Total synthesis of phorboxazole A

Article abstract of DOI:10.1002/anie.200390322

Asymmetric allylation reactions of stannyl-derived allyldiazaborolanes, a stereo-selective cationic cyclization reaction for the formation of the fully substituted C22-C26 tetrahydropyran, and the use of a Julia olefination for the incorporation of the se

Full text of DOI:10.1002/anie.200390322

Communications
Macrolide Synthesis
Total Synthesis of Phorboxazole A**
David R. Williams,* Andre A. Kiryanov, Ulrich Emde,
Michael P. Clark, Martin A. Berliner, and
Jonathan T. Reeves
Phorboxazole A (1; see Scheme 1), and its C13 diaster-
eoisomer phorboxazole B, are novel 21-membered macro-
lides isolated from the rare Indian Ocean sponge Phorbas
sp.[1] These substances have demonstrated extraordinary
potency against the National Cancer Institute (NCI) panel
of60 human tumor cell cultures (mean GI 50 < 1.6 nm).[2]
Moreover, phorboxazole A has been shown to arrest the
cell cycle in the S phase without affecting tubulin polymer-
[2a]
ization, suggesting a unique mechanism ofaction.
While
biological studies are severely limited by the scarcity ofthese
natural products, the unprecedented structural features and
remarkable antitumor activity have provided the impetus for
several synthesis studies.[3] Recently, total syntheses of
phorboxazole A[4,5] and phorboxazole B[6] have been
reported. Herein, we describe the culmination ofour
efforts[3d–f] leading to a convergent, enantiocontrolled total
synthesis of 1.
[*] Prof. D. R. Williams, Dr. A. A. Kiryanov, Dr. U. Emde, M. P. Clark,
Dr. M. A. Berliner, Dr. J. T. Reeves
Indiana University
Department of Chemistry
800 E. Kirkwood Ave., Bloomington, IN, 47405 (USA)
Fax: (+1)812-855-8300
E-mail: williamd@indiana.edu
[**] Generous financial support for this research was provided by the
NIH (GM-41560). We acknowledge Prof. Craig J. Forsyth for
providing us with detailed conditions for reproducing HRMS data
for phorboxazole A and 1H NMR spectra of natural and synthetic
material. We also thank Prof. Amos B. Smith for 1H NMR spectra of
synthetic phorboxazole A for our comparison.
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We envisioned in our retrosynthetic analysis the prepara-
tion offour nonracemic components 2–5 for the convergent
assembly ofthe target macrolide (Scheme 1). Stereoselective
formation of the C22–C26 tetrahydropyran moiety of 1 was a
central issue for the design strategy that featured the union of
components 3 and 4. Thus, the Horner–Wadsworth–Emmons
reaction would precede formation of the fully substituted
pyran through retention ofthe stereochemistry at C22 of
component 3 in the p-allyl cation cyclization event. Incorpo-
ration ofthe intact bispyran component 5 utilized the Wittig
reaction for construction of the (E)-C19–C20 alkene, and was
followed by the subsequent attachment of the labile C42–C46
segment by a modified Julia olefination. Finally, our strategy
culminated in a late-stage macrocyclization by installation of
the (Z)-C2–C3 enoate.
OH
13
O
Phorboxazole A (1)
19
N
O
20
Br
10
46
OMe
35
O
O
22
5
N
O
26
38
32
MeO
O
30
3
42
OH
O
O
OH
2
Br
OMOM
20
46
O
O
OPMB
22
O
O
(EtO)2P
S
26
OTES
S
MeO
42
N
3
2
OTBDPS
O
N
19
Synthesis ofthe C28–C41 aldehyde 4 began with non-
racemic b,g-unsaturated aldehyde 6 (Scheme 2).[7] Asymmet-
ric allylation of 6 was effected following the tin-to-boron
transmetalation ofallylstannane 7[8] using the boron bromide
reagent derived from (R,R)-1,2-diamino-1,2-diphenylethane
bis(sulfonamide) and boron tribromide.[9] Nucleophilic addi-
tion provided the homoallylic alcohol 8 as the major
component ofa mixture (96% yield) ofC37 diastereomers
(d.r. 7.2:1),[10] demonstrating anti-Felkin stereocontrol as
imparted by the chiral auxiliary. Selective oxidative cleavage
ofthe 1,1-disubstituted oleifn (OsO 4, K3Fe(CN)6; NaIO4),
and internally directed reduction[11] ofthe resultant b-hydroxy
ketone with Me4NBH(OAc)3 yielded 1,3-diol 9 with excellent
diastereoselectivity (d.r. > 95:5). Protection of 9 as the
corresponding acetonide (10) led to the expected diagnostic
MsO
O
O
OMe
O
H
28
N
O
41
O
PivO
OMe
3
OTBDPS
TIPSO
5
4
Scheme 1. Components 2–5 of phorboxazole A (1). MOM= methoxy-
methyl, Ms= methanesulfonyl, Piv= pivaloyl, PMB= p-methoxyben-
zyl, TBDPS= tert-butyldiphenylsilyl, TES= triethylsiyl, TIPS= triiso-
propylsilyl.
Cleavage ofthe silyl ether and oxidation ofthe resultant
primary alcohol 11 under Swern conditions[13] furnished the
aldehyde 12.
[12]
NMR evidence in support ofthe 1,3-anti relationship.
Ts
N
B
N
Ts
Ph
Ph
Br
O
OH
OH OH OTBS
a
b, c, d
PivO
H
PivO
OTBS
PivO
OTBDPS
OTBDPS
8
OTBDPS
9
6
Bu3Sn
OTBS
7
e
OTBDPS
N
OTBDPS
13
I
O
O
X
O
O
X
N
O
PivO
H
O
PivO
h
OTBDPS
OTBDPS
14 X = H, OH
15 X = O
i
10 X = H, OTBS
11 X = H, OH
12 X = O
f
g
j
OR
O
OMe
OTBDPS
l, m
H
N
N
PivO
O
O
PivO
O
O
OMe
OMe
OTBDPS
OTBDPS
16 R = H
17 R = Me
k
4
Scheme 2. a) (S,S)-1,2-Diamino-1,2-diphenylethane bis(sulfonamide), BBr3, CH2Cl2, 08C, 1 h; then 7, RT, 10 h; then 6, À788C, 1 h; 96%, 7.2:1 d.r.;
b) OsO4, K3Fe(CN)6, K2CO3, NaHCO3, DABCO, tBuOH/H2O (1:1); c) NaIO4, THF/H2O (1:1); 95% (two steps); d) Me4NBH(OAc)3, HOAc/CH3CN
(1:1), À208C, 10 h; 94%, >95:5 d.r.; e) 2,2-dimethoxypropane, cat. CSA, RT, 16 h; f) HF·pyr, THF; 87% for two steps; g) (COCl), DMSO,
2
CH2Cl2, À788C, then Et3N; h) 13, SmI2, THF, RT; 92% for two steps, 1:1 dr; i) TFAA, DMSO, CH2Cl2, À788C; then acetylacetone, Et3N, À608 to
À408C; 88%; j) cat. CSA, MeOH, RT, 1.5 h; 82%, 7.2:1 mixture of separable C37 epimers; k) MeI, CaSO , Ag2O, 3 d; 90%; l) TBAF, THF, 08C,
4
2 h; 92%; m) Dess–Martin periodinane, pyridine, CH2Cl2, 1 h; 95%. CSA=camphorsulfonic acid, DABCO= 1,4-diazabicyclo[2.2.2]octane,
pyr=pyridine, TBAF=tetra-n-butylammonium fluoride, TBS= tert-butyldimethylsilyl, TFAA= trifluoroacetic anhydride, Ts=p-toluenesulfonyl.
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We have previously explored direct incorporation ofthe
4 led to the desired C27-C28 E-trisubstituted alkene in 88%
yield with excellent selectivity (> 95:5 E/Z; Scheme 3).
Reduction ofthis a,b-unsaturated ketone under Luche
conditions gave the C26 alcohol 18 (d.r. 9:1).[17,18] Subsequent
treatment of 18 with triflic anhydride (2 equiv) and anhydrous
pyridine (5 equiv) in CH2Cl2 (À208C, 12 h) produced a single
tetrahydropyran 19 in 55% yield. The mechanism for product
formation is consistent with the production of an intermediate
transoid allyl cation for internal capture via participation of
the b-methoxymethyl ether at C22 with Re-face addition
followed by dealkylation of the oxonium species.[19] Stereo-
chemical assignments ofthe uflly substituted pyran were
supported by one- and two-dimensional NMR experiments
(COSY and NOESY). Removal ofthe PMB ether of 19
followed by Dess–Martin oxidation yielded the C20 aldehyde
20.
intact oxazole nucleus by the use ofa Barbier coupling of
aldehydes and 2-iodomethyl oxazoles in the presence of
SmI2.[3f] Application ofimproved conditions using iodide 13
and aldehyde 12 gave the desired alcohol adduct 14 as a 1:1
mixture ofdiastereomers in 92% yield (over two steps).
Oxidation ofthis mixture using a modiicfation ofthe
trifluoroacetic anhydride–DMSO–NEt3 protocol[14] provided
the corresponding ketone 15 in 88% yield. The inclusion of
acetylacetone (3–5 equiv) in the reaction mixture at À608C
immediately prior to addition oftriethylamine was necessary
to prevent C32-a-methylthiomethylation ofthe product
ketone. In fact, the ease of enolization of 15 was undoubtedly
responsible for problems encountered in IBX[15] and Dess–-
Martin oxidation[16] attempts, which led to varying amounts of
further oxidation to aldehydes produced by cleavage of the
À
C32 C33 bond. Subjecting ketone 15 to conditions ofacetal
Enantiocontrolled preparation ofthe C3–C19 bispyran
component 5 (Scheme 1) proceeded by a pathway featuring
our asymmetric allylation methodology as previously de-
scribed.[3f] In situ displacement ofthe reactive mesylate of 5[20]
with tri-n-butylphosphane in DMF at room temperature
provided an intermediate phosphorane for direct condensa-
tion with aldehyde 20 (Scheme 3). The resulting C19–C20
alkene 21 was isolated in nearly quantitative yield with
excellent E stereoselectivity (E:Z > 95:5). Reductive removal
ofthe allylic pivaloate and oxidation ofthe resulting primary
exchange with methanol in the presence ofa catalytic amount
ofcamphorsulfonic acid provided tetrahydropyran 16 in 82%
yield as a 7.2:1 mixture ofreadily separable C37,C35 epimers,
resulting from the original allylation reaction of 6. Methyl-
ation ofthe C35 alcohol of 16 followed by desilylation of 17
with TBAF and Dess–Martin oxidation delivered the key
C28–C41 aldehyde 4 in 39% overall yield from 6.
Coupling ofthe b-ketophosphonate 3, which was synthe-
sized as previously described,[3f] with oxazole carboxaldehyde
OMe
H
OMOM
OPiv
OMe
N
O
OH
OPMB
O
OPiv
a, b
OMe
O
N
O
4
OTES
OTBDPS
O
OMOM
OMe
OTBDPS
18
O
P
O
OPMB
c
EtO
EtO
OTBDPS
X
H
3
O
OTES
N
OMe
O
O
O
f
OPiv
OMe
O
N
O
OTES
O
O
X
OMe
N
OTES
TIPSO
OTBDPS
H
OMe
O
19 X = H, OPMB
20 X = O
d, e
OTBDPS
21 X = H, OPiv
22 X = O
g, h
OTBDPS
O
i, j, k
N
O
Br
OMe
n, o, p
O
Phorboxazole A (1)
O
H
N
O
O
MeO
O
OMe
O
O
X
OTBDPS
P(OCH3)2
23 X = H, OTIPS
24 X = O
l, m
Scheme 3. a) NaH, THF, RT, 0.5 h; 88%, >95:5 E:Z; b) NaBH4, CeCl3·7H20, MeOH, 08C, 1 h; 98%, >95:5 d.r.; c) Tf2O, pyr, CH2Cl2, À208C,
12 h; 55%; d) DDQ, CH2Cl2, pH 7 buffer, RT, 1 h; 94%; e) Dess–Martin periodinane, pyr, CH Cl2, RT, 2.5 h; 87%; f)5, PBu3, CH2Cl2, RT, 16 h, then
2
add 14, DBU, RT, 1 h; quant.; g) DIBAL-H, CH Cl2, À788C, 2 min; 98%; h) Dess–Martin periodinane, pyr, CH2Cl2, 1.5 h; 90%; i) 2, NaHMDS,
2
THF, À788C to RT ; 98%, >95:5 E:Z; j) CH2Cl2/MeOH/HOAc 2:1:1, 2 d, 86%; k) dimethylphosphonoacetic acid, DCC, CH2Cl2; l) CSA, MeOH;
m) Dess-Martin periodinane, CH2Cl2; 76% for three steps; n) K2CO3, [18]crown-6, toluene, À208C, two days; quant., 4:1 Z:E; o) TBAF, THF;
53%; p) 6% HCl, THF; 80%. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DBU= 1,8-diazabicyclo[5.4.0]undec-7-ene, DIBAL-H= diisobutyl-
aluminum hydride, HMDS= bis(trimethylsilyl)amide, DCC=N,N’-dicyclohexylcarbodiimide.
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Tetrahedron Lett. 1998, 39, 7185; j) A. B. Smith III, P. R.
allylic alcohol gave the unsaturated aldehyde 22 for attach-
ment ofthe remaining C42–C46 carbon chain. In this regard,
our previous studies have examined the adaptation ofthe
Kocienski modification of the Julia olefination.[21] Intrigu-
ingly, use ofthe corresponding N-phenyltetrazole sulfone of 2
resulted predominantly in the formation of the Z olefin. On
the other hand, the carbanion ofthe benzothiazole [22] sulfone
2, previously reported by Evans and co-workers,[6] cleanly
reacted with 22 under similar reaction conditions yielding the
desired E,E diene (98%; > 95:5 E:Z). Removal ofthe TES
ether at C24 (HOAc, CH2Cl2, MeOH, 86%) and esterifica-
tion ofthe alcohol at C24 with dimethylphosphonoacetic acid
(DCC, CH2Cl2) provided phosphonate 23. Selective removal
ofthe TIPS protecting group at C3 under mildly acidic
conditions (CSA, MeOH) followed by Dess–Martin oxidation
furnished the key aldehyde 24 in 76% yield over three steps.
Intramolecular Horner–Wadsworth–Emmons macrocycliza-
tion in toluene (K2CO3, [18]crown-6, À208C) gave the
macrocycle as a 4:1 mixture ofC2–C3 Z:E olefin isomers.
Deprotection ofboth TBDPS ethers with TBAF in THF
provided a diol (53% yield), which permitted the separation
ofthe minor ( E)-C2–C3 isomer by silica gel chromatography.
Finally, hydrolysis ofthe methyl ketal moiety under acidic
conditions (6% aqueous HCl, THF)[4a] furnished phorbox-
azole A (1) in 80% yield. Our synthetic material was identical
in all respects with physical and spectroscopic data provided
for the natural product.[1]
Verhoest, K. P. Minbiole, J. J. Lim, Org. Lett. 1999, 1, 909;
k) A. B. Smith III, K. P. Minbiole, P. R. Verhoest, T. J. Beau-
champ, Org. Lett. 1999, 1, 913; l) D. A. Evans, V. J. Cee, T. E.
Smith, K. J. Santiago, Org. Lett. 1999, 1, 87; m) P. Wolbers,
H. M. R. Hoffmann, Tetrahedron 1999, 55, 1905; n) P. Wolbers,
A. M. Misske, H. M. R. Hoffmann, Tetrahedron Lett. 1999, 40,
4527; o) J. Schaus, J. S. Panek, Org. Lett. 2000, 2, 469; p) G.
Pattenden, A. Plowright, Tetrahedron Lett. 2000, 41, 983; q) S.
Rychnovsky, C. Thomas, Org. Lett. 2000, 2, 1217.
[4] C. J. Forsyth, F. Ahmed, R. D. Cink, C. S. Lee, J. Am. Chem. Soc.
1998, 120, 5597.
[5] a) A. B. Smith III, P. R. Verhoest, K. P. Minbiole, M. Schelhaas,
J. Am. Chem. Soc. 2001, 123, 4834; b) A. B. Smith III, P. R.
Verhoest, K. P. Minbiole, M. Schelhaas, J. Am. Chem. Soc. 2001,
123, 10942; c) After submission of this manuscript for publica-
tion, we were informed that Prof. G. Pattenden et al. have also
completed a synthesis ofphorboxazole A. See preceding paper;
M. A. Gonzalez, G. Pattenden, Angew. Chem. 2003, 115, 1293;
Angew. Chem. Int. Ed. 2003, 42, 1255.
[6] a) D. A. Evans, V. J. Cee, T. E. Smith, D. M. Fitch, P. S. Cho,
Angew. Chem. 2000, 112, 2633; Angew. Chem. Int. Ed. 2000, 39,
2533; b) D. A. Evans, D. M. Fitch, Angew. Chem. 2000, 112,
2636; Angew. Chem. Int. Ed. 2000, 39, 2536.
[7] The aldehyde 6, which bears the primary pivaloate, was prepared
by the same route as previously described for the corresponding
MOM ether in 62% overall yield.[3f]
[8] Stannane 7 is conveniently prepared by deprotonation of3-
methyl-3-buten-1-ol with two equivalents ofSchlosser's base,
quenching the resulting dianion with tributyltin iodide, and
protection ofthe resultant alcohol (TBSCl, imidazole).
[9] E. J. Corey, C. M. Yu, S. S. Kim, J. Am. Chem. Soc. 1989, 111,
5495. For development ofthis asymmetric allylation method-
ology, see: D. R. Williams, D. A. Brooks, K. G. Meyer, M. P.
Clark, Tetrahedron Lett. 1998, 39, 7251.
[10] Small-scale reactions permitted the chromatographic separation
ofhomoallylic alcohol diastereomers ofr individual character-
ization. Preparative multigram reactions were conveniently
carried forward to acetal 16, where the desired C37 isomer was
easily purified by flash chromatography.
[11] D. A. Evans, E. Carreira, J. Am. Chem. Soc. 1988, 110, 3560.
[12] S. D. Rychnovsky, D. J. Skalitzky, Tetrahedron Lett. 1990, 31,
945; D. A. Evans, D. L. Rieger, J. R. Gage, Tetrahedron Lett.
1990, 31, 7099.
[13] A. J. Mancuso, S. L. Huang, D. Swern, J. Org. Chem. 1978, 43,
2480.
In summary, we have reported a highly convergent,
stereocontrolled total synthesis ofphorboxazole A
( 1).
Asymmetric allylation reactions ofstannyl-derived allyldi-
azaborolanes are demonstrated as a powerful protocol for the
enantiocontrolled assembly ofuf nctionally complex compo-
nents. Key features of the overall scheme include a stereo-
selective cationic cyclization reaction for formation of the
fully substituted C22–C26 tetrahydropyran, and the use of a
Julia olefination for incorporation of the sensitive C37–C46
dienyl system. The novel Barbier-type coupling ofan
iodomethyl oxazole provides a promising methodology for
the incorporation ofthe intact oxazole heterocycle. Full
details ofthis study will be reported in due course.
[14] S. L. Huang, K. Omura, D. Swern, Synthesis 1978, 297.
[15] J. D. More, N. S. Finney, Org. Lett. 2002, 4, 3001 – 3003.
[16] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155; D. B. Dess,
J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
Received: December 20, 2002 [Z50817]
Keywords: antitumor agents · asymmetric allylation ·
.
[17] J.-L. Luche, J. Am. Chem. Soc. 1978, 100, 2226.
macrolides · natural products · total synthesis
[18] The relative stereocontrol ofthe reduction was established on a
related compound by conversion (2,2’-dimethoxypropane (2,2-
DMP)) into the six-membered acetonide and application of
13C NMR spectroscopic analysis.[12]
[1] P. A. Searle, T. F. Molinski, J. Am. Chem. Soc. 1995, 117, 8126.
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[3] a) C. S. Lee, C. J. Forsyth, Tetrahedron Lett. 1996, 37, 6449;
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Ye, Tetrahedron Lett. 1998, 39, 6099; i) I. Paterson, E. A. Arnott,
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[19] Model studies had shown that individual diastereomeric allylic
alcohols were cyclized under these conditions to afford the same
tetrahydropyran product.
OMOM
Tf2O, pyridine
OH
OH
OPMB
OPMB
OPMB
OTES
–20°C
N
O
OTES
O
N
O
OMOM
Tf2O, pyridine
–20°C
N
O
OTES
[20] Methanesulfonate 5 was prepared from the previously reported
C3 pivaloate/C19 PMB ether[3d] by the following four-step
sequence: 1) LiOH, THF/MeOH/H2O; 2) TIPSOTf, 2,6-luti-
dine; 3) DDQ, CH2Cl2/pH 7 buffer; 4) MsCl, Et3N.
[21] P. R. Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett
1998, 26.
[22] J. B. Baudin, G. Hareau, S. A. Julia, O. Ruel, Bull. Soc. Chim. Fr.
1993, 130, 336.
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