Stereoselective synthesis of (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid and determination of the absolute stereochemistry of the natural product from callipeltin A

Article abstract of DOI:10.1016/S0957-4166(02)00328-2

A revised stereostructure of 3-hydroxy-2,4,6-trimethylheptanoic acid, the β-hydroxy acid that acylates the N-terminus of callipeltin A, is proposed on the basis of analysis of J-coupling in the ¹H NMR spectrum of the acetonide derivative obtain

Full text of DOI:10.1016/S0957-4166(02)00328-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1237–1239
Stereoselective synthesis of
(2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid and
determination of the absolute stereochemistry of the natural
product from callipeltin A
Angela Zampella and Maria Valeria D’Auria*
Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli ‘Federico II’, via D. Montesano 49,
80131 Naples, Italy
Received 3 June 2002; accepted 20 June 2002
Abstract—A revised stereostructure of 3-hydroxy-2,4,6-trimethylheptanoic acid, the b-hydroxy acid that acylates the N-terminus
1
of callipeltin A, is proposed on the basis of analysis of J-coupling in the H NMR spectrum of the acetonide derivative obtained
from the acid hydrolysate of callipeltin A. The proposed structure was definitively confirmed by enantioselective synthesis. © 2002
Elsevier Science Ltd. All rights reserved.
Recently, we reported the synthesis of (2R,3R,4S)-3-
hydroxy-2,4,6-trimethylheptanoic acid, the proposed b-
hydroxy acid unit that acylates the N-terminus of
protons.3 Thus, the (2R,3R) configuration was firmly
established.
1
callipeltin A 1.1 However, we found that its H NMR
From these results we reached the conclusion that the
correct stereochemistry of the natural b-hydroxy acid 2
must be (2R,3R,4R). This revised stereochemistry has
been confirmed by enantioselective synthesis as
described herein.
spectral data were not identical with those of the corre-
sponding unit obtained from the acid hydrolysate of
callipeltin A 1, thus indicating that the absolute
configuration of the aforementioned natural unit
should be revised. Because the (3R)-stereochemistry at
the carbinol centre was unambiguously established by a
modified Mosher’s method,2 the stereochemical revision
should concern the C(2) stereogenic centre, the C(4)
stereogenic centre, or both.
Our planned synthetic route to the above fragment 2,
outlined in Scheme 2, is similar to that used for the
synthesis of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylhept-
anoic acid.1 Indeed we elaborated a flexible synthetic
strategy which was amenable to the construction of the
different stereoisomers of the b-hydroxy acid unit in 1.
In order to gain more insights into the stereochemistry
of the natural b-hydroxy acid unit, we subjected a 40
mg sample of callipeltin A 1 to acid hydrolysis followed
by dichloromethane extraction, to obtain 4.0 mg of the
natural b-hydroxy acid 2. This latter was readily trans-
formed in the 1,3-O-isopropylidene derivative 4 by the
three steps sequence depicted in the Scheme 1. The
vicinal coupling constant for H2/H3 (8.2 Hz) was
indicative of an anti-relationship between these two
In this case Brown’s crotylboration4 was selected as the
key step for the assembly of the C3ꢀC4 anti-propionate
unit in b-hydroxy acid 2. Thus, aldehyde 8, obtained in
high yield (three steps, 87%) from commercially avail-
able methyl (2S)-2-methyl-3-hydroxy propionate 5, was
reacted with the allyl borane derived from (+)-B-
methoxydiisopinocampheyl borane and (E)-butene to
give the anti-homoallylic alcohol 9. The diastereomeric
purity of 9 was >98% as judged by the NMR spectra of
the crude reaction mixture. We encountered difficulties
in separating 9 in acceptable yield from the isopinocam-
pheol arising from the reaction. Thus, crude 9 was
converted into the TBS-protected derivative 10 which
was easily separated from the protected isopinocam-
* Corresponding author. Tel.: +39-081/678-527; fax: +39-081/678-552;
e-mail: madauria@cds.unina.it
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00328-2

1238
A. Zampella, M. V. D’Auria / Tetrahedron: Asymmetry 13 (2002) 1237–1239
NH2
O
OH
NH
OH
O
O
H
N
O
H2N
N
H
N
H
N
H
NH
NH2
O
NH OH
O
O
HN
O
N
H
HN
O
O
NH
MeN
O
O
O
OH
a
MeO
NMe
O
OH
N
H
OH
O
NH2
2
3
Callipeltin A 1
b, c
OH
OH
3
Coupling constants
1
4
2
JH2-H3 = 8.2 Hz
d
OH
O
O
4
J
H3-H4 = 3.3 Hz
Scheme 1. Reagents and conditions: (a) HCl 6N, 130°C, 6 h, then CH2Cl2 extraction; (b) CH2N2, rt, quantitative; (c) LiBH4, dry
MeOH, 2 h, 96%; (d) dimethoxypropane dry, p-TsOH (cat.), quantitative.
MeO
OH
MeO
OBn
OBn
OBn
HO
a
c
b
5
8
7
6
9
O
O
d
g
f
e
H
OBn
OBn
O
OH
OTBS
10
h
i
H
OBn
OH
OBn
O
OTBS
11
OTBS
OTBS
12
13
l
OH
OH
TBSO
14
O
OH
O
2
Scheme 2. Reagents and conditions: (a) BTCA, TfOH, 0°C to rt, 3 h, 94%; (b) LiBH4, dry MeOH, 2 h, 96%; (c) DMSO, (COCl2),
−78°C, 30 min, then 7, Et3N, −78°C to rt, 1 h, 97%; (d) t-BuOK, (E)-but-2-ene, n-BuLi, −78 to −45°C, (+)-B-methoxydi-
isopinocampheylborane, BF3·OEt2, aldehyde 8, −78°C, 4 h; (e) 2,6-lutidine, TBSOTf, 0°C to rt, 2 h, 76%, two steps; (f)
OsO4/N-methylmorfoline-N-oxide, rt, 12 h, then H5IO6 15 min, 97%; (g) isopropyltriphenylphosphonium iodide, n-BuLi, rt 3 h,
84%; (h) H2/Pd(OH)2, 3 atm, 2 days, 90%; (i) NaIO4/RuCl3·H2O (cat.), 97%; (l) MeOH/HCl, 25°C, 3 h, quantitative.
pheol by silica gel chromatography (76% yield of 10
from 8).5 Oxidative cleavage of the terminal double
bound (OsO4, NMO, acetone–water, H5IO6) led to the
aldehyde 11. This latter was subjected to the same
reaction sequence previously developed by us for the
synthesis of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylhept-
anoic acid.1 Thus, Wittig olefination followed by one-
pot reduction of the alkene bond and removal of the
benzyl protecting group, afforded alcohol 13 which was
smoothly oxidised to the protected b-hydroxy acid 14.
unit 2, unambiguously defined the (2R,3R,4R)-configu-
ration. Further confirmation of the absolute stereo-
chemistry of natural 2 was obtained from comparison
of specific rotation data (synthetic 2: [h]D=+14.9, (c
0.4), CHCl3; natural 2: [h]D=+14.4, (c 0.4, CHCl3).
In conclusion, the stereochemistry of the b-hydroxy
acid unit that acylates the N-terminus of the cyclodep-
sipeptide callipeltin A 1 was definitively established by
asymmetric synthesis. Furthermore, our synthesis of
the protected b-hydroxy acid 14 is short (nine steps
from the commercially available L-malate dimethyl
ester 5), efficient (47% overall yield) and amenable to
scale-up.
The complete overlap of the NMR data of the synthetic
derivative 2,6 obtained by acid hydrolysis of 14
(MeOH/HCl), with that of the corresponding natural

A. Zampella, M. V. D’Auria / Tetrahedron: Asymmetry 13 (2002) 1237–1239
1239
Acknowledgements
acetonide Me), 1.20 (1H, m, H-5a), 1.13 (1H, m, H-5b),
0.94 (3H, d, J=6.6 Hz, Me-8), 0.90 (3H, d, J=6.6 Hz,
Me-9), 0.86 (3H, d, J=6.6 Hz, Me-10), 0.84 (3H, d, J=6.6
Hz, Me-7).
This work was supported by grants from MURST
(PRIN 2001) ‘Sostanze naturali ed analoghi sintetici ad
attivita` antitumorale’ Rome, Italy. Mass spectra were
provided by the CRIAS Centro Interdipartimentale di
Analisi Strumentale, Faculty of Pharmacy, University
of Naples. We acknowledge the ungraduated student
Luigi Fontana for his kind assistance and the staff are
also acknowledged. The NMR spectra were recorded at
CRIAS Centro Interdipartimentale di Analisi Strumen-
tale, Faculty of Pharmacy, University of Naples.
4. Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem.
1989, 54, 1570–1576.
5. NMR data (CDCl3, 500 MHz) and specific rotation (chlo-
roform) for compound 10. 1H NMR l: 7.34 (5H, m,
benzyl), 5.95 (1H, m, H-5), 5.03 (1H, d, J=5.2, H-6a), 5.0
(1H, s, H-6b), 4.50 (2H, s, benzylic CH2), 3.60 (2H, m,
H-1a, H-3), 3.40 (1H, t, J=8.8 Hz, H-1b), 2.41 (1H, m,
H-4), 2.01 (1H, m, H-2) 1.08 (3H, d, J=6.6 Hz, Me-4),
1.02 (3H, d, J=6.6 Hz, Me-2), 0.95 (9H, s, Si-C(CH3)3, 0.1
(3H, s, Si-(CH3)), 0.12 (3H, s, Si-(CH3); 13C NMR l:
141.3, 138.8, 128.3, 127.6, 127.4, 115.1, 79.6, 77.8, 73.0,
72.9, 42.0, 38.2, 26.1, 18.4, 18.2, 14.9, −3.8, −4.0; [h]D=
−4.3 (c 2.2, CHCl3).
References
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2002, 13, 681–685.
1
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H-4), 1.64 (1H, m, H-6), 1.26 (3H, d, J=7.7 Hz, Me-2),
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