A novel approach to monobenzannulated spiroketals using styrenes in the Kulinkovich reaction

Article abstract of DOI:10.1055/s-0029-1217708

The synthesis of a series of 5,6-monobenzannulated spiroketals is reported. The use of various styrenes in a Kulinkovich reaction with an appropriately functionalized aliphatic ester affords cyclopropanol products which under basic conditions underwent ri

Full text of DOI:10.1055/s-0029-1217708

LETTER
2315
A Novel Approach to Monobenzannulated Spiroketals Using Styrenes in the
Kulinkovich Reaction
Novel
A
s
pproach to
a
M
onobenz
b
a
nnulated Sp
e
iroketals ll Haym, Margaret A. Brimble*
Department of Chemistry, The University of Auckland, 23 Symonds St., Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 26 May 2009
tive activity towards OVCAR-3, an ovarian cancer cell
Abstract: The synthesis of a series of 5,6-monobenzannulated
spiroketals is reported. The use of various styrenes in a Kulinkovich
reaction with an appropriately functionalized aliphatic ester affords
cyclopropanol products which under basic conditions underwent
line. It is also an inhibitor of MMP-3 and caspase-1, pro-
viding an attractive target for the development of antican-
cer agents. Recently, Fürstner et al.5 reported a synthesis-
ring opening to form ketone precursors to the spiroketals. Deprotec- driven structure revision of berkelic acid reassigning the
tion of the hydroxyl groups and subsequent cyclization afforded
stereochemistry at C18 and C19. Shortly after, Snider et
al.6 completed the first total synthesis of berkelic acid fur-
monobenzannulated spiroketals related to the core structure of ber-
kelic acid.
ther confirming the reassignment of stereochemistry at
C18 and C19, as well as assigning the stereochemistry at
C22. Chaetoquadrin A (2), containing an aryl 6,6-
Key words: Kulinkovich reaction, ring opening, cyclopropanol,
spiroketal, berkelic acid
spiroketal, was recently isolated from an ascomycete,
Chaetomium quadrangulatum, and possesses monoamine
oxidase inhibitory activity.4
Spiroketals are found in a wide range of natural products
that exhibit a variety of biological activities thus rendering
them privileged structures.1,2 An interesting subgroup of
aromatic spiroketals include the monobenzannulated
spiroketals such as berkelic acid (1)3 and chaetoquadrin A
(2,4 Figure 1).
Methods for the construction of monobenzannulated
spiroketals include use of a hetero-Diels–Alder reaction
between an o-quinone methide and an exo-enol ether,7
palladium-catalyzed synthesis via a one-pot, multicompo-
nent cascade reaction,8 and a cross-metathesis–radical
cyclization approach, developed in our laboratory.9
O
CO2H
O
Recently, our attention has focused on the formation of
the tricyclic spiroketal core 3 of berkelic acid. It was en-
visaged that monobenzannulated 5,6-spiroketals of type 3
could be synthesized via Kulinkovich coupling10–14 of a
substituted styrene 6 and g-butyrolactone (7) followed by
selective ring opening of the resulting cyclopropanol 5
and subsequent cyclization (Scheme 1).
22
MeO2C
19
O
O
OH
18
Me Et
Me
C5H11
berkelic acid (1)
Me
O
Me
spiroketalization
O
O
O
OR2
O
O
HO
O
OH
Me
R1
R1
OMe
chaetoquadrin A (2)
3
4
R1 = H, OMe; R2 = EM, TBS
Figure 1 Monobenzannulated spiroketal-containing natural pro-
ducts
OR2
R1
OR2
Berkelic acid (1) consists of a novel aromatic 5,6-
spiroketal embedded in a highly substituted tetracyclic
framework. Berkelic acid (1) was recently isolated from a
fungal extremophile, a Penicillium species, found in a
highly acidic and metal-contaminated abandoned copper
mine in Montana, USA.3 Berkelic acid (1) exhibits selec-
6
OH
R1
OH
O
+
ring opening
O
5
7
SYNLETT 2009, No. 14, pp 2315–2319
x
x
.x
x
.2
0
0
9
Scheme 1 Retrosynthesis of monobenzannulated spiroketals 3
Advanced online publication: 31.07.2009
DOI: 10.1055/s-0029-1217708; Art ID: D13009ST
© Georg Thieme Verlag Stuttgart · New York

2316
I. Haym, M. A. Brimble
LETTER
To the best of our knowledge, the use of styrenes in the vich reaction was first performed on readily available sty-
Kulinkovich reaction is limited to just one example,14 and rene 11. Kulinkovich studied the nature of the Grignard
the reaction itself has found limited use in natural product reagent in the reaction of styrene with ethyl acetate,14 es-
synthesis.15–17 We were therefore attracted to the possible tablishing that butylmagnesium bromide was the best
application of the Kulinkovich reaction to the synthesis of Grignard reagent for reactions using styrene. Adding bu-
monobenzannulated spiroketals related to berkelic acid tylmagnesium bromide dropwise to a solution of 11, 12,
(1).
and Ti(Oi-Pr)4 in ethyl acetate afforded cyclopropanol 13
in 26% yield after reflux for 2 hours (Table 1, entry 1).
Disappointingly, the reaction mixture also contained a
significant amount of isopropyl ester of 12 (36%).
Initially, the intent was to couple TBS-protected hydroxy-
styrene 8 with readily available g-butyrolactone (7)15,18 to
afford the diol 9.
Increasing the amount of Ti(Oi-Pr)4 and 12 did not afford
a better yield (entry 2). The last step in the reaction mech-
anism is the oxidative addition of the ester to the titana-
cyclopentane intermediate. Hence, the order of addition of
the reagents was changed and 12 was added last to the re-
action mixture (entries 3–7). The Grignard reagent was
also changed to cyclohexylmagnesium chloride, which
has been reported to shift the equilibrium of the ligand ex-
change to the desired titanacyclopropane.12b Thus, cyclo-
hexylmagnesium chloride was added to a solution of
Ti(Oi-Pr)4 in THF at –78 °C over 20 minutes in order to
form the titanacyclopropane complex.19 After addition of
11, the suspension was stirred for 1 hour, followed by the
addition of 12 with subsequent warming to room temper-
ature. Cyclopropanol 13 was only obtained in 16% yield
in this case (entry 3). On the other hand, raising the tem-
perature to –50 °C increased the yield to 50% (entry 4).
Increasing the amount of Ti(Oi-Pr)4 and Grignard reagent
gave a slightly improved 52% yield (entry 5). Raising the
temperature to –35 °C improved the yield further to 59%
(entry 6) but warming further to –20 °C decreased the
yield of cyclopropanol 13 (entry 7).
O
OTBS
OTBS
OH
+
O
OH
9
(a)
8
7
O
Me
HO
O
Me
10
Scheme 2 Reaction of 8 with g-butyrolactone. Reagents and condi-
tions: Ti(Oi-Pr)4 (3 equiv), c-C6H11MgCl (6 equiv), toluene, r.t., 19 h.
Coupling of 8 and 7 in the presence of cyclohexylmagne-
sium bromide and Ti(Oi-Pr)4 in toluene at room tempera-
ture failed to give 9, with isopropopyl ester 10 being the
only product formed (Scheme 2). Numerous variations in
the solvent, the quantity of Grignard reagent and Ti(Oi-
Pr)4 failed to provide cyclopropanol 9. This outcome
might be attributed to the steric hindrance of the TBS pro-
tecting group. Hence, the protecting group was changed to
an ethoxymethyl (EM) group. In addition, lactone 7 was
substituted by the linear butanoate 12, and the Kulinko-
Table 1 Optimization for Kulinkovich Coupling of 11 with 12
O
OBn
OBn
+
MeO
OH
12
13
11
Entry
Ti(Oi-Pr)4
11 (equiv)12 (equiv)Grignard (equiv)
Solvent
Temp
Time (h)
Yield of 13 (%)c
(equiv)
1a
2a
3b
4b
5b
6b
7b
0.1
0.5
1
2
1
1
1
1
1
1
1
2
1
1
1
1
1
n-BuMgBr (2.5)
n-BuMgBr (2.5)
c-C6H11MgCl (3)
c-C6H11MgCl (3)
c-C6H11MgCl (9)
c-C6H11MgCl (9)
c-C6H11MgCl (9)
Et2O
Et2O
THF
THF
THF
THF
THF
reflux
0.75
2
26
21
16
50
52
59
18
reflux
–78 °C then r.t.
–50 °C then r.t.
–50 °C then r.t.
–35 °C then r.t.
–20 °C then r.t.
18
3
1
3
3
3
1
3
2
a Addition sequence: Ti(Oi-Pr)4, 11, 12, then n-BuMgBr.
b Addition sequence: Ti(Oi-Pr)4, c-C6H11MgBr, 11, then 12.
c Yield of isopropyl ester of 12: entry 1: 36%; entries 2–7: trace.
Synlett 2009, No. 14, 2315–2319 © Thieme Stuttgart · New York

LETTER
Novel Approach to Monobenzannulated Spiroketals
2317
ketone 24, prompting investigation of alternative re-
agents.23 Use of NaOH in dioxane proceeded with 100%
selectivity for C1–C2 cleavage. The optimum conditions
involved using 0.2 N NaOH–dioxane (2:1) at reflux for
three days. Attempts to improve the reaction using micro-
wave irradiation afforded the desired ketone 24 in the
same yield after 15 minutes at 80 °C. Thus, these latter
conditions were used to effect the formation of ketones
25–28 from cyclopropanols 20–23 (Table 3).
Table 2 Kulinkovich Reaction of Olefins 14–18 with 12
OEM
R
OEM
Ti(Oi-Pr)4
c-C6H11MgCl
R = H, OMe
THF
OBn
14–18
R
OH
–40 to –35 °C, 2 h
then r.t., 1 h
+
O
19–23
OBn
MeO
Table 3 Ring-Opening Reactions of Cyclopropanols 19–23
12
OEM
OEM
O
Olefin
Product
Yield (%)
OBn
OBn
OEM
OEM
R
R
OH
OBn
OBn
42
30
R = H, OMe
OH
19–23
24–28
19
20
14
Cyclopropanol Product
Yield (%)
OEM
OEM
OEM
O
MeO
OBn
OH
19
48a
50a
15
24
OEM
OEM
OEM
OEM
O
O
OBn
33
30
MeO
OBn
OBn
20
OH
MeO
16
MeO
21
25
OEM
OEM
OBn
2121
50b
52a
42b
OH
MeO
26
OMe
OEM
OMe
17
22
23
OEM
O
OEM
OBn
OBn
22
25
OH
OMe
OMe
OMe
27
18
OEM
O
OBn
Having optimized the reaction conditions using styrene,
attention next turned to the use of olefins 14–18. Olefins
14 and 15 were synthesized from salicylaldehyde and o-
vanillin, respectively, in two steps by Wittig olefination20
followed by protection as an ethoxymethyl ether.21 Ole-
23
OMe
28
a Reaction conditions: 0.2 N NaOH–dioxane (2:1), reflux, 3 d.
fins 16–18 were obtained from their corresponding b Reaction conditions: 0.2 N NaOH–dioxane (2:1), MW, 200 W,
80 °C, 15 min.
dimethoxybenzaldehydes by monodeprotection using
BCl3,22 Wittig olefination and protection as an ethoxyme-
With ketones 24–28 in hand, deprotection and subsequent
cyclization to the desired spiroketals was finally exam-
ined.25
Hydrogenolysis of ketones 24 and 2626 over Pd/C in ethyl
acetate containing 10% HCl24 afforded spiroketals 29 and
31 in 66% and 38% yield, respectively. Pearlman’s cata-
lyst was used to form spiroketals 30, 32, and 33 from their
corresponding ketones in 35%, 37%, and 58% yield, re-
spectively (Table 4).
thyl ether. With the appropriate olefins in hand, the
Kulinkovich reaction was carried out using the conditions
optimized for styrene. All of the Kulinkovich reactions af-
forded complex mixtures from which the desired cyclo-
propanols 19–23 were isolated in low to moderate yields
(Table 2).
Having synthesized the required cyclopropanols 19–23,
attention next turned to their ring opening to the corre-
sponding ketones 24–28. Use of Fe(NO3)3 and Bu3SnH
in DMF15 did not effect cleavage of cyclopropanol 19 to
Synlett 2009, No. 14, 2315–2319 © Thieme Stuttgart · New York

2318
I. Haym, M. A. Brimble
LETTER
(5) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.;
Table 4 Acid-Catalyzed Spirocyclization of Ketones 24–28
Goddard, R.; Fürstner, A. Angew. Chem. Int. Ed. 2008, 47,
8450.
(6) Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem. Int. Ed. 2009,
48, 1283.
(7) Bray, C. D. Org. Biomol. Chem. 2008, 6, 2815.
(8) Barluenga, J.; Mendoza, A.; Rodríguez, F.; Fañanás, F. J.
Angew. Chem. Int. Ed. 2009, 48, 1644.
OEM
O
Pd/C (10 mol%)
HCl (1 drop)
O
OBn
O
H
2 (1 atm)
R
R
EtOAc
r.t., 18 h
R = H, OMe
24–28
29–33
(9) Liu, Y.-C.; Sperry, J.; Rathwell, D. C.; Brimble, M. A.
Ketone
Product
Catalyst
Yield (%)
66
Synlett 2009, 793.
O
O
(10) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;
Pritytskaya, T. S. J. Org. Chem. USSR (Engl. Transl.) 1989,
25, 2027; Zh. Org. Khim. 1989, 25, 2244.
(11) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;
Savchenko, A. I.; Pritytskaya, T. S. J. Org. Chem. USSR
(Engl. Transl.) 1991, 27, 250; Zh. Org. Khim. 1991, 27, 294.
(12) (a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem.
Soc. 1996, 118, 291. (b) Lee, J.; Kim, H.; Cha, J. J. Am.
Chem. Soc. 1996, 118, 4198.
O
24
Pd/C
29
OMe
O
25
Pd(OH)2
35
(13) Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 6079.
(14) Kulinkovich, O. G.; Epstein, O. L.; Savchenko, A. I.
Tetrahedron Lett. 1999, 40, 5935.
(15) Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 9, 2717.
(16) Keaton, K. A.; Phillips, A. J. Org. Lett. 2008, 10, 1083.
(17) Gollner, A.; Mulzer, J. Org. Lett. 2008, 10, 4701.
(18) Esposito, A.; Taddei, M. J. Org. Chem. 2000, 65, 9245.
(19) Eisch, J. J.; Adeosun, A. A.; Gitua, J. N. Eur. J. Org. Chem.
2003, 4721.
30
O
O
MeO
O
O
26
27
Pd/C
38
37
31
Pd(OH)2
(20) Marsault, E.; Hoveyda, H. R.; Peterson, M. L.; Saint-Louis,
C.; Landry, A.; Vézina, M.; Oullet, L.; Wang, Z.;
Ramaseshan, M.; Beaubien, S.; Benakli, K.; Beauchemin,
S.; Déziel, R.; Peeters, T.; Fraser, G. L. J. Med. Chem. 2006,
49, 7190.
(21) Bruijnincx, P. C. A.; Lutz, M.; Spek, A. L.; Hagen, W. R.;
van Koten, G.; Klein Gebinnk, R. J. M. Inorg. Chem. 2007,
46, 8391.
MeO
32
O
O
28
Pd(OH)2
58
OMe
33
(22) Cordoba, R.; Tormo, N. S.; Medarde, A. F.; Plumet, J.
Bioorg. Med. Chem. 2007, 15, 5300.
In conclusion, the synthesis of a series of monobenzannu-
lated 5,6-spiroketals, analogous to the spiroketal unit of
berkelic acid (1), has been achieved using a novel Kulin-
kovich cyclopropanol–ring opening strategy involving
union of a styrene with an aliphatic ester.
(23) (a) DePuy, C. H.; Van Lanen, R. J. J. Org. Chem. 1974, 29,
3360. (b) DePuy, C. H.; Breitbeil, F. W.; DeBruin, K. R.
J. Am. Chem. Soc. 1966, 88, 3347.
(24) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Tetrahedron
Lett. 2006, 47, 5409.
(25) General Procedure – Kulinkovich Reaction
A solution of Ti(Oi-Pr)4 (2.16 mmol) in THF (5 mL) was
cooled to an internal temperature of –40 °C. c-C6H11MgCl
(6.49 mmol) was added at such a rate that the internal
temperature did not exceed –35 °C. Styrene (0.72 mmol)
was added and the orange-brown suspension stirred for 2 h
at –35 °C. Ester (0.72 mmol) was added and the suspension
warmed to r.t. whereupon a brown color developed. After
stirring for 1 h, the suspension was diluted with EtOAc (75
mL) and poured into sat. NH4Cl solution (75 mL). The
emulsion was stirred vigorously for 30 min then filtered
through a pad of Celite®. The aqueous layer was extracted
with EtOAc (3 × 75 mL), then the combined organic phases
were dried over MgSO4, filtered, and the solvent removed in
vacuo. The crude product was purified by flash chromatog-
raphy (hexane–EtOAc, 2:1) to afford the cyclopropanol.
1-[3-(Benzyloxy)propyl]-2-[2-(ethoxymethoxy)-4-
methoxyphenyl]cyclopropanol (21)
Acknowledgment
We thank the Royal Society of New Zealand Marsden fund for
financial support.
References and Notes
(1) For reviews, see: (a) Vaillancourt, V.; Pratt, N. E.; Perron,
F.; Albizati, K. F. The Total Synthesis of Spiroketal-
Containing Natural Products, In Total Synthesis of Natural
Compounds, Vol. 8; ApSimon, J., Ed.; John Wiley and Sons:
New York, 2007. (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K.
Chem. Rev. 2005, 105, 4406.
(2) Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.;
Yokoyama, A.; Goto, Y.; Mizushina, M.; Sakaguchi, K.;
Hayashi, H. Biochemistry 2000, 39, 5995.
(3) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006,
71, 5357.
(4) Fujimoto, H.; Nozawa, M.; Okuyama, E.; Ishibashi, M.
Chem. Pharm. Bull. 2002, 50, 330.
Yellow oil. Rf = 0.23 (hexane–EtOAc, 2:1). IR (film):
n = 3440, 2928, 1711, 1610, 1505, 1453, 1360, 1279, 1254,
1199, 1156, 1100, 1075, 996, 842, 736, 689 cm–1. 1H NMR
(300 MHz, CDCl3): d = 0.89 (dd, J = 7.3, 5.7 Hz, 1 H, H-2),
1.12–1.29 (m, 4 H, CH3, H-3), 1.56 (dd, J = 14.4, 7.4 Hz, 2
H, H-1¢), 1.70 (quin, J = 6.3 Hz, 2 H, H-2¢), 2.30 (dd, J = 9.9,
Synlett 2009, No. 14, 2315–2319 © Thieme Stuttgart · New York

LETTER
7.3 Hz, 1 H, H-3), 3.48 (t, J = 5.8 Hz, 2 H, H-3¢), 3.74 (q,
Novel Approach to Monobenzannulated Spiroketals
2319
6-(Benzyloxy)-1-[2-(ethoxymethoxy)-4-methoxy-
phenyl]hexan-3-one (26)
Yellow oil. Rf = 0.38 (hexane–EtOAc, 4:1). IR (film):
J = 7.1 Hz, 2 H, OCH2CH3), 3.78 (s, 3 H, OMe), 4.47 (s, 2
H, OCH2Ph), 5.25 (q, J = 6.3 Hz, 2 H, OCH2O), 6.45 (dd,
J = 8.4, 2.5 Hz, 1 H, H-5¢), 6.73 (d, J = 2.5 Hz, 1 H, H-3¢),
n = 2927, 1712, 1610, 1587, 1506, 1444, 1361, 1284, 1256,
1199, 1154, 1100, 1077, 997, 842, 737, 698 cm–1. 1H NMR
(300 MHz, CDCl3): d = 1.22 (t, J = 7.1 Hz, 3 H, OCH2CH3),
1.88 (quin, J = 6.7 Hz, 2 H, H-5), 2.50 (t, J = 7.3 Hz, 2 H, H-
4), 2.66 (t, JA,B = 7.7 Hz, 2 H, H-2), 2.81 (t, JA,B = 7.4 Hz, 2
H, H-1), 3.46 (t, J = 6.4 Hz, 2 H, H-6), 3.71 (q, J = 7.0 Hz, 2
H, OCH2CH3), 3.77 (s, 3 H, OMe), 4.47 (s, 2 H, OCH2Ph),
5.22 (s, 2 H, OCH2O), 6.46 (dd, J = 8.3, 2.6 Hz, 1 H, H-5¢),
6.70 (d, J = 2.5 Hz, 1 H, H-3¢), 7.01 (d, J = 8.0 Hz, 1 H, H-
6¢). 13C NMR (75 MHz, CDCl3): d = 15.1 (CH3), 23.8 (CH2,
C-5), 24.3 (CH2, C-1), 39.4 (CH2, C-4), 43.2 (CH2, C-2),
55.3 (CH3, OMe), 64.3 (CH2, OCH2CH3), 69.4 (CH2, C-6),
72.8 (CH2, OCH2Ph), 93.1 (CH2, OCH2O), 101.4 (CH, C-3¢),
105.8 (CH, C-5¢), 127.5 (CH, C-4¢¢), 127.6 (CH, 2¢¢, C-6),
128.4 (CH, C-3¢¢, C-5¢¢), 130.1 (q, C-1¢), 130.2 (CH, C-6¢),
138.7.9 (q, C-1¢¢), 156.0 (q, C-2¢), 159.2 (q, C-4¢), 210.8 (q,
C-3). MS (EI, 70eV): m/z (%) = 97 (19), 151 (55), 177 (82),
207 (27), 235 (67), 253 (19), 275 (17), 311 (46), 341 (31),
385 (5) [M+], 409 (100) [M+ + Na]. HRMS (EI): m/z [M+ +
Na] calcd for C23H30NaO5: 409.1991; found: 409.1985.
6.79 (d, J = 8.4 Hz, 1 H, H-6¢), 7.27–7.34 (m, 5 H, OBn). 13
NMR (75 MHz, CDCl3): d = 15.1 (CH3), 17.1 (CH2, C-3),
25.9 (CH2, C-2¢), 26.1 (CH, C-2), 31.4 (CH2, C-1¢), 55.3
(CH3, OMe), 64.2 (q, C-1), 70.7 (CH2, OCH2CH3), 72.9
(CH2, OCH2Ph), 93.4 (CH2, OCH2O), 101.4 (CH, C-4¢¢),
105.6 (CH, C-5¢¢), 127.6 (CH, C-6¢¢), 127.7 (CH, C-2¢¢¢,
C-6¢¢¢), 128.2 (CH, C-4¢¢¢), 128.4 (CH, C-3¢¢¢, C-5¢¢¢), 148.7
(q, C-1¢¢, C-1¢¢¢), 159.0 (q, C-2¢¢, C-3¢¢). MS (EI, 70eV):
m/z (%) = 247 (16), 409 (100) [M+ + Na], 793 (2 M+ + Na].
HRMS (EI): m/z [M+ + Na] calcd for C23H30NaO5: 409.1991;
found: 409.1985.
C
(26) General Procedure – Ring Opening of Cyclopropanols
Cyclopropanol (0.34 mmol) was added to dioxane (3 mL)
and 0.2 N NaOH solution (6 mL). The reaction was stirred at
reflux for 3 d, then neutralized to pH 7 with 2 M HCl. The
aqueous layer was extracted with Et2O (5 × 10 mL). The
combined organic layers were dried over MgSO4, filtered,
and the solvent removed in vacuo. The crude product was
purified by flash chromatography (hexane–EtOAc, 4:1) to
afford the ketone.
Synlett 2009, No. 14, 2315–2319 © Thieme Stuttgart · New York