The power of visual imagery in synthesis planning. Stereocontrolled approaches to CGP-60536B, a potent renin inhibitor

Article abstract of DOI:10.1021/jo011184i

Two strategies were developed toward the stereocontrolled synthesis of 8-aryl-3-hydroxy-4-amino-2,7-diisopropyloctanoic acids with predetermined stereogenic centers. This is a generic motif in a new class of potent inhibitors of the enzyme renin, exemplified by CGP-60536B. The synthesis relies on the utilization of L-pyroglutamic acid as chiron, and proceeds through the incorporation of required functionality by exploiting internal induction. One of the strategies shows the power of visual imagery in synthesis planning, akin to a Dali-like representation of objects that can be viewed in more than one way. Thus, the entire carbon skeleton of the target molecule is encompassed in a partially functionalized bicyclic indolizidinone precursor. In a second strategy, an intermediate common to the first approach is elaborated into an appended -lactone which is alkylated through enolate chemistry and ultimately transformed into the intended target compound. X-ray crystallography was used to corroborate the structures and stereochemistries of several intermediates.

Full text of DOI:10.1021/jo011184i

J . Org. Chem. 2002, 67, 4261-4274
4261
Th e P ow er of Visu a l Im a ger y in Syn th esis P la n n in g.
Ster eocon tr olled Ap p r oa ch es to CGP -60536B, a P oten t Ren in
In h ibitor
Stephen Hanessian,* Stephen Claridge, and Shawn J ohnstone
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centre-ville,
Montre´al, Que´bec H3C 3J 7, Canada
stephen.hanessian@umontreal.ca
Received December 27, 2001
Two strategies were developed toward the stereocontrolled synthesis of 8-aryl-3-hydroxy-4-amino-
2,7-diisopropyloctanoic acids with predetermined stereogenic centers. This is a generic motif in a
new class of potent inhibitors of the enzyme renin, exemplified by CGP-60536B. The synthesis
relies on the utilization of L-pyroglutamic acid as chiron, and proceeds through the incorporation
of required functionality by exploiting internal induction. One of the strategies shows the power of
visual imagery in synthesis planning, akin to a Dali-like representation of objects that can be viewed
in more than one way. Thus, the entire carbon skeleton of the target molecule is encompassed in
a partially functionalized bicyclic indolizidinone precursor. In a second strategy, an intermediate
common to the first approach is elaborated into an appended γ-lactone which is alkylated through
enolate chemistry and ultimately transformed into the intended target compound. X-ray crystal-
lography was used to corroborate the structures and stereochemistries of several intermediates.
In tr od u ction
inhibitors has been replaced with nonpeptidic vinylogous
amides showing low micromolar inhibition in vitro.7
The aspartic protease renin1 has been associated with
the cascade of events involving the selective cleavage of
a Leu-Val bond in angiotensinogen to angiotensin I, in
the so-called renin-angiotensin system (RAS). Further
enzymatic cleavage produces the octapeptide angiotensi-
nogen II, a vasoconstricting peptide resulting eventually
in hypertension in man.2 A major advance was made in
1982 when renin inhibitors were synthesized on the basis
of a transition-state structure to replace the scissile
bond.3 Dipeptide hydroxyethylene and related isosteres
of the Leu-Val bond in the natural substrate were
actively pursued by many groups.4 Intensive efforts
on the chemical and biological fronts followed over the
past two decades, leading to a better understanding of
the molecular events involved in the release of renin in
animal models, and its inhibition by designed transition-
state-based inhibitors.5 Nonpeptidic inhibitors of renin
based on substituted piperidines with remarkable activity
have been reported.6 The amide backbone of renin
Several drug candidates were successfully developed
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* To whom correspondence should be addressed. Phone: (514) 343-
6738. Fax: (514) 343-5728.
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10.1021/jo011184i CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/14/2002

4262 J . Org. Chem., Vol. 67, No. 12, 2002
Hanessian et al.
F igu r e 1.
worldwide, culminating with compounds that exhibited
potent in vitro and in vivo activities, although good
bioavailability remained as a major challenge. Unfortu-
nately, these programs were eventually terminated vir-
tually in every pharmaceutical company, primarily for
strategic marketing reasons. Although good pharmaco-
kinetics and excellent antihypertensive activity were
achieved with some compounds in experimental animals,
a major obstacle was concerned with oral bioavailability
in man, and in devising cost-effective syntheses. The
structures of some of these compounds, harboring four
or more stereogenic centers, with heterocyclic, alkyl, and
hydroxy appendages on a peptidic backbone are shown
in Figure 1A. More recently, a new class of inhibitors
having the general structure 1 (Figure 1B), and exhibit-
ing sub-nanomolar specific binding affinity to human
renin, with excellent oral activity in primates, was
reported.8 The generic structure 1, varying in the nature
of the aromatic substituents, the amide moiety, and the
alkyl groups, represents a novel carbon backbone with
unique binding affinities to renin. Of particular signifi-
cance was the nonpeptidic nature of the truncated
tetrasubstituted 8-aryloctanoic acid amide backbone in
1, in which the P1-P4 units of peptide-type inhibitors
(Figure 1B) were modified by directly linking P1-P3
moieties as shown in another series.9,10 X-ray crystal
structure data of recombinant glycosylated renin with a
representative analogue of 1 revealed favorable hydro-
phobic and hydrogen-bonding interactions within the
configurations rather than methyl or combinations thereof,
as indicated in the generic structure 1.11
Very recently, two synthesis routes to CGP-60536B,
an analogue of 1 (where R1 ) 2,2-dimethylpropionamide,
R2, R3 ) dialkoxy; R4, R5 ) isopropyl), representing
original efforts at ex.Ciba-Geigy in Basel12 and the U.K.,13
respectively, were published. Both groups utilized a
convergent approach where a derivative of 2R-isopropyl-
4R-hydroxymethylbutyrolactone, obtained by auxiliary-
mediated asymmetric alkylation14 of appropriate amide
enolates, was a key chiron. Despite the need for chro-
matographic separation of mixtures of diastereomers, it
was possible to develop viable routes to the target
structure. The source of nitrogen in the â-hydroxy amino
alcohol portion of 1 was azide ion, introduced via an SN2-
type inversion of a suitably protected diol intermediate.
A third synthesis was based on nitrone chemistry, and
led to the target compound as a minor diastereomer.15
A
synthesis of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-
8-aryloctanoylamides has been reported in the recent
patent literature.16
We report herein a full account of our efforts toward
the development of stereocontrolled synthesis routes
aimed at the generic structure 1, while allowing flexibility
for variations in the aromatic substituents and the nature
of the amide moiety. In considering various practical
approaches, we chose to capitalize on a synthesis plan
that utilizes readily available N-containing chiral tem-
plates as starting materials, thus avoiding the potential
hazards of azide reagents. Added to this daunting task
was the desire to combine practicality with innovation,
even if the project was an academically based endeavor.17
S
3-S2′ subsites, which were not utilized by peptidic
inhibitors.11 Extensive optimization of the backbone
appendages in the 8-aryloctanoic acid motif revealed a
distinct preference for two isopropyl groups with 2R,7R-
(11) Rahuel, J .; Rasetti, V.; Maibuam, J .; Ru¨egger, H.; Go¨schke, R.;
Cohen, N. C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood, J . M.; Gru¨tter,
M. G. Chem. Biol. 2001, 7, 493.
(12) Ru¨egger, H.; Stutz, S.; Go¨schke, R.; Spindler, F.; Maibuam, J .
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(8) (a) Go¨schke, R.; Cohen, N. C.; Wood, J . M.; Maibuam, J . K.
Bioorg. Med. Chem. Lett. 1997, 7, 2735. (b) Go¨schke, R.; Maibaum, J .
K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N. C.;
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1982, 104, 1737.
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2001, 42, 4819.
(16) Herold, P.; Stutz, S.; Indolese, A. WO 109083, Feb 8, 2001.
(17) For a previous approach, see: Hanessian, S.; Raghavan, S.
Bioorg. Med. Chem. Lett. 1994, 4, 1696.

Stereocontrolled Approaches to CGP-60536B
J . Org. Chem., Vol. 67, No. 12, 2002 4263
F igu r e 2.
The retrosynthetic analysis of an 8-aryl-2R-isopropyl-
3S-hydroxy-4S-amino-6S-isopropyloctanoic acid amide
representing the prototypical structure of 1 (R2 = H,
p-methoxy; R3 = H; R4, R5 ) isopropyl) is shown in Figure
2. Inspection of the generic backbone structure of 1 with
the required substituents reveals that it may be derived
from 2 by two logical disconnections, involving cleavage
of the lactam and the hydrogenolysis of the N-benzyl
bond in the pyrrolidine motif (Figure 2). The alcohol 2
may, in turn, be obtained by a simple diastereoselective
reduction of ketolactam 3, originating from an intra-
molecular Dieckmann cyclization reaction between the
two ester moieties of 4. To simplify the process, our
original plan called for the utilization of a racemic 2-
isopropyl succinate side chain as in 4, with the hope
that the correct stereochemistry could be attained by
equilibration of the unwanted isomer en route to the
intended target 3. Amide 4 would be obtained from
the pyrrolidine 5, itself synthesized from pyrrolidinone
6 via the diastereoselective addition of aryl cuprates18
to an intermediate iminium ion precursor.19 Finally,
pyrrolidinone 6 would be prepared from the readily
available L-pyroglutamic acid20 by a stereocontrolled
introduction of the isopropyl group. The synthesis plan
shown in Figure 2 presented a number of practical
advantages, in addition to being innovative in design.
The principle of using conformational constraint to
control stereochemistry, as well as to avoid protective
group manipulations, is particularly noteworthy in this
strategy. It is also of heuristic interest to point out the
value of visual imagery in synthesis planning.21 Depicting
the familiar acyclic representation of the target structure
1 as one whose backbone overlaps better visually with
the bicyclic lactam 2 reveals a strategy that may not have
been so obvious otherwise. Once assembled as 2, it would
suffice to cleave two bonds, thereby unveiling the in-
tended acyclic target structure 1. Attractive as this
Dalie`sque synthetic plan appeared to be,22 it was impera-
tive to test its feasibility, particularly as related to
stereochemistry issues and overall efficacy.
Resu lts
The first task in this synthesis was the introduction
of the 2R-isopropyl group in a suitably protected L-
pyroglutamic acid. Unlike many examples of lactam
enolate alkylations with reactive halides such as methyl,
benzyl, or allyl in a pyroglutamic ester motif,23 the
introduction of an isopropyl group has few precedents.24
In fact, the treatment of the lithium, potassium, or
magnesium enolates of N-Boc-L-pyroglutamic acid methyl
ester 7 (Scheme 1) with isopropyl iodide failed to give
any of the desired 4-isopropylated lactam. We were
successful in adding acetone to the lithium enolate of 7
to give 8 in 85% yield as a 5:1 mixture of anti- and syn-
isomers, respectively, with no evidence of racemization
of the ester.25 The diastereoselectivity of the acetone
addition reaction could be raised to >10:1 in favor of the
desired anti-isomer by using the bulkier benzylhydryl
ester to direct the approach of the electrophile. It was
decided to proceed with the methyl ester and to separate
diastereomers further downstream. Moreover, we sur-
mised that the methyl ester would be a better intermedi-
ate in the intended intramolecular Dieckmann conden-
sation. Thus, protection of the tertiary alcohol of the 5:1
(22) For fascinating examples of concealed imagery in Salvador
Dali’s work, see, for example: (a) Slave Market with Visible Bust of
Voltaire, 1940, Dali Museum, St. Petersburg, FL. (b) Gala Looking at
the Mediterranean Sea-Concealed Portrait of Lincoln, 1976, Minami
Museum, Tokyo.
(23) See, for example: (a) Ezquerra, J .; Pedergal, C.; Yruretagoyena,
B.; Rubio, A.; Carreno, M. C.; Escribano, A.; Ruano, J . L. G. J . Org.
Chem. 1995, 60, 2925. (b) Brena-Valle, L. J .; Sanchez, R. C.; Cruz-
Almanza, R. Tetrahedron Lett. 1996, 37, 1019. (c) Dorsey, B. D.; Levin,
R. B.; McDaniel, S. L.; Vacca, J . P.; Guare, J . P.; Darke, P. L.; Zugay,
J . A.; Emmi, E. A.; Schleif, W. A.; Quintero, J . C., Liu, J . H.; Chen,
I.-W.; Holloway, H. K.; Fitzegerald, P. M. D.; Axel, M. G.; Ostovic, D.;
Anderson, P. S.; Huff, J . R. J . Med. Chem. 1994, 37, 3445. (d) Maldaner,
A.; Pilli, R. A. Tetrahedron 1999, 55, 13321. (e) Charrier, J .-D.; Duffy,
J . E.; Hitchcock, P. B.; Young, D. W. Tetrahedron Lett. 1998, 39, 2199.
(24) For lactone enolates, see: Takahashi, Y.; Hasegawa, S.; Izawa,
T.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1986, 34, 3020. For
lactam enolates, see: Meyers, A. I.; Wallace, R. H.; Harre, M.; Garland,
R. J . Org. Chem. 1990, 55, 3137.
(25) For examples of aldol reactions with lactam enolates, see: (a)
Dikshit, D. K.; Panday, S. K. J . Org. Chem. 1992, 57, 1920. (b) Dikshit,
D. K.; Bajpai, S. N. Tetrahedron Lett. 1995, 36, 3231. (c) Escribano,
A.; Ezquerra, J .; Pedregal, C.; Rubio, A.; Yruretagoyena, B.; Baker, S.
R.; Wright, R. A.; J ohnson, B. G.; Schoepp, D. D. Bioorg. Med. Chem.
Lett. 1998, 8, 765.
(18) (a) Kemp, D. S.; Renold, P.; McClure, K. F. J . Org. Chem. 1995,
60, 454. (b) Ludwig, C.; Wistrand, L.-G. Acta Chem. Scand. 1990, 44,
707. (c) Skrinjar, M.; Wistrand, L.-G. Tetrahedron 1991, 47, 573. (d)
Thanning, M.; Wistrand, L.-G. Acta Chem. Scand. 1992, 46, 194. (e)
Ludwig, C.; Wistrand, L.-G. Acta Chem. Scand. 1994, 48, 367. (f)
Zietlow, A.; Streckan, E. J . Org. Chem. 1994, 59, 5658. (g) Ce´lime`ne,
C.; Dhimane, H.; Le Bail, M.; Lhommet, G. Tetrahedron Lett. 1994,
35, 6105. (h) Collado, I.; Pedergal, C.; Ezquerra, J . J . Org. Chem. 1995,
60, 5011.
(19) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
(b) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, Chapter 4.5, p 1047.
(20) For a review, see: Najera, C.; Yus, M. Tetrahedron: Asymmetry
1999, 10, 2245.
(21) Hanessian, S.; Franco, J .; Larouche, B. Pure Appl. Chem. 1990,
62, 1887.

4264 J . Org. Chem., Vol. 67, No. 12, 2002
Hanessian et al.
Sch em e 1a
dimethyl sulfide complex, and boron trifluoride diethyl
etherate18i resulted in the formation of an adduct, 13, in
89% yield (Scheme 1). Deprotection of the N-Boc and
ester groups afforded a crystalline proline analogue, 14,
whose structure was ascertained by single-crystal X-ray
crystallography. Contrary to expectations based solely on
steric effects, the phenyl group had been introduced from
a trajectory of attack on the intermediate iminium ion
that was opposite the ester group and syn to the isopropyl
group. The coordination of the ester group with the excess
organometallic reagent, coupled with a possible confor-
mational change as a result of such a steric encumber-
ment, may explain the observed result. It is of interest
that the steric effect imposed by the 4-isopropyl group is
counterbalanced by the bulk of the coordinated ester in
directing the attack on the iminium ion. The formation
of anti-adducts in the reaction of N-Boc iminium ions
derived from L-pyroglutamic esters with organocopper
reagents has been rationalized on the basis of complex-
ation with the ester, resulting in a shielding of the syn-
face.18c,d,h This tendency also overrides the 1,2-induction
of a C-4 substitutent,18h as observed in the case of 13.
However, exceptions to this stereochemical course of anti-
addition can be found.18a
In an alternative approach, we opted to introduce the
phenyl group prior to deoxygenation of the tertiary
alcohol (Scheme 2). In this strategy one would expect the
nucleophile to approach the iminium ion from the side
opposite the bulky metal alkoxide organic complex,
provided excess reagent was used. Thus, treatment of 10
with 5 equiv of the phenylmagnesiocuprate reagent gave
the corresponding adduct 15 in 55% yield as a 5:1 mixture
of diastereomers. Reaction of the alcohol with mesyl
chloride, triethylamine, and DMAP gave the correspond-
ing alkene 17, which could be separated from the minor
syn-isomer by column chromatography. Catalytic hydro-
genation afforded 19 as a single isomer in high overall
yield. There was no evidence of any product arising from
ring opening by hydrogenolysis. Hydrolysis of the ester
with lithium hydroxide gave the acid 21, which after
X-ray analysis showed that the phenyl group had, in fact,
added to the iminium ion in an anti fashion to the alkoxy
isopropyl group. The same sequences were performed in
the p-methoxyphenyl series to give 16, which was further
transformed to 20 as described for the phenyl analogue
(Scheme 2). With both 4,5-syn-proline 14 and 4,5-anti-
prolines 19 and 20, available in enantiopure form, we
turned to the introduction of the second isopropyl group
and to test the prospects of a Dieckmann cyclization.29
It was interesting that a cursory literature search for
carrying out the synthesis of substituted indolizidinones
such as 3 (Figure 2) by a Dieckmann cyclization showed
no precedents,30 which heightened our interest to pursue
this strategy. The more directly accessible 4,5-anti-
proline analogue 19 was investigated. Removal of the Boc
group, and converting the resulting product to the
monobenzyl 2-isopropylsuccinamide 22 proceeded smoothly
to give a 1:1 mixture of diastereomers (Scheme 3).
a
Reagents and conditions: (a) LiHMDS, -78 °C, THF, then
acetone, 85%; (b) TMSCl, imidazole, DCM, 70%; (c) DIBAL, -78
°C, THF, then MeOH, pTSA, 95%; (d) MsCl, DMAP, Et3N, 72%;
separation of minor syn-isomer; (e) H2, Pd/C, EtOAc, NaHCO3,
82%; (f) PhMgBr, CuBr-Me2S, BF3‚OEt2, THF, 89%; (g) LiOH,
THF/H2O; (h) HCl, dioxane, 80% (two steps).
mixture of diastereomers 8 as a TMS ether afforded 9,
which was reduced with DIBAL-H to give the corre-
sponding mixture of hemiaminals. Subsequent treatment
with acidic methanol afforded the methoxy analogue 10
in high overall yield. Mesylation of 10, followed by base-
catalyzed elimination, proceeded regioselectively to give
the alkene 11 exclusively, which could be separated from
the minor syn-2-propenyl isomer by chromatography.
Hydrogenation over Pd/C in the presence of sodium
carbonate gave the desired O-methyl hemiaminal 12 in
excellent yield. An alternative synthesis of 12 in our
laboratory relied on a radical-induced deoxygenation26,27
of the half methyloxalate ester of 8.28 Thus, we had
successfully introduced an isopropyl group with the
desired regio- and enriched stereochemistry in six high-
yielding steps starting from the readily available 7. The
next task was to explore methods for the introduction of
an aryl group following the synthesis plan outlined in
Figure 1. We focused on introducing phenyl and p-
methoxyphenyl groups as prototypes, and further explor-
ing chemistry toward the elaboration of the generic
structure 1. Thus, treatment of 12 with 4 equiv of a
mixture of phenylmagnesium bromide, copper bromide-
Subsequent treatment with KHMDS at -50 °C gave
a bicyclic product, 23, which after hydrogenolysis and
decarboxylation was converted to 24, isolated as a single
isomer in only 30% yield. Numerous attempts at improv-
ing the yield by variations of bases proved futile. Having
reached this stage in our planned sequence, we decided
to continue the synthesis despite this apparent setback.
(26) Dolan, S. C.; MacMillan, J . J . Chem. Soc., Chem. Commun.
1985, 1588. See also ref 4h.
(27) Hanessian, S.; Abad-Grillo, T.; McNaughton-Smith, G. Tetra-
hedron 1997, 53, 6281.
(28) Hanessian, S.; McNaughton Smith, G. Unpublished results.

Stereocontrolled Approaches to CGP-60536B
J . Org. Chem., Vol. 67, No. 12, 2002 4265
Sch em e 2a
a
Reagents and conditions: (a) PhMgBr (or p-MeOC6H4Li, CuBr-Me2S, BF3‚OEt2, THF; (b) MsCl, DMAP, Et3N; (c) H2, 10% Pd/C,
EtOAc; (d) LiOH, MeOH, H2O, 95%.
Sch em e 3a
Reduction of the carbonyl group in 24 with L-Selectride
gave the corresponding alcohol whose structure and
absolute stereochemistry were definitively shown to be
25 on the basis of a single-crystal X-ray analysis. Except
for an important stereochemical caveat revealed in the
opposite orientation of the new isopropyl group, we had
indeed succeeded in elaborating the entire carbon skel-
eton and required functionalities in 1. Each chemical step
leading to the bicyclic product 25 had proceeded with
excellent stereoselectivity, thus validating to a large
measure our original synthetic plan (Figure 2). Attempts
to epimerize the 2S-isopropyl-bearing carbon using a
variety of conditions31 resulted in the recovery of starting
material with no trace of the desired epimer. A simple
rationalization of the results is illustrated in Scheme 4.
On the basis of the presence of equal proportions of
amides 22a and 22b, it is clear why isomer 23, possibly
arising from a hypothetical chairlike conformation in the
pro-S-isomer 22a with a predisposed pseudoequatorial
isopropyl group, is the observed product. An analogous
(29) For examples of monocyclic nitrogen heterocycles, see: (a)
Blake, J .; Willson, C. D.; Rapoport, H. J . Am. Chem. Soc. 1964, 86,
5293. (b) Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992,
48, 1145. (c) Toda, F.; Suzuki, T.; Higa, S. J . Chem. Soc., Perkin Trans.
1 1998, 3521. (d) Sibi, M. P.; Christensen, J . W.; Kim, S.-G.; Eggen,
M.; Stessman, C.; Oien, L. Tetrahedron Lett. 1995, 36, 6209. (e) Knight,
D. W.; Lewis, N.; Share, A. C.; Haigh, D. J . Chem. Soc., Perkin Trans.
1 1998, 3673. (f) Ma, D.; Sun, H. Tetrahedron Lett. 1999, 40, 3609.
For examples of bicyclic and polycyclic nitrogen heterocyles, see: (g)
a
Leonard, N. G.; Fulmer, R. W.; Hay, A. S. J . Am. Chem. Soc. 1956, 78,
3457. (h) Davies, W. A. M.; Pinder, A. R.; Morris, I. G. Tetrahedron
1962, 18, 405. (i) Holden, R. T.; Raper, R. J . Chem. Soc. 1963, 2545.
(j) Beckett, A. H.; Lingard, R. G.; Theobald, A. E. E. J . Med. Chem.
1969, 12, 563. Fulmer, R. W.; Hay, A. S. J . Am. Chem. Soc. 1956, 78,
3457. (k) Gensler, W. J .; Hu, M. W. J . Org. Chem. 1973, 38, 3848. (l)
Howard, A. S.; Gerrans, G. C.; Meerholtz, C. A. Tetrahedron Lett. 1980,
21, 1373. (m) Hatamaka, M.; Ishimaru, T. Tetrahedron Lett. 1983, 24,
4837. (n) J ackson, B. G.; Gardner, J . P.; Heath, P. C. Tetrahedron Lett.
1990, 31, 6317. (o) Neyer, G.; Ugi, I. Synthesis 1991, 743. (p) Bureau,
R.; Mortier, J .; J oucla, M. Tetrahedron 1992, 48, 8947. (q) Liu, R.;
Castelles, J .; Rapoport, H. J . Org. Chem. 1998, 63, 4069. (r) Andrews,
M. D.; Brewster, A. G.; Crapnell, K. M.; Ibbett, A. J .; J ones, T.;
Moloney, M. G.; Prout, K.; Watkin, D. J . Chem. Soc., Perkin Trans. 1
1998, 223. (s) Li, J .; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens,
D.; Grubisha, D.; Bennett, D.; Cook, J . M. J . Am. Chem. Soc. 1999,
121, 6998. (t) Harrison, J . R.; O’Brien, P.; Porter, D. W.; Smith, N. M.
J . Chem. Soc., Perkin Trans. 1 1999, 3623. (u) Haudrechey, A.;
Chassaing, C.; Riche, C.; Langlois, N. Tetrahedron 2000, 56, 3181.
(30) For the synthesis of indolizidinones and pyrrolizidinones by
Dieckmann condensations of proline-derived precursors, see refs 29t
and 29k,p, respectively.
Reagents and conditions: (a) TFA, toluene, 95%; (b) BOPCl,
iPr2NEt, HO2CCH(CHMe2)CH2CO2Bn, 85%; (c) KHMDS, THF,
-50 °C; (d) H2, Pd/C, 30% (two steps); (e) L-Selectride, THF, -78
°C, 60%.
pathway from the enolate formed from the desired pro-
R-isomer 22b would be unfavorable (Scheme 4).
Considering the modest 30% yield in the Dieckmann
cyclization, and excluding the possibility of equilibration
between the two isomers via the corresponding enolate
prior to cyclization, we assumed that the ester enolate
of the pro-R-isomer 22b must follow a different course
during the reaction, leading to unidentified products. To
lend credence to this supposition, we prepared 22b inde-
pendently, and subjected it to a Dieckmann cyclization
under the same conditions as for the mixture (Scheme
5). A complex mixture of unidentifiable products was
obtained with no trace of the expected bicyclic lactam 23.
(31) Baker, W. R.; Pratt, J . K. Tetrahedron 1993, 49, 8739.

4266 J . Org. Chem., Vol. 67, No. 12, 2002
Hanessian et al.
Sch em e 4
Sch em e 5a
moiety as the N-Boc derivative afforded the lactone 32.
Formation of the lithium enolate and treatment with
acetone afforded the corresponding adduct 33 as a single
isomer. Treatment of 33 with phosphorus pentachloride
in dichloromethane,33 in the absence of base, gave the
side chain alkene derivative 34 in excellent yield. Reduc-
tion of the double bond, followed by ring opening of the
resulting lactone 35 with 2-propylamine in the presence
of trimethylaluminum,34 and catalytic hydrogenation
afforded the prototypical target 36.
We turned our attention to an alternative route that
utilized the disubstituted proline scaffolds prepared from
L-pyroglutamic acid (Scheme 7). The reaction of the
p-methoxyphenyl derivative 20 with the lithium salt of
dimethyl methylphosphonate35 gave the corresponding
phosphonate in 88% yield. Horner-Emmons-Wadsworth
reaction in the presence of LiCl36 with methyl glyoxal
gave the unsaturated ester 38 as a mixture of cis- and
trans-isomers in 68% yield. Hydrogenation of the
double bond and subsequent reduction of both the ester
and the ketone groups with sodium borohydride in
methanol gave the diol 39 in 88% yield as a single
diasteroisomer, as ascertained by 1H NMR. Selective
oxidation of the primary alcohol with TEMPO and iodo-
benzene diacetate37 gave the corresponding lactone 40 in
75% yield. We were now poised to introduce the isopropyl
group via the corresponding lithium enolate as in the
phenyl series (Scheme 6). Thus, treatment of 40 with
LiHMDS, followed by addition of acetone, gave the aldol
product 41 as a single isomer in 87% yield. Treatment
of 41 with phosphorus pentachloride33 at -60 °C in
dichloromethane in the absence of added base gave the
desired alkene 42 in 80% yield, whose structure and
absolute configuration were ascertained by X-ray crystal-
lographic analysis. The remaining steps followed closely
the chemistry already described in Scheme 6. In this
series, we opened the lactone ring with 1-butylamine8,38
in the presence of trimethylaluminum34 to afford the
amide 43 in 75% yield.
a
i
Reagents and conditions: (a) Zn, PrOH, H2O, 60%; (b) OsO4/
NaIO4, then J ones oxidation; (c) BnOH, EDC, Et3N, DCM, 40%
(three steps).
This could account for the modest yield of cyclization
when the mixture of 2-isopropyl-2R- and 2-isopropyl-2S-
succinates 22a and 22b was used in the Dieckmann
reaction, since only the 2S-isomer reacted. The synthesis
of enantiopure succinate 28 from a known precursor27 is
shown in Scheme 5.
At this juncture, we decided to introduce the second
isopropyl group later in the sequence, without compro-
mising the original plan shown in Figure 2 (Scheme 6).
Removal of the N-Boc group in 19 followed by amide
formation with succinic acid monobenzyl ester afforded
29. In this case Dieckmann cyclization was best achieved
using sodium tert-pentoxide as a base. However, the yield
of the product 30 after decarboxylation was modest. In
the presence of other bases (NaH, KH, LiHMDS) yields
were substantially lower. Clearly the possibility of mul-
tiple enolate formation sites and different reactivities
must be controlling factors in the Dieckmann cyclizations
of polysubstituted proline analogues such as 29. Never-
theless, we continued this sequence with the phenyl
analogue 30. Reduction with L-Selectride afforded the
alcohol 31 as the only detectable isomer (NMR). Treat-
ment with hydrochloric acid in methanol resulted in the
hydrolysis of the lactam to afford the corresponding
lactone hydrochloride.32 Protection of the pyrrolidine
(33) Rehders, F.; Hoppe, D. Synthesis 1992, 859.
(34) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 2815.
(35) Chakravarty, P. K.; Combs, P.; Roth, A.; Greenlee, W. J .
Tetrahedron Lett. 1981, 28, 611.
(36) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(32) For a related acid-catalyzed lactam to lactone transformation,
see: Plata, D. J .; Leanna, M. R.; Morton, H. E. Tetrahedron Lett. 1991,
32, 3623.
(37) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J . Org. Chem. 1997, 62, 6974.

Stereocontrolled Approaches to CGP-60536B
J . Org. Chem., Vol. 67, No. 12, 2002 4267
Sch em e 6a
a
Reagents and conditions: (a) TFA, benzene, quantitative; (b) BOPCl, Et3N, iPr2NEt, HO2C(CH2)2CO2Bn, 85%; (c) sodium tert-pentoxide,
THF, -20 °C, then H2, 10% Pd/C, 46%; (d) L-Selectride, -78 °C, THF, 66%; (e) concentrated HCl, MeOH, reflux, then Boc2O, 60%; (f)
LiHMDS, -78 °C, THF, then acetone, 85%; (g) PCl5, DCM, 80%; (h) H2, 10% Pd/C, EtOAc, 90%; (i) NH2CHMe2, AlMe3, DCM; (j) H2, 10%
Pd/C, EtOAc, 60 psi, 3 days, 50% (two steps).
Sch em e 7a
a
i
Reagents and conditions: (a) MePO(OMe)2, nBuLi, THF, -78 °C, 88%; (b) CHOCO2Me, LiCl, MeCN, Pr2NEt, 68%; (c) H2, 10% Pd/C,
EtOAc, 90%; (d) NaBH4, MeOH, 88%; (e) TEMPO, DCM, PhI(OAc)2, 75%; (f) LiHMDS, THF, -78 °C, then acetone, 87%; (h) PCl5, DCM,
-60 °C, 80%; (i) H2, 10% Pd/C, EtOAc, 90%; (j) nBuNH2, AlMe3, DCM, 75%; (k) H2, 10% Pd/C, MeOH, 3 days, 60%.
Finally, cleavage of the pyrrolidine N-benzyl bond with
10% Pd/C under an atmosphere of hydrogen at 60 psi
gave the intended prototype 44 in 60% yield. The same
sequence was adopted in the case of the syn-oriented
analogue 45, prepared essentially as described for the
phenyl analogue 13 (Scheme 1). The sequence proceeding
through the steps shown in Scheme 8 led to the lactone
intermediate 49, which was transformed to the n-butyl
amide 50. Unfortunately, the same conditions that
resulted in smooth hydrogenolysis of the pyrrolidine
N-benzyl bond in 35 and 43 were not successful with 50.
A survey of other catalysts and conditions were tried,
but only unchanged starting material was recovered (10%
Pd/C, 10% Pd(OH)2, Pd black in methanol, at 60 psi for
3 days).
We have reported our strategies for the stereocon-
trolled synthesis of 2R-isopropyl-4S-hydroxy-5S-amino-
7S-isopropyl-8-aryloctanoic acid amides representing the
generic renin inhibitor structure 1, starting from the
readily available L-pyroglutamic acid. The resident chiral-
ity in this versatile template was efficiently exploited to
control the stereochemistry of the 4R-isopropyl group and
to introduce the 5-aryl group, as well as being the source
of the 5-amino group in the target structures (Schemes
1 and 2). The difficulty in achieving lactam enolate
alkylations with 2-propyl halides was circumvented by
an aldol-type condensation with acetone, followed by
(38) See, for example: (a) Poss, M. A.; Reid, J . A. Tetrahedron Lett.
1992, 33, 1411. (b) Kotsuki, H.; Miyazaki, A.; Ochi, M. Tetrahedron
Lett. 1991, 32, 4503.

4268 J . Org. Chem., Vol. 67, No. 12, 2002
Hanessian et al.
Sch em e 8a
in the usual way using silica gel (40-60 µm). Melting points
are uncorrected.
4R- a n d 4S-(1-Hyd r oxy-1-m eth yleth yl)-5-oxop yr r oli-
d in e-1,2S-d ica r boxylic Acid 1-ter t-Bu tyl Ester 2S-Meth yl
Ester , 8. To a solution of 7 (15 g, 61.7 mmol) in dry THF (600
mL) at -78 °C was added LiHMDS (62.6 mL, 62.6 mmol, 1 M
solution in THF), and the mixture was stirred at -78 °C for 2
h. Dry acetone (17.6 g, 5 equiv, 0.3 mol) was then added, and
the mixture was stirred at -78 °C for an additional 4 h. The
reaction mixture was quenched with saturated ammonium
chloride solution and allowed to warm to room temperature.
The organic phase was separated, and the aqueous phase was
extracted with ethyl acetate (3 × 100 mL). The organic extracts
were combined, dried over anhydrous sodium sulfate, and then
filtered. The solvent was removed, and the residual pale yellow
oil consisted of a 5:1 mixture of 8 and its 4-epimer, which was
used directly without further purification (18.5 g, quantita-
tive): 1H NMR (300 MHz, CDCl3) δ 4.56 (dd, 1H, J ) 2, 9 Hz),
3.77 (s, 3 H), 2.79 (dd, 1H, J ) 9, 12 Hz), 2.10 (m, 2 H), 1.48
(s, 9H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 174.9, 171.4, 148.9, 83.9, 71.0, 56.5, 52.6, 51.1, 27.8, 25.1,
24.9; LRMS (m/z) (M+ + 1) 302.2.
4R- a n d 4S-(1-Meth yl-1-tr im eth ylsila n yloxyeth yl)-5-
oxop yr r olid in e-1,2S-d ica r boxylic Acid 1-ter t-Bu tyl Ester
2S-Meth yl Ester , 9. To a solution of 8 (18.5 g, 61.4 mmol) in
dry dichloromethane (600 mL) was added imidazole (4.54 g, 2
equiv, 0.13 mol), and the mixture was stirred for 5 min.
Chlorotrimethylsilane (6.48 g, 60 mmol) was then added in
one portion, and the mixture was stirred at 0 °C for 2 h. The
reaction mixture was then filtered, and the filtrate was washed
rapidly with distilled water (30 mL). The organic layer was
dried over anhydrous sodium sulfate and filtered, and the
solvent was removed under reduced pressure to give a yellow
oil which was used without further purification (16.04 g,
70%): 1H NMR (300 MHz, CDCl3) δ 4.52 (dd, 1H, J ) 2, 9
Hz), 3.77 (s, 3H), 2.55 (m, 1H), 2.37 (m, 1H), 2.01 (m, 1H),
1.48 (s, 9H), 1.42 (s, 3H), 1.38 (s, 3H), 0.09 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 172.6, 172.2, 149.0, 83.1, 74.5, 57.0, 52.9,
52.3, 29.8, 27.8, 26.1, 24.4, 2.2; MS (m/z) (M+ + 1) 374.2; HRMS
(m/z) (M+ + 1) calcd for C17 H31NO6Si 374.1982, found
374.1999.
a
Reagents and conditions: (a) p-MeOC6H4Li, CuBr-Me2S,
BF3‚OEt2, 70%; (b) MePO(OMe)2, nBuLi, THF, -78 °C, 80%; (c)
CHOCO2Me, LiCl, MeCN, iPr2NEt, 60%; (d) H2, 10% Pd/C, EtOAc,
90%; (e) NaBH4, MeOH, then pTSA, toluene, reflux, 40%; (f)
LiHMDS, THF, -78 °C, then acetone, 66%; (g) PCl5, DCM, -60
°C, 62%; (h) H2, 10% Pd/C, EtOAc, 95%; (i) nBuNH2, AlMe3, DCM,
60%.
elimination to a 2-propenyl appendage, and subsequent
reduction. Further chemical elaboration of the 4,5-
disubstituted proline analogues afforded the enantiopure
8-aryl-7-isopropyl-5-amino-4-hydroxyoctanoic acid skel-
eton disguised as a pyrrolidinolactone, 40. Stereocon-
trolled enolate alkylation with acetone as a 7S-isopropyl
equivalent, amide formation, and cleavage of the benzylic
pyrrolidine bond led to the intended targets exemplified
by 36 and 44. The entire sequence shown in Schemes 1,
2, and 7 adopting the “â-ketophosphonate” route consti-
tutes 18 linear steps starting with N-Boc-pyroglutamic
acid methyl ester and proceeds in an overall yield of 2.5%.
Several intermediates were crystalline, and purifications
were easily accomplished in other cases.
Although the original plan as outlined in Figure 2 could
not be realized past the Dieckmann cyclization step, it
served as a visual stimulus to devise alternative strate-
gies that were successfully executed. The implementation
of these and related strategies to other aryl-substituted
congeners of 1, and variations in the amide portion,
should prove useful in further fine-tuning the biological
profile of this class of novel inhibitors of renin.
4R- a n d 4S-(1-Hyd r oxy-1-m eth yleth yl)-5-m eth oxyp yr -
r olid in e-1,2S-d ica r boxylic Acid 1-ter t-Bu tyl Ester 2S-
Meth yl Ester , 10. To a solution of 9 (16.0 g, 42.9 mmol) in
dry THF (400 mL) was added at -78 °C DIBAL-H (80 mL, 80
mmol, 1 M solution in toluene), and the mixture was stirred
at that temperature for 2 h. The reaction mixture was
quenched with distilled water, and the organic solvents were
removed under vacuum. The residue was suspended in 3 M
NaOH solution, and the suspension was rapidly washed with
ethyl acetate (3 × 150 mL). The organic extracts were
combined, dried over anhydrous sodium sulfate, and filtered.
The solvent was removed under reduced pressure to give the
hemiaminal (15 g, 40 mmol) as a yellow oil which was dissolved
in dry methanol (150 mL), pTSA(cat.) was added, and the
mixture was stirred overnight. Solid sodium bicarbonate was
added, and the mixture was stirred for 20 min before the
solvent was removed under vacuum. The residue was dissolved
in ethyl acetate and washed with distilled water. The organic
phase was dried over anhydrous sodium sulfate and filtered,
and the solvent was removed under reduced pressure to give
a yellow oil. The oil was dissolved in benzene, and any residual
water was removed azeotropically. The oil was then used
directly without further purification (11.4 g, 95%): IR (neat)
3516, 2976, 1750, 1710, 1479, 1458, 1438, 1368, 1300, 1203
Exp er im en ta l Section
Gen er a l P r oced u r es. All commercially available reagents
were used without further purification. Solvents were distilled
under positive pressure of dry nitrogen before use, THF and
ether were distilled from K/benzophenone, and CH2Cl2 and
toluene were distilled from CaCl2. NMR (1H, 13C, 31P) spectra
were recorded on 300, 400, and 600 MHz spectrometers in
CDCl3, and DEPT experiments were performed routinely. Low-
and high-resolution mass spectra were measured using fast
atom bombardment (FAB) or electrospray techniques. Optical
rotations were measured at the sodium line at ambient
temperature. Flash column chromatography39 was performed
cm-1
.
4S-Isop r op yl-5S-p h en ylp yr r olid in e-1,2S-d ica r boxylic
Acid 1-ter t-Bu tyl Ester 2S-Meth yl Ester , 13. To a solution
of 10 (1.0 g, 3.15 mmol) in DCM (50 mL) were added DMAP
(15.4 g, 12.6 mmol), triethylamine (12.7 g, 12.6 mmol), and
MsCl (14.4 g, 12.6 mmol), and the reaction mixture was stirred
overnight. The solvent was removed under reduced pressure,
(39) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Stereocontrolled Approaches to CGP-60536B
J . Org. Chem., Vol. 67, No. 12, 2002 4269
1
and the crude was dissolved in ethyl acetate and washed
sequentially with dilute HCl, saturated NaHCO3, and brine.
The organic layer was dried over anhydrous sodium sulfate
and filtered. The solvent was removed under reduced pressure,
and the crude was purified by column chromatography (1:9
ethyl acetate/hexane) to separate the minor 4R-isomer to give
11 as a colorless oil (0.68 g, 72%). To a solution of 11 (600 mg,
2.0 mmol) in ethyl acetate were added solid sodium bicarbon-
ate (large excess) and 10% Pd/C. The reaction mixture was
stirred under an atmosphere of hydrogen gas. The solids were
removed by filtration, and the solvent was removed to give 12
as a colorless oil, which was used without further purification
(500 mg, 82%). To a suspension of copper(II) bromide-
dimethyl sulfide complex (1.22 g, 4.4 equiv, 5.95 mmol) in
anhydrous ether (5 mL) at -78 °C was added phenylmagne-
sium bromide (5.95 mL, 4.4 equiv, 5.95 mmol), and the reaction
mixture was stirred at -40 °C for 45 min. BF3‚OEt2 (0.84 mL,
4.4 equiv, 5.95 mmol) was added at -78 °C, and the mixture
was stirred for a further 30 min. The aminal 12 (0.41 g, 1.36
mmol) was then added, and the reaction mixture was stirred
at -78 °C for 1 h and then slowly warmed to room tempera-
ture. The reaction mixture was quenched with a 1:1 mixture
of NH4OH/NH4Cl and extracted with EtOAc. The combined
organic extracts were washed with brine and dried over
anhydrous sodium sulfate. The mixture was concentrated and
purified by column chromatography (1:4 ethyl acetate/hexane)
to yield 13 (yield 420 mg, 89%): 1H NMR (300 MHz, CDCl3)
δ 7.38-7.10 (m, 5H), 4.97 (and rotamer at 5.1) (d, 1H, J )
7.19 Hz), 4.68 (and rotamer at 4.58) (d, 1H, J ) 10 Hz), 3.78
(s, 3H), 2.35-2.20 (m, 2H), 2.10-2.01 (m, 1H), 1.15 (s, 9H),
0.91-0.85 (m, 4H), 0.78-0.72 (m, 3H); HRMS (m/z) calcd for
(4.97 g, 55%): mp 122-124 °C; [R]D -11.92 (c 1, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.44 (m, 5H), 6.96 (br, 1H), 5.00 (d,
1H, J ) 14 Hz), 4.54 (m, 1H), 3.89 (s, 3H), 2.71-2.40 (m, 3H),
1.21 (s, 3H), 0.97 (s, 3H) (free amine); 13C NMR (75 MHz,
CDCl3) δ 174.0, 153.1, 144.0, 128.3, 128.0, 126.6, 80.1, 71.4,
63.9, 59.5, 57.9, 52.1, 30.2, 28.1, 27.9, 27.7; LRMS (m/z) (M+
+ 1) 364.1; HRMS (m/z) (M+ + 1) calcd for C20H30NO5
364.2130, found 364.2124.
4R- a n d 4S-(1-Hyd r oxy-1-m eth yleth yl)-5R-(4-m eth oxy-
p h en yl)p yr r olid in e-1,2S-d ica r boxylic Acid 1-ter t-Bu tyl
Ester 2S-Meth yl Ester , 16. To a solution of p-bromoanisole
(23.6 g, 0.126 mol) in dry THF (150 mL) at -78 °C was added
n-butyllithium (63.2 mL, 0.126 mol, 2 M in hexanes), and the
reaction mixture was stirred at -78 °C for 20 min. The lithium
reagent was added to a stirring suspension of copper(II)
bromide-dimethyl sulfide complex (26 g, 0.126 mol) at -78
°C in THF (150 mL), and the resultant black solution was
stirred at -78 °C for 1 h. BF3‚OEt2 (35.8 g, 0.25 mol) was then
added in one portion, and the reaction mixture was stirred
for a further 30 min. A solution of 10 as described above (8 g,
25.2 mmol) in dry THF (20 mL) was then added, and the
reaction mixture was then allowed to slowly warm to room
temperature. The black suspension was quenched with a 1:1
mixture of ammonium chloride solution and aqueous ammonia
and extracted with ethyl acetate (4 × 30 mL). The organic
fractions were combined, dried over anhydrous sodium sulfate,
and filtered. The solvent was removed under reduced pressure,
and the resultant yellow oil was purified by column chroma-
tography (1:4 ethyl acetate/hexane) to give a clear oil consisting
of 5:1 mixture of diastereomers (4.56 g, 46%): [R]D - 9.3 (c
1
1.3, CHCl3); H NMR (400 MHz, CDCl3) δ 7.51 (d, 2H, J ) 9
C
20H29NO4 347.2096, found 347.2084.
Hz), 6.84 (d, 2H, J ) 8 Hz), 4.90-4.46 (m, 2H), 3.79 (s, 6 H),
2.40-2.08 (m, 3 H), 1.35-1.10 (m, 15 H); 13C NMR (75 MHz,
CDCl3) δ 173.8, 158.3, 154.2, 136.6, 113. 3, 80.1, 71.2, 63.2,
60.3, 57.8, 55.1, 52.1, 30.1, 28.7, 28.1, 27.9, 27.8; LRMS (m/z)
(M+ + 1) 394; HRMS (m/z) (M+ + 1) calcd for C21H32NO6
394.2236, found 394.2229.
4S-Isop r op yl-5S-p h en yl-1,2S-d ica r boxylic Acid 1-ter t-
Bu tyl Ester , 14. To a solution of 13 (100 mg, 0.29 mmol) in
THF (5 mL) and water (2 mL) was added lithium hydroxide
(24 mg, 2 equiv, 0.57 mmol), and the reaction mixture was
stirred overnight. The THF was removed under vacuum, and
the solution was extracted with diethyl ether and then acidified
to pH 1. The aqueous phase was extracted with ethyl acetate,
the organic extracts were dried over anhydrous sodium sulfate,
and the solvent was removed to give an oil which was treated
with HCl in dioxane overnight. The solvent was removed under
reduced pressure to give an oil which was triturated with
diethyl ether to 14 as a white solid (76 mg, 80%): mp 162-
164 °C dec; 1H NMR (free amino acid) (300 MHz, CDCl3) δ
9.4-8.9 (br s, 2 H), 7.38-7.25 (m, 5H), 5.18 (d, 1H, J ) 7 Hz),
4.91 (s, 1H), 2.40-2.05 (m, 3H), 1.26 (m, 1H), 0.8 (dd, 6H, J )
4, 6 Hz); 13C (free amino acid) (75 MHz, CDCl3) δ 171.5, 132.7,
129.1, 128.6, 128.7, 65.9, 58.6, 49.6, 32.1, 27.6, 21.6, 21.3;
LRMS (m/z) (M+ + 1) 234; HRMS (m/z) (M+ + 1) calcd for
4S-Isop r op en yl-5R-p h en ylp yr r olid in e-1,2S-d ica r box-
ylic Acid 1-ter t-Bu tyl Ester 2S-Meth yl Ester , 17. To a
solution of 15 (3.2 g, 8.77 mmol) in dry dichloromethane (240
mL) were added dry triethylamine (3.56 g, 4 equiv, 35.2 mmol)
and DMAP (4.3 g, 4 equiv, 35.2 mmol), and the mixture was
stirred for 5 min at 0 °C. Methanesulfonyl chloride (4.01 g, 4
equiv, 35.2 mmol) was slowly added, and the deep red solution
was allowed to stir at room temperature overnight. The
reaction mixture was quenched by the addition of ammonium
chloride solution (20 mL) and ethyl acetate (100 mL). The
organic phase was separated, and the aqueous phase was
washed with ethyl acetate (3 × 100 mL). The organic layers
were combined, dried over anhydrous sodium sulfate, and
filtered. The solvent was removed under vacuum, and the
crude red oil was purified by column chromatography (1:9 ethyl
acetate/hexane) to give 17 as a colorless oil which solidified
on standing (2.46 g, 81%): mp 46-48 °C; [R]D -36.4 (c 0.9,
C
14H20NO2 234.1485, found 234.1494.
4R- a n d 4S-(1-Hyd r oxy-1-m eth yleth yl)-5R-p h en ylp yr -
r olid in e-1,2S-d ica r boxylic Acid 1-ter t-Bu tyl Ester 2S-
Meth yl Ester , 15. Copper(II) bromide-dimethyl sulfide com-
plex (20.4 g, 99.6 mmol) was suspended in dry THF (450 mL),
and the mixture was cooled to -40 oC. Phenylmagnesium
bromide (99.6 mL, 99.6 mmol, 1 M in THF) was then added
slowly at such a rate so as to keep the reaction temperature
between -40 and -30 °C. After complete addition of the
Grignard reagent, the yellow suspension was stirred at -30
°C for 1 h. The reaction mixture was then cooled to -78 °C
whereupon BF3‚OEt2 (14.04 g, 99 mmol) was added, and the
mixture was stirred at this temperature for 30 min. A solution
of 10 (7.5 g, 24.8 mmol) in dry THF (60 mL) was then added,
and the mixture was allowed to slowly warm to room temper-
ature and then stirred for 1 h. The black suspension was
quenched with a 1:1 mixture of aqueous ammonia and am-
monium chloride (60 mL), and the THF was removed under
vacuum. The residue was dissolved in diethyl ether (100 mL)
and washed with ammonium chloride solution. The aqueous
phase was extracted with diethyl ether (3 × 100 mL), and the
organic extracts were combined, dried over anhydrous sodium
sulfate, and then filtered. The solvent was removed, and the
dark oil was purified by column chromatography (1:4 ethyl
acetate/hexane) to afford 15 (5:1 mixture) as an off-white solid
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.53-7.17 (m, 5H), 4.8
(br, 1H), 4.67 (br, 1H), 4.3 (dd, 2H, J ) 9, 20 Hz), 3.84 (s, 3H),
3.76 (d, 1H, J ) 3 Hz), 2.84 (m, 1H), 2.15 (m, 2H), 1.75-1.09
(br m, 11H); 13C NMR (75 MHz, CDCl3) δ 173.5, 143.0, 127.8,
127.6, 126.6, 125.9, 113.0, 80.3, 66.4, 59.1, 54.9, 52.1, 33.4, 28.1,
27.8, 20.2; MS (m/z) (M+ + 1) 346; HRMS (m/z) (M+ + 1) calcd
for C20H28NO4 346.2013, found 346.2018.
4S-Isopr open yl-5R-(4-m eth oxyph en yl)pyr r olidin e-1,2S-
d ica r boxylic Acid 1-ter t-Bu tyl Ester 2S-Meth yl Ester , 18.
To a solution of 16 (3.1 g, 7.9 mmol) in dry dichloromethane
(200 mL) were added dry triethylamine (3.19 g, 4 equiv, 31.6
mmol) and DMAP (3.86 g, 4 equiv, 31.6 mmol), and the
mixture was stirred for 5 min at 0 °C. Methanesulfonyl
chloride (3.6 g, 4 equiv, 31.6 mmol) was then slowly added,
and the deep red solution was allowed to stir at room
temperature overnight. The reaction mixture was quenched
by the addition of ammonium chloride solution (20 mL) and
ethyl acetate (100 mL), and the organic phase was separated
and processed as described for 17 to give a red oil which was
purified by column chromatography (1:9 ethyl acetate/hexane)
to give 18 as a colorless oil (2.40 g, 81%): [R]D -12.55 (c 1,

4270 J . Org. Chem., Vol. 67, No. 12, 2002
Hanessian et al.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.35 (d, 2H, J ) 8 Hz),
127.1, 126.5, 66.2, 59.4, 55.6, 52.0, 45.2, 44.2, 33.3, 31.7, 29.7,
28.7, 28.2, 21.6, 20.8, 20.6, 18.9, 17.9, 14.0; LRMS (m/z) (M+
+ 1) 480; HRMS (m/z) (M+ + 1) calcd for C29H38NO5 480.2762
found 480.2750.
6.74 (d, 2H, J ) 7 Hz), 4.72-4.35 (m, 3H), 3.70 (s, 4H), 3.66
(s, 3H), 2.05 (m, 2H), 1.29 (m, 4H), 1.45-1.02 (m, 9H); 13C NMR
(75 MHz, CDCl3) δ 173.4, 158.3, 141.8, 135.1, 128.1, 127.6,
113.0, 79.7, 65.7, 60.0, 58.9, 54.8, 33.2, 28.0, 20.7, 13.9; LRMS
(m/z) (M+ + 1) 376; HRMS (m/z) (M+ + 1) calcd for C21H30NO5
376.2126, found 376.2124.
2S,6R-Diisop r op yl-3R-p h en ylh exa h yd r oin d olizin e-5,8-
d ion e, 24. To a solution of 22 (275 mg, 0.57 mmol) in dry THF
(50 mL) at -78 °C was added KHMDS (4.56 mL, 2.28 mmol,
0.5M in toluene), and the reaction mixture was allowed to
warm to -50 °C and stirred at that temperature for 3 h. The
reaction mixture was quenched with saturated ammonium
chloride solution (10 mL), and the organic phase was sepa-
rated. The aqueous phase was extracted with ethyl acetate (3
× 30 mL), the combined organic phases were dried over sodium
sulfate and filtered, and the solvent was removed under
reduced pressure to give 23 as a crude oil. The oil was dissolved
immediately in methanol (5 mL), 10% Pd/C was added, and
the mixture was stirred under an atmosphere of hydrogen gas
for 3 h. The catalyst was removed by passage through a pad
of Celite, and the solvent was removed. Purification of the
resultant oil by column chromatography (1:4 ethyl acetate/
hexane) gave 24 as a colorless oil (54 mg, 30%, two steps): [R]D
-25.8 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.32-7.05
(m, 5H), 5.30 (s, 1H), 4.29-4.10 (m, 1H), 2.86-2.74 (m, 2H),
2.43-2.38 (m, 1H), 2.25-2.05 (m, 2H), 1.93-1.87 (m, 1H),
1.83-1.72 (m, 1H), 1.71-1.67 (m, 1H), 1.10 (t, 3H, J ) 6 Hz),
0.99 (t, 3H, J ) 6 Hz); 13C NMR (75 MHz, CDCl3) δ 170.4,
142.4, 128.5, 128.3, 124.1, 64.6, 63.8, 52.3, 49.6, 39.2, 30.1, 29.6,
28.3, 28.0, 22.6, 21.2, 20.8, 20.8, 20.1; LRMS (m/z) (M+ + 1)
313.
8S-Hydr oxy-2S,6R-diisopr opyl-3R-ph en ylh exah ydr oin -
d olizin -5-on e, 25. To a solution of 24 (54 mg, 0.173 mmol) in
dry THF (2 mL) was added L-Selectride (0.21 mL, 0.21 mmol,
1 M solution in THF), and the reaction mixture was stirred at
-78 °C. After 2 h, the reaction was quenched by the addition
of saturated ammonium chloride solution, and the mixture was
warmed to room temperature. The organic phase was sepa-
rated, and the aqueous phase was extracted with ethyl acetate
(3 × 10 mL). The organic phases were combined, dried over
anhydrous sodium sulfate, and then filtered. The solvent was
removed under vacuum to give a clear oil. Purification by
column chromatography (1:3 ethyl acetate/hexane) gave 25 as
a white solid (33 mg, 60%): mp > 180 °C; [R]D +4.0 (c 0.3,
CHCl3); IR (CHCl3) 3684, 3620, 3019, 1658, 1602, 1522, 1476,
1423, 1046, 928 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.11
(m, 5H), 4.91 (br s, 1H), 4.18 (br s, 1H), 3.68 (dd, 2H, J ) 5,
12 Hz), 2.58-2.53 (m, 2H), 2.26-2.18 (dt, 1H, J ) 6, 12 Hz),
2.06-2.0 (m, 1H), 1.77-1.65 (m, 4H), 1.13 (d, 3H, J ) 6 Hz),
0.96 (d, 3H, J ) 6 Hz), 0.90 (d, 3H, J ) 7 Hz), 0.84 (d, 3H, J
) 7 Hz); 13C NMR (75 MHz, CDCl3) δ 170.5, 144.2, 128.1,
126.0, 125.3, 64.9, 64.3, 60.9, 52.8, 42.0, 30.1, 29.6, 27.8, 27.6,
21.3, 20.5, 19.8, 17.3; LRMS (m/z) (M+ + 1) 316; HRMS (m/z)
(M+ + 1) calcd for C20H30NO2 316.2291, found 316.2276.
2S-Isop r op ylp en t-4-en oic Acid , 27. To a solution of 26
(500 mg, 2.26 mmol) in a 2-propanol/water mixture (10:1, 50
mL) was added zinc metal (8.81 g, 135.6 mmol, 60 equiv), and
the mixture was heated to reflux for 5 h. The reaction mixture
was cooled, and the 2-propanol was removed under vacuum.
The aqueous phase was acidified to pH 1 and extracted with
ethyl acetate. The organic fractions were combined and dried
over anhydrous sodium sulfate, and the solvent was removed
under reduced pressure to give 27 as a dark oil which was
purified by column chromatography (ethyl acetate) to give a
colorless oil (193 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 5.70
(m, 1H), 5.03 (m, 1H), 4.97 (m, 1H), 2.19 (m, 2H), 2.38 (m,
1H), 2.15 (m, 1H), 1.01 (d, 6H).
4S-Isop r op yl-5R-p h en ylp yr r olid in e-1,2S-d ica r boxylic
Acid 1-ter t-Bu tyl Ester 2S-Meth yl Ester , 19. To a solution
of 17 (2.46 g, 7.13 mmol) in ethyl acetate (100 mL) was added
10% Pd/C (150 mg), and the mixture was reduced under an
atmosphere of hydrogen at 40 psi for 24 h. The catalyst was
filtered, and the solvent was removed under reduced pressure
to give a colorless oil which solidified on standing and was used
without further purification (2.23 g, 90%): mp 48-50 °C; [R]D
1
-31.6 (c 0.9, CHCl3); H NMR (300 MHz, CDCl3) δ 7.29 (m,
5H), 4.6 (br, 1H), 4.36 (m, 1H), 3.82 (dd, 1H, J ) 4, 9 Hz), 3.72
(s, 3H), 2.1-2.0 (m, 3H), 1.6 (m, 1H), 1.39 (s, 3H), 1.09 (s, 6H),
0.85 (d, 3H, J ) 7 Hz), 0.70 (d, 3H, J ) 6 Hz) (free amine); 13
C
NMR (75 MHz, CDCl3) δ 173.7, 143.9, 128.2, 127.9, 126.9,
126.6, 126.2, 80.3, 65.9, 59.1, 53.7, 52.1, 29.6, 28.1, 27.8, 26.9,
21.7, 17.6; HRMS (m/z) (M+ + 1) calcd for C20H30NO4 348.2168,
found 348.2175.
4S-Isop r op yl-5R-(4-m eth oxyp h en yl)p yr r olid in e-1,2S-
d ica r boxylic Acid 1-ter t-Bu tyl Ester 2S-Meth yl Ester , 20.
To a solution of 18 (2.3 g, 6.1 mmol) in ethyl acetate (100 mL)
was added 10% Pd/C (200 mg), and the mixture was reduced
under an atmosphere of hydrogen at 40 psi for 24 h. The
catalyst was filtered, and the solvent was removed under
reduced pressure to give 20 as a colorless oil which was used
without further purification (2.08 mg, 90%): [R]D -22.9 (c 0.8,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.47 (d, 2H, J ) 9 Hz),
6.85 (d, 2H, J ) 8 Hz), 4.61-4.30 (m, 2H), 3.80 (s, 6H), 2.13-
1.94 (m, 3H), 1.70-1.60 (m, 1H), 1.37 (s, 3H), 1.11 (s, 6H), 1.0-
0.73 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 173.7, 158.3, 154.3,
135.9, 128.1, 113.1, 79.6, 65.4, 59.9, 51.9, 29.6, 27.8, 21.6, 17.7.
4S-Isop r op yl-5R-p h en ylp yr r olid in e-1,2S-d ica r boxylic
Acid 1-ter t-Bu tyl Ester , 21. To a solution of 19 (100 mg, 0.29
mmol) in 10:1 MeOH/water (5 mL) was added lithium hydrox-
ide (1.5 equiv, 0.44 mmol), and the reaction mixture was
stirred at room temperature overnight. Methanol was removed
under reduced pressure, and the aqueous phase was extracted
with diethyl ether (2 × 10 mL), acidified to pH 1, and then
extracted with diethyl ether. The solvent was removed under
reduced pressure to give a white solid (91.7 mg, 95%): mp >
200 °C; 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 5H), 4.51 (d,
1H, J ) 8 Hz), 4.33 (d, 1H, J ) 7 Hz), 2.43 (m, 1H), 2.16 (m,
1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.1 (m, 15H); 13C NMR (75
MHz, CDCl3) δ 177.0, 142.9, 128.2, 127.0, 126.8, 66.4, 60.2,
53.7, 27.8, 21.6, 17.8; LRMS (m/z) (M+ + 1) 334; HRMS (m/z)
calcd for C19H28NO4 334.2025, found 334.2018.
1-(2-Ben zyloxyca r bon ylm eth yl-3-R,S-m eth ylbu tyr yl)-
4S-isop r op yl-5R-p h en ylp yr r olid in e-2S-ca r boxylic Acid
Meth yl Ester , 22. To a solution of 2-isopropylsuccinic acid
monobenzyl ester (405 mg, 2 equiv, 1.62 mmol) in dry dichlo-
romethane (4 mL) at 0 °C was added BOPCl (411 mg, 2 equiv,
1.62 mmol), and the reaction mixture was stirred at 0 °C for
2 h. A solution of the free amine of 19, obtained by treatment
with TFA (200 mg, 0.81 mmol), and diisopropylethylamine (627
mg, 6 equiv, 4.86 mmol) in dry dichloromethane (5 mL) was
then added, and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was diluted with
ethyl acetate and then washed sequentially with dilute
hydrochloric acid (15 mL), sodium bicarbonate solution (15
mL), and brine (15 mL). The organic layer was dried over
sodium sulfate and then filtered, and the solvent was removed
under vacuum to give a brown oil. Purification by column
chromatography (1:2 diethyl ether/hexane) gave 22 (1:1 mix-
ture of diastereomers) as a colorless oil (330 mg, 85%): 1H NMR
(300 MHz, CDCl3) δ 7.66-7.17 (m, 10H), 5.15-4.81 (m, 3H),
4.64-4.56 (m, 1H), 3.85-3.52 (m, 3H), 2.87-2.74 (m, 1H),
2.64-2.56 (m, 1H), 2.49-2.24 (m, 2H), 2.17-1.92 (m, 3H),
1.68-1.60 (m, 2H), 1.50-1.43 (m, 1H), 1.06-0.29 (multiple dd,
10H); 13C NMR (75 MHz, CDCl3) δ 175.9, 173.2, 172.9, 143.8,
128.5, 128.4, 128.2, 128.1, 127.9, 127.8, 127.7, 127.4, 127.2,
2S-Isop r op ylsu ccin ic Acid Mon oben zyl Ester , 28. To
a solution of 27 (150 mg, 1.06 mmol) in THF/water (9:1, 5 mL)
was added sodium metaperiodate (0.45 g, 2.1 mmol), and the
reaction mixture was stirred. Osmium tetroxide solution was
added (cat.), and the reaction mixture was stirred overnight.
The solvent was removed, and the aqueous phase was ex-
tracted with ethyl acetate. The combined organic extracts were
dried over anhydrous sodium sulfate and then concentrated.
The crude aldehyde was dissolved in acetone and treated with
the J ones reagent at 0 °C. The reaction mixture was quenched

Stereocontrolled Approaches to CGP-60536B
J . Org. Chem., Vol. 67, No. 12, 2002 4271
with excess 2-propanol, the solvents were removed, and the
crude acid was purified by column chromatography (ethyl
acetate) to give 2S-isopropylsuccinic acid as a colorless oil. To
a solution of the diacid (100 mg, 6.25 mmol) in dichloro-
methane (5 mL) were added benzyl alcohol (101 mg, 9.35
mmol), Et3N (94 mg, 9.31 mmol), and EDC (178 mg, 9.3 mmol),
and the reaction mixture was stirred overnight. The solvent
was removed under reduced pressure, and the residue was
dissolved in ethyl acetate and then washed sequentially with
dilute HCl (10 mL), NaHCO3 solution (10 mL), and finally
brine solution (10 mL). The organic phase was dried over
anhydrous sodium sulfate and concentrated. The crude
monoester was purified by column chromatography (1:4 ethyl
acetate/hexane) to give 28 as a colorless oil (62.5 mg, 40%):
1H NMR δ 7.19 (m, 5H), 5.34 (s, 2H), 2.98 (m, 1H), 2.48 (m,
2H), 2.15 (m, 1H), 1.01 (d, 6H).
1-(3-Ben zyloxyca r b on ylp r op ion yl)-4S-isop r op yl-5R-
p h en ylp yr r olid in e-2S-ca r boxylic Acid Meth yl Ester , 29.
To a solution of succinic acid monobenzyl ester (2.35 g, 11.3
mmol, 2 equiv) in a mixture of dry dichloromethane and DMF
(50 mL, 4:1) was added BOPCl (2.9 g, 11.4 mmol, 2 equiv),
and the mixture was stirred at 0 °C for 1 h. A solution of the
amine of 19, obtained by treatment with TFA (1.4 g, 5.7 mmol),
in dichloromethane (20 mL) and Hunig’s base (4.4 g, 34 mmol,
6 equiv) were then added, and the reaction mixture was stirred
at room temperature overnight. The solvents were removed,
and the residue was dissolved in ethyl acetate (10 mL). The
organic phase was washed sequentially with dilute HCl,
saturated sodium bicarbonate solution, and then brine. The
organic phase was dried over anhydrous sodium sulfate, and
the solvent was then removed to give a dark oil. Purification
by column chromatography (1:4 ethyl acetate/hexane) gave 29
as a pale yellow oil (2.2 g, 89%): [R]D -22.3 (c 0.6, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.62-7.18 (m, 10H), 5.10-5.02 (dd,
2H, J ) 24, 12 Hz), 4.69 (d, 1H, J ) 13 Hz), 4.63 (t, 1H, J )
7 Hz), 3.79 (s, 3H), 2.77-2.69 (m, 1H), 2.52-2.31 (m, 2H),
2.13-1.85 (m, 4H), 1.67 (m, 1H), 0.94 (d, 6H, J ) 7 Hz); 13C
NMR (75 MHz, CDCl3) δ 173.0, 172.5, 171.7, 142.4, 135.9,
128.7, 128.4, 128.1, 127.97, 127.9, 66.2, 66.1, 60.2, 59.4, 55.3,
52.1, 29.4, 29.0, 28.8, 28.7, 27.6, 21.6, 20.9, 18.3, 14.1; LRMS
(m/z) (M+ + 1) 438; HRMS (m/z) (M+ + 1) calcd for C26H32NO5
438.2288, found 438.2280.
solvents were removed, and the resultant oil was purified by
column chromatography (ethyl acetate) to give 31 as a white
solid (300 mg, 66%): mp > 200 °C; [R]D +6.12 (c 0.8, CHCl3);
IR (CDCl3) 3428, 2972, 1731, 1635, 1451, 1410, 1373, 1250
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.36-7.13 (m, 5H), 4.94
(s, 1H), 4.17 (s, 1H), 3.70 (dd, 1H, J ) 12, 5 Hz), 2.6-2.5 (m,
1H), 2.35-2.31 (m, 1H), 2.1-1.9 (m, 3H), 1.77 (dd, 1H, J )
13, 6 Hz), 1.66 (s, 2H), 1.14 (d, 3H, J ) 6 Hz), 0.95 (d, 3H, J
) 8 Hz); 13C NMR (75 MHz, CDCl3) δ 168.9, 143.7, 128.2,
126.2, 64.4, 63.8, 61.3, 53.1, 29.8, 29.2, 27.3, 27.1, 21.4, 20.5;
LRMS (m/z) (M+ + 1) 274; HRMS (m/z) (M+ + 1) calcd for
C17H24NO2 274.1819, found 274.1807.
3S-Isopropyl-5S-(5-oxotetrahydrofuran-2S-yl)-2R-phenyl-
p yr r olid in e-1-ca r boxylic Acid ter t-Bu tyl Ester , 32. To a
solution of 31 (300 mg, 1.1 mmol) in methanol (4 mL) was
added concentrated HCl (4 mL), and the reaction mixture was
heated to reflux for 3 days. The solvents were removed, the
crude lactone was dissolved in dry acetonitrile (5 mL), DMAP
(268 mg, 2 equiv, 2.2 mmol), triethylamine (450 mg, 4 equiv,
4.4 mmol), and Boc anhydride (650 mg, 2 equiv, 2.2 mmol)
were added, and the reaction mixture was stirred overnight.
The solvent was removed under reduced pressure, and the
crude was dissolved in ethyl acetate and then washed sequen-
tially with dilute HCl, saturated sodium bicarbonate solution,
and brine. The organic phase was collected and dried over
anhydrous sodium sulfate, and the solvent was removed to give
a dark oil which was purified by column chromatography (1:3
ethyl acetate/hexane) to give 32 as a colorless oil (245 mg, 60%,
two steps): [R]D -27.05 (c 0.8, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.29-7.18 (m, 5H), 4.63-4.61 (m, 1H), 4.40 (s, 1H),
4.21 (m, 1H), 2.59-2.49 (m, 2H), 2.36-2.15 (m, 3H), 1.96-
1.88 (m, 1H), 1.77-1.73 (m, 2H), 1.24 (s, 9H), 0.94 (d, 3H, J )
7 Hz), 0.82 (d, 3H, J ) 7 Hz); 13C NMR (75 MHz, CDCl3) δ
176.8, 155.9, 143.7, 128.0, 126.6, 82.7, 80.1, 66.5, 59.5, 52.3,
29.5, 28.7, 28.5, 28.3, 28.0, 27.6, 25.4, 21.9, 17.5; LRMS (m/z)
(M+ + 1) 374; HRMS (m/z) (M+ + 1) calcd for C22H32NO4
374.2320, found 374.2331.
5S-[4S-(1-H yd r oxy-1-m et h ylet h yl)-5-oxot et r a h yd r o-
fu r an -2S-yl]-3S-isopr opyl-2R-ph en ylpyr r olidin e-1-car box-
ylic Acid ter t-Bu tyl Ester , 33. To a solution of 32 (240 mg,
0.63 mmol) in dry THF (8 mL) at -78 °C was added LiHMDS
(0.7 mL, 1.15 equiv, 0.7 mmol, 1 M solution in THF), and the
reaction mixture was stirred for 1 h. Dry acetone (187 mg, 5
equiv, 3.2 mmol) was then added, and the reaction mixture
was stirred for an additional 1 h. The reaction mixture was
quenched by the addition of a saturated ammonium chloride
solution and extracted with ethyl acetate (3 × 10 mL). The
combined extracts were dried over anhydrous sodium sulfate,
and the solvent was removed to give a dark oil. Purification
by column chromatography (1:4 ethyl acetate/hexane) gave 33
as a colorless oil (235 mg, 85%): [R]D +2.18 (c 0.6, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 5H), 4.48 (s, 1H), 4.15
(t, 1H, J ) 8 Hz), 2.85 (t, 1H, J ) 10 Hz), 2.27-2.10 (m, 2H),
1.97-1.88 (m, 1H), 1.76-1.67 (s, 2H), 1.31 (s, 17H), 0.94 (d,
3H, J ) 7 Hz), 0.84 (d, 3H, J ) 7 Hz); 13C NMR (75 MHz,
CDCl3) δ 178.3, 143.6, 128.2, 126.7, 126.4, 80.3, 70.9, 59.7, 52.3,
48.9, 29.6, 28.6, 28.4, 29.9, 27.1, 25.4, 21.9, 17.3; LRMS (m/z)
(M+ + 1) 432; HRMS (m/z) (M+ + 1) calcd for C25H38NO5
432.2750, found 432.2749.
2S-Isop r op yl-3R-p h en ylh exa h yd r oin d olizin e-5,8-d i-
on e, 30. To a solution of 29 (2.0 g, 4.6 mmol) in dry THF (450
mL) at -20 °C was added sodium tert-pentoxide (1.5 g, 13.6
mmol), and the reaction mixture was stirred at that temper-
ature until there was no remaining starting material detected
by TLC. The reaction mixture was quenched by the addition
of saturated ammonium chloride solution, and the THF was
then separated. The aqueous phase was extracted with ethyl
actetate (3 × 30 mL), the organic extracts were combined and
dried over anhydrous sodium sulfate, and the solvent was
removed to give a yellow oil. The crude product was dissolved
in methanol (50 mL), 10% Pd/C was added, and the reaction
mixture was stirred under an atmosphere of hydrogen gas.
The catalyst was removed by filtration, the solvent was
removed, and the residue was purified by column chromatog-
raphy (1:1 ethyl acetate/hexane) to give 30 as a yellow oil (570
mg, 46%): [R]D +15.07 (c 0.7, CHCl3); IR (neat) 2962, 1732,
1
1693, 1602, 1429 cm-1; H NMR (400 MHz, CDCl3) δ 7.34-
5S-(4S-Isop r op en yl-5-oxot et r a h yd r ofu r a n -2S-yl)-3S-
isop r op yl-2R-p h en ylp yr r olid in e-1-ca r boxylic Acid ter t-
Bu tyl Ester , 34. To a solution of 33 (100 mg, 0.23 mmol) in
dry dichloromethane (4 mL) at -60 °C was added PCl5 (53
mg, 1.1 equiv, 0.25 mmol), and the reaction mixture was
stirred for 30 min. The reaction mixture was quenched with
saturated sodium bicarbonate solution and then extracted with
dichloromethane (3 × 10 mL). The combined organic extracts
were dried over anhydrous sodium sulfate, and the solvent was
removed to give a yellow oil. Purification by column chroma-
tography (1:9 ethyl acetate/hexane) gave 34 as a colorless oil
7.02 (m, 5H), 5.04 (s, 1H), 4.26 (t, 1H, J ) 8 Hz), 2.75 (m, 4H),
2.18 (m, 2H), 2.0-1.5 (m, 2H), 1.10-0.99 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 207.6, 169.2, 141.9, 130.3, 126.9, 126.1,
124.8, 64.9, 63.6, 34.9, 31.1, 30.8, 26.9, 20.9, 20.1; LRMS (m/
z) (M+ + 1) 272; HRMS (m/z) (M+ + 1) calcd for C17H22O2N
272.1659, found 272.1650.
8S-Hyd r oxy-2S-isop r op yl-3R-p h en ylh exa h yd r oin d oli-
zin -5-on e, 31. To a solution of 30 (451 mg, 1.6 mmol) in dry
THF (10 mL) at -78 °C was added L-Selectride (2.5 mL, 2.5
mmol, 1 M solution in THF), and the reaction mixture was
stirred at -78 °C for 1 h. The reaction mixture was quenched
by the addition of saturated ammonium chloride, and the
solution was extracted with ethyl acetate (3 × 10 mL) and
dichloromethane (3 × 10 mL). The organic extracts were
combined and then dried over anhydrous sodium sulfate. The
1
(77 mg, 80%): [R]D +3.63 (c 0.6, CHCl3) H NMR (400 MHz,
CDCl3) δ 7.29-7.16 (m, 5H), 5.0 (s, 2H), 4.55 (s, 1H), 4.40 (s,
1H), 4.20 (t, 1H, J ) 7 Hz), 3.38 (t, 1H, J ) 8 Hz), 2.40-2.26
(m, 3H), 1.97-1.62 (m, 5H), 1.50-1.0 (s, 9H), 1.0-0.8 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 182.1, 176.3, 143.7, 139.7, 128.1,

4272 J . Org. Chem., Vol. 67, No. 12, 2002
Hanessian et al.
126.6, 126.5, 114.3, 80.2, 68.8, 59.4, 52.3, 46.9, 30.9, 30.8, 28.9,
27.9, 27.4, 24.3, 21.9, 21.8, 17.4, 14.0; LRMS (m/z) (M+ + 1)
414; HRMS (m/z) (M+ + 1) calcd for C25H36NO4 414.2632, found
414.2644.
18.1; LRMS (m/z) (M+ + 1) 470; HRMS (m/z) (M+ + 1) calcd
for C23H36NNaO7P 492.2140, found 492.2127.
4S-Isop r op yl-5S-(3-m et h oxyca r b on yla cr yloyl)-2R-(4-
m eth oxyp h en yl)p yr r olid in e-1-ca r boxylic Acid ter t-Bu tyl
Ester , 38. To a solution of the â-ketophosphonate (1.5 g, 3.2
mmol) in dry acetonitrile (75 mL) were added LiCl (536 mg, 4
equiv, 12.8 mmol), CHOCO2Me (1.12 g, 4 equiv, 12.8 mmol),
and Hunig’s base (1.65 g, 4 equiv, 12.8 mmol), and the reaction
mixture was stirred overnight. The solvent was removed under
reduced pressure, and the residue was dissolved in ethyl
acetate and washed sequentially with dilute HCl, saturated
sodium bicarbonate solution, and brine. The organic phase was
dried over anhydrous sodium sulfate and then filtered. The
solvent was removed under reduced pressure to give a dark
oil which was purified by column chromatography (1:4 ethyl
acetate/hexane) to give 38 as a yellow oil (935 mg, 68%): [R]D
-33 (c 0.8, CHCl3); IR (CDCl3) 2960, 1731, 1693, 1613, 1513,
1392, 1304, 1247, 1175, 1034 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.40-7.26 (m, 3H), 6.86-6.83 (m, 3H), 4.76-4.32 (m, 2H),
3S-Isop r op yl-5S-(4S-isop r op yl-5-oxotetr a h yd r ofu r a n -
2S-yl)-2R-p h en ylp yr r olid in e-1-ca r boxylic Acid ter t-Bu tyl
Ester , 35. To a solution of 34 (75 mg, 0.18 mmol) in ethyl
acetate (5 mL) was added 10% Pd/C, and the reaction mixture
was stirred under an atmosphere of hydrogen gas. The catalyst
was removed by filtration, the solvent was removed, and the
residue was purified by column chromatography (1:9 ethyl
acetate/hexane) to give 35 as a colorless oil (68 mg, 90%): [R]D
+0.74 (c 0.6, CHCl3); IR (CDCl3) 2965, 2932, 1777, 1739, 1691,
1650, 1604, 1440, 1369, 1336, 1312 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.25-7.15 (m, 5H), 4.95 (s, 1H), 4.62 (s, 1H), 3.93 (t,
1H, J ) 6 Hz), 2.60 (m, 1H), 2.35-2.24 (m, 4H), 1.96-1.60
(m, 4H), 1.48-1.0 (s, 8H), 1.0-0.8 (m, 12H); 13C NMR (75 MHz,
CDCl3) δ 178.4, 160.3,139.7, 128.1, 125.7, 126.5, 82.8, 70.9,
54.9, 54.2, 51.7, 41.9, 28.6, 25.7, 25.4, 19.5; LRMS (m/z) (M+
+ 1) 416; HRMS (m/z) (M+ + 1) calcd for C25H38NO4 416.2788,
found 416.2801.
[1S-(2-Ben zyl-3S-m eth ylbu tyl)-2S-h yd r oxy-4S-isop r o-
p ylca r ba m oyl-5-m eth ylh exyl]ca r ba m ic Acid ter t-Bu tyl
Ester , 36. To a solution of isopropylamine (43 mg, 4 equiv,
0.72 mmol) in dry dichloromethane (1 mL) was added tri-
methylaluminum (0.37 mL, 2 M solution in toluene, 0.74
mmol), and the reaction mixture was stirred at room tem-
perature for 5 min. This solution was then transferred via
cannula to a solution of 35 (75 mg, 0.18 mmol) in dry di-
chloromethane (2 mL). The reaction mixture was then stirred
at room temperature overnight and quenched with a saturated
solution of ammonium chloride. The organic phase was
separated, and the aqueous phase was extracted with di-
chloromethane (3 × 10 mL). The combined organic extracts
were dried over anhydrous sodium sulfate and then filtered.
The solvent was removed to give a dark oil which was used
directly in the next step. To a solution of the amide (20 mg,
0.042 mmol) in methanol (3 mL) was added 10% Pd/C (40 mg),
and the reaction mixture was stirred under an atmosphere of
hydrogen gas at 60 psi for 3 days. The reaction mixture was
filtered, and the solvent was removed under reduced pressure
to give a pink oil. Purification by column chromatography
(1:3 ethyl acetate/hexane) gave 36 as a colorless oil (10 mg,
50%): [R]D -15 (c 0.6, CHCl3); IR (CDCl3) 3330, 2950, 1697,
1620, 1513, 1359, 1438, 1246, 1041 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.30-7.14 (m, 5H), 5.53 (s, 1H), 4.64 (d, 1H, J ) 9
Hz), 4.11 (m, 1H), 3.53 (d, 9H, J ) 7 Hz), 3.43 (m, 1H), 2.66
(dd, 1H, J ) 7, 5 Hz), 2.47 (dd, 1H, J ) 13, 7 Hz), 2.0-1.83
(m, 3H), 1.76-0.76 (m, 24H); 13C NMR (75 MHz, CDCl3) δ
178.2, 157.0, 139.4, 128.3, 125.7, 73.0, 70.2, 52.8, 44.1, 41.6,
39.6, 31.6, 30.5, 28.7, 26.4, 23.7, 20.1, 19.1; LRMS (m/z)
(M+ + 1) 477; HRMS (m/z) (M+ + 1) calcd for C28H48N2O4
477.3686, found 477.3692.
3.78 (s, 6H), 2.0 (s, 3H), 1.60 (s, 1H), 1.33-0.70 (m, 15H); 13
C
NMR (75 MHz, CDCl3) δ 198.0, 165.6, 158.4, 154.6, 137.1,
136.7, 131.2, 128.2, 127.5, 113.2, 80.1, 65.5, 64.6, 55.1, 53.5,
52.2, 28.1, 27.9, 21.7, 17.8; LRMS (m/z) (M+ + 1) 432; HRMS
(m/z) (M+ + 1) calcd for C24H34NO6 432.2400, found 432.2386.
5S-(1,4S-Dih ydr oxybu tyl)-4S-isopr opyl-2R-(4-m eth oxy-
p h en yl)p yr r olid in e-1-ca r boxylic Acid ter t-Bu tyl Ester ,
39. To a solution of 38 (900 mg, 2.1 mmol) in ethyl acetate (40
mL) was added 10% Pd/C, and the reaction mixture was stirred
under an atmosphere of hydrogen gas. The catalyst was
filtered, and the solvent was removed under reduced pressure
to give a colorless oil which was purified by column chroma-
tography (1:9 ethyl acetate/hexane) to give a colorless oil (813
mg, 90%): [R]D -29.89 (c 0.8, CHCl3); LRMS (m/z) (M+ + 1)
434; HRMS (m/z) (M+ + 1) calcd for C24H36NO6 434.2556, found
434.2542. To a solution of the above compound (750 mg, 1.73
mmol) in methanol (40 mL) was added sodium borohydride
(excess), and the reaction was stirred until no remaining
starting material was observed by TLC. The reaction mixture
was quenched with saturated ammonium chloride solution,
and the solvent was removed under reduced pressure. The
crude was dissolved in ethyl acetate and washed with water.
The organic phase was dried over anhydrous sodium sulfate
and then filtered. The solvent was removed under reduced
pressure to give a colorless oil which was purified by column
chromatography (ethyl acetate) to give 39 as a colorless oil
(620 mg, 88%): [R]D -37.88 (c 0.9, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.17 (d, 2H, J ) 8 Hz), 6.82 (d, 2H, J ) 8 Hz), 4.37
(d, 1H, J ) 8 Hz), 3.91 (t, 1H, J ) 9 Hz), 3.77 (s, 3H), 3.68 (m,
3H), 1.82 (m, 1H), 1.80-1.61 (m, 8H), 1.13 (s, 9H), 0.89 (d,
3H, J ) 7 Hz), 0.82 (d, 3H, J ) 9 Hz);13C NMR (75 MHz,
CDCl3) δ 158.3, 135.9, 127.5, 113.4, 80.8, 75.9, 65.6, 63.3, 62.8,
60.2, 55.1, 52.8, 32.9, 29.1, 28.9, 27.9, 27.5, 21.7, 17.9, 14.0;
LRMS (m/z) (M+ + 1) 408; HRMS (m/z) (M+ + 1) calcd for
C23H38NO5 408.2742, found 408.2750.
5S-[2-(Dim eth oxyp h osp h or yl)a cetyl]-4S-isop r op yl-2R-
(4-m eth oxyp h en yl)p yr r olid in e-1-ca r boxylic Acid ter t-
Bu tyl Ester , 37. To a solution of dimethyl methylphosphonate
(2.98 g, 6 equiv, 24.0 mmol) in dry THF (50 mL) at -78 °C
was added n-butyllithium (10.56 mL, 6.6 equiv, 26.4 mmol,
2.5 M in hexane), and the mixture was stirred for 30 min at
-78 °C. A solution of 20 (1.5 g, 4.0 mmol) in THF (50 mL)
was added, and the reaction mixture was stirred for 3 h at
-78 °C. The reaction mixture was quenched with saturated
ammonium chloride solution and then extracted with ethyl
acetate (3 × 30 mL). The organic phases were combined, dried
over anhydrous sodium sulfate solution, and filtered. The
solvent was removed to give a colorless oil which was purified
by column chromatography (1:1 ethyl acetate/hexane) to give
37 as a colorless oil (1.64 g, 88%): [R]D -106.3 (c 0.8, CHCl3);
IR (CDCl3) 2959, 1726, 1687, 1613, 1514, 1463, 1392, 1366,
4S-Isop r op yl-2R-(4-m eth oxyp h en yl)-5S-(5-oxotetr a h y-
d r ofu r a n -2S-yl)p yr r olid in e-1-ca r boxylic Acid ter t-Bu tyl
Ester , 40. To a solution of 39 (510 mg, 1.25 mmol) in
dichloromethane (12 mL) were added TEMPO (19 mg) and
iodobenzene diacetate (807 mg, 2 equiv, 2.5 mmol), and the
reaction mixture was stirred for 6 h. The reaction mixture was
quenched with sodium thiosulfate solution and then extracted
with dichloromethane (3 × 30 mL). The organic phases were
combined, then dried over anhydrous sodium sulfate, and
filtered. The solvent was removed under reduced pressure to
give a dark oil which was purified by column chromatography
(1:2 ethyl acetate/hexane) to give 40 as a colorless oil (379 mg,
75%): [R]D -8.53 (c 0.8, CHCl3); IR (CDCl3) 2961, 1778, 1691,
1613, 1513, 1389, 1366, 1247, 1173, 111, 1032 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.22 (d, 2H, J ) 9 Hz), 6.83 (d, 2H, J ) 9
Hz), 4.59 (m, 1H), 4.30 (s, 1H), 4.20 (m, 1H), 3.78 (s, 3H), 2.52
(m, 2H), 2.34-2.20 (m, 3H), 2.04-1.70 (m, 3H), 1.25 (s, 9H),
0.92 (d, 3H, J ) 7 Hz), 0.80 (d, 3H, J ) 7 Hz); 13C NMR (75
MHz, CDCl3) δ 177.0, 158.2, 135.7, 127.9, 113.4, 80.1, 66.2,
59.6, 55.4, 53.4, 52.3, 29.1, 28.5, 28.0, 26.0, 25.4, 21.8, 17.8;
1
1248, 1178, 1033 cm-1; H NMR (400 MHz, CDCl3) δ 7.36 (d,
2H, J ) 8 Hz), 6.83 (d, 2H, J ) 8 Hz), 4.60-4.30 (m, 2H), 3.32-
3.78 (2s, 9H), 3.60-3.2 (m, 2H), 2.16-1.94 (m, 3H), 1.63 (m,
1H), 1.37-1.30 (m, 3H), 1.11 (s, 6H), 0.92-0.79 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 201.6, 158.3, 154.7, 135.8, 128.2,
127.6, 113.2, 80.1, 65.6, 55.1, 53.5, 52.9, 39.4, 38.1, 27.9, 21.6,

Stereocontrolled Approaches to CGP-60536B
J . Org. Chem., Vol. 67, No. 12, 2002 4273
LRMS (m/z) (M+ + 1) 404; HRMS (m/z) (M+ + 1) calcd for
1H, J ) 8 Hz), 3.87 (t, 1H, J ) 8 Hz), 3.79 (s, 3H), 3.51 (t, 1H,
J ) 10 Hz), 3.34-3.20 (m, 2H), 2.24 (m, 1H), 2.17-1.62 (m,
C
23H34NO5 404.2427, found 404.2437.
5S-[4S-(1-Hyd r oxy-1-m eth yleth yl)-5-oxotetr a h yd r ofu -
6H), 1.51 (m, 2H), 1.41-1.15 (m, 14H), 1.0-0.73 (m, 12H); 13
C
r an -2S-yl]-4S-isopr opyl-2R-(4-m eth oxyph en yl)pyr r olidin e-
1-ca r boxylic Acid ter t-Bu tyl Ester , 41. To a solution of 40
(300 mg, 0.74 mmol) in dry THF (10 mL) at -78 °C was added
LiHMDS (0.82 mL, 1.1 equiv, 1 M solution in THF), and the
reaction mixture was stirred for 1 h. Dry acetone (215 mg, 5
equiv, 3.7 mmol) was then added, and the reaction mixture
was stirred for an additional 1 h. The reaction mixture was
quenched by the addition of a saturated ammonium chloride
solution and then extracted with ethyl acetate (3 × 10 mL).
The combined extracts were dried over anhydrous sodium
sulfate, and then the solvent was removed to give 41 as a dark
oil. Purification by column chromatography (1:4 ethyl acetate/
hexane) gave the product as a colorless oil (299 mg, 87%): [R]D
+3.06 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.21 (d,
2H, J ) 9 Hz), 6.84 (d, 2H, J ) 8 Hz), 4.61-4.1 (m, 2H), 3.79
(s, 3H), 2.83 (t, 1H, J ) 10 Hz), 2.40-2.1 (m, 2H), 1.91 (m,
1H), 1.66 (s, 2H), 1.31 (m, 17H), 0.93 (d, 3H, J ) 6 Hz), 0.82
(d, 3H, J ) 7 Hz); 13C NMR (75 MHz, CDCl3) δ 178.4, 158.3,
135.6, 127.6, 113.5, 80.2, 70.9, 59.7, 55.1, 52.2, 51.0, 48.9, 29.1,
28.9, 28.3, 28.0, 27.5, 25.4, 21.9, 17.5; LRMS (m/z) (M+ + 1)
462; HRMS (m/z) (M+ + 1) calcd for C26H40NO6 462.2845, found
462.2855.
NMR (75 MHz, CDCl3) δ 175.1, 158.2, 136.2, 127.6, 113.3, 80.7,
73.7, 65.5, 63.9, 55.1, 52.8, 50.5, 38.8, 36.6, 31.7, 30.2, 28.8,
27.8, 27.8, 21.6, 21.2, 21.1, 20.1, 19.9, 18.1, 13.6; LRMS (m/z)
(M+ + 1) 519; HRMS (m/z) (M+ + 1) calcd for C30H50N2O5
519.3806, found 519.3798.
2R-Isopr opyl-4S-h ydr oxy-5S-N-bu toxycar bam oylam in o-
7S-isop r op yl-8-p-m eth oxyp h en ylocta n oic Acid N-Bu tyl-
a m id e, 44. To a solution of 43 (30 mg, 0.058 mmol) in
methanol (3 mL) was added 10% Pd/C (50 mg), and the
reaction mixture was stirred under an atmosphere of hydrogen
gas at 60 psi for 3 days. The reaction mixture was filtered,
and the solvent was removed under reduced pressure to give
a colored oil which was purified by column chromatography
(1:2 ethyl acetate/hexane) to give 44 as a colorless oil (18 mg,
60%): [R]D +17.2 (c 0.7, CHCl3); IR (CDCl3) 3333, 2958, 1693,
1633, 1513, 1455, 1366, 1246, 1175, 1044 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.09 (d, 2H, J ) 9 Hz), 6.79 (d, 2H, J ) 8 Hz),
5.85 (s, 1H), 4.66 (d, 1H, J ) 10 Hz), 3.77 (s, 3H), 3.52-3.17
(m, 4H), 2.61 (m, 1H), 2.38 (m, 1H), 2.05-1.90 (m, 2H), 1.60
(m, 4H), 1.5 (s, 9H), 1.08-0.71 (m, 22H); 13C NMR (75 MHz,
CDCl3) δ 157.5, 156.6, 133.6, 129.9, 113.4, 79.1, 71.0, 55.1, 53.7,
51.3, 42.4, 39.6, 34.6, 32.2, 31.8, 31.6, 29.6, 29.2, 28.3, 27.9,
22.6, 21.1, 20.4, 20.0, 16.6, 14.0, 13.6, 12.1; LRMS (m/z) (M+
+ 1) 521; HRMS (m/z) (M+ + 1) calcd for C30H53N2O5 521.3941,
found 521.3954.
5S-(4S-Isop r op en yl-5-oxot et r a h yd r ofu r a n -2S-yl)-4S-
isop r op yl-2R-(4-m et h oxyp h en yl)p yr r olid in e-1-ca r b ox-
ylic Acid ter t-Bu tyl Ester , 42. To a solution of 41 (150 mg,
0.33 mmol) in dry dichloromethane (6 mL) at -60 °C was
added PCl5 (74 mg, 1.1 equiv, 0.36 mmol), and the reaction
mixture was stirred for 30 min. The reaction mixture was
quenched with saturated sodium bicarbonate solution and
extracted with dichloromethane (3 × 10 mL). The combined
organic extracts were dried over anhydrous sodium sulfate,
and the solvent was removed to give a yellow oil. Purification
by column chromatography (1:9 ethyl acetate/hexane) gave 42
as a white solid (115 mg, 80%): [R]D +5 (c 1, CHCl3); IR
(CDCl3) 2967, 1781, 1752, 1686, 1613, 1513, 1457, 1387, 1290,
4S-Isop r op yl-5S-(4-m et h oxyp h en yl)p yr r olid in e-1,2S-
d ica r boxylic Acid 1-ter t-Bu tyl Ester 2-Meth yl Ester , 45.
To a solution of p-bromoanisole (18.7 g, 5 equiv, 0.1 mol) in
dry THF (150 mL) at -78 °C was added n-butyllithium (44
mL, 0.11 mmol, 2.5 M in hexanes), and the reaction mixture
was stirred at -78 °C for 1 h. The lithium reagent was then
added to a stirring solution of copper(II) bromide-dimethyl
sulfide complex (20.5 g, 5 equiv, 0.1 mol) at -78 °C, and the
resultant black solution was stirred at -78 °C for 1 h. BF3‚
OEt2 (28.4 g, 10 equiv, 0.2 mol) was added in one portion, and
the reaction mixture was stirred for a further 30 min. A
solution of the aminal 12 (6 g, 20.0 mmol) in dry THF (20 mL)
was added, and the reaction mixture was allowed to slowly
warm to room temperature (black suspension). The mixture
was quenched with a 1:1 mixture of ammonium chloride
solution and aqueous ammonium hydroxide and extracted with
ethyl acetate (4 × 50 mL). The organic fractions were com-
bined, dried over anhydrous sodium sulfate, and filtered. The
solvent was removed under reduced pressure, and the result-
ant yellow oil was purified by column chromatography (1:4
ethyl acetate/hexane) to give 45 as a clear oil (5.29 g, 70%):
IR (neat) 3019, 2976, 1746, 1686, 1612, 1586, 1512, 1395, 1368,
1
1247, 1172, 1148 cm-1; H NMR (400 MHz, CDCl3) δ 7.21 (d,
2H, J ) 8 Hz), 6.82 (d, 2H, J ) 9 Hz), 4.99 (s, 1H), 4.92 (s,
1H), 4.53 (s, 1H), 4.35 (s, 1H), 4.15 (t, 1H, J ) 7 Hz), 3.76 (s,
3H), 3.34 (t, 1H, J ) 8 Hz), 2.33-2.24 (m, 3H), 2.02-1.71 (m,
6H), 1.23 (s, 9H), 0.90 (d, 3H, J ) 7 Hz), 0.79 (d, 3H, J ) 6
Hz); 13C NMR (75 MHz, CDCl3) δ 176.4, 158.3, 139.7, 127.8,
113.4, 80.1, 66.1, 59.6, 55.1, 52.2, 46.9, 30.9, 29.3, 28.0, 27.8,
21.8, 17.7; LRMS (m/z) (M+ + 1) 444; HRMS (m/z) (M+ + 1)
calcd for C26H38NO5 444.2736, found 444.2750.
5S-(3-Bu t ylca r b a m oyl-1S-h yd r oxy-4S-m et h ylp en t yl)-
3S-isop r op yl-2R-(4-m et h oxyp h en yl)p yr r olid in e-1-ca r -
boxylic Acid ter t-Bu tyl Ester , 43. To a solution of 42 (100
mg, 0.26 mmol) in ethyl acetate (7 mL) was added 10% Pd/C,
and the reaction mixture was stirred under an atmosphere of
hydrogen gas. The catalyst was removed by filtration, then
the solvent was removed, and the residue was purified by
column chromatography (1:9 ethyl acetate/hexane) to give a
colorless oil (90 mg, 90%): [R]D +2.4 (c 0.8, CHCl3); LRMS (m/
z) (M+ + 1) 446; HRMS (m/z) (M+ + 1) calcd for C26H38NO5
446.2910, found 444.2906. To a solution of n-butylamine (52.6
mg, 4 equiv, 0.72 mmol) in dry dichloromethane (1 mL) was
added trimethylaluminum (0.36 mL, 2 M solution in toluene,
0.71 mmol), and the reaction mixture was stirred at room
temperature for 5 min. This solution was then transferred via
cannula to a solution of the above compound (80 mg, 0.18
mmol) in dry dichloromethane (2 mL). The reaction mixture
was stirred at room temperature overnight and quenched with
a saturated solution of ammonium chloride. The organic phase
was separated, and the aqueous phase was extracted with
dichloromethane (3 × 10 mL). The combined organic extracts
were dried over anhydrous sodium sulfate and filtered, and
the solvent was removed. The residue was purified by column
chromatography (1:3 ethyl acetate/hexane) to give 43 as a
colorless oil (70 mg, 75%): [R]D -31.9 (c 0.8, CHCl3); IR (CDCl3)
3322, 2959, 1740, 1651, 1538, 1514, 1464, 1401, 1367, 1289,
1
1298, 1215, 1178, 1160, 1036, 757 cm-1; H NMR (400 MHz,
CDCl3) δ 7.09-6.77 (m, 4H), 4.90 (d, 1H, J ) 7 Hz), 4.63 (d,
1H, J ) 9 Hz), 3.77 (s, 3H), 3.71 (s, 3H), 2.22-2.0 (m, 4H),
1.33-1.15 (s, 9H), 0.84-0.7 (t, 6H); 13C NMR (75 MHz, CDCl3)
δ 173.8, 158.4, 152.9, 133.2, 128.7,115. 8, 113. 1, 79.9, 63. 8,
59. 3, 55.0, 52.2, 49.9, 31.9, 27.9, 27.6, 21.7, 20.9; LRMS (m/z)
(M+) 377; HRMS (m/z) (M+) calcd for C21H31NO5 377.2210,
found 377.2202.
4S-Isop r op yl-5S-(3-m et h oxyca r b on yla cr yloyl)-2S-(4-
m eth oxyp h en yl)p yr r olid in e-1-ca r boxylic Acid ter t-Bu tyl
Ester , 46. To a solution of dimethyl methylphosphonate (3.9
g, 6 equiv, 31.9 mmol) in dry THF (80 mL) at -78 °C was
added n-butyllithium (13.6 mL, 6.4 equiv, 34.1 mmol, 2.5M
solution in hexanes), and the mixture was stirred for 30 min
at -78 °C. A solution of 45 (2 g, 5.31 mmol) was then added,
and the reaction mixture was stirred for 3 h at -78 °C. The
reaction mixture was quenched with saturated ammonium
chloride solution and extracted with ethyl acetate (3 × 30 mL).
The organic phases were combined, dried over anhydrous
sodium sulfate solution, and then filtered. The solvent was
removed to give a colorless oil (1.99 g, 80%) which was used
immediately in the next step. To a solution of the â-ketophos-
phonate (1.94 g, 4.14 mmol) in dry acetonitrile (10 mL) were
added LiCl (870 mg, 5 equiv, 20.7 mmol), methyl glyoxalate
(1.82 g, 5 equiv, 20.7 mmol), and Hunig’s base (2.67 g, 5 equiv,
1
1247, 1175, 1153 cm-1; H NMR (400 MHz, CDCl3) δ 7.15 (d,
2H, J ) 8 Hz), 6.81 (d, 2H, J ) 8 Hz), 5.89 (s, 1H), 4.36 (d,

4274 J . Org. Chem., Vol. 67, No. 12, 2002
Hanessian et al.
21 mmol), and the reaction mixture was stirred overnight. The
solvent was removed under reduced pressure, and the residue
was dissolved in ethyl acetate and washed sequentially with
dilute HCl, saturated sodium bicarbonate solution, and brine.
The organic phase was dried over anhydrous sodium sulfate
and then filtered. The solvent was removed under reduced
pressure to give a brown oil which was purified by column
chromatography (1:4 ethyl acetate/hexane) to give 46 as a
yellow oil (1.0 g, 60%): [R]D -4.76 (c 0.6, CHCl3); IR (CHCl3)
2959, 1730, 1693, 1611, 1521, 1394, 1247, 1034 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.24 (d, 1H, J ) 16 Hz), 7.04 (d, 1H, J )
8 Hz), 6.85-6.79 (m, 4H), 4.93 (m, 2H), 3.77 (m, 6H), 2.24-
1.91 (m, 4H), 1.25-1.14 (s, 9H), 0.82 (t, 3H, J ) 6 Hz), 0.68 (t,
3H, J ) 6 Hz); 13C NMR (75 MHz, CDCl3) δ 197.8, 165.7, 158.5,
136.3, 133.0, 131.6, 128.7, 113.1, 79.9, 64.3, 63.9, 55.4, 52.2,
49.7, 30.6, 27.9, 27.6, 21.6, 20.9; LRMS (m/z) (M+ + 1) 432;
HRMS (m/z) (M+ + 1) calcd, for C24 H34NO6 432.2386, found
432.2396.
4S-Isop r op yl-2S-(4-m eth oxyp h en yl)-5S-(5-oxotetr a h y-
d r ofu r a n -2S-yl)p yr r olid in e-1-ca r boxylic Acid ter t-Bu tyl
Ester , 47. To a solution of 46 (1 g, 2.32 mmol) in ethyl acetate
(15 mL) was added 10% Pd/C, and the reaction mixture was
stirred under an atmosphere of hydrogen gas. The catalyst was
filtered, and the filtrate was processed as usual to give a
colorless oil which was purified by column chromatography
(1:9 ethyl acetate/hexane) to give the saturated ketoester as a
colorless oil (904 mg, 90%): [R]D -5.8 (c 0.5, CHCl3); LRMS
(m/z) (M+ + 1) 434; HRMS (m/z) (M+ + 1) calcd for C24H36NO6
434.2542, found 434.2551. To a solution of the above compound
(500 mg, 1.15 mmol) in methanol (20 mL) was added sodium
borohydride (excess), and the reaction was stirred at 0 °C until
there was no remaining starting material (observed by TLC).
The reaction mixture was quenched by the addition of a
solution of ammonium chloride, and the solvents were re-
moved. The mixture was triturated with diethyl ether, and
the solvent was removed under reduced pressure to give a dark
oil. The oil was dissolved in toluene (5 mL), pTSA(cat.) was
added, and the mixture was heated to reflux for 5 h. The
toluene was removed, and the crude was purified by column
chromatography (ethyl acetate) to give 47 as a colorless oil
(186 mg, 40%): [R]D -16 (c 0.7, CHCl3); IR (CDCl3) 2929, 1780,
1693, 1611, 1513, 1462, 1365, 1250, 1178, 1032 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.01 (d, 2H, J ) 8 Hz), 6.74 (d, 2H, J ) 8
Hz), 4.93 (m, 1H), 4.62 (s, 1H), 4.04 (m, 1H), 3.73 (s, 3H), 2.48-
2.20 (m, 5H), 2.06-1.70 (m, 3H), 1.31 (s, 9H), 1.01 (d, 3H, J )
8 Hz), 0.92 (d, 3H, J ) 8 Hz); 13C NMR (75 MHz, CDCl3) δ
172.8, 159.2, 159.1, 131.6, 129.3, 113.4, 83.8, 68.2, 56.0, 54.9,
51.0, 41.9, 35.8, 25.4, 25.4, 20.1, 17.8; LRMS (m/z) (M+ + 1)
404; HRMS (m/z) (M+ + 1) calcd for C23H34NO5 404.2427, found
404.2448.
32.1, 31.7, 29.3, 25.9, 25.4; LRMS (m/z) (M+ + 1) 462; HRMS
(m/z) (M+ + 1) calcd for C26H40NO6 462.2864, found 462.2855.
5S-(4S-Isop r op en yl-5-oxot et r a h yd r ofu r a n -2S-yl)-4S-
isop r op yl-2S-(4-m et h oxyp h en yl)p yr r olid in e-1-ca r b ox-
ylic Acid ter t-Bu tyl Ester , 49. To a solution of 48 (100 mg,
0.22 mmol) in dry dichloromethane (2 mL) at -60 °C was
added PCl5 (50 mg, 1.1 equiv, 0.24 mmol), and the reaction
mixture was stirred for 30 min. The reaction mixture was
quenched with saturated sodium bicarbonate solution and then
extracted with dichloromethane (3 × 10 mL). The combined
organic extracts were dried over anhydrous sodium sulfate,
and the solvent was removed to give a yellow oil which was
purified by column chromatography (1:9 ethyl acetate/hexane)
to give 49 as a colorless oil (59 mg, 62%): [R]D -65 (c 1, CHCl3);
IR (CDCl3) 2692, 1776, 1693, 1651, 1513, 1456, 1456, 1366,
1298, 1271, 1249, 1179, 1112 cm-1; 1H NMR (400 MHz, CDCl3)
δ 6.99 (d, 2H, J ) 9 Hz), 6.80 (d, 2H, J ) 9 Hz), 5.0-4.5 (m,
5H), 3.77 (s, 3H), 3.32 (t, 1H, J ) 8 Hz), 2.63 (m, 1H), 2.32-
2.20 (m, 3H), 2.09-1.65 (m, 5H), 1.04 (s, 9H), 0.98-0.75 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 176.3, 158.4, 155.7, 140.0,
133.9, 128.5, 114.3, 133.1, 81.0, 79.5, 65.7, 58.7, 55.1, 50.0, 47.1,
31.2, 30.5, 28.2, 27.7, 21.6, 21.1, 20.3; LRMS (m/z) (M+ + 1)
444; HRMS (m/z) (M+ + 1) calcd for C26H38NO5 444.2741, found
444.2750.
5S-(3-Bu t ylca r b a m oyl-1S-h yd r oxy-4S-m et h ylp en t yl)-
4S-isopr opyl-2S-(4-m eth oxyph en yl)pyr r olidin e-1-car box-
ylic Acid ter t-Bu tyl Ester , 50. To a solution of 49 (50 mg,
0.11 mmol) in ethyl acetate (3 mL) was added 10% Pd/C, and
the reaction mixture was stirred under an atmosphere of
hydrogen gas. The catalyst was filtered, solvent was removed,
and the residue was purified by column chromatography (1:9
ethyl acetate/hexane) to give a colorless oil (48 mg, 95%): [R]D
-28.8 (c 1, CHCl3); LRMS (m/z) (M+ + 1) 446; HRMS (m/z)
(M+ + 1) calcd for C26H38NO5 446.2914, found 446.2906. To a
solution of n-butylamine (26 mg, 4 equiv, 0.36 mmol) in dry
dichloromethane (1 mL) was added trimethylaluminum (0.18
mL, 2 M solution in toluene, 0.36 mmol), and the reaction
mixture was stirred at room temperature for 5 min. This
solution was transferred via cannula to a solution of the
lactone (40 mg, 0.09 mmol) in dry dichloromethane (2 mL).
The reaction mixture was stirred at room temperature over-
night and quenched with a saturated solution of ammonium
chloride, and the organic phase was separated. The aqueous
phase was extracted with dichloromethane (3 × 10 mL), and
the combined organic extracts were dried over anhydrous
sodium sulfate and filtered. The solvent was removed to give
a dark oil which was purified by column chromatography (1:3
ethyl acetate/hexane) to give 50 as a colorless oil (28 mg,
60%): [R]D -30.1 (c 0.9, CHCl3); IR (CDCl3) 3307, 2958, 1660,
1513, 1464, 1394, 1366, 1248, 1178, 1113 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.00 (d, 2H, J ) 8 Hz), 6.81 (d, 2H, J ) 9 Hz),
5.91 (m, 1H), 4.76 (d, 1H, J ) 7 Hz), 4.11 (t, 1H, J ) 9 Hz),
3.79 (s, 3H), 3.35 (t, 1H, J ) 11 Hz), 3.30-3.19 (m, 2H), 2.19-
1.20 (m, 17H), 1.08 (s, 9H), 0.95-0.71 (m, 22H); 13C NMR (75
MHz, CDCl3) δ 175.1, 158.3, 133.6, 128.4, 113.4, 80.2, 74.7,
65.0, 63.3, 55.1, 49.7, 38.7, 36.8, 31.7, 30.3, 30.3, 27.8, 27.6,
21.8, 21.1, 21.0, 20.0, 13.7; LRMS (m/z) (M+ + 1) 519; HRMS
(m/z) (M+ + 1) calcd for C30H51N2O5 519.3800, found 519.3798.
5S-[4S-(1-Hyd r oxy-1-m eth yleth yl)-5-oxotetr a h yd r ofu -
r an -2S-yl]-3S-isopr opyl-2S-(4-m eth oxyph en yl)pyr r olidin e-
1-ca r boxylic Acid ter t-Bu tyl Ester , 48. To a solution of 47
(150 mg, 0.037 mmol) in dry THF (4 mL) at -78 °C was added
LiHMDS (0.41 mL, 1.1 equiv, 1 M solution in THF), and the
reaction mixture was stirred for 1 h. Dry acetone (107 mg, 5
equiv, 0.18 mmol) was then added, and the reaction mixture
was stirred for an additional 1 h. The reaction mixture was
quenched by the addition of a saturated ammonium chloride
solution and then extracted with ethyl acetate (3 × 10 mL).
The combined extracts were dried over anhydrous sodium
sulfate, and the solvent was removed to give a dark oil.
Purification by column chromatography (1:4 ethyl acetate/
hexane) gave 48 as a colorless oil (113 mg, 66%): [R]D -6.5 (c
1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.00 (d, 2H, J ) 8
Hz), 6.81 (d, 2H, J ) 9 Hz), 4.78 (d, 1H, J ) 7 Hz), 4.60 (m,
1H), 4.41 (m, 1H), 3.78 (m, 3H), 2.75 (m, 2H), 2.40-1.70 (m,
3H), 1.34-1.17 (2s, 9H), 1.05 (s, 9H), 0.90-0.75 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 183.1, 162.6, 160.1, 138.1, 132.7,
117.3, 85.4, 83.8, 75.2, 70.0, 63.4, 59.4, 54.2, 53.3, 35.8, 32.4,
Ackn owledgm en t. We thank NSERCC and ex.Ciba-
Geigy for generous financial support through the
Medicinal Chemistry Chair Program. We thank Dr.
Michel Simard for X-ray analysis.
1
Su p p or tin g In for m a tion Ava ila ble: Selected H and 13C
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O011184I