General strategy for a short and efficient synthesis of 3-hydroxy-4-methylprolines (HMP)

Article abstract of DOI:10.1016/j.tetlet.2006.10.137

The non-proteinogenic amino acid 3-hydroxy-4-methylproline (HMP) is an active constituent of some potent antimicrobials including echinocandins, nostopeptins, pneumocandins, sporiofungin and mulundocandins. A synthesis has been achieved in 10 steps with 2

Full text of DOI:10.1016/j.tetlet.2006.10.137

Tetrahedron Letters 47 (2006) 9215–9219
General strategy for a short and efficient synthesis of
3-hydroxy-4-methylprolines (HMP)
Debendra K. Mohapatra,a,* Dhananjoy Mondal,a
Mukund S. Chorghadeb and Mukund K. Gurjara
aDivision of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
bChorghade Enterprises, 14, Carlson Circle, Natick, MA 01760, USA
Received 31 August 2006; revised 16 October 2006; accepted 26 October 2006
Abstract—The non-proteinogenic amino acid 3-hydroxy-4-methylproline (HMP) is an active constituent of some potent antimicro-
bials including echinocandins, nostopeptins, pneumocandins, sporiofungin and mulundocandins. A synthesis has been achieved in
10 steps with 29% overall yield; the Evans’ aldol reaction using Crimmins’ modified method was pivotal to the success of the
strategy.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Several substituted pyrrolidine alkaloids found in plants
and microorganisms have aroused considerable interest
as potential therapeutic agents and as tools for under-
standing biological recognition processes. Some micro-
bial cyclic peptides,1 containing a pyrrolidine or
proline moiety observed in Nature such as mulundocan-
dins2 (isolated from Aspergillus sydowi), aculeacin A3
(from Aspergillus aculeatus), echinocandins4 (from
Aspergillus ruglosus and Aspergillus nidulans), sporiofun-
gin A,5 nostopeptins6 and some pneumocandins7–9 were
found to have therapeutic activity as anticancer, anti-
fungal, antibiotic, antiviral and immune stimulating
agents.10 (2S,3S,4S)-3-Hydroxy-4-methylproline (HMP)
(1a) has emerged as one of the most common modules
of all these cyclic peptides (Fig. 1).
(2S,3S,4S)-HMP (1a), present in echinocandins, and
its antipode (2R,3R,4R)-HMP (1c).11 Our earlier re-
port12 on the synthesis of the spiro fused b-lactone-c-
lactam segment of oxazolomycin using Evans’ aldol
reaction following Crimmins’ modified method as the
key reaction, formed the basis of our strategy to develop
a short and efficient synthesis of (2S,3S,4S)-HMP and
its stereoisomers.
Retrosynthetically, HMP could be obtained from an
Evans’ aldol adduct which in turn could be derived from
commercially available Garner’s aldehyde and oxazoli-
din-2-one (Scheme 1).
Our primary focus was on the Evans’ aldol13a reaction
between the (S)-oxazolidinone derivative 3 and (R)-Gar-
ner’s aldehyde 4 using Crimmins’ modified method.
Since higher diastereomeric excess are known to be ob-
tained in aldol reactions with TiCl4,13b the outcome of
this reaction would be fascinating because both sub-
strates 3 and 4 would have independent (complementary
or opposing) influences on the course of the aldol reac-
tion. Execution of this reaction in the presence of TiCl4
(1.0 equiv) and DIEA (2.5 equiv) at 0 ꢁC gave two iso-
mers 2 (non-Evans’ anti) and 5 (non-Evans’ syn) in a
2:3 ratio as liquids whose stereochemical assignments
were confirmed on later stage. Similarly, (R)-oxazolidi-
none derivative 6 and (S)-Garner’s aldehyde 7 were sub-
jected to aldol reaction with TiCl4, two isomers were
obtained maintaining the same ratio (2:3). Much to
It is likely that this component would itself manifest
activity and could potentiate activity in analogues. For
the elucidation of defined structure activity relationships
and for the preparation of analogues of these cyclic pep-
tide antibiotics, it is essential to develop a short and effi-
cient synthesis of 1a and its stereoisomers. Different
strategies have been reported in the literature for the
synthesis of the naturally occurring active constituent
Keywords: Garner’s aldehyde; Crimmins’ aldol reaction; Non-proteino-
genic amino acids; 3,4-Disubstituted proline; RuO4 mediated oxidation.
*
Corresponding author. Tel.: +91 20 25902627; fax: +91 20
25902629; e-mail: dk.mohapatra@ncl.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.137

9216
D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 9215–9219
Me
OH
Me
OH
Me
OH
H
R1
N
N
OH
OH
OH
R1
NHCO
O
N
H
N
H
O
Me
O
O
3
O
R
NH
R2
O
O
(2R,
3
S,
4
R
)-HMP (1b)
(2S,
3S,4S)-HMP (1a)
O
NH
N
N
H
OH
Me
OH
HO
Me
OH
Me
OH
OH
Echinocandin
OH
OH
N
H
N
H
O
O
R1 = R2 = OH, R3 = C17H31
R1 = OH, R2 = H, R3 = C17H31
R1 = R2 = H, R3 = C17H31
Echinocandin B
C
D
(2R,3R,4R)-HMP (1c)
(2S,3R,4S)-HMP (1d)
R1 = R2 = OH
R3 =
LY303366
OC5H11
Figure 1. Echinocandins and HMPs.
O
OH
O
Me
OH
O
O
N
O
OH
O
N
H
N
Me
Boc
Bn
1a
2
O
O
CHO
O
N
+
N
Boc
Bn
3
4
Scheme 1. Retrosynthetic strategy.
our delight, isomer 8 crystallized out in 40% yield after
column purification of the crude material. Spectroscopic
and elemental data supported the structure of 8;14 a sin-
gle crystal X-ray diffraction study (CCDC 615731)15
conclusively proved the stereochemical assignments as
non-Evans anti–anti (Scheme 2). This stereochemical
outcome was in fact unexpected though we were aware
of some prior literature precedents of such double ste-
reodifferentiating reactions.16 We also performed the al-
dol reaction between (S)-oxazolidinone derivative 3 and
(S)-Garner’s aldehyde 7 and observed the formation
of 10, exclusively. The X-ray crystallographic analysis
(Fig. 2) confirmed the structure of 10 (CCDC
615732).15 (R)-Oxazolidin-2-one derivative 6 and (R)-
Garner’s aldehydes 4/12 under identical conditions gave
exclusively one isomer 11/13, the structures of which
were confirmed by X-ray crystallography.12 In sum-
mary, the combination of 3 and 4 or 6 and 7 were mis-
matched favouring both syn–anti (non-Evans’ anti) and
syn–syn (non-Evans’ syn) isomers, while that of 3 and 7
or 6 and 4 were matched leading to only the syn–syn
(Evans’ syn) isomer (Scheme 2).
Figure 2. ORTEP diagrams of 8 and 10.
proline. Reductive hydrolysis17 of the oxazolidinone ring
of 2 with lithium borohydride generated primary alcohol
14. A protection–deprotection sequence shown in
Scheme 3 furnished the tosyl derivative 15 which was
subjected to cyclization in the presence of p-TSA-MeOH
to give the appropriately substituted pyrrolidine deriva-
Our next task was to demonstrate the novel use of these
intermediates in the synthesis of 3-hydroxy-4-methyl-

D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 9215–9219
9217
OH
OH
O
O
O
O
O
O
OHC
a
O
O
N
O
O
N
O
+
O
O
N
N
+
+
N
N
N
84%
Me
Me
Boc
Bn
Bn
O
Boc
Boc
Bn
O
4
2
5
3
OH
OH
O
O
O
O
OHC
a
O
O
N
O
O
N
O
+
N
N
82%
N
Me
Me
Boc
Bn
Bn
Bn
Boc
Boc
6
7
9
8
OH
O
O
O
O
OHC
a
O
N
O
O
O
O
O
N
N
+
N
N
Me
77%
Bn
Boc
10
OH
Boc
Bn
O
3
7
O
O
O
OHC
a
O
N
O
O
+
81%
N
Me
Boc
N
Bn
Bn
O
Boc
11
6
4
OH
O
O
OHC
a
O
N
O
O
O
N
+
79%
N
Me
Cbz
N
Bn
Bn
Cbz
6
12
13
Scheme 2. Reagents and conditions: (a) TiCl4 (1.1 equiv), DIEA (2.5 equiv), CH2Cl2, 0 ꢁC, 2 h.
tive 16. The structure was confirmed from spectral and
analytical data.18 RuO4 oxidation of 16 afforded the 3-
benzoyloxy-4-methylproline derivative 17 where benzyl
ether had been oxidized to a benzoate ester during the
oxidation of hydroxymethyl functionally to a carboxyl
group, which on heating with 6 N HCl produced 3-hy-
droxy-4-methylproline as its hydrochloride salt. The
crude product was passed through a column of Dowex
50W · 4 (H+ form) resin to secure 3-hydroxy-4-
methylproline (1a) as a white solid whose 1H, 13C
OH
OH
O
O
a
HO
O
N
O
O
N
N
Me
Boc
Me
Boc
Bn
2
14
OBn
Me
OBn
OH
b
c
TsO
O
N
N
Me
Boc
16
Boc
15
NMR and IR data19 were in excellent agreement with
25
reported values.11k The specific rotation of 1a was ½aꢀD
25
ꢁ26.6 (c 1.0, H2O) {lit.11k for 1a ½aꢀD ꢁ27.0 (c 0.8,
OBz
OH
OH
Me
Me
d
e
H2O)} (Scheme 3). The stereochemistry of HMP 1a was
assigned on the basis of the vicinal coupling constants
(J3,4 = 3.8 Hz for the cis relationship) and the singlet
at 4.14 ppm indicating a trans relationship with respect
to H-2 and H-3. Further, a cis relationship between
the substituents at C-3 and C-4 in 1a was supported
by the strong nOe interaction between H-3 and H-4.
OH
N
N
H
O
O
Boc
17
1a
H
H
Me
OH
H
H
Similarly, compound 9 was taken through all nine steps
described above leading to the formation of (2R,3S,4R)-
HMP (1b) (Scheme 4). The structure of 1b was con-
firmed from spectral and analytical data;20 the absolute
configuration was ascertained from the NOESY
experiment.
OH
N
H
H
O
Some NOESY interactions
Scheme 3. Reagents and conditions: (a) LiCl, NaBH4, EtOH/THF
(2:1), 0 ꢁC, 4 h, 92%; (b) (i) TBDMSCl, Et3N, DMAP (cat.), CH2Cl2,
0 ꢁC, 6 h, 90%; (ii) NaH, BnBr, DMF, 0 ꢁC to rt, 1 h, 91%; (iii) TBAF,
THF, 0 ꢁC to rt, 3 h, 89%; (iv) TsCl, Et3N, CH2Cl2, 0 ꢁC, 6 h, 97%; (c)
p-TSA, MeOH, rt, 3 h, 76%; (d) RuCl3, NaIO4 (aq), EtOAc, rt, 1 h,
86%; (e) (i) 6 N HCl, 80 ꢁC, 40 h; (ii) Dowex 50 · 4 (H+ form), 82%.
In summary, we have comprehensively studied the
outcome of the Evans’ aldol reaction with both isomers
of oxazolidin-2-one and Garner’s aldehyde and
achieved the synthesis of (2S,3S,4S)-HMP (1a) (from

9218
D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 9215–9219
Benz, F.; Knusel, F.; Nuesch, J.; Treichler, H.; Voser, W.;
Nyfeler, R.; Keller-Schierlein, W. Helv. Chim. Acta 1974,
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¨
¨
OH
O
O
OH
O
Me
9 steps
O
N
O
OH
5. Hammond, M. L. Chemical and structure–Activity Stud-
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N
N
Me
Boc
Bn
H
1b
9
Scheme 4. Synthesis of 1b.
7. Noble, H. M.; Langley, D.; Sidebottom, P. J.; Lane, S. J.;
Fischer, P. J. Mycol. Res. 1991, 95, 1439–1440.
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Garner’s aldehyde) in 10 steps with 29% overall yield
better than that of Takeya’s method,11a one of the short-
est procedure in the literature (12 steps, 22% overall
yield). We have also demonstrated a short and efficient
stereoselective route to all stereoisomers of 3-hydroxy-
4-methylproline (HMP) starting from the aldol prod-
ucts. Different analogues of this class of cyclic peptides
are the focus of our ongoing work in order to study
the effect of this segment (HMP stereoisomers) on their
biological activity. Studies on the synthesis of other bio-
logically active natural products from Evans’ aldol ad-
ducts are in progress and will be reported in due course.
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Heterocycles 2005, 65, 2657–2665; (b) Meng, W.-H.; Wu,
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Acknowledgements
D.M. thanks CSIR, New Delhi, for the financial support
in the form of a research fellowship. We thank also Dr.
Mohan M. Bhadbhade and Dr. P. R. Rajmohanan for
the X-ray crystallographic assistance and NMR data,
respectively.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2006.10.137.
References and notes
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2477–2483.
2. (a) Mukhopadhyay, T.; Roy, K.; Bhat, R. G.; Sawant,
S. N.; Blumbach, J.; Ganguli, B. N.; Fehlhaber, H. W.;
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yay, T.; Ganguli, B. N.; Fehlhaber, H. W.; Kogler, H.;
Vertesy, L. J. Antibiot. 1987, 40, 281–289; (c) Roy, K.;
Mukhopadhyay, T.; Reddy, G. C. S.; Desikan, K. R.;
Ganguli, B. N. J. Antibiot. 1987, 40, 275–280.
3. (a) Abbott, B. J.; Fukuda, D. S. US Patent 4293 482, 1981;
Chem. Abstr. 1981, 96, 18653g and 4293 490, 1981; Chem.
Abstr. 1981, 96, 18652f; (b) Satoi, S.; Yagi, A.; Asano, K.;
Mizuno, K.; Watanabe, T. J. Antibiot. 1977, 30, 303–307;
(c) Mizuno, K.; Yagi, A.; Satoi, S.; Takada, M.; Hayashi,
M.; Asano, K.; Matsuda, T. J. Antibiot. 1977, 30, 297–302.
4. (a) Udodong, U. E.; Turner, W. W.; Astleford, B. A.;
Brown, F., Jr.; Clayton, M. T.; Dunlap, S. E.; Frank, S.
A.; Grutsch, J. L.; LaGrandeur, L. M.; Verral, D. E.;
Werner, J. A. Tetrahedron Lett. 1998, 39, 6115–6118; (b)
13. (a) Evans, D. A.; Reiger, D. L.; Bilodeau, M. T.; Urpi, F.
J. Am. Chem. Soc. 1991, 113, 1047–1049; (b) Crimmins,
M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894–902.
25
14. Analytical and spectral data of compound 8. ½aꢀD ꢁ37.7 (c
1.5, CHCl3); IR (CHCl3): 1688, 1781 cmꢁ1 1H NMR
;
(CDCl3, 200 MHz): d 1.40 (d, 3H, J = 7.2 Hz), 1.48 (s,
9H), 1.50 (s, 3H), 1.60 (s, 3H), 2.73 (dd, 1H, J = 11.2,
13.8 Hz), 3.48 (dt, 1H, J = 2.8, 11.2 Hz), 3.67 (dd, 1H,
J = 2.8, 13.8 Hz), 3.83 (dq, 1H, J = 2.8, 7.2 Hz), 3.94 (dd,
1H, J = 5.6, 9.0 Hz), 4.0 (d, 1H, J = 10.9 Hz), 4.09 (dd,
1H, J = 5.6, 9.0 Hz), 4.13–4.18 (m, 2H), 4.29 (d, 1H,
J = 9.0 Hz), 4.57–4.63 (m, 1H), 7.26–7.36 (m, 5H); 13C
NMR (CDCl3, 50 MHz): d 15.8, 24.0, 27.9, 28.4, 37.1,
37.8, 55.7, 59.9, 65.1, 65.8, 75.4, 80.2, 93.7, 126.9, 128.7,

D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 9215–9219
9219
129.1, 136.5, 152.2, 153.2, 177.8; Anal. Calcd for
C24H34N2O7: C, 62.32; H, 7.41; N, 6.06; Found: C,
62.20; H, 7.45; N, 6.10.
(m, 3H), 4.05 (t, 1H, J = 5.4 Hz), 4.45 (d, 1H,
J = 11.9 Hz), 4.65 (d, 1H, J = 11.9 Hz), 7.23–7.42 (m,
5H); 13C NMR (CDCl3, 50 MHz): d 11.3, 28.4, 35.7, 52.1,
64.7, 65.5, 71.1, 80.2, 81.7, 127.6, 127.7, 128.4, 138.0,
156.9; Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N,
4.36. Found: C, 67.22; H, 8.39; N, 4.31.
15. Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
615731 for 8 and CCDC 615732 for 10. Copies of the data
can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44 0
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
16. (a) Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org.
Chem. 2004, 69, 2569–2572; (b) Clive, D. L. J.; Yu, M.
Chem. Commun. 2002, 2380–2381; (c) Iseki, K.; Oishi, S.;
Kobayashi, Y. Tetrahedron 1996, 52, 71–84; (d) Evans, D.
A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J.
J. Am. Chem. Soc. 1990, 112, 7001–7031.
19. Analytical and spectral data of compound 1a. Mp 259–
25
260 ꢁC (decomp.); ½aꢀD ꢁ26.6 (c 1.0, H2O); IR (Nujol):
1377, 1460, 1620, 3059, 3311 cmꢁ1 1H NMR (D2O,
;
400 MHz): d 1.11 (d, 3H, J = 6.8 Hz), 2.25–2.36 (m, 1H),
3.11 (t, 1H, J = 11.5 Hz), 3.66 (dd, 1H, J = 7.8, 11.5 Hz),
4.14 (s, 1H), 4.48 (d, 1H, J = 3.8 Hz); 13C NMR
(D2O + acetone-d6, 100 MHz): 11.8, 39.0, 51.6, 71.8,
78.2, 174.1.
20. Analytical and spectral data of compound 1b. Mp 218–
25
219 ꢁC (decomp.); ½aꢀD +21.1 (c 1.0, H2O); IR (Nujol):
17. Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62,
7548–7549.
1377, 1454, 1461, 1604, 3062, 3363 cmꢁ1; 1H NMR (D2O,
400 MHz): d 1.10 (d, 3H, J = 7.3 Hz), 2.32–2.42 (m, 1H),
3.18 (dd, 1H, J = 7.5, 11.8 Hz), 3.66 (dd, 1H, J = 7.0,
11.8 Hz), 3.98 (d, 1H, J = 4.3 Hz), 4.21 (t, 1H,
J = 4.8 Hz); 13C NMR (D2O + acetone-d6, 100 MHz):
16.5, 42.8, 52.3, 69.4, 82.0, 174.6.
25
18. Analytical and spectral data of compound 16. ½aꢀD ꢁ53.7 (c
1.75, CHCl3); 1H NMR (CDCl3, 400 MHz): d 1.07 (d, 3H,
J = 6.4 Hz); 1.46 (s, 9H), 2.20–2.38 (m, 1H), 3.17 (t, 1H,
J = 10.3 Hz), 3.46 (dd, 1H, J = 7.3, 10.3 Hz), 3.58–3.84