Chiral Acetals as Stereoinductors: Diastereoface Selective Alkylation of Dihydrobenzoxazine-Derived Amide Enolates

Article abstract of DOI:10.1021/jo000352o

Novel dihydrobenzoxazine-derived acetals of type 3 have been developed for asymmetric C-alkylations of propionyl amide enolates. High stereoselectivities are obtained for amides 15 and 22 which are rationalized in terms of intramolecular metal chelate formation.

Full text of DOI:10.1021/jo000352o

6540
J . Org. Chem. 2000, 65, 6540-6546
Ch ir a l Aceta ls a s Ster eoin d u ctor s: Dia ster eofa ce Selective
Alk yla tion of Dih yd r oben zoxa zin e-Der ived Am id e En ola tes
J ohann Mulzer* and Oliver Langer
Institut fu¨r Organische Chemie der Universita¨t Wien, Wa¨hringerstr. 38, A-1090 Wien, Austria
Martin Hiersemann*
Institut fu¨r Organische Chemie der Technischen Universita¨t Dresden, D-01062 Dresden, Germany
J an W. Bats
Institut fu¨r Organische Chemie der J ohann Wolfgang Goethe-Universita¨t, Marie-Curie-Strasse 11,
D-60439 Frankfurt, Germany
J u¨rgen Buschmann and Peter Luger
Institut fu¨r Kristallographie der Freien Universita¨t, Takustrasse 6, D-14195 Berlin, Germany
mulzer@felix.orc.univie.ac.at
Received March 13, 2000
Novel dihydrobenzoxazine-derived acetals of type 3 have been developed for asymmetric C-
alkylations of propionyl amide enolates. High stereoselectivities are obtained for amides 15 and
22 which are rationalized in terms of intramolecular metal chelate formation.
In tr od u ction
tions (and related reactions) over the past 20 years by
several research groups. These efforts were pioneered by
Meyers,3 Evans,4 and Oppolzer5 and were, more recently,
continued by Myers,6 Masamune,7 Seebach,8 and others.9
Except for Myers’ compounds, the chiral information of
these auxiliaries is incorporated in a five-membered
heterocyclic ring, and the N-H group is part of a lactam,
oxazolidinone, or sultam structure so that an imide is
formed on N-acylation. Imide enolates 4 and 5 are
particularly noteworthy applications of this concept.
Chiral acetals of type 1 have been frequently used as
stereochemical inductors for additions to adjacent pro-
stereogenic sp2-carbons.1 However, in preparing these
systems stereocontrol of C2 is a problem unless this
carbon is chosen to be a chirotopic nonstereogenic center.
The necessity to separate C2-anomers was also a main
drawback in using chiral ansa acetals such as 2, which
proved quite efficient as stereoinductors for the epoxi-
dation or dihydroxylation of the olefinic double bond.2
(3) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J . Am. Chem.
Soc. 1976, 98, 567-576.
(4) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737-1739. (b) Evans, D. A.; Urpi, F.; Somers, T. C.; Clar,
J . S. J . Am. Chem. Soc. 1990, 112, 8215-8216.
(5) Oppolzer, W.; Moretti, R.; Rhomi, S. Tetrahedron Lett. 1989, 30,
5603-5606.
(6) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, L. J . Am. Chem.
Soc. 1994, 116, 9361-9362. Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J .; Gleason, J . L. J . Am. Chem. Soc. 1997,
119, 6496-6511. Myers, A. G.; McKinstry, L. J . Org. Chem. 1996, 61,
2428. Myers, A. G.; Gleason, J . L.; Yoon, T.; Kung, T. D. W. J . Am.
Chem. Soc. 1997, 119, 656-673.
In this paper we report on a different combination of
an acetal moiety with a rigid benzenoid template to
achieve highly diastereoface-controlled sp2 additions. Our
objective was to construct a rigid and conformationally
defined amide system by bringing the aminal nitrogen
into resonance interaction with the benzenoid ring. In
consequence, N-acylated dihydrobenzoxazines such as 3
were envisaged that could bear stereogenic centers at
C-2, C-4 and most simply, in the appendage at C-2. These
compounds to a certain degree resemble the chiral
auxiliaries that have been developed for enolate alkyla-
(7) Abiko, A.; Moriya, O.; Filla, S. A.; Masamune, S. Angew. Chem.
Int. Ed. 1995, 107, 793-795.
(8) Studer, A.; Hintermann, T.; Seebach, D. Helv. Chim. Acta 1995,
78, 1185-1206.
(9) Reviews on amino acid derived chiral auxiliaries: Studer, A.
Synthesis 1996, 793-815. Ager D. J .; Prakash, I.; Schaad, D. R.
Aldrichimica Acta 1997,30, 3-10. For individual applications, see also,
among others: (a) Denmark, S.; Marlin, J . E. J . Org. Chem. 1987, 52,
5742-5745. (b) Boeckman, R. K., J r.; Connell, B. T. J . Am. Chem. Soc.
1995, 117, 12368-12369. (c) Ghosh, A. K.; Onishi, M. J . Am. Chem.
Soc. 1996, 118, 2527-2528. (d) Maligres, P. E.; Upadhyay, V.; Rossen
K.; Cianciosi, S. J .; Purick, R. M.; Eng, K. K.; Reamer, E. A.; Askin,
D.; Volante, R. P.; Reider, P. J . Tetrahedron Lett. 1995, 36, 2195-
2198. (e) McWilliams, J . C.; Armstrong, J . D., III; Zheng, N.; Bhupathy,
M.; Volante, R. P.; Reider, P. J . J . Am. Chem. Soc. 1996, 118, 8. 11970-
11971. (f) Wang, Y.; Hung, A.; Chang, C.; Yan, T. J . Org. Chem. 1996,
61, 2038-2043. (g) Schrader, T. Chem. Eur. J . 1997, 3, 1273-1282.
(h) Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am. Chem. Soc. 1997,
119, 7883-788. (i) Chang, J . W.; J ang, D. P.; Uang, B. J .; Liao, F. L.,
Wang, S. L. Org. Lett. 1999, 1, 2061-2064. (k) Kim, S. M.; Byun, I. S.;
Kim, Y. H., Angew. Chem. Int. Ed. 2000, 39, 728-731.
(1) Alexakis, A.; Mangeney, P. Tetrahedron Asymmetry 1990, 1,
477-511.
(2) Mulzer, J .; Schein, K.; Bats, J .-W.; Buschmann, J .; Luger, P.
Angew. Chem. Int. Ed. 1998, 37, 1566-1569. Mulzer, J .; Schein,
K.;.Bo¨hm, I.; Trauner, D. Pure Appl. Chem. 1998, 70, 1487-1493.
Mulzer, J .; Bo¨hm, I.; Bats, J .-W. Tetrahedron Lett. 1998, 39, 9643-
9646.
10.1021/jo000352o CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Chiral Acetals as Stereoinductors
J . Org. Chem., Vol. 65, No. 20, 2000 6541
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) THF, p-TsOH, 22 °C, 15 min;
(b) MeC(OTMS)dNTMS, CH2Cl2, 22 °C, 1 h, then propionyl
chloride, 22 °C, 1 h.
allylic 1,3-strain effect.10 Consequently, the C4-substitu-
ent adopts a pseudoequatorial position in 11b and a
pseudoaxial one in 11e. To a certain degree the geometry
of our dihydrobenzoxazines is similar to the axially
twisted N-aryl amides described by Curran.10c Both in
Curran’s and in our auxiliaries the acyl moiety and the
aryl ring at the nitrogen are axially twisted. In Curran’s
systems it is the aryl group that is out of plane and in
our work it is both the aryl ring and the MeCHdCOMet
group.
Deprotonation of 11a ,b,d and allylation of the resulting
enolates proceeded with moderate stereoselectivity
(Scheme 2). The main diastereomers were tentatively
assigned to have structures 12a -c in analogy with the
results obtained later from systems 15 and 22.
a
Reagents and conditions: (a) TBDMSCl, DMF, NEt3, DMAP,
22 °C, 12 h; (b) propionyl chloride, pyridine, DMAP, 22 °C, 12 h;
(c) 60% AcOH, 22 °C, 12 h; (d) COCl)2, DMSO, NiPr2Et, -60 °C,
then isopropenyl magnesium bromide; (e) LiOH, MeOH, 22 °C,
3d; (f) LiAlH4, THF, 0 °C, 1 h; (g) pivaldehyde, H2SO4, CH2Cl2, 22
°C, 1 h; (h) MeC(OTMS)dNTMS, CH2Cl2, 22 °C, 1 h, then
propionyl chloride, 22 °C, 12 h; 11a , 63%, 11b/c, 52%; 11d /e, 45%.
Although it was not our main intention to enlarge this
collection of rather mature and well-established chiral
auxiliaries, it appeared an attractive idea to test our
compounds 3 in comparison with the abovementioned
examples.
In view of the unsatisfactory stereocontrol observed for
amides 11, we decided to transfer the stereogenic master
center from C4 into the side chain. Hence, amino alcohol
6 was treated with the known OTBDPS-lactic aldehyde
1411 to form an anomeric mixture of the acetals, which
were immediately N-acylated to furnish the amides 15a /b
in a ratio of 84:16 (Scheme 3).12
After chromatographic separation the amides 15a and
15b were deprotonated with KHMDS and alkylated with
four different alkyl halides (Scheme 4, Table 1). The
diastereomers 16/17 were obtained in diastereomeric
ratios of g85:15. For the corresponding pair 18/19, the
diastereomeric ratio was demonstrated similar. The
configuration of 16d was determined by X-ray single-
crystal diffraction (Figure S3). Allyl adducts 16a , 17a ,
and 18a were used to demonstrate the facile removal of
the dihydrobenzoxazine residue: LAH reduction of 16a
gave (R)-2-methyl-pentene-1-ol (R-20),13 whereas the
corresponding reduction of 17a and 18a delivered (S-20).
Resu lts a n d Discu ssion
Derivatives with stereogenic centers at C2 and C4 were
addressed first. Amino alcohol 6 was converted into a
racemic mixture of the isopropenyl derivative 8. The
second model system was generated by reduction of
commercially available 2-aminobenzophenone (9) to ra-
cemic amino alcohol 10. With pivaldehyde all three amino
alcohols, 6, 8, and 10 were converted into the acetals,
which were N-silylated and then acylated with propionyl
chloride to form the dihydrobenzoxazines 11a -e as
shown in Scheme 1. The diastereomers 11b/c (ratio 76:
24) and 11d /e (ratio 81:19) were separated by chroma-
tography. The relative configurations of 11b and 11e
were determined by crystal structure analysis (Figures
S1, S2). Remarkably, the dihydrobenzoxazine ring shows
a boat conformation due to the amide moiety which forces
the C2-tBu residue into a pseudoaxial location by its
(10) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860. Regarding
the influence of allylic 1,3-strain on the structure and reactivity of N,N-,
N,O-, and O,O-acetals, see: (a) Seebach, D.; Lamatsch, B.; Amstutz,
R.; Beck, A. K.; Dobler, M.; Egli, M.; Fitzi, R.; Gautschi, M.; Herrado`n,
B.; Hidber, P. C.; Irwin, J . J .; Locher, R.; Maestro, M.; Maetzke, T.;
Mourino, A.; Pfammater, E.; Plattner, D. A.; Schickli, C.; Schweizer,
W. B.; Seiler, P.; Stucky, G.; Petter, W.; Escalante, J .; J uaristi, E.;
Quintana, D.; Miravitlles, C.; Molins, E. Helv. Chim. Acta 1992, 75,
913-934. (b) Chu, K. S.; Negrete, G. R.; Konopelski, J . P.; Lakner, F.
J .; Woo, N.-T.; Olmstead, M. M. J . Am. Chem. Soc. 1992, 114, 1800-
1812. (c) Axially twisted N-aryl amides: Curran, D. P.; Qi, Hongyan;
Geib, S. J .; Demello, N. C. J . Am. Chem. Soc. 1994, 116, 3131-3132.
Review: Clayden, J . Synlett. 1998, 810-816.
(11) Brandla¨nge, S.; Lindquist, B. Acta Chem. Scand. 1985, B39,
589.
(12) Rajeswari, S.; J ones, R. J .; Cava, M. P. Tetrahedron Lett. 1987,
28, 5099-5102.

6542 J . Org. Chem., Vol. 65, No. 20, 2000
Mulzer et al.
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (a) THF, p-TsOH, 22 °C, 15 min;
(b) MeC(OTMS)dNTMS, CH2Cl2, 22 °C, 1 h, then propionyl
chloride, 22 °C, 1 h.
a
Reagents and conditions: (a) 21, THF, p-TsOH, 22 °C, 15 min;
(b) MeC(OTMS)dNTMS, CH2Cl2, 22 °C, 1 h, then propionyl
chloride, 22 °C, 1 h; (c) KN(SiMe3)2, THF, 20% (v/v) of additive,
-78 °C, 1 h, then R-X, -78 to 22 °C, 14 h; (d) LiAlH4, Et2O, 0 °C,
1 h.
Sch em e 4a
Ta ble 2. Dia ster eoselective Alk yla tion of Am id e 22
product 23
R-X
additive
% yielda
drb
a
b
b
b
c
c
d
d
d
e
allyl bromide
ethyl bromide
ethyl iodide
81
22 (35)
76
37 (8)
76 (8)
54
83
56
40
46 (37)
98:2
>99:1
99:1
99:1
99:1
99:1
98:2
98:2
96:4
98:2
HMPA
HMPA
ethyl iodide
propyl iodide
propyl iodide
benzyl bromide
benzyl bromide
benzyl bromide
pentyl bromide
HMPA
HMPA
DMPU
HMPA
a
In parentheses are the % reisolated starting material.
b
(2S,2′R,4′′R):(2R,2′R,4′′R), determined by HPLC.
the enolate carbon, and vice versa. This means that the
enolate alkylation follows a lk-topicity.15 Unfortunately,
the benzoxazine template was epimerized to amine 20′
in course of the reduction, which greatly detracts from
its applicability as a chiral auxiliary. Still, amine 20′ can
be recycled into the acylation step.
a
Reagents and conditions: (a) KN(SiMe3)2, THF, -78 °C, 1 h,
Despite these encouraging results, the overall stereo-
control exerted by system 15 was still unsatisfactory,
particularly due to the low selectivity in the acetal
forming step (84:16 mixture of 15a /b). To find a system
with higher stereocontrol, amino alcohol 6 was ketalized
with (R)-2,3-O-isopropylidene glyceraldehyde (21) in
place of lactaldehyde 14 (Scheme 5). Acetal amide 22 was
formed with >95:5 diastereoselectivity, the deprotonation
and enolate alkylation of which furnished diastereomer
23a -e with high selectivities (g96:4, Table 2). The
configuration of the benzyl adduct 23d was determined
by single-crystal diffraction (Figure S4). The removal of
the auxiliary from the allyl adduct 23a was performed
as described for 16a /17a /18a to give enantiopure (S)-20
(>99% ee according to Mosher analysis). In analogy to
amine 20′, now amine 20′′ was recovered as an epimeric
mixture. In this case this is no serious drawback, as only
one amide diastereomer (22) is from 20′′ on reacylation.
then R-X, to 22 °C, 14 h. (b) LiAlH4, Et2O, 0 °C, 1 h.
Ta ble 1. Alk yla tion of 15a /15b w ith Va r iou s Alk yl
Ha lid es
products 16/17
and 18/19
ratio of
% yield
alkyl halide
16:17a (18/19)a 16b (18)b
a
b
c
d
allyl bromide
93:7 (94:6)
85:15 (93:7)
95:5 (93:7)
96:4 (93:7)
74 (76)
73 (69)
70 (55)
58 (53)
ethyl bromide
n-propyl iodide
5-bromo-1-pentene
a
b
Determined by HPLC. Yield of pure diastereomer 16/18a -d
after chromatographic separation.
In both cases the optical purities of the alcohols were
determined by Mosher analysis14 to be >98%. These
results also corroborate the initial configurational as-
signments and demonstrate that the chiral induction is
mainly exerted by the acetal center at C2, to the effect
that the (S) configuration at C2 induces si-face attack at
Remarkably, addition of HMPA as a decomplexing
agent increased the yield of the alkylation without
affecting the stereoselectivity (Table 2).
(13) (a) Overman, L. E.; Robinson, L. A.; Zablocki, J . J . Am. Chem.
Soc. 1992, 114, 368-369. (b) Evans, D. A.; Bender, S. L.; Morris, J . J .
Am. Chem. Soc. 1988, 110, 2506-2526. (c) Gramatica, P.; Manitto, P.;
Monti, D.; Speranza, G. Tetrahedron 1988, 44, 1299-1304.
(14) Dale, J . D.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
513.
(15) . Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. 1982, 21, 654-
660.

Chiral Acetals as Stereoinductors
J . Org. Chem., Vol. 65, No. 20, 2000 6543
Sch em e 6
Discu ssion
The central question is how chiral information is
transferred with the observed lk-topicity from the ste-
reogenic center in the C2-appendage to the diastereofaces
of the enolate carbon. The first step in this relay is the
stereochemical course of the acetal formation. Originally
the N,O-acetals I are formed as 1:1 epimeric mixtures,
and only in the course of the acylation process is the
diastereomeric ratio gradually shifted toward 11b, 11d ,
15a , and 22, respectively. This N-acylation obviously
occurs via an equilibrium of acyclic (II) and cyclic (III)
nonacylated O-silylated intermediates (Scheme 6), and
from this equilibrium the most stable amide diastereomer
(IV) is formed with the highest rate.
F igu r e 1. Calculated potential curve18,19 of amide enolate 24
for varying torsion angles (φ).
The amide enolates could not be trapped with TMSCl,
as the resulting silyl enol ethers were too unstable to be
isolated. However the enolate geometry may be safely
assumed to be (Z), in accordance with literature prece-
dence.16 A crucial issue was to determine the ground state
conformation of the metalated dihydrobenzoxazine pro-
pionamides, particularly with respect to the rotational
barrier around the former CN amide bond. Recent results
by Streitweiser indicated a very low barrier (<10 kcal/
mol).17 Direct measurements were unsuccessful in our
case. Therefore, semiempirical calculations using MO-
PAC18 and the semiempirical Hamiltonian PM319 were
performed to analyze the energy potential for rotations
around the (exocyclic) C-N bond of the lithiated20 pro-
pionamide 24 (Figure 1). The dihedral angle φ (Figure
1) is set equal to 0 for a conformation with the enolate
side chain coplanar with the benzoxazine ring and the
OLi syn to C2. Starting from an unrestrained conforma-
tion an energy profile was calculated by restricting φ to
fixed values (φ ) 0-360°) in steps of 10° and allowing
the rest of the molecule to be minimized. Energies of the
resulting minima were recorded. Figure 1 shows a graph
F igu r e 2. Perspective view of 24 to show the accessibility of
the enolate re-face.
of the PM3 potential curve thus obtained. The sudden
decline of energy in the range between φ ) -90 and
-100° is caused by an inversion of configuration at N.
The local minimum is found at φ ) -100°, which means
that the plane of the enolate approximately bisects the
oxazine ring. Further rotation from φ ) -100° toward
-200° results in a strong increase in energy due to
interactions with the ortho-H combined with the loss of
chelate stabilization. The low-energy conformation is
shown in projection (Figure 2), which shows that the
overall boat conformation of the parent amide has
roughly been maintained, although the allylic 1,3-strain
around the CN bond is no longer existent. The ortho-H
of the benzenoid ring shields the si-face of the enolate
carbon quite efficiently, so that the attack of the electro-
phile is directed to the comparatively unhindered re-face.
The varying degree of diastereofacial selection for amides
11, 15, and 22 has then to be attributed to the ability of
the C2-residue for chelate formation with the enolate-
OK.21 Thus, the increase of the stereoselectivity in the
sequence 22 > 15 > 11 appears reasonable, although the
bulkiness of the C2-residues is in opposite order. Re-
markably, the presence of HMPA does not interfere with
this chelation. Quite consistently, analogous calculations
(16) Evans, D. A. Stereoselective Alkylation Reactions of Chiral Metal
Enolates. In Asymmetric Synthesis, Vol. 3, Stereodifferentiating Ad-
dition Reactions Part B; Morrison, J . D., Ed.; Academic Press: Orlando,
1984; pp 1-110.
(17) Kim, Y.-J .; Streitweiser, A.; Chow, A.; Fraenkel, G. Org. Lett.
1999, 1, 2069-2073.
(18) Stewart, J . J . P.; MOPAC: A General Molecular Orbital
Package Quantum Chem. Prog. Exch. 1990, 10, 86.
(19) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 210-220. Anders,
E.; Koch, R.; Freunscht, P. Comput. Chem. 1993, 14, 1301-1312.
(20) The experiments were carried out with the potassium enolate;
however, potassium was beyond the scope of our calcalutions. There-
fore, the lithium enolate was taken as a model system.

6544 J . Org. Chem., Vol. 65, No. 20, 2000
Mulzer et al.
115.84, 116.54, 118.52, 118.97, 121.19, 121.73, 124.65, 127.29,
127.37, 127.59, 127.64, 127.67, 129.75, 133.43, 133.68, 133.79,
135.71, 135.79, 135.89, 141.77, 142.21. HRMS (EI, 80 eV, 100
°C): m/e calcd for C26H31NO2Si 417.21241, found 417.21250.
Anal. Calcd for C26H31NO2Si: C, 74.78; H, 7.48; N, 3.35.
Found: C, 74.52; H, 7.63; N, 3.50.
for the lithium enolate of 11a revealed a very low barrier
of rotation around the exocyclic N-C bond; two minima
were found for dihedral angles of 90° and -100° with
nearly identical energy levels. Similarly, calculations
performed on enol methyl ether 25 which corresponds to
24 except for chelate formation revealed two energetically
similar bisectic ground state conformations 25A and 25B
(corresponding to dihedral angles of -100° and 95°).
In conclusion, we have shown that in systems such as
22 an almost complete chirality transfer is achieved from
an exocyclic sp3 reference center to an amide enolate sp2-
carbon via a chiral cyclic N,O-acetal attached to a rigid
benzenoid template. This chirality transfer proceeds in
a relay which first implies stereoselective acetal forma-
tion in favor of an anti-arrangement of the C2- and C5-
oxygens and then enolate formation of an enolate whose
ground-state conformation is determined by metal chelate
formation to C5-O. Research is underway in our labora-
tory to test a variety of R-chiral aldehydes for ketal
formation with amino alcohol 6 in order to increase the
applicability of the method.
N,O-Bis(trimethylsilyl)acetamide (0.35 mL, 1.44 mmol) was
added at 25 °C to the above N,O-acetal (1.0 g, 2.39 mmol) in
dry dichloromethane (5 mL). The solution was stirred for 1 h
and then cooled to -78 °C, and propionyl chloride (0.25 mL,
2.87 mmol) was added dropwise. The reaction was warmed to
25 °C overnight. The reaction mixture was filtered, evaporated
under reduced pressure, and purified by chromatography
(ethyl acetate/hexane 1:5). The diastereomers were separated
by HPLC (diisopropyl ether/hexane 3:97) to give 15a (0.89 g,
78%) and 15b (0.17 g, 17%) as viscous colorless oils. 15a : 1H
NMR: δ 0.96 (s, 9H), 1.05 (mc, 3H), 1.22 (mc, 3H), 2.69 (mc
(br), 2H), 3.78 (mc, 1H), 4.56 (mc, 2H), 5.74 (s, br, 1H), 6.95
(mc, 1H), 7.05-7.57 (m, 13H). 1H NMR (DMSO-d6, 120 °C, 500
MHz): δ 0.995 (s, 9H), 0.98 (d, J ) 6.25 Hz, 3H), 1.07 (t, J )
7.5 Hz, 3H), 2.45 (mc, 1H), 2.63 (mc, 1H), 3.88 (mc, 1H), 4.565
(mc, AB system, 2H), 5.76 (d, J ) 7.5 Hz, 1H), 7.11 (mc, 1H),
7.50 (mc, 1H), 7.28 (mc, 1H), 7.385 (mc, 2H), 7.31-7.42 (m,
5H), 7.46 (mc, 2H), 7.545 (mc, 2H). HRMS (EI, 80 eV, 150 °C):
m/e calcd for C28H32NO3Si ) M - CH3 458.21515, found
458.21502. 15b: 1H NMR: δ 1.02 (s, 9H), 1.04 (d, 3H), 1.13 (t,
J ) 7.5 Hz, 3H), 2.49 (mc, 1H), 2.50 (mc, 1H), 3.86 (mc, 1H),
4.21-4.53 (m, AB system, 2H), 5.82 (s, br, 1H), 6.81 (mc, 1H),
7.00-7.19 (m, 3H), 7.24-7.44 (m, 6H), 7.57 (mc, 2H), 7.66 (mc,
1
2H). H NMR (DMSO-d6, 120 °C, 500 MHz): δ 0.94 (d, J ) 6
Hz, 3H), 0.99 (s, 9H), 1.02 (t, J ) 7 Hz, 3H), 2.33 (mc, 1H),
2.58 (mc, 1H), 3.78 (mc, 1H), 4.40-4.51 (m, AB system, 2H),
5.79 (d, J ) 7 Hz, 1H)), 7.02 (mc, 1H), 7.12 (mc, 1H), 7.19-
7.26 (m, 2H), 7.13-7.43 (m, 6H), 7.55 (mc, 2H), 7.61 (mc, 2H).
Anal. Calcd for C29H35NO3Si: C, 73.53; H, 7.44; N, 2.96.
Found: C, 73.81; H, 7.20; N, 3.05.
En ola te Alk yla tion . To a solution of KHMDS (15% solu-
tion in toluene, 2,39 mL, 1.58 mmol) in THF (3 mL) was added
a solution of the amide (0.5 g, 1.06 mmol) 15a or 15b in THF
(5 mL) at -100 °C and the alkyl halide ((8.48 mmol), allyl
bromide (0,72 mL), ethyl bromide (0.63 mL), propyl iodide (0.83
mL), or 5-bromo-1-pentene (1.0 mL) was added. The reaction
mixture was warmed to 25 °C overnight, quenched with
saturated aqueous NH4Cl (5 mL) and water (50 mL), and
extracted with ether (3 × 50 mL). The combined organic
extracts were dried (MgSO4) and concentrated at reduced
pressure and purified by chromatography (ethyl acetate/
hexane 1:5). The diastereomers were separated by HPLC (ethyl
acetate/hexane 3:97) to give 16/17 or 18/19. Only the main
diastereomers in both series (16 and 18) were fully character-
ized.
Exp er im en ta l Section
All reaction with air- and moisture-sensitive compounds
were performed under an argon atmosphere. Reaction flasks
were flame-dried under a stream of argon. Tetrahydrofuran
(THF) was distilled from lithium aluminum hydride. Potas-
sium hexamethyldisilazide (KHDMS) was used as a 15%
solution in toluene. Preparative column chromatography was
performed on silica gel Merck 60, 230-400 mesh. Unless noted
otherwise, H and 13C NMR spectra were recorded at 270 or
1
500 MHz in CDCl3. HPLC was performed on Nucleosil 50-5
from Macherey-Nagel. Optical rotations were determined in
CHCl3 at 589 nm at 25 °C.
(1′′S,2′S)- a n d (1′′S,2′R)-1-[2′-(1′′-ter t-Bu tyld ip h en ylsil-
oxyet h yl)-4′H -b en zo[d ][1′,3′]oxa zin -1′-yl]-p r op a n -1-on e
(15a/15b) (1S,RS)-1-(2′,4′-Dih ydr o-1′H-ben zo[d][1′,3′]oxazin -
2′-yl)-ter t-bu tyld im eth ylsiloxyeth a n ol. 2-Aminobenzyl al-
cohol (6) (13.9 g, 112.7 mmol) in dry THF (150 mL) was treated
with p-toluenesulfonic acid (p-TsOH) (536 mg, 2.82 mmol). The
solution was stirred at room temperature and aldehyde 14 (32
g, 102.4 mmol) in dry THF (100 mL) was added. The mixture
was concentrated under reduced pressure and purified by
column chromatography (ethyl acetate/hexane v/v 1/10) to give
the N,O-acetal (37.5 g, 87%) as a colorless oil (1:1 mixture of
(1′′S,2R,2′S)-1-[2′-(1′′-ter t-Bu t yld ip h en ylsiloxyet h yl)-
4′H -b e n zo[d ][1′,3′]oxa zin -1′-yl]-2-m e t h yl-p e n t -4-e n -1-
on e (16a ). Preparative HPLC (ethyl acetate/hexane: 3/97)
1
gave 16a (390 mg, 73%) as colorless crystals. H NMR: δ 0.95
(mc, 12H), 1.30 (d, J ) 3 Hz, 3H), 2.00 (s, (br), 1H), 2.32 (s, br,
1H), 3.10 (mc, 1H), 3.85 (mc, 1H), 4.53 (mc, 2H), 4.73-5.24 (s,
br, 2H), 5.45 (s, br, 1H), 6.03 (s, br, 1H), 6.64-7,83 (m, 14H).
13C NMR: δ 17.61 (br), 18.99, 19.49 (br), 26.74, 36.69, 38.68
(br), 63.44 (br), 69.26 (br), 84.35 (br), 116.73, 124.79 (br), 125.33
(br), 127.28, 129.36, 134.05 (br), 135.73, 175.92. [R]25D: -123.7°
(c ) 0.83, CHCl3). Anal. Calcd for C32H39NO3Si: C, 74.81; H,
7.65; N, 2.73. Found: C, 74.70; H, 7.62; N, 2.49.
1
diastereomers). H NMR: δ 1.16 (s, 9 + 9H), 1.24 (d + d, J )
6 Hz, 3 + 3H), 4.11 (mc, 1H), 4.21 (mc, 1H), 4.43 (mc, 1H),
4.48 (mc, 1H), 4.50 (mc, 1H), 4.67 (mc, 1H), 4.75-5.0 (m, 2
AB systems, 2 + 2H), 6.51 (mc, 1H), 6.71 (mc, 1H), 6.88 (mc,
1 + 1H), 6.92 (mc, 1 + 1H), 7.11 (mc, 1 + 1H), 7.37-7.53 (m,
6 + 6H), 7.69-7.87 (m, 4 + 4H). 13C NMR: δ 16.58, 19.21,
19.31, 19.55, 27.02, 36.53, 67.39, 69.98, 71.45, 85.07, 87.33,
(1′′S,2R,2′S)-1-[2′-(1′′-ter t-Bu t yld ip h en ylsiloxyet h yl)-
4′H-ben zo[d][1′,3′]oxazin -1′-yl]-2-m eth ylbu tan -1-on e (16b).
Preparative HPLC (ethyl acetate/hexane 4:96) gave 16b (400
1
mg, 74%) as a viscous colorless oil. H NMR: δ 0.5-1.15 (m,
6H), 0.95 (s, 9H), 1.15 (mc, br, 1H), 1.61 (mc, br, 1H), 2.95
(mc, 1H), 3.85 (mc, 1H), 4.53 (mc, 2H), 6.10 (s, br, 1H), 6.65-
7.73 (m, 14H). 13C NMR: δ 11.49, 17.60 (br), 18.95, 19.50 (br),
26.52, 26.70, 27.66 (br), 38.19 (br), 63.25 (br), 68.90 (br), 84.11
(br), 124.80 (br), 125.23 (br), 125.47 (br), 127.25, 129.33, 133.99,
134.74, 135.69, 176.71. HRMS (EI, 80 eV, 150 °C): m/e calcd
for C30H36NO3Si ) M - CH3 486.24645, found 486.24689.
(21) Chelate-induced chirality transfer in the alkylation of potassium
amide enolates in the presence of HMPA has also been observed by
Evans (e.g., Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J . M.; Zahler,
R. J . Am. Chem. Soc. 1990, 112, 5290-5313). Potassium-induced Birch
reduction-alkylation sequences were reported by Schultz (e.g., Schultz,
A. G.; Wang, A. J . Am. Chem. Soc. 1999, 120, 8259-8260 and earlier
lit.)

Chiral Acetals as Stereoinductors
J . Org. Chem., Vol. 65, No. 20, 2000 6545
[R]25D: -128 °C (c ) 1.1, CHCl3). Anal. Calcd for C31H39NO3-
Si: C, 74.21; H, 7.89; N, 2.79. Found: C, 74.00; H, 8.13; N,
2.54.
(1′′S,2S,2′R)-1-[2′-(1′′-ter t-Bu tyld ip h en ylsiloxeth yl)-4′H-
ben zo[d][1′,3′]oxazin -1′-yl]-2-m eth ylh ept-6-en -1-on e (18d).
Preparative HPLC (diisopropyl ether/hexane 3:97) gave 18d
(120 mg, 21%) as a viscous colorless oil. 1H NMR: δ 0.71-1,39
(m, br, 3H), 1.00 (s, 12H), 1.23 (d, J ) 3 Hz, 3H), 1.50-1.97
(m, br, 3H), 2.97 (s, br), 3.80 (mc, 1H), 4.36 (mc, AB system,
low field part br, 2H), 4.83 (mc, br, 2H), 5.62 (s, br, 1H), 5.97
(s, br, 1H), 6.70-7.45 (m, 10H), 7.56 (mc, 2H), 7.65 (mc, 2H)).
13C NMR: δ 18.24, 19.22, 26.20 (-CH2-) (br), 26.84, 29.65
(-CH2-), 33.79 (-CH2-), 34.50 (br), 36.04 (q), 62.95 (-CH2-)
(br), 69.07 (br), 84.49 (br), 114.47 (-CH2-), 124.94 (br), 125.35,
127.34, 127.40, 129.39, 133.89 (q), 134.51 (q), 135.83, 176.72
(q) (br). HRMS (EI, 80 eV, 150 °C): m/e calcd for C30H34NO3Si
) M - C4H9 484.23080, found 484.23067. Anal. Calcd for
C34H43NO3Si: C, 75.37; H, 8.00; N, 2.59. Found: C, 75.11; H,
8.12; N, 2.87.
(1′′S,2R,2′S)-1-[2′-(1′′-ter t-Bu t yld ip h en ylsiloxyet h yl)-
4′H -b en zo[d ] [1′,3′]oxa zin -1′-yl]-2-m et h ylp en t a n -1-on e
(16c). Preparative HPLC (ethyl acetate/hexane 3:97) gave 16c
(380 mg, 70%) as a viscous colorless oil. 1H NMR: δ 0.61 (s,
br, 3H), 0.77-1.8 (m, 7H), 1.00 (s, 9H), 1.27 (d, J ) 3 Hz, 3H),
3.03 (mc, 1H), 3.85 (mc, 1H), 4.56 (mc, 2H), 6.09 (s, br, 1H),
6.83-7.68 (m, 14H). 13C NMR: δ 13.65 (br), 17.96 (br), 18.94,
19.33 (br), 20.10 (br), 26.67, 36.02 (br), 37.06 (br), 63. 48 (br),
69.10 (br), 83.99 (br), 125.34 (br), 127.23, 129.30, 133.99 (br),
135.68. HRMS (EI, 80 eV, 150 °C): m/e calcd for C31H38NO3Si
) M - CH3 500.26210, found 500.26283. [R]25D: -127° (c )
1.34, CHCl3). Anal. Calcd for C32H41NO3Si: C, 74.52; H, 8.01;
N, 2.72. Found: C, 74.34; H, 8.25; N, 2.54.
(2′R,4′′R)-[2′-(2′′-Dim eth yl-[1′′, 3′′]d ioxola n -4′′-yl)-4′H-
ben zo[d ][1′,3′]oxa zin -1′-yl]p r op a n -1-on e (22). 2-Aminoben-
zyl alcohol (6) (11 g, 89 mmol) in absolute THF (100 mL) was
treated with p-TsOH (425 mg, 2,23 mmol). Glyceraldehyde 21
obtained from diacetone d-mannitol (23 g) and NaIO4 (53 g)
in THF (40 mL) was added. The reaction was quenched after
15 min with aqueous saturated NaHCO3 (150 mL). Workup
with ether in the usual way, including column chromatography
(ethyl acetate/hexane 1:20), furnished the N,O-acetals (20′′)
as a 2:1 diastereomeric mixture (19.8 g, 65%). 1H NMR: δ 1.39
(s, 3 + 3H), 1.47 (s, 3Hmajor), 1.5 (s, 3Hminor), 3.99-4.18 (m, 3 +
3H), 4.32 (mc, 1Hminor), 4.43 (s, br, 1Hmajor), 4.53 (mc, 1Hmajor),
4.73 (mc, 1Hminor), 4.77-5.0 (2 AB systems, 4 + 4H): 6.69 (mc,
1 + 1H), 6.78 (mc, 1 + 1H), 6.89 (mc, 1 + 1H), 7.08 (mc, 1 +
1H). 13C NMR: δ 24.8, 25.0, 26.3, 26.7, 64.8, 66.3, 67.4, 67.5,
75.6, 83.1, 84.2, 109.8, 109.9, 116.3, 117.2, 119.2, 119.6, 121.2,
121.9, 124.7, 124.8, 127.4, 127.5, 141.2. MS (60 °C): m/e 235
([M]+).
(1′′S,2R,2′S)-1-[2′-(1′′-ter t-Bu t yld ip h en ylsiloxy-et h yl)-
4′H -b e n zo[d ][1′,3′]oxa zin -1′-yl]-2-m e t h ylh e p t -6-e n -1-
on e (16d ). Preparative HPLC (ethyl acetate/hexane 3:97) gave
1
16d (220 mg, 38%) as viscous colorless oil. H NMR: δ 0.77-
1.44 (m, 4H), 0.95 (s, 9H), 1.29 (d, J ) 3 Hz, 3H), 1.43-2.27
(m, br signals, 4H), 3.01 (s, br, 1H), 3.83 (mc, 1H), 4.51 (mc,
2H), 4.85 (mc, 2H), 5.71 (s, very br, 1H), 6.14 (s, br, 1H), 6.83-
7.80 (m, 14H). 13C NMR: δ 18.14 (br), 19.02 (q), 19.48 (br),
26.10 (-CH2-) (br), 26.75, 33.22 (-CH2-) (br), 34.35 (-CH2-)
(br), 36.03 (br), 63.45 (-CH2-) (br), 69.00 (br), 84.00 (br),
114.14 (-CH2-), 125.41 (br), 127.29, 129.37, 135.68, 135.76,
138.28, 176.83 (q) (br). HRMS (EI, 80 eV, 150 °C): m/e calcd
for C33H40NO3Si ) M - CH3 526.27775, found 526.27752).
[R]25D: -123.6° (c ) 0.6, CHCl3). Anal. Calcd for C34H43NO3-
Si: C, 75.37; H, 8.00; N, 2.59. Found: C, 75.43; H, 7.78; N
2.67.
(1′′S,2S,2′R)-1-[2′-(1′′-ter t-Bu t yld ip h en ylsiloxyet h yl)-
4′H -b e n zo[d ][1′,3′]oxa zin -1′-yl]-2-m e t h ylp e n t -4-e n -1-
on e (18a ). Preparative HPLC (diisopropyl ether/hexane 3:97)
The N,O-acetal mixture obtained above (200 mg, 0.85 mmol)
in dichloromethane (10 mL) at -20 °C was treated with
propionyl chloride (45 µL, 0.6 mol equiv) and NEt3 (12 µL).
After stirring for 15 min, additional propionyl chloride (45 µL,
0.6 mol equiv) and NEt3 (12µL) were added until a clear
solution was formed. The mixture was stirred at - 20 °C for
5 h, and NEt3 was added to dissolve any precipitate which was
formed. Ether (30 mL) was added and the mixture was treated
with saturated aqueous NaHCO3. The organic phase was
separated, dried (MgSO4), and chromatographed (ethyl acetate/
1
gave 18a (410 mg, 76%) as a viscous colorless oil. H NMR: δ
1.00 (s, 9H), 1.24 (d + d, 3 + 3H), 2.02 (s, br, 1H), 2.33 (s, br,
1H), 3.03 (s, br, 1H), 3.88 (mc, 1H), 4.23-4-53 (m, AB system,
low field part br, 2H), 4.88 (mc, br, 2H), 5.48 (s, br, 1H), 5.91
(s, br, 1H), 6.71-7,42 (m, 10H), 7.58 (mc, 2H), 7.67 (mc, 2H).
13C NMR: δ 19.12, 26.75, 29.54, 31.76, 36.36, 38.80, 62.97,
69.08, 84.71, 116.61, 124.86, 125.29, 127.24, 127.30, 129.29,
133.73, 134.36, 135.20, 135.68, 137.71, 175.74. HRMS (EI, 80
eV, 150 °C): m/e calcd for C28H30NO3Si ) M - C4H9 456.19949,
found 456.19950. Anal. Calcd for C32H39NO3Si: C, 74.81; H,
7.65; N, 2.73. Found: C, 75.43; H, 7.78; N, 2.67.
1
hexane 1:2) to give amide 22 (180 mg, 73%). H NMR: δ 1.15
(t, J ) 7 Hz, 3H), 1.26 (s, 3H), 1.44 (s, 3H), 2.45 (mc, 1H, br),
2.63 (mc, 1H), 3.95 (mc, 3H), 4.60 (mc, 2H), 5.98 (s, 1H, br),
7.15 (mc, 1H), 7.23 (mc, 1H), 7.35 (mc, 1H), 7.45 (s, 1H, br).
13C NMR: δ 9.1, 25.0, 26.3, 27.8, 63.6, 65.5, 74.8, 81.1 (br),
109.7, 124.9, 125.8, 125.8, 127.8, 135.4, (br), 173,3. HRMS (EI,
80 eV, 150 °C): m/e calcd for C16H21NO4 291.14706, found
291.14727. IR (cm-1) 1677 (ss). [R]20D: +92° (c ) 0.5, CHCl3).
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found:
C. 66.11; H, 7.12; N, 4.87.
(1′′S,2S,2′R)-1-[2′-(1′′-ter t-Bu t yld ip h en ylsiloxyet h yl)-
4′H-ben zo[d][1′,3′]oxazin -1′-yl]-2-m eth ylbu tan -1-on e (18b).
Preparative HPLC (diisopropyl ether/hexane 3:97) gave 18b
(320 mg, 60%) as a viscous colorless oil. 1H NMR: δ 0.71 (s,
3H), 1.03 (s, 12H), 1.21 (d, J ) 7.5 Hz, 3H), 1.32 (s, br, 1H),
1.64 (s, br, 1H), 2.89 (mc, br, 1H), 3.83 (mc, 1H, 4.36 (m, AB
system, low field part br, 1H), 5.95 (s, br, 1H), 6.74-7.47 (m,
10H), 7.59 (mc, 2H), 7.67 (mc, 2H). 13C NMR: δ 11.57, 17.86,
19.17, 26.81, 27.98, 29.59, 38.04, 62.86, 68.94 (br), 84.60 (br),
124.81 (br), 125.24 (br), 127.05 (br), 127.30, 127.36, 129.35,
133.82, 134.43, 135.77, 176.81. HRMS (EI, 80 eV, 150 °C): m/e
calcd for C27H30NO3Si ) M - C4H9 444.19950, found 444.19948.
Anal. Calcd for C31H39NO3Si: C, 74.21; H, 7.89; N, 2.79.
Found: C, 74.12; H, 8.01; N, 2.85.
(1′′S,2S,2′R)-1-[2′-(1′′-ter t-Bu t yld ip h en ylsiloxyet h yl)-
4′H-ben zo[d][1′,3′]oxazin -1′-yl]-2-m eth ylpen tan -1-on e (18c).
Preparative HPLC (diisopropyl ether/hexane 3:97) gave 18c
(300 mg, 55%) as a viscous colorless oil. 1H NMR: δ 0.65 (s,
br, 3H), 1.02 (s, 12H), 1.23 (d, J ) 7.5 Hz, 3H), 0.82-1.35 (m,
br, 3H), 1.71 (s, br, 1H), 2.98 (s, br, 1H), 3.83 (mc, 1H), 4.36
(mc, AB system, low field part br, 2H), 5.98 (s, br, 1H), 6.73-
7.48 (m, 10H), 7.58 (mc, 2H), 7.68 (mc, 2H). 13C NMR: δ 13.67,
18.14, 19.13, 20.15, 26.76, 35.91 (br), 37.22, 62.86 (br), 68.94
(br), 84.44 br, 124.81, 125.23, 127.02, 127.25, 133.77, 134.82,
En ola te Alk yla tion s of Am id e 22: KHDMS (1.03 g, 5.15
mmol) in THF (5 mL) was cooled to -78 °C under an argon
atmosphere and treated dropwise with a solution of 22 (5.0
mL, 0.687 M in THF). After 60 min allyl bromide (1.16 mL,
13.72 mmol) was added next and the mixture was stirred for
14 h without cooling. Phosphate buffer (pH 7) (5 mL) was
added, followed by ether (20 mL) and water (10 mL). The
organic layer was separated, washed with brine (10 mL), dried
(MgSO4), and chromatographed (ethyl acetate/hexane 1:2) to
give adduct 23a (911 mg, 81%) as a colorless crystals of mp
58 °C. The crude product was analyzed by HPLC (ethyl
acetate/hexane 15:85, Nucleosil 50-5) and showed a diaster-
eomeric purity of 98:2. The pure diastereomers were obtained
by preparative HPLC (ethyl acetate/hexane 10:90).
Similarly the alkylations of 22 with ethyl iodide (23b),
propyl iodide (23c), benzyl bromide (23d ), and pentyl bromide
(23e) were performed. Yields and diastereomeric ratios are
shown in Table 2.
135.72, 176.80. HRMS (EI, 80 eV, 150 °C): m/e calcd for C28H32
-
NO3Si ) M - C4H9 458.21515, found 458.21502. Anal. Calcd
for C32H41NO3Si: C, 74.52; H, 8.01; N, 2.72. Found: C, 74.61;
H, 7.73; N, 2.44.
(2S,2′R,4′′R)-[2′-(2′′-Dim eth yl-[1′′,3′′]d ioxola n -4′′-yl)-4′H-
ben zo[d][1′,3′]oxazin -1′-yl]-2-m eth ylpen t-4-en -1-on e (23a).
1H NMR: δ 1.30 (s, 3H), 1.35 (d, J ) 8 Hz, 3H), 1.48 (s, 3H),

6546 J . Org. Chem., Vol. 65, No. 20, 2000
Mulzer et al.
2.06 (s, 1H, br), 2.33 (s, 1H, br), 3.15 (mc, 1H), 3.95 (s, 3H,
br), 4.65 (mc, 2H, br), 4.94 (mc, 2H, br), 5.50 (s, 1H, br), 6.17
(s, 1H, br), 7.12-7.48 (m, 4H). 13C NMR: δ 17,5, 24.8, 26.0,
36.2, 38.2, 63.5, 65.0, 74.9 br, 80.1 br, 109.2, 116.4, 125.0,
125.8, 127.7, 133.0 (br), 134.9 (br), 135.6 (br), 175.3. MS (EI,
80 eV, 150 °C): m/z 331 [M]+). [R]20D: +177° (c ) 1.3, CHCl3).
Mp: 58 °C. Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N,
4.23. Found: C, 68.59; H, 7.45; N, 4.83.
(2S,2′R,4′′R)-[2′-(2′′-Dim et h yl-[1′′, 3′′]d ioxola n -4′′-yl)-
4′H-ben zo[d][1′,3′]oxazin -1′-yl]-2-m eth ylpr opan -1-on e (23b).
1H NMR: δ 0.78 (s, 3H, br), 1.23 (s, 3H), 1.30 (d, 3H), 1.33
(mc, 1H, br), 1.42 (s, 3H), 1.53 (mc, 1H, br), 2.92 (mc, 1H),
3.94 (s, br, 3H), 4.59 (mc, 2H, AB systems), 6.15 (s, 1H, br),
7.09-7,42 (m, 4H, br). 13C NMR: δ 11.4, 17.7, 25.0, 26.2, 27.5,
38.1, 63.7, 65.3, 75.0 (br), 80.2 (br), 109.3, 125.1 (br), 125.4
(br), 125.9 (br), 127.8, 132.7 (br), 135.8 (br), 176.5. HRMS (EI,
80 eV, 150 °C): m/e calcd for C18H25NO4 319.17836, found
319.17830. IR (cm-1): 1674 (ss). [R]20D: +79° (c ) 1,1, CHCl3).
Anal. Calcd for C18H25NO4: C, 67.68; H, 7.89; N, 4.39. Found:
C, 67.91; H, 7.65; N, 4.33.
(EI, 80 eV, 150 °C): m/e calcd for C21H31NO4 361.22531, found
361.22548. [R]20D: +167° (c ) 0.5, CHCl3). Anal. Calcd for
C21H31NO4: C, 69.77; H, 8.65; N, 3.87; Found: C, 70.02; H,
8.82; N, 3.73.
Rem ova l of th e Au xilia r y. Amide 16a (10.0 g, 19.5 mmol)
in ether (200 mL) at 0 °C was treated with solid lithium
aluminum hydride (4.43 g) in small portions and stirred
without cooling overnight. For workup the mixture was diluted
with moist ether, and water was added until all lithium
aluminum hydride was consumed. The organic layer was
separated, washed with brine, dried over MgSO4, and distilled
under normal pressure. The volatiles were redistilled under
normal pressure to furnish alcohol (R)-20 (1.83 g, 70%). The
nonvolatile residue was chromatographed to give aminal 20′
(4.81 g, 59%) as a 5:1 diastereomeric mixture.
(2R)-2-Meth ylp en ten -4-ol (R-20). 1H NMR: δ 0.91 (d, J
) 7 Hz,3H), 1.70 (mc, 1H), 1.89 (mc, 1H), 2.18 (mc, 1H), 3.17
(br, 1H), 3.47 (mc, 1 H), 5.01 (mc, 1H), 5.79 (mc, 1 H). [R]20
:
D
+2.40° (c ) 13, CHCl3), lit.13 [R]20D: +2.60 (c ) 1.5, CHCl3).
(1S,2′RS)-1-(2′,4′-Dih yd r o-1′H-ben zo[d ][1′,3′]oxa zin -2′-
yl)-ter t-bu tyld ip h en ylsiloxyeth a n ol (20′). 1H NMR: δ 1.16
(s,9 + 9H),1.24 (d + d, J ) 6 Hz, 3 + 3H), 4.11 (mc, 1H), 4.21
(mc,1 H), 4.43 (mc, 1 H), 4.48 (mc, 1H), 4.50 (mc, 1H), 4.67
(mc, 1H), 4.75-5.0 (m, d + d, 2 + 2 H), 6.51 (mc, 1H9, 6.71
(mc, 1H), 6.88 (mc, 1 + 1H), 6.92 (mc, 1 + 1 H), 7.11 (mc, 1 +
1H), 7.37-7.53 (m, 6 + 6H), 7.69-7.87 (m, 4 + 4H). 13C NMR:
δ 16.58, 19.21, 19.31, 19.55, 27.02, 27.39, 36.53, 69.98, 71.45,
85.07, 87.33, 115.84, 116.54, 118.52, 118.97, 121.19, 121.73,
124.65, 127.29, 127.37, 127.59, 127.64, 127.67, 129.75, 133.34,
133.68, 133.79, 135.71, 135.79, 135.89, 141.77, 142.21. Anal.
Calcd for C26 H31NO2Si: C, 74.78; H, 7.48; N, 3.35. Found: C,
74.26; H, 7.31; N, 3.35.
(2S,2′R,4′′R)-[2′-(2′′-Dim eth yl-[1′′,3′′]d ioxola n -4′′-yl)-4′H-
ben zo[d ][1′,3′]oxa zin -1′-yl]-2-m eth ylp en ta n -1-on e (23c).
1H NMR: δ 0.64 (s, 3H, br), 1.33-168 (m, 4H, br), 1.44 (mc,
6H), 1.42 (s, 3H), 3.03 (mc, 1H), 3.92 (s, 3H, br), 4.59 (mc, 2H,
AB systems), 6.15 (s, 1H, br), 7.08-7.42 (m, 4H, br). 13C
NMR: δ 13.4, 17.8, 19.9, 24.8, 26.0, 35.8, 36.5, 63.5, 65.1, 74.8
(br), 79.9 (br), 109.3, 125.2 (br), 125.7 (br), 127.7, 132.7 (br),
135.7 (br), 176.3. HRMS (EI, 80 eV, 150 °C): m/e calcd for
C
19H27NO4 333.19407, found 333.19417. IR (cm-1): 1674 (ss).
[R]20D: +120° (c ) 2, CHCl3). Anal. Calcd for C19H27NO4: C,
68.44; H, 8.16; N, 4.21. Found: C, 68.21; H, 7.95; N, 4.37.
(2S,2′R,4′′R)-[2′-(2′′-Dim eth yl-[1′′,3′′]d ioxola n -4′′-yl)-4′H-
ben zo[d ] [1′,3′]oxa zin -1′-yl]-2-m eth yl-3-p h en ylp r op a n -1-
1
on e (23d ). H NMR: δ 1.32 (s, 3H), 1.39 (d, 3H), 1.41 (s, 3H),
Ack n ow led gm en t. Financial support by the Deut-
sche Forschungsgemeinschaft is gratefully acknowl-
edged.
2.56 (mc, 1H, br), 2.80 (mc, 1H, br), 3.06 (mc, 1H, br), 3.27
(mc, 1H), 3.77 (mc, 2H), 3.94 (mc, 1H), 4.15 (mc, 1H, br), 5.86
(s, 1H, br), 6.8 (s, 2H, br), 7,0-7,36 (m, 7H). 13C NMR: δ 18.3,
25.0, 26.1, 38.9, 41.0, 63.2, 64.9, 75.3 (br), 80.4 (br), 109.3.
124,9, 125.1, 125.9, 126,0, 127.7, 128.0, 128.6, 134.5 (br), 135.5
(br), 139.1, 175.5. MS (EI, 80 eV, 150 °C): m/z 381 ([M]+).
[R]20D: +218° (c ) 1.7, CHCl3). Mp: 98-100 °C. Anal. Calcd
for C23H27NO4: C, 72.42; H, 7.13; N, 3.67. Found: C, 72.12;
H, 7.12; N, 3.43.
(2S,2′R,4′′R)-[2′-(2′′-Dim eth yl-[1′′,3′′]d ioxola n -4′′-yl)-4′H-
ben zo[d ][1′,3′]oxa zin -1′-yl]-2-m eth ylh ep ta n -1-on e (23e).
1H NMR: δ 0.77 (s, 3H, br), 0.88-1.36 (m, 7H, br), 1.24 (s,
3H), 1.27 (d, 3H), 1.42 (s, 3H), 1.58 (mc, 1H, br), 3.0 (mc, 1H),
3.92 (s, 3H, br), 4.59 (mc, AB systems, 2H), 6.15 (s, 1H, br),
7.09-7.42 (m, 4H, br). 13C NMR: δ 13.7, 17.9, 22.1, 24.9, 26.1,
26.5, 26.9, 31.2, 36.1, 63.6, 65.2, 75.0 (br), 80.1 (br), 109.4,
125.0, 125.3, 125.8, 127.8, 132.8 (br), 135.8 (br), 176.5. HRMS
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails on the preparation and characteristic analytical data of
compounds 7, 10, 11a -e, 12a -c, 13a -c. Drawings, tables of
crystal data, atomic coordinates, bond angles and bond lengths,
torsion angles, equivalent isotropic displacement parameters,
anisotropic thermal parameters, H-atom coordinates and
isotropic displacement coefficients for 11b, 11e, 16d . Drawing,
table of crystal data, positional parameters and their estinaled
standard deviations, general displacement parameters expres-
sions, bond distances, bond angles, torsion angles and least-
squares planes for 23d . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O000352O