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Diastereo- and Enantioselective Synthesis of 1 2-Amino Alcohols from Glycol Aldehyde Hydrazones; Asymmetric Synthesis of (R R)-Statin.

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should be those of single bonds, in this case close to 1.4 A.1'1 The
observed C - N distances from the aromatic ring to N 1
(1.356 A) and N 4 (1.374 A) are noticeably shorter, consistent
with a semiquinone-like ligand and an Fe"' formulation. Moreover, two of the C-C bonds in the aromatic ring (C 1 7 4 18,
C 1%C 20) are significantly shorter than the other four. Finally,
the methyl groups of the methoxy substituents lie in the plane of
the aromatic diamide unit, suggesting that oxygen K-donor interactions are important, as would be expected for an oxidized
aromatic ring. A Hiickel treatment (assuming C, symmetry)
suggests that the pattern of bond length changes results from
removing an electron from an A' molecular orbital of the ligand.
These high-field Mossbauer studies of 1 and 2 and the crystal
structure of l a delineate the electronic structure of 1. The values
of AEQ. 6, and perffor 1, taken alone, could easily mislead one
to suggest an Fe'" complex with S = 1. The oxidation of 2 to give
1 is fundamentally different from that reported for [Fe"'Cl(~c~MAC*)]'-, a tetraamide complex lacking the aromatic ring in
the macrocycle.r21As noted, oxidation of the latter is metal-centered and produces a high-spin Fe'" complex. With two axial
tert-butylisocyanides, the ( K ~ - M A C * ) ~ligand
stabilizes a
complex with an S = I state and an Fe'" ion (aFe=
- 0.04 m r n ~ C ' ) . [ ~
Thus,
]
the spin state depends on the axial
ligation, and the location of the oxidation can be locked at the
metal by ligdnd design or freed to range over ligand fragments
with delocalized electrons that remain in intimate contact with
the metal. We are particularly interested in understanding how
these details of electronic structure can be exploited in reactivity
and are currently exploring deprotonation procedures for 1 to
obtain stable oxidized hydroxo- and oxoiron complexes.
Experimental Procedure
2: [Et,N],[Feii'CI(~'-L)] (L = tetramido ligand in 1 and 2) (500 mg, 0.6 mmol),
prepared by standard techniques [16], was dissolved in deionized H,O (40 mL) and
the mixture was filtered. A solution of [PPh,]CI in H,O (1.2 g. 3.2 mmol, 10 mL)
was added and the solution was stirred (24 h). The burgundy precipitate was collected and washed with deionized water (2 x 10 mL). Yield: 255 mg(50%). IR (NuJo~):
1610 (v(C0)amide). 1562 (v(CO)amide), 1546 cm-' (v(C0)amide). Separate analyses on three different samples gave satisfactory. reproducible data for
C,,H,,N,FeO,P;H,O.
Anal. cakd: C 63.44, H 6.12, N 6.30; found: C 63.28, H
6.00, N 6.25. ESI-MS: [Ph,P]2 in CH,CN: m/r 514 [2 - H,O] (base peak), 573
(2 + CH,CN].
1 : [Et,N],[Feii'Cl(h.4-L)] (600 mg, 0.7 mmol) was dissolved in deionized water
(20 mL). A solution of AgBF, (720 mg, 3.7 mmol) in H,O ( 5 mL) was added and the
mixture was stirred ( 3 h). The solid was collected and extracted into CH,CN
(20mL). The mixture was filtered (celite), water was added (10mL). and the
CH,CN was removed under reduced pressure. The resulting purple crystalline solid
was collected (160mg. 0.3 mmol, 4 3 % yield). 1 was chromatographed (silica gel,
Davison Chemical, CH,CI,, lOcm x 1.5 cm column. 7.5% MeOH in CH,CI,.
200 mL) and the solvent removed under reduced pressure. The resulting purple solid
was recrystallized from CH,CN/H,O giving lb. IR (Nujol): 3667 (sharp), 3332
(br.), 3175 (br.) i'(OH)H,O, 1680,1599,1578. 1542 c m - ' v(C0)amide. Anal. calcd
for C,,H,,N,FeO;H,O:
C 50.19, H 6.23. N 10.18; found: C 50.33, H 6.20. N
10.18.
l a . 0.4(C2H,),O: Crystals of Ib.O.4(C,H5),O were recrystallized from teri-butyl
alcohol/ether. IR (Nujol): 3525 (sharp), 3365 (br.) v(OH)H,O, 1688, 1673. 1599.
v(C0)amide. Crystal structure: tetragonal, space group
1582. 1580. 1540 a n
f4,ja. u=35.697(8). c=10.052(3)A. v=3775(3)A3. T = - l o o " c , z = 1 6 ,
pLd,Ld
= 1 . 1 7 g c m ~ 3 , p , , , = l . 2 0 ( l ) g c m ~ 3 . p= 5,32cm-';6144uniquereflections
( 2 2 2 0 t 5 6 ) collected using c0/2H scans with graphite-monochromated Mo,, radiation (I. = 0.71069 A). Hydrogen atoms were located in a difference map. Methyl
hydrogen atoms were refined as rigid rotors; all other hydrogen atoms, including
those on the coordinated water. were refined individually. The crystal studied contained a poorly resolved diethyl ether molecule of solvation which had a purely
space-filling role. Its occupancy refined to 0.40. Refinement converged with R ,
(based on F ) = 0.058 for 4434 observed reflections [ f 3u(f)]. Further details ofthe
crystal structure investigation may be obtained from the Director of the Cambridge
Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB2 IEZ (UK), on
quoting the full journal citation.
Received: January 9, 1995 [Z7612IE]
German version: Angeu. Chem. 1995, 107. 1345-1348
Angrw. Chem. lni. Ed. Engl. 1995, 34. No. 11
c;
Keywords: complexes with oxygen ligands . electronic structure . iron compounds . macrocycles . oxidations
(11 T. J. Collins, Acc. Chem. Res. 1994, 27, 279. and references therein.
[2] K. L. Kostka, B. G . Fox, M. P. Hendrich, T. J. Collins, C . E. F. Rickard. L. J.
Wright, E. Munck, J. Am. Chem. Soc. 1993. 115, 6746.
[ 3 ] T. J. Collins, B. G. Fox. 2. G. Hu, K. L. Kostka, E. Munck, C. E. F, Rickard.
L. J. Wright, J. Am. Chem. Soc. 1992, 114. 8724.
[4] C. E. Schulz, H. Song, Y J. Lee, J. U. Mondal. K. Mohanrao, C . A. Reed, F. A.
Walker, W. R. Scheidt, J. Am. Chem. Soc. 1994. 116. 7196. and references
therein.
(51 E. Vogel, S. Will. A. Schulze-Tilling, L. Neumann. J. Lex, E. Bill, A. X .
Trautwein, K. Wieghardt, Angeu. Chem. 1994,106,771; Angcn. Chem. fnt. Ed.
Eng/. 1994, 33, 731, and references therein.
[6] J. D. Dunitz, F. K. Winkler, J. M o l . Biol. 1971, 59, 169.
[7] J. D. Dunitz, F. K. Winkler, Actu CrystuNogr. Scci. B 1975, 31, 251.
[8] T. J. Collins, R. J. Coots, T. T. Furutani. J. T. Keech, G . T. Peake. B. D. Santarsiero. J. Ant. Chem. Soc. 1986, 108, 5333.
191 W R. Scheidt. I. A. Cohen. M. E. Kastner, Biochemisyy 1979, 18. 3546.
[lo] E. Herdtweck, Z. Anorg. Allg. Chem. 1983, 5OI, 131.
[ l l ] P. Garge, R. Chikate, P. Subhash, J.-M. Savariault, P. de Loth, J.-P. Tuchagues, Inorg. Chem. 1990,29. 3315.
[12] Since the axial water ligand is hydrogen-bonded to neighboring ions in la, it is
not surprising that AEQ of the solution sample differs slightly from that of l a .
[13] Mossbauer studies of polycrystalline l b have also revealed dimer interactions.
However. these interactions are much weaker ( j % 3 cm ') than those of l a .
Calculations show that f o r j 2 3 cm-' and D f IOcm-'. pciris independent
ofD a n d j f o r T 2 50K. For this reason, we have chosen Ib rather than l a for
the magnetization studies.
[14] A. Bencini, D. Gatteschi. Electron Parumugnerk Resononce of E-whunge Coupled Systems, Springer, Berlin, 1990, see Table 3.3.
[15] While exchange coupling seems plausible, more information is needed to decide
on the most appropriate description of the electronic structure. Magnetization
studies above 2OOK will be sensitive to the population of the putative S = 2
manifold for J < 300 cm-'. While our preliminary data indicate the presence
of such a state, our samples d o not yet have the desired purity for presenting
a convincing case.
[16] T. J. Collins, R. D. Powell, C. Slebodnick. E. S. Uffelman. J. Am. Chem. Soc.
1991. 113, 8419.
~
Diastereo- and Enantioselective Synthesis
of 1,ZAmino Alcohols from Glycol Aldehyde
Hydrazones; Asymmetric Synthesis
of (R,R)-Statin" *
Dieter Enders* and Ulrich Reinhold
Dedicated to Professor Franz Dallacker
on the occasion of his 70th birthday
The I,2-amino alcohol unit A is found in many important
natural products and drugs."] In this context diastereo- and
enantiomerically pure amino alcohols are becoming increasingly important in the development of enzyme inhibitors. ?-AminoB-hydroxycarboxylic acids of type B such as statin (R = iBu),
3-amino-2-hydroxy-5-phenylpentanoic acid AHPPA (R =
CH,Ph = Bn), and cyclohexylstatin (R = CH,C,H,,) are important examples of peptide mimetics.[21Statin and AHPPA are
essential components of pepstatinr3] and a ~ h a t i n i n , respec~~]
[*I Prof. Dr. D. Enders, DipLChem. U . Reinhold
Institut fur Organische Chemie der Technischen Hochschule
Professor-Pirlet-Strasse 1, D-52074 Aachen (Germany)
Telefax: Int. code (241)8888127
[**I This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 380 and Leibniz Prize) and by the Fonds der Chemischen
Industrie. We thank the companies Degussa AG, BASF AG, Bayer AG.
Hoechst AG, and Wacker Chemie for the donation of chemicals.
VCH Yerlugsgesel/schuft mbH. 0-69451 Weinheim, I995
+
0S70-0833/95/IlII-I219 3 10.00+ .2.(:U
1219
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tively, both natural peptidic inhibitors of acidic proteases such
as renin and HIV-I-protease.
Despite the previously known syntheses of optically active
amino alcohols, in most cases from naturally occurring amino
acids, there is still demand for new, efficient, flexible, and highly
stereoselective methods; asymmetric synthesis, in particular,
has become increasingly important recently.", ',
Our retrosynthetic analysis of the amino alcohol A leads to
the 1,2-amino alcohol synthon C, which has a' reactivity with
regard to the amino group and d' reactivity with regard to the
hydroxyl function and to the corresponding nucleophile (Nu)
und electrophile (El). An enantiomerically pure protected glycol
aldehyde hydrazone D (P = protecting group) can serve as a
92-98%
I 2) Na I NH,
NHZ
OH
A
O
0
d
OCH3
H
F
-100% + 0°C
2) 3 equiv AcCI,
-70°C + 0°C
Ac,
P
p
Po
A<
r?'
64 - 70%
m
R
A
THF or Et90
A
NH2
H
-33°C
1) 2 equiv RLi
N/A<
R'jAR2
t
1) 3b,c: nBu,NF
THF FIT
(92-'gg%)
6)
-2
OCH,
R
( S B )-3
OH
89 to 298%de
0
Scheme 1. Enantioselective synthesis of N-acetyl-l,2-amino alcohols (R)-4.RT =
room temperature.
R = iBu, Bn, CHPCBHll
Table 1. N-Acetyl-protected 1.2-amino alcohols 4 prepared by 1Jaddition to hydrazones 2.
~
3,4
C
a [dl
D
b
c
synthetic equivalent of C. In principle, aldehydes can be both
electrophilically alkylated in the a-position and transformed into optically active amines by nucleophilic 1,2-addition to the
C=N bond with high diastereo- and enantioselectivities by the
SAMPIRAMP hydazone method.[71
We now wish to report a C-C bond forming, flexible, syndiastereo- and enantioselective synthesis of N-acetyl-protected
amino alcohols A (R' = allyl, H ; R2 = alkyl, allyl, benzyl).
Ozonolysis of a previously introduced alkenyl group and removal of the protecting groups opens up a new diastereo- and
enantioselective approach to (R,R)-statin.
Starting from cheap and readily accessible benzyl- (Bn) or
ter-t-butyldiphenylsilyl- (TBDPS) protected glycol aldehyde 1,
reaction with the chiral auxiliary (S)-l-amino-2-methoxymethylpyrrolidine (SAMP)[7d-'1 yields the corresponding
SAMP hydrazones (S)-2(Scheme 1). These are treated with two
equivalents of an organokthium reagent at low temperature,
and the lithium hydrazide formed was trapped with three equivalents of acetyl chloride.[*' After aqueous workup and purification by chromatography the N-acetyl-protected hydrazides
(S,R)-3 are obtained in good yields (64-70%) and with high to
very high diastereomeric excesses (89- 2 9 8 % de; Table
The silyl-protected acetyl hydrazides 3b and 3c are desilylated
with tetra-n-butylammonium fluoride prior to cleavage of the
N-N bond.[91Reductive N,N bond cleavage with concomitant
removal of the benzyl protecting group of (S,R)-3a is carried out
with sodium in ammonia.[7h.'I N-Acetyl-protected amino alcohols (R)-4 are obtained without racemization after column chromatography in good yields (92-98 YO)and with high enantioselectivities (89 to > 99 YOee; Table 1 ) .Izo1
Enantiomeric excesses were determined by gas chromatography (GC) with chiral stationary phases (CSP) and by 'HNMR
shift experiments." '1 The chiral amine auxiliary (S)-2-methoxymethylpyrrolidine (SMP) can be recovered.[' In a repre1220
$> VCH Verlugsgesells~hafrmhH, 0-69451 Weinheim,1995
P
R
3
Yield [a] dc [b]
[Oh]
[Yo]
CH,Ph Me 66 (51)
TBDPS nBu 64
TBDPS Ally1 70
96 ( > 9 9 )
89
2 98
Yield
["A]
er
[c]
[Yo]
4
[x]ET
( 1 , CHCI,)
Config
96 (97) 95 (>99) +21.7 [el (3.24) (R)[f]
98
89
+27.9 (0.85)
(R)[fl
92
>99
-15.0 (0.67)
(R)
[a] THF was used as solvent for 2a,b, diethyl ether for 2c. [b] de Values were determined by
gas chromatography for 3a (SE-30. FID), and by 'TNMR spectroscopy for 3b,c. [c] Based
on GC analysis with a chiral stationary phase and NMR shift experiments [I 11. [d] Values in
parentheses for yields after separation of the diastereomers of 3a ( S O 2 , diethyl ether/
petroleum ether 1 : 1). [el Optical rotation of the enantiomerically pure compound 4a.
[f] Determined by comparison of the optical rotation with the literature data [13].
sentative example, (S,R)-3a was obtained diastereomerically
pure (>99 YOde) by column chromatography and converted to
the enantiomerically pure protected 1,2-amino alcohols (R)-4a
( 1 9 9 % ee). The absolute configurations of 4a and 4b were
determined by comparing their optical rotations to literature
data.[''] The total yield (1 -+ (R)-4) over three or four steps is
54-63%.
Scheme 2 shows the successive introduction of two vicinal
stereogenic centers starting from benzyl-protected glycol aldehyde l a by a-alkylation and 1,2-addition to afford the amino
alcohols (R,R)-7.The known r-alkylation of l a provides (R,S)5 in very good yield (81 %, two steps) and with high asymmetric
inductions (86-88% de) with (S)-l-amino-2-(l-methyl-lmethoxyethy1)pyrrolidine (SADP)['41as chiral auxiliary.[7e1
The
SADP hydrazone (S,R)-5 is subsequently treated with five
equivalents of Crignard reagent in toluene" and then acetyl
chloride to give the syn-configurated N-acetyl hydrazides
(S,R,R)-6in 78-87 YOyield (Table 2)'". The diastereoselectivities achieved with regard to the newly generated stereogenic
center are greater than 98%. In addition to the directing effect
of the chiral hydrazone function, this very high induction can be
explained by the influence of the r-stereogenic center, which
should favor the same configuration according to the chelation
Hydrazide 6b (R = Bn) is obtained with 2 9 8 % de
after simple purification by column chromatography. After NN bond cleavage and simultaneous removal of the benzyl protecting group with Na/NH, , the functionalized N-protected
+
$ 10.00 .2510
0570-0~833/95/1111-12~0
Angru'. Chrm. Int. Ed. Engl. 1995, 34, No. I 1
-
0
03,NaOH/ MeOHi
CH2CI,, -78°C
BnO
(R,R)-7a
OH
46 - 56%
-1
n,
H
CH3
H C
3
C
O
d
C
H
( R R ) -7
la
2 96
to
.
.
z 98% de,
2 98% de
1) 6 N aq. HCI, lOO"C, l h
2) Dowex AG50 WX8
81%
Ho@CH,
0
2) 7 5 equiv AcCl
3
RT
+
I
95%
t
NH2 CH3
1) 5 equiv RMgBr
toluene, 4 0 % i RT
THF, -30°C
95% ee
H
z
C
:
78 - 87%
OH
k
R
Scheme 3. Diastereo- and enanlioselectire synthesis of (R,R)-statin (9)
B"0
(S,R,R) - 6
z 84
to 2 96% de
Scheme 2. sw-Diastereo- and eiiantioselective synthesis of 1,2-amino alcohols
(R.R)-7
amino alcohols (R,R)-7 are obtained with high optical purity
( 2 96 Yn d r ; 2 94 Yn ee; Table 2) after separation of the
diastereomers by flash column chromatography.
Table 2. N-Acetyl-protected 132-aminoalcohols 7 prepared by nucleophilic 1.2-addition
to 5 .
6.7
a
b
c
R
iBu
CH,Ph
CH,C,H,,
6
Yield dr. ['I]
["/.I
["h]
X6
78
87
2x4
296[f]
284
Yield [b] r k [a]
["'o]
[%I
81
73
75
7
ec [c]
[%I
298 [el 2 9 6
296
294
96
2 9 8 [el
(c.
CHCI,)
Config
[d]
+50.3 (0.78) ( R , R )
+37.5 (1.85) ( R , R )
+52.3 (0.65) (R,R)
[a] Determined b> I3C N M R spectroscopy. [b] Contained 3-11 %I impurites (NMR. GC)
after purification by coluiiin chromatography due to reduction of the allyic residue and
Birch reduction ofthe aromatic ring. [c] Determined by ' H NMR spectroscopy after esteracid (MTPA) 1161. [d]
itication with (S)-or (X)-~-iiielhoxy-r-trifluoromethylplienylacetic
Determined by comparison of the optical rotation of 9 with lilerature data [lo] and on the
basis of earlier 1-alkylations and 3.2-additions with SAMP or SADP hydrazones [7e, f].
[c] After flash column chromatography (SiO?. diethyl ether). [f] After purification by
column chromatography ( S O , . diethyl ether. petroleum ether 1 : 3 ) .
The 1,2-amino alcohols (R,R)-7, accessible in four steps with
yields of 46-56%, are precursors of (R,R)-statin (R = iBu),
AHPPA (R = Bn), and cyclohexylstatin (R = CH,C,H,
The
N-acetyl amino alcohol (R,R)-7a can be transformed to the
methyl ester (R,R)-8 by oxidative cleavage of the C=C bond
with ozone in basic methanol/dichloromethane in good yield
(71 YO)without ra~emization.['~]
The acid hydrolysis of the
methyl ester and the acetamide function proceeds at 100 "C in
6 N aqueous hydrochloric acid within one hour quantitatively,
yielding statin hydrochloride (R,R)-9,HCI.After ion exchange
chromatography free (R,R)-statin (9) is obtained in a total yield
of 38% over six steps[181(Scheme 3).
Compounds 6- 9 are assigned the ( R , R ) configuration by
comparison of the optical rotation of the synthesized statin with
literature data,'"' given the (X) configuration in the a-alkylat i ~ n [ ' ~and
] assuming a uniform reaction course. The natural
sjii-(S,S)-statin is analogously accessible by the use of the
auxiliary (R)-I-amino-2-( 1-methoxy-I -methylethyl)pyrrolidine
(RADP)""] instead of SADP.
The method described here opens up a new syn-diastereo- and
enantioselective route to N-acetyl-protected functionalized vici-
nal amino alcohols. The particular advantage is the high flexibility through variation of the nucleophilic and the electrophilic
component. As was shown for statin and its analogues, this
procedure should facilitate the asymmetric synthesis of a multitude of optically active 1,2-amino alcohols in the scope of natural product and drug synthesis.
E.xperimenta1 Procedure
( S , R ) - 3 :To a solution of 10 inmol of hydraLone (S)-2 in 40 mL of T H F (Et,O for
R = a11y1) was added dropwise 20 mmol of the organolithium solution at - 100 C
( f o r R = Me. -7O'C)withstirring. Thesolutionw~isallowedtowarm toO'Cover
12 h. Thc solution was then cooled to - 70 C, 30 mind of AcCl was added. and the
mixture w a s stirred for 1 h at this temperature and for a further 0.5-2 h at 0 ' C . It
is advisable to monitor the reaction by thin-layer chroinatography to avoid reduced
yields. For hydrolysis 80 m L of saturated NaHCO, solution was added and the
reaction mixture extracted three times with ether. The combined extracts were dried
over MgSO, and the ether was removed in vacuo. After purification of the yellowbrown crude products by llash column chromatography (SO,, diethyl ether1
petroleum ether 1: 1 to 1.2). colorless or pale yellow liquids were obtained.
( S . R , R ) - 6 :To a solution of 10 minol of hydrazone (S,R)-5 in 500 mL of toluene
under argon was added dropwise at -40 C with stirring SO minol of RMgBr ( 2 ~
in diethyl ether). This solution was then allowed to warm to room temperature over
12 h. T H F (100mL) was added. the solution was cooled to -30'C. and then
75 mmol of AcCl was added dropwise. The Folution was warmed to room temperature over 2 h and then stirred for a further 2 h (tlc control). Finally workup was
carried out as above to afford. after column chromatography (SiO,. diethyl ether,'
petroleum ether 1 : 3 to 1 :4), colorless to pale yellow liquids. 6 b precipitated as a
colorless crystalline solid.
( R ) - 4 and ( R , R ) - 7 :To 25 m L of liquid ammonia at -70'C was added dropwise a
solution of 1 inmol of acetyl hydradde 3a and 6 (3b and 3c were previously desilylated with 1.5 equiv n-Bu,NF in T H F at room temperature) in 6 mL of THF, and
then 10mmol of Na was added. The solution was warmed to reflux (- 33 'C).
Upon complete consumption of starting material (tlc control) 1.5 g of NH,CI was
added. The ammonia was evaporated, and the solid residue was extracted three
times with 30 mL ofdichloroinethane. The combined extracts were filtered. and the
solvent was removed in vacuo. Purification by flash column chromatography ( S O , ,
diethyl ether or diethyl ether/MeOH 6: 1 to 15.1) afforded either a colorless liquid
or solid.
Received: February 4. 1995 [Z7695 IE]
German version: Angeii.. Chem. 1995, 107. 1332 ~ 1 3 3 4
Keywords: amino alcohols . asymmetric syntheses . hydrazones .
nucleophilic additions . statins
[l] Reviews on the synthesis and applications of 1.2-amino alcohols: a) R. Henning. Atuchr. Chem 7 i k h L.rrh. 1990. 38. 460 464: bj M. T. Reetz. Angew.
Chem. 1991. 103, 1559-1573; Angew. Choii. Int. €d. Liigl. 1991, 30. 15311545; c) Y. Ohfune, Arc. Chen7. Re.\. 1992. 25. 360-366: d) T. Yokomatsu, Y.
Yuasa, S. Shibuya, Ilc,~crotyc/es1992, 33, 1051 -1078: e) A. Golebiowski. J.
Jurcmk. Synlert 1993. 241 -245; f ) T. Kunieda, T. Ishi7uka in Sinrlic.r k
Narurrrl Prorhici.r Chenns/ry, fid. 12 (Ed.: Atta-ur-Rahman). Elsevier. New
York. 1993. p. 411.
[2] Review: a) D. H Rich in Conzprrhiwsivi, Mrdicinul Chmzi.vtrj, Bd. 2 (Ed.: C .
Hansch, P. G . Sainmcs, J. B. Taylor), Pergamon, New York. 1990. p 3Y1: hj J.
Gante, A17,qriv. C'hem. 1994. 106, 1780-1802; A n p w . Chzn7. In[. ti/.€rig/.
1994. 33, 1699-1720.
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[3] a) H. Umezawa. T. Aoyagi, H. Morishima. M. Matsuzaki, M. Hamada, T.
Takeuchi, J. Anrihrutics 1970, 23. 259-265; h) H. Morishima. T, Takita. T.
Aoyagi, T. Takeuchi. H. Umezawa, ihid. 1970, 23, 263-265.
[4] a) D. H. Rich, E. T. Sun, J. M i d . Cizem. 1980, 2.3, 27- 33: b) S. Omura. N .
Imamura, K. Kawakita. Y. Mori, Y. Ydinaraki, R . Masuma. Y Takahachi, H.
7anaka. L.-Y. Huang, H. B. Woodruff. J. Anribiot. 1986. 3Y. 1079--1085.
[5] Asymmetric syntheses: a) D. Enders, U. Jegelka, B. Ducker, Angrn. Chrm.
1993, 105. 423 425; Angew. Chem. b i f . Ed. Engl. 1993, 32, 423-425: h) S.
Kanemasa, T. Mori. A. Tatwkawa, Tc.frahedron L e f t . 1993. 34, 8293-8296;
c) A. G. M. Barrett. M. A. Seefeld, letruhedron 1993, 49, 7857-7870; d) K.
Hattori, H. Yamamoto. ihid 1994, 50. 2785 -2792: e) M. E. Brunnage. A. J.
Burke. S. G. Davies. C. J. Goodwin, Trfruheclron: Aswznzetrj 1994, 5, 203206; f ) A. M. Kanarawa. J.-N. Denis, A. E. Greene, J. Org. Chrm 1994, 59,
1238-1240; asymmetric syntheses of primary 1.2-amino alcohols: g) Y.Ukaji,
K. Kume. T. Walai, T. Fujisawa. C%em.L e f t . 1991, 173-176; h) J. Schwerdtfeger. D. Hoppe, Angel?. Cliem. 1992, 104, 1547 1549; Angew. Chem. Int. En‘.
Engl. 1992. 31, 1505-1508: i) S. Matsubara. H. Ukita, T.Kodama, K. Utimoto. Clzem. Let(. 1994, 831 -834: j) 0. Lingibe, B. Graffe, M.-C. Sacquet, G.
Lhommet, Hetrroc;vcks 1994, 37, 1469- 1472.
[6] Review on statin synthesis: a) J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn,
11.-U. Reissig, Orgunic Swthesi.r Highlighrs, VCH, Weinheim,, 1991, p. 365;
h) ref. [Id]; recent statin syntheses: c) A.Bernardi, F. Micheli, D. Potcnza. C .
Scolastico, R. Villa, Tetruhcdron LPtf. 1990. 31. 4949-4952; d) D. Misti, G.
Zappa, ihirl. 1990. 31, 7359- 7362; e) T. Ohta, S. Shiokawa, R. Sakamoto, S.
Nozoe, ihid 1990, 31, 7329 -7332; f) K. Shinozaki. K. Miruno. H. Oda. Y.
Masaki, Cheni. Leu. 1992, 2365-2268; g) Y Lu. C. Miet, N. Kunesch. J. E.
Poisson, l&whec/ro.on.- A.,jmmelry 1993, 4, 893-902; h) J. W. B. Cooke, S. G.
Davis, A. Naylor. Terrahedron 1993. 49. 7955-7966; I) U. Schmidt, B. Riedl.
G. Haas, H. Griesser, A. Vetter, S. Weinbrenner, Sjnthe3i.r 1993.216-220, and
references therein; j) K. Otsuka, T. Ishiruka. K. Kimura, T. Kunieda, Chenz.
Phurni. Bull. 1994,42.748-750; asymmetric syntheses of statin: I) T. Ishiruka,
S. Ishihuchi, T. Kunieda, Tetruhechn 1993, 49, 1841 -1852 and references
therein; m) L. Bertelli, R. Fiaschi, E. Napolitano, Go,-;. Chrm. Ired. 1993, 123,
521-524; n) K:J. Hwang, C:M. YII. N.-K. Choi, K.-H. Park, Bzdl. Kurrun
Chem. Soc. 1994, 15, 525 526.
[7] Reviews oil the SAMP!RAMP method: a) D. Enders in Asymmetric Svnrhesis,
Vol. 3 B (Ed.: J. D. Morrison), Academic Press. Orlando, 1984. p. 275: b) D.
Enders, P. Fey. H. Kipphardt. Org. Sjnth. 1987.65, 173-202; c) D. Enders, M.
Klatt in Encjclopeilia uf Reagents f o r Orgunic Sjnr/iesi.s (Hrsg.: L. A. Paquette), Wiley, New Yoi-k, 1995, in press; examples of n-alkylation: d) D.
Enders, J. Tiebes, N. de Kimpe, M. Keppens, C. Steens, G. Smagghe, 0. Betr.
J. Org. Cheni. 1993. 58, 4881 4884; e) D. Enders. U. Reinhold, Swzlett 1994,
792-795: for 1.2-additions to hydrazones see: f) D. Enders. J. Schankat. M.
Klatt, ihid. 1994. 795-797 and references therein; for 1,2-additions to r-hydroxyaldehyde hydrazones see: g) D. A. Claremon, P. K. Lumma, B. T.
Philips, J. Am. Cliem. Soc. 1986, 108, 8265 ~ 8 2 6 6h)
; C. Nuhling, Dissertation.
Technische Hochschule, Aachen, 1987; i) W. R. Baker, S. L. Condon. J Org.
Chern. 1993. 58. 3277-3284.
[XI Allyllithium was prepared by transmetalation of allyl-tri-n-butylstannanewith
n-butyllithium in diethyl ethcr and used without further purification.
[9] S. Hanessian, P. Lavallee, Can. J Chen?. 1975, 53. 2975 -2977.
[lo] S. E. Denmark, 0. Nicaise, J. P. Edwards, .I: Org. Chrm. 1990,55, 6219-6223.
[l I ] Chiral stationary phases: heptakis(2,3,6-tri-O-niethyl)-~-cyclodextrin~polysiloxane (25 m, 0.25 mm internal diameter (ID)) for 4 a : heptakis(2,6-di-Omethyl)-/kyclodextrin/polysiloxane ( 2 5 m, 0.25 mm ID) for 4 b. (-)-(R)-l(9-Aiithryl)-2,2,2-trifluoroethanol
was used as c h i d cosolvent in the N M R
experiments.
[I21 D. Enders. R. Funk. M . Klatt, G. Raahe, Af7gW Chem. 1993, 105, 418-420;
Angew. C‘hrm. Int. Ed. Engl. 1993, 32, 418-420.
[I31 S. Fernlnde7. R. Brieva. F. Rebolledo, V. Gotor, J. Chi~m.Soc. Perkin P u n s .
I 1992, 2885-2889.
[14] D. Enders. H. Kipphardt. P. Gerdes, L. J. Brefia-Valle, V. Bushan, Bull. Soc.
Chim. Belg. 1988, 97, 691 -704.
[I51 a) A. Alexakis, N. Lensen, J:P. Tranchier, P. Mangeney, J. Org. Chem. 1992,
57, 4563-4565. b) Lower inductions were achieved for the 1,2-addition of
Grignard reagents in toluene to hydrazones 2 in comparison with that of
organolithium compounds (< 90% de)
[16] a) J. A. Dale. D. L. Dull, H. S. Mosher, .
I
Org. Cliem. 1969. 34, 2543 -2549, b)
J. A. Dale, H. S. Mosher, 1 Am. Chem. Sot.. 1973. 95. 512- 519.
I
Or,?. Chem. 1993, 58, 3675-3680.
[17] J. A. Marshall, A. W. Garofalo, .
[I81 For removal of the protecting group and subsequent ion exchange chromatography (Dowex AG50 WX8, 0 . 1 p~H 5 buffer (acetic acidlpyridine)): a) R.
Steulmann. H. Klosterineyer, Li6,big.Y Ann. C‘herir. 1975, 2245-2250; h) W.-S.
Liu, S. C. Smith, G. I. Glover, J. Med. Cham. 1979, 22, 577-579.
[19] (R,R)-9:[nli5 = +1X.4 (c = 0.43 in H,O),
= +19 to
20 ( c = 0.55-1.0
in H,O) [18b] and references cited therein ( R T = room temperature); m.p.
198-199 C (decamp. H,O/acetone), 200-202°C. 234-236’C [18b]. and references cited therein.
[20] All new compounds gave correct spectroscopic data (IR, NMR, MS) and
correct microanalyses oi- high-resolution mass spectra (HRMS).
~
+
1222
c) VCM ~~r/ngcgescllscho/i
mbH, D-69451 Weinhcim, I995
(DTEDT)[Au(CN),],., : An Organic
Superconductor Based on the Novel n-Electron
Framework of Vinylogous Bis-Fused
Tetrathiafulvalene**
Yohji Misaki,” Natsuko Higuchi, Hideki Fujiwara,
Tokio Yamabe,* Takehiko Mori,* Hatsumi Mori,* and
Shoji Tanaka
Highly conducting and superconducting organic solids have
attracted much attention in the fields of organic chemistry,
physical chemistry, and solid-state physics, amongst others.“]
The most appropriate strategy to stabilize the metallic state
down to low temperature and to reach the superconducting
transition has been thought to be the formation of a two-dimensional (2D) electronic structure, which is usually attained by
use of TTF with “capped” dichalcogeno groups, such as bis(ethy1enedithio)tetrathiafulvalene (BEDT-TTF).”, We have
now found that a bis-fused TTF, 2,5-bis(l,3-dithiol-2-ylidene)1,3,4,6-tetrathiapentalene(BDT-TTP),[31tends to produce 2D
“metals” without such s u b ~ t i t u e n t s . [The
~ ~ extended n-conjgation systems of BDT-TTP (bis-fused donors containing extended TTFs[’~61), which have received much attention recently, are
of considerable interest in the search for new donors for organic
superconductors. We report herein the synthesis of the first
vinylogous BDT-TTP, DTEDT, 1a, which contains one 2,2‘ethanediylidenebis(l,3-dithiole) (Z).[61 Furthermore, we have
found that the present donor produces a superconducting
Au(CN), salt, as well as many metallic cation radical salts stable
to liquid helium temperature.
BDT-TTP
DTEDT l a
The synthesis of DTEDT was achieved as shown in Scheme 1.
Treatment of 1,3-dithiol-2-one 3 with sodium methoxide, and
then with a,a-dichloromethyl methyl ether afforded 4. This onepot reaction was carried out in acetone to avoid reaction of
a,a-dichloromethyl methyl ether with usual solvent (methanol).
The reaction of 4 with aqueous hydrofluoroboric acid gave the
corresponding 1,3-dithiolium salt 5 , which was converted to a
phosphonate 6 by treatment with triethylphosphite in the presence of sodium iodide. The compound 6 was allowed to react
with lithium diisopropylamide in the presence of 2-formylmethylidene-4~5-bis(methoxycarbonyl)-l,3-dithiole(7)[6a1to give
8. The cross-coupling reaction between 8 and 4,5-bis(methoxy[*I
Dr. Y. Misaki, Prof. Dr. T. Yamahe, N. Higuchi, H. Fujiwara
Division of Molecular Engineering, Graduate School of Engineering
Kyoto University, Yoshida, Kyoto 606-01 (Japan)
Telefax: Int. code + (75) 751-7279
Dr. T. Mori
Department of Organic and Polymeric Materials
Faculty of Engineering, Tokyo Institute of Technology
0-okayama, Tokyo 152 (Japan)
Telefax: Int. code (3) 5734-2876
Dr. H. Mori, Dr. S. Tanaka
International Superconductivity Technology Center
Shinonome, Tokyo 135 (Japan)
Telefax: Int. code (3) 3536-5717
[**I This work was partially supported by a Grant-in-Aid for Scientific Research on
Priority Area “Molecular Conductors” (No. 06243215) from the Ministry of
Education, Science, and Culture of Japan. DTEDT = 2-(1.3-dithiol-2ylidene)-5-(2-ethanediylidene-l.3-dithiole)-l
6-tetrathiapentalene, T T F =
tetrathiafulvene.
+
+
0570-0833,’95/1111-I222 3 10.00+ ,2510
Angew. Chrm. Int. Ed. EngI. 1995, 34. No. 11
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aldehyde, asymmetric, synthesis, amin, hydrazones, enantioselectivity, diastereo, glycol, alcohol, statia
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