Stereoselective synthesis of constrained oxacyclic hydroxyethylene isosteres of aspartic protease inhibitors: Aldol and Mukaiyama aldol methodologies for branched tetrahydrofuran 2-carboxylic acids

Article abstract of DOI:10.1021/jo050749y

The synthesis of diastereomeric 3-substituted-tetrahydrofuran 2-carboxylic acids in enantiopure form was achieved relying on aldol condensations of N-substituted α-amino aldehydes with enolates and enol silyl ethers of γ-butyrolactone. Catalytic YbFOD lea

Full text of DOI:10.1021/jo050749y

Stereoselective Synthesis of Constrained Oxacyclic
Hydroxyethylene Isosteres of Aspartic Protease Inhibitors: Aldol
and Mukaiyama Aldol Methodologies for Branched
Tetrahydrofuran 2-Carboxylic Acids
Stephen Hanessian,*,† Yihua Hou,† Malken Bayrakdarian,† and Marina Tintelnot-Blomley‡
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Station Centre-ville, Montre´al,
P.Q., H3C 3J7, and Novartis Institutes of Biomedical Research, Novartis Pharma AG,
Postfach CH-4002, Basel, Switzerland
stephen.hanessian@umontreal.ca
Received April 14, 2005
The synthesis of diastereomeric 3-substituted-tetrahydrofuran 2-carboxylic acids in enantiopure
form was achieved relying on aldol condensations of N-substituted R-amino aldehydes with enolates
and enol silyl ethers of γ-butyrolactone. Catalytic YbFOD leads to a high yield of a syn/syn-R-
amino alcohol isomer. This was used as a constrained THF subunit in the synthesis of a
peptidomimetic intended as an inhibitor of the enzyme BACE1, which is implicated in the cascade
of events leading to plaque formation in Alzheimer’s disease.
Introduction
The advent of structure-based design of enzyme inhibi-
tors has instigated extensive studies on conceptually
novel approaches to peptidomimetic motifs.1 One of the
more commonly used replacements for a scissile bond in
a specific dipeptide portion of a peptidic inhibitor is the
hydroxyethylene isostere, especially in conjunction with
aspartic proteases.2 For example, the potent synthetic
heptapeptide inhibitor of â-secretase (BACE1, memapsin-
2) OM99-23 has such a hydroxyethylene subunit as part
of its structure (Figure 1). The length of this subunit
* To whom correspondence should be addressed. Phone: (514) 343-
6738. Fax: (514) 343-5728.
FIGURE 1. Tang-Ghosh inhibitor OM99-2 of â-secretase
(BACE1) and proposed P1′ constrained oxacyclic hydroxyeth-
ylene isosteres.
† Universite´ de Montre´al.
‡ Novartis Pharma AG.
(1) For selected reviews, see: (a) Ripka, A. S.; Rich D. H. Curr. Opin.
Chem. Biol. 1998, 2, 44. (b) Gante, J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1699. (c) Hanessian, S.; McNaughton-Smith, G.; Lombart,
H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. (d) Gillespie, P.;
Cicarello, J.; Olson, G. L. Biopolymers 1997, 43, 101. (e) Silverman,
R. B. The Organic Chemistry of Drug Design and Drug Action;
Academic: San Diego, CA, 1992.
corresponds to that of a Leu-Ala dipeptide, in which the
central amide bond is replaced by an S-hydroxyethylene
isostere. Thus, OM99-2 can be considered as a pseudo-
octapeptide encompassing a central unnatural γ-amino
acid. BACE1 is an important membrane-bound enzyme
that initiates the formation of â-amyloid peptide from the
amyloid precursor protein. A cascade of events follow,
ultimately leading to plaque formation in the brain.4 The
enzyme has been considered as an ideal target for small
(2) For excellent reviews, see: (a) Cooper, J. B. Curr. Drug Targets
2002, 3, 155. (b) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem.
2000, 43, 305. (c) Bender, S. L.; Babine, R. Chem. Rev. 1997, 97, 1359.
(3) (a) Hong, L.; Koelsch, G.; Lin, X.; Wu, W. S.; Terzyan, S.; Ghosh,
A. K.; Zhang, X. C.; Tang, J. Science 2000, 290, 150. See also: (b) Hong,
L.; Turner, R. T., III; Koelsch, G.; Shin, D.; Ghosh, A. K.; Tang, J.
Biochemistry 2002, 41, 10963.
10.1021/jo050749y CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/21/2005
J. Org. Chem. 2005, 70, 6735-6745
6735

Hanessian et al.
TABLE 1. Stereoselective Aldol Additions
molecule inhibitors, with the objective of developing a
drug for Alzheimer’s disease.5 X-ray crystal structures
of OM99-2 and close derivatives thereof bound to BACE13,6
show the critical role of the hydroxyl group at the P1 site
for interaction with the two Asp residues at the catalytic
site. Extensive SAR studies on OM99-2 has instigated
much interest in the synthesis of smaller, nonpeptidic
inhibitors of the enzyme.6,7
We have previously reported on the design and syn-
thesis of a number of prototypical enzyme inhibitors in
therapeutically relevant areas.8 Herein we report on our
results of the stereoselective synthesis of P1′ constrained
oxacyclic variants9 of the hydroxyethylene isostere present
in the Tang-Ghosh pseudo-octapeptide OM99-2.3
Molecular modeling suggested that such a P1′ con-
strained oxacycle bridging the C-methyl group with the
a Ratios of isomers determined from HPLC analysis. b Ratios
of isomers determined from isolated weights of individual products.
(4) For recent reviews, see: (a) Vassar, R. J. Mol. Neurosci. 2004,
23, 105. (b) Bullock, R. Expert Opin. Invest. Drugs 2004, 13, 303. (c)
Citron, M. Nat. Rev. Neurosci. 2004, 5, 677. (d) Cumming, J. N.; Iserloh,
U.; Kennedy, M. E. Curr. Opin. Drug Discovery Dev. 2004, 7, 536. (e)
John, V.; Beck, J. P.; Bienkowski, M. J.; Sinha, S.; Heinrikson, R. L.
J. Med. Chem. 2003, 46, 4626. (f) Selkoe, D. J.; Schenk, D. Annu. Rev.
Pharmacol. Toxicol. 2003, 43, 545. (g) Golde, T. E. Curr. Pharm. Des.
2003, 9, 427.
(5) For selected reviews, see: (a) Conway, K. A.; Baxter, E. W.;
Felsenstein, K. M.; Reitz, A. B. Curr. Pharm. Des. 2003, 9, 427. (b)
Ghosh, A.; Hong, L.; Tang, J. Curr. Med. Chem. 2002, 9, 1135. (c)
Roggo, S. Curr. Top. Med. Chem. 2002, 2, 359. (d) Schimmo¨ller, F.;
Higaki, J. N.; Cordell, B. Curr. Pharm. Des. 2002, 8, 2521. (e) Jacobsen,
J. S. Curr. Top. Med. Chem. 2002, 2, 243. (f) Cash, A. D.; Perry, G.;
Smith, M. A. Curr. Med. Chem. 2002, 9, 1605. (g) LeVine, H. Curr.
Med. Chem. 2002, 9, 1121. (h) Wolfe, M. S. J. Med. Chem. 2001, 44,
2039.
adjacent methylene carbon shown as a stereochemically
defined structure in Figure 1 would not unduly affect the
conformation of OM99-2 seen in the X-ray structure. On
the basis of this premise, we set out to study methods
for the stereoselective synthesis of a 2,3-trans-substituted
tetrahydrofuranyl δ-amino acid motif as an integral part
of a truncated version of OM99-2 (Figure 1).
Results and Discussion
Our initial studies focused on the aldol condensation
of a series of aldehydes readily prepared from N,N-
dibenzyl L-amino acids10 with the lithium enolate of
γ-butyrolactone 2.11,12 As seen in Table 1, the major
products derived from N,N-dibenzyl derivatives of L-
leucinal 1a, L-alaninal 1b, and L-phenylalaninal 1c were
the corresponding anti/anti-aldol 3-furanone products
3a-c, obtained in excellent to good yields. Only minor
amounts of the diastereomers 4a and 5a were formed
(Table 1, entry 1). Minor quantities of the other diaster-
eomers 4b,c, 5b,c, and 6b,c were formed in the case of
1b and 1c, respectively. (Table 1, entries 2 and 3). The
relative stereochemistry of several aldol products was
confirmed by single-crystal X-ray analysis.
(6) (a)Turner, R. T.; Koelsch, G.; Hong, L.; Castaheira, P.; Ghosh,
A. K.; Tang, J. Biochemistry 2001, 40, 10001. (b) Ghosh, A. K.; Shin,
D.; Downs, D.; Koelsch, G.; Lin, X.; Ermolieff, J.; Tang, J. J. Am. Chem.
Soc. 2000, 122, 3522. (c) Ghosh, A. K.; Bilcer, G.; Harewood, C.;
Kawahama, R.; Shin, D.; Hussain, K. A.; Hong, L.; Loy, J. A.; Nguyen,
C.; Koelsch, G.; Ermolieff, J.; Tang, J. J. Med. Chem. 2001, 44, 2865.
(7) (a) Coburn, C. A.; Stachel, S. J.; Li, Y.-M.; Rush, D. M.; Steele,
T. G.; Chen-Dodson, E.; Holloway, M. K.; Xu, M.; Hoang, Q.; Lai, M.-
T.; DiMuzio, J.; Crouthamel, M.-C.; Shi, X.-P.; Sardana, V.; Chen, Z.;
Munshi, S.; Kuo, L.; Makara, G. M.; Annis, D. A.; Takikonda, P. K.;
Nash, H. M.; Vacca, J. P.; Wang, T. J. Med. Chem. 2004, 47, 6117. (b)
Kimura, T.; Shuto, D.; Hamada, Y.; Igawa, N.; Kasai, S.; Liu, P.;
Hidaka, K.; Hamada, T.; Hayashi, Y.; Kiso, Y. Bioorg. Med. Chem. Lett.
2004, 14, 1527. (c) Hom, R. K.; Gailunas, A. F.; Mamo, S.; Fang, L. Y.;
Tung, J. S.; Walker, D. E.; Davis, D.; Thorsett, E. D.; Jewett, N.; Moon,
J. B.; John, V. J. Med. Chem. 2004, 47, 158-164. (d) Chen, S.-H.;
Lamar, J.; Guo, D.; Kohn, T.; Yang, H.-C.; McGee, J. E.; Timm, D.;
Erickson, J. A.; Yip, Y.; May, P.; McCarthy, J. R. Bioorg. Med. Chem.
Lett. 2004, 14, 245. (e) Lamar, J.; Hu, J.; Bueno, A. B.; Yang, H.-C.;
Guo, D.; Copp, J. D.; McGee, J. E.; Gitter, B.; Timm, D.; May, P. C.;
McCarthy, J. R.; Chem., S.-H. Bioorg. Med. Chem. Lett. 2003, 13, 4335.
(f) Shuto, D.; Kasai, S.; Kimura, T.; Liu, P.; Hidaka, K.; Hamada, T.;
Shibakawa, S.; Hayashi, Y.; Hattori, C.; Szabo, B.; Ishiura, S.; Kiso,
Y. Bioorg. Med. Chem. Lett. 2003, 13, 4273. (g) Jeon, S.-Y.; Back, K.;
Seong, Y.-H.; Song, K.-S. Bioorg. Med. Chem. Lett. 2003, 13, 3905. (h)
Hom, R. K.; Fang, L. Y.; Mamo, S.; Tung, J. S.; Guinn, A. C.; Walker,
D. E.; Davis, D. L.; Gailunas, A. F.; Thorsett, E. D.; Sinha, S.; Knops,
J. E.; Jewett, N. E.; Anderson, J. P.; John, V. J. Med. Chem. 2003, 46,
1799. (i) Tung, T. S.; Davis, D. L.; Anderson, J. P.; Walker, D. E.; Mamo,
S.; Jewett, N.; Hom, R. K.; Sinha, S.; Thorsett, E. D.; John, V. J. Med.
Chem. 2002, 45, 259.
With the N-Boc L-leucinal 1d, equal amounts of the
adducts 3d and 4d with only a minor amount of 5d were
isolated. The desired 3-furanone derivative 6d was not
formed under the lithium enolate conditions described
above. The relative stereochemistry of the adduct 3d was
determined by transformation to the corresponding pyr-
rolidinone 7 and correlated with 3a of known configura-
tion (X-ray) as shown in Scheme 1.
We next explored the Mukaiyama aldol reaction13 of
the same aldehydes with the trimethylsilyl enol ether of
(8) See, for example: (a) Thrombin: Hanessian, S.; Balaux, E.;
Nilsson, I. Bioorg. Med. Chem. Lett. 2000, 10, 243. (b) Factor VIIa:
Hanessian, S.; Therrien, E.; Granberg, K.; Nilsson, I. Bioorg. Med.
Chem. Lett. 2002, 12, 2907. (c) Metalloproteases: Hanessian, S.;
Moitessier, N.; Gauchet, C.; Viau, M. J. Med. Chem. 2001, 44, 3066.
(d) Hanessian, S.; Mackay, D. B.; Moitessier, N. J. Med. Chem. 2001,
44, 3074. (e) Neuraminidase: Hanessian, S.; Bayrakdarian, M.; Luo,
X. J. Am. Chem. Soc. 2002, 124, 4716. (f) Hanessian, S.; Wang, J.;
Montgomery, D.; Stoll, V.; Stewart, K. D.; Kati, W.; Maring, C.; Kempf,
D.; Hutchins, C.; Laver, W. G. Bioorg. Med. Chem. Lett. 2002, 12, 3425.
(g) Renin: Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem.
2002, 67, 4261.
(10) (a) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem.,
Int. Ed. Engl. 1997, 26, 1141. (b) Reetz, M. T. Pure Appl. Chem. 1988,
60, 160. (c) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(11) See, for example: (a) Widdowson, D. A.; Wiebecke, G. H.;
William, D. J. Tetrahedron 1982, 23, 4285. For review, see: (b) Evans,
D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 131. (c)
Heathcock, C. H. Science 1981, 214, 395. (d) Heathcock, C. H.
Comprehensive Carbanion Chemistry; Buncel, E., Durst, T., Eds.;
Elsevier: Amsterdam, 1984; Vol. 2.
(12) For a review on γ-butyrolactones, see: Canan Kosh, S. S.;
Chamberlin, A. R. In Stereoselective Synthesis, Part J; Rahman, A.-
U., Ed.; Studies in Natural Products Chemistry; Elsevier: New York,
1995; Vol. 16, p 687.
(9) For another example of the incorporation of a tetrahydrofuranyl
unit as a constrain element, see: Hanessian, S.; Moitessier, N.;
Wilmouth, S. Tetrahedron 2000, 56, 7643.
6736 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Oxacyclic Hydroxyethylene Isosteres
SCHEME 1
SCHEME 2
TABLE 2. Stereoselective Mukaiyama Aldol Additions
of the anti/syn-, syn/anti-, and syn/syn-isomers 4a-c, 5a-
c, and 6a-c, respectively, in good yields. On the other
hand, YbFOD was the preferred catalyst for the synthesis
of the desired isomer 6d in the case of the N-Boc
L-leucinal.
We observed an interesting interconversion of diaster-
eomers in our attempts to convert the isomeric 3a-c
adducts into the corresponding O-TBS ethers (Scheme
2). Thus, treatment of 3a (or 5a) with TBS triflate in the
presence of 2,6-lutidine afforded the syn/anti-isomer 9 in
96% yield (X-ray). Similarly, treatment of 4a (or 6a)
under the same conditions gave the syn/syn-isomer 10
in 95% yield. In each case, complete epimerization at the
furanone (C-3) branching site had taken place with
isomers 3a and 4a. This can be rationalized on the basis
of initial formation of a TBS silyl ether, followed by
enolate formation and concomitant participation of the
enolate hydroxyl group to give a transient hypervalent
dioxasilicon intermediate.16 Protonation from the least
hindered face affords the respective products 9 and 10,
as illustrated in the perspective drawings A and B
(Scheme 2). The same trend was observed in the case of
the TBS ethers of 3b and 3c, which were converted to
the diastereoimeric TBS ethers 5b and 5c, respectively.
Similarly, 4b and 4c afforded 6b and 6c (as TBS ethers).
The stereoselective formation of the major products
3a-c in the Li enolate aldol reaction with the N,N-
dibenzyl aldehydes 1a-c can be explained on the basis
of a preferred Re-face attack by the enolate in a Zim-
merman-Traxler-type transition state (Figure 2A). The
observed anti/anti-aldol products 3a-c (Table 1, entries
1-3) may be explained by considering a Felkin-Anh
model with a “pseudoequatorial” orientation of the large
N,N-dibenzylamino group in A (as compared to a Si-face
a Ratios of isomers determined from HPLC analysis. b Ratios
of isomers determined from isolated weights of individual products.
c The reaction was done at -78 °C. d The reaction was done at
room temperature with a catalytic quantity (5 mol %) of reagent.
γ-butyrolactone 8 in the presence of a variety of Lewis
acids in stoichiometric or catalytic quantities.14 The
distribution of diastereomeric adducts was drastically
changed compared to that of the lithium enolates, as seen
in Table 2. Thus, with EtAlCl2, BF3‚Et2O, MgBr2, and
ZnBr2, the syn/anti-aldol product 5a was the major
isomer (Table 2, entries 1-4). A reversal in favor of the
desired syn/syn-aldol 6a was observed with Cu(OTf)2
(Table 2, entry 6). This trend was also evident in the case
of 1b (Table 2, entry 8) and 1c (Table 2, entry 10). Using
catalytic quantities of YbFOD15 diminished the diaste-
reoselectivity with all three aldehydes to give mixtures
(13) (a) Mukaiyama, T. Org. React. 1982, 28, 203. (b) Mukaiyama,
T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
(14) See, for example: (a) Heathcock, C. H.; Davidsen, S. K.; Hug,
K. T.; Flippin, L. A. J. Org. Chem. 1986, 51, 3027. (b) Chen, C.-T.;
Chao, S.-D.; Yen, C.-C. Synlett 1998, 924. For a catalytic version, see:
(c) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos,
K. R.; Connell, B.-T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669.
(15) For reviews, see: (a) Kobayashi, S. Synlett 1994, 689. (b)
Molander, G. A. Chem. Rev. 1992, 92, 29. (c) Collin, J.; Giuseppone,
N.; van de Weghe, P. Coord. Chem. Rev. 1998, 178-180, 117. See
also: (d) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 4647.
(e) Gong, L.; Streitweiser, A. J. Org. Chem. 1990, 55, 6235.
(16) Mulzer, J.; Schollhorn, B. Angew. Chem., Int. Ed. 1990, 29, 431.
J. Org. Chem, Vol. 70, No. 17, 2005 6737

Hanessian et al.
FIGURE 2. Possible transition state models for aldol addi-
tions.
FIGURE 3. Possible chelated and nonchelated transition
state models for Mukaiyama aldol condensations.
attack B). The nature of the side chain does not have a
significant stereodirecting influence, since the major
isomer is the anti/anti-aldol product from 1a-c, albeit
with some differences in the case of phenyl analogue 1c.
The equal amounts of diastereomers 3d and 4d in the
case of the N-Boc-protected aldehydes (Table 1, entry 4)
may be due to loss of stereodifferentiation caused by
internally chelated intermediates involving the N-Boc
group. The same trend has been observed in related cases
by Reetz and co-workers.17
From a practical standpoint, we were pleased that,
depending on the type of catalyst or method used, each
of the four possible diastereomers of the adducts 3-6
could be obtained in preparatively significant amounts.
More rewarding, however, was the success of the Mu-
kaiyama aldol reaction in the presence of a catalytic
quantity of YbFOD to furnish the desired syn/syn-N-Boc
lactone 6d in high yield.
For the purposes of obtaining the intended P1′ con-
strained motif (Figure 1), we opted to proceed with the
syn/syn-N,N-dibenzyl lactone 10, obtained from 6a and
4a via TBS ether formation in excellent overall yield.
Treatment of 10 with lithio dithiane18 at -78 °C led to a
mixture of ketone 11a and the hemiacetals 11b,c (Scheme
3). Reduction of this mixture with NaBH4 gave essentially
a single isomer 12. Intramolecular cycloetherification
under Mitsunobu19 conditions led to 13 in 87% yield,
whose structure and absolute configuration were ascer-
tained from a single-crystal X-ray analysis. It follows that
the reduction of the ketone with NaBH4 had given the
2S-alcohol stereoselectively and that the cycloetherifica-
tion had proceeded without inversion of configuration,
as would be expected from the activation of a primary
alcohol. An alternative route involving cycloetherification
by tosylation of the primary alcohol in 12 and intra-
molecular displacement gave 13 in only 50% yield even
after 24 h. Treatment of 13 with HgCl2/CaCO3 or CH3I/
Na2CO3 did not give the desired aldehyde. However, a
mixture of HgO and BF3 etherate20 cleaved the dithianyl
The Mukaiyama aldol product favoring the syn/anti-
and syn/syn-aldol isomers 5a-c or 6a-c can be rational-
ized based on whether nonchelated or chelated transition
states are involved, respectively.14,15 Thus, with the N,N-
dibenzyl aldehydes 1a-c and monodentate Lewis acids
such as EtAlCl2 and BF3 etherate, the major product 5a
can arise from nonchelated intermediate A (Figure 3).
The bidentate MgBr2 gave a ca. 3:1 ratio of 5a and 6a,
reflecting a contribution from the chelated transition
state, leading to intermediate B (Figure 3, Table 2, entry
4). Curiously, ZnBr2 led to a preponderance of 5a,
although a chelated transition state may be expected
(Figure 3, Table 2, entry 3).10c In the presence of Cu(OTf)2,
the syn-aldol isomer 6a was formed, regardless of the
nature of the aldehyde, presumably arising from a
chelated transition state (Table 2, entries 6, 8, and 10).
Using catalytic quantities of the lanthanide YbFOD led
to mixtures of 4a-c, 5a-c, and 6a-c (Table 2, entries
5, 7, and 9). The nature of the side chain seems not to
have a significant effect on the ratio of isomers, although
a preference for 5b was observed compared to the larger
aldehyde precursors (Table 2, entries 5, 7, and 9). On the
other hand, catalytic YbFOD led to an excellent stereo-
selectivity in favor of the desired syn/syn-aldol isomer 6d
in the case of the N-Boc L-leucinal 1d, presumably arising
from a kinetically controlled addition proceeding via B
(Figure 3).
(17) Reetz, M. T. Chem. Rev. 1999, 99, 1121.
(18) Sanchez, M. E. L.; Michelet, V.; Besnier, I.; Genet, J. P. Synlett
1994, 705.
(19) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org.
React. 1992, 42, 335. (c) Hanessian, S.; Machaalani, R. Tetrahedron
Lett. 2003, 44, 8321. (d) Hanessian, S.; Marcotte, S.; Machaalani, R.;
Huang, G. Org. Lett. 2003, 5, 4273. (e) Guianvac, H.; Fourrey, J.-L.;
Tram Huu Dan, M.-E.; Guerineau, V.; Benhid, R. J. Org. Chem. 2002,
67, 3724.
6738 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Oxacyclic Hydroxyethylene Isosteres
SCHEME 3a
SCHEME 4a
a Reagents and conditions: (a) 1,3-Dithiane, n-BuLi, THF, -78
to 0 °C; (b) NaBH4, MeOH, room temperature, 58%, two steps; (c)
PPh3, DEAD, THF, room temperature, 87%; (d) TsCl, pyridine, 0
°C to room temperature 50%; (e) HgO, BF3 etherate, CH3CN/H2O,
room temperature, 84%; (f) (i) NaOCl2, 2-methyl-2-butene, buffer,
CH3CN/H2O, room temperature, 52%; (ii) CH2N2; (g) NaOMe/
MeOH, reflux; (h) NaOH, MeOH/H2O, 80% for two steps.
a Reagents and conditions: (a) n-Butylamine or L-Ala-methyl-
amide or L-Val-n-butylamide, PyBop, i-Pr2NEt, DCM, 0 °C to room
temperature; (b) (i) Pd-black, HCOOH/MeOH; (ii) Boc2O, NaHCO3,
MeOH; (iii) TBAF; (c) (i) HCl in dioxane (4 M); (ii) N′-Tr-L-AspOH
or N-Boc-MetOH, PyBOP, DIEA, DCM, 0 °C to room temperature;
(d) Ac-L-ValOH or Ac-L-LeuOH, HOBT, EDC, DCM/H2O, 0 to 5
°C; for 20a,b, TFA/H2O, room temperature.
group and produced 14 in high yield. Oxidation to the
acid with NaClO2,21 and esterification with CH2N2 gave
15, which was epimerized to 16 with NaOMe and MeOH.
The desired acid 17 was obtained by alkaline hydrolysis
and separated from the minor unepimerized isomer by
column chromatography. An alternative synthesis of a
precursor to 16 using nitroaldol methodology under
Shibasaki catalytic conditions22 was recently reported by
us.23
With a preparative route to the P1/P1′ constrained
tetrahydrofuran amino acid 17 in hand, we proceeded to
prepare three prototypical truncated mimics of OM99-2.
Extensive SAR studies on OM99-2 in conjunction with
X-ray crystallography of complexes with BACE1 have
shown that certain amino acid components of the hep-
tapeptide can be changed without significant loss of
activity.6c For example, the P2′-P4′ units can be trun-
cated and replaced by a simple alkylamide chain. The
Asp subunit has also been changed to Met in an effort to
decrease the polar nature of the inhibitor. We therefore
adapted these changes to our constrained oxacyclic
variant of OM99-2 to ultimately have three prototypical
and diversely substituted mimics. Thus, the free acid 17
was coupled with n-butylamine, with L-Ala methylamide,
and L-Val n-butylamide to give 18a-c, respectively
(Scheme 4). Catalytic transfer hydrogenation removed
the N,N-dibenzyl group, and the resulting amine was
protected as the N-Boc derivative before treatment with
TBAF to cleave the silyl ether group, to afford 19a-c in
excellent overall yield. Removal of the N-Boc group and
coupling with N′-Tr-BocAspOH, mediated by PyBop,
afforded 20a and 20b. In the case of 19c, coupling was
done with BocMetOH to give 20c. Further extension of
20a and 20b with AcValOH, followed by acid treatment,
gave the pseudopeptides 21a and 21b, respectively
(Scheme 4). Similarly, extension of 20c with AcLeuOH
gave 21c, thus completing the intended series of oxacyclic
analogues of OM99-2. To avoid epimerization, we found
EDC/HOBT in a two-phase system (CH2Cl2/H2O) to be
advantageous in the preparation of 21a-c.
Compounds 21a-c were tested for their ability to
inhibit BACE1. Weak inhibitory activity was observed
only with 21c (IC50 ) 8.5 µM).24 Although 21a was
inactive against BACE1, it showed inhibition against
pepsin and cathepsin D with IC50 values of 0.17 and 0.28
µM, respectively. Compound 21b was devoid of activity
with all three enzymes. The carbocyclic analogue of 21c
in which the tetrahydrofuran ring is replaced by a
cyclopentane and a cyclopentanone are low nanomolar
inhibitors of BACE1.24 The substantial loss of activity
(20) Vedejs, E.; Fuchs, P. L. J. Org. Chem. 1971, 36, 366.
(21) (a) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091. (b) Kraus, G. A.; Tashner, M. J. J. Org. Chem. 1980, 45, 1175.
(c) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(22) (a) Sasai, H.; Suzuki, T.; Arai, S.; Shibasaki, M. J. Am. Chem.
Soc. 1991, 111, 4418. (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev.
2002, 102, 2187.
(24) Hanessian, S.; Yun, H.; Hou, Y.; Yang, G.; Bayrakdarian, M.;
Therrien, E.; Moitessier, N.; Roggo, S.; Veenstra, S.; Tintelnot-Blomley,
M.; Rondeau, J.-M.; Paganetti, P.; Betschart, C. J. Med. Chem.,
published online July 15, 2005. http://dx.doi.org/10.1021/jm050142+.
(23) Hanessian, S.; Brassard, M. Tetrahedron 2004, 60, 7621.
J. Org. Chem, Vol. 70, No. 17, 2005 6739

Hanessian et al.
128.6, 128.7, 129.0, 130.0, 140.7, 141.0, 180.6; IR (film) 3506,
3062, 3026, 2916, 1751; MS (FAB) m/z 416.2 [M + 1]+; HRMS
calcd for C27H29NO3 [M + 1]+ 416.2225; found 416.2216.
when a cyclopentane is replaced by an oxacyclic analogue
might be the result of repulsive interactions of the ring
oxygen atom with amide carbonyls in the active site, thus
deviating from optimal conformations for binding. Fur-
ther studies aimed at the modification of the acyclic
backbone with azacyclic constrained isosteres OM99-2
are reported in the companion article.25
(3R)-3-[(1S,2S)-2-Dibenzylamino-1-hydroxy-3-phenyl-
propyl]-dihydro-furan-2-one (4c). The compound was iso-
lated as the second isomer in the preparation of 3c. Purifica-
tion by column chromatography (20% EtOAc in hexanes) gave
4c as a colorless oil (10%); mp 147-148 °C; [R]D +18.2 (c 0.4,
1
CHCl3); H NMR (CDCl3) δ 1.07 (1H, m), 1.59 (2H, m), 2.14
(1H, m), 2.59 (1H, dd, J ) 14.3 and 8.8 Hz), 2.85 (1H, m), 3.28
(1H, dd, J ) 14.2 and 3.9 Hz), 3.42 (2H, d, J ) 13.0 Hz), 3.80
(1H, m), 4.04 (3H, m), 4.24 (1H, dd, J ) 8.95 and 1.6 Hz), 4.71
(1H, s), 7.13-7.39 (15 H, m); 13C NMR (CDCl3) δ 20.9, 32.3,
43.1, 53.9, 62.0, 67.5, 69.5, 127.1, 128.0, 129.1, 129.3, 129.3,
129.6, 138.6, 139.9, 178.8; IR (film) 1770; MS (FAB) m/z 416.2
[M + 1]+; HRMS calcd for C27H29NO3 [M + 1]+ 416.2225; found
416.2223.
(3S)-3-[(1R,2S)-2-tert-Butoxycarbonylamino-1-hydroxy-
4-methyl-pentyl]-dihydro-furan-2-one (3d). The compound
was prepared from 1d as described above (Method A, LiH-
MDS). Purification by column chromatography (30% EtOAc
in hexanes) gave 3d as a colorless oil (24%); [R]D -24.1 (c 0.3,
CHCl3); 1H NMR (CDCl3) δ 0.92 (3H, d, J ) 6.6 Hz), 0.94 (3H,
d, J ) 6.7 Hz), 1.13 (1H, m), 1.43 (9H, s), 1.54 (1H, m), 1.69
(1H, m), 2.28 (2H, m), 2.49 (1H, m), 2.60 (1H, m), 3.67 (1H, t,
J ) 9.6 Hz), 3.85 (1H, m), 4.24 (1H, m), 4.35 (1H, t, J ) 7.0
Hz), 4.43 (1H, t, J ) 8.8 Hz), 4.95 (1H, d, J ) 9.4 Hz); 13C
NMR (CDCl3) δ 180.4, 156.3, 79.8, 74.8, 67.6, 50.9, 42.2, 37.3,
28.8, 25.6, 24.9, 24.3, 21.9; IR (film) 3391, 2958, 2871, 1759,
1698, 1512; MS (FAB) m/z 302.1 [M + 1]+; HRMS calcd for
C15H28NO5 [M + 1]+ 302.1967; found 302.1954.
(3R)-3-[(1S,2S)-2-tert-Butoxycarbonylamino-1-hydroxy-
4-methyl-pentyl]-dihydro-furan-2-one (4d). The compound
was isolated as the second isomer in the preparation of 3d.
Purification by column chromatography (30% EtOAc in hex-
anes) gave 4d as a colorless oil (27%); [R]D -37.3 (c 0.7, CHCl3);
1H NMR (CDCl3) δ 0.93 (3H, d, J ) 2.6 Hz), 0.94 (3H, d, J )
2.6 Hz), 1.34 (1H, m), 1.44 (9H, s), 1.64 (2H, m), 1.98 (1H, m),
2.61 (1H, m), 2.64 (1H, m), 3.68 (2H, m), 4.24 (1H, m), 4.43
(2H, m), 4.79 (1H, d, J ) 10.2 Hz); 13C NMR (CDCl3) δ 22.71,
23.3, 25.2, 26.3, 28.7, 42.1, 50.4, 67.7, 74.2, 79.7, 81.6, 156.5;
IR (film) 3453, 3360, 2960, 2871, 1755, 1707, 1503, 1455; MS
(EI) m/z 301.2 [M]+; HRMS calcd for C15H27NO5 [M]+ 301.1889;
found 301.1901.
(3R)-3-[(1R,2S)-2-tert-Butoxycarbonylamino-1-hydroxy-
4-methyl-pentyl]-dihydro-furan-2-one (5d). The compound
was isolated as the third isomer in the preparation of 3d.
Purification by column chromatography (30% EtOAc in hex-
anes) gave 5d as a white solid (4%); [R]D -4.2 (c 0.7, CHCl3);
1H NMR (CDCl3) δ 0.95 (3H, d, J ) 6.5 Hz), 0.98 (3H, d, J )
6.6 Hz), 1.27 (1H, m), 1.45 (9H, s), 1.60 (1H, m), 1.71 (1H, m),
2.40 (1H, m), 2.50 (1H, m), 2.81 (1H, m), 3.74 (1H, m), 3.99
(1H, dd, J ) 7.4 and 2.2 Hz), 4.22 (1H, dd, J ) 16.4 and 9.1
Hz), 4.38 (1H, m), 4.41 (1H, m); 13C NMR (CDCl3) δ 21.9, 22.7,
24.1, 25.2, 28.7, 41.1, 43.3, 52.3, 67.8, 73.6, 80.3, 156.7, 179.8;
IR (film) 3354, 2958, 1758, 1607, 1524, 1367; MS (FAB) m/z
302.2 [M + 1]+; HRMS calcd for C15H28NO5 [M + 1]+ 302.1967;
found 302.1968.
Experimental Section
(3S)-3-[(1R,2S)-2-Dibenzylamino-1-hydroxy-4-methyl-
pentyl]-dihydro-furan-2-one (3a). Method A, LiHMDS: To
a dry flask containing LiHMDS (1.4 mL, 1.0 M in THF) was
added THF (5 mL), and the solution was cooled to -78 °C.
γ-Butyrolactone (100 µL, 1.30 mmol) was added dropwise, and
the reaction mixture was stirred for 0.5 h. A cold solution of
1a (265 mg, 0.90 mmol) in THF (10 mL) was added dropwise
by cannula, and the reaction mixture was stirred for a further
2 h at -78 °C before quenching with saturated aqueous NH4-
Cl (10 mL). The reaction mixture was extracted with EtOAc
(15 mL × 3), and the organic phase was dried with Na2SO4
and concentrated. The residue was purified by column chro-
matography (20% EtOAc in hexanes) to afford 3a (252 mg,
66%) as a white solid; mp 114-115 °C; [R]D -27.5 (c 1.1,
CHCl3); 1H NMR (CDCl3) δ 0.55 (3H, d, J ) 6.4 Hz), 0.96 (3H,
d, J ) 6.7 Hz), 1.04 (1H, m), 1.90 (2H, m), 2.02 (2H, m), 2.00
(1H, m), 2.58 (2H, m), 3.55 (2H, d, J ) 14.0 Hz), 4.02 (2H, d,
J ) 14.0 Hz), 4.08 (1H, s), 4.12 (1H, m), 4.28 (1H, d, J ) 9.5
Hz), 4.34 (1H, m), 7.31 (10 H, m); 13C NMR (CDCl3) δ 22.1,
24.5, 24.6, 26.1, 34.5, 42.9, 54.9, 56.4, 67.1, 70.4, 127.3, 128.6,
129.3, 141.1, 181.0; IR (film) 3499, 3028, 2953, 1753; MS (FAB)
m/z 382 [M + 1]+; HRMS calcd for C24H32NO3 [M + 1]+
382.2382; found 382.2373.
(3S)-3-[(1R,2S)-2-Dibenzylamino-1-hydroxy-propyl]-di-
hydro-furan-2-one (3b). The compound was prepared from
1b as described above (Method A, LiHMDS). Purification by
column chromatography (20% EtOAc in hexanes) gave 3b as
a colorless oil (52%); [R]D +28.3 (c 0.4, CHCl3); 1H NMR (CDCl3)
δ 1.18 (3H, d, J ) 6.8 Hz), 1.72 (1H, m), 1.88 (1H, m), 2.75
(1H, m), 2.90 (1H, m), 3.60 (2H, d, J ) 13.8 Hz), 3.82 (1H, s),
3.84 (2H, d, J ) 13.8 Hz), 3.90 (1H, dd, J ) 7.2 and 4.5 Hz),
4.07 (1H, m), 4.27 (1H, td, J ) 8.8 and 1.5 Hz), 7.20-7.37 (10
H, m); 13C NMR (CDCl3): δ 8.3, 26.3, 42.5, 55.1, 55.3, 67.1,
74.5, 127.3, 128.6, 128.9, 129.2, 140.8, 179.8; IR (film) 3495,
3027, 2934, 1754; MS (FAB) m/z [M + 1]+; HRMS calcd for
C21H26NO3 [M + 1]+ 340.1912; found 340.1872.
(3R)-3-[(1S,2S)-2-Dibenzylamino-1-hydroxy-propyl]-di-
hydro-furan-2-one (4b). The compound was isolated as the
second isomer in the preparation of 3b. Purification by column
chromatography (20% EtOAc in hexanes) gave 4b as a color-
1
less oil (19%); [R]D +18.8 (c 0.3, CHCl3); H NMR (CDCl3) δ
1.15 (3H, d, J ) 6.7), 2.05 (2H, m), 2.73 (1H, td, J ) 8.3 and
3.6 Hz), 3.24 (1H, m), 3.36 (2H, d, J ) 13.2 Hz), 3.66 (1H, dd,
J ) 8.2 and 3.6 Hz), 3.86 (2H, d, J ) 13.2 Hz), 4.13 (1H, dd,
J ) 15.7 and 7.2 Hz), 4.31 (1H, dd, J ) 15.5 and 7.2 Hz), 4.58
(1H, br), 7.23-7.33 (10 H, m); 13C NMR (CDCl3) δ 9.1, 26.9,
41.3, 54.2, 54.9, 67.7, 74.1, 127.7, 128.9, 129.6, 139.4, 178.1; R
(film) 3500, 3028, 2918, 1766; MS (EI) m/z 339.1 [M + 1]+;
HRMS calcd for C21H25NO3 [M + 1]+ 339.1834; found 339.1834.
(3S)-3-[(1R,2S)-2-Dibenzylamino-1-hydroxy-3-phenyl-
propyl]-dihydro-furan-2-one (3c). The compound was pre-
pared from 1c as described above (Method A, LiHMDS).
Purification by column chromatography (20% EtOAc in hex-
anes) gave 3c as a colorless oil (46%); [R]D +23.2 (c 0.5, CHCl3);
1H NMR (CDCl3) δ 1.50 (2H, m), 2.24 (1H, m), 2.92 (1H, m),
3.08 (2H, m), 3.83 (4H, s), 3.89 (1H, m), 4.13 (1H, s), 4.20 (1H,
d, J ) 9.04), 4.62 (1H, m), 7.15-7.28 (15 H, m); 13C NMR
(CDCl3) δ 26.0, 30.9, 43.2, 55.1, 61.0, 67.0, 73.5, 126.5, 127.2,
(3R)-3-[(1R,2S)-2-Dibenzylamino-1-hydroxy-4-methyl-
pentyl]-dihydro-furan-2-one (5a). Method B, EtAlCl2: To
a solution of the aldehyde 1a (162 mg, 0.55 mmol) in CH2Cl2
(5 mL) at -78 °C was added EtAlCl2 (1.0 M in hexanes, 0.55
mL), and the reaction mixture was stirred for 10 min. (4,5-
Dihydro-furan-2-yloxy)-trimethylsilane (7) (130 mg, 0.82 mmol)
in CH2Cl2 (2 mL) was added dropwise, and the reaction
mixture was stirred at -78 °C for 2 h, after which it was
quenched by adding saturated aqueous NH4Cl (10 mL), then
warmed to room temperature. Extraction with EtOAc (15 mL
× 3) and concentration gave an oil that was redissolved in THF
(10 mL), aqueous HCl (1%, 1.0 mL) was added, and the
solution was stirred for 30 min before it was neutralized with
saturated NaHCO3 and extracted with EtOAc (3 × 10 mL).
(25) Hanessian, S.; Yun, H.; Hou, Y.; Tintelnot-Blomley, M. J. Org.
Chem. 2005, 70, 6746.
6740 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Oxacyclic Hydroxyethylene Isosteres
Concentration and purification by column chromatography
(20% EtOAc in hexanes) gave 5a as a colorless oil (162 mg,
78%); [R]D +26.2 (c 0.50, CHCl3); 1H NMR (CDCl3) δ 0.84 (1H,
m), 0.98 (6H, m), 1.55 (2H, m), 1.93 (2H, m), 2.40 (1H, m),
2.51 (1H, m), 3.23 (1H, t, J ) 9.4), 3.40 (2H, d, J ) 13.2 Hz),
3.70 (2H, d, J ) 13.2 Hz), 3.90 (1H, dd, J ) 8.7 and 16.7 Hz),
4.16 (1H, m), 4.25 (1H, m), 7.30 (10 H, m); 13C NMR (CDCl3)
δ 21.0, 23.3, 24.0, 26.7, 36.7, 44.2, 54.6, 57.2, 67.7, 71.9, 127.5,
128.7, 129.9, 140.4, 181.0; IR (film) 3509, 3028, 2956, 1753.
MS (FAB) m/z 382 [M + 1]+; HRMS calcd for C24H32NO3 [M +
1]+ 382.2382; found 382.2392.
(3S)-3-[(1S,2S)-2-Dibenzylamino-1-hydroxy-4-methyl-
pentyl]-dihydro-furan-2-one (6a). Method C, Cu(OTf)2: To
a solution of the aldehyde 1a (26 mg, 0.087 mmol) in CH2Cl2
(1 mL) was added Cu(OTf)2 (35 mg, 0.087 mmol) at room
temperature, and the reaction mixture was stirred for 15 min.
(4,5-Dihydro-furan-2-yloxy)-trimethyl-silane (7) (25 mg, 0.174
mmol) was added in one portion, and the reaction mixture was
stirred at room temperature until full consumption of the
starting aldehyde (5 h). Saturated NaHCO3 (2 mL) was added,
and the reaction mixture was extracted with EtOAc (3 × 5
mL). The organic phase was concentrated, the residue was
redissolved in THF (10 mL), aqueous HCl (1%, 1.0 mL) was
added, and the solution was stirred for 30 min before it was
neutralized with NaHCO3, extracted with EtOAc (3 × 10 mL),
dried over Na2SO4, and filtered. The filtrate was concentrated,
and the residue was purified by column chromatography (20%
EtOAc in hexanes) to afford 6a as a colorless oil (16 mg, 50%);
[R]D +0.8 (c 0.5, CHCl3); 1H NMR (CDCl3) δ 0.96 (6H, m), 1.25
(2H, m), 1.68 (3H, m), 2.58 (2H, m), 3.45 (2H, d, J ) 13.2 Hz),
3.90 (2H, d, J ) 13.2 Hz), 4.04 (1H, m), 4.23 (1H, m), 4.71
(1H, m), 7.30 (10 H, m); 13C NMR (CDCl3) δ 21.3, 23.4, 23.7,
27.1, 36.3, 42.9, 54.6, 57.8, 67.6, 70.1, 127.9, 129.0, 129.7, 179.1;
IR (film) 3400, 2957, 1769, 1453; MS (FAB) m/z [M + 1]+;
HRMS calcd for C24H32NO3 [M + 1]+ 382.2382; found 382.2372.
3469, 3028, 2955, 1748; MS (FAB) m/z 382.2 [M + 1]+; HRMS
calcd for C24H32NO3 [M + 1]+ 382.2382; found 382.2362.
(3R)-3-[(1R,2S)-2-Dibenzylamino-1-hydroxy-propyl]-di-
hydro-furan-2-one (5b). The compound was prepared from
1b as described above (Method D, YbFOD). Purification by
column chromatography (20% EtOAc in hexanes) gave 5b as
a white solid (55%); mp 158-159 °C; [R]D +35.9 (c 0.7, CHCl3);
1H NMR (CDCl3) δ 0.91 (1H, m), 1.21 (3H, d, J ) 6.6 Hz), 1.80
(1H, m), 2.21 (1H, m), 2.62 (1H, m), 3.26 (1H, m), 3.30 (2H, d,
J ) 12.8 Hz), 3.71 (2H, d, J ) 12.8 Hz), 3.96 (1H, dd, J ) 16.3
and 9.2 Hz), 4.14 (2H, m), 7.26-7.33 (10 H, m); 13C NMR
(CDCl3) δ 8.8, 20.6, 43.5, 54.5, 55.0, 67.7, 71.7, 127.6, 128.7,
128.8, 129.2, 129.6, 129.8, 140.1, 180.9; IR (film) 3469, 3028,
2917, 2807, 1753; MS (FAB) m/z 340.2 [M + 1]+; HRMS calcd
for C21H26NO3 [M + 1]+ 340.1912; found 340.1916.
(3R)-3-[(1R,2S)-2-Dibenzylamino-1-hydroxy-3-phenyl-
propyl]-dihydro-furan-2-one (5c). The compound was pre-
pared from 1c as described above (Method D, YbFOD).
Purification by column chromatography (20% EtOAc in hex-
anes) gave 5c as a white solid (33%); mp 125-126 °C; [R]D
+35.7 (c 0.4, CHCl3); 1H NMR (CDCl3) δ 0.88 (1H, m), 1.61
(1H, m), 1.80 (1H, s), 2.93 (1H, m), 3.13 (1H, m), 3.24 (1H, m),
3.40 (2H, d, J ) 12.9 Hz), 3.78 (2H, d, J ) 11.64 Hz), 3.92
(1H, dd, J ) 8.94 and 7.47 Hz), 4.13 (1H, td, J ) 8.70 and
2.28 Hz), 4.39 (1H, d, J ) 9.4 Hz), 7.14-7.39 (15 H, m); 13C
NMR (CDCl3) δ 20.8, 31.4, 33.2, 43.8, 54.7, 61.8, 67.6, 71.9,
126.6, 127.6, 128.0, 128.7, 129.1, 129.3, 129.6, 129.8, 129.8,
139.9, 141.8, 180.6; IR (film) 3488, 3027, 2915, 1752; MS (FAB)
m/z 416.2 [M + 1]+; HRMS calcd for C27H28NO3 [M + 1]+
416.2225; found 416.2229.
(3S)-3-[(1S,2S)-2-Dibenzylamino-1-hydroxy-3-phenyl-
propyl]-dihydro-furan-2-one (6c). The compound was iso-
lated as the second isomer in the preparation of 5c. Purifica-
tion by column chromatography (20% EtOAc in hexanes) gave
6c as a white solid (20%); mp 140-141 °C; [R]D +51.7 (c 0.7,
1
CHCl3); H NMR (CDCl3) δ 0.77 (1H, m), 1.09 (1H, m), 1.64
(3S)-3-[(1S,2S)-2-Dibenzylamino-1-hydroxy-propyl]-di-
hydro-furan-2-one (6b). The compound was prepared from
1b as described above (Method C, Cu(OTf)2). Purification by
column chromatography (20% EtOAc in hexanes) gave 6b as
a white solid (29%); mp 121-122 °C; [R]D +20.1 (c 1.0, CHCl3);
1H NMR (CDCl3) δ 1.08 (3H, d, J ) 6.6 Hz), 1.83 (2H, m), 2.54
(2H, m), 3.30 (2H, d, J ) 13.1 Hz), 3.86 (2H, d, J ) 13.1 Hz),
4.13 (2H, m), 4.22 (1H, m), 4.45 (1H, br), 7.26-7.38 (10 H, m);
13C NMR (CDCl3) δ 8.3, 20.8, 39.7, 42.4, 53.6, 55.8, 67.6, 69.8,
127.9, 129.0, 129.5, 130.2, 138.8, 179.1; IR (film) 3370, 3028,
2968, 1770; MS (EI) m/z 339.1 [M + 1]+; HRMS calcd for
C21H25NO3 [M + 1]+ 339.1834; found 339.184723.
(1H, s), 2.75 (1H, m), 2.94 (1H, dd, J ) 9.8 and 1.9 Hz), 3.17
(1H, m), 3.45 (2H, d, J ) 13.1 Hz), 3.50 (1H, dd, J ) 8.3 and
3.5 Hz), 3.84 (1H, m), 4.04 (1H, m), 4.23 (2H, m), 4.62 (1H,
m), 7.19-7.36 (15 H, m); 13C NMR (CDCl3) δ 25.6, 30.5, 41.2,
56.0, 60.7, 67.3, 73.1, 126.5, 127.5, 128.7, 128.8, 129.0, 129.8,
129.9, 140.5, 140.7, 181.5; IR (film) 3471, 3026, 1748; MS (FAB)
m/z 416.2 [M + 1]+; HRMS calcd for C27H29NO3 [M + 1]+
416.2225; found 416.2223.
(3S)-3-[(1S,2S)-2-tert-Butoxycarbonylamino-1-hydroxy-
4-methyl-pentyl]-dihydro-furan-2-one (6d). The compound
was prepared from 1d as described above (Method D, YbFOD).
Purification by column chromatography (30% EtOAc in hex-
anes) gave 6d as a white solid (71%); mp 96-97 °C; [R]D -48.9
(3R)-3-[(1S,S)-2-Dibenzylamino-1-hydroxy-4-methyl-
pentyl]-dihydro-furan-2-one (4a). Method D, YbFOD: To
a solution of aldehyde 1a (2.7 g, 9.11 mmol) in CH2Cl2 (100
mL) was added YbFOD (482 mg, 0.46 mmol, 5 mol %). After 5
min, (4,5-dihydro-furan-2-yloxy)-trimethyl-silane (7) (2.88 g,
18.22 mmol) was added in one portion. The reaction mixture
was stirred under Ar until full consumption of the starting
material (6 h), after which it was quenched with 10 mL of
water, and the organic phase was dried with Na2SO4 and
concentrated under reduced pressure. The residue was redis-
solved in THF (100 mL), aqueous HCl (1%, 10 mL) was added,
and the solution was stirred for 30 min before it was neutral-
ized with saturated NaHCO3, extracted with EtOAc (3 × 100
mL), and dried with Na2SO4. The combined organic phase was
concentrated, and the residue was purifed by column chroma-
tography (20% EtOAc in hexanes) to afford 4a as a white
crystalline solid (798 mg, 23%); mp 143-144 °C; [R]D +27.1 (c
1
(c 0.6, CHCl3); H NMR (CDCl3) δ 0.93 (3H, d, J ) 2.4 Hz),
0.94 (3H, d, J ) 2.4 Hz), 1.34 (1H, m), 1.44 (9H, s), 1.64 (2H,
m), 2.26 (1H, m), 2.53 (1H, m), 2.75 (1H, td, J ) 6.0 and 3.4
Hz), 3.10 (1H, b), 3.75 (1H, m), 4.05 (1H, s), 4.21 (1H, m), 4.39
(1H, td, J ) 7.5 and 2.3 Hz), 4.66 (1H, d, J ) 8.6 Hz); 13C
NMR (CDCl3) δ 22.4, 22.8, 23.6, 25.1, 28.7, 42.1, 44.7, 52.6,
67.7, 71.8, 80.0, 156.7, 179.3; IR (film) 3446, 2958, 2872, 1767,
1689, 1515; MS (EI) m/z 301.2 [M]+; HRMS calcd for C15H27-
NO5 [M]+ 301.1889; found 301.1898.
(4S)-4-Hydroxy-(3R)-(2-hydroxy-ethyl)-(5S)-5-isobutyl-
pyrrolidin-2-one (7). To a solution of 3a (43 mg, 0.11 mmol)
in MeOH (1.0 mL) was added HCOOH (100 µL). Pd-black (30
mg) was added, and the suspension was stirred at room
temperature for 1.5 h. The catalyst was removed by filtration,
and the filtrate was concentrated. The residue was dissolved
in EtOAc, and the solution was washed with saturated
NaHCO3 and dried with Na2SO4. The solvent was removed
under reduced pressure, and the residue was purified by
column chromatography (10% MeOH in CH2Cl2) to afford 7
1
0.6, CHCl3); H NMR (CDCl3) δ 0.91 (1H, s), 0.95 (3H, d, J )
6.4 Hz), 1.05 (3H, d, J ) 6.4 Hz), 1.44 (1H, m), 1.55 (1H, m),
1.73 (1H, m), 1.80 (1H, m), 2.65 (1H, m), 3.00 (1H, m), 3.35
(2H, d, J ) 13.2 Hz), 3.66 (1H, dd, J ) 4.04 and 7.58 Hz), 3.93
(1H, m), 4.00 (1H, b), 4.16 (1H, m), 4.67 (1H, s), 7.29 (10 H,
m); 13C NMR (CDCl3) δ 22.5, 24.4, 25.9, 26.2, 33.5, 41.2, 55.8,
56.2, 67.4, 74.2, 127.4, 128.6, 129.8, 140.9, 181.1; IR (film)
1
as a colorless oil (15 mg, 70%): [R]D -15.1 (c 0.8, CHCl3); H
NMR (CDCl3) δ 0.96 (6H, d, J ) 6.1 Hz), 1.37 (1H, m), 1.69
(1H, m), 2.00 (1H, m), 2.62 (1H, m), 3.56 (1H, m), 3.75 (1H,
m), 3.86 (1H, m), 3.93 (1H, m), 4.15 (1H, d, J ) 16.1 Hz); 13C
J. Org. Chem, Vol. 70, No. 17, 2005 6741

Hanessian et al.
NMR (CDCl3) δ 22.3, 23.6, 25.5, 26.9, 43.2, 45.9, 60.4, 62.0,
74.6, 178.6; IR (film); HRMS (FAB) calcd for C10H19NO3 [M +
1] 201.14; found 201.14.
(S)-Dibenzyl-(3S)-[(1S)-1-tert-butyl-dimethyl-silanyloxy)-
(2S)-2-[1,3]dithian-2-yl-tetrahydro-furan-3-yl)-methyl]-3-
methyl-butyl]-amine (13). To a solution of diol 12 (12 mg,
0.020 mmol) in anhydrous THF (1 mL), PPh3 (21 mg, 0.076
mmol) was added, and a solution of DEAD (12 mg, 1.006 mmol)
in THF (1 mL) was added dropwise. The reaction mixture was
stirred at room temperature for 3 h, the solvent was removed
under reduced pressure, and the residue was purified by
column chromatography (10% EtOAc in hexanes) to give 13
as white crystals (12 mg, 87%); [R]D +16.3 (c 0.6, CH2Cl2); 1H
NMR (CDCl3) δ 0.08 (3 H, s), 0.09 (3 H, s), 0.80 (9 H, s,), 1.03
(3 H, d, J ) 6.5 Hz), 1.08 (3 H, d, J ) 6.3 Hz), 1.45 (1 H, m),
1.65 (1 H, m), 1.81 (2 H, m), 1.96 (3 H, m), 2.35 (2 H, d, J )
8.7 Hz), 2.47 (1 H, m), 2.68 (2 H, m), 2.77 (2 H, m), 3.19 (1 H,
m), 3.27 (2 H, d, J ) 12.9 Hz), 3.58 (1 H, m), 3.63 (1 H, m),
4.00 (2 H, m), 4.11 (2 H, d, J ) 9.5 Hz), 7.26 (10 H, m); 13C
NMR (CDCl3) δ -2.9, -2.7, 18.9, 22.9, 24.6, 25.7, 25.9, 26.7,
30.6, 31.0, 31.5, 33.6, 46.1, 51.5, 56.4, 57.7, 69.0, 73.8, 77.6,
80.6, 127.4, 128.6, 129.7, 141.1; IR (film) 3028, 2954, 2857,
1454; MS (FAB) m/z 600 [M + 1]+; HRMS calcd for C34H54-
NO2S2Si [M + 1]+ 600.3365; found 600.3391.
(3R)-3-[(1R,2S)-1-(tert-Butyl-dimethyl-silanyloxy-2-di-
benzylamino-4-methyl- pentyl)]-dihydro-furan-2-one (9).
To a solution of the alcohol 3a (312 mg, 0.82 mmol) in
anhydrous CH2Cl2 (2 mL) at 0 °C was added 2,6-lutidine (202
µL, 2.05 mmol) followed by TBSOTf (282 µL, 1.23 mmol). The
mixture was stirred at 0 °C for 1 h before it was quenched
with aqueous NH4Cl. The mixture was extracted with EtOAc
(3 × 10 mL), and the combined organic phase was dried with
Na2SO4 and concentrated. The residue was purified by column
chromatography (10% EtOAc in hexanes) to afford 9 as a
crystalline solid (390 mg, 96%); mp 93-94 °C; [R]D +9.4 (c 0.8,
CH2Cl2); 1H NMR (CDCl3) δ 0.00 (3H, s), 0.10 (3H, s), 0.60
(1H, m), 0.85 (9H, s), 1.02 (6H, m), 1.58 (3H, m), 1.98 (1H, m),
2.52 (2H, m), 3.33 (1H, t, J ) 10.2 Hz), 3.48 (2H, d, J ) 13.0
Hz), 3.77 (2H, d, J ) 13.6 Hz), 3.79 (1H, m), 4.13 (2H, m),
7.27 (10 H, m); 13C NMR (CDCl3) δ -3.8, -3.6, 18.6, 20.4, 23.0,
24.1, 26.3, 26.6, 37.3, 43.7, 54.8, 58.1, 67.3, 72.7, 127.5, 128.7,
130.1, 140.4, 180.6; IR (film) 3064, 2956, 2858, 1770; MS (FAB)
m/z 496.3 [M + 1]+; HRMS calcd for C30H44NO3Si [M + 1]+
496.3246; found 496.3251.
(3S)-3-[(1S)-1-tert-Butyl-dimethyl-silanyloxy)-(2S)-2-
dibenzylamino-4-methyl-pentyl]-tetrahydro-furan-(2S)-
2-carbaldehyde (14). An amount of 13 (55 mg, 0.092 mmol)
was dissolved in a mixture of THF-H2O (9:1, 2 mL), a mixture
of red HgO (40 mg, 0.184 mmol) and BF3 etherate (23.2 µL,
0.184 mmol) in THF (1 mL) were added, and the resulting
mixture was stirred at room temperature for 24 h. The reaction
mixture was diluted with water (5 mL) and extracted with
EtOAc (3 × 10 mL), and the organic phase was dried with Na2-
SO4 and concentrated. The residue was purified by column
chromatography (10% EtOAc in hexanes) to afford 14 as a
(3S)-3-[(1S,2S)-1-(tert-Butyl-dimethyl-silanyloxy-2-di-
benzylamino-4-methyl-pentyl)]-dihydro-furan-2-one (10).
The compound was prepared from 4a or 6a as a colorless oil
1
(95%); [R]D -34.2 (c 0.95, CHCl3); H NMR (CDCl3): δ -0.10
(3H, s), -0.07 (3H, s), 0.82 (9H, s), 0.95 (6H, m), 1.49 (1H, m),
1.61 (2H, m), 1.77 (1H, m), 2.32 (1H, m), 2.36 (1H, m), 2.59
(1H, m), 2.68 (1H, m), 3.48 (2H, d, J ) 13.4 Hz), 3.98 (2H,, d,
J ) 13.4 Hz), 4.10 (1H, m), 4.28 (1H, m), 4.33 (1H, m), 7.30
(10 H, m); 13C NMR (CDCl3): δ -4.8, -4.1, 14.6, 18.6, 23.1,
23.5, 23.5, 24.2, 25.7, 26.1, 26.4, 26.6, 32.0, 34.1, 44.6, 55.8,
60.4, 67.3, 72.3, 127.4, 128.5, 128.7, 129.4, 130.1, 140.7, 180.0;
IR (film) 3028, 2930, 2857, 1770; MS (FAB) m/z 496.2 [M +
1]+; HRMS calcd for C30H46 NO3Si [M + 1]+ 496.3246; found
496.3247.
1
colorless oil (38 mg, 84%); [R]D +8.0 (c 0.9, CH2Cl2); H NMR
(CDCl3): δ 0.00 (3 H, s), 0.06 (3 H, s), 0.81 (9 H, s), 0.93 (2H,
m), 1.03 (6 H, q, J ) 4.4 and 6.2 Hz), 1.45 (2 H, m), 1.66 (2 H,
m), 2.11 (1 H, m), 2.41 (1 H, m), 2.56 (1 H, m, J ) 9.8 Hz),
3.23 (1 H, m), 3.30 (2 H, d, J ) 13.1 Hz), 3.75 (1 H, dd, J )
10.0 and 1.6 Hz), 3.86 (2 H, m), 4.11 (2 H, m), 7.28 (10 H, m),
9.31 (1 H, d, J ) 2.0 Hz); 13C NMR (CDCl3): δ -3.3, -2.9, 18.9,
22.7, 24.5, 25.3, 26.6, 31.1, 33.3, 47.8, 56.2, 57.3, 69.2, 73.8,
76.9, 82.2, 127.4, 128.6, 129.2, 129.4, 129.9, 130.2, 134.8, 141.2,
203.8; IR (film) 3085, 3063, 3028, 2955, 2928, 2857, 1730; MS
(FAB) m/z 510 [M + 1]+; HRMS calcd for C31H48NO3Si [M +
1]+ 510.3403; found 510.3389.
(2S)-2-[(1S,2S)-1-(tert-butyl-dimethyl-silanyloxy)-2-
dibenzylamino-4-methyl-pentyl]-(1S)-1-[1,3]dithian-2-
yl-butane-1,4-diol (12). To a solution of 1,3-dithiane (92 mg,
0.76 mmol) in anhydrous THF (4 mL) was added n-butyl-
lithium (2.5 M in hexane) (278 µL, 0.70 mmol) under Ar at
-78 °C. After 30 min, the solution was transferred by cannula
to a solution of lactone 10 (156 mg, 0.32 mmol) in THF (4 mL)
at -78 °C. The reaction mixture was stirred at -78 °C for a
further 40 min before it was quenched with saturated NH4Cl
and allowed to warm to room temperature. The mixture was
extracted with EtOAc (3 × 10 mL), the combined organic phase
was dried by Na2SO4 and concentrated under reduced pres-
sure, and the residue was purified by column chromatography
(10% EtOAc in hexanes) to afford a mixture of ketone 11a and
lactols 11b,c (131 mg). The mixture of products was dissolved
in anhydrous methanol, and NaBH4 (21 mg, 0.53 mmol) was
added in small portions at room temperature. The solution was
stirred until the disappearance of starting material by TLC
(about 1 h) and quenched with water. The solvent was removed
under reduced pressure, and the residue was extracted by
EtOAc (3 × 10 mL). Purification by column chromatography
(20% EtOAc in hexanes) gave diol 12 as a foamy white solid
(3S)-3-[(1S)-1-tert-Butyl-dimethyl-silanyloxy)-(2S)-2-
dibenzylamino-4-methyl-pentyl]-tetrahydro-furan-(2S)-
2-carboxylic acid methyl ester (15). To a solution of the
aldehyde 14 (34 mg, 0.067 mmol) and 2-methyl-2-butene (86
µL, 0.80 mmol) in a mixture of t-BuOH/CH3CN (0.8 mL 5:3)
was added dropwise a solution of NaClO2 (45 mg, 0.34 mmol),
and NaH2PO4 dihydrate (64 mg, 0.34 mmol) in water (0.67
mL) was added dropwise at 0 °C. The reaction mixture was
stirred at 0 °C for 0.5 h and quenched with 5% aqueous
Na2S2O3 (0.67 mL), and a few drops of 1% HCl were added to
pH 6. The mixture was extracted with EtOAc (3 × 5 mL). The
combined organic phase was dried with Na2SO4 and concen-
trated, and the crude acid was dissolved in CH2Cl2 (2 mL) and
cooled to 0 °C. An ethereal solution of CH2N2 was added until
the yellow color of the solution persisted. The solvent was
removed under reduced pressure, and the residue was purified
by column chromatography (10% EtOAc in hexanes) to give
ester 15 as a colorless oil (18 mg, 52%); [R]D +57.86 (c 0.8,
1
(113 mg, 58%); mp 48-50 °C; [R]D -19.5 (c 0.4, CH2Cl2); H
NMR (CDCl3) δ 0.04 (3H, s), 0.17 (3H, s), 0.82 (2H, m), 0.87
(9H, s), 0.98 (3H, d, J ) 6.0), 1.02 (3H, d, J ) 6.0), 1.50 (2H,
m), 1.74 (2H, m), 2.02 (2H, m), 2.20 (1H, m), 2.69 (2H, m),
2.90 (3H, m), 3.28 (2H, d, J ) 13.08), 3.51 (2H, m), 3.83 (1H,
d, J ) 2.55), 3.91 (1H, d, J ) 2.13), 4.16 (1H, b), 4.41 (2H, d,
J ) 8.34), 4.80 (1H, b), 7.30 (10 H, m); 13C NMR (CDCl3) δ
-4.6, -3.3, 14.1, 14.6, 18.6, 19.5, 21.5, 22.5, 24.6, 25.8, 26.5,
26.5, 26.7, 30.2, 31.0, 31.2, 33.5, 42.5, 53.1, 56.2, 61.5, 64.8,
75.2, 76.3, 77.6, 127.3, 127.5, 128.7, 129.4, 130.6, 139.7, 139.9;
IR (film) 3469, 3028, 2954, 2857, 1453; MS (FAB) m/z 618.3
[M + 1]+; HRMS calcd for C34H56NO3S2Si [M + 1]+ 618.3470;
found 618.3482.
1
CH2Cl2); H NMR (CDCl3) δ 0.04 (3 H, s), 0.08 (3 H, s,), 0.82
(9H, s), 1.00 (1 H, d, J ) 4.3 Hz), 1.05 (1 H, d, J ) 4.5 Hz),
1.47 (2 H, m), 1.72 (1 H, m), 1.92 (1 H, m), 2.09 (1 H, m), 2.49
(1 H, d, J ) 9.9 Hz), 2.56 (1 H, d, J ) 7.5 Hz), 3.26 (2 H, d, J
) 13.0 Hz), 3.33 (1H, m), 3.48 (1 H, d, J ) 10.1 Hz), 3.54 (3H,
s), 3.82 (1 H, m), 4.12 (1 H, m), 7.30 (10 H, m); 13C NMR
(CDCl3) δ -3.2, -2.9, 18.9, 22.5, 24.5, 25.4, 26.6, 29.7, 33.4,
46.8, 51.5, 56.3, 57.3, 69.1, 74.9, 127.3, 128.5, 129.9, 173.3; IR
6742 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Oxacyclic Hydroxyethylene Isosteres
(film): 3063, 3028, 2954, 2858, 1738; MS (FAB) m/z 540.3 [M
+ 1]+; HRMS calcd for C32H50NO4Si [M + 1]+ 540.3509; found
540.3488.
3063, 2954, 2931, 2858, 1655, 1513; MS (FAB) m/z 610.4 [M
+ 1]+
; HRMS calcd for C35H56N3O4Si [M + 1]+ 610.4040; found
610.4024.
(3S)-3-[(1S)-1-tert-Butyl-dimethyl-silanyloxy)-(2S)-2-
(3S)-3-[(1S)-1-tert-Butyl-dimethyl-silanyloxy)-(2S)-2-
dibenzylamino-4-methyl-pentyl] -tetrahydro-furan-(2S)-
2-carboxylic Acid (17). A solution of 15 (190 mg, 0.35 mmol)
in NaOMe (25% in weight in MeOH, 1 mL) was refluxed at 70
°C for 6 h. Water (100 µL) was added, and the mixture was
stirred at room temperature 12 h. The reaction mixture was
acidified with HCl (5N, 3.5 mL) to pH 3 and extracted with
EtOAc (3 × 20 mL), and the organic phase was dried with Na2-
SO4 and concentrated. The residue was purified by column
chromatography (75% of EtOAc in hexanes) to afford 17 as a
colorless oil (82 mg, 80%); [R]D -15.1 (c 0.6, CHCl3); 1H NMR
(CDCl3) δ -0.36 (3 H, s), -0.03 (3H, s,), 0.83 (9H, s), 0.91 (6H,
d, J ) 6.4 Hz), 1.54 (2H, m), 1.85 (1H, m), 2.05 (1H, m), 2.16
(1H, m), 2.56 (1H, m), 2.91 (1H, m), 3.65 (2H, d, J ) 13.6 Hz),
3.94 (2H, d, J ) 13.6 Hz), 4.08 (1H, d, J ) 8.16 Hz, 8.2 Hz),
7.19-7.42 (10 H, m); 13C NMR (CDCl3) δ -4.6, -3.9, 18.5, 22.6,
24.0, 25.7, 25.9, 26.4, 28.4, 34.8, 47.7, 55.7, 59.5, 70.1, 72.2,
79.5, 127.6, 128.8, 129.4, 139.6, 176.8; IR (film) 3583 (b), 3063,
3028, 2954, 2856, 1722; MS (FAB) m/z 525 [M + 1]+; HRMS
calcd for C31H47NO4Si [M + 1]+ 525.3274; found 525.3282.
(3S)-3-[(1S)-1-tert-Butyl-dimethyl-silanyloxy)-(2S)-2-
dibenzylamino-4-methyl-pentyl]-tetrahydro-furan-(2R)-
2-carboxylic Acid Butylamide (18a). To a solution of acid
17 (30 mg, 0.057 mmol) and n-butylamine (15 µL, 0.152 mmol)
in CH2Cl2 (2 mL) was added PyBop (30 mg, 0.057 mmol) at 0
°C followed by i-Pr2NEt (39 µL, 0.23 mmol). The reaction
mixture was stirred at 0 °C to room temperature for 14 h, and
then it was diluted with EtOAc (5 mL) and washed with
aqueous 1 N HCl and saturated NaHCO3. The organic phase
was dried with Na2SO4 and concentrated, and the residue was
purified by column chromatography (10% EtOAc in hexanes)
to afford 18a as a colorless oil (28 mg, 80%); [R]D -41.4 (c 1.15,
CH2Cl2); 1H NMR (CDCl3): δ -0.42 (3 H, s), 0.00 (3 H, s), 0.82
(9 H, s), 0.86 (3 H, d, J ) 5.9 Hz), 0.95 (6 H, m), 1.37 (2 H, m),
1.52 (4 H, m), 1.65 (1 H, m), 1.92 (2 H, m), 2.30 (2 H, m), 2.84
(1 H, m), 3.30 (1 H, m), 3.69 (2 H, d, J ) 13.8 Hz), 3.81 (2 H,
m), 3.86 (2 H, d, J ) 13.8 Hz), 3.96 (1 H, d, J ) 8.4 Hz), 4.46
(1 H, m), 6.59 (1 H, m), 7.21 (2 H, m), 7.31 (4 H, m), 7.43 (4 H,
m);13C NMR (CDCl3): δ -4.5, -4.0, 14.2, 18.5, 20.5, 22.4, 24.6,
25.6, 26.4, 27.5, 32.2, 35.6, 38.7, 47.8, 55.4, 59.6, 69.7, 71.4,
78.3, 80.7, 127.2, 128.6, 129.2, 140.9, 173.2; IR (film) 3424,
3063, 2955, 2929, 2857, 1675, 1524; MS (FAB) m/z 581.4 [M
+ 1]+ ; HRMS calcd for C35H57N2O3Si [M + 1]+ 581.4131; found
581.4138.
(3S)-3-[(1S)-1-tert-Butyl-dimethyl-silanyloxy)-(2S)-2-
dibenzylamino-4-methyl-pentyl]-tetrahydro-furan-(2R)-
2-carboxylic Acid N-Methyl-L-ala Amide (18b). Boc-L-
alanine methylamide (17 mg, 0.085 mmol) was stirred with
HCl in dioxane (4M, 1 mL) for 0.5 h and was concentrated
under reduced pressure. The residue was dissolved in CH2Cl2
(2 mL). To the solution, acid 17 (30 mg, 0.057 mmol), PyBop
(30 mg, 0.057 mmol), and i-Pr2NEt (39 µL, 0.23 mmol) were
added at 0 °C. The reaction mixture was stirred at 0 °C to
room temperature for 14 h, and then it was diluted with EtOAc
(10 mL). The organic phase was washed with aqueous 1 N HCl
and saturated NaHCO3. The organic phase was dried and
concentrated. The residue was purified with column chroma-
tography (20% EtOAc in hexanes) to afford 18b as a colorless
oil (22 mg, 63%); [R]D -40.4 (c 0.9 in CHCl3); 1H NMR (CDCl3):
δ -0.04 (3H, s), 0.01 (3H, s), 0.82 (9H, s), 0.86 (2H, m), 0.93 (3
H, d, J ) 6.0 Hz), 1.26 (1H, m), 1.42 (3 H, d, J ) 6.8 Hz), 1.50
(1 H, m), 1.93 (2 H, m), 2.29 (2 H, m), 2.69 (2 H, d, J ) 4.6
Hz), 2.84 (1 H, m), 3.70 (2 H, d, J ) 13.7 Hz), 3.81 (2 H, d, J
) 13.7 Hz), 3.91 (1 H, m), 4.01 (1H, m), 4.46 (1H, m), 6.19 (1
H, m), 7.02 (1 H, m), 7.21 (2 H, m), 7.29 (4 H, m), 7.43 (4 H,
m); 13C NMR (CDCl3) δ -4.5, -4.0, 14.2, 18.5, 20.6, 22.4, 24.6,
25.7, 26.4, 27.5, 32.2, 35.6, 38.7, 47.8, 55.4, 59.6, 69.7, 71.4,
78.3, 80.7, 127.2, 128.6, 129.2, 140.9, 173.2; IR (film) 3324,
dibenzylamino-4-methyl-pentyl]-tetrahydro-furan-(2R)-
2-carboxylic Acid N-Butyl-L-Val Amide (18c). Boc-L-valine
n-butylamide (49 mg, 0.18 mmol) was stirred with HCl in
dioxane (4 M, 1 mL) for 1 h. After removing the solvent under
reduced pressure, the compound was dissolved in CH2Cl2 (2
mL) and cooled to 0 °C. The acid 17 (63 mg, 0.12 mmol) was
added followed by PyBOP (65 mg, 0.12 mmol) and i-Pr2NEt
(65 µL, 0.375 mmol). The reaction mixture was stirred from 0
°C to room temperature for 3 h before it was diluted with
EtOAc (10 mL) and washed with aqueous 1 N HCl and
saturated NaHCO3. The organic phase was dried and concen-
trated, and the residue was purified by column chromatogra-
phy (20% EtOAc in hexanes) to afford 18c as a colorless oil
1
(64 mg, 79%); [R]D -37.9 (c 0.42, CHCl3); H NMR (CDCl3) δ
0.83 (3H, t, J ) 7.2 Hz), 1.23 (2H, m), 1.28 (3H, d, J ) 7.0
Hz), 1.37 (9H, s), 1.41 (2H, m), 3.15 (2H, m), 4.14 (1H, m),
5.44 (1H, d, J ) 7.7 Hz), 6.72 (1H, b); 13C NMR (CDCl3) δ -4.6,
-3.9, 14.0, 18.5, 18.8, 19.7, 20.4, 22.3, 24.6, 25.4, 26.3, 27.4,
30.9, 31.9, 35.4, 39.6, 48.2, 54.9, 58.8, 59.5, 69.9, 71.0, 80.7,
127.2, 128.6, 129.1, 140.9, 171.2, 173.8; IR (film) 3308, 2964,
2956, 2859, 16519, 1515; MS (FAB) m/z 680.5 [M + 1]+; HRMS
calcd for C40H66N3O4Si [M + 1]+ 680.4822; found 680.4791.
(3S)-3-[(1S)-1-Hydroxyl)-(2S)-2-tert-butoxycarbonylami-
no]-tetrahydro-furan-(2R)-2-carboxylic Acid Butylamide
(19a). To a solution of 18a (28 mg, 0.048 mmol) in HCOOH/
MeOH (5%) (1 mL) at room temperature was added Pd-black
(28 mg), and the suspension was stirred for 1 h. The solid was
filtered, and the solution was concentrated to dryness. The
residue was dissolved in MeOH (2.0 mL), and Boc2O (52.3 mg,
0.24 mmol) and NaHCO3 (200 mg) were added. The mixture
was stirred at room temperature for 14 h, the solid was
filtered, and the solution was concentrated to dryness. The
residue was treated with TBAF (1.0 M in THF, 0.5 mL) at 0
°C for 0.5 h before it was taken up by EtOAc (10 mL). The
EtOAc solution was washed with water and concentrated. The
residue was purified by column chromatography (50% EtOAc
in hexanes) to give 19a as a colorless oil (14 mg, 77%); [R]D
1
+3.02 (c 0.4, CH2Cl2); H NMR (CDCl3) δ 0.92 (9 H, m), 1.33
(3 H, m), 1.43 (9 H, s), 1.51 (2H, m), 1.67 (3H, m), 2.00 (1 H,
m), 2.10 (1 H, m), 2.40 (1 H, m), 3.26 (2 H, m), 3.64 (1 H, m),
3.77 (1 H, m), 3.83 (1 H, m), 3.98 (1 H, m), 4.10 (1 H, d, J )
5.7 Hz), 4.18 (1 H, d, J ) 7.7 Hz), 5.11 (1 H, d, J ) 8.3 Hz),
6.74 (1 H, m); 13C NMR (CDCl3) δ 14.1, 20.4, 22.4, 23.7, 25.2,
28.2, 28.8, 31.9, 38.9, 41.7, 48.5, 52.4, 69.2, 74.3, 79.8, 79.8,
157.4, 173.8; IR (film) 3329, 2957, 2871, 1688, 1661, 1531; MS
(FAB) m/z 387.2 [M + 1]+; HRMS calcd for C20H39N2O3Si [M
+ 1]+ 387.2858; found 387.2840.
(3S)-3-[(1S)-1-tert-Butyl-dimethyl-silanyloxy)-(2S)-2-
tert-butoxycarbonylamino-4-methyl-pentyl]-tetrahydro-
furan-(2R)-2-carboxylic Acid N-Methyl-L-ala Amide (19b).
By a similar procedure 19b was prepared and purified by
column chromatography to give a colorless oil (10% hexanes
1
in EtOAc) (13 mg, 91%); [R]D -33.0 (c 0.40, CHCl3); H NMR
(MeOD) δ 0.91 (6H, m), 1.39 (2H, m), 1.40 (3 H, d, J ) 7.0
Hz), 1.42 (9H, s), 1.62 (3 H, m), 1.97 (1 H, m), 2.10 (1 H, m),
2.37 (1 H, m), 2.82 (2 H, d, J ) 4.7 Hz), 3.62 (2 H, m), 3.75 (1
H, m), 3.88 (2H, m), 3.98 (1H, m), 4.21 (2 H, d, J ) 7.8 Hz),
4.41 (1 H, m), 4.99 (2 H, d, J ) 8.9 Hz), 6.18 (1 H, m), 7.23 (2
H, d, J ) 7.2 Hz); 13C NMR (MeOD) δ 14.2, 18.4, 20.8, 22.3,
23.7, 25.2, 26.7, 27.5, 28.7, 41.5, 48.4, 48.7, 52.7, 52.9, 69.5,
74.1, 79.7, 80.0, 157.3, 172.8, 174.0; IR (film) 3324, 2956, 1652,
1520; MS (FAB) calcd for C20H38N3O6 m/z 416.2 [M + 1]+;
HRMS found, 416.28.
Compound 20a. Compound 19a (14 mg, 0.036 mmol) was
stirred with HCl in dioxane (4 M, 0.5 mL) for 1 h at room
temperature. The mixture was concentrated to dryness under
reduced pressure, and the residue was dissolved in CH2Cl2 (1.0
mL). The solution was cooled to 0 °C, and N′-trityl-BocAspOH
J. Org. Chem, Vol. 70, No. 17, 2005 6743

Hanessian et al.
(25.6 mg, 0.054 mmol) was added followed by PyBop (18.8 mg,
0.036 mmol) and i-Pr2NEt (23 µL, 0.14 mmol). The mixture
was stirred at 0 °C to room temperature for 2 h before it was
diluted with EtOAc (5 mL), and the organic phase was washed
with aqueous 1 N HCl and NaHCO3. The organic phase was
dried and concentrated, and the residue was purified by
column chromatography (30% hexanes in EtOAc) to give 20a
Compound 21a. Compound 20a (12 mg, 0.017 mmol) was
stirred with HCl in dioxane (4 M, 0.5 mL) for 1 h at room
temperature. The mixture was concentrated to dryness under
reduced pressure, and the residue was dissolved in a mixture
of CH2Cl2 (0.5 mL) and water (0.5 mL). The solution was cooled
to 0 °C, and N-Ac-L-ValOH (2.7 mg, 0.017 mmol) was added
followed by HOBt (2.3 mg, 0.017 mmol) and EDC (3.8 mg 0.018
mmol). The reaction mixture was stirred at 0 to 5 °C for 24 h,
and then it was diluted with EtOAc (5 mL). The organic phase
was washed with aqueous 1 N HCl, aqueous 1 N NaHCO3,
and brine. The organic phase was dried and concentrated, and
the residue was purified by column chromatography (20%
MeOH in CH2Cl2) to give the peptide product (14 mg). This
was stirred with TFA/water (95:5, 0.5 mL) at room tempera-
ture for 1 h, MeOH (3 mL) was added, and the reaction mixture
was concentrated at room temperature to dryness under
reduced pressure. The residue was taken up with EtOAc (5
mL) and washed with aqueous NaHCO3 and brine. The organic
phase was dried and concentrated, and the residue was
purified by column chromatography (20% MeOH in CH2Cl2)
to give 21a as a white solid (8 mg, 61%); [R]D -24.1 (c 0.34,
MeOH); 1H NMR (CDCl3) δ 0.87-1.02 (15H, m), 1.38 (3 H,
m), 1.50 (3H, m), 1.60 (3 H, m), 1.85 (1 H, m), 2.02 (3 H, s),
2.09 (1 H, m), 2.33 (1 H, m), 2.74 (1 H, m), 3.20 (2 H, t, J ) 7.1
Hz), 3.77 (1 H, m), 3.93 (2 H, m), 4.14 (2 H, dd, J ) 6.8 Hz),
4.66 (1 H, t, J ) 5.4 Hz); 13C NMR (CDCl3) δ 13.1, 17.6, 18.6,
20.1, 21.2, 21.4, 22.9, 24.6, 25.9, 30.4, 31.6, 36.4, 38.6, 41.1,
48.3, 50.9, 52.1, 59.9, 69.1, 72.2, 80.3, 171.6, 172.6, 172.8, 174.2,
174.7; IR (film) 3308, 2959, 1635, 1451; MS (FAB) m/z 542.3
[M + 1]+; HRMS calcd for C26H47N5O7 [M + 1]+ 542.3553;
found 542.3542.
Compound 21b. By a similar procedure 21b was prepared
from 20b. Purification by column chromatography gave 21b
as an white solid (5.2 mg, 66%); [R]D -34.0 (c 0.20, MeOH);
1H NMR (CDCl3): δ 0.88 (3 H, d, J ) 6.5 Hz), 0.91 (3 H, d, J
) 6.5 Hz), 0.97 (6 H, d, J ) 6.3 Hz), 1.29 (2 H, m), 1.36 (3 H,
d, J ) 7.1 Hz), 1.54 (1H, m), 1.61 (1 H, m), 1.90 (1 H, m), 2.02
(3 H, s), 2.09 (1 H, m), 2.39 (1 H, m), 2.74 (3 H, s), 2.75 (1 H,
m), 3.71 (1 H, t, J ) 4.4 Hz), 3.95 (2 H, m), 4.00 (1 H, m), 4.10
(1 H, d, J ) 6.4 Hz), 4.23 (1 H, d, J ) 6.4 Hz), 4.35 (1 H, q, J
) 7.1 Hz), 4.66 (1 H, t, J ) 6.5 Hz); 13C NMR (CDCl3) δ 13.4,
17.7, 18.6, 21.2, 21.4, 22.9, 24.6, 25.4, 26.1, 30.4, 36.4, 40.8,
48.9, 50.1, 50.9, 51.8, 59.9, 69.1, 72.3, 80.1, 171.7, 172.6, 172.9,
174.1, 174.3, 174.4; IR (film) 3307, 2964, 1673, 1536. MS (FAB)
m/z 571.1 [M + 1]+, 593.1 [M + 23]+; HRMS calcd for
C26H47N6O8 [M + 1]+ 571.3455; found 571.3436.
1
as a white solid (27 mg, 99%); [R]D -9.04 (c 0.8, CHCl3); H
NMR (CDCl3) δ 0.88 (6H, dd, J ) 0.3 and 0.5 Hz), 0.92 (3 H,
t, J ) 7.3 Hz), 1.34 (3H, m), 1.43 (9 H, s), 1.48 (2 H, m), 1.58
(2 H, m), 1.85 (1 H, m), 2.02 (1 H, m), 2.38 (1 H, m), 2.62 (1 H
m), 2.90 (1 H, s), 3.00 (1 H, m), 3.10 (1 H, m), 3.27 (1 H, m),
3.66 (2 H, m), 3.83 (1 H, m), 3.90 (1 H, m), 4.08 (1 H, d, J )
7.3 Hz), 4.14 (1 H, d, J ) 6.3 Hz), 4.36 (1 H, m), 6.08 (1 H, d,
J ) 7.8 Hz), 6.64 (1 H, t, J ) 5.6 Hz), 6.99 (1 H, m), 7.07 (1 H,
d, J ) 8.4 Hz), 7.17-7.31 (15H, m); 13C NMR (CDCl3) δ 14.1,
20.4, 21.5, 22.4, 23.6, 25.2, 28.4, 28.6, 31.9, 38.3, 38.8, 40.3,
47.9, 52.0, 52.9, 60.8, 69.3, 71.1, 74.8, 127.5, 128.4, 129.1, 144.8,
156.3, 170.6, 172.9, 173.5; IR (film) 3326, 2958, 1657, 1526;
MS (FAB) m/z 743.9 [M + 1]+; HRMS calcd for C43H58N4O7
[M + 1]+ 743.4364; found 743.4383.
Compound 20b. By a similar procedure 20b was prepared
from 19b. Purification by column chromatography (10% MeOH
in EtOAc) gave 20b as a white solid (17 mg, 71%); [R]D -28.4
1
(c 0.7, CHCl3); H NMR (MeOD) δ 0.88 (6H, m), 1.25-1.49 (4
H, m), 1.32 (3H, d, J ) 6.6 Hz), 1.42 (9 H, s), 1.61 (2 H, m),
1.84 (1 H, m), 1.99 (1 H, m), 2.33 (1 H, m), 2.62 (3 H, d, J )
3.8 Hz), 2.69 (1 H, m), 2.95 (1 H, m), 3.62 (1 H, m), 3.84 (3 H,
m), 4.06 (1 H, m), 4.36 (2 H, m), 6.14 (1 H, b), 6.29 (1 H, b),
6.96 (1 H, b), 7.26 (15 H, m); 13C NMR (MeOD) δ 18.6, 22.3,
23.7, 25.1, 26.6, 27.8, 28.6, 38.5, 40.4, 47.9, 48.7, 52.2, 52.6,
69.3, 71.1, 74.4, 77.6, 79.7, 80.7, 127.5, 128.4, 129.1, 144.7,
156.2, 170.7, 172.7, 172.9, 173.9; IR (film) 3318, 2956, 1651,
1519; MS (FAB) m/z 772.4 [M + 1]+; HRMS calcd for
C43H58N5O8 [M + 1]+ 772.4298; found 772.4285.
Compound 20c. Compound 18c (56 mg, 0.082 mmol) was
dissolved in HCOOH/MeOH (5%) (4 mL), Pd-black (56 mg) was
added, and the suspension was stirred for 1 h. The catalyst
was filtered, the solvent was removed under reduced pressure,
and the residue was redissolved in EtOAc and washed with 1
N NaHCO. The organic phase was dried and concentrated, and
the residue was stirred with Boc2O (89.38 mg, 0.41 mmol) and
NaHCO3 (300 mg) in MeOH (3 mL) overnight. After removal
of the solid and the solvent, the residue was treated with TBAF
(1.0 M in THF, 1.5 mL, predried with molecular seives) at 0
°C for 1.5 h. The reaction mixture was diluted with EtOAc
(10 mL), washed with water, and dried with Na2SO4. After
concentration, the residue was purified by column chroma-
tography (50% EtOAc in hexanes) to give 19c (34 mg, 83%).
The compound was stirred with HCl in dioxane (4 M, 1 mL)
at room temperature for 1 h. After removing the solvent under
reduced pressure, the residue was dissolved in CH2Cl2 (1.5 mL)
and cooled to 0 °C. N-Boc-L-MetOH (20.3 mg, 0.082 mmol) was
added, followed by PyBOP (42.4 mg, 0.082 mmol) and i-Pr2-
NEt (35 µL, 0.204 mmol). The reaction mixture was stirred
from 0 °C to room temperature for 3 h before it was diluted
with EtOAc (10 mL) and washed with aqueous 1 N HCl and
saturated NaHCO3. The organic phase was dried and concen-
trated, and the residue was purified by column chromatogra-
phy (40% hexanes in EtOAc) to give 20c was as a colorless oil
Compound 21c. Compound 20c (13 mg, 0.021 mmol) was
treated with HCl in dioxane (4 M, 1 mL) for 1 h. After
removing the solvent under reduced pressure, the residue was
dissolved in EtOAc and washed with 1 N NaHCO3 and water.
The solvent was evaporated, and the residue was dissolved in
CH2Cl2/water (1:1) (1.0 mL) and cooled to 0 °C. N-Ac-LeuOH
(7.23 mg, 0.042 mmol) was added, followed by EDC (9 mg,
0.042 mmol) and HOBT (5.6 mg, 0.042 mmol). The reaction
mixture was stirred from 0 to 5 °C for 24 h. The reaction
mixture was diluted with EtOAc (5 mL) and washed with
aqueous 1 N HCl and 1 N NaHCO3. The organic phase was
dried and concentrated, and the residue was purified by
column chromatography (10% MeOH in CH2Cl2) to give 21c
1
1
as a white solid (13 mg, 92%). [R]D -49.1 (c 0.6, MeOH); H
(18 mg, 43%); [R]D -38.4 (c 0.69, MeOH); H NMR (CDCl3) δ
NMR (CDCl3) δ 0.91 (9H, m), 1.34 (3H, m), 1.37 (3H, d, J )
7.2 Hz), 1.43 (9H, s), 1.47 (2H, m), 1.63 (4H, m), 1.74 (2H, m),
1.88 (2H, m), 1.91 (2H, m), 2.10 (3H, s), 2.36 (1H, m), 2.38
(1H, m), 2.57 (2H, m), 3.21 (2H, m), 3.28 (1H, m), 3.40 (1H,
m), 4.22 (1H, q, J ) 7.0 Hz), 4.31 (1H, t, J ) 6.4 Hz), 5.0 (1H,
b), 5.26 (1H, d, J ) 6.9 Hz), 6.58 (1H, b), 7.27 (1H, b), 8.28
(1H, b); 13C NMR (CDCl3) δ 14.0, 15.2, 18.7, 19.6, 21.1, 22.1,
22.2, 22.3, 22.6, 23.3, 23.9, 24.9, 25.7, 25.9, 26.5, 27.0, 31.2,
32.2, 32.4, 32.5, 40.0, 41.7, 42.4, 46.8, 52.5, 53.5, 53.9, 59.5,
70.0, 72.7, 81.0, 173.1, 173.4, 173.4, 175.0, 175.3; IR (film)
0.92 (9H, m), 1.33 (3H, m), 1.36 (3H, d, J ) 6.9 Hz), 1.45 (12H,
s), 1.48 (2H, m), 1.58 (3H, s), 1.64 (4H, m), 1.67 (2H, m), 1.72
(1H, m), 1.88 (1H, m), 2.37 (1H, m), 2.47 (1H, m), 3.24 (2H,
dd, J ) 6.7 and 13.1 Hz), 3.63 (1H, m), 3.74 (1H, m), 4.52 (1H,
t, J ) 7.0 Hz), 6.40 (1H, t, J ) 6.8 Hz), 6.63 (1H, b); 13C NMR
(CDCl3) δ 13.1, 13.3, 14.2, 17.7, 18.7, 20.1, 20.6, 21.3, 22.9,
24.7, 26.2, 27.7, 27.8, 30.3, 31.4, 31.5, 31.6, 39.1, 41.4, 51.6,
53.6, 54.5, 58.5, 69.1, 71.8, 79.7, 80.1, 156.8, 172.1, 173.7, 174.4;
IR (film) 3304, 2960, 2932, 2872, 1651, 1525; MS (FAB) calcd
for C30H56N4O7S m/z [M + 1]+ 617.4; found 617.42.
6744 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Oxacyclic Hydroxyethylene Isosteres
3288, 3081, 2958, 2872, 1644, 1538; MS (FAB) m/z 672 [M +
1]+; HRMS calcd for C33H62N5O7S [M + 1]+ 672.4371; found
672.4362.
Acknowledgment. We thank the National Science
and Engineering Council of Canada (NSERC) and
Novartis Pharma (Basel, Switzerland) for generous
financial assistance. We also thank Dr. Michel Simard
for X-ray crystallography of analogues and Eric Therrien
for technical assistance.
Modeling of Compounds in BACE1. A 10 Å shell around
the inhibitor in the BACE1 OM99-2 cocrystal structure (PDB
ref 1FKN) was used for calculations. In this binding site model,
the Monte Carlo docking/energy minimization protocol of the
MCDOCK routine in the QXP program26 (within the Flow96
package) was applied. Depending on the size and flexibility of
the ligands, 1000 or 2000 search and energy minimization
cycles were performed to ensure an in-depth conformational
search and the exploration of different possible binding modes.
Supporting Information Available: NMR spectra for the
synthetic molecules and CIF files of X-ray structures 3a, 4a,
4c, 5b, 6c, 9, and 13. X-ray crystallographic data have been
deposited in the Cambridge Crystallographic Database. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) McMartin, C.; Bohacek, R. S. J. Comput.-Aided Mol. Des. 1997,
11, 333.
JO050749Y
J. Org. Chem, Vol. 70, No. 17, 2005 6745