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B. Schmidt, L. Staude / Journal of Organometallic Chemistry 691 (2006) 5218–5221
alcohol 8 with slightly lower diastereoselectivity (de 94%)
compared to camphor. O-allylation of 8 to yield allyl ether
9 turned out to be surprisingly difficult: even with eight
equivalents of NaH and three equivalents of allyl bromide
in refluxing THF only a mediocre yield of 9 was obtained
after 12 h. This is probably caused by strong steric hin-
drance due to the cis-arrangement of isopropyl and
hydroxy group in alcohol 8. A remarkable difference is also
observed in the reactivity in the RCM step. RCM of 9 was
directly conducted under the conditions required for the
Tandem sequence and resulted in a yield of 48%, whereas
the camphor analogue 4 was obtained in quantitative yield.
The reduced yield probably also reflects the strong steric
hindrance involved in the formation of spirocycle 10. With
respect to the experiences made in the camphor series we
were surprised to see that 9 under the conditions of proto-
col C is converted to enol ether 11 without formation of
any tetrahydropyran byproduct, even if the reaction is con-
ducted at 110 °C (Scheme 4).
i
ii
OH
O
O
7
8
9
iv
iii
O
O
11
10
Scheme 4. Reagents and conditions: (i) H2C@CHCH2MgBr, Et2O, ꢀ20 °C
(94%); (ii) NaH, allyl bromide, THF, 65 °C, 12 h (41%); (iii) A (5 mol%),
toluene, 40 °C (48%); (iv) A (5 mol%), toluene, 40 °C, then add 2-propanol
and NaOH (25 mol%), 110 °C for 10 h (57%).
Having established the routes to enantiopure spirocyclic
dihydropyrans 6 and 11,1 we undertook first attempts to
1
Representative procedures and analytical data.
evaluate the concept outlined in Scheme 2. To this end,
methyl glycolate was bound to 6 in the presence of a
Brønsted acid. In initial experiments, a catalytic amount
of para-toluene sulfonic acid was used. NMR-spectro-
scopic analysis of the reaction mixture revealed the pres-
ence of an aldehydic byproduct, which obviously did not
contain any glycolate. An additional signal in the olefinic
region suggests that structure 12 is assigned to this product.
The required acetal 13 was eventually obtained by using the
milder acid pyridinium para-tosylate (PPTS). No rear-
rangement product 12 could be detected in this case, the
mediocre yield of 57% might be attributed to decomposi-
tion of the acetal during column chromatography. We were
furthermore pleased to see that exclusively the equatorially
substituted product is formed during acetal formation.
This structural assignment is based on the observation of
a large coupling constant of 9.6 Hz for the acetal proton.
The methylene protons of the –OCH2CO2Me-group, which
are now diastereotopic, are separated by more than
0.1 ppm, indicating that the chemical surrounding is obvi-
ously quite different. In an attempt to stereoselectively
functionalize this compound, it was lithiated with
LiHMDS and subsequently treated with MeI. NMR-anal-
ysis of the reaction mixture shows that there is a moderate
face differentiating effect of the camphor-derived auxiliary,
with two diastereomeric lactates 14 being formed in a 2:1
ratio. The two quartets observed for the –CHMe– proton
are baseline separated in the 400 MHz-1H NMR-spectrum
(chemical shift difference 0.16 ppm), which might suggest
future use of 6 as a covalently bound shift reagent for alco-
hols (Scheme 5).
Tetrahydropyran 5. To a solution of diene 3 (0.40 g, 1.7 mmol) in
toluene (20 mL) was added catalyst A (70 mg, 5 mol%). The solution was
heated to 40 °C until the starting material was fully consumed (TLC), then
2-propanol (1.7 mL) and NaOH (17 mg, 0.4 mmol) were added. The
mixture was heated to reflux for 3.5 h. The organic layer was diluted with
MTBE, washed with water, dried with MgSO4, filtered and evaporated.
The solvent was removed in vacuo, and the residue was purified by flash
1
chromatography to give 5 (251 mg, 71%). H NMR (400 MHz, CDCl3) d
3.55 (dm, 11.8 Hz, 1H), 3.46 (ddd, 11.6 Hz, 11.3 Hz, 11.3 Hz, 1H), 2.07
(ddd, 12.8 Hz, 7.3 Hz, 3.8 Hz, 1H), 1.76–1.61 (3H), 1.57–1.24 (7H), 1.15
(d, 12.8 Hz, 1H), 1.02 (s, 3H), 0.92 (ddd, 12.0 Hz, 9.0 Hz, 5.5 Hz, 1H), 0.82
(s, 3H), 0.79 (s, 3H); 13C NMR (100 MHz, CDCl3) d 82.7 (0), 60.3 (2), 52.6
(0), 48.9 (0), 45.4 (1), 39.4 (2), 31.8 (2), 30.0 (2), 27.0 (2), 25.7 (2), 21.4 (3),
20
21.2 (2), 20.9 (3), 10.5 (3); ½aꢁD ꢀ64.3 (c 0.90, CH2Cl2); HRMS (EI)
calculated for C14H24O (M+) 208.1827, found: 208.1811; IR (film, KBr) m
2933 (s), 2856 (m) cmꢀ1
.
Dihydropyran 6: To a solution of 3 (500 mg, 2.1 mmol) in toluene
(20 mL) was added catalyst A (175 mg, 10 mol%) and the solution was
heated to 50 °C until the starting material was fully consumed (TLC).
Subsequently, NaH (43 mg, 60% dispersion in mineral oil, 1.1 mmol) is
added and the mixture is heated to reflux for 12 h. Workup was done as
described above for 5. Compound 6 was obtained as a colourless liquid
(430 mg, 98%). 1H NMR (400 MHz, CDCl3) d 6.23 (dm, 6.0 Hz, 1H), 4.62
(m, 1H), 2.16–1.98 (3 H), 1.75–1.60 (4H), 1.51–1.35 (2H), 1.25 (d, 13.3 Hz,
1H), 1.09 (s, 3 H), 0.98 (m, 1H), 0.88 (s, 3H), 0.85 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 142.0 (1), 99.6 (1), 84.1 (0), 52.2 (0), 49.5 (0), 45.0 (1),
20
44.7 (2), 30.1 (2), 27.5 (2), 27.1 (2), 21.5 (3), 21.2 (3), 18.4 (2), 10.8 (3); ½aꢁD
ꢀ40 (c 1.15, CH2Cl2); HRMS (EI) calculated for C14H22O (M+) 206.1671,
found 206.1648; IR (film, KBr) n 3058 (m), 2930 (s), 2846 (s), 1654 (s)
cmꢀ1
.
Dihydropyran 11. Following the procedure given above for 5, diene 9
(0.40 g, 1.7 mmol) was converted to 11 (199 mg, 57%). 1H NMR (400 MHz,
C6D6) d 6.35 (dm, 6.1 Hz, 1H), 4.52 (ddm, 6.0 Hz, 5.9 Hz, 1H), 2.18 (dm,
13.4 Hz, 1H), 2.11 (dseptett, 6.9 Hz, 2.2 Hz, 1H), 2.05–1.92 (2H), 1.86–1.69
(4H), 1.51–1.44 (m, 1H), 1.03 (d, 6.9 Hz, 3H), 1.02–0.92 (2H), 0.91 (d,
7.0 Hz, 3H), 0.84 (d, 6.4 Hz, 3H), 0.85 (m, 1H); 13C NMR (100 MHz, C6D6)
d 142.6 (1), 98.9 (1), 76.9 (0), 50.6 (1), 40.9 (2), 35.6 (2), 29.3 (2), 27.8 (1), 26.0
In conclusion, we describe the synthesis of two potential
chiral auxiliaries or reagents derived from camphor or
menthone, respectively. Key step is the Tandem RCM-
20
(1), 23.8 (3), 22.7 (3), 20.7 (2), 18.1 (3), 17.6 (2); ½aꢁD ꢀ5.1 (c 1.00, CH2Cl2);
HRMS (EI) calculated for C14H24O 208.1827 (M+), found: 208.1820; IR
(film, KBr) m 3058 (m), 2958 (s), 2857 (s), 1649 (s) cmꢀ1
.