Efficient total synthesis of manzacidin B

Article abstract of DOI:10.1016/j.tetlet.2012.04.042

The highly diastereoselective synthesis of the marine natural product, (-)-manzacidin B, is described. A novel copper-catalyzed aldol reaction of the α-methylserine-derived aldehyde with an isocyanoacetate possessing (1R)-camphorsultam as the chiral auxiliary proceeded in a highly diastereoselective manner to give the (4R,5R,6R)-adduct, which was converted into manzacidin B in a few steps.

Full text of DOI:10.1016/j.tetlet.2012.04.042

Tetrahedron Letters 53 (2012) 3250–3253
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Efficient total synthesis of manzacidin B
⇑
⇑
Tetsuro Shinada , Kentaro Oe, Yasufumi Ohfune
Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, 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:
The highly diastereoselective synthesis of the marine natural product, (À)-manzacidin B, is described. A
Received 9 March 2012
Revised 3 April 2012
Accepted 9 April 2012
Available online 20 April 2012
novel copper-catalyzed aldol reaction of the
a-methylserine-derived aldehyde with an isocyanoacetate
possessing (1R)-camphorsultam as the chiral auxiliary proceeded in a highly diastereoselective manner
to give the (4R,5R,6R)-adduct, which was converted into manzacidin B in a few steps.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Manzacidin B
[Bis(N-tert-butylsalicyliden-iminate)]copper
catalyst
Isocyanoacetate aldol reaction
Oppolzer’s camphorsultam
Bromopyrrole alkaloids are a novel family of marine natural
products possessing potentially useful pharmacological activities
the inversion of the stereoselectivity from (4S,5S)-7 to (4R,5R)-6
would provide an efficient synthetic route to manzacidin B. In this
letter, we describe the short and highly stereoselective synthesis of
2 by the Cu-catalyzed aldol reaction using an isocyanoacetate pos-
sessing a chiral auxiliary.
To achieve the requisite (4R,5R)-selectivity in the isocyanoace-
tate aldol reaction, reagent-controlled approaches (screening of
bases and catalysts), substrate-controlled approaches (the use of
structurally alternate aldehydes of 5a), and a double asymmetric
induction9 using a chiral aldol donor were extensively examined
(Scheme 1).
which include
a-adrenoceptor blockers, antagonists of serotoner-
gic receptors, and actomyosin ATPase activators.1 Among them,
manzacidins A (1), B (2), and C (3), isolated from the Okinawan
sponge Hymeniacidon sp. in 1991 by Kobayashi et al., possess a un-
ique structure consisting of an ester-linked bromopyrrolecarboxy-
lic acid and a 3,4,5,6-tetrahydropyrimidine ring in which one of the
amino groups is attached to the C6 quaternary carbon center.2,3
Due to their unique structures and detailed unexploited pharmaco-
logical profiles, the manzacidins have been intriguing synthetic
target molecules.4 The relative and absolute structures of 1 and 3
have been confirmed by our first total syntheses.5a The relative
structure of manzacidin B (2), reported by Kobayashi et al.,2 was
determined by the synthesis of four possible diastereomers with
respect to the C4 and C5 stereogenic centers.6a Finally, the struc-
ture was unambiguously assigned (4R,5R,6R)-2 by the X-ray crys-
tallographic analysis of its synthetic intermediate (4R,5R,6R)-4
(vide infra) (Fig. 1).6b The synthesis of 2 including its enantiomer
and diastereomer has, recently, been reported by Mohapatra et al.4i
In our previous studies, we performed the synthesis of manzac-
idin B using the Cu-catalyzed Ito–Hayashi type aldol reaction7 of
The catalyst screening was carried out according to the previous
reaction conditions6a using 5 mol % Et3N as the base, since other
organic bases, such as i-Pr2NH, i-Pr2NEt, DBU, and DABCO, did
not affect the reaction in terms of the reaction rate, diastereoselec-
Br
Br
HN
6
N
HN
N
H
4
O
O
CO2H
CO2H
CO2H
N
H
N
H
5
H
O
O
OH
Manzacidin A (1)
Manzacidin B (2)
the a-methyl-Garner aldehyde 5a with t-butyl isocyanoacetate as
the key step (Scheme 1). The reaction gave a mixture of trans-oxaz-
olines (4R,5R,6R)-6 and (4S,5S,6R)-7 (future manzacidin number-
ing) in 88% yield. Although the desired adduct 6 corresponding to
the natural 2 was obtained as the minor isomer (6/7 = 1:7),6a,8
ref. 6b
O
Br
OHCHN
HO
HN
N
H
O
O
N
H
O
NHBoc
4 (X-ray analysis)
Manzacidin C (3)
⇑
Corresponding authors. Tel.: +81 6 6605 2570; fax: +81 6 6605 3153 (Y.Ohfune).
E-mail addresses: shinada@sci.osaka-cu.ac.jp (T. Shinada), ohfune@sci.osaka-cu.
ac.jp (Y. Ohfune).
Figure 1. Structures of the manzacidins.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.042

T. Shinada et al. / Tetrahedron Letters 53 (2012) 3250–3253
3251
10b,14 and Oppolzer’s camphorsultam, (1R)-11a, and (1S)-11b.11,15
To investigate the unprecedented reactivity and diastereoselectivity
of the chiral isocyanoacetate aldol reaction, we performed the reac-
tions of 10b and 11b with achiral isobutyraldehyde. These reactions
were catalyzed by Cu(t-butSal)2 to give a mixture of the aldol prod-
ucts in excellent yields. The use of the (1S)-camphorsultam 11b
CN
CO2t-Bu
CuCl (5 mol%)
Et3N (5 mol%)
CO2t-Bu
1 : 7
CO2t-Bu
O
NBoc
CHO
DCE, 4 h
88%
O
N
O
N
(4R,5R)-6
(4S,5S)-7
5a
showed
a
significant (2S,3R)-selectivity ((2R,3S)-14/(2S,3R)-
15 = 1:9), while the (S)-oxazolidinone 10b afforded a 1:1 mixture
of the trans-oxazolines, 12, and 13 (cis/trans = 1/13).16–18 Thus, the
chiral camphorsultam 11 was found to be a superior chiral auxiliary
to the oxazolidinone 10 in view of the single asymmertric induction
(Scheme 3).
Manzacidin B
(4R,5R,6R)-2
natural form
(4S,5S,6R)-
isomer of 2
NR2Boc
NR2Boc
CHO
CN
COXp
R1O
COXp
With these results in hand, we attempted the double asymmet-
ric induction using the chiral aldehydes 5b,c with each enantiomer
of the chiral aldol donors, 10a,b, and 11a,b. Both Evans-type aldol
donors, 10a,b were ineffective for the (4R,5R)-selectivity in all
cases to give a mixture of the corresponding aldol adducts,
((4R,5R)-isomer/(4S,5S)-isomer = 1–2:3),19 as observed during the
aldol reaction of 5b,c with the achiral tert-butyl isocyanoacetate
(1–2:3). On the other hand, the use of camphorsultams, 11a,b
exhibited remarkable diastereoselectivities for the aldol reaction.
To our delight, the reaction of the ring-opened aldehyde 5b with
(1R)-11a showed the (4R,5R)-selectivity for the first time to give
the desired (4R,5R)-16a as the major isomer (59%, 16a/
17a = 13:1). The use of the MOM-protected 5c with (1R)-11a was
the best combination to obtain (4R,5R)-16b20 in view of the yield
and diastereoselectivity (84%, dr = 13:1). The reaction of 5b,c with
(1S)-11b, the enantiomer of 11a, afforded (4S,5S)-19a,b as an
exclusive diastereomer, respectively (Scheme 4).21 The exclusive
formation of (4S,5S)-19a,b (>20:1) from the aldehydes 5b,c with
(1S)-11b can be explained as a matched pair double asymmetric
induction.9 On the other hand, in spite of the mismatched pair be-
tween 5b,c and (1R)-camphorsultam 11a , the chiral auxiliary-
based diastereocontrol would be attributed to the high diastereo-
selective formation of the desired (4R,5R)-16a,b (13:1).
R1O
Cu catalyst
Et3N
R1, R2 = Protecting groups
Xp = Evans' or Oppolzer's chiral auxiliary
O
N
Scheme 1. Previous results and present synthetic plan.
tivity, and yields. Among the screening of several metal catalysts,
Cu(I) significantly accelerated the reaction rate and increased its
yield. In particular, the [bis(N-tert-butylsalicyliden-iminate)]cop-
per (Cu(t-butSal)2) catalyst dramatically enhanced the reaction
rate and its yield (5 min, 94%) in comparison to CuCl (4 h, 88%).
However, the diastereomeric ratio of the products, (4R,5R)-6/
(4S,5S)-7, was not affected by this and other catalysts.10 We con-
sidered that the above propensities would be due to the rigid
and densely functionalized structure of the aldehyde 5a which
facilitated the substrate-controlled aldol reaction. Therefore, we
turned our attention to the use of the ring-opened aldol acceptors
5b,c,11 readily prepared from -methylserine.12
a
The treatment of 5b,c under the same reaction conditions gave
a mixture of the trans-oxazolines, in which the undesired (4S,5S)-
selectivity was decreased, that is (4R,5R)-8a/(4S,5S)-9a = 1:3 and
(4R,5R)-8b/(4S,5S)-9b = 2:3 (Scheme 2).5b,13 These results indi-
cated that the released ring constraint of the aldol acceptors
was moderately associated with the diastereoselectivity
(6:7 = 1:7 vs 8:9 = 1–2:3).
A proposed transition state model of the chiral camphorsultam
aldol reaction to give 16b is depicted in Scheme 5. To avoid steric
and/or electronic repulsions between the isocyanide and sulfone
groups, the Z-enolate would be preferentially formed.15,16 In this
These results as mentioned above led us to speculate that the
combination of the ring-opened aldehyde 5b,c with an isocyanoac-
etate possessing a chiral auxiliary would inverse the undesired
(4S,5S)-selectivity to the desired (4R,5R)-isomer by the double
asymmetric induction, while the aldol reaction using a chiral isocy-
anoacetate has not yet been reported. We chose both enantiomers of
the isocyanoacetate bearing Evans’ oxazolidinone, (R)-10a, and (S)-
O
O
Cu(t-butSal)2 (5 mol%)
Et3N (5 mol%)
CN
N
O
+
CHO
DCE, rt, 5 min
80%
Bn
(S)-oxazolidinone 10b
O
O
O
O
N
O
N
O
+
O
N
O
N
Cu(t-butSal)2 (5 mol%)
Bn
Bn
(2S,3R)-13
NHBoc
CHO
Et3N (5 mol%)
(2R,3S)-12
+
CN
CO2t-Bu
12 : 13 = 1 : 1
RO
DEC, rt, 5 min
87% from 5b
91% from 5c
(1.2 eq)
5b R = TBS
5c R = MOM
O2
Cu(t-butSal)2 (5 mol%)
S
N
Et3N (5 mol%)
CN
+
CHO
NHBoc
NHBoc
DCE, rt, 5 min
93%
O
RO
5
4
CO2t-Bu
RO
CO2t-Bu
+
(1S)-sultam 11b
O
N
O
N
8a : 9a = 1 : 3
O
O
8b : 9b = 2 : 3
O2
O2
S
(4R,5R)-8a R = TBS
(4R,5R)-8b R = MOM
(4S,5S)-9a R = TBS
(4S,5S)-9b R = MOM
S
N
N
+
O
N
O
N
t-Bu
N
Cu
O
O
N
(2R,3S)-14
(2S,3R)-15
14 : 15 = 1 : 9
Cu(t-butSal)2
t-Bu
Scheme 3. Chiral auxiliary-assisted isocyanoacetate aldol reactions with
Scheme 2. Cu(t-butSal)2-catalyzed aldol reaction of 5b,c.
isobutyraldehyde.

3252
T. Shinada et al. / Tetrahedron Letters 53 (2012) 3250–3253
aldehyde 5c to 2, which did not involve any oxidation-reduction
sequences, included six steps and the overall yield was 48% (38%
from (R)- -methylserine). The key to the total synthesis was the
Cu(t-butSal)2 (5 mol%)
NHBoc
CHO
5b R = TBS
5c R = MOM
O
Et3N (5 mol%)
+
RO
CN
a
N
DCE, rt
S
Cu(t-butSal)2-catalyzed isocyanoacetate aldol reaction of the alde-
hyde 5c with (1R)-11a to give (4R,5R)-16b (13:1) in which the
undesired (4S,5S)-isomer was the predominant product upon the
aldol reaction of the structurally rigid aldehyde 5a with an achiral
isocyanoacetate. The Oppolzer’s camphorsultam was proven to be
an excellent chiral auxiliary for the diastereoselective isocyanoac-
etate aldol reactions even for mismatched pair double asymmetric
induction. Current efforts are focused on further application of the
present method for the synthesis of highly functionalized natural
products having consecutive amino and hydroxy groups.
O2
= 13 : 1 (59%)
16a : 17a
16b : 17b
= 13 : 1 (84%)
(1R)-sultam 11a
NHBoc
O
NHBoc O
+
RO
RO
5
4
N
N
S
S
O2
O2
O
N
O
N
(4R,5R)-16a or 16b
(4S,5S)-17a or 17b
16a-19a R = TBS
16b-19b R = MOM
O2
Cu(t-butSal)2 (5 mol%)
Acknowledgments
S
N
NHBoc
CHO
Et3N (5 mol%)
CN
+
RO
This study was supported by Grants-in-Aid (Nos. 16201045,
16073214, 18510191, 19201045, and Innovative Areas ‘Chemical
Biology of Natural Products’) for Scientific Research from the Japan
Society for the Promotion of Science (JSPS) and the Ministry of Edu-
cation, Culture, Sports, Science, and Technology, Japan.
DCE, rt
O
= 1 : >20 (51%)
= 1 : >20 (72%)
5b R = TBS
5c R = MOM
18a : 19a
18b : 19b
(1S)-sultam 11b
NHBoc
O
NHBoc O
O2
S
O2
S
+
RO
RO
5
4
N
N
Supplementary data
O
N
O
N
Supplementary data associated with this article can be found, in
(4R,5R)-18a or 18b
(4S,5S)-19a or 19b
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.
2012.04.042.
Scheme 4. Aldol reactions of ring-opened aldehydes 5b,c with isocyanoacetate
bearing the chiral camphorsultam.
References and notes
1. (a) Scala, F.; Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O.; Tierney, M.;
Kaiser, M.; Tasdemir, D. Mar. Drugs 2010, 8, 2162–2174; (b) Aiello, A.;
Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O. In Modern Alkaloids;
Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-VCH, 2007; pp 271–304; (c)
Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M.
R. Nat. Prod. Rep. 2008, 25, 35–94; (d) 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; (e) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2003, 20, 1–48; (f) Faulkner, D. J.
Nat. Prod. Rep. 2002, 19, 1–48; (g) Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113–
158.
O
H
5c
*
R
Et3N
C
L
Cu
H
O
O
(4R,5R)-16b
N
N
O
NHBoc
S
(1R)-11a
R* =
MOMO
O
H
*
R
2. Kobayashi, J.; Kanda, F.; Ishibashi, M.; Shigemori, H. J. Org. Chem. 1991, 56,
4574–4576.
3. Manzacidin D. The N-1 methylated debromo form of manzacidin A was isolated
from a fossil sponge, see: Jahn, T.; Konig, G. M.; Wright, A. D.; Worheide, G.;
Reitner, J. Tetrahedron Lett. 1997, 38, 3883–3884.
O
AcOH, THF, H2O
(3 : 1 : 1)
1. 6 N HCl
OHCHN
HO
2.
the same procedure
O
16a
16b
as those of 20 to 2
rt, 4 d
84%
4. For the total synthesis of manzacidins A and/or C: (a) Wehn, P. M.; Du Bois, J. J.
Am. Chem. Soc. 2002, 124, 12950–12951; (b) Lanter, J. C.; Chen, H.; Zhang, X.;
Sui, Z. Org. Lett. 2005, 7, 5905–5907; (c) Kano, T.; Hashimoto, T.; Maruoka, K. J.
Am. Chem. Soc. 2006, 128, 2174–2175; (d) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 3928–3930; (e) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett.
2007, 9, 1553–1556; (f) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem.
Soc. 2007, 129, 768–769; (g) Tran, K.; Lombardi, P. J.; Leighton, J. L. Org. Lett.
2008, 10, 3165–3167; (h) Ichikawa, Y.; Okumura, K.; Matsuda, Y.; Hasegawa, T.;
Nakamura, M.; Fujimoto, A.; Masuda, T.; Nakano, K.; Kotsuki, H. Org. Biomol.
Chem. 2012, 10, 614–622; For the synthesis of manzacidin B: (i) Sankar, K.;
Rahman, H.; Das, P. P.; Bhimireddy, E.; Sridhar, B.; Mohapatra, D. K. Org. Lett.
2012, 14, 1082–1085; For the synthesis of manzacidin D: (j) Drouin, C.; Woo, J.
C. S.; MacKay, D. B.; Lavigne, R. M. A. Tetrahedron Lett. 2004, 45, 7197–7199; For
a review: (k) Hashimoto, T.; Maruoka, K. Org. Biomol. Chem. 2008, 6, 829–835.
5. (a) Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122,
10708–10709; (b) Oe, K.; Shinada, T.; Ohfune, Y. Tetrahedron Lett. 2008, 49,
7426–7429.
NHBoc
Manzacidin B (2)
57% from 16b
4
1. 1 N LiOH
2. 6 N HCl
NH2 NH2
CO2H
HO
H
OH
20
Scheme 5. Proposed transition state model and conversion to manzacidin B.
model, approaches from the re-face of the Z-enolate of (1R)-11a
and the re-face of the aldehyde 5c would be the kinetically favored
process to give (4R,5R)-16b as the major diastereomer. The struc-
ture of 16a was unambiguously assigned to the (4R,5R,6R)-isomer
by converting it into the corresponding aminolactone 4 and its X-
ray crystallographic analysis (vide supra).22 Finally, the removal of
the camphorsultam group of the MOM-protected 16b under alka-
line hydrolysis followed by acidic treatment gave the amino acid
20, which, upon a three step conversion using our established
method,5 gave manzacidin B (2).23
6. (a) Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.; Ohfune, Y. Org. Lett.
2007, 9, 1765–1767; (b) Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.;
Ohfune, Y. Org. Lett. 2010, 12, 2170.
7. (a) Ito, Y.; Matsuura, T.; Saegusa, T. Tetrahedron Lett. 1985, 26, 5781–5784; (b)
Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405–6406; (c)
Togni, A.; Pastor, S. D. Helv. Chim. Acta 1989, 72, 1038–1042.
8. According to the transition state model proposed by Ito–Hayashi et al.,7 the
trans selectivity at C4 and C5 is derived from the enolate geometry to be Z and
the facial selectivity either 5R or 5S is controlled by the chiral catalyst in which
the internal organic base chelates to both the aldol donor and acceptor.
However, the stereochemical outcome of the undesired (4S,5S)-selectivity in
this case remained uncertain due to the structural complexity of the aldol
acceptor 5a which possessed an aldehyde attached to the quaternary carbon
center with the sterically bulky and polar functional groups
In summary, we have developed a short and diastereoselective
route to manzacidin B. The total number of processes from the

T. Shinada et al. / Tetrahedron Letters 53 (2012) 3250–3253
3253
9. Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl.
1985, 24, 1–30.
P. A., ; Smith, A. B., III J. Am. Chem. Soc. 1996, 118, 3584–3590. and other
references cited therein..
10. The examined catalysts (5 mol %), reaction time, and the ratio of 6/7 were as
follows: Cu(acac)2, 2 h, 1:9 (88% yield); Cu(salen), 72 h, 1:9 (85%); Cu(TPP), 2 h,
1:9 (57%); Ag(acac)2, 24 h, 1:8 (52%); AuCl, 168 h, 1:6 (89%); Pd(acac)2, 72 h,
1:5 (52%); without catalyst for 24 h, a trace amount of a mixture of 6/7 was
produced (ratio not determined).
19. The reactions of 5a–c with 10a, b in the presence of 5 mol % Cu(t-butSal)2 and
5 mol % Et3N in 1,2-dichoroethane at room temperature for 5 min afforded a
mixture of the (4R,5R)- and (4S,5S)-oxazolines. Their (4R,5R)- and (4S,5S)-
ratios were as follows: 5a with 10a = 3:4 (78% yield), 5a with 10b = 2:3 (68%),
5b with 10a = 2:3 (57%), 5b with 10b = 1:2 (55%), 5c with 10a = 2:3 (81%), and
5c with 10b = 2:3 (62%).
11. Preparation of 5b, see ref 5b. Preparation of 5c, and 11a, b, see Supplementary
data.
20. No interconversion between the aldol products 16b and 17b was observed
when the mixture was treated under the same reaction conditions.
21. The reaction of the acetonide 5a with each enantiomer of the camphorsultams
11a, b afforded a mixture of the corresponding aldol adducts. The ratios were
as follows: 5a with 11a, (4R,5R)/(4S,5S)-isomer = 2:1 (51%); 5a with 11b,
(4R,5R)/(4S,5S)-isomer = 1:20 (58%).
12. (a) Moon, S. –H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405–7406; (b) Alias,
M.; Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A.; Lapena, Y. Tetrahedron
1998, 54, 14963–14974; (c) Ohfune, Y.; Shinada, T. Bull. Chem. Soc. Jpn. 2003,
76, 1115–1129.
13. The product’s ratio was calculated from the 1H NMR spectra of the mixture. The
major isomers were assigned as the (4S,5S,6R)-isomers, 9a, b, by converting
them to the mixture of amino acids, 20 and its (4S,5S,6R)-isomer.6b See
Supplementary data.
22. The structure revision of manzacidin B in our previous paper 6b was guided by
this study involving the X-ray structural analysis of the aminolactone 4, and its
conversion to (4R,5R,6R)-manzacidin (2) whose spectroscopic data (1H and 13
C
14. Tang, J. S.; Verkade, J. G. J. Org. Chem. 1996, 61, 8750–8754.
15. (a) Oppolzer, W. Tetrahedron 1987, 43, 1969–2004; (b) Oppolzer, W. Pure Appl.
Chem. 1990, 62, 1241–1250.
NMR) as well as the sign of the optical rotation were identical to those of the
natural 2. For details of the preparation of the aminolactone 4 from 16a and its
conversion to 2, see the Supplementary data.
16. For
a
recent example of the Michael reaction with camphorsultam; see
23. Since manzacidins A and C are configurational isomers at C6 to be either 6S or
6R, we proposed that both natural products were biosynthesized from an (S)-
Kaniskan, H. Ü.; Garner, P. J. Am. Chem. Soc. 2007, 129, 15460–15461.
17. The stereochemistry of the major product was assigned to (2S,3R)-15 by
converting it into (2S,3R)-3-hydroxyisoleucine whose spectroscopic data as
well as the sign of the optical rotation were completely identical to the
reported values.18 See Supplementary data.
a
-amino acid.5a Based on this hypothesis, we considered that the structure of
manzacidin
B would be a C5 hydroxylated form of manzacidins A or C.
However, the absolute structure of manzacidin B, confirmed by our previous6b
and present studies, suggested its possible biosynthetic pathway as follows: (i)
18. For the synthesis of the optically active 3-hydroxyleucine; (a) Fraunhoffer, K. J.;
White, M. C. J. Am. Chem. Soc. 2007, 129, 7274–7276; (b) Makino, K.; Okamoto,
N.; Hara, O.; Hamada, Y. Tetrahedron: Asymmetry 2001, 12, 1757–1762; (c)
Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P. J. Org. Chem. 2000, 65,
7663–7666; (d) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler,
manzacidin
biosynthetic pathway from manzacidins
involved an epimerization at C4 after the hydroxylation of manzacidin C at C5
since both manzacidins B and C possessed the same (6R)-configuration.
B
was derived from an (R)-
a
-amino acid via
a different
A
and C, or (ii) its biosynthesis