Asymmetric synthesis of the polyol portion of the polyene macrolide antibiotic RK-397

Article abstract of DOI:10.1055/s-2002-35584

A highly convergent and asymmetric synthesis of a fully functionalized polyol portion of the new polyene macrolide antibiotic RK-397 has been achieved taking advantage of a novel polyol synthesis.

Full text of DOI:10.1055/s-2002-35584

2098
LETTER
Asymmetric Synthesis of the Polyol Portion of the Polyene Macrolide
Antibiotic RK-397
A
symmetric Syn
hPolyol
P
i
ortion
o
s
f
the Poly
t
ene
M
o
a
crolide
A
nti
p
biotic RK-39
h
7
Schneider,* Frank Tolksdorf, Markus Rehfeuter
Institut für Organische Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)399660; E-mail: cschnei1@gwdg.de
Received 10 September 2002
to develop efficient and stereoselective syntheses of the
polyol fragments of the natural products in particular.5
Abstract: A highly convergent and asymmetric synthesis of a fully
functionalized polyol portion of the new polyene macrolide antibi-
otic RK-397 has been achieved taking advantage of a novel polyol
synthesis.
We report here a convergent asymmetric synthesis of a
fully functionalized polyol fragment 2 of RK-397 (1),
Key words: RK-397, polyene macrolide antibiotics, total synthe- which may be used in a total synthesis of the natural pro-
sis, aldol reaction, Cope rearrangement
duct and is also amenable to the synthesis of other stereo-
isomers. In order to make the synthesis as convergent as
possible the polyol fragment 2 was assembled from two
triol building blocks of similar complexity (7 and 8),
which in turn were derived from the same chiral key com-
pound.
The polyene macrolide antibiotic RK-397 (1) was isolated
in 1993 from a streptomyces strain collected from a soil
sample in Japan and was shown to display antitumor, an-
tibacterial, and antifungal activity in preliminary screen-
ing studies (Figure 1).1 The constitution of 1 was assigned
based upon extensive spectroscopic measurements and
was found to be identical to 14-demethyl mycoticin A.2
The relative and absolute configuration of 1 was only re-
cently established through degradation of the natural
product to furnish smaller subunits, which were analyzed
by special NMR methods and CD spectroscopy suggest-
ing that the stereogenic centers at C(19) and C(21) have
the opposite configuration compared to mycoticin A.3
Our point of departure was the chiral 7-oxo-5-phenyldi-
methylsilyl-2-enimide 4 which was easily obtained in
good yield and enantiopure state on a multigram-scale
using the silyloxy-Cope rearrangement of aldol product 3
(Scheme 1).6 This multifunctional compound does not
contain any hydroxyl group yet but carries suitable func-
tional groups in the required 1,3,5-orientation, which were
to be traded for secondary hydroxy groups in a straightfor-
ward manner. Furthermore, two of these Cope products
were intended to be used for the synthesis of the advanced
intermediates 7 and 8.
OH OH OH OH OH OH
Me3SiO
O
t-Bu
19
11
21
O
SiMe2Ph O
28
1. 170 °C
2. pTsOH
t-Bu
O
OH
OH
PhMe2Si
N
H
N
70-75%
O
O
O
O
O
O
4
3
1
OSiMe3
COXc
PhMe2Si
O
O
O
O
O
O
O
AcO
Scheme 1
OTBS
28
11
2
We have previously shown that the Cope product 4 may
be readily and stereoselectively converted to protected tri-
ols of any configuration.7 Reagent-controlled allylbora-
tion of the aldehyde moiety in 4 with subsequent
benzylation installed the first oxy substituent with either
configuration depending on the borane reagent used (e.g.
7 vs 8). Then auxiliary-directed conjugate addition of a
phenyldimethylsilyl cuprate reagent to the enimide moi-
ety and oxidative cleavage of the two carbon-silicon
bonds introduced the second and third hydroxy groups
with retention of configuration. These were protected as a
1,3-diol acetonide giving rise to the diastereomeric triol
esters 5 and 6, respectively (Scheme 2).
Figure 1
Some of the polyene macrolide antibiotics known to date
such as amphotericin B are used clinically for the treat-
ment of life-threatening fungal infections.4 However, se-
rious side effects on various organs continue to hamper
the application of these drugs. On the search for better an-
tifungal agents a great deal of effort has been undertaken
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2098,2100,ftx,en;G26902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Asymmetric Synthesis of the Polyol Portion of the Polyene Macrolide Antibiotic RK-397
2099
For the coupling of the two subunits 5 and 6 we took ad- product 9 in 65% yield and with 84:16 diastereoselectivity
vantage of their terminal double bond. Thus, a Wacker ox- (Scheme 3).10 Substantial amounts of the aldehyde and
idation furnished the methyl ketone 7 from 5 in good yield ketone components were, however, recovered and could
with only traces of the aldehyde being formed. Secondly, be used for the aldol reaction again. Attempts to increase
compound 6 was converted to the corresponding silyl the diastereoselectivity of the aldol reaction by modifying
ether through a reduction-silylation sequence upon the boron substitutents were met with limited success. In
which the terminal double bond was easily oxidized to particular, the use of the (+)- and (–)-diisopinocampheyl
aldehyde 8.
boron enolates of 7 gave rise to 9 with 80:20 and 60:40
diastereoselectivity, respectively.8 Also, performing the
aldol condensation under Mukaiyama conditions, e.g.
BF3-catalysed addition of the trimethylsilyl enolate of 7 to
aldehyde 8, did not increase the diastereoselectivity.11
4
ref. 7
Aldol product 9 was reduced to anti-diol 10 with
(Me4N)BH(OAc)3 in good yield and selectivity
(Scheme 3).12 At this stage a reliable proof of con-
figuration was possible using Rychnovsky’s 13C NMR
method.13,14 The two benzyl protecting groups were sub-
sequently taken off through hydrogenolysis and the result-
ing tetraol was protected as the tetraacetonide 11. This
compound already comprised the complete polyol frag-
ment of RK-397 but had one carbon atom too many at the
left side. Therefore, a Barbier–Wieland degradation15 was
chosen to complete the synthesis of 2. Phenyl lithium ad-
dition to ester 11 and Burgess elimination16 yielded the
1,1-diphenylalkene 12 which was subjected to ozonolysis
to furnish the fully protected and functionalized polyol
portion of RK-397. For the purpose of safe storage the
intermediate aldehyde was converted to acetate 2 through
a reduction-acetylation sequence.17
OBn O
O
O
OBn O
O
O
OMe
OMe
5
6
a (73%)
b-d (88%)
O
O
OBn O
O
O
O
OBn O
OMe
H
OTBS
7
8
Scheme 2 a) PdCl2 (cat.), CuCl2 2H2O, DMF/H2O, 70 °C; b)
LiAlH4, THF, –78 °C; c) TBSCl, imidazol, DMF, 0 °C; d) N-methyl-
morpholine-N-oxide, OsO4 (cat.), acetone/H2O, r.t., then NaIO4, r.t.
With the two coupling partners in hand we next focused
on combining them. Studies by the groups of Paterson8
and Evans9 have revealed that methyl ketone-aldehyde
aldol additions may be stereoselectively executed with
boron enolates and the proper protecting group on the
-oxy substituent in the enolate component. This resulted
in typically good levels of 1,5-anti-stereoselectivity with
the -oxy-substitutent exerting the dominant stereocon-
trolling effect. Accordingly, aldol reaction of the dibutyl-
boron enolate of 7 with the aldehyde 8 furnished the aldol
In conclusion, we have synthesized the complete polyol
fragment of the new polyene macrolide antibiotic RK-397
in a highly convergent manner. The underlying synthetic
strategy also permits the stereoselective preparation of
virtually every other stereosisomer. The functional groups
at the termini of the polyol chain should allow for efficient
coupling to the polyene and aldol fragments.
O
O
O
OBn O
OH OBn O
O
OTBS
a
b
7 + 8
MeO
93% (>95:5)
65% (84:16)
9
O
O
O
O
O
O
O
O
O
OTBS
O
O
O
OBn OH OH OBn O
O
OTBS
c, d
MeO
MeO
69%
11
10
Ph
O
O
O
O
O
O
O
O
OTBS
O
O
O
O
O
O
O
O
OTBS
e, f
g, h
AcO
Ph
69%
54%
12
2
Scheme 3 a) Bu2BOTf, Et3N, CH2Cl2, –100 °C; b) (Me4N)BH(OAc)3, CH3CN, CH3COOH, –20 °C; c) Pd/C, NH4HCO2, MeOH, 64 °C; d)
2-methoxypropene, PPTS (cat.), CH2Cl2, r.t.; e) PhLi, THF, 0 °C; f) MeO2CNSO2NEt3, toluene, 55 °C; g) ozone, MeOH/CH2Cl2, –78 °C, then
NaBH4; h) Ac2O, pyridine, CH2Cl2, 0 °C.
Synlett 2002, No. 12, 2098–2100 ISSN 0936-5214 © Thieme Stuttgart · New York

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C. Schneider et al.
LETTER
through flash chromatography with diethyl ether/pentane
Acknowledgment
(1:2) as eluent yielded 145 mg (65%) of the desired aldol
product 9 as a colourless oil (84:16 mixture of stereo-
isomers) along with 34 mg (27%) of unreacted aldehyde 8
and 44 mg (30%) of methyl ketone 7 both of which were
used again in the aldol reaction. [ ]D20 +19.7 (c 0.58,
CHCl3); IR(film): = 3471 (OH), 2992, 2949, 2857 (CH),
1741 (C=O), 1712 (C=O) cm–1; 1H NMR (300 MHz,
CDCl3): = 0.05 (s, 6 H, SiMe2), 0.90 (s, 9 H, t-Bu), 1.07–
1.33 (m, 2 H), 1.36, 1.40, 1.41 [3 s, 12 H, 2 C(CH3)2],
1.50–1.97 (m, 10 H), 2.37 (dd, J = 15.5, 6.0 Hz, 1 H, 2-H),
2.43–2.65 (m, 4 H) 2.73 (dd, J = 15.5, 7.0 Hz, 1 H, 2-H),
3.68 (s, 3 H, OMe), 3.65–4.29 (m, 9 H), 4.45, 4.48, 4.55,
4.56 (4 d, J = 11.5 Hz, 4 H, 2 OBn), 7.25–7.36 (m, 10 H,
Financial support of this work by the Deutsche Forschungsgemein-
schaft (Schn 441/2) and the Fonds der Chemischen Industrie is gra-
tefully acknowledged. We would like to thank Prof. Nakata for
sharing information prior to publication and Degussa AG for the ge-
nerous supply of amino acids.
References
(1) Kobinata, K.; Koshino, H.; Kudo, T.; Isono, K.; Osada, H.
J. Antibiot. 1993, 46, 1616.
(2) Koshino, H.; Kobinata, K.; Isono, K.; Osada, H. J. Antibiot.
1993, 46, 1619.
(3) Suenaga, T.; Nakamura, H.; Koshino, H.; Kobinata, K.;
Osada, H.; Nakata, T. Tennen Yuki Kagobutsu Toronkai
Koen Yoshishu 1997, 39, 607.
(4) Omura, S. Macrolide Antibiotics: Chemistry, Biology,
Practice; Academic Press: New York, 1984.
(5) Reviews: (a) Oishi, T.; Nakata, T. Synthesis 1990, 635.
(b) Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021.
(c) Schneider, C. Angew. Chem. Int. Ed. 1998, 37, 1375;
Angew. Chem. 1998, 110, 1445. (d) For selected examples
see: Poss, C. S.; Rychnovsky, S. D.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 3360. (e) Rychnovsky, S. D.; Hoye,
R. C. J. Am. Chem. Soc. 1994, 116, 1753. (f) Mori, Y.;
Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron 1995,
51, 5299. (g) Weigand, S.; Brückner, R. Liebigs Ann. Recl.
1997, 1657. (h) Rychnovsky, S. D.; Khire, U. R.; Yang, G.
J. Am. Chem. Soc. 1997, 119, 2058. (i) Smith, A. B.; Boldi,
A. M. J. Am. Chem. Soc. 1997, 119, 6925. (j) Krüger, J.;
Carreira, E. M. Tetrahedron Lett. 1998, 39, 7013.
(k) Dreher, S. D.; Leighton, J. L. J. Am. Chem. Soc. 2001,
123, 341. (l) Paterson, I.; Collet, L. A. Tetrahedron Lett.
2001, 42, 1187.
(6) Review: Schneider, C. Synlett 2001, 1079; and references
cited therein.
(7) (a) Schneider, C.; Rehfeuter, M. Tetrahedron Lett. 1998, 39,
9. (b) Schneider, C.; Rehfeuter, M. Chem.–Eur. J. 1999, 5,
2850.
(8) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett.
1996, 37, 8585.
(9) Evans, D. A.; Coleman, P. J.; Cote, B. J. Org. Chem. 1997,
62, 788.
(10) Experimental Procedure: An amount of 149 mg (0.39
mmol) of methyl ketone 7 was dissolved in 4 mL diethyl
ether and cooled to –78 °C. For enolization 0.59 mL (0.59
mmol) of a 1 M solution of dibutylboron triflate in
dichloromethane were added and subsequently 92 L (0.66
mmol) triethyl-amine and the resulting solution was stirred
for 30 min at –78 °C and for 30 min at 0 °C. Then the
solution was cooled to –100 °C and 122 mg (0.27 mmmol)
of aldehyde 8, dissolved in 1 mL diethyl ether, were added
with a syringe. Stirring was continued for 3 h at –100 °C and
3 h at –78 °C after which the reaction was quenched with pH
7 buffer. After separation of the phases the aq phase was
repeatedly extracted with diethyl ether, the combined
organic extracts were dried over MgSO4, filtered and
evaporated in vacuo. Purification of the crude mixture
2
Ph); 13C NMR (75 MHz, CDCl3): = –5.35, 18.30,
19.81, 19.84, 25.94, 30.11, 30.26, 36.86, 37.41, 39.45,
40.20, 40.47, 41.18, 42.39, 49.29, 50.81, 51.60, 58.77,
65.28, 65.48, 65.76, 65.87, 66.49, 70.36, 72.44, 71.93,
74.63, 98.36, 98.81, 127.70, 127.80, 128.00, 128.10, 128.40,
138.10, 138.30, 171.30, 209.40; MS (200 eV, DCI/NH3):
+
m/z (%) = 847(100) [M + NH4 ]; calcd for C46H72O11Si
(829.15): C, 66.63; H, 8.75. Found: C, 66.82; H, 8.50.
(11) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett.
1994, 35, 8537.
(12) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(13) For an account on the stereochemical analysis of 1,3-diol
acetonides by 13C NMR see: Rychnovsky, S. D.; Rogers, B.
N.; Richardson, T. I. Acc. Chem. Res. 1998, 31, 9.
(14) (a) Direct acetonide formation on diol 10 furnished a
triacetonide with two syn- and one anti-stereochemical
relationships. When the reduction of aldol product 9 was
performed in a syn-selective manner with NaBH4 and
Et2BOMe according to Narasaka14b with subsequent
debenzylation and tetraacetonide formation the major
stereoisomer contained two syn- and two anti-stereo-
chemical relationships in agreement with the assigned
configurations. (b) Narasaka, K.; Pai, F.-C. Tetrahedron
1984, 40, 2233.
(15) (a) Wieland, H. Chem. Ber. 1912, 45, 484. (b) Barbier, P.;
Locquin, R. C. R. Chim. 1913, 156, 1443.
(16) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem.;
1973, 38, 26.
(17) Spectroscopic Data of 2: [ ]D20 0 (c 0.2, CHCl3); IR(film):
= 2990, 2938, 2857 (CH), 1745 (C=O) cm–1; 1H NMR (500
MHz, C6D6): = 0.06, 0.08 (2 s, 6 H, SiMe2), 0.98 (s, 9 H,
t-Bu), 1.10–1.60 (m, 14 H), 1.32, 1.37, 1.47, 1.49, 1.50, 1.54,
1.55 [7 s, 24 H, 8 C(CH3)2], 1.67 (s, 3 H, OAc), 1.73–1.82
(m, 1 H), 2.06 (quint, J = 7.0 Hz, 1 H), 3.68 (dt, J = 10.0, 5.0
Hz, 1 H, CH2OTBS), 3.82 (ddd, J = 10.0, 8.5, 5.0 Hz, 1 H,
CH2OTBS), 3.83–3.89 (m, 1 H), 3.96–4.34 (m, 9 H); 13
C
NMR (150 MHz, C6D6): = –5.38, 18.49, 19.82, 19.92,
19.97, 20.42, 24.86, 26.13, 30.39, 30.63, 30.67, 37.60,
37.80, 39.46, 40.16, 42.80, 43.08, 43.59, 59.20, 62.55,
62.69, 64.86, 65.34, 65.60, 65.71, 65.76, 67.38, 67.70,
98.54, 98.59, 98.80, 100.50, 170.10; MS (200 eV, EI): m/z
(%) = 715(34) [M+ – CH3], 414(4), 380(5), 337(10), 256(18),
149(21), 57(100) [C4H9]; HRMS calcd for C38H70O11Si: for
[M+ – CH3] 715.4453. Found: 715.4531.
Synlett 2002, No. 12, 2098–2100 ISSN 0936-5214 © Thieme Stuttgart · New York