Enzyme- and ruthenium-catalyzed dynamic kinetic asymmetric transformation of 1,5-diols. Application to the synthesis of (+)-Solenopsin A

Article abstract of DOI:10.1021/jo8025109

Dynamic kinetic asymmetric transformation (DYKAT) of 1,5-diols via combined lipase and ruthenium catalysis provides enantiomerically pure diacetates in high diastereoselectivity, which can serve as intermediates in natural product synthesis. This is demon

Full text of DOI:10.1021/jo8025109

Enzyme- and Ruthenium-Catalyzed Dynamic Kinetic Asymmetric
Transformation of 1,5-Diols. Application to the Synthesis of
(+)-Solenopsin A
Karin Leijondahl, Linne´a Bore´n, Roland Braun, and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
ReceiVed NoVember 10, 2008
Dynamic kinetic asymmetric transformation (DYKAT) of 1,5-diols via combined lipase and ruthenium
catalysis provides enantiomerically pure diacetates in high diastereoselectivity, which can serve as
intermediates in natural product synthesis. This is demonstrated by the synthesis of (+)-Solenopsin A.
Introduction
meric diol mixture, containing pairs of enantiomers, can be
transformed into one enantiopure diastereomer with a theoretical
yield of 100% compared with the theoretical yield of ∼25%
obtained in an enzymatic kinetic asymmetric transformation
(KAT) of the same substrates.
Chiral 1,5-diols are important synthetic intermediates, and
there are examples in the literature where they are used in the
synthesis of piperidine natural products.10 We recently reported
on the DYKAT of 1,5-diols,11 where enantio- and diastereo-
merically enriched 1,5-diacetates were obtained, and herein we
demonstrate their usefulness in the synthesis of (+)-Solenopsin
A, a 2-methyl-6-alkylpiperidine.
Ever since the first development of enzyme- and transition
metal-catalyzed dynamic kinetic resolution (DKR) of secondary
alcohols during the late 1990s,1 the interest in this methodology
has increased, and new catalysts have made the systems more
robust and efficient.2 This DKR method has also been extended
to dynamic kinetic resolutions of primary alcohols3 and
amines.4,5 When diols containing two chiral sec-alcohol centers
are used in these systems, the method is classified as a dynamic
kinetic asymmetric transformation (DYKAT).6 Previously, both
cyclic7 and acyclic8 1,3-diols have been studied as well as 1,2-
diols9 and symmetrical 1,4-diols.8b In these cases, a diastereo-
Results and Discussion
(1) (a) Stu¨rmer, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1173. (b) Larsson,
A. L. E.; Persson, B. A.; Ba¨ckvall, J.-E. Angew. Chem., Int. Ed. Engl. 1997, 36,
1211.
In our recent study of the enzyme- and ruthenium-catalyzed
DYKAT of 1,5-diols, we found that diols 1a-1e and 1g (Figure
1) could be efficiently resolved into the corresponding enan-
tiopure 1,5-diacetates in high yields and good diastereoselectivity
(Table 1, entries 1-6 and 8).11 The second-generation catalytic
system2b,12 proved to be the most efficient, and hence, catalyst
2 in combination with isopropenyl acetate as acyl donor and a
(2) (a) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim,
M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972–1977. (b) Mart´ın-Matute, B.; Edin,
M.; Boga`r, K.; Kaynak, F. B.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2005, 127,
8817–8825. (c) Kim, N.; Ko, S.-B.; Kwon, M. S.; Kim, M.-J.; Park, J. Org.
Lett. 2005, 7, 4523–4526.
(3) (a) Stru¨bing, D.; Krumlinde, P.; Piera, J.; Ba¨ckvall, J.-E. AdV. Synth. Catal.
2007, 349, 1577–1581. See also: (b) Atuu, M. R.; Hossian, M. M. Tetrahedron
Lett. 2007, 48, 3875.
(4) Paetzold, J.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 17620–17621.
(5) (a) Parvulescu, A. N.; Jacobs, P. A.; De Vos, D. E. Chem. Eur. J. 2007,
13, 2034–2043. (b) Kim, M. J.; Kim, W. H.; Han, K.; Choi, Y. K.; Park, J. Org.
Lett. 2007, 9, 1157–1159.
(9) Edin, M.; Mart´ın- Matute, B.; Ba¨ckvall, J.-E. Tetrahedron: Asymmetry
2006, 17, 708–715.
(6) Steinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060–
8072.
(7) (a) Fransson, A.-B.; Xu, Y.; Leijondahl, K.; Ba¨ckvall, J.-E. J. Org. Chem.
2006, 71, 6309–6316. (b) Olofsson, B.; Boga´r, K.; Fransson, A.-B.; Ba¨ckvall,
J.-E. J. Org. Chem. 2006, 71, 8256–8260.
(10) (a) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita, Y. J. Org. Chem.
1996, 61, 7309–7315. (b) Solladie´, G.; Huser, N. Recl. TraV. Chim. Pays-Bas
1995, 114, 153–156.
(11) Leijondahl, K.; Bore´n, L.; Braun, R.; Ba¨ckvall, J.-E. Org. Lett. 2008,
10, 2027–2030.
(8) (a) Edin, M.; Steinreiber, J.; Ba¨ckvall, J.-E. Proc. Natl. Acad. Sci. U. S. A.
2004, 101, 5761–5766. (b) Mart´ın- Matute, B.; Edin, M.; Ba¨ckvall, J.-E. Chem.
Eur. J. 2006, 12, 6053–6061.
(12) For a mechanistic study of the second generation ruthenium catalyst
see: Mart´ın-Matute, B.; Åberg, J. B.; Edin, M.; Ba¨ckvall, J.-E. Chem. Eur. J.
2007, 13, 6063–6072.
1988 J. Org. Chem. 2009, 74, 1988–1993
10.1021/jo8025109 CCC: $40.75 2009 American Chemical Society
Published on Web 02/05/2009

Synthesis of (+)-Solenopsin A
FIGURE 1. 1,5-Diols previously used in dynamic kinetic asymmetric transformation.
TABLE 1. DYKAT of 1,5-Diolsa
required, the reactions were cleaner and easier to purify. A
second advantage with this route is that alcohol 5 and epoxide
6 also are intermediates in the synthesis of diol 1d.11
The DYKAT of 1h afforded diacetate 3h in excellent en-
antio- and diastereoselectivity (Table 1, entry 9). In the DYKAT
of 1i, diacetate 3i was obtained in 95% ee, but in a moderate
anti:syn ratio (entry 10). Since aliphatic ꢀ-chlorohydrins are
known to give poor enantioselectivity in lipase-catalyzed
transesterification with PS-C II,15 it was of interest to study this
step separately for the diol. To investigate the enantioselectivity
of the acylation of the alcohol next to the chloride in substrate
1i, the appropriate diol monoacetate was prepared according to
Scheme 3. Alcohol 5 was obtained, as described previously,
from addition of 3-butenylmagnesium bromide to propylene
oxide.16 Subsequent kinetic resolution of 5 with CALB and
isopropenyl acetate afforded the corresponding enantiomerically
pure acetate (R)-7.17 Epoxidation of (R)-7 followed by chloride
opening18 afforded the requisite diol monoacetate (2RS,6R)-9.
Having obtained pure (2RS,6R)-9, we performed a KAT on
this monoacetate using PS-C II and isopropenyl acetate to
determine the enantioselectivity of the acylation of the alcohol
next to the chloride. The reaction was run at 50 °C and to 26%
conversion. The anti:syn ratio of the product was 97:3 which
corresponds to a pseudo E value of 44 (Scheme 4).19 This can
be compared to the E value of 3.2 which was obtained for
1-chloro-2-nonanol.15
According to the determined pseudo E value, it should be
possible to obtain diacetate 3i in a higher diastereoselectivity
than previously obtained in the DYKAT of 1i. This was
confirmed by performing a DYKAT of monoacetate (2RS,6R)-9
which afforded diacetate (2S,6R)-3i in high enantioselectivity
(>99% ee) and with an anti:syn ratio of 89:11 (Scheme 5).20
The results show the importance of the 6-acetoxy group for the
enzyme selectivity. Further improvement of the diastereoselec-
tivity in the DYKAT may be possible by decreasing the enzyme
loading, thereby assuring the epimerization to be fast enough.
Diacetate 3i should be a useful intermediate for further
synthetic transformations since the chloroacetate moiety can be
transformed to epoxide in one step,15 which in turn can be
functionalized by ring opening. Also the diacetate products 3a
and 3d allow further functionalization at one end: 3a at the
entry
diol
time (h) temp (°C) % eeb anti:synb % yieldb,c
1
2
3
4
5
6
7
8
9
1ad,e,f
1b
72
24
48
40
40
48
77
46
48
48
80
50
50
50
100
50
80
50
50
80
98
>99
>99
>99
>99
>99
37
>99
>99
95
80:20
96:4
94:6
96:4
94:6
>99:1
55:45
95:5
94:6
76:24
91 (71)
96 (80)
96 (73)
89
83 (61)
99 (83)
77
98 (81)
85 (49)
93 (78)
1cf
1c
1de,f,g
1e
1fe,h
1gi
1hj
10
1ie,f,k
a Unless otherwise stated, the reactions were performed on a 1 mmol
scale in 1 mL of toluene with 3 equiv of isopropenyl acetate, 2.5-5 mg
of CALB, 0.025 equiv of Ru-catalyst, 0.025 equiv of tBuOK, and 1
mmol of Na2CO3 under argon. Compounds 1a-1g and 3a-3g are fully
characterized in ref 11. b Determined by chiral GC. c Isolated yield in
parentheses. d The reaction was run on a 2 mmol scale using 60 mg of
CALB and 20 mg of PS-C II, where the latter was added after 5 h. e 6
equiv of isopropenyl acetate was used. f 0.05 equiv of Ru-catalyst and
0.05 equiv of BuOK in 2.5 mL of toluene. g 100 mg of CALB was
t
used. h 0.05 equiv of Ru-catalyst, 10 mg of PS-C II, and 0.06 equiv of
tBuOK in 2.5 mL of toluene was used. i The reaction was run on a 5
mmol scale. j The reaction was run in 1.5 mL of toluene. k 30 mg of
CALB was used, and 10 mg of PS-C II was added after 5 h.
lipase, CALB (Candida antarctica lipase B) or PS-C II
(Pseudomonas cepacia lipase), was used.13
In the present paper, we have completed this series, studied
the DYKAT of two additional substrates, 1h and 1i (Table 1,
entries 9 and 10), and applied one of the enantiomerically pure
diacetates in Table 1, 3d (entry 5), to the synthesis of (+)-
Solenopsin A. DYKAT of substrates 1h and 1i extends the
generality of the method. In particular, enantiomerically pure
diol derivatives of 1i are useful since they readily allow
functionalization at one end.
The syntheses of diols 1h and 1i are given in Scheme 1. Diol
1h was prepared from 1,2-propanediol and 1-butenoxide ac-
cording to a literature procedure.14 Diol 1i was obtained from
the reaction of 1-butyn-2-ol and epichlorohydrin and the
hydrogenation of the yne-diol 4 formed.
(14) (a) Sexton, A. R.; Britton, E. C. J. Am. Chem. Soc. 1953, 75, 4357–
4358. (b) Summerbell, R. K.; Jerina, D. M.; Grula, R. J. J. Org. Chem. 1962,
27, 4433–4436.
(15) Tra¨ff, A.; Boga´r, K.; Warner, M.; Ba¨ckvall, J.-E. Org. Lett. 2008, 10,
4807–4810.
(16) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. Synthesis 2005, 13, 2264–
2266.
(17) When a DKR was performed with catalyst 2, 82% conversion was
obtained after 22 h, and the acetate showed an ee of 84%, indicating that the
racemization has to be studied further.
(18) Hoff, B. H.; Anthonsen, T. Tetrahedron: Asymmetry 1999, 10, 1401–
1412.
(19) The reaction was run on a 0.2 mmol scale in 1 mL of toluene under
argon, and a sample was taken after 2 h. Analysis by chiral CG showed 94% de
(i.e., anti:syn ) 97:3) of the product at 26% conversion. This corresponds to a
pseudo E value of 44.
Diol 1i was also prepared by a three-step synthesis starting
from propylene oxide (Scheme 2). Although a third step was
(13) The use of two different enzymes in entry 1 of Table 1 (footnote d) is
because CALB only reacts with the alcohol next to the methyl group and is
essentially unreactive toward the alcohol next to the carboxy group. In this way,
a selective acylation of the former alcohol group is obtained by using CALB in
the beginning of the reaction (PS-C II gives a lower selectivity of that alcohol
group). In the second step PS-C II is required since CALB stops after the first
step.
J. Org. Chem. Vol. 74, No. 5, 2009 1989

Leijondahl et al.
SCHEME 1. Synthesis of New 1,5-Diols
SCHEME 2. Alternative Synthesis of Diol 1i
SCHEME 3. Synthesis of Monoacetate (2RS,6R)-9
SCHEME 4. Determination of a Pseudo E Value for KAT of (2RS, 6R)-9
SCHEME 5. DYKAT of Monoacetate (2RS,6R)-9
nately, poor yields were obtained in the mesylation of optically
pure (3S,7R)-1d due to elimination of the mesylate ꢀ to the
nitrile, which occurred rapidly. To circumvent this problem, the
enantiomerically pure diol was protected with silyl groups prior
to further modifications. Reduction of the nitrile group in 10
with DIBALH into the corresponding aldehyde 11,23 followed
by a Wittig reaction24 with (1-nonyl)triphenylphosphonium
bromide, afforded 12. Subsequent removal of the silyl protective
groups and reduction of the double bond using Adam’s catalyst25
afforded diol 14, which was transformed to dimesylate 15.
carboxyl group and 3d at the cyano group. We have demon-
strated the usefulness of one of these enantiomerically pure
diacetates, 3d, in natural product synthesis. Diacetate 3d (Table
1, entry 4), which has a cyano group at one end, was transformed
to (+)-Solenopsin A (17) in a few steps (Scheme 6). (+)-
Solenopsin A (17) is the unnatural enantiomer of one of the
constituents of the venom of the fire ant Solenopsis inVicta.21
Both enantiomers have been synthesized several times before,10b,22
and diols 1a, 1d, and 1i are potential starting materials for the
synthesis of this trans-2,6-disubstituted piperidine. In Scheme
6 we have demonstrated how diol 1d can be transformed to
(+)-Solenopsin A via (3S,7R)-3d.
DYKAT of racemic diol 1d using the conditions previously
described11 afforded diacetate (3S,7R)-3d in 67% isolated yield.
The diacetate obtained was hydrolyzed into (3S,7R)-1d in 89%
yield. The most straightforward route would be to form the
piperidine ring first and then modify the side chain. Unfortu-
(20) It is not clear why the DYKAT of diol 1i gives such a poor
diastereoselectivity, but one reason may be that the first acylation occurs to some
extent on the alcohol next to the chloro group. Sequential use of enzymes CALB
and PS-C II (added after 5 h) was employed since CALB reacts slowly with the
chlorohydrin alcohol but fast with the alcohol next to the methyl group. However,
the fact that DYKAT of the monoacetate (2RS,6R)-9 gave only a diastereose-
lectivity of 89:11, in spite of the fact that the pseudo E value is 44 (and is expected
to give a diastereoselectivity of 98:2 with an efficient epimerization), shows
that there are other explanations. One obvious explanation is that the rate of
epimerization is not fast enough. Another explanation is that some reversibility
of the acylation reactions is occurring and this will lower the final isomeric purity
of the product.
(21) Leclercq, S.; Thirionet, I.; Broeders, F.; Daloze, D.; Vander Meer, R.;
Braeckman, J. C. Tetrahedron 1994, 50, 8465–8478.
(22) (a) Grierson, D. S.; Royer, J.; Guerrier, L.; Husson, H.-P. J. Org. Chem.
1986, 51, 4475–4477. (b) Guilloteau-Bertin, B.; Compe`re, D.; Gil, L.; Marazano,
C.; Das, B. C. Eur. J. Org. Chem. 2000, 1391–1399. (c) Dobbs, A. P.; Guesne´,
S. J. J. Synlett 2005, 13, 2101–2103. (d) O’Hagan, D. Nat. Prod. Rep. 2000, 17,
435–446. For a review, see (e) Leclercq, S.; Daloze, D.; Braekman, J.-C. Org.
Prep. Proced. Int. 1996, 28, 501–543.
(23) Itoh, T.; Mitsukura, K.; Kanphai, W.; Takagi, Y.; Kihara, H.; Tsukube,
H. J. Org. Chem. 1997, 62, 9165–9172.
1990 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of (+)-Solenopsin A
SCHEME 6. Synthesis of (+)-Solenopsin A from Diol 1d
by chromatography (pentane:EtOAc 4:1 to EtOAc) afforded (2R,6R)-
3h (114 mg, 49%) as an oil. The ee and diastereomeric ratio were
determined by chiral GC: >99% ee, anti:syn ) 94:6. [R]22D +19.1
(c ) 1.0, EtOAc). 1H NMR (CDCl3, 400 MHz): δ 0.90 (t, J ) 7.4
Hz, 3H), 1.21 (d, J ) 6.5 Hz, 3H), 1.52-1.69 (m, 2H), 2.04 (s,
3H), 2.06 (s, 1H), 3.42 (dd, J ) 10.5, 4.3 Hz, 1H), 3.48 (dd, J )
10.8, 4.1 Hz, 1H), 3.54 (dd, J ) 10.5, 6.0 Hz, 1H), 3.56 (dd, J )
Dimesylate 15 had previously been transformed to Solenopsin
A via reaction with benzylamine followed by debenzylation.10b
However, we also chose an alternative pathway for formation
of the piperidine ring through the reaction of dimesylate 15 with
NaHNTs, since this method has proven to be efficient for
intramolecular substitutions in our previous work.11,26 Detosy-
lation with sodium naphthalide27 afforded (+)-Solenopsin A (17)
10.8, 6.0 Hz), 4.92 (m, 1H), 5.04 (ddq, J ) 6.5, 6.3, 4.3, 1H). 13
C
in a total yield of 8% from diol 1d ([R]22 +7.3 (c ) 1.17,
D
NMR (CDCl3, 100 MHz): δ 9.5, 16.5, 21.1, 21.2, 23.8, 69.2, 72.0,
73.5, 73.7, 170.5, 170.7.
CHCl3) for the HCl salt, lit.22a [R]22D +7.5 (c ) 1.30, CHCl3)),
which was 97% trans.
(2S,6R)-2,6-Diacetoxy-1-chloroheptane (3i). PS-C II (50 mg),
Na2CO3 (106 mg, 1 mmol), and ruthenium catalyst 2 (32 mg, 0.05
mmol) were put in a flame-dried Schlenk tube under argon. Toluene
Conclusions
t
(1.5 mL) and BuOK (0.5 M in THF; 100 µL, 0.05 mmol) were
Dynamic kinetic asymmetric transformation of 1,5-diols is a
powerful method for the synthesis of enantiomerically pure 1,5-
diol derivatives. The utility of these diols as synthetic intermedi-
ates in natural product synthesis was demonstrated by the
synthesis of (+)-Solenopsin A.
added. The reaction was lowered into an oil bath preheated to 50
°C, and after 6 min monoacetate 6 (209 mg, 1 mmol) dissolved in
0.5 mL toluene was added. After another 4 min, isopropenyl acetate
(165 µL, 1.5 mmol) was added, and the mixture was left stirring at
50 °C for 18 h. The mixture was cooled to rt and purified by
chromatography without filtration or evaporation (pentane, then
pentane:Et2O 9:1) to afford (2R,6R)-3i (212 mg, 84%) as an oil.
Experimental Section
The ee and diastereomeric ratio were determined by chiral GC:
1
>99% ee, anti:syn ) 89:11. [R]22 -6.8 (c ) 1.0, EtOAc). H
D
DYKAT Reactions. (R,R)-2-Acetoxybutyl 2-Acetoxypropyl
Ether (3h). CALB (5 mg), Na2CO3 (106 mg, 1 mmol), and
ruthenium catalyst 2 (16 mg, 0.025 mmol) were put in a flame-
NMR (CDCl3, 400 MHz): δ 1.96 (d, J ) 6.3 Hz, 3H), 1.30-1.71
(m, 6H), 2.02 (s, 3H), 2.08 (s, 3H), 3.55 (dd, J ) 11.6, 5.3 Hz),
3.60 (dd, J ) 11.6, 4.7 Hz, 1H), 4.87 (m, 1H), 5.01 (m, 1H). 13C
NMR (CDCl3, 100 MHz): δ 19.9, 20.9 (2 C), 21.3, 31.2, 35.5, 45.5,
70.5, 72.6, 170.4, 170.7. HRMS (ESI) (M + Na)+: m/z calcd for
C11H19ClNaO4 273.0864, obsd 273.0857.
t
dried Schlenk tube under argon. Then toluene (1 mL) and BuOK
(0.5 M in THF; 50 µL, 0.025 mmol) were added. The reaction was
lowered into an oil bath preheated to 50 °C, and after 6 min diol
1h (157 mg, 1 mmol) was added. After another 4 min isopropenyl
acetate (330 µL, 3 mmol) was added. The mixture was left stirring
at 50 °C for 48 h and then filtered and concentrated. Purification
Synthesis of (+)-Solenopsin A. (3S,7R)-3,7-Diacetoxyoctaneni-
trile ((3S,7R)-3d). CALB (100 mg), Na2CO3 (106 mg, 1 mmol),
and ruthenium catalyst 2 (32 mg, 0.05 mmol) were placed in a
flame-dried Schlenk tube under argon. Then toluene (2.5 mL) and
tBuOK (0.5 M in THF; 100 µL, 0.05 mmol) were added. The
reaction was lowered into an oil bath preheated to 100 °C, and
after 6 min diol 1d (157 mg, 1 mmol) was added. After another 4
min, isopropenyl acetate (660 µL, 6 mmol) was added, and the
mixture was left stirring at 100 °C for 48 h. The mixture was then
(24) Pettersson-Fasth, H.; Riesinger, S. W.; Ba¨ckvall, J.-E. J. Org. Chem.
1995, 60, 6091–6096.
(25) Ba¨ckvall, J.-E.; Bystro¨m, S. E.; Nordberg, R. E. J. Org. Chem. 1984,
49, 4619–4631.
(26) Ba¨ckvall, J.-E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990, 55,
826–831.
(27) Lu, Z.-H.; Zhou, W.-S. J. Chem. Soc. Perkin Trans. 1 1993, 593–596.
J. Org. Chem. Vol. 74, No. 5, 2009 1991

Leijondahl et al.
filtered and concentrated. Two similar reactions were started, and
the combined crude products were purified by chromatography
(pentane:Et2O 4:1 to Et2O) to afford (3S,7R)-3d (321 mg, 67%) as
an oil. The ee and diastereomeric ratio were determined by chiral
GC: >99% ee, anti:syn ) 92:8. Analytical data agreed with those
previously reported.11
3.77 (m, 1H), 5.40 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ -4.7,
-4.5, -4.4, -4.3, 14.1, 18.1 (2 C), 21.9, 22.7, 23.8, 25.9, 27.5,
29.3, 29.4, 29.5, 29.7, 31.9, 35.3, 37.1, 40.1, 68.7, 72.4, 125.8,
131.5. HRMS (ESI) (M + Na)+: m/z calcd for C29H62NaO2Si2
521.4181, obsd 521.4189.
(2R,6S)-2,6-Dihydroxy-8-heptadecene (13). To a solution of
12 (131 mg, 0.26 mmol) in 2 mL of dry THF was added TBAF
(413 mg, 1.58 mmol) dissolved in 2 mL of dry THF. The resulting
mixture was stirred under argon for 2.5 days, and then NH4Cl (aq)
was added. The mixture was extracted several times with EtOAc,
and the combined organic layers were dried over MgSO4 and
evaporated. Purification by chromatography (pentane:EtOAc 2:1
(3S,7R)-3,7-Dihydroxyoctanenitrile ((3S,7R)-1d).28 A 2 M
NaOH solution (aq) (1.58 mL, 3.2 mmol) was added to a solution
of (3S,7R)-3 (255 mg, 1.06 mmol) in 26 ml of MeOH. The resulting
mixture was stirred at rt for 40 min. MeOH was evaporated, and
the residue was dissolved in sat. NaCl (aq) and extracted several
times with EtOAc. The combined organic phases were dried over
MgSO4 and concentrated yielding the title compound (147 mg,
89%), which was used without further purification. 1H NMR
(CDCl3, 400 MHz): δ 1.20 (3H, d, J ) 6.2 Hz, CH3), 1.39-1.70
(6H, m, 3 × CH2), 2.50 (ABX, JAB ) 16.6 Hz, JAX ) 5.1 Hz, 1H),
2.56 (ABX, JAB ) 16.6 Hz, JBX ) 6.3 Hz, 1H), 3.83 (1H, m, CH),
3.95 (1H, m, CH). 13C NMR (CDCl3, 100 MHz): δ 21.5, 23.8,
26.2, 36.1, 38.2, 67.4, 67.8, 117.8.
1
to EtOAc) afforded diol 13 (64 mg, 90%). H NMR (CDCl3, 400
MHz): δ 0.88 (t, J ) 7.0 Hz, 3H), 1.20 (d, J ) 6.3 Hz, 3H),
1.23-1.54 (m, 18 H), 1.62 (br s, 2H), 2.05 (app. q, J ) 7.3 Hz,
2H), 2.22 (app. t, J ) 6.9, 2H), 3.63 (m, 1H), 3.81 (m, 1H), 5.39
(m, 1H), 5.57 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ 14.1, 22.0,
22.7, 23.6, 27.4, 29.3, 29.5, 29.7, 31.9, 35.5, 36.6, 39.1, 68.0, 71.3,
124.9, 133.7.
(2R,6S)-2,6-Heptadecanediol (14). Diol 13 (63 mg, 0.23 mmol)
was dissolved in 1.5 mL of MeOH, and PtO2 (2.1 mg, 0.009 mmol)
was added. The flask was evacuated and filled with argon, then
evacuated again. A balloon filled with H2(g) was attached to the
flask. The flask was filled with H2, and the mixture was stirred
under H2 (1 atm) for 4.5 h. The flask was evacuated and filled with
argon, and the mixture was filtered through silica and rinsed with
EtOAc. Evaporation of the solvent afforded 14 (61 mg, 90%) which
was used without further purification. 1H NMR (CDCl3, 400 MHz):
δ 0.88 (t, J ) 6.8 Hz, 3H), 1.19 (d, J ) 6.3 Hz, 3H), 1.22-1.52
(m, 24H), 3.60 (m, 1H), 3.81 (m, 1H). 13C NMR (CDCl3, 100 MHz):
δ 14.1, 21.8, 22.7, 23.6, 25.7, 29.3, 29.6 (4 C), 29.7, 31.9, 37.2,
37.6, 39.1, 68.0, 71.8.
(3S,7R)-3,7-Bis(tert-butyldimethylsilyloxy)octanenitrile (10).
(3S,7R)-1d (147 mg, 0.93 mmol) was dissolved in 2 mL of dry
DMF and cooled to 0 °C. A solution of TBDMS-Cl (562 mg, 3.7
mmol) in 2 mL of dry DMF was added followed by imidazole
(254 mg, 3.7 mmol) dissolved in 2 mL of dry DMF. The resulting
mixture was stirred at room temperature for 2 days. Then water
was added and the mixture was extracted three times with Et2O.
The combined organic layers were washed with water and brine,
dried over MgSO4, and evaporated. Purification by chromatography
(pentane:Et2O 95:5) afforded 10 (344 mg, 95%). 1H NMR (CDCl3,
400 MHz): δ 0.04, (s, 3H), 0.05 (s, 3H), 0.08 (s, 3H), 0.11 (s, 3H),
0.88 (s, 9H), 0.90 (s, 3H), 1.11 (d, J ) 6.0, 3H), 1.24-1.70 (m,
6H), 2.42 (ABX, JAB ) 16.5 Hz, JAX ) 5.5 Hz, 1H), 2.47 (ABX,
JAB ) 16.5 Hz, JBX ) 5.7 Hz, 1H), 3.78 (m, 1H), 3.93 (m, 1H).
13C NMR (CDCl3, 100 MHz): δ -4.7 (2 C), -4.6, -4.4, 17.9,
18.1, 21.2, 23.8, 25.7, 25.9, 26.1, 37.2, 39.6, 68.3, 68.4, 117.8.
HRMS (ESI) (M + Na)+: m/z calcd for C20H43NNaO2Si2 408.2725,
obsd 408.2707.
((3S,7R)-3,7-Bis(tert-Butyldimethylsilyloxy)octanal (11). A
solution of 10 (325 mg, 0.84 mmol) in 14 mL of dry toluene was
cooled to -78 °C. DIBALH (1.26 mL, 1 M in toluene, 1.26 mmol)
was added dropwise, and the resulting mixture was stirred at -78
°C under argon. After 4 h, 5 mL of water containing 0.9 g of SiO2
powder was added, and the mixture was stirred at room temperature
for another 30 min. The solid was filtered off, and the mixture was
extracted with Et2O three times. The combined organic layers were
dried over MgSO4 and evaporated. Purification by chromatography
(pentane:Et2O 95:5) afforded 11 (253 mg, 77%). 1H NMR (CDCl3,
400 MHz): δ 0.04 (s × 2, 3H × 2), 0.05 (s, 3H), 0.07 (s, 3H), 0.87
(s, 9H), 0.88 (s, 9H), 1.11 (d, J ) 6.1 Hz, 3H), 1.24-1.61 (m,
6H), 2.51 (m, 2H), 3.77 (m, 1H), 4.18 (m, 1H), 9.81 (t, J ) 2.5
Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ -4.7 (2 C), -4.4 (2 C),
18.0, 18.1, 21.4, 23.8, 25.8, 25.9, 38.0, 39.8, 50.8, 68.3, 68.4, 202.4.
HRMS (ESI) (M + Na)+: m/z calcd for C20H44NaO3Si2 411.2721,
obsd 411.2709.
(2R,6S)-2,6-Dimesylheptadecane (15). Diol 14 (51.5 mg, 0.19
mmol) was dissolved in 3 mL of dry THF and cooled to 0 °C.
Et3N (63 µL, 0.45 mmol) was added followed by a dropwise
addition of MsCl (35 µL, 0.45 mmol). The resulting mixture was
stirred at 0 °C for 1.5 h, and water was added. The aqueous phase
was extracted with Et2O, and the combined organic phases were
dried over MgSO4 and evaporated. Purification by chromatography
(pentane:EtOAc 2:1 to EtOAc) afforded the title compound (63.2
1
mg, 78%). H NMR (CDCl3, 400 MHz): δ 0.88 (t, J ) 7.0 Hz,
3H), 1.22-1.38 (m, 18H), 1.42 (d, J ) 6.3 Hz, 3H), 1.48-1.82
(m, 8H), 3.01 (s, 6H), 4.70 (m, 1H), 4.80 (m, 1H). 13C NMR
(CDCl3, 100 MHz): δ 14.1, 20.7, 21.2, 22.7, 25.0, 29.3 (2 C), 29.4,
29.5, 29.6, 31.9 (2 C), 33.9, 34.6, 36.2, 38.6, 38.7, 79.6, 83.5.
(S,S)-2-Methyl-6-undecyl-1-(toluene-4-sulfonyl)-piperidine (16).
Dimesylate 15 (61.2 mg, 0.14 mmol) was dissolved in dry DMF
(2 mL), and NaHNTs (82.8 mg, 0.43 mmol) and Cs2CO3 (46.5 mg,
0.14 mmol) were added. The resulting mixture was heated at 50
°C for 5 days and was allowed to cool to rt. Water was added, and
the mixture was extracted with Et2O. The organic phases were
washed with water and brine, dried over MgSO4, and evaporated.
Purification by chromatography (pentane:Et2O 9:1 to Et2O) afforded
16 (36 mg, 62%). 1H NMR (CDCl3, 400 MHz): δ 0.88 (t, J ) 7.0
Hz, 3H), 1.23 (d, J ) 7.0 Hz, 3H), 1.23-1.79 (m, 26 H), 2.40 (s,
3H), 3.60 (m, 1H), 4.15 (m, 1H), 7.24 (m, 2H), 7.71 (m, 2H). 13C
NMR (CDCl3, 100 MHz): δ 14.1, 19.3, 20.2, 21.4, 22.7, 26.9, 28.1,
29.3, 29.5, 29.6 (3 C), 29.7, 31.0, 31.9, 32.8, 50.5, 55.6, 127.0,
129.3, 141.7, 142.3.
(+)-Solenopsin A (17). Sodium (9 mg, 0.39 mmol) was added
to a solution of naphthalene (50 mg, 0.39 mmol) in 1 mL of DME,
and the mixture was stirred at rt for 30 min. The resulting dark
green mixture was cooled to -78 °C, and 16 (26 mg, 0.064 mmol)
in 0.5 mL of DME was added dropwise. After stirring for 1 h at
-78 °C, brine was added, and the reaction was warmed to rt. The
mixture was extracted with EtOAc × 3, and the combined organic
phases were dried over Na2SO4 and evaporated. Purification by
chromatography (CH2Cl2:MeOH:NH4OH 90:10:1) afforded (+)-
Solenopsin A (17) (11 mg, 68%) as a pale yellow oil. NMR data
(2R,6S)-2,6-Bis(tert-butyldimethylsilyloxy)-8-heptadecene (12).
tBuOK (55 mg, 0.49 mmol) was dissolved in 3 mL of dry THF
and cooled to -78 °C. (1-Nonyl)triphenylphosphonium bromide
(230 mg, 0.49 mmol) was added, and the resulting orange mixture
was stirred for 20 min. A solution of 11 in 1 mL of dry THF was
added slowly, and the yellow mixture was stirred at -78 °C for
2 h then for another hour at room temperature. Brine was added,
and the mixture was extracted with three portions of Et2O. The
combined organic layers were dried over MgSO4 and evaporated.
Purification by chromatography (pentane:Et2O 98:2) afforded the
1
title compound (135 mg, 72%). H NMR (CDCl3, 400 MHz): δ
0.04 (2s, 2 × 6H), 0.88 (s, 9H), 0.89 (s, 9H), 1.11 (d, J ) 6.1 Hz),
1.22-1.47 (m, 18H), 2.01 (m, 2H), 2.19 (m, 2H), 3.65 (m, 1H),
(28) Pa`mies, O.; Ba¨ckvall, J.-E. AdV. Synth. Catal. 2001, 343, 726–731.
1992 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of (+)-Solenopsin A
agreed with those reported in the literature.29 [R]22 +7.3 (c )
with Kazlauskas’ rule.31 The absolute configuration of compound
(2R,6R)-3h was assigned on the bassis of the known absolute
configuration of (2R,6R)-3g, which was established in ref 11. Both
compounds follow Kazlauskas’ rule31 and differ only in that one
terminal methyl (3h) is replaced by a terminal ethyl (3g).
D
1.17, CHCl3) for the HCl salt, lit.22a [R]22D +7.5 (c ) 1.30, CHCl3).
Absolute Configuration of Chiral Compounds. The absolute
configuration of compounds 3a-3h was established in ref 11. The
absolute configuration of compounds (3S,7R)-1d, 10, 11, 12, 13,
14, 15, and 16 follows from the configuration of (3S,7R)-3d, since
(3S,7R)-1d, 10, and 11 are derivatives of (3S,7R)-3d, 12, 13, 14,
15, and 16, which are obtained from 11 without changing the chiral
center. The absolute configuration of (3S,7R)-1d, 10, 11, 12, 13,
14, 15, and 16 was confirmed by their transformation to the known
17 ((+)-Solenopsin). The absolute configuration of the latter
compound (17) was established by the sign of the optical rotation
(see above). Compound (R)-7 was prepared according to a literature
procedure which was reported to give the (R)-configuration.30 The
absolute configuration of (2R,6RS)-8 and (2RS,6R)-9 follows from
the configuration of (R)-7. The absolute configuration of (2S,6R)-
3i follows from the fact that the 6R configuration is established
through (R)-7, and that the acylation of chlorohydrins are known
to give the (S)-configuration according to ref 15, which is consistent
Acknowledgment. Financial support from the Swedish
Foundation for Strategic Research, the Swedish Research
Council, and the K & A Wallenberg Foundation is gratefully
acknowledged. We thank Amano Europe Ltd. for a gift of PS-C
“Amano” II and Johnson Matthey (New Jersey, USA) for a gift
of Ru3(CO)12.
Supporting Information Available: General methods. Prepa-
1
ration of diols and copies of H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8025109
(29) Girard, N.; Hurvois, J.-P. Synth. Commun. 2005, 35, 711–723.
(30) Uenichi, J.; Ohmi, M.; Ueda, A. Tetrahedron Asymmetry 2005, 16, 1299–
1303.
(31) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A.
J. Org. Chem. 1991, 56, 2656–2665.
J. Org. Chem. Vol. 74, No. 5, 2009 1993