An asymmetric synthesis of the polyol fragment of the polyene macrolide antibiotic RK-397

Article abstract of DOI:10.1016/j.tetlet.2009.03.019

A highly convergent and asymmetric synthesis of the C11-C31 polyol fragment of RK-397 as a single isomer is accomplished via a catalytic enantioselective hetero-Diels-Alder reaction and an intermolecular olefin cross-metathesis as key steps.

Full text of DOI:10.1016/j.tetlet.2009.03.019

Tetrahedron Letters 50 (2009) 3530–3533
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Tetrahedron Letters
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An asymmetric synthesis of the polyol fragment of the polyene macrolide
antibiotic RK-397
*
Fan Fu, Teck-Peng Loh
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly convergent and asymmetric synthesis of the C11–C31 polyol fragment of RK-397 as a single iso-
mer is accomplished via a catalytic enantioselective hetero-Diels–Alder reaction and an intermolecular
olefin cross-metathesis as key steps.
Received 3 January 2009
Revised 24 February 2009
Accepted 5 March 2009
Available online 9 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Horner-Wadsworth-Emmons
Macrolactonization
The antibiotic RK-397, which is a member of a large family of
polyene macrolides,1 was isolated from a strain of soil bacteria
Streptomyces sp. 87-397, from a soil sample collected in Saku city,
Nagano prefecture of Japan. RK-397 exhibits antifungal and anti-
bacterial activities as well as promising anticancer activity. It was
isolated and structurally characterized by Osada et al.2 Due to its
potent biological activity and structural complexity, several syn-
theses of this natural product have been reported.3
10
O
1
OH
11
O
OH
31
RK-397
28
18
19
29
OH OH OH OH OH OH
Olefin metathesis
Aldol reaction
The main focus of the synthesis of RK-397 is on the absolute ste-
reocontrol of the ten stereogenic centres in the polyol chain. We
envisioned that the challenge could be resolved by synthetic meth-
odologies developed in our laboratory on catalytic enantioselective
allylation.4 Moreover, an asymmetric hetero-Diels–Alder protocol
using Jacobsen’s catalyst and an intermolecular olefin cross
metathesis strategy were employed for the asymmetric synthesis
of the polyol fragment. Herein, we report an efficient, enantioselec-
tive synthesis of the C11–C31 polyol fragment of RK-397 utilizing
these developed methods as key strategic steps.
Our retrosynthetic approach divides the natural product into
four modules (Scheme 1). Disconnections at the lactone linkage
and the C10–C11 double bond afforded the polyene phosphonate
fragment 4. Subsequent disconnections at the C18–C19 and C28–
C29 bonds afforded fragments 1, 2 and 3. In the forward synthesis,
a cross olefin metathesis step followed by a 1,5-anti aldol addition
would connect fragments 1, 2 and 3 together for the construction
of the C11–C31 polyol chain.
PO(OEt)2
1
O
10
BnO 11
O
O
4
OEt
OBn
31
18
2
3
28
19
1 29
O
OR OR OR OR OBn
R= TBDPS
Scheme 1. Retrosynthetic analysis of RK-397.
The preparation of key building block 2 began with mono-ben-
zyl ether protection of 1,3-propanediol followed by 2-iodoxyben-
zoic acid (IBX) oxidation6 to afford 3-(benzyloxy)propanal 6 in an
excellent yield of 95% (Scheme 3).
This synthetic plan commenced with the preparation of
homoallylic alcohol 1 synthesized from isobutyraldehyde using
The introduction of the first stereogenic centre was attempted
using the chiral (R)-BINOL–InCl3 complex and the chiral (R,R)-PY-
BOX–In(OTf)3 complex developed in our laboratory4 for the asym-
metric allylation of 3-(benzyloxy)propanal 6. The yields and
enantioselectivities of the allylation product 7 obtained were 64%
and 88% ee and 70% and 80% ee for the (R)-BINOL–InCl3 and
(R,R)-PYBOX–In(OTf)3 complexes, respectively. Unfortunately,
when we attempted the asymmetric allylation on a larger scale
(10 mmol), the yield remained high, however, the enantioselectiv-
ity was reduced to 51% ee with the (R)-BINOL–InCl3 complex. A
(+)-B-methoxy-diisopinocampheylborane
and
cis-but-2-ene.
-allylic alcohol
Asymmetric Brown crotylation5 afforded the syn-
c
5 in 76% yield and 92% ee, which was further protected as the
benzyl ether to give 1 in 90% yield (Scheme 2).
* Corresponding author. Tel.: +65 6316 8899; fax: +65 6791 1961.
E-mail address: teckpeng@ntu.edu.sg (T.-P. Loh).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.019

F. Fu, T.-P. Loh / Tetrahedron Letters 50 (2009) 3530–3533
3531
O
(Ipc)2BOMe,n
Bu-Li, KOt Bu
OBn
OH
BnBr, NaH
+
H
BF3·OEt2,THF, -78 o
76%
C
THF, 2 h, 90%
92% ee
1
5
CH3
BOMe
(Ipc)2BOMe =
2
Scheme 2. Synthesis of fragment 1.
(i)Ag2O, BnBr
OH
O
(iii) (+)-DIPBr
MgBr
-78 oC, 60%
98% ee
24h, 97%
HO
OH
(ii) IBX, DMSO BnO
rt,5h, 95%
H
BnO
6
7
(vi) (R,R)-Cr(III)-Salen-Cl
O
O
(iv) TBDPSCl, AgNO3
DMF,2 h, 92%
, 5 mol%,TBME,
10
TBDPSO
BnO
O
16h, TFA, 10 min
TMSO
OTBDPS
(v) OsO4, NMO, 12 h,
then NaIO4, 0.5 h,95%
H
OBn
8
11
9
OMe
OTBDPS
OTBDPS
OTBDPS
OTBDPS
O OBn
(vii) NaBH4, CeCl3
MeOH, 0oC
(ix) Hg(OAc)2, rt,
24h, THF:H2O
(x) NaCNBH3, 0 oC,
(viii) TBDPSCl, AgNO3,
DMF,rt, 2 h,87%
HO
O
OBn
2h , 72%
13
12
MgBr, THF,
(xi)
reflux, 6 h,87%
+
OH OR OH OR OBn
OH OR OH OR OBn
2
14
R = TBDPS
N
O
N
O
Cr
Cl-
t-Bu
t-Bu
t
-Bu
t-Bu
10
Scheme 3. Synthesis of fragment 2.
similar result was obtained with the (R,R)-PYBOX–In(OTf)3 com-
plex (46% ee). Eventually, we found Brown’s allylation,7 employing
(+)-DIPBr to be the most desirable protocol, which yielded 60% of
the homoallylic alcohol 7 with 98% ee. Moreover, the reaction
could be carried out on a large scale (20 mmol).
Protection of homoallylic alcohol 7 proceeded smoothly with
AgNO3 and TBDPSCl, followed by one-pot osmium tetraoxide-cata-
lyzed dihydroxylation and oxidative cleavage with sodium perio-
date to afford aldehyde 8 in 95% yield.
reduction step. The reaction mixture was quenched and the crude
alcohol was immediately subjected to protection with TBDPSCl to
afford dihydropyran 12 in 87% yield. Oxymercuration of the func-
tionalized dihydropyran 12 in THF:H2O (1:1) with mercury(II) ace-
tate proceeded smoothly and the intermediate was subsequently
demercurated with sodium cyanoborohydride via a radical process
to afford the corresponding lactol 13 in 72% yield. Immediate reac-
tion with the vinyl Grignard reagent afforded the corresponding
allylic alcohol in 87% yield10 as a 1:1 mixture of the desired frag-
ment 2 and the undesired isomer 14. The two isomers were sepa-
rated via flash chromatography and the undesired isomer 14 could
be converted to the desired isomer 2 via allylic oxidation with
With the desired aldehyde 8 in hand, the second chiral alcohol
was introduced via an asymmetric hetero-Diels–Alder reaction
between Danishefsky’s diene 9 and aldehyde 8 catalyzed by
Jacobsen’s (R,R)-(Salen)–Cr(III)–Cl complex8 10 to afford the 2,
3-dihydropyran-4-one 11 in 89% yield and an excellent diastereo-
meric ratio of 97:3 as determined by HPLC analysis.
MnO2 into the a,b-unsaturated ketone and subsequent regioselec-
tive 1,2-Luche reduction back to the alcohol 2.11
Similarly, an excellent diastereomeric ratio of 96:4 was
achieved when aldehyde 8 was subjected to Brown’s allylation
with (+)-DIPBr-allyl magnesium bromide. The homoallylic alcohol
15 was subjected to TBAF for removal of the TBDPS-protecting
group. The resulting 1,3-diol was subsequently protected as
Luche reduction9 with CeCl3 is known to be efficient for the reg-
ioselective 1,2-instead of 1,4-reduction of a-enones with NaBH4 in
methanol. As excellent stereo-control was achieved in the hetero-
Diels–Alder step, the syn isomer was obtained exclusively in the

3532
F. Fu, T.-P. Loh / Tetrahedron Letters 50 (2009) 3530–3533
(i) (+)-DIPBr, THF
AllylMgBr, -78 oC,
The aldol product 21 from aldehyde 20 and ketone 3 was ob-
(ii) TBAF,THF
2 h, 87%
TBDPSO
BnO
O
O
TBDPSO
BnO
OH
tained in 73% yield with moderate selectivity of 3:1 (dr) for 1,5-
anti-stereoinduction.15 The S configuration at C19 was established
by comparing the results of other chiral boron enolates where the
aldol product from (ꢀ)-DIPBr16 corresponded to the major diaste-
reomer 21 obtained from the reaction with n-Bu2BOTf. Stereo-
chemical outcomes of similar systems have also been confirmed
by Evans et al.17 The carbonyl group at C17 was reduced with tet-
ramethylammonium triacetoxyborohydride, and the resulting
anti-diol was protected as acetonide18 22 in 87% yield (dr >19/1).
Selective deprotection of the primary benzyl ether at C11 with LiD-
BB19 afforded the target C11–C31 polyol fragment of RK-397 23 in
67% yield.
In conclusion, the C11–C31 polyol fragment of RK-397 was syn-
thesized via a convergent synthetic strategy that features Brown’s
asymmetric allylation and crotylation, a catalytic enantioselective
hetero-Diels–Alder protocol employing Jacobsen’s (R,R)-Cr(III)–
Salen complex, and a 1,5-anti-stereo-induction by substrate-con-
trolled dibutylboron enolate aldol addition for absolute control of
the ten stereogenic centres in the polyol chain. The synthetic strat-
egy described herein allows the stereoselective construction of
practically every other stereoisomer by employment of either
enantiomeric form of chiral reagent and catalyst. The synthesis
also demonstrated a successful intermolecular cross-metathesis
between two elaborate molecular fragments. As excellent enantio-
and diastereocontrol was achieved during the synthesis, including
isolation of the desired diastereoisomer via column chromatogra-
phy, a single diastereoisomer of the target polyol chain 23 was
prepared.
74%, 96:4 dr
(iii) CSA, CH2Cl2,
Me2C(OMe)2,
89%
H
8
15
(iv) PdCl2,CuCl
O
O
O
O
DMF, O2, 6 h
70%
BnO
BnO
3
16
Scheme 4. Synthesis of fragment 3.
acetonide 16 in 89% yield. Wacker oxidation12 of 16 gave the desired
fragment 3 in 70% yield as a single diastereoisomer (Scheme 4).
With the three individual fragments 1, 2 and 3 in hand, we next
coupled the modules together (Scheme 5).
The first step involved coupling of fragment 1 (2 equiv) with 2
(1 equiv) via an intermolecular cross-metathesis with the Hov-
eyda–Grubbs 2nd generation catalyst 1713 which afforded 18 in
52% yield (trans:cis 9:1). The catalyst was dissolved in dichloro-
methane and added dropwise to the refluxing reaction mixture
over 30 min. Prior to the succeeding aldol coupling, it was neces-
sary to selectively deprotect the primary O-benzyl ether at C19 in-
stead of the secondary benzyl ether at C31, to enable Dess–Martin
oxidation to the aldehyde at C19. The cross metathesis product 18
was therefore subjected to alcohol protection with tert-butyldi-
phenylsilyl chloride followed by careful treatment with lithium
4,40-di(t-butyl)biphenyl14 and subsequent Dess–Martin oxidation
to afford the desired aldehyde 20 in an excellent yield of 87%.
OBn
17,
(i)
CH2Cl2,
1
+
2
(ii) TBDPSCl, AgNO3
DMF, rt, 2h, 91%
reflux, 6 h, 52%
OH OR OH OR OBn
18
(iii) LiDBB, THF,
-78 oC, 70%
OBn
OBn
31
19
O
H
(iv) DMP, CH2Cl2,
rt, 0.5 h, 87%
OR OR OR OR OBn
OR OR OR OR
19
20
R = TBDPS
11
BnO
O
(v) 3,
i-Pr2NEt, CH2Cl2,
n
-Bu2BOTf,
(vi) Me4NHB(OAc)3
MeCN, AcOH
OBn
BnO
O
31
dr 3:1, 73%
19
(vii) Me2C(OMe)2,
CSA, CH2Cl2,
87%, dr >19/1
17
OR OR OR OR OH
O
21
11
O
(viii) LiDBB, THF,
-78 oC, 67%
OBn
31
O
19
O
17
O
OR OR OR OR
22
N
N
11
Cl
HO
O
Ru
Cl
OBn
O
O
31
19
O
17
17
OR OR OR OR
O
23
Scheme 5. Synthesis of polyol fragment C11–C31 of RK-397.

F. Fu, T.-P. Loh / Tetrahedron Letters 50 (2009) 3530–3533
3533
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Acknowledgments
We gratefully acknowledge the Nanyang Technological Univer-
sity and Biomedical Research Council (A STAR Grant 05/1/22/19/
408) for funding of this research.
*
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