Convergent synthesis of (+)-xestodecalactone A via a Pd-catalyzed α-arylation reaction

Article abstract of DOI:10.1016/j.tetlet.2013.05.068

The convergent total synthesis of (+)-xestodecalactone A (1) is reported. In addition, a formal synthesis of (+)-sporostatin has been accomplished by means of intercepting a previously reported intermediate en route to 1. The key reaction utilized was a convergent Pd-catalyzed α-arylation between a boronic acid and an α-bromoester.

Full text of DOI:10.1016/j.tetlet.2013.05.068

Tetrahedron Letters 54 (2013) 3990–3992
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convergent synthesis of (+)-xestodecalactone A via a Pd-catalyzed
a
-arylation reaction q
⇑
Dripta De Joarder, Michael P. Jennings
Department of Chemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa, AL 35487-0336, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The convergent total synthesis of (+)-xestodecalactone A (1) is reported. In addition, a formal synthesis of
Received 2 April 2013
Revised 8 May 2013
Accepted 17 May 2013
Available online 23 May 2013
(+)-sporostatin has been accomplished by means of intercepting a previously reported intermediate en
route to 1. The key reaction utilized was a convergent Pd-catalyzed
and an -bromoester.
a-arylation between a boronic acid
a
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Allylation
Reduction
Natural products
Cross-metathesis
Caylobolide
Marine sources continually provide the synthetic community a
variety of structurally intriguing natural products.2 Biologically ac-
tive natural products continue to pique the interest of both syn-
thetic as well as medicinal chemists alike.3 As disclosed by
Bingmann and co-workers in 2002, the xestodecalactones were
isolated from the fungus Penicillium cf. montanense secured from
the marine sponge Xestospongia exigua.4 As shown in Figure 1, xes-
todectalactones A (1), B, C, and sporostatin share a 10-membered
macrolactone core with a sole chiral center coupled with a fused
1,3-dihydroxybenzene ring. The xestodecalactone family (includ-
ing ent-sporostatin) has garnered significant attention from the
synthetic community.5–8
eated in Scheme 1. Thus, final macrocyclization of 2 would be car-
ried out in accord with Bringmann’s report of an intramolecular
Friedel–Crafts reaction to afford 1. Working backward, the linear
acid 2 was envisioned to arise from
3 as a carboxylic acid surrogate due to a plausible chemoselective
hydrolysis of the tert-butyl ester in the presence of the -aryl
ab-unsaturated tert-butyl ester
a
methylene ester moiety. Lastly, the strategic convergence of the
aromatic and aliphatic portion should be accomplished via a Pd-
catalyzed
bromoesters 5 and/or 6.
With the synthetic blueprint in mind, our initial attention was
focused on investigating the Pd-catalyzed -arylation reaction as
a convergent focal point as described in Scheme 2. Thus, copper
a-arylation between substituted boronic acid 4 and a-
a
To date, only two syntheses of 1 have been described,5,6
whereas numerous approaches to xestodecalactones B and C have
been reported.7,8 The first total synthesis and subsequent absolute
configuration determination of 1 were communicated by Bring-
mann and utilized a very late stage macrocyclization by means of
an intramolecular Friedel–Crafts cyclization.5 A subsequent ac-
count by Danishefsky conveyed the completion of 1 via an inter-
molecular Diels–Alder reaction between a conjugated diene and
an unsymmetrical allene followed by chelotropic extrusion of iso-
butene to furnish the aromatic segment as the key step.6
OH
O
OH
O
HO
O
HO
O
O
O
xestodecalactone A (1)
sporostatin
Our approach to 1 initially centered on an under-utilized con-
OH
O
OH
OH
O
OH
O
vergence tactic by means of a Pd-catalyzed
a-arylation reaction.
With this idea in mind, the retrosynthetic analysis of 1 is delin-
HO
O
HO
O
O
q
See Ref. 1.
xestodecalactone B
xestodecalactone C
⇑
Corresponding author. Tel.: +1 (205) 348 0351; fax: +1 (205) 348 9104.
E-mail address: jenningm@bama.ua.edu (M.P. Jennings).
Figure 1. Strucutral similarities between the xestodecalactones and sporostatin.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.068

D. De Joarder, M. P. Jennings / Tetrahedron Letters 54 (2013) 3990–3992
3991
OH
OtBu
OH
O
OMe
O
OMe O
OMe O
O
a)
OtBu
O
O
O
10
HO
O
MeO
O
MeO
O
MeO
85%
O
1
9
3
2
OMe
N
N
Cl
b) TMSOTf,
2,6-lutidine
87%
Ru
10
Ph
Cl
OtBu
MeO
O
B(OH)2
PCy3
4
OMe O
OH
OH
+
O
O
O
OMe O
OMe O
Br
c) H2, Pd/C
90%
MeO
O
O
R
3
MeO
O
MeO
O
5: R = H
6: R = COOtBu
11
2
Scheme 3. Synthesis of intermediate 4. Reagents and conditions: (a) tert-butyl
acrylate (5 equiv), 10 (7 mol %), CH2Cl2, 24 h, 85%; (b) TMSOTf (2.3 equiv), 2,6-
lutidine (2.1 equiv), CH2Cl2, 0 °C to rt, 1 h, 87%; (c) Pd/C (10 wt %), EtOAc, rt, 12 h,
90%.
Scheme 1. Retrosynthetic analysis of (+)-xestodecalactone A (1).
catalyzed (CuI, 10 mol %) ring opening of (R)-propylene oxide with
2 equiv of vinyl Grignard reagent at ꢀ20 °C provided homoallylic
alcohol 8 in 70% yield.9 Subsequent transformation of the second-
ary alcohol moiety of 8 was accomplished upon treatment with
bromoacetal bromide in the presence of pyridine to afford
et al.16 Final reduction of the olefin moiety of acid 11 by means of a
Pd-catalyzed hydrogenation (10 wt % Pd/C, 1 atm H2) in EtOAc pro-
vided the fully saturated acid 2 in 90% yield and set the stage for
macrocyclization en route to (+)-xestodecalactone A (1).
a
a
-
-
bromoester 5 in 55% yield and set the stage for the convergent
-arylation reaction. Hence, after significant experimentation, the
a
While we were pleased that the Pd-catalyzed
tween boronic acid 4 and the bromoester 5 readily provided aryl
ester 9, we decided to investigate a similar -arylation reaction be-
a-arylation be-
Pd-catalyzed [Pd(OAc)2, P(o-tolyl)3, and K3PO4] a-arylation of bro-
mo ester 5 with boronic ester 4 provided 910 in a modest 60% yield
following the previous report of Gooßen.11 During reaction optimi-
zation, we established that the coupling reaction must be per-
formed under a strict O2 free environment to minimize the biaryl
coupling of 4.
a
tween 4 and a more elaborated ester coupling partner. With this in
mind, a diastereoselective cross metathesis between bromoester 5
with tert-butyl acrylate (13 equiv) in the presence of catalyst 10
(7 mol %) provided the
favoring the E olefin (>20:1) as described in Scheme 4. Based on the
previous Pd-catalyzed -arylation of 4 and 5, we investigated the
ab-unsaturated ester 6 in 70% yield strongly
With a-aryl ester 9 in hand, our focus was turned to completing
the aliphatic portion of the linear carboxylic acid 2. As shown in
Scheme 3, treatment of ester 9 with 7 mol % of Grubbs’ second gen-
eration catalyst (10) and tert-butyl acrylate (5 equiv) under the
a
coupling of 4 and 6 under identical reaction conditions. Much to
our delight, Pd-catalyzed coupling of boronic acid 4 with the more
elaborated bromo ester 6 as reported in Scheme 2 afforded a-aryl
ester 3 in 78% yield. It is worth noting that the coupling of 4 and
the more elaborate compound 6 provided the aryl ester product
3 in greater yield than that of 4 and 5 to furnish 9 (78% vs 60%).
With 3 in hand by means of the more convergent approach, the
standard cross-metathesis reaction conditions furnished the
ab-
unsaturated ester 312 in 85% yield with an E/Z ratio of P20/1 as de-
duced by 1H NMR.13 Much to our delight, an ensuing chemoselec-
tive hydrolysis of the tert-butyl ester moiety resident in 3 was
accomplished by utilizing TMSOTf (2.1 equiv) and 2,6-lutidine
(2.6 equiv) and furnished the a
b-unsaturated carboxylic acid 1114
in 87% yield while maintaining the olefin stereochemistry.15
At this point, the completion of acid 11 constituted a formal
synthesis of (+)-sporostatin based on the previous report of Yadav
O
O
O
Br
Br
O
a)
OtBu
O
O
OH
H
O
10
70%
a)
OtBu
MgBr
CuI
70%
5
6
7
8
b) 4, Pd(OAc)2
P(o-tolyl)3,
O
Br
K3PO4
78%
b)
Br
pyridine
55%
OH
O
OtBu
O
OMe
OMe O
OMe O
Br
4
c) , Pd(OAc)2
See Scheme 3
O
O
O
O
P(o-tolyl)3, K3PO4
MeO
O
60%
MeO
O
5
9
MeO
2
3
Scheme 2. Synthesis of intermediate 9. Reagents and conditions: (a) Vinylmagne-
sium bromide (2.0 equiv), Cul (0.1 equiv), THF, ꢀ20 °C, 12 h, 70%; (b) bromoacetyl
bromide (2.0 equiv), pyridine (2.0 equiv), CH2Cl2, rt, 6 h, 55%; (c) compound 4
(1.2 equiv), Pd(OAc)2 (3 mol %), P(o-Tol)3 (9 mol %), K3PO4 (5 equiv), H2O (2 equiv),
THF, rt, 24 h, 60%.
Scheme 4. Synthesis of intermediate 4. Reagents and conditions: (a) tert-butyl
acrylate (13 equiv), 10 (7 mol %), CH2Cl2, reflux, 12 h, 70%; (b) compound
(1.2 equiv), Pd(OAc)2 (3 mol %), P(o-Tol)3 (9 mol %), K3PO4 (5 equiv), H2O (2 equiv),
4
THF, rt, 24 h, 78%.

3992
D. De Joarder, M. P. Jennings / Tetrahedron Letters 54 (2013) 3990–3992
2. Bugni, T. S.; Ireland, C. M. Nat. Prod. Rep. 2004, 21, 143.
OH
O
3. Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311.
OR
O
4. Edrada, R.-A.; Heubes, M.; Brauers, G.; Wray, V.; Berg, A.; Graefe, U.; Wohlfarth,
M.; Muehlbacher, J.; Schaumann, K.; Sudarsono; Bringmann, G.; Proksch, P. J.
Nat. Prod. 2002, 65, 1598.
OMe O
a) TFA, TFAA
11%
5. Bringmann, G.; Lang, G.; Michel, M.; Heubes, M. Tetrahedron Lett. 2004, 45,
2829.
6. Yoshino, T.; Ng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 14185.
7. For syntheses of both xestodecalactones B and C, see: (a) Liang, Q.; Zhang, J.;
Quan, W.; Sun, Y.; She, X.; Pan, X. J. Org. Chem. 2007, 72, 2694; (b) Pal, R.;
Rahaman, H.; Gurjar, M. K. Curr. Org. Chem. 2012, 16, 1159.
RO
O
MeO
O
O
2
12
: R = Me
b) AlI3
10%
1
: R = H
8. For syntheses of xestodeaclactone C, see: (a) Yadav, J. S.; Thrimurtulu, N.;
Gayathri, K.; Uma Reddy, B. V. S.; Prasad, A. R. Tetrahedron Lett. 2008, 49, 6617;
(b) Rajesh, K.; Suresh, V.; Selvam, J. J. P.; Bhujanga Rao, C.; Venkateswarlu, Y.
Helv. Chim. Acta 2009, 92, 1866; (c) Yadav, J. S.; Rao, Y. G.; Ravindar, K.; Reddy,
B. V. S.; Narsaiah, A. V. Synthesis 2009, 3157.
Scheme 5. Synthesis of (+)-xestodecalactone 1. Reagents and conditions: (a) TFA
(0.05 M), TFAA (0.25 M), reflux, 0.5 h, 11%; (b) Al (41 equiv), I2 (30 equiv), nBu4N+Iꢀ
(0.13 equiv), benzene, rt, 1 h, 10%.
9. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
10. Data for 9: 1H NMR (360 MHz, CDCl3)
d 6.43 (d, J = 2.2 Hz, 2H), 6.36 (t,
stage was once again set to complete (+)-xestodecalactone A based
on a late-stage via acid 2.
J = 2.2 Hz, 1H), 5.71 (m, 1H), 5.02 (m, 3H), 3.77 (s, 6H), 3.51 (s, 2H), 2.30 (m,
2H), 1.21 (d, J = 6.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 170.7, 160.7, 136.2,
133.4, 117.6, 107.2, 99.1, 70.5, 55.2, 41.8, 40.1, 19.3. IR (CH2Cl2): 3425, 2947,
1729, 1598, 1463, 1205, 1159, 1066 cmꢀ1 Rf = 0.33 in 10% EtOAc in hexane.
Based on the macrocyclization as described by Bringmann, we
chose to replicate the intramolecular Friedel–Crafts conditions
with the anticipation of completing 1.5 Thus, a refluxing solution
of TFA, TFAA, and acid 2 provided macrocycle 12 with a disappoint-
ingly low, but reproducible, yield of 11% as highlighted in Scheme
5. It is worth noting that Bringmann observed a 42% yield for mac-
rocyclization on a similar, but not identical, substrate to that of 2.5
Final deprotection of 12 with a freshly prepared solution of AlI3 in
benzene based on previous reports for xestodecalactones B and C
afforded (+)-xestodecalactone A (1) in 10% yield.7,8 The spectral
data (1H NMR, 500 MHz; 13C NMR, 125 MHz) and HRMS data of
synthetic 1 were in agreement with the natural sample.4,5,17
In conclusion, we have completed a convergent total synthesis
of (+)-xestodecalactone A (1). In addition, a formal synthesis of
(+)-sporostatin has been accomplished by means of intercepting
an intermediate as reported by Yadav et al. en route to 1. The
½
a 2D4
ꢁ
þ 6:10 (c 0.00525 g/mL, CH2Cl2). HRMS (EI) calcd for C15H20O4 (M+):
264.1362, found 264.1359.
11. Gooßen, L. J. Chem. Commun. 2001, 669.
12. Data for 3: 1H NMR (360 MHz, CDCl3) d 6.72 (m, 1H), 6.37 (d, J = 2.2 Hz, 2H),
6.30 (t, J = 2.2 Hz, 1H), 5.72 (td, J = 15.6, 1.4 Hz, 1H), 4.96 (m, 1H), 3.71 (s, 6H),
3.47 (s, 2H), 2.36 (m, 2H), 1.42 (s, 9H), 1.18 (d, J = 6.3 Hz, 3H). 13C NMR
(125 MHz, CDCl3) d 170.6, 160.8, 141.1, 136.0, 125.9, 123.4, 107.2, 99.2, 80.2,
69.7, 55.2, 41.7, 38.1, 34.2, 27.8, 19.4. IR (CH2Cl2): 2975, 2937, 2839, 1733,
1712, 1597, 1464, 1428, 1363, 1325, 1293, 1248, 1207, 1062, 979,846 cmꢀ1
Rf = 0.20 in 10% EtOAc in hexane. ½a D24
þ 2:95 (c 0.0135 g/mL, CH2Cl2). HRMS
ꢁ
(EI) calcd for C20H28O6 (M+): 364.1886, found 364.1884.
13. For a very recent review, see: (a) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev.
2010, 110, 1746; (b) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
14. Data for 11: 1H NMR (360 MHz, CDCl3) d 6.93 (m, 1H), 6.41 (d, J = 2.2 Hz, 2H),
6.35 (t, J = 2.2 Hz, 1H), 5.81 (m, 1H), 5.04 (m, 1H), 3.76 (s, 6H), 3.51 (s, 2H), 2.47
(m.2H), 1.25 (d, J = 6.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 171.0, 170.7,
160.8, 146.1, 135.9, 123.4, 107.2, 99.2, 69.4, 55.2, 41.8, 38.3, 19.5. IR (CH2Cl2):
2969, 2839, 2670, 1718, 1653, 1461, 1428, 1407, 1293, 1062, 985, 837, 813,
736 cmꢀ1 Rf = 0.27 in 35% EtOAc in hexane. a 2D4
½ ꢁ þ 11:08 (c 0.003 g/mL,
key reaction utilized was a convergent Pd-catalyzed
a-arylation
CH2Cl2). HRMS (EI) calcd for C16H20O6 (M+): 308.1260, found 308.1269.
15. (a) Oikawa, M.; Ueno, T.; Oikawa, H.; Ichihara, A. J. Org. Chem. 1996, 60, 5048;
(b) Chou, T.-C.; Dong, H.; Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.;
Tong, W. P.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 4762.
16. Yadav, J. S.; Thrimurtulu, N.; Gayathri, K. U.; Reddy, B. V. S.; Prasad, A. R. Synlett
2009, 790.
between a boronic acid and an -bromoester. Studies toward the
a
total syntheses of other structurally related natural products (i.e.,
curvularin18 and curvulones A and B19) are ongoing and will be re-
ported in due course.
17. Data for 1: 1H NMR (360 MHz, CD3OD) d 6.27 (d, J = 2.2 Hz, 1H), 6.15 (d,
J = 2.2 Hz, 1H), 4.77 (m, 1H), 4.01 (d, J = 18.2 Hz, 1H), 3.47 (d, J = 18.2 Hz, 1H),
3.06 (m, 1H), 2.76 (m, 1H), 1.86 (m, 3H), 1.53 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H).
13C NMR (125 MHz, CD3OD) d 207.8, 171.1, 161.2, 158.0, 135.2, 122, 107.8,
101.1, 74.0, 46.1, 40.4, 36.8, 23.1, 20.7. IR (CH2Cl2): 2928, 2843, 1725, 1679,
1602, 1583, 1455, 1332, 1240, 1128, 1078, 1051 cmꢀ1 Rf = 0.20 in 60% EtOAc in
Acknowledgments
Support for this project was provided by the University of Ala-
bama and the National Science Foundation CAREER program under
CHE-0845011.
hexane. ½a 2D4
ꢁ
þ 27:1 (c 0.005 g/mL, MeOH); HRMS (EI) calcd for C14H16O5 (M+):
264.0998, found 264.0997.
18. (a) Musgrave, O. C. J. Chem. Soc. 1956, 4301; (b) Musgrave, O. C. J. Chem. Soc.
1957, 1104; (c) Birch, A. J.; Musgrave, O. C.; Richards, R. W.; Smith, H. J. Chem.
Soc. 1959, 3146.
References and notes
19. Dai, J.; Krohn, K.; Flörke, U.; Pescitelli, G.; Kerti, G.; Papp, T.; Kövér, K. E.; Bényei,
A. C.; Draeger, S.; Schulz, B.; Kurtán, T. Eur. J. Org. Chem. 2010, 6928.
1. This paper is dedicated to Mr. Robert Atkins (MPJ’s ERHS chemistry teacher) on
the occasion of his 70th birthday.