Synthesis of Phorboxazole B
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 10035
Scheme 2a
tetrahydropyran fragment 7 was obtained in five steps and 50%
overall yield from (benzyloxy)acetaldehyde.
In the synthesis plan outlined in Scheme 1, it was necessary
to establish whether 1,5-anti induction from the C9 oxygen-
bearing stereocenter in methyl ketone 7 in the aldol union with
aldehyde 8 was possible during the C12-C13 bond construction.
In our original study on related aldol reactions, the methyl
ketones employed contained either p-methoxybenzyl-protected
â-hydroxy groups or â-benzylidene acetals.10a As a consequence,
it was unclear whether the â-tetrahydropyranyl moiety, as in 7,
would afford an analogous directing effect. This point was tested
in a simple model study (eq 2). Addition of the dibutylboron
enolate derived from ketone 7 to dihydrocinnamaldehyde
provided the desired adduct 14 as a single isomer in good yield
(eq 2). The relative stereochemistry of the product, established
by X-ray crystallographic analysis, was found to possess the
desired 1,5-anti relationship (Figure 1) as predicted from related
aldol reactions.21
a Key: (a) HO(CH2)2OH, TMSCl, CH2Cl2, rt. (b) DIBALH, tol, -78
°C. (c) Ac2O, pyr, cat DMAP, CH2Cl2, rt. (d) TMSOTf, 2-(trimethyl-
silyloxy)propene, cat. pyr, CH2Cl2, -78 °C.
9 to (benzyloxy)acetaldehyde catalyzed by a bis(oxazolinyl)-
pyridine Cu(II) complex provided the desired aldol adduct 10
in excellent yield and enantioselectivity (eq 1).13a The δ-hy-
droxy-â-ketoester 10 was viewed as an ideal starting material
for the synthesis of both the C4-C9 and C33-C38 subunits of
phorboxazole B. Given the identical absolute configuration of
the C5 and C37 stereocenters, a single reaction provided material
for the construction of both fragments.
The synthesis of methyl ketone 7 began with the merged
cyclization-ketal protection of aldol adduct 10 upon treatment
with ethylene glycol and trimethylsilyl chloride to deliver lactone
11 in 75% yield (Scheme 2).14 Reduction of lactone 11
(DIBAlH, toluene, -78 °C) followed by acetylation (Ac2O,
pyridine, cat. DMAP, CH2Cl2) afforded 13 in quantitative yield
as a 92:8 mixture of â/R anomers.15,16 Treatment of the ano-
meric acetates with trimethylsilyl trifluoromethanesulfonate
(TMSOTf)17 and 2-(trimethylsilyloxy)propene resulted in an 89:
11 mixture of diastereomeric tetrahydropyrans,18 favoring the
desired trans isomer 7.19 The relative stereochemistry of the
major product was inferred from precedent and later established
by X-ray crystallographic analysis of aldol adduct 14 (vide
infra). Axial attack of the nucleophile from the bottom face of
the oxocarbenium ion derived from 13 (as depicted in TS1)
via a chairlike transition structure provides a rationalization for
the formation of the major product.20 This diastereoface is
partially hindered by the axial oxygen substituent associated
with the C7 ketal, which may explain the formation of a minor
amount of the undesired cis isomer. The desired C4-C12 trans
Figure 1. X-ray crystal structure of model aldol adduct 14.
With the requisite methyl ketone fragment in hand and
precedent for the 1,5-induction aldol reaction established, the
synthesis of the C13-C19 aldehyde 8 was investigated (Scheme
3). The use of auxiliary-based aldol additions of haloacetylox-
azolidinones as masked chiral acetate enolate equivalents has
proven reliable in this laboratory.22 To explore the viability of
subsequent fragment couplings, an approach to aldehyde 8 was
undertaken utilizing this methodology. The requisite aldehyde
17 was constructed from the known oxazole ester 1523 via
silylation of the primary hydroxyl (TIPSOTf, 2,6-lutidine, CH2-
Cl2, 0 °C; 100%) followed by partial reduction of the ester
(DIBAlH, CH2Cl2, -94 °C; 97%). An aldol reaction between
the dibutylboron enolate derived from chloroacetyloxazolidinone
1822 and aldehyde 17 provided the desired adduct 19 in excellent
yield (90%) and diastereoselectivity (>95:5).15 Dechlorination
of 19 was accomplished in 91% yield upon treatment with zinc
dust and glacial acetic acid at room temperature. Silylation of
the free hydroxyl (TESCl, imidazole, cat. DMAP, DMF, rt;
100%) was followed by reductive cleavage of the auxiliary
(LiBH4, Et2O, H2O, rt; 85%)24 and Swern oxidation (oxalyl
chloride, DMSO, CH2Cl2; Et3N, -78 °C; 99%) to afford
aldehyde 8 in seven steps and 67% overall yield from ester 15.
As is often the case, the synthesis of complex natural products
provides the impetus for extending the scope of known reactions.
(13) (a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121,
669-685. (b) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S.
W. J. Am. Chem. Soc. 1999, 121, 686-699. (c) Evans, D. A.; MacMillan,
D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859-10860.
(14) Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203-205.
(15) Product ratio determined by 1H NMR spectral analysis (500 MHz)
of the unpurified reaction mixture.
(16) Although the anomers were separable by silica gel chromatography,
the mixture was generally taken on without purification.
(17) Use of stronger Lewis acids such as BF3‚OEt2 or TiCl4 led to high
levels of decomposition.
(18) For an early example of nucleophilic addition to oxocarbenium ions
in the synthesis of C-glycosides, see: Lewis, M. D.; Cha, J. K.; Kishi, Y.
J. Am. Chem. Soc. 1982, 104, 4976-4978.
(19) Optimal results were obtained when buffering the reaction with 20
µol % pyridine. Diastereoselectivity was determined by 1H NMR and HPLC
analysis (Zorbax silica gel, 20% EtOAc/hexanes, 1.0 µL/min, λ ) 254 nm,
Tr major ) 11 min, Tr minor ) 13 min).
(20) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; Chapter 11.
(21) The diastereoselectivity of this reaction was previously misreported
as 89:11 (see ref 10a). The X-ray crystal structure of 14 was determined
by Mr. Kevin Campos. See Supporting Information for the coordinates.
(22) (a) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.
Tetrahedron Lett. 1987, 28, 39-42. For an application of this methodology
toward the synthesis of bryostatin 2, see: (b) Evans, D. A.; Carter, P. H.;
Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem.
Soc. 1999, 121, 7540-7552.
(23) Ester 15 is available in five steps from cinnamamide and ethyl
bromopyruvate; see: Panek, J. S.; Beresis, R. T. J. Org. Chem. 1996, 61,
6496-6497.
(24) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro,
J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307-312.