Model studies toward a synthesis of asperaculin A: Exploration of iterative intramolecular Pauson-Khand reaction based strategies to access the dioxa[5.5.5.6]fenestrane framework

Article abstract of DOI:10.1016/j.tetlet.2012.06.059

A concise strategy, involving tandem intramolecular Pauson-Khand reactions (IPKRs) on a readily available ene-diyne precursor, to access the dioxa-fenestrane framework is delineated.

Full text of DOI:10.1016/j.tetlet.2012.06.059

Tetrahedron Letters 53 (2012) 4558–4561
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Model studies toward a synthesis of asperaculin A: exploration of iterative
intramolecular Pauson–Khand reaction based strategies to access the
dioxa[5.5.5.6]fenestrane framework
⇑
Goverdhan Mehta , Tabrez Babu Khan
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 26 June 2012
A concise strategy, involving tandem intramolecular Pauson–Khand reactions (IPKRs) on a readily avail-
able ene-diyne precursor, to access the dioxa-fenestrane framework is delineated.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Natural product synthesis
Dioxafenestrane
Tandem reactions
Intramolecular Pauson–Khand reaction
For nearly a quarter of a century, diterpene laurenene 1 re-
mained the lone example1 of a fenestrane crafted by nature in
which a central carbon shares four rings. This unique reign of lau-
renene among natural products ended in 2006 when isolation and
characterization of a novel sesquiterpenoid penifulvin A 22a and its
sibling secondary metabolites2b penifulvins B–E 3–6, all embody-
ing a dioxa[5.5.5.6]fenestrane skeleton, was reported from the cul-
Earlier synthesis of fenestranes utilized classical transforma-
tions based on aldol chemistry,3 transannular cationic cyclization,6
and carbene insertion,3 intramolecular [2+2] cycloadditions and
cyclodehydrations3 as the key strategic steps. However, in recent
years economical and conceptually new approaches based on
intramolecular arene-olefin photocycloaddtion,4a,b,7 transition me-
tal mediated cyclization–carbonylation (like the Pauson–Khand
reaction, PKR)8,9 have proved quite versatile and effective in
accessing the fenestrane framework. Among these, the intramolec-
ular Pauson–Khand reaction (IPKR) appeared worthy of further
exploitation in generating hetero-fenestrane architecture9 present
in natural products 2–7 as it can be implemented on simple and
quite readily accessible enyne, diyne, and triyne precursors.
Our initial focus in the context of asperculin A synthesis was to
devise a viable route to a functionalized dioxa[5.5.5.6]fenestrane
system 8. For this purpose we began to scout for various precursors
which through iterative IPKR protocol could deliver the
dioxa[5.5.5.6]fenestrane framework either in a one pot operation
or in a stepwise process. A retrosynthetic perspective leading to
dioxa-fenestranes 9 and 10 through the intermediacy of 11–14
from two key precursors 15 and 16 is depicted in Scheme 1. Inter-
estingly, both the enyne precursors 15 and 16 can be prepared
tures of
a
fungicolous isolate of Penicillium griseofulvum
NRRL35584, Chart 1. Penifulvin A 2 was shown to exhibit signifi-
cant insecticidal activity2a and this attribute along with the un-
iquely fascinating dioxa[5.5.5.6]fenestrane architecture present in
it held an instant attraction to the synthetic chemists3 and the
endeavors of the Mulzer4a group culminated in its first total syn-
thesis in 2009 and of penifulvins B and C in the following year.4b
More recently, in 2011, research groups5 from Thailand have
reported the isolation and structure determination of a novel diox-
a[5.5.5.6]fenestrane based sesquiterpenoid asperculin A 7 (Chart 1)
from the mycelial extract of the marine-derived fungus Aspergillus
aculeatus GRI323-04. Interestingly, both penifulvin A and aspercu-
lin A bear dioxa[5.5.5.6]fenestrane core but differ in the substitu-
tion and functionalization pattern, particularly in the disposition
of oxacyclic segment of the fenestrane frame. As a part of our
ongoing interest in the synthesis of penifulvins A–E, we were
drawn toward a synthesis of asperculin A 7 and report here a strat-
egy that enables convenient access to the core dioxa[5.5.5.6]fenes-
trane skeleton 8 (Chart 1) present in this natural product.
either from glycerol or from D-mannitol.
Synthesis of 1510 and 1610 from glycerol derived solketal 17 and
the corresponding aldehyde 18 was quite straightforward and the
successfully executed reaction sequence is displayed in Scheme 2.
In the initial foray toward 9, we deployed enyne 15 and PKR
reaction on it delivered a readily separable mixture of diastereo-
mers 1910 and 2010 in a ratio of 2.5:1, respectively, Scheme 3.
We decided to proceed with the major diastereomer 19 and
⇑
Corresponding author. Tel.: +91 4023010785; fax: +91 4023012460.
E-mail addresses: gmsc@uohyd.ernet.in, gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.059

G. Mehta, T. B. Khan / Tetrahedron Letters 53 (2012) 4558–4561
4559
H
O
O
O
O
H
H
H
O
O
O
R4
O
O
O
OH
H
H
H
R3
R1
H
R2
H
Laurenene
1
Asperaculin A 7
8
R1, R2, R3, R4 = H
R1, R3, R4 = H;R2 = -OH
R2, R3, R4 = H; R1 = -OH
R1, R2, R3 = H; R4 = -OH
R1, R2, R4 = H; R3 = -OH
Penifulvin A 2
Penifulvin B 3
Penifulvin C 4
Penifulvin D 5
Penifulvin E 6
Chart 1. Architecture of fenestranes from nature.
H
O
O
H
H
O
OH
O
OP
O
11
H
O
O
H
O
15
O
OH
OH
OH
9
12
8
H
O
Glycerol
O
H
H
O
O
H
O
OP
13
HO
H
O
O
O
16
10
O
14
Scheme 1. Retrosynthetic considerations in the assembly of dioxa[5.5.5.6]fenestrane system.
OH
OH
H
O
O
H
H
OH
OH
OH
a
O
H
O
O
+
15
a, b
c, d
O
O
O
OH
17
15
19
20
HO
HO
Scheme 3. Reagents and conditions: (a) Co2(CO)8, TMNO, À15 °C to rt, 8 h, 54%
(19:20 = 2.5:1).
O
e, f
g, h
OH
O
O
O
protected the free hydroxyl group as the bulky TBS group to fur-
nish 21, Scheme 4. Luche reduction in 21 was diastereoselective
(9:1), engendered by the bulky OTBS group and directed hydride
addition from the opposite b-face, to furnish 22. The resultant b-
hydroxy group in 22 was differentially protected as PMB derivative
23 and the TBS protection was disengaged to furnish 24, Scheme 4.
Propargylation on 24 proceeded smoothly to deliver 25 and set-up
16
18
Scheme 2. Reagents and conditions: (a) allyl bromide, tBuOK, THF, À10 °C to rt, 4 h,
quantit.; (b) amberlyst-15 resin, EtOH, reflux, 4 h, 75%; (c) NaIO4, satd aq NaHCO3,
DCM, 0 °C to rt, 2 h, 85%; (d) ethynyl magnesium bromide 0.5 M in THF, THF, À60 °C
to rt, 2 h, 65%; (e) Ohira–Bestmann reagent, K2CO3, MeOH, rt, 12 h; (f) PTSA, MeOH,
rt, 12 h, 48% (over two steps); (g) (i) TBSCl, imidazole, DMF, À20 °C, 12 h, 56%; (ii)
allyl bromide, tBuOK, DMF, 60%; (h) TBAF, THF, 0 °C to rt, 1 h, 68%.

4560
G. Mehta, T. B. Khan / Tetrahedron Letters 53 (2012) 4558–4561
OTBS
H
OTBS
H
OH
H
OTBS
O
H
O
H
O
H
O
H
H
b
d
c
a
19
O
OH
OPMB
OPMB
21
22
23
24
e
H
H
O
H
O
O
O
O
O
f
g
H
H
H
H
O
PMBO
OPMB
H
O
O
Figure: ORTEP of 9 with 30%
9
26
25
probability
Scheme 4. Reagents and conditions: (a) TBSCl, imidazole, DMAP, DMF, 80 °C, 1 h, 90%; (b) NaBH4, CeCl3.7H2O, MeOH, À20 °C, 1 h, 80% (9:1); (c) PMBCl, TBAI, NaH, THF, reflux,
12 h, 75%; (d) TBAF, THF, 0 °C to rt, 1 h, 75%; (e) propargyl bromide, TBAI, NaH, THF, À10 °C to rt, 92%; (f) Co2(CO)8, TMNO, À15 °C to rt, 5 h, 55%; (g) (i) DDQ, DCM, H2O, 0 °C to
rt, 2–3 h, (ii) DMP, DCM, 0 °C to rt, 60% (over two steps).
the stage for IPKR. Pleasingly, exposure of 25 to Co2(CO)8–TMNO
under carefully crafted conditions furnished the tetracyclic dioxa-
fenestrane 26 in fair yield, Scheme 4. DDQ mediated deprotection
of the PMB protecting group in 26 and Dess–Martin oxidation fur-
nished a crystalline ene-dione 910 bearing the dioxa[5.5.5.6]fenes-
trane framework corresponding to 8, Scheme 4. Stereostructure of
9 was secured through a single crystal X-ray structure determina-
tion and an ORTP diagram is displayed in (Scheme 4).11
H
H
O
O
HO
O
R
R
a
O
O
R = αH 27a
R = βH 27b
R = αH 28a
R = βH 28b
Encouraged by the successful construction of the desired tetra-
cyclic framework 9, we were tempted to construct it through a tan-
dem IPKR in a single pot operation. For this purpose, 15 was
propargylated to ene-diyne 1210 and subjecting it further to
Co2(CO)8–TMNO milieu led directly to the dioxa[5.5.5.6]fenestrane
9 in 28% yield, Scheme 5. Formation of 9 was a delightful outcome
in which four rings and six C–C bonds were formed in a single pot
operation and three stereogenic centers were set as required. It
may be mentioned that a small amount (10%) of the bicyclic prod-
uct 19 was also formed alongside 9 during this process indicating
that de-propargylation is a debilitating side reaction under the
PKR conditions deployed.
Attention was now turned to enyne 16 for further elaboration to
the dioxafenestrane system. IPKR reaction on 16 was uneventful
and led to a diastereomeric mixture (1:1) of 28a,b which defied
separation, Scheme 6. Nonetheless, we decided to proceed further
toward 10 (Scheme 1) through propargylation of 28a,b to deliver
29a,b. However, we were surprised to observe that the seemingly
straightforward propargylation of 28a,b was repeatedly unsuccess-
ful. Disappointed, we turned to 1410 which could be obtained from
16
c
b
H
O
O
O
O
c
14
H
O
O
10
Scheme 6. Reagents and conditions: (a) Co2(CO)8, TMNO, À15 °C to rt, 6 h 28%
(27a:27b = ꢀ1:1); (b) propargyl bromide, TBAI, NaH, THF, À10 °C to rt 2 h, 62%; (c)
Co2(CO)8 (2.2 equiv), TMNO/NMMO (25 equiv), À15 °C to rt, 12 h, 8%
(27a:27b = 1:1).
16 via propargylation to attempt a single pot tandem IPKR. How-
ever, several attempts at implementing tandem IPKR on 14 to ob-
tain dioxa-fenestrane 10 proved unsuccessful despite many trials
under different reaction regimes. During these efforts, only bicyclic
enones 28a,b could be obtained through initial mono-IPKR reac-
tion and concurrent depropargylation under the reaction condi-
tions (see, vide supra). These observations are in alignment with
the earlier findings that point to the marked sensitivity of IPKR
reaction to substitution pattern, reaction conditions and in partic-
ular to the ability of the propargyl arm to acquire suitable ‘exo’
conformation.9
H
O
O
O
O
b
a
H
15
+
19
In summary, we have successfully and stereoselectively con-
structed the dioxa-[5.5.5.6]fenestrane core present in the marine
natural product asperculin A employing tandem IPKR strategy
either in a stepwise manner or in a single pot reaction. The stage
is now set for adaptation of this approach toward asperculin A as
well as penifulvin A.
12
H
O
O
9
Scheme 5. Reagents and conditions: (a) propargyl bromide, TBAI, NaH, THF, À10 °C
to rt 2 h, 82%; (b) Co2(CO)8 (2.2 equiv), TMNO(25 equiv), À15 °C to rt, 12 h, 9 (28%),
19 (10%).

G. Mehta, T. B. Khan / Tetrahedron Letters 53 (2012) 4558–4561
4561
134.27, 117.45, 79.20, 78.86, 75.34, 74.94, 72.43, 71.86, 67.45, 56.03; HRMS
Acknowledgments
(ES) m/z calcd for
C
10H12O2Na (M+Na)+: 187.0735; found: 187.0735;
Compound 14 IR (neat) mmax 3924, 2918, 1358, 1097, 935 cmÀ1
;
1H NMR
ꢀ
G.M. wishes to thank the Government of India for the award of
National Research Professorship and T.B.K. thanks the University
Grants Commission, India for the award of Dr. D. S. Kothari post-
doctoral fellowship. We also thank Mr. Nagarjuna Kumar S., for
the help in determining the X-ray crystal structure. G.M. acknowl-
edges the research support from Eli Lilly and Jubilant-Bhartia
Foundations and the facilities extended by the University of
Hyderabad.
(400 MHz, CDCl3) d 5.91–5.87 (m, 1H), 5.37–5.26 (m, 1H), 5.21 (dd, J = 10, 1 Hz,
1H), 4.35–4.17 (m, 4H), 4.07–4.00 (m, 1H), 3.78–3.68 (m, 2H), 2.47 (d, J = 2 Hz,
1H), 2.45 (t, J = 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 133.84, 117.87, 79.81,
79.19, 74.84 (2C), 71.70, 69.88, 67.91, 58.65; HRMS (ES) m/z calcd for
C
m
10H12O2Na (M+Na)+: 187.0735; found: 187.0735; Compound 15 IR (neat)
max 3412, 3296, 1423, 1082, 931 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.89 (ddd,
;
ꢀ
J = 16, 11, 6 Hz, 1H), 5.28 (dd, J = 17, 1 Hz, 1H), 5.20 (dd, J = 10, 1 Hz, 1H), 4.52
(d, J = 3 Hz, 1H), 4.10–4.03 (m, 2H), 3.61 (dd, J = 10, 4 Hz, 1H), 3.53 (dd, J = 10,
7 Hz, 1H), 2.88 (br s, –OH), 2.45 (d, J = 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
134.08, 117.80, 81.73, 73.69, 73.34, 72.40, 61.40; HRMS (ES) m/z calcd for
+
ꢀ
C7H10O2Na (M+Na) : 149.0578; found: 149.0579; Compound 16 IR (neat) mmax
3418, 3287, 2932, 1643, 1404, 1188, 1091 cmÀ1
;
1H NMR (400 MHz, CDCl3) d
References and notes
6.00–5.83 (m, 1H), 5.33 (ddd, J = 17, 3, 2 Hz, 1H), 5.23 (ddd, J = 10, 3, 1 Hz, 1H),
4.37–4.26 (m, 1H), 4.21 (td, J = 6, 2 Hz, 1H), 4.05–3.97 (m, 1H), 3.78–3.72 (m,
2H), 2.48 (d, J = 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 133.89, 118.32, 79.80,
75.37, 70.19, 69.57, 65.27; HRMS (ES) m/z calcd for C7H10O2Na (M+Na)+:
1. (a) Corbett, R. E.; Lauren, D. R.; Weavers, R. T. J. Chem. Soc., Perkin Trans. 1 1979,
1774–1790; (b) Corbett, R. E.; Couldwell, C. M.; Lauren, D. R.; Weavers, R. T. J.
Chem. Soc., Perkin Trans. 1 1979, 1791–1794.
2. (a) Shim, S. H.; Swenson, D. C.; Gloer, J. B.; Dowd, P. F.; Wicklow, D. T. Org. Lett.
2006, 8, 1225–1228; (b) Shim, S. H.; Gloer, J. B.; Wicklow, D. T. J. Nat. Prod.
2006, 69, 1601–1605.
3. For a recent review on fenestranes, see: Keese, R. Chem. Rev. 2006, 106, 4787–
4808.
4. (a) Gaich, T.; Mulzer, J. J. Am. Chem. Soc. 2009, 131, 452–453; (b) Gaich, T.;
Mulzer, J. Org. Lett. 2010, 12, 272–275; For a model study towards penifulvin A,
see: (c) Chakraborty, T. K.; Chattopadhyay, A. K.; Samanta, R.; Ampapathi, R. S.
Tetrahedron Lett. 2010, 51, 4425–4428.
ꢀ
145.0578; found: 145.0579; Compound 19 IR (neat) mmax 3402, 1709, 1630,
1093, 979, 858 cmÀ1
;
1H NMR (500 MHz, CDCl3) d 6.05 (d, J = 2 Hz, 1H), 4.63 (br
s, 1H), 4.33 (dd, J = 11, 6 Hz, 1H), 4.22–4.16 (m, 1H), 3.53 (dd, J = 12, 1 Hz, 1H),
3.45–3.38 (m, 1H), 3.07 (t, J = 11 Hz, 1H), 2.72 (br s, –OH), 2.51 (dd, J = 19, 7 Hz,
1H), 1.91 (dd, J = 19, 2 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 207.47, 177.36,
127.40, 74.42, 73.77, 66.09, 37.61, 36.99; HRMS (ES) m/z calcd for C8H10O3Na
(M+Na)+: 177.0528; found:177.0528; Compound 20 mp 116–118 °C IR (neat)
ꢀ
mmax 3356, 1703, 1622, 927, 893 cmÀ1 1H NMR (500 MHz, CDCl3) d 6.18 (t,
;
J = 1 Hz, 1H), 4.61 (t, J = 8 Hz, 1H), 4.30 (dd, J = 10, 6 Hz, 1H), 4.25 (dd, J = 10,
6 Hz, 1H), 3.14 (t, J = 10 Hz, 1H), 3.10–3.03 (m, 1H), 3.03–2.97 (m, 1H), 2.63 (br
s, –OH), 2.54 (dd, J = 19, 6 Hz, 1H), 1.99 (dd, J = 19, 2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 206.51, 182.21, 124.96, 73.39, 73.01, 68.21, 40.98, 36.94;
HRMS (ES) m/z calcd for C8H10O3Na (M+Na)+: 177.0528; found: 177.0528;
ꢀ
Compound 9 mp 192–194 °C IR (thin film) mmax 2924, 1757, 1705, 1643, 1460,
5. Ingavat, N.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. J. Nat. Prod. 2011, 74,
1650–1652.
6. Mehta, G.; Rao, K. S. J. Org. Chem. 1988, 53, 425–427.
7. For pioneering effort see: (a) Wender, P. A.; Teransky, R.; deLong, M.; Singh, S.;
987 cmÀ1 1H NMR (500 MHz, CDCl3) d 6.14 (t, J = 1 Hz, 1H), 4.96 (dd, J = 16,
;
Olivero, A.; Rice, K. Pure. Appl. Chem. 1990, 62, 1597–1602; For
a recent
example, see: (b) Penkett, C. S.; Woolford, J. A.; Day, I. J.; Coles, M. P. J. Am.
Chem. Soc. 2010, 132, 4–5.
2 Hz, 1H), 4.73 (d, J = 16 Hz, 1H), 4.28 (d, J = 13 Hz, 1H), 4.03 (dd, J = 12, 5 Hz,
1H), 3.72 (br s, 1H), 3.59 (dd, J = 13, 1 Hz, 1H), 3.13 (br s, 1H), 2.93–2.84 (m,
1H), 2.62–2.51 (m, 2H), 1.92 (dd, J = 16, 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
204.25, 198.42, 185.42, 124.25, 74.49, 68.87, 66.79, 64.93, 61.85, 56.61, 38.48,
32.66; HRMS (ES) m/z calcd for
243.0653.
8. Selected examples: (a) Smit, V. A.; Buhanjuk, S. M.; Simonyan, S. O.; Shashkov,
A. S.; Struchkov, Y. T.; Yanovsky, A. I.; Caple, R.; Gybin, A. S.; Andersen, L. G.;
Whiteford, A. J. Tetrahedron Lett. 1991, 32, 2105–2108; (b) Kim, D. H.; Son, S. U.;
Chung, Y. K.; Lee, S.-G. Chem. Commun. 2002, 56–57; (c) Son, S. U.; Park, K. H.;
Chung, Y. K. J. Am. Chem. Soc. 2002, 124, 6838–6839.
9. For an example of application of IPKR for fenestrane construction, see: (a)
Thommen, M.; Veretenov, A. L.; Guidetti-Grept, R.; Keese, R. Helv. Chim. Acta
1996, 79, 461–475; For recent examples of IPKR from our group, see: (b) Mehta,
G.; Samineni, R.; Srihari, P. Tetrahedron Lett. 2011, 52, 1663–1666; (c) Mehta,
G.; Samineni, R.; Srihari, P. Tetrahedron Lett. 2012, 53, 829–832.
C
12H12O4Na (M+Na)+: 243.0633; found:
11. Single crystal X-ray diffraction data were collected on a Bruker AXS SMART
APEX CCD diffractometer at 298 K using graphite monochromated MoK
a
radiation (k = 0.71073 Å). The data were reduced by SAINTPLUS; the crystal
structure was solved by direct methods using SHELXS-97 and refined by full-
matrix least-squares method using SHELXL-97. Crystal data for 9: C12H12O4,
M = 220.22, Monoclinic, P21/c, a = 13.099, b = 9.924, c = 7.861 Å, V = 1010.8 Å3,
a
= 90°, b = 98.46°,
c
= 90°, Z = 4,
q
calcd = 1.447 mg mÀ3
(I). Full-matrix last-squares
, 9201 reflections
10. All new compounds reported here are racemic and characterized on the basis
of spectroscopic data (IR, 1H, 13C NMR and mass). Spectral data for some of the
measured, 1755 unique reflections with I >2
r
ꢀ
key compounds follows: Compound 12 IR (neat) mmax 3294, 2862, 1647, 1091,
refinement led to a final R = 0.0403and wR2 = 0.1073 and GOF = 1.039. CCDC
875386 contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
927 cmÀ1
;
1H NMR (400 MHz, CDCl3) d 5.95–5.85 (m, 1H), 5.28 (ddd, J = 17, 3,
2 Hz, 1H), 5.18 (ddd, J = 10, 3, 1 Hz, 1H), 4.52 (td, J = 5, 2 Hz, 1H), 4.38 (dd,
J = 16, 2 Hz, 1H), 4.31 (dd, J = 16, 2 Hz, 1H), 4.09–4.04 (m, 2H), 3.67–3.62 (m,
2H), 2.48 (d, J = 2 Hz, 1H), 2.44 (t, J = 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d