Diastereo- and enantioselective formal synthesis of (+)-conagenin via asymmetric [2,3]-Wittig rearrangement

Article abstract of DOI:10.1055/s-1999-3398

The formal synthesis of the immunomodulator (+)-conagenin (1) is accomplished in a twelve-step sequence with good overall yield (19%), diastereoselectivity and enantiomeric excess (ds(syn) = 88%, ee = 91%). Key steps of the synthesis are the asymmetric [2

Full text of DOI:10.1055/s-1999-3398

PAPER
243
Diastereo- and Enantioselective Formal Synthesis of (+)-Conagenin via
Asymmetric [2,3]-Wittig Rearrangement
Dieter Enders,* Michael Bartsch, Jan Runsink
Institut fŸr Organische Chemie, Rheinisch-WestfŠlische Technische Hochschule, Professor-Pirlet-Stra§e 1, D-52074 Aachen, Germany
Fax: +49 (0)241 8888127; E-mail: Enders@RWTH-Aachen.de
Received 16 September 1998
and enantioselective formal synthesis of the title com-
Abstract: The formal synthesis of the immunomodulator (+)-con-
pound (+)-conagenin. This method has the advantage of
agenin (1) is accomplished in a twelve-step sequence with good
opening a preparative route to analogs differing at all the
stereogenic centers of the pentanoic acid moiety.
overall yield (19%), diastereoselectivity and enantiomeric excess
(dssyn = 88%, ee = 91%). Key steps of the synthesis are the asym-
metric [2,3]-Wittig rearrangement of crotyloxyacetaldehyde-
SAEP-hydrazone (S)-5 and the diastereoselective reduction of
methylketone (R,S)-12. The absolute configuration of the (4R)-ste-
Starting from the readily accessible stable Weinreb
amide8 3, the (E,S)-crotyloxyacetaldehyde hydrazone (S)-
5 can be generated by LiAlH4 reduction and, after subse-
quent workup, condensation with the commercially avail-
able chiral auxiliary (S)-1-amino-2-(1-ethyl-1-methoxy-
propyl)pyrrolidine (SAEP)9 in good overall yield (83%,
2 steps). Deprotonation of the hydrazone (S)-5 with lithi-
um diisopropylamide (LDA) in THF/DMPU (5:1) at
Ð78¡C and additional stirring for 22 hours affords the re-
arrangend product (S,R,S)-6 in excellent yield (93%).6,7 The
observed syn/anti-selectivity is very good (95% syn) and the
asymmetric induction is high (de = 91%) (Scheme 1).
1
reogenic center was determined by H NMR NOE-measurements
with respect to the known absolute configuration of the (2R,3S)-ste-
reogenic centers of lactone (R,S,R)-14.
Key words: conagenin, immunomodulator, [2,3]-Wittig rearrange-
ment, chiral hydrazone, asymmetric synthesis
(+)-Conagenin (1) was isolated from fermentation broths
of Streptomyces roseosporus MI696-AF3 in 19911 and its
structure and absolute configuration were determined by
X-ray analysis.1 (+)-Conagenin is of significant biological
interest due to its activity as immunomodulator.2 Unlike
most low molecular weight immunomodulators produced
by microorganisms, e.g. cytogenin and cytoblastin, (+)-
conagenin stimulates activated T-cells, and not macro-
phages.3 These T-cells produce lymphokines and generate
antitumor effector cells. In addition (+)-conagenin has
been shown to improve the efficiency of antitumor agents
given to tumor carrying mice, by acting as a chemoprotec-
tor against myelosuppression, a side effect caused by
these drugs in cancer chemotherapy.2,3
At this stage it is possible to enrich the predominant iso-
mer by column chromatography or HPLC, (de >98%), as
previously reported.6,7 In view of the further transforma-
tions the hydroxy group was protected as the benzyl
ether. Complete conversion of the hydroxy function only
took place by using a potassium hydride/18-crown-6/
BnBr reaction system. Thus the benzylated hydrazone
(S,R,S)-7 could be isolated without epimerization in ex-
cellent yield (97%). Oxidative removal of the auxiliary
with magnesium monoperoxyphthalate (MMPP)10 and
reductive conversion of the resulting nitrile (R,S)-8 with
diisobutylaluminium hydride (DIBAL-H)11 affords the
aldehyde (R,S)-9 in very good yield (76%, 2 steps). In
order to avoid epimerization, it was necessary to perform
the reduction in pentane, since in dichloromethane,6
even less than one equivalent of DIBAL-H lead to
epimerization at the α-center (20%). Attempts to hydro-
lyze the nitrile (R,S)-8 directly to the desired acid (R,S)-
10 or the methyl ester (R,S)-11 failed (decomposition or
recovery of starting material) under various conditions
(acidic or basic).
The novel biological activity and the unique highly func-
tionalized structure of (+)-conagenin, has fostered interest
in the total synthesis of 1. Until now an asymmetric
synthesis4 and an ex-chiral-pool synthesis of the (3R)-
epimer5 have been reported in the literature. Both synthe-
ses utilized a protected 2,4-dihydroxy-3-methylpentanoic
acid 2 as a central building block.
Oxidation of the aldehyde with pyridinium dichromate
(PDC)12 in DMF generates the acid (R,S)-10, which reacts
with diazomethane to afford the methyl ester (R,S)-11 in
excellent yield (92%, 2 steps). In order to prove that this
reaction sequence took place without epimerization or ra-
cemization, the enantiomeric excess of the acid (R,S)-10
was determined by 1H NMR spectroscopy using the chiral
cosolvent (Ð)-(R)-1-(9-anthryl)-2,2,2-trifluoroethanol and
compared with the corresponding racemate.13
Recently, we reported on the diastereo- and enantioselec-
tive synthesis of (Ð)-oudemansin A6 as an application of
our well established diastereo- and enantioselective syn-
thesis of protected b-substituted g,d-unsaturated a-hy-
droxyaldehydes by asymmetric [2,3]-Wittig rearrange-
ment of SAEP-hydrazones.7 We now wish to disclose a
further application of this methodology to the diastereo-
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244
D. Enders et al.
PAPER
mediate complex is therefore locked and the hydride an-
ion attacks from the least hindered face of the complex to
form the syn-product (R,S,R)-13 (93% syn) in good yield
(72%), in addition to 10% of the corresponding lactone
(R,S,R)-14 (93% syn) (Scheme 2).
Reagents and conditions: a) 1. LiAlH4 (10 equiv)/THF, 0¡C, 2. 3 N
HCl, 0¡C; b) SAEP, 0¡C to r.t. (16 h); c) LDA (2.5 equiv)/THF/
DMPU, Ð78¡C (22 h), 2. NH4Cl; d) 1. BnBr (2 equiv)/18-crown-6
(1 equiv)/KH (2 equiv)/THF, 0¡C, 2. NH4Cl; e) 1. MMPP (2.5
equiv)/MeOH, 0¡C (1 h), 2. NaHCO3; f) DIBAL-H (1 equiv)/pentane,
Ð78¡C (2 h), 2. MeOH, Ð78 to 0¡C (2 h), 3. 1 N H2SO4, 0¡C (1 h); g)
1. PDC (6 equiv)/DMF, r.t. (12 h), 2. 6 N HCl; h) CH2N2 (2 equiv)/
Et2O, r.t.; i) PdCl2 (0.1 equiv)/CuCl (1 equiv)/O2 (5 bar)/H2O/acetone,
70¡C (4 h)
Reagents and conditions: a) 1. LiI (10 equiv)/LiBH4 (10 equiv)/
Et2O, Ð100¡C (2 h), 2. H2O, r.t. (0.5 h), 3. 25% AcOH; b) O-benzyl-
Scheme 1
¥
trichloroacetimidate (2 equiv)/BF3 OEt2 (cat)/cyclohexane, r.t.
(0.5 h); c) 1.1 M K2CO3/MeOH, r.t. (12 h), 2. 1 N HCl
There are two main possibilities to introduce in a
Markownikow sense a hydroxy group on the terminal
double bond of ester (R,S)-11, these being the oxymercu-
ration and Wacker reaction. Since the oxymercuration
failed,14 we turned our attention to the Wacker reaction.
The original protocol of Tsuji et al.15 affords the meth-
ylketone (R,S)-12 in good yield (73%). Unfortunately,
Scheme 2
The lactone (R,S,R)-14, which is produced from (R,S,R)-
13 due to basic reaction and workup conditions and sepa-
rated from (R,S,R)-13 by column chromatography, was
formed with the same diastereoselectivity as alcohol
(R,S,R)-13 (1H NMR). The absolute configuration of the
newly generated stereogenic centre of lactone (R,S,R)-14
was determined by H NMR NOE-measurements and
shown to be 4R relative to the known absolute configura-
tion of the stereocentres 2R,3S (Figure). The absolute con-
1
epimerization up to 20% was observed in the H NMR
1
spectrum, possibly due to the formation of p-allylpalladi-
um(II)-comlexes in DMF/H2O. Fortunately, a change in
the solvent was found to repress this effect. In acetone/
H2O no epimerization was observed in the 1H NMR spec-
trum and the resulting methylketone (R,S)-12 could be
isolated in good yield (77%).
An initial test reaction according to the literature
showed,16 that a simple reduction of ketone (R,S)-12 with
LiBH4 at Ð100ûC proceeded with a syn-selectivity of 75%.
In order to improve the asymmetric induction, an excess
of lithium iodide was added to the ketone in diethyl ether,
based on a method of Suzuki et al.17 The lithium cation
probably chelates with the ketone and ether oxygens at
low temperature. The conformation of the resulting inter-
Figure NOE-effects of lactone (R,S,R)-14
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Diastereo- and Enantioselective Formal Synthesis of (+)-Conagenin
245
IR (neat): n = 3065 (CH=CH2), 3029, 2967, 2938, 2879, 2826, 1640
(CH=CH2), 1589 (C=N), 1496, 1455, 1376, 1344, 1303, 1282,
1207, 1132, 1117, 1086 (COC), 1068, 1029, 992, 953 (CH=CH2),
914, 734 (Ar), 697 (Ar) cmÐ1.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, 6 H, J = 7.4 Hz, CH2CH3),
1.10 (d, 3 H, J = 6.9 Hz, CHCH3), 1.55 (m, 2 H, CH2CH3), 1.68 (m,
1 H, CHCH3), 1.70 (m, 2 H, CH2CH3), 1.85 (m, 2 H,
NCH2CH2CH2), 1.97 (m, 2 H, NCH2CH2CH2), 2.56 (m, 1 H,
CHNHCH), 2.72 (m, 1 H, CHNHCH), 3.23 (s, 3 H, OCH3), 3.60 (m,
1 H, OCH), 3.72 (t, 1 H, J = 6.9 Hz, CHNCH2), 4.45 (d, 1 H, J =
12.1 Hz, OHCH), 4.60 (d, 1 H, J = 12.1 Hz, OHCH), 5.10 (m, 2 H,
=CH2), 5.86 (ddd, 1 H, J = 17.0/10.7/7.4 Hz, CH=), 6.28 (d, 1 H, J
= 12.1 Hz, CNH), 7.32 (m, 5 H, C6H5).
figuration of the newly generated stereogenic centre of the
corresponding alcohol (R,S,R)-13 is assigned based on the
assumption of a uniform reaction pathway in generating
lactone (R,S,R)-14.
Finally, the hydroxy group of (R,S,R)-13 is protected as
benzyl ether with O-benzyltrichloracetimidate under
Lewis acid catalysis (BF3¥OEt2).18 Direct saponification
of the resulting ester intermediate produced acid (R,S,R)-
15 in good yield (66%, 2 steps) and high selectivity (dssyn
= 88%, ee = 91%). This material was found to be consis-
tent with an intermediate in the epi-conagenin synthesis of
Herzegh and Sztaricskai et al.5 Thus, the synthesis of (+)-
conagenin can be completed in 3 steps according to these
authors, affording the natural product via coupling of acid
(R,S,R)-15 with the protected amino acid a-methyl
serine19 and final deprotection (Scheme 2).
13C NMR (75 MHz, CDCl3): d = 7.8, 8.5 (CH2CH3), 15.9, 23.7
(CH2CH3), 23.6 (CH3), 24.5, 26.2 (5-ring CH2), 41.9 (CHCH3), 50.3
(OCH3), 50.6 (NCH2), 68.4 (NCH), 70.2 (CH2Ph), 80.4 (OC), 83.5
(OCH), 114.4 (CH2=), 127.2, 127.7, 128.1 (CHarom), 133.0 (=CH),
139.1 (Carom), 140.4 (C=N).
MS (EI, 70¡C, 80 eV): m/z (%) = 271 (M+¥ + 1, Ð C6H13O, 4), 264
(M+¥ Ð C7H7O, 16), 163 (M+¥ Ð C7H7O, Ð C6H13O, 100), 94 (64), 70
(C4H8N+, 57).
In conclusion, the asymmetric [2,3]-Wittig-rearrange-
ment of crotyloxyacetaldehyde-SAEP-hydrazone opens
an efficient, diastereo- and enantioselective entry to con-
agenin and its analogues. With respect to potential drug
design, our synthesis offers several synthetic opportuni-
MS (CI, isobutane): m/z (%) = 373 (M+¥ + 1, 75), 341 (M+¥ Ð OCH3,
15), 271 (M+¥ + 1, Ð C6H13O, 21), 265 (M+¥, Ð C7H7O, 100).
ties for producing related compounds with potentially Anal. calcd for C23H36N2O2 (372.5): C 74.15, H 9.74, N 7.52; found
C 74.01, H 9.82, N 8.01.
higher biological activity than the natural product itself.
(2R,3S)-2-(Benzyloxy)-3-methylpent-4-enonitrile [(R,S)-8]
Solvents were dried and purified prior to use. THF was freshly dis-
tilled from K under Ar. CH2Cl2 was distilled from CaH2 and stored
under Ar. Et2O and pentane were distilled prior to use. Analytical
glass TLC plates (silica gel 60 F254) and silica gel (230Ð400 mesh)
were purchased from Merck, Darmstadt. Reagents and solvents of
commercial quality were used from freshly opened containers un-
less otherwise stated. Optical rotations were measured at 22¡C us-
ing a Perkin-Elmer P241 polarimeter using solvents of Merck
Uvasol quality. Microanalyses were obtained with a CHN-O-Rapid,
MMPP (1.45 g, 2.25 equiv) was added to a solution of hydrazone
(S,R,S)-7 (373 mg,1 mmol) in MeOH (20 mL) at 0¡C. The mixture
was stirred for 1 h at 0¡C and for 1 h at 25¡C, then poured into aq
NaHCO3 solution (20 mL) and extracted with Et2O (4 × 50 mL).
The Et2O extracts were combined, washed with brine (3 × 50 mL),
dried (MgSO4) and concentrated in vacuo (25¡C). Purification by
flash chromatography (silica gel: Et2O/pentane, 1:9) afforded
179 mg of a slightly yellow liquid of (R,S)-8 (89%); dssyn = 95%, ee
= 91%; [a]D + 82.19 (c = 1.40, CHCl3). It was possible to scale up
the reaction to 15 mmol of hydrazone (S,R,S)-7 without loss of se-
lectivity and yield.
1
Elementar Vario EL elemental analyser. H and 13C NMR spectra
were recorded on a Varian VXR 300, Gemini 300 (300 and 75
MHz), Unity 500 (500 and 125 MHz) using TMS as internal stan-
dard. IR spectra were recorded on a Perkin-Elmer FT/IR 1750 spec-
trophotometer. Mass spectra were obtained on a Varian MAT 212,
EI 70 eV. High resolution mass spectra were recorded on a Finnigan
MAT, MAT 95 spectrometer.
IR (neat): n = 3087 (=CH2), 3066, 3032, 2973, 2935, 2873, 2833,
2237 (CN), 1726, 1643 (C=C), 1497, 1455, 1421, 1397, 1377, 1340,
1208, 1183, 1090 (COC), 1027, 995 (COC), 962, 926, 881, 741
(Ar), 699 (Ar) cmÐ1.
1H NMR (300 MHz, CDCl3): d = 1.16 (d, 3 H, J = 6.9 Hz, CHCH3),
2.65 (m, 1 H, CHCH3), 3.99 (d, 1 H, J = 6.1 Hz, OCH), 4.54 (d, 1
H, J = 11.5 Hz, OHCH), 4.87 (d, 1 H, J = 11.6 Hz, OHCH), 5.20 (m,
2 H, =CH2), 5.84 (ddd, 1 H, J = 17.3, 10.4, 7.4 Hz, CH=), 7.36 (m,
5 H, C6H5).
Compounds 3 and (S,R,S)-6 were prepared according to literature
procedures.6
N-[(2R,3S)-2-(Benzyloxy)-3-methylpent-4-enylidene]-N-[(2'S)-
2-(1-ethyl-1-methoxypropyl)tetrahydro-1H-1-pyrrolyl]amine
[(S,R,S)-7]
13C NMR (75 MHz, CDCl3): d = 15.9 (CH3), 41.5 (CHCH3), 72.6
(CHO), 72.9 (CH2O), 117.8 (CN), 118.2 (CH2=), 128.7, 129.0,
129.2 1 (CHarom), 136.5 (Carom), 137.5 (=CH).
To a stirred solution of hydrazone (S,R,S)-6 (282 mg, 1 mmol) in an-
hyd THF (30 mL) at 0¡C under an atmosphere of Ar were added KH
(80 mg, 2 equiv). After 10 min 18-crown-6 (265 mg, 2 equiv) was
added, and stirred for additional 10 min. Benzyl bromide (206 mg,
2 equiv) was then added and the ice bath was removed. After stir-
ring for 2 h at 25¡C, the dark brown mixture was poured into aq
NH4Cl solution (5 mL) and extracted with Et2O (4 × 20 mL). The
Et2O extracts were combined, washed with brine (50 mL), dried
(MgSO4) and concentrated in vacuo. Purification by flash chroma-
tography (silica gel: Et2O/pentane, 1:9) afforded 357 mg of a slight-
ly yellow liquid of (S,R,S)-7 (97%); dssyn = 95%, de = 91%);
[a]D+52.59 (c = 0.72, CHCl3). It was possible to scale up the reac-
tion to 20 mmol of hydrazone (S,R,S)-6 without loss of selectivity
and yield.
MS (EI, 80¡C, 70 eV): m/z (%) = 201 (M+¥, 1), 172 (10), 91 (C7H7 ,
+
+
100), 65 (13), 55 (C4H7 , 31).
MS (CI, isobutane): m/z (%) = 259 (M+¥ + C4H10, 18), 258 (M+¥
+
C4H9, 100), 240 (4), 201 (M+¥, 2), 175 (M+¥ Ð CN, 13).
Anal. calcd for C13H15NO (201.3): C 77.50, H 7.51, N 6.59; found
C 77.58, H 7.63, N 6.69.
(2R,3S)-2-(Benzyloxy)-3-methylpent-4-enal [(R,S)-9]
To a solution of the nitrile (R,S)-8 (100 mg, 0.5 mmol) in pentane
(30 mL) at Ð78¡C was added DIBAL-H (1 M in hexane, 1 equiv)
under an Ar atmosphere. After stirring for 1 h MeOH (2 mL) was
added via a syringe and the mixture was allowed to warm to 0¡C.
After stirring additionally for 2 h, 1 N H2SO4 (2 mL) was added and
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246
D. Enders et al.
PAPER
the resulting mixture was stirred for a further 1 h. The mixture was
diluted with H2O (30 mL), extracted with Et2O (4 × 30 mL), and the
combined Et2O extracts were washed with brine (50 mL), dried
(MgSO4) and concentrated in vacuo (25¡C). Purification by flash
column chromatography (silica gel: Et2O/pentane, 1:9) afforded
87 mg of a colourless liquid of (R,S)-9 (85%); dssyn = 95%, ee =
91%; [a]D +23.17 (c = 0.77, CHCl3). It was possible to scale up the
reaction to 10 mmol of nitrile (R,S)-8 without loss of selectivity and
yield.
Et2O until TLC indicated complete conversion of the starting mate-
rial. The solution was dried (MgSO4) and concentrated in vacuo
which afforded 702 mg of a slightly yellow oil of (R,S)-11 (quant);
dssyn = 95%, ee = 91%; [a]D + 51.27 (c = 0.55, CHCl3).
IR (neat): n = 3067 (=CH2), 3031, 2978, 2978, 2952, 2934, 2873,
1751 (C=O), 1641 (C=C), 1497, 1455, 1435, 1398, 1351, 1313,
1268, 1203, 1164, 1136, 1098 (COC), 1061, 1028, 997 (COC), 919,
739 (Ar), 699 (m, Ar) cmÐ1.
1H NMR (300 MHz, CDCl3): d = 1.09 (d, 3 H, J = 6.9 Hz, CHCH3),
2.66 (m, 1 H, CHCH3), 3.38 (s, 3 H, OCH3), 3.82 (d, 1 H, J = 6.0
Hz, OCH), 4.41 (d, 1 H, J = 11.8 Hz, OHCH), 4.68 (d, 1 H, J = 11.8
Hz, OHCH), 5.05 (m, 2 H, =CH2), 5.76 (ddd, 1 H, J = 17.3, 10.4,
8.0 Hz, CH=), 7.35 (m, 5 H, C6H5).
IR (neat): n = 3066 (=CH2), 3032, 2970, 2931, 2871, 1732 (C=O),
1640 (C=C), 1497, 1455, 1421, 1376, 1343, 1208, 1092 (COC),
1028, 998 (COC), 919, 737 (Ar), 699 (Ar) cmÐ1.
1H NMR (300 MHz, CDCl3): d = 1.12 (d, 3 H, J = 6.9 Hz, CHCH3),
2.69 (m, 1 H, CHCH3), 3.62 (dd, 1 H, J = 5.5, 2.5 Hz, OCH), 4.53
(d, 1 H, J = 11.8 Hz, OHCH), 4.67 (d, 1 H, J = 11.8 Hz, OHCH),
5.07 (m, 2 H, =CH2), 5.84 (ddd, 1 H, J = 17.6, 10.4, 7.7 Hz, CH=),
7.35 (m, 5 H, C6H5), 9.62 (d, 1 H, J = 2.7 Hz, CHO).
13C NMR (75 MHz, CDCl3): d = 15.4 (CH3), 41.3 (CHCH3), 51.6
(OCH3), 72.5 (OCH2), 82.2 (CHO), 115.4 (CH2=), 127.8, 127.9,
128.3 (CHarom), 137.4 (Carom), 139.2 (=CH), 172.4 (CO2CH3).
+
MS (EI, 60¡C, 70 eV): m/z (%) = 128 (13), 112 (9), 91 (C7H7 , 100),
13C NMR (75 MHz, CDCl3): d = 15.5 (CH3), 40.0 (CHCH3), 73.4
(OCH2), 87.0 (CHO), 116.5 (CH2=), 128.5, 128.6, 129.0 (CHarom),
137.9 (Carom), 139.3 (=CH), 204.1 (C=O).
+
65 (11), 55 (C4H7 , 5).
MS (CI, isobutane): m/z (%) = 235 (M+¥ + 1, 100), 217 (M+¥ + 1,
ÐH2O, 30), 175 (M+¥, ÐCO2CH3, 42), 157 (5), 128 (6).
MS (EI, 80¡C, 70 eV): m/z (%) = 175 (M+¥ Ð CHO, 5), 147 (4), 91
+
+
(C7H7 , 100), 65 (12), 55 (C4H7 , 4).
Anal. calcd for C14H18O3 (234.3): C 71.77, H 7.74; found C 71.82,
H 8.08.
MS (CI, isobutane): m/z (%) = 205 (M+¥ + 1, 18), 187 (M+¥ + 1, Ð
H2O, 84), 175 (M+¥ Ð CHO, 51), 159 (24), 147 (53), 129 (16), 117
(24), 101 (12), 91 (22).
Methyl (2R,3S)-2-(Benzyloxy)-3-methyl-4-oxopentanoate
[(R,S)-12]
Anal. calcd for C13H16O2 (204.3): C 76.45, H 7.90; found C 76.42,
H 7.93.
A suspension of 10 mol% PdCl2 (23 mg) and CuCl (190 mg,
1 equiv) in (5 mL) water and acetone (30 mL) containing the ester
(R,S)-11 (702 mg, 3 mmol) was stirred under an atmosphere of ox-
ygen at 5 bar at 70¡C for 4 h. The mixture was allowed to cool to
r.t., Et2O/H2O (200 mL, 1:1) were added and extracted with Et2O
(3 × 100 mL). The Et2O extracts were combined, washed with brine
(2 × 50 mL), dried (MgSO4) and concentrated in vacuo. Purification
by flash chromatography (silica gel: Et2O/pentane, 1:2) afforded
578 mg of a brown liquid of (R,S)-12 (77%); dssyn = 95%, ee = 91%;
[a]D + 67.01 (c = 0.59, CHCl3).
(2R,3S)-2-(Benzyloxy)-3-methylpent-4-enoic acid [(R,S)-10]
To a vigorously stirred solution of the aldehyde (R,S)-9 (204 mg,
1 mmol) in DMF at 25¡C (25 mL) were added PDC (2.26 g,
6 equiv). The orange-brown solution was stirred overnight and di-
luted with H2O (50 mL). The mixture was acidified with 6 N HCl to
pH 1 and extracted with Et2O (4 × 30 mL). The Et2O extracts were
combined, washed with brine (2 × 50 mL), dried (MgSO4) and con-
centrated in vacuo. Purification by flash chromatography (silica gel,
Et2O) afforded 202 mg of a brown-yellow oil of (R,S)-10 (92%);
dssyn = 95%, ee = 91%; [a]D + 37.60 (c = 0.67, CHCl3). It is possible
to scale up the reaction to 8 mmol of aldehyde (R,S)-9 without loss
of selectivity and yield.
IR (neat): n = 3064, 3031, 2975, 2952, 2879, 1750 (C=O), 1719
(C=O), 1497, 1455, 1436, 1399, 1381, 1357, 1270, 1207, 1171,
1143, 1109 (COC), 1075, 1028, 1016 (COC), 741 (Ar),
700 (Ar) cmÐ1.
1H NMR (300 MHz, CDCl3): d = 1.19 (d, 3 H, J = 7.4 Hz, CHCH3),
2.13 (s, 3 H, CCH3), 2.99 (m, 1 H, CHCH3), 3.76 (s, 3 H, OCH3),
4.33 (d, 1 H, J = 5.4 Hz, OCH), 4.46 (d, 1 H, J = 11.4 Hz, OHCH),
4.77 (d, 1 H, J = 11.4 Hz, OHCH), 7.35 (m, 5 H, C6H5).
IR (neat): n = 3400 (OH), 3066 (=CH2), 3032, 2977, 2933, 2875,
1719 (C=O), 1642 (C=C), 1497, 1455, 1421, 1384, 1338, 1209,
1128, 1097 (COC), 1060, 1029, 996 (COC), 919, 737 (Ar),
698 (Ar) cmÐ1.
13C NMR (75 MHz, CDCl3): d = 11.7 (CH3), 28.5 (CH3C), 49.5
(CHCH3), 52.1 (OCH3), 73.1 (OCH2), 78.4 (CHO), 128.0, 128.2,
128.4 (CHarom), 137.1 (Carom), 172.0 (CO2CH3), 208.9 (CH3C).
1H NMR (300 MHz, CDCl3): d = 1.11 (d, 3 H, J = 6.9 Hz, CHCH3),
2.74 (m, 1 H, CHCH3), 3.90 (d, 1 H, J = 5.0 Hz, OCH), 4.47 (d, 1
H, J = 11.5 Hz, OHCH), 4.74 (d, 1 H, J = 11.5 Hz, OHCH), 5.10 (m,
2 H, =CH2), 5.84 (ddd, 1 H, J = 17.6, 10.4, 7.7 Hz, CH=), 7.35 (m,
5 H, C6H5), 9.76 (br s, 1 H, CO2H).
MS (EI, 60¡C, 70 eV): m/z (%) = 144 (M+¥ + 1, Ð C7H7O, 13), 101
+
(34), 91 (C7H7 , 100), 65 (12).
13C NMR (75 MHz, CDCl3): d = 15.4 (CH3), 41.5 (CHCH3), 73.5
(OCH2), 82.1 (CHO), 116.3 (CH2=), 128.6, 128.7, 129.0 (CHarom),
137.6 (Carom), 139.7 (=CH), 177.5 (CO2H).
MS (CI, isobutane): m/z (%) = 251 (M+¥ + 1, 100), 143 (M+¥,
ÐC7H7O, 21).
Anal. calcd for C14H18O4 (250.3): C 67.19, H 7.25; found C 67.63,
H 7.62.
+
MS (EI, 80¡C, 70 eV): m/z (%) = 114 (4), 107 (11), 91 (C7H7 , 100),
+
65 (14), 55 (C4H7 , 7).
MS (CI, isobutane): m/z (%) = 221 (M+¥ + 1, 100), 203 (M+¥ + 1,
ÐH2O, 22), 175 (M+¥, Ð CO2H, 62), 107 (C7H7O+, 60).
Methyl (2R,3S,4R)-2-(Benzyloxy)-4-hydroxy-3-methylpen-
tanoate [(R,S,R)-13]
To a solution of the ketone (R,S)-12 (375 mg, 1.5 mmol) in Et2O
(30 mL) at 25¡C under an atmosphere of Ar, were added LiI
(1.99 g, 10 equiv). After stirring for 5 min at Ð40¡C the mixture was
cooled to Ð100¡C and LiBH4 (217 mg, 10 equiv) was added. The
mixture was stirred for an additional 2 h at Ð100¡C and then hydrol-
ysed by addition of H2O (10 mL) and AcOH (10 mL, 25%). After
stirring for 30 min, Et2O (100 mL) was added and the aqueous phase
Anal. calcd for C13H16O3 (220.3): C 70.89, H 7.32; found C 70.33,
H 7.60.
Methyl-(2R,3S)-2-(Benzyloxy)-3-methylpent-4-enoate [(R,S)-11]
To a colorless stirred solution of the acid (R,S)-10 (660 mg, 3 mmol)
in Et2O (100 mL) at 25¡C was added a solution of diazomethane in
Synthesis 1999, No. 2, 243–248 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereo- and Enantioselective Formal Synthesis of (+)-Conagenin
247
extracted with Et2O (3 × 30 mL). The Et2O extracts were combined,
washed with aq NaHCO3 soln (2 × 50 mL) and pH 7 buffer (2 ×
50 mL), dried (MgSO4) and concentrated in vacuo. Purification by
flash chromatography (silica gel, Et2O/pentane, 1:2) afforded 272 mg
of (R,S,R)-13 (72%) and 25 mg of (R,S,R)-14 (10%) as colorless liq-
uids (induction = 93 % syn); dssyn = 88%, ee = 91%; [a]D + 66.38 (c
= 0.47, CHCl3).
(3R,4S,5R)-3-Benzyloxy-4,5-dimethyltetrahydrofuran-2-one
[(R,S,R)-14]
The lactone (R,S,R)-14 derived from (R,S,R)-13 by basic reaction
and workup conditions was separated from (R,S,R)-13 by column
chromatography (vide supra); (induction = 93% syn); dssyn = 88%,
ee = 91%; [a]D + 111.36 (c = 0.40, CHCl3).
IR (CHCl3): n = 3064, 3031, 2975, 2933, 2878, 1781 (C=O), 1497,
1455, 1387, 1354, 1327, 1240, 1191, 1162, 1135 (COC), 1050,
1030, 1002, 986, 957, 917, 742 (Ar), 698 (Ar) cmÐ1.
1H NMR (300 MHz, CDCl3): d = 1.10 (d, 3 H, J = 6.7 Hz, CHCH3),
1.39 (d, 3 H, J = 6.4 Hz, OCHCH3), 2.12 (m, 1 H, CHCH3), 3.82 (d,
1 H, J = 10.0 Hz, CHOPh), 4.00 (m, 1 H, OCOCH), 4.77 (d, 1 H, J
= 12.1 Hz, OHCH), 4.89 (d, 1 H, J = 12.1 Hz, OHCH), 7.36 (m, 5
H, C6H5).
13C NMR (75 MHz, CDCl3): d = 13.7 (CH3CHCHOBn), 18.1
(CH3CHO), 44.7 (CH3CHCHOBn), 72.1 (OCH2), 78.7 (CH3CHO),
79.6 (CHCHOBn), 128.0, 128.2, 128.4 (CHarom), 137.2 (Carom),
175.0 (C=O).
IR (CHCl3): n = 3427 (OH), 3088, 3064, 3031, 2973, 2951, 2936,
2880, 1748 (C=O), 1497, 1454, 1436, 1400, 1385, 1330, 1271,
1208, 1135 (COC), 1066, 1026 (COC), 911, 739 (Ar), 699 (Ar) cmÐ1.
1H NMR (300 MHz, CDCl3): d = 0.97 (d, 3 H, J = 7.1 Hz, CHCH3),
1.14 (d, 3 H, J = 6.4 Hz, OCHCH3), 1.93 (m, 1 H, CHCH3), 2.74 (br
s, 1 H, OH), 3.77 (s, 3 H, OCH3), 3.97 (m, 1 H, OCHCH3), 4.14 (d,
1 H, J = 3.7 Hz, OCHCO), 4.36 (d, 1 H, J = 11.1 Hz, OHCH), 4.77
(d, 1 H, J = 11.1 Hz, OHCH), 7.34 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 7.4 (CH3CHCHOC=O), 20.7
(CH3CHOH), 41.9 (CHCHOC=O), 51.8 (OCH3), 69.7 (CHOH),
72.7 (OCH2), 81.6 (CHOCH2), 128.2, 128.5, 128.5 (CHarom), 136.9
(Carom), 172.2 (CO2CH3).
MS (EI, 40¡C, 70 eV): m/z (%) = 221 (M+¥ + 1, 0.7), 99 (50), 91
MS (EI, 80¡C, 70 eV): m/z (%) = 146 (M+¥+1, Ð C7H7O, 7), 114
(C7H7 , 100), 65 (25).
+
+
(21), 91 (C7H7 , 100), 65 (12).
MS (CI, isobutane): m/z (%) = 221 (M+¥ + 1, 100), 131 (M+¥ + 1,
MS (CI, isobutane): m/z (%) = 253 (M+¥ + 1, 100), 221 (M+¥, ÐCH3O,
ÐC7H7, 4), 114 (M+¥ ÐC7H7O, 2).
48).
Anal. calcd for C13H16O3 (220.25): C 70.89, H 7.32; found C 70.78,
H 7.33.
Anal. calcd for C14H20O4 (252.3): C 66.65, H 7.99; found C 66.22,
H 7.95.
Acknowledgement
(2R,3S,4R)-2,4-Dibenzyloxy-3-methylpentanoic acid [(R,S,R)-
15]
a) Lewis Acid Catalyzed Benzylation:
This work was supported by the Deutsche Forschungsgemein-
schaft (Leibniz award) and the Fonds der Chemischen Industrie.
We thank Degussa AG, Bayer AG, BASF AG, and Hoechst AG for
providing us with chemicals.
To a stirred solution of the ester (R,S,R)-13 (100 mg, 0.4 mmol) and
O-benzyltrichloroacetimidate (2 equiv) in cyclohexane (15 mL) at
¥
25¡C, was added a catalytical amount of BF3 OEt2. After stirring
for 30 min pentane (10 mL) was added and the separated
trichloroacetamide was removed by filtration. The aqueous phase
was extracted with pentane (100 mL), the combined organic phases
were washed with brine (10 mL) and dried (MgSO4). The solvent
was removed in vacuo and the crude product, containing O-benzyl-
trichloroacetimidate, was used directly in the next step.
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Synthesis 1999, No. 2, 243–248 ISSN 0039-7881 © Thieme Stuttgart · New York