Stereoselective Total Synthesis of psiAβ - A Sporogenic Psi Factor from Aspergillus nidulans 1

Article abstract of DOI:10.1055/s-0033-1340834

The stereoselective total synthesis of psiAβ, a sporogenic psi factor of the fungus Aspergillus nidulans, has been accomplished starting from pentane-1,5-diol. The synthesis involves an enantioselective Keck allylation, an asymmetric alkynylzinc addition,

Full text of DOI:10.1055/s-0033-1340834

LETTER
▌975
lSettteer reoselective Total Synthesis of psiAβ – A Sporogenic Psi Factor from
Aspergillus nidulans1
Stereoselective Total Synthesis of psiAβ
Parigi Raghavendar Reddy, Maram Lingaiah, Biswanath Das*
Natural Products Chemistry Division, CSIR–Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received: 06.12.2013; Accepted after revision: 27.01.2014
O
Abstract: The stereoselective total synthesis of psiAβ, a sporo-
OTBS
C8H17
genic psi factor of the fungus Aspergillus nidulans, has been accom-
plished starting from pentane-1,5-diol. The synthesis involves an
enantioselective Keck allylation, an asymmetric alkynylzinc addi-
tion, and a TEMPO–bis(acetoxy)iodobenzene (BAIB) oxidation as
the key steps.
O
PMBO
OH
OH
OH
C8H17
3
2
Key words: psiAβ, total synthesis, Keck allylation, alkynylzinc ad-
dition, TEMPO, bis(acetoxy)iodobenzene , oxidation
HO
OH
PMBO
5
4
Scheme 1 Retrosynthetic analysis of psiAβ (2)
The hydroxylated unsaturated fatty acid derivatives psiAα
(1) and psiAβ (2) were isolated from the growth medium
of the fungus Aspergillus nidulans, strain WIM-145 (Fig-
ure 1).2 These compounds behave as precocious sexual in-
ducer (psi) factors, inducing premature sexual sporulation
in the fungus. They may function in a ‘hormonal’ role in
regulating the sporulation cycle.3
Our synthesis (Scheme 2) was initiated by protection of
one hydroxyl group of pentane-1,5-diol (5) by reaction
with PMBCl and NaH to form ether 6. The latter was ox-
idized with PCC, and the corresponding aldehyde under-
went
stereoselective
Keck
allylation6
with
allyl(tributyl)stannane in the presence of (R)-BINOL and
Ti(Oi-Pr)4 to produce the chiral homoallylic alcohol 4
(97% ee). The free hydroxyl group of 4 was protected
O
O
with TBDMSCl, and ether
7 was subjected to
hydroboration7 using BH3·SMe2 and NaOH/H2O2 to yield
primary alcohol 8. Alcohol 8 was oxidized with PCC, and
the generated aldehyde was subjected to an asymmetric
alkynylzinc addition8 [Et2Zn, (S)-BINOL, Ti(Oi-Pr)4,
PhOH] to produce propargyl alcohol 3 (92% de). The hy-
droxyl group of 3 was protected as its MOM ether, and the
PMB ether group of 9 was deprotected to give alcohol 10.
The TBS ether group of 10 was subsequently removed to
furnish diol 11. TEMPO–bis(acetoxy)iodobenzene
(BAIB) oxidation9 of this 1,5-diol afforded lactone 12,
which was subjected to hydrogenation using Lindlar’s
catalyst to produce cis-olefin 13.10 Removal of the MOM
ether group of 13 with DMS and BF3·OEt2 yielded the tar-
get compound 2, whose physical and spectroscopic prop-
erties were found to be identical to those reported for the
natural product. The specific rotation of the naturally oc-
curring compound was reported as [α]D30 +63.7 (c 0.0042,
MeCN)2 and that of our synthetic compound was found to
be [α]D25 +60.8 (c 0.25, CHCl3).
C5H11
OH
1
O
O
OH C8H17
2
Figure 1
In continuation of our work4 on the construction of bioac-
tive natural molecules, we herein disclose the stereoselec-
tive total synthesis of psiAβ (2). A chemoenzymatic
method for the synthesis of 2 has been previously report-
ed.5
Retrosynthetic analysis (Scheme 1) suggested that com-
pound 2 could be synthesized from the propargyl alcohol
3 which could, in turn, be prepared from the homoallylic
alcohol 4 derived from pentane-1,5-diol (5).
In conclusion, we have developed a stereoselective total
synthesis of psiAβ, a sporogenic psi factor of the fungus
Aspergillus nidulans, by applying a Keck allylation, an
asymmetric alkynyl zinc addition, and a TEMPO–BAIB
oxidation as the key steps.
SYNLETT 2014, 25, 0975–0976
Advanced online publication: 13.02.2014
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3
6
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5
2
1
4
1
4
3
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2
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DOI: 10.1055/s-0033-1340834; Art ID: ST-2013-D1115-L
© Georg Thieme Verlag Stuttgart · New York

976
P. R. Reddy et al.
LETTER
577 [M + H]+. Anal. Calcd (%) for C34H60O5Si: C, 70.78; H, 10.48.
Found: C, 70.80; H, 10.50. ESI-HRMS: m/z calcd for C34H61O5Si
[M + H]+: 577.42828; found: 577.42837.
OR
b
PMBO
HO
OH
5 R = H
4 R = H
25
1
c
Compound 11: pale yellow oil; [α]D +1.6 (c 0.25, CHCl3). H
NMR (200 MHz, CDCl3): δ = 4.97 (1 H, d, J = 9.0 Hz), 4.59 (1 H,
d, J = 9.0 Hz), 4.39–4.36 (1 H, m), 3.70–3.62 (3 H, m), 3.39 (3 H,
s), 2.19 (2 H, t, J = 7.0 Hz), 1.90–1.43 (10 H, m), 1.38–1.20 (13 H,
m), 0.82 (3 H, t, J = 7.0 Hz). 13C NMR (50 MHz, CDCl3): δ = 94.0,
86.9, 78.1, 71.4, 71.3, 62.8, 55.5, 37.0, 33.1, 32.5, 32.0, 31.9, 29.1,
29.0, 27.9, 27.8, 22.7, 21.9, 18.8, 14.0. ESI-MS: m/z = 343 [M +
H]+. Anal. Calcd (%) for C20H38O4: C, 70.13; H, 11.18. Found: C,
70.12; H, 11.20. ESI-HRMS: m/z calcd for C20H39O4 [M + H)+:
343.28429; found: 343.28425.
a
7 R = TBS
6 R = PMB
OTBS
e
d
OH
PMBO
OR2
8
C8H17
i
R1O
OR3
Compound 12: yellow liquid; [α]D25 +5.7 (c 0.25, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 4.97 (1 H, d, J = 9.0 Hz), 4.59 (1 H, d, J =
9.0 Hz), 4.40–4.29 (2 H, m), 3.39 (3 H, s), 2.64–2.41 (2 H, m), 2.20
(2 H, t, J = 7.0 Hz), 1.99–1.76 (4 H, m), 1.67–1.52 (2 H, m), 1.40–
1.21 (14 H, m), 0.89 (3 H, t, J = 7.0 Hz). 13C NMR (50 MHz,
CDCl3): δ = 171.3, 93.8, 87.0, 80.0, 55.6, 31.8, 31.0, 29.1, 29.0,
28.8, 28.7, 28.6, 28.3, 27.9, 22.2, 18.1, 18.0, 14.0. ESI-MS: m/z =
339 [M + H]+. Anal. Calcd (%) for C20H34O4: C, 70.97; H, 10.12.
Found: C, 70.95; H, 10.15. ESI-HRMS: m/z calcd for C20H34O4Na
[M + Na]+: 361.23493; found: 361.23499.
3
9
R1 = PMB, R2 = TBS, R3 = H
R1 = PMB, R2 = TBS, R3 = MOM
f
g
10 R1 = H, R2 = TBS, R3 = MOM
h
11 R1 = R2 = H, R3 = MOM
O
O
j
O
O
C8H17
Compound 2: colorless oil; [α]D25 +60.8 (c 0.25, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 5.36–5.33 (1 H, m), 5.29–5.23 (1 H, m),
4.39–4.26 (2 H, m), 2.50–2.40 (2 H, m), 1.99–1.91 (2 H, m), 1.90–
1.82 (2 H, m), 1.68–1.51 (6 H, m), 1.40–1.22 (12 H, m), 0.88 (3 H,
t, J = 7.0 Hz). 13C NMR (50 MHz, CDCl3): δ = 172.0, 130.2, 130.0,
80.8, 71.2, 32.6, 32.1, 32.0, 29.9, 29.7, 29.6, 27.9, 23.0, 18.9, 14.0.
ESI-MS: m/z = 297 [M + H]+. Anal. Calcd (%) for C18H32O3: C,
72.93; H, 10.88. Found: C, 72.95; H, 10.85. ESI-HRMS: m/z calcd
for C18H33O3 [M + H]+: 297.25807; found: 297.25797.
OR C8H17
13 R = MOM
OMOM
12
k
2
R = H
Scheme 2 Stereoselective synthesis of psiAβ (2). Reagents and con-
ditions: (a) NaH, PMBCl, dry THF, 0 °C to r.t., 3 h, 91%; (b) (i) PCC,
CH2Cl2, 0 °C to r.t., 2 h; (ii) Ti(Oi-Pr)4, (R)-BINOL, allyl(tri-
butyl)stannane, 4 Å MS, dry CH2Cl2, 0 °C, 25 h, 78% (97% ee); (c)
TBDMSCl, imidazole, DMAP, dry DMF, 0 °C to r.t., 2 h, 93%; (d)
BH3·SMe2, dry THF, 0 °C to r.t., 2 h, NaOH/H2O2, 80%; (e) (i) PCC,
CH2Cl2, 0 °C to r.t., 2 h; (ii) Et2Zn, (S)-BINOL, Ti(Oi-Pr)4, PhOH, 4
h, 90% (92% de); (f) MOMCl, EtNi-Pr2, dry CH2Cl2, 0 °C to r.t., 5 h,
88%; (g) DDQ, CH2Cl2–H2O (19:1), 0 °C to r.t., 4 h, 82%; (h) TBAF,
dry THF, 1 h, 89%; (i) TEMPO–BAIB, dry CH2Cl2, 0 °C to r.t., 4 h,
79%; (j) Lindlar’s catalyst, EtOAc, H2, r.t., 1 h, 88%; (k) DMS,
BF3·OEt2, –10 °C, 1 h, 89%.
Acknowledgment
The authors thank UGC and CSIR, New Delhi, for financial assi-
stance.
References and Notes
(1) Part 74 in the series ‘Synthetic Studies on Natural Products’.
(2) (a) Mazur, P.; Meyers, H. V.; Nakanishi, K.; El-Zayat, A. A.
E.; Champe, S. P. Tetrahedron Lett. 1990, 31, 3837.
(b) Mazur, P.; Nakanishi, K. E.; El-Zayat, A. A.; Champe, S.
P. J. Chem. Soc., Chem. Commun. 1991, 1486.
(3) (a) Champe, S. P.; Rao, P.; Chang, A. J. Gen. Microbiol.
1987, 133, 1383. (b) Champe, S. P.; El-Zayat, A. E.
J. Bacteriol. 1989, 171, 3982.
(4) (a) Kumar, J. N.; Das, B. Tetrahedron Lett. 2013, 54, 3865.
(b) Reddy, P. R.; Sudhakar, C.; Kumar, J. N.; Das, B. Helv.
Chim. Acta 2013, 96, 289. (c) Kumar, J. N.; Reddy, P. R.;
Das, B.; Kumar, C. G.; Sujitha, P. Bioorg. Med. Chem. Lett.
2013, 23, 5192.
(5) Mazur, P.; Nakanishi, K. J. Org. Chem. 1992, 57, 1047.
(6) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8457.
(7) Caprio, V.; Brimble, M. A.; Furkert, D. P. Tetrahedron
2001, 57, 4023.
(8) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4,
4143.
(9) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.;
Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57.
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2003, 14, 1127.
The Spectral Data of some Selected Compounds
25
1
Compound 4: colorless liquid; [α]D –12.9 (c 0.25, CHCl3). H
NMR (200 MHz, CDCl3): δ = 7.27 (2 H, d, J = 8.0 Hz), 6.68 (2 H,
d, J = 8.0 Hz), 5.85–5.75 (1 H, m), 5.15–5.08 (2 H, m), 4.42 (2 H,
s), 3.79 (3 H, s), 3.65–3.58 (1 H, m), 3.42 (2 H, t, J = 7.0 Hz), 2.29–
2.24 (1 H, m), 2.14–2.08 (1 H, m), 1.55–1.38 (4 H, m), 1.34–1.28 (2
H, m). 13C NMR (50 MHz, CDCl3): δ = 159.1, 134.0, 130.2, 129.1,
118.0, 113.9, 72.7, 70.1, 69.9, 55.1, 42.0, 36.8, 29.6, 22.1. ESI-MS:
m/z = 265 [M + H]+. Anal. Calcd (%) for C16H24O3: C, 72.69; H,
9.15. Found: C, 72.67; H, 9.17. ESI-HRMS: m/z calcd for C16H25O3
[M + H]+: 265.17982; found: 265.17974.
25
1
Compound 9: pale yellow liquid; [α]D –6.3 (c 0.25, CHCl3). H
NMR (200 MHz, CDCl3): δ = 7.28 (2 H, d, J = 8.0 Hz), 6.88 (2 H,
d, J = 8.0 Hz), 4.93 (1 H, d, J = 9.0 Hz), 4.59 (1 H, d, J = 9.0 Hz),
4.42 (2 H, s), 4.32–4.28 (1 H, m), 3.81 (3 H, s), 3.72–3.68 (1 H, m),
3.42 (2 H, t, J = 7.0 Hz), 3.36 (3 H, s), 2.19 (2 H, t, J = 7.0 Hz), 1.78–
1.20 (22 H, m), 0.92–0.82 (12 H, m), 0.04 (3 H, s), 0.03 (3 H, s). 13
C
NMR (50 MHz, CDCl3): δ = 159.1, 130.9, 129.2, 113.8, 94.0, 86.2,
78.7, 76.2, 72.6, 72.1, 70.0, 55.2, 55.1, 36.9, 32.2, 31.8, 31.7, 29.9,
29.1, 29.0, 28.9, 26.0, 22.6, 22.0, 18.9, 14.1, –4.9. ESI-MS: m/z =
Synlett 2014, 25, 975–976
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