Norbornanoid chiral ketones by desymmetrization of dibromoalkenes

Article abstract of DOI:10.1002/hlca.201300191

New optically active polycyclic ketones 6a-6d, amenable to a large variety of synthetic applications, have been prepared from readily available 2,3-dibromonorbornene and analogs (Scheme 2) via desymmetrization with (-)-ephedrine, followed by hydrolysis under mild acidic conditions. At variance with substrates 4a-4d, the sterically hindered norbornene derivative 4e reacts with the solvent N-methylpyrrolidin-2-one (NMP) leading to the formation of the unusual cyclopropanoid products 8a and 8b. Copyright

Full text of DOI:10.1002/hlca.201300191

Helvetica Chimica Acta – Vol. 97 (2014)
537
Norbornanoid Chiral Ketones by Desymmetrization of Dibromoalkenes
a
b
b
a
by Ramazan KoÅak ), Giuseppe Borsato ), Ottorino De Lucchi ), and Arif Da s¸ tan* )
a) Ataturk University, Science Faculty, Department of Chemistry, TR-25240, Erzurum
(
phone: þ 90-442-2314405; fax: þ 90-442-2360948; email: adastan@atauni.edu.tr)
b) Dipartimento di Scienze Molecolari e Nanosistemi, Universit a` Caꢀ Foscari di Venezia, Dorsoduro
137, I-30123 Venezia
2
New optically active polycyclic ketones 6a–6d, amenable to a large variety of synthetic applications,
have been prepared from readily available 2,3-dibromonorbornene and analogs (Scheme 2) via
desymmetrization with (ꢀ)-ephedrine, followed by hydrolysis under mild acidic conditions. At variance
with substrates 4a–4d, the sterically hindered norbornene derivative 4e reacts with the solvent N-
methylpyrrolidin-2-one (NMP) leading to the formation of the unusual cyclopropanoid products 8a and 8b.
Introduction. – The use of polycyclic ketones as intermediates in asymmetric
synthesis is one of the cornerstones of organic chemistry since the first synthesis of
prostaglandins developed at the end of 1960s [1]. During the last four decades, several
molecules have been prepared by procedures entailing this sort of molecules, and the
natural products dolabellatrienone [2] and (ꢀ)-sordarin [3] are some of the most recent
reported examples. The polycyclic ketones are known for their biological activities, for
example, as inhibitors of g-secretase [4], cannabinoid receptor ligands [5], and calcium
channel blockers [6]. Our interest regarding the enantiomerically pure norbornenone
types 1 (bicyclo[2.2.1]hept-5-en-2-one) is due to their role in the synthesis of
benzocylotrimers [7] as outlined in Scheme 1. The transformation of the C¼O moiety
to the reactive iodo derivatives 2 by known procedures [7h][8] is the preferred way to
produce selectively and in high yield enantiomerically pure syn-benzocyclotrimer 3.
Scheme 1. Enantiomerically Pure syn-Benzocyclotrimers 3 from Ketones 1
This type of compounds has recently been used as a platform to realize
nanocapsules [7g], molecular cages [7a][7d], and receptors [7b], as well as a sumanene
[
9] and its derivatives [10].
Herein, we present a three-step synthesis of chiral norbornanoid ketones via a
procedure that combines the versatility of high-temperature bromination [11] and the
ꢁ
2014 Verlag Helvetica Chimica Acta AG, Zꢂrich

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38
Helvetica Chimica Acta – Vol. 97 (2014)
desymmetrization of the formed 2,3-dibromonorbornenes with (ꢀ)-ephedrine [12].
Indeed, the high-temperature bromination allows an easy access to a variety of
symmetrical dibromo olefins, which can be subjected to desymmetrization with (ꢀ)-
ephedrine to give diastereoisomeric oxazolidines 5, which are readily hydrolyzed to
bromo ketones 6. The use of dibromo olefins 4, instead of the reported olefins bearing
Cl or PhSO groups [13] allows for simple operations [14], an advantageous atom
2
economy with respect to the PhSO groups [15], and, above all, a convenient access to a
2
wide variety of norbornanoid substrates 4, rendering this method of general utility in
the field [16].
Results and Discussions. – As depicted in Scheme 2, five polycyclic dibromo olefins
were submitted to desymmetrization with (ꢀ)-ephedrine to evaluate the effect of the
steric hindrance of the reagents on the yields and selectivity.
Scheme 2
i) 1.5 equiv. of (ꢀ)-ephedrine, 3.0 equiv. of tBuOK, NMP, 16 h, 808. ii) PPTS (Pyridinium p-
toluenesulfonate), H O, THF, 2 d, r.t.
2
The results are collected in the Table. When substrate 4a (Entry 1) was reacted with
(
ꢀ)-ephedrine under the reaction conditions that had turned out to be the best with
t
analogous substrates [12] ( BuOK as base, 1-methylpyrrolidin-2-one (NMP) as solvent
at 808), two out of the possible four diastereoisomers, 5a and 5a’, in a 90 :10 ratio were
obtained. This ratio was determined by integration of the doublets at ca. d(H) 5 in the
1
H-NMR spectrum attributed to the H-atoms H ꢀC(3) performed on the crude
exo
reaction mixture. The reaction is totally site-selective, i.e., it occurs at the same
prochiral C-atom, giving rise to two diastereoisomers with the same skeletal
configuration, rendering this approach straightforward, because the hydrolysis of the
crude reaction mixture gave a single enantiomer of ketone 6a without any further
resolution.
The configuration of 5a shown in Scheme 2 was determined by a thorough analysis
of dipolar interactions in the NOESY spectra (available as Supporting Information).

Helvetica Chimica Acta – Vol. 97 (2014)
539
Table. Desymmetrization of Dibromo Compounds 4
a
a
b
Entry
Substrate
Product ratio 5/5’/5’’ ) [%]
Yield of 5 [%]
de of 5 ) [%]
ee of 6 ) [%]
1
2
3
4
5
4a
4b
4c
4d
4e
90 : 10 : 0
80 : 7: 13
80 : 9 : 11
81 : 9 : 10
–
82
73
73
74
–
> 99
74
78
80
–
ꢁ 99
74
97
ꢁ 99
–
a) Calculated on the basis of H-NMR spectra. b) Calculated on the basis of HPLC analysis.
1
This study was performed on a single crystal of 5a grown by slow evaporation of the
solvent from the crude reaction mixture in CH Cl /hexane 1:3. As already described in
2
2
the literature for oxazolidines derived from dichloro olefins [8], also in the case of 5a
only one of the two possible epimers with exo-orientation of HꢀC(3) was detected. The
formation of product 5a’ was observed after rearrangement of 5a in the acidic medium,
which was slowly generated in solution of 5a in CDCl3.
1
In the case of dibromo derivatives 4b (Entry 2, Table), the H-NMR spectrum of
the crude reaction mixture exhibited three doublets for the benzylic H-atoms of the
oxazolidine ring at ca. 5 ppm. The ratio of the integrated signals was 80 :7:13. In the
same way as for 5a, these doublets were assigned to structures of 5b, 5b’, and 5b’’. Also
in this case, the re-equilibrium from 5b to 5b’ was detected by NMR analysis.
Unfortunately, due to the poor crystallinity of the diasteroisomers 5b, 5b’, and 5b’’, all
attempts to purify a sample by crystallization failed. Also, the use of standard
chromatographic methods did not allow isolation of any pure sample of one
diasteroisomer. The direct hydrolysis of the mixture of b-type oxazolidines using
pyridinium p-toluenesulfate (PPTS) as acid in THF/H O, gave ketone 6b in high yield.
2
The diastereoisomer ratio 5b/5b’/5b’’, calculated by NMR integration of the crude
mixture of products, provided an ee value of 74%, exactly matching, as described
below, the value calculated by HPLC analysis.
The desymmetrization reaction of the exo-dibromo bicycle 4c also gave three
diastereoisomers (Table, Entry 3), but, in this case, the major diastereoisomer 5c was
successfully isolated by column chromatography in an almost pure state. The cleavage
of the chiral auxiliary in 5c furnished 6c in 93% chemical yield and with 97% ee.
The tetrabromo compound 4d exhibited the same reactivity as 4c as indicated in the
Table (Entry 4). In this case, the major diastereoisomer 5d was purified by
crystallization (Et O/hexane 9 :1). Hydrolysis gave ketone 6d as a single enantiomer
2
in 88% chemical yield and > 99% ee. In this case, it is important to emphasize that the
nucleophile reacted with only one of the two dibromo olefin sides present in the
molecule. This reactivity is probably due to the steric hindrance induced by the
oxozalidine ring of 5d that prevents the entry of the second nucleophile at the other
reactive site of 4d.
Finally, the desymmetrization reaction was tested on endo-4e, but no oxazolidine
products could be detected. This unexpected result is probably due to the steric
hindrance exerted by the benzene moiety which is not present in the other olefins thus
far employed. When the reaction temperature was raised up to 1208, three products

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40
Helvetica Chimica Acta – Vol. 97 (2014)
Figure. Monobromo derivative 7, and cyclopropanoid compounds 8a and 8b
were isolated: monobromide 7, and the cyclopropanoid compounds 8a and 8b. These
two molecules are the reaction of NMP at 4e (Fig.).
The relative configurations of the lactams 8a and 8b were determined by the
chemical-shift variation of the atom Hsyn and methano-C-atom. According to the g-
gauche effect in NMR spectroscopy [17], the H-atoms subjected to Van der Waals
interactions are shifted to lower fields, whereas the ipso-C-atoms are shifted to higher
fields. This effect is highlighted in conformationally rigid systems like the bicyclic
structures of the present work. As indicated in the Figure, the signal of the atom Hsyn of
8a appears at d(H) 1.45; however, at d(H) 3.45 for 8b. There is also a remarkable
difference in the chemical shifts of the CH C-atoms of compounds 8a and 8b, from
2
d(C) 23 to 35 ppm. In agreement with the observations mentioned above, we assigned
the relative configurations of the lactams 8a and 8b as depicted in the Figure.
To determine the enantiomeric purity of the ketones 6a – 6d by HPLC, a sample of
the racemate as reference standard was prepared using achiral alcohols in place of (ꢀ)-
ephedrine. As shown in Scheme 3, ethylene glycol was used for 4a, while MeOH was
used for all other samples 4b – 4d, and, therefore, four acetals, (ꢂ)-9a – (ꢂ)-9d, and
ketones, (ꢂ)-6a – (ꢂ)-6d, were synthesized. The analysis was carried out by employing a
Chiralcel AS-Hꢃ column and hexane/ PrOH 95 :5 as mobile phase. The results are
compiled in the Table.
i
The absolute configurations of 6a and 6b were determined by comparison of the
optical rotations with those of the known compounds 10a and 10b [18][19], after
removal the Br-atom using Zn/AcOH as reductant as shown in Scheme 4.
2
5
In the case of 10a, the optical rotation found was [a] ¼ þ581 ([18]: for (ꢀ)-
D
2
5
25
25
stereoisomer [a] ¼ ꢀ578), while 10b had a [a] value of þ 27 ([19]: [a] ¼ þ34)
D
D
D
[
19]. These data established that the desymmetrization process proceeded as in the
cases of the dichloro [8] and bis(phenylsulfonyl) norbornadienes [9] affording, with
natural (ꢀ)-ephedrine, ketones with (R)-configuration at C(1).
Conclusions. – In this work, four new norbornanoid oxazolidines, 5a – 5d, and the
related a-bromoketones, 6a – 6d, were obtained through a three-steps synthesis in good
yield, diastereoselectivity, and excellent enatioselectivity. Enantiomer purities of 6a –
6d were determined by HPLC analysis, and the absolute configurations of 6a and 6b
were established.

Helvetica Chimica Acta – Vol. 97 (2014)
541
Scheme 3
t
i) 2.2 equiv. of alcohols, 2.2 equiv. of BuOK, NMP, 16 h, 808. ii) 1m HCl, H O, THF, 2 d.
2
Scheme 4
The authors are indebted to the Scientific and Technical Research Council of Turkey (TUBITAK
Project No. TBAG-110T091) for financial support. This work also has been supported by Atatꢂrk
University (BAP 2011/383) and Ca Foscari University. We would also like to thank Dr. Murat Gꢀney,
Prof. Hamdullah KılıÅ, and Res. Assist. Saffet ꢁelik for their technical assistance.
Experimental Part
General. TLC: Al-Backed silica-gel 60 F254 plates (SiO ; Merck). Prep. TLC: SiO 60 HF
254þ366
2
2
(
Merck). Column chromatography (CC): SiO2 60 (Merck); with hexane (b.p. 40 – 608)/AcOEt.
Enantiomeric excess (ee) was determined directly from the areas under the curve. Optical rotations:
89-nm spectropolarimeter at 258. Polarimetric ee values were determined using HPLC analysis on a
5
Thermo Spectra Analysis HPLC System equipped with a UV detector using a chiral column (Chiralcel
i
AS-H); hexane/ PrOH 95 :5 as the eluent, a flow rate of 1.0 ml/min; the detection performed at a
ꢀ1
wavelength of 220 nm. IR Spectra: Matson 1000 FT-IR spectrometer with KBr pellets; ˜n in cm . NMR
Spectra: Varian or Bruker 400-MHz spectrometer in CDCl unless stated otherwise; d in ppm rel. to
3
Me Si as internal standard; J in Hz. MS: Varian 300 MS (TQ mass spectrometer); in m/z (rel. %).
4
Elemental analyses: LECO CHNS-932 elemental analyzer.
General Procedure for the Reaction of 2,3-Dibromonorbornenes 4 with Nucleophiles. Amino
alcoholate, or alcoholate, or diolate (1.5 equiv.), prepared in situ by reaction with base (3 equiv.), in dry
NMP (N-methylpyrrolidin-2-one; 10 ml), was added to a soln. of 1.0 equiv. of dihalo olefin (4a – 4d;

5
42
Helvetica Chimica Acta – Vol. 97 (2014)
1.0 mmol) in dry NMP (5 ml). After 16 h at 808 (for 4e 1208 for 4 d) under Ar, the cooled mixture was
treated with H O (20 ml) and extracted with pentane (3 ꢃ 20 ml); the combined org. layers were dried
2
(
MgSO ), and the solvent was removed. Products 5a and 5d were purified by crystallization. Products 5b,
4
5
(
9
bꢀ, and 5b” were used for the following reaction without purification. Product 5c was purified by CC
hexane/AcOEt 95 :5). Products 7, 8a, and 8b were isolated by CC (hexane/AcOEt 96 :4). Acetals (ꢂ)-
a, (ꢂ)-9c, and (ꢂ)-9d were purified by crystallization, whereas (ꢂ)-9b was purified by CC (hexane/
AcOEt 95 :5).
(
1R,2S,3R,4S,4’S,5’R)-3-Bromo-3,4-dihydro-3’,4’-dimethyl-5’-phenyl-1H-spiro[1,4-methanonaphtha-
lene-2,2’-[1,3]oxazolidine] (5a). Yield: 315 mg (82%). Colorless crystals (from hexane/CH Cl 3 :1).
2
2
M.p. 137 – 1388. [a] ¼ þ14 (c ¼ 1.0, CHCl ). IR: 3746, 3024, 2978, 2932, 2798, 2874, 1471, 1459, 1291,
D
3
1
1
260, 1057, 1043, 770, 750, 704. H-NMR: 7.35 – 7.08 (m, 9 H); 5.00 (d, J ¼ 8.2, 1 H); 4.75 (d, J ¼ 4.2, 1 H);
.55 – 3.53 (m, 2 H); 3.29 (dq, J ¼ 8.2, 6.5, 1 H); 2.56 (s, 3 H); 2.21 – 2.20 (m, 2 H); 0.68 (d, J ¼ 6.5, 3 H).
C-NMR: 145.4; 144.4; 139.1; 128.0; 127.5; 127.3; 126.6; 125.5; 123.7; 122.6; 99.3; 80.3; 61.4; 56.4; 50.5;
3
13
þ
þ
4
(
6.3; 46.2; 34.4; 15.7. EI-MS: 385/383 (10, M ), 304 (87, [M ꢀ Br] ), 281 (14), 207 (23), 157 (34), 128
100), 118 (47), 91 (32), 77 (11), 63 (6). Anal. calc. for C H BrNO: C 65.63, H 5.77, N 3.64; found: C
21 22
6
5.69, H 5.77, N 3.60.
1S,2S,3R,4R,4’S,5’R)-3-Bromo-3’,4’-dimethyl-5’-phenylspiro[bicyclo[2.2.1]heptane-2,2’-[1,3]oxa-
(
zolidine] (5b). Yield: 248 mg (73%). Pale-yellow wax. [a] ¼ ꢀ67.5 (c ¼ 0.4, CHCl ). IR: 3087, 3063,
D
3
3
028, 2964, 2931, 2873, 2997, 1456, 1368, 1329, 1305, 1234, 1216, 1199, 1064, 1016, 758, 742, 721, 700.
1
H-NMR: 7.48 – 7.26 (m, 5 H); 4.96 (d, J ¼ 8.5, 1 H); 4.46 (dd, J ¼ 4.1, 2.1, 1 H); 3.06 (dq, J ¼ 8.5, 6.5, 1 H);
2
.50 – 2.47 (m, 2 H); 2.40 (s, 3 H); 1.91 – 1.89 (m, 1 H); 1.71 (br. d, J ¼ 10.8, A part of AB system, 1 H);
13
1.55 (br. d, J ¼ 10.8, B part of AB system, 1 H); 1.51 – 1.29 (m, 3 H); 0.60 (d, J ¼ 6.5, 3 H). C-NMR:
1
1
39.6; 128.3; 128.0; 127.8; 97.7; 81.0; 61.3; 60.5; 43.5; 38.0; 36.6; 34.2; 24.3; 22.6; 16.1. GC/MS-MS (CI,
þ
þ
50 eV): 338/336 (25, [M þ H] ), 256 (75, [M ꢀ Br] ), 176 (9), 148 (100), 118 (20), 81 (12), 58 (32).
Anal. calc. for C H BrNO: C 60.72, H 6.59, N 4.17; found: C 61.71, H 6.57, N 4.50.
17
22
(
1’S,2S,2’S,4S,5R,9’R,10’R,12’R)-12’-Bromo-3,4-dimethyl-5-phenylspiro[1,3-oxazolidine-2,11’-tetra-
2,9 3,8
cyclo[8.2.1.0 .0 ]trideca[3,5,7]triene] (5c). Yield: 298 mg (73%). Pale-yellow liquid. [a] ¼ ꢀ78.21
D
(
c ¼ 3.35, CHCl ). IR: 3033, 3063, 2965, 2872, 2854, 2798, 1495, 1455, 1294, 1271, 1072, 1045, 750, 701.
3
1
H-NMR: 7.49 – 6.89 (m, 9 H); 5.09 (d, J ¼ 8.5, 1 H); 4.59 (d, J ¼ 4.0, 1 H); 3.93 (d, J ¼ 3.7, 1 H); 3.84 (d,
J ¼ 3.7, 1 H); 3.15 (dq, J ¼ 8.5, 6.5, 1 H); 2.60 – 2.57 (m, 2 H); 2.41 (s, 3 H); 1.46 (br. d, J ¼ 11.8, A of AB,
13
1
1
(
H); 1.13 (dt, J ¼ 11.8, 1.7, B of AB, 1 H); 0.66 (d, J ¼ 6.5, 3 H). C-NMR: 145.3; 144.8; 139.3; 128.1;
27.9; 127.7 (3ꢃ); 122.4; 122.2; 97.8; 80.9; 61.2; 58.3; 44.8; 44.4; 43.8; 38.0; 34.1; 30.3; 15.9. GC/MS-MS
þ
þ
CI, 150 eV): 412/410 (28, [M þ H] ), 330 (98, [M ꢀ Br] ), 267 (8), 202 (16), 148 (100), 107 (28), 58 (40).
Anal. calc. for C H BrNO: C 67.32, H 5.90, N 3.41; found: C 67.55, H 5.92, N 3.42.
23
24
(
1S,2S,3R,4R,4’S,5’R)-3,5,6-Tribromo-3’,4’-dimethyl-5’-phenylspiro[bicyclo[2.2.1]hept-5-ene-2,2’-
[
1,3]oxazolidine] (5d). Yield: 363 mg (74%). Colorless crystals (from Et O/hexane 9 :1). M.p. 151 – 1538.
2
1
[
a] ¼ þ2.0 (c ¼ 1, CHCl ). IR: 3128, 3027, 2963, 1404, 1260, 1104, 800, 615. H-NMR: 7.47 – 7.45 (m,
D
3
2
2
1
4
3
H); 7.32 – 7.22 (m, 3 H); 5.11 (d, J ¼ 8.3, 1 H); 4.56 (d, J ¼ 3.2, 1 H); 3.29 – 3.20 (m, 3 H); 2.42 (s, 3 H);
13
.33 (dt, J ¼ 10.0, 1.7, A of AB, 1 H) 1.91 (dt, J ¼ 10.0, 1.5, B of AB, 1 H); 0.69 (d, J ¼ 6.4, 3 H). C-NMR:
39.1; 128.3; 128.2; 128.0; 127.9; 125.2; 100.8; 81.6; 61.5; 56.31; 53.6; 53.1; 46.1; 34.3; 15.8. EI-MS: 493/491/
þ
þ
89/495 (100, [M þ H] ), 416/414/412 (8, [M ꢀ Br] ), 148 (72). Anal. calc. for C H Br NO: C 41.50, H
17
18
3
.69, N 2.85; found: C 41.15, H 3.66, N 2.81.
rac-(1’R,3’R,4’S)-3’-Bromo-3’,4’-dihydro-1’H-spiro[1,3-dioxolane-2,2’-[1,4]methanonaphthalene]
(
1
9a). Yield: 240 mg (85%). Colorless crystals (from Et
463, 1402, 1291, 1262, 1197, 1163, 1098, 1035, 1003, 800, 765. H-NMR: 7.28 – 7.17 (m, 4 H); 4.44 – 4.43
2
O/hexane 9 :1). M.p. 105 – 1078. IR: 2967, 2882,
1
(
(
m, 1 H); 4.06 – 4.00 (m, 1 H); 3.96 – 3.90 (m, 3 H); 3.50 – 3.47 (m, 1 H); 3.19 – 3.17 (m, 1 H); 2.25 – 2.23
13
m, 2 H). C-NMR: 144.3; 142.9; 127.1; 126.5; 124.2; 123.5; 133.0; 66.2; 64.9; 59.7; 52.4; 50.3; 47.0. GC/
þ
þ
MS-MS (CI, 150 eV): 283/281 (13, [M þ H] ), 240/239 (65), 202/201 (85, [M ꢀ Br] ), 157 (51), 129 (63),
1
16 (38), 73 (100), 51 (15). Anal. calc. for C H BrO : C 55.54, H 4.66; found: C 55.62, H 4.52.
13
13
2
rac-(1R,3S,4S)-3-Bromo-2,2-dimethoxybicyclo[2.2.1]heptane (9b). Yield: 202 mg (86%). Pale-
1
yellow wax. IR: 2961, 2876, 2833, 1454, 1331, 1198, 1171, 1132, 1090, 1058, 1031, 968, 763. H-NMR:
4
1
.16 (d, J ¼ 3.9, 1 H); 3.25 (s, 3 H); 3.20 (s, 3 H); 2.48 – 2.45 (m, 1 H); 2.36 – 2.34 (m, 1 H); 1.90 – 1.81 (m,
H); 1.75 (br. d, J ¼ 10.4, A of AB, 1 H); 1.55 (br. d, J ¼ 10.4, B of AB, 1 H); 1.44 – 1.27 (m, 3 H).

Helvetica Chimica Acta – Vol. 97 (2014)
543
1
3
C-NMR: 104.3; 58.7; 51.0; 47.8; 43.6; 43.3; 35.0; 23.2; 21.8. GC/MS-MS (CI, 150 eV): 205/203 (23, [M ꢀ
þ
þ
þ
MeO] ), 125 (100, [M ꢀ Brꢀ MeO] ), 93 (52, [M ꢀ Brꢀ 2 MeO] ), 67 (6). Anal. calc. for C H BrO : C
9
15
2
4
5.98, H 6.43; found: C 45.63, H 6.79.
rac-(1R,2R,9S,10S,12S)-12-Bromo-11,11-dimethoxytetracyclo[8.2.1.02,9.03,8]trideca-3,5,7-triene (9c).
Yield: 266 mg (86%). Colorless crystals (from Et O/hexane 9 :1). M.p. 82 – 848. IR: 2963, 2833, 1455,
2
1
1
1
2
1
261, 1160, 1123, 1050, 801, 759, 615. H-NMR: 7.25 – 7.20 (m, 2 H); 7.05 – 6.99 (m, 2 H); 4.30 (d, J ¼ 4.4,
H); 3.87 (d, J ¼ 3.3, 1 H); 3.47 (d, J ¼ 3.3, 1 H); 3.39 (s, 3 H); 3.26 (s, 3 H); 2.60 – 2.58 (m, 1 H); 2.47 –
13
.45 (m, 1 H); 1.53 (br. d, J ¼ 11.3, A of AB, 1 H); 1.10 (br. d, J ¼ 11.3, B of AB, 1 H). C-NMR: 145.6;
44.3; 128.0; 128.0; 122.6; 122.4; 104.5; 57.6; 51.5; 48.5; 45.2; 43.8; 43.8; 42.9; 29.5. EI-MS: 310/308 (3,
þ
þ
þ
þ
M ), 277/275 (3, [M ꢀ MeO] ), 229 (100, [M ꢀ Br] ), 165 (29, [M ꢀ Brꢀ 2 MeO] ), 153 (35, [M ꢀ Brꢀ
þ
2
MeO ꢀ CH ] ), 141 (48), 101 (54), 76 (11). Anal. calc. for C H BrO : C 58.27, H 5.54; found: C 57.88,
2
15 17
2
H 5.60.
rac-(1R,4S,6R)-2,3,6-Tribromo-5,5-dimethoxybicyclo[2.2.1]hept-2-ene (9d). Yield: 313 mg (80%).
Colorless crystals (from Et O/hexane 9 :1). M.p. 88 – 908. IR: 2944, 2850, 1594, 1451, 1170, 1144, 1118,
2
1
1
3
1
[
(
[
068, 1048, 873. H-NMR: 4.34 (d, J ¼ 3.5, 1 H); 3.42 (s, 3 H); 3.31 (s, 3 H); 3.26 – 3.23 (m, 1 H); 3.16 –
13
.15 (m, 1 H); 2.31 (dt, J ¼ 9.5, 2.0, A of AB, 1 H); 1.95 (dt, J ¼ 9.5, 1.6, B of AB, 1 H). C-NMR: 127.2;
þ
24.5; 106.5; 56.9; 56.3; 53.3; 52.4; 50.1; 46.6. GC/MS-MS (CI, 150 eV): 394/393/390/388 (3, M ), 361 (83,
þ
þ
þ
þ
M ꢀ MeO] ), 313/311/309 (16, [M ꢀ Br] ), 279 (11, [M ꢀ Brꢀ MeO] ), 233/231 (33, [M ꢀ 2 Br] ), 201
þ
þ
þ
7, [M ꢀ 2 Brꢀ MeO] ), 168/166 (100, [M ꢀ 2 Brꢀ 2 MeO] ), 87/85 (19, [M ꢀ 3 Brꢀ 2 MeO] ), 75 (33,
þ
M ꢀ 3 Brꢀ 2 MeO ꢀ CH ] ), 75 (35). Anal. calc. for C H Br O : C 27.65, H 2.84; found: C 28.03, H
2
9
11
3
2
3
.14.
rac-(1R,2R,9R,10S)-11-Bromotetracyclo[8.2.1.02,9.03,8]trideca-3,5,7,11-tetraene (7; first fraction)
[
1
3
11c]. Yield: 101 mg (41%). Colorless crystals (from hexane). M.p. 518. IR: 3063, 2986, 2940, 2870,
1
587, 1452, 1317, 1279, 1247, 1138, 1003, 933, 817, 759. H-NMR: 7.19 – 6.94 (m, 4 H); 5.73 (d, J ¼ 3.1, 1 H);
.91 (t, J ¼ 4.7, 1 H); 3.74 (t, J ¼ 4.7, 1 H); 3.10 (br. d, J ¼ 4.7, 1 H); 3.01 – 3.00 (m, 1 H); 2.22 (br. d, J ¼ 8.5,
13
A of AB, 1 H), 1.70 (br. d, J ¼ 8.5, B of AB, 1 H). C-NMR: 147.0; 146.4; 132.3; 127.0; 126.6; 123.7; 122.4;
1
22.3; 54.3; 52.0; 47.0; 45.8; 44.7.
rac-(1R,2R,9S,10S,11S,13R)-1’-Methyl-2’H-spiro[pentacyclo[8.3.1.02,9.03,8.011,13]tetradeca-3,5,7-tri-
ene-12,3’-pyrrolidin]-2’-one (8a; second fraction). Yield: 93 mg (35%). Colorless crystals (from hexane/
1
CH Cl 4 :1). M.p. 92 – 938. IR: 3035, 3003, 2949, 2890, 1677, 1453, 1397, 1089, 733. H-NMR: 7.14 – 6.99
2
2
(
3
1
AA’BB’, 4 H); 3.62 (br. d, J ¼ 4.5, 2 H); 3.46 (dt, J ¼ 10.7, 1.6, A of AB, 1 H); 3.16 (t, J ¼ 6.7, 2 H); 2.82 (s,
13
H); 2.74 – 2.73 (m, 2 H); 1.51 (t, J ¼ 6.7, 2 H); 1.15 (br. d, J ¼ 10.7, B of AB, 1 H). C-NMR: 176.0;
þ
46.6; 126.9; 123.3; 50.2; 46.8; 36.8; 36.2; 29.9; 26.4; 26.3; 23.2. EI-MS: 265/264 (25, M ), 178 (45), 165
(
50), 154 (45), 141 (100), 136 (80), 128 (63), 115 (53). Anal. calc. for C H NO: C 81.47, H 7.22, N 5.28,
18 19
found: C 81.38, H 7.20, N 5.41.
rac-(1R,2R,9S,10S,11S,13R)-1’-Methyl-2’H-spiro[pentacyclo[8.3.1.02,9.03,8.011,13]tetradeca-3,5,7-tri-
ene-12,3’-pyrrolidin]-2’-one (8b; third fraction). Yield: 45 mg (17%). Colorless liquid. IR: 3061, 3029,
2
955, 2786, 1688, 1683, 1504, 1471, 1454, 1435, 1402, 1318, 1302, 1293, 1247, 1138, 1094, 759, 732, 711.
1
H-NMR: 7.16 – 7.00 (AAꢂBBꢂ, 4 H); 3.65 – 3.62 (m, 2 H); 3.35 – 3.32 (m, 2 H); 2.72 (s, 3 H); 2.59 – 2.57
(
0
m, 2 H); 2.18 – 2.15 (m, 2 H); 1.45 (br. d, J ¼ 11.0, A of AB, 1 H); 1.18 (br. d, J ¼ 11.0, B of AB, 1 H);
13
.89 – 0.87 (m, 2 H). C-NMR: 175.3; 147.8; 126.4; 123.2; 51.0; 46.0; 38.2; 35.9; 35.0; 32.6; 30.7; 29.3. EI-
þ
MS: 265/264 (30, M ), 178 (50), 165 (58), 154 (40), 141 (100), 136 (75), 128 (87), 102 (62), 77 (45). Anal.
calc. for C H NO: C 81.47, H 7.22, N 5.28; found: C 81.25, H 7.38, N 5.28.
18
19
General Procedure for the Synthesis of Racemic Ketones 6a – 6d. A soln. of 5 (0.76 mmol) and PPTS
(
pyridinium p-toluenesulfonate; 190 mg, 0.76 mmol) in THF (5 ml) and H O (5 ml) was stirred at r.t. for
2
2
d and then diluted with H O (20 ml) and extracted with pentane (3 ꢃ 20 ml). The combined org. layers
2
were dried (MgSO ). The crude reaction product was purified by crystallization or CC. The same
4
procedure was performed for hydrolyses of acetals 9 using 1m HCl instead of PPTS.
(
1R,3R,4S)-3-Bromo-3,4-dihydro-1,4-methanonaphthalen-2(1H)-one (6a). Yield: 180 mg (100%).
Colorless crystals (from hexane/CH Cl 4 :1). M.p. 59 – 608. [a] ¼ þ311.5 (c ¼ 1, CHCl ). IR: 3071, 3044,
2
2
D
3
1
2
1
1
947, 2873, 1797, 1752, 1460, 1308, 1273, 1121, 987, 808. H-NMR: 7.40 – 7.17 (m, 4 H); 4.51 (d, J ¼ 4.5,
H); 3.80 – 3.78 (m, 1 H); 3.75 – 3.73 (m, 1 H); 2.76 (ddd, J ¼ 10.4, 2.4, 1.4, A of AB, 1 H); 2.43 (dt, J ¼
13
0.4, 1.4, B of AB, 1 H). C-NMR: 205.9; 144.9; 138.7; 127.8; 127.4; 124.6; 123.3; 48.6; 48.2; 47.8; 43.5.

5
44
Helvetica Chimica Acta – Vol. 97 (2014)
þ
þ
GC/MS-MS (CI, 150 eV): 239/237 (23, [M þ H] ), 157 (83, [M ꢀ Br] ), 129 (100), 115 (10), 64 (5). Anal.
calc. for C H BrO: C 55.72, H 3.83; found: C 55.52, H 4.22.
11
9
(
1S,3R,4R)-3-Bromobicyclo[2.2.1]heptan-2-one (6b). Yield: 144 mg (100%). Pale-yellow wax.
[
a] ¼ ꢀ46.96 (c ¼ 0.58, CHCl ). IR: 2969, 2879, 1755, 1450, 1402, 1294, 1157, 1076, 941, 781.
D
3
1
H-NMR: 4.33 (d, J ¼ 4.3, 1 H); 2.85 – 2.82 (m, 1 H); 2.75 (d, J ¼ 4.9, 1 H); 2.10 – 2.02 (m, 1 H); 1.92 –
13
1
2
6
.82 (m, 3 H); 1.78 – 1.70 (m, 1 H); 1.59 – 1.52 (m, 1 H). C-NMR: 210.2; 55.1; 48.2; 42.2; 35.3; 25.0;
þ
þ
þ
2.7. GC/MS-MS (CI, 150 eV): 191/189 (12, [M þ H] ), 109 (20, [M ꢀ Br] ), 81 (100, [M ꢀ Brꢀ CO] ),
7 (8). Anal. calc. for C H BrO: C 44.47, H 4.80; found: C 44.83, H 5.16.
7
9
(
1S,2S,9R,10R,12R)-12-Bromotetracyclo[8.2.1.0 .03,8]trideca-3,5,7-trien-11-one (6c). Yield: 200 mg
2,9
(
100%). Colorless crystals (from hexane/CH Cl 4 :1). M.p. 88 – 898. [a] ¼ þ236.36 (c ¼ 0.11, CHCl ).
2
2
D
3
1
IR: 2958, 1760, 1456, 1280, 1143, 731. H-NMR: 7.30 – 7.26 (m, 2 H); 7.10 – 7.05 (m, 2 H); 4.43 (d, J ¼ 4.5,
H); 4.08 (d, J ¼ 3.6, 1 H); 3.53 (d, J ¼ 3.6, 1 H); 2.94 – 2.93 (m, 1 H); 2.87 (s, 1 H); 1.68 (br. d, J ¼ 11.8, A
1
13
of AB, 1 H); 1.49 (br. d, J ¼ 11.8, B of AB, 1 H). C-NMR: 207.9; 144.6; 141.0; 128.7; 128.6; 122.9; 122.3;
þ
þ
5
1
4
3.1; 49.1; 45.0; 44.0; 41.8; 29.8. GC/MS-MS (CI, 150 eV): 265/263 (15, [M þ H] ), 183 (92, [M ꢀ Br] ),
þ
65 (12), 155 (100, [M ꢀ Brꢀ CO] ), 142 (28), 115 (10), 55 (25). Anal. calc. for C H BrO: C 59.34, H
13
11
.21; found: C 59.49, H 4.30.
(
1S,3R,4R)-3,5,6-Tribromobicyclo[2.2.1]hept-5-en-2-one (6d). Yield: 262 mg (100%). Colorless
crystals (from Et O/hexane 9 :1). M.p. 142 – 1438. [a] ¼ þ201.0 (c ¼ 0.15, CHCl ). IR: 2963, 2927,
2
D
1
3
2
1
855, 1767, 1739, 1582, 1449, 1412, 1261, 1026, 864, 802. H-NMR: 4.31 (d, J ¼ 3.4, 1 H); 3.54 – 3.52 (m,
H); 3.35 – 3.34 (m, 1 H); 2.89 (ddd, J ¼ 10.3, 2.5, 1.6, A of AB, 1 H); 2.22 (dt, J ¼ 10.3, 1.6, B of AB, 1 H).
1
3
þ
C-NMR: 202.8; 131.5; 121.4; 61.7; 53.9; 47.7; 44.1. EI-MS: 348/346/344/342 (29, M ), 265 (13, [M ꢀ
þ
þ
þ
Br] ), 239/237/235 (40, [M ꢀ Brꢀ CO] ), 226/224 (100), 207 (36), 158/156 (64, [M ꢀ 2 Brꢀ CO] ),
þ
þ
1
1
45/143 (45, [M ꢀ 2 Brꢀ CO ꢀ CH ] ), 77 (30, [M ꢀ 3 Brꢀ CO] ). Anal. calc. for C H Br O: C 24.38, H
2
7
5
3
.46; found: C 24.29, H 1.46.
General Procedure for the Reduction of Bromo Ketones 6a and 6b. To a vigorously stirred suspension
of Zn dust (2.0 g, 0.03 mol) in 5 ml of glacial AcOH, a soln. of bromo ketone (0.42 mmol) in 2 ml of
glacial AcOH was added dropwise. After addition was complete, the temp. was raised to and maintained
at 708 for 20 h. The soln. was then cooled and filtered through Celite. The solvent was evaporated in
vacuo, CH
dried on CaCl2.
2
Cl
2
(30 ml) was added to the residue, and org. layer was washed with H
2
O (2 ꢃ 10 ml) and
(
1R,4R)-3,4-Dihydro-1,4-methanonaphthalen-2(1H)-one (10a). Yield: 50 mg (74%). Colorless wax.
1
[
2
a] ¼ þ581 (c ¼ 0.76, CHCl ). H-NMR: 7.28 – 7.09 (m, 4 H); 3.67 – 3.64 (m, 1 H); 3.57 – 3.56 (m, 1 H);
D
3
.46 (ddt, J ¼ 9.6, 4.6, 1.7, A of AB, 1 H); 2.30 (dd, J ¼ 17.0, 3.9, A of AB, 1 H); 2.26 (dt, J ¼ 9.6, 1.3, B of
13
AB, 1 H); 1.96 (dd, J ¼ 17.0, 4.5, B of AB, 1 H). C-NMR: 213.6; 148.8; 140.0; 127.6; 126.9; 123.8; 121.7;
5
8.2; 51.0; 41.9; 40.5.
(
1S,4R)-Bicyclo[2.2.1]heptan-2-one (10b). Yield: 36 mg (78%). Yellowish wax. [a] ¼ þ36.59 (c ¼
D
1
0
1
.41, CHCl ; 74% ee). H-NMR: 2.68 – 2.65 (m, 1 H); 2.61 – 2.58 (m, 1 H); 2.06 (br. d, J ¼ 15.6, 1 H);
3
.86 – 1.72 (m, 4 H); 1.57 – 1.39 (m, 3 H). 13C-NMR: 218.3; 49.9; 45.3; 37.7; 35.3; 27.2; 24.2.
REFERENCES
[
1] E. J. Corey, T. K. Schaaf, W. Huber, U. Koelliker, N. M. Weinshenker, J. Am. Chem. Soc. 1970, 92,
397; E. J. Corey, N. M. Weinshenker, T. K. Schaaf, W. Huber, J. Am. Chem. Soc. 1969, 91, 5675.
[
[
[
2] H. Miyaoka, Y. Isaji, H. Mitome, Y. Yamada, Tetrahedron 2003, 59, 61.
3] S. Chiba, M. Kitamura, K. Narasaka, J. Am. Chem. Soc. 2006, 128, 6931.
4] P. C. Belanger, I. J. Collins, J. C. Hannam, T. Harrison, S. J. Lewis, A. Madin, E. G. Mc Iver, A. J.
Nadin, J. G. Neduvelil, M. S. Shearman, A. L. Smith, T. J. Sparey, G. I. Stevenson, M. R. Teall, WO
0
1/70677A1, 2001.
5] M. Muthuppalaniappan, G. Balasubramanian, S. Gullapalli, N. K. Joshi, S. Narayanan, US 2008
234259A1, 2008.
6] K. Hilpert, F. Hubler, D. Renneberg, WO2010/46855, 2010; L. Liu, N. Ishida, M. Murakami, Angew.
Chem., Int. Ed. 2012, 51, 2485.
[
[
0

Helvetica Chimica Acta – Vol. 97 (2014)
545
[
7] a) S. Tartaggia, O. De Lucchi, A. Gambaro, R. Zangrando, F. Fabris, A. Scarso, Chem. – Eur. J. 2013,
9, 5701; b) F. Fabris, O. De Lucchi, I. Nardini, M. Crisma, A. Mazzanti, S. A. Mason, M.-H. Lemee-
1
Cailleau, F. A. Scaramuzzo, C. Zonta, Org. Biomol. Chem. 2012, 10, 2464; c) F. Fabris, C. Zonta, G.
Borsato, O. De Lucchi, Acc. Chem. Res. 2011, 44, 416; d) S. Tartaggia, A. Scarso, P. Padovan, O.
De Lucchi, F. Fabris, Org. Lett. 2009, 11, 3926; e) G. Mazzeo, E. Giorgio, C. Rosini, F. Fabris, E.
Fregonese, U. Toniolo, O. De Lucchi, Chirality 2009, 21, E86; f) E. DalkiliÅ, M. Gꢂney, A. Da s¸ tan, N.
SaraÅo g˘ lu, O. De Lucchi, F. Fabris, Tetrahedron Lett. 2009, 50, 1989; g) A. Scarso, L. Pellizzaro, O.
De Lucchi, A. Linden, F. Fabris, Angew. Chem., Int. Ed. 2007, 46, 4972; h) F. Fabris, L. Pellizzaro, C.
Zonta, O. De Lucchi, Eur. J. Org. Chem. 2007, 283; i) C. Zonta, F. Fabris, O. De Lucchi, Org. Lett.
2005, 7, 1003; j) G. Borsato, M. Crisma, O. De Lucchi, V. Lucchini, A. Zambon, Angew. Chem., Int.
Ed. 2005, 44, 7435; k) G. Borsato, S. Brussolo, M. Crisma, O. De Lucchi, V. Lucchini, A. Zambon,
Synlett 2005, 1125; l) F. Fabris, L. Zambrini, E. Rosso, O. De Lucchi, Eur. J. Org. Chem. 2004, 3313;
m) O. De Lucchi, A. Da s¸ tan, A. Altunda s¸ , F. Fabris, M. Balci, Helv. Chim. Acta 2004, 87, 2364; n) F.
Fabris, L. Bellotto, O. De Lucchi, Tetrahedron Lett. 2003, 44, 1211; o) G. Borsato, O. De Lucchi, F.
Fabris, V. Lucchini, M. Pasqualotti, A. Zambon, Tetrahedron Lett. 2003, 44, 561; p) G. Borsato, O.
De Lucchi, F. Fabris, L. Groppo, V. Lucchini, A. Zambon, J. Org. Chem. 2002, 67, 7894; q) L.
Zambrini, F. Fabris, O. De Lucchi, G. Gardenal, F. Visentin, L. Canovese, Tetrahedron 2001, 57, 8719;
r) F. Fabris, A. De Martin, O. De Lucchi, Tetrahedron Lett. 1999, 40, 9121.
[
[
8] S. Tartaggia, P. Padovan, G. Borsato, O. De Lucchi, F. Fabris, Tetrahedron Lett. 2011, 52, 4478.
9] H. Sakurai, T. Daiko, T. Hirao, Science 2003, 301, 1878.
[
10] S. Higashibayashi, H. Sakurai, J. Am. Chem. Soc. 2008, 130, 8592; S. Higashibayashi, A. F. G. M.
Reza, H. Sakurai, J. Org. Chem. 2010, 75, 4626; S. Higashibayashi, R. B. N. Baig, Y. Morita, H.
Sakurai, Chem. Lett. 2012, 41, 84 – 86; S. Higashibayashi, H. Sakurai, A. F. G. M. Reza, Chem. Asian
J. 2009, 4, 1329.
[
11] a) M. E. S¸ engꢂl, D. D. Gꢂltekin, S. E s¸ siz, E. S¸ ahin, A. Da s¸ tan, Tetrahedron 2009, 65, 4859; b) A.
Da s¸ tan, J. Chem. Res., Synop. 2006, 104; c) A. Da s¸ tan, E. Uzundumlu, M. Balci, F. Fabris, O.
De Lucchi, Eur. J. Org. Chem. 2004, 183; d) A. Da s¸ tan, F. Fabris, O. De Lucchi, M. Guney, M. Balci,
Helv. Chim. Acta 2003, 86, 3411; e) A. Da s¸ tan, E. Uzundumlu, M. Balci, Helv. Chim. Acta 2002, 85,
2
5
729; f) R. Altunda s¸ , A. Da s¸ tan, N. S. ꢄnaldi, K. Gꢂven, O. Uzun, M. Balci, Eur. J. Org. Chem. 2002,
26; g) A. Altunda s¸ , A. Da s¸ tan, M. M. McKee, M. Balci, Tetrahedron 2000, 56, 6115; h) E s¸ siz, M. E.
S¸ engꢂl, E. S¸ ahin, A. Da s¸ tan, Turk. J. Chem. 2011, 35, 587.
[
[
12] G. Borsato, A. Linden, O. De Lucchi, V. Lucchini, D. Wolstenholme, A. Zambon, J. Org. Chem. 2007,
72, 4272.
13] S. Cossu, P. Peluso, Tetrahedron Lett. 2006, 47, 4015; R. Ballini, G. Bosica, S. Cossu, O. De Lucchi, P.
Peluso, Tetrahedron 2001, 57, 4461; S. Cossu, O. De Lucchi, P. Peluso, R. Volpicelli, Tetrahedron Lett.
2
000, 41, 7263; F. Ch e´ ry, P. Rollin, O. De Lucchi, S. Cossu, Tetrahedron Lett. 2000, 41, 2357; S. Cossu,
O. De Lucchi, P. Peluso, R. Volpicelli, Tetrahedron Lett. 1999, 40, 8705; S. Cossu, O. De Lucchi, P.
Pasetto, Angew. Chem., Int. Ed. 1997, 36, 1504.
[
[
[
14] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2007, 41, 40.
15] B. M. Trost, Acc. Chem. Res. 2002, 35, 695.
16] K. Hermann, S. Sardini, Y. Ruan, R. J. Yoder, M. Chakraborty, S. Vyas, C. M. Hadad, J. D. Badji c´ , J.
Org. Chem. 2013, 78, 2984.
[
17] C. Kazaz, A. Da s¸ tan, M. Balcı, Magn. Reson. Chem. 2005, 43, 75; M. D. Gheorghiu, E. Olteanu, J.
Org. Chem. 1987, 52, 5158.
[
[
18] H. L. Goering, J. V. Clevenger, K. Humski, J. Org. Chem. 1972, 37, 3019.
19] E. Plettner, A. Mohle, M. T. Mwangi, J. Griscti, B. O. Patrick, R. Nair, R. J. Batchelor, F. Einstein,
Tetrahedron: Asymmetry 2005, 16, 2754.
Received May 6, 2013