Enantioselective synthesis of antiinfluenza compound A-315675

Article abstract of DOI:10.1021/jo0162890

Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuraminidase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent, stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone 2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The stereochemical outcome of this reaction depended critically on the choice of the imine functional group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a cyano group as a carboxylic acid equivalent at C2.

Full text of DOI:10.1021/jo0162890

VOLUME 67, NUMBER 16
AUGUST 9, 2002
© Copyright 2002 by the American Chemical Society
En a n tioselective Syn th esis of An tiin flu en za Com p ou n d A-315675
David A. DeGoey,* Hui-J u Chen, William J . Flosi, David J . Grampovnik, Clinton M. Yeung,
Larry L. Klein, and Dale J . Kempf
Infectious Disease Research Division, Abbott Laboratories, 200 Abbott Park Road,
Abbott Park, Illinois 60064
david.degoey@abbott.com
Received November 16, 2001
Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuramini-
dase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent,
stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone
2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective
condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The
stereochemical outcome of this reaction depended critically on the choice of the imine functional
group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields
as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven
subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a
cyano group as a carboxylic acid equivalent at C2.
In tr od u ction
The viral surface glycoproteins haemagglutinin and
neuraminidase mediate attachment and release of the
influenza virus at the surface of infected cells. The use
of inhibitors of viral neuraminidase has been shown to
be an effective therapy for the treatment and prevention
of influenza A and B infections,1 and three potent
inhibitors, namely, zanamavir (Relenza), oseltamivir
(Tamiflu), and RWJ -270201 (BCX-1812), have already
been developed (RWJ -270201 is in clinical trials). Re-
cently, Abbott scientists have discovered a novel inhibitor
series based on a pyrrolidine core structure, and struc-
ture-activity relationship (SAR) studies have led to the
identification of A-315675 (1, Figure 1) as a highly potent,
broad spectrum agent that is orally bioavailable when
administered as a prodrug ester of the carboxylic acid.2,3
The unique structural features found in 1, such as its
F IGURE 1. Structure of A-315675.
five stereogenic centers, the cis-propenyl group, and the
tertiary ether side chain, are not only crucial for its
biological activity but also add significant complexity to
its synthesis. In the initial discovery, A-315675 was
prepared through a racemic synthesis with low overall
diastereoselectivity and was resolved by chiral chroma-
tography at the end. To provide adequate material for
preclinical studies, however, an efficient enantioselective
synthesis of this highly functionalized pyrrolidine was
needed. In this paper, a convergent, stereoselective
synthesis of A-315675 is reported that utilized the
condensation of chiral imine 3 (Scheme 1) with silyloxy-
pyrrole 4 to provide pyrrolinone 2 as the key intermedi-
ate.4
(1) Gubareva, L. V.; Kaiser, L.; Hayden, F. G. Lancet 2000, 355,
827-835.
(2) Maring, C.; McDaniel, K.; Krueger, A.; Zhao, C.; Sun, M.;
Madigan, D.; DeGoey, D.; Chen, H.-J .; Yeung, M. C.; Flosi, W.;
Grampovnik, D.; Kati, W.; Klein, L.; Stewart, K.; Stoll, V.; Saldivar,
A.; Montgomery, D.; Carrick, R.; Steffy, K.; Kempf, D.; Molla, A.;
Kohlbrenner, W.; Kennedy, A.; Herrin, T.; Xu, Y.; Laver, W. G.
Presented at 14th International Conference on Antiviral Research,
Antiviral Res. 2001, 50, A76; Abstract 129.
(3) Raja, S. N.; George, K. ST.; Fan, L.; Nequist, G.; Reisch, T.;
Maring, C.; McDaniel, K.; DeGoey, D.; Darbyshire, K. Abstracts of
Papers, 41st Interscience Conference on Antimicrobial Agents and
Chemotherapy, Chicago, IL; American Society for Microbiology: Wash-
ington, DC, 2001; Abstract F-1683.
(4) This work has been presented in preliminary form. DeGoey, D.
A.; Chen, H.-J .; Flosi, W. J .; Grampovnik, D. J .; Yeung, C. M.; Klein,
L. L.; Kempf, D. J . Presented at the 221st National Meeting of the
American Chemical Society, San Diego, CA, April 2001; paper ORGN
320.
10.1021/jo0162890 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/29/2002
J . Org. Chem. 2002, 67, 5445-5453
5445

DeGoey et al.
SCHEME 1
SCHEME 2a
Resu lts a n d Discu ssion
Retrosynthetic analysis of A-315675 led to the syn-
thetic strategy shown in Scheme 1, which proposes
pyrrolinone 2 as an intermediate. It has been shown in
the literature that the 3-pyrrolin-2-one moiety can serve
as a Michael acceptor for organocuprate reagents at the
C4 position5 and that the resulting lactam can be used
to introduce a nitrile group as a carboxylic acid equivalent
at C2.6 In addition, several synthetic methods have
been developed for the synthesis of pyrrolinones,7 and
Casiraghi and co-workers have conducted extensive
research on their preparation from condensation reac-
tions of silyloxypyrrole 4.8 An advantage of the strategy
chosen in Scheme 1 was that the reaction between imine
3 and silyloxypyrrole 4 introduced the complex tertiary
ether side chain of 1 as a preassembled fragment. While
reactions of imines with 2-silyloxyfuran8 and silyl eno-
lates9 have been reported, reactions of aliphatic aldimines
with silyloxypyrroles have received little attention10 and
required investigation. Although the stereochemical out-
come of the reaction with sterically hindered imine 3 was
difficult to predict, the tertiary ether stereocenter could
be envisioned to direct the facial selectivity of nucleophilic
attack on the imine, and the choice of Lewis acid and
solvent could influence the C5, C6 erythro/threo selectiv-
ity. Selection of the optimal functional group (FG) on the
imine would influence its reactivity and allow for depro-
tection in the presence of other functionality in the
molecule.
a
Reagents and yields: (a) LAH (80%); (b) (i) AE; (ii) BzCl, Et3N
(65%); (c) LAH (63%); (d) BnBr, NaH (98%); (e) NaHMDS, MeI
(98%); (f) (i) Pd on C, H2; (ii) PCC (60%).
LAH, and the resulting allylic alcohol 6 was subjected to
Sharpless asymmetric epoxidation.12 For convenience, the
volatile epoxide was isolated as the benzoate ester 7,
which underwent reductive ring opening and removal of
the benzoate upon treatment with LAH to give the diol
8.13 The primary hydroxyl group of 8 was protected as a
benzyl ether, and the tertiary alcohol was methylated to
give 9. Catalytic hydrogenolysis and PCC oxidation gave
the aldehyde 10.
Aldehyde 10 was converted into imines 3a -3f under
standard conditions and reacted with silyloxypyrrole 414
(Scheme 3). Some conventional imine derivatives were
prepared, and their reactions with 4 were examined to
evaluate the viability of the condensation step. For
example, conversion of aldehyde 10 into a benzylic imine,
such as p-methoxybenzyl, benzhydryl, or trityl imine, and
subsequent condensation with 4 using various Lewis
acids, solvents, and temperatures led to no reaction and
mainly to decomposition of the imines. Conversion of
aldehyde 10 into p-methoxyphenyl (PMP) imine 3a and
subsequent condensation with 4 (Table 1, entries 1 and
2) using SnCl4, TiCl4, or ZnCl2 as Lewis acids led to no
reaction in CH2Cl2 and to only a trace of product using
BF3‚Et2O. Lanthanide triflates have been shown to
efficiently activate imines,9,10 and reaction of 3a with 4
using catalytic Yb(OTf)3 yielded two C5, C6 erythro
products, 11a and 11b (Scheme 3), in nearly equal
amounts (Table 1, entry 3) as the only products. Varying
the solvent and temperature for this condensation proved
to have only minor effects on the product ratio, although
The aldehyde 10 (Scheme 2), the precursor to imines
3, was prepared in seven steps starting from the com-
mercially available ester 5.11 The ester was reduced with
(5) For examples of organocuprate additions to pyrrolinones, see:
(a) Hanessian, S.; Ratovelomanana, V. Synlett 1990, 501-503. (b)
Meyers, A. I.; Snyder, L. J . Org. Chem. 1992, 57, 3814-3819. (c)
Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3, 1213-
1221. (d) Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron:
Asymmetry 1994, 5, 351-345. (e) Baussanne, I.; Royer, J . Tetrahedron
Lett. 1998, 39, 845-848.
(12) Asymmetric expoxidation of 6 has been reported: Rossiter, B.
E.; Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1981, 103, 464-
465.
(6) Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927-
964, and references cited therein.
(7) Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1998, 9, 1759-1769, and references cited
therein.
(8) Review: Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G.
Chem. Soc. Rev. 2000, 29, 109-118.
(9) For examples, see: Kobayashi, S.; Araki, M.; Ishitani, H.;
Nagayama, S.; Hachiya, I. Synlett 1995, 233-234, and references cited
therein.
(13) The ee was found to be 96%, as determined by conversion of 8
to the Mosher ester (mono-MTPA) under standard conditions and 19F
NMR analysis (19F NMR (CDCl3) δ -71.92 for 2-(S)-8 and -71.96 for
2-(R)-8). Preparation of diol 8 by asymmetric dihydroxylation of
2-methyl-1-pentene was examined and shown to provide material with
low ee (ca. 60%) using a modified Sharpless condition, which was
reported to show improvement in ee for some terminal olefins. See:
Torii, S.; Liu, P.; Bhuvaneswari, N.; Amatore, C.; J utand, A. J . Org.
Chem. 1996, 61, 3055-3060.
(10) Reactions of a silyloxypyrrole with aromatic aldimines have
recently been reported: Dudot, B.; Royer, J .; Sevrin, M.; George, P.
Tetrahedron Lett. 2000, 41, 4367-4371.
(14) For preparation of 4, see: Casiraghi, G.; Rassu, G.; Spanu, P.;
Pinna, L. J . Org. Chem. 1992, 57, 3760-3763, and references cited
therein.
(11) Available from Aldrich.
5446 J . Org. Chem., Vol. 67, No. 16, 2002

Enantioselective Synthesis of A-315675
SCHEME 3
(OTf)2, and Mg(OTf)2, also led to a mixture of 11a and
11b, but the choice of metal had little influence on the
product ratio. The use of TMSOTf as Lewis acid gave
modest selectivity, but the conversion of imine to product
was only 25% by NMR (Table 1, entry 5). Various means
of deprotecting the PMP-amine product 11a were at-
tempted and were problematic, leading to only traces of
product.
A higher degree of stereocontrol was realized by
conversion of aldehyde 10 into tritylsulfenimine (TrS) 3b
(Table 1, entries 6 and 7).15 Condensation of 3b with
silyloxypyrrole 4 in the presence of BF3‚Et2O in ether or
CH2Cl2 led to a mixture of C5, C6 erythro isomers 12a
and 12b (Scheme 3), favoring the desired isomer 12a . The
ratio of products (12a :12b) was found to be somewhat
variable, and selectivities ranged from 3:1 to 7:1. The
desired isomer 12a was crystalline, and the structural
assignment was determined by single-crystal X-ray analy-
sis, while the minor isomer 12b was obtained as an oil.
Optimized conditions for larger scale reactions required
larger amounts of BF3‚Et2O (2.5 equiv) and silyloxypyr-
role 4 (2 equiv) in order to obtain a complete reaction,
and yields ranged from 60% to 90%. A similar product
ratio for this condensation was observed using catalytic
Yb(OTf)3 (12a :12b, 3.6:1) in various solvents, and this
choice of Lewis acid made it possible to obtain a reason-
able yield of products by combining aldehyde 10, trityl-
sulfenamide, and silyloxypyrrole 4 in one pot in the
presence of MgSO4.
To address the generality of the product ratio observed
using sulfenimines, phenylsulfenimine (PhS) 3c (Table
1, entry 8) was prepared.16 Condensation of 3c with
silyloxypyrrole 4 using BF3‚Et2O resulted in 13a and 13b
(Scheme 3, after hydrolysis of the labile phenylsulfenyl
group and acetylation of the amine), which were obtained
in a ratio of 1:1.9, favoring the undesired isomer and in
contrast with the ratio observed using tritylsulfenimine
3b.
Stereoselective transformations using chiral auxiliary-
containing imines have recently attracted the attention
of organic chemists, and sulfinimines are especially
attractive due to the high degree of stereoselectivity
observed in their addition reactions and the mild condi-
tions required for removing the sulfinyl groups.17 As
entries 9 and 10 (Table 1) indicate, a level of complete
stereocontrol was observed in the condensation of the
diastereomeric toluenesulfinimines 3d and 3e with silyl-
oxypyrrole 4. Condensation of (R)-p-toluenesulfinimine
3d with 4 in the presence of TMSOTf resulted in the
production of the crystalline C5, C6 erythro isomer 14,
exclusively (Scheme 3). The structural assignment of
14 was determined by single-crystal X-ray analysis.
Employing the diastereomeric (S)-p-toluenesulfinimine
TABLE 1. Con d en sa tion of Im in es 3a -f w ith
Silyloxyp yr r ole 4a
Lewis
acid
solvent,
temp (°C)
products,
entry imine
(ratio), yieldb
1
2
3
3a
3a
3a
3a
3a
3b
SnCl4
CH2Cl2, -30
no reaction
trace product
BF3‚Et2O CH2Cl2, -30
Yb(OTf)3 CH2Cl2, rt
Yb(OTf)3 CH3CN, -25
TMSOTf Et2O, -30
BF3‚Et2O Et2O,
11a :11b, (1:1.1), 66%
11a :11b, (1:1.7)
11a :11b, (1:2.3)
12a :12b, (3:1 to 7:1),
60% to 90%
12a :12b, (3.6:1), 61%
13a :13b, (1:1.9), 41%
14, 59% to 82%
15, 61%
4
5c
6d
-78 to -50
7
3b
3c
3d
3e
3f
Yb(OTf)3 CH2Cl2, 0
BF3‚Et2O Et2O, -78
TMSOTf CH2Cl2, -23
TMSOTf CH2Cl2, -30
TMSOTf CH2Cl2, -30
8d,e
9 f
10 f
11f
16, 36%
a
(15) Branchaud reported the preparation and synthetic use of TrS
imines previously. Branchaud, B. P. J . Org. Chem. 1983, 48, 3531-
3538.
(16) For the preparation of phenylsulfenimines, see: Davis, F. A.;
Slegeir, W. A. R.; Evans, S.; Schwartz, A.; Goff, D. L.; Palmer, R. J .
Org. Chem. 1973, 38, 2809-2813.
(17) For a review on p-toluenesulfinimines, see: Davis, F. A.; Zhou,
P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13-18. For preparation of
p-toluenesulfinimines, see: Davis, F. A.; Zhang, Y.; Andemichael, Y.;
Fang, T.; Fanelli, D. L.; Zhang H. J . Org. Chem. 1999, 64, 1403-1406.
For preparation and uses of tert-butylsulfinimines, see: Liu, G.; Cogan,
D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A. J . Org. Chem. 1999, 64,
1278-1284, and references cited therein.
All reactions were carried out with 1.0 equiv of 4 and Lewis
acid or catalytic lanthanide triflates (0.1 equiv) unless otherwise
indicated. Ratio determined by 1H NMR; isolated yield based on
b
imine, where available. c Used 1.5 equiv of TMSOTf. Used 2.0
d
equiv of 4 and 2.5 equiv of BF3‚Et2O. e Treatment of unstable PhS
products with 80% AcOH/H2O and acetylation with Ac2O provided
13a and 13b. f Used 1.5 equiv of TMSOTf and 4.
a slight excess of the undesired product 11b could be
obtained (Table 1, entry 4). Using other catalytic metal
triflates, including La(OTf)3, Sc(OTf)3, Cu(OTf)2, Zn-
J . Org. Chem, Vol. 67, No. 16, 2002 5447

DeGoey et al.
SCHEME 4
SCHEME 5a
3e led to a reversal of the facial selectivity on the imine,
giving 15 (Scheme 3), exclusively, and demonstrating the
strong influence of the chirality of the sulfinyl group on
the stereochemical outcome of these reactions. Other
Lewis acids, such as Yb(OTf)3, BF3‚Et2O, TiCl4, and
TMSCl, were also examined and found to be less effective,
in that they led to sluggish coupling reactions. The
condensation with tert-butyl sulfinimine 3f (Table 1,
entry 11) also yielded the desired product 16 selectively
(Scheme 3), but the reaction was incomplete even under
prolonged reaction time, possibly due to the steric
hindrance associated with this sulfinyl group.
It is interesting to note that while the ratio of products
in reactions between 3a -3f and silyloxypyrrole 4 could
be controlled by the functional group on the imine, only
C5, C6 erythro stereoisomers were observed in each case.
1
The C5, C6 threo products could not be detected by H
a
Reagents and yields: (a) cis-1-propenylmagnesium bromide,
NMR, regardless of the choice of functional group,
solvent, or Lewis acid. In contrast, erythro/threo selectiv-
ity in the direct condensation of aldehyde 10 with 4
depended upon the choice of Lewis acid and solvent, as
Casiraghi demonstrated previously for the condensation
of 4 with other aldehydes.18 Reaction of aldehyde 10 with
4 using BF3‚Et2O in ether favored the C5, C6 erythro
isomer (erythro/ threo, 19:1), while using SnCl4 in ether
gave the C5, C6 threo isomer, exclusively. The facial
selectivity of nucleophilic attack on the aldehyde resulted
only in compounds with the R configuration at the
resulting stereocenter bearing the hydroxyl group.19
The structural determination of each product from the
condensations of imines 3a -3f with 4 was accomplished
through a combination of X-ray crystallography and the
synthesis of correlation compounds (Scheme 4). Since
many of the products were not crystalline, two correlation
compounds, 17 and 18, were prepared through the follow-
ing sequence: (1) reduction of the pyrrolinone double
bond (H2/Pd on C, or NaBH4/NiCl2) in order to avoid
possible epimerization at acidic C5, (2) removal of the
functional group under the appropriate conditions (ozo-
nolysis for PMP, PPTS/MeOH for TrS, and TFA/MeOH
or HCl/MeOH for sulfinyl groups), and (3) acetylation
(Ac2O, Et3N) of the amine. Compounds 12a and 14, the
structures of which were determined by single-crystal
X-ray analyses, were used to prepare and establish the
stereochemistry of compound 17. Correlation compound
18 was crystalline, and its stereochemistry was proven
Cu(I)Br‚DMS, TMSCl (89% from 12a ; 74% from 14); (b) (i)
DIBALH (87%); (ii) PPTS, MeOH; (iii) TMSCN, BF3‚Et2O (77%);
(c) (i) DIBALH; (ii) TMSCN, TMSOTf (97%); (d) (i) PPTS, MeOH,
reflux; (ii) Ac2O, Et3N (69%); (e) (i) TFA, MeOH; (ii) Ac2O, Et3N
(76%); (f) 6 N HCl, 60 °C (99%).
through single-crystal X-ray analysis. All condensation
products that were not crystalline were subjected to the
sequence above and correlated with either 17 or 18 by
1H NMR.
Compounds 12a and 14 were converted to the final
product 1 (Scheme 5). Introduction of the cis-propenyl
group at C4 required a stereoselective trans-addition
(relative to the C5 ring substituent) of a cis-propenyl
cuprate reagent, and excellent trans-selectivity with no
ring-opening has already been reported for the addition
of organocuprate reagents to pyrrolinones in the presence
of TMSCl.5 Although cis-vinylic cuprates with high
isomeric purity have been prepared from cis-propenyl-
lithium20 or through carbocupration of acetylenes,21
ease of preparation prompted us to explore addition of
propenyl cuprates prepared from Grignard reagents.
cis-1-Propenylmagnesium bromide, prepared under the
standard conditions from magnesium and cis-1-bromo-
propene (reportedly leading to isomerization (10%) of
olefin geometry22), was reacted with Cu(I)Br‚DMS to form
the required cuprate reagent. Reaction of this cuprate
(5 equiv) with 12a in the presence of TMSCl gave 89%
(20) Whitesides, G. M.; Casey, C. P.; Krieger, J . K. J . Am. Chem.
Soc. 1971, 93, 1379-1389. Linstrumelle, G.; Krieger, J . K.; Whitesides,
G. M. Org. Synth. 1976, 55, 103-113.
(21) Lipshutz, B. H. In Organometallics in Synthesis; Schlosser, M.,
Ed.; J ohn Wiley and Sons: New York, 1994; p 293.
(22) Isomerization of the propenyl olefin geometry has been reported
to occur under these conditions. Mechin, B.; Naulet, N. J . Organomet.
Chem. 1972, 39, 229-236.
(18) Zanardi, F.; Battistini, L.; Nespi, M.; Rassu, G.; Spanu, P.;
Cornia, M.; Casiraghi, G. Tetrahedron: Asymmetry 1996, 7, 1167-
1180.
(19) Experimental details of reaction of 10 with 4 are available in
the Supporting Information.
5448 J . Org. Chem., Vol. 67, No. 16, 2002

Enantioselective Synthesis of A-315675
yield of lactam 19a (Scheme 5) that was contaminated
with traces (from 2% to undetectable) of the trans-
propenyl isomer.23 We speculated that cis-1-propenyl-
cuprate may react with 12a more rapidly than the
corresponding trans-propenyl isomer, since the cis/trans
ratio of products did not appear to reflect the ratio
presumed for the reagent. In support of this hypothesis,
12a was reacted with cuprate reagent (5 equiv) prepared
from trans-1-propenylmagnesium bromide (prepared from
magnesium turnings with trans-1-bromopropene under
the standard conditions, and reported to result in 20%
isomerization of olefin geometry22), resulting in a mixture
of 19a and the trans-propenyl isomer in a ratio of 1.5:1,
respectively. Compound 19a was also the major product,
along with 11.5% of the trans-propenyl isomer, observed
using commercially available 1-propenylmagnesium
bromide (contains a mixture of olefin isomers)11 to
prepare the cuprate.
Partial reduction of 19a to the hemiaminal with
DIBALH (Scheme 5) was followed by conversion to the
R-methoxycarbamate through treatment with PPTS in
methanol. Reaction of this compound with TMSCN in the
presence of BF3‚Et2O gave compound 20a in 77% yield,
along with 4% of the epimeric cyano compound24 that was
removed by chromatography. A high degree of trans
selectivity (relative to the C5 substituent) for nucleophilic
addition to N-acyliminium ions generated from pyrro-
lidines has been reported previously.6 The tritylsulfenyl
protecting group in 20a proved to be susceptible to acidic
hydrolysis and was removed by refluxing in methanol
with PPTS.25 Acetylation of the amine gave crystalline
intermediate 21 (69% yield, X-ray crystallographic analy-
sis was obtained), and treatment with 6 N HCl at 60 °C
gave 1 in high yield.
Compound 14 also underwent smooth Michael addition
of the cis-1-propenylcuprate to give 19b along with a
minor side product identified as the toluenesulfenamide
from deoxygenation of the toluenesulfinamide.26 In this
case, introduction of the cyano group proceeded with
slight modifications to give exclusively the desired nitrile
20b. The intermediate hemiaminal was transformed
directly to the cyano compound by treatment with
TMSCN, and the choice of TMSOTf as Lewis acid
resulted in a much faster reaction rate than with
BF3‚Et2O. Deprotection of the toluenesulfinamide 20b
proceeded under standard conditions (TFA, methanol).17
The final product 1 was obtained by sequential acetyl-
ation of the amine and hydrolysis with 6 N HCl.
skeleton of the compound and also two important stereo-
centers in one step. Selection of tritylsulfenyl or (R)-
toluenesulfinyl as functional groups on imine 3 led to a
synthetically useful degree of stereocontrol in the con-
densation reactions. The resultant pyrrolinone products
12a and 14 were crystalline intermediates and served
as chiral templates that directed the subsequent stereo-
selective Michael addition of cis-1-propenylcuprate and
the introduction of the cyano group.
Exp er im en ta l Section
Gen er a l Meth od s. Tetrahydrofuran (THF) and ether were
freshly distilled from sodium benzphenone ketyl. All other
solvents and reagents were obtained from commercial suppli-
ers and were used without further purification. Where ap-
propriate, reactions were carried out in flame or oven-dried
1
glassware under an inert atmosphere. H NMR spectra were
obtained at either 300 or 500 MHz and chemical shifts are
reported in parts per million (ppm, δ), using as a reference
the appropriate signal for residual solvent protons. 13C NMR
spectra were obtained at 75 MHz without proton decoupling,
and chemical shifts are reported in parts per million, using
the center signal of the solvent signal as a reference. Elemental
analyses were performed by Robertson Microlit Laboratories,
Inc., Madison NJ . Column chromatography was carried out
using 230-400 mesh silica gel.
(2E)-2-Meth ylp en t-2-en -1-ol (6). To a slurry of lithium
aluminum hydride (4.72 g, 124.2 mmol) in ether (180 mL) at
0 °C was added a solution of methyl (2E)-2-methylpent-2-
enoate (6.37 g, 49.6 mmol) in ether (120 mL). After stirring at
0 °C for 30 min, the reaction mixture was stirred at room
temperature for 1.5 h. The reaction was cooled to 0 °C and
quenched very carefully with water (4.7 mL), 15% NaOH (4.7
mL), and water (14.1 mL). The mixture was filtered, dried
(MgSO4), filtered again, and concentrated. The crude product
was distilled (55 Torr, 85-87 °C) to give 6 (3.96 g, 80%): 1H
NMR (CDCl3) δ 5.44-5.38 (m, 1H), 4.00 (d, J ) 5.4 Hz, 2H),
2.10-2.00 (m, 2H), 1.67 (s, 3H), 0.97 (t, J ) 7.6 Hz, 3H); 13C
NMR (CDCl3) δ 134.1, 128.2, 68.9, 20.8, 13.9, 13.5. Anal. Calcd
for C6H12O: C, 71.95; H, 12.08. Found: C, 71.57; H, 12.12.
[(2R,3R)-3-Eth yl-2-m eth yloxir a n -2-yl]m eth yl Ben zoa te
(7). To a mixture of (-)-dimethyl D-tartrate (0.545 g, 3.06
mmol), titanium tetraisopropoxide (0.76 g, 2.55 mmol), mo-
lecular sieves (4 Å, 1.8 g), and tert-butylhydroperoxide (5 M
solution in decane, 20 mL) in dichloromethane (180 mL) at
-20 °C was added a solution of 6 (5.1 g, 51 mmol) in
dichloromethane (35 mL) over 30 min, and the reaction
mixture was stirred for 3.5 h. To this mixture at -20 °C were
added (cautiously) trimethyl phosphite (9 mL, 76.5 mmol),
triethylamine (8.5 mL, 61.2 mmol), and benzoyl chloride (5.92
mL, 51 mmol), and the mixture was stirred for 1.5 h before
being washed with 10% tartaric acid (2 × 200 mL), saturated
sodium bicarbonate (3 × 150 mL), and brine. The organic layer
was dried (MgSO4), filtered, and evaporated, and the residue
was purified by chromatography (gradient, hexanes to 85%
hexanes/15% ethyl acetate) to give 7 (7.35 g, 65%): 1H NMR
(CDCl3) δ 8.09-8.05 (m, 2H), 7.61-7.24 (m, 3H), 4.42 (d, J )
11.7 Hz, 1H), 4.20 (d, J ) 11.7 Hz, 1H), 2.94 (t, J ) 7.5 Hz,
1H), 1.71-1.53 (m, 2H), 1.40 (s, 3H), 1.06 (t, J ) 7.5 Hz, 3H);
13C NMR (CDCl3) δ 166.2, 133.1, 129.7, 128.4, 118.8, 69.1, 62.6,
58.6, 21.5, 14.3, 10.40. Anal. Calcd for C13H16O3: C, 70.89; H,
7.32. Found: C, 70.76; H, 7.20.
Con clu sion
In summary, an efficient, enantioselective synthesis of
the promising antiinfluenza compound A-315675 was
carried out.27 The key step involving condensation of
imine 3 with silyloxypyrrole 4 established the main
(23) The ratio was determined by 1H NMR integration.
(24) NOE analysis was consistent with this assignment.
(25) The tritylsulfenamide group has been reported to be generally
quite stable to acidic hydrolysis. Branchaud, B. P. J . Org. Chem. 1983,
48, 3538-3544.
(26) Careful attention had to be paid to the amount of reagents used,
as excess cuprate or TMSCl led to a significant amount of side product.
(27) An enantioselective total synthesis of A-315675 has recently
been completed by Stephen Hanessian and co-workers. We thank Prof.
Hanessian for informing us of the details of his synthesis; personal
communication.
(2S)-2-Meth ylp en ta n e-1,2-d iol (8). To a suspension of
lithium aluminum hydride (3.8 g, 0.1 mol) in THF (160 mL)
at 0 °C was added 7 (7.35 g, 0.033 mol) in THF (40 mL). After
stirring for 0.5 h, the mixture was warmed to room temper-
ature, cooled to 0 °C, and quenched cautiously with water (5
mL), 15% NaOH (5 mL), and water (15 mL). The mixture was
filtered, and the filtrate was concentrated. The residue was
purified by chromatography (gradient, hexanes to 60% hex-
J . Org. Chem, Vol. 67, No. 16, 2002 5449

DeGoey et al.
anes/40% ethyl acetate) to give 8 (2.48 g, 63%): 1H NMR
(CDCl3) δ 3.47 (dd, J ) 5.8, 10.9 Hz, 1H), 3.40 (dd, J ) 5.8,
10.9 Hz, 1H), 1.97 (t, J ) 5.8 Hz, 1H), 1.82 (s, 1H), 1.50-1.31
(m, 4H), 1.17 (s, 3H), 0.94 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3)
δ 73.0, 69.8, 41.1, 23.2, 17.0, 14.6. Anal. Calcd for C6H14O2:
C, 60.98; H, 11.94. Found: C, 60.84; H, 11.60.
acetate, and the organic layer was washed with water and
brine, dried (MgSO4), and concentrated. The residue was
purified by gradient chromatography (hexanes to 35% EtOAc/
65% hexanes) to provide 11a (25 mg, 31% yield, Rf 0.48 in 35%
EtOAc/65% hexanes) and 11b (28 mg, 35% yield, Rf 0.36 in
35% EtOAc/65% hexanes). 11a : 1H NMR (CDCl3) δ 7.42 (dd,
J ) 2.0, 6.1 Hz, 1H), 6.65 (m, 2H), 6.41 (m, 2H), 6.06 (dd, J )
1.7, 6.1 Hz, 1H), 4.91 (m, 1H), 4.28 (dd, J ) 3.4, 10.5 Hz, 1H),
3.70 (s, 3H), 3.42 (d, J ) 10.8 Hz, 1H), 3.26 (s, 3H), 1.90-1.29
({[(2S)-2-Meth oxy-2-m eth ylpen tyl]oxy}m eth yl)ben zen e
(9). To a suspension of sodium hydride (95% powder, 5.08 g,
0.212 mol) in THF (210 mL) at 0 °C was added 8 (10.02 g,
0.085 mol) in THF (85 mL). After stirring for 1 h, benzyl
bromide (12.1 mL, 0.102 mol) was added, and the reaction
mixture was warmed to room temperature and stirred for 16
h. The mixture was quenched with saturated NH4Cl (30 mL),
and the solvent was removed via Rotovap. The residue was
partitioned between water and ether, and the ether layer was
separated and dried (MgSO4). The crude product was purified
by chromatography (gradient, hexanes to 85% hexanes/15%
ethyl acetate) to give (2S)-1-(benzyloxy)-2-methylpentan-2-ol
(17.26 g, 98%): 1H NMR (CDCl3) δ 7.39-7.27 (m, 5H), 4.56 (s,
2H), 3.31 (dd, J ) 8.8, 17.0 Hz, 2H), 1.52-1.23 (m, 4H), 1.16
(s, 3H), 0.92 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 138.3,
128.4, 127.7, 127.6, 77.4, 73.4, 72.2, 41.5, 23.7, 17.0, 14.7. Anal.
Calcd for C13H20O2: C, 74.96; H, 9.68. Found: C, 74.92; H,
9.55.
To a solution of the above alcohol (17.26 g, 0.083 mol) in
THF (280 mL) at 0 °C was added sodium bis(trimethylsilyl)-
amide (NaHMDS) (1 M in THF, 166 mL, 0.166 mol). The
mixture was stirred for 1 h followed by the addition of methyl
iodide (25.8 mL, 0.415 mol). The mixture was warmed to room
temperature and stirred for 16 h. Upon completion, the
reaction mixture was quenched with saturated NH4Cl (25 mL)
and water (250 mL). The organic layer was separated, and the
aqueous layer was extracted with ether. The organic layers
were combined, washed with brine, and dried (MgSO4) and
concentrated. The residue was purified by chromatography
(gradient, hexanes to 90% hexanes/10% ethyl acetate) to give
9 (18.03 g, 98%): 1H NMR (CDCl3) δ 7.35-7.26 (m, 5H), 4.55
(s, 2H), 3.36-3.29 (m, 2H), 3.21 (s, 3H), 1.58-1.42 (m, 2H),
1.34-1.22 (m, 2H), 1.14 (s, 3H), 0.90 (t, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) δ 138.5, 128.3, 127.6, 127.5, 76.5, 74.2 73.4, 49.5,
37.6, 20.5, 16.6, 14.7. Anal. Calcd for C14H22O2: C, 75.63; H,
9.97. Found: C, 75.56; H, 9.79.
(2S)-2-Meth oxy-2-m eth ylp en ta n a l (10). To a solution of
9 (5 g, 22.5 mmol) in dichloromethane (75 mL) was added 20%
Pd(OH)2 on carbon (1.6 g), and the flask was fitted with a
hydrogen balloon. The mixture was stirred for 3.5 h after which
the catalyst was filtered and rinsed with dichloromethane (75
mL). The filtrate was reacted directly with pyridinium chlo-
rochromate (14.5 g, 67.5 mmol) at 0 °C in the presence of
molecular sieves (4 Å, 5 g) and Celite (5 g). The mixture was
stirred at room temperature for 1.5 h, diluted with ether (200
mL), and filtered through a short pad of silica gel with
additional ether. The solvent was removed by short-path
distillation, and the remaining liquid was distilled (60 Torr,
72-75 °C) to give 10 (1.74 g, 60% for two steps): 1H NMR
(CDCl3) δ 9.58 (s, 1H), 3.28 (s, 3H), 1.64-1.51 (m, 2H), 1.38-
1.23(m, 2H), 1.22 (s, 3H), 0.92 (t, J ) 7.1 Hz, 3H); 13C NMR
(CDCl3) δ 205.3, 82.4, 51.5, 36.8, 17.4, 16.2, 14.5. Anal. Calcd
for C7H14O2: C, 64.58; H, 10.84. Found: C, 61.27; H, 10.31.
ter t-Bu t yl (2R)-2-{(1R,2S)-2-Met h oxy-1-[(4-m et h oxy-
p h en yl)a m in o]-2-m et h ylp en t yl}-5-oxo-2,5-d ih yd r o-1H -
pyr r ole-1-car boxylate (11a) an d ter t-Bu tyl (2S)-2-{(1S,2S)-
2-Meth oxy-1-[(4-m eth oxyph en yl)am in o]-2-m eth ylpen tyl}-
5-oxo-2,5-d ih yd r o-1H-p yr r ole-1-ca r b oxyla t e (11b). To a
suspension of Yb(OTf)3 (12 mg, 0.019 mmol) and MgSO4 (70
mg, 0.58 mmol) in dichloromethane (0.50 mL) were added 10
(22 mg, 0.19 mmol) in dichloromethane (0.35 mL) and p-
anisidine (24 mg, 0.19 mmol) in dichloromethane (0.25 mL),
and the mixture was stirred at room temperature for 0.5 h.
Compound 4 (59 mg, 0.19 mmol) in dichloromethane (0.35 mL)
was added, and the reaction was stirred for 1 h and then
quenched with water. The reaction was diluted with ethyl
(m, 4H), 1.52 (s, 9H), 1.18 (s, 3H), 1.02 (t, J ) 7.1 Hz, 3H); 13
C
NMR δ 168.9, 151.7, 150.4, 148.6, 143.5, 127.3, 115.0, 114.0,
82.7, 79.7, 63.7, 60.3, 55.8, 49.3, 38.4, 28.1, 20.6, 17.5, 14.9.
Anal. Calcd for C23H34N2O5: C, 66.0; H, 8.19; N, 6.69. Found:
C, 65.70; H, 7.82; N, 6.81. 11b: 1H NMR (CDCl3) δ 7.39 (dd,
J ) 2.4, 6.1 Hz, 1H), 6.65 (m, 2H), 6.40 (m, 2H), 6.05 (dd, J )
1.7, 6.1 Hz, 1H), 4.93 (m, 1H), 4.29 (dd, J ) 2.4, 10.5 Hz, 1H),
3.70 (s, 3H), 3.45 (d, J ) 10.5 Hz, 1H), 3.26 (s, 3H), 1.58 (s,
9H), 1.55-1.10 (m, 4H), 1.39 (s, 3H), 0.69 (t, J ) 7.5 Hz, 3H);
13C NMR δ 169.0, 151.7, 150.1, 148.9, 143.0, 127.4, 115.0,
114.0, 82.7, 79.6, 64.3, 59.6, 55.8, 48.7, 37.4, 28.2, 20.6, 18.3,
14.5. Anal. Calcd for C23H34N2O5: C, 66.0; H, 8.19; N, 6.69.
Found: C, 65.97; H, 8.11; N, 6.65.
ter t-Bu tyl (2R)-2-{(1R,2S)-2-Meth oxy-2-m eth yl-1-[(tr i-
t ylt h io)a m in o]p en t yl}-5-oxo-2,5-d ih yd r o-1H -p yr r ole-1-
ca r b oxyla t e (12a ) a n d ter t-Bu t yl (2S)-2-{(1S,2S)-2-
Meth oxy-2-m eth yl-1-[(tr itylth io)a m in o]p en tyl}-5-oxo-2,5-
d ih yd r o-1H-p yr r ole-1-ca r boxyla te (12b). A mixture of 10
(3.87 g, 29.8 mmol), triphenylmethanesulfenamide (8.7 g, 29.8
mmol), MgSO4 (10.8 g, 89.4 mmol), and PPTS (150 mg, 0.60
mmol) in 60 mL of ether was stirred at room temperature for
18 h. The mixture was filtered, and the filtrate was concen-
trated. 3b: 1H NMR (CDCl3) δ 7.56 (s, 1H), 7.32-7.23 (m,
15H), 2.97 (s, 3H), 1.39-1.34 (m, 2H), 1.17-1.04 (m, 2H), 0.99
(s, 3H), 0.80 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 163.9,
144.2, 130.0, 127.9, 127.0, 80.1, 50.7, 39.8, 19.4, 16.7, 14.6.
Anal. Calcd for C26H29NOS: C, 77.38; H, 7.24; N, 3.47.
Found: C, 77.55; H, 7.11; N, 3.46.
To imine 3b (12.0 g, 29.8 mmol) and 4 (17.7 g, 59.6 mmol)
in ether (100 mL) at -78 °C was added BF3‚Et2O (9.4 mL,
74.4 mmol) dropwise and the reaction was stirred at -78 °C
for 2 h and then at -50 °C for 1 h. The reaction was quenched
with saturated sodium bicarbonate (180 mL) and allowed to
warm to room temperature. The mixture was diluted with
chloroform (500 mL), and the organic layer was separated and
washed with water and brine, dried (MgSO4), and concen-
trated. The residue was purified by chromatography (20% ethyl
acetate/80% hexanes) to provide 12a (9.1 g, 52% yield, Rf 0.54
in 35% EtOAc/65% hexanes) and 12b (2.85 g, 16% yield, Rf
0.41 in 35% EtOAc/65% hexanes). 12a : 1H NMR (CDCl3) δ
7.32 (dd, J ) 2.0, 6.1 Hz, 1H), 7.29-7.19 (m, 15H), 6.02 (dd, J
) 1.4, 6.1 Hz, 1H), 4.83(m, 1H), 3.86 (dd, J ) 3.1, 11.5 Hz,
1H), 3.05 (s, 3H), 2.62 (d, J ) 11.2 Hz, 1H), 1.62-1.50 (m,
2H), 1.36 (s, 9H), 1.36-1.26 (m, 1H), 1.15-0.97 (m, 1H), 0.92
(t, J ) 6.6 Hz, 3H), 0.43 (s, 3H); 13C NMR (CDCl3) δ 148.2,
144.8, 130.1, 127.6, 126.6, 82.4, 79.2, 66.9, 64.6, 48.9, 38.7, 27.9,
19.3, 17.1, 14.9. Anal. Calcd for C35H42N2O4S: C, 71.64; H, 7.21;
N, 4.77. Found: C, 71.45; H, 7.06; N, 4.59. 12b: 1H NMR
(CDCl3) δ 7.28-7.18 (m, 16H), 6.02 (dd, J ) 1.7, 6.1 Hz, 1H),
4.90 (m, 1H), 3.89 (dd, J ) 2.0, 11.5 Hz, 1H), 3.06 (s, 3H), 2.42
(d, J ) 11.5 Hz, 1H), 1.54 (s, 9H), 1.28-0.85 (m, 4H), 1.16 (s,
3H), 0.57 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 148.2, 144.3,
130.0, 127.7, 126.5, 82.6, 79.2, 67.2, 65.3, 49.2, 37.3, 28.3, 20.9,
17.5, 14.7. Anal. Calcd for C35H42N2O4S: C, 71.64; H, 7.21; N,
4.77. Found: C, 70.61; H, 7.05; N, 4.66.
ter t-Bu tyl (2R)-2-[(1R,2S)-1-(Acetyla m in o)-2-m eth oxy-
2-m eth ylp en tyl]-5-oxo-2,5-d ih yd r o-1H-p yr r ole-1-ca r box-
ylate (13a) an d ter t-Bu tyl (2S)-2-[(1S,2S)-1-(Acetylam in o)-
2-m eth oxy-2-m eth ylpen tyl]-5-oxo-2,5-dih ydr o-1H-pyr r ole-
1-ca r boxyla te (13b). Ammonia gas was bubbled through a
suspension of phenyl disulfide (34 mg, 0.15 mmol) and silver
nitrate (26 mg, 0.15 mmol) in methanol (2.5 mL) at 0 °C for
15 min. To the mixture was added a solution of 10 (40 mg,
5450 J . Org. Chem., Vol. 67, No. 16, 2002

Enantioselective Synthesis of A-315675
0.31 mmol) in methanol (0.5 mL), and the mixture was stirred
at room temperature for 68 h. The reaction mixture was
filtered, and the filtrate was concentrated. The residue was
dissolved in ether and refiltered. The resulting filtrate was
washed with water, dried (MgSO4), and concentrated to give
crude imine 3c (42 mg, 57%).
centrated. The crude residue was purified by chromatography
(gradient, dichloromethatne to 50% ethyl acetate/50% dichlo-
romethane) to provide 15 as a foaming solid (38.6 mg, 61%):
1H NMR (CDCl3) δ 7.54 (d, J ) 7.9 Hz, 2H), 7.27 (d, J ) 7.3
Hz, 2H), 7.25 (dd, J ) 1.8, 6.1 Hz, 1H), 6.02 (dd, J ) 1.2, 6.1
Hz, 1H), 4.85 (m, 1H), 4.39 (dd, J ) 3.1, 9.2 Hz, 1H), 4.22 (d,
J ) 9.2 Hz, 1H), 3.18 (s, 3H), 2.37 (s, 3H), 1.94 (m, 1H), 1.64-
1.55 (m, 2H), 1.60 (s, 9H), 1.40 (s, 3H), 1.21 (m, 1H), 1.07 (t, J
) 6.7 Hz, 3H); 13C NMR (CDCl3) δ 169.7, 149.2, 148.1, 142.7,
141.3, 129.5, 127.6, 125.1, 83.4, 77.6, 63.6, 61.1, 48.4, 36.4, 28.2,
21.3, 20.2, 18.3, 14.5. Anal. Calcd for C23H34N2O5S: C, 61.31;
H, 7.61; N, 6.22. Found: C, 61.02; H, 7.41; N, 6.04.
To a solution of the above imine 3c (42 mg, 0.18 mmol) and
4 (53 mg, 0.18 mmol) in dichloromethane (1.5 mL) at -78 °C
was added BF3‚Et2O (0.034 mL, 0.27 mmol). After stirring at
-78 °C for 2 h, the reaction was quenched with saturated
sodium bicarbonate (2 mL) and extracted with dichloromethane.
The organic layer was dried (MgSO4) and concentrated to give
the crude mixture of unstable phenylsulfenamide products.
These crude products were treated with 80% acetic acid (2 mL)
at room temperature for 1 h, and the volatiles were evaporated.
The crude residue was purified by chromatography (5%
methanol in dichloromethane with 0.2% ammonium hydroxide)
to give the amine (28 mg, 50%).
ter t-Bu tyl (2R)-2-((1R,2S)-2-Meth oxy-2-m eth yl-1-{[(R)-
(ter t-bu tyl)su lfin yl]a m in o}p en tyl)-5-oxo-2,5-d ih yd r o-1H-
p yr r ole-1-ca r boxyla te (16). The procedure of preparation of
15 was followed with 3f (20 mg, 0.086 mmol). Purification by
chromatography (gradient, 6% to 50% ethyl acetate/dichloro-
methane) provided 16 (12.9 mg, 36%): 1H NMR (CDCl3) δ 7.37
(dd, J ) 1.8, 6.1 Hz, 1H), 6.05 (dd, J ) 1.2, 6.1 Hz, 1H), 4.73
(m, 1H), 4.09 (dd, J ) 3.7, 8.5 Hz, 1H), 3.79 (d, J ) 8.5 Hz,
1H), 3.25 (s, 3H), 1.92 (m, 1H), 1.69-1.43 (m, 3H), 1.57 (s, 9H),
1.39 (s, 3H), 1.15 (s, 9H), 1.02 (t, J ) 2.3 Hz, 3H); 13C NMR
(CDCl3) δ 169.4, 149.6, 148.2, 127.4, 83.2, 78.2, 63.5, 61.6, 56.4,
49.2, 37.9, 28.3, 23.0, 21.0, 17.4, 14.8.
The amine product (28 mg, 0.09 mmol) in dichloromethane
(1 mL) was treated with acetic anhydride (0.017 mL, 0.18
mmol), triethylamine (0.028 mL, 0.2 mmol), and 4-(dimethyl-
amino)pyridine (2 mg, 0.02 mmol) for 1 h. The material was
purified directly by eluting with 5% methanol in dichloro-
methane to give 13a and 13b (26 mg, 82%) as a mixture
(1:1.9, respectively) of two inseparable disastereomers. 13a :
1H NMR (CDCl3) δ 7.33 (dd, J ) 2.0, 6.1 Hz, 1H), 6.08 (dd, J
) 1.4, 6.1 Hz, 1H), 5.37 (d, J ) 10.0 Hz, 1H), 4.89 (dd, J )
3.4, 9.8 Hz, 1H), 4.85 (m, 1H), 3.23 (s, 3H), 1.91 (s, 3H), 1.59
(s, 9H), 1.18 (s, 3H), 1.01 (t, J ) 7.1 Hz, 3H). 13b: 1H NMR
(CDCl3) δ 7.28 (dd, J ) 2.4, 6.1 Hz, 1H), 6.10 (dd, J ) 1.7, 6.4
Hz, 1H), 5.33 (d, J ) 10.5 Hz, 1H), 4.98 (dd, J ) 2.7, 10.2 Hz,
1H), 4.89 (m, 1H), 3.24 (s, 3H), 1.90 (s, 3H), 1.60 (s, 9H), 1.40
(s, 3H), 0.89 (t, J ) 7.1 Hz, 3H).
ter t-Bu tyl (2R)-2-[(1R,2S)-1-(Acetyla m in o)-2-m eth oxy-
2-m eth ylp en tyl]-5-oxop yr r olid in e-1-ca r boxyla te (17): 1H
NMR (CDCl3) δ 5.87 (d, J ) 9.9 Hz, 1H), 4.57 (dd, J ) 2.4, 9.8
Hz, 1H), 4.40 (m, 1H), 3.20 (s, 3H), 2.55-2.32 (m, 3H), 1.98
(s, 3H), 2.02-1.87 (m, 1H), 1.84-1.62 (m, 1H), 1.58 (s, 9H),
1.50-1.08 (m, 3H), 1.15 (s,3H), 0.98 (t, J ) 7.0 Hz, 3H); 13C
NMR (CDCl3) δ 174.1, 170.0, 149.9, 83.0, 78.6, 58.0, 54.7, 49.0,
37.3, 32.6, 28.1, 23.2, 20.5, 18.4, 17.3, 14.8. Anal. Calcd for
C
18H32N2O5: C, 60.65; H, 9.05; N, 7.86. Found: C, 60.92; H,
9.18; N, 7.66.
The mixture of 13a and 13b (20 mg, 0.06 mmol) was
subjected to catalytic hydrogenation with 20% Pd(OH)2 on
carbon (10 mg) in 2 mL of EtOAc for 2 h under balloon
pressure. The reaction was filtered and evaporated to give a
mixture of 17 and 18 (18 mg) in a 1:1.9 ratio by 1H NMR,
respectively.
ter t-Bu tyl (2S)-2-[(1S,2S)-1-(Acetyla m in o)-2-m eth oxy-
2-m eth ylp en tyl]-5-oxop yr r olid in e-1-ca r boxyla te (18): 1H
NMR (CDCl3) δ 5.87 (d, J ) 9.5 Hz, 1H), 4.68 (dd, J ) 2.0, 9.5
Hz, 1H), 4.44 (m, 1H), 3.20 (s, 3H), 2.52-2.33 (m, 3H), 1.97
(s, 3H), 2.02-1.89 (m, 1H), 1.58 (s, 9H), 1.55-1.12 (m, 4H),
1.29 (s, 3H), 0.88 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 174.3,
169.9, 149.3, 82.6, 78.1, 58.4, 53.1, 48.4, 38.3, 32.3, 28.0, 22.9,
20.0, 18.0, 17.7, 14.7. Anal. Calcd for C18H32N2O5: C, 60.65;
H, 9.05; N, 7.86. Found: C, 59.92; H, 8.94; N, 7.61.
ter t-Bu tyl (2R)-2-((1R,2S)-2-Meth oxy-2-m eth yl-1-{[(R)-
(4-m eth ylp h en yl)su lfin yl]a m in o}p en tyl)-5-oxo-2,5-d ih y-
d r o-1H-p yr r ole-1-ca r boxyla te (14). To a solution of (R)-p-
toluenesulfinimine 3d (2.9 g, 10.84 mmol) and 4 (6.1 g, 20.5
mmol) in dichloromethane (80 mL) at -78 °C was added
trimethylsilyl triflate (2.8 mL, 16.23 mmol). After stirring at
-78 °C for 10 min and then at -23 °C for 7 h, the reaction
was quenched with saturated sodium bicarbonate (100 mL)
and diluted with dichloromethane. The organic layer was
separated, dried (Na2SO4), and concentrated. The crude resi-
due was triturated with ether, and the resulting precipitate
was collected by filtration to give 14 as a white solid (2.86 g,
59%): 1H NMR (CDCl3) δ 7.56 (d, J ) 8.1 Hz, 2H), 7.29-7.26
(m, 3H), 6.00 (dd, J ) 6.1, 1.4 Hz, 1H), 4.81 (m, 1H), 4.28 (dd,
J ) 9.2, 3.1 Hz, 1H), 4.18 (d, J ) 8.8 Hz,1H), 3.17 (s, 3H),
2.38 (s, 3H), 1.93 (m, 1H), 1.72-1.38 (m, 3H), 1.59 (s, 9H), 1.43
(s, 3H), 1.03 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 169.4,
149.7, 148.0, 142.7, 141.4, 129.5, 127.4, 125.1, 83.5, 77.9, 63.2,
62.5, 49.0, 37.8, 28.3, 21.3, 21.0, 17.5, 14.8. Anal. Calcd for
ter t-Bu t yl (2R,3S)-2-{(1R,2S)-2-Met h oxy-2-m et h yl-1-
[(tr itylth io)a m in o]p en tyl}-5-oxo-3-[(1Z)-p r op -1-en yl]p yr -
r olid in e-1-ca r boxyla te (19a ). cis-1-Bromopropene (21 mL,
0.24 mmol), Mg turnings (7 g), and 5 drops of 1,2-dibromo-
ethane were refluxed in THF (470 mL) for 3 h and then cooled
to room temperature. To a slurry of Cu(I)Br‚DMS (12.6 g, 61.5
mmol) in THF (230 mL) at -78 °C was added cis-1-propenyl-
magnesium bromide (0.5M in THF, 246 mL, 123 mmol)
dropwise over 1.5 h followed by dropwise addition of trimeth-
ylsilyl chloride (4.6 mL, 36.9 mmol) over 10 min. To this
solution was added 12a (7.2 g, 12.3 mmol) in THF (230 mL)
at -78 °C, and the reaction mixture was stirred at this
temperature for 1 h. The reaction was quenched with saturated
NH4Cl (290 mL) and warmed to room temperature. The
mixture was extracted twice with ethyl acetate (0.5 L), and
the organic layers were combined, washed with brine, dried
(MgSO4), and concentrated. The crude residue was purified
by chromatography (10% ethyl acetate/ 90% hexanes) to give
19a (6.9 g, 89%): 1H NMR (CDCl3) δ 7.30-7.19 (m, 15H),
5.44-5.33 (m, 2H), 3.99 (d, J ) 1.4 Hz, 1H), 3.69 (m, 1H), 3.58
(dd, J ) 2.4, 10.5 Hz, 1H), 3.05 (d, J ) 10.9 Hz, 1H), 3.03 (s,
3H), 2.80 (dd, J ) 9.5, 18.0 Hz, 1H), 1.94 (dd, J ) 17.6, 1.4
Hz, 1H), 1.66-1.36 (m, 2H), 1.58 (d, J ) 4.7 Hz, 3H), 1.43 (s,
9H), 1.26-0.92 (m, 2H), 0.86 (t, J ) 6.6 Hz, 3H), 0.51 (s, 3H);
13C NMR (CDCl3) δ 173.3, 144.7, 133.1, 130.1, 127.7, 126.6,
123.2, 82.6, 79.8, 77.2, 66.5, 65.3, 48.9, 39.8, 37.9, 28.1, 27.4,
19.9, 16.9, 14.8, 13.0. Anal. Calcd for C38H48N2O4S: C, 72.58;
H, 7.69; N, 4.45. Found: C, 72.16; H, 7.70; N, 4.38.
C
23H34N2O5S: C, 61.31; H, 7.61; N, 6.22. Found: C, 61.35; H,
7.51; N, 6.14.
ter t-Bu tyl (2S)-2-((1S,2S)-2-Meth oxy-2-m eth yl-1-{[(S)-
(4-m eth ylp h en yl)su lfin yl]a m in o}p en tyl)-5-oxo-2,5-d ih y-
d r o-1H-p yr r ole-1-ca r boxyla te (15). To a solution of (S)-p-
toluenesulfininimine 3e (37.4 mg, 0.14 mmol) and 4 (63.6 mg,
0.21 mmol) in dichloromethane (0.6 mL) at -78 °C was added
trimethylsilyl triflate (0.038 mL, 0.21 mmol). After stirring at
-30 °C for 18 h, the reaction was quenched with saturated
sodium bicarbonate (4 mL) and diluted with dichloromethane
and warmed to room temperature. The layers were separated,
and the aqueous layer was extracted with dichloromethane.
The combined organic layers were dried (Na2SO4) and con-
J . Org. Chem, Vol. 67, No. 16, 2002 5451

DeGoey et al.
ter t-Bu tyl (2R,3S,5R)-5-Cya n o-2-{(1R,2S)-2-m eth oxy-2-
m eth yl-1-[(tr itylth io)a m in o]p en tyl}-3-[(1Z)-p r op -1-en yl]-
p yr r olid in e-1-ca r boxyla te (20a ). To a solution of 19a (6.4
g, 10.2 mmol) in THF (27 mL) at -78 °C was added diisobu-
tylaluminum hydride (1 M in hexane, 30.6 mL). After stirring
at -78 °C for 45 min, the reaction was quenched with
saturated NH4Cl (150 mL) and a 10% sodium potassium
tartrate solution (250 mL), diluted with ethyl acetate (250 mL),
and stirred at room temperature for 1 h. The organic layer
was separated, and the aqueous extracted again with ethyl
acetate (250 mL). The combined extracts were washed with
water and brine, dried (MgSO4), and concentrated to give a
crude oil (5.6 g, 87% yield), which was used directly in the
next step.
The above crude hemiaminal (8.9 mmol) was stirred in
methanol (100 mL) with pyridinium p-toluenesulfonic acid
(0.11 g, 0.43 mmol) at room temperature for 1 h. The reaction
was diluted with ethyl acetate (500 mL), washed with water
(150 mL) and brine (100 mL), and then dried (MgSO4) and
evaporated to give 6.1 g of an oil which was used directly for
the next step.
raphy (gradient, 17% to 33% ethyl acetate/hexane) to give 19b
(44.31 mg, 74%): 1H NMR (CDCl3) δ 7.62 (d, J ) 8.5 Hz, 2H),
7.32 (d, J ) 8.5 Hz, 2H), 5.43 (m, 2H), 4.58 (d, J ) 7.8 Hz,
1H), 3.99 (br d, J ) 2.7 Hz, 1H), 3.93 (dd, J ) 7.8, 2.7 Hz,
1H), 3.71 (m, 1H), 3.19 (s, 3H), 2.57 (dd, J ) 17.8, 9.7 Hz, 1H),
2.40 (s, 3H), 1.97 (dd, J ) 17.8, 1.5 Hz, 1H), 1.82 (m, 1H), 1.59
(s, 9H), 1.55 (s, 3H), 1.52 (m, 1H), 1.42 (s, 3H), 1.27 (m, 2H),
0.96 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 174.1, 150.5, 136.5,
133.2, 129.5, 127.7, 123.3, 82.6, 79.4, 69.2, 65.8, 49.0, 40.3, 37.7,
28.0, 21.1, 21.0, 16.9, 14.8, 13.0. Anal. Calcd for C26H40N2O5S:
C, 63.38; H, 8.18; N, 5.69. Found: C, 63.33; H, 8.09; N, 5.68.
ter t-Bu tyl (2R,3S,5R)-5-Cya n o-2-((1R,2S)-2-m eth oxy-2-
m eth yl-1-{[(R)-(4-m eth ylp h en yl)su lfin yl]a m in o}p en tyl)-
3-[(1Z)-p r op -1-en yl]p yr r olid in e-1-ca r boxyla te (20b). To a
solution of 19b (2.12 g, 4.31 mmol) in dichloromethane (21 mL)
at -78 °C was added diisobutylaluminum hydride (1 M in
hexane, 10.77 mL, 10.77 mmol). After stirring at -78 °C for
0.4 h, the reaction was quenched with saturated NH4Cl (35
mL) and 10% sodium potassium tartrate solution (35 mL),
diluted with ethyl acetate, and stirred at room temperature
for 1 h. The organic layer was separated, dried (Na2SO4), and
concentrated to give a crude oil (2.1 g), which was used directly
in the next step.
To a solution of crude product from above in dichloro-
methane (90 mL) at -78 °C were added trimethylsilyl cyanide
(3.5 mL, 26.7 mmol) and BF3‚Et2O (1.2 mL, 9.5 mmol) in
dichloromethane (8 mL). After 30 min at -78 °C, triethylamine
(2.5 mL) was added and the reaction was quenched with
saturated sodium bicarbonate (150 mL) and warmed to room
temperature. Ethyl acetate (500 mL) was added, and the
organic was washed with water and brine and dried (MgSO4).
The solvents were evaporated, and the crude residue was
purified by chromatography (5% EtOAc/95% hexanes) to give
20a (4.4 g, 77%): 1H NMR (CDCl3) δ 7.36-7.20 (m, 15H),
5.74-5.67 (m, 1H), 5.49-5.38 (m, 1H), 4.60 (d, J ) 9.2 Hz,
1H), 3.82 (dd, J ) 7.8, 10.5 Hz, 1H), 3.79 (d, J ) 1.7 Hz, 1H),
3.68 (dd, J ) 2.0, 10.5 Hz, 1H), 3.02 (d, J ) 10.5 Hz, 1H), 3.01
(s, 3H), 2.59-2.48 (m, 1H), 1.84 (d, J ) 13.2 Hz, 1H), 1.67-
1.39 (m, 2H), 1.60 (dd, J ) 1.7, 6.8 Hz, 3H), 1.34 (s, 9H), 1.12-
0.91 (m, 2H), 0.86 (t, J ) 6.6 Hz, 3H), 0.45 (s, 3H); 13C NMR
(CDCl3) δ 152.5, 144.6, 132.3, 130.1, 127.7, 126.7, 123.5, 120.5,
80.9, 79.7, 65.7, 62.9, 48.7, 47.0, 37.9, 36.8, 35.3, 28.2, 19.8,
16.8, 14.9, 12.8. Anal. Calcd for C39H49N3O3S: C, 73.20; H, 7.72;
N, 6.57. Found: C, 72.96; H, 7.84; N, 6.53. The epimeric nitrile
was also obtained (0.22 g. 4%, removed during chromatogra-
phy) and was identified as ter t-bu tyl (2R,3S,5S)-5-cya n o-
2-{(1R,2S)-2-m eth oxy-2-m eth yl-1-[(tr itylth io)a m in o]p en -
t yl}-3-[(1Z)-p r op -1-en yl]p yr r olid in e-1-ca r b oxyla t e: 1H
NMR (CDCl3) δ 7.34-7.17 (m, 15H), 5.49-5.39 (m, 1H), 5.27-
5.20 (m, 1H), 4.42 (t, J ) 7.0 Hz, 1H), 3.75-3.65 (m, 3H), 3.33
(d, J ) 10.8 Hz, 1H), 3.01 (s, 3H), 2.42 (m, 1H), 1.89-1.81 (m,
1H), 1.68-1.47 (m, 2H), 1.61 (dd, J ) 1.7. 6.8 Hz, 3H), 1.38 (s,
9H), 1.12-0.82 (m, 2H), 0.80 (t, J ) 6.5 Hz, 3H), 0.50 (s, 3H);
13C NMR (CDCl3) δ 148.9, 145.0, 131.5, 130.2, 127.6, 126.5,
124.5, 118.9, 79.9, 66.8, 64.2, 48.6, 47.3, 38.0, 37.1, 35.6, 28.2,
19.6, 16.7, 14.9, 13.0. Anal. Calcd for C39H49N3O3S: C, 73.20;
H, 7.72; N, 6.57; Found: C, 73.38; H, 7.54; N, 5.37.
ter t-Bu t yl (2R,3S)-2-((1R,2S)-2-Met h oxy-2-m et h yl-1-
{[(R)-(4-m et h ylp h en yl)su lfin yl]a m in o}p en t yl)-5-oxo-3-
[(1Z)-p r op -1-en yl]p yr r olid in e-1-ca r boxyla te (19b). To a
suspension of Cu(I)Br‚DMS (62.53 mg, 0.30 mmol) in THF (0.6
mL) at -78 °C was added cis-1-propenylmagnesium bromide
(0.5 M in THF, 1.22 mL, 0.61 mmol), and the solution was
stirred at -78 °C for 30 min. To the solution was added
trimethylsilyl chloride (0.017 mL, 0.13 mmol) followed by a
solution of 14 (54.96 mg, 0.12 mmol) in dichloromethane (0.4
mL). The reaction mixture was stirred at -78 °C for 1.5 h and
quenched with saturated NH4Cl and warmed to room tem-
perature for 1 h. The mixture was partitioned between
saturated NH4Cl (10 mL) and dichloromethane (45 mL). The
organic layer was washed with H2O (10 mL), and the combined
aqueous layers were extracted with dichloromethane (2 × 10
mL). The combined organic layers were dried (MgSO4) and
concentrated. The crude residue was purified by chromatog-
To the above hemiaminal in dichloromethane (20 mL) at
-78 °C were added trimethylsilyl cyanide (1.7 mL, 12.78
mmol) and trimethylsilyl triflate (1.12 mL, 6.18 mmol). After
stirring for 5 min, the reaction was quenched with triethyl-
amine (1.7 mL, 12.8 mmol) followed by saturated sodium
bicarbonate and warmed to room temperature and extracted
with dichloromethane. The solvents were evaporated, and the
crude residue was purified by chromatography (30% ethyl
acetate/hexane) to give 20b (2.1 g, 97% over two steps): 1H
NMR (CDCl3, rotamers) δ 7.53 (d, J ) 8.1 Hz, 2H), 7.32 (d, J
) 8.1 Hz, 2H), 5.73 (m, 1H), 5.48 (m, 1H), 4.58-4.46 (m, 2H),
4.01-3.69 (m, 3H), 3.18 (s, 0.6H), 3.16 (s, 2.4H), 2.42 (s, 3H),
2.38 (m, 1H), 1.81-1.66 (m, 3H), 1.61-1.55 (m, 12H), 1.26-
1.17 (m, 5H), 0.92 (m, 3H); 13C NMR (CDCl3) δ 152.6, 132.0,
129.9, 129.7, 124.1, 124.0, 123.8, 120.2, 81.8, 78.7, 65.4, 60.5,
48.9, 47.9, 47.5, 37.6, 36.8, 35.5, 28.6, 28.5, 21.4, 21.0, 17.1,
14.9, 12.7. Anal. Calcd for C27H41N3O4S: C, 64.38; H, 8.20; N,
8.34. Found: C, 64.26; H, 7.91; N, 8.30.
ter t-Bu t yl
(2R,3S,5R)-5-Cya n o-2-[(1R,2S)-1-(a cet yl-
a m in o)-2-m eth oxy-2-m eth ylp en tyl]-3-[(1Z)-p r op -1-en yl]-
p yr r olid in e-1-ca r b oxyla t e (21). P r ep a r a t ion fr om 20a .
Compound 20a (4.4 g, 6.9 mmol) was suspended in methanol
(75 mL), and PPTS (3.45 g, 13.7 mmol) was added. The mixture
was heated to reflux for 18 h and cooled to room temperature,
and the solvent was evaporated. To the crude residue dissolved
in dichloromethane (75 mL) were added acetic anhydride (2.0
mL, 20.7 mmol) and triethylamine (5.8 mL, 41.3 mmol), and
the mixture was stirred for 1 h. The reaction was quenched
with methanol (6 mL) and evaporated. The residue was
purified by chromatography (gradient, chloroform to 50% ethyl
acetate/50% chloroform) to give 21 (1.92 g, 69%).
P r ep a r a tion fr om 20b. To a solution of 20b (8.4 mg, 0.017
mmol) in MeOH (0.17 mL) was added trifluoroacetic acid
(0.0055 mL, 0.071 mmol) at room temperature. The solution
was stirred overnight and concentrated at reduced pressure.
The residue was azeotroped with chloroform and toluene. To
the crude amine in dichloromethane (0.17 mL) was added
triethylamine (0.0238 mL, 0.17 mmol) followed by acetic
anhydride (0.0081 mL, 0.086 mmol) at room temperature. The
solution was stirred for 20 min and concentrated in vacuo. The
residue was purified by chromatography (gradient, 33% to 67%
ethyl acetate/hexane) to give 21 (5.16 mg, 76%):
1H NMR
(CDCl3, rotamers) δ 5.91 (m, 1H), 5.80-5.68 (m, 1H), 5.55-
5.45 (m, 1H), 4.55 (dd, J ) 2.4, 9.5 Hz, 1H), 4.47-4.35 (m,
1H), 3.98-3.85(m, 1H), 3.73 (dd, J ) 9.2, 9.8 Hz, 1H), 3.21
and 3.20 (2s, 3H), 2.55-2.39 (m, 1H), 2.00 (s, 3H), 1.97-1.88
(m, 1H), 1.82-1.60 (m, 2H), 1.66 (dd, J ) 1.7, 6.8 Hz, 3H),
1.36-1.20 (m, 2H), 1.57 and 1.55 and 1.53 (3s, 9H), 1.18 and
1.14 and 1.12 (3s, 3H), 0.95 (t, J ) 6.8 Hz, 3H); 13C NMR
5452 J . Org. Chem., Vol. 67, No. 16, 2002

Enantioselective Synthesis of A-315675
(CDCl3, rotamers) δ 169.6, 152.5, 131.9, 123.9, 123.8, 81.4,
78.9, 64.6, 64.3, 54.9, 54.4, 49.0, 47.2, 46.6, 37.6, 37.2, 37.0,
36.8, 36.1, 35.86, 28.5, 28.3, 28.2, 23.5, 20.5, 20.4, 20.3, 17.5,
16.9, 14.9, 14.5, 12.8. Anal. Calcd for C22H37N3O4: C, 64.84;
H, 9.15; N, 10.31. Found: C, 64.82; H, 9.07; N, 10.27.
3H); 13C NMR (D2O) δ 177.0, 176.5, 131.6, 129.3, 82.7, 65.3,
62.6, 56.2, 51.4, 43.9, 38.5, 37.2, 24.7, 20.2, 18.0, 16.2, 15.1.
Anal. Calcd for C17H30N2O4: C, 62.55; H, 9.26; N, 8.58.
Found: C, 62.32; H, 9.12; N, 8.34.
Ack n ow led gm en t. We thank William Kohlbrenner
and Shing Chang for their support, Rodger Henry for
X-ray crystal structure analyses, Xiaolin Zhang and
Carmina Presto for NMR experiments, and Clarence
Maring and Steve Wittenberger for helpful discussions.
We thank Vincent Stoll and Kent Stewart for assistance
in creating the cover art.
(-)-(2R,4S,5R)-5-[(1R,2S)-1-(Acetyla m in o)-2-m eth oxy-
2-m et h ylp en t yl]-4-[(1Z)-p r op -1-en yl]p yr r olid in e-2-ca r -
boxylic Acid (1). Compound 21 (6.1 g, 14.9 mmol) was
combined with hydrochloric acid (6 N, 350 mL) and stirred at
60 °C for 42 h. The reaction was evaporated to give 6.4 g of
crude solid, which was purified by flash chromatography
(reversed phase, Biotage KP-C18-HS column, gradient elution
starting with 100% water (0.1% TFA) and ending with 100%
acetonitrile) to give 6.56 g (99%) of material (TFA salt form).
An analytical sample of 1 was prepared by ion exchange
chromatography (Dowex 50WX8-400): [R]D ) -50.2 (c 0.25,
water); 1H NMR (D2O) δ 5.66-5.59 (m, 1H), 5.33-5.28 (m, 1H),
4.38 (d, J ) 10.4 Hz, 1H), 4.16 (t, J ) 8.9 Hz, 1H), 3.65 (t, J
) 10.4 Hz, 1H), 3.26 (s, 3H), 3.22-3.11 (m, 1H), 2.60-2.54
(m, 1H), 1.95 (s, 3H), 1.74-1.61 (m, 2H), 1.59 (dd, J ) 1.5, 7.0
Hz, 3H), 1.39-1.26 (m, 3H), 1.24 (s, 3H), 0.85 (t, J ) 7.3 Hz,
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal struc-
ture data and ORTEP diagrams of compounds 12a , 14, 18 and
21. Experimental details and spectral data for reaction of
aldehyde 10 with 4 and additional spectral data for compounds
13a , 13b, and 16. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0162890
J . Org. Chem, Vol. 67, No. 16, 2002 5453