Formation of macrocycles via ring-closing olefin metathesis

Article abstract of DOI:10.1021/jo0158480

The enhanced metathesis activity of 1,3-dimesityl-4,5-dihydroimidazole-2-ylidene ruthenium carbene catalyst 3 significantly increases the feasibility of synthesizing macrocyclic compounds. Catalyst 3 exhibits sufficient activity in RCM to dimerize α,β-unsaturated ester substrates and afford the corresponding head-to-tail (E,E)-dimeric (and trimeric) macrocycles. The dimerization appears to be under thermodynamic control with the product mixture dependent not only on the electronic and steric nature of the substrate but also on concentration.

Full text of DOI:10.1021/jo0158480

J . Org. Chem. 2001, 66, 7155-7158
7155
F or m a tion of Ma cr ocycles via Rin g-Closin g Olefin Meta th esis
Choon Woo Lee and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and
Chemical Engineering, California Institute of Technology, Pasadena, California 91125
rhg@its.caltech.edu
Received J une 18, 2001
The enhanced metathesis activity of 1,3-dimesityl-4,5-dihydroimidazole-2-ylidene ruthenium carbene
catalyst 3 significantly increases the feasibility of synthesizing macrocyclic compounds. Catalyst 3
exhibits sufficient activity in RCM to dimerize R,â-unsaturated ester substrates and afford the
corresponding head-to-tail (E,E)-dimeric (and trimeric) macrocycles. The dimerization appears to
be under thermodynamic control with the product mixture dependent not only on the electronic
and steric nature of the substrate but also on concentration.
In tr od u ction
Ring-closing olefin metathesis (RCM) is a highly ef-
ficient reaction for the synthesis of carbocyclic, hetero-
1
,2
cyclic and fused ring frameworks. While most RCM
reactions are performed using either Cl (PCy Rud
(ArN)ModCH(t-Bu) (2) as
2
3 2
)
3
4
3 2 2
CHPh (1) or ((CF ) MeCO)
catalyst, the former complex has enjoyed wide application
in organic synthesis due to its high functional group
tolerance. The activity of 1 can be greatly enhanced via
the substitution of a single phosphine ligand with 1,3-
dimesityl-4,5-dihydroimidazol-2-ylidene, an N-heterocy-
increase the scope of macrocycle synthesis, especially
those containing (E)-olefins or (E)-R,â-unsaturated esters.
Herein, we report the synthesis of various macrocyclic
lactones (14-26 membered) via RCM using catalyst 3.
5
clic carbene. The resulting complex 3 exhibits metathesis
activity that not only approaches 2, but also maintains
the high thermal stability and excellent functional group
tolerance of 1.6 In particular, high yields and trans-
selectivity of 14-membered lactones are obtainable through
macrocyclic RCM using 3. This excellent selectivity is
apparently related to the ability of 3 to rapidly isom-
erize olefins through “secondary metathesis” and ulti-
mately afford the thermodynamically favored ring-closed
product.6b
Resu lts a n d Discu ssion
Knowing that 3 effectively catalyzes the metathesis of
R,â-unsaturated esters, we focused efforts on the prepa-
ration of those macrocycles shown in Table 1. Attempted
cyclization of substrate 4 with 1 afforded only the linear
homo-dimeric compound 5, not the ring-closed product
7
(
Table 1, entry 1). When the more active catalyst 3 was
employed, the expected seven-membered ring was again
not observed, but instead the 14-membered dimeric ring-
closed product 6 was obtained in 59% yield (entry 2).
Interestingly, this RCM product was not simply that of
homo-dimer 5, but rather its “head-to-tail dimer”. When
As established by related studies in our group, complex
3
also displays significant activity toward previously
8
metathesis-inactive substrates, including R,â-unsatur-
ated carbonyl compounds.6 These abilities significantly
a
9
the same reaction was performed at higher concentration
(
1) For recent reviews in olefin metathesis, see: (a) Grubbs, R. H.;
(entries 3 and 4), the yield of dimer decreased, presum-
Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Wright, D. L. Curr.
Org. Chem. 1999, 3, 211-240. (c) F u¨ rstner, A. Angew. Chem., Int. Ed.
ably due to competing oligomerization. Further evidence
that product distribution is strongly dependent on con-
2
2
000, 39, 3012-3043. (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
001, 34, 18-29.
(2) (a) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem.
Soc. 1996, 118, 9606-9614. (b) Yang, Z.; He, Y.; Vourloumis, D.;
(5) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
(6) (a) Chatterjee, A. K.; Morgan, J . P.; Scholl, M.; Grubbs, R. H. J .
Am. Chem. Soc. 2000, 122, 3783-3784. (b) Lee, C. W.; Grubbs, R. H.
Org. Lett. 2000, 2, 2145-2147. (c) Bielawski, C. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. 2000, 39, 2903-2906.
Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1997, 36,
1
66-168. (c) Meng, D. F.; Bertinato, P.; Balog, A.; Su, D. S.; Kame-
necka, T.; Sorensen, E. J .; Danishefsky, S. J . J . Am. Chem. Soc. 1997,
1
19, 10073-10092. (d) Lee, D.; Sello, J . K.; Schreiber, S. L. J . Am.
Chem. Soc. 1999, 121, 10648-10649. (e) Paquette, L. A.; Fabris, F.;
Tae, J . S.; Gallucci, J . C.; Hofferberth, J . E. J . Am. Chem. Soc. 2000,
(7) It appears that the reaction between complex 1 and acrylates is
slow and facilitates catalyst decomposition, see: Ulman, M.; Belder-
rain, T. R.; Grubbs, R. H. Tetrahedron Lett. 2000, 41, 4689-4693.
(8) The major RCM products of 4 and 7, assigned as the monomeric
ring-closed compounds in ref 6a, were later found to be dimeric or
trimeric rings by additional characterization, see: Lefloch, Y.; Yverg-
naux, F.; Toupet, L.; Gree, R. Bull. Soc. Chim. Fr. 1991, 742-759. The
dimeric product 6 was obtained by RCM using an analogue of complex
3, see: F u¨ rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H. J .; Nolan,
S. P. J . Org. Chem. 2000, 65, 2204-2207.
1
22, 3391-3398. (f) Smith, A. B.; Kozmin, S. A.; Adams, C. M.; Paone,
D. V. J . Am. Chem. Soc. 2000, 122, 4984-4985. (g) F u¨ rstner, A.; Thiel,
O. R.; Kindler, N.; Bartkowska, B. J . Org. Chem. 2000, 65, 7990-7995.
(h) Crimmins, M. T.; Emmitte, K. A. J . Am. Chem. Soc. 2001, 123,
1
533-1534. (i) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.; J amieson, J .
Y.; Schrock, R. R.; Hoveyda, A. H. J . Am. Chem. Soc. 2001, 123, 3139-
3
140.
(
3) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
1
18, 100-110.
(4) Schrock, R. R.; Murdzeck, J . S.; Bazan, G. C.; Robbin, J .; Dimare,
(9) For a previous example, “the head-to-tail” dimer of unfunction-
alized olefin was obtained by RCM using 1 or 3, see: ref. (2f).
M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875-3886.
1
0.1021/jo0158480 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/15/2001

7
156 J . Org. Chem., Vol. 66, No. 21, 2001
Ta ble 1. F or m a tion of Ma cr ocycles via RCMa
Grubbs and Lee
b
c
entry
substrates
conc (mM)
catalyst (mol %)
products (% yield )
1
2
3
4
5
6
7
8
9
4
4
4
4
7
30
3
30
100
2
6
100
2
3
1 (5.0)
3 (5.0)
3 (5.0)
3 (5.0)
3 (7.5)
3 (5.0)
3 (5.0)
3 (5.0)
3 (5.0)
5 (62)
6 (59)
6 (39)
6 (17)
8 (38), 9 (38)
8 (20), 9 (54)
9 (73)
7
7
d
10 (37)e
12 (75)
7
11f
a
Unless otherwise noted, reactions were performed in refluxing CH2Cl2 under an atmosphere of argon. b The spectroscopic data ( H,
1
1
3
C, IR, HR-MS) of the products were in agreement with their previously reported values (see ref 8). Isolated yields. d Reaction was
c
performed in refluxing THF. No starting material remained. f The compound 11 is methacrylate compound, CH2dC(CH3)COO(CH2)4CHdCH2.
e
Ta ble 2. RCM of Va r iou s r,â-Un sa tu r a ted Ester
centration was obtained from a study of substrate 7 (a
homologous isomer of 4). As shown in Table 1 (entries
Con ta in in g Su bstr a tes w ith 3a
5
-7), increasing initial concentration of substrate de-
creases yields of product 8. However, a close analysis of
the reaction mixtures reveals that the “head-to-tail”
trimeric ring-closed product 9 (24-membered) was formed
concomitantly with the loss of dimer. In fact, under more
concentrated conditions, the sole isolated product (73%)
was the cyclic trimer 9 (entry 7). Since olefin metathesis
presumed to be under thermodynamic control, the de-
pendence of product distribution on concentration is
presumably a reflection of the relative stabilities of the
various macrocycles (monomer, dimer, trimer, etc).10 In
all cases, only the thermodynamically favored E isomers
were observed, as noted previously in the metathesis of
other acrylic compounds.6
a
Macrocycle formation appears to be dependent not only
on activity of the catalyst, but also on solvent. THF
sufficiently attenuates catalyst activity (presumably due
to competitive solvent coordination). With THF as sol-
vent, the only acyclic homo-dimer 10 was isolated (entry
1
1
8
). Likewise, only acyclic homo-dimer was obtained
when an analogous substrate 11, containing a relatively
sterically hindered olefin (a methacrylate), was employed
a
Reactions were performed in refluxing CH2Cl2 using cata-
b
lyst 3 (5 mol %) under an atmosphere of argon. Isolated yields.
(
entry 9). Additional studies show that substrate struc-
c
Yield with using catalyst 1 (5 mol %). Only 26% yield is obtained
under these conditions for catalyst 3. E/ Z ) 3.6:1 on GC and
ture has a significant influence on product formation as
well (Table 2). The steric difference (i.e., a methyl group)
between 7 and 13 has a profound effect on the dimer-
trimer distribution in the product mixture (entry 10 vs
12
NMR.
chain length in substrates 7 and 15, the presence of
oxygen atoms in the latter influences the product distri-
bution presumably differences in bond angles in 15
stabilizes the ring-closed dimer even at similar concen-
trations. Conformational restriction must also play an
important role in the RCM of R,â-unsaturated ester
containing substrates (entry 13). The six-membered ring
in 17 should enforce the proximity of olefins, thereby
favoring the ring-closed monomeric compound. By com-
paring substrates 19 and 21, it is clear that the presence
of an R,â-unsaturated carbonyl in the substrate is critical
for the formation of dimerized macrocycles (entry 14 vs
15).
1
1 in Table 2).
The observed product distributions are also presum-
ably dependent on the relative thermodynamic stabilities
of macrocycles. Heteroatom substitution (i.e., carbon for
oxygen) in the substrate affects the observed products
distribution (entry 5 vs entry 12). Despite the similar
(10) Efforts towards elucidating the factors that determine this
distribution (e.g., the critical concentration, see: Chen, Z. R.; Claverie,
J . P.; Grubbs, R. H.; Kornfield, J . A. Macromolecules 1995, 28, 2147-
2
154.) are currently in progress. The dependence of product distribution
on concentration also applies to the RCM of normal olefins, see:
Arisawa, M.; Kato, C.; Kaneko, H.; Nishida, A.; Nakagawa, M. J . Chem.
Soc., Perkin Trans. 1, 2000, 1873-1876.
The ability to form R,â-unsaturated esters via olefin
metathesis opens a number of avenues for preparing
synthetically relevant large ring systems. For example,
(11) Reduced activity of Ru based complexes in THF has been
previously observed, see: Nguyen, S. T. Ph.D. Thesis, California
Institute of Technology, Pasadena, CA, 1995.

Ring-Closing Olefin Metathesis
J . Org. Chem., Vol. 66, No. 21, 2001 7157
Sch em e 1
the macrocyclic compound 8 has been previously oxidized
be under thermodynamic control, with the product mix-
ture dependent not only on the substrate (i.e., steric and
electronic factors) but also on concentration. This dimer-
ization process opens new vistas in the rapid synthesis
of macrocyclic compounds, including natural products.
Variation of substituent arrangement and reaction con-
centration provides the opportunity to easily produce a
wide array of macrocycles with readily adjustable ring
sizes.
1
3
to norpyrenophorin, a derivative of the anti-fungal, anti-
bacterial natural product pyrenophorin.14 Likewise, the
macrocycle formation strategy described above was ex-
tended toward a concise total synthesis of (-)-pyreno-
phorin itself (Scheme 1).
As shown in Table 2, RCM of 13 at standard concen-
tration (6 mM in CH
2
Cl
2
) afforded trimeric compound 14
(81%). Gratifyingly, the desired head-to-tail (E,E)-dimer
2
3 (46%) (along with trimer 14, 39%) is obtained under
1
4a
more dilute conditions (1 mM). As previously reported,
Exp er im en ta l Section
oxidation of 23 with CrO affords (-)-pyrenophorin (24)
3
in 76% yield.15 In an effort to understand the pathways
Gen er a l. NMR spectra were recorded on GE-300 NMR.
High-resolution mass spectra (EI or CI) were provided by the
UCLA Mass Spectrometry Facility (University of California,
Los Angeles). FTIR were obtained as thin films on NaCl plates.
Analytical thin-layer chromatography (TLC) was performed
using silica gel 60 F254 precoated plates (0.25 mm thickness)
with a fluorescent indicator. Flash column chromatography
was performed using silica gel 60 (230-400 mesh) from EM
Science. All other chemicals were purchased from the Aldrich,
Strem, or Nova Biochem Chemical Companies, and used as
involved in macrocycle formation, isolated homo-dimeric
compounds 5 and 25 were resubjected to catalyst 3 in
order to isolate the respective cyclic dimers 6 or 20 (eq
1
). The desired dimers were obtained in moderate to good
yield, depending on ring size.
delivered unless noted otherwise. CH
passage through a solvent column prior to use.
2 2
Cl was purified by
1
7
Gen er a l P r oced u r e for Ma cr ocyclic F or m a t ion via
Rin g-Closin g Olefin Meta th esis. To a solution of diene 7
(
3
16 mg, 0.10 mmol) in CH
(6.6 mg, 0.0050 mmol) in CH
2
Cl
2
(50 mL) was added Ru complex
Cl (2.0 mL) via cannula
2
2
tarnsfer, and the reaction mixture was refluxed under argon
for 11 h. The reaction mixture was then reduced in volume to
1
2
mL and purified directly on a silica gel column, eluting with
0% hexanes-ethyl acetate to give the cyclized products 8 (5.0
mg, 38%) and 9 (5.0 mg, 38%).
1
Com p ou n d 5. H NMR (300 MHz, CDCl
3
, ppm): δ 6.39 (2H,
dd, J ) 17.1, 1.8 Hz), 6.11 (2H, dd, J ) 17.1, 10.5 Hz), 5.81
While formation of macrocyclic trimer may proceed
analogously (i.e., from an acyclic trimer), an alternative
pathway via dimer-trimer metathetical equilibration
was independently established. As shown in eq 2, treat-
(
2H, dd, J ) 10.5, 1.8 Hz), 5.43 (2H, m), 4.14 (4H, t, J ) 6.6
1
3
3
Hz), 2.08 (4H, m), 1.72 (4H, m). C NMR (75 MHz, CDCl ,
ppm): δ 166.4, 130.8 ∼ 128.7 (m), 64.3, 29.2 ∼ 28.7 (m), 23.9.
-1
IR (cm ): 2955, 1725, 1637, 1409, 1296, 1271, 1190. R ) 0.33
f
2 2
ment of 8 with catalyst 3 (10 mM in CH Cl ) afforded
(
21 4
10% hexanes-ethyl acetate). HRMS (FAB) calcd for C14H O
trimer 9 in 50% yield.16 This observation demonstrates
that byproducts of metathesis reactions are easily re-
cycled. In summary, catalyst 3 exhibits sufficient activity
in RCM to dimerize R,â-unsaturated ester substrates,
affording the corresponding head-to-tail (E,E)-dimeric
+
[M+H] 253.1440, found 253.1436.
1
Com p ou n d 6. H NMR (300 MHz, CDCl
3
, ppm): δ 7.02 (2H,
dt, J ) 15.6, 7.2 Hz), 5.65 (2H, dt, J ) 15.6, 1.8 Hz), 4.27 (4H,
t, J ) 4.8 Hz), 2.37 (4H, m), 1.93 (4H, m). C NMR (75 MHz,
1
3
-
1
CDCl
961, 1704, 1635. R
HRMS (EI) calcd for C12
3
, ppm): δ 166.1, 150.9, 120.7, 65.0, 31.9, 28.4. IR (cm ):
2
f
) 0.46 (30% hexanes-ethyl acetate).
(and trimeric) macrocycles. The dimerization appears to
+
H
16
O
4
[M] 224.1049, found 224.1049.
Com p ou n d 8. H NMR (300 MHz, CDCl , ppm): δ 6.96 (2H,
dt, J ) 15.9, 6.6 Hz), 5.88 (2H, dt, J ) 15.9, 1.5 Hz), 4.16 (4H,
1
3
(12) The E/ Z ratio of compound 22 was obtained on GC and NMR
by comparison with the authentic sample prepared by reported method,
see: Cameron, A. G.; Knight, D. W. J . Chem. Soc., Perkin Trans. 1,
1
3
t, J ) 5.4 Hz), 2.30 (4H, m), 1.71 (8H, m). C NMR (75 MHz,
CDCl , ppm): δ 166.4, 149.0, 122.5, 64.2, 31.1, 27.3, 24.7. IR
1
1
986, 161-167.
13) Bestmann, H. J .; Schobert, R. Angew. Chem., Int. Ed. Engl.
985, 24, 791-792.
14) (a) Mali, R. S.; Pohmakotr, M.; Weidmann, B.; Seebach, D.
3
(cm 1): 2935, 1718, 1654. R
-
) 0.55 (30% hexanes-ethyl
(
f
+
acetate). HRMS (CI, NH
3
20 4
) calcd for C14H O
[M] 252.1362,
(
found 252.1368.
Com p ou n d 9. H NMR (300 MHz, CDCl
Liebigs Ann. Chem. 1981, 2272-2284. (b) Kobayashi, Y.; Nakano, M.;
Kumar, G. B.; Kishihara, K. J . Org. Chem. 1998, 63, 7505-7515. (c)
G o¨ tz o¨ , S. P.; Seebach, D.; Sanglier, J .-J . Eur. J . Org. Chem. 1999,
1
3
, ppm): δ 6.96 (3H,
dt, J ) 15.9, 6.9 Hz), 5.84 (3H, dt, J ) 15.9, 1.2 Hz), 4.17 (6H,
1
3
2
533-2544.
t, J ) 5.7 Hz), 2.24 (6H, m), 1.68 (6H, m), 1.56 (6H, m).
C
(
15) During the preparation of this manuscript, a similar synthesis
NMR (75 MHz, CDCl , ppm): δ 166.7, 148.8, 121.8, 64.0, 32.1,
3
of pyrenophorin was recently reported, see: F u¨ rstner, A.; Thiel, O. R.;
Ackermann, L. Org. Lett. 2001, 3, 449-451. Previous work has
suggested that catalyst identity is important; however, we believe that
the key issue for pyrenophorin synthesis by using catalyst 3 is the
use of RCM under high dilute substrate concentrations.
(17) The solvent columns are composed of activated alumina (A-2)
and supported copper redox catalyst (Q-5 reactant). See: Pangborn,
A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J .
Organometallics 1996, 15, 1518-1520.
(16) Dimer 8 (<50%) was also observed.

7
158 J . Org. Chem., Vol. 66, No. 21, 2001
8.6, 25.1. IR (cm-1): 2945, 1719, 1655. R
Grubbs and Lee
Com p ou n d 18. H NMR (300 MHz, CDCl , ppm): δ 6.45
1
2
f
) 0.46 (30%
) calcd for C21
3
hexanes-ethyl acetate). HRMS (CI, NH
3
H
30
O
6
(1H, ddd, J ) 11.1, 2.7, 0.6 Hz), 6.03 (1H, ddd, J ) 11.1, 2.7,
0.9 Hz), 4.32 (1H, m), 4.02 (1H,dquint, J ) 11.1, 2.4 Hz), 3.83
(1H, ddd, J ) 8.7, 7.8, 2.4 Hz), 3.45 (1H, ddd, J ) 12.0, 11.1,
2.4 Hz), 2.72 (1H, m), 2.37 (1H, m), 2.23 (1H, m), 2.04 (1H,
+
[M] 378.2042, found 378.2044.
1
Com p ou n d 10. H NMR (300 MHz, CDCl
3
, ppm): δ 6.41
(
5
6
2H, dd, J ) 17.4, 1.8 Hz), 6.12 (2H, dd, J ) 17.4, 10.5 Hz),
.82 (2H, dd, J ) 10.5, 1.8 Hz), 5.41 (2H, m), 4.15 (4H, t, J )
m), 1.78 (1H, m), 1.45 (1H, m). 13C NMR (75 MHz, CDCl
3
,
1
3
.6 Hz), 2.10 (4H, m), 1.70 ∼ 1.40 (8H, m). C NMR of major
ppm): δ 169.5, 139.0, 125.2, 77.0, 73.7, 67.9, 31.7, 28.2, 20.8.
1
-
(trans) component (75 MHz, CDCl
3
, ppm): δ 166.6, 130.7,
f
IR (cm ): 2957, 1723, 1691. R ) 0.15 (30% hexanes-ethyl
-1
+
1
1
30.5, 128.8, 64.8, 32.3, 28.3, 26.1. IR (cm ): 2998, 2361, 1726,
637, 1408, 1296, 1273, 1191. R
9 12 3
acetate). HRMS (EI) calcd for C H O [M] 168.0786, found
f
) 0.29 (10% hexanes-ethyl
168.0787.
+
1
acetate). HRMS (EI) calcd for C16
found 279.1606.
H
23
O
4
[M-H] 279.1596,
Com p ou n d 20. H NMR (300 MHz, CDCl , ppm): δ 6.95
3
(2H, dt, J ) 15.6, 6.9 Hz), 5.81 (2H, dt, J ) 15.6, 1.2 Hz), 4.15
1
13
Com p ou n d 12. H NMR (300 MHz, CDCl
3
, ppm): δ 6.09
(4H, t, J ) 6.0 Hz), 2.19 (4H, m), 1.52 ∼ 1.25 (28H, m).
C
(
2H, m), 5.54 (2H, t, J ) 1.5 Hz), 5.40 (2H, m), 4.14 (4H, t, J
NMR (75 MHz, CDCl , ppm): δ 166.9, 149.4, 121.6, 64.4, 32.3,
3
1
3
-1
)
6.6 Hz), 2.10 (4H, m), 1.94 (s, 6H), 1.70 ∼ 1.40 (8H, m).
C
29.3, 29.2, 29.0, 28.9, 28.0, 26.3. IR (cm ): 2922, 1717, 1643.
NMR of major (trans) component (75 MHz, CDCl
3
, ppm): δ
R ) 0.33 (10% hexanes-ethyl acetate). HRMS (EI) calcd for
f
-
1
+
1
67.8, 136.7, 130.5, 125.4, 64.9, 32.3, 28.3, 26.1, 18.6. IR (cm ):
2
C H O [M] 392.2927, found 392.2915.
2
4
40
4
1
931, 1720, 1639, 1453, 1322, 1297, 1164. R
hexanes-ethyl acetate). HRMS (EI) calcd for C18
09.2066, found 309.2069.
P r ep a r a tion of (R)-6-Hep ten -2-ol. To a mixture of (R)-
f
) 0.46 (10%
Com p ou n d 22. H NMR (300 MHz, CDCl , ppm): δ 5.83
3
+
H
29
O
4
[M+H]
∼ 5.61 (2H, m), 4.52 and 4.50 (2H, d, J ) 6.9 Hz and d, J )
3
7.5 Hz), 2.36 ∼ 2.10 (2H, m), 2.02 (2H, m), 1.70 ∼ 1.20 (12H,
m). 13C NMR (75 MHz, CDCl , ppm) δ 140.2, 139.3, 125.5,
3
1
8
propylene oxide (0.30 mL, 4.3 mmol) and CuCN (19 mg, 0.21
mmol) in THF (8 mL) was added the 3-butenylmagnesium
bromide (0.49 M in THF, 13 mL, 6.4 mmol) for 1h. The
resulting mixture was stirred below -30 °C for 1h, warmed
to 0 °C over 1h, and then poured into a NH
solution with stirring. The solution was extracted with diethyl
ether, washed with brine solution, dried over MgSO , and
concentrated to give a residue, which was purified by chro-
matography (20% hexanes-ethyl acetate) to afford (R)-6-
hepten-2-ol (0.40 g, 3.5 mmol) as a colorless liquid.
123.3, 63.6, 35.1, 31.4.31.0, 26.5, 25.9 ∼ 25.4 (m), 24.7, 24.6,
24.1. R ) 0.50 (10% hexanes-ethyl acetate). m/z: 196 (12%,
f
1
8
+
M ), 167 (7), 153 (10), 136 (16), 125 (19), 121 (19), 112 (40), 99
(11), 98 (56), 95 (57), 91 (72), 67 (84), 55 (100). HRMS (EI)
+
4
Cl saturated
calcd for C H O [M] 196.1463, found 196.1459.
1
2
20
2
1
Com p ou n d 23. H NMR (300 MHz, CDCl , ppm): δ 6.94
3
4
(
(
6
7
1
2H, dt, J ) 15.9, 7.2 Hz), 5.85 (2H, dt, J ) 15.9, 1.5 Hz), 5.01
2H, m), 2.21 (4H, m), 1.80 ∼ 1.50 (8H, m), 1.25 (6H, d, J )
13
3
.3 Hz). C NMR (75 MHz, CDCl , ppm): δ 166.0, 148.4, 122.8,
-1
0.5, 33.4, 31.0, 22.2, 19.4. IR (cm ): 2976, 2937, 1715, 1652,
454, 1354, 1268, 1195, 1172, 1133. R ) 0.61 (30% hexanes-
) calcd for C16
1
(
R)-6-Hep ten -2-ol. H NMR (300 MHz, CDCl
3
, ppm): δ 5.81
f
(1H, m), 4.98 (2H, m), 3.80 (1H, m), 2.06 (2H, m), 1.45 (4H,
+
ethyl acetate). HRMS (CI, NH
81.1753, found 281.1746.
3
H
25
O
4
[M+H]
1
3
3
m), 1.19 (3H, d, J ) 6.0 Hz). C NMR (75 MHz, CDCl , ppm):
δ 138.9, 114.8, 68.3, 39.1, 34.0, 25.4, 23.9. IR (cm ): 3351,
2
-
1
1
(
-)-P yr en op h or in 24. H NMR (300 MHz, CDCl
3
, ppm):
2
)
969, 2932, 2862, 1642, 1459, 1375, 1321, 1122, 996, 910. R
f
δ 6.95 (2H, d, J ) 15.6 Hz), 6.49 (2H, d, J ) 15.6 Hz), 5.04
2
6
0.59 (30% hexanes-ethyl acetate), [R]
) (reported value of (S)-6-hepten-2-ol: [R]
)), HRMS (EI) calcd for C
D
) -12.9° (c) 6.9
(
2H, m), 2.72 ∼ 2.48 (4H, m), 2.09 (4H, m), 1.29 (6H, d, J )
19 26
in CHCl
3
D
) +10.4°
13
6
1
1
.3 Hz). C NMR (75 MHz, CDCl
3
, ppm): δ 199.8, 165.1, 139.8,
+
(
1
c ) 0.79 in CHCl
3
7
H
15O [M+H]
-1
31.6, 72.5, 37.7, 32.4, 20.0. IR (cm ): 3066, 2974, 2929, 1720,
15.1123, found 115.1127.
26
690, 1654, 1637. R
f
) 0.30 (30% hexanes-ethyl acetate), [R]
D
1
Com p ou n d 13. H NMR (300 MHz, CDCl
3
, ppm): δ 6.39
20
20
)
-48.1° (c) 0.32 in CHCl
3
) (reported value: [R]
D
) -47.6°
(
5
1
1H, dd, J ) 17.4, 1.5 Hz), 6.10 (1H, dd, J ) 17.4, 10.5 Hz),
20
(
c) 0.17 in CHCl
3
)), mp 168 ∼ 169 °C (reported value: 170
+
21 6
.80 (2H, m), 4.98 (2H, m), 2.06 (2H, q, J ) 7.2 Hz), 1.70 ∼
∼
171 °C), HRMS (EI) calcd for C16
H
O
[M+H] 309.1338,
, ppm): δ 6.40
.38 (4H, m), 1.25 (3H, d, J ) 6.3 Hz)). 13C NMR (75 MHz,
found 309.1336.
CDCl
3
1
3
, ppm): δ 166.0, 138.6, 130.5, 129.2, 115.0, 71.4, 35.7,
1
Com p ou n d 25. H NMR (300 MHz, CDCl
3
-1
3.8, 25.0, 20.4. IR (cm ): 2979, 2938, 1724, 1640, 1406, 1381,
296, 1272, and 1199. R ) 0.50 (10% hexanes-ethyl acetate),
(
5
6
(
2
0
2H, dd, J ) 17.4, 1.5 Hz), 6.12 (2H, dd, J ) 17.4, 10.2 Hz),
f
.81 (2H, dd, J ) 10.2, 1.5 Hz), 5.36 (2H, m), 4.14 (4H, t, J )
+
HRMS (EI) calcd for C10
69.1233.
Com p ou n d 14. H NMR (300 MHz, CDCl
H
17
O
2
[M+H] 169.1229, found
13
.9 Hz), 1.90 (4H, m), 1.70 (4H, m), 1.30 (m, 12H). C NMR
1
75 MHz, CDCl
3
, ppm): δ 166.5, 130.7 ∼ 128.9 (m), 65.0, 33.0,
1
3
, ppm): δ 6.93
-1
9.8 ∼ 26.3 (m), 23.9. IR (cm ): 2922, 2854, 1726, 1636.R
f
)
(
(
3H, dt, J ) 15.6, 8.1 Hz), 5.79 (3H, dt, J ) 15.6, 1.5 Hz), 4.97
.33 (10% hexanes-ethyl acetate), HRMS (EI) calcd for
3H, m), 2.32 ∼ 2.03 (6H, m), 1.68 ∼ 1.42 (12H, m), 1.24 (9H,
+
C
26
H
44
O
4
[M] 421.3318, found 421.3307.
1
3
d, J ) 6.0 Hz). C NMR (75 MHz, CDCl
1
1
3
, ppm): δ 166.4, 148.8,
-1
21.9, 70.5, 36.3, 32.5, 24.6, 20.7. IR (cm ): 2975, 2937, 1716,
655, 1461, 1358, 1269, 1202, 1175. R ) 0.53 (30% hexanes-
) calcd for C24
Ack n ow led gm en t. Support has been generously
f
+
provided by the National Institutes of Health. J ohn P.
Morgan, Christopher W. Bielawski, Arnab K. Chatter-
jee, and Tae-Lim Choi are also acknowledged for helpful
discussions.
ethyl acetate). HRMS (CI, NH
21.2590, found 421.2603.
3
37 6
H O [M+H]
4
1
Com p ou n d 16. H NMR (300 MHz, CDCl
2H, dt, J ) 15.6, 4.2 Hz), 6.37 (2H, dt, J ) 15.6, 2.1 Hz), 4.30
4H, m), 4.22 (4H, m), 3.73 (4H, m). 13C NMR (75 MHz, CDCl
3
, ppm): δ 7.00
(
(
3
,
-1
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 5-25 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
ppm): δ 165.8, 145.3, 121.9, 70.3, 70.1, 64.1. IR (cm ): 2918,
1
ethyl acetate). HRMS (EI) calcd for C12
found 257.1029.
722, 1462, 1383, 1315, 1279, 1188. R ) 0.19 (30% hexanes-
f
+
17 6
H O [M+H] 257.1025,
J O0158480
(
(
18) Purchased from Aldrich and used as received.
19) Takahata, H.; Yotsui, Y.; Momose, T. Tetrahedron 1998, 54,
(20) Sugai, T.; Katoh, O.; Ohta, H. Tetrahedron 1995, 51, 11987-
11998.
1
3505-13516.