Diastereoselective addition of allyl reagents to variously N-monoprotected and N,N-diprotected L-alaninals

Article abstract of DOI:10.1002/1522-2675(20001004)83:10<2705::AID-HLCA2705>3.0.CO;2-Y

Diastereoselective C₃-elongation processes of N-Boc-, N-Z-, N-Bn-N-Boc-, and N-Bn-N-Z-L-alaninals (Boc = 'BuOCO, Z = PhCH₂OCO, Bn = PhCH₂) using various allyl reagents, such as allyl bromide in the presence of Zn/aqueous N

Full text of DOI:10.1002/1522-2675(20001004)83:10<2705::AID-HLCA2705>3.0.CO;2-Y

Helvetica Chimica Acta ± Vol. 83 ꢀ2000)
2705
Diastereoselective Addition of Allyl Reagents to Variously
N-Monoprotected and N,N-Diprotected l-Alaninals
a
a b
by Dorota Gryko ) and Janusz Jurczak ) )*
a) Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warszawa, Poland
b
)
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warszawa, Poland
Diastereoselective C
3
-elongation processes of N-Boc-, N-Z-, N-Bn-N-Boc-, and N-Bn-N-Z-l-alaninals
OCO, Bn ˆ PhCH ) using various allyl reagents, such as allyl bromide in the
Cl solution, of SnCl ´ 2H O/NaI or of Mg/CuCl ´ 2H O, as well as allyltrichloro-
t
ꢀ
Boc ˆ BuOCO, Z ˆ PhCH
2
2
presence of Zn/aqueous NH
4
2
2
2
2
silane, are described. A substantially different influence of the N-protecting groups replacing either one or two
amino protons was observed, allowing the selective synthesis of either the syn- or anti-diastereoisomer as a
major product.
1. Introduction. ± Many natural products have been synthesized starting from chiral
a-aminocarbaldehydes [1]. The most straightforward and commonly encountered
process is the addition of various types of nucleophiles to these important building
blocks [1][2]. Among them, allylation of aldehydes to homoallylic alcohols is an
important synthetic pathway to aminodeoxysugars, which are components of naturally
occurring antibiotics [3]. Furthermore, the homoallylic adducts provide access to
hydroxyethylene peptide isosteres which could play a role as potent inhibitors of
proteolytic enzymes [4]. Among various types of additions, the Barbier-type reaction
has recently become very popular [5]. The use of aqueous media for the Barbier
reaction offers some considerable advantages: the direct use of H O-soluble
2
compounds without derivatization and the general avoidance of anhydrous solvents
allow for an easier and environmentally friendlier synthesis than experienced with
traditional methods. Asymmetric chain elongation of the a-aminocarbaldehyde group
can favor syn- or anti-diastereoselectivity depending on the effects of the protective
group at the a-amino functionality, allylation method, solvent, etc. So far, Giannis et al.
[
6] showed that the reaction of N-monoprotected serinals with allyl halides proceeds
smoothly to give the desired homoallylic alcohols in moderate yields as a mixture of
syn- and anti-diastereoisomers. The stereochemical course of the reaction in aqueous
medium is similar to that in organic solvents.
Recently, we reported on the diastereoselective C -elongation of N-tosyl- and N-
3
benzyl-N-tosyl-l-alaninal by means of various allyl reagents under different reaction
conditions [7]. A large difference of the influence of the N-protecting groups replacing
either one or two amino protons on all C - and C -elongation processes was observed.
3
4
In the case of the addition to N-tosyl-l-alaninal, we obtained a good syn-diastereo-
selectivity ꢀ3 :1) but a very poor yield ꢀonly 20%). With the diprotected N-benzyl-N-
tosyl-l-alaninal, the direction of asymmetric induction was reversed, which was
explained by substantial changes in the nature of the amino group, varying from

2
706
Helvetica Chimica Acta ± Vol. 83 ꢀ2000)
chelating to sterically demanding. In many cases, the tosyl protection is difficult to
remove when mild conditions are required. The reaction with the N,N-diprotected l-
alaninal afforded both a moderate diastereoselectivity and a moderate chemical yield.
Thus, we considered it very important and interesting, especially from the synthetic
point of view, to extend our studies to other types of variously N-protected a-
aminocarbaldehydes with the intention to improve the diastereoselectivity. For this
purpose, we decided to study the addition reactions of the two allyl reagents 2a and 2b
to the N,N-diprotected and N-monoprotected l-alaninals 1a ± d ꢀScheme 1).
Scheme 1
All l-alaninals 1a ± d were obtained from the respective a-amino alcohols using the
TEMPO ꢀ2,2,6,6-tetramethylpiperidin-1-yloxy radical) oxidation method [8]. In all
reactions shown in Scheme 1, syn/anti-mixtures of the diastereoisomeric products 3 and
4
, respectively, were obtained ꢀthroughout this paper, we use the syn/anti notation as
proposed by Masamune and co-workers [9]).
2
. Results and Discussion. ± 2.1. C -Elongation of the N,N-Diprotected l-Alaninals
3
1
a and 1b. We chose for these studies N-Bn-N-Boc and N-Bn-N-Z protections of the
t
amino group ꢀBn ˆ PhCH , Boc ˆ BuOCO, Z ˆ PhCH OCO). On addition of allyl
2
2
bromide 2a to the N,N-diprotected aldehydes 1a and 1b, a high ꢀTable, Entries 1, 2, 5,
and 7) or very high ꢀEntries 3 and 6) anti-diastereoselectivity was observed. Yields were
generally also very high, except in the case of the addition of 2a performed in the
presence of magnesium and copperꢀII) chloride hydrate [10] ꢀEntries 3 and 7).
Table. Addition of Various Allyl Reagents 2 to N-Mono- and N,N-Diprotected l-Alaninals 1a ± d
Entry Aldehyde Allyl reagent Modifying additives Solvent Temp. Time [h] Yield [%] Ratio syn/anti
1
2
3
4
5
6
7
8
9
1
1
1
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1d
1d
2a
2a
2a
2b
2a
2a
2a
2b
2a
2b
2a
2b
Zn/aq. NH
SnCl ´ 2H
4
Cl soln. THF
r.t.
r.t.
r.t.
08
r.t.
r.t.
r.t.
08
r.t.
08
r.t.
08
3.5
2.5
20
2
3
1
20
5
22
2
2453
2
99
82
11
29
99
90
30
72
65
90
3a/4a 20 : 80
3a/4a 16 : 84
3a/4a 5 : 95
3a/4a 5 : 95
3b/4b 10 : 90
3b/4b 5 : 95
3b/4b 10 : 90
3b/4b 5 : 95
3c/4c 37 : 63
3c/4c 75 : 25
3d/4d 40 : 60
3d/4d 75 : 25
2
2
O/NaI
´ 2H
THF
DMF
DMF
Mg/CuCl
±
2
2
O
Zn/aq. NH
SnCl ´ 2H
4
Cl soln. THF
2
2
O/NaI
DMF
THF
DMF
THF
DMF
THF
DMF
Mg/CuCl
±
Mg/CuCl
±
Mg/CuCl
±
2
2
2
´ 2H
´ 2H
´ 2H
2
2
2
O
O
O
0
1
2
87

Helvetica Chimica Acta ± Vol. 83 ꢀ2000)
2707
Addition of allyltrichlorosilane ꢀ2b) [11] to N,N-diprotected l-alaninals 1a and 1b gave
very interesting results, i.e., almost exclusively anti-adducts 4a and 4b were obtained
ꢀ
Entries 4 and 8). With N-Bn-N-Boc-l-alaninal 1a, the yield was very low. It seems
most likely that this aldehyde is not stable enough under the reaction conditions; we did
not isolate any unreacted 1a. Thus, the use of the Boc or Z instead of the tosyl
protection causes the improvement of the anti-diastereoselectivity from 77:23 to 95 :5
[
7]. In summary, we can obtain anti-adducts with very high diastereoselection and in
very good yield using allyltrichlorosilane ꢀ2b) or allyl bromide ꢀ2a) in the presence of
tinꢀII) chloride dihydrate.
2
.2. C -Elongation of N-Monoprotected a-Aminocarbaldehydes 1c and 1d. Simple
3
addition of allylmagnesium chloride or of allylzinc reagent to N-Boc- or N-Z-l-
alaninals 1c and 1d, respectively, resulted in a moderate yield and low syn-
diastereoselectivity, in agreement with literature data [12]. Thus, we turned our
attention to the Barbier-type reaction [13]. Addition of allyl bromide ꢀ2a) in the
presence of aqueous ammonium chloride [6][13] or of tinꢀII) chloride dihydrate and
sodium iodide [14] to aldehydes 1c and 1d led to better yields than in the case of
addition to the N-Ts-l-alaninal, but unfortunately, we did not observe any diaster-
eoselectivity. When we used magnesium in the presence of copperꢀII) chloride hydrate
[
1
ꢀ
10] instead of zinc or tinꢀII) chloride, addition of 2a to N-monoprotected l-alaninals
c and 1d gave mixtures of diastereoisomers with moderate anti-diastereoselectivity
Table, Entries 9 and 11). Aiming at finding a more selective allylation of N-
monoprotected l-alaninals 1c and 1d, we decided to try allyltrichlorosilane ꢀ2b) as
reagent. We observed the same level of diastereoselectivity ꢀ3 :1) as for the addition to
N-Ts-l-alaninal, but the yield was much better ꢀEntries 10 and 12). In summary, we can
selectively obtain either the syn- or the anti-diastereoisomer as a major product. With
allyl bromide ꢀ2a) in the presence of magnesium and copperꢀII) chloride hydrate as
an allylation reagent, pronounced anti-diastereoselectivity was observed, whereas in
the case of addition of allyltrichlorosilane ꢀ2b), syn-diastereoselectivity ꢀ3 :1) was
observed.
2
.3. Determination of the Diastereoisomer Ratio 3/4 ꢀsyn/anti). For the N,N-
diprotected products 3a and 3b as well as 4a and 4b, the determination of the syn/anti
ratio was based on the integration of the separated signals derived from one of the
diastereotopic protons at the double bond. The thus-established ratios were confirmed
by analytical HPLC ꢀLiChrospher-100-NH ). In the case of the N-monoprotected
2
diastereoisomeric adducts 3c and 3d as well as 4c and 4d, the syn/anti pairs were
unseparable by any chromatographic method. Determination of the syn/anti ratio was,
1
therefore, based on their H-NMR spectra, i.e., on the integration of the Me signals.
2
.4. Chemical Correlations. Having determined the extent of asymmetric induction,
we studied its direction by establishing the configuration of the products. In both cases
of N,N-diprotected and N-monoprotected adducts 3 and 4, we used the method of
chemical correlations as shown in Scheme 2, because the anti-configuration of adduct
4e and the syn-configuration of adduct 3f are known from X-ray studies [7]. The syn/
anti mixture of adducts 3a and 4a ꢀ1:9) was transformed into the mixture 3e/4e in which
the anti-N-Bn-N-Ts-adduct 4e was the major diastereoisomer, thus establishing that the
adduct 4a possesses anti-configuration. The same mixture 3a/4a ꢀ1:9) was then
transformed into the mixutre 3b/4b with preserved level of diastereoselectivity ꢀ1:9);

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708
Helvetica Chimica Acta ± Vol. 83 ꢀ2000)
hence, the adduct 4b has the anti-configuration. Similar correlations were carried out
for the N-monoprotected products 3c/4c as well as for 3d/4d ꢀScheme 2). Thus, on
addition of allyltrichlorosilane ꢀ2b) to the N-monoprotected aldehydes 1c and 1d, the
syn-diastereoisomer was formed as the major one.
Scheme 2
a) CF
3
COOH, CH
2
Cl
2
, r.t. b) TsCl, Et
3
N, CH
2
Cl
2
, 08 ! r.t. c) PhCH
2
OCOCl ꢀˆ ZCl), NaHCO
3
, AcOEt, 08.
2
.5. Stereochemical Course of the Additions. For all additions with N-monoprotected
l-alaninals, diastereoselectivity is independent of the protecting group used, but it
depends on the method applied. Direction of the asymmetric induction can be
explained by three transition states A, B, or C, as shown in the Fig.
Figure. Possible transition states for the nucleophilic addition

Helvetica Chimica Acta ± Vol. 83 ꢀ2000)
2709
Attack by allyl reagents occurs from the less-hindered side of the chelation-
controlled cyclic Cram [15] model A or B, formed as a consequence of the H-bonding
between NH and the carbonyl group, giving the syn-amino alcohols 3c and 3d. But in
the Felkin-Anh [16] model C, this attack leads to anti amino alcohols 4c and 4d. In
agreement with this commonly accepted stereochemical model, addition of allylmag-
nesium chloride to aldehydes 1c and 1d led to syn-adducts according to the cyclic
transition states A or B. But in the case of addition of allylzinc bromide or allyl bromide
in the presence of magnesium and copperꢀII) chloride hydrate, the Felkin-Anh model
C should operate because we observed anti-diastereoselection. In the case of the N-
monoprotected a-aminocarbaldehydes 1c and 1d, addition of the allyl reagents led to
syn-adducts, according to the cyclic transition state formed as a consequence of the H-
bonding between NH and the carbonyl group or to the similar chelation-controlled
cyclic Cram model B. In the case of the addition to N,N-diprotected l-alaninals 1a and
1b, leading preferentially to anti-adducts 4a and 4b, the Felkin-Anh model should
operate.
3
. Conclusion. ± Along with previous results from this laboratory concerning the
influence of N-mono- and N,N-diprotection on the stereochemical course of cyclo-
addition, the present results establish the rationale for planning diastereoselective
syntheses that involve C -elongation processes. The results obtained appear to yield key
3
information for further studies on asymmetric syntheses involving a-aminocarbalde-
hydes and for a better knowledge of the rules governing the stereochemical course of
organometal addition to chiral a-aminocarbaldehydes.
Financial support from the National Committee for Scientific Research ꢀKBN Grant N8 3 T09A 048 11) is
gratefully acknowledged.
Experimental Part
General. Flash column chromatography ꢀFC): silica gel 60 ꢀMerck, 200 ± 400 mesh). M.p.: Kofler hot-stage
apparatus; uncorrected. Optical rotations: JASCO-DIP-360 polarimeter with a thermally jacketed 10-cm cell.
IR Spectra: Perkin-Elmer-1640-FTIR spectrophotometer NMR Spectra: Bruker-AM-500 spectrometer at 500
1
13
ꢀ
H) or 125 MHz ꢀ C); chemical shifts d in ppm rel. to SiMe
4
ꢀˆ0.00 ppm), and coupling constants J in Hz. Mass
spectra: AMD-604-Intectra instrument using the electron-impact ꢀEI) technique; m/z ꢀrel. %).
Addition of Allyl Reagents 2 to Protected a-Aminocarbaldehydes 1. Method A: Addition of Allyl Bromide
ꢀ
2a) in the Presence of Zn/NH
suspension of Zn powder ꢀ2 equiv.), the a-aminocarbaldehyde ꢀ1 mmol), sat. aq. NH
10 ml). After stirring at r.t. for several hours ꢀTLC monitoring), the mixture was extracted with Et
0 ml), the combined extract dried ꢀMgSO ) and evaporated, and the residue worked up as described in [7].
MethodB: Addition of Allyl Bromide ꢀ2a) in the Presence of SnCl ´ 2H O/NaI. To a stirred soln. of the a-
aminocarbaldehyde ꢀ1 mmol) and allyl bromide ꢀ2a; 1.5 mmol) in DMF ꢀ10 ml), SnCl ´ 2H O ꢀ1.5 mmol) was
added, followed by NaI ꢀ1.5 mmol). After stirring for several hours ꢀTLC monitoring), a sat. aq. NH F soln.
10 ml) and Et O ꢀ10 ml) were added. The aq. layer was separated and re-extracted with Et
O ꢀ2 Â 10 ml) and
4
Cl. Allyl bromide ꢀ2a; 2 mmol) was added dropwise at r.t. to the stirred
Cl soln. ꢀ0.5 ml), and THF
O ꢀ2 Â
4
ꢀ
1
2
4
2
2
2
2
4
ꢀ
2
2
the combined extract worked up as described in MethodA .
Method C: Addition of Allyl Bromide ꢀ2a) in the Presence of Mg/CuCl
.5 mmol) was added dropwise at r.t. under Ar to a stirred suspension of Mg powder ꢀ2.5 equiv.), CuCl
2
´ 2H
2
O. Allyl bromide ꢀ2a;
´ 2H
2.5 mmol), the a-aminocarbaldehyde ꢀ1 mmol), and THF ꢀ5 ml). The mixture was stirred for several hours
TLC monitoring). Then it was quenched with 1n HCl and extracted with Et
O ꢀ3 Â 10 ml). The combined
2
ꢀ
ꢀ
2
2
O
2
extracts were worked up as described in MethodA .
Method D: Addition of Allyltrichlorosilane ꢀ2b). A soln. of the a-aminocarbaldehyde ꢀ1 mmol) and
allyltrichlorosilane ꢀ2b; 1.2 mmol) in DMF ꢀ6 ml) was stirred at 08 for several hours ꢀTLC monitoring). Then it

2
710
Helvetica Chimica Acta ± Vol. 83 ꢀ2000)
was quenched with sat. aq. NH
were worked up as described in MethodA .
4
Cl soln. ꢀ10 ml) and extracted with Et
2
O ꢀ3 Â 10 ml). The combined extracts
;
2S,3S)- and;2 S,3R)-2-{Benzyl[;tert-butoxy)carbonyl]amino}hex-5-en-3-ol ꢀ3a and 4a, resp.; 3a/4a 1:4).
1
IR ꢀfilm): 3440, 2977, 2933, 1689, 1667, 1453, 1409, 1366, 1248, 1167, 1015, 913, 701. H-NMR ꢀꢀD
8
)toluene, 908):
);
Ar); 3.80
m, 0.8 H, CHN); 3.70 ꢀm, 0.2 H, CHN); 3.59 ꢀm, 0.2 H, CHOH); 3.52 ꢀddt, J ˆ 6.9, 4.2, 6.9, 0.8 H, CHOH); 2.20
7
5
ꢀ
ꢀ
.3 ± 7.0 ꢀ m, 5 arom. H); 5.88 ꢀddt, J ˆ 16.9, 10.5, 6.9, 0.2 H, CHCH
2
); 5.69 ꢀddt, J ˆ 17.1, 10.3, 6.9, 0.8 H, CHCH
2
.02 ꢀm, 0.2 H, CHCH ); 5.0 ± 4.9 ꢀm, 0.8 H, CHCH ); 4.45 ꢀm, 0.2 H, CH
2
2
2
Ar); 4.4 ± 4.2 ꢀm, 1.8 H, CH
2
t
t
m, 0.2 H, CH
2
ꢀAll)); 2.1 ± 2.0 ꢀm, 1.8 H, CH
2
ꢀAll)); 1.38 ꢀs, 7.2 H, Bu); 1.37 ꢀs, 1.8 H, Bu); 1.18 ꢀd, J ˆ 7.0, 2.4H,
)toluene, 908): 156.9; 156.5; 140.5; 140.2; 135.9; 135.8; 128.7;
28.6; 128.0; 127.9; 127.3; 127.2; 117.0; 116.9; 80.1; 80.0; 74.4; 74.0; 65.9; 58.8; 58.5; 51.6; 51.1; 40.2; 39.9; 28.6;
1
3
Me); 1.06 ꢀd, J ˆ 7.0, 0.6 H, Me). C-NMR ꢀꢀD
8
1
2
3
‡
8.5; 15.8; 15.5. EI-MS: 305 ꢀ0.3, M ), 234ꢀ29), 208 ꢀ 4) , 178 ꢀ92), 134ꢀ82), 91 ꢀ100), 57 ꢀ 47 ). HR-EI-MS:
05.21008 ꢀC18
‡
‡
H
27NO
3
, M , calc. 305.1991). Anal. calc. for C18
H
27NO
3
ꢀ305.2): C 70.8, H 8.9, N 4.6; found:
C 70.6, H 8.9, N 4.6.
;
2S,3S)- and;2 S,3R)-2-{Benzyl[;benzyloxy)carbonyl]amino}hex-5-en-3-ol ꢀ3b and 4b, resp.; 3b/4b 1:4).
1
IR ꢀfilm): 3443, 2977, 1692, 1678, 1453, 1415, 1330, 1244, 1211, 1027, 915, 733, 698. H-NMR ꢀꢀD
8
)toluene, 908):
7
.2 ± 7.0 ꢀ m, 10 arom. H.); 5.9 ± 5.8 ꢀm, 0.2 H, CHCH
each, OCH Ar); 4.99 ꢀm, 0.4H, CHC H ); 5.0 ± 4.9 ꢀm, 1.6 H, CHCH
H, CH Ar); 3.81 ꢀbr. s, 1 H, CHN); 3.62 ꢀbr. s, 1 H, CHOH); 2.2 ± 2.1 ꢀm, 0.2 H, CH
CH
2
); 5.7 ± 5.6 ꢀm, 0.8 H, CHCH
); 4.50 ꢀm, 0.2 H, CH
ꢀAll)); 2.1 ± 2.0 ꢀm, 1.8 H,
)toluene, 908): 157.5; 157.1;
39.9; 139.6; 137.7; 137.6; 135.8; 135.7; 135.6; 128.7; 128.6; 128.5; 128.4; 128.4; 128.3; 127.5; 127.4; 117.1; 74.2;
2
); 5.09, 5.06 ꢀAB, J ˆ 12.4, 1 H
2
2
2
2
Ar); 4.4 ± 4.3 ꢀm, 1.8
2
2
1
3
2
ꢀAll)); 1.18 ꢀd, J ˆ 7.0, 2.4H, Me); 1.05 ꢀ d, J ˆ 7.0, 0.6 H, Me). C-NMR ꢀꢀD
8
1
7
3
‡
‡
3.8; 67.7; 65.9; 58.8; 51.2; 51.0; 40.1; 39.7; 15.9; 15.5. LSI-MS: 362 ꢀ[M ‡ Na ]), 340 ꢀ[M ‡ H ]). HR-LSI-MS:
‡
‡
40.1915. ꢀC21
H
26NO
3
, [M ‡ H ]; calc. 340.1913). Anal. calc. for C21
3
H25NO ꢀ339.2): C 74.3, H 7.4, N 4.2; found:
C 74.3, H 7.6, N 4.2.
;
2S,3S)- and;2 S,3R)-2-{[;tert-Butoxy)carbonyl]amino}hex-5-en-3-ol ꢀ3c and 4c, resp.; 3c/4c 1 :1).
H-NMR ꢀꢀD )toluene, 908): 5.8 ± 5.7 ꢀm, 1 H, CHCH ); 4.96 ꢀm, 2 H, CHCH ); 4.77 ꢀbr. s, 1 H, NH); 3.7 ±
.6 ꢀm, 1 H, CHN); 3.50 ꢀddd, J ˆ 6.5, 6.5, 3.7, 0.5 H, CHOH); 3.31 ꢀddd, J ˆ 7.7, 5.1, 3.4, 0.5 H, CHOH); 2.44 ꢀbr.
1
8
2
2
3
t
t
2 2
s, 1 H, OH); 2.2 ± 2.1 ꢀm; 1 H, CH ꢀAll)); 2.1 ± 2.0 ꢀm, 1 H, CH ꢀAll)); 1.39 ꢀs, 4.5 H, Bu); 1.38 ꢀs, 4.5 H, Bu);
1
1
.03 ꢀd, J ˆ 6.8, 1.5 H, Me); 0.96 ꢀd, J ˆ 6.8, 1.5, Me). 13C-NMR ꢀꢀD
8
)toluene, 908): 156.3; 156.0; 135.6; 135.5;
17.3; 117.2; 79.1; 79.0; 74.3; 74.0; 51.0; 50.5; 39.5; 39.0; 28.7; 28.6; 18.5; 14.6. EI-MS: 215 ꢀ0.7, M ), 144 ꢀ34), 142
‡
‡
‡
ꢀ18), 118 ꢀ100), 100 ꢀ4), 88 ꢀ66), 81 ꢀ8), 74 ꢀ12). HR-EI-MS: 215.1524 ꢀC11H21NO , M ; calc. 215.1521). Anal.
3
3
calc. for C11H21NO ꢀ215.15): C 61.7, H 9.9, N 6.5; found: C 61.6, H 10.0, N 6.5.
;
2S,3S)- and;2 S,3R)-2-{[;Benzyloxy)carbonyl]amino}hex-5-en-3-ol ꢀ3d and 4d, resp.; 3d/4d 3 :1). IR
1
ꢀ
KBr): 3315, 1686, 1542, 1323, 1289, 1267, 1038, 919, 731, 697. H-NMR ꢀꢀD
H); 5.7 ± 5.6 ꢀm, 1 H, CHCH
H, NH); 3.65 ꢀm, 1 H, CHN); 3.42 ꢀm, 1 H, CHOH); 2.0 ± 1.9 ꢀm, 2 H, CH
8
)toluene, 908): 7.3 ± 7.0 ꢀm, 5 arom.
); 4.93 ꢀm, 1 H, CHCH ); 4.68 ꢀbr. s,
2
ꢀAll)); 1.67 ꢀbr. s, 1 H, OH); 0.99 ꢀd,
2
); 5.04ꢀ s, 2 H, OCH
2
Ar); 4.97 ꢀm, 1 H, CHCH
2
2
1
1
3
J ˆ 6.7, 0.1 H, Me); 0.92 ꢀd, J ˆ 6.7, 2.9 H, Me). C-NMR ꢀꢀD
8
)toluene, 908): 156.2; 137.8; 135.3; 129.3; 128.7;
‡
1
ꢀ
28.5; 128.2; 117.4; 73.6; 66.8; 51.3; 38.9; 14.5. EI-MS: 249 ꢀ0.2, M ), 208 ꢀ1.8), 178 ꢀ10), 134ꢀ16), 91 ꢀ100), 88
‡
‡
27). HR-EI-MS: 249.1363 ꢀC14
N 5.6; found: C 67.4, H 7.5, N 5.7.
General Procedures for Chemical Correlations. Removal of the Boc protecting group: To a stirred soln. of
the N-Boc-protected or N-Bn-N-Boc-diprotected adduct ꢀ1 mmol) in CH Cl ꢀ5 ml), CF COOH ꢀ5 mmol) was
added dropwise at r.t. Stirring was continued at r.t. until the disappearance of the substrate was noted ꢀTLC).
Then the mixture was diluted with sat. NaHCO soln. ꢀ10 ml) and extracted with CH Cl
), and evaporated. The crude product was
H19NO , M ; calc. 249.1365). Anal. calc. for C14H19NO ꢀ249.15): C 67.4, H 7.7,
3
3
2
2
3
3
2
2
ꢀ3 Â 5 ml). The
combined extracts were washed with brine ꢀ10 ml), dried ꢀMgSO
used for further treatment.
4
Introduction of the tosyl [17] or ꢀbenzyloxy)carbonyl [18] protecting group was carried out according to the
known literature procedures.
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ReceivedMarch 24, 2000