0 (c 1.00, CHCl₃); IR (film) 3350, 2945, 2866,

D

1

1724, 1701, 1518, 1425, 1249, 1104, 860, 837, 681 cm^-1; H

NMR (500 MHz, CDCl₃, 60 °C) δ 5.72 (d, J = 10.1 Hz, 1H),

5.58 (d, J = 10.1 Hz, 1H), 4.92 (m, 1H), 4.15 (t, J = 8.3 Hz, 2H),

4.00 (d, J = 18.3 Hz, 1H), 3.74 (d, J = 18.3 Hz, 1H), 3.67 (dt, J

= 9.8, 6.3 Hz, 1H), 3.64 (dt, J = 9.8, 6.3 Hz, 1H), 3.55 (brs, 1H),

3.27 (dd, J = 13.8, 7.8 Hz, 1H), 3.09 (brs, 1H), 3.02‒2.90 (m,

1H), 1.64‒1.45 (m, 2H), 1.48 (s, 9H), 1.45‒1.39 (m, 2H),

1.14‒1.01 (m, 21H), 0.98 (t, J = 8.3 Hz, 2H), 0.04 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ 157.1 (C),

157.1 (C), 155.4 (C), 154.7 (C), 131.7 (CH), 131.0 (CH), 126.0

(CH), 125.3 (CH), 80.2 (C), 80.0 (C), 63.9 (CH₂), 63.9 (CH₂),

63.1 (CH₂), 62.9 (CH₂), 47.5 (CH₂), 46.4 (CH₂), 46.2 (CH₂),

46.2 (CH₂), 44.1 (CH₂), 43.1 (CH₂), 40.1 (C), 40.1 (C), 31.3

(CH₂), 31.2 (CH₂), 28.5 (CH₃), 28.5 (CH₃), 27.3 (CH₂), 27.3

(CH₂), 18.2 (CH₃), 18.2 (CH₃), 17.8 (CH₂), 17.8 (CH₂), 12.1

(CH), 12.1 (CH), ‒1.4 (CH₃), ‒1.4 (CH₃); HRMS (ESI), calcd

for C₂₉H₅₉N₂O₅Si₂⁺(M+H)⁺571.3963, found 571.3991.

Carbamate (29): 2-Trimethylsilylethanol 28 (7.3 mL, 51

mmol) and pyridine (3.3 mL, 41 mmol) were added to a

solution of triphosgene (5.02 g, 16.9 mmol) and Et₂O (250 mL)

at –45 °C. The reaction mixture was stirred at this temperature

for 1 h, then allowed to warm to room temperature, stirred for 3

h, and recooled to 0 °C. Benzylamine (11 mL, 100 mmol) was

then added dropwise to the mixture at 0 °C. The resulting

mixture was stirred at 0 °C for 30 min, allowed to warm to

room temperature, and stirred for 16 h. The resulting mixture

was quenched with water (100 mL), and extracted with EtOAc

(2x 50 mL). The combined organic extracts were washed with

brine (50 mL), dried over Na₂SO₄, and concentrated. The

residue was purified by silica gel column chromatography

(EtOAc/hexane 1:9) to give carbamate 29 (10.1 g, 80%): a

colorless oil; IR (film) 3332, 2953, 1698, 1527, 1250, 1179,

1135, 1060, 1043, 969, 945, 860, 837, 752, 697 cm^-1; ¹H NMR

(500 MHz, CDCl₃) δ 7.35‒7.26 (m, 5H), 5.05‒4.65 (m, 1H),

4.37 (d, J = 5.7 Hz, 2H), 4.19 (t, J = 8.6 Hz, 2H), 0.99 (t, J =

8.6 Hz, 2H), 0.04 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 156.9

(C), 138.8 (C), 128.7 (CH), 127.6 (CH), 127.5 (CH), 63.3

(CH₂), 45.1 (CH₂), 17.9 (CH₂), ‒1.4 (CH₃); HRMS (ESI), calcd

for C₁₃H₂₁NO₂SiK⁺(M+K)⁺290.0979, found 290.0987.

at room temperature. The reaction vessel was removed from the

glove box. The reaction was stirred at 60 °C for 6 h, and then

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:19 to 1:6) to give an

inseparable mixture of enone 33 and 34 (10.1 g, 93%): a

colorless oil; IR (film) 2954, 1703, 1670, 1453, 1418, 1366,

1

1247, 1169, 1115, 843, 767, 699 cm^-1; H NMR (500 MHz,

CDCl₃, 60 °C, a mixture of two regioisomers, signals of the

major isomer are reported) δ 7.36‒7.13 (m, 5H), 4.48 (brs, 2H),

4.35‒4.26 (m, 4H), 4.07 (brs, 2H), 3.93 (brs, 2H), 1.49 (s, 9H),

1.06 (t, J = 8.6 Hz, 2H) 0.11 (s, 9H), 0.06 (s, 9H); ¹³C NMR

(125 MHz, CDCl₃, 60 °C, a mixture of two regioisomers,

signals of the major isomer are reported) δ 197.2 (C), 165.5 (C),

157.1 (C), 154.2 (C), 137.5 (C), 137.0 (C), 128.9 (CH), 127.9

(CH), 127.8 (CH), 80.8 (C), 64.7 (CH₂), 51.6 (CH₂), 50.8

(CH₂), 49.6 (CH₂), 44.7 (CH₂), 28.5 (CH₃), 18.2 (CH₂), 1.4

(CH₃), ‒1.4 (CH₃); HRMS (ESI), calcd for C₂₇H₄₄N₂O₅Si₂Na⁺

(M+Na)⁺555.2686, found 555.2683.

Alkyne (30): Sodium hydride (63% in oil, 874 mg, 23.0

mmol) was added to a solution of carbamate 29 (3.84 g, 15.3

mmol), propargyl bromide (1.4 mL, 1.8 mmol),

tetrabutylammonium iodide (565 mg, 1.53 mmol) and DMF

(77 mL) at 0 °C. The solution was maintained at this

temperature for 1 h, quenched with saturated aqueous NH₄Cl

(50 mL), and extracted with hexane (3x 50 mL). The combined

organic extracts were washed with brine (30 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel column chromatography (EtOAc/hexane 1:12) to give

alkyne 30 (4.35 g, 98%): a colorless oil; IR (film) 2954, 1701,

Trimethylborate (310 µL, 2.80 mmol) was added to a

solution of (R)-diphenyl(pyrrolidin-2-yl)methanol (595 mg,

2.35 mmol) in THF (39 mL) at room temperature. The resulting

solution was maintained at room temperature for

1 h.

Borane-methyl sulfide complex (1.1 mL, 12 mmol) was added

to the solution. The solution was maintained for another 1 h. A

solution of enone 33 and 34 (6.26 g, 11.7 mmol) and THF (78

mL) was added over 2 h using a syringe pump to the solution of

the CBS reagent at room temperature. The resulting solution

was maintained for an additional 3 h, and quenched with

aqueous HCl (1 M, 50 mL) at 0 °C. The resulting mixture was

extracted with EtOAc (2x 50 mL). The combined organic

extracts were washed with brine (50 mL), dried over Na₂SO₄,

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/toluene 1:19 to 1:4) to afford a

mixture of allylic alcohols 35 and 36. The mixture of 35 and 36

were then separated by MPLC (Yamazen Ultra Pack Column D,

50×300 mm, EtOAc/hexane 11:89 to 32:68, 20 mL/min, 35: T_R

= 62.0 min, 36: T_R= 58.0 min) to afford allylic alcohol 35

(4.89 g, 78%, 95% ee determined by HPLC (CHIRALPAK

AD-H, 250×4.6 mm, UV 210 nm, iPrOH/hexane 1:9 (v/v), 1.0

mL/min, 35: T_R= 6.7 min, ent-35: T_R= 11.5 min)) and 36 (452

mg, 7.2%, 95% ee determined by HPLC (CHIRALPAK AD-H,

250×4.6 mm, UV 210 nm, iPrOH/hexane 1:99 (v/v), 1.0

mL/min, 36: T_R= 26.9 min, ent-36: T_R= 36.1 min)). Allylic

1

1496, 1455, 1236, 1177, 1114, 945, 839, 699 cm^-1; H NMR

(500 MHz, CDCl₃, 1:1 mixture of rotamers) δ 7.35‒7.26 (m,

5H), 4.60 (s, 2H), 4.29‒4.23 (m, 2H), 4.05 (brs, 1H), 3.96 (brs,

1H), 2.22 (t, J = 2.6 Hz, 1H), 1.05 (brs, 2H), 0.04 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ 156.3 (C),

156.3 (C), 137.1 (C), 137.1 (C), 128.7 (CH), 128.7 (CH), 128.4

(CH), 127.8 (CH), 127.6 (CH), 127.6 (CH), 79.1 (CH), 79.1

(CH), 72.1 (C), 72.0 (C), 64.4 (CH₂), 64.4 (CH₂), 49.3 (CH₂),

49.0 (CH₂), 35.4 (CH₂), 35.1 (CH₂), 17.9 (CH₂), 17.9 (CH₂),

‒1.4 (CH₃), ‒1.4 (CH₃); HRMS (ESI), calcd for C₁₆H₂₄NO₂Si⁺

(M+H)⁺290.1576, found 290.1571.

TMS alkyne (31): n-Butyllithium (1.63 M in hexane, 2.6 mL,

4.2 mmol) was added to a solution of alkyne 30 (1.17 g, 4.04

mmol) and THF (20 mL) at –78 °C. After maintaining for 10

min, chlorotrimethylsilane (620 µL, 4.9 mmol) was added to

the solution at the same temperature. The mixture was

maintained at –78 °C for 30 min, quenched with saturated

aqueous NH₄Cl (5 mL). The resulting mixture was extracted

with hexane (2x 10 mL). The combined organic extracts were

washed with brine (5 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:19) to give TMS alkyne 31

(1.43 g, 98%): a colorless oil; IR (film) 2956, 2178, 1704, 1455,

alcohol 35: a white amorphous solid; mp 34.0‒35.5 °C; [α]²¹

D

‒60.8 (c 1.00, CHCl₃); IR (film) 3444, 2954, 1699, 1453, 1422,

1

1366, 1250, 1172, 1135, 1062, 838, 766, 697 cm^-1; H NMR

(500 MHz, CDCl₃, 60 °C) δ 7.32‒7.19 (m, 5H), 4.44 (s, 2H),

4.28‒4.10 (m, 6H), 3.93 (d, J = 13.5 Hz, 1H), 3.51 (d, J = 18.9

Hz, 1H), 2.96 (dd, J = 13.5, 2.9 Hz, 1H), 1.49 (s, 9H), 1.04 (t, J

= 8.1 Hz, 2H), 0.10 (s, 9H), 0.05 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃, 1:1 mixture of rotamers) δ 157.3 (C), 157.0 (C), 155.4

(C), 155.4 (C), 145.3 (C), 144.2 (C), 137.4 (C), 137.4 (C),

135.6 (C), 135.6 (C), 128.7 (CH), 128.7 (CH), 127.6 (CH),

127.4 (CH), 127.4 (CH), 126.9 (CH), 80.1 (C), 80.1 (C), 66.0

(CH), 66.0 (CH), 64.3 (CH₂), 64.3 (CH₂), 49.9 (CH₂), 49.7

(CH₂), 49.7 (CH₂), 49.4 (CH₂), 48.2 (CH₂), 47.2 (CH₂), 44.9

(CH₂), 44.9 (CH₂), 28.5 (CH₃), 28.5 (CH₃), 18.2 (CH₂), 17.9

(CH₂), 0.4 (CH₃), 0.4 (CH₃), ‒1.4 (CH₃), ‒1.4 (CH₃); HRMS

(ESI), calcd for C₂₇H₄₆N₂O₅Si₂Na⁺(M+Na)⁺557.2843, found

1

1415, 1250, 1235, 1178, 1114, 1012, 843, 762, 699 cm^-1; H

NMR (500 MHz, CDCl₃, 1:1 mixture of rotamers) δ 7.34‒7.25

(m, 5H), 4.59 (s, 2H), 4.25 (t, J = 8.6 Hz, 2H), 4.10 (brs, 1H),

3.97 (brs, 1H), 1.08‒1.00 (m, 2H), 0.16 (s, 9H), 0.04 (s,

9H);¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ

156.3 (C), 156.3 (C), 137.3 (C), 137.3 (C), 128.6 (CH), 128.6

(CH), 128.4 (CH), 127.9 (CH), 127.5 (CH), 127.5 (CH), 100.9

(C), 100.9 (C), 89.2 (C), 89.0 (C), 64.3 (CH₂), 64.3 (CH₂), 49.4

(CH₂), 48.9 (CH₂), 36.4 (CH₂), 36.3 (CH₂), 17.9 (CH₂), 17.9

(CH₂), 0.0 (CH₃), 0.0 (CH₃), ‒1.3 (CH₃), ‒1.3 (CH₃); HRMS

557.2843. Allylic alcohol 36: a colorless oil; [α]²⁵‒82.6 (c

D

+

(ESI), calcd for C₁₉H₃₂NO₂Si₂(M+H)⁺362.1972, found

1.00, CHCl₃); IR (film) 3428, 2954, 1698, 1453, 1422, 1366,

1250, 1172, 1130, 1062, 950, 856, 838, 760, 698 cm^-1; ¹H NMR

(500 MHz, CDCl₃, 60 °C) δ 7.35‒7.13 (m, 5H), 4.66 (d, J =

14.9 Hz, 1H), 4.60 (d, J = 16.3 Hz, 1H), 4.30‒4.17 (m, 3H),

4.04 (brs, 1H), 3.91 (brs, 2H), 3.79 (d, J = 14.9 Hz, 1H), 3.65

(brs, 1H), 3.39 (brs, 1H), 1.49 (s, 9H), 1.00 (t, J = 8.3 Hz, 2H),

362.1979.

Allylic alcohol (35): In a glove box, Ni(cod)₂(567 mg, 2.05

mmol) was added to a solution of alkyne 31 (7.41 g, 20.5

mmol), 1-Boc-3-azetidinone 32 (3.51 g, 20.5 mmol),

triphenylphosphine (1.07 g, 4.10 mmol) and toluene (210 mL)

0.05 (s, 9H), 0.03 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C)

δ 158.4 (C), 155.1 (C), 143.6 (C), 137.4 (C), 136.1 (C), 128.8

(CH), 127.4 (CH), 126.9 (CH), 80.0 (C), 64.8 (CH₂), 63.2 (CH),

49.5 (CH₂), 48.7 (CH₂), 47.1 (CH₂), 47.1 (CH₂), 28.6 (CH₃),

18.1 (CH₂), 0.1 (CH₃), ‒1.4 (CH₃); HRMS (ESI), calcd for

C₂₇H₄₆N₂O₅Si₂Na⁺(M+Na)⁺557.2843, found 557.2839.

Picolinate (37): Potassium tert-butoxide (1.36 g, 12.1 mmol)

was added to the solution of 35 (4.30 g, 8.04 mmol) and THF

(80 mL) at 0 °C. The solution was maintained at 0 °C for 15

min, 1 M HCl was added to the solution until TLC analysis

indicated the complete consumption of the TMS ether (total: 30

mL). The resulting mixture was extracted with EtOAc (2x 50

mL). The combined organic extracts were washed with brine

(50 mL), dried over Na₂SO₄, and concentrated. The residue was

purified by silica gel column chromatography (EtOAc/hexane

1:4) to give allylic alcohol 72 (3.04 g, 82%): a colorless oil;

[α]²¹_D‒26.2 (c 1.00, CHCl₃); IR (film) 3436, 2954, 1699, 1455,

1419, 1366, 1247, 1166, 1106, 1056, 936, 859, 838, 768, 700

cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 7.34‒7.20 (m, 5H),

5.67‒5.63 (m, 1H), 4.52 (d, J = 15.5 Hz, 1H), 4.42 (d, J = 15.5

Hz, 1H), 4.30‒4.23 (m, 2H), 4.17‒4.08 (m, 1H), 3.93‒3.84 (m,

2H), 3.82 (d, J = 15.8 Hz, 1H), 3.66 (d, J = 18.6 Hz, 1H), 3.46

(d, J = 4.6 Hz, 2H), 1.48 (s, 9H), 1.08‒1.02 (m, 2H), 0.06 (s,

9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 156.9 (C), 155.2

(C), 137.8 (C), 135.5 (C), 128.7 (CH), 128.1 (CH), 127.5 (CH),

125.7 (CH), 80.3 (C), 64.3 (CH₂), 63.8 (CH), 50.1 (CH₂), 49.4

(CH₂), 47.9 (CH₂), 44.5 (CH₂), 28.6 (CH₃), 18.2 (CH₂), ‒1.4

(CH₃); HRMS (ESI), calcd for C₂₄H₃₈N₂O₅SiNa⁺(M+Na)⁺

485.2448, found 485.2454.

mmol) was slowly added to a mixture of CuBr·Me₂S (918 mg,

4.46 mmol), ZnI₂(1.42 g, 4.46 mmol), and THF (25 mL) at

0 °C. The resulting mixture was stirred at this temperature for

30 min. A solution of picolinate 37 (1.41 g, 2.48 mmol) and

THF (25 mL) was added dropwise to the mixture dropwise at

0 °C. The mixture was stirred for 30 min, and quenched with

saturated aqueous NH₄Cl (50 mL). The resulting mixture was

extracted with hexane (2x 50 mL). The combined organic

extracts were washed with brine (50 mL), dried over Na₂SO₄,

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:9) and MPLC (Yamazen

Ultra Pack Column B, 26×300 mm, EtOAc/hexane 18:82, 20

mL/min, 73: T_R= 28.5 min) to afford S_N2’ product 73 (1.58 g,

97%): a colorless oil; [α]²¹+18.0 (c 1.00, CHCl₃); IR (film)

D

2945, 2866, 1699, 1464, 1419, 1365, 1249, 1175, 1144, 1103,

882, 858, 838, 770 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ

7.31‒7.14 (m, 5H), 5.70 (d, J = 10.9 Hz, 1H), 5.64 (d, J = 10.9

Hz, 1H), 4.56 (d, J = 15.8 Hz, 1H), 4.51 (d, J = 15.8 Hz, 1H),

4.19 (dt, J = 10.6, 7.2 Hz, 2H), 3.85 (brs, 2H), 3.65 (t, J = 5.5

Hz, 2H), 3.54‒3.25 (m, 4H), 1.60‒1.41 (m, 13H), 1.12‒1.04 (m,

21H), 1.05‒0.96 (m, 2H), 0.04 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃, 60 °C) δ 157.9 (C), 155.4 (C), 138.4 (C), 132.8 (CH),

128.6 (CH), 127.6 (CH), 127.3 (CH), 124.4 (CH), 79.8 (C),

64.2 (CH₂), 63.9 (CH₂), 52.7 (CH₂), 52.0 (CH₂), 48.1 (CH₂),

43.5 (CH₂), 41.4 (C), 33.4 (CH₂), 28.6 (CH₃), 27.6 (CH₂), 18.2

(CH₃), 18.1 (CH₂), 12.3 (CH), ‒1.4 (CH₃); HRMS (ESI), calcd

for C₃₆H₆₄N₂O₅Si₂Na⁺(M+Na)⁺683.4252, found 683.4232.

Sodium (1.10 g, 47.8 mmol) was added to a solution of 73

(1.58 g, 2.39 mmol), tBuOH (0.7 mL), and NH₃/THF (25:24,

34 mL) at –78 °C. The resulting mixture was stirred for 15 min

at –78 °C, quenched with solid NH₄Cl (3.84 g, 71.7 mmol),

allowed to warm to room temperature, and diluted with water

(20 mL). The resulting mixture was extracted with hexane (2x

20 mL). The combined organic extracts were washed with brine

(10 mL), dried over Na₂SO₄, and concentrated. The residue was

purified by silica gel column chromatography (EtOAc/hexane

1:19 to 1:9) to give tetrahydropyridine 27 (1.34 g, 99%, 95% ee

by HPLC (CHIRALPAK AD-H, 250×4.6 mm, UV 210 nm,

iPrOH/hexane 1:85 (v/v), 1.0 mL/min, 27: T_R= 6.9 min, ent-27:

T_R= 8.0 min)): [α]²¹_D‒11.5 (c 1.00, CHCl₃).

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

hydrochloride (EDCI, 1.89 g, 9.86 mmol) was added to a

solution of alcohol 72 (3.04 g, 6.57 mmol), DMAP (80.3 mg,

657 µmol), 2-picolinic acid (1.13 g, 9.20 mmol), and CH₂Cl₂

(66 mL) at 0 °C. The solution was maintained at this

temperature for 3 h, and quenched with H₂O (30 mL). The

resulting mixture was extracted with CH₂Cl₂(2x 30 mL). The

combined extracts were washed with brine (30 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel column chromatography (EtOAc/hexane 1:3 to 1:1) to give

picolinate 37 (3.48 g, 93%): a colorless oil; [α]²¹_D‒63.1 (c 1.00,

CHCl₃); IR (film) 2954, 1740, 1698, 1454, 1421, 1366, 1245,

1169, 1129, 1044, 939, 858, 839, 750, 702 cm^-1; ¹H NMR (500

MHz, CDCl₃, 60 °C) δ 8.77 (d, J = 4.3 Hz, 1H), 8.08 (d, J = 7.8

Hz, 1H), 7.81 (ddd, J = 7.8, 7.8, 1.5 Hz, 1H), 7.45 (dd, J = 7.8,

4.3 Hz, 1H), 7.32‒7.21 (m, 5H), 5.81 (brs, 1H), 5.49 (brs, 1H),

4.50 (d, J = 15.5 Hz, 1H), 4.45 (d, J = 15.5 Hz, 1H), 4.29‒4.23

(m, 2H), 4.04 (d, J = 17.8 Hz, 1H), 3.95 (d, J = 16.1 Hz, 1H),

3.89 (dd, J = 13.8, 4.6 Hz, 1H), 3.83 (d, J = 16.1 Hz, 1H), 3.74

(d, J = 17.8 Hz, 1H), 3.60 (dd, J = 13.8, 4.6 Hz, 1H), 1.43 (s,

9H), 1.08‒1.02 (m, 2H), 0.05 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃, 60 °C) δ 164.5 (C), 156.8 (C), 154.6 (C), 150.1 (CH),

148.4 (C), 139.0 (C), 137.5 (C), 136.8 (CH), 128.6 (CH), 128.0

(CH), 127.5 (CH), 126.8 (CH), 125.3 (CH), 120.9 (CH), 80.2

(C), 67.3 (CH), 64.2 (CH₂), 50.0 (CH₂), 49.3 (CH₂), 44.6 (CH₂),

44.3 (CH₂), 28.4 (CH₃), 18.1 (CH₂), ‒1.5 (CH₃); HRMS (ESI),

calcd for C₃₀H₄₁N₃O₆SiNa⁺(M+Na)⁺590.2662, found

590.2673.

Eneyne (38): Sodium hydride (63% in mineral oil, 257 mg,

6.75 mmol) was added to a solution of tetrahydropyridine 27

(2.57 g, 4.50 mmol), propargyl bromide (510 µL, 6.8 mmol),

tetrabutylammonium iodide (166 mg, 450 µmol) and DMF (45

mL) at 0 °C. This solution was maintained at this temperature

for 4 h, quenched with saturated aqueous NH₄Cl (25 mL), and

extracted with EtOAc/hexane = 1/3 (3x 25 mL). The combined

organic extracts were washed with brine (15 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel column chromatography (EtOAc/hexane 1:29 to 1:12) to

give eneyne 38 (2.63 g, 96%): a colorless oil; [α]²¹+10.5 (c

D

1.00, CHCl₃); IR (film) 3313, 2945, 2866, 1702, 1418, 1249,

1175, 1147, 1105, 839 cm^-1; ¹H NMR (500 MHz, CDCl₃,

60 °C) δ 5.74‒5.66 (m, 1H), 5.63 (ddd, J = 10.3, 2.0, 2.0 Hz,

1H), 4.25‒4.17 (m, 2H), 4.10 (brs, 2H), 3.88 (d, J = 18.1 Hz,

1H), 3.82 (d, J = 18.1 Hz, 1H), 3.65 (t, J = 6.0 Hz, 2H),

3.48‒3.36 (m, 1H), 3.43 (d, J = 14.9 Hz, 1H), 3.39 (d, J = 14.9

Hz, 1H), 3.33‒3.24 (m, 1H), 2.17 (brs, 1H), 1.64‒1.44 (m, 4H),

1.48 (s, 9H), 1.14‒1.00 (m, 23H), 0.06 (s, 9H); ¹³C NMR (125

MHz, CDCl₃, 1:1 mixture of rotamers) δ 157.1 (C), 157.1 (C),

155.3 (C), 155.2 (C), 132.3 (CH), 131.9 (CH), 125.1 (CH),

124.6 (CH), 80.2‒79.2 (C x4), 72.2‒71.3 (CH x2), 64.3 (CH₂),

64.3 (CH₂), 63.9 (CH₂), 63.9 (CH₂), 52.8 (CH₂), 52.1 (CH₂),

48.0 (CH₂), 46.8 (CH₂), 43.7 (CH₂), 42.9 (CH₂), 41.2‒40.4 (C

x2), 38.4 (CH₂), 38.4 (CH₂), 32.8 (CH₂), 32.5 (CH₂), 28.6

(CH₃), 28.6, (CH₃), 27.4 (CH₂), 27.4 (CH₂), 18.2 (CH₃), 18.2

A-ring (27): A 100 mL flask equipped with a rubber septa

connected to a bubbler was charged with magnesium (turnings,

700 mg, 28.8 mmol) and THF (40 mL). (3-Bromopropoxy)-

triisopropylsilane (4.5 mL, 16 mmol) was added to the mixture

at room temperature over a period of 5 min. The resulting

mixture was stirred vigorously for 1 h. The concentration of the

Grignard reagent was determined as 0.26 M by titration with

1,10-phenanthroline method.³⁴

The above Grignard reagent (0.26 M in THF, 31 mL, 7.5

(CH₃), 17.9 (CH₂), 17.8 (CH₂), 12.1 (CH), 12.1 (CH), –1.4

(CH₃), –1.4 (CH₃); HRMS (ESI), calcd for C₃₂H₆₁N₂O₅Si₂

(M+H)⁺609.4119, found 609.4130.

Methyl ester (41): Copper (I) chloride (264 mg, 2.67 mmol)

and NaBH₄(101 mg, 2.67 mmol) were added to a solution of

unsaturated methyl ester 40 (1.78 g, 2.67 mmol) and EtOH (27

mL) at ‒20 °C. Copper (I) chloride (264 mg, 2.67 mmol) and

NaBH₄(101 mg, 2.67 mmol) were added to the mixture every

15 min until TLC analysis indicated the complete consumption

of unsaturated methyl ester 40 (total: CuCl 3.0 equiv., NaBH₄

3.0 equiv.). The mixture was quenched with saturated aqueous

NH₄Cl (10 mL), and extracted with EtOAc (3x 10 mL). The

combined organic extracts were washed with brine (5 mL),

dried over Na₂SO₄, and concentrated. The residue was filtered

through a pad of silica gel (EtOAc/hexane 1:19). Two

diastereomers were then separated by MPLC (Yamazen Ultra

Pack Column D, 50×300 mm, EtOAc/hexane 9:91 to 30:70, 45

mL/min, 41: T_R= 38.0 min, 74: T_R= 42.0 min) to afford

methyl esters 41 (1.54 g, 86%) and 74 (142 mg, 7.9%). methyl

ester 41: a colorless oil; [α]²⁵_D‒10.3 (c 1.00, CHCl₃); IR (film)

2946, 2865, 1742, 1703, 1652, 1436, 1367, 1250, 1168, 1110

+

Methyl ynoate (39): n-Butyllithium (1.6 M in hexane, 1.3

mL, 2.2 mmol) was added to a solution of alkyne 38 (1.27 g,

2.09 mmol) and THF (21 mL) at –78 °C. After the solution was

maintained for 15 min, methyl chloroformate (240 µL, 3.1

mmol) was added at the same temperature. The solution was

maintained for 30 min, and quenched with saturated aqueous

NH₄Cl (10 mL) at –78 °C. The resulting mixture was extracted

with EtOAc (2x 10 mL). The combined organic extracts were

washed with brine (10 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:5) to give a mixture of

methyl ynoate 39 and alkyne 38. The mixture was then

separated by MPLC (Yamazen Ultra Pack Column B, 26×300

mm, EtOAc/hexane 24:76, 20 mL/min, 39: T_R= 30.0 min, 38:

T_R= 28.0 min) to afford methyl ynoate 39 (969 mg, 70%, brsm

79%) and alkyne 38 (140 mg, 11%). 39: a colorless oil; [α]²⁵

cm^-1; H NMR (500 MHz, C₆D₆, 79 °C) δ 7.20‒6.90 (m, 1H),

1

D

+12.3 (c 1.00, CHCl₃); IR (film) 2945, 2866, 2239, 1702, 1462,

1423, 1250, 1175, 1104, 839 cm^-1; ¹H NMR (500 MHz, CDCl₃,

60 °C) δ 5.76‒5.69 (m, 1H), 5.60 (d, J = 10.3 Hz, 1H),

4.28‒4.17 (m, 4H), 3.94‒3.86 (m, 1H), 3.84‒3.76 (m, 1H), 3.75

(s, 3H), 3.65 (t, J = 6.1 Hz, 2H), 3.56‒3.32 (m, 1H), 3.42 (d, J

= 14.9 Hz, 1H), 3.35 (d, J = 14.9 Hz, 1H), 3.25 (brs, 1H),

1.62‒1.45 (m, 4H), 1.48 (s, 9H), 1.13‒1.00 (m, 23H), 0.06 (s,

9H); ¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ

156.9 (C), 156.9 (C), 155.4 (C), 155.2 (C), 153.8 (C), 153.8 (C),

132.1 (CH), 131.7 (CH), 125.6 (CH), 125.2 (CH), 84.3 (C),

84.3 (C), 83.8 (C), 83.8 (C), 80.1 (C), 80.1 (C), 64.7 (CH₂),

64.7 (CH₂), 63.9 (CH₂), 63.9 (CH₂), 52.8 (CH₃), 52.8 (CH₃),

52.7 (CH₂), 52.7 (CH₂), 48.0 (CH₂), 46.7 (CH₂), 43.7 (CH₂),

43.0 (CH₂), 40.9 (C), 40.6 (C), 38.6 (CH₂), 38.5 (CH₂), 32.9

(CH₂), 32.1 (CH₂), 28.6 (CH₃), 28.6 (CH₃), 27.4 (CH₂), 27.4

(CH₂), 18.2 (CH₃), 18.2 (CH₃), 18.0 (CH₂), 17.9 (CH₂), 12.1

(CH), 12.1 (CH), ‒1.4 (CH₃), ‒1.4 (CH₃); HRMS (ESI), calcd

for C₃₄H₆₃N₂O₇Si₂⁺(M+H)⁺667.4174, found 667.4173.

4.43 (d, J = 8.3 Hz, 1H), 4.29 (t, J = 8.3 Hz, 2H), 4.12‒3.96 (m,

1H), 3.94‒3.72 (m, 2H), 3.64‒3.54 (m, 2H), 3.38 (s, 3H), 2.92

(d, J = 13.2 Hz, 1H), 2.87 (d, J = 13.5 Hz, 1H), 2.52‒2.40 (m,

2H), 2.23 (brs, 1H), 2.07 (dd, J = 16.0, 7.2 Hz, 1H), 2.02 (dd, J

= 15.8, 6.6 Hz, 1H), 1.65‒1.49 (m, 4H), 1.42 (s, 9H), 1.17‒1.05

(m, 21H), 1.02‒0.95 (m, 2H), ‒0.02 (s, 9H); ¹³C NMR (125

MHz, CDCl₃, 1:1 mixture of rotamers) δ 172.4 (C), 172.2 (C),

156.0 (C), 156.0 (C), 152.9 (C), 152.4 (C), 127.0 (CH), 126.8

(CH), 101.8 (CH), 101.4 (CH), 81.3 (C), 81.3 (C), 63.8 (CH₂),

63.7 (CH₂), 63.7 (CH₂), 63.6 (CH₂), 51.9 (CH₃), 51.9 (CH₃),

48.9 (CH₂), 47.9 (CH₂), 45.5 (CH₂), 45.1 (CH₂), 44.2 (CH₂),

43.9 (CH₂), 38.2 (CH), 37.5 (CH), 35.2 (CH₂), 35.0 (CH₂), 34.0

(C), 34.0 (C), 31.7 (CH), 31.4 (CH), 30.7 (CH₂), 30.5 (CH₂),

28.4 (CH₃), 28.4 (CH₃), 26.4 (CH₂), 26.4 (CH₂), 18.2 (CH₃),

18.2 (CH₃), 17.9 (CH₂), 17.9 (CH₂), 12.1 (CH), 12.1 (CH), –1.4

(CH₃), –1.4 (CH₃); HRMS (ESI), calcd for C₃₄H₆₄N₂O₇Si₂Na⁺

(M+Na)⁺691.4150, found 691.4172. methyl ester 74: a

colorless oil; [α]²⁷+30.6 (c 1.00, CHCl₃); IR (film) 2947,

D

Unsaturated methyl ester (40): Tris(dibenzylidenacetone)-

dipalladium chloroform adduct (39.4 mg, 38.1 µmol) was

added to a solution of methyl ynoate 39 (1.27 g, 1.90 mmol),

HCO₂H (350 µL, 9.5 mmol) and PhMe/MeCN = 49 (190 mL).

The solution was heated to 60 °C, maintained for 1 h, quenched

with saturated aqueous NaHCO₃(50 mL) at room temperature,

and extracted with EtOAc (3x 50 mL). The combined organic

extracts were washed with brine (50 mL), dried over Na₂SO₄,

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:19) to give unsaturated

2866, 1741, 1705, 1649, 1369, 1249, 1173, 1136, 1110 cm^-1; ¹H

NMR (500 MHz, C₆D₆, 79 °C) δ 7.10‒6.80 (m, 1H), 4.67 (dd, J

= 7.2, 7.2 Hz, 1H), 4.41‒4.20 (m, 3H), 4.13 (d, J = 13.5 Hz,

1H), 4.00‒3.75 (m, 1H), 3.61‒3.52 (m, 2H), 3.37 (s, 3H), 3.28

(d, J = 13.8 Hz, 1H), 2.71 (d, J = 13.2 Hz, 1H), 2.45 (dd, J =

12.9, 12.9 Hz, 1H), 2.30 (d, J = 12.1 Hz, 1H), 2.02‒1.88 (m,

2H), 1.62‒1.46 (m, 2H), 1.44‒1.38 (m, 1H), 1.42 (s, 9H),

1.36‒1.17 (m, 2H), 1.15‒1.03 (m, 21H), 1.01‒0.95 (m, 2H),

‒0.03 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of

rotamers) δ 172.6 (C), 172.6 (C), 155.6 (C), 155.6 (C), 153.0

(C), 152.4 (C), 125.4 (CH), 125.0 (CH), 104.2 (CH), 103.7

(CH), 81.1 (C), 81.1 (C), 63.8 (CH₂), 63.8 (CH₂), 63.7 (CH₂),

63.7 (CH₂), 51.8 (CH₃), 51.8 (CH₃), 50.5 (CH₂), 50.5 (CH₂),

48.5 (CH₂), 48.3 (CH₂), 44.3 (CH₂), 43.6 (CH₂), 42.0 (CH),

41.8 (CH), 38.5 (CH), 38.5 (CH), 36.0 (CH₂), 35.8 (CH₂), 34.4

(C), 34.3 (C), 32.1 (CH₂), 32.1 (CH₂), 28.4 (CH₃), 28.4 (CH₃),

26.8 (CH₂), 26.7 (CH₂), 18.1 (CH₃), 18.1 (CH₃), 17.9 (CH₂),

17.9 (CH₂), 12.0 (CH), 12.0 (CH), –1.3 (CH₃), –1.3 (CH₃);

methyl ester 40 (1.10 g, 87%): a colorless oil; [α]²⁵+62.0 (c

D

1.00, CHCl₃); IR (film) 2947, 2866, 1708, 1649, 1369, 1249,

1167, 1107, 858, 838 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C)

δ 7.07‒6.77 (m, 1H), 5.76 (s, 1H), 5.01 (brs, 1H), 4.57 (brs,

1H), 4.40‒4.12 (m, 1H), 4.19 (t, J = 8.6 Hz, 2H), 3.84‒3.56 (m,

4H), 3.73 (s, 3H), 3.30 (d, J = 9.2 Hz, 1H), 2.88 (d, J = 13.8 Hz,

1H), 2.66 (brs, 1H), 1.68‒1.36 (m, 4H), 1.50 (s, 9H), 1.12‒0.99

(m, 23H), 0.04 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 1:1

mixture of rotamers) δ 166.1 (C), 166.1 (C), 156.6 (C), 156.4

(C), 155.9 (C), 155.9 (C), 152.7 (C), 152.2 (C), 127.0 (CH),

126.8 (CH), 118.4 (CH), 118.0 (CH), 103.3 (CH), 103.3 (CH),

81.5 (C), 81.5 (C), 63.9 (CH₂), 63.9 (CH₂), 63.7 (CH₂), 63.7

(CH₂), 51.4 (CH₃), 51.4 (CH₃), 46.7 (CH₂), 46.3 (CH₂), 46.0

(CH), 46.0 (CH₂), 45.6 (CH), 45.4 (CH₂), 44.2 (CH₂), 44.2

(CH₂), 37.4 (C), 37.2 (C), 32.0 (CH₂), 31.7 (CH₂), 28.3 (CH₃),

28.3 (CH₃), 26.7 (CH₂), 26.7 (CH₂), 18.1 (CH₃), 18.1 (CH₃),

18.0 (CH₂), 17.9 (CH₂), 12.0 (CH), 12.0 (CH), –1.4 (CH₃), –1.4

(CH₃); HRMS (ESI), calcd for C₃₄H₆₂N₂O₇Si₂Na⁺(M+Na)⁺

689.3993, found 689.3984.

+

HRMS (ESI), calcd for C₃₄H₆₅N₂O₇Si₂(M+H)⁺669.4330,

found 669.4363.

Aldehyde (42): A 200 mL flask equipped with a rubber septa

connected to a bubbler was charged with magnesium (turnings,

751 mg, 30.9 mmol) and THF (47 mL). 1,2-Dibromoethane (12

µL, 140 µmol) and 2-bromopropane (2.64 mL, 28.2 mmol)

were added to the mixture at room temperature over a period of

5 min. The resulting mixture was stirred vigorously for 1 h. The

concentration of the resulting isopropylmagnesium bromide

was determined as 0.38 M by titration with 1,10-phenanthroline

method.³⁵

Isopropylmagnesium bromide (0.38 M in THF, 24 mL, 9.2

mmol) was added to a mixture of methyl ester 41 (1.53 g, 2.29

mmol), MeNHOMe･HCl (447 mg, 4.58 mmol), and THF (12

mL) at ‒20 °C. The mixture was stirred for 15 min, quenched

with saturated aqueous NH₄Cl (5 mL), and extracted with

EtOAc (2x 10 mL). The combined organic extracts were

washed with brine (5 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:3) to give Weinreb amide 75

1366, 1250, 1169, 1146, 1111, 883, 859, 839, 766, 722, 683

cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 6.84 (brs, 1H), 4.65

(brs, 1H), 4.17 (t, J = 8.3 Hz, 2H), 3.99 (brs, 1H), 3.81 (brs,

1H), 3.74‒3.52 (m, 3H), 3.08‒2.92 (m, 1H), 2.76 (d, J = 13.2

Hz, 1H), 2.52‒2.42 (m, 2H), 2.28‒2.08 (m, 3H), 1.99 (m, 1H),

1.60‒1.48 (m, 4H), 1.49 (s, 9H), 1.09‒1.04 (m, 21H), 1.00 (t, J

= 8.3 Hz, 2H), 0.05 (s, 9H); ¹³C NMR (125 MHz, CDCl₃,

60 °C) δ 156.1 (C), 152.7 (C), 127.1 (CH), 101.5 (CH), 81.4

(C), 81.2 (C), 70.2 (CH), 63.9 (CH₂), 63.6 (CH₂), 49.6‒47.8 (br,

CH₂), 45.6 (CH₂), 44.2 (CH₂), 37.8 (CH), 34.3 (C), 34.2 (CH),

30.8 (CH₂), 28.5 (CH₃), 26.6 (CH₂), 19.9 (CH₂), 18.2 (CH₃),

18.1 (CH₂), 12.3 (CH), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₃₄H₆₃N₂O₅Si₂⁺(M+H)⁺635.4276, found 635.4271.

(1.60 g, 100%): a colorless oil; [α]²⁷‒3.9 (c 1.00, CHCl₃); IR

D

(film) 2944, 2866, 1703, 1670, 1367, 1250, 1170, 1110 cm^-1; ¹H

NMR (500 MHz, CDCl₃, 60 °C) δ 7.02‒6.72 (m, 1H), 4.70 (brs,

1H), 4.17 (t, J = 8.4 Hz, 2H), 3.94‒3.84 (m, 1H), 3.84‒3.50 (m,

4H), 3.69 (s, 3H), 3.18 (s, 3H), 3.09‒2.91 (m, 1H), 2.80 (d, J =

14.0 Hz, 1H), 2.60‒2.42 (m, 3H), 2.41‒2.30 (m, 2H), 1.63‒1.46

(m, 4H), 1.49 (s, 9H), 1.13‒1.03 (m, 21H), 1.00 (m, 2H), 0.04

(s, 9H); ¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers)

δ 172.5 (C), 172.2 (C), 156.1 (C), 156.1 (C), 153.0 (C), 152.5

(C), 126.7 (CH), 126.6 (CH), 102.4 (CH), 102.1 (CH), 81.2 (C),

81.2 (C), 63.9 (CH₂), 63.6 (CH₂), 63.6 (CH₂), 63.6 (CH₂), 61.4

(CH₃), 61.4 (CH₃), 49.0 (CH₂), 47.9 (CH₂), 45.4 (CH₂), 45.2

(CH₂), 44.4 (CH₂), 44.3 (CH₂), 38.8‒37.0 (CH x4), 34.1 (C),

34.0 (C), 32.8‒32.0 (CH₃x2, CH₂x2), 31.0 (CH), 30.9 (CH),

30.7 (CH₂), 30.5 (CH₂), 28.4 (CH₃), 28.4 (CH₃), 26.5 (CH₂),

26.5 (CH₂), 18.1 (CH₃), 18.1 (CH₃), 17.9 (CH₂), 17.9 (CH₂),

12.0 (CH), 12.0 (CH), –1.4 (CH₃), –1.4 (CH₃); HRMS (ESI),

calcd for C₃₅H₆₈N₃O₇Si₂⁺(M+H)⁺698.4596, found 698.4590.

Diisobutylaluminium hydride (1.0 M in hexane, 3.4 mL, 3.4

mmol) was added to a solution of Weinreb amide 75 (1.60 g,

2.29 mmol) and THF (23 mL) at ‒78 °C. This solution was

maintained at this temperature for 1 h, and quenched with

saturated aqueous (+)-potassium sodium tartrate (50 mL). The

resulting mixture was allowed to warm to room temperature,

stirred for 1 h, and extracted with EtOAc (2x 50 mL). The

combined organic extracts were washed with brine (10 mL),

dried over Na₂SO₄, and concentrated. The residue was purified

by silica gel column chromatography (EtOAc/hexane 1:4) to

give aldehyde 42 (1.46 g, 79%, 95% ee by HPLC

(CHIRALPAK AD-H, 250×4.6 mm, UV 210 nm,

iPrOH/hexane 1:19 (v/v), 1.0 mL/min, 42: T_R= 5.3 min, ent-42:

Propargylsilane (7): n-Butyllithium (1.6 M in hexane, 1.1

mL, 1.8 mmol) was added to a solution of alkyne 43 (1.07 g,

1.68 mmol) and THF (15 mL) at –78 °C. After maintaining for

15 min, (iodomethyl)trimethylsilane (300 µL, 2.0 mmol) and

HMPA (2 mL) were added to the solution at –78 °C. The

mixture was stirred for 30 min at –78 °C, quenched with

saturated aqueous NH₄Cl (10 mL) at the same temperature, and

extracted with hexane (2x 5 mL). The combined organic

extracts were washed with brine (5 mL), dried over Na₂SO₄,

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:9) to give a mixture of

propargylsilane 7 and alkyne 43. The mixture was then

separated by MPLC (Yamazen Ultra Pack Column B, 26×300

mm, EtOAc/hexane 7:93 to 30:70, 20 mL/min, 7: T_R= 25.5

min, 43: T_R= 28.5 min) to afford propargylsilane 7 (1.01 g,

83%) and alkyne 43 (149 mg, 14%). propargylsilane 7: a

colorless oil; [α]²⁵_D‒21.1 (c 1.00, CHCl₃); IR (film) 2953, 2866,

1705, 1465, 1435, 1366, 1250, 1170, 1110, 946, 854, 765, 722,

1

681 cm^-1; H NMR (500 MHz, CDCl₃, 60 °C) δ 7.00‒8.68 (m,

1H), 4.80‒4.60 (m, 1H), 4.16 (t, J = 8.0 Hz, 2H), 4.00‒3.90 (m,

1H), 3.83 (brs, 1H), 3.74‒3.56 (m, 3H), 2.98 (brs, 1H), 2.74 (d,

J = 13.5 Hz, 1H), 2.48 (brs, 1H), 2.42 (t, J = 11.8 Hz, 1H),

2.26‒2.16 (m, 1H), 2.16‒2.00 (m, 2H), 1.60‒1.48 (m, 4H), 1.50

(s, 9H), 1.43 (m, 2H), 1.10‒1.04 (m, 21H), 1.00 (t, J = 8.9 Hz,

2H), 0.10 (s, 9H), 0.05 (s, 9H); ¹³C NMR (125 MHz, CDCl₃,

60 °C) δ 156.2 (C), 152.8 (C), 126.8 (CH), 102.3 (CH), 81.2

(C), 79.6 (C), 75.5 (C), 64.0 (CH₂), 63.6 (CH₂), 49.8‒47.6 (br,

CH₂), 45.6 (CH₂), 44.5 (CH₂), 38.0 (CH), 34.6 (CH), 34.3 (C),

30.9 (CH₂), 28.5 (CH₃), 26.7 (CH₂), 20.5 (CH₂), 18.22 (CH₃),

18.19 (CH₂), 12.3 (CH), 7.3 (CH₂), ‒1.3 (CH₃), ‒1.8 (CH₃);

T_R= 6.9 min)): a colorless oil; [α]²⁷‒7.6 (c 1.00, CHCl₃); IR

D

(film) 2945, 2866, 2723, 1703, 1367, 1250, 1169, 1111, 838

cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 9.79 (s, 1H),

7.02‒6.72 (m, 1H), 4.60(brs, 1H), 4.17 (t, J = 8.6 Hz, 2H),

3.91‒3.77 (m, 1H), 3.75‒3.55 (m, 4H), 3.09‒2.94 (m, 1H), 2.83

(d, J = 14.3 Hz, 1H), 2.63‒2.49 (m, 2H), 2.45 (dd, J = 17.8, 5.2

Hz, 1H), 2.38 (dd, J = 17.8, 6.9 Hz, 1H), 2.32 (brs, 1H),

1.63‒1.52 (m, 2H), 1.51‒1.45 (m, 2H), 1.50 (s, 9H), 1.14‒1.03

(m, 21H), 1.00 (m 2H), 0.05 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃, 60 °C) δ 200.0 (CH), 156.1 (C), 152.7 (C), 127.4 (CH),

101.4 (CH), 81.4 (C), 63.82 (CH₂), 63.78 (CH₂), 49.3‒47.5

(CH₂, broad), 45.7 (CH₂), 44.5 (CH₂), 44.3 (CH₂), 38.5 (CH),

34.3 (C), 31.1 (CH₂), 29.5 (CH), 28.5 (CH₃), 26.6 (CH₂), 18.2

(CH₃), 18.1 (CH₂), 12.3 (CH), –1.3 (CH₃); HRMS (ESI), calcd

for C₃₃H₆₃N₂O₆Si₂⁺(M+H)⁺639.4225, found 639.4222.

Alkyne (43): Ohira-Bestmann reagent (410 µL, 2.7 mmol)

was added to a mixture of aldehyde 42 (1.15 g, 1.80 mmol),

K₂CO₃(498 mg, 3.60 mmol), and MeOH (18 mL) at room

temperature. The mixture was stirred for 3 h, and quenched

with saturated aqueous NH₄Cl (10 mL) at 0 °C. The resulting

mixture was extracted with hexane (2x 10 mL). The combined

organic extracts were washed with brine (5 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel column chromatography (EtOAc/hexane 1:9) to give alkyne

43 (1.07 g, 94%): a colorless oil; [α]²⁷_D‒16.4 (c 1.00, CHCl₃);

IR (film) 3313, 2945, 2866, 1704, 1652, 1465, 1435, 1412,

+

HRMS (ESI), calcd for C₃₈H₇₃N₂O₅Si₃(M+H)⁺721.4827,

found 721.4825.

Tricyclic core (8): Trifluoroacetic acid (33 µL, 430 µmol)

was added to a solution of propargylsilane 7 (208 mg, 288

µmol) and MeCN/EtOH = 9 (29 mL). The solution was heated

to 50 °C, maintained for 5 h, quenched with Et₃N (80 µL, 580

µmol) at room temperature, and concentrated. The residue was

purified by silica gel column chromatography (EtOAc/hexane

1:14) and MPLC (Yamazen Ultra Pack Column B, 26×300 mm,

EtOAc/hexane 7:93 to 30:70, 20 mL/min, 8: T_R= 23.0 min) to

afford tricyclic core 8 (158 mg, 85%): a colorless oil; [α]²⁵

D

+40.8 (c 1.00, CHCl₃); IR (film) 3449, 2945, 2865, 1958, 1696,

1

1463, 1437, 1365, 1250, 1174, 1105, 839, 765, 682 cm^-1; H

NMR (500 MHz, CDCl₃, 60 °C) δ 5.00‒4.55 (m, 3H), 4.19 (t, J

= 8.6 Hz, 2H), 4.09‒3.95 (m, 1H), 3.92‒3.75 (m, 1H),

3.73‒3.58 (m, 3H), 3.13 (d, J = 13.5 Hz, 1H), 2.87 (d, J = 12.3

Hz, 1H), 2.63 (d, J = 13.2 Hz, 1H), 2.62‒2.50 (m, 1H), 2.35 (dd,

J = 15.8, 6.6 Hz, 1H), 2.15 (ddd, J = 13.2, 3.2, 3.2 Hz, 1H),

2.00 (brs, 1H), 1.70‒1.66 (m, 1H), 1.55‒1.40 (m, 14H),

1.11‒1.05 (m, 21H), 1.01 (t, J = 8.6 Hz, 2H), 0.06 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃, 60 °C) δ 205.5 (C), 156.8 (C), 155.8

(C), 99.6 (C), 79.7 (C), 74.0 (CH₂), 63.93 (CH₂), 63.88 (CH₂),

51.1 (CH₂), 49.3 (CH), 49.1 (CH₂), 47.4 (CH₂), 36.0‒34.9 (br,

C x1, CH x1), 34.8 (CH), 33.0 (CH₂), 29.9 (CH₂), 29.5 (CH₂),

28.6 (CH₃), 27.0 (CH₂), 18.2 (CH₃), 18.1 (CH₂), 12.3 (CH),

CHCl₃); IR (film) 2926, 2865, 1750, 1695, 1463, 1440, 1366,

1266, 1252, 1175, 1131, 945, 838, 682 cm^-1; ¹H NMR (500

MHz, CDCl₃, 60 °C) δ 5.40 (t, J = 6.9 Hz, 1H), 5.22‒4.90 (m,

2H), 4.78‒4.46 (m, 1H), 4.25‒4.12 (m, 2H), 4.09‒3.94 (m, 1H),

3.90‒3.79 (m, 1H), 3.77 (s, 3H), 3.74‒3.56 (m, 3H), 3.07 (d, J

= 14.4 Hz, 1H), 2.85 (d, J = 12.3 Hz, 1H), 2.63 (d, J = 12.6 Hz,

1H), 2.63‒2.50 (m, 1H), 2.32 (dd, J = 16.3, 6.3 Hz, 1H), 2.16

(ddd, J = 13.5, 3.4, 3.4 Hz, 1H), 2.02‒1.91 (m, 1H), 1.72‒1.66

(m, 1H), 1.60‒1.35 (m, 14H), 1.12‒1.04 (m, 21H), 1.01 (t, J =

8.3 Hz, 2H), 0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 1:1

mixture of rotamers) δ 156.8 (C), 156.8 (C), 155.8 (C), 155.8

(C), 155.3 (C), 155.2 (C), 143.6 (C), 142.9 (C), 119.7 (CH),

118.6 (CH), 80.4 (C), 79.8 (C), 64.2 (CH₂), 64.1 (CH₂), 63.9

(CH₂), 63.8 (CH₂), 63.8 (CH₂), 63.7 (CH₂), 54.8 (CH₃), 54.7

(CH₃), 50.8 (CH₂), 50.7 (CH₂), 48.8 (CH₂), 48.6 (CH₂), 47.3

(CH₂), 47.1 (CH₂), 45.1 (CH), 43.9 (CH), 35.6 (CH), 35.5 (CH),

35.4 (CH), 35.1 (CH₂), 35.1 (CH₂), 34.9 (C), 34.8 (CH), 34.7

(C), 32.8 (CH₂), 32.7 (CH₂), 29.8 (CH₂), 29.3 (CH₂), 28.6

(CH₃), 28.5 (CH₃), 26.8 (CH₂), 26.8 (CH₂), 18.1 (CH₃), 18.1

(CH₃), 17.9 (CH₂), 17.9 (CH₂), 12.0 (CH), 12.0 (CH), ‒1.3

(CH₃), ‒1.3 (CH₃); HRMS (ESI), calcd for C₃₇H₆₈N₂O₈Si₂Na⁺

(M+Na)⁺747.4412, found 747.4404.

+

‒1.3 (CH₃); HRMS (ESI), calcd for C₃₅H₆₅N₂O₅Si₂(M+H)⁺

649.4432, found 649.4434.

Z-Allylic alcohol ((Z)-47): 2-Methyl-2-butene (1.7 mL, 16

mmol) was added to borane THF complex (0.92 M in THF, 8.0

mL, 7.4 mmol) at 0 °C. The solution was maintained at this

temperature for 1 h to give disiamylborane (calculated as 0.76

M in THF).

Disiamylborane (0.76 M, 6.0 mL, 4.6 mmol) was added to a

solution of allene 8 (1.48 g, 2.28 mmol) and THF (23 mL) at

room temperature. The solution was maintained for 10 min at

room temperature, and quenched with NaOH aq (3 M, 10 mL)

and 30% H₂O₂aq (10 mL) at 0 °C. The resulting mixture was

maintained for 1 h at 0 °C, and extracted with EtOAc (2x 30

mL). The combined organic extracts were washed with brine

(30 mL), dried over Na₂SO₄, and concentrated. The residue was

purified by silica gel column chromatography (EtOAc/hexane

1:4) to give Z-allylic alcohol (Z)-47 (1.34 g, 88%) and E-allylic

alcohol (E)-47 (65.7 mg, 4.3%). (Z)-47: a colorless oil; [α]²⁷

D

+4.3 (c 1.00, CHCl₃); IR (film) 3450, 2945, 2866, 1688, 1463,

1

1437, 1415, 1250, 1175, 1132, 1105, 838, 765, 681 cm^-1; H

NMR (500 MHz, CDCl₃, 60 °C) δ 5.68‒5.38 (m, 1H),

5.18‒4.90 (m, 1H), 4.46‒4.33 (m, 1H), 4.30‒4.12 (m, 2H), 4.01

(d, J = 12.3 Hz, 1H), 3.92‒3.76 (m, 2H), 3.74‒3.63 (m, 2H),

3.58 (d, J = 14.1 Hz, 1H), 3.38 (brs, 1H), 3.10 (d, J = 14.1 Hz,

1H), 2.86 (d, J = 12.3 Hz, 1H), 2.63 (d, J = 13.5 Hz, 1H), 2.51

(dd, J = 13.2, 13.2 Hz, 1H), 2.28 (dd, J = 16.3, 6.9 Hz, 1H),

2.15 (ddd, J = 13.5, 3.5, 3.5 Hz, 1H), 1.99‒1.91 (m, 1H),

1.70‒1.65 (m, 1H), 1.58‒1.35 (m, 14H), 1.12‒1.04 (m, 21H),

1.01 (t, J = 8.3 Hz, 2H), 0.06 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃, 60 °C) δ 156.8 (C), 156.7 (C), 140.4 (C), 125.2 (CH),

80.7 (C), 63.9 (CH₂), 63.9 (CH₂), 57.1 (CH₂), 51.1 (CH₂), 49.1

(CH₂), 48.1 (CH₂), 44.3 (CH), 35.9 (CH), 35.6 (CH), 35.4

(CH₂), 35.0 (C), 33.4 (CH₂), 29.5 (CH₂), 28.7 (CH₃), 27.0

(CH₂), 18.2 (CH₃), 18.1 (CH₂), 12.3 (CH), ‒1.3 (CH₃); HRMS

(ESI), calcd for C₃₅H₆₆N₂O₆Si₂Na⁺(M+Na)⁺689.4357, found

689.4359. (E)-47: a colorless oil; [α]²⁷_D+11.1 (c 1.00, CHCl₃);

IR (film) 3461, 2944, 2866, 1693, 1463, 1437, 1414, 1366,

1250, 1175, 1132, 1104, 838, 765, 681 cm^-1; ¹H NMR (500

MHz, CDCl₃, 60 °C) δ 5.80‒5.40 (m, 1H), 4.80‒4.35 (m, 1H),

4.26‒4.13 (m, 3H), 4.09 (dd, J = 12.9, 5.7 Hz, 1H), 4.08‒3.96

(m, 1H), 3.84 (d, J = 11.8 Hz, 1H), 3.74‒3.57 (m, 3H),

3.13‒2.95 (m, 1H), 2.87 (d, J = 12.6 Hz, 1H), 2.70‒2.54 (m,

2H), 2.24 (dd, J = 15.5, 12.9 Hz, 1H), 2.13 (ddd, J = 13.5, 3.8,

3.8 Hz, 1H), 1.98‒1.86 (m, 1H), 1.72‒1.65 (m, 1H), 1.60‒1.38

(m, 14H), 1.12‒1.04 (m, 21H), 1.01 (t, J = 8.3 Hz, 2H), 0.06 (s,

9H); ¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ

156.8 (C), 156.8 (C), 155.7 (C), 155.4 (C), 139.1 (C), 138.5 (C),

126.6 (CH), 125.5 (CH), 79.7 (C), 79.7 (C), 63.9 (CH₂), 63.9

(CH₂), 63.8 (CH₂), 63.7 (CH₂), 58.4 (CH₂), 58.4 (CH₂), 53.0

(CH), 51.8 (CH), 50.9 (CH₂), 50.7 (CH₂), 49.0 (CH₂), 48.8

(CH₂), 47.1 (CH₂), 47.1 (CH₂), 35.8 (CH), 35.8 (CH), 35.1 (C),

35.0 (CH), 34.8 (CH), 34.7 (C), 32.8 (CH₂), 32.4 (CH₂), 29.5

(CH₂), 29.4 (CH₂), 28.6 (CH₂), 28.6 (CH₃), 28.6 (CH₃), 28.5

(CH₂), 26.8 (CH₂), 26.8 (CH₂), 18.1 (CH₃), 18.1 (CH₃), 17.9

(CH₂), 17.9 (CH₂), 12.0 (CH), 12.0 (CH), ‒1.3 (CH₃), ‒1.3

(CH₃); HRMS (ESI), calcd for C₃₅H₆₆N₂O₆Si₂Na⁺(M+Na)⁺

689.4357, found 689.4354.

Skipped diene ((Z,Z)-10): A solution of allylic carbonate 50

(667 mg, 920 µmol), vinylstannane 9 (960 mg, 2.30 mmol) and

DMF (9.2 mL) was added to a mixture of LiCl (195 mg, 4.60

mmol) and Pd₂(dba)₃∙CHCl₃(47.6 mg, 46.0 µmol) at room

temperature. After stirring at room temperature for 1 h, the

mixture was quenched with KF aq (1 M, 5 mL) at 0 °C, stirred

for 1 h at room temperature, and extracted with hexane (3x 10

mL). The combined organic extracts were washed with brine (5

mL), dried over Na₂SO₄and concentrated. The residue was

purified by silica gel column chromatography (EtOAc/hexane

1:19 to 1:14) to afford a mixture of skipped dienes (Z,Z)-10 and

(E,Z)-10. Two skipped dienes were then separated by MPLC

(Yamazen Ultra Pack Column B, 26×300 mm, Et₂O/hexane 1:4

to 2:3, 20 mL/min, (Z,Z)-10: T_R= 32.0 min, (E,Z)-10: T_R

=

36.0 min) to afford skipped diene (Z,Z)-10 (611 mg, 85%) and

skipped diene (E,Z)-10 (42.6 mg, 6%). Skipped diene (Z,Z)-10:

a colorless oil; [α]²⁶+26.5 (c 1.00, CHCl₃); IR (film) 2946,

D

2866, 1741, 1692, 1463, 1436, 1414, 1250, 1175, 1131, 859,

839, 765, 682 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ

5.40‒5.27 (m, 2H), 5.23‒4.90 (m, 2H), 4.25‒4.10 (m, 2H),

4.10‒3.91 (m, 1H), 3.91‒3.78 (m, 1H), 3.77‒3.55 (m, 6H), 3.12

(d, J = 14.0 Hz, 1H), 3.05‒2.90 (m, 2H), 2.84 (d, J = 13.2 Hz,

1H), 2.61 (d, J = 12.6 Hz, 1H), 2.55 (dd, J = 13.7, 13.7 Hz, 1H),

2.31 (t, J = 7.5 Hz, 2H), 2.26 (dd, J = 13.7, 6.9 Hz, 1H),

2.16‒2.07 (m, 3H), 1.98‒1.89 (m, 1H), 1.70 (tt, J = 7.5, 7.5 Hz,

2H), 1.78‒1.63 (m, 1H), 1.60‒1.40 (m, 13H), 1.35‒1.26 (m,

1H), 1.13‒1.04 (m, 21H), 1.00 (t, J = 8.3 Hz, 2H), 0.06 (s, 9H);

¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ 174.3

(C), 174.1 (C), 156.8 (C), 156.8 (C), 155.4 (C), 155.2 (C),

136.8 (C), 136.1 (C), 129.4 (CH), 129.3 (CH), 129.0 (CH),

128.8 (CH), 124.9 (CH), 123.9 (CH), 79.8 (C), 79.4 (C), 63.9

(CH₂), 63.9 (CH₂), 63.8 (CH₂), 63.8 (CH₂), 51.6 (CH₃), 51.5

(CH₃), 50.9 (CH₂), 50.7 (CH₂), 49.0 (CH₂), 48.7 (CH₂), 47.2

(CH₂), 47.2 (CH₂), 45.2 (CH), 44.0 (CH), 35.9 (CH), 35.7 (CH),

35.6 (CH₂), 35.6 (CH), 35.3 (CH₂), 35.22 (C), 35.18 (CH), 34.9

(C), 33.60 (CH₂), 33.56 (CH₂), 32.8 (CH₂), 32.5 (CH₂), 30.2

(CH₂), 29.7 (CH₂), 28.63 (CH₃), 28.57 (CH₃), 26.9 (CH₂), 26.9

(CH₂), 26.7 (CH₂), 26.6 (CH₂), 26.1 (CH₂), 26.0 (CH₂), 25.0

(CH₂), 24.9 (CH₂), 18.2 (CH₃), 18.2 (CH₃), 17.9 (CH₂), 17.9

(CH₂), 12.1 (CH), 12.1 (CH), ‒1.3 (CH₃), ‒1.3 (CH₃); HRMS

(ESI), calcd for C₄₂H₇₆N₂O₇Si₂Na⁺(M+Na)⁺799.5089, found

Allylic carbonate (50): Methyl chloroformate (140 µL, 1.8

mmol) was added to a solution of allylic alcohol (Z)-47 (614

mg, 920 µmol), pyridine (150 µL, 1.8 mmol) and CH₂Cl₂(9.0

mL) at 0 °C. This solution was maintained for 2 h at 0 °C, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:4) to give allylic carbonate

799.5090. Skipped diene (E,Z)-10: a colorless oil; [α]²⁴+2.1

D

(c 1.00, CHCl₃); IR (film) 2946, 2866, 1741, 1694, 1463, 1436,

1414, 1366, 1318, 1250, 1175, 1131, 882, 860, 839, 765, 687

50 (670 mg, 100%): a colorless oil; [α]²⁸+49.6 (c 1.00,

D

cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 5.54‒5.06 (m, 3H),

4.78‒4.36 (m, 1H), 4.25‒4.10 (m, 2H), 4.12‒3.94 (m, 1H),

3.92‒3.76 (m, 1H), 3.74‒3.56 (m, 5H), 3.61 (d, J = 14.4 Hz,

1H), 3.16‒2.94 (m, 1H), 2.87 (d, J = 13.5 Hz, 1H), 2.77 (ddd, J

= 16.1, 6.3, 6.3 Hz, 1H), 2.70‒2.50 (m, 3H), 2.31 (t, J = 7.5 Hz,

2H), 2.26‒2.16 (m, 1H), 2.16‒2.05 (m, 3H), 1.98‒1.85 (m, 1H),

1.70 (tt, J = 7.5, 7.5 Hz, 2H), 1.74‒1.64 (m, 1H), 1.60‒1.37 (m,

14H), 1.13‒1.04 (m, 21H), 1.01 (t, J = 8.3 Hz, 2H), 0.06 (s, 9H),

¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ 174.1

(C), 174.1 (C), 156.8 (C), 156.8 (C), 155.9 (C), 155.3 (C),

136.6 (C), 135.9 (C), 129.1 (CH), 129.0 (CH), 128.91 (CH),

128.87 (CH), 126.1 (CH), 124.8 (CH), 79.5 (C), 79.5 (C), 63.9

(CH₂), 63.8 (CH₂), 63.8 (CH₂), 63.7 (CH₂), 53.3 (CH), 52.0

(CH), 51.6 (CH₃), 51.6 (CH₃), 50.9 (CH₂), 50.7 (CH₂), 49.1

(CH₂), 48.9 (CH₂), 47.2 (CH₂), 47.0 (CH₂), 36.0 (CH), 35.5

(CH), 35.2 (C), 35.1 (CH), 34.74 (CH), 34.69 (C), 33.5 (CH₂),

33.5 (CH₂), 32.8 (CH₂), 32.3 (CH₂), 29.7 (CH₂), 29.6 (CH₂),

28.6 (CH₃), 28.6 (CH₃), 28.4 (CH₂), 28.4 (CH₂), 26.8 (CH₂),

26.8 (CH₂), 26.7 (CH₂), 26.7 (CH₂), 25.5 (CH₂), 25.4 (CH₂),

24.8 (CH₂), 24.8 (CH₂), 18.1 (CH₃), 18.1 (CH₃), 17.9 (CH₂),

17.9 (CH₂), 12.0 (CH), 12.0 (CH), ‒1.3 (CH₃), ‒1.3 (CH₃);

HRMS (ESI), calcd for C₄₂H₇₆N₂O₇Si₂Na⁺(M+Na)⁺799.5089,

found 799.5094.

acid, which was immediately used in the next reaction without

further purification.

2-Chloro-1-methylpyridinium iodide (CMPI, 204 mg, 800

µmol) was added to a solution of the above amino acid, DIPEA

(140 µL, 800 µmol) and CH₂Cl₂(160 mL) at room temperature.

The solution was maintained for 16 h at room temperature,

quenched with saturated aqueous NH₄Cl (50 mL), and

extracted with CH₂Cl₂(2x 50 mL). The combined organic

extracts were washed with brine (50 mL), dried over Na₂SO₄,

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:4) to give tetracyclic core 52

(77.0 mg, 75% for 2 steps, 95% ee by HPLC (CHIRALPAK

AD-H, 250×4.6 mm, UV 210 nm, iPrOH/hexane 1:20 (v/v), 1.0

mL/min, 52: T_R= 31.5 min, ent-52: T_R= 22.2 min)): a colorless

oil; [α]²⁸+87.0 (c 1.00, CHCl₃); IR (film) 2944, 2865, 1697,

D

1

1633, 1438, 1249, 1103, 923, 882, 859, 764, 731, 681 cm^-1; H

NMR (500 MHz, CDCl₃, 60 °C) δ 5.62‒5.48 (m, 1H),

5.48‒5.34 (m, 1H), 5.34‒5.10 (m, 1H), 5.10‒4.90 (m, 1H),

4.38‒4.08 (m, 3H), 4.08‒3.92 (m, 1H), 3.94‒3.75 (m, 1H),

3.74‒3.52 (m, 2H), 3.22‒3.02 (m, 1H), 3.00‒2.77 (m, 2H),

2.76‒2.35 (m, 4H), 2.35‒1.88 (m, 6H), 1.88‒1.66 (m, 2H),

1.64‒1.23 (m, 6H), 1.12‒0.98 (m, 23H), 0.06 (s, 9H); ¹³C NMR

(125 MHz, CDCl₃, 60 °C) δ 173.5 (C), 156.8 (C), 137.2 (C),

129.2 (CH), 128.0 (CH), 125.5 (CH), 63.91 (CH₂), 63.86 (CH₂),

50.9 (CH₂), 49.1 (CH₂), 48.1 (CH), 45.2 (CH₂), 36.3 (C), 35.8

(CH), 35.1 (CH), 34.5 (CH₂), 32.9 (CH₂), 32.5 (CH₂), 30.6

(CH₂), 27.8 (CH₂), 26.9 (CH₂), 26.5 (CH₂), 25.8 (CH₂), 18.2

(CH₃), 18.2 (CH₂), 12.3 (CH), ‒1.3 (CH₃); HRMS (ESI), calcd

for C₃₆H₆₅N₂O₄Si₂⁺(M+H)⁺645.4483, found 645.4487.

Common intermediate (11): 10-Camphorsulfonic acid

(CSA, 55.3 mg, 238 µmol) was added to a solution of

tetracyclic core 52 (77.0 mg, 119 µmol) and MeOH (2.4 mL) at

room temperature. The solution was heated to 40 °C,

maintained for 1 h at 40 °C, quenched with Et₃N (66 µL, 480

µmol) at room temperature, and concentrated. The residue was

purified by silica gel column chromatography (EtOAc/MeOH

19:1) to give common intermediate 11 (58.2 mg, 100%): a

white amorphous solid; mp 45.0‒47.0 °C; [α]²⁶_D+43.1 (c 1.00,

CHCl₃); IR (film) 3413, 2950, 2921, 1693, 1613, 1438, 1249,

1059, 936, 859, 839, 754, 698 cm^-1; ¹H NMR (500 MHz,

CDCl₃, 60 °C) δ 5.70‒5.50 (m, 1H), 5.46‒5.32 (m, 1H),

5.32‒5.15 (m, 1H), 5.12‒4.94 (m, 1H), 4.39‒4.26 (m, 1H),

4.25‒4.15 (m, 2H), 4.10‒3.80 (m, 2H), 3.70‒3.60 (m, 1H),

3.55‒3.45 (m, 1H), 3.10 (ddd, J = 14.9, 9.5, 9.5 Hz, 1H),

2.94‒2.76 (m, 2H), 2.76‒2.64 (m, 1H), 2.64‒2.40 (m, 3H),

2.35‒1.90 (m, 6H), 1.90‒1.74 (m, 1H), 1.74‒1.53 (m, 4H),

1.53‒1.36 (m, 2H), 1.22‒1.09 (m, 1H), 1.02 (t, J = 8.3 Hz, 2H),

0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 173.8 (C),

156.8 (C), 136.8 (C), 129.0 (CH), 128.1 (CH), 126.4 (CH), 63.9

(CH₂), 62.9 (CH₂), 50.9 (CH₂), 49.2 (CH₂), 48.4 (CH), 43.5

(CH₂), 37.1 (CH), 36.8 (C), 34.9 (CH), 33.9 (CH₂), 32.6 (CH₂),

31.8 (CH₂), 30.6 (CH₂), 27.8 (CH₂), 26.5 (CH₂), 26.3 (CH₂),

25.7 (CH₂), 18.2 (CH₂), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₂₇H₄₅N₂O₄Si⁺(M+H)⁺489.3149, found 489.3153.

Carboxylic acid (51): Aqueous LiOH (1 M, 2.6 mL) was

added to a solution of (Z,Z)-10 (611 mg, 786 µmol) and THF

(5.3 mL). The mixture was heated to 60 °C, maintained for 10 h

at 60 °C, quenched with saturated aqueous NH₄Cl (5 mL) at

room temperature, and extracted with EtOAc (2x 10 mL). The

combined organic extracts were washed with brine (5 mL),

dried over Na₂SO₄, and concentrated. The residue was purified

by silica gel column chromatography (EtOAc/hexane 1:4) to

give carboxylic acid 51 (583 mg, 97%): a colorless oil; [α]²⁹

D

+26.1 (c 1.00, CHCl₃); IR (film) 3158, 2944, 2866, 1736, 1691,

1463, 1438, 1415, 1366, 1321, 1250, 1175, 1132, 882, 858, 839,

765, 681 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 5.42‒5.25

(m, 2H), 5.25‒4.90 (m, 2H), 4.30‒4.10 (m, 2H), 4.10‒3.90 (m,

1H), 3.90‒3.77 (m, 1H), 3.77‒3.58 (m, 3H), 3.13 (d, J = 12.9

Hz, 1H), 3.05‒2.74 (m, 2H), 2.84 (d, J = 12.3 Hz, 1H),

2.70‒2.46 (m, 2H), 2.36 (t, J = 7.5 Hz, 2H), 2.32‒2.20 (m, 1H),

2.20‒2.06 (m, 3H), 1.98‒1.86 (m, 1H), 1.72 (tt, J = 7.5, 7.2 Hz,

2H), 1.70‒1.63 (m, 1H), 1.60‒1.36 (m, 13H), 1.36‒1.25 (m,

1H), 1.13‒1.03 (m, 21H), 1.01 (t, J = 8.4 Hz, 2H), 0.06 (s, 9H);

¹³C NMR (125 MHz, CDCl₃, 1:1 mixture of rotamers) δ 179.0

(C), 178.7 (C), 156.9 (C), 156.9 (C), 155.3 (C), 155.3 (C),

136.8 (C), 136.0 (C), 129.6 (CH), 129.4 (CH), 128.9 (CH),

128.8 (CH), 125.1 (CH), 123.9 (CH), 79.9 (C), 79.7 (C), 63.9

(CH₂), 63.9 (CH₂), 63.8 (CH₂), 63.8 (CH₂), 50.9 (CH₂), 50.7

(CH₂), 49.0 (CH₂), 48.7 (CH₂), 47.1 (CH₂), 47.1 (CH₂), 45.2

(CH), 44.1 (CH), 35.9 (CH), 35.7 (CH), 35.5 (CH₂), 35.5 (CH),

35.3 (C), 35.2 (CH₂), 35.1 (CH), 34.9 (C), 33.5 (CH₂), 33.5

(CH₂), 32.7 (CH₂), 32.5 (CH₂), 30.1 (CH₂), 29.7 (CH₂), 28.61

(CH₃), 28.58 (CH₃), 26.8 (CH₂), 26.8 (CH₂), 26.7 (CH₂), 26.5

(CH₂), 26.0 (CH₂), 26.0 (CH₂), 24.73 (CH₂), 24.67 (CH₂), 18.1

(CH₃), 18.1 (CH₃), 17.9 (CH₂), 17.9 (CH₂), 12.0 (CH), 12.0

(CH), ‒1.3 (CH₃), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₄₁H₇₄N₂O₇Si₂Na⁺(M+Na)⁺785.4932, found 785.4937.

Tetracyclic core (52): 2,6-Lutidine (74 µL, 640 µmol) and

TMSOTf (58 µL, 320 µmol) were added to a solution of

carboxylic acid 51 (122 mg, 160 µmol) and CH₂Cl₂(1.6 mL) at

room temperature. 2,6-Lutidine (7.4 µL, 64 µmol) and

TMSOTf (5.8 µL, 32 µmol) were added to the solution every

15 min until TLC analysis indicated the complete consumption

of carboxylic acid 51 (total: 2,6-lutidine 5.6 equiv., TMSOTf

2.8 equiv.). The resulting solution was quenched with Et₃N (76

µL, 550 µmol) and concentrated. The residue was filtrated

through a pad of silica gel (CHCl₃/MeOH 29:1) to give amino

Aldehyde (53): AZADOL^®(1.8 mg, 11.9 µmol) and

PhI(OAc)₂(57.5 mg, 179 µmol) were added to a solution of

alcohol 11 (58.2 mg, 119 µmol) and CH₂Cl₂(2.4 mL) at room

temperature. The solution was maintained for 17 h, quenched

with saturated aqueous Na₂S₂O₃(2 mL), and extracted with

CH₂Cl₂(2x 2 mL). The combined organic extracts were washed

with brine (5 mL), dried over Na₂SO₄, and concentrated. The

residue was purified by silica gel column chromatography

(EtOAc/hexane 1:2 to EtOAc) to give aldehyde 53 (49.2 mg,

85%): a colorless oil; [α]²⁶+122 (c 1.00, CHCl₃); IR (film)

D

2951, 2919, 1724, 1693, 1626, 1439, 1248, 1087, 1044, 936,

859, 839, 761, 697 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ

9.73 (s, 1H), 5.70‒5.48 (m, 1H), 5.46‒5.31 (m, 1H), 5.30‒5.14

(m, 1H), 5.12‒4.92 (m, 1H), 4.34‒4.10 (m, 3H), 4.08‒3.75 (m,

2H), 3.09 (ddd, J = 14.9, 9.5, 9.2 Hz, 1H), 2.96‒2.75 (m, 2H),

2.75‒2.41 (m, 5H), 2.33 (ddd, J = 17.2, 11.2, 5.2 Hz, 1H),

2.28‒1.93 (m, 6H), 1.91‒1.72 (m, 2H), 1.71‒1.57 (m, 1H),

1.50‒1.32 (m, 3H), 1.00 (t, J = 8.6 Hz, 2H), 0.05 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃, 60 °C) δ 201.1 (CH), 173.4 (C),

156.6 (C), 136.6 (C), 129.0 (CH), 128.0 (CH), 126.4 (CH), 64.0

(CH₂), 50.8 (CH₂), 49.2 (CH₂), 48.2 (CH), 43.1 (CH₂), 38.3

(CH₂), 37.1 (CH), 36.3 (C), 34.8 (CH), 34.0 (CH₂), 32.5 (CH₂),

30.6 (CH₂), 27.8 (CH₂), 27.6 (CH₂), 26.3 (CH₂), 25.7 (CH₂),

18.2 (CH₂), ‒1.3 (CH₃); HRMS (ESI), calcd for C₂₇H₄₃N₂O₄Si⁺

(M+H)⁺487.2992, found 487.2991.

(M+H)⁺599.3880, found 599.3878.

Tetrabutylammonium fluoride (1.0 M in THF, 160 µL, 160

µmol) was added to a solution of carboxylic acid 76 (23.4 mg,

39.1 µmol) and THF (3.9 mL) at room temperature. This

solution was maintained for 5 h, and concentrated to give

amino acid, which was immediately used in the next reaction

without further purification.

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

hydrochloride (EDCI, 37.5 mg, 196 µmol) was added to a

solution of the above amino acid, iPr₂EtN (67 µL, 390 µmol),

HOBt (26.6 mg, 196 µmol), and CH₂Cl₂(39 mL) at room

temperature. The solution was maintained for 24 h, quenched

with saturated aqueous NH₄Cl (20 mL), and extracted with

CH₂Cl₂(2x 20 mL). The combined organic extracts were

washed with brine (10 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:1 to 3:1) to pentacyclic

Methyl ester (55): In

a

glove box, sodium

hexamethyldisilazide (25.1 mg, 137 µmol) was added to a

mixture of phosphonium salt 54 (67.9 mg, 140 µmol) and THF

(1.0 mL) at room temperature. After stirring for 5 min, a

solution of aldehyde 53 (19.6 mg, 40.3 µmol) and THF (1.0

mL) was added to the mixture of the ylide. The reaction vessel

was removed from the glove box, and stirred at room

temperature for 1 h. The mixture was quenched with saturated

aqueous NH₄Cl (2 mL), and extracted with EtOAc (2x 5 mL).

The combined organic extracts were washed with brine (5 mL),

dried over Na₂SO₄, and concentrated. The residue was purified

by silica gel column chromatography (EtOAc/hexane 1:9 to

1:3) to give methyl ester 55 (21.8 mg, 88%): a colorless oil;

[α]²⁶_D+92.0 (c 1.00, CHCl₃); IR (film) 2926, 2856, 1738, 1695,

bislactam 77 (12.1 mg, 71% for 2 steps): a colorless oil; [α]²⁶

D

+144 (c 1.00, CHCl₃); IR (film) 2925, 2856, 1628, 1446, 1270,

1247, 923, 730 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 5.60 (t, J =

7.8 Hz, 1H), 5.50 (td, J = 10.6, 4.3 Hz, 1H), 5.45‒5.30 (m, 2H),

5.20 (td, J = 9.8, 4.3 Hz, 1H), 4.98 (brs, 1H), 4.45 (d, J = 13.8

Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H), 3.59 (d, J = 13.7 Hz, 1H),

3.17 (dt, J = 14.6, 10.1 Hz, 1H), 2.93 (d, J = 13.7 Hz, 1H), 2.81

(d, J = 13.8 Hz, 1H), 2.76‒2.66 (m, 2H), 2.59‒2.21 (m, 7H),

2.20‒1.48 (m, 13H), 1.48‒1.10 (m, 6H); ¹³C NMR (125 MHz,

CDCl₃) δ 174.0 (C), 173.8 (C), 136.2 (C), 129.7 (CH), 129.5

(CH), 128.3 (CH), 128.0 (CH), 126.8 (CH), 52.5 (CH₂), 48.0

(CH), 46.4 (CH₂), 43.6 (CH₂), 39.7 (CH), 36.6 (C), 34.43 (CH),

34.36 (CH₂), 34.1 (CH₂), 33.7 (CH₂), 32.5 (CH₂), 30.3 (CH₂),

28.2 (CH₂), 26.0 (CH₂), 25.9 (CH₂), 25.5 (CH₂), 25.0 (CH₂),

23.3 (CH₂), 22.9 (CH₂), 21.7 (CH₂); HRMS (ESI), calcd for

C₂₈H₄₁N₂O₂⁺(M+H)⁺437.3168, found 437.3167.

1

1631, 1437, 1249, 859, 839 cm^-1; H NMR (500 MHz, CDCl₃,

60 °C) δ 5.62‒5.47 (m, 1H), 5.47‒5.10 (m, 4H), 5.10‒4.88 (m,

1H), 4.30‒4.10 (m, 3H), 4.10‒3.76 (m, 2H), 3.66 (s, 3H), 3.12

(dt, J = 14.4, 9.5 Hz, 1H), 3.00‒2.76 (m, 2H), 2.76‒2.38 (m,

3H), 2.64 (d, J = 13.5 Hz, 1H), 2.30 (t, J = 7.5 Hz, 2H),

2.34‒1.86 (m, 10H), 1.85‒1.52 (m, 5H), 1.50‒1.18 (m, 7H),

1.01 (t, J = 8.3 Hz, 2H), 0.05 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃, 60 °C) δ 174.2 (C), 173.4 (C), 156.8 (C), 137.1 (C),

130.3 (CH), 129.5 (CH), 129.2 (CH), 128.0 (CH), 125.7 (CH),

63.9 (CH₂), 51.4 (CH₃), 50.9 (CH₂), 49.2 (CH₂), 48.1 (CH),

44.7 (CH₂), 36.7 (C), 36.3 (CH₂), 36.1 (CH), 35.1 (CH), 34.4

(CH₂), 34.2 (CH₂), 32.9 (CH₂), 30.7 (CH₂), 29.5 (CH₂), 29.0

(CH₂), 27.8 (CH₂), 27.2 (CH₂), 26.5 (CH₂), 25.8 (CH₂), 25.1

(CH₂), 21.3 (CH₂), 18.2 (CH₂), ‒1.3 (CH₃); HRMS (ESI), calcd

for C₃₅H₅₇N₂O₅Si⁺(M+H)⁺613.4037, found 613.4037.

In a glove box, LiAlH₄(1.0 M in THF, 140 µL, 140 µmol)

was added to a solution of pentacyclic bislactam 77 (6.3 mg, 14

µmol) and THF (1.4 mL) at room temperature. The reaction

vessel was removed from the glove box, stirred at room

temperature for 6 h, cooled to 0 °C, and quenched with a few

drops of distilled water. The resulting suspension was dried

over Na₂SO₄, and filtrated. The solid was washed with Et₂O (3

mL). The resulting filtrate was then concentrated. The residue

was purified by silica gel column chromatography

(Et₂O/hexane 1:19 to 1:5) to give madangamine C (3) (4.5 mg,

Madangamine C (3): Aqueous LiOH (1 M, 0.6 mL) was

added to a solution of ester 55 (21.8 mg, 35.6 µmol) and THF

(1.2 mL). The mixture was heated to 60 °C, maintained for 5 h

at that temperature, quenched with saturated aqueous NH₄Cl (1

mL) at room temperature, and extracted with EtOAc (2x 5 mL).

The combined organic extracts were washed with brine (2 mL),

dried over Na₂SO₄, and concentrated. The residue was purified

by silica gel column chromatography (EtOAc/hexane 1:1) to

76%): a colorless oil; [α]²⁶+133 (c 0.09, EtOAc); IR (film)

D

2928, 2857, 1458, 1438, 1126, 722, 685, 497 cm^-1; H NMR

1

(500 MHz, C₆D₆, 65 °C) δ 5.49‒5.35 (m, 3H), 5.20 (dt, J = 11.5,

3.2 Hz, 1H), 5.23‒5.13 (m, 1H), 3.72 (t, J = 3.2 Hz, 1H), 3.42

(dd, J = 12.1, 1.2 Hz, 1H), 3.35 (dt, J = 13.5, 11.5 Hz, 1H),

3.13 (ddt, J = 16.3, 12.1, 3.2 Hz, 1H), 2.83 (ddd, J = 13.8, 11.8,

5.2 Hz, 1H), 2.74 (dd, J = 12.1, 1.7 Hz, 1H), 2.73 (ddd, J =

12.0, 3.7, 2.0 Hz, 1H), 2.68 (d, J = 12.1 Hz, 1H), 2.60 (td, J =

13.8, 4.3 Hz, 1H), 2.36 (dt, J = 12.6, 3.2 Hz, 1H), 2.33 (d, J =

10.9 Hz, 1H), 2.36‒2.01 (m, 9H), 2.16 (dd, J = 10.9, 3.5 Hz,

1H), 1.89‒1.78 (m, 2H), 1.76‒1.57 (m, 3H), 1.57‒1.07 (m,

10H), 1.53 (d, J = 12.1 Hz, 1H), 1.27 (dt, J = 12.6, 3.2 Hz, 1H),

0.90 (ddt, J = 12.0, 9.5, 1.7 Hz, 1H); ¹³C NMR (125 MHz,

C₆D₆, 65 °C) δ 139.2 (C), 133.8 (CH), 129.2 (CH), 129.2 (CH),

129.1 (CH), 122.0 (CH), 63.4 (CH₂), 62.7 (CH₂), 56.2 (CH₂),

55.6 (CH₂), 53.7 (CH₂), 51.6 (CH), 40.0 (CH), 38.6 (CH₂), 38.2

(C), 37.4 (CH), 36.3 (CH₂), 32.1 (CH₂), 30.2 (CH₂), 28.0 (CH₂),

26.9 (CH₂), 26.4 (CH₂), 26.0 (CH₂), 25.5 (CH₂), 25.0 (CH₂),

24.9 (CH₂), 24.6 (CH₂), 23.4 (CH₂); HRMS (ESI), calcd for

C₂₈H₄₅N₂⁺(M+H)⁺409.3583, found 409.3585.

give carboxylic acid 76 (21.3 mg, 100%): a colorless oil; [α]²⁶

D

+104 (c 1.00, CHCl₃); IR (film) 3141, 2925, 2855, 1696, 1631,

1

1590, 1439, 1249, 932, 859, 839 cm^-1; H NMR (500 MHz,

CDCl₃, 60 °C) δ 5.66‒5.48 (m, 1H), 5.48‒5.10 (m, 4H),

5.10‒4.90 (m, 1H), 4.34‒4.10 (m, 3H), 4.10‒3.74 (m, 2H), 3.11

(dt, J = 14.0, 9.2 Hz, 1H), 3.00‒2.77 (m, 2H), 2.77‒2.40 (m,

3H), 2.63 (d, J = 13.2 Hz, 1H), 2.38‒2.25 (m, 3H), 2.24‒1.86

(m, 9H), 1.86‒1.56 (m, 5H), 1.54‒1.15 (m, 7H), 1.02 (t, J = 8.3

Hz, 2H), 0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ

176.7 (C), 173.9 (C), 156.9 (C), 136.8 (C), 130.4 (CH), 129.5

(CH), 129.2 (CH), 128.0 (CH), 126.0 (CH), 64.0 (CH₂), 51.0

(CH₂), 49.2 (CH₂), 48.2 (CH), 44.7 (CH₂), 36.8 (C), 36.3 (CH),

36.2 (CH₂), 35.1 (CH), 34.3 (CH₂), 34.1 (CH₂), 32.9 (CH₂),

30.7 (CH₂), 29.1 (CH₂), 28.7 (CH₂), 27.8 (CH₂), 27.1 (CH₂),

26.5 (CH₂), 25.8 (CH₂), 24.8 (CH₂), 21.3 (CH₂), 18.2 (CH₂),

‒1.3 (CH₃); HRMS (ESI), calcd for C₃₄H₅₅N₂O₅Si⁺

Bromide (56): Carbon tetrabromide (17.6 mg, 531 µmol)

was added to a solution of alcohol 11 (17.3 mg, 35.4 µmol),

PPh₃(13.9 mg, 53.1 µmol) and CH₂Cl₂(1.2 mL) at room

temperature. The solution was maintained for 1 h, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:9 to 1:3) to give bromide 56

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:9 to 1:1) to give alcohol 80

(21.1 mg, 95%): a colorless oil; [α]²⁷+90.4 (c 1.00, CHCl₃);

D

(17.4 mg, 89%): a colorless oil; [α]²²+86.7 (c 1.00, CHCl₃);

IR (film) 3421, 2927, 2854, 1695, 1616, 1437, 1248, 859, 838,

D

IR (film) 2950, 2916, 1693, 1627, 1438, 1248, 858, 838 cm^-1;

¹H NMR (500 MHz, CDCl₃, 60 °C) δ 5.65‒5.50 (m, 1H),

5.48‒5.33 (m, 1H), 5.33‒5.15 (m, 1H), 5.14‒4.94 (m, 1H),

4.30‒4.10 (m, 3H), 4.08‒3.95 (m, 1H), 3.94‒3.80 (m, 1H),

3.45‒3.35 (m, 1H), 3.33‒3.25 (m, 1H), 3.12 (ddd, J = 14.6, 9.8,

9.2 Hz, 1H), 2.96‒2.78 (m, 2H), 2.76‒2.64 (m, 1H), 2.64‒2.40

(m, 3H), 2.36‒1.64 (m, 10H), 1.59‒1.34 (m, 4H), 1.02 (t, J =

8.3 Hz, 2H), 0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C)

δ 173.4 (C), 156.7 (C), 136.8 (C), 129.1 (CH), 128.0 (CH),

126.1 (CH), 64.0 (CH₂), 50.9 (CH₂), 49.2 (CH₂), 48.1 (CH),

44.2 (CH₂), 36.6 (C), 36.5 (CH), 34.9 (CH), 34.8 (CH₂), 34.23

(CH₂), 34.17 (CH₂), 32.7 (CH₂), 30.6 (CH₂), 27.8 (CH₂), 26.8

(CH₂), 26.4 (CH₂), 25.7 (CH₂), 18.2 (CH₂), ‒1.3 (CH₃); HRMS

(ESI), calcd for C₂₇H₄₄N₂O₃SiBr⁺(M+H)⁺551.2305, found

551.2304.

760 cm^-1; H NMR (500 MHz, CDCl₃, 60 °C) δ 5.64‒5.46 (m,

1

1H), 5.46‒5.34 (m, 1H), 5.34‒5.12 (m, 1H), 5.08‒4.84 (m, 1H),

4.26‒4.10 (m, 3H), 4.08‒3.92 (m, 1H), 3.92‒3.74 (m, 1H), 3.63

(t, J = 6.6 Hz, 2H), 3.12 (ddd, J = 13.5, 10.1, 9.7 Hz, 1H),

2.98‒2.76 (m, 2H), 2.76‒2.64 (m, 1H), 2.60 (d, J = 13.5 Hz,

1H), 2.64‒2.36 (m, 2H), 2.35‒2.22 (m, 1H), 2.22‒1.90 (m, 5H),

1.87‒1.74 (m, 1H), 1.73‒1.64 (m, 1H), 1.57 (tt, J = 7.2, 6.6 Hz,

2H), 1.45‒1.10 (m, 18H), 1.02 (t, J = 8.3 Hz, 2H), 0.06 (s, 9H);

¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 173.5 (C), 156.8 (C),

137.1 (C), 129.2 (CH), 128.0 (CH), 125.6 (CH), 63.9 (CH₂),

63.1 (CH₂), 51.0 (CH₂), 49.1 (CH₂), 48.1 (CH), 45.0 (CH₂),

36.6 (C), 36.3 (CH₂), 36.1 (CH), 35.1 (CH), 34.5 (CH₂), 33.0

(CH₂), 32.9 (CH₂), 30.6 (CH₂), 30.4 (CH₂), 29.6 (CH₂), 29.52

(CH₂), 29.52 (CH₂), 29.46 (CH₂), 27.8 (CH₂), 26.5 (CH₂), 25.9

(CH₂), 25.8 (CH₂), 23.2 (CH₂), 18.2 (CH₂), ‒1.3 (CH₃); HRMS

(ESI), calcd for C₃₄H₅₉N₂O₄Si⁺(M+H)⁺587.4244, found

587.4244.

Tosylate (58): A 30 mL flask equipped with a rubber septa

connected to a bubbler was charged with magnesium (turnings,

41.5 mg, 1.71 mmol) and THF. ((7-Bromoheptyl)oxy)-

triisopropylsilane 78 (333 mg, 948 µmol) was added to the

mixture at room temperature over a period of 5 min. The

p-Toluenesulfonyl chloride (13.7 mg, 71.8 µmol) was added

to a solution of alcohol 80 (21.1 mg, 35.9 µmol), Et₃N (20 µL,

140 µmol), DMAP (0.9 mg, 7.2 µmol) and CH₂Cl₂(1.2 mL) at

room temperature. The solution was maintained at room

temperature for 15 h, and quenched with saturated aqueous

NH₄Cl (3 mL). The resulting mixture was extracted with

CH₂Cl₂(2x 5 mL). The combined extracts were washed with

brine (5 mL), dried over Na₂SO₄, and concentrated. The residue

was purified by silica gel column chromatography

(EtOAc/hexane 1:12 to 1:1) to give tosylate 58 (23.9 mg, 90%):

resulting mixture was stirred vigorously for

1 h. The

concentration of the resulting Grignard reagent 57 was

determined as 0.26 M by titration with 1,10-phenanthroline

method.³³

A 20 mL flask was charged with copper (II) chloride (2.1 mg,

16 µmol) and LiCl (1.3 mg, 32 µmol). The reagent was heated

under reduced pressure until blue copper (II) chloride became

orange. A solution of bromide 56 (17.4 mg, 31.5 µmol) and

THF (3.2 mL) was added to the solids via cannula at room

temperature. The solution of Grignard reagent 57 (0.26 M in

THF, 910 µL, 240 µmol) was then added to the resulting

solution at room temperature. The solution was maintained for

30 min at room temperature, and quenched with saturated

aqueous NH₄Cl (3 mL). The resulting mixture was extracted

with EtOAc (2x 5 mL). The combined extracts were washed

with brine (5 mL), dried over Na₂SO₄, and concentrated. The

residue was purified by silica gel column chromatography

(EtOAc/hexane 1:19 to 1:12) to give alkylation product 79

a colorless oil; [α]²⁵+84.9 (c 1.00, CHCl₃); IR (film) 2927,

D

2856, 1693, 1612, 1441, 1358, 1249, 1176, 925, 838, 664 cm^-1;

¹H NMR (500 MHz, CDCl₃, 60 °C) δ 7.78 (d, J = 8.3 Hz, 2H),

7.33 (d, J = 8.3 Hz, 2H), 5.62‒5.46 (m, 1H), 5.46‒5.33 (m, 1H),

5.33‒5.10 (m, 1H), 5.10‒4.84 (m, 1H), 4.25‒4.10 (m, 3H), 4.03

(t, J = 6.6 Hz, 2H), 4.06‒3.91 (m, 1H), 3.90‒3.72 (m, 1H), 3.12

(ddd, J = 13.8, 9.8, 9.2 Hz, 1H), 3.00‒2.76 (m, 2H), 2.76‒2.64

(m, 1H), 2.59 (d, J = 13.5 Hz, 1H), 2.64‒2.48 (m, 2H), 2.44 (s,

3H), 2.34‒2.21 (m, 1H), 2.21‒1.90 (m, 5H), 1.86‒1.73 (m, 1H),

1.72‒1.67 (m, 1H), 1.63 (tt, J = 6.9, 6.6 Hz, 2H), 1.45‒1.10 (m,

18H), 1.01 (t, J = 8.3 Hz, 2H), 0.05 (s, 9H); ¹³C NMR (125

MHz, CDCl₃, 60 °C) δ 173.5 (C), 156.8 (C), 144.6 (C), 137.2

(C), 134.0 (C), 129.9 (CH), 129.2 (CH), 128.0 (CH), 128.0

(CH), 125.6 (CH), 70.8 (CH₂), 63.9 (CH₂), 51.0 (CH₂), 49.2

(CH₂), 48.1 (CH), 45.0 (CH₂), 36.6 (C), 36.3 (CH₂), 36.1 (CH),

35.1 (CH), 34.5 (CH₂), 32.9 (CH₂), 32.9 (CH₂), 30.6 (CH₂),

30.5 (CH₂), 29.55 (CH₂), 29.45 (CH₂), 29.09 (CH₂), 29.05

(CH₂), 27.8 (CH₂), 26.5 (CH₂), 25.8 (CH₂), 25.5 (CH₂), 23.2

(CH₂), 21.7 (CH₃), 18.2 (CH₂), ‒1.3 (CH₃); HRMS (ESI), calcd

for C₄₁H₆₅N₂O₆SiS⁺(M+H)⁺741.4333, found 741.4329.

(20.5 mg, 88%): a colorless oil; [α]²³+85.8 (c 1.00, CHCl₃);

D

IR (film) 2927, 2863, 1698, 1633, 1462, 1438, 1249, 1105, 859,

1

838 cm^-1; H NMR (500 MHz, CDCl₃, 60 °C) δ 5.60‒5.48 (m,

1H), 5.48‒5.35 (m, 1H), 5.35‒5.12 (m, 1H), 5.10‒4.90 (m, 1H),

4.25‒4.10 (m, 3H), 4.06‒3.92 (m, 1H), 3.92‒3.75 (m, 1H), 3.69

(t, J = 6.6 Hz, 2H), 3.13 (ddd, J = 13.6, 10.5, 9.2 Hz, 1H),

2.96‒2.77 (m, 2H), 2.77‒2.65 (m, 1H), 2.61 (d, J = 13.2 Hz,

1H), 2.64‒2.37 (m, 2H), 2.36‒2.23 (m, 1H), 2.23‒1.90 (m, 5H),

1.87‒1.75 (m, 1H), 1.75‒1.66 (m, 1H), 1.54 (tt, J = 6.9, 6.6 Hz,

2H), 1.50‒1.14 (m, 18H), 1.12‒1.05 (m, 21H), 1.02 (t, J = 8.6

Hz, 2H), 0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ

173.5 (C), 156.8 (C), 137.2 (C), 129.2 (CH), 128.0 (CH), 125.6

(CH), 63.9 (CH₂), 63.7 (CH₂), 51.0 (CH₂), 49.2 (CH₂), 48.1

(CH), 45.1 (CH₂), 36.6 (C), 36.4 (CH₂), 36.0 (CH), 35.2 (CH),

34.4 (CH₂), 33.3 (CH₂), 32.9 (CH₂), 30.7 (CH₂), 30.6 (CH₂),

29.8 (CH₂), 29.71 (CH₂), 29.66 (CH₂), 29.62 (CH₂), 27.8 (CH₂),

26.5 (CH₂), 26.0 (CH₂), 25.8 (CH₂), 23.2 (CH₂), 18.2 (CH₃,

CH₂), 12.4 (CH), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₄₃H₇₉N₂O₄Si₂⁺(M+H)⁺743.5578, found 743.5580.

Madangamine E (5): Boron trifluoride ethyl ether complex

(10 µL, 76 µmol) was added to a solution of tosylate 58 (11.2

mg, 15.1 µmol) and CH₂Cl₂(1.5 mL) at room temperature. The

solution was maintained for 30 min, quenched with Et₃N (21

µL, 150 µmol) at room temperature. The solution was

concentrated to give the corresponding amine, which was

immediately used in the next step without further purification.

Potassium carbonate (10.4 mg, 75.5 µmol) was added to a

solution of the above amine and MeCN (15 mL) at room

temperature. The resulting solution was heated to 80 °C,

maintained for 80 h at 80 °C, and concentrated. The residue

was purified by silica gel column chromatography

(Et₂O/hexane 1:9 to 1:2) to give macrocyclic amine 81 (3.9 mg,

10-Camphorsulfonic acid (CSA, 17.6 mg, 75.9 µmol) was

added to a solution of alkylation product 79 (28.2 mg, 37.9

µmol) and MeOH (1.3 mL) at room temperature. The solution

was heated to 40 °C, maintained for 1 h at 40 °C, quenched

with Et₃N (21 µL, 150 µmol) at room temperature, and

61% for 2 steps): a colorless oil; [α]²⁷‒9.1 (c 0.50, EtOAc);

D

IR (film) 2925, 2856, 1629, 1447, 678 cm^-1; ¹H NMR (500

MHz, C₆D₆, 1.4:1 mixture of rotamers) δ 5.87‒5.79 (m, 5/12H),

5.44‒5.17 (m, 3H), 4.74‒4.67 (m, 7/12H), 4.55 (d, J = 14.0 Hz,

7/12H), 3.40 (ddd, J = 14.9, 10.6, 10.0 Hz, 5/12H), 3.23 (d, J =

14.0 Hz, 7/12H), 3.16 (d, J = 13.5 Hz, 5/12H), 3.13‒3.02 (m,

5/12H), 2.81 (ddd, J = 14.6, 9.5, 8.9 Hz, 7/12H), 2.69 (d, J =

13.5 Hz, 5/12H), 2.72‒2.61 (m, 7/12H), 2.50‒1.10 (m, 36H);

¹³C NMR (125 MHz, C₆D₆, mixture of two rotamers) δ 172.1

(C), 169.7 (C), 138.9 (C), 137.4 (C), 129.3 (CH), 129.0‒127.0

(CH x3), 126.4 (CH), 124.8 (CH), 60.4 (CH₂), 59.4 (CH₂), 59.3

(CH₂), 58.8 (CH₂), 57.5 (CH₂), 57.2 (CH₂), 52.2 (CH₂), 48.6

(CH), 46.3 (CH₂), 44.9 (CH), 36.9 (C), 36.7 (C), 35.9 (CH₂),

35.8 (CH₂), 35.2 (CH), 35.0 (CH₂), 34.6 (CH), 33.0 (CH₂), 32.7

(CH), 31.7 (CH₂), 30.1 (CH₂), 28.8 (CH₂), 28.4 (CH), 27.9

(CH₂), 27.6 (CH₂), 27.5 (CH₂), 27.14 (CH₂), 27.08 (CH₂), 26.4

(CH₂), 26.1 (CH₂), 26.0 (CH₂), 25.8 (CH₂), 25.7 (CH₂), 25.6

(CH₂), 25.4 (CH₂), 25.1 (CH₂), 25.04 (CH₂), 24.97 (CH₂),

24.87 (CH₂), 24.65 (CH₂), 24.56 (CH₂), 24.4 (CH₂), 23.7 (CH₂),

23.2 (CH₂), 22.1 (CH₂), 20.7 (CH₂); HRMS (ESI), calcd for

C₂₈H₄₅N₂O⁺(M+H)⁺425.3532, found 425.3532.

complete consumption of bromide 56 (total: 2.5 mL). The

resulting solution was maintained for 30 min at room

temperature, quenched with saturated aqueous NH₄Cl (3 mL),

and extracted with EtOAc (2x 5 mL). The combined extracts

were washed with brine (5 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:19 to 1:12) to give TIPS

ether 82 (46.3 mg, 84%): a colorless oil; [α]²²+80.2 (c 1.00,

D

CHCl₃); IR (film) 2927, 2863, 1698, 1633, 1463, 1437, 1249,

1105, 859, 838, 680 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ

5.60‒5.48 (m, 1H), 5.46‒5.34 (m, 1H), 5.32‒5.12 (m, 1H),

5.10‒4.90 (m, 1H), 4.25‒4.10 (m, 3H), 4.08‒3.91 (m, 1H),

3.90‒3.75 (m, 1H), 3.68 (t, J = 6.6 Hz, 2H), 3.12 (ddd, J = 14.9,

10.0, 8.3 Hz, 1H), 2.93‒2.76 (m, 2H), 2.75‒2.37 (m, 3H), 2.60

(d, J = 13.8 Hz, 1H), 2.36‒1.90 (m, 6H), 1.86‒1.75 (m, 1H),

1.74‒1.65 (m, 1H), 1.57‒1.50 (m, 2H), 1.45‒1.15 (m, 20H),

1.12‒1.04 (m, 21H), 1.02 (t, J = 8.3 Hz, 2H), 0.06 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃, 60 °C) δ 173.5 (C), 156.9 (C), 137.2

(C), 129.3 (CH), 128.0 (CH), 125.6 (CH), 63.9 (CH₂), 63.8

(CH₂), 51.0 (CH₂), 49.2 (CH₂), 48.1 (CH), 45.1 (CH₂), 36.6 (C),

36.4 (CH₂), 36.0 (CH), 35.2 (CH), 34.5 (CH₂), 33.3 (CH₂), 32.9

(CH₂), 30.7 (CH₂), 30.6 (CH₂), 29.82 (CH₂), 29.78 (CH₂),

29.76 (CH₂), 29.71 (CH₂), 29.66 (CH₂), 27.8 (CH₂), 26.5 (CH₂),

26.1 (CH₂), 25.8 (CH₂), 23.3 (CH₂), 18.2‒18.0 (CH₂, CH₃),

In a glove box, LiAlH₄(1.0 M in THF, 74 µL, 74 µmol) was

added to a solution of macrocyclic amine 81 (6.3 mg, 15 µmol)

and THF (1.5 mL) at room temperature. The reaction vessel

was removed from the glove box, stirred at room temperature

for 8 h, cooled to 0 °C, and quenched with a few drops of

distilled water. The resulting suspension was dried over Na₂SO₄,

and filtrated. The solid was washed with Et₂O (3 mL). The

resulting filtrate was then concentrated. The residue was

purified by silica gel column chromatography (Et₂O/hexane

1:19 to 1:5) to give madangamine E (5) (4.2 mg, 69%): a

+

12.4 (CH), ‒1.3 (CH₃); HRMS (ESI), calcd for C₄₄H₈₁N₂O₄Si₂

(M+H)⁺757.5735, found 757.5732.

10-Camphorsulfonic acid (CSA, 28.5 mg, 123 µmol) was

added to a solution of TIPS ether 82 (46.4 mg, 61.3 µmol) and

MeOH (2.0 mL) at room temperature. The solution was heated

to 40 °C, maintained for 3 h at 40 °C, quenched with Et₃N (40

µL, 310 µmol) at room temperature, and concentrated. The

residue was purified by silica gel column chromatography

(EtOAc/hexane 1:9 to 1:1) to give alcohol 83 (28.7 mg, 78%): a

colorless oil; [α]²²_D+110 (c 1.00, CHCl₃); IR (film) 3423, 2926,

colorless oil; [α]²²+90.9 (c 0.40, EtOAc); IR (film) 2925,

D

1

2853, 1458, 1445, 1350, 1129, 1116, 923, 862, 722 cm^-1; H

NMR (500 MHz, C₆D₆) δ 5.46 (td, J = 10.9, 4.3 Hz, 1H), 5.41

(tdd, J = 10.9, 6.3, 1.4 Hz, 1H), 5.20 (dt, J = 11.5, 2.6 Hz, 1H),

3.71 (t, J = 2.9 Hz, 1H), 3.34 (dt, J = 13.5, 11.5 Hz, 1H), 3.30

(d, J = 12.1 Hz, 1H), 3.02 (ddt, J = 15.8, 12.6, 2.6 Hz, 1H),

2.85 (ddd, J = 13.7, 11.7, 5.4 Hz, 1H), 2.63 (m, 1H), 2.58 (d, J

= 12.0 Hz, 1H), 2.70‒2.56 (m, 1H), 2.46 (d, J = 12.1 Hz, 1H),

2.36 (dt, J = 12.0, 2.9 Hz, 1H), 2.25 (m, 1H), 2.39‒2.20 (m,

4H), 2.12 (ddd, J = 12.9, 4.6, 3.7 Hz, 1H), 1.95‒1.74 (m, 4H),

1.83 (d, J = 12.0 Hz, 1H), 1.72‒1.61 (m, 1H), 1.61‒1.09 (m,

21H); ¹³C NMR (125 MHz, C₆D₆) δ 139.1 (C), 129.1 (CH),

129.0 (CH), 122.1 (CH), 62.3 (CH₂), 60.1 (CH₂), 57.4 (CH₂),

56.3 (CH₂), 55.3 (CH₂), 51.8 (CH), 39.0 (CH₂), 37.0 (C), 36.6

(CH), 36.5 (CH), 35.4 (CH₂), 32.2 (CH₂), 27.3 (CH₂), 27.1

(CH₂), 26.8 (CH₂), 26.1 (CH₂), 25.7 (CH₂), 25.4 (CH₂), 25.11

(CH₂), 25.09 (CH₂), 24.81 (CH₂), 24.76 (CH₂), 24.2‒23.4 (CH₂,

1

2854, 1695, 1613, 1438, 1248, 859, 838 cm^-1; H NMR (500

MHz, CDCl₃, 60 °C) δ 5.60‒5.48 (m, 1H), 5.46‒5.34 (m, 1H),

5.34‒5.12 (m, 1H), 5.10‒4.90 (m, 1H), 4.26‒4.10 (m, 3H),

4.07‒3.91 (m, 1H), 3.90‒3.75 (m, 1H), 3.63 (t, J = 6.6 Hz, 2H),

3.12 (ddd, J = 14.4, 10.0, 9.2 Hz, 1H), 2.93‒2.76 (m, 2H),

2.75‒2.37 (m, 3H), 2.60 (d, J = 13.5 Hz, 1H), 2.34‒1.90 (m,

6H), 1.87‒1.74 (m, 1H), 1.74‒1.66 (m, 1H), 1.57 (tt, J = 7.2,

6.9 Hz, 2H), 1.45‒1.10 (m, 20H), 1.01 (t, J = 8.3 Hz, 2H), 0.06

(s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 173.5 (C), 156.9

(C), 137.2 (C), 129.3 (CH), 128.0 (CH), 125.6 (CH), 63.9

(CH₂), 63.2 (CH₂), 51.0 (CH₂), 49.2 (CH₂), 48.1 (CH), 45.0

(CH₂), 36.6 (C), 36.4 (CH₂), 36.1 (CH), 35.2 (CH), 34.5 (CH₂),

33.1 (CH₂), 32.9 (CH₂), 30.7 (CH₂), 30.5 (CH₂), 29.7 (CH₂x2),

29.62 (CH₂), 29.60 (CH₂), 29.54 (CH₂), 27.8 (CH₂), 26.5 (CH₂),

25.9 (CH₂), 25.8 (CH₂), 23.2 (CH₂), 18.2 (CH₂), ‒1.3 (CH₃);

HRMS (ESI), calcd for C₃₅H₆₁N₂O₄Si⁺(M+H)⁺601.4401,

found 601.4405.

+

br), 22.8 (CH₂); HRMS (ESI), calcd for C₂₈H₄₇N₂(M+H)⁺

411.3739, found 411.3743.

Tosylate (60): A 30 mL flask equipped with a rubber septa

connected to a bubbler was charged with magnesium (turnings,

60.0 mg, 2.47 mmol) and THF. ((8-bromooctyl)-

oxy)triisopropylsilane³⁴(500 mg, 1.37 mmol) was added to the

mixture at room temperature over a period of 5 min. The

p-Toluenesulfonyl chloride (19.1 mg, 100 µmol) was added

to a solution of alcohol 83 (30.1 mg, 50.1 µmol), Et₃N (28 µL,

200 µmol), DMAP (1.2 mg, 10.0 µmol) and CH₂Cl₂(1.0 mL)

at room temperature. The solution was maintained at room

temperature for 15 h, and quenched with saturated aqueous

NH₄Cl (1 mL). The resulting mixture was extracted with

CH₂Cl₂(2x 5 mL). The combined organic extracts were washed

with brine (5 mL), dried over Na₂SO₄, and concentrated. The

residue was purified by silica gel column chromatography

(EtOAc/hexane 1:12 to 1:1) to give tosylate 60 (32.3 mg, 85%):

resulting mixture was stirred vigorously for

1 h. The

concentration of the resulting Grignard reagent 59 was

determined as 0.26 M by titration with 1,10-phenanthroline

method.³³

A 30 mL flask was charged with copper (II) chloride (49.2

mg, 364 µmol) and LiCl (30.8 mg, 727 µmol). The reagent was

heated under reduced pressure until blue copper (II) chloride

became orange. A solution of bromide 56 (40.1 mg, 72.7 µmol)

and THF (3.6 mL) was added to copper (II) chloride via

cannula at room temperature. The solution of Grignard reagent

59 (0.26 M in THF, 840 µL, 220 µmol) was then added to the

resulting solution at room temperature. The solution of the

Grignard reagent was added until TLC analysis indicated the

a colorless oil; [α]²²+84.4 (c 1.00, CHCl₃); IR (film) 2926,

D

1

2854, 1694, 1629, 1437, 1361, 1248, 1176, 838 cm^-1; H NMR

(500 MHz, CDCl₃, 60 °C) δ 7.79 (d, J = 8.3 Hz, 2H), 7.33 (d, J

= 8.3 Hz, 2H), 5.60‒5.48 (m, 1H), 5.48‒5.34 (m, 1H),

5.34‒5.14 (m, 1H), 5.10‒4.90 (m, 1H), 4.27‒4.10 (m, 3H), 4.04

(t, J = 6.6 Hz, 2H), 4.08‒3.91 (m, 1H), 3.91‒3.75 (m, 1H), 3.12

(ddd, J = 13.5, 10.1, 9.5 Hz, 1H), 2.94‒2.76 (m, 2H), 2.76‒2.38

(m, 3H), 2.60 (d, J = 13.7 Hz, 1H), 2.45 (s, 3H), 2.34‒1.90 (m,

6H), 1.88‒1.74 (m, 1H), 1.74‒1.68 (m, 1H), 1.64 (tt, J = 6.9,

6.6 Hz, 2H), 1.45‒1.10 (m, 20H), 1.02 (t, J = 8.6 Hz, 2H), 0.06

(s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 173.5 (C), 156.8

(C), 144.6 (C), 137.1 (C), 134.0 (C), 129.9 (CH), 129.3 (CH),

128.0 (CH x2), 125.6 (CH), 70.8 (CH₂), 63.9 (CH₂), 51.0 (CH₂),

49.2 (CH₂), 48.1 (CH), 45.0 (CH₂), 36.6 (C), 36.4 (CH₂), 36.1

(CH), 35.2 (CH), 34.5 (CH₂), 32.9 (CH₂), 30.7 (CH₂), 30.6

(CH₂), 29.7 (CH₂), 29.63 (CH₂), 29.59 (CH₂), 29.50 (CH₂),

29.11 (CH₂), 29.10 (CH₂), 27.8 (CH₂), 26.5 (CH₂), 25.8 (CH₂),

25.5 (CH₂), 23.2 (CH₂), 21.7 (CH₃), 18.2 (CH₂), ‒1.3 (CH₃);

HRMS (ESI), calcd for C₄₂H₆₇N₂O₆SiS⁺(M+H)⁺755.4489,

found 755.4461.

Madangamine D (4): Boron trifluoride ethyl ether complex

(22 µL, 170 µmol) was added to a solution of tosylate 60 (32.3

mg, 42.8 µmol) and CH₂Cl₂(4.3 mL) at room temperature. The

solution was maintained for 30 min, quenched with Et₃N (24

µL, 170 µmol) at room temperature. The solution was

concentrated to give the corresponding secondary amine, which

was immediately used in the next step without further

purification.

3.5 Hz, 1H), 1.88‒1.78 (m, 2H), 1.81 (d, J = 10.9 Hz, 1H),

1.78‒1.72 (m, 1H), 1.72‒1.65 (m, 1H), 1.50‒1.10 (m, 22H),

1.01 (dt, J = 13.5, 4.6 Hz, 1H); ¹³C NMR (125 MHz, C₆D₆) δ

139.2 (C), 129.1 (CH), 129.0 (CH), 122.0 (CH), 61.0 (CH₂),

59.6 (CH₂), 57.4 (CH₂), 56.3 (CH₂), 54.0 (CH₂), 51.8 (CH),

38.5 (CH₂), 37.7 (CH), 37.5 (C), 36.8 (CH), 35.7 (CH₂), 32.2

(CH₂), 30.2 (CH₂), 28.4 (CH₂), 27.3 (CH₂), 27.0 (CH₂), 26.8

(CH₂), 26.5 (CH₂), 26.2 (CH₂), 26.14 (CH₂), 26.05 (CH₂), 25.4

(CH₂), 25.1 (CH₂), 24.6 (CH₂), 21.6 (CH₂); HRMS (ESI), calcd

for C₂₉H₄₉N₂⁺(M+H)⁺425.3896, found 425.3883.

Alcohol (62): In a glove box, sodium hexamethyldisilazide

(21.1 mg, 115 µmol) was added to a mixture of phosphonium

salt 61 (75.4 mg, 118 µmol) and THF (1.0 mL) at room

temperature. After stirring for 5 min, a solution of aldehyde 53

(12.7 mg, 26.1 µmol) and THF (2.0 mL) was added to the

mixture of the ylide. The reaction vessel was then removed

from the glove box, and stirred at room temperature for 1 h.

The mixture was quenched with saturated aqueous NH₄Cl (2

mL), and extracted with EtOAc (2x 5 mL). The combined

organic extracts were washed with brine (5 mL), dried over

Na₂SO₄, and concentrated. The residue was purified by silica

gel column chromatography (EtOAc/hexane 1:19 to 1:5) to

give pentaene, which was immediately used in the next reaction

without further purification.

Potassium carbonate (59.2 mg, 428 µmol) was added to a

solution of the above secondary amine and MeCN (43 mL) at

room temperature. The resulting solution was heated to 80 °C,

maintained for 72 h at 80 °C, and concentrated. The residue

was purified by silica gel column chromatography

(Et₂O/hexane 1:9 to 1:2) to give macrocyclic amine 84 (15.9

10-Camphorsulfonic acid (CSA, 10.6 mg, 45.8 µmol) was

added to a solution of the above pentaene and MeOH (1.1 mL)

at room temperature. The solution was heated to 40 °C,

maintained for 1 h at 40 °C, quenched with Et₃N (13 µL, 92

µmol) at room temperature, and concentrated. The residue was

purified by silica gel column chromatography (EtOAc/hexane

1:9 to 1:2) to give alcohol 62 (10.9 mg, 69% for 2 steps): a

colorless oil; [α]²³_D+109 (c 1.00, CHCl₃); IR (film) 3426, 2949,

mg, 85% for 2 steps): a colorless oil; [α]²⁴+55.1 (c 1.00,

D

1

CHCl₃); IR (film) 2926, 2856, 1630, 1446, 678 cm^-1; H NMR

(500 MHz, C₆D₆, 3.4:1 mixture of rotamers, signals of the

major rotamer are reported) δ 5.45‒5.16 (m, 3H), 4.77‒4.68 (m,

1H), 4.57 (d, J = 14.1 Hz, 1H), 3.35 (d, J = 14.1 Hz, 1H),

3.02‒2.80 (m, 2H), 2.61 (d, J = 11.5 Hz, 1H), 2.64‒2.52 (m,

1H), 2.45‒2.33 (m, 2H), 2.32‒2.14 (m, 4H), 2.12‒1.81 (m, 4H),

1.77 (d, J = 11.5 Hz, 1H), 1.75‒1.66 (m, 2H), 1.66‒1.56 (m,

2H), 1.52‒0.95 (m, 20H), 0.87‒0.78 (m, 1H); ¹³C NMR (125

MHz, C₆D₆, mixture of two rotamers, signals of the major

rotamer are reported) δ 172.4 (C), 139.0 (C), 129.2 (CH),

129.0‒127.0 (CH), 124.4 (CH), 60.1 (CH₂), 59.3 (CH₂), 57.1

(CH₂), 48.2 (CH), 44.7 (CH₂), 37.2 (C), 37.1 (CH), 35.9‒35.7

(CH, CH₂), 35.0 (CH₂), 32.3 (CH₂), 30.7 (CH₂), 28.2 (CH₂),

28.0 (CH₂), 27.0 (CH₂), 26.8 (CH₂), 26.4 (CH₂), 26.3 (CH₂),

26.2 (CH₂), 26.0 (CH₂), 25.9 (CH₂), 25.0 (CH₂), 24.7 (CH₂),

21.4 (CH₂); HRMS (ESI), calcd for C₂₉H₄₇N₂O⁺(M+H)⁺

439.3688, found 439.3672.

1

2921, 1694, 1611, 1440, 1248, 1049, 858, 839 cm^-1; H NMR

(500 MHz, CDCl₃, 60 °C) δ 5.60‒5.48 (m, 2H), 5.46‒5.20 (m,

7H), 5.10‒4.90 (m, 1H), 4.36‒4.12 (m, 3H), 4.10‒3.80 (m, 2H),

3.65 (t, J = 6.6 Hz, 2H), 3.12 (ddd, J = 13.8, 10.3, 9.8 Hz, 1H),

2.87 (dd, J = 6.3, 6.0 Hz, 2H), 2.95‒2.75 (m, 4H), 2.73‒2.60 (m,

1H), 2.63 (d, J = 13.5 Hz, 1H), 2.60‒2.42 (m, 2H), 2.38 (dt, J =

6.9, 6.9 Hz, 2H), 2.30‒2.22 (m, 1H), 2.22‒1.90 (m, 7H),

1.86‒1.74 (m, 1H), 1.74‒1.65 (m, 1H), 1.62‒1.47 (m, 2H),

1.45‒1.36 (m, 1H), 1.30‒1.16 (m, 1H), 1.02 (t, J = 8.6 Hz, 2H),

0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃, 60 °C) δ 173.6 (C),

156.8 (C), 137.0 (C), 130.9 (CH), 129.8 (CH), 129.2 (CH),

128.5 (CH), 128.5 (CH), 128.38 (CH), 128.0 (CH), 126.1 (CH),

125.9 (CH), 64.0 (CH₂), 62.4 (CH₂), 51.0 (CH₂), 49.2 (CH₂),

48.1 (CH), 44.4 (CH₂), 36.8 (C), 36.6 (CH), 36.2 (CH₂), 35.2

(CH), 34.4 (CH₂), 32.9 (CH₂), 31.4 (CH₂), 30.7 (CH₂), 27.8

(CH₂), 26.5 (CH₂), 26.1 (CH₂), 25.9 (CH₂), 25.8 (CH₂), 21.4

(CH₂), 18.2 (CH₂), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₃₆H₅₇N₂O₄Si⁺(M+H)⁺609.4088, found 609.4081.

Madangamine A (1): p-Toluenesulfonyl chloride (27.9 mg,

146 µmol) was added to a solution of alcohol 62 (44.5 mg, 73.1

µmol), Et₃N (41 µL, 290 µmol), DMAP (1.8 mg, 15 µmol) and

CH₂Cl₂(1.5 mL) at room temperature. The solution was

maintained at room temperature for 15 h, and quenched with

saturated aqueous NH₄Cl (1 mL). The resulting mixture was

extracted with CH₂Cl₂(2x 5 mL). The combined extracts were

washed with brine (5 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:9 to 1:2) to give tosylate 85

(55.7 mg, 100%): a colorless oil; [α]²⁷_D+86.5 (c 1.00, CHCl₃);

IR (film) 2951, 2921, 1693, 1627, 1439, 1361, 1248, 1176, 959,

913, 859, 838 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C) δ 7.78

(d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 5.62‒5.18 (m, 9H),

5.10‒4.90 (m, 1H), 4.30‒4.11 (m, 3H), 4.04 (t, J = 6.9 Hz, 2H),

4.07‒3.94 (m, 1H), 3.94‒3.76 (m, 1H), 3.12 (ddd, J = 14.6, 9.8,

In a glove box, LiAlH₄(1.0 M in THF, 160 µL, 160 µmol)

was added to a solution of macrocyclic amine 84 (14.3 mg,

32.6 µmol) and THF (1.6 mL) at room temperature. The

reaction vessel was removed from the glove box, stirred at

room temperature for 8 h, cooled to 0 °C, and quenched with a

few drops of distilled water. The resulting suspension was dried

over Na₂SO₄, and filtrated. The solid was washed with Et₂O (3

mL). The resulting filtrate was then concentrated. The residue

was purified by silica gel column chromatography

(Et₂O/hexane 1:19 to 1:5) to give madangamine D (4) (11.1 mg,

80%): a colorless oil; [α]²⁵+96.3 (c 0.29, CHCl₃); IR (film)

D

1

2925, 2855, 1460, 1443 cm^-1; H NMR (500 MHz, C₆D₆) δ

5.47 (td, J = 10.9, 4.0 Hz, 1H), 5.41 (tdd, J = 10.9, 6.3, 1.5 Hz,

1H), 5.20 (dt, J = 11.5, 2.9 Hz, 1H), 3.71 (t, J = 3.7 Hz, 1H),

3.34 (dt, J = 13.5, 11.5 Hz, 1H), 3.31 (d, J = 11.8 Hz, 1H), 3.10

(ddt, J = 16.1, 12.6, 2.6 Hz, 1H), 2.84 (ddd, J = 13.8, 12.1, 5.8

Hz, 1H), 2.70 (d, J = 10.9 Hz, 1H), 2.68 (ddd, J = 12.6, 8.6, 3.5

Hz, 1H), 2.72‒2.59 (m, 1H), 2.45 (d, J = 11.8 Hz, 1H), 2.39 (dt,

J = 12.3, 3.7 Hz, 1H), 2.37‒2.21 (m, 6H), 2.20 (dd, J = 10.9,

9.2 Hz, 1H), 2.96‒2.80 (m, 2H), 2.80‒2.72 (m, 4H), 2.72‒2.60

(m, 1H), 2.64 (d, J = 13.8 Hz, 1H), 2.60‒2.50 (m, 3H), 2.44 (s,

3H), 2.50‒2.37 (m, 1H), 2.32‒2.21 (m, 1H), 2.20‒1.86 (m, 7H),

1.85‒1.75 (m, 1H), 1.74‒1.62 (m, 1H), 1.51‒1.37 (m, 2H),

1.36‒1.20 (m, 2H), 1.01 (t, J = 8.6 Hz, 2H), 0.06 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃, 60 °C) δ 173.4 (C), 156.8 (C), 144.8

(C), 137.0 (C), 134.0 (C), 131.9 (CH), 130.02 (CH), 129.95

(CH), 129.3 (CH), 128.9 (CH), 128.3 (CH), 128.1 (CH), 128.1

(CH), 127.8 (CH), 125.8 (CH), 123.6 (CH), 69.7 (CH₂), 63.9

(CH₂), 50.9 (CH₂), 49.2 (CH₂), 48.1 (CH), 44.7 (CH₂), 36.7 (C),

36.1 (CH), 36.1 (CH), 35.1 (CH), 34.4 (CH₂), 32.9 (CH₂), 30.7

(CH₂), 27.8 (CH₂), 27.5 (CH₂), 26.5 (CH₂), 25.94 (CH₂), 25.8

(CH₂), 25.8 (CH₂), 21.7 (CH₃), 21.4 (CH₂), 18.2 (CH₂), ‒1.3

(CH₃); HRMS (ESI), calcd for C₄₃H₆₃N₂O₆SiS⁺(M+H)⁺

763.4176, found 763.4177.

Hz, 1H), 2.24 (dd, J= 16.3, 7.7 Hz, 1H), 2.15 (ddd, J = 11.8, 5.5,

3.7 Hz, 1H), 2.11 (dd, J = 10.6, 3.2 Hz, 1H), 1.98‒1.89 (m, 2H),

1.89‒1.77 (m, 2H), 1.71 (m, 1H), 1.45 (m, 1H), 1.38 (d, J =

10.9 Hz, 1H), 1.29 (ddd, J = 12.4, 3.2, 2.6 Hz, 1H), 1.26‒1.13

(m, 2H), 1.15 (m, 1H), 1.01 (dddd, J = 10.3, 7.5, 2.0, 1.7 Hz,

1H); ¹³C NMR (125 MHz, C₆D₆) δ 139.4 (C), 132.9 (CH),

129.2 (CH), 129.1 (CH), 129.0 (CH), 128.7‒127.6 (CH x2),

127.5 (CH), 125.9 (CH), 121.9 (CH), 61.6 (CH₂), 59.4 (CH₂),

57.7 (CH₂), 55.7 (CH₂), 52.4 (CH₂), 51.8 (CH), 39.1 (CH), 38.4

(CH₂), 37.1 (CH), 37.0 (C), 36.1 (CH₂), 32.4 (CH₂), 26.9 (CH₂),

26.7 (CH₂), 26.6 (CH₂), 25.9 (CH₂), 25.5 (CH₂), 25.4 (CH₂),

23.9‒22.9 (CH₂, br), 22.7 (CH₂); HRMS (ESI), calcd for

C₃₀H₄₅N₂⁺(M+H)⁺433.3583, found 433.3582.

Aldehyde (64): tert-Butyl hydroperoxide (5.5 M in decane,

120 µL, 640 µmol) was added to a solution of aldehyde 53

(61.9 mg, 127 µmol), benzoic acid (17.1 mg, 140 µmol), TBAI

(4.7 mg, 13 µmol), piperidine (1.0 M in EtOAc, 6 µL, 6 µmol)

and EtOAc (13 mL). The solution was heated to 50 °C, and

maintained for 16 h at this temperature. This solution was

cooled to room temperature, quenched with saturated aqueous

NH₄Cl (5 mL), and extracted with EtOAc (2x 5 mL). The

combined organic extracts were washed with brine (5 mL),

dried over Na₂SO₄, and concentrated to give the corresponding

benzoyloxy aldehyde 63, which was immediately used in the

next step without further purification.

Boron trifluoride ethyl ether complex (18 µL, 140 µmol) was

added to a solution of tosylate 85 (21.4 mg, 28.0 µmol) and

CH₂Cl₂(2.8 mL) at room temperature. The solution was

maintained

for

30

min,

and

quenched

with

N,N-diisopropylethylamine (48 µL, 280 µmol) at room

temperature. The solution was concentrated to give the

corresponding amine, which was immediately used in the next

step without further purification.

N,N-Diisopropylethylamine (24 µL, 140 µmol) was added to

a solution of the above amine and MeCN (28 mL) at room

temperature. The resulting solution was heated to 70 °C,

maintained for 20 h at this temperature, and then concentrated.

The residue was purified by silica gel column chromatography

(Et₂O/hexane 1:9 to 1:2) to give macrocyclic amine 86 (7.4 mg,

Sodium tetrahydroborate (24.0 mg, 635 µmol) was added to

a solution of the above benzoyloxy aldehyde 63 and MeOH

(2.5 mL) at room temperature. After maintaining for 1 h,

potassium carbonate (87.8 mg, 635 µmol) was added to the

solution. The resulting mixture was stirred for 2 h, quenched

with saturated aqueous NH₄Cl (2 mL), and extracted with

EtOAc (2x 2 mL). The combined organic extracts were washed

with brine (2 mL), and dried over Na₂SO₄, and concentrated to

give the corresponding diol, which was immediately used in the

next step without further purification.

59% for 2 steps): a colorless oil; [α]²⁸+80.3 (c 1.00, EtOAc);

D

IR (film) 2918, 1627, 1446, 1417, 701 cm^-1; ¹H NMR (500

MHz, C₆D₆) δ 5.70‒5.59 (m, 1H), 5.53‒5.12 (m, 8H), 4.73 (brs,

1H), 4.70 (d, J = 14.1 Hz, 1H), 3.26 (d, J = 14.1 Hz, 1H),

3.20‒2.78 (m, 6H), 2.74 (d, J = 11.2 Hz, 1H), 2.70‒2.54 (m,

1H), 2.54‒1.84 (m, 13H), 1.91 (ddd, J = 13.2, 3.5, 3.5 Hz, 1H),

1.82‒1.50 (m, 3H), 1.58 (d, J = 11.2 Hz, 1H), 1.50‒1.20 (m,

1H), 1.20‒1.14 (m, 1H), 1.10 (d, J = 13.2 Hz, 1H), 0.94‒0.82

(m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ 172.2 (C), 138.8 (C),

131.9 (CH), 129.2 (CH), 129.1 (CH), 128.8 (CH), 128.5‒127.6

(CH x3), 127.2 (CH), 124.7 (CH), 60.8 (CH₂), 58.7 (CH₂), 58.4

(CH₂), 48.0 (CH), 44.6 (CH₂), 38.9 (CH), 36.8 (C), 36.1 (CH),

35.8 (CH), 35.4 (CH₂), 32.6 (CH₂), 30.8 (CH₂), 28.1 (CH₂),

26.5 (CH₂), 26.5 (CH₂), 26.3 (CH₂), 26.0 (CH₂), 25.2 (CH₂),

23.0 (CH₂); HRMS (ESI), calcd for C₃₀H₄₃N₂O⁺(M+H)⁺

447.3375, found 447.3375.

Lead tetraacetate (84.5 mg, 191 µmol) was added to a

solution of the above diol and CH₂Cl₂(2.5 mL) at room

temperature. The resulting solution was maintained for 20 min,

and concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:2 to EtOAc) to give

aldehyde 64 (30.2 mg, 50% for 3 steps): a colorless oil; [α]²³

D

+122 (c 1.00, CHCl₃); IR (film) 2952, 2923, 1693, 1627, 1440,

1

1249, 859, 839 cm^-1; H NMR (500 MHz, CDCl₃, 60 °C ) δ

9.82‒9.79 (m, 1H), 5.70‒5.50 (m, 1H), 5.50‒5.34 (m, 1H),

5.34‒5.18 (m, 1H), 5.16‒4.96 (m, 1H), 4.40‒4.27 (m, 1H),

4.26‒4.13 (m, 2H), 4.06 (d, J = 13.8 Hz, 1H), 4.10‒3.95 (m,

1H), 3.11 (ddd, J = 14.9, 10.1, 9.8 Hz, 1H), 3.06‒2.95 (m, 1H),

2.95‒2.83 (m, 1H), 2.87 (d, J = 13.8 Hz, 1H), 2.79‒2.65 (m,

1H), 2.64‒2.40 (m, 2H), 2.45 (d, J = 16.9 Hz, 1H), 2.35 (d, J =

16.9 Hz, 1H), 2.38‒2.25 (m, 1H), 2.25‒1.95 (m, 6H), 1.91‒1.86

(m, 1H), 1.86‒1.77 (m, 1H), 1.52‒1.45 (m, 1H), 1.02 (t, J = 8.3

Hz, 2H), 0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 201.5

(CH), 173.7 (C), 156.6 (C), 135.8 (C), 128.7 (CH), 128.0 (CH),

127.0 (CH), 64.2 (CH₂), 50.7 (CH₂), 48.8 (CH₂), 47.9 (CH),

44.9 (CH₂), 37.6 (C), 35.7 (CH), 34.5 (CH), 33.7 (CH₂), 32.7

(CH₂), 30.6 (CH₂), 29.8 (CH₂), 27.9 (CH₂), 26.2 (CH₂), 25.7

(CH₂), 18.0 (CH₂), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₂₆H₄₁N₂O₄Si⁺(M+H)⁺473.2836, found 473.2842.

In a glove box, LiAlH₄(1.0 M in THF, 160 µL, 160 µmol)

was added to a solution of macrocyclic amine 86 (14.0 mg,

31.3 µmol) and THF (1.6 mL) at room temperature. The

reaction vessel was removed from the glove box, stirred at

room temperature for 6 h, cooled to 0 °C, and quenched with a

few drops of distilled water. The resulting suspension was dried

over Na₂SO₄, and filtrated. The solid was washed with Et₂O (3

mL). The resulting filtrate was then concentrated. The residue

was purified by silica gel column chromatography

(Et₂O/hexane 1:19 to 1:5) to give madangamine A (1) (10.3 mg,

76%): a colorless oil; [α]²⁴+142 (c 0.500, EtOAc); IR (film)

D

3005, 2912, 2873, 2853, 2792, 2758, 1459, 1440, 1128, 1091,

923, 917, 723, 675 cm^-1; ¹H NMR (500 MHz, C₆D₆) δ 5.58 (m,

1H), 5.45 (td, J = 10.9, 4.3 Hz, 1H), 5.42‒5.30 (m, 6H), 5.18

(dt, J = 11.8, 2.9 Hz, 1H), 3.72 (t, J = 3.2 Hz, 1H), 3.36 (dt, J =

13.2, 11.2 Hz, 1H), 3.19‒3.05 (m, 2H), 3.13 (d, J = 12.3 Hz,

1H), 3.08 (t, J = 16.3 Hz, 1H), 2.84 (ddd, J = 13.8, 11.8, 5.8 Hz,

1H), 2.73 (dd, J = 10.9, 0.9 Hz, 1H), 2.70‒2.20 (m, 5H), 2.66

(brt, J = 13.4 Hz, 1H), 2.60 (m, 1H), 2.54 (ddd, J = 10.3, 3.2,

3.2 Hz, 1H), 2.48 (dt, J = 11.8, 5.2 Hz, 1H), 2.48 (d, J = 11.8

Hz, 1H), 2.42 (ddd, J = 12.4, 4.6, 3.2 Hz, 1H), 2.32 (d, J = 10.6

Aldehyde (66): Preparation of gem-diiodoalkane 65:

Hydrazine monohydrate (1.0 mL, 21 mmol) was added to a

solution of 3-(1,3-dioxan-2-yl)propanal³⁶(596 mg, 4.13 mmol)

and CH₂Cl₂(21 mL) at room temperature. The resulting

mixture was stirred for 1 h at room temperature, and extracted

with CH₂Cl₂(2x 5 mL). The combined organic extracts were

washed with brine (5 mL), and dried over Na₂SO₄. The solution

was

concentrated

to

give

(3-(1,3-dioxan-2-yl)propylidene)hydrazine,

immediately used in the next step without further purification.

Iodine (3.67 g, 14.5 mmol) was divided into three portions, and

which

was

(CH), 128.6 (CH), 128.0 (CH), 126.3 (CH), 125.8 (CH), 64.0

(CH₂), 50.7 (CH₂), 48.9 (CH₂), 47.9 (CH), 44.5 (CH₂), 43.5

(CH₂), 38.9 (CH₂), 37.1 (C), 35.8 (CH), 34.7 (CH), 33.9 (CH₂),

32.8 (CH₂), 30.4 (CH₂), 28.0 (CH₂), 26.2 (CH₂), 25.7 (CH₂),

25.4 (CH₂), 17.9 (CH₂), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₃₀H₄₆N₂O₄SiNa⁺(M+Na)⁺549.3125, found 549.3126.

added to

a solution of (3-(1,3-dioxan-2-yl)propylidene)-

hydrazine, Et₃N (1.2 mL, 8.3 mmol), and Et₂O (21 mL) every

15 min at room temperature. The resulting mixture was stirred

for 30 min, quenched with saturated aqueous Na₂S₂O₃(5 mL),

and extracted with EtOAc (2x 5 mL). The combined organic

extracts were washed with brine (5 mL), dried over Na₂SO₄,

and concentrated. The residue was filtered through a pad of

silica gel (EtOAc/hexane 1:19 to 1:14) to give crude

gem-diiodoalkane 65 (427 mg), which was immediately used in

the next reaction without further purification.

Skipped diene ((E)-68): In

a glove box, sodium

hexamethyldisilazide (73.3 mg, 400 µmol) was added to a

mixture of phosphonium salt 67 (242 mg, 405 µmol) and THF

(3.0 mL) at room temperature. The reaction vessel was then

removed from the glove box, and cooled to –78 °C. The

solution of aldehyde 66 (15.6 mg, 29.6 µmol) and THF (3.0

mL) was added to the mixture of the ylide at –78 °C. The

mixture was stirred at –78 °C for 15 min, then allowed to warm

to room temperature, and stirred for 30 min. The mixture was

quenched with saturated aqueous NH₄Cl (3 mL), and extracted

with hexane (2x 5 mL). The combined organic extracts were

washed with brine (5 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:19 to 1:12) to give a mixture

of (E)-68 and (Z)-68 (18.1 mg). Two diastereomers were then

separated by HPLC (PEGASIL Silica 120-5, 250×20 mm, UV

210 nm, hexane/Et₂O 1:1, 10 mL/min, (E)-68: T_R= 18.6 min,

(Z)-68: T_R= 16.9 min) to afford skipped dines (E)-68 (12.7 mg,

In a glove box, chromium(II) chloride (75.2 mg, 612 µmol)

was added to a solution of aldehyde 64 (19.3 mg, 40.8 µmol),

the above gem-diiodoalkane 65 (245 mg) and THF (4.1 mL) at

room temperature. The reaction vessel was then removed from

the glove box, and stirred at room temperature for 17 h. The

mixture was quenched with brine (3 mL), and extracted with

Et₂O (2x 3 mL). The combined organic extracts were washed

with brine (3 mL), dried over Na₂SO₄, and concentrated. The

residue was purified by silica gel column chromatography

(EtOAc/hexane 1:9 to 1:1) to give acetal 87 (18.9 mg, 79%): a

colorless oil; [α]²⁶_D+102 (c 1.00, CHCl₃); IR (film) 2952, 2923,

2853, 1694, 1630, 1436, 1247, 1143, 1085, 859, 839 cm^-1; H

56%) and (Z)-68 (2.0 mg, 8.8%). (E)-68: a colorless oil; [α]²⁶

1

D

NMR (500 MHz, (CD₃)₂CO, 50 °C, a 4.8:1 inseparable mixture

of two diastereomers) δ 5.65‒5.39 (m, 3H), 5.38‒5.28 (m, 1H),

5.27‒5.19 (m, 1H), 5.18‒4.95 (m, 1H), 4.55 (t, J = 4.9 Hz,

24/29H), 4.50 (t, J = 4.9 Hz, 5/29H), 4.25‒4.07 (m, 1H), 4.17 (t,

J = 8.0 Hz, 2H), 4.01 (dd, J = 11.5, 4.6 Hz, 2H), 3.96 (d, J =

13.2 Hz, 1H), 3.90‒3.69 (m, 1H), 3.75 (dd, J = 12.1, 11.5 Hz,

2H), 3.40‒3.05 (m, 1H), 3.01‒2.83 (m, 2H), 2.82‒2.73 (m, 1H),

2.72‒2.58 (m, 1H), 2.56‒2.36 (m, 2H), 2.34‒2.00 (m, 7H),

2.00‒1.68 (m, 7H), 1.64‒1.52 (m, 2H), 1.50‒1.37 (m, 1H); ¹³C

NMR (125 MHz, (CD₃)₂CO, a 4.8:1 inseparable mixture of two

diastereomers, signals of the major diastereomer are reported) δ

173.4 (C), 156.9 (C), 138.4 (C), 135.0 (CH), 129.5 (CH), 128.9

(CH), 126.0 (CH), 125.8 (CH), 102.2 (CH), 67.3 (CH₂), 63.9

(CH₂), 51.4 (CH₂), 49.5 (CH₂), 48.4 (CH), 45.2 (CH₂), 39.7

(CH₂), 37.7 (C), 36.6 (CH), 35.9 (CH), 35.8 (CH₂), 35.1 (CH₂),

33.4 (CH₂), 30.9 (CH₂), 28.6 (CH₂), 28.0 (CH₂), 26.8 (CH₂),

26.7 (CH₂), 26.5 (CH₂), 18.5 (CH₂), ‒1.2 (CH₃); HRMS (ESI),

calcd for C₃₃H₅₃N₂O₅Si⁺(M+H)⁺585.3724, found 585.3722.

Hydrochloric acid (1 M, 3.3 mL) was added to a solution of

acetal 87 (18.9 mg, 32.3 µmol) and THF (3.3 mL). The mixture

was heated to 60 °C, maintained for 2 h at 60 °C, quenched

with saturated aqueous NaHCO₃(5 mL) at 0 °C, and extracted

with EtOAc (2x 3 mL). The combined organic extracts were

washed with brine (3 mL), dried over Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane 1:6 to 1:1) to give aldehyde 66

+105 (c 1.00, CHCl₃); IR (film) 2922, 2863, 1698, 1637, 1464,

1

1437, 1249, 1108, 1091, 860, 838, 677 cm^-1; H NMR (500

MHz, CDCl₃, 60 °C) δ 5.60‒5.49 (m, 1H), 5.48‒5.32 (m, 7H),

5.32‒5.20 (m, 1H), 5.10‒4.95 (m, 1H), 4.25‒4.10 (m, 3H),

4.06‒3.90 (m, 1H), 3.85‒3.73 (m, 1H), 3.71 (t, J = 6.9 Hz, 2H),

3.12 (ddd, J = 14.6, 9.2, 8.3 Hz, 1H), 2.95‒2.76 (m, 2H), 2.79

(dd, J = 5.5, 5.4 Hz, 2H), 2.75‒2.66 (m, 1H), 2.62 (d, J = 14.1

Hz, 1H), 2.59‒2.38 (m, 2H), 2.33 (dt, J = 6.6, 6.6 Hz, 2H),

2.35‒2.23 (m, 1H), 2.22‒1.90 (m, 12H), 1.88‒1.76 (m, 1H),

1.75‒1.69 (m, 1H), 1.43‒1.33 (m, 1H), 1.15‒1.04 (m, 21H),

1.01 (t, J = 8.3 Hz, 2H), 0.06 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 173.6 (C), 156.9 (C), 136.6 (C), 134.6 (CH), 129.8

(CH), 129.5 (CH), 128.8 (CH), 128.4 (CH), 128.1 (CH), 126.3

(CH), 126.1 (CH), 124.7 (CH), 64.0 (CH₂), 63.3 (CH₂), 50.7

(CH₂), 48.9 (CH₂), 47.9 (CH), 45.1 (CH₂), 39.0 (CH₂), 37.0 (C),

35.3 (CH), 34.8 (CH), 34.0 (CH₂), 33.0 (CH₂), 32.9 (CH₂), 31.4

(CH₂), 30.4 (CH₂), 28.0 (CH₂), 27.3 (CH₂), 26.2 (CH₂), 26.0

(CH₂), 25.7 (CH₂), 18.2 (CH₃), 17.9 (CH₂), 12.1 (CH), ‒1.3

+

(CH₃); HRMS (ESI), calcd for C₄₅H₇₇N₂O₄Si₂(M+H)⁺

765.5422, found 765.5427. (Z)-68: a colorless oil; [α]²⁹_D+89.4

(c 0.200, CHCl₃); IR (film) 2924, 2864, 1698, 1635, 1463,

1

1437, 1249, 1107, 860, 838, 686 cm^-1; H NMR (500 MHz,

CDCl₃, 60 °C) δ 5.60‒5.33 (m, 8H), 5.32‒5.20 (m, 1H),

5.10‒4.96 (m, 1H), 4.25‒4.10 (m, 3H), 4.05‒3.92 (m, 1H),

3.88‒3.75 (m, 1H), 3.71 (t, J = 6.9 Hz, 2H), 3.13 (ddd, J = 15.5,

9.8, 8.6 Hz, 1H), 2.98‒2.78 (m, 2H), 2.80 (dd, J = 5.4, 5.2 Hz,

2H), 2.77‒2.66 (m, 1H), 2.63 (d, J = 13.5 Hz, 1H), 2.60‒2.40

(m, 2H), 2.33 (td, J = 6.9, 6.3 Hz, 2H), 2.35‒2.22 (m, 1H),

2.22‒1.95 (m, 12H), 1.88‒1.72 (m, 2H), 1.45‒1.40 (m, 1H),

1.14‒1.05 (m, 21H), 1.02 (t, J = 8.6 Hz, 2H), 0.06 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃) δ 173.7 (C), 156.9 (C), 136.7 (C),

132.8 (CH), 129.7 (CH), 129.4 (CH), 128.8 (CH), 128.7 (CH),

128.0 (CH), 126.4 (CH), 126.0 (CH), 124.0 (CH), 64.0 (CH₂),

63.3 (CH₂), 50.7 (CH₂), 48.9 (CH₂), 47.9 (CH), 45.5 (CH₂),

39.0 (C), 37.4 (CH₂), 35.2‒34.6 (CH x2), 34.1 (CH₂), 33.2

(CH₂), 31.4 (CH₂), 30.6 (CH₂), 27.9 (CH₂), 27.5 (CH₂), 27.3

(CH₂), 26.3 (CH₂), 26.0 (CH₂), 25.7 (CH₂), 18.2 (CH₃), 18.0

(CH₂), 12.2 (CH), ‒1.3 (CH₃); HRMS (ESI), calcd for

C₄₅H₇₇N₂O₄Si₂⁺(M+H)⁺765.5422, found 765.5426.

(15.7 mg, 92%): a colorless oil; [α]²⁸+125 (c 1.00, CHCl₃);

D

IR (film) 2950, 2910, 1692, 1627, 1438, 1247, 859, 839 cm^-1;

¹H NMR (500 MHz, CDCl₃, 60 °C, an inseparable mixture of

two diastereomers, signals of the major diastereomer are

reported) δ 9.75 (t, J = 1.7 Hz, 1H), 5.62‒5.52 (m, 1H),

5.52‒5.34 (m, 3H), 5.32‒5.16 (m, 1H), 5.10‒4.90 (m, 1H),

4.25‒4.12 (m, 3H), 4.05‒3.90 (m, 1H), 3.90‒3.70 (m, 1H), 3.12

(ddd, J = 13.5, 10.3, 9.5 Hz, 1H), 3.00‒2.76 (m, 2H), 2.76‒2.65

(m, 1H), 2.58 (d, J = 13.7 Hz, 1H), 2.63‒2.40 (m, 4H),

2.39‒2.30 (m, 2H), 2.30‒2.22 (m, 1H), 2.21‒1.94 (m, 7H), 1.91

(dd, J = 14.3, 5.7 Hz, 1H), 1.86‒1.73 (m, 1H), 1.72‒1.65 (m,

1H), 1.40 (d, J = 13.2 Hz, 1H), 1.01 (t, J = 8.6 Hz, 2H), 0.05 (s,

9H); ¹³C NMR (125 MHz, CDCl₃, an inseparable mixture of

two diastereomers, signals of the major diastereomer are

reported) δ 202.1 (CH), 173.5 (C), 156.9 (C), 136.5 (C), 132.9

Madangamine B (2): 10-Camphorsulfonic acid (CSA, 11.0

mg, 47.6 µmol) was added to a solution of skipped dines

(E)-68 (18.2 mg, 23.8 µmol) and MeOH (1.2 mL) at room

temperature. The solution was heated to 40 °C, maintained for

2 h at 40 °C, quenched with Et₃N (17 µL, 120 µmol) at room

temperature, and concentrated. The residue was purified by

silica gel column chromatography (EtOAc/hexane 1:9 to 1:1) to

give alcohol 88 (14.5 mg, 100%): a colorless oil; [α]²⁶_D+124 (c

1.00, CHCl₃); IR (film) 3423, 2949, 2921, 1695, 1612, 1437,

1248, 1052, 860, 839 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C)

δ 5.60‒5.32 (m, 8H), 5.32‒5.20 (m, 1H), 5.10‒4.92 (m, 1H),

4.26‒4.10 (m, 3H), 4.04‒3.90 (m, 1H), 3.88‒3.70 (m, 1H), 3.64

(t, J = 6.9 Hz, 2H), 3.12 (ddd, J = 13.8, 9.8, 8.3 Hz, 1H),

2.95‒2.77 (m, 2H), 2.82 (dd, J = 6.3, 5.7 Hz, 2H), 2.75‒2.65 (m,

1H), 2.59 (d, J = 13.8 Hz, 1H), 2.63‒2.40 (m, 2H), 2.36 (td, J =

6.9, 6.6 Hz, 2H), 2.32‒2.23 (m, 1H), 2.22‒1.94 (m, 11H), 1.90

(dd, J = 14.0, 7.2 Hz, 1H), 1.86‒1.75 (m, 1H), 1.74‒1.66 (m,

1H), 1.45‒1.30 (m, 1H), 1.01 (t, J = 8.6 Hz, 2H), 0.05 (s, 9H);

¹³C NMR (125 MHz, CDCl₃) δ 173.7 (C), 156.9 (C), 136.6 (C),

134.7 (CH), 131.0 (CH), 129.7 (CH), 128.7 (CH), 128.1 (CH),

128.0 (CH), 126.3 (CH), 125.6 (CH), 124.6 (CH), 64.0 (CH₂),

62.3 (CH₂), 50.8 (CH₂), 48.9 (CH₂), 48.0 (CH), 44.6 (CH₂),

39.1 (CH₂), 37.0 (C), 35.9 (CH), 34.8 (CH), 33.9 (CH₂), 32.9

(CH₂), 32.8 (CH₂), 31.2 (CH₂), 30.4 (CH₂), 28.0 (CH₂), 27.4

(CH₂), 26.2 (CH₂), 26.0 (CH₂), 25.7 (CH₂), 17.9 (CH₂), ‒1.3

(CH₃); HRMS (ESI), calcd for C₃₆H₅₇N₂O₄Si⁺(M+H)⁺

609.4088, found 609.4086.

p-Toluenesulfonyl chloride (9.1 mg, 48 µmol) was added to a

solution of alcohol 88 (14.5 mg, 23.8 µmol), Et₃N (13 µL, 95.0

µmol), DMAP (0.6 mg, 5 µmol) and CH₂Cl₂(1.2 mL) at room

temperature. The solution was maintained at room temperature

for 19 h, and quenched with saturated aqueous NH₄Cl (1.0 mL).

The resulting mixture was extracted with CH₂Cl₂(2x 3 mL).

The combined extracts were washed with brine (3 mL), dried

over Na₂SO₄, and concentrated. The residue was purified by

silica gel column chromatography (EtOAc/hexane 1:12 to 1:1)

to give tosylate 89 (15.3 mg, 84%): a colorless oil; [α]²⁶_D+96.7

(c 1.00, CHCl₃); IR (film) 2950, 2919, 1693, 1629, 1437, 1361,

1248, 1176, 967, 838 cm^-1; ¹H NMR (500 MHz, CDCl₃, 60 °C)

δ 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.60‒5.50

(m, 1H), 5.50‒5.20 (m, 8H), 5.10‒4.95 (m, 1H), 4.25‒4.10 (m,

3H), 4.04 (t, J = 6.9 Hz, 2H), 4.02‒3.90 (m, 1H), 3.85‒3.70 (m,

1H), 3.13 (ddd, J = 14.0, 9.8, 9.2 Hz, 1H), 2.95‒2.77 (m, 2H),

2.72 (dd, J = 7.2, 7.2 Hz, 2H), 2.75‒2.65 (m, 1H), 2.61 (d, J =

13.7 Hz, 1H), 2.65‒2.49 (m, 2H), 2.44 (s, 3H), 2.43 (dt, J = 7.5,

6.9 Hz, 2H), 2.35‒2.23 (m, 1H), 2.22‒1.90 (m, 11H), 1.95 (dd,

J = 14.4, 7.2 Hz, 1H), 1.88‒1.75 (m, 1H), 1.74‒1.68 (m, 1H),

1.44‒1.36 (m, 1H), 1.01 (t, J = 8.3 Hz, 2H), 0.05 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃) δ 173.6 (C), 156.9 (C), 144.8 (C),

136.6 (C), 134.4 (CH), 133.3 (C), 132.0 (CH), 130.0 (CH),

129.9 (CH), 128.7 (CH), 128.2‒127.9 (CH x2), 127.5 (CH),

126.2 (CH), 124.8 (CH), 123.2 (CH), 69.8 (CH₂), 63.9 (CH₂),

50.7 (CH₂), 48.9 (CH₂), 47.9 (CH), 44.9 (CH₂), 39.0 (CH₂),

36.9 (C), 35.4 (CH), 34.8 (CH), 33.9 (CH₂), 32.9 (CH₂), 32.8

(CH₂), 30.3 (CH₂), 28.0 (CH₂), 27.2‒25.9 (CH₂x2), 26.2 (CH₂),

25.9 (CH₂), 25.7 (CH₂), 21.8 (CH₃), 17.9 (CH₂), ‒1.3 (CH₃);

HRMS (ESI), calcd for C₄₃H₆₃N₂O₆SiS⁺(M+H)⁺763.4176,

found 763.4184.

room temperature. The resulting solution was heated to 70 °C,

maintained for 18 h at this temperature, and then concentrated.

The residue was purified by silica gel column chromatography

(Et₂O/hexane 1:9 to 1:1) to give macrocyclic amine 90 (6.8 mg,

76% for 2 steps): a colorless oil; [α]³¹_D+115 (c 0.680, EtOAc);

1

IR (film) 2917, 1628, 1446 cm^-1; H NMR (500 MHz, C₆D₆,

2.3:1 mixture of rotamers, signals of the major rotamer are

reported) δ 5.72‒5.60 (m, 1H), 5.56‒5.04 (m, 8H), 4.75‒4.68

(m, 1H), 4.62 (d, J = 14.3 Hz, 1H), 3.18 (d, J = 14.3 Hz, 1H),

3.11 (dd, J = 17.2, 12.3 Hz, 1H), 2.96‒2.84 (m, 2H), 2.60 (d, J

= 11.5 Hz, 1H), 2.63‒2.47 (m, 2H), 2.42 (dd, J = 12.1, 6.1 Hz,

1H), 2.45‒1.74 (m, 17H), 1.72‒1.63 (m, 1H), 1.61‒1.51 (m,

1H), 1.41 (dd, J = 12.1, 9.2 Hz, 1H), 1.30 (d, J = 11.5 Hz, 1H),

1.20‒1.14 (m, 1H), 1.14‒1.07 (m, 1H); ¹³C NMR (125 MHz,

C₆D₆) δ 172.0 (C), 138.7 (C), 134.0 (CH), 129.5 (CH), 129.3

(CH), 128.9 (CH), 128.8‒127.4 (CH x4), 124.9 (CH), 61.3

(CH₂), 59.2 (CH₂), 58.1 (CH₂), 48.0 (CH), 44.0 (CH₂), 39.4

(CH₂), 38.3 (CH), 36.9 (C), 36.1 (CH), 35.4 (CH₂), 32.5 (CH₂),

31.8 (CH₂), 30.9 (CH₂), 28.8 (CH₂), 28.2 (CH₂), 26.4 (CH₂),

26.2 (CH₂), 25.9 (CH₂), 24.6 (CH₂); HRMS (ESI), calcd for

C₃₀H₄₃N₂O⁺(M+H)⁺447.3375, found 447.3372.

In a glove box, LiAlH₄(1.0 M in THF, 76 µL, 76.0 µmol)

was added to a solution of macrocyclic amine 90 (6.8 mg, 15.2

µmol) and THF (1.5 mL) at room temperature. The reaction

vessel was removed from the glove box, stirred at room

temperature for 6 h, cooled to 0 °C, and quenched with a few

drops of distilled water. The resulting suspension was dried

over Na₂SO₄, and filtrated. The solid was washed with Et₂O (10

mL). The resulting filtrate was then concentrated. The residue

was purified by silica gel column chromatography

(Et₂O/hexane 1:19 to 1:5) to give madangamine B (2) (5.5 mg,

83%): a colorless oil; [α]²⁶_D+146 (c 0.0670, EtOAc); IR (film)

1

2927, 2875, 2853, 1459, 1439, 1127, 973, 723, 498 cm^-1; H

NMR (500 MHz, C₆D₆) δ 5.53‒5.36 (m, 7H), 5.25‒5.17 (m,

2H), 3.72 (t, J = 2.9 Hz, 1H), 3.35 (dt, J = 13.2, 11.2 Hz, 1H),

3.15 (d, J = 12.3 Hz, 1H), 3.12 (dddd, J = 16.3, 12.0, 3.2, 2.9

Hz, 1H), 3.02 (dd, J = 12.4, 7.5 Hz, 1H), 3.01 (ddd, J = 16.4,

8.9, 8.6 Hz, 1H), 2.90 (ddd, J = 13.8, 12.1, 5.8 Hz, 1H), 2.71

(td, J = 13.8, 3.7 Hz, 1H), 2.59‒2.51 (m, 2H), 2.51‒2.46 (m,

2H), 2.43‒2.30 (m, 2H), 2.39 (dt, J = 12.6, 2.9 Hz, 1H), 2.34

(brd, J = 10.9 Hz, 1H), 2.30‒2.22 (m, 1H), 2.26 (dd, J = 16.3,

8.3 Hz, 1H), 2.18 (ddd, J = 12.0, 6.6, 3.4 Hz, 1H), 2.20‒2.09

(m, 2H), 2.11 (dd, J = 10.9, 3.2 Hz, 1H), 2.01‒1.91 (m, 3H),

1.91‒1.79 (m, 2H), 1.77‒1.70 (m, 1H), 1.63 (dd, J = 12.4, 6.9

Hz, 1H), 1.57‒1.43 (m, 1H), 1.39 (d, J = 11.2 Hz, 1H), 1.30 (dt,

J = 12.6, 2.9 Hz, 1H), 1.26‒1.15 (m, 3H); ¹³C NMR (125 MHz,

C₆D₆) δ 139.2 (C), 133.1 (CH), 129.7 (CH), 129.5 (CH), 129.2

(CH), 129.1 (CH), 129.0 (CH), 128.5 (CH), 128.4‒127.7 (CH),

122.1 (CH), 61.2 (CH₂), 59.3 (CH₂), 57.7 (CH₂), 56.2 (CH₂),

53.0 (CH₂), 51.8 (CH), 40.1 (CH₂), 38.42 (CH), 38.39 (CH₂),

37.14 (C), 37.11 (CH), 32.4 (CH₂), 31.8 (CH₂), 28.9 (CH₂),

26.9 (CH₂), 26.4 (CH₂), 26.0 (CH₂), 25.4 (CH₂), 24.7 (CH₂),

+

24.1‒23.5 (CH₂); HRMS (ESI), calcd for C₃₀H₄₅N₂(M+H)⁺

433.3583, found 433.3588.

Cell culture: Human cell lines, lung adenocarcinoma A549,

melanoma CHL-1 and SK-MEL-28, colon carcinoma HCT116,

cervix adenocarcinoma HeLa, fibrosarcoma HT1080, breast

carcinoma MCF-7 and MDA-MB-23, bladder carcinoma T24,

and pancreatic carcinoma Panc-1, were cultured in Dulbecco’s

modified Eagle’s medium (Nissui Pharmaceutical Co., Ltd.)

including with 10% (v/v) fetal bovine serum, 100 units/mL

penicillin G, 100 mg/L kanamycin, 315 mg/L L-glutamine, and

2.5 g/L NaHCO₃at 37 °C in 5% CO₂. Other human cell lines,

pancreatic carcinoma PK-1, prostate adenocarcinoma PC-3,

and acute monocytic leukemia THP1, were cultured in Roswell

park memorial institute 1640 medium (Nissui Pharmaceutical

Boron trifluoride ethyl ether complex (13 µL, 100 µmol) was

added to a solution of tosylate 89 (15.3 mg, 20.0 µmol) and

CH₂Cl₂(1.0 mL) at room temperature. The solution was

maintained

for

30

min,

and

quenched

with

N,N-diisopropylethylamine (34 µL, 200 µmol) at room

temperature. The solution was concentrated to give the

corresponding secondary amine, which was immediately used

in the next step without further purification.

N,N-Diisopropylethylamine (17 µL, 100 µmol) was added to

a solution of the above secondary amine and MeCN (20 mL) at

Co., Ltd.) including with 10% (v/v) fetal bovine serum, 105

units/mL penicillin G, 105 mg/L kanamycin, 600 mg/L

L-glutamine, and 2.5 g/L NaHCO₃at 37 °C in 5% CO₂.

Evaluation of antiproliferative activity against human

cancer cells by MTT assay: The human cancer cells were

seeded in a 96-well plate (Corning Inc.) at 1.0 × 10⁴cells/well

and incubated for 24 h at 37 °C in 5% CO₂. The medium was

replaced with 200 μL of fresh medium, and 1 µL of various

concentrations of each compound in MeOH solution was added,

respectively. After 48 h, 20 µL of 5 mg/mL thiazolyl blue

tetrazolium bromide (Merck) was added and incubated for 4 h

at 37 °C in 5% CO₂. Next, the medium was removed, and the

precipitation was dissolved by 150 μL of DMSO. The amounts

of these products were determined by measuring absorbance at

570 nm using a microplate reader (infinite M200 PRO, Tecan

Group Ltd.)^37,38

6.

For recent selected examples on stereoselective and

convergent method for skipped dienes, see; a) K. Kaneda,

T. Uchiyama, Y. Fujiwara, T. Imanaka, S. Teranishi, J.

Org. Chem. 1979, 44, 55. b) B. M. Trost, A. Indolese, J.

Am. Chem. Soc. 1993, 115, 4361. c) B. M. Trost, A. F.

Indolese, T. J. J. Müller, B. Treptow, J. Am. Chem. Soc.

1995, 117, 615. d) A. N. Thadani, V. H. Rawal, Org. Lett.

2002, 4, 4317. e) A. N. Thadani, V. H. Rawal, Org. Lett.

2002, 4, 4321. f) T. R. Hoye, J. Wang, J. Am. Chem. Soc.

2005, 127, 6950. g) H. L. Shimp, G. C. Micalizio, Chem.

Commun. 2007, 4531. h) H. L. Shimp, A. Hare, M.

McLaughlin, G. C. Micalizio, Tetrahedron 2008, 64,

6831. i) H. He, W.-B. Liu, L.-X. Dai, S.-L. You, J. Am.

Chem. Soc. 2009, 131, 8346. j) T. K. Macklin, G. C.

Micalizio, Nature Chem. 2010, 2, 638. k) P. S. Diez, G. C.

Micalizio, J. Am. Chem. Soc. 2010, 132, 9576. l) V. Jeso,

G. C. Micalizio, J. Am. Chem. Soc. 2010, 132, 11422. m)

K.-Y. Ye, H. He, W.-B. Liu, L.-X. Dai, G. Helmchen, S.-L.

You, J. Am. Chem. Soc. 2011, 133, 19006. n) A. C.

Gutierrez, T. F. Jamison, Org. Lett. 2011, 13, 6414. o) M.

S. McCammant, L. Liao, M. S. Sigman, J. Am. Chem.

Soc. 2013, 135, 4167. p) F. Gao, J. L. Carr, A. H.

Hoveyda, J. Am. Chem. Soc. 2014, 136, 2149. q) S. Xu, S.

Zhu, J. Shang, J. Zhang, Y. Tang, J. Dou, J. Org. Chem.

2014, 79, 3696. r) H.-Y. Bin, X. Wei, J. Zi, Y.-J. Zuo, T.-C.

Wang, C.-M. Zhong, ACS Catal. 2015, 5, 6670. s) D. P.

Todd, B. B. Thompson, A. J. Nett, J. Montgomery, J. Am.

Chem. Soc. 2015, 137, 12788. t) M. Mailig, A. Hazra, M.

K. Armstrong, G. Lalic, J. Am. Chem. Soc. 2017, 139,

6969. u) X. Lian, W. Chen, L. Dang, Y. Li, C.-Y. Ho,

Angew. Chem. Int. Ed. 2017, 56, 9048. v) J. Mateos, E.

Rivera-Chao, M. Faꢀanꢁs-Mastral, ACS Catal. 2017, 7,

5340. w) S. M. Jing, V. Balasanthiran, V. Pagar, J. C.

Gallucci, T. V. RajanBabu, J. Am. Chem. Soc. 2017, 139,

18034. x) Y. Nagashima, K. Sasaki, T. Suto, T. Sato, N.

Chida, Chem. Asian J. 2018, 13, 1024. y) V. A. Schmidt,

C. R. Kennedy, M. J. Bezdek, P. J. Chirik, J. Am. Chem.

Soc. 2018, 140, 3443. z) S. Parisotto, L. Palagi, C. Prandi,

A. Deagostino, Chem. Eur. J. 2018, 24, 5484.

Acknowledgement

This research was supported by the Otsuka

Pharmaceutical Co. Award in Synthetic Organic Chemistry,

Japan, and a JSPS fellowship to T. Suto (18J11234). We

thank Prof. Raymond J. Andersen, The University of British

Columbia, Canada for giving ¹H and ¹³C NMR spectra of

madangamine alkaloids, and precious advice. Synthetic

assistance from T. Matsumoto, S. Hiraoka, Y. Komiya and A.

Azuma is gratefully acknowledged.

References

1.

For a review, see; M. Amat, M. Pérez, R. Ballette, S.

Proto, J. Bosch, The Alkaloids: Chem. Bio. 2015, 74, 159.

a) F. Kong, R. J. Andersen, T. M. Allen, J. Am. Chem. Soc.

1994, 116, 6007. b) F. Kong, E. I. Graziani, R. J.

Andersen, J. Nat. Prod. 1998, 61, 267. c) J. H. H. L. de

Oliveira, A. M. Nascimento, M. H. Kossuga, B. C.

Cavalcanti, C. O. Pessoa, M. O. Moraes, M. L. Macedo,

A. G. Ferreira, E. Hajdu, U. S. Pinheiro, R. G. S. Berlinck,

J. Nat. Prod. 2007, 70, 538.

2.

3.

a) M. Amat, M. Pérez, A. T. Minaglia, N. Casamitjana, J.

Bosch, Org. Lett. 2005, 7, 3653. b) M. Amat, M. Pérez, S.

Proto, T. Gatti, J. Bosch, Chem. Eur. J. 2010, 16, 9438. c)

S. Proto, M. Amat, M. Pérez, R. Ballette, F. Romagnoli, A.

Mancinelli, J. Bosch, Org. Lett. 2012, 14, 3916. d) M.

Amat, R. Ballette, S. Proto, M. Pérez, J. Bosch, Chem.

Commun. 2013, 49, 3149. e) R. Ballette, M. Pérez, S.

Proto, M. Amat, J. Bosch, Angew. Chem. Int. Ed. 2014,

53, 6202.

7.

8.

W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405.

a) F. K. Sheffy, J. K. Stille, J. Am. Chem. Soc. 1983, 105,

7173. b) L. D. Valle, J. K. Stille, L. S. Hegedus, J. Org.

Chem. 1990, 55, 3019. c) A. M. Castaño, A. M.

Echavarren, Tetrahedron Lett. 1996, 37, 6587. For a

selected review, see; V. Farina, V. Krishnamurthy, W. J.

Scott, Org. React. 1997, 50, 1.

4.

a) N. Matzanke, R. J. Gregg, S. M. Weinreb, M. Parvez, J.

Org. Chem. 1997, 62, 1920. b) N. Yamazaki, T. Kusanagi,

C. Kibayashi, Tetrahedron Lett. 2004, 45, 6509. c) H. M.

Tong, M.-T. Martin, A. Chiaroni, M. Bénéchie, C.

Marazano, Org. Lett. 2005, 7, 2437. d) Y. Yoshimura, J.

Inoue, N. Yamazaki, S. Aoyagi, C. Kibayashi,

Tetrahedron Lett. 2006, 47, 3489. e) Y. Yoshimura, T.

Kusanagi, C. Kibayashi, N. Yamazaki, S. Aoyagi,

Heterocycles 2008, 75, 1329. f) J. Quirante, L. Paloma, F.

Diaba, X. Vila, J. Bonjoch, J. Org. Chem. 2008, 73, 768.

g) F. Diaba, C. Pujol-Grau, A. Martínez-Laporta, I.

Fernández, J. Bonjoch, Org. Lett. 2015, 17, 568. h) A.

Bhattacharjee, M. V. Gerasimov, S. DeJong, D. J.

Wardrop, Org. Lett. 2017, 19, 6570.

a) Y. Yanagita, T. Suto, N. Matsuo, Y. Kurosu, T. Sato, N.

Chida, Org. Lett. 2015, 17, 1946. Part of this work was

published as preliminary communications, see: b) T. Suto,

Y. Yanagita, Y. Nagashima, S. Takikawa, Y. Kurosu, N.

Matsuo, T. Sato, N. Chida, J. Am. Chem. Soc. 2017, 139,

2952.

9.

For selected reviews on intramolecular cyclizations of

N-acyliminium ions, see: a) W. N. Speckamp, H.

Hiemstra, Tetrahedron 1985, 41, 4367. b) W. N.

Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56, 3817.

c) J. Royer, M. Bonin, L. Micouin, Chem. Rev. 2004, 104,

2311. d) B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J.

Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104, 1431. (e)

M. Petrini, E. Torregiani, Synthesis 2007, 159.

10. For selected examples on reactions via hydroboration of

allenes, a) R. H. Fish, J. Am. Chem. Soc. 1968, 90, 4435.

b) D. S. Sethi, G. C. Joshi, D. Devaprabhakara, Can. J.

Chem. 1968, 46, 2632. c) D. S. Sethi, G. C. Joshi, D.

Devaprabhakara, Can. J. Chem. 1969, 47, 1083. d) H. C.

Brown, R. Liotta, G. W. Kramer, J. Am. Chem. Soc. 1979,

101, 2966. e) K. K. Wang, Y. G. Gu, C. Liu, J. Am. Chem.

Soc. 1990, 112, 4424. f) H. C. Brown, G. Narla, J. Org.

Chem. 1995, 60, 4686.; g) S.-C. Hung, Y.-F. Wen, J.-W.

Chang, C.-C. Liao, B.-J. Uang, J. Org. Chem. 2002, 67,

1308. h) A. Fürstner, M. Bonnekessel, J. T. Blank, K.

Radkowski, G. Seidel, F. Lacombe, B. Gabor, R. Mynott,

5.

Chem. Eur. J. 2007, 13, 876. i) J. Kister, A. C. DeBaillie,

R. Lira, W. R. Roush, J. Am. Chem. Soc. 2009, 131,

14174. j) M. Chen, M. Handa, W. R. Roush, J. Am. Chem.

Soc. 2009, 131, 14602. k) D. H. Ess, J. Kister, M. Chen,

W. R. Roush, Org. Lett. 2009, 11, 5538. l) M. Chen, D. H.

Ess, W. R. Roush, J. Am. Chem. Soc. 2010, 132, 7881. m)

C. Sánchez, X. Ariza, J. Cornellà, J. Farràs, J. Garcia, J.

Ortiz, Chem. Eur. J. 2010, 16, 1153. n) M. Chen, W. R.

Roush, J. Am. Chem. Soc. 2011, 133, 5744. o) M. Chen,

W. R. Roush, J. Am. Chem. Soc. 2013, 135, 9512. p) M.

Chen, W. R. Roush, Tetrahedron 2013, 69, 5468. q) L.

Yang, Z. Lin, S.-H. Huang, R. Hong, Angew. Chem. Int.

Ed. 2016, 55, 6280. Metal-catalyzed hydroboration of

allenes was also reported, see; r) Y. Yamamoto, R.

Fujikawa, A. Yamada, N. Miyaura, Chem. Lett. 1999,

1069. s) M. J. Campbell, P. D. Pohlhaus, G. Min, K.

Ohmatsu, J. S. Johnson, J. Am. Chem. Soc. 2008, 130,

9180. t) W. Yuan, S. Ma, Adv. Synth. Catal. 2012, 354,

1867. u) K. Semba, M. Shinomiya, T. Fujihara, J. Terao,

Y. Tsuji, Chem. Eur. J. 2013, 19, 7125. v) W. Yuan, X.

Zhang, Y. Yu, S. Ma, Chem. Eur. J. 2013, 19, 7193. w) C.

Zhu, B. Yang, Y. Qiu, J.-E. Bäckvall, Chem. Eur. J. 2016,

22, 2939.

B. Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521.

26. a) K. G. Hancock, J. D. Kramer, J. Am. Chem. Soc. 1973,

95, 6463. b) K. G. Hancock, J. D. Kramer, J. Organomet.

Chem. 1974, 64, C29. c) G. W. Kramer, H. C. Brown, J.

Organomet. Chem. 1977, 132, 9. d) Y. N. Bubnov, M. E.

Gurskii, I. D. Gridnev, A. V. Ignatenko, Y. A. Ustynyuk, V.

I. Mstislavsky, J. Organomet. Chem. 1992, 424, 127. e) I.

D. Gridnev, M. E. Gursky, Y. N. Bubnov,

Organometallics 1996, 15, 3696. f) G. Y. Fang, V. K.

Aggarwal, Angew. Chem. Int. Ed. 2007, 46, 359. g) M. E.

Gurskii, P. A. Belyakov, K. A. Lyssenko, A. L. Semenova,

Y. N. Bubnov, Russian Chem. Bull. Int. Ed. 2014, 63, 480.

h) F. W. van der Mei, H. Miyamoto, D. L. Silverio, A. H.

Hoveyda, Angew. Chem. Int. Ed. 2016, 55, 4701.

27. a) T. Mukaiyama, M. Usui, K. Saigo, Chem. Lett. 1976,

49. b) K. Narasaka, T. Masui, T. Mukaiyama, Chem. Lett.

1977, 763.

28. M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am.

Chem. Soc. 2006, 128, 8412.

29. G. Cahiez, C. Chaboche, M. Jézéquel, Tetrahedron 2000,

56, 2733.

30. M. Uyanik, D. Suzuki, T. Yasui, K. Ishihara, Angew.

Chem. Int. Ed. 2011, 50, 5331.

11. J. M. Baxter, D. Steinhuebel, M. Palucki, I. W. Davies,

Org. Lett. 2005, 7, 215.

31. T. Okazoe, K. Takai, K. Utimoto, J. Am. Chem. Soc. 1987,

109, 951.

12. T. Moriwake, S. Hamano, D. Miki, S. Saito, S. Torii,

Chem. Lett. 1986, 815.

32. M. Iwasaki, S. Hayashi, K. Hirano, H. Yorimitsu, K.

Oshima, J. Am. Chem. Soc. 2007, 129, 4463.

13. a) M. Frigerio, M. Santagostino, S. Sputore, G. Palmisano,

J. Org. Chem. 1995, 60, 7272. b) M. Frigerio, M.

Santagostino, S. Sputore, J. Org. Chem. 1999, 64, 4537.

14. H. Takahashi, T. Kawakita, M. Ohno, M. Yoshioka, S.

Kobayashi, Tetrahedron 1992, 48, 5691.

15. For selected reviews on Claisen rearrangements, see: a) A.

M. M. Castro, Chem. Rev. 2004, 104, 2939. b) K. C.

Majumdar, S. Alam, B. Chattopadhyay, Tetrahedron 2008,

64, 597.

16. For selected examples on the Hofmann rearrangement

with PhI(OAc)₂, see: (a) R. M. Moriarty, C. J. Chany II,

R. K. Vaid, O. Prakash, S. M. Tuladhar, J. Org. Chem.

1993, 58, 2478. (b) N. Satoh, T. Akiba, S. Yokoshima, T.

Fukuyama, Tetrahedron 2009, 65, 3239.

33. B. R. Galan, K. P. Kalbarczyk, S. Szczepankiewicz, J. B.

Keister, S. T. Diver. Org. Lett. 2007, 9, 1203.

34. D. E. Bergbreiter, E. Pendergrass, J. Org. Chem. 1981, 46,

219.

35. S. G. Duron, D. Y. Gin, Org. Lett. 2001, 3, 1551.

36. K. Fuchs, L. A. Paquette, J. Org. Chem. 1994, 59, 528.

37. S. Simizu, K. Tanabe, E. Tashiro, M. Takada, K.

Umezawa, M. Imoto, Jpn. J. Cancer Res. 1998, 89, 970.

38. S. Katsuyama, K. Sugino, Y. Sasazawa, Y. Nakano, H.

Aono, K. Morishita, M. Kawatani, K. Umezawa, H.

Osada, S. Simizu, FEBS Lett. 2016, 590, 1152.

17. M. Scholl, S. Ding, C.-W. Lee, R. H. Grubbs, Org. Lett.

1999, 1, 953.

18. a) P. Kumar, J. Louie, Org. Lett. 2012, 14, 2026. b) A.

Thakur, J. L. Evangelista, P. Kumar, J. Louie, J. Org.

Chem. 2015, 80, 9951.

19. a) E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc.

1987, 109, 5551. b) E. J. Corey, C. J. Helal, Angew. Chem.

Int. Ed. 1998, 37, 1986.

20. Y. Kaneko, Y. Kiyotsuka, H. P. Acharya, Y. Kobayashi,

Chem. Commun. 2010, 46, 5482.

21. (a) B. M. Trost, G. J. Tanoury, M. Lautens, C. Chan, D. T.

MacPherson, J. Am. Chem. Soc. 1994, 116, 4255. (b) B.

M. Trost, D. L. Romero, F. Rise, J. Am. Chem. Soc. 1994,

116, 4268. (c) B. M. Trost, Y. Li, J. Am. Chem. Soc. 1996,

118, 6625. (d) B. M. Trost, E. M. Ferreira, A. C. Gutierrez,

J. Am. Chem. Soc. 2008, 130, 16176. (e) B. M. Trost, A.

C. Gutierrez, E. M. Ferreira, J. Am. Chem. Soc. 2010, 132,

9206.

22. Formation of the corresponding trans-fused bicyclic

compound was not observed.

23. M. Narisada, I. Horibe, F. Watanabe, K. Takeda, J. Org.

Chem. 1989, 54, 5308.

24. S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22,

3815.

25. a) S. Ohira, Synth. Commun. 1989, 19, 561. b) S. Müller,

Article Doi

Unified Total Synthesis of Madangamine Alkaloids

DOI: 10.1246/bcsj.20180334

Source and publish data:

Authors:

Article abstract of DOI:10.1246/bcsj.20180334

Full text of DOI:10.1246/bcsj.20180334

Products guided by the article

R&D Labs maybe for 81616-13-9

Relevant to this article

Hot Product