Synthetic studies of venturicidins: Stereoselective synthesis of the C15-C27 segment based on two types of stereospecific epoxide opening reactions

Article abstract of DOI:10.1016/j.tetlet.2011.10.073

The C15-C27 segment of venturicidins was stereoselectively synthesized by using two types of stereospecific methyl substitution reactions of epoxides and subsequent stereocontrolled methylation reactions of lactone derivatives as the key steps.

Full text of DOI:10.1016/j.tetlet.2011.10.073

Tetrahedron Letters 52 (2011) 6948–6951
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Tetrahedron Letters
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Synthetic studies of venturicidins: stereoselective synthesis of the
C15–C27 segment based on two types of stereospecific epoxide opening
reactions
Yuji Suzuki a, Shinji Nagumo a, , Eiko Yasui a, Megumi Mizukami b, Masaaki Miyashita a,
⇑
⇑
a Department of Applied Chemistry, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan
b Hokkaido Pharmaceutical University, School of Pharmacy, Katsuraoka 7-1, Otaru 047-0264, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The C15–C27 segment of venturicidins was stereoselectively synthesized by using two types of stereo-
specific methyl substitution reactions of epoxides and subsequent stereocontrolled methylation reactions
of lactone derivatives as the key steps.
Received 14 September 2011
Revised 11 October 2011
Accepted 13 October 2011
Available online 18 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Venturicidin
Epoxide opening reaction
Epoxy-unsaturated ester
Epoxy sulfide
Venturicidin A, B, and X are 20-membered macrolide antibiotics
isolated from Streptomyces sp., which have been demonstrated to
exhibit potent inhibitory activities against various fungi, notably,
in low toxicity toward higher plants and animals.1 They have been
noted as potential inhibitors of Escherichic coli H+-ATPase.2 Ventu-
ricidin X, the aglycone of venturicidin A and B, is composed of a
polypropionate-derived chain and a highly substituted tetrahydro-
pyran ring, and contains ten asymmetric carbon atoms in total,
among which seven stereogenic centers are involved in the poly-
propionate side chain. The absolute stereostructures of venturici-
dins were unambiguously determined by their spectroscopic
analyses and chemical degradation, and finally by X-ray crystallo-
graphic analyses.1c,d
The distinctive biological properties, combined with complex
stereostructures, make the venturicidin macrolides attractive tar-
gets for synthetic chemists.3 Akita and Oishi et al. have reported
the first successful synthesis of venturicidin X3a,b and since then,
several synthetic studies of these macrolides have been reported3
including a formal total synthesis of venturicidin X by Nakata
et al.3c,f
segments were designed to connect by a Julia–Lithgoe olefination
and subsequent macrolactonization. We also planned the synthesis
of the C15–C27 segment, that is, sulfone 2, which should be obtain-
able from acetal 3. In addition, we noticed that the structure of 3
involves the same five-carbon unit (unit A) bearing three asym-
metric centers. These analyses led us to synthetic routes for unit
A shown in Scheme 2, wherein (i) a regioselective and stereospe-
cific methyl substitution reaction of a cis-c,d-epoxy a,b-unsatu-
rated ester with Me3Al-H2O,4 (ii) stereospecific methylation of a
trans-epoxy sulfide with Me3Al with double inversion of configura-
tion,5 both of which we have already developed, and (iii) stereose-
lective methylation reactions of d-lactone derivatives, are involved
as the key steps. We report herein the stereoselective synthesis of
the C15–C27 segment 27 corresponding to 2 according to Schemes
1 and 2.
Our synthesis started with stereoselective construction of C19–
C25 segment as shown in Scheme 3. Allyl alcohol 46 was converted
to c,d-epoxy-a
,b-unsaturated ester 67 by the reaction sequence of
stereoselective epoxidation with MCPBA8 and Swern oxidation fol-
lowed by the Horner–Emmons olefination. The key methylation
reaction of 6 was successfully performed with Me3Al and H2O
We set about synthetic studies of venturicidins that aimed at
developing an efficient synthetic route flexible enough to provide
access to the venturicidin macrolides. Our retrosynthesis of ventu-
ricidin X is shown in Scheme 1. Namely, venturicidin X was divided
into the C1–C14 segment 1 and the C15–C27 segment 2, and both
giving rise to the desired syn-d-hydroxy-c-methyl unsaturated
ester 77 as a single stereoisomer in 93% yield.4 After catalytic
hydrogenation of the double bond in 7 over PtO2 in the presence
of Al2O3 in EtOAc, treatment of the crude ester with PPTS9 in
ClCH2CH2Cl afforded lactone 87 in 90% yield (2 steps). It should
be noted that the addition of Al2O3 to the former reaction was
essential to prevent deprotection of the silyl group. The crucial
⇑
Corresponding authors.
E-mail address: bt13071@ns.kogakuin.ac.jp (S. Nagumo).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.073

Y. Suzuki et al. / Tetrahedron Letters 52 (2011) 6948–6951
6949
PO
CHO
27
14
19
RO
COOH
OP
15
O
3
O
OH O
O
1
H
7
O
H
OH
1
Venturicidin X (R = H)
+
OH
OH
HO
H N
2
O
ArO2S
R =
O
R =
O
O
OH
OP
O
2
Venturicidin A
Venturicidin B
unit A
unit A
chiral pool
25
OP
PO
O
O
3
Scheme 1. Retrosynthetic analysis of venturicidins.
which was transformed into alcohol 117 by treatment with DIBAH
in THF in quantitative yield.
stereoselective methylation
of lactone ring
We next focused on the construction of the second unit A corre-
R
O
R
sponding to C15–C19. Although the substitution reaction of
epoxy- ,b-unsaturated esters with Me3Al–H2O is a very useful
methodology to introduce a methyl group at the -position stere-
c,d-
R
a
O
OP
OP
c
unit A
O
oselectively, the presence of an oxygen function in the vicinity of
epoxide is essential for these reactions. Therefore, we decided to
use the reaction of an epoxy sulfide with Me3Al as an alternative
method in order to introduce a methyl group at the C18 position.5
Since the methyl substitution reaction of epoxy sulfides with
Me3Al proceeds via episulfonium ions with retention of the config-
uration, trans-epoxy sulfide 15 was selected as our substrate
(Scheme 4). Toward this end, alcohol 11 was converted to trans-al-
lyl alcohol 137 in three steps (84%): (i) Swern oxidation; (ii) Horn-
er–Emmons reaction; (iii) reduction with DIBAH. The Katsuki–
Sharpless epoxidation11 of 13 with D-DET proceeded smoothly to
give trans-epoxide 147 in 85% yield, which was then converted to
sulfide 157 by treatment with PhSSPh and n-Bu3P in pyridine
(97%).12 The crucial methylation of sulfide 15 with Me3Al with
double inversion of configuration cleanly occurred in CH2Cl2 to fur-
nish the desired alcohol 167 quantitatively.
O
EtO2C
EtO
R
R
O
OH
O
stereospecific methyl
substitution of epoxide
PhS
R
PhS
O
R
OH
Scheme 2. Synthetic plan of unit A.
methylation of 8 with LDA and MeI in THF occurred stereoselec-
tively in the presence of HMPA to afford lactone 97 as a single iso-
mer in 86% yield.3b,g,10 The stereochemistry of the product was
unambiguously confirmed by NOE measurement between C20-H
and C22-Me peaks in 9. Subsequent treatment of the lactone 9 with
2,2-dimethoxypropane in the presence of a catalytic amount of
TsOH in MeOH produced the desired acetal ester 107 in 88% yield,
The next issue to introduce a methyl group at the C16 position
was performed as follows. First, alcohol 16 was converted to sulf-
oxide 177 in two steps: (i) protection of the hydroxyl group with
benzyl bromide; (ii) oxidation of the sulfide with NaIO4. Subse-
EtO2C
HO
HO
OTBS
a
b
c
EtO2C
OTBS
OTBS
OTBS
OH
O
O
4
5
6
7
NOE 3.7%
HO
OTBS
OTBS
h
22
MeO2C
d, e
f
g
25
H
O
O
O
O
O
O
20
10
11
8
O
9
O
Scheme 3. Reagents and conditions: (a) MCPBA, CH2Cl2, 84%; (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2, (ii) (EtO)2P(O)CH2CO2Et, NaH, THF, 80%; (c) Me3Al, H2O, CH2Cl2, À30 °C, 93%;
(d) H2, PtO2, Al2O3, EtOAc; (e) PPTS, ClCH2CH2Cl, 90% (in 2 steps); (f) LDA, HMPA, THF, then MeI, 86%; (g) Me2C(OMe)2, TsOH, MeOH, 88%; (h) DIBAH, THF, 99%.

6950
Y. Suzuki et al. / Tetrahedron Letters 52 (2011) 6948–6951
EtO2C
a
b
c
O
11
O
O
OH
O
O
HO
O
O
12
13
14
Ph
S
PhS
d
e
O
PhS
OH
O
O
O
O
O
O
O
Al
16
15
f, g
j, k
h
i
OHC
EtO2C
PhS
OBn
O
O
OBn
O
O
OH
19
O
O
O
17
18
NOE 4%
18
16
25
l
m, n
H
O
O
O
OTBS
OH
O
O
O
O
O
O
15
O
O
20
21
22
N
S
o, p
q
r-u
S
OH
OBn
O
OBn
O
O
24
23
v
N
S
N
S
CHO
S
S
OBn TBSO
OBn TBSO
OH
25
26
O
15S
O
w, x
N
S
17
20
22
27
OBn TBSO
OTES
27
Scheme 4. Reagents and conditions:(a) (i) (COCl)2, DMSO, Et3N, CH2Cl2, (ii) (EtO)2P(O)CH2CO2Et, NaH, THF, 87%; (b) DIBAH, THF, 97%; (c) D-DET, Ti(Oi-Pr)4, TBHP, CH2Cl2, 90%;
(d) PhSSPh, n-Bu3P, pyridine, 97%; (e) Me3Al, CH2Cl2, quant.; (f) BnBr, NaH, TBAI, DMF, 91%; (g) NaIO4, MeOH/H2O, 83%; (h) TFAA, 2,6-lutidine, CH3CN then NaHCO3 aq, HgCl2;
(i) (EtO)2P(O)CH2CO2Et, NaH, THF, 76% (in 2 steps); (j) H2, Pd(OH)2-C, Al2O3, EtOH; (k) PPTS, ClCH2CH2Cl, then Me2C(OMe)2, 80% (in 2 steps); (l) LDA, THF, then MeI, 92%; (m)
LAH, THF, 98%; (n) TBSCl, imidazole, CH2Cl2, 89%; (o) BnBr, KH, TBAI, THF, 54%; (p) TBAF, THF, 97%; (q) DIAD, PPh3, BTSH, THF, 78%; (r) HCl, MeOH, 87%; (s) TBSOTf, 2,6-
lutidine, CH2Cl2, 95%; (t) HFÁPy, pyridine, THF, 88%; (u) Dess–Martin periodinane, CH2Cl2; (v) EtMgBr, THF, 0 °C, 79% (in 2 steps); (w) MCPBA, CH2Cl2, 91%; (x) TESOTf, 2,6-
lutidine, CH2Cl2, 98%.
quent Pummerer rearrangement13 was successfully performed by
the initial treatment of 17 with TFAA and 2,6-lutidine in CH3CN fol-
lowed by the addition of HgCl214 and saturated NaHCO3 solution to
afford aldehyde 18,7 which was immediately transformed into
unsaturated ester 197 by a Horner–Emmons reaction in 76% yield
(2 steps). Conversion of 19 to lactone 207 was carried out in 2
steps: (1) catalytic hydrogenation over Pd(OH)2-C in the presence
of Al2O3 in EtOH; (2) lactonization with PPTS in ClCH2CH2Cl fol-
lowed by an addition of 2,2-dimethoxypropane. Addition of Al2O3
or 2,2-dimethoxypropane to these reactions was essential to pre-
vent partial hydrolysis of the acetonide group. Same as the meth-
ylation reaction of 8, that of lactone 20 with LDA and MeI in THF
occurred stereoselectively to furnish the desired product 217 in
92% yield, of which stereochemistry was unambiguously con-
firmed by NOE measurement between C16-H and C18-Me peaks.
Thus, seven asymmetric carbon centers in the C15–C25 segment
were constructed with complete stereoselectivity.
THF gave diol in 98%, whose primary hydroxyl group was protected
as a TBS ether (89%). In turn, alcohol 227 was converted to 237 in 2
steps: (i) benzylation with BnBr, KH, and TBAI in THF; (ii) removal
of the TBS group with TBAF in THF. Subsequent sulfenylation of
alcohol 23 was performed using diisopropyl azodicarboxylate,
Ph3P, 2-mercaptobenzothiazole in THF to afford the desired sulfide
247 in 78% yield. On the other hand, installation of the C26–C27
residue was carried out according to Scheme 4. Initially, acetal
24 was transformed into aldehyde 257 by a four-step reaction se-
quence: (i) treatment with HCl in MeOH; (ii) silylation of the
resulting diol with TBSOTf; (iii) selective removal of the primary
TBS group with HFÁPy in THF; (iv) Dess–Martin oxidation. The addi-
tion reaction of ethyl Grignard reagent to aldehyde 25 cleanly oc-
curred to produce alcohol 267 as an epimeric mixture (
a:b = ca.
5:1) in 79% yield. Finally, oxidation of the sulfide moiety in 26 with
MCPBA in CH2Cl2 followed by protection of the secondary hydroxyl
group with TESOTf gave the targeted compound 277 in high overall
yield.
In conclusion, we have completed the stereoselective synthesis
of the C15–C27 segment of venturicidins by means of two types of
stereospecific methyl substitution reactions of epoxides and
The remaining tasks were the introduction of a sulfone moiety
necessary for Julia coupling with the C1–C14 segment and coupling
of the terminal C26–C27 residue. These transformations were
carried out as follows. Reduction of lactone 21 with LiAlH4 in

Y. Suzuki et al. / Tetrahedron Letters 52 (2011) 6948–6951
6951
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Acknowledgments
Financial support from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (a Grant-in-Aid for Scientific
Research (B) (No. 19350027) and Advanced Promotion Research
Program for Education of Graduate School) is gratefully
acknowledged.
hydroxy-2-methylpropionate in
5 steps: (i) silylation, (ii) reduction with
DIBAH, (iii) Swern oxidation, (iv) Horner–Emmons reaction using Ando
reagent, and (v) DIBAH reduction.
7. All new compounds gave 1H NMR, 13C NMR, IR and HR-MS in accordance with
their structures.
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