Transition-state mimetics for HIV protease inhibitors: Stereocontrolled synthesis of hydroxyethylene and hydroxyethylamine isosteres by ester- derived titanium enolate syn and anti-aldol reactions

Article abstract of DOI:10.1021/jo980159i

Stereocontrolled syntheses of hydroxyethylene dipeptide isostere and aminoalkyl epoxides for hydroxyethylamine isosteres are described. The stereochemistry of both stereogenic centers of the aminoalkyl epoxides 10 and 15 as well as they γ-lactone 17 was assembled by our recently developed highly selective ester-derived titanium enolate aldol reactions. The Ti- enolate of 6 reacted with (benzyloxy)acetaldehyde and cinnamaldehyde to provide the syn-aldol product 7 and anti-aldol product 12, respectively. Removal of the chiral template followed by Curtius rearrangement of the resulting acid provided the desired amine functionality. The present syntheses represent practical and enantioselective entry to a range of other dipeptide isosteres, which are not limited to amino acid derived substituents.

Full text of DOI:10.1021/jo980159i

6146
J . Org. Chem. 1998, 63, 6146-6152
Tr a n sition -Sta te Mim etics for HIV P r otea se In h ibitor s:
Ster eocon tr olled Syn th esis of Hyd r oxyeth ylen e a n d
Hyd r oxyeth yla m in e Isoster es by Ester -Der ived Tita n iu m En ola te
Syn a n d An ti-Ald ol Rea ction s
Arun K. Ghosh* and Steve Fidanze1
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois, 60607
Received J anuary 29, 1998
Stereocontrolled syntheses of hydroxyethylene dipeptide isostere and aminoalkyl epoxides for
hydroxyethylamine isosteres are described. The stereochemistry of both stereogenic centers of the
aminoalkyl epoxides 10 and 15 as well as the γ-lactone 17 was assembled by our recently developed
highly selective ester-derived titanium enolate aldol reactions. The Ti-enolate of 6 reacted with
(benzyloxy)acetaldehyde and cinnamaldehyde to provide the syn-aldol product 7 and anti-aldol
product 12, respectively. Removal of the chiral template followed by Curtius rearrangement of
the resulting acid provided the desired amine functionality. The present syntheses represent
practical and enantioselective entry to a range of other dipeptide isosteres, which are not limited
to amino acid derived substituents.
Ever since the recognition that the virally encoded HIV
stereoselective synthesis of hydroxyethylene or hydroxy-
ethylamine isosteres with defined absolute configuration
is very important for biological activity.
It is not surprising that since the first synthesis of
these dipeptide mimics, a considerable effort has been
devoted to synthesizing these dipeptide isosteres and
their structural variants.7 The majority of previous
protease is essential for the replication of infective virus,
design and synthesis of protease inhibitors has become
the subject of immense interest.2 Consequently, numer-
ous potent and selective HIV protease inhibitors have
been designed based upon the transition-state mimetic
concept which incorporates hydroxyethylene and hy-
droxyethylamine dipeptide isosteres at the scissile site.3
Recently, three peptidomimetic protease inhibitors in-
corporating dipeptide isosteres have been approved by
the U.S. Food and Drug Administration for the treatment
of AIDS.4 In general, the absolute configuration of the
hydroxyl-bearing asymmetric center of these dipeptide
isosteres has a pronounced effect on HIV protease inhibi-
tory potencies. Protease inhibitors based upon the hy-
droxyethylene isostere have shown a distinct preference
for the S-configuration at the hydroxyl-bearing center.5
Protease inhibitors with a hydroxyethylamine isostere,
however, have shown a marked preference for the R-
configuration at the hydroxyl group.6 In either event,
(5) (a) Ghosh, A. K.; McKee, S. P.; Thompson, W. J .; Darke, P. L.;
Zugay, J . C. J . Org. Chem. 1993, 58, 1025. (b) Ghosh, A. K.; Thompson,
W. J .; McKee, S. P.; Duong, T. T.; Lyle, T. A.; Chen, J . C.; Darke, P.
L.; Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Huff, J . R.; Anderson, P.
S. J . Med. Chem. 1993, 36, 292. (c) Dreyer, G. B.; Metcalf, B. W.;
Tomaszek, T. A.; Carr, T. J .; Chandler, A. C.; Hyland, L.; Fakhoury,
S. A.; Magaard, V. W.; Moore, M. L.; Srickler, J . E.; Debouck, C.; and
Meek, T. D.; Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 9752. (d) McQuade,
T. J .; Tomasselli, A. G.; Liu, L.; Karacostas, V.; Moss, B.; Sawyer, T.
K.; Heinrickson, R. L.; Tarpley, W. G. Science 1990, 247, 454. (e)
Ashorn, P.; McQuade, T. J .; Thaisrivongs, S.; Tomasselli, A. G.;
Tarpley, W. G.; and Moss, B. Proc. Natl. Acad. Sci. U.S.A. 1990, 87,
7472 and references therein.
(6) (a) Ghosh, A. K.; Thompson, W. J .; Lee, H. Y.; McKee, S. P.;
Munson, P. M.; Duong, T. T.; Darke, P. L.; Zugay, J . A.; Emini, E. A.;
Schleif, W. A.; Huff, J . R.; Anderson, P. S. J . Med. Chem. 1993, 36,
924. (b) Ghosh, A. K.; Thompson, W. J .; Holloway, M. K.; McKee, S.
P.; Duong, T. T.; Lee, H. Y.; Munson, P. M.; Smith, A. M.; Wai, J . M.;
Darke, P. L.; Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Huff, J . R.;
Anderson, P. S. J . Med. Chem. 1993, 36, 2300. (c) Ghosh, A. K.; Lee,
H. Y.; Thompson, W. J .; Culberson, J . C.; Holloway, M. K.; McKee, S.
P.; Munson, P. M.; Duong, T. T.; Smith, A. M.; Darke, P. L.; Zugay, J .
A.; Emini, E. A.; Schleif, W. A.; Huff, J . R.; Anderson, P. S. J . Med.
Chem. 1994, 37, 1177. (d) Ghosh, A. K.; Thompson, W. J .; Fitzgerald,
P. M. D.; Culberson, J . C.; Axel. M. G.; McKee, S. P.; Huff, J . R.;
Anderson, P. S. J . Med. Chem. 1994, 37, 2506. (e) Vazquez, M. L.;
Bryant, M. L.; Clare, M.; DeCrescenzo, G. A.; Doherty, E. M.; Freskos,
J . N.; Getman, D. P.; Houseman, K. A.; J ulien, J . A.; Kocan, G. P.;
Mueller, R. A.; Shieh, H.-S.; Stallings, W. C.; Stegeman, R. A.; Talley,
J . J . J . Med. Chem. 1995, 38, 581. (f) Ghosh, A. K.; Thompson, W. J .;
Munson, P. M.; Liu, W.; Huff, J . R. Bioorg. Med. Chem. Lett. 1995, 5,
83. (g) Ghosh, A. K.; Kincaid, J . F.; Walters, D. E.; Chen, Y.; Chaudhuri,
N. C.; Thompson, W. J .; Culberson, C.; Fitzgerald, P. M. D.; Lee, H.
Y.; McKee, S. P.; Munson, P. M.; Duong, T. T.; Darke, P. L.; Zugay, J .
A.; Schleif, W. A.; Axel, M. G.; Lin, J .; Huff, J . R. J . Med. Chem. 1996,
39, 3278 and references therein.
(1) University Fellow, University of Illinois at Chicago.
(2) (a) O’Brien, W. A.; Hartigan, P. M.; Martin, D.; Esiinhart, J .;
Hill, A.; Benoit, S.; Rubin, M.; Simberkoff, M. S.; Hamilton, J . D. N.
Engl. J . Med. 1996, 334, 426. (b) Katz, R. A.; Skalka, A. M. Annu.
Rev. Biochem. 1994, 63, 133. (c) Debouck, C. AIDS Res. Hum.
Retroviruses 1992, 8, 153.
(3) (a) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med.
Chem. 1994, 29, 133. (b) Katz, R. A.; Skalka, A. M. Annu. Rev. Biochem.
1994, 63, 133. (c) Huff J . R. J . Med. Chem. 1991, 34, 2305 and
references therein.
(4) (a) Vacca, J . P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.;
McDaniel, S. L.; Darke, P. L.; Zugay, J .; Quintero, J . C.; Blahy, O. M.;
Roth, E.; Sardana, V. V.; Schlabach, A. J .; Graham, P. I.; Condra, J .
H.; Gotlib, L.; Holloway, M. K.; Lin, J .; Chen, I.-W.; Vastag, K.; Ostovic,
D.; Anderson, P. S.; Emini, E. A.; Huff, J . R. Proc. Natl. Acad. Sci.,
U.S.A. 1994, 91, 4096. (b) Kempf, D. J .; Marsh, K. C.; Denissen, J . F.;
McDonald, E.; Vasavononda, S.; Flentge, C. A.; Green, B. G.; Fino, L.;
Park, C. H.; Kong, X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati,
W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J .
J .; Leonard, J .; Norbeck, D. Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
2484. (c) Roberts, N. A.; Martin, J . A.; Kinchington, D.; Broadhurst,
A. V.; Craig, J . C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J .;
Krohn, A.; Lambert, R. W.; Merrett, J . H.; Mills, J . S.; Parkes, K. E.
B.; Redshaw, S.; Ritchie, A. J .; Taylor, D. L.; Thomas, G. J .; Machin,
P. J . Science 1990, 248, 358 and references therein.
(7) (a) Rich, D. H.; Salituro, F. G.; Holliday, M. W. Proc. Am. Pept.
Symp. 8th 1983, 511. (b) Holliday, M. W.; and Rich, R. H. Tetrahedron
Lett. 1983, 24, 4401. (c) Szelke, M.; J ones, D. M.; Atrash, B.; Hallett,
A.; Leckie B. J . Proc. Am. Pept. Symp. 8th 1983, 579. (d) Leckie, B. J .;
Grant, J .; Hallett, A.; Hughes, M.; J ones, D. M.; Szelke, M.; Tree, M.
Scott. Med. J . 1984, 29, 125.
S0022-3263(98)00159-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/11/1998

Transition-State Mimetics for HIV Protease Inhibitors
J . Org. Chem., Vol. 63, No. 18, 1998 6147
Sch em e 1a
syntheses involved the N-protected L-amino acids as the
starting materials.8 Beside limitations with regard to
stereochemical controls at the hydroxyl-bearing centers,
these syntheses are confined to natural amino acid de-
rived substitutents. Herein we report the stereocon-
trolled synthesis of hydroxyethylamine and hydroxyeth-
ylene isosteres in which all the stereogenic centers were
constructed by asymmetric synthesis. The present syn-
thesis is easily amenable to a range of dipeptide isosteres
with a wide variety of substituents that are not limited
to natural amino acid derived side chains.9
The key element of our synthesis involved the asym-
metric aldol reaction to set the C-5 and C-2, C-3 stereo-
genic centers of the hydroxyethylene and hydroxyethy-
lamine isosteres, respectively. The corresponding C-5
and C-3 amine functionalities were planned to be intro-
duced by a Curtius rearrangement of the resulting â-hy-
droxy acids.10 Therefore, stereocontrolled asymmetric
syn-aldol and anti-aldol reactions will provide access to
appropriate stereochemistry for the synthesis of hydroxy-
ethylamine and hydroxyethylene isosteres, respectively.
We recently demonstrated cis-1-arylsulfonamido-2-inda-
nyl ester-derived titanium enolate reacts with monoden-
tate and bidentate aldehydes to provide anti-aldol11 and
syn-aldol12 products with high diastereofacial selectivity.
Thus, the syn- or the anti-aldol product will be prepared
from the same chiral template depending upon the choice
of aldehyde. These aldol reactions have already been
shown to be amenable to a variety of side chains.11,12 The
aminoalkyl epoxide 2 is the precursor for the synthesis
a
Key: (a) dihydrocinnamic acid, 4-DMAP, DCC, CH2Cl2, 0 to
23 °C, 85%; (b) TiCl4, iPr2NEt, then BnOCH2CHO, TiCl4, CH2Cl2,
-78 °C, 97%; (c) 30% H2O2, LiOH, THF:H2O (3:1), 23 °C, 82%; (d)
DPPA, Et3N, CH2Cl2, 23 °C, 92%; (e) aq KOH, EtOH, 70 °C; (f)
Boc2O, CH2Cl2, 23 °C, 87%; (g) H2, Pd(OH)2, EtOAc:MeOH (4:1),
23 °C, quantitative; (h) PPh3, DEAD, CHCl3, reflux, 61%; (i)
Me2CHCH2NH2, 2-propanol, reflux, 3-5 h; (j) p-MeO-PhSO2Cl,
CH2Cl2, aq NaHCO3, 23 °C, 83% (from 10).
with DCC and DMAP afforded the 3-phenylpropionate
ester 6 in 85% yield. Generation of titanium enolate of
6 and subsequent reaction with (benzyloxy)acetaldehyde
afforded the aldol adduct 7 as a single diastereomer in
97% yield after silica gel chromatography.12 The chiral
auxiliary was removed by exposure to lithium hydro-
peroxide in aqueous THF at 23 °C for 3 h. The resulting
acid was subjected to Curtius rearrangement with di-
phenylphosphoryl azide and triethylamine in methylene
chloride to afford the oxazolidinone 8 in 75% yield (from
7). The stereochemistry of the oxazolidinone was set by
the precedence of the Curtius rearrangement proceeding
with retention of configuration at the migrating carbon.10
Also, the coupling constants of the vicinal protons at C-4
and C-5 of the oxazolidinone, which were established by
homonuclear decoupling experiments, are consistent with
syn stereochemistry (J AB ) 8 Hz).14 The oxazolidinone
8 was converted to protected amino alcohol derivative 9
by hydrolysis of the oxazolidinone with aqueous KOH at
70 °C followed by reaction of the resulting amine with
di-tert-butyl dicarbonate in a mixture of CH2Cl2 and
water in a one-pot procedure (87% yield). Catalytic
hydrogenation of benzyl ether 9 over Pd(OH)2/C (Pearl-
of hydroxyethylamine isostere 1, and the γ-lactone 4 is
intermediate for the synthesis of hydroxyethylene dipep-
tide isostere 3.5,6,13
As shown in Scheme 1, acylation of enantiomerically
pure (1S,2R)-sulfonamide 512 with dihydrocinnamic acid
(8) (a) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J . P.;
Hirshfield, J .; Veber, D. F. J . Org. Chem. 1985, 50, 4615. (b) Fray, A.
H.; Kaye, R. L.; and Kleinman, E. F. J . Org. Chem. 1986, 51, 4828. (c)
Kempf, D. J . J . Org. Chem. 1986, 51, 3921. (d) Bradbury, R. H.; Revill,
J . M.; Rivett, J . E.; Waterson, D. Tetrahedron Lett. 1989, 30, 3845. (e)
Herold, P.; Duthaler, R.; Rihs, G.; Angst, C. J . Org. Chem. 1989, 54,
1178. (f) Chakravarty, P. K.; de Laszlo, S. E.; Sarnella, C. S.; Springer,
J . P.; Schuda, P. F. Tetrahedron Lett. 1989, 30, 415, (g) Greenlee, W.
J . J . Med. Res. Rev. 1990, 10, 173 and references therein.
(9) For previous nonamino acid derived synthesis, see; (a) Ghosh,
A. K.; Hussain, K. A.; Fidanze, S. J . Org. Chem. 1997, 62, 6080. (b)
Ghosh, A. K.; McKee, S. P.; Lee, H. Y.; Thompson, W. J . J . Chem. Soc.,
Chem. Commun. 1992, 273, (c) Ghosh, A. K.; McKee, S. P.; Thompson,
W. J . J . Org. Chem. 1991, 56, 6500 and ref 6d.
(10) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc.
1972, 94, 6203. (b) Grunewald, G. L.; Ye, Q. J . Org. Chem. 1988, 53,
4021. (c) Ghosh, A. K.; Liu, W. J . Org. Chem. 1996, 61, 6175.
(11) Ghosh, A. K.; Onishi, M. J . Am. Chem. Soc. 1996, 118, 2527.
(12) Ghosh, A. K.; Fidanze, S.; Onishi, M.; Hussain, K. A. Tetrahe-
dron Lett. 1997, 38, 7171.
(13) (a) Rich, D. H.; Green, J .; Toth, M. V.; Marshall, G. R.; Kent,
S. B. H. J . Med. Chem. 1990, 33, 1285. (b) Rich, D. H.; Sun, C.-Q.;
Vara Prasad, J . V. N.; Pathiasseril, A.; Toth, M. V.; Marshall, G. R.;
Clare, M.; Mueller, R. A.; Houseman, K. J . Med. Chem. 1991, 34, 1222.
(14) Ghosh, A. K.; McKee, S. P.; Thompson, W. J . Tetrahedron Lett.
1991, 32, 5729 and references therein.

6148 J . Org. Chem., Vol. 63, No. 18, 1998
Ghosh and Fidanze
Sch em e 2a
man’s catalyst) in a mixture of ethyl acetate and MeOH
(4:1) furnished the corresponding diol quantitatively.
Exposure of the resulting diol to Mitsunobu reaction con-
ditions with triphenylphosphine and diethyl azodicar-
boxylate in chloroform afforded the aminoalkyl epoxide
10 in 61% yield after chromatography.15 Epoxide 10 is
the versatile precursor for the synthesis of numerous
hydroxyethylamine-derived potent HIV protease inhibi-
tors including recently approved saquinavir.4c,6,13 Reac-
tion of the epoxide 10 with isobutylamine in 2-propa-
nol at reflux provided the corresponding amino alcohol
which, upon reaction with p-methoxybenzenesulfonyl
chloride, furnished the protected hydroxyethylsulfona-
mide isostere 11.6e
The synthesis of hydroxyethylene isostere is depicted
in Scheme 2. Titanium enolate of 6 was prepared as
described previously. Reaction of this enolate with cin-
namaldehyde precomplexed with TiCl4 afforded the anti-
aldol product 12 exclusively in 48% yield. When the
same titanium enolate was reacted with 2.5 equiv of
cinnamaldehyde precomplexed with 2.5 equiv of di-n-
butyl boron triflate, the anti-aldol product 12 was ob-
tained as a major product (6.1:1 mixture ratio by 1H NMR
and HPLC) in 68% isolated yield after silica gel chroma-
tography.16 Removal of the chiral auxiliary, followed by
Curtius rearrangement as described above, provided the
oxazolidinone 13 in 78% yield from 12. The vicinal
coupling constant of oxazolidinone 13, which was also
established by homonuclear decoupling experiments, is
consistent with an anti stereochemical relationship (J AB
) 6.3 Hz).14 At this point, 1H and 13C NMR data showed
only a single diastereomer. Basic hydrolysis of 13 and
subsequent protection of amine furnished the protected
amino alcohol 14. BOC-protected amino alcohol 14 was
converted to aminoalkyl epoxide 15 as well as the
γ-lactone 18, a precursor for the hydroxyethylene isos-
tere. Thus, ozonolytic cleavage of the double bond
followed by reductive workup with NaBH4 afforded the
corresponding diol.17 The resulting diol was subjected
to Mitsunobu conditions to afford the 2R,3S-epoxide 15
which has been previouly converted to both hydroxyeth-
ylene and hydroxyethylamine isosteres.5,6,13
The BOC-derivative 14 was then transformed into the
hydroxyethylene isostere. As shown, ozonolytic cleavage
of the olefin 14 followed by reductive workup with tri-
phenylphosphine gave the corresponding aldehyde. The
crude aldehyde was then subjected to a Horner-Emmons
olefination with triethyl phosphonoacetate and sodium
hydride to provide the unsaturated ester 16 in 44% yield
in a two-step sequence. Catalytic hydrogenation of 16
over 10% Pd/C provided the saturated ester quantita-
tively. The resulting ester was then lactonized with
acetic acid in refluxing toluene to afford the γ-lactone 17
in 68% yield. The lactone 17 is the versatile intermediate
for the synthesis of numerous hydroxyethylene isostere-
a
Key: (a) TiCl4, iPr2NEt, then (E)-PhCHdCHCHO, Bu2BOTf,
CH2Cl2, -78 °C, 68%; (b) 30% H2O2, LiOH, THF:H2O (3:1), 23 °C,
85%; (c) DPPA, Et3N, benzene, reflux, 92%; (d) aq KOH, EtOH,
70 °C; (e) BOC2O, CH2Cl2, 23 °C, 85%; (f) O3, EtOH, -78 °C, then
NaBH4, EtOH, 23 °C, 71%; (g) PPh3, DEAD, CHCl3, reflux, 88%;
(h) O3, CH2Cl2, PPh3, -78 to 23 °C; (i) NaH, (EtO)2P(O)CH2CO2Et,
THF, 0 to 23 °C, 44% (from 14); (j) H2, 10% Pd/C, EtOAc:MeOH
(1:1), 23 °C, 99%; (k) AcOH, toluene, 110 °C, 68%; (l) LiHMDS,
BnI, THF, -78 °C, 77%; (m) Me3Al, PhCH2NH2, CH2Cl2, 40 °C, 2
h, 72%.
derived HIV protease inhibitors as well as renin inhi-
bitors.5,8g For introduction of a suitable substituent at
C-5, stereoselective alkylation of a similar lactone has
been accomplished previously.8b For the preparation of
hydroxyethylene Phe-Phe isostere, alkylation of 17 was
carried out with lithium hexamethyldisilazide and benzyl
iodide in THF at -78 °C to afford the alkylated lactone
18 as the major diastereomer (about 5% cis-alkylation
product) which was separated by silica gel chromatog-
raphy. The reaction of lactone 18 with benzylamine in
the presence of trimethylaluminum in CH2Cl2 according
to Weinreb procedure furnished the hydroxyamide 19 in
72% yield.18 Compounds 11 and 19 have exhibited
enzyme inhibitory potencies of (IC50 values) 34 and 75
nM, respectively, in the assay protocol developed by Toth
and Marshall.19 The lactone 18 has been previously
(15) (a) Branalt, J .; Kvarnstrom, I.; Classon, B.; Samuelsson, B.;
Nillroth, U.; Danielson, U. H.; Karlen, A.; Hallberg, A. Tetrahedron
Lett. 1997, 38, 3483. (b) Robinson, P. L.; Barry, C. N.; Bass, S. W.;
J arvis, S. E.; Evans, S. A. J . Org. Chem. 1983, 48, 5396.
(16) Mechanistic details of this reaction is the subject of ongoing
investigation.
(17) Barrish, J . C.; Gordon, E.; Alam, M.; Lin, P.-F.; Bisacchi, G. S.;
Chen, P.; Cheng, P. T. W.; Fritz, A. W.; Greytok, J . A.; Hermsmeier,
M. A.; Humphreys, W. G.; Lis, K. A.; Marella, M. A.; Merchant, Z.;
Mitt, T.; Morrison, R. A.; Obermeier, M. T.; Pluscec, J .; Skoog, M.;
Slusarchyk, W. A.; Spergel, S. H.; Stevenson, J . M.; Sun, C.-Q.;
Sundeen, J . E.; Taunk, P.; Tino, J . A.; Warrack, B. M.; Colonno, R. J .;
Zahler, R. J . Med. Chem. 1994, 37, 1758.
(18) Basha, A.; Lipton, M.; and Weinreb, S. M. Tetrahedron Lett.
1977, 4171.

Transition-State Mimetics for HIV Protease Inhibitors
J . Org. Chem., Vol. 63, No. 18, 1998 6149
(1S ,2R )-ci s-N -(2,3-d ih y d r o -2-((2S,3S)-3-h y d r o x y -2-
(p h en ylm eth yl)-4-(p h en ylm eth oxy)-1-oxobu toxy)-1H-in -
d en -1-yl)-4-m eth ylben zen esu lfon a m id e (7). To a stirred
solution of phenylpropionate ester 6 (1.18 g, 2.71 mmol) in
CH2Cl2 (30 mL) at 0 °C was added a 1 M solution of TiCl4 (3.28
mL, 3.28 mmol, Aldrich) in CH2Cl2. The resulting solution
was allowed to warm to 23 °C and stirred an additional 15
min. To this solution was added N,N-diisopropylethylamine
(1.79 mL, 10.3 mmol) in a dropwise manner. The mixture was
stirred for 2.0 h at 23 °C. In a separate flask, to a stirred
solution of (benzyloxy)acetaldehyde (880 mg, 5.85 mmol) in
CH2Cl2 (30 mL) at -78 °C, was added a 1 M solution of TiCl4
(5.91 mL, 5.91 mmol) in CH2Cl2. The resulting mixture was
stirred for 30 min at -78 °C, and the above enolate solution
was added to the aldehyde solution dropwise via syringe over
a period of 5 min. The mixture was stirred at -78 °C for 2 h
and then quenched by addition of aqueous ammonium chloride.
The resulting mixture was warmed to 23 °C. The layers were
separated, and the aqueous layer was extracted with CHCl3.
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure to afford the crude aldol products. Silica gel chro-
matography of the crude product yielded the title aldol product
converted into potent and selective HIV protease inhibi-
tors.4
In conclusion, we have achieved convenient and enan-
tioselective syntheses for aminoalkyl epoxides 10 and 15
as well as the substituted γ-lactone 18. The important
utility of these intermediates in the synthesis of various
potent HIV protease inhibitors has been previously
documented.2 The key steps of the current synthesis are
the ester-derived Ti-enolate-based asymmetric syn- or
anti-aldol reaction and Curtius rearrangement of the
resulting â-hydroxy acid. The present syntheses should
provide access to a structurally diverse class of inhibitors
of HIV protease and other important aspartyl proteases.
Application of these methods in the synthesis of novel
HIV protease inhibitors is currently in progress.
Exp er im en ta l Section
All melting points are uncorrected. Analytical HPLC analy-
ses were performed on a µBondapak C-18 column, 4.6 mm ×
25 cm, 40% CH3CN/H2O as solvent, flow rate 1.5 mL/min.
Anhydrous solvents were obtained as follows: methylene
chloride and chloroform, distillation from CaH2; tetrahydro-
furan, distillation from sodium/benzophenone. All other sol-
vents were HPLC grade. All air-sensitive reactions were run
under a N2 atmosphere. Column chromatography was per-
formed with Whatman 240-400 mesh silica gel under low
pressure of 5-10 psi. Thin-layer chromatography (TLC) was
carried out with E. Merck silica gel 60 F-254 plates.
7 (1.54 g, 97% yield) as a white solid (mp 97-99 °C). [R]23
D
1
-25.5 (c ) 2.51, CHCl3); H NMR (200 MHz, CDCl3): δ, 2.42
(s, 3H), 2.55 (d, 1H, J ) 17.1 Hz), 2.82 (m, 2H), 2.96 (m, 1H),
3.31 (d, 1H, J ) 3.7 Hz), 3.43-3.55 (m, 2H), 4.13 (m, 1H), 4.48
(dd, 2H, J ) 4.5, 17.2 Hz), 4.84 (dd, 1H, J ) 4.8, 9.7 Hz), 5.18
(t, 1H, J ) 4.5 Hz), 6.17 (d, 1H, J ) 9.8 Hz), 6.92 (m, 2H),
7.18-7.42 (m, 14H), 7.77 (d, 2H, J ) 8.2 Hz); 13C NMR (50
MHz, CDCl3): δ, 21.5, 31.5, 36.9, 50.1, 59.6, 70.6, 71.5, 73.3,
75.8, 124.3, 124.8, 126.3, 127.0, 127.3, 127.8, 128.3, 128.4,
128.7, 129.7, 137.6, 137.8, 138.5, 138.8, 140.0, 143.4, 171.9;
IR: 3420, 3284, 1732, 1337, 1160 cm-1; mass (CI) m/z 584 (M+
- H), 302, 155. Anal. Calcd for C34H35NO6S: C, 69.72; H,
6.02; N, 2.39. Found: C, 69.38; H, 6.23; N, 2.12.
(1S,2R)-cis-N-(2,3-Dih yd r o-2-h yd r oxy-1H-in d en -1-yl)-4-
m et h ylben zen esu lfon a m id e (5). To a stirred mixture of
optically active (1S,2R)-1-aminoindan-2-ol (5.00 g, 33.5 mmol),
p-toluenesulfonyl chloride (6.50 g, 33.6 mmol), and DMAP (0.24
g, 2.4 mmol) in CH2Cl2 (200 mL) at 23 °C was added
triethylamine (14.0 mL, 101 mmol). The resulting mixture
was stirred for 2 h at 23 °C. After this period, the reaction
mixture was washed with water, saturated aqueous sodium
bicarbonate, and brine and dried over anhydrous Na2SO4.
Removal of solvent under reduced pressure afforded a pale
yellow residue, which was recrystallized from CHCl3/hexane
to provide the title sulfonamide (9.37 g, 92% yield) as a white
(4S,5S)-4-(P h en ylm eth yl)-5-[(p h en ylm eth oxy)m eth yl]-
2-oxa zolid in on e (8). To a stirred solution of aldol adduct 7
(1.50 g, 2.56 mmol) in a mixture (3:1) of THF and H2O (25
mL) were added 30% H2O2 (1.74 mL, 15.4 mmol) and LiOH‚
H2O (322 mg, 7.68 mmol). The resulting mixture was stirred
at 23 °C for 3 h. After this period, 1.5 M aqueous Na2SO3 and
saturated aqueous sodium bicarbonate were added. The
resulting mixture was concentrated under reduced pressure,
and the residue was extracted with CHCl3. The aqueous layer
was then acidified with 1 N HCl to pH 3 and then extracted
thoroughly with CHCl3. This organic layer was dried over
anhydrous Na2SO4 and concentrated to yield the (2S,3S)-2-
Benzyl-4-(benzyloxy)-3-hydroxybutanoic acid (633 mg, 82.3%
solid (mp 135-136 °C). [R]23 +38.4 (c ) 1.12, CHCl3); 1H
D
NMR (200 MHz, CDCl3): δ, 1.87 (br s, 1H), 2.46 (s, 3H), 2.88
(dd, 1H, J ) 1.5, 16.6 Hz), 3.07 (dd, 1H, J ) 4.9, 16.6 Hz),
4.34 (td, 1H, J ) 1.6, 5.0 Hz), 4.70 (dd, 1H, J ) 4.8, 9.2 Hz),
5.22 (d, 1H, J ) 8.7 Hz), 7.08-7.26 (m, 4H), 7.35 (d, 2H, J )
8.2 Hz), 7.88 (d, 2H, J ) 8.3 Hz); IR (neat): 3434, 1644, 1430,
1333, 1157 cm-1; mass (EI) m/z 302 (M+ - H), 148, 130, 103,
91. Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62.
Found: C, 63.73; H, 6.02; N, 4.42.
yield) as a white solid (mp 96-97 °C). [R]23 -9.09 (c ) 10.1,
D
CHCl3); 1H NMR (200 MHz, CD3COCD3): δ, 3.00 (m, 3H), 3.60
(m, 2H), 4.11 (m, 1H), 4.54 (s, 2H), 7.22-7.42 (m, 10 H); 13C
NMR (50 MHz, CD3COCD3): δ, 33.7, 50.2, 70.4, 71.7, 73.4,
126.4, 127.8, 128.4, 128.9, 137.5, 138.8, 178.3. IR: 3420, 1645,
1239, 1186; mass (EI) m/z 300 (M+), 149, 91.
(1S,2R)-cis-N-[2,3-Dih yd r o-2-(3-p h en yl-1-oxop r op oxy)-
1H-in d en -2-yl]-4-m eth ylben zen esu lfon a m id e (6). To a
stirred solution of N-tosyl-1-aminoindan-2-ol 5 (2.00 g, 6.57
mmol), DMAP (0.40 g, 3.29 mmol), and dihydrocinnamic acid
(0.99 g, 6.57 mmol) in CH2Cl2 (30 mL) was added N,N′-
dicyclohexylcarbodiimide (2.03 g, 9.86 mmol) in CH2Cl2 (5 mL).
The resulting slurry was stirred at 23 °C for 18 h. The slurry
was then filtered through a cotton plug and concentrated to
afford a residue which was purified by silica gel chromatog-
raphy to yield the title ester 6 (2.40 g, 85% yield) as a white
To a stirred solution of the above acid (550 mg, 1.83 mmol)
in CH2Cl2 (25 mL) were added diphenylphosphoryl azide (0.59
mL, 2.75 mmol) and triethylamine (0.38 mL, 2.75 mmol). The
mixture was stirred at 23 °C for 48 h, and then the solvent
was removed under reduced pressure. The residue was
chromatographed over silica gel to afford the title oxazolidi-
none 8 as an oil (499 mg, 92% yield). [R]23 -65.4 (c ) 0.52,
D
CHCl3); 1H NMR (200 MHz, CDCl3): δ, 2.7 (dd, 1H, J ) 13.3,
11.1 Hz), 2.95 (dd, 1H, J ) 3.5, 13.5 Hz), 3.74 (d, 2H, J ) 5.6
Hz), 4.05 (m, 1H), 4.58 (s, 2H), 4.84 (q, 1H, J ) 5.6 Hz), 5.83
(br s, 1H), 7.02-7.38 (m, 10H); 13C NMR (50 MHz, CHCl3): δ,
36.0, 55.8, 67.5, 73.6, 77.4, 126.9, 127.8, 128.5, 128.9, 137.0,
137.5, 158.5; IR (neat): 3446, 1643, 1071 cm-1; mass (CI) m/z
298 (M+ + H), 220, 155, 121.
solid (mp 152-153 °C). [R]23 -68.9 (c ) 1.03, CHCl3); 1H
D
NMR (400 MHz, CDCl3): δ, 2.43 (s, 3H), 2.50 (t, 2H, J ) 7.6
Hz), 2.80 (m, 3H), 3.04 (dd, 1H, J ) 5.0, 17.2 Hz), 4.86 (d, 1H,
J ) 10.3 Hz), 4.95 (dd, 1H, J ) 5.0, 10.3 Hz), 5.10 (t, 1H, J )
4.9 Hz), 7.07-7.28 (m, 11H), 7.74 (d, 2H, J ) 8.2 Hz); IR
(neat): 3503, 3275, 1713, 1643, 1338, 1162 cm-1; mass (EI)
m/z 435 (M+), 355, 302, 130, 91. Anal. Calcd for C25H25
-
(2S,3S)-3-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-p h en yl-
1-(p h en ylm eth oxy)bu ta n -3-ol (9). To a stirred solution of
oxazolidinone 8 (470 mg, 1.58 mmol) in 30 mL of EtOH:H2O
(1:1) was added powdered KOH (355 mg, 6.32 mmol). The
resulting mixture was heated at reflux for 17 h. The solution
was then neutralized to pH ) 7 with 1 N HCl, and the
NO4S: C, 68.94; H, 5.79; N, 3.22. Found: C, 68.73; H, 6.07;
N, 3.51.
(19) Toth, M. V.; Marshall, G. R. Int. J . Pep. Prot. Res. 1990, 36,
544.

6150 J . Org. Chem., Vol. 63, No. 18, 1998
Ghosh and Fidanze
resulting mixture was concentrated under reduced pressure
to a small volume. To the resulting residue was added
CH2Cl2 (15 mL) followed by di-tert-butyl dicarbonate (0.73 mL,
3.16 mmol). The resulting mixture was then stirred at 23 °C
for 3 h. After this period, the layers were then separated, and
the aqueous layer was extracted with CHCl3. The combined
organic layers were then washed with brine, dried over
anhydrous Na2SO4, and concentrated. The residue was chro-
matographed over silica gel to yield the title alcohol 9 (493
mg, 87% yield) as a white solid (mp 111-112 °C). [R]23D -21.7
(c ) 0.46, CHCl3); 1H NMR (400 MHz, CDCl3): δ, 1.40 (s, 9H),
2.90 (d, 2H, J ) 4.4 Hz), 3.57 (m, 3H), 3.81 (m, 1H), 4.01 (m,
1H), 4.55 (s, 2H), 5.01 (d, 1H, J ) 8.9 Hz), 7.22-7.42 (m, 10H).
13C NMR (100 MHz, CHCl3): δ, 28.3, 36.2, 53.9, 71.6, 71.8,
73.4, 79.2, 126.2, 127.8, 128.3, 128.4, 129.5, 137.8, 138.0, 155.8;
IR (neat): 3426, 1689, 1527, 1172 cm-1; mass (EI) m/z 372 (M+
+ H), 280, 180, 120.
2(S)-[1′-(S)-N-((ter t-Bu tyloxyca r bon yl)a m in o)-2-p h en -
yleth yl]oxir a n e (10). To a stirred solution of 9 (470 mg, 1.27
mmol) in 15 mL of EtOAc:MeOH (4:1) was suspended 20% Pd-
(OH)2 (135 mg, 0.25 mmol), and the resulting mixture was
hydrogenated under a balloon filled with hydrogen for 12 h.
After this period, the reaction mixture was filtered through a
Celite pad, and the pad was washed with EtOAc. The filtrate
was concentrated under reduced pressure to provide the
(2S,3S)-3-[N-(tert-Butyloxycarbonyl)amino]-3-benzyl-2-hydroxy-
(100 MHz, CHCl3): δ, 19.9, 20.0, 27.0, 28.2, 35.4, 53.5, 54.6,
55.5, 58.4, 72.7, 79.5, 114.2, 126.2, 128.3, 129.4, 129.5, 129.9,
137.9, 155.9, 162.9; IR (neat): 1695, 1597, 1496, 1259, 1155
cm-1; mass (EI) m/z, 506 (M+); HRMS: m/z (M+) calcd for
C26H38N2O6S, 506.2451, found 506.2466. Anal. Calcd for
C
26H38N2O6S: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.79; H,
7.75; N, 5.61.
(1S,2R)-N-[2,3-Dih ydr o-2-((2S,2S)-(E)-3-h ydr oxy-5-ph en -
yl-2-(p h en ylm eth yl)-1-oxop en t-4-en oxy)-1H-in d en -1-yl]-
4-m eth ylben zen esu lfon a m id e (12). To a stirred solution
of ester 6 (2.00 g, 4.59 mmol) in CH2Cl2 (120 mL) at 0 °C was
added a 1 M solution of TiCl4 (5.05 mL, 5.05 mmol) in
CH2Cl2. The resulting solution was allowed to warm to 23 °C
and stirred an additional 15 min. To this solution was then
added N,N-diisopropylethylamine (3.04 mL, 17.4 mmol) drop-
wise over a period of 5 min, and the mixture was stirred for 2
h at 23 °C and then cooled to -78 °C. In a separate flask, to
a stirred solution of cinnamaldehyde (1.45 mL, 11.5 mmol) in
dry CH2Cl2 (120 mL) at -78 °C was added a 1 M solution of
di-n-butyl boron triflate (11.5 mL, 11.5 mmol) in CH2Cl2. The
resulting solution was stirred for 30 min at -78 °C and then
added to the above enolate at -78 °C via cannula. The
resulting mixture was continued to stir at -78 °C for an
additional 1.5 h, MeOH (40 mL), pH 7 buffer (20 mL), and
30% H2O2 (10 mL) were added successively, and the mixture
was allowed to warm to 23 °C. The resulting mixture was
concentrated under reduced pressure to a small volume, and
the residue was thoroughly extracted with CHCl3. The
combined organic layers were washed with saturated aqueous
sodium bicarbonate and brine and dried over anhydrous
Na2SO4. Evaporation of the solvent afforded a residue which
was chromatographed over silica gel to yield the title aldol
product 12 (1.80 g, 68% yield) as an inseparable mixture (anti:
syn ratio, 6.1:1 by HPLC) of diastereomers, mp ) 78-80 °C.
1H NMR (major isomer, 400 MHz, CHCl3): δ, 2.37 (s, 3H), 2.74
(d, 1H, J ) 17.1 Hz), 2.81-2.97 (m, 4H), 3.71 (d, 1H, J ) 4.4
Hz), 4.37 (m, 1H), 4.81 (dd, 1H, J ) 4.8, 9.4 Hz), 5.24 (t, 1H,
J ) 4.7 Hz), 6.12 (dd, 1H, J ) 7.1, 15.9 Hz), 6.55 (d, 1H, J )
15.8 Hz), 6.62 (d, 1H, J ) 9.4 Hz), 7.02-7.45 (m, 16H), 7.77
(d, 2H, J ) 12.2 Hz); 13C NMR (100 MHz, CHCl3): δ, 21.5,
34.9, 37.1, 53.8, 59.6, 73.4, 75.3, 124.5, 124.8, 126.6, 126.7,
127.2, 127.3, 127.9, 128.3, 128.4, 128.5, 128.7, 128.8, 129.0,
129.7, 132.7, 136.2, 137.5, 138.2, 138.4, 140.2, 143.4, 171.4.
IR (neat): 3416, 3028, 2930, 1731, 1633, 1158 cm-1; mass
(EI) m/z 549 (M+ - H2O), 435, 378, 116, 91. Anal. Calcd for
propan-1-ol (356 mg, quantitative) as a white solid (mp 118-
1
119 °C). [R]23 +8.06 (c ) 0.62, CHCl3); H NMR (400 MHz,
D
CHCl3): δ, 1.36 (s, 9H), 2.88 (dd, 1H, J ) 7.9, 14.1 Hz), 3.06
(dd, 1H, J ) 3.8, 14.1 Hz), 3.41 (d, 1H, J ) 7.9 Hz), 3.53 (br,
2H), 3.66 (s, 2H), 3.86 (m, 1H), 4.70 (d, 1H, J ) 8.7 Hz), 7.22-
7.32 (m, 5H); 13C NMR (100 MHz, CHCl3): δ, 28.2, 36.4, 52.4,
63.0, 73.1, 80.2, 126.5, 128.5, 129.4, 137.4, 156.9; IR: 1658,
1536, 1169; mass (EI) m/z 282 (M+ + H), 120, 57.
To a stirred solution of the above diol (350 mg, 1.24 mmol)
and Ph3P (326 mg, 1.24 mmol) in CHCl3 (25 mL) at 23 °C was
added diethyl azodicarboxylate (0.20 mL, 1.24 mmol). The
resulting mixture was heated at reflux for 72 h. After this
period, the reaction mixture was cooled to 23 °C and then
quenched with water. The layers were separated, and the
aqueous layer was extracted with CHCl3. The combined
organic layers were washed with saturated aqueous sodium
bicarbonate and brine and dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue which was purified
by silica gel chromatography to furnish the title oxirane 10
(201 mg, 61% yield) as a white solid (mp 121-122 °C). [R]23
C34H33NO5S: C, 71.93; H, 5.86; N, 2.47. Found: C, 72.23; H,
6.14; N, 2.22.
D
1
+6.45 (c )1.86, CHCl3); H NMR (200 MHz, CHCl3): δ, 1.36
(s, 9H), 2.70-3.00 (m, 5H), 3.68 (m, 1H), 4.67 (d, 1H, J ) 7.5
Hz), 7.16-7.33 (m, 5H); 13C NMR (50 MHz, CHCl3): δ, 28.2,
37.6, 46.6, 52.6, 53.2, 79.4, 126.5, 128.4, 129.3, 136.8, 155.2;
IR (neat): 3387, 2981, 1680, 1546 cm-1; mass (EI) m/z 264 (M+
- H), 219, 131. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04;
N, 5.32. Found: C, 68.21; H, 8.07; N, 5.12.
(4S,5S)-4-(P h en ylm eth yl)-5-[(E)-p h en ylvin yl]-2-oxa zo-
lid in on e (13). To a stirred solution of aldol adduct 12 (1.80
g, 3.14 mmol) at 23 °C in a mixture (3:1) of THF:H2O (28 mL)
were added 30% H2O2 (2.14 mL, 18.9 mmol), and LiOH‚H2O
(396 mg, 9.43 mmol). The resulting mixture was stirred at
23 °C for 48 h, and the reaction was quenched with 1.5 M
aqueous Na2SO3 (25 mL). The mixture was concentrated
under reduced pressure to a small volume, and the residue
was extracted with CHCl3. The aqueous layer was then
acidified to pH 3 with 1 N HCl, and the resulting mixture was
thoroughly extracted with CHCl3. This organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pres-
sure to afford the (2S,3S)-(E)-2-Benzyl-3-hydroxy-5-phenyl-
pent-4-enoic acid (750 mg, 85% yield) as a white solid (mp
149-151 °C). 1H NMR (200 MHz, CD3COCD3): δ, 2.93 (m,
3H), 4.46 (m, 1H), 6.39 (dd, 1H, J ) 6.6, 15.9 Hz), 6.66 (d, 1H,
J ) 15.9 Hz), 7.11-7.44 (m, 10H); 13C NMR (50 MHz, CD3-
COCD3): δ, 35.4, 55.0, 73.8, 126.8, 127.3, 128.2, 129.0, 129.3,
129.7, 130.0, 131.8, 137.8, 140.7, 174.8. IR (neat): 3420, 1704,
1622, 1210 cm-1; mass (EI) m/z 282 (M+), 133, 91, 55.
To a stirred suspension of the above acid (800 mg, 2.83
mmol) in benzene (30 mL) were added diphenylphosphoryl
azide (0.92 mL, 4.25 mmol) and triethylamine (0.59 mL, 4.25
mmol). The resulting solution was heated at reflux for 16 h.
The reaction mixture was cooled to 23 °C, washed with
saturated aqueous sodium bicarbonate and brine, and dried
over anhydrous Na2SO4. Evaporation of the solvent and silica
gel chromatography of the residue yielded the title oxazolidi-
(2S,3S)-N-(2-Met h ylp r op yl)-N-[2-h yd r oxy-4-p h en yl-3-
(N′-ter t-b u t yloxyca r b on yl)a m in o]-4-m et h oxyb en zen e-
su lfon a m id e (11). To a stirred solution of epoxide 10 (110
mg, 0.42 mmol) in 2-propanol (5 mL) was added isobutylamine
(0.21 mL, 2.1 mmol), and the resulting solution was heated to
68 °C for 3.5 h. After this period, the reaction mixture was
cooled to 23 °C and then concentrated under reduced pressure.
The residue was dissolved in CH2Cl2 (3 mL), and 4-methoxy-
benzenesulfonyl chloride (86.0 mg, 0.42 mmol) followed by
concentrated aqueous sodium bicarbonate (1.0 mL) was added.
The resulting mixture was stirred at 23 °C for 16 h. The layers
were separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting residue was chromatographed on
silica gel to afford the title sulfonamide 11 (177 mg, 83% yield)
as a white solid (mp 112-114 °C). [R]23 +15.6 (c ) 2.25,
D
CHCl3); 1H NMR (400 MHz, CHCl3): δ, 0.85 (dd, 6H, J ) 6.6,
11.8 Hz), 1.31 (s, 9H), 1.84 (m, 1H), 2.77-2.93 (m, 3H), 2.99
(dd, 1H, J ) 4.0, 14.2 Hz), 3.07 (d, 2H, J ) 5.6 Hz), 3.75 (m,
2H), 3.82 (s, 3H), 4.74 (d, 1H, J ) 8.3 Hz), 6.94 (d, 2H, J ) 8.8
Hz), 7.15-7.27 (m, 5H), 7.68 (d, 2H, J ) 8.8 Hz); 13C NMR

Transition-State Mimetics for HIV Protease Inhibitors
J . Org. Chem., Vol. 63, No. 18, 1998 6151
none 13 (728 mg, 92% yield) as an oil. 1H NMR (200 MHz,
CHCl3): δ, 2.93 (m, 2H), 3.87 (m, 1H), 4.84 (m, 1H), 6.07 (ddd,
1H, J ) 2.2, 7.0, 15.8 Hz), 6.52 (d, 1H, J ) 15.8 Hz), 6.73 (s,
1H), 7.14-7.39 (m, 10H); 13C NMR (50 MHz, CHCl3): δ, 40.5,
59.7, 82.0, 124.9, 126.8, 127.1, 128.4, 128.6, 128.8, 129.0, 129.3,
133.8, 135.5, 135.8, 159.1; IR (neat): 1752, 1652, 1383, 981
cm-1; mass (EI) m/z 279 (M+), 188, 144, 91, 77.
(4S,5S)-(E)-Eth yl-5-(N-(ter t-bu tyloxyca r bon yl)a m in o)-
4-h yd r oxy-6-p h en ylh ex-2-en oa te (16). To a stirred solution
of allyl alcohol 14 (1.20 g, 3.4 mmol) in CH2Cl2 (200 mL) at
-78 °C was bubbled a stream of ozonized oxygen until the blue
color persisted (15 min). After the solution was flushed with
nitrogen for 5 min, a solution of Ph3P (908 mg, 3.46 mmol) in
CH2Cl2 (5 mL) was then slowly added, and the resulting
mixture was allowed to warm to 23 °C. After stirring for 1.5
h, the reaction mixture was concentrated under reduced
pressure, and the crude aldehyde was used for next reaction
without further purification.
(1S,2S)-(E)-4-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-1,5-d i-
p h en ylp en t-1-en -3-ol (14). To a stirred solution of oxazoli-
dinone 13 (760 mg, 2.72 mmol) in a mixture (1:1) of EtOH and
H2O (20 mL) at 23 °C was added powdered KOH (610 mg, 10.9
mmol). The resulting mixture was heated at reflux for 19 h.
The reaction mixture was cooled to 23 °C and neutralized to
pH 7 with 1 N HCl solution. The resulting mixture was
concentrated under reduced pressure to a small volume. To
the resulting residue was added CH2Cl2 (10 mL) followed by
di-tert-butyl dicarbonate (1.25 mL, 5.44 mmol). The reaction
mixture was stirred at 23 °C for 3.5 h. After this period, the
layers were then separated, and the aqueous layer was
extracted with CHCl3. The combined organic layers were then
washed with brine, dried over anhydrous Na2SO4, and con-
centrated. The residue was chromatographed over silica gel
to yield the title alcohol 14 (818 mg, 85% yield) as a white
solid (mp 114-117 °C). 1H NMR (200 MHz, CHCl3): δ, 1.39
(s, 9H), 2.95 (m, 2H), 3.95 (m, 1H), 4.31 (m, 1H), 5.18 (d, 1H,
J ) 8.9 Hz), 6.24 (dd, 1H, J ) 5.8, 15.8 Hz), 6.60 (d, 1H, J )
16.2 Hz), 7.23-7.36 (m, 10H); 13C NMR (50 MHz, CHCl3): δ,
28.2, 37.9, 56.4, 72.2, 79.5, 126.3, 126.5, 127.5, 128.4, 129.4,
129.7, 131.1, 136.7, 138.4, 156.2; IR (neat): 3409, 1683, 1495,
1166 cm-1; mass (EI) m/z 354 (M+ + H), 220, 164, 120, 57.
Anal. Calcd for C22H27NO3: C, 74.76; H, 7.67; N, 3.96.
Found: C, 74.53; H, 7.42; N, 3.62.
NaH (60% dispersion in mineral oil, 543 mg, 13.6 mmol)
was washed with hexanes, then THF (30 mL) was added, and
the resulting slurry was cooled to 0 °C. Triethyl phospho-
noacetate (2.69 mL, 13.6 mmol) was added at 0 °C, and after
stirring for 5 min, the resulting reaction mixture was allowed
to warm to 23 °C. The mixture was stirred an additional 40
min at 23 °C and then cooled to 0 °C. The above crude
aldehyde in THF (15 mL) was added dropwise in 2 min. The
resulting reaction mixture was allowed to warm to 23 °C and
stirred for 3 h. After this period, the reaction was quenched
with aqueous NH4Cl solution. The layers were separated, and
the aqueous layer was extracted with EtOAc (2 × 15 mL). The
combined organic extracts were washed with brine and dried
over anhydrous Na2SO4. Evaporation of the solvents under
reduced pressure gave a residue which was chromatographed
over silica gel to afford the title ester 16 (519 mg, 44% yield
for two steps) as a viscous oil. [R]23 -62.2 (c ) 0.45, CHCl3);
D
1H NMR (200 MHz, CHCl3): δ, 1.23 (t, 3H, J ) 7.2 Hz), 1.35
(s, 9H), 2.91 (m, 2H), 3.86 (m, 1H), 4.13 (q, 2H, J ) 7.1 Hz),
4.28 (m, 1H), 5.07 (d, 1H, J ) 9.0 Hz), 6.07 (dd, 1H, J ) 1.4,
15.6 Hz), 6.91 (dd, 1H, J ) 4.0, 15.6 Hz), 7.14-7.29 (m, 5H).
13C NMR (50 MHz, CHCl3): δ, 14.1, 28.1, 37.4, 55.8, 60.3, 70.7,
79.6, 121.4, 126.4, 128.4, 129.2, 138.0, 148.2, 156.0, 166.4; IR
(neat): 2981, 1749, 1672, 1367, 1165 cm-1; mass (EI) m/z 350
(M+ + H), 164, 120, 91, 57.
2(R)-[1′-(S)-N((ter t-Bu tyloxyca r bon yl)a m in o)-2-p h en -
yleth yl]oxir a n e (15). To a stirred solution of allyl alcohol
14 (411 mg, 1.16 mmol) in EtOH (100 mL) at -78 °C was
bubbled a stream of ozonized oxygen until the blue color
persisted (45 min). After the solution was flushed with
nitrogen for 5 min, NaBH4 (3.05 g, 11.6 mmol) in EtOH (20
mL) was then added slowly, and the reaction mixture was
allowed to warm to 23 °C. The mixture was continued to stir
for 1 h, and acetone was added. The reaction mixture was
concentrated under reduced pressure to a small volume. The
residue was extracted with EtOAc, and the combined organic
extracts were washed with saturated aqueous sodium bicar-
bonate and dried over anhydrous Na2SO4. Evaporation of the
solvents afforded a residue which was chromatographed over
silica gel to provide the (2R,3S)-3-[N-(tert-Butyloxycarbonyl)-
amino]-3-benzyl-2-hydroxypropan-1-ol (232 mg, 71% yield) as
(5S,1′S)-5-[1′-[N-(ter t-Bu tyloxycar bon yl)am in o]-2′-ph en -
yleth yl]d ih yd r ofu r a n -2(3H)-on e (17). To a stirred solution
of ester 16 (518 mg, 1.48 mmol) in a mixture (1:1) of EtOAc
and MeOH (60 mL) was suspended 10% Pd/C (150 mg), and
the resulting mixture was stirred under a balloon filled with
hydrogen for 18 h. After this period, the catalyst was filtered
off through a Celite pad, and the pad was washed with EtOAc.
The filtrate was concentrated to yield the corresponding
saturated ester (513 mg, 99% yield) as a white solid (mp 100-
1
104 °C). [R]23 -17.2 (c ) 0.58, CHCl3); H NMR (400 MHz,
D
CHCl3): δ, 1.19 (t, 3H, J ) 7.1 Hz), 1.38 (s, 9H), 1.71 (m, 1H),
1.82 (m, 1H), 2.40 (m, 2H), 2.87 (m, 2H), 3.56 (m, 1H), 3.70
(m, 1H), 4.06 (q, 2H, J ) 7.1 Hz), 5.01 (d, 1H, J ) 9.1 Hz),
7.16-7.28 (m, 5H); 13C NMR (100 MHz, CHCl3): δ, 14.0, 28.2,
29.5, 31.0, 38.4, 56.0, 60.5, 70.9, 79.2, 126.2, 128.3, 129.2, 138.4,
156.1, 174.4; IR (neat): 2982, 1771, 1691, 1367, 1046; mass
(EI) m/z 352 (M+ + H), 260, 160, 114, 91.
a white solid (mp 70-72 °C). [R]23 -32.5 (c ) 1.17, CHCl3);
D
1H NMR (200 MHz, CHCl3): δ, 1.36 (s, 9H), 2.87 (d, 2H, J )
7.5 Hz), 3.50 (m, 2H), 3.61 (m, 1H), 3.88 (m, 1H), 4.00 (br s,
2H), 5.25 (d, 1H, J ) 9.3 Hz), 7.16-7.29 (m, 5H); 13C NMR
(50 MHz, CHCl3): δ, 28.2, 38.1, 52.6, 63.9, 71.6, 79.7, 126.3,
128.4, 129.2, 138.1, 156.7; IR (neat): 3352, 1695, 1523, 1172
cm-1; mass, (EI) m/z 282 (M+ + H), 190, 90, 57.
To a stirred suspension of the above saturated ester (513
mg, 1.46 mmol) in toluene (15 mL) was added glacial acetic
acid (0.44 mL, 7.74 mmol), and the mixture was heated at
reflux for 5.5 h. The reaction mixture was cooled to 23 °C,
and the solvents were removed under reduced pressure to
provide a residue which was chromatographed over silica gel
To a stirred solution of the above diol (277 mg, 0.99 mmol)
and Ph3P (260 mg, 0.99 mmol) in CHCl3 at 23 °C was added
diethyl azodicarboxylate (0.16 mL, 0.99 mmol). The resulting
solution was heated at reflux for 50 h. After this period, the
reaction was cooled to 23 °C and quenched with water. The
layers were separated, and the aqueous layer was extracted
with CHCl3. The combined organic layers were washed
successively with saturated aqueous sodium bicarbonate and
brine and then dried over anhydrous Na2SO4. Evaporation of
the solvents under reduced pressure gave a residue which was
chromatographed over silica gel to furnish the title epoxide
to yield the title lactone 17 (306 mg, 68% yield) as a white
1
solid (mp 88-89 °C). [R]23 -4.1 (c ) 0.73, CHCl3); H NMR
D
(200 MHz, CHCl3): δ, 1.36 (s, 9H), 2.09 (m, 2H), 2.48 (m, 2H),
2.89 (m, 2H), 3.98 (m, 1H), 4.45 (td, 1H, J ) 1.3, 7.5 Hz), 4.78
(m, 1H), 7.15-7.31 (m, 5H); 13C NMR (50 MHz, CHCl3): δ,
24.0, 28.1, 28.6, 39.2, 54.0, 79.7, 79.9, 126.6, 128.5, 129.2, 137.2,
155.8, 177.1; IR (neat): 2979, 1759, 1682, 1647, 1169 cm-1
;
15 (205 mg, 88% yield) as an oil. [R]23 +2.53 (c ) 1.58,
mass (EI) m/z 305 (M+), 214, 114, 91, 57. Anal. Calcd for
C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.93; H,
D
1
CHCl3); H NMR (400 MHz, CHCl3): δ, 1.37 (s, 9H), 2.54 (s,
1H), 2.66 (m, 1H), 2.82-3.00 (m, 3H), 4.12 (m, 1H), 4.62 (d,
1H, J ) 8.1 Hz), 7.18-7.30 (m, 5H); 13C NMR (100 MHz,
CHCl3): δ, 28.2, 39.6, 44.4, 50.4, 52.5, 79.4, 126.5, 128.4, 129.3,
7.82; N, 4.28.
(3R,5S,1′S)-5-[1′-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-2′-
p h en yleth yl]-3-(p h en ylm eth yl)d ih yd r ofu r a n -2(3H)-on e
(18). To a stirred solution of lactone 17 (115 mg, 0.38 mmol)
in THF (2 mL) at -78 °C was added a 1 M solution of lithium
bis(trimethylsilyl)amide (Aldrich, 0.75 mL, 0.75 mmol) in THF.
After stirring for 0.5 h, benzyl iodide (82 mg, 0.38 mmol) in
137.3, 155.4; IR (neat): 3338, 1682, 1648, 1247, 1168 cm-1
;
mass (EI) m/z 264 (M+ + H), 172, 91, 72, 57. Anal. Calcd for
15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.10; H,
7.99; N, 5.27.
C

6152 J . Org. Chem., Vol. 63, No. 18, 1998
Ghosh and Fidanze
THF (2 mL) was added. The resulting solution was stirred
for 30 min, propionic acid (0.2 mL) was added, and the reaction
mixture was stirred at -78 °C for 5 min. The mixture was
then allowed to warm to 23 °C, and 10% citric acid and EtOAc
were added. After separating the layers, the aqueous layer
was extracted with EtOAc, and the combined organic extracts
were washed with saturated aqueous sodium bicarbonate and
brine, dried over anhydrous Na2SO4, and concentrated. Silica
gel chromatography of the residue yielded the title alkylated
lactone 18 (115 mg, 77% yield) as a white solid (mp 75-77
72% yield) as a white solid (mp 179-180 °C). [R]23 -17.6 (c
D
1
) 1.08, CHCl3); H NMR (200 MHz, CHCl3): δ, 1.24 (s, 9H),
1.68 (m, 2H), 2.50-2.90 (m, 6H), 3.62 (m, 2H), 3.99 (dd, 1H, J
) 4.7, 14.9 Hz), 4.30 (dd, 1H, J ) 6.5, 14.9 Hz), 5.01 (d, 1H, J
) 9.2 Hz), 6.54 (t, 1H, J ) 5.4 Hz), 6.81-7.26 (m, 15H); 13C
NMR (50 MHz, CHCl3): δ, 28.1, 37.0, 38.0, 38.4, 43.0, 45.9,
55.9, 68.4, 79.0, 126.0, 126.9, 127.3, 128.2, 128.7, 129.0, 129.2,
129.5, 137.9, 138.5, 139.4, 156.2, 175.2; IR (neat): 1670, 1626,
1524, 1248 cm-1; mass (EI) m/z, 502 (M+), 411, 355, 282;
HRMS: m/z (M+) calcd for C31H38N2O4, 502.2832, found
502.2839. Anal. Calcd for C31H38N2O4: C, 74.08; H, 7.62; N,
5.57. Found: C, 73.71; H, 7.55; N, 5.66.
°C). [R]23 -40 (c ) 0.1, CHCl3); 1H NMR (200 MHz, CHCl3):
D
δ, 1.36 (s, 9H), 1.97 (m, 1H), 2.23 (m, 1H), 2.81 (m, 3H), 2.97
(m, 1H), 3.12 (dd, 1H, J ) 4.2, 13.2 Hz), 3.95 (q, 1H, J ) 8.4
Hz), 4.22 (td, 1H, J ) 0.8, 6.6 Hz), 4.84 (d, 1H, J ) 9.7 Hz),
7.12-7.30 (m, 10 H); 13C NMR (50 MHz, CHCl3): δ, 28.1, 29.2,
36.8, 38.8, 41.2, 54.5, 78.4, 79.7, 126.6, 126.8, 128.5, 128.6,
128.8, 129.2, 137.2, 137.8, 155.8, 179.0; IR (neat): 1767, 1710,
1151; mass (EI) m/z 395 (M+), 204, 120, 91, 57.
(2R,5S,6S)-2,N-Bis(ph en ylm eth yl)-4-h ydr oxy-[5-N′-(ter t-
bu tyloxyca r bon yl)a m in o]-6-p h en ylh exa n a m id e (19). To
a stirred solution of benzylamine (0.10 mL, 0.96 mmol) in
CH2Cl2 (6 mL) at 23 °C was added a 2 M solution of
trimethylaluminum (Aldrich, 0.48 mL, 0.96 mmol) in heptane.
After stirring 10 min, a solution of lactone 18 (190 mg, 0.48
mmol) in CH2Cl2 was added, and the resulting solution was
heated to 40 °C for 2.5 h. After this period, the reaction
mixture was cooled to 23 °C and quenched with 1 N HCl (8
mL). The layers were separated, and the aqueous layer was
extracted with CHCl3. The combined organic layers were
washed with concentrated aqueous sodium bicarbonate and
brine, dried over Na2SO4, and concentrated. Silica gel chro-
matography of the residue yielded the title amide 19 (173 mg,
Ack n ow led gm en t. Financial support of this work
by the National Institute of Health is gratefully ac-
knowledged. We also thank Merck Research Laborato-
ries and BASF, Germany, for (1S,2R)-aminoindan-2-ol
used for the chiral auxiliary preparation. S.F. thanks
the University of Illinois at Chicago for a University
Fellowship. Ms. Hanna Cho is thanked for the enzyme
inhibition data.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
compounds 8, 9, 13, 18 and 1H NMR spectrum for compound
16 (5 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O980159I