An aldol approach to the total synthesis of (+)-brefeldin a

Article abstract of DOI:10.1016/j.tetlet.2003.10.130

A convergent selective route to (+)-brefeldin A (BFA) and 7-epi-BFA was developed, with the crucial C-4/C-5 stereogenic centers were established using Crimmins asymmetric aldolization.

Full text of DOI:10.1016/j.tetlet.2003.10.130

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 199–202
An aldol approach to the total synthesis of (+)-brefeldin A
Yikang Wu,* Xin Shen, Yong-Qing Yang, Qi Hu and Jia-Hui Huang
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 31 July 2003; revised 15 October 2003; accepted 17 October 2003
Abstract—A convergent selective route to (+)-brefeldin A (BFA) and 7-epi-BFA wasdeveloped, with the crucial C-4/C-5 stereogenic
centers were established using Crimmins asymmetric aldolization.
Ó 2003 Elsevier Ltd. All rights reserved.
Brefeldin A (BFA, 1a) was first isolated1 from Penicil-
lium decumbens in 1958. The structure of BFA, however,
tions, the corresponding oxazolidinone failed to react.
The yield of 7 wasimproved to 96% by uisng LiBH
/
4
2
wasnot fully established until 1971. Early biological
ether (using MeOH instead of H2O in the original19
recipe).
studies showed that BFA possesses antifugal,3 antiviral,4
antitumor,5 and nematocidal6 activities. Since the first7
total synthesis of BFA by Corey, around 30 total/formal
syntheses8 have been recorded in the literature. Inter-
est9;10 in probing the mode of action aswell asetsab-
lishing the structure–activity relationship is also growing
Due to the presence of the thiolane protecting group,
oxidation of 7 could be realized in satisfactory yields
only with SO3ÆPy in DMSO/CH2Cl2. PCC, IBX, Dess-
Martin, or Swern oxidation all led to drastically lowered
yields. Further direct masking (ethylene glycol/PPTS)
the carbonyl gave 9 in 60% yield. However, conversion
of 8 to the corresponding dimethyl acetal ((MeO)3CH/
MeOH/TsOH) followed by treatment with ethylene
glycol/PPTS afforded 9 in ca. 95% (two-step) yield. The
first step was somewhat tricky, to prevent deprotection
of the TBS while driving the acetal formation to com-
pletion, (MeO)3CH must be in large excess (used as
solvent) and the MeOH (which accelerated the acetal-
ization) content must be minimized. Hydrolysis of the
thio protecting group in 9 was also troublesome. Vari-
ous reagents (such as the classical NBS, NBS (or NCS)/
AgNO2 with or without 2,6-lutidine, or the recently re-
in recent years. Herein we wish to report a new selective
11
route to (+)-BFA, which exploitsCrimmins
asym-
metric aldolization and Jacobsen12 HKR (hydrolytic
kinetic resolution) to establish the C-4/C-5 and C-15
stereogenic centers, respectively. Along with BFA, 7-epi-
BFA13 (1b, also a natural product with biological
activity untested and has been synthesized14 only once)
was also synthesized.
The key intermediate cyclopentenone 12 wassynthesized
ashsown in Scheme 1 from 3 (which wasreadily pre-
pared in 95% yield from the corresponding acid15). Re-
action of 3 with the known (E)-4-benzyloxy-2-butenal16
(4) under the Crimmins11 conditionsgave aldol 5 (iso-
lated asa single enantiomer) in 78% yield. Protection of
5 wasfirts done in CH 2Cl2 using TBSOTf (3 equiv) as
reported17 by Sulikowski. Later we found that TBSCl
(2 equiv) also worked very well if using DMF instead of
CH2Cl2 asthe os lvent. The auxiliary wasthen cleaved
with NaBH4/THF-H2O18 using Prashadꢀsprocedure,
resulting in 7 in ca. 70% yield. Under the same condi-
20
ported H5IO6 and PhI(OAc)221) failed to give satis-
factory results here. Finally, the problem was solved by
using22 I2 in aq acetone in the presence of NaHCO3
buffer. Under these conditions, ketone 10 could be ob-
tained in 89% yield.
Subsequent formation of the five-membered ring using
an intramolecular Mukaiyama23 reaction wasrealized in
73% yield by conversion of 10 into corresponding silyl
enol ether with LDA/TMSCl followed by treatment with
TiCl4 in CH2Cl2 at )78 °C. Elimination of the alkoxyl
with DBU in MeOH at 0 °C proceeded rapidly and gave
the key intermediate 12 in 97% yield within 1 h.
Keywords: cyclization; asymmetric aldolization; macrolides; lactones;
natural products.
* Corresponding author. E-mail: yikangwu@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.130

200
Y. Wu et al. / Tetrahedron Letters 45(2004) 199–202
OH
O
OTBS
O
OTBS
OTBS
O
HO
S
O
b
d
Nx
S
c
a
H
S
Nx
S
S
N
S
S
S
S
Bn
S
S
S
BnO
BnO
5
3
BnO
BnO
8
6
7
OTBS
OTBS
OTBS
OTBS
O
O
O
H
H
h
g
f
e
O
S
O
O
O
O
HO
S
BnO
12
BnO
BnO
BnO
9
10
11
Scheme 1. Reagentsand condition:s N ¼ the auxiliary; (a) TiCl4/TMEDA/4, 78%; (b) TBSCl/2,6-lutidine, 97%; (c) LiBH4/Et2O–MeOH, 96%
x
(d) SO3ÆPy/iPr2NEt/DMSO/CH2Cl2, 96%; (e) (i) excess (MeO)3CH/tracesMeOH/cat ÆTsOH/rt, 98%; (ii) PPTS/ethylene glycol/benzene/reflux, 97%;
(f) I2/NaHCO3/acteone–H2O, 89%; (g) (i) LDA/TMSCl/THF/)78 °C/1 h, then warmed to rt over 3 h, (ii) TiCl4/CH2Cl2/)78 °C/1 h, 73% (from 10);
(h) DBU/MeOH, 97%.
The lower chain was constructed as shown in Scheme 2.
The known alkene 1324 wasconverted to rac-14 with
m-CPBA (95% yield). A Jacobsen HKR using (R,R)-
salenCo(III)OAc as the catalyst was then performed at
25 °C to afford (R)-14 in 44% yield, with the ee value
>99%. It is interesting to note that if using benzyl to
replace the benzoyl protecting group, the ee value was
lowered to 97% under the same conditions.
higher than those for the comparable steps in the liter-
ature, 3 equiv of the cuprate must be utilized. Reduction
of 20 with variousreducing agentsalwaysafforded two
epimers, with the b-OH isomer as the major product in
most cases. The best selectivity for the b-OH wasob-
served with L-Selectride (90% yield, 21b/21b ¼ 1:8).
After screening many reducing agents/conditions, we
found that (S)-2-methyl-CBS-oxazaborolidine/BH3 gave
more a-OH epimer than the b one. (96.4% yield, 21a/
21b ¼ 3:2). The two epimers could be easily separated
and the unwanted one could be re-oxidized back to 20
with Dess–Martin periodinane (92%) and recycled.
The (R)-14 wasthen hydrogenated (90% yield) over 10%
Pd–C and the resulting OH was protected using
BnOCNCCl3/TMSOTf25 (other reagents/conditions al-
waysled to partial migration of the benzoyl group to the
secondary OH). The benzoyl group was hydrolyzed and
replaced by a tosyl. Treatment of the intermediate tosyl-
ate with LiCBCHÆEDA26 gave 17 (86% from 16).
Finally, addition of catecholborane (72% yield) followed
by substitution of the boron (95% yield) with iodine
afforded 19.
The OH at the five-membered ring wasthen maksed
with TBSOTf and the benzyl groupswere removed with
Li/naphthalene to furnish diols 23a and 23b, respec-
tively. The allylic alcoholswere oxidized into the cor-
responding carboxylic acids 24a and 24b, respectively,
by sequential treatment with MnO2 and NaClO2 in 70–
76% overall yields. Macro-ring closure of 24a and 24b
using the Yamaguchi27 procedure resulted in 25a and
25b, respectively, in 81–83% yields. Finally, the TBS
groupswere cleaved with 2 N HCl/THF, providing the
end products28 1a and 1b, respectively.
The vinyl iodide 19 wasthen transformed into the cor-
responding cuprate by sequential treatment with n-BuLi
and CuCN/MeLi before the Michael addition to 12 to
yield 20 (93%, Scheme 3). To achieve yieldssignificantly
OBn
OH
BzO
BzO
O
BzO
c
b
d
a
HO
O
BzO
H
13
rac-14
15
(R)-14
16
OBn
OBn
OH
B
OBn
g
e
f
I
OH
19
18
17
Scheme 2. Reagentsand conditions: (a) m-CPBA, 95%; (b) (R,R)-salenCo(III)OAc, 44%, ee>99%; (c) Pd–C/H2, 90%; (d) (i) BnOCNCCl3/TMSOTf,
(ii) MeONa/MeOH, 94% (from 15); (e) (i) p-TsCl/NEt3, 73.7%; (ii) LiCBCHÆH2N(CH2)2NH2/DMSO, 86%; (f) Catecholborane, 72%; (g) NaOH/I2,
95%.

Y. Wu et al. / Tetrahedron Letters 45(2004) 199–202
201
OTBS
OTBS
OTBS
H
H
H
H
H
OBn
OBn
BnO
a
Y
X
b
21a X = H, Y = OH
21b X = OH, Y = H
O
O
BnO
BnO
12
20
OTBS
OTBS
OTBS
H
H
H
H
H
OH
OBn
BnO
c
Y
X
e
Y
X
Y
X
f
d
CO2H
HO
HO
H
22a X = H, Y = OTBS
22b X = OTBS, Y = H
23a X = H, Y = OTBS
23b X = OTBS, Y = H
24a X = H, Y = OTBS
24b X = OTBS, Y = H
OTBS
H
OH
O
H
Y
1
O
g
1a X = H, Y = OH
1b X = OH, Y = H
4
Y
O
7
X
O
X
H
10
15
H
25a X = H, Y = OTBS
25b X = OTBS, Y = H
Scheme 3. Reagentsand condition:s (a) n-BuLi/19, CuCN/MeLi, 93% of 20; (b) L-Selectride, 90% of 21a/21b (1:8) or (S)-2-methyl-CBS-oxa-
zaborolidine/BH3ÆSMe2/THF/0 °C, 96.4% of 21a/21b (3:2); (c) TBSOTf/NEt3, 96% for 22a, 95% for 22b; (d) Li–naphthalene, 72% for 23a, 70% for
23b; (e) (i) MnO2/CH2Cl2, (ii) NaClO2/NaH2PO4/2-methyl-2-butene, 71% for 24a, 76% for 24b (2-step yields); (f) 2,4,6-trichlorobenzoyl chloride/
NEt3, DMAP, 81% for 25a, 83% for 25b; (g) 2 N HCl/THF, 91% for 1a, 93% for 1b.
10. (a) Zhu, J.-W.; Nagasawa, H.; Nagura, F.; Mohamad,
S. B.; Uto, Y.; Ohkura, K.; Hori, H. Biorg. Med. Chem.
2000, 8, 455–463; (b) Weigele, M.; Loewe, M. F.; Poss,
C. S. US 5516921 A 14 May 1996, p 14; Chem. Abstr.
1996, 125, 58201.
11. Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary,
K. J. Org. Chem. 2001, 66, 894–902.
12. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 277, 936–938.
Acknowledgements
Financial support from the National Natural Science
Foundation of China (20025207, 20272071, 20372075),
the Chinese Academy of Sciences (Knowledge Innova-
tion Project, KGCX2-SW-209), and the Major State
Basic Research Development Program (G2000077502) is
gratefully acknowledged.
13. Gorst-Allman, C. P.; Stevn, P. S. J. Chem. Soc., Perkin
Trans. 1 1982, 2387–2390.
References and Notes
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17. Sulikowski, G. A.; Lee, W.-M.; Jin, B.; Wu, B. Org. Lett
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18. Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron
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19. Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth.
Commun. 1990, 20, 307–312.
20. Shi, X.-X.; Khanapure, S. P.; Rokach, J. Tetrahedron
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3. Betina, V.; Betinova, M.; Kutkova, M. Arch. Mikrobiol.
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4. Takatsuki, A.; Yamaguchi, I.; Tamura, G.; Misato, T.;
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7. Corey, E. J.; Wollenberg, R. H. Tetrahedron Lett. 1976,
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8. For recent total syntheses, see e.g.: (a) Wang, Y.; Romo,
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Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328–9329;
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D.-Y.; Lee, Y.-S.; Kim, S.-H.; Park, H.-J. J. Org. Chem.
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781.
21. Shi, X.-X.; Wu, Q. Q. Synth. Commun. 2000, 30, 4081–
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22. (a) Russell, G. A.; Ochrymowycz, L. A. J. Org. Chem.
1969, 34, 3618–3624; (b) Nicolaou, K. C.; Bunnage, M. E.;
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Eur. J. 1999, 5, 599–617.
23. Although examplesof uins g Mukaiyama reaction to
synthesize seven- or eight-membered rings are well
known, we are not aware of any precedentsof formation
9. Argade, A. B.; Devraj, R.; Vroman, J. A.; Haugwitz, R.
D.; Hollingshead, M.; Cushman, M. J. Med. Chem. 1998,
41, 3337–3346.

202
Y. Wu et al. / Tetrahedron Letters 45(2004) 199–202
of five- or six-membered rings using Mukaiyama reaction
in the literature.
24. Nishimura, T.; Kakiuchi, N.; Onoue, T.; Ohe, K.;
Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 1915–
1918.
25. (a) Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.;
Schmeck, C. Tetrahedron 1993, 49, 1619–1624; (b) Dankl-
maier, J.; Hoenig, H. Liebigs Ann. Chem. 1989, 665–669.
26. Beumel, O. F., Jr, Harris, R. F. J. Org. Chem. 1963, 28,
2775.
27. Yamaguchi, M.; Innaga, J.; Hirata, K.; Saeki, H.;
Katsuki, T. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
28. Physical and spectroscopic data for 1a: mp 202–203 °C
35.3, 33.3, 28.3, 21.3; FT-IR (KBr) 3366, 1713, 1257 cmÀ1
;
ESI-MS m=z 281 ([M+H]þ). Physical and spectroscopic
23
D
data for 1b: mp 126–127 °C (lit.13 124–125 °C); ½aŠ
20
D
+109.2° (c 1.15, MeOH); (lit.13 ½aŠ +108.6° (c 1.03));
1H NMR(500 MHz, CDCl3) d 7.41 (dd, J ¼ 2:9, 15.6 Hz,
1H, H-3), 5.91 (dd, J ¼ 1:6, 15.6 Hz, 1H, H-2), 5.79 (ddd,
J ¼ 4:6, 10.2, 15.0 Hz, 1H, H-11), 5.16 (dd, J ¼ 9:6,
15.1 Hz, 1H, H-10), 4.85 (m, 1H, H-15), 4.36 (m, 1H, H-
7), 4.23 (d, J ¼ 1:0 Hz, 1H, H-4), 2.72 (quintet,
J ¼ 9:0 Hz, 1H, H-9), 2.20 (ddd, J ¼ 4:7, 10.1, 14.7 Hz,
1H, H-8a), 2.00 (m, 1H, H-12), 1.86 (m, 4H, H-6b, H-8b,
H-12 and H-13), 1.74 (m, 1H, H-14), 1.66 (m, 1H, H-5),
1.58–1.50 (m, 2H, H-6a and H-14), 1.26 (d, J ¼ 6:2 Hz,
3H, H-16), 0.94 (m, 1H, H-13); 13C NMR (125 MHz,
CDCl3) d 166.5 (C-1), 152.1 (C-3), 135.2 (C-10), 131.3
(C-11), 117.4 (C-2), 76.3 (C-4), 73.1 (C-7), 71.8 (C-15),
52.1 (C-5), 44.4 (C-9), 43.7 (C-6), 40.2 (C-8), 34.1 (C-14),
32.0 (C-12), 26.7 (C-13), 20.8 (Me at C-15). FT-IR (KBr)
3302, 1712, 1257 cmÀ1; EI-MS m=z (%) 280 (Mþ, 1), 262
(Mþ)H2O, 2), 119 (41), 55 (100). The assignments of the
NMR signals were made with the aid of COSY, NOESY,
DEPT, and HMQC experiments.
20
D
20
D
(lit.29 203–204 °C); ½aŠ +92.7° (c 0.45, MeOH); (lit.29 ½aŠ
1
+92.2° (c 0.51, MeOH)); H NMR (400 MHz, CD3OD) d
7.45 (dd, J ¼ 3:0, 15.6 Hz, 1H), 5.82 (dd, J ¼ 2:0, 15.6 Hz,
1H), 5.75 (ddd, J ¼ 4:6, 10.2, 15.0 Hz, 1H), 5.27 (dd,
J ¼ 9:6, 15.1 Hz, 1H), 4.78 (m, 1H), 4.21 (m, 1H), 4.03 (m,
1H), 2.38 (quintet, J ¼ 8:7 Hz, 1H), 2.12 (ddd, J ¼ 5:4,
8.7, 13.6 Hz, 1H), 2.05–1.97 (m, 2H), 1.90–1.70 (m, 5H),
1.55 (m, 1H), 1.42 (m, 1H), 1.23 (d, J ¼ 6:2 Hz, 3H), 0.90
(m, 1H); 13C NMR (100 MHz, CD3OD) d 168.7, 155.4,
138.4, 131.7, 118.1, 76.9, 73.5, 73.3, 53.5, 45.8, 44.4, 42.1,
29. Kitahara, T.; Mori, K. Tetrahedron 1984, 40, 2935–2944.