Enantiospecific synthesis of functionalized polyols from tartaric acid using Ley's dithiaketalization: Application to the total synthesis of achaetolide

Article abstract of DOI:10.1016/j.tet.2016.11.035

Synthesis of chiral tetrols and 1,2,4-triols with varied substitutions was accomplished from tartaric acid. Pivotal reaction in the synthesis was the use of Ley's dithianylation of an alkynyl ketone derived from tartaric acid. Application of the strategy

Full text of DOI:10.1016/j.tet.2016.11.035

Accepted Manuscript
Enantiospecific synthesis of functionalized polyols from tartaric acid using Ley's
dithiaketalization: Application to the total synthesis of achaetolide
Amit K. Bali, Sunil Kumar Sunnam, Kavirayani R. Prasad
PII:
S0040-4020(16)31190-5
10.1016/j.tet.2016.11.035
TET 28249
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 October 2016
Revised Date: 3 November 2016
Accepted Date: 14 November 2016
Please cite this article as: Bali AK, Sunnam SK, Prasad KR, Enantiospecific synthesis of functionalized
polyols from tartaric acid using Ley's dithiaketalization: Application to the total synthesis of achaetolide,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.035.
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ACCEPTED MANUSCRIPT
Enantiospecific synthesis of functionalized polyols from Tartaric Acid Using Ley’s
Dithiaketalization: Application to the Total Synthesis of Achaetolide
Amit K. Bali, Sunil Kumar Sunnam and Kavirayani R. Prasad*

ACCEPTED MANUSCRIPT
Enantiospecific Synthesis of Functionalized polyols from Tartaric Acid Using
Ley’s Dithiaketalization: Application to the Total Synthesis of Achaetolide
Amit K. Bali, Sunil Kumar Sunnam and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
E-mail: prasad@orgchem.iisc.ernet.in, FAX: +91-80-23600529
Abstract: Synthesis of chiral tetrols and 1,2,4-triols with varied substitutions was accomplished from
tartaric acid. Pivotal reaction in the synthesis was the use of Ley’s dithianylation of an alkynyl ketone
derived from tartaric acid. Application of the strategy was demonstrated in the total synthesis of
decanolactone achaetolide.
Keywords: polyols, total synthesis, macrolactones, natural products, polyketides
Introduction
Polyols with varied substitutions are ubiquitous structural units present in a number of polyketide
natural products.1 Amongst the polyol containing compounds, the 1,2,4-triol unit 1 is a core/latent
structural unit frequently encountered in a number of macrolactone natural products. Some of the
examples include macrolactone natural products such as achaetolide 2, (6S,7R,9R)-6,7-dihydroxy-9-
propylnon-4-eno-9-lactone 3, seimatopolide A 4, Sch725674 5, and the linear polyol containing
natural product fostriecin 6 (Fig. 1).
Fig 1. Natural products possessing the 1,2,4-triol unit
One of the best ways to synthesize the 1,3-diol present in a triol system is the reduction of the
corresponding β-hydroxy ketone, which in turn can be accessed by the well-established asymmetric
aldol reaction.2 While the aldol reaction strategy renders the products with high degree of selectivity,
development of non-aldol reaction for aldol products is of significant importance in organic synthesis.
In this context, pioneering work by Smith’s group established the use of 1,3-dithiane linchpins as
excellent acyl anion equivalents and has exemplified their use in the synthesis of structurally complex
natural products.3 An attractive strategy for the synthesis of β-ketodithianes, a virtual surrogate of 1,3-
diols is the procedure reported by Ley’s group utilized the addition of 1,3-propanedithiol to alkynyl
ketones.4 Generality of this reaction is showcased by Ley’s group by the synthesis of an impressive
array of compounds. Herein, we report a facile approach for polyol synthesis, particularly to the
synthesis of 1,2,4-triols utilizing a combination of chiral pool tartaric acid and Ley’s dithiaketalization
reaction and application of the strategy to the total synthesis of decanolactone natural product
achaetolide.
Results and Discussion
For a decade, our efforts in the use of chiral pool tartaric acid in natural product synthesis culminated
in establishing the γ-hydroxy amides derived from tartaric acid as excellent building blocks.5 Key
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reaction in our methodology is the desymmetrization of tartaric acid amide 7 with various alkyl/aryl
and alkenyl Grignard reagents followed by stereoselective reduction of the resultant ketones. We
reasoned that the addition of alkynyl Grignard reagents would lead to the mono keto amide 8, which
on Ley’s dithiaketalization should provide the β-1,3-dithianyl ketone 9. Elaboration of 9 will lead to
the polyol systems 10, 11 or 12 present in a number of natural products (Scheme-1).6
Scheme 1: Proposed synthesis of polyols from the bis-Weinreb amide of tartaric acid
Accordingly, the synthetic sequence commenced with the addition of R-C≡C-Li/MgBr to the bis-
Weinreb amide 77 derived from tartaric acid to afford the mono-keto amides 8a-h in 48-89% yield.
Addition of 1,3-propanedithiol to the alkynyl ketones 8a-h under Ley’s conditions
(NaOMe/MeOH) was facile and the corresponding β-dithianyl ketones 9a-h were obtained in
excellent yields (see table-1). Stereoselective reduction of 9a-h with excess NaBH4 afforded the
corresponding 1,4-diol 13a-h in good yields as a single diastereomer (erythro isomer) (Scheme-
2).8 It is worth noting that the reduction of structurally similar γ-oxoamides devoid of the dithiane
moiety with K-Selectride furnished the corresponding threo isomer.6a, 8b This observation has been
used for the assignment of stereochemistry at the newly formed center in 13a-h.
Scheme 2: Synthesis of polyhydroxy 1,3-dithiane from tartaric acid amide
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Table 1: Synthesis of alkynyl ketones 8a-h from the bis-Weinreb amide 7 and their elaboration to
polyhydroxy 1,3-dithiane 13a-h
S. No.
Yield % a
9
9a (84)
9b (88)
R-C≡C-M
8
13
13a (75)
13b (81)
1
2
8a (48)b
8b (65)
H-C≡C-MgBr
H3C-C≡C-MgBr
3
8i (63)
9i (97)
13i (95)
CH2=CH-(CH2)2-C≡C-MgCl
4
5
6
7
8
9
8c-c
9c (64)d,e 13a (75)f
Me3Si-C≡C-Li
Ph-C≡C-Li
H7C3-C≡C-Li
8d (60)
8e (88)
8f (63)
8g (89)
8h (76)
9d (90)
9e (98)
9f (95)
9g (96)
9h (95)
13d (71)
13e (82)
13f (85)
13g (82)
13h (87)
H13C6-C≡C-Li
H15C7-C≡C-Li
TBSO-(CH2)3-C≡C-Li
aAll yields refer to yields after chromatography. bFormation of the enamine 8aa (29% yield) resulting from the addition of
N,O-dimethoxy hydroxylamine (Weinreb amine) to the alkynone 8a is observed. See ref. 9 and supporting information.
cMonoalkyl ketone 8c is not isolated and is proceeded to the next step without purification. dYield obtained after two steps.
e24% of the desilyalted product 9a was also obtained. fReduction always led to the formation of desilylated product 13a.
Thus, desulfurization of the 1,3-dithiane moiety in 13g furnished the 1,4-diol 14 possessing the
erythro stereochemistry was compared with the corresponding known threo isomer 16 obtained by
from the γ-oxo-amide 15 (see Supporting Information for the synthesis of 16) (Scheme-3).
Scheme 3: The assignment of stereochemistry at the newly formed stereogenic center in 13a-h
After successfully establishing the route for synthesis of the masked polyol unit from tartaric acid,
application of the strategy in the total synthesis of achaetolide 2, a decanolactone natural product was
undertaken. Achaetolide (2) is a 10-membered lactone isolated in 1983 from the culture broth of
Achaetonium cristalliferum and the structure was established in 2009 by Takada’s group by extensive
NMR studies.10 It was envisaged that formation of the lactone can be accomplished by ring closing
metathesis of the diene ester 17. The alcohol fragment 18 of the ester can be synthesized by
elaboration of the triol unit 13g obtained from tartaric acid (Scheme-4).
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Scheme 4: Retrosynthesis for achaetolide
Thus, primary alcohol in 13g was transformed to the iodide 20, via the tosylate 19, which on reaction
with MeI and CaCO3 unmasked the dithiane to yield the β-hydroxy ketone 21 in 80% yield.
11
Stereoselective directed reduction of the keto group in 21 with Me4NBH(OAc)3 furnished the 1,3-
anti-diol 22 in 91% yield. Treatment of 22 with zinc dust in refluxing ethanol produced the 1,2,4-triol
23 in excellent yield. Reaction of the triol 23 with 2,2-dimethoxy propane in DCM afforded the
acetonide 18 in 80% yield. Coupling of 18 with the known acid 2412 furnished the ester 25 in 87%
yield. Deprotection of the TBDPS group in 25 with TBAF gave the diene ester 17 in 91% yield
(Scheme-5).
Scheme 5: Synthesis of the diene ester 17
We then examined the ring closing metathesis (RCM) reaction of the ester 17 with Grubbs’ 2nd
generation catalyst. In the reported RCM reaction of the ester with Grubbs’ catalyst by different
groups, an element of discrepancy is observed. Different groups10c,f,g reported varied yields of the
required lactone 26 along with formation of other products in the RCM reaction of the ester 17.13 We
investigated this reaction and consistently found that the reaction of the ester 17 with catalytic amount
of Grubbs’ catalyst furnished the required E-lactone 26 in 24% yield, the Z-isomer 27 in 25% yield,
along with the dimer 2814 in 29% yield. Performing the reaction at higher dilutions could not mitigate
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ACCEPTED MANUSCRIPT
the formation of the dimer. Interestingly, protection of the free hydroxy group in 17 as the MOM ether
29 and performing the RCM reaction mitigated the formation of the dimer completely and the E and Z
lactones 31 and 30 respectively were formed in 54% and 34% yields respectively. Deprotection of the
acetonide as well as the MOM group in 31 afforded the natural product achaetolide 2 in 68% yield.
The spectral data of 2 is in agreement with that reported in the literature (Scheme-6).
Scheme 6: Total synthesis of achaetolide 2
In conclusion, a general procedure for the synthesis of 1,2,4-triol unit frequently encountered in
natural products was accomplished from chiral pool tartaric acid using Ley’s dithiaketalization
strategy. Application of the methodology is exemplified in the total synthesis of decanolactone natural
product achaetolide in 14 steps from the bis-Weinreb amide of tartaric acid in 9.5% overall yield.
Experimental:
General Procedures: Column chromatography was performed on silica gel, Acme grade 100-200
mesh. TLC plates were visualized either with UV, in an iodine chamber, or with phosphomolybdic
acid spray, unless noted otherwise. All reagents were purchased from commercial sources and used
without additional purification. THF was freshly distilled over Na-benzophenone ketyl. Melting points
1
were uncorrected. H NMR and 13C NMR spectra were recorded either on a 400 or on a 300 mHz
machine in CDCl3 as solvent with TMS as reference unless otherwise indicated. Unless stated
otherwise, all the reactions were performed under inert atmosphere. All the specific rotations were
determined at 24 °C. HRMS was obtained using a micromass-QTOF spectrometer using electrospray
ionization (ESI).
General procedure for the addition of alkynes to the bis-Weinreb amide: The following
preparation of 8g is representative:
5

ACCEPTED MANUSCRIPT
To a stirred solution of 1-nonyne (2.5 mL, 15.1 mmol) in dry THF (15 mL) at −78 °C was added n-
BuLi (8.8 mL of 1.6 M solution in hexanes, 14 mmol) and the resulting reaction mixture was stirred at
the same temperature for 1h. A solution of the bis-Weinreb amide 7 (3.0 g, 10.8 mmol) in THF (10
mL) was added dropwise to the pre-formed alkynyllithium at −78 °C. The reaction mixture was stirred
at −78 °C for another 40 min. After completion of the reaction (TLC), it was quenched with sat.
NH4Cl solution (20 mL) and was extracted with EtOAc (3×20 mL). The combined organic extracts
were washed with brine (30 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent
followed by silica gel column chromatography of the resultant residue with petroleum ether: EtOAc
24
(9:1) as eluent afforded the keto-amide 8g as yellow oil in 89% (3.4 g) yield. [α]D −16.7 (c 1.0,
CHCl3).; IR (neat) 2932, 1684, 1458, 1097 cm-1; 1H NMR (400 MHz, CDCl3 ) δ 5.13 (bd, J = 4.0 Hz,
1H), 4.87 (bd, J = 4.0 Hz, 1H), 3.71 (s, 3H), 3.23 (s, 3H), 2.40 (t, J = 7.2 Hz, 2H), 1.58 (pent., J = 7.2
Hz, 2H), 1.50 (s, 3H), 1.48 (s, 3H), 1.45-1.31 (m, 2H), 1.30-1.15 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 184.8, 169.5, 113.6, 99.8, 83.1, 78.9, 74.9, 61.6, 32.5, 31.6, 28.7, 28.6,
27.5, 26.8, 26.5, 22.5, 19.2, 14.0; HRMS for C18H29O5N+Na calcd 362.1943; found 362.1942.
Preparation of 8f: Following the general procedure, reaction of 1-octyne (0.37 mL, 2.53 mmol) with
24
the bis-Weinreb amide 7 (0.5 g, 1.81 mmol) afforded the product 8f in 63% (0.37 g) yield. [α]D
−17.0 (c 1.3, CHCl3); IR (neat) 2927, 2210, 1677, 1428 cm-1; 1H NMR ( 400 MHz, CDCl3) δ 5.12 (d, J
= 4.8 Hz, 1H), 4.85 (d, J = 4.8 Hz, 1H), 3.69 (s, 3H), 3.21 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.56 (pent.,
J = 7.2 Hz, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 1.41-1.32 (m, 2H), 1.31-1.18 (m, 4H), 0.89 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 184.7, 169.4, 113.5, 99.7, 83.0, 78.8, 74.9, 61.6, 32.4, 31.1, 28.4,
27.4, 26.7, 26.4, 22.4, 19.1, 13.9; HRMS for C17H27O5N+Na calcd 348.1787; found 348.1786.
nC3H7
O
O
O
O
N
Me
OMe
Preparation of 8e: Following the general procedure, reaction of 1-pentyne (0.5 mL, 5.07 mmol) with
24
the bis-Weinreb amide 7 (1.0 g, 3.62 mmol) afforded the product 8e in 88% (0.9 g mg) yield. [α]D
−20.9 (c 1.2, CHCl3).; IR (neat) 2212, 1677, 1383, 852 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.1 (d, J =
4.4 Hz, 1H), 4.84 (d, J = 4.8 Hz, 1H), 3.68 (s, 3H), 3.19 (s, 3H), 2.36 (t, J = 7.2 Hz, 2H), 1.58 (hex, J =
7.2 Hz, 2H), 1.46 (s, 3H), 1.44 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 184.6,
169.3, 113.5, 99.4, 83.0, 78.9, 74.8, 61.5, 32.4, 26.7, 26.4, 20.99, 20.96, 13.3; HRMS for
C14H21O5N+Na calcd 306.1317; found 306.1315.
6

ACCEPTED MANUSCRIPT
Ph
O
O
O
O
N
Me
OMe
Preparation of 8d: Following the general procedure, reaction of phenyl acetylene (0.3 mL, 2.7 mmol)
with the bis-Weinreb amide 7 (0.5 g, 1.81 mmol) afforded the product in 60% (0.34 g) yield (73%
based on recovery of starting material). [α]D24 −22.1 (c 0.9, CHCl3); IR (neat) 2939, 2205, 1668, 1065
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.39 ( t, J = 7.6
Hz, 2H), 5.21 (d, J = 4.8 Hz, 1H), 5.0 (d, J = 4.8 Hz, 1H), 3.71 (s, 3H), 3.24 (s, 3H), 1.54 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 184.6, 169.3, 133.3 (2C), 131.2, 128.7 (2C), 119.4, 113.8, 95.7, 86.0, 83.1,
75.1, 61.6, 32.5, 26.8, 26.5; HRMS for C17H19O5N+Na calcd 340.1161; found 340.1161.
Preparation of 8h: Following the general procedure, reaction of 1-silyloxy-4-pentyne (6.32 g, 31.9
mmol) with the bis-Weinreb amide 7 (8.0 g, 28.95 mmol) afforded the product 8h in 76% (9.1 g)
1
yield. [α]D25 −12.7 (c 2.0, CHCl3); IR (Neat): νmax 2953, 1681, 1468, 1257, 1102, 958, 838 cm−1; H
NMR (400 MHz, CDCl3): δ 5.14 (d, J = 4.8 Hz, 1H), 4.87 (d, J = 4.8 Hz, 1H), 3.71 (s, 3H), 3.68 (t, J =
5.6 Hz, 2H), 2.51 (t, J = 7.2 Hz, 2H), 1.78 (quint, J = 6.4 Hz, 2H), 1.51 (s, 3H), 1.48 (s, 3H), 0.88 (s,
13
9H), 0.05 (s, 6H); C NMR (100 MHz, CDCl3): δ 184.7, 169.6, 113.5, 99.3, 83.0, 78.9, 74.8, 61.5,
61.0, 32.4, 30.6, 26.7, 26.4, 25.8 (3 × C), 18.2, 15.7, −5.4 (2 × C). HRMS: m/z calcd for
C20H35NO6Si+Na 436.2131; found: 436.2138.
Preparation of 8b: To a stirred solution of the bis-Weinreb amide 7 in (0.5 g, 1.81 mmol) in THF (9
mL) was added propynylmagnesium bromide (5.4 mL of 0.5 M solution in THF, 2.7 mmol) dropwise
at 0 °C. The reaction mixture was allowed to warm up to room temperature and was stirred at the same
temperature for 1h. After completion of the reaction (TLC), it was quenched by addition of sat. NH4Cl
(5 mL) solution, poured into water (10 mL) and was extracted with EtOAc. The combined organic
extracts were washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent
followed by silica gel column chromatography of the resultant residue with petroleum ether:EtOAc
24
(5:5) as eluent afforded 8b as a colourless oil in 65% (0.3 g) yield. [α]D −22.7 (c 1.35, CHCl3); IR
(neat) 2921, 2214, 1676, 1434 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.14 (d, J = 4.8 Hz, 1H), 4.87 (d, J
= 4.8 Hz, 1H), 3.70 (s, 3H), 3.23 (s, 3H), 2.07 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 184.5, 169.3, 113.5, 95.3, 82.9, 78.1, 74.7, 61.5, 32.4, 26.6, 26.4, 4.3; HRMS for
C12H17O5N+Na calcd 278.1004; found 278.1009.
7

ACCEPTED MANUSCRIPT
H
N
O
O
O
O
Me
OMe
Preparation of 8a: The reaction was performed similar to the procedure described above, except
quenching the reaction with ice-cold 1N HCl (2 mL), instead of saturated NH4Cl. Accordingly,
reaction of ethynylmagnesium bromide (0.8 mL of 0.5M solution in THF, 0.4 mmol) with the bis-
Weinreb amide 7 (0.1 g, 0.37 mmol) afforded the product 8a in 48% (42 mg) yield (68% based on
recovery of starting material) and 8aa resulting from the Michael addition of N,O-
dimethoxyhydroxylamine to 8a (0.03 g) in 29% yield. Data for 8a. [α]D24 −15.0 (c 1.0, CHCl3); IR
(neat) 3246, 2095, 1685, 853 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.15 (d, J = 4.8 Hz, 1H), 4.89 (d, J
= 4.8 Hz, 1H), 3.71 (s, 3H), 3.48 (s, 1H), 3.22 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 184.3, 169.1, 113.9, 83.1, 82.8, 79.3, 74.9, 61.6, 32.5, 26.7, 26.4. HRMS for C11H15O5N+Na
calcd 264.0848; found 264.0842.
O
Me
O
O
N
Me
OMe
N
OMe
O
Data for 8aa: [α]D24 −42.1 (c 1, CHCl3); IR (neat) 1662, 1575, 1423, 873 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.55 (d, J = 12.8 Hz, 1H), 5.71 (d, J = 12.8 Hz, 1H), 5.12 (d, J = 4.8 Hz, 1H), 4.87 (d, J =
5.2 Hz, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 3.22 (s, 3H), 3.19 (s, 3H), 1.51 (s, 3H), 1.45 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 194.5, 170.3, 148.5, 112.5, 92.5, 81.9, 74.6, 61.7, 59.8, 39.5, 32.4, 26.8, 26.5;
HRMS for C13H22O6N2+Na calcd 325.1376; found 325.1373.
General procedure for the addition of propane 1,3-dithiol to the alkynyl ketone 8a-h: The
following preparation for 9g is representative:
To a stirred solution of the alkynylketone 8g (0.67 g, 2.0 mmol) in MeOH:CH2Cl2 (4:1, 12.0 mL) was
added propane-1,3-dithiol (0.21 mL, 2.2 mmol) at room temperature. The reaction mixture was cooled
to −10 °C and solid NaOMe (0.14 g, 2.54 mmol) was added in one portion at −10 °C. The reaction
mixture was allowed to warm up to room temperature and was stirred at room temperature for 1.5 h.
After completion of the reaction (TLC), it was quenched by addition of saturated solution of NH4Cl (5
mL). The reaction mixture was poured into water (10 mL) and was extracted with diethyl ether (2×10
mL). The combined ethereal extracts were washed with brine (10 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by silica gel column chromatography of the resultant
residue with petroleum ether: EtOAc (7:3) as eluent afforded the dithioketo-amide 9g as a viscous pale
yellow oil in 98% (0.85 g) yield. [α]D24 +21.9 (c 1.2, CHCl3); IR (neat) 2930, 1684, 1438, 1213 cm-1;
1H NMR (400 MHz, CDCl3) δ 5.04 (d, J = 3.2 Hz, 1H), 4.85 (d, J = 3.6 Hz, 1H), 3.65 (s, 3H), 3.53 (d,
J = 15.6 Hz, 1H), 3.16 (s, 3H), 3.12 (d, J = 16 Hz, 1H), 3.05-2.87 (m, 2H), 2.76-2.63 (m, 2H), 2.09-
1.96 (m, 3H), 1.93-1.73 (m, 1H), 1.44 (s, 3H), 1.49-1.39 (m, 2H), 1.37 (s, 3H), 1.28-1.15 (m, 8H),
13
0.80 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 203.8, 169.6, 112.5, 83.1, 73.4, 61.5, 49.9,
44.5, 38.8, 32.3, 31.6, 29.4, 28.9, 26.5, 26.2 (2C), 26.1, 24.9, 23.6, 22.4, 13.9; HRMS for
C21H37O5N+Na calcd 470.2011; found 470.2010.
8

ACCEPTED MANUSCRIPT
Preparation of 9d: Following the general procedure, reaction of propane 1,3-dithiol with compound
8d (0.158 g, 0.5 mmol) afforded the product 9d in 90% (0.19 g) yield. [α]D24 +12.2 (c 1.45, CHCl3);
1
IR (neat) 2937, 1728, 1668, 1444 cm-1; H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.37
(t, J = 7.6 Hz, 2H), 7.26 (d, J = 6.8 Hz, 1H), 4.93 (d, J = 4.4 Hz, 1H), 4.48 (d, J = 4.4 Hz, 1H), 3.61 (d,
J = 16.4 Hz, 1H), 3.57 (s, 3H), 3.40 (d, J = 16.0 Hz, 1H), 3.16 (s, 3H), 2.83-2.69 (m, 4H), 2.07-1.88
13
(m, 2H), 1.42 (s, 3H), 1.31 (s, 3H); C NMR (100 MHz, CDCl3) δ 202.4, 169.7, 140.4, 128.6 (2C),
128.4 (2C), 127.4, 112.7, 82.8, 73.4, 61.5, 54.7, 51.5, 32.4, 27.6 (2C), 26.5, 26.2, 24.6; HRMS for
C20H27O5S2N+Na calcd 448.1228; found 448.1228.
Preparation of 9f: Following the general procedure, reaction of propane 1,3-dithiol with compound
8f (0.044 g, 0.14 mmol) afforded the product 9f in 95% (0.055 g) yield. [α]D24 +25.3 (c 1.15, CHCl3);
1
IR (neat) 2931, 1669, 1374, 1018 cm-1; H NMR (400 MHz, CDCl3) δ 5.11 (d, J = 5.2 Hz, 1H), 4.90
(d, J = 5.2 Hz, 1H), 3.71 (s, 3H), 3.59 (d, J = 15.6 Hz, 1H), 3.22 (s, 3H), 3.17 (d, J = 15.6 Hz, 1H),
3.10-2.91 (m, 2H), 2.83-2.67 (m, 2H), 2.11-2.02 (m, 3H), 1.92-1.85 (m, 1H), 1.50 (s, 3H), 1.42 (s,
13
3H), 1.55-1.37 (m, 2H), 1.36-1.18 (m, 6H), 0.86 (t, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ
204.0, 169.8, 112.7, 83.2, 73.6, 61.7, 50.1, 44.7, 39.0, 32.4, 31.5, 29.3, 26.7, 26.4 (2C), 26.3, 25.1,
23.8, 22.5, 14.0; HRMS for C20H35O5S2N+Na calcd 456.1854; found 456.1853.
Preparation of 9h: Following the general procedure, reaction of propane 1,3-dithiol with compound
8h (8.0 g, 19.3 mmol) afforded the product 9h in 95% (9.58 g) yield. [α]D25 +15.9 (c 2.0, CHCl3); IR
(Neat): νmax 2934, 1667, 1463, 1383, 1257, 1091, 991, 836 cm−1; 1H NMR (400 MHz, CDCl3): δ 5.10
(d, J = 4.8 Hz, 1H), 4.87 (d, J = 4.8 Hz, 1H), 3.70 (s, 3H), 3.61 (t, J = 6.4 Hz, 2H), 3.55 (d, J = 15.6
Hz, 1H), 3.21 (s, 3H), 3.14 (d, J = 15.6 Hz, 1H), 2.96 – 3.01 (m, 2H), 2.74–2.80 (m, 2H), 2.08–2.14
(m, 2H), 2.01–2.06 (m, 1H), 1.84–1.93 (m, 1H), 1.65–1.75 (m, 2H), 1.50 (s, 3H), 1.41 (s, 3H), 0.87 (s,
13
9H), 0.03 (s, 6H); C NMR (100 MHz, CDCl3): δ 203.8, 169.8, 112.7, 83.3, 73.5, 62.8, 61.7, 49.9,
44.9, 35.1, 32.4, 27.4, 26.7, 26.3 (2 × C), 26.2, 25.9 (3 × C), 24.9, 18.2, -5.3 (2 × C). HRMS: m/z
calcd for C23H43NO6S2Si +Na 544.2199; found: 544.2197.
O
S
S
nC2H5
O
O
Me
N
OMe
O
Preparation of 9e: Following the general procedure, reaction of propane 1,3-dithiol with compound
8e (1.8 g, 6.36 mmol) afforded the product 9e in 99% (2.47 g) yield. [α]D24 +25.9 (c 1.45, CHCl3); IR
(neat) 1670, 1382, 1085 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.10 (d, J = 4.8 Hz, 1H), 4.90 (d, J = 5.2
Hz, 1H), 3.71 (s, 3H), 3.59 (d, J = 16.0 Hz, 1H), 3.21 (s, 3H), 3.17 (d, J = 15.6 Hz, 1H), 3.08-2.94 (m,
9

ACCEPTED MANUSCRIPT
2H), 2.83-2.67 (m, 2H), 2.10-1.99 (m, 3H), 1.92-1.86 (m, 1H), 1.60-1.42 (m, 5H), 1.42 (s, 3H), 0.93 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.1, 169.7, 112.7, 83.2, 73.5, 61.7, 50.0, 44.6, 41.1,
32.4, 26.7, 26.4 (2C), 26.2, 25.1, 17.2, 14.1; HRMS for C17H29O5NS2+Na calcd 414.1385; found
414.1382.
O
S
S
O
O
TMS
Me
N
OMe
O
Preparation of 9c: Following the general procedure, reaction of TMS-acetylene (0.08 mL, 0.5 mmol)
with the bis-Weinreb amide 7 (0.1 g, 0.36 mmol) afforded the crude keto amide which on treatment
with propane 1,3-dithiol gave the product 9c in 64% (for 2 steps) (0.092 g) yield along with the
24
desilylated product 9a in 24% (0.029 g) yield. Data for 9c: [α]D +27.7 (c 1.0, CHCl3); IR (neat)
1673, 1248, 1085, 846 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.14 (d, J = 5.2 Hz, 1H), 4.97 (d, J = 4.8
Hz, 1H), 3.89 (d, J = 15.6 Hz, 1H), 3.71 (s, 3H), 3.37 (d, J = 15.6 Hz, 1H), 3.22 (s, 3H), 3.24-3.20
(m, 1H), 3.18-3.14 (m, 1 H), 2.52-2.45 (m, 2H), 2.19-2.05 (m, 1H), 1.89 (qt, J = 12.8, 3.2 Hz, 1H),
1.53 (s, 3H), 1.44 (s, 3H), 0.22 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 205.4, 170.0, 112.7, 83.4, 73.6,
61.7, 45.4, 34.8, 32.5, 26.8, 26.4, 24.8, 23.9, 23.8, −2.6 (3C); HRMS for C17H31O5NSiS2+Na calcd
444.1311; found 444.1312.
Preparation of 9b: Following the general procedure, reaction of propane 1,3-dithiol with compound
8b (0.054 g, 0.2 mmol) afforded the product 9b in 88% (0.071 g) yield. [α]D24 +29.5 (c 1.1, CHCl3);
1
IR (neat) 2922, 1668, 1374, 1081 cm-1; H NMR (400 MHz, CDCl3) δ 5.10 (d, J = 5.2 Hz, 1H), 4.89
(d, J = 5.2 Hz, 1H), 3.70 (s, 3H), 3.61 (d, J = 15.2 Hz, 1H), 3.20 (s, 3H), 3.16-2.95 (m, 3H), 2.83-2.68
13
(m, 2H), 2.15-2.00 (m, 1H), 1.91-1.76 (m, 1H), 1.73 (s, 3H), 1.49 (s, 3H), 1.41 (s, 3H); C NMR (
100 MHz, CDCl3) δ 204.1, 169.7, 112.7, 83.2, 73.5, 61.7, 47.8, 45.6, 32.4, 27.9, 26.9, 26.8, 26.6, 26.2,
24.6; HRMS for C15H25O5S2N+Na calcd 386.1072; found 386.1078.
O
S
S
O
O
H
Me
N
OMe
O
Preparation of 9a: Following the general procedure, reaction of propane 1,3-dithiol with compound
8a (0.037 g, 0.15 mmol) afforded the product 9a in 84% (0.042 g) yield. [α]D24 +1.6 (c 1.65, CHCl3);
IR (neat) 1672, 1382, 1213, 854 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.06 (d, J = 5.2 Hz, 1H), 4.83 (d,
J = 5.2 Hz, 1H), 4.51 (t, J = 6.8 Hz, 1H), 3.70 (s, 3H), 3.21 (s, 3H), 3.18 (dd, J = 18.0, 6.4 Hz, 1H),
3.03 (dd, J = 18.0, 6.4 Hz, 1H), 2.95-2.77 (m, 4H), 2.17-2.01 (m, 1H), 1.97-1.78 (m, 1H), 1.48 (s, 3H),
1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.9, 169.4, 113.1, 82.3, 73.8, 61.7, 44.5, 40.0, 32.4,
29.8, 29.7, 26.7, 26.2, 25.1; HRMS for C14H23O5NS2+Na calcd 372.0915; found 372.0933.
10

ACCEPTED MANUSCRIPT
General procedure for the reduction of dithio keto-amide 9a-h to 1,4-diol3a-h : The following
preparation of 13g is representative:
OH
S
S
nC6H13
O
O
OH
To a stirred solution of dithioketo-amide 9g (4.2 g, 9.45 mmol) in methanol (50 mL) was added
NaBH4 (0.720 g, 19 mmol) at −78 °C and the resulting reaction mixture was stirred at the same
temperature for 40 minutes. The progress of the reaction was monitored through TLC. Once the keto
reduction is over, the temperature of the reaction was allowed to come to room temperature and
additional NaBH4 (3.59 g, 94.5 mmol) was added. The reaction mixture was stirred at room
temperature for 7 h. After the completion of the reaction (TLC), it was quenched with water (5 mL),
excess MeOH was evaporated, diluted with water (20 mL), extracted with EtOAc (3 × 15 mL),
washed with brine (20 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent followed by
silica gel column chromatography of the residue with petroleum ether: EtOAc (7:3) as eluent afforded
24
the diol 13g as colourless oil in 81% (3 g) yield. [α]D −27.1 (c 0.8, CHCl3); IR (neat) 3424, 2930,
2857, 1432 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.14 (s,1H), 4.02 (dd, J = 11.6, 5.6 Hz, 1H), 3.86 (t, J
= 8.4 Hz, 1H), 3.77-3.63 (m, 2H), 3.58 (t, J = 8.0 Hz, 1H ), 3.12 (brs, 1H), 3.01 (t, J = 12.0 Hz, 1H),
2.92 (t, J = 12.0 Hz, 1H), 2.78-2.65 (m, 2H), 2.41-2.20 (m, 2H), 2.10-1.99 (m, 1H), 1.98-1.77 (m,3H),
1.36 (s, 3H), 1.34 (s, 3H), 1.30-1.19 (m, 10H), 0.84 (t, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
108.9, 81, 80.7, 70.7, 63.2, 51.7, 40.7, 39.7, 31.6, 29.6, 29.0, 26.9, 26.7, 26.4, 25.8, 24.8, 23.3, 22.5,
14.0; HRMS for C19H36O4S2+Na calcd 415.1953; found 415.1953.
Preparation of 13d: Following the general procedure, reduction of compound 9d (0.1 g, 0.24 mmol)
with NaBH4 afforded the product 13d in 71% (0.062 g) yield. [α]D24 +13.5 (c 1, CHCl3); IR (neat)
1
3437, 1052, 854, 701 cm-1; H NMR ( 400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6
Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 3.96 (dd, J = 12.0, 4.8 Hz, 1H), 3.84 (t, J = 8.8 Hz, 1H), 3.70 (d, J =
4.8 Hz, 2H), 3.58 (t, J = 7.6 Hz, 1H), 3.03 (brs, 1H), 2.89-2.76 ( m, 3H), 2.74-2.71 (m, 2H), 2.64 (d, J
= 14.8 Hz, 1H), 2.34 (dd, J = 14.8, 9.2 Hz, 1H), 2.09-1.89 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H); 13C
NMR ( 100 MHz, CDCl3) δ 141.5, 128.8 (2C), 128.2 (2C), 127.6, 109.0, 80.5, 80.4, 70.6, 63.3, 56.7,
27.9 (2C), 27.4, 27.0, 26.6, 24.5; HRMS for C18H26O4S2+Na calcd 393.1170; found 393.1176.
Preparation of 13f: Following the general procedure, reduction of compound 9f (0.030 g, 0.07 mmol)
with NaBH4 afforded the product 13f in 85% (0.022 g) yield. [α]D24 −29.9 (c 1.1, CHCl3); IR (neat)
3422, 1243, 1053, 856 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.21 (brs, 1H), 4.06-4.03 (m, 1H), 3.89 (td,
J = 8.0, 2.8 Hz, 1H), 3.79 (dd, J = 11.6, 4.0 Hz, 1H), 3.73 (dd, J = 11.2, 6.0 Hz, 1H), 3.61 (t, J = 8.0
Hz, 1H), 3.05 (ddd, J = 14.4, 11.2, 2.8 Hz, 1H), 2.96 (ddd, J = 14.4, 10.8, 2.8 Hz, 1H), 2.78 (dd, J =
5.6, 3.2 Hz, 1H), 2.74 (dd, J = 5.6, 3.2 Hz, 1H), 2.44-2.25 (m, 2H), 2.15-1.99 (m, 1H), 2.01-1.82 (m,
3H), 1.68 (brs, 1H), 1.56-1.43 (m, 2H), 1.40 (s, 3H), 1.37 (s, 3H), 1.34- 1.20 (m, 6H), 0.88 (t, J = 5.6
13
Hz, 3H); C NMR (100 MHz, CDCl3) δ 109.0, 81.1, 80.7, 70.8, 63.3, 51.7, 40.7, 39.8, 31.6, 29.4,
27.0, 26.7, 26.5, 25.9, 24.9, 23.3, 22.5, 14.0; HRMS for C18H34O4S2+Na calcd 401.1796; found
401.1799.
11

ACCEPTED MANUSCRIPT
Preparation of 13h: Following the general procedure, reduction of compound 9h (9.4 g, 18.0 mmol)
with NaBH4 afforded the product 13h in 87% (7.3 g) yield. [α]D25 −21.6 (c 0.8, CHCl3); IR (Neat):
νmax 3417, 2952, 2930, 1650, 1469, 1371, 1255, 1099, 835 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.16
(bs, 1H), 4.04 (dd, J = 10.8, 6.4 Hz, 1H), 3.93 (t, J = 8.8 Hz, 1H), 3.70–3.79 (m, 2H), 3.59–3.65 (m,
3H), 2.91–3.04 (m, 3H), 2.74–2.80 (m, 2H), 2.42 (d, J = 15.2 Hz, 1H), 2.28 (dd, J = 15.2, 9.6 Hz, 1H),
1.99–2.07 (m, 3H), 1.86–1.94 (m, 1H), 1.65–1.81 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H), 0.89 (s, 9H),
0.05 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 108.9, 81.1, 80.8, 70.7, 63.4, 62.7, 51.5, 41.2, 35.9, 26.9
(2 × C), 26.7 (2 × C), 25.9 (3 × C), 25.8, 24.8, 18.3, -5.4 (2 × C); HRMS: m/z calcd for C21H42O5S2Si
+Na 489.2141; found: 489.2141.
OH
S
S
nC2H5
O
O
OH
Preparation of 13e: Following the general procedure, reduction of compound 9e (0.9 g, 2.94 mmol)
with NaBH4 afforded the product 13e in 82% (0.63 g) yield. [α]D24 −40.8 (c 1.05, CHCl3); IR (neat)
3418, 1381, 1051, 855 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.15 (brs, 1H), 4.11-3.96 (m, 1H), 3.88 (t,
J = 8.4 Hz, 1H), 3.81-3.64 (m, 2H), 3.59 (t, J = 7.6 Hz, 1H), 3.13-3.03 (m, 1H), 3.03-2.90 (m, 2H),
2.81-2.66 (m, 2H), 2.36 (dd, J = 15.6, 2.0 Hz,1H), 2.29 (dd, J = 15.6, 9.2 Hz,1H), 2.12-1.96 (m, 1H),
13
1.96-1.82 (m, 3H), 1.60-1.42 (m, 2H), 1.38 (s, 3H), 1.35 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H). C NMR
(100 MHz, CDCl3) δ 108.9, 81.0, 80.6, 70.7, 63.2, 51.7, 42.0, 40.8, 26.9, 26.7, 26.4, 25.8, 24.8, 16.8,
14.1; HRMS for C15H28O4S2+Na calcd 359.1327; found 359.1325.
Preparation of 13b: Following the general procedure, reduction of compound 9b (0.055 g, 0.14
mmol) with NaBH4 afforded the product 13b in 81% (0.035 g) yield. [α]D24 −45.9 (c 1.6, CHCl3); IR
1
(neat) 3422, 1215, 1077, 855 cm-1; H NMR (400 MHz, CDCl3) δ 4.05 (m, 1H), 3.94 (t, J = 8.0 Hz,
1H), 3.79 (dd, J = 11.2, 4.0 Hz, 1H), 3.74 (dd, J = 11.2, 5.6 Hz, 1H), 3.63 (t, J = 7.6 Hz, 1H), 3.11-
2.92 (m, 2H), 2.86-2.69 (m, 2H), 2.36 (dd, J = 14.8, 9.2 Hz, 1H), 2.28 (dd, J = 15.2, 1.6 Hz, 1H), 2.13-
1.99 (m, 1H), 1.97-1.78 (m, 1H), 1.66 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 109.0, 81.0, 80.5, 70.9, 63.3, 47.4, 44.0, 28.4, 27.0, 26.82, 26.76, 26.5, 24.4; HRMS for
C13H24O4S2+Na calcd 331.1014; found 317.1017.
OH
S
S
O
O
H
OH
Preparation of 13a: Following the general procedure, reduction of compound 9a (0.033 g, 0.1 mmol)
with NaBH4 afforded the product 13a in 75% (0.020 g) yield. [α]D24 −22.4 (c 0.45, CHCl3); IR (neat)
1
3413, 1250, 1067, 854 cm-1; H NMR (400 MHz, CDCl3) δ 4.26 (dd, J = 8.8, 5.6 Hz, 1H), 4.12-3.93
(m, 2H), 3.77 (d, J = 4.8 Hz, 2H), 3.70 (t, J = 7.2 Hz, 1H), 2.96-2.81 (m, 4H), 2.19 (ddd, J = 14.4, 8.8,
2.4 Hz,1H), 2.16-2.11 (m, 1H), 2.00-1.85 (m, 2H), 1.40 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 109.2,
12

ACCEPTED MANUSCRIPT
80.6, 79.5, 70.1, 63.1, 43.8, 39.1, 29.9, 29.7, 27.0, 26.9, 25.7. HRMS for C12H22O4S2+Na calcd
317.0857; found 317.0854.
Preparation of 19: To a solution of diol (2.7 g, 6.88 mmol) in dry CH2Cl2 (30 mL) at 0 °C was added
Et3N (1.06 mL, 7.56 mmol), TsCl (1.4 g, 7.56 mmol) followed by DMAP (0.17 g, 1.37 mmol). The
reaction mixture was stirred at room temperature for 3.5 h. After completion of the reaction (TLC), it
was quenched with ice-cold water (10 mL), extracted with diethyl ether (3 × 15 mL), washed with
brine (20 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent followed by silica gel
column chromatography of the crude residue with petroleum ether:EtOAc (9:1) as eluent afforded the
24
monotosylate 19 as colourless viscous liquid in 92% (3.4 g) yield. [α]D −39.3 (c 1.9, CHCl3); IR
(neat) 3445, 2923, 1600, 1372 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.2 Hz, 2H), 7.34 (d, J
= 8.0 Hz, 2H), 4.36 (d, J = 10.4 Hz, 1H), 4.22-4.14 (m, 1H), 4.13-4.09 (m, 1H), 3.87 (t, J = 8.0 Hz,
1H), 3.67-3.55 (m, 2H), 3.10-2.85 (m, 2H), 2.83-2.68 (m, 2H), 2.44 (s, 3H), 2.36-2.13 (m, 2H), 2.08-
1.98 (m, 1H), 1.98-1.84 (m, 3H),1.57-1.38 (m, 2H), 1.33 (s, 6H), 1.32-1.22 (m, 8H), 0.87 (t, J = 6.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.6, 132.7, 129.6 (2C), 127.8 (2C), 109.8, 78.4, 77.7, 70.6,
70.1, 51.5, 40.8, 39.6, 31.5, 29.5, 28.9, 26.7, 26.6, 26.2, 25.6, 24.7, 23.2, 22.4, 21.4, 13.9; HRMS for
C26H42O6S3+Na calcd 569.2041; found 569.2041.
Preparation of 20: To a solution of 19 (3.3 g, 6.04 mmol) in acetone (25 mL) was added NaI (14.5 g,
96.6 mmol) and the resulting reaction mixture was refluxed for 20 h. After the completion of the
reaction, it was diluted with water (10 mL) and extracted with diethyl ether (3 × 10 mL), washed with
brine (20 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent followed by silica gel
column chromatography of the residue with petroleum ether: EtOAc (9:1) as eluent afforded the iodide
24
20 as colourless viscous liquid in 96% (3.0 g) yield. [α]D −46.6 (c 1.8, CHCl3); IR (neat) 3441,
1
2930, 1635, 1380 cm-1; H NMR (400 MHz, CDCl3) δ 3.93-3.81 (m, 2H), 3.67 (s,1H), 3.58-3.45
(m,2H), 3.32 (dd, J = 10.4, 5.6 Hz, 1H), 3.03-2.97 (m, 1H), 2.94-2.89 (m, 1H), 2.79-2.62 (m, 2H),
2.32-2.21 (m, 2H), 2.08-1.94 (m, 1H), 1.96-1.76 (m, 3H), 1.54-1.34 (m, 2H), 1.42 (s, 3H), 1.33 (s,
13
3H), 1.29-1.14 (m, 8H), 0.83 (t, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 109.4, 82.6, 78.9,
70.7, 51.6, 40.7, 39.7, 31.6, 29.6, 28.9, 27.3, 27.1, 26.4, 25.7, 24.8, 23.3, 22.4, 13.9, 8.7; HRMS for
C19H35O3S2I+Na calcd 525.0970; found 525.0968.
Preparation of 21: To a solution of iodide 20 (0.52 g, 1.04 mmol) in 2:1 CH3CN: water mixture (9
mL) was added MeI (0.64 mL, 10.38 mmol) followed by CaCO3 (0.42 g, 4.2 mmol) at room
temperature. The reaction mixture was then heated to 45 °C and stirred for 6 h. After completion of
the reaction (TLC), it was cool down to room temperature and excess CH3CN was removed under
reduced pressure, the crude reaction mixture was poured into water (5mL), extracted with diethyl ether
(3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous
Na2SO4. Evaporation of the solvent followed by silica gel column chromatography of the residue with
13

ACCEPTED MANUSCRIPT
petroleum ether: EtOAc (8:2) as eluent afforded the beta hydroxy ketone 21 as colourless oil in 81%
(0.35 g) yield. [α]D −42.8 (c 1.6, CHCl3); IR (neat) 3487, 2928, 1713, 1372 cm-1; H NMR (400
MHz, CDCl3) δ 4.09-3.94 (m, 1H), 3.93-3.79 (m, 1H), 3.56 (t, J = 7.6 Hz,1H), 3.51 (dd, J = 10.8, 3.6
Hz, 1H), 3.48 (d, J = 3.6 Hz, 1H). 3.33 (dd, J = 10.4, 5.6 Hz, 1H), 2.84 (dd, J = 18.0, 2.0 Hz, 1H), 2.58
(dd, J = 18.0, 9.2 Hz, 1H), 2.42 (t, J = 7.6 Hz, 2H), 1.61-1.48 (m, 2H), 1.43 (s, 3H), 1.34 (s, 3H), 1.24
(brs, 8H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 212.4, 109.6, 82.0, 79.2, 69.5, 45.7,
43.6, 31.5, 29.0, 28.9, 27.3, 27.2, 23.5, 22.5, 14.0, 8.2; HRMS for C16H29O4I+Na calcd 435.1008;
found 435.1005.
24
1
OH OH
nC6H13
O
I
O
Preparation of 22: Tetramethylammoniumtriacetoxy borohydride (2.2 g, 8.48 mmol) was added to a
solution of anhydrous 1:1 mixture of CH3CN: AcOH (10 mL) at room temperature and stirred for 30
min. The reaction mixture was then cooled to −20 °C and a solution of beta–hydroxy ketone 21 (1.6 g,
4.24 mmol) in CH3CN: AcOH (1:1, 10 mL) was added dropwise and stirred at the same temperature
for additional 5 h. After completion of the reaction (TLC), it was carefully quenched by the addition of
sat. solution of sodium–potassium tartrate (10 mL). The reaction mixture was diluted with EtOAc (20
mL) and was washed with sat. solution of NaHCO3 (10 mL). The aqueous layer was extracted with
EtOAc (2 × 10 mL), and the combined organic extracts were washed with brine (10 mL), dried over
anhydrous Na2SO4. Evaporation of the solvent followed by silica gel column chromatography of the
residue with petroleum ether: EtOAc (7:3) as eluent afforded the 1,3 anti-diol 22 as colourless oil in
93% (1.5 g) yield. [α]D24 −24.9 (c 1.8, CHCl3); IR (neat) 3424, 2929, 1638, 1238 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.99-3.81 (m, 3H), 3.67 (t, J = 6.8 Hz, 2H), 3.50 (dd, J = 10.8, 3.6 Hz, 1H), 3.33 (dd, J
= 10.8, 5.6 Hz, 1H), 1.68 (t, J = 5.6 Hz, 2H), 1.40 (s, 3H), 1.54-1.35 (m, 2H), 1.36 (s, 3H), 1.26 (brs,
10H), 0.85 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 109.4, 82.8, 78.2, 70.0, 69.3, 38.9, 37.5,
31.7, 29.4, 29.1, 27.4, 27.3, 25.6, 22.5, 14.0, 8.6; HRMS for C16H31O4I+Na calcd 437.1165; found
437.1164.
Preparation of 23: To a solution of the iodide 22 (0.21 g, 0.48 mmol) in ethanol (5 mL) was added
freshly activated Zn dust (0.25 g, 3.84 mmol) and the resulting reaction mixture was stirred under
refluxing conditions for 2 h. After completion of the reaction (TLC), the reaction mixture was filtered
through a short pad of celite with EtOAc (10 mL). Evaporation of the solvent followed by silica gel
column chromatography of the residue with petroleum ether: EtOAc (1:1) as eluent afforded the triol
23 as amorphous solid in 98% (0.115 g) yield. mp: 79-80 °C; [α]D24 −3.2 (c 0.75, CHCl3); IR (neat)
1
3403, 2922, 1942, 1454 cm-1; H NMR (400 MHz, CDCl3) δ 5.89 (ddd, J = 17.2, 10.4, 6.4 Hz, 1H),
5.33 (d, J = 17.6 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 4.20-4.09 (m, 1H), 4.01 (d, J = 10.0 Hz, 1H),
3.91 (brs, 2H), 3.75 (brs, 1H), 3.45 (brs, 1H), 1.66-1.61 (m, 1H), 1.55-1.36 (m, 4H), 1.26 (brs, 9H),
13
0.87 (t, J = 6.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 136.0, 117.7, 76.1, 71.0, 69.2, 37.7, 37.4,
31.8, 29.6, 29.3, 25.8, 22.6, 14.1; HRMS for C13H26O3+Na calcd 253.1780; found 253.1790.
Preparation of 18: To a solution of the triol 23 (0.1 g, 0.478 mmol) in CH2Cl2 (4 mL) was added 2,2-
dimethoxy propane (0.1 mL, 0.96 mmol) followed by p-TSA (0.005 g, 0.02 mmol) and the resulting
14

ACCEPTED MANUSCRIPT
reaction mixture was stirred at rt for 20 minutes. After completion of the reaction (TLC), it was
quenched with sat. solution of NaHCO3 (5 mL), extracted with EtOAc (2 × 5 mL). The combined
organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of the
solvent followed by silica gel column chromatography of the residue with petroleum ether: EtOAc
(4:1) as eluent afforded 18 as yellow oil in 80% (0.094 g) yield. [α]D24 −19.6 (c 0.85, CHCl3). Lit10c
[α]D −14.0 (c 0.2, CHCl3).; IR (neat) 3431, 2929, 1458, 1047 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.77
(ddd, J = 17.2, 10.4, 7.6 Hz, 1H), 5.29 (d, J = 17.2 Hz, 1H), 5.22 (d, J = 10.4 Hz, 1H), 4.53 (t, J = 6.8
Hz, 1H), 4.52-4.37 (m, 1H), 3.85-3.74 (m, 1H), 2.14 (brs, 1H), 1.65-1.58 (m, 1H), 1.47 (s, 3H), 1.52-
1.31 (m, 3H), 1.36 (s, 3H), 1.32-1.22 (m, 10H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 134.3, 118.2, 108.3, 79.6, 74.9, 68.9, 37.8, 37.4, 31.8, 29.5, 29.2, 28.1, 25.7, 25.6, 22.6, 14.0; HRMS
for C16H30O3+Na calcd 293.2093; found 293.2099.
Preparation of 25: To a solution of the alcohol 18 (0.075 g, 0.28 mmol) and acid 24 (0.14 g, 0.39
mmol) in DCM ( 10 mL) was added DCC (0.086 g, 0.42 mmol) followed by DMAP (0.051 g, 0.42
mmol) at 0 °C and the resulting reaction mixture was stirred at room temperature for 14 h. After
completion of the reaction (TLC), excess CH2Cl2 was evaporated off and the crude residue was
filtered through a short pad of celite and the celite pad was washed with diethyl ether (10 mL).
Evaporation of the solvent followed by silica gel column chromatography of the residue with
petroleum ether: EtOAc (9:1) as eluent afforded the ester 25 as colourless oil in 92% (0.16 g) yield;
1
[α]D24 −3.4 (c 2.1, CHCl3); IR (neat) 2932, 1736, 1370, 1112 cm-1; H NMR (400 MHz, CDCl3) δ
7.76-7.60 (m, 4H), 7.48-7.30 (m, 6H), 5.87 (ddd, J = 17.2, 10.4, 6.8 Hz, 1H), 5.76 (ddd, J = 17.6, 10.4,
7.6 Hz, 1H), 5.37-5.17 (m, 2H), 5.10-4.91 (m, 3H), 4.58 (q, J = 6.4 Hz, 1H), 4.43 (t, J = 6.8 Hz, 1H),
4.08 (ddd, J = 9.6, 6.4, 3.2 Hz, 1H), 2.55 (dd, J = 14.4, 5.2 Hz, 1H), 2.46 (dd, J = 14.4, 8.0 Hz, 1H),
1.61-1.55 (m, 1H), 1.53-1.50 (m, 3H), 1.45 (s, 3H), 1.30 (s, 3H), 1.35-1.19 (m, 10H), 1.07 (s, 9H),
0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 139.2, 135.89 (2C), 135.87 (2C),
134.2, 133.8, 133.7, 129.7, 129.6, 127.5 (2C), 127.4 (2C), 118.3, 115.3, 108.3, 79.4, 74.7, 72.1, 71.5,
43.4, 35.1, 34.7, 31.7, 29.4, 29.1, 28.2, 26.9 (3C), 25.6, 25.0, 22.6, 19.2, 14.0; HRMS for
C37H54O5Si+Na calcd 629.3638; found 629.3633.
Preparation of 17: To a solution of 25 (0.085 g, 0.14 mmol) in THF (1 mL) was added TBAF (0.17
mL, 0.17 mmol) at 0 °C and the resulting reaction mixture was stirred at room temperature for 3 h.
After completion of the reaction (TLC), it was diluted with ice-cold water (2 mL) and extracted with
EtOAc (2 × 5 mL), The combined organic extracts were washed with brine (10 mL) and dried over
anhydrous Na2SO4. Evaporation of the solvent followed by silica gel column chromatography of the
crude residue with petroleum ether: EtOAc (4:1) as eluent afforded the ester 17 as colourless oil in
91% (0.047 g) yield. [α]D24 −23.3 (c 0.6, CHCl3). Lit10c −19.8 (c 0.53, CHCl3). ; IR (neat) 3450, 2930,
1720, 1043 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.89 (ddd, J = 17.2, 10.4, 5.2 Hz, 1H), 5.77 (ddd, J =
17.2, 10.4, 7.6 Hz, 1H), 5.34-5.24 (m, 3H), 5.22-5.03 (m, 2H), 4.59-4.43 (m, 2H), 4.19 (ddd, J = 10.0,
6.4, 2.8 Hz, 1H), 3.12 (s, 1H), 2.58 (dd, J = 15.6, 4.0 Hz, 1H), 2.50 (dd, J = 15.6, 8.0 Hz, 1H), 1.77-
13
1.50 (m, 5H), 1.47 (s, 3H), 1.34 (s, 3H), 1.39-1.21 (m, 9H), 0.87 (t, J = 6.0 Hz, 3H); C NMR (100
15

ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 171.8, 138.8, 134.0, 118.5, 115.3, 108.5, 79.5, 74.4, 72.5, 69.0, 41.5, 35.0, 34.6, 31.7,
29.4, 29.1, 28.2, 25.6, 25.1, 22.6, 14.0; HRMS for C21H36O5+Na calcd 391.2460; found 391.2462.
Preparation of 26: To a solution of the diene 17 (0.056 g, 0.15 mmol) in freshly distilled dry CH2Cl2
(75 mL) was added Grubbs’ 2nd gen catalyst (0.013 g, 0.015 mmol) at room temperature. The reaction
mixture was refluxed under argon atmosphere for 2 h. After completion of the reaction (TLC), excess
CH2Cl2 was evaporated off and the crude reaction mixture was purified by silica gel column
chromatography using petroleum ether: EtOAc (3:2) as eluent to afford the E-lactone 26 as brown oil
in (0.011 g, 21%) yield along with the Z-lactone 27 (0.013g) 25% yield and the dimer 28 (0.015g) in
29% yield. Data for E-lactone 26: [α]D24 −26.4 (c 0.25, CHCl3) Lit10f −30 (c 0.4, CHCl3); IR (neat)
1
3422, 2929, 1640, 1246 cm-1; H NMR (400 MHz, CDCl3+C6D6 (1:1)) δ 5.56 (dd, J = 16.0, 9.2 Hz,
1H), 5.42 (dd, J = 16.0, 8.0 Hz, 1H), 4.72-4.56 (m, 1H), 4.39 (dd, J = 9.2, 6.0 Hz, 1H), 4.30-4.18 (m,
1H), 3.92 (dd, J = 10.0, 6.0 Hz, 1H), 2.64 (dd, J = 13.2, 7.6 Hz, 1H), 2.24-2.01 (m, 2H), 1.55-1.36 (m,
13
2H), 1.42-1.22 (m, 1H), 1.34 (s, 3H), 1.25-1.09 (m, 14H), 0.81 (t, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl3+C6D6 (1:1)) δ 170.0, 133.5, 129.7, 108.6, 80.8, 77.3, 74.9, 70.0, 43.8, 38.0, 35.7, 31.8,
29.3, 29.2, 28.1, 25.6, 25.3, 22.6, 14.0; HRMS for C19H32O5+Na calcd 363.2147; found 363.2147.
1
Data for Z-lactone 27: [α]D24 +27.2 (c 0.5, CHCl3); IR (neat) 3422, 2929,1637, 1165 cm-1; H NMR
(400 MHz, CDCl3) δ 5.72-5.59 (m, 2H), 5.59-5.45 (m, 1H), 5.20-5.04 (m, 1H), 4.82-4.71 (m, 1H),
4.34-4.19 (m,1H), 2.66 (dd, J = 12.0, 5.2 Hz, 1H), 2.47 (dd, J = 12.0, 2.8 Hz, 2H), 2.03-1.89 (m, 2H),
13
1.72-1.42 (m, 4H), 1.34 (s, 3H), 1.25 (s, 3H), 1.34-1.25 (m, 8H), 0.87 (t, J = 6.4 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 169.6, 132.1, 130.8, 107.3, 77.8, 74.1, 72.0, 68.4, 41.2, 35.5, 31.7, 30.9, 29.3,
29.1, 28.4, 25.7, 25.2, 22.6, 14.1; HRMS for C19H32O5+Na calcd 363.2147; found 363.2144.
1
Data for dimer 28: [α]D24 +5.7 (c 0.35, CHCl3); IR (neat) 3407, 2920, 1733, 1570 cm-1; H NMR
(400 MHz, CDCl3) δ 5.89 (dd, J = 15.6, 6.4 Hz, 1H), 5.75 (dd, J = 15.6, 7.2 Hz, 1H), 4.96 (t, J = 6.0
Hz, 1H), 4.51 (t, J = 6.0 Hz, 2H), 4.14 (q, J = 6.4 Hz, 1H), 2.86 (brs, 1H), 2.67 (dd, J = 15.6, 5.6 Hz,
1H), 2.54 (dd, J = 15.6, 5.2 Hz, 1H), 1.81-1.56 (m, 5H), 1.46 (s, 3H), 1.35 (s, 3H), 1.46-1.26 (m, 9H),
13
0.88 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 171.3, 135.4, 127.7, 108.3, 78.4, 75.7, 72.9,
68.7, 41.4, 35.1, 34.2, 31.7, 29.3, 29.1, 28.2, 25.6, 25.2, 22.6, 14.1; HRMS for C38H64O10+Na calcd
703.4397; found 703.4396.
16

ACCEPTED MANUSCRIPT
Preparation of 29: To a solution of 17 (0.100 g, 0.27 mmol) in dry CH2Cl2 (2 mL) were added
diisopropylethyl amine (0.94 mL, 5.4 mmol), DMAP (14 mg, 0.1 mmol) and MOMCl (0.16 mL, 2.17
mmol) at 0 °C and the resulting reaction mixture was refluxed for 19 h. After completion of the
reaction (TLC), it was diluted with water (2 mL) and extracted with diethyl ether (2 × 10 mL).
Combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent followed by silica gel column chromatography of the crude residue with
24
petroleum ether: EtOAc (9:1) as eluent afforded 29 as colourless oil in 91% (0.102 g) yield. [α]D
−47.3 (c 1.15, CHCl3); IR (neat) 2928, 1737, 1373, 1034 cm-1; H NMR (400 MHz, CDCl3) δ 5.82-
1
5.69 (m, 2H), 5.34-5.31 (m, 1H), 5.29-5.25 (m, 1H), 5.23-5.20 (m, 2H), 5.10-5.03 (m, 1H), 4.68 (d, J
= 6.4 Hz, 1H), 4.55 (d, J = 6.8 Hz, 1H), 4.50 (d, J = 7.2 Hz, 1H), 4.47(d, J = 7.2 Hz, 1H), 4.18 (ddd, J
= 9.2, 6.4, 4.0 Hz, 1H), 3.35 (s, 3H), 2.62 (dd, J = 15.2, 8.4 Hz, 1H), 2.48 (dd, J = 15.2, 8.4 Hz, 1H),
1.66-1.54 (m, 4H), 1.45 (s, 3H), 1.32 (s, 3H), 1.30-1.22 (m, 10H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.2, 136.8, 134.2, 118.3, 118.1, 108.2, 94.1, 79.5, 74.7, 73.9, 72.3, 55.6, 41.1,
35.2, 34.8, 31.7, 29.4, 29.1, 28.2, 25.6, 25.1, 22.6, 14.0; HRMS for C23H40O6+Na calcd 435.2723;
found 435.2726.
Preparation of 31: To a solution of the diene 29 (0.022 g, 0.053 mmol) in freshly distilled dry CH2Cl2
(30 mL, 0.0018 M) was added Grubbs’ II catalyst (0.0045 g, 0.005 mmol) at room temperature. The
reaction mixture was refluxed under argon atmosphere for 2.5 h. After completion of the reaction
(TLC), excess CH2Cl2 was evaporated off and the crude reaction mixture was purified by silica gel
column chromatography using petroleum ether: EtOAc (85:15) as eluent to afford the E-lactone 31 as
colourless oil in (0.011 g, 54%) yield and the Z-lactone (0.007g) in 34% yield. Data for E-lactone 31:
1
[α]D24 −57.1 (c 0.45, CHCl3); IR (neat) 2928, 1730, 1374, 1045 cm-1; H NMR (400 MHz, CDCl3) δ
5.82 (dd, J = 15.6, 9.2 Hz, 1H), 5.62 (dd, J = 16.0, 9.2 Hz, 1H), 4.89-4.83 (m, 1H), 4.70 (d, J = 6.8 Hz,
1H), 4.64 (dd, J = 9.2, 6.0 Hz, 1H), 4.58 (d, J = 6.8 Hz, 1H), 4.53 (dd, J = 17.2, 9.2 Hz, 1H), 4.14 (dd,
J = 10.4, 6.4 Hz, 1H), 3.36 (s, 3H), 3.00 (dd, J = 13.2, 8.0 Hz, 1H), 2.40 (dd, J = 13.6, 9.2 Hz, 1H),
2.28-2.18 (m, 1H), 1.68-1.48 (m, 1H), 1.43 (s, 3H), 1.33 (s, 3H), 1.31-1.24 (m, 12H), 0.87 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 131.9, 131.3, 108.9, 94.5, 80.8, 77.1, 74.9, 74.1, 55.5,
42.1, 38.0, 35.7, 31.7, 29.2, 29.1, 28.1, 25.6, 25.4, 22.6, 14.0; HRMS for C21H36O6+Na calcd
407.2410; found 407.2409.
nC7H15
O
O
MOMO
O
O
1
Data for Z-lactone 30: [α]D24 +4.0 (c 0.2, CHCl3); IR (neat) 2928,1735, 1373, 1168 cm-1; H NMR
(400 MHz, CDCl3) δ 5.71-5.65 (m, 1H), 5.54 (dd, J = 11.6, 5.6 Hz, 1H), 5.30 (dd, J = 10.4, 6.0 Hz,
1H), 5.12-5.06 (m, 1H), 4.79 (d, J = 7.2 Hz, 1H), 4.68 (d, J = 6.8 Hz,1H), 4.60 (td, J = 5.2, 3.2 Hz,
1H), 4.23 (dd, J = 14.0, 6.0 Hz, 1H), 3.41 (s, 3H), 2.70 (dd, J = 12.4, 5.2 Hz, 1H), 2.45 (dd, J = 12.4,
3.2 Hz, 1H), 1.97-1.93 (m, 2H), 1.62-1.56 (m, 2H), 1.46 (s, 3H), 1.32 (s, 3H), 1.30-1.23 (m, 10H),
13
0.87 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 169.3, 132.9, 127.6, 107.2, 94.5, 77.7, 74.2,
17

ACCEPTED MANUSCRIPT
71.8, 71.1, 55.8, 39.7, 35.5, 35.4, 31.7, 29.3, 29.1, 28.5, 25.7, 25.2, 22.6, 14.0; HRMS for
C21H36O6+Na calcd 407.2410; found 407.2410.
Preparation of 2: To a solution of the lactone 31 (0.011 g, 0.029 mmol) in CH2Cl2 (1 mL) was added
TFA (0.013 mL, 0.17 mmol) at 0 °C and the resulting reaction mixture was stirred at room
temperature for 12 h. After completion of the reaction (TLC), the volatiles were evaporated off and the
resulting crude reaction mixture was purified through silica gel column chromatography using
petroleum ether: EtOAc (1:9) as eluent to afford achaetolide 2 in 68% (0.006 g) yield. [α]D24 −26.0 (c
0.2, MeOH); Lit10b [α]D24 −27.0 (c 0.52, MeOH); IR (KBr) 3436, 2925, 1703, 1636 cm-1; H NMR
1
(400 MHz, CD3OD) (67:33 mixture of major and minor conformers) δ 5.97 (ddd, J = 16.0, 3.2, 2.4
Hz, 1H major), 5.69 (ddd, J = 16.0, 2.4, 1.2 Hz, 1H major), 5.58 (dd, J = 16.4, 7.2 Hz, 1H minor), 5.42
(dd, J = 16.4, 8.8 Hz, 1H minor), 4.92 (m, 1H minor), 4.75-4.70 (m, 1H), 4.69-4.64 (m, 1H), 4.44 (m,
1H × b), 4.44 (m, 1H major), 4.28 (dd, J = 7.2, 3.2 Hz, 1H minor), 3.64 (d, J = 10.0 Hz, 1H major),
3.45 (m, 1H minor), 2.93 (dd, J = 13.2, 7.6 Hz, 1H minor), 2.53 (dd, J = 12.0, 4.0 Hz, 1H major), 2.49
(dd, J = 12.0, 3.6 Hz, 1H major), 2.37 (m, 1H minor), 2.37 (m, 1H major), 2.27 (dd, J = 13.6, 8.8 Hz,
1H minor), 1.70 (m, 1H minor), 1.55 (m, 1H minor), 1.52 (m, 2H major), 1.45-1.41 (m, 1H major),
13
1.40-1.37 (m, 1H minor), 1.28 (m, 10H), 0.89 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CD3OD) δ
172.3 (minor), 172.1 (major), 136.6 (minor), 131.6(major), 131.1 (minor), 127.6 (major), 78.3
(minor), 77.6 (minor), 76.7 (major), 74.8 (major), 74.6 (minor), 74.5 (major), 71.6 (minor), 68.0
(major), 44.9 (major), 38.3 (minor), 37.9 (major), 37.6 (major), 36.0 (minor), 32.9 (major), 30.8
(minor), 30.5 (major), 30.3 (major), 26.9 (minor), 26.2 (major), 23.7, 14.4; HRMS for C16H28O5+Na
calcd 323.1834; found 323.1834.
(4S,5E,7R,8S,10R,14S,15E,17R,18S,20R)-10,20-diheptyl-4,7,8,14,17,18-hexahydroxy-1,11-
dioxacycloicosa-5,15-diene-2,12-dione (32): To a solution of 28 (0.004 g, 0.0058 mmol) in CH2Cl2
(1 mL) was added TFA (0.0008 mL, 0.0012 mmol) at 0 °C and the resulting reaction mixture was
stirred at room temperature for 2 h. After completion of the reaction (TLC), the volatiles were
evaporated off and the resulted crude reaction mixture was purified through silica gel column
chromatography using EtOAc as eluent to afford achaetolide dimer 32 as white solid in 86% (0.003 g)
yield. mp: 184-186 °C; [α]D24 −5.0 (c 0.1, MeOH ); IR (KBr) 3433, 1640, 1406, 1018 cm-1; 1H NMR
(400 MHz, CD3OD) δ 5.78-5.56 (m, 2H), 5.20-5.08 (m, 1H), 4.55-4.42 (m, 1H), 3.68 (t, J = 8.0 Hz,
1H), 3.32-3.20 (m, 1H), 2.76 (dd, J = 12.4, 4.4 Hz, 1H), 2.37 (t, J = 11.6 Hz, 1H), 2.13 (t, J = 12.8,
1H), 1.61-1.51 (m, 2H), 1.47-1.25 (m, 11H), 0.90 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ
171.7, 136.0, 135.9, 77.8, 72.5, 70.93, 70.87, 45.4, 39.0, 36.4, 33.1, 30.8, 30.5, 26.4, 23.9, 14.6.
HRMS for C32H56O10+Na calcd 623.3771; found 623.3776.
18

ACCEPTED MANUSCRIPT
Preparation of 15: To a solution of bis-Weinrebamide 7 (0.1 g, 0.36 mmol) in THF (5 mL) was
added nonylmagnesiumbromide (1.5 mL, 0.54 mmol) dropwise at −20 °C. The resulting reaction
mixture was stirred for 15 minutes at the same temperature. After completion of the reaction (TLC), it
was quenched with saturated solution of NH4Cl (5 mL), extracted with EtOAc (2 × 5 mL) and dried
over anhydrous Na2SO4. Evaporation of the solvent followed by silica gel column chromatography of
the crude residue with petroleum ether: EtOAc (7:3) as eluent afforded the keto-amide 15 as colourless
oil in 81% (0.1 g) yield. [α]D24 +5.0 (c 0.8, CHCl3); IR (neat) 2928, 1716, 1674, 1382 cm-1; 1H NMR
(400 MHz, CDCl3) δ 5.02 (d, J = 5.2 Hz, 1H), 4.80 (d, J = 4.8 Hz, 1H), 3.69 ( s, 3H), 3.21 (s, 3H),
2.76-2.48 (m, 2H), 1.64-1.51 (m, 2H), 1.48 (s, 3H), 1.42 (s, 3H), 1.30-1.19 (m, 12H), 0.85 (t, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.4, 169.8, 112.7, 82.2, 73.9, 61.6, 39.3, 32.4, 31.8, 29.35,
29.31, 29.2, 29.1, 26.6, 26.2, 23.0, 22.6, 14.0; HRMS for C18H33O5N+Na calcd 366.2256; found
366.2258.
(4R,5S)-5-((R)-1-hydroxydecyl)-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-carboxamide (15a):
To a stirred solution of keto–amide 15 (0.062 g, 0.18 mmol) in THF (2.0 mL) was added K-selectride
(0.36 mL, 0.36 mmol) at −78 °C. The reaction mixture was allowed to stir at the same temperature for
2 h. After completion of the reaction (TLC), it was quenched with brine (5 mL), extracted with EtOAc
(2 × 5 mL) and dried over anhydrous Na2SO4. The crude residue obtained after evaporation of solvent
was subjected to silica gel column chromatography using petroleum ether: EtOAc (3:2) as eluent
afforded the compound 15a as colourless oil in 90% (0.056 g) yield. [α]D24 −8.2 (c 0.15, CHCl3); IR
(neat) 3448, 2928, 1676, 1376 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.75 (s, 1H), 4.35 (s, 1H), 3.73 (s,
3H), 3.64-3.53 (m, 1H), 3.21 (s, 3H), 1.99 (d, J = 8.0 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 1.55-1.38 (m,
13
2H), 1.29-1.19 (m, 14H), 0.85 (t, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 170.6, 111.0, 80.9,
73.8, 70.3, 61.7, 34.6, 32.4, 31.9, 29.5 (3C), 29.3, 27.0, 26.1, 25.8, 22.6, 14.1; HRMS for
C18H35O5N+Na calcd 368.2413; found 368.2413.
Preparation of 16: To a solution of the amide 15 (0.048 g, 0.14 mmol) in MeOH (3 mL) was added
NaBH4 (0.054 g, 1.4 mmol) at room temperature and the reaction mixture was stirred at the same
temperature for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction
(TLC), it was quenched with water (3 mL), extracted with EtOAc (3 × 5 mL), washed with brine (5
mL) and dried over anhydrous Na2SO4. Evaporation of the solvent followed by silica gel column
chromatography of the residue with petroleum ether: EtOAc (3:2) as eluent afforded the diol 16 as
colourless oil in 95% (0.038g) yield. [α]D24 −5.7 (c 1.4, CHCl3); IR (neat) 3418, 2926, 1380, 1047 cm-
1; 1H NMR ( 400 MHz, CDCl3) δ 4.05 (dt, J = 8.0, 3.6 Hz, 1H), 3.88-3.71 (m, 2H), 3.63 (dd, J = 12.0,
4.0 Hz, 1H), 3.58-3.48 (m, 1H), 2.4-2.16 (m, 2H), 1.42 (s, 3H), 1.39 (s, 3H), 1.54-1.40 (m, 2H), 1.30-
1.20 (m, 14H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR ( 100 MHz, CDCl3) δ 109.2, 80.0, 77.7, 70.5, 62.0,
34.3, 31.8, 29.5 (3C), 29.3, 27.2, 27.1, 25.7, 22.6, 14.1; HRMS for C16H32O4+Na calcd 311.2198;
found 311.2198.
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Preparation of 14: To a solution of the diol 13g (0.043 g, 0.11 mmol) in EtOH (2 mL) under
hydrogen atmosphere was added Raney Nickel (2 mL suspension in ethanol) and was allowed to
reflux for 12 h. After completion of the reaction (TLC), it was filtered through a short pad of celite and
the celite pad was washed with EtOAc (10 mL), evaporation of the solvent followed by purification of
the crude residue with silica gel column chromatography using petroleum ether: EtOAc (3:2) as eluent
afforded diol 14 as colourless oil in (0.026 g, 84%) yield. [α]D24 −6.7 (c 1.2, CHCl3); IR (neat) 3418,
2926, 1047 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.12-3.98 (m, 1H), 3.84-3.63 (m, 4H), 2.70 (brs, 2H),
1.92-1.21 (m, 16H), 1.40 (s, 3H), 1.26 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
108.8, 80.7, 78.7, 71.9, 63.1, 33.5, 31.9, 29.5 (3C), 29.3, 27.0 (2C), 25.4, 22.6, 14.1; HRMS for
C16H32O4+Na calcd 311.2198; found 311.2198.
Acknowledgement
We thank SERB, Department of Science and Technology, New Delhi for funding. A.K.B thanks
CSIR, New Delhi for a fellowship. We thank Dr. P. Srihari, IICT, Hyderabad and Dr. B. K. Swamy
for providing us with the copies of the spectra of 26 and 2.
References
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For some applications of γ-keto amides derived from tartaric acid in natural product synthesis from
our group see: (b) Prasad, K. R.; Kumar, S. M. Synthesis 2013, 785. (c) Prasad, K. R.; Metri, P. K.
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Weinreb amide 7 and application to the total synthesis of macrolactone natural product Sch725674:
Bali, A.; Sunnam, S. K.; Prasad, K. R. Org. Lett, 2014, 16, 4001.
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8) Controlled exclusive reduction of the keto group in 9a-h was always accompanied with formation of
the 1,4-diol 13 and the purification was very cumbersome. Hence, both the keto and amide groups
were reduced to the 1,4-diol 13a-h with excess NaBH4. Formation of the other diastereomer was not
1
observed within detectable limits in H NMR. b) Investigations concerning the influence of the
dithianyl moiety in the exclusive formation of the erythro diastereomer in the reduction of the keto
group in 9a-h are currently underway.
9) The following enamine 8aa is obtained in 29% yield, formed possibly by the addition of Weinreb
amine to the unsaturated ketone 8a. See Supporting Information for the spectral data of 8aa.
Formation of enamino ketones by in the addition of alkynyl Grignard reagents to Weinreb amides is
reported in literature. a) Persson, T.; Nielsen, J. Org. Lett. 2006, 8, 3219. b) Pirc, S.; Bevk, D.;
Golobic, A.; Stanovnik, B.; Svete, J. Helv. Chim. Acta, 2006, 89, 30.
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10) a) Bodo, B.; Molho, L.; Davoust, D.; Molho, D. Phytochemistry, 1983, 22, 447. b) Tayone, W. C.;
Shindo, S.; Murakami, T.; Hashimoto, M.; Tanaka, K.; Takada, N. Tetrahedron 2009, 65, 7464. For
earlier synthesis of achaetolide see: c) Chandrasekhar, S.; Balaji, S. V.; Rajesh, G. Tetrahedron Lett,
2010, 51, 5164. d) Das, T.; Bhuniya, R.; Nanda, S. Tetrahedron: Asymmetry, 2010, 21, 2206. e) Rao,
K. S.; Chattapadyay, A. K.; Ghosh, S. Synlett, 2010, 3078. f) Srihari, P.; Kumaraswamy, B.; Shankar,
P.; Ravishashidhar, V.; Yadav, J. S. Tetrahedron Lett 2010, 51, 6174. g) Thakur, P.; Kumaraswamy,
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12) The known β-hydroxy acid 24 was prepared by hydrolysis of the corresponding tert-butyl ester.
13) Chadrasekhar et. al. (ref. 10c) reported the formation of required E-lactone 26 in 47% yield along with
the Z-isomer 27 in 23% yield, while Srihari et. al. (ref. 10f) reported the formation of 26 in 40% yield
along with the ester 33 in 24% yield in the RCM of reaction of 17 with Grubbs’ 2nd generation
catalyst. Thakur et. al. (ref. 10g) reported the formation of 26 in 61% yield with no other side
products.
14) Formation of the dimer is further confirmed by deprotection of the acetonide in 28 to yield the known
achaetolide dimer 32. For dimer of achaetolide See Zhang, S. – M.; Lu, X. – W.; Wu, Y. Asian. J.
Org. Chem. 2012, 1, 245.
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