Efficient method for introducing vineomycin-fridamycin-type side chain. Total synthesis of fridamycin E

Article abstract of DOI:10.1016/S0040-4039(00)93439-7

An effective approach for introducing vineomycin-fridamycin-type side chain was developed. Tin-lithium exchange of arylstannane 5 followed by the reaction with chiral aldehyde 6 gave the desired adduct 7. Total synthesis of (R)-(+)-fridamycin E was accomplished.

Full text of DOI:10.1016/S0040-4039(00)93439-7

Tetrahedron Letters, Vol.32, No.38, pp5103-5106, 1991
Printed ~n Great Britain
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E f f i c i e n t M e t h o d for I n t r o d u c i n g Vineomycin-Fridamycin-Type Side C h a i n .
T o t a l S y n t h e s i s of F r i d a m y c i n E
Takashi Matsumoto, Hideki Jona, Miyoko Katsuki, and Keisuke Suzuki*
Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223, Japan
Summary: An effective approach for introducing vineornycin-fridarnycin-type side chain was
developed. Tin-lithium exchange ofarylstannane 5followed by the reaction with chiral aldehyde 6
gave the desired adduct 7. Total synthesis of (R)-(+)-fridamycin E was accomplished.
Vineomycinl)-fridamycin2) antibiotics constitute a novel class of antitumor compounds with synthetically
attractive structures: Three dissimilar components, i.e., the anthraquinone, the C-glycosidated sugar, and the
characteristic aliphatic side chain, are connected together through two C-C bonds (A and B, Figure 1). For
the formation of aryl C-glycoside bond A, we developed a new method which proved to be effective in
synthesizing the C-glycoside sector of these compounds.3) In order to accomplish the total synthesis, we
elected to investigate the approach for forming the bond B, that is, the connection of the chiral, non-racemic
side chain to the aromatic moiety in regioselective manner.
In this communication, we wish to report an effective approach for the side chain connection and its
successful application to the total synthesis of (R)-(+)-fridamycin E (1), one of the components of fridamycin
antibiotics lacking the C-glycoside portion.4, 5)
Figure 1
O
OH B
Fridamycin E (1)
R = H
Me
0
R , , A t t t ~ ~ , ~ Me OH cO2H
FridarnycinA (2)
R=
I
~
~
(---Vineomycinone B2)
HO
O
Fddamycin B 0)
R =
HMeO ~
HO
MOM-Ether 4, prepared from 1,5-dihydroxy-9,10-anthraquinone (anthrarufin) in 4 steps,3b) was treated
with t-BuOK - n-BuLi (2.0 equiv, each / THF / -78 °C) for 10 min to effect the regioselective ortho-metallation
at C(2).6,7) Since excess base was required to complete the metallation, it was impractical to use this
metallation mixture for the reaction with the electrophilic partner. Therefore, the reaction was once quenched
with Me3SnC1 to afford arylstannane 5 in 86% yield.8) It should be noted here that use of the magic base was
5103

5104
essential for the clean ortho-metallation, since the conventional conditions (e.g. n-BuLi-TMEDA)9) were totally
ineffective for this purpose.7)
MeO
OMOM
MeO
OMOM
SnMe3
2
2) Me3SnCI
THF, -78°C
MeO
OMe
MeO
OMe
4
5
Arylstannane 5, thus obtained, served as an equivalent of nucleophilic anthraquinone derivative. Tin-
lithium exchange of 5 was carried out in toluene by adding MeLi (-78 --~ 0 °C)10) and subsequent reaction
with (S)-aldehyde 611) at 0 °C for 15 min afforded the adduct 7 as a mixture of diastereomers. After
benzoylation of 7, the resulting anthracene 8 was oxidized with cerium(IV) ammonium nitrate to give the
corresponding anthraquinone, the crude product of which was further subjected to acidic conditions to give 9.
Oxidative removal of the benzyl group was then effected by treatment with DDQ in two-phase system
(CH2C12 - H20) 12) to afford tert-alcohol 10. At this stage the two diastereomers were easily separated with
silica-gel chromatography to give the less polar isomer 10a (Rf: 0.40, CHC13 / Et20 = 9/1) and the more polar
isomer 10b (Rf: 0.30).
Double bond of 10a was cleaved with ozone (MeOH / -78 °C) and subsequent treatment with acetic
anhydride and triethylamine gave methyl ester lla in 71% yield. 13) Similarly, 10b was converted to the
diastereomeric ester lib in 75% yield. Configurational assignment of these diastereomers was not attempted.
Catalytic hydrogenation of 11 with Lindlar catalyst in the presence of HUnig base in ethyl acetate quickly
gave the desired methylene compound 12 in excellent yield from each diastereomers, l l a and lib. The
reaction proceeds most probably via the initial formation of the corresponding hydroquinone followed by the
1,6-elimination of the benzoyloxy group. 14) Other catalysts such as 10% Pd-C gave lower yield of 12 along
with undefined over-reduction products. Treatment of 12 with boron tribromide effected clean deprotection of
methyl ether to give triol 13.15) Finally, hydrolysis of methyl ester with t-BuOK - H20 in 1,4-dioxane 16)
cleanly furnished fridamycin E (I) as a yellow solid in 86% yield after recrystallization from methanol. All the
physical data were in agreement with those reported.2,17)
In summary, an effective approach for introducing vineomycin-fridamycin-type side chain was
developed, which was applied to the total synthesis of fridamycin E. Total synthesis of vineomycins will be
reported elsewhere.

5105
Scheme 17)
MeO
OR
OR'
MeO
OMOM
SnMe3
MeLi / THF, -78---)0 °C
r
~
then O H C ~ # ,
MeO
OMe
MeO
OMe
Me_~.OBn
6
7
8
R
R
=
MOM, R ' =
MOM, R'
H
Bz ~"
~
(92%)
O
OH OBz
O
OH OBz
b)C)
99%
~
~ ~
e) f)
C02Me
~
(2 steps)
MeO
O
MeO
O
9
10
R = B n
g
11a 71% (2 steps)
11b 75% (2 steps)
H ~"~'~d'
(10a 51"/o, 10b 47%)
O
O
OH
g)
CO2R
92% from 11a
96% from 1 lb
RO
12
R = R' - Me
-
•
h) (81%)
13
1
R
H, R'
= M e ~ i) (87%)
R = R ' = H
Keys: a) BzCI, DMAP / Pyr, 10 hr; b) CAN / MeCN-H20, -20 °C -~ rt, 15 min; c) 3 N HCI / dioxane,
rt, 4 hr; d) DDQ / CH2C12 - H20, rt, 22 hr; e) 03 / CH2Cl2 - MeOH, -78 °C; f) Ac20, Et3N / CH2Cl2,
0 °C, 1 hr; g) H2, Pd-CaCO3, ipr2NEt / EtOAc, rt, 5 min; h) BBr3 / CH2C12, -78 ---) -20 °C, 40 min; i)
t-BuOK - H20 / dioxane, rt, 10 hr.
Acknowledgments: Financial support from the Ministry of Education, Science and Culture of
Japan [Grant-in-aid for Scientific Research on Priority Area (No. 02231228)] is deeply acknowledged. The
authors thank Professor A. Zeeck, University of G6ttingen, for sending us the unpublished data. 2)

5106
References and Notes
1) S. Omura, H. Tanaka, R. Oiwa, J. Awaya, R. Masuma, K. Tanaka, J. Antibiot., 30, 908 (1977); N.
Imamura, K. Kakinuma, N. Ikekawa, H. Tanaka, S. Omura, J. Antibiot., 34, 1517 (1981).
2) P. Kricke, Ph.D. Thesis, University G6ttingen 1984.
3) a) T. Matsumoto, M. Katsuki, K. Suzuki, Tetrahedron Lett., 29, 6935 (1988); b) T. Matsumoto, M.
Katsuki, H. Jona, K. Suzuki, ibid., 30, 6185 (1989).
4) The antibiotic activity against Gram-positive bacteria of fridamycin E is stronger than the other
components with C-glycoside structures. See ref. 2.
5) Total synthesis of the enantiomer of I was reported: K. Krohn, W. Baltus, Tetrahedron, 44, 49 (1988).
6) M. Schlosser, Pure Appl. Chem., 60, 1627 (1988); M. Schlosser, J. Organomet. Chem., 8, 9 (1967);
L. Lochmann, J. Pospisil, D. Lim, Tetrahedron Lett., 1966, 257.
7) Use of two equivalents of both bases is essential for the completion of the metallation, s~ T. Matsumoto,
H. Kakigi, K. Suzuki, Tetrahedron Letters, in press.
8) All new compounds were fully characterized by 1H NMR (400 MHz), IR, and HRMS.
9)
H.W. Gschwend, H. R. Rodriguez, Org. React., 26, 1 (1979).
10) For the successful tin-lithium exchange, use of toluene as the solvent was essential, since the alkyl anion
attacked the C(9)/C(10)-position in ether or THF. MeLi gave better results than BuLi.
11) (S)-Aldehyde 6 was prepared from (S)-acid 14, which is available in optically pure form. Tr~Sugai, H.
Kakeya, H. Ohta, J. Org. Chem., 55, 4643 (1990).
~ ¢
H02C*~Ia~
Mt~'OBn
14
l) LAH lEt2O, 0 °C (99%)
2) Swem Oxidn. (96%)
OHC~..~.~
~ " ~
~
Me41r~OBnv
. /
6
12) K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemitsu, Tetrahedron, 42, 3021 (1986).
13) R.E. Claus, S. L. Schreiber in Organic Synthesis, A. S. Kende, Ed., Wiley: N. Y., 64, 150 (1985).
14) Use of sodium dithionite turned out to be less effective in terms of reproducibility in this case. Cf. K.
Krohn, Tetrahedron, 46, 291 (1990).
15) 13:[c¢]28D -12° (c 0.80, CHC13); 1H NMR 8 (CDC13) 13.18 (s, 1H), 12.67 (s, 1H), 7.84 (dd, 1H, J
7.7, J2 = 1.0 Hz), 7.81 (d, 1H, J = 7.7 Hz), 7.70 (d, 1H, J = 7.7 Hz), 7.68 (dd, 1H, J1 = 8.1, J2 =
7.7 Hz), 7.32 (dd, 1H, J1 = 8.1, J2 = 1.0 Hz), 3.8 - 4.0 (br, 1H), 3.72 (s, 3H), 3.10 (d, 1H, J = 13.7
Hz), 3.04 (d, 1H, J = 13.7 Hz), 2.59 (d, 1H, J = 16.2 Hz), 2.55 (d, 1H, J = 16.2 Hz), 1.31 (s, 3H);
13C NMR 8 (CDC13) 188.3, 187.8, 173.3, 162.7, 161.4, 139.7, 136.6, 134.6, 133.2, 131.8, 125.0,
119.4, 118.9, 116.1, 115.6, 71.8, 51.7, 44.4, 40.5, 27.3; IR (neat) 3540, 2970, 1730, 1630, 1600,
1580, 1430, 1375, 1320, 1260, 1080, 790 cm-1; HRMS m/z 352.0976 (352.0946 calcd for C20H1606,
M+-H20).
16) P.G. Gassman, W. N. Schenk, J. Org. Chem., 42, 918 (1977).
17) 1:[(x]27D +8.9° (c 1.1, dioxane); mp. 164-165 °C (methanol); 1H NMR 8 (d6-DMSO) 12.8 - 13.2 (br,
1H), 12.5 (s, 1H), 11.8 - 12.3 (br, 1H), 7.84 (dd, 1H, J1 = 8.1, J2 = 7.7 Hz), 7.83 (d, 1H, J = 7.9
Hz), 7.78 (dd, 1H, J1 = 7.7, J2 = 1.3 Hz), 7.73 (d, 1H, J = 7.9 Hz), 7.42 (dd, 1H, J1 = 8.1, J2 = 1.3
Hz), 3.08 (d, 1H, J = 13.1 Hz), 2.90 (d, 1H, J = 13.1 Hz), 2.41 (s, 2H), 1.19 (s, 3H); 13C NMR
(d8-dioxane) 189.2, 188.7, 173.8, 163.1, 161.8, 140.2, 137.0, 135.5, 134.4, 132.6, 125.0, 119.3,
118.8, 117.2, 116.4, 71.9, 45.2, 40.7, 27.1; IR (KBr) 3440, 2940, 1700, 1630, 1605, 1580, 1430,
1375, 1315, 1270, 790 cm-1; HRMS m/z 357.0973 (357.0973 calcd for C19H1707, M++I).
(Received in Japan 16 May 1991; accepted 17 June 1991)