Catalytic asymmetric synthesis of macrocyclic (E)-allylic alcohols from ω-alkynals via intramolecular 1-alkenylzinc/aldehyde additions

Article abstract of DOI:10.1021/jo000463n

The ω-alkynals yielded macrocyclic (S)-allylic alcohols in a one-pot reaction sequence involving alkyne monohydroboration, boron to zinc transmetalation, and ((+)-DAIB)-catalyzed enantioselective intramolecular ring closure to the aldehyde function. A general study of this macrocyclization methodology is presented with respect to ligand type, size, and nature of the formed rings.

Full text of DOI:10.1021/jo000463n

4766
J . Org. Chem. 2001, 66, 4766-4770
Ca ta lytic Asym m etr ic Syn th esis of Ma cr ocyclic (E)-Allylic Alcoh ols
fr om ω-Alk yn a ls via In tr a m olecu la r 1-Alk en ylzin c/Ald eh yd e
Ad d ition s
Wolfgang Oppolzer,† Rumen N. Radinov,‡ and Emad El-Sayed*,§
De´partement de Chimie Organique, Universite´ de Gene`ve, CH-1211 Gene`ve 4, Switzerland
emadel-sayed@carbogen.com
Received March 28, 2000 (Revised Manuscript Received March 27, 2001)
The ω-alkynals yielded macrocyclic (S)-allylic alcohols in a one-pot reaction sequence involving
alkyne monohydroboration, boron to zinc transmetalation, and ((+)-DAIB)-catalyzed enantioselective
intramolecular ring closure to the aldehyde function. A general study of this macrocyclization
methodology is presented with respect to ligand type, size, and nature of the formed rings.
Sch em e 1. Gen er a l Ap p r oa ch to Ma cr ocyclic
In tr od u ction
(E)-a llylic Alcoh ols
Asymmetric catalytic processes have found increasing
application in the synthesis of complex chiral molecules
and natural products.1 Rate acceleration of reactions
apart, the use of chiral catalysts benefits the transfer and
multiplication of chirality. A prime example, and often a
test case for new chiral ligands, is the catalytic enantio-
selective addition of dialkylzinc reagents to aldehydes.2
Oppolzer and Radinov have broadened the scope of
applications of this methodology to include the catalytic
enantioselective addition of alkenylzinc reagents to ali-
phatic as well as aromatic aldehydes.3 Intramolecular
addition of alkenylzinc reagents to the aldehyde function
has subsequently been applied to the synthesis of two
macrocyclic natural products, (R)-(-)-muscone4a and (+)-
aspicilin.4b
Herein, we report a systematic study of this macrocy-
clization methodology with respect to (i) reproducibility,
(ii) ligand type, and (iii) size and nature of the macrocycle.
Sch em e 2. Syn th esis of Ca r bocycle P r ecu r sor s
Resu lts a n d Discu ssion
Our general approach to macrocyclic (E)-allylic alcohols
is outlined in Scheme 1.4 Selective monohydroboration
of readily available ω-alkynals 1 (X ) CH2 or an ester
group as part of the tether), boron/zinc-transmetalation
(2 f 3) and chiral ligand-catalyzed intramolecular ad-
dition of the alkenylzinc intermediate 3 to the aldehyde
group offers an efficient approach to chiral allyl alcohol-
containing carbocycles and macrolides 4.
† Deceased on March 15, 1996.
‡ Present address: Hoffmann-LaRoche, Inc., Chemical Synthesis
Department, 66/208, 340 Kingsland Street, Nutley, NJ 07110-1199.
§ Present address: CarboGen Laboratories (Neuland) AG, Neuland-
weg 5, CH-5502 Hunzenschwil, Switzerland.
(1) (a) Noyori, R. In Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Seyden-Penne, J . In Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; Wiley: New York, 1995.
(2) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49. (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (c) Erdik, E. In
Organozinc Reagents in Organic Synthesis; CRC: New York, 1996; pp
107-206.
As indicated in Scheme 2, lithiation of the com-
mercially available THP-protected propargyl alcohol 5
followed by reaction with alkyl bromides,5 base-induced
alkyne isomerization of the resulting 2-alkyn-1-ols 6,6 and
finally Parikh-Doering oxidation7 afforded ω-alkynals 8
(3) (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645.
(b) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777. (c)
Oppolzer, W.; Radinov, R. N. Helv. Chem. Acta 1992, 75, 170.
(4) (a) Oppolzer, W.; Radinov, R. N. J . Am. Chem. Soc. 1993, 115,
1593. (b) Oppolzer, W.; Radinov, R. N.; De Brabander, J . Tetrahedron
Lett. 1995, 36, 2607.
(5) (a) Schwarz, M.; Waters, R. M. Synthesis 1972, 567. (b) Mitra,
R. B.; Reddy, G. B. Synthesis 1989, 694.
(6) KAPA ) Potassium 3-aminopropylamide. Abrams, S. R. Can. J .
Chem. 1984, 62, 1333.
(7) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
10.1021/jo000463n CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/20/2001

Macrocyclic (E)-Allylic Alcohols from ω-Alkynals
J . Org. Chem., Vol. 66, No. 14, 2001 4767
Ta ble 2. Syn th esis of ω-Alk yn a ls 16
Sch em e 3. Syn th esis of Ma cr olid e P r ecu r sor s
yield (%)a
chain
entry
n
m
length
11
12
13
14
15
16
a
b
c
d
4
7
4
4
4
4
8
12
15
16
20
53
76
-
92
88
-
95
99
-
65
67
65
70
93
91
97
96
83
83
90
75
12
-
-
-
a
Yields refer to isolated and purified compounds.
Ta ble 3. Syn th esis of ω-Alk yn a ls 19
yield (%)a
method A
method B
chain
length
Sch em e 4. Syn th esis of Ma cr olid e P r ecu r sor s
Ha vin g th e Op p osite Disp osition of th e Ester
F u n ction
entry
x
y
18
19
20
19
a
b
2
2
9
10
15
16
56
51
76
71
81
60
-
-
a
Yields refer to isolated and purified compounds.
optimum conditions for the transmetalation/intramolecu-
lar alkenylzinc-aldehyde addition (eq 1). Thus reaction
Ta ble 1. Syn th esis of ω-Alk yn a ls 8
yield (%)a
chain
entry
z
length
6
7
10
7
8b
of 8c with freshly prepared dicyclohexylborane dimethyl
sulfide complex at -20 °C to 0 °C led to a selective
monohydroboration of the alkyne function. This was
followed by dilution and slow addition (over 4 h) to 2 mol
% 21/Et2Zn mixture at 0 °C. Workup with aq NH4Cl
provided the expected (S)-allylic alcohol 25c.
a
b
c
d
e
8
13
14
15
18
21
85
-
77
79
68
70
-
76
82
77
-
54
-
-
-
-
72
-
-
-
76 (A)
87 (B)
81 (A)
52 (A)
72 (A)
9
10
13
16
a
b
Yields refer to isolated and purified compounds. The method
used for the synthesis is indicated in parentheses.
Our early attempts to effect the macrocyclization by
the original procedure4a using the (+)-DAIB ligand 21 (1
mol %) afforded the 15-membered macrocycle 25c in only
36-39% yield (84% ee) together with 7% of the open
chain reduced product 26c. Yields and selectivities were
improved by (i) careful drying (over LiAlH4) and degas-
sing of n-hexane (HPLC-grade), (ii) drying (over CaH2)
and degassing of cyclohexene, (iii) distilling 21 prior to
its use, (iv) weighing the chiral ligands in a glovebox and
preparing stock solutions in dry degassed n-hexane for
more precise and practical manipulation, and (v) distill-
ing Et2Zn under high vacuum (20 °C/0.2 mmHg).
Carring out the reaction at 0.3-0.4 M dilution using
(1S)-(+)-3-exo-(dimethylamino)isoborneol ((+)-DAIB) (21)13
as chiral ligand resulted in product polymerization rather
than cyclization (Table 4, entry 1). At higher dilution,
macrocyclization was successful and after some experi-
mentation, optimal conditions were found using dilution
values of 0.05 M for both hydroborated intermediate and
the Et2Zn/(+)-DAIB mixture (Table 4, entries 2-5).
Using the optimized procedure for the macrocycliza-
tion of ω-alkynal 8c (eq 1), a number of chiral ligands
were tested in the reaction: (+)-DAIB 21,13 (S,S)-Zn-
(STDMBA)2 22,14 (1R)-23,15 and (1S)-24.15
in good yields. Alternatively, 8 was obtained via conver-
sion of the R,ω-diol 9 into ω-bromoalkanol 10,8 followed
by O-protection, alkylation with the lithium acetylide‚
EDA complex,9 deprotection, and finally oxidation.
Ester alcohols 11, accessed via esterification of ꢀ-cap-
rolactone,10 or via a selective reduction of monomethyl
azelate,11 were O-protected with tert-butyldiphenylchlo-
rosilane (TBDPSCl) as depicted in Scheme 3. This was
followed by methyl ester hydrolysis, esterification with
the corresponding ω-alkynols as well as 7, tetrabutylam-
monium fluoride (TBAF) silyl ether deprotection, and
subsequent oxidation to produce 16.
The ω-alkynals 19 having the differently connected
ester function in the tether were accessed via esterifica-
tion of 4-pentynoic acid with the corresponding diols 17
followed by oxidation of the resulting ω-alkynols 18, as
illustrated in Scheme 4. Alternatively, esterification with
bromo alcohol 20 followed by anhydrous trimethylamine
N-oxide oxidation12 of the resulting ω-bromoalkyne yielded
the ω-alkynal 19. Tables 1-3 summarize the results
obtained in the syntheses of ω-alkynals 8, 16, and 19
respectively. ω-Alkynal 8c was selected to elaborate
(13) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem.
Soc. 1986, 108, 6071.
(8) Kang, S.-K.; Kim, W.-S.; Moon, B.-H. Synthesis 1985, 1161.
(9) EDA ) Ethylenediamine. Rossi, R. Synthesis 1981, 359.
(10) Bosone, E.; Farina, P.; Guazzi, G.; Innocenti, S.; Marotta, V.
Synthesis 1983, 942.
(11) Kanth, J . V. B.; Periasamy, M. J . Org. Chem. 1991, 56, 5964.
(12) Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1990, 31, 4825.
(14) Rijnberg, E.; J astrzebski, J . T. B. H.; J anssen, M. D.; Boersma,
J .; van Koten, G. Tetrahedron Lett. 1994, 35, 6521
(15) (a) Bernardinelli, G.; Fernandez, D.; Gosmini, R.; Meier, P.;
Ripa, A.; Schu¨pfer, P.; Treptow, B.; Ku¨ndig, E. P. Chirality 2000, 12,
529. (b) See also Ku¨ndig, E. P.; Meier, P. Helv. Chem. Acta 1999, 82,
1360.

4768 J . Org. Chem., Vol. 66, No. 14, 2001
Oppolzer et al.
Ta ble 4. Con cen tr a tion Dep en d en ce of th e
Ma cr ocycliza tion Step a
Ta ble 6. Ma cr ocycliza tion of 8 to Ca r bocyclics 25a
yield (%)b
ring
size
ee (%)c
of 25
(+)-DAIB
hydroborated
species, M
Et2Zn/DAIB
mixture, M
yield
(%)b
entry
n
25
26
entry
(mol %)
a
b
c
d
e
1
2
3
6
9
13
14
15
18
21
20
35
60
61
43
9
7
3
7
8
90
91
88
91
88
1
2
3
4
5
2
5
0
1
2
0.33
0.03
0.03
0.05
0.01
0.38
0.02
0.02
0.05
0.01
polymer
67
traces
73c
16d
a
All reactions were run on a 1 mmol scale of 8 in n-hexane at
a
b
All reactions were run on a 1 mmol scale of 8c at 0 °C. Yields
b
0 °C in the presence of 2 mol % 21. Yields are based on isolated
refer to isolated and purified products. c This reaction refers to
and purified compounds and corrected by 1H NMR. c Enantiomeric
excess (ee) determined by 19F NMR of the corresponding (1R)-R-
methoxy-R-(trifluoromethyl)phenylacetate esters.16
d
that obtained in ref 4a. A mixture of products was obtained
including 25c, 14-pentadecen-1-ol 26c, and 14-pentadecenal in
16%, 13%, and 14%, respectively.
Ta ble 7. Ma cr ocycliza tion of 16 to Ma cr olid es 27a
Ta ble 5. Effect of Liga n d Typ e a n d Qu a n tity on Yield
a n d Selectivitya
yield (%)d
temp,c
°C
ee (%)e
of 25c
entry
ligandb
25c
26c
1
2
3
4
5
6
21 (1)
21 (2)
21 (3)
21 (4)
22 (0.5)
22 (0.5)
22 (2)
(R)-23 (2)
(S)-24 (2)
0
0
0
0
0
53
60
61
66
60
57
53
19
23
3
3
4
4
4
4
3
3
4
87
88
90
88
65
62
62
27
33
yield (%)b
ring
size
ee (%)c
of 27
-10
-30
0
entry
n
m
27
28
7
a
b
c
d
4
4
8
1
4
1
1
13
16
17
21
14
65
45
48
9
8
3
4
71
89
90
90
8f
9g
0
a
12
All reactions were run on a 1 mmol scale of 8c in n-hexane.
b
Values in parentheses refer to the precatalyst load expressed in
a
All reactions were run on a 1 mmol scale of 16 in n-hexane at
mol %. c Temperature refers to that used during the transmeta-
b
0 °C in the presence of 2 mol % 21. Yields are based on isolated
d
lation and intramolecular addition steps. Yields are based on
and purified compounds and corrected by 1H NMR. c Enantiomeric
excess (ee) determined by 19F NMR of the corresponding (1R)-R-
methoxy-R-(trifluoromethyl)phenylacetate esters.16
isolated and purified compounds and corrected by 1H NMR.
e Enantiomeric excess (ee) determined by 19F NMR of the (1R)-R-
methoxy-R-(trifluoromethyl)phenylacetate.16 f This reaction af-
g
forded the opposite absolute stereochemistry (cf. eq 1). This
reaction was run on 0.5 mmol scale of 8c.
18-membered rings 25c and 25d were isolated in yields
of about 60%. Due to its increased ring size and low
solubility, the 21-membered ring 25e was isolated in only
43% yield.
On the basis of our earlier results in the asymmetric
ring closure for the total synthesis of (+)-aspicilin,4b we
then explored the effect of incorporating an ester group
into the ω-alkynal tether with variable chain lengths
(m, n) between the internal ester group and the terminal
reactive units. Under standard conditions 13- to 21-
membered lactones 27 were synthesized as outlined in
eq 2, Table 7.
Alkynal esters 19, having the alternative disposition
of the ester oxygen and carbonyl group, also provide
macrocyclic (S)-allyl alcohols 29 by standard ring closure
of 4-pentynoyl esters 19 (eq 3, Table 8).
Inspection of Tables 6, 7, and 8 reveals the fact that
unlike carbocyclic (S)-allylic alcohols 25, macrolides 27
and 29 are produced in moderate yields, reaching a
maximum of 65% with the 16-membered rings 27b and
29a . This observation is in line with previously reported
ring closure of ω-alkynal 31 yielding the corresponding
18-membered macrolide 32 in 25-52% and in 79% ee as
outlined in eq 4.4b
As seen by the results of Table 5, by increasing the
load of 21, higher yields were progressively obtained
while selectivity16 remained practically constant. This
indicates the independence of the aldehyde diastereo-
facial discrimination vis-a`-vis ligand load. On the other
hand, zinc complex 22 and aminophenols 23 and 24
afforded 25c in moderate and low selectivities, respec-
tively (Table 5, entries 5-9).
Application of this macrocyclization protocol to ω-al-
kynals 8 afforded the expected (S)-allylic alcohols 25 in
88-91% enantiomeric excess (eq 1, Table 6).
Not surprisingly, 13- and 14-membered rings 25a and
25b were obtained in only low yields, reflecting the strain
due to an endocyclic (E)-double bond. The larger, 15- and
We noted that aldehyde π-face discrimination is con-
stant at about 90% ee. Only in cases (e.g., 27a ) where
(16) Determined via 19F NMR of the corresponding Mosher esters:
Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543.

Macrocyclic (E)-Allylic Alcohols from ω-Alkynals
J . Org. Chem., Vol. 66, No. 14, 2001 4769
Ta ble 8. Ma cr ocycliza tion of 19 to Ma cr olid es 29a
concentrated and the residue flash chromatographed (SiO2;
n-hexane:ether ) 3/1) to give the product (see Table 1).
Gen er a l Meth od for th e Ba se-In d u ced Alk yn e Isom er -
iza tion 7. Lithium wire (709 mg, 102.2 mmol) was cut into
fine pieces in dry n-hexane and mixed with dry distilled 1,3-
diaminopropane (50 mL). The mixture was stirred at 75 °C
(bath temperature) overnight to yield a milky white reaction
mixture. After cooling to room temperature, potassium tert-
butoxide (6 g, 54 mmol) was added in one portion. The pale
yellow colored mixture was stirred at room temperature for
15 min before addition of 6 (14 mmol) in one portion. The now
pale brown reaction mixture was stirred at room temperature
for 5 h. The reaction mixture was quenched by pouring into
ice-cold water followed by extraction with ether and drying
(MgSO4). After concentration, the yellow solid residue was
flash chromatographed (SiO2; n-hexane:ether ) 2/1) to give
the product (see Table 1).
Gen er a l P r oced u r e for th e P a r ik h -Doer in g Oxid a tion
of 7. Triethylamine (14 mL, 100.44 mmol) was added to a
stirred solution of 7 (10 mmol) in dry CH2Cl2 (9 mL) at room
temperature and the resulting mixture treated with a solution
of sulfur trioxide pyridine complex (5.6 g, 35.18 mmol) in
DMSO (35 mL) at room temperature under a dry argon
atmosphere. The reaction mixture was stirred for 2-5 h at
room temperature and then quenched by pouring into water
and extracted with ether. The combined ether extracts were
washed with 0.2 M HCl solution, water, and brine. After drying
(MgSO4) and concentration, the residual yellow oil was flash
chromatographed (SiO2; n-pentane:ether ) 10/1) to afford the
product (see Table 1).
yield (%)b
ring
size
ee (%)c
of 29
entry
x
y
29
30
a
b
2
2
6
7
16
17
65
44
8
6
90
73
a
All reactions were run on a 1 mmol-scale of 19 in n-hexane at
b
0 °C in the presence of 2 mol % 21. Yields are based on isolated
and purified compounds and corrected by 1H NMR. c Enantiomeric
excess (ee) determined by 19F NMR of the corresponding (1R)-R-
methoxy-R-(trifluoromethyl)phenylacetate esters.16
the ester and alkenylzinc units are proximal in the
cyclization precursor do we find lower selectivities (e.g.,
Table 7, entry a). In the case of 29b and 32, the chain
length contributes to the structural mobility which,
unfortunately, leads to higher degrees of freedom in the
transition state4a and, consequently, to lower ee’s.
Con clu sion
ω-((1,1-Dim eth yleth yl)diph en ylsilyloxy)car boxylic Acid
ω-Alk yn yl Ester 14. To a solution of 13 (15 mmol) in dry ether
(75 mL) was added 5-hexynol, or 7 (16.5 mmol), followed by
DMAP (0.18 g, 1.47 mmol) and DCC (3.4 g, 16.5 mmol) at room
temperature. The reaction mixture was stirred overnight at
room temperature and then filtered and the precipitate washed
with ether. The combined filtrates were concentrated, and the
resulting oily residue was flash chromatographed (SiO2; n-
hexane:ether ) 15/1), affording the ester (see Table 2).
ω-Hyd r oxyca r boxylic Acid ω-Alk yn yl Ester 15. A solu-
tion of 14 (8 mmol) in dry THF (2 mL) was treated with TBAF
(1 M solution in THF, 18 mL, 18 mmol) with stirring at room
temperature. The resulting reaction mixture was stirred for
1.5 h at room temperature, diluted with ether, washed with
water, brine, dried (MgSO4), concentrated, and flash chro-
matographed (SiO2; n-hexane:ether ) 2/3) to afford the free
alcohol (see Table 2).
We conclude that asymmetrically catalyzed macrocy-
clizations offer an efficient approach to naturally occur-
ring chiral carbocycles and macrolides as exemplified by
a synthesis of (R)-(-)-muscone4a and (+)-aspicilin.4b The
methodology produces low to moderate yields of 13- and
14-membered carbocycles, respectively, while yields level
off at 60% for 15-membered and larger carbocycles.
Macrolides are generally produced in moderate yields and
reach a maximum of 65% in the case of 16-membered
rings regardless of the ester group disposition within the
tether between the alkyne and aldehyde reactive sites.
Proximity of the ester and alkenylzinc units in the
cyclization precursor may diminish the reaction yield.
Enantiomeric excess remains constant at about 90%
albeit that ring size affects selectivity in some cases.
4-P en tyn oic Acid ω-Hyd r oxya lk yl Ester 18. A solution
of 4-pentynoic acid (0.5 g, 5.1 mmol) in dry CH2Cl2 (5 mL) was
treated with dry DMF (20 mL, 0.26 mmol) and oxalyl chloride
(0.55 mL, 6.4 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 2 h before
distilling off CH2Cl2. The remaining residue was dissolved in
dry THF (2.5 mL). Separately, R,ω-alkanediol 17 (7.63 mmol)
was added to a suspension of NaH (60% in mineral oil, 0.31 g,
7.75 mmol) in dry THF (10 mL) and then refluxed overnight.
After cooling to room temperature, the acid chloride solution
was added dropwise to the diol/NaH reaction mixture during
3 h. After complete addition, the reaction mixture was stirred
at room temperature for further 2 h before dilution with ether
and wash with 10% aq K2CO3 solution, water, and brine. After
drying (MgSO4) and flash chromatography (SiO2; n-hexane:
ether ) 1/2), the pure product was obtained (see Table 3).
Gen er a l Ma cr ocycliza tion P r oced u r e. A solution of
borane-dimethyl sulfide complex (100 µL, 1 mmol) in dry
degassed n-hexane (1 mL) was treated by dropwise addition
of dry degassed cyclohexene (205 µL, 2 mmol) at 0 °C. The
reaction mixture was stirred for 3 h at 0 °C where a white
suspension of dicyclohexylboranedimethyl sulfide complex was
formed. A solution of ω-alkynal 8, 16, or 19 (1 mmol) in dry
degassed n-hexane (4 mL) was dropwised into the white
suspension at -20 °C during 1-2 min. The reaction mixture
was then allowed to reach 0 °C during 30 min and stirred at
0 °C for 1 h where a clear colorless reaction mixture was
obtained. Separately, diethylzinc (155 µL, 1.5 mmol) in dry
Exp er im en ta l Section
Gen er a l. All solvent distillations and glovebox manipula-
tions were carried under a dry nitrogen atmosphere. All
reactions and reagent distillations were carried under an argon
atmosphere with magnetic stirring. “Workup” denotes extrac-
tion with ether, drying (Na2SO4 or MgSO4), and evaporation
(rotary evaporator). Column flash chromatography (FC): SiO2
(Merck 9385). Solvents were dried by distillation from drying
agents as follows: ether (Na/benzophenone), dichloromethane
(CaH2), n-hexane (LiAlH4), HMPA (BaO).
Gen er a l Meth od for th e Syn th esis of 2-Alk yn -1-ols 6.
A solution of tetrahydro-2-(2-propynyloxy)-2H-pyran 5 (2.81
mL, 20 mmol) in dry THF (20 mL) was cooled to 0 °C in an ice
bath and treated with 1.6 M solution of n-butyllithium in
hexane (5.5 mL, 23 mmol). Thereafter, 1-bromoalkane (23
mmol) in dry distilled HMPA (40 mL) was added at 0 °C and
the resulting reaction mixture stirred 1.5 h at room temper-
ature. The reaction was quenched with saturated aqueous
NH4Cl solution followed by extraction with pentane. The
combined organic extracts were washed with water and dried
(MgSO4). After concentration, the residual oil was dissolved
in methanol (50 mL), and 4-toluenesulfonic acid monohydrate
(2 g, 10.5 mmol) was added at room temperature. The reaction
mixture was stirred at room-temperature overnight, poured
into ice-cold water, extracted with ether, dried (MgSO4), and

4770 J . Org. Chem., Vol. 66, No. 14, 2001
Oppolzer et al.
degassed n-hexane (3 mL) was treated at 0 °C with a solution
of (1S)-(+)-3-exo-(dimethylamino)isoborneol 21 (0.02 mmol)
and the resulting mixture diluted with dry degassed n-hexane
(27 mL) to 0.05 M at 0 °C during 20 min using a syringe pump.
The borane derivative reaction mixture was then diluted with
dry degassed n-hexane (15 mL) to 0.05 M at 0 °C then was
added dropwise to Et2Zn/(+)-DAIB mixture via syringe pump
at 0 °C during 4 h with vigorous stirring. After complete
addition, the reaction mixture was stirred for an additional
period of 30 min at 0 °C before quenching with saturated
aqueous NH4Cl solution and extraction with ether, followed
by drying (MgSO4). After concentration, the colorless oily
residue was flash chromatographed (SiO2; n-hexane:ether )
5/2 for carbocycles 25 and 1/1 for macrolides 27 and 29),
affording the macrocycles as in Tables 6, 7, and 8.
edged. We thank Profs. E. Peter Ku¨ndig and J ef De
Brabander for discussions and help with the manu-
script. We thank Mr. J . P. Saulnier, and Mr. A. Pinto
and Mrs. D. Klink, for NMR and MS measurements,
respectively. Profs. E. Peter Ku¨ndig and Gerard van
Koten are gratefully acknowledged for their generous
donation of precatalysts 23, 24, and 22, respectively.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of all compounds and copies of 19F NMR spectra
of the Mosher esters of the corresponding macrocycles. Char-
acterization data for compounds 6a , 6c, 6d , 6e, 7a , 7b, 7c,
7d , 7e, 8a , 8b, 8c, 8d , 8e, 14a , 14b, 14c, 14d , 15a , 15b, 15c,
15d , 16a , 16b, 16c, 16d , 18a , 18b, 19a , 19b, 25a , 25b, 25c,
25d , 25e, 27a , 27b, 27c, 27d , 29a , 29b. Synthetic procedures
for compounds 11b, 12a , 12b, 13a , 13b, 20a . This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. Financial support of this work
by Swiss National Science Foundation (CHIRAL-2) and
Givaudan-Roure AG., Du¨bendorf, is gratefully acknowl-
J O000463N