Asymmetric total synthesis of (+)-carneic acid A and structure revision of its natural form

Article abstract of DOI:10.1016/j.tetlet.2009.07.024

This Letter describes the asymmetric total synthesis of (+)-carneic acid A via the stereoselective IMDA reaction of (E,E,E)-triene, which was prepared from the commercially available methyl (S)-3-hydroxy-2-methylpropionate. By this asymmetric total synthe

Full text of DOI:10.1016/j.tetlet.2009.07.024

Tetrahedron Letters 50 (2009) 5372–5375
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric total synthesis of (+)-carneic acid A and structure revision
of its natural form
*
Shuhei Yamakoshi, Nobuyuki Hayashi, Takahiro Suzuki, Masahisa Nakada
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the asymmetric total synthesis of (+)-carneic acid A via the stereoselective IMDA
reaction of (E,E,E)-triene, which was prepared from the commercially available methyl (S)-3-hydroxy-
2-methylpropionate. By this asymmetric total synthesis, we verified that the reported absolute structure
of naturally occurring carneic acid A must be revised.
Received 17 June 2009
Revised 3 July 2009
Accepted 7 July 2009
Available online 10 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Carneic acid A was isolated as a major constituent of the stro-
mata of Hypoxylon carneum, which showed a highly specific sec-
ondary metabolite profile in the study on xylariaceous
ascomycetes using HPLC profiling.1 Carneic acids showed weak
antibacterial and moderate antifungal activities against selected
microbial organisms in the serial dilution assay.1 The relative ste-
reochemistry of naturally occurring carneic acid A was determined
based on the NMR data, and its absolute structure was elucidated
by using the exciton chirality method.1 The final absolute structure
of naturally occurring carneic acid A was reported as that shown in
Figure 1.
Although carneic acid A shows weak bioactivities, we were
interested in its reported structure because it is closely related to
that of phomopsidin (2) and MK8383 (3) (Fig. 1). The relative con-
figuration of the reported structure of 1 is identical to that of 2, ex-
cept for the presence of the C12 stereogenic center; however, the
reported structure of 1 is almost a mirror image of that of 2.
In 20042 and 2009,3 we reported the first total syntheses of 2
and 3, respectively. Therefore, to explore the structure–activity
relationships of these related compounds and to confirm the abso-
lute structure of 1, we carried out the asymmetric total synthesis of
1 and report herein the revised structure of the naturally occurring
carneic acid A as well as the first asymmetric total synthesis of (+)-
carneic acid A.
which would be converted to 1 via the formation of alkyne 4; this
conversion was thought to be possible when it was carried out
according to the method used in the total syntheses of 2 and 3.
The IMDA substrate 6 can be prepared from the aldehyde 7 by its
Horner–Wadsworth–Emmons (HWE) reaction and then subjecting
it to the reduction-oxidation sequence. The aldehyde 7 is expected
to be prepared via the Suzuki–Miyaura coupling of the alkyne 8
with the iodoalkene 9.
The alkyne 8 was prepared using methyl (S)-3-hydroxy-2-
methylpropionate as the starting material by following the proce-
dure reported2 for the preparation of ent-8 (Scheme 2). Then, the
Suzuki–Miyaura coupling5 of 8 with 9 was carried out. The alkyne
8 was first made to react with 9-BBN and then treated with benz-
aldehyde to convert the byproduct, a 1,1-bisboryl adduct, into the
desired trans-alkenylborane;6 finally, the trans-alkenylborane
formed was reacted with 9 under the conditions shown in Scheme
2. The coupling reaction proceeded successfully; however, the
product 10 was found to have structurally unknown impurities.
Therefore, the crude product 10 was used in the next step without
purification. The crude product 10 was treated with PPTS in etha-
nol, and to our delight, we obtained pure alcohol 11 by silica gel
chromatography (76%, two steps). The oxidation of 11 with
The total syntheses of 2 and 3 were successfully carried out via
the transannular Diels–Alder (TADA) reaction of a 13-membered
macrolide; this reaction effectively led to the formation of the
cis-dehydrodecaline core that is incorporated in 2 and 3. On the
other hand, carneic acid A consists of a trans-dehydrodecaline core,
which is speculated to be formed by the intramolecular Diels–Al-
der (IMDA) reaction of a substrate having a (E,E,E)-triene moiety.4
Consequently, the IMDA reaction of the linear precursor 6
(Scheme 1) was considered to yield the trans-fused compound 5,
CO2H
CO2H
H
H
H
H
R2
12
R1
HO
HO
phomopsidin (2): R1 = H, R2 = Me
carneic acid A (1) MK8383 (3): R1 = Me, R2 = H:
* Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
Figure 1. Structures of carneic acid A, phomopsidin, and MK8383.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.024

S. Yamakoshi et al. / Tetrahedron Letters 50 (2009) 5372–5375
OTBS
5373
CHO
1) Et2AlCl (1.0 equiv)
CH2Cl2, _30 oC, 4 h
H
H
2) NaBH4, EtOH, 0 o
71%, dr = 7/1
C
carneic acid A (1)
OBn
TIPSO
TIPSO
6
4
OH
CHO
H
CHO
H
OBn
OBn
IMDA
reaction
H
TIPSO
H
OBn
13
TIPSO
TIPSO
5
6
Scheme 3.
CHO
of 12 (95%) followed by Dess–Martin oxidation (86%) yielded the
aldehyde 6, which serves as the substrate for the IMDA reaction.
As the IMDA reaction of 6 proceeded sluggishly at elevated tem-
perature, we examined the Lewis acid-catalyzed IMDA reaction.
Among the various Lewis acids examined, EtAlCl2 effectively accel-
erated the IMDA reaction of 6 at ꢀ30 °C to afford the desired prod-
uct 5, which was reduced with NaBH4 to afford 13 in 71% yield
(two steps) with a diastereomeric ratio of 7/1 (Scheme 3). The crys-
talline triol 13a (Fig. 2), which was derived from the major product
13, was suitable for X-ray crystallographic analysis to confirm its
absolute structure,7 because it was synthesized from a structurally
known starting compound, that is, methyl (S)-3-hydroxy-2-meth-
ylpropionate. Although the minor product was not a crystalline
derivative, analysis of the NOESY spectrum of its dinitrobenzoate
derivative indicated that the minor compound has a cis-fused core.
However, the whole structure has not been determined.
Horner-Wadsworth-
Emmons reaction
OBn
TIPSO
OEE
7
+
I
OBn
Suzuki-
TIPSO
Miyaura
9
coupling
8
Scheme 1.
Dess–Martin periodinane (89%) and subsequent HWE reaction
afforded an
a
,b-unsaturated ester 12 (96%); the DIBAL reduction
The cycloadduct 13 was converted to the TBS ether (92%)
(Scheme 4), and then, the benzyl group was removed by lithium
naphthalenide to give 14 (93%). The Dess–Martin oxidation of 14
(88%) followed by the Corey–Fuchs protocol8 gave the alkyne 4.
Negishi’s carbometalation–iodination protocol9 was carried out
under Wipf’s conditions10 to afford 15 in a yield of 86%. The
Pd(0)-catalyzed coupling reaction11 of 15 with dimethylzinc pro-
ceeded smoothly and was followed by the selective removal of
the TBS group and Dess–Martin oxidation to produce the aldehyde
16.
The HWE reaction of aldehyde 16 with phosphonate, with
which it would react to give the TIPS-protected carneic acid A, gave
no products under the same conditions as those used in the total
synthesis of phomopsidin (2). However, the HWE reaction of 16
with triethyl phosphonoacetate under Masamune’s conditions12
OEE
ref. 2
OH
MeO2C
TIPSO
TIPSO
methyl (S)-3-hydroxy-
2-methylpropionate
8
(i) 9-BBN, THF, reflux
(ii) PhCHO, room temp
OEE
(iii) 9 (1.5 eq)
OBn
[Pd2(dba)3] -CHCl3 (1 mol %)
AsPh3 (5 mol %)
10
1M-KOH (3.0 eq)
DMF, THF, room temp
OH
proceeded slowly to afford the
a,b-unsaturatedester 17 (96%).
PPTs (cat.)
The NMR studies of 16 suggested that the epimerization of the
C6 stereogenic center occurred during the HWE reaction.13 To con-
firm the occurrence of this epimerization, 17 was converted to the
corresponding enal by subjecting it to the reduction (90%)-oxida-
OBn
EtOH, room temp
TIPSO
76% (2 steps)
11
CO2Et
1) DMP, CH2Cl2
room temp, 89%
2) (EtO)2P(O)CH2CO2Et
OBn
TIPSO
DIPEA, LiCl, CH3CN
room temp, 96%
12
CHO
1) DIBAL-H, CH2Cl2
_78 oC, 1 h, 95%
2) DMP, CH2Cl2
room temp, 86%
OBn
TIPSO
Scheme 2.
6
Figure 2. X-ray crystallographic structure of 13a.

5374
S. Yamakoshi et al. / Tetrahedron Letters 50 (2009) 5372–5375
1) TBSCl, Et3N
DMAP, CH2Cl2
room temp, 92%
CHO
OTBS
OH
H
vinylmagnesium bromide
THF, 0 oC, 96%
H
H
13
H
2) Li, naphthalene
THF, 0 oC
5 min, 93%
TIPSO
16
TIPSO
14
HO
H
1) SOCl2, Py, THF
room temp, 67%
1) DMP, CH2Cl2
OTBS
room temp, 88%
2) CBr4, PPh3, CH2Cl2
room temp, 59%
H
H
2) DMSO, NaHCO3
toluene, 80 oC, 73%
H
TIPSO
3) nBuLi, THF
18
TIPSO
_78 oC, 83%
4
CHO
OTBS
1) (EtO)2P(O)CH2CO2Et
DIPEA, LiCl, CH3CN
room temp, quant
H
H
Cp2ZrCl2 (10 eq), Me3Al (30 eq)
I
H2O (10 eq), CH2Cl2, -20 to 0 o
C
H
H
2) LiOH-H2O, EtOH, H2O
room temp, 71%
then, I2 (20 eq), THF, r.t., 2 h, 86%
TIPSO
H
3) TBAF, THF
15
TIPSO
room temp, quant
19
1) PdCl2(PPh3)2 (5 mol %)
Me2Zn (1.5 eq), THF
room temp, quant
CHO
CO2Me
CO2H
2) PPTs (cat.), EtOH
room temp, 72%
H
TMSCHN2
TIPSO
PhH, MeOH
3) DMP, CH2Cl2
room temp, 95%
H
H
H
16
room temp
89%
CO2Et
H
(EtO)2P(O)CH2CO2Et
DBU, LiCl, CH3CN
HO
HO
(+)-carneic acid A
H
H
20
8
6
room temp, 2 days, 96%
Scheme 5.
TIPSO
17
1) DIBAL, CH2Cl2
_78 oC, 90%
2) DMP, CH2Cl2
CO2H
CO2H
room temp, 84%
3) (EtO)2P(O)CH2CO2Et
DIPEA, LiCl, CH3CN
room temp, 94%
H
H
H
H
4) LiOH-H2O, EtOH, H2O
room temp, 72%
5) TBAF, THF
HO
HO
(_)-carneic acid A (natural product)
C6-epi-carneic acid A
room temp, 91%
Figure 3. Revised absolute structure of naturally occurring carneic acid A.
Scheme 4.
Although all spectroscopic data of the synthesized carneic acid
A methyl ester 20 were nearly identical to the reported data,15
the specific rotation of the synthesized carneic acid A was found
tion (84%) sequence followed by the HWE reaction (94%), hydroly-
sis of the ester (72%), and removal of the TIPS ether (91%) to afford
the final product. This compound was not identical to the naturally
to be ½a 2D8
ꢁ
+1.30 (c 0.4, CHCl3); this value was different from that
of naturally occurring carneic acid A, that is, ½a D20
ꢁ
ꢀ4.0 (c 0.5,
occurring carneic acid A. Thus, it was confirmed that the a,b-unsat-
CHCl3).1,12 Moreover, the CD spectrum of the p-nitrobenzoate der-
ivate of 20 showed negative (283 nm) and positive (243 nm) Cot-
ton effects, which are reverse of those described in the literature.1
With the difference in sign (+ and ꢀ) in both their specific rota-
tion and their CD spectrum, we speculate that the absolute struc-
ture of the naturally occurring carneic acid, (ꢀ)-carneic acid A,
corresponds to that shown in Figure 3, and that the compound syn-
thesized in our study must be its antipode, that is, (+)-carneic acid
A because the total synthesis was carried out using a known start-
ing compound having a definite absolute configuration.16
urated ester 17 has a C6 configuration dissimilar to that of carneic
acid A, and the final product was thought to be the C6-epimer of
carneic acid A.
The reaction of 16 with a bulky nucleophile was slow, while its
reactions with small nucleophiles afforded the products. Therefore,
16 was made to react with a vinylmagnesium bromide to afford the
allylic alcohol 18 (96%), which was converted to primary allylic
chloride using thionyl chloride (67%) (Scheme 5). The resulting
chloride was treated with DMSO14 in the presence of sodium bicar-
bonate to afford the aldehyde 19 (73%); 19 underwent the HWE
reaction with triethyl phosphonoacetate (quant) followed by
hydrolysis of the ester (71%) and removal of the TIPS ether with
TBAF (quant) to afford the final product.
In conclusion, we successfully carried out the asymmetric total
synthesis of (+)-carneic acid A via the stereoselective IMDA reac-
tion of (E,E,E)-triene, which was prepared from the commercially

S. Yamakoshi et al. / Tetrahedron Letters 50 (2009) 5372–5375
5375
7. Crystallographic data (excluding structure factors) for the structures in this
Letter have been deposited with the Cambridge Crystallographic Data center as
supplementary publication number CCDC 736405. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
IEZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
8. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–3772.
9. Negishi, E. Pure Appl. Chem. 1981, 53, 2333–2356. and references therein.
10. Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068–1071.
11. For reviews, see: (a) Roush, W. R.. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 435–480. and
references therein; (b) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–
2188.
available methyl (S)-3-hydroxy-2-methylpropionate. By this asym-
metric total synthesis, we verified that the reported absolute struc-
ture of naturally occurring carneic acid A must be revised as that
shown in Figure 3. The bioactivity of (+)-carneic acid A and its
C6-epimer is currently being investigated.
Acknowledgments
This work was supported in part by a Waseda University Grant
for Special Research Projects, a Grant-in-Aid for Scientific Research
(B), and the Global COE program ‘Center for Practical Chemical
Wisdom’ by MEXT.
12. Blanchette, M.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W.
R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
13. Although the C6-epimer of 16 possesses two pseudoaxial substituents,
a
formyl group and (E)-1-methyl-1-propenyl group, the C6-epimer of 16 would
be energetically more favorable than 16 because the steric strain between C8
methyl and C6 substituent in 16 is large.
14. (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.;
Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, 6562; See also: (b)
Carnduff, J. Quart. Rev. (London) 1966, 20, 169–189; (c) Epstein, W. W.; Sweat, F.
W. Chem. Rev. 1967, 67, 247–260; (d) Mancuso, A. J.; Swern, D. Synthesis 1981,
165–185; (e) Tidwell, T. T. Synthesis 1990, 857–870; (f) Tidwell, T. T. Org. React.
1990, 39, 297–572.
Supplementary data
Supplementary data (all spectroscopic data of (+)-carneic acid A
and its methyl ester, and comparison of the NMR data for natural
and synthetic carneic acid A) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.07.024.
15. The synthesized carneic acid A showed slightly different spectroscopic data in
part (see Supplementary data). We speculate that the difference in the
chemical shift values of the NMR spectra and the difference in the ½a D
ꢁ
values
between the naturally occurring and the synthesized carneic acid A could be
attributed to the different forms of the carboxylic acid. In other words, the
naturally occurring carneic acid A used for the measurement of NMR spectra
and specific rotation might be in the form of salt, which results in a different
value; this speculation is based on a similar past experience during the total
References and notes
1. Quang, D. N.; Stadler, M.; Fournier, J.; Asakawa, Y. J. Nat. Prod. 2006, 69, 1198–
1202.
2. (a) Suzuki, T.; Usui, K.; Miyake, Y.; Namikoshi, M.; Nakada, M. Org. Lett. 2004, 6,
553–556; (b) Hayashi, N.; Suzuki, T.; Usui, K.; Nakada, M. Tetrahedron 2009, 65,
888–895.
3. Hayashi, N.; Nakada, M. Tetrahedron Lett. 2009, 50, 232–235.
4. Reviews on the IMDA reactions: Takao, K.; Munakata, R.; Tadano, K. Chem. Rev.
2005, 105, 4779–4807. and references cited therein.
5. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. and references therein.
6. Colberg, J. C.; Rane, A.; Vaquer, J.; Soderquist, J. A. J. Am. Chem. Soc. 1993, 115,
6065–6071.
synthesis of phomopsidin. However, according to Dr. Marc Stadler,
a
corresponding author of the paper on structure elucidation of carneic acid A,
there are no naturally occurring carneic acid A currently available; hence, we
cannot verify our speculation.
16. The reversal of the Cotton effects indicates that the authors of Ref. 1 made a
mistake in the assignment of the CD spectrum.