Total synthesis of rutamycin B via Suzuki macrocyclization

Article abstract of DOI:10.1039/a707251a

The macrolide rutamycin B containing 17 stereogenic centres and a 26-membered ring was synthesized by a route which features a chelate-controlled, double differentiating aldol reaction and ring closure by means of a vinyl-vinyl coupling.

Full text of DOI:10.1039/a707251a

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Total synthesis of rutamycin B via Suzuki macrocyclization
James D. White,* Thomas Tiller, Yoshihiro Ohba, Warren J. Porter, Randy W. Jackson, Shan Wang, and
Roger Hanselmann
Department of Chemistry, Oregon State University, Corvallis, OR 97331-4003, USA
The macrolide rutamycin B containing 17 stereogenic
centres and a 26-membered ring was synthesized by a route
which features a chelate-controlled, double differentiating
aldol reaction and ring closure by means of a vinyl–vinyl
coupling.
Coupling of the (Z)-chlorotitanium enolate9 of 12 and 17
gave the syn,syn (Felkin) aldol product 28 as the sole
stereoisomer (Scheme 3).10 A rationale for this high stereo-
selectivity invoking secondary complexation of the aldehyde
carbonyl with the PMB ether has been suggested previously,7
and it is noteworthy that the aldol reaction of 12 with 27 is
completely nonstereoselective when the PMB group of 12 is
replaced by a Et3Si ether. Thus, it appears that the PMB ether
not only obstructs the anti-Felkin pathway in this coupling, but
Rutamycins A and B are structurally complex macrolide
antibiotics isolated from Streptomyces species.1 A total synthe-
sis of rutamycin B (1) by Evans2 confirmed the structural
assignment,3 and the absolute configuration of 1 was deduced
from synthesis of the spiroketal segment obtained by degrada-
tion of the rutamycins.4 Herein, we report a convergent
synthesis of rutamycin B in which the 26-membered ring is
closed by means of a Suzuki macrocyclization.
R1O
OR3
O
O
OR2
8
OH
9
OH
O
OH
O
16
17
2 R1 = R2 = R3 = H
i
O
18
3 R1 = SiMe2But, R2 = R3 = H
4 R1 = R2 = SiMe2But, R3 = H
5 R1 = R2 = SiMe2But, R3 = Bz
19
1
ii
O
iii
iv
25
O
6 R1 = H, R2 = SiMe2But, R3 = Bz
O
OH
v
X
1
OR
O
Selective silylation of triol 25 took advantage of the different
steric environments of the three hydroxy groups in this structure
and was accomplished by reaction with ButMe2SiCl, which
gave 3, and then by treatment with ButMe2SiOSO2CF3 to yield
4 (Scheme 1). The remaining secondary alcohol was converted
to its benzoate 5, and the primary silyl ether was selectively
removed by treatment with HF·pyridine complex. The resultant
primary alcohol 6 was oxidized to aldehyde 7, which was
subjected to a Takai reaction6 with CHI3 in the presence of
CrCl2 to yield trans iodo alkene 8. After saponification of the
benzoate, the liberated alcohol 9 was reacted with diethoxy-
phosphorylacetyl chloride to give 10. Horner–Emmons con-
densation of the lithio anion of 10 with keto aldehyde 11,
previously prepared from methyl (2R)-3-hydroxy-2-methylpro-
pionate,7 afforded a,b-unsaturated ester 12.
O
OSiMe2But
7 R = Bz, X = O
vi
8 R = Bz, X = CHI (E)
9 R = H, X = CHI (E)
vii
viii
10 R = C(O)CH2P(O)(OEt)2, X = CHI (E)
OSiMe2But
O
O
I
O
O
O
Synthesis of the C9–C16 segment 26 of 1 was initiated by
asymmetric crotylation of (R)-13 with (E)-crotylboronate 14
derived from (S,S)-tartrate (Scheme 2).8 The alcohol 15
resulting from re face addition to the aldehyde was converted to
the bis(silyl ether) 16, and the primary ether was selectively
cleaved to give 17. The tosylate 18 of this alcohol was displaced
with cyanide and the resultant nitrile 19 was reduced to 20 and
then to alcohol 21. The latter was converted to its bis(silyl ether)
22 before ozonolysis to 23. The reaction of 23 with
(E)-crotylboronate 24 derived from (R,R)-tartrate8 afforded
alcohol 25 with good stereoselectivity ( > 95:5) in this matched
(Felkin) addition to the si face of the aldehyde. Alcohol 25 was
protected as its p-methoxybenzyl (PMB) ether 26 and the latter
upon ozonolysis yielded 27.
O
OSiMe2But
O
11
OSiMe2But
12
Scheme 1 Reagents and conditions: i, ButMe2SiCl, pyridine, AgNO3, THF;
ii, ButMe2SiOSO2CF3, 2,6-lutidine, CH2Cl2, 278 °C, 66%; iii, BzCl, Et3N,
DMAP, CH2Cl2, 90%; iv, HF·pyridine, pyridine, 61%; v, (COCl)2, DMSO,
Et3N; CH2Cl2, 278 °C, 96%; vi, CHI3, CrCl2, THF, 0 °C, 76%; vii, LiOH,
MeOH–H2O–THF, ~ 100%; viii, (EtO)2(O)PCH2COCl, pyridine, DMAP,
82%; ix, LDA, THF, then 11, 278 ? 0 °C, 88%
Chem. Commun., 1998
79

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ButMe2SiO
H
R1O
X
OSiMe2But
i
v
OSiMe2But
O
O
O
O
O
OR2
I
X
SiMe2But
SiMe2But
O
13
15 R1 = SiMe2But, R2 = H
16 R1 = R2 = SiMe2But
17 R1 = H, R2 = SiMe2But
19 X = CN
ii
vi
20 X = CHO
iii
iv
i
O
30
18 R1 = Ts, R2 = SiMe2But
vii
O
O
OSiMe2But
X
X
ButMe2SiO
RO
x
ButMe2SiO
OR
OSiMe2But
31 X = OSiMe2But, H
32 X = OH, H
ii
iii
iv
25 R = H, X = CH2
26 R = PMB, X = CH2
27 R = PMB, X = O
21 R = H, X = CH2
xi
viii
ix
O
22 R = SiMe2But, X = CH2
23 R = SiMe2But, X = O
Cl2HC
B
xii
33 X = O
O
O
35 X =
CH
B
34
O
CO2Pri
O
CO2Pri
O
B
B
v
O
O
CO2Pri
CO2Pri
14
24
OSiMe2But
Scheme 2 Reagents and conditions: i, 14, 4 Å MS (powder), toluene,
278 °C, 86% (78% de); ii, ButMe2SiOSO2CF3, Et3N, CH2Cl2, 99%; iii,
NH4F, MeOH, heat, 85%; iv, TsCl, pyridine, 92%; v, NaCN, DMSO, 94%;
vi, DIBAL-H, toluene, 278 °C, 75%; vii, NaBH4, PriOH, 0 °C, 87%; viii,
ButMe2SiCl, imidazole, DMF, 96%; ix, O3, CH2Cl2–MeOH, 278 °C,
Me2S, 94%; x, 24, 4 Å MS (powder), toluene, 278 °C, 78% ( > 98% de); xi,
PMBOC(NNH)CCl3, CF3SO3H, 210 °C, 68%; xii, O3, MeOH–CH2Cl2,
79%
O
O
O
O
SiMe2But
SiMe2But
O
iv
O
1
O
O
OSiMe2But
plays a positive role by favouring attack at the re face of the
aldehyde carbonyl by the si face of the titanium enolate.
b-Hydroxy ketone 28 was converted to its silyl ether 29, and
the PMB ether was cleaved to give 30, which was immediately
oxidized to 31 (Scheme 4). The primary silyl ether was
selectively removed from 31 and the resultant alcohol 32 was
oxidized to 33. Condensation of 33 with the dichlorome-
thylboronic ester 3411 of pinacol in the presence of CrCl2 and
LiI afforded (E)-vinyl boronate 3512 which was subjected to
palladium-catalysed intramolecular coupling13 in the presence
of Ag2O14 and AsPh3. The ensuing macrocyclization proceeded
in good yield and furnished the tetrasilyl ether 36 of rutamycin
B, identical in all respects with a sample prepared from the
natural material by exhaustive silylation with ButMe2SiO-
SO2CF3. Final cleavage of the four ButMe2Si ethers from 36 by
sequential addition of aq. HF in pyridine gave 1, identical with
natural rutamycin B.
36
Scheme 4 Reagents and conditions: i, Dess–Martin periodinane, 93% from
29; ii, HF·pyridine, MeCN–H2O–CHCl3, 79%; iii, Dess–Martin period-
inane, 95%; iv, 34, CrCl2, LiI, THF, 76%; v, Pd(MeCN)2Cl2, AsPh3, Ag2O,
THF, 70%; vi, aq. HF, pyridine, 4 d, 70%
fully acknowledged by T. T. (Fonds der Chemischen Industrie,
Germany) and R. W. J. (US NIH GM16472).
Footnote and References
* E-mail: whitej@ccmail.orst.edu
1 S. Omura, in Macrolide Antibiotics: Chemistry, Biology, and Practise,
ed. S. Omura, Academic Press, Orlando, Florida, 1984, p. 511.
2 D. A. Evans, H. P. Ng and D. L. Rieger, J. Am. Chem. Soc., 1993, 115,
11446.
3 D. Wulthier, W. Keller-Schierlein and B. Wahl, Helv. Chim. Acta, 1984,
67, 1208.
We thank Dr Herbert Kirst and Ms Margaret Niedenthal,
Eli Lilly Co., Indianapolis (USA) for a sample of natural
rutamycin B, and Professor David Evans (Harvard University)
for a generous quantity of a derivative of 2. This research was
supported by grants from the U.S. National Institutes of Health
(GM50574 and AI10964). Postdoctoral fellowships are grate-
4 D. A. Evans, D. L. Rieger, T. K. Jones and S. W. Kaldor, J. Org. Chem.,
1990, 55, 6260.
5 J. D. White, Y. Ohba, W. J. Porter and S. Wang, Tetrahedron Lett.,
1997, 38, 3167.
6 K. Takai, K. Nitta and K. Utimoto, J. Am. Chem. Soc., 1986, 108,
7408.
OSiMe2But
OR1 OR2
SiMe2But
O
O
7 J. D. White, W. J. Porter and T. Tiller, Synlett, 1993, 535.
8 W. R. Roush, A. D. Palkowitz and K. Ando, J. Am. Chem. Soc., 1990,
112, 6348.
9 D. A. Evans, D. L. Rieger, M. T. Bilodeau and F. Urpi, J. Am. Chem.
Soc., 1991, 113, 1047.
O
ButMe2SiO
I
O
i
12
10 For a similar result in a closely related aldol reaction, see D. A. Evans
and H. P. Ng, Tetrahedron Lett., 1993, 34, 2229.
11 P. M. G. Wuts and P. A. Thompson, J. Organomet. Chem., 1982, 234,
137.
12 K. Takai, N. Shinomiya, H. Kaihara, N. Yoshida and T. Moriwake,
Synlett, 1995, 963.
O
O
OSiMe2But
28 R1 = PMB, R2 = H
29 R1 = PMB, R2 = SiMe2But
30 R1 = H, R2 = SiMe2But
ii
iii
13 A. Suzuki, Pure Appl. Chem., 1994, 66, 213.
14 T. Gillmann and T. Weeber, Synlett, 1994, 649.
Scheme 3 Reagents and conditions: i, TiCl4, Pri2NEt, CH2Cl2, 278 °C, then
27, 52% ( > 98% de); ii, ButMe2SiOSO2CF3, Et3N, CH2Cl2, 0 °C, 86%; iii,
DDQ, H2O–CH2Cl2
Received in Cambridge, UK, 7th October 1997; 7/07251A
80
Chem. Commun., 1998