Stereoselective synthesis of the C1-C12 fragment of the cytotoxic macrolide FD-891

Article abstract of DOI:10.1055/s-2004-835653

A stereoselective synthesis of the C1-C12 fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. The initial chirality was created via an asymmetric Evans aldol reaction. Two other asymmetric reactions, a Sharpless epoxidation and

Full text of DOI:10.1055/s-2004-835653

2830
LETTER
Stereoselective Synthesis of the C1-C12 Fragment of the Cytotoxic Macrolide
FD-891
S
tereosele
u
ctive
S
ynthe
a
sis of the
C
n
1-C12
F
ragment of
M
Macrolide FD-891 urga,a Jorge García-Fortanet,a Miguel Carda,*a J. Alberto Marco*b
a
Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, 12071 Castellón, Spain
b
Depart. de Q. Orgánica, Univ. de Valencia, 46100 Burjassot, Valencia, Spain
Fax +34(96)3544328; E-mail: alberto.marco@uv.es
Received 9 September 2004
Abstract: A stereoselective synthesis of the C1-C12 fragment of
the naturally occurring, cytotoxic macrolide FD-891, is described.
The initial chirality was created via an asymmetric Evans aldol re-
action. Two other asymmetric reactions, a Sharpless epoxidation
and an aldehyde Brown allylation were further key steps of the
synthesis.
HO
O
O
O
OH OH OMe
Old structure
HO
Key words: antitumor agents, aldol reactions, chiral auxiliaries,
stereoselective synthesis, asymmetric allylations
6
1
O
7
HO
3
5
O
O
OH OH
OMe
26
19
18
16
The cytotoxic metabolite FD-891 was isolated from the
fermentation broth of Streptomyces graminofaciens A-
8890 and was found active against several tumor cell
lines. In addition, it was found to potently prevent both
perforin- and FasL-dependent CTL-mediated killing path-
ways. In contrast to the structurally related concanamycin
A, however, it was unable to inhibit vacuolar acidifica-
tion. According to the results of chemical degradations
and X-ray diffraction analyses of the degradation prod-
ucts, the structure of FD-891 was reported two years ago
to be that depicted below (Figure 1).1 In line with this
structural assignment, we performed a stereoselective
synthesis of the whole side chain of the molecule, a frag-
ment with seven stereocenters.2 However, the group
which investigated FD-891 two years ago reported this
year a correction of its structure, which now turns out to
be as shown in Figure 1.3 While no changes in stereo-
chemistry have resulted from this structural change, one
olefinic bond has now been moved from inside the ring to
the side chain. In view of this, we have seen ourselves in
the need of carrying out a substantial modification of the
initial synthetic plan. Fortunately, most of the ring part of
the molecule has remained untouched by the structural
amendment, so that we have been able to use a part of our
previous synthetic sequence.
10
14
OH
Corrected structure
FD-891
Figure 1
lactonization
O
HO
O
O
OH OH
OMe
OH
Julia olefination
FD-891
1
COOEt
PO
PO
OP
OMe
26
19
18
O
ArSO2
A
C
12
OP
OMOM
13
P´O
OP´´
B
Scheme 1 Retrosynthetic analysis of FD-891.
For our modified synthesis of this bioactive metabolite,
we have chosen the retrosynthetic plan shown in
Scheme 1 (P, P¢, P¢¢ = protecting groups). According to it,
the molecule of FD-891 is disconnected to fragments A
(C1-C12, the extra carbon atom is to be removed later via
oxidative cleavage), B (C13-C18) and C (C19-C26). The
reactions planned to connect these three fragments are a
macrolactonization4 and two Julia olefinations.5
In the present communication, we describe the synthetic
work performed to achieve the preparation of fragment A
(P = TBDMS).6 This fragment contains five out of the
twelve sp3 stereocenters of the molecule and was retrosyn-
thetically disconnected as shown below in Scheme 2. One
key structural retrotransformation (A → I) is the stereose-
lective allylation of a chiral a,b-epoxyaldehyde while the
SYNLETT 2004, No. 15, pp 2830–2832
0
7
.1
2
.2
0
0
4
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835653; Art ID: G33604ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of the C1-C12 Fragment of Macrolide FD-891
2831
other (III → IV) is an aldol reaction intended to add the Scheme 3 depicts the actual synthetic sequence, which led
Me-C4-C5 propionate segment. The other two propionate to A. The commercially available (Z)-2-butene-1,4-diol
segments are added via Wittig olefinations (II → III).
was first converted into its monoprotected derivative 1
( = IV with R = PMB, p-methoxybenzyl),7 PCC oxidation
of which afforded the (E)-2-butenal 2.8 The aldol reaction
which generates the initial chirality was performed with
the aid of the Evans methodology.9 To this purpose, N-
propionyl oxazolidinone (10) was converted into its boron
Z-enolate and added to aldehyde 2. This furnished aldol
adduct 3, which was then converted into Weinreb amide
4.10 Since this product proved difficult to purify, it was
used in crude form in the next silylation step. Compound
5 was then reduced with DIBAL to the corresponding al-
dehyde (H replacing NMeOMe), which, without chro-
matographic purification, was taken to the Wittig
olefination step. This afforded the conjugated enoate 6,11
which was subjected to a second reduction–olefination se-
quence to yield the conjugated dienoate 7. Cleavage of the
PMB protecting group with DDQ12 in wet CH2Cl2 was
followed by an asymmetric Sharpless epoxidation.13 The
resulting epoxy alcohol 9 was then oxidized to the corre-
sponding aldehyde and the latter was subjected in crude
form to asymmetric allylation using the chiral B-allyl di-
isopinocampheylborane (allylBIpc2) prepared from allyl-
magnesium bromide and (+)-DIP-Cl (diisopino-
campheylboron chloride).14 This procedure furnished in
66% overall yield a homoallyl alcohol as an 85:15 mixture
of diastereomers. Subsequent silylation finally gave the
desired product A.15–17
COOEt
PO
COOEt
PO
O
O
allylation
Sharpless epoxidation
CHO
OP
A
I
aldol
PO
CHO
COOEt
PO
OHC
Wittig
OR
IV
OR
OR
III
II
Scheme 2 Retrosynthetic analysis of fragment A.
b
PMBO
R
PMBO
c
COR
OH
1
2
R = (Z)-CH2OH
R = (E)-CHO
3
4
R = Xq
a
R = NMe(OMe)
d
OMe
N
e,f
PMBO
COOEt
PMBO
OTBDMS
g,h,i
TBDMSO
O
In summary, a stereoselective synthesis of the C1-C12
fragment of the cytotoxic macrolide FD-891 has been
achieved. Studies towards the total synthesis of the natural
product are underway and will be published in due course.
6
5
COOEt
COOEt
TBDMSO
TBDMSO
k
Acknowledgment
O
OH
Financial support has been granted by the Spanish Ministry of
Education (project BQU2002-00468), by the AVCYT (project
GRUPOS03/180) and by the BANCAJA-UJI foundation (project
PI-1B2002-06). J. M. and J. G.-F. thank the Spanish Ministry of
Education and Science for a Ramón y Cajal and for a pre-doctoral
fellowship, respectively.
R
9
7
8
R = CH2OPMB
R = CH2OH
j
l,m,n
O
O
COOEt
TBDMSO
O
N
Xq
O
References
10
Bn
A
(1) (a) Eguchi, T.; Kobayashi, K.; Uekusa, H.; Ohashi, Y.;
Mizoue, K.; Matsushima, Y.; Kakinuma, K. Org. Lett. 2002,
4, 3383. (b) Detailed spectral data of FD-891 are given in:
Seki-Asano, M.; Tsuchida, Y.; Hanada, K.; Mizoue, K. J.
Antibiot. 1994, 47, 1234.
(2) Murga, J.; García-Fortanet, J.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2004, 45, 7499.
(3) Eguchi, T.; Yamamoto, K.; Mizoue, K.; Kakinuma, K. J.
Antibiot. 2004, 57, 156.
(4) Bartra, M.; Urpí, F.; Vilarrasa, J. In Recent Progress in the
Chemical Synthesis of Antibiotics and Related Microbial
Products, Vol. 2; Lukacs, G., Ed.; Springer Verlag: Berlin,
1993, 1–65.
(5) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(6) The synthesis of a compound structurally related to fragment
A has recently been reported: Chng, S.-S.; Xu, J.; Loh, T.-P.
Tetrahedron Lett. 2003, 44, 4997.
OTBDMS
Scheme 3 Reagents and conditions: a) PCC, CH2Cl2, r.t., 4 d, 52%;
b) 10, Bu2BOTf, Et3N, CH2Cl2, –78 °C, 30 min, then 2, –40 °C, 12 h,
86%; (c) N,O-dimethylhydroxylamine, Me3Al, THF, r.t., 1 h, then 3,
3 h; (d) TBDMSOTf, 2,6-lutidine, CH2Cl2, r.t., 1 h, 77% overall yield
for the two steps; e) DIBAL, THF, –78 °C, 30 min; (f)
Ph3P=C(Me)COOEt, 1,2-dichloroethane, 60 °C, 12 h, 55% overall
yield for the two steps; g) DIBAL, hexane, r.t., 1 h, 76%; h) MnO2,
CH2Cl2, D, 2 h; i) (EtO)2P(O)CH(Me)COOEt, n-BuLi, THF, 0 °C,
then addition of the crude aldehyde, 12 h, 84% overall yield for the
two steps; j) DDQ, wet CH2Cl2, r.t., 2 h, 89%; (k) diethyl L-tartrate,
Ti(Oi-Pr)4, t-BuOOH, powdered 4 Å MS, CH2Cl2, –23 °C, 24 h, 60%;
(l) Swern oxidation; (m) allylBIpc2 [from (+)-DIP-Cl and allylmagne-
sium bromide, see text], Et2O, 1 h, –90 °C, 66% overall yield for the
two steps (dr, 85:15); (n) TBDMSOTf, 2,6-lutidine, CH2Cl2, r.t., 1 h,
90%.
Synlett 2004, No. 15, 2830–2832 © Thieme Stuttgart · New York

2832
J. Murga et al.
LETTER
(7) Trost, B. M.; Chisholm, J. D.; Wrobleski, S. T.; Jung, M. J.
Am. Chem. Soc. 2002, 124, 12420.
H), 1.85 (d, J = 1.0 Hz, 3 H), 1.30 (t, J = 7.0 Hz, 3 H), 1.06
(d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.09 (s, 3 H),
0.05 (s, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H). 13C NMR (125
MHz, CDCl3): d = 169.1, 142.7, 138.1, 134.5, 131.9, 125.9,
117.3, 73.6, 73.0, 60.6, 58.5, 57.2, 39.5, 37.7, 25.9 (× 3),
25.8 (× 3), 18.3, 18.2, 16.6, 15.7, 14.3, 14.0, –4.2, –4.4, –4.8,
–4.9.
(8) This Z → E isomerization during the oxidation with PCC has
been reported to occur with the corresponding benzyl
derivative: Danishefsky, S. J.; Berman, E. M.; Ciufolini, M.;
Etheredge, S. J.; Segmuller, B. E. J. Am. Chem. Soc. 1985,
107, 3891.
(9) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23–32.
(b) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Fleming, I.; Winterfeldt, E., Eds.; Pergamon Press: Oxford,
1993, 239–276. (c) See also: Cowden, C. J.; Paterson, I.
Org. React. 1997, 51, 1.
(10) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
(11) This olefination gave a better yield in 1,2-dichloroethane at
60 °C than in toluene at 110 °C, in contrast to that observed
in a structurally similar situation: Marshall, J. A.; Adams, N.
D. J. Org. Chem. 2002, 67, 733.
(12) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021.
(13) Katsuki, T.; Martín, V. S. Org. React. 1996, 48, 1.
(14) (a) Brown, H. C.; Ramachandran, P. V. J. Organomet.
Chem. 1995, 500, 1. (b) Ramachandran, P. V. Aldrichimica
Acta 2002, 35, 23.
(16) None of the intermediates in the way towards A nor
compound A itself was crystalline. Therefore, X-ray
analyses aimed at configurational confirmation could not be
performed. However, the key asymmetric transformations
used here (Evans aldolization, Sharpless epoxidation and
Brown allylboration) are well-known processes with safely
predictable stereochemical outcomes. We are thus confident
that the structure of synthetic intermediate A is that depicted
in Scheme 3. Furthermore, a comparison of 1H/13C NMR
chemical shift and coupling constants values within the
relevant fragment of FD-891 with those of compound A (see
Table 1 below, atom numbering is shown in Figure 1,
coupling constant values are given in parenthesis) gives
support to our structural assignment (the observed
differences can be accounted for with the fact that the cyclic
FD-891 is much more rigid than A from the conformational
point of view; moreover, A bears two bulky TBSO groups
instead of the free hydroxyls).
(15) Compound A: 1H NMR (500 MHz, CDCl3): d = 7.10 (br s, 1
H), 5.83 (m, 1 H), 5.55 (d, J = 10.0 Hz, 1 H), 5.10–5.00 (m,
2 H), 4.20 (q, J = 7.0 Hz, 2 H), 3.61 (dd, J = 5.0, 4.0 Hz, 1
H), 3.48 (dt, J = 5.5, 6.5 Hz, 1 H), 2.96 (dd, J = 5.5, 2.2 Hz,
1 H), 2.88 (dd, J = 4.0, 2.2 Hz, 1 H), 2.68 (ddq, J = 10.0, 5.0,
6.8 Hz, 1 H), 2.28 (t, J = 6.5 Hz, 2 H), 2.00 (d, J = 1.3 Hz, 3
(17) Preliminary experiments have shown that oxidative cleavage
of the terminal double bond in A can be performed via
sequential osmylation and NaIO4 oxidation to yield an
unstable aldehyde.
Table 1 Comparison of Spectroscopic Data of Compounds A and FD-891
Atom
H-3
FD-891
A
Atom
C-1
FD-891
168.9
124.3
144.0
135.7
141.6
35.9
A
7.30, t (1.3)
7.10, br s
169.1
125.9
138.1
131.9
134.5
37.7
73.0
57.2
58.5
73.6
39.5
14.0
15.7
16.6
H-5
5.53, d (10.3)
3.12, ddq (10.3, 4.1, 6.9)
4.17, dd (6.0, 4.1)
3.25, dd (6.0, 2.5)
3.15, dd (2.5, 0.8)
3.55, m
5.55, d (10.0)
2.68, ddq (10.0, 5.0, 6.8)
3.61, dd (5.0, 4.0)
2.88, dd (4.0, 2.2)
2.96, dd (5.5, 2.2)
3.48, dt (5.5, 6.5)
2.28, t, 2 H (6.5)
2.00, d (1.3)
C-2
H-6
C-3
H-7
C-4
H-8
C-5
H-9
C-6
H-10
H-11
MeC2
MeC4
MeC6
C-7
70.8
2.55, m, 2 H
C-8
55.1
2.10, d (1.2)
C-9
56.0
2.03, d (1.2)
1.85, d (1.0)
C-10
C-11
MeC2
MeC4
MeC6
71.1
1.15, d (6.9)
1.06 d (6.8)
37.9
13.6
15.5
16.5
Synlett 2004, No. 15, 2830–2832 © Thieme Stuttgart · New York