Total synthesis of beauveriolide I

Article abstract of DOI:10.1016/j.tetlet.2005.09.188

The first total synthesis of beauveriolide I (1a), a selective ACAT inhibitor, is described. The key steps in this synthesis involved a diastereoselective aldol condensation sequence and a macrocyclization.

Full text of DOI:10.1016/j.tetlet.2005.09.188

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 8579–8581
Total synthesis of beauveriolide I
Hua Tian, Xiaozhen Jiao, Ping Xie* and Xiaotian Liang
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Received 18 July 2005; revised 29 September 2005; accepted 30 September 2005
Available online 14 October 2005
Abstract—The first total synthesis of beauveriolide I (1a), a selective ACAT inhibitor, is described. The key steps in this synthesis
involved a diastereoselective aldol condensation sequence and a macrocyclization.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Beauveriolide I (1a) was first isolated in 1975 from the
mycelium of the strain Beauveria sp.1 Itsstructure was
elucidated as cyclo-[(3S,4S)-3-hydroxy-4-methyl-octa-
ase (ACAT) activity specifically, resulting in the
blockage of cholesterol ester (CE) synthesis, leading to
a reduction of lipid dropletsin macrophages.
5
noyl-L-phenylalanyl]-D-leu-Cine,
a member of the
cyclodepsipeptide family,2 by spectral analyses and
chemical degradation.
Intrigued by beauveriolidesÕ bioactivity and interested in
their SAR studies, we began the synthetic study and
achieved the first total synthesis of beauveriolide I
Recent studies show beauveriolide I (1a) and III (1b) can
cause a reduction in both number and size of cytosolic
lipid dropletsin macrophageswithout any cytotoxic
effect on macrophages.3,4 Among these beauveriolides,
beauveriolide I (1a) and III (1b) are the most potent
inhibitorsof lipid dropletsformation in mouse macro-
phages. They inhibit Acyl-CoA: cholesterol acyltransfer-
(1a). The retrosynthetic analysisisshown in
Figure 1.
Asthe macrocyclization can be achieved by either
amide bond or ester bond formation, the major
endeavor isthe ysntheissof the fragment
3-hydroxy-4-methyloctanic acid], which isa common
intermediate in beauveriolide I (1a), III (1b) and other
beauveriolides.6
2 [(3S,4S)-
Diastereoselective aldol condensation has been utilized
for the synthesis of compound (2). Reaction of 3-benzyl-
oxypropionaldehyde7 and chiral imide (5)8 under Crim-
minsÕ condition9 furnished syn aldol (6a)10 in excellent
yield and diastereoselectivity. Installation of TBDMS
protecting group followed by reduction with LiBH4 gave
alcohol (7)11. Alcohol (7) wasoxidized under Swern
1a, Beauveriolide I
R=
O
O
O
R
NH
HN
O
1b, Beauveriolide III R=
N
H
O
OTBDMS
OTBDMS
O
OH
BnO
O
BnO
HO
+
Beauveriolide I
1a
4
2
3
L-Phe-L-Alal-D-Leu
Figure 1. Retrosynthetic analysis of beauveriolide I.
Keywords: ACAT inhibitor; Beauveriolide I; Total synthesis.
*
Corresponding author. Tel.: +86 10 63165245; fax: +86 10 63017757; e-mail: pingxie123@vip.sohu.net
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.188

8580
H. Tian et al. / Tetrahedron Letters 46 (2005) 8579–8581
R
O
O
O
OTBDMS
R
O
O
a
c
e
BnO
BnO
N
N
O
O
Bn
Bn
7 R=CH2OH
4 R=CHO
6a R=H
6b R=TBDMS
d
5
b
OTBDMS
OTBDMS
O
OTBDMS
f
g
HO
BnO
HO
9a
3
8
Scheme 1. Reagentsand condition:s (a) 3-benzyloxypropionaldehyde, TiCl 4, DIPEA, NMP, CH2Cl2, ꢀ5 ꢁC to rt, 3.5 h, 97%; (b) TBDMSCl,
imidazole, DMF, rt, 30 h, 79%; (c) 2 M LiBH4, H2O, Et2O, 0 ꢁC to rt, 73%; (d) 1. (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC, 2. NEt3, ꢀ78 ꢁC to rt, 90%; (e)
[Ph3PCH2CH2CH3]Br, 1.6 M n-BuLi, THF, rt, 2 h, 91%; (f) H2, 10% Pd–C, EtOH, rt, 82%; (g) NaIO4, RuCl3(cat.), CCl4/CH3CN/H2O (v/v/v = 2/2/3),
rt, 2 h, 78%.
O
O
O
O
O
O
OTBDMS
R1
O
d
a
NH
OR2
HO
NH
HN
O
HN
O
N
N
H
O
H
O
10a R1=TBDMS, R2=Bn
10b R1=TBDMS, R2=H
10c R1=H, R2=H
9a
b
c
1a
Scheme 2. Reagentsand conditions: (a) L-Phe-L-Ala-D-Leu-OBn, DCC, CH2Cl2, 0 ꢁC to rt, 6 h; (b) H2, 10% Pd–C, THF; (c) HOAc, heating; (d) 2-
methyl-6-nitrobenzoic anhydride, DMAP, toluene.
R1
O
O
O
O
e
O
c
R2
O
O
R2
HN
R1
9a R1=TBDMS, R2=H
a
b
=4-nitrobenzyl
9b R1=TBDMS, R2=4-nitrobenzyl
9c R1=H, R2=4-nitrobenzyl
11a R1=Boc, R2
d
11b R =H.HC
l, R2=4-nitrobenzyl
1
O
O
O
O
R2
O
O
O
g
R
1 NH
NH
HN
O
HN
O
N
N
H
H
O
O
12a R1=Cbz, R2=4-nitrobenzyl
12b R1=H, R2=H
f
1a, Beauveriolide I
Scheme 3. Reagentsand conditions: (a) 4-nitrobenzyl bromide, DIPEA, DMF, rt, 7 h, 66%; (b) 65–75% HF-Py, THF, rt, 20 h, 70%; (c) DCC,
DMAP(cat.), CH2Cl2, rt; (d) HCl/EtOAc, 4 h, 0 ꢁC to rt; (e) N-Cbz-L-Phe-L-Ala, EDCI, DIPEA, HOSu(cat.), DMF, 0 ꢁC to rt; (f) H2, 10% Pd–C,
THF/isopropanol (v/v = 1/2.5), rt; (g) BOP, DMAP, CH3CN, rt, 68%.

H. Tian et al. / Tetrahedron Letters 46 (2005) 8579–8581
8581
condition,12 and the resulting aldehyde (4) wasallowed
to react with propyltriphenylphosphonium bromide in
the presence of n-BuLi to afford the corresponding
olefinic isomers (3). Hydrogenation of the olefinic bond
and removal of the benzyl protecting group were accom-
plished in one step over a catalytic amount of 10% Pd/C.
7. Davis, F. A.; Qi, H.; Sundarababu, G. Tetrahedron 2000,
56, 5303–5310.
8. James, R. G.; David, A. E. Org. Synth. Coll. 1993, Vol. 8,
339.
9. Crimmins, M. T.; She, J. Synlett 2004, 8, 1371–1374.
25
10. Analytical data of compound 6a: pale-yellow oil, ½aꢁD
ꢀ44.3 (c 0.3, CHCl3). IR (film): 1778, 1695, 1387, 1209,
13
1109 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.24–1.28
.
Oxidation with NaIO4 in the presence of RuCl3 gave
the desired acid (9a) in 89% yield (Scheme 1).
(m, 2H), 1.29 (d, 3H, J = 4.5 Hz), 1.71–1.79 (m, 1H),
1.83–1.93 (m, 1H), 2.77 (dd, 1H, J = 13.2, 9.6 Hz), 3.25
(dd, 1H, J = 13.2, 3.3 Hz), 3.62–3.70 (m, 2H), 3.78–3.86
(m, 1H), 4.09–4.22 (complex, 3H), 4.52 (s, 2H), 4.64–4.72
(m, 1H), 7.19–7.38 (complex, 10H). FABMS: 398
(M+H+), HR-FABMS: calcd for C23H28NO5: (M+H+),
398.1967, found: 398.1979.
With the acid (9a) in hand, we tried to perform the mac-
rocyclization by ester bond formation as shown in
Scheme 2, where the suitably protected liner precursor
10a wasysntheiszed by coupling
9a with L-Phe-L-Ala-
D-Leu-OBn in the presence of DCC and DMPA, fol-
lowed by hydrolysis to remove the TBDMS group.
However, unfortunately, the desired compound 1a could
25
11. Analytical data of compound 7: ½aꢁD ꢀ8.5 (c 1.3, CHCl3).
1H NMR (500 MHz, CDCl3): d 0.054 (s, 3H), 0.096
(s, 3H), 0.81 (d, 3H, J = 7 Hz), 0.88 (s, 9H), 1.78–1.84
(m, 2H), 1.98 (br, 1H), 3.50–3.56 (m, 3H), 3.69 (t, 1H,
J = 9.5 Hz), 3.71–3.96 (m, 1H), 4.49 (q, 2H, J = 11.5 Hz),
7.26–7.36 (complex, 5H). 13C NMR (125 MHz, CDCl3) d
ꢀ4.8, ꢀ4.5, 12.4, 17.9, 25.8, 32.2, 39.9, 65.8, 67.1, 72.8,
73.0, 127.6, 127.7, 128.4, 138.4.
14
not be obtained under variousconditions.
We therefore selected the macrocyclization through
amide bond formation. The synthetic sequence of com-
pound 12a wasshown in Scheme 3. Protection of 9a using
4-nitrobenzyl bromide in the presence of DIPEA in DMF
yielded ester 9b. Removal of the TBDMS protecting
group by treating with HF-pyridine afforded compound
9c,15 which wascoupled with N-Boc-D-Leu16 by using
DCC and catalytic amount of DMAP to give diester
(11a). After removing the Boc group the corresponding
protected tetradepsipeptide (12a) could be obtained by
coupling with the N-Cbz-L-Phe-L-Ala17 by using EDCI
in the catalysis of HOSu. Subsequent reductive removal
of the 4-nitrobenzyl group and the Cbz group gave the
deprotected tetradepsipeptide (12b). The macrocycliza-
tion was performed successfully using BOP in acetonitrile
under highly dilute conditions(5.3 · 10ꢀ3 mol/L)18 to
furnish beauveriolide I (1a)19 in 68% yield. The structure
of the product (1a) wasconfirmed by NMR and mas
analysis for its structural data and rotation value match-
ing well with the natural product.2,20
12. Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
13. Ashby, E. C.; Goel, A. B. J. Org. Chem. 1981, 46, 3936–
3938.
14. Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J.
Org. Chem. 2004, 69, 1822–1830.
15. Analytical data of compound 9c: pale-yellow oil, 1H
NMR (400 MHz, CDCl3): d 0.89 (t, 3H, J = 6.4 Hz), 0.92
(d, 3H, J = 6.4 Hz), 1.11–1.54 (m, 7H), 2.13 (br, 1H),
2.51–2.57 (complex, 2H), 3.98 (dt, 1H, J = 4.4, 8.4 Hz),
5.25 (s, 2H), 7.52 (d, 2H, J = 8.4 Hz), 8.23 (d, 2H,
J = 8.4 Hz). 13C NMR (100 MHz, CDCl3) d 14.0, 14.2,
22.9, 29.4, 32.4, 38.1, 38.8, 64.9, 71.3, 123.8, 128.4, 142.9,
147.7, 172.8. FABMS: 310.2 (M+H+), HR-FABMS:
calcd for C16H24NO5: (M+H+), 310.1654, found:
310.1664.
16. Sutherl, A.; Willis, C. L. J. Org. Chem. 1998, 63, 7764–
7769.
17. Goldschmidt, S.; Gupta, K. K. CHBEAM. Chem. Ber.
1965, 98, 2831.
18. Boger, D. L.; Keim, H.; Oberhauser, B.; Schreiner, E. P.;
Foster, C. A. J. Am. Chem. Soc. 1999, 121, 6197–6205.
19. Analytical data of compound 1a: colorless needles, mp
In conclusion, the first total synthesis of beauveriolide I
(1a), an antibiotic from the culture broth of fungal Beau-
veria sp. FO-6979 was achieved. The synthesis is flexible
and amenable to other analogues for SAR studies.
25
242–244 ꢁC (from MeOH); ½aꢁD ꢀ23.7 [c 0.7, CHCl3–
MeOH (4:1)]; IR (KBr): 3309, 1726, 1684, 1643,
1537 cmꢀ1 1H NMR (500 MHz, CDCl3–CD3OD = 4:1):
.
d 0.79 (t, 3H, J = 6.5 Hz), 0.80 (d, 3H, J = 6.5 Hz), 0.83
(d, 3H, J = 6.0 Hz), 0.85 (d, 3H, J = 5.5 Hz), 0.93–1.00
(m, 1H), 1.07–1.15 (m, 1H), 1.18 (d, 3H, J = 7.0 Hz,
overlapped with 2H signal), 1.20–1.28 (m, 1H), 1.30–1.36
(m, 1H), 1.41–1.50 (m, 3H), 2.01–2.04 (m, 1H), 2.36 (dd,
1H, J = 14.0, 9.5 Hz), 2.42 (dd, 1H, J = 14.0, 5.5 Hz);
2.90 (dd, 1H, J = 13.5, 8.0 Hz), 2.99 (dd, 1H, J = 13.5,
8.5 Hz), 3.81 (dd, 1H, J = 14.0, 7.0 Hz), 4.16 (t, 1H,
J = 8.0 Hz), 4.53–4.56 (m, 1H), 4.84–4.88 (m, 1H),
6.87–7.24 (m, 5H). 13C NMR (125 MHz, CDCl3–
CD3OD = 4:1) d 13.4, 14.5, 15.0, 21.7, 22.5, 24.5, 29.0,
30.3, 35.1, 35.3, 35.5, 40.8, 49.0, 52.3, 56.6, 76.0, 126.5,
128.1, 128.6, 136.0, 169.4, 171.0, 171.3, 171.8. FABMS:
488.3 (M+H+), HR-FABMS: calcd for C27H42N3O5:
(M+H+), 488.3124, found 488.3147.
References and notes
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Chin. J. Antibiot. 1999, 24, 1–3.
4. Namatame, I.; Tomoda, H.; Si, S.; Yamaguchi, Y.;
Masuma, R.; Omura, S. J. Antibiot. 1999, 52, 1–6.
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Natl. Acad. Sci. U.S.A. 2004, 101, 737–742.
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