Resolution of 2-silyloxy-1-oxiranyl-4-pentenes by HKR: Total synthesis of (5S,7R)-kurzilactone

Article abstract of DOI:10.1055/s-2005-922774

Enantiomerically pure syn- and anti-2-silyloxy-1-oxiranyl-4-pentenes were prepared by using Jacobsen's hydrolytic kinetic resolution (HKR) method. A resolved epoxypentenol generated in this fashion was used in the total synthesis of (5S,7R)-kurzilactone b

Full text of DOI:10.1055/s-2005-922774

LETTER
61
Resolution of 2-Silyloxy-1-oxiranyl-4-pentenes by HKR: Total Synthesis of
(5S,7R)-Kurzilactone
Total
S
ynthesis of
o
(5
S
,7
R
)
-Kurz
u
ilactone ng-Ju Kim, Jinsung Tae*
Department of Chemistry and Center for Bioactive Molecular Hybrids (CBMH), Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received 21 September 2005
Importantly, nucleophilic ring-opening reactions of the
epoxides formed in this way could enable easy access to
structurally diverse 1,3-diol units found in many biologi-
cally active compounds (Figure 1), exemplified by apicu-
Abstract: Enantiomerically pure syn- and anti-2-silyloxy-1-oxira-
nyl-4-pentenes were prepared by using Jacobsen’s hydrolytic kinet-
ic resolution (HKR) method. A resolved epoxypentenol generated
in this fashion was used in the total synthesis of (5S,7R)-kurzilac-
tone by a pathway employing epoxide ring-opening and RCM reac- laren (1),7 kurzilactone (2),8 milbemycin b3 (3),9 and
atorvastatin (4).10 Only few examples, in which the HKR
tions in key steps.
method has been used to prepare enantiomerically pure 2-
hydroxy-1-oxirane units, have been reported thus far.
However, in these cases the alcohol moieties were intro-
duced first by using known asymmetric methods and then
HKR was employed to resolve the diastereomeric ep-
oxides.11 Consequently, the two asymmetric centers were
installed separately through the use of two asymmetric
reactions.
Key words: epoxides, hydrolytic kinetic resolution, kurzilactone,
metathesis, total synthesis
1,3-Diol subunits are present in numerous biologically
active natural products and pharmaceuticals.1 As a result,
a large effort has been devoted to the development of
methods for the stereoselective synthesis of 1,3-diols.2
Common procedures developed to date rely on chiral pool
strategies3 or asymmetric reaction methodologies4 for the
introduction of the first asymmetric centers in these sub-
stances. Installation of the second asymmetric centers is
typically orchestrated by the initial hydroxyl group by
using various 1,3-syn- or anti-selective ketone reduction
methods.5
We envisioned an alternative approach to chiral 1,3-diol
synthesis that utilizes kinetic resolution of racemic syn- or
anti-2-hydroxy-1-oxirane derivatives. In this strategy, the
relative stereochemistry between the alcohol and the
epoxide groups is established prior to the HKR step and in
this way a single asymmetric reaction can be used to form
the key enantiomerically pure 2-hydroxy-1-oxirane inter-
mediates. Below, we describe the results of studies of
HKR reactions of racemic syn- and anti-2-hydroxy-1-ox-
iranes and an application to the asymmetric synthesis of
(5S,7R)-kurzilactone.
H
N
O
O
O
OH
O
OH O
O
O
Enantiomerically pure syn- and anti-2-alkoxy-1-oxiranyl-
4-pentenes 5 (Scheme 1) are versatile synthetic building
blocks. Ring-opening reactions of these substances with
aryl or vinyl nucleophiles could lead to alkenyl-1,3-diols
6, structural units found in apicularen (1) and milbemycin
b3 (3). In addition, carbon frameworks found in kurzilac-
tone (2) and atorvastatin (4) could be accessed by ring-
opening reactions of 5 with acyl anion equivalents
(Scheme 1).
OH
apicularen (1)
kurzilactone (2)
F
O
O
OH OH
O
O
O
Ca2+
O
2
N
Ph
O
NHPh
OH OR
OH
milbemycin b3 (3)
atorvastatin (4)
OR
6
O
Figure 1
O
OH OR
O
5
X
X
Jacobsen’s method for hydrolytic kinetic resolution
(HKR) of 2-hydroxy-1-oxiranes6 represents another po-
tential enantiocontrolled strategy for 1,3-diol synthesis.
7
Scheme 1
Existing methods for asymmetric synthesis of 5 have
utilized (S)-malic acid as a chiral pool12 reactant or
enzyme-catalyzed asymmetric epoxidation of 1,6-hepta-
SYNLETT 2006, No. 1, pp 0061–0064
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922774; Art ID: U27405ST
© Georg Thieme Verlag Stuttgart · New York
0
5.
0
1.
2
0
0
6

62
Y.-J. Kim, J. Tae
LETTER
dien-4-ol.13 The later method gives 5 in only a 65% ee and
general methods to prepare both enantiomers of syn- and
anti-5 have not yet been described. We envisioned that
application of the HKR method would enable access to
both enantiomers of syn- and anti-5 depending on the
chiral ligand chosen. To test this proposal, we prepared
the syn-epoxide ( )-9 by using a modification of the liter-
ature procedure14 starting from 1,6-heptadien-4-ol (8,
Scheme 2). The anti-epoxide ( )-12 was generated by
Mitsunobu inversion reaction of ( )-9. The racemic TBS-
protected epoxides ( )-10 and ( )-13 were then prepared
for the HKR studies.
H
N
H
N
Co
t-Bu
O
O
t-Bu
OAc
t-Bu
(R,R)-14
t-Bu
TBS
TBS
(R,R)-
TBS
OH
O
O
O
O
14
O
HO
+
H2O
15
(–)-10
(±)-10
2. NaH
THF
(87%)
1. p-TsCl, Et3N
n-Bu2SnO
CH2Cl2 (98%)
4 steps
(89%)
1. n-BuLi, THF
CO2 then I2 (84%)
TBS
TBS
O
O
OH
OH
(±)-9
TBSCl
imidazole
DMF
(97%)
O
O
O
2. 1 N KOH/THF (1:1)
n-Bu4NI (cat.)
8
(+)-13
(+)-10
(99%)
Scheme 3
Ph3P, DIAD
(p-NO2)PhCO2H
R
O
O
THF (98%)
THF, 98%; (3) K2CO3, MeOH, 95%; (4) TBSCl, DMAP,
imidazole, DMF, 97% (Scheme 3). Also, the diol 15 can
be recycled to (+)-10 by using known conditions (p-TsCl,
Et3N, n-Bu2SnO in CH2Cl2).17
K2CO3
MeOH
(±)-11: R = O2CPh(p-NO2)
(±)-12: R = H (95%)
OTBS
O
(±)-10
TBSCl, imidazole
DMF (97%)
This new enantiocontrolled method for 2-silyloxy-1-ox-
iranyl-4-pentene preparation should have wide applica-
tions in synthesis. Kurzilactone (2), which has strong
cytotoxicity against KB cells (IC50 = 1 mg/mL), is an ideal
target on which to test this proposal. The relative C(5)–
C(7) stereochemistry of this substance was incorrectly
assigned as syn8 initially and then corrected to be anti by
using total synthesis.18 As shown in the retrosynthetic
plan given in Scheme 4 for preparation of the enantiomer-
ic form of natural kurzilactone (ent-2), our strategy relies
on two key transformations. The first involves ring-open-
ing reaction of the epoxide (+)-13 with the acyl anion
equivalent 16 and the second RCM reaction of 17.
OTBS
O
(±)-13
Scheme 2
The activated Jacobsen’s (R,R)-(–)-Co(salen) catalyst
(R,R)-14 and general conditions described earlier were
used for the resolution studies.6b Treatment of syn-ep-
oxide ( )-10 with (R,R)-14 (0.3–0.5 mol%) and H2O (0.8
equiv) at room temperature led to formation of the ep-
oxide (–)-10 in good yield (42–48%) and high enantiopu-
rity (98–99% ee) as shown in Table 1 (entries 1 and 2).15
The diol 15 was also formed in 48–49% yield and 93–94%
ee. In contrast, hydrolytic resolution of the anti-epoxide
( )-13 was much less enantiospecific (69–88% ee) when
conducted under the same conditions (Table 1, entries 3
and 4). Variations in catalyst loading and reaction time
had little impact on the enantiospecificities of these reac-
tions. Therefore, the syn-epoxide ( )-10 is superior to the
anti-epoxide ( )-13 in the HKR reaction.16
O
O
RCM
O
OH O
O
OH
7
O
5
17
epoxide opening
(5S,7R)-kurzilactone
(ent-2)
O
OTBS
O
16
(+)-13
The anti-epoxide (+)-13 can be prepared from the re-
solved syn-epoxide (–)-10 by using a four step route: (1)
TBAF, THF, 99%; (2) DIAD, PPh3, (p-NO2)PhCO2H,
Scheme 4 Retrosynthetic plan for preparation of (5S,7R)-kurzilac-
tone (ent-2)
Table 1 Hydrolytic Kinetic Resolution (HKR) of syn- and anti-5
Entry
Substrate
( )-10
( )-10
( )-13
( )-13
(R,R)-14 (mol%) H2O (equiv)
Reaction time (h) Epoxide yield (%, ee)
Diol yield (%, ee)
48 (94)
1
2
3
4
0.3
0.5
0.3
0.5
0.8
0.8
0.8
0.8
16
18
18
18
48 (98)
42 (99)
49 (88)
46 (69)
49 (93)
42 (99)
41 (99)
Synlett 2006, No. 1, 61–64 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (5S,7R)-Kurzilactone
63
The synthetic pathway begins with reaction of the acyl an-
ion equivalent, generated from the thioacetal 18, with (+)-
13 in the presence of BF3·OEt2 to afford 19 in 54% yield
(Scheme 5). Protection of the secondary alcohol of 19
proved to be critical for the success of the synthesis. For
example, acetate protection was problematic since remov-
al of the TBS group (n-Bu4NF in THF) was accompanied
by acetate migration to give a ca. 1:1 mixture of hydroxy-
acetates. Protection with a MOM group was complicated
by low yields (ca. 20%) of the protection processes carried
out under several known conditions. A solution to this
problem was found by using an ethoxyethyl group intro-
duced using ethylvinyl ether (EVE) in the presence of cat-
alytic PPTS (pyridine/p-TsOH). This produced 20 as a ca.
1:1 mixture of diastereomers in 84% yield. Removal of
the TBS group followed by introduction of the acryloyl
group afforded the RCM precursor 21. Ring-closing
metathesis19 of 21, utilizing the second generation
Grubbs’catalyst 22, furnished the lactone 23 in 95% yield.
The ethoxyethyl ether was then cleaved with 0.5 N HCl–
THF (1:1) at room temperature in good yield. Removal of
thioketal by using Hg(ClO4)2, CaCO3 in THF–H2O (5:1)20
took place in 10 minutes at 0 °C but the isolated yield of
(5S,7R)-kurzilactone (ent-2) was low (20–38%). To solve
this problem, we screened several conditions and found
that the AgNO2–I2 method21 is highly efficient. Accord-
ingly, treatment of thioacetal 23 with AgNO2–I2 in THF–
H2O (5:1) at room temperature for 4 hours led to forma-
tion of ent-2 in 62% yield. The synthetic material was
shown to have the same spectroscopic properties as with
Acknowledgment
This work was supported by the Center for Bioactive Molecular
Hybrids (CBMH) and Korea Research Foundation Grant (KRF-
2003-015-C00360).
References and Notes
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20
the natural product. The observed optical rotation {[a]D
–85 (c 0.235, CHCl3)} was found to be opposite to that
20
reported for natural (5R,7S)-kurzilactone {[a]D +84 (c
0.231, CHCl3)}.18
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(+)-13
n-BuLi (2 equiv)
BF3·OEt2 (2 equiv)
OH OTBS
S
S
S
S
THF, –78 °C
(54%)
18
19
2. TBAF, THF
(99%)
1. EVE, PPTS
CH2Cl2 (84%)
EtO
EtO
O
O
(12) Kocienski, P. J.; Yeates, C.; Street, S. D. A.; Campbell, S. F.
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O
OH
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S
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(15) The ee (%) of the resolved epoxides and diols were
determined by HPLC using the Chiralpak-OD-H column
after conversion to the corresponding para-nitrobenzoates
by Mitsunobu inversion reactions.
21
20 (~1:1)
Et3N (5 equiv)
ClCOCH=CH2 (2 equiv)
CH2Cl2
(75%)
22 (5 mol%)
CH2Cl2
(0.001 M)
reflux, 8 h
(95%)
Mes N
Cl
N Mes
Cl
Ru
Ph
PCy3
22
(16) The preference of the syn-epoxide ( )-10 over the anti-
epoxide ( )-13 in the HKR reaction is not clear at this point.
(17) Murga, J.; Falomir, E.; Carda, M.; Marco, J. M.
Tetrahedron: Asymmetry 2002, 13, 2317.
EtO
O
1. 0.5 N HCl–THF (1:1)
r.t., 1 h (99%)
(5S,7R)-
kurzilactone
O
O
S
S
2. AgNO2 (2.4 equiv)
I
2 (1.2 equiv)
THF–H2O (5:1)
r.t., 4 h (62%)
(18) Jiang, B.; Chen, Z. Tetrahedron: Asymmetry 2001, 12, 2835.
23
Scheme 5 Asymmetric total synthesis of (5S,7R)-kurzilactone
Synlett 2006, No. 1, 61–64 © Thieme Stuttgart · New York

64
Y.-J. Kim, J. Tae
LETTER
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Synlett 2006, No. 1, 61–64 © Thieme Stuttgart · New York