Stereoselective synthesis of 3-hydroxyproline benzyl esters from N-protected β-aminoaldehydes and benzyl diazoacetate

Article abstract of DOI:10.1021/jo030360f

The synthesis of a series of 3-hydroxyproline benzyl esters from α-alkyl and α-alkoxy N-protected aminoaldehydes with benzyl diazoacetate is described. Aldehydes with α-alkyl substituents afforded prolines as a single diastereomer with a trans-cis relativ

Full text of DOI:10.1021/jo030360f

Ster eoselective Syn th esis of 3-Hyd r oxyp r olin e Ben zyl Ester s fr om
N-P r otected â-Am in oa ld eh yd es a n d Ben zyl Dia zoa ceta te
Steven R. Angle* and Dominique S. Belanger
Department of Chemistry, University of California-Riverside, Riverside, California 92521-0403
steven.angle@ucr.edu
Received November 21, 2003
The synthesis of a series of 3-hydroxyproline benzyl esters from R-alkyl and R-alkoxy N-protected
aminoaldehydes with benzyl diazoacetate is described. Aldehydes with R-alkyl substituents afforded
prolines as a single diastereomer with a trans-cis relative configuration in 14-77%. An R-tert-
butyldimethylsilyloxy aminoaldehyde afforded a proline as a single diastereomer with a trans-
trans relative configuration in 37% yield.
Prolines are common structural elements found in
natural products with important biological activity that
have been targets of syntheses.1,2 A variety of methods
for the stereoselective synthesis of substituted prolines
have been reported.2-6 Despite these previous synthetic
efforts, there is still a need for a new, efficient, stereo-
selective route to these compounds.
drofuran methodology could be adapted for the synthesis
of substituted proline benzyl esters (2b, Scheme 1).
Our working hypothesis for the mechanism of the THF
synthesis, and presumably what would also be the
mechanism for the proline synthesis, is one in which the
diazoester acts as a nucleophile10 toward the aldehyde
to afford intermediate 4 or participates in a 1,3-dipolar
cycloaddition11 to afford 5 (Scheme 1). Both 4 and 5 could
then afford either the cyclized heterocycle 2 (pathway a)
or â-ketoester 3 (pathway b).
For the proline synthesis to be effective, the protecting
group on nitrogen must be selected, such that nitrogen
is still a viable nucleophile in the presence of a Lewis
acid to effect closure of the proline ring. N-Protected
â-amino aldehydes were easily prepared using known
methods including imino,12 benzylamino,13 dibenzylami-
no,13 amide, carbamate, and sulfonamide, and several
different amine protecting groups were also screened. We
report here the successful extension of our methodology
to the synthesis
We have previously reported a novel method for the
stereoselective synthesis of tetrahydrofurans 2a from
silyloxy aldehydes 1a and benzyl diazoacetate.7-9 Given
the importance of prolines, we hoped that our tetrahy-
* To whom correspondence should be addressed. Fax: (909) 787-
4713.
(1) For current examples and leading references to the synthesis of
substituted biologically active proline natural products, see: (a) Stapon,
A.; Li, R.; Townsend, C. A. J . Am. Chem. Soc. 2003, 125, 8486-8493.
(b) Makino, K.; Kondoh, A.; Hamada, Y. Tetrahedron Lett. 2002, 43,
4695-4698. (c) Decicco, C. P.; Grover, P. J . Org. Chem. 1996, 61, 3534-
3541. (d) Nakao, Y.; Maki, T.; Matsunaga, S.; van Soest, R. W. M.;
Fusetani, N. Tetrahedron 2000, 56, 8977-8987. (e) Wipf, P.; Methot,
J .-L. Org. Lett. 2000, 2, 4213-4216. (f) Trost, B. M.; Rudd, M. T. Org.
Lett. 2003, 5, 1467-1470.
(2) For the synthesis of a substituted, nonnatural biologically active
proline, see: Hanessian, S.; Bayrakdarian, M.; Luo, X. H. J . Am. Chem.
Soc. 2002, 124, 4716-4721.
(3) For current examples and leading references to the synthesis of
substituted prolines using nucleophilic displacement or addition reac-
tions, see: (a) Flamant-Robin, C.; Wang, Q.; Chiaroni, A.; Sasaki, N.
A. Tetrahedron 2002, 58, 10475-10484. (b) Pellegrini, N.; Schmitt, M.;
Guery, S.; Bourguignon, J .-J . Tetrahedron Lett. 2002, 43, 3243-3246.
(c) Taylor, C. M.; Barker, W. D.; Weir, C. A.; Park, J . H. J . Org. Chem.
2002, 67, 4466-4474. (d) Qiu, X.; Qing, F. J . Chem. Soc., Perkin Trans.
(5) For current examples and leading references to the synthesis of
substituted prolines using amino-zinc-enolate carbometalation reac-
tions, see: (a) Karoyan, P.; Quancard, J .; Vaissermann, J .; Chassaing,
G. J . Org. Chem. 2003, 68, 2256-2265. (b) Karoyan, P.; Chassaing,
G. Tetrahedron Lett. 2002, 43, 1221-1223. (c) Karoyan, P.; Chassaing,
G. Tetrahedron Lett. 2002, 43, 253-255. For current examples and
leading references to the synthesis of substituted prolines using Rh-
catalysts, see: (d) Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002,
4, 1599-1602. (e) Li, G.-Y.; Chen, J .; Yu, W.-Y. Hong, W.; Che, C.-M.
Org. Lett. 2003, 5, 2153-2156.
(6) For a current example and leading references to the synthesis
of substituted prolines using radical cyclizations, see: Agami, C.;
Comesse, S.; Guesne, S.; Kadouri-Puchot, C.; Martinon, L. Synlett 2003,
7, 1058-1060.
(7) Angle, S. R.; Bernier, D. S.; ElSaid, N. A.; J ones, D. E.; Shaw, S.
Z. Tetrahedron Lett. 1998, 39, 3919-3922.
(8) Angle, S. R.; Wei, G. P.; Ko, Y. K.; Kubo, K. J . Am. Chem. Soc.
1995, 117, 8041-8042.
(9) Angle, S. R.; Bernier, D. S.; Chann, K.; J ones, D. E.; Kim, M.;
Neitzel, M. L.; White, S. L. Tetrahedron Lett. 1998, 39, 8195-8198.
(10) Lo´pez-Herrera, F. J .; Valpuesta-Ferna´ndez, M.; Garc´ıa-Claros,
S. Tetrahedron 1990, 46, 7165-7174.
(11) Zhu, Z.; Espenson, J . H. J . Org. Chem. 1995, 60, 7090-7091.
(12) Angle, S. R.; Kubo, K. Unpublished results from our laborato-
ries.
1
2002, 2052-2057. (e) J acobsen, M. F.; Turks, M.; Hazell, R.;
Skrydstrup, T. J . Org. Chem. 2002, 67, 2411-2417. (f) Lee, J . H.; Kang,
J . E.; Yang, M. S.; Kang, K. Y.; Park, K. H. Tetrahedron 2001, 57,
10071-10076. (g) Knight, D. W.; Redfern, A. L.; Gilmore, J . J . Chem.
Soc., Perkin Trans. 1 2001, 2874-2883. (h) Wang, Q.; Dau, M.-E. T.
H.; Sasaki, N. A.; Potier, P. Tetrahedron 2001, 57, 6455-6462. (i)
Khalaf, J . K.; Datta, A. J . Org. Chem. 2004, 69, 387-390.
(4) For current examples and leading references to the synthesis of
substituted prolines using [3 + 2] cycloadditions, see: (a) Gothelf, A.
S.; Gothelf, K. V.; Hazell, R. G.; J orgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 4236-4238. (b) Gu, Y. G.; Xu, Y.; Krueger, A. C.;
Madigan, D.; Sham, H. L. Tetrahedron Lett. 2002, 43, 955-957. (c)
Merino, I.; Laxmi, S.; Florez, J .; Barluenga, J .; Ezquerra, J .; Pedregal,
C. J . Org. Chem. 2002, 67, 648-655. (d) Chinchilla, R.; Falvello, L.
R.; Galindo, N.; Najeria, C. Eur. J . Org. Chem. 2001, 3133-3140. (e)
Casas, J .; Grigg, R.; Najera, C.; Sansano, J . M. Eur. J . Org. Chem.
2002, 1971-1982.
(13) Shaw, S. Z. Ph.D. Dissertation, University of California,
Riverside, 2001.
10.1021/jo030360f CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/20/2004
J . Org. Chem. 2004, 69, 4361-4368
4361

Angle and Belanger
Evans’ procedure)19 was protected as the sulfonamide and
tert-butyldimethylsilyl ether. The resulting alkene un-
derwent ozonolysis to give R-silyloxy aldehyde 15 in 43%
yield (3 steps). It should be noted that aldehyde 15
decomposed rapidly and was therefore used immediately
without purification.
SCHEME 1. P r op osed P r olin e An n u la tion
Rea ction
Syn th esis of P r olin e Ben zyl Ester s. Aldehyde 12a
was reacted with benzyl diazoacetate to give proline 16
(Table 1, entries 1 and 2). When 1.1 equiv of benzyl
diazoacetate was used, proline 16 was isolated in 64%
(Table 1, entry 1). When 3 equiv of benzyl diazoacetate
was used, proline 16 was isolated in 77% yield (Table 1,
entry 2). In both cases, proline 16 was formed as a single
diastereomer, and the corresponding â-ketoester was not
detected in either case. Reaction of aldehyde 13 (P ) Cbz)
with benzyl diazoacetate failed to afford any proline
product (Table 1, entry 3). All subsequent studies used
a tosyl protecting group on nitrogen.
Aldehyde 12b was reacted with 3 equiv of benzyl
diazoacetate to give proline 17 in 54% yield (Table 1,
entry 4). When the amount of benzyl diazoacetate was
decreased to 1.1 equiv (Table 1, entry 5) the reaction
afforded proline 17 and what appeared to be â-keto ester
18 (1H NMR analysis) as an inseparable 1:1 mixture in
12% yield.
of 3-hydroxyprolines 2b from â-(N-tosyl)amino aldehydes
1b (P ) SO2C6H6p-CH3, Scheme 1).
Resu lts a n d Discu ssion
Reaction of R-silyloxy aldehyde 15 with benzyl diazo-
acetate (3.0 equiv) gave proline ester 19 in 37% yield
(Table 1, entry 6). The yield may be lower as a result of
the rapid decomposition of unstable aldehyde 15, which
was made and used immediately. No â-keto ester was
isolated.
When aldehyde 12c was reacted with benzyl diazoace-
tate (3.0 equiv), proline 20 was formed in 56% yield as
an inseparable 2:1 mixture (1H NMR) of proline 20 and
a compound tentatively assigned as â-keto ester 21 (Table
1, entry 7). HPLC purification afforded an analytical
sample of 20 for characterization; however, â-keto ester
21 could not be isolated.
Aldehyde 12d was reacted with benzyl diazoacetate
(3.0 equiv) to afford proline 22 and â-keto ester 23 in 71%
as a 1:4 mixture (Table 1, entry 8). Unlike proline 20,
proline 22 was readily purified by flash chromatography
(3:1 hexanes/ethyl acetate) to afford 22 in 14% isolated
yield. Homogeneous â-keto ester 23 could not be isolated.
When aldehyde 12e was reacted with benzyl diazoace-
tate (3.0 equiv) no proline was isolated, and only â-keto
ester was observed (1H NMR analysis). In the case of the
R,R-dihydrogen aldehyde used in the THF synthesis with
benzyl diazoacetate7 and diazosulfones,20 the same ob-
servation was made: the R,R-dihydrogen aldehyde gave
the lowest yield of product.
Syn th esis of R-Alk yl Am in oa ld eh yd es. Several N-
protected aminoaldehydes were synthesized to study the
scope and limitations of the proline synthesis. Scheme 2
shows the synthesis of aminoaldehydes 12a -e. Diols
6a -c were monoprotected with TES-Cl and treated with
MsCl14 to give mesylates 7a -c (Scheme 2). Crude me-
sylates 7a -c were heated with NaN3 to give azides 8a -
c.14 The TES protecting group was partially removed in
the case of the isopropyl and methyl substrates (7b and
7c) to afford a mixture of silyloxy azides (8b,c) and
compounds tentatively identified (1H NMR) as azido-
alcohols (9b,c). These compounds were separated by flash
chromatography. Azides 8a -c were reduced with LiAlH4
to give amino alcohols 10a -c. Amino alcohols 10a -e15
were protected with TsCl using modified Schotten-
Baumann reaction conditions16 to give tosylamides 11a -
e, which were then oxidized with Dess-Martin periodi-
nane (DMP)17 to give aldehydes 12a -e. Aldehyde 13 was
prepared from amino alcohol 10b as shown in Scheme 3.
Syn th esis of R-Silyloxy Ald eh yd e 15. The synthesis
of R-silyloxy aldehyde 15 was nontrivial. Several different
approaches were investigated, all of which involved the
oxidation of an alcohol to an aldehyde as the final step.
During these studies it became apparent that aldehyde
15 is unstable and decomposes rapidly.18 Therefore, we
devised a new route that did not require the oxidation of
an alcohol or purification after the final step (Scheme 4).
Amino alcohol 14 (prepared from crotonaldehyde using
Ster eoch em istr y of P r olin es. X-ray quality crystals
of proline 17 were obtained by recrystallization from
hexanes/ethyl acetate. The X-ray21 clearly shows that
proline 17 possesses a trans orientation between the ester
and the hydroxyl group and a cis orientation between the
hydroxyl and the isopropyl substituent. It should be noted
that proline 17 has the same trans-cis relative configu-
(14) Banfi, L.; Guanti, G.; Riva, R. Tetrahedron: Asymmetry 1999,
10, 3571-3592.
(15) Amino alcohol 10d is commercially available from Lancaster,
Windham, NH. Amino alcohol 10e is commercially available from
Aldrich, Milwaukee, WI.
(16) Maurer, P. J .; Knudsen, C. G.; Palkowitz, A. D.; Rapaport, H.
J . J . Org. Chem. 1985, 50, 325-332.
(17) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 43, 4155-4156.
(18) Belanger, D. S. Ph.D. Dissertation, University of California,
Riverside, 2002.
(19) Evans, D. A.; Carroll, G. L.; Truesdale, L. J . Org. Chem. 1974,
39, 914-917.
(20) Angle, S. R.; Shaw, S. Z. Tetrahedron 2001, 57, 5227-5232.
(21) See Supporting Information for the ORTEP diagram of proline
17.
4362 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of 3-(Hydroxy)proline Benzyl Esters
SCHEME 2. Syn th esis of Am in oa ld eh yd es 12a -e
SCHEME 3. Syn th esis of Ca r ba m a te 13
In conclusion, we have found the reaction of â-amido
aldehydes with benzyl diazoacetate affords proline benzyl
esters in fair to good yields. The mechanism of the
reaction and the origin of the stereoselectivity are cur-
rently under investigation.
Exp er im en ta l Section
SCHEME 4. Syn th esis of r-Silyloxy Ald eh yd e 15
Gen er a l In for m a tion . All HPLCs were done on a high-
performance silica Si 83-121-c column (21.4 × 250 mm). Unless
otherwise stated, the following parameters were used: flow
rate ) 9.9 mL/min; the appropriate mixture of hexanes/ethyl
acetate was used. In all cases, solvents were removed in vacuo.
Meth a n esu lfon ic Acid 2-P h en ylm eth yl-3-(tr ieth ylsil-
yloxy)p r op yl Ester (7a ). To a solution of known diol 6a 14
(2.30 g, 13.8 mmol) and Et3N (2.12 mL, 15.2 mmol) in CH2Cl2
(55 mL) at 0 °C was added TES-Cl (2.31 mL, 13.8 mmol)
dropwise. The ice bath was removed, and the reaction mixture
was stirred for 2 h. The reaction mixture was diluted with
water (25 mL). The organic layer was washed with a saturated
aqueous solution of NH4Cl, a saturated aqueous solution of
NaHCO3, and brine, dried (MgSO4), and concentrated. Flash
chromatography (9:1 hexanes/ethyl acetate) gave the known9
silyl ether (3.23 g, 83%) as a clear, colorless oil.
Using the procedure of Banfi and co-workers,14 a solution
of the above silyl ether (2.00 g, 7.13 mmol) in CH2Cl2 (17.8
mL) at -30 °C was treated with Et3N (1.29 mL, 9.27 mmol),
followed by MsCl (0.66 mL, 8.6 mmol). The reaction mixture
was stirred for 5 h, and then saturated aqueous NH4Cl (10
mL) was added. The aqueous layer was extracted with ethyl
acetate (3 × 15 mL). The combined organic layers were washed
with a saturated aqueous solution of CuSO4 (15 mL) and brine,
dried (MgSO4), and concentrated to give the mesylate 7a (2.57
g, 100%). The product was used without further purification:
1H NMR (300 MHz, CDCl3) δ 7.32-7.17 (m, 5H), 4.22 (m, 2H),
3.64 (dd, J ) 10.3, 4.6 Hz, 1H), 3.56 (dd, J ) 10.3 6.2 Hz, 1H),
2.97 (s, 3H), 2.69 (m, 2H), 2.18 (m, 1H), 0.95 (t, J ) 8.0 Hz,
9H), 0.59 (q, J ) 8.0 Hz, 6H); 13C (75 MHz, CDCl3) δ 138.9,
129.0, 128.5, 126.4, 69.5, 61.1, 42.8, 36.9, 33.7, 6.8, 4.3.
Meth a n esu lfon ic Acid 3-Meth yl-2[(tr ieth ylsilyloxy)-
m eth yl]bu tyl Ester (7b). The procedure given previously for
the preparation of 7a was carried out using known diol 6b24,25
(1.40 g, 11.8 mmol), Et3N (1.83 mL, 13.0 mmol) in CH2Cl2 (59
mL), and TES-Cl (1.99 mL, 11.8 mmol). Flash chromatogra-
phy (9:1 hexanes/ethyl acetate) gave the known9 silyl ether
ration as that of the 4-alkyl-substituted THFs synthe-
sized in our laboratory.7-9
X-ray quality crystals of proline 19 were obtained by
recrystallization from hexanes/ethyl acetate. The X-ray22
clearly shows that proline 19 possesses a trans orienta-
tion between the ester and hydroxyl substituents. The
hydroxyl group and the silyl ether are also in a trans
orientation to each other. Here, too, it is interesting to
note that proline 19 has the same trans-trans relative
configuration as the 4-alkoxy-substituted tetrahydro-
furans synthesized in our laboratory.23
The stereochemistry of prolines 16 and 20 was as-
signed by correlation of the H3-H4 coupling constant to
that of proline 17 (J H3-H4 was determined to be 3.6 Hz;
Table 2, entry 1). The J H3-H4 coupling constant for
prolines 16 and 20 was 3.8 and 4.2 Hz, respectively
(Table 2, entries 2 and 3); thus the relative stereochem-
istry was assigned as also being the same as 17 with the
substituents arranged with a cis-trans orientation about
the ring. In proline 19 the substituents are arranged with
a cis-trans orientation around the ring, and J H3-H4 was
determined to be 0 Hz.
The relative orientation of the ester and hydroxyl
substituents was assigned to be trans, the same as for
our tetrahydrofuran work, on the basis of the X-ray
structures of 17 and 19 and the consistency of and J H2-H3
to each other and to the tetrahydrofurans with similar
substitution.7,8
(22) See Supporting Information for the ORTEP diagram of proline
19.
(24) Neitzel, M. L. Ph.D. Dissertation, University of California,
Riverside, 2000.
(23) Bernier, D. S. Ph.D. Dissertation, University of California,
Riverside, 2001.
(25) Ohta, H.; Tetsukawa, H.; Noto, N. J . Org. Chem. 1982, 47,
2400-2404.
J . Org. Chem, Vol. 69, No. 13, 2004 4363

Angle and Belanger
TABLE 1. Syn th esis of N-P r otected Su bstitu ted P r olin es
a
b
The only product detected by 1H NMR was proline. Ratio of proline to â-keto ester. c Yield is for proline and â-keto ester product
mixture. Proline 22 was isolated in 14% yield. e Only â-keto ester was isolated.
d
1H), 1.64 (m, 1H), 0.95 (s, 15H), 0.59 (q, J ) 7.7 Hz, 6H); 13C
(75 MHz, CDCl3) δ 68.8, 60.0, 46.7, 36.9, 26.0, 20.1, 6.8, 4.3;
IR (neat) 2958, 2912, 2877, 1466, 1415, 1352, 1239, 1175, 842
cm-1.
TABLE 2. Ster eoch em istr y of P r olin es
Meth a n esu lfon ic Acid (2-Meth yl-3-tr ieth ylsilyloxy)-
p r op yl Ester (7c). The procedure given previously for the
preparation of 7a was carried out using commercially available
2-methyl-1,3-propanediol 6c26 (5.00 mL, 56.3 mmol) in CH2-
Cl2 (225 mL), Et3N (8.63 mL, 62.0 mmol), and TES-Cl (9.45
mL, 56.3 mmol). Flash chromatography (9:1 hexanes/ethyl
acetate) gave the known silyl ether (8.74 g, 76%) as a clear,
colorless oil: 1H NMR (CDCl3, 300 MHz) δ 3.74 (dd, J ) 9.8,
4.5 Hz, 1H), 3.61 (dd, J ) 10.6, 3.5 Hz, 2H), 3.54 (dd, J ) 9.8,
8.2 Hz, 1H), 2.95 (br s, 1H), 1.96 (m, 1H), 0.96 (t, J ) 7.84 Hz,
9H), 0.83 (d, J ) 6.9 Hz, 3H), 0.61 (q, J ) 7.9 Hz, 6H); IR
(neat) 3355, 2957, 2940, 2909, 2876, 2735, 1458, 1415, 1239,
1088, 1039, 1016 cm-1. The above silyl ether (4.88 g, 23.9
mmol) gave mesylate 7c (6.71 g, 100%), which was used
without further purification in the next reaction: 1H NMR (300
MHz, CDCl3) δ 4.24 (dd, J ) 5.9, 9.5 Hz, 1H,), 4.16 (dd, J )
proline
R
J H3-H4 (Hz)
1
2
3
4
17
16
20
19
iPr
Bn
Me
OTBS
3.6
3.8
4.2
0
(2.37 g, 86%). The above silyl ether (2.00 g, 8.60 mmol) in CH2-
Cl2 (22 mL), Et3N (1.56 mL, 11.2 mmol), and MsCl (0.80 mL,
7.0 mmol) gave mesylate 7b (2.76 g, quantitative) as a clear,
colorless oil. The product was used without further purifica-
tion: 1H NMR (300 MHz, CDCl3) δ 4.36 (dd, J ) 9.5, 4.9 Hz,
1H), 4.30 (dd, J ) 10.0, 6.7 Hz, 1H), 3.73 (dd, J ) 10.3, 4.6
Hz, 1H), 3.58 (dd, J ) 10.3, 7.2 Hz, 1H), 2.99 (s, 3H), 1.80 (m,
(26) Commercially Available from Aldrich, Milwaukee, WI.
4364 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of 3-(Hydroxy)proline Benzyl Esters
5.7, 9.2 Hz, 1H), 3.60 (dd, J ) 4.9, 10.0, 1H), 3.50 (dd, J ) 6.7,
10.3 Hz, 1H), 3.00 (s, 3H), 2.05 (m, 1H), 0.98 (d, J ) 6.7 Hz,
3H), 0.95 (t, J ) 8.4 Hz, 9H), 0.59 (q, J ) 8.4 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 71.8, 63.5, 37.0, 35.8, 13.2, 6.7, 4.3;
sequentially. The resulting suspension was stirred overnight,
filtered, and concentrated to give amino alcohol 10a 14 (133 mg,
99%) as a clear, colorless oil. The product was used without
further purification: 1H NMR (300 MHz, CDCl3) δ 7.30-7.15
(m, 5H), 3.80 (dd, J ) 11.3, 3.1 Hz, 1H), 3.64 (dd, J ) 10.8,
8.2 Hz, 1H), 3.07 (broad m, 3H), 2.79 (dd, J ) 11.8, 9.2 Hz,
1H), 2.58 (dd, J ) 7.2, 13.9 Hz, 1H), 2.48 (dd, J ) 7.2, 13.9
Hz, 1H), 2.03 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 139.7,
128.9, 128.4, 126.2, 67.6, 46.0, 42.3, 35.9; IR (CCl4) 3295, 3260,
IR (neat) 2957, 2877, 1467, 1357, 1178, 1098 cm-1
.
[(3-Azido-2-ph en ylm eth yl)pr opyloxy]tr ieth ylsilan e (8a).
To a solution of mesylate 7a (1.00 g, 2.77 mmol) in DMF (11.1
mL) was added sodium azide (541 mg, 8.32 mmol). The
reaction was heated at 50 °C for 24 h. Water (20 mL) was
added, and the aqueous layer was extracted with ether (3 ×
10 mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated. Flash chromatography (9:1
to 7:3 pet. ether/diethyl ether) gave the silyloxy azide 8a (707
mg, 83%) as a clear, colorless oil: 1H NMR (300 MHz, CDCl3)
δ 7.28 (m, 2H), 7.19 (m, 3H), 3.59 (dd, J ) 10.0, 4.9 Hz, 1H),
3.52 (dd, J ) 10.3, 6.2 Hz, 1H) 3.38 (dd, J ) 11.8, 5.1 Hz, 1H),
3.39 (dd, J ) 11.8, 6.2 Hz, 1H), 2.69 (dd, J ) 13.3, 7.2 Hz,
1H), 2.59 (dd, J ) 13.3, 7.4 Hz, 1H), 1.99 (m, 1H), 0.96 (t, J )
7.9 Hz, 9H), 0.50 (q, J ) 7.9 Hz, 6H); 13C (75 MHz, CDCl3) δ
139.6, 129.1, 128.4, 126.1, 62.1, 51.7, 43.1, 34.8, 6.8, 4.3; IR
(neat) 2956, 2911, 2876, 2099, 1239, 742 cm-1; MS (CI/NH3)
m/ z 306 (3, MH+), 278 (6), 146 (3), 132 (100); HRMS (CI/NH3)
m/z calcd for C16H28N3OSi 306.2002, found 306.1999.
3000, 2923, 1453, 1031, 760 cm-1
.
2-Am in om eth yl-3-m eth ylbu ta n -1-ol (10b). To a solution
of LiAlH4 (92.0 mg, 24.1 mmol) in ether (35 mL) was added
silyloxy azide 8b in ether (12 mL) at 0 °C. The reaction mixture
was stirred for 4 h, and then water (0.92 mL), a solution of
15% aqueous NaOH (0.92 mL), and water (2.76 mL) were
sequentially added. The resulting suspension was stirred
overnight. The reaction mixture was filtered, and the filter
cake was washed with ether (100 mL) and concentrated to give
amino alcohol 10b (1.05 g, 97%) as a clear, colorless oil. The
product was used without purification: 1H NMR (300 MHz,
CDCl3) δ 4.74 (s, 2H), 3.80 (ddd, J ) 1.5, 3.6, 10.8 Hz, 1H),
3.73 (dd, J ) 10.3, 8.2 Hz, 1H), 3.08 (apparent dt, J ) 1.5,
12.3 Hz, 1H), 2.81 (dd, J ) 12.3, 9.2 Hz, 1H), 2.68-1.80 (broad
s, 1H), 1.65 (m, 1H), 1.42 (m, 1H), 0.90 (d, J ) 1.0 Hz, 3H),
0.87 (d, J ) 1.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 66.7,
47.0, 44.9, 27.5, 20.1, 20.0.
3-Am in o-2-(m et h yl)p r op a n -1-ol (10c). The procedure
given previously for the preparation of 10a was carried out
using LiAlH4 (861 mg, 22.7 mmol) in ether (44 mL), azide 10c
(2.01 g, 8.72 mmol) in ether (10 mL), NaF (3.81 g, 90.7 mmol),
water (1.23 mL, 68.0 mmol), and Na2SO4‚10H2O (2.00 g) to
give amino alcohol 10c (704 mg, 91%) as a clear, yellow oil:
1H NMR (300 MHz, CDCl3) δ 4.84 (br s, 1H), 3.67 (ddd, J )
1.5, 4.1, 10.8 Hz, 1H), 3.55 (dd, J ) 8.2, 10.8 Hz, 1H), 2.95
(dd, J ) 4.1, 12.3 Hz, 1H), 2.66 (dd, J ) 8.7, 12.3 Hz, 1H),
1.79 (m, 1H), 0.81 (d, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 69.6, 48.4, 36.5, 14.6.
[(2-Azid om eth yl-3-m eth yl)bu t-1-oxy]-tr ieth ylsilyla n e
(8b) a n d 2-Azid om eth yl-3-m eth ylbu ta n -1-ol (9b). The
procedure previously given for the preparation of 8a was
carried out using mesylate 8b (5.10 g, 16.4 mmol), DMF (66
mL), and sodium azide (3.20 mg, 49.3 mmol). Flash chroma-
tography (pet. ether, then 9:1 pet. ether/diethyl ether) gave
silyloxy azide 8b (3.33 mg, 79%) as a clear, colorless oil: 1H
NMR (300 MHz, CDCl3) δ 3.68 (dd, J ) 10.0, 4.0 Hz, 1H), 3.56
(dd, J ) 10.0, 6.7 Hz, 1H), 3.41 (m, 2H), 1.78 (sextet, J ) 6.7
Hz, 1H), 1.48 (m, 1H), 0.98 (m, 15H), 0.60 (q, J ) 7.7 Hz, 6H);
13C (75 MHz, CDCl3) δ 61.0, 50.6, 46.9, 26.6, 20.1, 20.0, 6.8,
4.3; IR (neat) 2959, 2912, 2877, 1459, 1414, 1389, 1369, 1104,
1016, 817, 777, 743, 675 cm -1; MS (CI/NH3) m/ z 258 (MH+,
75), 230 (100), 200 (36), 170 (10), 132 (47); HRMS (CI/NH3)
m/z calcd for C12H28N3OSi (MH+) 258.2002, found 258.1995.
In some cases the TES group was removed during the reaction
to give alcohol 9b as a clear, colorless oil: 1H NMR (300 MHz,
CDCl3) δ 3.73 (dd, J ) 4.4, 11.0 Hz, 1H), 3.63 (dd, J ) 6.9,
11.0 Hz, 1H), 3.53 (dd, J ) 5.1, 12.3 Hz, 1H), 3.41 (dd, J )
7.2, 12.3 Hz, 1H), 1.78 (m, 2H,), 1.53 (m, 1H), 0.93 (d, J ) 6.7
Hz, 6H); 13C (75 MHz, CDCl3) δ 62.1, 51.3, 46.5, 26.8, 19.9,
N-[(3-Hyd r oxy-2-p h en ylm eth yl)p r op yl]-4-m eth ylben z-
en esu lfon a m id e (11a ). To a solution of amino alcohol 10a
(250 mg, 1.51 mmol) in water (2.25 mL) was added Na2CO3
(481 mg, 4.54 mmol). The mixture was stirred until all Na2-
CO3 dissolved, and then TsCl (433 mg, 4.54 mmol) was added.
The reaction mixture was stirred for 6.5 h and then diluted
with water (10 mL) and ethyl acetate (10 mL). The aqueous
layer was extracted with ethyl acetate (3 × 4 mL). The
combined organic layers were washed with brine, dried (K2-
CO3), and concentrated. Flash chromatography (1:3 hexanes/
ethyl acetate) gave amide 11a (428 mg, 89%) as a white solid:
19.9; IR (neat) 3356, 2962, 2876, 2099, 1466, 1370, 1269 cm-1
;
MS (CI/NH3) m/ z 144 (MH+, 5), 116 (100), 98 (12); HRMS (CI/
NH3) m/z calcd for C6H14N3O (MH+) 144.1137, found 144.1139.
[(3-Azid o-2-m eth yl)p r op yloxy]tr ieth ylsila n e (8c) a n d
3-Azid o-2-m eth yl-p r op a n -1-ol (9c). The procedure given
previously for the preparation of 8a was carried out using
mesylate 7c (10.0 g, 35.4 mmol), DMF (71 mL), and sodium
azide (6.90 g, 106 mmol). Flash chromatography (50:1 to 3:1
hexanes/ethyl acetate) gave silyloxy azide 8c (1.96 g, 24%) and
alcohol 9c (2.01 g, 49%) as clear, colorless oils. [(3-Azid o-2-
m eth yl)p r op yloxy)tr ieth ylsila n e (8c): 1H NMR (300 MHz,
CDCl3) δ 3.54 (dd, J ) 5.1, 10.3 Hz, 1H), 3.46 (dd, J ) 6.7,
10.3 Hz, 1H), 3.37 (dd, J ) 5.9, 12.0 Hz, 1H), 3.22 (dd, J )
6.7, 11.8 Hz, 1H), 1.88 (m, 1H), 0.96 (t, J ) 7.7 Hz, 9H), 0.94
(d, J ) 7.2 Hz, 3H), 0.60 (q, J ) 8.0 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 66.7, 54.3, 36.2, 14.5, 6.7, 4.3; IR (neat) 2955,
2912, 2878, 2099, 1458, 1281, 1240 cm-1; MS (CI/NH3) m/z 230
(MH+, 63), 202 (100), 132 (89); HRMS (CI/NH3) m/z calcd for
1
mp 92-94 °C; H NMR (300 MHz, CDCl3) δ 7.70 (d, J ) 8.2
Hz, 2H), 7.30 _ 7.19 (m, 5H), 7.09 (d, J ) 6.7 Hz, 2H), 3.73
(dd, J ) 11.0, 3.9 Hz, 1H), 3.56 (dd, J ) 10.8, 6.7 Hz, 1H),
3.06 (dd, J ) 4.4, 13.1 Hz, 1H), 2.95 (dd, J ) 6.9, 13.1 Hz,
1H), 2.56 (m, 2H), 2.43 (s, 3H), 1.97 (m, 1H), 1.70 (broad s,
2H); 13C NMR (75 MHz, CDCl3) δ 143.4, 139.2, 136.9, 129.7,
128.9, 128.6, 127.0, 126.3, 63.6, 44.6, 42.1, 35.1, 21.5; IR (neat)
3566 1616, 1623, 1419 cm-1; MS (CI/NH3) m/z 320 (MH+, 100),
260 (7), 184 (3), 166 (12), 155 (4), 118 (5), 91 (12); HRMS (CI/
NH3) m/z calcd for C17H22NO3S (MH+) 320.1320, found 320.1307.
N-[(3-H yd r oxy-2-m et h ylet h yl)p r op yl]-4-m et h ylb en z-
en esu lfon a m id e (11b). The procedure given previously for
the preparation of 11a was carried out using amino alcohol
11b (1.56 g, 13.3 mmol) in water (22 mL), Na2CO3 (4.23 g, 39.9
mmol), and TsCl (3.81 g, 20.0 mmol). Flash chromatography
(1:1 hexanes/ethyl acetate) gave amide 11b (1.55 g, 43%) as a
clear, colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J )
8.2 Hz, 2H), 7.30 (d, J ) 8.2 Hz, 2H), 5.45 (t, J ) 6.2 Hz, 1H),
3.76 (dt, J ) 10.8, 3.9 Hz, 1H), 3.61 (m, 1H), 3.09 (ddd, J )
3.9, 6.9, 12.6 Hz, 1H), 2.95 (ddd, J ) 5.4, 7.7, 12.8 Hz, 1H),
2.42 (s, 3H), 2.22 (t, J ) 4.4 Hz, 1H), 1.66 (m, 1H), 1.42 (m,
1H), 0.85 (d, J ) 5.1 Hz, 3H), 0.83 (d, J ) 5.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 143.3, 136.8, 129.7, 127.0, 63.4, 45.9,
43.8, 27.0, 21.5, 20.0; IR (neat) 3523, 3323, 2881, 1599, 1495,
C
10H24N3OSi (MH+) 230.1689, found 230.1681. 3-Azid o-2-
m eth yl-p r op a n -1-ol (9c): 1H NMR (300 MHz, CDCl3) δ 3.57
(m, 2H), 3.34 (m, 2H), 1.93 (m, 1H), 1.66 (br s, 1H), 0.97 (d, J
) 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 65.4, 54.6, 35.8,
14.4.
3-Am in o-2-(p h en ylm eth yl)p r op a n -1-ol (10a ).14 To a so-
lution of LiAlH4 (93.0 mg, 2.45 mmol) in ether (2.0 mL) at 0
°C was added silyl ether 8a (250 mg 0.818 mmol) in ether (2.0
mL). The reaction mixture was stirred 3 h, and then NaF (412
mg, 9.80 mmol) and water (0.135 mL, 7.35 mmol) were added
J . Org. Chem, Vol. 69, No. 13, 2004 4365

Angle and Belanger
1469, 1336, 1184, 1153 cm-1; MS (CI/NH3) m/z 289 (MNH4
,
and concentrated. Flash chromatography (4:1 to 3:1 hexanes/
ethyl acetate) gave aldehyde 12b (752 mg, 49%) as a clear,
colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.69 (s, 1H), 7.74
(d, J ) 8.2 Hz, 2H), 7.32 (d, J ) 8.7 Hz, 2H), 4.87 (t, J ) 6.0
Hz, 1H), 3.10 (m, 2H), 2.48 (m, 1H), 2.40 (s, 3H), 2.14 (m, 1H),
1.02 (d, J ) 6.7 Hz, 3H), 0.96 (d, J ) 6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 204.7, 143.5, 136.9, 129.8, 127.0, 57.6, 39.5,
+
7), 272 (MH+, 100), 189 (2), 118 (10), 98 (40); HRMS (CI/NH3)
m/z calcd for C13H22NO3S (MH+) 272.1320, found 272.1318.
N -[(3-H yd r oxy-2-m e t h yl)p r op yl]-4-m e t h ylb e n ze n e -
su lfon a m id e (11c). The procedure given previously for the
preparation of 11a was carried out using 10c (300 mg, 3.36
mmol) in water (6 mL), Na2CO3 (1.07 g, 10.1 mmol), and TsCl
(962 mg, 5.05 mmol). Flash chromatography (1:1 hexanes/ethyl
acetate) gave amide 11c (420 mg, 51%) as a clear, colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J ) 8.2 Hz, 2H),
7.31 (d, J ) 8.2 Hz, 2H), 5.09 (broad s, 1H), 3.67 (m, 1H), 3.47
(m, 1H), 3.02 (m, 1H), 2.88 (m, 1H), 2.43 (s, 3H), 1.85 (m, 1H),
1.61 (broad s, 1H), 0.86 (d, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 143.4, 136.9, 129.7, 127.0, 66.1, 46.8, 35.2, 21.5, 14.3;
IR (neat) 3530, 3286, 2930, 2926, 2880, 1598, 1455, 1326, 1159
cm-1; MS (CI/NH3) m/z 261 (MNH4+, 17), 244 (MH+, 100), 226
(5); HRMS (CI/NH3) m/z calcd for C11H18NO3S (MH+) 244.1007,
found 244.1005.
N-[(2,2-Dim eth yl-3-h yd r oxy)p r op yl]-4-m eth ylben zen e-
su lfon a m id e (11d ). The procedure given previously for the
preparation of 11a was carried out using commercially avail-
able amino alcohol 10d 15 (110 mg, 1.07 mmol) in water (1.6
mL), Na2CO3 (509 mg, 4.80 mmol), and TsCl (305 mg, 1.60
mmol). Flash chromatography (1:1 hexanes/ethyl acetate) gave
amide 11d (127 mg, 47%) as a white solid: mp 101-105 °C;
1H NMR (300 MHz, CDCl3) δ 7.74 (d, J ) 8.2 Hz, 2H), 7.31 (d,
J ) 8.2 Hz, 2H), 5.15 (t, J ) 6.0 Hz, 1H), 3.40 (s, 2H), 2.77 (d,
J ) 6.2 Hz, 2H), 2.42 (s, 3H), 2.15-1.85 (broad s, 1H), 0.85 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 143.4, 136.9, 129.7, 127.0,
69.3, 50.5, 36.0, 22.2, 21.5; IR (neat) 3488, 3159, 2964, 1596,
1456, 1327, 1154 cm-1; MS (CI/NH3) m/z 258 (MH+, 100), 223
(4), 104 (11), 91 (2); HRMS (CI/NH3) m/z calcd for C12H20NO3S
(MH+) 258.1164, found 258.1161.
N-[(3-H yd r oxy)p r op yl]-4-m et h ylb en zen esu fon a m id e
(11e). The procedure given previously for the preparation of
11a was carried out using commercially available 3-amino
propanol 10e15 (0.305 mL, 3.99 mmol) in water (6.0 mL), Na2-
CO3 (1.27 g, 12.0 mmol), and TsCl (1.14 g, 5.99 mmol). Flash
chromatography (1:1 hexanes/ethyl acetate) gave amide 11e
(776 mg, 84%) as a clear, colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.74 (d, J ) 8.2 Hz, 2H), 7.30 (d, J ) 8.2 Hz, 2H),
5.24 (broad s, 1H), 3.71 (t, J ) 5.6 Hz, 2H), 3.10 (q, J ) 5.9,
11.8 Hz, 2H), 2.42 (s, 3H), 2.17 (broad s, 1H), 1.69 (pentuplet,
J ) 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 143.4, 136.8,
129.7, 127.0, 60.5, 40.9, 31.4, 21.5; IR (neat) 3495, 3293, 2946,
2880, 1598, 1495, 1327, 1159 cm-1; MS (CI/NH3) m/z 230 (MH+,
27.2, 21.5, 20.1, 19.7; IR (neat) 3526, 3290, 2964, 1714, 1598,
1464, 1334, 1154, 1092 cm-1; MS (CI/NH3) m/z 287 (MNH4
,
+
33), 270 (MH+, 90), 189 (100), 155 (18), 124 (14), 108 (46), 91
(40); HRMS (CI/NH3) m/z calcd for C13H20NO3S (MH+) 270.1164,
found 270.1174.
N-(2-Meth yl-3-(4-m eth yl)p h en ylsu lfon yla m id o-p r op a -
n a l (12c). The procedure given previously for the preparation
of 12a was carried out using 11c (200 mg, 0.822 mmol) in CH2-
Cl2 (4.1 mL) and DMP17 (523 mg, 1.23 mmol) to give aldehyde
12c (135 mg, 68%) as a clear, colorless oil: 1H NMR (300 MHz,
CDCl3) δ 9.60 (s, 1H), 7.74 (d, J ) 8.2 Hz, 2H), 7.32 (d, J )
2H), 4.92 (broad t, J ) 6.0 Hz, 1H), 3.08 (dt, J ) 2.9, 6.3 Hz,
2H), 2.66 (m, 1H), 2.43 (s, 2H), 1.60 (broad s, 1H), 1.17 (d, J )
7.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.6, 143.5, 136.7,
129.8, 127.0, 46.3, 43.2, 21.5, 11.4; IR (neat) 3529, 3290, 3266,
2968, 2924, 1715, 1598, 1455, 1327, 1160, 1093 cm-1; MS (CI/
NH3) m/z 259 (MNH4+, 100), 242 (MH+, 91), 229 (4), 189 (25),
108 (26), 91 (17); HRMS (CI/NH3) m/z calcd for C11H16NO3S
(MH+) 242.0851, found 242.0848.
N-(2,2-Dim eth yl-3-(4-m eth yl)ph en ylsu lfon ylam ido-pr o-
p a n a l (12d ). The procedure given previously for the prepara-
tion of 12a was carried out using amide 11d (95.0 mg, 0.369
mmol) in CH2Cl2 (1.8 mL) and DMP17 (235 mg, 0.554 mmol).
Flash chromatography (3:2 hexanes/ethyl acetate) gave alde-
hyde 12d (56 mg, 60%) as a white solid: mp 68-71 °C; 1H NMR
(300 MHz, CDCl3) δ 9.35 (s, 1H), 7.73 (d, J ) 8.2 Hz, 2H),
7.32 (d, J ) 7.7 Hz, 2H), 4.90 (t, J ) 5.9 Hz, 1H), 2.94 (d, J )
6.7 Hz, 2H), 2.43 (s, 3H), 1.12 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 205.0, 143.5, 136.9, 129.8, 127.0, 48.3, 46.7, 21.5, 19.8;
IR (neat) 3551, 3288, 1723, 1329, 1160, 1094 cm-1; MS (CI/
NH3) m/z 273 (MNH4+, 43), 256 (MH+, 100), 226 (11), 184 (29),
155 (13), 118 (24), 91 (11); HRMS (CI/NH3) m/z calcd for C12H18
-
NO3S (MH+) 256.1007, found 256.1012.
N-3-(4-Meth yl)ph en ylsu lfon ylam ido-pr opan al (12e). The
procedure given previously for the preparation of 12a was
carried out using amide 11e (400 mg, 1.74 mmol) in CH2Cl2
(9 mL) and DMP17 (1.11 g, 2.61 mmol). Flash chromatography
(1:1 hexanes/ethyl acetate) gave aldehyde 12e (310 mg, 78%)
as a clear, colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.74 (s,
1H), 7.74 (d, J ) 8.2 Hz, 2H), 7.32 (d, J ) 8.2 Hz, 2H), 4.89
(broad s, 1H), 3.21 (dd, J ) 5.6, 12.3 Hz, 2H), 2.75 (t, J ) 5.9
Hz, 2H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.8, 143.6,
100), 155 (3), 76 (12); HRMS (CI/NH3) m/z calcd for C10H16
-
NO3S (MH+) 230.0851, found 230.0846.
N-(2-P h en ylm eth yl)-3-(4-m eth yl)ph en ylsu lfon yla m ido-
p r op a n a l (12a ). To a solution of amide 11a (420 mg, 1.31
mmol) in CH2Cl2 (6.6 mL) at 0 °C was added Dess-Martin
periodinane17 (836 mg, 1.97 mmol). The reaction mixture was
stirred for 5 h and then filtered through SiO2. The filter cake
was washed (ethyl acetate) and concentrated. Flash chroma-
tography (1:1 hexanes/ethyl acetate) gave aldehyde 12a (341
136.7, 129.8, 127.0, 43.6, 36.8, 21.5; IR (neat) 3283, 2927, 2877,
1721, 1598, 1327, 1158 cm-1; MS (CI/NH3) m/z 245 (MNH4
,
+
57), 228 (MH+, 100), 184 (13), 155 (12), 91 (13); HRMS (CI/
NH3) m/z calcd for C10H14NO3S (MH+) 228.0694, found 228.0697.
[(2-For m yl-3-m eth yl)bu tyl]car bam ic Acid P h en ylm eth -
yl Ester (13). To a solution of amino alcohol 10b (1.00 g, 8.53
mmol) in CH2Cl2 (17.0 mL) was added a saturated aqueous
solution of NaHCO3 (8.53 mL). The two-phase solution was
cooled to 0 °C. CbzCl (1.83 mL, 12.8 mmol) was added, and
the reaction was stirred for 8 h. The reaction was diluted with
water (10 mL), and the aqueous layer was extracted with CH2-
Cl2 (3 × 25 mL). The combined organic layers were washed
with brine, dried (K2CO3), and concentrated. Flash chroma-
tography (3:1, then 1:1 hexanes/ethyl acetate) gave the car-
bamate (1.50 g, 70%) as a clear, colorless oil: 1H NMR (300
MHz, CDCl3) δ 7.28 (m, 5H), 5.11 (s, 2H), 3.74-3.67 (m, 1H),
3.60-3.51 (m, 1H), 3.44 (ddd, J ) 4.1, 10.7, 14.4 Hz, 1H), 3.26
(dd, J ) 14.1, 6.9 Hz, 1H), 2.76 (t, J ) 5.9 Hz, 1H), 1.70-1.60
(m, 2H), 1.40-1.34 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H); 13C (75
MHz, CDCl3) δ 157.6, 136.4, 128.5, 128.2, 128.1, 66.9, 62.0,
1
mg, 82%) as a white solid: mp 82.7-84.7 °C; H NMR (300
MHz, CDCl3) δ 9.67 (s, 1H), 7.67 (d, J ) 8.2 Hz, 2H), 7.27 (m,
5H), 7.15 (d, J ) 8.2 Hz, 2H), 5.00 (t, J ) 6.7 Hz, 1H), 3.07
(m, 2H), 3.01 (dd, J ) 6.2, 13.3 Hz, 1H), 2.87 (m, 1H), 2.77
(dd, J ) 8.0, 13.1 Hz, 1H), 2.42 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 203.2, 143.5, 137.2, 136.5, 129.7, 128.8, 128.8, 127.0,
126.9, 52.9, 41.2, 32.6, 21.5; IR (neat) 3255, 1727, 1458, 1328,
1162, 1152 cm-1; MS (CI/NH3) m/z 335 (MNH4+, 100), 318
(MH+, 47), 301 (3), 189 (74), 164 (18), 146 (10), 118 (8), 108
(11), 91 (5); HRMS (CI/NH3) m/z calcd for C17H20NO3S (MH+)
318.1164, found 318.1152.
N-(Meth yleth yl-3-(4-m eth yl)p h en ylsu lfon yla m id o-p r o-
p a n a l (12b). To a solution of amide 11b (1.54 g, 5.67 mmol)
in CH2Cl2 (28 mL) was added powdered 4Å MS (2.90 g), NMO
(997 mg, 8.51 mmol) and then TPAP27 (99 mg, 0.28 mmol).
The reaction mixture was stirred 1 h and then filtered through
SiO2. The filter cake was washed (1:1 hexanes/ethyl acetate)
(27) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625-1627.
4366 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of 3-(Hydroxy)proline Benzyl Esters
47.4, 40.4, 27.1, 20.5, 20.4; IR (neat) 3399, 2958, 1693, 1455,
1254, 1137 cm-1; MS (CI/NH3) m/z 252 (100, MH+), 234 (4),
208 (85), 144 (55), 108 (24), 91 (58); HRMS (CI/NH3) m/z calcd
for C14H22NO3 (MH+) 252.1600, found 252.1608.
(s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.0, 143.8,
136.4, 129.8, 127.2, 75.7, 44.7, 40.9, 25.6, 21.5, 18.1, -4.8, -5.0;
MS (CI/NH3) m/z 375 (MNH4+, 58), 358 (MH+, 80), 340 (9),
328 (17), 286 (28), 271 (100), 226 (23), 184 (64), 155 (45), 129
(65), 91 (21); HRMS (CI/NH3) m/z calcd for C16H28NO4SiS
(MH+) 358.1508, found 358.1500.
Gen er a l Exp er im en ta l P r oced u r e for P r olin e Syn th e-
sis. To a solution of aldehyde (1.0 equiv) in CH2Cl2 (0.2 M) at
-78 °C was added benzyl diazoacetate (3.0 equiv). The reaction
mixture was stirred 10 min, and BF3‚OEt2 (1.0 equiv) was
added dropwise over 20-50 min. The reaction mixture was
stirred and then poured into a stirring saturated aqueous
solution of NaHCO3 (10 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. Flash
chromatography (hexanes/ethyl acetate) gave the proline.
The procedure given previously for the preparation of 12a
was carried using the above amide (150 mg, 0.593 mmol) in
CH2Cl2 (3.00 mL) and DMP17 (377 mg, 0.890 mmol) to give
aldehyde 13 (137 mg, 92%) as white solid: mp 68.6-70.8 °C;
1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 7.34 (m, 5H), 5.08
(ABq, J ) 13.2 Hz, ∆υ ) 15.3 Hz, 3H), 3.46 (m, 1H), 3.36 (ddd,
J ) 5.1, 9.2, 13.9 Hz, 1H), 2.47 (m, 1H), 2.14 (m, 1H), 1.07 (d,
J ) 6.7 Hz, 3H), 1.01 (d, J ) 6.7 Hz, 3H); 13C (75 MHz, CDCl3)
δ 204.9, 156.3, 136.4, 128.5, 128.1, 128.1, 66.7, 58.2, 37.4, 27.2,
20.1, 19.8; IR (neat) 3315, 2973, 1718, 1685, 1541, 1276 cm-1
;
MS (CI/NH3) m/z 250 (MH+, 100), 206 (8), 144 (12), 120 (6),
108 (33), 91 (46); HRMS (CI/NH3) m/z calcd for C14H20NO3
(MH+) 250.1443, found 250.1435.
(()-(2S*,3R*,4R*)-3-Hyd r oxy-1-[(4-m eth ylp h en yl)su lfo-
n yl]-4-(ph en ylm eth yl)-pyr r olidin e-2-car boxylic Acid P h e-
n ylm eth yl Ester (16). Using the general experimental pro-
cedure, aldehyde 12a (50 mg, 0.16 mmol) afforded proline ester
16 (56 mg, 77%) as a clear, colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.74 (d, J ) 8.2 Hz, 2H), 7.37-7.18 (m, 10H), 7.09
(d, J ) 6.7 Hz, 2H), 5.14 (ABq, ∆ν ) 15.9 Hz, J ) 12.3 Hz,
2H), 4.34 (broad s, 1H), 4.13 (s, 1H), 3.53 (apparent t, J ) 8.0
Hz, 1H), 3.15 (apparent t J ) 9.5 Hz, 1H), 2.76 (dd, J ) 8.2,
13.3 Hz, 1H), 2.65 (dd, J ) 7.2, 13.8 Hz, 1H), 2.56 (m, 1H),
2.42 (s, 3H), 1.74 (d, J ) 3.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 169.6, 143.7, 139.1, 135.3, 135.0, 129.6, 128.6, 128.5,
125.5, 128.1, 127.6, 126.4, 75.0, 69.8, 67.3, 50.5, 44.8, 32.0, 21.6;
(E)-N-(2-ter t-Bu t yld im et h ylsilyloxy)3(4-m et h yl)p h e-
n ylsu lfon yla m id o-p r op a n a l (15). To a solution of known
amino alcohol 1419 (500 mg, 4.94 mmol) in CH2Cl2 (55 mL) at
0 °C was added pyridine (1.20 mL, 14.8 mmol) and then TsCl
(942 mg, 4.90 mmol). The reaction mixture was stirred 24 h,
and the solvent removed in vacuo. The residue was dissolved
in ethyl acetate (25 mL) and water (25 mL), and the aqueous
layer was extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were washed with brine, dried
(MgSO4), and concentrated. Flash chromatography (2:1 hex-
anes/ethyl acetate) gave the protected amide (766 mg, 61%)
as a clear, colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.74 (d,
J ) 8.2 Hz, 2H), 7.31 (d, J ) 8.2 Hz, 2H), 5.72 (m, 1H), 5.38
(ddd, J ) 15.4, 6.9, 1.8 Hz, 1H), 4.77 (m, 1H), 4.15 (m, 1H),
3.09 (broad d, J ) 12.3 Hz, 1H), 2.87 (dd, J ) 12.3, 7.7 Hz,
1H), 2.43 (s, 3H), 1.68 (dd, J ) 5.6, 1.0 Hz, 3H), 1.63 (d, J )
1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.5, 136.7, 130.0,
129.7, 129.4, 127.1, 71.1, 48.4, 21.5, 17.7; IR (neat) 3493, 3283,
3033, 2920, 2883, 1598, 1447, 1324 cm-1; MS (CI/NH3) m/z 273
(MNH4+, 13), 255 (1), 238 (100), 189 (8), 116 (7); HRMS (CI/
NH3) m/z calcd for C12H21N2O3S (MNH4+) 273.1273, found
273.1264.
To a solution of the above amide (500 mg, 1.96 mmol) in
CH2Cl2 (2 mL) at 0 °C was added 2,6-lutidine (0.456 mL, 3.92
mmol) and then TBDMS-OTf (0.675 mL, 2.94 mmol). The
reaction mixture was stirred 1 h, and then water (3 mL) was
added. The organic layer was washed sequentially with a
saturated aqueous solution of NaHCO3 (5 mL), a saturated
aqueous solution of NH4Cl (5 mL), and brine, dried (MgSO4),
and concentrated. Flash chromatography (9:1 hexanes/ethyl
acetate) gave the silyl ether (551 mg, 76%) as a clear, colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J ) 8.2 Hz, 2H),
7.29 (d, J ) 8.2 Hz, 2H), 5.58 (partially overlapping dq, J )
15.4, 6.7 Hz, 1H), 5.25 (ddd, J ) 1.5, 7.2, 15.4 Hz, 1H), 4.59 (t,
J ) 5.9 Hz, 1H), 4.09 (apparent q, J ) 5.9 Hz, 1H), 2.95
(collapsed dd, J ) 4.6, 6.8 Hz, 1H), 2.85 (overlapping dd, J )
5.6, 6.7 Hz, 1H), 2.42 (s, 3H), 1.63 (dd, J ) 6.4, 1.3 Hz, 3H),
0.83 (s, 9H), -0.02 (s, 3H), -0.03 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 143.3, 136.9, 130.9, 129.7, 128.4, 127.1, 72.0, 49.1,
25.8, 21.5, 18.1, 17.6, -4.3, -4.9; IR (neat) 3292, 2951, 2927,
2856, 1599, 1462, 1406, 1361, 1331, 1254, 1163 cm-1; MS (CI/
NH3) m/z 370 (MH+), 312 (3), 255 (4), 238 (100); HRMS (CI/
NH3) m/z calcd for C18H32NO3SiS (MH+) 370.1872, found
370.1859.
IR (neat) 3506, 3067, 3031, 2962, 1731, 1599, 1496, 1337 cm-1
;
MS (CI/NH3) m/z 483 (MNH4+, 2), 466 (MH+, 31), 448 (12),
332 (25), 310 (22), 294 (42), 242 (19), 204 (24), 160 (58), 139
(64), 108 (89), 91 (100); HRMS (CI/NH3) m/z calcd for C26H28
-
NO5S (MH+) 466.1688, found 466.1704.
(()-(2S*,3R*,4R*)-3-Hyd r oxy-4-m eth yleth yl-1-[(4-m eth -
ylp h en yl)su lfon yl]-p yr r olid in e-2-ca r boxylic Acid P h e-
n ylm eth yl Ester (17). Using the general experimental pro-
cedure, aldehyde 12b (500 mg, 1.86 mmol) afforded proline
ester 17 (404 mg, 54%) as a white solid: mp 152.4-154.9 °C;
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J ) 8.2 Hz, 2H), 7.36 (s,
5H), 7.27 (d, J ) 7.7 Hz, 2H), 5.18 (s, 2H), 4.37 (s, 1H), 4.26 (t,
J ) 3.6 Hz, 1H), 3.61 (t, J ) 8.2 Hz, 1H), 3.06 (dd, J ) 8.5,
11.0 Hz, 1H), 2.41 (s, 4H), 1.86 (m, 1H), 1.71 (m, 1H), 1.61 (s,
1H), 0.86 (apparent t, J ) 6.7 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 169.7, 143.6, 135.3, 135.0, 129.6, 128.6, 128.5, 128.2,
127.6, 74.7, 70.2, 67.3, 50.6, 50.1, 25.8, 21.5, 21.4, 20.9; IR
(neat) 3488, 2959, 1746, 1336, 1289, 1163 cm-1; MS (CI/NH3)
m/z 435 (MNH4+, 100), 418 (MH+, 57), 401 (6), 282 (25), 262
(6); HRMS (CI/NH3) m/z calcd for C22H28NO5S (MH+) 418.1688,
found 418.1674. Proline 17 was recrystallized from hexanes/
ethyl acetate as a white solid (X-ray quality).
(()-(2S*,3R*,4S*)-4-(ter t-Bu tyld im eth ylsilyloxy)-3-h y-
d r oxy-1-[(4-m et h ylp h en yl)-su lfon yl]-p yr r olid in e-2-ca r -
boxylic Acid P h en ylm eth yl Ester (19). Using the general
experimental procedure, aldehyde 15 (40 mg, 0.11 mmol)
afforded proline ester 19 (21 mg, 37%) as a white solid: mp )
103-104 °C; 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 8.2
Hz, 2H), 7.36 (s, 5H), 7.24 (d, J ) 9.8 Hz, 2H), 5.16 (ABq, ∆ν
) 10.9 Hz, J ) 12.3 Hz, 2H), 4.38 (d, J ) 2.05 Hz, 1H), 4.35
(s, 1H), 4.02 (overlapping dt, J ) 2.6, 5.1 Hz, 1H), 3.61 (dd, J
) 5.1, 10.3 Hz, 1H), 3.23 (dd, J ) 2.6, 10.3 Hz, 1H), 2.40 (s,
3H), 1.92 (broad s, 1H), 0.81 (s, 9H), -0.01 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 169.0, 143.7, 135.3, 135.3, 129.5, 128.5,
128.3, 128.1, 127.8, 67.3, 67.1, 53.7, 25.5, 21.5, 17.9,-5.0; IR
(neat) 3486, 2947, 2928, 2893, 2857, 1759, 1462, 1341, 1252,
1158 cm-1; MS (CI/NH3) m/z 523 (MNH4+, 5), 506 (MH+, 100),
350 (67), 260 (13), 216 (41), 139 (23), 108 (44), 91 (73); HRMS
(CI/NH3) m/z calcd for C25H36NO6SiS (MH+) 506.2033, found
506.2026.
A solution of the above amide (200 mg, 0.78 mmol) in CH2-
Cl2 (10 mL) at -78 °C was cleaved with ozone. Dimethyl sulfide
was added, and the reaction mixture was stirred for 2 h and
concentrated. The residue was dissolved in CH2Cl2 (5 mL),
washed with water (3 × 10 mL) and brine, dried (K2CO3), and
concentrated to give aldehyde 15 (184 mg, 93%) as a clear,
colorless oil. This compound rapidly decomposed and was used
immediately in the next reaction: 1H NMR (300 MHz, DMSO-
d6) δ 9.56 (s, 1H), 7.73 (d, J ) 8.2 Hz, 2H), 7.31 (d, J ) 8.2 Hz,
2H), 4.90 (t, J ) 6.2 Hz, 1H), 4.08 (t, J ) 5.4 Hz, 1H), 3.18 (m,
2H,), 2.63 (solvent, DMSO-d6), 2.43 (s, 3H), 0.89 (s, 9H), 0.10
(()-(2S*,3R*,4R*)-3-Hydr oxy-4-m eth yl-1-[(4-m eth ylph e-
n yl)su lfon yl]-p yr r olid in e-2-ca r boxylic Acid P h en ylm eth -
yl Ester (20). Using the general experimental procedure,
J . Org. Chem, Vol. 69, No. 13, 2004 4367

Angle and Belanger
aldehyde 12c (51 mg, 0.21 mmol) afforded an inseparable 2:1
mixture (1H NMR) of proline ester 20 and a compound believed
to be â-keto ester 21 (45 mg, 56%) as a clear oil. An analytical
sample of proline ester 20 was obtained by HPLC (3:1 hexanes/
ethyl acetate): tR 53.4 min; 1H NMR (300 MHz, CDCl3) δ 7.74
(d, J ) 8.2 Hz, 2H), 7.36 (s, 5H), 7.27 (d, J ) 8.2 Hz, 2H), 5.18
(s, 2H), 4.31 (s, 1H), 4.16 (d, J ) 4.1 Hz, 1H), 3.56 (t, J ) 8.0
Hz, 1H), 3.00 (t, J ) 9.0 Hz, 1H), 2.41 (s, 3H), 2.37 (m, 1H),
1.76 (s, 1H), 0.95 (d, J ) 6.7 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 169.9, 143.6, 135.3, 134.9, 129.6, 128.6, 128.4, 128.2,
127.6, 69.5, 67.4, 51.9, 37.5, 29.7, 21.6, 10.3; IR (neat) 3504,
2963, 2924, 2885, 1746, 1598, 1340, 1306, 1162 cm-1; MS (CI/
NH3) m/z 407 (MNH4+, 100), 390 (MH+, 87), 254 (21), 236 (20),
234 (34), 218 (4), 108 (20), 100 (19), 91 (10); HRMS (CI/NH3)
m/z calcd for C20H24NO5S (MH+) 390.1375, found 390.1363.
4-Meth yl-3-oxo-5-[(4-m eth ylph en yl)su lfon ylam in o)-pen -
ta n oic Acid Ben zyl Ester (21). To a solution of SnCl2 (5.0
mg, 0.03 mmol) in CH2Cl2 (0.8 mL) was added benzyl diazo-
acetate (54 mg, 0.31 mmol), and the mixture was cooled to -78
°C. Aldehyde 12c (70.0 mg, 0.290 mmol) was dissolved in CH2-
Cl2 (0.5 mL) and added to the reaction mixture. The reaction
mixture was stirred for 6 h and diluted with ether (5.0 mL)
and brine (5.0 mL). The aqueous layer was extracted with
ether (3 × 2.0 mL), washed with brine, dried (MgSO4), and
concentrated. Flash chromatography (2:1 hexanes/ethyl ace-
tate) gave â-keto ester 21 as a clear, colorless oil: 1H NMR
(300 MHz, CDCl3) δ 7.71 (d, J ) 8.2 Hz, 2H), 7.38 (m, 5H),
7.29 (d, J ) 7.7 Hz, 2H), 5.16 (s, 2H), 5.07 (t, J ) 6.4 Hz, 1H),
3.51 (s, 1H), 3.05 (m, 2H), 2.92 (m, 1H), 2.41 (s, 3H), 1.11 (d,
J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 205.4, 166.7,
143.4, 136.8, 135.1, 129.7, 128.6, 128.5, 128.4, 126.9, 67.2, 47.5,
46.5, 44.6, 21.4, 14.1.
(()-(2S*,3R*)-3-Hyd r oxy-4,4-d im eth yl-1-[(4-m eth ylp h e-
n yl)su lfon yl]p yr r olid in e-2-ca r boxylic Acid P h en ylm e-
th yl Ester (22). Using the general experimental procedure,
aldehyde 12d (50 mg, 0.20 mmol) afforded proline ester 22
(11 mg, 14%) and â-keto ester 23 (45 mg, 57%) as clear,
colorless oils: 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J ) 8.2
Hz, 2H), 7.38 (m, 5H), 7.35 (d, J ) 7.7 Hz, 2H), 5.24 (ABq, J
) 12.1 Hz, ∆ν ) 12.9, 2H), 4.09 (d, J ) 6.2 Hz, 1H), 3.94 (d, J
) 6.7 Hz, 1H), 3.25 (d, J ) 10.3 Hz, 1H), 3.15 (d, J ) 10.3 Hz,
1H), 2.42 (s, 3H), 1.95 (s, 1H), 1.00 (s, 3H), 0.70 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.2, 143.7, 135.4, 134.9, 129.6,
128.6, 128.4, 128.3, 127.7, 81.4, 67.4, 66.5, 58.4, 41.6, 23.5, 21.6,
18.7; IR (neat) 3481, 2963, 2929, 1746, 1598, 1339, 1160 cm-1
;
MS (CI/NH3) m/z 404 (MH+, 2), 218 (82), 201 (100), 155 (4),
128 (4); HRMS (CI/NH3) m/z calcd for C21H26NO5S (MH+)
404.1532, found 404.1530.
Ack n ow led gm en t. We thank UCR for partial sup-
port of this research. We thank Professor M. Mark
Midland for helpful discussions. We would like to thank
Dr. Fook Tham at the UCR X-ray facility for the X-ray
structures.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra and X-rays (where applicable) for compounds
7a -c, 8a -c, 9b,c, 10a -c, 11a -e, 12a -e, 13, 15, 16, 17, 19,
and 20-22. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O030360F
4368 J . Org. Chem., Vol. 69, No. 13, 2004