A short synthesis of trans-(+)-laurediol

Article abstract of DOI:10.1016/S0040-4039(00)00190-8

A highly convergent and short synthesis of trans-(+)-laurediol is presented. The synthesis features a highly efficient construction of a cis-3- hydroxy-γ-butyrolactone through a Sharpless AD reaction of a β,γ- unsaturated ester. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00190-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2503–2505
A short synthesis of trans-(+)-laurediol
Tomás Martín and Víctor S. Martín ∗
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Universidad de La Laguna, C/Astrofísico Francisco Sánchez, 2,
38206 La Laguna, Tenerife, Spain
Received 9 December 1999; revised 19 January 2000; accepted 25 January 2000
Abstract
A highly convergent and short synthesis of trans-(+)-laurediol is presented. The synthesis features a highly
efficient construction of a cis-3-hydroxy-γ-butyrolactone through a Sharpless AD reaction of a β,γ-unsaturated
ester. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: marine metabolites; Sharpless asymmetric dihydroxylation reaction; asymmetric synthesis.
An important group of marine natural products named lauroxanes has been isolated from the red algae
of the genus Laurencia and from the herbivorous opisthobranch molluscs that consume them.1 These
compounds are characterized by the presence in their structure of polysubstituted cyclic ethers of different
sizes. Irie and co-workers reported the isolation from Laurencia nipponica Yamada of the enantiomers of
(3E,9Z,12E)-pentadeca-3,9,12-trien-1-yne-6,7-diol (trans-laurediol) and (3Z,9Z,12E)-pentadeca-3,9,12-
trien-1-yne-6,7-diol (cis-laurediol).2 These compounds have been repeatedly proposed as biosynthetic
precursors of lauroxanes by electrophilic cyclization.1
To the best of our knowledge, until now only two syntheses of laurediols have been reported.
Masamune et al. accomplished a synthesis of 1 in 21 steps from (2R,3R)-(+)-tartaric acid.3 Almost
simultaneously, from our laboratory was published an enantioselective synthesis of both cis- and trans-
laurediol in 28 steps from propargylic alcohol.4 We have been focusing our attention on the synthesis of
the above-mentioned cyclic compounds by intramolecular cyclization of hydroxyalkenes induced by a
bromonium ion.5 Prompted by the necessity of having a more efficient synthesis of 1, we describe here a
shorter and highly convergent synthesis of trans-laurediol (1) that permits us to scale up the preparation of
the final products to perform cyclization studies. Our approach to 1 is based on the retrosynthetic analysis,
Scheme 1, in which we disconnect to the γ-lactone 2 with the correct stereochemical requirements that
could be fulfilled by an asymmetric dihydroxylation of 3.6
Selective monobenzylation of commercially available butane-1,4-diol provided 4 that was oxidized
to the corresponding aldehyde. Modified Knoevenagel condensation with malonic acid under nonpolar
conditions7 and further esterification provided the E-unsaturated-β,γ-ester 5. The application of the
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00190-8
tetl 16470

2504
Scheme 1.
Sharpless asymmetric dihydroxylation reaction provided exclusively the disubstituted-γ-lactone 6 (93%
ee),8 permitting us also to differentiate between the two hydroxy groups. Protection of the free secondary
alcohol as a silyl ether and cleavage of the benzyl ether afforded the γ-lactone 7 (Scheme 2).
Scheme 2. (a) NaH, BnBr, n-Bu4NI (cat.), THF, 0°C, 3 h, 78%; (b) (i) SO3·Py, DMSO, Et3N, CH2Cl2, 2 h, (ii) malonic acid,
piperidine (cat.), xylene, reflux, 5 h, (iii) TMSCl, MeOH, rt, 2 h, 58% from 4; (c) AD-mix-β, CH3SO2NH2, t-BuOH: H2O (1:1),
0°C, 20 h, 90%; (d) (i) TBDPSCl, imidazole, CH2Cl2, rt, overnight, (ii) H2, 10% Pd–C/AcOEt, overnight, 93% from 6; (e) (i)
PCC, NaOAc, CH2Cl2, 4 Å MS, 2 h, (ii) (E)-EtCH_CHCH2CH2PPh3+I−,9 KN(TMS)2, THF, −78°C, 4 Å MS, 3 h, 36% from
7; (f) (i) DIBAL-H (1 equiv.), Et2O, −78°C, 5 min, (ii) TMSC^CCH2PPh3+Br−, KOBu-t, Et2O, 0°C to rt, 4 h, (iii) n-Bu4NF,
THF, rt, 1 h, 78% from 8
At this stage of the synthesis we were ready to homologate in both directions to build the carbon
framework. Thus, oxidation of 7 produced an aldehyde that was converted to the corresponding (Z)-olefin
8 through a stereoselective Wittig reaction. For the completion of the synthesis, the γ-lactone was reduced
with one equivalent of DIBAL-H, and the lactol submitted to Wittig-olefination with the ylide derived
from commercially available [3-(trimethylsilyl)-2-propynyl]triphenylphosphonium bromide to yield the
trans-enyne. Fluoride-induced cleavage of the silyl-protecting groups furnished (+)-trans-laurediol (1)
25
[α] +19.8 (c 1.2, CCl4).10
D
In summary, we have described a convergent and enantioselective short synthesis of (+)-trans-laurediol
(1) with an 11% overall yield (12 steps), which will be useful for studies on biomimetic synthesis of
lauroxanes. Although the presented methodology has been described only for one enantiomeric series,
the alternative choice of the AD-mix in the Sharpless asymmetric dihydroxylation reaction for 5 permits
us to control the absolute configuration in the final product.
Acknowledgements
This research was supported by the DGES (PB95-0751) of Spain and the Consejería de Educación,
Cultura y Deportes del Gobierno de Canarias. T.M. thanks the M.E.C. of Spain for a Reincorporación
Contract.
References
1. (a) Moore, R. E. In Marine Natural Products; Scheuer, P. J., Ed.; Academic Press: New York, 1978; Vol. 1, pp. 43–121. (b)
Erickson, K. L. In Marine Natural Products; Scheuer, P. J., Ed.; Academic Press: New York, 1983; Vol. V, pp. 131–257. (c)
Faulkner, D. J. Nat. Prod. Rep. 1984, 1, 251. (d) Ibid 1986, 3, 1. (e) Ibid 1987, 4, 539. (f) Ibid 1988, 5, 613. (g) Ibid 1990,

2505
7, 269. (h) Ibid 1991, 8, 97. (i) Ibid 1992, 9, 323. (j) Ibid 1993, 10, 497. (k) Ibid 1994, 11, 355. (l) Ibid 1995, 12, 223. (m)
Ibid 1997, 14, 259. (n) Ibid 1998, 15, 113. (o) Ibid 1999, 16, 155.
2. Kurosawa, E.; Kukusawa, A.; Irie, T. Tetrahedron Lett. 1972, 2121.
3. Fukusawa, A.; Sato, H.; Miyamoto, M.; Masamune, T. Tetrahedron Lett. 1986, 27, 2901.
4. Añorbe, B.; Martín, V. S.; Palazón, J. M.; Trujillo, J. M. Tetrahedron Lett. 1986, 27, 4991.
5. Martín, T.; Soler, M. A.; Betancort, J. M.; Martín, V. S. J. Org. Chem. 1997, 62, 1570.
6. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (b) Harcken, C.; Brückner, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2750.
7. Ragoussis, N. Tetrahedron Lett. 1987, 28, 93.
8. The enantiomeric excess was determined by the 1H NMR analysis of the corresponding (R)- and (S)-Mosher esters. Dale, J.
A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
9. The phosphonium salt was prepared by refluxing (Ph)3P and (3E)-C2H5CH_CHCH2CH2I in CH3CN. The iodide was
synthesized from the commercially available alcohol [(Ph)3P, imidazole, I2, C6H6, rt].
10. [α] reported in the literature for (+)-trans-laurediol (Ref. 2) was 27.2, but no concentration data were provided.