Enantioselective formal total synthesis of (-)-trachyspic acid

Article abstract of DOI:10.1016/j.tetlet.2009.01.057

An enantioselective formal total synthesis of (-)-trachyspic acid was carried out using, as key steps, an asymmetric aldol reaction of a chiral oxazolidinone and a diastereoselective alkylation of a chiral 1,3-dioxolan-2-one. The key lactone 3 was synthes

Full text of DOI:10.1016/j.tetlet.2009.01.057

Tetrahedron Letters 50 (2009) 1566–1567
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Enantioselective formal total synthesis of (ꢀ)-trachyspic acid
Frederick Calo a, Jeffery Richardson b, Andrew J. P. White a, Anthony G. M. Barrett a,
*
a Department of Chemistry, Imperial College, London SW7 2AZ, England, United Kingdom
b Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, England, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective formal total synthesis of (ꢀ)-trachyspic acid was carried out using, as key steps, an
asymmetric aldol reaction of a chiral oxazolidinone and a diastereoselective alkylation of a chiral 1,3-
dioxolan-2-one. The key lactone 3 was synthesized in five steps starting from dioxolanone 9.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 November 2008
Revised 9 January 2009
Accepted 13 January 2009
Available online 19 January 2009
t
Trachyspic acid was isolated from the culture broth of Talaromy-
ces trachyspermus SANK 12191 and was identified as a potent inhib-
itor of heparanase with an IC50 of 36 lM. Structurally, this
compound is characterized as a spiroketal consisting of a 4-nonyl-
3-furanone and of a tetrahydrofuran containing a citric acid unit
(Fig. 1).
CO2 Bu
O
t
O
CO2 Bu
1
O
O
C9H19
t
Br
CO2 Bu
3
4
The Hatakeyama group first reported its structure and relative
stereochemistry.1 Subsequently, Rizzacasa et al. reported the first
enantioselective total synthesis of (ꢀ)-trachyspic acid (1) via lac-
tone 3 (Scheme 1), which led to the determination of the absolute
stereochemistry of the natural product as the antipode 2.2,3
Recently, we reported an enantioselective total synthesis of
citrafungin A using dioxolanone 9,4 and we have now extended
the methodology to the formal total synthesis of (ꢀ)-trachyspic
acid (1) by making key Rizzacasa lactone 3. As described in full
in our synthesis of citrafungin A, dioxolanone 9 was prepared in
eight steps starting from commercially available 4-(benzyl-
oxy)butyric acid using, as key steps, an Evans aldol reaction5 of
oxazolidinone 6 to 7 and a stereoselective Seebach enolate self-
Scheme 1. Rizzacasa approach to (ꢀ)-trachyspic acid (1).
Hydrogenolysis of benzyl ether 9 followed by acid catalyzed
cyclization gave lactone 10 as a white solid (Scheme 3), the struc-
ture of which was confirmed by an X-ray structure determination
(Fig. 2).7
Bu2BOTf,
CH2=CHCHO
EtO2CCl,
LiXp
O
O
regeneration of stereochemistry alkylation of
8 with t-butyl
bromoacetate (Scheme 2).6
N
O
85%
91%
OBn CO2H
OBn
Bn
6
5
O
CO2H
Xp = (R)-4-benzyl-oxazolidinone
O
tBu
CO2H
CO2H
LiN(SiMe3)2,
BrCH2CO2 Bu
O
O
t
5 steps
64%
OH
H
O
O
(-)-(3R,4R,6R)-trachypsic acid (1)
H
72%
COXp
CO2H
OBn
OBn
O
CO2H
8
7
O
tBu
CO2H
CO2H
O
O
O
(+)-(3S,4S,6S)-trachypsic acid (2)
O
t
CO2 Bu
Figure 1. Structures of (ꢀ)-trachyspic acid (1) and (+)-trachyspic acid (2).
CO2H
OBn
9
* Corresponding author. Tel.: +44 20 759 45766; fax: +44 20 759 45805.
E-mail address: agmb@ic.ac.uk (A.G.M. Barrett).
Scheme 2. Key steps in the synthesis of dioxolanone 9.4
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.057

F. Calo et al. / Tetrahedron Letters 50 (2009) 1566–1567
1567
tBu
yield over the two steps. Sequential benzyl ether hydrogenolysis
and tetrapropylammonium perruthenate (TPAP) oxidation9 of 12
gave lactone 3 in 92% yield over the two steps.
O
(1) H2, Pd/C
(2) HCl
O
O
9
t
CO2 Bu
Lactone 3 showed data identical10 to those reported by the Riz-
zacasa group,2,3 and this was confirmed by redetermining its X-ray
crystallographic structure (see Supplementary data). In summary,
we have reported the formal total synthesis of (ꢀ)-trachyspic acid
(1) using an Evans aldol reaction and a Seebach dioxolanone alkyl-
ation. The synthesis of lactone 3 was achieved in 21% yield over 13
steps.
O
92%
O
10
Scheme 3. Synthesis of lactone 10.
Acknowledgments
We thank GlaxoSmithKline for the generous endowment (to
A.G.M.B.), Eli Lilly and Company and the Engineering and Physical
Sciences Research Council for grant support (to F. Calo), and Peter
R. Haycock and Richard N. Sheppard, both at Imperial College, for
high-resolution NMR spectroscopy.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.057.
References and notes
Figure 2. X-ray crystallographic ORTEP structure of lactone 10.
1. Hirai, K.; Ooi, H.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 857–
859.
2. Zammit, S. C.; White, J. M.; Rizzacasa, M. A. Org. Biomol. Chem. 2005, 3, 2073–
2074.
3. Zammit, S. C.; Ferro, V.; Hommond, E.; Rizzacasa, M. A. Org. Biomol. Chem. 2007,
5, 2826–2834.
4. Calo, F.; Richardson, J.; Barrett, A. G. M. J. Org. Chem. 2008, 73, 9692–9697.
5. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434–9453.
6. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. 1996, 35, 2708–
2748.
.
tBuO2C OH
(1) LiOH
BF3 OEt2,
MeOH
MeO2C OH
t
CO2 Bu
CO2Me (2) 13
9
t
90%
72%
CO2 Bu
OBn
CO2Me
OBn
12
11
(1) H2, Pd/C
(2) TPAP, NMO
4 steps
7. Crystal data for 10: C17H26O7, M = 342.38, orthorhombic, P212121 (no. 19),
(-)-trachyspic acid (1)
a = 5.94340(11), b = 13.4581(3), c = 22.8780(4) Å, V = 1829.94(6) Å3, Z = 4,
3
Dc = 1.243 g cmꢀ3 ) = 0.096 mmꢀ1, T = 173 K, colorless block needles,
, l(Mo-Ka
92%
OtBu
Oxford Diffraction Xcalibur 3 diffractometer; 6146 independent measured
reflections, F2 refinement, R1 = 0.037, wR2 = 0.080, 3909 independent observed
absorption-corrected reflections [|Fo| > 4r(|Fo|), 2hmax = 65°], 217 parameters.
The absolute structure of 10 could not be determined by either R-factor tests
N
N
H
[Rþ1 ¼ 0:0366, Rꢀ1 ¼ 0:0366] or by use of the Flack parameter [x+ = +0.0(6),
ꢀ = +1.0(6)], and so it was assigned based on the known stereochemistry at
13
x
C(6). CCDC 704898.
8. Papke, M.; Schulz, S.; Tichy, H.; Gingl, E.; Ehn, R. Angew. Chem., Int. Ed. 2000, 39,
4339–4341.
Scheme 4. Synthesis of key lactone 3.
9. Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13–19.
10. Analytical data for lactone 3: ½a D25
ꢁ
ꢀ15.1 (c 1, CH2Cl2); IR (KBr) 1803, 1735,
1369, 1251, 1147, 1066, 842 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 3.40 (dd,
Alternatively, dioxolanone 9 was smoothly ring-opened using
boron trifluoride diethyl etherate in methanol at reflux in a sealed
tube,8 which gave the triester 11 (Scheme 4). Lithium hydroxide-
mediated saponification gave the corresponding tricarboxylic acid,
which was directly re-esterified using freshly prepared N,N0-di-iso-
propyl-O-t-butylisourea (13) to afford tri-tert-butyl ester 12 in 72%
J = 8.6, 3.8 Hz, 1H), 3.08 (d, J = 17.3 Hz, 1H), 2.88 (d, J = 17.3 Hz, 1H), 2.84 (dd,
J = 17.8, 8.3 Hz, 1H), 2.76 (dd, J = 17.5, 3.8 Hz, 1H), 1.49 (s, 9H), 1.48 (s, 9H), 1.45
(s, 9H); 13C NMR (100 MHz, CDCl3) d 174.0, 169.0, 168.3, 167.7, 83.7, 83.7, 83.2,
82.0, 47.6, 39.0, 32.1, 28.0, 27.9, 27.7; HRMS (ESI) calcd for C20H32O8Na:
(M+Na)+, 423.1995, found: (M+Na)+, 423.2004.