Asymmetric, stereocontrolled total synthesis of paraherquamide A

Article abstract of DOI:10.1002/1521-3773(20000717)39:14<2540::AID-ANIE2540>3.0.CO;2-R

Paraherquamide A (1), a potent anthelmintic agent, isolated from various Penicillium species with activity against ivermectin-resistant intestinal parasites, has been synthesized. The synthesis of a key intermediate, the α-isoprenylated, β-substituted hydroxyproline derivative, exploited a highly diastereoselective intramolecular S(N)2' cyclization as a key step. This procedure is the first asymmetric, stereocontrolled, total synthesis of 1.

Full text of DOI:10.1002/1521-3773(20000717)39:14<2540::AID-ANIE2540>3.0.CO;2-R

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electrospray mass spectrometry, ultraviolet spectroscopy,
(À788C) and decomposed upon warming, see M. M. Midland, A.
Tramontano, J. R. Cable, J. Org. Chem. 1980, 45, 28 ± 29. Displacement
of this model trifluoromethanesulfonate with the dianion of propiolic
acid was complicated by O alkylation and double alkylation, which
was surpressed through use of the alternative nucleophile 15. For a
complex example of the use of an N-phenylamide as a carboxyl
surrogate with attenuated nucleophilicity, see D. A. Evans, P. H.
Carter, E. M. Carreira, A. B. Charette, J. A. Prunet, M. Lautens, J.
Am. Chem. Soc. 1999, 121, 7540 ± 7552. For the synthesis of 15, see
G. M. Coppola, R. E. Damon, Synth. Commun. 1993, 23, 2003 ± 2010.
For the alkylation of carbonyl compounds with the dianion of N-
benzylpropynamide, see G. M. Coppola, R. E. Damon, J. Heterocycl.
Chem. 1995, 32, 1133 ± 1139.
infrared spectroscopy, and optical rotation values.[30]
Received: April 25, 2000 [Z15025]
[
[
1] D. A. Evans, V. J. Cee, T. E. Smith, D. M. Fitch, P. S. Cho, Angew.
Chem. 2000, 112, 2633 ± 2636; Angew. Chem. Int. Ed. 2000, 39, 2533 ±
2
536.
2] Abbreviations: Ac ˆ acetyl; Ms ˆ methanesulfonyl; TIPS ˆ tiisopro-
pylsilyl; TES ˆ triethylsilyl; TMS ˆ trimethylsilyl; DIBAlH ˆ diiso-
butylaluminum hydride; Tf ˆ trifluoromethanesulfonyl; Bn ˆ benzyl;
DMAP ˆ 4-dimethylaminopyridine; pyr ˆ pyridine; tol ˆ toluene;
TBAF ˆ tetra-n-butylammonium fluoride; DBU ˆ 1,8-diazabicy-
clo[5.4.0]undec-7-ene; lut ˆ 2,6-lutidine; Boc ˆ tert-butyloxycarbonyl.
3] D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey, K. R.
Campos, B. T. Connell, R. J. Staples, J. Am. Chem. Soc. 1999, 121,
[23] Similar conditions have recently appeared in the literature for an
oxazole-stablized Wittig coupling, see P. Liu, J. S. Panek, J. Am. Chem.
Soc. 2000, 122, 1235 ± 1236.
[24] For the hydrolysis of the N-Boc derivatives of secondary amides and
lactams with LiOH, see D. L. Flynn, R. E. Zelle, P. A. Grieco, J. Org.
Chem. 1983, 48, 2424 ± 2426.
[
6
69 ± 685.
[
[
4] T. H. Chan, M. A. Brook, T. Chaly, Synthesis 1983, 203 ± 205.
5] The product ratio was determined by H NMR analysis (500 MHz) of
1
[25] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 ± 1993.
the unpurified reaction mixture.
1
[
[
[
6] Although the anomers were separable by chromatography on silica
[26] The regioselectivity of the cyclization was determined by 1D H NMR
gel, the mixture was generally taken on without purification.
and 2D COSY experiments.
7] Use of stronger Lewis acids such as BF
levels of decomposition.
3
´ OEt
2
or TiCl
4
led to high
[27] The difference in the selectivity between the two bases is perhaps a
result of the formation of a more active silylating agent derived from
the reaction of imidazole with the silyl chloride. Presumably there is
no reaction between the silyl chloride and 2,6-lutidine, which simply
acts as a base.
8] For an early example of nucleophilic addition to oxocarbenium ions in
the synthesis of C-glycosides, see M. D. Lewis, J. K. Cha, Y. Kishi, J.
Am. Chem. Soc. 1982, 104, 4976 ± 4978.
[
9] Optimal results were obtained when buffering the reaction with
[28] The use of 1-hexene as a co-solvent was found to effectively surpress
any overreduction. For related conditions, see T.-L. Ho, S.-H. Liu,
Synth. Commun. 1987, 17, 969 ± 973.
[29] J. R. Parikh, W. von E. Doering, J. Am. Chem. Soc. 1967, 89, 5505 ±
5507.
20 mol% of pyridine. The diastereoselectivity was determined by
HPLC analysis of the unpurified reaction mixture (Zorbax silica gel,
À1
2
0% EtOAc in hexanes, flow rate ˆ 1.0 mLmin , 254 nm UV cutoff,
major isomer (trans) T
r
ˆ 11 min, minor isomer (cis) T ˆ 13 min).
r
[
[
10] E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic
Compounds, Wiley, New York, 1994, chap. 11.
[30] We thank Professor T. F. Molinski for kindly providing a sample and
1
copies of H NMR spectra of natural phorboxazole B for comparison.
11] Aldehyde 8 was obtained from reduction (DIBAlH, CH
5% yield) of the known ethyl ester. See J. S. Panek, R. T. Beresis, J.
Org. Chem. 1996, 61, 6496 ± 6497.
2
Cl
2
, À918C,
9
[
[
12] Dr. David MacMillan is gratefully acknowledged for the development
of this reaction.
13] Reported results for the reaction run on >60 mmol scale (18.5 g
isolated product). Enantiomeric excess values were determined by
Asymmetric, Stereocontrolled Total Synthesis
of Paraherquamide A**
chiral HPLC analysis (Chiralcel OD-H column, 4% EtOH in hexanes,
À1
flow rate ˆ 1.0 mLmin , R enantiomer T
r
ˆ 34.2 min, S enantiomer
T
r
ˆ 36.8 min).
14] D. A. Evans, D. W. C. MacMillan, K. R. Campos, J. Am. Chem. Soc.
997, 119, 10859 ± 10860.
Robert M. Williams,* Jeffrey Cao, and
Hidekazu Tsujishima
[
[
1
15] Dihydroxylation was performed using the achiral ligand, quinuclidine.
For a review of asymmetric dihydroxylation under these conditions,
see H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
[
1±4]
marcfortines (3, 4),[5]
The paraherquamides (1, 2, 5, 6),
[6]
[3b]
brevianamides, VM55599 (9),
and, most recently, the
and aspergimides (8)[8] are indolic
secondary metabolites isolated from various fungi
(Scheme 1). The parent and most potent member, paraher-
1
994, 94, 2483 ± 2547.
[7]
sclerotamides (10)
[
16] D. A. Evans, B. W. Trotter, P. J. Coleman, B. C oà t e , L. C. Dias, H. A.
Rajapakse, A. N. Tyler, Tetrahedron 1999, 55, 8671 ± 8726.
[
17] D. A. Evans, P. J. Coleman, B. Co
Ãt e , J. Org. Chem. 1997, 62, 788 ± 789.
See also I. Paterson, K. R. Gibson, R. M. Oballa, Tetrahedron Lett.
996, 37, 8585 ± 8588.
18] A model aldol reaction with ketone 3 and dihydrocinnamaldehyde
under unoptimized conditions (nBu BOTf, iPr NEt, Et
1
[
*] Prof. Dr. R. M. Williams, J. Cao, H. Tsujishima
Department of Chemistry
Colorado State University
[
2
2
2
O, À788C)
resulted in a 72% yield of the desired anti adduct with >95:5
1
Fort Collins, CO 80523 (USA)
Fax : (‡1)970-491-3944
diastereoselectivity as determined by H NMR analysis (500 MHz) of
the unpurified reaction mixture. The relative stereochemistry of this
product was determined by X-ray crystallography.
19] The remainder of the material was comprised of cleanly recovered 3
and 4.
20] Hemiketal 2 existed as a 92:8 mixture of the closed hemiketal and
open hydroxy ketone. This mixture was taken on together in the
subsequent reduction.
E-mail: rmw@chem.colostate.edu
[
[
[**] This work was supported by the NIH (Grant CA 70375). The Japanese
Society for the Promotion of Science (JSPS) is acknowledged for
providing support to H.T. Mass spectra were obtained on instruments
supported by the NIH Shared Instrumentation Grant (GM 49631). We
also wish to thank Dr. Timothy Blizzard (Merck & Co.) for providing
an authentic sample of natural paraherquamide A. We also wish to
acknowledge Dr. Byung H. Lee (Pharmacia ± Upjohn Co.) for provid-
ing NMR spectra and an authentic specimen of 14-oxoparaherqua-
mide B. We also wish to thank Dr. Alfredo Vazquez for assistance with
purification and characterization of synthetic paraherquamide A.
[
21] K. S. Kim, Y. H. Song, B. H. Lee, C. S. Hahn, J. Org. Chem. 1986, 51,
4
04 ± 407.
[
22] The lithium anions of methyl and ethyl propiolate failed to alkylate a
model primary trifluoromethanesulfonate derived from the commer-
cial available tetrahydropyran-2-methanol at low temperature
2540
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Angew. Chem. Int. Ed. 2000, 39, No. 14

COMMUNICATIONS
2
3
O
derivatives of paraherquamide A hold potential as
2
2
O
1
Me
Me Me
NH
Me
H
NH
drugs for the treatment of intestinal parasites in
2
9
H
1
9
21
8
24
[13]
R1
3
O
O
O
O
20
animals.
The relatively low culture yields of
1
7
R2
29
7
6
1
3
O18 Me
25
O
R
N
1
0
paraherquamide A obtained for biological study
have slowed the development of these agents.
Recently, Lee and Clothier reported the interest-
ing semisynthetic conversion of marcfortine A, a
metabolite more readily available by fermenta-
tion, into paraherquamide A via paraherquami-
14
1
1
4
26
N
Me 27
N
Me
Me
1
5
16
N
5
1
2
28 Me
: paraherquamide A: R1 = OH, R2 = Me
: paraherquamide B: R1 = H, R2 = H
3: marcfortine A: R = Me
: marcfortine B: R = H
1
2
4
O
Me
Me
Me Me
NH
O
[13]
H
Me
de B. To date, a total synthesis of paraherqu-
Me
H
N
O
R1
amide A has not been reported in the literature.
We have previously described an asymmetric
synthesis of the simplest paraherquamide deriva-
3
R2
O
R
Me
Me
N
O
N
H
N
OH
O
N
: paraherquamide F: R1 = H, R2 = Me, R = Me
: paraherquamide G: R1 = OH, R2 = Me, R3 = Me
: VM55595: R1 = H, R2 = Me, R = H
3
[14]
5
6
7
tive, paraherquamide B (2), from (S)-proline. In
O
8: aspergamide A
approaching the synthesis of paraherquamide A,
which contains the unusual b-hydroxy-b-methyl pro-
line residue, a new method needed to be developed
to generate a suitably functionalized a-alkylated-b-
hydroxyproline moiety that could be conscripted
for the multistep construction of paraherquami-
de A. Despite the apparent similarity in the
structures of paraherquamide A and B, the syn-
thesis of the former turned out to be a significantly
more challenging endeavor. We recently described
a potentially general method to construct a-
3
O
Me Me
H
NH
H
Me
Me
H
N
1
7
Me
20
O
N
Me
N
Me
Me
O
N
H
N
OH
O
H
14
O
9
: VM55599
10: sclerotamide
Scheme 1. Structures of the paraherquamides and related metabolites.
quamide A (1) was isolated from cultures of Penicillium
paraherquei, first described by Yamazaki in 1981.[ The
simplest member, paraherquamide B (2), plus five other
structurally related paraherquamides C ± G were isolated
from Penicillium charlesii (fellutanum) (ATCC 20841) in
alkylated-b-hydroxyproline residues by the dianion alkylation
of the readily available N-Boc-b-hydroxyproline ethyl ester
1]
derivative 12 with net retention of stereochemistry (Boc ˆ
tert-butylcarbonyl).[
15]
We have successfully applied this
methodology to a concise asymmetric and stereocontrolled
synthesis of paraherquamide A in 27steps from the racemic b-
keto ester 11, as shown in Scheme 2.
[2]
1
990 at Merck & Co. and concomitantly at SmithKline
[3]
Beecham. Subsequently, three additional related com-
pounds, VM55596, VM55597, and VM55599 (9) were discov-
ered by the same group at SmithKline Beecham from
Penicillium strain IMI 332995. More recently, a Pfizer
group[ reported the isolation of anthelmintic metabolites
VM54159, SB203105, and SB200437along with the non-
tryptophan derived metabolites, that possessing the common
As described previously,[ b-ketoester 11 was subjected to
Bakerꢁs yeast reduction to afford the optically active b-
hydroxyester 12 (60 ± 80%, erꢀ 95:5). Dianion alkylation of
12 with (E)-3-methyl-4-(O-tert-butyldimethylsilyl)-2-butene
afforded the desired a-alkylated product 13 in 58 ± 70%
isolated yield without attendant O-alkylation.[ Protection of
the secondary alcohol as the corresponding methoxy methyl
(MOM) ether, followed by removal of the Boc group with
ZnBr2 in dichloromethane and acylation of the incipient
secondary amine with bromoacetyl bromide in the presence of
potassium carbonate afforded the bromoacetamide 14 in 86%
overall yield from 13. Treatment of 14 with methanolic
ammonia afforded the corresponding glycinamide which was
directly subjected to cyclization in the presence of sodium
hydride in toluene/HMPA to afford the bicyclic substance 15
in 79% overall yield from 14. Next, a one-pot double
carbomethoxylation reaction was performed by the sequential
addition of nBuLi in THF followed by addition of methyl-
chloroformate, that carbomethoxylated the amide nitrogen
atom. Subsequent addition of four equivalents of methyl-
chloroformate followed by the addition of five equivalents of
16]
[4]
5]
15]
[4]
bicyclo[2.2.2] nucleus, aspergillimide (which is identical to
[9]
asperparaline A ) and 16-keto-aspergillimide from Aspergil-
lus strain IMI 337664. This report, and a recent paper by
Whyte and Gloer,[ that described the isolation of sclerot-
amide (10) from Aspergillus sclerotiorum, constitute the first
examples of paraherquamide derivatives isolated outside of
the Penicillia. In addition, Zeeck et al. have isolated the inter-
esting paraherquamide-type metabolites aspergamides A (8)
and B.[
7]
8]
These substances have attracted considerable attention due
to their molecular complexity, intriguing biogenesis,[
10, 11]
and
some members, most notably paraherquamide A, display
potent antiparasitic activity and antinematodal properties.[
Due to the development of drug resistance by the helminths,
the commonly employed broad spectrum antihelmintic
agentsÐsuch as the benzimidazoles, the levamisoles/moran-
tel, and the avermectinsÐare beginning to lose efficacy and
there has arisen an urgent need for discovering new classes of
antiparasitic agents. The paraherquamides represent an
entirely new structural class of antiparasitic agents that
promise to play a significant role in the near future and the
12]
LiN(TMS) afforded 16 as a mixture of diastereomers in 93%
2
yield that were taken on directly without separation.
[
17]
Somei ± Kametani coupling
of 16 with the gramine
derivative 17[ in the presence of tri(n-butyl)phosphine gave
the tryptophan derivative 18 as a 3:1 mixture of diastereomers
(epimeric at the newly created stereogenic center) in 70%
18]
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COMMUNICATIONS
Scheme 2. Synthesis of paraherquamide A. a) Bakerꢁs yeast; b) Li(NiPr)
2
, THF, HMPA, (E)-ICH
Cl , 08C; f) NH in MeOH (5.7m solution), 258C; g) 3 equiv NaH, toluene,
Me, À788C; then 4 equiv ClCO Me, 5 equiv LiN(TMS) , À788C; i) 0.7equiv ( nBu) P, MeCN;
OBF , CH Cl , Cs CO , 258C; l) DMAP, 3 equiv (Boc) O, CH Cl , 08C; m) 3.3 equiv TBAF, THF,
, 08C; o) 2 equiv TBSOTf, 2,6-lutidine, CH Cl , 08C; p) 20 equiv NaH, THF, reflux, 30 h; q) 3.1 equiv AgBF
, MeCN, propylene oxide; then NaBH , EtOH; r) 0.1m HCl, THF; s) 2-hydroxypyridine, toluene, 1208C, 2 h; t) 5 equiv (iBu) AlH, CH Cl
8C; u) NaH, MeI, DMF, 08C; v) 6 equiv B-bromocatechol borane, CH Cl , 08C; w) 5 equiv Dess ± Martin periodinane, CH Cl , 258C; x) TFA, CH
58C; y) 1.5 equiv tBuOCl, py; then 5 equiv p-TsOH, THF, H O, reflux; z) 5 equiv (PhO)
PMeI, DMPU; aa) MeMgBr, THF. Abbreviations: HMPA ˆ
2
CHˆC(Me)CH
2 2
OTBS; c) 5.7equiv MOMCl, ( iPr) NEt,
CH
HMPA, 258C; h) 1.3 equiv nBuLi, THF, 1.1 equiv ClCO
j) 5 equiv LiCl, H O, HMPA, 1058C, 5 h; k) 2.5 equiv Me
58C; n) 1.1 equiv MsCl, collidine, CH Cl
.68 equiv PdCl
2
Cl
2
; d) 2.7equiv ZnBr
2
, CH
2
Cl
2
; e) K
2
CO
3
, 2 equiv BrCH
2
COBr, CH
2
2
3
2
2
2
3
2
3
4
2
2
2
3
2
2
2
2
4
0
2
2
2
2
2
4
2
,
,
2
4
2
2
2
2
2
2
2
Cl2,
2
3
hexamethylphosphoramide; TBS ˆ tert-butyldimethylsilyl; MOMCl ˆ chloromethyl methyl ether; TMS ˆ trimethylsilane; DMAP ˆ 4-(dimethylamino)pyr-
idine; (Boc)
2
O ˆ dicarbonic acid bis(tert-butyl) ester; TBAF ˆ tetrabutylammonium fluoride; MsCl ˆ methanesulfonyl chloride; TBSOTf ˆ tert-butyldime-
thylsilyl trifluoromethanesulfonate; Dess ± Martin periodinane ˆ 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; TFA ˆ trifluoroacetic acid;
tBuOCl ˆ tert-butyl hypochlorite; py ˆ pyridine; p-TsOH ˆ para-toluenesulfonic acid; DMPU ˆ N,N'-dimethylpropyleneurea.
yield. Decarbomethoxylation of 18 was effected by treatment
of 18 with LiCl in hot, aqueous HMPA at 1058C providing 19
as a mixture of diastereomers that were separated and carried
forward individually. Protection of the secondary amide group
as the corresponding methyl lactim ether was accomplished
by treating 19 with trimethyloxonium tetrafluoroborate in
dichloromethane that contained cesium carbonate. Next, the
indole nitrogen atom was protected as the corresponding Boc
derivative by treatment with dicarbonic acid bis(tert-butyl)
ester in the presence of DMAP and the silyl ether was
removed with tetrabutylammonium fluoride to provide diol
triflate in the presence of 2,6-lutidine afforded the key allylic
chloride 21 in 68 ± 71% yield over the two steps.
The stage was now set for the critical intramolecular S 2'
N
cyclization that sets the relative stereochemistry at C-20
during formation of the bicyclo[2.2.2]octane ring nucleus.
Based on a solid precedent from the paraherquamide B
synthesis,[ it was found that treatment of 21 with NaH in
14]
refluxing THFafforded the desired S 2' cyclization product 22
N
in 87% exclusively as the desired syn-isomer.[ This remark-
19]
ably syn-selective intramolecular S 2' cyclization reaction
N
proceeds through a tight, intramolecular, ion-pair driven
cyclization (ªclosedº transition state),[
20]
as shown in
20 in 52 ± 78% overall yield from 19. Selective conversion of
the allylic alcohol to the corresponding allylic chloride was
accomplished by mesylation in the presence of collidine.
Silylation of the secondary alcohol with tert-butyldimethylsilyl
Scheme 3. Closure of the seventh ring was effected by
treatment of 22 with 4.68 equivalents of PdCl and 3.1 equiv-
2
alents of AgBF4[ in acetonitrile containing propylene oxide
21]
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COMMUNICATIONS
N
Scheme 3. Diastereoselective, intramolecular S 2' cyclization.
as an acid scavenger. It was found that without propylene
oxide to buffer this reaction, the MOM ether suffered
extensive cleavage. The incipient heptacyclic s-palladium
adduct was worked up immediately by the addition of ethanol
and sodium borohydride to afford the desired 2,3-disubsti-
tuted indole 23.
Cleavage of the lactim ether of 23 was effected with 0.1m
HCl to give the corresponding ring-opened amine methyl
ester that was recyclized by treatment of this material with
that subsequently rearranges stereospecifically to the desired
spiro oxindole 28 (Scheme 4).
The dioxepin ring was then formed by dehydration of the
secondary alcohol of 28 with methyl triphenoxyphosphonium
iodide (MTPI) in DMPU to afford 14-oxoparaherquamide B
29, (55%).[ This intermediate has been previously described
by a Pharmacia ± Upjohn group (obtained semi-synthetically
from marcfortine A) and comparison of the authentic and
13]
1
13
synthetic materials ( H and C NMR, IR, exact mass, mobility
on thin-layer chromatography (TLC)) confirmed the identity
of this substance. The final step, a methyl Grignard addition to
the ketone group of 29 has been previously described to give
paraherquamide A along with a trace of the corresponding
2-hydroxypyridine in hot toluene (63% overall from 22).
Chemoselective reduction of the secondary amide in the
presence of the tertiary amide was effected by treatment of
the product obtained in the previous step with excess
diisobutylaluminum hydride in dichloromethane (50 ± 72%)
to furnish 24.[ Methylation of the secondary amide of 24
proceeded in 96% yield. Cleavage of the MOM ether with
bromocatecholborane[ (91% yield) followed by oxidation
of the secondary alcohol with Dess ± Martin periodinane[
[
13a]
C-14 epimer in ꢀ50% yield when MeMgBr was employed.
22]
Employment of this protocol using MeMgBr with our
synthetic ketone gave (À)-paraherquamide A (1) as the
exclusive product (the C-14 epimer was not detected) in
23]
24]
1
13
42% yield that was identical in all respects ( H and C NMR,
(
85% yield) and cleavage of the
Boc group and TBS ether with
TFA (97% yield) gave ketone 25.
The final, critical oxidative spi-
rocyclization of the 2,3-disubstitut-
ed indole to the spiro oxindole was
effected by treatment of 25 with
tert-butyl hypochlorite in pyridine,
which provided a labile 3-chloroin-
dolenine. It was necessary to rigor-
ously remove all of the pyridine
solvent prior to the Pinacol-type
rearrangement, that was conducted
by treating the incipient 3-chloro-
indolenine with para-toluenesul-
OH
OH
O
Me
O
Me
Me
H
Me
Me
N
Me
H
O
Me
N
Me
H
O
tBuOCl
pyridine
TsOH, THF, H2O
O
O
O Me
N
O Me
N
Cl
26
N
N
2
5
OH
O
O
Me
Me
Me
Me
H
H
NH
Me HO
N
Me
H
O
O
3
(PhO) PMeI
O
O Me
N
N
OH
Me
O
DMPU
O Me
N
Cl
O
Me
N
fonic acid in THF/H O. It is as-
2
2
7
sumed that the chlorination of 25
proceeds from the least hindered
face of the indole, to give the a-
chloroindolenine 26. The hydration
of the imine functionality must,
interestingly, also occur from the
same a-face that is syn to the
relatively large chlorine atom fur-
nishing the syn-chlorohydrin 27,
28
O
Me
Me
H
NH
MeMgBr
O
O
O
1
O Me
N
N
Me
Me
29: 14-oxoparaherquamide B
Scheme 4. Formation of the spiro oxindole.
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IR, exact mass, mobility on TLC, m.p. (2508C (decomp.)),
Michael, H. W. Haines, C. H. Eary, Vet. Parasitol. 1992, 43, 259;
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25
[25]
[
a] ˆ À22 (c ˆ 0.2 MeOH)) to natural paraherquamide A.
D
The approach developed in this study makes it feasible to
examine the design and synthesis of other members of the
paraherquamide family and should also permit access to
structurally unique paraherquamides, which may have sig-
nificant biological properties. The application of this method-
ology to the asymmetric, stereocontrolled, total synthesis of
other members of the paraherquamide family and the
evaluation of their properties is currently under study in
these laboratories.
[
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Me
Me
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[
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N
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Y
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( )n
( )n
syn
anti
1
977.
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[
[
[
[
[
25] The synthetic sample was recrystallized from ether. A sample of
natural paraherquamide A recrystallized from ether under the same
conditions rendered a sample with a m.p. ˆ 2508C (decomp.) and
6
33; i) J. Coetzer, Acta Crystallogr. Sect. B 1974, 30, 2254.
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[
7] A. C Whyte, J. B. Gloer, J. Nat. Prod. 1996, 59, 1093.
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[
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D
ˆ À21 (c ˆ 0.2 in MeOH), lit. [1] [a] ˆ À28 (c ˆ 0.43 in MeOH).
8] ªBeeinflussung der Sekundarstoffbildung bei Aspergillus ochraceus
durch Variation der Kulturbedingungen sowie Isolierung, Struktur-
aufklarung und Biosynthese der neuen Naturstoffeº: J. Fuchser, PhD
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All intermediates up to the final product have an ꢀ97.5:2.5 er; the
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optically pure.
[
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[
2544
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