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Synthesis of Enantiomerically Pure Bicyclo[4.2.0]octanes by Cu-Catalyzed [2+2] Photocycloaddition and Enantiotopos-Differentiating Ring Opening

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Angewandte
Chemie
Cyclizations
DOI: 10.1002/anie.200600946
Synthesis of Enantiomerically Pure
Bicyclo[4.2.0]octanes by Cu-Catalyzed
[2+2] Photocycloaddition and EnantiotoposDifferentiating Ring Opening**
Ingbert Braun, Florian Rudroff, Marko D. Mihovilovic,
and Thorsten Bach*
Dedicated to Professor Jochen Mattay
on the occasion of his 60th birthday
The wide distribution of bicyclo[4.2.0]octanes in natural
products[1] and the inherently difficult synthesis of strained
cyclobutanes[2] renders the synthesis of compounds with the
general framework A (Scheme 1) a challenging task. Quite
The alternative approach by Cu-catalyzed, intramolecular
[2+2] photocycloaddition reactions[5] of open-chain 1,7dienes is not viable. When we attempted [2+2] photocycloaddition reactions of substrates 1 and 2, there was no indication
for the formation of the desired bicyclo[4.2.0]octane. Apparently Cu-catalyzed photocycloaddition reactions require the
coordination of both double bonds to the metal atom,[6] which
is feasible only for reactions with 1,6-dienes leading to
bicyclo[3.2.0]heptanes.
We now propose a retrosynthetic concept (Scheme 1) that
encompasses an enantiotopos-differentiating ring-opening
reaction of substrates such as C (Z = CO) for the synthesis
of enantiomerically pure bicyclo[4.2.0]octanes, represented
by structure B. Because tricyclic compound C encompasses
both bicyclo[4.2.0]octane and bicyclo[3.2.0]heptane structures, it should be accessible by Cu-catalyzed [2+2] photocycloaddition reaction of diene D. Herein, we report the
successful application of this concept to a specific example.
We envisioned an enantioselective Baeyer–Villiger oxidation as the enantiotopos-differentiating reaction,[7] which
thus requires a carbonyl group as the functional group Z
(Scheme 1, C, Z = CO). The instability of a 1,3-divinyl-2cyclopentanone and its undesired photochemical reactions
(a-cleavage, oxa-di-p-methane rearrangement) prompted us
to incorporate the carbonyl group in protected form (Z =
CHOTBDMS, TBDMS = tert-butyldimethylsilyl). Accordingly, we attempted a Cu-catalyzed [2+2] photocycloaddition
reaction with the readily available[8] diene 3 (Scheme 2). The
Scheme 1. Top: Structures of the bicyclo[4.2.0]octane skeleton A and of
possible starting materials 1 and 2 for [2+2] photocycloaddition
reactions; bottom: retrosynthetic analysis for the synthesis of enantiomerically pure bicyclo[4.2.0]octanes B.
clearly, the cyclobutane part invites a photochemical key step,
and [2+2] photocycloaddition reactions with cyclohexenones
have been studied intensively.[3] In these examples enantiomerically pure products have always been obtained from
enantiomerically pure starting materials.[4]
[*] Dipl.-Chem. I. Braun, Prof. Dr. T. Bach
Lehrstuhl f1r Organische Chemie I
Technische Universit3t M1nchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (+ 49) 89-2891-3315
E-mail: thorsten.bach@ch.tum.de
Dipl.-Ing. F. Rudroff, Prof. Dr. M. D. Mihovilovic
Institut f1r Angewandte Synthesechemie
Technische Universit3t Wien
Getreidemarkt 9/163-OC, 1060 Vienna (Austria)
[**] This project was supported by the Deutsche Forschungsgemeinschaft (Ba 1372/11), by the Fonds der Chemischen Industrie, and by
the Fond zur FErderung der wissenschaftlichen Forschung Fsterreich (FWF, P-I19-B10).
Angew. Chem. Int. Ed. 2006, 45, 5541 –5543
Scheme 2. Diastereoselective preparation of ketone 5 and its enantioselective Baeyer–Villiger oxidation.
reaction proceeded smoothly, and the desired product 4[9] was
obtained in good yields and with high endo diastereoselectivity (endo/exo > 90:10). As mentioned in previous papers,[10]
following the observation of Mattay et al.,[11] the more stable
copper(II) trifluoromethanesulfonate (Cu(OTf)2) can be used
instead of CuOTf, which facilitates the experimental procedure significantly. Cleavage of the protecting group with
tetrabutylammoniumfluoride (TBAF), followed by oxidation
with 2-iodoxybenzoic acid (IBX) afforded ketone 5, which
was submitted to different conditions for the Baeyer–Villiger
oxidation.
Among the protocols for metal-catalyzed oxidations, the
method developed by Bolm et al.[12] gave the best results. The
desired product 6[13] could be obtained with complete
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5541
Communications
conversion in 32 % ee (Table 1, entry 1) and in 72 % yield.
Significantly higher enantiomeric excesses were achieved
with different recombinant Escherichia coli whole-cell
expression systems of flavin-dependent monooxygenases[14]
Table 1: Enantioselective Baeyer–Villiger oxidations of substrate 5 under
different conditions (cf. Scheme 2).
Entry
Method
Conv. [%]
e.r.[a]
ee[b] [%]
100
66:34
32
O2, tBuCHO (3 equiv)
1
(3 mol %)
C6H6, RT, 3 d
2
CHMOBrevi1
(LBAmp)[c] 24 8C, 24 h
100
2:98
96
3
CHMOBrachy
(LBAmp)[c] 24 8C, 24 h
100
4:96
92
4
CPMOComa
(LBAmp)[c] 24 8C, 24 h
56
93:7
86
5
CHMOBrevi2
(LBAmp)[c] 24 8C, 24 h
30
87:13
74
Scheme 3. Proof of the absolute configuration of lactone 6 by the
Mosher ester method.[18]
R-configured alcohol, shows a downfield shift for the proton
attached to the larger a-carbon substituent compared to the
analogous shift of the S,S diastereomer, and vice versa. This
chemical-shift difference was observed for the proton on the
cyclobutane ring indicated in 9 (Scheme 3). In the 1H NMR
spectrum of the major diastereomer the a protons of the
cyclohexyl ring are shifted upfield relative to those of the
minor isomer.
It is apparent that many other methods can be employed
for the suggested enantiotopos differentiation.[19] The substrates are limited to compounds bearing a mirror plane.
Further photocycloaddition reactions, which were shown to
proceed in good yields and which led to new substrates for the
desymmetrization step, are depicted in Scheme 4. Divinyl-
[a] Enantiomeric ratio 6/ent-6. Ratios were determined by gas chromatrography on a chiral stationary phase (BGB-175: 50 % 2,3-diacetyl-6-tertbutyldimethylsilylated g-cyclodextrin). [b] The enantiomeric excess was
calculated from the enantomeric ratios. [c] Recombinant E. coli strains in
Luria–Bertani (LB) media supplemented with ampicillin (Amp) were
used. The overexpressed monooxygenases originate from Brachymonas
(CHMOBrachy), Brevibacterium (CHMOBrevi1, CHMOBrevi2), and Comamonas
(CPMOComa).[17]
(Table 1). In particular, the formation of enantiocomplementary lactone products depending on the enzyme used
(entry 2, 3 vs. 4, 5) is very appealing from a synthetic chemist?s
point of view. This observation is congruent with the recent
identification of two distinct groups (family clusters) of
Baeyer–Villiger monooxygenases.[15] Using monooxygenase
CHMOBrevi1, we obtained predominantly ent-6 (96 % ee),
while CHMOBrevi2 and CPMOComa gave the enantiomeric
lactone 6. So far,[16] monooxygenases producing predominantly enantiomer 6 gave lower conversions and selectivities
than monooxygenases with a preference for enantiomer ent-6
(entries 2 and 3, Table 1). Other cyclohexanone monooxygenases (CHMOArthro, CHMORhodo1, CHMORhodo2, CHMOAcineto)
were less successful with regard to the desired enantiotopos
differentiation and are not listed in Table 1.
The configuration assignment was conducted by a method
described by Mosher et al.[18] for secondary alcohols. Accordingly, d-lactone 6 and its enantiomer ent-6 underwent
quantitative ring-opening to give the methyl d-hydroxycarboxylates 7 and ent-7, respectively (Scheme 3), and the free
hydroxyl group was acylated with reagent 8. Owing to the
preferred conformation of the resulting Mosher ester, the 1H
NMR chemical shifts for the protons at the a-carbon atoms
are differentiated.[18] The S,R diastereomer, obtained with an
5542
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Scheme 4. Cu-catalyzed [2+2] photocycloaddition reactions leading to
the tri- and tetracyclic products 13 and 11, respectively.
substituted bicyclo[(4+n).3.0]alkanes 10 a and 10 b reacted
smoothly in good yields and with excellent diastereoselectivities to give products 11. Pentasubstituted cyclopentane 12
also underwent a [2+2] photocycloaddition reaction to
provide the desired tricyclic product 13. Hence, the introduction of the bridge (Z = CHOTBDMS, Scheme 1) indeed
enables the otherwise impossible [2+2] photocycloaddition
reaction.
Further investigations in our group currently focus on the
development and application of other enantiotopos-differentiating reactions to ketones similar to 5, and on the
variation of the bridge Z in intermediates of type C.
Saponification of lactone 6 or ester 7 to give the corresponding d-hydroxycarboxylic acid should facilitate the synthesis of
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 5541 –5543
Angewandte
Chemie
enantiomerically pure bicyclo[4.2.0]octane-2-ol and bicyclo[4.2.0]octane-2-one, which are not accessible from 1 a or 1 b.
Received: March 10, 2006
Revised: May 2, 2006
Published online: July 19, 2006
.
Keywords: asymmetric synthesis · cycloaddition ·
enantioselectivity · lactones · oxidation
[1] a) M. Cueto, L. D?Croz, J. L. Mate, A. San-Martin, J. Darias,
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Synthesis 1998, 683 – 703; d) S. A. Fleming, C. L. Bradford, J. J.
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[4] Examples: a) E. Garcia-Exposito, A. Alvarez-Larena, V. Branchadell, R. M. Ortuno, J. Org. Chem. 2004, 69, 1120 – 1125;
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[5] Reviews: a) G. Salomon, Tetrahedron 1983, 39, 485 – 575; b) P.
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[6] Structural investigations: a) T. Nickel, K.-R. PLrschke, R. Goddard, C. KrMger, Inorg. Chem. 1992, 31, 4428 – 4430; b) P. H. M.
Budzelaar, P. J. J. A. Timmermans, A. Mackor, A. L. Spek,
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[7] Reviews: a) C. Bolm, C. Palazzi, O. Beckmann in Transition
Metals for Organic Synthesis, 2nd ed., Vol. 2 (Eds.: M. Beller, C.
Bolm), Wiley-VCH, Weinheim, 2004, pp. 267 – 274; b) M. D.
Mihovilovic, F. Rudroff, B. Groetzl, Curr. Org. Chem. 2004, 8,
1057 – 1069.
Angew. Chem. Int. Ed. 2006, 45, 5541 –5543
[8] Prepared from anti-norbornenol (P. R. Story, J. Org. Chem. 1961,
26, 287 – 290) after TBDMS protection (E. J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 1972, 94, 6190 – 6191) and ringopening metathesis (P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am.
Chem. Soc. 1996, 118, 100 – 110).
[9] Analytical data for compound 4: Rf = 0.55 (pentane). IR (neat):
ñ = 2953 (s, C-H), 2856 (s, C-H), 1471 (s, H-C-H), 1256 (s, Si-C),
1125 (s, C-O), 1060 (s), 907 (s, Si-C), 863 (s, C-O-Si), 835 cm1 (s,
Si-C). 1H NMR (360 MHz, CDCl3): d = 3.77 (virt. t, 3Jffi1.7 Hz,
1 H, H-9), 2.52–2.45 (m, 2 H, H-2/5), 2.00–1.93 (m, 4 H, H-3/4),
1.88–1.83 (m, 2 H, H-1/6), 1.83–1.78 (m, 4 H, H-7/8), 0.86 (s, 9 H,
C(CH3)3), 0.04 ppm (s, 6 H, Si(CH3)2). 13C NMR (90.6 MHz,
CDCl3): d = 4.9 (Si(CH3)2), 18.0 (C(CH3)3), 19.7 (C-3/4), 21.1
(C-7/8), 25.9 (C(CH3)3), 35.6 (C-2/5), 44.7 (C-1/6), 81.5 ppm (C9). Elemental analysis (%) calcd for C15H28OSi (252.47): C 71.36,
H 11.18, Si 11.12; found: C 71.31, H 11.30 Si, 11.13. HRMS (EI):
[C15H28OSi]+: calcd 252.1909, found 252.1906.
[10] a) T. Bach, C. KrMger, K. Harms, Synthesis 2000, 305 – 320; b) T.
Bach, A. Spiegel, Eur. J. Org. Chem. 2002, 645 – 654; c) T. Bach,
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[11] K. Langer, J. Mattay, A. Heidbreder, M. MLller, Liebigs Ann.
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[12] a) C. Bolm, G. Schlingloff, K. Weickhardt, Angew. Chem. 1994,
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1849; b) C. Bolm, G. Schlingloff, F. Bienewald, J. Mol. Catal. A
1997, 117, 347 – 350.
[13] Analytical data for compound 6: M.p. 107 8C. [a]20
D = + 66.4 (c =
1.05, CHCl3) IR (KBr): ñ = 2959 (m, C-H), 1752 (s, CO),
1006 cm1 (m, C-O). 1H NMR (360 MHz, CDCl3): d = 4.63 (ddd,
3
J = 5.5 Hz, 3J = 4.2 Hz, 3J = 1.5 Hz, 1 H, H-6), 2.87–2.69 (m, 2 H,
H-2/5), 2.56 (ddd, 3J = 4.6 Hz, 3J = 3.4 Hz, 3J = 2.4 Hz, 1 H, H-1),
2.40 (dddd, 2J = 13.5 Hz, 3J = 11.1 Hz, 3J = 4.9 Hz, 3J = 2.4 Hz,
1 H, H-3), 2.28–2.09 (m, 4 H, H-4, H-9/10), 2.00–1.74 ppm (m,
3 H, H-3, H-9/10). 13C NMR (90.6 MHz, CDCl3): d = 17.3 (C-4),
17.9 (C-3), 19.1 (C-10), 21.3 (C-9), 32.2 (C-5), 34.5 (C-2), 38.5 (C1), 78.9 (C-6), 176.6 ppm (C-8). Elemental analysis (%) calcd for
C9H12O2 (152.19): C 71.03, H 7.95; found: C 70.91, H 8.00.
HRMS (EI, C9H12O2): calcd 152.0837, found 152.0835.
[14] Reviews: a) N. M. Kamerbeek, D. B. Janssen, W. J. H. van Berkel, M. W. Fraaije, Adv. Synth. Catal. 2003, 345, 667 – 678;
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[16] Possible optimization: a) M. Bocola, F. Schulz, F. Leca, A. Vogel,
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[17] For details of recombinant expression systems, see a) M. G.
Bramucci, P. C. Brzostowicz, K. N. Kostichka, V. Nagarajan, P. E.
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[18] a) J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512 –
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[19] Examples: a) K. Sahasrabudhe, V. Gracias, K. Furness, B. T.
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