Enantiospecific synthesis of (-)-trachyspic acid

Article abstract of DOI:10.1039/b504258e

The enantiospecific synthesis of (-)-trachyspic acid is presented. The D-oxyribose derived alcohol was oxidized in one step to the acid and esterification with allyl alcohol provided ester. Alkylation of the anion derived from dimethyl malonate with nonyl

Full text of DOI:10.1039/b504258e

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C O M M U N I C A T I O N
Enantiospecific synthesis of (−)-trachyspic acid
Steven C. Zammit, Jonathan M. White and Mark A. Rizzacasa*
School of Chemistry, Bio21 Institute, 30 Flemington Rd, The University of Melbourne, 3010,
Victoria, Australia. E-mail: masr@unimelb.edu.au; Fax: 61 3 9347 8396; Tel: 61 3 8344 2397
Received 24th March 2005, Accepted 25th April 2005
First published as an Advance Article on the web 6th May 2005
The enantiospecific synthesis of (−)-trachyspic acid (1) is
presented. This has allowed for the assignment of the
absolute configuration of natural (+)-trachyspic acid as
3S,4S,6S.
In the course of screening for heparanase inhibitors, a new
metabolite named trachyspic acid (1) (Fig. 1) was isolated from
the culture broth of Talaromyces trachyspermus.1 Trachyspic acid
inhibited heparananse with an IC50 of 36 lM and its structure
was deduced by NMR techniques and chemical analysis.1
Recently, Hatakeyama and coworkers2 reported a synthesis of
( )-1 which served to confirm the relative configuration. Herein,
we report the first enantiospecific synthesis of (−)-1 which
allowed for the determination of the absolute configuration of
this natural product.
Scheme 1 Reagents and conditions: (a) NaOCl, NaClO2, TEMPO;
(b) DCC, DMAP, allyl alcohol; (c) (i) TMSCl/NEt3, LDA, THF/HMPA,
◦
−95 C; (ii) aq. NaOH; (iii) N,Nꢀ-diisopropyl-O-tert-butylisourea;
(d) (i) 10% HCl; (ii) PCC; (e) (i) DDQ; (ii) MsCl, pyridine; (f) CuI,
vinylMgBr, DMS, −45 ◦C; (g) (i) O3, DMS; (ii) NaClO2, NaH2PO4;
(iii) N,Nꢀ-diisopropyl-O-tert-butylisourea.
Fig. 1 Retrosynthetic analysis of trachyspic acid.
Our approach to trachyspic acid (1) is shown in Fig. 1. We
envisaged that 1 could be secured from intermediate acetal
2 by acid induced deprotection–spiroketalisation followed by
oxidative alkene cleavage and elimination in a manner similar
to that utilised for the synthesis of racemic 1.2 Compound 2 in
turn could be synthesised via addition of the anion derived from
vinyl bromide 4 to the chiral lactone 3.
The synthesis of key chiral lactone 3 is outlined in Scheme 1.
The D-deoxyribose derived alcohol 53 was oxidised4 in one step
to the acid and esterification with allyl alcohol provided ester
6. Ireland–Claisen rearrangement of ester 6 under conditions
previously described by us5 proceeded in a stereoselective
manner (ds > 95%) without any b-elimination to afford tert-
butyl ester 7 in good yield after esterification6 following the
rearrangement. The stereochemistry of 7 was confirmed by an
NOE observed between the H4 and H2 protons (numbering as
for 1). Acetal hydrolysis followed by oxidation afforded lactone
8 which upon PMB group removal and elimination gave a,b-
unsaturated lactone 9. Conjugate addition afforded alkenes 10
and 11 in a good yield but with poor stereoselectivity. The
stereochemistry of isomer 11 was assigned on the basis of a
single crystal X-ray structure (Fig. 2)† determined on the derived
tri-tert-butyl ester 3 (see below). It should be noted that at the
Fig. 2 X-Ray structure of lactone 3.
inception of this study, the relative configuration between C3 and
C4 of 1 was not confirmed so access to both diastereoisomers
was desirable. In any event, the correct isomer 11 was subjected
to ozonolysis and subsequent oxidation and protection to yield
the required lactone fragment 3.
The bromide fragment 4 was synthesised as outlined in
Scheme 2. Alkylation of the anion derived from dimethyl
malonate (12) with nonyl bromide produced diester 13 which
was reduced to diol 14 in excellent yield. Monoprotection and
alkyne homologation using the Corey–Fuchs protocol7 afforded
alkyne 15. Bromoboration and acid induced deboronation8 gave
vinyl bromide 16 which was deprotected, oxidised and converted
into the dioxolane fragment 4.
The final steps to (−)-trachyspic acid (1) are detailed in
Scheme 3. Treatment of the vinyl bromide 4 with t-BuLi resulted
in halogen–metal exchange9 and the resultant anion added
selectively to the lactone carbonyl group in compound 3 to
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 0 7 3 – 2 0 7 4
2 0 7 3
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(+)-trachyspic acid using the methodology described herein is
underway in our laboratories and will be reported in due course.
Acknowledgements
We thank Dr Hideyuki Shiozawa (Sankyo Co., Ltd.) for copies
of the NMR spectra of natural trachyspic acid (1) and trachyspic
acid trimethyl ester (18). This work was funded by the Australian
Research Council-Discovery Projects Grants Scheme.
Notes and references
˚
† X-Ray data for 3: C20H32O8 M = 400.46, T = 295 K, k = 0.71069 A,
monoclinic, space group P21, a = 11.267(1), b = 19.608(2), c =
◦
3
˚
˚
12.035(1) A, b = 117.463 , V = 2359.2(3) A , Z = 4, Dc = 1.127
Mg m−3, l(Mo-Ka) 0.086 mm−1, F(000) 864, crystal size 0.5 × 0.25,
0.05 mm. 12556 reflections measured, 6113 independent (Rint 0.629)
the final wR (F2 all data) was 0.0979 and final R was 0.0457 for 3200
data with [I > 2r(I)]. Flack parameter = 0.0(10). CCDC reference
number 268561. See http://www.rsc.org/suppdata/ob/b5/b504258e
for crystallographic data in cif format.
Scheme 2 Reagents and conditions: (a) NaOMe, nonyl bromide, MeOH,
reflux; (b) LiAlH4, 0 ◦C; (c) (i) NaH, TBDPSCl; (ii) Dess Martin reagent;
(iii) PPh3, CBr4, 0 ◦C; (iv) BuLi, −78 ◦C; (d) B-Br-9-BBN, AcOH, 0 ◦C;
(e) (i) TBAF; (ii) Dess Martin reagent; (iii) p-TsOH, HOCH2CH2OH,
benzene, reflux.
‡ Data for synthetic (−)-1: [a]2D1 −3.5 (c 0.213, MeOH); [a]2D3 −8.4 (c
0.350, CH2Cl2); Lit.1 [a]D21 +3.1 (c 1.0, MeOH); mmax (thin film) 3425,
2927, 2856, 1724, 1611, 1370, 1139, 1000 cm−1; dH (400 MHz, DMSO-
d6) 0.84 (t, J = 6.6 Hz, 3H), 1.23 (br s, 12H), 1.39 (m, 2H), 2.02 (t,
J = 7.8 Hz, 1H), 2.36 (m, 2H), 2.67 (d, J = 16.8 Hz, 1H), 2.85 (d, J =
16.8 Hz, 1H), 3.56 (dd, J = 7.8, 11.8 Hz, 1H), 8.45 (s, 1H); dC (100 MHz,
DMSO-d6) 14.0, 20.5, 22.1, 27.5, 28.6, 28.7, 28.9, 31.3, 37.6, 38.7, 48.4,
86.5, 108.1, 116.7, 170.1, 170.6, 171.3, 174.5, 198.2 HRMS (ESI): Calcd
for C20H28O9H [M + H]+ 413.1812, found 413.1809.
§ Data for triester 18: [a]D23 −20.4 (c 0.130, CH2Cl2); mmax (thin film) 2926,
2854, 1742, 1612, 1367, 1135, 1007 cm−1; dH (400 MHz, DMSO-d6) 0.84
(t, J = 6.8 Hz, 3H), 1.23 (br s, 12H), 1.38 (m, 2H), 2.02 (t, J = 7.6 Hz,
1H), 2.39 (dd, J = 12.8, 13.2 Hz, 1H), 2.47 (dd, J = 7.2, 13.2 Hz, 1H),
2.87 (d, J = 16.8 Hz, 1H), 2.93 (d, J = 16.8 Hz, 1H), 3.55 (s, 3H), 3.64
(s, 3H), 3.70 (s, 3H), 3.80 (dd, J = 7.6, 12.6 Hz, 1H), 8.47 (s, 1H); dC
(100 MHz, DMSO-d6) 14.0, 20.5, 22.2, 27.5, 28.7, 28.8, 29.0, 31.4, 37.3,
38.5, 47.7, 51.9, 52.6, 53.0, 86.5, 107.7, 117.0, 169.1, 169.5, 169.8, 174.7,
197.7 HRMS (ESI): Calcd for C23H34O9Na [M + Na]+ 477.2101, found
477.2093.
Scheme 3 Reagents and conditions: (a) t-BuLi, Et2O–hexane, −78 ◦C
then lactone 3; (b) 3M HClO4, THF; (c) (i) Ac2O, DMAP, pyridine;
(ii) O3, NaHCO3, DMS; (d) TFA, CH2Cl2; (e) CH2N2, Et2O.
1 H. Shiozawa, M. Takahashi, T. Takatsu, T. Kinishita, K. Tanzawa,
T. Hosoya, K. Furuya, S. Takahashi, K. Furihata and H. Seto,
J. Antibiot., 1995, 48, 357.
2 K. Hirai, H. Ooi, T. Esumi, Y. Iwabuchi and S. Hatakeyama, Org.
Lett., 2003, 5, 857.
3 Compound 5 was synthesised from D-deoxyribose in an analogous
fashion to that described for the corresponding benzyl compound see:
R. M. Giuliano and F. J. Villani, Jr., J. Org. Chem., 1995, 60, 202; T.
Suami, K. I. Tadano, Y. Iimura and H. Yokoo, J. Carbohydr. Chem.,
1986, 5, 1.
provide the acetal 2 as a mixture of isomers at the anomeric
centre. Acid induced deprotection of the dioxolane resulted in
concomitant spirocyclisation which upon acetylation and subse-
quent ozonolysis–elimination2 provided spiroacetal 17 as a ∼4 : 1
mixture of spiroisomers favouring the desired compound 17.
TFA induced deprotection then gave (−)-(3R,4R,6R)-trachyspic
acid (1) which was identical to natural 1 in all respects except
for the sign of optical rotation.‡ Synthetic 1 was also further
characterised by conversion into the known trimethyl ester
derivative 18.§ This confirms that natural (+)-trachyspic acid
has the absolute configuration opposite to that shown in Fig. 1,
namely 3S,4S,6S.
4 M. Zhao, J. Li, E. Mano, Z. Song, D. M. Tschaen, E. J. J. Grabowski
and P. J. Reider, J. Org. Chem., 1999, 64, 2564.
5 R. Di Florio and M. A. Rizzacasa, J. Org. Chem., 1998, 63, 8595; A. N.
Cuzzupe, R. Di Florio and M. A. Rizzacasa, J. Org. Chem., 2002, 67,
4392; A. N. Cuzzupe, R. Di Florio, J. M. White and M. A. Rizzacasa,
Org. Biomol. Chem., 2003, 1, 3572.
6 L. J. Mathias, Synthesis, 1979, 561.
7 E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 3769.
8 H. Shoji, D. Hedetaka, T. Satoru and S. Akira, Tetrahedron Lett.,
1983, 731.
In conclusion, we have achieved an enantiospecific synthesis
of the unnatural enantiomer of trachyspic acid, confirming the
absolute configuration of this compound. A synthesis of natural
9 W. F. Bailey and E. R. Punzalan, J. Org. Chem., 1990, 55, 5404.
2 0 7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 0 7 3 – 2 0 7 4