Synthesis of the C7-C24 fragment of (-)-Macrolactin F

Article abstract of DOI:10.1016/j.tetlet.2008.07.113

An enantioselective and convergent synthesis of the C7-C24 fragment of Macrolactin F was achieved from four main fragments. A hydrotelluration/transmetalation sequence was used to install the E,Z diene present in the molecule, while a hydrozirconation/transmetalation sequence was used to connect two advanced intermediates.

Full text of DOI:10.1016/j.tetlet.2008.07.113

Tetrahedron Letters 49 (2008) 5759–5761
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Tetrahedron Letters
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Synthesis of the C7–C24 fragment of (À)-Macrolactin F
Roberta A. Oliveira a, Juliana M. Oliveira a, Luis H. S. Rahmeier b,*, , Joao V. Comasseto b,
Joseph P. Marino c, Paulo H. Menezes a,
*
a Departamento de Química Fundamental, Universidade Federal de Pernambuco, CCEN, UFPE, Recife-PE, Brazil
b Instituto de Química, Universidade de São Paulo, Avenue Professor Lineu Prestes, 748, São Paulo, SP, Brazil
c University of Notre Dame, Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall Notre Dame, IN, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective and convergent synthesis of the C7–C24 fragment of Macrolactin F was achieved
from four main fragments. A hydrotelluration/transmetalation sequence was used to install the E,Z diene
present in the molecule, while a hydrozirconation/transmetalation sequence was used to connect two
advanced intermediates.
Received 11 May 2008
Revised 15 July 2008
Accepted 19 July 2008
Available online 24 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The Macrolactins are a class of secondary metabolites first
isolated by Fenical from a taxonomically unclassifiable deep sea
bacterium found in the North Pacific. Reported with their initial
findings were general structural assignments for Macrolactins
A–F.1 The absolute stereochemistry was later established for Mac-
OH
7
O
O
13
rolactins B and F through degradation, chemical correlation and 13
C
HO
24
19
acetonide analysis.2 Macrolactin A exhibits significant antiviral and
cytotoxic activities. More recently, several Macrolactins have been
isolated3 and some of them had their biological properties
screened.4
15
O
1
Figure 1. (À)-Macrolactin F.
Approaches to fragments of (À)-Macrolactin A,5 and the total
syntheses of (À)-Macrolactin A6 and (+)-Macrolactin E7 were com-
pleted, confirming the structure and the stereochemical assign-
ment previously reported. However, there are no described
studies toward total synthesis of (À)-Macrolactin F (Fig. 1).
Vinylcopper intermediates are synthetically useful reagents and
are classically prepared by reacting the corresponding lithium or
Grignard reagent with an appropriate copper salt.8 One of the most
important methods to prepare E- or Z-vinylic higher order cuprates
is through transmetalation reactions. The driving force for both
transformations is mainly the change of an sp3-hybridized ligand
in the coordination sphere of copper for an sp2-hybridized ligand.9
In our disconnection approach, (À)-Macrolactin F was divided
into five main intermediates, A–E.
from a literature procedure. Finally, Fragment E could be prepared
from the same precursor as Fragment A.
The required telluride for the synthesis of Fragment A was pre-
pared as shown in Scheme 1. (E)-2-Penten-4-yn-1-ol, 2, was pre-
pared from epichlorohydrin according to a known procedure.12
Protection of the alcohol 2 as its tetrahydropyranil ether13 3 was
accomplished with DHP at room temperature. Conversion to the
vinyl telluride was achieved by treating the terminal alkyne 3 with
dibutyl ditelluride in the presence of sodium borohydride10 to give
OP
X
Fragment A contains an E,Z diene unit which was prepared from
the hydrotelluration reaction of the corresponding alkyne.10 Frag-
ment B was prepared according to a literature procedure.11 Frag-
ment C is commercially available. Fragment D was also prepared
CO2R
E
A
OP
TeBu
O
1
B
* Corresponding authors. Tel.: +55 81 2126 7473; fax: +55 81 2126 8442
(P. H. Menezes).
E-mail address: pmenezes@ufpe.br (P. H. Menezes).
Present address: Nufarm do Brasil Rua Samuel Morse, 74, Cj 152, CEP 04576-060,
Brooklin, São Paulo, SP, Brazil.
BrMg
D
PO
C
Scheme 1. Retrosynthetic analysis for 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.113

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R. A. Oliveira et al. / Tetrahedron Letters 49 (2008) 5759–5761
OTHP
OTHP
ii
OTHP
vi
O
iii
OR
i
OTBS
TeBu
R1O
Fragment B
MOMO
2
, R = H
5
Fragment A
OR2
O
4
3
, R = THP
9
6
, R1 = H, R2 = TBS
6
iv
v
7, R1 = MOM, R2 = TBS
8, R1 = MOM, R2 = H
Scheme 2. Reagents and conditions: (i) DHP, PPTS, CH2Cl2, 25 °C, 3 h (90%); (ii) BuTeTeBu, NaBH4, EtOH, reflux, 3 h (80%); (iii) (2-Th)BuCu(CN)Li2, THF, À78 to 25 °C, 1 h then
5, 3 h, À78 to 25 °C (80%); (iv) MOMCl, DIPEA, CH2Cl2, 18 h, 25 °C (78%); (v) TBAF, THF, 25 °C, 1 h (90%); (vi) Dess–Martin periodinane, CH2Cl2, 25 °C, 1 h (90%).
the desired Fragment A (4), as a single diastereoisomer. Transmeta-
lation14 of 4 with a higher order cyanocuprate, followed by treat-
ment with the Fragment B (5)11 gave the homoallylic alcohol 6
with the correct stereochemistry at C13. Protection of 6 with
MOM–Cl15 gave 7, which was selectively deprotected using TBAF16
to yield 8. Finally, treatment with Dess–Martin periodinane17 gave
the aldehyde 9 (Scheme 2).
7
OTHP
OTBS
i, ii
16
MOMO
24
O
Addition of vinylmagnesium bromide (Fragment C) to 9 occurred
in low yield; this problem might be caused by an enolization process
by the Grignard reagent acting as a base.18 By transforming the
Grignard reagent into the corresponding organocesium com-
pound,19 the alcohol 10 was obtained in good yield (ca. 70% vs
17
Scheme 5. Reagents and conditions: (i) Cp2Zr(H)Cl, THF, 25 °C, then MeLi (2 equiv)
À30 to À78 °C, THF; (ii) CuCN, MeLi (1 equiv), À30 to À78 °C, THF, then 11, À78 °C,
2 h (65%).
40%), and re-oxidized to the corresponding a,b-unsaturated ketone
11 in 92% (Scheme 3). The overall yield for this sequence after 8 steps
Noyori’s protocol21 to yield 14 in high enantiomeric excess. Finally,
14 was subjected to prototropic migration of the triple bond using
potassium 3-aminopropanamide (KAPA)22 to give 15, which was
protected as its TBS ether16 16 (Scheme 4).
Hydrozirconation of Fragment D (16), followed by treatment of
the alkenylzirconium intermediate with 2 equiv of methyllithium,
and sequential addition of 1 equiv of CuCN and methyllithium gave
the corresponding higher order cyanocuprate,23 to which was
added 11 at low temperature. Using this sequence, fragment C7–
C24, 17 was obtained in 65% (Scheme 5).
In summary, an advanced intermediate in the synthesis of Mac-
rolactin F was achieved. The synthesis features the use of a vinyl
telluride and a vinyl zirconium as precursors for the preparation
of the corresponding Z and E vinyl cuprates, respectively. Two of
the three stereocenters and three of the five double bonds of Mac-
rolactin F were installed in a convergent approach in 12% overall
yield. Further progress toward Macrolactin F will be reported in
the due course.
was 23%.
Fragment D was prepared according to a literature protocol20
(Scheme 4).
Reaction of the lithium anion of 1-pentyne with acetic an-
hydride gave propargylic ketone 13, which was reduced using
OTHP
OTHP
ii
i
9
MOMO
HO
MOMO
O
10
11
Scheme 3. Reagents and conditions: (i) CeCl3, THF, 25 °C, 18 h, then vinylmagne-
sium bromide, À78 °C, 3 h (70%); (ii) Dess–Martin periodinane, CH2Cl2, 25 °C, 1 h
(92%).
Acknowledgments
The authors gratefully acknowledge CNPq and FACEPE for finan-
cial support. R.A.O., J.M.O., and P.H.M. are also thankful to CNPq for
their fellowships.
ii
i
OH
O
14
12
13
Supplementary data
OH
OTBS
iii
iv
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.113.
15
Fragment D
16
References and notes
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