Role of conformational effects on the regioselectivity of macrocyclic INOC reactions: Two new asymmetric total syntheses of (+)-brefeldin A

Article abstract of DOI:10.1021/jo010744a

We have gained some insight into the role of conformational effects on the regioselectivity of the macrocyclic intramolecular nitrile oxide cycloaddition observed in our (+)-brefeldin A synthesis. During the course of this regiochemical study, we have developed two novel stereoselective and regioselective schemes for total synthesis of (+)-brefeldin A (i.e. intramolecular nitrile oxide cycloaddition - isomerization and intermolecular nitrile oxide cycloaddition - ring closing metathesis strategies).

Full text of DOI:10.1021/jo010744a

772
J . Org. Chem. 2002, 67, 772-781
Role of Con for m a tion a l Effects on th e Regioselectivity of
Ma cr ocyclic INOC Rea ction s: Tw o New Asym m etr ic Tota l
Syn th eses of (+)-Br efeld in A†,1
Deukjoon Kim,*,‡ J ongkook Lee,‡ Phil J ong Shim,‡ J oong Inn Lim,‡ Takayuki Doi,§ and
Sanghee Kim|
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University,
San 56-1, Shillim-Dong, Kwanak-Ku, Seoul 151-742, Korea, Department of Applied Chemistry,
Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, J apan, and Natural Products
Research Institute, Seoul National University, 28 Yungun-Dong, J ongro-Ku, Seoul 110-460, Korea
deukjoon@plaza.snu.ac.kr
Received J uly 25, 2001
We have gained some insight into the role of conformational effects on the regioselectivity of the
macrocyclic intramolecular nitrile oxide cycloaddition observed in our (+)-brefeldin A synthesis.
During the course of this regiochemical study, we have developed two novel stereoselective and
regioselective schemes for total synthesis of (+)-brefeldin A (i.e. intramolecular nitrile oxide
cycloaddition-isomerization and intermolecular nitrile oxide cycloaddition-ring closing metathesis
strategies).
Sch em e 1
In tr od u ction
In the preceding paper2 we described an asymmetric
total synthesis of (+)-brefeldin A taking advantage of a
triple chirality transfer process for remote stereocontrol.
An intramolecular nitrile oxide cycloaddition (INOC)
reaction was utilized for the efficient construction of the
macrocycle but unfortunately was nonregioselective. The
regioselectivity problem was overcome by way of inter-
molecular nitrile oxide cycloaddition and macrolacton-
ization route, which is somewhat less efficient.
Previous studies on the macrocyclic INOC reactions by
Asaoka showed that the regioselectivity between bridged
and fused isomers is dependent upon the ring size.3 In
the case of a 13-membered ring, which is of relevance to
us, the desired bridged isomers are favored over the fused
isomers in the ratio of about 5:1. To understand our
observed regiochemical discrepancy with Asaoka’s model
system (bridged isomers:fused isomer ) 1:1 compared to
5:1), we decided to synthesize all four possible diastere-
omers of INOC substrates 4 as shown in Scheme 1. We
felt that Mori-type4 intermediate 1 would be ideal for our
purposes, since we could obtain both trans and cis olefins
from an acetylene functional group by either a dissolving
metal reduction or a partial catalytic hydrogenation,
respectively.
Resu lts a n d Discu ssion
* To whom correspondence should be addressed. Tel: +82-2-880-
7850. Fax: +82-2-888-0649.
To obtain the key intermediate 1, we developed a
shorter stereorational synthetic route rather than em-
ploying Mori’s synthesis, as depicted in Scheme 2. Silyl
protection of the primary alcohol of readily available
lactone 7,5 followed by vinyl cuprate addition,6 provided
lactone 8 in 81% overall yield. Lactone opening with a
catalytic amount of titanium tetraisopropoxide in metha-
nol7 afforded hydroxy ester 9 with minimum migration
of the silyl group. After protection of the secondary
† Dedicated to Professor Steven M. Weinreb on the occasion of his
60th birthday.
‡ College of Pharmacy, Seoul National University.
§ Department of Applied Chemistry, Tokyo Institute of Technol-
ogy.
| Natural Products Research Institute, Seoul National University.
(1) (a) Taken in part from the doctoral thesis of P.J .S., Seoul
National University, 2000. (b) Taken in part from the doctoral thesis
of J .L., Seoul National University, 2001.
(2) Kim, D.; Lee, J .; Shim, P. J .; Lim, J . I.; Kim, S. J . Org. Chem.
2002, 67, 764.
(3) Asaoka, M.; Abe, M.; Mukata, T.; Takei, H. Chem. Lett. 1982,
215.
(4) (a) Kitahara, T.; Mori, K.; Matsui, M. Tetrahedron Lett. 1979,
20, 2935. (b) Kitahara, T.; Mori, K. Tetrahedron 1984, 40, 2935.
(5) Roth, B. D.; Roark, W. H. Tetrahedron Lett. 1988, 29, 1255.
(6) Yoshikoshi, A.; Kido, F.; Sinha, S. C.; Abiko, T.; Watanabe, M.
Tetrahedron 1990, 40, 4887.
10.1021/jo010744a CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

Regioselectivity of Macrocyclic INOC Reactions
J . Org. Chem., Vol. 67, No. 3, 2002 773
Sch em e 2a
aKey: (i) TBDPSCl, DMAP, Et3N, rt, CH2Cl2, 97%; (ii) CH2dCHMgBr, CuI, slow addition for 3 h, -35 to -25 °C, 83%; (iii) Ti(O-i-Pr)4,
MeOH, reflux, overnight, 88% (based on 92% conversion); (vi) MOMCl, i-Pr2NEt, CH2Cl2, rt, 18 h, 98%; (v) TBAF, THF, rt, overnight,
96%; (vi) I2, Ph3P, imidazole, THF, rt, 3 h, 96%; (vii) LHMDS, THF, 0 °C, 30 min, 92%; (viii) LiAlH4, THF, 0 °C, 2 h, 100%; (ix) BnBr,
TBAI, NaH, DMF, rt, overnight, 96%; (x) pyr‚HBr3, pyridine, CH2Cl2, 0 °C, 40 min, 82%; (xi) NaNH2, NH3, reflux, 30 min, 81%; (xii)
TBDMSCl, imidazole, DMF, rt, 1 h, 99%; (xiii) DIBALH, toluene, -78 °C, 30 min, 77%; (xiv) Ph3PdCHCO2Et, CH2Cl2, 40 °C, 1 h, 82-
95%; (xv) H2, Pd/Al2O3, hexane, rt, 5 h, 99%; (xvi) LiAlH4, THF, 0 °C to room temperature, 1 h, 92%; (xvii) I2, Ph3P, imidazole, THF, 0 °C
to room temperature, 30 min, 87-92%.
hydroxyl group of 9 as a MOM ether, deprotection of the
silyl group and subsequent iodination gave the intramo-
lecular ester enolate alkylation substrate 10. The in-
tramolecular cyclization of ω-iodo ester 10 was success-
fully performed under standard conditions8 (LHMDS,
THF, 0 °C) to produce the desired cyclopentanecarboxy-
late 11 with excellent stereoselectivity and in high yield
(92%).
respectively. The acetylenes 3 were reduced to the trans
and cis olefins by a dissolving metal reduction and partial
catalytic hydrogenation, respectively, to furnish the four
isomers 15. Access to all four INOC substrates 4 was
secured by applying the following four-step sequence to
15: iodination of the primary hydroxyl group, transfor-
mation to nitro compound 16,12 deprotection of the silyl
ether by mild acid treatment, and acryloylation led to
the requisite four INOC substrates 4.
With ester 11 in hand, the elaboration of cyclopentane-
carboxylate 11 to the key intermediate 1 proceeded
without difficulty. First, the ester group of 11 was re-
duced to the corresponding alcohol 12. After alcohol
protection as a benzyl ether, the olefin moiety of com-
pound 12 was converted to an acetylene via the dibro-
mide,9 furnishing the desired Mori-type4 intermediate 1.
We next synthesized two optically active alkylating
agents 2(S) and 2(R) from the commercially available
methyl lactates 13 via a conventional six-step sequence.
Protection of the hydroxyl groups of methyl lactates 13
as the silyl ethers and subsequent reduction with DIBALH
generated the corresponding known aldehydes 14.10
Three-step chain elongation, involving a Wittig reaction
and a catalytic hydrogenation followed by reduction with
LiAlH4, afforded the corresponding alcohols. These alco-
hols were then treated with iodine and triphenylphos-
phine to give iodides 2(S) and 2(R) in good overall yield.
With all the fragments necessary for the acetylenic
coupling reactions11 in hand, we were able to synthesize
all four possible isomers as planned (Scheme 3). Coup-
lings between the lithium acetylide of 1 and the corre-
sponding iodides, 2(S) and 2(R), afforded 3(S) and 3(R),
The four isomers 4 were then subjected to the INOC
reactions,13 and the regiochemical outcome is sum-
marized in Scheme 3.14 The most important isomer, 4a
(trans, C15-(S)), required for the synthesis of (+)-brefel-
din A, exhibited the worst regioselectivity. In contrast,
the desired bridged isomers were formed almost exclu-
sively in the cases of 4b (cis, C15-(S)) and 4c (trans, C15-
(R)). To understand the conformational effects on INOC
reactions, we performed MM2 calculations as sum-
marized in Table 1. The transition state structures were
generated by a systematic multiconformer conformational
search and subsequent MM2 energy minimizations using
the force field methods (rigid model) described by Houk.15
The observed stereoselectivity at C2 of the INOC reac-
tions is consistent with the calculated results except for
bridged isomers 5d (cis, C15-(R)). Our regioselectivity
data for the INOC reactions cannot be fully explained
by calculations, which did not take the electronic effect
of the carbonyl groups into account. However, it could
be inferred from the calculated data that the lower energy
transition states for 6a (C2-(S)) compared to the fused
(12) Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry, D.
D.; Oliveto, E. P.; Graham, G. E. J . Am. Chem. Soc. 1956, 78, 1497.
(13) The experimental procedure of INOC of 4a was described in
the preceding paper.2
(14) For the structure determination of INOC products 5a -d and
6a -d , see the Supporting Information.
(7) Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zu¨ger, M. Synthesis 1982, 138.
(8) (a) Stork, G.; Uyeo, S.; Wakamatsu, T.; Grieco, P.; Labovitz, J .
J . Am. Chem. Soc. 1971, 93, 4945. (b) Kim, D.; Kim, I. H. Tetrahedron
Lett. 1997, 38, 415 and references cited.
(9) (a) Vaughn, T. H. J . Am. Chem. Soc. 1934, 56, 2064. (b) Vaughn,
T. H.; Vogt, R. R.; Nieuwland, J . A. J . Am. Chem. Soc. 1934, 56, 2120.
(10) Massad, S.; Hawkins, L. D.; Baker, D. C. J . Org. Chem. 1983,
48, 5180.
(15) (a) Houk, K. N.; Firestone, R. A.; Munchausen, L. L.; Mueller,
P. H.; Arison, B. H.; Garcia, L. A. J . Am. Chem. Soc. 1985, 107, 7227.
(b) Brown, F. K.; Raimond, L.; Wu, Y.-D.; Houk, K. N. Tetrahedron
Lett. 1992, 33, 4409. (c) All calculations were performed on Macro-
Model/BATCHMIN (version 6.0).
(11) Schwarz, M.; Waters, R. M. Synthesis 1987, 276.

774 J . Org. Chem., Vol. 67, No. 3, 2002
Kim et al.
Sch em e 3a
a
Key: (i) n-BuLi, HMPA/THF (7:11), 2(S) or 2(R), 0 °C, 25 min then rt, 1 h, 78-81%; (ii) (a) Na, NH3/THF, -78 °C, 1 h, 71% (trans),
(b) Pd/CaCO3/Pb, quinoline, H2, hexane, rt, 8 h, 85-92%; Na, NH3/THF, -78 °C, 1 h, 94-99% (cis); (iii) I2, Ph3P, imidazole, THF, rt, 30
min, 95-99%; (iv) NaNO2, urea, DMF, rt, 12 h, 67-72%; (v) PPTS, ethanol, 50 °C, 12 h, 78-97%; (vi) CH2dCHCOCl, N,N-dimethylaniline,
CH2Cl2, 0 °C, 30 min, 81-89%; (vii) p-ClC6H4NCO, Et3N, benzene, reflux, 20 h, 78-87%.
Sch em e 4a
Ta ble 1. MM2 Ca lcu la tion s of INOC Rea ction s
bridged 5
fused 6
substrate
param
expt
C2-(R):C2-(S)
C2-(R):C2-(S)
4a
47:53
65:35
0.00:0.31
(113.86)
21:79
30:70
-0.10:0.09
91:9
<1:>99
<1:>99
6.52:0.00
(53.07)
50:50
calcd
energy
(kcal/mol)
expt
calcd
energy
expt
calcd
energy
expt
4b
4c
4d
23:77
3.59:2.90
<1:>99
<1:>99
4.48:0.57
92:8
86:14
-0.22:1.43
84:16
calcd
22:78
88:12
energy
0.75:0.11
1.94:3.18
a
Key: (i) PhSH, AIBN, benzene, reflux, 5 h, 81-82% based
isomers 6b-d are responsible for the observed poor
regioselectivity.
on 55-56% conversion.
From a synthetic point of view, conversion of bridged
isomers 5b (cis, C15-(S)) to the corresponding isomers
5a (trans, C15-(S)) as shown in Scheme 4 constitutes a
regioselective synthesis of (+)-brefeldin A based on the
INOC strategy. After some experimentation, we found
to our delight that treatment of the cis isomers 5b with
thiophenol and AIBN in refluxing benzene16 produced the
corresponding trans isomers 5a (82% based on 55%
conversion), which have been converted to (+)-brefeldin
A as described in our preceding paper.2
improved brevity and efficiency. The required nitro
compound 17 for this new strategy was prepared from
the previously mentioned alcohol 12 in two steps in 80%
yield. Routine intermolecular nitrile oxide cycloaddition
between nitro compound 17 and optically active acrylate
1917 furnished a separable 1:1 mixture of the bridged
products 20 and 21. To our surprise, only C2-(R) isomer
21 provided the key (+)-brefeldin A intermediates 23
(trans:cis ) 2.2:1, 42%) under typical RCM conditions.18
In addition, this isomerization result prompted us to
test the intermolecular nitrile oxide cycloaddition-ring
closing metathesis (RCM) strategy outlined in Scheme
5, which we believed might be attractive for reasons of
(17) The optically active acrylate 19 was synthesized from known
(S)-heptenol (18) by treatment with acryloyl chloride and N,N-
dimethylamine in 83% yield. For a preparation of (S)-heptenol (18),
see: Kobayashi, Y.; Watatani, K.; Kikori, Y.; Mizojiri, R. Tetrahedron
Lett. 1996, 37, 6125.
(18) (a) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 100. (b) For recent comprehensive reviews, see: Fu¨rstner,
A. Top. Catal. 1997, 4, 285. Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. Maier, M. E. Angew. Chem., Int. Ed. Engl. 2000, 39, 2073.
(16) Schwarz, M.; Graminski, G. F.; Waters, R. M. J . Org. Chem.
1986, 51, 260.

Regioselectivity of Macrocyclic INOC Reactions
J . Org. Chem., Vol. 67, No. 3, 2002 775
Sch em e 5a
a
Key: (i) I2, Ph3P, imidazole, THF, rt, 4 h, 93%; (ii) NaNO2, urea, DMSO, rt, 6 h, 76%; (iii) p-ClC6H4NCO, Et3N, benzene, reflux, 24
h, 85%; (iv) Cl2(Cy3P)2RuCHC6H5, CH2Cl2, reflux, 42% (E/Z ) 2.2:1); (v) p-ClC6H4NCO, Et3N, benzene, reflux, overnight, 76%; (vi) LiOH‚H2O,
THF/H2O (2:1), rt, 12 h; (vii) (a) 2,4,6-trichlorobenzoyl chloride, THF, rt, 4 h, (b) DMAP, toluene, reflux, 18 h, 72% for the two steps.
at room temperature and filtered through a pad of silica gel.
The filtrate was concentrated at reduced pressure, and the
resulting residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:10) to afford the silyl ether (172.0
mg, 97%): 1H NMR (CDCl3, 500 MHz) δ 7.67 (t, J ) 7.8 Hz,
2H), 7.67 (t, J ) 7.7 Hz, 2H), 7.45-7.38 (m, 6H), 6.88 (ddd, J
) 9.6, 6.0, 2.7 Hz, 1H), 6.00 (dd, J ) 9.8, 1.9 Hz, 1H), 4.51
(dddd, J ) 11.2, 4.6, 4.6, 4.6 Hz, 1H), 3.87-3.81 (m, 2H), 2.59
(dddd, J ) 18.5, 11.3, 2.6, 2.6 Hz, 1H), 2.41 (ddd, J ) 18.5,
4.9, 4.9 Hz, 1H), 1.07 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ
163.8, 145.0, 135.44, 135.37, 132.7, 132.6, 129.8, 127.7, 120.9,
77.5, 64.5, 26.6, 25.7, 19.1; IR (neat) 1731 cm-1; [R]20D ) -52.3
(c ) 1.8, CHCl3); HRMS (EI) calcd for C21H23O3Si (M+ - Me)
351.1416, found 351.1420.
We could synthesize the important C2-(R) isomer 21 in
a stereoselective manner by using the acrylate derivative
24 of Oppolzer’s camphor sultam.19 The intermolecular
nitrile oxide cycloaddition between nitro compound 17
and acrylamide 24 yielded the bridged product 25 with
high diastereoselectivity (94:6).20 Hydrolysis of sultam 25,
followed by esterification21 with alcohol 18, led to the C2-
(R) isomer 21 in high overall yield.
Con clu sion
In conclusion, we have gained some insight into the
role of conformational effects on the regioselectivity of
the macrocyclic INOC in our (+)-brefeldin A synthesis.
During the course of this regiochemical study, we have
developed two novel stereoselective and regioselective
schemes for total synthesis of (+)-brefeldin A (i.e. INOC
isomerization and intermolecular nitrile oxide cycload-
dition-RCM strategies).
2. Cu p r a te Ad d ition . To a suspension of CuI (145 mg, 0.76
mmol) in anhydrous THF (4.0 mL) was added vinylmagnesium
bromide (3.8 mL, 1.0 M solution in THF) at -78 °C. After 30
min at -35 °C, the above silyl ether (557.0 mg, 1.52 mmol) in
THF (8.0 mL) was added slowly to the cuprate mixture over 3
h at -35 to -25 °C. The mixture was stirred for 1 h at the
same temperature and was quenched with saturated aqueous
NH4Cl solution. The mixture was filtered through a pad of
Celite, and the filtrate was concentrated at reduced pressure.
The resulting residue was dissolved in EtOAc, and the solution
was washed with brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:15) to afford lactone 8 (494.5 mg, 83%): 1H NMR
(CDCl3, 500 MHz) δ 7.67-7.65 (m, 4H), 7.46-7.39 (m, 6H),
5.81 (ddd, J ) 17.0, 10.6, 6.2 Hz, 1H), 5.14 (d, J ) 10.4 Hz,
1H), 5.09 (d, J ) 17.2 Hz, 1H), 4.48 (dddd, J ) 8.3, 4.4, 4.4,
4.4 Hz, 1H), 3.80-3.75 (m, 2H), 2.88-2.82 (m, 1H), 2.63 (dd,
J ) 17.2, 5.7 Hz, 1H), 2.46 (dd, J ) 17.2, 7.7 Hz, 1H), 2.10
(ddd, J ) 13.9, 8.2, 5.6 Hz, 1H), 1.85-1.80 (m, 1H), 1.06 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 170.8, 139.2, 135.5, 135.4,
132.7, 132.5, 129.8, 127.7, 115.3, 77.1, 65.2, 34.4, 32.2, 29.3,
26.6, 19.1; IR (neat) 1739 cm-1; [R]20D ) +25.1 (c ) 2.0, CHCl3);
HRMS (EI) calcd for C24H30O3Si (M+) 394.1964, found 394.1956.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were reagent grade and
used as purchased. All moisture-sensitive reactions were
performed under an inert atmosphere of N2 or Ar using
distilled dry solvents. Reactions were monitored by TLC
analysis using E. Merck silica gel 60 F254 thin layer plates.
Flash chromatography was carried out on E. Merck silica gel
60 (230-400 mesh). Optical rotations were measured using
sodium light (D line 589.3 nm).
(6S,4R)-6-(ter t-Bu t yld ip h en ylsila n yloxym et h yl)-4-vi-
n yltetr a h yd r op yr a n -2-on e (8). 1. P r otection of Hyd r oxyl
Gr ou p . A mixture of alcohol 7 (62.0 mg, 0.48 mmol), DMAP
(59 mg, 0.48 mmol), Et3N (0.61 mL, 4.38 mmol), and TBDPSCl
(0.38 mL, 1.46 mmol) in CH2Cl2 (2.4 mL) was stirred for 72 h
(19) (a) Vandewalle, M.; Van der Eycken, J .; Oppolzer, W.; Vullioud,
C. Tetrahedron 1986, 42, 4035. (b) Evans, D. A.; Chapman, K. T.;
Bisaha, J . J . Am. Chem. Soc. 1988, 110, 1238.
(20) Curran, D. P.; Kim, B. H.; Daugherty, J .; Heffner, T. A.
Tetrahedron Lett. 1988, 29, 3555.
(21) Innaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(3R )-3-[(2S )-3-(t er t -Bu t yld ip h e n ylsila n yloxy)-2-h y-
d r oxyp r op yl]p en t-4-en oi c Acid Meth yl Ester (9). To a
solution of lactone 8 (356.0 mg, 0.90 mmol) in dry MeOH (9.0
mL) was added Ti(O-i-Pr)4 (0.27 mL, 0.91 mmol) at room
temperature. The mixture was refluxed for 24 h and filtered
through a pad of Celite. The filtrate was concentrated at

776 J . Org. Chem., Vol. 67, No. 3, 2002
Kim et al.
reduced pressure, and the resulting residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:10) to
give hydroxy ester 9 (275.6 mg, 88% based on 92% conver-
sion): 1H NMR (CDCl3, 500 MHz) δ 7.67-7.64 (m, 4H), 7.44-
7.38 (m, 6H), 5.67 (ddd, J ) 17.1, 10.3, 8.3 Hz, 1H), 4.97 (d, J
) 10.2 Hz, 1H), 4.95 (d, J ) 17.4 Hz, 1H), 3.79-3.73 (m, 1H),
3.66 (dd, J ) 10.1, 3.5 Hz, 1H), 3.63 (s, 3H), 3.49 (dd, J )
10.2, 7.4 Hz, 1H), 2.65-2.58 (m, 1H), 2.58 (d, J ) 3.5 Hz, 1H),
2.41 (dd, J ) 15.1, 6.0 Hz, 1H), 2.30 (dd, J ) 15.0, 8.2 Hz,
1H), 1.56 (ddd, J ) 13.9, 7.7, 7.7 Hz, 1H), 1.48 (ddd, J ) 13.9,
6.1, 6.1 Hz, 1H), 1.06 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
172.7, 140.7, 135.53, 135.51, 133.09, 133.07, 129.8, 127.8,
115.2, 69.8, 67.6, 51.4, 39.5, 37.3, 37.1, 26.8, 19.2; IR (neat)
3462, 1739 cm-1; [R]20D ) +6.2 (c ) 0.97, CHCl3); HRMS (FAB)
calcd for C21H25O4Si (M+ - t-Bu) 369.1522, found 369.1515.
(3R)-3-[(2S)-3-Iod o-2-(m eth oxym eth oxy)p r op yl]p en t-4-
en oic Acid Meth yl Ester (10). 1. P r otection of Hyd r oxyl
Gr ou p . A mixture of alcohol 9 (275.6 mg, 0.65 mmol), MOMCl
(0.15 mL, 1.97 mmol), and diisopropylethylamine (0.68 mL,
3.90 mmol) in CH2Cl2 (2.2 mL) was stirred for 18 h at room
temperature and concentrated at reduced pressure. The
resulting residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:10) to afford the MOM ether (276.2
mg, 91%): 1H NMR (CDCl3, 500 MHz) δ 7.69-7.67 (m, 4H),
7.45-7.37 (m, 6H), 5.66 (ddd, J ) 16.9, 10.5, 8.4 Hz, 1H), 4.98
(d, J ) 10.0 Hz, 1H), 4.97 (d, J ) 18.0 Hz, 1H), 4.77 (d, J )
6.8 Hz, 1H), 4.61 (d, J ) 6.9 Hz, 1H), 3.72-3.66 (m, 1H), 3.65
(dd, J ) 4.8, 2.2 Hz, 2H), 3.63 (s. 3H), 3.36 (s, 3H), 2.69-2.61
(m, 1H), 2.48 (dd, J ) 14.8, 5.2 Hz, 1H), 2.26 (dd, J ) 14.8,
9.2 Hz, 1H), 1.65 (ddd, J ) 14.0, 6.5, 6.5 Hz, 1H), 1.58 (ddd, J
) 14.0, 7.1, 7.1 Hz, 1H), 1.05 (s, 9H); 13C NMR (CDCl3, 125
MHz) δ 170.6, 140.6, 135.5, 133.2, 129.7, 127.7, 127.6, 115.3,
96.0, 75.5, 65.9, 55.6, 51.4, 39.4, 36.9, 36.3, 26.7, 19.1; IR (neat)
NH4Cl solution and concentrated in vacuo. The resulting
residue was dissolved in EtOAc, and the solution was washed
with brine. The organic layer was dried over anhydrous
Na2SO4 and concentrated at reduced pressure. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:10) to afford cyclopentanecarboxylate 11 (177 mg,
92%): 1H NMR (CDCl3, 500 MHz) δ 5.82 (ddd, J ) 17.2, 10.1,
7.2 Hz, 1H), 5.05 (d, J ) 17.0 Hz, 1H), 4.98 (dd, J ) 10.2, 1.3
Hz, 1H), 4.63 (s, 2H), 4.24 (dddd, J ) 5.9, 5.2, 5.2, 5.2 Hz,
1H), 3.68 (s, 3H), 3.36 (s, 3H), 2.78-2.72 (m, 2H), 2.31 (ddd, J
) 13.7, 7.5, 6.3 Hz, 1H), 2.07 (dd, J ) 8.6, 5.1 Hz, 2H), 1.58
(ddd, J ) 13.7, 8.9, 4.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
δ 175.5, 140.2, 114.6, 95.1, 76.9, 55.2, 51.6, 48.0, 46.3, 39.3,
36.9; IR (neat) 1732 cm-1; [R]20 ) -58.5 (c ) 1.2, CHCl3);
D
HRMS (CI) calcd for C11H19O4 (MH+) 215.1283, found 215.1291.
[(1R,2S,4S)-4-(Meth oxym eth oxy)-2-vin ylcyclop en tyl]-
m eth a n ol (12). A solution of cyclopentanecarboxylate 11
(189.6 mg, 0.89 mmol) in THF (3.0 mL) was added dropwise
to a suspension of LiAlH4 (53 mg, 1.40 mmol) in THF (4.0 mL)
at 0 °C. After 2 h at the same temperature, water (0.05 mL),
3 N NaOH (0.05 mL), and water (0.15 mL) were sequentially
added to the mixture. The mixture was stirred for 3 h and
filtered through a pad of Celite. The filtrate was concentrated
at reduced pressure, and the resulting residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:5)
to afford alcohol 12 (164.5 mg, 100%): 1H NMR (CDCl3, 500
MHz) δ 5.81 (ddd, J ) 17.2, 9.9, 8.1 Hz, 1H), 5.03 (dd, J )
17.1, 1.5 Hz, 1H), 4.96 (dd, J ) 10.0, 1.8 Hz, 1H), 4.64 (d, J )
6.8 Hz, 1H), 4.63 (d, J ) 7.3 Hz, 1H), 4.18-4.14 (m, 1H), 3.66
(dd, J ) 10.4, 5.0 Hz, 1H), 3.50 (dd, J ) 10.7, 6.4 Hz, 1H),
3.36 (s, 3H), 2.27-2.17 (m, 3H), 2.09-2.01 (m, 1H), 1.92 (ddd,
J ) 13.1, 8.5, 4.1 Hz, 1H), 1.67 (ddd, J ) 13.5, 9.3, 7.0 Hz,
1H), 1.59-1.53 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 142.1,
114.2, 95.1, 76.9, 65.0, 55.2, 45.5, 45.2, 39.9, 35.9; IR (neat)
1739 cm-1; [R]20 ) -21.3 (c ) 1.6, CHCl3); HRMS (EI) calcd
D
for C26H35O4Si (M+ - OMe) 439.2305, found 439.2287.
3444 cm-1; [R]20 ) -44.8 (c ) 4.1, CHCl3); HRMS (EI) calcd
D
2. Rem ova l of Silyl Gr ou p . To a solution of the above silyl
ether (142.5 mg, 0.30 mmol) in THF (1.0 mL) was added TBAF
(0.33 mL, 1.0 M solution in THF) at room temperature. The
mixture was stirred overnight and filtered through a pad of
silica gel. The filtrate was concentrated at reduced pressure,
and the residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:10) to afford the primary alcohol
(67.5 mg, 96%): 1H NMR (CDCl3, 500 MHz) δ 5.67 (ddd, J )
17.3, 10.0, 8.5 Hz, 1H), 5.08 (d, J ) 17.3 Hz, 1H), 5.04 (d, J )
10.0 Hz, 1H), 4.72 (d, J ) 7.0 Hz, 1H), 4.67 (d, J ) 7.0 Hz,
1H), 3.66 (s, 3H), 3.66-3.57 (m, 2H), 3.54-3.51 (m, 1H), 3.43
(s, 3H), 3.32 (br s, 1H), 2.68-2.61 (m, 1H), 2.43 (dd, J ) 15.1,
6.0 Hz, 1H), 2.32 (dd, J ) 15.1, 8.3 Hz, 1H), 1.66-1.55 (m,
2H); 13C NMR (CDCl3, 125 MHz) δ 172.5, 140.1, 115.5, 96.5,
for C9H14O2 (M+ - MeOH) 154.0994, found 154.0981.
[(1R,2R,4S)-2-E t h yn yl-4-(m et h oxym et h oxy)cyclop en -
tylm eth oxym eth yl]ben zen e (1). 1. P r otection of th e Hy-
d r oxyl Gr ou p . To a stirred suspension of NaH (321 mg, 7.36
mmol, 55% dispersion in oil) in THF (2.0 mL) was added
dropwise a solution of alcohol 12 (914 mg, 4.91 mmol) in THF
(9.8 mL). After 30 min, benzyl bromide (0.82 mL, 6.86 mmol)
and tetrabutylammonium iodide (20 mg, 0.054 mmol) were
added to the mixture at 0 °C. The mixture was stirred
overnight at room temperature and poured into ice water. The
mixture was extracted with ether (50 mL × 3). The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (EtOAc/hex-
ane, 1:10) to give the benzyl ether (1.303 g, 96%): 1H NMR
(CDCl3, 500 MHz) δ 7.36-7.27 (m, 5H), 5.78 (ddd, J ) 17.3,
9.9, 7.6 Hz, 1H), 4.96 (dd, J ) 17.9, 1.7 Hz, 1H), 4.93 (dd,
J ) 10.5, 1.7 Hz, 1H), 4.63 (d, J ) 6.7 Hz, 1H), 4.62 (d, J )
6.7 Hz, 1H), 4.53 (d, J ) 12.2 Hz, 1H), 4.48 (d, J ) 12.2 Hz,
1H), 4.17-4.13 (m, 1H), 3.49 (dd, J ) 9.2, 4.4 Hz, 1H), 3.36 (s,
3H), 3.32 (dd, J ) 9.2, 6.8 Hz, 1H), 2.25-2.18 (m, 2H), 2.14-
2.08 (m, 1H), 1.98-1.92 (m, 1H), 1.78-1.71 (m, 1H), 1.59-
1.52 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 142.0, 138.7, 128.3,
127.44, 127.41, 113.9, 95.2, 77.1, 73.0, 72.3, 55.2, 45.0, 43.5,
39.8, 36.5; IR (neat) 1642, 1042 cm-1; [R]25D ) -39.3 (c ) 0.50,
CH3OH); HRMS (EI) calcd for C17H24O3 (M+) 276.1725, found
276.1726.
64.8, 55.6, 51.5, 39.4, 36.9, 35.8; IR (neat) 3444, 1731 cm-1
;
[R]20D ) +45.1 (c ) 2.4, CHCl3); HRMS calcd for C11H19O4 (M+
-OH) 215.1283, found 215.1284.
3. Iod in a tion . To a solution of the above primary alcohol
(58.3 mg, 0.25 mmol) in THF (2.5 mL) were added Ph3P (132
mg, 0.50 mmol), imidazole (51 mg, 0.75 mmol), and iodine (191
mg, 0.75 mmol) at 0 °C. After 3 h at room temperature, the
mixture was filtered through a pad of silica gel and the filtrate
was concentrated at reduced pressure. The resulting residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:10) to afford ω-iodo ester 10 (82.9 mg, 96%): 1H
NMR (CDCl3, 500 MHz) δ 5.68 (ddd, J ) 17.2, 10.1, 8.5 Hz,
1H), 5.08 (d, J ) 17.2 Hz, 1H), 5.04 (d, J ) 10.1 Hz, 1H), 4.69
(d, J ) 7.2 Hz, 1H), 4.66 (d, J ) 7.2 Hz, 1H), 3.66 (s, 3H), 3.42
(s, 3H), 3.42-3.36 (m, 2H), 3.32-3.27 (m, 1H), 2.67-2.60 (m,
1H), 2.45 (dd, J ) 15.0, 5.8 Hz, 1H), 2.33 (dd, J ) 15.0, 8.3
Hz, 1H), 1.74-1.67 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
172.2, 140.0, 115.7, 95.8, 74.0, 56.1, 51.5, 39.61, 39.58, 36.9,
11.0; IR (neat) 1739, 1036 cm-1; [R]20D ) -4.7 (c ) 1.8, CHCl3);
HRMS (FAB) calcd for C11H20IO4 (MH+) 343.0406, found
343.0400.
2. Con ver sion of Dou ble Bon d to Tr ip le Bon d . A
mixture of the above benzyl ether (4.00 g, 14.47 mmol),
pyridinium tribromide (5.40 g, 15.23 mmol), and pyridine (1.2
mL, 15.23 mmol) in CH2Cl2 (38 mL) was stirred for 30 min at
0 °C. The mixture was diluted with CH2Cl2 and washed with
saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and
brine. The organic layer was dried over anhydrous Na2SO4 and
concentrated at reduced pressure to give the crude dibromide
(5.50 g). To a solution of NaNH2 (67.86 mmol) prepared from
Na (1.56 g, 67.86 mmol) and Fe(NO3)3‚9H2O (717 mg, 1.77
mmol) in refluxing ammonia (340 mL) was rapidly added a
solution of the crude dibromide (5.50 g, 12.6 mmol) in THF
(38 mL). The mixture was refluxed for 30 min, and to the
(1R,2S,4S)-4-(Meth oxym eth oxy)-2-vin ylcyclop en ta n e-
ca r boxylic Acid Met h yl E st er (11). To a solution of
ω-iodo ester 10 (306 mg, 0.90 mmol) in THF (90 mL) was
added LHMDS (2.7 mL, 1.0 M solution in THF). After 30 min,
the reaction mixture was quenched with saturated aqueous

Regioselectivity of Macrocyclic INOC Reactions
J . Org. Chem., Vol. 67, No. 3, 2002 777
mixture was added portionwise NH4Cl (1.30 g) with vigorous
stirring at -78 °C. After the mixture was concentrated at
reduced pressure, water and ether were added to the residue.
The organic layer was separated, and the aqueous phase was
reextracted with ether. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (EtOAc/hexane, 1:5) to give acetylene 1
(3.25 g, 82%): 1H NMR (CDCl3, 500 MHz) δ 7.36-7.26 (m,
5H), 4.63 (s, 2H), 4.54 (s, 2H), 4.15-4.10 (m, 1H), 3.58 (dd, J
) 9.3, 4.3 Hz, 1H), 3.48 (dd, J ) 9.3, 5.7 Hz, 1H), 3.36 (s, 3H),
2.51(ddd, J ) 17.7, 9.0, 2.2 Hz, 1H), 2.48-2.37 (m, 2H), 2.07
(d, J ) 2.3 Hz, 1H), 1.95-1.92 (m, 1H), 1.85-1.80 (m, 1H),
1.75-1.68 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 138.5, 128.3,
127.43, 127.39, 95.2, 87.0, 76.7, 73.0, 71.3, 68.4, 55.2, 45.1, 40.2,
N NaOH (0.05 mL), and water (0.15 mL). The mixture was
filtered through a pad of Celite, and the filtrate was concen-
trated in vacuo. The resulting residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:3) to give the
alcohol (260 mg, 92%): 1H NMR (CDCl3, 500 MHz) δ 3.92-
3.87 (m, 1H), 3.67-3.59 (m, 2H), 1.67-1.61 (m, 2H), 1.58-
1.50 (m, 2H), 1.16 (d, J ) 6.1 Hz, 3H), 0.89 (s, 9H), 0.07 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 68.3, 63.0, 36.0, 28.5, 25.8,
23.2, 18.1, -4.5, -4.8; IR (neat) 3443, 1053 cm-1; [R]25
)
D
+11.2 (c ) 1.1, C2H5OH); HRMS (EI) calcd for C11H25O2Si (M+
- H) 217.1624, found 217.1618.
4. Iod in a tion . To a stirred solution of the above alcohol
(260 mg, 1.19 mmol) in THF (12 mL) was added imidazole (178
mg, 2.61 mmol) and Ph3P (343 mg, 1.31 mmol). After 5 min,
iodine (332 mg, 1.31 mmol) was added at 0 °C and the mixture
was allowed to warm to room temperature over 30 min. The
mixture was diluted with hexane and filtered through a short
pad of silica gel. Concentration of the filtrate in vacuo and
purification of the residue by column chromatography on silica
gel (EtOAc/hexane, 1:30) afforded iodide 2(S) (340 mg, 87%):
1H NMR (CDCl3, 500 MHz) δ 3.82 (sextet, J ) 6.0 Hz, 1H),
3.19 (ddd, J ) 7.0, 7.0, 1.4 Hz, 2H), 1.98-1.80 (m, 2H), 1.53-
1.48 (m, 2H), 1.13 (d, J ) 6.1 Hz, 3H), 0.88 (s, 9H), 0.05 (s,
3H), 0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 67.6, 40.3, 29.9,
35.9, 30.4; IR (neat) 3291, 2120 cm-1; [R]27 ) -70.9 (c ) 1.0,
D
CH3OH); HRMS (EI) calcd for C17H22O3 (M+) 274.1569, found
274.1552.
(2S )-2-(t er t -B u t y ld im e t h y ls ila n y lo x y )p r o p io n a l-
d eh yd e (14(S)). A mixture of lactate 13(S) (1.00 g, 9.61 mmol),
TBDMSCl (1.74 g, 11.54 mmol), and imidazole (981 mg, 14.41
mmol) in DMF (9.6 mL) was stirred for 1 h at room temper-
ature. The mixture was diluted with EtOAc and washed with
brine. The organic layer was dried over anhydrous Na2SO4 and
concentrated at reduced pressure. The resulting residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:20) to give the silyl ether (2.07 g, 99%). To a solution
of the above silyl ether (1.00 g, 4.58 mmol) in toluene was
added DIBALH (6.0 mL, 1.0 M in toluene) at -78 °C. After 30
min at the same temperature, methanol was added to the
mixture. The white precipitate was filtered off using a pad of
Celite, and the filtrate was concentrated. The residue was
purified by column chromatography (ether/hexane, 1:10) on
silica gel to give lactaldehyde 14(S) (664 mg, 77%) which,
without characterization, was used in the next step.
25.9, 23.8, 18.1, 7.3, -4.4, -4.8; IR (neat) 2928 cm-1; [R]25
)
D
+13.9 (c ) 1.0, C2H5OH); HRMS (EI) calcd for C11H24IOSi (M+
- H) 327.0641, found 327.0620.
{(1S )-6-[(1R ,2R ,4S )-2-(B e n zy lo x y m e t h y l)-4-(m e t h -
oxym et h oxy)cyclop en t yl]-1-m et h ylh ex-5-yn yloxy}-ter t-
bu tyld im eth ylsila n e (3(S)). To a solution of acetylene 1
(1.888 g, 6.88 mmol) in THF (7.0 mL) was added dropwise
n-BuLi (4.5 mL, 1.6 M solution in hexane) over 10 min at 0
°C. After 5 min, a solution of iodide 2(S) (2.485 g, 7.60 mmol)
in dry HMPA (11 mL) was added to the mixture over 10 min
at 0 °C. The mixture was stirred at room temperature for 1 h,
poured into ice water, and extracted with ether (100 mL × 3).
The combined organic layers were washed with water and
brine, dried over anhydrous MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:13) to give acetylene 3(S) (1.280 g,
81%): 1H NMR (CDCl3, 500 MHz) δ 7.35-7.33 (m, 4H), 7.29-
7.26 (m, 1H), 4.62 (s, 2H), 4.53 (s, 2H), 4.13-4.09 (m, 1H),
3.81-3.76 (m, 1H), 3.60 (dd, J ) 9.3, 4.0 Hz, 1H), 3.43 (dd, J
) 9.3, 6.1 Hz, 1H), 3.36 (s, 3H), 2.43-2.30 (m, 3H), 2.16-2.13
(m, 2H), 1.93-1.90 (m, 1H), 1.76-1.69 (m, 2H), 1.58-1.42 (m,
4H), 1.12 (d, J ) 6.1 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 138.7, 128.3, 127.4, 95.2,
82.5, 80.5, 73.0, 71.8, 68.2, 55.3, 45.3, 40.7, 38.8, 35.9, 31.0,
t er t -Bu t yl[(1S )-4-iod o-1-m e t h ylb u t oxy]d im e t h ylsi-
la n e (2(S)). 1. Wittig Rea ction . A mixture of aldehyde 14(S)-
(300 mg, 1.59 mmol) and (carbethoxymethylene)triphenyl-
phosphorane (1.17 g, 3.36 mmol) in CH2Cl2 (3.2 mL) was re-
fluxed for 1 h. The mixture was diluted with hexane and fil-
tered through a short pad of silica gel. The filtrate was con-
centrated in vacuo, and the residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:50) to give the
R,â-unsaturated esters (336 mg, 82%). Z-Olefin: 1H NMR
(CDCl3, 500 MHz) δ 6.22 (dd, J ) 11.6, 7.9 Hz, 1H), 5.65 (d, J
) 11.6 Hz, 1H), 5.48-5.41 (m, 1H), 4.17 (q, J ) 7.1 Hz, 2H),
1.30 (t, J ) 7.1 Hz, 3H), 1.26 (d, J ) 6.4 Hz, 3H), 0.88 (s, 9H),
0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.9,
154.6, 116.9, 65.5, 60.1, 25.8, 23.5, 18.1, 14.2, -4.8, -4.9; IR
25.9, 25.3, 23.8, 18.9, 18.1, -4.4, -4.7; IR (neat) 1042 cm-1
;
(neat) 1717, 1652 cm-1; [R]27 ) +65.5 (c ) 0.30, CH3OH);
[R]24D ) -40.5 (c ) 1.0, CH3OH); HRMS (EI) calcd for C24H37O4-
D
HRMS (EI) calcd for C13H25O3Si (M+ - H) 257.1573, found
257.1579. E-Olefin: 1H NMR (CDCl3, 500 MHz) δ 6.93 (dd, J
) 15.5, 4.0 Hz, 1H), 5.98 (dd, J ) 15.5, 1.6 Hz, 1H), 4.78-4.44
(m, 1H), 4.23-4.16 (m, 2H), 1.30 (t, J ) 7.1 Hz, 3H), 1.26 (d,
J ) 6.6 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 166.8, 151.9, 118.9, 67.7, 60.3, 25.8,
Si (M+ - t-Bu) 417.2461, found 417.2453.
{(1R )-6-[(1R ,2R ,4S )-2-(B e n zy lo x y m e t h y l)-4-(m e t h -
oxym et h oxy)cyclop en t yl]-1-m et h ylh ex-5-yn yloxy}-ter t-
bu tyld im eth ylsila n e (3(R)). To a stirred solution of acety-
lene 1 (310 mg, 1.13 mmol) in THF (3.8 mL) was added
dropwise n-BuLi (0.85 mL, 1.6 M solution in hexane) over 10
min at 0 °C. After 5 min, a solution of iodide 2(R) (520 mg,
1.58 mmol) in dry HMPA (8.0 mL) was added to the mixture
over 10 min at 0 °C. The mixture was stirred for 1 h at room
temperature, poured into ice water, and extracted with ether
(50 mL × 3). The combined organic layers were washed with
water and brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (EtOAc/hexane, 13:1) to give acetylene
3(R) (416 mg, 78%): 1H NMR (CDCl3, 500 MHz) δ 7.35-7.33
(m, 4H), 7.29-7.26 (m, 1H), 4.62 (s, 2H), 4.53 (s, 2H), 4.13-
4.09 (m, 1H), 3.81-3.76 (m, 1H), 3.60 (dd, J ) 9.3, 4.0 Hz,
1H), 3.43 (dd, J ) 9.3, 6.1 Hz, 1H), 3.36 (s, 3H), 2.43-2.30 (m,
3H), 2.16-2.13 (m, 2H), 1.93-1.90 (m, 1H), 1.76-1.69 (m, 2H),
1.58-1.42 (m, 4H), 1.12 (d, J ) 6.1 Hz, 3H), 0.88 (s, 9H), 0.05
(s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 138.7, 128.3,
127.4, 95.2, 82.5, 80.5, 73.0, 71.8, 68.2, 55.3, 45.3, 40.7, 38.8,
36.0, 31.0, 25.9, 25.3, 23.7, 18.9, 18.1, -4.4, -4.7; IR (neat)
1042 cm-1; [R]29D ) -53.7 (c ) 1.5, CH3OH); HRMS (EI) calcd
for C28H45O4Si (M+ - H) 473.3087, found 473.3090.
23.5, 18.2, 14.2, -4.90, -4.92; IR (neat) 1716, 1660 cm-1; [R]28
D
) +4.0 (c ) 0.50, CH3OH); HRMS (EI) calcd for C13H26O3Si
(M+) 258.1651, found 258.1670.
2. Ca ta lytic Hyd r ogen a tion . A mixture of the above R,â-
unsaturated esters (336 mg, 1.30 mmol) and 5% Pd/Al2O3 (10
mg) in hexane (6.5 mL) was stirred under
a hydrogen
atmosphere for 5 h. The mixture was filtered through a short
pad of Celite, and the filtrate was concentrated in vacuo to
give the saturated ester (337 mg, 99%): 1H NMR (CDCl3, 500
MHz) δ 4.12 (q, J ) 7.1 Hz, 2H), 3.86-3.82 (m, 1H), 2.41-
2.30 (m, 2H), 1.77-1.66 (m, 2H), 1.25 (t, J ) 7.1 Hz, 3H), 1.14
(d, J ) 6.1 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13
C
NMR (CDCl3, 75 MHz) δ 173.8, 67.4, 60.1, 34.3, 30.4, 25.8,
23.6, 18.0, 14.2, -4.5, -4.9; IR (neat) 1738 cm-1; [R]25D ) +25.0
(c ) 1.0, CH3OH).
3. LiAlH4 Red u ction . To a solution of the above ester (337
mg, 1.30 mmol) in THF (13 mL) was added portionwise LiAlH4
(50 mg, 1.32 mmol) at 0 °C. The mixture was warmed to room
temperature over 1 h and quenched with water (0.05 mL), 2

778 J . Org. Chem., Vol. 67, No. 3, 2002
Kim et al.
{(1R,2S,4S)-2-[(1E ,6S)-6-(ter t-Bu t yld im e t h ylsila n yl-
oxy)-h e p t -1-e n yl]-4-(m e t h oxym e t h oxy)cyclop e n t yl}-
m eth a n ol (15a ). To a mixture of acetylene 3(S) (974 mg, 2.05
mmol), THF (20 mL) and liquid ammonia (20 mL) was added
portionwise Na (566 mg, 24.62 mmol), and the mixture was
refluxed for 1 h. To the mixture was added portionwise
NH4Cl (1.00 g, 18.70 mmol) at -78 °C, and the mixture was
concentrated at reduced pressure. Water and ether were added
to the residue, the organic layer was separated, and the
aqueous phase was reextracted with ether. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:3)
to give E-olefin 15a (560 mg, 71%): 1H NMR (CDCl3, 500 MHz)
δ 5.48-5.36 (m, 2H), 4.64 (d, J ) 7.4 Hz, 1H), 4.63 (d, J ) 7.4
Hz, 1H), 4.17-4.11 (m, 1H), 3.79-3.73 (m, 1H), 3.68-3.64 (m,
1H), 3.54-3.50 (m, 1H), 3.36 (s, 3H), 2.23 (ddd, J ) 13.2, 6.6,
6.6 Hz, 1H), 2.18-2.10 (m, 1H), 2.06-1.96 (m, 3H), 1.92-1.88
(m, 1H), 1.67-1.60(m, 2H), 1.51 (ddd, J ) 13.2, 9.8, 5.7 Hz,
1H), 1.46-1.28 (m, 4H), 1.11 (d, J ) 6.1 Hz, 3H), 0.88 (s, 9H),
0.044 (s, 3H), 0.041 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 133.8,
130.6, 95.2, 76.9, 68.4, 65.4, 55.2, 45.9, 44.4, 40.6, 39.1, 35.9,
hexane, 1:2) to give the alcohol (140 mg, 97%): 1H NMR
(CDCl3, 500 MHz) δ 5.38 (ddd, J ) 15.2, 6.7, 6.7 Hz, 1H), 5.26
(dd, J ) 15.2, 8.6 Hz, 1H), 4.54 (s, 2H), 4.37 (dd, J ) 12.1, 5.0
Hz, 1H), 4.15-4.08 (m, 2H), 3.76-3.70 (m, 1H), 3.28 (s, 3H),
2.50-2.42 (m, 1H), 2.21 (ddd, J ) 14.3, 7.8, 6.4 Hz, 1H), 2.07-
1.93 (m, 4H), 1.58-1.49 (m, 2H), 1.45-1.30 (m, 4H), 1.24 (br
s, 1H), 1.12 (d, J ) 6.2 Hz, 3H); 13C NMR (CDCl3, 50 MHz) δ
132.2, 131.6, 95.2, 78.7, 76.0, 67.9, 55.3, 45.7, 42.1, 40.2, 38.6,
37.4, 32.2, 25.4, 23.5; IR (neat) 3412, 1553, 1040 cm-1; [R]18
D
) -21.6 (c ) 0.50, CH3OH); HRMS calcd for C14H24 NO4 (M+
- OMe) 270.1705, found 270.1702.
2. Acr yloyla tion . To a solution of the above alcohol (93 mg,
0.47 mmol) and N,N-dimethylaniline (0.40 mL, 3.16 mmol) in
CH2Cl2 (4.6 mL) was added dropwise acryloyl chloride (0.20
mL, 2.46 mmol). After 30 min at 0 °C, saturated aqueous
NH4Cl solution was added to the mixture. The organic layer
was separated, washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:4)
to give acrylate 4a (93 mg, 89%): 1H NMR (CDCl3, 500 MHz)
δ 6.31 (dd, J ) 17.3, 1.5 Hz, 1H), 6.03 (dd, J ) 17.8, 10.4 Hz,
1H), 5.72 (dd, J ) 10.4, 1.4 Hz, 1H), 5.36 (ddd, J ) 15.2, 6.6,
6.6 Hz, 1H), 5.26 (dd, J ) 15.2, 8.6 Hz, 1H), 4.93-4.90 (m,
1H), 4.54 (s, 2H), 4.37 (dd, J ) 12.1, 4.8 Hz, 1H), 4.14-4.08
(m, 2H), 3.28 (s, 3H), 2.50-2.42 (m, 1H), 2.21 (ddd, J ) 13.9,
8.0, 6.3 Hz, 1H), 2.06-1.92 (m, 4H), 1.59-1.42 (m, 4H), 1.40-
1.28 (m, 2H), 1.18 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 50
MHz) δ 165.9, 132.0, 131.8, 130.2, 129.1, 95.3, 78.7, 76.0, 71.0,
55.3, 45.6, 42.1, 40.2, 37.4, 35.3, 32.0, 25.0, 19.9; IR (neat) 1721,
1553 cm-1; [R]20D ) -6.1 (c ) 0.10, CH3OH); HRMS (EI) calcd
for C17H26NO5 (M+ - OMe) 324.1811, found 324.1818.
32.3, 25.9, 25.6, 23.8, 18.1, -4.5, -4.8; IR (neat) 3444 cm-1
;
[R]19D ) -20.2 (c ) 1.0, CH3OH); HRMS (EI) calcd for C19H37O3-
Si (M+ - MOM) 341.2512, found 341.2513.
ter t-Bu tyl{(1S,5E)-6-[(1S,2R,4S)-(4-(m eth oxym eth oxy)-
2-(n it r om et h yl)cyclop en t yl)]-1-m et h ylh ex-5-en yloxy}-
d im eth ylsila n e (16a ). 1. Iod in a tion . To a solution of alcohol
15a (440 mg, 1.14 mmol) in THF (11 mL) were added imidazole
(201 mg, 2.96 mmol), Ph3P (388 mg, 1.48 mmol), and iodine
(375 mg, 1.48 mmol) at 0 °C. After 30 min, the mixture was
diluted with hexane and filtered through a short pad of silica
gel. Concentration of the filtrate in vacuo and purification of
the residue by column chromatography on silica gel (EtOAc/
hexane, 1:20) gave the iodo compound (543 mg, 96%): 1H
NMR (CDCl3, 500 MHz) δ 5.45 (ddd, J ) 15.2, 6.7, 6.7 Hz,
1H), 5.26 (dd, J ) 15.2, 8.6 Hz, 1H), 4.63 (s, 2H), 4.16-4.14
(m, 1H), 3.79-3.75 (m, 1H), 3.39 (dd, J ) 9.7, 3.3 Hz, 1H),
3.36 (s, 3H), 3.09 (dd, J ) 9.7, 7.5 Hz, 1H), 2.32 (ddd, J )
13.5, 7.0, 7.0 Hz, 1H), 2.05 (ddd, J ) 17.9, 8.6, 8.6 Hz, 1H),
2.01-1.96 (m, 3H), 1.82-1.75 (m, 1H), 1.62-1.58 (m, 2H),
1.46-1.31 (m, 4H), 1.12 (d, J ) 6.1 Hz, 3H), 0.89 (s, 9H), 0.05
(s, 6H); 13C NMR (CDCl3, 75 MHz) δ 132.1, 131.8, 95.3, 75.9,
68.5, 55.3, 47.9, 45.2, 40.9, 40.1, 39.2, 32.4, 25.9, 25.6, 23.8,
{(1R,2S,4S)-2-[(1Z,6S)-6-(t er t-Bu t yld im e t h ylsila n yl-
oxy)-h e p t -1-e n yl]-4-(m e t h oxym e t h oxy)cyclop e n t yl}-
m eth a n ol (15b). 1. P a r tia l Red u ction of th e Tr ip le Bon d .
To a stirred solution of acetylene 3(S) (757 mg, 1.59 mmol) in
hexane (8.0 mL) were added Lindlar catalyst (378 mg, 50 wt
%) and quinoline (0.35 mL, 378 mg, 50 wt %). The mixture
was stirred for 8 h under a hydrogen atmosphere and filtered
through a short pad of Celite. The filtrate was concentrated
in vacuo, and the resulting residue was purified by column
chromatography (EtOAc/hexane, 1:15) to give the cis-olefin
(700 mg, 92%): 1H NMR (CDCl3, 500 MHz) δ 7.38-7.29 (m,
4H), 7.28-7.25 (m, 1H), 5.38-5.27 (m, 2H), 4.63 (d, J ) 6.7
Hz, 1H), 4.61 (d, J ) 6.7 Hz, 1H), 4.50 (d, J ) 12.1 Hz, 1H),
4.47 (d, J ) 12.1 Hz, 1H), 4.19-4.13 (m, 1H), 3.77-3.72 (m,
1H), 3.46 (dd, J ) 9.1, 4.0 Hz, 1H), 3.35 (s, 3H), 3.29 (dd, J )
9.1, 6.7 Hz, 1H), 2.55 (quintet, J ) 9.1 Hz, 1H), 2.19 (ddd,
J ) 13.5, 7.0, 7.0 Hz, 1H), 2.05-1.92 (m, 4H), 1.79-1.74 (m,
1H), 1.47-1.25 (m, 5H), 1.10 (d, J ) 6.0 Hz, 3H), 0.89 (s, 9H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 138.7,
133.6, 130.0, 128.3, 127.44, 127.38, 95.2, 77.2, 73.0, 72.2, 68.5,
55.2, 44.6, 40.6, 39.3, 38.5, 36.6, 27.5, 26.1, 25.9, 23.8, 18.1,
18.2, 12.8, -4.4, -4.7; IR (neat) 1047 cm-1; [R]23 ) -30.2 (c
D
) 0.80, CH3OH); HRMS (EI) calcd for C21H41IO3Si (M+)
496.1870, found 496.1855.
2. Con ver sion to Nitr o Com p ou n d . To a solution of the
above iodo compound (540 mg, 1.09 mmol) in DMF (11 mL)
were added sodium nitrite (375 mg, 5.45 mmol) and urea (457
mg, 7.63 mmol). After the reaction mixture was stirred for 12
h at room temperature, the mixture was poured into ice water
and extracted with ethyl acetate. The combined organic layers
were washed with water and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:13)
to give nitro compound 16a (307 mg, 68%): 1H NMR (CDCl3,
500 MHz) δ 5.45 (ddd, J ) 15.2, 6.7, 6.7 Hz, 1H), 5.31 (dd, J
) 15.2, 8.6 Hz, 1H), 4.61 (s, 2H), 4.45 (dd, J ) 12.1, 4.7 Hz,
1H), 4.20-4.15 (m, 2H), 3.78 (dddd, J ) 11.9, 5.9, 5.9, 5.9 Hz,
1H), 3.35 (s, 3H), 2.56-2.48 (m, 1H), 2.28 (ddd, J ) 13.9, 7.8,
6.4 Hz, 1H), 2.12-2.05 (m, 2H), 2.00-1.94 (m, 2H), 1.66-1.54
(m, 3H), 1.46-1.31 (m, 3H), 1.11 (d, J ) 6.1 Hz, 3H), 0.88 (s,
9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
132.6, 131.3, 95.3, 78.7, 77.2, 76.0, 68.4, 55.3, 45.7, 42.2, 40.2,
39.1, 37.4, 32.3, 25.9, 25.5, 23.8, 18.1, -4.4, -4.7; IR (neat)
1553, 1044 cm-1; [R]17D ) -13.2 (c ) 1.5, CH3OH); HRMS (EI)
calcd for C21H40NO5Si (M+ - t-Bu) 358.2050, found 358.2061.
Acr ylic Acid (1S,5E)-6-[(1S,2R,4S)-(4-(Meth oxym eth oxy)-
2-(n itr om eth yl)cyclop en tyl)]-1-m eth ylh ex-5-en yl Ester
(4a ). 1. Rem ova l of Silyl Gr ou p . To a solution of silyl ether
16a (200 mg, 0.48 mmol) in ethanol (32 mL) was added PPTS
(242 mg, 0.96 mmol). After the mixture was stirred for 12 h
at 50 °C, the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/
-4.4, -4.7; IR (neat) 1042 cm-1; [R]26 ) -8.0 (c ) 0.80, CH3-
D
OH); HRMS (EI) calcd for C28H46O4Si (M+) 476.3322, found
476.3323.
2. Rem ova l of Ben zyl Gr ou p . To a mixture of the above
benzyl ether (1.114 g, 2.34 mmol), THF (8.0 mL), and liquid
ammonia (50 mL) was added portionwise Na (160 mg, 6.96
mmol). The mixture was refluxed for 30 min, quenched with
NH4Cl (300 mg, 5.61 mmol) at -78 °C, and concentrated in
vacuo. The residue was dissolved in ether, and the solution
was washed with water and brine. The organic layer was dried
over anhydrous MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 2:5) to give alcohol 15b (851 mg, 94%): 1H NMR
(CDCl3, 500 MHz) δ 5.42-5.32 (m, 2H), 4.63(d, J ) 6.8 Hz,
1H), 4.62 (d, J ) 6.8 Hz, 1H), 4.19-4.14 (m, 1H), 3.80-3.75
(m, 1H), 3.63 (dd, J ) 10.4, 5.1 Hz, 1H), 3.51 (dd, J ) 10.4,
6.2 Hz, 1H), 3.36 (s, 3H), 2.50 (quintet, J ) 9.1 Hz, 1H), 2.21
(ddd, J ) 13.4, 7.3, 7.3 Hz, 1H), 2.05-1.98 (m, 3H), 1.96-1.90
(m, 1H), 1.69-1.62 (m, 1H), 1.53-1.50 (m, 1H), 1.49-1.30 (m,
5H), 1.12 (d, J ) 6.1 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 133.6, 130.2, 95.2, 77.0,
68.4, 65.3, 55.2, 46.7, 40.6, 39.2, 38.8, 36.0, 27.5, 25.9, 25.8,
23.7, 18.1, -4.5, -4.8; IR (neat) 3444, 1042 cm-1; [R]22
)
D

Regioselectivity of Macrocyclic INOC Reactions
J . Org. Chem., Vol. 67, No. 3, 2002 779
-15.4 (c ) 1.0, CH3OH); HRMS (EI) calcd for C20H39O3Si (M+
- OMe) 355.2669, found 355.2670.
89%): 1H NMR (CDCl3, 500 MHz) δ 6.39 (dd, J ) 17.2, 1.2
Hz, 1H), 6.10 (dd, J ) 17.2, 10.4 Hz, 1H), 5.81 (dd, J ) 10.4,
1.2 Hz, 1H), 5.44 (ddd, J ) 10.8, 7.4, 7.4 Hz, 1H), 5.30 (t, J )
10.1 Hz, 1H), 5.02-4.97 (m, 1H), 4.61 (s, 2H), 4.40 (dd, J )
11.9, 4.5 Hz, 1H), 4.20 (dd, J ) 11.9, 8.8 Hz, 1H), 4.23-4.18
(m, 1H), 3.35 (s, 3H), 2.58-2.44 (m, 2H), 2.27 (ddd, J ) 13.5,
7.4, 7.4 Hz, 1H), 2.09 (ddd, J ) 13.4, 6.9, 2.3 Hz, 1H), 2.06-
1.96 (m, 2H), 1.70-1.47 (m, 4H), 1.46-1.28 (m, 2H), 1.25 (d,
J ) 6.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.8, 131.5,
131.4, 130.3, 128.9, 95.2, 78.5, 76.1, 70.7, 55.3, 42.8, 40.3, 39.9,
t er t -Bu t yl{(1S ,5Z)-6-[(1S ,2R ,4S )-(4-(m e t h oxym e t h -
oxy)-2-(n itr om eth yl)cyclopen tyl)]-1-m eth ylh ex-5-en yloxy}-
d im eth ylsila n e (16b). 1. Iod in a tion . To a solution of alcohol
15b (850 mg, 2.20 mmol) in THF (22 mL) were added imidazole
(419 mg, 6.15 mmol), Ph3P (807 mg, 3.08 mmol), and iodine
(781 mg, 3.08 mmol) at 0 °C. After 30 min at room tempera-
ture, the mixture was diluted with hexane and filtered through
a short pad of silica gel. Concentration of the filtrate in vacuo
and purification of the residue by column chromatography on
silica gel (EtOAc/hexane, 1:20) gave the iodo compound (1.08
g, 99%): 1H NMR (CDCl3, 500 MHz) δ 5.43 (ddd, J ) 10.0,
7.4, 7.4 Hz, 1H), 5.22 (t, J ) 10.3 Hz, 1H), 4.62 (s, 2H), 4.20-
4.15 (m, 1H), 3.81-3.76 (m, 1H), 3.38-3.35 (m, 1H), 3.36 (s,
3H), 3.11 (dd, J ) 9.5, 7.1 Hz, 1H), 2.43 (quintet, J ) 9.1 Hz,
1H), 2.30 (ddd, J ) 13.5, 7.0, 7.0 Hz, 1H), 2.08-2.03 (m, 2H),
2.01-1.96 (m, 1H), 1.83-1.76 (m, 1H), 1.67-1.60 (m, 1H),
1.58-1.52 (m, 1H), 1.48-1.31 (m, 4H), 1.12 (d, J ) 6.0 Hz,
3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ
132.1, 131.4, 95.2, 76.1, 68.4, 55.2, 45.8, 42.3, 41.0, 40.1, 39.3,
27.8, 26.1, 25.9, 23.8, 18.1, 12.9, -4.4, -4.7; IR (neat) 1045
37.4, 35.4, 27.1, 25.4, 19.9; IR (neat) 1715, 1556 cm-1; [R]13
)
D
-17.0 (c ) 0.40, CH3OH); HRMS (EI) calcd for C17H26NO5 (M+
- OMe) 324.1811, found 324.1801.
In tr a m olecu la r Nitr ile Oxid e Cycloa d d ition of Acr y-
la te 4b. A mixture of acrylate 4b (190.0 mg, 0.54 mmol),
p-chlorophenyl isocyanate (821 mg, 5.35 mmol), and Et3N (0.75
mL, 0.54 mmol) in benzene (160 mL) was refluxed for 20 h.
The reaction mixture was filtered through a short pad of Celite
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:4). The first
fraction was collected and rechromatographed (EtOAc/hexane,
1:6) to give C2-(R) fused isomer 6b (2.3 mg, 1%) as a white
solid: 1 H NMR (CDCl3, 500 MHz) δ 5.75 (t, J ) 11.2 Hz, 1H),
5.29 (ddd, J ) 11.2, 11.2, 3.4 Hz, 1H), 5.20-5.13 (m, 1H), 4.63
(s, 2H), 4.59 (dd, J ) 11.0, 8.4 Hz, 1H), 4.57 (dd, J ) 11.0, 8.4
Hz, 1H), 4.48-4.43 (m, 1H), 4.22 (t, J ) 10.9 Hz, 1H), 3.36 (s,
3H), 3.12 (t, J ) 8.3 Hz, 1H), 2.75-2.64 (m, 3H), 2.04 (ddd, J
) 14.3, 7.7, 7.7 Hz, 1H), 1.98-1.83 (m, 4H), 1.62 (d, J ) 14.5
Hz, 1H), 1.55-1.47 (m, 1H), 1.33-1.22 (m, 1H), 1.28 (d, J )
6.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 168.6, 157.1, 134.0,
129.5, 95.9, 77.9, 74.2, 72.3, 55.4, 54.4, 45.2, 39.1, 36.9, 35.2,
31.3, 27.0, 24.0, 18.1; IR (neat) 1732, 1651 cm-1; HRMS (EI)
calcd for C18H27NO5 (M+) 337.1889, found 337.1884.
cm-1; [R]23 ) -19.5 (c ) 1.1, CH3OH); HRMS (EI) calcd for
D
C
21H40IO3Si (M+ - H) 495.1792, found 495.1808.
2. Con ver sion to Nitr o Com p ou n d . To a solution of the
above iodo compound (1.08 g, 2.18 mmol) in DMF (22 mL) were
added sodium nitrite (300 mg, 4.35 mmol) and urea (392 mg,
6.53 mmol). The reaction mixture was stirred for 12 h at room
temperature, poured into ice water, and extracted with ethyl
acetate (50 mL × 3). The combined organic layers were washed
with water and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:13) to give nitro
compound 16b (654 mg, 72%): 1H NMR (CDCl3, 500 MHz) δ
5.46 (ddd, J ) 10.6, 7.4, 7.4 Hz, 1H), 5.28 (dd, J ) 10.6, 9.7
Hz, 1H), 4.61 (s, 2H), 4.42 (dd, J ) 12.0, 4.4 Hz, 1H), 4.23-
4.18 (m, 1H), 4.19 (dd, J ) 12.0, 9.0 Hz, 1H), 3.80-3.74 (m,
1H), 3.35 (s, 3H), 2.57-2.42 (m, 2H), 2.27 (ddd, J ) 14.1, 7.1,
7.1 Hz, 1H), 2.09 (ddd, J ) 13.5, 7.1, 2.2 Hz, 1H), 2.01-1.95
(m, 2H), 1.65 (ddd, J ) 13.7, 10.2, 7.1 Hz, 1H), 1.54-1.49 (m,
1H), 1.47-1.30 (m, 4H), 1.11 (d, J ) 6.1 Hz, 3H), 0.89 (s, 9H),
0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 132.0,
131.1, 95.2, 78.5, 76.1, 68.3, 55.2, 42.9, 40.3, 39.9, 39.2, 37.4,
The second fraction was collected and rechromatographed
(MeOH/CH2Cl2, 1:40) to give C2-(S) fused isomer 6b (2.5 mg,
1%) and C2-(R) bridged isomer 5b (28.1 mg, 16%) as white
1
solids. C2-(S) fused isomer 6b: H NMR (CDCl3, 500 MHz) δ
5.40-5.35 (m, 2H), 5.04-4.97 (m, 1H), 4.64 (d, J ) 6.7 Hz,
1H), 4.62 (d, J ) 6.7 Hz, 1H), 4.56 (dd, J ) 8.7, 6.0 Hz, 1H),
4.44 (dd, J ) 10.9, 8.7 Hz, 1H), 4.26-4.21 (m, 1H), 3.90 (dd, J
) 10.9, 6.0 Hz, 1H), 3.36 (s, 3H), 3.21-3.14 (m, 1H), 2.72 (q,
J ) 7.7 Hz, 1H), 2.36 (ddd, J ) 13.5, 8.8, 6.1 Hz, 1H), 2.32-
2.22 (m, 1H), 2.11-2.07 (m, 2H), 1.97-1.85 (m, 1H), 1.80-
1.70 (m, 2H), 1.58-1.51 (m, 1H), 1.40-1.31 (m, 1H), 1.28-
1.18 (m, 1H), 1.22 (d, J ) 6.2 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 168.0, 159.5, 135.2, 130.4, 95.3, 77.2, 73.6, 72.6, 58.5,
55.3, 42.9, 41.6, 40.3, 39.1, 33.9, 27.7, 25.3, 20.2; IR (neat) 1731
cm-1; HRMS (EI) calcd for C18H27NO5 (M+) 337.1889, found
337.1877. C2-(R)-bridged isomer 5b: 1H NMR (CDCl3, 500
MHz) δ 5.45-5.33 (m, 2H), 5.18-5.11 (m, 1H), 4.99 (dd, J )
12.1, 4.7 Hz, 1H), 4.62 (s, 2H), 4.31-4.26 (m, 1H), 3.35 (s, 3H),
3.35 (dd, J ) 17.6, 12.1 Hz, 1H), 3.17 (dd, J ) 17.6, 4.7 Hz,
1H), 2.86 (dddd, J ) 9.7, 9.7, 9.7, 8.8 Hz, 1H), 2.56 (ddd, J )
10.8, 10.8, 3.9 Hz, 1H), 2.40-2.20 (m, 3H), 2.10-2.05 (m, 1H),
1.93-1.88 (m, 1H), 1.84-1.78 (m, 1H), 1.68-1.60 (m, 1H),
1.53-1.41 (m, 2H), 1.28 (d, J ) 6.4 Hz, 3H), 1.27-1.18 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 171.6, 160.2, 133.2, 130.9,
95.2, 76.9, 76.4, 72.8, 55.4, 45.1, 45.1, 42.2, 40.7, 38.2, 32.7,
27.5, 25.9, 25.8, 23.8, 18.0, -4.4, -4.8; IR (neat) 1555 cm-1
;
-
[R]19 ) -7.4 (c ) 1.0, CH3OH); HRMS (EI) calcd for C21H40
D
NO5Si (M+ - H) 414.2676, found 414.2671.
Acr ylic Acid (1S,5Z)-6-[(1S,2R,4S)-(4-(Meth oxym eth oxy)-
2-(n itr om eth yl)cyclop en tyl)]-1-m eth ylh ex-5-en yl Ester
(4b). 1. Rem ova l of Silyl Gr ou p . To a solution of silyl ether
16b (652 mg, 1.57 mmol) in ethanol (78 mL) was added PPTS
(788 mg, 3.14 mmol). The mixture was stirred for 12 h at 50
°C, and the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:2) to give the alcohol (400 mg, 85%): 1H NMR
(CDCl3, 500 MHz) δ 5.47 (ddd, J ) 10.8, 7.4, 7.4 Hz, 1H), 5.30
(dd, J ) 10.8, 9.5 Hz, 1H), 4.62 (s, 2H), 4.42 (dd, J ) 12.0, 4.6
Hz, 1H), 4.22 (dd, J ) 12.0, 8.5 Hz, 1H), 4.23-4.18 (m, 1H),
3.84-3.77 (m, 1H), 3.36 (s, 3H), 2.58-2.46 (m, 2H), 2.28 (ddd,
J ) 13.4, 6.7, 6.7 Hz, 1H), 2.12-2.08 (m, 1H), 2.05-2.01 (m,
2H), 1.69-1.62 (m, 1H), 1.60-1.41 (m, 5H), 1.40-1.35 (m, 1H),
1.20 (d, J ) 6.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 131.7,
131.3, 95.2, 78.5, 76.1, 67.9, 55.3, 42.9, 40.3, 39.9, 38.7, 37.3,
26.8, 24.7, 19.0; IR (neat) 1747, 1652 cm-1; [R]18 ) -148.7 (c
D
) 0.45, CH3OH); HRMS (EI) calcd for C18H27NO5 (M+) 337.1889,
found 337.1885.
27.4, 25.8, 23.5; IR (neat) 3443, 1555 cm-1; [R]25 ) -18.2 (c
The third fraction was collected and rechromatographed
(EtOAc/hexane, 1:2) to give C2-(S)-bridged isomer 5b (110.0
mg, 61%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 5.42
(ddd, J ) 10.3, 10.3, 4.7 Hz, 1H), 5.23 (t, J ) 10.3 Hz, 1H),
5.16-5.09 (m, 1H), 5.03 (dd, J ) 11.1, 2.8 Hz, 1H), 4.62 (s,
2H), 4.26-4.21 (m, 1H), 3.35 (s, 3H), 3.31 (dd, J ) 16.9, 2.8
Hz, 1H), 3.18 (dd, J ) 16.9, 11.1 Hz, 1H), 3.19-3.11 (m, 1H),
2.77 (quintet, J ) 9.6 Hz, 1H), 2.35-2.29 (m, 1H), 2.12-2.00
(m, 2H), 1.92-1.82 (m, 2H), 1.78 (ddd, J ) 13.4, 11.5, 6.9 Hz,
1H), 1.68-1.53 (m, 2H), 1.43-1.38 (m, 1H), 1.27 (d, J ) 6.4
Hz, 3H), 1.06-0.97 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 169.2,
159.5, 131.8, 130.4, 95.2, 76.9, 76.5, 73.1, 55.2, 42.2, 41.1, 40.3,
D
) 0.40, CH3OH); HRMS (EI) calcd for (M+ - OMe) 270.1705,
found 270.1691.
2. Acr yloyla tion . The above alcohol (186 mg, 0.94 mmol)
and N,N-dimethylaniline (0.80 mL, 6.32 mmol) were dissolved
in CH2Cl2 (4.6 mL) and cooled to 0 °C. To the solution was
added dropwise acryloyl chloride (0.40 mL, 4.92 mmol), and
the resulting mixture was stirred at 0 °C for 30 min. After
saturated aqueous NH4Cl was added, the mixture was diluted
with CH2Cl2 and washed with water and brine. The organic
layer was dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1:4) to give acrylate 4b (185 mg,
37.0, 36.1, 33.8, 27.5, 25.7, 19.5; IR (neat) 1747 cm-1; [R]19
)
D

780 J . Org. Chem., Vol. 67, No. 3, 2002
Kim et al.
+39.1 (c ) 2.0, CH3OH); HRMS (EI) calcd for C18H27NO5 (M+)
337.1889, found 337.1875.
for 24 h. After the mixture was filtered through a short pad of
Celite, the filtrate was concentrated in vacuo and the resulting
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 10:1) to afford C2-(S) isomer 20 (91.7 mg, 42%)
and C2-(R) isomer 21 (92.3 mg, 43%). C2-(S) isomer 20: 1H
NMR (CDCl3, 500 MHz) δ 5.83-5.74 (m, 2H), 5.06 (d, J ) 17.1
Hz, 1H), 5.02-4.95 (m, 4H), 4.92 (dd, J ) 11.3, 6.4 Hz, 1H),
4.62 (s, 2H), 4.26-4.22 (m, 1H), 3.36 (s, 3H), 3.24 (dd, J )
17.1, 11.4 Hz, 1H), 3.12 (dd, J ) 17.1, 6.3 Hz, 1H), 2.88 (ddd,
J ) 10.2, 10.2, 7.8 Hz, 1H), 2.54 (quintet, J ) 8.9, 1H), 2.34
(ddd, J ) 14.1, 8.1, 6.2 Hz, 1H), 2.13-2.07 (m, 1H), 2.06 (q, J
) 7.1 Hz, 2H), 1.96 (ddd, J ) 13.6, 10.9, 6.5 Hz, 1H), 1.68-
1.61 (m, 2H), 1.57-1.49 (m, 1H), 1.48-1.34 (m, 2H), 1.24 (d,
J ) 6.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.0, 159.4,
140.4, 138.2, 115.3, 114.9, 95.2, 77.2, 76.5, 72.7, 55.3, 47.0, 42.0,
39.8, 39.7, 37.3, 35.1, 33.3, 24.6, 19.8; IR (neat) 1733, 1041
Isom er iza tion of Cis-Br id ged Isom er s 5b to Tr a n s-
Br id ged Isom er s 5a . A mixture of C2-(R)-bridged isomer 5b
(10.2 mg, 0.027 mmol), thiophenol (0.014 mL, 0.14 mmol), and
AIBN (22 mg, 0.13 mmol) in benzene (0.9 mL) was refluxed
for 6 h. The mixture was concentrated in vacuo, and the
resulting residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:5) to give C2-(R)-bridged isomer
5a (4.6 mg, 82% based on 55% conversion). The conversion of
C2-(S)-bridged isomer 5b to C2-(S)-bridged isomer 5a was also
carried out under the same conditions (81% based on 56%
conversion).
(1R,2S,4S)-4-(Met h oxym et h oxy)-1-(n it r om et h yl)-2-vi-
n ylcyclop en ta n e (17). 1. Iod in a tion . To a solution of alcohol
12 (78.2 mg, 0.42 mmol) in THF (1.4 mL) were added imidazole
(86 mg, 1.26 mmol), triphenylphosphine (220 mg, 0.84 mmol),
and iodine (320 mg, 1.26 mmol) at 0 °C. After 5 min at the
same temperature, the reaction mixture was stirred for 4 h at
room temperature. The mixture was filtered through a short
pad of silica gel, and the filtrate was concentrated at reduced
pressure. The resulting residue was purified by column chro-
matography on silica gel (EtOAc/hexane, 1:7) to afford the iodo
compound (116.2 mg) in 93% yield: 1H NMR (CDCl3, 500 MHz)
δ 5.70 (ddd, J ) 17.1, 9.8, 8.6 Hz, 1H), 5.06 (d, J ) 16.7 Hz,
1H), 5.01 (dd, J ) 10.1, 1.4 Hz, 1H), 4.62 (s, 2H), 4.19-4.14
(m, 1H), 3.40 (dd, J ) 9.8, 3.5 Hz, 1H), 3.36 (s, 3H), 3.12 (dd,
J ) 9.8, 7.3 Hz, 1H), 2.34 (ddd, J ) 14.1, 7.6, 6.5 Hz, 1H),
2.12 (quintet, J ) 9.0 Hz, 1H), 2.01 (ddd, J ) 13.4, 7.5, 2.7
Hz, 1H), 1.86 (dddd, J ) 17.1, 10.1, 7.1, 3.1 Hz, 1H), 1.69-
1.59 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 140.5, 115.4, 95.3,
cm-1; [R]20 ) +78.8 (c ) 1.7, CHCl3); HRMS (FAB) calcd for
D
C20H32O5N (MH+) 366.2280, found 366.2277. C2-(R) isomer
21: 1H NMR (CDCl3, 500 MHz) δ 5.85-5.73 (m, 2H), 5.06 (d,
J ) 17.1 Hz, 1H), 5.02-4.95 (m, 4H), 4.93 (dd, J ) 11.3, 6.2
Hz, 1H), 4.62 (s, 2H), 4.25-4.21 (m, 1H), 3.36 (s, 3H), 3.24
(dd, J ) 17.1, 6.2 Hz, 1H), 3.12 (dd, J ) 17.1, 11.4 Hz, 1H),
2.87 (ddd, 10.2, 10.2, 7.8 Hz, 1H), 2.52 (quintet, J ) 8.9, 1H),
2.33 (ddd, J ) 14.0, 8.1, 6.2 Hz, 1H), 2.11-1.97 (m, 4H), 1.68-
1.60 (m, 2H), 1.57-1.50 (m, 1H), 1.48-1.33 (m, 2H), 1.25 (d,
J ) 6.3 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 170.0, 159.6,
140.6, 138.2, 115.4, 114.9, 95.2, 77.2, 76.5, 72.7, 55.4, 47.2, 41.9,
39.9, 39.8, 37.4, 35.1, 33.4, 24.5, 19.8; IR (neat) 1733, 1041
cm-1; [R]20D ) -122.8 (c ) 1.9, CHCl3); HRMS (FAB) calcd for
C
20H32O5N (MH+) 366.2280, found 366.2277.
(2R,4S,6S,12S)-4-(Met h oxym et h oxy)-12-m et h yl-13,16-
75.9, 55.3, 48.8, 44.8, 40.4, 40.1, 12.4; IR (neat) 1044 cm-1
;
d ioxa -17-a za tr icyclo[13.2.1.02,6]octa d eca -1(17),7-d ien -14-
on e (23). A mixture of olefin 21 (36.5 mg, 0.10 mmol) and
Cl2(Cy3P)2RuCHC6H5 (74.0 mg, 0.090 mmol) in degassed
CH2Cl2 (100 mL) was refluxed for 30 h. The mixture was
filtered through a pad of silica gel, and the filtrate was
concentrated in vacuo. The resulting residue was purified by
column chromatography on silica gel (hexane/EtOAc, 5:1) to
[R]20 ) -51.1 (c ) 1.1, CHCl3); HRMS (EI) calcd for C10H17
-
D
IO2 (M+) 296.0273, found 296.0271.
2. Con ver sion to Nitr o Com p ou n d . To a solution of the
above iodo compound (98.0 mg, 0.33 mmol) in DMSO (1.7 mL)
was added urea (139 mg, 2.31 mmol). After 5 min, NaNO2 was
added to the mixture, which was stirred for 6 h at room
temperature. The mixture was diluted with EtOAc and washed
with brine. The organic layer was dried over anhydrous
Na2SO4 and concentrated at reduced pressure. The resulting
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:10) to afford nitro compound 17 (53.8 mg)
in 76% yield: 1H NMR (CDCl3, 500 MHz) δ 5.73 (ddd, J )
17.0, 9.9, 8.9 Hz, 1H), 5.05 (d, J ) 17.5 Hz, 1H), 5.04 (d, J )
9.9 Hz, 1H), 4.61 (s, 2H), 4.47 (dd, J ) 12.2, 4.8 Hz, 1H), 4.22
(dd, J ) 12.1, 9.2 Hz, 1H), 4.22-4.18 (m, 1H), 3.35 (s, 3H),
2.63-2.54 (m, 1H), 2.32 (ddd, J ) 14.0, 8.0, 6.3 Hz, 1H), 2.16
(quintet, J ) 9.3 Hz, 1H), 2.10 (ddd, J ) 13.5, 7.4, 2.4 Hz,
1H), 1.67-1.60 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 139.7,
116.2, 95.3, 78.5, 76.1, 55.4, 46.6, 41.8, 39.8, 37.5; IR (neat)
1556, 1383, 1041 cm-1; [R]20D ) -32.9 (c ) 0.32, CHCl3); HRMS
(CI) calcd for C10H18O4N (MH+) 216.1236, found 216.1239.
Acr ylic Acid (1S)-1-Meth ylh ex-5-en yl Ester (19). To a
solution of (S)-heptenol (18) (1.759 g, 15.41 mmol) in CH2Cl2
(22.0 mL) were added N,N-dimethylaniline (5.9 mL, 46.55
mmol) and acryloyl chloride (1.9 mL, 23.39 mmol) at 0 °C. After
3 h at this temperature, the mixture was diluted with ether
and washed with 1 N HCl solution. The organic layer was
concentrated at reduced pressure, and the resulting residue
was purified by column chromatography on silica gel (hexane/
ether, 20:1) to afford acrylate 19 (2.155 g) in 83% yield: 1H
NMR (CDCl3, 500 MHz) δ 6.39 (dd, J ) 17.4, 1.3 Hz, 1H), 6.11
(dd, J ) 17.4, 10.4 Hz, 1H), 5.83-5.75 (m, 2H), 5.03-4.95 (m,
3H), 2.07 (q, J ) 7.1 Hz, 2H), 1.65 (dddd, J ) 13.1, 10.5, 7.5,
5.2 Hz, 1H), 1.58-1.51 (m, 1H), 1.50-1.36 (m, 2H), 1.25 (d, J
) 6.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 165.8, 138.3,
130.2, 128.9, 114.7, 70.9, 35.2, 33.4, 24.5, 19.9; IR 1723, 1199
1
afford a mixture of macrolides 23 (E/ Z ) 2.2:1, 500 MHz H
NMR analysis, 14.2 mg) in 42% total yield. The two isomers
were then separated by column chromatography on silica gel
(EtOAc/hexane, 1:10) to afford E-isomer 23 (9.5 mg) and
Z-isomer 23 (4.4 mg). The spectral data for both of the isomers
were in good agreement with our data obtained by INOC
reactions.
P r ep a r a tion of Acr yl Am id e 25. A mixture of nitro
compound 17 (10.7 mg, 0.050 mmol) and acrylate derivative
24 of Oppolzer’s camphor sultam (17 mg, 0.063 mmol), p-
chlorophenyl isocyanate (53 mg, 0.35 mmol), and Et3N (0.05
mL) in benzene (1.7 mL) was refluxed for 14 h. The mixture
was filtered through a short pad of Celite, and the filtrate was
concentrated at reduced pressure. The resulting residue was
purified by column chromatography on silica gel (hexane/
EtOAc, 5:1) to afford a mixture of isoxazoline 25 and its
1
C2-(S) epimer (94:6, 500 MHz H NMR analysis, 18.8 mg) in
81% yield. The two isomers were then separated by column
chromatography on silica gel (EtOAc/hexane, 1:10) to give
isoxazoline 25 (17.3 mg) and its C2-(S) epimer (0.9 mg).
Isoxazoline 25: 1H NMR (CDCl3, 500 MHz) δ 5.80 (ddd, J )
17.4, 9.8, 7.9 Hz, 1H), 5.48 (dd, J ) 10.9, 6.5 Hz, 1H), 5.08 (d,
J ) 17.1 Hz, 1H), 5.01 (d, J ) 9.9 Hz, 1H), 4.62 (s, 2H), 4.25-
4.21 (m, 1H), 3.92 (dd, J ) 7.2, 5.0 Hz, 1H), 3.54 (d, J ) 13.7
Hz, 1H), 3.44 (d, J ) 13.7 Hz, 1H), 3.35 (s, 3H), 3.39-3.34 (m,
1H), 3.14 (dd, J ) 17.3, 11.1 Hz, 1H), 2.89 (ddd, J ) 10.1, 10.1,
7.9 Hz, 1H), 2.54 (quintet, J ) 8.9 Hz, 1H), 2.32 (ddd, J )
14.0, 8.1, 6.2 Hz, 1H), 2.20-2.14 (m, 1H), 2.12-2.06 (m, 2H),
2.03-1.88 (m, 4H), 1.65-1.61 (m, 1H), 1.60-1.32 (m, 2H), 1.19
(s, 3H), 0.98 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 168.6, 159.6,
140.4, 115.4, 95.2, 76.5, 65.2, 53.3, 52.9, 49.0, 47.9, 46.8, 44.6,
41.8, 39.7, 39.6, 38.1, 37.3, 32.9, 26.4, 20.9, 19.9; IR (neat) 1698,
1040 cm-1; [R]20D ) -221.6 (c ) 0.70, CHCl3); HRMS (EI) calcd
(neat) cm-1; [R]20 ) +8.7 (c ) 1.5, CHCl3).
D
3-[(1R,2S,4S)-4-(Meth oxym eth oxy)-2-vin ylcyclopen tyl]-
4,5-d ih yd r oisoxa zole-5-ca r boxylic Acid (1S)-1-Meth yl-
h ex-5-en yl Ester s 20 a n d 21. A mixture of nitro compound
17 (128.0 mg, 0.60 mmol), acrylate 19 (110.5 mg, 0.66 mmol),
p-chlorophenyl isocyanate (547 mg, 3.56 mmol), and triethyl-
amine (0.1 mL, 0.72 mmol) in benzene (6.0 mL) was refluxed
for
C
23H34O6N2S (M+) 466.2138, found 466.2156. C2-(S)
epimer: 1H NMR (CDCl3, 500 MHz) δ 5.79 (ddd, J ) 17.5,
9.7, 7.5 Hz, 1H), 5.52 (dd, J ) 11.7, 6.3 Hz, 1H), 5.04 (d, J )
17.2 Hz, 1H), 5.00 (d, J ) 10.5 Hz, 1H), 4.61 (s, 2H), 4.25-

Regioselectivity of Macrocyclic INOC Reactions
J . Org. Chem., Vol. 67, No. 3, 2002 781
4.20 (m, 1H), 3.92 (t, J ) 6.3 Hz, 1H), 3.48 (d, J ) 3.5 Hz,
2H), 3.41 (dd, J ) 17.3, 11.6 Hz, 1H), 3.35 (s, 3H), 2.95 (dd, J
) 17.5, 6.2 Hz, 1H), 2.88-2.82 (m, 1H), 2.52 (quintet, J ) 9.0
Hz, 1H), 2.32 (ddd, J ) 14.3, 7.3, 6.4 Hz, 1H), 2.10-2.07 (m,
3H), 2.00-1.89 (m, 4H), 1.65-1.55 (m, 1H), 1.46-1.33 (m, 2H),
1.18 (s, 3H), 1.13 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 168.7,
158.9, 140.4, 115.5, 95.2, 76.4, 65.1, 55.4, 52.8, 49.1, 47.9, 47.2,
44.5, 41.9, 41.8, 39.8, 38.0, 37.4, 32.7, 26.3, 20.8, 19.8; IR (neat)
1698, 1041 cm-1; [R]20D ) -49.8 (c ) 0.24, CHCl3); HRMS (EI)
calcd for C21H29O4N2S (M+ - OMOM) 405.1848, found 405.1856.
P r ep a r a tion of Olefin 21 fr om Am id e 25. A mixture of
amide 25 (10.0 mg, 0.021 mmol) and LiOH‚H2O (9 mg, 0.21
mmol) in THF/H2O (2:1, 1.5 mL) was stirred for 12 h. The
mixture was neutralized with saturated NH4Cl solution,
diluted with EtOAc, and washed with brine. The organic layer
was dried over anhydrous Na2SO4 and concentrated at reduced
pressure. The resulting residue was purified by column chro-
matography on silica gel (CH2Cl2/MeOH, 3:1) to afford the
crude acid. Without further purification, a mixture of the crude
acid, Et3N (0.15 mL, 1.08 mmol), DMAP (3 mg, 0.025 mmol),
and 2,4,6-trichlorobenzoyl chloride (0.05 mL, 0.32 mmol) in
THF (1.0 mL) was stirred for 4 h at room temperature. To the
mixture was added a solution of (S)-heptenol (18) (35 mg, 0.31
mmol) in toluene (2 mL). The reaction mixture was refluxed
for 18 h and filtered through a short pad of silica gel. The
filtrate was concentrated at reduced pressure, and the result-
ing residue was purified by column chromatography on silica
gel (hexane/EtOAc, 4:1) to afford olefin 21 (5.8 mg) in 72%
yield.
Ack n ow led gm en t. This research was supported by
the KMOE (Grant BSRI-97-3420), the Ministry of
Health and Welfare (Grant HMP-00-CD-02-0004), and
the 2001 BK21 Project for Medicine, Dentistry, and
Pharmacy.
Su p p or tin g In for m a tion Ava ila ble: Data for the struc-
ture elucidation of 5a -d and 6a -d , results of MM2 calcula-
tions, experimental procedures and spectral characterization
1
of 15c,d , 16c,d , 4c,d , 5c,d , and 6c,d , and copies of the H and
13C NMR spectra for 1, 5a -d , 6a -d , 12, 20, and 21 and the
1H-1H COSY and NOESY spectra of 5a ,b and 6a ,b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O010744A