Synthetic studies of the spirocyclic cyclohexene part of versipelostatin, a novel GRP78/Bip molecular chaperone downregulator

Article abstract of DOI:10.1038/ja.2012.124

The spirocyclic part consisting of an -acylated tetronic acid and a multisubstituted cyclohexene embedded in versipelostatin, a novel GRP78/Bip molecular chaperone downregulator, has been synthesized in enantiomerically pure form. The asymmetric synthesis of the targeted spiro4.5-1-oxa-7-decen-2,4-dione derivative was characterized by (1) stereoselective allylation at the -carbon of methylmalonate diester, in which one carboxylic acid was esterified with a D-glucose-derived chiral template, (2) construction of the tetrasubstituted cyclohexenone substructure by high-yielding ring-closing metathesis and (3) stereoselective construction of the spirocyclic tetronic acid part starting from the cyclohexenone obtained as the ring-closing metathesis product.

Full text of DOI:10.1038/ja.2012.124

The Journal of Antibiotics (2013) 66, 147–154
2013 Japan Antibiotics Research Association All rights reserved 0021-8820/13
www.nature.com/ja
&
ORIGINAL ARTICLE
Synthetic studies of the spirocyclic cyclohexene part
of versipelostatin, a novel GRP78/Bip molecular
chaperone downregulator
Shu Sasaki, Suguru Samejima, Tomoki Uruga, Kai Anzai, Natsumi Nishi, Eriko Kawakita, Ken-ichi Takao
and Kin-ichi Tadano
The spirocyclic part consisting of an a-acylated tetronic acid and a multisubstituted cyclohexene embedded in versipelostatin, a
novel GRP78/Bip molecular chaperone downregulator, has been synthesized in enantiomerically pure form. The asymmetric
synthesis of the targeted spiro[4.5]-1-oxa-7-decen-2,4-dione derivative was characterized by (1) stereoselective allylation at the
a-carbon of methylmalonate diester, in which one carboxylic acid was esterified with a D-glucose-derived chiral template, (2)
construction of the tetrasubstituted cyclohexenone substructure by high-yielding ring-closing metathesis and (3) stereoselective
construction of the spirocyclic tetronic acid part starting from the cyclohexenone obtained as the ring-closing metathesis
product.
The Journal of Antibiotics (2013) 66, 147–154; doi:10.1038/ja.2012.124; published online 30 January 2013
Keywords: a-acyltetronic acid; asymmetric quaternary carbon; ring-closing metathesis; spirocyclic cyclohexene; versipelostatin
INTRODUCTION
In 2002, Shin-ya et al.1 reported the isolation and structural tetronic acid part is connected with a highly functionalized trans-
elucidation of macrocyclic compound of microbial origin fused octahydronaphthalenone (C4-C13) through a carbonyl carbon
versipelostatin is accordant with that used in reference 1.) The
a
designated as versipelostatin (1) (Figure 1). Compound 1 was isolated (C3). The whole 17-membered macrocyclic structure of the aglycon is
from the culture broth of Streptomyces versipellis 4083-SVS6 as a novel formed by connecting both the spirocyclic cyclohexene and the
GRP78 molecular chaperone downregulator. The protein GRP78 acts octahydronaphthalenone parts through a 10-carbon tether (C14-
as a molecular chaperone in endoplasmic reticulum (ER) by C23). The C14-C23 chain, which is considered to be a polyketide
associating transiently with incipient proteins as they traverse the array, includes an E-trisubstituted olefin and four stereogenic centers.
ER and aiding in their folding and transport. GRP78 is induced under The biosynthetic studies of 1 were also reported by Shin-ya et al.,4
various kind of stresses such as glucose starvation, inhibition of which were executed by means of feeding experiments using 13C-
protein glycosylation triggered by tunicamycin, perturbation of ER labeled precursors such as [1-13C]acetate, [3-13C]propionate,
function and protein movement triggered by brefeldin A and so on. [1-13C]butyrate and [1,2,3-13C]glycerol. Regarding the trisaccharide
The enhancement of ER stress response causes an increase in gene unit, the early papers from the Shin-ya group reported an incorrect
expression of a number of ER chaperones, thus compounds that structure for the trisaccharide unit as a b-D-digitoxosyl-(1,4)-a-D-
directly down- and upregulate grp78 transcription are expected to be cymarosyl-(1,4)-b-D-digitoxose.1–4 Furthermore, the absolute
promising candidates as cancer chemotherapeutic agents. The struc- stereochemistry of the aglycon part was determined based on the
ture of 1 was elucidated based on extensive NMR analyses, such as structure of the trisaccharide unit.4 In 2006, Kunst and Kirschnig5
DQF-COSYand HMBC techniques. As a result, the structure of 1 was declared the synthesis of the proposed structure of the trisaccharide
determined to consist of a novel 17-membered carbocyclic aglycon unit. Recently, Tanaka et al. have reported the synthesis of the
and
stereochemistries of the aglycon in 1 were fully determined as Though their synthetic work, the structure of the trisaccharide was
shown in Figure 1, including an a-acylated tetronic acid that shared revised to be b-D-digitoxosyl-(1,4)-a-L-oleandrosyl-(1,4)-b-D-
a
trisaccharide unit.2 Later, the relative and absolute trisaccharide unit in versipelostatin and revision of its structure.6
a
a spiro[5.4]-1-oxa-7-decen-2,4-dione structure with a tetrasubstituted digitoxose as shown in Figure 1. Since the first report of versipelos-
cyclohexene.3 The cyclohexene part includes an all-carbon asymmetric tatin (1) in 2002, the Shin-ya group has further investigated the
quaternary carbon as C24.(Numbering of the skeletal carbon in secondary metabolites isolated from S. versipellis 4083-SVS56. As a
Department of Applied Chemistry, Keio University, Yokohama, Japan
Correspondence: Professor K Tadano, Department of Applied Chemistry, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
E-mail: tadano@applc.keio.ac.jp
This paper is dedicated to Professor Kuniaki Tatsuta with respect and admiration for his achievement of the total syntheses of more than 100 natural products including important
antibiotics.
Received 29 November 2012; revised 13 December 2012; accepted 18 December 2012; published online 30 January 2013

Synthetic studies of versipelostatin
S Sasaki et al
148
result, they reported the isolation and characterization of a novel the spirocyclic part (segment B) sharing a tetronic acid and a highly
analog of 1, designated as versipelostatin F (2) as shown in Figure 1.7 functionalized cyclohexene. Our synthesis of the cyclohexene part of
Compound
2 is an analog regarding the trisaccharide unit. segment B was efficiently achieved though a highly stereoselective
Furthermore, the Shin-ya group reported additional four differently introduction of an all-carbon asymmetric quaternary center (C24) by
glycosylated derivatives of versipelostatin, designated as versipelostatin stereoselective a-alkylation of a sugar-bound methylmalonate diester,
B-E.8 All of these analogs inhibited the expression of GRP78 induced and a ring-closing metathesis for constructing the (Z)-trisubstituted
by 2-deoxyglucose. They also suggested that the structure of the olefin (C25-C26).
deoxysugar parts such as a- or b-configured trisaccharides or
disaccharides may have an important role in downregulating
GRP78 expression. Besides the synthetic studies on the trisaccharide
RESULTS AND DISCUSSION
During these decades, some notable synthetic approaches toward
unit, the synthesis of the 17-membered aglycon has been an interest of functionalized tetronic acid and related compounds in the context of
9
natural product synthesis have been published,12–14 and well
reviewed.15 We selected spirocyclic compound 3 as a synthetic
some groups including ours. Recently, Katsuta et al. reported their
synthetic effort on the enantiospecific construction of the spirocyclic
part. They used a cyclic monoterpene (R)-( þ )-pulegone as a starting precursor of segment B. Our retrosynthetic approach to 3 is
material. In their synthetic studies, after introduction of the summarized in Scheme 1.16 The protected tetronic acid part in 3
spirocyclic tetronate, the cyclohexane ring of pulegone was
would be accessible through the 1,4-addition of an oxygen
functionalized via a somewhat lengthy route, providing the spiro- nucleophile such as a methoxy anion to methylpropiolate 4,
cyclic part of versipelostatin (1) in an unnatural enantiomeric form. followed by transesterification (lactonization). The propiolate 4
We have been involved for these several years in the total synthesis
could be obtained by a stereoselective addition of the acetylide
of versipelostatin (1) in natural form, especially in stereoselective derived from methyl propiolate to cyclohexenone 5. The 2,2,4,5-
synthesis of the aglycon of 1. Our grand design for synthesizing the tetrasubstituted 3-cyclohexen-1-one 5 (C24-C29 in 1) would be
aglycon A is shown in Figure 2. The properly protected aglycon A is
divided into three segments B, C and D. These segments would be
obtained by the ring-closing metathesis of a 3,3,6,7-tetraalkylated
1,7-octadien-4-one 6, which in turn would be obtained by the
connected sequentially for constructing the 17-membered macrocyclic Grignard coupling between aldehyde 7 and an organometallic
skeleton, through a cross metathesis between segments B and C,
through a Julia–Kocienski olefination between segments C and D, and
species 8 followed by oxidation. For enantioselective synthesis of
aldehyde 7, we envisioned the sugar-template-based introduction of
through an aldol-like bond-forming reaction between segments B and the all-carbon asymmetric quaternary center in 7, which has been
D. We have already developed stereoselective and scalable synthetic extensively developed in our group during the later half of 2000s. On
routes to segment C, a linear polyketide part (C15-C21)10 and to
the other hand, the Grignard reagent 8 would be readily accessible
segment D, a highly functionalized octahydronaphthalene part (C3- from commercially available methyl (R)-(–)-3-hydroxyisobutyrate (9)
C14),11 both with all the necessary stereogenic centers in correct using
a
slight modification of known procedure.17 In the
stereochemistry. In this article, we report our synthetic efforts on
efficient and enantioselective access to a compound corresponding to
retrosynthetic plan, 7 would be obtainable from a 4-O-acylated
D-glucopyranoside 10 by removal of the sugar moiety. In relation to
this sugar derivative 10, we have developed a stereoselective
quaternarization at the a-carbon of acetoacetates attached at
C4 of methyl 6-deoxy-2,3-di-O-(tert-butyl)dimethylsilyl-a-D-gluco-
pyranoside (12) or at C2 of methyl 6-deoxy-3,4-di-O-(tert-
butyl)dimethylsilyl-a-D-glucopyranoside, both of which produced
the corresponding a-methyl-a-allylacetoacetate highly stereo-
selectively.18–20 The sugar template 12, served as an efficient chiral
auxiliary for asymmetric synthesis, is readily prepared in a multi-10-
gram scale from methyl D-glucopyranoside,21 and its utility has been
well recognized through a variety of diastereoselective carbon–carbon
bond-forming reactions.22–24
Me
Me
25
Me
Me
24
29
Me
22
O
O
O
Me
Me
21
O
30
HO
O
O
HO
O
O
OH
2
1
Me
HO
MeO
Me
R
OH
O
3
Me
15
14
the trisaccharide unit
H
Me
O
4
5
13
10
Me
H
versipelostatin (1) R=H
versipelostatin F (2) R=OH
OH
With this synthetic design in mind, we embarked on the synthesis
of 3. In Scheme 2, the stereoselective construction of an all-carbon
asymmetric quaternary center corresponding to C24 in 3, which was
the aglycon
Figure 1
Me
Me
Me
Me
Me
Me
PO
Me
CHO
H
Me
O
PO
Me
PO
O
O
OP
Me
Me
PO
Me
PO
Me
Me
PO
O
Me
Me
O
H
H
H
OP
Me
OP
SO2BT
segment C
BT =
O
segment D
Me
segment B
S
OP
an aglycon equivalent A
P as aproper protecting group
N
Figure 2
The Journal of Antibiotics

Synthetic studies of versipelostatin
S Sasaki et al
149
achieved using the sugar-template 12, is summarized. Diethyl was converted into methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-
methylmalonate (13) was quantitatively hydrolyzed with KOH 4-O-((2R)-2-allyl-2-methyl-3-oxo-butanoyl)-a-D-glucopyranoside,
in EtOH provided 2-(ethoxycarbonyl)propionic acid (14).25 The compound 918, as follows: (1) Selective reduction of the
attachment of monocarboxylic acid 14 to the chiral template 12 ethoxycarbonyl moiety with diisobutyl aluminium hydride (Dibal-H)
was achieved using dicyclohexylcarbodiimide as a dehydrating in toluene at ꢀ781C (80%); (2) tetrapropylammonium perruthenate
reagent, producing the 4-O-(2-ethoxycarbonyl)propionyl derivative (TPAP) oxidation of the resulting primary alcohol in the presence
15 of 12, as an inseparable 1:1 diastereomeric mixture, quantitatively. of N-methylmorpholine N-oxide (NMO) in CH2Cl2 and molecular
˚
For the quaternization at the a-carbon of the resulting diester 15, allyl sieves (MS) 4 A (93%); (3) MeMgCl addition to the resulting
bromide was used as an electrophile after deprotonation with NaOEt aldehyde in Et2O at ꢀ781C (60%); (4) Dess–Martin oxidation of
analogously to our previous reports.18,19 As expected, the attack of the resulting diastereomeric mixture of the addition products in the
allyl bromide to thus formed enolate proceeded with complete presence of NaHCO3 in CH2Cl2 (91%). Thus, obtained product was
p-facial selectivity to produce the allylation product 11 as a single identical with the authentic sample in all spectral means.)
diastereomer in almost quantitative yield. The stereochemistry at the
As shown in Scheme 3, ozonolysis of the vinyl group in 11 followed
newly formed stereogenic center in 11 as shown was determined by reductive workup with Ph3P produced the formylmethyl derivative
unambiguously by chemical transformation of 11 to an authentic 16 in 90% yield. The aldehyde group in 16 was protected as a
specimen of our previously reported compound. (Compound 11 1,3-dioxolan-2-yl form by treatment with ethylene glycol in the
Me
Me
Me
Me
Me
Me
Me
Me
1,4-addition/
lactonization
Me
Me
Me
O
Me
O
O
24
O
O
O
MeO
O
MeO
O
OH
O
MeO2C
O
O
5
substrate 4 for spirocy
segment B
a precursor of segment B 3
clization
Me
Me
Me
Me
Grignard reaction
then oxidation
MeO2C
Me
RCM
O
O
Me
Me
5
7
OH
MgBr
CHO
O
9
O
O
6
8
7
O
O
Me
O
reductive removal of
the sugar-template
Me
O
HO
TBSO
Me
O
O
EtO
Me
O
O
TBSO
TBSO
OMe
TBSO
Me
TBSO
TBSO
OMe
OMe
O
11
10
our D-glucose-derived
chiral template 12
O
TBS=(tert-Bu)Me2Si
Scheme 1
allyl bromide,
NaOEt, THF,
–78 to 0 ºC
O
O
O
O
Me
Me
O
O
DCC, DMAP, CH2Cl2
(quant.)
O
O
O
EtO
EtO
O
TBSO
EtO
OR
TBSO
Me
Me
(96%)
TBSO
OMe
TBSO
OMe
Me
KOH,
EtOH
(99%)
Me
O
15
13 R=Et
14 R=H
HO
TBSO
11 as a single diastereomer
determined by 1H-NMR
TBSO
OMe
12
Scheme 2
O
O
1) DIBAL-H, toluene, –78 ºC
2) TPAP, NMO, MS4A, CH2Cl2
O3, CH2Cl2, –78 ºC;
then PPh3
(CH2OH)2,TsOH·H2O,
benzene, 70 ºC
Me
O
O
Me
O
EtO
O
O
11
TBSO
EtO
O
Me
O
(88% for 2 steps)
TBSO
TBSO
(84%)
(90%)
Me
OMe
TBSO
OMe
O
17
OHC
16
O
O
DIBAL-H, CH2Cl2,
–18 °C to r.t.
Ph3PCH3Br, n-BuLi,
THF, 0 ºC
Me
Me
OHC
O
O
O
OH
Me
O
O
TBSO
TBSO
Me
O
Me
O
HO
TBSO
Me
O
+
TBSO
TBSO
OMe
(87%)
OMe
HO
O
OMe
O
O
18
10
20 (96%)
19 (88%)
Scheme 3
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Synthetic studies of versipelostatin
S Sasaki et al
150
presence of TsOHꢁ H2O in hot benzene. The thus obtained
As shown in Scheme 5, the homoallylic alcohol 19 was converted
acetal 17 was reduced with Dibal-H and the resulting mixture of into aldehyde 7 by Dess–Martin oxidation. The Grignard addition of
aldehyde 18 and the primary alcohol was oxidized without purifica- the homoallylmagnesium bromide prepared from 22 to 7 produced
tion with TPAP in the presence of NMO to produce 18 in 88% the adduct 23 as an inseparable diastereomeric mixture (1:1) in 59%
yield for two steps. Wittig olefination of aldehyde 18 with methyl- yield. The reduction product 19 was obtained in 36% yield as a result
triphenylphosphonium bromide in the presence of n-BuLi at 0 1C of hydride transfer from the Grignard reagent to the aldehyde 7.
provided the vinyl derivative 10. Removal of the sugar-template Despite searching more efficient Grignard reaction conditions, we
from 10 was best achieved by Dibal-H reduction at ꢀ181C, could not find the reliable conditions for avoiding this reduction
producing a neopentyl alcohol 19 in a good yield of 88%. The reaction. The diastereomeric mixture 23 was then oxidized smoothly
3-O-silylated D-glucopyranoside 20 was also obtained in 96% yield. to ketone 6 by Dess–Martin oxidation. The ring-closing metathesis
Under these reduction conditions, the tert-butyldimethylsilyl group of dienone 6 proceeded smoothly using 5 mol% of the Grubbs
at C2 in 12 was selectively removed. (Treatment of 20 with tert- second-generation catalyst 2426 in toluene at 801C for 19h to
buthyldimethylsilyl chloride (1.5 eq) in the presence of imidazole (3.0 produce a tetrasubstituted 3-cyclohexen-1-one 5 in 90% yield.
eq) in DMF at room temperature (rt) for 15h provided the sugar- (The use of the Grubbs first-generation catalyst in toluene at 801C
template 12 selectively in 72% yield and 20 was recovered in did not promote the ring-closing metathesis reaction, and 6 was
28% yield.)
For preparing the Grignard reagent 8 in Scheme 1, the correspond-
recovered quantitatively.)
In Scheme 6, our approach to the spirocyclic segment B precursor 3
ing alkyl bromide 22 was prepared as shown in Scheme 4. According is depicted. According to some precedent reports,12,27 we explored
to the reported procedure,17 (R)-(–)-Roche ester (9) was converted first the reaction between cyclohexenone 5 and methyl trans-3-
into tosylate 21 in an overall yield of 55%. Replacement of the methoxyacrylate for
a one-step access to 3 using lithium
tosyloxy group in 21 by a bromide anion provided the homoallyl diisopropylamide as the base at –781C in tetrahydrofuran (THF) in
bromide 22.
the absence or presence of CeCl3. Both cases resulted in complete
1) MeMgCl, Et2O
2) TsCl, pyridine, 0 °C
3) MsCl, Et3N, Et2O
O
LiBr, THF, reflux
TsO
Me
Br
Me
HO
OMe
(56% for 3 steps)
Me
Me
Me
22
21
9
Scheme 4
Dess-Martin periodinane,
NaHCO3, CH2Cl2
Me
O
Me
22, Mg, THF
O
+ 19 (36%)
19
*
O
Me
O
(96%)
CHO
OH Me
7
23
as a mixture of diastereomer (59%)
(ca. 1:1 determined by 1H-NMR)
Me
Dess-Martin periodinane,
NaHCO3, CH2Cl2
Me
N
Me
N
O
24, toluene, 80 °C
Me
Mes
Mes
Ph
O
Cl
(90%)
O
Me
Ru
O
(87%)
Cl
O
PCy3
Me
O
5
6
Grubbs 2nd generation
cat.24
Scheme 5
Me
Me
Me
O
H2, Lindlar cat.
EtOAc (74%)
O
Me
H
O
1.3%
NOE
Me
Me
O
ethyl propiolate,
O
n-BuLi, THF, –78 ºC
25
5
O
(86%)
OH
Me
Me
Me
Me
Me
Me
O
4
O
EtO2C
NaOMe, MeOH
O
O
+
MeO
O
MeO
OH
26
(21%)
O
3
(28%)
EtO2C
Scheme 6
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Synthetic studies of versipelostatin
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151
recovery of 5. Next, the addition of the lithium acetylide prepared The residue was purified by column chromatography on silica gel (EtOAc/
hexane, 1:40) to provide 2.44g (98% from 12) of 15 (ca. 1:1 diastereomeric
from ethyl propiolate with n-BuLi in THF at –781C to 5 was
mixture) as a colorless oil: TLC Rf 0.60 (EtOAc/hexane, 1:5); IR (neat) 2931,
1
examined. Fortunately, the addition product
stereoselectively in 86% yield. The stereochemistry at the newly
introduced chiral center in was ascertained by the NOE
experiment of 25, obtained by hemihydrogenation of acetylenic
ester 4 using Lindler catalyst followed by spontaneous lactonization
occurred between the resulting ethyl cis-propenoate and the tertiary
hydroxyl group. Consequently, the attack of the acetylide occurred
exclusively from the less hindered Re-face of the carbonyl in 5. The
4 was obtained
1757 cmꢀ1; H-NMR (300 MHz, CDCl3) d 0.05 (s, 3H), 0.07 (s, 3H), 0.10 (s,
6H), 0.83 (s, 9H ꢂ 1/2), 0.86 (s, 9Hꢂ 1/2), 0.92 (s, 9H), 1.13 (d, 3H ꢂ 1/2,
J ¼ 6.6 Hz), 1.18 (d, 3Hꢂ 1/2, J ¼ 6.6Hz), 1.27 (t, 3Hꢂ 1/2, J ¼ 7.2Hz), 1.28
(t, 3H ꢂ 1/2, J ¼ 7.2 Hz), 1.42 (d, 3H ꢂ 1/2, J ¼ 7.2 Hz), 1.46 (d, 3H ꢂ 1/2,
J ¼ 7.2 Hz), 3.36 (s, 3Hꢂ 1/2), 3.37 (s, 3H ꢂ 1/2), 3.42–3.52 (m, 1H), 3.66 (dd,
1H, J ¼ 3.5, 8.9 Hz), 3.91 (t, 1Hꢂ 1/2, J ¼ 8.9 Hz), 3.92 (t, 1Hꢂ 1/2, J ¼ 8.9
Hz), 4.19 (q, 2H, J ¼ 7.2 Hz), 4.61 (d, 1H, J ¼ 3.5 Hz), 4.69 (dd, 1H ꢂ 1/2,
J ¼ 6.0, 8.9 Hz), 4.72 (dd, 1Hꢂ 1/2, J ¼ 6.0, 8.9 Hz); 13C-NMR (125MHz,
4
expected 1,4-addition of a methoxide ion from NaOMe to the b- CDCl3) d ꢀ4.5 (3/2C), ꢀ4.4 (1/2C), ꢀ3.4, ꢀ3.0 (1/2C), ꢀ2.9 (1/2C), 13.6
(1/2C), 14.0 (1/2C), 14.0 (1/2C), 14.1 (1/2C), 17.4 (1/2C), 17.6 (1/2C), 17.8 (1/
2C), 17.8 (1/2C), 18.4, 25.8 (3/2C), 25.9 (3/2C), 26.1 (3C), 46.3 (1/2C), 46.3
(1/2C), 55.0 (1/2C), 55.0 (1/2C), 61.3 (1/2C), 61.5 (1/2C), 65.3 (1/2C), 65.5
(1/2C), 71.6 (1/2C), 71.7 (1/2C), 74.4, 77.6 (1/2C), 77.6 (1/2C), 100.0, 169.0
(1/2C), 169.6 (1/2C), 169.7 (1/2C), 170.2 (1/2C); HRMS (EI) calculated for
C21H41O8Si2 (Mþ ꢀt-C4H9) m/z 477.2340, found 477.2349.
carbon of the propiolate 4 followed by lactonization did not occur at
room temperature. Only the corresponding methyl propiolate was
obtained as a result of transesterification. After some experimentation,
we found eventually that treatment of 4 with NaOMe in MeOH for
prolonged heating at 601C provided the desired spirocyclic tetranote
3 in a yield of 28%. Another isolable product was the b-methoxy-a,b-
unsaturated ester 26, the 1,4-addition product with Z-configuration,
which was obtained in 21% yield.
Methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-((2 R)-2-ethoxycarbo-
nyl-2-methylpent-4-enoyl)-a-D-glucopyranoside (11). The following reaction
was carried out under Ar. To a cooled (–781C) stirred solution of 15
(2.44 g, 4.56 mmol) in THF (49 ml), NaOEt (1.0M in EtOH, 4.79 ml,
In summary, we have developed the stereoselective synthesis of 3 as
a synthetic equivalent to the spirocyclic part in versipelostatin. Our 4.79mmol) was added. The mixture was stirred at –781C for 15min, and
allyl bromide (0.711ml, 8.22 mmol) was added. After being stirred at –781C
for 30min, the mixture was warmed to 0 1C and stirred for 17h. The mixture
was quenched with saturated aqueous NH4Cl (30 ml), diluted with EtOAc
(50 ml) and washed with saturated aqueous NH4Cl (50 mlꢂ 3). The organic
layer was dried and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:50) to provide 2.44 g (96%) of
11 as a colorless oil: TLC Rf 0.68 (EtOAc/hexane, 1:5); [a]D27 þ 48.2 (c 0.880,
approach to 3 is featured by (1) exclusive construction of the desired
all-carbon quaternary center (C24) using our D-glucose-derived
chiral-template approach; (2) convenient synthesis of tetrasubstituted
cyclohexenone by a ring-closing olefin-metathesis approach and (3)
spirocyclic formation via the 1,4-addion of a methoxide ion to the
propiolate 4. We are seeking a more efficient access to 3 using 5 as an
advanced intermediate.
CHCl3); IR (neat) 2956, 1735cmꢀ1 1H-NMR (300 MHz, CDCl3) d 0.08 (s,
;
12H), 0.85 (s, 9H), 0.93 (s, 9H), 1.17 (d, 3H, J ¼ 6.2Hz), 1.26 (t, 3H, J ¼ 7.2
Hz), 1.43 (s, 3H), 2.47 (dd, 1H, J ¼ 7.8, 13.7 Hz), 2.84 (dd, 1H, J ¼ 6.8,
13.7Hz), 3.37 (s, 3H), 3.69 (dd, 1H, J ¼ 3.4, 8.1 Hz), 3.75 (qd, 1H, J ¼ 6.2,
9.7 Hz), 3.92 (t, 1H, J ¼ 8.1 Hz), 4.17 (q, 2H, J ¼ 7.2 Hz), 4.62 (d, 1H, J ¼ 3.4
Hz), 4.75 (dd, 1H, J ¼ 8.1, 9.7Hz), 5.11 (d, 1H, J ¼ 11.3Hz), 5.12 (d, 1H,
EXPERIMENTAL PROCEDURE
General
Specific rotations were measured in a 100-mm cell. 1H NMR spectra were
recorded at 300 or 500MHz with tetramethylsilane as an internal standard. J ¼ 15.6Hz), 5.62-5.76 (m, 1H); 13C-NMR (125 MHz, CDCl3) d ꢀ4.3, ꢀ4.3,
13C NMR spectra were recorded at 125MHz. High-resolution mass spectra
(HRMS) were measured in electron ionization (EI) mode (70 eV). Thin-layer 61.4, 65.6, 71.9, 74.3, 78.5, 99.6, 119.3, 132.6, 171.1, 171.7; HRMS (EI)
ꢀ3.3, ꢀ2.8, 14.0, 17.8 (2C), 18.5, 20.3, 26.0 (3C), 26.2 (3C), 40.1, 54.0, 55.0,
chromatography (TLC) was performed on Merck Kieselgel 60 F254 plates. The calculated for C24H45O8Si2 (Mþ ꢀt-C4H9) m/z 517.2653, found 517.2631.
crude reaction mixtures and extracted materials were purified by column
Methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-((2 R)-2-ethoxycarbo-
chromatography on Silica gel 60 (Merck, Darmstadt, Germany). Unless nyl-2-formylmethylpropanoyl)-a-D-glucopyranoside (16). To a cooled (–781C)
otherwise noted, the reactions were carried out at room temperature. stirred solution of 11 (1.48 g, 2.60mmol) in CH2Cl2 (30 ml), O3 was bubbled
Combined organic extracts were dried over anhydrous Na2SO4. The solvents at –78 1C for 10min and Ph3P (810mg, 3.09mmol) was added. After being
were removed from the reaction mixture and the combined organic extracts stirred at 0 1C for 30min, the mixture was warmed to rt, stirred for 1 h and
by concentration under reduced pressure using an evaporator with bath concentrated in vacuo. The residue was purified by column chromatography on
at 35–451C.
silica gel (EtOAc/hexane, 1:40) to provide 1.33 g (90%) of 16 as a colorless oil:
2-(Ethoxycarbonyl)propanoic acid (14). To a cooled (01C), stirred solution of TLC Rf 0.50 (EtOAc/hexane, 1:5); [a]D31þ 55.2 (c 1.03, CHCl3); IR (neat) 2932,
diethyl methylmalonate (13) (2.00 ml, 11.7mmol) in EtOH (40 ml), KOH 1730 cmꢀ1; 1H-NMR (300 MHz, CDCl3) d 0.07 (s, 12H), 0.85 (s, 9H), 0.92 (s,
(789 mg, 14.1mmol) was added. After being stirred at rt for 2 hours, the 9H), 1.15 (d, 3H, J ¼ 6.2 Hz), 1.26 (t, 3H, J ¼ 7.1 Hz), 1.59 (s, 3H), 2.84 (dd,
mixture was diluted with H2O (60 ml) and washed with hexane/THF (2:3, 1H, J ¼ 1.2, 17.5Hz), 3.20 (dd, 1H, J ¼ 1.2, 17.5Hz), 3.37 (s, 3H), 3.68 (dd,
100 ml). 1 M aqueous HCl (30 ml) was added to the aqueous layer. The mixture 1H, J ¼ 3.4, 8.0 Hz), 3.73 (qd, 1H, J ¼ 6.2, 9.8 Hz), 3.90 (t, 1H, J ¼ 8.0 Hz), 4.21
was extracted with CH2Cl2 (20 mlꢂ 3). The combined extracts were dried and (q, 2H, J ¼ 7.1 Hz), 4.61 (d, 1H, J ¼ 3.4 Hz), 4.74 (dd, 1H, J ¼ 8.0, 9.8Hz), 9.73
concentrated in vacuo to provide 1.70g (100%) of 14 as a colorless oil, which (t, 1H, J ¼ 1.2 Hz); 13C-NMR (125MHz, CDCl3) d ꢀ4.2 (2C), ꢀ3.3, ꢀ2.9,
was used in the next step without further purification: TLC Rf 0.50 (EtOAc/ 13.9, 17.7, 17.8, 18.5, 21.4, 25.9 (3C), 26.2 (3C), 48.8, 51.4, 55.0, 62.0, 65.3,
1
hexane, 3:1); H-NMR (300MHz, CDCl3) d 1.28 (t, 3H, J¼ 7.1 Hz), 1.45 (d, 71.9, 74.3, 79.2, 99.5, 170.3, 170.4, 198.2; HRMS (EI) calculated for
3H, J ¼ 7.4 Hz), 3.47 (q, 1H, J ¼ 7.4 Hz), 4.22 (q, 2H, J ¼ 7.1 Hz); 13C-NMR C26H49O8Si2 (Mþ ꢀOMe) m/z 545.2965, found 545.2966.
(125 MHz, CDCl3) d 13.5, 14.0, 45.9, 61.7, 169.9, 175.8.
Methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-((2R)-2-(1,3-dioxolan-
Methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-(2-(ethoxycarbonyl)- 2-yl)methyl-2-(ethoxycarbonyl)propanoyl)-a-D-glucopyranoside (17). To a stirred
propanoyl)-a-D-glucopyranoside (15). To a stirred solution of 12 (1.90 g, solution of 16 (1.32 g, 2.30mmol) in benzene (26 ml), (CH2OH)2 (0.191ml,
4.67 mmol) in CH2Cl2 (38 ml), DMAP (57.1 mg, 0.467 mmol), a solution of 3.40mmol) and TsOH ꢁ H2O (131mg, 0.69 mmol) were added. After being
14 (818mg, 5.60mmol) in CH2Cl2 (10 ml) and dicyclohexylcarbodiimide stirred at 701C for 3 h, the mixture was quenched with saturated aqueous
(1.16 g, 5.60mmol) were added. The mixture was stirred at rt for 15h, and a NaHCO3 (30 ml) at 0 1C and extracted with CH2Cl2 (20 mlꢂ 3). The
solution of 14 (273mg, 1.87 mmol) in CH2Cl2 (2.4ml) and dicyclohexylcar- combined extracts were dried and concentrated in vacuo. The residue was
bodiimide (387mg, 1.87mmol) were added. After being stirred at rt for 3 h, purified by column chromatography on silica gel (EtOAc/hexane, 1:20) to
the mixture was diluted with H2O (80 ml) and extracted with CH2Cl2 provide 1.20 g (84%) of 17 as a colorless oil: TLC Rf 0.38 (EtOAc/hexane, 1:5);
(20 mlꢂ 3). The combined extracts were dried and concentrated in vacuo. [a]D28 þ 45.6 (c 1.03, CHCl3); IR (neat) 2932, 1732cmꢀ1; 1H-NMR (300MHz,
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CDCl3) d 0.08 (s, 12H), 0.84 (s, 9H), 0.92 (s, 9H), 1.17 (d, 3H, J ¼ 6.3 Hz), quenched with H2O (15 ml) at –181C and diluted with aqueous solution
1.25 (t, 3H, J ¼ 7.1 Hz), 1.56 (s, 3H), 2.17 (dd, 1H, J ¼ 5.0, 14.4Hz), 2.48 (dd, (25 ml) of potassium sodium ( þ )-tartrate tetrahydrate (4.96 g) and warmed
1H, J ¼ 5.0, 14.4Hz), 3.37 (s, 3H), 3.68 (dd, 1H, J ¼ 3.4, 8.2 Hz), 3.76–3.85 (m, to rt. The mixture was stirred vigorously for 2 h, and the organic layer was
3H), 3.87–3.98 (m, 2H), 3.92 (t, 1H, J ¼ 8.2 Hz), 4.18 (q, 2H, J ¼ 7.1 Hz), 4.61 separated. The aqueous layer was extracted with EtOAc (15 mlꢂ 3). The
(d, 1H, J ¼ 3.4 Hz), 4.73 (dd, 1H, J ¼ 8.2, 9.7Hz), 4.94 (t, 1H, J ¼ 5.0 Hz); 13C- combined extracts were dried and concentrated in vacuo. The residue was
NMR (125MHz, CDCl3) d ꢀ4.3, ꢀ4.2, ꢀ3.3, ꢀ2.9, 13.9, 17.8 (2C), 18.4,
purified by column chromatography on silica gel (EtOAc/hexane, 1:15) to
20.6, 26.0 (3C), 26.2 (3C), 39.1, 52.3, 54.9, 61.5, 64.5, 64.8, 65.6, 71.8, 74.3, provide 221 mg (88%) of 19 and 413 mg of 20 (96%). Compound 19 was
78.7, 99.6, 101.9, 171.1, 171.5; HRMS (EI) calculated for C28H53O9Si2 (Mþ
obtained as a colorless oil: TLC Rf 0.16 (EtOAc/hexane, 1:3); [a]D27–2.4 (c 1.14,
ꢀOMe) m/z 589.3228, found 589.3217.
CHCl3); IR (neat) 3485, 3018cmꢀ1 1H-NMR (300 MHz, CDCl3) d 1.07 (s,
;
Methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-((2R)-2-(1,3-dioxolan- 3H), 1.77 (dd, 1H, J ¼ 4.8, 14.5Hz), 1.82 (dd, 1H, J ¼ 4.8, 14.5Hz), 3.41 (d,
2-yl)methyl-2-formylpropanoyl)-a-D-glucopyranoside (18). The following reac- 1H, J ¼ 11.3Hz), 3.49 (d, 1H, J ¼ 11.3Hz), 3.82-3.86 (m, 2H), 3.96-4.00 (m,
tion was carried out under Ar. To a cooled (–781C) stirred solution of 17 2H), 4.92 (t, 1H, J ¼ 4.8 Hz), 5.06 (d, 1H, J ¼ 17.5Hz), 5.10 (d, 1H, J ¼ 11.0
(1.20 g, 1.93mmol) in toluene (24 ml), Dibal-H (1.01M in toluene, 4.78ml,
Hz), 5.83 (dd, 1H, J ¼ 11.0, 17.5Hz); 13C-NMR (125 MHz, CDCl3) d 22.2,
4.83mmol)was added. After being stirred at –781C for 30min, the mixture
40.4, 41.2, 64.7, 64.8, 69.4, 102.5, 113.4, 143.9; HRMS (EI) calcd for C9H15O3
was quenched with H2O (15 ml) at –781C and diluted with aqueous solution (Mþ –H) m/z 171.1021, found 171.1024. Compound 20 was obtained as a
(20 ml) of potassium sodium ( þ )-tartrate tetrahydrate (4.09 g) and warmed colorless oil: TLC Rf 0.29 (EtOAc/hexane, 1:3); 1H-NMR (300 MHz, CDCl3)
to rt. The mixture was stirred vigorously for 2 h, and the organic layer was d 0.13 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H), 1.29 (d, 3H, J¼ 6.3Hz), 1.93 (d, 1H,
separated. The aqueous layer was extracted with EtOAc (20 ml ꢂ 3). The
J ¼ 9.3 Hz, ꢀOH at C-2), 2.12 (d, 1H, J ¼ 2.5 Hz, ꢀOH at C-4), 3.12 (dt, 1H,
combined extracts were dried and concentrated in vacuo to provide a crude J ¼ 2.5, 9.0 Hz), 3.41 (s, 3H), 3.45 (dt, 1H, J ¼ 3.9, 9.3Hz), 3.61 (t, 1H,
product, which was used in the next step without further purification.
The following reaction was carried out under Ar. To a stirred solution of
J ¼ 9.0 Hz), 3.65 (qd, 1H, J ¼ 6.3, 9.0 Hz), 4.69 (d, 1H, J ¼ 3.9 Hz).
(3S)-2,3-dimethyl-4-(p-toluenesulfonyl)oxybut-1-ene (21). The following
reaction was carried out under Ar. To a cooled (01C) stirred solution of
MeMgCl (3.0M in Et2O, 9.96ml, 26.9mmol) in Et2O (30 ml), a solution of
˚
crude product obtained above in CH2Cl2 (60 ml), MS 4 A powder (1.80 g) and
N-methylmorpholine N-oxide (113mg, 0.965mmol) were added. The mixture
was stirred at rt for 10min and tetrapropylammonium perruthenate (34.0 mg, methyl (R)-(–)-3-hydroxyisobutyrate (9) (0.90 ml, 8.15 mmol) in Et2O (4.5ml)
0.097 mmol) was added. After being stirred at rt for 1 h, the mixture was was slowly added. After being stirred at rt for 1.5h, the mixture was quenched
filtered through a pad of Celite and washed with EtOAc. The combined filtrate
with aqueous 1 M HCl (60 ml) at 0 1C and the organic layer was separated. The
and washings were concentrated in vacuo. The residue was purified by column aqueous layer was diluted with saturated aqueous NaHCO3 (100ml) and
chromatography on silica gel (EtOAc/hexane, 1:25) to provide 973 mg (88%) extracted with EtOAc (20 mlꢂ 15). The combined extracts were washed with
of 18 as a colorless oil: TLC Rf 0.50 (EtOAc/hexane, 1:4); [a]D28 þ 39.0 (c 1.13, saturated aqueous NaHCO3 (10 ml) and saturated aqueous NaCl (10 ml). The
CHCl3); IR (neat) 2932, 1723 cmꢀ1
;
1H-NMR (300 MHz, CDCl3) d 0.01 (s,
organic layer was dried and concentrated in vacuo to provide 966 mg of
3H), 0.08 (s, 3H), 0.09 (s, 6H), 0.82 (s, 9H), 0.91 (s, 9H), 1.10 (d, 3H, dimethylated tertiary alcohol, which was used in the next step without further
purification: TLC Rf 0.45 (EtOAc/hexane, 2:1).
J ¼ 6.3 Hz), 1.43 (s, 3H), 2.22 (dd, 1H, J ¼ 4.4, 14.4Hz), 2.37 (dd, 1H, J ¼ 5.5,
14.4Hz), 3.35 (s, 3H), 3.66 (dd, 1H, J ¼ 3.4, 8.4 Hz), 3.73 (dd, 1H, J ¼ 6.2,
The following reaction was carried out under Ar. To a cooled (01C) stirred
9.8 Hz), 3.77–3.82 (m, 2H), 3.87–3.98 (m, 2H), 3.91 (t, 1H, J ¼ 8.4 Hz), 4.60 solution of the product obtained above (966 mg) in pyridine, (8ml) TsCl
(d, 1H, J ¼ 3.4 Hz), 4.75 (dd, 1H, J ¼ 8.4, 9.8Hz), 4.98 (dd, 1H, J ¼ 4.4, (1.90 g, 9.97mmol) was added. After being stirred at 01C for 15 h, the mixture
5.5 Hz), 9.70 (s,1H); 13C-NMR (125MHz, CDCl3) d –4.3, –4.1, –3.2, –2.8, 17.8 was quenched with H2O (10 ml) at 0 1C and extracted with EtOAc (10 mlꢂ 3).
(3C), 18.5, 25.9 (3C), 26.2 (3C), 38.5, 55.0, 55.7, 64.8, 64.9, 65.3, 71.8, 74.5, The combined extracts were washed with saturated aqueous KHSO4 (10 ml),
78.6, 99.7, 101.3, 171.3, 198.4; HRMS (EI) calculated for C26H49O8Si2 (Mþ
–
saturated aqueous NaHCO3 (10 ml) and saturated brine (10 ml). The organic
layer was dried and concentrated in vacuo to provide 2.06g of monotosylate,
OMe) m/z 545.2966, found 545.2974.
Methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-((2R)-2-((1,3-dioxo- which was used in the next step without further purification: TLC Rf 0.63
1
lan-2-yl)methyl)-2-methyl-3-butenoyl)-a-D-glucopyranoside (10). The following (EtOAc/hexane, 2:1); H-NMR (300MHz, CDCl3) d 0.95 (d, 3H, J ¼ 7.2 Hz),
reaction was carried out under Ar. To a cooled (–781C) stirred solution of 1.11 (s, 3H), 1.18 (s, 3H), 1.81–1.87 (m, 1H), 2.44 (s, 3H), 3.91 (dd, 1H,
methyltriphenylphosphonium bromide (1.50 g, 4.20mmol) in THF (50 ml), n- J ¼ 7.8, 9.5Hz), 4.23 (dd, 1H, J ¼ 4.4, 9.5 Hz), 7.34 (d, 2H, J ¼ 8.4 Hz), 7.79 (d,
BuLi (2.69 M in hexane, 1.26ml, 3.39mmol) was added. After being stirred at – 2H, J ¼ 8.4 Hz).
781C for 30 min, the mixture was warmed to 0 1C and a solution of 18
The following reaction was carried out under Ar. To a stirred solution of
(967mg, 1.68mmol) in THF (8.0ml) was added at 0 1C. After being stirred at monotosylate obtained above (2.06 g) in Et2O (60 ml), MsCl (1.29 ml,
0 1C for 1 h, the mixture was quenched with saturated aqueous NH4Cl (30 ml)
at 0 1C and extracted with EtOAc (20 mlꢂ 3). The combined extracts were
dried and concentrated in vacuo. The residue was purified by column
16.7 mmol) was added. Then Et3N (15.8ml, 113 mmol) was added slowly at
0 1C. After being stirred at rt for 15h, the mixture was quenched with aqueous
1 M HCl (60 ml) at 0 1C and extracted with EtOAc (30 mlꢂ 3). The combined
chromatography on silica gel (EtOAc/hexane, 1:30) to provide 842 mg (87%) extracts were washed with aqueous 1 M HCl (30 ml), saturated aqueous
of 10 as a colorless oil: TLC Rf 0.59 (EtOAc/hexane, 1:4); [a]D26 þ 39.5 (c 1.07, NaHCO3 (30 ml) and saturated brine (30 ml). The organic layer was dried
CHCl3); IR (neat) 2932, 1730 cmꢀ1
;
1H-NMR (300 MHz, CDCl3) d 0.03 (s,
3H), 0.08 (s, 3H), 0.10 (s, 6H), 0.82 (s, 9H), 0.92 (s, 9H), 1.10 (d, 3H, graphy on silica gel (EtOAc/hexane, 1:15) to provide 1.15g (56% over three
and concentrated in vacuo. The residue was purified by column chromato-
J ¼ 6.2 Hz), 1.41 (s, 3H), 2.05 (dd, 1H, J ¼ 5.6, 14.5Hz), 2.20 (dd, 1H, J ¼ 3.8,
steps) of 21 as a colorless oil: TLC Rf 0.60 (EtOAc/hexane, 1:4); [a]D27þ 7.4 (c
14.5Hz), 3.37 (s, 3H), 3.67 (dd, 1H, J ¼ 3.4, 8.3 Hz), 3.73 (dd, 1H, J ¼ 6.2, 0.910, CHCl3); IR (neat) 2974, 1649cmꢀ1; 1H-NMR (300 MHz, CDCl3) d 1.02
9.8 Hz), 3.73-3.83 (m, 2H), 3.89-3.98 (m, 2H), 3.91 (t, 1H, J ¼ 8.3 Hz), 4.61 (d,
1H, J ¼ 3.4 Hz), 4.71 (dd, 1H, J ¼ 8.3, 9.8 Hz), 4.84 (dd, 1H, J ¼ 3.8, 5.6 Hz),
5.17 (d, 1H, J ¼ 17.3Hz), 5.19 (d, 1H, J ¼ 10.5 Hz), 6.03 (dd, 1H, J ¼ 10.5,
17.3Hz); 13C-NMR (125MHz, CDCl3) d –4.3, –4.0, –3.3, –2.7, 17.8, 17.9, 18.5,
(d, 3H, J ¼ 6.9Hz), 1.62 (d, 3H, J ¼ 0.6Hz), 2.47 (m, 1H), 2.45 (s, 3H), 3.86
(dd, 1H, J ¼ 7.1, 9.5 Hz), 3.99 (dd, 1H, J ¼ 6.6, 9.5 Hz), 4.69 (m, 1H), 4.78 (m,
1H), 7.34 (d, 2H, J ¼ 8.3 Hz), 7.78 (d, 2H, J ¼ 8.3Hz); 13C-NMR (125MHz,
CDCl3) d 15.9, 20.1, 21.6, 40.1, 73.1, 112.0, 127.9 (2C), 129.8 (2C), 133.1,
20.3, 26.0 (3C), 26.2 (3C), 42.2, 46.9, 54.9, 64.3, 64.7, 65.6, 71.9, 74.5, 77.8, 144.6, 144.9; HRMS (EI) calculated for C13H18O3S (Mþ ) m/z 254.0977 found
99.7, 102.2, 115.0, 140.5, 174.4; HRMS (EI) calculated for C27H51O7Si2 (Mþ
OMe) m/z 543.3173, found 543.3172.
(2R)-2-((1,3-dioxolan-2-yl)methyl)-2-methylbut-3-en-1-ol (19) and methyl
–
254.0981.
(3S)-4-bromo-2,3-dimethylbut-1-ene (22). The following reaction was carried
out under Ar. To a stirred solution of 21 (2.60 g, 10.2mmol) in THF (26 ml)
3-O-(tert-butyldimethylsilyl)-6-deoxy-a-D-glucopyranoside (20). The following LiBr (3.55 g g, 40.8mmol) was added. After being stirred under reflux for 3.5h,
reaction was carried out under Ar. To a cooled (–181C) stirred solution of 10 the mixture was cooled to rt, diluted with Et2O (50 ml), and washed with
(842mg, 1.46 mmol) in CH2Cl2 (17 ml), Dibal-H (1.02 M in toluene, 5.74ml, saturated aqueous NH4Cl (80 mlꢂ 3) and saturated brine (80 ml).
5.85mmol) was added. After being stirred at rt for 45min, the mixture was The organic layer was dried and concentrated by distillation to provide
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1.67 g of crude 22, which was used in the next step without further
(2R,5R)-2-((1,3-dioxolan-2-yl)methyl)-2,4,5-trimethylcycohex-3-en-1-one (5).
1
purification: TLC Rf 0.78 (EtOAc/hexane, 1:10); H-NMR (300MHz, CDCl3) The following reaction was carried out under Ar. To a stirred solution of 6
d 1.17 (d, 3H, J ¼ 6.9Hz), 1.72 (s, 3H), 2.50–2.57 (m, 1H), 3.33 (dd, 1H, (305 mg, 1.21mmol) in degassed toluene (62 ml), Grubbs 2nd generation
J ¼ 7.4, 9.8 Hz), 3.44 (dd, 1H, J ¼ 6.2, 9.8 Hz), 4.78-4.79 (m, 1H), 4.84–4.86 catalyst 24 (54 mg, 0.060mmol) was added. After being stirred at 801C for
(m, 1H).
18h, the mixture was cooled to rt and concentrated in vacuo. The residue was
(2R)-2-((1,3-dioxolan-2-yl)methyl)-2-methylbut-3-enal (7). To a cooled (0 1C) purified by column chromatography on silica gel (EtOAc/hexane, 1:30) to
stirred solution of 19 (390mg, 2.27mmol) in CH2Cl2 (8ml), NaHCO3 provide 245 mg (90%) of 5 and 22mg (7%) of recovered 6. Compound 5 was
(572mg, 6.81mmol) and Dess–Martin periodinane (1.44 g, 3.41 mmol) were obtained as a colorless oil: TLC Rf 0.36 (EtOAc/hexane, 1:4); [a]D26 þ 103.3 (c
1
added. After being stirred at rt for 1 h, the mixture was quenched with 1.00, CHCl3); IR (neat) 2965, 1714 cmꢀ1; H-NMR (300MHz, CDCl3) d 1.07
saturated aqueous NaHCO3/20 wt% aqueous Na2S2O3 (1:1, 20 ml) at 0 1C and (d, 3H, J ¼ 7.2 Hz), 1.14 (s, 3H), 1.73 (dd, 1H, J ¼ 4.1, 14.1 Hz), 1.77 (d, 3H,
extracted with CH2Cl2 (10 mlꢂ 3). The combined extracts were dried and J ¼ 0.6 Hz), 2.16 (dd, 1H, J ¼ 6.0, 14.1Hz), 2.31 (dd, 1H, J ¼ 5.0, 14.0Hz),
concentrated in vacuo. The residue was purified by column chromatography on 2.45–2.56 (m, 1H), 2.73 (dd, 1H, J ¼ 6.4, 14.0Hz), 3.73–3.79 (m, 2H), 3.87–
silica gel (EtOAc/hexane, 1:15) to provide 370 mg (96%) of 7 as a colorless oil: 3.94 (m, 2H), 4.84 (dd, 1H, J ¼ 4.1, 6.0 Hz), 5.25 (br s, 1H); 13C-NMR
TLC Rf 0.71 (EtOAc/hexane, 1:1); [a]D26 þ 6.0 (c 0.990, CHCl3); IR (neat) 3020, (125 MHz, CDCl3) d 19.6, 21.3, 26.9, 36.2, 42.4, 44.4, 46.2, 64.4, 64.6, 102.4,
1727 cmꢀ1; 1H-NMR (300 MHz, CDCl3) d 1.26 (s, 3H), 1.99 (dd, 1H, J ¼ 4.5, 128.1, 137.5, 213.8; HRMS (EI) calculated for C13H20O3 (Mþ ) m/z 224.1413,
14.4 Hz), 2.06 (dd, 1H, J ¼ 5.5, 14.4Hz), 3.78–3.83 (m, 2H), 3.92–3.96 (m, found 224.1414.
2H), 4.91 (dd, 1H, J ¼ 4.5, 5.5 Hz), 5.16 (d, 1H, J ¼ 17.6Hz), 5.27 (d, 1H,
(1S,2R,5R)-2-((1,3-Dioxolan-2-yl)methyl)-1([2-(ethoxycarbonyl)ethynyl)-
J ¼ 10.8Hz), 5.83 (dd, 1H, J ¼ 10.8, 17.6Hz), 9.38 (s, 1H); 13C-NMR 2,4,5-trimethylcyclohex-3-en-1-ol (4). The following reaction was carried out
(125MHz, CDCl3) d 18.7, 39.9, 50.7, 64.8, 64.9, 101.9, 116.7, 138.4, 201.5; under Ar. To a cooled (–78 1C) stirred solution of ethyl propiolate
HRMS (EI) calculated for C9H14O3 (Mþ ) m/z 170.0943, found 170.0944.
(0.087 ml, 0.90 mmol) in THF (0.5 ml) n-BuLi (2.69 M in hexane, 0.34 ml,
1:1 mixture of (3R,4R and S,6R)-3-[(1,3-dioxolan-2-yl)methyl]-3,6,7-tri- 0.92 mmol) was added. The mixture was stirred at –78 1C for 1 h, and a
methylocta- 1,7-dien-4-ols (23). The following reaction was carried out under solution of 5 (27.6 mg, 0.123 mmol) in THF (1.3 ml) was added. After being
Ar. To magnesium turnings (372mg, 10.2mmol) soaked with THF (8ml) were stirred at –78 1C for 1.5 h, the mixture was quenched with saturated
added 1,2-dibromoethane (131ml, 1.53 mmol) and a solution of crude 22 aqueous NH4Cl (5 ml) at –78 1C and extracted with EtOAc (5 ml ꢂ 3). The
obtained above (1.67 g) in THF (2ml). The mixture was stirred under reflux combined extracts were dried and concentrated in vacuo. The residue was
for 1 h, and a solution of 7 (370 mg, 2.17mmol) in THF (3ml) was added. purified by column chromatography on silica gel (EtOAc/hexane, 1:20) to
After being stirred at rt for 1 h, the mixture was quenched with saturated provide 34.1 mg (86%) of 4 as a colorless oil: TLC Rf 0.39 (EtOAc/hexane,
aqueous NH4Cl (20 ml) at 0 1C and extracted with EtOAc (10 mlꢂ 3). The 1:2); [a]D25 þ 7.8 (c 1.07, CHCl3); IR (neat) 3437, 3020, 2233, 1707 cmꢀ1
;
combined extracts were washed with saturated brine (10 ml), dried and 1H-NMR (300 MHz, CDCl3) d 1.07 (d, 3H, J ¼ 7.2 Hz), 1.29 (s, 3H), 1.30 (t,
concentrated in vacuo. The residue was purified by column chromatography 3H, J ¼ 7.1 Hz), 1.67 (s, 3H), 1.83 (dd, 1H, J ¼ 8.7, 13.2 Hz), 1.85 ꢀ1.90 (m,
on silica gel (EtOAc/hexane, 1:20) to provide 326 mg (59%) of 23 as a ca. 1:1 2H), 2.07 (dd, 1H, J ¼ 6.6, 13.2 Hz), 2.35–2.40 (m, 1H), 3.35 (br s, 1H),
diastereomeric mixture and 135 mg (36%) of 19. Compound 23 was obtained 3.81–3.88 (m, 2H), 3.95–4.01 (m, 2H), 4.21 (q, 2H, J ¼ 7.1 Hz), 5.00 (dd,
as a colorless oil: TLC Rf 0.24 (EtOAc/hexane, 1:4); [a]D27–6.5 (c 1.31, CHCl3); 1H, J ¼ 4.3, 5.4 Hz), 5.07 (s, 1H); 13C-NMR (125 MHz, CDCl3) d 14.0, 19.2,
1
IR (neat) 3491, 2965cmꢀ1; H-NMR (500MHz, CDCl3) d 1.01 (d, 3Hꢂ 1/2, 21.0, 23.8, 33.6, 41.1, 41.6, 42.2, 61.9, 64.6, 64.9, 73.7, 76.4, 89.8, 102.6,
J ¼ 6.9 Hz), 1.02 (d, 3H ꢂ 1/2, J ¼ 6.9 Hz), 1.04 (s, 3Hꢂ 1/2), 1.06 (s, 3H ꢂ 1/ 128.4, 136.6, 153.6; HRMS (EI) calculated for C18H26O5 (Mþ ) m/z
2), 1.33-1.51 (m, 2H), 1.61 (s, 3Hꢂ 1/2), 1.68–1.77 (m, 1H), 1.71 (s, 3 Hꢂ 1/ 322.1780, found 322.1775.
2), 1.83–1.94 (m, 1H), 2.33–2.39 (m, 1Hꢂ 1/2), 2.48–2.58 (m, 1Hꢂ 1/2), 3.28
(5R,6R,9R)-6-((1,3-dioxolan-2-yl)methyl)-6,8,9-trimethyl-1-oxaspiro[4.5]
(d, 1Hꢂ 1/2, J ¼ 10.5Hz), 3.28 (d, 1Hꢂ 1/2, J ¼ 10.5Hz), 3.80–3.90 (m, 2H), deca-3,7-dien-2-one (25). To a stirred solution of 4 (4.8 mg, 0.015 mmol) in
3.93–4.10 (m, 2H), 4.67–4.69 (m, 1H), 4.73–4.74 (m, 1H), 4.90 (dd, 1Hꢂ 1/2, EtOAc (1 ml), Lindlar catalyst (1.0 mg) under Ar was added, and then the
J ¼ 2.7, 6.7Hz), 4.93 (dd, 1Hꢂ 1/2, J ¼ 4.0, 5.5 Hz), 5.03 (dd, 1Hꢂ 1/2, atmosphere was replaced to H2. The mixture was stirred for 1.5 h under H2,
J ¼ 1.3, 17.5Hz), 5.07 (dd, 1H ꢂ 1/2, J ¼ 1.2, 17.0 Hz), 5.12 (dd, 1Hꢂ 1/2, filtered through a pad of Celite, and washed well with EtOAc. The combined
J ¼ 1.3, 10.9Hz), 5.13 (dd, 1H ꢂ 1/2, J ¼ 1.2, 11.0 Hz), 5.85 (dd, 1Hꢂ 1/2, filtrate and washings were concentrated in vacuo. The residue was purified by
J ¼ 10.9, 17.5Hz), 5.87 (dd, 1Hꢂ 1/2, J ¼ 11.0, 17.0 Hz); 13C-NMR (125 MHz, column chromatography on silica gel (EtOAc/hexane, 1:20) to provide 3.1 mg
CDCl3) d 18.1 (1/2C), 18.6 (1/2C), 18.7 (1/2C), 19.4 (1/2C), 19.9 (1/2C), (74%) of 25 as a colorless oil: TLC Rf 0.52 (EtOAc/hexane, 1:2); IR (neat) 3020,
20.8 (1/2C), 36.1 (1/2C), 37.1 (1/2C), 38.0 (1/2C), 38.2 (1/2C), 41.3 (1/2C), 1755 cmꢀ1
42.6 (1/2C), 43.1 (1/2C), 43.2 (1/2C), 64.4 (1/2C), 64.6 (1/2C), 64.8 (1/2C),
;
1H-NMR (500 MHz, CDCl3) d 0.90 (s, 3H), 1.09 (d, 3H, J¼ 7.2
Hz), 1.66 (dd, 1H, J¼ 6.3, 12.8 Hz), 1.71 (s, 3H), 1.93 (dd, 1H, J¼ 6.3, 14.3 Hz),
65.0 (1/2C), 74.4 (1/2C), 74.6 (1/2C), 102.5 (1/2C), 102.7 (1/2C), 108.7 (1/2C), 1.99 (dd, 1H, J¼ 4.0, 14.3 Hz), 2.15 (dd, 1H, J¼ 10.6, 12.8 Hz), 2.19–2.25 (m,
110.6 (1/2C), 113.8, 143.7 (1/2C), 143.8 (1/2C), 149.0 (1/2C), 151.7 1H), 3.78–3.86 (m, 2H), 3.92–3.98 (m, 2H), 5.00 (dd, 1H, J¼ 4.0, 6.3 Hz), 5.29
(1/2C); HRMS (EI) calculated for C15H26O3 (Mþ ) m/z 254.1882, found (s, 1H), 6.05 (d, 1H, J¼ 5.7 Hz), 7.46 (d, 1H, J¼ 5.7 Hz); 13C-NMR (125 MHz,
254.1894.
CDCl3) d 19.5, 20.9, 22.1, 34.5, 38.3, 39.4, 43.0, 64.4, 64.7, 92.9, 102.8, 121.0,
128.6, 136.3, 159.5, 172.5; HRMS (EI) calculated for C16H22O4 (Mþ ) m/z
(3R,6R)-3-[(1,3-dioxolan-2-yl)methyl]-3,6,7-trimethylocta-1,7-dien-4-one
(6). To a cooled (01C), stirred solution of the mixture 23 (326mg, 1.28 mmol) 278.1518, found 278.1513.
in CH2Cl2 (6.5ml) were added NaHCO3 (323mg, 3.84mmol) and Dess–
(5S,6R,9R)-6-((1,3-dioxolan-2-yl)methyl)-4-methoxy-6,8,9-trimethyl-1-oxaspiro
Martin periodinane (815mg, 1.92mmol). The mixture was stirred at rt for 1 h, [4.5]deca-3,7-dien-2-one (3) and (1S,2R,5R)-2-((1,3-dioxolan-2-yl)methyl)-1-
and then quenched with 20% aqueous Na2S2O3 (15 ml). The mixture was ((Z)-1-methoxy-2-(ethoxycarbonyl)ethenyl)-2,4,5-trimethylcyclohex-3-en-1-ol
stirred vigorously for 1 h, and extracted with CH2Cl2 (10 ml ꢂ 4). The (26). The following reaction was carried out under Ar. To a stirred solution of
combined extracts were dried and concentrated in vacuo. The residue was 4 (34.6mg, 0.107mmol) and MS 3A powder (200mg) in MeOH (1.0ml) was
purified by column chromatography on silica gel (EtOAc/hexane, 1:30) to added NaOMe (1.0M in MeOH, 0.27 ml, 0.27mmol). After being stirred at rt
provide 281mg (87%) of 6 as a colorless oil: TLC Rf 0.59 (EtOAc/hexane, 1:4); for 18 h, the mixture was warmed to 601C. The mixture was stirred at 601C for
1
[a]D32–33.7 (c 0.990, CHCl3); IR (neat) 2969, 1708 cmꢀ1; H-NMR (300 MHz, 16.5h, quenched with saturated aqueous NH4Cl (5ml) and extracted with
CDCl3) d 0.97 (d, 3H, J ¼ 6.9 Hz), 1.30 (s, 3H), 1.69 (s, 3H), 2.06 (d, 2H, EtOAc (5mlꢂ 3). The combined extracts were dried and concentrated in
J ¼ 4.9 Hz), 2.45 (dd, 1H, J ¼ 7.6, 17.3 Hz), 2.61 (dd, 1H, J ¼ 5.1, 17.3 Hz), vacuo. The residue was purified by column chromatography on silica gel
2.64–2.76 (m, 1H), 3.58–3.80 (m, 2H), 3.90-3.95 (m, 2H), 4.67 (s, 2H), 4.84 (t, (EtOAc/hexane, 1:10) to provide 9.2mg (28%) of 3 and 7.5 mg of 26 (21%).
1H, J ¼ 4.9 Hz), 5.18 (d, 1H, J ¼ 17.5 Hz), 5.22 (d, 1H, J ¼ 10.5 Hz), 5.92 (dd, Compound 3 was obtained as a colorless oil: TLC Rf 0.17 (EtOAc/hexane, 1:2);
1H, J ¼ 10.5, 17.5Hz); 13C-NMR (125 MHz, CDCl3) d 19.4, 20.3, 20.4, 35.6, [a]D26 þ 11.1 (c 0.465, CHCl3); IR (neat) 3020, 1745, 1627 cmꢀ1
;
1H-NMR
41.1, 43.4, 52.3, 64.5, 64.7, 102.3, 109.0, 115.3, 141.1, 149.7, 210.4; HRMS (EI) (500 MHz, CDCl3) d 0.97 (s, 3H), 1.05 (d, 3H, J ¼ 6.9 Hz), 1.68 (s, 3H), 1.88
calculated for C15H24O3 (Mþ ) m/z 252.1726, found 252.1729.
(dd, 1H, J ¼ 6.5, 14.0Hz), 1.89 (dd, 1H, J ¼ 6.2, 14.3Hz), 1.93 (dd, 1H, J ¼ 3.8,
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Synthetic studies of versipelostatin
S Sasaki et al
154
14.3Hz), 2.05 (dd, 1H, J ¼ 9.7, 14.0 Hz), 2.33-2.41 (m, 1H), 3.77–3.86 (m, 2H),
3.79 (s, 3H), 3.91-3.96 (m, 2H), 5.01 (s, 1H), 5.02 (dd, 1H, J ¼ 3.8, 6.2 Hz),
5.19 (s, 1H); 13C-NMR (125 MHz, CDCl3) d 19.5, 21.0, 21.2, 32.6, 37.4, 39.1,
43.2, 59.2, 64.3, 64.7, 88.2, 89.1, 102.8, 126.9, 136.7, 171.8, 185.8; HRMS (EI)
calculated for C17H24O5 (Mþ ) m/z 308.1624, found 308.1633. Compound 26
was obtained as a colorless oil: TLC Rf 0.59 (EtOAc/hexane, 1:2); [a]D21 þ 33.8
(c 0.575, CHCl3); IR (neat) 3462, 3020, 1708, 1626cmꢀ1; 1H-NMR (500 MHz,
CDCl3) d 0.99 (s, 3H), 1.11 (d, 3H, J ¼ 7.0Hz), 1.61 (dd, 1H, J ¼ 4.6, 13.8Hz),
1.70 (s, 3H), 1.74 (dd, 1H, J ¼ 3.2, 14.9Hz), 2.00 (dd, 1H, J ¼ 6.0, 14.9Hz),
2.22 (dd, 1H, J ¼ 7.3, 13.8Hz), 2.25–2.30 (m, 1H), 3.34 (s, 1H), 3.68 (s, 3H),
3.80–3.89 (m, 2H), 3.91 (s, 3H), 3.95–4.00 (m, 2H), 4.99 (dd, 1H, J ¼ 3.2,
6.0 Hz), 5.17 (s, 1H), 5.60 (s, 1H); 13C-NMR (125MHz, CDCl3) d 20.5, 21.6,
25.7, 33.0, 38.8, 41.7, 42.6, 51.0, 62.4, 64.7, 64.8, 78.0, 95.8, 103.2, 128.1, 136.3,
166.2, 176.0; HRMS (EI) calculated for C18H27O6 (Mþ –H) m/z 339.1808,
found 339.1810.
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