Literature Seminar(D1 part)

Xu Yingjie (D1)2010/4/28

Epidithiodiketopiperazine
O
Me
N

OH

2'

N

S
Me

H
N

H

O
3'

S

3
6

15

10

1

H

N
H

8

S

N

2

N

S

12

S

18

13
11

O

O

Me

Me

N

Me

N

S

isolated from chaetomium minutum(D. Hause et al. Helv. Chim. Acta 1970, 53,1061.)(+)-chaetocin (2): in addition to its antibacterial andcytostatic activity, 2 is known to be a potent inhibitor oflysine-specific histone methyltransferases (HMTs).

H
N

O

Me
Me

S

O
12'

HO

OH

S

12

O

N
N
H

H

OH

Sodeoka, M. et al.
JACS 2010, 132, 4078.

(+)-11,11'-dideoxyverticillin (1): potently inhibits
the tyrosine kinase activity of the epidermal growth
factor receptor, exhibits antiangiogenic activity, andhas efficacy against several cancer cell lines

NO(+)-chaetocin (2)isolated from a marine Penicillium sp.
(W. Fenical et al. Nat. Prod. Res. 1999, 13, 213.)

S

H

N
H

Me

S

N

2

O

N

S

O

17

Me

Isolation:

Me

O
3'
3

Movassaghi, M. et al.
Science 2009, 324, 238.

H

2'

N

S

(+)-11,11'-dideoxyverticillin (1)

O

H
N

H

S

N

Me

Me

N

S

H
N

H
N

O
12'

HO

OH
O
N
H

H

N

Me

S

N

Me

O

S

12

O

Me
Me

(+)-verticillin A (3)(+)-leptosin K (4)isolated from a basidiocarp of Coltricia cinnamomea(Katagiri, K. et al. J. Antibiot. 1970, 23, 420.)

isolated from a strain of Leptosphaeia sp.
(Numata, A. et al. Tetrahedron, 1995, 51, 3483)

0. Retrosynthetic Analysis
1. Strategies for The Synthesis of Hexahydropyrroloindole Alkaloids
2. Quadruple C -Methine Hydroxylation
3. Stereoselective Tetrathiolation and Disulfide Formation
4. Synthesis of Dimerization Precursor (+)-12
5. Over View
6. Sodeoka's Route10. Retrosynthetic Analysis
Me
HS
N
Me

disulf ide
f ormation

(+)-1

N
HS
O

SH

Me

N
HO
O

N
SH
Me
N H
O
H

H
H N

O

O

OH

N

Me

N
OH
Me
N H
O
H

6

tetrahydroxylation

OH
NH2
L-alanineO

condensation

dimerization
NH

O
HN

HN

OH
NH2

HN

Me
HO
stereoselectiveN
tetrathiolation Me

O
N

5

O
Me

H
H N

O

8

L-tryptophan

Me
O

Me
H
N
Me

O

N
H
O

Imposing challenges:

H
H N
O

H

N

Me

N
H
Me
N H
O
H

7

Absolute and relative stereochemical control of the six tetrasubstituted carbons of (+)-1
posed noteworthy strategic concerns.
highly acid-, base-, and redox-sensitive functional groupings
Quadruple C -methine hydroxylation of 7 and the tetrathiolation of intermediate 6.

1. Strategies for The Synthesis of Hexahydropyrroloindole Alkaloids
1.1 Background
Hendrickson et al.'s synthesis of chimonanthines
Proc. Chem. Soc., London 1962, 383.

Hino's synthesis of ( )-folicanthine

JACS 1964, 86, 302.

24
21

Scott et al's elegant synthesis of chimonanthines

Chem. Pharm. Bull. 1961, 9, 979.

25

22
22

28

27
23

MeMgI, Et2O;
FeCl3.

26

conditions: (a) ClCH2CN, K2CO3, NaI; (b) PtO2, H2, AcOH,
30% yield (2 steps); (c) imine formation; MeI, 100°C; HCl, H2O,
yields and specific conditions not given; d) LiAlH4, 1,4-dioxane,
yield not given.

23 6%

conditions: (a) NaH, THF; I2, benzene; (b) LiAlH4, THF.

Rodrigo and co-workers' synthesis of ( )-folicanthine

29

30

23
23

Overman's enantioselective total syntheses of (-)- and (+)-chimonanthine
JACS 1999, 121, 7702. ; ACIE 2000, 39, 213.

JACS. 1994, 116, 9480.

35

NaH; CI4

31

32
36

37

38
(-)-233927( )-32

Takayama's synthesis of chimonanthines
Tetrahedron Lett. 2002, 43, 5637.

40

41

42

( )-23

conditions: (a) 10 mol% Pd(PPh3)2Cl2, Et3N, DMA, 100°C, 90% yield;(b) LiHMDS (2.1 equiv), THF, DMPU, -78 °C, 55% yield.
33

34
34
23
34
23

conditions: (a) PIFA, TFE; (b) Red-Al, toluene.

In the first enantioselective total synthesis of chimonanthinethe key
transformation proceeded via two intramolecular Heck cyclizations
to sequentially secure the two quaternary stereocenters.
Second approach relied on two alkylation reactions to sequentiallyintroduce the vicinal quaternary stereocenters2

1.2 Cobalt(I)-Promoted Reductive Dimerization Strategy
1.2.1. Related works
Danishefsky, S. J. et al. JACS. 1994, 121, 11953.
H

PhSe

N

H
CO2Me

Boc
N H
43
Boc
(exo:endo=5:1)

a

N

c

Boc

N
N H
Boc

CO2Me

Compound 46 represents a potential solution toward natural
products of the dimeric tryptamine and tryptophan class ofindole alkaloids.

Boc
H N

10-15%

H

observed dimerization products during the radical prenylation.

Boc
N H
44
Boc
(exo:endo=5:1)

b
CO2Et

CO2Me

N

MeO2C
H

Boc
45

(a) allyl-Sn(n-Bu)3, (n-Bu)6Sn2, toluene, hv, 23 °C, 94%;(b) (n-Bu)6Sn2, toluene, hv, 23 °C;(c) (n-Bu)6Sn2, ethyl -tri(n-butyl)stannylacrylate, toluene,hv, 23°C, 21%.

H
CO2Me

N
Boc
N H
Boc 46

Reductive coupling of benzylic halides by CoCl(PPh3)3

Radical Coupling of Organobromides Using Mn2(CO)10
B. C. Gilbert et al. Synth. Commun. 1999, 29, 2711.

Yamada, Y. et al. Chem. Lett. 1981, 1277.

Mn2(CO)10(0.5 equive)

Ph

Br
51

DCM, hv

Ph

Ph
99%
52

The photolytic cleavage of the weak Mn-Mn bond in dimanganese
decacarbonyl complex [Mn2(CO)10] could lead to bromide abstraction
by {Mn(CO)5} under mild reaction conditions.

CoCl(PPh3)3 is a rather stalble coplex to manipulate and can be easily prepared.
The reaction can be under mild non-basic conditions and can be accomlished invarious organic solvents.
In the case of benzyl bromide the reaction was completed, within 5 minutes,
faster than the reaction of the corresponding chloride under same conditions
to give bibenzyl in a similar yield.

Cobalt-Mediated Dimerization of Chloro Lactone
Jack E. Baldwin et al. JOC. 2004, 69, 9100.
H
O
O
34%
(tBuO)2 dl/ meso = 6/1(0.5 equive)acetone, 140°C,
18h

47

Cl
O

CoCl(PPh3)3(1.2 equive)
benzene57%
O rt, 2h dl/ meso = 98/2

O

O
O

O
O
O

49
50a RR/SS(dl)50b RS/SR(meso)

48
Although 48 was a successful dimerization agent for butenolide 47,
the reaction yield could not be further optimized.
47

50
50

This method was found to work well using a variety of substrates
containing a number of functional groups.
( included alcohols,esters and acids)
Allylic radicals, which could couple in more than one position,
reacted predominantly at the least hindered position.

31.2.2. Movassaghi's Total Synthesis of (+)-Chimonanthine.
ACIE 2007, 46, 3725.

condition(+)-5354

54(+)-23(+)-chimonanthine(+)-55A variety of reduction conditions were explored for the generation of the C3 radical center, including the use of magnesium, lithium,samarium(II) iodide, a wide range of reducing copper complexes, iron(III) chloride.magnesiumsystems, and hexabutyldistannane,along with heat or photochemical activation.
First successful dimerization:[Mn2(CO)10](0.5 equive), DEM, 16h.

18% yield(single diastereomer), >99% ee.

[Mn2(CO)10](1.0 equive)

33% yield(single diastereomer), >99% ee.

``

No further improvement was observed after an extensive survey of the reaction conditions
Given the expected second-order dependence of the dimerization rate on the concentration of the activated monomer.
Cobalt(I) complex CoCl(PPh3)3 as a potential solution because of its ability to perform more rapid halogen abstraction
from benzylic chlorides in benzene.
60% yield(single diastereomer), >99% ee.(3-g scale)[CoCl(PPh3)3](1.2 equive), acetone, 23°C, 15 min

1.2.3. Total Synthesis of (+)-WIN 64821(a nonpeptide neurokinin antagonist).
Movassaghi, M. et al. ACIE. 2008, 47, 1485.
O
Br

O
NH

PhO2S
H N

O
O

N

N

HN

a

N H
O
SO2Ph
(+)-58

H
N
O

N
HN

NH

b

N

O

H

NH
N

O

N H
O
SO2Ph
a) [CoCl(PPh3)3] (1.8 equiv), acetone, 23°C, 30 min, 48%. b) SmI2 (6.0 equiv), NMP, tBuOH, THF, 0°C, 1 h, 75%.

N
H(-)-59H

O(+)-WIN 64821

2. Quadruple C -Methine Hydroxylation
2.1 Methods for C -oxidation.
N-hydroxylation-dehydration strategy
H. C. Ottenheijm, et al. J. Org. Chem. 1980, 45, 1880.

Oxidation of enol tautomers or corresponding enolates
Langlois, Y. et al. Tetrahedron Lett. 1985, 26, 3563.

Nu
HO

O

N

O

O

N
O

60

HN
O

61

OTMS

O

MeO2C

NMe

62

mCPBA

MeO2C

O
OH
NMe

63

64

These strategies including electrophilic amide activation and soft-enolization were failed to provide the necessary C -methineoxidation by formation of partially oxidized and diastereomeric products in addition to substantial competing decomposition.

2.2 Sensitivity and epimerization of tetracyclic and dimeric octacyclic diketopiperazines.
O

H
Br

11

N
N H
SO2Ph O(+)-12

N

Me

H

KOEt
EtOH, 23°C
61%

Me

SO2Ph
O
H N
Me
HO 15' N
O
H
N 11'
Me
Me
N
11
H
15
O
N
OH

67

N H
SO2Ph OBr
11

N

Octacyclic dimer 66 is less prone to enolization at C11 as compared to (+)-13

Me

Oxidation of 66 using the optimal reaction conditions:
The C11 and C11' methines were not hydroxylated,
whereas C15 and C15' methines were both hydroxylated.

N
Me
N H
SO2Ph O
(11R)-diastereomer 65

Py2AgMnO4
CH2Cl2, 23°C
2h
68%

O

SO2Ph
O H
N
Me
H 15' N
O
H
N 11'
Me
Me
N
11
H
O
N 15 HN H
SO2Ph O

Me

66

Me

NaOEt, EtOH
23°C
75%

SO2Ph
O
H N
Me
H 15' N
Cs2CO3, CD3OD
O
H
23°C
N 11'
Me
Me
N
11
H
O
N 15 HMeN H
SO2Ph O(+)-13
23°C

SO2Ph
O
H N
Me
D 15' N
O
D
N 11'
Me
Me
N
11
D
O
N 15 DMeN H
SO2Ph O

66-d 4

Cs2CO3, CD3OD
reflux, 12h4

2.3 Radical-based abstraction of C -methine
The C -methine of amino acids has an approximate bond dissociation energies(BDE) of 82-96 kcal/mol that varies as a function of the
Ruchardt, C. et al. Tetrahedron Lett. 1997, 38, 7721.
Rauk, A. et al. Biochemistry 1999, 38, 9089.
The BDE of all of the amino acid residues, modeled by HC(O)NHCH(R)C(O)NH2 (PH(res)),
were determined at the B3LYP/6-31G*//B3LYP/6-31G* level, coupled with isodesmic reactions.
Weak C -H bonds resulting from stabilization of the ensuing C -radicals in diketopiperazines.

, angles.

An effective strategy: using mild oxidants typically reserved for hydrogen atom abstraction from formyl groups.
Me

H

O

11

N
N H
SO2Ph OMe nBu N+•MnO 4
4
N(3.0 equiv)
15
H
pyridine, 23°C
Me

68

Me

HO

O
N

11

15

N
N H
SO2Ph OnBu4N+•MnO4(3.0 equiv)

Me

OH
Me

(+)-1314' (diastereomeric mixture)(40%)

competing epimerization of C -methines and incomplete oxidation occured.

69 (one diastereomer)(78%)

A mild and selective oxidant

pyridine, 23°C

bis(pyridine)-silver(I) permanganate (Py2AgMnO4)

H. Firouzabadi, et al. Tetrahedron Lett. 1982, 23, 1847.
O
H
Me
H 15' N
N 11'
Me
H
O

SO2Ph
N
H

O
N

11

15

N

Me

H
Me

N H
SO2Ph O

Py2AgMnO4(4.8 equive)
CH2Cl2, 23°C
2h
63%

SO2Ph
O
H N
Me
HO 15' N
O
HO
N 11'
Me
Me
N
11
OH
15
O
N
OH
Me
N H
SO Ph O
2(+)-13(+)-14(single diastereomer)(+)-14O
H
Me
H 15' N
N 11'
Me
H
O

NaOEt, EtOH
23°C

SO2Ph
N
H

Me
HO

O

11

N
N H
SO2Ph O

N
15

Me

H
Me

Py2AgMnO4(4.8 equive)
CH2Cl2, 23°C
2h
68%

Me

O

SO2Ph
N

N

15'

N

H

O

O

H

11'

H

11

N
N H
SO2Ph O

66

N
15

Me

OH
Me

67

Oxidation of 66 using the optimal reaction conditions:
The C11 and C11' methines were not hydroxylated, whereas C15 and C15' methines were both hydroxylated.
(only oxidated at the alanine C (L-Ala)-methines, leaved the C (D-Trp)-methines unchanged.)
This observation, which has important consequences for the choice of natural or unnatural amino acid precursors, is attributed to a nonoptimal
conformation of the C-H bond for abstraction and/or the sterically disfavored approach of the oxidant from the concave face of the 5,5-ring system.

2.4 Mechanism of Permanganate Oxidation: Hydrogen Abstraction and Oxygen Rebound(i) H• Transf er in the Oxidation of Toluene by Permanganate
J. M. Mayer et al. Science 1995, 269, 1849.

water
toluene

In water, the reaction proceeds by hydride (H-)
transfer from toluene to a permanganate oxygen.
The oxidation in neat toluene is more than 1000
times slower than the reaction in water.
Rate-limiting step of the oxidation in neat toluene is
attack of MnO4- to cleave the benzylic C-H bond,as in the aqueous reactions. The nature of this bondcleavage is different in the two solvents.

Fig. 2. Plot of the log of the rate constant k forhydrogen atom abstraction at 303 K versus H° forhydrogen atom transfer [BDE(PhCH2-H) - BDE(ROH)].
[BDE(PhCH2-H) = 88.5 1.5 kcal/mol]

Oxidation in neat toluene most likely occurs by H• transfer from toluene to MnO4-.
MnO4- can make a strong bond to a hydrogen atom,and reactivity correlates with bond strengths and H° for H-atom transfer.
Permanganate abstracts H• at essentially the rates expected foran oxygen radical that would make an 80 kcal/mol O-H bond.
This occurs even though permanganate is not a radical.

5

(ii) Hydrogen Abstraction and Oxygen ReboundK. N. Houk et al. JACS, 2000, 122, 7821

The preferred mechanism is a hydrogen atom abstraction followed by immediate
collapse (oxygen rebound) of the radical pair to alkyl manganate ester.
The manganese(V) product of Mn(OH)(OMe)O2- is 20.7 kcal/mol more stable than
the reactants.
In both permanganate transition states, two oxygens of the permanganate are
involved significantly in the transfer of the hydrogen. The hydrogen is clearlytransferred to one, but a second oxygen is in the vicinity of the forming radical.

(a) CH4/MnO4-

The interaction between the permanganate O and the CH2 group stabilizes thetransition state. The activation energy of the reaction is calculated to be 21.8 kcal/mol.

(b) toluene/MnO4-

Figure 3. UB3LYP/6-311+G** transition state forthe hydrogen abstraction from CH4 and toluene.

3. Stereoselective Tetrathiolation and Disulfide Formation

The dimeric octacyclic tetraol (+)-14 proved
highly acid- and base-sensitive.

(+)-14

Even dissolution of (+)-14 in methanol atambient temperature led to slow decomposition.
70

71

Synthesis of the pentacyclic epidithiodiketopiperazine 73.( tetracyclic model system)

3

3

68

72

The level of diastereoselection favoring the desired and natural stereochemistry is
greatly enhanced in the dimeric system with a larger C3 (and C3') substituent.

73(11S,15S)/(11R,15R) > 2/1
(+)-1

O
Me
(+)-14

Me

H
H N
O

S

S N
N S S

S N
N S

O
75
74(unstable)
diastereomeric mixture
Conditions:(a) 5% Na(Hg), Na2HPO4, MeOH, 23°C. (b) H2S, CH2Cl2, [Hf(OTf)4], -78 23°C, 14 hours.
(c) KI3, pyridine, CH2Cl2, 23°C, 2-15% for three steps.

N H
O
H
(+)-1

Me
Me

Low overall yields may be due in part to competing reduction of the tautomeric -ketoamide 71
or the corresponding derivative from the highly sensitive diaminotetraol 74.

3.1 Selective silylation and Removal of the benzenesulfonyl groups

15'

b.

a.

11'
15
11

(+)-14
DMAP : 46%(+)-15(+)-164-pyrrolidinopyridine : 52%

Conditions: (a)TBSCl(5.0 equive), PPY(5 mole %), Et3N(6.0 equive), DMF, 23°C, 30 min.
(b) 5% Na(Hg), NaH2PO4(40.0 equive), MeOH, 23°C.
A simple tactical conversion of the tetraol (+)-14 to the diol (+)-15 imparted considerable stability to this structure.
(prevent from undesired diketopiperazine ring opening)
Only one t-butyldimethylsilyl group per diketopiperazine substructure is allowed, and the attenuation of the C15 alcohol reactivity is critical.
Fu's (R)-(+)-4-pyrrolidinopyridinyl(pentamethylcyclopentadienyl)-iron (PPY) catalyst (5 mole %) was optimal for theselective derivatization of both alaninederived hemiaminals of (+)-14.
Comparison of the base stability of octacyclic tetraol (+)-14 with octacyclic diol (+)-15.

6

3.2 Woodward-Prevost cis-dihydroxylation
R. B. Woodward, F. V. Brutcher, JACS. 1958, 80, 209.
It is important to note that simple exposure of the penultimate intermediate 5 toair leads to direct and rapid formation of (+)-1, suggesting the cis-dithiodiketopiperazine
stereochemistry of 5 as illustrated.(page 2)
A series of studies for the nucleophilic introduction of the carbon-sulfur bonds at
C11 and C15, all point to a high preference for nucleophilic thiol addition at C11
favoring the (11S)-stereochemistry.

cis-three-atom bridge formation using trithiocarbonate
D. D. MacNicol et al. Tetrahedron Lett. 1975, 16, 1345.

3.3 Intramolecular dithiepanethione formation using potassium trithiocarbonate.
15'
11'
15
11

(+)-16(11R,11'S,15R,15'S)-18a(+)-(11S,11'S,15S,15'S)-18 + (11R,11'R,15R,15'R)-18b
18:18a:18b = 25:7:1(+)-17

Conditions: K2CS3(10.0 equive), TFA, CH2Cl2, 23°C, 28 min.

four carbon-oxygen bonds are exchanged for four carbon-sulfur bonds,
the stereochemistry at all four tertiary thiols is secured
the targeted cis-dithiodiketopiperazine substructure of 5 is attained.
conversion of (+)-16 to (+)-18 enabled tetrathiolation with concomitant inversion of all four C -stereocenters,
allowing rapid epidithiodiketopiperazine formation.

3.4 Diaminotetrathiol formation and triiodide oxidation(+)-18b. KI3a. ethanolamine

pyridine
62%

S
HN

O

20

19

(+)-1

5

Conditions: (a) ethanolamine, acetone, 23°C; (b) KI3, pyridine, CH2Cl2, 23°C.

4. Synthesis of Dimerization Precursor (+)-12
Me

CO2Me

+

NH2•HCl
L-alanine derivativeBr2(4.12 equive)Me

CO2Me EDC•HCl, HOBt
Et3N, CH2Cl2NHBoc
PhO2SN
23°C, 14 h
95 %PhO2SNN-sulfonylated L-tryptophan

H(-)-10
MeCN, 0°C, 5 min

N
N H
SO2Ph O(+)-11, 76%

+
H

O
NHBoc
(-)-9

H
NH
H
Me

O

Br
N
N H +
SO2Ph O(-)-11', 19%

NH
H
Me

Acetone, 23 °C
77 %2. t-BuOH, morpholine
48 h, 23°C
84%

NH
PhO2SN(-)-10

HN

Me
O

O

Br
K2CO3, MeI

CO2Me

HN

O

Br

O
1. TFA
CH2Cl2, 0°C

NN
N H
SO2Ph OMeH
Me(+)-12
Use of excess bromine was necessary for complete conversion of (-)-10
to tetracyclic bromide (+)-11. The amount of bromine used did not affectthe level of diastereoselection.
Lower reaction temperatures (-40°C) resulted in a slightly higher level ofdiastereoselection (5:1) albeit with less efficient conversion.
The use of several other less electrophilic halogenating agents was less effective.

75. Over View Movassaghi, M. et al. Science 2009, 324, 238.

Concise enantioselective total synthesis of (+)-11,11'-dideoxyverticillin A (1). Isolated yields are given for each step. Reaction conditions
are as follows: (a) trifluoroacetic acid (TFA), dichloromethane (CH2Cl2), 23°C, 4 hours; tert-butanol (tBuOH), morpholine, 23°C, 48 hours.
(b) Br2, acetonitrile (MeCN), 0°C, 5 min. (c) methyl iodide (MeI), K2CO3, acetone, 23°C, 5 days. (d) tris(triphenylphosphine)cobalt(I) chloride[CoCl(PPh3)3], acetone, 23°C, 30 min. (e) bis(pyridine)silver(I) permanganate (Py2AgMnO4), CH2Cl2, 23°C, 2 hours. (f) tert-butyl(chloro)-dimethylsilane(TBSCl), PPY 5 mole %, triethylamine (Et3N), N,N-dimethyl formamide (DMF), 23°C, 30 min. (g) 5% Na(Hg), NaH2PO4,
methanol (MeOH),23°C. (h)K2CS3, TFA, CH2Cl2, 23°C, 28 min. (i) ethanolamine, acetone, 23°C; KI3, pyridine, CH2Cl2, 23°C. The thermal
ellipsoid representation of synthetic (+)-1 from x-ray crystallographic analysis is shown with most hydrogens omitted for clarity.

Cobalt(I)-Promoted Reductive Dimerization
Highly stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions
A mild strategy for the introduction of the epidithiodiketopiperazine core in the final step

6. Sodeoka's RouteMovassaghi's strategy
natural amino acidMe+NH2•HCl
L-alanine derivative

NHBoc

PhO2SNOOCO2Me 80%

CO2Me

NH 59%

PhO2SNtetrathiolation(with inversion)and S-S bond formation-Hydroxylation of monomer

Dimerization

HN

N-sulfonylated L-tryptophan

Br

NMe 46%
N
N H O
SO2Ph

Me
O

(-)-10SO Ph
O H N 2
N

Me
Me

Me

N

H
O

(+)-12

O

H

N
N
N H O
SO2Ph

(+)-13

Me
TBSO
30%
N
Me
Me

O H H
N
N
HO
O

Me

OH

(+)-16

O

35%
N

Me

(+)-1

N
OTBS
N H O MeH

Sodeoka's strategy-Hydroxylation of monomer

unnatural amino acid
OH
CO2H
N

+

Cbz
Me
D-serine derivative

76

O

CO2Me
NH2•HClHN
D-Try-OMe•HCl

77

NMe

69%
N
Boc

HN
O

(+)-78

88%

OTBS

Br

H

Dimerization

O

Br
NMe

N
N H OH
Boc(+)-79

47%

OTMS

HO

O

tetrathiolation and
S-S bond formation
TMSO HO

Boc
O H N
N

NMe
N
55% MeNOHO
N H O OH OTMS
Boc(+)-81HOO

Me 44%NN
N H O OH OTMS(+)-82 Boc

(+)-2

8

Comparison of bromocyclization reaction

2
3

A

C

(+)-79(-)-10B(-)-79'DThe difference in stereoselectivity depends upon whether or not an N-methyl group is present.
The diketopiperazine ring being co-planar, the N-Me group is considered to be on the same plane.
TBS-oxymethyl group is located at the pseudo-axial position.
(In order to avoid steric interaction with the N-Me group)

Comparison of final-stage
Movassaghi
SO2Ph
O
H N
Me
HO 15' N
O
N 11'
HO
Me
Me
OH
N
15
O
11
OH
N
N H O Me
SO2Ph

2-15%

74

(+)-14

Me
TBSO
N
Me

75

unstable

unstable

(+)-1

KI3

SO Ph
O H N 2N
Na(Hg)
O
HO
Me
OH
N
O
N
OTBS
N H O Me
SO2Ph(+)-15

Me
TBSO
N
Me

O

H
H N
N
HO

O

OH

O
N

Me

Me
HS
N
Me

O

H
H N
N
HS

O

N

Me

N
SH
Me
N H
O
H

N
OTBS
Me
N H
O
H

(+)-16OSH

5Sodeoka
TMSO HO

O

H

Boc
N

N
Me

N

HO

O

OH

O

N

I2

Me

44%

N
N H
Boc

O

(+)-82 (unstable ?)(+)-2

OH OTMS

83

84

iminium ion intermediate
CoCl(PPh3)3
55%

The diol (+)-81 was relatively unstable in CDCl3.
HO

O

Br

N

Me

N
N H
Boc

O

OH OTMS(+)-81 (unstable)

However,the hemiaminal was not sensitive to a reductive coupling reaction using a Co(I) complex.
The unprotected diol (+)-81 could be directly used to furnish the desired octacyclic
tetraol (+)-82 as a single isomer in 55% yield
The stereochemistry at the -position would be cancelled by formation of the iminium ion.
Hydrogen sulfide mainly attacked from the outer surface of the double-decker core structure,
affording the tetrathiol precursor stereoselectively.

9

Sodeoka, M. et al. JACS 2010, 132, 4078.

76

77

N-Cbz-N-Me-serine(+)-78(+)-7980(+)-81(+)-822

a Conditions: (a) NBS, MeCN, -30°C, 10 h; (b) NBS, V70, CCl , rt, 5 h;
4then pH7 phosphate buffer/MeCN ) 1/1, rt, 3 h; (c) CoCl(PPh3)3, acetone, rt, 1.5 h;(d) H2S, BF3.Et2O, CH2Cl2, -78°C to rt, sealed tube, 1.5 h; then I2.

In the final step, no less than ten bond-forming and cleaving events.
four substitution reactions (OH SH)
deprotection of four Lewis acid-sensitive protecting groups (TBS and Boc groups)
two S-S bond formations
The first total synthesis of (+)-chaetocin has been accomplished in only nine steps starting from the known N-Cbz-N-Me-serine.

10