Selective inversion of the proximal or distal hydroxyl groups in syn,syn-3-[N-(alkoxycarbonyl)ammo] 1,2-diols via cyclic sulfates

Article abstract of DOI:10.1021/jo961060j

The formation of cyclic sulfates (4) from syn, syn-3-[N-(benzyloxycarbonyl)amino] 1,2-diols provides a common intermediate to access other diastereomers via two inversion procedures. Thermolysis of the cyclic sulfates in acetonitrile normally leads to inversion of the distal hydroxyl group to form a 1,3-oxazin-2-one (6). Catalytic hydrogenation of the cyclic sulfates under basic conditions (NEt₃) results in inversion at the proximal hydroxyl group to form a 1,3-oxazolidin-2-one (5).

Full text of DOI:10.1021/jo961060j

7162
J . Org. Chem. 1996, 61, 7162-7167
Selective In ver sion of th e P r oxim a l or Dista l Hyd r oxyl Gr ou p s in
syn ,syn -3-[N-(Alk oxyca r bon yl)a m in o] 1,2-Diols via Cyclic Su lfa tes
Scott J . Kemp, J ianming Bao, and Steven F. Pedersen*
Department of Chemistry, University of California, Berkeley, California 94720
Received J une 5, 1996X
The formation of cyclic sulfates (4) from syn,syn-3-[N-(benzyloxycarbonyl)amino] 1,2-diols provides
a common intermediate to access other diastereomers via two inversion procedures. Thermolysis
of the cyclic sulfates in acetonitrile normally leads to inversion of the distal hydroxyl group to form
a 1,3-oxazin-2-one (6). Catalytic hydrogenation of the cyclic sulfates under basic conditions (NEt3)
results in inversion at the proximal hydroxyl group to form a 1,3-oxazolidin-2-one (5).
Recent advances1,2 in selective pinacol cross coupling
reactions using the vanadium(II) reagent, [V2Cl3(THF)6]2-
[Zn2Cl6], have made many 1,2-diol systems readily avail-
able for the first time. An important advance in this
technology is the synthesis of optically pure syn,syn-3-
amino-1,2-diols (3) via the pinacol coupling of a 2-[N-
(alkoxycarbonyl)amino] aldehyde and an aliphatic alde-
hyde.1 Having developed this route to such diols, we felt
it would be desirable to have available a method for
selectively inverting either of the two hydroxyl groups
in order to produce optically pure 1,2-anti-2,3-syn-3-
amino 1,2-diols (1) and 1,2-anti-2,3-anti-3-amino 1,2-diols
(2) (Figure 1).
F igu r e 1.
Ta ble 1
Our approach to this problem has relied on cyclization
reactions to achieve high regioselectivity. Precedent for
choosing an intramolecular versus an intermolecular
route to achieve high regioselectivity is well documented.3
The intramolecular inversion of activated hydroxyl groups
by the carbonyl of amide, thioureido and carbamate
groups has been known for some time.4,5 Since the syn,-
syn-3-amino 1,2-diols we wanted to convert are N-
protected as alkyl carbamates, we reasoned that inver-
sion of properly derivatized substrates should be possible.
Activation of the hydroxyl groups by transformation into
their cyclic sulfates6 was chosen because it eliminates the
need for selective activation of only one hydroxyl group.
Furthermore, after inversion takes place at one carbon
center, the other hydroxyl group is deactivated as the
anionic sulfate ester, which can later be hydrolyzed.7
R1
R2
isolated yield (%)
4a
4b
4c
4d
4e
4f
Bn
Bn
Bn
i-Pr
i-Pr
i-Bu
99
92
97
94
89
91
89
PhCH2CH2
i-Pr
PhCH2CH2
i-Pr
n-C14H29
n-C12H25
TBDMSOCH2
BnOCH2
4g
Resu lts a n d Discu ssion
The amino diols1 3 were converted to cyclic sulfates 4
in excellent yield (89-99%) by modification of the Sharp-
less method (Table 1).6a Attempts to use the Alloc group
in this procedure were unsuccessful due to cleavage of
the allyl double bond by RuO4.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) Konradi, A. W.; Kemp, S. J .; Pedersen, S. F. J . Am. Chem. Soc.
1994, 116, 1316.
(2) (a) Freudenberger, J . H.; Konradi, A. W.; Pedersen, S. F. J . Am.
Chem. Soc. 1989, 111, 8014. (b) Takahara, P. M.; Freudenberger, J .
H.; Konradi, A. W.; Pedersen, S. F. Tetrahedron Lett. 1989, 30, 7177.
(c) Park, J .; Pedersen, S. F. J . Org. Chem. 1990, 55, 5924. (c) Konradi,
A. W.; Pedersen, S. F. J . Org. Chem. 1990, 55, 4506. (d) Raw, A. S.;
Pedersen, S. F. Ibid. 1991, 56, 830. (e) Konradi, A. W.; Pedersen, S. F.
Ibid. 1992, 57, 28.
Phytosphingosines are a class of biological molecules
that contain the anti,anti-3-amino 1,2-diol core.8 C16-
Phytosphingosine9 was chosen as a model compound for
initial study because peracetylated derivatives of all four
diastereomers have been synthesized and completely
(3) (a) Roush, W. R.; Brown, R. J . J . Org. Chem. 1982, 47, 1371. (b)
Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.;
Sharpless, K. B.; Tuddenham, D.; Walker, F. J . J . Org. Chem. 1982,
47, 1373. (c) J ager, V.; Stahl, U.; Hummer, W. Synthesis 1991, 776.
(4) (a) Kempf, D. J .; Sowin, T. J .; Doherty, E. M.; Hannick, S. M.;
Codavoci, L.; Henry, R. F.; Green, B. E.; Spanton, S. G.; Norbeck, D.
W. J . Org. Chem. 1992, 57, 5692. (b) Kano, S.; Yokomatsu, T.; Iwasawa,
H.; Shibuya, S. Tetrahedron Lett. 1987, 28, 6331. (c) Baker, B. R.;
Hullar, T. L. J . Org. Chem. 1965, 30, 4049 and references therein.
(5) (a) Sakaitanti, M.; Ohfune, Y. J . Am. Chem. Soc. 1990, 112, 1150.
(b) Sakaitanti, M.; Ohfune, Y. J . Org. Chem. 1990, 55, 870 and
references therein.
(8) (a) Birk, R.; J ung, J .; Schmidt, R. R. Liebigs Ann. Chem. 1994,
83. (b) Murakami, T.; Minamikawa, H.; Hato, M. Tetrahedron Lett.
1994, 35(5), 745 and references therein.
(9) For some previous syntheses see: (a) Sugiyama, S.; Honda, M.;
Higuchi, R.; Komori, T. Liebigs Ann. Chem. 1991, 349. (b) Dondoni,
A.; Fantin, G.; Fogagnolo, M.; Paola, P. J . Org. Chem. 1990, 55, 1439.
(c) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron Lett. 1989, 30, 5507.
(d) Kulmacz, R. J .; Schroepfer, G. J ., J r. J . Am. Chem. Soc. 1978, 100,
3963. (e) Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem.
1988, 619. (f) Mulzer, J .; Brand, C. Tetrahedron 1986, 42, 5961. (g)
Schwab, W.; J ager, V. Angew. Chem., Int. Ed. Engl. 1981, 20, 603. (h)
Gigg, J .; Gigg, R.; Warren, C. D. J . Chem. Soc. C 1966, 1872. (i) Gigg,
J .; Gigg, R. J . Chem. Soc. C 1966, 1876. (j) Gigg, R.; Warren, C. D. J .
Chem. Soc. C 1966, 1879. (k) Gigg, J .; Gigg, R.; Warren, C. D. J . Chem.
Soc. C 1966, 1882. (l) Prostenik, M.; Majhofer-Orescanin, B.; Ries-Lesic,
B.; Stanacev, N. Z. Tetrahedron 1965, 21, 651.
(6) (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655.
(b) Lohray, B. B.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 2623.
(c) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(7) Goren, M. B.; Kochansky, M. E. J . Org. Chem. 1973, 38, 3510.
S0022-3263(96)01060-2 CCC: $12.00 © 1996 American Chemical Society

Selective Inversion of Proximal or Distal Hydroxyl Groups
J . Org. Chem., Vol. 61, No. 20, 1996 7163
Sch em e 1
Sch em e 2
characterized,10 allowing rapid determination of the
stereochemistry obtained from the inversion reactions.
To avoid the possible removal of minor isomers, the
transformation of 4g to a known phytosphingosine was
performed without any purification. The cyclic sulfate
4g was heated at reflux in acetonitrile for 5 h, hydrolyzed
to remove the sulfate, hydrogenated, saponified, and
acetylated to give the syn,anti-tetraacetate (1a ) and an
unknown impurity (Scheme 1). The unknown impurity
was shown not to be any of the other three possible
diastereomers. The tetraacetate 1a is the diastereomer
resulting from a 6-membered ring cyclization (giving 6g).
The regioselective inversion of the hydroxyl group by
this method is of practical importance because it provides
effective access to 1,2-anti-2,3-syn-3-amino 1,2-diols (1).
Although the natural phytosphingosine was not obtained
in the foregoing synthesis, we realized that the stereo-
chemistry observed is that found in an important class
of pharmaceutically active compounds, namely renin
inhibitors. Recently, much attention has been focused
on the development of effective rennin inhibitors, and one
class in particular utilizes the 1,2-anti-2,3-syn-3-amino
1,2-diol functional unit 8e to obtain subnanomolar inhi-
bition of human renin.11,12 The key building block to 8e
is the dipeptide isostere 8a , and several syntheses of this
compound have been published.12 Our synthesis of 8c
is outlined in Scheme 2.
Our approach to the synthesis of 8c was to utilize 3a ,
which is prepared in 74% yield from N-Cbz-L-phenyla-
laninal by a one-step pinacol coupling.1 Heating of 4a
in acetonitrile, followed by hydrolysis using THF-2%
aqueous H2SO4 (200:1), gave a mixture of 6a /5a (6:1) and
the byproduct N-benzylacetamide. The oxazinone 6a is
crystalline and the oxazolidinone 5a is an oil, which
allows the complete separation of the two regioisomers
by one recrystallization. However, fractional recrystal-
lization was required to remove all of the N-benzylac-
etamide, yielding pure 6a in 67% yield from 4a . The
synthesis of 6a was thus accomplished in an overall yield
of 46% from L-phenylalanine and gave the desired isos-
tere (8a ) after basic hydrolysis (96%). The stereochem-
istry of 6a was assigned by protecting 8a with Boc2O to
provide 8c.12a The stereochemistry of 5a was confirmed
by catalytic hydrogenation of the phenyl ring (5% Rh/
Al2O3, H2, 50 psi)13 to give the known cyclohexyl analog
5k (R1 ) cyclohexyl, R2 ) i-Bu).12d
The formation of N-benzylacetamide from 4a suggested
that the intermediate “oxonium ion” 11 was reacting with
(11) (a) Baker, W. R.; Condon, S. L. Tetrahedron Lett. 1992, 33, 1577.
(b) Rosenberg, S. H.; Spina, K. P.; Woods, K. W.; Polakowski, J .; Martin,
D. L.; Yao, Z.; Stein, H. H.; Cohen, J .; Barlow, J . L.; Egan, D. A.;
Tricarico, K. A.; Baker, W. R.; Kleinert, H. D. J . Med. Chem. 1993, 36,
449. (c) Rosenberg, S. H.; Spina, K. P.; Condon, S. L.; Polakowski, J .;
Yao, Z.; Kovar, P.; Stein, H. H.; Cohen, J .; Barlow, J . L.; Klinghofer,
V.; Egan, D. A.; Tricarico, K. A.; Perun, T. J .; Baker, W. R.; Kleinert,
H. D. J . Med. Chem. 1993, 36, 460. (d) Patt, W. C.; Hamilton, H. W.;
Taylor, M. D.; Ryan, M. J .; Taylor, D. G., J r.; Connolly, C.; Doherty,
A. M.; Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batley, B. L.;
Painchaud, C. A.; Rapundalo, S. T.; Michniewicz, B. M.; Olson, S. C.
J . Med. Chem. 1992, 35, 2562. (e) Martin, S. F.; Austin, R. E.; Oalmann,
C. J .; Baker, W. R.; Condon, S. L.; deLara, E.; Rosenberg, S. H.; Spina,
K. P.; Stein, H. H.; Cohen, J .; Kleinert, H. D. J . Med. Chem. 1992, 35,
1710. (f) Baker, W. R.; Fung, A. K. L.; Kleinert, H. D.; Stein, H. H.;
Plattner, J . J .; Armiger, Y.; Condon, S. L.; Cohen, J .; Egan, D. A.;
Barlow, J . L.; Verburg, K. M.; Martin, D. L.; Young, G. A.; Polakowski,
J .; Boyd, S. A.; Perun, T. J . J . Med. Chem. 1992, 35, 1722. (g) Repine,
J . T.; Kaltenbronn, J . S.; Doherty, A. M.; Hamby, J . M.; Himmelsbach,
R. J .; Kornberg, B. E.; Taylor, M. D.; Lunney, E. A.; Humblet, C.;
Rapundalo, S. T.; Batley, B. L.; Ryan, M. J .; Painchaud, C. A. J . Med.
Chem. 1992, 35, 1032. (h) Plattner, J . J .; Marcotte, P. A.; Kleinert, H.
D.; Stein, H. H.; Greer, J .; Bolis, G.; Fung, A. K. L.; Bopp, B. A.; Luly,
J . R.; Sham, H. L.; Kempf, D. J .; Rosenberg, S. H.; Dellaria, J . F.; De,
B.; Merits, I.; Perun, T. J . J . Med. Chem. 1988, 31, 2277. (i) Mazdiyasni,
H.; Konopacki, D. B.; Dickman, D. A.; Zydowsky, T. M. Tetrahedron
Lett. 1993, 34, 435. (j) Hurley, T. R.; Colson, C. E.; Hicks, G.; Ryan,
M. J . J . Med. Chem. 1993, 36, 1496. (k) Stein, H. H.; Fung, A. K. L.;
Cohen, J .; Baker, W. R.; Rosenberg, S. H.; Boyd, S. A.; Dayton, B. D.;
Armiger, Y.; Condon, S. L.; Mantei, R. A.; Kleinert, H. D. FEBS Lett.
1992, 300(3), 301. (l) Kleinert, H. D.; Rosenberg, S. H.; Baker, W. R.;
Stein, H. H.; Klinghofer, V.; Barlow, J .; Spina, K.; Polakowski, J .;
Kovar, P.; Cohen, J .; Denissen, J . Science 1992, 257, 1940.
(12) (a) Pfizer Inc. EP 0438233A2 1991, 59. (b) Baker, W. R.; Condon,
S. L. Tetrahedron Lett. 1992, 33, 1581. (c) Wood, J . L.; J ones, D. R.;
Hirschmann, R.; Smith, A. B. Tetrahedron Lett. 1990, 31, 6329. (d)
Luly, J . R.; BaMaung, N.; Soderquist, J .; Fung, A. K. L.; Stein, H.;
Kleinert, H. D.; Marcotte, P. A.; Egan, D. A.; Bopp, B.; Merits, I.; Bolis,
G.; Greer, J .; Perun, T. J .; Plattner, J . J . J . Med. Chem. 1988, 31, 2264.
(e) Luly, J . R.; Hsiao, C.; BaMaung, N.; Plattner, J . J . J . Org. Chem.
1988, 53, 6109. (f) Baker, W. R.; Condon, S. L. J . Org. Chem. 1993,
58, 3277. (g) Chan, M. F.; Hsiao, C. Tetrahedron Lett. 1992, 33, 3567.
(h) Kobayashi, Y.; Matsumoto, T.; Takemoto, Y.; Nakatani, K.; Ito, Y.;
Kamijo, T.; Harada, H.; Terashima, S. Chem. Pharm. Bull. 1991, 39,
2550.
(13) Boger, J .; Payne, L. S.; Perlow, D. S.; Lohr, N. S.; Poe, M.;
Blaine, E. H.; Ulm, E. H.; Schorn, T. W.; LaMont, B. I.; Lin, T.; Kawai,
M.; Rich, D. H.; Veber, D. F. J . Med. Chem. 1985, 28, 1779.
(10) Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem. 1990,
1069.

7164 J . Org. Chem., Vol. 61, No. 20, 1996
Kemp et al.
Ta ble 2
Sch em e 3
isolated yield isolated yield crudea
R1
R2
(%) of 6
(%) of 5
6/5
4a Bn
4b Bn
4c Bn
4d i-Pr PhCH2CH2
4e i-Pr i-Pr
i-Bu
PhCH2CH2
i-Pr
67
75
89
88
45
12
15
6.0
6.7
-
6:1
7:1
16:1
13:1
19:1
a
Determined by 13C{1H} NMR.
hopes of forming the oxazolidinone 5, which should be
kinetically favored.18 We were attracted to Sakaitani and
Ohfune’s work on the use of silyl carbamates as N-
carboxylate ion equivalents.5 Therefore, we explored
their approach by converting 4i into the tert-butyldim-
ethylsilyl carbamate 4j using tert-butyldimethylsilyl tri-
flate (Scheme 4). Treatment of this product with tetra-
n-butylammonium fluoride in THF at 0 °C followed by
hydrolysis of the sulfate with THF-20% aqueous H2SO4
(250:1) gave the oxazolidinone 5a exclusively (71% from
4i). Attempts to generate the silyl carbamate from 4a
by Sakaitani and Ohfune’s hydrosilylation procedure (t-
BuMe2SiH, Pd(OAc)2) were unsuccessful. Driven by our
desire to have procedures that would supply compounds
5 or 6 from a common intermediate, we reasoned that
the N-carboxylate anion should be available directly from
an N-Cbz derivative under basic hydrogenation condi-
tions. This goal was realized when 4a was hydrogenated
on 5% Pd/C (50 psi) in THF in the presence of excess
triethylamine, followed by hydrolysis in THF-20% aque-
ous H2SO4 (250:1), giving a mixture of 5a and 6a (12:1)
that was chromatographed to afford 69% of 5a and 6%
of 6a .
To demonstrate the application of this new hydrogena-
tion-cyclization procedure, the synthesis of natural
phytosphingosines was reexamined. Thus, hydrogena-
tion-cyclization of 4f gave a protected form of natural
C18-phytosphingosine (5f) as the only detectable isomer
in 71% yield (Table 3). This represents an overall yield
of 38% from L-serine methyl ester hydrochloride.1 To
prove our assignment, 5f was deprotected with HF/CH3-
CN, hydrolyzed, and then peracytlated to give the known
tetraacetate of D-ribo-C18-phytosphingosine (9).9c,f
As with the thermolysis reaction, the effect of substit-
uents R1 and R2 on the regioselectivity was examined
(Table 3). As expected, increasing the size of R2 increased
the ratio of 5 to 6, due to blocking of the distal postion
(4a and 4b vs 4c). Increasing the size of R1 decreased
the regioselectivity (4b vs 4d ). One of the most surpris-
ing results occurs when R1 and R2 are isopropyl (4e): an
aziridine (7e) is formed as the major product. The
aziridines 7c and 7e presumably result from decarboxy-
lation due to a slow/unfavorable cyclization of the car-
bamate anion, followed by cyclization of the free amine.
Regioisomer assignments for 5 and 6 were arrived at
by conversion to a known substrate (5a , 5f, 6a , and 6g)
acetonitrile in one of two manners (Scheme 3). In
pathway A, one can envision SN2 attack by acetonitrile
to afford the intermediate oxazinone sulfate 13, and the
nitrilium ion, which upon hydrolysis, would afford the
N-benzylacetamide. Alternatively, pathway B shows an
SN1-type reaction that involves initial ionization of the
carbon-oxygen bond in 11 resulting in the formation of
a carbocation that is then trapped by acetonitrile (the
Ritter reaction14 ) to form the nitrilium ion. We reasoned
that if pathway A were operative in this chemistry, then
changing to substrate 4h should also work well, although
somewhat slower,15 and would produce the more easily
removable N-methylacetamide. However, refluxing 4h
in acetonitrile for 80 h, followed by hydrolysis and NMR
analysis, showed an incomplete reaction (6a to 4h , 7:3).
Increased reaction times or higher temperature led to
extensive decomposition. These results suggested that
pathway B is the primary reaction course taken in the
cyclization of 4a . This is further substantiated by the
fact that when cyclic sulfate 4i was thermolyzed, the rate
of cyclization was even faster (<30 min, refluxing aceto-
nitrile), as anticipated, based on the greater stability of
the tert-butyl cation relative to the benzyl cation.16
However, in this case 4i gave a 2:1 mixture of 6a and 5a
after hydrolysis, a significant decrease from 4a . The
regioselectivity in this reaction of 4i can be increased by
lowering the temperature and increasing the reaction
time; ratio of 6a /5a ) 4:1 at 40 °C (12 h) and 6:1 at 20
°C (5 d).
To further examine the effect of substiuents R1 and R2
on the regioselectivity, several N-Cbz cyclic sulfates were
thermolyzed (Table 2). The cyclizations follow the gen-
eral pattern of providing the 6-membered ring (6) as the
major product. When either R1 or R2 is isopropyl (4c or
4d ) the selectivity and the yield increases. However,
when both R1 and R2 are isopropyl (4e) the yield of 6e is
lower. The structure of 6e was confirmed by an X-ray
crystal structure.17
After obtaining the results described thus far, we were
interested in examining other cyclization procedures in
(14) Ritter, J . J .; Kalish, J . J . Am. Chem. Soc. 1948, 70, 4048.
(15) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper and Row: New York, 1987; p 377.
(16) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper and Row: New York; 1987; p 407.
(17) The stereochemistry of 6e was confirmed by X-ray analysis. The
authors have deposited atomic coordinates for this structure with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(18) Five-membered rings typically form faster than 6-membered
rings. March, J . Advanced Organic Chemistry, 3rd ed.; Wiley-
Interscience: New York, 1985; p 186.

Selective Inversion of Proximal or Distal Hydroxyl Groups
Sch em e 4
J . Org. Chem., Vol. 61, No. 20, 1996 7165
Ta ble 3
Con clu sion
We anticipate the regioselective inversion of the distal
or proximal hydroxyl groups in syn,syn-3-amino 1,2-diols
by the methodology outlined in this paper is of practical
importance because it allows access to 1,2-anti-2,3-syn-
3-amino 1,2-diols and/or 1,2-anti-2,3-anti-3-amino 1,2-
diols from a common intermediate. This methodology
also provides a direct route to 1,3-oxazin-2-ones of 1,2-
anti-2,3-syn-3-amino 1,2-diols (e.g., 6), a class of com-
pounds not readily prepared from the unprotected diol.
Exp er im en ta l Section
Gen er a l Meth od s. For more details see ref 1. Triethy-
lamine (Et3N) was distilled and stored over molecular sieves
prior to use. Acetonitrile (CH3CN) was used directly from
Aldrich “Sure Seal” bottles. Hexanes:ethyl acetate mixtures
used for chromatography are abbrieviated as h:ea. 1H NMR
chemical shifts are reported in ppm relative to solvent
resonance: CDCl3, δ 7.24; (CD3)2SO, δ 2.49; CD3OD, δ 3.30
(CD3). Coupling constants (J ) are reported in Hz. 13C{1H}
NMR chemical shifts are reported in ppm relative to solvent
resonance: CDCl3, δ 77.0; (CD3)2SO, δ 39.5; CD3OD, δ 49.0.
(2S,3R,4R)-2-[N-(Ben zyloxyca r bon yl)a m in o]-5-m eth yl-
1-p h en ylh exa n e-3,4-d iol (3c) was prepared from N-Cbz-L-
phenylalaninal and isobutyraldehyde using the general pro-
cedure outlined in ref 1. The product was purified by
chromatography on silica gel (75:25 h:ea) to give 4.10 g of a
white solid (83%). An analytical sample was obtained by
recrystallization from ethyl acetate-hexanes to give pure
yielda yielda
yielda
(%)
of 7
(%)
(%)
crudeb
5/6
R1
R2
of 5
of 6
4a Bn
4b Bn
4c Bn
4d i-Pr
4e i-Pr
i-Bu
69
77
48
55
6
5
2
12:1
13:1
20:1
2.8:1
PhCH2CH2
i-Pr
PhCH2CH2
i-Pr
12
57
23
4f TBDMSOCH2 n-C14H29
71
>16:1
Isolated yield. Determined by 13C{1H} NMR.
a
b
Ta ble 4. In fr a r ed Absor ba n ce (cm -1) a n d 13C{1H} NMR
Reson a n ce (p p m , MeOH-d 4) of th e Ca r bon yl Gr ou p in 5
a n d 6
1
diol: mp 119-120 °C; Rf 0.57 (1:1 h:ea); H NMR (400 MHz,
cm-1 (ppm)
cm-1 (ppm)
(CD3)2SO, 30 °C) δ 0.68 (dd, J ) 6.9, 3H), 0.79 (dd, J ) 7.0,
3H), 1.73 (m, 1H), 2.66 (m, 1H), 2.85 (m, 1H), 3.14 (m, 1H),
3.30 (m, 1H), 3.77 (m, 1H), 4.22 (br, 1H), 4.42 (br, 1H), 4.95
(s, 2H), 6.93 (m, 1H), 7.13-7.35 (m, 10H); 13C{1H} NMR (100
MHz, (CD3)2SO, 30 °C) δ 16.3, 19.9, 29.4, 37.2, 37.2, 54.4, 64.7,
71.4, 74.5, 125.8, 127.5, 128.0, 128.2, 129.1, 137.4, 139.3, 155.8.
Anal. Calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92.
Found: C, 70.60; H, 7.69; N, 4.08.
5a
5b
5c
5d
5e
5f
1745 (161.1)
1746 (161.1)
1745 (161.1)
1742 (162.2)
6a
6b
6c
6d
6e
6f
1687 (155.6)
1686 (155.8)
1682 (155.9)
1692 (156.1)
1688 (156.2)
1754 (162.0)
(3S,4R,5R)-3-[N-(Ben zyloxyca r bon yl)a m in o]-2-m eth yl-
7-p h en ylh ep ta n e-4,5-d iol (3d ) was prepared from N-Cbz-
L-valinal and 3-phenylpropanal using the general procedure
outlined in ref 1. Chromatography on silica gel (75:25 h:ea)
gave 4.40 g (83% mass rocovery) of a viscous oil that contained
approximately 15-20% (by NMR) of an inseparable impurity
(Rf 0.16, 7:3 h:ea). This mixture was taken to the next step
where flash chromatography of the cyclic sulfite diastereomers
led to purification.
P r oced u r e for th e F or m a tion of Cyclic Su lfa tes 4a -i
fr om 1,2-Diols 3a -i (adapted from the procedure of Sharpless
et al.6a). Thionyl chloride (220 µL, 3.0 mmol) in CH2Cl2 (280
µL) was added dropwise over 10 min to a stirring solution of
diol 31 (2.0 mmol) and Et3N (1.1 mL, 8.0 mmol) in CH2Cl2 (10
mL) at 0 °C. Stirring was continued for 5 min, at which time
TLC (7:3 h:ea) indicated completion. Water (1 mL) was added,
and stirring was continued for 5 min. Hexanes (8 mL) and
water (10 mL) were added, and the ice bath was removed. After
being stirred for an additional 5 min the aqueous layer was
removed. The organic layer was washed with water (3 × 5
mL), saturated NaHCO3 (5 mL), and saturated NaCl (5 mL),
or X-ray crystallography (6e). Once several of the cyclic
carbamates (5 and 6) were in hand we made a compari-
son of the physical data to see if any useful trends existed.
As expected, the CdO stretch in the infrared spectra of
5 and 6 displayed a trend (Table 4).19 The oxazolidiones
(5) absorbed at approximately 1745 cm-1 and the oxazi-
nones (6) absorbed at approximately 1685 cm-1. Slightly
unexpected was a trend in the chemical shift of the
carbonyl carbon as observed by 13C{1H} NMR (Table 4):
161-162 ppm for 5 and 155-156 ppm for 6. This
information may be useful when more complicated struc-
tures fail to allow assignment by other methods.
(19) The effect of ring size on the IR absorbance of carbonyls is well
known (cyclohexanone, 1715 cm-1; cyclopentaone 1751 cm-1; cyclobu-
tanone 1775 cm-1). Silverstein, R. M.; Bassler, G. C.; Morrill, T. C.
Spectrometric Identification of Organic Compounds, 3rd ed.; J ohn Wiley
& Sons, Inc.: New York, 1974; p 99.

7166 J . Org. Chem., Vol. 61, No. 20, 1996
Kemp et al.
dried (MgSO4), and concentrated to give cyclic sulfite (pair of
diastereomers by NMR and TLC) as an oil. After being dried
under vacuum for 2 h, the oil was dissolved in CCl4 (6 mL)
and CH3CN (6 mL). Water (9 mL), RuCl3‚3H2O (6.0 mg), and
NaIO4 (856 mg, 4 mmol) were added with stirring at 0 °C. The
reaction was monitored closely by TLC for completion (ap-
proximately 1 h). Hexanes (25 mL) and ether (25 mL) were
added, the layers were separated, and the aqueous layer was
extracted with hexanes (2 × 20 mL). The combined organics
were washed with saturated NaCl (8 × 10 mL, or until the
organic layer is nearly colorless), dried (MgSO4), and concen-
trated to a white solid. Cyclic sulfates could be further purified
by flushing through a plug of silica (7:3 h:ea) to give 4a -i as
a white solid or clear oil.
placed into a glass Parr bottle, and the bottle was flushed with
H2 and pressurized to 50 psi with H2. The bottle was shaken
for about 18 h, at which time TLC indicated the disappearence
of starting material. The mixture was filtered through Celite
with CHCl3 and then concentrated. The yellow oil was
dissolved in THF20 (50 mL) and 20% aqueous H2SO4 (200 µL)
and stirred at 25 °C for 30 min. The solution was then
neutralized with 20% aqueous KOH, dried (MgSO4), filtered
through Celite, and concentrated to give the crude products.
1
The crude material was analyzed by H and 13C{1H} NMR in
CD3OD. The isomer ratios were determined from 13C NMR
spectra.
Th er m olysis of 4a . Reflux for 4.5 h in CH3CN. The
oxazinone 6a was separated from the N-benzylacetamide by
fractional crystallization (acetone-hexanes) to provide 6a (75
mg, 67%) as a white solid. The mother liquors were chro-
matographed to give 5a (13 mg, 12%) as a clear oil.
(2S,3R,4R)-2-[N-(Ben zyloxyca r bon yl)a m in o]-6-m eth yl-
1-p h en ylh ep ta n e-3,4-cyclic Su lfa te (4a ): TLC of cyclic
sulfite intermediate Rf 0.64, 0.68 (7:3 h:ea); yield 793 mg (92%)
1
of a white solid; mp 111 °C dec; Rf 0.68 (7:3 h:ea); H NMR
Hyd r ogen a tion of 4a . Chromatography (95:5 CH2Cl2-
methanol) gave 5a (72 mg, 69%) and 6a (6.5 mg, 6%).
(400 MHz, CDCl3) δ 0.84 (d, J ) 6.4, 3H), 0.90 (d, J ) 6.5,
3H), 1.43 (dd, J ) 7.1, 12.1, 1H), 1.63-1.76 (m, 2H), 2.86 (dd,
J ) 8.9, 13.8, 1H), 2.99 (dd, J ) 7.3, 13.8, 1H), 4.15 (q, J )
8.5, 1H), 4.44 (d, J ) 8.5, 1H), 4.78, (t, J ) 9.3, 1H), 5.04 (d,
J ) 12.3, 1H), 5.10 (d, J ) 12.3, 1H), 5.24 (d, J ) 6.6, 1H),
7.19-7.36 (m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ 21.2,
22.8, 25.0, 38.8, 40.2, 51.2, 67.3, 83.4, 86.9, 127.3, 127.7, 128.2,
128.5, 128.97, 129.00, 135.6, 135.9, 156.2; [R]20D +4.50° (c 3.87,
CHCl3). Anal. Calcd for C22H27NO6S: C, 60.95; H, 6.28; N,
3.23. Found: C, 60.57; H, 6.05; N, 2.92.
Silyla tion -In ver sion P r oced u r e of 4i (adapted from the
procedure of Sakaitani and Ohfune5). To a stirring solution
of 4i (800 mg, 2.0 mmol) and 2,6-lutidine (463 µL, 4.0 mmol)
in CH2Cl2 (6 mL) was added tert-butyldimethylsilyl triflate
(690 µL, 3.0 mmol) dropwise over 5 min. After 20 min,
saturated NH4Cl (10 mL) was added. The mixture was stirred
and separated, and the aqueous layer was extracted with Et2O
(3 × 15 mL). The combined organic layers were washed with
water (2 × 10 mL) and saturated NaCl (10 mL), dried (MgSO4),
and concentrated to give the crude silyl carbamate (4j). 4j
was dissolved in THF (10 mL) and cooled to 0 °C. A 1.0 M
solution of TBAF in THF (2 mL, 2 mmol) was added over 5
min, and then the solution was stirred at 0 °C for 1 h. The
solution was concentrated and chromatographed (95:5 CH2-
Cl2-methanol) through a small plug of silica to give the tetra-
n-butylammonium sulfate intermediate (882 mg, 75%) as a
clear oil. The residue was dissolved in THF20 (40 mL) and
20% aqueous H2SO4 (200 µL) and stirred for 30 min at room
temperature. The solution was neutralized with 20% aqueous
KOH (∼500 µL), dried (MgSO4), concentrated, and chromato-
graphed (95:5 CH2Cl2-methanol) to give 5a (363 mg, 71% from
4i), as a clear oil.
Th er m olysis-Cycliza tion P r oced u r e. A solution of 4 (1
mmol) in dry CH3CN (60 mL) was heated. The disappearance
of starting material was monitored by TLC. The solution was
cooled to room temperature and concentrated. The solid was
dissolved in THF (60 mL) and 2% aqueous H2SO4 (300 µL)
and stirred for 1 h. The solution was neutralized with 20%
aqueous KOH with stirring. The mixture was dried (MgSO4),
concentrated, and flushed through a plug of silica with ethyl
acetate to give the crude products. The crude material was
analyzed by 1H and 13C{1H} NMR in CD3OD. The isomer
ratios were determined from 13C{1H} NMR spectra. One
equivalent of N-benzylacetamide was obtained from the N-Cbz
cyclic sulfates.
N-Ben zyla ceta m id e: 1H NMR (500 MHz, CD3OD) δ 1.96
(s, 3H), 4.33 (s, 2H), 7.23-7.32 (m, 5H); 13C{1H} NMR (125
MHz, CD3OD) δ 22.5, 44.2, 128.2, 128.6, 129.5, 139.9, 173.0.
Hyd r ogen a tion -Cycliza tion P r oced u r e. A test tube
was charged with 4 (0.40 mmol) in THF (6 mL), Et3N (220
µL, 1.58 mmol), and 5% Pd/C (179 mg). The test tube was
(4S,5S)-4-Ben zyl-5-[(1R)-1-h yd r oxy-3-m eth ylbu tyl]-1,3-
oxa zolid in -2-on e (5a ) was obtained as a viscous oil: Rf 0.35
1
(95:5 CH2Cl2-methanol); H NMR (400 MHz, CD3OD) δ 0.97
(d, J ) 6.6, 1H), 0.99 (d, J ) 6.7, 1H), 1.42-1.57 (m, 2H), 1.89-
1.97 (m, 1H), 2.67 (dd, J ) 11.1, 13.3, 1H), 3.24 (dd, J ) 2.9,
13.4, 1H), 3.97 (ddd, J ) 2.8, 9.4, 9.6, 1H), 4.08 (ddd, J ) 3.2,
7.2, 11.1, 1H), 4.33 (dd, J ) 7.3, 9.2, 1H), 7.21-7.33 (m, 5H);
13C{1H} NMR (100 MHz, CD3OD) δ 21.9, 24.4, 25.0, 37.2, 45.1,
57.9, 67.3, 83.5, 127.7, 129.8, 130.4, 139.0, 161.1; IR (film)
3410, 3300, 1745 cm-1; FABMS (NBA) m/ z 527 (2MH+, 18),
264 (MH+, 100), 220 (7); FAB HRMS m/ z calcd for C15H22
NO3 264.1600, found 264.1607.
-
+
(4S,5R,6S)-3,4,5,6-Tetr a h yd r o-4-ben zyl-5-h yd r oxy-6-(2-
m eth ylp r op yl)-2H-1,3-oxa zin -2-on e (6a ). An analytical
sample was obtained by recrystallization from methanol: mp
188-190 °C; Rf 0.34 (95:5 CH2Cl2-methanol); 1H NMR (400
MHz, CD3OD) δ 0.89 (d, J ) 6.6, 3H), 0.92 (d, J ) 6.7, 3H),
1.23 (ddd, 1H), 1.50 (ddd, 1H), 1.77 (m, 1H), 2.79 (dd, J ) 13.1,
6.3, 1H), 3.04 (dd, J ) 13.1, 8.6, 1H), 3.47 (t, J ) 3.2, 1H),
3.66 (ddd, J ) 3.2, 6.3, 8.6, 1H), 4.33 (dt, J ) 9.8, 3.4, 1H),
7.19-7.32 (m, 5H); 13C{1H} NMR (100 MHz, CD3OD) δ 22.1,
23.4, 25.6, 37.2, 42.3, 54.5, 64.8, 81.6, 127.7, 129.6, 130.4, 138.1,
155.6; IR (Nujol) 3381, 1687 cm-1; FABMS (NBA) m/ z 264
(MH+, 100), 220 (4); [R]20 -66.8° (c 3.08, methanol). Anal.
D
Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C,
68.32; H, 7.98; N, 5.08.
(2S,3R,4S)-2-[N-(ter t-Bu tyloxycar bon yl)am in o]-6-m eth -
yl-1-p h en ylh ep ta n e-3,4-d iol (8c). Oxazinone 6a (100 mg,
0.380 mmol), LiOH (273 mg, 11.4 mmol), EtOH (7 mL), and
water (3 mL) were heated at reflux for 12 h. The reaction
mixture was concentrated to 2 mL and extracted with ether
(2 × 15 mL) and THF (3 × 10 mL). The combined organic
extracts were dried (MgSO4) and concentrated to give the free
amino diol 8a as a white solid (89.4 mg, 96%). The amino diol
8a was dissolved in CH2Cl2 (4 mL), and a solution of di-tert-
butyl dicarbonate (83 mg, 0.380 mmol) in CH2Cl2 (2 mL) was
added dropwise over 5 min. The reaction was stirred for 16
h, concentrated, flushed through silica (1:1 h:ea), and recrys-
tallized from ethyl acetate-hexanes to give pure 8c as a white
1
solid (76 mg, 59%): mp 137.5-138 °C; Rf 0.45 (7:3 h:ea); H
NMR (400 MHz, CDCl3) δ 0.85 (d, J ) 6.6, 3H), 0.90 (d, J )
6.7, 3H), 1.32-1.37 (m, 2H), 1.39 (s, 9H), 1.86 (sept., J ) 6.8,
1H), 2.87 (m, 2H), 3.20 (d, J ) 8.2, 1H), 3.36 (m, 1H), 3.9 (br,
1H), 4.21 (m, 1H), 4.72 (d, J ) 8.5, 1H), 7.18-7.29 (m, 5H);
13C{1H} NMR (100 MHz, CDCl3) δ 21.3, 23.9, 24.3, 28.2, 38.2,
42.1, 51.7, 69.4, 75.6, 80.3, 126.5, 128.5, 129.0, 137.9, 157.4;
[R]20 -57.0° (c 3.24, CHCl3) [lit.12a mp 139-140 °C; [R]20
D
D
-56.4° (c 1, CHCl3)].
(4S,5S,6R)-4-(Cycloh exylm eth yl)-5-(1-h yd r oxy-3-m eth -
ylbu tyl)-1,3-oxa zolid in -2-on e (5k , R1 ) Cycloh exyl, R2
)
Isop r op yl). Using an adapted literature procedure,13 the
phenyl ring of 5a was hydrogenated (5% Rh/Al2O3, H2, 50 psi)
to give the crude cyclohexyl analog. An analytical sample was
obtained by chromatography (6:4 h:ea), giving 5k as a white
solid. Comparison of 1H NMR to the four known diastereomers
verified the stereochemical assignment of 5a .12d
(20) When THF from a Na/benzophenone still is combined with 20%
aqueous H2SO4 for the hydrolysis, we have noticed that significant
quantities of polymerized THF were obtained in the products. This
results from the fact that the THF is still warm. Therefore, the THF
was allowed to cool to room temperature before addition of 20%
aqueous H2SO4.

Selective Inversion of Proximal or Distal Hydroxyl Groups
J . Org. Chem., Vol. 61, No. 20, 1996 7167
(2S,3R,4S)-2-Acet a m id o-1,3,4-t r ia cet oxyh exa d eca n e
(1a ). A solution of cyclic sulfate 4g (95 mg, 0.165 mmol) in
CH3CN (15 mL) was refluxed for 4.5 h and concentrated and
the residue dissolved in THF (20 mL) and 2% aqueous H2SO4
(100 µL) and stirred for 1 h. Na2CO3 (50 mg) was added, and
the reaction mixture was concentrated, dissolved in ether (4
mL) and CH2Cl2 (10 mL), dried (MgSO4), and concentrated to
a solid (107 mg). The solid was dissolved in EtOH (5 mL),
and HCO2H (250 µL) along with 10% Pd/C (100 mg) were
added. The mixture was stirred for 24 h, filtered, and
concentrated (67 mg). The solid was dissolved in ethanol (10
mL) and 2 N NaOH (10 mL) and refluxed for 3 h. The solution
was concentrated to 10 mL and extracted with CH2Cl2 (4 ×
10 mL). The organic layer was dried (MgSO4), concentrated,
and dissolved in pyridine (2 mL) and acetic anhydride (2 mL).
The solution was stirred for 135 min and concentrated and
flushed through silica gel with h:ea (1:1) to give 1a and an
unknown impurity as a 1:1 mixture (17 mg). Comparison of
mL) and 15% NaOH (10 mL) and heated at 70 °C for 14 h.
The solution was concentrated to 10 mL and diluted with
saturated NaCl (50 mL). The aqueous layer was extracted
with CHCl3
concentrated, and dissolved in acetic anhydride (3 mL), pyri-
dine (10 mL), and 4-(N,N-dimethylamino)pyridine (10 mg). The
solution was stirred for 24 h, concentrated, and chromato-
graphed (Rf 0.27, 1:1 h:ea) to give 9 (60 mg, 0.124 mmol, 60%).
1H and 13C{1H} NMR spectra, were identical with the
literature.9c,e,f The only exception was the proton reported to
be at 4.69 in ref 9f; we observed this proton at 4.90, which
was consistant with ref 9c,e.
(6 × 25 mL). The organic layer was dried (MgSO4),
Ack n ow led gm en t. We thank J ingrong Cui for
preparation of 4c and 4d . S.J .K. is grateful for financial
support through a Miles Fellowship 1992-1993. S.F.P.
is grateful to the NIH (GM-38735) for support of this
work.
1
the H NMR spectra with the literature10 clearly showed the
formation of 1a , but the impurity could not be assigned as one
of the three other diastereomers.
Su p p or tin g In for m a tion Ava ila ble: Spectral and sup-
porting experimental information for compounds 4b-i, 5b-
d ,f, 6b-e, and 7c,e (9 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(2S,3S,4R)-2-Aceta m id o-1,3,4-tr ia cetoxyocta d eca n e (9).
A solution of hydroxy carbamate 5f (95 mg, 0.21 mmol) in CH3-
CN (25 mL) and 48% aqueous HF was stirred for 30 min. The
solution was diluted with saturated NaHCO3 (25 mL) and
extracted with CHCl3 (4 × 50 mL). The organic layer was
dried, filtered, and concentrated to give the dihydroxy car-
bamate as an oil. The residue was dissolved in ethanol (25
J O961060J