Studies on the total synthesis of macrolactin A. A stereoselective synthesis of the C3-C13 and C14-C24 fragments

Article abstract of DOI:10.1016/S0040-4039(00)00412-3

Synthetic studies towards the C₃-C₁₃ (2) and C₁₄-C₂₄ (3) segments of the potent antiviral and antitumor compound macrolactin A (1) are presented. Segment 2 was constructed via a convergent and facile approach, exploiting Wittig olefination to generate the sensitive E,Z-diene-moiety. Segment 3 was obtained from the chiral pool derived sulfone 4 via an α- alkylation-desulfonation reaction sequence. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00412-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3463–3466
Studies on the total synthesis of macrolactin A. A stereoselective
synthesis of the C3–C13 and C14–C24 fragments
Shukun Li, Rui Xu and Donglu Bai ∗
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China
Received 26 January 2000; revised 3 March 2000; accepted 7 March 2000
Abstract
Synthetic studies towards the C3–C13 (2) and C14–C24 (3) segments of the potent antiviral and antitumor
compound macrolactin A (1) are presented. Segment 2 was constructed via a convergent and facile approach,
exploiting Wittig olefination to generate the sensitive E,Z-diene moiety. Segment 3 was obtained from the chiral
pool derived sulfone 4 via an α-alkylation–desulfonation reaction sequence. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: macrolactin A; antiviral; stereoselective synthesis; Wittig olefination; sulfone alkylation.
Macrolactin A (1) is the parent aglycone of a novel family of bioactive 24-membered macrolides
isolated from a deep sea bacterium,1 and its stereochemistry is established as 7S,13S,15R,23R.2 Macro-
lactin A inhibits B16-F10 murine melanoma cancer cells and mammalian Herpes simplex viruses I and
II, and protects human T-lymphoblasts against HIV replication. Several research groups have reported
their approaches to the synthesis of macrolactin A;3 however, only two groups have finished the total
synthesis.4 In the reported syntheses, a similar strategy was adopted, namely, the conjugated double
bond structures were constructed by palladium-catalyzed sp2–sp2 cross-coupling reactions.
Recently, we were also involved in the synthesis of this molecule with a totally different approach.
Our strategy for the construction of macrolactin A is depicted in Scheme 1. Disconnections at the lactone
linkage, the C2–C3 double bond and the C13–C14 bond gave the key intermediates 2 and 3, and 3 was
envisioned to be formed by alkylation of sulfone 4 with bromide 5. Fragment 2 and sulfone 4 could be
derived from the chiral compounds (S)-malic acid and poly[(R)-3-hydroxybutyric acid], respectively.
The synthesis of fragment 2 started with the known protected triol 6 prepared in two steps from (S)-
malic acid.5 Oxidation of 6 under Swern conditions followed by Wittig olefination with carbethoxy-
methylenetriphenylphosphorane gave the corresponding E-α,β-unsaturated ester 7 in 74% yield.6 The
latter was hydrolyzed with p-toluenesulfonic acid yielding the corresponding diol followed by selective
tritylation of the primary hydroxyl group to afford trityl ether 8 in 98% yield for the two steps from 7.
∗
Corresponding author. Fax: 86-21-64370269; e-mail: dlbai@mail.shcnc.ac.cn (D. Bai)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00412-3
tetl 16692

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Scheme 1.
Protection of the secondary hydroxyl group in 8 as a MEM ether 9 (91%) followed by removal of the
trityl group in 9 by exposure to formic acid in ether smoothly afforded 10 in 96% yield. Dess–Martin
oxidation of 10 furnished the corresponding aldehyde,7 which was subjected to Wittig condensation with
formylmethylenetriphenylphosphorane giving the E,E-α,β-unsaturated aldehyde 11 in 92% yield over
the two steps. The 1,3-dithiane unit in ester 13 was introduced directly via Wittig reaction of aldehyde
11 and the thioacetal phosphonium salt 12 in ether.8 Some conventional solvents (THF, benzene and
toluene) were also tested. We found that the solvent was critical to the success of this reaction and the
ether was the best one. The E,E,Z-dithiane 13 thus obtained was reduced with DIBAL-H in methylene
chloride furnishing the allylic alcohol 14 (91%). Finally, oxidation of alcohol 14 under Swern conditions
afforded the corresponding aldehyde which was further protected in methanol in the presence of trimethyl
orthoformate and p-toluene sulfonic acid giving the C3–C13 segment, acetal 2,9 in a quantitative yield
(Scheme 2).
Scheme 2. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C–rt, 1 h, then Ph3P_CHCOOEt, 0°C, 5 h, 74%;
(b) MeOH, p-TsOH, rt, 2 h; (c) Ph3CCl, Et3N, DMAP, CH2Cl2, reflux, 6 h, 98% (for two steps); (d) MEMCl, i-Pr2NEt, CH2Cl2,
rt, 30 h, 91%; (e) HCOOH, Et2O, rt, 50 min, 96%; (f) Dess–Martin periodinane, CH2Cl2, rt, 2 h; (g) Ph3P_CHCHO, CHCl3, rt,
8 h, 92% (for two steps); (h) 12, t-BuOK, Et2O, 30 min, 90%; (i) DIBAL, CH2Cl2, −78°C, 30 min, 91%; (j) (COCl)2, DMSO,
Et3N, CH2Cl2, −78°C, 40 min, rt, 1 h, 88%; (k) MeOH, HC(OMe)3, p-TsOH, rt, 20 min, 100%
The retrosynthetic analysis of the C14–C24 fragment 3 showed that a coupling reaction between sulfone
4 and allylic bromide 5 seemed to be the most straightforward method to build this fragment. The

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synthesis of 5 started with O,O-isopropylidene-L-glyceraldehyde 15.10 Condensation of aldehyde 15
with triethyl 4-phosphonocrotonate gave the corresponding E,E-diene ester 16 as the major product.11
Reduction of 16 to the corresponding primary alcohol 17 with LiAlH4/AlCl3 followed by treatment with
NBS/PPh3 furnished the allylic bromide 512 (Scheme 3).
Scheme 3. Reagents and conditions: (a) ethyl diethylphosphonocrotonate, LDA, THF, 0°C, 1 h, 63%; (b) LiAlH4, AlCl3, ether,
0°C, 1 h, 97%; (c) NBS, PPh3, DMF, rt, 30 min, 93%
The synthesis of sulfone 4 was elaborated from ester 18.13 Protection of the hydroxyl group in 18 as
its PMB ether followed by reduction of ester 19 with DIBAL-H gave the alcohol 20. Alcohol 20 was then
converted into the iodide 21 with PPh3/I2 in 90% yield. Treatment of 21 with sodium p-toluenesulfinate
produced sulfone 4 which was treated with a slight excess of lithium hexamethyldisilazane in THF
followed by addition of bromide 5 in one portion. The coupling products 22 were obtained as a mixture
of diastereomers. Desulfonation of 22 with Na(Hg) in methanol gave E,E-23 as a single isomer in 68%
overall yield from 4. Hydrolysis of acetonide 23 and subsequent conversion of the primary hydroxyl
group in diol 24 to the p-toluenesulfonate afforded compound 25. The secondary hydroxyl group in 25
was protected as TBS ether 26. Finally, p-toluenesulfonate 26 was treated with sodium iodide obtaining
the C14–C24 fragment 39 (Scheme 4). The 1H NMR and 13C NMR chemical shifts and coupling constants
recorded for 2 and 3 match the corresponding data for the C3–C13 and C14–C24 segments in natural
macrolactin A.2
Scheme 4. Reagents and conditions: (a) PMBOC(_NH)CCl3, CSA (cat.), CH2Cl2, rt, 36 h, 95%; (b) DIBAL-H, toluene, 0°C,
0.5 h, 99%; (c) I2, PPh3, imidazole, toluene, rt, 1 h, 90%; (d) NaSO2Ph, n-Bu4NBr (cat.), DMF, 40°C, 2 h, 84%; (e) LiHDMS,
THF, −78°C, 15 min; then 5, THF, −78°C, 15 min; (f) Na(Hg) (6%), Na2HPO4, MeOH, 0°C, 30 min, 68%; (g) CSA (cat.),
MeOH, rt, 3 h, 83%; (h) TsCl, Et3N, CH2Cl2, 0°C, 12 h, 69%; (i) TBDMSOTf, Et3N, CH2Cl2, 0°C, 15 min, 92%; (j) NaI,
acetone, reflux, 24 h, 58%
The coupling of the C3–C13 and the C14–C24 fragments is in progress.
Acknowledgements
This work was supported by a grant from the National Natural Science Foundation of China and a
grant from the State Key Laboratory of Bio-organic and Natural Products Chemistry.

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cm−1; 1H NMR (400 MHz, C6D6) 6.55 (dd, 1H, J=15.2, 11.2 Hz), 6.12 (dd, 1H, J=11.4, 9.3 Hz), 5.83 (m, 1H), 5.62 (dd,
1H, J=15.1, 7.4 Hz), 5.50 (m, 2H), 4.80 (d, 1H, J=7.5 Hz), 4.73 (d, 1H, J=7.4 Hz), 4.65 (d, 1H, J=7.4 Hz), 4.18 (t, 1H, J=6.6
Hz), 3.73 (m, 1H), 3.60 (m, 1H), 3.50 (m, 3H), 3.32 (s, 3H), 3.25 (s, 3H), 3.22 (s, 3H), 2.78–3.0 (m, 4H), 2.62 (m, 2H),
2.38 (m, 2H), 2.15 (m, 1H), 1.73 (m, 1H); 13C NMR (75 MHz, C6D6) δ 134.7, 130.9, 130.5, 130.2, 128.3, 127.7, 102.9,
93.0, 76.0, 72.1, 67.3, 58.6, 52.1×2, 50.6, 38.8, 33.9, 30.2×2, 25.8; MS (m/z) 418 (M+, 1), 403 (1), 313 (2), 119 (100),
89 (45); HRMS (m/z): calcd for [M−OMEM]+ C16H25O2S2: 313.1296; found: 313.1290. Compound 3: [α]D18=−27.6 (c
1
0.72, MeOH); IR 1614, 1514, 1248, 1097, 1040, 991 cm−1; H NMR (400 MHz, CDCl3) δ 7.76 (2H, m), 6.87 (2H, d,
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(2H, m), 1.3–1.7 (4H, m), 1.17 (3H, d, J=6.1 Hz), 0.91 (9H, s), 0.08 (3H, s), 0.03 (3H, s); 13C NMR (100 MHz, CDCl3)
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13.6, −4.3, −4.7; anal. calcd for C25H41IO3Si: C, 55.14; H, 7.59; found: C, 55.47; H, 7.70.
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