Synthesis of unsaturated lactone moieties by asymmetric hetero Diels-Alder reactions with binaphthol-titanium complexes

Article abstract of DOI:10.1016/S0040-4039(00)02213-9

Natural products like ratjadone and callystatin A contain an α,β-unsaturated lactone moiety which adds to the biological activity of these compounds. Here we report a rapid and practical access to lactone precursor 3 by an asymmetric hetero Diels-Alder reaction as the key step and its subsequent transformation into a suitable building block 4.

Full text of DOI:10.1016/S0040-4039(00)02213-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1263–1265
Synthesis of unsaturated lactone moieties by asymmetric hetero
Diels–Alder reactions with binaphthol-titanium complexes
Monika Quitschalle, Mathias Christmann, Ulhas Bhatt and Markus Kalesse*
Institut fu¨r Organische Chemie, Universita¨t Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
Received 29 November 2000; accepted 30 November 2000
Abstract—Natural products like ratjadone and callystatin A contain an a,b-unsaturated lactone moiety which adds to the
biological activity of these compounds. Here we report a rapid and practical access to lactone precursor 3 by an asymmetric hetero
Diels–Alder reaction as the key step and its subsequent transformation into a suitable building block 4. © 2001 Elsevier Science
Ltd. All rights reserved.
The asymmetric hetero Diels–Alder (HDA) reaction1 is
a powerful method which is used in natural product
synthesis. During our total synthesis of ratjadone2 we
investigated the reaction of ethyl glyoxylate (1) and
1-methoxy-1,3-butadiene (2) in order to find an efficient
route for the construction of the lactone moiety
(Scheme 1). Since we were interested in the use of
compound 3 in the total syntheses of ratjadone3 and
callystatin A,4 the creation of R-configuration at C5 in
high ee was essential.
prior to the reaction. Since this particular protocol gave
unsatisfactory results in our hands, we envisioned that
it might be more practical to generate the catalyst in
situ. In a systematic study, the influence of the equiva-
lents of Ti(OiPr)4 and BINOL used in the reaction and
the effect of MS were examined. The results are sum-
marized in Table 1. We generated the catalyst by
mixing Ti(OiPr)4 and (R)-BINOL in CH2Cl2, refluxing
this mixture for 30 min and then cooling to −30°C. The
reaction catalyzed by a 1:1 mixture of Ti(OiPr)4 and
BINOL gave only low enantiomeric excess (22% ee,
entry 1)6 of the desired compound. Interestingly, in-
creasing the amount of BINOL in this reaction resulted
in significantly higher ee-values. Thus the catalyst pre-
pared from 25 mol% BINOL and 10 mol% of Ti(OiPr)4
(entry 5) gave 89% ee. This interesting effect of the
Mikami et al.5 reported on conditions for the asymmet-
ric HDA reaction using a catalyst generated from
equimolar amounts of Ti(OiPr)4 and 1,1%-binaphthol
(BINOL). Their best results were obtained with a
molecular sieves (MS) free catalyst isolated and purified
3 steps
O
HDA
O
O
5
OMe
O
1
OMe
O
OiPr
O
see Table 1
OEt
OEt
H
1
2
3
4
OH
OH
O
O
OH
5
5
O
O
O
O
Callystatin A
Ratjadone
Scheme 1. Ratjadone and callystatin A with their important lactone moiety.
* Corresponding author. Fax: +49-511-762-3011; e-mail: kalesse@mbox.oci.uni-hannover.de
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02213-9

1264
M. Quitschalle et al. / Tetrahedron Letters 42 (2001) 1263–1265
Table 1. Hetero Diels–Alder reaction of aldehyde 1 and diene 2 to give 3
Entry
(R)-BINOL
Ti(OiPr)4
MS
Yield (%)
C1:C5 Anti:syn
% ee at C5
1
2
3
4
5
6
7
8
0.1 equiv.
0.12 equiv.
0.15 equiv.
0.2 equiv.
0.25 equiv.
0.1 equiv.
0.1 equiv.
0.02 equiv.
0.2 equiv.
0.2 equiv.
0.1 equiv.
–
0.1 equiv.
0.1 equiv.
0.1 equiv.
0.1 equiv.
0.1 equiv.
–
0.05 equiv.
0.01 equiv.
0.1 equiv.
0.1 equiv.a
0.1 equiv.
–
+
+
+
+
+
+
+
+
–
30
33
52
53
61
57
55
31
65
63
33
32
1:2.9
1:3.4
1:5.6
1:6.8
1:6.0
1:2.3
1:7.2
1:2.5
1:10
22
47
81
86
89
0
81
51
98
97
60
0
9
10
11
12
–
–
+
1:7.7
1:4.2
1:2.8
a MS were filtered off after complex formation.
Ratjadone
OTBS
I
O
O
OTBS
PBu3Br
O
OR
H
A
C
B
Scheme 2. Retrosynthetic analysis of ratjadone.
a
c
b
O
HO
HO
O
O
OMe
O
OMe
O
OiPr
O
OiPr
OEt
H
3
5
6
4
Scheme 3. Synthesis of the C-fragment. (a) LiAlH4, Et2O, 0°C; (b) iPrOH, PPTS; (c) Swern oxidation, 77% (over 3 steps).
PPTS=pyridinium p-toluenesulfonate.
BINOL concentration was also observed by Keck and
coworkers7 and it was proposed that a more reactive
catalyst is generated by the addition of a second equiv-
alent BINOL. In order to exclude an uncatalyzed reac-
tion we performed the HDA reaction in the absence of
any catalyst (i.e. without (R)-BINOL and Ti(OiPr)4).
Still a substantial amount of the racemic product could
be isolated (entry 12). At that point we rationalized that
the molecular sieves evidently catalyze a background
HDA reaction, which is completely non selective. When
we performed the reaction without MS the HDA
product was obtained in 65% yield and 98% ee (entry
9).8 Also in these MS-free reactions a 2:1 ratio of
BINOL and Ti(OiPr)4 was superior to the catalyst
generated from a 1:1 mixture (entries 9 and 11).
We therefore changed the methoxy group into the
isopropyloxy group concomitantly converting the b-
anomer into the thermodynamically more stable a-
anomer 6 (Scheme 3). Swern oxidation of 6 then
established fragment C (4) in 50% overall yield which
was coupled to the B-fragment in the course of the total
synthesis.
Scheme 4 depicts how changing the configuration at the
anomeric position prevents racemization of the alde-
hyde during the Wittig reaction. The a-anomer repre-
sents not only the thermodynamically more stable
epimer but also suppresses deprotonation due to the
1,3-diaxial hindrance.
For our synthesis of ratjadone we anticipated that
aldehyde C could be joined with phosphonium salt B
through a Wittig reaction followed by a Heck reaction
for the connection with tetrahydropyran A (Scheme 2).
Further transformations from 3 towards a suitable
building block required the reduction of the resulting
ester with LiAlH4 to furnish alcohol 5. During the
course of our investigations it became clear that the
aldehyde generated from the oxidation of 5 led to
substantial epimerization at C5 in the Wittig reaction.
O
O
H
OMe
OHC
OHC
vs
O
H
H
H
partial epimerization
in the course of the
Wittig reaction.
deprotonation is disfavored
due to 1,3-diaxial hindrance.
Scheme 4. Transacetalization leads to the stable a-anomer 4.

M. Quitschalle et al. / Tetrahedron Letters 42 (2001) 1263–1265
1265
a
b,c
O
O
OiPr
Ph
O
OiPr
Ph
O
O
H
4
(+)-Goniothalamin
7
Scheme 5. Synthesis of (+)-goniothalamin; (a) C6H5CH2P(nBu)3Br, KOtBu, 79%; (b) PPTS, acetone, H2O, (c) MnO2, CH2Cl2,
60% over two steps.
To demonstrate the utility of 4 as a building block for
a,b-unsaturated lactones we synthesized the polyketide
(+)-goniothalamin9 in just three further steps (Scheme
5). The Wittig reaction between benzyltributylphospho-
nium bromide and 4 afforded 7 in 79% yield. Hydroly-
sis of the acetal and subsequent oxidation of the
M.; Tsutsui, Y.; Sugimoto, M.; Kobayashi, M. Tetra-
hedron Lett. 1998, 39, 2349–2352; (d) Crimmins, M. T.;
King, B. W. J. Am. Chem. Soc. 1998, 120, 9084–9085.
5. (a) Mikami, K.; Motoyama, Y.; Tereda, M. J. Am.
Chem. Soc. 1994, 116, 2812–2820; for related work, see:
(b) Dosseter, A. G.; Jamison, T. F.; Jacobsen, E. N.
Angew. Chem. 1999, 111, 2549–2552; Angew. Chem., Int.
Ed. 1999, 38, 2398–2400.
resulting
lactol
with
MnO2
furnished
(+)-
goniothalamin.10
6. The enantioselectivity was determined on GC: HP 5890
II; Lipodex E column (Macherey–Nagel).
7. Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem.
1995, 60, 5998–5999.
In conclusion, we have shown the asymmetric HDA
reaction to provide a rapid and efficient access to
lactone moieties that can be used in the synthesis of
complex natural products such as ratjadone and
callystatin.
8. Synthesis of 3: (R)-BINOL (429 mg, 1.5 mmol) was
dissolved in CH2Cl2 (2 ml) and a solution of Ti(OiPr)4
(223 ml, 0.75 mmol) in CH2Cl2 (1 ml) was added. The
mixture was heated upon reflux for 1 h and then cooled
to −30°C. First freshly distilled ethyl glyoxylate (870 mg,
7.5 mmol) dissolved in CH2Cl2 (1 ml) and then 1-
methoxy-1,3-butadiene (504 mg, 6.0 mmol) also dissolved
in CH2Cl2 (1 ml) was added. The reaction mixture was
stirred at −30°C for 2.5 h and then warmed to 25°C. The
mixture was quenched with sat. NaHCO3 solution and
the aqueous layer was extracted with MTB ether (5×50
ml). The combined organic layers were dried over
Na2SO4 and concentrated. Flash chromatography on sil-
ica gel with hexane:diethyl ether=8:1 gave 780 mg (3.9
References
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K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.;
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Angew. Chem., Int. Ed. 2000, 39, 3532–3556.
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mmol, 65%) of 3: [h]D20= +45.6° (c=1, CHCl3); H NMR
(400 MHz, CDCl3) (1,5-syn): l 1.28 (t, J=7.2 Hz, 3H),
2.27–2.36 (m, 1H), 2.42–2.52 (m, 1H), 3.48 (s, 3H),
4.12–4.27 (m, 2H), 4.36 (dd, J=5.1, 6.5 Hz, 1H), 5.15 (m,
1H), 5.67 (dq, J=10.3, 2.0 Hz, 1H), 6.01 (ddt, J=1.5,
10.3, 4.0 Hz, 1H).
9. Selected previous syntheses: (a) Meyer, H. H. Liebigs
Ann. Chem. 1979, 484–491; (b) O’Connor, B.; Just, G.
Tetrahedron Lett. 1986, 27, 5201–5202; (c) Tsubuki, M.;
Kanai, K.; Honda, T. Heterocycles 1993, 35, 281–288.
10. The NMR data and optical rotation were in accordance
with those reported in literature (Ref. 9c); [h]2D0= +160
(c=0.50, CHCl3); Lit.:+177.5.
.
.