Short and stereoselective synthesis of manzacidins A and C, and their enantiomers

Article abstract of DOI:10.1016/j.tetlet.2008.10.074

A short and stereoselective synthesis of manzacidins A and C, and their enantiomers was achieved via stereoselective hydrogenation reactions of dehydroamino acid esters 5-8 using a chiral Rh catalyst.

Full text of DOI:10.1016/j.tetlet.2008.10.074

Tetrahedron Letters 49 (2008) 7426–7429
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Short and stereoselective synthesis of manzacidins
A and C, and their enantiomers
*
*
Kentaro Oe, Tetsuro Shinada , Yasufumi Ohfune
Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and stereoselective synthesis of manzacidins A and C, and their enantiomers was achieved via
stereoselective hydrogenation reactions of dehydroamino acid esters 5–8 using a chiral Rh catalyst.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 17 September 2008
Revised 10 October 2008
Accepted 16 October 2008
Available online 21 October 2008
Keywords:
Manzacidin
Total synthesis
Stereoselective synthesis
Enantiomer
Hydrogenation reaction
Manzacidin A (1) and manzacidin C (2), a novel class of 1,3-
dehydropyrimidine alkaloids possessing a bromopyrrole ester unit,
were isolated from the Okinawan sponge Hymeniacidon sp. by
Kobayashi et al. in 1991 (Scheme 1).1 Bromopyrrole alkaloids exhi-
Br
Br
HN
6
N
4
HN
N
H
6
4
O
O
CO2H
N
H
CO2H
N
H
H
O
O
Manzacidin C (2)
Manzacidin A (1)
bit a diverse array of pharmacological activities represented by a-
adrenoceptor blockers, antagonists of serotonergic receptors, or
actomyosin ATPase activators.2 In spite of their intriguing biologi-
cal activities, the pharmacological evaluation of manzacidins A and
C has not yet been undertaken due to the limited availability of
these natural products. These facts together with the unique struc-
tural features of the manzacidins have attracted much attention as
a synthetic target from the synthetic community. Many synthetic
efforts focusing on the stereoselective construction of the 1,3-dia-
mino stereogenic centers attached to the C4 methine and C6 qua-
ternary carbon centers have been made since our first total
synthesis in 2000.3–5 We now report the short and stereoselective
synthesis of manzacidins A (1) and C (2), and their enantiomers 3
and 4 via the diastereoselective hydrogenation reaction of optically
Chiral Rh(I) catalyzed-
hydrogenation reaction
O
NBoc
BocHN
TBSO
NHBoc
CO2Me
NHBoc
CO2Me
5
(R )-
Natural form
Enantiomers
7
(S)-
O
NBoc
BocHN
TBSO
NHBoc
CO2Me
NHBoc
CO2Me
8
(R )-
(
S
)-6
Chiral Rh(I) catalyzed-
hydrogenation reaction
Br
Br
active
a,b-unsaturated esters 5–8 using a chiral [Rh(I)(COD)-Et-
HN
O
N
HN
N
DuPHOS]+OTfꢀ catalyst (Scheme 1).
O
CO2H
N
H
CO2H
N
The N-Boc dehydroamino acid esters 5–8, and N-Cbz esters 15
and 16 were used in this study. These olefins were prepared from
the chiral a-methylserine esters 9 and 10, which were readily pre-
H
H
H
O
O
ent -Manzacidin A (3)
ent -Manzacidin C (4)
pared on a multi-gram scale by the stereoselective Strecker synthe-
Scheme 1.
sis of an acetol ester (Scheme 2).5a,c,6 The dehydroamino acid esters
5, 6, 15, and 16 were synthesized by olefination reactions of the a-
* Corresponding authors. Tel./fax: +81 6 6605 2570 (T.S).
E-mail addresses: shinada@sci.osaka-cu.ac.jp (T. Shinada), ohfune@sci.osaka-cu.
ac.jp (Y. Ohfune).
methyl Garner’s aldehydes 11 and 127,8 with the phosphonates 13
and 14.9 The TBS-protected derivatives 7 and 8 were prepared from
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.074

K. Oe et al. / Tetrahedron Letters 49 (2008) 7426–7429
7427
Based on the above results, we turned our attention to the chiral
Rh catalyst-controlled hydrogenation reaction. Recently, Sasaki et
al. reported the stereoselective reduction of a highly functionalized
olefin with a chiral [Rh(I)(COD)-Et-DuPHOS]+OTfꢀ catalyst12 during
the synthesis of neodysiherbaine (Eq 3).13 The N-Cbz derivative 20
was a superior substrate when compared to the N-Boc derivative
21. In terms of the double asymmetric induction,14 the combina-
tion of 20 and the (S,S)-[Rh(I)(COD)-Et-DuPHOS]+OTf- catalyst
was apparently the matched case to obtain the desired reduction
product.
O
NBoc
NHBoc
CO2Me
O
NBoc
CHO
a) or b)
NHP
HO
CO2Me
9
(R)-
11
R )-
(
6 11
S )- P = Boc, 43% ( , 50%)
15 11
(S )- P = Cbz, 46% ( , 19%)
(
NHBoc
O
NBoc
a) or b)
O
NBoc
CHO
HO
NHP
CO2Me
10
(S)-
CO2Me
12
(S)-
H2 (0.8 MPa)
O
(
R
)-5 P = Boc, 36% (12, 45%)
R )-16 P = Cbz, 40% (12, 45%)
NHR
NHR
Rh(I)(COD)-
(
H
O
(S,S
)-Et-DuPHOS]+OTf-
MeO2C
MeO2C
O
O
(5 mol%)
THF, rt, 96 h
BocHN
TBSO
NHBoc
c-f
MeO2C
MeO2C
NHP
O
9
(R)-
O
H
CO2Me
)-7, 67% (9, 32%)
BocHN NHBoc
TBSO
(MeO)2P
CO2Me
22
(85%, >20:1)
R = Cbz
20
R = Cbz
21 R = Boc
(S
23 R = Boc (90%, 6:1)
13
P = Boc
14 P = Cbz
ð3Þ
c-f
10
S)-
(
CO2Me
R)-8, 69% (10, 20%)
The N-Cbz-olefin 15 was used for the chiral [Rh(I)(COD)-Et-Du-
PHOS]+OTf-catalyzed hydrogenation reaction (Scheme 3). The use
of the (S,S)-Et-DuPHOS Rh catalyst resulted in the recovery of the
starting olefin (entry 1). Switching the chiral catalyst to the (R,R)-
Et-DuPHOS Rh catalyst allowed the hydrogenation reaction to give
a 1:5 mixture of 24 and 25 (48 h, entry 2), in which the major (4R)-
isomer 25 possessed the requisite (4R,6S)-stereochemistry of ent-
manzacidin A. To improve the diastereoselectivity, the N-Boc olefin
6 was subjected to the same reduction conditions. The reduction
with the (R,R)-Et-DuPHOS Rh catalyst proceeded in a highly stere-
oselective manner to give (4R,6S)-27 (26:27 = 1:13, entry 4). In
contrast, the (S,S)-Et-DuPHOS Rh catalyst gave a 1:1 mixture of
26 and 27 (168 h, entry 3). These results indicated that the reaction
of (S)-N-Boc 6 with the (R,R)-catalyst in the matched case of these
hydrogenation reactions and the hydrogenation of (R)-5 with the
(S,S)-catalyst would afford (4S,6R)-29 corresponding to manzacidin
A (1).
The treatment of (R)-5 with the chiral (S,S)-Et-DuPHOS Rh cat-
alyst gave 29 in a stereoselective manner (dr = 13:1, Scheme 4).
(4S,6R)-29 was converted to 1 by the following sequence of trans-
formations:3,15 (i) hydrolysis of the methyl ester, (ii) removal of the
Boc groups, (iii) tetrahydropyrimidine ring formation, and (iv)
esterification with 28. Similarly, (4R,6S)-27 derived from (S)-6
was converted to ent-manzacidin A (3). The spectral data of the
synthetic 1 were identical to those of the authentic data, confirm-
ing the stereochemical outcome of the chiral catalyst-controlled
hydrogenation reactions of (R)-5. The spectral data of ent-manzac-
idin A (3) were identical to that of 1 except for the sign of the opti-
(
Scheme 2. Reagents and conditions: (a) 13 (3.0 equiv), DBU (3.0 equiv), CH2Cl2, 0 °C
to rt, 22 h; (b) 14 (3.0 equiv), DBU (3.0 equiv), CH2Cl2, 0 °C to rt, 22 h; (c) TBSCl
(2.0 equiv), imidazole (2.0 equiv), DMF, 0 °C to rt, 17 h; (d) LiBH4 (4.0 equiv), MeOH
(4.2 equiv), Et2O, 0 °C, 1 h; (e) TEMPO (0.1 equiv), PhI(OAc)2 (1.2 equiv), CH2Cl2, 0 °C
to rt, 18 h; (f) 13 (3.0 equiv), DBU (3.0 equiv), CH2Cl2, 0 °C to rt, 22 h.
9 and 10 by a conventional silylation, reduction, oxidation, and
olefination with 13 and 14, respectively. These olefination reac-
tions allowed the stereoselective formations of Z-isomers (>20:1).
The conversion efficiency was satisfactory in terms of the yields
based on the recovery of the starting materials (>80%).10
We were initially interested in the substrate-controlled hydro-
genation reaction of 6 or 15. Avenoza et al. reported the hydroge-
nation reaction of Z-17 to give 18 in a stereoselective manner
(18:19 = 94:6 (Eq. 1)).11 The inverse diastereoselectivity occurred
when E-17 was employed (18:19 = 5:95). In view of the structural
analogy of 17 with the a-methyl analogs 5 and 6, we attempted the
hydrogenation reactions of 6 prior to examining the chiral Rh
catalyst-controlled hydrogenation reaction.
H2
Pd/C
O
NHBoc
NHBz
O
NHBoc
NHBz
O
NHBoc
NHBz
+
ð1Þ
2-PrOH
H
H
H
H
CO2Me
18:19 = 94:6
18:19 = 5:95 from
H
CO2Me
-isomer
CO2Me
-isomer 17
18
19
Z
cal rotation. Thus, manzacidin
A and its enantiomer were
E
synthesized in 6 steps from the (S)-aldehyde 11 and (R)-aldehyde
12, respectively.
The Z-olefin 6 underwent a smooth hydrogenation reaction (Pd/
C, H2). However, the diastereoselectivity was found to be moderate
(ca 3:2, (Eq. 2)). Although other hydrogenation reaction conditions
[H2, catalysts: Pd/Al2O3, Rh/Al2O3, PtO2, [Ir(COD)(Cy3P)(Py)]PF6,
solvents: MeOH, 2-PrOH, AcOEt] and the 1,4-reduction condition
using Mg/MeOH were examined, the diastereoselectivities were
not improved to a satisfactory level. The use of the N-Cbz-15, the
E-isomers of 6, and an acyclic dehydroamino acid 7 were not effec-
tive at all to give the corresponding reduced products in moderate
selectivities. The more sterically congested nature of the quarter-
nary amino carbon center of 6 would hamper the diastereoselec-
tive hydrogenation pathway.
H2 (0.8 MPa)
cat.a (5 mol%)
O
NBoc
O
NBoc
O
NBoc
S
6
S
NHP
6
S
NHP
NHP
+
4
R
4
S
THF, rt
H
CO2Me
H
CO2Me
25 P = Cbz
27
CO2Me
24 P = Cbz
P =Boc
15 P = Cbz
26
6
P = Boc
P = Boc
Entry
Catalyst
Olefin
Time(h) Yield Product ratio
15
15
6
(
S,S
)
)
)
)
---
1
2
3
4
72
48
168
48
0b
96
76
98
(
R,R
24:25 = 1:5c,d
26:27 = 1:1
(S,S
6
(
R,R
26:27 = 1:13
H2
O
NHBoc
NHBoc
b
acat. [Rh(I)(COD)-Et-DuPHOS]+OTf- Recovery of
.
Pd/C
O
NHBoc
NHBoc
15
c Numbering system accords with those of the manzacidins.
ð2Þ
d Product ratio was determined by the conversion to manzacidins.
2-PrOH
product ratio
ca 3:2
CO2Me
H
CO2Me
6
Scheme 3.

7428
K. Oe et al. / Tetrahedron Letters 49 (2008) 7426–7429
H2 (0.8 Mpa),
S,S)-cat. (5 mol%)
O
NBoc
R
O
NBoc
(
NHBoc
CO2Me
6
R
NHBoc
S
THF, rt, 48 h
95%
dr = 13:1
4
H
29
CO2Me
5
36%
(4 steps)
Br
a-d
CCl3
Manzacidin A (1)
ent -Manzacidin A (3)
N
H
28
O
40%
a-d
(4 steps)
H2 (0.8 Mpa),
O
NBoc
S
O
NBoc
(
R,R)-cat. (5 mol%)
6
S
NHBoc
CO2Me
NHBoc
THF, rt, 48 h
99%
dr = 13:1
4
R
H
CO2Me
6
27
Scheme 4. Reagents and conditions: (a) 1 N NaOH, THF, 1 h; (b) TFA, CH2Cl2, 0 °C to
rt, 30 min; (c) TFA, CH(OMe)3, rt, 17 h; (d) 28, (2.0 equiv), NaH (2.0 equiv), DMF, 0 °C
to rt, 2 h.
Although the use of the cyclic unsaturated esters 5 and 6 was
found to be the appropriate substrates to access manzacidin A
(1) and its enantiomer 3, these reductions forced limitations on
the stereoselective synthesis of manzacidin C (2) and its enantio-
mer 4. We assumed that the release of the ring strain to reduce
the steric hindrance of the cyclic oxazolidine 5 could facilitate
the reagent-controlled hydrogenation reaction. As expected, the
reduction of the acyclic olefin 7 with the (S,S)-Rh catalyst smoothly
proceeded to give (4S,6S)-31 as the major product (30:31 = 1:8).
The diastereoselectivity was inverted to give (4S,6S)-30 as the ma-
jor product (30:31 = 6:1) when the (R,R)-catalyst was employed. As
a result, the use of the acyclic dehydroamino acid esters, attributed
to the stereoselective formation of (4S,6S)-31 was involved in the
synthesis of manzacidin C (2). The (4R,6R)-32 was prepared using
the (R,R)-catalyst. The resulting (4S,6S)-31 and its enantiomer
(4R,6R)-32 derived from 8 were converted into manzacidin C (2)
and its enantiomer 4, respectively, in a manner similar to the syn-
thesis of manzacidin A (1) (Scheme 5).
Figure 1. HPLC profiles of manzacidins.
tiomers 3 and 4 by the chiral catalyst-controlled hydrogenation
reactions of the dehydroamino acid esters 5–8. The improved HPLC
purification protocol allows for ample of the enantiomerically pure
manzacidins and their enantiomers for further evaluation of their
biological activities.
Acknowledgments
This study was supported by Grants-in-Aids (Nos. 16201045,
16073214, and 19201045) for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology, Japan. We
thank Dr. M. Oikawa for helpful discussions on the Rh-catalyzed
hydrogenation reaction.
Purification of the major stereoisomer of the manzacidins by
recrystallization was initially not successful. Therefore, we exam-
ined the HPLC separation conditions and found that heptafluorobu-
tyric acid (the lower chart) was the superior additive to
trifluoroacetic acid (the upper chart) for the distinct separation of
a mixture of the manzacidins (Fig. 1).
Supplementary data
Supplementary data (experimental details) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2008.10.074.
In summary, we have established a short and efficient synthetic
route to access manzacidin A (1), manzacidin C (2), and their enan-
References and notes
H2 (0.8 MPa),
1. Kobayashi, J.; Kanda, F.; Ishibashi, M.; Shigemori, H. J. Org. Chem. 1991, 56,
4574–4576.
BocHN
NHBoc
CO2Me
BocHN
cat. (5 mol%),
S
TBSO
2. (a) Endo, T.; Tsuda, M.; Okada, T.; Mitsuhashi, S.; Shima, H.; Kikuchi, K.;
Mikami, Y.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2004, 67, 1262–1267; (b)
Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Princep, P. R. Nat.
Prod. Rep. 2003, 20, 1–48; (c) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48.
3. Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122,
10708–10709.
4. (a) Hashimoto, T.; Maruoka, K. Org. Biomol. Chem. 2008, 6, 829–835; (b) Tran,
K.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2008, 10, 3165–3167; (c) Sibi, M. P.;
Stanley, L. M.; Soeta, T. Org. Lett. 2007, 9, 1553–1556; (d) Wang, B.; Wu, F.;
Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768–769; (e) Wang, Y.;
Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928–3930; (f) Kano, T.; Hashimoto,
T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2174–2175; (g) Lanter, J. C.; Chen,
H.; Zhang, X.; Sui, Z. Org. Lett. 2005, 7, 5905–5907; (h) Drouin, C.; Woo, J. C. S.;
MacKay, D. B.; Lavigne, R. M. A. Tetrahedron Lett. 2004, 45, 7197–7199; (i) Woo,
J. C. S.; MacKay, D. B. Tetrahedron Lett. 2003, 44, 2881–2883; (j) Wehn, P. M.; Du
Bois, J. J. Am. Chem. Soc. 2002, 124, 12950–12951.
THF, rt, 48 h
7
BocHN
a-d
NHBoc
NHBoc
6
S
6
S
4
S
4
R
TBSO
TBSO
+
CO2Me
CO2Me
H
H
31
30
)-cat. 83% (30:31 = 1:8)
R,R)-cat. 96% (30:31 = 6:1)
46%
(4 steps)
(
(
S,S
Manzacidin C (2)
ent-Manzacidin C (4)
48%
(4 steps)
a-d
H2 (0.8 MPa),
(R,R)-cat.
BocHN
NHBoc
CO2Me
BocHN
NHBoc
(5 mol%),
R
4
R
6
R
TBSO
TBSO
CO2Me
THF, rt ,48 h
85%
dr = ca. 8:1
H
5. (a) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 24, 5127–5143; (b) Kang, S.
H.; Kang, S. Y.; Lee, H.; Buglass, A. J. Chem. Rev. 2005, 105, 4537–4558; (c)
Ohfune, Y.; Shinada, T. Bull. Chem. Soc. Jpn. 2003, 76, 1115–1129.
6. Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405.
7. Synthesis of the Garner’s aldehyde: Garner, P.; Park, J. M. Org. Syn. 1992, 70, 18–
28.
8
32
Scheme 5. Reagents and conditions: (a) 1 N NaOH, THF, 0 °C, 1 h; (b) 6 N HCl, rt,
18 h; (c) TFA, CH(OMe)3, rt, 17 h; (d) 28 (2.0 equiv), NaH (2.0 equiv), DMF, 0 °C to rt,
2 h.

K. Oe et al. / Tetrahedron Letters 49 (2008) 7426–7429
7429
8. (a) Tsuji, T.; Iio, Y.; Takemoto, T.; Nishi, T. Tetrahedron: Asymmetry 2005, 16,
3139–3142; (b) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.; Sucunza,
D.; Zurbano, M. M. Tetrahedron: Asymmetry 2001, 12, 949–957; (c) Alias, M.;
Cativiela, C.; Diaz-De-Villegas, M. D.; Galvez, J. A.; Lapena, Y. Tetrahedron 1998,
54, 14963–14974.
11. Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Zurbano, M. M. Tetrahedron:
Asymmetry 1997, 8, 863–871.
12. (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993,
115, 10125–10138; (b) Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372.
13. Shoji, M.; Akiyama, N.; Tsubone, K.; Lash, L. L.; Sanders, J. M.; Swanson, G. T.;
Sakai, R.; Shimamoto, K.; Oikawa, M.; Sasaki, M. J. Org. Chem. 2006, 71, 5208–
5220.
14. Masamune, S.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1–30.
15. Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.; Ohfune, Y. Org. Lett.
2007, 9, 1765–1767.
9. Liu, S.; Ben, R. N. Org. Lett. 2005, 7, 2385–2388.
10. These olefination reactions proceeded slowly and required more than 3 equiv
of DBU and phosphonates. Although we attempted several reaction conditions
(the base, the amount of DBU and phosphonates, and reaction period), the
yields were not improved significantly.