Synthesis of the human aldose reductase inhibitor rubrolide L

Article abstract of DOI:10.1016/j.tetlet.2010.06.129

The first synthesis of rubrolide L, a marine ascidian butenolide and a potent inhibitor of human aldose reductase, has been achieved by two tactically distinct pathways in 4-5 steps and 37-42% overall yield from commercially available 3-chlorotetronic acid.

Full text of DOI:10.1016/j.tetlet.2010.06.129

Tetrahedron Letters 51 (2010) 4636–4639
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Tetrahedron Letters
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Synthesis of the human aldose reductase inhibitor rubrolide L
*
John Boukouvalas , Lucas C. McCann
Département de Chimie, Université Laval, Quebec City, Que., Canada G1V 0A6
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of rubrolide L, a marine ascidian butenolide and a potent inhibitor of human aldose
reductase, has been achieved by two tactically distinct pathways in 4–5 steps and 37–42% overall yield
from commercially available 3-chlorotetronic acid.
Received 31 May 2010
Revised 16 June 2010
Accepted 28 June 2010
Available online 3 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Diabetes
Selective bromination
Suzuki–Miyaura cross-coupling
Vinylogous aldol condensation
All forms of diabetes are characterized by high levels of blood
glucose that can be caused by defects in insulin production, insulin
action, or both. The resulting hyperglycemia overwhelms the nor-
mal glycolytic pathway and an increased flux of glucose through
the polyol pathway occurs (Scheme 1).1 Aldose reductase (ALR2),
the first and rate-determining enzyme of the polyol pathway, cat-
alyzes the reduction of glucose to sorbitol which is then converted
to fructose by sorbitol dehydrogenase (SDH).
Mounting evidence suggests that the polyol pathway plays a
pivotal role in the long-term development of diabetic complica-
tions such as neuropathy, renal failure, blindness, and cardiovascu-
lar disease.1 Thus, aldose reductase inhibitors (ARIs) offer the
possibility of preventing or arresting these complications even in
the presence of elevated blood glucose.2 Furthermore, recent
in vitro and animal studies suggest that ARIs could be clinically
beneficial for preventing inflammatory diseases including asthma,
sepsis, and colon cancer.3
fidarestat, and epalrestat (Fig. 1).4 Although epalrestat was
launched in Japan in 1992, where it is still used for the treatment
of diabetic neuropathy,5 none of these ARIs were proven safe or
effective enough to meet FDA’s standards.4 The low tolerability of
some of these drugs (e.g., sorbinil)3a may arise from poor selectiv-
ity for ALR2 over aldehyde reductase (ALR1), a closely related en-
zyme that plays a role in the detoxification of aldehydes.2b,4a
Also, many spiroimides cause skin reactions or liver toxicity limit-
ing the doses usable in humans to subtherapeutic.6 On the other
hand, the low pKa values of the carboxylic acids (ca. 3–4) lead to
poor tissue penetration and pharmacokinetic profiles.3a,6 Hence,
attention is currently focused on new ARIs that are neither spiroi-
mides nor carboxylic acids.6,7
One such compound is rubrolide L (1, Fig. 1), first described by
Salvá in 2000 as an antitumor metabolite of the red tunicate Syno-
icum blochmanni, collected near the Spanish island of Tarifa.8 In
2006, it was discovered that 1 inhibits human ALR2 at the submi-
cromolar level with a 5-fold greater potency than sorbinil.9 Seven
congeners of 1, including rubrolide C and M (2–3), were also tested
So far, all ARIs taken to clinical trials on diabetic patients are
either spiroimides or carboxylic acids, as represented by sorbinil,
aldose
sorbitol
OH OH
O
OH OH
OH OH
dehydrogenase
reductase
HO
HO
HO
H
OH
OH
OH OH
glucose
OH OH
sorbitol
OH O
+
+
NAD
NADH
NADPH
NADP
fructose
Scheme 1. Polyol pathway.
* Corresponding author. Tel.: +1 418 656 5473; fax: +1 418 656 7916.
E-mail address: john.boukouvalas@chm.ulaval.ca (J. Boukouvalas).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.129

J. Boukouvalas, L. C. McCann / Tetrahedron Letters 51 (2010) 4636–4639
4637
Given the dismal prospects of arriving at 1 from 5 and 7
(Scheme 2, also vide infra), we opted for a customized strategy that
hinged upon installation of the bromo-substituents to a fully
assembled rubrolide scaffold 10 (Scheme 3). The desired regiose-
lectivity in the bromination step would arise from the more pow-
erful directing effect of the free phenol group over that of its
protected counterpart. Moreover, a bulky protecting group (PG),
such as i-propyl or t-butyl, could further improve the selectivity,
if necessary.19 Practical access to 10 was envisioned from commer-
cial 3-chlorotetronic acid (11) by the sequential attachment of the
O
NH
O
HN
COOH
F
O
N
S
O
R
S
R = H, sorbinil (Pfizer)
R = CONH , fidarestat (SKK)
2
epalrestat (Ono)
HO
HO
b- and c
-substituents.12a,20
The synthesis commenced with the conversion of 11 to triflate
12, obtained in 73% yield after purification by Kugelrohr distilla-
tion21 (Scheme 4). Since triflates can undergo hydrolysis under
harsher Suzuki conditions,22,23 we also prepared the more robust,
crystalline tosylate 13 (91%).24 Both of these reagents were sub-
jected to Suzuki–Miyaura coupling with 4-methoxyphenylboronic
acid (18) under a variety of conditions, including those shown in
Table 1. With either sulfonate, the best results were obtained using
Fu’s Pd(OAc)2/P(Cy)3 catalyst system,25 albeit under different base/
Cl
O
O
O
O
Br
X
X
X
HO
HO
X = Br, rubrolide L (1)
X = H, rubrolide M (2)
X = Br, rubrolide C (3)
X = H, rubrolide E (4)
Figure 1. Structures of some synthetic ARIs and rubrolides.
HO
PGO
but none were nearly as potent.9 These findings were recently cor-
roborated by molecular docking studies indicating that the binding
mode of 1 to hALR2 is different from that of other rubrolides.10
Besides ALR2 inhibition and tumor cell toxicity, members of the
rubrolide family have been known to possess other potentially use-
ful biological properties, including antibacterial and anti-inflam-
matory activities.11 Not surprisingly, their synthesis has captured
the attention of several groups, including our own.12–15 Three of
the sixteen known rubrolides have been synthesized (C, E, and
M)12 along with the putative structure of rubrolide N (shown to
be incorrect)13 and various analogs.14,15
Cl
Cl
O
O
O
O
10
1
Br
Br
HO
HO
HO
Cl
PG = Me, i-Pr, t-Bu
O
O
11
However, no synthesis of rubrolide L has been reported to date.
Nor is there irrefutable proof for the proposed structure 1.16,17 Previ-
ous attempts by Bellina et al. to synthesize a close relative of 1 have
been unsuccessful due to the difficulties in attaching the benzyli-
dene unit onto the butenolide nucleus through aldol reaction of 5
with 6 (Scheme 2).12b,c In sharp contrast, the aldol condensation of
Scheme 3. Retrosynthetic analysis of rubrolide L (1).
5 with butenolides lacking an a
-halo substituent works well,12a as
MeO
MeO
does the condensation of the parent 4-methoxybenzaldehyde with
a host of substituted butenolides,12a,13,18 including 6 and 7.12b,c
RO
a
Cl
Cl
Cl
d
c
O
O
O
O
O
O
MeO
11 R = H
12 R = Tf
13 R = Ts
7
14
b
CHO
OMe
X
Cl
f
HO
+
O
O
e
Br
Br
6 X = Cl
7 X = H
RO
5
CHO
Cl
various
methods
X
X
15 R = Me
1 R = H
g
O
OH
O
MeO
16 X = H
17 X = Br
Br
X
Cl
Br
HO
O
O
Scheme 4. Reagents and conditions: (a) Tf2O/Et3N (1.2 equiv each), CH2Cl2,
0 °C?rt, 2 h (73%); (b) TsCl/Et3N (1.2 equiv each), CH2Cl2, 0 °C?rt, 2 h (91%); (c)
see entries 5 and 8 in Table 1 (87% from 12, 55% from 13); (d) TBSOTf (2.2 equiv), 16
(1.2 equiv), i-Pr2NEt (3 equiv), CH2Cl2, rt, 1 h; DBU (2 equiv), rt, 3 h; aq HCl (3 N)/
THF (1:5), rt, 12 h (72%); (e) Br2 (2.1 equiv), KBr (0.2 equiv), dioxane/H2O (8:1),
5 °C?rt, 1 h (96%); (f) as in (d) but using 17 instead of 16 (61%); (g) BBr3 (3 equiv),
CH2Cl2, À78 °C to rt, 16 h, (95%).
8 X = Cl (ref. 12b,c)
9 X = H (this work)
Br
MeO
Br
Scheme 2. Attempted synthesis of butenolides 8 and 9.

4638
J. Boukouvalas, L. C. McCann / Tetrahedron Letters 51 (2010) 4636–4639
Table 1
Condition screen for the Suzuki–Miyaura coupling of boronic acid 18 with sulfonates 12 and 13a
MeO
B(OH)
2
RO
Cl
Cl
+
O
O
O
O
OMe
18
12 R = Tf
13 R = Ts
7
Entry
Sulfonate
Palladium catalyst
Ligand
Base/solvent
Reaction temp. (°C)/time (h)
Yield of 7b (%)
1
2
12
12
12
12
12
13
13
13
13
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(dppf)
—
—
—
P(Cy)3
P(Cy)3
P(Cy)3
P(Cy)3
P(Cy)3
—
Na2CO3/THF-H2O
KF/THF-H2O
60/24
60/12
80/12
24/12
24/3
60/2
60/2?24/10
60/2?24/10
60/24
18
9
3c
4c
5c
6c
7d
8d
9
Na2CO3/PhMe-H2Ob
Na2CO3/PhMe-H2Ob
Na2CO3/PhMe-H2Ob
Na2CO3/PhMe-H2Ob
Na2CO3/MeOH
54
59
87
<5
25
55
18
NaHCO3/MeOH
Cs2CO3/THF-H2O
a
b
c
Boronic acid (1.2 equiv); Pd-cat. (5 mol %); P(Cy)3 (5 mol %); base (3 equiv).
Yields are based on the sulfonate; they refer to isolated 7 after flash chromatography (except for entry 6).
BnEt3N+ClÀ (5 mol %) was used in these experiments (entries 3–6).
d
A larger amount of P(Cy)3 (10 mol %) was used (entries 7–8).
solvent/temperature combinations (entries 5 and 8). However, the
triflate proved substantially more reactive affording the highest
yield of 726 (87% vs 55%) under milder reaction conditions.
Acknowledgments
We thank NSERC of Canada and FQRNT (Québec) for the finan-
cial support.
Appendage of the benzylidene unit proceeded without incident
by application of our one-pot vinylogous aldol condensation proto-
col, originally developed during the synthesis of rubrolides C and
E.12a Thus, aldol reaction of 7 with 4-hydroxybenzaldehyde (16)
in the presence of TBSOTf and i-Pr2NEt, followed by in situ b-elim-
ination with DBU and eventual treatment of the crude product
with aq HCl provided the corresponding (Z)-benzylidenebuteno-
References and notes
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lide 1427 as a single stereoisomer in 72% yield (Scheme 4). Next,
28
bromination of 14 with KBr3
generated in situ from Br2
(2.1 equiv) and a catalytic amount of KBr delivered lactone 1529
as the only detectable product in excellent yield (96%).
In an ancillary study, a more convergent pathway to the bromi-
nated rubrolide scaffold was also explored. As we had anticipated
on the basis of Bellina’s work,12c all attempts to accomplish aldol
condensation of 7 with 3,5-dibromo-4-methoxybenzaldehyde (5)
by using several variants of our method,12a,18a,b and other proce-
dures (e.g., heating with Na2CO3 in MeOH),30 failed to give 9
(Scheme 2). We were therefore pleased to discover that by simply
replacing 5 with unprotected 3,5-dibromo-4-hydroxybenzalde-
hyde (17), from which 5 is prepared,12a the desired product 1529
was obtained in a decent yield of 61% (Scheme 4). It is worthy of
note that despite numerous applications of our method in recent
years, there have been no examples involving unprotected
hydroxybenzaldehydes.13,15b,c,18
Finally, demethylation of 15 with boron tribromide afforded
rubrolide L (1) as an amorphous yellow-orange solid (95%, Scheme
4) whose 1H and 13C NMR properties31 were in excellent agree-
ment with those reported in the literature.8
8. Ortega, M. J.; Zubía, E.; Ocaña, J. M.; Naranjo, S.; Salvá, J. Tetrahedron 2000, 56,
3963–3967.
9. Manzanaro, S.; Salvá, J.; de la Fuente, J. Á. J. Nat. Prod. 2006, 69, 1485–1487.
10. Wang, Z.; Ling, B.; Zhang, R.; Suo, Y.; Liu, Y.; Yu, Z.; Liu, C. J. Mol. Graphics Model.
2009, 28, 162–169.
To conclude, the first synthesis of rubrolide L has been achieved
from commercially available 3-chlorotetronic acid by two tacti-
cally distinct pathways in 4 or 5 steps and overall yields of 37%
and 42%, respectively. The synthesis confirms the proposed struc-
ture (1) while making the natural product accessible for further
biological studies, such as ALR2/ALR1 selectivity, and efficacy in
diabetic mice. In conjunction with the existing SAR picture on a
series of rubrolides9 and supporting computational studies,10 the
above chemistry provides the groundwork for production of new,
custom-designed analogs of improved therapeutic performance.
11. (a) Miao, S.; Andersen, R. J. J. Org. Chem. 1991, 56, 6275–6280; (b) Pearce, A. N.;
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Copp, B. R. J. Nat. Prod. 2007, 70, 111–113.
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Trudeau, M. Tetrahedron Lett. 1998, 39, 7665–7668; (b) Bellina, F.; Anselmi, C.;
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Martina, F.; Rossi, R. Eur. J. Org. Chem. 2003, 2290–2302; (d) Kar, A.; Argade, N.
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13. Bellina, F.; Anselmi, C.; Viel, S.; Mannina, L.; Rossi, R. Tetrahedron 2001, 57,
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J. Boukouvalas, L. C. McCann / Tetrahedron Letters 51 (2010) 4636–4639
4639
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21. Data for 12: colorless oil, bp (Kugelrohr internal temp) 72 °C/0.1 mmHg; 1H
NMR (400 MHz, CDCl3) d 5.05 (s, 2H); 13C NMR (100 MHz, CDCl3) d 164.6,
159.3, 118.5 (q, JCF = 321 Hz), 112.0, 67.0; 19F NMR (376 MHz, CDCl3) d À72.87;
HRMS: calcd for C5H2ClF3O5S (m/z): 265.9264, found: 265.9274.
23. For some recent examples on the Suzuki arylation of related sulfonates, see: (a)
Yoon-Miller, S. J. P.; Opalka, S. M.; Pelkey, E. T. Tetrahedron Lett. 2007, 48, 827–
830; (b) Dorward, K. M.; Guthrie, N. J.; Pelkey, E. T. Synthesis 2007, 2317–2322;
(c) Bellina, F.; Marchetti, C.; Rossi, R. Eur. J. Org. Chem. 2009, 4685–4690.
24. Data for 13: white powder (mp 88–89 °C); 1H NMR (400 MHz, CDCl3) d 7.89 (d,
J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 5.06 (s, 2H), 2.52 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 165.9, 160.7, 147.6, 131.0, 130.6, 128.4, 108.0, 67.3, 21.8; HRMS: calcd
for C11H9ClO5S (m/z): 287.9859, found: 287.9867.
25. (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020–4028; (b) Fu,
G. C. Acc. Chem. Res. 2008, 41, 1555–1564.
26. Data for 7: white powder (mp 173–175 °C, lit.12c 174–175 °C); 1H NMR
(400 MHz, CDCl3) d 7.79 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.19 (s, 2H),
3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) d 169.7, 162.5, 151.6, 129.3, 121.5,
115.0, 114.9, 70.2, 55.8; Anal. Calcd for C11H9ClO3: C, 58.81; H, 4.04. Found: C,
58.52; H, 4.24.
27. Data for 14: amorphous yellow solid (mp 225 °C, dec); 1H NMR (400 MHz,
acetone-d6) d 8.89 (br s, 1H) 7.70 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.14
(d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.23 (s, 1H), 3.89 (s, 3H); 13C NMR
(100 MHz, acetone-d6) d 164.9, 162.3, 159.8, 151.0, 145.5, 133.7, 131.8, 125.7,
121.2, 116.8, 116.7, 115.4, 115.3, 55.9; HRMS: calcd for C18H13ClO4 (m/z):
328.0502, found: 328.0507.
28. Kumar, L.; Sharma, V.; Mahajan, T.; Agarwal, D. D. Org. Process Res. Dev. 2010,
14, 174–179.
29. Data for 15: amorphous light-orange solid (mp 228 °C, dec); 1H NMR (400 MHz,
CDCl3) d 7.89 (s, 2H) 7.48 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.13 (br s,
1H), 5.97 (s, 1H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) d 164.5, 161.7, 150.4,
149.6, 146.7, 134.2, 130.9, 128.0, 120.0, 118.3, 114.8, 111.4, 110.6, 55.7; HRMS:
calcd for C18H11Br2ClO4 (m/z): 483.8713, found: 483.8702.
30. Xu, H.-W.; Wang, J.-F.; Liu, G.-Z.; Hong, G.-F.; Liu, H.-M. Org. Biomol. Chem.
2007, 5, 1247–1250.
31. Data for 1: amorphous reddish-orange solid (mp 238 °C, dec); 1H NMR
(400 MHz, acetone-d6)
d 8.05 (s, 2H) 7.52 (d, J = 8.8 Hz, 2H), 7.04 (d,
J = 8.8 Hz, 2H), 6.28 (s, 1H); 13C NMR (100 MHz, acetone-d6) d 163.9, 159.9,
151.7, 150.1, 146.7, 134.6, 131.3, 128.1, 119.0, 117.1, 116.1, 111.1 (Â2); Anal.
Calcd for C17H9Br2ClO4: C, 43.21; H, 1.92. Found: C, 43.49; H, 2.30.