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First Total Synthesis of (▒)-Rabelomycin.

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12: A solution o f 4 (71 mg, 0.08 mmol) in benzene (10 mL) was treated with CNlBu
(9 pL, 0.08 mmol) and stirred for 1 h at room temperature. The solvent was removed. the residue repeatedly washed with acetone and dried in vacuum. An
orange-red solid was isolated which was stable in air for short periods: yield 56 mg
(98%); m.p. 2 2 2 - C (decomp).
13: A solution of 4 (87 mg, 0.10 mmol) in T H F ( I S mL) was treated with NaC,H,
(44 mg, 0.50 mmol) and stirred for 1 h at room temperature. The solvent was removed, the residue was extracted with pentane/benzene (1: 1; 3 mL), and the sohtion chromatographed on A1,0, (see 4). Withether a violet fraction was eluted from
which after evaporation of the solvent and recrystallization from ether/pentane
violet needles were isolated; yield 53 mg (80%); m.p. 208 'C (decomp). Compound
14 was prepared analogously; yield 78%: m.p. 132 'C (decamp).
Received: July 31, 1993 [Z 6251 IE]
German version: Angrw. Chen?. 1994. 106, 82
1 ) U. Weber. L. Zsolnai, G . Huttner, 1 Orgunomet. Chem. 1984,260,281-291;
b) G . Huttner, U. Weber, 9. Sigwarth, 0. Scheidsteger, H . Lang. L. Zsolnai,
ibid. 1985, 282, 331 -348.
a) A. R. Barron, A. M. Cowley, R. A. Jones, C. M. Nunn, D. L. Westmoreland,
Polyhedron 1988. 7,77- 78; b) A. L. Balch. V. J. Catalano. M. A. Chatfield. J. K.
Nagle, M. M. Olmstedd. P. E. Reedy, Jr., J. Am. Chrm. Soc. 1991, 113, 12521258.
a) W. Levason. C. A. McAuliffe, Phosphine, Arsine und Stibine Complr.\-esoJ [he
Trunsitiun Elrmrnts, Elsevier. Amsterdam, 1977: b) W. Levason, C. A. McAuliffe, Acc. Chrm. Res. 1978, 11. 363-368: c) N . R. Champness, W. Levason, M.
Webster. Coord. Chem. Rev., in press.
P. Schwab, N . Mahr, J. Wolf, H. Werner, Angew. Chem. 1993, 105, 1498-1500;
Angeiv. Chem. Inr. Ed. Engl. 1993, 32. 1480- 1482.
Crystals from THF/S-propanol: crystal size 0.3 x 0.2 x 0.2 mm: orthorhomhic,
space group Pnmu (no. 62), Z = 4; u =17.730(7). b =13.008(1), r =
14.919(1) A; Y = 3441.0(7) A'. pcalEd
=1.660 g ~ m - ~max.
: 2 8 = 54" (Mo,,,
2 = 0.70930 .&.graphite monochromator. w/28-Scan, T = 293 K); 4264 reflec> 3 O(Fa)]. Lorentzian
tions measured. 4028 independent, 2777 observed
polarization correction ( p = 19.0 cm- '), direct methods (SHELXS-86). refinement with program package SDP (Enraf-Nonius), position of hydrogen atoms
calculated according to ideal geometry (C-H distance 0.95 A), refined with the
riding model; R = 0.027, R , = 0.033; reflexiparameter ratio 13.16; residual
electron density f0.7381-0.554 e k ' . Further details of the X-ray structure
analysis are available on request from the Fachinformationszentrum Karlsruhe.
D-76344 Eggenstein-Leopoldshafen (FRG), on quoting the depository number
CSD-57659. the names of the authors. and the journal citation.
T. Yamamoto, A. R. Garber, J. R. Wilkinson. C. 9 . Boss, W. E. Streib, L. J.
Todd. J. Chew. Soc. Chem. Commun. 1974, 354-356.
H. Ueda. Y. Kai. N. Yasuoka, N. Kasai, Bull. Chem. Suc. Jpn. 1977,50.2250-2254.
P. Hong. N . Nishii, K. Sonogashira. N. Hagihara, 1 Chem. Suc. Chem. C u m
mun. 1972, 993.
[c3
compounds, which include 9, carry a labile tertiary hydroxyl
group to the C1 carbonyl group. This inherent lability is one
of the reasons that, with the exception of the biomimetically
oriented urdamycin-B synthesis of Yamaguchi et al.,['I no total
synthesis of angucyclins is known.
We now present the first synthesis of racemic rabelomycin
(rac-9), in which the synthetic problem is solved in a simple and
productive manner with the help of a Diels-Alder reaction and
a new type of photooxygenation of a nonfunctionalized C-atom.
Previously, only model compounds lacking the tertiary hydroxyl group could be prepared with the Diels- Alder reaction.".
Retrosynthetic analysis yielded a diene (OH instead of
%,Me, in 6 , see Scheme 2) which, as preliminary experiments
indicated, is probably extremely labile and, furthermore, not
easily accessible. We therefore had the idea of replacing the
hydroxyl group in the diene with a substituent that is a poorer
leaving group. Our original intention was to use the dimethylphenylsilyl group, which could be replaced by a hydroxyl
group in a later step." However, to study the Michael addition
of lithiated silanes to Michael acceptors such as 3-methylcyclohexenone, the cheaper trimethylsilyllithium was chosen.
This reagent is prepared by Still by treatment of hexamethyldisilane (1) with methyllithium in hexamethylphosphoric triamide (HMPT).[12]However, on carrying out the reaction on a
larger scale, it was discovered that the C-Si bond and not the
Si-Si bond in 1 is broken, leading to the formation of pentamethyldisilyllithium (2, Scheme 1). This result is in agreement
with an observation of H ~ d r l i k [ ' ~and
" ] was recently confirmed
for cyclic silanes by Allred et al.[13b1
Under the conditions described in the Experimental Section the cleavage of the C-Si
bond in hexamethyldisilane by alkyllithium compounds to afford 2 is a general reaction which takes place not only with
methyllithium in ether, but also, for example, with n-butyllithium. Obviously, the negative charge on the silicon is stabilized by
the second silicon atom in the t( position. This effective stabilization is also noticeable in the reactivity of the species. The "soft"
anion adds to the a,fl-unsaturated carbonyl compounds cyclohexenone (3 a), 3-methylcyclohexenone (3b), and 3,4-dimethylcyclohexenone (3c) to give exclusively the 1,4 addition products
(Scheme l).[14=]The adducts 4a-4c that are formed are chiral,
and further evidence for the presence of a SiMe,SiMe, unit is
provided by the splitting of the signal of the diastereotopic
methyl groups in the SiMe, group in both the 'H and 13CNMR
spectra (see Experimental for 4b).
+
First Total Synthesis of ( )-Rabelomycin **
Karsten Krohn * and Karamali Khanbabaee
Dedicated to Professor Ulrich Wannagat on the occasion
of his 70th birthday
Rabelomycin (9), known since 1970,['] is a structurally simple
member of the rapidly expanding class of angucyclin antibiotics.[*]The name angucyclins was given to the class on the basis
of the analogy with the anthracyclins and the angular benz[a]anthracene framew~rk.[~I
In particular, angucyclin antibiotics
are characterized by antif~ngal,[~]
antiviral,[51enzyme inhibitory,[61and antitumor activity.['] Most of the biologically active
[*I
[**I
Prof. K. Krohn, Dip1.-Chem. K. Khanbabaee
Fachbereich Chemie und Chemietechnik der Universitit-Gesamthochschule
Warburger Strasse 100, D-33098 Paderborn (FRG)
Telefax: Int. code + (5251)60-3245
Synthetic Angucyclins, Part 2. This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie. Part 1 : K.
Krohn. F. Ballwanz, W. Baltus, Liehigs Ann. Chem. 1993, 991-913.
Angen. Chem. 1111. Ed. E n d . 1994, 33. No. 1
0 VCH
-
RZ
R'
R2
R'
MeLl
MegSiSiMeg
LiSiMepSiMeg
HMPTITHF
+
Scheme 1
Thus, the reagent is already sufficiently selective towards 1,4addition that the formation of silylcuprates, through the addition of copper salts to the reagent (cf. ref. [ll]), is not necessary.
The reagent even adds smoothly to sterically hindered enones.
The easily accessible pentamethyldisilyllithium (2) is a new synthetic reagent, whose usefulness in the synthesis of tertiary alcohols is demonstrated by this first synthesis of rabelomycin.
The first advantage of having a silyl group on the tertiary
carbon atom is shown in the next step of the synthesis. Chain
Verlagsgesellschaft mbH, 0-69451 Weinheim.1994
0S70-0833/94/0101-0099 $10.00+ .25N
99
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extension of the b-silylketone 4b to the unsaturated ester 5 in a
Wittig-Horner reaction with triethylphosphonoacetate can be
carried out without the risk of a base-catalyzed fl elimination in
95 % yield. The presence of two signals in the 29Si N M R spectrum at S = - 7.63 (SiMe,) and at 6 = - 19.51 (SiMe,) confirms
that the Si-Si bond survives the transformation intact."
The silyl group provides a further benefit in the next step
through its property of destabilizing anions in the /l
position to
the silicon atom. Theoretically, two regioisomeric dienolates
can be formed by the deprotonation of 5 with lithium diisopropylamine (LDA). Our plan assumed, however, that proton
abstraction ct to the tertiary carbon atom in 5 would be suppressed by a combination of the steric shielding afforded by the
methyl and silyl groups and the p-effect of the silicon. This
expectation was completely fulfilled, and after selective enolate
formation with LDA and trapping with trimethylsilyl chloride
only the desired regioisomer of the diene 6 (76%) could be
isolated. The subsequent Diels- Alder reaction proceeded regiospecifically to give a 1 :1 mixture of the phenol 8 a (32 YO)
and
the ethyl ether 8 b (33 YO)(Scheme 2). However, the formation of
4b
0
0
"Si,Me5
:;::kAoEt
0
-
1 LDA, -78 "C
Me,SiO
J,,.,.,=15Hz;1H,2-H,).3.04(d.J,,,,=15Hr;1H.2-H,),3.0~(s;2H,4-H,),6.9
( s : 1 H, 5-H). 7.25 (dd. J9, ,, = 2.0.Jg,," =7.3 Hz: 1 H. 9-H). 7.65 (dd, J9, I I = 2.0.
J,,,=7.3H~.1H.Il-H).7.67(t,J~,,~=J,,,=7.3Hz;1H,10-H),1I.65(~;1H,
-OH). 12.30(s: 1 H. OH): I3C N M R : 6 = 30.05 (prim.), 44.26 (sec.), 53.89 (sec.),
76.95 (quat.). 115.03 (quat.). 116.83 (quat.), 120.10 (tert.), 122.04 (tert.), 124.02
(tert.). 128.04(quat.). 135.46(quat.), 137.82(tert.), 138.06(quat.), 150.63 (quat.).
162.06 (quat.). 163.77 (quat.), 183.19 (quat.), 192.57 (quat.), 196.05 (quat.). MS
(160 C ) ??I;= (Yo): 338 (13)[ M i ] ,321 (25).320 (100)[ M t - H,O], 310 (54) 305
(15).295 (21). 292 (25). 281 (23), 280 (94).
2 MeSSEI
EtO
Experimental Section
Preparation of 2 and Michael addition to 3 b to form 4 b: A solution of hexamethyldisilane (50.0 mL. 0.34mol) in HMPT (200mL) was cooled to 0 -C and treated with
a 5 % solution of methyllithium in ether (88mL. 0.2 mol) under nitrogen. After
15 min dry T H F (0.5 L) was added over 10 min. the reaction mixture cooled to
-78'C. followed by treatment with a solution of 3 b (16.5g, 0.15mol) in dry T H F
(100 mL). After 15 min the reaction was quenched by the addition of dry methanol
(20mL), and the mixture then warmed to 0 ° C . The product was extracted with
n-pentane (I L), the pentane solution washed twice with water (a total of 1 L) and
dried over magnesium sulfate. The solution was concentrated under vacuum, and
the residue fractionally distilled under oil pump vacuum; yield 21.2g (58%) (9599 C: 1.3Torr). colorless oil. ' H N M R (200 MHr. CDCI,): 6 = - 0.07 (s; 3H.
SiMe,). 0.08 (s: 3 H , SiMe2).0.00(s: 9 H . SiMe,). 0.86(s: 3 H , CH,), 1.39-1.47(m;
I H ) . 1.61-1.80(dt: I H ) , 1.84-1.94 (m: 3H). 2.14-2.35 (m: 3 H ) : l 3 C N M R
(50MHz. CDCI,): 6 = - 5.57 (prim.). -5.42 (prim.). -0.94 (3 x prim.). 20.46
(prim.). 22.95(sec.),27.02(quat.),32.12(sec..41.46(sec.).49.55(sec.)213.31 (quat.)
(Assignments from DEPT).
Photooxygenation of Sd to 9: A solution of S d (30 mg, 0.092 mmol) in dichloromethane (6 mL) was exposed to diffuse daylight for 10 hours in three N M R tubes.
After plate chromatographic purification on silica gel (dich1oromethane:ether =
80:20) orange crystals of 9 were obtained from the fraction of medium polarity.
(22 mg, 70%): M p. 192-C (decomp.): (ref. [I]for (+)-rabelomycin: M.p. 193 "C
(decomp.). 'H NMR (400 MHr. CDCI,): 6 =1.49 (s; 3H. CH,). 2.95 (d,
OEt
Received: June 12, 1993
Revised: September I . 1993 [Z6138 IE]
German version: Angew Cheni. 1994. 106. 100
7
9
Scheme 2.
this mixture is not a disadvantage, since the ethyl ether can be
quantitatively converted into the phenol by treatment with aluminum trichloride. Under these conditions the Si-Si bond is
also cleaved, and after hydrolytic workup the silanol 8 c is obtained (76% over both steps). Alternatively, the Si-Si bond can
be cleaved under mild conditions with bromine.['4b1Silyl groups
with electronegative substituents can be oxidatively replaced
with hydroxyl groups.["b1 In this way 8c could be converted into the tertiary alcohol I-deoxyrabelomycin (8d, 78 YO)
by mild treatment with potassium fluoride and hydrogen
peroxide." 61
Due to the initially mentioned instability of the tertiary alcohol, the introduction of the oxygen at C1 of 8d was carried out
in the last step of the synthesis. The oxygenation of 8 d to give
rabelomycin 9 was successfully carried out in a new type of
photooxygenation, in which a dilute solution of 8 d was exposed
to daylight (70 YO).This photochemical introduction of oxygen
at the angular benzylic position at C1 to form labile P-hydroxyketones has already proved successful in the synthesis of angucyclin analogues.["1 This reaction will, in our opinion, be an
important step in future angucyclin syntheses, because base-catalyzed oxygenation["] of compounds with tertiary hydroxyl
groups such as 8 d invariably leads to decomposition.
[ l ] W.-C. Liu. W. L. Parker. D. S. Slusarchyk. G. L. Greenwood. S . F. Graham, E.
Meyers. J. Arifihiof. 1970. 23. 437-441.
[2] J. Rohr. R. Thiericke, N u t . Prod. Rep. 1992, 9. 103-137.
[3] H. Drautr. H. Zihner. J. Rohr. A. Zeeck, J. Antihiof. 1986. 39, 1657-1669.
[4] T. Oki. 0. Tenmyo. M. Hirano. K. Tomatsu, H. Kamai, J. Antihiot. 1990. 43.
763 -770.
[ 5 ] S. Kondo. S. Gomi. D. Ikeda, M. Hamada. T. Takeuchi, H. Iwai, J. Seki, H.
Hoshino, J. Antihior. 1991. 44. 1228-1236.
[6] K. Ohta, E. Mlzutd, H. Okazaki, T. Kishi, Cliern. Pharm. Bull. 1984,32,43504359.
[7] J. H. Wilton. D. C. Cheney, G . C . Hokanson. J. C . French, H. Cun-heng, J.
Clardy. J. Org. Cliem. 1985, 50. 3936- 3938.
[XI M. Yamaguchi, T.Okuma. A. Horiguchi. C. Ikeura, T. Minami, J Og.C/iem.
1992. 57. 1647-1649.
[9] a) A. Guingant, M. M. Barreto, Trtrahedron Lett. 1987, 28,3107-3110;b) K.
Kim, J. Reihenspies. G . Sulikowski, J. Org. Chem. 1992, 55, 5557-5559.
[I01 J. A. Vdlderrdma, R. Araya-Maturana, M. F. Gonaalez, R. Tapia, F. Fariiia.
M. C. Pdredes. J. Chrm. So<. Prrkin Trans. I 1991, 555-559.
1111 a) D. J. Ager, I . Fleming, J. Chem. Soc. Chem. Commun. 1978. 177-178: h) I.
Fleming, R. Henning. H. Plaud, ihid. 1984, 29-31.
[I21 W. C.Still. J. Org. Chrm. 1976, 41. 3063 -3064.
[I31 a) P. F.Hudrlik. M. A. Waugh, A. M.Hudrlik, J. Organornet. Chem. 1984,271,
69 -76;h) A. L.Allred, R. T. Smart. D. A. Van Beek, Orgunometallics 1992,11,
4225-4230.
[14] a) K . Krohn. P. Ritzenhoff. unpublished: h) G. Pilcher, M. L. P. LeitHo, Y
Meng-Yan, R. Walsh. J. CAem. Soc. Furaday Truns. 1991. 87.841 -846.
[15] We thank Prof. H. Marsmdnn (Universitit-GesamthochschulePaderhorn), for
recording the 29Si NMR spectra
[I61 T. H. Chan. K. T. Nwe, J. Org. C/iem. 1992,57, 6107-6111.
[I71 K. Krohn, F. Ballwanz. W. Baltus. Lrehigs Ann. Cliem. 1993, 911 -913.
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