Enantioselective synthesis of (-)-β-Santalol by a copper-catalyzed enynol cyclization-fragmentation reaction

Full text of DOI:10.1002/anie.200903449

Angewandte
Chemie
DOI: 10.1002/anie.200903449
Rearrangement Reactions
Enantioselective Synthesis of (ꢀ)-b-Santalol by a Copper-Catalyzed
Enynol Cyclization–Fragmentation Reaction**
Charles Fehr,* Iris Magpantay, Jeremy Arpagaus, Xavier Marquet, and Magali Vuagnoux
We report herein the first enantioselec-
tive, direct synthesis of the highly prized
natural sandalwood odorant (ꢀ)-b-san-
new synthesis of (ꢀ)-b-santalol ((ꢀ)-1). If enynol 2 could be
induced to preferentially undergo the cyclization–fragmenta-
tion to afford 3 (E or Z) with an exo-oriented enal side chain,
at the expense of the cyclopropanation product 4, this
transformation would open a new direct route to (ꢀ)-1
(Scheme 2).
[
1]
talol ((ꢀ)-1). The key step in the
synthesis is an efficient copper-catalyzed
rearrangement of an enynol.
The increasing scarcity of East
[2]
Indian sandalwood oil has motivated research chemists
over the last 40 years to develop a synthesis of the most
valuable component, (ꢀ)-b-santalol (ꢀ)-1, which makes up
[
1]
2
0–25% of the composition of the oil, or its racemate.
Despite extensive efforts, this excellent fragrance ingredient
is still not commercially available.
Recently, we reported the cost-efficient copper-catalyzed
cycloisomerization of 5-en-1-yn-3-ols (cyclopropanation/1,2-
[
3]
[4]
alkyl shift; Scheme 1, A!E) and related enynol esters.
Scheme 2. Projected cyclization–fragmentation reaction en route to
(ꢀ)-1.
The successful realization of this synthetic plan began with
a highly enantioselective and exo-selective Diels–Alder
reaction between cyclopentadiene and crotonaldehyde
(Scheme 3). Chiral amines have been employed as efficient
catalysts for enantioselective Diels–Alder reactions through
[
10]
the reversible formation of a dienophilic iminium salt. The
most impressive results in terms of enantioselectivity and exo
selectivity for the formation of 6 were reported by the
[
10a]
[10b]
Scheme 1. Enynol cycloisomerization pathways.
research groups of MacMillan,
ashi.
Maruoka,
and Hay-
[
10c]
[10c]
The system described by Hayashi et al.,
a con-
[
5]
These cyclopropanation reactions, which lead selectively to
complex polycyclic compounds, are generally catalyzed by
centrated two-phase system in water at 208C, is by far the
most practical. Hayashi et al. used catalyst 5 (5 mol%) and a
threefold excess of cyclopentadiene and obtained 6 (99% ee)
and 7 (99% ee) in a 72:28 ratio in 72% combined yield. When
we carried out the reaction under the same conditions, we
obtained 6 (96% ee) and 7 (77% ee) in a 72:28 ratio and 55%
combined yield. We were able to optimize this reaction by
using equimolar amounts of cyclopentadiene and crotonalde-
hyde and only 1.5 mol% of catalyst 5 (6 + 7: 61% yield; 6
[
6]
[7]
platinum or gold. During further studies on enynols of
type A, we discovered that a cyclization–fragmentation
pathway (Scheme 1, A!D) could compete with the cyclo-
propanation, and that [Cu(CH CN) ]BF was the reagent of
3
4
4
[
8]
choice for promoting this rearrangement, as opposed to Ag,
[7b]
[9]
Au, or Pt catalysts. These results prompted us to devise a
[
11]
(
95% ee)/7 (78% ee) 70:30). The use of just 1 mol% of 5
still led to the formation of 6 (94% ee) and 7 (80% ee) in a
[
+]
[*] Dr. C. Fehr, I. Magpantay, J. Arpagaus, X. Marquet, Dr. M. Vuagnoux
Firmenich SA, Corporate R&D Division
P. O. Box 239, 1211 Geneva 8 (Switzerland)
Fax: (+41)22-780-3334
6
9:31 ratio.
The cycloadducts 6 and 7 were hydrogenated as a mixture
to give the corresponding saturated alcohols, which were
converted into methyl carbonates and pyrolyzed to afford
E-mail: charles.fehr@firmenich.com
+
[
] Postdoctoral fellow at Firmenich SA (July 2007–June 2008).
[12,13]
hydrocarbons 8 and 9 in high overall yield.
Upon
8 underwent the
expected ene reaction to afford 2 after desilylation. However,
[
**] We thank Dr. S. Samanta and Prof. Y. Hayashi (Tokyo University of
Science (Japan)) for helpful advice concerning the Diels–Alder
reaction.
[
14]
treatment with trimethylsilylpropynal,
Angew. Chem. Int. Ed. 2009, 48, 7221 –7223
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7221

Communications
(
5 mol%) efficiently promoted the desired cyclization–frag-
[
16]
mentation reaction to afford the desired aldehyde 3 in high
yield with excellent chemoselectivity and face selectivity (3/4
9
[17]
[8]
8:2). The use of AgNO (10 mol%) and KNO (1 equiv)
3
3
also led to a selective reaction (3/4 99:1); however, the
reaction was slower (87% conversion after 8 h) and the yield
lower (64%).
The ee value of 3 could be increased to 97% through one
low-temperature crystallization (pentane). Finally, site-selec-
tive hydrogenation with Pd/CaCO , followed by a Wittig
3
reaction under the modified conditions described by Corey
and Yamamoto with hydroxyalkylation of the intermediate
[
18]
betaine
(
afforded the target (ꢀ)-1 (Z/E 97:3; 43%
[
19]
2 steps)), the sandalwood odor of which was excellent.
In conclusion, we have developed an efficient enantiose-
lective synthesis of (ꢀ)-b-santalol. The key step in the
synthesis consists of a highly selective copper-catalyzed
cyclization–fragmentation of an enynol. The scope and
generality of this novel methodology will be reported in due
course.
Experimental Section
6
and 7: A mixture of catalyst 5 (314 mg, 0.45 mmol), water (3.78 mL,
210 mmol), toluene (0.24 mL; internal standard), and crotonaldehyde
(95% trans; distilled and stored in the freezer; 2.10 g (2.46 mL),
30.0 mmol) was stirred at 208C for 5 min and then treated with freshly
prepared cyclopentadiene monomer (stored in a dewar containing dry
ice; 1.98 g (2.44 mL), 30.0 mmol). The two-phase system was stirred at
238C for 6 h, then cooled to 108C, treated with saturated aqueous
NaHCO solution (2.5 mL) and solid NaCl (100 mg), and stirred for
3
15 min. The two-phase system was separated, and the aqueous phase
was washed with pentane (3 mL). Concentration (08C, 50 mbar) and
bulb-to-bulb distillation (oven temperature 1008C, 4 mbar) afforded
a mixture of 6 and 7 (70:30; 2.07 g, 61%) with 88% purity. This
material, which contained traces of toluene, dicyclopentadiene, and
two unidentified products that may have originated from cis-
crotonaldehyde, was used for the ensuing hydrogenation.
Scheme 3. Reagents and conditions: a) Raney Ni (2%), 20 bar, 808C,
2
4 h (100%); b) ClCO Me (2 equiv), pyridine, toluene, 08C!RT, 1 h
2
(
90%); c) pyrolysis (4158C; quartz tube, 3 m; N stream; 90%);
2
d) TMSCCCHO (1.0 equiv with respect to 8), Me AlCl (1.0 equiv),
2
CH Cl , ꢀ208C (72%); e) K CO (10 equiv), MeOH (89%); f) H , 5%
(ꢀ)-3: [Cu(CH CN) ]BF (0.294 g, 0.93 mmol) was added to a
2
2
2
3
2
3
4
4
Pd/CaCO
3
(5%), MeOH/H
2
O (96:4), 4 h (85%); g) EtPPh
3
I
solution of 2 (3.24 g, 18.4 mmol) in 1,2-dichloroethane (100 mL) at
room temperature under nitrogen, and the resulting mixture was
stirred at 508C for 140 min. The dark-gray mixture was then cooled to
room temperature, filtered through a short pad of silica gel, and
concentrated under vacuum to give an orange oil (3.87 g). Bulb-to-
bulb distillation of this oil (oven temperature 1008C, 0.08 mbar)
afforded (ꢀ)-3 (3.12 g, 94%, 92% ee) with 98% purity (the impurity
corresponding to the remaining 2% was 4). Crystallization once from
(
1.1 equiv), BuLi (1.1 equiv), THF, ꢀ788C; then BuLi (1.2 equiv),
788C!08C; then paraformaldehyde (6 equiv), 08C!RT, 1 h (50%).
ꢀ
[
1
A] toluene, 708C, 1 h; [B] CH Cl , ꢀ108C, 2 h; [C] ClCH CH Cl, 508C,
2
2
2
2
40 min; [D] THF, H O, 708C, 8 h (87% conversion). TMS=trimethyl-
2
silyl.
9, which has a less accessible a hydrogen atom, underwent a
2
D
0
pentane at ꢀ788C afforded (ꢀ)-3 (2.79 g) with 97% ee. ½aꢁ
=
“
homoene reaction” exclusively to afford 10 after desilyla-
3
ꢀ1
ꢀ1
ꢀ2
ꢀ3
ꢀ
267.4 degcm g dm (CHCl , c = 1.06 ꢀ 10 gcm ).
[
15]
3
tion. The formation of 10 could be prevented completely by
1
H NMR (400 MHz, CDCl ): d = 9.52 (d, J = 7.8 Hz, 1H), 6.77 (d,
3
adapting the amount of trimethylsilylpropynal used to that of
J = 15.7 Hz, 1H), 6.09 (dd, J = 15.7, 7.8 Hz, 1H), 5.01 (s, 1H), 4.58 (s,
1H), 2.76 (br s, 1H), 2.18 (br s, 1H), 1.69–1.80 (m, 2H), 1.52–1.58 (m,
2H), 1.30–1.37 (m, 1H), 1.24–1.27 (m, 1H), 1.23 ppm (s, 3H).
8.
We tested Pt, Au, and Cu catalysis for the key cyclo-
isomerization reaction of enynol 2, which existed as one major
1
3
C NMR (100 MHz, CDCl ): d = 194.5 (d), 165.4 (d), 160.4 (s),
3
1
2
30.1 (d), 104.1 (t), 49.7 (s), 46.5 (d), 46.3 (d), 37.1 (t), 29.8 (t), 23.0 (t),
2.7 ppm (q).
and one minor diastereomer. PtCl catalysis led exclusively to
2
the undesired cyclopropane 4 in 88% yield. In the presence of
+
MS: m/z (%): 176 [M ] (23), 161 (71), 147 (63), 133 (75), 119 (62),
catalytic amounts of [PPh AuCl] and AgSbF , the cyclo-
3
6
105 (100), 91 (99), 79 (58), 77 (58), 39 (34).
isomerization leading to 4 was again favored (4/3 91:9).
Evidently, the AgCl formed in situ does not influence the
reaction course. In sharp contrast, [Cu(CH CN) ]BF
4
Received: June 25, 2009
Published online: August 24, 2009
3
4
7222
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7221 –7223

Angewandte
Chemie
Keywords: copper · cyclopropanes · enantioselectivity ·
fragrances · rearrangement
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3
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Angew. Chem. Int. Ed. 2009, 48, 7221 –7223
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7223