First stereoselective total synthesis of helicascolides A and C

Article abstract of DOI:10.1016/j.tetlet.2012.07.018

The first total synthesis of helicascolides A and C is reported via acid catalyzed acetonide deprotection followed by intramolecular lactonization in one-pot as the key step.

Full text of DOI:10.1016/j.tetlet.2012.07.018

Tetrahedron Letters 53 (2012) 4997–4999
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Tetrahedron Letters
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First stereoselective total synthesis of helicascolides A and C
⇑
Palakodety Radha Krishna , Venkata Satyanarayana Mallula, Pendyala Venkata Arun Kumar
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of helicascolides A and C is reported via acid catalyzed acetonide deprotection
followed by intramolecular lactonization in one-pot as the key step.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 8 June 2012
Revised 6 July 2012
Accepted 8 July 2012
Available online 16 July 2012
Keywords:
Helicascolides A and C
d-Lactone
1,3-Syn-diol
Rychnovsky’s analogy
Intramolecular lactonization
Helicascolides A (1) and B (2) are the isomeric d-lactones iso-
lated from the marine fungus Helicascus kamaloanus (ATCC
18591)1 with no significant antifungal activity. Recently, structur-
ally similar helicascolide C (3), isolated from marine alga Gracilaria
sp. SGR-1, showed antifungal activity against phytopathogenic fun-
gus from Cladosporium cucumerinum.2 As a part of our interest in
the total synthesis of lactone ring-containing bioactive natural
products,3 herein we report stereoselective total synthesis of helic-
ascolides A and C by acid catalyzed acetonide deprotection fol-
lowed by lactonization in one-pot. Helicascolides are
architecturally unique in the sense that the lactone rings are highly
substituted, endowed with gem-dimethyl group next to ketone
functionality, chiral groups at C3 (ketone in case of compound 3),
C4, and at C5 make them synthetically attractive targets.
Accordingly, acid 4 on exposure to acid (HCl) would lead to the
helicascolide A (1) via the deprotection of acetonide group fol-
lowed by an intramolecular lactonization in one-pot. Compound
1 on oxidation would result in helicascolide C (3). While acid 4
in turn could be accessed from 5 by the functional group transfor-
mations like vinylation on the right-hand side of the fragment fol-
lowed by a deprotection-double oxidation reaction set of the PMB
ether group next to gem-dimethyl carbon on the other side. Com-
pound 5 was envisioned through the Gilman reaction of the corre-
sponding epoxide, while the epoxide itself was obtained from
commercially available neopentyl glycol.
Thus, the synthesis (Scheme 2) began with the commercially
available neopentyl glycol and its transformation into known4 con-
jugate ester 6 which upon treatment with DIBAL-H in CH2Cl2 gave
allylic alcohol 7 in high yield. Allylic alcohol 7 was converted into
chiral epoxy alcohol 8 using Sharpless5 conditions {(ꢀ)-DIPT/
Ti(OiPr)4/ TBHP/CH2Cl2/ꢀ20 °C/92%}. Later epoxide 8 was treated
with Gilman’s reagent6 (Me2CuLi) followed by the oxidative cleav-
age of the minor 1,2-diol with NaIO4 in THF/H2O (4:1) to afford the
desired 1,3-diol 5 (75%) as the major isomer. Next, primary alcohol
of 1,3-diol was protected as its benzoate ester 9 (Bz-Cl/Et3N/rt/2 h)
and the secondary alcohol as its MOM-ether (MOMCl/DIPEA/
CH2Cl2/rt) to furnish the all protected intermediate 10 which on
reductive cleavage of benzoate ester gave primary alcohol 11. Later
11 was oxidized under Swern conditions {(COCl)2/DMSO/Et3N/
CH2Cl2/ꢀ78 °C} to afford the corresponding chiral aldehyde which
was subjected to Grignard reaction with (E)-1-methyl-2-propen-
ylmagnesiumbromide to afford the olefinic compound 12 (68%)
as a 3:1 diastereomeric ratio (as determined from 1H NMR). Hence,
the inseparable mixture 12 was treated with 3 N HCl to afford the
O
O
O
8
1
O
5
O
O
9
2
7
4
HO
3
HO
O
12
11
10
2
1
Helicascolide B.
3
Helicascolide C.
Helicascolide A.
Accordingly, the envisaged retrosynthetic strategy for helicas-
colides A and C is delineated in Scheme 1. Linear strategy was in-
voked wherein acid 4 was conceived as the ideal precursor to 1.
⇑
Corresponding author. Tel.: +91 40 27183158; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.018

4998
P. Radha Krishna et al. / Tetrahedron Letters 53 (2012) 4997–4999
O
OH
O
O
O
O
O
PMBO
OH
HO
HO
4
5
1
O
HO
OH
O
Neopentyl glycol
3
Scheme 1. Reterosynthetic analysis.
O
b
a
Ref. 4
PMBO
OH
HO
OH
PMBO
OEt
7
6
Neopentyl glycol
OH
OH
O
d
c
PMBO
OH
OH
PMBO
PMBO
OBz
5
9
8
OMOM
OMOM
f
e
PMBO
OBz
g
PMBO
OH
10
11
MOM
O
OH
O
O
O
O
h
PMBO
PMBO
PMBO
12
75:25 diastereomeric ratio
13a
13b
Scheme 2. Reagents and conditions: (a) DIBAL-H, CH2Cl2, 0 °C, 0.5 h, 98%; (b) (ꢀ)-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ20 °C, 8 h, 92%; (c) (i) (CH3)2CuLi, dry ether, ꢀ20 °C, 2 h (ii)
NaIO4, THF/H2O (4:1), (over two steps 75%); (d) BzCl, Et3N, CH2Cl2, 0 °C–rt, 2 h, 95%; (e) MOMCl, DIPEA, CH2Cl2, 0 °C–rt, 3 h, 94%; (f) K2CO3, MeOH, 0 °C–rt, 4 h, 85%; (g) (i)
(COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, (ii) (E)-1-methyl-2-propenylmagnesiumbromide, THF, ꢀ40 °C, (over two steps 68%); (h) (i) 3 N HCl, CH2Cl2, 0 °C–rt 0.5 h, 65%; (ii) 2,2-
DMP, PTSA, CH2Cl2, 0 °C, 12 h, 90%.
corresponding free 1,3-diol which was then protected as its aceto-
nide to afford the separable major diastereomer 13a (75%).
The 1,3-syn stereochemistry of the major isomer 13a was
proved by the Rychnovsky’s analogy.7 For instance, the 13C NMR
of 13a revealed the carbon atoms due to the acetonide methyls
at d 19.4 and at d 30.1 ppm characteristic of the acetonide of a
syn-1,3-diol moiety. The 1,3-diaxial interactions in syn-diol (13a),
which assumes a chair-conformation, between one of the aceto-
nide methyl groups and proton prompt the two methyl carbons
resonate differently unlike anti-diol (13b), which due to its
twisted-boat conformation induces chemical shifts of both the
methyl groups of the acetonide group appear at the near same
ppm (Fig. 1).
Cleavage (DDQ/CH2Cl2/H2O/rt/0.5 h) of ether linkage in 13a
afforded the primary alcohol 14 (85%, Scheme 3). The alcohol 14
was oxidized to carboxylic acid 4 under TEMPO/BIAB8 and acid cat-
alyzed lactonization9 of 4 to result in helicascolide A (1). Finally, 1
was oxidized using Dess-Martin periodinane (DMP/CH2Cl2/0 °C/
92%) to furnish 6-membered keto lactone (helicascolide C) 3. The
physical and spectroscopic data of 1 and 3 are in consistent with
the reported values.1,2,10
In summary, the first total synthesis of helicascolide A (8.15%
overall yield) and helicascolide C (7.5% overall yield) is reported
via acid catalyzed acetonide deprotection followed by lactoniza-
tion in one-pot as the key step. It is pertinent to mention that helic-
ascolide B could be accessed by the same methodology albeit using
an appropriate precursor.
(E)
H
H
O
O
(S)
(E)
H
H
O
(S)
(S)
(S)
(R)
O
(S)
H
H
OPMB
OPMB
13a
13b
Figure 1. Conformers of syn-diol and anti-diol.

P. Radha Krishna et al. / Tetrahedron Letters 53 (2012) 4997–4999
4999
O
O
O
O
O
a
b
13a
HO
O
HO
14
4
O
O
O
c
d
O
HO
1
Helicascolide C
3
Scheme 3. Reagents and conditions: (a) DDQ, CH2Cl2/H2O (19:1), 0 °C–rt, 1.5 h, 85%; (b) TEMPO/BIAB, CH2Cl2/H2O (19:5), 0 °C–rt, 1.5 h, 90%; (c) 5 N HCl, THF, reflux, 0.5 h,
78%; (d) DMP, CH2Cl2, 0 °C–rt, 92%.
4.00 (m, 1H), 3.78 (s, 3H), 3.44–3.41 (m, 5H), 3.31 (d, 1H, J = 8.7 Hz), 3.14 (d, 1H,
Acknowledgements
J = 8.7 Hz), 2.27 (m, 1H), 1.2 (d, 3H, J = 6.86 Hz), 0.98 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 166.6, 158.9, 132.7, 129.4, 129.0, 128.2, 113.6, 99.2, 87.3, 76.8, 72.2,
Two of the authors (M.V.S. and P.V.A.) thank the CSIR, New Del-
hi for the financial support in the form of fellowships.
67.9, 56.2, 55.1, 40.2, 33.0, 29.6, 21.9, 20.8, 19.0; HRMS m/z: calcd for C25H34O6
Na [M+Na]+ 453.2236 found: 453.2239. Compound 5: Colorless oil; ½a 2D5
ꢀ10.
ꢁ
03 (c 0.8, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.21 (d, 2H, J = 8.6 Hz), 6.87 (d,
2H, J = 8.4 Hz), 4.44 (s, 2H), 4.1 (br. s, 1H), 3.80 (s, 3H), 3.77–3.66 (m, 1H), 3.65–
3,57 (m, 1H), 3.53 (d, 1H, J = 4.5 Hz), 3.32 (s, 2H), 1.93 (m, 1H), 1.62 (d, 3H,
J = 1.7 Hz), 1.08–1.07 (m, 6H); 13C NMR (75 MHz, CDCl3): d 159.2, 129.2, 113.7,
83.97, 80.8, 73.4, 66.4, 54.9, 35.4, 22.5, 19.0, 17.8; HRMS m/z: calcd for
References and notes
1. Poch, G. K.; Gloer, J. B. J. Nat. Prod. 1989, 52, 257–260.
2. Tarman, K.; Palm, G. J.; Porzel, A.; Merzweiler, K.; Arnold, N.; Wessjohann, L. A.;
Unterseher, M.; Lindequist, U. Phytochem. Lett. 2012, 5, 83–86.
C
½
16H26O4Na [M+Na]+ 305.1726. found: 305.1723. Compound 11: Colorless oil;
ꢁ
a 2D5
ꢀ2.45 (c 0.25, CHCl3) : 1H NMR (300 MHz, CDCl3): d 7.25 (d, 2H, J = 8.3 Hz),
6.89 (d, 2H, J = 8.0 Hz), 4.69–4.64 (m, 2H), 4.43–4.40 (m, 2H), 3.80 (s, 3H), 3.70–
3.51 (m, 2H), 3.40 (s, 3H), 3.26 (m, 1H), 3.07 (d, 1H, J = 9.06 Hz), 2.04–1.92 (m,
1H), 1.49–0.91 (m, 9H); 13C NMR (75 MHz, CDCl3): d 129.1, 113.6, 99.7, 88.8,
76.7, 72.7, 66.0, 55.2, 36.2, 21.8, 20.5, 18.1; HRMS m/z: calcd for C18H30O5Na
3. (a) Radha Krishna, P; Ramana Reddy, V. V. Tetrahedron Lett. 2005, 46, 3905–
3907; (b) Radha Krishna, P; Srinivas Reddy, P Tetrahedron 2007, 63, 3995–3999;
(c) Radha Krishna, P; Srinivas, R Tetrahedron Lett. 2007, 48, 2013–2015; (d)
Radha Krishna, P; Srinivas, P Tetrahedron Lett. 2010, 51, 2295–2296.
4. Paterson, I.; Di Francesco, M. E.; Kuhn, T. Org. Lett. 2003, 5, 599–602.
5. Sharpless, K. B.; Behrens, H. C.; Katsuki, T.; Lee, M. W. A.; Martin, S. V.; Takatani,
M.; Viti, M. S.; Walker, J. F.; Woodard, S. S. Pure Appl. Chem. 1983, 55, 589–604.
6. Komatsu, K.; Tanino, K.; Miyashita, M. Angew. Chem. 2004, 116, 4441–4445.
7. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945–948; (b)
Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099–7103; (c)
Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511–3515.
8. Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293–295.
[M+Na]+ 3491992. found: 349.1990. Compound 13a: Colorless oil; ½a 2D5
ꢁ
+13.20
(c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.25 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H,
J = 8.6 Hz), 5.55–5.46 (m, 1H) 4.47–4.35 (m, 3H), 3.80 (s, 3H), 3.58 (d, 1H,
J = 9.8 Hz), 3.38 (d, 1H, J = 8.6 Hz), 3.11(d, 1H, J = 8.1 Hz), 1.76–1.60 (m, 4H),
1.56 (s, 3H), 1.44–1.39 (m, 6H), 1.01–0.93 (m, 6H), 0.74 (d, 3H, J = 6.7 Hz); 13C
NMR (75 MHz, CDCl3): d 128.8, 124.7, 113.5, 77.7, 77.1, 72.8, 72.1, 55.2, 32.3,
30.1, 23.7, 20.9, 19.4, 18.0, 13.3, 13.2; HRMS m/z: calcd for
C
23H36O4Na
[M+Na]+ 399.2514. found: 399.2511. Compound 14: Colorless oil; ½a 2D5
ꢁ ꢀ5.55 (c
0.15, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.51 (q, 1H, J = 6.4 Hz), 4.45 (d, 1H,
J = 10.1 Hz), 3.89–3.77 (m, 1H), 3.63–3.51 (m, 1 H), 3.42 (d, 1H, J = 4.5 Hz),
3.07–2.90 (m, 1H), 1.88–1.56 (m, 7H), 1.51–1.26 (m, 6H), 0.99 (s, 6H), 0.77 (d,
3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d 126.9, 125.1, 97.8, 82.4, 72.8, 72.0,
41.4, 30.1, 24.8, 19.6, 19.4, 17.9, 13.8, 13.2; HRMS m/z: calcd for C15H28O3Na
[M+Na]+ 279.1934. found: 279.1930. Compound 4: white solid; mp 125–126 °C.
9. Nagarapu, L.; Shuklachery, K.; Rajashaker, B. Tetrahedron 2012, 68, 5829–5832.
and references cited therein.
10. Spectral data for selected compounds. Compound 7: Pale yellow oil; ½a D25
ꢀ5.73 (c
ꢁ
0.6, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.26 (d, 2H, J = 9.4 Hz), 6.87 (d, 2H,
J = 9.4 Hz), 5.76–5.59 (m, 2H), 4.47 (s, 2H), 4.08 (d, 2H, J = 4.5 Hz), 3.80 (s, 3H),
3.16 (s, 2H), 1.02 (s, 6H); 13C NMR (75 MHz, CDCl3): d 159.1, 139.9, 129.0,
126.2, 113.6, 78.9, 72.9, 63.8, 55.2, 37.2, 24.5; HRMS m/z: calcd for C15H22O3Na
½
a 2D5
ꢁ
ꢀ10.56 (c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3):
d 5.49 (q, 1H,
[M+Na]+ 273.1466. found: 273.1460. Compound 8: Pale yellow oil; ½a 2D5
ꢁ
+18.6 (c
J = 6.6 Hz), 4.47 (d, 1H, J = 10.1 Hz), 4.01–3.88 (m, 1H), 1.78–1.68 (m, 7H), 1.50–
1.46 (m, 3H), 1.43–1.31 (m, 3H), 1.29–1.18 (m, 6H), 0.67 (d, 3H, J = 6.7 Hz); 13
C
0.65, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.25 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H,
J = 8.4 Hz), 4.43 (s, 2H), 3.85 (dd, 1H, J = 12.4, 2.2 Hz), 3.80 (s, 3H), 3.59 (dd, 1H,
J = 12.2, 4.4 Hz), 3.25 (m, 1H), 3.10–3.07 (m, 1H), 2.90 (d, 1H, J = 2.0 Hz), 0.91 (s,
3H), 0.90 (s, 3H); 13C NMR (75 MHz, CDCl3): d 158.9, 130.4, 128.8, 113.6, 76.5,
72.8, 62.1, 60.9, 55.3, 55.1, 34.9, 20.9, 20.5; HRMS m/z: calcd for C15H22O4Na
NMR (75 MHz, CDCl3): d 183.0, 133.3, 124.8, 98.4, 71.9, 45.9, 33.7, 30.1, 23.4,
19.5, 19.2, 17.9, 13.2, 11.4; HRMS m/z: calcd for C15H26O4Na [M+Na]+ 293.1523.
found: 293.1520. Helicascolide A (1): white solid; mp 99–100 °C. ½a D25
ꢀ33.1 (c
ꢁ
0.15, CH3OH), lit.2 value ½a D25
ꢁ
ꢀ35.2 (c 0.14, CH3OH); 1H NMR (300 MHz,
[M+Na]+ 289.1415. found: 289.1413. Compound 9: colorless oil; ½a 2D5
ꢀ34.36 (c
ꢁ
CD3OD): d 5.58 (qq, 1H, J = 6.7, 1.3 Hz), 4.64 (d, 1H, J = 11.1 Hz), 3.45 (d, 1H,
J = 1.8 Hz), 2.34–2.32 (m, 1H), 1.68–1.63 (m, 6H), 1.29–1.27 (m, 6H), 0.90 (d,
3H, J = 6.7 Hz); 13C NMR (75 MHz, CD3OD): d 180.6, 133.4, 127.2, 90.1, 77.4,
0.6, CHCl3); 1H NMR (500 MHz, CDCl3): d 8.05 (m, 2H), 7.55 (m, 1H), 7.40 (m,
2H), 7.22 (d, 2H, J = 8.2 Hz), 6.86 (d, 2H, J = 8.0 Hz), 4.66 (dd, 1H, J = 11.4,
4.4 Hz), 4.44 (s, 2H), 4.15 (dd, 1H, J = 11.4, 8.0 Hz), 3.78 (s, 3H), 3.49–3.44 (m,
2H), 3.27 (d, 1H, J = 9.1 Hz), 2.21–2.15 (m, 1H), 1.68–1.48 (m, 1H), 1.18 (d, 3H,
J = 6.86 Hz), 1.00 (d, 6H, J = 9.1 Hz); 13C NMR (75 MHz, CDCl3): d 166.8, 159.2,
132.7, 129.4, 129.2, 128.2, 113.8, 82.2, 80.2, 73.2, 67.3, 55.2, 38.9, 34.4, 23.4,
45.6, 32.4, 26.9, 23.3, 14.2, 13.3, 10.4; HRMS m/z: calcd for
C12H20O3Na
[M+Na]+ 235.1416. found: 235.1415. Helicascolide C (3): white solid; mp 87–
88 °C. ½a 2D5
ꢁ
+20.8 (c 0.15, CH3OH), lit.2 value ½a D25
ꢁ
+21.2 (c 0.34, CH3OH); 1H
NMR (300 MHz, CD3OD): d 5.72–5.70 (m, 1H), 4.69 (d, 1H, J = 11.5 Hz), 2.94–
2.92 (m, 1H), 1.72–1.69 (m, 6H), 1.40–1.38 (m, 6H), 0.95 (d, 3H, J = 6.7 Hz), 13
NMR (75 MHz, CD3OD): d 177, 132.3, 129.1, 86.4, 52.6, 44.5, 23.9, 23.8, 13.3,
C
20.5, 18.6; HRMS m/z: calcd for
C
23H30O5Na [M+Na]+ 409.1974 found:
409.1975. Compound 10: Colorless oil; ½a D25
ꢁ
ꢀ59.35 (c 0.9, CHCl3); 1H NMR
10.2, 9.7; HRMS m/z: calcd for
C
12H18O3Na [M+Na]+ 233.1145. found:
(300 MHz, CDCl3): d 8.05 (m, 2H), 7.55 (m, 1H), 7.40 (m, 2H), 7.22 (d, 2H,
J = 8.6 Hz), 6.84 (d, 2H, J = 8.4 Hz), 4.63–4.60 (m, 2H), 4.44–4.35 (m, 2H), 4.13–
233.1148.