Total synthesis of (+)-rottnestol

Article abstract of DOI:10.1039/a904379i

The first total synthesis of the marine metabolite (+)-rottnestol is described.

Full text of DOI:10.1039/a904379i

Total synthesis of (+)-rottnestol†
Ivona R. Czuba and Mark A. Rizzacasa*
School of Chemistry, The University of Melbourne, Parkville, Victoria 3052, Australia.
E-mail: m.rizzacasa@chemistry.unimelb.edu.au
Received (in Cambridge, UK) 2nd June 1999, Accepted 18th June 1999
The first total synthesis of the marine metabolite (+)-rottnes-
tol is described.
followed by silylation provided alkene 7 in good yield. Wacker
oxidation7 using catalytic palladium chloride gave the ketone 8
which upon treatment with camphorsulfonic acid in MeOH
afforded the pyran 9 as one anomer. Conversion of the alcohol
9 into an unstable triflate followed by lithium acetylide
displacement and silyl group removal provided acetylene 10.
Radical hydrostannylation8 of 10 in boiling benzene then
afforded stannane 5 ready for Stille coupling.
Marine sponges provide a large range of novel and bioactive
metabolites that generally fall into defined chemotaxonomic
groups. Recently, some tetrahydropyran containing secondary
metabolites have been isolated from sponges that are chemically
quite different to compounds that were previously isolated from
the same sources. Chemical investigation of the sponge genus
Haliclona sp., collected around Rottnest Island off the coast of
Western Australia, yielded the hemiketal rottnestol (1).1 The
structure of 1 was determined using NMR techniques and by
comparison to the related compounds, the raspailols A (2) and
The synthesis of both enantiomers of the sidechain vinyl
iodide 4 is outlined in Scheme 2. Addition of but-3-enylmagne-
sium bromide to methacrolein gave the known allylic alcohol9
O
OTBDPS
Me
iii
22
Me
21
Me
i, ii
O
O
O
O
CHO
OH
6
10
4
OH
Me
20
6
7
19
12
O
9
15
Me
1
OTBDPS
O
1 Rottnestol
Me
OMe
O
HO
OTBDPS
Me
iv
Me
O
OH
5
Me
OH
Me
8
9
Me
12
O
21
OMe
Me
R
Me
1
v, vi, vii
viii
OH
Me
2 R = H Raspailol A
3 R = Me Raspailol B
5
O
10
B (3), which were isolated from the sponge Raspailia sp. and
possess antibiotic activity.2 However, only small amounts of
1–3 were isolated which precluded oxidative degradation to
determine the absolute configuration at C12.1,2 We now report
the first total synthesis of each of the possible C12 epimers of 1
which allowed for the assignment of the absolute configuration
of this compound.
Scheme 1 Reagents and conditions: (i) (+)-Ipc2B-(Z)-crotyl then NaOH,
H2O2 (76%) (ii) TBDPSCl, imidazole, DMF (85%); (iii) 20 mol% PdCl2,
1.1 equiv. CuCl, O2, aq. DMF, 50 °C (85%); (iv) 20 mol% CSA, MeOH,
RT, 3 h (72%); (v) Tf2O, 2,6-lutidine, CH2Cl2, 278 °C; (vi) LiC·CTMS,
THF–HMPA, 278 to 0 °C; (vii) TBAF·3H2O, THF, RT (71% for 3 steps);
(viii) 1.1 equiv. Bu3SnH, 10 mol% AlBN, benzene, reflux, 2 h (54%). Ipc
= Isopinocampheyl.
In designing a synthetic approach to both C12 epimers of 1,
we noted that a pivotal retrosynthetic bond cleavage would be
between C9–C10. To generate this linkage, we elected to utilise
a Stille cross-coupling protocol because of its remarkable
success in constructing diene systems.3,4 Therefore, coupling
between an optically pure C10–C19 fragment 4 and a suitable
vinylstannane such as 5 could provide each of the C12 epimers
of 1 in a highly convergent manner.
Me
Me
iii
i, ii
OHC
O
11
O
Me
Me
Me
Me
v
OH
CO2R
1
(R)-13
12 R = H
+ (S)-13
iv
R = (S)-methyl mandelate
Pd0
Me
Me
12
10
OMe
Me
Me
Me
Bu3Sn
OH
Me
I
vi, vii
O
9
I
+
(R)- or (S)-4
5
(R)-4
+(S)-4
Our approach to the C12 isomers of 1 began with the
synthesis of pyran fragment 5 as outlined in Scheme 1. Brown
crotylmetallation5 of the (S)-malic acid derived aldehyde 66
Scheme 2 Reagents and conditions: (i) CH2NCHCH2CH2MgBr, Et2O
(65%); (ii) propionyl chloride, pyridine, CH2Cl2 (91%); (iii), LDA, THF–
HMPA, TBSCl, 278 °C to rt, then aq. HCl (84%); (iv) (S)-methyl
mandelate, DCC, 10 mol% DMAP, normal phase HPLC separation (86%);
(v) LiAlH4, Et2O (86%); (vi) Dess–Martin reagent, CH2Cl2 (100%) (vii) 7.5
equiv. CrCl2, 1.9 equiv. CHl3, 6+1 dioxane–THF, rt (71%).
† Dedicated to Professor Robert E. Ireland on the occasion of his 70th
birthday.
Chem. Commun., 1999, 1419–1420
1419

1
comparison and copies of the H and 13C NMR spectra. This
(R)-4
5
(S)-4
OR
+
work was financially supported by the Australian Research
Council.
i, ii
Me
Me
12S
OH
4S
OH
Me
3R
6R
Notes and references
O
‡ For the (R,S)-MTPA ester (derived from (R)-13 and (S)-MTPA) the C1
methylene protons appear as a doublet at d 4.14 (J = 5.2 Hz) while for the
(S,S)-MTPA ester the same protons appear as well separated doublets of
doublets at d 4.03 (J = 10.8, 6.4 Hz) and 4.24 (J = 10.8, 4.8 Hz): see refs.
12 and 13.
2S
(12S)-1
Me
[α]D25+33.8 (c 0.35, CH2Cl2)
1
OR
Me
Me
OH
6R
§ Interestingly, the C4-TBDPS ether of 5 and (±)-4 failed to undergo cross
coupling under a variety of conditions.
4S
OH
Me
3R
12R
O
¶ Selected data for (12R)- and (12S)-1: dH(400 MHz, C6D6) 0.97 (d, J 6.8,
3H, CH3), 1.13 (d, J 6.4, 3H, CH3), 1.14 (q, J 12.4, 1H, H5ax), 1.18 (s, 3H,
CH3), 1.25 (m, 1H, H3), 1.50 (s, 3H, CH3), 1.71 (ddd, J 12.4, 4.8, 2.4, 1H,
H5eq), 1.92 (dd, J 13.2, 7.6, 1H, H13a), 2.05 (m, 5H, H13b, H16, H17), 2.18
(ddd, J 14.0, 7.2, 6.8, 1H, H7a), 2.34 (ddd, 14.0, 7.2, 6.8, 1H, H7b), 3.58 (dt,
J 10.4, 4.4, 1H, H4), 3.84 (m, 1H, H6), 5.00 (d, J 10.4, 1H, H19), 5.05 (dd,
J 17.2, 1.6, 1H, H19), 5.17 (br t, J 6.4, 1H, H15), 5.54 (dd, J 14.4, 7.6, 1H,
H11), 5.70 (dt, 14. 7.2, 1H, H8), 5.79 (m, 1H, H18), 6.10 (m, 1H, H10), 6.13
(m, 1H, H9); dC (100 MHz, C6D6) 12.3 (C20), 16.1 (C22), 20.1 (C21), 27.8
(C16), 28.2 (C1), 34.4 (C17), 34.9 (C12), 39.7 (C7), 41.3 (C5), 47.2 (C3),
47.9 (C13), 68.3 (C6), 69.7 (C4), 98.9 (C2), 114.8 (C19), 126.2 (C15), 128.4
(C8), 128.8 (C10), 133.2 (C9), 133.8 (C14), 138.75 (C11), 138.81 (C18).
2S
Me
(12R)-1
[α]D25 +58.4 (c 0.18, CH2Cl2)
1
Natural rottnestol [α]D + 67.4 (c 0.43,CH2Cl2)
Scheme 3 Reagents and conditions: (i) 10 mol% Pd(MeCN)2Cl2, i-Pr2NEt,
DMF, rt (54–62%); (ii) 5% aq. HCl, THF, 0 °C (55–66%).
which was propionylated to provide ester 11. Ireland–Claisen
rearrangement10,11 of 11 gave the racemic acid 12 in high yield
upon acidic work-up. Resolution of the a-methyl chiral acid 12
was achieved by conversion to the corresponding (S)-mandelate
esters followed by HPLC separation of the diastereoisomeric
(R,S)- and (S,S)-mandelates.11 Reduction of each mandelate
ester then gave the optically pure alcohols (R)-13 {[a]2D5 +6.5 (c
1.0, CHCl3)} and (S)-13 {[a]2D5 26.6 (c 1.0, CHCl3)} and the
absolute configurations of each were determined by the 1H
NMR analysis of the derived (S)-MTPA esters.12,13‡ Dess–
Martin oxidation14 of (R)- and (S)-13 followed by vinyliodina-
tion15 then provided iodides (R)- and (S)-4.
1 K. L. Erickson, J. A. Beutler, J. H. Cardellina II and M. R. Boyd,
Tetrahedron, 1995, 51, 11953.
2 C. M. Cerda-García-Rojas and D. J. Faulkner, Tetrahedron, 1995, 51,
1087.
3 J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508.
4 V. Farina, V. Krishnamurthy and W. J. Scott, in Organic Reactions, ed.
L. A. Paquette, Wiley, New York, 1997, pp. 1–652.
5 H. C. Brown and K. S. Bhat, J. Am. Chem. Soc., 1986, 108, 293.
6 J. W. Burton, J. S. Clark, S. Derrer, T. C. Stork, J. G. Bendall and A. B.
Holmes, J. Am. Chem. Soc., 1997, 119, 7483.
7 J. Tsuji, Synthesis, 1984, 369.
8 A. J. Leusink and H. A. Budding, J. Organomet. Chem., 1968, 11,
533.
9 M. Nishizawa and R. Noyori, Bull. Chem. Soc. Jpn., 1981, 54, 2233.
10 R. E. Ireland and R. H. Meuller, J. Am. Chem. Soc., 1972, 94, 5897.
11 E. J. Corey and A. Tramontano, J. Am. Chem. Soc., 1984, 106, 462.
12 F. Yasuhara, S. Yamaguchi, R. Kasai and O. Tanaka, Tetrahedron Lett.,
1986, 27, 4033.
Palladium-mediated coupling of (R)- or (S)-4 with stannane 5
proceeded smoothly§ and subsequent acid hydrolysis afforded
(12R)- and (12S)-1 respectively (Scheme 3). Not surprisingly,
1
(12R)- and (12S)-1 could not be differentiated by either H or
13C NMR spectroscopy and both were identical to rottnestol in
all respects apart from the optical rotation of (12S)-1.¶ As
shown in Scheme 3, (12R)-1 possesses a rotation with the same
sign and similar value to that of natural rottnestol1 while (12S)-1
had a much lower value. We therefore propose the absolute
configuration of rottnestol (1) to be 2S,3R,4S,6R,12R. Applica-
tion of this approach to the synthesis of the raspailols is now
underway.
13 F. D. Riccardis, L. Minale, R. Riccio, B. Giovannitti, M. Iorizzi and C.
Debitus, Gazz. Chim. Ital., 1993, 123, 79.
14 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
15 K. Takai, K. Nitta and K. Utimoto, J. Am. Chem. Soc., 1986, 108,
7408.
We thank Dr M. Boyd and Dr J. Beutler of the NCI Maryland,
USA for the generous gift of natural rottnestol (1) for TLC
Communication 9/04379I
1420
Chem. Commun., 1999, 1419–1420