Synthesis of the C38-C44 segment of altohyrtin A - with an addendum on the preparation of 8-oxabicyclo[3,2.1]oct-6-en-3-one

Article abstract of DOI:10.1002/1099-0690(200006)2000:12<2195::AID-EJOC2195>3.0.CO;2-C

The densely funtionalized C38-C44 segment F of altohyrtin A with its five contiguous stereogenic centers was prepared in 10 steps and in 28% overall yield (two steps per stereogenic center), from 8- oxabicyclo[3.2.1]oct-6-en-3-one as a template. The preparation of the title compound 1, m.p. 38 °C, is described on a 0.5 m scale in a three-step-two- stage reaction from acetone anti furan. The oxacycle was stored without change at room temperature.

Full text of DOI:10.1002/1099-0690(200006)2000:12<2195::AID-EJOC2195>3.0.CO;2-C

FULL PAPER
Synthesis of the C38؊C44 Segment of Altohyrtin A ؊ With an Addendum on
the Preparation of 8-Oxabicyclo[3.2.1]oct-6-en-3-one
H. Kim,[a] H. M. R. Hoffmann*[a]
Keywords: Natural products / Spongistatins / Antitumor agents / Asymmetric synthesis / 8-Oxabicyclo[3.2.1]oct-6-en-3-one
The densely funkctionalized C38−C44 segment F of altohyr- as a template. The preparation of the title compound 1, m.p.
tin A with its five contiguous stereogenic centers was pre- 38 °C, is described on a 0.5-m scale in a three-step-two-stage
pared in 10 steps and in 28 % overall yield (two steps per
stereogenic center), from 8-oxabicyclo[3.2.1]oct-6-en-3-one
reaction from acetone and furan. The oxacycle was stored
without change at room temperature.
Introduction
Results and Discussion
The altohyrtins[1] have recently been isolated and shown
to be extremely potent cancer growth inhibitors, especially
against chemoresistant tumor types.[2] The absolute stereo-
chemistry of altohyrtin A was proposed by Kitagawa et
al.[3] and was confirmed by total synthesis.[4] Although sev-
eral synthetic approaches[5] leading to fragments of altohyr-
tin A have been published, including that of the C38ϪC44
segment, so far only Evans et al. and Kishi et al. have
achieved a total synthesis of altohyrtin A and C, respect-
ively (Figure 1).[4]
We here report a simple and efficient synthesis of the pro-
tected C38ϪC44 F-segment 11 (Scheme 1). We started with
the inexpensive and easily accessible meso-8-oxabicy-
clo[3.2.1]oct-6-en-3-one (1), deprotonated it with chiral li-
thium amide base and trapped the resulting enolate with
triethylsilyl chloride, to obtain 2. mCPBA oxidation of the
silyl enol ether 2 in dichloromethane (DCM) at Ϫ35 °C fur-
nished the rearranged Rubottom product, which was desily-
lated in situ to bicyclic α-hydroxy ketone 3. The alcohol
Scheme 1. Reagents: (a) (i) LiCl, (ϩ)-bis[(R)-1-phenylethyl]amine,
THF, Ϫ78 °C, (ii) BuLi, meso-1, THF, Ϫ115 °C, (iii) TESCl, NEt3,
Ϫ78 °C (95%); (b) (i) m-CPBA, DCM, Ϫ35 to Ϫ25 °C, (ii) TFA,
Ϫ25 °C (71%, 95% ee); (c) TBSCl, imidazole, DMF (96%); (d)
LDA, TMEDA, MeI, THF, Ϫ78 °C (91%); (e) (i) 2  HCl, EtOH,
room temp., 5 h, (ii) PMB trichloroacetimidate, (ϩ)-camphorsul-
fonic acid (CSA), DCM (84%); (f) (i) -Selectride, THF, Ϫ78 °C,
(ii) NaOH, H2O2, 0 °C (87%); (g) 2,6-lutidine, TIPSOTf, DCM,
Ϫ40 °C (97%); (h) (i) O3, DCM/MeOH, Ϫ95 °C, (ii) NaBH4 (94%);
Figure 1. Retrosynthesis of F-segment 11 from 1
[a]
Department of Organic Chemistry, University of Hannover,
Schneiderberg 1 B, 30167 Hannover, Germany
Fax: (internat.) ϩ 49-(0)511/762-3011
˚
(i) DDQ, molecular sieves (3 A), degassed DCM, Ϫ60 to 0 °C, 4 h
(82%); (j) N-methylmorpholine N-oxide (NMO), Pr4NRuO4,
DCM, room temp., 1.5 h (79%)
E-mail: hoffmann@mbox.uni-hannover.de
Eur. J. Org. Chem. 2000, 2195Ϫ2201
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0612Ϫ2195 $ 17.50ϩ.50/0
2195

H. Kim, H. M. R. Hoffmann
FULL PAPER
Scheme 2. Oxabicyclic ketone 1, synthetic equivalent of a polyacetate aldol adduct
group was protected as TBS ether 4. After axial methylation Addendum on the Synthesis of
at the αЈ-position to form 5 (91% yield),[6] the TBS ether
8-Oxabicyclo[3.2.1]oct-6-en-3-one, a Universal
was reprotected as the p-methoxybenzyl (PMB) ether 6.
Treatment of the ketone with -Selectride yielded the axial
alcohol 7 exclusively. All three substituents of the bridged
tetrahydropyran 7 are axial. After being protected as the
TIPS ether 8, its olefinic bridge was cleaved by ozonolysis
and was reduced in situ with NaBH4. Oxidative ring closure
of the resulting (3-hydroxymethylcyclohexyl)methanol 9
with DDQ in degassed DCM[7] led to the formation of the
benzylidene acetal 10 in good yield. The hydroxy group at
C38 did not interfere with this acetalization. Our sequence
was completed by oxidation at C38, giving the desired pro-
tected aldehyde 11 of the F-segment. All five substituents
of the tetrahydropyran moiety in 9, 10 and 11 adopted
equatorial positions. Aldehyde 11 is ready for coupling with
the neighboring E-segment C31ϪC37.
Building Block
Title compound 1 has been known for over two decades[8]
and continues to be highly useful and versatile in organic
synthesis. Recent applications include the synthesis of a
variety of tetrahydropyran units that occur in marine nat-
ural products, pseudo-C-glycosides and other bioactive sub-
stances. Oxabicycle 1 is not only a source of cyclic and
acyclic polyketides of the simple polyacetate pattern, it is
also possible to ‘‘load’’ stereochemistry on 1 and to intro-
duce further stereogenic centers. Representative examples
are outlined in Scheme 2.[9] Originally, 1 was prepared by
reaction of 2-methoxyallyl bromide with silver trifluo-
roacetate in the presence of furan (Scheme 3).[10] Soon af-
terwards, further routes to 1 began to appear.[11] Our
1,1,3,3-tetrabromopropanone/triethyl borateϪZn/Cu pro-
Conclusion
In summary, the densely functionalized C38ϪC44 F-seg-
ment 11 of altohyrtin A with its five contiguous stereogenic
centers was prepared from 1 in 10 steps and in 28% overall
yield. To our knowledge, this is one of the shortest and
most efficient routes to this segment.
Scheme 3. Silver salt route to oxabicycle
2196
Eur. J. Org. Chem. 2000, 2195Ϫ2201

Synthesis of the C38ϪC44 Segment of Altohyrtin A
FULL PAPER
Scheme 4. Synthesis of 1 from furan and acetone
cedure[12] has been used widely (Scheme 4). However, scale-
up has not been straightforward. Unfortunately, a persistent
error has also crept into the literature, in that oxabicycle 1
has been described as a sensitive compound which has to
be stored under argon at Ϫ20 °C in the dark.[13] These com-
ments and general experimental difficulties may have dis-
couraged further extensive applications of 1.
We show here that 1 is not oily, but is a crystalline color-
less solid, m.p. 38 °C, as we reported originally.[8] When 1
is pure, it is indefinitely stable at room temperature. We de-
scribe here a verified procedure for the preparation of 1 on
a 0.5- scale in 52Ϫ56% yield (31Ϫ34.9 g isolated). The
following Notes should be borne in mind:
1. 1,1,3,3-Tetrabromopropanone (12) was obtained as a
crystalline colorless solid after recrystallization from cooled
light petroleum ether (step A). Lengthy and tedious workup
is circumvented if the crystalline product is directly frozen
out from the mother liquor. There is also no need to neut-
ralize large amounts of HBr (Scheme 4, step A). Crystalline
12 facilitates handling and overall control during the fol-
lowing two steps B and C (Scheme 4).
2. Cycloaddition was initiated by the addition of a cata-
lytic amount of bromine. (Note that volatile bromine-con-
taining compounds are lachrymatory.)
3. After the flask had been charged with reagents, the
reaction was kept going by temperature control. If the reac-
tion breaks off, it is difficult or impossible to restart it, and
the yield drops sharply. The preferred reaction temperature
is above that of boiling tetrahydrofuran (b.p. 66 °C, temper-
ature control by ice/water).
4. In step C, a ‘‘high-temperature reduction’’ of the first-
formed brominated cycloadducts is feasible. The temper-
ature window for this reduction was widened to 0Ϫ10 °C.
Under these conditions, reductive removal of bromine pro-
ceeds steadily, without an induction period.
5. It is essential to first of all work up the reaction mix-
ture with brine. If water or ice are added first, to quench
the reaction mixture, emulsions are formed, and many ex-
tractions with CHCl3 are required to isolate 1. Product is
lost, also because 1 is highly soluble in water (ca. 125 g/l)
and tends to decompose at room temperature on extended
contact with acid.
Scheme 5. Proposed mechanism (see Scheme 4)
6. After removal of CHCl3, the crude cycloadduct was
filtered through a short column containing solid K2CO3 on
filter paper. During this stage, HBr, which adheres persist-
ently to 1, was removed. If the HBr was not removed at
this stage, the cycloadduct decomposed, presumably with
formation of 2-acetonylfuran. We also isolated 1 by kugel-
rohr distillation.[13b] However, scale-up was problematic,
and decomposition of the cycloadduct tended to take place,
especially if the HBr was not removed beforehand. Purifica-
tion of 1 by removal of major quantities of HBr by column
chromatography (alumina or silica gel) is not feasible.
The cycloaddition may be visualized as single electron
transfer (SET), facilitated by triethyl borate, alternating
with Lewis acid mediated ionic steps, to generate the crucial
boron oxyallyl cation, such as i, which is captured by furan
to yield the dibromo bicycle 13. A simplified, abbreviated
reaction sequence is outlined in Scheme 5.
In summary, after many iterative experiments, we have
optimized our route to oxabicycle 1.
Experimental Section
General Remarks: IR: PerkinϪElmer 1710 infrared spectrometer.
Ϫ 1H NMR and 13C NMR: Bruker AM 400 spectrometer; in deu-
terated chloroform with tetramethylsilane as internal standard.
13C-NMR signal assignments for each signal; DEPT measure-
ments; multiplicities are indicated by 1° (primary), 2° (secondary),
3° (tertiary) and 4° (quaternary). Ϫ MS: Finnigan MAT 312
(70 eV) or a VG Autospec spectrometer at room temp. unless other-
wise stated. Ϫ Preparative column chromatography was performed
on J. T. Baker silica gel (particle size 30Ϫ60 µm). Ϫ Analytical TLC
was carried out on aluminum-backed 0.2-mm silica gel 60 F254
plates (E. Merck). Ϫ E (diethyl ether) and THF were distilled from
sodium and benzophenone before use. CH2Cl2 (DCM) was distilled
from CaH2 before use. DMF was dried with BaO and distilled from
CaH2 before use. tert-Butyl methyl ether (MTBE), ethyl acetate
(EA) and light petroleum ether (PE, bp 40Ϫ60 °C) were distilled
before use.
(؉)-(1R,5R)-3-(Triethylsiloxy)-8-oxabicyclo[3.2.1]octa-2,6-diene
[(؉)-2]: (ϩ)-Bis[(R)-1-phenylethyl]amine (18.1 g, 80.5 mmol) in
Eur. J. Org. Chem. 2000, 2195Ϫ2201
2197

H. Kim, H. M. R. Hoffmann
THF (50 mL) was added under argon to dry LiCl (1.93 g, (C7), 129.4 (C6), 83.1 (C3), 77.5 (C1), 75.5 (C5), 45.0 (C4), 25.6
FULL PAPER
45.5 mmol). The mixture was cooled to Ϫ78 °C and nBuLi
(52.5 mL, 84.0 mmol, 1.6  solution in hexane) was added drop-
wise over 40 min. The resulting pink solution was stirred for 15 min
at Ϫ78 °C, for 15 min at room temp., and was then recooled to
Ϫ115 °C. A solution of 1 (8.7 g, 70 mmol) in THF (250 mL) was
added slowly over 130 min. The mixture was stirred for 1 h at Ϫ115
°C and was then allowed to reach Ϫ78 °C. Triethylsilyl chloride
(16.5 mL, 98.0 mmol) was added by syringe, followed by triethyla-
mine (13.7 mL, 98.0 mmol). The mixture was allowed to reach
room temp. and was then filtered through Celite. After the solvent
was removed, the crude product was purified by column chromato-
graphy (E/PE) to afford (؉)-2 (15.9 g, 95%), a yellowish, viscous
liquid. The stereoselectivity of the asymmetric deprotonation was
conveniently estimated after the last stage, yielding (؉)-11, 83% ee.
Ϫ IR (CHCl3): ν˜ ϭ 3001 cmϪ1, 2960, 2876, 1640, 1456, 1416, 1352,
[SiC(CH3)3], 18.1 [SiC(CH3)3], 5.7 [SiC(CH3)2]. Ϫ MS; m/z: 254
(23) [Mϩ], 197 (31), 195 (5), 171 (31), 169 (23), 138 (15), 130 (30),
129 (35), 128 (100), 125 (21), 103 (28), 101 (30), 99 (15), 81 (32),
75 (41). Ϫ HRMS: calcd. for C13H22O3Si [Mϩ] 254.1338; found
254.1335.
(؉)-(1R,2R,4S,5R)-2β-(tert-Butyldimethylsilyloxy)-4-methyl-8-oxa-
bicyclo[3.2.1]oct-6-en-3-one [(؉)-5]: nBuLi (37.4 mL, 59.8 mmol,
1.6  solution in hexane) was added at Ϫ78 °C to a solution of
diisopropyl amine (7.80 mL, 55.2 mmol) in THF (40 mL). The mix-
ture was stirred for 15 min at Ϫ78 °C and 30 min at room temp.
Then the LDA solution was recooled to Ϫ78 °C and silyl ether
(؊)-4 (11.7 g, 46.0 mmol) in THF (40 mL) was added dropwise
over 10 min. After being stirred for 1 h at Ϫ78 °C and 30 min at
room temp., the mixture was cooled again to Ϫ78 °C and TMEDA
(9.0 mL, 60 mmol) and methyl iodide (14.4 mL, 230 mmol) were
added. The mixture was stirred for 30 min, was then allowed to
reach room temp., and was diluted with MTBE (100 mL). The or-
ganic layer was washed with sat. aq. NaHCO3 solution and brine.
The combined aqueous layers were extracted with MTBE (3 ϫ
200 mL). The combined organic layers were dried (MgSO4), con-
centrated and purified by column chromatography (E/PE) to yield
(؉)-5 (11.2 g, 91%), yellow liquid. Ϫ [α]2D0 ϭ ϩ27.1 (c ϭ 1 in
CHCl3). Ϫ IR (KBr): ν˜ ϭ 3088 cmϪ1, 3072, 2944, 2880, 2856, 1716,
1
1312, 1240, 1196, 1016. Ϫ H NMR: δ ϭ 6.43 (dd, J ϭ 2, 6 Hz, 1
H, H7), 5.94 (dd, J ϭ 2, 6 Hz, 1 H, H6), 5.15 (d, J ϭ 5 Hz, 1 H,
H2), 4.88 (dd, J ϭ 1, 5 Hz, 1 H, H5), 4.75 (d, J ϭ 5 Hz, 1 H, H1),
2.61 (dd, J ϭ 8, 16 Hz, 1 H, H4ax), 1.69 (d, J ϭ 16 Hz, 1 H, H4eq),
0.92 [t, J ϭ 8 Hz, 9 H, Si(CH2CH3)3], 0.06 [q, J ϭ 8 Hz, 6 H,
Si(CH2CH3)3]. Ϫ 13C NMR: δ ϭ 147.4 (C3), 128.1 (C7), 126.3
(C6), 106.7 (C2), 77.5 (C1), 75.2 (C5), 32.8 (C4), 6.7 [Si(CH2CH3)3],
5.1 [Si(CH2CH3)3]. Ϫ MS; m/z: 238 (3) [Mϩ], 219 (10), 218 (20),
217 (100), 189 (80), 162 (10), 161 (46), 159 (27), 145 (22), 133 (21),
105 (23), 103 (19), 87 (24), 75 (32). Ϫ HRMS: calcd. for
C13H22O2Si [Mϩ] 238.1389; found 238.1388.
1
1684, 1408, 1388, 1264, 1004, 936. Ϫ H NMR: δ ϭ 6.37 (dd, J ϭ
2, 6 Hz, 1 H, H7), 6.12 (dd, J ϭ 2, 6 Hz, 1 H, H6), 4.74 (s br, 1 H,
H1), 4.63 (s, 1 H, H5), 3.58 (t, J ϭ 1 Hz, 1 H, H2), 2.31 (m, 1 H,
H4), 1.42 (d, J ϭ 7 Hz, 3 H, H9), 0.88 [s, 9 H, Si(CH3)3], 0.11/0.09
[s, 6 H, Si(CH3)2]. Ϫ 13C NMR: δ ϭ 207.5 (C3), 137.1 (C7), 19.5
(C6), 83.0 (C1), 82.0 (C5), 75.5 (C2), 50.7 (C4), 25.6 [SiC(CH3)3],
18.0 [SiC(CH3)3], 17.0 (C9), Ϫ5.0/Ϫ5.2 [SiC(CH3)2]. Ϫ MS; m/z:
269 (2) [Mϩϩ1], 268 (4) [Mϩ], 253 (1), 237 (2), 185 (5), 165 (1),
143 (100), 129 (3), 115 (3), 101 (7), 81 (5), 75 (19), 73 (22). Ϫ
HRMS: calcd. for C14H24O3Si [Mϩ] 268.1493; found 268.1495.
(؊)-(1R,2R,5R)-2β-Hydroxy-8-oxabicyclo[3.2.1]oct-6-en-3-one
[(؊)-3]: mCPBA (17.9 g, 72.6 mmol) was added portionwise at Ϫ35
°C to a solution of (؉)-2 (15.7 g, 66.0 mmol) in DCM (190 mL).
The temperature of the reaction mixture was kept below Ϫ25 °C.
After 1 h, trifluoroacetic acid (5.1 mL, 66 mmol) was added. The
mixture was allowed to reach 0 °C, was then diluted with DCM
(100 mL) and quenched with sat. aq. NH4Cl solution. The organic
layer was washed with water (200 mL) and brine (200 mL). The
combined aqueous layer was extracted with EA (3 ϫ 300 mL). The
combined organic layer was dried (MgSO4) and the solvent was
evaporated. The precipitated solid was suction-filtered, washed
with PE, and purified by column chromatography (E/PE) to give
(؉)-(1R,2R,4S,5R)-2β-(p-Methoxybenzyloxy)-4β-methyl-8-oxabi-
cyclo[3.2.1]oct-6-en-3-one [(؉)-6]: A solution of (؉)-5 (11.0 g,
41.0 mmol) in EtOH (62 mL) and 2  HCl (90 mL) was stirred for
about 12 h at room temp. The reaction mixture was extracted with
DCM (4 ϫ 200 mL), the organic layer was dried (MgSO4), and the
solvent was removed. The crude product and trichloroacetimidate
[preparation: to a solution of p-methoxybenzyl alcohol (13.8 g,
100 mmol) in E (300 mL) was added NaH (0.8 g, 20 mmol, 60%
suspension in mineral oil) at 0 °C. After 5 min, trichloroacetonitrile
(10.0 mL, 100 mmol) was added and the mixture was stirred for
50 min at 0 °C and 2 h at room temp., then the solvent was re-
moved] were dissolved in DCM (200 mL), and CSA (1.9 g,
40 mmol) was added. The mixture was stirred for about 12 h and
was then quenched by addition of sat. aq. NaHCO3 solution. The
organic layer was washed with 10% NaOH (2 ϫ 100), dried
(MgSO4), the solvent was removed, and the crude product was
purified by column chromatography (E/PE) to give (؉)-6 (9.2 g,
82%), yellow oil. Ϫ [α]2D0 ϭ ϩ83.6 (c ϭ 1 in CHCl3). Ϫ IR (KBr):
ν˜ ϭ 3076 cmϪ1, 3060, 2968, 2908, 2872, 2840, 1712, 1612, 1512,
(؊)-3 (6.57 g, 71%), colorless solid. Ϫ IR (CHCl3): ν˜ ϭ 3432 cmϪ1
,
3084, 2980, 2912, 1824, 1716, 1648, 1404, 1332, 1272, 1176, 1064,
1040, 1008, 948. Ϫ 1H NMR: δ ϭ 6.46 (dd, J ϭ 2, 6 Hz, 1 H, H7),
6.32 (dd, J ϭ 2, 6 Hz, 1 H, H6), 5.31 (m, 1 H, H5), 4.94 (s, 1 H,
H1), 3.71 (s, 1 H, H2), 3.62 (s br, 1 H, O-H), 3.06 (dd, J ϭ 5,
16 Hz, 1 H, H4ax), 2.33 (d, J ϭ 16 Hz, 1 H, H4eq). Ϫ 13C NMR:
δ ϭ 205.4 (C3), 136.6 (C6), 129.5 (C7), 82.4 (C2), 77.4 (C5), 75.3
(C1), 44.5 (C4). Ϫ MS; m/z: 140 (5) [Mϩ], 111 (1), 97 (5), 94 (3),
81 (14), 72 (2), 70 (5), 69 (100), 65 (3). Ϫ HRMS: calcd. for C7H8O3
[Mϩ] 140.0473; found 140.0474.
(؊)-(1R,2R,5R)-2β-(tert-Butyldimethylsilyloxy)-8-oxabicyclo[3.2.1]-
oct6-en-3-one [(؊)-4]: NEt3 (0.6 mL, 4.6 mmol) was added to a so-
lution of (؊)-3 (6.40 g, 46.1 mmol), imidazole (7.80 g, 115 mmol)
and TBSCl (8.30 g, 55.3 mmol) in DMF (23 mL); the resulting mix-
ture was stirred at 30 °C for about 12 h. The reaction mixture was
purified by column chromatography (E/PE) to afford (؊)-4 (11.2 g,
91%), yellow liquid. Ϫ [α]2D0 ϭ Ϫ29.4 (c ϭ 1 in CHCl3). Ϫ IR
1
1248, 1176, 1056. Ϫ H NMR: δ ϭ 7.30 (m, 2 H, arom. H), 6.89
(m, 2 H, arom. H), 6.39 (dd, J ϭ 2, 6 Hz, 1 H, H7), 6.10 (dd, J ϭ
2, 6 Hz, 1 H, H6), 4.90 (s br, 1 H, H1), 4.67 (s br, 1 H, H5), 4.39/
4.65 (d, J ϭ 12 Hz, 2 H, H10), 3.80 (s, 3 H, H17), 3.34 (t, J ϭ
1 Hz, 1 H, H2), 2.39 (m, 1 H, H4), 1.48 (d, J ϭ 7 Hz, 3 H, H9). Ϫ
(CHCl3): ν˜ ϭ 2959 cmϪ1, 2932, 1720, 1256, 1104, 1084, 856, 840.
1
Ϫ H NMR: δ ϭ 6.39 (dd, J ϭ 2, 6 Hz, 1 H, H7), 6.13 (dd, J ϭ 13C NMR: δ ϭ 207.3 (C3), 159.6 (C14), 137.4 (C11), 130.6 (C7),
2, 6 Hz, 1 H, H6), 4.97 (br. d, J ϭ 5 Hz, 1 H, H5), 4.77 (br. s, 1
H, H1), 3.63 (s, 1 H, H2), 3.03 (dd, J ϭ 5, 16 Hz, 1 H, H4ax), 2.25
129.6 (C6), 114.0 (C12, C13, C15, C16), 82.4 (C1), 81.4 (C5), 80.0
(C2), 71.7 (C10), 55.5 (C17), 50.8 (C4), 16.9 (C9). Ϫ MS (80 °C);
(br. d, J ϭ 16 Hz, 1 H, H4eq), 0.88 [t, J ϭ 3 Hz, 9 H, SiC (CH3)3], m/z: 274 (1) [Mϩ], 245 (1), 153 (1), 137 (5), 121 (100), 109 (3), 95
0.13/0.07 [s, 6 H, SiC(CH3)2]. Ϫ 13C NMR: δ ϭ 204.1 (C3), 136.9
(3), 77 (6).
2198
Eur. J. Org. Chem. 2000, 2195Ϫ2201

Synthesis of the C38ϪC44 Segment of Altohyrtin A
(1R,2R,3S,4S,5R)-3α-Hydroxy-2β-(p-methoxybenzyloxy)-4β- 0 °C within ca. 3 h. MTBE (50 mL) and sat. aq. NH4Cl solution
FULL PAPER
methyl-8-oxabicyclo[3.2.1]oct-6-ene (7): -Selectride (46.0 mL,
46.0 mmol, 1  solution in THF) was added over 100 min (per-
(50 mL) were added. The aqueous layer was saturated with NaCl
and extracted with EA. The combined organic layers were dried
fusor) at Ϫ78 °C to a solution of (؉)-6 (8.90 g, 32.5 mmol) in THF (MgSO4). After the solvent was removed, the crude product was
(135 mL). After complete addition, the mixture was stirred for
30 min at Ϫ78 °C and then allowed to reach 0 °C. Water (2 mL)
was added, followed by NaOH (10.9 g, 273 mmol) in water
(25 mL). H2O2 (27.8 mL, 273 mmol, 30% solution in water) was
added slowly, the mixture was stirred for 1 h and was then neutral-
ized with half-conc. HCl. The aqueous layer was saturated with
NaCl and was extracted with DCM (4 ϫ 200 mL). The organic
layer was dried (MgSO4), the solvent was removed and the crude
product was purified by column chromatography (E/PE) to afford
7 (7.8 g, 87%), yellow liquid. Ϫ IR (CHCl3): ν˜ ϭ 3548 cmϪ1, 3000,
purified by column chromatography (EE/PE) to give (؉)-9 (2.02,
94%), colorless foam. Ϫ [α]2D0 ϭ ϩ22.8 (c ϭ 1 in CHCl3). Ϫ IR
(KBr): ν˜ ϭ 3404 cmϪ1, 2940, 2864, 1612, 1512, 1464, 1248, 1132,
1
1116, 1088, 1056. Ϫ H NMR: δ ϭ 7.19Ϫ6.82 (m, 4 H, arom. H),
4.52/4.41 (d, J ϭ 11 Hz, 2 H, H10), 4.20 (m, 1 H, HOCH2CH),
3.92Ϫ3.88 (m, 1 H, HOCH2CH), 3.81 (dd, J ϭ ϭ 2, 12 Hz, 1 H,
H8), 3.77 (s, 3 H, OCH3), 3.71 (dd, J ϭ ϭ 2, 12 Hz, 1 H, H7), 3.65
(m, 1 H, H8), 3.63Ϫ3.59 (m, 1 H, H4), 3.50 (dd, J ϭ 5, 12 Hz, 1
H, H7), 3.27 (m, 1 H, H3), 1.67 (m, 1 H, H5), 1.09Ϫ0.98 {m, 21
H, Si[CH(CH3)2]3, H9}, 0.92 {d, J ϭ 7 Hz, 3 H, Si[CH(CH3)2]3}.
1
2952, 2880, 1612, 1584, 1464, 1408, 1300, 1248, 1112, 1036. Ϫ H
Ϫ
13C NMR: δ ϭ 159.2 (C14), 130.2 (C11), 129.5 (C15, C13), 113.6
NMR: δ ϭ 7.30 (m, 2 H, arom. H), 6.89 (m, 2 H, arom. H), 6.21 (C16, C12), 77.3 (C6), 76.2 (C2), 74.0 (C3), 72.9 (C4), 72.1 (C10),
(dd, J ϭ 2, 6 Hz, 1 H, H7), 6.14 (dd, J ϭ 2, 6 Hz, 1 H, H6), 4.83
(s br, 1 H, H1), 4.74 (d, J ϭ 12 Hz, 1 H, H10), 4.59 (s br, 1 H,
63.2 (C8), 62.4 (C7), 55.2 (C17), 37.4 (C5), 18.5 {Si[CH(CH3)2]3},
13.9 (C9), 13.2 {Si[CH(CH3)2]3}. Ϫ MS (50 °C); m/z: 468 (0) [Mϩ],
H5), 4.43 (d, J12 Hz, 1 H, H10), 4.00 (m, 1 H, H3), 3.80 (s, 3 H, 265 (4), 254 (5), 195 (3), 179 (2), 155 (2), 131 (3), 121 (100), 105
H17), 3.46 (m, 1 H, H2), 2.66 (d, J ϭ 11 Hz, 1 H, OH), 1.85 (m, (45), 87 (10), 73 (9). Ϫ FAB-MS; m/z: 491 (27) [Mϩ ϩ Na], 221
1 H, H4), 1.19 (d, J ϭ 7 Hz, 3 H, H9). Ϫ 13C NMR: δ ϭ 159.5 (6), 147 (12), 133 (6), 121 (100).
(C14), 133.8 (C7), 130.2 (C11), 129.4 (C6), 114.1 (C12, C13, C15,
(؉)-(2R,3S,4S,5R,6S)-[10-p-(Methoxyphenyl)-5-methyl-4-(triiso-
propylsilyloxy)hexahydropyrano[3,2-d][1,3]dioxin-6-yl]methanol
[(؉)-10]: A reaction flask was dried (heat gun) and charged with
C16), 83.5 (C1), 78.6 (C5), 75.2 (C2), 71.6 (C10), 55.4 (C15), 34.5
(C4), 13.9 (C9). Ϫ MS (80 °C); m/z: 276 (1) [Mϩ], 155 (3), 137 (2),
122 (27), 121 (100), 110 (2), 95 (50), 91 (12). Ϫ HRMS: calcd. for
C16H20O4 [Mϩ] 276.1360; found 276.1362.
˚
activated molecular sieves (3 A, approx. 2 g) and DDQ (909 mg,
4.00 mmol) under a stream of argon. DCM (40 mL, degassed) was
added. Diol (؉)-9 (937 mg, 2 mmol) in DCM (20 mL, degassed)
was added dropwise at Ϫ60 °C. The reaction mixture turned dark-
green immediately. The mixture was allowed to reach 0 °C within
4 h, then MTBE (50 mL) and sat. aq. NaHCO3 solution (25 mL)
were added. After filtration, the organic layer was washed with
water and brine. The aqueous phase was extracted with MTBE and
the combined organic layers were dried (MgSO4). The solvent was
evaporated and the crude product was purified by column chroma-
tography (MTBE/PE) to afford (؉)-10 (762 mg, 82%), colorless,
(؉)-(1R,2R,3S,4S,5R)-2β-(p-Methoxybenzyloxy)-4β-methyl-3α-(tri-
isopropylsilyloxy)-8-oxabicyclo[3.2.1]oct-6-ene [(؉)-8]: 2,6-Lutidine
(6.90 mL, 31.2 mmol) was added at Ϫ40 °C to a solution of alcohol
7 (7.30 g, 26.0 mmol) in DCM (100 mL); this was followed by the
addition of TIPS triflate (6.8 mL) in DCM (27.2 mL). The mixture
was allowed to reach 0 °C and the reaction was monitored by TLC.
To complete the reaction, the mixture was cooled again and a fur-
ther portion of TIPS triflate (113 µL) in DCM (450 µL) was added.
After complete reaction, cyclohexane (110 mL) and NaHCO3 solu-
tion (0.15 ) were added. The organic phase was washed with brine
and the combined aqueous layers were extracted with DCM (3 ϫ
200 mL). The combined organic phases were dried (MgSO4), the
solvent was removed and the crude product was purified by column
chromatography (E/PE) to yield (؉)-8 (11.2 g, 97%), colourless
solid. Ϫ [α]2D0 ϭ ϩ18.6 (c ϭ 1 in CHCl3). Ϫ IR (KBr): ν˜ ϭ 3056
1
viscous oil. Ϫ H NMR: δ ϭ 7.40 (m, 2 H, arom. H), 6.87 (m, 2
H, arom. H), 5.48 (s, 1 H, H10), 4.36 (dd, J ϭ ϭ 5, 10 Hz, 1 H,
H8), 4.03 (dd, J ϭ ϭ 5, 10 Hz, 1 H, H8), 3.99 (t, J ϭ ϭ 5 Hz, 1
H, H3), 3.80 (s, 3 H, H17), 3.76 (dd, J ϭ ϭ 2, 12 Hz, 1 H, H7),
3.69 (dd, J ϭ ϭ 4, 12 Hz, 1 H, H7), 3.63 (t, J ϭ ϭ 10 Hz, 1 H,
H4), 3.54 (m, 1 H, H2), 3.50 (m, 1 H, H6), 2.10 (br. s, 1 H, OH),
cmϪ1, 2940, 2864, 1612, 1512, 1464, 1248, 1144, 1104, 1064, 1012. 1.84 (m, 1 H, H5), 1.09Ϫ0.98 [m, 21 H, Si(CH3)2]3, H9), 0.92 {d,
1
Ϫ H NMR: δ ϭ 7.34 (m, 2 H, arom. H), 6.86 (m, 2 H, arom. H),
J ϭ 7 Hz, 3 H, Si[CH(CH3)2]3}. Ϫ 13C NMR: δ ϭ 159.9 (C14),
6.16 (s, 2 H, H7, H6), 4.80 (d, J ϭ 12 Hz, 1 H, H10), 4.69 (s br, 1 130.2 (C11), 127.5 (C15, C13), 113.4 (C16, C12), 102.1 (C10), 81.7
H, H1), 4.61 (d, J ϭ 12 Hz, 1 H, H10), 4.58 (s br, 1 H, H5), 4.25 (C3), 77.4 (C2), 71.1 (C6), 69.5 (C8), 65.5 (C4), 63.4 (C7), 55.2
(dd, J ϭ 1, 5 Hz, 1 H, H3), 3.78 (s, 3 H, H17), 3.46 (dd, J ϭ 2, (C17), 37.3 (C5), 18.6 {Si[CH(CH3)2]3}, 14.0 (C9), 13.3
5 Hz, 1 H, H2), 1.79 (m, 1 H, H4), 1.05 {s, 21 H, H9, Si{CH[CH3)2]3}.
Si[CH(CH3)2]3}, 1.03 {s, 3 H, Si[CH(CH3)2]3}. Ϫ 13C NMR: δ ϭ
(؉)-(2R,3S,4S,5R,6S)-[10-(p-Methoxyphenyl)-5-methyl-4-(triiso-
propylsilyloxy)hexahydropyrano[3,2-d][1,3]dioxin-6-yl]carbaldehyde
[(؉)-11]: A mixture of (؉)-10 (760 mg, 1.60 mmol), NMO (281 mg,
158.8 (C14), 133.4 (C7), 131.5 (C11), 130.5 (C6), 128.8 (C13, C15),
113.5 (C12, C16), 83.2 (C1), 80.8 (C5), 75.7 (C2), 72.4 (C10), 68.0
(C3), 55.1 (C15), 35.4 (C4), 17.6 {Si[CH(CH3)2]3}, 13.8 (C9), 12.2
{Si[CH(CH3)2]3}. Ϫ MS (100 °C); m/z: 432 (0) [Mϩ], 389 (6)
[MϩϪC3H7), 311 (2), 269 (2), 201 (5), 122 (13), 121 (100), 115 (3),
95 (53), 84 (28), 77 (3), 69 (3). Ϫ FAB-MS; m/z: 455 (100)
[MϩϩNa], 431 (87) [MϩϪ1], 389 (17), 325 (45), 295 (27), 157 (35).
˚
2.40 mmol) and activated molecular sieves (3 A) in DCM (16 mL)
was stirred for 10 min under N2. Then Pr4NRuO4 (TPAP) (34 mg,
0.096 mmol) was added and stirring was continued for 1 h. The
reaction mixture was filtered through a short column (silica gel,
MTBE/PE) to give (؉)-11 (590 mg, 79%), colorless, viscous oil. Ϫ
[α]2D0 ϭ ϩ19.6 (c ϭ 1 in CHCl3), 83% ee by NMR shift measure-
ments. Ϫ IR (KBr): ν˜ ϭ 2940 cmϪ1, 2864, 2740, 2036, 1740, 1616,
(؉)-(2R,3S,4S,5R,6S)-[2-(Hydroxymethyl)-3-p-(methoxybenzyl-
oxy)-5-methyl-4-(triisopropylsilyloxy)tetrahydropyran-6-yl]methanol
[(؉)-9]: A solution of (؉)-8 (1.99 g, 4.6 mmol) in DCM/methanol
1
1516, 1464, 1384, 1216, 1148, 1080. Ϫ H NMR: δ ϭ 9.58 (m, 1
(1:4, 40 mL) was ozonolyzed at Ϫ95 °C. The reaction was mon- H, H7), 7.36 (m, 2 H, arom. H), 6.84 (m, 2 H, arom. H), 5.50 (s,
itored by TLC. After complete reaction, N2 was bubbled through
the solution to destroy excess ozone. The ozonide was reduced with
NaBH4 (382 mg, 10.1 mmol) and the mixture was allowed to reach
1 H, H10), 4.35 (dd, J ϭ 5, 10 Hz, 1 H, H8), 4.27 (m, 1 H, H6),
4.09 (dd, J ϭ 5, 10 Hz, 1 H, H8), 4.01 (dd, J ϭ 2, 10 Hz, 1 H, H2),
3.79 (s, 3 H, H17), 3.71 (t, J ϭ 10 Hz, 1 H, H3), 3.56 (dd, J ϭ 2,
Eur. J. Org. Chem. 2000, 2195Ϫ2201
2199

H. Kim, H. M. R. Hoffmann
FULL PAPER
10 Hz, 1 H, H4), 1.94 (m, 1 H, H5), 1.12Ϫ0.98 {m, 24 H, H9, cycloadduct was continued (temperature of the reaction mixture:
Si[CH(CH3)2]3}. Ϫ 13C NMR: δ ϭ 200.3 (C7), 159.9 (C14), 130.2
0Ϫ10 °C, see Note 4). After complete addition, the mixture was
(C11), 127.3 (C15, C13), 113.1 (C16, C12), 101.8 (C10), 81.0 (C3), stirred for 1 h at room temperature; it was then cooled to 0 °C and
80.8 (C2), 71.2 (C6), 69.2 (C8), 64.6 (C4), 55.2 (C7), 37.7 (C5), 18.3 suction-filtered. The residue was washed with several portions of
{Si[CH(CH3)2]3}, 13.1 {Si[CH(CH3)2]3}, 12.7 (C9). Ϫ MS (120 °C); E. The combined organic phases were washed once with brine
m/z: 464 (0) [Mϩ], 421 (100) [Mϩ-C3H7], 286 (15), 267 (3), 242 (4), (500 mL) (see Note 5) and the aqueous layer was re-extracted with
241 (23), 199 (33), 187 (9), 159 (9), 135 (11), 121 (46), 103 (12), 75
CHCl3 (5 ϫ 300 mL). The combined organic phases were dried
(15). Ϫ HRMS: calcd. for C25H40O6Si [Mϩ] 421.2048; found (MgSO4), concentrated and then filtered through solid K2CO3 (see
421.2046.
Note 6). The residue was washed with CHCl3, the solvent was re-
moved and the crude product was purified by column chromato-
graphy (silica gel, solvent E/PE, 1:10) to afford 1 (31Ϫ34.9 g,
52Ϫ56%), m.p. 38 °C, the aqueous solution of which was neutral
to pH indicator paper. Ϫ IR (KBr): ν˜ ϭ 2969 cmϪ1, 2909, 1713,
1,1,3,3-Tetrabromopropanone (12). ؊ Step A: HBr (51 mL, 0.45
mol, 48% aqueous solution) was added at 0 °C to acetone (110 mL,
1.5 mol). Bromine (310 mL, 5.9 mol) was added dropwise over ca.
3 h to the well-stirred solution. The mixture was cooled until the
evolution of HBr ceased (ca. 2 h) and was then stirred for 10 d
at room temperature with exclusion of light. Usually the product
precipitates as an orange solid. The reaction mixture was shock-
frozen with liquid N2. After 3Ϫ4 h at room temperature, the super-
natant aqueous layer was decanted and the waxy residue was suc-
tion-filtered (exposure to metallic surfaces and apparatus should
be avoided during workup). The filter cake was washed several
times with ice-cold PE until the filtrate became colorless. The re-
sulting white solid was dried (oil pump) to afford 12, 499 g (89%);
m.p. 38 °C (see Note 1). Ϫ IR (KBr): ν˜ ϭ 3009 cmϪ1, 1734, 1270,
1219, 1140, 1089, 1027. Ϫ 1H NMR: δ ϭ 6.35 (s, 2 H). Ϫ 13C
NMR: δ ϭ 183.3 (CϭO), 34.0 (CH). Ϫ MS; m/z: 378 (1), 377 (2),
376 (6), 374(8) [Mϩ], 215 (7), 203 (48), 210 (90), 199 (50), 175 (40),
173 (77), 133 (13), 123 (63), 122 (100), 121 (63), 120 (98).
1
1246, 1039. Ϫ H NMR: δ ϭ 6.27 (s, 2 H, H6, H7), 5.04 (d, J ϭ
5, 2 H, H1, H5), 2.76 (dd, J ϭ 5, 16.6, 2 H, H2ax, H4ax), 2.34 (dd,
J ϭ 0.6, 16.6, 2 H, H2eq, H4eq). Ϫ 13C NMR: δ ϭ 205.3 (C3),
133.3 (C6, C7), 77.1 (C1, C5), 46.5 (C2, C4).
Acknowledgments
We thank Marc Nowakowski, Tom Lampe, Ingo Rose, Ralf Dun-
kel, Matthias Mentzel, Oliver Gaertzen, Peter Wolbers, Alex Vakal-
opolous, Henning Reuter and Ulrike Eggert for their contributions
and the Fonds der Chemische Industrie for continued support of
our work.
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8-Oxabicyclo[3.2.1]oct-6-en-3-one (1). ؊ Step B: A 1-L flask was
charged with activated zinc dust (35.9 g, 550 mmol) (obtained by
brief treatment with dil. HCl, washing with water, acetone, E and
drying), heated, and flushed with N2. Furan (43.7 mL, 600 mmol)
in THF (100 mL) was added. A solution of 12 (187 g, 500 mol) and
triethyl borate (110 mL, 650 mmol) in THF (100 mL) was added
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of the tetrabromopropanone/triethyl borate solution, bromine
(250 µL) was added (see Note 2). After complete addition, the tem-
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30 min and was heated slightly. After 5 min, the exothermic reac-
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tetrahydrofuran (see Note 3). The mixture was stirred for 1 h at
room temp. and was then cooled to Ϫ15 °C. Ice-cold water
(300 mL) was added, and the mixture was stirred for 20 min at
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phases were washed with water (2 ϫ 200 mL) and brine (400 mL).
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combined organic phases were dried (MgSO4) and concentrated
(max. 30 °C). The residue (209 g) was dissolved in MeOH
(125 mL). Ϫ Step C: Zinc dust (114 g, 1.74 mol) was added under
vigorous stirring (KPG stirrer) to a refluxing solution of copper
acetate (6.5 g, 325 mmol) in glacial acetic acid (166 mL). After
5 min, the mixture was cooled to room temperature and the super-
natant liquid was decanted. The Zn/Cu couple was washed with
glacial acetic acid (200 mL), water (200 mL), acetone (200 mL),
and E (3 ϫ 200 mL) and was then dried (oil pump). To a suspen-
sion of the resulting Zn/Cu couple and NH4Cl (125.7 g, 2.35 mol)
in MeOH (500 mL) was added a small portion of cycloaddition
product in MeOH (ca. 10%) at Ϫ78 °C. After 15 min at Ϫ78 °C,
the mixture was placed into an ice bath and addition of brominated
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Eur. J. Org. Chem. 2000, 2195Ϫ2201

Synthesis of the C38ϪC44 Segment of Altohyrtin A
FULL PAPER
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[9b]
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H. M. R. Hoffmann, M. N. Iqbal, Tetrahedron Lett. 1975,
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[13b]
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Received September 30, 1999
[O99545]
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Eur. J. Org. Chem. 2000, 2195Ϫ2201
2201