Asymmetric synthesis of (+)-trachyspic acid

Article abstract of DOI:10.1016/j.tetlet.2008.07.004

Aldol reaction of di-tert-butyl 4-(4-methoxybenzyloxy)-2-oxobutanoate with pent-4-enal using (S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(pyrrolidin-2-ylmethyl)thiourea hydrochloride as a catalyst, followed by Pinnick oxidation and tert-butyl esterification, gave (2S,3S)-di-tert-butyl 2-(2-(4-methoxybenzyloxy)ethyl)-3-allyl-2-hydroxysuccinate in high optical purity (85% ee), from which the total synthesis of (+)-trachyspic acid, a tumor cell heparanase inhibitor, was accomplished.

Full text of DOI:10.1016/j.tetlet.2008.07.004

Tetrahedron Letters 49 (2008) 6043–6045
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Tetrahedron Letters
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Asymmetric synthesis of (+)-trachyspic acid
Kenji Morokuma, Yuko Taira, Yumiko Uehara, Setsuya Shibahara, Keisuke Takahashi,
*
Jun Ishihara, Susumi Hatakeyama
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Aldol reaction of di-tert-butyl 4-(4-methoxybenzyloxy)-2-oxobutanoate with pent-4-enal using (S)-1-
(3,5-bis(trifluoromethyl)phenyl)-3-(pyrrolidin-2-ylmethyl)thiourea hydrochloride as a catalyst, followed
by Pinnick oxidation and tert-butyl esterification, gave (2S,3S)-di-tert-butyl 2-(2-(4-methoxybenzyl-
oxy)ethyl)-3-allyl-2-hydroxysuccinate in high optical purity (85% ee), from which the total synthesis of
(+)-trachyspic acid, a tumor cell heparanase inhibitor, was accomplished.
Received 11 June 2008
Revised 30 June 2008
Accepted 2 July 2008
Available online 4 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Trachyspic acid (1) was isolated from the culture broth of Talar-
omyces trachyspermus SANK 12191 as a potent inhibitor of hepa-
pent-4-enal (6) and a-keto ester 7 under chiral proline-based
catalysis8 (Scheme 1). We expected that this aldol reaction would
preferentially proceed through six-membered chairlike transition
state 10 locked by hydrogen bonding to produce diastereomer 8,
convertible to 4 via 9.
ranase with an IC50 of 36 l
M.1 Structurally, this compound is
characterized by a novel spiroketal moiety consisting of the 4-non-
yl-3-furanone and the tetrahydrofuran containing a citric acid unit.
The two-dimensional structure was elucidated by NMR analysis
and degradation experiments,1 and the relative configuration was
confirmed by our racemic synthesis.2 Recently, Rizzacasa et al.
unambiguously determined the absolute configuration to be
3S,4S,6S by the enantiospecific synthesis of both enantiomers from
Before we examined the key organocatalytic aldol reaction, we
prepared (2S,3S)-diester 9 by a reliable route (Scheme 2). The syn-
thesis started from compound 11 which had been used for the syn-
thesis of virigiofungin A.4b Thus, protection of 11 as its TIPS ether
followed by selective removal of the THP protecting group afforded
alcohol 12, which was subjected to Katsuki–Sharpless asymmetric
epoxidation9 to produce epoxide 13 in 88% ee. Nucleophilic open-
ing of 13 with allylmagnesium chloride proceeded with excellent
regio- and stereoselectivity to give diol 14 quantitatively. It is
important to note that the use of allylmagnesium bromide in place
D
-deoxyribose.3 In connection with a project directed toward the
synthesis of the alkyl citrate family of natural products such as vir-
idiofungins4 and citrafungins,5 we were interested in developing
an efficient enantioselective approach to a common alkyl citrate
structure 2. Herein, we report an asymmetric synthesis of (+)-
trachyspic acid (1) employing an organocatalytic aldol reaction of
an
rate core.
a
-keto ester6 with an aldehyde for the assembly of the alkyl cit-
CO2tBu
CO2tBu
CO2tBu
CO2tBu
O
O
O
O
OHC
Cr(II)/Ni(II)
+
TMSO
OTf
1
OH
8
8
CO2H
CO2H
4
TMSO
CO2R
CO2R
O
OPMB
OPMB
*
*
R
3
5
4
6
O
3
CO2H
HO
CO2R
O
1
2
CHO
CHO
CO2tBu
6
N
H
CO2tBu
CO2tBu
XH
+
HO
4
HO
O
We have developed an effective methodology for the synthesis
of 1 via Cr(II)/Ni(II)-mediated Nozaki–Hiyama–Kishi reaction7 of
triflate 3 and aldehyde 4, an alkyl citrate core, giving 5 in the race-
mic synthesis.2 We therefore focused on the enantioselective prep-
aration of aldehyde 4 for the synthesis of (+)-trachyspic acid (1). To
expeditiously access 4, we envisaged asymmetric aldol reaction of
CO2tBu
OPMB
OPMB
8
9
OPMB
7
N
O
PMBO
H
X
tBuO
O
10
* Corresponding author. Tel./fax: +81 95 819 2426.
E-mail address: susumi@nagaski-u.ac.jp (S. Hatakeyama).
Scheme 1. Strategy leading to key intermediate 4.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.004

6044
K. Morokuma et al. / Tetrahedron Letters 49 (2008) 6043–6045
and CH2Cl2. (4R)-4-TBSO-L
-proline 19b15 gave a comparable result
OH
OTIPS
OH
1) TIPSOTf, 2,6-lutidine
CH2Cl2, –78 °C
2) PPTS, iPrOH
L-DET, Ti(OiPr)4
to that obtained by the proline-catalyzed reaction (entry 2). Either
19c16 or 19d17 brought about poorer diastereo- and enantioselec-
tivity (entries 3 and 4). However, it is gratifying to find that the
use of the hydrochloride of 19d (19dꢀHCl) markedly improved
the enantio- and diastereoselectivity as well as chemical yield.
Thus, when the reaction was carried out for 2 days, 9 (85% ee)
and 21 (33% ee) were obtained in a ratio of 2:1 in 49% total yield
from 7 (entry 5). Amino alcohol 19e did not show any catalytic
OTHP
TBHP,CH2Cl2. –20 °C
OPMB
OPMB
12
81%
100%
11
OTIPS
Br
MgCl
OH
OTIPS
OPMB
14
OH
O
HO
HO
OH
OTIPS
THF, –20 °C
OPMB
OPMB
100%
ability, and
a-keto ester 7 was recovered in 95% yield even after
13 (88% ee)
15
8 days. Furthermore, aldol reaction of 6 with
a-keto acid 18 using
basic catalyst 19f6d was also examined under various conditions
with expectation of stronger acid–base interaction leading to rate
acceleration as well as high enantio- and diastereoselectivity.
However, the results were not encouraging at all.
CO2tBu
1) SO3-pyridine, DMSO, Et3N, CH2Cl2
2) NaClO2,NaH2PO4, tBuOH-H2O
TBAF, THF
HO
3) i
PrHN NHiPr
OTIPS
–40 °C
97%
, CH2Cl2
Ot Bu
OPMB
16
Following the procedure we established in the synthesis of race-
88%
mic tracyspic acid,2 the total synthesis of (+)-trachyspic acid was
CO2tBu
CO2tBu
1) SO3-pyridine, DMSO, Et3N, CH2Cl2
2) NaClO2,NaH2PO4, tBuOH-H2O
3
HO 2 CO2tBu
HO
3) i
PrHN NHiPr
OH
CO2tBu
CO2tBu
CO2tBu 1) TMSCl, imidazole
, CH2Cl2
94%
OtBu
OPMB
OPMB
OHC
CH2Cl2
3 (1.8 equiv)
9
17
HO
CO2tBu
TMSO
CrCl2 (4 equiv)
NiCl2 (0.1 equiv)
2) OsO4, NMO
THF-H2O
then NaIO4
99%
OPMB
OPMB
Scheme 2. Synthesis of (2S,3S)-diester 9 via a reliable route.
DMF
9
4
91%
CO2tBu
CO2tBu
CO2tBu
O
8
O
O
O
of allylmagnesium chloride provided bromide 15 as a major
product. Upon successive Parikh–Doering oxidation,10 Pinnick
oxidation,11 and esterification using N,N0-diisopropyl-O-2-tert-
butylisourea,12 14 afforded 16 in good overall yield. After desilyla-
tion of 16, diol 17 was converted to (2S,3S)-diester 913 by the same
procedure as employed for the transformation of 14 to 16.
1) Swern oxidation
2) aq HF
CO2tBu
OH
O
8
TMSO
HO
pyridine-MeCN
OPMB
OPMB
5
22
95%
CO2tBu
CO2tBu
HO
CO2tBu
CO2tBu
1) Ac2O, DMAP
pyridine
AcO
O
O
With an authentic sample of (2S,3S)-diester 9 in hand, we then
3 M HClO4
THF
O
O
investigated aldol reaction of aldehyde 6 with
a-keto ester 7 or a-
2) DDQ
8
8
aq CH2Cl2
OH
keto acid 18 under various conditions using -proline and five other
L
OPMB
4:1 dr at C6
85%
23
24
99%
catalysts (Table 1). The reactions were evaluated by HPLC analysis
using a chiral column after converting the aldol products 20 to the
corresponding di-tert-butyl esters by Pinnick oxidation followed by
esterification. When the reaction was carried out using 0.5 equiv of
1) Dess-Martin oxidation
2) NaClO2, NaHPO4
CO2H
CO2H
CO2H
O
O
2-methyl-2-butene, aq tBuOH
O
3) O3, NaHCO3
L
-proline 19a in toluene at room temperature for 21 h, (2S,3S)-iso-
CH2Cl2-MeOH, –78 ˚C then Me2S
4) TFA, CH2Cl2
50%
1
mer 9 (61% ee) and (2S,3R)-isomer 21 (19% ee)14 were obtained in a
ratio of 2:3 in 46% total yield from 7 (entry 1). This proline-cata-
lyzed reaction turned out to be very low yielding in DMSO, DMF,
Scheme 3. Completion of the total synthesis of (+)-trachyspic acid (1).
Table 1
Asymmetric aldol reaction of 6 and 7a
CHO
1) NaClO2, NaH2PO4
tBuOH-H2O
CO2tBu
CO2tBu
CO2tBu
CO2tBu
O
*
catalyst 19
CO2R
*
HO
CO2R
HO
HO
+
+
CHO
iPrHN NHiPr
2)
OPMB
7: R = tBu
18: R = H
6
OPMB
OPMB
OPMB
OtBu
CH2Cl2
20
21
9
F3C
CF3
TBSO
Ph
Ph
O
N
N
H
N
N
N
CO2H
N
N
H
H
H
HN
CO2H
HN
NH
N
H
19b
H
HN
OH
19e
N
N
19a
S
19c
19d
19f
Entry
Solvent
Catalyst
Time (h)
Yield (9 + 21)b (%)
Ratio (9:21)c
ee % of 9c
ee % of 21c
1
2
3
4
5
Toluene
Toluene
CH2Cl2
DMF
19a
19b
19c
19d
21
25
68
24
48
46
45
29
34
49
2:3
1:1
1:1
1:1
2:1
61
65
41
49
85
19
23
0
0
33
DMF
19dꢀHCl
a
The reactions were conducted at room temperature using aldehyde 6 (3 equiv),
Isolated yield.
Determined by HPLC analysis using a chiral column.
a-ketoester 7 (1 equiv), and catalyst 19 (0.5 equiv).
b
c

K. Morokuma et al. / Tetrahedron Letters 49 (2008) 6043–6045
6045
6. For related organocatalytic reactions, see (a) Bogevig, A.; Kumaragurubaran, N.;
Jørgensen, K. Chem. Commun. 2002, 620–621; (b) Dambruso, P.; Massi, A.;
Dondoni, A. Org. Lett. 2005, 7, 4657–4660; (c) Tokuda, O.; Kano, T.; Gao, W.-G.;
Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7, 5103–5105; (d) Tang, Z.; Cun, L.-F.;
Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006, 8, 1263–1266; (e)
Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128, 7442–7443.
7. For a review, see Saccomano, N. A. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon: Oxford, 1991; Vol. 1, Chapter 1.6.4, pp 193–201.
8. For a review, see Tanaka, F.; Barbas, F. F. In Comprehensive Organic Synthesis;
Dalko, P. I., Ed.; Wiley: Weinheim, 2007; pp 19–55.
9. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765–5780.
10. Parikh, J. P.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505–5507.
11. (a) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096;
(b) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567–569.
accomplished from (2S,3S)-diester 9 as illustrated in Scheme 3.
Thus, 9 was first converted to aldehydes 4 by silylation followed
by oxidative cleavage of the olefinic double bound. Upon reaction
of 4 with triflate 3 in the presence of 4 equiv of CrCl2 and 0.1 equiv
of NiCl2 in DMF at room temperature, the coupling reaction oc-
curred very cleanly to produce alcohol 5 in good yield. After Swern
oxidation of 5 followed by desilylation, exposure of 22 to 3 M
HClO4 in THF at room temperature promoted spiroacetalization
to give spiroacetal 23 as a diastereoisomeric mixture in good yield.
In this case, the C6 spirocenter was preferentially formed in S con-
figuration (dr = 4:1).18 Upon acetylation and oxidative removal of
the p-methoxybenzyl protecting group, 23 gave alcohol 24. Finally,
(+)-trachyspic acid (1)19 was successfully obtained from 24 by
four-step sequence involving Dess–Martin oxidation, Pinnick oxi-
dation, ozonolysis, and treatment with TFA. The specific rotation
and spectroscopic properties (1H and 13C NMR) were in good
agreement with those of natural trachyspic acid.
12. Santini, C.; Ball, R. G.; Berger, G. D. J. Org. Chem. 1994, 59, 2261–2266.
13. ½ ꢁ
a 2D5 +10.5 (c 0.780, CHCl3) (88% ee); 1H NMR (300 MHz, CDCl3) d 1.44 (s, 9H),
1.45 (s, 9H), 1.93 (dt, J = 13.2, 6.2 Hz, 1H), 2.08 (m, 1H), 2.17 (dt, J = 13.5, 6.6 Hz,
1H), 2.46 (ddd, J = 6.7, 12.0, 15.0 Hz, 1H), 2.68 (dd, J = 2.7, 11.7 Hz, 1H), 3.50 (dt,
J = 2.1, 6.3 Hz, 2H), 3.79 (s, 3H), 4.37 (dd, J = 11.4, 13.8 Hz, 2H), 4.49 (dd, J = 1.5,
12.3 Hz, 1H), 5.05 (dd, J = 1.2, 16.8 Hz, 1H), 5.72 (ddt, J = 9.3, 16.5, 6.3 Hz, 1H),
6.85 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) 28.0,
28.1, 32.2, 37.2, 54.1, 55.3, 65.5, 72.9, 76.6, 81.4, 82.9, 113.8, 116.8, 129.6,
130.2, 135.5, 159.3, 171.7, 173.2; FTIR (neat) 3779, 2712, 3480, 2971, 1722,
1594, 1249, 1157, 840 cmꢂ1; MS (EI) m/z 44, 57, 121 (100), 137, 201, 393, 450
In conclusion, although there still remain the selectivity issues
to be improved in the key organocatalytic aldol reaction, we have
developed a concise enantioselective approach to an alkyl citrate
structure and successfully achieved a total synthesis of (+)-trachy-
spic acid via Cr(II)/Ni(II)-mediated Nozaki–Hiyama–Kishi coupling
of the alkyl citrate moiety and the long chain triflate.
t
(M+); HRMS (EI) calcd for C21H29O5 [(Mꢂ Bu)+]: 393.1913, found, 393.2060.
14. The absolute configuration was deduced from the fact that treatment of 21
with LDA in THF at ꢂ40 °C followed by aq NH4Cl gave 9 and 21 in a ratio of 1:9
in 90% yield. 1H NMR (300 MHz, CDCl3) d 1.41 (18H, s), 1.97 (1H, dt, J = 7.5,
14.1 Hz), 2.13 (1H, ddd, J = 5.7, 7.8, 13.5 Hz), 2.42 (2H, m), 2.66 (1H, dd, J = 4.2,
10.2 Hz), 3.48 (1H, ddd, J = 7.5, 9.0, 16.5 Hz), 3.56 (1H, dt, J = 5.4, 9.0 Hz), 3.78
(3H, s), 4.38 (2H, d, J = 3.3 Hz), 5.00 (1H, d, J = 10.2 Hz), 5.06 (1H, dd, J = 1.2,
16.8 Hz), 5.78 (1H, ddt, J = 7.2, 10.2, 14.1 Hz), 7.23 (2H, d, J = 8.4 Hz); 13C NMR
(75 MHz, CDCl3) d 27.9, 28.1, 31.4, 45.9, 53.0, 55.3, 65.4, 72.8, 76.0, 81.5, 82.6,
113.8, 116.9, 129.5, 130.3, 135.8, 159.2, 172.1, 173.6; FTIR (neat) 3498, 1724,
1573, 1612, 1514, 1458, 1392, 1367, 1248, 1149, 1036 cmꢂ1; HRMS (EI) calcd
for C25H38O7 (M+): 450.2617, found, 450.2625.
Acknowledgment
This work was supported by Grant-in-Aid for Scientific Re-
search on Priority Areas (16073213) from The Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT).
15. Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Shoji, M.;
Hashizume, D.; Koshino, H. Adv. Synth. Catal. 2004, 346, 1435–1439.
16. Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1983–1986.
References and notes
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18. Dehydration of 23 with methanesulfonyl chloride in pyridine afforded the
corresponding diene as a 4:1 epimeric mixture. NOE measurement of this
mixture allowed us to determine the configuration of the C6 spirocenter of the
major isomer to be S.
1. Shiozawa, H.; Takahashi, M.; Takatsu, T.; Kinoshita, T.; Tanzawa, K.; Hosoya, T.;
Furuya, K.; Furihata, K.; Seto, H. J. Antibiot. 1995, 48, 357–369.
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859.
3. (a) Zammit, S. C.; White, J. M.; Rizzacasa, M. A. Org. Biomol. Chem. 2005, 3,
2073–2074; (b) Zammit, S. C.; Fero, V.; Hammond, E.; Rizzacasa, M. A. Org.
Biomol. Chem. 2007, 5, 2826–2834.
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19.
½
a 2D7
ꢁ
+4.9 (c 0.94, MeOH) [lit.1 a 2D5 +3.1 (c 1.00, MeOH)]; 1H NMR (500 MHz,
½ ꢁ
DMSO-d6) d 0.84 (t, J = 7.0 Hz, 3H), 1.23 (br s, 12H), 1.38 (m, 2H), 2.02 (t,
J = 8.0 Hz, 2H), 2.34 (m, 2H), 2.67 (d, J = 17.0 Hz, 1H), 2.85 (d, J = 16.5 Hz, 1H),
3.57 (dd, J = 8.0, 11.5 Hz, 1H), 8.44 (s, 1H); 13C NMR (125 MHz, CDCl3) 13.9,
20.4, 22.0, 27.5, 28.6, 28.6, 28.8, 31.2, 37.4, 38.7, 48.4, 86.5, 108.0, 116.7, 170.0,
170.5, 171.3, 174.4, 198.1; FTIR (neat) 3446, 2925, 2858, 2613, 1936, 1722,
1604, 1396, 1223, 1140, 1066, 1003 cmꢂ1
[(M+Na)+], 457 [(M+2Na)+].
; MS (FAB) m/z 41 (100), 435