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Estramycins A New Diyl Precursor Family Derived from Estradiol.

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matogram ol'the analytical separation of a mixture consisting of
dTDP-glucose. the resulting 6-deoxy-4-dose 2. two contaminants present in the commercial starting material, and d T M P
and dTDP.
In general the instability of product 2 leads to problems.[', ' ' I
We found that 2 partially decomposed with formation of d T M P
and dTDP during storage in salt and buffer solutions at 4 ' C
and -20' c'. respectively, and on lyophilization from volatile
butlers and uncompletely desalted solutions, as well as on precipitation b i t h organic solvents. Ulose 2 was isolated after
preparative HPLC with an overall yield of 70%. The product
can he stored at -20°C for at least four months. Spectroscopic
characterization of compound 2 as a 1 : 5 mixture of the keto and
hydrate forms proved it to be a pure compound.
+
Lihlc I Sclccrcd p h p c ; i i data of compounds 2. 5. .tnd 7
2 . ' H N ~ R ~ 4 l J l l M DH2~0 .) . i i =1.13(d.3H.6"-H). 1.84(d.3H.CH,).2.24 1.32
(ni. 111. 2;i'-H. 2h'-H). 3 53 (ddd. 2"-H). 3.69 (d. 3"-H), 4.01 (q. 5"-H), 4.07-4.11
5b'-Hj. 4 53 (m. 3'-H)- 5.46(dd. I"-H). 6.25 (dd. I'-H). 7.65 (d,
.I, , , = 7 . 0 . 4 J 2 , 0 = 3 . 1 . J 2 , =10.2.Jj.,, = 6 , 5 H z ; l ' C N M R
d = 1 l.7(C-6"j. 12.1 (CH,). 39.O(C-2').65.9(C-i').70.0(C-S"),
71.1 ( ( ' - 2 " ) . 71 3 (( -3'j. 7.3 6 (C-3").X5.4 (C-1'). 85.8 ( C - 4 ) .94.1 (C-4". hydrated).
95.8 i C ' - l ' ) . 112.2 (C-5). 137.7 (C-6). 152.2 (C-2). 167.0 (C-4).: 'JC I ,.= 8.6.
'Jc
,. = 5 7 I{/:bSI-MS (negative mode, + 3 kV): n i l : : 562.7 [ , U - - Na]; keto
Ibrm "(' NMR (100.7 MHr, [D,,]DMSO): 6 = 206 4 (C"-4); ESI-MS (negative
inodc. + 3 k V i : I H 1: 545 [.U
Na].
5 . ' H NMR (400 MH7. D,OJ: 6 =1.09(d, 3H. 6 - H ) , 1.84(s. 3H. CH,j,2.25 2.47
(:&I m d d d . 2 H . W-ti,iiid3~-H).3.74(m.2"-~-1).4.02(q.5-H),5.38[dd.
1"-H):
.I,
= 3 I, ' I ! ,, = 6 . 5 . J 2 . , , . = 5.5. J1 , , b =11.6.
'J
6 0 H / . ' ' ( ' N M R (100.7 MHr. D,O):$ = 1 1 . 6 ( C H , J . 11.2(
( d . ( " - 2 ) . O Y 8 iC"'-S). 93.2 (C"-4. hydrated). 95.7 (d. C"-I): ' J c , = 6.4.
'.I,
,. = X 5 tH/. '.'C' NMR (100.7 MHr. [DJDMSO) 6 = 203.1 (C"-4. not
11) d I , I I c d )
2: The disodium salt of dTDP-glucose (41 mp, 60 pinol: Stgin;i) was dis,olved i n
2 mL oTTri?:HCI buffer pH 7.5 (50 mw) i n a 2 m L Eppendorl'Il;i\k. I U ofrecombinant dTDP-~-gIticose-4.6-dehydr~it~ise
( 6 5 i.lL crudc crtract. 9.5 m g m L protein) w s a d d e d . and the ieliction mixture was incubatcd a1 .37 f.Afiercoinplete
conversion (ca 2 h) the reaction mixture \+.:is incubated for Z min at 95 C. celltrifuuged for 2 min at 12400 x ,?%and filtered through a 0 4, p i membrane. The
separation \\as performed by preparative HPLC (Hypersil ODS-IO }I, 2 x 25 cm.
Macherey N q e l . Diiren (German!). 0.04 h.l NH,CO, solutiun (pH 3). 0.0038%
(v'v) ocqlamine. l " 6 (..'v) methanol. isocratic elution. tlon rate 20 mLmin-l.
detection at 260 nm). Thc fractions containing the product \\
with doubly distilled water. and pumped with 250 mLmiii ' onto a membrane
iiiiioii-cxchange module (KN107Q. Sartorius. Gdttingen ((lei-many)).The aalts of
the HPLC solvent were removed with a 5 mM NaCI 51:>1ut1on.
. i d 2 \\:IS eluted with
I50 mM NaCl solution. The product solution wiis conccnll-,itcd to 11) m L under
vacuum at 30 'C and subsequently desalted on a S c p h d c x G-10 column
(2.6 x 93 cm, flow rate 1 m L m i n - ' ) . Aftcr lyophili~atioiithc diwdium salt of the
product wah obtmned a s tluffy white solid Yield 24 mg (70'1.0) F.ven traces of 3
wcrc iiot detectable in this batch.
Received Mni-cii 17. 1995 [Z78061E]
German version: A t i p i t Uim IYYS. 1/17. I881 - 1883
Keywords: biotechnology . chromatography . dehydratases deoxycarbohydrates . enzymes
[1] S. F. Lo. V. P. Miller. Y. Lei. J S Thorson, H.-W. Liu, J. L. Schottel, J. Bacrrriol. 1994. 176(2). 460 468.
[2] S. Chang. B Duerr, G. Serif, J B i d C/wi?i. 1988. 263(4). 1 6 9 3 ~1697.
[3] B. W. Jarvis, C . R. Hutchinson. Arch. BiocIlrni. Bioplii 5 . 1994, 3fIA'(lj. 175-
~
~
~
7 : ' 1 1 N M K (400 MHz. D 2 0 ) .b = I 2 1 (d. 3H. H"-6). 1.84 (s. 3H. CH,), 3.40 (m.
2H. ti"-2. H ' - i ) . 4.71 (q. H"-5). 5 4 3 (dd. H"-1). J,
=3.X. ' J , , , , = 7 . 0 .
.I,
6.3 HI. "C' NMR (100.7 MHr. D,O). 6 =13.3 (CH,). 13.6 (C"-6J, 60.2
(("'-.3.XI! 3 td. ("'-2). 94 1 (C"-4, hydrated). 95.7 (d. C"-I): 'J, = 6.4.
'.I,
,, = X I H/. I3C NMR (100.7 MH7. [DJDMSO):
= 201.4 (C"-4. not hy(,
7
dl-atcd)
To the best of our knowledge, these experiments describe the
first N M R spectroscopic characterization of the dehydratasecatalyzed synthesis of the deoxy intermediate 2. The successful
conversion of nonnatural dTDP-3-deoxy-x-~-uibo-and -3-azido-x-i)-.\-l./o-liexopyranoses
4 and 6, respectively, open a new
enzymatic route to artificial nucleoside diphosphate activated
glycosyl donors in which easily available crude extracts are used.
The HPLC method described should enable the first complete
characterization of the dTDP-L-rhamnose biosynthesis in one
step. In addition. preparative amounts of 2 and related compounds can now be isolated.
Expcv-iiiietI i d Procca'tare
2. 5. .ifid 7 Tliv disodiuni salt ofdTDP-glucose 1 (50 mug. 82 pmol) or I t s 3-deoxy
deriv,iciw\ 4 .ind 6 (available by ion exchange from the chemically synthesized
dilitliiiiin d t s 112,131) was dissolved in 5 mL of Tris"HCI buffer pH 7.5 (50 mM.
0.5 mhl DTTJ. The dehydratase was added (0.083 U : 1 U = 1 Nmol rnin-' . 1 45 m L
crudc cxtr;ict from E i d i B [XI). the reaction flask filled with 10 mL of distilled
wiitr'r. . i n J the wlution incubated at 37 C with constant shaking. After 2 d the
reaction n i i s coinplete according to TLC (2-propanol.ethano1:w;iter = 5.3'2.5%
HOAc. 2 " 0 tricth)laminc, product R, = 0.4. starting material 1 K , = 0.3. d T M P
R , 0.5, d I'DI' R , = 0.1).The enzyme reaction was stopped by heating for 30 s in
boiling w,iIcr: the ireaction mixture war lyophilized to B volume o f 3 mL and separated on 'I Scplixicx G I 0 column (2 x I60 cm: l m l m i n - ' ) The fractionscontaining tlic tnuclco~idc\ugars were collected, purified by ion exchange chromatography
(Doucx I x 1. ( ' I
form. 5 x 18 cm. 800 mL linear gradient 0 0.X M LiCI), and
coticeriri;itcd Ihciltiiig on Sepliadex G 1 0 and stibsequent lyophilization gave the
o1 the products as white fo'ima. Yield of 2 and 3 (ca. 3:2
dilithiiim
x c i v d i i i g l o ' tl N M R ) : 76 nig ( 5 4 % ) :yield o f 5 : 20 mg (41 " 6 ) ;yield o f 7 . 23 nig
(24".,,)
7
181.
[4]C E. Snipes. C . J. Chang. H. G. Floss. J
,4f?i ( - h c i ? i . .So<.
1979. 101. 701 706.
[5] C E. Snipes. G. U. Brillinger. L. Sellen. L Mascai-v. H. G. Floss. J Biol.
C/icwi. 1977. 752, 8113-8117.
[6] K. Marumo. L. Lindqvist. N. Verma. A. Weintrauh. P. R Reeves, A. A. Lindberg. Eur. J 5iodicwi. 1992. 2/14. 53Y 545.
K . H. Schscda. P. R. Reeves. A .4 Lmdberg. Eur. J Biodieiii.
1994. 275, 863-872.
[a] R D. Bevill i n Merhoileif iler cwizji?iuri.whcn Aiio/i~,sr( E d H U Bergemeyerj.
Verlag Chemie. Weinhemi. 1974. pp. 226X . 2269.
[9] R Okaiaki. T Okaraki. J. L. Strommgcr. A. M . Michelson, J. B i d C'himi.
1962. 237, 3014-3026.
[lo] T. Y. A\+, D. P. Jones. h i d B i d i i v ~ i .1982. 177. 3 2 - 36
[ I l l H. P. Wahl. H. Gnsebach, Biochrin. BiophJ.5. ilcra 1979 56H. 24.3 252.
[I?] J G. Moffatt. Mrrhotls Enzjniol. 1966. 136 142.
[I31 B Leon. S . Liemann. W. Klaffke. J Curbohid?. C-hcii
Naundorl'. S. Licmann. W Klaffke. LY~nrhc~sir
of D
Eurocarb V I I , Krakow. 1993, Abstr C004.
'
Estramycins: A New Diyl Precursor Family
Derived from Estradiol**
Jing Wang and Pierre J. De Clercq*
The recent discovery of a new class of anticancer antibiotics
From a bacterial source, presently consisting of neocarzinostatin, the esperainycin and calicheamycin families, dynemicin,
kedarcidin, and C-1027, which exert their biological activity
through D N A cleavage, opens new perspectives in cancer
chemotherapy.['] D N A cleavage is effected by diradicals that
are generated from cyclic polyunsaturated core structures upon
suitable activation. Quite recently diyl-based DNA cleaving
agents have been reported in which the core of the diradical
precursor is tethered to known minor groove DNA binding
agents or D N A intercalators."] Also, a new family of artificial
enediynes (taxamycins) has been described in which the unsatu[*] Prof. Dr. P. J. De Clercq. Dr. J. Wang
Univei-sity of Gent. Department of Organic Chcinistr\.
Krijgrliian. 281 (S.4). 8-9000 Gent (Belgium)
T e l e f w Int. code (9j264-49YX
+
[**I This work was supported by the National Fund foi- Scicntilic Research
rated core is intimately embedded within a structure with known
antitumor activity, like tax01.I~'In the same context we aimed to
study the chemotherapeutic potential of estramycins, derivatives in which the diradical precursor core is incorporated into
estradiol. It is indeed known that the chemotherapeutic activity
of cytostatics against hormone-responsive tumors can be enhanced by linking them to hormones.[41Since human mammary
cancers are usually rich in estrogen receptor, estrogens, and
estradiol in particular. are potential vectors to transfer cytotoxic
agents into the nuclei of receptor rich cells.[51As shown in
Scheme 1 potential candidates include cyclic enediynes and
enyne-allenes that would generate the diradical intermediates
through Bergman and Myers cyclization processes, respective-
0
n
l y , [ h . 71
W
€,I
= 0.0
kJ molr'
cd
=
305 pm
6
n
I
I
Bergman
Myers
[p[@
H
H
Scheinc 1. Poasible route5 from estramycins to diradicals
Obviously. in designing such hybrid molecules both the binding affinity of the modified estradiol for the estrogen receptor
and the reactivity of the unsaturated system should be taken
into account. The knowledge of the various structural features
that are necessary for the activity of estradiol is crucial to the
design of a successful candidate. The structure 1 (see Scheme 2)
was proposed based on the following:[811) Both the phenolic
C3-hydroxy and /&oriented C17-hydroxy groups are intimately
involved in the recognition process. 2) An x-oriented ethynyl
group at C17 enhances the binding affinity. 3) Estradiol derivatives a-substituted at C16 bind well to the estrogen receptor."'
For the design of an appropriate enediyne core one can apply.
at least in the first instance, the critical distance ((YO criterium
introduced by Nicolaou.r'ol The distance between the terminal
alkyne atoms of the enediyne is taken as a measure of its ease of
cyclization; the crucial turning point froin stability to spontaneous cyclization lies between 331 and 320 pm. Depending
on ring size candidates 1 possess varying c ~ d s(Scheme 2):['11
only the ten-membered ring derivative (1. 17 = 2) is of potential
use. From the low distance of 305 pm that is found in the lowest
energy conformation of this compound one may expect the
derivative to be rather unstable. Consequently, in the design of
a synthesis. the enediyne core should be realized at a very late
stage.["] We now further dcscribe the synthesis of a few derivatives of 1 and their cyclization behavior.
After protection of estrone a s the tert-butyldimethylsilyl
(TBDMS) ether." 3 1 the required stereoselective introduction of
E,eI=l 74kJmol'
0
cd=318pm
Scheme 2 Cnlcularcd ( ( 1 ~ a l u o si n estramvcin 1
a 2.2-dimethoxyethyl side chain in x position at C16, as in 4. was
accomplished as follows (Scheme 3): 1) Ketone 2 was enolized
(0.95 equiv. of lithium diisopropylamide (LDA). T H F ) , and
subsequently treated with 3-bromo-1 -propene to form the corresponding 16x-(2-propenyl) derivative (83 % yield) .[' 3 . 14]
2) Oxidative cleavage of the double bond with osmium tetroxideisodium periodate gave the aldehyde 3 (71 YO yield).
3) Selective protection of the aldehyde with trimethyl orthoformate in tetrachloromethane, catalyzed by Montmorillonite
K-10 clay. resulted in a mixture of desired 4 (57 YOyield) besides
the cyclic mixed double acetal 5 as a mixture of two isomers
(30% yield).[l5I The stereochemistry at C16 predicted on steric
grounds was further corroborated by 'H N M R NOE difference
spectroscopy: irradiation of the angular methyl group Icd to an
increase of the signal of the H atom on C16.
Quite recently the intramolecular version of Nozaki's chromiuni(~i);'nickeI(ii)salt mediated coupling of haloalkynes with
aldehydes has been applied successfully in the synthesis of
The method is especially useful
enediyne ring systems."'.
when dealing with cnolizable aldehydes a s in our case. The rcquired cyclization precursor 8 was obtained by reaction of 4
with the alkynyl anion obtained froin 6.I"' which led to 7 as an
approximate 1 : 1 mixture of diastereomers at C22 in 67%)yield.
and subsequent protection of the hydroxy group a t C17 with
trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2.6-lutidine in dichloromethane. Simultaneously the aldehyde function was deprotected (86% yield of 8a. but contaminated with
about 30% of dciodinated 8b, which could not be separated at
this stage).'"' The [I-hydroxy configuration at C17 (shown in
Scheme 3) was assigned on the basis of literature precedents and
of the magnitude of the ' H N M R shift of the resonance for the
angular methyl group that is observed for 7 in pyridine relative
- hC&
= - 0.22).[20.'11
The
to that in chloroform
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gb, R' = R3 = TBDMS: R Z = TMS, R4 = H
10, R' = R4 = H, R' = TMS, R3 = TBDMS
1 1 , R' = R4 = Ac: R2 = TMS, R3 = TBDMS
12, R' = R 4 = A c ; RZ = R 3 = H
13,R' = R4 = Ac, R' = H, R3 = MS
14, R' = R4 = AC, R' = TMS, R3 = MS
2
Montrnorillonite K-10
14
DBU (20 equiv), 50"-60'C. 3h
5
4
I
TBDN
15
Scheme 4. S y n t h e m and CyCloaroiniiliLation of cutraniycin\ 15 M I
sulfonyl.
8a. R
1: Sb, R = H
=
i
CrC12, NiClp
crucial intramolecular cyclization of the iodoalkyne-aldehyde
8 a succeeded in the presence of seven equivalents of chrom i u m ( ~chloride
~)
and 10 mol %I of nickel(11)chloride in THF at
room temperature. The ring-closed alcohol was obtained in
54%) yield (based on the 80%) iodide content of the starting
material) and consisted of a mixture of three out of the four
possihle diastereomers. which could be separated by careful
chloinatography: 9 a (26%). 9 b (21 Yo).and 26-epi-9b as a minor component (6 %). The relative stereochemistry at positions
2 1 and 26 was assigned on the following basis : the stereochemistry at C26 in 9 b follows from the elucidation by ' H NMR
spectroscop? of a later intermediate (16); comparison of the
calculated vicinal coupling constants for H22" with the experimental V ~ L I ~ (for
S .
9 a : calcd. 5.3/2.7 Hz, exp. 5.415.4 Hz; for
9 b : calcd 9.0:6.9 Hz, exp. 8.4,16.7Hz)'~']and for 26-epi-9b (8.2!
6.7 HL): oxidation of 26-qi-9b with Dess-Martin periodinane
leads to an d k y i o n e that is identical with the one obtained from
9b. but different from that obtained from 9 a .
The con\ersion of 9 into a precursor for cycloaromatization
further requires the elimination of the C22-oxy function in a
selectivc manner.['" Scheme 4 depicts the laborious sequence by
16
=
methme-
which this was accomplished for 9b. Selective deprotection
of the phenolsilyl ether (81 YOyield) followed by acetylation
of 10 afforded diacetate 11 (95% yield). After further
desilylation with hydrofluoric acid in acetonitrile to 12
(95 YO yield), the free C22-hydroxy group was converted
into the corresponding methanesulfonate 13 (86 YO yield).
The elimination of the methanesulfonate was first attempted
on the unprotected 17-oxy derivative 13.['31Treatment with
ten equivalents of 1.8-diazabicyclo[5.4.0]undec-5-ene(DBU) at
room temperature proved difficult. Even after six hours
most of the starting methanesulfonate was still present.
When the reaction was followed by ' H NM R spectroscopy
(25 C. [D2]dichloromethane), an isolated AB system (6 =
6.01, 5.93. J = 9.4 Hz; integration indicated less than 10%
of the starting material) as expected for the two hydrogen atoms of a (Z)-enediyne system wab observed but
gradually disappeared, presumably through Bergman cyclization.
At several stages during the synthesis we found that C17alkynylated derivatives were rather unstable when they possessed a free Cl7-hydroxy group. The same procedure was
therefore also studied on derivative 14. in which the C17-hydroxy group is protected as the trimethylsilyl ether (90'1/0yield
with TMSOTf and 2.6-lutidine. CH2C12, -78 C. 45 min).
Upon treatment of 14 with DBU in toluene at room temperature for 1 h the expected enediyne 15 could be isolated in about
50% yield after fast workup and chroinatography as well as
31 YOof starting methanesulfonate. The rate of its disappearance. presumably through Bergman cyclization, was estimated
by means of ' H NMR spectroscopy ([D]chloroform, 25 'C) at
t , = 108 min (25 ' C ) . When methanesulfonate 14 was treated
with 20 equivalents of DBU in the presence of' 1,4-cyclohexadiene (50' -60 C. 3 h), the expected cycloaroniatized acetate 16
was isolated in 3 3 % yield. The assignment of the configuration
at C26 was based on comparison with calculated vicinal
coupling constant values for H26,'lL1 (3.1 3.0 Hz for 16;
1 l.li4.3 Hz for 26-~pi-16);[~"]
the experimental values are 3.01
3.0 Hz.
Although the estramycin derivative that has been synthesized and shown to cycloaromatize still possesses a protected
C17-hydroxy group, we have shown that a 10-membered ring
derivative of this type, in particular with ;I ci.s-ring fusion,
does cycloaromatize at a rate useful for posxible chemothera-
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peutic use. We are convinced that this knowledge will be crucial
in the development of more sophisticated estramycin derivatives.
Substituent-Controlled Reactions of
Iminophosphoranes with Methyllithiurn""
Alexander Steiner and Dietmar Stalke*
Received: March 1 1 . 1995
Revised version: May 3, 1995 [ Z 7790 IE]
German version: Angeu. C/irni. 1995. 107. 1898-1901
Keywords: antibiotics . antitumor agents diradicals . enediynes
. estrogens
[I] Review: K. C. Nicolaou, W:M. Dai. A n ~ y r w .C%erii. 1991, 103. 1453-1481:
A q e Chem.
~
1 f i z . Ed. Engl. 1991, 30, 1387 - 1416: recent progress in the
chemistry of enediyne antibiotics: Terrtrher/ron 1994. 50 (Tetrahedron Sytnposia-imprint no. 53).
[2] a ) K. C. Nicolaou, Y. Ogawa. G . Zuccarello. H. Kataoka. J A m Clieni. so^^.
1988. 110.7247 -7248; b) M. Tokuda, K. Fujiwora, T. Goiiiibuchi. M. H i d m a ,
M. Ucsugi, Y. Sugiura. R~rrohrdronLerr 1993. 34, 669-672; c) D. Boger. J.
Zhou, J Org. Ciimi. 1993, 58. 3018-3024; d) M . F Semmelhack. .I.
J. Callaghes. W.-D. Ding, G. Krishndmurthy. R . Bahine. G . A. Ellestad, J. Org. Ciimi.
1994, 59, 4357-4359: e) K. Toshima. K . Onta. A. Ohashi. T. Nakamura. M.
Nakata. S. Matsumura. J. Ciirm. Soc. C h ~ ~ nCo~nniim.
r.
1993. 1525- 1527; Reblew: K. Nicolaou. A. Smith. E.Yue, Proc &'or/. Acml. Sri. U S A 1993. YO.
58x1-5888
[3] Y.-F Lu. C. W. Harwig. A. G. Fallis, J. Org. C ~ H1993.
. 58. 4202 4204.
[4] Cyrotoxic E\frojien.c i i i Hornionc Recepriw Tumors (Eds: J. Raus, H. Martens.
G. Leclercq), Academic Press, London. 1980.
[5] For example, estramustine (estradiol to which nitrogen mustard [hi>(?chloroethyl)sulfide] is hound) H . Hamacher, A r x e i m . Forsc/i. 1979. 39. 463;
see also: S . Top. A. Vessieres, G. Jaouen, J. Chem. So<,.C/i?ni. Conlmior. 1994.
453-454, and references therein
[6] R. G. Bergman, Ace. Ciierii. Res. 1973. 6 , 25 -31.
[7] A . G Myers, F Y. Kuo, N . S. Finney. 1 Am. Clieni. So<. 1989. 111, 8057
8059.
[XI T, Ojasoo. J.-P. Raynaud, J.-P Mornon in Compi-rh~n,siwMdrt.rul C h m i \ r r j ,
b?d. 3 (Eds : C. Hansch, P. G. Sammes, G . B. Taylor). Pergamon. New York.
1990, pp. 1175-1226.
[9] a) D. F. Heiman. S G . Senderoff. J. A. Katzenellenbogen. R. L. Neeley. J
Mrd. C h n . 1980,23.994-999: h) D . 0 Kiescwetter. J. A . Katrenelienhogen,
M. R. Kilbourn, M. J. Welch. J. Org. C/iem. 1984. 49, 4900-4905.
[lo] K . C Nicolaou, G. Zuccarello. Y. Ogawa, E. J. Schweiger. T. Kumazawa. J.
Am. Chein. Sor. 1988, 110. 4866-4868; hut see also: J. P Snyder. ihid. 1990.
111, 5367-5369; P. Magnus, P. Carter. J. Elliot, R. Lewis. J. Harling. T Pitterna. W. E. Bauta. S. Fortt, ihid. 1992, 1I4. 2544-2559.
[ I l l Calculations were performed with MacroModel (MM2): W. C. Still. F. Mohamadi. N . G. J. Richards. W C. Guida, M. Lipton, R. Liskamp, G. Chang. T.
Hendrickson. F. De Gunst. W. Hasel. .MUUOMU&/ V3.0. Department of
Chemistry. Columbia Universitv, New York.
An excellent, recent account of the strategies for the generation of rcnctive
cnediynes from stable precursors: M. E . Maier, Kmrakre 1994 ( 2 ) , 3- 17.
T. L. Fewg, J. A. Katzenellenhogen, J. Org Chem. 1987. 52. 247 251.
K. M. Sam, R. P. Boivin. S. Auger. D. Poirier, Bioorg. il4~il.C/IPI?ILcrf. 1994.
4, 2129-2131.
E. C. Taylor, C . 3 . Chiang. S~,~irhe$i.s
1977, 467.
K. Takai. T Kuroda, S. Nakatsukasa. K. Oshima. H Nozaki. TrrroAdron
Lert. 1985. 26, 5585-5588.
a ) C . Crevisy. J.-M. Beau, Tetraheifrun Lerr. 1991, 31. 3171-3174; b) M. E.
Maier. T. Brdndstetter. hid. 1992, 3.3. 7511 7514: c) see also: P. A. Wender.
J. A. McKinney. C Mukai, J Am. C1iem. SOC.1990. 112. 5369 5370.
Complete details (synthesis. experimental procedures. spectral data) will he
published in a full paper.
H Emde, D. Domsch. H. Feger, U. Frick. A. Gotz, H. H. Hergott, K. Hofinann, W Koher, K. Krigeloh. T. Oesterle, W. Steppan, W. West. G.Simchen.
Srnthe.sD 1982, 1
G. Neef. U. Eder, R. Wiechert. J. Orji. Chem 1978. 43, 4679-4680
P V. Demarco, E. Farkas, D. Doddrell. €3. Mylari. E. Wcnkert, J. A m . C%mr.
Soc 1968, YO. 5480-5486.
Calculations were performed on an unprotected model lacking the C?h-suhstituent.
An example in which the enediyne system is generated by the elimination o l a
methanesulfonate (4equiv of DBU in T H F : 1.4-cyclohexadiene, 3 : l ) : a ) H.
Audrain, T. Skrydstrup. G. Uliharri. D. S. Grierson. Sjdcvr 1993. 20 22;
h) H. Audrain, T. Skrydstrup. G. Uliharri. C Richc, A. Chiaroni, D. S. Gricrson, Teelrufiudron 1994. 50. 1469-1502.
Calculations were performed on the unprotected trio1 derivative.
Dedicated to Profcwor Paul von RuguP Si izlejw
oil the occusion of his 65th birthckiy
Phosphorus ylides R,P=CR, and phosphine oxides R,P=O
can react with nucleophiles via hypervalent intermediates. These
intermediates might be regarded as electronically similar to the
valence-expanded [PXJ ions.".
The Wittig reaction, in
which an intermediately formed oxaphosphetane resulting from
the reaction of a phosphorus ylide and a carbonyl compound
decomposes to give phosphine oxide and the related olefin, has
been well studied.[31Another example of the above-mentioned
reactions is that of a pyridyl-substituted phosphine oxide with
organometallic bases.[41 Aryl- and heteroaryl-substituted tertiary phosphanes can react to give either ~ u b s t i t u e n t - e x c h a n g e ~ ~ ~
(Scheme 1, top) or substituent-coupling[6]products (Scheme 1,
bottom).
Scheme 1 .
In our ongoing studies of the influence of pyridyl substituents
at phosphorus,['] we were interested in the reaction of organolithium compounds with iminophosphoranes R,P=NR', which
can be regarded as unsaturated PV-N compounds and hence as
N analogues of phosphorus ylides and phosphine oxides.[']
Both Py,P=NSiMe, (1) (Py = 2-pyridyl) and the isoelectronic phenyl derivative Ph,P=NSiMe, (2) were treated with
methyllithium, and the structures of the resulting lithium compounds were determined. Compound 1 can readily be made by
the Staudinger reaction of tri(2-pyridy1)phosphane and
trimethylsilylazide [Eq. (a)].
Compound 1 reacts spontaneously with methyllithium in diethyl ether even at - 78 " C , during which the solution changes
from colorless to dark green. Golden brown needles can be
grown from the reaction mixture on storing the flask at 0 - C for
two days.
The results of the single-crystal X-ray structure analysis['] are
shown in Figure 1. The iminophosphorane 1 is converted into
the lithium phosphine amide 3 during which the oxidation state
of the central phosphorus atom decreases from v to III. The
coordination sphere of the lithium ion is saturated by the substituent-coupling product 2,2'-bipyridyl obtained in this reaction. Scheme 2 shows one plausible reaction mechanism.
[*] Priv.-Dor. D r . D Stalke. Dr. A. Steiner
[**I
Inatitut fur Anorganische Chemie der Universitlt
Tamniannstrassc 4. D-37077 Gottingen (Germany)
Telelax: Int. code + (5513392582
This work WLIS supported hy the Deutsche Forschungsgemelnschaft and the
Fonds der Chemischen Industrie.
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