Total synthesis of (-)-pateamine, a novel polyene bis-macrolide with immunosuppressive activity from the sponge Mycale sp.

Article abstract of DOI:10.1016/S0040-4039(00)01241-7

A concise and convergent synthesis of the polyene thiazole-containing 19-membered bis-lactone (-)-pateamine 1 is described. The synthesis features both the intra- and intermolecular Stille sp²-sp² coupling reactions to elaborate the E,Z-diene macrolide core and the side-chain all-E polyene portion of the natural product, and highlights the scope for enantiopure sulfinimine intermediates in the synthesis of chiral β-amino ester moieties in complex structures. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01241-7

Tetrahedron Letters 41 (2000) 7367±7371
Total synthesis of ( )-pateamine, a novel polyene
bis-macrolide with immunosuppressive activity from the
sponge Mycale sp.
Modesto J. Remuinan and Gerald Pattenden*
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
Received 5 June 2000; accepted 20 July 2000
Abstract
A concise and convergent synthesis of the polyene thiazole-containing 19-membered bis-lactone
( )-pateamine 1 is described. The synthesis features both the intra- and intermolecular Stille sp2±sp2
coupling reactions to elaborate the E,Z-diene macrolide core and the side-chain all-E polyene portion of
the natural product, and highlights the scope for enantiopure sul®nimine intermediates in the synthesis of
chiral b-amino ester moieties in complex structures. # 2000 Elsevier Science Ltd. All rights reserved.
Pateamine 1 is a unique thiazole-containing 19-membered-bis-lactone isolated from the marine
sponge Mycale sp.1 The compound exhibits potent immunosuppressant properties with low
cytotoxicity.1,2 The bis-lactone core in pateamine accommodates four asymmetric centres
together with an E,Z-1,3-diene unit, and is substituted by an unusual all-E trienamine residue.
Degradative studies, in tandem with synthetic work and NMR measurements, have led to the
stereochemical assignment shown in structure 1, to naturally occurring (±)-pateamine,3 and this
assignment has been vindicated by total synthesis.4 In an earlier communication we described a
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01241-7

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concise approach to the 19-membered bis-lactone core in pateamine.5 In this Letter we summarise
the extension to this study, culminating in a total synthesis of this intriguing secondary metabolite.
The synthetic approach we adopted to pateamine 1 was based on: (i) elaboration of the thiazole
propanal 2 from chiral pool starting materials; (ii) conversion of the propanal 2 to the b-amino
ester 5 via the corresponding enantiopure sul®nimine 3 and reaction with the enolate derived
from the acetate 4; (iii) elaboration of 5 to 6 followed by an intramolecular Stille coupling
reaction leading to the bis-lactone core 7; and ®nally (iv) homologation of the side chain in 7 to
the vinyl iodide 8 and an intermolecular Stille reaction with the aminostannane 9 (Scheme 1).
Scheme 1.
Thus, starting with commercially available dimethyl l-malate 10 and (S)-methyl 3-hydroxy-2-
methylpropionate 12, the thioamide 11 and the a-bromoketone 13, respectively were ®rst
elaborated using well established methods. A modi®ed Hantzsch thiazole synthesis,6 between 11
and 13, next produced the substituted thiazole 14. Cleavage of the TBS protecting group in 14
followed by a one carbon homologation from the resulting alcohol, via the nitrile 15a, then led to
the thiazole propanal intermediate 15b (ꢀ2) (Scheme 2). Using the procedure described by Davis
et al.7a treatment of the aldehyde 2 with (R)-p-toluenesul®namide in the presence of titanium
ethoxide at 50ꢁC next led to the sul®nimine 3 (64%) which, on reaction with the enolate derived
from the chiral acetate 48 at ^78ꢁC, gave the substituted b-amino ester 16a with 85% diastereo-
selectivity in 63% yield.7b Cleavage of the p-toluenesul®nyl group in 16a, by treatment with TFA-
methanol, then provided the free b-amino ester 16b whose con®guration was established unam-
biguously using the NMR spectroscopic procedure reported by Riguera et al.9 The amine 16b was

7369
next protected as the corresponding TcBoc carbamate 16c prior to cleavage of the PMB ether,
leading to the carbinol 17. Esteri®cation of Z-3-tri-n-butylstannylpropenoic acid10 with the
resulting secondary alcohol 17 under Yamaguchi conditions11 then led to the key intermediate 6.
When the stannane-iodide 6 was treated with Ph3As Pd(0) dibenzylideneacetone in DMF at
55ꢁC12 for 1 h, it underwent smooth sp2±sp2 coupling with complete preservation of the E/Z
stereochemistry in the starting material leading to the 19-membered bis-lactone diene core 7 in
pateamine in 65% yield (Scheme 2).
.
Scheme 2. Reagents and conditions: (i) BH3 SMe2, NaBH4, THF, 92%; (ii) TPSCl, Et3N, DMAP, DCM, rt, 12 h, 93%;
(iii) PMBoc(ˆNH)CCl3, CSA, DCM, rt, 3 days, 76%; (iv) LiOH, H2O/THF, rt, 12 h, 90%; (v) ClCO2Et, Et3N,
NH4OH, rt, 30 min, 93%; (vi) Lawesson's reagent, THF, rt, 30 min, 99%; (vii) TBSCl, Et3N, DMAP, DCM, rt, 24 h,
ꢁ
.
95%; (viii) HNMeOMe HCl, AlMe3, DCM, Á, 5 h, 61%; (ix) 1.5 equiv. MeMgBr, THF, 0 C, 1 h, 94%; (x) LiHMDS,
^78ꢁC, TMSCl, Br2, 86%; (xi) 2,6-lutidene, DCM, rt, 12 h; (xii) (CF3CO)2O, Py, DCM, ^30ꢁC, 30 min, 64% (two
steps); (xiii) AcOH/THF/H2O, rt, 12 h, 92%; (xiv) MsCl, Et3N, DCM, 0ꢁC, 1 h; (xv) NaCN, DMSO, 60ꢁC, 6 h, 77%
(two steps); (xvi) DIBAL, toluene, 0ꢁC, 2 h, 85%; (xvii) (R)-tolylsul®namide, Ti(OEt)4, DCM, 50ꢁC, 4 h, 64%; (xviii)
LiHMDS, THF, ^78ꢁC, 10 min, 63%; (xix) TFA, MeOH, rt, 4 h, 95%; (xx) TcBocCl, Py, DCM, 0ꢁC, 2 h, 89%; (xxi)
DDQ, DCM, H2O, rt, 2 h, 87%; (xxii) (Z)-3-tributylstannylpropenoic acid, 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, toluene, ^30ꢁC, 1 h, 67%; (xxiii) Pd(dba)2, Ph3As, DMF, 55ꢁC, 1 h, 65%
A number of procedures to install the all-E-trienamine side chain in pateamine, starting from
the substituted bis-lactone 7, were examined. Ultimately, we used a route which proceeded via the
vinyl iodide 8 and featured an intermolecular Stille coupling with the vinylstannane 9.

7370
Thus, deprotection of 7 followed by oxidation of the resulting alcohol using the pyridine-bu€ered
Dess±Martin procedure ®rst led to the aldehyde 18 (Scheme 3). Homologation of 18 using
2-(triphenylphosphoranylidene)propionaldehyde next gave the E-a,b-unsaturated aldehyde 19
exclusively, which was then converted into the all-E-iodotriene 8 using the procedure of Takai.13
14
Treatment of a mixture of 8 and 9 with Pd(CH3CN)2Cl2 in DMF at room temperature for 6 h
24
resulted in their smooth coupling15 and the formation of TcBoc pateamine 20, ‰ꢀŠ
^235.0 (c
0.1, CHCl3), which had identical spectroscopic properties to those of the same compound pre-
D
26
pared by a di€erent route by Romo et al. [Lit.4 ‰ꢀŠ
^243.5 (c 0.46, CHCl3)]. Finally, depro-
D
tection of 20, following the procedure of Ciufolini et al.16 using a Cd/Pb couple with
NH4OAc, gave (^)-pateamine 1 showing NMR spectroscopic and chiroptical data which were
identical to those described for the natural product.
Scheme 3. Reagents and conditions: (i) TBAF, AcOH, THF, rt, 24 h, 78%; (ii) Dess±Martin, Py, DCM, 2 h, rt, 70%;
(iii) 2-(triphenylphosphoralidene)propionaldehyde, 3 h, Á, 73%; (iv) CrCl2, CHI3, THF, 1.5 h, rt, 68%; (v)
Pd(CH3CN)2Cl2, DMF, rt, 6 h, 36%; (vi) 10% Cd±Pb, 1 M NH4OAc, THF, rt, 5 h, 73%
Acknowledgements
We thank the EU for a Marie Curie Fellowship (to M.J.R.) and P®zer Ltd (purchase of
consumables) for their support of this work.
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7371
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