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Asymmetric Total Synthesis of the Macrolides Brefeldin A and 7-epi-Brefeldin A.

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14
R
=
THP
a: X
= OMEM, Y =
H;b: Y
= OMEM, X = H
R = H ; b : Y = OH, X = H, R = H). The configurations of
17a and 17b (4 : 1) were assigned by conversion into 2 and
4-epi-2 (4 :
respectively.
Received: September 26, 1983 [Z 570 IE]
German version: Angew. Chem. 96 (1984) 142
CAS Registry numbers:
2, 83710-00-3; 4-epi-2, 88586-99-6; 8, 72036-30-7; 9a, 2043-61-0; 9b, 1000979-7; 9c, 638-66-4; (f)-10a (RZ=H), 88525-82-0; ( + ) - l o p (R2=Li), 8852585-3; (+)-lob, 88525-83-1; (+)-lOc, 88525-84-2; ( k ) - l l a , 88525-86-4; l l b ,
88525-87-5; (*)-llc, 88525-88-6; ( k ) - l l d , 88525-89-7; (*)-lie, 88525-900; ( + ) - l l f , 88525-91-1; (+)-12a, 88525-92-2; (R*,S*)-(i)-lZb, 88525-93-3;
(R*,R*)-(k)-lZb, 88526-04-9; (k)-12c, 88525-94-4; (*)-12d, 88525-95-5;
(f)-12e, 88525-96-6; (*)-lZf, 88525-97-7; (+)-13a, 88525-98-8; (R*,S*)(+)-13b, 88525-99-9: (R*,R*)-( +)-13b, 88526-05-0; (*)-13c, 88526-00-5;
14, 88526-01-6; 15a, 88526-02-7; 15b, 88586-95-2; 16a, 88526-03-8; 16b,
88586-96-3: 17a, 88586-97-4; 17b, 88586-98-5; MEM-CI, 3970-21-6;
TBDMS-CI, 18162-48-6; Bz-CI, 98-88-4; LiSCzHS,30383-01-8
[l] a) H. P. Weber, D. Hauser, H. P. Sigg, Helv. Chim. Acta 54 (1971) 2763; b)
C. P. Gorst-Allman, P. S. Steyn, C. J. Rabie, J. Chem. SOC.Perkin Trans. 1
1982, 2387; c) R. Amstutz, E. Hungerbiihler, D. Seebach, Helu. Chim.
Acta 64 (1981) 1796; d) M. Binder, C. Tamm, Angew. Chem. 85 (1973)
369; Angew. Chem. Int. Ed. Engl. 12 (1973) 370.
[2] Indirect methods: H. J. Bestmann, F. Seng, H. Schulz, Chem. Ber. 96
(1963) 465; H. J. Bestmann, G. Graf, H. Hartung, Justus Liebigs Ann.
Chem. 706 (1967) 68, see also: M. Honda, K. Hirata, H. Sueoka, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 22 (1981) 2679; E. W. Colvin, T. A.
Purcell, R. A. Raphael, J. Chem. Soc. Perkin Trans. I 1976, 1718; P. A.
Bartlett, J. Am. Chem. Soc. 98 (1976) 3305; P. A. Bartlett, F. R. Green,
ibid. 100 (1978) 4858.
131 P. Bakuzis, M. L. F. Bakuzis, T. F. Weingartner, Tetrahedron Lett. 1978,
2371; T. Kitahara, K. Mori, M. Matsui, ibid. 1979, 3021.
[4] E. J. Corey, R. H. Wollenberg, Tetrahedron Lett. 1976, 4705.
[5] H.-J. Gais, T. Lied, Angew. Chem. 96 (1984) 143; Angew. Chem. Int. Ed.
Engl. 23 (1984) 145.
[6] K. Yamada, N. Miyaura, M. Itoh, A. Suzuki, Synthesis 1977, 679.
171 Cf. also: a) E. J. Corey, C. U. Kim, R. H. K. Chen, M. Takeda, J. Am.
Chem. SOC.94 (1972) 4395; b) J. L. Herrmann, M. H. Berger, R. H.
Schlessinger, ibid. I01 (1979) 1544; c) M. M. Midland, A. Tramontano, J.
R. Cable, J. Org. Chem. 45 (1980) 28.
[8] C. E. Castro, R. D. Stephens, J. Am. Chem. Soc. 86 (1964) 4359.
[9] Hydrogenation of 4-hydroxy-2-alkynoic acids: A. A. Jakubowski, F. S.
Guziec, Jr., M. Tishler, Tetrahedron Lett. 1977, 2399; see also [7b].
of interesting biological activity, the macrolides brefeldin
A l[la,bl
and 7-epi-brefeldin A 2[Ic1,biosynthesized by Curuularia lunata, are attractive target molecules for chemical
synthesis['d1.In 1981 we prepared the intermediate 7-epi-14
(tBuMe,Si for THP)['], formally the first asymmetric total
synthesis of 1[3a3b1;
later, a second asymmetric total synthesis was described"d1. Here, we report a novel asymmetric
total synthesis of 1 and the first of 2, in which we employ
new methods for the stereoselective construction of the
C1-C4 structure element and for the macrolactonization.
Our synthetic strategy can be deduced from the synthons
1-111 ; in their connection sequence, the corresponding
building blocks are the cyclopentanolactone 3b, the lithiosulfone 5d, and the lithiopropiolate 4 (Scheme 1).
OH
OH
X-SCH,
d3@c0,~
I1
H 0 U a 4
'%,/
10
1
. 0
?
,',
'
1 , x = HO',,,,,
H.
2 , x = H,,,.,
H04
d''
dCH3
I11
,,,,q
,
I
1 i - C -C-C02Et
4
OTHP
3b
P
h
0
2
s
h
CH3
5d
Scheme 1. MEM = (2-methoxyethoxy)methyl, THP= 2-tetrahydropyranyl.
The synthesis of the cyclopentanoid building block 3b
commences with the cleavage of the p-keto ester 6 (299%
ee)["l to afford the bicyclic ketone 7[5a1
(96%)[61,
which after
catalytic hydrogenation yields the p-alcohol 3a[5b1(97%,
98% ds), and which is subsequently protected as the MEM
ether 3bc5'](91%, 299% ee) (Scheme 2).
Regioselective ring-opening of (S)-propylene oxide 8
(97% ee)"] with the organolithium compound 9 ( E E = l ethoxyethyl)[81leads via the alcohol
and the sulfide
lOd['"] to the sulfone 5cr5'] (50% overall yield, 97% ee)['l
(Scheme 2).
b)
--+
ROO
3a, H = H
3b, R = M E M
Asymmetric Total Synthesis of the Macrolides
Brefeldin A and 7-epi-Brefeldin A**
By Hans-Joachim Gais* and Thomas Lied
Because of their interesting structures, which resemble
those of the prostaglandins, and unusually broad spectrum
?CHZPh
X dCH3
10a, X = OEE
lob, X
I*]Priv.-Doz. Dr. H.-J. Gais, Dr. T. Lied ['I
Institut fur Organische Chemie und Biochemie
der Technischen Hochschule
Petersenstrasse 22, D-6100 Darmstadt (FRG)
['I Present address: Degussa AG, D-6450 Hanau (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie. We thank Dr. A . von Wartburg,
Sandoz AG, Basel, for a sample of brefeldin A from Penicillium brefeldianum and Dr. C. P. Gorst-Allman, NCRL, Pretoria, for a sample of 7epi-brefeldin A from Curvularia lunata.
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 2
-
X
OR
h)
'LlOc, X
l'h02S
= OH
= OTs
Scheme 2. a) MeZNCHO, H20, NaCI, 120°C. b) H2, Pd/C, MeC02Me. c)
MEM-CI, CH2C12,EtN(iPr)2. d) Tetrahydrofuran (THF), -30°C; PhCHzBr.
e) Ha, H20. f ) TsCI, pyridine. g) LiSPh, THF, 25°C. h) m-CI-C6H4-C03H,
CHCI,, - 10°C. i) HZ, Pd/C, MeOH. j) Dihydropyran, H". k) nBuLi, THF,
-78°C.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0202-0145 $02.50/0
145
The C4-C10 building block 3b is linked smoothly in
three steps to the Cll-C16 building block with the correct
configuration at C9: ring-opening of the lactone 3b with
the lithiosulfone 5d to give the dilithio compound 11 and
chemoselective benzoylation; the initially formed (9s)keto sulfone 12a is isomerized to the more stable (9R)-keto
sulfone 12b[5g1( l 3 0 : l ) (Scheme 3). 12b (90% overall
(94%),
yield) is converted into the enol phosphate 13[5h1
which was reduced to the (@-alkene 14I5'] (76%)"" with
concomitant release of the hydroxymethyl function, Oxidation of the alcohol 14 to the aldehyde 1Fir5j1(87%) completes the requirements for the coupling of the still absent
Cl-C3 structure element. A novel, potent method for
this["l starts with the re-selective addition of 4 to 15,
3b
77
5d
PhOzS
( 9 s ) - 12a
11
(9R)-12b
which affords, via the alkynes 16[5k1
(90%, 80% ds) and the
(2)-alkenes 17[511(92%), the (@-alkenes 18[5m1
(91%). Saponification of 18 leads to the seco-acids 19'5n1(949/0),
which were lactonized using a novel, efficient method"']:
chernoselective reaction of 19 with the "push-pull" alkyne
20[131to give the stable enol esters 2lC5O1
(96%) and their
H@-catalyzed cyclization to the macrolides 22[5p1(74%)
(Scheme 3). These are cleaved to furnish 2 and 4-epi-2
(4 : 1, 83%), which are separated readily by chromatography. Inversion of the configuration at C 7 of 2a, prepared
by selective acylation of 2["], according to Mits~nobu"~],
and cleavage of the diacetate l b thus obtained lead to 1.
Similarly, the synthesis of 2 from 1 can be carried out via
la['" and 2b['"l. The flexibility of this synthetic strategy for
1 and 2 permits use of the equally readily accessible ent3bL4Ias educt instead of 3b, and now with the inversion of
configuration 5,7-epi-15 -+7-epi-15 leads primarily to 1.
The macrolides brefeldin A 1 [m.p.=203"C, [a]g +92.1
(0.25, MeOH)] and 7-epi-brefeldin A 2 [m.p.= 121-123"C,
[a] + 109.6 (0.19, MeOH)] thus obtained are indistinguishable both chromatographically and spectroscopically (300
MHz 'H-NMR) from 1 obtained from Penicillium brefeldianum and 2 from Curvularia lunata.
Received: October 26, 1983;
revised: December 1, 1983 [Z 603 IE]
German version: Angew. Chem. 95 (1984) 143
PhOzS4
14, R = CHzOH
OTHP
U
15, R
C H3
= CHO
13
X
X
''
16a, b, R = - C - C - C 0 2 E t
h)
17a, b, R = - C H = C H - C O z E t
1)
18a, b, R
1)
b, R
'19a,
= -CH=CH-C02Et
= -CH=CH-C02H
22a, b
(z)
(E)
(E)
L 2 1 a . b, R = -€H=CH-COz<(Me)=CH<ONMe2
MEMO,
b,X =
%
"'
a, X =
H
%
',
Me2N-C -C-C 0-Me
20
MEMO'
H'
(E,Z)
QR3
R'
2 ' , R'
" ,2 a~
, R'
l.z
"LI b ,
= OH,
4- epi - 2
R2 = R3 = H
= OH, R2 = H , R3 = Ac
R' = H , R 2 = OAc, R3 = Ac
1 , R' = R3
n)Ll a , R'
Zb, R'
= H,
R2 = OH
= H , R 2 = OH, R3 = Ac
=
OAc, R 2 = H , R3
=
Ac
Scheme 3. a) LiN(SiMe3)z,THF, -78"C--2OoC.
b) PhCOC1; MeC02H,
CH2C12,0°C. d) CI-PO(OPh)2,
0°C. c) 1,8-Diazabicyclo[5.4.0]undec-7-ene,
MeCN, NEt,, 4-dimethylaminopyridine. e) Na, NH3, -78°C. f ) Pyridinium
chlorochromate, CHZCIz,0°C. g) 4, THF, -78°C; MEM-C1, -78°C-0°C;
MeOH, H". h) H2, Pd/BaSOa, quinoline, MeOH. i) LiSEt, THF, 30°C; 0.1 N
HC1,O"C. j) LiOH, MeOH; 0.1 N HC1,O"C. k) 20, THF, 0°C. 1) 5 mol-% 10camphersulfonic acid, PhMe, 8O"C, dilution. m) TiCl,, CH2C1,O"C. n) Ac20,
pyridine. 0) Ph3P, diethyl azodicarboxylate, MeC02H,THF, 0°C. p) MeOH,
KzCO3, 0°C.
146
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
CAS Registry numbers:
1, 20350-15-6; la, 83710-02-5; lb, 29129-37-1; 2, 83710-00-3; 4-epi-2,
88586-99-6; 2a, 83692-17-5;2b, 83710-01-4;3a, 88587-00-2; 36, 88526-06-1;
4, 72036-30-7; Sa, 88526-07-2; Sb, 88526-08-3; Sc, 88526-09-4; Sd, 8852610-7; 6, 88526-11-8; 7, 88587-01-3; 8, 16088-62-3; 9, 37494-03-4; 10a,
88526-12-9; lob, 88526-13-0; ~ O C ,88526-14-1; 10d, 88526-15-2; 11, 8852616-3; 12a, 88526-17-4; 12b, 88587-02-4; 13, 88526-18-5; 14, 88526-19-6; 15,
88526-01-6; 16a, 88526-20-9; 16b, 88587-03-5; 17a, 88526-21-0; 17b, 8858704-6; 18a, 88587-05-7; 18b, 88587-06-8; 19a, 88587-07-9; 19b, 88587-08-0;
20, 20568-22-3; 21a, 88588-18-5; 21b, 88526-22-1; ZZa, 88587-09-1; 22b,
88588-19-6
[I] a) E. Harri, W. Loeffler, H. P. Sigg, C. Tamm, Helu. Chim. Acfa 46 (1963)
1235; h) C. T. Mabuni, L. Garlaschelli, R. A. Ellison, C. R. Hutchinton,
J. Am. Chem. SOC.101 (1979) 707; c) C. P. Gorst-Allman, P. S. Steyn, C.
J. Rabie, J. Chem. SOC.Perkin Truns. I 1982, 2387; d) C. Le Drian, A. E.
Greene, J. Am. Chem. SOC.104 (1982) 5473 and previously described total syntheses of racemic hrefeldin A 1 reported there.
[2] T. Kitahara, K. Mori, M. Matsui, Tetrahedron Left. 1979, 3021.
[31 a) H.-J. Gais, T. Lied, K. L. Lukas, unpublished; paper presented at the
Chemiedozententagung, Tiibingen, March 1981; b) H.-J. Gais, Hubilifationsschrift, Technische Hochschule Darmstadt 1981.
141 HA. Gais, K. L. Lukas, Angew. Chem. 96 (1984) 140; Angew. Chem. Int.
Ed. Engl. 23 (1984) 142.
[5] a) M.p.=84"C, [a]g -67.8 (c=2.59, CH2CI2); b) m.p.=7l0C, [a]$
+61.2 (2.64, CHZCl2);c) m.p.=48"C, [a]b +21.1 (1.86, CH2C12);d)
[a]% +26.5 (1.00, CHCI3); e) [a]? f18.9 (2.86, CH2ClZ);f ) [a]g +7.7
(3.90, EtOH); g) [a]% -13.5 (1.00, CHzC12); h) [a]$ -12.5 (1.70,
CH2C12); i) [a]? - 11.1 (1.02, CHzC12);j) [a]$ -25.9 (1.29, CHzC12);k)
[a]g -6.1 (1.73, ethyl acetate) for a : b=4:1; 1) [a]$-11.8 (1.62, ethyl
acetate) for a : b = 4 : 1 ; m) [a]$ -31.9 (1.82, ethyl acetate) for
a : b = 4 : 1 ; n) [a]? -27.8 (1.88, THF) for a : b = 4 : 1 ; 0) [a]g -28.7
(2.00, CH2C12) for a : b = 4 : 1; p) [a]$ +8.6 (1.19, ethyl acetate) for
a:b=4:1.
[6] Enantioselective, enzymatic oxidation of cis-1,4-dioxaspiro[4,4]nonane7,8-dimethanol, readily accessible from meso-tetrahydrophthalic anhydride, with HLADH/NAD"/FMN affords 7 in 60% chemical yield and
45% ee [3b].
[7] B. Seuring, D. Seebach, Helu Chim. Acfa 60 (1977) 1175.
[S] P. E. Eaton, G. F. Cooper, R. C. Johnson, R. H. Mueller, J. Org. Chem.
37 (1972) 1947.
[9] Synthesis of 5e from (S)-ethyl-3-hydroxybutanoate:T. Lied, Dissertation, Technische Hochschule Darmstadt 1983; from D-Glutamic acid:
[3hl.
[lo] Cf. also: P. A. Bartlett, F. R. Green, J. Am. Chem. SOC.100 (1980) 7583;
B. Lythgoe, I. Waterhouse, J. Chem. SOC.Perkin Trans. 11979, 242.
Ill] H.-J. Gais, Angew. Chem. 96 (1984) 142; Angew. Chem. Inf. Ed. Engl. 23
(1984) 143.
[12] H.-J. Gais, Tetrahedron Left. 25 (1984) 273.
[I31 H.-J. Gais, T. Lied, Angew. Chem. 90 (1978) 283; Angew. Chem. Znt. Ed.
Engl. 17 (1978) 267 and literature cited therein.
[14] 0. Mitsunobu, Synthesis 1981, 1.
0570-0833/84/0202-0146 $02.50/0
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 2
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