A formal, one-pot β-chlorination of primary alcohols and its utilization in the transformation of terpene feedstock and the synthesis of a C 2-symmetrical terminal bis-epoxide

Article abstract of DOI:10.1021/jo402422b

A one-pot transformation of alkan-1-ols into 2-chloroalkan-1-ols is described. As a practical application, terpene-derived primary alcohols were converted into semiochemicals such as olfactory lactones (aerangis lactone, whisky lactone, and cognac lactone) and pheromones (cruentol and ferrugineol). Using heptane-1,7-diol as a bifunctional substrate, the corresponding bis-epoxide was synthesized by bidirectional synthesis in good yield and high enantioselectivity.

Full text of DOI:10.1021/jo402422b

Article
pubs.acs.org/joc
A Formal, One-Pot β‑Chlorination of Primary Alcohols and Its
Utilization in the Transformation of Terpene Feedstock and the
Synthesis of a C2‑Symmetrical Terminal Bis-Epoxide
Jorg Swatschek,† Lydia Grothues,† Jonathan O. Bauer,‡ Carsten Strohmann,‡ and Mathias Christmann*,†
̈
†Institute of Chemistry and Biochemistry, Organic Chemistry, Freie Universitat Berlin, Takustrasse 3, 14195 Berlin, Germany
̈
‡Department of Chemistry and Chemical Biology, Technische Universitat Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund,
̈
Germany
S
* Supporting Information
ABSTRACT: A one-pot transformation of alkan-1-ols into 2-chloroalkan-1-ols is
described. As a practical application, terpene-derived primary alcohols were converted
into semiochemicals such as olfactory lactones (aerangis lactone, whisky lactone, and
cognac lactone) and pheromones (cruentol and ferrugineol). Using heptane-1,7-diol as a
bifunctional substrate, the corresponding bis-epoxide was synthesized by bidirectional
synthesis in good yield and high enantioselectivity.
this purpose, a mild oxidation protocol was sought that would
not interfere with the rather sensitive subsequent organo-
catalytic chlorination step. In this sense, harsh reaction
conditions and reactive stoichiometric byproducts from the
terminal oxidant were to be avoided. In 2011, Hoover and
Stahl18 reported a mild protocol for the Cu-catalyzed aerobic
oxidation19 of primary alcohols to aldehydes based on
INTRODUCTION
■
The conversion of biomass into high-value chemicals1 is a
central goal in catalysis.2 In recent years, terpenes have been
utilized increasingly as feedstock3 for the synthesis of
biologically active natural products,4 fragrance compounds,5
and fine chemicals.6 The key methodological challenge in this
approach is to achieve site-selective functionalization of the
terpene scaffold, thereby allowing for subsequent C−C
coupling reactions. To this end, our group has developed
protocols for the conversion of terpene aldehydes into the
corresponding 1,2-epoxides7 as well as an allylic substitution of
terpene acetates with vinyl nucleophiles to give 1,4-dienes.8
Taking advantage of both methods, we have assembled a major
part of ripostatin B’s polyketide backbone from two molecules
of geranyl acetate.9
pioneering work by Semmelhack,20 Marko,21 Sheldon,22 and
́
Koskinen.23 With water as the only stoichiometric byproduct,
we envisioned this protocol to be an ideal starting point for
telescoping an oxidation with subsequent organocatalytic
transformations.24 In a proof-of-concept study, we joined
Stahl’s oxidation conditions with a DMAP-catalyzed isomer-
ization and an organocatalytic Diels−Alder reaction,25 while
Jang et al. reported a similar oxidation in conjunction with an
organocatalytic Michael addition/oxyamination.26
Herein, we describe the development of a telescoped
oxidation−chlorination−reduction and its application to the
conversion of primary alcohols into enantioenriched 1,2-
epoxides and a C2-symmetrical terminal bisepoxide via
chlorohydrin intermediates. Using terpene-derived alcohols as
substrates has allowed us to synthesize a range of semi-
ochemicals while bisepoxides might prove useful in the
bidirectional synthesis of polyols.
RESULTS AND DISCUSSION
■
Before we investigated the one-pot reaction, the conditions for
the organocatalytic α-chlorination27 were optimized for
citronellal (1a) as the substrate. Our previously described
procedure is based on the work of Jørgensen28,29 and
MacMillan30,31 and employs catalyst 232 together with N-
chlorosuccinimide (NCS) as an inexpensive chlorine source.
The screening of the α-chlorination was carried out using (R)-
citronellal with 96% ee, and the sensitive α-chloroaldehyde was
converted to the corresponding alcohol by in situ reduction
with sodium borohydride (Table 1). While the reaction
exhibited high diastereoselectivity over a wide temperature
range, between 23 and 0 °C the isolation of pure (2S,3R)-3a
was hampered by the formation of unidentified side products.
Halogen-bearing chiral centers10 constitute a useful handle
for subsequent transformations, and halogenation of carbonyl
compounds11 provides a highly stereoselective entry into this
substrate class. In particular, α-haloaldehydes represent versatile
building blocks for heterocyclic scaffolds12 and for natural
product synthesis.13 For example, the Britton group has
demonstrated the broad utility of α-chloroaldehydes in the
synthesis of carbohydrates,14 alkaloids,15 and acetogenins.16
The merging of the oxidation and the chlorination step into a
single reaction vessel (one-pot reaction)17 obviates the need to
isolate and purify possibly unstable aldehyde intermediates. For
Received: November 1, 2013
© XXXX American Chemical Society
A
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starting alcohol (5b). Treatment of the chlorohydrins 4a−c
with NaOH afforded the corresponding terminal epoxides
6a−c in 93−97% yield.
Table 1. Optimized Organocatalytic α-Chlorination of
Citronellal
a
The epoxide function (a2-synthon) is a useful handle for
carbon chain extension. With the optimized procedure in hand,
we next demonstrated the utility of monoterpene-derived 1,2-
epoxides as chiral building blocks. Apart from the Roche
ester,33 citronellol is one of only a few viable resources for
transferring methyl group bearing stereogenic centers from the
chiral pool into target molecules and that is readily available in
both enantiomeric forms. While citronellol’s trisubstituted
double bond represents a masked carbonyl group, the primary
hydroxyl group can be transformed into a chiral 1,2-epoxide via
one-pot oxidation−chlorination.
b
T [°C]
t [h]
yield [%]
syn:anti
ee [%]
1
2
3
4
+23
0
1.5
1.5
4
65
68
73
82
98:2
97:3
97:3
99
99
98
99
−15
−28
Thus, the citronellol-derived epoxide 6a was converted into
the main odor component of the African orchids Aerangis kirkii
and A. confusa, (−)-cis-aerangis lactone 8,34 in just two
synthetic steps.35−40 As shown in Scheme 1, a Cu-catalyzed
c
8
2:98
a
30 mol % 2·TFA, 1.30 equiv of NCS, then 2.50 equiv of NaBH4, 0
b
c
°C. ee of the major diastereomer. ent-2 (30 mol %) was used.
This problem was circumvented efficiently by lowering the
temperature to −15 °C. Accordingly, the alcohol (2S,3R)- 3a
was isolated in 73% yield with >99% ee. The syn/anti ratio of
98:2 reflects the 96% ee of the starting material. Using the
enantiomeric MacMillan catalyst ent-2 at −28 °C afforded the
anti-diastereomer (2R,3R)-4a in a 98:2 ratio in >99% ee. From
these results we conclude that the α-chlorination appears to be
catalyst-controlled.
Scheme 1. Synthesis of (−)-cis-Aerangis Lactone
We next turned our attention to the possibility of employing
alcohols as substrates in a three-step one-pot sequence
consisting of oxidation, α-chlorination, and reduction. Explor-
atory experiments indicated that reagents for the Cu-catalyzed
aerobic oxidation do not interfere with chlorination. As shown
in Table 2, the reactions using alcohols 5a−c proceeded
smoothly and were completely catalyst-controlled. The low
anti/syn ratio of 4b is a direct consequence of the low ee of the
regioselective opening of 6a with n-butyllithium using CuCN
(20 mol %) as the catalyst afforded 7a in 89% yield. Using
Marshall’s ozonolytic esterification41/lactonization42 protocol,
(−)-cis-aerangis lactone 8 was obtained in 83% yield.
Alternatively, 6a can be converted into palm weevil
pheromones.43 Epoxide opening with Grignard reagent derived
cuprates afforded the alcohols 7b and 7c in good yields.
Acetylation of the hydroxyl group was followed by an
ozonolysis with a reductive workup to give the primary
alcohols 9b and 9c. Finally, tosylation and global reduction
completed the synthesis of cruentol44 10b and ferrugineol45,46
10c (Scheme 2).
Table 2. Scope of the Telescoped Oxidation−Chlorination−
a
Reduction Sequence
In a similar vein, 1,2-epoxydiene 6c was subjected to a
CuCN-catalyzed opening with n-BuLi and n-propylmagnesium
bromide, respectively to afford the alcohols 11a (81%) and 11b
(74%). A reductive ozonolysis was followed by an oxidative
lactonization and yielded cognac lactone47−52 (12a, R = n-Bu,
77%) and whisky lactone53−57 (12b, R = n-Pr, 73%), two major
flavor contributing constituents of most alcoholic beverages
aged in smoked oak or other wooden casks.58 Moreover,
avoidance of the isolation of the labile and volatile aldehyde
proved time-saving and led to satisfactory overall yields
(Scheme 3).
Two-directional chain extension59 is a multibond forming
approach60 to molecules with repeating functional group
patterns. While this strategy has been applied to various
achiral, prochiral,61 meso- and C2-symmetrical substrates,62
examples of regioselective double opening of C2-symmetrical
terminal bis-epoxides with C-nucleophiles are scarce.63 The
currently established synthesis of C2-symmetrical bis-epoxides
involves peracid-mediated double epoxidation of two terminal
a
5.0 mol % CuOTf, 5.0 mol % 2,2′-bipyridine, 5.0 mol % TEMPO, 10
mol % NMI (1-methylimidazole), rt, then 30 mol % 2·TFA, 1.30 equiv
of NCS, −28 °C, then 2.50 equiv of NaBH4, 0 °C; 22.3 equiv of
NaOH, rt.
B
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Scheme 2. Synthesis of Cruentol and Ferrugineol
Scheme 4. Synthesis of Terminal Bis-Epoxide 15
EXPERIMENTAL SECTION
■
(2R,3R)-2-Chloro-3,7-dimethyloct-6-en-1-ol 4a. To a solution
of (R)-citronellal 1a (135 mg, 0.88 mmol) in MeCN (1.75 mL)
(2S,5R)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one-TFA-salt (74.8
mg, 0.30 mmol, 0.30 equiv) and NCS (152 mg, 0.65 mmol, 1.30
equiv) were added successively at −28 °C. The reaction was stirred for
8 h at −28 °C and warmed to 0 °C. After the addition of EtOH (1.0
mL) and NaBH4 (82.8 mg, 2.50 mmol, 2.50 equiv) the reaction was
stirred for 30 min at 0 °C, quenched by the addition of a saturated
aqueous solution of NH4Cl (2 mL), and extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude product was purified
by column chromatography on silica (n-pentane/Et2O = 25:1), and 4a
was obtained as a colorless liquid (136 mg, 82%, 98:2 dr, >99:1 er).
Scheme 3. Synthesis of Whisky Lactone and Cognac Lactone
1
[α]2D0 = +16.7 (c 0.75, CHCl3); H NMR (400 MHz, CDCl3): δ 5.09
(t, J = 7.1 Hz, 1H), 3.98 (ddd, J = 8.3, 5.1, 3.8 Hz, 1H), 3.71−3.85 (m,
2H), 2.04−2.13 (m, 2H), 1.88−1.99 (m, 2H), 1.69 (s, 3H), 1.61 (s,
3H), 1.52−1.60 (m, 1H), 1.27−1.35 (m, 1H), 1.03 (d, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 132.0, 123.9, 71.0, 64.9, 36.3,
32.7, 25.7, 25.3, 17.7, 16.3; IR 3375, 2965, 2928, 2877, 2858, 1455,
1379, 1259, 1199, 1071, 1031, 987, 953, 824, 669 cm−1; HRMS (EI)
m/z calcd for C10H19OCl [M]•+ 190.11189, found 190.11225; calcd
for C10H19O37Cl [M]•+ 192.10894, found 192.10772; GC (Hydrodex-
β-TBDM, 130 °C isotherm, 1.1 mL/min He, 50:1 split) T(2R,3R) = 25.5
min, T(2S,3R) = 26.4 min, T(2R,3S) = 29.6 min, T(2S,3S) = 31.2 min, isomeric
ratio = 70:1:1:0.
(2S,3S)-2-Chloro-3,7-dimethyloct-6-en-1-ol 4a (One-Pot Pro-
cedure). To a solution of (S)-citronellol 5a (3.12 g, 20 mmol) in
MeCN (20 mL) were added solutions of CuOTf·4MeCN (377 mg,
0.05 mmol, 0.05 equiv), 2,2′-bipyridine (156 mg, 0.05 mmol, 0.05
equiv), TEMPO (156 mg, 0.05 mmol, 0.05 equiv), and 1-
methylimidazole (164 mg, 0.10 mmol, 0.10 equiv) each in 20 mL of
MeCN. The reaction mixture was degassed for 5 min, the atmosphere
in the reaction vessel was replaced by O2, and the reaction mixture was
stirred for 2 h at rt. After the reaction was cooled to −28 °C, (2R,5S)-
2-(tert-butyl)-3,5-dimethylimidazolidin-4-one-TFA-salt (1.60 g, 6.00
mmol, 0.30 equiv) and NCS (3.47 g, 26.0 mmol, 1.30 equiv) were
added successively, and the reaction was stirred 24 h at −28 °C and
warmed to 0 °C. After the addition of EtOH (50 mL) and NaBH4
(189 g, 50.0 mmol, 2.50 equiv) the reaction was stirred for 30 min at 0
°C, quenched by the addition of a saturated aqueous solution of
NH4Cl (100 mL), and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography on silica (n-pentane/Et2O = 10:1), and 4a was
directly submitted to the following reaction conditions.
alkene moieties64 followed by hydrolytic kinetic resolution65 of
the resulting meso/rac-mixture.66,67 As a consequence, the
theoretical yield is limited to 25% of either of the two
enantiomeric C2-symmetrical bis-epoxides and 50% of the meso-
diastereomer. To test the hypothesis whether a formal double
chlorination of symmetrical diols would serve as an entry into
C2-symmetrical bis-epoxides, we subjected 1,7-heptanediol (13)
to the previously established conditions. Gratifyingly, the
(2S,6S)-2,6-dichloroheptane-1,7-diol (14) was obtained as a
crystalline solid in good yield and selectivity. The high
enantiomeric excess of the C2-symmetrical diastereomer is
due to the fact that the minor enantiomer in the first
chlorination is preferentially converted to the meso-diaster-
eomer in the second chlorination (Horeau principle).68 The
minor meso-isomer can be removed efficiently by recrystalliza-
tion. Treatment of 14 with NaOH in dichloromethane affords
the desired bisepoxide 15 in 92% yield and >99% enantiomeric
excess (Scheme 4).
CONCLUSION
■
In summary, we have demonstrated that alkan-1-ols can be
converted to the corresponding 2-chloroalkan-1-ols in an
efficient one-pot procedure involving a Cu-catalyzed oxidation
and an enamine chlorination/reduction. Using terpene derived
alcohols as feedstock, several chiral semiochemicals have been
synthesized in an efficient manner via the corresponding 1,2-
epoxides. Application of this telescoped sequence to bisep-
oxides in the bidirectional synthesis of more complex targets
will be the subject of forthcoming reports from our laboratory.
Alternatively after column chromatography on silica (n-pentane/
Et2O = 35:1−25:1−15:1), 4a can be obtained as a colorless liquid
(3.05 g, 79%, 98:2 dr, >99:1 er).
[α]2D0 = −13.5 (c 1.09, CHCl3); GC (Hydrodex-β-TBDM, 130 °C
isotherm, 1.1 mL/min He, 50:1 split) T(2R,3R) = 25.5 min, T(2S,3R) = 26.4
min, T
= 29.6 min, T
= 31.2 min, isomeric ratio = 0:1:1:83.
(2R,3S)
(2S,3S,E)-2-Chloro-3(,72S,,31S1) -trimethyldodeca-6,10-dien-1-ol
4b. The same procedure as above was applied to (S,E)-dihydro-
farnesol 5b (449 mg, 2.00 mmol). The crude product was purified by
column chromatography on silica (n-pentane/Et2O = 35:1), and 4b
C
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was obtained as a colorless liquid (444 mg, 86%, 58:42 dr, 90:10 er).
[α]2D0 = −9.64° (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.10
(d, J = 6.0 Hz, 2H), 4.11−4.02 (m, 1H), 3.86−3.79 (m, 2H), 1.87−
2.13 (m, 8H), 1.69 (s, 3H), 1.61 (m, 7H), 1.28−1.38 (m, 1H), 1.04 (d,
J = 6.8 Hz, 1/2 3H), 0.98 (d, J = 6.7 Hz, 1/2 3H); 13C NMR (100
MHz, CDCl3): δ 135.6, 135.6, 131.4, 131.3, 124.2, 124.2, 123.8, 123.7,
71.1, 70.2, 65.7, 64.9, 39.7 (2C), 36.3, 35.3, 34.2, 32.7, 26.6 (2C), 25.7
(2C), 25.2, 25.1, 17.7 (2C), 16.3, 16.0 (2C), 14.6; IR 3387, 2965,
2926, 2856, 1667, 1452, 1380, 1107, 1074, 1030, 831, 669 cm−1;
HRMS (ESI) m/z calcd for C15H29OCl [M+H]+ 259.18232, found
259.18244; calcd for C15H29O37Cl [M+H]+ 261.17937, found
261.17944; GC (Lipodex E, 130 °C isotherm, 1.1 mL/min He, 20:1
equiv). Over 30 min AllylMgCl (1.7 M in Et2O, 5.88 mL, 10.0 mmol,
2.00 equiv) was added, and the reaction was stirred 1.5 h at rt. The
reaction was quenched by the addition of a saturated aqueous solution
of NH4Cl-Lsg. (10 mL) and H2O (20 mL) and extracted with CH2Cl2
(3 × 35 mL), and the combined organic layers were dried over MgSO4
and concentrated under reduced pressure. The crude product was
solved in MeOH (5 mL) at rt, and K2CO3 (1.83 g, 12.5 mmol, 2.50
equiv) was added and stirred 17 h at rt. The reaction was quenched by
the addition of a saturated aqueous solution of NH4Cl-Lsg. (2.5 mL)
and extracted with Et2O (3 × 15 mL), and the combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. The crude product was purified by column chromatography
on silica (n-pentane/EtOAc = 25:1), and 5c was obtained as a
colorless liquid (612 mg, 80%). (S,E)-2,6-Dimethyloct-2-en-1,8-diol:
[α]2D0 = −4.25° (c 0.91, CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.35
(td, J = 7.2, 1.1 Hz, 1H), 3.92 (s, 2H), 3.54−3.65 (m, 2H), 2.72 (br. s.,
2H), 1.94−2.09 (m, 2H), 1.62 (s, 3H), 1.51−1.59 (m, 2H), 1.29−1.38
(m, 2H), 1.12−1.23 (m, 1H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 134.5, 126.0, 68.5, 60.6, 39.6, 36.6, 28.8, 24.9, 19.4,
13.5; IR 3320, 2923, 1455, 1377, 1219, 1057, 1011, 848, 667 cm−1;
HRMS (ESI) m/z calcd for C10H17 [M + H − 2H2O]+ 137.13248,
split) T(2R,3R) = 83.0 min, T(2S,3R) = 90.1 min, T(2R,3S) = 97.6 min, T
= 105.0 min, isomeric ratio = 1:1:20:14.
(2S,3S)
(2S,3S,E)-2-Chloro-3,7-dimethylocta-5,7-dien-1-ol 4c. The
same procedure as above was applied to (S,E)-3,7-dimethylocta-5,7-
dien-1-ol 5c (425 mg, 2.75 mmol) with a reaction temperature of 50
°C for the oxidation. The crude product was purified by column
chromatography on silica (n-pentane/Et2O = 15:1), and 4c was
obtained as a colorless liquid (422 mg, 82%, 95:5 dr, 98:2 er). [α]D20
=
−20.8° (c 1.12, CHCl3); 1H NMR (400 MHz, CDCl3): δ 6.19 (d, J =
15.4 Hz, 1H), 5.59 (dt, J = 15.4, 7.4 Hz, 1H), 4.90 (s, 2H), 3.97 (ddd, J
= 7.4, 6.2, 3.5 Hz, 1H), 3.74−3.89 (m, 2H), 2.36−2.43 (m, 1H), 2.01−
2.17 (m, 3H), 1.84 (d, J = 0.8 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 141.7, 135.3, 127.2, 115.1, 70.1, 64.9,
37.1, 36.2, 18.6, 16.5; IR 3382, 3080, 3019, 2967, 2937, 1646, 1608,
1454, 1378, 1310, 1136, 1073, 967, 885 cm−1; HRMS (EI) m/z calcd
for C10H17OCl [M]•+ 188.09624, found 188.09702; calcd for
C10H17O37Cl [M]•+ 190.09329, found 190.09356; GC (Lipodex E,
+
found 137.13219; calcd for C10H19O [M + H − H2O] 155.14304,
found 155.14290, calcd for C10H21O2 [M + H]+ 173.15361, found
173.15347. (S,E)-2,6-Dimethyloct-2-en-1,8-diyldiacetate: [α]D20
=
1
−2.01° (c 1.89, CHCl3); H NMR (400 MHz, CDCl3): δ 5.38 (t, J
= 7.1 Hz, 1H), 4.38 (s, 2H), 3.98−4.08 (m, 2H), 1.92−2.07 (m, 8H),
1.56−1.66 (m, 4H), 1.45−1.54 (m, 1H), 1.29−1.42 (m, 2H), 1.12−
1.21 (m, 2H), 0.86 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 170.8, 170.6, 129.9, 129.4, 70.0, 62.6, 36.2, 35.2, 29.3, 24.9, 20.8,
20.7, 19.2, 13.7; IR 2959, 2927, 2873, 1743, 1458, 1369, 1241, 1147,
1024, 957, 850, 639, 608 cm−1; HRMS (ESI) m/z calcd for C14H25O4
[M + H]+ 257.17474, found 257.17506; calcd for C14H25O4Na [M +
Na]+ 279.15668, found 279.15701. 5c: [α]2D0 = −8.62° (c 1.39,
100 °C isotherm, 1.1 mL/min He, 20:1 split) T
= 42.7 min,
(2R,3R)
T
(2S,3R) = 44.7 min, T(2R,3S) = 63.5 min, T(2S,3S) = 71.7 min, isomeric ratio
= 1:2:357:20.
(S,E)-3,7-Dimethylocta-5,7-dien-1-ol 5c. To a solution of SeO2
(140 mg, 1.26 mmol, 0.05 equiv) and salicylic acid (348 mg, 2.52
mmol, 0.10 equiv) in CH2Cl2 (12 mL) at rt, t-BuOOH (70% in H2O,
15.6 mL, 114 mmol, 4.50 equiv) was added slowly. After 15 min (S)-
citronellol 5a (5.00 g, 25.2 mmol) was added and stirred 48 h at rt.
SeO2 (140 mg, 1.26 mmol, 0.05 equiv) was added and stirred for
another 72 h at rt. The reaction was quenched by the addition of
MeOH (25 mL) and a saturated aqueous solution of Na2S2O3 (40
mL). After 1 h of stirring at rt the reaction was filtered and extracted
with Et2O (3 × 50 mL), the combined organic layers were washed
with an aqueous solution of NaOH (1 M, 200 mL), and the basic
aqueous layer was washed with Et2O (1 × 100 mL). The combined
organic layers were washed with a saturated aqueous solution of
NH4Cl (1 × 150 mL), dried over Na2SO4, and concentrated under
reduced pressure. The crude product was solved in dry MeOH (25
mL) and cooled to 0 °C, and NaBH4 (2.39 g, 63.0 mmol, 2.5 equiv)
was added successively. After stirring for 1 h at 0 °C the reaction was
quenched by the addition of a saturated aqueous solution of NH4Cl
(25 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica (n-pentane/EtOAc = 3:1−2:1−1:1−0:1),
and (S,E)-2,6-dimethyloct-2-en-1,8-diol was obtained as a colorless
liquid (3.69 g, 66%).
To a solution of (S,E)-2,6-dimethyloct-2-en-1,8-diol (2.88 g, 16.7
mmol) in dry CH2Cl2 (17 mL) at 0 °C were added Et3N (6.13 mL,
44.2 mmol, 2.64 equiv), DMAP (205 mg, 1.67 mmol, 0.10 equiv), and
Ac2O (3.80 mL, 40.18 mmol, 2.40 equiv) and stirred for 1.5 h at 0 °C.
The reaction was quenched by the addition of a saturated aqueous
solution of NaHCO3 (20 mL) and extracted with CH2Cl2 (3 × 50
mL), and the combined organic layers dried over MgSO4 and
concentrated under reduced pressure. The crude product was purified
by column chromatography on silica (n-pentane/EtOAc = 30:1), and
(S,E)-2,6-dimethyloct-2-en-1,8-diyldiacetate was obtained as a color-
less liquid (4.20 g, 98%).
1
CHCl3); H NMR (400 MHz, CDCl3): δ 6.13 (d, J = 15.6 Hz, 1H),
5.59−5.66 (m, 1H), 4.86 (s, 2H), 3.60−3.72 (m, 2H), 2.13 (dt, J =
13.9, 7.0 Hz, 1H), 1.95−2.02 (m, 1H), 1.82−1.84 (m, 3H), 1.79 (br. s.,
1H), 1.59−1.73 (m, 2H), 1.35−1.42 (m, 1H), 0.91 (d, J = 6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 142.0, 134.3, 128.8, 114.3, 60.9,
40.2, 39.3, 29.9, 19.5, 18.6; IR 3337, 3080, 2925, 1741, 1644, 1608,
1455, 1376, 1242, 1055, 1003, 966, 882 cm−1; HRMS m/z calcd for
C10H17 [M + H − H2O]+ 137.13248, found 137.13227.
(R)-2-((S)-6-Methylhept-5-en-2-yl)oxirane 6a. To a solution of
4a (3.23 g, 17.0 mmol) in MeCN (20 mL) was added a solution of
NaOH (17.8 g, 0.45 mmol, 22.3 equiv) in EtOH (24 mL) and H2O
(50 mL). After the reaction was stirred for 2 h at rt, n-pentane (50
mL) was added, the layers were separated, and the aqueous layer was
extracted with n-pentane (3 × 50 mL). The combined organic layers
were dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica
(n-pentane/Et2O = 20:1), and 6a obtained as a colorless liquid (2.53 g,
97%, 94:6 dr). [α]2D0 = −3.97 (c 0.92, CHCl3); H NMR (400 MHz,
1
CDCl3): δ 5.07 (td, J = 6.4, 1.3 Hz, 1H), 2.71−2.76 (m, 1H), 2.65−
2.70 (m, 1H), 2.51 (dd, J = 5.0, 2.7 Hz, 1H), 1.95−2.08 (m, 2H), 1.67
(s, 3H), 1.59 (s, 3H), 1.38−1.47 (m, 1H), 1.24−1.33 (m, 2H), 1.02 (d,
J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 131.6, 124.2, 56.9,
46.8, 35.7, 33.6, 25.6, 25.5, 17.6 16.9; IR 3043, 2966, 2919, 2856, 1483,
1455, 1376, 1257, 1114, 1088, 929, 916, 892, 856, 823 cm−1; HRMS
(ESI) calcd for C10H19O [M+H]+ 155.14304, found 155.14289.
(R)-2-((S,E)-6,10-Dimethylundeca-5,9-dien-2-yl)oxirane 6b.
The same procedure as above was applied to (2S,3S,E)-4b (597 mg,
2.31 mmol). The crude product was purified by column chromatog-
raphy on silica (n-pentane/Et2O = 100:1), and 6b was obtained as a
colorless liquid (480 mg, 93%, 56:44 dr). 1H NMR (400 MHz,
CDCl3): δ 5.05−5.16 (m, 2H), 2.66−2.77 (m, 2H), 2.46−2.53 (m,
1H), 2.02−2.10 (m, 4H), 1.96−2.01 (m, 2H), 1.68 (d, J = 0.9 Hz,
3H), 1.59−1.62 (m, 6H), 1.43 (s, 4H), 1.26−1.38 (m, 2H), 1.03 (d, J
= 6.4 Hz, 1/2 3H), 0.93 (d, J = 6.5 Hz, 1/2 3H); 13C NMR (100 MHz,
CDCl3): δ 135.2, 135.1, 131.3, 131.2, 124.3, 124.3, 124.2, 124.1, 56.9,
56.9, 46.8, 45.5, 39.7, 39.7, 35.7, 35.6, 34.5, 33.6, 26.9 (2C), 26.7, 26.6,
To a solution of (S,E)-2,6-dimethyloct-2-en-1,8-diyldiacetate (1.28
g, 5.00 mmol) in dry THF (15 mL) at rt were added ZnCl2 (682 mg,
5.00 mmol, 1.00 equiv) and Pd(PPh3)4 (57.8 mg, 0.05 mmol, 0.01
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1
25.6, 25.3, 25.2, 17.6, 17.0, 15.9, 15.9, 15.4; HRMS (ESI) calcd for
C15H27O [M + H]+ 223.20578, found 223.20564.
[α]2D0 = −57.8 (c 1.01, CHCl3); H NMR (400 MHz, CDCl3): δ 4.25
(ddd, J = 8.6, 4.4, 3.1 Hz, 1H), 2.50 (t, J = 7.3 Hz, 2H), 1.94−2.05 (m,
2H), 1.58−1.68 (m, 2H), 1.41−1.55 (m, 2H), 1.22−1.34 (m, 5H),
0.93 (d, J = 6.9, 3H), 0.86 (t, J = 6.7, 3H); 13C NMR (100 MHz,
CDCl3): δ 172.0, 82.9, 31.8, 31.5, 29.2, 26.6, 25.9, 25.1, 22.4, 13.9,
12.3; IR 3465, 2934, 2872, 1735, 1462, 1380, 1344, 1244, 1204, 1123,
1097, 1070, 994, 909, 732 cm−1; HRMS (ESI) calcd for C11H21O2 [M
+ H]+ 185.15361, found 185.15422.
(R)-2-((S,E)-6-Methylhepta-4,6-dien-2-yl)oxirane 6c. The same
procedure as above was applied to (2S,3S,E)-4c (422 mg, 2.24 mmol).
The crude product was purified by column chromatography on silica
(n-pentane/Et2O = 20:1), and 6c was obtained as a colorless liquid
(317 mg, 93%, 96:4 dr). [α]2D0 = +15.8° (c 1.25, CHCl3); H NMR
1
(400 MHz, CDCl3): δ 6.18 (d, J = 15.4 Hz, 1H), 5.63 (dt, J = 15.6, 7.4
Hz, 1H), 4.89 (s, 2H), 2.73−2.77 (m, 2H), 2.54 (t, J = 4.4 Hz, 1H),
2.21−2.28 (m, J = 7.5, 6.5 Hz, 1H), 2.06−2.13 (m, 1H), 1.84 (s, 3H),
1.39−1.48 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 141.8, 134.6, 127.8, 114.8, 56.6, 46.7, 36.9, 36.5, 18.7, 16.7;
IR: 2968, 2921, 1608, 1456, 1375, 966, 883, 756 cm−1; HRMS m/z
calcd for C10H17O [M + H]+ 153.12739, found 153.12722.
(4S,5S)-8-Hydroxy-5-methyloctan-4-yl Acetate 9b. To a
solution of 7b (777 mg, 4.21 mmol) in dry CH2Cl2 (21 mL) at 0
°C were added Et3N (1.54 mL, 11.2 mmol, 2.64 equiv), DMAP (102
mg, 0.84 mmol, 0.20 equiv), Ac2O (0.96 mL, 10.1 mmol, 2.40 equiv)
and stirred for 2.5 h at 0 °C. The reaction was quenched by the
addition of a saturated aqueous solution of NaHCO3 (10 mL) and
extracted with CH2Cl2 (3 × 20 mL), and the combined organic layers
were dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica
(n-pentane/Et2O = 25:1) and (4S,5S)-5,9-dimethyldec-8-en-4-yl
acetate was obtained as a colorless liquid (914 mg, 96%, 97:3 dr). A
solution of (4S,5S)-5,9-dimethyldec-8-en-4-yl acetate (869 g, 3.84
mmol) in MeOH (20 mL) was cooled to −78 °C, ozone enriched O2
was bubbled through the solution until it turned blue, followed by
stirring for 5 min, and air was bubbled through the solution until the
blue color disappeared. The reaction was quenched by the addition of
NaBH4 (348 mg, 9.20 mmol, 2.40 equiv), stirred for 1 h while
warming to rt, and extracted with CH2Cl2 (3 × 25 mL), and the
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography on silica (n-pentane/Et2O = 2:1−1:1), and 9b was
obtained as a colorless liquid (632 mg, 80%, 96:4 dr). (4S,5S)-5,9-
(6S,7S)-7,11-Dimethyldodec-10-en-6-ol 7a. To a solution of
CuCN (254 mg, 2.84 mmol, 0.20 equiv) in THF (25 mL) at −78 °C
were added 6a (2.20 g, 14.2 mmol) and, after 20 min of stirring,
dropwise n-BuLi (1.6 M in n-hexane, 28 mL, 2.00 equiv). The reaction
was stirred for 7 h at −78 °C, warmed to 0 °C, quenched by the
addition of a saturated aqueous solution of NH4Cl (25 mL), and
extracted with EtOAc (3 × 25 mL). The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica (n-
pentane/EtOAc = 220:1−150:1−100:1), and 7a was obtained as a
colorless liquid (2.66 g, 89%, 92:8 dr). [α]2D0 = −5.9 (c 1.04, CHCl3);
1H NMR (400 MHz, CDCl3): δ 5.07−5.12 (m, 1H), 3.47−3.51 (m,
1H), 1.91−2.08 (m, 2H), 1.68 (s, 3H), 1.60 (s, 3H), 1.37−1.53 (m,
6H), 1.25−1.36 (m, 5H), 1.16−1.25 (m, 1H), 0.85−0.92 (m, 6H); 13
C
NMR (100 MHz, CDCl3): δ 131.3, 124.6, 75.0, 37.7, 34.4, 33.4, 31.9,
25.9, 25.7, 25.6, 22.6, 17.6, 14.0, 13.5; IR 3377, 2959, 2928, 2857,
1458, 1378, 1118, 1082, 1013, 983, 943, 828 cm−1; HRMS (ESI) calcd
for C14H29O [M+H]+ 213.22129, found 213.22134.
Dimethyldec-8-en-4-yl acetate: [α]2D0 = −21.2 (c 1.46, CHCl3); H
1
NMR (400 MHz, CDCl3): δ 5.06 (tt, J = 6.5, 1.5 Hz, 1H), 4.86 (dt, J =
8.7, 4.3 Hz, 1H), 1.89−2.06 (m, 5H), 1.57−1.69 (m, 7H), 1.53 (dd, J
= 9.6, 5.0 Hz, 1H), 1.21−1.48 (m, 4H), 1.09−1.17 (m, 1H), 0.87−0.92
(m, 6H); 13C NMR (100 MHz, CDCl3): δ 170.8, 131.4, 124.4, 76.8,
35.8, 33.5, 33.0, 25.6, 25.6, 21.0, 18.9, 17.6, 14.3, 13.9; IR 2962, 2930,
2874, 1736, 1456, 1375, 1241, 1019 cm−1; HRMS (ESI) calcd for
C14H27O2 [M + H]+ 227.20056, found 227.20060. 9b: [α]2D0 = −27.4
(c 1.52, CHCl3); 1H NMR (400 MHz, CDCl3): δ 4.85−4.90 (m, 1H),
3.60 (t, J = 6.5 Hz, 2H), 2.03 (d, J = 0.8 Hz, 3H), 1.11−1.69 (m, 10H),
0.86−0.93 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 171.1, 76.7,
63.0, 36.2, 33.5, 30.4, 29.1, 21.1, 19.0, 14.4, 13.9; IR 3397, 2960, 2937,
2874, 1733, 1458, 1373, 1247, 1056, 1022, 756, 406 cm−1; HRMS
(ESI) calcd for C11H23O3 [M + H] 203.16417, found 203.16423.
(4S,5S)-1-Hydroxy-4-methylnonan-5-yl Acetate 9c. The same
procedure as above was applied to 7c (771 mg, 3.89 mmol). The crude
products were purified by column chromatography on silica as above.
(5S,6S)-6,10-Dimethylundec-9-en-5-yl acetate (916 mg, 98%, 93:7 dr)
and 9c (761 mg, 97%, 97:3 dr) were obtained as colorless liquids.
(5S,6S)-6,10-Dimethylundec-9-en-5-yl acetate: [α]2D0 = −16.6 (c 1.12,
(4S,5S)-5,9-Dimethyldec-8-en-4-ol 7b. The same procedure as
above was applied to 6a (849 mg, 5.50 mmol), using EtMgBr (1.0 M
in THF, 16.5 mL, 3.00 equiv). The crude product was purified by
column chromatography on silica (n-pentane/EtOAc = 250:1), and 7b
was obtained as a colorless liquid (803 mg, 79%, 93:7 dr). [α]D20
=
1
−22.7 (c 1.33, CHCl3); H NMR (400 MHz, CDCl3): δ 5.10 (t, J =
7.1 Hz, 1H), 3.51 (dt, J = 7.5, 4.0 Hz, 1H), 1.91−2.09 (m, 2H), 1.68
(s, 3H), 1.60 (s, 3H), 1.27−1.53 (m, 7H), 1.16−1.25 (m, 1H), 0.93 (t,
J = 7.1 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 131.3, 124.6, 74.8, 37.7, 36.6, 33.4, 25.7, 25.6, 19.4, 17.6,
14.1, 13.5; IR 2280, 2960, 2938, 2872, 1457, 1378, 1113, 974 cm−1;
HRMS (ESI) calcd for C12H25O [M + H]+ 185.18999, found
185.18994.
(5S,6S)-6,10-Dimethylundec-9-en-5-ol 7c. The same procedure
as above was applied to 6a (849 mg, 5.50 mmol), using nPrMgCl (2.0
M in Et2O, 5.5 mL, 2.00 equiv). The crude product was purified by
column chromatography on silica (n-pentane/EtOAc = 250:1), and 7c
was obtained as a colorless liquid (803 mg, 74%, 93:7 dr). [α]D20
=
1
1
CHCl3); H NMR (400 MHz, CDCl3): δ 5.04−5.09 (m, 1H), 4.84
−23.1 (c 1.18, CHCl3); H NMR (400 MHz, CDCl3): δ 5.10 (tt, J =
7.1, 1.3 Hz, 1H), 3.49 (dt, J = 7.6, 4.0 Hz, 1H), 1.91−2.09 (m, 2H),
1.68 (d, J = 0.7 Hz, 3H), 1.60 (s, 3H), 1.16−1.53 (m, 11H), 0.91 (t, J
= 7.1 Hz, 3), 0.87 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 131.3, 124.6, 75.0, 37.7, 34.1, 33.4, 28.4, 25.7, 25.6, 22.8, 17.6, 14.0,
13.5; IR 3380, 2959, 2928, 2859, 1457, 1378, 1116, 1079, 978 cm−1;
HRMS (ESI) calcd for C13H27O [M + H]+ 199.20564, found
199.20565.
(dt, J = 8.5, 4.4 Hz, 1H), 1.89−2.06 (m, 5H), 1.58−1.68 (m, 7H),
1.43−1.57 (m, 2H), 1.17−1.42 (m, 5H), 1.08−1.17 (m, 1H), 0.84−
0.91 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 170.8, 131.4, 124.4,
77.0, 35.7, 33.0, 31.0, 27.9, 25.6, 25.6, 22.6, 21.1, 17.6, 14.2, 13.9; IR
2960, 2929, 2860, 1736, 1456, 1375, 1241, 1018 cm−1; HRMS (ESI)
calcd for C15H29O2 [M + H]+ 241.21621, found 241.21622. 9c: [α]2D0
=
−19.4 (c 1.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 4.86 (dt, J =
8.7, 4.3 Hz, 1H), 3.61 (t, J = 6.5 Hz, 2H), 2.04 (s, 3H), 1.12−1.68 (m,
12H), 0.85−0.92 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 171.1,
77.0, 76.7, 63.0, 36.2, 31.0, 30.5, 29.1, 27.9, 22.6, 21.1, 14.3, 13.9; IR
3397, 2957, 2936, 2872, 1735, 1716, 1458, 1373, 1242, 1057, 1021,
406 cm−1; HRMS (ESI) calcd for C12H25O3 [M + H]+ 217.17982,
found 217.18003.
(5S,6S)-5-Methyl-6-pentyltetrahydro-2H-pyran-2-one 8,
(−)-cis-Aerangis Lactone. A solution of 7a (106 mg, 0.50 mmol)
and NaOH (200 mg, 5.00 mmol, 10.0 equiv) in MeOH−CH2Cl2 (1:1,
5 mL) was cooled to −78 °C, and ozone enriched O2 was bubbled
through the solution until the color changed from red to yellow and
finally to blue with a yellowish precipitate. Air was bubbled through
the solution until the blue color disappeared. The precipitate was
dissolved by the addition of water (5 mL). After extraction with
CH2Cl2 (3 × 10 mL) the combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica (n-pentane/Et2O =
5:1), and 8 was obtained as a colorless liquid (75.6 mg, 83%, 95:5 dr).
(4S,5S)-5-Methyloctan-4-ol 10b, Cruentol. To a solution of 9b
(405 mg, 2.00 mmol) in dry CH2Cl2 (1.4 mL) at 0 °C were added
DMAP (48.9 mg, 0.40 mmol, 0.20 equiv), Et3N (360 μL, 2.60 mmol,
1.30 equiv), and TsCl (458 mg, 2.40 mmol, 1.20 equiv) and stirred for
4 h while warming to rt. The reaction was quenched by the addition of
H2O (2 mL) and extracted with EtOAc (3 × 5 mL), and the combined
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organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica (n-pentane/Et2O = 5:1) and (4S,5S)-5-
methyl-8-(tosyloxy)octan-4-yl acetate obtained as a yellowish liquid
(639 mg, 90%, 94:6 dr). To a solution of LiAlH4 (171 mg, 4.53 mmol,
3.00 equiv) in dry THF (4.53 mL) at 0 °C a solution of (4S,5S)-5-
methyl-8-(tosyloxy)octan-4-yl acetate (538 mg, 1.51 mmol) in dry
THF (2.16 mL) was added and heated to 75 °C for 5 h. After cooling
to 0 °C the reaction was quenched by the addition of MeOH (5 mL)
and a saturated aqueous solution of NaK-tatrate (10 mL) and
extracted with EtOAc (3 × 25 mL), and the combined organic layers
were dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica
(n-pentane/Et2O = 10:1), and 10b was obtained as a colorless liquid
(210 mg, 96%, 97:3 dr). (4S,5S)-5-Methyl-8-(tosyloxy)octan-4-yl
acetate: [α]2D0 = −17.9° (c 1.30, CHCl3); 1H NMR (400 MHz,
CDCl3): δ 7.77 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.79 (dt,
J = 8.8, 4.0 Hz, 1H), 3.94−4.03 (m, 2H), 2.44 (s, 3H), 2.01 (s, 3H),
1.07−1.74 (m, 9H), 0.88 (t, J = 7.3 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 170.8, 144.6, 133.1, 129.7 (2C),
127.8 (2C), 76.3, 70.6, 35.8, 33.2, 28.6, 26.6, 21.5, 21.0, 18.9, 14.2,
13.8; IR 2960, 2874, 1731, 1598, 1462, 1360, 1244, 1188, 1177, 1120,
1097, 1020, 964, 917, 815, 664 cm−1; HRMS (ESI): m/z calcd for
C18H32O5NS [M + NH4]+ 374.19957, found 374.20048, calcd for
The crude product was purified by column chromatography on silica
(n-pentane/EtOAc = 250:1), and 11b (178 mg, 81%, 96:4 dr) was
obtained as a colorless liquid. [α]2D0 = −12.7 (c 1.13, CHCl3); 1H NMR
(400 MHz, CDCl3): δ 6.17 (d, J = 15.6 Hz, 1H), 5.61−5.68 (m, 1H),
4.87 (s, 2H), 3.53 (td, J = 6.1, 3.7 Hz, 1H), 2.23−2.30 (m, 1H), 2.02
(dt, J = 14.5, 7.5 Hz, 1H), 1.84 (s, 3H), 1.57−1.66 (m, 1H), 1.40−1.47
(m, 4H), 1.26−1.35 (m, 6H), 0.87−0.92 (m, 6H); 13C NMR (100
MHz, CDCl3): δ 141.9, 134.2, 129.2, 114.4, 74.6, 38.5, 36.9, 34.5, 31.9,
25.9, 22.6, 18.7, 14.0, 13.3; IR 3379, 2958, 2929, 2860, 1608, 1457,
1377, 1124, 1017, 965, 881 cm−1; HRMS (ESI) calcd for C14H27O [M
+ H]+ 211.20564, found 211.20571.
(4S,5S)-5-Butyl-4-methyldihydrofuran-2(3H)-one 12a,
(−)-cis-Whisky Lactone. A solution of 11a (80.0 mg, 0.40 mmol)
in MeOH (5 mL) was cooled to −78 °C, ozone enriched O2 was
bubbled through the solution until it turned blue, following by stirring
for 5 min, and air was bubbled through the solution until the blue
color disappeared. The reaction was quenched by the addition of
NaBH4 (36.3 mg, 0.96 mmol, 2.40 equiv), stirred for 1 h while
warming up to rt, and extracted with CH2Cl2 (3 × 5 mL), and the
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The crude product was solved in MeCN (1
mL), and solutions of CuOTf·4MeCN (7.54 mg, 0.02 mmol, 0.05
equiv), 2,2′-bipyridine (3.13 mg, 0.02 mmol, 0.05 equiv), TEMPO
(3.13 mg, 0.02 mmol, 0.05 equiv), and 1-methylimidazole (3.29 mg,
0.04 mmol, 0.10 equiv) each in MeCN (1 mL) were added. The
reaction mixture was degassed for 5 min, the atmosphere in the
reaction vessel was replaced by O2, and the reaction was stirred for 2 h
at 50 °C, quenched by the addition of H2O (1 mL), and extracted with
CH2Cl2 (3 × 5 mL); the combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica (n-pentane/Et2O =
5:1), and 12a was obtained as a colorless liquid (50.0 mg, 73%, 98:2
dr). [α]2D0 = −59.2° (c 1.18, CHCl3); 1H NMR (400 MHz, CDCl3): δ
4.39−4.44 (m, 1H), 2.68 (dd, J = 17.0, 7.8 Hz, 1H), 2.53−2.61 (m,
1H), 2.18 (dd, J = 17.0, 4.0 Hz, 1H), 1.59−1.69 (m, 1H), 1.43−1.55
(m, 2H), 1.29−1.40 (m, 3H), 1.00 (d, J = 7.1 Hz, 3H), 0.91 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 176.8, 83.6, 37.5, 32.9, 29.5,
28.0, 22.4, 13.8, 13.8; IR 3523, 2958, 2873, 1774, 1465, 1422, 1383,
1336, 1293, 1209, 1170, 1092, 1080, 994, 974, 940, 928 cm−1; HRMS
(ESI) m/z calcd for C9H17O2 [M + H]+ 157.12231, found 157.12216.
(4S,5S)-4-Methyl-5-pentyldihydrofuran-2(3H)-one 12b,
(−)-cis-Cognac Lactone. The same procedure as above was applied
to 11b (127 mg, 0.60 mmol). The crude product was purified by
column chromatography on silica as above, and 12b (78.8 mg, 77%,
98:2 dr) was obtained as a colorless liquid. [α]2D0 = −64.8 (c 1.23,
C18H28O5NaS [M + Na]+ 379.15497, found 379.15546. 10b: [α]2D0
=
1
−31.9 (c 1.03, CHCl3); H NMR (400 MHz, CDCl3): δ 3.51 (dt, J =
7.5, 4.3 Hz, 1H), 1.24−1.54 (m, 9H), 1.12−1.20 (m, 1H), 0.93 (t, J =
7.2 Hz, 3H), 0.90 (t, J = 6.9 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 74.9, 37.9, 36.7, 35.6, 20.4, 19.4, 14.3,
14.1, 13.5; IR 3374, 2958, 2931, 2872, 1465, 1378, 1286, 1220, 1148,
1114, 1062, 1012, 970 cm−1; HRMS (ESI): m/z calcd for C9H19 [M +
H − H2O]+ 127.14813, found 127.14775.
(4S,5S)-4-Methylnonan-5-ol 10c, Ferrugineol. The same
procedure as above was applied to 9c (432 mg, 2.00 mmol). The
crude products were purified by column chromatography on silica as
above. (4S,5S)-4-Methyl-1-(tosyloxy)nonan-5-yl acetate (639 mg,
90%, 97:3 dr) and 10c (261 mg, 93%, 98:2 dr) were obtained as
yellowish or colorless liquids, respectively. (4S,5S)-4-Methyl-1-(tosyl-
oxy)nonan-5-yl acetate: [α]2D0 = −14.7 (c 1.39, CHCl3); 1H NMR (400
MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H),
4.78 (dt, J = 8.5, 4.4 Hz, 1H), 3.95−4.04 (m, 2H), 2.44 (s, 3H), 2.02
(s, 3H), 1.08−1.73 (m, 12H), 0.87 (t, J = 7.3 Hz, 3H), 0.84 (d, J = 6.9
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.8, 144.6, 133.2, 129.7
(2C), 127.8 (2C), 76.5, 70.6, 35.8, 30.8, 28.6, 27.9, 26.6, 22.5, 21.5,
21.0, 14.2, 13.9; IR 2958, 2870, 1732, 1598, 1461, 1363, 1242, 1177,
1097, 1020, 955, 890, 815, 765 cm−1; HRMS (ESI) calcd for
1
CHCl3); H NMR (400 MHz, CDCl3): δ 4.41 (ddd, J = 9.4, 5.4, 4.4
C19H30O5NaS [M + Na]+ 393.17062, found 393.17096. 10c: [α]2D0
=
Hz, 1H), 2.67 (dd, J = 17.0, 7.8 Hz, 1H), 2.52−2.60 (m, 1H), 2.17
(dd, J = 17.0, 4.0 Hz, 1H), 1.63 (q, J = 9.3 Hz, 1H), 1.45−1.53 (m,
2H), 1.26−1.39 (m, 5H), 0.99 (d, J = 7.3 Hz, 3H), 0.85−0.91 (m,
3H); 13C NMR (100 MHz, CDCl3): δ 176.8, 83.6, 37.5, 32.9, 31.5,
29.8, 25.5, 22.4, 13.9, 13.7; IR 2956, 2865, 1779, 1462, 1423, 1383,
1335, 1294, 1212, 1168, 1079, 1006, 978, 932 cm−1; HRMS (ESI)
calcd for C10H19O2 [M + H]+ 171.13796, found 171.13783.
(2S,6S)-2,6-Dichloroheptane-1,7-diol 14. To a solution of
freshly distilled 1,7-heptandiol 13 (512 mg, 4.00 mmol) in MeCN
(40 mL) were added CuOTf·4MeCN (149 mg, 0.30 mmol, 0.075
equiv), 2,2′-bipyridine (46.8 mg, 0.30 mmol, 0.075 equiv), TEMPO
(46.8 mg, 0.30 mmol, 0.075 equiv), and 1-methylimidazole (49.7 mg,
0.60 mmol, 0.15 equiv). The reaction mixture was degassed for 5 min,
and the atmosphere in the reaction vessel was replaced by O2. The
reaction mixture was stirred for 3 h at rt, and (2R,5S)-2-(tert-butyl)-
3,5-dimethylimidazolidin-4-one-TFA-salt (457 mg, 1.60 mmol, 0.40
equiv) and NCS (1.33 g, 10.0 mmol, 2.50 equiv) were added
successively. The reaction was stirred for 18 h at rt, cooled to 0 °C,
and diluted with EtOH (40 mL). After successive addition of NaBH4
(756 mg, 20 mmol, 5.00 equiv) the reaction was stirred for 30 min at 0
°C, quenched by the addition of a saturated aqueous solution of
NH4Cl (20 mL), and extracted with EtOAc (3 × 60 mL). The
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by column
1
−27.2 (c 1.02, CHCl3); H NMR (400 MHz, CDCl3): δ 3.48 (dt, J =
7.9, 4.1 Hz, 1H), 1.23−1.52 (m, 11H), 1.11−1.19 (m, 1H), 0.91 (t, J =
7.1 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H); 13C
NMR 75.1, 37.9, 35.6, 34.2, 28.5, 22.8, 20.4, 14.3, 14.0, 13.5; IR 3379,
2958, 2930, 2870, 1462, 1379, 1145, 1114, 1015, 974 cm−1; HRMS
+
(ESI) calcd for C10H21 [M + H − H2O]
141.16351.
141.16378, found
(5S,6S,E)-6,10-Dimethylundeca-8,10-dien-5-ol 11a. The same
procedure to synthesize 7a was applied to 6c (256 mg, 1.68 mmol),
using nPrMgCl (2.0 M in Et2O, 1.68 mL, 2.00 equiv). The crude
product was purified by column chromatography on silica (n-pentane/
EtOAc = 250:1−100:1), and 11a (244 mg, 74%, 94:6 dr) was obtained
as a colorless liquid. [α]D20 = −13.3 (c 1.23, CHCl3); H NMR (400
1
MHz, CDCl3): δ 6.17 (d, J = 15.6 Hz, 1H), 5.61−5.69 (m, 1H), 4.87
(s, 2H), 3.54 (td, J = 6.1, 3.7 Hz, 1H), 2.27 (dt, J = 13.7, 6.6 Hz, 1H),
1.98−2.06 (m, 1H), 1.84 (s, 3H), 1.57−1.66 (m, 1H), 1.24−1.48 (m,
7H), 0.87−0.94 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 142.0,
134.2, 129.2, 114.4, 74.6, 38.5, 36.9, 34.2, 28.4, 22.7, 18.7, 14.0, 13.3;
IR 3380, 3080, 2958, 2930, 2871, 1646, 1608, 1457, 1378, 1312, 1123,
1004, 966, 881 cm−1; HRMS (ESI) calcd for C13H25O [M + H]+
197.18999, found 197.18996.
(6S,7S,E)-7,11-Dimethyldodeca-9,11-dien-6-ol 11b. The same
procedure to synthesize 7a was applied to 6c (158 mg, 1.04 mmol).
F
dx.doi.org/10.1021/jo402422b | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
chromatography on silica (n-pentane/Et2O = 1:5), and 14 was
obtained as a white solid (547 mg, 68%, 95:5 dr, >99:1 er). After
recrystallization from CHCl3, the dr can be enriched to >99:1. Mp:
79.3 °C; [α]2D0 = +51.1° (c 1.18, CHCl3); 1H NMR (400 MHz,
CDCl3): δ 4.00−4.06 (m, 2H), 3.78−3.83 (m, 2H), 3.68−3.73 (m,
2H), 1.90 (br. s, 2H), 1.76−1.86 (m, 4H) 1.67−1.76 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 66.9 (2C), 64.6 (2C), 33.6 (2C), 23.3; IR
3324, 2962, 2866, 1455, 1391, 1286, 1073, 1020, 998, 745, 611, 568,
510, 455 cm−1; HRMS (ESI): m/z calcd for C7H15O2Cl2 [M + H]+
201.04436, found 201.04433, calcd for C7H15O2Cl37Cl [M + H]+
203.04141, found 203.04138, calcd for C7H15O37Cl2 [M + H]+
205.03846, found 205.03825; GC (Hydrodex-β-TBDAC, 170 °C
isotherm, 1.1 mL/min He, 50:1 split) T(2R,6R) = 60.6 min, T(meso) = 63.6
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= 70.5 min, isomeric ratio = 0:1:351.
(2R,6S)
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1.1, EtOH); H NMR (400 MHz, CDCl3): δ 2.89−2.95 (m, 2H),
2.71−2.79 (m, 2H), 2.48 (dd, J = 5.0, 2.7 Hz, 2H), 1.62−1.68 (m,
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ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental, 1H and 13C NMR spectra, GC
chromatograms, and crystal data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: mathias.christmann@fu-berlin.de.
Notes
■
(35) Fink, M. J.; Schon, M.; Rudroff, F.; Schnurch, M.; Mihovilovic,
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M. D. ChemCatChem 2013, 5, 724−727.
The authors declare no competing financial interest.
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