Formal total synthesis of (+)-methynolide

Article abstract of DOI:10.1055/s-2002-25364

A convergent total synthesis of (+)-methynolide was achieved in 23 steps highlighted by a ring-closing metathesis, a Takai reaction, a Sharpless kinetic resolution of an allylic alcohol and a crotylboration.

Full text of DOI:10.1055/s-2002-25364

LETTER
715
Formal Total Synthesis of (+)-Methynolide
F
J
ormal To
a
tal Synthes
n
is of (+)-Me
t
i
hynoli
n
de e Cossy,* David Bauer, Véronique Bellosta
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 27 December 2001
O
Abstract: A convergent total synthesis of (+)-methynolide was
achieved in 23 steps highlighted by a ring-closing metathesis, a Ta-
kai reaction, a Sharpless kinetic resolution of an allylic alcohol and
a crotylboration.
8
7
6
HO
O
1
1
0
(+)-Methynolide
3
Key words: macrocycles, crotylboronate, metathesis, Takai reac-
tion, kinetic resolution
11
O
OH
O
Complex molecules like macrolide antibiotics with multi-
ple stereocenters have received much attention due to
their powerful biological activities. One member of this
1
O
O
macrolide family is methynolide, the aglycone of methy-
2
mycin. The first total synthesis of methymycin (31 steps,
OTBS
3
overall yield of 0.12%) by Masamune as well as subse-
OH
quent syntheses of methynolide or its corresponding seco-
1
6
4
5
6
acid by the groups of Grieco, Yamaguchi, White,
7
8
O
Yonemitsu and Ditrich combined two enantioenriched
fragments giving an open-chain precursor which was cy-
I
8
7
X
3
–5,8
clized by an intramolecular esterification
or an in-
R2O
+
7
10
tramolecular Wittig-type reaction. Three of these
3
syntheses combined the chiral C –C fragment with the
11
1
8
OR1
OR'
3
,7,8
C –C fragment
and three of them combined the C –
1
9
11
1
4
-6
B
A
C fragment with the C –C fragment. Linear strategies
OR
7
8
11
9
10
11
were also reported by Ireland, Vedejs and Bartlett.
[O]
Takai
O
O
7
For our part, we planned the synthesis of (+)-methynolide
from the previously synthesized intermediate 16.4 The
retrosynthetic analysis of this intermediate suggested a
convergent approach, i. e., the assemblage of 16 from two
enantioenriched fragments A (C –C ) and B (C –C ).
,6
OR
O
OR
O
3
1
OH
1
7
8
11
D
C
(
+)-11
These two fragments would be linked by addition of a vi-
nyl lithium reagent, derived from the vinyl iodide B, to the
O
carboxylic functionality of A. The synthesis of the C –C7
1
fragment was envisaged from lactone C that would be ob-
tained from the unsaturated lactone D that could be pro-
duced from the corresponding diene E by a ring-closing
metathesis (RCM). The precursor of this diene is the com-
mercially available methyl (2S)-3-hydroxy-2-methylpro-
pionate (+)-1. The synthesis of fragment B was envisaged
OR
1
O
7
OH
O
3
OMe
H
O
(+)-1
20
E
Methacrolein
1
2
Scheme 1 Retrosynthetic scheme
by a Takai reaction applied to an aldehyde that can be
obtained by dihydroxylation and subsequent selective ox-
idation of the enantioenriched allylic alcohol (+)-11. Al- The synthesis of the C –C fragment A was achieved
1
7
cohol (+)-11 will be synthesized from methacrolein 20 starting from methyl (2S)-3-hydroxy-2-methylpropionate
(
Scheme 1).
(+)-1 (Scheme 2). The -hydroxy ester (+)-1 was trans-
formed to the silyl ether (+)-2 in quantitative yield by us-
ing tert-butyldimethylsilyl chloride (TBSCl, imidazole,
DMF) that was then converted to aldehyde (+)-313 in two
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
437-2096,E;2002,0,05,0715,0718,ftx,en;G24701ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
steps by reduction with DIBAL-H followed by pyr SO
oxidation. The overall yield for the conversion of (+)-1 to
aldehyde (+)-3 was 82%. Control of the stereogenic cen-
3
1
©

7
16
J. Cossy et al.
LETTER
ters at C and C was achieved by addition of crotylbor-
onate ( )-4 to aldehyde (+)-3. Compound (–)-5 was
3
4
OH
O
TBSO
O
1
4
14
a)
OMe
OMe
isolated in 81% yield and with a diastereomeric excess up
1
5
to 95%. The next step was the transformation of (–)-5
to the precursor of the unsaturated lactone (+)-7. When
(+)-1
(+)-2
b), c)
(
–)-5 was treated with methacryloyl chloride at 0 °C in the
CO2iPr
CO2iPr
O
O
presence of triethylamine and a catalytic amount of
DMAP, the unsaturated diene ester (+)-6 was isolated in
B
TBSO
OH
TBSO
O
(-)-4
7
9% yield. To transform the unsaturated diene ester (+)-6
H
to the corresponding unsaturated lactone, several RCM
d)
catalysts were examined. The use of catalyst I16 (15
(-)-5
(+)-3
mol%, CH Cl , reflux, 14 h) led to lactone (+)-7 in 77%
2
2
yield for a conversion of 80%. A better result was ob-
MesN
NMes MesN
Cl
NMes
1
7
tained with catalyst II (15 mol%, CH Cl , reflux, 14 h)
2
2
e)
Cl
Cl
as lactone (+)-7 was isolated in 98% yield for complete
conversion of (+)-6. After hydrogenation (H , PtO ) and
Ru
Ru
Cl
Ph
Ph
PCy3
PCy3
2
2
I
II
treatment with LDA, a 2.3:1 mixture of lactones (+)-8 and
+)-8 (epimer at C ) was obtained in 97% yield. These
(
6
O
O
two compounds were separated by flash chromatogra-
1
8
phy, and lactone (+)-8 was transformed to the required
amide (–)-9 in two steps. After treatment of lactone (+)-8
with Weinreb’s amine hydrochloride in the presence of
TBSO
O
TBSO
O
f)
1
9
trimethylaluminium, the resulting hydroxy amide was
(+)-6
(+)-7
protected by using tert-butyldimethylsilyl chloride in the
2
0
presence of AgNO3 to produce the desired amide (–)-9
in 70% yield for the two steps. By using these two key
steps reactions, a crotylboration and a ring-closing met-
athesis, methyl (2S)-3-hydroxy-2-methylpropionate (+)-1
was transformed to the desired amide (–)-9 in 10 steps
with an overall yield of 23%.
g), h)
O
7
TBSO
1
OTBS
3
O
7
TBSO
1
O
3
i), j)
O
N
The C –C fragment B was synthesized from metha-
8
11
crolein 10 (Scheme 3). When methacrolein 10 was treated
with ethylmagnesium bromide in ether, the resulting alco-
hol 11, isolated in 68% yield, was converted to (+)-11 of
(
-)-9
(+)-8
Scheme 2 a) TBSCl, imidazole, DMF. b) DIBAL-H, THF.
2
1
9
0% enantiomeric excess, by using a Sharpless kinetic c) pyr SO , DMSO, Et N, CH Cl , 0 °C, 82% (3 steps). d) (–)-4,
3
3
2
2
2
2
MS 4Å, toluene, 81%. e) methacryloyl chloride, Et N, cat. DMAP,
CH Cl , 0 °C, 79%. f) I or II (15 mol%), CH Cl , reflux, 96–98%.
g) H (4 atm), PtO , EtOH, 8/8 = 1/1. h) LDA, –78 °C, 1.5 h; then
0% aqueous citric acid, –78 °C, 8 (65% yield, 2 steps) and 8 (32%
resolution [Ti(iPrO) , (+)-DIPT, t-BuOOH, MS 4 Å].
3
4
2
2
2
2
After protection of the alcohol functionality (tert-bu-
tyldimethylsilyl chloride) the silyl ether was treated with
2
2
1
OsO in the presence of NMO (acetone, H O) to produce
4
2
yield, 2 steps). i) Me(MeO)NH.HCl, AlMe , CH Cl . j) TBSCl,
3
2
2
the monoprotected triols 12 and 12 in 75% yield as 5.5:1 AgNO , DMF, 70% (2 steps).
3
mixture of two diastereomers which were not separable.23
After oxidation of the mixture of 12 and 12 (pyr SO3,
DMSO, Et N), the resulting aldehydes were transformed completed the carbon skeleton of methynolide by addition
3
to vinyl iodides 13 and 13 in 78% yield by using a Takai of vinyllithium reagent 14 , which was obtained from
1
2
reaction (HCI , CrCl ). The stereoselectivity E/Z > 97:3 the corresponding vinyl iodide by metal-halogen ex-
3
2
1
was determined by H NMR analysis. Compounds 13 and change (t-BuLi, ether, –78 °C), to the previously obtained
3 were then deprotected (TBAF) and the resulting diols amide (–)-9. The coupling product (+)-15 was obtained in
1
25
were transformed to the ketal derivatives by using 2,2- quantitative yield. A selective deprotection to the known
dimethoxypropane (PPTS, acetone). The two diastereo- intermediate (+)-1626 was achieved (Scheme 4) by treat-
meric products were separated by flash chromatography ment of (+)-15 with HF pyridine in a mixture of pyridine–
2
4
on silica gel and ketal (+)-14 was isolated in 74% yield. THF. As (+)-16 has been previously converted to meth-
ynolide in 3 steps,3 a formal total synthesis of methynol-
,4
The transformation of methacrolein 10 to (+)-14 was
achieved in 8 steps with an overall yield of 27%. With
ide is thus achieved in 23 steps.
both building blocks ( )-9 and (+)-14 in hand, we next
Synlett 2002, No. 5, 715–718 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Formal Total Synthesis of (+)-Methynolide
717
References
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HO
a)
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(
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OTBS
OTBS
(
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Scheme 3 a) EtMgBr, Et O, 68%. b) Ti(OiPr ), (+)-DIPT,
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2
4
2
2
4
2
3
3
2
2
2
3
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(
(
O
I
8
1
7
8
1
) t-BuLi, Et2O
O
O
O
O
2)
(-)-9
1
11
OTBS
OTBS
quantitative
(
6) White, J. D. In Strategies and Tactics in Organic Synthesis;
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1
(+)-14
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(
1
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O
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(
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O
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O
O
1
1
ref. 3, 4
O
OH
OTBS
OH
1
(
+)-Methynolide
(
+)-16
Scheme 4
(
(
(
(
(
(
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Compared to other syntheses of methynolide, the synthe-
sis reported in this paper represents one of the shortest
routes to the 11-membered macrocyclic lactone.
3
1
1
Acknowledgement
1
We thank Prof A. Fürstner and Pr. S. P. Nolan for a generous gift of
catalyst II. D. B. thanks the CNRS and Rhône–Poulenc–Rorer–
Aventis for a grant.
1
15) The diastereomeric purity of ( )-5 was determined by H
NMR analysis.
16) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) I was prepared according to: Garber, S. B.;
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Soc. 2000, 122, 8168.
Synlett 2002, No. 5, 715–718 ISSN 0936-5214 © Thieme Stuttgart · New York

7
18
J. Cossy et al.
LETTER
(23) The diastereoselectivity is in agreement with the results
(
17) (a) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247. (b) Huang, J.; Stevens, E.
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Chem. 1990, 55, 1698
2
674. (c) Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S.
(24) The ketalization was quantitative and the separation of (+)-
14 and its C10 epimer was performed by flash
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Organometallics 2000, 19, 2055.
chromatography on silica gel (hexanes–Et O, 100:0 to
2
90:10).
(25) For a conversion of 66% of ( )-9.
1
(
18) Purification by flash chromatography was performed on
(26) Analytical data of (+)-16: H NMR (CDCl , 300 MHz)
3
silica gel (hexanes:Et O, 95:5). Physical and spectral data of
(ppm) = 6.80 (d, 1 H, J = 15.4 Hz), 6.44 (d, 1H, J = 15.4
Hz), 3.82 (apparent t, 1 H, J = 6.6 Hz), 3.65–3.40 (m, 3 H),
2.82 (m, 1 H), 1.94–0.84 (m, 22 H), 1.12 (d, 3 H, J = 7.0 Hz),
1.03 (t, 3 H, J = 7.4 Hz), 0.91 (s, 9 H), 0.05 (s, 3 H), 0.04 (s,
2
(+)-8 are in accordance with the literature. See: Pilli, R. A.;
de Andrade, C. K. Z.; Souto, C. R. O.; de Meijere, A. J. Org.
Chem. 1998, 63, 7811.
1
3
(
19) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
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3
1
977, 4171. (b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth.
154.5 (d), 126.9 (d), 107.9 (s), 85.9 (d), 81.8 (s), 76.2 (d),
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(t), 25.9 (3q), 24.5 (q), 23.1 (t), 18.1 (s), 17.8 (q), 16.1 (q),
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Tetrahedron 2001, 57, 5173; and references therein.
(
(
(
–
1
1630 cm ; MS (EI, 70eV) m/z 455 (M-Me, 1), 411(7),
1
21) The enantiomeric purity of (+)-11 was determined by H
355(8), 263(23), 239(12), 225(13), 213(16), 203(100),
2
0
NMR analysis of the corresponding mandelate.
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D
0.86, CHCl3).
109, 5765. (b) Paterson, I.; Perkins, M. V. Tetrahedron
1996, 52, 1811.
Synlett 2002, No. 5, 715–718 ISSN 0936-5214 © Thieme Stuttgart · New York