Synthetic studies toward the marine metabolite prorocentin-4: Synthesis of the C1-C23 fragment

Article abstract of DOI:10.1039/c8ob00388b

A synthetic study of the construction of the C1-C23 fragment of prorocentin-4, a novel linear polyketide, is described. The synthetic highlights include the acid catalyzed epoxide opening, Gilman reaction, Pd(OH)₂ catalyzed transformation of a

Full text of DOI:10.1039/c8ob00388b

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DOI: 10.1039/C8OB00388B
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Synthetic studies toward marine metabolite prorocentin-4:
Synthesis of the C1–C23 fragment
Received 00th January 20xx,
Accepted 00th January 20xx
Praveen AnkiReddy, Sandeep AnkiReddy and Gowravaram Sabitha*
DOI: 10.1039/x0xx00000x
A synthetic study on the construction of the C1–C23 fragment of prorocentin-4, a novel linear polyketide is described. The
synthetic highlights include acid catalyzed epoxide opening, Gilman reaction, Pd(OH)2 catalyzed transformation of primary
propargylic alcohol into an aldehyde, Oxa-Michael cyclization, and Horner-Wadsworth-Emmons (HWE) olefination reaction
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as
key
steps.
Introduction
Results and Discussion
Retrosynthetically (Scheme 1), the prorocentin-4 (1) is disconnected
into three fragments at the C6-C7 alkene, and at C16-C17 bond.
Wittig olefination and HWE reactions were envisioned to
accomplish these junctions. As outlined in Scheme 1, our synthetic
strategy for C1-C23 fragment (2) is convergent and involves the
assembly of C7-C16 fragment (3) and C17-C23 fragment (4) by HWE
olefination and hydrogeation sequence to give C7-C23 fragment (5),
Followed by Wittig olefination of C1-C6 fragment (6) with C7-C23
fragment 5.
Prorocentins1,2 are linear polyketides and ethers isolated from
marine dinoflagellates of the genus Prorocentrum sp.
distributed in temperate and tropical oceans worldwide.2
Prorocentins isolated from an okadaic acid producing organism
showed potent cytotoxic activities.3 Among them, prorocentin-
42
(1) (Figure 1) was isolated in 2010 from the same
Prorocentrum strain (PL040104002). Embedded within this
molecule are two 2,5-trans tetrahydrofuran rings and 7
sterocenters. Even though, it shows very less cytotoxic activity,
insufficient quantities of material are available to fully
establish its therapeutic potential. The unique structural
features render prorocentin-4
challenging target for total synthesis. Herein we report
synthetic progress toward , focusing on the syntheses of the
C1-C6 ( ), C7-C23 ( ) fragments and their coupling to get the
(1) very attractive and
1
6
5
C1-C23 fragment of prorocentin-4. To the best of our
knowledge, this is the first report on synthetic studies of
prorocentin-4.
Figure 1. Prorocentin-4 (1)
aNatural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 607, India.
E-mail: gowravaramsr@yahoo.com, sabitha@iict.res.in; Fax: +91-40-27160512
Scheme 1. Retrosynthetic analysis for C1-C23 fragment of
prorocentin-4 (2)
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra of all
compounds.
See DOI: 10.1039/x0xx00000x
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The synthesis of tetrahydrofuran-containing (A ring) C7-C16 Next, we turned our attention to prepare the C17-C23 fragment of
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fragment 3 is outlined in Scheme 2. The preparation of this oxo prorocentin-4 (Scheme 3).
DOI: 10.1039/C8OB00388B
phosphonate 3 was initiated by (–)-(2S,3S)-5-(benzyloxy)-3-(tert-
butyldimethylsilyloxy)-2-methylpentan-1-ol (7).4 Alcohol
7 was
Synthesis of the C17-C23 fragment commenced from the known
secondary chiral propargylic alcohol7 (10) with the TBS protection
and subsequent formaldehyde reaction, to give the primary
propargylic alcohol 11. The primary propargylic alcohol 11 was
converted in to an α,β-unsaturated ester 20 E-selectively in good
yield (90%) in a single step by Pd(OH)2 catalyzed8 transformation of
primary propargylic alcohol into an aldehyde and subsequent
treatment with two carbon ylide. Removal of TBS group and the
resulting free alcohol 21 on exposure to Triton-B9 underwent a
smooth Oxa-Michael cyclization under thermodynamic conditions
to provide exclusively the 2,5-trans-tetrahydrofuran compound 22
(B ring) (92%).
subjected to a IBX oxidation/two carbon Wittig reaction sequence
to afford α,β-unsaturated ester 13. Ester on reduction with DIBAL-H
followed by Sharpless asymmetric epoxidation5 with (-)-
DIPT/Ti(OiPr)4/tBuOOH yielded an epoxy alcohol 14 in 93% yield.
Alcohol was converted to the terminal epoxide 8 by reacting with
DIBAL-H followed by treatment of the resuting 1,2-diol with tosyl
imidazole in the presence of NaH in dry THF. Epoxide 8 on
treatment with PTSA in DCM at 0 oC delivered the required 2,6-
trans-THF ring with concomitant loss of the O-silyl group to afford
15 with excellent diastereocontrol. IBX oxidation of the primary
alcohol followed by HWE olefination with a phosphonate gave α,β-
unsaturated ester 16. Ester on reduction with DIBAL-H followed by
Sharpless asymmetric epoxidation with (-)-DIPT/Ti(OiPr)4/tBuOOH
yielded an epoxy alcohol 17 in 90% yield. Next, the regioselective
ring-opening of epoxide with
a
Gilman reagent (MeLi/CuI)6
proceeded selectively to give a 1,3-diol compound 17 in 80% yield.
The contamination of the 1,2-diol was eliminated by exposing the
crude reaction mixture to NaIO4 followed by simple
chromatography afforded 1,3-diol. which was protected as di-TBS
ether 18 using TBSOTf followed by selective cleavage of primary TBS
group resulted alcohol 19. DMP oxidation of the primary hydroxyl
group furnished the corresponding aldehyde, which was condensed
with lithiated diethyl methylphosphonate, followed by oxidation to
provide the desired phosphonate, C7-C16 fragment (3).
Scheme 3. Synthesis of 4, 4a and 4b
Reagents and conditions: a) TBDMSCl, imidazole, CH2Cl2, 1 h, 90%;
b) EtMgBr, (CH2O)n, anhydrous THF, rt, 5 h, 90%; c) H2-preactivated
Pd(OH)2/C (7 mol%) Et3N (5 mol%), benzene r.t., 1 h then
Ph3P=CHCOOEt, benzene, ∆, 1 h, 90%; d) PPTS, MeOH, 0 oC, 93%; e)
Triton B, rt, MeOH, 15 min, 92%; f) i) DIBAL-H, CH2Cl2, -78 oC, 1 h, ii)
Allyl tri butyl phophine, n-BuLi, anhydrous THF, -78 oC, 1 h, 85%
over two steps; g) DDQ, CH2Cl2/buffer (9:1), 0 °C, 85%; h) Dess–
Martin periodinane, NaHCO3, CH2Cl2, 0 °C, 1.5 h; i) Ba(OH)2·8H2O,
o
anhydrous THF, rt, decomposed; j) DIBAL-H, CH2Cl2, 0 C, 1 h, 95%;
k) TBDMSCl, imidazole, CH2Cl2, 1 h, 90%; l) DDQ, CH2Cl2/buffer (9:1),
0 °C, 90%.
Scheme 2. Synthesis of the C7-C16 fragment (3)
Reagents and conditions: a) i) IBX, CH3CN, ∆, 1 h ii) Ph3P=CHCO2Et,
o
o
C6H6, 80 C, 2 h, 80%; b) DIBAL-H, CH2Cl2, -78 C, 1 h, 95%; c) (-)-
DIPT, Ti(iPrO)4, t-BuOOH, CH2Cl2, 4 Å MS, -23 oC, 20 h, 93%; d) i)
DIBAL-H, CH2Cl2, -78 oC, 1 h, 95%; ii) NaH, tosyl imidazole, THF, 0 oC,
2 h, 80%; e) PTSA, CH2Cl2, rt, 5 h, 95%; f) i) IBX, CH3CN, ∆, 1 h ii)
The trans-stereochemistry of the newly generated tetrahydrofuran
ring in 22 was assigned based on 1H NMR (400 MHz, CDCl3) data and
assignments were made with the aid of TOCSY and NOESY
experiments (Figure 2). The less NOE between C2H/C5H suggested
that both the protons are anti to each other (trans related).
o
(H3CCH2O)2POCH2COOEt, NaH, THF, -78 C, 1 h, 80% for 2 steps; g)
DIBAL-H, CH2Cl2, -78 oC, 1 h, 95%; h) (-)-DIPT, Ti(iPrO)4, t-BuOOH,
CH2Cl2, 4 Å MS, -23 oC, 20 h, 90%; i) MeLi, CuI, E2O, -40 oC, 2 h then
o
NaIO4 80% for 2 steps; j) TBSOTf, Et3N, CH2Cl2, 0 C, 93%; k) PPTS,
o
MeOH, 0 C, 93%; l) (i) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0
°C, 1.5 h; (ii) (MeO)2P(O)CH2Li, THF, –78 °C; (m) Dess–Martin
periodinane, NaHCO3, CH2Cl2, 0 °C, 1.5 h, 81% for 3 steps.
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DOI: 10.1039/C8OB00388B
Scheme 4. Synthesis of the C7-C23 fragment (5)
Reagents and conditions: a) Dess–Martin periodinane, NaHCO3,
CH2Cl2, 0 °C, 1.5 h; b) Ba(OH)2·8H2O, anhydrous THF, rt, 85%; c)
Pd/C, MeOH, H2, rt, 4 h, 90%; d) i) Dess–Martin periodinane,
NaHCO3, CH2Cl2, 0 °C, 1.5 h; ii) MeMgBr, anhydrous THF, -78 oC, 1 h;
iii) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 °C, 1.5 h, 75% over
3 steps.
Figure 2. NOESY spectrum showing the characteristic NOE
correlations of compound 22
Conversion of 5 into 28 is crucial which required optimization of
methyl Grignard reaction under different reaction conditions (Table
1).
Table 1. Optimization of Grignard reaction conditions of 5b
prepared from 5a
Figure 3. Chemical structure of 22
In the next step, DIBAL-H reduction of this key intermediate
provided aldehyde, at which point C-C diene unit could be readily,
incorporated using allyltributylphosphine in the presence of n-BuLi
at -78 oC to furnish a diene compound 24. The PMB group was
oxidatively removed with DDQ to obtain 4a, which was oxidized to
give an unstable aldehyde 4b. Initially, a Horner–Wadsworth–
Emmons (HWE) reaction was attempted for the synthesis of the C1–
C13 fragment between oxo phosphonate 3 and aldehyde 4b
generated from 4a (Scheme 3) was unsuccessful in our hands and
led to decomposition of the starting material. In order to
circumvent this, the preparation of aldehyde 4c was undertaken
without a diene unit. Accordingly, the ester group in 23 was
reduced with DIBAL-H to give a primary alcohol 25. After protection
of the resulting primary hydroxyl group as TBS ether 26, the PMB
group was oxidatively removed with DDQ to obtain C17-C23 subunit
4 (Scheme 3).
Now, sets the stage for Horner-Wadsworth-Emmons (HWE)
condensation reaction of a β-ketophosphonate (northern fragment)
3 with the aldehyde 4c generated from 4. Thus, aldehyde 4c
generated by oxidation of 4 with IBX was subjected to HWE
Optimized conditions are shown in red color.
10
Next, we focused on the preparation of C1-C6 fragment. The
aldehyde 29 (obtained from commercially available 1,3-propane
diol in a two-step sequence i.e., PMB protection followed by
oxidation using literature procedures) was subjected to standard
Wittig olefination with the anion of phosphonium bromide to give
alkene 30 in good yield (Scheme 5). Ester 30 on reduction with
DIBAL-H followed by TBDPS protection gave compound 31.
Oxidative Removal of the PMB group with DDQ gave alcohol 32
olefination reaction with the phosphonate 3 using Ba(OH)2
successfully furnished the desired enone 27 in 85% yield (Scheme
4). Hydrogenation of double bond using Pd/C proceeded smoothly
to give a saturated compound C7-C23 (5) by simultaneous removal
of benzyl group. The compound 5 was converted into the desired
keto compound 27 by a three reaction sequence, i.e., oxidation of
alcohol to aldehyde, methyl Grignard reaction, followed by DMP
oxidation.
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(85%), which was converted into triphenylphosphonium iodide 6 via
iodide.
Acknowledgements
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DOI: 10.1039/C8OB00388B
PA and SA thank CSIR, India for the award of fellowships. All
the authors thank CSIR, New Delhi, India for financial support
as part of XII Five Year Plan Programme under title ORIGIN
(CSC-0108).
Notes and references
1
C. K. Lu.; H. N. Chou.; C. K. Lee.; T. H. Lee. Org. Lett. 2005, 7,
3893–3896.
2
C. K. Lu.; Y. M. Chen.; S. H. Wang. Tetrahedron Lett. 2010
51, 6911–6914.
,
Scheme 5. Synthesis of the C1-C6 fragment (6)
3
4
5
J. D. Dodge. Bot. J. Linn. Soc. 1975, 67, 175–187.
C. Bauder. Eur. J. Org. Chem. 2010, 6207–6216.
a) T. Katsuki.; K. B Sharpless. J. Am. Chem. Soc.1980, 102,
5974–5976. b) Y. Gao.; J. M. Klunder.; R. M. Hanson.; H.
Masamune; S. Y. Ko.; K. B. Sharpless. J. Am. Chem. Soc. 1987
109, 5765-5780.
M. T. Crimmins and A. C. DeBaillie. J. Am. Chem. Soc., 2006
128, 4936–4937.
J. S. Yadav, C. C. Madhavi and B. V. Joshi. Tetrahedron Lett.
1988, 29, 2737–2740.
G. Sabitha, A. Y. Reddy, S. Nayak and J. S. Yadav. Synthesis,
2012, 44, 1657–1662.
(a) I. Hayakawa.; M. Ueda.; M. Yamaura.; Y. Ikeda.; Y.
Suzuki.; K. Yoshizato.; H Kigoshi. Org. Lett. 2008, 10, 859–
861. (b) S. Ko.; L. Klein.; K. Pfaff.; Y. Kishi. Tetrahedron Lett.
1982, 23, 4415–4418.
o
Reagents and conditions: a) DIBAL-H, CH2Cl2, 0 C, 1 h then Et3N,
TBDPSCl, 90% ; b) DDQ, CH2Cl2/buffer (9:1), 0 °C, 85%; c) i) Ph3P,
ImH, I2, THF, 0 oC; ii) Ph3P, DIPEA, CH3CN, ∆, 10 h, 90% over two
steps.
,
6
7
8
9
,
Coupling12 of methyl ketone 28 with the salt 6 proceeded smoothly
to give C1-C23 fragment 2 in good yield (80%) (Scheme 6). The
geometry (cis) of the newly formed double bond was established by
its coupling constant, while one of the olefinic proton signals
appeared at  5.15 ppm as a triplet (t, Jcis coupling constant 7.3 Hz).
10 a) C. C. Sánchez and G. E. Keck, Org. Lett. 2005, 7(14), 3053–
3056; b) M. T. Crimmins, M. Shamszad and A. E. Mattson,
Org. Lett. 2010, 12, 2614–2617.
11 T. K. Chakraborty, S. Purkait and S. Das. Tetrahedron 2003
59, 9127–9135.
,
12 Q. Chen, D. Schweitzer, J. Kane, V. Jo Davisson, and P.
Helquist. J. Org. Chem. 2011, 76, 5157–5169.
Scheme 6. Synthesis of C1-C23 fragment (2)
Reagents and conditions: a) n-BuLi, anhydrous THF, -78 oC, 4 h,
80%.
Conclusions
In conclusion, we have developed a highly stereoselective
synthetic route for the C1-C23 fragment
2 of Prorocentin-4 (1).
The key features of the developed strategy are acid catalyzed
epoxide opening, Gilman reaction, Pd(OH)2 catalyzed
transformation of primary propargylic alcohol into an
aldehyde, Oxa-Michael cyclization, and Horner-Wadsworth-
Emmons (HWE) olefination reaction. Total synthesis is
currently under progress in our group.
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DOI: 10.1039/C8OB00388B
Synthetic studies toward marine metabolite prorocentin-4: Synthesis of the C1–C23
fragment
Praveen AnkiReddy, Sandeep AnkiReddy and Gowravaram Sabitha*
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad – 500 007,
India.
Corresponding author: Tel.: +91-40-27191629; fax: +91-40-27160512
e-mail: gowravaramsr@yahoo.com, sabitha@iict.res.in
HWE olefination
Wittig olefination
O
Oxa-Michael cyclization
O
O
HO
OH
Gilman reaction
Epoxide opening
Prorocentin-4