Synthesis of non-racemic 1-hydroxycycloalkene-1-carboxylic-acid derivatives by metathesis of α,α-dialkylated glycolate derivatives

Article abstract of DOI:10.1002/1522-2675(20000705)83:7<1625::AID-HLCA1625>3.0.CO;2-W

A particularly flexible general way to synthesize 1-hydroxycycloalkene- 1-carboxylic-acid derivatives from 2-(tert-butyl)-2-methyl-1,3-dioxolan-4-one (1), a chiral equivalent of glycolic acid, is reported. The method is based on a double enolate alkylation of the glycolate derivative, followed by ring closing metathesis. A formal synthesis of (-)-quinic acid is reported to demonstrate the potential of this approach.

Full text of DOI:10.1002/1522-2675(20000705)83:7<1625::AID-HLCA1625>3.0.CO;2-W

Helvetica Chimica Acta ± Vol. 83 (2000)
1625
Synthesis of Non-Racemic 1-Hydroxycycloalkene-1-carboxylic-Acid
Derivatives by Metathesis of a,a-Dialkylated Glycolate Derivatives
by Liliana Parra Rapado, Vajira Bulugahapitiya, and Philippe Renaud*
Universit e de Fribourg, Institut de Chimie Organique, P e rolles, CH-1700 Fribourg
Aparticularly flexible general way to synthesize 1-hydroxycycloalkene-1-carboxylic-acid derivatives from
2
-(tert-butyl)-2-methyl-1,3-dioxolan-4-one (1), a chiral equivalent of glycolic acid, is reported. The method is
based on a double enolate alkylation of the glycolate derivative, followed by ring closing metathesis. Aformal
synthesis of (À)-quinic acid is reported to demonstrate the potential of this approach.
Introduction. ± During the recent years, ring closing metathesis has emerged as an
extremely useful tool for the synthesis of cyclic compounds of various sizes [1].
Recently, we have reported the preparation of the enantiomerically pure dioxolanone
1, a chiral equivalent of glycolic acid [2]. Based on this chemistry, we report here the
preparation of 1-hydroxycycloalkene-1-carboxylic acids by use of a sequence of enolate
alkylation and olefin metathesis 1) ) ). The formal synthesis of (À)-quinic acid is
reported to illustrate the potential of the method.
2 3
Results and Discussion. ± The preparation of dioxolanones 3 and 4 was performed
via double alkylation of the chiral glycolate derivative 1 (Scheme 1). The dioxolanone 1
was first allylated by treatment with lithium diisopropylamide (LDA) and allyl
bromide (ˆ 3-bromoprop-1-ene) to afford 2 as a trans/cis 3 :1 mixture of diaste-
4
5
reoisomers ) ). When 2 was deprotonated with LDAand alkylated with 4-iodobut-1-
ene and propargyl bromide (ˆ 3-bromoprop-1-yne), the alkylated products 3 and 4
were obtained as trans/cis 2 :1 and 2.5 :1 mixture of diastereoisomers. Attempts to use
other bases (KHMDS and NaHMDS; HMDS ˆ hexamethyldisilazanide) and cosol-
vents (HMPA(hexamethylphosphoric triamide) and DMPU ( N,N'-dimethylpropyle-
neurea)) did not bring any enhancement of the stereoselectivity. This reaction merits
some comments since the stereoselectivity of the second alkylation was not as high as
1)
2)
3)
These results have been presented as a poster during the ꢀ3rd Electronic Conference on Synthetic Organic
Chemistryꢁ (ECSOC-3, ªhttp://www.mdpi.org/ecsoc-3.htmº, Poster a0018).
For a related preparation of 1-hydroxycyclopentane-1-carboxylic-acid derivatives via a radical pathway, see
[
3].
Hammer and Undheim have reported a similar approach for the synthesis of cyclic a-aminocarboxylic acids
starting from a chiral glycine equivalent (Schöllkopf bislactim ether) via olefin ring closing metathesis [4].
Asimilar approach to cyclic amino acids via enyne metathesis has been recently reported [5].
The stereochemical outcome of the first alkylation gave also modest diastereoselectivities, this point will be
discussed in detail in a forthcoming paper.
4)
5)
The trans/cis descriptors are describing the relative configuration of the tert-butyl group at C(2) and the
largest (according to CIP rules) substituent at C(5).

1
626
Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme 1
expected. Indeed, it has been reported by Seebach that alkylation of 2-(tert-butyl)-5-
methyldioxolan-4-one occurs with very high stereoselectivity [6][7], and we have
confirmed this observation in the 2-(tert-butyl)-2,4-dimethyldioxolanone series [2]. The
modest stereochemical control observed here was attributed to the allylic 1,3-strain
1
,3
(A
strain) effect at the enolate level (Fig.). Indeed, to avoid repulsion with the tert-
1,3
butyl group and to minimize A strain, the vinyl moiety of the propenyl substituent is
adopting the configuration depicted in model A, in which the vinyl group is anti to the
tert-butyl substituent, and in which one of the two diastereotopic H-atoms is coplanar
with the enolate moiety. The stereochemical outcome of the reaction is then controlled

Helvetica Chimica Acta ± Vol. 83 (2000)
1627
by the antagonist steric effect of the tert-butyl and the vinyl groups. Related effects have
been reported in enolate alkylations [8] and radical reactions [9]. Kellog has also
observed a drop of selectivity during the alkylation of N,S-acetals from a-alkyl-a-
thiocarboxylic acids when the a-alkyl group is a benzyl group; however, this
observation remained unexplained [10]. This model was confirmed during the synthesis
of 7. Indeed compound 6, which was prepared by acetalization of the corresponding a-
hydroxy acid ethyl ester 5 with pivalaldehyde (ˆ2,2-dimethylpropanal), was allylated
6
in a totally stereoselective fashion ). This result is expected from the model discussed
above since the enolate derived from 6 should adopt the conformation depicted in
model B (Fig.). The two vinyl groups shield both faces of the enolate in a similar way.
Therefore, the stereoselectivity is exclusively controlled by the acetal center (alkylation
anti to the tert-butyl group, ul topicity) as in the Seebachꢁs case of lactic acid [7b].
Figure. Stereochemical models A and B for the alkylation of Li-enolates derived from 2 and 6, respectively: effect
of the adjacent prochiral center
The three compounds 3, 4, and 7 were then treated with Grubbs catalyst 8 [2] to
afford the spirocyclic derivatives 9 ± 11 (Scheme 2). The cyclohexene derivative 9 was
obtained in 90% yield when the reaction was run with 2 mol-% of catalyst at room
temperature in benzene. As expected, a cis/trans 2.0 :1 mixture of isomers was formed
since cis/trans-3 was used. Surprisingly, 10 was isolated in 65% yield as a single
diastereoisomer when the reaction was performed in refluxing CH Cl with 10 mol-%
2
2
7
of catalyst and a trans/cis (2.5 :1) mixture 4 ). The minor cis isomer was lost during this
process by decomposition. Finally, the substrate 7 gave the vinylcyclopentene
derivative 11 as a 60:40 mixture of diastereoisomers.
The utility of this approach was demonstrated by a formal synthesis of (À)-quinic
acid (Scheme 3), a ubiquitous natural product that plays an important regulating role in
8
the shikimate pathway ). Double alkylation of (R)-1 (80% ee) gave the diene (2R,5S)-
3
in 51% yield after separation of the diastereoisomer by chromatography. The diene
(2R,5S)-3 afforded diastereoisomerically pure (2R,5S)-9 in 94% yield upon treatment
with 2 mol-% of 8. Treatment of (2R,5S)-9 with methanolic HCl gave the ester (S)-12,
which was saponified and treated with Br to afford the product of bromolactonization
2
6)
7)
8)
The alkylation was performed with pure trans-6. Attempts to deprotonate cis-6 led mainly to decomposition
products.
For early examples of enyne metathesis catalyzed by a tungsten carbene, see [11]. Ruthenium-catalyzed
enyne metathesis has been reported; for pioneer examples, see [12].
For syntheses of racemic quinic acid, see [13]. For the synthesis of (À)-quinic acid, see [14]. Quinic acid has
been widely applied as chiral building block for the synthesis of natural products; for a review, see [15].

1
628
Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme 2
Scheme 3

Helvetica Chimica Acta ± Vol. 83 (2000)
1629
1
3 (89% ee after one recrystallization). Conversion of 13 to (À)-quinic acid has already
been reported [13c].
Conclusions. ± We have presented here an efficient synthesis of cyclic non-racemic
1-hydroxycycloalkene-1-carboxylic-acid derivatives. The absolute configuration at C(1)
can be preestablished by the choice of the starting enantiomer of 1 or by the sequence
of the alkylations. This approach is particularly flexible and should be applicable to a
wide range of biologically relevant compounds.
We are very grateful to the Swiss National Science Foundation and to the Office F e d e ral pour lꢀEducation et
la Science (Projet COST-D12) for funding. V.B. was generously supported by a Bourse de la Conf e d e ration
Suisse.
Experimental Part
2 2 2 2 2
1. General. THF was freshly distilled from K under N , CH Cl and benzene from CaH under N . Flash
column chromatography (FC): Merck silica gel 60 (70 ± 230 mesh). Low-pressure flash chromatography (LP-
ꢂ
FC): Lobar , Merck, LiChroprep Si 60 (40 ± 63 mm). TLC: Merck silica gel 60 F254 anal. plates; detection by UV,
I
2
, or spraying with a soln. of phosphomolybdic acid (25 g), Ce(SO
4 2 2 4
) ´ 4H O (10 g), conc. H SO soln. (60 ml),
and H O (940 ml) with subsequent heating. GC: diastereoselectivity measurements by means of a column
2
Macherey-Nagel Optima-1701, if not stated otherwise; enantiomer-excess measurements by means of a chiral
column 6-TBDMS-2,3-DiAc g-cyclodextrine, 65% cyclodextrine in OV 1701. M.p.: not corrected; Reicher
À1
Thermovar Kofler hot-stage apparatus. IR Spectra: Perkin-Elmer Mattson Unicam 500 16PC FT-IR; nÄ in cm
.
1
13
1
NMR Spectra: Varian Gemini 200 (200 ( H) and 50.3 MHz ( C)), Bruker AM 360 (360 ( H) and 90.55 MHz
1
3
1
13
(
C)), Bruker Avance DRX-500 (500 ( H) and 125.76 MHz ( C)); d(H) in ppm rel. to CHCl
d(C) in ppm rel. to CDCl , unless otherwise stated;
(ˆ 77.0 ppm); coupling constants J in Hz in CDCl
multiplicities by APT sequence. NOE: irradiated signal ! affected signal (%). MS: Vaccum Generators
Micromass VG70/70E DS 11-250; EI (70 eV), CI (CH ) gas; in m/z (%); FAB: matrix 3-nitrobenzyl alcohol
NBA); Xe bombardment (8 kV, 1 mA).
. Lithium Diisopropylamide (LDA) Solution. To a soln. of (i-Pr)
at 08 under N , 2.5m BuLi in hexane (40.0 ml, 0.1 mol) was added, and the soln. was stirred for 10 min. This 1m
LDAsoln. was stored in a refrigerator and used within 2 weeks.
. Alkylation of 1: General Procedure 1. To 1m LDA(6.0 ml, 6.0 mmol) in THF (5.0 ml) containing HMPA
1.0 ml) at À788 under N , a soln. of 1 (790 mg, 5.0 mmol) in THF (5.0 ml) was added slowly. After stirring for
5 min, a soln. of the electrophile (5.0 mmol) in THF (5.0 ml) was added, and the soln. was allowed to warm up
to r.t. within 2 h. Sat. NaHCO soln. (10 ml) was added, the aq. layer was extracted with Et
3
(ˆ 7.26 ppm) and
13
3
3
C
4
(
2
2
NH (14.1 ml, 0.1 mol) in THF (45.9 ml)
2
3
(
2
1
3
2
O (3 Â 30 ml), the
3 4
soln. and brine, dried (MgSO ), and evaporated. The crude
combined org. phase was washed with sat. NaHCO
mixture was purified by FC.
4
. (Æ)-2-(tert-Butyl)-2-methyl-5-(prop-2-enyl)-1,3-dioxolan-4-one (2). According to GP 1, from (Æ)-1
(
790 mg, 5.0 mmol), LDA(10.0 ml, 10.0 mmol), and 3-bromoprop-1-ene (1.20 g, 10.0 mmol). FC ( Ac OEt/
hexane, 1:20) gave trans/cis-2 3 :1 (804 mg, 81%). IR (Film); 2978, 2966, 1795, 1380, 1253, 1211, 1151, 953. CI-
‡
MS: 199 (100, [M ‡ 1] ), 141 (22), 101 (12), 99 (16), 83 (38). Anal. calc. for C11
18 3
H O (198.27): C 66.64, H 9.15;
found: C 66.28, H 9.43.
1
trans-2: H-NMR (360 MHz): 5.78 (m, CHˆCH
2
); 5.13 (m, CHˆCH
2
); 4.4 (dd, J ˆ 4.9, 6.2, HÀC(5)); 2.48
(
m, CH
2
CHˆCH
2
); 1.45 (s, Me); 0.99 (s, t-Bu). NOE (500 MHz): 4.4 (HÀC(5)) ! 0.99 (6.2%); 1.45 (Me) !
1
3
2
4
.48 (1.0%); 0.99 (t-Bu) ! 4.4 (1.0%). C-NMR (50.3 MHz): 172.6 (s); 131.9 (d); 119.1 (t); 116.2 (s); 75.6 (d);
0.1 (s); 36.9 (t); 24.3 (q); 22.5 (q).
1
cis-2: H-NMR (360 MHz): 5.8 (m, CHˆCH
2
); 5.2 (m, CHˆCH
); 1.46 (s, Me); 0.94 (s, t-Bu). C-NMR (50.3 MHz): 172.4 (s); 132.3 (d); 118.4 (t); 115.3 (s);
3.1 (d); 37.8 (s); 35.2 (t); 24.3 (q); 19.1 (q).
. (Æ)-5-(But-3-enyl)-2-(tert-butyl)-2-methyl-5-(prop-2-enyl)-1,3-dioxolan-4-one (3). According to GP 1,
from trans/cis 2 3 :1 (428 mg, 2.16 mmol), LDA(4.32 ml, 4.32 mmol) and 4-iodobut-1-ene (786 mg, 4.32 mmol).
2
); 4.37 (dd, J ˆ 4.5, 8, HÀC(5)); 2.5
1
3
(
7
m, CH
2
CHˆCH
2
5
FC (Et
2
O/hexane 1 :20) gave cis/trans-3 2 :1 (390 mg, 60%). IR (Film): 3080, 2079, 2879, 1790, 1643, 1485, 1379,
‡
1
153, 1068, 997, 929. CI-MS: 253 (34, [M ‡ 1] ), 167 (58), 153 (58), 135 (82), 125 (61), 101 (38), 83 (100), 55
24 3
(68). Anal. calc. for C15H O (252.36): C 71.39, H 9.59; found: C 71.41, H 9.76.

1
1
CH
(
(
630
Helvetica Chimica Acta ± Vol. 83 (2000)
1
trans-3: H-NMR (500 MHz): 5.85 ± 5.69 (m, 2 CHˆCH
H, CHˆCH ); 4.90 (dq, J ˆ 10.1, 1.7, 1 H, CHˆCH ); 2.51 (m, CH
CH ); 2.14 ± 2.06 (m, 1 H, CH CH CHˆCH ); 1.82 (ddd, J ˆ 14, 11.9, 4.9, CH
CHˆCH
ddd, J ˆ 14.0, 12.1, 4.9, CH CH ); 1.49 (s, Me); 0.94 (s, t-Bu). NOE (500 MHz): 2.51 (CH CHˆCH
0.72%); 1.82 (CH CH CH ) ! 0.94 (2.3%); 1.49 (Me) ! 2.51 (0.95%); 0.95 (t-
) ! 0.94 (1.8%); 1.72 (CH
2
); 5.20 ± 5.02 (m, CHˆCH
2
); 4.96 (dq, J ˆ 17.1, 1.7,
); 2.28 ± 2.26 (m, 1 H,
CH ); 1.72
) ! 1.49
2
2
2
CHˆCH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
3
Bu) ! 1.82 (0.14%), 1.72 (0.45). C-NMR (125.76 MHz): 175.1 (s); 137.8 (d); 131.9 (d); 119.8 (t); 115.3 (t);
1
15.1 (s); 81.0 (s); 40.9 (t); 39.1 (s); 34.9 (t); 27.2 (t); 25.2 (q); 23.4 (q).
1
cis-3: H-NMR (500 MHz): 5.93 ± 5.73 (m, 2 CHˆCH
2
); 5.20 ± 5.15 (m, CHˆCH
CHˆCH ); 2.20 ± 2.10 (m, CH CH
); 1.55 (s, Me); 1.05 (s, t-Bu). C-NMR (125.76 MHz): 175.1 (s); 137.6 (d); 131.7 (d); 119.7 (t); 115.4
t); 113.1 (s); 80.9 (s); 41.0 (s); 39.9 (t); 35.9 (t); 27.6 (t); 25.2 (q); 23.3 (q).
. 2-(tert-Butyl)-2-methyl-5-(prop-2-enyl)-5-(prop-2-ynyl)-1,3-dioxolan-4-one (4). According to GP 1,
2
); 4.95 (m, CHˆCH
2
);
2
(
(
.58 ± 2.52 (m, CH
m, CH CH
2
CHˆCH
2
); 2.34 ± 2.24 (m, CH
2
CH
2
2
2
2
CHCH ); 1.92 ± 1.75
2
1
3
2
2
6
from (Æ)-1 (400 mg, 2.01 mmol), LDA(4.04 ml, 4.04 mmol), and 3-bromoprop-1-yne (478 mg, 4.02 mmol).
FC (Et
2
O/hexane, 1 :20) gave trans/cis-4 2.5 :1 (280 mg, 70%). IR (Film): 3295, 2978, 2920, 2880, 1790, 1485,
‡
1
381, 1285, 1153, 925. CI-MS: 237 (50, [M ‡ 1] ), 179 (57), 151 (27), 137 (33), 109 (18); 101 (52), 83 (29), 69
(100), 57 (50). Anal. calc. for C14
H
20
O
3
(236.14): C 71.16, H 8.53; found: C 71.24, H 8.52.
); 5.27 ± 5.21 (m, CHˆCH
); 2.13 (t, J ˆ 2.7, CH CCH); 1.62 (s, Me); 1.01 (s, t-Bu). C-NMR
1
trans-4: H-NMR (500 MHz): 5.92 ± 5.80 (m, CHˆCH
2
2
); 2.68 (d, J ˆ 2.7,
13
CH
2
CCH); 2.67 ± 2.63 (m, CH
2
CHˆCH
2
2
(
(
125.76 MHz): 173.4 (s); 130.9 (s); 120.8 (t); 115.7 (s); 80.1 (s); 78.5 (s); 72.6 (s); 40.5 (t); 39.1 (s); 27.4 (t); 25.1
q); 23.1 (q).
cis-4: H-NMR (500 MHz): significant peaks 1.52 (s, Me); 1.03 (s, t-Bu). 13C-NMR (125.76 MHz): 130.9 (s);
1
4
1 (s); 27.2 (s).
7
. Ethyl 3-Ethenyl-2-hydroxypent-4-enoate (5). Asoln. of 5-bromopenta-1,3-diene (2.0 g, 13.6 mmol) in
THF (5.0 ml) was added to a suspension of Zn (890 mg, 13.6 mmol) and AlCl (1.8 g, 13.6 mmol) in THF
. After stirring for 15 min, a soln. of ethyl glyoxylate (1.38 g, 13.86 mmol) in THF
5.0 ml) was added, and the mixture was stirred for 8 h until all starting material was consumed. Then, the
Cl soln. (10.0 ml) and extracted with Et
O (3 Â 40 ml). The combined org.
phase was washed with brine, dried (MgSO ), and evaporated, and the crude product was purified by FC
3
(
(
32.0 ml) at r.t. under N
2
mixture was poured into sat. NH
4
2
4
(
1
hexane/AcOEt 4 :1): 5 (1.20 g, 52%). Pale yellow oil. IR (Film): 3501, 3080, 2982, 2937, 2936, 2935, 1737, 1639,
1
371, 1255, 1250, 1109. 922. H-NMR (360 MHz): 5.87 ± 5.78 (m, 2 CHˆCH
2
); 5.18 ± 5.11 (m, 2 CHˆCH
2
); 4.2
O).
(
m, CHOH, MeCH
2
O); 3.18 ± 3.17 (m, CH(CHˆCH
2
)
2
); 2.85 (d, J ˆ 6.1, OH); 1.27 (t, J ˆ 5, MeCH
2
1
3
C-NMR (50.3 MHz): 173.424 (s); 136.48 (s); 134.7 (s); 117.76 (s); 116.91 (s); 73.54 (s); 61.59 (s); 51.92 (s); 14.2
‡
‡
(
(
s). CI-MS: 171 (4, [M ‡ 1] ), 170 (36, M ), 152 (11), 151 (5), 142 (3), 124 (14), 123 (8), 122 (5), 106 (10), 102
6), 96 (35), 80 (12), 78 (30), 77 (7), 68 (27), 67 (54), 66 (100), 54 (24). Anal. calc. for C (170.21): C 63.51,
9
14 3
H O
H 8.29; found: C 62.95, H 7.99.
. 2-(tert-Butyl)-5-(1-ethenylprop-2-enyl)-1,3-dioxolan-4-one (6). Amixture of 5 (2.0 g, 11.76 mmol), 2,2-
dimethylpropanal (4.0 g, 94.08 mmol), TsOH (50 mg), and 1 drop of conc. H SO soln. in pentane (20 ml) was
heated under reflux with azeotropic removal of H O. After completion of the reaction (overnight), the soln. was
washed with H O, dried (MgSO ), and evaporated. The crude product was purified by FC (pentane/Et O 20 :1):
8
2
4
2
2
4
2
cis/trans-6 1 :1 (1.60 g, 65%). IR (Film): 3583, 3084, 2976, 2910, 2876, 1799, 1485, 1363, 1201, 1103. CI-MS: 211
‡
(
(
42, [M ‡ 1] ), 194 (7), 193 (57), 189 (4), 183 (9), 175 (8), 171 (19), 167 (7), 166 (27), 152 (25), 147 (12), 142
‡
‡
11), 137 (68), 126 (12), 124 (100), 114 (16). HR-MS: 211.13261 (C12
H
19
O
3
, [M ‡ 1] ; calc. 211.13286).
1
trans-6: H-NMR (500 MHz): 5.97 ± 5.83 (m, 2 CHˆCH
2
); 5.27 ± 5.25 (m, HÀC(2), 2 CHˆCH
2
); 4.45 ±
1
3
4
(
.44 (dd, J ˆ 3.35, 1.6, HÀC(5)); 3.31 ± 3.25 (m, CH(CHˆCH
2 2
) ); 0.94 (s, t-Bu). C-NMR (126.76 MHz): 172
s); 135.4 (s); 132.5 (s); 119.2 (s); 118.1 (s); 111.4 (s); 78.1 (s); 50.3 (s); 23.1 (s).
1
cis-6: H-NMR (500 MHz): 5.99 ± 5.82 (m, 2 CHˆCH
2
); 5.25 ± 5.16 (m, 2 CHˆCH
); 0.98 (s, t-Bu). C-NMR
126.76 MHz): 172 (s); 135.9 (s); 134.2 (s); 121 (s); 119 (s); 109.6 (s); 78.3 (s); 48.7 (s); 24 (s).
. 2-(tert-Butyl)-5-(1-ethenylprop-2-enyl)-5-(prop-2-enyl)-1,3-dioxolan-4-one (cis-7). According to GP 1,
without HMPA, from trans-6 (250 mg, 1.141 mmol), LDA(2.28 ml, 2.28 mmol), and 3-bromoprop-1-ene
2
); 5.1 (d, J ˆ 1.3,
13
HÀC(2)); 4.36 ± 4.34 (dd, J ˆ 3.27, 1.37, HÀC(5)); 3.36 ± 3.32 (m, CH(CHˆCH
2 2
)
(
9
(
552 mg, 6.45 mmol). FC (hexane/AcOEt 20 :1) gave cis-7 (155 mg, 53%) as a single diastereoisomer. IR
(
Film): 3583, 3082, 2978, 2963, 2936, 2910, 2876, 1796, 1484, 1409, 1365, 1198, 1152, 1085, 1045, 996, 973, 922.
1
H-NMR (500 MHz): 5.88 ± 5.84 (m, 3 CHˆCH
m, CH(CHˆCH ); 2.64 ± 2.59 (ddt, J ˆ 14.18, 7.3, 1.2, 1 H, CH
.2, 1 H, CH ); 1.0 (s, t-Bu). NOE (500 MHz): 5.16 (HÀC(2)) ! 2.64 ± 2.49 (1.2%); 2.64 ± 2.59
CHˆCH
CH ) ! 5.16 (HÀC(2), 2.7%); 2.54 ± 2.49 (CH CHˆCH ) ! 5.16 (HÀC(2), 2.6%); 1.0 (t, Bu) ! 3.1
CHˆCH
2
); 5.2 ± 5.13 (m, 3 CHˆCH
2
,
HÀC(2)); 3.19
(
1
(
2
)
2
2
CHˆCH ); 2.54 ± 2.49 (ddt, J ˆ 12.99, 7.3,
2
2
2
2
2
2
2

Helvetica Chimica Acta ± Vol. 83 (2000)
1631
(
CH(CHˆCH
2
)
2
), 0.1%), 5.8 (CH(CHˆCH
2 2
)
), 0.6%). 13C-NMR (125.7 MHz): 173 (s); 135.4 (s); 134.5 (s);
1
1
1
31.1 (s); 120.8 (s); 119.5 (s); 118.6 (s); 108.9 (s); 84 (s); 53.5 (s); 38.4 (s); 34.5 (s); 24.5 (s). CI-MS: 251 (9, [M ‡
‡
] ), 239 (9), 233 (3), 205 (9), 180.9 (6), 164 (11), 154 (14), 152 (2), 146 (3), 137 (8), 136 (100), 120 (6), 118 (10).
14 (39), 94 (10), 80 (10), 68 (5), 66 (7). Anal. calc. for C15 (250.34): C 71.97, H 8.86; found: C 71.93, H 8.94.
0. 2-(tert-Butyl)-2-methyl-1,3-dioxaspiro[4.5]dec-7-en-4-one (9). To a soln. of cis/trans-3 2 :1 (225 mg,
.90 mmol) in dry benzene (10.0 ml), 8 (2 mol-%, 15.0 mg, 0.02 mmol) was added at r.t. and stirred overnight.
22 3
H O
1
0
After evaporation, the crude product was purified by FC (AcOEt/hexane 1 :10): cis/trans-9 2 :1 (200 mg, 98%).
‡
IR (Film): 2976, 2967, 2933, 1790, 1485, 1379, 1286, 1265, 1153, 1089, 1028, 929. CI-MS: 225 (100, M ), 199 (12),
1
20 3
67 (50), 139 (38), 125 (31), 101 (53), 97 (83), 79 (48), 57 (63). Anal. calc. for C13H O (224.303): C 69.61,
H 8.99; found: C 69.47, H 9.04.
1
cis-9: H-NMR (500 MHz): 5.86 ± 5.82 (m, CHˆCH); 5.66 ± 5.62 (m, CHˆCH); 2.59 ± 2.57 (m, 1 H); 2.33 ±
.21 (m, 3 H); 1.93 ± 1.89 (m, 2 H); 1.56 (s, Me); 1.03 (s, t-Bu). 13C-NMR (125.76 MHz): 175.8 (s); 127.3 (d);
22.5 (d); 115.3 (s); 38.9 (s); 35.4 (t); 29.8 (t); 25.0 (q); 23.4 (q); 21.6 (t).
2
1
1
trans-9: H-NMR (500 MHz); 5.84 ± 5.75 (m, CHˆCH); 5.64 ± 5.60 (m, CHˆCH); 2.61 ± 2.50 (m, 1 H);
1
3
2
.32 ± 2.18 (m, 3 H); 1.98 ± 1.87 (m, 2 H); 1.55 (s, Me); 1.00 (s, t-Bu). C-NMR (125.76 MHz): 175.7 (s); 126.7
(
d); 123.0 (d); 114.9 (s); 39.1 (s); 34.0 (t); 31.2 (t); 25.0 (q); 23.4 (q); 21.7 (t).
1. 2-(tert-Butyl)-7-ethenyl-2-methyl-1,3-dioxaspiro[4.4]non-7-en-4-one (trans-10). To a soln. of trans/cis-4
.5 :1 (101 mg, 0.45 mmol) in dry CH Cl (4.0 ml), 8 (10 mol-%, 37.0 mg, 0.045 mmol) was added at r.t. The soln.
1
2
2
2
was heated under reflux for 8 days. After evaporation, the crude product was purified by FC (AcOEt/hexane
1
1
:10): trans-10 (80 mg, 65%) as a single diastereoisomer. IR (Film): 2976, 2967, 2933, 1790, 1485, 1379, 1286,
1
265, 1153, 1089, 1028, 929. H-NMR (500 MHz): 6.50 (dd, J ˆ 10.6, 17.4, CHˆCÀCHˆCH
2
); 5.67 ± 5.66
); 3.13 ± 3.07
(
(
(
(
m, CHˆCÀCHˆCH
2
); 5.12 (d, J ˆ 10.6, 1 H, CHˆCH
2
); 5.05 (d, J ˆ 17.4, 1 H, CHˆCH
2
1
3
m, 2 H); 2.84 ± 2.80 (m, 2 H); 1.55 (s, Me); 1.00 (s, t-Bu). C-NMR (125.76 MHz): 176.8 (s); 139.6 (s); 132.7
‡
d); 126.8 (d); 119.6 (s); 115.5 (t); 84.5 (s); 45.7 (t); 45.3 (t); 38.8 (s); 24.8 (q); 22.5 (q). CI-MS: 237 (2, M ), 179
8), 165 (11), 151 (13), 137 (100), 119 (19), 101 (71), 91 (9), 79 (9), 57 (13). Anal. calc. for C14
20 3
H O (236.314):
C 71.16, H 8.53; found: C 71.45, H 8.55.
2. 2-(tert-Butyl)-6-ethenyl-1,3-dioxaspiro[4.4]non-7-en-4-one (11). Asoln. of 7 (130 mg, 0.52 mmol) and 8
3 mol-%, 5.0 mg, 0.018 mmol) in dry CH Cl (7.5 ml) was stirred at r.t. for 6 h. The solvent was evaporated, and
1
(
2
2
the crude product was purified by FC (hexane/AcOEt 20 :1): 11 (100 mg, 87%) as a non-separable 66 :34
mixture of diastereoisomers. IR (Film): 3565, 3510, 3474, 3453, 3438, 3427, 3414, 3405, 3395, 3384, 3376, 3362,
1
3
341, 3253, 2965, 2940, 2910, 2877, 1793, 1733, 1484, 1465, 1409. H-NMR (500 MHz): 5.90 ± 5.65 (m, CHˆCH
2
,
CHˆCH); 5.20 ± 5.11 (m, CHˆCH
2
, HÀC(2)); 3.8 (m, CHCHˆCH , min.); 2.92
CHˆCH); 1.0 (s, t-Bu). C-NMR (125.7 MHz): 176.1 (s, min.); 174.0
s, maj.); 135.0 (s, min.); 134.5 (s, maj.); 132.3 (s, maj.); 131.8 (s, min.); 127.5 (s, min.); 127.1 (s, maj.); 117.8 (d);
2
, maj.); 3.65 (m, CHCHˆCH
2
1
3
(
(
m, 1 H, CH
2
CHˆCH); 2.88 (m, 1 H, CH
2
1
3
1
1
08.7 (d); 87.6 (s, maj.); 86.7 (s, min.); 60.1 (s, min.); 57.1 (s, maj.); 42.4 (s, min.); 41.9 (s, maj.); 34.8 (s, maj.);
‡
‡
4.6 (s, min.); 24.0 (s, maj.); 23.8 (s, min.). CI-MS: 223 (28, [M ‡ 1] ), 222 (6, M ), 205 (15), 186 (21), 178 (9),
76 (5), 164 (26), 158 (4), 152 (6), 148 (10), 137 (9), 136 (100), 135 (11), 134 (4), 120 (14), 118 (29), 114 (10),
08 (30), 107 (20), 92 (40), 86 (28), 80 (32), 79 (81), 78 (9). Anal. calc. for C13
18 3
H O (222.28): C 70.24, H 8.16;
found: C 70.20, H 8.18.
3. Synthesis of (À)-Quinic acid. (2R,5S)-5-(But-3-enyl)-2-(tert-butyl)-2-methyl-5-(prop-2-enyl)-1,3-diox-
olan-4-one ((2R,5S)-3). According to GP 1, from (R)-1 (800 mg, 5.1 mmol; 80% ee), LDA(10.2 ml,
0.2 mmol), and 4-iodobut-1-ene (3.8 mg, 20.4 mmol). FC (Et O/hexane 1:20) gave (2R)-2 (730 mg, 67%) as
1
1
2
a trans/cis 3 :1 diastereoisomer mixture. To this diastereoisomer mixture (993 g, 4.7 mmol) in THF (3.0 ml) at
À788, 0.5m KHMDS in toluene (19.0 ml, 9.5 mmol) was added slowly. After 30 min, a soln. of 3-bromoprop-1-
ene (1.20 ml, 14.1 mmol) in THF (3.0 ml) was added. The resultant mixture was allowed to warm to r.t.
overnight, then treated with sat. NaHCO
org. phase was washed with sat. NaHCO
purified by FC (Et O/hexane 1:20): 3 (950 mg, 80%) as a cis/trans 2 :1 diastereoisomer mixture. Separation of
the diastereoisomers was performed by LP-FC (Et
.13, CH Cl
). IR, NMR, and CI-MS: identical with those of (Æ)-trans-3.
2R,5S)-2-(tert-Butyl)-2-methyl-1,3-dioxaspiro[4.5]dec-7-en-4-one ((2R,5S)-9). As described for racemic 9
see above), from (2R,5S)-3 (195 mg, 0.77 mmol) in dry benzene (5.0 ml) and 8 (2 mol-%, 13.0 mg, 0.02 mmol).
3
soln. (10.0 ml), and extracted with Et
2
O (3 Â 30 ml). The combined
3
soln., dried (MgSO ), and evaporated, and the crude product was
4
2
2
0
2
O/hexane 1:40): (2R,5S)-3 in 51% yield. [a]
D
ˆ À16.3 (c ˆ
1
2
2
(
(
2
0
FC (AcOEt/hexane 1:20) gave (2R,5S)-9 (162 mg, 94%). [a]
CI-MS: identical with those of (Æ)-trans-9.
D
ˆ À14.05 (c ˆ 1.31, CH
2 2
Cl ). IR, NMR, and
Methyl (S)-1-Hydroxycyclohex-3-enecarboxylate ((S)-12). Anh. HCl was bubbled through a soln. of
2R,5S)-9 (136 mg, 0.61 mmol) in abs. MeOH (5.0 ml) for 2 min, and the soln. was heated under reflux
(

1
632
Helvetica Chimica Acta ± Vol. 83 (2000)
overnight. After cooling to r.t., solid NaHCO
The solvent was evaporated, and the residue was dissolved in H
CH Cl
(3 Â 20 ml), the combined org. phase was washed with sat. NaHCO
3
was added, and the heterogeneous soln. was stirred for 10 min.
O (10 ml). The aq. phase was extracted with
soln. and brine, dried (MgSO ), and
2
2
2
3
4
evaporated, and the crude product was purified by FC (AcOEt/hexane 1:10): (S)-12 (94 mg, 98%). Colorless
2
0
1
oil. [a]
5
D
ˆ ‡20.11 (c ˆ 0.92, CH
2
Cl
2
) and 80% ee (GC, 808). H-NMR (500 MHz): 5.80 ± 5.77 (m, CHˆCH);
.67 ± 5.62 (m, CHˆCH); 3.79 (s, CO
2 2 2
Me); 3.0 (s, OH); 2.63 ± 2.57 (m, 1 H, CH CH ); 2.36 ± 2.27 (m, 1 H,
CH
2
CH
CH
2
); 2.15 ± 2.07 (m, CH
2
CHˆCH); 1.97 ± 1.91 (m, 1 H, CH
2
CH
2
CHˆCH); 1.8 ± 1.76 (m, 1 H,
1
3
CH
2
2
CHˆCH). C-NMR (125.76 MHz): 177.6 (s); 126.7 (d); 123.1 (d); 72.7 (s); 53.1 (q); 35.3 (t); 31.0
‡
(
t); 21.7 (t). IR (Film): 3497 (br., OH), 2980, 2931, 1728, 1447, 1255, 1221, 1095, 1043. CI-MS: 157 (72, [M ‡ 1] ),
1
8 12 3
39 (100), 125 (9), 107 (9), 97 (43), 79 (93), 67 (4), 54 (4). Anal. calc. for C H O (156.183): C 61.52, H 7.74;
found: C 61.28, H 7.73.
-Bromo-1-hydroxy-6-oxabicyclo[3.2.1]octan-7-one (13). To a soln. of (S)-12 (120 mg, 0.76 mmol) in
MeOH (6.0 ml), 1m NaOH (1.0 ml, 0.91 mmol) was added at r.t. and stirred for 3 h. After evaporation, the white
residue was dissolved in H O (4.0 ml), and Br (0.08 ml, 1.52 mmol) was added. After 3 h at r.t., the mixture was
extracted with CH Cl SO soln. and brine, dried
(3 Â 15 ml), the combined org. phase was washed with sat. Na
MgSO
Pale yellow oil. [a]
4
2
2
2
2
2
3
(
4
), and evaporated, and the crude product was purified by FC (AcOEt/hexane 1:5): 13 (120 mg, 65%).
2
0
1
D
ˆ À9.12 (c ˆ 1.36, CH
2
Cl
2
) and 82% ee (GC, 1808). H-NMR (500 MHz): 4.84 (ddd, J ˆ
0
1
1
.84, 4.21, 6.2, CHO); 4.34 (t, J ˆ 4.7, CHBr); 2.98 (s, OH); 2.84 (d, J ˆ 11.9, 1 HÀC(8)); 2.48 (dd, J ˆ 6.2, 11.8,
13
HÀC(8)); 2.40 ± 2.13 (m, 3 H, CH
2 2 2 2
CH CHBr); 1.83 ± 1.79 (m, 1 H, CH CH CHBr). C-NMR (125.76 MHz):
78.0 (s); 77.8 (d); 43.5 (d); 38.9 (t); 28.7 (t). Spectral data in accordance with [13c].
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Received March 28, 2000