Synthesis and absolute stereochemistry of the acyl moiety of quillajasaponins

Article abstract of DOI:10.1016/S0040-4039(99)02124-3

The acyl moiety of the quillajasaponins, one of the most important immunological adjuvants, was determined to be 3-(S), 5-(S)-dihydroxy-6-(S)- methyl-octanoic acid by enantioselective synthesis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02124-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 717–719
Synthesis and absolute stereochemistry of the acyl moiety of
quillajasaponins
a
a,∗
a,∗
b,∗
b
Xiangming Zhu, Biao Yu, Yongzheng Hui, Ryuichi Higuchi, Takanori Kusano and
Tomofumi Miyamoto b
a
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Faculty of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
b
Received 21 June 1999; revised 2 November 1999; accepted 10 November 1999
Abstract
The acyl moiety of the quillajasaponins, one of the most important immunological adjuvants, was determined to
be 3-(S), 5-(S)-dihydroxy-6-(S)-methyl-octanoic acid by enantioselective synthesis. © 2000 Elsevier Science Ltd.
All rights reserved.
Quillajasaponins, the saponins from the Quillaja saponaria Molina (Rosaceae), have historically been
used as commercial saponins, as well as foaming agents, in beverages, confectioneries, baked goods,
dairy desserts, cosmetics, etc. Recently, tremendous attention has been given to the quillajasaponins due
to the discovery that they are potent immunological adjuvants and are unique constituents in immuno-
1
stimulating complexes (ISCOM); ISCOM provides an effective means of presenting antigens to the
1
a
immune system and are being used to prepare vaccines for influenza, hepatitis B, and AIDS. However,
2
the number of quillajasaponins most likely exceeds 100. One of the essential structural features of the
quillajasaponins is attachment of an acyl moiety which is also important to the adjuvant activities of the
2
quillajasaponins. A C acid was obtained after mild alkaline hydrolysis of quillajasaponins and it was
9
readily converted into a δ lactone upon silica gel column chromatography. The chemical structure of the
3
resulting lactone has been determined to be compound 1 (Fig. 1) by spectroscopic methods, however,
its stereochemistry has not been established.
The H NMR signals ascribable to 2-, 3-, 4-, and 5-H having large J values (8–12 Hz) were observed,3
1
that indicated the existence of the trans diaxial relationships between 2-H and 3-H, 3-H and 4-H, and
4-H and 5-H, respectively. Therefore, the relative stereochemistries at C-3 and C-5 of 1 were suggested
to be as shown in Fig. 1. The absolute configurations of C-3 and C-5 were determined by application
4
of the modified Mosher method. The (+)-MTPA and (−)-MTPA esters of 1 (2 and 2 , respectively)
R
S
were prepared. The positive and negative ∆δ values were found on the right and left sides of the MTPA
∗
Corresponding authors.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02124-3
tetl 16052

7
18
Fig. 1.
planes, respectively, indicating S configuration for C-3. Accordingly, the absolute configuration of C-
was determined as S (Fig. 1). The stereochemistry at C-6 could not be established by spectroscopic
5
methods, and therefore two diastereoisomers, 12(6R) and 12(6S), were synthesized enantioselectively
and compared to the natural compound (Scheme 1).
i
Scheme 1. Reagents and conditions: (a) L-(+)-DET, Ti(O Pr)
4
, TBHP, 4 Å MS, CH
2
Cl
2
, −20°C, overnight; (b) Red-Al,
THF, −20°C, 3 h, 91%; (c) Me
2
C(OMe)
2
, p-TsOH, 100%; (d) H
2
, Pd/C, EtOH, rt, 4 h, 99%; (e) Swern [O], 98%; (f)
(
R,R)-diisopropyltartrate-(Z)-(−)-crotylboronate, 4 Å MS, toluene, 73%; (f) (R,R)-diisopropyltartrate-(E)-(−)-crotylboronate,
4
Å MS, toluene, 69%; (g) PivCl, Py; (h) H
2
, Pd/C, EtOH, rt, 5 h; (i) AcOH:H
2
O (4:1), 73% (3 steps); (j) PivCl, Py, CH
2
Cl
2
,
9
5%; (k) TESOTf, Et N, CH Cl , 0°C; (l) DIBAL-H, CH
3
2
2
2
Cl
2
, −78°C, 82% (2 steps); (m) NMO, RuCl
(PPh ) , acetone, 74%;
2 3 3
(n) TBAF, THF, 88%
5
The allylic alcohol 4, prepared from 1,3-propanediol, was converted into (2R,3S)-epoxide 5 under
6
Sharpless conditions in >94% ee and 93% yield. Regioselective opening of the epoxide 5 with Red-Al
7
provided the 3,5-diol 6 in 91% yield, which was then readily converted into aldehyde 7 in three steps in
98% overall yields, i.e. protection of the diol with an isopropylidene group; removal of the 1-O-benzyl
protection; and Swern oxidation. Asymmetric crotylation of aldehyde 7 with (R,R)-diisopropyltartrate-
8
(
(
Z)-(−)-crotylboronate (Roush conditions) provided the (5S,6S)-homoallylic alcohol 8(6S) in good yield
9
73%). Alternatively, crotylation of 7 with (R,R)-diisopropyltartrate-(E)-(−)-crotylboronate gave the
9
corresponding (5S,6R)-homoallylic alcohol 8(6R) in 69% yield. Protection of the 5-OH of 8(6S) with
a pivaloyl group followed by hydrogenation of the double bond and removal of the isopropylidene
protection produced the 1,3-diol 9 in 73% yields. Diol 9 was then subjected to PivCl and TESOTf,
respectively, followed by removal of the two pivaloyl groups with DIBAL-H, to provide 1,5-diol 11 in
10,11
high yields. Regioselective oxidation of diol 11 in the presence of NMO and RuCl (PPh ) ,
after
2
3 3
desilylation, furnished the desired lactones 12(6S) in satisfactory yields. The same procedure was then
readily applied to convert 8(6R) into 12(6R).

7
19
2
0
The optical rotation of the synthetic lactone 12(6S) ([α]
+38.2, c 1.07, MeOH) is closer to that of
+39.5, c 1.15, MeOH) than the corresponding value of the synthetic 12(6R)
+34.7, c 1.32, MeOH), however this evidence is not conclusive. Fortunately, differences between
the H NMR spectra of 12(6S) and 12(6R) are clearly observable, with the former being completely
D
2
0
the natural sample ([α]
D
2
0
(
[α]
D
1
1
2,13
overlapped with that of the authentic sample.
These results were further confirmed by taking NMR
spectra of mixed samples of 12(6S) and 12(6R) with the natural sample, respectively. Therefore, the
natural lactone was unambiguously assigned to be 12(6S).14 Accordingly, the C acyl moiety existing in
9
the quillajasaponins is determined to be the 3-(S), 5-(S)-dihydroxy-6-(S)-methyl-octanoic acid.
Acknowledgements
This work is supported by the State Science and Technology Committee of China.
References
1
. (a) Morein, B. Nature 1988, 332, 287. (b) Rouhi, A. M. C&EN 1995, September 11, 28. (c) Livingston, P. O.; Ragupathi, G.
Cancer Immunol. Immunother. 1997, 45, 10. (d) Sjölander, A.; Cox, J. C. Advanced Drug Delivery Review 1998, 34, 321.
. (a) Kensil, C. R.; Soltysik, S.; Wheeler, D. A.; Wu, J. Y. In Saponins Used in Traditional and Modern Medicine; Waller,
G. R.; Yamasaki, K., Eds.; Plenum Press: New York and London, 1995; p.165. (b) van Settern, D. C.; van de Werken, G.
In Saponins Used in Traditional and Modern Medicine; Waller, G. R.; Yamasaki, K., Eds.; Plenum Press: New York and
London, 1995; p.185.
2
3
4
5
6
7
8
. Higuchi, R.; Komori, T. Phytochemistry 1987, 26, 2357.
. Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawa, H. Tetrahedron Lett. 1988, 29, 4731.
. Oka, T.; Murai, A. Tetrahedron 1998, 54, 1.
. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
. Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Viti, S. M. J. Org. Chem. 1982, 47, 1378.
. (a) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339. (b)
Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348.
9
. Here we assumed that the stereochemistries at C-5 and C-6 of the resulting homoallylic alcohol (8) were controlled by Roush
reagents based on mechanistic grounds, regardless of the β-chirality occurring in the aldehyde substrate (7).
8
1
1
0. Sharpless, K. B.; Akashi, K.; Oshima, K. Tetrahedron Lett. 1976, 29, 2503.
1. Oxidation of 6-methyl-1,3,5-octanetriol, prepared from 8(6S), in the presence of NMO and RuCl
the desired δ lactone 12(6S).
2
3 3
(PPh )
,10 did not lead to
20
1
12. Compound 12(6S): [α]
D
+38.2 (c 1.07, MeOH); H NMR (300 MHz, CDCl
3
): 4.22 (1H, m, H-3), 4.11 (1H, ddd, J=12.1,
3
.0, 4.1 Hz, H-5), 2.90 (1H, ddd, J=17.0, 5.9, 1.2 Hz, H-2eq), 2.42 (1H, dd, J=17.0, 8.1 Hz, H-2ax), 2.15 (1H, m, H-4eq),
0
13
1
.50–1.72 (3H, m, H-6, H-4ax, H-7), 1.26 (1H, m, H-7 ), 0.95 (3H, d, J=6.9 Hz), 0.92 (3H, t, J=7.4 Hz); C NMR (CDCl
3
):
1
70.87, 80.33, 64.15, 39.66, 38.78, 34.88, 24.85, 13.86, 11.52; HRMS (m/z): calcd for C : 172.1100, found: 172.1102.
9 16 3
H O
20
1
Compound 12(6R): [α]
D
+34.7 (c 1.32, MeOH); H NMR (300 MHz, CDCl
3
): 4.25 (1H, m, H-3), 4.10 (1H, ddd, J=12.0,
5
.7, 2.9 Hz, H-5), 2.92 (1H, ddd, J=17.1, 5.9, 1.4 Hz, H-2eq), 2.45 (1H, dd, J=17.1, 8.2 Hz, H-2ax), 2.19 (1H, m, H-4eq), 1.78
0
13
(1H, m, H-7), 1.52–1.68 (2H, m, H-6, H-4ax), 1.26 (1H, m, H-7 ), 0.93 (6H, m); C NMR (CDCl
3
): 171.60, 80.95, 64.87,
3
9 16 3
9.62, 38.74, 33.90, 24.74, 14.01, 11.41; HRMS (m/z): calcd for C H O : 172.1100, found: 172.1120.
1
1
1
3. In the H NMR spectra of 12(6S) and 12(6R), the differences between the signals for the protons adjacent to the stereogenic
center C-6 are observable: (i) the signal for H-5 of 12(6S) shows ddd peak with J=3.0, 4.1, 12.1 Hz, while that for 12(6R)
shows ddd peak with J=2.9, 5.7, 12.0 Hz; (ii) the signal for one of the H-7 of 12(6S) appears at 1.57 ppm, while that for
1
2(6R) moves downfield to 1.78 ppm.
4. The stereochemistry at C-5 (S) of 12, generated by Roush crotylation, was consistent with that established by the
spectroscopic methods. This result confirmed the previous assumed stereochemistry produced by Roush crotylation.
8
,9