Asymmetric synthesis of the enantiopure C28-C41 segment of the phorboxazoles A and B

Article abstract of DOI:10.1055/s-1999-3470

The phorboxazoles A and B are a new class of biologically highly active macrolides. The enantiopure C28-C41 segment containing four stereogenic centers, an E-configurated trisubstituted double bond and the 2,4- difunctionalized oxazole moiety has been prepared in 16 steps in 10% overall yield. The synthesis represents advances in strategy and methodology.

Full text of DOI:10.1055/s-1999-3470

PAPER
797
Asymmetric Synthesis of the Enantiopure C28–C41 Segment of the
Phorboxazoles A and B
P. Wolbers, H. M. R. Hoffmann*
Institut für Organische Chemie, Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011, E-mail: hoffmann@mbox.oci.uni-hannover.de
Received 23 December 1998
ed double bonds, five stereogenic centers and a 2,4-disub-
stituted oxazole moiety.
Abstract. The phorboxazoles A and B are a new class of biological-
ly highly active macrolides. The enantiopure C28–C41 segment
containing four stereogenic centers, an E-configurated trisubstitut-
ed double bond and the 2,4-difunctionalized oxazole moiety has
been prepared in 16 steps in 10% overall yield. The synthesis repre-
sents advances in strategy and methodology.
As part of our program towards the total synthesis of the
phorboxazoles A and B we considered the approach from
8-oxabicyclo[3.2.1]oct-6-en-3-one (1) as outlined in the
Figure.
Key words: oxazoles, marine natural products, oxabicyclic ke-
tones, cytotoxicity, HWE reaction, E,E-selectivity
The efficient synthesis of enantiopure methoxyacetal es-
ter 2 from oxabicyclic ketone 1 has been described by us
recently in gram quantities.9 Starting from a-methoxyace-
tal ester 2 we first aimed to prepare the 2,4-disubstituted
oxazole moiety. Among several procedures to install this
5-membered heterocycle the biomimetic pathway using L-
serine as the nitrogen source seemed to be the method of
choice. The a-methoxyacetal ester 2 was quantitatively
hydrolyzed to the acid 3, converted into the mixed anhy-
dride using isobutyl chloroformate and subsequently cou-
pled with L-serine methyl ester to the N-acylserine ester 4
in good yield. Cyclodehydration (4 Æ 5) to the oxazoline
occurred smoothly in the presence of the Burgess re-
agent.10 The oxidative aromatisation of oxazolines to ox-
azoles has been a difficult step for a long time.11 An
inexpensive and efficient method has been developed at
Bristol-Myers Squibb using a CuBr2/HMTA/DBU com-
plex.12 This method proved to be very useful in the pres-
ence of the electron-withdrawing ester functionality at the
4-position of the oxazoline. Treating oxazoline 5 under
these conditions we obtained oxazole ester 6 in a fast and
The phorboxazoles A and B first described by Molinski in
1995,1 are two new macrolides with an unprecedented
molecular skeleton. The structural assignment has result-
ed from exhaustive NMR studies and comparison of syn-
thetic samples with derivatized fragments of the
phorboxazoles after degradation.2 Together with the
altohyrtins3 and the bryostatins4 they are amongst the
most cytotoxic natural products as they inhibit growth of
tumor cells at sub-nanomolar concentrations in vitro
(mean GI50 1.58 ¥ 10–9 M).2b Unlike antimitotic natural
products such as Taxol5 or the epothilones6 the phorbox-
azoles arrest the cell cycle during S phase.
Only a few synthetic approaches towards the total synthe-
sis have been published so far including a total synthesis
of phorboxazole A by Forsyth and his co-workers.7,8 The
side chain beginning with C27 contains four E-configurat-
O
N
R1
R2
13
28
11
O
O
OP OMe
OP
N
O
OP
31
38
OMe
35
EtO2C
35
33
41
O
9
28
5
OMe
OP
N
41
O
31
7
38
Br
43
P = protecting group
O
3
46
O
H
O
OH
OH
Phorboxazole A: R1 = OH, R2 = H
Phorboxazole B: R1 = H, R2 = OH
OMe
35
OMe
35
33
O
28
35
O
37
N
OP
32
31
O
33
31
37
O
33
MeO
37
31
O
MeO
OMe
O
1
2
Figure 1 Retrosynthetic analysis of the side chain
Synthesis 1999, No. 5, 797–802 ISSN 0039-7881 © Thieme Stuttgart · New York

798
P. Wolbers, H. M. R. Hoffmann
PAPER
high yielding reaction without any side products. DIBAH presence of sodium hydride in dichloromethane at 0 °C
reduction of the oxazole ester 6 to oxazole alcohol 7 con- gave the (2E,4E)-deca-2,4-dienoic ester 11 in excellent
cluded the synthesis of the C28–C37 building block.
yield and with good E,E-stereocontrol (E:Z > 10:1) of
both disubstituted and trisubstituted alkenic double bonds.
Asymmetric dihydroxylations of polyalkenated carbonyl
compounds usually give diols in high yields and with ex-
cellent diastereoselectivity whilst conjugation of the p
system is generally retained.16 Treatment of deca-2,4-di-
enoic ester 11 with three equivalents of b-AD-mix in the
presence of methanesulfonamide in t-BuOH/H2O at room
temperature was site-selective and provided the C28–C41
segment 12 in good chemical yield and with excellent
asymmetric induction.
Scheme 1
The opening of the methoxyacetal ring of alcohol 7 is
shown in Scheme 2. Lewis acid mediated transthioacetal-
isation of tetrahydropyran methoxyacetals affords
polyketides in high yields.13 When oxazole alcohol 7 was
treated with propane-1,3-dithiol in the presence of boron
trifluoride–diethyl ether complex anti 1,3-diol oxazole 8
(with one alcohol group methylated) was obtained in ex-
cellent yield. Protection of both hydroxy groups in one
step under standard procedures with TBS-triflate/2,6-luti-
dine in dichloromethane afforded O-diprotected oxazole
9. Removal of a dithiane moiety can sometimes be te-
dious. After optimization on a model compound the
dithiane 9 was converted into the aldehyde 10 rapidly and
under mild reaction conditions by treatment with mercuric
perchlorate in aqueous acetonitrile, the pH being con-
trolled with solid calcium carbonate.14 Coupling of alde-
hyde 10 with the BASF phosphonoester ethyl [(E)-4-
(diethoxyphosphonyl)-2-methylbut-2-enoate]15 in the
Scheme 2
In summary, we have described a highly diastereoselec-
tive and efficient de novo synthesis of the C28–C41 seg-
ment 12 of the phorboxazoles A and B. The synthesis
consists of only 16 steps, most of which have been opti-
mized with respect to stereocontrol and chemical yields,
and proceeds in 10% overall yield. Further synthetic ap-
proaches to the other segments of the phorboxazole A and
B and towards a convergent total synthesis are in
progress.17
IR spectra were recorded on a Perkin-Elmer 1710 infrared spec-
trometer. 1H NMR and 13C NMR spectra were recorded on a Bruker
AM 400 spectrometer in deuterated CHCl3 unless otherwise stated,
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Asymmetric Synthesis of the Enantiopure C28–C41 Segment of the Phorboxazoles A and B
799
with TMS as internal standard. Mass spectra were recorded on a
Finnigan MAT 312 (70 eV) or a VG Autospec spectrometer at r.t.
unless otherwise stated. Preparative column chromatography was
performed on J. T. Baker silica gel (particle size 30–60 mm). Ana-
lytical TLC was carried out on aluminium-backed 0.2-mm silica gel
60 F254 plates (E. Merck). THF was distilled over Na and benzophe-
none before use. CH2Cl2 was distilled over CaH2 before use. DMF
was dried over BaO and distilled over CaH2 before use. tert-Butyl
methyl ether (MTBE), EtOAc and light petroleum (PE, bp 40–60
°C) were distilled before use.
MS (140 °C): m/z (%) = 287 (M+ – H2O, 1.3), 274 (M+ – OCH3, 3.9),
273 (5.8), 255 (7.5), 243 (37.7), 211 (53.4), 182 (18.1), 155 (18.7),
140 (11.5), 120 (25.2), 94 (19.2), 81 (100).
HRMS calcd for C12H20NO6 (M+ – OCH3) 274.1290, found
274.1286.
Methyl (4S)-2-{[(2S,4S,6S)-4,6-Dimethoxytetrahydropyran-2-
yl]methyl}-4,5-dihydro-1,3-oxazole-4-carboxylate (5)
To a solution of amide 4 (1.30 g, 4.26 mmol) in THF (70 mL) was
added Burgess reagent (1.22 g, 5.11 mmol) and the mixture was
heated to reflux for 1 h. The solvent was removed and the crude
yield the oxazoline 5 (1.0 g, 82%) as a colourless oil. [a]2D0 = +169.5
(c = 1 in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 4.86 (d, 3J = 3 Hz, 1 H, H-
37), 4.76 (dd, 3J = 10.7 Hz, 3J = 7.8 Hz, 1 H, H-29), 4.53 (dd, 3J =
8.7 Hz, 3J = 7.8 Hz, 1 H, H-30), 4.39 (dd, 3J = 10.7 Hz, 3J = 8.8 Hz,
1 H, H-30’), 4.15–4.08, 3.68–3.60 (m, 2 H, H-35, H-33), 3.77 (s, 3
H, CO2CH3), 3.33, 3.31 (2 s, 6 H, OCH3), 2.64–2.46 (m, 2 H, H-32,
H-32’), 2.18–2.14 (m, 2 H, H-36eq, H-34eq), 1.43 (ddd, 2J = 12.9 Hz,
3J = 11.4 Hz, 3J = 3.0 Hz, 1 H, H-36ax), 1.31 (q, 2/3J = 11.7 Hz, 1 H,
H-34ax).
(2S,4S,6S)-(4,6-Dimethoxytetrahydropyran-2-yl)acetic Acid (3)
To a solution of ester 2 (1.09 g, 5 mmol) in THF (5 mL) and H2O
(5 mL) was added LiOH·H2O (450 mg, 5 mmol) and the mixture
was stirred for 15 h at r.t. The mixture was acidified with concd HCl
(pH 1) and extracted with CH2Cl2 (5 ¥ 20 mL). The combined or-
ganic layer was dried (MgSO4) and evaporated to afford acid 3 (1.02
g, 100%) as a colourless oil. [a]2D0 = +100.1 (c = 1 in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 4.88 (d, 3J = 2.9 Hz, 1 H, H-
37), 4.22–4.16 (m, 1 H, H-33), 3.72–3.65 (m, 1 H, H-35), 3.36 (s, 6
H, 2 ¥ OCH3), 2.62–2.49 (m, 2 H, H-32, H-32’), 2.20–2.15 (m, 1 H,
H-36eq), 2.12–2.08 (m, 1 H, H-34eq), 1.51–1.42 (m, 1 H, H-36ax),
1.25 (q, 2J = 11.7 Hz, 1 H, H-34ax).
13C NMR (100 MHz, CDCl3/TMS): d = 171.5 (C-28), 168.0 (C-31),
99.2 (C-37), 72.1 (C-35), 69.4 (C-29), 68.1 (C-30), 65.1 (C-33),
55.5 (OCH3), 54.6 (OCH3), 52.6 (CO2CH3), 37.1, 35.9 (C-34, C-
36), 34.7 (C-32).
13C NMR (100 MHz, CDCl3/TMS): d = 176.3 (C-31), 99.2 (C-37),
72.1 (C-35), 64.3 (C-33), 55.5 (OCHOCH3), 54.7 (CHOCH3), 40.7
(C-32), 37.0, 35.7 (C-34, C-36).
IR (CHCl3): n = 3000, 2952, 2936, 2832, 1740, 1660, 1600, 1580,
1440, 1352, 1304, 1228, 1184, 1156, 1124, 1080, 1044, 972, 924,
868, 844 cm–1.
MS (r.t.): m/z (%) = 287 (M+, 3.1), 272 (14.7), 256 (17.0), 224
(24.9), 197 (19.1), 169 (54.3), 143 (100), 113 (52.4), 87 (45.9), 81
(58.0).
IR (CHCl3) n = 3000, 2936, 2832, 2748, 2676, 1712, 1448, 1412,
1384, 1348, 1304, 1268, 1228, 1188, 1152, 1124, 1080, 1044, 972,
928, 848 cm–1.
MS (r.t.): m/z (%) = 204 (M+, 1.2), 173 (M+ – OCH3, 13.3), 172
(43.3), 154 (30.9), 141 (100), 129 (17.3), 112 (33.6), 103 (30.9), 97
(19.1), 87 (48.0), 81 (70.1), 71 (54.9).
HRMS calcd for C13H21NO6 (M+) 287.1369, found 287.1369.
HRMS calcd for C8H13O4 (M+ – OCH3) 173.0813, found 173.0804.
Methyl 2-{[(2S,4S,6S)-4,6-Dimethoxytetrahydro-2H-pyran-2-
yl]methyl}-1,3-oxazole-4-carboxylate (6)
Methyl (2S)-2-[2-(2S,4S,6S)-(4,6-Dimethoxytetrahydropyran-
2-yl)acetylamino]-3-hydroxypropanoate (4)
To a solution of CuBr (2.68 g, 11.84 mmol) and HMTA (1.67 g,
11.84 mmol) in oxygen-free CH2Cl2 (25 mL) was added DBU (1.78
mL, 11.84 mmol) dropwise. The reaction is slightly exothermic and
the solution becomes dark. To this mixture was added oxazoline 5
(850 mg, 2.96 mmol) in CH2Cl2 (5 mL) dropwise. After being
stirred for 1 h at r.t. the mixture was treated with 2 M HCl (50 mL)
and EtOAc (50 mL). The mixture was stirred until the dark precip-
itate had dissolved. The layers were separated and the aqueous layer
was extracted with EtOAc (5 ¥ 30 mL). The combined organic layer
was dried (MgSO4), evaporated and the crude product purified by
azole ester 6 (658 mg, 78%) as a colourless oil. [a]2D0 = +79.1 (c =
1 in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 8.18 (s, 1 H, H-30), 4.82 (d,
3J = 3 Hz, 1 H, H-37), 4.33–4.29 (m, 1 H, H-35), 3.72 (s, 3 H,
CO2CH3), 3.70–3.62 (m, 1 H, H-33), 3.33, 3.21 (2 s, 6 H, 2 ¥
OCH3), 3.10–2.96 (m, 2 H, H-32, H-32’), 2.16–2.08 (m, 2 H, H-
34eq, H-36eq), 1.44 (ddd, 2J = 12.5 Hz, 3J = 11.4 Hz, 3J = 3.0 Hz, 1
H, H-36ax), 1.31–1.22 (m, 1 H, H-34ax).
To a solution of acid 3 (1.1 g, 5.4 mmol) in CH2Cl2 (10 mL) was
added N-methylmorpholine (0.7 mL, 0.62 g, 6.1 mmol) followed by
iso-butyl chloroformate (0.72 mL, 0.76 g, 5.4 mmol) at –25 °C. The
mixture was stirred for 15 min, then L-serine methyl ester hydro-
chloride (1.0 g, 6.4 mmol) and N-methylmorpholine (1.4 mL, 1.24
g, 12.2 mmol) were added. The mixture was stirred for 30 min at
–25 °C and then allowed to reach r.t. slowly and stirred for a further
hour. Sat. aq NaHCO3 (10 mL) was added and the mixture was ex-
tracted with CH2Cl2 (10 ¥ 20 mL). The combined organic layer was
dried (Na2SO4), the solvent was removed and the crude product pu-
rified by column chromatography (silica gel; EtOAc Æ EtOAc/ oil.
[a]2D0 = +82.1 (c = 1 in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 7.15 (br d, 1 H, NH), 4.86
(d, 3J = 2.8 Hz, 1 H, H-37), 4.68–4.64 (m, 1 H, H-29), 4.18–4.12 (m,
1 H, H-33), 4.01–3.91 (m, 2 H, H-30, H-30’), 3.79 (s, 3 H,
CO2CH3), 3.71–3.63 (m, 1 H, H-35), 3.34 (s, 6 H, 2 ¥ OCH3), 3.21
(br. s, 1 H, OH), 2.54–2.44 (m, 2 H, H-32, H-32’), 2.18–2.14 (m, 1
H, H-36eq), 2.11–2.05 (m, 1 H, H-34eq), 1.43 (ddd, 2J = 12.7 Hz, 3J
= 11.3 Hz, 3J = 2.8 Hz, 1 H, H-36ax), 1.29–1.20 (m, 1 H, H-34ax).
13C NMR (100 MHz, CDCl3/TMS): d = 163.0 (C-28), 161.7 (C-31),
143.9 (C-29), 133.4 (C-30), 99.2 (C-37), 72.0 (C-35), 65.7 (C-33),
55.5 (OCH3), 54.7 (OCH3), 52.1 (CO2CH3), 37.1, 35.8 (C-34, C-
36), 34.7 (C-32).
13C NMR (100 MHz, CDCl3/TMS): d = 170.9 (C-28), 170.8 (C-31),
99.3 (C-37), 71.9 (C-35), 64.8 (C-33), 63.1 (CH2OH), 55.5 (OCH3),
54.9 (OCH3), 54.7 (C-30), 52.8 (CO2CH3), 42.8 (C-32), 37.1, 35.9
(C-34, C-36).
IR (CHCl3): n = 2988, 2936, 2832, 1736, 1584, 1440, 1380, 1348,
1324, 1276, 1232, 1112, 1088, 1044, 1004, 976, 844 cm–1.
MS (r.t.): m/z (%) = 285 (M+, 0.8), 270 (0.9), 254 (11.1), 222 (21.5),
210 (8.1), 194 (7.1), 167 (24.4), 145 (39.7), 113 (100), 101 (13.1),
87 (59.7).
IR (CHCl3): n = 3624, 3428, 3380, 3000, 2936, 2832, 1744, 1672,
1604, 1512, 1440, 1384, 1348, 1300, 1232, 1200, 1152, 1120, 1088,
1044, 1000, 972, 924, 604, 544 cm–1.
HRMS calcd for C13H19NO6 (M+) 285.1212, found 285.1212.
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P. Wolbers, H. M. R. Hoffmann
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{2-[(2S,4S,6S)-4,6-Dimethoxytetrahydropyran-2-yl]methyl-1,3-
oxazol-4-yl}methanol (7)
to afford bis-O-silyl ether 9 (88 mg, 96%) as a colourless oil. [a]2D0
= –8.8 (c = 1 in CHCl3).
To a solution of ester 6 (0.57 g, 2 mmol) in THF (10 mL) was added
DIBAH (5 mL, 6 mmol, 1.2 M solution in toluene) at –20 °C under
Ar. The mixture was stirred for 2 h at 0 °C, then MeOH (1 mL) was
added carefully. The mixture was treated with sat. aq potassium so-
dium tartrate solution (20 mL) and EtOAc (20 mL) and stirred for
30 min. The aqueous layer was extracted with EtOAc (5 ¥ 20 mL),
the combined organic layer was dried (MgSO4) and evaporated. The
crude product was purified by column chromatography (SiO2;
EtOAc) to give oxazole alcohol 7 (430 mg, 85%) as a colourless oil.
[a]2D0 = +101.1 (c = 1 in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 7.44 (t, 4J = 1.3 Hz, 1 H, H-
30), 4.63 (d, 4J = 1.3 Hz, 2 H, H-28), 4.30–4.24 (m, 1 H, H-35), 4.14
(t, 3J = 7.3 Hz, 1 H, H-37), 3.72–3.66 (m, 1 H, H-33), 3.32 (s, 3 H,
OCH3), 2.94–2.78 (m, 6 H, SCH2, H-32, H-32’), 2.15–2.08, 2.04–
1.95 (2 m, 2 H, H-36, H-36’), 1.93–1.58 (m, 4 H, CH2, H-34, H-
34’), 0.95–0.85 (m, 18 H, Si(C(CH3)3), 0.13–0.03 (m, 12 H,
Si(CH3)2).
13C NMR (100 MHz, CDCl3/TMS): d = 162.1 (C-31), 141.3 (C-29),
134.7 (C-30), 73.8 (C-33), 67.7 (C-35), 58.7 (C-28), 55.7 (OCH3),
43.7 (C-37), 42.3, 39.6 (C-34, C-36), 37.3 (C-32), 30.42, 30.36 (2 ¥
SCH2), 25.95 (CH2), 25.89, 25.83 (SiC(CH3)3), 18.4, 17.9
(SiC(CH3)3), –4.60, –4.66, –5.32 (Si(CH3)2).
1H NMR (400 MHz, CDCl3/TMS): d = 7.52 (d, 4J = 0.9 Hz, 1 H, H-
3
30), 4.83 (d, J = 3.2 Hz, 1 H, H-37), 4.57 (2 H, s, H-28, H-28´),
4.21–4.14 (m, 1 H, H-35), 3.70–3.63 (m, 1 H, H-33), 3.33, 3.22 (2
s, 6 H, OCH3), 3.05–2.89 (m, 2 H, H-32, H-32’), 2.17–2.09 (m, 2 H,
H-36eq, H-34eq), 1.45 (ddd, 2J = 13.6 Hz, 3J = 11.5 Hz, 3J = 3.2 Hz,
1 H, H-36ax), 1.31–1.22 (m, 1 H, H-34ax).
13C NMR (100 MHz, CDCl3/TMS): d = 162.5 (C-31), 140.4 (C-30),
135.0 (C-29), 99.2 (C-37), 72.1 (C-35), 65.7 (C-33), 56.6 (C-28),
55.5 (OCH3), 54.6 (OCH3), 37.1, 35.8 (C-34, C-36), 34.8 (C-32).
IR (CHCl3): n = 2956, 2928, 2900, 2856, 1600, 1568, 1472, 1424,
1380, 1360, 1256, 1180, 1096, 1004, 960, 936, 908, 836 cm–1.
MS (90 °C): m/z (%) = 562 (M+ + 1, 8.2), 561 (18.0) (M+), 472
(11.9), 398 (9.2), 372 (8.5), 340 (5.5), 296 (6.7), 266 (4.0), 240
(4.7), 198 (5.1), 170 (3.0), 133 (3.3), 119 (100), 89 (14.7), 73 (30.8).
HRMS calcd for C26H51NO4Si2S2 (M+) 561.2798, found 561.2791.
IR (CHCl3): n = 3608, 3436, 3000, 2936, 2832, 1572, 1448, 1380,
1344, 1304, 1264, 1228, 1184, 1152, 1124, 1088, 1044, 960, 916,
844 cm–1.
MS (r.t.): m/z (%) = 257 (M+, 2.8), 242 (1.1), 226 (6.9), 220 (3.0),
194 (10.8), 176 (4.4), 166 (1.5), 145 (40.2), 113 (100), 101 (12.6),
87 (63.8), 81 (15.6).
(3S,5S)-5-tert-Butyldimethylsilyloxy-3-methoxy-6-(4-tert-bu-
tyldimethylsilyloxymethyl-1,3-oxazol-2-yl)hexanal (10)
To a solution of oxazole 9 (150 mg, 0.27 mmol) and CaCO3 (78 mg,
0.81 mmol) in MeCN (2 mL) was added a solution of Hg(ClO)4·5
H2O (~264 mg, ~0.54 mmol) in H2O (0.3 mL) dropwise at 0 °C. The
mixture was stirred for 1 h at r.t.. CH2Cl2 (1 mL) was added and a
yellow solid precipitated. Silica gel was added and the resulting
mixture was purified by column chromatography (silica gel; MTB/
PE, 1:3) to give aldehyde 10 (104 mg, 82%) as a colourless oil. [a]2D0
= –12.3 (c = 1 in CHCl3).
HRMS calcd for C12H19NO5 (M+) 257.1263, found 257.1272.
(2S,4S)-5-[1,3]Dithian-2-yl-1-(4-hydroxymethyl-1,3-oxazol-2-
yl)-4-methoxypentan-2-ol (8)
To a solution of oxazole alcohol 7 (52 mg, 0.2 mmol) and propane-
1,3-dithiol (0.03 mL, 0.3 mmol) in CH2Cl2 (2 mL) was added
BF3·Et2O (0.024 mL, 0.2 mmol) dropwise at 0 °C. The resulting
mixture was stirred for 2 h at r.t. Silica gel was added and the mixure
oxazole diol 7 (61 mg, 92%) as a white foam. [a]2D0 = –11.4 (c = 1
in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 9.70 (t, 3J = 2.3 Hz, 1 H, H-
37), 7.43 (t, 4J = 1.3 Hz, 1 H, H-30), 4.62 (d, 4J = 1.3 Hz, 2 H, H-
28), 4.31–4.24 (m, 1 H, H-35), 3.93–3.87 (m, 1 H, H-33), 3.31 (s, 3
H, OCH3), 2.92–2.88 (m, 2 H, H-32, H-32’), 2.67–2.54 (m, 2 H, H-
36, H-36’), 1.85–1.78, 1.67–1.62 (2 m, 2 H, H-34, H-34’), 0.92,
0.86 (2 s, 18 H, Si(C(CH3)3), 0.10–0.02 (m, 12 H, Si(CH3)2).
1H NMR (400 MHz, CDCl3/TMS): d = 7.51 (s, 1 H, H-30), 5.30 (s,
2 H, H-28), 4.53 (s, 1 H, OH), 4.38–4.29 (m, 1 H, H-35), 4.18–4.10
(m, 1 H, H-37), 3.84–3.78 (m, 1 H, H-33), 3.48 (s, 1 H, OH), 3.40
(s, 3 H, OCH3), 2.92–2.78 (m, 6 H, 2 ¥ SCH2, H-32, H-32’), 2.15–
1.98 (2 m, 2 H, H-36, H-36’), 1.92–1.58 (m, 4 H, CH2, H-34, H-
34’).
13C NMR (100 MHz, CDCl3/TMS): d = 163.1 (C-31), 140.1 (C-29),
135.0 (C-30), 75.3 (C-33), 66.2 (C-35), 57.5 (C-28), 53.5 (OCH3),
43.6 (C-37), 40.3, 39.8 (C-34, C-36), 36.2 (C-32), 30.4, 30.2 (2 ¥
SCH2), 25.9 (CH2).
13C NMR (100 MHz, CDCl3/TMS): d = 201.0 (C-37), 161.8 (C-31),
141.3 (C-29), 134.8 (C-30), 72.7 (C-33), 67.4 (C-35), 58.6 (C-28),
56.1 (OCH3), 47.8 (C-36), 42.6 (C-34), 37.2 (C-32), 25.85, 25.75
(SiC(CH3)3), 18.3, 17.9 (SiC(CH3)3), –4.6, –4.8, –5.4 (Si(CH3)2).
IR (CHCl3): n = 2956, 2928, 2896, 2856, 2736, 1724, 1568, 1472,
1376, 1360, 1256, 1188, 1160, 1092, 1004, 936. cm–1.
MS (60 °C): m/z (%) =456 (M+ – CH3,, 4.8), 425 (1.8), 416 (29.9),
414 (92.3), 384 (32.0), 383 (100), 297 (29.8), 250 (53.9), 214 (19.2),
199 (10.6), 169 (14.4), 155 (4.3), 129 (7.0), 101 (7.2), 73 (44.9).
HRMS calcd for C22H42NO5Si2 (M+ – CH3) 456.2601, found
456.2594.
IR (CHCl3): n = 3608, 3452, 3216, 2980, 2940, 2904, 2832, 1588,
1572, 1460, 1424, 1364, 1308, 1276, 1228, 1192, 1176, 1080, 1020,
992, 908, 848, 812, 548 cm–1.
(2E,4E,7R,9S)-9-tert-Butyldimethylsilyloxy-10-(4-tert-bu-
tyldimethylsilyloxymethyl-1,3-oxazol-2-yl)-7-methoxy-2-meth-
yldeca-2,4-dienoate (11)
MS (120 °C): m/z (%) = 333 (M+, 2.5), 301 (1.2), 226 (1.9), 194
(3.0), 182 (3.7), 169 (9.7), 150 (1.6), 119 (5.6), 99 (6.6), 73 (100).
HRMS calcd for C14H23NO4S2 (M+) 333.1069, found 333.1062.
To a solution of aldehyde 10 (65 mg, 0.138 mmol) and ethyl [(E)-4-
(diethoxyphosphonyl)-2-methylbut-2-enoate] (80 mg, 0.3 mmol) in
CH2Cl2 (5 mL) was added NaH (12 mg, 0.3 mmol, 60% suspension
in mineral oil) at 0 °C. The mixture was stirred for 2 h at the same
temperature, then silica gel was added and the mixture was purified
by column chromatography (silica gel; MTBE/PE, 1:4) to give ester
11 (71 mg, 91%; E:Z = 10:1) as a colourless oil. [a]2D0 = –19.5 (c =
1 in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 7.45 (m, 1 H, H-30), 7.18 (d,
3J = 11.3 Hz, 1 H, H-39), 6.42 (dd, 3J = 15.1 Hz, 3J = 11.3 Hz, 1 H,
H-38), 6.08–6.02 (dt, 3J = 15.1 Hz, 3J = 7.3 Hz, 1 H, H-37), 4.63 (d,
2-[(2S,4S)-2-tert-Butyldimethylsilyloxy-5-[1,3]dithian-2-yl-4-
methoxypentanyl]-4-tert-butyldimethylsilyloxymethyl-1,3-ox-
azole (9)
To a solution of diol 8 (55 mg, 0.165 mmol) and 2,6-lutidine (0.074
mL, 0.62 mmol) in CH2Cl2 (1 mL) was added trifluormethane-
sulfonic acid tert-butyldimethylsilyl ester (0.08 mL, 0.35 mmol)
slowly dropwise at 0 °C. The mixture was stirred for 30 min at the
same temperature, MTBE (2 mL) was added and the crude product
was purified by column chromatography (silica gel; MTBE/PE, 1:5)
Synthesis 1999, No. 5, 797–802 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of the Enantiopure C28–C41 Segment of the Phorboxazoles A and B
801
4J = 1.4 Hz, 2 H, H-28), 4.33–4.27 (m, 1 H, H-35), 4.22 (q, 3J = 7.2
Hz, 2 H, OCH2CH3), 3.52–3.46 (m, 1 H, H-33), 3.31 (s, 3 H, OCH3),
2.89 (d, 3J = 6.2 Hz, 2 H, H-32, H-32’), 2.44–2.39 (m, 2 H, H-36,
H-36’), 1.93 (d, 4J = 1.0 Hz, 3 H, CH3), 1.70–1.56 (m, 2 H, H-34,
H-34’), 1.31 (t, 3J = 7.2 Hz, 2 H, OCH2CH3), 0.92, 0.86 (2 s, 18 H,
Si(C(CH3)3), 0.10–0.02 (m, 12 H, Si(CH3)2).
13C NMR (100 MHz, CDCl3/TMS): d = 168.6 (C-41), 162.1 (C-31),
141.3 (C-29), 138.1, 137.7 (C-37, C-39), 134.7 (C-30), 128.4 (C-
38), 125.8 (C-40), 76.4 (C-33), 67.6 (C-35), 60.5 (OCH2CH3), 58.7
(C-28), 56.0 (OCH3), 42.4 (C-34), 37.4, 36.9 (C-32, C-36), 25.9,
25.8 (SiC(CH3)3), 18.4, 17.9 (SiC(CH3)3), 14.3 (OCH2CH3), 12.6
(CH3), –4.6, –4.8, –5.3 (Si(CH3)2).
Acknowledgment
We thank the BASF AG, Ludwigshafen (Rhein) for a generous gift
of ethyl [(E)-4-(diethoxyphosphonyl)-2-methylbut-2-enoate], the
Fonds der Chemischen Industrie for financial support and the Deut-
sche Forschungsgemeinschaft (Graduiertenkolleg Chemische und
technische Grundlagen der Naturstofftransformation) for a PhD
fellowship (P. W.). The Volkswagen Foundation (Nieders. Vorab)
is thanked for support of our program.
References
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(3) Altohyrtins (Spongistatins):
IR (CHCl3): n = 2956, 2928, 2856, 2736, 1696, 1636, 1608, 1568,
1464, 1368, 1256, 1160, 1108, 1004, 972, 936, 904, 836 cm–1.
MS (90 °C): m/z (%) = 581 (M+, 1.7), 566 (6.9), 524 (100), 428
(25.0), 361 (16.2), 296 (88.4), 240 (7.4), 198 (11.9), 168 (6.1), 124
(13.3), 89 (21.0), 73 (46.6).
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therein.
HRMS calcd for C30H55NO6Si2 (M+) 581.3568, found 581.3569.
(2E,4R,5R,7R,9S)-9-tert-Butyldimethylsilyloxy-10-(4-tert-bu-
tyldimethylsilyloxymethyl-1,3-oxazol-2-yl)-4,5-dihydroxy-7-
methoxy-2-methyldec-2-enoate (12)
To a solution of ester 11 (71 mg, 0.122 mmol. E:Z = 10:1) in t-
BuOH (0.15 mL) and H2O (0.15 mL) were added AD-b-mix (170
mg) and methanesulfonamide (12 mg, 0.125 mmol) and the result-
ing mixture was stirred for 2 d at r.t.. The reaction was incomplete
and a further portion of AD-b-mix (340 mg) and methanesulfona-
mide (24 mg, 0.25 mmol) was added. Stirring was continued for 24
h. The mixture was cooled to 0 °C, sodium sulfite (550 mg, 5.33
mmol) was added and the mixture was stirred for 20 min. H2O (5
mL) and CH2Cl2 (10 mL) were added. The aqueous layer was ex-
tracted with MTBE (5 ¥ 10 mL), the combined organic layer was
dried (MgSO4) and evaporated. The crude product was purified by
column chromatography (silica gel; MTBE/PE, 2:1) to afford 12
(4) Bryostatins:
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.;
Prunet, J. A.; Lautens, M. Angew. Chem. 1998, 110, 2526;
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Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.;
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See also in:
(53 mg, 78%, 92% de) as a colourless oil. [a]2D0 = +2.2 (c = 1 in
Nicolaou, K. C. and Sorensen, E. J.: Classics in Total
Synthesis, VCH: Weinheim, 1996 and references cited
therein.
20
365
CHCl3), [a]
= +19.1 (c = 1 in CHCl3).
1H NMR (400 MHz, CDCl3/TMS): d = 7.47 (t, 4J = 1.4 Hz, 1 H, H-
30), 6.69 (dq, 3J = 9 Hz, 4J = 1.4 Hz, 1 H, H-39), 4.65 (d, 4J = 1.4
Hz, 2 H, H-28), 4.27–4.17 (m, 5 H, H-6, H-29, OH, OCH2CH3),
3.87–3.82 (m, 1 H, H-37), 3.75–3.71 (m, 1 H, H-35), 3.68 (s, 1 H,
OH), 3.38 (s, 3 H, OCH3), 2.94 (d, 3J = 6.2 Hz, 2 H, H-32, H-32’),
(6) An excellent review of the epothilones is given in:
Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew.
Chem. 1998, 110, 2120; Angew. Chem. Int. Ed. 1998, 37,
2014 and references cited therein.
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Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T.
Tetrahedron Lett. 1998, 39, 6099.
4
1.96 (d, J = 1.5 Hz, 3 H, CH3), 1.95–1.86 (m, 2 H, H-34, H-36),
1.63 (ddd, 2J = 14.3 Hz, 3J = 6.9 Hz, 3J = 4.3 Hz, 1 H, H-34’), 1.48
(ddd, 2J = 14.7 Hz, 3J = 6.4 Hz, 3J = 2.5 Hz, 1 H, H-36’), 1.33 (t, 3J
= 7.1 Hz, 2 H, OCH2CH3), 0.96, 0.89 (2 s, 18 H, Si(C(CH3)3), 0.13–
0.02 (m, 12 H, Si(CH3)2).
13C NMR (100 MHz, CDCl3/TMS): d = 167.6 (C-41), 162.0 (C-31),
141.3 (C-29), 138.8 (C-39), 134.8 (C-30), 131.2 (C-40), 75.8 (C-
35), 71.9 (C-38), 71.5 (C-37), 67.9 (C-33), 60.8 (OCH2CH3), 58.6
(C-28), 56.3 (OCH3), 41.5 (C-34), 37.0 (C-32), 35.1 (C-36), 25.8,
25.7 (SiC(CH3)3), 18.3, 17.9 (SiC(CH3)3), 14.2 (OCH2CH3), 13.3
(CH3), –4.6, –4.7, –5.4 (Si(CH3)2).
Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185.
Williams, D. R.; Brooks, D. A.; Meyer, K. G.; Clark, M. P.
Tetrahedron Lett. 1998, 39, 7251.
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1992, 114, 9434.
IR (CHCl3): n = 3556, 3524, 3488, 3464, 3436, 2956, 2928, 2896,
2856, 1708, 1652, 1568, 1472, 1388, 1256, 1188, 1092, 1004, 968,
936, 940, 908, 836, 796 cm–1.
MS (110 °C): m/z (%) = 558 (M+ – C4H9, 2.1), 472 (1.3), 430 (1.4),
400 (4.3), 382 (5.1), 314 (18.8), 279 (20.9), 250 (5.7), 198 (8.0), 167
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HRMS calcd for C26H48NO8Si2 (M+ – C4H9) 558.2919, found
558.2919.
Synthesis 1999, No. 5, 797–802 ISSN 0039-7881 © Thieme Stuttgart · New York

802
P. Wolbers, H. M. R. Hoffmann
PAPER
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1437-210X,E;1999,0,05,0797,0802,ftx,en;H11598SS.pdf
Synthesis 1999, No. 5, 797–802 ISSN 0039-7881 © Thieme Stuttgart · New York