Acylnitrene route to vicinal amino alcohols. Application to the synthesis of (-)-bestatin and analogues

Article abstract of DOI:10.1021/jo9823893

Bestatin, valinoctin A, and microginin are naturally occurring small peptides containing a nonproteinogenic α-hydroxy-α-amino acid at the N-terminus of the peptide chain. We report here our development of a general method for the synthesis of α-hydroxy-β-amino acids and exemplify this with a synthesis of (-)-bestatin and analogues. Our synthesis utilizes an intramolecular acylnitrene-mediated aziridination to generate a key bicyclic aziridine in excellent yield and stereoselectivity. This bicyclic aziridine can be opened with a number of organometallic reagents to provide a series of substituted oxazolidinones. The oxazolidinones are readily converted to bestatin and a series of bestatin analogues. As part of this approach, we have developed a new method for the synthesis of azidoformates. We have also demonstrated that oxazolidinones can be selectively hydrolyzed in the presence of peptide bonds. This acylnitrene route to bestatin should prove useful for the synthesis of a variety of analogues of bestatin as well as other α-hydroxy-β-amino acids and their corresponding peptides.

Full text of DOI:10.1021/jo9823893

2852
J . Org. Chem. 1999, 64, 2852-2859
Acyln itr en e Rou te to Vicin a l Am in o Alcoh ols. Ap p lica tion to th e
Syn th esis of (-)-Besta tin a n d An a logu es
Stephen C. Bergmeier*,† and Dionne M. Stanchina
Division of Medicinal Chemistry, College of Pharmacy, and the Comprehensive Cancer Center,
The Ohio State University, Columbus, Ohio 43210
Received December 7, 1998
Bestatin, valinoctin A, and microginin are naturally occurring small peptides containing a
nonproteinogenic R-hydroxy-â-amino acid at the N-terminus of the peptide chain. We report here
our development of a general method for the synthesis of R-hydroxy-â-amino acids and exemplify
this with a synthesis of (-)-bestatin and analogues. Our synthesis utilizes an intramolecular
acylnitrene-mediated aziridination to generate a key bicyclic aziridine in excellent yield and
stereoselectivity. This bicyclic aziridine can be opened with a number of organometallic reagents
to provide a series of substituted oxazolidinones. The oxazolidinones are readily converted to bestatin
and a series of bestatin analogues. As part of this approach, we have developed a new method for
the synthesis of azidoformates. We have also demonstrated that oxazolidinones can be selectively
hydrolyzed in the presence of peptide bonds. This acylnitrene route to bestatin should prove useful
for the synthesis of a variety of analogues of bestatin as well as other R-hydroxy-â-amino acids and
their corresponding peptides.
In tr od u ction
may be promising as an anticancer agent.2 Microginin is
an ACE inhibitor and could be useful as an antihyper-
tensive agent.5
Bestatin,1 valinoctin A,2 and microginin3 are naturally
occurring small peptides containing a nonproteinogenic
R-hydroxy-â-amino acid at the N-terminus of the peptide
chain. The compounds are representative of a class of
compounds which numbers over 30 different peptides
with widely varying biological activities. Bestatin, for
example, is an aminopeptidase inhibitor that exhibits
immunostimulatory activity as well as cytotoxic activity.4
Bestatin is used clinically as an anticancer agent. Vali-
noctin A is a potent inhibitor of farnesyl transferase and
While the peptides have some structural differences,
a core structure of all of these compounds can be drawn
as compound 4 (Figure 1). In this core structure, R is a
variety of aliphatic or aryl groups and aa can be a single
amino acid residue or a small peptide chain. Given the
wide variations in biological activity and the correspond-
ing variations in the carbon chain of the N-terminal
R-hydroxy-â-amino acid, a general synthetic route to
R-hydroxy-â-amino acids is desirable. A synthesis of
R-hydroxy-â-amino acids that both installs R and forms
the peptide bond late in the synthesis will be a general
route to any and all of these compounds.
Our acylnitrene aziridination/aziridine opening method
is a versatile method for the synthesis of this group of
molecules.6 As shown in Scheme 1, an allylic alcohol is
converted to an azidoformate (6) and thermally cyclized
to a bicyclic aziridine (7). This step transfers the stereo-
chemical information of the allylic alcohol to the aziridine.
The aziridine can then be readily opened with both
carbon and heteroatom nucleophiles to provide oxazoli-
dinone 8. The oxazolidinone can be hydrolyzed by a
number of methods to produce the amino alcohol 9. We
report here our development of a general method for the
synthesis of these nonproteogenic peptides and exemplify
this with a synthesis of (-)-bestatin and analogues.
* To whom correspondence should be addressed.
† Telephone: 614-292-5499. E-mail: bergmeier.1@osu.edu.
(1) Isolation and structure determination of bestatin: (a) Umezawa,
H.; Aoyagi, T.; Suda, H.; Hamada, M.; Takeuchi, T. J . Antibiot. 1976,
29, 97. (b) Nakamura, H.; Suda, H.; Takita, T.; Aoyagi, T.; Umezawa,
H. J . Antibiot. 1976, 29, 102. For some recent syntheses of bestatin,
see: (c) De, A.; Basak, P.; Iqbal, J . Tetrahedron Lett. 1997, 38, 8383
and references therein. (d) Fuji, K.; Kawabata, T.; Diryu, Y.; Sugiura,
Y. Heterocycles 1996, 42, 701. (e) Koseki, K.; Ebata, T.; Matsushita,
H. Biosci. Biotechnol. Biochem. 1996, 60, 534. (f) Palomo, C.; Aizpurua,
J . M.; Cuevas, C. J . Chem. Soc., Chem. Commun. 1994, 1957. (g)
Herranz, R.; Castro-Pichel, J .; Garcia-Lopez, M. T.; Gomez-Monterrey,
I.; Perez, C.; Vinulesa, S. Arch. Pharm. (Weinheim, Ger.) 1993, 326,
395. (h) Matsuda, F.; Matsumoto, T.; Ohsaki, M.; Ito, Y.; Terashima,
S. Bull. Chem. Soc. J pn. 1992, 65, 360. (i) Norman, B. H.; Morris, M.
L. Tetrahedron Lett. 1992, 33, 6803. (j) Matsuda, F.; Matsumoto, T.;
Ohsaki, M.; Ito, Y.; Terashima, S. Chem. Lett. 1990, 723. (k) Pearson,
W. H.; Hines, J . V. J . Org. Chem. 1989, 54, 4235.
(2) Sekizawa, R.; Iinuma, H.; Muraoka, Y.; Naganawa, H.; Ki-
noshita, N.; Nakamura, H.; Hamada, M.; Takeuchi, T.; Umezawa, K.
J . Nat. Prod. 1996, 59, 232. (b) Tsuda, M.; Muraoka, Y.; Takeuchi, T.
J . Antibiot. 1996, 49, 1031.
(3) Isolation of microginin: (a) Okino, T.; Matsuda, H.; Murakami,
M.; Yamaguchi, K. Tetrahedron Lett. 1993, 34, 501. For some syntheses
of microginin, see: (b) Bunnage, M. E.; Burke, A. J .; Davies, S. G.;
Goodwin, C. J . Tetrahedron: Asymmetry 1994, 5, 203. (c) Matsuura,
F.; Hamada, Y.; Shioiri, T. Tetrahedron 1994, 50, 11303. (d) Bunnage,
M. E.; Burke, A. J .; Davies, S. G.; Goodwin, C. J . Tetrahedron:
Asymmetry 1995, 6, 165. (e) Matsuura, F.; Hamada, Y.; Shioiri, T.
Tetrahedron 1995, 51, 12193. (f) J efford, C. W.; McNulty, J .; Lu, Z.
H.; Wang, J . B. Helv. Chim. Acta 1996, 79, 1203. (g) Tuch, A.; Saniere,
M.; Le Merrer, Y.; Depexay, J .-C. Tetrahedron: Asymmetry 1996, 7,
2901.
Resu lts a n d Discu ssion
A retrosynthesis of the dipeptides is shown in Scheme
2. The core structure (4) should be readily obtained from
the corresponding R-hydroxy-â-amino acid 10. Compound
10 can be prepared from bicyclic aziridine 11 through
aziridine opening and oxazolidinone hydrolysis. The
(4) Umezawa, H.; Ishizuka, M.; Aoyagi, T.; Takeuchi, T. J . Antibiot.
1976, 29, 857. (b) Ino, K.; Goto, S.; Nomura, S.; Isobe, K.-I.; Nawa, A.;
Okamoto, T.; Tomoda, Y. Anticancer Res. 1995, 15, 2081.
(5) See ref 3a.
(6) Bergmeier, S. C.; Stanchina, D. M. J . Org. Chem. 1997, 62, 4449.
10.1021/jo9823893 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/26/1999

Acylnitrene Route to Vicinal Amino Alcohols
J . Org. Chem., Vol. 64, No. 8, 1999 2853
Sch em e 3
Sch em e 4
F igu r e 1.
Sch em e 1
On the basis of these considerations, glyceraldehyde
was used as the source of chirality for this synthesis. We
converted mannitol to (R)-glyceraldehyde acetonide.8 As
shown in Scheme 3, our plan was to prepare olefin 14
and hydrolyze the acetonide to provide diol 17. Unfortu-
nately, the olefin 14 was inseparable from the reaction
mixture. Attempts to distill this volatile olefin led to
mixtures of 14, THF, and hexane. Attempts to use other
solvents for the Wittig reaction or to use the crude olefin
in the next reaction were not successful. We then turned
to the cyclohexanone ketal 15.9 This compound was
readily converted to the olefin 16. Olefin 16 was not as
volatile as 14 and could be chromatographically purified.
The ketal was readily hydrolyzed with Dowex-(H+) resin
to provide the nonracemic diol 17 in excellent yield.
As shown in Scheme 4, diol 17 could be selectively
monosilylated with tert-butyldiphenylsilyl chloride
(TBDPS-Cl) (18) in good yield. We initially attempted to
convert allylic alcohol 18 to the corresponding azidofor-
mate 19 using the procedure of Yuan et al.10 This
procedure uses CDI to make an initial imidazolide which,
upon treatment with NaN3 at pH 4, produces azidofor-
mates in generally excellent yields.6 The use of 18 under
these reaction conditions gave only a 41% yield of
azidoformate 19. We suspect that the neighboring azido-
formate (or imidazolide) assists in the acid-catalyzed
deprotection of the normally robust silyl ether. We were
Sch em e 2
group X will need to be either a carboxylic acid or a
CH2OH group. If X is COOH, then our chiral starting
material would be (R)- or (S)-vinyl glycolic acid. While
this is a known compound, its resolution is difficult and
it is not easily prepared on a large scale.7 When X is
CH2OH, compound 12 could be readily derived in opti-
cally pure form from glyceraldehyde, a well-known and
easily prepared chiral starting material.8
(7) Li, R.; Powers, V. M.; Kozarich, J . W.; Kenyon, G. L. J . Org.
Chem. 1995, 60, 3347.
(8) (a) Schmid, C. R.; Bryant, J . D. In Organic Syntheses; Coffen,
D. L., Ed.; New York, 1993; Vol. 72; pp 6-12. (b) Earle, M. J .; Abdur-
Rashid, A.; Priestley, N. J . Org. Chem. 1996, 61, 5697.
(9) Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita, K. Agric.
Biol. Chem. 1984, 48, 1841.
(10) Yuan, P.; Plourde, R.; Shoemaker, M. R.; Moore, C. L.; Hansen,
D. E. J . Org. Chem. 1995, 60, 5360.

2854 J . Org. Chem., Vol. 64, No. 8, 1999
Bergmeier and Stanchina
Sch em e 6
Sch em e 5
Sch em e 7
thus forced to develop a new method of azidoformate
formation that proceeded under neutral or basic condi-
tions. Treatment of alcohol 18 with p-nitrophenyl chlo-
roformate gave the intermediate carbonate in almost
quantitative yield. The carbonate could not be purified
via chromatography but was simply treated with NaN3
in DMF to provide excellent yields of azidoformate 19.
Following our standard protocol, the azidoformate 19
was heated in a sealed tube at 109 °C for 13 h to provide
the bicyclic aziridine 20 in good yield. The use of CH2Cl2
in a sealed tube has continued to be the optimal method
for this transformation. Using other solvents (e.g., tolu-
ene, tetrachloroethane) produces products arising from
the reaction of the acylnitrene with the solvent.6,11 1H
NMR showed the presence of a single bicyclic aziridine.
As we have noted previously, these bicyclic aziridines
cannot be chromatographically purified but are moder-
ately stable to storage.12
To prepare bestatin, we needed only to open the
aziridine with a phenyl anion. To demonstrate the utility
of the method for the preparation of analogues, a variety
of other organometallic reagents were used as well. As
we have previously reported, neither Grignard nor or-
ganolithium reagents effectively opened the aziridine
ring.6 Optimum yields are obtained with an organocu-
prate reagent derived from the organolithium reagent
and CuCN. We have used several commercially available
organolithium reagents (Scheme 5). These include nBuLi,
nHexLi, Me3SiCH2Li, and PhLi. We have also prepared
o-MeO-PhLi through the ortholithiation13 of anisole.
These organocuprate reagents provided the aziridine
opened products 21a -21e in generally good yields. The
organolithium reagent Ph(CH2)3Li was also prepared14
and used, but the yield of the aziridine-opened product
was very low (15-20%).
the protected alcohol to a carboxyl group and couple with
the appropriate amino acid. The alcohol was deprotected
with nBu4NF to provide alcohols 22a -22f in good yield.
Of particular note is alcohol 22e in which the side chain
contains a trimethylsilyl group. This compound gave an
excellent yield of 22e from 21e.
As shown in Scheme 6, oxidation of 22a directly to the
carboxylic acid was accomplished with RuCl3‚xH2O/NaIO4
although in very poor isolated yield (∼20%).15 The
coupling of the crude acid with benzyl alcohol using DCC
gave an improved yield of the ester 23a . At this stage
we were faced with several options on the conversion of
acid 23a to the dipeptide. Our initial strategy was to
directly convert oxazolidinone 23a to the N-BOC-pro-
tected R-hydroxy-â-amino acid 24. Our first attempt at
this transformation involved an initial hydrolysis of the
oxazolidinone followed by in situ protection of the amine
with a BOC group. This reaction sequence gave a very
low yield of 24. Believing that milder conditions should
improve the yields in this transformation, we next sought
to convert 23a to the N-BOC-oxazolidinone and hydrolyze
this to 24 using Cs2CO3.16 This hydrolysis only resulted
in the cleavage of the N-BOC from the oxazolidinone. Use
of other reaction conditions (base, temperature, solvent)
gave no significant improvement in the yield of 24. This
is not too surprising considering the recent observation
that the Cs2CO3-mediated hydrolysis of N-BOC-oxazoli-
dinone only works well when a carboxyl group is adjacent
to the nitrogen of the oxazolidinone ring.16b
With the aziridine ring opened using the desired
organocuprate reagent, all that remained was to convert
Faced with these results, we decided to couple the acid
to the C-terminal amino acid and then attempt oxazoli-
dinone hydrolysis (Scheme 7). In an attempt to improve
the yield, the acid was not purified but was directly
coupled to O-t-BuLeu (25) using 2-(1H-benzotriazol-1-yl)-
(11) Bergmeier, S. C.; Stanchina, D. M. Tetrahedron Lett. 1995, 36,
4533.
(12) The stability of the bicyclic aziridines is dependent upon their
purity and the identity of the aziridine. Aziridine 20 for example begins
to decompose after 5-7 days in the freezer. However, a related bicyclic
aziridine in which the TBDPS group is replaced with a trityl group is
stable at room temperature for several weeks.
(13) (a) Finnegan, R. A.; Altshuld, J . W.; J . Organomet. Chem. 1967,
9, 193. (b) Shirley, D. A.; J ohnson, J . R., J r.; Hendrix, J . P. J .
Organomet. Chem. 1968, 11, 209.
(14) (a) Bailey, W. F.; Punzalan, E. R. J . Org. Chem. 1990, 55, 5404.
(b) Negishi, E.; Swanson, D. R.; Rousset, C. J . J . Org. Chem. 1990, 55,
5406.
(15) Carlsen, P. J .; Katsuki, T.; Marin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936.
(16) (a) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 36, 4185.
(b) DiGiovanni, M. C.; Misiti, D.; Villani, C.; Zappia, G. Tetrahedron:
Asymmetry 1996, 8, 2277.

Acylnitrene Route to Vicinal Amino Alcohols
J . Org. Chem., Vol. 64, No. 8, 1999 2855
Sch em e 8
lidinones can be selectively hydrolyzed in the presence
of peptide bonds. This acylnitrene route to bestatin
should prove useful for the synthesis of a variety of
analogues of bestatin as well as other R-hydroxy-â-amino
acids and their corresponding peptides.
Exp er im en ta l Section 20
2,3-O-Cycloh exylid en e-D-glycer a ld eh yd e. To a solution
of 1,2:5,6-di-O-cyclohexylidene-D-mannitol9 (27.39 g, 80.0 mmol)
in 60% aqueous CH3CN (120 mL) cooled to 5 °C was added
NaIO4 (34.56 g, 160 mmol) in small portions at room temper-
ature over 40 min. After the addition was complete, the
solution stirred at room temperature for 1 h and filtered. The
filtrate was mixed with water and extracted with CHCl3 (3 ×
100 mL). The combined organic layers were washed with water
(2 × 100 mL) and brine (2 × 100 mL), dried (MgSO4), filtered,
and concentrated under reduced pressure. The resulting syrup
was distilled under vacuum and used immediately in the next
reaction. Analytical data matched that reported for the known
compound.9
(2S)-1,2-O-Cycloh exylid en ebu t-3-en e-1,2-d iol (16). To a
suspension of methyltriphenylphosphonium iodide (38.80 g,
96.0 mmol) in THF (296 mL) at 0 °C was added nBuLi (42.0
mL of a 2.3 M solution in hexanes, 96.0 mmol). The reaction
mixture was stirred for 15 min at 0 °C and was then warmed
to room temperature where stirring continued for 45 min. The
solution was then recooled to -78 °C, and a solution of 2,3-
O-cyclohexylidene-D-glyceraldehyde (13.61 g, 80.0 mmol) in
THF (99 mL) was added. The reaction mixture was stirred at
-78 °C for 1 h and was then warmed to room temperature
where stirring continued for 16 h. The reaction mixture was
quenched with a saturated aqueous solution of NH4Cl, ex-
tracted with EtOAc (3 × 100 mL), washed with brine (2 × 100
mL), dried (MgSO4), filtered, concentrated, and chromato-
graphed (hexanes) to give 9.12 g of 16 (68%) from 15 as a
1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as
the coupling agent.17 This procedure led to dramatically
improved yields of the dipeptide from the alcohol (72-
84% over two steps). Apparently our previous attempts
at purifying the acid led to lower yields, possibly through
loss of the product on the column. Several other coupling
agents including DCC and carbonyldiimidazole were
examined, but the yields of 26 were significantly lower
than with TBTU.
Once the peptide bond had been formed, all that
remained was to hydrolyze the oxazolidinone ring to
provide the free amino alcohol. We were quite concerned
about this step as we were attempting to selectively
hydrolyze a carbamate (oxazolidinone ring) in the pres-
ence of another carbamate (BOC) and an amide bond.
We chose to first activate the oxazolidinone ring by
putting a tert-butoxycarbonyl group on the nitrogen.18
This was accomplished by treating 26a -26e with 1.2
equiv of (BOC)2O to provide 27a -27e in 73-95% yield
(Scheme 8) . Again, hydrolysis of 27 with Cs2CO3 only
yielded the deprotected oxazolidinone 26. The examina-
tion of a variety of bases showed that a selective hydroly-
sis of the oxazolidinone ring could be accomplished in
good yield with LiOH at 0 °C.19
With the oxazolidinone ring hydrolyzed, we had in
hand a diprotected version of our target dipeptides. The
BOC and tBu ester were concurrently removed by treat-
ment with TFA to provide the TFA salt. This provided
(-)-bestatin as well as a series of aryl and alkyl ana-
logues.
In conclusion we have developed and applied a novel
method for the synthesis of R-hydroxy-â-amino acids to
the synthesis of (-)-bestatin and analogues. This new
method installs a variety of alkyl and aryl groups on the
carbon chain of bestatin. As part of this approach, we
have developed a new method for the synthesis of
azidoformates. We have also demonstrated that oxazo-
1
colorless oil: [R]D + 4.0° (c 1.7, EtOAc); H NMR δ 5.75 (m,
1H), 5.28 (d, 1H, J ) 21.0 Hz), 5.15 (d, 1H, J ) 10.2 Hz), 4.45
(q, 1H, J ) 5.1 Hz), 4.05 (dd, 1H, J ) 5.1, 7.8 Hz), 3.55 (t, 1H,
J ) 7.6 Hz), 1.70-1.20 (m, 10H); 13C NMR δ 136.4, 117.3,
109.9, 76.9, 68.9, 36.2, 35.4, 25.1, 23.9, 23.8; IR (neat) 3084,
1647, 1440 cm-1. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59.
Found: C, 71.00; H, 9.95.
(2S)-3-Bu ten e-1,2-d iol (17). To a solution of 16 (4.50 g,
26.74 mmol) in MeOH (60 mL) was added Dowex 50X8-200
acidic ion-exchange resin (30.0 g) at room temperature. The
reaction mixture stirred for 23 h at room temperature and was
then filtered and washed with MeOH. The filtrate was
concentrated and chromatographed (70% EtOAc/hexanes) to
afford 1.91 g of 17 (91% taking into account 500 mg of
recovered 18) as a colorless oil: [R]D -28.4° (c 5.0, EtOAc); 1H
NMR δ 5.80 (m, 1H), 5.30 (d, 1H, J ) 21.0 Hz), 5.18 (d, 1H, J
) 10.0 Hz), 4.20 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H); 13C NMR
(20) General Methods. Thin-layer chromatography (TLC) was per-
formed on Whatman precoated silica gel F254 aluminum foils. Visual-
ization was accomplished with UV light and/or phosphomolybdic acid
solution followed by heating. Purification of the reaction products was
carried out by flash column chromatography using glass column dry
packed with silica gel (230-400 mesh ASTM) according to the method
of Still.21 1H NMR spectra referenced to TMS were recorded using a
Bruker AF 250 or Bruker AF 270 model spectrometer. Data are
reported as follows: chemical shift in ppm from internal standard
tetramethylsilane on the δ scale, multiplicity (b ) broad, s ) singlet,
d ) doublet, t ) triplet, q ) quarte,t and m ) multiplet), integration,
coupling constant (Hz). Unless otherwise noted all spectra were
recorded in CDCl3. All reactions were carried out under an atmosphere
of nitrogen unless specified otherwise. Glassware was flame dried
under a flow of nitrogen. Tetrahydrofuran and diethyl ether were
distilled over sodium/benzophenone ketyl immediately prior to use.
Dichloromethane was distilled over CaH2 prior to use. Organolithium
reagents used for the reactions were purchased from Aldrich Chemical
Co. or prepared via the method of Negishi.14b CAUTION: Azid es a r e
p oten tia lly exp losive, esp ecia lly u p on h ea tin g. Wh ile w e h a ve
obser ved n o p r oblem s w ith sta bility or for m a tion of th e a zid o-
for m a tes, ca r e sh ou ld be exer cised .
(17) We substituted HBTU used in this procedure with TBTU. This
was the only modification made to the reported procedure: Dourtoglow,
V.; Gross, B. Synthesis 1984, 572.
(18) Burk, M. J .; Allen, J . G. J . Org. Chem. 1997, 62, 7054.
(19) (a) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983,
48, 8, 2424. (b) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron
Lett. 1987, 28, 6141.
(21) Still, C. W.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 50, 2923.

2856 J . Org. Chem., Vol. 64, No. 8, 1999
Bergmeier and Stanchina
δ 136.8, 116.5, 73.3, 66.2; IR (neat) 3355, 1647, 1426 cm-1
Anal. Calcd for C4H8O2: C, 54.53; H, 9.15. Found: C, 54.21;
H, 9.47.
.
saturated aqueous solution of NH4Cl, extracted with EtOAc
(3 × 40 mL), washed with brine (2 × 40 mL), dried (MgSO4),
filtered, concentrated, and chromatographed (22% EtOAc/
hexanes) to afford 630 mg of 21a (74%) as a yellow oil: [R]D
(2S)-1-O-(ter t-Bu tyldiph en ylsilyl)-3-bu ten e-1,2-diol (18).
To a solution of 17 (920 mg, 10.44 mmol) and imidazole (1.56
g, 22.92 mmol) in DMF (10.4 mL) at 0 °C was added a solution
TBDPSCl (3.15 g, 11.46 mmol) in DMF (2.5 mL). The reaction
mixture was warmed to room temperature where stirring was
continued for 22 h. The reaction mixture was quenched with
saturated aqueous NH4Cl, extracted with EtOAc (3 × 30 mL),
dried (MgSO4), filtered, concentrated, and chromatographed
(2% EtOAc/hexanes) to afford 3.12 g of 18 (91%) as a colorless
1
+58.6° (c 0.7, EtOAc); H NMR δ 7.60 (m, 6H), 7.40 (m, 9H),
4.40 (m, 1H), 4.05 (m, 1H), 3.80 (m, 2H), 3.55 (d, 2H, J )
7.5 Hz), 2.85 (m, 2H), 1.05 (s, 9H); 13C NMR δ 158.5, 135.6,
135.5, 132.7, 130.0, 129.6, 127.9, 114.6, 79.5, 64.1, 55.2, 45.9,
26.7, 19.2; HRMS calcd for C27H31NO3Si 445.6255, found
445.6258.
(4R,5S)-5-[(2-Met h oxyp h en yl)m et h yl]-4-(ter t-b u t yld i-
p h en ylsilyloxym eth yl)-1,3-oxa zolid in -2-on e (21b). Anisole
(1.76 g, 16.24 mmol) in Et2O (19.3 mL) was heated to reflux,
and nBuLi (6.81 mL of a 2.5 M solution in hexane, 17.02 mmol)
was added dropwise over 15 min. Refluxing continued for 22.5
h. The reaction mixture was then cooled to room temperature
for use in the next reaction. To a suspension of CuCN (470
mg, 5.28 mmol) in Et2O (18.2 mL) cooled to -78 °C was added
the previously prepared organolithium reagent. The reaction
mixture was then warmed to -40 °C and stirred for 45 min.
The solution was recooled to -78 °C, and 20 (1.94 g, 5.28
mmol) in Et2O (8.6 mL) was added and stirring continued at
-78 °C for 20 min. The reaction was warmed to room
temperature by removing the ice bath, and stirring was
continued for 4 h. The reaction was quenched with saturated
aqueous NH4Cl and extracted with EtOAc (2 × 30 mL). The
organic layer was washed with brine (2 × 30 mL), dried
(MgSO4), filtered, concentrated, and chromatographed (25%
EtOAc/hexanes) to afford 1.99 g of 21b (80%): [R]D +17.2° (c
1
oil: [R]D -18.4° (c 2.6, EtOAc); H NMR δ 7.75 (m, 4H), 7.45
(m, 6H), 5.85 (m, 1H), 5.38 (d, 1H, J ) 22.0 Hz), 5.22 (d, 1H,
J ) 10.0 Hz), 4.30 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 2.80 (d,
1H, J ) 4.2 Hz), 1.15 (s, 9H); 13C NMR δ 136.8, 135.5, 135.4,
134.8, 133.1, 133.0, 129.8, 129.4, 127.7, 127.6, 116.2, 72.9, 67.7,
26.8, 19.2; IR (neat) 3430, 1890, 1590, 1472 cm-1. Anal. Calcd
for C20H26O2Si: C, 73.57; H, 8.03. Found: C, 73.39; H, 8.03.
(2S)-1-O-(ter t-Bu tyld ip h en ylsilyl)-2-[(a zid oca r bon yl)-
oxy]-3-bu ten e (19). CAUTION: Azid es a r e p oten tia lly
exp losive, esp ecia lly u p on h ea tin g. Wh ile w e h a ve ob-
ser ved n o p r oblem s w ith sta bility or for m a tion of th e
a zid ofor m a tes, ca r e sh ou ld be exer cised . To a solution of
18 (7.50 g, 22.97 mmol) in benzene (73 mL) and pyridine (5.46
g, 69.03 mmol) at room temperature was added p-nitrophenyl
chloroformate (9.26 g, 45.94 mmol). After stirring for 2.5 h at
room temperature, the reaction mixture was diluted with
EtOAc, washed with saturated aqueous NaHCO3 (2 × 70 mL)
and brine (2 × 70 mL), dried (MgSO4), filtered, and concen-
trated to give a yellow solid. This crude material was dissolved
in DMF (106 mL), and NaN3 (14.93 g, 229.7 mmol) was added
at room temperature. The reaction mixture was then warmed
to 35 °C where stirring continued for 19 h. The reaction
mixture was cooled to room temperature, quenched with
saturated aqueous NH4Cl, washed with brine (2 × 50 mL),
dried (MgSO4), filtered, concentrated, and chromatographed
(hexanes) to give 7.26 g of 19 (80%) as a colorless oil: [R]D
1
0.4, EtOAc); H NMR δ 7.65 (m, 5Η), 7.40 (m, 5H), 7.20 (m,
2H), 7.05 (m, 1H), 6.90 (m, 2H), 4.35 (m, 1H), 4.15 (m, 1H),
3.75 (m, 5H), 3.55 (dd, 1H, J ) 2.7, 8.1 Hz), 2.90 (m, 2H), 1.05
(s, 9H); 13C NMR δ 157.3, 135.6, 135.5, 135.4, 131.1, 129.8,
128.5, 127.8, 127.7, 124.3, 120.7, 110.5, 107.0, 81.4, 63.7, 55.1,
53.7, 36.6, 26.7, 19.1; HRMS calcd for C28H32NO4Si 474.6500,
found 474.6497.
(4R,5S)-5-P en tyl-4-(ter t-bu tyld ip h en ylsilyloxym eth yl)-
1,3-oxa zolid in -2-on e (21c). To a suspension of copper(I)
cyanide (570 mg, 6.39 mmol) in THF (22.5 mL) cooled to -78
°C was added n-BuLi (5.12 mL of a 2.5 M solution in hexanes,
12.79 mmol). The reaction mixture was warmed to -40 °C and
stirred for 40 min. The solution was then cooled to -78 °C,
and 20 (2.35 g, 6.39 mmol) in THF (10 mL) was added and
stirring continued at -78 °C for 20 min. The reaction mixture
was slowly warmed to room temperature by removing the ice
bath. After 5 h, the reaction was quenched with a saturated
aqueous solution of NH4Cl, extracted with EtOAc (3 × 40 mL),
washed with brine (2 × 40 mL), dried (MgSO4), filtered,
concentrated, and chromatographed (20% EtOAc/hexanes) to
afford 1.41 of 21c (52%) as a yellow oil: [R]D +7.4° (c 0.4,
1
-20.8° (c 1.7, EtOAc); H NMR δ 7.75 (m, 4H), 7.45 (m, 6H),
5.85 (m, 1H), 5.35 (m, 3H), 3.80 (d, 2H, J ) 6.1 Hz), 1.15 (s,
9H); 13C NMR δ 156.8, 135.6, 135.5, 133.1, 133.0, 131.9, 129.8,
129.7, 127.7, 119.3, 79.7, 65.0, 26.9, 19.2; IR (neat) 2133, 1733
cm-1. Anal. Calcd for C21H25N3O3Si: C, 63.77; H, 6.37; N, 10.62.
Found: C, 63.85; H, 6.42; N, 10.34.
(4R,5S)-5-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-1-oxa -3-
a za bicyclo[3.1.0]h exa n -2-on e (20). A solution of 19 (400 mg,
1.91 mmol) and BHT (42 mg, 0.19 mmol) in CH2Cl2 (30 mL)
was placed in an ACE Glass Model 8648B 100 mL capacity
pressure tube. CAUTION: Rea ction s con d u cted in p r es-
su r e tu bes a r e p oten tia lly exp losive a n d sh ou ld be
ca r r ied ou t beh in d a p r otective sh ield . Wh ile w e h a ve
obser ved n o p r oblem s, ca r e sh ou ld be excer cised . The
reaction vessel was cooled to -78 °C, evacuated, and sealed.
The reaction mixture was then warmed to 109 °C in an oil
bath for 13 h. It was then cooled to room temperature and
concentrated to afford 300 mg (87%) of 20. An 1H NMR
analysis of the crude material using the signal for the aromatic
protons (6.85 ppm) of BHT as an internal standard was used
to determine the yield of the reaction. This material was used
directly in the following organocuprate reactions without any
further purification:6 1H NMR δ 7.65 (m, 4 H), 7.35 (m, 6H),
4.60 (m, 1H), 3.80 (m, 2H), 3.10 (t, 1H, J ) 3.8 Hz), 2.50 (d,
1H, J ) 4.6 Hz), 2.15 (d, 1H, J ) 4.6 Hz), 1.10 (s, 9H); 13C
NMR δ 166.8, 135.6, 135.5, 132.7, 130.0, 130.0, 129.6, 127.9,
1
EtOAc); H NMR δ 7.65 (m, 5H), 7.40 (m, 5H), 4.20 (m, 1H),
3.75 (m, 3 H), 1.50 (m, 2H), 1.30 (m, 6H), 1.05 (s, 9H), 0.85 (t,
3H, J ) 5.3 Hz); 13C δ 159.3, 135.6, 135.5, 132.8, 129.7, 127.8,
81.8, 64.3, 54.5, 35.6, 31.4, 26.7, 24.7, 22.3, 19.2, 13.8; HRMS
calcd for C25H35NO3Si 425.2388, found 425.2396.
(4R,5S)-5-Hep tyl-4-(ter t-bu tyld ip h en ylsilyloxym eth yl)-
1,3-oxa zolid in -2-on e (21d ). To a suspension of CuCN (180
mg, 2.03 mmol) in THF (7.1 mL) cooled to -78 °C was added
n-hexyllithium (2.03 mL of a 2.0 M solution in hexane, 4.06
mmol). The reaction mixture was then warmed to -40 °C and
stirred for 45 min. After the solution was cooled to -78 °C, 20
(746 mg, 2.03 mmol) in THF (3.1 mL) was added and stirring
continued at -78 °C for 20 min. The reaction was warmed to
room temperature by removing the ice bath, and stirring was
continued for 5 h. The reaction was quenched with saturated
aqueous NH4Cl and extracted with EtOAc (2 × 30 mL). The
organic layer was washed with brine (2 × 30 mL), dried
(MgSO4), filtered, concentrated, and chromatographed (15%
EtOAc/hexanes) to afford 680 mg of 21d (74%) as a pale yellow
78.0, 64.3, 39.7, 26.7, 19.2; IR (neat) 1793 cm-1
.
(4R,5S)-5-Ben zyl-4-(ter t-bu tyld ip h en ylsilyloxym eth yl)-
1,3-oxa zolid in -2-on e (21a ). To a suspension of copper(I)
cyanide (170 mg, 1.91 mmol) in THF (6.7 mL) cooled to -78
°C was added PhLi (2.20 mL of a 1.8 M solution in cyclohexane/
Et2O, 3.82 mmol). The reaction mixture was warmed to -40
°C and stirred for 40 min. The solution was then cooled to -78
°C, and 20 (700 mg, 1.91 mmol) in THF (2.6 mL) was added
and stirring continued at -78 °C for 20 min. The reaction
mixture was slowly warmed to room temperature by removing
the ice bath. After 5 h, the reaction was quenched with a
1
oil: [R]D + 13.7° (c 0.7, EtOAc); H NMR δ 7.65 (m, 4H), 7.40
(m, 6H), 4.20 (m, 1H), 3.75 (m, 3H), 1.55 (m, 2H), 1.30 (s, 13H),
1.05 (s, 9H); 13C NMR δ 159.3, 135.6, 135.5, 133.0, 132.9, 132.8,
129.9, 127.8, 81.8, 64.3, 54.5, 35.6, 31.6, 29.2, 28.9, 26.7, 25.1,
22.5, 19.2, 14.0, 13.9; HRMS calcd for C27H39NO3Si 453.2701,
found 453.2698.

Acylnitrene Route to Vicinal Amino Alcohols
J . Org. Chem., Vol. 64, No. 8, 1999 2857
(4R ,5S )-5-(2-(Tr im e t h ylsilyl)e t h yl)-4-(t er t -b u t yld i-
p h en ylsilyloxym eth yl)-1,3-oxa zolid in -2-on e (21e). To a
suspension of CuCN (340 mg, 3.78 mmol) in THF (13.8 mL)
cooled to -78 °C was added methyltrimethylsilyllithium (7.56
mL of a 1.0 M solution in pentane, 7.56 mmol). The reaction
mixture was then warmed to -40 °C and stirred for 45 min.
After the solution was cooled to -78 °C, 20 (1.39 g, 3.78 mmol)
in THF (4.8 mL) was added and stirring continued at -78 °C
for 20 min. The reaction was warmed to room temperature by
removing the ice bath, and stirring was continued for 5 h. The
reaction was quenched with saturated aqueous NH4Cl and
extracted with EtOAc (2 × 30 mL). The organic layer was
washed with brine (2 × 30 mL), dried (MgSO4), filtered,
concentrated, and chromatographed (20% EtOAc/hexanes) to
afford 930 mg of 21e (54%) as a yellow oil: [R]D +8.6° (c 0.5,
water (1.5 mL) was added NaIO4 (235 mg, 1.1 mmol) followed
by RuCl3‚xH2O (1.7 mg, 0.008 mmol). The reaction mixture
was stirred vigorously for 15.5 h. The upper aqueous phase
was extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated. The
resulting crude material was diluted with EtOAc (30 mL), and
a saturated aqueous solution of K2CO3 was added. This
solution was extracted with EtOAc (2 × 30 mL). The aqueous
layer was acidified with 6 M HCl to pH 1 and extracted with
EtOAc (4 × 30 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated to afford 70 mg of the acid
(85%) as a colorless oil. The acid was not subjected to further
purification and was used immediately in the next reaction:
1H NMR δ 9.40 (bs, 1H), 7.20 (m, 5H), 4.65 (d, 1H, J ) 4.6
Hz), 4.15 (m, 1H), 3.00 (dd, 1H, J ) 13.7, 25.1 Hz), 2.90 (dd,
1H, J ) 13.7, 25.1 Hz); 13C NMR δ 171.3, 158.9, 135.0, 129.3,
129.0, 127.4, 60.5, 57.2, 41.2, 14.1; IR (neat) 3030, 1755, 1417
cm-1. To a solution of H-Leu-OtBu‚HCl (71 mg, 0.32 mmol) in
CH3CN (2.35 mL) at 0 °C was added iPr2NEt (82 mg, 0.63
mmol). The resulting mixture was added to a solution of the
acid (70 mg, 0.32 mmol) and TBTU (100 mg, 0.32 mmol) in
CH3CN (0.77 mL). The reaction mixture stirred at room
temperature for 21.5 h, concentrated, and chromatographed
(15% EtOAc/hexanes) to afford 100 mg of 26a (71% from 22a )
as a colorless solid, mp 128-130 °C: [R]D +31.6° (c 0.5, CHCl3);
1H NMR δ 7.25 (m, 5H), 4.60 (d, 1H, J ) 5.0 Hz), 4.45 (m,
1H), 4.25 (m, 1H), 3.20 (dd, 1H, J ) 3.9, 13.5 Hz), 2.80 (dd,
1H, J ) 9.4, 8.0 Hz), 1.60 (m, 3H), 1.40 (s, 9H), 0.90 (m, 6H);
13C NMR δ 171.0, 168.2, 156.0, 136.8, 135.7, 129.2, 129.1,
127.5, 82.3, 78.3, 57.3, 51.4, 42.2, 41.5, 28.0, 25.0, 22.7, 22.0;
IR (CCl4) 1770, 1731, 1682, 1216 cm-1. Anal. Calcd for
1
EtOAc); H NMR δ 7.65 (m, 5H), 7.40 (m, 5H), 4.20 (m, 1H),
3.70 (m, 4H), 1.50 (m, 2H), 1.05 (s, 9H), 0.00 (s, 9H); 13C NMR
δ 158.6, 135.6, 135.5, 133.1, 132.8, 129.9, 127.8, 81.4, 64.5, 56.7,
30.8, 26.6, 19.3, 11.6, -1.9. Anal. Calcd for C25H37NO3Si2: C,
65.89; H, 8.18; N, 3.07. Found: C, 65.62; H, 7.91; N, 2.96.
(4R,5S)-5-Ben zyl-4-(h yd r oxym eth yl)-1,3-oxa zolid in -2-
on e (22a ). To a solution of 21a (1.75 g, 3.93 mmol) in THF
(7.6 mL) at 0 °C was added nBu4NF (4.34 mL of a 1.0 M
solution in THF, 4.34 mmol) dropwise over 5 min. The reaction
mixture stirred at 0 °C for 3 h. It was then diluted with EtOAc,
washed with water (3 × 40 mL), dried (MgSO4), filtered,
concentrated, and chromatographed (75% EtOAc/hexanes) to
give 660 mg of 22a (81%): [R]D +71.6° (c 1.1, EtOAc); 1H NMR
δ 7.20 (m, 5H), 5.92 (bs, 1H), 4.30 (m, 1H), 3.95 (m, 1H), 3.70
(dd, 1H, J ) 3.1, 11.7 Hz), 3.40 (dd, 1H, J ) 4.7, 11.7 Hz),
2.85 (m, 2H); 13C NMR δ 158.7, 135.8, 129.1, 128.9, 127.2, 81.9,
62.7, 54.9, 41.5; IR (neat) 3580, 1754 cm-1; HRMS calcd for
C
21H30N2O5: C, 64.60; H, 7.74; N, 7.17. Found: C, 64.86; H,
C
11H13NO3 207.2247, found 207.2237.
7.42; N, 6.95.
(4R,5S)-5-(2-Met h oxyp h en yl)-4-(h yd r oxym et h yl)-1,3-
Meth oxyp h en yl Oxa zolid in on e Dip ep tid e 26b. The
dipeptide 26b was prepared by the same method used to
prepare 26a . The carboxylic acid, which was used immediately
in the next reaction, was prepared on a 0.97 mmol scale in
82% crude yield from 22b: 1H NMR δ 10.10 (s, 1H), 7.25 (m,
2H), 7.10 (m, 1H), 6.85 (m, 2H), 4.70 (d, 1H, J ) 4.4 Hz), 4.20
(m, 1H), 3.70 (s, 3H), 2.90 (m, 2H); 13C NMR δ 171.5, 158.9,
131.2, 128.9, 123.5, 120.8, 110.8, 77.5, 56.3, 55.3, 36.1; IR
(CCl4) 3305, 1755, 1752, 1246 cm-1. The coupling reaction was
done on a 0.80 mmol scale which after chromatography (25%
EtOAc/hexanes) gave 241 mg of 26b (59% from 22b) as a
yellow oil: [R]D +32.2° (c 0.3, EtOAc); 1H NMR δ 7.25 (m, 2H),
7.15 (m, 1H), 6.85 (m, 2H), 4.70 (m, 1H), 4.50 (m, 1H), 4.25
(m, 1H), 3.85 (m, 5H), 3.20 (dd, 1H, J ) 12.5, 25.0 Hz), 2.90
(m, 1H), 1.60 (m, 12H), 0.90 (m, 6H); 13C NMR δ 174.3, 171.0,
168.4, 157.6, 131.3, 128.9, 124.0, 121.0, 110.9, 82.1, 78.5, 56.3,
55.5, 51.3, 41.5, 36.5, 28.1, 25.0, 22.7, 22.0; HRMS-FAB (M +
NH4+) calcd for C22H32N2O6 - NH4 438.2606, found 438.2610.
Bu tyl Oxa zolid in on e Dip ep tid e 26c. The dipeptide 26c
was prepared by the same method used to prepare 26a . The
carboxylic acid, which was used immediately in the next
reaction, was prepared on a 0.37 mmol scale in 81% crude yield
from 22c: 1H NMR δ 10.20 (s, 1H), 4.60 (d, 1H, J ) 4.7 Hz),
3.90 (m, 1H), 1.70 (m, 2H), 1.30 (m, 6H), 0.85 (t, 3H, J ) 5.0
Hz); 13C NMR δ 176.6, 158.5, 56.5, 35.7, 31.2, 24.4, 22.3, 20.6,
13.8; IR (CCl4) 3278, 1759, 1216, 1418 cm-1. The coupling
reaction was done on a 0.30 mmol scale which after chroma-
tography (20% EtOAc/hexanes) gave 91 mg of 26c (66% from
oxa zolid in -2-on e (22b). The alcohol 22b was prepared from
21b (5 mmol) by the same method used for 22a which after
chromatography (75% EtOAc/hexanes) gave 0.83 g of 22b
(70%) as a yellow oil: [R]D +7.4° (c 0.7, EtOAc); 1H NMR δ
7.25 (m, 2H), 7.10 (m, 1H), 6.85 (m, 2H), 4.35 (m, 1H), 3.95
(m, 1H), 3.85 (s, 3H), 3.70 (m, 1H), 3.50 (m, 1H), 2.90 (m, 2H);
13C NMR δ 157.4, 131.0, 128.7, 124.1, 120.8, 110.6, 109.7,
105.3, 82.0, 62.9, 55.3, 53.4, 36.3; IR (CCl4) 3415, 1753, 1216
cm-1; HRMS calcd for C12H15NO4 237.1001, found 237.0986.
(4R,5S)-5-P en t yl-4-(h yd r oxym et h yl)-1,3-oxa zolid in -2-
on e (22c). The alcohol 22c was prepared from 21c (3.3 mmol)
by the same method used for 22a which after chromatography
(65% EtOAc/hexanes) gave 0.50 g of 22c (81%) as a yellow oil:
[R]D +104.8° (c 0.1, EtOAc); 1H NMR δ 4.20 (m, 1H), 3.70 (m,
4H), 1.50 (m, 2H), 1.30 (s, 6H), 0.80 (t, 3H, J ) 5.3 Hz); 13C
NMR δ 159.5, 82.7, 62.8, 53.8, 35.3, 31.4, 24.6, 22.3; IR (neat)
3460, 1752, 1215 cm-1. Anal. Calcd for C9H17NO3: C, 57.73;
H, 9.15; N, 7.48. Found: C, 57.49; H, 9.06; N, 7.33.
(4R,5S)-5-Hep tyl-4-(h yd r oxym eth yl)-1,3-oxa zolid in -2-
on e (22d ). The alcohol 22d was prepared from 21d (3.3 mmol)
by the same method used for 22a which after chromatography
(65% EtOAc/hexanes) gave 0.53 g of 22d (75%) as a colorless
solid, mp 65-67 °C: [R]D +50.1° (c 1.1, EtOAc); 1H NMR δ
4.20 (m, 1H), 3.70 (m, 4H), 1.50 (m, 2H), 1.20 (m, 8H), 0.80 (t,
3H, J ) 7.2 Hz); 13C NMR δ 159.5, 82.7, 62.8, 53.6, 35.3, 31.6,
29.2, 28.2, 25.0, 22.5, 13.6; IR (neat) 3290, 1752, 1215 cm-1
.
Anal. Calcd for C11H21NO3: C, 61.37; H, 9.83; N, 6.51. Found:
C, 61.52; H, 9.85; N, 6.44.
1
22c) as a colorless oil: [R]D +37.2° (c 0.2, EtOAc); H NMR δ
(4R,5S)-5-(2-(Tr im eth ylsilyl)eth yl)-4-(h yd r oxym eth yl)-
1,3-oxa zolid in -2-on e (22e). The alcohol 22e was prepared
from 21e (1.7 mmol) by the same method used for 22a which
after chromatography (65% EtOAc/hexanes) gave 0.26 g of 22e
(70%) as a colorless solid, mp 116-118 °C: [R]D +5.1° (c 0.5,
4.45 (m, 2H), 3.85 (m, 1H), 1.70-0.09 (m, 14H); 13C NMR δ
171.0, 168.6, 157.4, 82.1, 79.0, 56.3, 51.4, 41.4, 36.1, 31.3, 27.9,
25.0, 24.6, 22.7, 22.3, 22.0, 13.8. Anal. Calcd for C19H34N2O5:
C, 61.59; H, 9.25; N, 7.56. Found: C, 61.56; H, 8.99; N, 7.32.
Hexyl Oxa zolid in on e Dip ep tid e 26d . The dipeptide 26d
was prepared by the same method used to prepare 26a . The
carboxylic acid, which was used immediately in the next
reaction, was prepared on a 0.46 mmol scale in 100% crude
yield from 22d : 1H NMR δ 10.70 (s, 1H), 4.60 (d, 1H, J ) 4.9
Hz), 4.10 (m, 1H), 3.90 (m, 1H), 1.60 (m, 2H), 1.25 (9H), 0.80
(m, 3H); 13C NMR δ 171.6, 159.5, 77.8, 60.5, 56.5, 35.6, 31.6,
29.0, 28.9, 24.7, 22.5, 20.9, 14.0, 13.9; IR (CCl4) 3300, 1759,
1418, 1230 cm-1. The coupling reaction was done on a 0.46
1
EtOAc); H NMR δ 4.20 (m, 1H), 3.80 (m, 1H), 3.60 (m, 2H),
3.30 (t, 1H, J ) 6.1 Hz), 1.50 (m, 1H), 0.45 (m, 2H), 0.00 (s,
9H); 13C NMR δ 159.2, 82.2, 63.3, 56.2, 29.7, 11.4, -1.9; IR
(CCl4) 3460, 1755, 1422, 1215 cm-1. Anal. Calcd for C9H19NO3-
Si: C, 49.74; H, 8.81; N, 6.44. Found: C, 50.00; H, 8.48; N,
6.26.
P h en yl Oxa zolid in on e Dip ep tid e 26a . To a solution of
22a (77 mg, 0.37 mmol) in CCl4 (1 mL), CH3CN (1 mL), and

2858 J . Org. Chem., Vol. 64, No. 8, 1999
Bergmeier and Stanchina
mmol scale which after chromatography (25% EtOAc/hexanes)
used to prepare 27a which after chromatography (5% EtOAc/
hexanes) gave 205 mg of 27e (91%) as a colorless oil: [R]D
gave 150 mg of 26d (82% from 22d ) as a colorless oil: [R]D
1
1
+31.4° (c 0.4, EtOAc); H NMR δ 4.45 (m, 2H), 3.85 (m, 1H),
+12.5° (c 0.3, EtOAc); H NMR δ 4.40 (m, 4H), 1.80 (m, 3H),
1.80-1.15 (m, 12H), 0.90 (m, 9H); 13C NMR δ 171.0, 168.6,
157.3, 79.0, 77.5, 56.3, 51.4, 41.4, 36.1, 31.6, 29.1, 28.9, 27.9,
25.0, 22.7, 22.5, 22.0, 13.9; IR (neat) 1768, 1765, 1751, 1215
cm-1. Anal. Calcd for C21H38N2O5: C, 63.29; H, 9.61; N, 7.03.
Found: C, 63.23; H, 9.32; N, 6.90.
1.70-1.55 (m, 6 H), 1.55-1.40 (m, 24 H), 0.85 (m, 6H), 0.45
(m, 2H), 0.00 (s, 9H); 13C NMR δ 170.9, 168.1, 150.6, 148.6,
84.2, 82.3, 74.5, 60.3, 51.6, 41.4, 28.0, 27.6, 25.1, 22.6, 22.1,
9.5, -1.9. Anal. Calcd for C24H44N2O7Si: C, 57.57; H, 8.85; N,
5.59. Found: C, 57.41; H, 8.64; N, 5.20.
Tr im eth ylsilylm eth yl Oxa zolid in on e Dip ep tid e 26e.
The dipeptide 26e was prepared by the same method used to
prepare 26a . The carboxylic acid, which was used immediately
in the next reaction, was prepared on a 0.97 mmol scale in
82% crude yield from 22e: 1H NMR δ 11.40 (s, 1H), 4.60 (d,
1H, J ) 4.2 Hz), 3.85 (m, 1H), 1.60 (m, 2H), 0.50 (m, 2H), 0.00
(s, 9H); 13C NMR δ 171.9, 159.6, 77.5, 60.6, 58.7, 30.1, 20.9,
14.0, 10.9, -1.98; IR (CCl4) 3023, 1755, 1418, 1250 cm-1. The
coupling reaction was done on a 0.79 mmol scale which after
chromatography (15% EtOAc/hexanes) gave 237 mg of 26e
(61% from 22e) as a colorless oil: [R]D +4.5° (c 0.5, EtOAc);
1H NMR δ 4.45 (m, 2H), 3.80 (m, 1H), 1.50 (m, 12H), 0.85 (m,
6H), 0.50 (m, 2H), -0.05 (s, 9H); 13C NMR δ 171.1, 168.7, 157.6,
82.1, 78.5, 58.6, 51.2, 41.3, 30.6, 27.9, 24.9, 22.7, 21.9, 11.2,
-1.9; HRMS-FAB (M + NH4+) calcd for C19H36N2O5Si - NH4
418.2739, found 418.2727.
Boc P h en yl Am in o Alcoh ol 28a . To a 0.05 M solution of
27a (80 mg, 0.16 mmol) in 3:1 THF/H2O (3.29 mL) at 0 °C
was added LiOH‚H2O (14 mg, 0.33 mmol). The solution was
slowly warmed to room temperature where stirring continued
for 21 h. The reaction mixture was extracted with EtOAc (3 ×
25 mL), dried (MgSO4), filtered, concentrated, and chromato-
graphed (15% f 25% EtOAc/hexanes) to afford 55 mg of 28a
(73%): [R]D +3.9° (c 0.3, CHCl3); 1H NMR δ 7.25 (m, 5H), 4.50
(m, 1H), 4.15 (m, 1H), 3.95 (m, 1H), 3.05 (m, 2H), 1.60 (m,
2H), 1.30 (s, 9H), 1.40 (s, 9H), 0.85 (m, 6H); 13C NMR δ 172.3,
168.2, 158.2, 138.2, 129.3, 128.5, 126.6, 81.9, 80.2, 56.8, 51.2,
41.9, 28.2, 28.0, 24.9, 22.9, 21.9. HRMS-FAB (M + H) calcd
for C25H40N2O6 465.2966, found 465.2955.
Boc Meth oxyp h en yl Am in o Alcoh ol 28b. The amino
alcohol 28b was prepared from 27b (0.19 mmol) by the same
method used for the preparation of 28a which after chroma-
tography (25% EtOAc/hexanes) gave 81 mg of 28b (86%) as a
Boc P h en yl Dip ep tid e 27a . To a solution of 26a (60 mg,
0.15 mmol) and DMAP (13 mg, 0.11 mmol) in THF (0.85 mL)
at 0 °C was added Boc2O (36 mg, 0.165 mmol). The reaction
mixture was warmed to room temperature by removing the
ice bath. Stirring continued at room temperature for 21.5 h.
The reaction mixture was diluted with EtOAc (25 mL), washed
with brine (3 × 25 mL), dried (MgSO4), filtered, concentrated,
and chromatographed (15% EtOAc/hexanes) to afford 70 mg
of 27a (95%) as a colorless solid, mp 133-135 °C: [R]D -7.7°
1
colorless oil: [R]D +13.6° (c 0.1, EtOAc); H NMR δ 7.20 (m,
2H), 6.85 (m, 2H), 5.30 (m, 1H), 5.00 (m, 1H), 4.50 (m, 1H),
4.05 (m, 2H), 3.80 (s, 3H), 3.05 (m, 2H) 1.45 (s, 9H), 1.40 (s,
9H), 0.85 (m, 6H); 13C NMR δ 173.6, 171.9, 157.6, 131.6, 128.0,
126.3, 121.0, 110.5, 81.7, 79.9, 55.5, 51.0, 42.0, 28.2, 28.0, 25.0,
22.9, 21.9; HRMS-FAB (M + H) calcd for C26H42N2O7 495.2994,
found 495.2974.
Boc Bu tyl Am in o Alcoh ol 28c. The amino alcohol 28c was
prepared from 27c (0.74 mmol) by the same method used for
the preparation of 28a which after chromatography (15%
EtOAc/hexanes) gave 230 mg of 28c (70%) as a colorless solid,
mp 114-116 °C: [R]546 +11.7° (c 0.1, EtOAc); 1H NMR δ 5.25
(m, 2H), 4.45 (m, 1H), 4.10 (m, 1H), 3.70 (m, 1H), 1.70-1.50
(m, 6 H), 1.50-1.15 (m, 23 H), 0.85 (m, 9H); 13C NMR δ 171.0,
168.5, 163.4, 82.2, 79.0, 56.7, 54.2, 51.4, 41.8, 36.1, 31.5, 28.3,
28.0, 26.0, 24.9, 22.3, 21.9, 13.9. Anal. Calcd for C23H44N2O6:
C, 62.13; H, 9.97; N, 6.30. Found: C, 62.33; H, 9.81; N, 6.23.
Boc Hexyl Am in o Alcoh ol 28d . The amino alcohol 28d
was prepared from 27d (0.20 mmol) by the same method used
for the preparation of 28a which after chromatography (15%
EtOAc/hexanes) gave 66 mg of 28d (70%) as a clear oil: [R]546
1
(c 0.6, CHCl3); H NMR δ 7.25 (m, 5H), 4.75 (m, 1H), 4.50 (d,
1H, J ) 2.2 Hz), 4.40 (m, 1H), 3.20 (dd, 1H, J ) 13.9 25.0 Hz),
3.05 (m, 1H), 1.60 (m, 3H), 1.55 (s, 9H), 1.40 (s, 9H), 0.90 (m,
6H); 13C NMR δ 170.8, 167.6, 150.1, 134.2, 129.5, 129.0, 127.6,
84.5, 82.3, 73.8, 58.8, 51.6, 41.3, 38.6, 27.9, 25.0, 22.6, 22.1;
IR (CCl4) 1823, 1731, 1686, 1524, 1370, 1216 cm-1. Anal. Calcd
for C26H38N2O7: C, 63.65; H, 7.81; N, 5.71. Found: C, 63.49;
H, 7.85; N, 5.51.
Boc Meth oxyp h en yl Dip ep tid e 27b. The dipeptide 27b
was prepared from 26b (0.66 mmol) by the same method used
to prepare 27a which after chromatography (15% EtOAc/
hexanes) gave 251 mg of 27b (73%) as a yellow solid, mp 95-
97 °C: [R]D +12.5° (c 0.1, EtOAc); 1H NMR δ 7.25 (m, 2H),
7.10 (m, 1H), 6.85 (m, 2H), 4.80 (m, 1H), 4.60 (d, 1H, J ) 2.1
Hz), 4.40 (m, 1H), 3.80 (s, 3H), 3.15 (m, 2H), 1.60-1.25 (m,
22H), 0.85 (m, 6H); 13C NMR δ 176.5, 170.9, 168.0, 157.9,
150.4, 148.6, 131.6, 129.0, 122.9, 120.9, 110.9, 84.0, 82.2, 74.2,
58.5, 55.4, 51.6, 41.4, 33.4, 27.9, 25.1, 22.6, 22.1. Anal. Calcd
for C27H40N2O8: C, 62.29; H, 7.74; N, 5.38. Found: C, 62.24;
H, 7.73; N, 5.15.
1
+15.0° (c 1.5, EtOAc); H NMR δ 5.30 (m, 2H), 4.45 (m, 1H),
4.10 (m, 1H), 3.70 (m, 1H), 1.70-1.50 (m, 9 H), 1.45-1.40 (m,
18 H), 1.40-1.15 (m, 6 H), 0.85 (m, 9H); 13C NMR δ 171.7,
168.5, 157.2, 82.2, 77.4, 56.2, 54.2, 51.3, 41.9, 31.8, 29.3, 29.0,
28.2, 28.0, 26.3, 25.0, 22.8, 22.5, 22.0, 14.0. Anal. Calcd for
C
25H48N2O6: C, 63.52; H, 10.23; N, 5.93. Found: C, 63.50; H,
10.14; N, 5.77.
Boc Bu tyl Dip ep tid e 27c. The dipeptide 27c was prepared
from 26c (1.0 mmol) by the same method used to prepare 27a
which after chromatography (10% EtOAc/hexanes) gave 377
mg of 27c (80%) as a colorless solid, mp 133-135 °C: [R]D
+13.3° (c 0.1, EtOAc); 1H NMR δ 4.45 (m, 3H), 1.80-1.55 (m,
13 H), 1.40 (s, 9 H), 1.35 (s, 9 H), 1.25 (m, 2 H), 0.85 (m, 6H);
13C NMR δ 170.9, 168.0, 150.4, 148.6, 84.3, 82.3, 77.5, 77.0,
58.6, 51.7, 41.4, 33.3, 31.3, 28.0, 25.1, 23.4, 22.6, 22.1 13.8.
Anal. Calcd for C24H42N2O7: C, 61.25; H, 8.99; N, 5.95.
Found: C, 61.45; H, 8.92; N, 5.84.
Boc Tr im eth ylsilylm eth yl Am in o Alcoh ol 28e. The
amino alcohol 28e was prepared from 27e (0.36 mmol) by the
same method used for the preparation of 28a which after
chromatography (15% EtOAc/hexanes) gave 119 mg of 28e
(70%) as a clear oil: [R]D +34.2° (c 0.3, EtOAc); 1H NMR δ
5.25 (m, 2H), 4.50 (m, 1H), 4.15 (m, 1H), 3.60 (m, 1H), 1.60
(m, 6H), 1.45 (s, 9H), 1.40 (s, 9H), 0.85 (m, 6H), 0.50 (m, 2H),
0.00 (s, 9H); 13C NMR δ 172.5, 171.8, 157.3, 81.9, 79.9, 74.1,
57.1, 51.0, 41.8, 28.3, 28.0, 24.8, 22.9, 21.9, 13.3, -1.8. Anal.
Calcd for C23H46N2O6Si: C, 58.19; H, 9.77; N, 5.90. Found: C,
58.19; H, 9.57; N, 5.67.
Boc Hexyl Dip ep tid e 27d . The dipeptide 27d was pre-
pared from 26d (0.25 mmol) by the same method used to
prepare 27a which after chromatography (10% EtOAc/hex-
anes) gave 115 mg of 27d (92%) as colorless plates, mp 135-
(-)-Besta tin (TF A Sa lt) 29a . A solution of 28a (30 mg,
0.065 mmol) in TFA (65 µL) was stirred at 0 °C for 10 min.
The reaction mixture was then warmed to room temperature
where stirring continued for 5.5 h. The reaction was concen-
trated. The crude solid was then purified by filtering and
rinsing with Et2O to afford 25 mg of 29a (92%) as a colorless
solid, mp 150-152 °C: [R]D -14.0° (c 0.5, 1 N HCl) [lit.1k [R]D
1
137 °C: [R]D -14.4° (c 0.1, EtOAc); H NMR δ 4.40 (m, 4H),
1.90-1.70 (m, 4 H), 1.70-1.05 (m, 26H), 0.85 (m, 6H); 13C NMR
δ 170.9, 168.0, 150.1, 148.6, 84.3, 82.3, 75.1, 58.6, 51.6, 41.4,
33.3, 31.6, 29.1, 29.0, 28.0, 27.9, 25.1, 23.7, 22.6, 22.1, 13.9.
Anal. Calcd for C26H46N2O7: C, 61.63; H, 9.29; N, 5.62.
Found: C, 62.81; H, 9.19; N, 5.45.
1
-14.3° (c 0.5, 1 N HCl)]; H and 13C NMR data matched that
reported for the known compound.1k
Boc Tr im eth ylsilylm eth yl Dip ep tid e 27e. The dipeptide
27e was prepared from 26e (0.45 mmol) by the same method
An isole An a logu e 29b. The salt 29b was prepared from
28b (49 mg, 0.10 mmol) by the same procedure used for the

Acylnitrene Route to Vicinal Amino Alcohols
J . Org. Chem., Vol. 64, No. 8, 1999 2859
preparation of 29a to yield 26 mg of 29b (78%) as a colorless
solid, mp 134-136 °C: [R]D +88.3° (c 0.1, EtOAc); 1H NMR
(d6-DMSO) δ 7.25 (m, 2H), 7.05 (m, 1H), 6.90 (m, 1H), 4.20
(m, 1H), 3.95 (m, 1H), 3.75 (s, 3H), 3.35 (m, 3H), 2.85 (m, 2H),
1.50 (m, 3H), 0.85 (m, 6H); 13C NMR (d6-DMSO) δ 170.9, 167.8,
157.4, 130.8, 128.4, 123.8, 120.3, 110.9, 94.1, 68.1, 55.2, 50.8,
24.2, 22.5, 21.4; HRMS-FAB (M + H) calcd for C17H26N2O5
339.1921, found 339.1919.
21.3, 14.9, 13.6. HRMS-FAB (M+ H) calcd for C16H33N2O4
318.4522, found 318.4509.
Tr im eth ylsilylm eth yl An a logu e 29e. The salt 29e was
prepared from 28e (66 mg, 0.14 mmol) by the same procedure
used for the preparation of 29a to yield 41 mg of 29e (91%) as
colorless needles, mp 106-108 °C: [R]D +50.0° (c 0.2, EtOAc);
1H NMR (d6-DMSO) δ 4.25 (m, 1H), 4.10 (m, 1H), 1.50 (m,
6H), 0.85 (m, 6H), 0.60 (m, 1H), 0.55 (m, 1H), 0.00 (s, 9H); 13
C
Bu tyl An a logu e 29c. The salt 29c was prepared from 28c
(15 mg, 0.034 mmol) by the same procedure used for the
preparation of 29a to yield 8 mg of 29c (88%) as a colorless
solid, mp 158-160 °C: [R]D +68.0° (c 0.1, CHCl3); 1H NMR
(d6-DMSO) δ 4.25 (m, 1H), 4.05 (m, 1H), 1.70-1.00 (m, 8H),
0.85 (m, 9H); 13C NMR (d6-DMSO) δ 175.4, 170.9, 69.6, 53.2,
50.2, 30.8, 28.3, 24.2, 22.6, 21.5, 21.3, 13.6; HRMS-FAB (M +
H) calcd for C14H28N2O4 289.2128, found 289.2112.
NMR (d6-DMSO) δ 173.6, 171.1, 69.5, 55.9, 50.0, 24.3, 22.8,
22.7, 21.3, 11.6, -1.9; HRMS-FAB (M + H) calcd for C14H30N2O4-
Si 319.2054, found 319.2051.
Ack n ow led gm en t. This work was supported by
Grant IRG 16-35 from the American Cancer Society.
Supported in part by grant P30CA16058, National
Cancer Institute, Bethesda, MD.
Hexyl An a logu e 29d . The salt 29d was prepared from 28d
(127 mg, 0.27 mmol) by the same procedure used for the
preparation of 29a to yield 79 mg of 29d (92%) as a colorless
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 16, 17, 18, 19, 20, 21a , 21b, 21c, 21d , 22a , 22b,
26b, 26e, 28a , 28b, 29b, 29c, 29d , and 29e. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
solid, mp 78-80 °C: [R]D +25.2° (c 0.1, EtOAc); H NMR (d6-
DMSO) δ 4.25 (m, 1H), 4.10 (m, 1H), 3.35 (m, 2H), 3.15 (m,
1H), 1.70-1.30 (m, 7 H), 1.30-1.15 (m, 13 H), 1.05 (t, 3H, J )
6.4 Hz), 0.85 (m, 6H); 13C NMR (d6-DMSO) δ 173.5, 171.1, 94.3,
69.7, 53.4, 50.2, 31.0, 28.7, 28.5, 28.3, 24.7, 24.3, 22.6, 21.9,
J O9823893