A convergent total synthesis of phorboxazole A

Article abstract of DOI:10.1002/anie.200390321

The potent cytostatic marine metabolite phorboxazole A (see structure) was prepared from three key fragments. Following attachment of a major portion of the side chain through C32-C33 and an intermolecular E-selective olefination reaction to form the C19-

Full text of DOI:10.1002/anie.200390321

Angewandte
Chemie
Macrolide Synthesis
A Convergent Total Synthesis of
Phorboxazole A**
Miguel A. Gonzµlez and Gerald Pattenden*
Marine organisms have delivered a fascinating variety of
structurally novel and biologically important secondary
metabolites in recent years, many of which are now beginning
to provide leads for the development of new chemothera-
peutic agents. Phorboxazole A (1) and B( 2) are unique
oxane–oxazole-based macrolide structures isolated from the
Indian Ocean sponge Phorbas sp,[1] which exhibit extraordi-
nary cytostatic activity (GI50 < 8 ” 10ꢀ10 m) against the entire
panel of human tumor cell lines in the NCI database. Not
surprisingly, therefore, these compounds have aroused con-
46
MeO
Br
R2
R1
O
19
N
O
MeO
20
OH
O
33 O
O
28
HO
32
N
O
27
3
O
2
O
1, R1= OH, R2= H
2, R1= H, R2= OH
MeO
OTIPS
Br
O
N
O
OR
O
MeO
OTBS
O
HO
OPMB
O
OH
MeO
R1O
CO2Et
4
5
3
a R= PMB, R1= H
b R= Ms, R1= TBS
[*] Prof. G. Pattenden, Dr. M. A. Gonzµlez
School of Chemistry, University of Nottingham
Nottingham, NG72RD (UK)
Fax: (+44)115-951-3535
E-mail: GP@nottingham.ac.uk
[**] We thank the EPSRC and The University of Nottingham for support
of this work. We also thank Dr. P. Little and Dr. D.S. Millan, in
particular, for their contributions, as well as Merck Sharp and
Dohme and Pfizer Ltd for continued financial support of our work.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
siderable interest within the medicinal and synthetic chemis-
end, we envisaged coupling the oxane 4 to the phorboxazole
side chain via the corresponding oxane–oxazole 11 and the
lactone 8 by using the metalated oxazole chemistry developed
by Evans et al.[3b]
try communities. Already three total syntheses of the
phorboxazoles have been reported,[2–4] and the results of
several structure–activity studies are beginning to emerge.[5]
In previous publications we described synthetic routes to the
key fragments 3,[6] 4,[7] and 5a[8] in phorboxazole A.[9] We now
show how we have brought these fragments together, leading
to a new and convergent total synthesis of the natural product
itself.
Thus, the lactone 8 was first elaborated from the known
aldehyde 6[6] and the sulfone 7[11] in four relatively straightfor-
ward steps, and the oxane–oxazole 11 was prepared through
an E-selective Wadsworth–Emmons olefination between the
oxane methyl ketone 9, derived from 4,[7] and the oxazole
phosphonate ester 10,[12] as highlighted in Scheme 1. To our
satisfaction, when the oxane-substituted 2-methyloxazole 11
was deprotonated with lithium diethylamide generated in situ
at ꢀ788C, and treated with the lactone 8, the desired cyclic
hemiketal 12a was obtained in high yield and was immedi-
ately protected as its corresponding triethylsilyl ketal 12b in
66% overall yield (Scheme 1). After selective cleavage of the
dimethylacetal unit in 12b with dimethylboron bromide[13] at
ꢀ788C, an E-selective Wittig reaction between the resulting
aldehyde 13 and the phosphonium salt obtained from the
substituted bisoxane 5b,[8] in the presence of DBU,[14] then led
¼
With two disubstituted double bonds (C2 C3 and
¼
¼
C19 C20), and one trisubstituted double bond (C27 C28),
separating the structural units 3, 4, and 5, it was clear from the
outset of our studies that the ordered, stereocontrolled
synthesis of these three double bonds would play a crucial
role in any successful synthesis of phorboxazole A. After
some initial disappointing forays,[10] we ultimately decided on
ꢀ
a strategy to phorboxazole A whereby the C28 C46 side
chain was first attached to the oxane 4, then the bisoxane 5
ꢀ
was added, and finally the macrolide C2 C3 double bond was
elaborated in a final key step (see Schemes 1 and 2). To this
O
MeO
MeO
MeO
Br
Br
Br
O2S
S
b–d
a
MeO
OTBS
+
N
OPMB
MeO
MeO
OTBS
OTBS
MeO
OMe
OPMB
OMe
O
6
7
8
MeO
O
OMe
CHO
OMe
O
O
O
e–g
h, i
j, k
O
4
OPMB
OPMB
OPMB
OTBS
OTBS
9
MeO
Br
OMe
OMe
OMe
N
O
m, n
l
MeO
P(O)(OMe)2
OMe
OTBS
N
OPMB
8
O
O
O
O
RO
N
OPMB
10
11
O
12
a, R = H
b, R = TES
Scheme 1. Synthesis of the side chain 8 and oxazole–pyran 11 and coupling. a) NaHMDS, THF, ꢀ788C!RT, 93% pure all-E isomer; b) Me2BBr,
Et2O, ꢀ788C, 98%; c) DDQ, CH2Cl2/H2O (10:1), 08C, 85%; d) TPAP, NMO, powdered 4-Š molecular sieves, CH2Cl2, 82%; e) Ts–imidazole, NaH,
Et2O, ꢀ788C!08C; f) LiAlH4, Et2O; g) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C!RT; h) OsO4, NMO, acetone/water; i) NaIO4 on silica, CH2Cl2;
j) CSA, MeOH/CH2Cl2; k) DMP, 2,6-lutidine, CH2Cl2, 43% overall yield from 4; l) LDA, ꢀ788C, 30 min, then 9, 89% (49% conversion); m) Et2NH,
nBuLi, THF, ꢀ788C, then 8; n) TESOTf, pyridine, MeCN/Et2O (10:1), ꢀ478C, 36 h, 74% (66% conversion, two steps); HMDS=hexamethyldisila-
zide, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TPAP=tetrapropylammonium perruthenate, NMO=4-methylmorpholine N-oxide,
Ts =p-toluenesulfonyl, Tf=Trifluoromethanesulfonyl, CSA=camphorsulfonic acid, DMP=Dess–Martin periodinane, TBS=tert-butyldimethylsilyl,
LDA=lithium diisopropylamide, TES=triethylsilyl, PMB=p-methoxybenzyl
1256
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Angewandte
Chemie
to the advanced bisoxazole–trisoxane intermediate 14, as a
single stereoisomer in excellent overall yield (Scheme 2).
The stage was now set to complete our synthesis of
phorboxazole A through an intramolecular Wadsworth–
Emmons reaction of 17 as the penultimate step. Thus,
selective cleavage of the primary TBS ether in 14 with
HF·pyr[3] at 08C proceeded smoothly and the resulting alcohol
was then oxidized to the corresponding aldehyde 15 under
Dess–Martin conditions[15] (Scheme 2). Removal of the PMB
protecting group in 15 with DDQ next led to the secondary
alcohol 16, which was converted into the corresponding
fluorophosphonate ester 17.[2] Intramolecular cyclization of
MeO
MeO
Br
Br
OTIPS
O
N
O
CHO
MeO
MeO
a
b
OTBS
OTBS
12 b
O
O
O
O
O
TESO
TESO
N
N
OPMB
OPMB
OTBS
O
O
13
14
MeO
Br
OTIPS
O
N
O
MeO
e
c, d
OTBS
O
O
O
TESO
N
OPMB
CHO
O
15
MeO
MeO
Br
Br
OTIPS
OTIPS
O
O
N
N
O
O
MeO
MeO
f
g
OTBS
OTBS
O
O
O
O
O
O
TESO
TESO
N
N
O
OH
CHO
P(OCH2CF3)2
CHO
O
O
O
16
17
O
MeO
MeO
Br
Br
OTIPS
OH
O
O
N
N
h
O
O
O
MeO
MeO
OTBS
OH
O
O
O
O
O
TESO
HO
N
N
O
O
O
O
O
O
18
1: (+)-phorboxazole A
Scheme 2. Completion of the synthesis of 1. a) Me2BBr, Et2O, ꢀ788C, 85%; b) 5b, Bu3P, DMF, then 13 and DBU, room temperature or 08C, 85–
87%; c) HF·pyr, pyridine, THF, 08C!RT, 65–70%; d) DMP, pyridine, CH2Cl2, 94%; e) DDQ, CH2Cl2–pH 7 buffer, 85%; f) EDCl·MeI, HOBT,
HO2CCH2PO(OCH2CF3)2, CH2Cl2, >80%; g) K2CO3, [18]crown-6, toluene, room temperature, 82% (3:1 Z/E); h) TBAF, THF, 08C!RT, 75%;
reversed-phase HPLC purification; DMF=N,N-dimethylformamide, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, pyr=pyridine, DMP=Dess–Martin
periodinane, EDCl=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chloride, HOBT=1-hydroxybenzotriazole, TBAF=tetrabutylammonium fluo-
ride, TIPS=triisopropylsilyl.
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Communications
[14] Similar conditions were used earlier by Evans et al; see
reference [3a].
[15] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 –
7287.
[16] W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405 – 4408.
This macrocyclization tactic had earlier been used by Forsyth
et al.[2] and Smith et al.[4] in their total synthesis of phorboxa-
zole A.
[17] The Z/E ratio followed from examination of the absorptions
associated with the Z (d = 5.92 ppm) and E (d = 6.90 and
5.85 ppm) olefinic H atoms in the 1H NMR spectrum of the
mixture.
the aldehyde–phosphonate 17 under the conditions of Still
and Gennari[16] gave the Z-a,b-unsaturated macrolide 18,
containing approximately 25% of the corresponding E
isomer.[17] Removal of the three silyl protecting groups in 18
with tetrabutylammonium fluoride in THF at 08C, followed
by chromatography, finally produced (þ)-phorboxazole A
ꢀ
(1), contaminated with its C2 C3 E isomer. Further purifi-
cation by reversed-phase HPLC provided pure (þ)-phorbox-
azole A, whose 1H and 13C NMR spectra, together with high-
resolution
mass
spectrometric
data
(calcd
for
C53H71N2O1379BrNa [MþNa, 79Br]+: 1045.4037; found:
[18] Naturally derived phorboxazole A had [a]D = + 44.88 (c = 1.0,
MeOH). All new compounds reported in this study showed
satisfactory spectroscopic and mass spectrometric data.
1045.4053 (100%) (ESI)) and optical rotation data ([a]D20
=
+ 43.3, c = 0.12, CHCl3) corresponded to those reported for
the natural product.[1a,18]
Received: October 28, 2002 [Z50447]
Keywords: antifungal agents · antitumor agents · natural
.
products · olefination · total synthesis
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[10] P. Little, D. S. Millan, unpublished results.
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