Further studies on total synthesis of sarain A. Efforts toward annulation of the macrocyclic rings

Article abstract of DOI:10.1021/jo981821d

Studies have been conducted on testing strategies for annulation of the two macrocyclic rings onto the central tricyclic nucleus of sarain A (1). In particular, methodology has been developed for introduction into the core of C-3' and C-3 substituents, which are necessary for construction of the 'eastern' and 'western' macrocyclic rings of 1, respectively. Formation of the western ring has been successfully addressed via a ring-closing olefin metathesis strategy utilizing the Grubbs ruthenium catalyst. With this macrocyclization approach, a key intermediate lactam has been prepared which will be utilized in a total synthesis of the natural product.

Full text of DOI:10.1021/jo981821d

J . Org. Chem. 1999, 64, 587-595
587
F u r th er Stu d ies on Tota l Syn th esis of Sa r a in A. Effor ts Tow a r d
An n u la tion of th e Ma cr ocyclic Rin gs
Osamu Irie, Kiyohiro Samizu, J ames R. Henry, and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
Received September 8, 1998
Studies have been conducted on testing strategies for annulation of the two macrocyclic rings onto
the central tricyclic nucleus of sarain A (1). In particular, methodology has been developed for
introduction into the core of C-3′ and C-3 substituents, which are necessary for construction of the
“eastern” and “western” macrocyclic rings of 1, respectively. Formation of the western ring has
been successfully addressed via a ring-closing olefin metathesis strategy utilizing the Grubbs
ruthenium catalyst. With this macrocyclization approach, a key intermediate lactam has been
prepared which will be utilized in a total synthesis of the natural product.
Marine sponges produce a series of complex polycyclic
alkaloids which appear to have a common biogenesis from
simple bis-pyridine macrocycles. This group of alkaloids
has spurred a considerable amount of innovative syn-
thetic work worldwide, particularly with regard to the
manzamines, and we have recently reviewed the progress
in this field.1 Included among these marine alkaloids are
sarain A (1), B (2), and C (3), produced by the sponge
Reniera sarai.2 The structures of these three unusual
for synthesis of the nucleus of 1-3. In addition, the
Heathcock group has reported some interesting model
studies directed toward synthesis of the “eastern” mac-
rocyclic ring of the sarains.
Our strategy for building the tricyclic core of the
sarains was to prepare a bicyclic system like 4 via a
stereospecific [3 + 2]-azomethine ylid/olefin cycloaddition
(vide infra), which would undergo an allyl silane/N-
sulfonyliminium ion cyclization (cf. 5) to give a tricycle 6
(Scheme 1). In fact, this concept has proven viable, and
sarain tricycle 6 could be prepared efficiently.3 To con-
tinue the synthetic route, it was necessary to next
introduce functional handles at some stage for attach-
ment of the “eastern” and “western” macrocyclic rings at
C-3′ and C-3, respectively. In this paper, we describe
recent work toward this end and, in addition, report on
some modifications of our initial route3 to simplify and
improve the overall sequence of steps.
The starting point for the synthesis was commercially
available dihydroanisole (7), which was ozonized to afford
ester acetal 8 (Scheme 2). The ester was converted to
alcohol 9 and then via the mesylate 10 to N-benzylamine
11 (54% from 7). Condensation of this amine with the
aziridine mixed anhydride 12 yielded amide 13 in excel-
lent yield. Thermolysis of aziridine olefin 13 at 325 °C
in o-DCB led to a stereospecific cyclization via [3 +
2]-dipolar cycloaddition of azomethine ylid 14 to bicyclic
lactam 15.5 It might be noted that in our previous work3
we had employed a protected alcohol in the side chain
due to concerns as to whether an acetal moiety would
survive the high temperatures required for the cycload-
dition step. Introduction of a functionalized C-3′ sub-
stituent into the system proved quite easy. Thus, lactam
15 was first deprotonated with LiHMDS followed by
alkylation with bromomethyl methyl ether, leading to the
desired cis-fused bicycle 16 in good yield.
alkaloids were elucidated by Cimino and co-workers
using a combination of spectral methods and X-ray
crystallography. The sarains 1-3 were also found to have
moderate antitumor, antibacterial, and insecticidal
activity.2d We have previously reported some initial
synthetic studies directed toward constructing the tricy-
clic core of these exceptionally challenging and interest-
ing molecules.3 Heathcock et al.4 also revealed some
preliminary results based on a dipolar cycloaddition
strategy similar to that which we successfully executed
(1) Matzanke, N.; Gregg, R. J .; Weinreb, S. M. Org. Prep. Proced.
Int. 1998, 30, 1 and references therein. See also: Magnier, E.; Langlois,
Y. Tetrahedron 1998, 54, 6201. For a modified biogenetic proposal,
see: Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.; Das, B.
C. J . Am. Chem. Soc. 1998, 120, 8026.
(2) (a) Cimino, G.; Mattia, C. A.; Mazzarella, L.; Puliti, R.;
Scognamiglio, G.; Spinella, A.; Trivellone, E. Tetrahedron 1989, 45,
3863. (b) Cimino, G.; Scognamiglio, G.; Spinella, A.; Trivellone, E. J .
Nat. Prod. 1990, 53, 1519. (c) Guo, Y.; Madaio, A.; Trivellone, E.;
Scognamiglio, G.; Cimino, G. Tetrahedron 1996, 52, 8341. (d) Caprioli,
V.; Cimino, G.; DeGiulio, A.; Madaio, A.; Scognamiglio, G.; Trivellone,
E. Comp. Biochem. Physiol. 1992, 103B, 293.
(3) (a) Sisko, J .; Weinreb, S. M. J . Org. Chem. 1991, 56, 3210. (b)
Sisko, J .; Henry, J . R.; Weinreb, S. M. J . Org. Chem. 1993, 58, 4945.
(c) Henry, J . R. Ph.D. Thesis, The Pennsylvania State University,
1994.
(4) (a) Henke, B. R.; Kouklis, A. J .; Heathcock, C. H. J . Org. Chem.
1992, 57, 7056. (b) Heathcock, C. H.; Clasby, M.; Griffith, D. A.; Henke,
B. R.; Sharp, M. J . Synlett 1995, 467.
Before continuing with the synthesis, we decided to
explore the possibility of incorporating the C-3′ substitu-
ent into an early intermediate prior to the cycloaddition
step. Thus, aziridine ester 173c,6 was combined with
(5) cf. (a) DeShong, P.; Kell, D. A.; Sidler, D. R. J . Org. Chem. 1985,
50, 2309. (b) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J . Am. Chem.
Soc. 1987, 109, 5523. Takano, S.; Tomita, S.; Iwabuchi, Y.; Ogasawara,
K. Heterocycles 1989, 29, 1473. Takano, S.; Iwabuchi, Y.; Ogasawara,
K. J . Chem. Soc., Chem. Commun. 1988, 1204.
10.1021/jo981821d CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/29/1998

588 J . Org. Chem., Vol. 64, No. 2, 1999
Irie et al.
28 with OsO4/J ones reagent9 led to the desired carboxylic
acid, which could be converted to ethyl ester 32 with
diazoethane (54%).3c However, despite extensive effort,
we were unable to alkylate this ester. In addition, the
ester substrate bearing an N-benzyl group rather than
the methyl carbamate functionality was also resistant
to alkylation at C-3.3a We therefore turned to the nitrile
31 as an alternative. This compound was prepared in
excellent yield by ozonolysis of alkene 28 to aldehyde 29,
followed by formation of oxime 30, and dehydration with
triphosgene.
Sch em e 1
Nitrile 31 has in fact proven quite amenable to C-3
alkylation. Treatment of 31 with KHMDS and iodo acetal
33 led to a single stereoisomeric alkylation product 35
(Scheme 5). The stereochemistry of this product was
established as shown by 1H NMR NOE experiments after
conversion to benzyl ether 36.10 It therefore appears that
alkylation of nitrile carbanion 34 occurs from a preferred
equatorial direction, as is observed in cases of simpler
exocyclic cyclohexyl nitrile anions.11 Attempts were also
made to utilize acetal 36 in construction of the “western”
macrocyclic ring of sarain A. Removal of the N-tosyl
group (Na/naphthalene) and cleavage of the acetal with
TFA provided amino aldehyde 37. However, we have
been unable to effect a reductive amination of 37 to afford
macrocycle 38.12,13
Another strategy which was briefly examined for
annulation of this ring involved an intramolecular nitrile
carbanion alkylation.14 Thus, iodonitrile 39 was prepared
(Scheme 6), but we have unfortunately been unable to
effect closure to macrocycle 40.15
In view of these disappointing results, we next turned
to a ring-closing olefin metathesis strategy for building
the “western” macrocyclic ring.16 Alkylation of nitrile 31
with mesylate 41 afforded a single stereoisomeric product
42 (70%) along with a small amount of recovered starting
material (Scheme 7). It was then possible to convert this
alkylated nitrile to the benzyl ether 43 in three steps.
Selective cleavage of the N-tosyl group of 43 could be
effected with sodium naphthalenide, and acylation of the
resulting amine with 6-heptenoyl chloride afforded amide
amine 183 in the presence of trimethylaluminum7 to
afford amide 19 (Scheme 3). Attempts at thermolysis of
compound 19 at >320 °C led only to recovery of starting
material. Because it seemed possible that this lack of
reactivity might be due to an unfavorable amide confor-
mation, secondary amide 19 was N-benzylated to afford
aziridine olefin 20. In this case, heating substrate 20 at
320 °C for 2.5 h indeed led to the desired bicylic lactam
21. Despite the success of these experiments, however,
it was deemed simpler and more convenient to proceed
via the lactam alkylation route shown in Scheme 2 and
this alternative sequence was therefore not pursued.
At this point, lactam 16 was selectively mono-deben-
zylated by a dissolving metal reduction, and the resulting
lactam 22 was N-tosylated to afford 23 (Scheme 4).
Because we have experienced some difficulties in explor-
atory work3c due to the presence of a basic nitrogen in
various intermediates, it was decided to replace the
remaining N-benzyl group with a carbamate function at
this point. Therefore, the benzyl compound 23 was
hydrogenolyzed to the corresponding secondary amine,
which was converted to the methyl carbamate derivative.
Hydrolysis of the acetal moiety then afforded aldehyde
carbamate 24 in good overall yield. Addition of vinyl-
magnesium bromide to this aldehyde in the presence of
cerium trichloride afforded a diastereomeric mixture of
allylic alcohols 25, which was acetylated to yield ace-
tates 26. Application of the Fleming silyl cuprate meth-
odology8 allowed conversion of allylic acetates 26 to
allyl silane 27 as a 1:1 mixture of geometric isomers. We
were pleased to find that the C-3′ substituent which had
been installed did not adversely affect the N-sulfonyl
imine/allylsilane addition step. Thus, selective partial
reduction of the N-tosyl lactam carbonyl group of 27,
followed by treatment of the resulting R-hydroxy sul-
fonamide with anhydrous ferric chloride led to the sarain
A tricyclic nucleus 28 (3:2 mixture of diastereomers) in
high yield.
(9) Henry, J . R.; Weinreb, S. M. J . Org. Chem. 1993, 58, 4745.
(10) To confirm this assignment, nitrile 31 was converted via
alkylation product i to compound ii, which is the epimer of 36. 1H NMR
NOE experiments on ii established its stereochemistry.
(11) Evans, D. A. Stereoselective Alkylation Reactions of Chiral
Metal Enolates. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: Orlando, 1984; Vol. 3, p 1.
(12) See, for example: Ina, H.; Ito, M.; Kibayashi, C. J . Org. Chem.
1996, 61, 1023.
(13) Meng, Q.; Hesse, M. Ring Closure Methods in the Synthesis of
Macrocyclic Natural Products. In Topics in Current Chemistry; Steck-
han, E., Ed.; Springer-Verlag: Berlin, 1991; 161, p 107.
(14) For some examples of macrocycle formation via intramolecular
nitrile anion alkylations, see: Takahashi, T.; Nemoto, H.; Tsuji, J .
Tetrahedron Lett. 1983, 24, 2005. Takahashi, T.; Nagashima, T.; Ikeda,
H.; Tsuji, J . Tetrahedron Lett. 1982, 23, 4361.
Our initial plan was to next cleave the double bond of
tricycle 28 to produce ester 32 and then to alkylate the
derived ester enolate at C-3. Treatment of intermediate
(6) Anderson, G. T.; Henry, J . R.; Weinreb, S. M. J . Org. Chem. 1991,
56, 6946.
(7) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171. Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. 1979, 59,
49.
(8) Fleming, I.; Thomas, A. P. J . Chem. Soc., Chem. Commun. 1985,
411. Fleming, I.; Newton, T. W. J . Chem. Soc., Perkin Trans. 1 1984,
1805.
(15) Samizu, K.; unpublished results.
(16) For ring-closing olefin metathesis reviews, see: (a) Grubbs, R.
H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schmalz,
H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833. (c) Armstrong, S.
K. J . Chem. Soc., Perkin Trans. 1 1998, 371.

Further Studies on Total Synthesis of Sarain A
J . Org. Chem., Vol. 64, No. 2, 1999 589
Sch em e 2
Sch em e 3
macrolactam 51, along with a macrocyclic dimer and
some starting material. Although this particular sub-
strate has not yet been examined in detail, the results
to date appear to be quite similar to those obtained with
diene 44.
In conclusion, we have developed a successful strategy
for preparation of the key macrocyclic intermediate 47
for the total synthesis of sarain A (1). Work is currently
in progress on improving the metathesis process for
construction of the “western” macrolactam ring of 47 and
on developing appropriate chemistry for efficient annu-
lation of the functionally complex “eastern” ring.
Exp er im en ta l Section
P r ep a r a tion of Ben zyla m in e 11. A solution of 1-methoxy-
1,4-cyclohexadiene (7, 21.25 g, 0.19 mol) in 50 mL of methanol
was cooled to -78 °C and was exposed to ozone gas with
efficient stirring for 2 h. While still at -78 °C, the solution
was flushed with argon. After 10 min, dimethyl sulfide (17.6
mL, 0.24 mol) was added and the resulting solution was
gradually warmed to room temperature over 2 h. Methanol
and excess dimethyl sulfide were removed in vacuo, and 100
mL of methanol followed by pyridinum p-toluenesulfonate
(2.32 g, 9.22 mmol) was added to the residue. The mixture was
heated at reflux for 2 h, and methanol was then removed in
vacuo. The residue was diluted with 50 mL of saturated
NaHCO3 solution and extracted with ether (2 × 100 mL). The
organic extract was dried (K2CO3) and concentrated to give
the crude ester 8 as a brown oil: IR (film) 2950, 1740, 1435,
44. Exposure of diene amide 44 to the Grubbs ruthenium
catalyst 45 in refluxing methylene chloride (0.5 mM) for
2 days led to the desired macrocyclic lactam 46 as a
mixture of geometric isomers (49%) along with a dimeric
product (39%) and some recovered starting material (7%).
The dimer appears to be a macrocycle derived from either
head-to-head or head-to-tail coupling of diene 44.17 It was
then possible to hydrogenate 46 to produce the macro-
lactam alcohol 47, which we hope to use in the total
synthesis of sarain A.
We have briefly examined two other permutations of
this metathesis strategy for construction of the “western”
ring. Thus, by use of the chemistry described for synthe-
sis of diene 44, diene 48 was prepared (Scheme 8).
Treatment of 48 with the Grubbs catalyst led to forma-
tion of an inseparable mixture of the desired macrocycle
49 along with a linear dimer in poor overall yield. The
metathesis reaction proved sluggish in this case, and a
considerable amount of starting material was also re-
covered. We believe that in diene 48 the C-3 alkenyl chain
is positioned too close to the tricylic core, thus slowing
the metathesis process. This may also explain why a
noncyclic dimer is formed in this particular case.
One other diene system which was explored is 50
(Scheme 9). Metathesis of this compound gave the desired
1
1125 cm-1; H NMR (200 MHz, CDCl3) δ 5.67 (2H, m), 4.36
(1H, t, J ) 5.7 Hz), 3.68 (3H, s), 3.32 (6H, s), 3.11 (2H, d, J )
6.8 Hz), 2.37 (2H, t, J ) 5.7 Hz); 13C NMR (90 MHz, CDCl3) δ
172.4, 127.6, 123.8, 104.3, 53.4, 52.1, 33.3, 31.6; CIMS m/z
(relative intensity) (M+ - OMe) 157 (95), 127 (18), 97 (20), 75
(100).
The above crude ester 8 was dissolved in 50 mL of THF and
was added to a solution of LiAlH4 (4.20 g, 0.10 mol) in 100 mL
of THF over 30 min at 0 °C. After 10 min, 15 mL of a 50%
KOH solution and 100 mL of ether were added at 0 °C. The
solution was stirred overnight at room temperature and was
filtered through a pad of Celite which was further washed with
ether. The organic phase was concentrated to produce alcohol
9 as a yellow oil suitable for use in the next step without
1
purification: IR (film) 3420, 2940, 1125, 1055 cm-1; H NMR
(200 MHz, CDCl3) δ 5.58 (2H, m), 4.36 (1H, t, J ) 5.7 Hz),
3.75 (2H, m), 3.34 (6H, s), 2.43 (2H, t, J ) 5.7 Hz), 2.32 (2H,
q, J ) 6.1 Hz), 2.14 (1H, br s); 13C NMR (90 MHz, CDCl3) δ
128.8, 126.7, 104.5, 62.2, 53.6, 31.5, 31.3; EIMS m/z (relative
intensity) (M+ - OMe) 129 (7), 109 (6), 97 (12), 75 (100).
(17) Ozonolysis of this cyclic dimer followed by treatment with
Ph3PdCH2 gave back diene 44.

590 J . Org. Chem., Vol. 64, No. 2, 1999
Irie et al.
Sch em e 4
Sch em e 5
(K2CO3), and concentrated. Flash chromatography of the
residue eluting with ethyl acetate yielded 28.03 g (51% overall
from 7) of amine 11 as a yellow oil: IR (film) 3310, 2935, 2830,
Sch em e 6
1
1455, 1125 cm-1; H NMR (200 MHz, CDCl3) δ 7.31 (5H, m),
5.48 (2H, m), 4.36 (1H, t, J ) 5.7 Hz), 3.78 (3H, s), 3.29 (6H,
s), 2.66 (2H, t, J ) 6.7 Hz), 2.38 (2H, t, J ) 5.7 Hz), 2.26 (2H,
q, J ) 6.7 Hz), 1.57 (1H, br s); 13C NMR (90 MHz, CDCl3) δ
140.7, 130.1, 128.8, 128.5, 127.3, 125.9, 104.5, 54.3, 53.4, 49.2,
31.5, 28.5; CIMS m/z (relative intensity) (M+ + 1) 250 (100),
218 (78), 186 (10), 120 (40), 91 (32).
Con ver sion of Am in e 11 to Azir id in e Am id e 13. Potas-
sium trimethylsilanolate (3.33 g, 25.92 mmol) was added in
one portion to a solution of methyl N-benzylaziridine-1-
carboxylate5a (4.95 g, 25.92 mmol) in 100 mL of THF. After
14 h, the solution was concentrated in vacuo. The residue was
dissolved in 70 mL of CH2Cl2 and cooled to 0 °C. Pivaloyl
chloride (3.16 mL, 25.67 mmol) was added slowly, and the
resulting solution was gradually warmed to room temperature
over 2 h. After the mixture was recooled to -78 °C, a solution
of amine 11 (6.40 g, 25.67 mmol) in 30 mL of CH2Cl2 was added
over 30 min. The solution was stirred for 30 min at -78 °C,
diluted with 50 mL of saturated NaHCO3 solution, and
extracted with CH2Cl2 (100 mL). After drying (K2CO3) and
concentration of the extract, flash chromatography of the
residue eluting with hexanes/ethyl acetate (1:2) provided
aziridine amide 13 (8.59 g, 82%) as a yellow oil: IR (film) 3480,
2935, 1645, 1450, 1120, 1065 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.25 (10H, m), 5.43 (2H, m), 4.72 (0.5H, d, J ) 14.8 Hz),
4.51 (0.5H, d, J ) 14.8 Hz), 4.51 (1H, t, J ) 7.4 Hz), 4.33 (0.5H,
d, J ) 11.3 Hz), 4.31 (0.5H, d, J ) 11.3 Hz), 3.72 (0.5H, d, J
The above alcohol 9 was dissolved in 100 mL of CH2Cl2, and
the mixture was cooled to 0 °C. Et3N (18.27 mL, 0.13 mol) and
methanesulfonyl chloride (9.7 mL, 0.13 mol) were added
sequentially via syringe, and the resulting solution was stirred
for 10 min. The mixture was washed with H2O (2 × 100 mL)
and brine (100 mL), dried (MgSO4), and concentrated to give
the unstable mesylate 10 as a brown oil: IR (film) 2940, 1355,
1
1175, 1125 cm-1; H NMR (200 MHz, CDCl3) δ 5.55 (2H, m),
4.36 (1H, t, J ) 5.7 Hz), 4.21 (2H, t, J ) 6.7 Hz), 3.32 (6H, s),
2.98 (3H, s), 2.49 (2H, q, J ) 6.7 Hz), 2.36 (2H, t, J ) 5.7 Hz);
13C NMR (90 MHz, CDCl3) δ 128.3, 126.2, 104.6, 69.9, 53.8,
37.8, 31.9, 28.1; CIMS m/z (relative intensity) (M+ + 1) 237
(10), 207 (100), 111 (30), 85 (40), 75 (95).
To a solution of the above mesylate 10 and Et3N (51.8 mL,
0.37 mol) in 100 mL of THF was added benzylamine (42.14
mL, 0.39 mol), and the mixture was heated at reflux overnight.
The solution was cooled to 0 °C, and 50 mL of ether was added.
The resulting salts were filtered, and the organics were
concentrated. The residue was extracted twice with 100 mL
of ether. The extract was washed with brine (100 mL), dried

Further Studies on Total Synthesis of Sarain A
J . Org. Chem., Vol. 64, No. 2, 1999 591
Sch em e 7
in 25 mL of THF was added over 30 min at -78 °C. The
solution was stirred for 30 min at 0 °C and recooled to -78
°C, and bromomethyl methyl ether (1.20 mL, 13.22 mmol)
was added in one portion. The mixture was stirred for 2 h
at room temperature, diluted with 100 mL of saturated
NaHCO3 solution, and extracted with ethyl acetate (2 ×
75 mL) and brine (100 mL). The organic extract was dried
(K2CO3) and concentrated. Flash chromatography of the
residue eluting with hexanes/ethyl acetate (1:1) provided
lactam 16 (4.65 g, 93%) as a yellow oil: IR (film) 3415,
Sch em e 8
2930, 1635, 1455, 1125 cm-1 1H NMR (300 MHz, CDCl3) δ
;
Sch em e 9
7.28 (10H, m), 4.89 (1H, d, J ) 14.9 Hz), 4.65 (1H, d, J )
13.8 Hz), 4.40 (1H, d, J ) 14.9 Hz), 4.26 (1H, dd, J ) 5.0,
6.4 Hz), 4.07 (1H, d, J ) 8.4 Hz), 3.76 (1H, d, J ) 13.8 Hz),
3.46 (1H, d, J ) 8.4 Hz), 3.39 (3H, s), 3.29 (3H, s), 3.28 (2H,
m), 3.27 (3H, s), 2.71 (1H, t, J ) 8.9 Hz), 2.64 (1H, t, J ) 8.9
Hz), 2.54 (2H, m), 1.73 (3H, m), 1.53 (1H, m); 13C NMR (75
MHz, CDCl3) δ 170.8, 141.6, 137.7, 128.7, 128.2, 128.0, 127.3,
126.5, 104.0, 72.5, 69.0, 59.6, 56.1, 53.6, 53.4, 53.1, 50.5, 46.5,
42.4, 34.0, 32.7, 21.9; FABMS m/z (relative intensity) (M+
+
1) 454 (14), 453 (44), 452 (28), 421 (22), 406 (28), 407 (100),
357 (12).
) 13.8 Hz), 3.51 (0.5H, d, J ) 13.4 Hz), 3.48 (0.5H, d, J )
13.4 Hz), 3.35 (0.5H, d, J ) 13.8 Hz), 3.34 (1H, m), 3.30 (6H,
s), 3.21 (1H, m), 2.33 (6H, m), 1.73 (0.5H, d, J ) 6.2 Hz), 1.62
(0.5H, d, J ) 6.2 Hz); 13C NMR (75 MHz, CDCl3) δ 169.6, 169.4,
138.5, 138.4, 137.7, 137.2, 129.7, 128.7, 128.6, 128.4, 128.3,
128.2, 127.7, 127.6, 127.5, 127.5, 126.8, 126.6, 126.1, 104.4,
104.2, 64.5, 53.5, 53.3, 51.3, 49.1, 46.8, 46.3, 37.2, 36.9, 34.6,
34.3, 31.5, 31.2, 27.3, 26.0; FABMS m/z (relative intensity) (M+
+ 1) 409 (38), 408 (2), 407 (2), 407 (5), 393 (6), 363 (3); HRMS
calcd for C25H33N2O3 (M+ + 1) 409.2491, found 409.2477.
Cycliza tion of Azir id in e 13 to La cta m 15. A solution of
aziridine 13 (2.21 g, 5.41 mmol) in 13 mL of o-dichlorobenzene
in a resealable glass tube was degassed twice and sealed under
vacuum. The tube was heated at 325 °C for 25 min and cooled
to room temperature. The solvent was removed by vacuum
distillation, and the product was isolated by flash chromatog-
raphy eluting with hexanes/ethyl acetate (1:1) to yield 1.61 g
(73%) of lactam 15 as a yellow oil: IR (film) 3485, 2935, 1645,
1450, 1125 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.28 (10H, m),
4.88 (1H, d, J ) 14.7 Hz), 4.67 (1H, d, J ) 13.8 Hz), 4.36 (1H,
d, J ) 14.7 Hz), 4.26 (1H, t, J ) 5.7 Hz), 3.60 (1H, d, J ) 13.8
Hz), 3.27 (3H, m), 3.29 (3H, s), 3.27 (3H, s), 2.74 (1H, t, J )
9.5 Hz), 2.65 (1H, t, J ) 9.5 Hz), 2.32 (2H, m), 1.85 (1H, m),
1.61 (3H, m); 13C NMR (75 MHz, CDCl3) δ 170.2, 140.6, 137.5,
128.8, 128.7, 128.3, 128.1, 127.5, 126.7, 103.9, 65.9, 59.4, 56.6,
53.2, 49.9, 46.9, 41.1, 35.8, 32.4, 21.2; FABMS m/z (relative
intensity) (M+ + 1) 409 (100), 408 (41), 407 (86), 393 (20), 377
(53), 317 (14); HRMS calcd for C25H33N2O3 (M+ + 1) 409.2491,
found 409.2468.
P r ep a r a tion of Azir id in e Am id e 19. To a solution of
amine 183b (0.75 g, 3.4 mmol) in 50 mL of CH2Cl2 was added
a 2.0 M solution of trimethylaluminum in hexanes (2.6 mL,
5.1 mmol). After 20 min, aziridine 17,6 dissolved in 5 mL of
CH2Cl2, was slowly added at room temperature, and the
resulting solution was stirred overnight. The reaction was
quenched with 10 mL of 5% HCl, filtered through Celite,
washed with 20 mL of brine, dried (MgSO4), and concentrated.
Flash chromatography of the residue using ethyl acetate
yielded aziridine 19 as a yellow oil (0.73 g, 52%): IR (film)
3345, 2920, 1650, 1500, 1440 cm -1; 1H NMR (200 MHz, CDCl3)
δ 7.33 (5H, m), 6.31 (4H, m), 5.50 (2H, m), 4.39 (1H, d, J )
14.8 Hz), 4.10 (1H, d, J ) 10.0 Hz), 3.85 (2H, m), 3.74 (3H, s),
3.62 (1H, d, J ) 14.8 Hz), 3.30 (6H, m), 2.49 (2H, m), 2.24
(2H, m), 1.95 (1H, s), 1.72 (1H, s).
Con ver sion of Azir id in e Am id e 19 to N-Ben zyl Am id e
20. Aziridine amide 19 (0.12 g, 0.28 mmol) was dissolved in
10 mL of THF and cooled to 0 °C. A 0.5 M solution of lithium
bis(trimethylsilyl)amide in THF (0.84 mL, 0.42 mmol) was
added dropwise via syringe, and the resulting mixture was
stirred for 15 min. Benzyl bromide (96 mg, 0.56 mmol) was
added rapidly, and the solution was warmed to room temper-
ature over 2 h. The solution was diluted with ethyl acetate
and washed with 10 mL of water and 10 mL of brine, and the
organic extracts were dried (MgSO4) and concentrated. Pre-
parative TLC of the residue using hexanes/ethyl acetate (2:1)
yielded the N-benzyl amide 20 (73 mg, 52%) as a yellow oil:
IR (film) 2940, 1640, 1520, 1460, 1245 cm-1 1H NMR (200
;
MHz, CDCl3) δ 7.21 (10H, m), 6.74 (4H, m), 5.43 (2H, m), 4.89
(1H, m), 4.34 (2H, m), 3.71 (6H, m), 3.14 (5H, m), 2.30 (5H,
m), 1.71 (3H, m).
C-Alk yla tion of La cta m 15. A 1.68 M solution of nBuLi
in hexane (7.87 mL, 13.22 mmol) was added to a solution of
bis(trimethylsilyl)amine (2.79 mL, 13.22 mmol) in 40 mL of
THF at 0 °C. After 10 min, lactam 15 (4.50 g, 11.01 mmol)

592 J . Org. Chem., Vol. 64, No. 2, 1999
Irie et al.
Cycloa d d ition of Azir id in e 20 to La cta m 21. The aziri-
dine 20 (39 mg, 0.076 mmol) was dissolved in 3 mL of o-DCB
and degassed in a resealable tube. The tube was sealed under
vacuum and heated at 320 °C for 2.5 h. After the mixture
cooled to room temperature, the solvent was removed by
vacuum distillation, and the product 20 (23 mg, 59%) was
isolated as a yellow oil by preparative TLC using hexanes/
ethyl acetate (2:1): 1H NMR (200 MHz, CDCl3) δ 7.30 (10H,
m), 6.78 (4H, m), 4.90 (1H, d, J ) 15.0 Hz), 4.64 (1H, d, J )
13.9 Hz), 4.38 (1H, d, J ) 15.0 Hz), 4.06 (1H, d, J ) 8.5 Hz),
3.79 (5H, m), 3.46 (1H, d, J ) 8.5 Hz), 3.29 (4H, m), 2.64 (4H,
m), 1.65 (6H, m).
Mon o-Deben zyla tion of La cta m 16 to La cta m 22. To a
solution of sodium metal (905 mg, 39.33 g atm) in 70 mL of
ammonia at -78 °C was added a solution of lactam 16 (3.56
g, 7.87 mmol) in 25 mL of THF and 1 mL of tBuOH. After 5
min, the cold bath was removed, and the reaction was
quenched with 10 mL of saturated NH4Cl solution. The NH3
was allowed to evaporate, the solution was extracted with
ether (3 × 80 mL), and the organic extract was washed with
brine (100 mL). The organic phase was dried (MgSO4) and
concentrated to give colorless prismatic crystals of 22, which
were further purified by recrystallization using ethyl acetate/
hexane (2.15 g, 75%): mp 150-1 °C; IR (CH2Cl2) 3405, 2935,
2830, 1660, 1495, 1455, 1255 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.24 (5H, m), 5.86 (1H, br s), 4.46 (1H, d, J ) 13.8 Hz), 4.28
(1H, dd, J ) 6.4, 5.0 Hz), 3.98 (1H, d, J ) 8.4 Hz), 3.78 (1H,
d, J ) 13.8 Hz), 3.42 (1H, d, J ) 8.4 Hz), 3.37 (3H, s), 3.31
(2H, m), 3.30 (3H, s), 3.29 (3H, s), 2.71 (1H, t, J ) 8.5 Hz),
2.61 (1H, t, J ) 8.5 Hz), 2.56 (2H, m), 1.73 (3H, m), 1.55 (1H,
ddd, J ) 13.4, 8.2, 5.0 Hz); 13C NMR (75 MHz, CDCl3) δ 173.1,
141.3, 128.0, 127.8, 126.3, 103.8, 72.4, 68.3, 59.3, 55.9, 53.5,
53.1, 52.9, 42.0, 40.9, 33.9, 32.5, 21.8; FABMS m/z (relative
intensity) (M+ + 1) 363 (76), 362 (12), 361 (38), 331 (24), 317
(100), 285 (8); HRMS calcd for C20H31N2O4 (M+ + 1) 363.2284,
found 363.2254.
(2H, s), 3.59 (2H, m), 3.41 (3H, s), 3.36 (1H, m), 3.37 (3H, s),
3.07 (3H, s), 2.94 (1H, t, J ) 9.3 Hz), 2.81 (1H, m), 2.73 (1H,
m), 2.47 (3H, s), 2.12 (1H, br d, J ) 10.8 Hz), 1.74 (3H, m); 13
C
NMR (90 MHz, CDCl3) δ 168.7, 145.8, 134.8, 129.7, 129.0,
104.2, 74.7, 72.5, 59.4, 54.5, 54.2, 48.5, 45.7, 43.1, 36.4, 31.1,
23.5, 22.0; CIMS m/z (relative intensity) (M+ + 1) 427 (100),
396 (98), 271 (48), 241 (50), 157 (80).
To methyl chloroformate (3.42 mL, 44.22 mmol) was slowly
added a solution of the above amine (3.37 g, 7.91 mmol) in 30
mL of pyridine at 0 °C. The solution was stirred for 4 h at
room temperature. The pyridine was removed in vacuo, and
to the residue were added 30 mL of CH2Cl2 and 30 mL of H2O.
The mixture was extracted with 20 mL of CH2Cl2 and washed
with 5% HCl solution (2 × 30 mL) and brine (30 mL). The
organic extract was dried (MgSO4) and concentrated to give
the crude methyl carbamate as a colorless amorphous solid:
IR (CH2Cl2) 2955, 1700, 1450, 1370, 1170 cm-1; 1H NMR (360
MHz, CDCl3) δ 7.83 (2H, d, J ) 8.1 Hz), 7.23 (2H, d, J ) 8.1
Hz), 4.27 (1H, t, J ) 5.4 Hz), 4.02 (1H, m), 3.78 (2H, m), 3.55
(2H, m), 3.46 (3H, s), 3.26 (6H, s), 3.23 (3H, s), 2.97 (1H, t, J
) 9.3 Hz), 2.62 (2H, m), 2.35 (3H, s), 1.88 (1H, m), 1.63 (3H,
m); 13C NMR (90 MHz, CDCl3) δ 170.4, 154.7, 145.0, 136.5,
129.8, 129.0, 104.2, 72.9, 70.4, 59.8, 53.9, 52.9, 45.3, 44.3, 35.3,
33.0, 25.2, 22.0; CIMS m/z (relative intensity) (M+ + 1) 453
(100), 393 (10), 331 (15), 267 (35), 157 (90).
To a solution of the above carbamate in 50 mL of THF and
50 mL of H2O was added p-toluenesulfonic acid (150 mg, 0.79
mol), and the mixture was heated at reflux overnight. The
solution was cooled to room temperature, extracted with ethyl
acetate (2 × 50 mL), and washed with brine (50 mL). The
organics were dried (MgSO4) and concentrated. Flash chro-
matography of the residue eluting with ethyl acetate yielded
3.12 g (86%) of aldehyde 24 as a colorless amorphous solid:
IR (CH2Cl2) 3050, 2955, 1725, 1700, 1595, 1450, 1370, 1170
1
cm-1; H NMR (300 MHz, CDCl3) δ 9.69 (1H, s), 7.81 (2H, d,
J ) 8.3 Hz), 7.24 (2H, d, J ) 8.3 Hz), 4.04 (1H, m), 3.82 (1H,
dd, J ) 9.3, 7.7 Hz), 3.75 (1H, d, J ) 10.1 Hz), 3.66 (1H, d, J
) 10.1 Hz), 3.51 (1H, m), 3.47 (3H, s), 3.22 (3H, s), 3.02 (2H,
m), 2.74 (1H, m), 2.54 (2H, d, J ) 6.2 Hz), 2.34 (3H, s), 1.73
(1H, br d, J ) 14.6 Hz), 1.53 (1H, m); 13C NMR (75 MHz,
CDCl3) δ 199.8, 169.9, 154.2, 144.8, 136.0, 129.4, 128.4, 72.8,
70.1, 59.4, 52.9, 52.5, 44.8, 43.6, 43.2, 33.0, 24.9, 21.6; FABMS
m/z (relative intensity) (M+ + 1) 439 (18), 393 (16), 317 (7),
283 (8); HRMS calcd for C20H27N2O7S (M+ + 1) 439.1539, found
439.1508.
Con ver sion of La cta m 22 to N-Su lfon ylla cta m 23. A
1.98 M solution of nBuLi in hexane (0.52 mL, 1.04 mmol) was
added to a solution of bis(trimethylsilyl)amine (0.22 mL, 1.04
mmol) in 3 mL of THF at 0 °C. After 20 min, lactam 22 (250
mg, 0.69 mmol) in 3 mL of THF was added at 0 °C. The
solution was stirred for 1 h at 0 °C, and p-toluenesulfonyl
chloride (197 mg, 1.04 mmol) was added in one portion. The
mixture was stirred for 1 h at room temperature, diluted with
10 mL of saturated NaHCO3 solution, and extracted with 2 ×
15 mL of ethyl acetate. The organics were dried (MgSO4) and
concentrated. Flash chromatography of the residue eluting
with hexanes/ethyl acetate (1:1) provided sulfonyl lactam 23
(290 mg, 83%) as colorless crystals, which were recrystalized
from ethyl acetate to give colorless prisms: mp 132-3 °C; IR
F or m a tion of Aceta te 26. Cerium chloride heptahydrate
(1.70 g, 4.57 mmol) was dried at 140 °C for 2 h in vacuo, 20
mL of THF was added at 0 °C, and the mixture was stirred
overnight at room temperature. To this suspension was added
a solution of aldehyde 24 (1.18 g, 2.69 mmol) in 10 mL of THF
at 0 °C, and the mixture was stirred for 30 min. To the
resulting solution was added 1.0 M vinylmagnesium bromide
in THF (2.96 mL, 2.96 mmol) at 0 °C. After being stirred for
2 h at the same temperature, the mixture was diluted with
30 mL of saturated NH4Cl solution and 20 mL of ethyl acetate.
The suspension was filtered through a pad of Celite which was
washed with ethyl acetate. The filtrate was extracted with 20
mL of ethyl acetate, washed with 40 mL of brine, and dried
(MgSO4). The organic extract was concentrated to produce
allylic alcohol 25 (912 mg) as a colorless amorphous solid which
was a mixture of diastereomers suitable for use in the next
step without purification: IR (CH2Cl2) 3610, 2955, 1725, 1700,
1450, 1370, 1170 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.94 (2H,
d, J ) 8.1 Hz), 7.48 (2H, d, J ) 8.1 Hz), 6.04 (1H, ddd, J )
17.1, 10.4, 6.5 Hz), 5.42 (1H, dd, J ) 17.1, 1.1 Hz), 5.31 (1H,
d, J ) 10.4 Hz), 4.30 (2H, m), 4.02 (2H, m), 3.78 (3H, m), 3.71
(3H, s), 3.47 (3H, s), 3.27 (1H, q, J ) 11.1 Hz), 3.00 (1H, m),
2.60 (3H, s), 1.83 (2H, m), 1.44 (3H, m); CIMS m/z (relative
intensity) (M+ + 1) 467 (100), 440 (58), 313 (25), 285 (20);
HRMS calcd for C24H33N2O8S (M+ + 1) 509.1958, found
509.1963.
1
(CH2Cl2) 2930, 2835, 1690, 1595, 1455, 1170 cm-1; H NMR
(300 MHz, CDCl3) δ 7.90 (2H, d, J ) 8.3 Hz), 7.26 (2H, d, J )
8.3 Hz), 7.18 (3H, m), 6.97 (2H, m), 4.25 (1H, m), 4.23 (1H,
dd, J ) 6.5, 4.9 Hz), 4.02 (1H, d, J ) 13.8 Hz), 3.73 (1H, d, J
) 8.4 Hz), 3.67 (1H, m), 3.54 (1H, d, J ) 13.8 Hz), 3.34 (1H, d,
J ) 8.4 Hz), 3.27 (3H, s), 3.25 (3H, s), 3.12 (3H, s), 2.66 (1H,
t, J ) 8.5 Hz), 2.52 (2H, m), 2.51 (1H, t, J ) 8.5 Hz), 2.38 (3H,
s), 1.80 (2H, m), 1.70 (1H, dt, J ) 13.8, 5.9 Hz); 1.51 (1H, ddd,
J ) 13.4, 8.5, 4.9 Hz); 13C NMR (75 MHz, CDCl3) δ 171.5,
144.5, 140.4, 136.4, 129.3, 128.7, 128.2, 128.0, 126.6, 103.9,
72.6, 71.2, 59.2, 56.0, 53.3, 53.1, 52.8, 45.6, 42.8, 34.0, 32.3,
23.1, 21.7; FABMS m/z (relative intensity) (M+ + 1) 517 (68),
515 (28), 485 (42), 417 (67), 361 (100); HRMS calcd for
C
27H37N2O6S (M+ + 1) 517.2372, found 517.2361.
P r ep a r a tion of Ald eh yd e 24. Palladium hydroxide on
carbon (410 mg) was added to a solution of benzylamine 23
(4.09 g, 7.91 mmol) in 40 mL of methanol and 40 mL of
CH2Cl2. The mixture was stirred overnight under 1 atm of
hydrogen at room temperature and was filtered through a pad
of Celite which was further washed with CH2Cl2. The filtrate
was concentrated to produce the secondary amine (3.37 g) as
a colorless amorphous solid suitable for use in the next step
without purification: IR (CH2Cl2) 3355, 2935, 1685, 1595,
1355, 1275, 1170 cm-1; 1H NMR (360 MHz, CDCl3) δ 8.10 (2H,
d, J ) 8.1 Hz), 7.37 (2H, d, J ) 8.1 Hz), 4.39 (2H, m), 3.77
The above alcohol 25 (912 mg) was dissolved in 20 mL of
CH2Cl2, and the mixture was cooled to 0 °C. Acetic anhydride
(0.22 mL, 2.35 mmol), NEt3 (0.35 mL, 2.54 mmol), and DMAP
(22 mg, 0.20 mmol) were added sequentially. The mixture was

Further Studies on Total Synthesis of Sarain A
J . Org. Chem., Vol. 64, No. 2, 1999 593
stirred for 3 h at room temperature, diluted with CH2Cl2 (20
mL), and washed with H2O (20 mL) and brine (30 mL). After
drying (MgSO4) and concentration of the solution, the acetate
26 (840 mg, 84%) was purified by flash chromatography eluting
with hexanes/ethyl acetate (2:1) to give a colorless amorphous
solid as a mixture of diastereomers: IR (CDCl3) 2955, 1735,
1695, 1450, 1375, 1235, 1170 cm-1; 1H NMR (360 MHz, CDCl3)
δ 8.02 (2H, d, J ) 8.1 Hz), 7.43 (2H, d, J ) 8.1 Hz), 6.13 (1H,
ddd, J ) 17.6, 10.4, 6.7 Hz), 5.66 (1H, d, J ) 17.6 Hz), 5.37
(1H, d, J ) 10.4 Hz), 5.36 (1H, m), 4.28 (1H, m), 3.91 (3H, m),
3.81 (1H, m), 3.68 (3H, s), 3.40 (3H, s), 3.33 (1H, m), 2.79 (2H,
m), 2.55 (3H, s), 2.18 (3H, s), 2.09 (1H, m), 1.84 (3H, m); 13C
NMR (90 MHz, CDCl3) δ 170.4, 170.3, 154.6, 145.1, 136.5,
136.1, 135.9, 129.8, 128.9, 118.2, 118.0, 73.8, 73.8, 59.8, 52.9,
45.3, 45.1, 44.3, 44.1, 35.9, 35.5, 34.0, 33.9, 25.0, 24.9, 22.0,
21.5; FABMS m/z (relative intensity) (M+ + 1) 509 (3), 507
(1), 495 (1).
ethyl acetate (1:1) gave the tricyclic product 28 (342 mg, 86%)
as a colorless amorphous solid which was a 3:2 mixture of
diastereomers at C-3: IR (CH2Cl2) 2935, 1695, 1450, 1265,
1
1160 cm-1; H NMR (360 MHz, CDCl3) δ 7.63 (2H, d, J ) 8.1
Hz), 7.27 (0.8H, d, J ) 8.1 Hz), 7.25 (1.2H, d, J ) 8.1 Hz),
5.54 (1H, m), 4.92 (0.6H, d, J ) 17.3 Hz), 4.85 (0.6H, d, J )
9.6 Hz), 4.79 (0.4H, d, J ) 9.0 Hz), 4.75 (0.4H, d, J ) 17.4
Hz), 4.31 (2H, m), 3.74 (1H, m), 3.71 (1.8H, s), 3.67 (1.2H, m),
3.32 (1.8H, s), 3.27 (3H, m), 3.22 (1.2H, s), 2.40 (3H, s), 2.33
(2H, br s), 1.95 (5H, m), 1.60 (1H, m); 13C NMR (90 MHz,
CDCl3) δ 155.6, 154.7, 143.4, 142.0, 138.9, 130.1, 129.7, 127.5,
115.4, 113.1, 70.2, 68.8, 63.7, 62.6, 59.6, 59.5, 57.9, 56.4, 55.7,
54.5, 54.3, 53.6, 52.4, 52.1, 40.3, 39.8, 39.0, 38.6, 38.4, 36.8,
36.4, 35.5, 32.5, 30.9, 22.5, 21.8; EIMS m/z (relative intensity)
(M+) 434 (12), 389 (70), 351 (4), 279 (70), 247 (30); HRMS calcd
for C22H30N2O5S (M+) 434.1875, found 434.1899.
P r ep a r a tion of Nitr ile 31. A solution of tricyclic olefin 28
(290 mg, 0.67 mmol) in 10 mL of CH2Cl2 was cooled to -78 °C
and was exposed to ozone gas with efficient stirring for 5 min.
While still at -78 °C, the solution was flushed with argon.
After 10 min, dimethyl sulfide (0.49 mL, 6.67 mmol) was
added, and the resulting solution was gradually warmed to
room temperature. After being stirred overnight, the solution
was diluted with 20 mL of H2O, extracted with CH2Cl2 (2 ×
40 mL), and washed with brine (30 mL). The organics were
dried (MgSO4) and concentrated to produce the colorless
amorphous aldehyde 29 as a 1:1 mixture of diastereomers: IR
P r ep a r a tion of Allylsila n e 27 fr om Aceta te 26. Hexa-
methyldisilane (2.74 mL, 12.65 mmol) dissolved in 5 mL of
HMPA was cooled to 0 °C and treated with a solution of 1.32
M MeLi in ether (8.52 mL, 11.25 mmol). After being stirred
for 15 min, the solution was diluted with 15 mL of THF, and
CuCN (509 mg, 5.62 mmol) was added in one portion. The
resulting solution was stirred for 40 min and cooled to -25
°C, and allylic acetate 26 (1.43 g, 2.81 mmol) was added as a
solution in 10 mL of THF. After 1 h, the reaction was quenched
with 20 mL of saturated NH4Cl solution. The resulting solution
was filtered through a pad of Celite which was washed with
ether (40 mL). After being washed with saturated NH4Cl
solution (40 mL), the organic extract was dried (MgSO4) and
concentrated. Flash chromatography of the residue eluting
with hexanes/ethyl acetate (2:1) provided colorless amorphous
allysilane 27 (0.94 g, 64%) as a 1:1 mixture of E and Z olefin
isomers: IR (CH2Cl2) 2955, 1720, 1700, 1560, 1450, 1370, 1170
1
(CH2Cl2) 2955, 2730, 1725, 1690, 1450, 1380, 1160 cm-1; H
NMR (360 MHz, CDCl3) δ 9.73 (0.5H, s), 9.60 (0.5H, s), 8.13
(2H, d, J ) 8.1 Hz), 7.91 (1H, d, J ) 8.1 Hz), 7.87 (1H, d, J )
8.1 Hz), 5.25 (0.5H, br s), 5.08 (0.5H, br s), 4.51 (0.5H, br s),
4.36 (0.5H, br d, J ) 10.5 Hz), 4.03 (2.5H, m), 3.93 (1.5H, s),
3.84 (1.5H, s), 3.68 (0.5H, m), 3.54 (1.5H, s), 3.48 (2.5H, m),
3.42 (1.5H, s), 3.05 (0.5H, m), 2.64 (3H, s), 2.59 (3H, m), 2.41
(0.5H, m), 2.14 (1H, dd, J ) 14.8, 4.8 Hz), 2.05 (1H, dd, J )
14.8, 4.8 Hz), 1.82 (0.5H, dd, J ) 14.7, 7.7 Hz); 13C NMR (90
MHz, CDCl3) δ 201.6, 199.4, 144.4, 130.5, 130.2, 127.5, 127.2,
68.2, 63.3, 59.6, 59.5, 54.5, 53.3, 52.6, 50.7, 48.5, 40.3, 36.1,
35.4, 26.6, 22.5, 22.3, 21.9; CIMS m/z (relative intensity) (M+
+ 1) 437 (70), 423 (12), 405 (25), 283 (36), 281 (40).
To a solution of the above aldehyde 29 in 6 mL of CH2Cl2
was added pyridine (0.21 mL, 2.67 mmol) and hydroxylamine
hydrochloride (93 mg, 1.33 mmol) at room temperature. After
being stirred for 16 h at the same temperature, the mixture
was diluted with 20 mL of H2O and extracted with CH2Cl2 (2
× 40 mL). After being washed with brine (30 mL), the organics
were dried (MgSO4) and concentrated to give the colorless
amorphous oxime 30 as a 1:3 mixture of syn /anti oxime
isomers and a mixture of C-3 isomers: IR (CH2Cl2) 3350, 2930,
1695, 1450, 1335, 1200, 1160 cm-1; 1H NMR (360 MHz, CDCl3)
δ 8.80 (0.25H, br s), 8.57 (0.75H, br s), 7.57 (2H, d, J ) 8.1
Hz), 7.22 (1H, d, J ) 8.1 Hz), 7.18 (0.75H, m), 6.32 (1H, m),
4.45 (2H, m), 3.67 (0.75H, s), 3.62 (2H, m), 3.55 (2.25H, s),
3.25 (2.25H, s), 3.21 (3H, m), 3.14 (0.75H, s), 3.00 (0.5H, m),
2.73 (0.5H, m), 2.32 (1.5H, s), 2.31 (1.5H, s), 2.78 (2H, br s),
2.13 (2H, m), 2.04 (1H, m), 1.80 (1.5H, m), 1.60 (0.5H, dd, J )
14.2, 7.3 Hz); CIMS m/z (relative intensity) (M+ + 1) 452 (100),
434 (30), 421 (20), 402 (14), 296 (25).
1
cm-1; H NMR (360 MHz, CDCl3) δ 7.90 (2H, d, J ) 8.1 Hz),
7.30 (2H, d, J ) 8.1 Hz), 5.45 (1H, m), 5.16 (1H, m), 4.13 (1H,
d, J ) 10.0 Hz), 3.82 (1H, d, J ) 10.0 Hz), 3.75 (1H, m), 3.64
(2H, m), 3.51 (3H, s), 3.28 (3H, s), 3.04 (1H, q, J ) 7.9 Hz),
2.67 (2H, m), 2.41 (3H, s), 2.08 (2H, m), 2.02 (1H, m), 1.63
(1H, m), 1.45 (1H, dd, J ) 7.9, 3.5 Hz), 1.40 (1H, d, J ) 7.9
Hz), 0.00 (4.5H, s), -0.03 (4.5H, s); 13C NMR (90 MHz, CDCl3)
δ 171.9, 156.1, 146.4, 138.0, 131.2, 130.4, 130.3, 129.5, 127.0,
125.4, 74.5, 72.2, 61.1, 55.4, 54.2, 46.8, 45.2, 41.2, 34.1, 28.3,
26.3, 26.2, 24.5, 23.4, 20.6, -0.2, -0.3; EIMS m/z (relative
intensity) (M+) 522 (4), 507 (5), 477 (11), 367 (7), 335(6); HRMS
calcd for C25H39N2O6SSi (M+ + 1) 523.2297, found 523.2298.
Cycliza tion of Allylsila n e 27 to Tr icycle 28. To a
solution of lactam 27 (476 mg, 0.91 mmol) in 10 mL of CH2Cl2
at -78 °C was added a 1.0 M solution of DIBALH in hexane
(2.73 mL, 2.73 mmol). After the mixture was stirred for 35
min, 2.5 mL of saturated NH4Cl solution was added. The
mixture was stirred for 1 h at room temperature and filtered
through a pad of Celite which was washed with CH2Cl2. The
filtrate was concentrated to give the colorless amorphous
aminal as a mixture of diastereomers: IR (film) 3405, 2955,
1685, 1450, 1250, 1165 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.81 (2H, d, J ) 8.1 Hz), 7.31 (2H, d, J ) 8.1 Hz), 5.69 (1H, br
d, J ) 3.5 Hz), 5.45 (1H, m), 5.22 (1H, m), 3.99 (1H, d, J )
10.0 Hz), 3.73 (1H, d, J ) 10.0 Hz), 3.70 (3H, s), 3.66 (3H, m),
3.32 (3H, s), 3.31 (1H, q, J ) 7.9 Hz), 3.02 (2H, m), 2.57 (2H,
m), 2.42 (3H, s), 2.22 (1H, m), 2.02 (2H, m), 1.66 (1H, m), 1.45
(1H, m), 0.07 (4.5H, s), 0.00 (4.5H, s); 13C NMR (75 MHz,
CDCl3) δ 157.4, 145.2, 137.4, 131.3, 131.1, 129.6, 129.4, 129.0,
128.8, 127.8, 126.3, 79.7, 75.8, 72.8, 61.1, 60.9, 54.3, 54.1, 53.9,
44.3, 42.9, 40.1, 39.2, 27.6, 24.5, 23.3, 20.4, 20.1, 0.0, -0.3;
FABMS m/z (relative intensity) (M+ - OH) 509 (30), 508 (38),
507 (80), 449 (100), 435(28).
To a solution of the above oxime 30 in 6 mL of CH3CN was
added a triphosgene (1.07 g, 3.97 mmol). The mixture was
stirred for 24 h at room temperature, and CH3CN was removed
in vacuo. To the residue was added 40 mL of CH2Cl2 and 20
mL of H2O. The mixture was extracted with CH2Cl2 (2 × 30
mL) and washed with brine (30 mL). The organics were dried
(MgSO4) and concentrated. Flash chromatography of the
residue eluting with hexanes/ethyl acetate (1:2) gave the
colorless amorphous nitrile 31 (277 mg, 96%) as a 1:1 mix-
ture of C-3 diastereomers: IR (CH2Cl2) 2930, 2445, 1700,
The above aminal was dissolved in 10 mL of CH2Cl2 and
cooled to -78 °C. Anhydrous ferric chloride (427 mg, 2.63
mmol) was added in one portion, and the resulting solution
was warmed to room temperature. After 10 min, the solution
was diluted with 10% NaOH solution (2.5 mL) and stirred for
1 h. The mixture was extracted with CH2Cl2 (2 × 30 mL),
washed with brine (30 mL), dried (MgSO4), and concentrated.
Flash chromatography of the residue eluting with hexanes/
1450, 1380, 1275, 1160 cm-1 1H NMR (360 MHz, CDCl3) δ
;
7.76 (1H, d, J ) 8.1 Hz), 7.68 (1H, d, J ) 8.1 Hz), 7.36 (1H, d,
J ) 8.1 Hz), 7.28 (1H, d, J ) 8.1 Hz), 4.75 (1H, m), 4.27 (1H,
m), 3.79 (2H, m), 3.72 (3H, s), 3.47 (2H, m), 3.31 (1.5H, s),
3.27 (1.5H, s), 3.12 (1H, m), 2.45-2.14 (5H, m), 2.40 (3H, 2 s),
2.06 (1H, m), 1.86 (1H, dd, J ) 15.0, 3.7 Hz); 13C NMR (90
MHz, CDCl3) δ 154.9, 144.8, 135.9, 130.7, 130.0, 127.9, 127.5,

594 J . Org. Chem., Vol. 64, No. 2, 1999
Irie et al.
121.0, 68.4, 62.5, 59.7, 59.6, 54.0, 53.6, 52.8, 52.4, 39.5, 36.0,
34.6, 31.1, 28.4, 25.8, 22.0, 21.8, 21.4, 14.6; CIMS m/z (rela-
tive intensity) (M+ + 1) 434 (100), 419 (15), 402 (82), 338 (50),
307 (100).
tetrabutylammonium iodide (14.7 mg, 0.04 mmol) were added
sequentially. The mixture was stirred overnight at room
temperature, diluted with saturated NH4Cl solution (20 mL),
and washed with ethyl acetate (2 × 30 mL). After drying
(MgSO4) and concentration of the solution, the benzyl ether
43 (203 mg, 65%) was isolated as a colorless amorphous solid
by flash chromatography eluting with hexanes/ethyl acetate
Alk yla tion of Nitr ile 31 to Nitr ile 42. To a solution of
nitrile 31 (301 mg, 0.69 mmol) in 5 mL of THF at -78 °C was
added a 0.5 M solution of KHMDS in hexane (3.47 mL, 1.74
mmol). After the mixture was stirred for 30 min at 0 °C, a
solution of mesylate 41 (285 mg, 1.74 mmol) in 2 mL of THF
at -78 °C was added. After 30 min of stirring at room
temperature, 18-Crown-6 (50.9 mg, 0.21 mmol) was added, and
the resulting mixture was warmed to 70 °C. The solution was
stirred overnight at the same temperature, and 20 mL of
saturated NH4Cl solution was added at 0 °C. After extraction
with ethyl acetate (2 × 30 mL), the organics were washed with
brine (20 mL), dried (MgSO4), and concentrated. Flash chro-
matography of the residue eluting with hexanes/ethyl acetate
(1:1) gave the nitrile 42 (245 mg, 70%) as a colorless oil and
eluting with ethyl acetate afforded the starting nitrile 31 (43
mg, 14%) as a colorless oil. 42: IR (CH2Cl2) 2930, 2360, 1700,
1
(1:2): IR (film) 2925, 1700, 1455, 1360, 1340, 1155 cm-1; H
NMR (360 MHz, CDCl3) δ 7.59 (2H, d, J ) 8.1 Hz), 7.26 (5H,
m), 7.19 (2H, d, J ) 8.1 Hz), 5.65 (1H, ddt, J ) 17.1, 10.2, 6.6
Hz), 5.65 (1H, br s), 4.91 (1H, dd, J ) 17.1, 1.5 Hz), 4.88 (1H,
d, J ) 10.2 Hz), 4.34 (2H, s), 4.32 (1H, br s), 3.78 (1H, d, J )
12.3 Hz), 3.74 (1H, d, J ) 12.3 Hz), 3.54 (3H, s), 3.47 (1H,
ddd, J ) 10.6, 5.0, 2.2 Hz), 3.34 (1H, d, J ) 10.6 Hz), 3.33
(3H, s), 3.18 (2H, m), 3.02 (3H, m), 2.32 (3H, s), 2.28 (2H, m),
2.14 (1H, m), 1.98 (1H, m), 1.95 (2H, q, J ) 7.1 Hz), 1.55 (3H,
m), 1.30 (1H, m); 13C NMR (90 MHz, CDCl3) δ 155.7, 143.5,
137.9, 137.8, 137.3, 130.0, 128.8, 128.1, 128.8, 127.5, 115.7,
77.9, 77.5, 73.2, 72.4, 71.0, 63.7, 59.5, 55.4, 52.2, 48.1, 47.5,
41.3, 32.4, 32.2, 31.2, 28.2, 24.8, 21.9; FABMS m/z (relative
intensity) (M+ + 1) 597 (7), 566 (4), 489 (25), 307 (22).
1
1370, 1160 cm-1; H NMR (360 MHz, CDCl3) δ 7.59 (2H, d, J
) 8.1 Hz), 7.24 (2H, d, J ) 8.1 Hz), 6.56 (1H, br s), 5.68 (1H,
ddt, J ) 17.1, 10.2, 6.6 Hz), 4.94 (1H, dd, J ) 17.1, 1.5 Hz),
4.92 (1H, d, J ) 10.2 Hz), 4.17 (1H, m), 3.59 (3H, s), 3.51 (2H,
m), 3.29 (3H, s), 3.29 (1H, m), 3.19 (1H, m), 3.04 (3H, m), 2.47
(2H, m), 2.39 (3H, s), 2.29 (1H, m), 2.21 (1H, m), 1.97 (2H, q,
J ) 7.1 Hz), 1.59 (3H, m), 1.18 (1H, m); 13C NMR (90 MHz,
CDCl3) δ 155.6, 143.8, 137.7, 137.1, 130.2, 127.5, 118.2, 115.9,
70.7, 68.9, 62.9, 59.7, 55.5, 52.7, 48.2, 47.2, 41.2, 33.1, 32.2,
31.2, 28.2, 24.3, 22.6, 21.9; CIMS m/z (relative intensity) (M+
+ 1) 502 (6), 470 (5), 348 (8), 316 (4), 251 (4).
P r ep a r a tion of Am id e 44. To a solution of naphthalene
(260 mg, 4.20 mmol) in 4 mL of THF was added sodium metal
(100 mg, 4.40 g atm) at room temperature. After 2 h of stirring,
part of the mixture (3 mL) was added to a solution of amide
43 (22.0 mg, 0.04 mmol) in 2 mL of THF at -78 °C. After 5
min, 5 mL of saturated NH4Cl solution was added. The
mixture was extracted with ethyl acetate (2 × 30 mL). The
organic extract was dried (K2CO3) and concentrated. Flash
chromatography of the residue eluting with ethyl acetate gave
the secondary amine (14.7 mg, 90%) as a brown oil: IR (film)
3330, 2930, 1700, 1455, 1360, 1130, 1065 cm-1; 1H NMR (360
MHz, CDCl3) δ 7.35 (5H, m), 5.86 (1H, ddt, J ) 17.1, 10.2, 6.6
Hz), 5.79 (1H, br s), 5.06 (1H, dd, J ) 17.1, 1.5 Hz), 5.01 (1H,
d, J ) 10.2 Hz), 4.50 (1H, m), 4.47 (2H, s), 3.93 (1H, d, J )
12.3 Hz), 3.88 (1H, d, J ) 12.3 Hz), 3.68 (3H, s), 3.63 (1H, m),
3.47 (1H, d, J ) 10.6 Hz), 3.44 (3H, s), 3.36 (1H, m), 2.71 (4H,
Con ver sion of Nitr ile 42 to Ben zyl Eth er 43. To a
solution of nitrile 42 (263 mg, 0.52 mmol) in 10 mL of CH2Cl2
at -78 °C was added a 1.0 M solution of DIBALH in hexane
(0.89 mL, 0.89 mmol). After the mixture was stirred for 35
min, 5 mL of a 5% HCl solution and 10 mL of ether were
added. The mixture was stirred for 2 h at room temperature,
extracted with ether (2 × 20 mL), and washed with brine (20
mL). The organics were dried (MgSO4) and concentrated to
give the aldehyde as a colorless oil: IR (film) 2930, 2815, 1680,
m), 2.41 (4H, m), 2.15 (3H, m), 2.13 (3H, m), 1.31 (1H, m); 13
C
NMR (90 MHz, CDCl3) δ 155.7, 138.7, 138.5, 128.8, 128.1,
128.0, 115.1, 77.8, 77.5, 73.2, 72.2, 70.8, 63.8, 59.6, 55.4, 52.2,
49.7, 49.0, 41.7, 32.9, 32.3, 31.9, 29.4, 26.0; CIMS m/z (relative
intensity) (M+ + 1) 443 (14), 442 (34), 351 (4), 335 (12).
The above amine (62.0 mg, 0.15 mmol) was dissolved in 3
mL of CH2Cl2, and the mixture was cooled to 0 °C. NEt3 (0.41
mL, 0.29 mmol), a solution of 6-heptenoyl chloride (110 mg,
0.73 mmol) in 3 mL of CH2Cl2, and DMAP (1.8 mg, 14.60 µmol)
were sequentially added at 0 °C. The resulting solution was
stirred overnight at room temperature, and 10 mL of saturated
NaHCO3 solution was added. The mixture was extracted with
CH2Cl2 (2 × 30 mL) and washed with saturated NaHCO3
solution (30 mL). The organic extract was dried (MgSO4) and
concentrated. Flash chromatography of the residue eluting
with hexanes/ethyl acetate (1:1) afforded the amide 44 (64.0
mg, 81%) as a yellow oil: IR (film) 2930, 1700, 1640, 1455,
1360, 1110, 1065 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.53 (5H,
m), 6.00 (3H, m), 5.28 (1H, dd, J ) 17.1, 1.5 Hz), 5.24 (2H, m),
5.17 (1H, d, J ) 10.2 Hz), 4.66 (1H, m), 4.64 (2H, s), 4.08 (2H,
s), 3.85 (3H, s), 3.82 (1H, m), 3.67 (1H, d, J ) 10.3 Hz), 3.62
(3H, s), 3.52 (3H, m), 3.44 (2H, t, J ) 7.7 Hz), 2.71 (1H, m),
2.50 (2H, m), 2.36 (1H, m), 2.28 (5H, m), 1.88 (6H, m), 1.65
(3H, m); 13C NMR (90 MHz, CDCl3) δ 173.0, 172.7, 155.7, 139.0,
138.9, 138.6, 138.3, 128.8, 128.1, 128.0, 116.1, 115.3, 114.9,
77.7, 77.5, 73.2, 72.3, 70.9, 63.8, 59.6, 55.4, 52.2, 47.4, 45.8,
44.6, 33.7, 33.4, 32.7, 32.3, 31.5, 31.2, 29.2, 29.1, 28.5, 27.3,
25.3, 23.7; CIMS m/z (relative intensity) (M+ + 1) 553 (1), 445
(2), 415 (1), 303 (1); HRMS calcd for C33H49N2O5 (M+ + 1)
553.3641, found 553.3643.
1445, 1360, 1340, 1155 cm-1 1H NMR (360 MHz, CDCl3) δ
;
9.35 (1H, s), 7.57 (2H, d, J ) 8.1 Hz), 7.22 (2H, d, J ) 8.1 Hz),
6.73 (1H, br s), 5.66 (1H, ddt, J ) 17.1, 10.2, 6.6 Hz), 4.92
(1H, dd, J ) 17.1, 1.5 Hz), 4.90 (1H, d, J ) 10.2 Hz), 4.32 (1H,
br s), 3.56 (3H, s), 3.53 (2H, m), 3.32 (3H, s), 3.25 (2H, m),
2.99 (4H, m), 2.37 (1H, m), 2.34 (3H, s), 2.30 (2H, m), 1.94
(2H, q, J ) 6.3 Hz), 1.56 (3H, m), 1.17 (1H, m); 13C NMR (90
MHz, CDCl3) δ 199.3, 155.7, 143.7, 137.7, 137.0, 130.2, 127.4,
115.8, 70.9, 63.5, 59.6, 55.8, 52.5, 48.1, 47.3, 42.1, 31.9, 28.2,
27.6, 24.5, 21.8, 21.4, 14.6; CIMS m/z (relative intensity) (M+
+ 1) 505 (100), 490 (22), 474 (64), 349 (50), 252 (70).
To a solution of the above the aldehyde in 6 mL of methanol
was added sodium borohydride (19.5 mg, 0.52 mmol) at 0 °C.
After being stirred for 10 min at the same temperature, the
mixture was diluted with 10 mL of H2O and 1 mL of acetone.
Methanol and excess acetone were removed in vacuo, and to
the residue were added 30 mL of CH2Cl2 and 20 mL of H2O.
The mixture was extracted with CH2Cl2 (2 × 20 mL). After
being washed with brine (30 mL), the organics were dried
(MgSO4) and concentrated to give the alcohol as a colorless
oil: IR (film) 3450, 2930, 1695, 1450, 1365, 1335, 1155 cm-1
;
1HNMR (360 MHz, CDCl3) δ 7.59 (2H, d, J ) 8.1 Hz), 7.22
(2H, d, J ) 8.1 Hz), 5.66 (1H, ddt, J ) 17.1, 10.2, 6.6 Hz), 5.61
(1H, br s), 4.93 (1H, dd, J ) 17.1, 1.5 Hz), 4.90 (1H, d, J )
10.2 Hz), 4.34 (1H, br d, J ) 7.7 Hz), 3.88 (2H, s), 3.54 (3H, s),
3.47 (1H, m), 3.28 (1H, d, J ) 10.4 Hz), 3.29 (3H, s), 3.14 (1H,
m), 3.03 (2H, m), 2.34 (3H, s), 2.32 (2H, m), 2.14 (2H, m), 1.97
(3H, m), 1.56 (3H, m), 1.18 (1H, m); 13C NMR (90 MHz, CDCl3)
δ 155.7, 143.6, 137.8, 137.2, 130.1, 127.5, 115.7, 77.7, 71.0, 63.6,
59.5, 55.4, 52.2, 48.2, 47.5, 41.3, 32.3, 31.7, 31.2, 28.2, 24.9,
21.8, 14.6; FABMS m/z (relative intensity) (M+ + 1) 507 (2),
489 (3), 391 (2), 341 (2).
Rin g-Closin g Olefin Meth a th esis of Dien e 44 to Ma c-
r ocyclic La cta m 46. A solution of diene 44 (16.4 mg, 29.70
µmol) in CH2Cl2 was added Cl2(PCy3)2RudCHPh (45, 5.2 mg,
5.94 µmol) in a drybox. The reaction mixture was refluxed for
2 d under an argon atomsphere. The CH2Cl2 was evaporated
under reduced pressure, and flash chromatography of the
residue eluting with hexanes/ethyl acetate (1:2) produced the
starting diene 44 (1.1 mg, 7%) as a yellow oil. Elution with
The above alcohol was dissolved in 5 mL of THF and cooled
to 0 °C. Benzyl bromide (0.09 mL, 0.79 mmol), 60% sodium
hydride dispersion in mineral oil (39.7 mg, 0.99 mmol), and

Further Studies on Total Synthesis of Sarain A
J . Org. Chem., Vol. 64, No. 2, 1999 595
hexanes/ethyl acetate (1:4) gave macrocyclic lactam 46 (7.7 mg,
49%, colorless oil) as a mixture of cis and trans isomers, and
elution with ethyl acetate afforded the macrocyclic dimer (6.1
mg, 39%) as a colorless oil.
µmol) in 3 mL of methanol. The mixture was stirred overnight
under 1 atm of hydrogen at 55 °C and was filtered through a
pad of Celite which was washed with methanol. The filtrate
was concentrated, and flash chromatography of the residue
eluting with ethyl acetate/methanol (10:1) afforded the mac-
rocyclic lactam 47 (8.1 mg, 86%) as a yellow oil: IR (film) 3415,
2925, 1695, 1620, 1445, 1375, 1195, 1110 cm-1; 1H NMR (360
MHz, CDCl3) δ 4.17 (1H, m), 3.63 (2H, s), 3.59 (3H, s), 3.41
(4H, m), 3.28 (2H, s), 3.28 (3H, s), 3.22 (2H, m), 2.45 (1H, m),
2.31 (1H, m), 1.98 (2H, m), 1.61 (11H, m), 1.31 (8H, m); FABMS
m/z (relative intensity) (M+ + 1) 437 (24), 419 (50), 387 (19),
330 (20), 182 (100); HRMS calcd for C24H41N2O5 (M+ + 1)
437.3015, found 437.2998.
46: IR (film) 2925, 1700, 1635, 1445, 1360, 1200, 1110, 1065
cm-1; 1H NMR (360 MHz, CDCl3) δ 7.27 (5H, m), 5.66 (1H, br
s), 5.30 (2H, m), 4.38 (1H, m), 4.34 (2H, s), 3.79 (2H, s), 3.56
(3H, s), 3.36 (2H, d, J ) 10.6 Hz), 3.31 (3H, s), 3.26 (3H, m),
2.41 (3H, m), 2.06 (6H, m), 1.54 (6H, m), 1.18 (5H, m); 13C NMR
(90 MHz, CDCl3) δ 174.7, 173.6, 172.9, 155.5, 138.6, 138.4,
137.3, 136.9, 133.5, 128.8, 128.1, 77.6, 77.4, 73.3, 72.3, 70.9,
63.8, 59.6, 55.4, 52.2, 45.3, 41.5, 34.1, 32.7, 32.3, 31.8, 30.6,
30.1, 27.3, 26.2, 25.7, 25.0, 23.7, 22.9; FABMS m/z (relative
intensity) (M+ + 1) 525 (4), 417 (5), 375 (3), 315 (4); HRMS
calcd for C31H45N2O5 (M+ + 1) 525.3328, found 525.3300.
Dim er : IR (film) 2925, 1700, 1640, 1445, 1360, 1200, 1110,
Ack n ow led gm en t. We are grateful to the National
Institutes of Health for support of this research on grant
GM-32299.
1
1065 cm-1; H NMR (360 MHz, CDCl3) δ 7.27 (10H, m), 5.65
(2H, br s), 5.32 (4H, m), 4.38 (2H, m), 4.34 (4H, s), 3.78 (4H,
s), 3.55 (6H, s), 3.52 (2H, m), 3.34 (4H, d, J ) 10.6 Hz), 3.32
(6H, s), 3.37 (6H, m), 2.66 (4H, m), 2.42 (6H, m), 2.22 (12H,
m), 1.94 (2H, m), 1.60 (12H, m), 1.51 (4H, m); FABMS m/z
(relative intensity) (M+ + 1) 1050 (5), 1017 (2), 942 (10), 449
(10), 297 (100).
Su p p or tin g In for m a tion Ava ila ble: Copies of proton and
carbon NMR spectra of new compounds (49 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Hyd r ogen a tion of La cta m Ben zyl Eth er 46 to La cta m
Alcoh ol 47. Ten percent palladium on activated carbon (4.0
mg) was added to a solution of lactam olefin 46 (11.3 mg, 21.5
J O981821D